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Anakinra’s Efficacy is Variable inRefractory Gout: Report of Ten Cases

Kun Chen, MD, PhD, Theodore Fields, MD, Carol A. Mancuso, MD,Anne R. Bass, MD, and Lisa Vasanth, MD

Objectives: To evaluate the efficacy of anakinra for patients with acute gout.Methods: We reviewed the charts of 10 patients who received anakinra for urate crystal-inducedarthritis at the Hospital for Special Surgery since 2007. Demographic information, comorbidities,short-term treatment outcomes, and subsequent flares were reviewed.Results: Patients in our study had a high prevalence of comorbidities. All patients received corti-costeroids before anakinra treatment. The mean number of anakinra injections was 3.2 per patient(100 mg subcutaneously per day). Six patients had a good response. Three patients had a partialresponse and 1 patient had no response. Nine patients had documented recurrent flares afterdiscontinuing anakinra (ranging from 3 to 45 days after).Conclusion: Anakinra is a therapeutic option for patients with acute urate crystal-induced arthritiswho do not respond to or have a contraindication to traditional treatments. Although a shortcourse of anakinra resulted in favorable outcomes for some of our patients, response rates werepoorer in our study than in previously published reports, and relapses were common.© 2010 Published by Elsevier Inc. Semin Arthritis Rheum 40:210-214Keywords: anakinra, gout, efficacy, arthritis

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outy arthritis is caused by monosodium urate inthe joints or soft tissues (1). Gout is a commondisease affecting the elderly population (2). Pa-

ients initially present with episodic acute monoarticularoint pain, swelling, and erythema. Without proper treat-

ent, they can later develop polyarticular joint involve-ent. Nonsteroidal anti-inflammatory drugs (NSAIDs)

nd corticosteroids are the mainstays of the treatment3-5). Corticosteroids can be given by local injection if 1r 2 joints are involved or orally or intravenously (IV) ifultiple joints are involved. Alternative treatments for

cute gout flares include oral or IV colchicine. Althoughost patients with acute gout respond well to NSAIDs,

orticosteroids, or colchicine, a fraction of patients areefractory to these treatments. Typically these patientsave a long history of gout and a history of polyarticular

oint involvement (6).

heumatology Division, Weill Cornell Medical College, Hospital for Special Sur-ery, New York, NY.Disclaimers: Dr. Theodore Fields serves on the Advisory Board, Speakers’ Bureau

or Takeda Pharmaceuticals.

pAddress reprint requests to Kun Chen, MD, PhD, 535 East 70th St., New York, NY

0021. E-mail: chenk@hss.edu.

10 0049-0172/10/$-see front matter © 2010 Published by Elsevier Inc.doi:10.1016/j.semarthrit.2010.03.001

Gout is typically seen in elderly patients with medicalroblems that represent relative or absolute contraindica-ions to using NSAIDs, corticosteroids, or colchicine2,7). NSAIDs are contraindicated in patients with pepticlcer disease, renal insufficiency, and moderate to severeongestive heart failure. NSAIDs can be used only cau-iously in patients with a history of cardiovascular events.orticosteroids can cause an exacerbation of diabetes, hy-ertension, or glaucoma as well as cataracts, mood swings,sychosis, myopathy, and osteoporosis. Colchicine canesult in bone marrow suppression, neuropathy, and my-pathy, particularly in patients with renal insufficiency.

Recent studies showed that activation of the NACHT-,RR-, and PYD domain-containing protein 3 (NALP3)

nflammasome is an important mechanism underlyingrate crystal-induced inflammation (8). Urate crystals ac-ivate macrophages via an unidentified initiation process9). This results in the assembly of the inflammasome com-lex and activation of Caspase I (8). Activated Caspase Iatalyzes the cleavage of pro IL-1� to mature IL-1� (10).L-1� is a key proinflammatory cytokine that serves to am-lify other inflammatory pathways that lead to the produc-ion of cytokines such as TNF and IL-6 (8). The IL-1�

roinflammatory pathway is carefully balanced by anti-in-

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ammatory cytokines. One of the anti-inflammatory cyto-ines is IL-1 receptor antagonist (IL-1ra). IL-1ra is producedy macrophages. It competes with IL-1� to bind to the IL-1eceptor but is biologically inactive (11).

