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Curr Rheumatol Rep (2016) 18:14

DOI 10.1007/s11926-016-0562-3

SYSTEMIC LUPUS ERYTHEMATOSUS (BN CRONSTEIN AND S GAY, SECTION EDITORS)

What Causes Lupus Flares?


David Fernandez 1 & Kyriakos A. Kirou 1

# Springer Science+Business Media New York 2016

Abstract Systemic lupus erythematosus (SLE), the pro- Introduction


totypic systemic autoimmune disease, follows a chronic
disease course, punctuated by flares. Disease flares often Systemic lupus erythematosus (SLE) is the prototypic system-
occur without apparent cause, perhaps from progressive ic autoimmune disease that is characterized by anti-nuclear
inherent buildup of autoimmunity. However, there is ev- and many other autoantibodies as well as protean clinical
idence that certain environmental factors may trigger the manifestations that span multiple organs. It often presents with
disease. These include exposure to UV light, infections, acute symptoms that require prompt treatment with anti-
certain hormones, and drugs which may activate the inflammatory immunosuppressive medications. Such disease
innate and adaptive immune system, resulting in inflam- flares often recur after treatment and continue to punctuate the
mation, cytotoxic effects, and clinical symptoms. disease course. Of note, both flares and the attendant treat-
Uncontrolled disease flares, as well as their treatment, ments can result in significant organ damage [1] and are asso-
especially with glucocorticoids, can cause significant or- ciated with substantial diminishment of health-related quality
gan damage. Tight surveillance and timely control of of life [2]. Improving our ability to understand the varied
lupus flares with judicial use of effective treatments to triggers of flare, with the aim of predicting or preventing
adequately suppress the excessive immune system acti- flares, is an important goal of lupus research.
vation are required to bring about long term remission
of the disease. We hope that new clinical trials will
soon offer additional effective and target-specific biolog- Definition and Measurement of Flares
ic treatments for SLE.
An international consensus definition of disease flares was
recently established using the Delphi method: BA flare is a
Keywords Systemic lupus erythematosus . Flare . Triggers . measurable increase in disease activity in one or more organ
Hormones . Drugs . Infections systems involving new or worse clinical signs and symptoms
and/or laboratory measurements. It must be considered clini-
cally significant by the assessor and usually there would be at
least consideration of a change or an increase in treatment.^
[3]. Flares can affect multiple organ systems and vary widely
Topical Collection on Systemic Lupus Erythematosus in severity. This breadth of phenotypic variation has made it
difficult to generate individual instruments that can capture the
* Kyriakos A. Kirou full range of SLE manifestations as well as to capture im-
kirouk@hss.edu provement over time. Additionally, distinguishing active dis-
ease from chronic damage can be challenging.
1
Division of Rheumatology, Hospital for Special Surgery and Weill
Some of the most popular instruments that are used to cap-
Medical College of Cornell University, 535 East 70th Street, New ture flare are the Safety of Estrogens in Lupus Erythematosus:
York, NY 10021, USA National Assessment (SELENA) SLE Disease Activity Index
14 Page 2 of 10 Curr Rheumatol Rep (2016) 18:14

