Case of anakinra as a steroid-sparing agent for gout inflammation

Authors


Introduction

Over the past few years, it has become clear that the inflammasome plays a major role in the initiation of acute gout. Monosodium urate crystals attach to the NALP3 component of the inflammasome, leading to the release of interleukin-1β (IL-1β) that mediates the acute inflammation of acute gouty arthritis (1). Although the symptoms of acute gout can generally be treated with nonsteroidal antiinflammatory drugs (NSAIDs), corticosteroids, or colchicine, the treatment of choice for recurrent or tophaceous gout is hypouricemic agents. Unfortunately, there are patients in whom these symptomatic and therapeutic agents are either contraindicated or ineffective, leaving a subset of patients with poorly controlled gouty inflammation. In such patients, IL-1 blockade with anakinra has proven to be effective in the short-term control of acute attacks (2). We herein report our experience with the long-term use of anakinra in the treatment of inflammation from recalcitrant tophaceous gout.

Case Report

The patient, a 59-year-old man with crystal-proven, poorly controlled erosive tophaceous gout of a duration of 8 years, transferred care to our facility 1 year ago. Past medical history revealed type 2 diabetes mellitus, Hashimoto thyroiditis, and hypertension. The patient reported that he had received 4 years of symptomatic management with NSAIDs and colchicine prior to developing debilitating, recurrent polyarticular gouty arthropathy. Allopurinol was added to his therapeutic regimen, but within 3 weeks he developed keratitis, oral ulcers, a desquamating rash, renal insufficiency, and liver enzymemia, consistent with allopurinol-induced Stevens-Johnson syndrome. A subsequent trial of probenecid 500 mg twice a day was reported to be ineffective at reducing his recurrent attacks of acute synovitis, and it was stopped when he developed urate nephrolithiasis. During this time, he required oral prednisone up to 20 mg per day to control recurrent gouty synovitis.

He was admitted at our facility and was found to have a creatinine level of 4.3 mg/dl. An inpatient evaluation revealed acute and chronic renal insufficiency due to poorly controlled diabetes mellitus, the recent use of an angiotensin receptor antagonist, and probable gouty nephropathy. He was discharged once his creatinine level stabilized at 3.0 mg/dl and was given an appointment to establish care in our rheumatology clinic.

In the clinic, he reported requiring 20–30 mg of prednisone per day for more than 2 months in an effort to suppress recurrent attacks of acute synovitis. In fact, while receiving 20 mg per day, he still had acute podagra with intracellular negatively birefringent monosodium urate crystals demonstrated on first metatarsophalangeal joint aspiration. Multiple gouty erosions were seen on radiographs of the hands, knees, ankles, and feet. The serum uric acid level was 10.1 mg/dl. A thorough evaluation to rule out other etiologies for his recurrent synovitis was unrevealing. Because he was not a candidate for either allopurinol or probenecid, he was treated with recurrent intraarticular injections of triamcinolone, chronic oral prednisone ranging from 10 to 40 mg per day, and oral colchicine 0.6 mg per day, but he continued to experience recurrent episodes of aspiration-proven monarticular and polyarticular gouty arthropathy.

Subsequently, he was readmitted with persistent polyarticular synovitis despite self-titrating his prednisone dosage to as high as 100 mg per day. Complications of his steroid therapy included weight gain, moon facies, skin fragility, and worsening diabetes mellitus with diabetic neuropathy and nephropathy. Over the ensuing months, he was admitted 4 times and spent 43 inpatient days in an effort to treat his polyarticular synovitis, which remained uncontrolled despite high-dose prednisone, low-dose colchicine, and multiple triamcinolone joint injections. During the last hospitalization, he developed recurrent acute gout in the bilateral feet and knees, the left elbow, and the left acromioclavicular joint as the prednisone was tapered from 50 to 20 mg per day. A trial of anakinra 100 mg subcutaneously 3 times a week was initiated, and the prednisone dosage was tapered to 15 mg per day. He improved significantly while on this regimen, but his gout tended to flare at the end of his dosing cycle. Therefore, the anakinra dosage was increased to 100 mg subcutaneously 4 times a week. He has had no gout flares on this regimen and has remained out of the hospital for the last 8 months. His erythrocyte sedimentation rate has fallen to 11 mm/hour, having hovered between 94 and 122 mm/hour for the previous 2 years. He is now taking 7.5 mg of prednisone per day, with plans to taper him off of the medication entirely over the next several months (Figure 1). With the recent Food and Drug Administration (FDA) approval of a new xanthine oxidase inhibitor, febuxostat, it is hopeful that the patient's hyperuricemia can finally be successfully treated, thus eventually eliminating the need for ongoing symptomatic therapy with anakinra.

