Interleukin 1 inhibitors: Biology, principles of use, and adverse events

INTRODUCTION — Interleukin (IL) 1 is a highly potent proinflammatory mediator that is important in immune defense and in immune-mediated disease. Three pharmacologic inhibitors (sometimes termed blockers) of IL-1 are commercially available: anakinra, canakinumab, and rilonacept (table 1).

General considerations regarding the use of these agents are presented here. The use of these agents for the treatment of specific inflammatory and autoimmune diseases is described in detail separately. (See "Cryopyrin-associated periodic syndromes and related disorders" and "Systemic juvenile idiopathic arthritis: Treatment" and "Treatment of adult-onset Still's disease" and "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)", section on 'Management' and "Hyperimmunoglobulin D syndrome: Management" and "Management of familial Mediterranean fever" and "Treatment of gout flares".)

OVERVIEW OF IL-1 BIOLOGY

Major components — Interleukin (IL) 1 encompasses two distinct cytokines, IL-1alpha and IL-1beta, that signal via the same receptor, IL-1 receptor, type 1 (IL-1R1) [1]. A related IL-1 family member, IL-1 receptor antagonist (IL-1ra), serves as an inhibitor that competes with both cytokines for binding to the receptor. IL-1R1 is expressed by most immune and nonimmune cells, accounting for the broad proinflammatory impact of IL-1.

A second IL-1 receptor, IL-1R2, serves as a nonsignaling decoy receptor both in membrane-bound and soluble forms, especially for IL-1beta. IL-1beta (evolutionarily older than IL-1alpha) is more important than IL-1alpha in most systemic inflammatory diseases.

●IL-1beta – IL-1beta is produced predominantly by myeloid cells such as macrophages, neutrophils, and mast cells. Release of IL-1beta is closely regulated. In most contexts, it is not expressed constitutively but is induced by proinflammatory stimuli such as lipopolysaccharides that turn on transcription of the IL-1beta gene. The resulting 41 kDa pro-IL-1beta is inert until cleaved by the inflammasome, a protein complex that activates caspase-1, also called IL-1 converting enzyme.

Caspase-1 cleaves pro-IL-1beta into active 17 kDa IL-1beta, which is released by cells through mechanisms including cytoplasmic membrane pores formed by gasdermin D, another protein cleaved by the inflammasome. At least six distinct inflammasomes are known, varying by assembly trigger and tissue distribution; aberrant activation of these complexes results in a set of autoinflammatory syndromes known as the inflammasomopathies. (See "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)".)

IL-1beta can also be cleaved through inflammasome-independent pathways. For example, activated T cells induce macrophages to process pro-IL-1beta to active IL-1beta through caspase 8 [2,3]. Thus, IL-1beta can be produced by antigen-driven immune activation as well as antigen-independent processes such as autoinflammatory diseases. (See "The autoinflammatory diseases: An overview" and "Autoinflammatory diseases mediated by inflammasomes and related IL-1 family cytokines (inflammasomopathies)".)

●IL-1alpha – IL-1alpha arose from IL-1beta through a gene duplication event and subsequent functional specialization [4]. Resulting differences in protein sequence between these cytokines result in for important functional differences. Further, whereas IL-1beta is expressed primarily by immune cells, IL-1alpha is expressed constitutively in keratinocytes in the skin, in epithelium of lung and gut, and by platelets and megakaryocytes; myeloid cells express IL-1alpha when activated [1,5]. IL-1alpha also can be expressed on the cell membrane, activating neighboring cells via contact as well as through microvesicles budded from the cell surface [6].

