Inflammation plays an important role in all stages of atherosclerosis - from endothelial dysfunction, to formation of fatty streaks and atherosclerotic plaque, and its progression to serious complications, such as atherosclerotic plaque rupture. Although dyslipidemia is a key driver of atherosclerosis, pathogenesis of atherosclerosis is now considered interplay between cholesterol and inflammation, with the significant role of the immune system and immune cells. Despite modern therapeutic approaches in primary and secondary cardiovascular prevention, cardiovascular diseases remain the leading cause of mortality worldwide. In order to reduce residual cardiovascular risk, despite the guidelines-guided optimal medical therapy, novel therapeutic strategies are needed for prevention and management of coronary artery disease. One of the innovative and promising approaches in atherosclerotic cardiovascular disease might be inflammation-targeted therapy. Numerous experimental and clinical studies are seeking into metabolic pathways underlying atherosclerosis, in order to find the most suitable pathway and inflammatory marker/s that should be the target for anti-inflammatory therapy. Many anti-inflammatory drugs have been tested, from the well-known broad range anti-inflammatory agents, such as colchicine, allopurinol and methotrexate, to targeted monoclonal antibodies specifically inhibiting a molecule included in inflammatory pathway, such as canakinumab and tocilizumab. To date, there are no approved anti-inflammatory agents specifically indicated for silencing inflammation in patients with coronary artery disease. The most promising results came from the studies which tested colchicine, and studies where the inflammatory-target was NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome/interleukin-1 beta (IL-1 β )/interleukin-6 (IL-6)/C-reactive protein (CRP) pathway. A growing body of evidence, along with the ongoing clinical studies, suggest that the anti-inflammatory therapy might become an additional strategy in treating atherosclerotic cardiovascular disease. Herein we present an overview of the role of inflammation in atherosclerosis, the most important inflammatory markers chosen as targets of anti-inflammatory therapy, along with the critical review of the major clinical trials which tested non-targeted and targeted anti-inflammatory drugs in patients with atherosclerotic cardiovascular disease.

UNASSIGNED: To demonstrate the long-term safety profile of canakinumab over a nine-year period by documenting adverse events in patients with various pediatric rheumatic diseases.
UNASSIGNED: This retrospective observational study was conducted at the Pediatric Rheumatology Department of Istanbul University Cerrahpasa between 2015 and 2023. The analysis concerned individuals who had been administered canakinumab treatment for at least six months. The exposure-adjusted event rates were calculated as adverse events per 100 patient days and were compared among three groups based on the cumulative canakinumab dose of <35 mg/kg, 35-70 mg/kg, and >70 mg/kg.
UNASSIGNED: Among 189 patients, the median exposure time to canakinumab was 2.9 (1.5-4.1) years, corresponding to 573.4 patient years. The median cumulative dose of canakinumab was 2205 (1312-3600) mg. The most common adverse event was upper respiratory tract infection (0.76), followed by urinary tract infection (0.02), pneumonia (0.009), latent tuberculosis (0.009) and lymphadenitis (0.004). A total of 55 serious adverse events (0.025) were reported, 12 (0.006) of which led to drug discontinuation. The event rate of macrophage activation syndrome and disease exacerbation was statistically higher in patients receiving <35 mg/kg cumulative canakinumab dose (p < 0.05).
UNASSIGNED: An increase in side effect was not observed with the increasing cumulative doses of canakinumab. Canakinumab demonstrated long-term safety with appropriate indication and monitoring.

Atherosclerotic cardiovascular disease (ASCVD) remains a leading cause of morbidity and mortality despite effective low-density lipoprotein cholesterol-targeted therapies. This review explores the crucial role of inflammation in the residual risk of ASCVD, emphasizing its impact on atherosclerosis progression and plaque stability. Evidence suggests that high-sensitivity C-reactive protein (hsCRP), and potentially other inflammatory biomarkers, can be used to identify the inflammatory residual ASCVD risk phenotype and may serve as future targets for the development of more efficacious therapeutic approaches. We review the biological basis for the association of inflammation with ASCVD, propose new therapeutic strategies for the use of inflammation-targeted treatments, and discuss current challenges in the implementation of this new treatment paradigm for ASCVD.

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.

Yao syndrome, a rare autoinflammatory disorder linked to mutations in the nucleotide-binding oligomerization domain-containing protein-2 (NOD2) gene, manifests through periodic fever, polyarthritis, dermatitis, gastrointestinal disturbances, and sicca-like symptoms. The therapeutic landscape is limited, primarily encompassing glucocorticoids, interleukin-1 (IL-1), and IL-6 inhibitors. This report details the case of a teenager with periodic fevers, arthritis, livedo reticularis, and NOD2 gene mutations R702W and IVS8+158C consistent with Yao syndrome. The individual demonstrated significant improvement with canakinumab therapy. This case report aims to enhance recognition and understanding of Yao syndrome\'s clinical spectrum and management options.

