Arthritis & rheumatology (Hoboken, N.J.), Dec 7, 2016
To compare the efficacy and safety of ABT-494, a novel selective Janus kinase 1 inhibitor, with p... more To compare the efficacy and safety of ABT-494, a novel selective Janus kinase 1 inhibitor, with placebo, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to ≥1 anti-tumor necrosis factor (TNF) therapy. In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 patients with ≥1 prior anti-TNF therapy on a stable methotrexate dose were randomized equally to immediate-release ABT-494 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was the proportion of patients achieving an ACR20 response at Week 12. At Week 12, significantly more patients in the ABT-494 groups (53-71%) versus placebo (34%) achieved an ACR20 response (NRI, P<0.05), with a dose-response relationship among all ABT-494 doses (P<0.001). ACR50/70 response rates were significantly higher in the ABT-494 groups (35-42% and 22-26%) versus placebo (ACR50, 16% and ACR70, 4%). Changes in DAS28(CRP) [ΔDAS28(CRP)] were significantly greater ...
To define the prevalence and clinical associations of clinical and imaging definitions of synovit... more To define the prevalence and clinical associations of clinical and imaging definitions of synovitis in unselected SLE patients with musculoskeletal (MSK) symptoms. 112 patients with SLE (excluding RF and CCP positive patients); 88 consecutive with inflammatory MSK symptoms and 24 asymptomatic SLE controls were recruited. Patients had clinical assessment (BILAG, SLEDAI, joint counts, patient and physician visual analogue score), routine laboratory tests and US of two hands and wrists (synovitis and tenosynovitis, OMERACT definitions). Overall, 68% (60/88) of symptomatic patients had US inflammation (grey scale ⩾ 2 and/or PD ⩾ 1 or tenosynovitis) compared with 17% (4/23) of asymptomatic patients. In symptomatic patients, clinical inflammation was seen defined by BILAG A or B in 38% (34/88) or defined by the SLEDAI-MSK criterion in 32% (28/88). BILAG A/B had sensitivity (95% CI) of 56% (41, 69%) and specificity of 89% (72, 96%) for US-confirmed inflammation. SLEDAI-MSK criterion had se...
Health technology assessment (Winchester, England), 2018
Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic in... more Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population. To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy. Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status. UK outpatient rheumatology departments. Patients...
ObjectiveTo assess factors associated with primary and secondary non-response to rituximab in sys... more ObjectiveTo assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR).Methods125 patients with SLE treated with rituximab over 12 years were studied prospectively. A major clinical response was defined as improvement of all active British Isles Lupus Assessment Group (BILAG)-2004 domains to grade C/better and no A/B flare. Partial responders were defined by one persistent BILAG B. B-cell subsets were measured using highly sensitive flow cytometry. Patients with 2NDNR, defined by infusion reaction and defective depletion, were treated with ocrelizumab or ofatumumab.Results117 patients had evaluable data. In cycle 1 (C1), 96/117 (82%) achieved BILAG response (major=50%, partial=32%). In multivariable analysis, younger age (OR 0.97, 95% CI 0.94 to 1.00) and B-cell depletion at 6 weeks (OR 3.22, 95% CI 1.24 to 8.33) increased the odds of major response. Comp...
The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis.... more The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the past few decades from arthroplasty and blind needle biopsy to the use of arthroscopic and ultrasonographic technologies that enable easier visualization and improve the reliability of synovial biopsies. Rapid progress has been made in using synovial tissue to study disease pathogenesis, to stratify patients, to discover biomarkers and novel targets, and to validate therapies, and this progress has been facilitated by increasingly diverse and sophisticated analytical and technological approaches. In this Review, we describe these approaches, and summarize how their use in synovial tissue research has improved our understanding of rheumatoid arthritis and identified candidate biomarkers that could be used in disease diagnosis and stratification, as well as in predicting disease course and treatment response.
Improvements in the control of inflammation in rheumatoid arthritis (RA) by conventional syntheti... more Improvements in the control of inflammation in rheumatoid arthritis (RA) by conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have led to a substantial change in the clinical outcomes of patients during the last 30 years. Current treatment can lead to sustained remission in some patients raising questions about the optimal management strategies in this subgroup of patients. Today, tapering of DMARDs and even their discontinuation appears as an interesting concept for achieving a more tailored and dynamic treatment approach of RA, especially in patients, who achieved full disease control by DMARD treatment. In this review article, current developments of DMARD tapering are discussed. The article provides an overview of existing studies on this topic and addresses new strategies to reach drug-free remission. Furthermore, concepts for defining patients eligible for DMARD tapering are described and potential future strategies in using biomarkers in predi...
