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The Journal of Allergy and Clinical... Dec 2023Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes.
OBJECTIVE
We sought to systematically synthesize the benefits and harms of AD systemic treatments.
METHODS
For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna).
RESULTS
The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain.
CONCLUSIONS
Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.
Topics: Humans; Dermatitis, Atopic; Network Meta-Analysis; Quality of Life; Randomized Controlled Trials as Topic; Eczema; Asthma; Treatment Outcome
PubMed: 37678577
DOI: 10.1016/j.jaci.2023.08.029 -
The Journal of Allergy and Clinical... Dec 2023Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects. (Meta-Analysis)
Meta-Analysis
BACKGROUND
Atopic dermatitis (AD) is a common skin condition with multiple topical treatment options, but uncertain comparative effects.
OBJECTIVE
We sought to systematically synthesize the benefits and harms of AD prescription topical treatments.
METHODS
For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, ICTRP, and GREAT databases to September 5, 2022, for randomized trials addressing AD topical treatments. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. We classified topical corticosteroids (TCS) using 7 groups-group 1 being most potent. This review is registered in the Open Science Framework (https://osf.io/q5m6s).
RESULTS
The 219 included trials (43,123 patients) evaluated 68 interventions. With high-certainty evidence, pimecrolimus improved 6 of 7 outcomes-among the best for 2; high-dose tacrolimus (0.1%) improved 5-among the best for 2; low-dose tacrolimus (0.03%) improved 5-among the best for 1. With moderate- to high-certainty evidence, group 5 TCS improved 6-among the best for 3; group 4 TCS and delgocitinib improved 4-among the best for 2; ruxolitinib improved 4-among the best for 1; group 1 TCS improved 3-among the best for 2. These interventions did not increase harm. Crisaborole and difamilast were intermediately effective, but with uncertain harm. Topical antibiotics alone or in combination may be among the least effective. To maintain AD control, group 5 TCS were among the most effective, followed by tacrolimus and pimecrolimus.
CONCLUSIONS
For individuals with AD, pimecrolimus, tacrolimus, and moderate-potency TCS are among the most effective in improving and maintaining multiple AD outcomes. Topical antibiotics may be among the least effective.
Topics: Humans; Dermatitis, Atopic; Tacrolimus; Network Meta-Analysis; Quality of Life; Randomized Controlled Trials as Topic; Dermatologic Agents; Asthma; Eczema; Anti-Bacterial Agents
PubMed: 37678572
DOI: 10.1016/j.jaci.2023.08.030 -
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 -
Annals of the Rheumatic Diseases May 2024To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA).
Efficacy and safety of pharmacological treatment of psoriatic arthritis: a systematic literature research informing the 2023 update of the EULAR recommendations for the management of psoriatic arthritis.
OBJECTIVES
To obtain an overview of recent evidence on efficacy and safety of pharmacological treatments in psoriatic arthritis (PsA).
METHODS
This systematic literature research (SLR) investigated the efficacy and safety of conventional synthetic (cs), biological (b) and targeted synthetic (ts) disease-modifying antirheumatic drugs (DMARDs) in patients with PsA. A systematic database search using Medline, EMBASE, Cochrane CENTRAL was conducted to identify relevant articles published since the previous update in 2019 until 28 December 2022. Efficacy was assessed in trials while for safety observational data were also considered. Adverse events of special interest were infections (including herpes zoster, influenza and tuberculosis), malignancies, major adverse cardiovascular events, venous thromboembolisms, liver disease, laboratory changes and psychiatric adverse events. No meta-analyses were performed.
RESULTS
For efficacy, of 3946 articles screened, 38 articles (30 trials) were analysed. The compounds investigated included csDMARDs (leflunomide, methotrexate), bDMARDs inhibiting IL17 (bimekizumab, brodalumab, ixekizumab, izokibep, secukinumab,), IL-23 (guselkumab, risankizumab, tildrakizumab), IL-12/23 (ustekinumab) as well as TNF (adalimumab, certolizumab-pegol, etanercept, infliximab, golimumab) and Janus Kinase inhibitors (JAKi) (brepocitinib, deucravacitinib, tofacitinib, upadacitinib). The compounds investigated were efficacious in improving signs and symptoms of PsA, improving physical functioning and quality of life. For safety, 2055 abstracts were screened, and 24 articles analysed: 15 observational studies and 9 long-term follow-ups of trials, assessing glucocorticoids, TNFi, IL-17i, JAKi, IL-12/23i and PDE4i (apremilast). Safety indicators were generally coherent with the previous SLR in 2019.
