Department of Medicine, Jagiellonian University School of Medicine, Krakow, Poland
Correspondence to:
J. Musia, Department of Medicine, Jagiellonian University, Skawinska 8, PL-31-066 Krakow, Poland. E-mail: mmmusia{at}cyf-kr.edu.pl
SIR, Treatment of rheumatoid arthritis (RA) with the chimeric anti-tumour necrosis factor (TNF-
) monoclonal antibody infliximab has been proven efficacious and well tolerated [1, 2]. However, there are concerns about the safety of such treatment, with reports about induction of autoimmune phenomena [anti-double-stranded DNA (dsDNA) antibodies] and, rarely, development of systemic lupus erythematosus [35]. We describe a patient with RA who developed polymyositis following treatment with infliximab.
A 52-yr-old woman presented in January 2001 with advanced joint deformities and symmetrical polysynovitis. There was a 20-yr history of inadequately controlled seropositive RA with typical radiological changes, which had been treated recently with non-steroidal anti-inflammatory drugs, methotrexate (15 mg/wk) and prednisone (15 mg/day). Erythrocyte sedimentation rate (ESR) was 60 mm/h, C-reactive protein (CRP) was 35 mg/l [normal range (NR) <5 mg/l]. Serum aminotransferase levels were within the normal range. There was no history of any muscular disorder in the past. Treatment with infliximab was initiated. The drug was administered intravenously in doses of 3 mg/kg body weight at weeks 0, 2 and 6, and then at 8-weekly intervals. After three doses of infliximab, a significant clinical improvement was observed and serum CRP level decreased to the normal value. Therapy with unchanged doses of methotrexate and prednisone was continued.
In March 2002, after the sixth dose of infliximab, the patient was admitted to hospital because of diffuse pain in the lower and upper limbs and progressive symmetrical proximal muscle weakness, especially affecting the pelvic and shoulder girdles. This was accompanied by fever, dysphagia, dyspnoea and weight loss. Physical examination revealed dry crackles on inspiration at the lung bases.
Laboratory evaluation showed the following results. ESR was 100 mm/h, CRP was 28 mg/l, rheumatoid factor was 155 IU/ml (NR <15 IU/ml), creatine kinase (CK) was >12000 U/l (NR <170 U/l), CK-MB isoenzyme 529U/l, aspartate aminotransferase (AST) was 542U/l (NR < 59 U/l), alanine aminotransferase was 218 U/l (NR < 52 U/l) and lactic dehydrogenase was 4533 U/l (NR < 618 U/l). The indirect immunofluorescence autoantibody (IIF) test was positive for antinuclear antibodies (ANA) at a titre of 1:320, with anti-dsDNA antibodies (1:20), along with anti-neutrophil cytoplasmic antigen (ANCA) antibodies of the p-ANCA type (1:20). Double immunodiffusion revealed the presence of anti-Jo-1 antibodies, confirmed by immunoblotting (EUROASSAY, Euroimmune AG, Luebeck, Germany).
A chest radiogram showed diffuse, symmetrical honeycomb-pattern changes that were most prominent in the lower lung zones. These had been noted 1 yr earlier but to a lesser extent. Reductions in total lung capacity, vital capacity and residual volume were observed. Blood gases were normal. High-resolution computed tomography showed features of pulmonary fibrosis. A muscle tissue biopsy performed at admission showed diffuse necrosis of fibres as well as focal inflammatory infiltrates, with phagocytosis and early features of fibrosis in the absence of vasculitis.
A diagnosis of polymyositis, most likely induced by infliximab, was established, the drug was discontinued, and treatment with high doses of intravenous methylprednisolone (1000 mg on three consecutive days) was initiated, followed by prednisone (1 mg/kg/day). This resulted in marked improvement in muscle strength and reduction in serum CK (765 U/l) and AST (103 U/l) levels within 3 weeks. At onset and during a 6-month follow-up, myositis induced by infections, metabolic or hereditary disorders and cancer were excluded by history and additional investigations. At that time we obtained serum that had been taken from the patient before the initiation of infliximab therapy and stored at 80°C. The IIF test performed on this sample was positive for ANA (1:320) and anti-Jo-1 antibodies were present; tests for dsDNA and p-ANCA antibodies were negative. The patient was discharged on the 30th day, and 6 months later she was in good condition on 10 mg/day prednisone.
To the best of our knowledge, this is the first case of severe polymyositis associated with anti-Jo-1 antibodies that developed in temporal association with anti-TNF- therapy. Polymyositis/dermatomyositis may develop in RA patients [6]. However, if such an overlap syndrome had existed in our case, it was clinically silent for the entire 20 yr of her disease duration. Its presence would be marked only by anti-Jo-1 antibodies, detected in a blood sample taken just before initiating infliximab therapy. Rheumatoid myositis could be excluded, as its mild histological changes differed from severe features detected in our patient [7]. Pulmonary fibrosis, a relatively common complication of long-standing RA, was most likely exacerbated by the development of anti-Jo-1 antibody syndrome. We could find only one case of pulmonary fibrosis and anti-Jo-1 antibodies detected in an RA patient, but without any signs of myositis [8]. In contrast to RA, anti-TNF-
therapy of polymyositis/dermatomyositis is disputable, with case reports showing both favourable [9] and unfavourable outcomes [10].
Antinuclear antibodies have been found in several RA patients before infliximab therapy [5]. If anti-Jo-1 antibodies are present prior to treatment it is advisable, however, to initiate such therapy with caution and monitor all such patients strictly.
The patient signed a consent form regarding disclosure of her medical data for publication in a scientific journal.
The authors have declared no conflicts of interest.
References