Anakinra is a commercially produced IL-1ra that isDA-approved for the treatment of rheumatoid arthritis.t differs from endogenous IL-1ra by an extra methionineesidue at its amino-terminus (12). Several case reportsave suggested anakinra is effective in the treatment ofout (13-15). So and coworkers studied the use of anak-nra prospectively in a series of 10 patients (16). The studynrolled patients with acute gout who had either a pooresponse to traditional treatment or a contraindication toraditional treatment. Patients were given anakinra 100g subcutaneously daily for 3 days and all had clinical

mprovement in less than 3 days. There were no reportedout flares in 80% of the patients at follow-up visits rang-ng from 1 to 2 months (16). Based on this data, someheumatologists have begun to use anakinra for the man-gement of refractory acute gout.

The purpose of this study was to analyze the use ofnakinra for acute urate crystal-induced arthritis at ournstitution. Specifically, we were interested in the indica-ions for treatment, and the drug’s efficacy and safety.

ETHODS

his is a retrospective chart review of patients who re-eived anakinra for urate crystal-induced arthritis. Pa-ients were identified to the authors through recall by thereating rheumatologists and by searching electronic med-cal records if available with the keyword “anakinra” orKineret,” and data were collected through chart review.

e excluded patients treated with anakinra who wereiagnosed with autoimmune diseases such as rheumatoidrthritis or Still’s disease. Inclusion criteria included aiagnosis of gout and at least 1 documented visit after the

ndex flare. A diagnosis of gout could be made by eitherhe presence of tophi on examination or the presence ofntracellular monosodium urate crystals on synovial fluidnalysis documented in the patient’s medical record oristopathology report (17).The outcome of anakinra treatment was categorized as

good response, partial response, or no response. A goodesponse was defined as a report of complete or near com-lete resolution of joint symptoms or documentation inhe chart of the word “good” response after anakinra treat-ent. A partial response was defined as a report of im-

rovement in joint symptoms but not a “good” responser complete resolution. No response was defined as thebsence of improvement with the treatment.

The study was approved by the Institutional Reviewoard at the Hospital for Special Surgery.

ESULTS

able 1 shows a summary of clinical data for all 10 cases.

ean age was 63. Diagnostic crystals were documented a

n joint fluid analysis in all cases. Ninety percent of theatients had renal insufficiency. All patients receivedral/IV steroids or intra-articular steroid injections toontrol gout flares before the use of anakinra. NSAIDsere avoided in most cases due to renal insufficiency.one of the patients received increased doses of colchi-

ine to control the index flare. Seventy percent of theatients were on colchicine prophylaxis (0.6 mg everyther day to 0.6 mg daily) at the time of index flare.ighty percent of the patients were on allopurinol at the

ime of index flare.The mean number of anakinra injections was 3.2 for

he acute flare. The indication for anakinra in all patientsas an acute flare responding poorly to oral or intra-

rticular steroids. Case 3 had a history of a stem cell trans-lant and received anakinra in part due to concern overhe immunosuppressive effects of chronic steroids. Case 5ad an open wound from a draining tophus and alsoeceived anakinra partly out of concern for the immuno-uppressive effects of chronic steroids.

Obtaining anakinra was difficult for most of the pa-ients. Insurance typically does not cover anakinra forout treatment. Few pharmacies are willing to distributenakinra in 3 to 5 doses out of a monthly supply package.hree patients received anakinra as inpatients. The acuteout flare in case 3 responded well to 3 doses of anakinra,ut he continued to experience recurrent gout flare. Heas able to purchase a 1-month supply of anakinra andsed it daily for 3 to 5 days at a time when his joints startedo become painful. At the end of 3 months, he had used all8 doses of anakinra and reported that his gout-relatediscomfort was at its lowest level in years.The patient in case 6 received 2 weeks of high-doseethylprednisone intravenously in the hospital without

mprovement of the acute gout flare and respondeduickly to 3 doses of anakinra in April 2008. He contin-ed to experience gout flares once per month after dis-harge. His renal function became progressively worsend he started hemodialysis in July 2009. At around theame time, he was able to obtain anakinra through annsurance assistance program. After starting anakinra in-ections 3 times per week, he reported no further goutares through his last visit in November 2009.Anakinra was generally well tolerated. The only adverse

eaction was in 1 patient who reported an injection siteeaction 1 week after the injection. Interestingly, this washe 1 patient who had no short-term clinical response tohe drug. Nine patients had documented flares after stop-ing anakinra. Overall flare frequency did not changefter the short-term use of anakinra.

