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JAMA Network Open Jun 2023Alopecia areata (AA) is a common chronic tissue-specific autoimmune disease. Several studies have reported outcomes of Janus kinase (JAK) inhibitors for treating AA, but... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Alopecia areata (AA) is a common chronic tissue-specific autoimmune disease. Several studies have reported outcomes of Janus kinase (JAK) inhibitors for treating AA, but limited evidence has emerged.
OBJECTIVE
To evaluate the effectiveness and safety associated with JAK inhibitors for AA.
DATA SOURCES
MEDLINE, Embase, and CENTRAL (Cochrane Central Register of Controlled Trials) were searched from inception until August 2022.
STUDY SELECTION
Only randomized clinical trials (RCTs) were included. Pairs of reviewers independently and in duplicate selected the studies.
DATA EXTRACTION AND SYNTHESIS
Hartung-Knapp-Sidik-Jonkman random-effects models were used for meta-analysis. Certainty of evidence was evaluated using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. This study is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.
MAIN OUTCOMES AND MEASURES
The primary outcomes of interest were (1) proportion of patients who achieved 30%, 50%, and 90% improvement in Severity of Alopecia Tool (SALT) score from baseline, (2) change from baseline SALT score, and (3) treatment-related adverse event (AE).
RESULTS
Seven RCTs with 1710 patients (1083 females [63.3%]; mean [SD] age range, 36.3 [10.4] to 69.7 [16.2] years) were eligible and included in the study. JAK inhibitors were associated with more patients achieving 50% improvement (odds ratio [OR], 5.28 [95% CI, 1.69-16.46]; GRADE assessment: low certainty) and 90% improvement (OR, 8.15 [95% CI, 4.42-15.03]; GRADE assessment: low certainty) in SALT score from baseline compared with placebo. JAK inhibitors were associated with more lowered SALT scores from the baseline compared with placebo (mean difference [MD], -34.52 [95% CI, -37.80 to -31.24]; GRADE assessment: moderate certainty), and JAK inhibitors were not associated with more treatment-related AEs (relative risk [RR], 1.25 [95% CI, 1.00-1.57]; GRADE assessment: high certainty) compared with placebo. High certainty of evidence showed that JAK inhibitors may not be associated with more severe AEs compared with placebo (RR, 0.77; 95% CI, 0.41-1.43). The subgroup analysis showed that oral JAK inhibitors were more efficient than placebo (change from baseline SALT scores: MD, -36.80; 95% CI, -39.57 to -34.02), and no difference was found between external JAK inhibitors and placebo (change from baseline SALT scores: MD, -0.40; 95% CI, -11.30 to 10.50).
CONCLUSIONS AND RELEVANCE
Results of this systematic review and meta-analysis suggest that JAK inhibitors, compared with placebo, were associated with hair regrowth and that the outcome of oral JAK inhibitors was better than the external route of administration. Although the safety and tolerability of JAK inhibitors were acceptable, longer RCTs are needed to further assess the effectiveness and safety of these treatments for AA.
Topics: Female; Humans; Adult; Janus Kinase Inhibitors; Alopecia Areata; Chronic Disease; Network Meta-Analysis
PubMed: 37368402
DOI: 10.1001/jamanetworkopen.2023.20351 -
Journal of the American Academy of... Jun 2022Alopecia areata (AA) is an autoimmune, nonscarring hair loss disorder with slightly greater prevalence in children than adults. Various treatment modalities exist;... (Review)
Review
BACKGROUND
Alopecia areata (AA) is an autoimmune, nonscarring hair loss disorder with slightly greater prevalence in children than adults. Various treatment modalities exist; however, their evidence in pediatric AA patients is lacking.
OBJECTIVE
To evaluate the evidence of current treatment modalities for pediatric AA.
METHODS
We conducted a systematic review on the PubMed database in October 2019 for all published articles involving patients <18 years old. Articles discussing AA treatment in pediatric patients were included, as were articles discussing both pediatric and adult patients, if data on individual pediatric patients were available.
