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Sjögren‟s syndrome (SS) is a systemic progressive autoimmune disease characterized by a complex pathogenesis requiring a predisposing genetic background and involving

immune cell activation and autoantibody production. The immune response is directed to the exocrine glands, causing the typical „sicca syndrome‟, but major organ involvement is also often seen. The etiology of the disease is unknown. Infections could play a pivotal role: compared to normal subjects, patients with SS displayed higher titers of anti-Epstein-Barr virus (EBV) early antigens, but lower titers of other infectious agent antibodies such as rubella and cytomegalovirus (CMV) suggest that some infections may have a protective role against the development of autoimmune disease. Recent findings seem to show that low vitamin D levels in patients with SS could be associated with severe complications such as lymphoma and peripheral neuropathy. This could open new insights into the disease etiology. The current treatments for SS range from symptomatic therapies to systemic immunosuppressive drugs, especially B cell-targeted drugs in cases of organ involvement. Vitamin D supplementation may be an additional tool for optimization of SS treatment.

Anti-B cell therapies; Autoantibodies; Autoimmune diseases; Chronic sialoadenitis; Dry eye syndrome; Lymphoma; Peripheral neuropathy; Sicca syndrome; Sjögren’s syndrome; Vitamin D

Sjögren syndrome (SS) is a chronic autoimmune inflammatory disease that primarily involves the exocrine glands, resulting in their functional impairment. The syndrome can present either alone (primary Sjögren‟s syndrome (pSS)) or in the context of an underlying connective tissue disease, most commonly rheumatoid arthritis (RA) or systemic lupus erythematosus (SLE) (secondary Sjögren‟s syndrome (sSS)) [1]. SS is the second most common autoimmune rheumatic disease, with an estimated prevalence ranging from 0.1 to 4.8% in different studies. It mainly affects middle-aged women, with a female to male ratio reaching 9:1 [2]. Although the etiology of SS remains unknown, susceptibility to the disease can be ascribed to the interplay between genetic, environmental and hormonal factors. The chronic immune system stimulation is thought to play a central role in the pathogenesis of the disorder, as illustrated by several indices of immunological hyperactivity, including various autoantibodies, in particular antiRo/SS-A (anti-Ro) and anti-La/SS-B (anti-La) [1]. A genetic predisposition to SS has been suggested [3]. Familial clustering of different autoimmune diseases and coassociation of multiple autoimmune diseases in individuals have both frequently been reported. It is common for a SS patient to have relatives with other autoimmune diseases (30%) [1]. The polymorphic major histocompatibility complex (MHC) genes are the best documented genetic risk factors for the development of autoimmune diseases; with regard to SS, DRB1*0301-DQB1*0201-DQA1*0501 haplotypes are the strongest risk factors for the formation of an anti-Ro/La response and to the development of the disease [4]. Although many human leukocyte antigen (HLA) haplotypes have been found in SS subjects from different ethnic boundaries, the majority of patients with SS carry a common allele, DQA1*0501, probably involved in predisposition to the disease [5]. Regardless, no significant different geographic distribution has been described in pSS to date [6]. In the current review we present the complexity of SS from different points of view, reporting on the current cutting edge of knowledge about this disease. This multidisciplinary approach to SS is the result of a symposium held in Brescia (Italy) in June 2012, involving several specialists who take care of different aspects of the diagnosis, management and therapy of SS.

Clinical features and classification
SS typically presents as dry eyes (xerophthalmia or keratoconjunctivitis sicca (KCS)) and dry mouth (xerostomia) [7]. KCS usually presents insidiously over a period of several years. Affected patients may describe a „gritty‟ or „sandy‟ feeling in their ey es [8]. Complications of xerophthalmia include corneal ulceration and infection of the eyelids. Dryness of the mouth may give rise to difficulties in the swallowing of dry foods without fluid, and need for frequent small sips of water, also at night. Loss of the protective and antimicrobial properties of saliva may increase dental caries and predispose patients to oral candidiasis. Parotid swelling and other xeroses, such as dryness of the nose, throat, skin, and vagina, also often occur [8]. Establishing the diagnosis of SS is often difficult. The symptoms are non-specific: sicca symptoms are extremely common, especially in older patients, partly due to age-related atrophy of secreting tissues and partly due to other conditions, especially use of drugs. No single laboratory test allows for definitive diagnosis of SS. However, a combination of abnormal test results is frequently observed: elevated erythrocyte sedimentation rate (ESR), mild normochromic normocytic anemia, leukopenia and polyclonal hypergammaglobulinemia.

Autoantibodies are present in the majority of SS cases: rheumatoid factor (RF), Anti-nuclear antibodies (ANA) and anti-Ro and antiLa are strongly indicative of SS, although not exclusive [8]. There is no single disease-specific diagnostic criterion for SS. The most widely used classification criteria are those revised in 2002 by a joint effort by research groups in Europe and in the USA (American-European Consensus Group (AECG)) (Table 1) [9,10]. In addition to the subjective symptoms of dry eyes and dry mouth, the following objective signs should be present: ocular signs by Schirmer‟s I test and/or Rose Bengal score; focal sialadenitis by histopathology; salivary gland i nvolvement by salivary scintigraphy, parotid sialography or unstimulated salivary flow; and autoantibodies of anti-Ro and/or anti-La specificity. The diagnostic role of the histopathology of minor salivary glands has been considered important and is curren tly considered as a „gold standard‟, although a recent meta-analysis has shown that the diagnostic usefulness has actually only been evaluated in a few studies [11]. Table 1. Comparisons between the 2002 and 2012 criteria for Sjögren’s syndrome (SS) Recently, the Sjögren‟s International Collaborative Clinical Alliance (SICCA) proposed a new expert consensus approach consisting of classification criteria based entirely on objective measures [12]. In particular, not only have ocular and oral symptoms have been deleted, but also the study of salivary gland involvement has been excluded from the criteria (Table 1). In fact, the evaluation of salivary gland involvement in SS is still a matter of debate. In addition to standard tests for assessment of salivary gland involvement, namely the unstimulated salivary flow test, salivary gland scintigraphy and contrast sialography, other methods have been studied such as magnetic resonance sialography and ultrasonography (US) [14]. It has been suggested that US may provide useful diagnostic information comparable to that of biopsy of the minor salivary glands, but US is less expensive and non-invasive [15,16].

Differential diagnosis of ‘dry eye’
The importance of objective tests for the definition of ocular dryness has been stressed by the 2012 criteria [12]. Therefore, correct evaluation of a „dry eye‟ becomes critical in the investigation of patients with a suspected case of SS. Dry eye syndrome is a common but very complex disorder of the tear film. Over the last few decades substantial progress has been made in understanding the structural elements of the tear film and ocular surface leading ultimately to revised concepts about the way in which the tear film is formed and maintained, and the pathophysiologic events operative in the development of dry eye. The structure of tear film can be subdivided into an anterior lipid layer, a middle aqueous layer and an innermost mucin layer. Meibomian glands, lacrimal glands, goblet cells and epithelial cells of the ocular surface produce these layers. In the 1980s, for the first time, researchers started to consider that the ocular surface is a functional unit (lacrimal functional unit (LFU)), and its components are represented by the lacrimal gland, corneal epithelium, conjunctival epithelium and goblet cells, tear film and the eyelid border with Meibomian glands [17]. The ocular surface is essential for visual function and is considered as an interface between the external environment and the host. Hydrodynamic factors, such as eyelid blinking and closure, are essential to maintain ocular surface functionality. In 1995, the Dry Eye Study Group [18] described „dry eye syndrome‟ as a tear film pathology that occurs due to either decreased tear production or increased evaporation. It causes damage to the interpalpebral ocular surface and is associated with a variety of symptoms reflecting ocular discomfort (Figure 1). Until recently this was the common definition of „dry eye syndrome‟. However, the international report of the Dry Eye Workshop (DEWS) changed the definition of dry eye in 2007 [19]. According to DEWS, „dry eye syndrome‟ is a multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance, and tear film instability with potential damage to the ocular surface itself. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface. The tear film is a very important and highly dynamic part of the ocular surface system, which promptly responds to pathological events with modifications of quantity and quality of tear production, an increase in proliferation and migration of epithelial cells and permeability of conjunctival vessels. Another crucial component of the system is the neural network. Sensory receptors monitor conditions of the tears and cells, sending afferent signals to the central nervous system that, in turn, send efferent impulses mainly to the secretory glands and cells, effecting changes in composition and volume to maintain homeostasis and to respond to injury and stress. As stated before, dry eye is a multifactorial disorder of the LFU; it involves several interacting mechanisms. Dysfunction of any component can lead to dry eye disease by causing alterations in the volume, composition, distribution, stability and clearance of the tear film. A key role is played by decreased tear production and epithelial damage along with tear hyperosmolarity and tear film instability. Altogether these events start self-perpetuating and mutually reinforcing complex global mechanisms, ultimately leading to ocular surface inflammation [20]. The latter, regardless of the initiating event, is a key factor perpetuating dry eye.

Figure 1. Severe ocular surface damage in a dry eye patient.

According to the DEWS report, dry eye disease comprises two major etiopathogenic groups: evaporative dry eye and aqueous teardeficient dry eye (Figure 2). Hyperevaporative dry eye can be due to intrinsic and extrinsic causes. Among the first group are changes in tear composition, eyelid disorders, incomplete blinking or reduced blinking rate, ocular surface irregularities and drug action. Extrinsic causes include, among others, vitamin A deficiency, topical drug preservatives, contact lens wear and ocular surface disease. Aqueous tear deficient dry eye can be subdivided into SS and non-SS syndrome dry eye groups. The latter group has several primary causes, including the lack of a lacrimal gland (congenital or acquired), impairment or dysfunction of the lacrimal gland, reflex block and drug action. Non-SS dry eye can also be secondary to a variety of conditions. SS dry eye is associated with autoimmune inflammation in the lacrimal glands [19].

Figure 2. Dry eye classification flow chart (Dry Eye Workshop Report, 2007) [19]. The causes of „dry eye syndrome‟ are subdivided into aqueous-deficient and evaporative groupings. Sjögren‟s syndrome (SS) belongs to the first group. Modified from [19]. It should be remembered, however, that instances of hyperevaporative and aqueous tear deficient dry eye in most cases are not clinically so well defined and often there is a certain degree of overlap between these two dry eye groups. A hyperevaporative dry eye over time also becomes aqueous tear deficient, and vice versa, making it difficult to precisely classify the condition. Ophthalmologists should recognize and diagnose dry eye syndrome to prevent or treat ocular surface pathologies. As it may be associated with a variety of causes, it is important to perform a comprehensive evaluation. This should include a complete clinical history, accurate examination of the patient (skin, blinking rate, eye and lid morphology, and so on), a slit-lamp examination and laboratory tests that can help towards a diagnosis of dry eye related to SS. Lacking a single conclusive test to diagnose dry eye syndrome, a lot of different procedures, easy or complicated, cheap or expensive and more or less useful, have been developed in order to help ophthalmologists. The tests of choice to diagnose dry eye include break-up time (BUT), ocular surface staining and Schirmer‟s test [12]. The reasons for their use lay in their reproducibility, sensitivity and in the fact that all of them are quite easy to perform. Ocular surface dyes used in clinical practice are fluorescein and lissamine green (Figure  3). Rose Bengal was progressively abandoned because of patient discomfort. The lissamine green dye test is very sensitive and stains damaged epithelial cells without causing any discomfort to patients.

Figure 3. Lissamine green staining of the conjunctiva in dry eye syndrome. Once a diagnosis is confirmed, management of dry eye depends on the cause and severity of the condition. New treatment approaches are designed to modify the underlying disease process. Every associated condition must be treated. Therapy should normalize the tear film, decrease ocular surface inflammation, stimulate epithelial healing, improve neural feedback, decrease lacrimal gland inflammation and improve its function. In conclusion, therapy should be aimed at protecting the ocular surface, alleviating the signs and symptoms of dry eye and, most importantly, at breaking the vicious cycle leading to chronic inflammation, thus improving the quality of life of patients.

Not only ‘sicca syndrome’: extraglandular manifestations of SS
Despite glandular involvement being the major and typical feature of pSS, this autoimmune disease can have several systemic manifestations. In fact, 30% to 70% of patients develop systemic involvement before or after the diagnosis of pSS [21-24]. In addition, it must be considered that this group of patients more commonly has circulating anti-Ro and anti-La autoantibodies, in comparison with the group of patients with sicca-limited disease [25]. Most extraglandular manifestations, similar to the exocrine gland involvement, can be considered as expression of the so-called „autoimmune epithelitis‟ because the primary target of the autoimmune response is the epithelial component [26,27]. Nevertheless, in other clinical manifestations the pathogenesis seems to be completely different as it may involve vasculitis and/or immune complex deposition and complement activation, as is the case in skin vasculitis, glomerulonephritis and peripheral neuropathy. One of the most frequent symptoms in pSS is represented by fatigue, prominent in approximately 70% of patients. Though the instruments for fatigue assessment are still inadequate or lacking, it seems that the physical and somatic rather than mental aspects of

and subsequently they determine the atrophic involution of the acina. The histopathological picture of SS is the chronic periductal sialoadenitis [43]. erythema anulare. Of note. some morphological alterations described in SS („epimyoepithelial sialoadenitis‟) can also be found in the absence of overt disease (no clinical and serological features of SS). 1 f ocus must be detected in a tissue area of at least 4 mm2 (see Figure 4). However. Such a histopathological picture can be defined as a „benign lymphoepithelial lesion‟. hyaline material. Gastrointestinal manifestations include nausea. Approximately 20% of patients with pSS develop autoimmune thyroiditis (primarily Hashimoto thyroiditis and to a lesser extent. though very rarely it is an expression of acute or chronic pancreatitis. the histological criteria for the definition of SS are both qualitative and quantitative: the „focus‟ must be composed of at least 50 lymphocytes infiltrating the periductal area. Likewise. autonomic neuropathy (for example. The lymphocyte infiltrate then spreads from the periductal position to the parenchyma. including certain HLA phenotypes and polymorphisms in genes encoding cytokines or factors implicated in cytokine signaling. . Initially. With regard to skin involvement. by the environment (such as viruses) and by the hormonal milieu [42].7% to 4% of patients with pSS. The major clinicopathological entity is interstitial nephritis (IN). with the final result of a diffuse infiltration of lymphocytes and loss of tissue architecture. One possible explanation is that fatigue and depression share common underlying biological mechanisms. glomerulonephritis (GMN) is more rarely detected in patients with pSS and is strongly associated with low C4 levels and mixed cryoglobulinemia. Autoantibodies against thyroid peroxidase (anti TPO) and thyroglobulin (anti-TG) can be used as primary indicators of patients who are prone to developing thyroid disease in the future [34]. diffuse encephalopathy and dementia as reported manifestations [36]. Arthralgias are commonly reported in patients with pSS while typical non-erosive arthritis is less frequent [32]. seizures. epistaxis. In addition. angular cheilitis. Abnormal liver tests are not uncommon but autoimmune hepatitis is diagnosed in 1. recurrent sinusitis. transverse myelitis. which appears early or even may precede the onset of sicca symptoms [30]. Sensorimotor polyneuropathy and polyradiculopathy. mainly constituted by activated T and B cells [37. Respiratory manifestations are frequently detected but they are clinically significant in only 10% of patients [29].fatigue are more severely and frequently affected in pSS [28]. They are caused by dry nose. dry cough and dyspnea. IN is frequently subclinical and overt clinical renal disease is detectable in approximately 5% of patients with pSS. nearly half of all patients with pSS may present cutaneous manifestations consisting of skin xerosis. Non-specific interstitial pneumonia (NSIP) seems to be the most frequent histological pattern of ILD but lymphocytic IP (LIP) and usual IP (UIP) are also present. Pathogenesis. The epithelial cells of salivary glands from patients with SS also display alterations in cell adhesion and shape [41].12]. The typical histological pattern is chronic atrophic gastritis with lymphoid infiltration.38]. The kidneys are often involved in pSS. while autoimmune cholangitis (with histological changes similar to stage I primary biliary cirrhosis) develops mainly within the 5% to 10% of patients with antimitochondrial antibodies [33].35]. Graves‟ disease) and more than 50% of them have subclinical hypothyroidism. in which IN and GMN are almost equally distributed. The immune dysregulation seems to be orchestrated by genetic factors. Aside from IN. small airway obstruction and/or interstitial lung disease (ILD). Adie‟s pupils and orthostatic hypotension). the lymphocytes initiate the damage to the ducts with the formation of epimyoepithelial lesions. is present in the lumen of the ducts. mononeuritis multiplex. In the early stages of disease. the lymphocytes infiltrate the space around small interlobular-intralobular ducts. with multiple sclerosis-like changes. Central nervous system involvement is much less common than PNS involvement. The more common clinical symptoms are represented by nasal crusting. trigeminal and other cranial neuropathies are other manifestations of the involvement of peripheral nervous system (PNS) in pSS. The prevalence of neurological manifestations in pSS varies between 2% to 60% with pure or predominantly sensory polyneuropathies being the most common manifestations (for example. As a result. A moderate correlation between depression and fatigue has also been found. According to the international guidelines [9. sensory ataxic or small fiber sensory painful neuropathy) [21. aseptic meningitis. focal aggregates of lymphocytes appear in the glandular lobules. dry trachea. chilblain lupus and skin vasculitis that includes flat or palpable purpura and urticarial vasculitis [31]. myalgias are frequent while myositis is rarely diagnosed in pSS. optic neuritis. dysphagia or epigastric pains that are frequently due to dryness of the pharynx and esophagus or to esophageal dysmotility and gastritis. Distal renal acidosis (both type I and II) is the most frequent clinical presentation. histopathology and progression to lymphoma The pathological hallmark of SS is a chronic inflammatory infiltrate in the exocrine glands. The immune-mediated damage appears in the apoptosis of glandular epithelial cells [39] and seems to be mediated by several proinflammatory T helper 1-type cytokines [40]. similar to a basal membrane. Hyperamylasemia is rather frequent.

