-
Clinical Rheumatology Sep 2023Systematic r eview to evaluate the quality of the clinical practice guidelines (CPG) for rheumatoid arthritis (RA) management and to provide a synthesis of high-quality... (Review)
Review
Systematic r eview to evaluate the quality of the clinical practice guidelines (CPG) for rheumatoid arthritis (RA) management and to provide a synthesis of high-quality CPG recommendations, highlighting areas of consistency, and inconsistency. Electronic searches of five databases and four online guideline repositories were performed. RA management CPGs were eligible for inclusion if they were written in English and published between January 2015 and February 2022; focused on adults ≥ 18 years of age; met the criteria of a CPG as defined by the Institute of Medicine; and were rated as high quality on the Appraisal of Guidelines for Research and Evaluation II instrument. RA CPGs were excluded if they required additional payment to access; only addressed recommendations for the system/organization of care and did not include interventional management recommendations; and/or included other arthritic conditions. Of 27 CPGs identified, 13 CPGs met eligibility criteria and were included. Non-pharmacological care should include patient education, patient-centered care, shared decision-making, exercise, orthoses, and a multi-disciplinary approach to care. Pharmacological care should include conventional synthetic disease modifying anti-rheumatic drugs (DMARDs), with methotrexate as the first-line choice. If monotherapy conventional synthetic DMARDs fail to achieve a treatment target, this should be followed by combination therapy conventional synthetic DMARDs (leflunomide, sulfasalazine, hydroxychloroquine), biologic DMARDS and targeted synthetic DMARDS. Management should also include monitoring, pre-treatment investigations and vaccinations, and screening for tuberculosis and hepatitis. Surgical care should be recommended if non-surgical care fails. This synthesis offers clear guidance of evidence-based RA care to healthcare providers. TRIAL REGISTRATION: The protocol for this review was registered with Open Science Framework ( https://doi.org/10.17605/OSF.IO/UB3Y7 ).
Topics: Adult; Humans; Antirheumatic Agents; Arthritis, Rheumatoid; Hydroxychloroquine; Methotrexate; Sulfasalazine; Practice Guidelines as Topic
PubMed: 37291382
DOI: 10.1007/s10067-023-06654-0 -
The Cochrane Database of Systematic... Jul 2023Psoriasis is an immune-mediated disease with either skin or joints manifestations, or both, and it has a major impact on quality of life. Although there is currently no... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Psoriasis is an immune-mediated disease with either skin or joints manifestations, or both, and it has a major impact on quality of life. Although there is currently no cure for psoriasis, various treatment strategies allow sustained control of disease signs and symptoms. The relative benefit of these treatments remains unclear due to the limited number of trials comparing them directly head-to-head, which is why we chose to conduct a network meta-analysis.
OBJECTIVES
To compare the benefits and harms of non-biological systemic agents, small molecules, and biologics for people with moderate-to-severe psoriasis using a network meta-analysis, and to provide a ranking of these treatments according to their benefits and harms.
SEARCH METHODS
For this update of the living systematic review, we updated our searches of the following databases monthly to October 2022: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and Embase.
SELECTION CRITERIA
Randomised controlled trials (RCTs) of systemic treatments in adults over 18 years with moderate-to-severe plaque psoriasis, at any stage of treatment, compared to placebo or another active agent. The primary outcomes were: proportion of participants who achieved clear or almost clear skin, that is, at least Psoriasis Area and Severity Index (PASI) 90; proportion of participants with serious adverse events (SAEs) at induction phase (8 to 24 weeks after randomisation).
DATA COLLECTION AND ANALYSIS
We conducted duplicate study selection, data extraction, risk of bias assessment, and analyses. We synthesised data using pairwise and network meta-analysis (NMA) to compare treatments and rank them according to effectiveness (PASI 90 score) and acceptability (inverse of SAEs). We assessed the certainty of NMA evidence for the two primary outcomes and all comparisons using CINeMA, as very low, low, moderate, or high. We contacted study authors when data were unclear or missing. We used the surface under the cumulative ranking curve (SUCRA) to infer treatment hierarchy, from 0% (worst for effectiveness or safety) to 100% (best for effectiveness or safety).
