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.

Behçet's disease uveitis: is there a need for new emerging drugs?

Introduction: Behçet's disease uveitis (BDU) is a potentially blinding disorder. Systemic treatment with disease-modifying anti-rheumatic drugs (DMARDs) is mandatory in patients with intraocular inflammation involving the posterior segment of the eye. Areas covered: This article discusses existing systemic treatment with corticosteroids and conventional and biologic DMARDs as well as adjunctive local therapy in BDU. An overview is provided for a wide range of biologic DMARDs that have shown promise or investigated in clinical trials. Most recently introduced biologic DMARDs and targeted synthetic DMARDs are also reviewed for their potential in the treatment of BDU. Expert opinion: The prognosis of patients with BDU has remarkably improved after the introduction of biologic DMARDs. An expanding therapeutic armamentarium will allow treatment of most refractory cases. The ultimate goal is to provide drug-free remission with preservation of 20/20 vision.

Treatment of Idiopathic Recurrent Pericarditis With Goflikicept: Phase II/III Study Results.

BACKGROUND: Idiopathic recurrent pericarditis (IRP) is a rare autoinflammatory disease. Interleukin (IL)-1α and IL-1ß are the pivotal cytokines in the pathophysiology of acute pericarditis and its recurrence. We created a phase II/III study with a new IL-1 inhibitor-goflikicept in IRP. OBJECTIVES: This study sought to evaluate the efficacy and safety of goflikicept treatment in patients with IRP. METHODS: We conducted a 2-center open-label study of goflikicept in patients with IRP with and without recurrence at time of enrollment. The study consisted of 4 periods: screening, run-in (open-label treatment period), randomized withdrawal, and follow-up. Patients with clinical response to goflikicept in the run-in period were randomized (1:1) to a placebo-controlled withdrawal period, where the time to first pericarditis recurrence (primary endpoint) was evaluated. RESULTS: We enrolled 22 patients, and 20 of these patients were randomized. Reduction of C-reactive protein level accompanied by reduction of chest pain and pericardial effusion compared to baseline was demonstrated during the run-in period. Recurrence of pericarditis occurred in 9 of 10 patients in the placebo group, and there were no recurrence events in goflikicept group within 24 weeks after randomization (P < 0.001). A total of 122 adverse events were reported in 21 patients (95.5%), with no deaths and no new safety signals identified for goflikicept. CONCLUSIONS: Treatment with goflikicept prevented recurrences and maintained IRP remission with a favorable risk-benefit ratio. Goflikicept reduced the risk of recurrence compared with placebo. (Study to Evaluate the Efficacy and Safety of RPH-104 Treatment in Patients With Idiopathic Recurrent Pericarditis; NCT04692766).

Comparison of Analgesic Efficacy between Epidural and Perineural Administration of Autologous Conditioned Serum in the Conservative Treatment of Low Back Pain Due to Lumbar Degenerative Disc Disease: A Randomized, Open-Label, Controlled Clinical Trial.

Lumbar degenerative disc disease (LDDD) is widely acknowledged as a significant contributor to low back pain (LBP), which is a prevalent and debilitating health condition affecting millions of individuals worldwide. The pathogenesis of LDDD and associated pain mechanisms are thought to be mediated by inflammatory mediators. Autologous conditioned serum (ACS, Orthokine) may be used for symptomatic treatment of LBP due to LDDD. This study aimed to compare the analgesic efficacy and safety of two routes of ACS administration, perineural (periarticular) and epidural (interlaminar), in the conservative treatment of LBP. This study used an open-label, randomized, controlled trial protocol. A group of 100 patients were enrolled in the study and randomly allocated into two comparative groups. Group A (n = 50) received the epidural (interlaminar) approach-2 ultrasound-guided injections as control intervention (each containing two doses of ACS-8 mL). Group B (n = 50) received the perineural (periarticular) approach-2 ultrasound-guided injections as experimental intervention at 7-day intervals (the same volume of ACS). Assessments consisted of an initial assessment (IA) and control assessments at 4 (T1), 12 (T2), and 24 (T3) weeks after the last intervention. Primary outcomes comprised Numeric Rating Scale (NRS), Oswestry Disability Index (ODI), Roland Morris Questionnaire (RMQ), and Euro Quality of Life-5 Dimensions-5 Levels (EQ-5D-5L): Index, Visual Analogue Scale (VAS), and Level Sum Score (LSS). Secondary outcomes included differences between groups in specific endpoints for the above-mentioned questionnaires. In conclusion, this study revealed that both perineural (periarticular) and epidural ACS injections tended to perform in a very similar way. Both routes of Orthokine application show significant improvement in the primary clinical parameters, such as pain and disability, and therefore, both methods can be considered equally effective in managing LBP due to LDDD.