Arthritis & rheumatology (Hoboken, N.J.), Jan 23, 2015
Objective The immunopathogenesis of SLE is heterogeneous. Responses to rituximab in skin are vari... more Objective The immunopathogenesis of SLE is heterogeneous. Responses to rituximab in skin are variable. We performed a detailed assessment of cutaneous responses to determine the phenotype of rituximab-responsive disease. Methods 82 SLE patients receiving rituximab were prospectively studied. 32 had significant skin involvement before or after treatment. Disease activity was assessed using BILAG-2004. Cutaneous lupus subtype was classified by a dermatologist as acute, subacute or chronic cutaneous lupus erythematosus (ACLE, SCLE, CCLE) or other skin diseases, with supportive photographs or biopsies where necessary. Results 10/26 (39%) patients with baseline skin disease had a beneficial cutaneous response to rituximab at 6 months with good response in ACLE (6/14, 43%), and poor responses in CCLE (0/8, p=0.034). Clinical response was associated with negative anti-RNP (p=0.024) and anti-Ro (p=0.035) serology. Flares of SCLE and CCLE occurred in 12 patients who either had no skin diseas...
Data from clinical trials highlighted the potential and pitfalls of the use of biologics to treat... more Data from clinical trials highlighted the potential and pitfalls of the use of biologics to treat systemic lupus erythematosus. With improved understanding of immunopathogenesis and lessons learned from controlled trials, there is a growing optimism for personalized treatment from an increasing range of targeted therapies.
Objective.Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in ... more Objective.Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA).Methods.Patients from the 1-year, double-blind Abatacept in Inadequate Responders to Methotrexate (AIM) study (NCT00048568) received open-label ABA (∼10 mg/kg) in the longterm extension (LTE). Safety was assessed for patients who received ≥ 1 ABA dose, and efficacy for patients randomized to ABA and treated in the LTE. Radiographs were evaluated for changes in Genant-modified Sharp scores.Results.Out of 652 patients, 539 entered the LTE (ABA, n = 378; placebo, n = 161). At Year 5, 72.4% were ongoing; discontinuation rates declined over time. Incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 13.87, 2.84, 1.45, and 0.99 events/100 patient-years exposure, respectively. American College of Rheumatology 20 response was 82.3% (n = 373) and 83.6% (n = 268) at years 1 and 5...
Objective.To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years i... more Objective.To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis.Methods.Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years.Results.Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respective...
Objective.To determine the relationship between radiographic progression and clinical response fo... more Objective.To determine the relationship between radiographic progression and clinical response for adalimumab plus methotrexate (MTX) versus either monotherapy in patients with early rheumatoid arthritis (RA) in the PREMIER study.Methods.Patients with early RA who received adalimumab plus MTX (n = 240), adalimumab (n = 222), or MTX (n = 216) were grouped by American College of Rheumatology (ACR) response, 28-joint Disease Activity Score (DAS28), or remission-like state [tender joint count (TJC) = 0; DAS28 < 2.6; swollen joint count = 0; ACR100] at 26 and 104 weeks. Radiographic progression was assessed by cumulative probability plots, mean changes in total Sharp score (ΔTSS), and percentages of progressors (ΔTSS > 0.5).Results.Across the spectrum of clinical outcomes, including ACR20 nonresponses and remission-like responses, therapy with adalimumab plus MTX permitted less radiographic progression at Weeks 26 and 104 than MTX monotherapy. Adalimumab monotherapy was generally i...
Arthritis & rheumatology (Hoboken, N.J.), Dec 7, 2016
To compare the efficacy and safety of ABT-494, a novel selective Janus kinase 1 inhibitor, with p... more To compare the efficacy and safety of ABT-494, a novel selective Janus kinase 1 inhibitor, with placebo, in patients with moderate-to-severe rheumatoid arthritis (RA) and an inadequate response or intolerance to ≥1 anti-tumor necrosis factor (TNF) therapy. In this 12-week, double-blind, placebo-controlled, dose-ranging study, 276 patients with ≥1 prior anti-TNF therapy on a stable methotrexate dose were randomized equally to immediate-release ABT-494 3, 6, 12, or 18 mg twice daily or placebo. The primary endpoint was the proportion of patients achieving an ACR20 response at Week 12. At Week 12, significantly more patients in the ABT-494 groups (53-71%) versus placebo (34%) achieved an ACR20 response (NRI, P<0.05), with a dose-response relationship among all ABT-494 doses (P<0.001). ACR50/70 response rates were significantly higher in the ABT-494 groups (35-42% and 22-26%) versus placebo (ACR50, 16% and ACR70, 4%). Changes in DAS28(CRP) [ΔDAS28(CRP)] were significantly greater ...
