RESUMO
OBJECTIVES: FMF is the most common hereditary monogenic fever syndrome marked by recurrent attacks of fever and polyserositis. Colchicine is the current recommended first-line treatment for FMF. However, a small portion of FMF patients are unresponsive or intolerant to colchicine. Anti-IL-1 agents are alternative treatment options for colchicine-resistant or -intolerant FMF patients. This systematic review and meta-analysis aimed to provide qualitative and quantitative evidence for the efficacy and safety of anti-IL-1 agents in adult and paediatric FMF patients. METHODS: MEDLINE, EMBASE, CENTRAL and Web of Science were screened from inception to May 2023. We included adult and paediatric FMF patients who received continuous treatment with at least one of the anti-IL-1 drugs: anakinra, canakinumab and rilonacept. The primary efficacy outcome was the proportion of patients who achieved complete remission of attacks and the primary safety outcome was the proportion of patients who experienced at least one adverse event during treatment. A random-effects meta-analysis was performed for the quantitative synthesis. RESULTS: Fourty-four reports consisting of 1399 FMF patients were included. Sixty percent (95% CI 49%, 72%) of the adult patients and 81% (95% CI 72%, 89%) of the paediatric patients achieved complete remission. Anti-IL-1 agents significantly decreased levels of inflammatory markers. At least one adverse event was observed in 25% (95% CI 13%, 37%) of the adult patients and 12% (95% CI 3%, 21%) of the paediatric patients. CONCLUSION: Anti-IL-1 agents were effective and demonstrated a low adverse event profile in paediatric and adult FMF patients.
Assuntos
Febre Familiar do Mediterrâneo , Adulto , Humanos , Criança , Febre Familiar do Mediterrâneo/tratamento farmacológico , Interleucina-1 , Colchicina/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Resposta Patológica CompletaRESUMO
OBJECTIVES: The aim of this study is to investigate the effect of anti-interleukin (IL)-1/-6 biologics on systemic juvenile idiopathic arthritis (sJIA)-associated macrophage activation syndrome (MAS). METHODS: Demographic, clinical, and laboratory data of patients followed up with a diagnosis of sJIA-associated MAS assessed from sixteen pediatric rheumatology centers across the country. The clinical and laboratory features of MAS developing while on biological drugs were compared with those without this treatment. RESULTS: One hundred and sixty-two patients were included in the study. 45 of the MAS events were detected under the effect of anti-IL-1/-6 biologics, while the patients experiencing the remaining 155 events have not received biological treatment in the last three months. Platelet count [128 (72-232) vs 199 (130-371) 109/l], ferritin level on admission [1107 (676-2050) vs 2863 (1193-9562) ng/ml], C-reactive protein level [15.4 (2.9-56) vs 90 (32-160) mg/l], erythrocyte sedimentation rate [13 (3-36) vs 43.5 (13-77) mm/h] and fever duration [5 (4-7.5) vs 10 (7-14.3) days] were found lower in the group under the impact of anti-IL-1/-6 biologics. Among patients treated with biologics, 26.6% did not meet the published 2016 MAS classification criteria at presentation. The rates of hepatomegaly and splenomegaly were relatively lower in the canakinumab-treated group when compared with those receiving other biologicals or to patients, not on biologicals. CONCLUSION: Anti-IL-1/-6 therapies can mask the clinical and laboratory features of MAS, and proposed guidelines for MAS classification criteria may not be met.
