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Gout is the most common type of inflammatory arthritis. Nonsteroidal anti-inflammatory drugs, corticosteroids, and colchicine are the first-line agents, although they are contraindicated in many patients. Blockade of IL-1 with anakinra can be an alternative. To present a case series of 10 difficult-to-treat gout patients treated with anakinra and perform a scoping review of the effectiveness and safety of anakinra in gout patients. A total of 1,519 citations were screened. The reviewers ran a two-stage screening process by title/abstract and full-text reading. Thirty-eight articles finally met the selection criteria and were included for data extraction and synthesis. Experience in difficult-to treat and complex clinical scenarios, such as active infection, hemodialysis, and transplantation, were specifically described. The study sample comprised 551 patients, from whom 648 flares were finally analyzed. The mean age was 57.9 years, and 82.9% were men. The clinical presentation was polyarticular in 47.5% and tophaceous in 66.9%. Sixty-five patients with an active infection, 41 transplanted patients and 14 in haemodyalisis treated with anakinra are described. More than half of the patients had >1 associated comorbidity. Anakinra was effective both for flares (94%) and for long-term treatment (91%) and well tolerated. In the case of flares, 34 (6.7%) adverse effects were registered. Adverse events were more prevalent in long-term treatment. Anakinra was effective and safe for management of gout flares in difficult-to-treat patients. It has been used in multiple complex scenarios, such as active infections, dialysis, transplantation, chronic kidney disease, and polyarticular gout. Anakinra has also proven effective as long-term treatment, although there are more concerns about its safety.

Schnitzler’s syndrome (SchS) is a rare autoinflammatory disorder characterized by urticarial rash and monoclonal gammopathy which is currently regarded as IL-1 mediated disease. We present the case of a 21-year-old woman presenting with urticarial rash, arthralgias, and elevated inflammatory markers. She has been suffering these symptoms for 2 years and was treated with antihistamines, omalizumab, steroids, and non-steroidal anti-inflammatory drugs (NSAIDs) without success. After an extensive diagnostic workout, we suspected SchS even without monoclonal gammopathy, and started Anakinra 100 mg daily with a dramatic response and achieving complete remission after 48 h of the beginning of the treatment, so we decided to confirm SchS diagnosis. We performed a search of the literature and found seven more cases of patients diagnosed with SchS without monoclonal gammopathy at the presentation. Five were treated with IL-1 blocking therapies and all achieved remission. We, therefore, prompt the possible role of IL-1 blockade therapy remission as support in diagnosing SchS without monoclonal gammopathy.

Autoinflammatory diseases, characterized by recurrent systemic inflammation due to innate immune dysregulation, often present with fever, arthritis, abdominal pain, and cutaneous involvement, with elevated acute-phase reactants during flare-ups. These rare conditions, arising from monogenic mutations or environmental triggers, can be challenging to diagnose, yet accurate identification is critical for effective targeted therapy. In 2022, Kanderova et al. reported a heterozygous c.1545C>A (p.Tyr515Ter) HCK gene mutation causing early-onset cutaneous pulmonary vasculitis due to increased kinase activity from a truncated HCK protein, leading to chronic inflammation and fatal progression despite partial suppression with ruxolitinib. HCK , a SRC family tyrosine kinase predominantly expressed in granulocytic and monocytic cells, regulates immune functions like phagocytosis and cytokine production. We report a 6-year-old female patient with recurrent fevers, cutaneous petechial rashes, chronic cough, exertional dyspnea, and persistent symptoms despite multiple antibiotic treatments for suspected recurrent lower respiratory tract infections since age  1.5 years, treated for presumed recurrent lower respiratory tract infections with multiple antibiotic courses, though symptoms persisted. No cutaneous manifestations were observed during the current admission, but elevated acute-phase reactants and pulmonary findings were noted. Based on clinical and laboratory features, a rare autoinflammatory condition was suspected. No pathogenic variants were identified in an autoinflammatory disease gene panel. Whole-exome sequencing (WES) using next-generation sequencing (NGS) revealed a novel splice site mutation (c.1016-5T>C) in the HCK gene, absent from existing genomic databases. Anti-IL1B targeted therapy achieved complete clinical and laboratory remission. This study identifies a novel HCK gene mutation as the cause of a hereditary autoinflammatory disease with early-onset pulmonary and cutaneous manifestations, consistent with classical autoinflammatory syndromes.

