Treatment of Acute Gouty Arthritis in Complex Hospitalized Patients With Anakinra

Authors


Abstract

Objective

To report our experience with the efficacy and safety of anakinra for acute gouty arthritis in medically complex hospitalized patients.

Methods

We reviewed the hospital charts of 26 patients treated with anakinra for crystal-induced arthritis since 2007. Demographics, comorbid conditions, reason for anakinra use, response to treatment, and any adverse outcomes were recorded.

Results

Twenty-six patients received 40 courses of anakinra therapy. In 67% of patients, pain improved significantly within 24 hours, and complete resolution of signs and symptoms of gout occurred by day 5 in 72.5% of patients. Seven patients received multiple courses with no decrement in response with repeated treatments. Anakinra was well tolerated and no adverse outcomes were attributed to the medication. Only 1 patient appeared to be refractory to this form of interleukin-1 inhibition.

Conclusion

Anakinra is an effective and safe alternative treatment for acute gouty arthritis in medically complex hospitalized patients who fail or cannot undergo more conventional therapy.

Introduction

Gout is a chronic inflammatory disease mediated by monosodium urate crystals and characterized by recurrent attacks of monarthritis or polyarthritis. Gouty inflammation commonly flares during the bed rest required by hospitalized patients, and also can be precipitated by acidosis or medications such as diuretics. The hallmark of gouty arthritis is the articular influx of neutrophils mediated by cytokines such as interleukin-1β (IL-1β), tumor necrosis factor α, and IL-6 ([1, 2]). Martinon et al showed that monosodium urate crystals as well as calcium pyrophosphate dihydrate crystals can mediate the production of IL-1β via activation of the NALP3 inflammasome ([3]). The inflammasome is a component of the innate immune system and when activated, binds and activates caspase 1, which in turn cleaves pro–IL-1β into the active cytokine, IL-1β ([1]). Mice deficient in various components of the inflammasome are unable to mount an inflammatory response to either of these crystals.

Available treatments for acute gouty arthritis have not changed in many years. Standard therapies include nonsteroidal antiinflammatory drugs (NSAIDs), oral or injectable steroids, and oral colchicine. Some patients respond poorly to these therapies and/or they cannot be safely utilized due to comorbid medical conditions. Given the pathophysiologic mechanism for IL-1β activation by monosodium urate crystals, IL-1β inhibition comprises an appealing therapy for gouty arthritis. In a study of 10 patients with gout who had failed standard gout medications, treatment with 100 mg daily for 3 days with the IL-1 receptor antagonist, anakinra, resulted in impressive improvement in signs and symptoms of inflammation ([4]). In addition, chronic tophaceous gout with persistent inflammation was brought under control by daily administration of anakinra ([5]). Therapy-resistant pseudogout has also been successfully controlled with anakinra ([6]).

We report our experience with the use of anakinra in acute gouty arthritis in hospitalized patients who were either resistant to standard therapy or had significant comorbidities that precluded the use of NSAIDs, colchicine, or steroids.

Box 1. Significance & Innovations

  • We report the largest retrospective series detailing the successful use of anakinra in acute gout.
  • Anakinra therapy resulted in rapid improvement in the symptoms of gout.
  • There was no decrement in response to anakinra when used more than once in the same patient.
  • No significant safety signals were identified after 5 years of use in hospitalized patients with acute gout who often had 1 or more significant medical comorbidities.

Materials and methods

Approval from the institutional review board was obtained for this study. Retrospective chart review was done for all hospitalized patients who had been treated with anakinra for acute gouty arthritis. Data collected included age, sex, body mass index (BMI), joint(s) affected, comorbid conditions, reasons for choosing anakinra over standard therapy, anakinra dosing schedule, time to pain improvement and time to complete resolution of symptoms, and serum urate level.

Results

Our chart review found 26 hospitalized patients who had been treated with anakinra for 40 episodes of acute gouty arthritis since 2007. There were 22 men and 4 women with a mean age of 56.8 years (range 32–86 years). Seven patients had multiple courses of anakinra: 4 patients had 2 courses, 2 patients had 4 courses, and 1 patient had 5 courses. Comorbid conditions are shown in Table 1. In general these were very complex patients, with ≥1 underlying medical conditions. Anakinra is generally not used in patients with a creatinine clearance <30 ml/minute. Seven of our 26 patients had a creatinine level of ≥2.0 mg/dl (mean glomerular filtration rate [GFR] 25 ml/minute, range 18–41), with 5 of the 7 having a GFR of ≤30 ml/minute. These 5 patients received a total of 11 courses of anakinra, with 6 of these courses being either every day for 2 days or every day for 3 days without any side effects. The patient with a creatinine clearance of 41 ml/minute was obese, with a BMI of 51 kg/m2, and had 4 courses of anakinra at a higher dose than usual (3 courses of 100 mg twice daily for 5 days and 1 course of 100 mg daily for 5 days), again without any side effects.