Figure 1.

Erythrocyte sedimentation rate (ESR), prednisone dose, and number of inpatient days by month, before and after the start of anakinra.

Discussion

Gout is a common disease and its prevalence is increasing, possibly due to its association with the metabolic syndrome, which includes insulin resistance, obesity, and hypertension (3). Because of multiple comorbid conditions, including but not limited to renal insufficiency, diabetes mellitus, peptic ulcer disease, nephrolithiasis, and chronic congestive heart failure, many patients cannot use common gout medicines such as NSAIDs, colchicine, and prednisone, or uricosuric agents such as probenecid or benzbromarone. In addition, severe allergic reactions may prevent the use of allopurinol; in this patient's case, allopurinol desensitization is contraindicated due to the severity of his prior reaction. Therapy for gout has changed little in the last decades, but alternative therapies are being investigated for use in refractory gout. Rasburicase, a recombinant uricase enzyme that cleaves uric acid into highly soluble allantoin, is FDA approved for single use in the treatment of the tumor lysis syndrome, and has been shown to lower serum uric acid transiently but dramatically within hours of administration. Case reports have documented the successful use of recurrent rasburicase infusions for the treatment of chronic gout, but the drug's short half-life, immunogenicity, high cost, and potential toxicities, including production of H2O2 as a byproduct, raise uncertainties about the widespread and long-term use of this medication. Recent clinical trials of a PEGylated uricase designed to prolong the enzyme's half-life and possibly reduce the immunogenicity have demonstrated efficacy in clinical trials of gouty arthropathy and may be useful in the future (4). The nonpurine xanthine oxidase inhibitor, febuxostat, has just received FDA approval and, because it did not demonstrate any cross-reactivity in patients with sensitivity to allopurinol, it provides a much needed addition to the limited regimen of hypouricemic agents currently available. Importantly, although these new agents are designed to decrease total body uric acid levels and therefore may further lower the incidence of refractory gouty arthritis, they do not have any effect on the inflammatory process itself. For the few who have severe disease refractory to available therapies or contraindications to these therapies, there remains a need for new, less toxic approaches to controlling the inflammation of acute and chronic gout.

One of the mechanisms by which monosodium urate crystals cause inflammation is stimulation of the NALP3 inflammasome in monocytes and macrophages via Toll-like receptor activation, leading to cytokine production. Foremost among these cytokines is IL-1, which mediates pyrexia, leukocytosis, anemia, thrombocytosis, vascular permeability, diapedesis, and inflammatory cell activation. It has been shown that blocking IL-1 with the IL-1 receptor antagonist anakinra results in a rapid and sustained decrease in local and systemic inflammation in juvenile idiopathic arthritis, adult-onset Still's disease, and the cryopyrin-associated periodic syndrome (CAPS) (5). In 2007, So et al (2) hypothesized that IL-1 inhibition may reduce the inflammation of acute gout. They treated 10 subjects with refractory gout, or intolerance to standard therapy, with anakinra 100 mg subcutaneously daily for 3 days with or without hypouricemic treatment, and saw a mean reduction in pain of 79% within 48 hours. Our observations of a dramatic antiinflammatory response to anakinra in a patient with severe refractory tophaceous gout confirm the value of anakinra in both the treatment of the acute inflammation of gouty arthropathy and as a potentially less toxic alternative to chronic moderate-dose prednisone in those individuals with frequent refractory attacks who do not have treatment alternatives. In the future, additional IL-1 inhibitors may be considered for gout therapy as well. One such therapy is rilonacept, also known as IL-1 Trap, a soluble decoy receptor for IL-1 and currently under investigation to treat CAPS (6).

In conclusion, we demonstrated that in this patient with severe refractory chronic tophaceous gout, the IL-1 inhibitor anakinra was used effectively as a steroid-sparing agent for the inflammation of severe, chronic gout. Although several new therapies for hyperuricemia offer much needed hope of further reducing the incidence of refractory gout, during the transition to these new therapies and for those few who fail to respond, IL-1 inhibitory therapy may provide significantly greater symptomatic relief and less toxicity than high-dose steroids.

AUTHOR CONTRIBUTIONS

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Gratton 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.

Study conception and design. Gratton, Scalapino, Fye.

Acquisition of data. Gratton.

Analysis and interpretation of data. Gratton, Scalapino.

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