BACKGROUND: Targeting interleukin (IL)-6 has become a major therapeutic strategy in the treatment of immune-mediated inflammatory disease. Interference with the IL-6 pathway can be directed at the specific receptor using anti-IL-6Rα antibodies or by directly inhibiting the IL-6 cytokine. This paper is an update of a previous consensus document, based on most recent evidence and expert opinion, that aims to inform on the medical use of interfering with the IL-6 pathway. METHODS: A systematic literature research was performed that focused on IL-6-pathway inhibitors in inflammatory diseases. Evidence was put in context by a large group of international experts and patients in a subsequent consensus process. All were involved in formulating the consensus statements, and in the preparation of this document. RESULTS: The consensus process covered relevant aspects of dosing and populations for different indications of IL-6 pathway inhibitors that are approved across the world, including rheumatoid arthritis, polyarticular-course and systemic juvenile idiopathic arthritis, giant cell arteritis, Takayasu arteritis, adult-onset Still's disease, Castleman's disease, chimeric antigen receptor-T-cell-induced cytokine release syndrome, neuromyelitis optica spectrum disorder and severe COVID-19. Also addressed were other clinical aspects of the use of IL-6 pathway inhibitors, including pretreatment screening, safety, contraindications and monitoring. CONCLUSIONS: The document provides a comprehensive consensus on the use of IL-6 inhibition to treat inflammatory disorders to inform healthcare professionals (including researchers), patients, administrators and payers.

• MeSH
• COVID-19 MeSH
• dospělí MeSH
• interleukin-6 MeSH
• lidé MeSH
• receptory interleukinu-6 * antagonisté a inhibitory   MeSH
• revmatoidní artritida farmakoterapie   MeSH
• Stillova nemoc dospělých farmakoterapie   MeSH
• zánět * farmakoterapie   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• konsensus - konference MeSH
• práce podpořená grantem MeSH

OBJECTIVES: RF and ACPA are used as diagnostic tools and their presence has been associated with clinical response to some biologic DMARDs (bDMARDs) in RA. This study compared the impact of seropositivity on drug discontinuation and effectiveness of bDMARDs in patients with RA, using head-to-head comparisons in a real-world setting. METHODS: We conducted a pooled analysis of 16 observational RA registries. Inclusion criteria were a diagnosis of RA, initiation of treatment with rituximab (RTX), abatacept (ABA), tocilizumab (TCZ) or TNF inhibitors (TNFis) and available information on RF and/or ACPA status. Drug discontinuation was analysed using Cox regression, including drug, seropositivity, their interaction, adjusting for concomitant and past treatments and patient and disease characteristics and accounting for country and calendar year of bDMARD initiation. Effectiveness was analysed using the Clinical Disease Activity Index evolution over time. RESULTS: Among the 27 583 eligible patients, the association of seropositivity with drug discontinuation differed across bDMARDs (P for interaction <0.001). The adjusted hazard ratios for seropositive compared with seronegative patients were 1.01 (95% CI 0.95, 1.07) for TNFis, 0.89 (0.78, 1.02)] for TCZ, 0.80 (0.72, 0.88) for ABA and 0.70 (0.59, 0.84) for RTX. Adjusted differences in remission and low disease activity rates between seropositive and seronegative patients followed the same pattern, with no difference in TNFis, a small difference in TCZ, a larger difference in ABA and the largest difference in RTX (Lundex remission difference +5.9%, low disease activity difference +11.6%). CONCLUSION: Seropositivity was associated with increased effectiveness of non-TNFi bDMARDs, especially RTX and ABA, but not TNFis.