Such lymphomas can also be found in other organs (stomach. anti-centromere. B cell NH lymphoma with diffuse giant cells an d centrofollicular histotypes and T cell NH lymphoma [44]. Figure 5. The main complication of SS is hematological neoplasia. can activate caspase 3 and determine apoptosis in human salivary gland cells. more rarely. in vitro[49]. . The lymphoid infiltrate is constituted by medium-sized cells. Anti-Ro and anti-La autoantibodies from SS sera. Initially. these autoantibodies seem to have a pathogenic role for the impairment of the secretory function in the salivary glands. there might be several different clones of B cells. which comes from mucosa -associated lymphoid tissue (MALT). detected in about 60% and 40% of SS. anti-Ro/SS-A antibodies stimulate the production of proinflammatory cytokines interleukin (IL)-6 and IL-8 by human healthy salivary gland epithelial cells [50]. The „score‟ is the number of foci in 4 mm2 of tissue. Anti-Ro and anti-La antibodies define a disease with a higher rate of extraglandular manifestations and more active immunological status. Moreover. cryoglobulins and a high risk of developing lymphoma [47]. Anti-Ro and anti-La antibodies are considered the classical hallmark of SS. In addition. mostly CD4+) in 4 mm2 of tissue is diagnostic for SS. anti-carbonic anhydrase. Microscopy of a minor salivary gland in Sjögren’s syndrome (SS): ‘periductal lymphoid focus’. with a cleaved nucleus and a large cytoplasm. The finding of at least 1 focus (periductal aggregate of at least 50 lymphocytes. and included in both the AECG and SICCA classification criteria[9. Anti-Ro/La-positive patients with SS can show severe hypergammaglobulinemia. anti-Ro. probably involved in the pathogenesis of different aspect of the disease. Circulating levels of anti-Ro/La do not correlate with disease activity. Patients displaying these risk factors should be monitored closely [44]. but over time a single clone can progressively expand and invade the glandular parenchyma with the formation of a lymphoma. Such cells cluster in the epimyoepithelial islets. rheumatoid factor and. regardless.Figure 4. Therefore. Figure 6. Anti-CD20 staining of non-Hodgkin’s (NH) marginal B cell lymphoma. anti-Ki/SL. Microscopy of non-Hodgkin’s (NH) marginal B cell lymphoma. the development of lymphoma involves the B cells. patients with SS have a 10 to 50 times higher risk of lymphoma and. respectively. anti-La. the IgA anti-Ro titer seems to be associated with the rate of lymphocyte glandular infiltration. 2% to 9% of patients with SS develop lymphoma [7]. such as anti-α fodrin [45]. Serological profile SS is an autoimmune disease characterized by a strong polyclonal B cell activation and different circulating autoantibodies. anti-Ku or anti-p80 coilin. The most frequent lymphoma in Sjögren‟s syndrome (SS) is the NH marginal B cell type. and anti-muscarinic receptor antibodies [46]. Other types of lymphoma are rare in SS: Hodgkin‟s lymphoma. a strong correlation was found between circulating autoantibodies and Ro/La producing cells in salivary glands [48]. lungs and kidney).12]. The lymphoma cells in the marginal zone NH type are medium-sized cells with a cleaved nucleus and large cytoplasm (Figure 5) and with a positive CD20 reaction (Figure 6). which are factors strongly positive for CD20. according to a large case series. Compared to healthy individuals. Risk factors for the development of lymphoma have been identified in patients with SS and include the presence of palpable purpura. classically represented by anti-nuclear antibodies. Other autoantibodies have been described in SS. Despite the inflammatory infiltrate in the salivary glands being mostly made up of T cells. the expression of La and 60 kDa Ro antigens in ductal glandular cells could represent a trigger for inducing and maintaining a local inflammation and tissue-specific immune response. low C4 and mixed monoclonal cryoglobulinemia. The parotid gland is affected in the majority of cases and the most frequent type of non-Hodgkin‟s (NH) lymphoma is the marginal zone lymphoma of the mucosa-associated lymphoid tissue (MALT). when compared with „seronegative‟ SS cases (without anti-Ro or anti-La antibodies). In addition. but not healthy IgG.

Regardless. In a series of 114 patients with pSS [60]. Other autoantibodies. 7 (6%) had 2. In a cohort in Austria the reported prevalence of sSS was 22% [66]. The evolution towards SLE in patients with pSS has also been addressed. and the presence of anti-La at the time of diagnosis of pSS [63]. Isolated anti52 kDa Ro antibodies can be found in SS. Interest has been raised for anti-52 kDa Ro. dysphagia and teleangectasia. ELISAs and multiplex microbead immunoassays show variable results depending on antigen purification. cutaneous lupus and/or myositis. as associated or substitutes of anti-Ro antibodies [46]. In a larger cohort of 445 patients with pSS. As the presence of a concomitant autoimmune disease involves nearly one-third of patients with SS. This association is termed secondary SS. though these tended to be less frequent. anti-double-stranded DNA antibodies were equally present in both groups. the development of SLE was observed in only 1. and anti-Sm and anti-cardiolipin antibodies were less prevalent in SLE-SS than SLE alone. originally found in SLE with sicca. especially when associated with primary biliary cirrhosis [57].Anti-Ro antibodies recognize a macromolecular complex. With regard to autoantibodies. 38 patients (33%) were diagnosed as having 1 additional autoimmune disease. RA is frequently associated with both sicca symptoms and true sSS. Other autoantibodies can be detected in SS. By contrast. puffy hands. or in conjunction with another connective tissue disease. while anti-Ro and anti-La were more frequent. Anti-Ro antibodies recognize isolated 60 kDa Ro (which contains only conformational epitopes) or 60 kDa Ro associated with 52 kDa Ro (which has only linear epitopes). the estimated prevalence of SS was 17. The prevalence of systemic diseases such as RA and SLE was around 8%. In summary. In a cohort of 100 patients with pSS. a cumulative prevalence of sSS was described in 17% of the patients at a disease duration of 10 years [65]. (ii) increased frequency of oral ulcers and arthritis and (iii) proteinuria and CNS involvement. according to the AECG. Association of SS with other autoimmune diseases SS may occur in isolation. lower C3 concentration. the combined disease SLE-SS seems to be characterized by less organ involvement. a range of 13 associated autoimmune diseases was detected. but due to a high rate of lymphocyte infiltration as well as anti-Ro/La-positive SS. as there are new insights on the mechanisms of intracellular immunity mediated by these autoantibodies when they penetrate into cells [53]. ACA-positive SS shows SSc features. as observed in SSc. after a mean period of 77 months [64]. but has a lower rate of pulmonary involvement compared to ACA + SSc. 15% of them could be classified as having SLE after a follow-up period of 10 years. In a total of 2489 SLE patients. anti-Ku and anti-p80 coilin antibodies are more rarely found in SS. such as ACA and anti-Ku. The clinical features of SLE-SS patients were found to be: (i) older age. anti-Ro and La antibodies likely play a pathogenic role in inducing local inflammation and damage and are serological markers of systemic complications. may define a more complex disease with overlap features and different prognosis. anti-Ku antibodies are usually considered markers of overlap SSc-myositis or SSc/SLE syndrome [58]. Overall. the correct assays for anti-Ro antibodies should use raw or conformational antigens in order to detect autoantigens with the best sensitivity and specificity. Anti-Ki/SL. using raw spleen extracts.3% of the patients. a common pathogenic background may be advocated and the search for polyautoimmunity is warranted in every SS patient.52]. The 60 kDa Ro is directly bound to RNA of the Ro complex and seems to have a role in DNA replication. The most common autoimmune disorder was hypothyroidism (14%). In all. Anti-Ki/SL antibodies. but they can also be frequently detected in other autoimmune disorders [51. 52 kDa Ro does not contain an RNA-binding sequence but could be considered part of the „Ro protein‟ through the link with 60 kDa Ro: it seems to have a role in ubiquitination and modulation of innate immune system though regulation of proinflammatory cytokines and interferon related factors. Anti-p80 coilin has been detected in SS or SSc. Patients who developed SLE had a lower age. even if SS was diagnosed as secondary disease many years before the primary disease [9]. Almost every assay can accurately detect anti-La antibodies. The relationship between SS and SLE has been recently addressed in a meta-analysis [62]. higher level of IgG. Counterimmunoelectrophoresis. Similarly. synthesis and maintenance of conformational epitopes of Ro peptides [54]. most patients with SS show a mild disease with a simple autoantibody profile. often referred to as primary SS.8%. a more specific autoantibody profile and a favorable clinical outcome.6%). SS has been described in association with a large variety of both organ-specific and systemic autoimmune diseases.5%). most commonly RA or SLE [59]. They have been detected in SS with features of SSc. In a Spanish cohort of RA patients. By contrast. The 60 kDa and 52 kDa Ro antigens are encoded by different genes and are completely different in amino -acid sequence. a more recent cohort of 410 patients with SS [61] showed the presence of polyautoimmunity in 134 (32. shows a similar performance level to the „gold standard‟ immunoprecipitation assay. . usually found in limited systemic sclerosis (SSc). Moreover. such as Raynaud‟s phenomenon. constituted by 60 kDa and 52 kDa Ro proteins and short cytoplasmic RNA molecules. are detected in 5% to 10% of SS cases as an alternative to anti-Ro/La antibodies. epitopes and biological role within the cell. with thyroid disease being the most common (21. and 2 (2%) had 3. have been described in primary SS in association with anti-Ro or as isolated markers [56]. These patients show sicca symptoms not due to glandular fibrosis. Anti-centromere antibodies (ACA). These data suggest that ACA-positive SS could be considered an overlap SS/SSc disease [55]. Western blotti ng tests.

respectively. age and ethnicity [75-80]. Saluggia. a certain infectious agent may determine why an individual with the „proper‟ genetic ba ckground will develop one AID rather than others. Vitamin D levels were determined in 176 patients with pSS and 163 matched healthy volunteers utilizing LIAISON chemiluminescent immunoassays (DiaSorin. immunologic. several multicenter studies analyzed a large number of sera samples (>2. Novel aspects of SS: the role of infections and vitamin D Infections and SS The etiology of autoimmune diseases (AID) is multifactorial where genetic. In the interplay between infectious agents and autoimmunity it was found that the same infectious agent (that is. For instance. Interestingly. Overall.0003).5 ng/ml vs 22. in some diseases lower titers of anti-infectious agents were found. and so on) [74]. who had lower levels of vitamin D.2 ± 6. 13. Lymphoma was diagnosed in 4. it was found that SS associated with SSc was more often complicated by peripheral neuropathy and additional autoimmune disease or autoantibodies. Vitamin D and its metabolites have been shown to have an antiproliferative effect on lymphoma cell lines and to attenuate their vitamin D receptor (VDR) expression [90].64]. In 2 more recent studies involving 133 patients with SSc and sicca syndrome (14% classified as sSS) [71] and 27 patients with SSc + sSS compared with 202 SSc patients without sSS [72]. The levels of vitamin D and their association with manifestations of SS were studied in a large international multicenter cohort [81]. In Finland. cytomegalovirus (CMV). there is some evidence from case–control studies that low dietary intake of vitamin D is associated with an increased risk for NHL in the normal population [88. RA patients with high titers of RF were reported to be more likely to have sSS[67]. rubella. Mean vitamin D levels were comparable between patients with SS and controls: 21. Helicobacter pylori. hormonal and environmental factors play in concert in their induction. . vasculitides. This study reported for the first time the presence of low vitamin D levels in patients with pSS with peripheral neuropathy. treponema. SLE.25 ng/ml.02). antiphospholipid syndrome (APS).3% of patients with SS. as well as its clinical manifestations and severity. The development of MCTD in pSS has not been described so far[60. Furthermore. such as the lower prevalence and titers of rubella and CMV antibodies (IgM) detected in patients with SS compared to controls ( P <0. such as vitamin D.4 ± 10 ng/ml. RA. The prevalence of anti-ribonucleoprotein autoantibodies (antiRNP) in the absence of coexisting MCTD has been reported in 4% of patients with pSS [55]. Limited SSc was predominantly associated with SS in these studies (81% and 95%. Recently. There have been no studies to date of patients with mixed connective tissue disease (MCTD) that report the prevalence of SS. it seems that vitamin D deficiency may be a component in the pathogenesis of neuropathy in pSS. This may allude indirectly to the notion that some infectious agents may have a protective rather than a pathogenic role for a specific autoimmune disease. While the relationship between vitamin D and the risk for lymphoma in pSS has not been reported previously. Epstein-Barr Virus (EBV)) may be involved in inducing many autoimmune diseases. in patients with SS the prevalence and titers of antibodies against EBV-early antigen were significantly higher than in their control group (P = 0. Peripheral neuropathy was diagnosed in 23% of patients with SS and associated with lower vitamin D levels (18. It was suggested that SS may be protective against systemic sclerosis-associated pulmonary fibrosis. Other clinical and serological manifestations did not correlate with vitamin D status. Italy). Herpes virus and toxoplasmosis.In a Greek cohort. Low levels of vitamin D are associated with neuropathy and lymphoma among patients with SS The morbidity of SS is mainly determined by extraglandular disease and increased prevalence of lymphoma. In original cohorts of SSc patients the prevalence of sSS was reported to be 17% and 29%[69. may play a role in the pathogenic process and disease expression. compared to patients with SS without lymphoma (22 ± 8 ng/ml. a doubled standardized incidence ratio for NH lymphoma in RA patients with sSS when compared with RA patients without SS was described [68]. Patients with pSS are at increased risk for NH lymphoma compared to healthy populations [44].4 ng/ml and 22. The final step determining the date of emergence of an AID is most probably an environmental trigger. and may be used for monitoring and treatment of this condition [82-87].89].04)). H.03). In several diseases a higher prevalence and titers of anti-infectious antibodies were found compared with healthy controls matched for sex. Environmental and hormonal factors. which is generally of infectious origin [73]. pylori. P = 0.500) from patients with AID such as SS.70].6 ± 8 ng/ml (P = 0.2 ± 9. respectively). EBV. Thus. Sicca syndrome is also common among patients with SSc due to fibrotic changes of the salivary glands. and others for the presence of a profile of anti-infectious agents antibodies including EBV. low vitamin D levels may join low complements components and the presence of cryoglobulins in predicting eventual development of lymphoma in patients with SS.6 ± 5. while the same autoimmune disease may be caused by various agents (that is. not typical for either pSS or SSc. CMV.

A recent study conducted in Sweden found out that a greater proportion of children with CHB were born during the summer [92]. A recent Cochrane review of 36 randomized controlled trials (RCTs). toothpastes. These problems could lead to a relevant impairment of sexual function in women with SS [96]. and sugar-free gums. Sjögren’s syndrome: a female disease Interestingly. whereas dry mouth can be complicated by dental caries. Symptomatic treatment Symptomatic treatment not only has beneficial effects on oral and ocular dryness. Estrogen-deficient women need to produce dehydroepiandrosterone (DHEA) in the adrenal glands and convert it to DHT in the exocrine glands through complex enzymatic mechanisms. The female dominance and the late onset (40 to 50 years of age) in SS can be explained by the regulatory role of sex hormones [97]. The aim of disease-modifying drugs is to restore the deregulated immunological pathways that are accountable for the disease process. the presence of anti-Ro and anti-La antibodies does not seem to affect the gestational outcome as compared with pregnant women with autoimmune diseases negative for anti-Ro and anti-La. mothers with SS seem to give birth to offspring of lower birthweight and a normal delivery is less common. and concluded that there is no strong evidence that any topical therapy is effective for relieving the symptoms of dry mouth [99]. enrolling a low number of patients and using a shortterm follow-up [98]. when compared to age-matched healthy pregnant women. hydroxymethilcellulose) available in the following forms: lubricating gels. In addition. mouthwashes. This means that the gestational period of enhanced CHB susceptibility (18 to 24 weeks of gestation) occurred during January t o March. lozenges. contribute to abnormal apoptosis of secretory acinar cells. in part systemic endocrine but predominantly local intracrine. the male hormone (testosterone) is converted in exocrine glands to dihydrotestosterone (DHT). nicotine. oils. gels. oral candidiasis. intraoral longrelease inserts and mucin spray. avoidance of irritants (coffee. . (b) saliva substitutes (mucin. it has also recently been claimed that vitamin D may be linked with a severe complication that may affect pregnant women with anti-Ro and anti-La: congenital heart block (CHB). lozenges and maltose lozenges to increase salivary flow. In SS. giving rise to the complex pathogenic mechanisms of SS. In fact. In a large case–control study. caboxymethycellulose. Three out of four RCTs showed an effectiveness of saliva substitutes in relieving dry symptoms. prompt treatment of candidal infections). intrauterine fetal deaths. substitution or reduction of xerostomizing drugs. sprays. Dry mouth topical treatment Dry mouth topical treatment encompasses the following approaches: (a) non-pharmacological measures including adequate hydration. involving 1. analyzed the effect of different saliva stimulants and substitutes including lozenges. meticulous oral hygiene (fluoride application. CHB is the result of the passive transfer of maternal autoantibodies to the fetus in the presence of genetic predisposing factors that allow antibody-mediated cardiac damage [91]. no difference was found in terms of pregnancy loss. such machinery is deranged so that hormonal changes. untreated severe dry eye can result in corneal ulceration. Aside from the severe complication of CHB. which is antiapoptotic and protects against acinar cell apoptosis. The authors concluded that the seasonal timing of the pregnancy may be critical to the onset of CHB and that vitamin D could be a possible mediator of such seasonal variation. alcohol. Estrogens seem to protect secretory glandular acinar cells against apoptosis while the lack of estrogens during menopause specifically leads to increased apoptosis of the exocrine cells. The effect of saliva substitutes on patients with SS was evaluated in four RCTs. Vaginal dryness and dyspareunia affect more than half of patients. kissing can be difficult and unpleasant due to dry mouth [96]. chewing gum or toothpastes. Patients with SS can also suffer from gynecological problems more often than healthy women. vascularization. but can also prevent complications of sicca syndrome. preterm delivery and small-for-gestational-age infants [93]. Symptomatic treatment with saliva substitutes and eye drops is effective in the relief of sicca syndrome complaints. opacification and perforation. and periodontal disease. mouth rinses. but they did not observe any increase in salivary flow. it can be proposed that vitamin D supplementation should be given to every patient with SS. The therapeutic challenge: old and new treatments The therapeutic management of pSS is based on symptomatic treatment of glandular manifestations and on the use of diseasemodifying drugs for systemic involvement [98]. whereas immunomodulatory and immunosuppressive agents are used in patients with severe extraglandular manifestations and should be tailored to the specific organ involved. Conversely.Given the associations between hypovitaminosis D and severe complications of SS. and so on). frequent dental examinations. which is the time of the year when vitamin D levels were at their lowest. with a significant difference with age-matched normal controls [94-96].597 subjects. The clearance of this overload of apoptotic material may lead to the breakdown of autotolerance in immunogenetically predisposed individuals. However.