Like IL-1beta, IL-1alpha is synthesized as a pro-form, but pro-IL-1alpha is functional, activating cells via IL-1R1 with a potency approximately half that of IL-1beta and of cleaved IL-1alpha [7]. Pro-IL-1alpha includes protein-protein interaction domains relevant for its activity, including a nuclear localization sequence that enables it to function as a transcription factor [1,4]. During apoptosis, chromatin binding prevents escape of pro-IL-1alpha into the cellular milieu, whereas necrotic cell death releases the cytokine into the environment to mediate tissue inflammation [1,8]. Taken together, these functions translate into a role for IL-1alpha primarily in local inflammatory responses as a tissue-restricted danger signal (an "alarmin" function), whereas IL-1beta plays a more prominent role in systemic disease because of its release by circulating and tissue-infiltrating inflammatory cells as well as by resident macrophages and mast cells.

IL-1 function — Interleukin (IL) 1 participates in both innate and adaptive immune function. Engagement of IL-1R1 by IL-1alpha or IL-1beta engages a membrane-bound coreceptor, IL-1 receptor accessory protein (IL-1RAcP) (figure 1), and the trimolecular IL-1/IL-1R1/IL-1RAcP complex initiates an intracellular kinase-dependent signaling process mediated by the adaptor protein MyD88 (also termed myeloid differentiation primary response 88), resulting in a wide range of cell-activation events, including new gene transcription mediated through the nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) pathway.

Downstream effects depend upon the responding lineage and may include production of cytokines such as IL-6 (and IL-1beta itself) and upregulation of adhesion molecules on leukocytes and endothelial cells to promote cell migration. IL-1 is the major endogenous pyrogen, triggering fever via the hypothalamus [9]. Beyond these acute effects, IL-1 skews the differentiation of T cells toward proinflammatory T helper 17 (Th17) cells, while also aiding the function of CD4+ and CD8+ T cells and promoting effector T cell cytokine production [10-13].

PRETREATMENT TESTING — We perform the following testing and evaluation before initiating treatment with an interleukin (IL) 1 inhibitor:

●Baseline laboratory studies should include a complete blood count with differential, electrolytes and creatinine, hepatic transaminases, and bilirubin. Additional testing may be required for assessment of disease activity, which varies depending upon the disorder being treated.

●Females of reproductive age should be screened for pregnancy and counseled appropriately with respect to reproductive risk. Additional information regarding risk during pregnancy and breastfeeding is provided separately, including in the respective drug information topics for each agent. (See "Safety of rheumatic disease medication use during pregnancy and lactation", section on 'Ixekizumab'.)

●Screening for latent tuberculosis, hepatitis B, and hepatitis C is generally performed prior to initiating treatment. However, IL-1 inhibition does not appear to complicate these conditions [14]. Thus, when treatment is urgently indicated, it is reasonable to initiate therapy while awaiting screening results.

SPECIFIC AGENTS

Anakinra

Structure and mechanism of action — Anakinra is recombinant interleukin (IL) 1 receptor antagonist (IL-1ra) (figure 1). At 153 amino acids in length (17 kDa), it differs from endogenous IL-1ra by the inclusion of an additional methionine at the amino terminus; it is otherwise identical to the endogenous nonglycosylated variant of IL-1ra and appears to be a pure receptor antagonist [15-17]. IL-1ra binds IL-1 receptor, type 1 (IL-1R1) with an affinity equivalent to IL-1alpha and IL-1beta but does not recruit IL-1 receptor accessory protein (IL-1RAcP) and so fails to initiate a signal [18]. Less than 5 percent of surface IL-1R1 must be bound by the cytokine to elicit an activating signal, so IL-1ra must be present in substantial (>100-fold) excess to serve as an effective competitor [19].

While antidrug antibodies may form with anakinra use, most are non-neutralizing and do not appear to block efficacy or correlate with adverse events, although neutralizing antidrug antibodies have been reported in some patients exhibiting treatment nonresponse [20,21]. Unlike the other IL-1 inhibitors, anakinra penetrates the blood-brain barrier and achieves antiinflammatory concentrations in the brain [22,23].

