Recurrent Pericarditis: a Stubborn Opponent Meets New Treatments in 2022.

PURPOSE OF REVIEW: Our goal in writing this review was to provide a comprehensive appraisal of current therapies for idiopathic recurrent pericarditis with a particular focus on the newest therapeutic agents. We sought to understand the role of the inflammasome in the pathophysiology of pericarditis and how it informs the use of interleukin-1 (IL-1)-directed therapies. RECENT FINDINGS: The latest research on this topic has focused on the critical role of the NLRP3 (NACHT, leucine-rich repeat, and pyrin domain-containing protein) inflammasome. Very recently, components of the NLRP3 inflammasome were detected by immune staining in pericardial tissue from patients with recurrent idiopathic pericarditis. In a mouse model of pericarditis, anti-IL-1 agents anakinra and rilonacept reduced NLRP3 immunostaining. Subsequent study of these drugs in human subjects with idiopathic recurrent pericarditis demonstrated their efficacy. Recurrent idiopathic pericarditis, while relatively rare, poses a continued treatment challenge and contributes to a diminished quality of life for those patients who are afflicted. Recent developments, including an animal model of the disease and the use of IL-1-directed therapies, represent an exciting leap forward in our understanding of treatment targets. These advances offer not only new tools in our fight against this disease, but also the promise of earlier intervention and attenuation of disease morbidity. As our experience with these new agents expands, we can address questions about the ideal timing of introduction of anti-IL-1 therapy and duration of therapy and better understand the potential side effect profile.

The effectiveness of anti-interleukin-1 therapy on subclinical inflammation parameters during the attack-free period in familial Mediterranean fever patients: A case-control study.

BACKGROUND: : Anti IL-1 therapy is useful in suppressing attacks in FMF patients with colchicine resistance, however, it is not certain whether subclinical inflammation can sufficiently be inhibited with anti-IL-1 therapy in FMF patients with amyloidosis. METHODS: Forty-six FMF patients receiving anti-interleukin-1 therapy and 36 healthy control patients were compared in terms of laboratory parameters. Also, FMF patients were further divided into two groups; those with amyloidosis and those without it, and these subgroups were compared to each other in terms of clinical and laboratory findings. RESULTS: In comparison between the FMF and healthy control groups, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and red cell distribution width (RDW) level were detected to be higher and hemoglobin level lower in the patient group. Within the FMF patient group, the ESR, CRP, fibrinogen, RDW, and NLR values were significantly higher in the subgroup with amyloidosis in comparison to the subgroup without amyloidosis. DISCUSSION: Anti-interleukin-1 therapy could not fully suppress the subclinical inflammatory parameters when compared to healthy individuals.

The effectiveness of anti-interleukin-1 therapy on subclinical inflammation parameters during the attack-free period in familial Mediterranean fever patients: A case-control study.

Background/aim: Anti IL-1 therapy is useful in suppressing attacks in FMF patients with colchicine resistance, however, it is not certain whether subclinical inflammation can sufficiently be inhibited with anti-IL-1 therapy in FMF patients with amyloidosis. Materials and methods: Forty-six FMF patients receiving anti-interleukin-1 therapy and 36 healthy control patients were compared in terms of laboratory parameters. Also, FMF patients were further divided into two groups; those with amyloidosis and those without it, and these subgroups were compared to each other in terms of clinical and laboratory findings. Results: In comparison between the FMF and healthy control groups, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) level, and red cell distribution width (RDW) level were detected to be higher and hemoglobin level lower in the patient group. Within the FMF patient group, the ESR, CRP, fibrinogen, RDW, and NLR values were significantly higher in the subgroup with amyloidosis in comparison to the subgroup without amyloidosis. Conclusion: Anti-interleukin-1 therapy could not fully suppress the subclinical inflammatory parameters when compared to healthy individuals.

Long-term renal outcome of Cryopyrin-associated periodic syndrome (CAPS) under anti-Interleukin-1 therapy.