A benefit on sicca symptoms without significant improvement . Importantly. and improvements in salivary flow rate and ocular tests results. In addition. and preservative-free products that are less irritating when applied chronically on a daily basis. that is bromhexine or N-acetylcysteine. and immunological abnormalities. including avoidance of dry. increased urinary frequency. Antimalarials Antimalarial agents have been shown to improve sicca features and constitutional symptoms such as fatigue and arthromyalgia [102. (b) replacement of tear volume. topical NSAIDs can be effective in relieving ocular pain. which are promising treatments especially for patients intolerant to artificial tears or with refractory KCS (the major limitation to a widespread use of these products is related to their preparation and preservation). use of humidifiers. Corticosteroids There are too few studies on oral corticosteroid treatment in patients with SS to draw definitive conclusions. it seems to prevent mutations in cells with high mitotic rate as well as to increase cellular mechanisms of DNA protection and repair [105].103]. therefore. methotrexate. γ-globulin. Thus. computer use. The most frequent side effects of muscarinic receptor agonist therapy are sweating. There are few rigorous studies on the effect of topical medications for eyes in patients with SS. but there is no evidence that they increase salivary and lacrimal flow rates. azathioprine. smoky. Notably. predisposing users to corneal damage. prolonged reading. beta blockers. Muscarinic receptor agonists. surgery). anti-La. Disease-modifying drugs All the drugs currently used in the treatment of autoimmune rheumatic diseases have also been administered to patients with pSS in order to improve sicca symptoms and modify the immune inflammatory pathways involved in disease progression [98]. Patients with severe dryness and refractory KCS may also require topical corticosteroid treatment. As far as artificial teardrops are concerned. seem to be the best options [98]. and emulsions). Immunosuppressants Immunosuppressant agents as ciclosporin A. and non-steroidal antiinflammatory drugs (NSAIDs). artificial tears (preservative-free products. RF. goggles with side seals/moisture chambers. (c) topical drugs counting ciclosporin A. A number of studies were carried out with the use of topical ciclosporin A in patients with KCS and SS. Mucolytic agents. they should only be used for a short time since they can induce severe side effects such as glaucoma and cataracts.Dry eye topical treatment Dry eye topical treatment approach is based on [100]: (a) non-pharmacologic measures. have been used for dry mouth although evidence of their efficacy is lacking. hydroxychloroquine has been reported to increase salivary flow rate by inhibiting glandular cholinesterase [104]. and punctual occlusion in refractory cases (plugs. windy environments. that is. a decrease of B cell activating factor (BAFF) in the tear fluid of patients using hydroxychloroquine has recently been reported [103]. the chronic use of corticosteroids at high dosage should be avoided in order to prevent severe side effects. decrease inflammatory indices. hypotonic solutions that decrease the tear film osmolality. anti-Ro. In fact. Systemic drugs for sicca symptoms Secretagogues are indicated in patients with moderate or severe SS who have dryness and residual esocrinal gland function [100]. Although glucocorticoids exert a rapid and intense anti-inflammatory effect. corticosteroids. only a few studies including a low number of patients and using a short-term follow-up (6 months) have been published. ESR and C reactive protein (CRP). autologous serum eye drops and platelet releasate. This is an interesting finding since patients with pSS have a significantly higher risk of developing lymphoma than the general population. and flushing. that is. Corticosteroids at high dosage downregulate the immune inflammatory process within the salivary and lacrimal glands [101]. cauterization. emulsions containing hyaluronate and hydroxypropylmethyl-cellulose. tricyclic antidepressants. evidence supporting the use of these agents is limited. Cevimeline was approved for the treatment of dry mouth and dry eye by the FDA but not by the EMA. mycophenolic acid and leflunomide are all used empirically in SS. Unfortunately. IgM. their conclusions have a low level of evidence. corticosteroids are currently used primarily in patients with extraglandular manifestations or in cases with parotid swelling. pilocarpine and cevimeline. showing good results in terms of dry symptom relief and tear production. have been used for both dry mouth and dry eye and data from RCTs demonstrated a substantial benefit on sicca symptoms. Moreover. IgG. antihistamines). but they should only be used for a short time and under medical supervision since they reduce corneal sensitivity. Indeed. that is. In patients with severe KCS. avoidance of aggravating drugs (diuretics. that is. hypotonic solutions. hydroxychloroquine has recently been shown to exhibit antineoplastic properties. which was approved for the treatment of dry eye by the US Food and Drug administration (FDA) but not by the European Medicine Agency (EMA).

The fact that CHB is also more frequent during winter and associates with hypovitaminosis D supports the idea that the role of vitamin D should be further investigated in SS and adequate supplementation should be given to these patients. IN: Interstitial nephritis. EBV: Epstein-Barr virus. IFN: Interferon. phase I/II study. some published studies have analyzed the off-label therapeutic potential of the following biological agents in pSS: tumor necrosis factor (TNF)α antagonists (etanercept and infliximab). fatigue. KCS: Keratoconjuctivitis sicca. Interestingly. Since then. CRP: C-reactive protein. EMA: European Medicine Agency. In comparison with baseline values. unstimulated whole saliva flow rate. skin vasculitis. FDA: Food and Drug Administration. it has been recently shown that rituximab treatment does not alter the characteristic features of increased clonal expansions seen in the parotid salivary glands of patients with pSS [122]. Extraglandular manifestations are still a challenge in the management of SS. and sicca symptoms. the drug effect lasted 24 weeks and stimulated whole saliva flow rate declined when CD20+ B cells started to repopulate. LFU: Lacrimal functional unit. The recent finding that severe complications such as lymphoma and peripheral neuropathy are associated with low vitamin D levels opens new avenues in the understanding of the disease and in its treatment. only a modest effect on sicca features was demonstrated [121]. Notably. Anti-CD22 mAb (4 infusions of 360 mg/m2 of epratuzumab once every 2 weeks) was administered to 16 patients with SS in an open label. CHB: Congenital heart block. After three open-label studies in which anti-TNFα agents were shown to improve glandular and extraglandular manifestations. AID: Autoimmune diseases. Conclusions SS is rather far from being considered a simple disease of „dry mouth and dry eyes‟. anti-TNFα agents should be avoided in patients with autoimmune diseases. Since type I IFN and BAFF seem to be involved in the pathogenesis of SS as well as of other autoimmune diseases[42]. which is overexpressed in the peripheral B cells of patients with SS. with 6 months of follow-up [123]. Anti-La: Anti-La/SS-B antibodies. including SS. rituximab was found to be effective in controlling extraglandular manifestations of the disease including arthritis. Abbreviations ACA: Anti-centromere antibodies. among which the most serious is B cell NH lymphoma. Epratuzumab acts through a downregulation of CD22. A substantial number of patients achieved a significant clinical response based on a composite endpoint and the drug was well tolerated. According to these preliminary findings. These drugs are currently used in the treatment of extraglandular manifestations and tailored to the organ specific involvement [106]. The role of infections in the emergence of SS has been recently addressed. no further studies with the use of these agents have been carried out. AECG: American-European Consensus Group. anti-CD20 and antiCD22 monoclonal antibodies (mAbs). and quality of life. Biological drugs No biologic drugs are currently approved for pSS. which can account for disease relapse after treatment [122]. increased type I interferon (IFN)-pathway activation and elevated BAFF serum levels in patients with SS treated with etanercept have been shown [108]. RF levels. the 2012 SICCA Criteria). particularly when associated with cryoglobulins. ANA: Anti-nuclear antibodies. MALT: Mucosa- . Research on SS is extremely active and aims at improving the classification of patients through more objective criteria (for example. CMV: Cytomegalovirus. In uncontrolled studies. Anti-Ro: Anti-Ro/SS-A antibodies. showing that some infectious agents may promote the disease. However. The presence of clonally related immunoglobulin producing cells before and after rituximab treatment strongly suggests that immunoglobulin-producing cells persist in the salivary glands of patients with pSS despite B cell objective tests has been reported by some of them. ILD: Interstitial lung disease. BAFF: B cell activating factor. while others may have a protective action against the development of autoimmunity. DHT: Dihydrotestosterone. Despite these promising results. epratuzumab seems to be a promising treatment in patients with SS. Table 2. DEWS: Dry Eye Workshop. lacrimal gland function. two RCTs failed to demonstrate the superiority of infliximab and etanercept over placebo [107]. however. 20 patients affected with active primary SS and residual salivary gland function were treated with rituximab and compared to 10 patients on placebo [119]. GMN: Glomerulonephritis. ESR: Erythrocyte sedimentation rate. rituximab treatment significantly improved the stimulated whole saliva flow rate and several other variables including B cell number. probing deeper into the etiology and the complex pathogenesis of the disease and providing evidence for the use of new targeted treatments. such as antiB cell drugs. quality of life. A number of uncontrolled studies and two RCTs have been published on anti-CD20 treatment (rituximab) in patients with SS (Table 2) [109-120]. fatigue. APS: Antiphospholipid syndrome. Studies including patients affected with Sjögren’s syndrome (SS) treated with rituximab In a recently published RCT. LIP: Lymphocytic interstitial pneumonia.

US: Ultrasound. VDR: Vitamin D receptor. SS: Sjögren‟s syndrome. RF: Rheumatoid factor. NSAIDs: Non-steroidal antiinflammatory drugs. LA is supported by a Research Grant financed by an agreement between the Government of Lombardy and the University of Brescia („Dote Ricercatore e Dote Ricerca Applicata ai sensi dell‟accordo regionale per lo sviluppo del capitale umano nel sistema universitario Lombardo sottoscritto tra Regione Lombardia e Università Lombarde il 20-10-2009. References . Italy) for the concept and production of the figure on the cover page. sSS: Secondary Sjögren‟s syndrome.associated lymphoid tissue. RCT: Randomized controlled trial. Brescia. NSIP: Non-specific interstitial pneumonia. Università degli Studi di Brescia‟). Competing interests The authors declare that they have no competing interests. PNS: Peripheral nervous system. Acknowledgements We thank Dr Mirko Scarsi (Rheumatology and Clinical Immunology Unit. SSc: Systemic sclerosis. Brescia) for support in the preparation of the „dry eye‟ section. pSS: Primary Sjögren‟s syndrome. MCTD: Mixed connective tissue disease. and to Dr Barbara Arcidiacono (Ophthalmology Unit. UIP: Usual interstitial pneumonia. Authors’ contributions All authors were involved in drafting the manuscript and approved the final version. SICCA: Sjögren‟s International Collaborative Clinical Alliance. NH: Non-Hodgkin‟s.


Scleroderma renal crisis. which is usually characterized by severe hypertension. rarely in inflammatory auto-immune myopathies. Connective tissue diseases. systemic scleroderma (SSc).2]. Sjögren syndrome. Dermatomyositis/polymyositis. Treatment of the underlying autoimmune disorder or discontinuation of specific therapeutic agents improves kidney function in most patients with Sjögren syndrome.Connective tissue diseases (CTDs) are a heterogeneous group of disorders that share certain clinical presentations and a disturbed immunoregulation. autoimmune myopathies (dermatomyositis and polymyositis). antiphospholipid syndrome nephropathy (APSN) as well as rheumatoid arthritis (RA) are frequently present and physicians should be aware of that. Systemic lupus erythematosus. auto-immune myopathies. Subclinical or overt renal manifestations are frequently observed and complicate the clinical course of CTDs. progressive decline of renal function and thrombotic microangiopathy. leading to autoantibody production. roughly 5% in systemic scleroderma (SSc)[3]. Patients with scleroderma renal crisis (SRC). Rheumatoid arthritis Background Impairment of renal function is present to some extent in many connective tissue diseases (CTDs) with variable occurrence in Sjögren syndrome [1. Antiphospholipid syndrome. Keywords: Renal involvement. and rare occurrence in antiphospholipid syndrome [5] . show a significant benefit of early angiotensin-converting-enzyme (ACE) inhibitor use in particular and strict blood pressure control in general. a prevalence of approximately 50% in systemic lupus erythematosus (SLE) [4]. APSN and RA. systemic lupus erythematosus (SLE). In SLE. Alterations of kidney function in Sjögren syndrome. In this review we focus on impairment of renal function in relation to underlying disease or adverse drug effects and implications on treatment decisions. renal prognosis significantly improved based on specific classification and treatment strategies adjusted to kidney biopsy findings.

has been reported in patients with auto-immune myopathies[14. The histopathologic classification of lupus nephritis guides therapeutic interventions with the aim to reduce proteinuria and preserve kidney function. which is associated with a poorer prognosis and a prompter need for dialysis [11-13]. kidney involvement can be of significant prognostic value and often entails specific therapeutic implications. Interestingly. Table 1summarizes specific kidney biopsy findings in the context of CTDs. Apart from that. renal failure and nephrotic syndrome [18]. potentially life-threatening complication in scleroderma and is. alternative immunosuppressive therapies (hydroxychloroquine.7% of them [25]. IgA nephropathy or diffuse proliferative glomerulonephritis. SLE. needs aggressive immunosuppressive therapy. all patients with distal RTA had positive anti-nuclear antibodies and either SSA or SSB antibodies were detected in 85. Conclusion Corticosteroids are a mainstay in the treatment of TIN. proximal (type II) RTA has been reported in some cases [6. Lupus nephritis is one of the most severe organ manifestations of the disease and.23]. in most cases. glomerular disease.6. resulting in keratoconjunctivitis sicca (dry eyes disease) and/or xerostomia (dry mouth disease) [18]. central and peripheral nervous system.2% [1] to 67% [2] of patients. In another cohort. Besides corticosteroids. It was shown that renal function maintained or improved during a median follow-up period of 38 months after treatment with immunosuppressive drugs [6].16]. leading to mild symptoms but also to potentially life-threatening complications. skin.15]. mesangial proliferative glomerulonephritis. the gastrointestinal tract. Lymphocytic infiltration. extraglandular manifestations of PSS can affect organ systems.and rheumatoid arthritis (RA). overexpression of pro-inflammatory cytokines and rapid decline of renal function [810]. Patients with RA are at an increased risk of developing secondary amyloidosis due to long-lasting chronic inflammation as well as mesangial glomerulonephritis and membranous nephropathy related to specific drugs [17]. such as hypokalemic paralysis [22]. such as RA. focal segmental glomerulosclerosis (FSGS). muscular skeletal apparatus and the kidney [19. as well as hypergammaglobulinemia.7]. when indicated. in one study SSA/Ro. including minimal change disease. . SSB/La and rheumatoid factor. should be commenced. is the predominant renal pathology in Sjögren syndrome [2.6. in particular lymphomas of B -cell origin [21]. Rhabdomyolysis with acute tubular necrosis or glomerular disorders. Distal (type I) renal tubular acidosis (RTA) is the most common clinical finding. In addition.24]. were detected in all subjects with biopsy-proven renal involvement [6]. accompanied by malignant hypertension. different study designs and small cohorts examined as well as selection bias.26]. such as the lungs. Histopathology/kidney involvement Acute or chronic tubulointerstitial nephritis (TIN) with defects in tubular function is the predominant lesion in biopsy-proven renal involvement [2. Further histologic findings require specifically-tailored immunosuppression and most importantly. A single case of long-lasting TIN in a patient with PSS led to a secondary (AA) amyloidosis with. SSc and others. long-term bicarbonate and/or electrolyte supplementation should be commenced in a majority of patients to prevent life-threatening complications [26]. membranous nephropathy and minimal change disease have been reported [2. Scleroderma renal crisis (SRC) is a severe. leading to acute or chronic tubulointerstitial nephritis.20]. Secondary Sjögren syndrome is associated with other rheumatic disorders. In rare cases patients present with normotensive SRC. Albeit considered to be rare. rituximab. Therapy Treatment with glucocorticoids should be initiated as first line therapy in patients with PSS and renal involvement since a good response to early treatment has been reported [6. blood vessels. Renal manifestation in primary and secondary antiphospholipid syndrome (APS) is a well-described complication.6]. cyclophosphamide) should be prescribed based on kidney biopsy findings as well as comorbidities. depending on biopsy findings. Early commencement of angiotensin-converting-enzyme (ACE)-inhibitors and other antihypertensive drugs is mandatory in the management of SRC. The variation is considered to be associated with the different diagnostic criteria used. Renal disease with PSS is reported to occur in 4. In addition. frequently leading to arterial hypertension and occasionally impairment of renal function [5. membranous nephropathy. Table 1. Affected patients are at increased risk of developing non-Hodgkin‟s lymphoma.7. consequently. Moreover. Overview of kidney biopsy findings in patients with connective tissue diseases Review Sjögren syndrome Introduction Primary Sjögren syndrome (PSS) is an autoimmune disorder of hitherto unknown origin which is characterized by polyclonal B-cell activation as well as lymphocytic infiltration of the exocrine glands. supplementation of bicarbonate and/or electrolytes. such as cryoglobulinemic membrano-proliferative glomerulonephritis.

a calcineurin-inhibitor free immunosuppressive regimen might be chosen. which is characterized by a violaceous skin discoloration around the eyes. SRC occurs in roughly 5% of patients with SSc [3]. electromyographic alterations and extra muscular manifestations.Scleroderma renal crisis Introduction SSc is a CTD characterized by deposition and overproduction of extracellular matrix proteins and collagen. Blood pressure levels greater than 150/90 mmHg were observed in almost 90% of patients experiencing SRC. Discontinuation of dialysis was reported in some patients. Hypertensive SRC is accompanied by clinical signs of malignant hypertension with left ventricular failure. Blood pressure control.36]. Among those. such as proximal muscle weakness.37]. Several growth factors. Based on the finding that cyclosporine A (CSA) may be responsible for acute renal failure in patients with SSc [39]. Normotensive renal crisis was more frequently present in patients treated with high doses of corticosteroids and in patients with redundant microangiopathic hemolytic anemia and thrombocytopenia in consequence to the underlying disease [11]. whereas the presence of anti-topoisomerase and anti-centromere antibodies in scleroderma indicates a favorable disease course [33]. on the basis of most experience in particular captopril. in 10% of patients. watermelon stomach. If blood pressure is not adjustable or the patient shows signs of fluid overload. In patients with chronic hemodialysis and renal transplantation. Dermatomyositis and polymyositis Introduction Auto-immune myopathies. Detection of anti-RNA polymerase III antibodies displays a strong risk marker for the presence of SRC. calcineurin inhibitors are not generally recommended as immunosuppressants after kidney transplantation. development of onion-skin lesions and/or fibrointimal sclerosis [13]. share common clinical features.31]. is essential. is recognized as a crucial part of the development of tissue fibrogenesis [30. are involved in tissue remodelling. Epithelial to mesenchymal transition (EMT). SRC occurs in the absence of hypertension. severe clinical manifestations of vascular dysfunction can be observed in some patients leading to pulmonary fibrosis and pulmonary artery hypertension. In a cohort of 260 patients with SSc who underwent kidney transplantation. a case control study revealed a significant positive association between long-lasting high-dose corticosteroid treatment (≥15 g/d) and the onset of SRC [34]. Additional antihypertensive therapy (calcium channel blockers. accumulation of myxoid material and later in the disease course. Histopathology/kidney involvement Diagnosis of SRC is confirmed by renal biopsy. Immediate use with a progressive increase of ACE inhibitor dosage. as well as other mediators. particularly affecting small vessels. muscle inflammation. On average. Furthermore. tissue dysfunction. After a stable disease course with continuous dialysis. such as endothelin-1 [10]. the recurrence of disease after transplantation was 6. . a condition that conveys a phenotypic conversion from differentiated epithelial cells to matrix-producing fibroblasts and myofibroblasts. cardiac involvement. Several risk factors with a predictive value were established: duration of SSc onset of less than four years. Conclusion Renal involvement in SSc is often accompanied by progressive renal failure and rapid initiation of therapeutic interventions is mandatory. Therapy Early use of ACE inhibitors.37]. Affected organs and tissues include the skin. heart. the overall five-year graft survival rate was 56. esophageal motility dysfunction. even in the presence of deteriorating kidney function. Discontinuation of dialysis treatment could be accomplished in 16 to 55% patients with SRC [3. renal transplantation should be considered when contraindications are ruled out. presence of autoantibodies. is undoubtedly a cornerstone in the management of hypertensive SRC. Recent findings suggest that dialysis was required in more than 50% of patients either in case of volume overload together with renal deterioration or to control blood pressure due to therapy-resistant hypertension [3. namely dermatomyositis (DM) and polymyositis (PM). Involvement of the vascular system generally results in the development of Raynaud‟s phenomenon early in the disease course. Vascular changes are accompanied by thrombosis. new development of anemia and cardiac involvement (pericardial effusion or congestive heart failure) [32].7%. one has to keep in mind that ANCA-associated vasculitis is a rare complication of SSc and in general presents with antibodies directed against myeloperoxidase and p-ANCA [35]. subsequently. gastrointestinal tract. Consecutively. elevated muscle enzymes. The presence of a heliotrope rash. such as transforming growth factor ß (TGFß) [8]. hypertensive encephalopathy and arrhythmia [12]. alpha/beta-adrenoreceptor antagonists and/or minoxidil) is mandatory when blood pressure is insufficiently controlled [28. In addition. normotensive renal failure in SSc was associated with a higher mortality rate and an earlier need for dialysis treatment[11-13]. resulting in tissue fibrosis and. as well as scleroderma renal crisis (SRC) [27-29].7% in a report of the United Network of Organ Sharing (UNOS) [38]. dialysis should be considered early in the disease course. connective tissue growth factor (CTGF) [9]. both differ regarding muscle biopsy findings and DM is associated with cutaneous involvement. lungs and kidneys. in particular with ACE-inhibitors and additional antihypertensive medication. In addition. which shows a thrombotic microangiopathic process. higher incidence of progressive skin thickening prior to renal involvement. is considered to prevent or even reverse renal failure [36.12]. Despite clinical similarities.

