The role of interleukin-1 in the pathogenesis of rheumatoid arthritis

Rheumatology 2004;43(Suppl. 3):iii2 iii9 The role of interleukin-1 in the pathogenesis of rheumatoid arthritis J. Kay and L. Calabrese 1 doi:10.1093/rheumatology/keh201 A significant body of experimental evidence has implicated the proinflammatory cytokine IL-1 in the pathogenesis of RA. For example, IL-1b overexpression in rabbit knee joints causes arthritis with clinical and histological features characteristic of RA, whereas IL-1 deficiency is associated with reduced joint damage. In experimental models, IL-1 blockers, including IL-1 receptor antagonist (IL-1Ra), significantly reduce clinical and histological disease parameters. In RA patients, plasma and synovial fluid concentrations of IL-1 are elevated, and these correlate with various parameters of disease activity. The production of endogenous IL-1Ra, however, appears to be insufficient to balance these higher IL-1 levels. The efficacy of blocking IL-1 in patients with active RA has been established in controlled clinical trials of anakinra, a recombinant human IL- 1Ra (r-methuil-1ra). When used alone or in combination with methotrexate, anakinra significantly reduces the clinical signs and symptoms of RA compared with placebo. Taken together, these results indicate that IL-1 plays an important role in the pathogenesis of RA. KEY WORDS: Anakinra, Biological therapy, Inflammation, Interleukin-1, Interleukin-1 receptor antagonist, Joint damage, Pathogenesis, Rheumatoid arthritis. RA is a chronic inflammatory disease characterized by pain and inflammation, progressive joint destruction, significant disability, systemic manifestations and premature mortality [1]. The exact pathogenesis of RA remains to be fully delineated, but an important feature involves communication between a number of different inflammatory cells, notably macrophages and T lymphocytes, and cells resident in the joint. These cells communicate via a network of proteins known as cytokines, some of which exert proinflammatory actions and others that provide anti-inflammatory or immunoregulatory effects. In normal physiology, these cytokines are maintained in balance; however, in RA the balance shifts in favour of the proinflammatory cytokines. The most important proinflammatory cytokines in RA are IL-1 and TNF- [2, 3]. These cytokines produce an overlapping spectrum of biological actions, but it is likely that they act in concert with each other and other cytokines to produce many of their pathophysiological effects. RA pathogenesis The earliest lesions seen in RA include injury to the microvasculature and proliferation of fibroblast-like synoviocytes in the synovial lining of the joint [4]. The synoviocytes continue to increase in number and subsequently attach to the articular surface at the joint margin. Mononuclear cells infiltrate the joint, where they produce large quantities of proinflammatory cytokines that induce further synoviocyte proliferation and activation, leading to pannus formation. Ultimately, oedema develops in the joint and pannus invades the articular surface, starting from the joint margin. The fibroblast-like synoviocytes of the invading pannus, as well as the chondrocytes in cartilage, are activated to release matrix metalloproteinases (MMPs) and other proteolytic enzymes that degrade the articular matrix [5]. These cells are also additional sources of proinflammatory cytokines. In addition, osteoclast precursors are triggered to differentiate into mature osteoclasts, which swing the balance of normal bone turnover in favour of net resorption. These events lead to the clinical features of disease: swollen and tender joints, pain and disability, morning stiffness, systemic manifestations and joint erosion. The pathogenesis of RA, therefore, depends on a number of different cell types (Fig. 1). Macrophages, which are the primary source of the proinflammatory cytokines, express HLA class II molecules. By virtue of their proximity to T cells, they may also function as antigen-presenting cells, thereby perpetuating immunological responses within the joint. Chondrocytes share these properties and possess the ability to present cartilage-specific