Efficacy and safety of rituximab in the treatment of refractory inflammatory myopathies in adults: results from the AIR registry

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1 RHEUMATOLOGY Rheumatology 2011;50: doi: /rheumatology/ker305 Advance Access publication 22 October 2011 Original article Efficacy and safety of rituximab in the treatment of refractory inflammatory myopathies in adults: results from the AIR registry Marion Couderc 1, Jacques-Eric Gottenberg 2, Xavier Mariette 3, Eric Hachulla 4, Jean Sibilia 2, Olivier Fain 5, Arnaud Hot 6, Maxime Dougados 7, Liana Euller-Ziegler 8, Pierre Bourgeois 9, Claire Larroche 10, Anne Tournadre 1, Zahir Amoura 11, Bernard Mazières 12, Philippe Arlet 13, Michel De Bandt 14, Thierry Schaeverbeke 15 and Martin Soubrier 1 Abstract Objectives. To assess the efficacy and safety of rituximab (RTX) in patients with refractory idiopathic inflammatory myopathies (IIMs). Methods. RTX efficacy was based on improvement in three criteria: creatine phosphokinase (CPK) level, daily CS dose and physicians opinion. A decrease in CPK level or CS dose was significant if it was >25%. Results. Thirty patients were studied (21 women; age 52.5 years, disease duration 6.1 years). All had previously received immunosuppressors (ISs). Twenty-five patients received 1 g of RTX twice 2 weeks apart and five received 4 weekly RTX infusions (375 mg/m 2 ). RTX was given in association with IS in 21 patients. Twenty-eight patients received CS (mean dose 21.2 mg/day). Mean follow-up was 17.2 months. Thirteen adverse events were reported, including seven infections and one serious infection (pyelonephritis). RTX was effective in 16 patients. Duration of efficacy was 15.5 months. Of the 20 patients with baseline CPK level 52 upper limit of normal (ULN), 11 (55%) improved. The main level fell from 20.7 to 11 ULN. CS decreased in 15 patients, stopped in 4, remained stable in 8 and increased in the remaining 3. The CS dose decreased from 21.2 to 9.9 mg/day. The physicians opinion was favourable in 21 patients. Manual muscle testing was performed in only five patients: it increased from 87 to 91/100 at 6 months. Conclusions. RTX was well tolerated and had some beneficial effects on patients with IIM, the main limitation of this study resulted in a lack of manual muscle testing. Key words: Inflammatory myopathy, Rituximab, Efficacy, Tolerance, Adverse event. 1 Rheumatology Department, CHU, Clermont-Ferrand, 2 Rheumatology Department, CHU, Strasbourg 3 Rheumatology Department, Hôpital Bicêtre APHP, Paris, 4 Internal Medicine Department, CHU, Lille, 5 Rheumatology Department, Hôpital Jean Verdier APHP, 6 Internal Medicine Department, CHU, Lyon, 7 Rheumatology Department, Hôpital Cochin APHP, Paris, 8 Rheumatology Department, CHU, Nice, 9 Rheumatology Department, Hôpital La Pitié-Salpêtrière APHP, Paris, 10 Internal Medicine Department, Hôpital Avicenne APHP, Paris, 11 Internal Medicine Department, Hôpital La Pitié-Salpêtrière APHP, Paris, 12 Rheumatology Department, 13 Internal Medicine Department, Hôpital Purpan CHU, Toulouse, 14 Rheumatology Department, Hôpital Ballanger, Aulnay and 15 Rheumatology Department, Hôpital Pellegrin, CHU, Bordeaux, France. Submitted 14 September 2010; revised version accepted 22 July Correspondence to: Marion Couderc, Rheumatology Department, CHU, Clermont-Ferrand, France. mcouderc@chu-clermontferrand.fr Introduction Treatment of idiopathic inflammatory myopathies (IIMs) relies on corticotherapy [1]. Primary or secondary resistance, intolerance or cortico-dependence is observed in 30 50% of cases and requires treatment with immunosuppressors (ISs) [2]. Many ISs have been proposed, including MTX, LEF, ciclosporin, AZA, cyclophosphamide (CYC), MMF, IVIGs and anti-tnf-a [3 18]. Rituximab (RTX), a chimeric anti-cd20 monoclonal antibody, effective in treating RA, is currently being evaluated for various autoimmune diseases, including SLE, primary SS and vasculitis [19 25]. Data concerning the efficacy of RTX in IIMs come from small series (up to 11 patients) and CLINICAL SCIENCE! The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Marion Couderc et al. isolated observations [26 44]. Using a national French registry, the Auto-immunity and Rituximab (AIR) registry, which contains data from patients with autoimmune diseases treated with RTX since 2005, we analysed the efficacy and tolerance of RTX in 30 patients with refractory IIMs. Methods AIR, set up by the French Society of Rheumatology and its subsection [the Club Rhumatismes et Inflammation (CRI)], receives financial support (unrestricted educational grant) from Roche. However, Roche was not