Efficacy and safety of anti-interleukin-1 treatment in familial Mediterranean fever patients: a systematic review and meta-analysis.

OBJECTIVES: FMF is the most common hereditary monogenic fever syndrome marked by recurrent attacks of fever and polyserositis. Colchicine is the current recommended first-line treatment for FMF. However, a small portion of FMF patients are unresponsive or intolerant to colchicine. Anti-IL-1 agents are alternative treatment options for colchicine-resistant or -intolerant FMF patients. This systematic review and meta-analysis aimed to provide qualitative and quantitative evidence for the efficacy and safety of anti-IL-1 agents in adult and paediatric FMF patients. METHODS: MEDLINE, EMBASE, CENTRAL and Web of Science were screened from inception to May 2023. We included adult and paediatric FMF patients who received continuous treatment with at least one of the anti-IL-1 drugs: anakinra, canakinumab and rilonacept. The primary efficacy outcome was the proportion of patients who achieved complete remission of attacks and the primary safety outcome was the proportion of patients who experienced at least one adverse event during treatment. A random-effects meta-analysis was performed for the quantitative synthesis. RESULTS: Fourty-four reports consisting of 1399 FMF patients were included. Sixty percent (95% CI 49%, 72%) of the adult patients and 81% (95% CI 72%, 89%) of the paediatric patients achieved complete remission. Anti-IL-1 agents significantly decreased levels of inflammatory markers. At least one adverse event was observed in 25% (95% CI 13%, 37%) of the adult patients and 12% (95% CI 3%, 21%) of the paediatric patients. CONCLUSION: Anti-IL-1 agents were effective and demonstrated a low adverse event profile in paediatric and adult FMF patients.

Efficacy and Safety of Biological Drugs in Still's Disease: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials.

OBJECTIVES: Still's disease is a rare autoinflammatory disorder characterized by systemic inflammation, fever, rash, and arthritis. The term "Still's disease" covers the pediatric subtype systemic Juvenile Idiopathic Arthritis (sJIA) and adult-onset Still's disease (AOSD), which affects adults. Biological drugs, including anti-interleukin-1 agents anakinra, canakinumab, rilonacept, and the interleukin-6 antagonist tocilizumab, are used in the management of Still's disease. METHODS: We conducted a systematic review and network meta-analysis of randomized controlled trials, and the study protocol was registered in PROSPERO (CRD42023450442). MEDLINE, EMBASE, and CENTRAL were screened from inception until September 17, 2023. We included patients with Still's disease who received placebo or biological drugs: anakinra, canakinumab, rilonacept, or tocilizumab. The primary efficacy and safety outcomes were achievement of ACR50 response and occurrence of serious adverse events, respectively. The interventions were ranked using rankograms and SUCRA values. RESULTS: Nine trials with 430 patients were included. All biological drugs were associated with greater odds of ACR50 response compared with placebo. There was no statistically significant association between biological drugs and serious adverse events. The multivariate meta-analysis found no difference between biological drugs. As per SUCRA rankings, anakinra was the most effective and safe option with respect to ACR50 response and occurrence of serious adverse events. CONCLUSION: This is the first systematic review and meta-analysis to assess the efficacy and safety of biological drugs in pediatric and adult patients with Still's disease. Biological drugs were effective in achieving ACR response and demonstrated a low adverse event profile in the management of Still's disease.

Novel Pathophysiological, Diagnostic and Therapeutic Concepts in Acute and Recurrent Pericarditis.