• MeSH
• antirevmatika * klasifikace   imunologie   terapeutické užití   MeSH
• biologické přípravky * klasifikace   imunologie   terapeutické užití   MeSH
• lékové interakce imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mezinárodní spolupráce MeSH
• monitorování imunologické * metody   statistika a číselné údaje   MeSH
• nenasazení léčby statistika a číselné údaje   MeSH
• posouzení stavu pacienta MeSH
• registrace statistika a číselné údaje   MeSH
• revmatoidní artritida * diagnóza   farmakoterapie   epidemiologie   imunologie   MeSH
• revmatoidní faktor krev   MeSH
• trvání terapie MeSH
• výběr pacientů MeSH
• výsledek terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH

BACKGROUND: Biopharmaceutical products (BPs) are widely used to treat autoimmune diseases, but immunogenicity limits their efficacy for an important proportion of patients. Our knowledge of patient-related factors influencing the occurrence of antidrug antibodies (ADAs) is still limited. METHODS AND FINDINGS: The European consortium ABIRISK (Anti-Biopharmaceutical Immunization: prediction and analysis of clinical relevance to minimize the RISK) conducted a clinical and genomic multicohort prospective study of 560 patients with multiple sclerosis (MS, n = 147), rheumatoid arthritis (RA, n = 229), Crohn's disease (n = 148), or ulcerative colitis (n = 36) treated with 8 different biopharmaceuticals (etanercept, n = 84; infliximab, n = 101; adalimumab, n = 153; interferon [IFN]-beta-1a intramuscularly [IM], n = 38; IFN-beta-1a subcutaneously [SC], n = 68; IFN-beta-1b SC, n = 41; rituximab, n = 31; tocilizumab, n = 44) and followed during the first 12 months of therapy for time to ADA development. From the bioclinical data collected, we explored the relationships between patient-related factors and the occurrence of ADAs. Both baseline and time-dependent factors such as concomitant medications were analyzed using Cox proportional hazard regression models. Mean age and disease duration were 35.1 and 0.85 years, respectively, for MS; 54.2 and 3.17 years for RA; and 36.9 and 3.69 years for inflammatory bowel diseases (IBDs). In a multivariate Cox regression model including each of the clinical and genetic factors mentioned hereafter, among the clinical factors, immunosuppressants (adjusted hazard ratio [aHR] = 0.408 [95% confidence interval (CI) 0.253-0.657], p < 0.001) and antibiotics (aHR = 0.121 [0.0437-0.333], p < 0.0001) were independently negatively associated with time to ADA development, whereas infections during the study (aHR = 2.757 [1.616-4.704], p < 0.001) and tobacco smoking (aHR = 2.150 [1.319-3.503], p < 0.01) were positively associated. 351,824 Single-Nucleotide Polymorphisms (SNPs) and 38 imputed Human Leukocyte Antigen (HLA) alleles were analyzed through a genome-wide association study. We found that the HLA-DQA1*05 allele significantly increased the rate of immunogenicity (aHR = 3.9 [1.923-5.976], p < 0.0001 for the homozygotes). Among the 6 genetic variants selected at a 20% false discovery rate (FDR) threshold, the minor allele of rs10508884, which is situated in an intron of the CXCL12 gene, increased the rate of immunogenicity (aHR = 3.804 [2.139-6.764], p < 1 × 10-5 for patients homozygous for the minor allele) and was chosen for validation through a CXCL12 protein enzyme-linked immunosorbent assay (ELISA) on patient serum at baseline before therapy start. CXCL12 protein levels were higher for patients homozygous for the minor allele carrying higher ADA risk (mean: 2,693 pg/ml) than for the other genotypes (mean: 2,317 pg/ml; p = 0.014), and patients with CXCL12 levels above the median in serum were more prone to develop ADAs (aHR = 2.329 [1.106-4.90], p = 0.026). A limitation of the study is the lack of replication; therefore, other studies are required to confirm our findings. CONCLUSION: In our study, we found that immunosuppressants and antibiotics were associated with decreased risk of ADA development, whereas tobacco smoking and infections during the study were associated with increased risk. We found that the HLA-DQA1*05 allele was associated with an increased rate of immunogenicity. Moreover, our results suggest a relationship between CXCL12 production and ADA development independent of the disease, which is consistent with its known function in affinity maturation of antibodies and plasma cell survival. Our findings may help physicians in the management of patients receiving biotherapies.

