Connective Tissue Diseases: Concepts and Pathogenesis, Overlap Syndromes, Mixed CTD and Undifferentiated CTD

EULAR on-line course on Rheumatic Diseases
Connective tissue diseases:

Concepts and pathogenesis,
overlap syndromes, mixed CTD
and undifferentiated CTD
Chiara Tani, Marta Mosca, Silvia Bellando Randone
A previous version was co-authored by Gemma Lepri, Silvia Bellando Randone,
Christian Beyer, Oliver Distler, Jorge H.W. Distler
LEARNING OBJECTIVES
 Acknowledge that patients with symptoms suggestive of one or more inflammatory rheumatic
diseases who do not fulfil classification criteria for a specific entity often present in daily clinical
practice
 Describe and explain the prospects and limitations of classification criteria in the diagnosis of
connective tissue diseases
 Apply knowledge of clinical symptoms and diagnostic findings suggestive of undifferentiated
connective tissue disease, overlap syndromes and mixed connective tissue disease
 Describe and explain the course and prognosis of undifferentiated connective tissue disease, overlap
syndromes and mixed connective tissue disease and their clinical warning signs for major organ
involvement
 Use diagnostic screening algorithms for the individual patient depending on her/his risks for major
organ involvement, such as pulmonary arterial hypertension in a patient with mixed connective tissue
disease
 Apply treatment strategies for patients with undifferentiated connective tissue disease, overlap
syndromes and mixed connective tissue disease depending on their disease activity and individual
organ involvement
 Evaluate the limited scientific evidence for the treatment of undifferentiated connective tissue
disease, overlap syndromes and mixed connective tissue disease
CTD: Concepts and pathogenesis, overlap syndromes, mixed CTD and undifferentiated CTD – Module 16
1 Introduction
Diagnosis of rheumatic diseases can be challenging. Many clinical signs and symptoms as well as laboratory
markers are not specific for a certain rheumatic disease but may occur in different diseases. This includes
Raynaud’s phenomenon, arthritis, interstitial lung disease and small vessel vasculitis, as well as antinuclear
antibodies (ANAs), rheumatoid factor (RF), anti-Ro/SSA and anti-La/SSB antibodies. Only a few clinical findings
like scleroderma and some biomarkers, including anti-cyclic citrullinated antibodies in rheumatoid arthritis
(RA), anti-Sm and anti-double-stranded DNA antibodies in systemic lupus erythematosus (SLE) and anti-
topoisomerase and anticentromere antibodies in diffuse and limited systemic sclerosis (SSc), have a relatively
high specificity for the corresponding disease.
Thus, 25–50% of patients referred to tertiary rheumatology centres do not carry a diagnosis of a clearly
defined rheumatic disease or present with features of two or more rheumatic diseases (LeRoy et al, 1980*;
Cervera et al, 1990*). These patients are classified as having either undifferentiated connective tissue disease
or overlap syndrome. Mixed connective tissue disease, however, should not be confused with undifferentiated
connective tissue disease or overlap syndrome. This, in fact, is a distinct clinical entity that manifests as a
mixture of certain clinical features also seen in other rheumatic diseases. The following article will shed light
on the subtle differences among these three rheumatic entities; it will explain the different organ
manifestations and risks for severe complications; it will further demonstrate the consequences for organ
screening, follow-ups and treatment of these diseases; this article will finally show why it is important to
differentiate between each of these entities and separate them from other rheumatic diseases.
2 Undifferentiated connective tissue diseases
2.1 Introduction and definition
Patients who present with features of a connective tissue disease but who do not fulfil current criteria for a
specific connective tissue disease are diagnosed as having ‘undifferentiated connective tissue disease’ (UCTD)
(LeRoy et al, 1980; Mosca et al, 2014). Classification criteria for UCTD have not been defined, but there is a
general consensus that the term UCTD refers to unclassifiable systemic autoimmune diseases which share
clinical and serological manifestations with definite connective tissue diseases but not fulfilling any of the
existing classification criteria. Some authors even add undifferentiated arthritis to the group of UCTDs. Since
UCTD in significant numbers of these patients will evolve into RA, spondyloarthritis or other rheumatic
diseases that do not belong to the group of connective tissue diseases, we believe that these patients should
not be grouped as UCTDs. This is particularly true for patients with undifferentiated arthritis positive for anti-
CCP antibodies. As many as 83% of these patients will fulfil the American College of Rheumatology (ACR)
criteria for RA after 1 year and up to 93% after 3 years of follow-up (van Gaalen et al, 2004). Undifferentiated
©2007-2017 EULAR 2
arthritis might evolve into a defined connective tissue disease in only a minority of patients (<10%) (Wolfe et
al, 1993).
2.2 Clinical features of UCTD
The definition of UCTD includes a wide spectrum of diseases that can be referred to the following scenarios
with variable disease course and prognosis:
• Patients with recent onset of symptoms and unclassifiable clinical picture; in this group of patients, the
undifferentiated condition better refers to a “incomplete”, “atypical” or “mild” disease presentation
which is very likely to progress into a definite CTD in the short time or, sometimes, even years after
symptoms onset. This group of undifferentiated conditions represents the “early phase” of a CTD and
their effective recognition has a crucial clinical importance in term of treatment decision making and
disease monitoring.
• Patients with “stable UCTD”, a distinct clinical entity with peculiar clinical findings; the proposed
preliminary classification criteria for UCTD include at least one clinical manifestation of CTDs,
positive ANA results, and disease duration of at least three years (Mosca M, 1999). In these
patients severe organ involvements (such as renal or neurological manifestations) are only
occasionally reported, the clinical picture is usually stable over time and necessitates mild
therapeutic intervention (Bodolay E, 2003 ; Mosca M, 2013, Danieli MG, 1999)
• Patients with ‘organ-dominant’ conditions (e.g., idiopathic non-specific interstitial pneumonia) and
antinuclear antibodies or other serological features or mild clinical symptoms suggesting an
autoimmune process.
Typical presenting symptoms of patients with UCTD are Raynaud’s phenomenon (80%), arthralgias (60–70%),
arthritis (30–40%), sicca symptoms (25%), alopecia (20%), photosensitivity (15–25%), malar rash (3–10%),
sclerodactyly (10%), leucopenia (10–25%), thrombocytopenia (5–15%) and anaemia (5%) (Danieli et al, 1999;
Mosca et al, 2002).
When suspecting an early form of a specific rheumatic disease that does not fulfil classification criteria, the
suffixes ‘pre-’ or ‘early’ might help to distinguish this condition from a “true” (stable) UCTD. For example,
patients with new-onset Raynaud’s phenomenon, typical changes detected at nailfold capillaroscopy,
telangectasias and specific antibodies for SSc, might be classified as pre- or early SSc, also according to the new
ACR/EULAR classification criteria (Van den Hoogen et al, 2013). It is necessary to emphasise the importance of
one of the earliest signs of many connective tissue diseases: Raynaud’s phenomenon. This may precede by
several years the onset of a connective tissue disease, such as SSc, where it is considered a pivotal sign. For
©2007-2017 EULAR 3
this reason, a careful history and physical examination of these patients is mandatory to identify potential
organ manifestations suggestive of rheumatic disease (Koening et al, 2008).
When we encounter patients with Raynaud’s phenomenon (RP) it is important to distinguish between the
primary and the secondary form, and also to exclude patients with other causes of Raynaud’s syndrome, such
as vibration injury, drugs (eg, β blockers, ergotamines or cocaine), chemicals (eg, vinyl chloride), occlusive
arterial disease and hyper viscosity syndrome. Studies have shown that after an extended screening
programme during a mean follow-up of 11.2 years, the prevalence of transition from primary to secondary RP,
was 14.9% of all patients (Hirschl et al, 2006). This result suggests that patients initially identified as having a
primary RP should be followed up with a nailfold capillaroscopy examination in order to identify alterations of
the capillary network as soon as possible. Screening of patients with SSc for ANAs and—in certain cases—for
cryoglobulins will complete the basic investigation. In addition to the patient’s clinical history, clinical findings
(eg, severe digital ischaemia, asymmetrical attacks, later age at onset), suspicious findings on capillaroscopy
and the presence of ANAs at high titres increase the probability of a rheumatic disease and reject the diagnosis
of primary RP (fig. 1)
Figure 1 The concept of undifferentiated connective tissue disease. DM, dermatomyositis; MCTD, mixed
connective tissue disease; PM, polymyositis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis;
UCTD, undifferentiated connective tissue disease.
2.3 Prognosis of UCTDs
Several large, prospective studies have examined the outcome of patients with UCTD. These studies show
consistently that most patients with UCTD will have the same diagnosis even after several years of follow-up.
In the remaining patients, the development of a defined rheumatological disease is more common than
complete resolution of the symptoms.
©2007-2017 EULAR 4
In a prospective study of 143 patients with a mean follow-up of 10 years, the diagnosis of UCTD persisted in
65% (Williams et al, 1999). At the end of the follow-up, a total of 29% fulfilled the criteria for a defined
rheumatic disease, most commonly SSc (15%) and SLE (13%), but also RA and mixed connective tissue disease
(MCTD) (3% each). Remission of symptoms was found in only 6% of the patients. In 165 Italian patients, 82%
were still classified as having UCTD after 5 years and only 6% developed defined connective tissue diseases,
with SLE being most common. Twelve per cent of the patients were asymptomatic after 5 years (Danieli et al,
1999). In a Hungarian prospective study, 53% of 665 patients still carried the diagnosis of an UCTD after 5
years. A defined rheumatological disease developed in 35% of cases with 13% of patients being diagnosed with
RA, 7% with Sjögren’s syndrome, 4% with SLE, 4% with MCTD, 3% with SSc and <1% with polymyositis (PM) or
dermatomyositis (DM). In addition, 3% of patients developed systemic vasculitis. Complete remission of
clinical findings occurred in 12% of patients with UCTD (Bodolay et al, 2003).
Based on available data, several factors may be predictive for the development of SLE. These predictors
include serological findings such as anti-dsDNA antibodies, anti-Sm antibodies, anticardiolipin antibodies, false-
positive test for syphilis, positive Coombs test, a homogeneous ANA pattern and multiple antibody
specificities. The following clinical findings are also predictive for the development of SLE: alopecia, acute or
subacute skin rash, discoid lesions, serositis and cardiac complications (Alarcon et al, 1996; Mosca et al, 2002;
Bodolay et al, 2003; Bortoluzzi A, 2016). Of note, anti-Sm antibodies, anticardiolipin antibodies, a
homogeneous ANA pattern, discoid lesions and serositis may be the strongest predictors.
Furthermore, oesophageal dysfunction might predispose for the development of a connective tissue disease.
In a study on 145 patients with UCTD, 46% were found to have oesophageal dysfunction by radionucleotide
oesophageal transit scintigraphy (Gaal et al, 2005). Of note, 71% of the patients with oesophageal dysfunction
were asymptomatic. Pathological findings from radionucleotide oesophageal transit scintigraphy predicted the
development of a defined connective tissue disease.
In addition to studies investigating the outcome of patients with UCTD, in general, several studies have
analysed the outcome of patients with UCTD with particular manifestations. A meta-analysis of 10 articles with
a total of 639 patients concluded that a secondary connective tissue disease develops in about 13% of those
patients presenting with isolated RP by an average of 10 years from its onset (Spencer-Green, 1998). The best
predictor for the transition to a connective tissue disease was an abnormal nailfold capillary study
demonstrating avascular areas and giant capillaries with an overall reduced capillary density. The positive
predictive value for developing a connective tissue disease in a patient presenting with RP was 47%.
Isolated positive ANA testing is a poor predictor for the development of a specific connective tissue disease,
with a positive predictive value of 30% (Spencer-Green, 1998). In contrast, positive ANAs together with
anticentromeric staining patterns are good predictors for the development of SSc. In a small series of 46
©2007-2017 EULAR 5
patients with RP and one other symptom, the disease evolved into SSc in 24%. The best predictor for the
development of SSc was the presence of autoantibodies with a sensitivity of 60% and a specificity of 98% in
this population (Kallenberg et al, 1988; Kallenberg, 1995*).
Autoantibodies might be detectable several years before disease onset. In a study of 130 patients with SLE, at
least one autoantibody was present in 88% of patients before diagnosis (Arbuckle et al, 2003*). On average,
the time between the first appearance of autoantibodies and the diagnosis of SLE was 3.3 years, but the onset
of disease could be delayed by up to 9.4 years. ANAs were present in 78%, anti-dsDNA antibodies in 55%, anti-
Ro antibodies in 47%, anti-La antibodies in 34%, anti-Sm antibodies in 32%, anti-RNP antibodies in 26% and
antiphospholipid antibodies in 18% of patients. ANAs, anti-Ro antibodies, anti-La antibodies and
antiphospholipid antibodies were the first autoantibodies to appear, followed by anti-dsDNA antibodies and
finally, anti-Sm and anti-RNP antibodies.
Direct comparison of mortality in patients with UCTD and other connective tissue diseases does not exist.
Comparison of results from different studies, however, showed that the mortality of patients with UCTD was
intermediate in comparison with other connective tissue diseases. In patients with UCTD, 5- and 10-year
survival rates have been reported as 83% and 76%, respectively (Mosca et al, 2002). Two studies on patients
with SLE reported survival rates of >90% after 5 and 10 years (Trager and Ward, 2001; Cervera et al, 2003). By
contrast, patients with diffuse SSc have survival rates of about 63% after 7–10 years (Ferri et al, 2002; Scussel-
Lonzetti et al, 2002). Nevertheless, comparability of these different studies is limited owing to several
confounding factors, including patient selection, data acquisition, ethnic populations, available treatments and
organ manifestations. For instance, patients with SLE-associated kidney disease or SSc-associated pulmonary
arterial hypertension (PAH) had a poor prognosis, while patients with SLE and SSc with skin disease only had a
relatively long survival compared with the overall survival of the disease groups of these studies.
2.4 Management of patients with UCTDs
Although most patients will continue to have a diagnosis of UCTD, they should be followed up closely since
additional disease manifestations may develop, fulfilling the criteria for a defined rheumatological disease.
Both new disease manifestations and the new diagnosis might change the further management of the patient.
For instance, patients with accumulating symptoms suggestive of SLE need to be closely monitored for
potentially life-threatening manifestations, such as glomerulonephritis. Patients with RP and anticentromere
antibodies have a higher risk of developing PAH and need to be monitored by echocardiography.
Treatment of patients with UCTD usually includes antimalarial agents, low doses of steroids and symptomatic
drugs depending on the presenting clinical manifestations. Treatment options derive from study results and
experiences in other rheumatic diseases. We will discuss later the treatment options for patients with UCTD
together with management principles in patients with MCTD.
©2007-2017 EULAR 6
2.5 Overlap syndromes
Overlap syndrome is often defined as an entity that satisfies the classification criteria of at least two
connective tissue diseases occurring at the same time or at different times in the same patient (Iaccarino et al,
2013). Virtually any combinations of coexisting rheumatic diseases have been reported in the literature. In this
chapter, we will discuss selected overlap syndromes that are particularly characteristic or very common.
Cardinal signs of one specific connective tissue disease may also be part of the normal clinical spectrum of
another, since many clinical findings and laboratory markers lack specificity. For instance, myositis or
myopathies may occur in a subset of patients with SSc (Pope et al, 2002). Four large studies have evaluated the
SSc/myositis overlap syndrome and reported 282/633 cases; SSc/myositis seemed to be the second most
common SSc overlap syndrome after SSc/RA (Balbir-Gurman et al, 2001; Caramaschi et al, 2007; Pakozdi et al,
2011; Koschik et al, 2012; Iaccarino et al, 2013). Patients with this overlap syndrome do not necessarily fulfil
the classification criteria for polymyositis and might have myositis as part of the clinical spectrum of SSc. To
make this issue more complicated, classification criteria are of limited value in the early diagnosis of rheumatic
diseases. Therefore, patients with SSc and myositis might still have an incomplete or early form of polymyositis
as well as SSc. This example highlights the challenges in the diagnosis and classification of connective tissue
diseases. Similar considerations may account for many overlap syndromes. In our own clinical practice, we
reserve the diagnosis of overlap syndromes for patients who clearly present with classic features of two
different rheumatic diseases, including the presence of specific autoantibodies (figure 2). Nevertheless, there
is no general consensus about this subject.
Figure 2 The concept of overlap syndrome. PM, polymyositis; SSc, systemic sclerosis.
2.5.1 SLE–RA overlap
Paying tribute to the name of both diseases, the overlap of RA and SLE is called ‘rhupus’ (Panush et al, 1988).
The exact definition of ‘rhupus’ syndrome is still debated. In some cases it has been defined as a condition in
which patients present clinical features of SLE and RA, and this hypothesis is supported by the simultaneous
©2007-2017 EULAR 7
presence of SLE-specific autoantibodies (anti-DNA, anti-Sm) and RA-specific autoantibodies (anti-citrullinated