Aims Interleukin‐1 (IL‐1) blockade may improve exercise capacity in patients with heart failure (HF) patients. The extent of the improvement and its persistence beyond discontinuation of IL‐1 blockade is unknown. Methods and results The primary objective was to determine changes in cardiorespiratory fitness and cardiac function on‐treatment with IL‐1 blocker, anakinra, and off‐treatment, after treatment cessation. We performed cardiopulmonary exercise testing, Doppler echocardiography, and biomarkers in 73 patients with HF, 37 (51%) females, 52 (71%) Black–African–American, before and after treatment with anakinra 100 mg daily. In a subset of 46 patients, testing was also repeated after treatment cessation. Quality of life was assessed in each patient using standardized questionnaires. Data are presented as median and interquartile range. Treatment with anakinra for 4 [2–12] weeks was associated with a significant improvement in high‐sensitivity C‐reactive protein (from 6.2 [3.3–15.4] to 1.4 [0.8–3.4] mg/L, P < 0.001), peak oxygen consumption (VO2peak, from 13.9 [11.6–16.6] to 15.2 [12.9–17.4] mL/kg/min, P < 0.001). Ventilatory efficiency, exercise time, Doppler‐derived signs and biomarkers of elevated intracardiac pressures, and quality‐of‐life measures also improved with anakinra. In the 46 patients in whom off‐treatment data were available 12 [4–12] weeks later, many of the favourable changes seen with anakinra were largely reversed (from 1.5 [1.0–3.4] to 5.9 [1.8–13.1], P = 0.001 for C‐reactive protein, and from 16.2 [14.0–18.4] to 14.9 [11.5–17.8] mL/kg/min, P = 0.017, for VO2peak). Conclusions These data validate IL‐1 as an active and dynamic modulator of cardiac function and cardiorespiratory fitness in HF.

Background Withholding live-attenuated vaccines in patients using interleukin (IL)-1 or IL-6 blocking agents is recommended by guidelines for both pediatric and adult rheumatic diseases, since there is a risk of infection in an immune suppressed host. However, this has never been studied. This retrospective, multicenter survey aimed to evaluate the safety of live-attenuated vaccines in patients using IL-1 or IL-6 blockade. Methods We contacted physicians involved in the treatment of autoinflammatory diseases to investigate potential cases. Patients were included if a live-attenuated vaccine had been administered while they were on IL-1 or IL-6 blockade. Results Seventeen patients were included in this survey (7 systemic juvenile idiopathic arthritis (sJIA), 5 cryopyrin associated periodic syndrome (CAPS), 4 mevalonate kinase deficiency (MKD) and 1 familial Mediterranean fever (FMF). Three patients experienced an adverse event, of which two were serious adverse events (a varicella zoster infection after varicella zoster booster vaccination, and a pneumonia after MMR booster). One additional patient had diarrhea after oral polio vaccine. Further, seven patients experienced a flare of their disease, which were generally mild. Eight patients did not experience an adverse event or a flare. Conclusion We have described a case series of seventeen patients who received a live-attenuated vaccine while using IL-1 or IL-6 blocking medication. The findings of this survey are not a reason to adapt the existing guidelines. Prospective trials are needed in order to acquire more evidence about the safety and efficacy before considering adaptation of guidelines.