To define the prevalence and clinical associations of clinical and imaging definitions of synovit... more To define the prevalence and clinical associations of clinical and imaging definitions of synovitis in unselected SLE patients with musculoskeletal (MSK) symptoms. 112 patients with SLE (excluding RF and CCP positive patients); 88 consecutive with inflammatory MSK symptoms and 24 asymptomatic SLE controls were recruited. Patients had clinical assessment (BILAG, SLEDAI, joint counts, patient and physician visual analogue score), routine laboratory tests and US of two hands and wrists (synovitis and tenosynovitis, OMERACT definitions). Overall, 68% (60/88) of symptomatic patients had US inflammation (grey scale ⩾ 2 and/or PD ⩾ 1 or tenosynovitis) compared with 17% (4/23) of asymptomatic patients. In symptomatic patients, clinical inflammation was seen defined by BILAG A or B in 38% (34/88) or defined by the SLEDAI-MSK criterion in 32% (28/88). BILAG A/B had sensitivity (95% CI) of 56% (41, 69%) and specificity of 89% (72, 96%) for US-confirmed inflammation. SLEDAI-MSK criterion had se...
Health technology assessment (Winchester, England), 2018
Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic in... more Rheumatoid arthritis (RA), the most common autoimmune disease in the UK, is a chronic systemic inflammatory arthritis that affects 0.8% of the UK population. To determine whether or not an alternative class of biologic disease-modifying antirheumatic drugs (bDMARDs) are comparable to rituximab in terms of efficacy and safety outcomes in patients with RA in whom initial tumour necrosis factor inhibitor (TNFi) bDMARD and methotrexate (MTX) therapy failed because of inefficacy. Multicentre, Phase III, open-label, parallel-group, three-arm, non-inferiority randomised controlled trial comparing the clinical and cost-effectiveness of alternative TNFi and abatacept with that of rituximab (and background MTX therapy). Eligible consenting patients were randomised in a 1 : 1 : 1 ratio using minimisation incorporating a random element. Minimisation factors were centre, disease duration, non-response category and seropositive/seronegative status. UK outpatient rheumatology departments. Patients...
ObjectiveTo assess factors associated with primary and secondary non-response to rituximab in sys... more ObjectiveTo assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR).Methods125 patients with SLE treated with rituximab over 12 years were studied prospectively. A major clinical response was defined as improvement of all active British Isles Lupus Assessment Group (BILAG)-2004 domains to grade C/better and no A/B flare. Partial responders were defined by one persistent BILAG B. B-cell subsets were measured using highly sensitive flow cytometry. Patients with 2NDNR, defined by infusion reaction and defective depletion, were treated with ocrelizumab or ofatumumab.Results117 patients had evaluable data. In cycle 1 (C1), 96/117 (82%) achieved BILAG response (major=50%, partial=32%). In multivariable analysis, younger age (OR 0.97, 95% CI 0.94 to 1.00) and B-cell depletion at 6 weeks (OR 3.22, 95% CI 1.24 to 8.33) increased the odds of major response. Comp...
The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis.... more The synovium is the major target tissue of inflammatory arthritides such as rheumatoid arthritis. The study of synovial tissue has advanced considerably throughout the past few decades from arthroplasty and blind needle biopsy to the use of arthroscopic and ultrasonographic technologies that enable easier visualization and improve the reliability of synovial biopsies. Rapid progress has been made in using synovial tissue to study disease pathogenesis, to stratify patients, to discover biomarkers and novel targets, and to validate therapies, and this progress has been facilitated by increasingly diverse and sophisticated analytical and technological approaches. In this Review, we describe these approaches, and summarize how their use in synovial tissue research has improved our understanding of rheumatoid arthritis and identified candidate biomarkers that could be used in disease diagnosis and stratification, as well as in predicting disease course and treatment response.
Improvements in the control of inflammation in rheumatoid arthritis (RA) by conventional syntheti... more Improvements in the control of inflammation in rheumatoid arthritis (RA) by conventional synthetic and biologic disease-modifying antirheumatic drugs (DMARDs) have led to a substantial change in the clinical outcomes of patients during the last 30 years. Current treatment can lead to sustained remission in some patients raising questions about the optimal management strategies in this subgroup of patients. Today, tapering of DMARDs and even their discontinuation appears as an interesting concept for achieving a more tailored and dynamic treatment approach of RA, especially in patients, who achieved full disease control by DMARD treatment. In this review article, current developments of DMARD tapering are discussed. The article provides an overview of existing studies on this topic and addresses new strategies to reach drug-free remission. Furthermore, concepts for defining patients eligible for DMARD tapering are described and potential future strategies in using biomarkers in predi...