MAIN RESULTS
This update includes an additional 12 studies, taking the total number of included studies to 179, and randomised participants to 62,339, 67.1% men, mainly recruited from hospitals. Average age was 44.6 years, mean PASI score at baseline was 20.4 (range: 9.5 to 39). Most studies were placebo-controlled (56%). We assessed a total of 20 treatments. Most (152) trials were multicentric (two to 231 centres). One-third of the studies (65/179) had high risk of bias, 24 unclear risk, and most (90) low risk. Most studies (138/179) declared funding by a pharmaceutical company, and 24 studies did not report a funding source. Network meta-analysis at class level showed that all interventions (non-biological systemic agents, small molecules, and biological treatments) showed a higher proportion of patients reaching PASI 90 than placebo. Anti-IL17 treatment showed a higher proportion of patients reaching PASI 90 compared to all the interventions. Biologic treatments anti-IL17, anti-IL12/23, anti-IL23, and anti-TNF alpha showed a higher proportion of patients reaching PASI 90 than the non-biological systemic agents. For reaching PASI 90, the most effective drugs when compared to placebo were (SUCRA rank order, all high-certainty evidence): infliximab (risk ratio (RR) 49.16, 95% CI 20.49 to 117.95), bimekizumab (RR 27.86, 95% CI 23.56 to 32.94), ixekizumab (RR 27.35, 95% CI 23.15 to 32.29), risankizumab (RR 26.16, 95% CI 22.03 to 31.07). Clinical effectiveness of these drugs was similar when compared against each other. Bimekizumab and ixekizumab were significantly more likely to reach PASI 90 than secukinumab. Bimekizumab, ixekizumab, and risankizumab were significantly more likely to reach PASI 90 than brodalumab and guselkumab. Infliximab, anti-IL17 drugs (bimekizumab, ixekizumab, secukinumab, and brodalumab), and anti-IL23 drugs except tildrakizumab were significantly more likely to reach PASI 90 than ustekinumab, three anti-TNF alpha agents, and deucravacitinib. Ustekinumab was superior to certolizumab. Adalimumab, tildrakizumab, and ustekinumab were superior to etanercept. No significant difference was shown between apremilast and two non-biological drugs: ciclosporin and methotrexate. We found no significant difference between any of the interventions and the placebo for the risk of SAEs. The risk of SAEs was significantly lower for participants on methotrexate compared with most of the interventions. Nevertheless, the SAE analyses were based on a very low number of events with very low- to moderate-certainty evidence for all the comparisons. The findings therefore have to be viewed with caution. For other efficacy outcomes (PASI 75 and Physician Global Assessment (PGA) 0/1), the results were similar to the results for PASI 90. Information on quality of life was often poorly reported and was absent for several of the interventions.
AUTHORS' CONCLUSIONS
Our review shows that, compared to placebo, the biologics infliximab, bimekizumab, ixekizumab, and risankizumab were the most effective treatments for achieving PASI 90 in people with moderate-to-severe psoriasis on the basis of high-certainty evidence. This NMA evidence is limited to induction therapy (outcomes measured from 8 to 24 weeks after randomisation), and is not sufficient for evaluating longer-term outcomes in this chronic disease. Moreover, we found low numbers of studies for some of the interventions, and the young age (mean 44.6 years) and high level of disease severity (PASI 20.4 at baseline) may not be typical of patients seen in daily clinical practice. We found no significant difference in the assessed interventions and placebo in terms of SAEs, and the safety evidence for most interventions was very low to moderate quality. More randomised trials directly comparing active agents are needed, and these should include systematic subgroup analyses (sex, age, ethnicity, comorbidities, psoriatic arthritis). To provide long-term information on the safety of treatments included in this review, an evaluation of non-randomised studies is needed. Editorial note: This is a living systematic review. Living systematic reviews offer a new approach to review updating, in which the review is continually updated, incorporating relevant new evidence as it becomes available. Please refer to the Cochrane Database of Systematic Reviews for the current status of this review.
Topics: Adult; Male; Humans; Female; Ustekinumab; Methotrexate; Infliximab; Network Meta-Analysis; Systematic Reviews as Topic; Psoriasis; Tumor Necrosis Factor-alpha; Biological Products
PubMed: 37436070
DOI: 10.1002/14651858.CD011535.pub6 -
Journal of the American Academy of... Feb 2024For people with atopic dermatitis (AD) refractory to topical therapies, treatment with phototherapy and systemic therapies can be considered. Multiple biologic therapies...
BACKGROUND
For people with atopic dermatitis (AD) refractory to topical therapies, treatment with phototherapy and systemic therapies can be considered. Multiple biologic therapies and Janus kinase (JAK)inhibitors have been approved since 2014 to treat AD. These guidelines update the 2014 recommendations for management of AD with phototherapy and systemic therapies.
OBJECTIVE
To provide evidence-based recommendations on the use of phototherapy and systemic therapies for AD in adults.
METHODS
A multidisciplinary workgroup conducted a systematic review and applied the GRADE approach for assessing the certainty of evidence and formulating and grading recommendations.
RESULTS
The workgroup developed 11 recommendations on the management of AD in adults with phototherapy and systemic agents, including biologics, oral JAK inhibitors, and other immunomodulatory medications.
LIMITATIONS
Most randomized controlled trials of phototherapy and systemic therapies for AD are of short duration with subsequent extension studies, limiting comparative long-term efficacy and safety conclusions.
CONCLUSIONS
We make strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and upadacitinib. We make conditional recommendations in favor of using phototherapy, azathioprine, cyclosporine, methotrexate, and mycophenolate, and against the use of systemic corticosteroids.
Topics: Adult; Humans; Cyclosporine; Dermatitis, Atopic; Immunosuppressive Agents; Janus Kinase Inhibitors; Methotrexate; Phototherapy
PubMed: 37943240
DOI: 10.1016/j.jaad.2023.08.102 -
Medicina (Kaunas, Lithuania) Oct 2023Elderly-onset rheumatoid arthritis (EORA) is a distinct clinical entity defined as the onset of rheumatoid arthritis (RA) in individuals aged over 60 years. EORA... (Review)
Review
Elderly-onset rheumatoid arthritis (EORA) is a distinct clinical entity defined as the onset of rheumatoid arthritis (RA) in individuals aged over 60 years. EORA presents unique clinical features, including a more equitable distribution of sexes, a potential predilection for male involvement, a higher incidence of acute onset characterized by constitutional symptoms, a propensity for systemic manifestations, elevated sedimentation rates at disease onset, a reduced occurrence of rheumatoid factor positivity, increased titers of anti-citrullinated protein antibodies, a preference for involvement of large joints, elevated disease activity, the presence of bone erosions, and heightened patient disability. RA is recognized to consist of three partially overlapping subsets. One subset mirrors the classical RA clinical presentation, while the remaining subsets exhibit either a polymyalgia rheumatica-like phenotype or present with remitting seronegative symmetrical synovitis accompanied by pitting edema syndrome. In the initial stages of EORA management, non-steroidal anti-inflammatory drugs (NSAIDs) are not typically the first-line treatment choice, because seniors are much more prone to develop side effects due to NSAIDs, and the use of NSAIDs is in reality contraindicated to the majority of seniors due to comorbidities. Disease-modifying antirheumatic drugs (DMARDs), frequently methotrexate, are introduced immediately after the diagnosis is made. In cases where elderly patients demonstrate resistance to conventional DMARD therapy, the introduction of biological or targeted synthetic DMARDs becomes a viable treatment option. EORA presents a unique clinical profile, necessitating tailored treatment strategies. Our study emphasizes the challenges of NSAID use in seniors, highlighting the imperative shift toward DMARDs such as methotrexate. Future research should explore personalized DMARD approaches based on disease activity, comorbidities, and safety considerations, aiming to optimize treatment outcomes and minimize glucocorticoid reliance, thereby enhancing the quality of care for EORA patients.
Topics: Aged; Humans; Male; Middle Aged; Methotrexate; Arthritis, Rheumatoid; Antirheumatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Treatment Outcome
PubMed: 37893596
DOI: 10.3390/medicina59101878 -
JAAPA : Official Journal of the... Sep 2023Rheumatoid arthritis (RA) affects about 1% of the world's population and can lead to loss of joint function, reduced mobility, and permanent damage to cartilage and... (Review)
Review
Rheumatoid arthritis (RA) affects about 1% of the world's population and can lead to loss of joint function, reduced mobility, and permanent damage to cartilage and bone. Treatment options for RA primarily include disease-modifying antirheumatic drugs (DMARDs) such as methotrexate, but the development of new drugs has complicated treatment decisions. Weighing treatment options for patients with RA largely depends on three major factors: efficacy, adverse reaction profile, and cost. A review of the literature supports methotrexate monotherapy as the current best-practice model for treating RA, compared with combination therapy of methotrexate and/or other DMARDs.
Topics: Humans; Methotrexate; Arthritis, Rheumatoid; Antirheumatic Agents; Combined Modality Therapy
PubMed: 37668490
DOI: 10.1097/01.JAA.0000937316.70181.ff -
Annals of the Rheumatic Diseases May 2024New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the...
OBJECTIVE
New modes of action and more data on the efficacy and safety of existing drugs in psoriatic arthritis (PsA) required an update of the EULAR 2019 recommendations for the pharmacological treatment of PsA.
METHODS
Following EULAR standardised operating procedures, the process included a systematic literature review and a consensus meeting of 36 international experts in April 2023. Levels of evidence and grades of recommendations were determined.
RESULTS
The updated recommendations comprise 7 overarching principles and 11 recommendations, and provide a treatment strategy for pharmacological therapies. Non-steroidal anti-inflammatory drugs should be used in monotherapy only for mild PsA and in the short term; oral glucocorticoids are not recommended. In patients with peripheral arthritis, rapid initiation of conventional synthetic disease-modifying antirheumatic drugs is recommended and methotrexate preferred. If the treatment target is not achieved with this strategy, a biological disease-modifying antirheumatic drug (bDMARD) should be initiated, without preference among modes of action. Relevant skin psoriasis should orient towards bDMARDs targeting interleukin (IL)-23p40, IL-23p19, IL-17A and IL-17A/F inhibitors. In case of predominant axial or entheseal disease, an algorithm is also proposed. Use of Janus kinase inhibitors is proposed primarily after bDMARD failure, taking relevant risk factors into account, or in case bDMARDs are not an appropriate choice. Inflammatory bowel disease and uveitis, if present, should influence drug choices, with monoclonal tumour necrosis factor inhibitors proposed. Drug switches and tapering in sustained remission are also addressed.
CONCLUSION
These updated recommendations integrate all currently available drugs in a practical and progressive approach, which will be helpful in the pharmacological management of PsA.
Topics: Arthritis, Psoriatic; Humans; Antirheumatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Methotrexate; Biological Products
PubMed: 38499325
DOI: 10.1136/ard-2024-225531 -
Arthritis & Rheumatology (Hoboken, N.J.) Nov 2023We investigated the comparative risk of infection with belimumab versus oral immunosuppressants for the treatment of systemic lupus erythematosus (SLE).
OBJECTIVE
We investigated the comparative risk of infection with belimumab versus oral immunosuppressants for the treatment of systemic lupus erythematosus (SLE).
METHODS
Using observational data from a US multicenter electronic health record database, we identified patients with SLE but without lupus nephritis who initiated belimumab, azathioprine, methotrexate, or mycophenolate between 2011 and 2021. We designed and emulated hypothetical target trials to estimate the cumulative incidence and hazard ratios (HRs) of serious infection and hospitalization for serious infection comparing belimumab versus each oral immunosuppressant. We used propensity score overlap weighting to balance baseline covariates and adjusted for adherence to treatment group using inverse probability of treatment weighting. We also assessed the control outcome of traumatic injury.
RESULTS
Among 21,481 patients, we compared 2841 and 6343 initiators of belimumab and azathioprine, 2642 and 8242 initiators of belimumab and methotrexate, and 2813 and 8407 initiators of belimumab and mycophenolate, respectively. After propensity score overlap weighting, all covariates were balanced in each comparison. The mean age of the cohort was 45 years, and 94% were women. Compared with azathioprine and mycophenolate, belimumab was associated with lower risks of both serious infection (HR 0.82; 95% confidence interval [CI] 0.72-0.92 and HR 0.69; 95% CI 0.61-0.78) and hospitalization for infection (HR 0.73; 95% CI 0.57-0.94 and HR 0.56 95% CI 0.43-0.71). The risk of infection was also lower for belimumab compared with methotrexate (HR 0.86; 95% CI 0.76-0.97). There were no differences in traumatic injury risks across treatment groups.
CONCLUSION
Belimumab was associated with lower risks of serious infection than with oral immunosuppressants. This finding should inform risk/benefit considerations for SLE treatment.
Topics: Humans; Female; Middle Aged; Male; Immunosuppressive Agents; Azathioprine; Methotrexate; Lupus Erythematosus, Systemic; Treatment Outcome
PubMed: 37262382
DOI: 10.1002/art.42620 -
Pediatric Dermatology 2023Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use,...
Methotrexate (MTX) is a readily accessible drug, first used in 1948 and employed for a wide variety of indications since then. However, despite widespread off-label use, FDA labeling does not include approved indications for the use of MTX for many inflammatory skin diseases in pediatric patients, including morphea, psoriasis, atopic dermatitis, and alopecia areata, among others. Without published treatment guidelines, some clinicians may be hesitant to use MTX off-label, or uncomfortable prescribing MTX in this population. To address this unmet need, an expert consensus committee was convened to develop evidence- and consensus-based guidelines for use of MTX to treat pediatric inflammatory skin disease. Clinicians with experience and expertise in clinical research, drug development, and treating inflammatory skin disease in pediatric patients with MTX were recruited. Five committees were created based on major topic areas: (1) indications and contraindications, (2) dosing, (3) interactions with immunizations and medications, (4) adverse effects (potential for and management of), and (5) monitoring needs. Pertinent questions were generated and addressed by the relevant committee. The entire group participated in a modified Delphi process to establish agreement on recommendations for each question. The committee developed 46 evidence- and consensus-based recommendations, each with >70% agreement among members, across all five topics. These are presented in tables and text, along with a discussion of supporting literature, and level of evidence. These evidence- and consensus-based recommendations will support safe and effective use of MTX for the underserved population of pediatric patients who may benefit from this valuable, time-honored medication.
Topics: Humans; Child; Methotrexate; Consensus; Psoriasis; Dermatitis, Atopic
PubMed: 37316462
DOI: 10.1111/pde.15327 -
Lancet (London, England) Nov 2023Hand osteoarthritis is a disabling condition with few effective therapies. Hand osteoarthritis with synovitis is a common inflammatory phenotype associated with pain. We... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Hand osteoarthritis is a disabling condition with few effective therapies. Hand osteoarthritis with synovitis is a common inflammatory phenotype associated with pain. We aimed to examine the efficacy and safety of methotrexate at 6 months in participants with hand osteoarthritis and synovitis.
METHODS
In this multisite, parallel-group, double-blind, randomised, placebo-controlled trial, participants (aged 40-75 years) with hand osteoarthritis (Kellgren and Lawrence grade ≥2 in at least one joint) and MRI-detected synovitis of grade 1 or more were recruited from the community in Melbourne, Hobart, Adelaide, and Perth, Australia. Participants were randomly assigned (1:1) using block randomisation, stratified by study site and self-reported sex, to receive methotrexate 20 mg or identical placebo orally once weekly for 6 months. The primary outcome was pain reduction (measured with a 100 mm visual analogue scale; VAS) in the study hand at 6 months assessed in the intention-to-treat population. Safety outcomes were assessed in all randomly assigned participants. This trial was registered with the Australian New Zealand Clinical Trials Registry (ACTRN12617000877381).
