IL-1 Blocker Shows Promise in Refractory Gout
Total Page：16
File Type：pdf, Size：1020Kb
24 Arthritis R HEUMATOLOGY N EWS • September 2008 IL-1 Blocker Shows Promise in Refractory Gout Rilonacept resulted in a 75% improvement in pain actively inflamed joints for at least the past way is believed to figure prominently. month at enrollment. These include juvenile idiopathic arthri- scores in 5 of 10 patients after 6 weeks of injections. Standard gout therapies were either in- tis, familial Mediterranean fever, and effective or laden with unacceptable side rheumatoid arthritis. BY BRUCE JANCIN protein and high-affinity blocker of the in- effects in this overweight/obese popula- Earlier this year, rilonacept received Denver Bureau terleukin-1 receptor type 1 and the IL-1 ac- tion with numerous comorbid conditions. Food and Drug Administration marketing cessory protein. Its therapeutic efficacy in High-sensitivity C-reactive protein levels approval for the treatment of two rare PARIS — The investigational long-acting this multicenter proof-of-concept study (a measure of disease activity) dropped by cryopyrin-associated periodic syndromes: interleukin-1 inhibitor rilonacept showed reinforces preclinical evidence and a small an average of 59% after 6 weeks of rilona- Muckle-Wells syndrome and familial cold potential as an important new treatment case series suggesting that IL-1 plays an im- cept, then trended back up toward baseline autoinflammatory syndrome. option in patients with severe refractory portant role in gouty inflammation, and during 6 weeks of follow-up off the drug. One audience member indicated that he chronic active gout in a small pilot study, that blockade of the IL-1 pathway repre- The number of affected joints decreased wasn’t bowled over by the 50% response according to a rheumatologist whose re- sents a new treatment strategy in gouty during active treatment, a trend that just rate reported by Dr. Sundy. search focus is chronic gout. arthritis. missed statistical significance in this small He questioned the merits of developing Five of 10 patients in the single-blind The pathophysiologic sequence in- study. a sophisticated and costly new therapy for nonrandomized study showed at least a volves the engulfing of monosodium The same was true for physicians’ glob- a familiar disease for which far simpler al- 75% improvement in pain scores after 6 urate crystals by monocytes, which acti- al ratings. ternatives—including intra-articular cor- weekly subcutaneous injections of rilona- vates the cryopyrin inflammasome with Rilonacept was generally well tolerated. ticosteroid injections—are often highly cept at a fixed dose of 160 mg. resultant release of IL-1 into surrounding The most common reported side effect effective. These were patients with severe refrac- tissues. consisted of mild to moderate injection Dr. Sundy replied that rilonacept is tar- tory pain and disability at baseline, and The IL-1β induces expression of site reactions. geted at the minority of patients in whom none of them responded to 2 weeks of chemokines and adhesion molecules, Speaking at the annual European Con- tried-and-true therapies aren’t effective or placebo injections, commented Dr. John which draw polymorphonuclear leuko- gress of Rheumatology, Dr. Sundy said are intolerable. S. Sundy, the director of rheumatology cytes to the site of acute inflammation, that in addition to much larger and Given that gout is the most common in- and allergy research at the Duke Clinical thereby making the inflamed joint even longer-term placebo-controlled trials of flammatory arthritis in men and its inci- Research Institute, Duke University, hotter, he explained. rilonacept in refractory chronic active dence is climbing, that’s not an insignifi- Durham, N.C. The 10 participants in the pilot study gout, other trials are planned or under- cant number of patients. He disclosed that he is a consultant to had a mean age of 62 years, a 13-year his- way to evaluate the IL-1 inhibitor for “This is the severe end of the spectrum Regeneron Pharmaceuticals Inc., which tory of gout, and a mean visual analog prevention of acute flares in patients with of gout. It’s the small tail on the curve, not sponsored the pilot study. scale pain score of 5.1 at enrollment. chronic gout, as well as in other inflam- the typical everyday presentation of gout,” Rilonacept is a soluble dimeric fusion The