RESULTS
Inclusion criteria were met by 122 total reports discussing 1032 patients. Reports consisted of 2 randomized controlled trials, 4 prospective comparative cohorts, 83 case series, 2 case-control studies, and 31 case reports. Included articles assessed the use of aloe, apremilast, anthralin, anti-interferon gamma antibodies, botulinum toxin, corticosteroids, contact immunotherapies, cryotherapy, hydroxychloroquine, hypnotherapy, imiquimod, Janus kinase inhibitors, laser and light therapy, methotrexate, minoxidil, phototherapy, psychotherapy, prostaglandin analogs, sulfasalazine, topical calcineurin inhibitors, topical nitrogen mustard, and ustekinumab.
LIMITATIONS
English-only articles with full texts were used. Manuscripts with adult and pediatric data were only incorporated if individual-level data for pediatric patients were provided. No meta-analysis was performed.
CONCLUSION
Topical corticosteroids are the preferred first-line treatment for pediatric AA, as they hold the highest level of evidence, followed by contact immunotherapy. More clinical trials and comparative studies are needed to further guide management of pediatric AA and to promote the potential use of pre-existing, low-cost, and novel therapies, including Janus kinase inhibitors.
Topics: Adolescent; Adrenal Cortex Hormones; Alopecia; Alopecia Areata; Autoimmune Diseases; Child; Humans; Janus Kinase Inhibitors; Prospective Studies
PubMed: 33940103
DOI: 10.1016/j.jaad.2021.04.077 -
Acta Dermato-venereologica Aug 2022The aim of this study was to compare the efficacies of systemic treatments with dupilumab, tralokinumab and Janus kinase inhibitors for moderate-to-severe atopic... (Meta-Analysis)
Meta-Analysis
The aim of this study was to compare the efficacies of systemic treatments with dupilumab, tralokinumab and Janus kinase inhibitors for moderate-to-severe atopic dermatitis. A systematic review following Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines was performed using Medline, EMBASE and Cochrane library. All randomized controlled trials investigating the efficacy of systemic treatments for moderate-to-severe atopic dermatitis in adults were included. Primary outcomes were the proportion of patients with atopic dermatitis achieving 50%, 75%, and 90% improvement in Eczema Area and Severity Index (EASI) score after dupilumab, tralokinumab or Janus kinase inhibitors. Nineteen studies totalling 6,444 patients were included. In monotherapy studies, upadacitinib 30 mg once daily had the numerically highest efficacy regarding EASI-50, EASI-75 and EASI-90. In combination therapy studies with topical corticosteroids, dupilumab 300 mg once every other week had highest efficacy regarding EASI-50, and abrocitinib 200 mg once daily had the highest score regarding EASI-75 and EASI-90. Analysis provided evidence that dupilumab, tralokinumab and Janus kinase inhibitors all had an acceptable efficacy profile and resulted in clinically relevant improvements in EASI score. Furthermore, upadacitinib and abrocitinib seem to have great potential to treat patients with atopic dermatitis. However, further studies are needed to determine the long-term efficacy of Janus kinase inhibitors in adults with moderate-to-severe atopic dermatitis.
Topics: Adult; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Dermatitis, Atopic; Double-Blind Method; Humans; Janus Kinase Inhibitors; Randomized Controlled Trials as Topic; Severity of Illness Index; Treatment Outcome
PubMed: 35818735
DOI: 10.2340/actadv.v102.2075 -
Clinical and Experimental Rheumatology Mar 2023Dermatomyositis (DM) is an idiopathic inflammatory myopathy that commonly manifests with proximal muscle weakness and is associated with extramuscular pathology,... (Review)
Review
Dermatomyositis (DM) is an idiopathic inflammatory myopathy that commonly manifests with proximal muscle weakness and is associated with extramuscular pathology, including characteristic skin lesions such as Gottron's papules and heliotrope rash, as well as lung, gastrointestinal, joint, and cardiac involvement. Systemic corticosteroids are a cornerstone of therapy, and more recently intravenous immunoglobulin (IVIG; OCTAGAM®) has been approved by the US Food and Drug Administration for the treatment of adults with DM. Both steroids and IVIG represent nonspecific anti-inflammatory therapy, and more targeted approaches are lacking. Transcriptomics has identified upregulation of interferon (IFN)-regulated genes as key features of both adult DM and juvenile DM (JDM). Accordingly, blocking IFN signalling through inhibition of the Janus kinase (JAK) pathway represents a potential treatment option for DM. Placebo-controlled trial data assessing the use of JAK