How to treat refractory arthritis in lupus? Mathieu Artifoni , Xavier Puéchal Review

Joint Bone Spine 79 (2012) 347–350
Available online at
www.sciencedirect.com
Review
How to treat refractory arthritis in lupus?
Mathieu Artifoni a , Xavier Puéchal a,∗,b
a
b
Center for Rare Systemic Auto-immune Diseases, Department of Rheumatology, Le Mans General Hospital, 194, avenue Rubillard, 72000 Le Mans, France
National Referral Center for Rare Systemic Auto-immune Diseases, Necrotizing Vasculitides, Cochin Hospital, 27, rue du Faubourg-Saint-Jacques, 75679 Paris cedex 14, France
a r t i c l e
i n f o
Article history:
Accepted 20 December 2011
Available online 14 February 2012
Keywords:
Systemic lupus erythematosus
Arthritis
Biodrugs
a b s t r a c t
Arthritis in systemic lupus erythematosus (SLE) is episodic and self-limited in most patients. However, in
some cases, refractory joint problems occur and may be poorly controlled by NSAIDs and other treatments.
Damage to joints and to other organs must be considered when making any decision to prescribe such
other treatments. In the context of new and potent biodrugs, we have reviewed and analysed here all
Medline published data on arthritis treatment in SLE, as well as the French recommendations (Protocol
national de diagnostic et de soins [PNDS] and Club Rhumatismes et Inflammation [CRI]). In SLE patients with
isolated, intermittent joint symptoms, short courses of NSAIDs should be used as the first-line treatment.
If joint symptoms are more severe or recurrent, a combination of low-dose corticosteroids (≤ 10 mg/day)
and antimalarial drugs is recommended. Corticosteroid infiltrations may be useful on occasions, in cases of
persistent localised arthritis. If joint symptoms persist, treatment indications depend on the other organs
affected. In joint forms that are refractory to treatment or corticodependent and requiring an unacceptable
dose of prednisone in a patient with confirmed compliance with treatment, methotrexate should be
proposed initially, in combination with antimalarial drugs. In cases of treatment failure or intolerance,
mycophenolate mofetil or even azathioprine may be considered as an alternative treatment. As a last
resort, after having weighed up the individual benefit-risk ratio, leflunomide, belimumab, rituximab or
abatacept may be considered, on a case-by-case basis, and anti-TNF antibodies may be considered in
exceptional cases.
© 2012 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
The aim of treatment for joint symptoms in systemic lupus
erythematosus (SLE) is to decrease inflammation and pain, and
to preserve function, increasing the quality of life of the patient
whilst limiting adverse effects. Given the episodic and limited
nature of articular flare-ups in most SLE patients, non-steroidal
anti-inflammatory drugs (NSAIDs) are routinely prescribed as a
first-line, short-term treatment [1]. In a cohort of patients with SLE,
the prevalence of NSAID prescription during the course of the disease was found to be about 75% [2]. Renal involvement should be
considered a contraindication to the use of NSAIDS in SLE patients,
and rigorous renal and hepatic monitoring is required when these
drugs are prescribed. Similarly, the cardiac toxicity of NSAIDS
should be taken into account, given the frequency and severity
of the cardiovascular complications observed during the course
of the disease. Finally, NSAIDS may increase skin photosensitivity and a few cases of aseptic meningitis have been reported. Some
patients with SLE present episodes of refractory joint problems or
of joint problems poorly controlled by NSAIDs. Other treatments
are therefore required, but possible damage to other organs must
∗ Corresponding author. Tel.: +02 43 43 26 56; fax: +02 43 43 28 10.
E-mail address: [email protected] (X. Puéchal).
be considered when making any decision to prescribe such other
treatments.
In the context of new and potent biodrugs, we have reviewed all
Medline published data on arthritis treatment in SLE, the recommendations of the Protocol national de diagnostic et de soins (PNDS;
the French national diagnosis and care protocol) [3] and of the Club
Rhumatismes et Inflammation (CRI) [4]. EULAR has issued no recommendations concerning articular manifestations of lupus [5]. Very
few double blind randomised trials have been published on this
topic and therapy is often based on expert’s opinion. We propose
here to review and criticise the efficacy and safety data of all published articles on arthritis treatment in SLE. Based on these data,
a course of action to be followed, according to the details of the
clinical circumstances, has been developed and is shown in Box 1 .