RESUMO
OBJECTIVES: Fibrodysplasia ossificans progressiva (FOP) is one of the most catastrophic forms of genetic heterotopic ossification (HO). FOP is characterized by severe, progressive inflammatory flare-ups, that often lead to HO. The flare-ups are associated with increased inflammatory cytokine production, suggesting auto-inflammatory features driven by interleukin-1ß (IL-1ß). This study describes the short- and long-term responses of FOP patients to anti-IL-1 therapy. METHODS: Previously, we reported that a patient with FOP treated with anti-IL-1 agents showed dramatically lower rates of flare-ups, improved flare-up symptoms, decreased use of glucocorticoids, and apparently decreased size of residual lesions. Plasma analyses also showed marked elevation in IL-1ß levels during a FOP flare, further supporting a role of IL-1ß in the pathogenesis of FOP flares. Here, we report results from long-term therapy with IL-1 inhibitors in that patient, and describe 3 additional patients, from two medical centers. RESULTS: All 4 patients showed persistent improvement in flare activity during treatment with IL-1 inhibitors, with minimal formation of new HO sites. Two patients who stopped therapy experienced resurgence of flare activity that was re-suppressed upon re-initiation. These patients had IL-1ß levels comparable to those in IL-1ß-driven diseases. Child Health Assessment Questionnaires confirmed extensive subjective improvements in the pain and general health visual analogue scales. CONCLUSION: This case series demonstrates significant benefits from IL-1 inhibitors for reducing flare activity and improving the general health of patients with FOP. These data provide strong support for additional studies to better understand the function of IL-1 inhibition, primarily in reducing formation new HO. FUNDING: RH received support from the International FOP Association ACT grant; ECH received support from NIH/NIAMS R01AR073015 and the UCSF Robert Kroc Chair in Connective Tissue and Rheumatic Diseases III.
RESUMO
OBJECTIVES: 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. CONCLUSION: 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.
RESUMO
OBJECTIVES: 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. CONCLUSION: 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.
RESUMO
BACKGROUND: Clinical trials of anti-inflammatories in schizophrenia do not show clear and replicable benefits, possibly because patients were not recruited based on elevated inflammation status. Interleukin 1-beta (IL-1ß) mRNA and protein levels are increased in serum, plasma, cerebrospinal fluid, and brain of some chronically ill patients with schizophrenia, first episode psychosis, and clinical high-risk individuals. Canakinumab, an approved anti-IL-1ß monoclonal antibody, interferes with the bioactivity of IL-1ß and interrupts downstream signaling. However, the extent to which canakinumab reduces peripheral inflammation markers, such as, high sensitivity C-reactive protein (hsCRP) and symptom severity in schizophrenia patients with inflammation is unknown. TRIAL DESIGN: We conducted a randomized, placebo-controlled, double-blind, parallel groups, 8-week trial of canakinumab in chronically ill patients with schizophrenia who had elevated peripheral inflammation. METHODS: Twenty-seven patients with schizophrenia or schizoaffective disorder and elevated peripheral inflammation markers (IL-1ß, IL-6, hsCRP and/or neutrophil to lymphocyte ratio: NLR) were randomized to a one-time, subcutaneous injection of canakinumab (150 mg) or placebo (normal saline) as an adjunctive antipsychotic treatment. Peripheral blood hsCRP, NLR, IL-1ß, IL-6, IL-8 levels were measured at baseline (pre injection) and at 1-, 4- and 8-weeks post injection. Symptom severity was assessed at baseline and 4- and 8-weeks post injection. RESULTS: Canakinumab significantly reduced peripheral hsCRP over time, F(3, 75) = 5.16, p = 0.003. Significant hsCRP reductions relative to baseline were detected only in the canakinumab group at weeks 1, 4 and 8 (p's = 0.0003, 0.000002, and 0.004, respectively). There were no significant hsCRP changes in the placebo group. Positive symptom severity scores were significantly reduced at week 8 (p = 0.02) in the canakinumab group and week 4 (p = 0.02) in the placebo group. The change in CRP between week 8 and baseline (b = 1.9, p = 0.0002) and between week 4 and baseline (b = 6.0, p = 0.001) were highly significant predictors of week 8 change in PANSS Positive Symptom severity scores. There were no significant changes in negative symptoms, general psychopathology or cognition in either group. Canakinumab was well tolerated and only 7 % discontinued. CONCLUSIONS: Canakinumab quickly reduces peripheral hsCRP serum levels in patients with schizophrenia and inflammation; after 8 weeks of canakinumab treatment, the reductions in hsCRP are related to reduced positive symptom severity. Future studies should consider increased doses or longer-term treatment to confirm the potential benefits of adjunctive canakinumab in schizophrenia. Australian and New Zealand Clinical Trials Registry number: ACTRN12615000635561.
Assuntos
Esquizofrenia , Humanos , Esquizofrenia/tratamento farmacológico , Proteína C-Reativa/análise , Anticorpos Monoclonais/uso terapêutico , Interleucina-6 , Austrália , Inflamação/tratamento farmacológico , Doença Crônica , Método Duplo-Cego , Resultado do TratamentoRESUMO
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.