Background: Pulmonary involvement in systemic juvenile idiopathic arthritis (SJIA) is a rare but dangerous complication. The main risk factors are already known, such as macrophage activation syndrome, a refractory course of systemic juvenile arthritis, infusion reaction to interleukin 1 and/or interleukin 6 blockers, trisomy 21, and eosinophilia. However, information about respiratory system involvement (RSI) at the onset of SJIA is scarce. Our study aimed to evaluate the specific features of children with SJIA with RSI and their outcomes. Methods: In a single-center retrospective cohort study, we compared the information from the medical records of 200 children with SJIA according to ILAR criteria or SJIA-like disease (probable/possible SJIA) with and without signs of RSI (dyspnea, shortness of breath, pleurisy, acute respiratory distress syndrome, and interstitial lung disease (ILD)) at the disease onset and evaluated their outcomes (remission, development of chronic ILD, clubbing, and pulmonary arterial hypertension). Results: A quarter (25%) of the SJIA patients had signs of the RSI at onset and they more often had rash; hepato- and splenomegaly; heart (pericarditis, myocarditis), central nervous system, and kidney involvement; hemorrhagic syndrome; macrophage activation syndrome (MAS, 44.4% vs. 9.0%, p = 0.0000001); and, rarely, arthritis with fewer active joints, compared to patients without RSI. Five patients (10% from the group having RSI at the onset of SJIA and 2.5% from the whole SJIA cohort) developed fibrosing ILD. All of them had a severe relapsed/chronic course of MAS; 80% of them had a tocilizumab infusion reaction and further switched to canakinumab. Unfortunately, one patient with Down\'s syndrome had gone. Conclusion: Patients with any signs of RSI at the onset of the SJIA are required to be closely monitored due to the high risk of the following fibrosing ILD development. They required prompt control of MAS, monitoring eosinophilia, and routine checks of night oxygen saturation for the prevention/early detection of chronic ILD.

Cynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time.Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house.Four pharmacokinetic parameters for a two-compartment model (i.e. clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration-time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted.Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs.

OBJECTIVE: Cryopyrin-Associated Periodic Syndromes (CAPS) encompasses a spectrum of Interleukin-1 (IL-1) driven systemic diseases with dramatic individual and societal burden. The study aimed to identify parameters and instruments to refine real-life Treat-to-Target (T2T) strategies and control CAPS disease activity.
METHODS: A single-centre, longitudinal study of consecutive children and adults diagnosed with CAPS and treated with anti-IL-1 therapy was performed. Demographics, clinical phenotype and NLRP3 gene variants in addition to serial inflammatory markers and Physician and Patient/Parent Global Assessments (PGA/PPGA) were captured. Effectiveness of anti-IL-1 T2T strategies and factors associated with therapy escalation were determined.
RESULTS: A total of 54 CAPS patients with 759 follow-up visits were included; 31/54 (57%) were children; the median follow-up was 108 months (12-620). The moderate CAPS phenotype was present in 89%; overall 59% had pathogenic/likely pathogenic NLRP3 variants. Therapy adjustments were documented in 50/759 visits including 35 therapy escalations and 15 reductions; 74% of the therapy escalation visits were for children. At time of visit, 63% showed moderate, 37% severe clinical disease activity. Inflammatory markers remained largely normal. Significant improvement was observed in both PGA/PPGA throughout the study (p< 0.01). At the last follow-up, 96% of patients achieved remission.
CONCLUSIONS: Guidance for refining real-life T2T strategies in CAPS cohorts can be drawn from serial assessments of PGA and PPGA reliably reflecting changes in disease activity. Individual parameters including age and NLRP3 gene variants are important predictors, while the sensitivity of inflammatory markers is limited due to the confounding anti-IL-1 therapy.