Rilonacept for the treatment of recurrent pericarditis.

INTRODUCTION: Recurrent pericarditis (RP) is a debilitating disease that has an underlying autoinflammatory pathophysiology mediated by cytokine interleukin (IL)-1. Rilonacept, a recombinant dimeric fusion protein that blocks IL-1α and IL-1ß signaling has emerged as a valuable therapeutic option of RP. Rilonacept has been evaluated in Phase 2 and 3 clinical trials and was recently approved for RP treatment. AREAS COVERED: This article reviews available clinical trials assessing the efficacy and safety of rilonacept for the treatment of RP. EXPERT OPINION: Findings from the Rhapsody study) trial suggest that rilonacept represents a promising new therapy for those patients with colchicine resistant or glucocorticoid-dependent disease. Treatment leads to rapid clinical response, with a median resolution of symptoms in 5 days, normalization of C-reactive protein (CRP) in a median of 7 days, and successful weaning from glucocorticoids. This novel therapy also reduces recurrence rates compared with placebo. Rilonacept has also demonstrated a good safety profile, with the most common adverse events including injection-site reactions and upper respiratory tract infections. This anti-IL 1 agent has emerged as an efficacious treatment for RP, with potential use for glucocorticoid-free regimens and as monotherapy. Future trials are needed to explore these treatment options and to clarify the appropriate therapy duration.

Efficacy of Anakinra in Pericarditis: A Systematic Review.

Inflammation of the pericardium is referred to as pericarditis, which can cause sharp chest pain and has a high chance of recurrence even after treatment. This review will explore anakinra, which is an interleukin-1 receptor antagonist, as a potential new treatment for pericarditis. The systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines by searching PubMed and GoogleScholar from the years 2012 to 2022. After applying inclusion and exclusion criteria, thorough screening, and quality appraisal, a total of eleven studies were included in the review; eight case reports and three clinical trials. All studies showed that 100 mg/day of anakinra caused a remarkable improvement in patient outcomes. In addition, the pericarditis resolved quicker and had a lower chance of recurrence in comparison to conventional therapy.

A randomized controlled clinical trial on efficacy and safety of anakinra in patients with severe COVID-19.

INTRODUCTION: Hyperinflammatory state has a role in the pathogenesis of COVID-19. Anakinra could reduce inflammation and help to combat the condition. In this study, we aimed to assess the safety and efficacy of anakinra (PerkinRA®) in severe COVID-19. METHOD: The study was an open-label, randomized, controlled trial conducted in Imam Hossein Medical Center from May to July 2020. Patients with a confirmed diagnosis of COVID-19 were included in this study. We administered anakinra 100 mg daily intravenously. All patients received COVID-19 pharmacotherapy based on the represented national guideline. The need for invasive mechanical ventilation is considered the primary outcome. RESULTS: Thirty patients were included in this study, and 15 of them received Anakinra. Nineteen patients were male (63.3%), and 11 were female (36.7%). The mean age of patients was 55.77 ± 15.89 years. In the intervention group, the need for invasive mechanical ventilation was significantly reduced compared to the control group (20.0% vs. 66.7%, p = .010). Also, these patients had a significantly lower length of hospital stay (p = .043). No significant higher rate of infection was recorded. CONCLUSION: Anakinra as an immunomodulatory agent has been associated with the reduced need for mechanical ventilation in patients admitted to intensive care units because of severe COVID-19. The medication reduced the hospital length of stay. Furthermore, no increased risk of infection was observed. Further randomized placebo-controlled trials with a larger sample size are needed to confirm these findings.

Erosive Hand OsteoArthritis (EHOA): analysis of consecutive patients presenting with EHOA in a hospital-based rheumatology practice and its implications for an upcoming interventional study.

