JAK Inhibitors for Treatment of VEXAS Syndrome: A Systematic Review of 186 Cases

Topical Janus kinase (JAK) and phosphodiesterase-4 (PDE4) inhibitors are novel treatment approaches for atopic dermatitis (AD). This study aimed to compare the efficacy and safety of JAK and PDE4 inhibitors for AD treatment. The databases of PubMed, EMBASE, Web of Science, and Cochrane Library were searched until June 2021 for eligible studies of AD patients treated with topical JAK and PDE4 inhibitors. Baseline and follow-up data were extracted. Efficacy of JAK inhibitors was evaluated using Investigator's Global Assessment (IGA) achieving "clear" or "almost clear", with 2 points or more improvement from baseline at the end of treatment, referred to as "IGA response"). A Bayesian multiple treatment network meta-analysis with fixed effects was performed. Odds ratio (OR) with 95% credibility interval (CrI) were used for comparing the efficacy of JAK and PDE4 inhibitors with placebo for AD. A total of 10 randomized controlled trials of topical JAK and PDE4 inhibitors with 4689 patients were included for analysis. A total of three topical JAK inhibitors and two topical PDE4 inhibitors were included. Compared with placebo, all JAK and PDE4 inhibitors had higher IGA response at 4weeks of treatment. Notably, with similar safety profile, tofacitinib 2% b.i.d., ruxolitinib 1.5% b.i.d., and delgocitinib 3% b.i.d. showed favorable IGA response compared with topical tacrolimus and corticosteroids. Ranking analysis suggested that among all included JAK and PDE4 inhibitors, tofacitinib 2% b.i.d. had the highest probability of achieving IGA response (SUCRA=0.880). Besides, JAK and PDE4 inhibitors showed non-inferior safety profile with placebo. This study confirmed that topical JAK and PDE4 inhibitors had promising treatment efficacy and safety for AD patients. Tofacitinib 2% b.i.d., ruxolitinib 1.5% b.i.d. and delgocitinib 3% b.i.d. showed superior efficacy over other JAK and PDE4 inhibitors.

In this study, we aimed to assess the safety and efficacy of Janus kinase (JAK) inhibitors in patients with ankylosing spondylitis (AS). We conducted aBayesian network meta-analysis using direct and indirect data from randomized controlled trials (RCTs), and examined the safety and efficacy of JAK inhibitors in active AS patients exhibiting inadequate response or intolerance to two or more non-steroidal anti-inflammatory drugs (NSAIDs). RCTs included atotal of 406patients (203 experimental subjects and 203 controls) from three studies on upadacitinib, filgotinib, and tofacitinib. Assessment of SpondyloArthritis International Society 20% improvement (ASAS20), ASAS40, and ASAS5/6 responses were significantly higher in the JAK inhibitor group than in the placebo group. Other efficacy outcomes, such as ASAS partial remission, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI50), Ankylosing Spondylitis Disease Activity Score (ASDAS), Spondyloarthritis Research Consortium of Canada (SPARCC) Magnetic Resonance Imaging (MRI) scores, and Bath Ankylosing Spondylitis Functional Index (BASFI) were also significantly higher in the JAK inhibitor group compared to the placebo group. The JAK inhibitors significantly improved disease activity (ASAS partial remission, BASDAI50, ASDAS), function (BASFI), and MRI outcomes (SPARCC MRI spine). However, the incidence of adverse events (AEs) and serious adverse events (SAEs), and the rate of withdrawal attributed to AEs did not differ between the JAK inhibitor and placebo groups. JAK inhibitors were effective in active AS patients exhibiting an inadequate response or intolerance to two or more NSAIDs, without the risk of SAEs; this suggests that based on our data, studies are warranted to further investigate the use of JAK inhibitors for treating AS.