Acute pericarditis is the most frequent pericardial disease characterized by inflammation of the pericardial layers resulting in pain, dyspnea and fatigue. Often limited to an isolated event, up to 30% of patients experience one or more recurrences. There is limited knowledge about the pathophysiology of this disease, possibly due to the limited availability of animal models. More recently, following seminal clinical trials with colchicine and interleukin-1 (IL-1) blockers and a novel murine model of acute pericarditis using zymosan A, it has become clear that the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome/IL-1 ß axis plays a central role in driving acute pericardial inflammation and in sustaining this process during recurrences. Diagnostic management of pericarditis has been implemented with multimodality imaging including echocardiography, cardiac computed tomography, and cardiac magnetic resonance. These imaging modalities provide essential diagnostic and pathogenetic information, and are able to characterize pericardial inflammation, allowing to refine risk stratification and personalize treatment. Recent acquisitions yield relevant implications with regard to the therapeutic management of acute and recurrent pericarditis. Non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine are cornerstone therapies either for acute and recurrent pericarditis. However, the benefits of targeted agents, such as anakinra - a recombinant human IL-1 receptor antagonist - and rilonacept - an IL-1 α /IL-1 ß trap, are being increasingly recognized. To this end, phenotyping patients with pericarditis and addressing such therapies to those presenting with auto-inflammatory features (elevated C-reactive protein, sustained pericardial and systemic inflammation, multiple recurrences) is of utmost importance to identify patients who might be more likely to benefit from NLRP3 inflammasome/IL-1 ß pathway blockade.

Paradigm Shift in Diagnosis and Targeted Therapy in Recurrent Pericarditis.

PURPOSE OF THE REVIEW: We review the pathophysiology, diagnosis, and contemporary treatment for recurrent pericarditis, with focus on interleukin-1 (IL-1) inhibitors. RECENT FINDINGS: Recurrent pericarditis occurs in about 15-30% of patients who have acute pericarditis. With increased understanding of the autoinflammatory pathophysiology of recurrent pericarditis, IL-1 inhibitors including anakinra, canakinumab, and rilonacept have been applied to this condition with great promise. In particular, the RHAPSODY trial found rilonacept significantly improves pain and inflammation, while also reducing recurrence with few adverse events. The next IL-1 inhibitor on the block for pericarditis, goflikicept, is also discussed. Understanding the role of the inflammasome via the autoinflammatory pathway in pericarditis has led to incorporation of IL-1 inhibitors in the treatment of recurrent pericarditis, with proven efficacy and safety and randomized trials. This will lead to increase uptake of this agent which demonstrated lower rates of recurrence and faster time to resolution.

Anti-interleukin-1 agents for pericarditis: a primer for cardiologists.

Anti-interleukin (IL)-1 agents have been developed for the treatment of autoinflammatory and rheumatic conditions, where overproduction of IL-1 is an important pathophysiologic process. IL-1α and IL-1ß are the most studied members of the IL-1 family of cytokines and have the strongest proinflammatory effects. A naturally occurring antagonist (IL-1Ra) mitigates their proinflammatory effects. Overproduction of both IL-1α (released by inflamed/damaged pericardial cells) and IL-1ß (released by inflammatory cells) is now a well-recognized therapeutic target in patients with recurrent idiopathic pericarditis. Currently, there are three available anti-IL-1 agents: anakinra (recombinant human IL-1Ra), rilonacept (a soluble decoy receptor 'trap', binding both IL-1α and IL-1ß), and canakinumab (human monoclonal anti-IL-1ß antibody). For patients with corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation, as evidenced by elevated C-reactive protein, the efficacy and safety of anakinra (2 mg/kg/day up to 100 mg/day subcutaneously usually for at least 6 months, then tapered) and rilonacept (320 mg subcutaneously for the first day followed by 160 mg subcutaneously weekly) have been clearly demonstrated in observational studies and randomized controlled clinical trials. Severe side effects are rare and discontinuation rates are very low (<4%). The most common reported side effect is injection site reactions (>50% of patients). In this article, we describe the historical and pathophysiological background and provide a comprehensive review of these agents, which appear to be the most significant advance in medical therapy of recurrent pericarditis in the last 5 years.

Targeting the residual cardiovascular risk by specific anti-inflammatory interventions as a therapeutic strategy in atherosclerosis.