FINDINGS
Between Nov 22, 2017, and Nov 8, 2021, of 202 participants who were assessed for eligibility, 97 (48%) were randomly assigned to receive methotrexate (n=50) or placebo (n=47). 68 (70%) of 97 participants were female and 29 (30%) were male. 42 (84%) of 50 participants in the methotrexate group and 40 (85%) of 47 in the placebo group provided primary outcome data. The mean change in VAS pain at 6 months was -15·2 mm (SD 24·0) in the methotrexate group and -7·7 mm (25·3) in the placebo group, with a mean between-group difference of -9·9 (95% CI -19·3 to -0·6; p=0·037) and an effect size (standardised mean difference) of 0·45 (0·03 to 0·87). Adverse events occurred in 31 (62%) of 50 participants in the methotrexate group and 28 (60%) of 47 participants in the placebo group.
INTERPRETATION
Treatment of hand osteoarthritis and synovitis with 20 mg methotrexate for 6 months had a moderate but potentially clinically meaningful effect on reducing pain, providing proof of concept that methotrexate might have a role in the management of hand osteoarthritis with an inflammatory phenotype.
FUNDING
National Health and Medical Research Council of Australia.
Topics: Female; Humans; Male; Australia; Double-Blind Method; Methotrexate; Osteoarthritis; Pain; Synovitis; Treatment Outcome
PubMed: 37839420
DOI: 10.1016/S0140-6736(23)01572-6 -
Modern Rheumatology Aug 2023The aim is to assess the efficacy and safety of a 52-week subcutaneous ozoralizumab treatment at 30 and 80 mg without methotrexate (MTX) in active rheumatoid arthritis. (Randomized Controlled Trial)
Randomized Controlled Trial
Efficacy and safety of anti-TNF multivalent NANOBODY® compound 'ozoralizumab' without methotrexate co-administration in patients with active rheumatoid arthritis: A 52-week result of phase III, randomised, open-label trial (NATSUZORA trial).
OBJECTIVES
The aim is to assess the efficacy and safety of a 52-week subcutaneous ozoralizumab treatment at 30 and 80 mg without methotrexate (MTX) in active rheumatoid arthritis.
METHODS
This randomised, open-label, multicentre phase III trial randomly allocated 140 patients in 2:1 ratio as subcutaneous ozoralizumab at 30 or 80 mg every 4 weeks for 52 weeks without MTX.
RESULTS
Both groups administered ozoralizumab at 30 and 80 mg showed good clinical improvement. The American College of Rheumatology response rates were high at Week 24 and maintained through 52 weeks. The ozoralizumab groups also showed good improvement in other end points, and improvements observed from Week 1 were maintained through 52 weeks. Improvements in many efficacy assessments were similar between doses. No deaths were reported, and serious adverse events occurred in a total of 20 patients in the ozoralizumab groups. Increased antidrug antibodies were observed in approximately 40% of patients in the ozoralizumab groups, and 27.7% of the patients in the 30 mg group were neutralising antibody-positive.
CONCLUSIONS
Ozoralizumab, at 30 and 80 mg, demonstrated significant therapeutic effects without MTX, and the efficacy was maintained for 52 weeks with active rheumatoid arthritis. Ozoralizumab showed an acceptable tolerability profile over 52 weeks.
Topics: Humans; Methotrexate; Tumor Necrosis Factor Inhibitors; Antirheumatic Agents; Treatment Outcome; Drug Therapy, Combination; Arthritis, Rheumatoid; Antibodies, Monoclonal; Double-Blind Method
PubMed: 36201360
DOI: 10.1093/mr/roac126