(SLEDAI) flare index (SFI) [4, 5] and the British Isles Lupus 2004 A flares are severe flares and B flares are mild flares.
Activity Group-2004 (BILAG-2004) [6]. When two B flares coexist, they indicate a moderate flare.
According to the SFI, severe clinical flares are defined by
specific disease manifestations, such as central nervous system
involvement, vasculitis, nephritis, myositis, and severe anemia Rates of SLE Flare
or thrombocytopenia, or manifestations requiring doubling of
prednisone dose, an increase in prednisone to >0.5 mg/kg/day, Reported flare rates differ substantially in the literature, depend-
or hospitalization. Additionally, initiating cyclophosphamide, ing on the features of the cohort examined (Table 1).
azathioprine, or methotrexate for SLE activity, or increase in Interestingly, substantially lower flare rates are seen in
the physician global assessment (PGA) to >2.5 (out of a pos- population-based registries of SLE patients in Northern
sible 0–3) qualifies as a severe flare. Finally, a change in the Europe [9, 10]. This may be related to genetic differences in
SELENA-SLEDAI score to >12 constitutes a severe flare. Northern European patients but could also reflect decreased
Mild-moderate clinical flares are defined by new or worsening severity of disease in SLE patients in the community setting
rash (including discoid, photosensitive, profundus, cutaneous relative to that described in cohorts drawn from tertiary referral
vasculiits, bullous lupus), oral ulcers, pleuritis, pericardiits, centers. The flare rates in clinical trials are distinct from obser-
arthritis, or fever, an increase in the PGA by ≥1.0, an increase vational studies. Clinical trials for novel therapeutics generally
in the SELENA-SLEDAI score by 3 points or more (but not to report higher rates (0.23–0.57 BILAG A flares per patient-year)
more than 12), or moderate increase in prednisone (not to >0.5 than cohort studies, as they are enriched for refractory, difficult-
mg/Kg/day). New use of NSAIDs or hydroxychloroquine also to-control patients, while the trials of contraceptive and
qualifies as a flare. Medication changes, when implemented hormone-replacement methods were enriched for stable pa-
for safety or other non-disease activity related issues, can lead tients (0.049–0.087 severe SFI flares per patient-year) (Table 2).
to errors. Accordingly, one revision of this score saw better
discrimination of the severity of flares when eliminating the
medication component of flare scoring [7]. Pathophysiology and Biomarkers of Lupus Disease
The BILAG-2004 is a more extensive instrument, assessing Flares
nine organ systems and scoring different manifestations of each
separately, 101 in all, along with an assessment of change over The pathogenesis of SLE is complex and includes interactions
time. It is meant to capture changes in disease manifestations of the innate and adaptive immune systems. The two comple-
that would prompt a change in management by the physician mentary immune systems can amplify each other; innate im-
and, in validation studies, appears to correlate well with chang- munity contributes to activation of autoreactive T and B cells,
es in management, especially for severe flares [6, 8]. BILAG- which make autoantibodies, especially directed at nucleic

Table 1 Rates of disease flare in SLE—observational studies

Flare rate (per pt-year) Cohort Size Definition of flare Authors

0.65 Hopkins SLE Cohort (MD, USA) 185 patients PGA change >1 Petri M, et al. [85]
0.25 (BILAG A) Hopkins SLE Cohort (MD, USA) 299 patients New BILAG A or B Petri M, et al. [86]
1.64 (BILAG B)
0.46 Lupus Registry—Arctic Region 94 patients Modified SLEDAI increase >3 van den Berg L, et al.
(Norway) [10]
0.10 (BILAG A) Lupus Clinics in Birmingham 250 patients New BILAG A or B Gordon C, et al. [87]
0.51 (BILAG B) and London (UK)
0.89 (pre-MMF) Mayo Clinic SLE Cohort, in patients 67 patients SELENA-SLEDAI Flare Index Nannini C, et al. [88]
0.53 (post-MMF) starting MMF (MN, USA)
0.39 (flares) University of Toronto Lupus Clinic 202 patients SLEDAI-2K Flare Index Nikpour M, et al. [89]
0.62 (flares and persistent (Canada)
disease
activity)
0.21 Lupus Registry—Funen County 94 patients SLEDAI ≥4 Laustrup H, et al. [9]
(Denmark)
0.23 Multi-center (14 sites in Europe) 200 patients Disease manifestations Nossent J, et al. [90]
requiring change to
medications
(excluding NSAIDs)
Table 2 Rates of disease flare in non-nephritis clinical trial populations

Flare rate (per pt-year) Trial Size Definition of flare Authors

1.46—placebo arm Plaquenil Withdrawal Study 47 patients New symptoms or worsening Canadian Hydroxychloroquine Study Group [42]
0.72—HCQ maintenance arm symptoms attributable to SLE
Severe flares SELENA 183 patients SELENA-SLEDAI flare index Petri M, et al. [5]
0.084—OCP arm
Curr Rheumatol Rep (2016) 18:14

