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 . In a cohort of patients with SLE, the prevalence of NSAID prescription during the course of the disease was found to be about 75% . 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)  and of the Club Rhumatismes et Inﬂammation (CRI) . EULAR has issued no recommendations concerning articular manifestations of lupus . 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 . 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 . 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 . 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  and the PNDS  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 . 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  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. 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 . 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 . 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 . 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 . 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 . 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 . 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 . 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) . 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) . 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 . 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 . 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  or renal  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 . 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 . 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 . 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 . 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  (rhupus) with symptoms resistant to classical treatments . 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. 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