Second. environmental and hormonal factors have been identified as possible risk factors for developing SLE [64. Moreover. Earlier diagnosis. Systemic lupus erythematosus Introduction SLE depicts a remarkable complex autoimmune disease with considerable heterogeneity in clinical manifestations and disease course. First. Moreover. Classification of SLE was last edited by the American College of Rheumatology (ACR) in 1997 [60] (Table 2). Patients with active lupus nephritis had significantly lower levels of C3 and C4 compared to patients with inactive lupus nephritis [71]. Genetic complete complement deficiencies can resemble a SLE-like disease [70].41]. contradictory to these reports. Antibodies directed against C1q were detected in all patients with active nephritis in a large cohort [74]. This hypothesis is supported by the finding that glomerular deposition of anti-dsDNA antibodies in lupus nephritis is mediated by nucleosomes [66. The kidneys are a major source of autoantibody-producing plasma cells in lupus nephritis and these differentiated plasma cells are frequently observed in patients with severe renal involvement (mainly classes III through V). corticosteroids might be effective as one therapeutic component. Follow-up of the patients with DM revealed a high mortality rate due to cancer or multi-organ failure.65]. Additional autoantibodies include anti-Smith (Sm) antibodies with a high specificity for SLE. in particular against chromatin components. Conclusion Management of patients with auto-immune myopathies and renal involvement require special caution. potentially acting in amplifying the renal disease course [68]. glomerulonephritis and “severe” onset of SLE[ 62]. Histopathology/kidney involvement Two types of renal involvement have been described in patients with PM/DM. Therapy High-dose oral corticosteroids are the cornerstone of DM/PM therapy. mesangial proliferative glomerulonephritis represents the leading glomerular lesion [46. Levels of complement C3 and C4 correlate with the overall disease activity. malignancies were detected in 9. anti-nuclear antibodies (ANA). Complement levels are frequently reduced in patients with active disease. Genetic. histones. rhabdomyolysis with release of myoglobin can lead to acute tubular necrosis with deterioration of renal function[14. In most cases.55-58]. Assessment of the relationship between serum levels of C3 or C4 and renal flares revealed that C4 is critical for initiating a renal four-fold greater in non-Caucasian populations [63]. the predominant finding in DM with renal involvement is membranous nephropathy[55-57]. In contrast to these reports. Serum C3 has generally higher sensitivity than serum C4. such as nucleosomes. both mesangial proliferative glomerulonephritis [58] and diffuse proliferative glomerulonephritis [49] have been reported in single case reports. the addition of immunosuppressive drugs. double-stranded DNA antibodies (dsDNA) and ribonucleoproteins. However. Moreover. CYC. Table 2.and Gottron‟s sign (erythematous papules with involvement of joints) are pathognomonic for DM [40. The incidence is much higher in young woman and the prevalence is two. several reports revealed the occurrence of chronic glomerulonephritis in patients with PM/DM [14. Histopathology/kidney involvement Involvement of the kidney in the natural history of disease is present in a majority of patients and is supposed to appear in almost 50% in the first year of diagnosis [4].4 to 32% of patients in DM and in 4. it was suggested that the nucleosome might be the driving autoantigen in SLE. Special therapeutic intervention with immunosuppression should be tailored to the underlying histology. anti-C1q antibodies were not significantly associated with active lupus nephritis [76]. but both tests have only modest specificity for active lupus nephritis [72]. such as azathioprine (AZA) or cyclophosphamide (CYC). Recent findings even suggest a higher incidence. since a considerable proportion of patients . one patient progressed to end-stage renal disease despite immunosuppressive treatment[59]. while C3 activation is involved in the actual tissue damage [73]. In contrast. membranous nephropathy [53] and crescentic glomerulonephritis with FSGS [54]. In large cohorts. Both entities are associated with concurrent incidence of neoplasms. intravenous immunoglobulins and CSA in PM has been reported to improve the renal outcome in DM/PM [14. Revised criteria of the American College of Rheumatology Autoantibodies are directed against various nuclear antigens.15]. Nevertheless.49. Negative predictive factors with respect to survival include male gender.4 to 17% in PM patients [42-45] with a predominance of adenocarcinomas[45]. while SSA and SSB are present in other CTDs as well [69]. positive lupus anticoagulant. anti-C1q antibodies showed the strongest association with proteinuria among potential biomarkers and were significantly correlated with Renal Activity Score [75]. Recently.50. in a cohort of 126 patients. other biopsy specimens showed lipoid nephrosis with FSGS [52]. because disease-related mortality due to rhabdomyolysis and hyperkalemia is greatly feared.51]. In PM.67]. while mortality in PM was high due to acute rhabdomyolysis followed by severe hyperkalemia and metabolic acidosis in a case report [14]. more intensive treatment regimens and diverse alternative strategies and possibilities to treat co-morbidities have contributed to improvement of prognosis [61].46-49]. as well as anti-malaria medication in DM and methotrexate.

Specific treatment follows the class of lupus nephritis. In a small cohort. In a subgroup analysis a beneficial effect of RTX was observed in the African-American/Hispanic subgroup [100]. Since a majority of the subjects were white in this trial.5 g). MMF was superior to AZA with respect to maintaining a renal response and preventing relapse in patients with lupus nephritis [98]. In a more diversified cohort (>50% blacks) MMF (mean daily dosage 2. at a fixed dose of 500 mg. long-term immunosuppression is mandatory to avoid severe flares and to maintain stabilization of disease activity. Both strata were followed by AZA as remission-maintaining treatment. whereas relapse of nephrotic syndrome occurred more frequently in patients with prior CSA therapy [94]. MMF and AZA are deemed suitable and have shown efficacy in maintaining remission of lupus nephritis [96]. but the low dose CYC group had fewer severe infections. class IV (diffuse) and class V (membranous nephropathy) lupus nephritis and usually consists of high dose glucocorticoid therapy along with intravenous CYC or mycophenolate mofetil (MMF) as induction therapy. Thus. high-dose steroid therapy rapidly resolved nephrotic syndrome in a majority of SLE patients with minimal change disease either in the absence or with underlying class II lupus nephritis based on renal biopsy findings [82. multi-target therapy (MMF and tacrolimus) in patients with class IV and class V lupus nephritis revealed a higher rate of complete remission with a good tolerability when compared to intravenous CYC [95]. In proof of the efficacy of RTX treatment in moderately to severely active SLE and lupus nephritis. which was published on behalf of the International Society of Nephrology (ISN)/Renal Pathology Society (RPS) [78] (Table 3). immunosuppressants with a favorable safety profile and good efficacy are mandatory. Table 3. Equivalence of MMF and AZA was reported in the MAINTAIN Nephritis Trial. FSGS. in a larger trial. Revised classification lupus nephritis according to the International Society of Nephrology/Renal Pathology Society (ISN/RPS) 2003[78] Therapy In general. with a cumulative dose of 3 g) with the previously established high dose CYC (NIH) regimen (mean cumulative dose 8.47 g) to CYC failed to meet the primary end point. no significant difference with regard to severe adverse events or infections was reported [92]. Enthusiasm was also dampened by reports on the development of progressive multifocal leukoencephalopathy in SLE patients following treatment with RTX [103]. even though a trend towards fewer renal flares in the MMF group (19% vs. Following induction therapy. Concomitant use of antimalarial drugs (chloroquine and hydroxychloroquine) at diagnosis of lupus nephritis reduced the risk of progression to end-stage renal failure and frequency of hypertension[87]. More recently. . such as collapsing glomerulopathy [79]. two large multi-center trials were conducted. even though the difference was not statistically significant [89]. Class I and class II require no therapy directed at the kidney in consequence of good long-term renal outcome [88]. these results might be less applicable to other ethnicities. Both treatment arms achieved virtually identical rates of complete and partial remission.68 g) has been reported to be superior as induction therapy when compared to monthly CYC (0. Diagnosis in the latter group was significantly earlier compared to the overt lupus nephritis group and urinary sediment as well as renal function tests were normal [77]. minimal change disease [82]/glomerular podocytopathy [83] can occur as well and alterations in kidney function due to rhabdomyolysis with acute kidney failure [84].with SLE have silent lupus nephritis.5 g to 1 g/m2) in patients with class III through V lupus nephritis [91]. However. In patients with proliferative lupus nephritis and background immunosuppression (MMF) no difference was noted when RTX was added with regard to safety and efficacy (LUNAR trial) [101] even though opportunistic infections are reported to be rather common in SLE patients related to RTX treatment [102]. Response to MMF as induction treatment in pure class V (membranous nephropathy) lupus nephritis in patients with diverse racial background appeared to show no difference in comparison to CYC [93]. Renal outcome was similar in both treatment arms. Reports from this trial with a 10-year duration of follow-up confirmed the efficacy of the Euro Lupus regimen [90]. A further large. 25% in the AZA group) was reported [97]. IgM nephropathy [81]. multi-center trial in a balanced cohort with respect to ethnicities designed to show superiority of MMF (mean daily dosage 2. as well as type I and IV RTA [85]. In contrast. Renal biopsy findings are categorized according to the current classification of lupus nephritis. Furthermore. IgA nephropathy [80].83]. Patients (>60% black) with class V lupus nephritis showed a better response regarding induction of remission after CSA when compared to CYC. use of ACE inhibitors significantly reduced the development of proteinuria and/or biopsy-proven lupus nephritis and was associated with a decreased risk of disease activity [86]. The EXPLORER trial (moderate to severe active SLE) demonstrated no difference in primary/secondary end points between RTX and placebo. which is defined by the revised ISN criteria. The Euro Lupus Nephritis Trial compared low dose CYC (fortnightly. one should be aware that other glomerular changes. Immunosuppressive treatment is required in the management of class III (focal). B-cell depleting therapy with anti-CD20 antibody rituximab (RTX) proved efficient in patients with active SLE including patients with lupus nephritis. have also been reported. who were nonresponsive to standard immunosuppressive therapy [99].

a humanized anti-CD22 antibody [108. a case of fibrillary glomerulonephritis in a patient with APS was published recently [125]. minimal-change disease/focal segmental glomerulosclerosis (three cases). and pauci-immune crescentic glomerulonephritis (one case). neutralizes the activity of BLyS and a proliferation-inducing ligand (APRIL) and their heterotrimers [110]. Thrombotic microangiopathy is characterized by distinctive microscopic and ultrastructural changes and clinical presentation commonly includes hypertension. even though this clinical benefit was associated with increased mortality rates in most studies conducted so far [113]. while in patients with an INR <3. and/or chronic. In both trials. Tektonidou et al.Novel approaches with focus on targeted therapy have been developed and are currently being evaluated in clinical trials. Atacicept. The APS is classified as primary APS in the absence of associated autoimmune disease. plus standard of care (SOC) than to SOC alone[105]. in the case of arteriosclerosis. Further trials assessing the efficacy and safety are currently ongoing.0 renal function significantly deteriorated and blood pressure was poorly controlled [118]. complications during pregnancy (including unexplained consecutive spontaneous abortions.127]. atacicept was well tolerated and demonstrated a dose-dependent reduction of immunoglobulin levels and mature/total B cell numbers [111]. CSA might be an alternative to these immunosuppressive agents in pure class V lupus nephritis. leading to renovascular hypertension [117]. mild to nephrotic-range proteinuria and renal impairment [119. Intravenous immunoglobulins have shown benefits in patients nonresponsive to other therapies and as a steroid-sparing agent [114]. In patients with highly active lupus nephritis with failure of conventional therapy. a soluble receptor fusion protein. as well as the significance of novel therapeutic approaches in the therapy of lupus nephritis. Interestingly. Patients with serologically active SLE responded significantly better to belimumab.123]. However. patients with APS. compared with only 4.0 had better blood pressure control and renal function remained stable or improved.3% of patients without aPL [16]. . The role of RTX in the treatment of lupus nephritis has to be further elucidated. The efficacy of belimumab was further corroborated in two large phase III trials. short-term as well as prolonged immunoadsorption led to a significant reduction in proteinuria and to sustained remission rates [112]. In patients not responding to initial treatment. multi-target therapy might be an effective alternative. whereas secondary APS is found alongside other autoimmune disorders[116]. Arterial hypertension is a well-documented complication of APS. Promising results have been obtained in a phase II trial for epratuzumab. Conclusion The histopathologic classification of lupus nephritis still guides the therapy. Kidney disease in antiphospholipid syndrome Introduction Antiphospholipid syndrome (APS) is defined by the association of vascular thrombosis potentially affecting all segments of the vascular bed. an antibody that binds to BLyS and inhibits its biological activity. in patients with active lupus nephritis. Kleinknecht et al. fibrous intimal hyperplasia and focal cortical atrophy [119. In a phase I trial. and the presence of antiphospholipid antibodies (aPL). CYC and MMF have shown almost identical therapeutic responses as induction therapy in large trials. In a retrospective study. Furthermore. Renal artery stenosis (RAS) is a common complication of APS. premature births because of severe preeclampsia.109]. mesangial c3 nephropathy (two cases). BLISS 52[106] and BLISS 76 [107]. RAS and hypertension receiving oral anticoagulation with a target trough International Normalized Ratio (INR) >3. belimumab met its primary efficacy end point and was consequently approved by the FDA in the treatment of SLE with the exception of severe active lupus nephritis or central nervous system lupus. In a series of patients with primary APS. a phase II trial was terminated due to an increased number of infections [109]. Further investigations addressed to evaluate the role in active lupus nephritis are necessary. a large proportion of patients presented with hypertension. examined kidney biopsies obtained from patients with SLE with or without presence of aPL. APSN was detected in almost 40% with aPL. Fakhouri et al. namely anticardiolipin antibodies (aCL) and lupus anticoagulant (LAC) [115]. examined 29 kidney biopsies of patients with APS [124]. Thrombosis of the renal vein and inferior vena cava usually presents with nephrotic-range proteinuria in primary and secondary APS [121]. the presence of aPL in patients undergoing renal transplantation significantly increases the risk of renal vascular thrombosis and graft failure [126. reported that all patients had severe hypertension and renal insufficiency in a small cohort of patients with secondary APS due to SLE [120]. eclampsia or placental insufficiency or unexplained death before the 10 th week of gestation). Circulating B-lymphocyte stimulator (BLyS) is elevated in SLE. MMF seems to be superior to AZA in maintaining remission. especially in those with circulating LAC [122].123]. which was attributed to biopsy-proven vascular nephropathy [119]. Autologous stem cell transplantation achieved sustained clinical remissions in patients refractory to conventional immunosuppressive treatment. Histopathology/kidney involvement Renal manifestations in the context of APS may result from thrombosis occurring at any location in the renal vasculature. In nine of these biopsies predominant pathological features distinct from ASPN were noted: membranous nephropathy (three cases). In proliferative lupus nephritis (III and IV). in case of the presence of thrombotic microangiopathy. and titers correlate with increased disease activity and elevated dsDNA antibody concentrations [104]. APSN refers to kidney damage caused by intrarenal vascular damage and may be acute.

129] and is not routinely recommended in APS-related renal manifestations. Histopathology/kidney involvement A study of renal biopsy specimens indicated that mesangial glomerulonephritis is the predominant histopathologic finding in RA.142. adequate therapy to reduce disease activity may be effective in preventing this late-onset complication. Contrasting. Specific therapeutic interventions should be tailored to the underlying histologic kidney involvement. have completed patient recruitment and the first results are expected soon [145]. in particular gold thiomalate. Deposition of mesangial IgA correlated with the duration of RA and elevated serum IgA levels. Since there is a steady increase of knowledge regarding the pathophysiology behind auto-immune disorders. In addition. single reports reveal the presence of FSGS [139] and fibrillary glomerulonephritis [140] in RA patients. The role of anticoagulation with a target through INR above 3. The ASSIST trial clearly depicted the efficacy of HSCT in patients with scleroderma. more specific therapeutic approaches have been developed and are currently in clinical trials. D-penicillamine and bucillamine. systemic inflammation and autoantibodies (particularly to rheumatoid factor and citrullinated peptides).143]. usually receive a combination therapy. Deposition of amyloid in renal tissue correlated significantly with parameters of renal function [132]. Rheumatoid arthritis Introduction RA is characterized by persistent synovial. since all 10 patients in the HSCT-group improved when compared to none in the . followed by amyloidosis.134. Results from hematopoietic stem cell transplantation (HSCT) in SSc are promising. Therapy Improvement of clinical and laboratory parameters was achieved in most cases after drug withdrawal and in case of necessary initiation of immunosuppression [133. patients with catastrophic APS. whereas mesangial IgM deposition was correlated with serum levels of IgM class RF [138]. Current studies. Acute or chronic TIN is the predominant kidney biopsy finding in Sjögren syndrome. Conclusion and future directions Renal involvement is frequently present in CTDs and has variable phenotypes. Furthermore. including anticoagulation. since its occurrence was associated with higher titers of rheumatoid factor (RF) when compared with RA patients without nephropathy. membranous nephropathy. intravenous immunoglobulins and plasmapheresis. Conclusion Therapy related deterioration of kidney function has to be excluded in patients with RA. Thus. Evidence supporting immunosuppressive therapy in these patients is limited to case series [125. larger studies. steroids. which is manifested primarily in a decline in creatinine clearance [143]. Besides the renal side effects of gold salts. which is characterized by severe multiple organ dysfunction in consequence of diffuse small vessel ischemia and thromboses predominantly affecting the parenchymal organs. the persisting inflammation can lead to deposition of amyloid. In addition. focal proliferative glomerulonephritis. CSA as another DMARD has a serious potential for renal toxicity. but despite this aggressive approach mortality is still high[130]. In addition. several glomerular lesion patterns have been described in Sjögren syndrome.0 in patients with APSN and microthrombi to prevent kidney function deterioration has to be elucidated in further. D-penicillamine and bucillamine[132]. namely the SCOT and ASTIS trials. such as etanercept and adalimumab [133. Secondary AA amyloidosis was prevalent in 5.0 mg/dl at the onset of amyloidosis [144]. etanercept treatment reduced proteinuria as well as serum amyloid A. Development of membranous nephropathy is related either to therapy with disease modifying antirheumatic drugs (DMARDs).8% of patients with RA and was accompanied by a shortened life expectancy [136].Therapy Blood pressure control is the key intervention in the treatment of APS-related renal involvement. Kidney function normalizes in most cases after corticosteroids are initiated [2. Genetic as well as environmental factors contribute to the risk of developing RA [131]. and anti-TNF alpha therapy. minimal-change nephropathy and acute interstitial nephritis [17].134]. it entailed a decrease in serum creatinine in patients with creatinine values <2. Mesangial glomerulonephritis is probably related to RA itself. In patients with amyloid deposition. or rarely occurs concomitant with RA [135]. Renal involvement is relatively common in patients with RA.6]. Conclusion Blood pressure control is mandatory in patients with APSN. Adequate anticoagulation (if evidence of microthrombi is present) has shown encouraging results in small cohorts and may prevent progression to end-stage renal disease [128]. while a lack of amyloid deposition in the glomerulus may characterize subjects with stable renal function [137]. Anti-TNF alpha therapy can be causative for the development of necrotizing crescentic glomerulonephritis and proliferative lupus nephritis [141.142].