antigens. In RA, chondrocytes release degradative enzymes and have a reduced capacity to synthesize new matrix components. T cells in the rheumatoid joint generally have a memory CD4 þ phenotype, express various activation markers, and are often found in close proximity to antigen-presenting cells [4]. The general association of disease severity and progression with HLA-DR4 and DR1 alleles suggests that T cells are important in RA pathogenesis [6]. B cells are also found in large numbers in the rheumatoid joint: they produce immunoglobulins and autoantibodies, such as rheumatoid factor and anticollagen antibodies, which form immune complexes that can trigger local inflammation as well as IL-1 and TNF release by macrophages. Although not represented in Figure 1 (and generally understudied in the pathogenesis of RA), neutrophils are the most abundant cellular infiltrators in the inflamed joints of patients with RA, constituting about 90% of the cells found in synovial fluid (SF). These infiltrating neutrophils differ considerably from healthy neutrophils, being degranulated and living for days instead of hours. Expressing class II MHC molecules, these SF neutrophils have recently been found to stimulate T-cell proliferation [7]. Such an interaction between neutrophils and T cells could eventually prove important in RA pathogenesis and lead to the development of new therapeutic targets. Rheumatology Unit, Massachusetts General Hospital, Boston, Massachusetts and 1 Cleveland Clinic Foundation, Cleveland, Ohio, USA Correspondence to: J. Kay, Rheumatology Unit, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, USA (e-mail: jkay@partners.org) or L. Calabrese, Cleveland Clinic Foundation, Department of Rheumatology, 9500 Euclid Avenue, Cleveland, OH 44195, USA (e-mail: calabrl@ccf.org). iii2 Rheumatology Vol. 43 Suppl. 3 ß British Society for Rheumatology 2004; all rights reserved

IL-1 in RA pathogenesis iii3 Antigenpresenting cells T cell HLA--DR B cell IL-1 Soluble factors and Direct contact Rheumatoid factors Macrophage Immune complexes bacterial products IL-1, TNF-α, etc. B cell or macrophage Pannus Synoviocytes IL-1 and TNF-α Chondrocytes Articular cartilage Production of collagenase and other neutral proteases FIG. 1. Cells involved in the pathophysiology of rheumatoid arthritis. Adapted from Arend and Dayer [45]. Endothelial cells and synoviocytes in the rheumatoid synovium exhibit distinctive features. Endothelial cells have the appearance of high endothelial venules, which are characteristic of lymphoid organs [4]. They express specific cell adhesion molecules (CAMs) on their surface, including intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin, which control the infiltration of inflammatory cells into the joint. The fibroblast-like synoviocytes, which predominate in activated pannus, appear to have a transformed phenotype, inasmuch as their growth is not arrested in a manner similar to normal fibroblasts in vitro [7]. It has been suggested that the inflammatory environment of the rheumatoid joint impairs the normal apoptotic mechanisms of these cells. IL-1 and TNF play an important role in the communication among the many cells in the rheumatoid joint. These cytokines up-regulate the expression of CAMs on endothelial cells, thereby directing the emigration of blood cells from the circulation into the synovium [8, 9]. They also stimulate production of chemokines, which provide important signals for the process of cell infiltration. IL-1 and TNF stimulate synoviocytes and chondrocytes to release MMPs and other proteinases that degrade cartilage, and they up-regulate the expression of proinflammatory genes, including cyclooxygenase-2 and nitric oxide synthase, leading to increased production of various proinflammatory mediators, such as prostaglandin E 2 and nitric oxide [10, 11]. Both cytokines also trigger the differentiation of osteoclasts by stimulating T cells to produce RANK ligand (RANKL), and they both activate mature osteoclasts leading to erosion of subchondral bone [12, 13]. Finally, each cytokine up-regulates production of the other: IL-1 stimulates TNF production, and TNF induces IL-1 production. The relative importance