0.087—placebo arm
Mild/moderate flares
1.40—OCP arm
1.44—placebo arm
Severe flares Combined estrogen/progesterone hormone 351 patients SELENA-SLEDAI flare index Buyon J, et al. [4]
0.081—HRT arm replacement therapy in SLE
0.049—placebo arm
Mild/moderate flares
1.14—HRT arm
0.86—placebo arm
0.86—combined OCP arm Contraceptive methods in SLE 162 patients Increase in SLEDAI by >3 Sanchez-Guerrero J, et al. [57]
1.14—progestin-only arm (mild/moderate) or >12
0.91—IUD arm (severe) points
1.52—placebo arm ROSE 238 patients SELENA-SLEDAI flare index Kalunian K, et al. [91]
1.30—Rontalizumab arm (Rontalizumab)
0.43—standard therapy arm PLUS 171 patients SELENA-SLEDAI flare index Costedoat-Chalumeau N, et al. [92]
0.46—adjusted HCQ dosing arm (Plaquenil dose modification)
0.24—Severe SFI flare BLISS-52/ BLISS-76 562 patients SELENA-SLEDAI flare index Petri M, et al. [35]
0.23—New BILAG A (Belimumab) New BILAG A
0.32—New BILAG A or 2 BILAG B New BILAG A or ≥2 BILAG B
BILAG A flares Abatacept in non-life threatening SLE 175 patients New BILAG A or BILAG B Merrill JT, et al. [93]
0.41—Abatacept arm
0.57—Placebo arm
All flares (A or B)
0.80—Abatacept arm
0.83—Placebo arm
BILAG A or BILAG B APRIL-SLE 316 patients New BILAG A or BILAG B Isenberg D, et al. [94]
0.58—placebo arm (Atacicept)
0.54—Atacicept 75 mg arm
BILAG A flares EXPLORER 185 patients New BILAG A or ≥2 BILAG B Merrill JT, et al. [95]
0.34—RTX arm (Rituximab)
0.47—placebo arm
All flares
0.64—both treatment arms
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acids and nuclear components. Autoantibodies can form im- self nucleic acids that could serve as a substrate for autoanti-
mune complexes, leading to efficient stimulation of neutro- body formation or deposition in times of disease flare.
phils, macrophages, and dendritic cells to generate proinflam- Upregulation of IFN-inducible genes has been repeatedly de-
matory cytokines. In addition, immune complexes can deposit tected in peripheral blood mononuclear cells in 60–70 % of
in tissues, causing direct tissue damage via complement acti- adult SLE patients and in nearly all pediatric SLE patients
vation, further amplifying the innate and adaptive immune [26–28]. Phase II trials of anifrolumab, an antagonist of the
response. These processes can result in clinical symptoms of IFN receptor, have shown promise in treatment of lupus pa-
SLE flare if they reach a certain threshold, while therapeutic tients, and phase III trials are ongoing.
interventions can interrupt this cycle (Fig. 1). While IFN appears to be important in SLE pathogenesis,
With regard to the innate immune system, it has been in- and is consistently seen in a majority of SLE patients, it is not
creasingly appreciated that several proinflammatory cytokines a universal feature of the disease. Presence of an IFN signature
may play a role in creating a permissive environment for lupus has been associated with increased disease severity in multiple
flares and are important in propagating inflammation once the studies, but studies differ as to whether the IFN signature
flares have begun. There is evidence of increased activity of changes over time with disease activity in a predictable fash-
tumor necrosis factor-α, interleukin-6, B lymphocyte stimula- ion [29–32]. As such, the interferon signature may be useful as
tor, and interferon-γ, some of which have been targeted ther- a biomarker in select patients, but it is clear that other mech-
apeutically [11–15]. In particular, there is a wide body of anisms of disease are important in driving SLE flares as well.
evidence supporting type I interferon (IFN), especially Given the overall complexity and variability of the pheno-
interferon-α, as having central importance to lupus pathogen- types observed in SLE patients, it is likely that there are dif-
esis, in Mendelian disorders associated with SLE or lupus-like ferent pathophysiologic mechanisms playing a role in differ-
disease as well as SLE patients more broadly [16]. IFN pro- ent people and in specific disease manifestations within indi-
duction is triggered by viral and bacterial nucleic acids bind- viduals. Different types of flares affect different organs and
ing to intra- and extracellular pattern-recognition receptors require treatment for varying lengths of time. Even within the
like Toll-like receptors (TLRs) RIG-I/MDA5 and cGAS/ same target organ, there are differences between disease man-
STING [17, 18, 19••]. It has been hypothesized that endoge- ifestations. Hypocomplementemia is often absent in patients
nous nucleic acids can also activate these pathways in certain with isolated class V membranous lupus nephritis, whereas it
circumstances, such as when released in neutrophil extracel- is nearly universally present in patients with class III or IV
lular traps or when part of immune complexes, and this may proliferative nephritis. With respect to eye disease, episcleritis
be relevant in generation of autoantibodies in SLE patients can sometimes be treated with ophthalmic NSAID drops,
[20–23]. Patients with diminished clearance of extracellular while retinal vasculitis or choroiditis requires prolonged sys-
and intracellular nucleic acids, such as those deficient in early temic immunosuppression. The mechanisms for the underly-
complement proteins or in DNase activity, may be prone to ing differences are not fully clear at this time, but our ability to
persistent stimulation of nucleic acid-sensing pathways and classifying disease manifestations according to the mecha-
upregulation of IFN [24, 25]. And normal events such as in- nisms of disease is likely to be more informative than the
jury or infection may lead to periods of increased release of organ system.

