Idiopathic recurrent pericarditis – a new orphan autoinflammatory disease? A retrospective analysis of cases of idiopathic recurrent pericarditis and a design of а double-blind, randomized, placebo-controlled study to evaluate the efficacy and safety of RPH-104 treatment in patients with idiopathic recurrent pericarditis

Aim To analyze cases of idiopathic recurrent pericarditis (IRP) in the structure of pericardial diseases of various origins from patient visits to the Multidisciplinary Federal Center.Material and methods A retrospective analysis of case records was performed for patients admitted to the V.A. Almazov National Medical Research Center from January 1, 2015 through January 1, 2020 for pericardial effusion of different etiologies.Results For the study period, 4 981 new cases of pericardial damage of different etiologies were found. Among these cases, postpericardiotomy syndrome accounted for 4 360 cases and pericarditis for 621 cases. IRP was detected in 34 cases, which amounted to 5.4 %. Based on the study data, the estimated IRP prevalence in the Russian Federation can be 1.1 cases per 100 thousand population.Conclusion IRP should be regarded as a new autoinflammatory disease, the prevalence of which borders on that of adult Still disease and should be addressed within the concept of orphan diseases. Current knowledge of the pathogenesis and data from recent studies demonstrated a great importance of interleukin-1 blockade as a leading mechanism for achieving remission. This has justified conduction of a randomized clinical study at the Center.

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A multicenter, double-blind, dose-ranging, randomized, placebo-controlled study of recombinant human interleukin-1 receptor antagonist in patients with rheumatoid arthritis: Radiologic progression and correlation of genant and larsen scores

Arthritis & Rheumatism ◽

10.1002/1529-0131(200005)43:5<1001::aid-anr7>3.0.co;2-p ◽

2000 ◽

Vol 43 (5) ◽

pp. 1001 ◽

Cited By ~ 252

Author(s):

Yebin Jiang ◽

Harry K. Genant ◽

Iain Watt ◽

Mark Cobby ◽

Barry Bresnihan ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Receptor Antagonist ◽

Interleukin 1 ◽

Controlled Study ◽

Double Blind ◽

Interleukin 1 Receptor Antagonist ◽

Dose Ranging ◽

Radiologic Progression

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Acute recurrent pericarditis: from pathophysiology towards new treatment strategy

Heart ◽

10.1136/heartjnl-2019-316481 ◽

2020 ◽

Vol 106 (14) ◽

pp. 1046-1051 ◽

Cited By ~ 2

Author(s):

Patrice Cacoub ◽

Cindy Marques

Keyword(s):

Immune System ◽

Inflammatory Response ◽

Interleukin 1 ◽

Treatment Algorithm ◽

Real Life ◽

Adaptive Immune System ◽

Immunosuppressive Drugs ◽

Controlled Study ◽

Recurrent Pericarditis ◽

Receptor Antagonists

Acute idiopathic or so-called viral pericarditis is a frequent and usually benign disease, although recurrences are frequent. Data strongly suggest the presence of underlying autoinflammatory and/or autoimmune disorders. It has been reported that there is an inflammatory response of the innate immune system typical of ‘autoinflammatory diseases’, predominantly mediated by interleukin-1 (IL-1). This may result from the activation of the inflammasome by a cardiotropic virus or a non-specific agent. The inflammatory response of the adaptive immune system, typical of ‘autoimmune diseases’—mainly mediated by autoantibodies or autoreactive T lymphocytes—seems also involved as anti-heart or anti-intercalated disk autoantibodies were associated with a higher number of recurrences and hospitalisations. Current guidelines recommend that aspirin/non-steroidal anti-inflammatory drugs for a few weeks should be associated to colchicine for 6 months in recurrent pericarditis. In refractory cases, low-dose corticosteroids or immunosuppressive drugs have been proposed with limited efficacy. Growing evidences suggest a place of IL-1 receptor antagonists in the treatment of recurrent pericarditis. Many retrospective studies, one recent randomised placebo-controlled study and data of a real-life large international registry showed the good efficacy of anakinra with a good safety profile. Other IL-1 receptor antagonists showed promising results (canakinumab, rilonacept). However, IL-1 receptor antagonists’ position in the treatment algorithm of recurrent pericarditis needs further evaluation in larger prospective clinical trials to replicate initial findings as well as to assess safety, cost-effectiveness and long-term efficacy.

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Comparative analysis of the concentrations of proinflammatory cytokines and glycosylated ferritin in patients with idiopathic recurrent pericarditis and adult-onset Still's disease

Russian Journal of Cardiology ◽

10.15829/1560-4071-2021-4715 ◽

2021 ◽

Vol 26 (11) ◽

pp. 4715

Author(s):

V. Yu. Myachikova ◽

A. L. Maslyansky ◽

O. Yu. Tkachenko ◽

M. Yu. Pervakova ◽

E. S. Kuvardin ◽

...