Arthritis & rheumatology (Hoboken, N.J.), Jan 23, 2015
Objective The immunopathogenesis of SLE is heterogeneous. Responses to rituximab in skin are vari... more Objective The immunopathogenesis of SLE is heterogeneous. Responses to rituximab in skin are variable. We performed a detailed assessment of cutaneous responses to determine the phenotype of rituximab-responsive disease. Methods 82 SLE patients receiving rituximab were prospectively studied. 32 had significant skin involvement before or after treatment. Disease activity was assessed using BILAG-2004. Cutaneous lupus subtype was classified by a dermatologist as acute, subacute or chronic cutaneous lupus erythematosus (ACLE, SCLE, CCLE) or other skin diseases, with supportive photographs or biopsies where necessary. Results 10/26 (39%) patients with baseline skin disease had a beneficial cutaneous response to rituximab at 6 months with good response in ACLE (6/14, 43%), and poor responses in CCLE (0/8, p=0.034). Clinical response was associated with negative anti-RNP (p=0.024) and anti-Ro (p=0.035) serology. Flares of SCLE and CCLE occurred in 12 patients who either had no skin diseas...
Data from clinical trials highlighted the potential and pitfalls of the use of biologics to treat... more Data from clinical trials highlighted the potential and pitfalls of the use of biologics to treat systemic lupus erythematosus. With improved understanding of immunopathogenesis and lessons learned from controlled trials, there is a growing optimism for personalized treatment from an increasing range of targeted therapies.
Objective.Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in ... more Objective.Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA).Methods.Patients from the 1-year, double-blind Abatacept in Inadequate Responders to Methotrexate (AIM) study (NCT00048568) received open-label ABA (∼10 mg/kg) in the longterm extension (LTE). Safety was assessed for patients who received ≥ 1 ABA dose, and efficacy for patients randomized to ABA and treated in the LTE. Radiographs were evaluated for changes in Genant-modified Sharp scores.Results.Out of 652 patients, 539 entered the LTE (ABA, n = 378; placebo, n = 161). At Year 5, 72.4% were ongoing; discontinuation rates declined over time. Incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 13.87, 2.84, 1.45, and 0.99 events/100 patient-years exposure, respectively. American College of Rheumatology 20 response was 82.3% (n = 373) and 83.6% (n = 268) at years 1 and 5...
Objective.To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years i... more Objective.To evaluate the safety and efficacy of abatacept plus methotrexate (MTX) over 5 years in patients with rheumatoid arthritis.Methods.Patients were randomized to abatacept 10 or 2 mg/kg or placebo, plus MTX. Patients completing the 1-year, double-blind period entered the longterm extension, where all patients received a fixed dose of abatacept ~10 mg/kg. We describe safety analyses for all patients who received at least 1 dose of abatacept and efficacy analyses for the original ~10 mg/kg abatacept-treated group, over 5 years.Results.Of the 235 abatacept- or placebo-treated patients completing the double-blind period, 219 entered the longterm extension; 130 (59.4%) were continuing at Year 5. No unexpected safety events were observed during the longterm extension compared with the double-blind period. Incidence rates of adverse events (AE) and serious AE were 489.7 and 20.0/100 patient-years in Year 1 versus 374.9 and 18.9/100 patient-years in the cumulative period, respective...
Objective.To determine the relationship between radiographic progression and clinical response fo... more Objective.To determine the relationship between radiographic progression and clinical response for adalimumab plus methotrexate (MTX) versus either monotherapy in patients with early rheumatoid arthritis (RA) in the PREMIER study.Methods.Patients with early RA who received adalimumab plus MTX (n = 240), adalimumab (n = 222), or MTX (n = 216) were grouped by American College of Rheumatology (ACR) response, 28-joint Disease Activity Score (DAS28), or remission-like state [tender joint count (TJC) = 0; DAS28 < 2.6; swollen joint count = 0; ACR100] at 26 and 104 weeks. Radiographic progression was assessed by cumulative probability plots, mean changes in total Sharp score (ΔTSS), and percentages of progressors (ΔTSS > 0.5).Results.Across the spectrum of clinical outcomes, including ACR20 nonresponses and remission-like responses, therapy with adalimumab plus MTX permitted less radiographic progression at Weeks 26 and 104 than MTX monotherapy. Adalimumab monotherapy was generally i...
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