protein antibodies (ACPA). Rhupus seems to be as common as the chance of simultaneously having both SLE
and RA (Panush et al, 1988). This supports the concept that rhupus represents the coexistence of two separate
diseases in the same patient, rather than an additional disease entity. Others authors prefer to consider the
‘rhupus’ syndrome as an erosive subset of SLE arthropathy (Iaccarino et al, 2013).
The serological overlap between RA and SLE is well known with up to 20% of RA patients exhibiting antinuclear
antibodies. However, patients with a true concomitance of RA and SLE are rare. The real prevalence, clinical
picture and the natural history of this condition are documented in the literature by case series and small
cohorts with significant discrepancies among case definitions and assessment methods Indeed, in most recent
studies, the reported prevalence of rhupus in SLE cohorts ranges between <1% and 17% depending on the
adopted inclusion criteria and assessment methods. (LiJ, 2014, Tani C, 2013, Gormezano NM, 2016)
Although erosive changes are rarely noted on plain radiographs in patients with SLE, more sensitive imaging
techniques, such as magnetic resonance imaging, can disclose erosions in up to 60% of patients (Ostendorf et
al, 2003; Iaccarino et al, 2013). In addition, flexion deformities, ulnar deviation, soft tissue laxity and swan neck
deformities, as seen in RA, have been noted in 15–50% of patients with SLE (fig.3). (Weissman et al, 1978;
Cronin, 1988; Van Vugt et al, 1998).
Recently, the characteristics of a small series of patients with rhupus identified among SLE patients were
assessed from the clinical, serological and the instrumental (US and MRI) point of view; in this series arthritis
was responsible for the major disease burden at the time of the evaluation; indeed, clinical signs of active
synovitis and clinically detectable joint deformities were present respectively in 90% and in 60% of the cases.
Interestingly, the severity of the joint disease was also highlighted by the instrumental data which revealed a
high prevalence of inflammatory signs (synovial effusion, synovial hyperplasia) and severe joint damage (bone
oedema and erosions). From the laboratory point of view, high levels of ESR and CRP were a clinical hallmark
of rhupus patients with respect to the entire SLE cohort (Tani C, 2013).
The prevalence of ACPA in ‘rhupus’ patients is estimated around 57% and 100% (Amezcua-Guerra et al, 2006;
Iaccarino et al, 2013) that is significantly higher than in SLE patients; moreover, some studies report a lower
prevalence of these antibodies in patients with non-erosive arthritis in comparison with those with erosive
disease (Chan et al, 2008; Iaccarino et al, 2013).
In patients with ‘rhupus’, severe SLE extra-articular manifestations (such as glomerulonephritis and
neurological involvement) are less common than in patients with SLE. (Li J, 2014; Tani C et al, 2013)
©2007-2017 EULAR 8
Figure 3 Picture showing the left hand of a patient with rhupus. Please note that the clinical appearance is
indistinguishable from RA.
Figure 4 Hand-wrist plain radiograph of a patient with rhupus. Please note extensive carpal collapse,
erosions and subluxations.
©2007-2017 EULAR 9
2.5.2 SSc overlap syndromes (PM-SSc and RA-SSc overlap)
Symptoms of SSc can occur in combination with those of other connective tissue diseases (CTD); this condition
is defined as SSc-overlap syndrome. No classification criteria for SSc-overlap syndrome are available, however,
it is generally considered when musculoskeletal involvement (myositis, arthritis) or clinical signs of other
rheumatic diseases are substantially greater than usually found in SSc patients (Pakozdi A, 2011). It is reported
that up to 20% of patients with SSc have overlapping features with other rheumatologic diseases, being
polymyositis/dermatomyositis (43%) and rheumatoid arthritis (32%) the most frequently reported (Pakozdi A,
2011)
Recently, 10% of SSc-overlap syndromes have been identified among the 3240 SSc patients registered in the
database of the German Network for Systemic Scleroderma and prospectively followed between 2003 and
2013; interestingly, these subgroup of patients showed distinct serological and clinical profile with respect to
the rest of cohort thus supporting the concept that SSc-overlap syndromes should be regarded as a separate
SSc subset, distinct from both the limited and the diffuse cutaneous SSc. (Moinzadeh P, 2015)
Autoantibodies are helpful to separate SSc-overlap syndromes from other SSc subsets. In particular, two
distinct autoantibody specificities have been associated with the PM–SSc overlap. However, these antibodies
can also be found in other connective tissue diseases or overlap syndrome in 17% of cases (Jablonska and
Blaszyk, 2004; Iaccarino et al, 2013). In the study of Pakozdi et al, anti-PM-Scl antibodies were found in 33.1%
of the patients with SSc/myositis (Pakozdi et al, 2011). In the United States, anti-PM-Scl antibodies are
significantly more common in patients with PM–SSc overlap (Targoff et al, 1992). This association could not be
confirmed in a Japanese population. By contrast, anti-Ku antibodies were predictive of PM–SSc overlap in the
Japanese study population. The differences between the American and the Japanese study might be—at least
in part—explained by different frequencies of HLA-DR3 in the two populations, since the genotype is closely
associated with anti-PM-Scl antibodies (Ioannou et al, 1999). Other studies showed a prevalence of anti-Ku
antibodies in patients with PM–SSc, ranging from 2.3% to 55% (Cavazzana et al, 2008; Belizca et al, 2010;
Pakozdi et al, 2011).
Inflammatory joint involvement is another frequent manifestation in patients with SSc-overlap syndromes.
These patients are often identified by typical SSC-clinical symptoms (usually limited skin involvement) together
with high titers of anticyclic citrullinated peptides (ACPA) and/or higher rheumatoid factor (Ueda-Hayakawa M,
2010, Szuc G, 2007)
Among all patients with SSc, ACPA positivity has been reported in 1.7–14.8% (Avouac et al, 2006; Szucs et al,
2007; Iaccarino et al, 2013). In these patients, ACPA were strongly associated with erosions detected by X-ray
examination or with arthritis. In the study by Szucs et al the metacarpophalangeal, carpal, proximal
interphalangeal joints and the ulnar heads were found to be more frequently affected by arthritis in patients
©2007-2017 EULAR 10
with SSc–RA. Most of these subjects had a limited SSc. The extra-articular manifestations included RP, present
in 100% of patients, and pulmonary fibrosis, present in 77.3% (Iaccarino et al, 2013).
Overlap-syndrome management
Patients with overlap syndromes are treated according to study protocols and experience with the underlying
rheumatic diseases and mainly based on the type of organ involvement. Owing to small patient numbers and
poor definition of overlap syndromes, randomized controlled trials have not been performed, and separate
guidelines for the treatment of overlap syndromes have not been established.
3 Mixed connective tissue disease
3.1 Introduction
Although the terminology might be misleading, MCTD (formerly, Sharp’s syndrome) is a distinct rheumatic
disorder. Sharp and colleagues first described the disease in 1972 as a connective tissue disease with features
of SLE, SSc and polymyositis. High titres of anti-U1-RNP autoantibodies further defined this disease (Sharp et
al, 1972*; Tani et al, 2014). Later, a high prevalence for the development of arthritis resembling the RA joint
pattern was seen in patients with MCTD (figure 5).
Figure 5 The concept of mixed connective tissue disease. MCTD, mixed connective tissue disease; PM,
polymyositis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SSc, systemic sclerosis.
The clinical features of MCTD often develop over several years and the complete clinical findings are rarely
present at the start of the disease. In early stages, patients often present with one of the following features:
Raynaud’s phenomenon, puffy fingers of the hands (figure 4), sclerodactyly, arthralgias, arthritis, myalgias,
myositis and malaise. These clinical features are the most frequently reported in the different cohorts during
the course of the disease, together with lung involvement and oesophageal symptoms (Tani et al, 2014).
©2007-2017 EULAR 11
Figure 6 Swollen fingers.
Mixed connective tissue disease is rare with a prevalence of 3.8 per 100 000 adults (as assessed in a
Norwegian population). There is a female predominance with a male to female ratio of about 1:3 (Gunnarsson
et al, 2011).
3.2 Mixed connective tissue disease: a distinct disease entity?
Since the initial description, several authors challenged the concept of MCTD as a distinct clinical entity for the
following reasons (Smolen and Steiner, 1998*): First, most patients diagnosed as MCTD also satisfy the criteria
for another connective tissue disease, especially in later stages of the disease. Second, there are not any
commonly classification criteria for MCTD, although several criteria sets have been tested successfully. Third,
the initial description of MCTD as a benign connective tissue disease not involving major organ systems and
promptly responding to low-dose glucocorticoids has not been confirmed by other studies.
Several genetic, serological and clinical features, however, argue for MCTD as an distinct rheumatic disease
and against the concept of an early form of other connective tissue diseases such as SLE, SSc, PM or RA: MCTD
is associated with HLA-DR1, HLA-DR4 and to a lesser degree with HLA-DR2 (Black et al, 1988; Kaneoka et al,
1992). In contrast, SLE is associated with HLA-DR2 and HLA-DR3, SSc with HLA-DR3 and HLA-DR5 and PM with
HLA-DR3. The linkage disequilibrium and the association with different HLA class II molecules argues for MCTD
being distinct from SLE, SSc and PM. Similar to MCTD, RA is associated with HLA-DR1 and HLA-DR4. Apart from
erosive arthritis, however, RA barely shares clinical features with MCTD and usually does not show
autoantibodies against U1-snRNP.
Serological features also support the concept of MCTD as a distinct disease entity. Although 20–30% patients
with SLE might also express anti-U1-snRNP antibodies, per definition a sine qua non for the diagnosis of MCTD,
©2007-2017 EULAR 12
high titres of these antibodies are specific for patients with MCTD (Habets et al, 1985). Furthermore, SLE
patients with anti-U1-snRNP antibodies often retain IgM-U1-snRNP, instead of showing a class switch to IgG
antibodies as found in MCTD (Vlachoyiannopoulos et al, 1996). Finally, anti-U1-RNP antibodies in patients with
SLE seem to differ from those in patients with MCTD by their antigen recognition (Barakat et al, 1991). Thus,
high titres of IgG-autoantibodies against U1-snRNP seem to be specific for MCTD.
In addition to genetic and serological differences, certain clinical manifestations are also unique for patients
with high titres of anti-U1-snRNP antibodies. Patients with high titres of antibodies against U1-snRNP rarely
develop severe CNS (eg, psychosis, seizures or diffuse) or renal manifestations (eg, diffuse proliferative
glomerulonephritis). By contrast, they develop RF-positive, erosive arthritis more frequently. Furthermore,
they are more likely to develop pulmonary arterial hypertension than patients with other connective tissue
diseases except for SSc. Thus, we agree with many other experts that MCTD is a distinct clinical entity based
upon genetic, serologic and clinical features (table 1).
Table 1 Mixed connective tissue disease (MCTD) as a distinct disease entity?
MCTD as a distinct disease entity?