The main purpose of this Research Topic is to discuss and evaluate some current knowledge on IL-1 biology and the rational approach toward its blockade in different conditions. [...]two articles investigate the beneficial effects of plant-derived natural compounds in in vitro and animal models of inflammation. The effect of curcumin is discussed in the original research byKong et al.In this paper the authors show how this natural polyphenol effectively suppressed the expression of NLRP3 inflammasome in macrophages involving toll-like receptor (TLR)4/myeloid differentiation primary response 88 (MyD88)/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and P2X7R pathways. Conflict of Interest Statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Background Mevalonate kinase deficiency (MKD) is a rare autoinflammatory condition caused by biallelic loss-of-function (LOF) mutations in mevalonate kinase ( MVK ) gene encoding the enzyme mevalonate kinase. Patients with MKD display a variety of non-specific clinical manifestations, which can lead to diagnostic delay. We report the case of a child presenting with vasculitis that was found by genetic testing to be caused by MKD, and now add this autoinflammatory disease to the ever-expanding list of causes of monogenic vasculitides. Case presentation A 2-year-old male presented with an acute 7-day history of high-grade fever, abdominal pain, diarrhoea, rectal bleeding and extensive purpuric and necrotic lesions, predominantly affecting the lower limbs. He had been suffering from recurrent episodes of fever from early in infancy, associated with maculopapular/petechial rashes triggered by intercurrent infection, and after vaccines. Extensive infection screen was negative. Skin biopsy revealed small vessel vasculitis. Visceral digital subtraction arteriography was normal. With a diagnosis of severe idiopathic cutaneous vasculitis, he was treated with corticosteroids and mycophenolate mofetil. Despite that his acute phase reactants remained elevated, fever persisted and the vasculitic lesions progressed. Next-generation sequencing revealed compound heterozygous mutation in MVK c.928G > A (p.V310M) and c.1129G > A (p.V377I) while reduced mevalonate enzyme activity was confirmed suggesting a diagnosis of MKD as a cause of the severe vasculitis. Prompt targeted treatment with IL-1 blockade was initiated preventing escalation to more toxic vasculitis therapies and reducing unnecessary exposure to cytotoxic treatment. Conclusions Our report highlights the broad clinical phenotype of MKD that includes severe cutaneous vasculitis and emphasizes the need to consider early genetic screening for young children presenting with vasculitis to exclude a monogenic vasculitis which may be amenable to targeted treatment.

The treatment of neutrophilic panniculitis can be challenging. We report a patient with a difficult-to-treat neutrophilic panniculitis who had a spectacular response to a short treatment course with the IL-1 antagonist anakinra. A 61-year-woman had a 12-year history of a serious febrile neutrophilic panniculitis and a personal history of steroid- induced pancreatitis and life-threatening methemoglobinemia under antimalarials and dapsone. When she developed a new flare, she was treated successfully with a 15-day course of subcutaneously administered injections of 100 mg anakinra. This observation is the first report attesting the efficiency of anakinra in neutrophilic panniculitis. It expands the potential indications of IL-1 inhibition in the field of the neutrophilic dermatoses, or more generally, in neutrophil-mediated systemic diseases. It underscores the potential pathogenic involvement of IL-1 in those diseases, a hallmark of autoinflammation, and supports their nosologic classification among diseases involving primarily the innate immune system.

Abstract Cryopyrin-associated periodic syndromes (CAPS) are caused by mutations of the gene encoding the NLR family protein NLRP3, which together with caspase-1 and adaptor proteins constitutes a protein complex termed the inflammasome. In innate immune reactions, a variety of stimuli activate the NLRP3 inflammasome, triggering caspase-1 to process proIL-1 and thus to produce mature IL-1. Excessive production of IL-1 by monocytes/macrophages is the central pathophysiology of CAPS, and daily injection of the IL-1 receptor antagonist anakinra rapidly ameliorates the inflammatory symptoms in most cases. Furthermore, double-blind, placebo-controlled clinical trials have recently confirmed the efficacy and safety of rilonacept, a fusion protein of the IL-1 receptor and IgG Fc, and canakinumab, a human anti-IL-1 monoclonal antibody, as novel long-lasting agents for treating CAPS.

Cryopyrin-associated periodic syndromes (CAPS) are caused by mutations of the gene encoding the NLR family protein NLRP3, which together with caspase-1 and adaptor proteins constitutes a protein complex termed the inflammasome. In innate immune reactions, a variety of stimuli activate the NLRP3 inflammasome, triggering caspase-1 to process proIL-1 and thus to produce mature IL-1. Excessive production of IL-1 by monocytes/macrophages is the central pathophysiology of CAPS, and daily injection of the IL-1 receptor antagonist anakinra rapidly ameliorates the inflammatory symptoms in most cases. Furthermore, double-blind, placebo-controlled clinical trials have recently confirmed the efficacy and safety of rilonacept, a fusion protein of the IL-1 receptor and IgG Fc, and canakinumab, a human anti-IL-1 monoclonal antibody, as novel long-lasting agents for treating CAPS.