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-
totypic systemic autoimmune disease, follows a chronic
disease course, punctuated by flares. Disease flares often
occur without apparent cause, perhaps from progressive
inherent buildup of autoimmunity. However, there is ev-
idence that certain environmental factors may trigger the
disease. These include exposure to UV light, infections,
certain hormones, and drugs which may activate the
innate and adaptive immune system, resulting in inflam-
mation, cytotoxic effects, and clinical symptoms.
Uncontrolled disease flares, as well as their treatment,
especially with glucocorticoids, can cause significant or-
gan damage. Tight surveillance and timely control of
lupus flares with judicial use of effective treatments to
adequately suppress the excessive immune system acti-
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-
ic treatments for SLE.
Keywords Systemic lupus erythematosus . Flare . Triggers .
Hormones . Drugs . Infections
Topical Collection on Systemic Lupus Erythematosus
* Kyriakos A. Kirou
kirouk@hss.edu
1
Division of Rheumatology, Hospital for Special Surgery and Weill
Medical College of Cornell University, 535 East 70th Street, New
York, NY 10021, USA
Introduction
Systemic lupus erythematosus (SLE) is the prototypic system-
ic autoimmune disease that is characterized by anti-nuclear
and many other autoantibodies as well as protean clinical
manifestations that span multiple organs. It often presents with
acute symptoms that require prompt treatment with anti-
inflammatory immunosuppressive medications. Such disease
flares often recur after treatment and continue to punctuate the
disease course. Of note, both flares and the attendant treat-
ments can result in significant organ damage [1] and are asso-
ciated with substantial diminishment of health-related quality
of life [2]. Improving our ability to understand the varied
triggers of flare, with the aim of predicting or preventing
flares, is an important goal of lupus research.
Definition and Measurement of Flares
An international consensus definition of disease flares was
recently established using the Delphi method: BA flare is a
measurable increase in disease activity in one or more organ
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
in severity. This breadth of phenotypic variation has made it
difficult to generate individual instruments that can capture the
full range of SLE manifestations as well as to capture im-
provement over time. Additionally, distinguishing active dis-
ease from chronic damage can be challenging.
Some of the most popular instruments that are used to cap-
ture flare are the Safety of Estrogens in Lupus Erythematosus:
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
Activity Group-2004 (BILAG-2004) [6].
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
or thrombocytopenia, or manifestations requiring doubling of
prednisone dose, an increase in prednisone to >0.5 mg/kg/day,
or hospitalization. Additionally, initiating cyclophosphamide,
azathioprine, or methotrexate for SLE activity, or increase in
the physician global assessment (PGA) to >2.5 (out of a pos-
sible 0–3) qualifies as a severe flare. Finally, a change in the
SELENA-SLEDAI score to >12 constitutes a severe flare.
Mild-moderate clinical flares are defined by new or worsening
rash (including discoid, photosensitive, profundus, cutaneous
vasculiits, bullous lupus), oral ulcers, pleuritis, pericardiits,
arthritis, or fever, an increase in the PGA by ≥1.0, an increase
in the SELENA-SLEDAI score by 3 points or more (but not to
more than 12), or moderate increase in prednisone (not to >0.5
mg/Kg/day). New use of NSAIDs or hydroxychloroquine also
qualifies as a flare. Medication changes, when implemented
for safety or other non-disease activity related issues, can lead
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].
The BILAG-2004 is a more extensive instrument, assessing
nine organ systems and scoring different manifestations of each
separately, 101 in all, along with an assessment of change over
time. It is meant to capture changes in disease manifestations
that would prompt a change in management by the physician
and, in validation studies, appears to correlate well with chang-
es in management, especially for severe flares [6, 8]. BILAG-
2004 A flares are severe flares and B flares are mild flares.
When two B flares coexist, they indicate a moderate flare.
Rates of SLE Flare
Reported flare rates differ substantially in the literature, depend-
ing on the features of the cohort examined (Table 1).
Interestingly, substantially lower flare rates are seen in
population-based registries of SLE patients in Northern
Europe [9, 10]. This may be related to genetic differences in
Northern European patients but could also reflect decreased
severity of disease in SLE patients in the community setting
relative to that described in cohorts drawn from tertiary referral
centers. The flare rates in clinical trials are distinct from obser-
vational studies. Clinical trials for novel therapeutics generally
report higher rates (0.23–0.57 BILAG A flares per patient-year)
than cohort studies, as they are enriched for refractory, difficult-
to-control patients, while the trials of contraceptive and
hormone-replacement methods were enriched for stable pa-
tients (0.049–0.087 severe SFI flares per patient-year) (Table 2).
Pathophysiology and Biomarkers of Lupus Disease
Flares
The pathogenesis of SLE is complex and includes interactions
of the innate and adaptive immune systems. The two comple-
mentary immune systems can amplify each other; innate im-
munity contributes to activation of autoreactive T and B cells,
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
Page 3 of 10 14
14 Page 4 of 10
acids and nuclear components. Autoantibodies can form im-
mune complexes, leading to efficient stimulation of neutro-
phils, macrophages, and dendritic cells to generate proinflam-
matory cytokines. In addition, immune complexes can deposit
in tissues, causing direct tissue damage via complement acti-
vation, further amplifying the innate and adaptive immune
response. These processes can result in clinical symptoms of
SLE flare if they reach a certain threshold, while therapeutic
interventions can interrupt this cycle (Fig. 1).