1. Antimalarial drugs
Two synthetic antimalarial drugs have been authorised for use
in the treatment of SLE: hydroxychloroquine and chloroquine. The
most frequently used doses are 400 mg/day for hydroxychloroquine (≤ 6.5 mg/kg/day, to limit the risks of ocular toxicity) and
4 mg/kg/day for chloroquine. Recent data have implicated toll-like
receptors in SLE and may represent further indirect evidence for
1297-319X/$ – see front matter © 2012 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
doi:10.1016/j.jbspin.2011.12.010
348
M. Artifoni, X. Puéchal / Joint Bone Spine 79 (2012) 347–350
Box 1: How should joint symptoms associated with systemic lupus erythematosus (SLE) be treated?
In SLE patients with isolated, intermittent joint symptoms,
short courses of NSAIDs should be used as the first-line treatment.
If joint symptoms are more severe or recurrent, a combination of low-dose corticosteroids (≤ 10 mg/day) and antimalarial
drugs is recommended.
Corticosteroid infiltrations may be useful on occasions, in
cases of persistent localised arthritis.
If joint symptoms persist, treatment indications depend on
the other organs affected. In joint forms that are refractory to
treatment, or corticodependent, and requiring an unacceptable
dose of prednisone in a patient with confirmed compliance
with treatment, methotrexate should be proposed initially, in
combination with antimalarial drugs. In cases of treatment failure or intolerance, mycophenolate mofetil or even azathioprine
may be considered as an alternative treatment.
As a last resort, after having weighed up the individual
benefit-risk ratio, leflunomide, belimumab, rituximab or abatacept may be considered, on a case-by-case basis, and anti-TNF
antibodies may be considered in exceptional cases.
a role of antimalarial drugs in the treatment of this auto-immune
disease [6]. In a double-blind, prospective, randomised multicentre study, 71 patients with moderate SLE and arthritis or arthralgia
were randomised to two groups, one receiving hydroxychloroquine
and the other receiving placebo, for 48 weeks [7]. No improvement
was observed for any of the articular index, synovitis index or overall evaluation of the disease by the patient or the investigator. In
another double-blind, randomised, controlled study, 11 patients
were treated with chloroquine and 12 patients were treated with
placebo for 12 months [8]. Chloroquine significantly decreased joint
symptoms and the dose of prednisone prescribed during the course
of the study, in 82% of patients, whereas such decreases were
achieved in only 25% of the patients in the placebo group. Several authors [9] and the PNDS [4] have highlighted the importance
of amino-4-quinolines as a maintenance treatment for all patients
with SLE, specifying that the time lag to efficacy against joint symptoms is 2 to 12 weeks.
2. Corticosteroids
Low-dose corticosteroids are widely used in the treatment of SLE
and its joint signs. The beneficial effects of such treatment were suggested, in particular, by a double-blind, prospective, randomised
study comparing corticosteroids with placebo for the prevention
of clinical relapses in 41 patients suffering from SLE with an isolated increase in markers of biological activity [10]. In the placebo
group, there were six severe flare-ups, including three with joint
symptoms, whereas no flare-ups were observed in the prednisone
group (P = 0.007).
No other study, to our knowledge, has specifically evaluated
the efficacy of corticosteroids for treating joint symptoms of lupus.
Nevertheless, corticosteroids are clearly very effective against such
symptoms. Small doses should be used (≤ 10 mg/day of prednisone
equivalent), principally to limit the risk of infection, cardiovascular
complications, osteoporosis and cataracts. When higher doses are
required, a corticoid sparing agent should be added to decrease the
corticosteroid daily dose, keeping in mind that such high dose are
justified only in cases of other associated systemic signs [1] and
are associated with long term damage. In addition to this systemic
use, the direct injection of corticosteroids into joints is sometimes
useful in the therapeutic management of certain refractory joint
symptoms, particularly those affecting large joints. The PNDS
recommends the use of low doses of corticosteroids
(< 0.25 mg/kg/day) in cases of arthritis resistant to NSAIDs and
hydroxychloroquine, together with infiltrations of corticosteroids
into joints in cases of chronic arthritis not responding to NSAIDs
or antimalarial drugs [3].
3. Methotrexate
Methotrexate is the molecule most studied for the treatment
of joint symptoms associated with lupus. A double-blind, randomised study compared methotrexate (15–20 mg/week) with
placebo over a period of 6 months, in 41 SLE patients; more than
80% of the patients presented arthralgia or arthritis, the frequencies of these conditions being similar in the two groups [11].
