Cryopyrinopathies, a group of rare autoinflammatory syndromes, are a distinct class of hereditary disorders of cytokine dysregulation with significant cutaneous features. They include familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystemic inflammatory disease (NOMID). These syndromes were initially thought to be distinct disease entities despite some clinical similarities. However, mutations of the same gene have since been found in all three cryopyrinopathies. Thus, these diseases are not separate, but represent a continuum of phenotypes with FCAS being the mildest and NOMID being the most severe phenotype. The gene in question, NLRP3 (nucleotide-binding domain, leucine rich family, pyrin domain containing, also known as CIAS1 and NALP3), encodes cryopyrin, which has led to the adoption of the term cryopyrin-associated periodic syndromes (CAPS) for this group of diseases. Cryopyrin is an important mediator of inflammation and interleukin 1beta (IL-1b) processing. Interleukin-1 acts as a messenger for the regulation of inflammatory responses, but in excess it can be harmful and has been shown to be key in the inflammation observed in patients with CAPS (Sinkai et al, 2008; Neven et al, 2008).
Cryopyrin-associated periodic syndromes are usually caused by autosomal-dominant mutations in the CIAS1 gene with male and female offspring equally affected. The FCAS and MWS disorders affect approximately 300 individuals in the United States. Fifty percent of CAPS cases are associated with a gene mutation in the CIAS1 gene. The incidence of CAPS is about 1 in 1,000,000 people in the United States. Patients with CAPS are characterized by life-long, recurrent symptoms such as arthralgia, conjunctivitis, fatigue, fever/chills, myalgias, and urticaria-like rash, and with potential for developing end-organ damage due to chronic inflammation. Intermittent, disruptive exacerbations or flares can be triggered at any time by exposure to stress, exercise, cooling temperatures, or other unknown stimuli. Moreover, patients with MWS are associated with more severe inflammation and may include hearing loss or deafness. In addition, some MWS patients may be afflicted with amyloidosis.
Attempts to treat CAPS with anti-inflammatory drugs or immunosuppressants have generally been disappointing. As a result, there is a need for novel therapies. Rilonacept (also known as IL-1 trap), an Interleukin-1 (IL-1) blocker, is an engineered dimeric fusion protein consisting of the ligand-binding domains of the extracellular portions of the human IL-1 receptor component (and IL-1 receptor accessory protein linked in-line to the Fc portion of human immunoglobulin G1. This "cytokine trap" blocks IL-1 signaling by acting as a soluble decoy receptor that binds to IL-1, thus preventing its interaction with cell-surface receptors.
Hoffman et al (2004) developed an experimental cold challenge protocol to (i) examine the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients, and (ii) investigate the effects of pre-treatment with an antagonist of IL-1 receptor (IL-1Ra). Real-time PCR, ELISA, and immunohistochemistry were used to measure cytokine responses. After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1 to 4 hours. Significant increases in serum concentrations of IL-6 and white-blood-cell (WBC) counts were seen 4 to 8 hours after cold challenge. Serum concentrations of IL-1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of IL-1 protein and mRNA were high in affected skin. Administration of IL-1Ra before cold challenge blocked symptoms and increases in WBC counts and serum IL-6. The ability of IL-1Ra to prevent the clinical features and hematological and biochemical changes in patients with FCAS indicated a central role for IL-1b in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-kappaB signaling suggested that it might have a role in many chronic inflammatory diseases. The authors stated that these findings support a new therapy for a disorder with no previously known acceptable treatment.
In a pilot study, Goldbach-Mansky and colleagues (2008) assessed the safety and effectiveness of rilonacept in patients with FCAS. A total of 5 patients were studied in an open-label trial. All patients received an initial loading dose of 300 mg of rilonacept by subcutaneous injection, were evaluated 6 and 10 days later for clinical effectiveness, and remained off treatment until a clinical flare occurred. At the time of flare, patients were again treated with 300 mg of rilonacept and then given maintenance doses of 100 mg/week. Patients whose FCAS was not completely controlled were allowed a dosage increase to 160 mg/week and then further to 320 mg/week during an intra-patient dosage-escalation phase. Safety, disease activity measures (daily diary reports of rash, joint pain and/or swelling, and fever), health quality measures (Short Form 36 health survey questionnaire), and serum markers of inflammation such as erythrocyte sedimentation rate (ESR), high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), and IL-6 were determined at 3, 6, 9, 12, and 24 months after initiation of rilonacept and were compared with baseline values. In all patients, clinical symptoms (e.g., rash, fever, and joint pain/swelling) typically induced by cold improved within days of rilonacept administration. Serum markers of inflammation (ESR, hsCRP, and SAA) showed statistically significant reductions (p < 0.01, p < 0.001, and p < 0.001, respectively) at doses of 100 mg. Dosage escalation to 160 mg and 320 mg resulted in subjectively better control of the rash and joint pain. Furthermore, levels of the acute-phase reactants ESR, hsCRP, and SAA were lower at the higher doses; the difference was statistically significant only for the ESR. All patients continued taking the study drug, which was well-tolerated. Weight gain in 2 patients was noted. No study drug-related serious adverse events were seen. The authors concluded that this study presented 2-year safety and effectiveness data on rilonacept treatment in 5 patients with FCAS. The dramatic improvement in clinical and laboratory measures of inflammation, the sustained response, and the good tolerability suggested that this drug may be a promising therapeutic option in patients with FCAS, and the data led to the design of a phase III study in this patient population.
In February 2008, rilonacept (Arcalyst) received approval from the Food and Drug Administration (FDA). It is indicated for the treatment of CAPS, including FCAS and MWS in adults as well as children aged 12 years and older. However, rilonacept has not been studied in patients with NOMID. The most commonly reported side effects associated with use of rilonacept were injection-site reactions and upper respiratory tract infections.
The FDA's approval of Arcalyst was based on a phase III clinical trial by Hoffman and colleagues (2008). A total of 47 adult patients with CAPS, as defined by mutations in the causative NLRP3 (CIAS1) gene and pathognomonic symptoms, were enrolled in 2 consecutive studies. Study 1 entailed a 6-week randomized double-blind comparison of weekly subcutaneous injections of rilonacept (160 mg) versus placebo. Study 2 consisted of a 9-week single-blind treatment with rilonacept (part A), followed by a 9-week, randomized, double-blind, placebo-controlled withdrawal procedure (part B). Primary effectiveness was evaluated using a validated composite key symptom score. A total of 44 patients completed both studies. In Study 1, rilonacept therapy reduced the group mean composite symptom score by 84 %, compared with 13 % with placebo therapy (primary end point; p < 0.0001 versus placebo). Rilonacept also significantly improved all other effectiveness end points in Study 1 (numbers of multi-symptom and single-symptom disease flare days, single-symptom scores, physician's and patient's global assessments of disease activity, limitations in daily activities, as well as hsCRP and SAA levels). In Study 2-part B, rilonacept was superior to placebo for maintaining the improvements seen with rilonacept therapy, as shown by all effectiveness parameters (primary end point; p < 0.0001 versus placebo). Rilonacept was generally well-tolerated. The authors concluded that treatment with weekly rilonacept provided marked and lasting improvement in the clinical signs and symptoms of CAPS, and normalized the levels of SAA from those associated with risk of developing amyloidosis. Rilonacept exhibited a generally favorable safety and tolerability profile.
The FDA-approved labeling states that treatment with rilonacept should not be initiated in persons with active or chronic infections. The labeling states that taking rilonacept with tumor necrosis factor (TNF) inhibitors is not recommended because this may increase the risk of serious infections.