With regard to the innate immune system, it has been in-
creasingly appreciated that several proinflammatory cytokines
may play a role in creating a permissive environment for lupus
flares and are important in propagating inflammation once the
flares have begun. There is evidence of increased activity of
tumor necrosis factor-α, interleukin-6, B lymphocyte stimula-
tor, and interferon-γ, some of which have been targeted ther-
apeutically [11–15]. In particular, there is a wide body of
evidence supporting type I interferon (IFN), especially
interferon-α, as having central importance to lupus pathogen-
esis, in Mendelian disorders associated with SLE or lupus-like
disease as well as SLE patients more broadly [16]. IFN pro-
duction is triggered by viral and bacterial nucleic acids bind-
ing to intra- and extracellular pattern-recognition receptors
like Toll-like receptors (TLRs) RIG-I/MDA5 and cGAS/
STING [17, 18, 19••]. It has been hypothesized that endoge-
nous nucleic acids can also activate these pathways in certain
circumstances, such as when released in neutrophil extracel-
lular traps or when part of immune complexes, and this may
be relevant in generation of autoantibodies in SLE patients
[20–23]. Patients with diminished clearance of extracellular
and intracellular nucleic acids, such as those deficient in early
complement proteins or in DNase activity, may be prone to
persistent stimulation of nucleic acid-sensing pathways and
upregulation of IFN [24, 25]. And normal events such as in-
jury or infection may lead to periods of increased release of
Fig. 1 SLE flare as a balance of opposing factors. The immune system of
a patient with SLE, as a result of genetic and stochastic factors, gets
activated to a certain level and, if left untreated, has the potential to
self-amplify, i.e., with epitope spreading. If the level of activation
remains below a certain threshold, inflammation/cytotoxicity levels do
not get high enough to cause clinical symptoms (flare). However, under
the influence of potential triggers of immunologic activity, such as
exposure to UV light, viral or bacterial infections, high levels of
Curr Rheumatol Rep (2016) 18:14
self nucleic acids that could serve as a substrate for autoanti-
body formation or deposition in times of disease flare.
Upregulation of IFN-inducible genes has been repeatedly de-
tected in peripheral blood mononuclear cells in 60–70 % of
adult SLE patients and in nearly all pediatric SLE patients
[26–28]. Phase II trials of anifrolumab, an antagonist of the
IFN receptor, have shown promise in treatment of lupus pa-
tients, and phase III trials are ongoing.
While IFN appears to be important in SLE pathogenesis,
and is consistently seen in a majority of SLE patients, it is not
a universal feature of the disease. Presence of an IFN signature
has been associated with increased disease severity in multiple
studies, but studies differ as to whether the IFN signature
changes over time with disease activity in a predictable fash-
ion [29–32]. As such, the interferon signature may be useful as
a biomarker in select patients, but it is clear that other mech-
anisms of disease are important in driving SLE flares as well.
Given the overall complexity and variability of the pheno-
types observed in SLE patients, it is likely that there are dif-
ferent pathophysiologic mechanisms playing a role in differ-
ent people and in specific disease manifestations within indi-
viduals. Different types of flares affect different organs and
require treatment for varying lengths of time. Even within the
same target organ, there are differences between disease man-
ifestations. Hypocomplementemia is often absent in patients
with isolated class V membranous lupus nephritis, whereas it
is nearly universally present in patients with class III or IV
proliferative nephritis. With respect to eye disease, episcleritis
can sometimes be treated with ophthalmic NSAID drops,
while retinal vasculitis or choroiditis requires prolonged sys-
temic immunosuppression. The mechanisms for the underly-
ing differences are not fully clear at this time, but our ability to
classifying disease manifestations according to the mecha-
nisms of disease is likely to be more informative than the
organ system.
estrogen or prolactin, and drugs that affect DNA methylation, or the
cytokine milieu, the immune system gets even further activated above
the clinical threshold and flare occurs. Conversely, medications to treat
lupus, such as glucocorticoids, antimalarials, DMARDs (such as
methotrexate, mycophenolate mofetil, azathioprine, cyclophosphamide),
and biologics (i.e., B cell depleting agents, BAFF inhibitors, or type I
interferon inhibitors), help shift the balance towards remission of flare
Curr Rheumatol Rep (2016) 18:14
In addition to differing with respect to the organ systems
affected and specific type of flares, patients also vary in terms
of frequency of heightened disease activity. Some patients
remain quiescent for many years following a disease flare,
while others develop intermittent flares or even persistent dis-
ease activity [33]. Recently, studies of global messenger RNA
(mRNA) transcription in subsets of lymphocytes from patients
with ANCA-associated vasculitis and SLE revealed a novel
expression signature in T cells, termed the Bexhaustion^ sig-
nature, so called as it resembles changes seen in patients with
chronic viral infection. Presence of this transcriptional signa-
ture at baseline was associated with substantial reduction in
disease flares during follow-up [34].
Clinical and laboratory features can also aid in prognosti-
cation with regard to flare frequency and accumulation of
organ damage. Analysis of baseline characteristics from pa-
tients who entered in the BLISS-52 and BLISS-76 trials
showed that patients with very high levels of anti-dsDNA
antibodies, the highest quartile of BLyS expression, or history
of prior renal, neurologic, or vasculitic involvement were
more likely to flare [35•]. Interestingly, high BLyS levels were
not associated with greater response rates to belimumab, but
high dsDNA levels and low C3/C4 levels were [36]. Patients
with clinically inactive disease in general fare better, even if
they have serologically active disease. However, even such
patients can flare 59 % after a median of 3 years [37].
Change in the standard laboratory markers in SLE patients
is used in clinical practice to predict flare, though there may be
subsets of patients for whom these measures are more infor-
mative. A study of dynamic changes in C3 and C4 noted
decline in those parameters only in two thirds of patients with
flares but found that polymorphisms in the complement regu-
latory protein factor H were associated with an increase like-
lihood of C3 fall with SLE flare [38]. One study found that an
increase in dsDNA titers by greater than two dilutions was
associated with a disease flare at the subsequent visit, though
there was often a fall of dsDNA titers on the day of acute flares
[39]. A study of ours identified patients with a Bsurge^ in
dsDNA titers, defined as an increase from 0 to 3+/4+ or 1+
to 4+ within a 1-year span. These patients had a higher likeli-
hood of severe flare in the subsequent 6 months relative to
other lupus patients [40].
Tremendous effort has been invested in biomarkers to
guide therapy in SLE, but prediction of disease flares re-
mains inexact. Trials of pre-emptive therapy in patients
with specific patterns of serologic activity have been per-
formed [41], but this practice has not become widespread
as it requires treating substantial numbers of patients who
may not flare to prevent severe flares in a subset of pa-
tients. However, the hope is that our ability to identify
patients at the highest risk of flare will improve, and that
toxicity of our therapy will diminish as newer, targeted
therapies become available.