Chronic subclinical inflammation is a key process in the pathogenesis of atherosclerotic cardiovascular disease (ASCVD). Along with lipids, inflammation is essential for the initiation and progression of atherosclerosis with macrophages playing a pivotal role through the induction of oxidative stress and cytokine secretion. Several pro-inflammatory cytokines have been described in the primary and secondary prevention of ASCVD. Although extensive work over the past decades has established the role of lipid-lowering medications in the prevention and treatment of ASCVD, modulation of inflammation is a subject of active debate. It remains to be confirmed whether targeting the residual cardiovascular risk by adding anti-inflammatory agents to the conventional cardiovascular treatment becomes a shifting paradigm for ASCVD management. This review aims to discuss novel therapeutic agents targeting inflammatory pathways in ASCVD in light of the canakinumab anti-inflammatory thrombosis outcomes study (CANTOS) trial results. Further we discuss the effects of different anti-inflammatory agents administered in patients with ASCVD and their potential to change clinical practice in preventive cardiology.

Conventional and novel therapeutic options in children with familial Mediterranean fever: A rare autoinflammatory disease.

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease and is usually diagnosed in childhood, especially in the first decade of life. Paediatric FMF is characterized by a protean clinical expression and a variable therapeutic response, which can make its medical management very challenging. However, even if long-term complications of untreated FMF (e.g. amyloidosis and related organ damage) are less frequent in children compared to adults, they are not uncommon. Colchicine is the mainstay of the therapy in paediatric FMF; however, if children develop colchicine intolerance and/or resistance, biologics, particularly interleukin-1 antagonists, must be considered. Other conventional or biological therapeutic options do not currently have appropriate evidence-based support, except for some specific clinical presentations (e.g., arthritis). In this review, we discuss the biological basis and the clinical evidence for the current pharmacological treatment options available for paediatric FMF.

Rilonacept: A Newly Approved Treatment for Recurrent Pericarditis.

OBJECTIVE: To review the pharmacology, efficacy, and safety of rilonacept for the prevention and treatment of recurrent pericarditis (RP). DATA SOURCES: A MEDLINE search was conducted between January 2006 and April 2021 using the following terms: rilonacept, pharmacology, pericarditis, recurrent pericarditis, interleukin (IL) antagonist, and pharmacology; prescribing information was also used. STUDY SELECTION AND DATA EXTRACTION: English-language studies assessing pharmacology, efficacy, and safety of IL antagonists were reviewed. DATA SYNTHESIS: Rilonacept traps IL-1α and IL-1ß. In the Phase III trial, rilonacept was associated with a lower risk of recurrence, more persistent clinical response, and higher amount of days with no or minimal pericarditis symptoms, compared with placebo. The median time to pain response was 5 days, and median time to normalization of C-reactive protein was 7 days with rilonacept. All patients receiving rilonacept during the run-in period were able to be weaned off of standard background therapy, leading to transition to rilonacept monotherapy. The most common adverse effects were upper respiratory tract infections and injection site reactions. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Rilonacept may be used for the prevention and treatment of multiple recurrences in patients receiving background therapy for RP, and reduction in risk of recurrence in adults and adolescents ≥12 years with elevated C-reactive protein. Rilonacept may be considered to wean patients from standard background therapy. CONCLUSION: Rilonacept is a safe, once weekly, subcutaneously administered IL-1 "trap," indicated for the treatment of RP, and reduction in risk of recurrent pericarditis in adults and children ≥12 years of age.

Rilonacept (Interleukin-1 Inhibition) for the Treatment of Pericarditis.

PURPOSE OF REVIEW: We reviewed the contemporary literature and clinical trials to discuss the applications of the interleukin-1 (IL-1) inhibitor rilonacept to treat pericarditis, with regards to pathophysiology, pharmacology, efficacy, and safety. RECENT FINDINGS: Rilonacept is an emerging novel agent for treating recurrent pericarditis, with phase II and III clinical trials recently published. Rilonacept rapidly resolved pericarditis pain and inflammation, markedly reduced recurrent pericarditis episodes, and had few adverse events indicating a high safety profile. Recurrent pericarditis is associated with significant morbidity and unmet need for novel therapies. Inflammasomes and the IL-1 pathways were found to be critical in its pathophysiology, leading to IL-1 inhibitors being developed. The high efficacy and safety of rilonacept for recurrent pericarditis means it could potentially be considered as a second-line therapy ahead of or as an alternative to corticosteroids, and highlight the great promise of targeted immunomodulatory therapy in this field.

Current treatment options for monogenic periodic fever syndromes - the role of interleukin 1 inhibitors.