Indications — Anakinra is approved by the US Food and Drug Administration (FDA) for patients with moderate to severe rheumatoid arthritis and for patients with cryopyrin-associated periodic syndromes (CAPS) [24]. The European Medicines Agency has approved anakinra for these indications and for Still's disease (encompassing both systemic juvenile idiopathic arthritis [sJIA] and adult-onset Still's disease) [25]. Other indications for which anakinra is routinely employed include idiopathic recurrent pericarditis resistant to colchicine [26], autoinflammatory diseases without established genetic diagnosis [27], and gout flares, especially in patients with contraindications to conventional therapy with nonsteroidal antiinflammatory drugs (NSAIDs), glucocorticoids, and colchicine [28-30]. The uses of anakinra for these and other indications and the evidence supporting such uses are described separately in the topic reviews on treatment of these disorders. (See "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Resistant to standard therapies' and "Cryopyrin-associated periodic syndromes and related disorders", section on 'Anakinra' and "The autoinflammatory diseases: An overview" and "Systemic juvenile idiopathic arthritis: Treatment", section on 'Interleukin 1 inhibitors' and "Recurrent pericarditis", section on 'Other immune therapy' and "Treatment of gout flares", section on 'Resistant or refractory disease' and "Treatment of adult-onset Still's disease", section on 'Canakinumab and rilonacept'.)

Canakinumab

Structure and mechanism of action — Canakinumab is an immunoglobulin G1 (IgG1) monoclonal antibody against IL-1beta that blocks binding to the IL-1 receptor complex (figure 1). It does not bind IL-1alpha or IL-1ra. While antidrug antibodies may form with canakinumab use, they do not appear to block efficacy or correlate with adverse events [31].

Indications — Canakinumab is approved by the FDA and European Medicines Agency for patients with CAPS, tumor necrosis factor receptor-associated periodic syndrome (TRAPS), hyperimmunoglobulin D syndrome (HIDS)/mevalonate kinase deficiency (MKD), familial Mediterranean fever (FMF), sJIA, and adult onset Still’s disease, and gout [32,33]. The uses of canakinumab for these and other indications and the evidence supporting such uses are described separately in the topic reviews on treatment of these disorders. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Canakinumab' and "Tumor necrosis factor receptor-1 associated periodic syndrome (TRAPS)", section on 'Frequent or poorly controlled symptoms and/or risk factors for amyloidosis' and "Hyperimmunoglobulin D syndrome: Management", section on 'IL-1 inhibition' and "Management of familial Mediterranean fever", section on 'Interleukin 1 inhibition' and "Systemic juvenile idiopathic arthritis: Treatment", section on 'Interleukin 1 inhibitors' and "Treatment of gout flares", section on 'Resistant or refractory disease' and "Treatment of adult-onset Still's disease", section on 'Canakinumab and rilonacept'.)

Rilonacept

Structure and mechanism of action — Rilonacept is a synthetic protein composed of the extracellular domains of IL-1R1 and IL-1RAcP (two molecules of each) fused to a human IgG1 Fc domain (figure 1). By incorporating both components of the receptor, rilonacept is able to bind IL-1beta with an affinity approximately 100-fold that of surface IL-1R1, enabling it to serve as an effective soluble decoy receptor [34]. Affinity for IL-1alpha is comparable to or slightly lower than for IL-1beta, and for IL-1ra (the main natural antagonist of IL-1), 23-fold lower than for IL-1beta [34]. The equilibrium dissociation constants for rilonacept binding to IL-1beta, IL-1alpha, and IL-1ra are 0.5 pM, 1.4 pM, and 6.1 pM [35]. Antidrug antibodies may form with rilonacept use, some with neutralizing capacity in vitro, but no obvious correlation with respect to efficacy or adverse events has been observed [36]. The molecular weight of rilonacept is approximately 250 kDa.

Indications — Rilonacept is approved by the FDA for patients with CAPS, recurrent pericarditis, and deficiency of the IL-1-receptor agonist (DIRA) [35,37]. The European Medicines Agency had previously approved rilonacept for CAPS, but approval was withdrawn by the sponsor [38]. Other indications for which rilonacept has shown promise are gout and sJIA [37,39,40]. The uses of rilonacept for these and other indications and the evidence supporting such uses are described separately in the topic reviews on treatment of these disorders. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Rilonacept' and "Treatment of gout flares", section on 'Resistant or refractory disease' and "Systemic juvenile idiopathic arthritis: Treatment", section on 'Interleukin 1 inhibitors' and "Cryopyrin-associated periodic syndromes and related disorders", section on 'Deficiency of the IL-1-receptor antagonist (DIRA)' and "Recurrent pericarditis", section on 'Interleukin 1 inhibitors'.)

ADVERSE EFFECTS — The most commonly reported adverse effect in patients on interleukin (IL) 1 inhibitors is injection site reactions. Hepatitis is rare. There does not appear to a large increase in risk of serious infections overall, although patients with comorbidities and those on additional immunosuppressive agents may be at higher risk.

Injection site reactions — Injection site reactions tend to be mild and occur in most patients on anakinra [41], approximately 50 percent of patients on rilonacept [35], and approximately 10 percent of patients on canakinumab [42].

Patients receiving anakinra frequently report stinging, potentially related to the citrate buffer (pH 6.5) that prevents aggregation of recombinant IL-1 receptor antagonist (IL-1ra) [41]. More than 50 percent of patients experience a second kind of injection site reaction, wherein multiple prior injection sites simultaneously become red and painful (picture 1). Typically, this reaction occurs within the first month of therapy or not at all, and all but uniformly resolves within two months [41]. The basis for this reaction is unknown, but its transient course and failure to evolve into anaphylaxis suggest a nonallergic mechanism. Management of injection site reactions includes allowing the syringe to come to room temperature before injection, systemic antihistamines, and topical or occasionally low-dose systemic glucocorticoids. Patients should be warned in advance of this reaction to avoid unnecessary concern and reassured that the reaction passes without sequelae in the large majority of individuals.

Infection — Despite the immune functions of IL-1alpha and IL-1beta, the impact of IL-1 inhibition on infection risk in human patients has been surprisingly modest. Overall, IL-1 inhibition exhibits relative safety, including in the setting of overt bacterial sepsis [43-45], although sustained use in patients with other comorbidities that predispose to infection likely results in increased risk.

A 2009 systematic review and meta-analysis of five randomized trials of anakinra involving 2876 patients with rheumatoid arthritis found that serious infections were numerically more common with anakinra than placebo (1.8 versus 0.6 percent), but this effect was not statistically significant [46]. No opportunistic infections (including tuberculosis) were noted, although rare infections with atypical pathogens have been observed at the case-report level [47]. Increased risk of severe infection was reported in a randomized trial when anakinra was combined with etanercept therapy (dosed once or twice weekly) in 244 patients with rheumatoid arthritis compared with etanercept alone (3.7, 7.4, and 0 percent, respectively) [48].

The Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial, which randomly assigned 10,061 adults with prior myocardial infarction to canakinumab or placebo, found that a reduction in risk for a second cardiovascular event was counterbalanced by an increase in death from infections (0.31 versus 0.18 events per 100 person-years), largely in patients who were older or had diabetes [49]. The incidence of tuberculosis was equivalent in the two groups. In trials of canakinumab for autoinflammatory diseases, neutropenia has been observed in several patients, and the rate of serious infections was 5.6 to 7.4 per 100 patient-years [50].

Adverse events from rilonacept include upper respiratory infections and neutropenia [35]. The rate of serious infections in patients on rilonacept is unknown.

Hepatitis — Marked elevation of hepatic transaminases together with the appearance of inflammatory liver infiltrates, sometimes eosinophilic, has been reported rarely in patients receiving anakinra treatment [14,51]. Progression to symptomatic liver dysfunction with histologic foci of hepatocellular necrosis can occur [52]. Most reported patients have had systemic juvenile idiopathic arthritis (sJIA) or adult-onset Still's disease. Resolution with cessation of therapy and recurrence with rechallenge suggests a causative role for anakinra, although the basis for this effect is unknown [14,53]. Permanent liver injury has not been reported. Patients developing hepatitis on anakinra may be safely treated with other IL-1 antagonists.

Transaminase elevations (4 percent) have also been reported with canakinumab, although without reported progression to liver injury [42], and mild elevation of lipids are common in patients on rilonacept [35].

Systemic juvenile idiopathic arthritis-associated lung disease — Since the early 2000s, some patients with sJIA (up to 7 percent by one estimate) have been observed to develop inflammatory lung disease with high mortality [54-56]. The appearance of this disease complication coincident with expanded therapeutic use of IL-1 and IL-6 inhibition, including anakinra and canakinumab, has raised concerns for a causal relationship, particularly for IL-1 inhibition, although not all affected patients were exposed to cytokine inhibitors [56]. The etiologic relationship between cytokine antagonists and lung disease in sJIA remains unclear because some patients have stabilized and even improved while still receiving IL-1 inhibition [55,57]. An association has been noted between carriage of the human leukocyte antigen (HLA) allele DRB1*15 and development of allergic-type reactions to IL-1 blockade (as well as IL-6 blockade) in patients with sJIA, raising the possibility that these agents induce drug reaction with eosinophilia and systemic symptoms (DRESS) that could play a role in the development of sJIA lung disease [58]. However, this interpretation remains controversial; an alternate possibility (termed the cytokine plasticity hypothesis) is that the agents are not themselves antigenic but may contribute to immune-mediated Th2 reactions and lung pathology in the inflammatory context of sJIA [59]. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis", section on 'Other clinical findings'.)

ADDITIONAL DISTINCTIONS BETWEEN IL-1 INHIBITORS

Administration and half-life — Practical considerations largely drive the clinical choice among IL-1 inhibitors including availability (insurance formularies, regulatory approval, and cost), mode of administration, and half-life. All three agents are administered by subcutaneous injection. Anakinra injections are daily and often sting. Canakinumab and rilonacept are injected less frequently (every one to two months and weekly, respectively), and injection site pain is less common, especially for canakinumab. However, the short half-life and rapid onset of action of anakinra represent major advantages for the use of anakinra in acutely ill patients and for diagnostic investigation of the role of IL-1 in a patient's illness, particularly given the documented safety of anakinra in the context of infection. As an example, we use anakinra in this "exploratory" capacity in the evaluation of patients with presumed systemic juvenile idiopathic arthritis (sJIA), in which fevers typically respond briskly to anakinra, as well as in the diagnostic evaluation in autoinflammatory disorders [60,61] (see "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Systemic juvenile idiopathic arthritis: Treatment" and "The autoinflammatory diseases: An overview"). The short half-life of anakinra also enables facile titration, including rapid tapering of patients in remission [62].

Mechanism of action — Anakinra and rilonacept block both IL-1alpha and IL-1beta, while canakinumab blocks only IL-1beta. Because IL-1beta is dominant in systemic inflammatory diseases, this difference has not proven to represent a substantive difference between agents [63], although the unique functions of IL-1alpha raises the possibility that situations exist in which IL-1alpha inhibition could be an advantage (or a disadvantage).

Potency — The relative capacities of anakinra, canakinumab, and rilonacept to neutralize IL-1 signaling in vivo have never been compared directly. Anecdotally, patients who fail to respond to one may still respond to another. As an example, some patients with sJIA who have responded to canakinumab had previously received anakinra, although whether they had failed the latter agent due to lack of efficacy or because of intolerance of daily injections was unclear [64]. While comparison across studies is intrinsically problematic, the reported efficacy of rilonacept in familial Mediterranean fever (FMF), sJIA, and acute gout has been modest, suggesting underperformance relative to anakinra and canakinumab [40,65,66]. If genuine, this difference may reflect the fact that rilonacept neutralizes IL-1 receptor antagonist (IL-1ra) as well as IL-1alpha and IL-1beta.