RESUMO
To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.
Assuntos
Amiloidose , Febre Familiar do Mediterrâneo , Doenças Hereditárias Autoinflamatórias , Humanos , Adolescente , Estudos Retrospectivos , Doenças Hereditárias Autoinflamatórias/diagnóstico , Doenças Hereditárias Autoinflamatórias/tratamento farmacológico , Doenças Hereditárias Autoinflamatórias/genética , Febre/diagnóstico , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Sistema de Registros , Pirina/genética , Proteína Amiloide A SéricaRESUMO
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.
Assuntos
Síndrome de Schnitzler , Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Adulto , Síndrome de Schnitzler/tratamento farmacológico , Síndrome de Schnitzler/diagnóstico , Idoso , Federação Russa/epidemiologia , Idoso de 80 Anos ou mais , Estudos Retrospectivos , Estudos de CoortesRESUMO
Although numerous trials have convincingly shown benefits of statin therapy in both primary and secondary prevention of atherosclerotic cardiovascular disease (ASCVD), most showed relative risk reductions of 25-40%, and thus many individuals continue to have ASCVD events despite statin therapy. Substantial progress has been made in developing therapies that address the residual risk for ASCVD despite statin therapy. In this review, we summarize progress of currently available therapies along with therapies under development that further reduce low-density lipoprotein cholesterol and apolipoprotein B-containing lipoproteins, reduce lipoprotein(a), reduce ASCVD events in patients with high triglycerides, and directly target inflammation to reduce ASCVD risk.
Assuntos
Doenças Cardiovasculares/prevenção & controle , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Inflamação/tratamento farmacológico , Lipoproteínas/sangue , Prevenção Primária/métodos , Prevenção Secundária/métodos , Biomarcadores/sangue , Doenças Cardiovasculares/sangue , Humanos , Inflamação/sangue , Lipoproteínas/efeitos dos fármacosRESUMO
OBJECTIVES: There is no consensus on canakinumab treatment tapering and discontinuation strategies in colchicine-resistant FMF patients. In this study, we aimed to establish a treatment management and discontinuation protocol in paediatric FMF patients treated with canakinumab. METHODS: Fifty-eight FMF patients treated with canakinumab were included. Since 2020, we have applied a protocol based on our experience whereby canakinumab is administered monthly in the first 6 months, followed by bimonthly for 6 months, and a final period of every 3 months (for 6 months). The patients were divided into two groups: 2012-2019 (group A) and 2020-2022 (group B). RESULTS: In group A (n = 33), the median duration of canakinumab treatment was 2.5 years [interquartile range (IQR) 1.9-3.7]. A total of 25 of 33 patients discontinued canakinumab after a median of 2.1 years (IQR 1.8-3.4). In two patients, canakinumab was restarted because of relapse. In group B (n = 25), canakinumab was discontinued in 18 patients at the end of 18 months. After a median follow-up of 0.8 years (IQR 0.6-1.1), two patients had a relapse and canakinumab treatment was reinitiated. The remaining 16 patients still have clinically inactive disease and are receiving only colchicine. When we compared the characteristics between groups A and B, there were no significant differences regarding demographics, clinical features, and outcomes. CONCLUSION: This is the largest study in the literature suggesting a protocol for discontinuing canakinumab in paediatric FMF patients. It was possible to discontinue canakinumab successfully in more than half of the patients in 18 months. Thus we suggest that this protocol can be used in paediatric FMF patients.