Page 5 of 10 14
Triggers
Lupus flares can begin in response to a number of stimuli,
only some of which are well understood. These triggers prob-
ably tip the balance towards more immunologic activity be-
yond a critical threshold that leads to significant levels of
inflammation to cause symptoms (Fig. 1). There are important
contributions of medications, environmental factors, and spe-
cific genetic susceptibilities to the end result of lupus flares,
each of which contributes to a greater or lesser extent in each
individual patient. While many flares have no clear precipitat-
ing event, for others there is a clear temporal relationship with
some other factor that may have served to trigger that flare.
SLE patients and rheumatologists have implicated a wide va-
riety of stimuli that may be potentially causative of lupus
flares. Some of the major triggers will be reviewed below.
BUnmasking^ by Tapering
A well-established cause of disease flare is the tapering (espe-
cially if too fast) of steroids or immunosuppressive agents.
This scenario is common, as it is imperative to try to minimize
the use of high doses of steroids in particular. This flare likely
represents a recrudescence of prior subclinical disease activity,
and thus, no other external trigger is required. These flares
generally resolve with resumption of the previously successful
regimen, though often require a short burst of increased doses
of glucocorticoids. Besides glucocorticoids, withdrawal of
HCQ has been associated with more flares [42].
Ultraviolet Light
Ultraviolet (UV) light is the most widely recognized trigger of
SLE flares, and photosensitive rash is included as one of the
diagnostic criteria for SLE. Patients also frequently report oth-
er symptoms with sun exposure, such as arthralgia, weakness,
and headaches [43]. Estimates of the prevalence of photosen-
sitivity in SLE reach up to 50 % of patients and is clearly
implicated in disease flares, both cutaneous and systemic.
Broad spectrum sunscreen use is associated with decreased
inflammatory cell infiltration of the skin and decreased inter-
feron signaling, as well as decreased formation of skin lesions
in photoprovocation studies [44, 45].
The mechanism by which UV light achieves these effects is
only partially understood. UV light exposure is known to di-
rectly damage DNA and proteins in cells, leading to
keratinocyte cell death and the release of proinflammatory
cytokines, such as interleukin-1α and tumor necrosis
factor-α [46]. Additionally, UV light is known to affect the
localization of characteristic autoantigens such as Ro, Sm, and
RNP, redirecting them to the cell surface or to the surface of
apoptotic vesicles [47–50], perhaps rendering them accessible
to binding by autoantibodies and complement proteins.
14 Page 6 of 10
UV light is specifically associated with increased produc-
tion of IFN-α in cutaneous lupus lesions. pDCs have the ca-
pacity to generate large amounts of IFN-α and have been
demonstrated to be present in skin lesions of lupus patients,
though not universally; there appear to be larger number of
pDCs in skin lesions of patients with skin-limited disease rel-
ative to SLE patients [51–53]. One group studying only SLE
patients did not demonstrate increased influx of pDCs with
photoprovocation, but did see an elevation in MxA staining in
lesional skin versus non-lesional skin, correlating with the
influx of T cells and macrophages, implying multiple sources
of IFN-α generation [54].
Hormones and Pregnancy
The extreme discrepancy in SLE incidence between males and
females, and a peak in onset of disease in late adolescence and
young adulthood, has suggested possible hormonal contribu-
tions to SLE, especially estrogens. Estrogens may enhance
immune system activation via several effects, including stim-
ulation of antibody production by B cells and decreased apo-
ptosis of dendritic cells and macrophages. They enhance IL-
10, IL-2, and interferon-γ production and inhibit TNF secre-
tion [55]. During the reproductive years, women have higher
immunoglobulin levels than age-matched males as baseline
and in response to immunizations and infections. Of note,
estrogens have prothrombotic effects, and thus, may trigger
thrombosis in SLE patients with active disease and/or anti-
phospholipid (aPL) antibodies.
The effect of estrogens in the form of oral contraceptive
pills (OCPs) on lupus flares has been examined in clinical
trials. An early trial of high dose estrogen-containing OCPs
in patients with active renal involvement demonstrated an
increased risk of flares [56]. However, Sanchez-Guerrero et
al. found no impact of low-dose estrogen-containing OCPs
relative to progesterone-only OCPs or copper intrauterine de-
vice placement in terms of lupus flare risk in a study of 162
SLE patients [57]. Similarly, Petri et al. found no significant
difference in flare rates among 183 SLE patients with stable
low disease activity or inactive disease receiving combination
estrogen/progesterone OCPs or placebo. In that study, the rate
of mild/moderate flares was 69 % in the OCP group versus
60 % in the placebo group, while the rates of severe flares
were 7.7 versus 7.6 % over the course of the study [5]. A
separate placebo-controlled trial of hormone-replacement
therapy (HRT) in 351 postmenopausal SLE patients did not
find a significant difference in severe flare rate between those
receiving HRT versus those receiving placebo, though there
was an increased risk of mild/moderate flares in the HRT
group, with a relative risk of 1.34. Additionally, while the
study was not powered to evaluate rare thrombotic endpoints
fully, more thrombotic events occurred in the HRT group than
in the placebo group [4].
Curr Rheumatol Rep (2016) 18:14
High amounts of estrogens are naturally found in pregnan-
cy. Whether or not lupus flares are increased during pregnancy
has been a subject of some dispute [58]. A meta-analysis using
data from 37 studies of pregnant SLE patients reported an
overall flare rate of 25.6 % (during 747/2751 pregnancies),
with 16.1 % of flares consisting of nephritis [59]. The largest
single study of pregnancy outcomes, using data obtained from
the PROMISSE cohort, showed that severe flare rates by
weeks 23 and 35 of gestation were 2.5 and 3 %, respectively,
while rates of mild-moderate flares were 12.7 and 9.6 %.