The objectives of the study were to present the experience of diagnosis, management, and therapy with IL-1 inhibitors in patients with Schnitzler\'s syndrome (SchS) according to a multicenter Russian cohort. An observational retrospective study for a 10-year period (2012-2022) involved 17 patients with SchS who were admitted to the hospital or were observed on an outpatient basis (eight women and nine men). The diagnosis of all of them corresponded to the Strasbourg diagnostic criteria. The age of patients ranged from 25 to 81 years (Me 53[46; 56]). The age at the time of the onset of the disease ranged from 20 to 72 years (Me 46[39; 54]), the duration of the disease before diagnosis ranged from 1 to 35 years (Me 6.5[3; 6]), in three patients it exceeded 10 years, in the rest it ranged from 1 to 8 years. Infectious and lymphoproliferative diseases, monogenic AIDs (CAPS, TRAPS, and HIDS) were excluded from all patients at the prehospital stage. The referral diagnosis for all of them was Still \'s disease in adults. Clinical manifestations of the disease in all patients included fatigue, lethargy, fatigue, rash, and fever. In all patients, skin elements were urticular and were accompanied by itching in 6 (37.5%) patients. Bone pain was observed in 12 (70.6%) patients; arthralgias, in 16 (94.1%); arthritis, in 9 (52.9%); myalgia, in 7 (41.2%); and weight loss, in 4 (23.5%). Lymphadenopathy was detected in 6 (35.3%) patients; enlarged liver, in 6 (35.3%); pericarditis, in 4 (23.5%); angioedema, in 6 (35.3); redness and dryness in the eyes, in 3 (17.6%); sore throat, in 2 (11.8%); abdominal pain, in 1 (5.9%), distal polyneuropathy, in 2 (11.8%); paraesthesia, in 1 (5.9%); and chondritis of the auricles, in 1 (5.9%). Monoclonal gammopathy was detected in all patients with a secretion level of 2.9-15.1 g/L: IgMk (n = 10, 64.7%), less often IgMλ (n = 2), IgGk (n = 2), IgGλ (n = 1), and IgAλ (n = 1). Ben-Jones protein was not detected in any of them. All patients had an increased level of ESR and CRP. Before inclusion in the study, 16 patients received GCs (94.1%) with a temporary effect that disappeared with dose reduction or cancellation. Seven patients received cDMARDs, including methotrexate (5), hydroxychloroquine (2), and cyclophosphamide (1). All patients received NSAIDs and antihistamines, as well as biologics, including the anti-B-cell drug rituximab (1), monoclonal ABs to IgE omalizumab (2, 1 without effect and 1 with partial effect), IL-1i canakinumab (n = 10, 58.8%) subcutaneously once every 8 weeks, and anakinra (n = 4, 23.5%) subcutaneously daily. The duration of taking anakinra, which was prescribed in the test mode, ranged from 1 week to 2.5 months with a further switch to canakinumab in 3 patients. The duration of taking canakinumab at the time of analysis ranged from 7 months to 8 years. Against the background of treatment with IL-1i, 10 out of 11 (90.9%) patients received a complete response in terms of the clinical manifestations of the disease and a decrease in the level of ESR and CRP within a few days. In one patient, a partial response to the administration of anakinra was detected; however, after switching to canakinumab, the effect of treatment was finally lost. One patient received IL-6i for 8 months with an incomplete effect and a positive dynamics after switching to anakinra. Thus, anakinra was initially prescribed to four patients and changed to canakinumab in two of them; canakinumab was started as the first drug in seven patients. Treatment with anakinra was continued in two patients; with canakinumab, in nine patients. In one patient, due to the persistent absence of relapses, the interval between canakinumab injections was increased to 5 months without signs of reactivation; however, subsequently, against the background of stress and relapses of the disease, the intervals were reduced to 4 months. A healthy child was born by the same patient on the background of treatment. The tolerability of therapy was satisfactory in all patients, no SAEs were noted. SchS is a rare multifactorial/non-monogenic AID that should be differentiated from a number of rheumatic diseases and other AIDs. The onset in adulthood, the presence of recurrent urticarial rashes in combination with fever and other manifestations of a systemic inflammatory response are indications for examination for monoclonal secretion. The use of short- or long-acting IL-1i is a highly effective and safe option in the treatment of such patients.

OBJECTIVE: Still\'s disease is a rare autoinflammatory disorder characterized by systemic inflammation, fever, rash, and arthritis. The term \"Still\'s disease\" covers the pediatric subtype systemic Juvenile Idiopathic Arthritis (sJIA) and adult-onset Still\'s disease (AOSD), which affects adults. Biological drugs, including anti-interleukin-1 agents anakinra, canakinumab, rilonacept, and the interleukin-6 antagonist tocilizumab, are used in the management of Still\'s disease.
METHODS: We conducted a systematic review and network meta-analysis of randomized controlled trials, and the study protocol was registered in PROSPERO (CRD42023450442). MEDLINE, EMBASE, and CENTRAL were screened from inception until September 17, 2023. We included patients with Still\'s disease who received placebo or biological drugs: anakinra, canakinumab, rilonacept, or tocilizumab. The primary efficacy and safety outcomes were achievement of ACR50 response and occurrence of serious adverse events, respectively. The interventions were ranked using rankograms and SUCRA values.
RESULTS: Nine trials with 430 patients were included. All biological drugs were associated with greater odds of ACR50 response compared with placebo. There was no statistically significant association between biological drugs and serious adverse events. The multivariate meta-analysis found no difference between biological drugs. As per SUCRA rankings, anakinra was the most effective and safe option with respect to ACR50 response and occurrence of serious adverse events.
CONCLUSIONS: This is the first systematic review and meta-analysis to assess the efficacy and safety of biological drugs in pediatric and adult patients with Still\'s disease. Biological drugs were effective in achieving ACR response and demonstrated a low adverse event profile in the management of Still\'s disease.