Pro Contra
• Association with certain HLA types • Patients might satisfy the classification criteria of
• High titres of anti-U1-RNP IgG other connective tissue diseases in later stages of
autoantibodies with unique antigen the disease
recognition • Not one commonly accepted set of criteria
• Specific set of clinical manifestations
3.3 Anti-U1-RNP antibodies
MCTD was initially described as a connective disease with high titres of autoantibodies directed against a
complex named ‘ribonuclease-sensitive extractable nuclear antigen’. Further studies showed that the U1-RNP
particle is a major component of the spliceosome, which is a nuclear particle processing pre-messenger RNA
(mRNA) splicing into mRNA (Routsias et al, 2010). Different parts of the spliceosome represent targets of
autoimmunity in several connective tissue diseases. The immunogenic potential of spliceosomal components
may be increased by post-translational modifications during apoptosis (Mamula et al, 1999).
The small nuclear ribonucleoprotein particles (snRNPs) and the heterogeneous nuclear ribonucleoprotein
particles (hnRNPs), two spliceosomal subunits, are the major targets of autoimmunity. SnRNPs contain small
RNAs ranging from 80 to 350 nucleotides complexed with proteins. U1-RNPs are a subset of snRNPs with high
amounts of uridine nucleotides (called U1-RNA). The U1-RNA molecules form double-stranded secondary
structures, which make up the backbone of the U1-RNP complex. The protein components of the U1-RNP
complex can be further classified into proteins specific for the U1-RNP complex and non-specific proteins.
©2007-2017 EULAR 13
Specific proteins are U1-A, U1-C and U1 68 kDa proteins. Non-specific proteins include the Smith proteins (Sm
proteins) and the SR proteins, a group of splicing factors rich in serine (S) and arginine (R). Autoantibodies
against U1-RNP and other snRNPs mainly recognise the protein components of the complex. Sm proteins are
common targets of autoimmunity in SLE, whereas patients with MCTD usually have high antibody titres for the
U1 68 kDa protein (Fenning et al, 1995).
hnRNPs contain pre-mRNAs and a variety of structurally related proteins with molecular weights between 33
and 43 kDa. Anti-RA33 antibodies target 33 kDa hnRNP-A2 proteins of the hnRNP complex. Raised titres of
anti-hnRNP-A2 antibodies are present in about 30% of patients with RA, SLE and MCTD. The antigen
recognition pattern in MCTD, however, differs from that of RA and SLE (Smolen and Steiner, 1998*).
In an animal model of MCTD, mice expressing the HLA-DR4 molecule (HLA-DRA*0101/DRB1*0401) develop
anti-U1-RNP antibodies after a single exposure to the 70 kDa polypeptide/U1-RNA autoantigen. Clinically,
these mice develop pulmonary inflammatory infiltrates characteristic of MCTD. They do not develop anti-Sm
or anti-DNA antibodies, which distinguishes the model from SLE (Greidinger et al, 2008).
Molecular mimicry may lead to the development of anti-U1-RNP antibodies. This hypothesis suggests the
presence of antigens (eg, infectious agents) that closely resemble the U1-RNPs and cause the production of
cross-reactive antibodies. While the exogenous antigen might be cleared over time, the immune reaction
against the endogenous U1-RNP structures might persist. Although some evidence for the role of molecular
mimicry in connective tissue disease exists, including associations of Epstein–Barr virus with anti-Sm
antibodies, and cytomegalovirus with anti-U1 68 kDa antibodies (McClain et al, 2003; Newkirk et al, 2001), it
still needs further scientific proof.
Apart from anti-U1-RNP antibodies, a variety of other antibody specificities, may be present in patients with
MCTD; in a recent study, Anti-Ro52 antibodies were present in 29%, anti-Ro60 in 19% and anti-SSB in 6% of
the MCTD sera. Interestingly, anti-Ro52 antibodies were significantly associated with lung fibrosis
(Gunnarssonn R, 2016).
Antigen spreading to molecules in close proximity to the original antigen (ie, the U1-RNP complex) may play a
role. Nevertheless, several antigens do not show structural homologies or colocalize with the U1-RNP complex.
In these cases, defective clearance of apoptotic material with a high immunogenic potential, might lead to the
formation of antibodies against other antigens (Rosen and Casciola-Rosen, 2001). Ro/SSA antigens, for
example, occur in high concentrations on apoptotic blebs. Incomplete B or T cell tolerance to apoptotically
modified antigens might also be of importance (Casciola-Rosen et al, 1999).
Although anti-U1-RNP antibodies are a sine qua non for the diagnosis of MCTD, their role in the pathogenesis
of MCTD is unclear. In this context, recent data from an animal model suggest that anti-U1-RNP antibodies can
©2007-2017 EULAR 14
mediate tissue injury (Provost et al, 1987; Mason et al, 2004). Mice immunized with apoptotically modified U1
68 kDa proteins developed a MCTD-like interstitial lung disease, whereas mice immunized with control
antigens did not. This animal model is of interest because a diversifying autoimmune response is seen in
response to immunization with apoptotically modified U1 68 kDa proteins. In addition to antibodies against
the exogenous U1 68 kDa protein complex, these animals also show antibody formation against epitopes on
endogenous U1 68 kDa proteins and non-U1-RNP proteins. This mimics, at least in part, the situation in human
MCTD.
3.4 Sequential clinical and laboratory features of patients with anti-U1-RNP antibodies
MCTD evolves over time and patients typically develop new clinical and laboratory features in the course of
the disease. Thus, patients might display few features of the disease and may not fulfil the classification
criteria for MCTD at their initial presentation. Furthermore, patients with antibodies against U1-RNP might
meet the classification criteria for rheumatic diseases other than MCTD (Reichlin, 1976*; Habets et al, 1985).
In the first prospective study on patients with anti-U1-RNP antibodies, 60% of patients presented with
symptoms compatible with a specific connective tissue disease other than MCTD. After a mean follow-up of 6
years, however, 90% fulfilled the criteria for MCTD (Sullivan et al, 1984*).
At the start of another study of 32 patients with high- and low-titer anti-U1-RNP antibodies, only three
patients fulfilled the classification criteria for MCTD and 11 patients for other connective tissue diseases. The
remaining 18 patients were classified as having UCTD. After a mean observation period of 6 years, 15 of the 18
patients (83%) initially diagnosed with UCTD met the classification criteria for specific connective tissue
diseases: 11 for MCTD, two for SLE and two for both MCTD and SLE (Lundberg et al, 1991b).
Diagnosis of other rheumatic diseases (in particular, UCTD) may evolve into a diagnosis of MCTD over time.
The initial diagnosis of MCTD may also change into the diagnosis of another rheumatic disease. In a study on
46 patients positive for anti-U1-RNP antibodies, 33 were classified with MCTD, 10 were diagnosed with SLE,
two with RA and one with SSc (Van den Hoogen et al, 1994). After 5 years, 55% of the patients initially
diagnosed with MCTD fulfilled the classification criteria for another connective tissue disease. Twenty-one per
cent developed SSc, 15% SLE, 9% RA and 9% an overlap syndrome. Of the 10 patients in this study, who
fulfilled the criteria for SLE at the initial presentation, four developed clinical SSc features. In a recent
retrospective study, 161 patients had initially been diagnosed as having MCTD by three different sets of
classification criteria (Sharp, Alarcon-Segovia and Kasukawa (discussed in detail in the next section)). After a
mean follow-up of 7.9 years, 57.9% of patients still had the diagnosis of MCTD. By then, the other patients
carried a diagnosis of SSc (17.3%), SLE (9.1%), RA (2.5%), UCTD (11.5%) and overlap syndrome (1.7%).
Interestingly, the presence of autoantibodies and specific clinical features helped to predict the evolution into
©2007-2017 EULAR 15
another rheumatic disease: the presence of anti-dsDNA antibodies was associated with evolution into SLE,
hypomotility or dilatation of the oesophagus and sclerodactyly with evolution into SSc (Cappelli et al, 2011).
3.5 Proposed classification criteria for MCTD
For MCTD, there is not one widely accepted set of classification criteria. Four different sets of classification
criteria for MCTD are available—namely, the criteria of Sharp, Alarcon-Segovia, Kahn and Kasukawa (Alarcon-
Segovia and Villareal, 1987; Kasukawa et al, 1987; Sharp, 1987; Kahn, 1991). Since none of those criteria is
convincingly better than the others, all four sets of criteria may be used.
Sharp’s criteria consist of five major and 11 minor criteria to distinguish between definite MCTD and probable
MCTD (table 2). In contrast to the three other sets of criteria, Sharp’s criteria do not demand the presence of
high titres of U1-RNP antibodies for the diagnosis of MCTD. According to Sharp, a patient can have probable
MCTD in the absence of anti-U1-RNP antibodies. Nevertheless, for the diagnosis of definite MCTD, anti-U1-
RNP antibodies are necessary.
Table 2 Sharp’s criteria for mixed connective tissue disease
Major criteria Minor criteria

1. Severe myositis 1. Alopecia
2. Lung involvement with a TLCO <70% 2. Leucopenia
and/or PAH and/or proliferative vascular 3. Anaemia
lesions on biopsy 4. Pleuritis
3. Raynaud’s phenomenon and/or 5. Pericarditis
oesophageal hypomobility 6. Arthritis
4. Swollen hands and/or sclerodactyly 7. Trigeminal neuralgia
5. anti-ENA ≥1:10 000, positive for anti-U1- 8. Malar rash
RNP antibodies and negative for anti-Sm 9. Thrombocytopenia
antibodies 10. Mild myositis
11. History of swollen hands
• Definite MCTD: four major criteria, no anti-Sm antibodies, anti-U1-RNP antibodies >1:4000
• Probable MCTD: three major criteria and no anti-Sm antibodies or two major criteria plus
one minor criterion plus anti-U1-RNP antibodies >1:1000
ENA, extractable nuclear antigen; PAH, pulmonary arterial hypertension; RNP, ribonucleoprotein; TLCO, carbon
monoxide tranfer factor.
©2007-2017 EULAR 16
Table 3 Alarcon–Segovia’s criteria for mixed connective tissue disease
Clinical criteria Serological criterion

1. Swollen hands Anti-RNP antibodies with a titre of
2. Acrosclerosis with or without proximal SSc >1:1600 at the haemagglutinin assay
3. Raynaud’s phenomenon
4. Myositis: biologically or histologically proved
5. Synovitis
Diagnosis of MCTD, if the serological criterion is present and three or more clinical criteria (if 1, 2
and 3 are present, 4 and 5 are also required to distinguish MCTD from SSc)
MCTD, mixed connective tissue disease; RNP, ribonucleoprotein; SSc, systemic sclerosis.
Kahn’s criteria (table 4) are similar to those of Alarcon-Segovia. Besides the presence of high titres of anti-RNP
antibodies, four clinical criteria are included.
Table 4 Kahn’s criteria for mixed connective tissue disease
Clinical criteria Serological criterion

1. Raynaud’s phenomenon High titres of anti-RNP antibodies,
2. Swollen fingers corresponding to a speckled ANA titre
3. Myositis of ≥1:2000
4. Synovitis
Diagnosis of MCTD, if the serological criterion is present plus Raynaud’s phenomenon plus two or all
of the other three clinical criteria
ANA, antinuclear antibodies; MCTD, mixed connective tissue disease; RNP, ribonucleoprotein.
Kasukawa’s criteria (table 5) include anti-snRNP antibodies, as well as common clinical symptoms and features
of the defined connective tissue diseases SLE, SSc and PM.
Table 5 Kasukawa’s criteria for mixed connective tissue disease

Common symptoms Symptoms of SLE, SSc and PM Serological
criterion
1. Raynaud’s SLE: anti-snRNP
phenomenon 1. polyarthritis antibodies
2. Swollen fingers 2. adenopathies
3. malar rash
4. serositis
5. leucopenia and/or thrombocytopenia
SSc:
1.sclerodactyly
2.pulmonary fibrosis and/or restrictive changes and/or
reduced TLCO
3. oesophageal hypomobility or dilatation
PM:
1. muscle weakness
2. raised muscle enzymes
3. myogenic changes in EMG
Diagnosis of MCTD, if one or two common symptoms plus one or more symptom of the mentioned signs of
two or three of the defined connective tissue diseases SLE, SSc and PM plus the serological criterion
EMG, electromyogram; MCTD, mixed connective tissue disease; PM, polymyositis; RNP, ribonucleoprotein; SLE,
systemic lupus erythematosus; SSc, systemic sclerosis; TLCO, carbon monoxide transfer factor.
©2007-2017 EULAR 17
Sharp’s, Alarcon-Segovia’s and Kasukawa’s criteria have been tested for their specificity by applying them to
patients with other rheumatic diseases, including SLE, RA, SSc, DM/PM and Sjögren’s syndrome (Alarcon-
Segovia and Cardiel, 1989). These studies were limited by the lack of a commonly accepted, typical clinical
presentation of patients with MCTD to test the criteria. Alarcon-Segovia’s and Kasukawa’s criteria both had a
very high specificity for patients with MCTD. Only one of 200 patients with SLE was diagnosed as having MCTD
according to Alarcon-Segovia’s criteria and none according to Kasukawa’s criteria. According to these two sets
of criteria, none of the patients with RA, SSc and DM/PM was diagnosed with MCTD. Finally, one of 80 patients
with Sjögren’s syndrome was positive for MCTD according to the Alarcon-Segovia and Kasukawa criteria.
The specificity of Sharp’s criteria, however, was significantly lower and several patients were falsely identified
as having probable MCTD. Sharp’s criteria distinguished patients with RA and Sjögren’s syndrome well (100%
and 96%, respectively), but was less accurate for patients with SLE, DM/PM and, in particular, SSc (88%, 84%
and 55%, respectively). Of 80 patients with high anti-RNP antibody titres with the genuine diagnosis of MCTD,
Sharp’s criteria and Alarcon-Segovia’s criteria had a sensitivity of 100%. Using Kasukawa’s criteria, two of the
80 patients were not identified (Alarcon-Segovia and Cardiel, 1989).
In another comparative study of the four classification criteria evaluating 45 patients with anti-U1-RNP
antibodies, the criteria by Alarcon-Segovia and Kahn performed best (Amigues et al, 1996). Twenty-five of the
45 patients included in the study had other rheumatological diseases such as SLE, RA, SSc or overlap
syndromes. Sixty-four per cent of the patients with anti-U1-RNP antibodies fulfilled Sharp’s criteria, 42% those
of Kasukawa and 14% each those of Alarcon-Segovia and Kahn. Of the 25 patients with other rheumatic
diseases, 56% also fulfilled Sharp’s criteria, 40% Kasukawa’s and 14% each Alarcon-Segovia’s and Kahn’
criteria.
Except for Sharp’s criteria, the diagnosis of MCTD depends on high titres of anti-U1-RNP antibodies. Thus, the
method of detection and the cut-off point between high and low titres should be well defined. Several
methods are used to measure the titres of U1-RNP antibodies but a defined cut-off value is lacking (Venables,
2006). In early studies, the haemagglutinin assay was the standard test. Other assays used are
immunodiffusion, immunoblotting and immunoprecipitation. Nowadays, enzyme-linked immunosorbent
assays with cloned antigens as standards are widely used.
3.6 Clinical manifestations of MCTD
The first clinical symptoms of MCTD are usually non-specific. At this stage of the disease, patients often have
malaise, myalgias, arthralgias, Raynaud’s phenomenon and low-grade fever. In later stages of the disease, a
set of five cardinal signs should lead to the suspicion of MCTD:
©2007-2017 EULAR 18
• the presence of high titres of anti-U1-RNP autoantibodies—in particular, IgG antibodies that
recognise the 68 kDa protein of the U1-RNP complex;
• the lack of severe kidney and central nervous system (CNS) involvement;
• severe arthritis and the presence of RF;
• pulmonary arterial hypertension;
• Raynaud’s phenomenon in association with puffy hands.
Apart from these classic manifestations, almost any other organ system may be affected (Sharp et al, 1972*;
Bennett and O’Connell, 1980; Alarcon-Segovia, 1994), including the vascular system, skin, gastrointestinal
tract, musculoskeletal system, lungs, heart, haematological system, kidneys and CNS. Table 6 compares the
clinical features of patients with UCTD and MCTD at presentation and after 5 years of follow-up.
3.6.1 Musculoskeletal manifestations of MCTD
In MCTD, joint involvement may vary from mild arthralgias to severe arthritis in small or large joints that
sometimes may lead to erosions typical of RA and to mutilating arthritis (Ortega-Hernandez and Shoenfeld,
2012). As described above, the joint involvement in MCTD tends to be more severe than in SLE and SSc.
Inflammatory arthritis is a frequent presenting symptom of MCTD and occurs in 60–100% of patients. Most
commonly, joint involvement is present in a RA-like pattern with symmetrical, polyarticular involvement of the
small joints of the hands and feet. As with RA, mono- or oligoarticular presentations can also occur (Piirainen,
1990). The arthritis in patients with MCTD is erosive in 30–70% of cases as shown by X-ray examination. In
patients with MCTD, RF is a risk factor for erosive joint disease (O’Connel et al, 1977; Udoff et al, 1977;
Bennett and O’Connell, 1980). Periarticular osteopenia, subchondral cysts and subluxations are also common.
In addition, swan neck deformities and boutonniere changes are seen in up to 30% of affected patients.
Another very common feature, which might occur in up to 60% of patients, is resorption of the digital tuft.
Arthritis mutilans can occur in rare cases. Non-erosive Jaccoud's arthropathy and atlantoaxial subluxation may
be present in single cases (Alarcon-Segovia and Uribe-Uribe, 1979; Bennett and O’Connell, 1980; Catoggio et
al, 1983; Piette et al, 1988). Nevertheless, despite the close resemblance to joint disease in RA, the course of
MCTD-associated arthritis is more benign than in erosive RA, with erosions being small and scattered even
after several years of active arthritis.
Between 80% and 90% of patients with MCTD develop muscle involvement, with proximal muscles being more
frequently involved (Ortega-Hernandez and Shoenfeld, 2012). The prevalence of myositis in MCTD varies from
15% to 75% in different studies. This considerable variation might be explained by differences in the diagnostic
methods. Myositis is often present early in the course of the disease. The clinical presentation is identical to
that of other inflammatory myopathies. Most patients show weakness of the proximal muscles of the
©2007-2017 EULAR 19
shoulders and pelvic girdle and little if any wasting. Focal myopathies, however, have been reported in single
cases. Diaphragmatic dysfunction and dysphagia due to myositis can occur, but are rare.
Table 6 Comparison of the clinical features of mixed connective tissue disease and undifferentiated
connective tissue disease. Modified from Swanton and Isenberg (2005)
MCTD (Burdt et al, 1999) UCTD (Danieli et al, 1999;

