Rituximab treatment of the anti-synthetase syndrome ... - Oxford Journals

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Jun 16, 2009 - Objective. Interstitial lung disease (ILD) is the major determinant of morbidity and mortality in the anti-synthetase syndrome (ASS). Here we.
Rheumatology 2009;48:968–971 Advance Access publication 16 June 2009

doi:10.1093/rheumatology/kep157

Concise Report

Rituximab treatment of the anti-synthetase syndrome—a retrospective case series Marthe Sem1,2,*, Øyvind Molberg1,*, May Brit Lund3 and Jan Tore Gran1 Objective. Interstitial lung disease (ILD) is the major determinant of morbidity and mortality in the anti-synthetase syndrome (ASS). Here we have retrospectively assessed 11 ASS patients with ILD treated with the anti-CD20 mAB rituximab at our tertiary referral hospital. Methods. Data on clinical and laboratory parameters, lung imaging by high-resolution CT thorax and pulmonary function tests were collected from patient examinations done up to 6 months before rituximab was initiated, and at 3 and 6 months post-treatment. Results. All the 11 ASS patients had severe and progressive ILD and most of them had previously failed on cyclophosphamide and/or other immuno-modulating agents. Rituximab appeared to stabilize and/or improve the ILD in 7 of 11 ASS patients during the first 6 months after treatment. The rituximab treatment appeared to decrease the serum level of anti-Jo-1 antibodies, but the decrease was most often modest. One patient developed a fatal infection 3 months after the last infusion with rituximab. In the other ASS patients, the treatment was well tolerated. Conclusions. This retrospective case series indicates a short-term beneficial effect of rituximab in ASS. Prospective, controlled studies are needed to validate this finding and further assess safety issues. KEY

WORDS:

Rituximab, Anti-synthetase syndrome, Treatment, Anti-Jo-1, Anti-aminoacyl tRNA synthetase.

Introduction

Methods

The notion that serum anti-histidyl tRNA synthetase antibodies (anti-Jo-1) was associated with a distinct clinical syndrome that originated 70% of the patients [2–4, 7–9]. In accordance with the appreciation of ILD as the major clinical challenge in ASS, new treatment strategies, including the T-lymphocyte inhibitors tacrolimus and CSA, have been introduced [5, 10]. These drugs have shown effect in selected patients, but there is still a definite need for better therapeutic alternatives. The anti-CD20 mAB rituximab was originally used to eradicate CD20þ B-cell lymphomas. More recently, the drug has been applied with success in RA and has shown promising results in other immuno-mediated inflammatory disorders, including vasculitides [11, 12]. Single case reports also indicate that it has effects on myositis in anti-Jo-1-positive ASS patients [13–17]. To further assess the potential role of rituximab in ASS, we have retrospectively assessed 11 ASS patients with severe ILD treated at our tertiary referral hospital.

Patient group Eleven ASS patients (4 males, 7 females, mean age 52 years) with severe ILD were treated with rituximab at our tertiary referral centre (Department of Rheumatology, Rikshospitalet) from 2005 to 2007. The patients were classified with gradual- or acute-onset ILD as described [4]. The decision to initiate rituximab treatment was made after complete clinical work-up and assessment by at least two consulting rheumatologists. After having provided informed consent, all the patients were included in our clinical research database: the Connective Tissue Disease Registry at Rikshospitalet. This database has been approved by the Regional Medical Ethics Committee in Southern Norway. All the patients, except Patients #3 and 9, were followed at our Department for 56 months after treatment. Patient data were extracted from hospital charts and retrospectively assessed.

Patient assessment Generally, our patients with ASS and ILD are clinically evaluated every 3–4 months. If the disease appears to progress, pulmonary function tests (PFTs) are done at every visit. Before initation of rituximab, every patient was assessed by laboratory tests, PFTs and high-resolution (HR) CT thorax. The same parameters were assessed at controls 3 and 6 months after rituximab. All measurements of serum anti-Jo-1 titres were performed in the same laboratory by an automated ELISA (EliA Jo-1, Phadia, Freiburg, Germany). Maximum muscle strength was evaluated by a manual muscle test (MMT) performed by a physiotherapist. Nine muscle groups on left and right sides were scored from 1 to 10, giving a maximum score of 180. The results of the PFTs, including forced vital capacity (FVC) and forced expiratory volume during the first second (FEV1) and the diffusing capacity for carbon monoxide (DLCO) were expressed as the percentage of expected reference values [18]. The DLCO values were adjusted for total alveolar volume. According to an international consensus statement of the American Thoracic Society on idiopathic pulmonary fibrosis [19], changes 510% in

1

Department of Rheumatology, Rikshospitalet University Hospital, 2Faculty of Medicine, University of Oslo and 3Department of Respiratory Medicine, Rikshospitalet University Hospital, Oslo, Norway. Submitted 20 February 2009; revised version accepted 14 May 2009. Correspondence to: Øyvind Molberg, Department of Rheumatology, Rikshospitalet University Hospital, N-0027 Oslo, Norway. E-mail: [email protected] *Marthe Sem and Øyvind Molberg equally contributed to this work.

968 ß The Author 2009. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: [email protected]

Rituximab in the anti-synthetase syndrome FVC and/or 515% in DLCO were considered to be clinically significant, and were used as determinants of improvement or deterioration. HRCT thorax images were scored for ground-glass attenuation, reticulation, air space consolidation and honeycombing [20].

Rituximab treatment

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supplementary data at Rheumatology Online). The serum levels of total IgG remained stable across the treatment period (see supplementary figure 1, available as supplementary data at Rheumatology Online). Blood CD19þ cell counts before and after rituximab were available in seven patients. All the patients had >90% reduction in CD19þ cells after treatment (see supplementary figure 1, available as supplementary data at Rheumatology Online).

Except prednisolone, all other immuno-modulating drugs were discontinued prior to the rituximab infusions. Prednisolone was not increased between or after rituximab infusions (see supplementary table 1, available as supplementary data at Rheumatology Online). Nine patients were treated according to the rituximab protocol for RA. Eight received two infusions of 1000 mg rituximab, at Days 0 and 14, whereas Patient #1, due to increased infection risk, received two doses of 700 mg. Patients #7 and 11 were treated according to the protocol for lymphoma and received four weekly infusions of 375 mg/m2 body surface. The levels of blood CD19þ cells before and after rituximab treatment was assessed by flow cytometry.

To assess changes in pulmonary function over time, every FEV1, FVC and DLCO measurement performed in the last 8 months prior to rituximab and in the first 7 months post-treatment were recorded (Fig. 1). The data indicated that all the eight patients with gradual-onset ILD deteriorated in lung function in the months prior to rituximab (Fig. 1). Interestingly, six of the patients displayed >10% improvement in FVC and three had >15% better DLCO values 3–6 months after the rituximab treatment (Fig. 1).

Results

Lung imaging by HRCT thorax

Disease characteristics The 11 patients in this study were diagnosed with ASS based on three criteria: (i) the presence of serum antibodies against an aminoacyl tRNA synthetase, (ii) the presence of ILD and (iii) exclusion of other causes (including other systemic CTDs). Three patients (#1, 5 and 9) had an acute-onset ILD with development of severe respiratory symptoms within