of IL-1 and TNF in RA remains the subject of much debate. Some animal models suggest that IL-1 plays a more important role in processes involved in joint destruction, whereas TNF is more important in inflammatory processes [14]. These interpretations of the experimental data probably represent an oversimplification of the processes inherent to RA pathogenesis. Randomized clinical trials with drugs that inhibit these cytokines demonstrate that both cytokines play important roles in RA. It remains to be determined, however, whether one cytokine is more important than the other in individual patients or at different stages of disease. In the following sections, the role of IL-1 in RA will be considered in greater detail. The IL-1 family The IL-1 family consists of three members: IL-1 and IL-1 produce the biological effects attributed to this cytokine, and IL-1 receptor antagonist (IL-1Ra) is an endogenous inhibitor that blocks the actions of the other two members [2, 15, 16]. The threedimensional structures of the family members are related, yet each has a distinct amino acid sequence. IL-1 and IL-1 are produced as 31 kda precursor proteins, termed pro-il-1 and pro-il-1, which are subsequently cleaved by cellular proteases into the mature 17 kda protein. IL-1 is generally retained within the cell or expressed on the cell surface, and consequently it is believed to function as an autocrine messenger. IL-1, in contrast, is secreted and acts on other cells to produce its biological actions. IL-1Ra is synthesized and secreted as a 17 kda protein by the same cells that express IL-1. IL-1Ra production is stimulated by cytokines, viral products and acute-phase proteins, and therefore it is believed to be important in buffering the actions of IL-1 in chronic and infectious disease. In addition, several intracellular variants of IL-1Ra have been identified and, accordingly, these may be more important in regulating the autocrine actions of IL-1. Each member of the IL-1 family binds with high affinity to specific receptors located on the surface of target cells. Binding of IL-1 or IL-1 to type I IL-1 receptors (IL-1RI), which is enhanced by an accessory protein, IL-1R-AcP, leads to intracellular signal transduction and regulation of gene expression and, as a result, cellular responses (Fig. 2). Binding to the type II IL-1 receptors (IL-1RII) on these cells does not cause cell activation, because the receptor contains a very short cytoplasmic domain that is unable to transduce signals following IL-1 binding. Therefore, IL-1RII serves as a decoy receptor. IL-1Ra binds to both IL-1RI and IL- 1RII and, as its name implies, does not induce signal transduction. Instead, it competitively antagonizes the binding of IL-1 and IL-1, thereby reducing the biological effects of these cytokines. The magnitude of the biological response to IL-1 in the rheumatoid joint depends on a number of factors. First, IL-1 and IL-1Ra have similar affinity for IL-1RI on synoviocytes,

iii4 J. Kay and L. Calabrese Activated Macrophage IL-1β IL-1Ra IL-1RI IL-1R-AcP IL-1RI IL-1R-AcP Signalling Nucleus ACTIVATION No Signalling Nucleus ACTIVATION BLOCKED FIG. 2. IL-1 induces cellular responses by binding to the type 1 IL-1 receptor (IL-1RI), whereas IL-1Ra blocks these IL-1-induced responses. IL-1 binding to the type 2 IL-1 receptor (IL-1RII) does not produce a cellular response, because this receptor has a very short intracellular domain. IL-1 is generally retained within the cell or expressed on the cell surface, in contrast with IL-1, which is secreted and acts on other cells. IL-1R-AcP is an accessory protein that forms a complex with IL-1RI and enhances high-affinity IL-1 binding with that receptor. Adapted from Bresnihan [40]. chondrocytes and other cells. Consequently, the relative concentrations of these molecules are important in determining the extent of cell activation and biological responses. Secondly, a greater number of IL-1RII reduces the amount of IL-1, as well as of IL- 1Ra, that is available for binding to IL-1RI. Similarly, soluble IL-1 receptors, representing the extracellular domains of IL-1RI and IL-1RII, are found in synovial fluid and in the circulation; these also