Maternal flares, higher disease activity, and smaller increases
in C3 levels later in pregnancy predicted adverse pregnancy
outcomes [60••]. The apparently low rates of flares reflect the
fact that patients with significant proteinuria, elevated creati-
nine, and prednisone requirements greater than 20 mg/day at
baseline were excluded from the latter study. In older and
retrospective pregnancy studies, flare rates are much higher,
especially if patients had active lupus in the 6 months before
pregnancy (up to 77 %, though estimates vary widely) [58,
61–64]. Among severe flares, renal flares appear to be partic-
ularly prevalent in pregnancies, especially if patients already
had a history of lupus nephritis and were not in complete renal
remission [65, 66]. The best likelihood of good pregnancy
outcomes in SLE patients occur in patients in a sustained
period of low or absent disease activity, especially renal activ-
ity, prior to conception of at least 6 months, and this should be
a goal of pre-conception counseling and management of pa-
tients planning pregnancy.
Prolactin may also be immunostimulatory and is also at high
levels in pregnancy and postpartum. Of note, there is limited
evidence that bromocriptine for 14 days after delivery de-
creased flares of SLE for up to a year compared to controls [67].
Infections
Bacterial and viral infections are often cited by SLE patients as
triggers for their disease; however, the association between
specific infections and specific patients is less clear [68].
Many of the proposed inflammatory mechanisms thought to
contribute to SLE pathogenesis and interferon production,
such as TLR, STING, RIG-I, and MDA5 signaling, are acti-
vated appropriately by bacterial or viral nucleic acids and
proteins. In SLE patients, where these same pathways may
be abnormally activated by self nucleic acids and proteins, it
is plausible that the presence of foreign DNA or molecular
patterns may cause inflammatory responses that are even more
amplified. However, it is also clear that SLE disease flares do
not occur exclusively after infections or with every infection,
so certain infections may be more relevant than others.
One group reviewed 88 cases of identifiable viral infections
in SLE patients. Parvovirus B19 and cytomegalovirus (CMV)
were associated most often with newly diagnosed SLE.
Disseminated infections that resulted in death usually were
Curr Rheumatol Rep (2016) 18:14
herpesviruses, specifically CMV, herpes simplex virus (HSV),
Epstein-Barr virus (EBV), and varicella zoster virus (VZV).
Of note, serious viral infections associated with disease activ-
ity in SLE were reported most often in Asian patients [69].
CMV was studied in detail in 105 SLE patients in a Chinese
cohort, where CMV was detectable at disease onset in 42
cases, associated with disease flare in 31 more, and mimicking
disease flare in 32 cases [70].
Each recognition pathway that drives interferon production
senses different molecules. Control of individual viruses is
often pathway-specific; RNA viruses such as Sendai virus
and vesicular stomatitis virus induce interferon in a MAVS-
dependent fashion, where DNA viruses such as HSV primar-
ily, though not exclusively, stimulate interferon production by
the STING pathway [19]. An SLE-associated polymorphism
in MAVS a sso ciat ed with SLE w as fou nd to b e
hypofunctional, with decreased ability to promote interferon
production [71]. It is tempting to speculate that patients with
specific defects or signaling abnormalities in one pathway
may undergo disease flare after viral or bacterial infection that
is inadequately controlled by that pathway and potentially not
in response to infections controlled by other means.
In addition to directly contributing to disease flares, there is
some evidence for EBV as a contributor to the initial events in
SLE pathogenesis. EBV is a ubiquitous human pathogen, and
serologic evidence of infection is very highly prevalent in almost
all human populations [72]. Studies of key autoantibodies in
SLE led to the discovery that the epitopes recognized by the
Sm and Ro-60kd autoantibodies are structurally very similar to
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
preceding disease onset by years [75]. Periodic reactivation of
EBV can occur, especially in the setting of significant immuno-
suppression. However, there is currently no definitive evidence
that this precedes or is associated with disease flares in SLE.
Medications
SLE can develop in patients receiving certain medications,
such as quinidine, hydralazine, and procainamide. IFN-α has
been associated infrequently with drug-induced lupus (DIL)
when used as a treatment for hepatitis C, which indicates that
IFN may suffice to drive disease in a few susceptible individ-
uals [76, 77]. DIL is classically abrupt in onset, associated with
drug exposure, usually with manifestations affecting the skin,
musculoskeletal, and hematologic systems, only rarely affect-
ing the kidneys or the CNS. Hypocomplementemia and anti-
dsDNA antibodies are also very infrequent. Isolated anti-
histone antibodies are commonly seen in DIL, while SLE pa-
tients usually have additional autoantibodies in addition to
anti-histone. The mainstay of treatment is cessation of the drug
implicated in a given patient [78].
Page 7 of 10 14
Several mechanisms have been proposed for DIL due to
these medications. The drugs could act as haptens, leading to
aberrant presentation of self peptides and driving autoimmu-
nity. An interesting hypothesis is that drugs such as procain-
amide and hydralazine inhibit DNA methyltransferases and
that excessive demethylation causes important alterations of
T cell function, such as amplifying proinflammatory cytokine
production and lysing antigen presenting cells [79, 80]. There
is reduced DNA methylation globally in T cells in SLE pa-
tients [81], indicating that this mechanism may be important in
SLE pathogenesis more broadly than just in DIL.
As antiarrhythmic drugs and hydralazine are used less fre-
quently, the DIL seen with these agents is increasingly rare.
However, DIL has been described in patients receiving anti-
TNF therapy, and this phenomenon will likely grow more
prevalent with the widespread use of these medications.
Isolated seroconversion, with development of new ANA or
anti-dsDNA antibodies, is actually quite common in patients
on anti-TNF therapy, though this does not result in clinical
disease the vast majority of the time [82]. In addition to in-
creased frequency of dsDNA antibodies, SCLE and DLE is
more common, especially in patients receiving etanercept, and
renal and CNS disease have been reported [83]. Cessation of
the anti-TNF medication sufficed to control disease in 94 % of
the reported cases, though steroids were sometimes used for
symptomatic management. Interestingly, rechallenge with the
TNF-alpha inhibitor has been described, but the DIL only
recurred in two of eight reported instances where this was
done [84].
