Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis.

BACKGROUND: Interleukin-1 has been implicated as a mediator of recurrent pericarditis. The efficacy and safety of rilonacept, an interleukin-1α and interleukin-1ß cytokine trap, were studied previously in a phase 2 trial involving patients with recurrent pericarditis. METHODS: We conducted a phase 3 multicenter, double-blind, event-driven, randomized-withdrawal trial of rilonacept in patients with acute symptoms of recurrent pericarditis (as assessed on a patient-reported scale) and systemic inflammation (as shown by an elevated C-reactive protein [CRP] level). Patients presenting with pericarditis recurrence while receiving standard therapy were enrolled in a 12-week run-in period, during which rilonacept was initiated and background medications were discontinued. Patients who had a clinical response (i.e., met prespecified response criteria) were randomly assigned in a 1:1 ratio to receive continued rilonacept monotherapy or placebo, administered subcutaneously once weekly. The primary efficacy end point, assessed with a Cox proportional-hazards model, was the time to the first pericarditis recurrence. Safety was also assessed. RESULTS: A total of 86 patients with pericarditis pain and an elevated CRP level were enrolled in the run-in period. During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days. A total of 61 patients underwent randomization. During the randomized-withdrawal period, there were too few recurrence events in the rilonacept group to allow for the median time to the first adjudicated recurrence to be calculated; the median time to the first adjudicated recurrence in the placebo group was 8.6 weeks (95% confidence interval [CI], 4.0 to 11.7; hazard ratio in a Cox proportional-hazards model, 0.04; 95% CI, 0.01 to 0.18; P<0.001 by the log-rank test). During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group. In the run-in period, 4 patients had adverse events leading to the discontinuation of rilonacept therapy. The most common adverse events with rilonacept were injection-site reactions and upper respiratory tract infections. CONCLUSIONS: Among patients with recurrent pericarditis, rilonacept led to rapid resolution of recurrent pericarditis episodes and to a significantly lower risk of pericarditis recurrence than placebo. (Funded by Kiniksa Pharmaceuticals; RHAPSODY ClinicalTrials.gov number, NCT03737110.).

Molecular Mechanisms of Fetal and Neonatal Lupus: A Narrative Review of an Autoimmune Disease Transferal across the Placenta.

This study, conducted by searching keywords such as "maternal lupus", "neonatal lupus", and "congenital heart block" in databases including PubMed and Scopus, provides a detailed narrative review on fetal and neonatal lupus. Autoantibodies like anti-Ro/SSA and anti-La/SSB may cross the placenta and cause complications in neonates, such as congenital heart block (CHB). Management options involve hydroxychloroquine, which is able to counteract some of the adverse events, although the drug needs to be used carefully because of its impact on the QTc interval. Advanced pacing strategies for neonates with CHB, especially in severe forms like hydrops, are also assessed. This review emphasizes the need for interdisciplinary care by rheumatologists, obstetricians, and pediatricians in order to achieve the best maternal and neonatal health in lupus pregnancies. This multidisciplinary approach seeks to improve the outcomes and management of the disease, decreasing the burden on mothers and their infants.

Pediatric Recurrent Pericarditis: Appropriateness of the Standard of Care and Response to IL-1 Blockade.

OBJECTIVE: To analyze, in a cohort of pediatric patients with recurrent pericarditis undergoing anti-interleukin (IL)-1 treatment: the agent and dosing used as first-line treatment, the long-term efficacy of IL-1 blockers, the percentage of patients achieving a drug-free remission, and the presence of variables associated with drug-free remission. STUDY DESIGN: Data were collected from patients' charts. The annualized relapse rate (ARR) was used for evaluation of treatment efficacy, and bivariate logistic regression analysis was used for variables associated with drug-free remission. RESULTS: Fifty-eight patients, treated between 2008 and 2018, were included in the study (mean follow-up. 2.6 years). Of the 56 patients treated with first-line drugs, 14 not responsive patients were underdosed. Fifty-seven patients were treated with anakinra: the ARR before and during daily treatment was 3.05 and 0.28, respectively (P < .0001); an increase to 0.83 was observed after the reduction/withdrawal of treatment (P < .0001). The switch from anakinra to canakinumab (5 patients) was associated to an increase of the ARR (0.49 vs 1.46), but without statistical significance (P = .215). At last follow-up, only 9 of the 58 patients had withdrawn all treatments. With the limits of a retrospective study and the heterogeneity between the patients enrolled in the study, a shorter duration of treatment with anakinra was the only variable associated with drug-free remission. CONCLUSIONS: This study shows that most pediatric patients with recurrent pericarditis needing IL-1 blockade received an inadequate treatment with first-line agents. The effectiveness of anakinra is supported by this study, but few patients achieved drug-free remission. The different rate of response to anakinra and canakinumab may suggest a possible role of IL-1α in the pathogenesis of recurrent pericarditis.

