Interleukin-1 (IL-1) is a key pro-inflammatory cytokine involved in innate immunity. It plays a central role in the pathophysiology of numerous diseases. The neutralization of IL-1 has proven effective in several rheumatologic and autoinflammatory conditions. In patients with rheumatic diseases, IL-1 inhibition may offer clinical benefits beyond the control of osteoarticular manifestations. The aim of this article is to review the current indications for IL-1 inhibitors in the field of rheumatology.
The IL-1 family includes 11 members: seven pro-inflammatory cytokines (IL-1α, IL-1β, IL-18, IL-36α, IL-36β, IL-36γ, and IL-33), and three with anti-inflammatory properties (IL-1Ra, which blocks IL-1α and IL-1β; IL-36Ra, which blocks IL-36α, β, and γ; and IL-37). The function of IL-38 remains unclear. The three best-known members of the IL-1 family are IL-1α and IL-1β, which bind to the same receptor, and the IL-1 receptor antagonist (IL-1Ra). These molecules are produced by macrophages, monocytes, dendritic cells, fibroblasts, and epithelial cells in response to infection, trauma, or immune stimulation
Various forms of cellular stress can lead to mitochondrial production of reactive oxygen species (ROS). These ROS may serve as a priming signal that activates the NLRP3 inflammasome. The precursors of IL-18 and IL-1β require cleavage by intracellular caspase-1 or extracellular neutrophil-derived proteases to become active and bind their receptor. These cytokines induce cell damage and sustain the inflammatory process
Three IL-1 inhibitors are currently available: anakinra, a recombinant form of the IL-1 receptor antagonist (IL-1Ra); rilonacept, a dimeric fusion protein that traps IL-1; and canakinumab, a humanized monoclonal antibody that prevents IL-1β binding to its receptor
IL-1 inhibitors are generally well tolerated, but clinicians should be aware of common adverse events. The most frequently reported are injection-site reactions, upper respiratory tract infections, neutropenia, and increased risk of serious infections, particularly in immunocompromised patients. Long-term data suggest that most adverse events are manageable, though careful monitoring is warranted when treating chronic diseases
Recent studies suggest that the pathogenesis of sJIA may follow a biphasic pattern. The early phase is primarily driven by innate immunity, with IL-1β identified as a key cytokine. In contrast, the later phase appears to be dominated by adaptive immunity and IL-17A, with chronic arthritis becoming the predominant clinical feature. Based on these observations, IL-1 blockade represents a rational therapeutic strategy in the initial phase of sJIA, while in persistent disease with chronic arthritis, other biologic agents may offer better efficacy
In a study by Vastert et al., anakinra was administered at a dose of 2 mg/kg in 20 patients with new-onset sJIA. Fever resolved within three days in 90% of patients, and inflammatory markers (CRP and ferritin) normalized in 80% of those receiving anakinra monotherapy within 30 days of treatment initiation
Rilonacept was evaluated in three patients with Still’s disease refractory to DMARDs and anakinra; all achieved complete remission, with partial improvement observed as early as the first month
Several studies also highlight the efficacy of anakinra in AOSD. A de novo mutation in the inflammasome component NLRC4 has been identified as causing constitutive caspase-1 activation and deregulated release of IL-1β and IL-18, leading to recurrent macrophage activation syndrome. In such cases, treatment with anakinra has shown favorable outcomes
IL-1 plays a central role in the inflammatory response observed in FMF, making IL-1 inhibitors a promising therapeutic option. These agents effectively control chronic inflammation and prevent disease progression to amyloidosis and organ failure. In a case series from a referral centre involving adult patients with FMF complicated by amyloidosis, four patients were treated with anakinra. The treatment showed a marked effect on both inflammatory manifestations and overall clinical condition, potentially altering the prognosis of these patients
This autosomal recessive autoinflammatory disorder, also known as mevalonate kinase deficiency, is clinically characterized by recurrent fever, myalgia, rash, aphthous ulcers, and lymphadenopathy. Several intracellular pathways link mevalonate kinase deficiency to the activation of caspase-1 and subsequent IL-1 production. IL-1 blocking agents have proven effective in reducing both the frequency and severity of inflammatory flares.
CAPS refers to a spectrum of three clinical entities: familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID). These conditions are caused by mutations in the NLRP3 inflammasome, leading to dysregulated activation of caspase-1 and excessive release of IL-1β. CAPS is characterized by a continuum of increasing severity—from episodic fever, myalgia, and skin rash to chronic systemic inflammation, with serious neurologic complications and growth retardation. Anakinra, rilonacept, and canakinumab have all demonstrated high efficacy in the treatment of CAPS.