Conclusions
Patients with SLE, as a result of their genetic makeup, envi-
ronmental triggers, and stochastic factors, progressively de-
velop immune system aberrations that manifest with produc-
tion of anti-nuclear as well as many other autoantibodies.
Abnormal immune system activation then leads to inflamma-
tion in various organs and symptoms of lupus flares.
Reduction of immune system activation by use of glucocorti-
coids and immunosuppressive medications brings resolution
of symptoms for some time. However, subclinical immuno-
logic activity commonly persists and with time can lead again
to new flares. This process may be accelerated by certain
triggers of the immune system, such as various infections,
drugs, and hormones. Unfortunately, after each flare, more
damage accumulates in the patients’ organs, as a result of both
the flare itself and the glucocorticoids used to treat it.
We believe that tight surveillance and timely control of
lupus flares with judicial use of effective treatments to ade-
quately suppress the excessive immune system activation are
required to bring about long-term remission of the disease. We
hope that new clinical trials will soon offer additional effective
14 Page 8 of 10
and target-specific biologic treatments for SLE that will help
us achieve these goals without the high toxicity currently seen
with glucocorticoids and other immunosuppressive
medications.
Compliance with Ethics Guidelines
Conflicts of Interest The authors declare that they have no competing
interests.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
References
Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance
1. Stoll T, Sutcliffe N, Mach J, Klaghofer R, Isenberg DA. Analysis of
the relationship between disease activity and damage in patients
with systemic lupus erythematosus—a 5-yr prospective study.
Rheumatology (Oxford). 2004;43(8):1039–44.
2. Zhu TY, Tam L-S, Lee VWY, Lee KK, Li EK. Relationship be-
tween flare and health-related quality of life in patients with sys-
temic lupus erythematosus. J Rheumatol. 2010;37(3):568–73.
3. Ruperto N, Hanrahan LM, Alarcón GS, et al. International consen-
sus for a definition of disease flare in lupus. Lupus. 2011;20(5):
453–62.
4. Buyon JP, Petri MA, Kim MY, et al. The effect of combined estro-
gen and progesterone hormone replacement therapy on disease ac-
tivity in systemic lupus erythematosus: a randomized trial. Ann
Intern Med. 2005;142(12 Pt 1):953–62.
5. Petri M, Kim MY, Kalunian KC, et al. Combined oral contracep-
tives in women with systemic lupus erythematosus. N Engl J Med.
2005;353(24):2550–8.
6. Isenberg DA, Rahman A, Allen E, et al. BILAG 2004.
Development and initial validation of an updated version of the
British Isles Lupus Assessment Group’s disease activity index for
patients with systemic lupus erythematosus. Rheumatology
(Oxford). 2005;44(7):902–6.
7. Thanou A, Chakravarty E, James JA, Merrill JT. How should lupus
flares be measured? Deconstruction of the safety of estrogen in
lupus erythematosus national assessment-systemic lupus erythema-
tosus disease activity index flare index. Rheumatology (Oxford).
2014;53(12):2175–81.
8. Isenberg DA, Allen E, Farewell V, et al. An assessment of disease
flare in patients with systemic lupus erythematosus: a comparison
of BILAG 2004 and the flare version of SELENA. Ann Rheum Dis.
2011;70(1):54–9.
9. Laustrup H, Voss A, Green A, Junker P. SLE disease patterns in a
Danish population-based lupus cohort: an 8-year prospective study.
Lupus. 2010;19(3):239–46.
10. van den Berg L, Nossent H, Rekvig O. Prior anti-dsDNA antibody
status does not predict later disease manifestations in systemic lupus
erythematosus. Clin Rheumatol. 2006;25(3):347–52.
Curr Rheumatol Rep (2016) 18:14
11. Furie R, Petri M, Zamani O, et al. A phase III, randomized, placebo-
controlled study of belimumab, a monoclonal antibody that inhibits
B lymphocyte stimulator, in patients with systemic lupus erythema-
tosus. Arthritis Rheum. 2011;63(12):3918–30.
12. Manzi S, Sánchez-Guerrero J, Merrill JT, et al. Effects of beli-
mumab, a B lymphocyte stimulator-specific inhibitor, on disease
activity across multiple organ domains in patients with systemic
lupus erythematosus: combined results from two phase III trials.
Ann Rheum Dis. 2012;71(11):1833–8.
13. Navarra SV, Guzmán RM, Gallacher AE, et al. Efficacy and safety
of belimumab in patients with active systemic lupus erythematosus:
a randomised, placebo-controlled, phase 3 trial. Lancet (London,
England). 2011;377(9767):721–31. doi:10.1016/S0140-6736(10)
61354-2.
14. Welcher AA, Boedigheimer M, Kivitz AJ, et al. Blockade of
interferon-γ normalizes interferon-regulated gene expression and
serum CXCL10 levels in patients with systemic lupus erythemato-
sus. Arthritis Rheumatol (Hoboken, NJ). 2015;67(10):2713–22.
15. Chiche L, Jourde-Chiche N, Whalen E, et al. Modular transcrip-
tional repertoire analyses of adults with systemic lupus erythema-
tosus reveal distinct type I and type II interferon signatures. Arthritis
Rheumatol (Hoboken, NJ). 2014;66(6):1583–95.
16. Crow YJ, Manel N. Aicardi-Goutières syndrome and the type I
interferonopathies. Nat Rev Immunol. 2015;15(7):429–40.
17. Barbalat R, Ewald SE, Mouchess ML, Barton GM. Nucleic acid
recognition by the innate immune system. Annu Rev Immunol.
2011;29:185–214.
18. Ishikawa H, Ma Z, Barber GN. STING regulates intracellular
DNA-mediated, type I interferon-dependent innate immunity.
Nature. 2009;461(7265):788–92.
19.•• Pandey S, Kawai T, Akira S. Microbial sensing by Toll-like recep-
tors and intracellular nucleic acid sensors. Cold Spring Harb
Perspect Biol. 2015;7(1):a016246. Excellent overview of extracel-
lular and intracellular nucleic acid recognition pathways.
