Successful treatment of resistant pseudogout with anakinra

Authors

  • Dennis McGonagle,

    Corresponding author
    1. Calderdale Royal Hospital, Halifax, UK
    2. University of Leeds, and Chapel Allerton Hospital, Leeds, UK
    • Academic Unit of Musculoskeletal Disease, University of Leeds, Chapel Allerton Hospital, Chapeltown Road, Leeds LS7 4SA, UK
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  • Ai Lyn Tan,

    1. University of Leeds, and Chapel Allerton Hospital, Leeds, UK
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  • Julie Madden,

    1. Calderdale Royal Hospital, Halifax, UK
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  • Paul Emery,

    1. University of Leeds, and Chapel Allerton Hospital, Leeds, UK
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    • Dr. Emery is an Arthritis Research Campaign Professor of Rheumatology at Leeds University.

    • Dr. Emery has received consulting fees, speaking fees, and/or honoraria (less than $10,000 each) from Schering-Plough/Centocor, Wyeth/Amgen, Abbott, Roche/Genentech, and Bristol–Myers Squibb.

  • Michael F. McDermott

    1. Leeds Institute of Molecular Medicine, St. James's University Hospital, Leeds, UK
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Abstract

We describe herein the case of a 63-year-old man with pseudogout affecting multiple joints that was resistant to treatment with allopurinol, steroids, and antiinflammatory drugs. Based on recent data on the molecular mechanism of pseudogout that demonstrated overproduction of interleukin-1 (IL-1), we treated the patient with anakinra, an IL-1 receptor antagonist. The patient responded to treatment with anakinra within 2 weeks, with resolution of the signs and symptoms of pseudogout and normalization of levels of inflammation markers.

The treatment options for steroid-resistant pseudogout are limited. Recently, the pivotal role of both monosodium urate monohydrate and pyrophosphate crystals acting via the NALP3 inflammasome to convert pro–interleukin-1 (proIL-1) into IL-1 has been demonstrated. Also, there is proof of principle that anakinra, the IL-1 receptor antagonist, may be effective in treating gout. Herein we describe a patient with severe steroid- resistant pseudogout who had excellent response to anakinra. Given the modest effect of anakinra in rheumatoid arthritis, the present findings support the idea that IL-1 is a pivotal proinflammatory cytokine in the pathogenesis of pseudogout.

CASE REPORT

The patient, a 63-year-old man with treatment-resistant pseudogout, had a 3-month history of severe swelling, pain, and erythema of the right index finger. The finger was examined by a hand orthopedist, during which no abscess was found. Both swabs and cultures of material obtained from the affected region during surgical exploration failed to define a causative infection. The patient's complete blood cell count and levels of inflammation markers were normal. After failing to respond to prolonged antibiotic therapy, the patient was referred to the rheumatology department for further evaluation.

During the rheumatologic evaluation, the patient reported that he had been admitted to another hospital 30 years earlier with a severely swollen and erythematous right knee. He said that a diagnosis of gout had been considered but, when prompted, also stated that pseudogout may have been mentioned. In fact, he was seen by a rheumatologist 8 years ago with another bout of swelling in the knee, and the radiographs showed chondrocalcinosis consistent with pseudogout. Crystal analysis of fluid obtained from the knee at that time showed no evidence of gout, and the knee swelling improved following corticosteroid injection. He did report swelling and erythema of the right knee and ankle intermittently thereafter, but these usually improved after treatment with nonsteroidal antiinflammatory drugs (NSAIDs). The uric acid level had been measured on several occasions, always with normal results. Further rheumatology input had therefore not been sought until the chronic episode that led to the present clinical presentation. In addition to steroids and NSAIDs, he had also taken colchicine, of which he was found to be intolerant. There was no history suggestive of podagra and no history of inflammatory bowel disease or psoriasis.

The positive findings during rheumatologic examination were swelling and erythema of the right index finger proximal interphalangeal (PIP) joint, and also a lesser degree of swelling of the third PIP joint, which had been intermittent. Hand and chest radiography findings were normal, the C-reactive protein (CRP) level was marginally elevated at 11 mg/liter (normal <10), and the uric acid level was 0.52 mmoles/liter (normal 0.20–0.42). Rheumatoid factor and antinuclear antibodies were negative.