ISCUSSION

ncreased knowledge of the pathogenesis of crystal-in-uced arthritis at the molecular level has led to the explo-ation of specific target-directed treatments. Both in vitro

nd murine models suggested that crystal-induced in-

Table 1 Case Summaries

CaseAge/Sex Tophi

ComorbidConditions

Serum Cr(0.4 to 1.2

mg/dL) Joint InvolvedReason forAnakinra

Steroid Used Prior toAnakinra

FlareFrequency

Prior toAnakinra Response

Time toNext Flare

AfterAnakinra

1 69/M Yes Htn, cataract,osteoporosis

Dialysis Elbow, shoulder,knee

Poor response tosteroids

20 mg prednisone daily Once perweek

Partial 4 days

2 65/M No Cad, Htn,cataract,DM

1.6 Knee, toe Poor response tosteroids

Bil knee 40 mg depomedrolinjection

Once permonth

Partial 30 days

3 62/M No Htn, DM 1.4 Knee, toe Poor response tosteroids

Immunosuppressionon chronicsteroids

IV solumedrol 60 mg �130 mg prednisone taperR MTP 4.5 mg celestone

injection

Once permonth

Good 20 days

4 53/M No 1.3 Toe Poor response tosteroids

50 mg prednisone 1 weektaper

Then 30 mg prednisone 1week taper

Once permonth

None No response

5 86/F Yes Htn 2.0 Hand Poor response tosteroids, infectionrisk with chronicsteroids

5 mg prednisone daily Unknown Good 20 days

6 54/M Yes CAD, Htn,cataract,DM

3.0 Hand, wrist,elbow, neck,knee, feet

Poor response tosteroids

2 weeks of 48 mg IVsolumedrol daily

Once permonth

Good 15 days

7 78/M Yes Htn, gastriculcer

1.8 Finger, toe Poor response tosteroids

20 mg prednisone daily �3 weeks

Unknown Good Unknown

8 52/M Yes Htn 1.5 Elbow, knee,ankle

Poor response tosteroid

40 mg prednisone � 10days taper

Right elbow 20 mgmethylprednisoneinjection

Once permonth

Good 24 days

9 79/F Yes Htn, DM 1.5 Fingers, elbow,knee

Poor response tosteroids

Right knee 40 mgmethylprednisone injection

Right elbow 40 mgmethylprednisone injection

40 mg prednisone daily �3 days

Once per 3months

Good 45 days

10 33/M Yes 1.1 Fingers, knee,ankle

Poor response tosteroids

10 mg prednisone dailyIV solumedrol 60 mg

daily � 3 days

Once per 2months

Partial 14 days

M, male; F, female; Htn, hypertension; DM, diabetes mellitus; CAD, coronary artery disease; R, right; MTP, metatarsophalangeal; Bil, bilateral.

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ammation is mediated through the NALP3 inflamma-ome pathway and that activation of IL-1 is important inrate crystal-induced inflammation (8).Three anti-IL-1 biologic therapies are currently ap-

roved for use by the FDA. These include anakinra,ilonacept, and canakinumab. Anakinra is an IL-1 recep-or antagonist similar but not identical to endogenousL-1ra, which is approved for the treatment of rheuma-oid arthritis (18,19). Of the 3 anti-IL 1 biologics, anak-nra has the shortest half-life. This makes it a potentially

Table 2 IL-1 Inhibition Literature Review on Gout Treatmen

Author (yr) Type of Study

Gratton et al (13)(2009)

Case report 59tir

McGonagle et al(15) (2007)

Case report 74gp

Singh et al (14)(2009)

Case report 58ip

So et al (16) (2007) Pilot open-labeled study withanakinra

10tr

So et al (21) (2009) 8 weeks, dose-ranging,multicenter, single-blinded,canakinumab vstriamcinolone trial (TA)

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Schumacher et al(22) (2009)

16 weeks, multicenterrandomized, phase 2 trial,rilonacept vs placebo ingout patients startingurate-lowering therapy