decrease the amount of IL-1 and IL-1Ra available to interact with IL-1RI. Finally, the response to IL-1, as well as to other proinflammatory cytokines, is regulated by various antiinflammatory and immunomodulatory cytokines, including IL-4, IL-10, IL-11, IL-13 and transforming growth factor- [17]. IL-1 imbalance in RA RA patients have elevated plasma IL-1 concentrations, which have been shown to correlate with several measures of disease activity, including the Ritchie articular index, the duration of morning stiffness, and pain score [18]. The IL-1 concentrations in RA synovial fluids are also elevated, being 10 times greater those found in patients with OA or non-inflammatory joint disease [19]. The concentration of IL-1Ra is also elevated significantly in RA patients compared with those with OA or chronic osteomyelitis, but the ratio of IL-1Ra to IL-1 nevertheless is lowest in RA patients [20]. The production of IL-1 and IL-1Ra has been evaluated in tissue culture using synovial cells isolated from RA patients. In one study, spontaneous IL-1Ra production predominated in one-third of the synovial specimens; however, in the other two-thirds, IL-1 was produced in higher amounts than IL-1Ra [17]. In another study, synovial cells produced 1.2 to 3.6 times higher amounts of IL-1Ra than IL-1 [21]. Purified synoviocytes from these specimens contained IL-1Ra but secreted very low amounts. When RA patients were grouped according to the number of synovial cell layers, cells from patients with more synovial proliferation produced less IL-1Ra than those from patients with less proliferation [22]. Taken together, these results suggest that an imbalance between IL-1Ra and IL-1 may exist in many RA patients [23]. Notably, IL-1Ra production does not appear sufficient to achieve the 10- to 100-fold excess that is believed necessary for IL-1Ra to effectively block IL-1 activity by 50%. This IL-1Ra excess appears necessary, because IL-1 is able to produce cellular responses by activating only a small number of IL-1RI. IL-1 in experimental RA models IL-1 gene transfer The role of IL-1 in the joint has been evaluated by gene transfer studies, in which rabbit synovial cells were first transfected with a retroviral vector containing a DNA fragment encoding mature IL-1 and then introduced into the knee joint of recipient rabbits by intra-articular injection [24]. The transfected cells produced 100 200 ng of human IL-1 per million cells over a 48-h period. Ten million cells were injected intra-articularly in the initial studies, but severe systemic manifestations, including fever, diarrhoea, weight loss, listlessness and death, were observed. In subsequent studies, 2.5 million cells were injected. Within the first 2 weeks, human IL-1 was detected in knee lavage fluid at a mean concentration of 100 pg/ml, but by 4 weeks the secretion of human IL-1 had declined to non-detectable levels (Fig. 3). The production of human IL-1 led to secretion of rabbit IL-1 and TNF, which followed a time course similar to that of the human cytokine. Clinically, the knee joints injected with transfected cells became swollen within 24 h and subsequently increased in size by 30 50%

IL-1 in RA pathogenesis iii5 300 hil-1 ril-1 rtnfα 900 IL-1 in pg/ml 200 100 600 300 TNFα in pg/ml 0 hil-1+ Control hil-1+ Control hil-1+ Control Day 7 Day 14 Day 28 FIG. 3. Expression of human IL-1 and rabbit IL-1 and TNF- in the knee following intra-articular human IL-1 gene transfer in rabbits. Reprinted with permission from Ghivizzani et al. [24], ß 1997 The American Association of Immunologists, Inc. relative to the contralateral joints that had been injected with nontransfected synoviocytes. Within the first few days of injecting the transfected cells, synovial hypertrophy and neutrophil infiltration were evident. As time progressed, however, the neutrophils were replaced by lymphoid aggregates at 7 10 days, and then the aggregates coalesced into lymphoid foci by 2 3 weeks. By this time the thickened synovium showed signs of neovascularization. A highly aggressive pannus had attached to and eroded all periarticular bone surfaces on the femoral condyles as well as in other regions of the cartilage. The most invasive