Monogenic periodic fever syndromes are heterogeneous group of autoinflammatory diseases including distinct syndromes, such as cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor alpha receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyper IgD syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). Individual diseases differ in pathogenesis, clinical manifestations, and severity. However, cytokines from the interleukin 1 (IL-1) family play a key role in all of them. Inhibition of these cytokines, especially IL-1, thus plays a crucial role in their treatment. At present, we have a wide range of drugs that differ in structure, mechanism of action, efficacy, and spectrum of side effects. The most available are anakinra, canakinumab and rilonacept. Moreover, several clinical trials are currently underway with other very promising drugs, such as gevokizumab, tadekinig alfa or tranilast. In the following review, we provide a new perspective on the efficacy and safety of IL-1 inhibitors that have provided the novel results coming from recently published clinical trials.

IL-1ß blockade in periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome: case-based review.

Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA) syndrome and familial Mediterranean fever (FMF) are considered as inflammasome disorders associated with uncontrolled interleukin (IL)-1ß production. Anti-IL1 agents are used in colchicine-resistant cases of FMF. Increase in pro-inflammatory mediators even between febrile attacks in PFAPA suggests that anti-IL1 treatment might be beneficial in these patients. We describe a child presenting with recurrent, self-limited febrile attacks at 1 year of age who was diagnosed as FMF being heterozygous for M694 V mutation. Her clinical findings were only controlled by the addition of canakinumab (2 mg/kg/8 week) to colchicine treatment. However, she developed typical PFAPA attacks during this treatment at 3 years of age. We conducted a literature search focusing on English articles with keywords including PFAPA, anakinra, canakinumab, and rilonacept. Five children and one adult patient with PFAPA were found and evaluated. Anakinra was reported to abort PFAPA attacks in children, while the adult patient first responded and then became resistant to anakinra. Canakinumab was effective in preventing febrile attacks in this patient. Failure of canakinumab to prevent PFAPA attacks in our case may arise from the differences in the pathophysiology of PFAPA and FMF. Thus, further experience with higher doses or shorter intervals of canakinumab is needed in children with PFAPA.

Recurrent pericarditis is less scary: the new therapeutic solutions.

Pericarditis is a common inflammatory disease affecting the pericardial sac, resulting from a variety of stimuli that trigger a stereotyped immune response. Generally self-limiting, this condition can be burdened by a significant risk of acute complications and relapses, with recurrence rates affecting up to 30% of patients, especially in the case of diagnostic and therapeutic delay. Therapeutic options in recurrent forms, initially based only on the use of traditional drugs such as colchicine, non-steroidal anti-inflammatory drugs, and corticosteroids, have recently been enriched with new molecules, such as interleukin 1 blockers anakinra and rilonacept, particularly indicated in refractory forms dependent on corticosteroids. Other medically relevant therapeutic possibilities in refractory disease include azathioprine, methotrexate, and intravenous immunoglobulins. This brief review aims to summarize the treatment strategies of recurrent pericarditis in light of the most up-to-date evidence and recommendations.

Autoimmune and Autoinflammatory Pericarditis: Definitions and New Treatments.

PURPOSE OF THE REVIEW: The purpose of the review is to analyze the pathogenetic mechanisms that underlie acute pericarditis, with attention to autoimmune and autoinflammatory pericarditis, and, in addition, to review the available therapeutic armamentarium. RECENT FINDINGS: Several studies have been published on the use of anti-IL-1 drugs in recurrent pericarditis, including anakinra and rilonacept. The latest, the RHAPSODY study, based on the use of rilonacept in recurrent pericarditis, has recently reached phase 3 with promising results in terms of efficacy and safety. Alterations in the function of the inflammasome and the consequent overproduction of IL-1 play a pivotal role in the genesis of autoinflammatory pericarditis. Recent studies added evidence to the importance of anti-IL-1 drugs in the treatment of recurrent pericarditis with raised C-reactive protein. In the era of tailored medicine, anti-IL-1 agents may be very useful in the subset of patients with recurrent pericarditis and a clear inflammatory phenotype.