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Terkeltaub et al(23) (2009)

14 weeks, multicenter,nonrandomized, single-blind pilot study withrilonacept

10tr

M, male; TA, triamcinolone acetonide; DM, diabetes mellitus; SC,

ood option to treat acute crystal-induced flares because it I

llows for a rapid onset of action and a short duration ofmmunosuppression. Rilonacept is an IL-1 inhibitor thatinds and neutralizes circulating IL-1, while canaki-umab is an anti-IL-1 monoclonal antibody. Both haveeen approved for cryopyrin-associated periodic syn-romes in which the NALP3 inflammasome pathway isnown to be activated (20). In addition, rilonacept andanakinumab in recent clinic trials showed encouragingesults in treating acute gout and gout flare prevention21,22). Table 2 shows the summaries of published anti-

nical Picture Treatment; Outcome

ld M, DM,eous gout, renaliency, poorse to steroid

Treated with anakinra 100 mg 3 to4 times per week �8 months;good response

ld M, tophaceousenal insufficiency,sponse to steroid

Treated with anakinra 100 mg daily�6 months; good response

ld M, DM, renaliency, no tophi,sponse to steroid

Treated with anakinra 100 mg daily�7 months; good response

ts, 30% witheous gout, 70%sufficiency

Received anakinra 100 mg daily for3 days; all patients with �50%pain improvement at 48 hr afterinjection, 70% patients with�70% pain improvement at 48hr after injection

nts with acutearthritis flares,ry to or

ndicated tos and/orine

Treated with 1 SC dose ofcanakinumab (10, 25, 50, 90, or150 mg) vs 1 IM 40-mg dose ofTA; 150 mg canakinumabprovides statistic significantgreater pain relief as measured byVAS from 24 to 72 hr than TA,150 mg canakinumab also has a94% relative risk reduction forrecurrent gout flares 8 weekspost treatment compared to TA

uricemic patientsout, initiation ofinol 300 mg dailyrget uric acid �6, 10% patientsphaceous gout

Treated with rilonacept 160 mgweekly vs placebo for 16 weeks;rilonacept markedly reduced theoccurrence of gout flares duringinitiation of urate-loweringtherapy. At week 12, mean flareper patient decreased by 81% inrilonacept group compared toplacebo group

ts, 50% witheous gout, 20%sufficiency

6 weeks of rilonacept weeklytreatment; 60% patients reported�50% pain relief and 50%patients reported �75% painrelief after 6 weeks of treatment.Significant decrease in high-sensitivity C-reactive protein withrilonacept treatment

taneous; IM, intramuscular; VAS, visual analog scale.

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214 Variable anakinra efficacy in refractory gout

ith rilonacept and canakinumab are underway for acuteout flare and gout flare prevention.

In the case series by So and coworkers (16), all 10atients responded quickly to anakinra with at least 50%ain improvement. Only 1 or 2 patients had recurrentares at follow-up after �1 month. Our study suggests a

ower response rate. Ninety percent had recurrent flares 1o 6 weeks after the index flare. The poor outcomes seenn our patients are likely due to the fact that our patientseceived anakinra only after failure of steroid treatment.n the So study only 2 patients received steroids beforenakinra (16). Of those patients only 1 was a steroid fail-re while the other received anakinra due to steroid-in-uced diabetes. Our population was clearly enriched withatients refractory to multiple anti-inflammatory treat-ents, but they are representative of the cases where anak-

nra is likely to be used in clinical practice.Our study demonstrates that the short-term treatment

ith anakinra does not affect the likelihood of gout recur-ence following attack resolution. This is not surprisingiven the short half-life of anakinra. The 2 patients (casesand 6) who were able to use anakinra in an ongoing

ashion (as needed at the beginning of a flare, or everyther day) reported a decrease in flare frequency and se-erity. In line with our findings, 3 gout patients requiredrolonged anakinra treatment over 6 months to controlnd prevent flares in 3 independent case reports (13-15).

In summary, the short-term use of anakinra can help toontrol flares in steroid-refractory patients with gout, buthe drug is less effective than previously reported and theffect is short-lived. Some patients require repeated orrolonged courses of anakinra to control their disease.onger acting IL-1 antagonists may prove to be moreseful in treating such patients.

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