20. Pazmandi K, Agod Z, Kumar BV, et al. Oxidative modification
enhances the immunostimulatory effects of extracellular mitochon-
drial DNA on plasmacytoid dendritic cells. Free Radic Biol Med.
2014;77:281–90.
21. Garcia-Romo GS, Caielli S, Vega B, et al. Netting neutrophils are
major inducers of type I IFN production in pediatric systemic lupus
erythematosus. Sci Transl Med. 2011;3(73):73ra20.
22. Lande R, Ganguly D, Facchinetti V, et al. Neutrophils activate
plasmacytoid dendritic cells by releasing self-DNA-peptide com-
plexes in systemic lupus erythematosus. Sci Transl Med.
2011;3(73):73ra19.
23. Wang H, Li T, Chen S, Gu Y, Ye S. Neutrophil extracellular trap
mitochondrial DNA and its autoantibody in systemic lupus erythe-
matosus and a proof-of-concept trial of metformin. Arthritis
Rheumatol (Hoboken, NJ). 2015;67(12):3190–200.
24. Truedsson L, Bengtsson AA, Sturfelt G. Complement deficiencies
and systemic lupus erythematosus. Autoimmunity. 2007;40(8):
560–6.
25. Rice GI, Rodero MP, Crow YJ. Human disease phenotypes associ-
ated with mutations in TREX1. J Clin Immunol. 2015;35(3):235–
43.
26. Baechler EC, Batliwalla FM, Karypis G, et al. Interferon-inducible
gene expression signature in peripheral blood cells of patients with
severe lupus. Proc Natl Acad Sci U S A. 2003;100(5):2610–5.
27. Bennett L, Palucka AK, Arce E, et al. Interferon and granulopoiesis
signatures in systemic lupus erythematosus blood. J Exp Med.
2003;197(6):711–23.
28. Kirou KA, Lee C, George S, et al. Coordinate overexpression of
interferon-alpha-induced genes in systemic lupus erythematosus.
Arthritis Rheum. 2004;50(12):3958–67.
29. Feng X, Wu H, Grossman JM, et al. Association of increased
interferon-inducible gene expression with disease activity and lupus
Curr Rheumatol Rep (2016) 18:14
nephritis in patients with systemic lupus erythematosus. Arthritis
Rheum. 2006;54(9):2951–62.
30. Landolt-Marticorena C, Bonventi G, Lubovich A, et al. Lack of
association between the interferon-signature and longitudinal
changes in disease activity in systemic lupus erythematosus. Ann
Rheum Dis. 2008;68(9):1440–6.
31. Bauer JW, Petri M, Batliwalla FM, et al. Interferon-regulated
chemokines as biomarkers of systemic lupus erythematosus disease
activity: a validation study. Arthritis Rheum. 2009;60(10):3098–
107.
32. Petri M, Singh S, Tesfasyone H, et al. Longitudinal expression of
type I interferon responsive genes in systemic lupus erythematosus.
Lupus. 2009;18(11):980–9.
33. Barr SG, Zonana-Nacach A, Magder LS, Petri M. Patterns of dis-
ease activity in systemic lupus erythematosus. Arthritis Rheum.
1999;42(12):2682–8.
34. McKinney EF, Lee JC, Jayne DRW, Lyons PA, Smith KGC. T-cell
exhaustion, co-stimulation and clinical outcome in autoimmunity
and infection. Nature. 2015;523(7562):612–6.
35.• Petri MA, van Vollenhoven RF, Buyon J, et al. Baseline predictors
of systemic lupus erythematosus flares: data from the combined
placebo groups in the phase III belimumab trials. Arthritis Rheum.
2013;65(8):2143–53. This is a comprehensive analysis of clinical
and laboratory predictors of lupus flare derived from patients
enrolled in clinical trials of beliumumab.
36. Stohl W, Hiepe F, Latinis KM, et al. Belimumab reduces autoanti-
bodies, normalizes low complement levels, and reduces select B
cell populations in patients with systemic lupus erythematosus.
Arthritis Rheum. 2012;64(7):2328–37.
37. Steiman AJ, Gladman DD, Ibañez D, Urowitz MB. Prolonged se-
rologically active clinically quiescent systemic lupus erythemato-
sus: frequency and outcome. J Rheumatol. 2010;37(9):1822–7.
38. Birmingham DJ, Irshaid F, Nagaraja HN, et al. The complex nature
of serum C3 and C4 as biomarkers of lupus renal flare. Lupus.
2010;19(11):1272–80.
39. Ho A, Magder LS, Barr SG, Petri M. Decreases in anti-double-
stranded DNA levels are associated with concurrent flares in pa-
tients with systemic lupus erythematosus. Arthritis Rheum.
2001;44(10):2342–9.
40. Pan N, Amigues I, Lyman S, et al. A surge in anti-dsDNA titer
predicts a severe lupus flare within Six months. Lupus.
2014;23(3):293–8.
41. Tseng C-E, Buyon JP, Kim M, et al. The effect of moderate-dose
corticosteroids in preventing severe flares in patients with serolog-
ically active, but clinically stable, systemic lupus erythematosus:
findings of a prospective, randomized, double-blind, placebo-
controlled trial. Arthritis Rheum. 2006;54(11):3623–32.
42. A randomized study of the effect of withdrawing
hydroxychloroquine sulfate in systemic lupus erythematosus.
The Canadian Hydroxychloroquine Study Group. N Engl J Med.
1991;324(3):150-54.
43. Foering K, Chang AY, Piette EW, Cucchiara A, Okawa J, Werth VP.
Characterization of clinical photosensitivity in cutaneous lupus er-
ythematosus. J Am Acad Dermatol. 2013;69(2):205–13.
44. Kuhn A, Gensch K, Haust M, et al. Photoprotective effects of a
broad-spectrum sunscreen in ultraviolet-induced cutaneous lupus
erythematosus: a randomized, vehicle-controlled, double-blind
study. J Am Acad Dermatol. 2011;64(1):37–48.