CONCLUSION
The results of this SLR informed the task force responsible for the 2023 update of the European Alliance of Associations for Rheumatology recommendations for pharmacological management of PsA.
Topics: Arthritis, Psoriatic; Humans; Antirheumatic Agents; Treatment Outcome; Practice Guidelines as Topic; Biological Products
PubMed: 38503473
DOI: 10.1136/ard-2024-225534 -
Frontiers in Pharmacology 2023Janus kinase (JAK) inhibitors are a novel class of drugs that have shown efficacy in treating immune-mediated inflammatory diseases (IMIDs). However, their safety...
Janus kinase (JAK) inhibitors are a novel class of drugs that have shown efficacy in treating immune-mediated inflammatory diseases (IMIDs). However, their safety profile in terms of herpes zoster infection remains unclear. We aimed to evaluate the risk of herpes zoster associated with JAK inhibitors in patients with IMIDs. A systematic search of electronic databases was conducted to identify randomized controlled trials (RCTs) that evaluated the safety of JAK inhibitors in patients with IMIDs including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriasis (PsO), and psoriatic arthritis (PsA). The primary outcome of interest was the incidence of herpes zoster infection. Network meta-analysis was performed to compare the risk of herpes zoster among different JAK inhibitors and placebo. A network meta-analysis was conducted using data from 47 RCTs including 24,142 patients. In patients with IMIDs, peficitinib 100 mg QD was associated with the highest risk of herpes zoster infection in patients with IMIDs, followed by baricitinib 4 mg QD and upadacitinib 30 mg QD. No difference in herpes zoster risk was found for other JAK inhibitors compared with placebo. Subgroup analysis indicated that higher incidence of herpes zoster was found in patients treated by baricitinib 4 mg QD, peficitinib 100 mg QD, and upadacitinib 30 mg QD only in patients with RA. Our study suggests that some JAK inhibitors, particularly peficitinib, baricitinib, and tofacitinib, are associated with a higher risk of herpes zoster infection in patients with IMIDs.
PubMed: 37614317
DOI: 10.3389/fphar.2023.1241954 -
RMD Open Dec 2023Synovitis acne pustulosis hyperostosis osteitis (SAPHO) is a rare heterogeneous disease of unknown aetiopathology. Externally validated and internationally agreed... (Review)
Review
BACKGROUND AND OBJECTIVES
Synovitis acne pustulosis hyperostosis osteitis (SAPHO) is a rare heterogeneous disease of unknown aetiopathology. Externally validated and internationally agreed diagnostic criteria or outcomes and, as a result, prospective randomised controlled trials in SAPHO are absent. Consequently, there is no agreed treatment standard. This study aimed to systematically collate and discuss treatment options in SAPHO.
METHODS
Following 'Preferred Reporting Items for Systematic Reviews and Meta-Analyses' guidance, a systematic literature search was conducted using PubMed, Scopus and Web of Science databases. Prospective clinical studies and retrospective case collections discussing management and outcomes in SAPHO involving five or more participants were included. Articles not published in English, studies not reporting defined outcomes, and studies solely relying on patient-reported outcomes were excluded.