involved in the design, protocol, data collection or statistical analysis of this study. Briefly, all French hospital- and communitybased units (mainly rheumatology and internal medicine) were invited to take part in the registry. Centres were informed that inclusion of patients in this observational registry would not interfere with their current practice and would not involve specific collection of laboratory results. Centres were also informed that study nurses would help to collect data, to increase the participation rate. The registry includes data from 82 centres. All eligible patients identified in these centres [adult patients receiving RTX for refractory IIMs according to European Neuromuscular Centre (ENMC)) workshop classification criteria] were included [45]. The IIM was considered as refractory if it did not respond to at least one IS before RTX. Patients who had concomitant IS were given stable doses 3 months before RTX and remained on stable doses during the treatment. No new IS within 3 months before the treatment or anytime after the treatment was started except when re-treatment was needed. Likewise, patients who were receiving concomitant steroids were stable 3 months before RTX and there was no escalation of steroids after the treatment dose. Data were analysed for patient characteristics (including manual muscle testing such as Kendall s testing) [46], RTX indication, administration regimen and tolerance. They were collected at baseline and at 3- and 6-month follow-up times, then every 6 months or at disease relapse, using an e-case report form (e-crf). Laboratory data [creatine phosphokinase (CPK) level, antibodies including specific autoantibodies and those associated with IIM] were collected in each laboratory centre. Study nurses were specifically trained in RTX treatment and use of the e-crf by the study coordinators (J.-E.G. and X.M.). Study nurses visited each centre regularly to update the clinical and biological data for the patients included. Missing data were minimized by providing the physician in charge of the patient and the study nurses with summaries of gaps in data for each patient in each centre. Data management was also performed and inconsistencies were noted. We contacted the primary care physician or the private rheumatologist for patients, who did not have follow-up visits for 510 months. This study was approved by the local ethics committee [Comité Consultatif sur le Traitement de l information en matière de Recherche dans le domaine de la Santé (CCTIRS) and Commission Nationale de l Informatique et des Libertés (CNIL)]. Written informed consent was obtained from all patients. Efficacy of RTX was assessed on the basis of CPK level, daily dose of CSs and the opinion of the physician. A decrease in CPK level was significant if it was >25%. A decrease in CS daily dose was significant if it was >25% of the initial dose. A responder was defined as a patient with improvement in all three criteria except if CPK levels were already <1 upper limit of normal (ULN), in which case the other two criteria had to be fulfilled for improvement. Likewise, if the patient was already on a low dose of steroid (45 mg/day prednisone), improvement was considered to be achieved if the other two criteria were met. A patient was considered to be in complete remission if CPK level was normal and corticotherapy had been stopped for a period of at least 3 months. An adverse event was considered serious if it led to hospitalization of the patient. An infection was considered to be serious if it was fatal or if it required hospitalization or i.v. administration of an antibiotic. Statistical analysis Continuous variables are expressed as means and quantitative variables as percentages. Fisher s test was used to analyse qualitative variables. Results Study population Thirty patients with refractory IIMs treated with RTX were included in the study. The demographic characteristics of the study population are given in Table 1. There were 21 (70%) women and 9 men [mean age 52.5 (14.7) years (range years)]. Twelve (40%) patients had PM, 6 (20%) had DM and 12 (40%) had anti-synthetase syndrome (ASS; 5 associated with DM and 7 with PM). The mean duration of IIM was 6.1 (4.3) years (range 1 18 years). Five (16.7%) patients had a history of cancer: multiple IgG kappa latent myeloma for 3 years; lobular adenocarcinoma of the breast and in complete remission for 1 year; appendicular adenocarcinoma and in complete remission for 7 years; ovarian cancer and in remission for 14 years; and prostatic T2N0M0 adenocarcinoma and in complete remission for 1 year after surgical treatment. Nine (30%) patients had a systemic disease associated with the IIM: primary SS (n = 4), scleroderma (n = 1), RA (n = 2), lupus (n = 1) and overlap syndrome (n = 1). At the time of diagnosis, all patients had clinical signs of muscular involvement, 29 (96%) had an increase in muscular enzymes, 19/25 (76%) had myogenic syndrome on electromyography and 8/23 (35%) had signs of muscular inflammation on MRI. Of the 28 patients who had a muscular biopsy, 20 (71%) had characteristic histological features. Seventeen (56.7%) patients had autoantibodies associated with IIMs: 12 (40%) had specific antibodies (anti-jo1, n = 8; anti-pl-12, n = 2; anti-srp, n = 2) and 5 had other antibodies associated with IIMs (anti-pm- Scl, n = 3; anti-u-rnp, n = 2)

3 Efficacy and safety of rituximab TABLE 1 Demographic data for the study population and modalities of treatment with RTX Patient Disease Age, years Sex Disease duration, years Previous treatment No. of infusions dose, mg Concomittant IS 1 PM 48 F 5 MTX + IVIG + HCQ MTX 2 PM 74 F 12 AZA + MTX + IVIG MTX 3 PM 60 F 8 MTX + INF + AZA + IVIG PM 33 F 9 ETA + MTX + IVIG + AZA + ciclosporin IVIG + MMF 5 PM 32 F 3 IVIG + RTX PM 52 F 3 MTX PM 55 F 11 MTX MTX 8 PM 32 F 2 IVIG + MMF + PE PM 71 F 4 MTX + IVIG + MMF + ETA MTX 10 PM 60 M 8 MTX + IVIG + INF MTX + IVIG 11 PM 62 M 7 MTX + IVIG MTX 12 PM 40 M 1 MTX + CYC IVIG 13 DM 54 F 1 AZA + IVIG + HCQ MTX + HCQ + IVIG 14 DM 31 F 3 MTX + IVIG DM 55 F 5 MTX + IVIG + PE MTX 16 DM 76 F 1 MTX DM 48 F 1 MTX + IVIG MTX 18 DM 36 M 5 MTX + IVIG + HCQ MTX + IVIG 19 ASS 26 F 5 MTX + HCQ + IVIG AZA 20 ASS 66 M 8 IVIG + MMF AZA 21 ASS 69 F 13 AZA + MTX + MMF + HCQ AZA 22 ASS 59 F 14 AZA + MTX + MMF ASS 30 M 4 CYC + IVIG + MMF MTX 24 ASS 54 M 2 MTX + IVIG + MMF MMF + IVIG 25 ASS 47 F 1 AZA + MTX + ciclosporin + IVIG MMF 26 ASS 70 M 18 MTX + IVIG ASS 73 F 9 MTX + CYC + IVIG MTX 28 ASS 50 M 6 MTX + IVIG + AZA MMF + MTX 29 ASS 55 F 11 AZA + MTX + CYC ASS 58 M 5 AZA + MTX + IVIG + INF MMF + IVIG F: female; M: male; ETA: etanercept, INF: infliximab. All patients had previously received at least one IS (one IS, n =4, 13.3%; two ISs, n = 6, 20%; three ISs, n = 15, 50%; four ISs, n = 4, 13.3%; five ISs, n = 1, 3.4%). All patients had already received CS. Twenty-five (83%) patients had received MTX, 23 (77%) IVIG, 10 (33%) AZA, 8 (27%) MMF, 4 (13%) CYC, 3 (10%) anti-tnf (infliximab for two patients, etanercept for one patient) and 1 had received ciclosporin. Two patients had been given plasma exchange (PE). Treatment with RTX and co-medications Twenty-five (83.3%) patients received 1 g of RTX 2 weeks apart and five received 375 mg/m 2 /week for 4 weeks. Seventeen (56.6%) patients received pre-medication with an association of anti-histamines, methylprednisolone and paracetamol; eight (26.7%) patients received a combination of paracetamol and anti-histamines; two (6.7%) patients received only anti-histamines; and three (10%) did not receive any pre-medication before perfusion of RTX. RTX was administered as a monotherapy in nine patients, and in association with at least one IS in the others (MTX, n = 9; AZA, n = 3; MMF, n = 1; IVIG, n = 1; IVIG and MTX, n = 3; IVIG and MMF, n = 3; MTX and MMF, n = 1). Twenty-eight patients received CS at an initial dose of 21.2 (19.5) mg/day. Safety of RTX Mean duration of follow-up was 17.2 (11.3) months (range 1 50 months). Thirteen adverse events were reported (incidence of 30.2 per 100 patient-years), two of which were serious:. Two perfusion reactions occurred: (i) a pruriginous eruption during the first perfusion, which was resolved with anti-histamines in a patient who had premedication with anti-histamines; and (ii) a cutaneous eruption 48 h after the second RTX perfusion which led to hospitalization with a favourable outcome 48 h later in a patient who had CSs, anti-histamine and paracetamol in their premedication.. Two patients had an unexplained fever early after RTX perfusion (on the 5th day after the first perfusion in one and on the 22nd day after in the other) without

4 Marion Couderc et al. any clinically identified infectious source. However, there was a favourable outcome after antibiotic treatment (amoxicillin and clavulanic acid in one, fluoroquinolone in the other).. Eight infectious episodes were reported in seven patients, of which seven did not require hospitalization (two lower urinary tract infections due to Klebsiella in the same patient, one urinary tract infection due to Pseudomonas aeruginosa, one dental cellulitis, one herpetic eruption on the ankle, one Herpes zoster of the eye treated with valacyclovir for 3 weeks with a favourable outcome and one fever of viral origin). Only one severe infection occurred: pyelonephritis due to Escherichia coli, which required hospitalization. These infections usually occurred (87.5%) in the 6 months after treatment [4.3 (2.8) months (range months)].. One patient who had adenocarcinoma of the breast 1 year before RTX developed metastasis 1 year after TABLE 2 Parameters evaluating the efficacy of RTX Patient Disease CTS before RTX, mg/day CTS after RTX, mg/day CPK before RTX ( normal range) CPK after RTX ( normal range) RTX treatment, which required radiotherapy, chemotherapy and hormone therapy. It was considered a serious event because it required hospitalization of the patient. No patient had delayed serum sickness-like reactions. Two patients who had pulmonary tuberculosis received RTX without reactivation of the disease. Efficacy of RTX The efficacy of RTX is given in Table 2. Muscular signs RTX was effective in 16 (53.3%) patients: 5 (31.2%) PM, 5 (31.2%) DM and 6 (37.6%) ASS. The mean time between the first infusion and improvement was 3.2 months (median 3.1, range 2 5 months). In the 24 patients with increased CPK at the time of RTX treatment, the level decreased in Physician opinion Efficacy (Y/N) Duration of efficacy of first course, months Second course, months Duration of efficacy of second course, months 1 PM Y 16 3 PM Y 7 7 Not evaluated 4 PM Y PM Y PM Y DM ,4 1 Y DM Y DM Y 4 17 DM Y DM Y ASS Y ASS Y 7 26 ASS Y ASS Y 8 28 ASS Y ASS Y PM N NR 18 Ineffective at 6 months 5 PM N NR 6 PM N NR 8 PM N NR 9 PM N NR PM N NR PM N NR 13 DM N NR 19 ASS N NR 20 ASS N NR 21 ASS N NR 22 ASS N NR 23 ASS N NR 29 ASS N NR CTS before RTX means CS dose on the day RTX was started; CTS after RTX means CS dose at the last follow-up. CPK before RTX means CPK level on the day RTX was started; CPK after RTX means CPK level at the last follow-up. NR: not relevant; Y: yes; N: no

5 Efficacy and safety of rituximab 18, remained stable in 2 and increased in 4. The mean level fell from 20.7 (29.9) to 11 (24.6) ULN. Of the 20 patients with baseline CPK level 52 ULN, 11 improved (11/20, 55%). Corticotherapy was decreased in 15 patients and stopped altogether in 4. It remained stable in eight patients and was increased in the remaining three. Overall, the mean dose of CS decreased from 21.2 (19.5) to 9.9 (8.5) mg/day. The opinion of the physician on the efficacy of RTX was reported as favourable in 21 patients and unfavourable in 9. In five patients, the physician s opinion differed from the overall criteria: these five patients with favourable physician s opinion were not considered as responders since CPK level and/or CS dose did not improve. Two (6.7%) patients were considered to be in complete remission with normal CPK levels and corticotherapy was withdrawn. Two of them were also withdrawn from IS treatment (MMF in one and MTX in the other). In patients who responded, the duration of efficacy was 15.3 (10.1) months (range 4 50 months). In nine patients treated with RTX as monotherapy, eight were given steroids at a mean dose of 11 mg/day and 5/9 (55.5%) improved. Ten patients were re-treated with RTX, three systematically at 6, 7 and 18 months, and seven on relapse at 15 (5.2) months (range months). The protocol used and the dose of RTX were identical to those used initially. Of the 10 retreated patients, 8 were responders after a period of 7.4 months, 1 did not respond and the 10th patient has not yet been re-evaluated. There was a trend in favour of a better response in patients with specific antibodies associated with myositis [10/17 (58.8%)] compared with those without autoantibodies [6/13 (46.1%)] (P = 0.71). We are unable to analyse the correlation between the efficacy of RTX and the decrease in specific antibodies because information on the titre of specific autoantibodies is unavailable. Kendall s muscular manual testing was performed in only five patients at D 0, 3 months and 6 months after RTX. The results are given in Table 3. The mean Kendall s score at the time of RTX was 87.4 (13.8) (range ). At 3 months, it was 87 (12.8) (range ) and at 6 months 91 (15.5) (range ). TABLE 3 Kendall s score at D 0, 3 months and 6 months after RTX Patient Kendall D 0 Kendall 3M Kendall 6M D 0 : time of RTX, 3M: 3 months after RTX, 6M: 6 months after RTX. Extra-muscular signs The efficacy of RTX against extra-muscular involvement of IIMs was more difficult to analyse because of incomplete data. Eleven patients treated with RTX had systemic manifestations, but the evolution of this extra-muscular involvement was only evaluated in four patients. Of these, one had improvement of myocardial involvement in parallel with improvement in their muscular symptoms. Pulmonary involvement in a patient with anti-srp antibodies worsened together with the muscular flare. In another patient, the diffusing capacity of the lung carbon monoxide (DL CO ) was stabilized at 76% after a period of 13 months. A cutaneous flare was improved in one patient in parallel with improvement in their muscular involvement. Discussion In this study, which is the largest reported to date, RTX was effective in 53.3% of patients (16/30) treated for refractory IIM. This confirms the results of previous open studies with small population sizes (49 patients overall) [26 44]. However, our study, which analysed patients with refractory myositis who were treated with RTX, and were included in a prospective national registry (the AIR registry of the French Society of Rheumatology), has several limitations related to the small population size, the absence of standardization of treatment, the absence of a control group and the short follow-up duration. The choice of judgement criteria could be challenged. The best efficacy parameter would be muscle manual testing, such as Kendall testing, but this was performed in only five patients [46]. In four of them, Kendall testing results seem to be in accordance with the surrogate marker data, but in one patient (n = 1), who is defined as a responder, the MMT value at 6 months post-rtx appears to be lower than at baseline. These results could be considered as a discrepancy. However, a difference in 2 points on 100 on the manual muscle testing (MMT) value is not clinically relevant. Hence, improvement in MMT was considered as significant by two authors if improvement of muscle strength was >12% or reduction in muscle strength deficit was at least 50% [28, 29]. As we had only a few manual muscle tests, we used a composite index including daily corticoid dose, CPK level and physician s opinion. The main objective of registries is to assess tolerance, but they can also provide interesting information concerning the efficacy of some treatments in rare diseases for which data from controlled trials are absent or limited [23]. Taking all previous published cases together (49 cases), RTX was effective in 38 (77.5%) adult patients treated for inflammatory myositis. Of these 49 patients, the efficacy of RTX was similar in the presence and absence of specific antibodies (24/32 patients had an efficacious response with specific antibodies vs 10/17 in those without, P = 0.33) [26 42]. RTX was not effective in one of the two patients with anti-srp antibodies. However, this was a particularly refractory case of myositis (previously treated with four ISs). Myositis with anti-srp remains difficult to treat, and the

6 Marion Couderc et al. efficacy of RTX in these severe forms of myositis varies according to different articles. Whelan et al. [43] reported a lack of efficacy of RTX in one patient, whereas three patients reported by Pavy et al. [40] and two described by Arlet et al. [44], were improved. However, in the latter two patients, RTX was associated with PE and a high dose of CS [44]. In our study, RTX was also non-effective in one patient with ASS and previous ovarian cancer and in one patient with ASS and breast cancer. It is well-known that all types of IIMs can be associated with malignancies; in addition, improvement of myositis is generally obtained by treatment of the underlying malignant disease [47]. Data concerning the efficacy of RTX on extra-muscular involvement of myositis could not be fully assessed in our study. One patient who had myocardial involvement clearly improved with RTX, like the patient described by Touma et al. [26]. It is noteworthy that RTX was well tolerated in this last case despite some controversies about heart toxicity [48]. In previous studies, pulmonary involvement was reported to be particularly sensitive to RTX, and efficacy was observed in 11/14 (78%) patients with ASS, and also in one patient in whom pulmonary involvement did not occur within the context of ASS [28, 30, 34, 39]. Only one with skin involvement had improvement of cutaneous lesions. The results for skin manifestations vary between studies. The three patients of Dinh et al. [27] showed improvement. In contrast, the lesions were stable in seven of eight patients reported by Chung et al. [29], but became worse in the eighth patient. The prospective data from the AIR registry show a satisfactory tolerance to RTX and some beneficial effects in patients with IIM. Efficacy or inefficiency of RTX in IIM is being investigated in a randomized, double-blinded, control vs placebo clinical trial [49]. Rheumatology key message. 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