Bodolay et al, 2003)
At the time of Cumulative At the time of 5 Years after
diagnosis (%) findings diagnosis (%) the diagnosis
after 5 years (%) (%)
Raynaud's disease 89 96 50–60 89
Arthralgias/arthritis 85 96 35–50 89
Puffy hands 60 66
Oesophageal 47* 66* 5† 7†
dysfunction
Reduced TLCO 43* 66* 7† 8†
Serositis 34 43 5–10 5–15
Haematological 30 53 20–30 20–40
abnormalities
Skin rash 30 53 25–50 30–55
Myositis 28 51 0–1 0–1
PAH 9 23 † †
Skin fibrosis 4 19 5 5
Neurological 0 17 5–10 5–15
manifestations
Renal manifestations 2 11 0 0
Sicca symptoms Up to 30 in other series 10–25 15–25
*Functional test performed on all patients, including asymptomatic patients.
†No functional tests performed in asymptomatic patients.
MCTD, mixed connective tissue disease; PAH, pulmonary arterial hypertension; TLCO, carbon monoxide tranfer
factor; UCTD, undifferentiated connective tissue disease.
On histological examination, patients with MCTD-associated myositis show histological findings similar to
those of patients with PM or SLE (Ortega-Hernandez and Shoenfeld, 2012), or perivascular and endomysial
lymphocytic infiltrates, similar to the histological findings in DM (Cooke and Lurie, 1977; Bennett and
O’Connell, 1980). Myositis in patients with MCTD commonly manifests as acute flares and can be associated
with high-grade fever. Less often, myositis presents as a smouldering process. Several case studies report
myasthenia gravis in patients with MCTD, suggesting that there might be some association between these two
diseases (Yasuda et al, 1993).
©2007-2017 EULAR 20
3.6.2 Vascular manifestations of MCTD
The majority of patients with MCTD display vascular changes (Grader-Beck and Wigley, 2005). About 75–90%
of patients have Raynaud’s phenomenon, which may precede the appearance of other clinical manifestations
by years (Sharp et al, 1972*; Ortega-Hernandez and Shoenfeld, 2012). In addition, microvascular changes,
similar to those seen in patients with SSc occur. Typical SSc-like findings of MCTD on nailfold capillaroscopy,
such as avascular fields, micro-haemorrhages, bushy capillaries and giant capillaries with a general reduction
of the capillary density and reduced blood flow, are present in 54% of patients with MCTD (Blockmans et al,
1993). Furthermore, Hejas et al observed a capillaroscopic ‘scleroderma pattern’ in 31.4% of patients at the
time of diagnosis and in 40.3% after a mean of 13.1 years of follow-up, with significant progression of
microvascular alterations (Hejas et al, 2013). In addition to changes of the capillaries, small and medium-sized
arteries often show signs of occlusion on arteriographic studies. These occlusions, however, are asymptomatic
in most cases. Interestingly, an imbalance of angiogenic and angiostatic factors reflects the capillaroscopic
alterations in both MCTD and SSc, although there appear to be differences in the expression profiles of these
two diseases. In MCTD, levels of vascular endothelial growth factor (VEGF) were higher in patients with PAH,
acrosclerosis and myositis, suggesting that VEGF levels might help to predict the development of these disease
manifestations (Distler et al, 2011).
A severe vascular manifestation of MCTD is PAH. Patients with PAH show a pulmonary artery pressure of >25
mm Hg at rest and pulmonary capillary wedge pressure <15 mm Hg, as tested by right-heart catheterisation
(Simonneau et al, 2009). PAH is seen in 20–30% of patients with MCTD (Burdt et al, 1999) and the presence of
anticardiolipin antibodies is associated with its development. In addition, a higher prevalence of anti-
endothelial cell antibodies was found in patients with MCTD plus PAH than in those patients with MCTD but no
PAH (Vegh et al, 2006). In a recent follow-up study of patients with MCTD, PAH developed in 17.8% of patients
at a mean of 14.5 ± 3.71 years after diagnosis. All these patients showed a continuously high level of anti-RNP
and 84% of them were positive for anti-endothelial cell antibodies (Hejas et al, 2013).
In contrast to other forms of pulmonary hypertension, which might occur in patients with MCTD, PAH is
characterised by hypertrophy of the intima and proliferation of smooth muscle cells in small pulmonary
arteries and arterioles, leading to a reduction of the vascular lumen. Since PAH is the major cause of death in
MCTD, regular evaluation for PAH is essential. Patients with PAH usually present with a history of progressive
dyspnoea on exertion. Many other clinical symptoms and signs are suggestive of PAH but are not always
present.
Physical examination may disclose an accentuated second pulmonary heart sound and might also show a
systolic pulsation at the left sternal border. Chest X-ray examination may demonstrate a dilatation of the
pulmonary arteries and right atrial enlargement and ventricular hypertrophy. Similarly, signs of right atrial and
©2007-2017 EULAR 21
ventricular hypertrophy may be seen on electrocardiography. The sensitivity and specificity of chest X-ray
examination and electrocardiography, however, are relatively poor; the PAH-related findings often occur late,
after haemodynamic changes are already established.
Screening tests for patients at risk, however, need to detect PAH at earlier stages. Transthoracic
echocardiography is becoming the first choice for PAH screening. Despite the need for a highly experienced
sonographer, echocardiography is a non-invasive, cheap and feasible screening test. Transthoracic
echocardiography may be inaccurate in patients with borderline or slightly raised pulmonary pressure,
resulting in both false-negative and false-positive results. Serum biomarkers, such as pro-brain-type natriuretic
peptide (pro-BNP), may help to increase sensitivity of echocardiographic PAH screening (Allanore et al, 2003).
A Delphi consensus study has detected the tests that may lead to a suspicion of PAH in patients with SSc.
Additionally, N-terminal pro-BNP and echocardiography, and also pulmonary function tests, may provide
additional information, as a decrease of the carbon monoxide transfer factor (TLCO) of <50% in the absence of
pulmonary fibrosis may suggest that right heart catheterisation should be carried out. There is general
consensus that a suspicion of PAH needs verification by right heart catheterisation, which is the diagnostic
‘gold standard’ (Avouac et al, 2014).
In the study of Khanna et al, new recommendations for screening and detection of PAH associated with
connective tissue disease, in particular SSc and connective tissue diseases with scleroderma features, have
been published. According to these recommendations, patients should be evaluated with pulmonary function
tests (including TLCO), transthoracic echocardiography and N-terminal pro-BNP initially and at least once a
year thereafter. If patients have new signs or symptoms, complete screening needs to be repeated (Khanna et
al, 2013).
3.6.3 Pulmonary manifestations of MCTD
A significant number of patients with MCTD have a pulmonary involvement. However, in most patients with
MCTD, pulmonary changes are mild and many patients are asymptomatic (Bodolay et al, 2005). PAH, a severe
complication of the disease, is the major cause of death in patients with MCTD. Apart from PAH, pleural
effusions and interstitial lung disease (non-specific interstitial pneumonia or usual interstitial pneumonia
pattern) are also common in MCTD. The prevalence of interstitial lung disease may be as high as 67% based on
high-resolution computed tomography (HRCT) and DTPA scans (Black and Isenberg, 1992). Applying strict
HRCT-based diagnostic criteria, 35 of the patients in the Norwegian nationwide MCTD cohort showed reticular
patterns consistent with lung fibrosis. Lung fibrosis was quantified as minor in seven, moderate in nine and
severe in 19 of all patients. Mortality was significantly increased in patients with severe lung fibrosis compared
with patients with normal HRCT findings (20.8 vs 3.3 during a 4.2 years’ follow-up) (Gunnarsson et al, 2012).
©2007-2017 EULAR 22
Reductions of the transfer factor for carbon monoxide are the most common abnormality in lung function
tests (Black and Isenberg, 1992). Most patients with this abnormal finding, however, are asymptomatic and
only a minority have exertional dyspnoea. Pleural disease is found in up to 40% of patients with MCTD. It can
manifest as pleural effusion and pleural thickening. As with interstitial lung disease, pleural involvement is
often asymptomatic. Rare pulmonary manifestations of MCTD are diaphragmatic dysfunction, alveolar
haemorrhage, pulmonary vasculitis and thromboembolic disease. Table 7 summarizes the pulmonary
manifestations of MCTD.
Table 7 Overview of the pulmonary manifestations of mixed connective tissue disease
Common manifestations Rare manifestations