Janus kinase (JAK) inhibitors are novel treatment approaches for psoriasis. However, there is no direct comparison of JAK inhibitors in plaque psoriasis. In order to compare the efficacy and safety of JAK inhibitors in psoriasis, we conducted a network meta-analysis using eligible randomized clinical trials (RCTs). The efficacy of JAK inhibitors was evaluated using a 75% improvement in Psoriasis Area and Severity Index (PASI75) from baseline, and the proportion of patients achieving the Physician's Global Assessment (PGA) response. The incidence of treatment-related adverse events (AEs) was also assessed. A total of eight RCTs with tofacitinib, peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib were included. A total of 3612 participants who were diagnosed with moderate-to-severe plaque psoriasis were analysed. Overall, JAK inhibitors showed superior PASI75 response over placebo at both 8 and 12 weeks. Among all included JAK inhibitors, tofacitinib 15 mg twice a day (BID) had the highest probability of achieving PASI75 at both 8 and 12 weeks (SUCRA = 0.938 and 0.937, separately), followed by tofacitinib 10 mg BID (SUCRA = 0.905 and 0.908, separately) and deucravacitinib 12 mg once daily (QD) (SUCRA = 0.874 and 0.837, separately). A similar finding was observed for PGA response. Safety assessment showed that all JAK inhibitors had non-inferior safety compared with placebo, except for deucravacitinib 6 mg BID and 12 mg QD. Tofacitinib 2 mg BID was the first-ranked drug for safety profile followed by deucravacitinib 3 mg QD, and tofacitinib 5 mg BID. When comprehensively evaluated the efficacy and safety, tofacitinib (2 mg, 5 mg, 10 mg, 15 mg BID) was superior to other included JAK inhibitors with satisfying PASI75 and PGA response, as well as relatively low incidence of AEs. Our study confirmed that JAK inhibitors had promising treatment efficacy for moderate-to-severe plaque psoriasis. Tofacitinib showed superior efficacy and safety over peficitinib, solcitinib, baricitinib, abrocitinib and deucravacitinib.

ObjectivesVacuoles, E1 enzyme, X-linked, autoinflammatory and somatic (VEXAS) syndrome is an adult-onset autoinflammatory disease associated with somatic ubiquitin-like modifier-activating enzyme 1 (UBA1) mutations. We aimed to evaluate the efficacy and...

ABSTRACTIntroduction: Treatment of rheumatoid arthritis (RA) has improved considerably following the advent of biologic disease-modifying anti-rheumatic drugs (DMARDs). However, these drugs require special storage and transportation. Janus kinase (JAK) inhibitors are oral synthetic DMARDs that inhibit the non-receptor tyrosine kinase family Janus kinase. Recently, many JAK inhibitors are being developed as new therapies for patients with RA.Areas covered: In this article, we mainly review the efficacy and safety of JAK inhibitors currently under investigation. Tofacitinib has already been approved in 43 countries except in the EU. Results of three JAK inhibitors (baricitinib, decernotinib, and peficitinib) in phase III are consistent with that of tofacitinib. Tofacitinib and baricitinib were partially effective in patients who had an inadequate response to biological DMARDs.Expert commentary: JAK kinase inhibitors provide a new therapeutic approach for rheumatoid arthritis. Meanwhile, further studies are needed to determine their risk-benefit ratio and the most appropriate patients suitable for such therapy.

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.

Rheumatoid Arthritis (RA) is a complex autoimmune disorder characterized by chronic synovial inflammation, leading to progressive joint deterioration and substantial morbidity. While conventional disease-modifying antirheumatic drugs (DMARDs) have been the cornerstone of RA management, the emergence of Janus Kinase (JAK) inhibitors has revolutionized the treatment paradigm. This comprehensive review paper analyzes the efficacy, safety, and practical considerations associated with JAK inhibitors in managing RA juxtaposed with conventional therapies. Through an exploration of the mechanism of action, the efficacy of JAK inhibitors in ameliorating disease activity and improving patient outcomes is underscored. The review also addresses the safety concerns surrounding using JAK inhibitors, emphasizing the need to monitor potential adverse events. Furthermore, the paper discusses the role of nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and DMARDs in RA management, highlighting their limitations and benefits. Practical clinical recommendations for using JAK inhibitors are elucidated, considering their positioning as a second-line therapy for patients with inadequate response or intolerance to conventional DMARDs. Finally, the abstract emphasizes the importance of ongoing research and post-marketing surveillance to comprehensively evaluate the long-term implications of JAK inhibitors, aiming to optimize their integration within personalized treatment strategies for RA.