Cryopyrin-associated periodic syndromes (CAPS) are orphan hereditary auto-inflammatory diseases with various phenotypes, including chronic kidney disease (CKD). Current therapies inhibit interleukin-1 (IL-1) to achieve clinical and serological remission; however, the effect on kidney involvement remains unclear. The objective of this study was to investigate the long-term efficacy of anti-IL-1 treatment with special emphasis on renal outcome. We retrospectively analysed clinical, genetic and laboratory data of patients with CAPS under anti-IL-1 therapy from a single-centre university outpatient clinic. Patients with CAPS (n = 28) were followed for a median of 11 (IQR 8.5-13) years. Four patients at various ages (19%), bearing the most common CAPS mutation R260W, had significant CKD at presentation. All affected patients were related; however, other family members with the same genetic variant did not develop CKD. While anti-IL-1 therapy was effective in lowering symptom burden and inflammatory parameters in all CAPS patients, two of the four individuals with significant CKD had persistent proteinuria and worsening kidney function. None of the patients without renal affection at therapy initiation developed relevant CKD in the follow-up period. We showed that in patients with CAPS: (1) CKD is a common complication; (2) renal involvement shows familial predisposition beyond the mutational status and is independent of age; (3) anti-IL-1 therapy results in sustained improvement of inflammatory parameters and symptom load and (4) may prevent development of CAPS-associated CKD but not affect kidney involvement when already present. Overall, early therapy initiation might sufficiently prevent renal disease manifestation and attenuate progression.

Immunomodulating Therapies in Acute Myocarditis and Recurrent/Acute Pericarditis.

The field of inflammatory disease of the heart or "cardio-immunology" is rapidly evolving due to the wider use of non-invasive diagnostic tools able to detect and monitor myocardial inflammation. In acute myocarditis, recent data on the use of immunomodulating therapies have been reported both in the setting of systemic autoimmune disorders and in the setting of isolated forms, especially in patients with specific histology (e.g., eosinophilic myocarditis) or with an arrhythmicburden. A role for immunosuppressive therapies has been also shown in severe cases of coronavirus disease 2019 (COVID-19), a condition that can be associated with cardiac injury and acute myocarditis. Furthermore, ongoing clinical trials are assessing the role of high dosage methylprednisolone in the context of acute myocarditis complicated by heart failure or fulminant presentation or the role of anakinra to treat patients with acute myocarditis excluding patients with hemodynamically unstable conditions. In addition, the explosion of immune-mediated therapies in oncology has introduced new pathophysiological entities, such as immune-checkpoint inhibitor-associated myocarditis and new basic research models to understand the interaction between the cardiac and immune systems. Here we provide a broad overview of evolving areas in cardio-immunology. We summarize the use of new imaging tools in combination with endomyocardial biopsy and laboratory parameters such as high sensitivity troponin to monitor the response to immunomodulating therapies based on recent evidence and clinical experience. Concerning pericarditis, the normal composition of pericardial fluid has been recently elucidated, allowing to assess the actual presence of inflammation; indeed, normal pericardial fluid is rich in nucleated cells, protein, albumin, LDH, at levels consistent with inflammatory exudates in other biological fluids. Importantly, recent findings showed how innate immunity plays a pivotal role in the pathogenesis of recurrent pericarditis with raised C-reactive protein, with inflammasome and IL-1 overproduction as drivers for systemic inflammatory response. In the era of tailored medicine, anti-IL-1 agents such as anakinra and rilonacept have been demonstrated highly effective in patients with recurrent pericarditis associated with an inflammatory phenotype.

The Efficacy, Safety and Tolerability of Canakinumab in the Treatment of Familial Mediterranean Fever: A Systematic Review of the Literature.

Familial Mediterranean Fever (FMF) is the most prevalent genetic autoinflammatory disorder. In most patients, treatment with colchicine can prevent attacks of fever and inflammation. However, 5%-10% of patients are resistant to colchicine treatment, while a similar percentage cannot tolerate colchicine in doses needed to prevent attacks. For these patients, Canakinumab, a full human antibody against IL-1ß, has been approved recently by the FDA and EMA. In this article, we present a systematic review of the long-term efficacy, safety, and tolerability of Canakinumab in FMF patients who cannot tolerate colchicine or who are resistant to colchicine treatment.