Interstitial lung disease Diaphragmatic dysfunction
Pleural effusion Alveolar haemorrhage
Pulmonary arterial hypertension Pulmonary vasculitis
Thromboembolic disease
Aspiration pneumonia
3.6.4 Mucocutaneous manifestations of MCTD
Patients with cutaneous involvement often present with typical SSc- or SLE-like skin manifestations (Sharp et
al, 1972*; Baurle and Hornstein, 1979; Magro et al, 1997; Sen et al, 2014). Swollen digits or oedema of the
entire hands, also known as puffy hands, are a common feature of MCTD and are often the presenting signs of
the disease. These findings can also occur during the early course of SSc. Other common features of both
diseases are sclerodactyly and calcinosis cutis. In contrast, truncal skin fibrosis does not usually occur in MCTD.
Patients might also develop digital ulcers and gangrene due to severe Raynaud’s phenomenon or
telangiectasias. SLE-like manifestations of MCTD include discoid plaques, subacute lupoid skin changes,
photosensitivity and malar rashes, which can be indistinguishable from SLE. A recent study, evaluating
cutaneous manifestations in 23 patients who fulfilled the Alarcon-Segovia and Villareal criteria, showed that
five patients presented malar rash (21.7%) and two patients had discoid lupus erythematosus. Acrosclerosis
and hand oedema were identified as the commonest cutaneous features (in 17 and nine patients, respectively)
(Sen et al, 2014). Besides SSc- and SLE-like features, livedo reticularis, livedo vasculitis and cutaneous
leucocytoclastic vasculitis have been described. Manifestations of MCTD at the mucosal membranes, which
occur in a small percentage of patients, are oral and genital ulcerations and nasal septum perforation.
MCTD often overlaps with, or may reflect, features of Sjögren’s syndrome. Forty per cent to 95% of patients
with MCTD have sicca symptoms, including dry eyes, dry mouth and salivary or lachrymal gland inflammation.
Many of these patients are positive for anti-Ro/SSA and some also for anti-La/SSB (Alarcon-Segovia 1976;
Helenius et al, 2001; Setty et al, 2002).
©2007-2017 EULAR 23
3.6.5 Gastrointestinal manifestations of MCTD
Oesophageal hypomotility is found in 45–85% of patients with MCTD and initially it is often subclinical. As for
SSc, oesophageal manometry and barium swallow can demonstrate a reduction of the peristalsis, particularly
in the lower third, and a decline of the lower sphincter pressure. Consequently, patients have gastro-
oesophageal reflux and might have swallowing problems in later stages. Nevertheless, oesophageal
manifestations may be less severe in MCTD than in SSc. One study compared the lower oesophageal sphincter
pressure in patients with MCTD and SSc. The prevalence of oesophageal involvement was similar in SSc and
MCTD, but the lower oesophageal sphincter pressure in patients with MCTD was higher than in patients with
SSc (Doria et al, 1991).
Besides the oesophagus, disturbed peristalsis might also occur in other parts of the gastrointestinal tract.
Delayed gastric emptying was noted in 6% of patients and up to 75% of patients in one study had abnormal
findings in a small bowel series, including slow transit and dilatation. Malabsorption might occur owing to
bacterial overgrowth and small bowel dilatation. Pseudo-diverticula and colonic perforation are also found
with increased frequency in patients with MCTD. Rare gastrointestinal manifestations that can be associated
with MCTD are serositis, protein losing enteropathy, mesenteric vasculitis, Budd–Chiari syndrome,
autoimmune hepatitis, primary biliary cirrhosis and pancreatitis (Marshall et al, 1990; Weston et al, 1998).
3.6.6 Cardiac manifestations of MCTD
Cardiac disease may occur in 20–30% of patients (Dutschmann et al, 1989; Smolen and Steiner, 1998*).
Pericarditis is the most common manifestation, but is often mild (Lundberg et al, 2005). A recent review
including 616 patients showed that the prevalence of cardiac involvement varies from 13% to 65% according
to patient selection and method used for its detection. However, it highlighted that pericarditis was the most
common cardiac diagnosis, with a prevalence ranging from 30% to 43% in two prospective studies (Patampong
et al, 2014). In MCTD mitral valve prolapse (in up to 25%) and conduction defects may also occur. In rare cases
potentially lethal myocarditis may occur. Other abnormalities such as right atrial enlargement or right
ventricular hypertrophy are secondary due to PAH. Finally, patients with MCTD may have a higher risk for
cardiovascular events, sometimes due to accelerated atherosclerosis—similar to patients with other chronic
inflammatory diseases (eg, RA). Cardiovascular risk factors, including dyslipidaemia, low vitamin D levels and
endothelial stiffness, may occur in patients with MCTD and require aggressive treatment to reduce the long-
term risk for cardiovascular events (Bodolay et al, 2008; Hajas et al, 2010; Soltesz et al, 2010).
3.6.7 Renal manifestations of MCTD
Renal involvement is one of the most common complication in MCTD (Ortega-Hernandez and Shoenfeld,
2012), occurring in 11–40% of patients (Kobayashi et al, 1985; Kitridou et al, 1986). In contrast to SLE, severe
©2007-2017 EULAR 24
renal disease is very rare in MCTD, and the presence of anti-RNP antibodies may be protective against the
development of an important renal manifestation with a diffuse proliferative glomerulonephritis (Lemmer et
al, 1982). This is true for patients with MCTD and also for patients with SLE carrying anti-U1-RNP antibodies.
Nevertheless, few cases of patients with MCTD and renal crisis, a potentially life-threatening complication with
abrupt onset of severe hypertension and renal dysfunction, have been reported. In these patients, similar
histopathological findings to those of scleroderma renal crisis have been reported (Satoh et al, 1994).
Other rare renal manifestations of MCTD are renal amyloidosis and renal infarcts in patients with
anticardiolipin-positive MCTD. Finally, membranous nephropathy may occur. Usually, membranous
nephropathy is mild in patients with MCTD, but might also be associated with significant proteinuria.
3.6.8 Neuropsychiatric manifestations of MCTD
Like renal disease, severe CNS manifestations are usually absent in MCTD, although there are a few case
reports of CNS haemorrhage, myelitis, retinal vasculitis and progressive multifocal leucoencephalopathy in
patients diagnosed with MCTD. Although severe manifestations are unusual, mild CNS involvement occurs in
25% of patients. As in patients with SSc, neuropathy of the trigeminal nerve is a common problem in MCTD.
Headaches are an unspecific symptom. Vascular headaches are another frequent problem. Aseptic meningitis
is a rare problem, but may be more common in MCTD than in the general population. Of note, anti-U1-RNP
antibodies in the cerebrospinal fluid are associated with central neuropsychiatric manifestations, including
aseptic meningitis, demyelinating syndromes, cognitive dysfunction, seizures and psychosis in patients with
SLE and MCTD (Sato et al, 2010).
3.6.9 Haematological manifestations of MCTD
Anaemia and lymphopenia are commonly seen in patients with MCTD (Segond et al, 1978; Poullin et al, 1999).
Low-grade anaemia, normally due to chronic disease, is observed in up to 75% of patients. In rare cases,
patients present with Coombs positive haemolytic anaemia. Leukopenia and lymphopenia tend to correlate
with disease activity. Autoimmune-mediated thrombocytopenia can become severe and manifest as
thrombocytopenic purpura. Thrombocytopenia may be associated with the presence of antiphospholipid
antibodies.
3.6.10 Laboratory abnormalities associated with MCTD
All patients diagnosed with MCTD have by definition high titres of ANAs with specificity against U1-RNP. Anti-
IgG-U1-RNP autoantibodies against the 68 kDa protein of the U1-RNP complex of the spliceosome are
particularly specific for MCTD. By immunofluorescence, anti-U1-RNP antibodies produce a speckled ANA
pattern, very similar to that of anti-Sm and anti La/SSB autoantibodies.
©2007-2017 EULAR 25
The titres of U1-RNP autoantibodies tend to correlate with disease activity. A significant reduction of the anti-
U1-RNP antibody titres was seen in patients in remission, whereas persistently raised titres were measured in
patients with chronically active disease (Burdt et al, 1999).
Fifty per cent to 70% are also positive for RF. Antibodies directed to single-stranded DNA occur in 80% of
patients, but anti-dsDNA-antibodies are rare. Antiphospholipid antibodies occur in about 15% of patients with
MCTD compared with almost 40% of patients with SLE (Komatireddy et al, 1997). Unlike in SLE, most
anticardiolipin antibodies in MCTD are β2-glycoprotein independent (Mendonca et al, 1998). Antiphospholipid
antibodies tend to correlate with thrombocytopenia, but not with thrombosis or abortion.
Other autoantibodies often detected in patients with MCTD are anti-hnRNP-A2, anti-fibrillin-1 and
antinucleosome antibodies. A false-positive Venereal Disease Research Laboratory test is seen in about 10% of
patients. Besides the presence of autoantibodies, hypergammaglobulinaemia is a common feature of MCTD.
Furthermore, hypocomplementaemia or cryoglobulins might be found, but they seem not to be associated
with renal disease or involvement of other organs in patients with MCTD (Smolen and Steiner, 1998*).
3.6.11 Clustering of clinical and laboratory features in MCTD
To identify specific subtypes of patients with MCTD, Szodoray and colleagues applied statistical cluster analysis
to a group of 201 patients fulfilling the Alarcon-Segovia diagnostic criteria. The authors identified the three
following clusters: (1) 77 patients with increased likelihood of having PAH, Raynaud’s phenomenon and livedo
reticularis; (2) 79 patients prone to interstitial lung disease, myositis and oesophageal hypomotility; and (3) 45
patients with a high rate of anti-CCP positivity and erosive arthritis. Survival was worst in cluster (1) with PAH
being the major disease complication, resulting in the death of patients. Despite limitations in diagnosing
certain disease manifestations (eg, PAH), this study may provide a preliminary system for further classification
of the broad disease spectrum of MCTD (Szodoray et al, 2012).
3.7 MCTD and pregnancy
The data for the outcome of pregnancy in patients with MCTD are limited to a few retrospective studies and
some case reports (Bennett and O’Connell, 1980; Kaufman and Kitridou, 1982; Siamopoulou-Mavridou et al,
1988; Lundberg et al, 1991a; Kitridou, 2005; Hoshino et al, 2008). Prospective, controlled studies of foetal and
maternal morbidity and mortality in MCTD are lacking. Several conclusions can be drawn from the available
studies. First, there is no evidence that the fertility of patients with MCTD is impaired. Second, patients might
have a new onset of MCTD or the disease might flare up during pregnancy. Third, most reports suggest that
foetal outcome is favourable in patients with MCTD, like that in healthy individuals. One study, however,
showed a poor outcome and the rate of live births was reduced to 31% compared with 83% in controls. Finally,
©2007-2017 EULAR 26
neonatal lupus manifesting predominantly at the skin can occur in MCTD even in the absence of anti-Ro/SSA
and anti-La/SSB antibodies. Nevertheless, neonatal lupus seems to be very rare in MCTD.
To sum up, the reports available suggest a modest risk of maternal flares during pregnancy. The foetal
outcome remains controversial. Based on these findings and experiences in patients with SLE, the following
guidelines have been proposed:
• The pregnancy should be planned for times of controlled disease activity.