inhibitors for the treatment of DM are limited; as such, a systematic literature review was undertaken to assess the evidence of JAK inhibitors in the treatment of patients with DM. Terms related to DM and JAK inhibitors were searched using PubMed, Embase, Web of Science, Scopus, and Dimensions to identify peer-reviewed publications reporting patients with DM who were treated with a JAK inhibitor. Baseline demographics, clinical characteristics, and treatment outcome data were extracted. A total of 48 publications reporting 145 unique patients (adult DM, n=84; JDM, n=61) were identified. Among cases of adult DM, 61 of 84 (73%) had refractory skin disease at baseline, and all (61 of 61) reported improvement in cutaneous symptoms. Of patients with adult DM, 16 of 84 (19%) had refractory muscle disease at baseline, and all (16 of 16) reported improvement in muscle symptoms. In patients with adult DM complicated by interstitial lung disease (ILD; n=33), 31 (94%) patients improved with JAK inhibitor treatment. Among cases of JDM with refractory skin disease at baseline (60 of 61), most patients (57 of 60; 95%) showed improvements in skin symptoms after JAK inhibitor treatment. Of patients with JDM with refractory muscle disease at baseline (36 of 61), most (30 of 36; 83%) reported improvement in muscle symptoms. Four patients with JDM and ILD experienced improvement in lung disease activity following treatment with a JAK inhibitor. Among both DM and JDM cases, all patients (17 with DM and 16 with JDM) who had elevated serum IFN and/or IFN-stimulated gene expression at baseline showed reduction in IFN or IFN gene expression. Although the conclusions that can be drawn from this analysis are limited because of the differences in assessments used across publications, overall treatment of patients with DM or JDM with a JAK inhibitor was associated with significant improvement of a wide range of DM manifestations, including skin lesions, muscle weakness, and ILD. Our systematic literature review suggests that JAK inhibitors may be a viable treatment option for DM/JDM, and randomised controlled trials are necessary to confirm these findings.
Topics: Adult; Humans; Dermatomyositis; Janus Kinase Inhibitors; Immunoglobulins, Intravenous; Muscular Diseases; Muscle Weakness; Lung Diseases, Interstitial
PubMed: 35766013
DOI: 10.55563/clinexprheumatol/hxin6o -
Acta Dermato-venereologica Jan 2023The aim of this study was to compare the efficacy and safety of treatment with Janus kinase inhibitors for alopecia areata, measured by change in Severity of Alopecia... (Meta-Analysis)
Meta-Analysis
The aim of this study was to compare the efficacy and safety of treatment with Janus kinase inhibitors for alopecia areata, measured by change in Severity of Alopecia Tool (SALT) score. A systematic review following Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines was performed using Medline, EMBASE and Cochrane library. All studies investigating the efficacy of treatments for alopecia areata were included. Primary outcomes were the proportion of patients with alopecia areata achieving 30%, 50%, 75%, 90% and 100% improvement in SALT score after treatment with a Janus kinase inhibitor. A meta-analysis was performed including all randomized controlled trials investigating Janus kinase inhibitors. A total of 37 studies matched the inclusion criteria and were included. Meta-analysis was performed based on 5 randomized studies. Regarding patients with alopecia areata defined as ≥ 50% scalp hair loss, baricitinib 4 mg once daily demonstrated the highest efficacy. However, among patients with alopecia areata defined as a SALT score ≥ 50, oral deuruxolitinib 12 mg twice daily demonstrated the highest efficacy. Deuruxolitinib and baricitinib appear to be promising drugs for the treatment of alopecia areata. However, the response depends on the dosage of the drug. More randomized trials, with identical inclusion criteria and dose and duration of treatment, are required to confirm these findings.
Topics: Humans; Alopecia Areata; Janus Kinase Inhibitors; Alopecia; Pyrazoles
PubMed: 36695751
DOI: 10.2340/actadv.v103.4536 -
JAMA Dermatology Nov 2022The risk of venous thromboembolism (VTE) among patients with atopic dermatitis (AD), especially when receiving treatment with Janus kinase (JAK) inhibitors, is unclear. (Meta-Analysis)
Meta-Analysis
IMPORTANCE
The risk of venous thromboembolism (VTE) among patients with atopic dermatitis (AD), especially when receiving treatment with Janus kinase (JAK) inhibitors, is unclear.
OBJECTIVE
To determine the association of AD with incident VTE and evaluate the risk of incident VTE among patients with AD who were receiving treatment with JAK inhibitors.