ACR: American college of rheumatology. TNF: Tumor-necrosis factor. An interdisciplinary approach to optimize treatment is the aim for patients with CTDs. LDL: Low-density lipoprotein. TGFß: Transforming growth factor ß. Despite efficacy in patients with pulmonary arterial hypertension in SSc [148]. Chronic inflammation. APRIL: A proliferation-inducing ligand. controlled trial with inclusion of active lupus nephritis is currently being designed. AZA: Azathioprine. DM: Dermatomyositis. counselling against smoking should be mandatory in patients with SLE and RA [156]. increase of proteinuria or signs of nephritic syndrome (summarized in Table 4). SOC: Standard of care. RAAS: Renin-angiotensin-aldosterone system. immuno-adsorption and stem cell transplantation [112-114]. physicians should be aware of severe infectious complications following RTX treatment in SLE patients [102. In SLE.CYC–treated cohort [146]. endothelin receptor antagonists in combination with dual blockade of the renin-angiotensinaldosterone system (RAAS) significantly reduced proteinuria and stabilized the serum creatinine level after an initial increase in a patient with SRC [147]. SLE: Systemic lupus erythematosus. RAS: Renal artery stenosis. and efficacy was furthermore confirmed in a recent meta-analysis evaluating patients with refractory lupus nephritis [150]. DMARD: Disease modifying antirheumatic drug. trials with the aim to show benefits of endothelin receptor antagonists in SRC have yet to be conducted. patients with renal involvement in CTDs should receive RAAS blocking agents once proteinuria is >1 g/day [149. ISN: International society of nephrology. Etanercept has shown encouraging results in reduction of serum amyloid A in amyloidosis and patients with a baseline serum creatinine below 2 mg/dl tended to show a benefit following TNF-alpha inhibition [144]. EMT: Epithelial to mesenchymal transition. RTX failed to show superiority in two large phase III trials with patients either presenting without renal involvement (EXPLORER) or with renal involvement (LUNAR) [100. Furthermore. B-cell depleting therapy with RTX was effective in a larger cohort including patients with lupus nephritis [99]. RF: Rheumatoid factor. RTX is nevertheless one alternative in refractory SLE [99]. such as immunoglobulin administration. FDA: Food and drug administration. renal manifestations of CTDs are frequent. is causative of kidney involvement in RA. One of these novel agents is belimumab. Renal biopsy to ensure diagnosis is necessary in most patients presenting with deterioration of renal function. CSA: Cyclosporine A. . aPL: Antiphospholipid antibodies. HSCT: Hematopoietic stem cell transplantation. In patients with SLE. MMF: Mycophenolate mofetil. ANA: Anti-nuclear antibodies. as well as drug related adverse effects. RPS: Renal pathology society. Despite other strategies. In addition. Guided therapy with the aim to treat the underlying disease improves kidney function in most cases. RA: Rheumatoid arthritis. whereas the role and the target level of oral anticoagulation needs to be further elucidated. Suggested kidney biopsy indications in connective tissue diseases Abbreviations AA: Amyloid A. INR: International normalized ratio. aCL: Anticardiolipin antibodies.103]. PM: Polymyositis. RTX: Rituximab. BLyS: B-lymphocyte stimulator. CTGF: Connective tissue growth factor. Accelerated atherosclerosis is a common finding in patients with chronic inflammation and in CTDs in particular [154]. In addition. which was recently approved by the FDA for treatment of SLE with the exception of active lupus nephritis and central nervous system involvement. PSS: Primary sjögren syndrome. an inhibitor of serum BLyS.150]. new therapeutic approaches have gained attention. Persistent B-cell presence was associated with no clinical response following RTX treatment [152]. In summary. APS-related renal manifestation potentially affects any segment of the vascular bed and is commonly accompanied by arterial hypertension. UNOS: United network of organ sharing. Renal function needs to be monitored as well as serum potassium levels and blood pressure. In addition. BLyS inhibition may also be effective in the treatment of PSS. Blood pressure control is crucial. A randomized. LAC: Lupus anticoagulant. Sm: Smith. since patients with Sjögren syndrome exhibit increased BLyS levels [149]. APSN: Antiphospholipid syndrome nephropathy. Based on studies in non-diabetic nephropathy. dsDNA: Double-stranded DNA antibodies. TIN: Tubulointerstitial nephritis. In chronic kidney disease in the pre-dialysis state the lowering of LDL-cholesterol safely reduced the risk of major atherosclerotic events [153]. APS: Antiphospholipid syndrome. Diverse glomerular alterations and rhabdomyolysis have been reported in patients with auto-immune myopathies. SRC: Scleroderma renal crisis. However. ACE: Angiotensin-converting-enzyme. FSGS: Focal segmental glomerulosclerosis. CTD: Connective tissue disease. modification of the risk factors contributing to the evolution of cardiovascular disease is crucial in these patients. RTA: Renal tubular acidosis.101] even though a post hoc analysis of the EXPLORER trial indicated that RTX-treated patients achieved lower disease activity without a subsequent severe disease flare when compared to those treated with placebo [151]. CYC: Cyclophosphamide. Moreover. SSc: Systemic scleroderma. adherence to therapeutic advice may be an underestimated problem. Thus. Table 4. since a recent study indicated that only onequarter of patients with SLE had an adherence rate ≥80% [155].

suggesting distinct autoimmune-promoting pathways. Greater understanding of the innate mechanisms responsible for idiopathic and environmentally induced autoimmunity should yield new information into the processes that instigate and drive systemic autoimmunity. Scavenger receptors and the inflammasome may contribute to silica-induced autoimmunity. Innate immunity. Although the specific environmental agents and how they promote autoimmunity remain largely unknown. idiopathic and pristane-induced systemic autoimmunity require both type I interferon and proinflammatory cytokines whereas the less aggressive mercury-induced autoimmunity. mercury. Environment. environmentally induced autoimmune models can provide insights into potential mechanisms. Some of these differences may be related to the bifurcation of toll-like receptor signaling that distinguishes interferon regulatory factor 7-mediated type I interferon production from nuclear factor-κB-driven proinflammatory cytokine expression. Pristane. Silica. there are clear differences in the molecular and cellular innate components that mediate specific systemic autoimmune diseases. By contrast.Competing interests There is substantial evidence that environmental triggers in combination with genetic and stochastic factors play an important role in spontaneous autoimmune disease. Lupus. in part because of diverse etiologies. Keywords: Autoimmunity. does not require type I interferon but needs proinflammatory cytokines. although the innate immune system is indispensable for autoimmunity. Studies of idiopathic and environmentally induced systemic autoimmunity show that they are mediated by common adaptive immune response genes. although dependent on nucleic acid-binding toll-like receptors. Accordingly. Type I interferon .

Surveillance mechanisms involve secreted. but also to host-derived damageassociated molecular patterns such as ATP. C1q preferentially promotes binding of immune complexes to monocytes rather than pDCs and . such as multiple sclerosis and type I diabetes. can be modified to generate highly specific antibodies and T cells capable of targeting virtually all foreign antigens.17. environmental factors and stochastic events [6]. leading to inflammatory cell recruitment and activation. Deficiency of macrophage migration inhibitory factor reduces macrophage recruitment and glomerulonephritis in MRL-Faslpr mice [29]. In this review we compare and contrast the innate immune system requirements for idiopathic systemic autoimmunity with systemic autoimmunity induced by exposure to mercury and pristane. anti-chromatin autoantibodies and glomerulonephritis [25]. We also discuss the innate immune components in silica-induced inflammatory responses that may contribute to silica-induced autoimmunity.5. in MRL-Faslpr mice reduces disease severity [28]. and expression of co-stimulatory molecules crucial for the induction of adaptive immunity [2]. Under normal circumstances. in lupus-prone MRL-Faslpr mice reduces disease severity including lymphocyte expansion. Deletion of DCs. To varying extents. Most significantly. especially DCs [9.21]. Deficiency of colonystimulating factor-1.15. NOD-like receptors and RIG-I-like receptors [4. However. In mammals. bacteria. Innate immunity in idiopathic systemic autoimmunity Systemic autoimmunity is thought to result from a mix of genetics. These recent findings implicate pDCs and their ability to produce type I IFN as major contributors to the pathogenesis of lupus. it is becoming clear that differences exist [8]. cytokine production and antigen presentation has also identified them as influential players in the innate immune response in systemic autoimmunity [27]. Given the multitude of susceptibility genes.12]. dermatomyositis. although idiopathic and environmentally induced systemic autoimmunity share common requirements [6. the principal growth factor for macrophages. from the host's healthy tissues. it is clear that numerous pathogenic pathways contribute to systemic autoimmune disease [5.9. but does not confer long-lasting or protective immunity [1]. including viruses. macrophages from MRL-Faslpr mice have dysregulated gene expression compared with non-lupus-prone mice [30]. lipoproteins and carbohydrates. cell surface and intracellular pattern recognition receptors. neutrophils and other less common leukocytes. Cultured in the presence of serum. member 4 do not develop autoimmunity [26]. including bacterial and viral nucleic acids. is hard-wired to recognize and respond rapidly to pathogens. The recognition by pattern recognition receptors of these pathogen-associated molecular patterns and/or damage-associated molecular patterns results in cell signaling and activation of transcription factors such as NF-κB and IFN regulatory factors (IRFs) [10]. plasmacytoid (pDC) and monocyte-derived [22]. pDCs produce large amounts of type I IFN in humans and mice and they are considered the main source of type I IFN in systemic autoimmunity [24]. high-mobility group box 1 and self-DNA. including organ-specific disease with restricted tissue involvement.15.11. Innate immunity The innate immune response provides an immediate response to infection and injury and is mainly mediated by circulating factors and non-lymphocytic cell types that include macrophages.Review Immunity requires contributions from both the innate and adaptive arms of the immune system. unlike the innate system. more effective responses to previously encountered antigens. This is based on the early observation of increased expression of IFN-α inducible genes (or IFN signature) in the peripheral blood cells of patients with SLE [17].16]. The important role that monocytes and macrophages play in phagocytosis. DCs act as antigen presenting cells. However more recent research has identified the innate immune response as a major player in the initiation and expansion of systemic autoimmune pathology [4. Upon stimulation. fungi and parasites.14]. For most idiopathic autoimmune diseases. Pattern recognition receptors respond not only to pathogen-associated molecular patterns. are migratory and can control T cell responses [23]. The central role of type I IFN in SLE places special focus on the role of cells of the innate immune system. polymyositis or systemic sclerosis [19] but less frequently in patients with rheumatoid arthritis or multiple sclerosis [20]. the immune system protects against infectious organisms. such as toll-like receptors (TLRs). it is essential for the activation of the evolutionarily younger adaptive immune response[2]. which. including pDCs. conventional. DCs can be divided into three categories. A major thrust of systemic autoimmunity research has centered on elucidation of abnormalities in the adaptive immune response [13. The type I IFN signature is found in 60% to 70% of patients with SLE. dendritic cells (DCs). components of both the innate and adaptive immune responses are needed [3-5]. lupus-predisposed mice lacking pDCs due to the absence of IRF8 or showing pDC-specific defects in type I IFN production due to mutation of peptide/histidine transporter solute carrier family 15. can result in the development of autoimmune diseases. environmental factors also contribute to the development of autoimmunity. which facilitates faster.9]. however. The resulting gene expression includes cytokines and chemokines.18]. found in all classes of plant and animal life. or more systemic involvement such as systemic lupus erythematosus (SLE). requiring it to distinguish foreign agents. The innate component. symptoms and immunological abnormalities. The presence of the complement component C1q also enhances immune-complex-mediated gene expression in monocytes of patients with SLE [31]. Adaptive immunity also mediates immunological memory.7]. Failure to distinguish foreign from host. The current paradigm for the disease process of idiopathic systemic lupus-like autoimmunity argues for a central role of type I IFN [15.

In susceptible strains of mice. By contrast. expressed by TLR or NF-κB signaling also play a significant role. T and B cell activation and autoantibody production [6.10. Exposure to environmental agents such as mercury [79-81]. However. Accordingly. particularly nephritis. the role that innate immunity plays is only beginning to be examined. especially medications. these observations come with two clear caveats. is well established in both humans and animal models [6. Treatment with recombinant IL-1 receptor [66] reduces the severity of systemic autoimmunity as does IL-1 receptor antagonist [67]. Second. Moreover sustained production of type I IFN by injection of adenovirus-expressing IFN-α also exacerbates disease.74.45]. Complete deficiency of IL-6 in MRL-Faslpr mice reduces clinical. Immunol. modulation of certain individual proinflammatory cytokines can have significant effects on the expression of idiopathic autoimmunity. However.65]. common mechanisms of adaptive immunity exist for both induced and idiopathic disease in human and animals including loss of tolerance. TLR7 and TLR9 [55. hypergammaglobulinemia and anti-nucleolar autoantibodies (ANoA) does substantially reduce disease severity [25]. TNFα) [4. where absence of IFNAR leads to more severe disease [43] and antibody blocking of the IFNAR has minimal beneficial effect [44]. NZW hybrid [35] and NZB/NZWF1 [36] mice. All TLR signaling pathways lead to activation of the transcription factor NF-κB and production of proinflammatory cytokines (for example. however.thus indirectly reduces type I IFN production by pDCs [32]. For example. TNFα. Type I IFN plays a significant role in the onset and severity of idiopathic autoimmunity. The 'triple D' mutation in Unc-93 homolog B1 (Unc93b1). in C57BL/6-Faslpr[34].57. abolishes endosomal TLR signaling [55] and suppresses disease in lupus-prone C57BL/6-Faslpr. deletion of DCs (including pDCs) in this model while still allowing T and B cell activation.60] whereas recombinant IL-6 exacerbates glomerulonephritis [61].53]. involved in the trafficking of TLR3. partially recovers disease [51]. pristane injection causes a lupus-like disease characterized by a wide . mineral oil or petroleum waste has been associated with rheumatoid arthritis and possibly lupus [84]. J. The contributions of the separate α and β forms of IL1 remain to be determined. In press).70] and loss of Tnf[71] or Tnfreceptors [72] accelerates disease. Induction of type I IFN by TLR3 and melanoma differentiation-associated protein-5 agonist. an integral component of endoplasmic reticulum. In addition early components of the complement cascade are protective. hese studies show that innate immune responses contribute significantly to disease severity in idiopathic systemic autoimmunity. However it is clear that proinflammatory cytokines. nor are there criteria that distinguish environmentally associated autoimmunity from types of idiopathic autoimmune diseases [76]. they are limited by incomplete representation of the full spectrum of human disease [77]. The ability of C1q to suppress type I IFN may be an additional reason that C1q deficiency enhances susceptibility to SLE [33]. immunological and histological indices of lupus and improves survival [62]. is a component of mineral oil that induces chronic inflammation and plasmacytomas in mice [85]. is elevated in idiopathic lupus models [64.58]. Treatment with TNFα increases survival in lupus-prone mice [69. Type I IFN expression relies on activation of TLRs and signaling via IRF7 [4. which consists of α and β forms [63]. published as well as our preliminary studies suggest that specific environmental triggers induce or modulate systemic autoimmunity through distinct components of the innate immune system. Principal contributions. However.83] and pristane [84] are known to result in a lupus-like systemic autoimmunity in animal models. also known as 2. Innate immunity in environmentally induced systemic autoimmunity That systemic autoimmunity can be elicited by exogenous factors. Although the mechanisms of induction are poorly understood. The role of another proinflammatory cytokine. treatment with anti-TNF receptor increases survival [73]. particularly TLR7 and TLR9.42] except MRL-Faslpr. deficiency of type I IFN receptor (IFNAR) reduces disease severity in most autoimmune models[41. although studies of animal models have provided critical understanding of many facets of human systemic autoimmunity [12]. polyinosinic:polycytidylic acid (poly(I:C)). come from pDCs and TLR. Numerous studies have determined that endosomal TLRs. Pristane Pristane. IL-1. there are no accepted criteria for diagnosis or classification of environmentally associated autoimmunity in humans. Nonetheless. IL-6. specific endosomal TLRs make different contributions to disease severity.78]. including glomerulonephritis in idiopathic lupus models [37-40]. The mechanism whereby IFNAR deficiency exacerbates disease in MRLFaslpr mice is unknown.6. crystalline silica [82. Loss of TLR3 does not impact disease [50] although TLR3 stimulation of myeloid differentiation factor 88 (MyD88)-deficient mice. By contrast.14-tetramethylpentadecane (or TMPD).or IRF7-mediated type I IFN production. influence idiopathic systemic autoimmunity [46-49]. First.56]. Absence of TLR7 partially ameliorates disease [52-54] whereas deficiency of TLR9 exacerbates autoimmunity in a TLR7-dependent manner [52.75]. IL-1. exacerbates idiopathic systemic autoimmunity. These can trigger disease in individuals with or without susceptibility to idiopathic autoimmunity or can lead to enhancement of existing autoimmune disease. identified to date. BXSB [46] and MRL-Faslpr (Koh YT et al. especially IL-6. which lack TLR7 and TLR9 signaling. suggesting that DCs are required for promoting autoimmune disease by mechanisms beyond the production of type I IFN. although the latter appears not to be effective against established disease [68]. In humans. treatment with anti-IL-6 or anti-IL-6 receptor antibody results in reduced severity of kidney damage in lupus-prone mice [59. in systemic autoimmunity is less clear.