Table 1. Comorbid medical conditions in 26 patients with acute gouty arthritis treated with anakinra*
 No.
  1. AVN = avascular necrosis of bone.
Chronic kidney disease15
Diabetes mellitus9
Congestive heart failure8
Recent surgery7
Solid organ transplantation4
Acute infection3
Acute leukemia2
Steroid-associated AVN1
≥2 comorbidities10

Distribution of joint involvement included both large and small joints of the upper and lower extremities and also the tendons. In 29 (72.5%) of the 40 episodes, the gouty arthritis was polyarticular. Foot and ankle joints were most commonly affected (44.5%), followed by hand and wrist (25%), knees (18.5%), and shoulders, elbows, and tendons (12%).

There were 35 serum urate levels available for the 26 patients. The serum urate level was >6.8 mg/dl in 14 patients at the time of their gout attack(s) and <6.8 mg/dl in 10 patients. Two additional patients did not have serum urate levels available. Twenty-two patients (85%) had a known diagnosis of gout prior to hospitalization and 9 of the 22 had tophaceous disease. In only 4 patients was the diagnosis made during hospitalization and in all but 1 of these patients, the diagnosis was confirmed by crystal demonstration from synovial fluid. In the only patient without a crystal diagnosis, the affected joint was a first metatarsophalangeal joint and the patient refused arthrocentesis. Overall, 13 of the 40 gouty attacks were crystal proven and the rest were made by typical signs and symptoms of gouty arthritis. Four patients refused arthrocentesis, and in at least 2 cases the referring service would not allow us to perform arthrocentesis. Symptoms and signs of the presumed gouty attack responded promptly to anakinra therapy in these patients.

It should be noted that the 26 patients reported in this study are not the total number of patients with gout evaluated by our service during the study period. Patients with gouty arthritis who responded to steroids or other conventional gout medications are not included in this report. With regard to pre–anakinra treatment failures, 8 of the reported 26 patients had no response to intraarticular steroids, oral steroids, or both during the initial attack. Three patients had failed colchicine and 7 patients had failed both steroids and colchicine. The colchicine failures were almost all failures of prophylactic dosing, not therapeutic dosing. For 4 of the 15 steroid failures, steroid dosing was likely inadequate (≤20 mg of prednisone), but the dosing reflected the concern of the referring service for using higher-dose therapy. In the remaining 8 patients, it was thought that underlying comorbidities and/or the number of joints involved precluded the use of oral/intraarticular steroids. Therapeutic colchicine was problematic in a significant number of our patients, and none of the patients had tried to take NSAIDs because of concern for side effects.

Seven different dosing schemes were used and are outlined in Table 2 by the number of episodes in which they were used. The chosen dose was based on the circumstances of the individual patient and the rheumatologist who evaluated the patient. Dosing was influenced by the number of joints involved; the BMI of the patient (twice a day dosing in heavier patients); the presence of chronic kidney disease (CKD; every other day dosing with exceptions noted above); the early, complete response of the patient (1 dose); or the persistence of symptoms (every day for 5 days).

Table 2. Dosing schedule used for 40 episodes of acute gouty arthritis treated with anakinra
 No.
Single dose4
Once daily for 2 days4
Once daily for 3 days17
Once daily for 4 days1
Once daily for 5 days3
One dose every other day for 3 days7
Twice daily for 5 days4

The majority of patients responded to anakinra therapy within ≤1 day of treatment initiation. A significant response was defined as movement of the affected joint(s) with minimal pain (i.e., 0–3 on a 10-point scale) and the ability to bear weight if lower extremity joint(s) were affected. Overall, 67% of the anakinra courses (27 of 40) resulted in significant pain improvement within 24 hours of the first dose. For another 18% of the courses (7 of 40), significant pain improvement occurred within 48 hours of the first dose. Therefore, 85% of patients had significant pain improvement within 2 days. Only 15% of the courses (6 of 40) required 3–6 days to achieve pain improvement (Figure 1). Complete resolution of symptoms (pain, swelling, erythema, and warmth) was achieved in 72.5% of patients within 5 days, and by 10 days all but 1 patient had complete resolution of their attack. The delayed responder was a particularly complex patient with underlying acute lymphocytic leukemia in blast crisis. She received rasburicase prior to her attack and was receiving allopurinol and colchicine. Her serum uric acid level dropped from 15.9 to 1.3 mg/dl the day after rasburicase administration and she developed acute ankle swelling. She initially responded dramatically to anakinra every day for 3 days, but did not resolve completely until 14 days following her initial dose. Her index case of presumed gouty arthritis was not crystal proven due to refusal of arthrocentesis, but she had had previous attacks of crystal-proven gout prior to hospitalization.