patients had a mean of nearly three matory diseases in which the IL-1 path- he stressed. ■ Allopurinol, Benzbromarone Both Effective in High Doses BY JEFF EVANS affected by doubling the dosage in pa- ature: the extremities. It is often said that microscopic evidence of urate crystals in Senior Writer tients not reaching target levels,” study in- serum urate (uric acid) concentration—a punctate from synovial fluid or periartic- vestigator Mattheus Reinders, a hospital well-accepted biomarker for evaluation of ular structures or presence of tophi. The out patients have equal rates of suc- pharmacist at the Atrium Medisch Cen- gout treatment—must be lower than the patients were indicated for serum Gcess in attaining a serum urate con- trum, Heerlen (the Netherlands), said in solubility at 37 °C (0.42 mmol/L) for urate–lowering treatment if they had centration of 0.30 mmol/L or less—a val- an interview. good treatment. tophi or more than two gout attacks per ue thought to predict good control of The results of the study make it clear But solubility drops dramatically with year. None of the patients had relevant liv- flares and a reduction of tophi—with ei- that there is no difference in efficacy be- lower temperature, and so lower serum er or renal disease, and none had previ- ther allopurinol or benzbromarone, as tween allopurinol and benzbromarone urate values are ously received ei- long as the doses are slightly higher than when given in adequate doses, despite needed. ‘Allopurinol must ther medication. normal and based on serum urate values, their different mechanisms of action. It A serum urate be dosed higher Mr. Reinders con- according to the results of a randomized, also shows “allopurinol must be dosed concentration of than usually done ducted the research open-label trial. higher than usually done in trials and in 0.30 mmol/L or in trials and in when he was in The data were presented at the annual clinical practice [300 mg/day] to reach lower has been clinical practice training at the meeting of the European League Against target serum levels,” Mr. Reinders said. shown to be ade- to reach target Medisch Centrum Rheumatism in Paris. Gout flares and tophi mostly occur in quate in previous re- serum levels.’ Leeuwarden, also “In this small study, tolerability is not those body parts with the lowest temper- search, Mr. Reinders in the Netherlands, said in the interview. MR. REINDERS which funded the EULAR’s evi- study. dence-based recommendations for gout After 2 months of treatment, a signifi- THE LEADER advise titrating the allopurinol dosage ac- cantly greater percentage of patients who IN NEWS cording to the level of serum urate that took benzbromarone 100 mg/day reached AND is attained. There is a lack of information the target serum urate concentration of MEETING about this approach and the effects of the 0.30 mmol/L (13 of 25 patients, or 52%) COVERAGE higher dosages of serum urate–lowering than did patients who took allopurinol 300 Rheumatology News drugs that will be required to decrease mg/day (8 of 30 patients, or 27%). serum urate in patients who are not After the investigators doubled the dai- reaching target levels. Many clinicians ly dosage of each drug in patients who had also are prescribing only a fixed dosage of not met the treatment target, there was no allopurinol 300 mg/day, he said. significant difference in the total percent- Therefore, Mr. Reinders and his coin- age of patients who had successful treat- Thanks For vestigators randomized 55 patients with ment with allopurinol (21 of 27, or 78%), newly diagnosed gout in an open-label tri- compared with benzbromarone (18 of 23, al comparing the efficacy and tolerability or 78%). Making Us of allopurinol and benzbromarone. Al- Even before the dose increase, two pa- lopurinol began at a dosage of 300 tients stopped taking allopurinol and three mg/day and was increased to 600 mg/day stopped taking benzbromarone because of if necessary, while benzbromarone start- adverse drug reactions. Source: The Nielsen Company, Focus® Medical/Surgical June 2008 Readership Summary; ed at 100 mg/day and could be increased No more adverse reactions occurred af- Internal Medicine Specialties Section, Rheumatology Office & Hospital, Table 512 Projected Average Issue Readers. to 200 mg/day. ter the dosages were increased in the The gout diagnosis was confirmed by nonresponders. ■ Pages 24a—24dŅ.