independent of NF-κB [103-105]. to some extent. our recent studies indicate that mHgIA is independent of type I IFN. Pristane-induced autoimmunity may also fall under a common syndrome called ASIA (autoimmune syndrome induced by adjuvants) [89]. In other studies. which are required for disease [84]. IL-6 [87] and IL-12p35 [88]. TLR deficiency differentially affects lupus-specific autoantibody production. specifically IL-1α.113]. Notably. This lack of dependence on type I IFN is further supported by the observation that mercury-induced hypergammaglobulinemia and .117] and transcription factors [8. This was confirmed in pure Irf5-deficient mice lacking a spontaneousDock2 mutation found in some Irf5 knockout lines that alters pDC and B cell development and type I IFN production [108-110]. when exposed to mercury. whereas type I IFN signaling pathways predominate in idiopathic and pristane-induced autoimmune disease. TNF-α. proteinuria and glomerular hypercellularity [92]. Irf5 deficiency reduced pristane-induced disease severity including the expansion of Ly6C high monocytes.44]. In addition. mercury exposure from skincare products was associated with membranous nephropathy[79. with absence of TLR7 or TLR9 reducing anti-ribonucleoprotein responses but not anti-DNA [94. Similar to SLE. IL-6. pyrin domain containing 3 (NLRP3) and apoptosis-associated speck-like protein containing a CARD (ASC) (which are required for caspase 1 activation [100]) are not required for neutrophil recruitment in pristane-induced chronic inflammation [99]. co-stimulation factors[116.113]. it does induce expression of IL-6 [101]. IL-12. The most severe aspects of disease are dependent on type I IFN. type I IFN receptor-deficient (Ifnar−/−) mice exposed to pristane exhibit markedly reduced lupus-specific autoantibodies. Pristane-treated Ifnar−/− mice also have reduced expression and activation of TLR7 and TLR9 in B cells[96]. By contrast. the severity of systemic disease that was induced by mercury exposure appears mild compared to that of idiopathic SLE. unpublished observations). Unlike idiopathic lupus. which is required for pristane-induced hypergammaglobulinemia and the production of anti-DNA and anti-chromatin [87].and MyD88-dependent pathway [93. Thus. Possible mechanisms for mercury-induced systemic autoimmunity have come largely from studies of susceptible mice and rats that. although only limited human populations at potential risk for mercury-induced autoimmunity have been studied in detail [75.112]. The adaptive immune responses required for murine mercury-induced autoimmunity (mHgIA) share common requirements with idiopathic lupus including certain cytokines [114. ANA and deposits of immune complexes in blood vessels and glomeruli [77]. Studies of South American gold miners documented that mercury exposure was associated with higher levels of proinflammatory cytokines (IFN-γ. acts as a transcription factor to mediate TLR induction of proinflammatory cytokines IL-6. However. IL-1β. deficiencies in TLR4 and TLR9 also impact disease severity [95]. caspase 1 and the inflammasome components NOD-like receptor family. Mercury Exposure to mercury in humans has been associated with autoimmune manifestations in small surveys. Ifnar1-deficient C57BL/6. type I IFN signature. but is produced by immature Ly6Chigh inflammatory monocytes [97]. Severity of disease including IgG autoantibodies and glomerulonephritis are reduced in the absence of IFN-γ [86]. TNFα and. but not IRF7 [99]. Interestingly. and is mediated by MyD88 and IL-1 receptor-associated kinase.94].spectrum of primarily antinuclear autoantibodies (ANA) and immune complex-mediated glomerulonephritis [84].91]. type I IFN production is produced by immature monocytes rather than pDCs. The protein product of IRF5. which in contrast to monocytes requires IL-1. which likely results in a positive feedback signal and further acceleration of IFN production. although a feature of this model is chronic inflammation. but more definitive largescale epidemiological studies are lacking [111]. IL-1 [98] and IFN-γ. This expansion of monocytes by type I IFN appears to be relatively specific because the lack of the inflammatory cytokines TNF-α.118]. pristane-induced autoimmunity is associated with increased expression of type I IFN-inducible genes in peripheral blood cells (IFN signature) [90. In contrast to spontaneous lupus. develop lymphocyte activation. Although IL-1alpha. autoantibody production and glomerulonephritis in pristane-treated mice are primarily mediated via a TLR7. increases in Ly6Chigh monocyte numbers correlates with greater amounts of lupus-specific autoantibodies [97]. a lupus susceptibility gene [102]. Type I IFN is also required for the chemokine expression necessary for recruitment of inflammatory monocytes [98]. type I IFN production in pristane-induced autoimmunity is not dependent on DCs. suggesting a positive feedback mechanism in which type I IFN augments TLR-mediated B cell responses. inflammasome components and IL-1β appear to play little if any role.115]. These studies suggest that disease expression and severity in the pristane model are tightly linked to nucleic acid-sensing TLR and MyD88 signaling leading to type I IFN production analogous to idiopathic lupus. NZB and BXSB mice all have similar autoimmune responses to mercury exposure as wild-type mice (Kono and Pollard. IL-1β) and autoantibodies [80. has not been directly linked to the autoimmunity elicited by pristane. however. Accordingly. autoantibodies and renal disease [106-109].95] whereas lack of TLR4 reduced production of both antiribonucleoprotein and anti-DNA autoantibodies [95]. have no effect on Ly6Chigh monocyte recruitment. The chronic inflammatory response to pristane also includes neutrophil infiltration. IFN-α. Type I IFN expression. in contrast to the known type I IFN-dependence of spontaneous autoimmunity in both NZB and BXSB strains [41.

Silica-induced inflammation is mainly caused by the toxic effects of silica on alveolar macrophages. NKT or NK cells [143]. Death of alveolar macrophages by silica might further promote inflammation and autoimmunity by impairing the clearance of silica and apoptotic cells. NF-κB-associated pathways. or IL-12 [148]. We have. rheumatoid arthritis and systemic sclerosis [83. bricklaying and cement work. but its effect on TLR stimulation of alveolar macrophages. construction work. severity of mHgIA is impacted by TLR activation because the TLR4 ligand lipopolysaccharide exacerbates disease [120].129-131]. suggesting that IL-1β is not required. if mHgIA can be exacerbated by exogenous type I IFN. Alternatively.80]. Notably. unpublished observations). we also examined the effects of IL-6. mercury-exposed autoimmune-prone BXSB mice with the triple D mutation in Unc93b1 (required for endosomal TLR3.155]. chronic inflammation is dependent on type 1 IFN and IRF7 [150]. the primary cell-type responsible for inflammasome-mediated lung inflammation [142]. and by generating apoptotic material. the US Occupational Safety and Health Administration estimated that almost two million individuals in the USA are occupationally exposed to respirable crystalline silica [127] and exposure continues to be a national and worldwide problem [128]. which is induced by NF-κB [101]. Although the specific TLRs required for mHgIA remain to be examined. It remains to be determined. one possibility is that the chronic inflammatory milieu present in silicosis might induce or exacerbate autoimmunity through the production of proinflammatory cytokines and release of self-antigens [139-141]. our preliminary studies show that mercury exposure suppresses IFN-α induction mediated by poly(I:C) (TLR3 agonist) while proinflammatory cytokine (for example. Further support has come from animal models in which lupus in susceptible mice is exacerbated by exposure to silica [135.122-124]. concentration and frequency) of exposure [133. It is possible that mercury exposure can replace type I IFN by activating the IFNAR pathway or related genes downstream of IFNAR activation.142]. Nevertheless. requirements similar to those of mHgIA [8. but not IRF7 were implicated. unpublished observations). mHgIA may not be mediated by type I IFN.S-Il6−/− mice exposed to HgCl2 had reduced serum IgG autoantibodies and kidney deposits of IgG compared to wild-type mice [126]. unpublished observations). The lack of dependence on type I IFN but requirement for endosomal TLRs is similar to spontaneous lupus in the MRL background[43. granite cutting.138]. pro-IL-1β and TNF-α via the NF-κB pathway[4. are also required for silicosis [142. resulting in the release of proinflammatory chemokines and cytokines including TNF and IL-1 [128.134]. Related to this. silica has been shown to suppress TLR-mediated activation of DCs [144]. are not reduced compared to the wild-type (Kono and Pollard. Additionally. In 2007.114]. shown that neither NLRP3 nor caspase 1 deficiency impacts expression of mHgIA [8]. deficiency of either scavenger receptors macrophage receptor with a collagenous structure (MARCO) or CD204. which is characterized by chronic inflammation and scarring in the upper lobes of the lungs [128].53]. epidemiologic data have repeatedly associated silica exposure with systemic autoimmunity [111] including SLE. although acute lung inflammation requires IL-17[149]. macrophages. Although the role of individual TLRs has not been examined. taken together. IL-1 signaling also activates NF-κB [101] and we have shown that cell bound IL-1α is required for mercury-induced T cell proliferation in vitro[125]. silica dust exposure is associated with high titers of ANA [132] and both the presence of autoantibodies and clinical symptoms are positively correlated with intensity (that is. on mHgIA and found B10.autoantibodies in Inept mice. Dependence on endosomal TLRs but not Irf7 or Ifnar suggests that mHgIA may be primarily mediated by NF-κB signaling [4]. these studies point to the endosomal TLRs. Notably.151-153] and our preliminary findings indicate that caspase-1 is required for autoantibody induction (Kono and Pollard. expressed mainly on macrophages.136] and ANAs develop in non-autoimmune mice and rats exposed to silica products [137. although endosomal TLRs contribute to mHgIA. DCs and lymphocytes [143-145]. Furthermore.111. is not known. LRR and PYD domains-containing protein 3) inflammasome components. The mechanisms mediating silica-induced autoimmunity are not yet defined. unpublished observations). MARCO-deficient mice are defective in clearing apoptotic cells [156] and both MARCO and CD204 have been argued . however. In other experiments. TLR7 and TLR9 signaling [121]) do not develop ANA or increased serum IgG unlike wild-type BXSB (Kono and Pollard. and the influx of neutrophils. the proinflammatory cytokines IL-1α and IL-6 but not type I IFN as the major innate factors that drive autoimmunity following exposure to mercury. rock drilling. IL-6) production is unaffected (Kono and Pollard. Endosomal TLR signaling leads to cell activation and to type I IFN production via IRF7 and the induction of proinflammatory cytokines IL-6. Inhalation of crystalline silica can cause silicosis. caspase-1 and IL-1β. Additionally. Innate immunity mediates this process as silicainduced inflammation and fibrosis can occur in the absence of T. B. Although the pathways have yet to be defined. This supports the latter possibility that mHgIA is not mediated by type I IFN and may also explain why mHgIA is a relatively mild disease compared to idiopathic lupus [19. In support of this. Thus. Silica-induced pulmonary inflammation is dependent on IFN-γ [146] but not Th2 cytokines such as IL-4 and IL-13 [147]. however.53] and pristane-induced autoimmunity [93-95]. Similar to idiopathic [47. was shown to impair silica clearance and exacerbate silica-induced lung inflammation [154. NALP3 (NACHT. Silica Silica exposure is common in mining. type I IFN is not required in both autoimmuneprone and healthy genetic backgrounds. suggesting that cell signaling via the IL-1 receptor may also be important for mHgIA. which are deficient in IRF7 and consequently do not produce IFN-α after TLR7 or TLR9 stimulation [119]. sandblasting.

Interestingly. However. thus linking the innate and adaptive responses in mHgIA. viperin. . unlike pristane. can initiate sterile inflammation involving neutrophils [173]. released from dying cells. IL-1α. Innate immune mechanisms contributing to environmentally induced autoimmunity As is clear from the studies discussed above. innate mechanisms involving IRF7 and type I IFN might play pivotal roles.167]. leading to NF-κB-regulated proinflammatory cytokine production (NF-κB endosome). pristane [169] or silica [170] leads to the availability of nucleic acid/protein self-antigens. innate immunity plays an essential role in both idiopathic and environmentally induced lupus-like autoimmunity. Studies with silica-induced lung inflammation. could impact selftolerance [158.165] and may thus impact AP-3 controlled TLR trafficking to the IRF7 endosome.56]. These are then brought into the endolysosomal machinery of antigen presenting cells such as DCs. inflammasome activation and IL-1β are also likely to make significant contributions. Mercury is known to accumulate in lysosomes [164. while only indirectly implying mechanisms of silica-induced autoimmunity. which is involved in the sorting of transmembrane proteins to lysosomes and lysosome-related organelles (LRO). We propose that the toxic response to mercury [168]. however given the type I IFN-dependence of pristane-induced autoimmunity [92].and mercury-induced disease [4]. mHgIA may not require NF-κB independent proinflammatory cytokine production mediated by IRF5. mercury. macrophages and/or B cells where they complex with TLRs and traffic to early endosomes (NF-κB endosome). supporting its role in granulocyte recruitment in pristane-induced chronic inflammation [99]. the adaptive response and autoimmunity. particularly in macrophages [166. Signaling by these TLRs leads to cell activation and the production of proinflammatory cytokines via NF-κB and type I IFNs by IRF7 activation [4]. we expect pristane not to hamper TLR trafficking and/or signaling. IL-1α is also important for mercury-induced T cell proliferation [125] and may contribute to enhanced CD4+ T cell expansion and differentiation [171]. with the requirement for endosomal TLRs and/or Unc93b1 providing a unifying mechanism for idiopathic and pristane. The importance of endosomal location in DC responses has been shown by studies using different classes of CpG oligonucleotide ligands to stimulate TLR9 signaling [160-162]. We can find no evidence that pristane affects lysosome function. Recent studies suggest that adaptor protein complex 3 (AP-3). In addition.159] and promote autoimmunity. which is a component of the signaling complex of lipid bodies [4]. supporting our contention that environmental factors can induce or enhance lupus-like autoimmunity through several different innate mechanisms. like idiopathic lupus and pristane-induced promote tolerance to apoptotic cell material [157]. as presented above. may bifurcate these signaling pathways because AP-3 is required for TLR7 and TLR9 induction of type I IFN but not proinflammatory cytokines [56]. is required for endosomal TLR-mediated type I IFN by pDCs but does not contribute to proinflammatory cytokine production in pDCs or type I IFN production by other cell types [163].and silica-induced autoimmune diseases that mediate the induction of inflammation. leading to reduced type I IFN production. Thus UNC93B1-mediated endosomal TLR trafficking moves to early endosomes in an AP-3 independent manner.99] and mHgIA [8]. in turn. a component of endoplasmic reticulum-derived lipid storage granules or lipid bodies. The bifurcation of TLR trafficking and signaling regulated by AP-3 may explain the dependence of mHgIA on Unc93b1 and proinflammatory cytokines like IL-6 as well as its type I IFN independence. In addition. The requirement for the inflammasome pathway is clearly different from the innate immune responses required for the development of pristane-induced autoimmunity[84. Silica can also affect lysosomal function. cell death. We would argue that. AP-3 mediates trafficking of TLRs and UNC93B1 to the lysosome-associated membrane protein 2+ (LAMP2+) late endosomes and LROs but not to vesicle-associated membrane protein 3+ (VAMP3+) early endosomes [4. and then in an AP-3 dependent step to late endosomes/LRO and IRF7-mediated type I IFN production (IRF7 endosome)[4]. By contrast. IL-1α synergizes with IFN-γ to regulate IFN-γ induced gene expression in an NFκB-dependent manner [172]. a few possible explanations can be postulated. leading to NF-κB-regulated proinflammatory cytokine production. particularly as IRF5 requires TNF receptor-associated factor 6 (TRAF6) [103]. In Figure 1 we outline our view of the mechanisms of innate immunity in environmentally induced autoimmunity with emphasis on the contribution of bifurcation of TLR signaling to mHgIA. Viperin may thus be central to the role of pDCs and type I IFN production in systemic autoimmunity. The important role of the mercury-induced NF-κB-mediated inflammatory response is likely aided by IL-1α from dead and dying cells. IRF7-mediated type I IFN production via late endosomes/LRO (IRF7 endosome) has little role in mHgIA as suggested by the failure of Ifnar andIrf7 deficiency to suppress mHgIA. which. different innate pathways have been implicated in the development of pristane-. suggest that. Silica-induced killing of scavenger receptor-bearing macrophages. How the different innate responses are elicited and how they consequently promote autoimmunity remains to be determined. suggesting that silica-induced autoimmunity may also be influenced by effects on lysosome function. These observations suggest that scavenger receptor-mediated uptake of silica and subsequent macrophage cell death may adversely affect clearance of dead and dying cells.

tumor necrosis factor. pDC: Plasmacytoid dendritic cell. IL. In idiopathic autoimmunity. Abbreviations AP-3: Adaptor protein complex 3. Innate immune mechanisms contributing to environmentally induced autoimmunity. The large box signifies signaling events in innate immune responses that may occur in one or more cell types. Steps required for mHgIA are shown in rectangles with a thick black line while those not required are shown by ovals with a broken line. NF: Nuclear factor. AP-3. LRO: Lysosome-related organelles.Figure 1. TLR. UNC93B1-mediated trafficking of endosomal TLRs leads first to VAMP3+ early endosomes. lysosome-associated membrane protein 2. T helper type 1. both type I IFN and proinflammatory cytokines are needed for disease with pDCs being the primary cells involved in type I IFN production. interleukin. TNF: Tumor necrosis factor. TRAF6: TNF receptor associated factor 6. Steps required for pristaneinduced autoimmunity include those leading to type I IFN and proinflammatory cytokine production and may also include pathways involving IL-1α. TLRs. Hg: Mercury. IL: Interleukin. nuclear factor. Unc-93 homolog B1. A greater understanding of the specific innate processes that initiate or exacerbate disease will be key to understanding the role of environmental factors in autoimmunity. TNF. Hg. IL-1α may also contribute to adaptive immunity via differentiation and expansion of CD4+ T cells and enhanced expression of IFN-γ-stimulated genes such as IRF1. These findings from several environmentally induced models suggest that environmental triggers can induce autoimmunity through diverse innate pathways. but rather shows significant dependence on proinflammatory cytokines such as IL1α and IL-6. particularly IL-1α-driven NF-κB activation. mHgIA: Murine mercury-induced autoimmunity. interferon. Conclusions Innate immunity plays an essential role in both idiopathic and environmentally induced autoimmunity. LAMP2. By contrast. type I IFN receptor. where signaling results in NF-κB activation and proinflammatory cytokine production. SLE: Systemic lupus erythematosus. TNF receptor associated factor 6. Si. Lipid bodies. leading to type I IFN and proinflammatory cytokines. Ig: Immunoglobulin. Toll-like receptor. IFNAR: Type I IFN receptor. silica. mercury. Competing interests . does not require DCs. TLR/MyD88 signaling. Si: Silica. adaptor protein complex 3. NK: Natural killer. LAMP2: Lysosome-associated membrane protein 2. MARCO: Macrophage receptor with a collagenous structure. Th1. TLR: Toll-like receptor. lysosome-related organelle. UNC93B1. Mercury-induced autoimmunity. DC: Dendritic cells. vesicle-associated membrane protein 3. however there are clear differences in the required molecular and cellular components that mediate disease development. Activation of IRF5 in complex with TRAF6 can lead to proinflammatory cytokine production. also traffic to LAMP2+ LROs where IRF7 is activated to stimulate type I IFN expression. in pristane-induced autoimmunity. interferon regulatory factors. but rather immature monocytes. IFN: Interferon. may contribute to type I IFN particularly in pDCs. NF-κB-mediated proinflammatory cytokine production may be augmented by release of constitutively expressed IL-1α from dead and dying cells. IRF: Interferon regulatory factors. IFN. MyD88: Myeloid differentiation factor 88. VAMP3. IRF. particularly in macrophages. LRO. It can be speculated that some of these differences may be related to the bifurcation of TLR signaling that distinguishes IRF7-mediated type I IFN production and NF-κB-driven proinflammatory cytokine expression. IFNAR. NF. Unc93b1: Unc-93 homolog B1. VAMP3: Vesicle-associated membrane protein 3. TRAF6. The toxic response to environmental agents results in self nucleic acid/protein complexes that may become ligands for endosomal TLRs via scavenger receptors. although showing clear evidence of TLR involvement does not require type I IFN. again in concert with Unc93b1. Additional pathways may apply to silica-induced autoimmunity as scavenger receptors and the inflammasome are central to silica-induced inflammatory responses. which contain components of the TLR signaling complex.