RESULTS
A total of 28 studies (20 observational, 8 open-label clinical studies) reporting 796 patients of predominantly European ethnicity were included. Reported therapies varied greatly, with many centres using multiple treatments in parallel. Most patients (37.1%) received non-steroidal anti-inflammatory drugs alone or in combination. Bisphosphonates (22.1%), conventional (21.7%) and biological (11.3%) disease-modifying antirheumatic drugs were the next most frequently reported treatments. Reported outcomes varied and delivered mixed results, which complicates comparisons. Bisphosphonates demonstrated the most consistent improvement of osteoarticular symptoms and were associated with transient influenza-like symptoms. Paradoxical skin reactions were reported in patients treated with TNF inhibitors, but no serious adverse events were recorded. Most treatments had limited or mixed effects on cutaneous involvement. A recent study investigating the Janus kinase inhibitor tofacitinib delivered promising results in relation to skin and nail involvement.
CONCLUSIONS
No single currently available treatment option sufficiently addresses all SAPHO-associated symptoms. Variable, sometimes descriptive outcomes and the use of treatment combinations complicate conclusions and treatment recommendations. Randomised clinical trials are necessary to generate reliable evidence.
Topics: Humans; Acquired Hyperostosis Syndrome; Osteitis; Retrospective Studies; Prospective Studies; Synovitis; Hyperostosis; Acne Vulgaris; Diphosphonates
PubMed: 38151265
DOI: 10.1136/rmdopen-2023-003688 -
BMJ Open Nov 2023Head-to-head clinical trials are common in psoriasis, but scarce in psoriatic arthritis (PsA), making treatment comparisons between therapeutic classes difficult. This... (Meta-Analysis)
Meta-Analysis
OBJECTIVES
Head-to-head clinical trials are common in psoriasis, but scarce in psoriatic arthritis (PsA), making treatment comparisons between therapeutic classes difficult. This study describes the relative effectiveness of targeted synthetic (ts) and biologic (b) disease-modifying antirheumatic drugs (DMARDs) on patient-reported outcomes (PROs) through network meta-analysis (NMA).
DESIGN
A systematic literature review (SLR) was conducted in January 2020. Bayesian NMAs were conducted to compare treatments on Health Assessment Questionnaire Disability Index (HAQ-DI) and 36-item Short Form (SF-36) Health Survey including Mental Component Summary (MCS) and Physical Component Summary (PCS) scores.
DATA SOURCES
Ovid MEDLINE (including Epub Ahead of Print, In-Process & Other Non-Indexed Citations and Daily),Embase and Cochrane Central Register of Controlled Trials.
ELIGIBILITY CRITERIA
Phase III randomised controlled trials (RCTs) evaluating patients with PsA receiving tsDMARDS, bDMARDs or placebo were included in the SLR; there was no restriction on outcomes.
DATA EXTRACTION AND SYNTHESIS
Two independent researchers reviewed all citations. Data for studies meeting all inclusion criteria were extracted into a standardised Excel-based form by one reviewer and validated by a second reviewer. A third reviewer was consulted to resolve any discrepancies, as necessary. Risk of bias was assessed using the The National Institute for Health and Care Excellence clinical effectiveness quality assessment checklist.
RESULTS
In total, 26 RCTs were included. For HAQ-DI, SF-36 PCS and SF-36 MCS scores, intravenous tumour necrosis factor (TNF) alpha inhibitors generally ranked higher than most other classes of therapies available to treat patients with PsA. For almost all outcomes, several interleukin (IL)-23, IL-17A, subcutaneous TNF and IL-12/23 agents offered comparable improvement, while cytotoxic T-lymphocyte-associated antigen 4, phosphodiesterase-4 and Janus kinase inhibitors often had the lowest efficacy.
CONCLUSIONS
While intravenous TNFs may provide some improvements in PROs relative to several other tsDMARDs and bDMARDs for the treatment of patients with PsA, differences between classes of therapies across outcomes were small.
Topics: Humans; Arthritis, Psoriatic; Antibodies, Monoclonal; Network Meta-Analysis; Antirheumatic Agents; Patient Reported Outcome Measures
PubMed: 37940157
DOI: 10.1136/bmjopen-2022-062306 -
Frontiers in Immunology 2024Clinicians and healthcare policymakers have been drenched with a deluge of overlapping meta-analyses (MAs), and the necessity for comprehensive and clearly defined...