Assuntos
Febre Familiar do Mediterrâneo , Humanos , Criança , Febre Familiar do Mediterrâneo/tratamento farmacológico , Colchicina/uso terapêutico , Estudos de Viabilidade , Resultado do Tratamento , Estudos Retrospectivos , RecidivaRESUMO
OBJECTIVE: We describe a family with a novel mutation in the TNF Receptor Superfamily Member 1A (TNFRSF1A) gene causing TNF receptor-associated periodic syndrome (TRAPS) with renal AA amyloidosis. METHODS: Case series of affected family members. We further investigated the plasma metabolome of these patients in comparison with healthy controls using mass spectrometry. RESULTS: In all symptomatic family members, we detected the previously undescribed variant c.332A>G (p.Q111R) in the TNFRSF1A gene. Canakinumab proved an effective treatment option leading to remission in all treated patients. One patient with suspected renal amyloidosis showed near normalization of proteinuria under treatment. Analysis of the metabolome revealed 31 metabolic compounds to be upregulated and 35 compounds to be downregulated compared with healthy controls. The most dysregulated metabolites belonged to pathways identified as arginine biosynthesis, phenylalanine, tyrosine and tryptophan biosynthesis, and cysteine and methionine metabolism. Interestingly, the metabolic changes observed in all three TRAPS patients seemed independent of treatment with canakinumab and subsequent remission. CONCLUSION: We present a novel mutation in the TNFRSF1A gene associated with amyloidosis. Canakinumab is an effective treatment for individuals with this new likely pathogenic variant. Alterations in the metabolome were most prominent in the pathways related to arginine biosynthesis, tryptophan metabolism, and metabolism of cysteine and methionine, and seemed to be unaffected by treatment with canakinumab. Further investigation is needed to determine the role of these metabolomic changes in the pathophysiology of TRAPS.
Assuntos
Amiloidose , Febre Familiar do Mediterrâneo , Humanos , Receptores do Fator de Necrose Tumoral , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/complicações , Cisteína/genética , Triptofano , Receptores Tipo I de Fatores de Necrose Tumoral/genética , Amiloidose/complicações , Mutação , Metionina , ArgininaRESUMO
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 ß )/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.
RESUMO
BACKGROUND: Data on use of interleukin (IL)-1 blockers in kidney transplant recipients (KTRs) with familial Mediterranean fever (FMF) are very limited. We aimed to evaluate the efficacy and safety of anakinra and canakinumab in the transplantation setting. METHODS: In this retrospective cohort study, we included KTRs who suffered from AA amyloidosis caused by FMF and treated with anakinra or canakinumab (study group, n = 36). Using propensity score matching, we selected 36 patients without FMF or amyloidosis from our database of 696 KTRs as the control group. Primary outcomes were patient and graft survival. Biopsy-confirmed graft rejection, changes in estimated glomerular filtration rate (eGFR), high-sensitivity CRP (hsCRP), erythrocyte sedimentation rate (ESR), proteinuria and number of monthly attacks were secondary outcomes. RESULTS: All KTRs with FMF began IL-1 blocker therapy with anakinra and nine (25%) were switched to canakinumab. Overall death was more frequent in the study group (19.4% vs 0%) (P = .005); however, overall graft loss was comparable between study (27.8%) and control groups (36.1%) (P = .448). Five- and 10-year graft survival rates were significantly higher in the study group (94.4% and 83.3%, respectively) than in the control group (77.8% and 63.9%, respectively) (P = .014 and P < .001, respectively). Rejections were numerically lower in study group (8.3% vs 25%), but it did not reach to statistical significance (P = .058). When compared with the pre-treatment period, with IL-1 blockers, the number of attacks per month (P < .001), and eGFR (P = .004), hsCRP (P < .001) and ESR (P = .026) levels were lower throughout the follow-up, whereas proteinuria levels were not. CONCLUSIONS: Anakinra and canakinumab are effective in KTRs suffering from FMF; however, the mortality rate may be of concern.
Assuntos
Febre Familiar do Mediterrâneo , Transplante de Rim , Humanos , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/tratamento farmacológico , Estudos de Coortes , Colchicina , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Transplante de Rim/efeitos adversos , Interleucina-1 , Estudos Retrospectivos , Proteína C-Reativa , Pontuação de Propensão , Proteinúria/complicaçõesRESUMO
BACKGROUND: The aim of this study was to evaluate the efficacy and safety of anti-interleukin-1 (IL-1) therapies in colchicine-resistant pediatric patients with familial Mediterranean fever (FMF). METHODS: In this study, we retrospectively evaluated 656 children with FMF and 27 patients who had been treated with anti-IL-1 therapies (anakinra/canakinumab) . Clinical and laboratory features, MEFV gene mutations, treatment responses were investigated. RESULTS: Twenty of the patients were treated with anakinra (the treatment of 6 patients who initially used anakinra was switched to canakinumab in the follow-up period), and 13 patients were treated with canakinumab. Clinical symptom and severity scores decreased in all patients A decrease in acute phase reactants was also observed in patients. A total of 18 (66%) patients had a M694V homozygous mutation, while 24 (89%) patients had a M694V mutation, at least in one allele. CONCLUSIONS: FMF patients with colchicine resistance may progress to amyloidosis. IL-1 antagonist treatment could be used safely with a favorable outcome in pediatric patients with FMF resistance to colchicine therapy and/or who have renal amyloidosis.
Assuntos
Amiloidose , Febre Familiar do Mediterrâneo , Humanos , Criança , Febre Familiar do Mediterrâneo/tratamento farmacológico , Febre Familiar do Mediterrâneo/genética , Febre Familiar do Mediterrâneo/diagnóstico , Colchicina/efeitos adversos , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/efeitos adversos , Interleucina-1/uso terapêutico , Estudos Retrospectivos , Amiloidose/induzido quimicamente , Amiloidose/tratamento farmacológico , Pirina/genéticaRESUMO
PURPOSE OF THE REVIEW: We review the pathophysiology, diagnosis, and contemporary treatment for recurrent pericarditis, with focus on interleukin-1 (IL-1) inhibitors. RECENT FINDINGS: Recurrent pericarditis occurs in about 15-30% of patients who have acute pericarditis. With increased understanding of the autoinflammatory pathophysiology of recurrent pericarditis, IL-1 inhibitors including anakinra, canakinumab, and rilonacept have been applied to this condition with great promise. In particular, the RHAPSODY trial found rilonacept significantly improves pain and inflammation, while also reducing recurrence with few adverse events. The next IL-1 inhibitor on the block for pericarditis, goflikicept, is also discussed. Understanding the role of the inflammasome via the autoinflammatory pathway in pericarditis has led to incorporation of IL-1 inhibitors in the treatment of recurrent pericarditis, with proven efficacy and safety and randomized trials. This will lead to increase uptake of this agent which demonstrated lower rates of recurrence and faster time to resolution.
Assuntos
Pericardite , Humanos , Pericardite/tratamento farmacológico , Pericardite/induzido quimicamente , Inflamação , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Recidiva , Interleucina-1RESUMO
Familial Mediterranean fever (FMF) is a genetic autoinflammatory disease that is characterized by recurrent episodes of fever, serositis, and synovitis. FMF synovitis attacks resemble the clinical presentation of acute monoarthritis with pain and hydrarthrosis, which always resolve spontaneously. In most cases, colchicine will prevent these painful arthritis attacks in FMF. However, distinguishing these arthritis episodes from other febrile attacks with various clinical manifestations, including serositis, is important. We describe a Japanese patient with FMF who presented a febrile attack with severe abdominal and upper back pain (peri-scapula lesion), without any other joint involvement. A 44-year-old female patient presented with recurrent episodes of fever with abdominal and back pain. She carried heterozygous variants in exon 3 of the MEFV gene (P369S/R408Q). She was diagnosed with FMF according to Tel-Hashomer's diagnostic criteria for FMF. Colchicine treatment improved her febrile attcks with peritonitis, however, severe back pain was sustained. This unique aspect of severe pain attack was successfully resolved by canakinumab treatment, which is a specific interleukin-1ß monoclonal antibody, and was finally diagnosed as FMF-related shoulder joint synovitis. Further investigations were needed to evaluate the effectiveness of interleukin-1 antagonists against colchicine-resistant arthritis in FMF patients.
Assuntos
Artrite , Febre Familiar do Mediterrâneo , Serosite , Sinovite , Humanos , Feminino , Adulto , Febre Familiar do Mediterrâneo/complicações , Febre Familiar do Mediterrâneo/diagnóstico , Febre Familiar do Mediterrâneo/tratamento farmacológico , Serosite/tratamento farmacológico , Colchicina/uso terapêutico , Dor nas Costas/etiologia , Dor nas Costas/tratamento farmacológico , Artrite/tratamento farmacológico , Sinovite/tratamento farmacológico , Pirina/genéticaRESUMO
Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease characterized by intermittent fever and a combination of symptoms, such as an evanescent rash synchronous with fever, arthralgia/arthritis, lymphadenopathy and hepatosplenomegaly. The diagnosis is based on a characteristic constellation of symptoms and the exclusion of infections, hemato-oncological diseases, infectious diseases and alternative rheumatological causes. The systemic inflammatory reaction is reflected by high levels of ferritin and Creactive protein (CRP). The pharmacological treatment concept includes glucocorticoids often in combination with methotrexate (MTX) and ciclosporine (CSA) for reduction of steroids. The interleukin 1 (IL-1) receptor antagonist anakinra, the IL-1beta antibody canakinumab or an IL6 receptor blockage with tocilizumab (off label for AOSD) are used where there is no response to MTX or CSA. Anakinra or canakinumab can be used as a primary option in AOSD in cases of moderate and severe disease activity.
Assuntos
Artrite , Reumatologia , Doença de Still de Início Tardio , Adulto , Humanos , Doença de Still de Início Tardio/diagnóstico , Doença de Still de Início Tardio/tratamento farmacológico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Metotrexato/uso terapêutico , Artrite/tratamento farmacológico , Febre/etiologiaRESUMO
OBJECTIVES: The objective of the study was to report the efficacy and safety of canakinumab treatment in Japanese patients with systemic juvenile idiopathic arthritis (sJIA) over a 48-week study period. METHODS: Patients were administered canakinumab 4 mg/kg (maximum dose 300 mg) every 4 weeks, with no dose adjustments. The key outcome measures included adapted American College of Rheumatology paediatric (aACR pedi) 30/50/70/90/100 response, proportion of patients with inactive disease, and corticosteroid (CS) tapering. RESULTS: In total, 16/19 (84.2%) patients received canakinumab for ≥96 weeks reaching end-of-study (EOS) visit without premature discontinuation. Regardless of the level of joint involvement at baseline, high aACR pedi responses were observed throughout the study; at the EOS, aACR pedi 90/100 response rates were 84.2%/63.2%, respectively. The proportion of patients who successfully tapered CSs at EOS was 66.7% (12/18), of which 10 patients were steroid-free. The most common adverse events were infections (238.3 events/100 patient-years). Serious adverse events were observed in 52.6%. The event (n=1) adjudicated as possible macrophage activation syndrome was preceded by sJIA flare. No deaths were reported. CONCLUSIONS: Canakinumab treatment resulted in a sustained treatment response in sJIA patients over 48 weeks and was associated with CS tapering in majority of patients. No new safety findings were reported.
Assuntos
Antirreumáticos , Artrite Juvenil , Humanos , Criança , Artrite Juvenil/tratamento farmacológico , Anticorpos Monoclonais/uso terapêutico , População do Leste Asiático , Anticorpos Monoclonais Humanizados/uso terapêutico , Corticosteroides/uso terapêutico , Resultado do Tratamento , Antirreumáticos/uso terapêuticoRESUMO
OBJECTIVES: To assess the real-world safety and effectiveness of canakinumab in patients in Japan with tumour necrosis factor receptor-associated periodic syndrome (TRAPS) or mevalonate kinase deficiency/hyperimmunoglobulinaemia D with periodic fever syndrome (MKD/HIDS). METHODS: All patients with TRAPS or MKD/HIDS who received canakinumab following drug approval in Japan were registered in a post-marketing all-patient surveillance with a 2-year observation period. Herein, the interim results are reported. RESULTS: Fifteen patients with TRAPS and seven with MKD/HIDS were included in the safety and effectiveness analysis set. Adverse drug reactions were reported in 26.67% (n = 4) and 42.86% (n = 3) of TRAPS and MKD/HIDS patients, respectively. Most common adverse drug reactions were upper respiratory tract inflammation (13.33%, n = 2) and pyrexia (42.86%, n = 3) in TRAPS and MKD/HIDS patients, respectively. No serious adverse drug reactions were observed in either TRAPS or MKD/HIDS patients. The proportion of responders was 46.67% and 14.29% in the TRAPS and MKD/HIDS groups, respectively; 72.73% and 66.67% achieved clinical remission, while 90.91% and 66.67% achieved serological remission by Week 4 in the TRAPS and MKD/HIDS groups, respectively. CONCLUSIONS: These interim results provide the first evidence of the real-world effectiveness of canakinumab in patients with TRAPS or MKD/HIDS in Japan. No new safety concerns were identified.