• Patients should be followed up closely by an obstetrician and a rheumatologist
• Anti-U1-RNP, anti-Ro/SSA, anti-La/SSB, anticardiolipin antibodies and lupus anticoagulant should
be determined at the onset of pregnancy, if not already known.
• Disease flares should be treated promptly with glucocorticoids.
3.8 Prognosis of MCTD
MCTD was initially described as a connective tissue disease with a good prognosis and an excellent response to
glucocorticoids (Sharp et al, 1972*). Indeed, the prevalence of severe renal and CNS manifestations, which are
a major cause of morbidity and mortality in SLE, is low (Lemmer et al, 1982; Burdt et al, 1999). Nevertheless,
the incidence of PAH, which shortens life significantly, is high in MCTD (Burdt et al, 1999). The excellent
response to glucocorticoids was challenged by the results of subsequent follow-up studies (Nimelstein et al,
1980; Sullivan et al, 1984*). In general, the prognosis of MCTD is better than that of SLE and diffuse SSc (Burdt
et al, 1999). In many patients, the disease follows a benign course and goes into remission. Other patients
show an aggressive disease course and may only have a partial response to immunosuppressive therapies.
Several studies, which included almost 200 patients at tertiary referral centres, showed a mortality rate of 16–
28% after 10–12 years (Nimelstein et al, 1980; Burdt et al, 1999). Comparison with mortality data from age-
and sex-matched controls is missing. Nevertheless, since MCTD mainly affects young women, the reported
mortality rate may indicate an increased risk of premature death in patients with MCTD. PAH remains the
leading cause of death in MCTD (Harmon and Leatherman, 1988; Burdt et al, 1999; Szodoray et al, 2012; Hajas
et al, 2013), followed by infections. Other causes of death are rare and include myocarditis and renal crisis
(Lash et al, 1986; Burdt et al, 1999). In children, deaths due to haemolytic uremic syndrome and
glomerulonephritis have been reported. Death due to cardiovascular disease seems to be less common than in
RA and SLE.
The morbidity in patients with MCTD can be high. Patients commonly have fatigue, arthralgias and arthritis,
myalgias and myositis, serositis or gastrointestinal problems. In rare cases, patients may be disabled owing to
deforming or mutilating arthritis. Secondary fibromyalgia with widespread musculoskeletal pain might also
develop.
©2007-2017 EULAR 27
Treatment-induced increase of morbidity and mortality is another concern in patients with MCTD, and is
mainly due to the prolonged use of glucocorticoids. The side effects of glucocorticoids include osteoporosis,
aseptic bone necrosis, steroid myopathy, hypertension, steroid diabetes, acne, Cushing syndrome,
gynecomastia and an increased risk of infections.
3.9 Treatment of MCTD
Unfortunately, no randomised controlled trials on the treatment of MCTD have been carried out. Thus, the
management of patients with MCTD relies on interpolation of treatment guidelines for equivalent
manifestations in SLE, SSc, RA and PM. In general, inflammatory manifestations such as arthritis, myositis, SLE-
like skin disease and autoimmune-mediated anaemia and thrombocytopenia respond to immunosuppressive
therapy. In contrast, other features such as Raynaud’s phenomenon, acrosclerosis and most gastrointestinal
manifestations are usually unresponsive to immunosuppression. Furthermore, treatment should be
individualised for each patient, depending on the specific organs affected and the severity of the disease.
3.9.1 Treatment of the musculoskeletal manifestations of MCTD
All patients with MCTD with arthritis should have a radiographic evaluation of the hands and feet to screen for
erosions. Arthralgias and mild non-erosive arthritis can be treated symptomatically with non-steroidal anti-
inflammatory drugs (NSAIDs).
NSAIDs, however, might increase the risk of aseptic meningitis in MCTD. In more severe cases of arthritis, or if
arthritis persists despite NSAID treatment, a trial of low-dose glucocorticoids and/or hydroxychloroquine
should be started. For refractory cases or erosive arthritis, methotrexate is the first choice. If methotrexate
fails to induce remission or if it is contraindicated, other DMARDs such as leflunomide may be used (Ortega-
Hernandez and Shoenfeld, 2012).
Experience with biological agents targeting tumour necrosis factor α (TNFα) is limited. Two case reports of the
use of TNFα antagonists for refractory, polyarticular arthritis in MCTD have been published. Both papers
reported beneficial effects on the joint symptoms. Both patients, however, developed a SLE-like syndrome
with fever, generalised arthralgias and myalgias, malaise and anaemia. In addition, anti-dsDNA antibodies
became detectable and transient hypocomplementaemia developed, which resolved after discontinuation of
the TNFα antagonists. Thus, TNFα antagonists cannot be recommended for treatment of arthritis in MCTD.
Myalgias in the absence of myositis can be treated with NSAIDs. Patients with diffuse musculoskeletal
complaints should be evaluated carefully for the presence of reactive depression or fibromyalgia. In the
absence of myositis, glucocorticoids should be avoided. Myositis in MCTD is often acute and can be
accompanied by high-grade fever and in this case, it may respond to treatment with glucocorticoid in doses of
0.5–1.0 mg/kg/day prednisolone equivalent (Nimelstein et al, 1980; Burdt et al, 1999). Azathioprine,
©2007-2017 EULAR 28
methotrexate or intravenous immunoglobulins are further options for escalating treatment in severe cases
with persistently raised muscle enzymes (Ortega-Hernandez and Shoenfeld, 2012).
3.9.2 Treatment of the vascular manifestations of MCTD
The management of Raynaud’s phenomenon and PAH in patients with MCTD is dealt with in the online in-
depth discussions. Briefly, conservative approaches, such as avoiding cold exposure, maintaining high core
body temperature, gloves, smoking cessation and exogenous vasoconstrictors such as caffeine and
sympathomimetic drugs, are the mainstay for treatment of Raynaud’s disease (Sinnathurai and Schirber,
2013). Calcium channel blockers are the first line of medical treatment. Other medical approaches are topical
glyceryl trinitrate and infusion of prostaglandins, which is particularly useful in patients with digital ulcers and
gangrene. Smaller studies reported good effects of the angiotensin receptor blocker losartan and the selective
serotonin reuptake inhibitor fluoxetine, which might be alternative choices for treatment of refractory cases.
Randomised controlled trials show prophylactic effects of the endothelin receptor antagonist bosentan in
patients with multiple digital ulcers. Bosentan, however, neither accelerated the healing of digital ulcers nor
could it completely prevent their development (Korn et al, 2004; Matucci-Cerinic et al, 2011). Digital
sympathectomy treatment should be reserved as the last resort for patients with critical ischaemia.
Almost all the presented data and recommendations on pharmacological and non-pharmacological treatment
of Raynaud’s phenomenon and digital ulcers derive from studies of patients with SSc or primary Raynaud’s
phenomenon. There are virtually no studies on patients with MCTD. One case report suggests that
microvascular alterations in patients with MCTD might regress upon autologous haematopoietic stem cell
transplantation (Aschwanden et al, 2008). The severely pathological scleroderma-like pattern at baseline
improved to almost normal at most fingers of this patient after stem cell transplantation.
The treatment of PAH is complex and should be adjusted to the functional WHO class. Patients should be
managed at specialised centres. General measures include diuretics (in patients with oedema), continuous
oxygen supply (in patients with hypoxaemia), digoxin (in patients with supraventricular tachycardias
associated with right ventricular dysfunction) and adapted regular cardiopulmonary exercise. Although
evidence may be good for idiopathic PAH, data that support these general measures (therapeutic
anticoagulation) in PAH associated with MCTD and other connective tissue diseases are limited.
Like Raynaud’s phenomenon, the treatment suggestions for MCTD-associated PAH are mainly based on studies
with idiopathic PAH or PAH associated with other connective tissue diseases, mainly SSc. PAH-specific drugs
include prostacyclins, PDE5 inhibitors or endothelin receptor antagonists. In idiopathic PAH, patients who have
a positive vasoreactivity testing during right heart catheterisation may respond well to calcium channel
blockers. Recommendations for the use of calcium channel blockers in patients with CTD-associated PAH are
changing. Since it is negative in most patients with CTD-associated PAH, vasoreactivity testing will be no longer
©2007-2017 EULAR 29
recommended in this group of patients. In parallel, calcium channel blockers will no longer be routinely used in
CTD-associated PAH.
A report on 28 patients with connective tissue disease-associated PAH, including eight patients with MCTD,
suggested that some patients might respond to immunosuppressive therapy with cyclophosphamide and
glucocorticoids. Three out of eight patients with MCTD and PAH responded to the treatment and had a
significantly improved 6 min walking distance and an improvement in haemodynamic function after 1 year of
immunosuppressive therapy (Sanchez et al, 2006). A similar response rate was also seen in patients with SLE,
whereas none of the patients with SSc responded.
The same group reported recently the outcome of 23 patients with MCTD- and SLE-associated PAH treated
with immunosuppressant agents alone or in combination with pulmonary vasodilators for 6 months (Jais et al,
2008). All patients were in New York heart Association (NYHA) class II or III and most patients had not received
disease-modifying antirheumatic drugs (DMARDs) before. Twelve patients responded to the treatment with
cyclophosphamide and prednisolone with improvements in NYHA class, 6 min walking distance and mean
pulmonary arterial pressure. Most responders had NYHA class II disease and a cardiac index >3.1 at baseline,
suggesting that patients, particularly those with milder disease, might benefit from immunosuppressive
therapy.
In another case, IL-6 blockade with tocilizumab improved functional activity and haemodynamic parameters in
a patient with a severe and refractory form of MCTD-associated PAH (Furuya et al, 2010). The efficacy of
immunomodulatory drugs for the treatment of MCTD- and SLE-associated PAH, however, needs to be
confirmed in randomised controlled trials, before recommending them for routine treatment of connective
tissue-associated PAH.
3.9.3 Treatment of the gastrointestinal manifestations of MCTD
Treatment of gastrointestinal symptoms of MCTD is often difficult and follows the same principles as the
treatment of gastrointestinal involvement in SSc. Gastro-oesophageal reflux disease should be treated with
proton pump inhibitors. In contrast to SSc, patients with MCTD with severe oesophageal dysfunction might
benefit from glucocorticoid treatment (Marshall et al, 1990). A longitudinal study showed that patients with
MCTD receiving oral glucocorticoids at an average dose of 25 mg/day had a significant increase of the lower
oesophageal sphincter pressure and a trend to an improvement in oesophageal body peristaltic pressures.
Secondary complications such as dysphagia due to strictures or mucosal rings should no longer occur with the
consequent use of proton pump inhibitors but, if present, might require the use of endoscopic dilatation.
Screening for Barrett’s oesophagus might be indicated in patients with severe and longstanding gastro-
oesophageal reflux disease.
©2007-2017 EULAR 30
Constipation is common in patients with MCTD. These patients should be advised to increase their fibre
ingestion and fluid intake and to exercise. In more severe cases with pseudo-obstruction or intestinal
pneumatosis, hospitalisation and bowel rest might be required. Case reports in patients with SSc report
positive effects of octreotide, but the clinical experience is less encouraging.
3.9.4 Treatment of the pulmonary manifestations of MCTD
Pulmonary disease is common in MCTD, but is often asymptomatic and does not require specific treatment.
Symptomatic pleuritis can often be managed with NSAIDs alone. In more severe cases, oral glucocorticoids
should be added in a dose of 0.5–1.0 mg/kg/day. DMARDs are rarely indicated for pleural disease. Active
alveolitis might warrant aggressive treatment: this includes oral glucocorticoids in doses of 1 mg/kg/day or
intravenous pulses of high-dose steroids in severe cases as well as cyclophosphamide. The efficacy of oral
cyclophosphamide for the treatment of active alveolitis and interstitial lung disease in patients with SSc has
been analysed in a multicentre, placebo-controlled trial (Tashkin et al, 2006). After 12 months of treatment
with a maximum dose of 2 mg/kg of body weight per day, a modest, but significantly higher forced vital
capacity (2.53) was seen in the cyclophosphamide group than in the placebo group. This difference was
maintained through the follow-up period of 1 year after treatment. In contrast, the TLCO did not differ
significantly between the groups.
3.9.5 Treatment of the mucocutaneous manifestations of MCTD
Patients with SLE-like skin manifestations should be instructed to avoid sun exposure and to use sunscreen
lotions. If these conservative approaches are not sufficient, patients might benefit from topical steroids or
hydroxychloroquine. Systemic glucocorticoids or DMARDs should be avoided, but might be needed for severe,
refractory cases.
3.9.6 Treatment of the cardiac manifestations of MCTD
Pericarditis in patients with MCTD is usually mild and can be treated with NSAIDs. In persistent cases, patients
benefit from a short trial of glucocorticoids in doses of 0.5–1.0 mg/kg. In the rare cases of large effusions with
cardiac tamponade, percutaneous or even surgical drainage might be necessary.
Myocarditis is a potentially life-threatening manifestation, which requires more aggressive treatment. Milder
cases can be treated with oral glucocorticoids in a dose of 1 mg/kg/day. Severe cases often require
intravenous pulses of glucocorticoids for the first 3 days followed by oral glucocorticoids. Since myocarditis
tends to relapse, remission maintenance with azathioprine, mycophenolate mofetil or cyclophosphamide is
often needed. Treatment for heart failure might be needed in severe cases. Digoxin should be avoided in
patients with MCTD and myocarditis because it predisposes to ventricular arrhythmias.
©2007-2017 EULAR 31
3.9.7 Treatment of the renal manifestations of MCTD
Although severe renal manifestations are rare, some patients with MCTD might present with raised serum
creatinine or high-grade proteinuria. These patients undergo renal biopsy to clarify the underlying pathology
and guide treatment. Membranous glomerulonephritis is the most common manifestation. Milder forms with
low-grade proteinuria can often be treated with ACE inhibitors alone. In the case of overt nephrotic syndrome,
glucocorticoids are indicated, sometimes in combination with mycophenolate mofetil or cyclophosphamide.
Supportive treatment with aggressive blood pressure control and lowering of cholesterol levels plays an
important role in the long-term outcome of renal disease.
Renal crisis, which has been described in few cases, is managed according to the guidelines for SSc. High-dose
ACE inhibitors with aggressive control of the blood pressure are the mainstay of treatment and should be
started immediately upon suspicion. Angiotensin receptor antagonists might also be beneficial.
3.9.8 Treatment of the neural manifestations of MCTD
Although rare, neurological manifestations of MCTD can be severe. No randomised clinical trials in MCTD are
available and all evidence is provided by SLE trials or case reports (Ortega-Hernandez and Shoenfeld, 2012).
Vascular headache is a common problem in patients with MCTD. These can be treated with NSAIDs, low-dose
tricyclic antidepressants or selective serotonin reuptake inhibitors. Triptans should be used with caution,
because they can induce vasospasms and aggravate Raynaud’s phenomenon. NSAIDs themselves might also be
the cause of headaches in patients with MCTD. The prolonged use of high doses of NSAIDs might result in
analgesia-induced headaches.
NSAIDs can also trigger aseptic meningitis, and in this case, all NSAIDs should be discontinued. Aseptic
meningitis often responds promptly to a short course of glucocorticoids. The incidence of trigeminal
neuropathy is also significantly increased in MCTD. Trigeminal neuropathy, the most common neurological
symptom, is less responsive to glucocorticoids or immunosuppressive agents (Hagen et al, 1990). Patients with
chronic pain may benefit from analgesics, antidepressants or anticonvulsant drugs.
3.9.9 Treatment of the haematological manifestations of MCTD
Mild anaemia or leukopenia tends to correlate with disease activity in MCTD and improves usually without
specific treatment when the overall disease activity declines. Anaemic patients should be analysed for iron
deficiency and, if present, treated appropriately. In cases of severe immune-mediated anaemia or
thrombocytopenia, steroids at high doses of 1 mg/kg/day may be effective. In refractory cases, intravenous
immunoglobulins, danazol, rituximab or splenectomy might be considered, and evidence from case studies for
the use of rituximab is accumulating. These studies highlight a potential effect in correcting haematological
disorders and other manifestations of patients with MCTD; they also demonstrate, however, that serious
©2007-2017 EULAR 32
adverse events (eg, serum sickness) might occur when treating patients with MCTD, and highlight the urgent
need for controlled trials (Fearnley et al, 1978; Haroon et al, 2007; Rudolph et al, 2009).
Acknowledgement
Previous editions of this chapter were authored by Gemma Lepri, Silvia Bellando-Randone and Jörg H W
Distler,
Affiliations
Chiara Tani1, Marta Mosca1, Silvia Bellando Randone2
1
Department of Clinical and Experimental Medicine, University of Pisa, Italy
2
Department of Experimental and Clinical Medicine, Division of Rheumatology, University of Florence, Italy
SUMMARY POINTS
 Patients presenting with features of rheumatological diseases, who do not fulfil the criteria for a
defined rheumatic disease, are diagnosed as having undifferentiated connective tissue disease
(UCTD).
 In most patients with UCTD, no defined rheumatological disease will be diagnosed after several years
of follow-up. For the remaining patients with UCTD, development of a defined rheumatological
disease is more common than resolution of symptoms.
 Patients with overlap syndromes fulfil the criteria for two or more rheumatological diseases.
 Mixed connective tissue disease (MCTD) shares several features of systemic lupus erythematosus,
systemic sclerosis, polymyositis and rheumatoid arthritis. Specific genetic, serological and clinical
features, however, support the concept of MCTD as a separate clinical entity.
 Anti-U1-RNP antibodies directed against the U1-RNP complex of the spliceosome are the key
biomarker for the diagnosis of MCTD.
 Four different classification criteria have been proposed for MCTD
 Characteristic, even not exclusive, clinical features of MCTD are Raynaud’s phenomenon, puffy
hands, the presence of severe arthritis, the high incidence of pulmonary arterial hypertension.
 Pulmonary arterial hypertension is the major cause of death in patients with MCTD.
 The prognosis of MCTD seems to better than that of other defined connective tissue diseases such as
systemic lupus erythematosus. The mortality of patients with MCTD, however, is significantly
increased compared with age- and sex-matched controls.
 No clinical trials are available to guide the treatment of UCTD, overlap syndromes or MCTD.
Treatment is based on experience with therapeutic approaches in other rheumatological diseases.
©2007-2017 EULAR 33
Key references*
Arbuckle MR, McClainMT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of
systemic lupus erythematosus. N Engl J Med 2003; 349 :1526–33.
Cervera R, Khamashta MA, Hughes GR. ‘Overlap’ syndromes. Ann Rheum Dis 1990; 49 :947–8.
Kallenberg CG. Overlapping syndromes, undifferentiated connective tissue disease and other fibrosing
conditions. Curr Opin Rheumatol 1995; 7 :568–73.
LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum 1980; 23
:341–3.
Reichlin M. Problems in differentiating SLE and mixed connective-tissue disease. N Engl J Med 1976; 295
:1194–5.
Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease—an apparently distinct rheumatic disease
syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972; 52
:148–59.
Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be? Arthritis Rheum 1998; 41 :768–77.
Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation emphasizing pulmonary involvement in
patients with mixed connective tissue disease. Medicine (Baltimore) 1984; 63 :92–107.
References
Alarcon GS, Willkens RF, Ward JR, et al. Early undifferentiated connective tissue disease. IV.Musculoskeletal
manifestations in a large cohort of patients with undifferentiated connective tissue diseases compared with
cohorts of patients with well-established connective tissue diseases: followup analyses in patients with
unexplained polyarthritis and patients with rheumatoid arthritis at baseline. Arthritis Rheum 1996;39:403–14.
Alarcon-Segovia D. Symptomatic Sjogren's syndrome in mixed connective tissue disease. J Rheumatol

1976;3:191–5.
Alarcon-Segovia D. Mixed connective tissue disease and overlap syndromes. Clin Dermatol 1994;12:309–16.
Alarcon-Segovia D, Cardiel MH. Comparison between 3 diagnostic criteria for mixed connective tissue disease.
Study of 593 patients. J Rheumatol 1989;16:328–34.
Alarcon-Segovia D, Uribe-Uribe O. Mutilans-like arthropathy in mixed connective tissue disease. Arthritis

Rheum 1979;22:1013–18.
Alarcon-Segovia D, Villareal M. Diagnostic criteria for MCTD. Amsterdam: Elsevier, 1987.
Allanore Y, Borderie D, Meune C, et al. N-terminal pro-brain natriuretic peptide as a diagnostic marker of early
pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium-channel blockers.
Arthritis Rheum 2003;48:3503–8.
Amezcua-Guerra L, Springall R, Marquez-Velasco R, et al. Presence of antibodies against cyclic citrullinated

peptides in patients with "rhupus": a cross sectional study. Arthritis Res Ther 2006;8:R144.
©2007-2017 EULAR 34
Amigues JM, Cantagrel A, Abbal M, et al. Comparative study of 4 diagnosis criteria sets for mixed connective
tissue disease in patients with anti-RNP antibodies. Autoimmunity Group of the Hospitals of Toulouse. J
Rheumatol 1996;23:2055–62.
*Arbuckle MR, McClain MT, Rubertone MV, et al. Development of autoantibodies before the clinical onset of
systemic lupus erythematosus. N Engl J Med 2003;349:1526–33.
Aschwanden M, Daikeler T, Jaeger KA, et al. Rapid improvement of nailfold capillaroscopy after intense
immunosuppression for systemic sclerosis and mixed connective tissue disease. Ann Rheum Dis 2008;67:1057–
59.
Avouac J, Guerini H, Wipff J, et al. Radiological hand involvement in systemic sclerosis. Ann Rheum Dis
2006;65:1088–92.
Avouac J, Huscher D, Furst DE, et al. Expert consensus for performing right heart catheterisation for suspected
pulmonary arterial hypertension in systemic sclerosis: a Delphi consensus study with cluster analysis. Ann
Rheum Dis 2014;73:191–7.
Balbir-Gurman A, Braun-Moscovici Y. Scleroderma overlap syndrome. Isr Med Assoc J 2001;13:14–20
Barakat S, Briand JP, Abuaf N, et al. Mapping of epitopes on U1 snRNP polypeptide A with synthetic peptides
and autoimmune sera. Clin Exp Immunol 1991;86:71–8.
Baurle G, Hornstein OP. Generalized cutaneous calcinosis and mixed connective tissue disease. Dermatologica
1979;158:257–68.
Belizca C, Henrion D, Beucher A, et al. Anti-Ku antibodies: clinical, genetic and diagnostic insights. Autoimmun
Rev 2010:9:691–4.
Bennett RM, O’Connell DJ. Mixed connective tisssue disease: a clinicopathologic study of 20 cases. Semin
Black C, Isenberg DA. Mixed connective tissue disease--goodbye to all that. Br J Rheumatol 1992;31:695–700.
Black CM, Maddison PJ, Welsh KI, et al. HLA and immunoglobulin allotypes in mixed connective tissue disease.
Blockmans D, Vermylen J, Bobbaers H. Nailfold capillaroscopy in connective tissue disorders and in Raynaud’s
phenomenon: Acta Clin Belg 1993;48:30–41.
Bodolay E, Csiki Z, Szekanecz Z, et al. Five-year follow-up of 665 Hungarian patients with undifferentiated
connective tissue disease (UCTD). Clin Exp Rheumatol 2003;21:313–20.
Bodolay E, Szekanecz Z, Devenyi K, et al. Evaluation of interstitial lung disease in mixed connective tissue
disease (MCTD). Rheumatology (Oxford);2005;44:656–61.
Bodolay E, Seres I, Szodoray P, et al. Evaluation of paraoxonase activity in patients with mixed connective
tissue disease. J Rheumatol 2008;35:237–43.
©2007-2017 EULAR 35
Bortoluzzi A, Furini F, Campanaro F et al. Application of SLICC classification criteria in undifferentiated