Spondyloarthritis. Targeted therapies such as these are often well tolerated by patients. „tocilizumab‟. Authors' contributions Biologic therapies for rheumatologic diseases. We matched the terms: „rheumatoid arthritis‟. Based on the screening results. The review concentrates on nine drugs: tocilizumab. rituximab. The choice of biologic agent for rheumatologic diseases is then tailored to the patient's needs and lifestyle. Case reports and any reports of biologic therapies that are not yet available for clinical use were excluded. abatacept. we provide an update on some of the new agents that have become available in the past 5 years for clinical tr eatment of rheumatoid arthritis (RA). spondyloarthritis. ofatumumab. and co-stimulation molecules. Research is ongoing to identify other molecular targets. We excluded articles that were in a language other than English. Roactemra) is a recombinant monoclonal IgG1 anti-human IL-6 receptor (IL-6R) antibody (Table 1) [1]. and this complex in turn binds to the 130 gp signal transducer. epratuzumab. „belimumab‟. others are specific for a single disease. „spondyloarthropathy‟. chest radiography). golimumab. Vasculitis Introduction The use of biologic therapies as an adjunct to disease-modifying anti-rheumatic drugs (DMARDs) for the treatment of autoimmune and rheumatologic diseases is rapidly expanding. Methods We performed a thorough literature review of all papers in English published in PubMed during the period 1 January 2007 to 30 April 2012. „abatacept‟. the current drawbacks of biologic therapies. systemic lupus erythematosus. which are used as therapies for rheumatoid arthritis. Screening for biologic treatment Over a decade has passed since the introduction of biologic therapies for autoimmune diseases. as well as the high costs and adverse events (AEs) associated with these drugs prevent their wide use as first-line medications. However. However. and the better understanding of the initial targets of altered immune regulation and activity in various diseases. In this review. „systemic lupus erythematosus‟. Systemic sclerosis. prevent their wide use as first-line medications. owing to the good efficacy and safety profiles of these drugs. purified protein derivative (PPD) test. and „vasculitis‟ with the terms „biologics‟. or vasculitis. „certolizumab‟. „rituximab‟. Anti-cytokines include anti-tumor necrosis factor (TNF)-α. the physician will assess which biologic treatment is recommended or if prior treatment is warranted before the initiation of the biologic therapy. „systemic sclerosis‟. systemic sclerosis. and vasculitis. certolizumab. inducing angiogenesis and amplifying the activity of adhesion molecules and the . serological evidence of hepatitis B and C. and sifalimumab. B cell depletion. and the adverse events associated with them. Screening consists of evaluation for previous or current tuberculosis (TB) infection (based on history. history of malignancies or neurological disease. including the inconvenience of intravenous administration. and „sifalimumab‟. Anti-TNF. „epratuzumab‟.The authors declare that they have no competing interests. This process enhances the inflammatory cascade. „golimumab‟. The major targets of most biologic therapies are cytokines. B-cell depletion includes use of anti-CD20 antibodies and B cell receptor (BCR) modulation by the B-lymphocyte stimulator (BLyS). systemic lupus erythematosus (SLE). the inconvenience of intravenous (IV) administration. Tocilizumab Mechanism Tocilizumab (TCZ. belimumab. the high costs of these drugs. Although some of the biologic therapies have been found to be useful in more than one disease. systemic sclerosis (SyS). which are targeted at molecules involved in the mechanisms of the immune system. IL-6 binds to either membrane-bound or soluble IL-6R. and is often performed during the initial visits to the outpatient clinic to prevent unnecessary waits for the patient when a biologic is indicated. Reports of randomized controlled trials (RCTs) and case series were included. antiinterleukin (IL)-1. This review provides an update of the recent literature on the new biologic therapies available. Rheumatoid arthritis. screening is routine practice prior to administration of these drugs. B cells. Systemic lupus erythematosus. spondyloarthropathy. and anti-IL-6 molecules. Keywords: Biologics. „ofatumumab‟. provide an alternative to the existing treatment methods of disease-modifying anti-rheumatic drugs and other immunosuppressive medications. Autoimmune diseases. Currently. trade names Actemra.

196 patients with RA who responded partially to MTX. placebo-controlled trials that indirectly compared TCZ with one or more of the following biologics: abatacept. and was superior for a 70% improvement (ACR70)[8]. Other studies reported response to TCZ in patients with RA who failed to respond to anti-TNF-alpha blockers [9].4 years of treatment.3% for patients treated for 5 years on monotherapy [7]. the response to TCZ occurred early. which were predominantly infections [1]. Update on biologic therapy in autoimmune diseases In patients with RA. and hematological disturbances [10]. non-melanoma skin tumors. In conclusion. in patients with inadequate response to DMARDs and/or anti-TNF-alpha blockers. or anti-TNF-alpha blockers (etanercept. and adalimumab). Some patients developed grade 4 neutropenia. but rates were still similar to those encountered with DMARDs or anti-TNF-alpha blockers [10]. with the dose of 4 to 8 mg/kg IV administered as a single infusion every 4 weeks for RA and 12 mg/kg or 8 mg/kg IV (depending on body weight) for SJIA [6]. In a study integrating the three phases of TCZ safety. Only 2. rituximab. which were mild to moderate and transient. and of total to HDL cholesterol [11]. soon after the first infusion [1]. Indications and dosage TCZ is indicated for the treatment of RA following an inadequate response or treatment failure with DMARDs or TNF alpha antagonists (anti-TNF alpha drugs). Higher rates of serious infections were related to previous anti-TNF-alpha treatment. injecting TCZ into the inflamed joints reduced the swelling and the inflammatory response [2.9]. Rituximab Mechanism . A small number of patients experienced serious AEs. The drug was approved for RA in January 2010 in the USA. a dose reduction was sufficient for the continuation of the study. mostly of the upper respiratory tract (URTI) and gastrointestinal (GI) tract [10]. Adverse effects and safety Favorable safety results for TCZ were reported for both short-term and long-term treatment of moderate to severe RA. In a 24-week study of 286 patients with RA. Higher doses of TCZ (8 mg/kg) were associated with higher risks for infection. TCZ was found to be non-inferior to MTX in the first week and superior to MTX in the second week in the intention-to-treat group. Some patients were diagnosed with TB despite being screened before treatment in accordance with the guidelines. in Disease Activity Score(DAS) remission rate was 55. and the AEs were less severe compared with other biolo gic therapies [8]. The most common AEs were infections. The recommended dose of TCZ is 8 mg/kg every 4 weeks. Several other studies comparing monotherapy of MTX with that of TCZ have also shown superiority of TCZ [3. The most common infections were pneumonia.TNF-alpha blockers [3]. and is involved in B-cell differentiation. In a 24-week study comparing TCZ and methotrexate (MTX). GI perforation occurred in 16 patients (predominantly women) exposed to TCZ in the phase III trials. There was no difference in the incidence of AEs with TCZ compared with anti. as measured by ACR20 [3]. TCZ is beneficial and safe for treatment of RA in cases of non-response to anti-TNF-alpha therapy or when anti-TNFalpha therapy is contraindicated.6]. More severe AEs included cardiac events. serious infections. but the US recommendations are for a starting dose of 4 mg/kg once every 4 weeks. GI symptoms. In one metaanalysis. which stabilized after 2 weeks of therapy.1% experienced AEs related to the drug. Monotherapy with TCZ for 52 weeks resulted in significantly reduced radiographic change (total Sharp score) compared with DMARDs [2]. and urinary-tract infections [10]. There was a reduction in neutrophil count in patients receiving TCZ. Efficacy A meta-analysis examined published articles on double-blind. randomized. TCZ was associated with increases in cholesterol levels and in the ratios of low-density lipoprotein (LDL) to high-density lipoprotein (HDL) cholesterol. Within an RA population. 66. The route of administration is IV. Table 1. the AEs were similar to the other treatment groups (DMARDs or anti-TNFalpha). In a study of 1. the AEs reported were nasopharyngitis. infliximab. Some patients developed a significant increase in liver-function tests. a high level of IL-6 is present in the blood and in the synovium of involved joints. gastroenteritis. treatment with TCZ led to suppression in radiographic progression and improvement in physical function [9]. Furthermore.3]. In an animal study. thus by blocking IL-6. and infections. It is also indicated as first-line therapy for patients with severe systemic juvenile idiopathic arthritis (SJIA) and for Castleman's disease (Table 1). IL-6 is also responsible for activating both T and B helper cells. followed by an increase to 8 mg/kg depending on clinic al response [5. indicating liver dysfunction. TCZ was well tolerated for more than 2.4]. with 11 of them developing diverticuli [10].3% of TCZ-exposed patients had to discontinue treatment because of liver abnormalities [10]. TCZ was non-inferior compared with the other biologic therapies according to the American College of Rheumatology (ACR) criteria for a 20% (ACR20) or 50% (ACR50) improvement. but the neutrophil count normalized after discontinuation of therapy [10]. In other studies of monotherapy with TCZ.activation of osteoclasts [2. solid-organ malignancies. the inflammatory response is decreased [2].

and lymphoma[22]. Rituximab is beneficial for other off-label indications in patients with autoimmune disease (such as SLE) and Castleman's disease (Table 1). Additional treatment with steroids may also be warranted. In the SUNRISE (Study of Retreatment with Rituximab in Patients with Rheumatoid Arthritis Receiving Background Methotrexate) trial. Most AEs occurred during the first course of therapy. there was a significant benefit for rituximab therapy. The lack of efficacy in the overall trial could be associated with the clinical set-up of the trial. and memory B cells.578 patients with RA withdrew because of malignancy. and face). with a significant response compared with the placebo group. However. In patients with RA responding to rituximab treatment. rituximab affects the interferon (IFN) I response genes. including long-term therapy.IFNI44L. a history of demyelinating disease. Mx1) increased. the Bcell infiltrate was depleted in the skin after rituximab infusion. expression of IFN response genes (RSAD2. rituximab was administered as monotherapy. the reaction is immediate (30 minutes to 2 hours). Adverse effects and safety One of the AEs associated with rituximab is an infusion reaction. The most popular protocol for RA is IV infusion of 1000 mg/m2 on days 1 and 15 in combination with MTX. inducing remission in 36 patients for periods of 8 to 64 months. and complement activation. or cardiac event [22]. and if there i s no reaction. Mabthera) is a chimeric human monoclonal antibody against the CD20 protein found on naive. For refractory pemphigus vulgaris (PV). characterized by fever. Pretreatment with acetaminophen and an anti-histamine is recommended to prevent this infusion reaction. Furthermore. 40% of patients achieved a steady platelet level [15]. Of the total 559 patients in the study. For patients with RA. rituximab was found to be superior [18]. inclusion of too many subsets. bronchospasm. In a number of studies measuring markers for immature B cells. thrombocytopenia. Rituximab was evaluated for chronic immune thrombocytopenic purpura (ITP) in a multi-center phase II study of 60 patients. chills. The initial infusion should be started at 50 mg/hour. 475 patients received the second cycle of therapy. but no sooner than ever y 16 weeks. 559 patients with RA with inadequate response to one or more TNF-alpha inhibitors were given two treatment cycles of rituximab to assess the efficacy and safety profile of the drug. LY6E. TB. and 3 of a 4-week cycle. Indications and dosage For autoimmune diseases. and hypotension. pre-medication with IV methylprednisolone 100 mg (or equivalent) is recommended. For granulomatosis with polyangiitis (GP) (previously Wegener's granulomatosis). disease activity was not significantly improved compared with placebo.Rituximab (trade names Rituxan. and arthritis-related SLE [20]. Rituximab depletes the B-cell population via apoptosis. usually during the first infusion. In a study of eight patients with SyS. Rituximab treatment requires monitoring of several AEs. A few studies also suggested that low-dose treatment with 100 mg/m2. In a study of 646 patients with RA who had treatment failure with anti-TNF-alpha blockers. followed by one dose per month for 4 months (total of ten doses in 6 months) [16]. which is repeated for one additional cycle. Another study of 15 patients with SyS also showed histological improvement in the skin after rituximab therapy [17]. including infections. The incidence of malignancies was not increased in patients with RA treated with rituximab [22]. . cellular cytotoxicity. the infusion rate should be decreased or discontinued. whereas the non-responding patients had limited or no IFN gene-expression activity (Table 1) [12]. In those patients requiring an additional dose. may be repeated. feet. In addition. B-cell depletion occures after treatment with rituximab [12]. infection. in a subgroup analysis of African American and Hispanic patients. In a study of 42 patients with severe PV. and if necessary. a severe infusion reaction. who received an IV infusion of 375 mg/m2 once weekly for 4 doses. live vaccination. in open trials for long-term treatment. In a study of 257 patients with SLE treated with rituximab and prednisone. further data on this dose are lacking [15]. In most cases. mature. as measured by the ACR20 [13]. and pre-B cell colony-enhancing factor (visfatin). and a 5-year history of non-lymphoproliferative cancer [23]. The protocol for microscopic polyangiitis (MPA) is similar to that of GP [14]. Efficacy Several studies suggest that rituximab may be beneficial for the treatment of SyS [17]. A case series indicated that rituximab might be beneficial in hemolytic anemia. severe congestive heart failure. Subsequent courses may be administered every 24 weeks (based on clinical evaluation). either alone or in combination with steroids would suffice and result in fewer AEs. HERC5. the protocol is different: IV infusion with 375 mg/m2 once weekly for four doses (in combination with IV methylprednisolone for 1 to 3 days followed by daily prednisone). the only indication for which rituximab is approved by the Food and Drugs Administration (FDA) is active RA unresponsive to DMARDs and anti-TNF-alpha agents. rash. 123 of 2. follow-up at 6 months after therapy with rituximab resulted in a good clinical response and even remission of the disease [21]. the rate should be increased by 50 mg every 30 minutes (100 mg/hour). the recommended treatment is IV infusion of 375 mg/m2rituximab once weekly in weeks 1. or non-stratification of patients positive or negative for anti-double-stranded DNA antibodies [19]. In a meta-analysis assessing the safety of rituximab. If the infusion reaction occurs. active infections. swelling (of hands. 30 minutes before each dose of rituximab [13]. but is less severe with subsequent infusions. 2. memory B cells. It is contraindicated in the case of pregnancy and breastfeeding. however. signifying that the drug might be a possible therapy for skin fibrosis [17]. the safety profile remained good [16].

which was mild to moderate and occurred mainly with the first and second administrations [24]. significantly higher rates of ACR20 were seen in the ofatumumab groups compared with the placebo group. no improvement in the SLE responder index (SRI). ofatumumab 700 mg was compared with placebo. then once every 4 weeks [26. URT infections.27] (Table 1). Indications and dosage Ofatumumab is indicated for the treatment of chronic lymphocytic leukemia. patients received three escalating doses of ofatumumab (300. there was a significant effect of belimumab after 52 weeks of treatment and a steroid -sparing effect. a significant number of AEs occurred in the highest-dose (1000 mg) group [24]. which binds to and inhibits the soluble form of the BLyS protein [26. and severe infections. the main AEs were related to infusion reaction. disease activity score was significant in SLE patients with severe active disease [26]. and diarrhea. a significant improvement was seen in both the 1 mg/kg and the 10 mg/kg groups compared with the placebo group [28]. and URT infections. anti-histamine.25]. In another multi-center double-blind RCT of biologic therapies in naive patients with RA. A few cases of progressive multifocal leukoencephalopathy (PML) were reported in some patients after rituximab therapy [22]. No difference in infections was noted between the different dosage groups and the placebo [24]. Efficacy In a phase II trial. Significant changes were also reported in the SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment –Systemic Lupus Erythematosus Disease Activity Index) trial. headaches. Other AEs included rash. Ofatumumab Mechanism Ofatumumab (trade name Arzerra) is a fully human monoclonal antibody directed against the membrane proximal epitope on the CD20 molecule (Table 1) [24.25]. nausea. it is also used in the USA and Europe as an off-label treatment for patients with RA who have failed MTX therapy (Table 1). diarrhea. however. The recommended protocol for maximum efficacy and safety is IV administration of 700 mg over 4 hours with appropriate premedication. However.Rituximab causes a decrease in gammaglobulin concentrations. fatigue. infusion reaction. Less common side effects are fever. and 1000 mg). comparing the efficacy of ofatumumab (three different dose groups) with patients treated with placebo or MTX. Efficacy Two studies reported efficacy of ofatumumab compared with placebo or MTX in patients previously treated with DMARDs or biologic therapies. this does not seem to lead to a higher risk for severe infection [23]. and glucocorticoids. as measured by the Physician‟s Global Assessment (PGA) [26].27]. Indications and dosage Belimumab is approved by the FDA for the treatment of mild to moderate SLE. which incorporates disease activity scores to compile a single score. all such therapies were discontinued prior to study entry [24. the most common reactions were urticaria and rash on the day of the first infusion.27]. In another double-blind multi-center study. repeated every 2 weeks [24. In one study. It inhibits B cell apoptosis and stimulates the differentiation of B cells into immunoglobulin-producing plasma cells. all patients in the high-dose groups received premedication with acetaminophen. Studies have shown that the number of AEs associated with . Most of the reactions were mild to moderate. dyspnea. and severe AEs were infrequent [25]. In addition. No case of PML was reported [25]. headaches. However. Belimumab (trade name (Benlysta) is a human monoclonal immunoglobulin (IgG1γ).25]. Adverse effects and safety AEs associated with belimumab treatment include nausea. pruritus. leucopenia. 700. cystitis. In a combined phase I and II study. as assessed by the ACR20 and the circulating B-cell population [24]. rhinitis. after 24 weeks of treatment. Owing to its B-cell-suppressing effect. Prior to administration. and is presently not indicated for active LE nephritis or neuropsychiatric involvement (Table 1) [26. hypertension. depending on the cumulative dose. flushing. It is given by slow IV infusion over 1 hour at a recommended dose of 10 mg/kg at 2-week intervals for three cycles. Belimumab Mechanism The BLyS protein is a member of the superfamily of TNFs. In the phase III clinical trials assessed using the SRI. the efficacy was dose-dependent. Adverse effects and safety In a study comparing the safety of ofatumumab (three different dose groups). No significant differences were noted between seronegative and seropositive patients in this study [25]. with each dose given as two separate IV administrations with 2 weeks between them. and a significantly higher rate of improvement as measured by ACR20 was noted in the ofatumumab group [25]. over a period of 24 weeks [25]. with non-inferiority of belimumab compared with placebo.

or 3. Abatacept Mechanism T cells play a major role in the pathogenesis of RA. For RA treatment. several studies have assessed the drug for these two conditions (excluding patients who were previously treated with rituximab). but due to safety issues. compared with 30% in the placebo group. The initial IV dose can be repeated by additional doses after 2 and 4 weeks. with a dose of approximately 10 mg/kg (patients weighing less than 60 kg receive 500 mg. the response to abatacept was superior and was maintained for 3 years including physical function scores [34].400. Owing to its antiCD22 targeting activity. Epratuzumab Mechanism Epratuzumab is an IgG1 monoclonal antibody directed against the CD22 molecule. those weighing 60 to 100 kg received 750 mg. improvement in disease activity in patients with RA. The same protocol as described above for patients with RA was used in a multi-center double-blind placebo-controlled study of 180 patients with SLE with discoid rash. with further doses every 4 weeks after that. most of the AEs were minor. Indications and dosage Abatacept is approved by the FDA for the treatment of RA that is non-responsive to DMARDs and anti-TNF-alpha blockers. the dose is based on body weight. epratuzumab is indicated for the treatment of SLE and Sjögren‟s syndrome (Table  1) [30]. and infusion reaction [30]. Abatacept (trade name Orencia) is a CTLA-4 IgG1 that binds to CD80/86 on APCs. For JIA.29]. and for JIA (Table 1). 2. the route of administration is also IV. causing early apoptosis and thus shortening the cell‟s life span (Table 1) [28. general pain. Co-activation of CD28 with the antigen-presenting cell (APC) protein CD80/86 results in release of inflammatory cytokines. and included nausea. and those weighing more than 100 kg receive 1000 mg). as measured by the ACR warranted [32]. which inhibits T-cell activation by blocking the CD28 binding. Efficacy In a meta-analysis comparing phase II and III studies including an extension phase. The results of the study suggest some abatacept efficacy in patients with non-life-threatening manifestations of SLE.32]. CD22 is a B-cell-specific transmembrane sialoglycoprotein that inhibits the B-cell receptor complex. 67% of patients responded to 6 months of epratuzumab therapy. further assessment. including swelling of the nasal mucosa and increased pressure in the glottis[30]. Ano ther treatment option after the initial IV dose is to administer a subcutaneous (SC) injection of 125 mg at 24 hours afte r the first infusion. In a different study of patients with Sjögren‟s syndrome.600 mg epratuzumab with placebo for 12 weeks. fatigue. or polyarthritis.belimumab were similar to that in the placebo group. There was an average improvement of 50% in ACR20 in the abatacept group. Similar results were found for ACR50 and ACR70 in the abatacept group compared with the placebo group and with other treatment groups [33]. indicating regeneration of glandular tissue [30]. repeated by weekly SC injections of 125 mg [31. Efficacy Although epratuzumab has not received regulatory approval for SLE and Sjogren's syndrome. Indications and dosage The therapeutic dose of epratuzumab is 360 mg/m2 IV over 1 hour every 2 weeks for up to four cycles. In the study of patients with SLE. all patients had a decrease in disease activity of more than 50% [30]. Adverse effects and safety In the phase II trial of 227 patients described above. Patients with Sjögren‟s syndrome had more severe AEs during the infusion. Cytotoxic T lymphocyte-associated (CTLA)-4 is a protein with a high affinity to CD80/86. all epratuzumab groups had a significant response as measured by BILAG score [29]. and those weighing over 100 kg receive 1000 mg). and the dose is based on body weight and age (children 6 years over weighing less than 75 kg receive 10 mg/kg. Evaluation of radiographic changes identified a reduction in bone . there was no significant difference in AEs between the placebo group and any of the epratuzumab groups [30]. In a larger study of 227 patients with moderate to severe SLE.27]. was reported with combined therapy with abatacept and DMARDs within 6 months. comparing doses of 600. inhibiting the co-stimulation of CD28 on T cells (Table 1) [31]. In a long-term study comparing abatacept with placebo (with background therapy for both groups of a steady dose of MTX). In a study measuring scores on the British Isles Lupus Assessment Group (BILAG) scale during a follow-up of 6 months. those weighing 75 to 100 kg receive 750 mg. and that the severity and number of AEs did not increase in the high-dose (10 mg/kg) group compared with the low-dose (1 mg/kg) group [26. 800. This included patients who had not responded to prior anti-TNF-alpha therapy. It is recommended that acetaminophen and anti-histamine should be administered prior to infusion to minimize infusion reaction [30]. serositis.