BACKGROUND
Clinicians and healthcare policymakers have been drenched with a deluge of overlapping meta-analyses (MAs), and the necessity for comprehensive and clearly defined evidence of Janus kinase inhibitors (JKIs) in atopic dermatitis (AD) is urgent.
METHODS
Six databases were searched for MAs published until October 2023. Qualitative description of MAs was mainly used, and Investigator's Global Assessment response (IGA response), the 75% improvement in Eczema Area and Severity Index (the EASI75), peak pruritus Numerical rating score (PP-NRS), and adverse effects were cited to describe the efficacy and safety of JKIs. The methodological quality of the included MAs was assessed by A Measurement Tool to Assess Systematic Reviews II (AMSTAR II), and the quality of evidence was evaluated by the grading of recommendations, assessment, development, and evaluation (GRADE).
RESULTS
Sixteen MAs were pooled in this review, of which five studies appraised JKIs, five appraised systemic JKIs, five papers assessed abrocitinib only, and one assessed baricitinib. Two studies were of "high" methodological quality and 14 MAs were of "moderate" quality. Eleven MAs integrated the results of JKIs and reported that JKIs provide faster onset of IGA response (RR=2.83, 95% CI [2.25, 3.56], high-quality evidence). Similarly, 10 MAs showed that JAK inhibitors were more effective in improving the EASI75 (RR=2.84, 95% CI [2.2, 3.67], high-quality evidence). Results from 12 MAs showed JKIs were active in reducing the PP-NRS (SMD=-0.49, 95% CI [-0.67, -0.32]). All MAs affirmed JKIs added no adverse effects leading to discontinuation and serious adverse events (P<0.05). However, 200mg of abrocitinib had a higher risk of acne (RR=4.34, 95% CI [1.61, 11.71), herpes zoster (RR=1.64, 95% CI [0.42, 6.39]), headache (RR=1.76, 95% CI [1.03, 3]), and nausea (RR=7.81, 95% CI [3.84, 15.87]). Upadacitinib was known to increase acne (RR=6.23, 95% CI [4.08, 9.49]), nasopharyngitis (RR=1.36, 95% CI [1.03, 1.8]) and blood creatine phosphokinase (blood CPK) (RR=2.41, 95% CI [1.47, 3.95]). Baricitinib at 2mg was associated with increased blood CPK (RR=2.25, 95% CI [1.1, 2.97]).
CONCLUSION
Compared to placebo or dupilumab, the administration of JKIs can ameliorate IGA response more effectively, improve the EASI75, and relieve pruritus without severe adverse effect, while accompanied by more acne, nasopharyngitis, headache, and digestive disturbances. The curative effect of 200 mg of abrocitinib is significant and more caution should be given in patients with gastrointestinal dysfunction, herpes zoster, and those who are acne-prone. Baricitinib and upadacitinib should be avoided in populations at high risk for cardiovascular events.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=369369, PROSPERO (CRD42022369369).
Topics: Humans; Dermatitis, Atopic; Janus Kinase Inhibitors; Nasopharyngitis; Pruritus; Acne Vulgaris; Headache; Herpes Zoster; Immunoglobulin A; Purines; Sulfonamides; Pyrazoles; Pyrimidines; Azetidines
PubMed: 38464512
DOI: 10.3389/fimmu.2024.1342810 -
Rheumatology and Therapy Dec 2023Baricitinib, an orally available small-molecule inhibitor of Janus kinase (JAK)1 and JAK2, is indicated to treat active moderate-to-severe rheumatoid arthritis (RA). (Review)
Review
INTRODUCTION
Baricitinib, an orally available small-molecule inhibitor of Janus kinase (JAK)1 and JAK2, is indicated to treat active moderate-to-severe rheumatoid arthritis (RA).
OBJECTIVE
This systematic review described the real-world clinical characteristics of baricitinib-treated patients with RA, prescription patterns, effectiveness, drug persistence, patient-reported outcomes (PROs; physical function, pain, health-related quality of life [HRQoL]), patient global assessment (PGA), and safety of baricitinib.
METHODS
A PRISMA systematic review of real-world studies was conducted to identify relevant literature published between January 2016 and September 2022 using MEDLINE®, EMBASE®, and evidence-based medicine review databases. Websites or online repositories of the American College of Rheumatology and the European Alliance of Associations for Rheumatology were searched manually to include relevant abstracts from conferences held between January 2016 and November 2022.
RESULTS
A total of 11,472 records were identified by searching online databases. Seventy studies were included in the study, of which 40 were abstracts. Most patients were older (51-71 years), female, and with mean RA duration of 4-19 years. Baricitinib was mostly used after the failure of one or more bDMARDs, and 4 mg dosing was prevalent in patients with RA (range 22-100%). Clinical effectiveness of baricitinib was reported in real-world settings regardless of prior biologic/targeted synthetic disease-modifying antirheumatic drug (DMARD) use and concomitant conventional synthetic DMARD use. Achievement of Clinical Disease Activity Index (CDAI) remission was reported in 8.7-60% of patients at week 12 and CDAI low disease activity (LDA) in 20.2-81.6% at week 24. The proportion of patients attaining Simple Disease Activity Index (SDAI) remission was reported in 12% at week 4 to 45.4% at 24 weeks. Drug persistence was high, similar, or equal to anti-tumor necrosis factor drugs. No new safety signals were identified.
CONCLUSION
Baricitinib demonstrated effectiveness in the real-world setting with a consistent safety profile observed in clinical studies. Better persistence rates for baricitinib compared to bDMARDs with improvement in PROs were reported, although baricitinib-treated patients had RA with poor prognostic characteristics.
PubMed: 37715917
DOI: 10.1007/s40744-023-00591-9 -
Frontiers in Pharmacology 2023Janus kinase (JAK) inhibitors have emerged as a progressively utilized therapeutic approach for the management of rheumatoid arthritis (RA). However, the complete...
Janus kinase (JAK) inhibitors have emerged as a progressively utilized therapeutic approach for the management of rheumatoid arthritis (RA). However, the complete determination of their cardiovascular safety remains inconclusive. Hence, the primary objective of this network meta-analysis is to meticulously assess and juxtapose the cardiovascular risks linked to distinct JAK inhibitors employed in RA patients. A systematic review and network meta-analysis were meticulously conducted, encompassing a collection of randomized controlled trials (RCTs) that focused on investigating the incidence of major adverse cardiovascular events (MACE) and all-cause mortality associated with Janus kinase (JAK) inhibitors administered to patients with rheumatoid arthritis (RA). Extensive exploration was performed across multiple electronic databases, incorporating studies published until March 2023. To be included in this analysis, the RCTs were required to involve adult participants diagnosed with RA who received treatment with JAK inhibitors. To ensure accuracy, two authors independently undertook the selection of eligible RCTs and meticulously extracted aggregate data. In order to examine the outcomes of MACE and all-cause mortality, a frequentist graph theoretical approach within network meta-analyses was employed, utilizing random-effects models. Third study has been registered on PROSPERO under the reference CRD42022384611. A specific selection encompassing a total of 14 meticulously chosen randomized controlled trials was undertaken, wherein 13,524 patients were assigned randomly to distinct treatment interventions. The analysis revealed no notable disparity in the occurrence of major adverse cardiovascular events (MACE) between the interventions and the placebo group. However, in comparison to adalimumab, the employment of JAK inhibitors exhibited an association with higher rates of all-cause mortality [odds ratio (OR): 1.7, 95% confidence interval (CI): 1.02-2.81]. This observed increase in risk primarily stemmed from the usage of tofacitinib (OR: 1.9, 95% CI: 1.12-3.23). None of the other JAK inhibitors exhibited a statistically significant variance in all-cause mortality when compared to adalimumab. Our study suggests that JAK inhibitors may not increase the risk of MACE in RA patients but may be associated with a higher risk of all-cause mortality compared to adalimumab, primarily due to tofacitinib use. Rheumatologists should carefully consider the cardiovascular risks when prescribing JAK inhibitors, particularly tofacitinib, for RA patients. https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=384611, CRD42022384611.
PubMed: 37614310
DOI: 10.3389/fphar.2023.1237234