connective tissue disease and evolution in systemic lupus erythematosus: analysis of a large monocentric
cohort with a long-term follow-up. Lupus. 2016 Oct 4. pii: 0961203316671814. [Epub ahead of print]
Burdt MA, Hoffman RW, Deutscher SL, et al. Long-term outcome in mixed connective tissue
disease:longitudinal clinical and serological findings. Arthritis Rheum 1999;42:899–909.
Cappelli S, Bellando Randone S, Martinovic D, et al. "To Be or Not To Be," Ten Years After: Evidence for Mixed
Connective Tissue Disease as a Distinct Entity. Semin Arthritis Rheum 2012;41:589–98.
Casciola-Rosen L, Andrade F, Ulanet D. Cleavage by granzyme B is strongly predictive of autoantigen status:

implications for initiation of autoimmunity. J Exp Med 1999;190:815–26.
Catoggio LJ, Evison G, Harkness JA, et al. The arthropathy of systemic sclerosis (scleroderma); comparison with
mixed connective tissue disease. Clin Exp Rheumatol 1983;1:101–12.
Cavazzana I, Ciribelli A, Quinzanini M, et al. Prevalence and clinical associations of anti-Ku antibodies in
systemic autoimmune diseases. Lupus 2008;17:727–32.
*Cervera R, Khamashta MA, Hughes GR. 'Overlap' syndromes. Ann Rheum Dis 1990;49:947–8.
Cervera R, Khamashta MA, Font J, et al. Morbidity and mortality in systemic lupus erythematosus during a 10-
year period: a comparison of early and late manifestations in a cohort of 1,000 patients. Medicine (Baltimore)
2003;82:299–308.
Chan MT, Owen P, Dunphy J, et al. Association of erosive arthritis with anti-cyclic citrullinated peptide
antibodies and MHC class II alleles in systemic lupus erythematosus. J Rheumatol 2008;35:77–83.
Cooke CL, Lurie HI. Case report: fatal gastrointestinal hemorrhage in mixed connective tissue disease. Arthritis
Rheum 1977;20:1421–7.
Cronin ME. Musculoskeletal manifestations of systemic lupus erythematosus. Rheum Dis Clin North Am
1988;14:99–116.
Danieli MG, Fraticelli P, Franceschini F, et al. Five-year follow-up of 165 Italian patients with undifferentiated
connective tissue diseases. Clin Exp Rheumatol 1999;17:585–91.
Distler JH, Strapatsas T, Huscher D, et al. Dysbalance of angiogenic and angiostatic mediators in patients with
mixed connective tissue disease. Ann Rheum Dis 2011;70:1197–202.
Doria A, Bonavina L, Anselmino M, et al. Oesophageal involvement in mixed connective tissue disease. J
Rheumatol 1991;18:685–90.
Dutschmann L, Ferreira C, De Sousa G, et al. Cardiac manifestations of connective tissue diseases. Acta Med
Port 1989;2:103–10.
Fearnley M, Hodgkinson A, Holmes AL, et al. The effect of oophorectomy on plasma oestrone and
androstenedione levels in the rat. Acta Endocrinol (Copenh) 1978;88:562–6.
Fenning S, Wolff-Vorbeck G, Hackl W, et al. T cell lines recognizing the 70-kD protein of U1 small nuclear
ribonucleoprotein (U1snRNP). Clin Exp Immunol 1995;101:408–13.
©2007-2017 EULAR 36
Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical and serologic features and survival
in 1,012 Italian patients. Medicine (Baltimore) 2002;81:139–53.
Furuya Y, Satoh T, Kuwana M. Interleukin-6 as a potential therapeutic target for pulmonary arterial
hypertension. Int J Rheumatol 2010;2010:720305.
Gaal J, Varga J, Szabados L, et al. High prevalence of oesophageal involvement in patients with
undifferentiated connective tissue disease using radionuclide oesophageal transit scintigraphy. Nucl Med
Commun 2005;26:1113–17.
Gormezano NW, Silva CA, Aikawa NE et al. Chronic arthritis in systemic lupus erythematosus: distinct features
in 336 paediatric and 1830 adult patients. Clin Rheumatol. 2016;35:227-31.
Grader-Beck T, Wigley FM. Raynaud’s phenomenon in mixed connective tissue disease. Rheum Dis Clin North
Am 2005;31:465–81.
Greidinger EL, Zang YJ, Jaimes K, et al. CD4(+) T cells target epitopes residing within the RNA-binding domain of
the U1-70-kDa small nuclear ribonucleoprotein autoantigen and have restricted TCR diversity in an HLA-DR4-
transgenic murine model of mixed connective tissue disease. J Immunol 2008;180:8444–54.
Gunnarsson R, Molberg O, Gilboe IM, et al. The prevalence and incidence of mixed connective tissue disease: a
national multicentre survey of Norwegian patients. Ann Rheum Dis 2011;70:1047–51.
Gunnarsson R, Aalokken TM, Molberg O, et al. Prevalence and severity of interstitial lung disease in mixed
connective tissue disease: a nationwide, cross-sectional study. Ann Rheum Dis 2012;71:1966–72.
Gunnarsson R, El-Hage F, Aaløkken TM, et al. Associations between anti-Ro52 antibodies and lung fibrosis in
mixed connective tissue disease. Rheumatology (Oxford). 2016 Jan;55:103-8.
Habets WJ, de Rooij DJ, Hoet MH, et al. Quantitation of anti-RNP and anti-Sm antibodies in MCTD and SLE
patients by immunoblotting. Clin Exp Immunol 1985;59:457–66.
Hagen NA, Stevens JC, Michet CJ Jr. Trigeminal sensory neuropathy associated with connective tissue diseases.
Neurology 1990;40:891–6.
Hajas A, Sandor J, Csathy L, et al. Vitamin D insufficiency in a large MCTD population. Autoimmun Rev
2011;10:317–24.
Hajas A, Szodaray P, Nakken B, et al. Clinical curse, prognosis and causes of death in Mixed Connective Tissue
Disease. J Rheumatol 2013;40:1134–42.
Harmon KR, Leatherman JW. Respiratory manifestations of connective tissue disease. Semin Respir Infect
1988;3:258–73.
Haroon M, O’Grandaigh D, Foley-Nolan D. A case of Raynaud's phenomenon in mixed connective tissue

disease responding to rituximab therapy. Rheumatology (Oxford) 2007;46:718–19.
Helenius LM, Hietanen JH, Helenius I, et al. Focal sialadenitis in patients with ankylosing spondylitis and
spondyloarthropathy: a comparison with patients with rheumatoid arthritis or mixed connective tissue
disease. Ann Rheum Dis 2001;60:744–9.
©2007-2017 EULAR 37
Hirschl M, Hirschl K, Lenz M, et al. Transition from primary Raynaud's phenomenon to secondary Raynaud's
phenomenon identified by diagnosis of an associated disease: result of ten years of prospective surveillance.
Hoshino T, Kita M, Takahashi T, et al. Management of two pregnancies in a woman with mixed connective
tissue disease, pulmonary fibrosis, frequent pneumothorax and oxygen inhalation therapy along with a
published work review. J Obstet Gynaecol Res 2008;34:613–18.
Iaccarino L, Gatto M, Bettio S, et al. Overlap connective tissue disease syndromes. Autoimmun Rev
2013;12:363–73.
Ioannou Y, Sultan S, Isenberg DA. Myositis overlap syndromes. Curr Opin Rheumatol 1999;11:468–74.
Jablonska S, Blaszyk M. Scleromyositis (scleroderma/polymyositis overlap) is an entity. J Eur Acad Dermatol

Venereol 2004;18:265–6.
Jais X, Launay D, Yaici A, et al. Immunosuppressive therapy in lupus- and mixed connective tissue disease-
associated pulmonary arterial hypertension: a retrospective analysis of twenty-three cases. Arthritis Rheum
2008;58:521–31.
Kahn MF, Appelboom T. Syndrome de Sharp. Paris: Flammarion, 1991.
*Kallenberg CG. Overlapping syndromes, undifferentiated connective tissue disease and other fibrosing
conditions. Curr Opin Rheumatol 1995;7:568–73.
Kallenberg CG, Wouda AA, Hoet MH, et al. Development of connective tissue disease in patients presenting
with Raynaud's phenomenon: a six year follow up with emphasis on the predictive value of antinuclear
antibodies as detected by immunoblotting. Ann Rheum Dis 1988;47:634–41.
Kaneoka H, Hsu KC, Takeda Y, et al. Molecular genetic analysis of HLA-DR and HLA-DQ genes among anti-U1-
70-kd autoantibody positive connective tissue disease patients. Arthritis Rheum 1992;35:83–94.
Kasukawa R, Tojo T, Miyawaki S, et al. Preliminary diagnostic criteria for classification of mixed connective
tissue disease. Amsterdam: Elsevier, 1987: 41.
Kaufman RL, Kitridou RC. Pregnancy in mixed connective tissue disease: comparison with systemic lupus
erythematosus. J Rheumatol 1982;9:549–55.
Khanna D, Gladue H, Channick R, et al. Recommendations for screening and detection of connective-tissue
disease associated pulmonary arterial hypertension. Arthritis Rheum 2013;65:3194–201.
Kitridou RC. Pregnancy in mixed connective tissue disease. Philadelpia: Elsevier, 2005.
Kitridou RC, Akmal M, Turkel SB, et al. Renal involvement in mixed connective tissue disease: a longitudinal
clinicopathologic study. Semin Arthritis Rheum 1986;16:135–45.
Kobayashi S, Nagase M, Kimura M, et al. Renal involvement in mixed connective tissue disease. Report of 5
cases. Am J Nephrol 1985;5:282–9.
©2007-2017 EULAR 38
Koening M, Joyal F, Fritzler M, et al. Autoantibodies and microvascular damage are independent factors for the
progression of Rynaud's phenomenon to systemic sclerosis: a twenty-year prospective study of 586 patients,
with validation of proposed criteria for early systemic sclerosis. Arthritis Rheum 2008;58:3902–12.
Komatireddy GR, Wang GS, Sharp GC, et al. Antiphospholipid antibodies among anti-U1-70 kDa autoantibody
positive patients with mixed connective tissue disease. J Rheumatol 1997;24:319–22.
Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with
bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004;50:3985–93.
Lash AD, Wittman AL, Quismorio FP Jr. Myocarditis in mixed connective tissue disease: clinical and pathologic
study of three cases and review of the literature. Semin Arthritis Rheum 1986;15:288–96.
Lemmer JP, Curry NH, Mallory JH, et al. Clinical characteristics and course in patients with high titer anti-RNP
antibodies. J Rheumatol 1982;9:536–42.
*LeRoy EC, Maricq HR, Kahaleh MB. Undifferentiated connective tissue syndromes. Arthritis Rheum
1980;23:341–3.
Li J, Wu H, Huang X et al. Clinical analysis of 56 patients with rhupus syndrome: manifestations and
comparisons with systemic lupus erythematosus: a retrospective case-control study. Medicine (Baltimore).
2014;93:e49.
Lundberg IE. Cardiac involvement in autoimmune myositis and mixed connective tissue disease. Lupus
2005;14:708–12.
Lundberg I, Hedfors E. Pregnancy outcome in patients with high titer anti-RNP antibodies. A retrospective
study of 40 pregnancies. J Rheumatol 1991a;18:359–62.
Lundberg I, Hedfors E. Clinical course of patients with anti-RNP antibodies. A prospective study of 32 patients. J
Rheumatol 1991b;18:1511–19.
Magro CM, Crowson AN, Regauer S. Mixed connective tissue disease. A clinical, histologic and
immunofluorescence study of eight cases. Am J Dermatopathol 1997;19:206–13.
Mamula MJ, Gee RJ, Elliott JI, et al. Isoaspartyl post-translational modification triggers autoimmune responses
to self-proteins. J Biol Chem 1999;274:22321–7.
Mason LJ, Ravirajan CT, Rahman A, et al. Is alpha-actinin a target for pathogenic anti-DNA antibodies in lupus
nephritis? Arthritis Rheum 2004;50:866–70.
Marshall JB, Kretschmar JM, Gerhardt DC, et al. Gastrointestinal manifestations of mixed connective tissue
disease. Gastroenterology 1990;98:1232–8.
Matucci-Cerinic M, Denton CP, Furst DE, et al. Bosentan treatment of digital ulcers related to systemic
sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis
2011;70:32–8.
Mendonca LL, Amengual O, Atsumi T, et al. Most anticardiolipin antibodies in mixed connective tissue disease
are beta2-glycoprotein independent. J Rheumatol 1998;25:189–90.
©2007-2017 EULAR 39
McClain MT, Rapp EC, Harley JB, et al. Infectious mononucleosis patients temporarily recognise a unique,
cross-reactive epitope of Epstein-Barr virus nuclear antigen-1. J Med Virol 2003;70:253–7.
Moinzadeh P, Aberer E, Ahmadi-Simab et al. Disease progression in systemic sclerosis-overlap syndrome is

significantly different from limited and diffuse cutaneous systemic sclerosis. Ann Rheum Dis. 2015
Apr;74(4):730-7.
Mosca M, Neri R, Bencivelli W, et al. Undifferentiated connective tissue disease: analysis of 83 patients with a
minimum followup of 5 years. J Rheumatol 2002;29:2345–9.
Mosca M, Tani C, Carli L, et al. Analysis of the evolution of UCTD to defined CTD after a long term follow-up.
Clin Exp Rheumatol 2013;31:471.
Mosca M, Tani C, Vagnani S, et al. The diagnosis and classification of undifferentiate connective tissue disease.
J Autoimmun 2014;48–49:50–2.
Newkirk MM, van Venrooij WJ, Marshall GS. Autoimmune response to U1 small nuclear ribonucleoprotein (U1
snRNP) associated with cytomegalovirus infection. Arthritis Res 2001;3:253–8.
Nimelstein SH, Brody S, McShane D, et al. Mixed connective tissue disease: a subsequent evaluation of the
original 25 patients. Medicine (Baltimore) 1980;59:239–48.
O’Connell DJ, Bennett RM. Mixed connective tissue disease--clinical and radiological aspects of 20 cases. Br J
Radiol 1977;50:620–5.
Ortega-Hernandez OD, Shoenfeld Y. Mixed connective tissue disease: an overview of clinical manifestations,
diagnosis and treatment. Best Pract Res Clin Rheumatol 2012;26:61–72.
Ostendorf B, Scherer A, Specker C, et al. Jaccoud's arthropathy in systemic lupus erythematosus:

differentiation of deforming and erosive patterns by magnetic resonance imaging. Arhritis Rheum
2003;48:157–65.
Pakozdi A, Nihtyanova S, Moinzadeh P, et al. Clinical and serological hallmarks of systemic sclerosis overlap
syndrome. J Rheumatol 2011;38:2406–9.
Panush RS, Edwards NL, Longley S, et al. "Rhupus" syndrome. Arch Intern Med 1988;148:1633–6.
Patampong U, Thepat W, Theppharit P, et al. Cardiac involvement in mixed connective tissue disease: a
systematic review. Int J Cardiol 2014;171:326–30.
Piette JC, Le Thi HD, Ziza JM, et al. Jaccoud's rheumatism in Sharp's syndrome. Rev Rhum Mal Osteoartic
1988;55:153–4.
Piirainen HI. Patients with arthritis and anti-RNP antibodies: a 10 years follow-up. Br J Rheumatol
1990;29:345–8.
Pope J. Scleroderma overlap syndromes. Curr Opin Rheumatol 2002;14:704–10.
Poullin P, Lefevre P, Durand JM. Mixed connective tissue disease with hemolytic anaemia and severe
thrombocytopenia due to thrombotic thrombocytopenic purpura. Am J Hematol 1999;61:275.
©2007-2017 EULAR 40
Provost TT, Watson R, Gammon WR, et al. The neonatal lupus syndrome associated with U1RNP (nRNP)
antibodies. N Engl J Med 1987;316:1135–8.
*Reichlin M. Problems in differentiating SLE and mixed connective-tissue disease. N Engl J Med
1976;295:1194–5.
Rosen A, Casciola-Rosen L. Clearing the way to mechanisms of autoimmunity. Nat Med 2001;7:664–5.
Routsias JG, Kyriakidis N, Latreille M, et al. RNA recognition Motif (RRM) of La/SSB: The bridge for Interparticle
Spreading of Autoimmune Response to U1-RNP. Mol Med 2010;16:19–26.
Rudolph SE, Kouba M, Hrdlicka P. Severe corticoid-refractory autoimmune thrombocytopenia associated with
mixed connective tissue disease (Sharp's syndrome). Treatment with rituximab. Dtsch Med Wochenschr
2009;134:1734–8.
Sanchez O, Sitbon O, Jais X, et al. Immunosuppressive therapy in connective tissue diseases-associated

pulmonary arterial hypertension. Chest 2006;130:182–9.
Sato T, Fujii T, Yokoyama T, et al. Anti-U1 RNP antibodies in cerebrospinal fluid are associated with central
neuropsychiatric manifestations in systemic lupus erythematosus and mixed connective tissue disease.
Satoh K, Imai H, Yasuda T, et al. Sclerodermatous renal crisis in patients with mixed connective tissue disease.
Am J Kidney Dis 1994;24:215–18.
Scussel-Lonzetti L, Joyal F, Raynauld JP, et al. Predicting mortality in systemic sclerosis: analysis of a cohort of
309 French Canadian patients with emphasis on features at diagnosis as predictive factors for survival.
Medicine (Baltimore) 2002;81:154–67.
Segond P, Yeni P, Jacquot JM, et al. Severe autoimmune anaemia and thrombopenia in mixed connective
tissue disease. Arthritis Rheum 1978;21:995–7.
Sen S, Sinhamahapatra P, Choudhury S, et al. Cutaneous manifestations of mixed connective tissue disease:
study from a tertiary care hospital in eastern India. Indian J Dermatol 2014;59:35–40.
Setty YN, Pittman CB, Mahale AS, et al. Sicca symptoms and anti-SSA/Ro antibodies are common in mixed
connective tissue disease. J Rheumatol 2002;29:487–9.
Sharp G. Diagnostic criteria for MCTD. Philadelphia: Elsevier, 1987.
*Sharp GC, Irvin WS, Tan EM, et al. Mixed connective tissue disease--an apparently distinct rheumatic disease
syndrome associated with a specific antibody to an extractable nuclear antigen (ENA). Am J Med 1972;52:148–
59.
Siamopoulou-Mavridou A, Manoussakis MN, Mavridis AK, et al. Outcome of pregnancy in patients with
autoimmune rheumatic disease before the disease onset. Ann Rheum Dis 1988;47:982–7.
Simonneau G, Robbins IM, Beghetti M, et al. Updated clinical classification of pulmonary hypertension. J Am
Coll Cardiol 2009;54:S43–54.
©2007-2017 EULAR 41
Sinnathurai P, Schirber L. Treatment of Raynaud phenomenon in systemic sclerosis. Intern Med J 2013;43:476–
83.
*Smolen JS, Steiner G. Mixed connective tissue disease: to be or not to be? Arthritis Rheum 1998;41:768–77.
Soltesz P, Bereczki D, Szodoray P, et al. Endothelial cell markers reflecting endothelial cell dysfunction in
patients with mixed connective tissue disease. Arthritis Res Ther 2010;12:R78.
Spencer-Green G. Outcomes in primary Raynaud phenomenon: a meta-analysis of the frequency, rates and
predictors of transition to secondary diseases. Arch Intern Med 1998;158:595–600.
*Sullivan WD, Hurst DJ, Harmon CE, et al. A prospective evaluation emphasizing pulmonary involvement in
patients with mixed connective tissue disease. Medicine (Baltimore) 1984;63:92–107.
Swanton J, Isenberg D. Mixed connective tissue disease: still crazy after all these years. Philadelphia: Elsevier,
2005.
Szodoray P, Hajas A, Kardos L, et al. Distinct phenotypes in mixed connective tissue disease: subgroups and
survival. Lupus 2012;21:1412–22.
Szucs G, Szekanecz Z, Zilahi E, et al. Systemic sclerosis-rheumatoid arthritis overlap syndrome: a unique
combination of features suggests a distinct genetic, serological and clinical entity. Rheumatology 2007;46:989–
93.
Tani C, D'Aniello D, Delle Sedie A et al. Rhupus syndrome: assessment of its prevalence and its clinical and
instrumental characteristics in a prospective cohort of 103 SLE patients. Autoimmun Rev. 2013;12:537-41.
Tani C, Carli L, Vagnani S, et al. The diagnosis and classification of mixed connective tissue disease. J
Autoimmun 2014;48–49:46–9.
Targoff IN. Autoantibodies in polymyositis. Rheum Dis Clin North Am 1992;18:455–82.
Tashkin DP, Elashoff R, Clements PJ, et al. Cyclophosphamide versus placebo in scleroderma lung disease. N
Engl J Med 2006;354:2655–66.
Trager J, Ward MM. Mortality and causes of death in systemic lupus erythematosus. Curr Opin Rheumatol
2001;13:345–51.
Udoff EJ, Genant HK, Kozin F, et al. Mixed connective tissue disease: the spectrum of radiographic
manifestations. Radiology 1977;124:613–18.
Ueda-Hayakawa I, Hasegawa M, Kumada S, et al. Usefulness of anti-cyclic citrullinated peptide antibody and
rheumatoid factor to detect rheumatoid arthritis in patients with systemic sclerosis. Rheumatology
2010;49:2135–9.
Ungprasert P(1), Crowson CS(1), Chowdhary VR(1), Ernste FC(1), Moder KG(1), Matteson EL(1). Epidemiology
of Mixed Connective Tissue Disease, 1985-2014: A Population-Based Study. Arthritis Care Res (Hoboken). 2016
Dec;68(12):1843-1848.
van den Hoogen FH, Spronk PE, Boerbooms AM, et al. Long-term follow-up of 46 patients with anti-(U1)snRNP
antibodies. Br J Rheumatol 1994;33:1117–20.
©2007-2017 EULAR 42
Van den Hoogen F, Khanna D, Fransen J, et al. 2013 Classification criteria for systemic sclerosis: an American
College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum
2013;65:2737–47.
van Gaalen FA, Linn-Rasker SP, van Venrooij WJ, et al. Autoantibodies to cyclic citrullinated peptides predict
progression to rheumatoid arthritis in patients with undifferentiated arthritis: a prospective cohort study.
van Vugt RM, Derksen RH, Kater L, et al. Deforming arthropathy or lupus and rhupus hands in systemic lupus
erythematosus. Ann Rheum Dis 1998;57:540–4.
Vegh J, Szodoray P, Kappelmayer J, et al. Clinical and immunoserological characteristics of mixed connective
tissue disease associated with pulmonary arterial hypertension. Scand J Immunol 2006;64:69–76.
Venables PJ. Mixed connective tissue disease. Lupus 2006;15:132–7.
Vlachoyiannopoulos PG, Guialis A, Tzioufas G, et al. Predominance of IgM anti-U1RNP antibodies in patients
with systemic lupus erythematosus. Br J Rheumatol 1996;35:534–41.
Weissman BN, Rappoport AS, Sosman JL, et al. Radiographic findings in the hands in patients with systemic
lupus erythematosus. Radiology 1978;126:313–17.
Weston S, Thumshirn M, Wiste J, et al. Clinical and upper gastrointestinal motility features in systemic sclerosis
and related disorders. Am J Gastroenterol 1998;93:1085–9.
Williams HJ, Alarcon GS, Joks R, et al. Early undifferentiated connective tissue disease (CTD). VI. An inception
cohort after 10 years: disease remissions and changes in diagnoses in well established and undifferentiated
CTD. J Rheumatol 1999;26:816–25.
Winfield JB, Koffler D, Kunkel HG. Development of antibodies to ribonucleoprotein following short-term
therapy with procainamide. Arthritis Rheum 1975;18:531–4.
Wolfe F, Ross K, Hawley DJ, et al. The prognosis of rheumatoid arthritis and undifferentiated polyarthritis
syndrome in the clinic: a study of 1141 patients. J Rheumatol 1993;20:2005–9.
Yasuda M, Loo M, Shiokawa S, et al. Mixed connective tissue disease presenting myasthenia gravis. Intern Med
1993;32:633–7.
©2007-2017 EULAR 43

Connective Tissue Diseases: Concepts and Pathogenesis, Overlap Syndromes, Mixed CTD and Undifferentiated CTD

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Connective Tissue Diseases: Concepts and Pathogenesis, Overlap Syndromes, Mixed CTD and Undifferentiated CTD

Uploaded by

Copyright:

Available Formats

EULAR on-line course on Rheumatic Diseases

Connective tissue diseases:

2 Undifferentiated connective tissue diseases

2.1 Introduction and definition

2.2 Clinical features of UCTD

2.3 Prognosis of UCTDs

2.4 Management of patients with UCTDs

2.5 Overlap syndromes

2.5.1 SLE–RA overlap

presence of SLE-specific autoantibodies (anti-DNA, anti-Sm) and RA-specific autoantibodies (anti-citrullinated

2.5.2 SSc overlap syndromes (PM-SSc and RA-SSc overlap)

3 Mixed connective tissue disease

Figure 6 Swollen fingers.

3.2 Mixed connective tissue disease: a distinct disease entity?

Table 1 Mixed connective tissue disease (MCTD) as a distinct disease entity?

MCTD as a distinct disease entity?

3.3 Anti-U1-RNP antibodies

3.5 Proposed classification criteria for MCTD

Table 2 Sharp’s criteria for mixed connective tissue disease

Major criteria Minor criteria

Table 3 Alarcon–Segovia’s criteria for mixed connective tissue disease

Clinical criteria Serological criterion

Table 4 Kahn’s criteria for mixed connective tissue disease

Clinical criteria Serological criterion

Table 5 Kasukawa’s criteria for mixed connective tissue disease

3.6 Clinical manifestations of MCTD

3.6.1 Musculoskeletal manifestations of MCTD

MCTD (Burdt et al, 1999) UCTD (Danieli et al, 1999;

3.6.2 Vascular manifestations of MCTD

3.6.3 Pulmonary manifestations of MCTD

Table 7 Overview of the pulmonary manifestations of mixed connective tissue disease

Common manifestations Rare manifestations

3.6.4 Mucocutaneous manifestations of MCTD

3.6.5 Gastrointestinal manifestations of MCTD

3.6.6 Cardiac manifestations of MCTD

3.6.7 Renal manifestations of MCTD

3.6.8 Neuropsychiatric manifestations of MCTD

3.6.9 Haematological manifestations of MCTD

3.6.10 Laboratory abnormalities associated with MCTD

3.6.11 Clustering of clinical and laboratory features in MCTD

3.7 MCTD and pregnancy

• The pregnancy should be planned for times of controlled disease activity.

3.8 Prognosis of MCTD

3.9 Treatment of MCTD

3.9.1 Treatment of the musculoskeletal manifestations of MCTD

3.9.2 Treatment of the vascular manifestations of MCTD

3.9.3 Treatment of the gastrointestinal manifestations of MCTD

3.9.4 Treatment of the pulmonary manifestations of MCTD

3.9.5 Treatment of the mucocutaneous manifestations of MCTD

3.9.6 Treatment of the cardiac manifestations of MCTD

3.9.7 Treatment of the renal manifestations of MCTD

3.9.8 Treatment of the neural manifestations of MCTD

3.9.9 Treatment of the haematological manifestations of MCTD

Chiara Tani1, Marta Mosca1, Silvia Bellando Randone2

Alarcon-Segovia D. Symptomatic Sjogren's syndrome in mixed connective tissue disease. J Rheumatol

Alarcon-Segovia D, Uribe-Uribe O. Mutilans-like arthropathy in mixed connective tissue disease. Arthritis

Alarcon-Segovia D, Villareal M. Diagnostic criteria for MCTD. Amsterdam: Elsevier, 1987.

Amezcua-Guerra L, Springall R, Marquez-Velasco R, et al. Presence of antibodies against cyclic citrullinated

Balbir-Gurman A, Braun-Moscovici Y. Scleroderma overlap syndrome. Isr Med Assoc J 2001;13:14–20

Bortoluzzi A, Furini F, Campanaro F et al. Application of SLICC classification criteria in undifferentiated

Casciola-Rosen L, Andrade F, Ulanet D. Cleavage by granzyme B is strongly predictive of autoantigen status:

Haroon M, O’Grandaigh D, Foley-Nolan D. A case of Raynaud's phenomenon in mixed connective tissue

Jablonska S, Blaszyk M. Scleromyositis (scleroderma/polymyositis overlap) is an entity. J Eur Acad Dermatol