Keyword(s):

Proinflammatory Cytokines ◽

Interleukin 1 ◽

Study Groups ◽

Adult Onset Still’S Disease ◽

Adult Onset ◽

Still’S Disease ◽

Recurrent Pericarditis ◽

Still's Disease ◽

Pericardial Diseases ◽

Adult Onset Still's Disease

Idiopathic recurrent pericarditis (IRP) and adult-onset Still's disease (AOSD) are polygenic autoinflammatory diseases, in the pathogenesis of which pro-inflammatory cytokines from the interleukin-1 superfamily play a central role.Aim. To compare serum concentrations of proinflammatory cytokines and glycosylated ferritin (GF) in patients with IRP and AOSD during an exacerbation.Material and methods. The study included 15 patients with AOSD, 15 — IRP. The diagnosis of AOSD was established using the Yamaguchi criteria (1992). IRP was diagnosed in accordance with the 2015 European Society of Cardiology on the diagnosis and management of pericardial diseases. Blood sampling from all patients was carried out during the recurrence period prior to the anti-inflammatory therapy initiation. The serum levels of interleukin-1β (IL-1β), interleukin-6 (IL-6), interleukin-18 (IL-18), procalcitonin, total ferritin and GF was assessed. The results obtained were compared with levels of biochemical parameters, high-sensitivity C-reactive protein (CRP), as well as with white blood cell (WBC) and neutrophil counts.Results. The median age in the AOSD group was 28 years, and the IRP — 55 years. An increase WBC count >10*109/L was detected in 10 and 9 patients in the AOSD and IRP groups, respectively. The concentration of CRP was increased in all patients and did not differ in the study groups (p=0,836).The highest values of ferritin and GF levels were found in the AOSD group (1416 ng/ml vs 408 ng/ml, p=0,008) and (12% vs 33,9%, p=0,067), respectively. In both groups, increased concentrations of IL-6 and IL-18 were determined. In the AOSD group, the concentration of IL-18 was higher than in the IRP group (2114 pg/ml vs 161,5 pg/ml, p<0,001). IL-6 concentrations in the study groups did not differ (33,9 pg/ml vs 24,9 pg/ml, p=0,4). IL-1β serum concentration in all subjects corresponded to normal values.Correlation analysis in the AOSD group revealed a direct relationship between the IL-18 and ferritin concentrations (rs=0,73, p=0,03).Conclusion. The study established a similar pattern of changes in inflammatory biomarkers in patients with AOSD and IRI. The most informative marker of inflammation was IL-18.

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P3349RHAPSODY: a pivotal phase 3 trial to assess efficacy and safety of rilonacept, an interleukin 1 alpha and beta blocker, in patients with recurrent pericarditis

European Heart Journal ◽

10.1093/eurheartj/ehz745.0225 ◽

2019 ◽

Vol 40 (Supplement_1) ◽

Author(s):

M Imazio ◽

A Klein ◽

A Brucato ◽

P Cremer ◽

M Lewinter ◽

...

Keyword(s):

Clinical Response ◽

Pain Score ◽

Rating Scale ◽

Interleukin 1 ◽

Efficacy And Safety ◽

Recurrent Pericarditis ◽

Phase 3 ◽

Pivotal Phase ◽

Double Blind ◽

Double Blind Placebo

Abstract Background Recurrent pericarditis (RP) is managed with nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids (CS), and colchicine; up to 15% of pericarditis patients experience multiple recurrences. Interleukin 1 (IL-1) is an important cytokine in the pathophysiology of RP. Rilonacept (KPL-914) is a recombinant fusion protein which binds IL-1α and IL-1β. An ongoing Phase 2 study of rilonacept demonstrated improvements in RP symptoms and inflammation. Purpose To evaluate the efficacy and safety of subcutaneous (SC) rilonacept in patients with RP in a Phase 3, randomized, placebo-controlled trial. Methods RHAPSODY is a double-blind, placebo-controlled, randomized-withdrawal trial; ∼50 patients will be enrolled (Figure). Patients (≥12 y) must present with at least a third pericarditis episode (all etiologies except infectious and malignant) characterized by a pain score ≥4 on the 11-point Numeric Rating Scale (NRS) and C-reactive protein (CRP) ≥1 mg/dL at screening. Patients may be receiving stable doses of analgesics, NSAIDs, colchicine, and/or CS. After a loading dose (320 mg SC in adults and 4.4 mg/kg SC in children), all patients will receive weekly rilonacept (160 mg SC in adults and 2.2 mg/kg SC in children) during the run-in period. Patients able to taper and discontinue concomitant pericarditis medications and achieve clinical response (mean daily NRS score ≤2.0 during the 7 days before randomization and CRP level ≤0.5 mg/dL) will be randomized 1:1 in a blinded fashion to continued rilonacept or matching placebo weekly SC injections. Investigators may choose different treatments for pericarditis recurrences based on patient clinical status, including bailout rilonacept, while maintaining the blind to prior treatment assignment. The primary efficacy endpoint is time to pericarditis recurrence (adjudicated by an independent committee) in the randomized-withdrawal portion of the study. Secondary efficacy endpoints are the proportion of patients maintaining a clinical response, percentage of days with NRS pain score ≤1, and percentage of patients with no-to-minimal pericarditis symptoms based on patient global assessment. Safety evaluations include adverse events monitoring, physical examinations, and laboratory tests. Figure 1 Conclusions RHAPSODY is a pivotal Phase 3 trial evaluating the efficacy and safety of rilonacept in patients with RP using a double-blind, placebo-controlled, randomized-withdrawal design. The results of this study may inform the management of RP. Acknowledgement/Funding This study is sponsored by Kiniksa Pharmaceuticals, Ltd.