INTRODUCTION: Erosive Hand OsteoArthritis (EHOA) is a common rheumatological problem. We aim to determine characteristics of EHOA patients: comorbidities, radiographic erosivity and pain experienced after being diagnosed, in order to find which of these are potentially relevant in upcoming interventional trials. METHOD: Retrospective analysis of EHOA patients within the electronic database in one centre, with a telephone interview on pain as experienced even exceeding 12 months after being diagnosed. RESULTS: Eighty-four non-academic EHOA patients were found: 89% females (median age 69 years), 11% males (similar age distribution). Kellgren-Lawrence (KL) erosivity scores in both sexes were comparable; DIPs scored higher than PIP's. Comorbid conditions were crystal-induced arthritis, rheumatoid arthritis (RA) and psoriatic arthritis (PsA) in 8%, 5% and 1%, respectively; seropositivity for rheumatoid factor and anti-citrullinated protein antibodies in 8% and 1% respectively. Pain worst experienced often exceeded a visual analogue score of 5.0, but was unrelated to the total KL score. Some pain reduction was reached with non-steroidals (perorally/transcutaneously) as deduced from continued use in 1 in 3. CONCLUSIONS: In many EHOA patients, there is an unmet need regarding the treatment of pain, which per se was not directly correlated with erosivity score. Future studies may be designed considering the aforementioned characteristics, acting on the inflammatory process resulting in PIP/DIP erosions, with the exclusion of RA and PsA in order to get a clean study on EHOA. Several studies with monoclonal antibodies have been performed but demonstrated ineffectivity on the outcome of pain. Hope glooms with the arrival of innovative small molecules that may reach EHOA target cells. Key Points • Erosive handOA is a common problem in non-academic rheumatology; it is often associated with significant pain in both sexes exceeding a VASpain of 5.0 even years after being diagnosed; 1 in 3 found some relief in non-steroidals perorally/transcutaneously. • Future studies will have to focus on (episodic) inflammatory hand OA resulting in proven erosivity (EHOA) located in PIP plus DIP joints and may have to exclude comorbid active crystal-induced arthritis as well as rheumatoid/psoriatic arthritis and possibly even RF/ACPA seropositivity in order to get a clean study on EHOA. • As several big monoclonals have failed in EHOA, we may have to search for promising new drugs within the group of small molecules. These will have to show a significant pain-reducing effect and preferably also a disease-modifying osteoarthritis drug (DMOAD) effect.

The Role of Rilonacept in Recurrent Pericarditis.

Recurrent pericarditis is associated with significant morbidity and adverse impact on quality of life. Contemporary studies have emphasized the key role of autoinflammatory pathways in its pathophysiology, mainly through the activation of inflammasomes and the production of interleukin (IL)-1α and IL-1ß. The IL-1 pathway has emerged as a promising target for the treatment of these patients. A novel IL-1 inhibitor, rilonacept, functions as an IL-1 trap binding to the circulating IL-1α and IL-1ß mitigating their inflammatory response. Recently, the RHAPSODY phase III clinical trial evaluated the use of rilonacept in patients with recurrent pericarditis, who were refractory to colchicine, or steroid-dependent. Rilonacept significantly reduced symptoms, inflammatory markers and recurrent episodes, and increased successful withdrawal of steroids. The safety profile of the medication is favourable and well tolerated by patients, with local injection site reaction being the most common side effect described. These results have shifted the paradigm of the understanding of the disease and promise to become part of the armamentarium of medications for the standard of care of these patients, with potential use as monotherapy. The changing landscape of therapeutics and pathophysiology warrants increased recognition and understanding from the international cardiology community about this novel drug and its implication in managing these complex patients.The objective of this review is to describe the bio-action of rilonacept in the treatment of recurrent pericarditis.

Use of Anakinra in steroid dependent recurrent pericarditis: a case report and review of literature.

Non-steroidal anti-inflammatory drugs and colchicine are the cornerstone treatment for recurrent pericarditis. Corticosteroids are frequently used in patients with recurrent episodes of pericarditis. In patients with corticosteroid dependent and corticosteroid-resistant pericarditis, several steroid-sparing options like azathioprine, intravenous immunoglobulin (IVIG), and anakinra are being recently tried. In this article, we present the case of a 44-year-old male with recurrent pericarditis, who was successfully treated with anakinra. Abbreviations: Non-steroidal anti-inflammatory drugs, NSAIDS; Aspirin, ASA; Erythrocyte sedimentation rate, ESR; Serum Protein Electrophoresis, SPEP; Magnetic Resonance Imaging, MRI; C-Reactive Protein, CRP; Aspartate Aminotransferase, AST; Alanine Aminotransferase, ALT; Idiopathic recurrent pericarditis, IRP; Intravenous Immunoglobulin, IVIG.

