IntroductionInflammatory arthritis (IA) conditions, including rheumatoid arthritis, psoriatic art... more IntroductionInflammatory arthritis (IA) conditions, including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, are characterised by inflammatory infiltration of the joints. Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), respectively, reduce the effects of proinflammatory cytokines and immune cells to ameliorate disease. However, immunosuppression can be associated with high rates of serious adverse events (SAEs), including serious infections, and maybe an increased risk of malignancies and cardiovascular events. Currently, there is no empirical evidence on the extent to which contextual factors and risk of bias (RoB) domains may modify these harm signals in randomised trials.Methods and analysisWe will search MEDLINE (via PubMed) for systematic reviews published since April 2015 and all Cochrane reviews. From these reviews, randomised trials will be eligible if they include pat...
Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment de... more Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks’ treatment with baricitinib, adalimumab or placebo in the 52-week RA-BEAM phase III study. Adults with active RA and inadequate response to methotrexate received baricitinib 4 mg once daily, adalimumab 40 mg every two weeks or placebo, with background methotrexate. Patients (N = 1010) were categorised as in remission, in remission or low disease activity, or not in remission or low disease activity at week 24. For patients in remission or low disease activity (n = 310), improvements in mean pain and physical function scores at week 24 were significantly greater with baricitinib than placebo (p < 0.001 and p < 0.01, respectively) and adalimumab (p < 0.05 for both). For both outcomes, differences between adalimumab and placebo we...
Objective To evaluate flare risk when tapering or withdrawing biologic or targeted synthetic DMAR... more Objective To evaluate flare risk when tapering or withdrawing biologic or targeted synthetic DMARDs (bDMARDs or tsDMARDs) compared with continuation in patients with inflammatory arthritis in sustained remission or with low disease activity. Methods Articles were identified in the Cochrane Library, PubMed, Embase and Web of Science. Eligible trials were randomized controlled trials comparing tapering and/or withdrawal of bDMARDs and/or tsDMARDs with the standard dose in inflammatory arthritis. Random effects meta-analysis was performed with risk ratio (RR) or Peto’s odds ratio (POR) for sparse events and 95% CI. Results The meta-analysis comprised 22 trials: 11 assessed tapering and 7 addressed withdrawal (4 assessed both). Only trials with an RA or axial SpA (axSpA) population were identified. An increased flare risk was demonstrated when b-/tsDMARD tapering was compared with continuation [RR 1.45 (95% CI 1.19, 1.77), I2 = 42.5%] and potentially increased for persistent flare [POR ...
Comorbidities in patients with rheumatoid arthritis (RA) are often associated with poor health ou... more Comorbidities in patients with rheumatoid arthritis (RA) are often associated with poor health outcomes and increased mortality. Treatment decisions should take into account these comorbidities due to known or suspected associations with certain drug classes. In clinical practice, it is critical to balance potential treatment benefit against the possible risks for comorbidities as well as the articular manifestations of RA. This review summarises the current literature relating to prevalence and risk factors for the important comorbidities of cardiovascular disease, infections, lymphomas and nonmelanoma skin cancers in patients with RA. The impact on patient outcomes and the interplay between these comorbidities and the therapeutic options currently available, including tumour necrosis factor inhibitors and newer biological therapies, are also explored. As newer RA therapies are developed, and patients gain wider and earlier access to advanced therapies, in part due to the emergence...
Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis... more Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis (RA) at every stage of its evolution. Its attributes include good overall efficacy for signs and symptoms, inhibition of structural damage and preservation of function with acceptable and manageable safety, a large dose-titratable range, options for either an oral or parenteral route of administration, and currently unrivalled cost-effectiveness. It has a place as a monotherapy and also as an anchor drug that can be safely used in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or used concomitantly with biological DMARDs or targeted synthetic DMARDs. MTX is not without potential issues regarding toxicity, notably hepatotoxicity and bone marrow toxicity, as well as tolerability problems for some, but not all, patients. But many of these issues can be mitigated or managed. In the face of a welcome expansion in available targeted therapies fo...
International Journal of Rheumatic Diseases, May 17, 2023
AimCertolizumab pegol (CZP), an Fc‐free, PEGylated tumor necrosis factor inhibitor (TNFi), has sh... more AimCertolizumab pegol (CZP), an Fc‐free, PEGylated tumor necrosis factor inhibitor (TNFi), has shown rapid and sustained reduction in signs and symptoms of rheumatoid arthritis (RA). Elevated rheumatoid factor (RF) level has been associated with RA disease progression and poorer TNFi response. We assessed the efficacy of CZP in patients with early and established RA across baseline RF levels.MethodsThis post‐hoc analysis included data from 6 trials: C‐OPERA (NCT01451203), pooled RAPID trials (RAPID‐1 [NCT00152386], RAPID‐2 [NCT00160602], J‐RAPID [NCT00791999], RAPID‐C [NCT02151851]), and EXXELERATE (NCT01500278). Patients who received CZP or placebo/comparator with methotrexate (MTX) were categorized by baseline RF quartiles. Efficacy was assessed with Disease Activity Score‐28 erythrocyte sedimentation rate (DAS28‐ESR).ResultsOverall, 316, 1537, and 908 patients were included in C‐OPERA, pooled RAPID trials, and EXXELERATE, respectively. Patient demographics and baseline disease characteristics were similar between treatment groups and across RF quartiles. DAS28‐ESR low disease activity (LDA) and remission (REM) rates were numerically higher in the CZP + MTX group than PBO + MTX group at weeks 12 and 24, across RF quartiles. LDA and REM rates in the CZP + MTX groups were comparable across RF quartiles at weeks 12 and 24. Mean DAS28‐ESR decreased from week 0 to week 24 in the CZP + MTX groups, across RF quartiles.ConclusionCZP showed steady efficacy across baseline RF quartiles in patients with early and established RA, over 24 weeks. CZP treatment may be considered in patients with RA irrespective of baseline RF levels and time from diagnosis.
Therapeutic Advances in Musculoskeletal Disease, 2022
Anti-tumour necrosis factors (anti-TNFs) are established as first-line biological therapy for rhe... more Anti-tumour necrosis factors (anti-TNFs) are established as first-line biological therapy for rheumatoid arthritis (RA) with over two decades of accumulated clinical experience. Anti-TNFs have well established efficacy/safety profiles along with additional benefits on various comorbidities. However, up to 40% of patients may respond inadequately to an initial anti-TNF treatment because of primary non-response, loss of response, or intolerance. Following inadequate response (IR) to anti-TNF treatment, clinicians can consider switching to an alternative anti-TNF (cycling) or to another class of targeted drug with a different mechanism of action, such as Janus kinase inhibitors, interleukin-6 receptor blockers, B-cell depletion agents, and co-stimulation inhibitors (swapping). While European League Against Rheumatism recommendations for pharmacotherapeutic management of RA, published in 2020, are widely regarded as helpful guides to clinical practice, they do not provide any clear recommendations on therapeutic choices following an IR to first-line anti-TNF. This suggests that both cycling and swapping treatment strategies are of equal value, but that the treating physician must take the patient’s individual characteristics into account. This article considers which patient characteristics influence clinical decision-making processes, including the reason for treatment failure, previous therapies, comorbidities, extra-articular manifestations, pregnancy, patient preference and cost-effectiveness, and what evidence is available to support decisions made by the physician.
IntroductionInflammatory arthritis (IA) conditions, including rheumatoid arthritis, psoriatic art... more IntroductionInflammatory arthritis (IA) conditions, including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, are characterised by inflammatory infiltration of the joints. Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), respectively, reduce the effects of proinflammatory cytokines and immune cells to ameliorate disease. However, immunosuppression can be associated with high rates of serious adverse events (SAEs), including serious infections, and maybe an increased risk of malignancies and cardiovascular events. Currently, there is no empirical evidence on the extent to which contextual factors and risk of bias (RoB) domains may modify these harm signals in randomised trials.Methods and analysisWe will search MEDLINE (via PubMed) for systematic reviews published since April 2015 and all Cochrane reviews. From these reviews, randomised trials will be eligible if they include pat...
Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment de... more Patients with rheumatoid arthritis (RA) may experience residual pain and functional impairment despite good control of disease activity. This study compared improvements in pain and physical function in patients with well-controlled RA after 24 weeks’ treatment with baricitinib, adalimumab or placebo in the 52-week RA-BEAM phase III study. Adults with active RA and inadequate response to methotrexate received baricitinib 4 mg once daily, adalimumab 40 mg every two weeks or placebo, with background methotrexate. Patients (N = 1010) were categorised as in remission, in remission or low disease activity, or not in remission or low disease activity at week 24. For patients in remission or low disease activity (n = 310), improvements in mean pain and physical function scores at week 24 were significantly greater with baricitinib than placebo (p < 0.001 and p < 0.01, respectively) and adalimumab (p < 0.05 for both). For both outcomes, differences between adalimumab and placebo we...
Objective To evaluate flare risk when tapering or withdrawing biologic or targeted synthetic DMAR... more Objective To evaluate flare risk when tapering or withdrawing biologic or targeted synthetic DMARDs (bDMARDs or tsDMARDs) compared with continuation in patients with inflammatory arthritis in sustained remission or with low disease activity. Methods Articles were identified in the Cochrane Library, PubMed, Embase and Web of Science. Eligible trials were randomized controlled trials comparing tapering and/or withdrawal of bDMARDs and/or tsDMARDs with the standard dose in inflammatory arthritis. Random effects meta-analysis was performed with risk ratio (RR) or Peto’s odds ratio (POR) for sparse events and 95% CI. Results The meta-analysis comprised 22 trials: 11 assessed tapering and 7 addressed withdrawal (4 assessed both). Only trials with an RA or axial SpA (axSpA) population were identified. An increased flare risk was demonstrated when b-/tsDMARD tapering was compared with continuation [RR 1.45 (95% CI 1.19, 1.77), I2 = 42.5%] and potentially increased for persistent flare [POR ...
Comorbidities in patients with rheumatoid arthritis (RA) are often associated with poor health ou... more Comorbidities in patients with rheumatoid arthritis (RA) are often associated with poor health outcomes and increased mortality. Treatment decisions should take into account these comorbidities due to known or suspected associations with certain drug classes. In clinical practice, it is critical to balance potential treatment benefit against the possible risks for comorbidities as well as the articular manifestations of RA. This review summarises the current literature relating to prevalence and risk factors for the important comorbidities of cardiovascular disease, infections, lymphomas and nonmelanoma skin cancers in patients with RA. The impact on patient outcomes and the interplay between these comorbidities and the therapeutic options currently available, including tumour necrosis factor inhibitors and newer biological therapies, are also explored. As newer RA therapies are developed, and patients gain wider and earlier access to advanced therapies, in part due to the emergence...
Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis... more Methotrexate (MTX) is a remarkable drug with a key role in the management of rheumatoid arthritis (RA) at every stage of its evolution. Its attributes include good overall efficacy for signs and symptoms, inhibition of structural damage and preservation of function with acceptable and manageable safety, a large dose-titratable range, options for either an oral or parenteral route of administration, and currently unrivalled cost-effectiveness. It has a place as a monotherapy and also as an anchor drug that can be safely used in combination with other conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or used concomitantly with biological DMARDs or targeted synthetic DMARDs. MTX is not without potential issues regarding toxicity, notably hepatotoxicity and bone marrow toxicity, as well as tolerability problems for some, but not all, patients. But many of these issues can be mitigated or managed. In the face of a welcome expansion in available targeted therapies fo...
International Journal of Rheumatic Diseases, May 17, 2023
AimCertolizumab pegol (CZP), an Fc‐free, PEGylated tumor necrosis factor inhibitor (TNFi), has sh... more AimCertolizumab pegol (CZP), an Fc‐free, PEGylated tumor necrosis factor inhibitor (TNFi), has shown rapid and sustained reduction in signs and symptoms of rheumatoid arthritis (RA). Elevated rheumatoid factor (RF) level has been associated with RA disease progression and poorer TNFi response. We assessed the efficacy of CZP in patients with early and established RA across baseline RF levels.MethodsThis post‐hoc analysis included data from 6 trials: C‐OPERA (NCT01451203), pooled RAPID trials (RAPID‐1 [NCT00152386], RAPID‐2 [NCT00160602], J‐RAPID [NCT00791999], RAPID‐C [NCT02151851]), and EXXELERATE (NCT01500278). Patients who received CZP or placebo/comparator with methotrexate (MTX) were categorized by baseline RF quartiles. Efficacy was assessed with Disease Activity Score‐28 erythrocyte sedimentation rate (DAS28‐ESR).ResultsOverall, 316, 1537, and 908 patients were included in C‐OPERA, pooled RAPID trials, and EXXELERATE, respectively. Patient demographics and baseline disease characteristics were similar between treatment groups and across RF quartiles. DAS28‐ESR low disease activity (LDA) and remission (REM) rates were numerically higher in the CZP + MTX group than PBO + MTX group at weeks 12 and 24, across RF quartiles. LDA and REM rates in the CZP + MTX groups were comparable across RF quartiles at weeks 12 and 24. Mean DAS28‐ESR decreased from week 0 to week 24 in the CZP + MTX groups, across RF quartiles.ConclusionCZP showed steady efficacy across baseline RF quartiles in patients with early and established RA, over 24 weeks. CZP treatment may be considered in patients with RA irrespective of baseline RF levels and time from diagnosis.
Therapeutic Advances in Musculoskeletal Disease, 2022
Anti-tumour necrosis factors (anti-TNFs) are established as first-line biological therapy for rhe... more Anti-tumour necrosis factors (anti-TNFs) are established as first-line biological therapy for rheumatoid arthritis (RA) with over two decades of accumulated clinical experience. Anti-TNFs have well established efficacy/safety profiles along with additional benefits on various comorbidities. However, up to 40% of patients may respond inadequately to an initial anti-TNF treatment because of primary non-response, loss of response, or intolerance. Following inadequate response (IR) to anti-TNF treatment, clinicians can consider switching to an alternative anti-TNF (cycling) or to another class of targeted drug with a different mechanism of action, such as Janus kinase inhibitors, interleukin-6 receptor blockers, B-cell depletion agents, and co-stimulation inhibitors (swapping). While European League Against Rheumatism recommendations for pharmacotherapeutic management of RA, published in 2020, are widely regarded as helpful guides to clinical practice, they do not provide any clear recommendations on therapeutic choices following an IR to first-line anti-TNF. This suggests that both cycling and swapping treatment strategies are of equal value, but that the treating physician must take the patient’s individual characteristics into account. This article considers which patient characteristics influence clinical decision-making processes, including the reason for treatment failure, previous therapies, comorbidities, extra-articular manifestations, pregnancy, patient preference and cost-effectiveness, and what evidence is available to support decisions made by the physician.
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