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Inborn error of immunity as the cause of recurrent pericarditis

BMJ Case Reports ◽

10.1136/bcr-2020-241449 ◽

2021 ◽

Vol 14 (5) ◽

pp. e241449

Author(s):

Zane Lucane ◽

Dace Freidenberga ◽

Natalja Kurjane

Keyword(s):

Positron Emission Tomography ◽

Inborn Error ◽

Laboratory Tests ◽

Autoinflammatory Disease ◽

Interleukin 1 ◽

Emission Tomography ◽

Recurrent Pericarditis ◽

Positron Emission ◽

Mediterranean Fever ◽

Inflammatory Drugs

Familial Mediterranean fever (FMF) is an autoinflammatory disease caused by a pyrin dysfunction, leading to uncontrolled interleukin-1 production that triggers the attacks. Here we report a case of a 36-year-old female patient repeatedly admitted to the cardiology ward with recurrent episodes of pericarditis, with intervals of 1 and 2 months between the episodes. During the attacks, chest pain and fever were the only symptoms. Following the administration of steroids and non-steroidal anti-inflammatory drugs, the patient became afebrile. She also had lymphoma and thyroid carcinoma in anamnesis essential for differential diagnosis. Laboratory tests for infection and autoimmune disease were all negative, and the positron emission tomography–CT scan did not reveal lymphoma relapse. Genetic testing revealed a mutation in the MEFV gene. It is very rare for pericarditis to be the first and only manifestation of FMF.

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Carbohydrate and the cytokine response to 2.5 h of running

Journal of Applied Physiology ◽

10.1152/jappl.1997.82.5.1662 ◽

1997 ◽

Vol 82 (5) ◽

pp. 1662-1667 ◽

Cited By ~ 188

Author(s):

S. L. Nehlsen-Cannarella ◽

O. R. Fagoaga ◽

D. C. Nieman ◽

D. A. Henson ◽

D. E. Butterworth ◽

...

Keyword(s):

Significant Interaction ◽

Plasma Cortisol ◽

Interleukin 1 ◽

Cytokine Response ◽

Controlled Study ◽

Double Blind ◽

Marathon Runners ◽

Carbohydrate Ingestion ◽

Cytokine Responses ◽

Cytokine Levels

Nehlsen-Cannarella, S. L., O. R. Fagoaga, D. C. Nieman, D. A. Henson, D. E. Butterworth, R. L. Schmitt, E. M. Bailey, B. J. Warren, A. Utter, and J. M. Davis. Carbohydrate and the cytokine response to 2.5 h of running. J. Appl. Physiol. 82(5): 1662–1667, 1997.—This randomized, double-blind, placebo-controlled study was designed to determine the influence of 6% carbohydrate (C) vs. placebo (P) beverage ingestion on cytokine responses (5 total samples over 9 h) to 2.5 h of high-intensity running (76.7 ± 0.4% maximal O2uptake) by 30 experienced marathon runners. For interleukin-6 (IL-6), a difference in the pattern of change between groups was found, highlighted by a greater increase in P vs. C immediately postrun (753 vs. 421%) and 1.5 h postrun (193 vs. 86%) [ F(4,112) = 3.77, P = 0.006]. For interleukin-1-receptor antagonist (IL-1ra), a difference in the pattern of change between groups was found, highlighted by a greater increase in P vs. C 1.5 h postrun (231 vs. 72%) [ F(2,50) = 6.38, P = 0.003]. No significant interaction effects were seen for bioactive IL-6 or IL-1β. The immediate postrun plasma glucose concentrations correlated negatively with those of plasma cortisol ( r = −0.67, P < 0.001); postrun plasma cortisol ( r = 0.70, P < 0.001) and IL-6 levels ( r = 0.54, P = 0.003) correlated positively with levels of IL-1ra. Taken together, the data indicate that carbohydrate ingestion attenuates cytokine levels in the inflammatory cascade in response to heavy exertion.

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