45. Zahn S, Graef M, Patsinakidis N, et al. Ultraviolet light protection
by a sunscreen prevents interferon-driven skin inflammation in cu-
taneous lupus erythematosus. Exp Dermatol. 2014;23(7):516–8.
46. Achtman JC, Werth VP. Pathophysiology of cutaneous lupus ery-
thematosus. Arthritis Res Ther. 2015;17:182.
47. LeFeber WP, Norris DA, Ryan SR, et al. Ultraviolet light induces
binding of antibodies to selected nuclear antigens on cultured hu-
man keratinocytes. J Clin Invest. 1984;74(4):1545–51.
Page 9 of 10 14
48. Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in
systemic lupus erythematosus are clustered in two populations of
surface structures on apoptotic keratinocytes. J Exp Med.
1994;179(4):1317–30.
49. Caricchio R, McPhie L, Cohen PL. Ultraviolet B radiation-induced
cell death: critical role of ultraviolet dose in inflammation and lupus
autoantigen redistribution. J Immunol. 2003;171(11):5778–86.
50. Lawley W. Rapid lupus autoantigen relocalization and reactive ox-
ygen species accumulation following ultraviolet irradiation of hu-
man keratinocytes. Rheumatology. 2000;39(3):253–61.
51. Farkas L, Beiske K, Lund-Johansen F, Brandtzaeg P, Jahnsen FL.
Plasmacytoid dendritic cells (natural interferon-α/β-producing
cells) accumulate in cutaneous lupus erythematosus lesions. Am J
Pathol. 2001;159(1):237–43.
52. Vermi W, Lonardi S, Morassi M, et al. Cutaneous distribution of
plasmacytoid dendritic cells in lupus erythematosus. Selective tro-
pism at the site of epithelial apoptotic damage. Immunobiology.
2009;214(9-10):877–86.
53. Meller S, Winterberg F, Gilliet M, et al. Ultraviolet radiation-
induced injury, chemokines, and leukocyte recruitment: an ampli-
fication cycle triggering cutaneous lupus erythematosus. Arthritis
Rheum. 2005;52(5):1504–16.
54. Reefman E, Kuiper H, Limburg PC, Kallenberg CGM, Bijl M.
Type I interferons are involved in the development of ultraviolet
B-induced inflammatory skin lesions in systemic lupus
erythaematosus patients. Ann Rheum Dis. 2008;67(1):11–8.
55. Zen M, Ghirardello A, Iaccarino L, et al. Hormones, immune re-
sponse, and pregnancy in healthy women and SLE patients. Swiss
Med Wkly. 2010;140(13-14):187–201.
56. Jungers P. Lupus nephropathy and pregnancy. Arch Intern Med.
1982;142(4):771.
57. Sánchez-Guerrero J, Uribe AG, Jiménez-Santana L, et al. A trial of
contraceptive methods in women with systemic lupus erythemato-
sus. N Engl J Med. 2005;353(24):2539–49.
58. Lockshin MD. Pregnancy does not cause systemic lupus erythema-
tosus to worsen. Arthritis Rheum. 1989;32(6):665–70.
59. Smyth A, Oliveira GHM, Lahr BD, Bailey KR, Norby SM, Garovic
VD. A systematic review and meta-analysis of pregnancy outcomes
in patients with systemic lupus erythematosus and lupus nephritis.
Clin J Am Soc Nephrol. 2010;5(11):2060–8.
60.•• Buyon JP, Kim MY, Guerra MM, et al. Predictors of pregnancy
outcomes in patients with lupus: a cohort study. Ann Intern Med.
2015;163(3):153–63. Largest and most methodologically rigor-
ous cohort study examining pregnancy outcomes in patients
with lupus, supporting the conclusion that pregnancy can be
safely undertaken in patients with low disease activity at time
of conception.
61. Petri M, Howard D, Repke J. Frequency of lupus flare in pregnancy.
The Hopkins Lupus Pregnancy Center experience. Arthritis
Rheum. 1991;34(12):1538–45.
62. Ruiz-Irastorza G, Lima F, Alves J, et al. Increased rate of lupus flare
during pregnancy and the puerperium: a prospective study of 78
pregnancies. Br J Rheumatol. 1996;35(2):133–8.
63. Saavedra MA, Sánchez A, Morales S, Navarro-Zarza JE, Ángeles
U, Jara LJ. Primigravida is associated with flare in women with
systemic lupus erythematosus. Lupus. 2015;24(2):180–5.
64. Koh JH, Ko HS, Kwok S-K, Ju JH, Park S-H. Hydroxychloroquine
and pregnancy on lupus flares in Korean patients with systemic
lupus erythematosus. Lupus. 2015;24(2):210–7.
65. Chen S, Sun X, Wu B, Lian X. Pregnancy in women with systemic
lupus erythematosus: a retrospective study of 83 pregnancies at a
single centre. Int J Environ Res Public Health. 2015;12(8):9876–
88.
66. Imbasciati E, Tincani A, Gregorini G, et al. Pregnancy in women
with pre-existing lupus nephritis: predictors of fetal and maternal
outcome. Nephrol Dial Transplant. 2009;24(2):519–25.
14 Page 10 of 10
67. Qian Q, Liuqin L, Hao L, et al. The effects of bromocriptine on
preventing postpartum flare in systemic lupus erythematosus pa-
tients from South China. J Immunol Res. 2015;2015:316965.
68. Rigante D, Esposito S. Infections and systemic lupus erythemato-
sus: binding or sparring partners? Int J Mol Sci. 2015;16(8):17331–
43.
69. Ramos-Casals M, Cuadrado MJ, Alba P, et al. Acute viral infections
in patients with systemic lupus erythematosus: description of 23
cases and review of the literature. Medicine (Baltimore).
2008;87(6):311–8.
70. Zhang J, Dou Y, Zhong Z, et al. Clinical characteristics and therapy
exploration of active human cytomegalovirus infection in 105 lupus
patients. Lupus. 2014;23(9):889–97.