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.

Mortality among Italians and immigrants with COVID-19 hospitalised in Milan, Italy: data from the Luigi Sacco Hospital registry.

BACKGROUND: To compare differences in the probability of COVID-19-related death between native Italians and immigrants hospitalised with COVID-19. METHODS: This retrospective study of prospectively collected data was conducted at the ASST Fatebenefratelli-Sacco Hospital in Milan, Italy, between 21 February and 31 November 2020. Uni- and multivariable Cox proportional hazard models were used to assess the impact of the patients' origin on the probability of COVID-19-related death. RESULTS: The study population consisted of 1,179 COVID-19 patients: 921 Italians (78.1%) and 258 immigrants (21.9%) who came from Latin America (99, 38%), Asia (72, 28%), Africa (50, 19%) and central/eastern Europe (37, 14%). The Italians were significantly older than the immigrants (median age 70 years, interquartile range (IQR) 58-79 vs 51 years, IQR 41-60; p < 0.001), and more frequently had one or more co-morbidities (79.1% vs 53.9%; p < 0.001). Mortality was significantly greater among the Italians than the immigrants as a whole (26.6% vs 12.8%; p < 0.001), and significantly greater among the immigrants from Latin America than among those from Asia, Africa or central/eastern Europe (21% vs 8%, 6% and 8%; p = 0.016). Univariable analysis showed that the risk of COVID-19-related death was lower among the immigrants (hazard ratio [HR] 0.43, 95% confidence interval [CI] 0.30-0.63; p < 0.0001], but the risk of Latin American immigrants did not significantly differ from that of the Italians (HR 0.74, 95% CI 0.47-1.15; p = 0.183). However, after adjusting for potential confounders, multivariable analysis showed that there was no difference in the risk of death between the immigrants and the Italians (adjusted HR [aHR] 1.04, 95% CI 0.70-1.55; p = 0.831), but being of Latin American origin was independently associated with an increased risk of death (aHR 1.95, 95% CI 1.17-3.23; p = 0.010). CONCLUSIONS: Mortality was lower among the immigrants hospitalised with COVID-19 than among their Italian counterparts, but this difference disappeared after adjusting for confounders. However, the increased risk of death among immigrants of Latin American origin suggests that COVID-19 information and prevention initiatives need to be strengthened in this sub-population.

Diagnosis and treatment of cardiac amyloidosis: a position statement of the ESC Working Group on Myocardial and Pericardial Diseases.

Cardiac amyloidosis is a serious and progressive infiltrative disease that is caused by the deposition of amyloid fibrils at the cardiac level. It can be due to rare genetic variants in the hereditary forms or as a consequence of acquired conditions. Thanks to advances in imaging techniques and the possibility of achieving a non-invasive diagnosis, we now know that cardiac amyloidosis is a more frequent disease than traditionally considered. In this position paper the Working Group on Myocardial and Pericardial Disease proposes an invasive and non-invasive definition of cardiac amyloidosis, addresses clinical scenarios and situations to suspect the condition and proposes a diagnostic algorithm to aid diagnosis. Furthermore, we also review how to monitor and treat cardiac amyloidosis, in an attempt to bridge the gap between the latest advances in the field and clinical practice.

Impact of gender on patients hospitalized for SARS-COV-2 infection: A prospective observational study.