Figure 1.

Time in hours to significant response in 40 episodes of acute gouty arthritis treated with anakinra.

Of the 7 patients who received multiple courses, 5 were treated during different hospital admissions. No decrement in response was noted during the repeat courses for those whose courses were given during separate hospitalizations or for the 2 patients who received multiple courses during the same hospitalization.

Anakinra was well tolerated in our population, with no injection site reactions or allergic reactions noted. In addition, there were no instances of documented leukopenia. Seven patients with perioperative gout flares and 4 patients who were immunosuppressed (receiving medications related to organ transplantation or with underlying hematologic malignancy) were given anakinra without any adverse events. Two patients under appropriate antibiotic treatment for infection (pneumonia and sepsis) were given anakinra courses without exacerbation of infection. One patient developed a postoperative wound infection; however, his wound site was draining and possibly infected 4 days prior to the first anakinra dose.

Discussion

We have found anakinra to be a useful therapy for treating acute gouty arthritis in medically complex, hospitalized patients. Anakinra was chosen due to the pain of our patients and the lack of better options. The majority of our patients responded to anakinra within 24 hours of the first dose. Eighty-five percent of the courses resulted in complete resolution of pain within 2 days. Complete resolution of signs and symptoms (pain, swelling, erythema, and warmth) was achieved in 10 days in all but one anakinra course. Seven of the 26 patients required multiple courses and there was no decrement in response with the subsequent treatments. One patient required repeated anakinra dosing for gouty arthritis involving the same joint. This raises the possibility of a small subset of patients who are unresponsive or only minimally responsive to IL-1 inhibition. Although our findings are positive, we recognize the limitations of a retrospective, open-label study, and confirmation of our results would require a randomized controlled trial.

We have found short-term anakinra treatment to be well tolerated, with no recognized adverse reactions other than one instance of a postoperative wound infection during anakinra therapy. After much discussion, anakinra was used in individual patients with ongoing infections, recent surgery, and concurrent immunosuppression. All of these patients had either failed or had relative contraindications to conventional management for gouty arthritis. In the one postoperative patient who developed a wound infection, wound drainage began prior to anakinra administration, which may or may not have contributed to the developing infection, but serves as a point of caution.

A literature search revealed 7 previous publications reporting anakinra use in acute and chronic gouty arthritis in 26 patients ([4, 5, 7-11]). Almost all of the patients included in these studies had significant comorbidities, with the majority of them having some level of CKD and many having tophaceous gout. Two patients were reported to have had 2 courses, whereas 4 patients were given anakinra on an ongoing basis. All but one reported patient had some response and there was no decrement in response with multiple courses or with prolonged use. Of great importance is the almost complete lack of reported side effects in this population of patients with high disease burden. In addition, it seems likely that both the frequency and duration of hospitalizations were diminished for patients receiving anakinra. Gouty arthritis can also add to hospital time for patients with other illnesses. Lin et al documented that a gouty arthritis attack in patients hospitalized for cerebrovascular disease increased the hospital time by more than 3 days ([12]). Anakinra is expensive; however, its cost may be offset by reducing the need for hospitalization and/or length of stay for inpatients with gouty arthritis.

Two long-acting IL-1 inhibitors, canakinumab and rilonacept, have also been used successfully to treat gouty arthritis and prevent gout attacks with initiation of urate-lowering therapy ([13, 14]). As with anakinra, these IL-1 inhibitors were reported to have few side effects, but approval for use in gouty arthritis is pending long-term safety data.

Our experience has doubled the number of reported patients for whom anakinra has been used for the treatment of gouty arthritis and has confirmed the efficacy and safety of anakinra in complex patients. In addition, several of our patients received more than 2 courses of anakinra with no decrement in response. The variety of dosing schemes used reflects individual patient characteristics and may be one of the advantages of anakinra. It has a short half-life of 4–6 hours and does not accumulate even with long-term therapy. It is eliminated via the kidneys and the mean plasma clearance is decreased by 70–75% in patients with a creatinine clearance of 30 ml/minute or less ([15]). However, we found no issues in the short-term use of anakinra in patients with CKD even when dosed in a standard fashion, although our numbers are small.

In conclusion, we found anakinra to be an effective, versatile, and safe medication to treat acute gouty arthritis in a medically complex population, and advocate for its wider use in this setting. We encourage others to report their experience with anakinra in patients with gouty arthritis.

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. Gardner 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. Ghosh, Simkin, Gardner.

Acquisition of data. Ghosh, Cho, Rawat, Gardner.

Analysis and interpretation of data. Ghosh, Cho, Simkin, Gardner.

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