Janus kinase inhibitors in rheumatoid arthritis-associated interstitial lung disease: A systematic review and meta-analysis.

OBJECTIVE: The treatment of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) remains challenging due to the scarcity of proven effective therapeutic options. This study aimed to investigate the effectiveness and safety of Janus kinase inhibitors (JAKi) in RA-ILD. METHODS: We systematically reviewed the literature to identify studies evaluating the efficacy and safety of JAK inhibitors in RA-ILD. A meta-analysis was performed using the random-effects model. RESULTS: The literature search identified seven observational studies assessing the safety and efficacy of JAKi in RA-ILD and three studies analyzing the risk of developing de novo ILD in RA patients treated with JAKi. Among 183 patients with RA-ILD, the pooled analysis demonstrated an increase of 2.07 % in %pFVC (95 % CI: 0.57-3.58; p = 0.007) and 3.12 % in %pDLCO (95 % CI: 2.11-4.12; p < 0.001). Thoracic HRCT scans showed improvement in 11 % of patients (95 % CI: 0.01-0.29). The pooled proportion of patients experiencing worsening of pre-existing ILD was 5 % (95 % CI: 0.01-0.11). Adverse events were reported in 14 % of cases (95 % CI: 0.08-0.21), with the frequency of clinically significant infections ranging from 4.5 % to 25 %. The risk of developing de novo ILD in patients receiving JAKi was low, with an incidence rate of 0.20 per 1000 person-years (95 % CI: 0.14-0.25). Comparisons with abatacept and rituximab suggested similar efficacy and safety profiles. CONCLUSION: JAKi are well tolerated and might be a viable treatment option for RA-ILD, offering comparable safety and efficacy to abatacept and rituximab.

Sarcoidosis and Polymethyl Methacrylate (PMMA) Granulomas following COVID-19 Vaccination (ChAdOx1): Successful Treatment with Tofacitinib.

Sarcoidosis and complications related to fillers have been reported following the COVID-19 vaccination. Additionally, cutaneous sarcoidosis has been observed around polymethyl methacrylate (PMMA) injection sites. Foreign-body reactions to PMMA can occur simultaneously with systemic sarcoidosis, suggesting a shared pathogenic mechanism between both conditions. To report a case of sarcoidosis and PMMA granulomas following COVID-19 vaccination (ChAdOx11), successfully treated with tofacitinib. We present a 59-year-old woman who developed systemic sarcoidosis and a granulomatous reaction to PMMA filler following the COVID-19 vaccination (ChAdOx11). Notably, both PMMA and the vaccine were potential triggers for sarcoidosis. Treatment with tofacitinib produced marked improvement in both the cutaneous and pulmonary involvement of sarcoidosis and the granulomatous reaction to PMMA. This successful outcome suggests tofacitinib, a pan-JAK inhibitor, an alternative treatment for cutaneous and systemic sarcoidosis, as well as a potential therapy for granulomatous complications of dermal fillers, such as PMMA.

JAK inhibitors inhibit angiogenesis by reducing VEGF production from rheumatoid arthritis-derived fibroblast-like synoviocytes.

INTRODUCTION/OBJECTIVES: JAK/STAT signaling inhibition exerts therapeutic effects on angiogenesis in rheumatoid arthritis (RA). However, whether the inhibitory effect differs among JAK inhibitors because of differing selectivity is unknown. Therefore, we compared the inhibitory effects of tofacitinib, baricitinib, peficitinib, upadacitinib, and filgotinib on angiogenesis. METHOD: RA-derived fibroblast-like synoviocytes (RA-FLS) were seeded on type I collagen gel, and human umbilical vein endothelial cells (HUVECs) were directly added. The control and aforementioned JAK inhibitors were added to the medium, followed by stimulation with interleukin (IL)-6 and soluble IL-6 receptor (sIL-6R). Each JAK inhibitor's concentration was determined based on estimated blood concentrations. The vascular endothelial growth factor (VEGF) concentration was evaluated with an enzyme-linked immunosorbent assay using the medium from the first exchange. A migration assay was performed, and HUVEC migration was evaluated using CD31 fluorescence immunostaining. RESULTS: Hematoxylin-eosin staining showed that compared with the non-JAKi treatment group, the JAKi treatment group markedly degenerated in the sub-lining and deep lining, with decreased lymphocyte infiltration and neovascularization [Rooney's score subscale, non-JAKi vs JAKi (median, 6.5 vs 2.5, p = 0.005)]. In vitro, IL-6 and sIL-6R administration increased VEGF production from RA-FLS and promoted neovascularization in HUVECs, and JAK-inhibitor administration, which decreased VEGF production from RA-FLS and suppressed HUVEC migration, inhibited neovascularization in RA-FLS and HUVEC co-cultures. CONCLUSIONS: The JAK inhibitors suppressed IL-6-induced angiogenesis via decreased VEGF production and HUVEC migration in RA-FLS and HUVEC co-cultures. No significant differences were observed among the JAK inhibitors, whose anti-angiogenic effect may be an important mechanism for RA treatment. Key Points • JAK inhibitors inhibit angiogenesis in RA by reducing VEGF production from RA-derived fibroblast-like synoviocytes. • Our study provides new insights into RA treatment by elucidating the anti-angiogenic effect of JAK inhibitors.