Biological sex could affect the natural history of severe acute respiratory syndrome coronavirus 2 infection. We enrolled all COVID-19 patients admitted to two COVID-19 hospitals in Milan in a prospective observational study. The primary outcome was death during the study period and the secondary outcome was critical disease at hospital admission. The association(s) between clinically relevant, noncollinear variables, and the primary outcome was assessed with uni- and multivariable Logistic regression models. A total of 520 patients were hospitalized of whom 349 (67%) were males with a median age 61 (interquartile range: 50-72). A higher proportion of males presented critically ill when compared to females (30.1% vs. 18.7%, p < .046). Death occurred in 86 (24.6%) males and 27 (15.8%) females (p = .024). In multivariable analysis age (per 10 years more) (adjusted odds ratio [AOR]: 1.83 [95% confidence interval {CI}: 1.42-2.35], p < .0001), obesity (AOR: 2.17 [95% CI: 1.10-4.31], p = .026), critical disease at hospital admission (AOR 6.34 [95% CI: 3.50-11.48], p < .0001) were independently associated to higher odds of death whereas gender was not. In conclusion, a higher proportion of males presented critically ill at hospital admission. Age, critical disease at hospital admission, obesity, anemia, D-dimer, estimated glomerular filtration rate, lactate dehydrogenase, and creatine kinase predicted death in hospitalized COVID-19 patients.

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.

RHAPSODY: Rationale for and design of a pivotal Phase 3 trial to assess efficacy and safety of rilonacept, an interleukin-1α and interleukin-1ß trap, in patients with recurrent pericarditis.

Recurrent pericarditis (RP) occurs in 15% to 30% of patients following a first episode, despite standard treatment with nonsteroidal anti-inflammatory drugs, colchicine, and corticosteroids; many patients become dependent on corticosteroids. Rilonacept (KPL-914), an interleukin-1α and ß inhibitor, is in development for the treatment of RP. RHAPSODY, a double-blind, placebo-controlled, randomized-withdrawal (RW) pivotal Phase 3 trial (NCT03737110), enrolls patients 12 years or older presenting with at least a third pericarditis episode, pericarditis pain score ≥4 (11-point numeric rating scale [NRS]), and C-reactive protein ≥1 mg/dL at screening. After a subcutaneous loading dose (adults, 320 mg; children, 4.4 mg/kg), all patients receive blinded weekly subcutaneous rilonacept (adults, 160 mg; children, 2.2 mg/kg) during the run-in period. Patients must taper and discontinue concomitant pericarditis medications during the blinded run-in period and achieve clinical response (C-reactive protein ≤0.5 mg/dL and weekly average NRS ≤2.0 during the 7 days prior to and including the day of randomization) by end of the run-in (while on rilonacept monotherapy) to be randomized to either continued rilonacept or placebo in the RW period. Primary efficacy end point was time to adjudicated pericarditis recurrence during the RW period; secondary efficacy end points were proportion of patients maintaining clinical response, percentage of days with NRS ≤2, and percentage of patients with no-to-minimal pericarditis symptoms at week 16 of the RW period. Safety evaluations include adverse event monitoring, physical examinations, and laboratory tests. The RHAPSODY trial will evaluate the efficacy and safety of rilonacept in the treatment of RP to improve outcomes and patient health-related quality of life.

Association between treatment with colchicine and improved survival in a single-centre cohort of adult hospitalised patients with COVID-19 pneumonia and acute respiratory distress syndrome.

OBJECTIVES: The outbreak of COVID-19 posed the issue of urgently identifying treatment strategies. Colchicine was considered for this purpose based on well-recognised anti-inflammatory effects and potential antiviral properties. In the present study, colchicine was proposed to patients with COVID-19, and its effects compared with 'standard-of-care' (SoC). METHODS: In the public hospital of Esine, northern Italy, 140 consecutive inpatients, with virologically and radiographically confirmed COVID-19 admitted in the period 5-19 March 2020, were treated with 'SoC' (hydroxychloroquine and/or intravenous dexamethasone; and/or lopinavir/ritonavir). They were compared with 122 consecutive inpatients, admitted between 19 March and 5 April 2020, treated with colchicine (1 mg/day) and SoC (antiviral drugs were stopped before colchicine, due to potential interaction). RESULTS: Patients treated with colchicine had a better survival rate as compared with SoC at 21 days of follow-up (84.2% (SE=3.3%) vs 63.6% (SE=4.1%), p=0.001). Cox proportional hazards regression survival analysis showed that a lower risk of death was independently associated with colchicine treatment (HR=0.151 (95% CI 0.062 to 0.368), p<0.0001), whereas older age, worse PaO2/FiO2, and higher serum levels of ferritin at entry were associated with a higher risk. CONCLUSION: This proof-of-concept study may support the rationale of use of colchicine for the treatment of COVID-19. Efficacy and safety must be determined in controlled clinical trials.