Interleukin-1 and the NLRP3 Inflammasome in Pericardial Disease.

PURPOSE OF REVIEW: Pericarditis is a generally benign disease, although complications and/or recurrences may occur in up to 30% of cases. New evidence on the pathophysiology of the disease has accumulated in recent years. RECENT FINDINGS: Recently, it has been shown that the activation of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein 3) inflammasome is central in the pathophysiology of pericarditis. These findings derive from clinical data, an experimental animal model of acute pericarditis supporting a role for the NLRP3 inflammasome in pericarditis, and from indirect evidence of inhibitors of NLRP3 inflammasome in clinical trials. Pericarditis is regarded as a stereotypical response to an acute damage of the mesothelial cells of the pericardial layers. NLRP3 inflammasome, a macromolecular structure sensing damage and releasing pro-inflammatory cytokines, is centrally involved as it releases interleukin (IL)-1ß, whose auto-induction feeds an autoinflammatory disease, mostly responsible for recurrences. Colchicine, an inhibitor of NLRP3 inflammasome formation, and IL-1-targeted therapies, such as anakinra and rilonacept, were found to effectively blunt the acute inflammation and reduce the risk for recurrences.

Clinical Trials in Pericardial Disease: New Paradigm Shift.

PURPOSE OF REVIEW: Aim of the review is to discuss the results of major clinical trials and how they can have impact on clinical practice. RECENT FINDINGS: Pericardial diseases have been the Cinderella of cardiovascular diseases for many years, but improvements in the knowledge of etiology and the pathophysiology especially of recurrent pericarditis have led to first clinical trials that have demonstrated the efficacy and safety of colchicine on top of standard anti-inflammatory therapies and of anti-IL-1 agents (anakinra and rilonacept) in corticosteroid-dependent and colchicine-resistant pericarditis. Current pooled data suggest that anti-IL-1 agents should be a first option for corticosteroid-dependent and colchicine-resistant recurrent pericarditis with evidence of systemic inflammation by means of elevated C-reactive protein. This could translate into an upgraded recommendation for these agents in future guidelines. Treatment of pericardial diseases is improving moving towards a more personalized therapy according to the presentation and etiology, and new or old drugs could be important to expand the therapeutic spectrum.

Efficacy and safety of treatments in Familial Mediterranean fever: a systematic review.

Familial Mediterranean fever (FMF) is an autoinflammatory disease, which can be well controlled with lifelong use of colchicine. Since studies dealing with the efficacy and safety of colchicine were conducted mainly in the sixties and seventies of the previous century, it seems that this topic needs to be updated. Recently, an international expert panel was undertaken for the establishment of recommendations on how to manage FMF. We aimed to summarize the efficacy and safety of the current treatments available to prevent FMF attacks and to avert the appearance of amyloidosis secondary to FMF. A systematic review was performed. Two reviewers and methodologist established the protocol of the review and the epidemiological questions in PICO terms. MEDLINE through PubMed, Embase, and Cochrane Central Trials Register all up to May 31, 2014, were searched, and only randomized controlled trials or quasicontrolled trials were accepted. For each study, a judgment on risk of bias was then rated as high, moderate, or low. Of 1222 initially captured publications, 153 articles were studied in detail. Finally, only seven studies met all criteria and were included. Among these seven studies, four were randomized crossover clinical trials of colchicine including a total of 57 patients, one RCT of Andrographis paniculata Herba Nees extract employed in 24 patients, one randomized crossover clinical trial of Rilonacept used in 12 patients, and one RCT of interferon treating 34 acute abdominal attacks in 22 patients. The quality of the colchicine trials was low compared with the other drugs trials. Safety was not clearly mentioned in the trials. Colchicine is an effective treatment in FMF.

Prophylaxis for acute gout flares after initiation of urate-lowering therapy.