part of the pannus was observed near the edge of the articular surface, with severe cartilage degradation and penetration of the pannus through bone and into the marrow. Systemic manifestations included fever, diarrhoea, weight loss and an increase in ESR. The synovitis and systemic symptoms diminished by 4 weeks in conjunction with the loss of IL-1 expression. However, the synovial tissue remained thickened and vascularized, and it continued to contain lymphoid follicles. Complementary studies were conducted by the same investigators, in which an adenovirus encoding TNF was injected intraarticularly into rabbits. The expression of the TNF transgene generally led to mild synovitis with neutrophilic infiltration, but bone erosions and aggressive pannus formation were usually not observed. IL-1 deficiency The impact of deleting the IL-1 gene in mice has been evaluated in the streptococcal cell wall arthritis model [25, 26]. Although joint swelling was not reduced in these IL-1-deficient mice, sustained cellular infiltration in the synovium and cartilage damage, as measured by proteoglycan loss, were greatly reduced relative to wild-type control animals. In comparison, TNF-deficient mice showed reduced joint swelling and moderate reductions in synovial infiltration, but cartilage damage was unaffected in the acute cell wall arthritis model. By periodically injecting small amounts of streptococcal cell walls at sites of ongoing arthritis, it is possible to mimic the disease flares seen in clinical disease. In this chronic relapsing model, synovial infiltration was greatly reduced and cartilage erosion was essentially abolished in IL-1-deficient mice. In the chronic relapsing model, joint swelling was also reduced in the TNF-deficient mice, but these animals still showed synovial infiltration, loss of cartilage proteoglycan, and an aggressive pannus leading to cartilage and bone erosion. In this model, joint damage appears to depend on IL-1, whereas TNF appears to play a greater role in joint swelling. It remains to be determined whether these results are reflective of other animal models or human disease or are instead specific to the model and methods used. IL-1 antagonism Blocking IL-1 with anti-il-1 antibodies, recombinant soluble IL- 1RII or recombinant IL-1Ra is effective in a variety of animal models of RA [14, 15, 27 29]. Depending on the model, IL-1 inhibition prevented disease onset or reduced clinical and histopathological indices of joint swelling, cellular infiltration, and cartilage and bone erosion. Similarly, gene transfer of IL-1Ra reduced the diameter of joints expressing the transgene but not of contralateral control joints in the chronic relapsing streptococcal cell wall arthritis model [30]. Moreover, cartilage and bone erosion were also reduced significantly. In an acute antigen-induced arthritis model in rabbits, gene transfer of human IL-1Ra significantly reduced leucocyte infiltration and caused a small decrease in joint swelling [31]. The antigen-induced cartilage breakdown and inhibition of new cartilage matrix synthesis were nearly normalized in joints expressing the human IL-1Ra transgene. In the experimental arthritis model induced by overexpression of IL-1 in rabbits, intra-articular injection of an IL-1Ra gene vector significantly reduced synovitis and leucocytosis [32]. Finally, cartilage degradation was abolished when the human IL-1Ra gene was transfected into RA synovial fibroblasts and then co-implanted with normal human cartilage in SCID mice [33].

iii6 J. Kay and L. Calabrese IL-1Ra deletion IL-1Ra gene deletion in mice resulted in the spontaneous development of a chronic polyarthropathy, which was dependent on the genetic background of the mice [34]. In BALB/cA mice, 80% developed arthritis by 8 weeks of age, and all animals had disease by 16 weeks of age. In comparison, only 15% of C57BL/6J mice had developed arthritis by 32 weeks. The polyarthritis in BALB/cA mice was characterized by synovial hyperplasia, leucocyte infiltration and erosive pannus formation. IL-1 levels were increased 10-fold in the IL-1Ra-deficient animals compared with wild-type controls, whereas TNF levels were only slightly increased. In another