BACKGROUND: JAK-inhibitors (JAKi), recently approved in rheumatoid arthritis (RA), have changed the landscape of treatment choices. We aimed to compare the effectiveness of four current second-line therapies of RA with different modes of action, since JAKi approval, in an international collaboration of 19 registers. METHODS: In this observational cohort study, patients initiating tumour necrosis factor inhibitors (TNFi), interleukin-6 inhibitors (IL-6i), abatacept (ABA) or JAKi were included. We compared the effectiveness of these treatments in terms of drug discontinuation and Clinical Disease Activity Index (CDAI) response rates at 1 year. Analyses were adjusted for patient, disease and treatment characteristics, including lines of therapy and accounted for competing risk. RESULTS: We included 31 846 treatment courses: 17 522 TNFi, 2775 ABA, 3863 IL-6i and 7686 JAKi. Adjusted analyses of overall discontinuation were similar across all treatments. The main single reason of stopping treatment was ineffectiveness. Compared with TNFi, JAKi were less often discontinued for ineffectiveness (adjusted HR (aHR) 0.75, 95% CI 0.67 to 0.83), as was IL-6i (aHR 0.76, 95% CI 0.67 to 0.85) and more often for adverse events (aHR 1.16, 95% CI 1.03 to 1.33). Adjusted CDAI response rates at 1 year were similar between TNFi, JAKi and IL-6i and slightly lower for ABA. CONCLUSION: The adjusted overall drug discontinuation and 1 year response rates of JAKi and IL-6i were similar to those observed with TNFi. Compared with TNFi, JAKi were more often discontinued for adverse events and less for ineffectiveness, as were IL-6i.

• Klíčová slova
• Arthritis, Rheumatoid, Biological Therapy, Epidemiology, Therapeutics, Tumor Necrosis Factor Inhibitors,
• MeSH
• abatacept terapeutické užití   MeSH
• antirevmatika * terapeutické užití   MeSH
• inhibitory Janus kinas * terapeutické užití   MeSH
• inhibitory TNF MeSH
• interleukin-6 MeSH
• lidé MeSH
• revmatoidní artritida * chemicky indukované   farmakoterapie   MeSH
• TNF-alfa MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• abatacept MeSH
• antirevmatika * MeSH
• inhibitory Janus kinas * MeSH
• inhibitory TNF MeSH
• interleukin-6 MeSH
• TNF-alfa MeSH

OBJECTIVE: To assess the long-term safety, tolerability, and effectiveness of tocilizumab (TCZ) as monotherapy or in combination with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) in clinical practice in patients with moderate to severe rheumatoid arthritis (RA). METHODS: Patients in the 24-week, open-label ACT-SURE study who had at least a moderate EULAR response by week 24 and were from a participating country were eligible for this long-term extension (LTE); the patients continued to receive TCZ 8 mg/kg intravenously every 4 weeks as monotherapy or in combination with ≥ 1 csDMARD for up to an additional 108 weeks. The primary endpoint was the incidence of adverse events (AEs) and serious AEs (SAEs). Effectiveness endpoints included Disease Activity Score in 28 joints (DAS28) responses, American College of Rheumatology (ACR) responses, and patient-reported outcomes (PROs). RESULTS: Of the 1102 patients who completed the core 24-week study, 934 participated in the LTE; the median exposure to TCZ was 64.3 weeks. From baseline to the end of the LTE, AEs and SAEs occurred in 90% and 9% of patients, respectively. The overall event rates (95% CI) of AEs and SAEs were 406.5 per 100 patient-years (PY) (395.5, 417.8) and 8.8 per 100 PY (7.3, 10.6), respectively. Mean (SD) improvement in DAS28 was 4.12 (1.18), P < 0.0001. The DAS28 remission rates, ACR response rates, and PRO scores were maintained during the LTE study. CONCLUSION: In clinical practice, TCZ as monotherapy or in combination with csDMARDs was safe, well tolerated, and efficacious in patients with moderate to severe RA.

• Klíčová slova
• Monotherapy, Rheumatoid arthritis, Safety, Tocilizumab,
• MeSH
• antirevmatika škodlivé účinky   terapeutické užití   MeSH
• dospělí MeSH
• glukokortikoidy škodlivé účinky   terapeutické užití   MeSH
• humanizované monoklonální protilátky škodlivé účinky   terapeutické užití   MeSH
• inhibitory TNF škodlivé účinky   terapeutické užití   MeSH
• kombinovaná farmakoterapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• revmatoidní artritida diagnóza   farmakoterapie   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• antirevmatika MeSH
• glukokortikoidy MeSH
• humanizované monoklonální protilátky MeSH
• inhibitory TNF MeSH
• tocilizumab MeSH Prohlížeč

BACKGROUND: This double-blind, active-controlled, randomized, multinational study evaluated the efficacy, safety, pharmacokinetics (PK), and immunogenicity of PF-06438179/GP1111 (IxifiTM/Zessly®), an infliximab biosimilar, vs infliximab (Remicade®) reference product sourced from the European Union (infliximab-EU) in biologic-naïve patients with moderate to severe active rheumatoid arthritis (RA) despite methotrexate therapy. This paper reports results from the initial 30-week treatment period. METHODS: Patients (N = 650) were stratified by geographic region and randomized 1:1 to PF-06438179/GP1111 or infliximab-EU (3 mg/kg intravenous at weeks 0, 2, and 6, then every 8 weeks). Dose escalation to 5 mg/kg was allowed starting at week 14 for patients with inadequate RA response. The primary endpoint was American College of Rheumatology criteria for ≥ 20% clinical improvement (ACR20) response at week 14. Therapeutic equivalence was declared if the two-sided 95% CI for the treatment difference was within the symmetric equivalence margin of ± 13.5%. Statistical analysis was also performed with a two-sided 90% CI using an asymmetric equivalence margin (- 12.0%, 15.0%). RESULTS: Patients (80.3% female; 79.4% seropositive) had a mean RA duration of 6.9 years, and mean baseline Disease Activity Score in 28 joints, four components based on C-reactive protein was 6.0 in both arms. Week 14 ACR20 in the intention-to-treat population was 62.7% for PF-06438179/GP1111 and 64.1% for infliximab-EU. Week 14 ACR20 using nonresponder imputation was 61.1% for PF-06438179/GP1111 and 63.5% for infliximab-EU, and the 95% (- 9.92%, 5.11%) and 90% (- 8.75%, 4.02%) CIs for the treatment difference (- 2.39%) were entirely contained within the prespecified symmetric and asymmetric equivalence margins, respectively. No differences were observed between arms for secondary efficacy endpoints. Overall postdose antidrug antibody (ADA) rates through week 30 were 48.6% and 51.2% for PF-06438179/GP1111 and infliximab-EU, respectively. Efficacy and immunogenicity were similar between treatments for patients with dose escalation (at or after week 14), as well as between treatments for patients without dose escalation. Safety profiles of PF-06438179/GP1111 and infliximab-EU were similar, with no clinically meaningful differences observed between arms, including after ADA development. Serum drug concentrations were similar between arms at each time point during the initial 30-week treatment period. CONCLUSION: PF-06438179/GP1111 and infliximab-EU demonstrated similar efficacy, safety, immunogenicity, and PK with or without dose escalation in patients with moderate to severe active RA on background methotrexate. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02222493 . Registered on 21 August 2014. EudraCT, 2013-004148-49 . Registered on 14 July 2014.

• Klíčová slova
• Biosimilar, Dose escalation, Infliximab, PF-06438179/GP1111, Rheumatoid arthritis,
• MeSH
• antirevmatika farmakokinetika   terapeutické užití   MeSH
• biosimilární léčivé přípravky farmakokinetika   terapeutické užití   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• infliximab farmakokinetika   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát terapeutické užití   MeSH
• revmatoidní artritida farmakoterapie   MeSH
• senioři MeSH
• terapeutická ekvivalence 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
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antirevmatika MeSH
• biosimilární léčivé přípravky MeSH
• GP1111 MeSH Prohlížeč
• infliximab MeSH
• methotrexát MeSH

OBJECTIVES: SB2 is a biosimilar to the reference infliximab (INF). Similar efficacy, safety and immunogenicity between SB2 and INF up to 30 weeks were previously reported. This report investigates such clinical similarity up to 54 weeks, including structural joint damage. METHODS: In this phase III, double-blind, parallel-group, multicentre study, patients with moderate to severe RA despite MTX were randomized (1:1) to receive 3 mg/kg of either SB2 or INF at 0, 2, 6 and every 8 weeks thereafter. Dose escalation by 1.5 mg/kg up to a maximum dose of 7.5 mg/kg was allowed after week 30. Efficacy, safety and immunogenicity were measured at each visit up to week 54. Radiographic damage evaluated by modified total Sharp score was measured at baseline and week 54. RESULTS: A total of 584 patients were randomized to receive SB2 (n = 291) or INF (n = 293). The rate of radiographic progression was comparable between SB2 and INF (mean modified total Sharp score difference: SB2, 0.38; INF, 0.37) at 1 year. ACR responses, 28-joint DAS, Clinical Disease Activity Index and Simplified Disease Activity Index were comparable between SB2 and INF up to week 54. The incidence of treatment-emergent adverse events and anti-drug antibodies were comparable between treatment groups. Such comparable trends of efficacy, safety and immunogenicity were consistent from baseline up to 54 weeks. The pattern of dose increment was also comparable between SB2 and INF. CONCLUSION: SB2 maintained similar efficacy, safety and immunogenicity with INF up to 54 weeks in patients with moderate to severe RA. Radiographic progression was comparable at 1 year. TRIAL REGISTRATION: ClinicalTrials.gov (http://clinicaltrials.gov; NCT01936181) and EudraCT (https://www.clinicaltrialsregister.eu; 2012-005733-37).

• Klíčová slova
• Flixabi, Remicade, Renflexis, Sharp score, biosimilar, infliximab, monoclonal antibody, radiographic progression, rheumatoid arthritis, tumour necrosis factor blocker,
• MeSH
• antirevmatika aplikace a dávkování   škodlivé účinky   MeSH
• biosimilární léčivé přípravky aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• infliximab aplikace a dávkování   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nežádoucí účinky léčiv epidemiologie   etiologie   MeSH
• progrese nemoci MeSH
• rentgendiagnostika metody   MeSH
• revmatoidní artritida diagnostické zobrazování   farmakoterapie   MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antirevmatika MeSH
• biosimilární léčivé přípravky MeSH
• infliximab MeSH

OBJECTIVES: To compare the efficacy, safety, immunogenicity and pharmacokinetics (PK) of SB2 to the infliximab reference product (INF) in patients with moderate to severe rheumatoid arthritis (RA) despite methotrexate therapy. METHODS: This is a phase III, randomised, double-blind, multinational, multicentre parallel group study. Patients with moderate to severe RA despite methotrexate therapy were randomised in a 1:1 ratio to receive either SB2 or INF of 3 mg/kg. The primary end point was the American College of Rheumatology 20% (ACR20) response at week 30. Inclusion of the 95% CI of the ACR20 response difference within a ±15% margin was required for equivalence. RESULTS: 584 subjects were randomised into SB2 (N=291; 290 analysed) or INF (N=293). The ACR20 response at week 30 in the per-protocol set was 64.1% in SB2 versus 66.0% in INF. The adjusted rate difference was -1.88% (95% CI -10.26% to 6.51%), which was within the predefined equivalence margin. Other efficacy outcomes such as ACR50/70, disease activity score measured by 28 joints and European League against Rheumatism response were similar between SB2 and INF. The incidence of treatment-emergent adverse events was comparable (57.6% in SB2 vs 58.0% in INF) as well as the incidence of antidrug antibodies (ADA) to infliximab up to week 30 (55.1% in SB2 vs 49.7% in INF). The PK profile was similar between SB2 and INF. Efficacy, safety and PK by ADA subgroup were comparable between SB2 and INF. CONCLUSIONS: SB2 was equivalent to INF in terms of ACR20 response at week 30. SB2 was well tolerated with a comparable safety profile, immunogenicity and PK to INF. TRIAL REGISTRATION NUMBER: NCT01936181.

• Klíčová slova
• Anti-TNF, DMARDs (biologic), Disease Activity, Rheumatoid Arthritis,
• MeSH
• antirevmatika škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• biosimilární léčivé přípravky škodlivé účinky   farmakokinetika   terapeutické užití   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• infliximab škodlivé účinky   imunologie   farmakokinetika   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• methotrexát terapeutické užití   MeSH
• protilátky krev   MeSH
• revmatoidní artritida farmakoterapie   MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• terapeutická ekvivalence 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
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• antirevmatika MeSH
• biosimilární léčivé přípravky MeSH
• infliximab MeSH
• methotrexát MeSH
• protilátky MeSH

OBJECTIVES: Our initiative aimed to produce recommendations on post-randomised controlled trial (RCT) trial extension studies (TES) reporting using European League Against Rheumatism (EULAR) standard operating procedures in order to achieve more meaningful output and standardisation of reports. METHODS: We formed a task force of 22 participants comprising RCT experts, clinical epidemiologists and patient representatives. A two-stage Delphi survey was conducted to discuss the domains of evaluation of a TES and definitions. A '0-10' agreement scale assessed each domain and definition. The resulting set of recommendations was further refined and a final vote taken for task force acceptance. RESULTS: Seven key domains and individual components were evaluated and led to agreed recommendations including definition of a TES (100% agreement), minimal data necessary (100% agreement), method of data analysis (agreement mean (SD) scores ranging between 7.9 (0.84) and 9.0 (2.16)) and reporting of results as well as ethical issues. Key recommendations included reporting of absolute numbers at each stage from the RCT to TES with reasons given for drop-out at each stage, and inclusion of a flowchart detailing change in numbers at each stage and focus (mean (SD) agreement 9.9 (0.36)). A final vote accepted the set of recommendations. CONCLUSIONS: This EULAR task force provides recommendations for implementation in future TES to ensure a standardised approach to reporting. Use of this document should provide the rheumatology community with a more accurate and meaningful output from future TES, enabling better understanding and more confident application in clinical practice towards improving patient outcomes.

• Klíčová slova
• DMARDs (biologic), Epidemiology, Rheumatoid Arthritis,
• MeSH
• delfská metoda MeSH
• lidé MeSH
• poradní výbory MeSH
• randomizované kontrolované studie jako téma * MeSH
• revmatologie * MeSH
• výzkumná zpráva normy   MeSH
• výzkumný projekt MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• směrnice MeSH

Rheumatoid arthritis (RA) is a model of multigenic inflammatory disorder in which tumor necrosis factor-alpha (TNF-alpha) plays an important role. Genetic factors may be implicated in the susceptibility to disease initiation as well as in severity of disease course. Elevated levels of TNF-alpha in the plasma and synovial fluid from RA patients may be associated with polymorphisms in the promoter region of the TNF-alpha gene. The aim of this study was to elucidate putative association between the -308 G/A polymorphism in the promoter region of the TNF-alpha gene and susceptibility to onset and severity of RA. A total of 130 RA patients and a control group of 150 healthy subjects with similar age and sex distribution were available for the study. All patients fulfilled the American College of Rheumatology revised criteria for RA. RA patients had a disease duration of at least 2 years. Radiographs of both hands of all RA patients were scored with the Steinbrocker method. There were 15 patients of stage I (nonerosive form) of RA and 114 patients of stages II-IV (erosive form). To assess the RA patient's functional ability, the Health Assessment Questionnaire (HAQ) was used. The -308 G/A promoter polymorphism of the TNF-alpha gene was detected by polymerase chain reaction and restriction fragment length polymorphism analysis. No differences in genotype distribution and allelic frequences of -308 G/A TNF-alpha promoter polymorphism have been found between RA patients and the control group. Significant differences have been observed within the RA group divided according to the radiographic progression of disease based on the Steinbrocker radiographic score and functional ability (HAQ). These results suggest an association of the -308 G/A polymorphism of the TNF-alpha gene with the severity of RA.

• MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetické markery MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymorfismus délky restrikčních fragmentů * MeSH
• promotorové oblasti (genetika) * MeSH
• průzkumy a dotazníky MeSH
• revmatoidní artritida krev   diagnóza   genetika   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stupeň závažnosti nemoci MeSH
• synoviální tekutina metabolismus   MeSH
• TNF-alfa genetika   metabolismus   MeSH
• zdravotní stav 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
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• genetické markery MeSH
• TNF-alfa MeSH