DATA SOURCES
The MEDLINE, Embase, Cochrane Library, and Web of Science databases were searched with no restrictions on language nor geographic locations from their respective inception to February 5, 2022.
STUDY SELECTION
Cohort studies examining the association of AD with incident VTE and randomized clinical trials (RCTs) reporting VTE events in participants with AD receiving JAK inhibitors were included. Around 0.7% of initially identified articles met the selection criteria.
DATA EXTRACTION AND SYNTHESIS
The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guideline was followed. The risk of bias of included cohort studies and RCTs was assessed by the Newcastle-Ottawa Scale and the Cochrane Risk of Bias Tool 2, respectively. A random-effects model meta-analysis was conducted to calculate the pooled hazard ratio (HR) and risk difference for incident VTE.
MAIN OUTCOMES AND MEASURES
The HRs for incident VTE associated with AD and risk difference for incident VTE between participants with AD who were receiving treatment with JAK inhibitors and controls receiving placebo or dupilumab.
RESULTS
Two cohort studies and 15 RCTs with a total of 466 993 participants were included. The meta-analysis found no significant association of AD with incident VTE (HR, 0.95; 95% CI 0.62-1.45; incidence rate of VTE, 0.23 events/100 patient-years). Overall, 3 of 5722 patients with AD (0.05%) who were receiving treatment with JAK inhibitors experienced VTE compared with 1 of 3065 patients with AD (0.03%) receiving placebo or dupilumab (Mantel-Haenszel risk difference, 0; 95% CI, 0-0). The incidence rate of VTE was 0.15 and 0.12 events per 100 patient-years in participants with AD receiving JAK inhibitors and placebo, respectively. The findings were similar in 4 unique JAK inhibitors (abrocitinib, baricitinib, upadacitinib, and SHR0302).
CONCLUSIONS AND RELEVANCE
The results of this systematic review and meta-analysis suggest that the currently available evidence does not detect an increased risk of VTE associated with AD or treatment with JAK inhibitors. These findings may provide a reference for clinicians in prescribing JAK inhibitors for patients with AD.
Topics: Humans; Venous Thromboembolism; Janus Kinase Inhibitors; Dermatitis, Atopic
PubMed: 36001310
DOI: 10.1001/jamadermatol.2022.3516 -
Pharmacology 2022Janus kinase (JAK) inhibitors and secukinumab have been demonstrated to be effective treatments for ankylosing spondylitis (AS). However, there have been no head-to-head... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Janus kinase (JAK) inhibitors and secukinumab have been demonstrated to be effective treatments for ankylosing spondylitis (AS). However, there have been no head-to-head trials comparing the effectiveness and safety characteristics of JAK inhibitors with secukinumab. This study aimed to evaluate the relative effectiveness and safety of JAK inhibitors and secukinumab in patients with active AS.
SUMMARY
A Bayesian network meta-analysis was conducted using direct and indirect data from randomized controlled trials (RCTs) that examined the efficacy and safety of tofacitinib 5 mg, upadacitinib 15 mg, filgotinib 200 mg, and secukinumab 150 mg in patients with active AS who had a poor response or intolerance to nonsteroidal anti-inflammatory drugs (NSAIDs) and were tumor necrosis factor (TNF) inhibitor-naïve. Data from six RCTs comprising 937 patients were analyzed. The Assessment of SpondyloArthritis International Society 20 (ASAS20) response rates were significantly higher in the JAK inhibitors and secukinumab groups than in the placebo group. The surface under the cumulative ranking curve (SUCRA)-based ranking probability based on the ASAS20 response rate suggested that tofacitinib 5 mg had the highest likelihood of being the best treatment for achieving the ASAS20 response rate, followed by filgotinib 200 mg, upadacitinib 15 mg, secukinumab 150 mg, and placebo. The SUCRA-based ranking probability based on the ASAS20 response rate suggested that tofacitinib 5 mg had the highest likelihood of being the best treatment for achieving the ASAS40 response rate, followed by upadacitinib 15 mg, secukinumab 150 mg, filgotinib 200 mg, and placebo.
KEY MESSAGES
Tofacitinib 5 mg was the most effective treatment for AS, whereas JAK inhibitors and secukinumab 150 mg were effective treatments in patients with active AS who had a poor response or intolerance to NSAIDs and were TNF inhibitor-naïve.