series of IL-1Ra-deficient mice with a genetic background different from that of the mice in the previous study, lethal arterial inflammation developed at branch points and flexures of the aorta and its primary and secondary branches [35]. Histological evaluation showed massive infiltration by neutrophils, macrophages and CD4 þ T cells in the inflammatory lesions. These studies suggest that IL-1Ra may play an important role in keeping IL-1 levels and activity in check, depending on the genetic background of the animal. Clinical trials of IL-1-based therapy The wide range of experimental data supporting a role of IL-1 in RA pathogenesis prompted clinical trials with agents that selectively block this cytokine. In a small study, recombinant human IL-1RI showed biochemical evidence of activity in patients with active RA, but dose-limiting rashes at the active dose precluded further clinical evaluation [36]. In contrast, therapy with anakinra, a recombinant human IL-1Ra that is identical to naturally occurring non-glycosylated IL-1Ra with the exception of the terminal methionine (r-methuil-1ra), provided evidence of clinical improvement in a randomized, double-blind, dose-ranging study of 175 patients with active RA [37]. Although the study was not placebo-controlled, daily subcutaneous administration of anakinra appeared to provide more clinical benefit than regimens involving dosing once or three times weekly. The efficacy and safety of anakinra in patients with active RA was subsequently established in several randomized, double-blind, placebo-controlled trials. The results from two pivotal trials have been published. The first evaluated anakinra monotherapy in 472 patients with active RA based on ACR criteria [38]. The primary efficacy endpoint was the percentage of patients achieving ACR20 criteria [39]. After 24 weeks, anakinra 150 mg showed significantly greater activity than placebo in terms of the ACR20 response (43 vs 27%; P ¼ 0.014). [The ACR20 response rates in the other two anakinra groups (39 and 34% at the 30 mg and 75 mg doses, respectively) did not achieve statistical significance.] The clinical response in the anakinra 150 mg/day group was statistically better than placebo for swollen joint counts (P ¼ 0.009), tender joints (P ¼ 0.0009), CRP (P ¼ 0.0017) and ESR (P<0.0001). The clinical response was seen after 2 weeks of therapy [40]. Serial hand X-rays showed that anakinra significantly reduced radiographic progression of disease, compared with placebo, when evaluated according to the Larsen method or the Genant-modified Sharp method [41]. The second study evaluated anakinra therapy in combination with methotrexate in patients with severely active RA despite methotrexate therapy [42]. Patients were randomly assigned to receive anakinra 0.04, 0.1, 0.4, 1.0 or 2.0 mg/kg or placebo once daily for 24 weeks in addition to their regular methotrexate therapy. After 12 and 24 weeks, anakinra increased the ACR20 response rate in a dose-dependent manner at week 12 (P ¼ 0.001) and week 24 (P ¼ 0.004) (Figs 4 and 5). The highest response rates, compared with placebo, were achieved with anakinra 1.0 mg/kg: 46% at week 12 (P ¼ 0.001) and 42% at week 24 (P ¼ 0.018). Similarly, when ACR50 and ACR70 criteria were used at week 24, the response rates to anakinra 1.0 mg/kg were significantly higher than placebo: ACR50, 24 vs 4%; ACR70, 10 vs 0%. Combination therapy with anakinra and methotrexate was well tolerated. The efficacy of anakinra 100 mg was evaluated in a randomized, double-blind, placebo-controlled trial conducted in the USA, Canada and Australia [43]. Five hundred patients with active RA were randomized to receive daily subcutaneous injections of either anakinra 100 mg (n ¼ 250) or placebo (n ¼ 251) for Percent of Patients 60 50 40 30 20 10 Dose response: P = 0.001 * P < 0.05 ** P < 0.001 19% 25% * 35% 25% ** 46% ** 38% 0 Placebo (N = 74) 0.04 mg/kg (N = 63) 0.1 mg/kg (N = 74) 0.4 mg/kg (N = 77) 1.0 mg/kg (N = 59) 2.0 mg/kg (N = 72) Combination Therapy Study FIG. 4. Effect of combination anakinra methotrexate therapy vs placebo plus methotrexate in patients with active RA. ACR 20% response rates at week 12. Adapted from Cohen et al. [42].