Tocilizumab for treatment of cutaneous and systemic manifestations of vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic (VEXAS) syndrome without myelodysplastic syndrome

Introduction Cytokine blockers have revolutionized the management of psoriasis. While efficacious, not all patients respond, and treatment may lose efficacy over time. Janus kinase (JAK) inhibitors target the Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) transduction cascade from transmitting cytokine signals in psoriasis. Areas covered A PubMed search of phase I, II, and III clinical trials published between 2012 and 2021 utilizing the key terms: Janus kinase and psoriasis. Our search was expanded from clinical trials to further investigate the pathophysiology, standard of care, and safety and efficacy of JAK inhibitors in psoriasis. Expert opinion Current treatments for psoriasis include topicals, phototherapy, and systemic therapy. The subcutaneous or intravenous route of biologic administration presents a challenge as patients often prefer oral medications over injections and because of anti-drug antibody development. Tofacitinib is effective and has an overall mild-to-moderate safety profile but includes an FDA black box warning for increased risk of cardiovascular events and malignancy. Other JAK inhibitors have an acceptable safety profile and are effective in early clinical trials. Poor topical medication adherence should be considered when evaluating JAK inhibitors. Oral JAK inhibitors may provide a preferable route of administration and improved clinical outcomes.

Background:Excessive and inappropriate production of pro-inflammatory cytokines such as interleukin (IL)-1, IL-6 or IL-18, is a pathogenic cornerstone in adult and childhood onset Still’s disease. Beyond therapies targeting IL-1 or...

Rheumatoid arthritis (RA) is a prevalent autoimmune disorder. This study examines the comparative efficacy of Janus kinase inhibitors (JAKi) and adalimumab (ADA) in managing RA. As of May 2024, four electronic databases were systematically reviewed: PubMed, Web of Science, Embase, and the Cochrane Library. Data were analysed using Review Manager (RevMan) software. The risk ratio (RR) and its 95% confidence interval (CI) represented dichotomous outcomes. Evaluated outcome measures included ACR20, ACR50, ACR70, Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and Disease Activity Score 28-4 (C-reactive protein) (DAS28-4(CRP)). The analysis encompassed 6 studies, totalling 4048 patients with RA. There was no statistically significant difference in efficacy between JAKi and ADA when assessing ACR20 (p=0.25) and DAS28-4(CRP) (p=0.57). However, JAKi demonstrated superior efficacy compared to ADA for ACR50 (RR=1.20; p=0.02), ACR70 (RR=1.24; p=0.03), CDAI (RR=1.17; p=0.01), and SDAI (RR=1.19; p=0.006) outcomes. Longitudinal analysis revealed that over a 52-week period, JAKi did not exhibit superior efficacy to ADA for ACR50 (RR=1.16; p=0.19) and ACR70 (RR=1.10; p=0.26). Specifically, the tofacitinib subgroup outperformed ADA (RR=1.49; p=0.003), while other JAKi treatments did not show a significant difference (RR=1.19; p=0.11) compared to ADA. JAKi generally offers better efficacy than ADA in the treatment of RA, though this advantage appears to be influenced by the duration of treatment.

Introduction Alopecia areata (AA) is an autoimmune disorder causing non-scarring hair loss on the scalp, eyebrows, eyelashes, and other areas. Janus kinase (JAK) inhibitors have emerged as promising treatments, but data on their efficacy in Middle Eastern populations, including Jordanians, are limited. The Severity of Alopecia Tool (SALT) score is commonly used to assess disease severity, while Clinician-Reported Outcome (ClinRO) measures provide additional insights. Aim To evaluate the efficacy of JAK inhibitors in Jordanian AA patients using the SALT score as the primary outcome measure. Methods A retrospective cohort study was conducted at King Hussein Hospital, Jordanian Royal Medical Services, from January 2020 to December 2023. Medical records of AA patients aged ≥18 years treated with JAK inhibitors were reviewed. Data included demographics, disease duration, previous treatments, and adverse effects. Efficacy was assessed by the percentage change in SALT scores at six and 12 months. Statistical analyses included repeated-measures MANCOVA (Multivariate Analysis of Covariance), Chi-square, and independent t-test. A p-value <0.05 was considered significant. Results Our analysis included 57 patients, of which 31 (54.4%) received tofacitinib and 26 (45.6%) received baricitinib. A significantly higher proportion of baricitinib users had treatment durations >12 months (53.8%) compared to tofacitinib users (12.9%), while shorter durations (three to six months) were more common among tofacitinib users (41.9% vs. 15.4%; p = 0.003). Baricitinib users showed greater improvement in SALT scores between six to 12 months (92.77% vs. 82.93%; p = 0.030, partial η² = 0.084), with a trend toward greater total improvement at 12 months (96.64% vs. 93.11%; p = 0.055, partial η² = 0.067). Although not statistically significant, baricitinib showed numerically higher ClinRO improvement in eyebrows from six to 12 months (84.58% vs. 70.29%; p = 0.212) and in eyelashes (83.92% vs. 73.40%; p = 0.313), suggesting better late-stage response compared to tofacitinib. Conclusion JAK inhibitors demonstrated efficacy in Jordanian patients with alopecia areata, leading to enhanced SALT scores and noticeable hair regrowth, with baricitinib demonstrating greater improvement in SALT scores compared to tofacitinib.

