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Letter

Sustained Response to Infliximab in 2 Patients with Refractory Relapsing Polychondritis

To the Editor:

Relapsing polychondritis (RP) is a rare inflammatory disease of unknown etiology causing recurrent inflammatory reactions in the cartilaginous structures and joints¹. Because precise knowledge of the pathogenesis of RP is lacking, many therapeutic approaches have been reported. There are important clinical similarities and overlaps between RP and rheumatoid arthritis (RA). The decision to use tumor necrosis factor-a (TNF-a) blocking agents was supported by recent reports of successful use of these agents in different rheumatic diseases, especially RA^2,3. We describe the results obtained with infliximab in 2 patients with RP over a 9-month period.

A 20-year-old Caucasian woman was diagnosed with RP in November 1997, based on symmetrical auricular and nasal cartilage inflammation, with leakage of the aortic valve, and 3 years of nonerosive seronegative polyarthritis.

Laboratory tests including rheumatoid factor, antinuclear antibody, and antineutrophil cytoplasmic antibody were negative. She had been treated initially with prednisone 20 mg per day, which led to the resolution of the polyarthritis. However, she had repeated relapses of polyarthritis, and satisfactory control of the nasal and auricular symptoms was not achieved, despite multiple treatments including prednisone, hydroxychloroquine, gold salts, azathioprine (2.5 mg/kg/day), D-penicillamine, and methotrexate (MTX; 20 mg weekly).

Because of polyarthritis relapse, systemic inflammation [erythrocyte sedimentation rate (ESR) 53 mm/h, C-reactive protein (CRP) 42 mg/l], failure to control the ear and nose cartilage inflammation, and hepatic toxicity due to azathioprine and MTX, TNF-a blocking therapy was initiated in September 2001. Infliximab 5 mg/kg body weight was selected for TNF-a blockade in addition to prednisone 15 mg per day. Infliximab infusions were given at 0, 2, 6, 14, 22, 30, 38, and 46 weeks. Before each infusion a premedication with intravenous betamethasone 10 mg was given.

After the first infusion CRP decreased to the normal range (Figure 1A) and clinical improvement was observed. No further episode of synovitis occurred and auricular and nasal cartilage inflammation disappeared. Sustained clinical and biological response was observed after 8 infusions, with no adverse events. In addition, the prednisone dose was reduced from 15 to 3 mg per day (Figure 1A).

A 20-year old Caucasian woman was diagnosed with RP in 1993, based on auricular and nasal cartilage inflammation, bilateral episcleritis, and polyarthritis. On examination there was no evidence of cartilage involvement in the respiratory tract. Soon after she developed necrotic cutaneous lesions of the left foot, which led to amputation of the second toe. Histological examination of the toe revealed a necrotizing vasculitis. Laboratory findings were negative. Episcleritis was treated with topical steroids with complete resolution of symptoms. Treatment with 20 mg/day oral prednisone controlled her synovitis, but inflammation of her ears and nose often needed a higher dose. Repeated attempts to reduce steroid dosage below 20 mg per day failed. MTX (25 mg weekly), dapsone, cyclosporine, azathioprine (3 mg/kg/day), and cyclophosphamide were added to her treatment to better control disease and to reduce steroid dose, but all were ineffective. Therefore, TNF-a blocking therapy with infliximab was initiated in October 2001. Infliximab 5 mg/kg body weight was added to prednisone 20 mg per day. Infliximab infusions were given at 0, 2, 6, 14, 22, 30, and 38 weeks. After the first infusion clinical improvement was observed. No further episode of synovitis, episcleritis, or vasculitis occurred and auricular and nasal cartilage inflammation disappeared. CRP decreased to the normal range after 2 infusions (Figure 1B). Sustained clinical and biological response was observed after 7 infusions, with no adverse events. Prednisone dose was reduced from 20 to 8 mg per day (Figure 1B).

RP and RA share several clinical symptoms and signs. Interestingly, Buckner, et al have recently described, in a patient with RP, production of interferon-g in response to DR1 autologous antigen-presenting cells, athough the cytokine profile was dependent on the DRB1 restriction element used⁴. Further, Ohwatari, et al have shown that RP patients exhibited significantly higher levels of macrophage migration inhibitory factor⁵. These findings and reports of successful use of TNF-a blocking agents in RA provided us with a rationale for using these agents to treat 2 RP patients who where unresponsive to immunosuppressive drugs.

Our 2 cases fulfilled McAdam's and Damiani's criteria of RP^1,6. Both these patients had a history of therapy with immunosuppressive agents, none of which had been sufficient to control clinical symptoms or systemic inflammation. In both cases, repeated relapses required longterm use of steroids. After the first infusion of infliximab, clinical and biological improvement was observed. Prednisone dose was reduced in both cases. Over a 9-month period sustained response was observed, with no adverse event.

Infliximab seems to be an effective therapy for RP that is unresponsive to conventional therapy; it is also useful as a steroid-sparing agent. Longterm controlled studies of TNF-a blocking agents in patients with RP are warranted.

DAVID SAADOUN, MD; CHANTAL JOB DESLANDRE, MD; YANNICK ALLANORE, MD; CAROLINE CHARLIER, MD, XUÂN-VIÊT PHAM, MD, and ANDRÉ KAHAN, MD, PhD, Paris V University, Rheumatology A Department, Cochin Hospital, Paris, France.

REFERENCES

1. McAdam LP, O'Hanlan MA, Bluestone R, Pearson CM. Relapsing polychondritis: Prospective study of 23 patients and a review of the literature. Medicine 1976;55:193-215.

2. Taylor PC, Peters AM, Paleolog E, et al. Reduction of chemokine levels and leukocyte traffic to joints by tumor necrosis factor alpha blockade in patients with rheumatoid arthritis. Arthritis Rheum 2000;43:38-47.

3. Brandt J, Haibel H, Cornely D, et al. Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor a monoclonal antibody infliximab. Arthritis Rheum 2000;43:1346-52.

4. Buckner JH, Van Landeghen M, Kwok WW, Tsarknaridis L. Identification of type II collagen peptide 261-273-specific T cell clones in a patient with relapsing polychondritis. Arthritis Rheum 2002;46:238-44.

5. Ohwatari R, Fukuda S, Iwabuchi K, Inuyama Y, Onoe K, Nishihira J. Serum level of macrophage migration inhibitory factor as a useful parameter of clinical course in patients with Wegener's granulomatosis and relapsing polychondritis. Ann Otol Rhinol Laryngol 2001;110:1035-40.

6. Damiani JM, Levine HL. Relapsing polychondritis -- report of ten cases. Laryngoscope 1979;89:929-45.