Fluorinated steroids are not superior to any treatment to ameliorate the outcome of autoimmune mediated congenital heart block: a systematic review of the literature and meta-analysis.

OBJECTIVES: Fluorinated steroids are largely the therapeutic approach of autoimmune mediated congenital heart block (CHB). We performed a meta-analysis to assess the efficacy of fluorinated steroids for the treatment of CHB. METHODS: Studies evaluating the efficacy of fluorinated steroids versus no treatment in CHB patients were identified in electronic databases. Random-effects model was used to pool odds ratio (OR) (with 95% CI) of live births as the primary outcome. ORs of CHB progression, pacemaker implantation and extranodal disease were the secondary outcome. Subgroup analysis according to CHB grade and study type was performed. RESULTS: Data from nine studies involving 747 patients were analysed. The overall live birth rates were 86.8% and 86.7%, respectively, in the fluorinated steroids exposed foetuses and in the non-exposed ones. Fluorinated steroids did not ameliorate overall survival in CHB (OR 1.02; 95% CI: 0.65-1.61) with any significant statistical heterogeneity between studies (I2 0%, p=0.45). No significant differences for the progression of CHB, the pacing and the presence of extranodal disease were observed. Subgroup analysis revealed a significant protective role of fluorinated steroids for survival in 3rd degree CHB and for pacing in monocentric studies, OR 4.07; 95% CI: 1.10-15.08 and OR 0.15; 95% CI: 0.02-0.99, respectively. CONCLUSIONS: This meta-analysis shows that fluorinated steroids are not superior to any treatment in patients with CHB in terms of live birth, prevention of progression of incomplete CHB, pacemaker implantation and extranodal disease. Thus, considering their side effects, their use in CHB patients should be discouraged.

Novel Pharmacotherapies for Recurrent Pericarditis: Current Options in 2020.

Recent advances have shown impressive results by anti-interleukin 1 (IL-1) agents in refractory idiopathic recurrent pericarditis. PURPOSE OF REVIEW: We critically discuss the current state of the art of therapy of relapsing pericarditis, with a focus on new pharmacological approaches and on specific clinical settings such as pregnancy, pediatric patients, and secondary forms of relapsing pericarditis. RECENT FINDINGS: Antagonism of the IL-1 is highly effective in idiopathic recurrent pericarditis with autoinflammatory features. Currently, available anti-IL-1 agents are anakinra and canakinumab. Rilonacept is another IL-1 antagonist, currently studied in the phase-3 clinical trial RHAPSODY. Available data suggest similar efficacy and safety profiles of these three agents, although only anakinra has been tested in randomized clinical trials. These agents have slightly different pharmacological properties, being canakinumab a specific IL-1ß antagonist while anakinra and rilonacept are unselective IL-1α and IL-1ß blockers. To date, there is no evidence that specificity against IL-1ß affects safety and efficacy in patients with relapsing pericarditis, although it has been proposed that unspecific blockage might be useful in severe disease. Anakinra is the first anti-IL-1 agent with well-documented efficacy and safety in adult and pediatric patients with idiopathic relapsing pericarditis. Other anti-IL-1 agents are currently under study. Future research should clarify the optimal duration of therapy and tapering schedule of treatment with these agents. Moreover, biomarkers would be required to understand which patients will benefit from early administration of IL-1 blockers due to refractoriness to conventional therapy and which others will suffer from recurrences during the tapering of these agents. Lastly, future studies should focus on the subjects with the autoimmune or the pauci-inflammatory phenotype of idiopathic refractory pericarditis.

Use of Interleukin-1 Blockers in Pericardial and Cardiovascular Diseases.

