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Efficacy and Safety of Etanercept in the Treatment of Scleroderma-Associated Joint Disease

To the Editor:

Joint pain and stiffness are common complaints in scleroderma and may represent a true inflammatory synovitis in a subset of patients¹. Yet effective treatment remains problematic. We describe the efficacy and safety of etanercept in scleroderma patients with active joint disease.

We conducted a retrospective analysis of patients with scleroderma seen at the Johns Hopkins Scleroderma Center (JHSC) who had active joint disease and were treated with standard doses of etanercept (25 mg twice weekly or 50 mg once weekly). Patients studied either met American College of Rheumatology criteria for scleroderma² or had at least 3 of 5 features of the CREST syndrome (calcinosis, Raynaud's, esophageal dysmotility, sclerodactyly, telangiectasias). Inflammatory joint involvement was defined by the detection of synovitis or inflammatory signs on examination, which were identified on chart review by the use of the terms "erythema," "edema," "warmth," "active joint disease," or "synovitis" in describing the joint examination. Demographic data, clinical characteristics of disease, duration of treatment with etanercept, and clinical outcome measures were recorded from the JHSC database and are summarized in Table 1. Primary efficacy outcome measures included a positive response at last followup visit if a significant decrease in synovitis was noted by the physician and if complete resolution of symptoms of joint pain was documented. The Health Assessment Questionnaire (HAQ) score was a secondary outcome measure. The Rodnan skin scores and pulmonary function test results were followed with therapy.

Table 1. Patient characteristics and response to etanercept therapy. All patients here were female. Positive responses were those in which a dramatic decrease in signs of inflammation or synovitis was noted by the physician at followup and if resolution of patient symptoms of joint pain was documented.

Eighteen patients were treated with etanercept for inflammatory joint involvement from December 1998 to May 2005, with duration of therapy ranging from 2 to 66 months (mean 30). All 18 patients were female, ranging in age from 25 to 71 years (mean 44). Three of 18 patients (17%) were positive for antiribonucleoprotein (RNP) antibodies; 8 of 17 patients (47%) were positive for rheumatoid factor (RF); and 3 of 12 (25%) were positive for antibodies to cyclic citrullinated peptides (CCP). Concomitant medications used during the course of etanercept treatment included nonsteroidal antiinflammatory drugs (18 patients), methotrexate (15 patients; doses ranging from 2.5 mg to 25 mg weekly, average dosage 12 mg), hydroxychloroquine (5 patients), prednisone (9 patients; doses ranging from 0.5 mg to 15 mg daily, average dosage 5 mg), and minocycline (2 patients).

Fifteen of 18 (83%) patients treated with etanercept had positive responses, with a significant decrease in signs of inflammation or synovitis on followup examination and complete resolution of joint symptoms. One patient was able to discontinue etanercept due to prolonged remission with inactive joints. Three patients (17%) had persistent signs of synovitis and/or joint symptoms, and they were considered nonresponders. These nonresponders were treated for an average of 14 months and had waxing and waning musculoskeletal findings during treatment. However, at the time of latest followup, their responses were deemed not significantly improved. No association was noted between RF, CCP, or RNP status with response to etanercept.

Mean HAQ scores from baseline to latest available followup decreased from 1.08 ± 0.70 to 0.74 ± 0.56 (p = 0.13). The mean skin score decreased during therapy from 6.63 ± 6.35 to 3.94 ± 2.38 (p = 0.12).

A slight decline in pulmonary function was observed in the cohort as a whole during treatment with etanercept. The mean percentage predicted DLCO of the cohort decreased 5.1 percentage points (95% confidence interval –10.4 to +0.18), and the mean percentage predicted FVC decreased by 1.4 percentage points (95% CI –5.8 to +2.9). Both these decreases were not statistically significant, and when a case-control comparison was done with a group of patients who were not treated with etanercept or another tumor necrosis factor (TNF) antagonist (n = 36), a similar decline was seen (data not shown). These data suggest that the changes observed likely reflect the natural decline that can occur in a population of patients with scleroderma and that etanercept therapy does not appear to have any clinically appreciable effect on lung function in these patients.

There were no reported incidents of opportunistic infections, anaphylaxis, hospitalizations, or death attributed to etanercept therapy. Etanercept was discontinued in one patient after development of a lupus-like reaction (as reported³). In a second patient, etanercept was discontinued after a marked decline in lung function was observed.

Our case series demonstrates that etanercept appeared to be efficacious in improving active inflammatory joint disease in a subset of scleroderma patients, and it was generally safe and well tolerated. Mean HAQ scores also decreased with therapy, paralleling the improvement in joint disease. Etanercept did not appear to worsen scleroderma skin disease, as the cohort's mean modified Rodnan skin score declined, despite some concerns that TNF antagonists may worsen fibrosis associated with scleroderma by allowing increased production of profibrotic cytokines by transforming growth factor-ß⁴. Prospective, randomized, blinded controlled trials are warranted to further define the role of etanercept or other TNF antagonists in the treatment of scleroderma-associated joint disease.

GORDON K. LAM, MD, Postdoctoral Fellow; LAURA K. HUMMERS, MD, Assistant Professor of Medicine; ADRIANNE WOODS, BS; FREDRICK M. WIGLEY, MD, Professor of Medicine, Associate Director, Division of Rheumatology, Department of Medicine, Johns Hopkins University School of Medicine, 5200 Eastern Avenue, Mason F. Lord Building, Center Tower, Suite 4100, Baltimore, Maryland 21224, USA. Address reprint requests to Dr. Wigley. E-mail: fwig@jhmi.edu

We thank April Thurman for technical support; Pamela Hill for editorial assistance; and the Scleroderma Research Foundation for its support of the JHSC.

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