A working clinical diagnosis of either a crystal-induced arthropathy or a seronegative inflammatory arthropathy was made. A local corticosteroid injection into the most symptomatic PIP joint led to temporary improvement. Because of hyperuricemia and persistent symptoms, the patient was offered a trial treatment of allopurinol taken in conjunction with indomethacin plus 30 mg daily of prednisolone initially for the active disease, which was tapered gradually. However, the patient felt no better and had persistent pain, stiffness, and erythema of the involved joints and required 10–30 mg of prednisolone per day to control his symptoms. The patient gained weight while taking steroids, and he had increasingly Cushingoid features with a moonlike facies.

While taking 10 mg prednisolone daily, 600 mg allopurinol daily, and 150 mg indomethacin daily, the patient presented with a severe arthropathy that affected the right index finger PIP joint, the right thumb metacarpophalangeal joint, the right knee, and the right ankle (Figures 1A–C). All these joints were swollen and very painful and the patient had difficulty walking. Analysis of synovial fluid from the right knee joint demonstrated the presence of pyrophosphate crystals but no uric acid crystals, consistent with psuedogout. Gram stain and cultures of the synovial fluid were negative. His CRP level had risen to 97 mg/liter, his erythrocyte sedimentation rate (ESR) was 16 mm/hour (normal 1–14), and his uric acid level was 0.27 mmoles/liter. He continued to take prednisolone, up to 30 mg daily, with little response.

Figure 1.

Affected joints prior to treatment with anakinra (AC) and 6 months after commencement of anakinra treatment (DF). The proximal interphalangeal (PIP) joint of the index finger (A), the metacarpophalangeal (MCP) joint of the thumb (B), and the right ankle (C) were swollen and erythematous (arrows) despite treatment with allopurinol, steroids, and nonsteroidal antiinflammatory drugs. Six months after commencement of anakinra treatment, resolution of the swelling and erythema of the PIP joint of the index finger (D), the MCP joint of the thumb (E), and the right ankle (F) can be seen.

Based on the lack of response to steroids and recent data on the molecular basis of pseudogout that incriminate activation of a cytoplasmic protein complex termed the NALP3 inflammasome, which leads to excess IL-1 production (1), we treated the patient with anakinra at a dosage of 100 mg per day by subcutaneous injections. He responded within 14 days, which was longer than has been reported for responses to IL-1 blockade treatment in the cryopyrin-associated periodic syndrome group of disorders (2, 3). Within 3 months the patient was totally asymptomatic, had been able to stop taking prednisolone and indomethacin, and his CRP level and ESR normalized. At 6 months, the only notable finding was a small, 1-cm2 patch of erythema over the involved PIP joint (Figures 1D–F). Once prednisolone was discontinued, he also lost the weight he had gained. At the time of writing, the patient is extremely reluctant to consider tapering the anakinra dosage. In general, attacks of pseudogout are self-limited, and the continued use of anakinra in such patients would have considerable financial implications.

DISCUSSION

Compared with gout, resistant pseudogout is much less common, and treatment options are far more limited. Management of pseudogout is often based on symptomatic control with NSAIDs and steroids, and colchicine may have a role as a prophylaxis in recurrent pseudogout (4, 5). A small study has shown the potential for use of methotrexate in resistant pseudogout, but the response was only noted ∼2 months after initiation of therapy (6). Anakinra has been shown to be effective in treating the hereditary autoinflammatory conditions, which are characterized by the production of IL-1β due to increased inflammasome activity (7–9). Recently, the pathogenesis of crystal-induced arthropathy, including gout and pseudogout, was shown to mimic that of the hereditary autoinflammatory conditions (1, 10). Furthermore, pseudogout falls into a category of inflammation against self that appears to be dominated by innate immune responses, and, as such, targeting of the relevant pathways might predict good responses (11, 12). Previous studies have suggested the efficacy of anakinra in gouty inflammation (13, 14).

To the best of our knowledge, this represents the first case of successful treatment of resistant pseudogout with anakinra. Our patient had Cushingoid features, and steroids had failed to control the inflammation. Given the modest effect of anakinra in rheumatoid arthritis, but the good responses noted herein in pseudogout and in previous studies of gout, these findings support the idea of a NALP3-related IL-1 cytokine hierarchy in pseudogout, and support an emerging scientific rationale for IL-1–based treatment strategies for resistant crystal-induced arthritis.

AUTHOR CONTRIBUTIONS

Dr. McGonagle had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Acquisition of data. McGonagle, Tan, Madden.

Analysis and interpretation of data. McGonagle, Tan, Emery, McDermott.

Manuscript preparation. McGonagle, Tan, Madden, Emery, McDermott.

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