TRAPS is an autosomal dominant autoinflammatory disorder caused by mutations in the type 1 TNF receptor. Clinically, it presents with recurrent episodes of fever. The condition is also characterized by a deficiency of soluble TNF-α receptors, which normally bind and neutralize circulating TNF-α. Anakinra has shown effectiveness in refractory TRAPS cases, suggesting that IL-1 plays a significant role in its pathophysiology, as in other autoinflammatory diseases
The role of IL-1 as a key cytokine in the pathogenesis of Behçet’s disease (BD) supports its classification among polygenic autoinflammatory diseases. Notably, IL-1 levels have been shown to be significantly elevated in both active and inactive forms of BD compared to healthy controls. Additionally, increased serum levels of IL-33 have also been observed in patients with BD
Crystal-Induced Arthropathies
Monosodium urate crystals activate the inflammasome, triggering the release of IL-1β. Treatment with anakinra, canakinumab, or rilonacept results in a marked reduction of joint inflammation. IL-1 blockade with anakinra has shown greater efficacy than corticosteroids, leading to longer flare-free periods. Its short half-life among IL-1 inhibitors offers an additional advantage in the management of acute gouty arthritis
Giant Cell Arteritis (GCA)
Histopathological analysis of temporal arteries has shown local expression of IL-1 in inflamed vessels. Three cases of refractory giant cell arteritis were successfully treated with anakinra. The treatment was effective in all patients
Osteoarthritis (OA)
IL-1 plays a role in the pathogenesis of osteoarthritis. The benefits of intra-articular anakinra injections in patients with knee OA have been shown to be short-lived, lasting less than one month. Systemic administration of IL-1 inhibitors has also been evaluated, but only modest improvement has been observed.
Rheumatoid Arthritis (RA)
Although IL-1 is found in plasma and synovial fluid of RA patients, IL-1 inhibition has shown limited success in established RA. This may be explained by redundancy in cytokine pathways, with TNF and IL-6 playing dominant roles. However, IL-1 inhibitors may provide added value in RA patients with comorbid metabolic or cardiovascular conditions, where anti-inflammatory and vascular effects are clinically relevant.
IL-1 Blockade in RA and Comorbidities
Compared to the general population, patients with RA are at higher risk for developing type 2 diabetes (T2D) and cardiovascular events. Due to their favorable effects on these comorbidities, IL-1 inhibitors in RA may offer benefits that extend beyond joint inflammation. IL-1 is known to contribute to atherosclerosis progression, ischemia-reperfusion injury, and cardiac remodeling. Positive outcomes have been reported in two RA patients with comorbid T2D treated with IL-1 inhibitors. These findings suggest that targeting IL-1 could represent a valuable therapeutic option for managing RA associated with type 2 diabetes
The indications of IL-1 inhibitors across rheumatologic diseases are summarized in
Dose Adjustments and Long-Term Outcomes
Anakinra is typically administered at 100 mg/day subcutaneously, though dose escalation to 200 mg/day has been reported in refractory cases with acceptable tolerability. Canakinumab, given every 4 - 8 weeks, allows sustained suppression of IL-1β, while rilonacept provides weekly dosing. Dose adjustments are sometimes necessary in renal impairment or in cases of incomplete clinical response. Long-term extension studies in Still’s disease, CAPS, and gout have shown that sustained efficacy can be achieved over 3 - 5 years, with no new safety signals. Nevertheless, more data from real-world registries are needed to confirm persistence of benefit and to evaluate risks of prolonged immunosuppression
Disease Category |
Conditions |
IL-1 Inhibitors Evaluated |
Reported Efficacy/Level of Evidence |
Autoinflammatory Diseases |
Adult-onset Still’s disease (AOSD)-Systemic juvenile idiopathic arthritis (sJIA) |
Anakinra, Canakinumab, Rilonacept |
Strong efficacy in systemic and early-onset disease |
Familial Mediterranean Fever (FMF) |
Anakinra |
Effective for flare control and amyloidosis prevention |
|
Hyper-IgD syndrome (Mevalonate kinase deficiency) |
Anakinra, Canakinumab |
Reduces frequency and severity of inflammatory attacks |
|
Cryopyrin-Associated Periodic Syndromes (CAPS) |
Anakinra, Canakinumab, Rilonacept |
High efficacy across the CAPS spectrum (FCAS, MWS, NOMID) |
|
TNF Receptor-Associated Periodic Syndrome (TRAPS) |
Anakinra |
Effective in refractory cases |
|
Mixed Autoimmune Conditions |
Behçet’s disease |
Anakinra, Canakinumab |
Effective in refractory cases; elevated IL-1 and IL-33 levels observed |
Crystal-Induced Arthropathies |
Gout (acute and chronic) |
Anakinra, Canakinumab, Rilonacept |
Greater efficacy than corticosteroids; prolongs flare-free periods |
Vasculitis |
Giant Cell Arteritis (GCA) |
Anakinra |
Clinical response in refractory cases |
Degenerative Joint Diseases |
Knee Osteoarthritis |
Anakinra |
Modest and short-lived benefit (<1 month) |
Rheumatoid Arthritis (RA) and Comorbidities |
RA with Type 2 Diabetes-RA with high cardiovascular risk |
Anakinra, Canakinumab |
Limited efficacy on joint inflammation, but metabolic and vascular benefit |
IL-1 inhibitors have revolutionized the management of autoinflammatory diseases such as Still’s disease, CAPS, FMF, and TRAPS, where their efficacy is robust and sustained. They are also emerging as valuable therapeutic options in gout and Behçet’s disease. In RA, their role remains limited due to cytokine redundancy, though metabolic and cardiovascular benefits may support their use in select patients. Overall, IL-1 blockade is a valuable addition to the rheumatologist’s therapeutic armamentarium. Future research should focus on long-term safety, optimization of dosing strategies, and better stratification of patients who will benefit most.