IL-1 in RA pathogenesis iii7 60 Percent of Patients 50 40 30 20 10 Dose response: P = 0.004 * P 0.018 30% 23% 19% 36% * 42% 35% 0 Placebo (N = 48) 0.04 mg/kg (N = 63) 0.1 mg/kg (N = 46) 0.4 mg/kg (N = 55) 1.0 mg/kg (N = 59) 2.0 mg/kg (N = 46) Combination Therapy Study FIG. 5. Effect of combination anakinra-methotrexate therapy versus placebo plus methotrexate in patients with active RA. ACR 20% response rates at week 24. Adapted from Cohen et al. [42]. 24 weeks. All patients maintained a stable dose of methotrexate (10 25 mg/week). The use of NSAIDs and oral corticosteroids was permitted. Eligible patients were required to present with a minimum of six swollen joints and nine tender/painful joints, radiographic evidence of at least one bone erosion in the hands, wrists or feet, and either CRP 1.5 mg/dl or ESR 28 mm/h. At baseline, mean duration of disease was 10.8 yr. The primary efficacy endpoint was the percentage of patients achieving ACR20 response criteria. Non-responders, defined as subjects whose dose of DMARDs or corticosteroids was increased from baseline and those who withdrew from the study after receiving one or more doses of study drug were included in the analysis of the ACR composite score. Thirty-eight per cent of patients treated with anakinra achieved an ACR20 response at 24 weeks compared with 22% of patients treated with placebo (P<0.001) [43]. Twentyseven per cent of patients treated with anakinra achieved a sustained ACR20 response throughout the 24-week evaluation period compared with 12% of patients treated with placebo (P<0.001). In addition, anakinra treatment resulted in early onset of action, ACR20 responses being evident at 4 weeks in twice as many anakinra-treated patients as placebo-treated patients. The safety of anakinra has been evaluated in a large, doubleblind, placebo-controlled study (n ¼ 1414) designed to represent a patient population typically seen in clinical practice; i.e. patients with a broad range of RA activity, a wide range of comorbidities, and various combinations of concomitant RA therapies [44]. Patients were allowed use of NSAIDs, corticosteroids and DMARDs, with the exception of TNF inhibitors. Patients were randomized to anakinra 100 mg (n ¼ 1116) or placebo (n ¼ 283). Rates of serious adverse events were similar after 6 months: 7.7% in the anakinra group and 7.8% in the placebo group. Serious infections were more frequent in the anakinra group (2.1%) than in the placebo group (0.4%), but 17 of the 23 anakinra patients with serious infections resumed anakinra therapy after the infection resolved. No opportunistic infections were reported. As was seen in the monotherapy and combination studies, injection-site reaction was the most commonly reported adverse event (anakinra, 72.6%; placebo, 32.9%). Most reactions were transient and of mild or moderate severity. Premature study withdrawal rates were similar (anakinra, 21.6%; placebo, 18.7%). A 30-month, open-label phase of this study will provide further results. Conclusion The efficacy of anakinra in reducing the signs and symptoms of RA provides clinical evidence that IL-1 plays an important role in the pathophysiology of RA. However, several questions about biological therapy with anakinra still need to be addressed. It is important to recognize that RA is a long-term disease that will require treatment for several decades. The consequences of longterm inhibition of such a pivotal cytokine need to be evaluated carefully in terms of disease control, outcomes and, most importantly, long-term safety. In addition, cost-effectiveness analyses are needed to determine how anakinra compares with traditional DMARDs and the other biological response modifiers (etanercept, infliximab and adalimumab) in the setting of usual clinical practice. Once these issues have been addressed satisfactorily, the role of IL-1 inhibition in the treatment of RA will become clearer. Rheumatology Acknowledgement This work was supported by an educational grant from Amgen. J. Kay has received research grant support and honoraria from, and has served as a consultant to, Amgen, Inc. L. Calabrese is a member of a speakers bureau for Amgen Inc. and Abbott. References Key messages Patients with RA have excessive amounts of IL-1. Anakinra competitively inhibits binding of IL-1 to the IL-1 type I receptor. IL-1 blockade with anakinra efficaciously reduces signs and symptoms of RA. 1. Pincus T. Long-term outcomes in rheumatoid arthritis. Br J Rheumatol 1995;34(Suppl. 2):59 73. 2. Dinarello CA. Biological basis for interleukin-1 in disease. Blood 1996;87:2095 147.

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