Blood-brain barrier — Anakinra enters the cerebrospinal fluid, whereas blood-brain barrier penetration by canakinumab and rilonacept is undefined [22]. In cryopyrin-associated periodic syndromes (CAPS) patients with central nervous system inflammation, anakinra treatment was associated with lower cerebrospinal fluid white blood cell counts and IL-6 levels [23]. These findings suggest that anakinra is likely preferable for IL-1 inhibition in diseases characterized by inflammation in the brain and spinal cord.

DISCONTINUING IL-1 INHIBITION — Discontinuation of interleukin (IL) 1 inhibition is typically undertaken in patients who experience adverse events or inefficacy, or who are in clinical remission and may no longer need treatment. When discontinuing IL-1 inhibition, the substantially different half-lives of anakinra (4 to 6 hours), canakinumab (26 days), and rilonacept (7 days) result in highly divergent "off rates." IL-1beta induces its own production, so abrupt withdrawal of IL-1 inhibition has the potential to trigger a self-perpetuating inflammatory cycle, especially with anakinra, because of its short duration of action.

We taper anakinra by spacing injections to every other day, then every third day, followed by discontinuation.

Canakinumab and rilonacept can be tapered by either the dose per injection or, more commonly, by spacing out the interval between administrations (for example, changing canakinumab injections from monthly to every two months then every three months before discontinuing altogether) [67].

For patients with conditions that are prone to abrupt and severe flares, such as systemic juvenile idiopathic arthritis (sJIA) and adult-onset Still's disease, we ask patients to maintain a supply of the IL-1 inhibitor on hand for ready reinitiation if needed.

Notably, the well-documented safety of anakinra in the setting of bacterial sepsis implies that, unlike most immunosuppressants, therapy should generally not be discontinued in patients experiencing acute infection [43]. Abrupt withdrawal in the setting of immune activation (for example, intercurrent viral or bacterial infection) has the potential to trigger an inflammatory spiral, especially in patients with sJIA and adult-onset Still's disease; in the context of infection, these patients may require more rather than less IL-1 inhibition to secure a positive outcome [60,68].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Side effects of anti-inflammatory and anti-rheumatic drugs".)

SUMMARY AND RECOMMENDATIONS

●Roles of interleukin 1 – Interleukin (IL) 1alpha and IL-1beta are potent proinflammatory cytokines involved in immune defense and in inflammatory diseases. IL-1beta typically predominates for systemic inflammation, while IL-1alpha plays a role primarily in local inflammation and in skin. (See 'Overview of IL-1 biology' above.)

●Types of IL-1 inhibitors – Three agents are available for pharmaceutical inhibition of IL-1: the recombinant IL-1 receptor antagonist (IL-1ra) anakinra; the anti-IL-1beta antibody canakinumab; and the IL-1 "trap" fusion molecule rilonacept. (See 'Anakinra' above and 'Canakinumab' above and 'Rilonacept' above.)

●Adverse effects – Pharmacologic inhibition of IL-1 is typically well tolerated. The most commonly reported adverse effect in patients on IL-1 inhibitors is injection site reactions. Hepatitis is rare. There does not appear to be a significant increased risk of serious infections overall. (See 'Infection' above and 'Adverse effects' above.)

●Differences among IL-1 inhibitors that affect choice of which to use – The choice among IL-1 inhibitors integrates considerations including mode of administration, half-life, mechanism of action, potency, and penetration of the central nervous system. As an example, anakinra is administered by daily subcutaneous injection due to its short half-life, whereas canakinumab and rilonacept are administered by subcutaneous injection at longer intervals (every one to two months for canakinumab, weekly for rilonacept). (See 'Additional distinctions between IL-1 inhibitors' above.)

●Discontinuing IL-1 inhibition – IL-1 inhibitors should be tapered gradually when discontinued. Unlike other immunosuppressive agents, discontinuation of IL-1 inhibitors in the context of infection is not required, both because they appear generally safe in this context and because serious flares of some IL-1-dependent inflammatory diseases may occur in the context of infection. (See 'Discontinuing IL-1 inhibition' above.)