71. Pothlichet J, Niewold TB, Vitour D, Solhonne B, Crow MK, Si-
Tahar M. A loss-of-function variant of the antiviral molecule
MAVS is associated with a subset of systemic lupus patients.
EMBO Mol Med. 2011;3(3):142–52.
72. Balfour HH, Sifakis F, Sliman JA, Knight JA, Schmeling DO,
Thomas W. Age-specific prevalence of Epstein-Barr virus infection
among individuals aged 6-19 years in the United States and factors
affecting its acquisition. J Infect Dis. 2013;208(8):1286–93.
73. McClain MT, Heinlen LD, Dennis GJ, Roebuck J, Harley JB,
James JA. Early events in lupus humoral autoimmunity suggest
initiation through molecular mimicry. Nat Med. 2005;11(1):85–9.
74. Arbuckle MR, Reichlin M, Harley JB, James JA. Shared early
autoantibody recognition events in the development of anti-Sm B/
B’ in human lupus. Scand J Immunol. 1999;50(5):447–55.
75. Arbuckle MR, McClain MT, Rubertone MV, et al. Development of
autoantibodies before the clinical onset of systemic lupus erythe-
matosus. N Engl J Med. 2003;349(16):1526–33.
76. Fukuyama S, Kajiwara E, Suzuki N, Miyazaki N, Sadoshima S,
Onoyama K. Systemic lupus erythematosus after alpha-interferon
therapy for chronic hepatitis C: a case report and review of the
literature. Am J Gastroenterol. 2000;95(1):310–2.
77. Ho V, Mclean A, Terry S. Severe systemic lupus erythematosus
induced by antiviral treatment for hepatitis C. J Clin Rheumatol.
2008;14(3):166–8.
78. Rubin RL. Etiology and mechanisms of drug-induced lupus. Curr
Opin Rheumatol. 1999;11(5):357–63.
79. Quddus J, Johnson KJ, Gavalchin J, et al. Treating activated CD4+
T cells with either of two distinct DNA methyltransferase inhibitors,
5-azacytidine or procainamide, is sufficient to cause a lupus-like
disease in syngeneic mice. J Clin Invest. 1993;92(1):38–53.
80. Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S,
Richardson B. Hydralazine and procainamide inhibit T cell DNA
methylation and induce autoreactivity. J Immunol. 1988;140(7):
2197–200.
81. Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S, Johnson
M. Evidence for impaired T cell DNA methylation in systemic
lupus erythematosus and rheumatoid arthritis. Arthritis Rheum.
1990;33(11):1665–73.
82. Takase K, Horton SC, Ganesha A, et al. What is the utility of routine
ANA testing in predicting development of biological DMARD-
Curr Rheumatol Rep (2016) 18:14
induced lupus and vasculitis in patients with rheumatoid arthritis?
Data from a single-centre cohort. Ann Rheum Dis. 2014;73(9):
1695–9.
83. Araújo-Fernández S, Ahijón-Lana M, Isenberg DA. Drug-induced
lupus: including anti-tumour necrosis factor and interferon induced.
Lupus. 2014;23(6):545–53.
84. Ramos-Casals M, Brito-Zerón P, Muñoz S, et al. Autoimmune dis-
eases induced by TNF-targeted therapies: analysis of 233 cases.
Medicine (Baltimore). 2007;86(4):242–51.
85. Petri M, Genovese M, Engle E, Hochberg M. Definition, incidence,
and clinical description of flare in systemic lupus erythematosus. A
prospective cohort study. Arthritis Rheum. 1991;34(8):937–44.
86. Petri M, Singh S, Tesfasyone H, Malik A. Prevalence of flare and
influence of demographic and serologic factors on flare risk in
systemic lupus erythematosus: a prospective study. J Rheumatol.
2009;36(11):2476–80.
87. Gordon C, Sutcliffe N, Skan J, Stoll T, Isenberg DA. Definition and
treatment of lupus flares measured by the BILAG index.
Rheumatology (Oxford). 2003;42(11):1372–9.
88. Nannini C, Crowson CS, Matteson EL, Moder KG. Mycophenolate
mofetil is effective in reducing disease flares in systemic lupus
erythematosus patients: a retrospective study. Lupus. 2009;18(5):
394–9.
89. Nikpour M, Urowitz MB, Ibañez D, Gladman DD. Frequency and
determinants of flare and persistently active disease in systemic
lupus erythematosus. Arthritis Rheum. 2009;61(9):1152–8.
90. Nossent J, Kiss E, Rozman B, et al. Disease activity and damage
accrual during the early disease course in a multinational inception
cohort of patients with systemic lupus erythematosus. Lupus.
2010;19(8):949–56.
91. Kalunian KC, Merrill JT, Maciuca R, et al. A Phase II study of the
efficacy and safety of rontalizumab (rhuMAb interferon-α) in pa-
tients with systemic lupus erythematosus (ROSE). Ann Rheum Dis.
2016;75(1):196–202.
92. Costedoat-Chalumeau N, Galicier L, Aumaître O, et al.
Hydroxychloroquine in systemic lupus erythematosus: results of
a French multicentre controlled trial (PLUS study). Ann Rheum
Dis. 2013;72(11):1786–92.
93. Merrill JT, Burgos-Vargas R, Westhovens R, et al. The effi-
cacy and safety of abatacept in patients with non-life-
threatening manifestations of systemic lupus erythematosus:
results of a twelve-month, multicenter, exploratory, phase
IIb, randomized, double-blind, placebo-controlled trial.
Arthritis Rheum. 2010;62(10):3077–87.
94. Isenberg D, Gordon C, Licu D, Copt S, Rossi CP, Wofsy D.
Efficacy and safety of atacicept for prevention of flares in patients
with moderate-to-severe systemic lupus erythematosus (SLE): 52-
week data (APRIL-SLE randomised trial). Ann Rheum Dis.
2015;74(11):2006–15.
95. Merrill J, Buyon J, Furie R, et al. Assessment of flares in lupus
patients enrolled in a phase II/III study of rituximab
(EXPLORER). Lupus. 2011;20(7):709–16.