In a pilot study, Terkeltaub et al (2009) explored the potential utility of rilonacept in patients with chronic active gouty arthritis. This 14-week, multi-center, non-randomized, single-blind, mono-sequence cross-over study of 10 patients included a placebo run-in (2 weeks), active rilonacept treatment (6 weeks) and a 6-week post-treatment follow-up. Rilonacept was generally well-tolerated. No deaths and no serious adverse events occurred during the study. One patient withdrew owing to an injection-site reaction. Patients' self-reported median pain visual analog scale scores significantly decreased from week 2 (after the placebo run-in) to week 4 (2 weeks of rilonacept) (5.0 to 2.8; p < 0.049), with sustained improvement at week 8 (1.3; p < 0.049); 5 of 10 patients reported at least a 75 % improvement. Median symptom-adjusted and severity-adjusted joint scores were significantly decreased; and hsCRP levels fell significantly. The authors concluded that this proof-of-concept study demonstrated that rilonacept is generally well-tolerated and may offer therapeutic benefit in reducing pain in patients with chronic refractory gouty arthritis, supporting the need for larger, randomized, controlled studies of IL-1 antagonism such as with rilonacept for this clinical indication.
McDermott (2009) stated that rilonacept is a long-acting IL-1 blocker developed by Regeneron. Initially, Regeneron entered into a joint development effort with Novartis to develop rilonacept for the treatment of rheumatoid arthritis (RA) but this was discontinued following the review of phase II clinical data showing that IL-1 blockade appeared to have limited benefit in RA. In February 2008, Regeneron received Orphan Drug approval from the FDA for rilonacept in the treatment of 2 CAPS disorders -- FCAS and MWS -- for children and adults 12 years and older. Cryopyrin-associated periodic syndromes are a group of inherited inflammatory disorders consisting of FCAS, MWS, NOMID, also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome, all associated with heterozygous mutations in the NLRP3 (CIAS1) gene, which encodes the protein NLRP3 or cryopyrin. Prior to the discovery of the NLRP3 (CIAS1) mutations and the advent of IL-1-targeted therapy, treatment was aimed at suppressing inflammation but with limited success. The dramatic success of selective blockade of IL-1beta, initially with the IL-1 receptor antagonist (IL-1Ra; anakinra), not only provided supportive evidence for the role of IL-1beta in CAPS but also demonstrated the effectiveness of targeting IL-1beta for treatment of these conditions. Rilonacept was developed by Regeneron; its longer half-life offers potential alternatives to patients who do not tolerate daily injections very well or have difficulty with drug compliance. The initial evidence for the beneficial effects of rilonacept for MWS and FCAS suggests that it would also be a suitable treatment for CNICA/NOMID. It is yet to be determined if rilonacept would be an effective treatment for other chronic inflammatory conditions such as gout, familial Mediterranean fever and systemic juvenile idiopathic arthritis (JIA).
Sundy (2010) discussed approved and emerging drugs used to treat hyperuricemia or the clinical manifestations of gout. Results of several clinical trials provided new data on the safety and effectiveness of the approved urate-lowering drugs, allopurinol and febuxostat. New recommendations have been presented on appropriate dosing of colchicine for acute gout flares and potential toxicities of combining colchicine with medications such as clarithromycin. Emerging therapies, including pegloticase, the uricosuric agent RDEA596, and the IL-1 inhibitors, rilonacept and canakinumab, have shown promise in early and late phase clinical trials. The author concluded that recent publications demonstrate an opportunity to use existing gout therapies more effectively in order to improve both safety and efefctiveness. Emerging therapies for gout show promise for unmet needs in selected gout populations.
Breda and colleagues (2011) stated that advances in understanding the pathogenesis of rheumatic diseases have led to the discovery of mechanisms of inflammation and autoimmunity and have made possible the invention of new target-specific drugs. Biologic drugs, designed to inhibit specific components of the immune system, such as cytokines, cytokine gene expression, and their complex interactions, have revolutionized the treatment options in pediatric rheumatology. Only 3 agents are currently available for treating JIA: (i) etanercept, at the dose of 0.8 mg/kg once-weekly, (ii) adalimumab at the dose of 24 mg/m(2) every 2 weeks, and (iii) abatacept at the dose of 10 mg/kg at weeks 0, 2, 4, and then every 4 weeks. They are well-tolerated and relatively safe in children. Side effects are generally mild and include injection site reactions and infections. Infliximab, rilonacept, and canakinumab are also approved by the FDA for treatment of pediatric autoimmune disorders and are currently investigated in JIA.
Canakinumab (Ilaris) is a recombinant, human anti-human-IL-1beta monoclonal antibody. It is indicated for the treatment of CAPS, including FCAS and MWS in adults and children 4 years of age and older (Walsh, 2009).
The approval of canakinumab by the FDA in June 2009 was based on a 3-part, 48-week, double-blind, placebo-controlled, randomized withdrawal study of canakinumab in patients with CAPS (Lachmann et al, 2009). In part 1, 35 patients received 150 mg of canakinumab subcutaneously. Those with a complete response to treatment entered part 2 and were randomly assigned to receive either 150 mg of canakinumab or placebo every 8 weeks for up to 24 weeks. After the completion of part 2 or at the time of relapse, whichever occurred first, patients proceeded to part 3 and received at least 2 more doses of canakinumab. These investigators evaluated therapeutic responses using disease-activity scores and analysis of levels of CRP and SAA. In part 1 of the study, 34 of the 35 patients (97 %) had a complete response to canakinumab. Of these patients, 31 entered part 2, and all 15 patients receiving canakinumab remained in remission. Disease flares occurred in 13 of the 16 patients (81 %) receiving placebo (p < 0.001). At the end of part 2, median CRP and SAA values were normal (less than 10 mg/L for both measures) in patients receiving canakinumab; but were elevated in those receiving placebo (p < 0.001 and p = 0.002, respectively). Of the 31 patients, 28 (90 %) completed part 3 in remission. In part 2, the incidence of suspected infections was greater in the canakinumab group than in the placebo group (p = 0.03). Two serious adverse events occurred during treatment with canakinumab: 1 case of urosepsis and an episode of vertigo. The authors concluded that treatment with subcutaneous canakinumab once every 8 weeks was associated with a rapid remission of symptoms in most patients with CAPS.
Dhimolea (2010) stated that canakinumab was approved by the FDA for the treatment of FCAS and MWS, which are inflammatory diseases related to cryopyrinCAPS. The drug is currently being evaluated for its potential in the treatment of chronic obstructive pulmonary disease, ocular diseases, rheumatoid arthritis, systemic-onset juvenile idiopathic arthritis, as well as type 1 and type 2 diabetes.
Dinarello and colleagues (2012) noted that monotherapy blocking IL-1 activity in autoinflammatory syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-myocardial infarction (MI) heart failure, and trials targeting a broad spectrum of new indications are underway. So far, 3 IL-1-targeted agents have been approved: (i) the IL-1 receptor antagonist anakinra, (ii) the soluble decoy receptor rilonacept, and (iii) the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.
Abbate et al (2012) stated that the inflammatory hypothesis of atherosclerosis postulates that inflammation within the plaque promotes plaque progression and complications. Interleukin-1 is a key pro-inflammatory cytokine responsible for the amplification of the inflammatory response following injury. Animal studies show that IL-1 blockade is effective in limiting atherosclerosis and atherothrombosis and improving outcomes in acute MI and ischemic stroke. Preliminary data in patients with acute MI, ischemic stroke, and heart failure are promising. A large secondary prevention trial with canakinumab in patients with prior acute MI is currently ongoing. The authors noted that many unanswered questions remain regarding the optimal use of IL-1 blockade and the preferred agent.
Lipsker and Lenormand (2012) stated that anecdotal observations suggested that IL-1 antagonists may be effective for the treatment of patients with different types of inflammatory dermatological diseases. These investigators reviewed the current evidence on the use of IL-1 antagonists in dermatology. A Medline search was performed combining the keywords: "anakinra; canakinumab; rilonacept" and "skin; neutrophilic dermatoses; Sweet syndrome; pyoderma gangrenosum; hidradenitis suppurativa; Schnitzler syndrome; Still disease". The precise dermatological phenotype of patients with IL-1 antagonist-responsive auto-inflammatory disorders was analysed in order to compare it to related complex disorders. Double-blind randomized controlled trials have demonstrated the efficacy of these treatments in cryopyrinopathies with dermatological involvement including chronic infantile neurological cutaneous and articular (CINCA) syndrome, Muckle-Wells syndrome and familial cold urticaria. Anakinra is the only treatment for Schnitzler syndrome that is almost constantly efficacious, even in refractory disease, as attested by numerous case reports. It is also efficacious in the treatment of patients with adult-onset Still disease and systemic juvenile arthritis. Neutrophilic dermatoses constitute the cutaneous hallmark of IL-1-responsive auto-inflammatory disorders, and neutrophilic dermatoses could thus form an indication for this treatment. However, to-date, only 9 reports have been published showing efficiency in patients with Sweet syndrome, in 1 case of neutrophilic panniculitis, and in 2 cases of pustular psoriasis. Anakinra appears less efficacious in patients with pyoderma gangrenosum. The authors concluded that IL-1 antagonists are a first-line treatment in patients with Schnitzler syndrome and cryopyrinopathies. They could become important alternatives in patients with acute and febrile neutrophilic dermatoses either unresponsive to or with contraindications to conventional treatments, but this requires confirmation by further clinical trials.
In a prospective, single-center, open-label study, Krause et al (2012) evaluated the effects of rilonacept on the clinical signs and symptoms of Schnitzler syndrome (SchS). A total of 8 patients with SchS were included in this study. After a 3-week baseline, patients received a subcutaneous loading dose (300-mg) of rilonacept followed by weekly subcutaneous doses of 160-mg for up to 1 year. Efficacy was determined by patient-based daily health assessment forms, physician's global assessment (PGA), and measurement of inflammatory markers including CRP, SAA, and S100 calcium-binding protein A12 (S100A12). Treatment with rilonacept resulted in a rapid clinical response as demonstrated by significant reductions in daily health assessment scores and PGA scores compared with baseline levels (p < 0.05). These effects, which were accompanied by reductions in CRP and SAA, continued over the treatment duration. Rilonacept treatment was well-tolerated. There were no treatment-related severe adverse events and no clinically significant changes in laboratory safety parameters. The authors concluded that rilonacept was effective and well- tolerated in patients with SchS and may represent a promising potential therapeutic option.
Vanderschueren and Knockaert (2012) tested canakinumab in patients with Schnitzler syndrome. A patient with Schnitzler syndrome was treated with canakinumab, 150 mg subcutaneously injection every 8 weeks for 6 consecutive months. Injections were resumed in case of a flare following discontinuation. Canakinumab induced a swift and sustained clinical response, with disappearance of fever and arthralgias, near abolishment of fatigue and rash, and substantial reduction of CRP levels. Interruption of canakinumab after four 8-weekly injections led to a flare 10 weeks after the last administration, which was countered as soon as canakinumab injections were resumed. The patient remained in complete remission. Canakinumab was well-tolerated. No injection site reactions, other adverse events, or laboratory abnormalities were observed. The authors concluded that canakinumab has potential for the treatment of Schnitzler syndrome.
Giampietro and Fautrel (2012) stated that IL-1β is emerging as a master mediator of adult-onset Still's disease (AOSD) pathogenesis. This pleiotropic cytokine has a wide type of effects. As a key mediator of innate immunity, it is a potent pyrogen and facilitates neutrophilic proliferation and diapedesis into the inflamed tissues, which are key AOSD manifestations. The study of pro-inflammatory cytokines profiles in sera and pathological tissues of AOSD patients has shown elevated levels of IL-1β, these levels being highly correlated with disease activity and severity. These experimental evidences as well as the analogy with other auto-inflammatory diseases that share with AOSD clinical and biological characteristics have suggested the blockade of IL-1β as a possible new therapeutic option for the AOSD, especially in conventional therapy resistant cases. Anakinra, the first anti-IL-1 agent put on the market, has demonstrated capable to induce a rapid response sustained over time, especially in systemic forms, where anti-TNFα failed to control symptoms. While a growing number of evidences supports the utilization of anakinra in AOSD, a new generation of anti-IL1β antagonists is developing. Canakinumab and rilonacept could improve the management of this disease.