Fig. 1 SLE flare as a balance of opposing factors. The immune system of estrogen or prolactin, and drugs that affect DNA methylation, or the
a patient with SLE, as a result of genetic and stochastic factors, gets cytokine milieu, the immune system gets even further activated above
activated to a certain level and, if left untreated, has the potential to the clinical threshold and flare occurs. Conversely, medications to treat
self-amplify, i.e., with epitope spreading. If the level of activation lupus, such as glucocorticoids, antimalarials, DMARDs (such as
remains below a certain threshold, inflammation/cytotoxicity levels do methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide),
not get high enough to cause clinical symptoms (flare). However, under and biologics (i.e., B cell depleting agents, BAFF inhibitors, or type I
the influence of potential triggers of immunologic activity, such as interferon inhibitors), help shift the balance towards remission of flare
exposure to UV light, viral or bacterial infections, high levels of
Curr Rheumatol Rep (2016) 18:14 Page 5 of 10 14

In addition to differing with respect to the organ systems Triggers


affected and specific type of flares, patients also vary in terms
of frequency of heightened disease activity. Some patients Lupus flares can begin in response to a number of stimuli,
remain quiescent for many years following a disease flare, only some of which are well understood. These triggers prob-
while others develop intermittent flares or even persistent dis- ably tip the balance towards more immunologic activity be-
ease activity [33]. Recently, studies of global messenger RNA yond a critical threshold that leads to significant levels of
(mRNA) transcription in subsets of lymphocytes from patients inflammation to cause symptoms (Fig. 1). There are important
with ANCA-associated vasculitis and SLE revealed a novel contributions of medications, environmental factors, and spe-
expression signature in T cells, termed the Bexhaustion^ sig- cific genetic susceptibilities to the end result of lupus flares,
nature, so called as it resembles changes seen in patients with each of which contributes to a greater or lesser extent in each
chronic viral infection. Presence of this transcriptional signa- individual patient. While many flares have no clear precipitat-
ture at baseline was associated with substantial reduction in ing event, for others there is a clear temporal relationship with
disease flares during follow-up [34]. some other factor that may have served to trigger that flare.
Clinical and laboratory features can also aid in prognosti- SLE patients and rheumatologists have implicated a wide va-
cation with regard to flare frequency and accumulation of riety of stimuli that may be potentially causative of lupus
organ damage. Analysis of baseline characteristics from pa- flares. Some of the major triggers will be reviewed below.
tients who entered in the BLISS-52 and BLISS-76 trials
showed that patients with very high levels of anti-dsDNA BUnmasking^ by Tapering
antibodies, the highest quartile of BLyS expression, or history
of prior renal, neurologic, or vasculitic involvement were A well-established cause of disease flare is the tapering (espe-
more likely to flare [35•]. Interestingly, high BLyS levels were cially if too fast) of steroids or immunosuppressive agents.
not associated with greater response rates to belimumab, but This scenario is common, as it is imperative to try to minimize
high dsDNA levels and low C3/C4 levels were [36]. Patients the use of high doses of steroids in particular. This flare likely
with clinically inactive disease in general fare better, even if represents a recrudescence of prior subclinical disease activity,
they have serologically active disease. However, even such and thus, no other external trigger is required. These flares
patients can flare 59 % after a median of 3 years [37]. generally resolve with resumption of the previously successful
Change in the standard laboratory markers in SLE patients regimen, though often require a short burst of increased doses
is used in clinical practice to predict flare, though there may be of glucocorticoids. Besides glucocorticoids, withdrawal of
subsets of patients for whom these measures are more infor- HCQ has been associated with more flares [42].