However. a significant improvement wa s found in the AS International Working Group criteria (20% improvement. dizziness. ASAS20) for all golimumab groups compared with the placebo group [37]. In a study of long-term safety. and prostate. The most significant results were seen in the MTX plus golimumab groups (both doses) compared with MTX alone. and for AS. Certolizumab pegol Mechanism Certolizumab (trade name Cimzia) is a pegylated Fab fragment of a humanized TNF-alpha monoclonal antibody. acting on both soluble and membrane-bound TNF-α (Table 1) [36]. In another study (GO-BEFORE study [39]). The primary outcome of ACR50 was not achieved. no significant difference occurred between th e two groups. or golimumab 100 mg plus placebo. MTX plus golilumab 100 mg. In a similar study in patients with PsA. Additional AEs include hypertension. abatacept had a steroid-sparing effect and resulted in a lower rate of flares. which binds to and inhibits TNF-alpha. lung. and some cases of malignancy (basal and squamous cell carcinomas. 96% of patients experienced AEs. MTX plus golimumab 50 mg. those who received 100 mg golilumab had significantly higher rates of infections than those who received 50 mg. for PsA it may be administered alone or with MTX. The indicated dose for all three diseases is 50 mg monthly by SC injection. Indications and dosage . however. in the abatacept group. it may be administered alone [40]. abnormal liver function (patients with latent TB were required to take prophylactic treatment. Adverse effects and safety The main AEs are infections (mostly of the URT) and nausea. fever. In the study on patients with PsA. which could be attributable to lower disease activity in these patients compared with patients receiving other biologic therapy-based studies. a higher incidence of AEs was noted in the golilumab 100 mg group [38]. Furthermore. hypertension. In another study of 180 patients with SLE. using the same protocol as the previous study but in MTX naïve patients with RA. significant improvement in well being was reported by the HAQ (Health Assessment Questionnaire) [32]. and 40% of patients had no radiographic progression after 3 years[35]. URT symptoms. the modified intention-to-treat analysis of the primary endpoint and other pre-specified efficacy measures did show efficacy in both the golimumab plus MTX groups in these patients [39]. local skin reaction. constipation. and breast cancers) were reported [37-40]. The pegylation extends the half-life of the antibody. Novel anti-TNF-α blockers Golimumab Mechanism Golimumab (trade name Simponi) is a fully human monoclonal IgG1 antibody. most of them were mild to moderate and mostly related to infections.erosion scores (Genant-modified Sharp scoring method) every year within the 3-year follow-up. resulting in greater liver abnormalities). nausea. more infections occurred in patients receiving golimumab compared with those receiving placebo [36-39]. 28-item Disease Activity Score (DAS28). In studies performed to assess golimumab safety. This effect was predominant in the lupus patients with polyarthritis [32].42]. In a study comparing treatment groups given doses of 50 or 100 mg golimumab SC. ACR90. a significant improvement was encountereed in both golimumab groups compared with placebo [37]. and ankylosing spondylitis (AS) (Table 1) [37-40]. No significant differences in AEs were noted when the abatacept group and the placebo group (receiving DMARDs only) were compared [35]. psoriatic arthritis (PsA). were compared. a significant response was seen with golimumab as measured by ACR70. as well as to group size and possibly C-reactive protein levels. The lower dosage is recommended by the FDA [37]. (GO-FORWARD study [38]) the efficacy of MTX plus placebo. and HAQ [39]. Efficacy In a study of patients with AS comparing different doses of golimumab with placebo for 24 weeks. there was a significant improvement in both enthesitis and Dactylitis Severity Score[37]. In a study of patients with RA who were not responsive to MTX. using two different doses of golimumab. headache. For RA. Adverse effects and safety The main AEs caused by abatacept are infections. and the missing Fc fragment reduces the risk of cytotoxicity (Table 1) [41. golimumab is administered in combination with MTX. and back and limb pain. However. paresthesia. but these were mainly minor infections involving the URT [38]. Indications and dosage Golimumab is approved by the FDA for RA. infusion reaction. Furthermore.

modulates IL-1 receptor antagonists. diarrhea. usually for up to 6 months. a higher incidence of serious infections was noted with certolizumab [42].html webcite ). including familial cold auto-inflammatory syndrome (FCAS) and Muckle-Wells syndrome (MWS) (Table 1). To reduce AEs. and increases in blood creatinine and urea levels[42]. it is administered via SC injection at a dose of 150 mg every 8 weeks. IVIG has a direct neutralization effect on pathogenic antibodies. Rilonacept (trade name Arcalyst) is an IL-1 blocker that is also indicated for the treatment of CAPS. Efficacy In a study of patients diagnosed with RA for no less than 6 months and no more than 15 years. safe.2 mg/kg or up to 160 mg for chi ldren) maintained long-term efficacy and safety in an extension study of 72 to 96 weeks. menorrhagia. The safety of sifalimumab was evaluated in a phase I trial of SLE. therapy remains beneficial [50]. prevents the presentation of self antigens. The first group was treated with MTX plus placebo and the second with MTX plus certolizumab. in adults and in children aged 12 years and older. B and T cells. Two of these are indicated for the treatment of disorders collectively known as cryopyrin-associated periodic syndromes (CAPS). the AEs reported for certolizumab were headache. Canakinumab (trade name Ilaris) is specifically indicated in adults and in children aged 4 years and older for the treatment of a single dose of hydrocortisone 100 to 200 mg should be administered on day 1 before initiation of the IVIG therapy. Dosage protocols The characteristics of the various IVIG products are not discussed here. and is beneficial for autoimmune diseases [48]. there was improvement in disease activity with sifalimumab compared with placebo [44]. Sifalimumab Sifalimumab is an anti-interferon (IFN)-alpha monoclonal antibody.44]. The immunoglobulins are derived from a pool of thousands of healthy donors. including normalization of the inflammatory markers CRP and SAA. Intravenous immunoglobulin therapy Mechanisms IVIG is a well established therapy for immunodeficiency diseases. and then every 2 to 3 months if required. and sinusitis [42]. consisting of 2 g/kg divided over 5 days. salmonella arthritis. A significantly higher incidence of serious AEs were detected in patients receiving certolizumab. Adverse effects and safety Other than the AEs already recognized for treatment with TNF-alpha blockers. For adults. It inhibits the differentiation and maturation of dendritic cells. ischemic stroke. and they influence the immune system at many levels. but had responded to anti -TNF-alpha blockers in the past. In a safety study of patients with RA. Canakinumab is beneficial. a significant ACR20 response of up to 50% was accomplished with certolizumab monotherapy. and arthritic pain [42]. and reduction in radiographic progression were achieved more rapidly in the certolizumab group compared with the placebo group over a 1-year period [41]. Compared with normal controls. Treatment with a . overexpression of B cell activation factor (BAFF) mRNA in whole blood characterizes patients with SLE. and the drug is currently in phase III trials [20]. these AEs occurred with the lower dose of 200 mg but not the higher dose of 400 mg [42]. Recently. other IL-1 blockers became available. IL-1 inhibitors are currently under investigation for the treatment of acute gout flares [47]. who had not received any biologic therapy for 6 months before the beginning of the study. Patients with SLE carry a typical type I IFN signature. Different IVIG protocols are in use. Long term. but can be readily found online (http://www. and inhibits BLyS activity (Table 1) [49]. given as SC injection of 400 mg every 2 weeks for three consecutive cycles. and PCR identified suppression of BAFF mRNA (Table 1) [43. Similar improvements were also encountered for disease activity. In the trial. mastitis. containing antibodies to both self and foreign antigens. There were no drug-related AEs and no increase in viral infections. physical improvement. Interleukin-1 inhibitors Anakinra (trade name Kineret) is approved by the FDA for treatment of RA. In systemic autoimmune diseases such as SLE. and these included bacterial arthritis. Rilonacept (160 mg SC weekly for adults and 2.Certolizumab is approved by the FDA for the treatment of active RA disease (Table 1). a period that allows the immunoglobulin level in the serum to return to normal. and included injection site reactions and URTI [46]. depending on the disease. followed by maintenance therapy of 200 mg SC every 2 weeks. including FCAS and MWS. There were no fatalities or cases of drug-induced SLE [42]. a high-dose protocol is often used. AEs were mild to moderate. physical function. The associated AEs include infections [45]. and leads to a reduction in serum amyloid A (SAA) and C-reactive protein (CRP) levels.medprorx. Several mechanisms of action are suggested for immunoglobulins. ACR20 response. and macrophage regulation. In a different study of patients with RA who had experienced treatment failure with DMARDs. nasopharyngitis. were enrolled. Th e cycle repeats every month. This is repeated every 4 weeks. The effect of anti-IFN-alpha antibody was examined using B lymphocyte stimulator/BAFF.

Lowdose IVIG therapy (400 mg/kg over 1 day every 3 to 4 weeks) is beneficial for organ -specific disease. refractory myasthenia gravis. In a study of 130 patients receiving ofatumumab. Adverse effects and safety IVIG is usually associated with mild and transient AEs. patients may develop immunogenicity to these agents. In a trial comparing the immunogenicity of epratuzumab with rituximab. In cases where there is a high risk of thromboembolic event. renal disease. only two patients developed drug-related antibodies. With the availability of fully human antibody biologic agents. In addition. the development of HACA may be negligible.1% of patients developed anti-drug antibodies. dermatomyositis. In the GO-FORWARD study of golimumab.58]. Low-dose IVIG is beneficial for Guillain–Barré syndrome. In a phase I multi-center double-blind trial of 33 patients treated with sifalimumab. it appears that high-dose IVIG is beneficial for moderate to severe SLE. headache. only 5. which was not statistically significant [42]. myalgia. no patients developed drug antibodies [25]. which include antibodies and receptor blockers. However. and in a study of belimumab treatment. multifocal motor neuropathy. druginduced SLE secondary to biologic therapies is not a mild disease. Lambert–Eaton syndrome. Although the development of antinuclear antibodies and anti-double-stranded DNA antibodies have been reported secondary to biologic treatment. In many cases. High-dose IVIG was beneficial for SLE. Other diseases in which IVIG is used include refractory uveitis. Graves' disease. It is beneficial for the treatment of serositis. thromboembolic events. autoimmune hemolytic anemia. The more severe AEs include anaphylactic reaction. The common mild AEs include arthralgia. fewer anti-chimeric antibodies developed compared to epratuzumab [29]. Immunogenicity of biologic therapies Biologic agents are engineered molecular targeted therapies. and do not usually worsen with long-term IVIG therapy [50]. Still‟s disease. It may also be useful for some cases of mild to moderate SLE [52]. Several studies of TCZ showed that the development of anti-chimeric antibodies had no significant clinical effect [5]. may lead to a decrease in the efficacy of the medication. patients received short-term therapy with moderate or low doses [48]. termed human anti-chimeric antibodies (HACA). or the development of pathogenic autoantibodies that can lead in some cases to the development of another autoimmune disease. cardiopulmonary disease. Immunogenicity of specific drugs The newly developed drugs may not cause significant immunogenicity effects. but rather a severe systemic disease with renal impairment [59]. seizures. In a study of 619 patients treated with certolizumab. polyneuropathy in SLE and vasculitis respond well to IVIG therapy [57]. the development of frank SLE is infrequent.1% of patients with RA developed drug antibodies [39]. LMW heparin is to be administered before initiation of the IVIG course. chills. diffuse neuropsychiatric disease. and led to a decrease in various scores of disease activity. Antibodies targeted against the biologic therapy. as usually seen for other medications. Based on the various case reports and case series. asthma exacerbation. hematological conditions. predominantly neurological conditions [50]. only 2. and relapsing anti-neutrophil cytoplasmic antibody-associated vasculitis [49]. abdominal pain. and aseptic meningitis [55. IVIG has a steroid-sparing effect [56]. Discussion . severe PV. It may also be an option for young women who do not wish to risk the problems of disfigurement or sterility associated with conventional immunosuppressive therapies. acute respiratory distress syndrome. fatigue.single dose of low-molecular-weight (LMW) heparin before IVIG initiation may prevent possible thromboembolic AEs [51]. weakness. polyneuropathy. hence a DMARD (usually MTX) is often recommended as co-treatment to counteract the increased levels of HACA. diarrhea. renal failure with acute tubular necrosis. In a study of 339 patients receiving abatacept. and stiff person syndrome [48]. negative seroconversion occurred significantly more frequently in the belimumab treatment group [27]. which was not statistically significant [32]. As a result. fever. refractory multiple sclerosis. In patients with SLE. drowsiness. there were no anti-sifalimumab antibodies detected prior to administration or at several points during the study[44]. neutropenia. characterized as development of antibodies to the biologic agent itself. diabetes). IVIG causes a serological improvement including a decrease in antibody titer levels and an increase in complement levels [49]. dizziness. hepatic dysfunction. and ocular involvement in Behcet's disease [48]. Antibodies may be chimeric or fully human. and changes in blood pressure or heart rate [50]. IVIG may be useful for recalcitrant cases of organ-specific cutaneous LE including discoid LE and subacute cutaneous LE. IVIG is contraindicated in patients with IgA deficiency [49]. chronic inflammatory demyelination polyneuropathy. and lupus nephritis [53-55]. pancytopenia. Efficacy IVIG may be an adjunctive therapy for patients with SLE who are refractory to conventional therapies. AEs occurring with the first course may return with further courses [50]. IVIG may be beneficial as off-label for a number of other autoimmune diseases including Sjogren's syndrome. Special attention is advised when treating patients with pro-thrombotic risk and those with renal failure or who are at risk of renal tubular injury (dehydration.

whereas SC therapy may be suitable for patients who feel confident injecting the drug in the privacy of their own home. AS: Ankylosing spondylitis. SJIA: Systemic juvenile idiopathic arthritis. EC50: Half-maximal effective concentration. CD22).We reviewed the literature on new biologic therapies that have recently become available and how they are used to treat various autoimmune diseases. the choice of biologic may be customized to include considerations of co-morbidities or the need for concomitant drug treatment. ITP: Immune thrombocytopenic purpura. JIA: Juvenile idiopathic arthritis. ASAS: Assessment in Ankylosing Spondylitis. with the severe AEs including serious infections. IFN I inhibitors. The AEs are similar for all the biologic therapies reviewed. Belimumab is the first FDA-approved targeted therapy for SLE. co-activation signaling (CTLA4Ig). IL-1 inhibitors). B-cell-directed therapies (to CD20. Furthermore. With the various available biologic therapies. URT: Upper respiratory tract. BILAG: British Isles Lupus Assessment Group. a switch to a different biologic class may achieve a favorable result. DMARD: Disease-modifying anti-rheumatic drug. Abbreviations ACR: American College of Rheumatology. MPA: Microscopic polyangiitis. the efficacy and safety for biologics in off-label indications are encouraging for patients with resistant autoimmune conditions. probably due to economic concerns. and IVIG. B-cell modulators). they can be switched to a different TNF alpha blocker or to another class of drugs (for example. TB: Tuberculosis. It is advantageous to have a range of effective biologic drugs available for patients with severe or resistant disease. BLySS: B lymphocyte stimulator. If a patient develops an AE from one TNF-alpha blocker. Authors' contributions . persistent disease despite conventional therapy or even persistent and non-responsive disease despite biologic therapies. DAS28: 28-item Disease Activity Score. IV therapy may be suitable for patients who need medical supervision. RA: Rheumatoid arthritis. Although most of the FDA-approved biologic therapies are for RA. GI: Gastrointestinal. HAQ: Health Assessment Questionnaire. if there was an initial efficacy response that ceased over time. costs may be driven down. allowing biologic therapies to be used at an early stage of disease and hence enable prevention of irreversible damage. In addition. TCZ: Tocilizumab. For example. CRP: Creactive protein. IL-6). IFN: Interferon. TNF: Tumor necrosis factor-α. Conclusions The arsenal of biologic therapies available to treat autoimmune diseases is quickly expanding as a result of better understanding of molecular mechanisms together with improved production capacity. IVIG: IV immunoglobulin. Competing interests The authors do not have any competing interests. MTX: Methotrexate. Because the complexity of preparing biologic drugs has diminished over the years. There is a focus on early treatment. SELENA-SLEDAI: Safety of Estrogens in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index. Anti-TNF: Tumor necrosis factor antagonist. SAA: Sserum amyloid A. Severe disease can include involvement of vital systems. TB recurrence has been virtually eradicated due to the accepted screening recommendations before starting biologic therapy. They include (by class): novel anti-TNF alpha blockers (fully humanized or pegylated). Some of these are new drugs in known classes (TNF alpha blockers and B cell modulators). Different drugs from the same class (for example anti-TNF-alpha blockers) may provide further treatment options. the therapy can be tailored to the individual patient. In addition.whereas others are of a new class (BLyS inhibitors. anti-IL agents (to IL-1. RCT: Randomized controlled trial. yet none of the biologic therapies is yet available as first-line medication for autoimmune diseases.