The role of IL-1 inhibition in systemic juvenile idiopathic arthritis: current status and future perspectives.

The pathogenesis, clinical course, and response to treatment in systemic juvenile idiopathic arthritis (SJIA) differ from other types of juvenile idiopathic arthritis and are similar to other interleukin-1 (IL-1)-mediated diseases. The main cytokine involved in the pathogenesis of SJIA is IL-1ß, which can be neutralized by targeted anti-IL-1 therapy. In SJIA, no antibodies have been found and there is growing evidence that it is mainly an autoinflammatory and not an autoimmune disease. Before the era of biologic therapy, treatment of SJIA was primarily based on long-term treatment with high doses of glucocorticosteroids (GCS). The side effects of GCS could have a significant impact on the outcome of the disease and could cause long-term damage. Treatment with anti-IL-1 agents early in the disease course has revolutionized the management principles of SJIA. However, not all SJIA patients respond equally well to anti-IL-1 therapy, and it has been shown that age at the onset of disease, duration of the disease, number of affected joints, neutrophil count, and ferritin level can predict the response to anti-IL-1 therapy. In particular, an elevated ferritin level should prompt testing for macrophage activation syndrome (MAS), the most severe complication of SJIA. Anti-IL-1 therapy has been shown to be effective also in patients with MAS. Although anti-IL-1 agents are currently not recommended as first-line treatment, there is growing evidence that anti-IL-1 agents introduced at the beginning of SJIA could enable lower doses and a shorter duration of GCS therapy, change the long-term disease outcome, and even influence molecular disease patterns. There are currently three anti-IL-1 agents available: anakinra, canakinumab, and rilonacept. In this review, we present the current knowledge on the pathogenesis of SJIA, the rational for anti-IL-1 treatment, and future perspectives on the treatment of SJIA.

Schnitzler syndrome co-occurring with idiopathic multicentric Castleman disease that responds to anti-IL-1 therapy: A case report and clue to pathophysiology.

Patients with HHV-8-negative/idiopathic multicentric Castleman disease (iMCD) experience systemic inflammatory symptoms and polyclonal lymphoproliferation due to an unknown etiology. Schnitzler's syndrome (SS) is characterized by recurrent urticarial rash, monoclonal IgM gammopathy, and other clinical signs of inflammation. To our knowledge, we report the first case of iMCD associated with SS and the fourth case of anakinra inducing a complete response for an iMCD patient. A forty-four year old woman with a history of a recurrent urticarial rash, presented to our hospital complaining of 6 months of night sweats, fever, chronic urticaria, iliac bone pain, and generalized lymphadenopathy. An IgM Kappa monoclonal component was measured at 7.8g/L. A lymph node biopsy revealed histopathological features consistent with the plasma cell variant of iMCD. She was diagnosed with SS and iMCD. Anti-IL-1 treatment with anakinra (100mg/day) was introduced. Within 48h, we observed improvement in the fever and the urticarial rash. By one month, we considered the patient in complete remission. Two years later, the remission is persistent while the patient is still under therapy. Though this is only the fourth reported case of anakinra in iMCD, this is yet another case demonstrating the effectiveness of anti-IL-1 blockade in SS. We hypothesize that uncontrolled cytokine production is responsible for both the SS and the iMCD. The etiologies of SS and iMCD are unknown, and future research is necessary.

Non-response to Interleukin-1 Antagonist Canakinumab in Two Patients with Refractory Pyoderma Gangrenosum and Hidradenitis Suppurativa.

Pyoderma gangrenosum and hidradenitis suppurativa are skin conditions characterized by an intense neutrophil-mediated inflammatory response that is often difficult to effectively treat. Successful use of interleukin (IL)-1ß inhibition using canakinumab and anakinra has been reported in patients with concomitant pyoderma gangrenosum and hidradenitis suppurativa. We report two cases where targeted therapy with canakinumab failed to lead to improvement for patients with pyoderma gangrenosum and hidradenitis suppurativa. The reason behind the non-response to IL-1ß blockade seen in these patients is unclear. Our report suggests that further controlled studies are warranted to help clinicians predict treatment responses to anti-IL-1 therapies in these challenging patients.