Canakinumab for the treatment of hyperimmunoglobulin D syndrome.

INTRODUCTION: Mevalonate Kinase Deficiency (MKD) is a rare monogenic autoinflammatory disorder (AID) with autosomal recessive inheritance caused by mutations in the MVK gene. It includes hyperimmunoglobulinemia D syndrome (HIDS) and mevalonic aciduria (a severe form). Patients have recurrent inflammatory attacks with high fever, gastrointestinal symptoms, lymphadenopathy, splenomegaly, arthralgia, rash, pharyngitis, aphtosis and constitutional complaints. Heightened understanding of molecular mechanisms in monogenic autoinflammatory disorders has provided tools for targeted treatment. HIDS is an extrinsic inflammasomopathy and is responsive to anti-IL-1 therapies, such as the recombinant IL-1-receptor antagonist anakinra, the monoclonal antibody against IL-1b canakinumab (CAN), and the recombinant IL-1R fusion protein rilonacept. Areas covered: CAN is a human monoclonal anti-IL-1ß antibody that binds with high affinity and neutralizes the activity of IL-1 ß. Both observational registries and some case reports have seemed promising in the efficacy of CAN in the HIDS treatment. Two clinical trials have corroborated CAN as an effective and safe drug. Expert commentary: CAN is effective and safe for the treatment of HIDS patients. Some data suggest these patients may need higher dosage or shorter dosing interval than other AIDs, to achieve and maintain complete clinical and laboratory response. Reported adverse events were mild, most often non-complicated infections.

Anakinra in resistant gout: a case report.

Gout is a common cause of inflammatory arthritis. The classical treatment options in an acute gout attack are non-steroidal anti-inflammatory drugs, colchicine, and corticosteroids. Interleukin-1 inhibition has been shown to be an effective alternative when non-biologic therapies are ineffective or contraindicated. Herein, we report the case of a 69-year-old female who presented with polyarticular tophaceous gout treated successfully with anakinra.

Emerging therapies for gout.

Over the past decade much has been learned about the mechanisms of crystal-induced inflammation and renal excretion of uric acid, which has led to more specific targeting of gout therapies and a more potent approach to future management of gout. This article outlines agents being developed for more aggressive lowering of urate and more specific anti-inflammatory activity. The emerging urate-lowering therapies include lesinurad, arhalofenate, ulodesine, and levotofisopam. Novel gout-specific anti-inflammatories include the interleukin-1ß inhibitors anakinra, canakinumab, and rilonacept, the melanocortins, and caspase inhibitors. The historic shortcomings of current gout treatment may, in part, be overcome by these novel approaches.

Interleukin 1 inhibition with anakinra in adult-onset Still disease: a meta-analysis of its efficacy and safety.

BACKGROUND: Anakinra is the first interleukin-1 inhibitor to be used in clinical practice, and recent evidence showed that interleukin-1 plays a pivotal role in the pathogenesis of adult-onset Still disease (AoSD). However, data concerning efficacy with anakinra use in different clinical trials has not been evaluated, and the overall remission of AoSD with anakinra treatment has not been well defined. METHODS: We conducted a search on Embase, PubMed, and the Cochrane Library for relevant trials. Statistical analyses were conducted to calculate the overall remission rates, odds ratios (OR), and 95% confidence intervals (CI), by using either random effects or fixed effect models according to the heterogeneity. RESULTS: Of the 273 articles that were identified, 265 were excluded. Eight studies were eligible for inclusion. The overall remission rate and complete remission rate of anakinra in AoSD patients were 81.66% (95% CI: 69.51%-89.69%) and 66.75% (95% CI: 59.94%-75.3%), respectively. Compared with the controls, the use of anakinra was associated with a significant remission in AoSD, with an OR of 0.16 (95% CI: 0.06-0.44, P=0.0005). There were also significant reductions of the dosage of corticosteroid (mean difference =21.19) (95% CI: 13.2-29.18, P<0.0001) from anakinra onset to the latest follow up time. Clinical and laboratory parameters were all improved, and anakinra was well tolerated in patients with AoSD. No evidence of publication bias was observed. CONCLUSION: Our study has shown that anakinra is effective in remitting the manifestations of AoSD, with reduction of the dose of corticosteroid in patients with AoSD. Further, anakinra therapy was not associated with increased risk of adverse events, and it was well tolerated in patients with AoSD. Further research is still recommended to investigate these findings.