mative. A study of dynamic changes in C3 and C4 noted
decline in those parameters only in two thirds of patients with Ultraviolet Light
flares but found that polymorphisms in the complement regu-
latory protein factor H were associated with an increase like- Ultraviolet (UV) light is the most widely recognized trigger of
lihood of C3 fall with SLE flare [38]. One study found that an SLE flares, and photosensitive rash is included as one of the
increase in dsDNA titers by greater than two dilutions was diagnostic criteria for SLE. Patients also frequently report oth-
associated with a disease flare at the subsequent visit, though er symptoms with sun exposure, such as arthralgia, weakness,
there was often a fall of dsDNA titers on the day of acute flares and headaches [43]. Estimates of the prevalence of photosen-
[39]. A study of ours identified patients with a Bsurge^ in sitivity in SLE reach up to 50 % of patients and is clearly
dsDNA titers, defined as an increase from 0 to 3+/4+ or 1+ implicated in disease flares, both cutaneous and systemic.
to 4+ within a 1-year span. These patients had a higher likeli- Broad spectrum sunscreen use is associated with decreased
hood of severe flare in the subsequent 6 months relative to inflammatory cell infiltration of the skin and decreased inter-
other lupus patients [40]. feron signaling, as well as decreased formation of skin lesions
Tremendous effort has been invested in biomarkers to in photoprovocation studies [44, 45].
guide therapy in SLE, but prediction of disease flares re- The mechanism by which UV light achieves these effects is
mains inexact. Trials of pre-emptive therapy in patients only partially understood. UV light exposure is known to di-
with specific patterns of serologic activity have been per- rectly damage DNA and proteins in cells, leading to
formed [41], but this practice has not become widespread keratinocyte cell death and the release of proinflammatory
as it requires treating substantial numbers of patients who cytokines, such as interleukin-1α and tumor necrosis
may not flare to prevent severe flares in a subset of pa- factor-α [46]. Additionally, UV light is known to affect the
tients. However, the hope is that our ability to identify localization of characteristic autoantigens such as Ro, Sm, and
patients at the highest risk of flare will improve, and that RNP, redirecting them to the cell surface or to the surface of
toxicity of our therapy will diminish as newer, targeted apoptotic vesicles [47–50], perhaps rendering them accessible
therapies become available. to binding by autoantibodies and complement proteins.
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UV light is specifically associated with increased produc- High amounts of estrogens are naturally found in pregnan-
tion of IFN-α in cutaneous lupus lesions. pDCs have the ca- cy. Whether or not lupus flares are increased during pregnancy
pacity to generate large amounts of IFN-α and have been has been a subject of some dispute [58]. A meta-analysis using
demonstrated to be present in skin lesions of lupus patients, data from 37 studies of pregnant SLE patients reported an
though not universally; there appear to be larger number of overall flare rate of 25.6 % (during 747/2751 pregnancies),
pDCs in skin lesions of patients with skin-limited disease rel- with 16.1 % of flares consisting of nephritis [59]. The largest
ative to SLE patients [51–53]. One group studying only SLE single study of pregnancy outcomes, using data obtained from
patients did not demonstrate increased influx of pDCs with the PROMISSE cohort, showed that severe flare rates by
photoprovocation, but did see an elevation in MxA staining in weeks 23 and 35 of gestation were 2.5 and 3 %, respectively,
lesional skin versus non-lesional skin, correlating with the while rates of mild-moderate flares were 12.7 and 9.6 %.
influx of T cells and macrophages, implying multiple sources Maternal flares, higher disease activity, and smaller increases
of IFN-α generation [54]. in C3 levels later in pregnancy predicted adverse pregnancy
outcomes [60••]. The apparently low rates of flares reflect the
Hormones and Pregnancy fact that patients with significant proteinuria, elevated creati-
nine, and prednisone requirements greater than 20 mg/day at
The extreme discrepancy in SLE incidence between males and baseline were excluded from the latter study. In older and
females, and a peak in onset of disease in late adolescence and retrospective pregnancy studies, flare rates are much higher,
young adulthood, has suggested possible hormonal contribu- especially if patients had active lupus in the 6 months before
tions to SLE, especially estrogens. Estrogens may enhance pregnancy (up to 77 %, though estimates vary widely) [58,
immune system activation via several effects, including stim- 61–64]. Among severe flares, renal flares appear to be partic-
ulation of antibody production by B cells and decreased apo- ularly prevalent in pregnancies, especially if patients already
ptosis of dendritic cells and macrophages. They enhance IL- had a history of lupus nephritis and were not in complete renal
10, IL-2, and interferon-γ production and inhibit TNF secre- remission [65, 66]. The best likelihood of good pregnancy
tion [55]. During the reproductive years, women have higher outcomes in SLE patients occur in patients in a sustained
immunoglobulin levels than age-matched males as baseline period of low or absent disease activity, especially renal activ-
and in response to immunizations and infections. Of note, ity, prior to conception of at least 6 months, and this should be
estrogens have prothrombotic effects, and thus, may trigger a goal of pre-conception counseling and management of pa-
thrombosis in SLE patients with active disease and/or anti- tients planning pregnancy.
phospholipid (aPL) antibodies. Prolactin may also be immunostimulatory and is also at high
The effect of estrogens in the form of oral contraceptive levels in pregnancy and postpartum. Of note, there is limited
pills (OCPs) on lupus flares has been examined in clinical evidence that bromocriptine for 14 days after delivery de-
trials. An early trial of high dose estrogen-containing OCPs creased flares of SLE for up to a year compared to controls [67].
in patients with active renal involvement demonstrated an
increased risk of flares [56]. However, Sanchez-Guerrero et Infections
al. found no impact of low-dose estrogen-containing OCPs
relative to progesterone-only OCPs or copper intrauterine de- Bacterial and viral infections are often cited by SLE patients as
vice placement in terms of lupus flare risk in a study of 162 triggers for their disease; however, the association between
SLE patients [57]. Similarly, Petri et al. found no significant specific infections and specific patients is less clear [68].
difference in flare rates among 183 SLE patients with stable Many of the proposed inflammatory mechanisms thought to
low disease activity or inactive disease receiving combination contribute to SLE pathogenesis and interferon production,
estrogen/progesterone OCPs or placebo. In that study, the rate such as TLR, STING, RIG-I, and MDA5 signaling, are acti-
of mild/moderate flares was 69 % in the OCP group versus vated appropriately by bacterial or viral nucleic acids and
60 % in the placebo group, while the rates of severe flares proteins. In SLE patients, where these same pathways may
were 7.7 versus 7.6 % over the course of the study [5]. A be abnormally activated by self nucleic acids and proteins, it
separate placebo-controlled trial of hormone-replacement is plausible that the presence of foreign DNA or molecular
therapy (HRT) in 351 postmenopausal SLE patients did not patterns may cause inflammatory responses that are even more
find a significant difference in severe flare rate between those amplified. However, it is also clear that SLE disease flares do
receiving HRT versus those receiving placebo, though there not occur exclusively after infections or with every infection,
was an increased risk of mild/moderate flares in the HRT so certain infections may be more relevant than others.
group, with a relative risk of 1.34. Additionally, while the One group reviewed 88 cases of identifiable viral infections
study was not powered to evaluate rare thrombotic endpoints in SLE patients. Parvovirus B19 and cytomegalovirus (CMV)
fully, more thrombotic events occurred in the HRT group than were associated most often with newly diagnosed SLE.
in the placebo group [4]. Disseminated infections that resulted in death usually were
Curr Rheumatol Rep (2016) 18:14 Page 7 of 10 14