At the end of the study, 16 patients in the placebo group and
one of the 18 patients in the group treated with methotrexate
still had arthralgia or arthritis (P < 0.001). Equally significantly, 13
patients in the methotrexate group were able to decrease their daily
intake of corticosteroids, whereas this was possible for only one
patient in the placebo group. Another double-blind, randomised,
placebo-controlled study including about 60 patients, demonstrated methotrexate to be effective, allowing modest reductions
in corticosteroid use, with no reports of joint symptoms [12].
Other prospective studies have focused on the efficacy of
methotrexate against joint signs in lupus, but these studies were
not randomised and included only small numbers of patients.
One prospective open study included 12 patients treated with
methotrexate for SLE, seven of whom had joint symptoms refractory to treatment [13]. All showed an improvement over 2 to
8 weeks, with a significant decrease in the mean number of episodes
of synovitis. Another prospective study included 22 patients suffering from SLE not affecting the kidney or the central nervous system, 12 of whom had joint signs. All the patients were treated with
15 mg of methotrexate per week for 6 months [14]. Joint symptoms
disappeared completely in 10 patients, with a significant decrease
in mean activity score for SLE (SLEDAI; P = 0.001) and in mean corticosteroid dose (P = 0.01). None of the patients withdrew from the
study and methotrexate was well tolerated. The PNDS recommends
low-dose methotrexate (off-label prescription) in cases of chronic
polyarthritis resistant to amino-4-quinolines and to corticosteroids
[3]. The dose generally prescribed is 15 to 20 mg per week. This
treatment may make it possible to reduce cortisone treatment.
4. Other immunosuppressants
According to the PNDS guidelines published in 2009, the efficacy
of other immunosuppressants (azathioprine, off-label mycophenolic acid, cyclophosphamide) against joint symptoms remains
unproven [3].
4.1. Mycophenolate mofetil (MMF)
Few studies have evaluated the efficacy of MMF against
extrarenal manifestations of lupus. An open, uncontrolled, prospective study included 21 patients with refractory lupus, 20 of
whom initially had active joint disorders [15]. MMF (2 g/day)
significantly decreased SLEDAI scores (P = 0.0001) and the daily
dose of corticosteroids (P = 0.0001). The efficacy of this treatment
against joint symptoms was not reported. Another randomised,
open, prospective study compared MMF treatment with monthly
cyclophosphamide perfusions over 6 months, in addition to corticosteroids prescribed at decreasing doses but initially at up to
60 mg/day, in 370 patients with renal involvement (classes III, IV
and V) [16]. If we consider only the patients with moderate to severe
musculoskeletal signs, BILAG classification A or B, the 23 (85%) of
M. Artifoni, X. Puéchal / Joint Bone Spine 79 (2012) 347–350
349
the 27 patients in the MMF group displayed improvements in joint
symptoms over a period of 6 months, versus 30 (91%) of the 33
patients in the group treated with cyclophosphamide. This difference is not significant. The efficacy of treatment against extrarenal
symptoms, including joint symptoms, in both arms of the study may
be accounted for by the high doses of corticosteroids administered
in parallel. Thus, evidence from the literature are lacking to suggest
that MMF may be efficient for treating lupus arthritis since all the
patients in the randomised controlled trials received also moderate
to high corticosteroid dose.
improvement in SELENA-SLEDAI or musculoskeletal BILAG score.
Belimumab has been approved by the European regulatory agency
for adult patients with active autoantibody-positive SLE with a high
degree of disease activity despite standard therapy. It has potential
for use as a treatment for severe joint symptoms in lupus that are
resistant to corticosteroid treatment or refractory to conventional
treatment.
4.2. Azathioprine
A double-blind, prospective, randomised, placebo-controlled
study evaluated abatacept as a treatment for the extrarenal signs
of SLE (polyarthritis, discoid lesions or pleurisy and/or pericarditis) [28]. In total, 175 patients received abatacept or placebo for
a period of 1 year, with corticosteroid initially administered at a
dose of 30 mg/day for one month, and subsequently tapered in a
planned manner. More than half the patients presented arthritis
on inclusion. The study showed no benefit of abatacept in terms
of the principal or secondary outcome measures. In the subgroup
of 95 patients with joint symptoms, a posteriori analysis indicated
a lower proportion of BILAG A flare-ups during the year: 36.5% in
the abatacept group, versus 62.5% in the placebo group (treatmentlinked difference of −26.1 [95% CI: −47; −4.8]. However, severe
adverse effects were more frequent in the abatacept group (19.8%)
than in the placebo group (6.8%). The CRI recommendations note
the lack of efficacy of abatacept and the associated increase in
the frequency of serious adverse effects in this first controlled
study; therefore, they state that whilst awaiting the results of the
placebo-controlled studies on lupus-associated glomerulonephritis, patients with SLE should not be treated with abatacept [4].
Nevertheless, for patients with lupus manifesting essentially as a
corticodependent joint disease, this treatment may be considered,
in discussion with a reference centre or other experts, if there has
been treatment failure with all other strategies attempted.
There have been many published reports concerning the efficacy
of azathioprine against the renal signs of SLE [17,18], but only the
older series reported an efficacy of azathioprine against non-renal
signs [19,20]. Azathioprine could be used to decrease cortisone
doses during the treatment of severe joint symptoms of SLE.
4.3. Leflunomide
Only one randomised, double-blind study, including 12 patients
with SLE of low to moderate activity levels, has compared leflunomide with placebo [21]. Six of the patients had joint symptoms
and six had renal signs. After 24 weeks of treatment, the decrease
in SLEDAI score was significantly greater in the leflunomide group
than in the placebo group, with no change in the dose of corticosteroids. The four patients with arthritis in the leflunomide group
responded to treatment, versus only one of the two patients with
arthritis in the placebo group. It should be noted that several cases
of cutaneous lupus flare-up among the patients on leflunomide
were reported.
5. Biodrugs
5.3. Abatacept
5.1. Rituximab
Two large, double-blind, randomised studies have reported no
significant benefits of rituximab in the treatment of extrarenal [22]
or renal [23] signs of SLE. These results contrast with the results
obtained in many open studies. However, neither of these two studies specifically reported findings for joint symptoms. The French
AIR Registry has analysed the data of 136 patients with lupus who
had been treated with rituximab [24]. Joint symptoms were present
and evaluable in 50 of these patients before treatment: 26 (52%)
displayed a complete response and 10 (20%) displayed a partial
response in terms of the severity of joint symptoms, but combined
treatment with corticosteroids was permitted.
5.2. Belimumab
The BLISS-52 and BLISS-76 double-blind, randomised studies
included 867 and 819 patients, respectively, with anti-nuclear
antibodies and/or antibodies against native DNA; they found
belimumab to be more effective than placebo associated with conventional treatment [25,26]. In these two studies, the patients
were randomised to three groups: 1 mg/kg belimumab, 10 mg/kg
belimumab or placebo, delivered intravenously. The principal outcome measure was a composite criterion of lupus activity. In a
post hoc analysis, the BLISS-52 and BLISS-76 studies were pooled
and analysed as a function of the various types of organ damage
[27]. Musculoskeletal signs were significantly better (for doses of
1 mg/kg or 10 mg/kg) or tended to be better in the group treated
with belimumab (10 mg/kg) than in the placebo group, depending
on the parameter used to evaluate joint symptoms. About 10% more
of the patients on belimumab than of those on placebo displayed an
5.4. Tocilizumab
An open study of 16 patients treated for 12 weeks suggested
that tocilizumab was potentially effective [29]. In the seven patients
with arthritis at the start of the study, the mean number of synovitis
episodes decreased considerably during treatment, with the complete resolution of arthritis in four patients. However, this effect
was only temporary, and arthritis recurred in five of these seven
patients, 2 months after the cessation of tocilizumab treatment.
5.5. Anti-TNF-˛ antibodies
In an open, uncontrolled study, 13 patients with SLE treated
with infliximab were followed for more than 5 years [30]. The five
patients with joint symptoms displayed rapid remission of those
symptoms. However, anti-TNF treatment may induce the formation of autoantibodies in more than one third of patients and cause
rare cases of induced lupus. According to the CRI recommendations, given that anti-TNF antibodies have not been demonstrated
to be beneficial for the treatment of renal signs of lupus, their use in
lupus cannot currently be recommended other than for rheumatoid
arthritis-associated lupus [31] (rhupus) with symptoms resistant to
classical treatments [4].
In conclusion, there is no definitive evidence that biologics can
be effective and safe for treating arthritis in SLE patients. Some
new and potent biodrugs are promising but few double blind
randomised trials have been published. Such therapy has to be
discussed according to recommendations (PNDS, CRI) and expert’s
opinion, with individual benefit-risk ratio always being weighed.
350
M. Artifoni, X. Puéchal / Joint Bone Spine 79 (2012) 347–350
Based on these reviewed data, we propose one therapeutic strategy
for arthritis management in SLE (Box 1).
Disclosure of interest
The authors declare that they have no conflicts of interest concerning this article.
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