This review summarizes evidence relating to prophylaxis for gout flares after the initiation of urate-lowering therapy (ULT). We searched MEDLINE via PubMed for articles published in English from 1963 to 2013 using MEsH terms covering all aspects of prophylaxis for flares. Dispersion of monosodium urate crystals during the initial phase of deposit dissolution with ULT exposes the patient to an increased rate of acute flares that could contribute to poor treatment adherence. Slow titration of ULT might decrease the risk of flares. According to the most recent international recommendation, the two first-line options for prophylaxis are low-dose colchicine (0.5 mg once or twice a day) or low-dose NSAIDs such as naproxen 250 mg orally twice a day. They can be given for up to 6 months. If these drugs are contraindicated, not tolerated or ineffective, low-dose corticosteroids (prednisone or prednisolone) might be used. Recently, reports for four trials described the efficacy of canakinumab and rilonacept, two IL-1 inhibitors, for preventing flares during the initiation of allopurinol therapy. Prophylaxis for flares induced by ULT is an important consideration in gout management. Low-dose colchicine and low-dose NSAIDs are the recommended first-line therapies. Although no IL-1 blockers are approved as prophylactic treatment, this class of drug could become an interesting option for patients with gout with intolerance or contraindication to colchicine, NSAIDs or corticosteroids.

Clinical Utility of Rilonacept for the Treatment of Recurrent Pericarditis: Design, Development, and Place in Therapy.

Recurrent pericarditis (RP) has been traditionally regarded as a "nightmare" for both clinicians and patients. Until approximately a decade ago, available treatments were thin on the ground with non-steroidal anti-inflammatory medications, glucocorticoids, colchicine, and classical immunosuppressants being the only options. The first important step in the tale of RP was the advent of colchicine in clinical practice, which has been shown to halve the rate of first and subsequent pericarditis recurrences. The second major breakthrough advance in this setting was the introduction of interleukin-1 inhibitors based on the recently unveiled autoinflammatory nature of pericarditis. At present, anti-interleukin-1 inhibitors available for clinical use in patients with refractory RP include anakinra and rilonacept, with the latter having obtained FDA approval for this indication. Apart from the remarkable efficacy and good safety profile which is a common feature of all anti-interleukin-1 compounds, rilonacept has the advantage of weekly administration (instead of daily compared to anakinra) which is important in terms of adherence to treatment and improved quality of life albeit at the expense of a higher cost. This review aims to summarize the available evidence on the role of rilonacept in the treatment of RP and the reduction of the recurrences risk.

Sustained Pericarditis Recurrence Risk Reduction With Long-Term Rilonacept.

BACKGROUND: Rilonacept, a once-weekly interleukin-1 alpha and beta cytokine trap, reduced pericarditis recurrence in the phase 3 study, RHAPSODY (Rilonacept Inhibition of Interleukin-1 Alpha and Beta for Recurrent Pericarditis: A Pivotal Symptomatology and Outcomes Study). The RHAPSODY long-term extension further explored recurrent pericarditis natural history and treatment duration decision-making during 24 additional months of open-label rilonacept treatment. METHODS AND RESULTS: Seventy-four patients commenced the long-term extension, with a median (maximum) total rilonacept duration of 22 (35) months. Individually, 18 months after the most proximal pericarditis recurrence, investigators decided to continue rilonacept on study, suspend rilonacept for off-treatment observation (rescue allowed), or discontinue the study. The annualized incidence of pericarditis recurrence on rilonacept up to the 18-month decision milestone was 0.04 events/patient-year versus 4.4 events/patient-year prestudy while on oral therapies. At the 18-month decision milestone, 64% (33/52) continued rilonacept, 15% (8/52) suspended rilonacept for observation, and 21% (11/52) discontinued the study. Among the 33 patients (1/33; 3.0%) continuing rilonacept (median time to recurrence could not be estimated due to too few events), a single recurrence occurred 4 weeks after a treatment interruption. Among patients suspending rilonacept, 75% (6/8) experienced recurrence (median time to recurrence, 11.8 weeks [95% CI, 3.7 weeks to not estimable]). There was a 98% reduction in risk of pericarditis recurrence among patients continuing rilonacept treatment after the 18-month decision milestone versus those suspending treatment for observation (hazard ratio, 0.02; P<0.0001). CONCLUSIONS: In the RHAPSODY long-term extension, continued rilonacept treatment resulted in continued response; treatment suspension at the 18-month decision milestone was associated with pericarditis recurrence. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03737110.