Kontzias and Efthimiou (2012) described the successful treatment of AOSD with canakinumab on patients refractory to anakinra and rilonacept. In many cases the expected positive therapeutic effect of short-acting IL-1 inhibitors is transient or completely absent, leading to the hypothesis that their short half-life may be associated with incomplete IL-1 blockade, given the cyclic nature of the disease. These investigators reported 2 cases of AOSD resistant to short-acting IL-1 blockade, which were subsequently treated with canakinumab. A retrospective chart review was conducted of patients diagnosed with AOSD in the authors' regional referral center. Response to treatment was assessed by its effect on the systemic symptoms (resolution of fever and rash), polyarthritis (using the disease activity score 28 -- CRP score), and the levels of serum ferritin. Canakinumab demonstrated sustained efficacy in both patients as evidenced by clinical and laboratory parameters with minimal adverse reactions. The authors concluded that this is the first documented report of successful use of canakinumab in AOSD patients refractory to traditional disease-modifying anti-rheumatic drugs and short- to moderate-acting IL-1 blockade. Moreover, they stated that prospective comparative studies are needed to validate canakinumab's safety and effectiveness in the treatment of AOSD.
Galeotti et al (2012) described the safety and effectiveness of IL-1-targeting drugs, anakinra and canakinumab, in patients with mevalonate kinase deficiency (MKD). A questionnaire was sent to French pediatric and adult rheumatologists to retrospectively collect information on disease activity before and after treatment with IL-1 antagonists from genetically confirmed MKD patients. The authors assessed the frequency of crises and their intensity using a 12-item clinical score built for the purpose of the study. A total of 11 patients were included. Anti-IL-1-targeting drugs were used continuously in all but 1 patient who received anakinra on demand. Daily anakinra (9 patients) or canakinumab injections every 4 to 8 weeks (6 patients, in 4 cases following anakinra therapy) were associated with complete remission in 4 cases and partial remission in 7. The median score during MKD attacks decreased from 7/12 before treatment to 3/12 after anakinra and 1/12 after canakinumab. The number of days with fever during attacks decreased from 5 before treatment to 3 after anakinra and 2 after canakinumab. Marked decrease of CRP and SAA protein were recorded. Side effects were mild or moderate; they consisted of local pain and inflammation at injection site, infections and hepatic cytolysis. The authors concluded that continuous IL-1 blockade brings substantial benefit to MKD patients. More over, they stated that controlled trials are needed to further evaluate the clinical benefit and treatment modalities in these patients.
The dosage for Arcalyst is as follows:
Adult patients 18 years and older: Initiate treatment with a loading dose of 320 mg delivered as two, 2-ml, subcutaneous injections of 160 mg on the same day at 2 different sites. Continue dosing with a once-weekly injection of 160 mg administered as a single, 2-ml, subcutaneous injection. Do not administer rilonacept more often than once-weekly.
Pediatric patients aged 12 to 17 years: Initiate treatment with a loading dose of 4.4 mg/kg of body weight, up to a maximum of 320 mg, delivered as 1 or 2 subcutaneous injections with a maximum single-injection volume of 2 ml. Continue dosing with a once-weekly injection of 2.2 mg/kg, up to a maximum of 160 mg, administered as a single subcutaneous injection, up to 2 ml. If the initial dose is given as 2 injections, they should be given on the same day at 2 different sites. Do not administer rilonacept more often than once-weekly.
The dosage for Ilaris is as follows:
The recommended dose of Ilaris is 150 mg for CAPS patients with body weight greater than 40 kg. For CAPS patients with body weight between 15 kg and 40 kg, the recommended dose is 2 mg/kg. For children weighing 15 to 40 kg with an inadequate response, the dose can be increased to 3 mg/kg. Ilaris is administered every 8 weeks as a single dose via subcutaneous injection.