PURPOSE OF REVIEW: This review aims to summarize the role of the interleukin-1 (IL-1) blocking agents in cardiovascular diseases, briefly describing the pathogenetic rationale and the most relevant clinical studies. RECENT FINDINGS: IL-1 is a pivotal cytokine of the innate immune system. Anti-IL-1 agents are currently used for the treatment of several autoimmune and autoinflammatory conditions. Recently, the role of IL-1 has also emerged in cardiovascular diseases. Indeed, two recent randomized controlled trials have shown that the IL-1 receptor antagonist anakinra is effective for the treatment of idiopathic recurrent pericarditis and the IL-1ß blocking agent canakinumab is effective in reducing myocardial infarction in people at risk. Interestingly, interfering with IL-1 has proved to be also effective in other cardiovascular manifestations, such as myocarditis, arrhythmias, and heart failure. Blocking the IL-1 pathway is a possible new therapeutic strategy, potentially leading to innovative therapies in many acute and chronic cardiovascular diseases.

Acute rhabdomyolysis and delayed pericardial effusion in an Italian patient with Ebola virus disease: a case report.

BACKGROUND: During the 2013-2016 West Africa Ebola virus disease (EVD) epidemic, some EVD patients, mostly health care workers, were evacuated to Europe and the USA. CASE PRESENTATION: In May 2015, a 37-year old male nurse contracted Ebola virus disease in Sierra Leone. After Ebola virus detection in plasma, he was medically-evacuated to Italy. At admission, rhabdomyolysis was clinically and laboratory-diagnosed and was treated with aggressive hydration, oral favipiravir and intravenous investigational monoclonal antibodies against Ebola virus. The recovery clinical phase was complicated by a febrile thrombocytopenic syndrome with pericardial effusion treated with corticosteroids for 10 days and indomethacin for 2 months. No evidence of recurrence is reported. CONCLUSIONS: A febrile thrombocytopenic syndrome with pericardial effusion during the recovery phase of EVD appears to be uncommon. Clinical improvement with corticosteroid treatment suggests that an immune-mediated mechanism contributed to the pericardial effusion.

A randomized trial of colchicine for acute pericarditis.

BACKGROUND: Colchicine is effective for the treatment of recurrent pericarditis. However, conclusive data are lacking regarding the use of colchicine during a first attack of acute pericarditis and in the prevention of recurrent symptoms. METHODS: In a multicenter, double-blind trial, eligible adults with acute pericarditis were randomly assigned to receive either colchicine (at a dose of 0.5 mg twice daily for 3 months for patients weighing >70 kg or 0.5 mg once daily for patients weighing ≤70 kg) or placebo in addition to conventional antiinflammatory therapy with aspirin or ibuprofen. The primary study outcome was incessant or recurrent pericarditis. RESULTS: A total of 240 patients were enrolled, and 120 were randomly assigned to each of the two study groups. The primary outcome occurred in 20 patients (16.7%) in the colchicine group and 45 patients (37.5%) in the placebo group (relative risk reduction in the colchicine group, 0.56; 95% confidence interval, 0.30 to 0.72; number needed to treat, 4; P<0.001). Colchicine reduced the rate of symptom persistence at 72 hours (19.2% vs. 40.0%, P=0.001), the number of recurrences per patient (0.21 vs. 0.52, P=0.001), and the hospitalization rate (5.0% vs. 14.2%, P=0.02). Colchicine also improved the remission rate at 1 week (85.0% vs. 58.3%, P<0.001). Overall adverse effects and rates of study-drug discontinuation were similar in the two study groups. No serious adverse events were observed. CONCLUSIONS: In patients with acute pericarditis, colchicine, when added to conventional antiinflammatory therapy, significantly reduced the rate of incessant or recurrent pericarditis. (Funded by former Azienda Sanitaria Locale 3 of Turin [now Azienda Sanitaria Locale 2] and Acarpia; ICAP ClinicalTrials.gov number, NCT00128453.).

Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial.

Importance: Anakinra, an interleukin 1ß recombinant receptor antagonist, may have potential to treat colchicine-resistant and corticosteroid-dependent recurrent pericarditis. Objective: To determine the efficacy of anakinra for colchicine-resistant and corticosteroid-dependent recurrent pericarditis. Design, Setting, and Participants: The Anakinra-Treatment of Recurrent Idiopathic Pericarditis (AIRTRIP) double-blind, placebo-controlled, randomized withdrawal trial (open label with anakinra followed by a double-blind withdrawal step with anakinra or placebo until recurrent pericarditis occurred) conducted among 21 consecutive patients enrolled at 3 Italian referral centers between June and November 2014 (end of follow-up, October 2015). Included patients had recurrent pericarditis (with ≥3 previous recurrences), elevation of C-reactive protein, colchicine resistance, and corticosteroid dependence. Interventions: Anakinra was administered at 2 mg/kg per day, up to 100 mg, for 2 months, then patients who responded with resolution of pericarditis were randomized to continue anakinra (n = 11) or switch to placebo (n = 10) for 6 months or until a pericarditis recurrence. Main Outcomes and Measures: The primary outcomes were recurrent pericarditis and time to recurrence after randomization. Results: Eleven patients (7 female) randomized to anakinra had a mean age of 46.5 (SD, 16.3) years; 10 patients (7 female) randomized to placebo had a mean age of 44 (SD, 12.5) years. All patients were followed up for 12 months. Median follow-up was 14 (range, 12-17) months. Recurrent pericarditis occurred in 9 of 10 patients (90%; incidence rate, 2.06% of patients per year) assigned to placebo and 2 of 11 patients (18.2%; incidence rate, 0.11% of patients per year) assigned to anakinra, for an incidence rate difference of -1.95% (95% CI, -3.3% to -0.6%). Median flare-free survival (time to flare) was 72 (interquartile range, 64-150) days after randomization in the placebo group and was not reached in the anakinra group (P <.001). During anakinra treatment, 20 of 21 patients (95.2%) experienced transient local skin reactions: 1 (4.8%) herpes zoster, 3 (14.3%) transaminase elevation, and 1 (4.8%) ischemic optic neuropathy. No patient permanently discontinued the active drug. No adverse events occurred during placebo treatment. Conclusion and Relevance: In this preliminary study of patients with recurrent pericarditis with colchicine resistance and corticosteroid dependence, the use of anakinra compared with placebo reduced the risk of recurrence over a median of 14 months. Larger studies are needed to replicate these findings as well as to assess safety and longer-term efficacy. Trial Registration: clinicaltrials.gov Identifier: NCT02219828.

Efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis (CORP-2): a multicentre, double-blind, placebo-controlled, randomised trial.

BACKGROUND: Colchicine is effective for the treatment of acute pericarditis and first recurrences. However, conclusive data are lacking for the efficacy and safety of colchicine for treatment of multiple recurrences of pericarditis. METHODS: We did this multicentre, double-blind trial at four general hospitals in northern Italy. Adult patients with multiple recurrences of pericarditis (≥two) were randomly assigned (1:1) to placebo or colchicine (0·5 mg twice daily for 6 months for patients weighing more than 70 kg or 0·5 mg once daily for patients weighing 70 kg or less) in addition to conventional anti-inflammatory treatment with aspirin, ibuprofen, or indometacin. Permuted block randomisation (size four) was done with a central computer-based automated sequence. Patients and all investigators were masked to treatment allocation. The primary outcome was recurrent pericarditis in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT00235079. FINDINGS: 240 patients were enrolled and 120 were assigned to each group. The proportion of patients who had recurrent pericarditis was 26 (21·6%) of 120 in the colchicine group and 51 (42·5%) of 120 in the placebo group (relative risk 0·49; 95% CI 0·24-0·65; p=0·0009; number needed to treat 5). Adverse effects and discontinuation of study drug occurred in much the same proportions in each group. The most common adverse events were gastrointestinal intolerance (nine patients in the colchicine group vs nine in the placebo group) and hepatotoxicity (three vs one). No serious adverse events were reported. INTERPRETATION: Colchicine added to conventional anti-inflammatory treatment significantly reduced the rate of subsequent recurrences of pericarditis in patients with multiple recurrences. Taken together with results from other randomised controlled trials, these findings suggest that colchicine should be probably regarded as a first-line treatment for either acute or recurrent pericarditis in the absence of contraindications or specific indications. FUNDING: Azienda Sanitaria 3 of Torino (now ASLTO2).