• MeSH
• adalimumab terapeutické užití   MeSH
• autoimunitní nemoci farmakoterapie   genetika   MeSH
• biologická terapie metody   MeSH
• biologické přípravky imunologie   terapeutické užití   MeSH
• celogenomová asociační studie metody   MeSH
• Crohnova nemoc farmakoterapie   genetika   MeSH
• dospělí MeSH
• HLA-DQ alfa řetězec genetika   MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• imunosupresiva terapeutické užití   MeSH
• infliximab terapeutické užití   MeSH
• interferon beta 1a terapeutické užití   MeSH
• kohortové studie MeSH
• lidé středního věku MeSH
• lidé MeSH
• prospektivní studie MeSH
• revmatoidní artritida farmakoterapie   genetika   MeSH
• rituximab terapeutické užití   MeSH
• roztroušená skleróza farmakoterapie   genetika   MeSH
• ulcerózní kolitida farmakoterapie   genetika   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Some evidences suggest that obesity impairs the effectiveness of TNF inhibitors. We examined the impact of body mass index (BMI) on the clinical effectiveness of abatacept in rheumatoid arthritis (RA) patients. This is a pooled analysis of 10 prospective cohorts of RA patients. All patients with available BMI were included in this study. The primary endpoint was drug retention of abatacept in the different BMI categories. Multivariable Cox regression was used to estimate hazard ratios (HRs) for drug discontinuation. A secondary endpoint was EULAR/LUNDEX response rates at 6/12 months. Of the 2015 RA patients initiating therapy with IV abatacept, 380 (18.9%) were classified as obese. Obese patients had more functional disability, and were less often RF positive. The median abatacept retention time was 1.91 years for obese RA patients compared to 2.12 years for non-obese patients (p = 0.15). The risk of abatacept discontinuation was not significantly different for overweight (HR 1.03 (95% CI 0.89-1.19)), or for obese (HR 1.08 (95% CI 0.89-1.30)) compared to normal-weight patients. Rheumatoid factor positivity reduced the risk of abatacept discontinuation (HR 0.83 (95% CI 0.72-0.95)), while previous biologic therapy was positively associated with drug interruption (HRs increasing from 1.68 to 2.16 with the line of treatments). Obese and non-obese patients attained similar rates of EULAR/LUNDEX clinical response at 6/12 months. Drug retention and clinical response rates to abatacept do not seem to be decreased by obesity in RA patients.

• MeSH
• abatacept aplikace a dávkování   škodlivé účinky   MeSH
• antirevmatika aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• index tělesné hmotnosti * MeSH
• indukce remise MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• multivariační analýza MeSH
• proporcionální rizikové modely MeSH
• prospektivní studie MeSH
• registrace MeSH
• revmatoidní artritida farmakoterapie   MeSH
• revmatoidní faktor krev   MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• multicentrická studie MeSH
• Geografické názvy
• Evropa MeSH

BACKGROUND: Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes. METHODS: Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD. RESULTS: Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population. CONCLUSION: This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.

• MeSH
• antirevmatika terapeutické užití   MeSH
• B-buněčný lymfom epidemiologie   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lymfom T-buněčný epidemiologie   etiologie   MeSH
• lymfom epidemiologie   etiologie   patologie   MeSH
• nehodgkinský lymfom epidemiologie   etiologie   MeSH
• registrace MeSH
• revmatoidní artritida komplikace   farmakoterapie   MeSH
• rizikové faktory MeSH
• tumor nekrotizující faktory antagonisté a inhibitory   MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH

OBJECTIVES: Some studies have reported a possible association between exposure to tumour necrosis factor (TNF) inhibitors and an increased risk of melanoma. The aim of this study was to investigate the incidence of invasive cutaneous melanomas in patients with rheumatoid arthritis (RA) treated with TNF inhibitors (TNFi), other biologic disease modifying drugs and non-biologic therapy. METHODS: Eleven biologic registers from nine European countries participated in this collaborative project. According to predefined exposure definitions, cohorts of patients with RA were selected. Using the country-specific general population of each register as reference, age, sex and calendar year standardised incidence ratios (SIRs) of invasive histology-confirmed cutaneous melanoma were calculated within each register. Pooled SIR and incidence rate ratios (IRRs) comparing biologic cohorts to biologic-naïve were calculated across countries by taking the size of the register into account. RESULTS: Overall 130 315 RA patients with a mean age of 58 years contributing 579 983 person-years were available for the analysis and 287 developed a first melanoma. Pooled SIRs for biologic-naïve, TNFi and rituximab-exposed patients were 1.1 (95% CI 0.9 to 1.4), 1.2 (0.99 to 1.6) and 1.3 (0.6 to 2.6), respectively. Incidence rates in tocilizumab and abatacept-exposed patients were also not significantly increased. IRR versus biologic-naïve patients were: TNFi 1.1 (95% CI 0.8 to 1.6); rituximab 1.2 (0.5 to 2.9). CONCLUSIONS: This large European collaborative project did not confirm an overall increased risk of melanoma following exposure to TNFi.

• MeSH
• abatacept terapeutické užití   MeSH
• antirevmatika terapeutické užití   MeSH
• biologické přípravky terapeutické užití   MeSH
• dospělí MeSH
• humanizované monoklonální protilátky terapeutické užití   MeSH
• incidence MeSH
• lidé středního věku MeSH
• lidé MeSH
• melanom epidemiologie   MeSH
• nádory kůže epidemiologie   MeSH
• registrace * MeSH
• revmatoidní artritida farmakoterapie   MeSH
• rituximab terapeutické užití   MeSH
• rizikové faktory MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Evropa epidemiologie   MeSH

Recent insights in rheumatoid arthritis (RA) necessitated updating the European League Against Rheumatism (EULAR) RA management recommendations. A large international Task Force based decisions on evidence from 3 systematic literature reviews, developing 4 overarching principles and 12 recommendations (vs 3 and 14, respectively, in 2013). The recommendations address conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) (methotrexate (MTX), leflunomide, sulfasalazine); glucocorticoids (GC); biological (b) DMARDs (tumour necrosis factor (TNF)-inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab), abatacept, rituximab, tocilizumab, clazakizumab, sarilumab and sirukumab and biosimilar (bs) DMARDs) and targeted synthetic (ts) DMARDs (Janus kinase (Jak) inhibitors tofacitinib, baricitinib). Monotherapy, combination therapy, treatment strategies (treat-to-target) and the targets of sustained clinical remission (as defined by the American College of Rheumatology-(ACR)-EULAR Boolean or index criteria) or low disease activity are discussed. Cost aspects were taken into consideration. As first strategy, the Task Force recommends MTX (rapid escalation to 25 mg/week) plus short-term GC, aiming at >50% improvement within 3 and target attainment within 6 months. If this fails stratification is recommended. Without unfavourable prognostic markers, switching to-or adding-another csDMARDs (plus short-term GC) is suggested. In the presence of unfavourable prognostic markers (autoantibodies, high disease activity, early erosions, failure of 2 csDMARDs), any bDMARD (current practice) or Jak-inhibitor should be added to the csDMARD. If this fails, any other bDMARD or tsDMARD is recommended. If a patient is in sustained remission, bDMARDs can be tapered. For each recommendation, levels of evidence and Task Force agreement are provided, both mostly very high. These recommendations intend informing rheumatologists, patients, national rheumatology societies, hospital officials, social security agencies and regulators about EULAR's most recent consensus on the management of RA, aimed at attaining best outcomes with current therapies.

• MeSH
• antirevmatika terapeutické užití   MeSH
• časové faktory MeSH
• glukokortikoidy terapeutické užití   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• Janus kinasy antagonisté a inhibitory   MeSH
• kombinovaná farmakoterapie MeSH
• lidé MeSH
• methotrexát terapeutické užití   MeSH
• monoklonální protilátky terapeutické užití   MeSH
• náhrada léků MeSH
• revmatoidní artritida farmakoterapie   MeSH
• TNF-alfa antagonisté a inhibitory   MeSH
• zapojení pacienta MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH