Abstract 518: Placebo-Controlled Pilot Study of Rilonacept (IL-1 Trap), A Long Acting IL-1 Inhibitor, In Refractory Chronic Active Gouty Arthritis
Robert Terkeltaub, H. Ralph Schumacher, Jr., John Sundy, Frederick Murphy, Stephen Bookbinder, Stephanie Biedermann, Scott Mellis, Ke Yang, Allen Radin.
Interleukin-1 (IL-1) may be a principal mediator of pain and inflammation in gout and pseudogout, and its release may be triggered by monosodium urate and calcium pyrophosphate dihydrate crystals. Blocking IL-1, therefore, may be a viable strategy to control pain and inflammation in these disorders. Inhibition of IL-1 has been previously demonstrated by Rilonacept, a soluble receptor-Fc fusion protein. The safety and clinical effectiveness of this agent in treating chronic active gouty arthritis in humans was evaluated in this study.
Ten patients with a history of at least six months of chronic gouty arthritis were studied in a non-randomized, single-blinded fashion. Two weekly subcutaneous injections of placebo were followed by six (one loading dose then five additional) weekly injections of rilonacept. Evaluations were conducted every two weeks then at six weeks after the last dose. Clinical responses were evaluated by subject pain visual analogue scale (VAS), subject and physician global VAS, joint count, and hs-CRP levels. The primary endpoint was safety. The secondary endpoints were VAS ratings, patient pain responder analysis, hs-CRP levels.
All 10 patients exhibited a treatment emergent adverse event at some point during follow-up, the most common being mild to moderately severe injection site reactions; however, no patient had a severe adverse reaction.
7/10 subjects had at least 50% improvement in subject pain VAS (p<0.0001) while 6/10 subjects had at least 75% improvement (p=0.0001). Neither level of improvement was observed during the placebo phase of the study
Median hs-CRP levels decreased 59% by week 8 of the study (p=0.004) but trended toward returning to baseline six weeks after discontinuing the rilonacept.
Rilonacept is a well tolerated medication that can suppress gouty arthritis pain and reduce hs-CRP levels compared to placebo.
This is a very small but useful study where rilonacept was shown to offer promise as an agent to treat gouty arthritis. It is associated with symptomatic improvement and no significant major adverse effects. The study is very preliminary, however. The sample size is exceedingly small (10 patients), and the lack of a double-blinded experimental design limits definitive conclusions on the safety and efficacy profile of this agent in the broad population of gout patients. Nonetheless, it is a well constructed first step toward what will possibly be the incorporation of another effective strategy in gout therapy.
Abstract 755: Mouse IL-1 Trap Reduces Pain and Inflammation in Animal Models of Gout
Richard Torres, Lynn Macdonald, Joel Reinhardt, Susan D. Croll, Donna M. Hylton, John S. Rudge, George D. Yancopoulos, Andrew J. Murphy.
Interleukin-1 (IL-1) may be a principal mediator of pain and inflammation in gout and pseudogout, and its release may be triggered by monosodium urate and calcium pyrophosphate dihydrate crystals. Blocking IL-1, therefore, may be a viable strategy to control pain and inflammation in these disorders. This hypothesis was addressed in a murine joint pain model of gout through the use of IL-1 receptor 1 knockout mice as well as mIL-1 Trap, a high-affinity mouse IL-1 blocker.
The authors developed a novel joint pain model of gout by injecting monosodium urate into murine ankle joints and recording measures of pain and swelling. IL-1 receptor 1 knock-out mice and mice treated with mIL-1 Trap were studied. In addition, peritonitis induced by crystal injection as well as subcutaneous air pouch models of gout and pseudogout inflammation were also studied.
Crystal-induced peritonitis and subcutaneous air pouch models of gout and pseudogout inflammation in IL-1R1-knock out mice exhibited diminished neutrophil influx compared to controls (p<0.05).
Neutrophil infiltration was prevented in crystal-induced peritonitis mouse models by administering mIL-1 Trap (at 35 mg/kg) (p<0.05). This efficacy was equivalent to the effect of maximum dose colchicine (2mg/kg), and histology confirmed the abrogation of ankle inflammation by mIL-1 Trap.
Pain, inflammation, and SAA levels were significantly diminished in IL-1R1 knock-out mice, and mIL-1 Trap significantly diminished thermal and mechanical pain, swelling, and SAA rises in mice whose ankles were injected with monosodium urate crystals.
The authors conclude that inhibiting IL-1 decreases inflammation and pain in mouse models of gout, suggesting that rilonacept (human IL-1 Trap) may be a viable therapeutic option for treating gout in humans.
This is a small and elegant proof-of-concept study that provides compelling evidence for the role of IL-1 in the pain and inflammation associated with gout. Two lines of study—a murine IL-1R1 knock-out model and an IL-1 inhibitor (mIL-1 Trap)—are employed to demonstrate the decrease in inflammation and pain seen in crystal-induced mouse gout. Evidence is presented suggesting comparable efficacy of mIL-1 Trap therapy with colchicine, suggesting that this approach may be just as effective, but probably not superior, to colchicine therapy in humans. Certainly, conclusions on the relevance of these data to human therapy with rilonacept await randomized clinical trials of this agent in humans. The identification of an alternative therapy for gout would certainly be a welcome development.
Abstract 757: Urate-Lowering Therapy (Febuxostat [FEB] or Allopurinol [ALLO]) in Subjects with Gout: Interim Results from the Febuxostat Comparative Extension Long-Term Study (EXCEL)
M. A. Becker, H. R. Schumacher, Jr, P. A. MacDonald, E. J. Lloyd, C. Lademacher,
Febuxostat is a non-purine selective inhibitor of xanthine oxidase. Results from the FACT study, a phase 3, randomized, double-blind, 52-week, multi-center trial, recently showed that febuxostat dosed at 80mg and 120mg daily is more effective than allopurinol 300 mg daily in decreasing serum uric acid levels in patients with gout and serum uric acid levels ≥ 8mg/dl. M.A. Becker et al, N Engl J Med. 2005 Dec 8;353(23):2450-61. There was no difference between treatment groups in gout flares or tophus area. The authors’ objective in this study was to assess the efficacy of febuxostat compared to allopurinol in lowering serum urate levels to less than 6.0g/dl at and beyond 24 months of follow up.
The EXCEL study was an open-label extension study where 735 subjects from two phase 3 clinical trials of febuxostat and allopurinol (FACT and APEX trials), were randomized to daily febuxostat (80 mg or 120 mg) or daily allopurinol 300 mg (100 mg for subjects with renal failure).
During the first 6 months of this trial, cross-over into different treatment arms was permitted to maintain serum uric acid levels between 3.0 and 6.0 mg/dl, handle adverse events (AEs) or at the investigator’s discretion, with no required washout period. Subjects whose serum urate concentrations remained ≥6.0 mg/dL at six months were terminated from the study and considered treatment failures.
184 (25%) subjects discontinued treatment by the end of the study. The proportion of participants who remained in their initial treatment groups were: 78% of those on febuxostat 80mg, 71% of those on febuxostat 120mg, and 41% of those on allopurinol. Treatment failure occurred in 18% of subjects treated with febuxostat 80mg, 8% treated with febuxostat 120mg, and 57% treated with allopurinol. In the subset of these allopurinol patients who subsequently were treated with febuxostat 80mg, 54% remained treatment failures. After increasing the febuxostat dose to 120 mg daily in this subgroup of dual-drug failures, 59% achieved a serum urate concentration below 6.0 mg/dl. Therefore, 67% of subjects initially treated with allopurinol were successfully treated with febuxostat.
Adverse event rates were similar for both drugs tested in this trial. The most common observed adverse events (≥ 5 events per 100 patient-years) included upper respiratory tract infections, musculoskeletal and connective tissue signs and symptoms, joint related signs and symptoms, headaches, and diarrhea. The serious adverse event rate was similar for both agents (10 events per 100 patient-years for febuxostat) and (11 events per 100 patient years for allopurinol). The most frequent of these serious adverse events were cardiac disorders (3 events per 100 patient-years for both agents). These particular subjects all had a prior history of cardiovascular disease or cardiac risk factors.
Greater than 50% of the subjects in this study who were randomized to allopurinol therapy at standard doses were treatment failures (defined as inability to achieve or maintain serum uric acid levels <6.0 mg/dl). The majority of these patients (67%) were successfully treated with febuxostat.
This large, unblinded extension trial provides compelling data for the efficacy of febuxostat in reducing serum urate in gout patients. It proved to be particularly useful therapy in patients who failed traditional allopurinol treatment. The larger question that remains, however, is whether simple pharmacologic reduction and maintenance of reduction of serum urate will directly correlate with clinical improvement in gout. This study is an important first step, particularly because it establishes that febuxostat confers no significantly increased risk of adverse effects over allopurinol.
Abstract 758: Gout Flare Incidence in Relation to Average Serum Urate during the First Year of Urate-Lowering Therapy
M. A. Becker, P. A. MacDonald, B. J. Hunt, C. Lademacher, N. Joseph-Ridge.
Reducing serum levels of urate to <6.0 mg/dL has been shown to reduce the incidence of gout flares in patients. This prospective study analyzed the relationship between serum urate levels and gout flare incidence among a large group of gout patients who underwent urate reducing therapy for up to one year.
1832 patients with a history of gout and a baseline serum urate ≥8.0 mg/dL were randomized to receive daily placebo, allopurinol (300mg, or 100mg in case of renal insufficiency), or febuxostat (80mg, 120mg, or 240mg) therapy. This cohort’s subjects were participants of the APEX trial (a 28-week) or the FACT trial (a 52-week), both were double blind clinical trials set out to assess the safety and efficacy of febuxostat in the treatment of gout. Serum urate levels and the incidence of acute gouty flares which necessitated treatment were tracked in all subjects. During the first two months of the trials, all subjects received gout flare prophylaxis with colchicine or naproxen.
During weeks 9 to 12 of therapy, flare incidence tended to be significantly lower in those with lower average post baseline serum urate levels. During weeks 25 to 28 of therapy, the rates of gout flares were not significantly related to average post baseline serum urate levels.
During weeks 49 to 52 of therapy, incidence of gouty flares was significantly lower in subjects with baseline serum urate levels <6.0 mg/dL than those whose baseline urate levels were >6.0 mg/dL.
|Average post baseline sUA||% of subjects with at least one flare during|
|Weeks 9 to 12*||Weeks 25 to 28||Weeks 49 to 52*|
|< 4.0 mg/dL||42% (141/335)||12% (36/291)||4% (4/89)|
|4.0 to < 5.0 mg/dL||38% (130/343)||15% (43/287)||5% (7/132)|
|5.0 to < 6.0 mg/dL||34% (116/344)||13% (38/296)||7% (9/125)|
|6.0 to < 7.0 mg/dL||33% (83/249)||18% (39/217)||11% (10/94)|
|7.0 to < 8.0 mg/dL||28% (37/133)||15% (17/117)||16% (7/43)|
|≥ 8.0 mg/dL||28% (56/197)||17% (26/154)||18% (4/22)|
|*Statistically significant relationship with sUA using Cochran-Armitage trend test|
The authors concluded that during early urate-reducing therapy for gout, lower baseline serum urate levels are associated with increased flare risk in patients who are not undergoing prophylaxis. Continued urate-reducing therapy reverses this pattern, and at one year, significantly lower flare rates are observed in subjects whose average post baseline serum urate levels were <6.0 mg/dL.
This is a well designed, large study that illustrates the complexity of the relationship between post baseline serum urate levels and the risk for gout flare. The current study suggests that sustaining low serum urate levels (<6.0 mg/dl) is as crucial as decreasing serum urate early in the treatment course in preventing gouty flares long term (up to one year in this study). The appropriate duration of prophylaxis with colchicine or non-steroidal Anti-inflammatory Drugs remains to be answered. Participants in this study were on prophylaxis for a relatively brief eight weeks. In contrast, prophylaxis for up to 12 months has been reported in other studies. This may have implications for the relevance of these results in clinical practice.
Abstract #756 Disordered Osteoclast Development in Patients with Tophaceous Gout; Uric Acid Crystals Promote Osteoclastogenesis Through Interactions with Stromal Cells
Nicola Dalbeth, Timothy Smith, Kate Gregory, Barnaby Clark, Karen Callon, Fiona McQueen, Ian Reid, Jillian Cornish. University of Auckland, Auckland, New Zealand
Any clinician who cares for patients with tophaceous gout knows how destructive this process can be. The mechanisms underlying the development of bony erosions in this condition, and what contribution the uric acid crystals themselves play in this process is unknown.
Tissue samples (blood, synovium, and tophaceous material) were collected from patients with chronic gout. Osteoclast precursor cells (CD14+/CD11b+)and post-culture osteoclast-like cells were evaluated by flow cytometry in both the peripheral blood and joint fluid. The activity of the osteoclast-like cells was confirmed by resorption of co-cultured bone slices. The effects of uric acid on osteoclast development were examined in vitro by culture with osteoclast precursor cell lines.
Though patients with chronic gout did not have increased numbers of circulating osteoclast precursor cells, they did have an increased ability to form these cells in culture; this number correlated with the number of tophi seen clinically. Immunohistochemical analysis of tophi revealed numerous multinucleated cells surrounding uric acid crystals. These crystals inhibited osteoprotegerin production in bone marrow derived stromal cells, and the media of these cells cultured with uric acid promoted osteoclast formation in precursor cells.
The discoveries of additional unique biologic effector functions activated by uric acid crystals seem to increase each year. To its well-known abilities to stimulate neutrophil degranulation and respiratory burst, turn on the bradykinin system, fix complement, ligate TLR 2 and 4, and turn on the IL-1 mediated inflammasome is now added the capacity to promote osteoclastogenesis and directly impact bone erosion. This finding, if validated in other studies, provides a rationale for the use of bisphosphonate therapy in the treatment of chronic gouty arthritis.