Topics: Humans; Janus Kinase Inhibitors; Spondylitis, Ankylosing; Antirheumatic Agents; Treatment Outcome; Anti-Inflammatory Agents, Non-Steroidal
PubMed: 35817017
DOI: 10.1159/000525627 -
EBioMedicine Mar 2023To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing...
BACKGROUND
To explore the associations of genetically proxied TYK2 inhibition with a wide range of disease outcomes and biomarkers to identify therapeutic repurposing opportunities, adverse effects, and biomarkers of efficacy.
METHODS
The loss-of-function missense variant rs34536443 in TYK2 gene was used as a genetic instrument to proxy the effect of TYK2 inhibition. A phenome-wide Mendelian randomization (MR) study was conducted to explore the associations of genetically-proxied TYK2 inhibition with 1473 disease outcomes in UK Biobank (N = 339,197). Identified associations were examined for replication in FinnGen (N = 260,405). We further performed tissue-specific gene expression MR, colocalization analyses, and MR with 247 blood biomarkers. A systematic review of randomized controlled trials (RCTs) on TYK2 inhibitor was performed to complement the genetic evidence.
FINDINGS
PheWAS-MR found that genetically-proxied TYK2 inhibition was associated with lower risk of a wide range of autoimmune diseases. The associations with hypothyroidism and psoriasis were confirmed in MR analysis of tissue-specific TYK2 gene expression and the associations with systemic lupus erythematosus, psoriasis, and rheumatoid arthritis were observed in colocalization analysis. There were nominal associations of genetically-proxied TYK2 inhibition with increased risk of prostate and breast cancer but not in tissue-specific expression MR or colocalization analyses. Thirty-seven blood biomarkers were associated with the TYK2 loss-of-function mutation. Evidence from RCTs confirmed the effectiveness of TYK2 inhibitors on plaque psoriasis and reported several adverse effects.
INTERPRETATION
This study supports TYK2 inhibitor as a potential treatment for psoriasis and several other autoimmune diseases. Increased pharmacovigilance is warranted in relation to the potential adverse effects.
FUNDING
None.
Topics: Male; Humans; Mendelian Randomization Analysis; Genome-Wide Association Study; Autoimmune Diseases; Biomarkers; Psoriasis; Polymorphism, Single Nucleotide; TYK2 Kinase
PubMed: 36842216
DOI: 10.1016/j.ebiom.2023.104488 -
Clinical Pharmacokinetics Apr 2023Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to...
BACKGROUND AND OBJECTIVE
Ruxolitinib is a tyrosine kinase inhibitor targeting the Janus kinase (JAK) and signal transducer and activator of transcription (STAT) pathways. Ruxolitinib is used to treat myelofibrosis, polycythemia vera and steroid-refractory graft-versus-host disease in the setting of allogeneic stem-cell transplantation. This review describes the pharmacokinetics and pharmacodynamics of ruxolitinib.
METHODS
Pubmed, EMBASE, Cochrane Library and web of Science were searched from the time of database inception to march 15, 2021 and was repeated on November 16, 2021. Articles not written in English, animal or in vitro studies, letters to the editor, case reports, where ruxolitinib was not used for hematological diseases or not available as full text were excluded.
RESULTS
Ruxolitinib is well absorbed, has 95% bio-availability, and is bound to albumin for 97%. Ruxolitinib pharmacokinetics can be described with a two-compartment model and linear elimination. Volume of distribution differs between men and women, likely related to bodyweight differences. Metabolism is mainly hepatic via CYP3A4 and can be altered by CYP3A4 inducers and inhibitors. The major metabolites of ruxolitinib are pharmacologically active. The main route of elimination of ruxolitinib metabolites is renal. Liver and renal dysfunction affect some of the pharmacokinetic variables and require dose reductions. Model-informed precision dosing might be a way to further optimize and individualize ruxolitinib treatment, but is not yet advised for routine care due to lack of information on target concentrations.
CONCLUSION
Further research is needed to explain the interindividual variability of the ruxolitinib pharmacokinetic variables and to optimize individual treatment.
Topics: Animals; Humans; Female; Janus Kinases; Protein Kinase Inhibitors; Pyrazoles; Nitriles
PubMed: 37000342
DOI: 10.1007/s40262-023-01225-7 -
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