herpesviruses, specifically CMV, herpes simplex virus (HSV), Several mechanisms have been proposed for DIL due to
Epstein-Barr virus (EBV), and varicella zoster virus (VZV). these medications. The drugs could act as haptens, leading to
Of note, serious viral infections associated with disease activ- aberrant presentation of self peptides and driving autoimmu-
ity in SLE were reported most often in Asian patients [69]. nity. An interesting hypothesis is that drugs such as procain-
CMV was studied in detail in 105 SLE patients in a Chinese amide and hydralazine inhibit DNA methyltransferases and
cohort, where CMV was detectable at disease onset in 42 that excessive demethylation causes important alterations of
cases, associated with disease flare in 31 more, and mimicking T cell function, such as amplifying proinflammatory cytokine
disease flare in 32 cases [70]. production and lysing antigen presenting cells [79, 80]. There
Each recognition pathway that drives interferon production is reduced DNA methylation globally in T cells in SLE pa-
senses different molecules. Control of individual viruses is tients [81], indicating that this mechanism may be important in
often pathway-specific; RNA viruses such as Sendai virus SLE pathogenesis more broadly than just in DIL.
and vesicular stomatitis virus induce interferon in a MAVS- As antiarrhythmic drugs and hydralazine are used less fre-
dependent fashion, where DNA viruses such as HSV primar- quently, the DIL seen with these agents is increasingly rare.
ily, though not exclusively, stimulate interferon production by However, DIL has been described in patients receiving anti-
the STING pathway [19]. An SLE-associated polymorphism TNF therapy, and this phenomenon will likely grow more
in MAVS a sso ciat ed with SLE w as fou nd to b e prevalent with the widespread use of these medications.
hypofunctional, with decreased ability to promote interferon Isolated seroconversion, with development of new ANA or
production [71]. It is tempting to speculate that patients with anti-dsDNA antibodies, is actually quite common in patients
specific defects or signaling abnormalities in one pathway on anti-TNF therapy, though this does not result in clinical
may undergo disease flare after viral or bacterial infection that disease the vast majority of the time [82]. In addition to in-
is inadequately controlled by that pathway and potentially not creased frequency of dsDNA antibodies, SCLE and DLE is
in response to infections controlled by other means. more common, especially in patients receiving etanercept, and
In addition to directly contributing to disease flares, there is renal and CNS disease have been reported [83]. Cessation of
some evidence for EBV as a contributor to the initial events in the anti-TNF medication sufficed to control disease in 94 % of
SLE pathogenesis. EBV is a ubiquitous human pathogen, and the reported cases, though steroids were sometimes used for
serologic evidence of infection is very highly prevalent in almost symptomatic management. Interestingly, rechallenge with the
all human populations [72]. Studies of key autoantibodies in TNF-alpha inhibitor has been described, but the DIL only
SLE led to the discovery that the epitopes recognized by the recurred in two of eight reported instances where this was
Sm and Ro-60kd autoantibodies are structurally very similar to done [84].
epitopes present on Epstein-Barr virus Nuclear Antigen-1 [73,
74]. The Ro autoantibody is frequently the initial autoantibody
that appears in patients who go on to develop SLE, sometimes Conclusions
preceding disease onset by years [75]. Periodic reactivation of
EBV can occur, especially in the setting of significant immuno- Patients with SLE, as a result of their genetic makeup, envi-
suppression. However, there is currently no definitive evidence ronmental triggers, and stochastic factors, progressively de-
that this precedes or is associated with disease flares in SLE. velop immune system aberrations that manifest with produc-
tion of anti-nuclear as well as many other autoantibodies.
Medications Abnormal immune system activation then leads to inflamma-
tion in various organs and symptoms of lupus flares.
SLE can develop in patients receiving certain medications, Reduction of immune system activation by use of glucocorti-
such as quinidine, hydralazine, and procainamide. IFN-α has coids and immunosuppressive medications brings resolution
been associated infrequently with drug-induced lupus (DIL) of symptoms for some time. However, subclinical immuno-
when used as a treatment for hepatitis C, which indicates that logic activity commonly persists and with time can lead again
IFN may suffice to drive disease in a few susceptible individ- to new flares. This process may be accelerated by certain
uals [76, 77]. DIL is classically abrupt in onset, associated with triggers of the immune system, such as various infections,
drug exposure, usually with manifestations affecting the skin, drugs, and hormones. Unfortunately, after each flare, more
musculoskeletal, and hematologic systems, only rarely affect- damage accumulates in the patients’ organs, as a result of both
ing the kidneys or the CNS. Hypocomplementemia and anti- the flare itself and the glucocorticoids used to treat it.
dsDNA antibodies are also very infrequent. Isolated anti- We believe that tight surveillance and timely control of
histone antibodies are commonly seen in DIL, while SLE pa- lupus flares with judicial use of effective treatments to ade-
tients usually have additional autoantibodies in addition to quately suppress the excessive immune system activation are
anti-histone. The mainstay of treatment is cessation of the drug required to bring about long-term remission of the disease. We
implicated in a given patient [78]. hope that new clinical trials will soon offer additional effective
14 Page 8 of 10 Curr Rheumatol Rep (2016) 18:14

and target-specific biologic treatments for SLE that will help 11. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-
controlled study of belimumab, a monoclonal antibody that inhibits
us achieve these goals without the high toxicity currently seen
B lymphocyte stimulator, in patients with systemic lupus erythema-
with glucocorticoids and other immunosuppressive tosus. Arthritis Rheum. 2011;63(12):3918–30.
medications. 12. Manzi S, Sánchez-Guerrero J, Merrill JT, et al. Effects of beli-
mumab, a B lymphocyte stimulator-specific inhibitor, on disease
Compliance with Ethics Guidelines activity across multiple organ domains in patients with systemic
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