Systemic Janus kinase inhibitors (JAKIs) have markedly advanced the therapeutic landscape for alopecia areata (AA). Although baricitinib and ritlecitinib are approved in the United States (US) and Europe, and deuruxolitinib in the US for severe AA, the lack of head-to-head randomized controlled trials (RCTs) limits evidence-based prescribing decisions. Moreover, prior meta-analyses excluded data on certain oral JAKIs or incorporated findings from agents and dosing regimens that were abandoned, investigational, clinically ineffective, or associated with unacceptable safety profiles. To compare the efficacy of oral JAKIs, limited to FDA, EMA, or MHRA approved drugs and doses-baricitinib (2 and 4 mg QD), ritlecitinib (50 mg QD), and deuruxolitinib (8 mg BID)-for severe AA, using advanced indirect comparison methodologies. A systematic review was performed following PRISMA 2020 guidelines (CRD420251116775). Bayesian network meta-analysis (NMA) synthesized data from RCTs reporting Week 24 outcomes on Severity of Alopecia Tool (SALT) ≤ 10 and SALT ≤ 20 thresholds. Multilevel network meta-regression (ML-NMR) evaluated heterogeneity and adjusted for baseline imbalances. Additionally, unanchored matching-adjusted indirect comparisons (MAIC) were conducted using individual patient-level data from THRIVE trials. Surface under the cumulative ranking (SUCRA) values were calculated to rank treatments. Seven RCTs (n = 4560 participants) were included. Deuruxolitinib 8 mg significantly outperformed baricitinib 2 and 4 mg on both SALT endpoints. Differences with ritlecitinib 50 mg were directionally favorable for deuruxolitinib but not statistically significant in NMA and ML-NMR models. MAICs confirmed superior odds for deuruxolitinib versus baricitinib 2 mg (OR = 71.55) and ritlecitinib (OR = 18.27) for SALT ≤ 20. SUCRA rankings also consistently favored deuruxolitinib. Among approved oral JAKIs, deuruxolitinib 8 mg shows the highest short-term efficacy for severe AA. These findings provide preliminary evidence to guide treatment decisions but should be interpreted as exploratory pending confirmation.

Background:The efficacy of Janus Kinases inhibitors (JAKi) in patients with rheumatoid arthritis (RA) has been univocally shown. However, the available information about comparative drug retention rates (DRR) of different JAKi...

Tumor necrosis factor-alpha inhibitors (TNF-i) are commonly used to treat immune-mediated diseases such as psoriasis, psoriatic arthritis (PsA), inflammatory bowel disease (IBD), spondyloarthritis (SpA) and rheumatoid arthritis (RA). However, paradoxical psoriasis induced by TNF-i has been described and is not uncommon, particularly with infliximab and etanercept. The presentation of TNF-i-induced psoriasis is most commonly plaque or palmoplantar morphology. Optimal treatment strategies for recalcitrant psoriatic disease are not well understood. In this case series, we report three patients with TNF-i-induced psoriasis who were treated with upadacitinib and experienced complete resolution of their psoriatic eruptions. The efficacy of Janus kinase inhibitors (JAK-i) is possibly explained by mechanisms involving uncontrolled production of type 1 IFNs as well as increases in IL-23 and T-helper 17 cells upstream of relevant JAK/STAT pathways. We also offer a proposed treatment algorithm that includes the use of JAK-i as a promising management option in patients with recalcitrant disease. However, larger studies are needed to confirm the efficacy and safety of JAK-i in this patient population. J Drugs Dermatol. 2024;23(2): doi:10.36849/JDD.7645.