Review of Janus Kinase Inhibitors as Therapies for Noninfectious Uveitis.

Uveitis remains one of the leading causes of blindness worldwide, with different etiologies requiring separate approaches to treatment. For over a decade, oral, topical, and local injection of corticosteroids as well as systemic conventional disease-modifying antirheumatic drugs (DMARDs) have remained the most effective treatment for noninfectious uveitis (NIU). Systemic administration of antitumor necrosis factor-α and other biological DMARDs have been used for treating cases that responded inadequately to conventional treatments. Unfortunately, some refractory patients still suffer from frequent attacks despite the combination of multiple treatments. Recently, there has been promising evidence for Janus kinase (JAK) inhibitors as the next-generation therapy for NIU. The JAK/signal transducers and activators of the transcription (STAT) signaling pathway mediate the downstream events involved in immune fitness, tissue repair, inflammation, apoptosis, and adipogenesis by binding various ligands, such as cytokines, growth hormones, and growth factors. The mutation or loss of JAK/STAT components is implicated in autoimmune diseases, thus inhibition of such pathways has been an important area of research in therapeutic development.1 In this review, we provide a comprehensive overview of the efficacy and safety of JAK inhibitors for the management of NIU, with evidence from current trials and case reports.

Analysis of publicly available adverse events reported for pediatric patients treated with Janus kinase inhibitors.

Janus kinase inhibitors (JAKi) are drugs that block tyrosine kinases responsible for transducing cytokine signals. The first JAKi was approved by the US Food and Drug Administration (FDA) in 2011 to treat rheumatoid arthritis in adults. A pediatric indication was not approved until 8 years later, for acute graft-versus-host disease. Since then, topical and oral formulations have gained FDA approval for pediatric patients with dermatologic diseases. While increasing evidence supports the safety of these medications in adults, data are limited in children. We sought to determine whether JAKi adverse events (AEs) as reported in clinical trials and via postapproval pharmacovigilance services are comparable in adult and pediatric patients. Pharmacovigilance data were extracted from the FDA's Adverse Event Reporting System and the Canada Vigilance Adverse Reaction Online Database for baricitinib, upadacitinib, abrocitinib, ruxolitinib, and tofacitinib. The pooled data were analyzed to detect the most common AEs for specific JAKi and for the drug class. We assessed 399,649 AEs from 133,216 adults and 2883 AEs from 955 patients under 18 years old and identified slightly different AE profiles for the two age groups. Both populations had increased risk for infections and gastrointestinal AEs. However, pediatric patients reported a higher proportion of blood and lymphatic disorders, while reports of nervous system and musculoskeletal/connective tissue disorders were more common in adults. The spectrum of AEs extracted from pharmacovigilance reports was similar to clinical trials. The JAKi AE profiles we observed may prove helpful in counseling patients and their parents before starting therapy and for monitoring once patients are on therapy.

Adult-onset chronic recurrent multifocal osteomyelitis: A case report of a rare entity.

Background: Chronic recurrent multifocal osteomyelitis is a rare autoimmune disorder causing inflammatory joint lesions. It has an estimated prevalence of 1-2 per million while adult-onset disease constitutes only 6.3% of patients. Case report: We present a case of a 44 years old male who presented to the rheumatology clinic with lower back pain for twelve years. Magnetic resonance imaging of the lumbosacral spine showed ovoid areas of abnormal signal intensities along superior and inferior endplates of multiple vertebrae of the dorsolumbar and sacral spine. Computed tomography guided biopsy of L4 vertebrae was done. Histopathology revealed linear cores of degenerating fibrocartilage focally exhibiting small spicules of mineralized bone and fibro-collagenous tissue. He initially did not respond to traditional therapy. His symptoms improved with the addition of a Janus Kinase inhibitor. To the best of our knowledge, this is the first case of chronic recurrent multifocal osteomyelitis to be reported from Pakistan.

Janus kinase inhibitors and adverse events of acne in dermatologic indications: a systematic review and network meta-analysis.

Background: The occurrence of acne in patients treated with Janus kinase (JAK) inhibitors for skin diseases is a potential issue, which may reduce treatment adherence.Purpose: To systematically analyzes randomized clinical trials (RCTs) of JAK inhibitors in dermatological indications for the risk of acne as an adverse event.Methods: A meta-analysis of odds ratios (ORs) for acne incidence was conducted. Data were quantitatively synthesized using random-effects meta-analysis. Surface under the cumulative ranking curve (SUCRA) values representing the relative ranking probabilities of treatments were obtained. Analyses were performed using R statistical software version 4.4.0.Results: A total of 11,396 patients were included from 24 studies. The incidence of acne for JAK inhibitors was ranked according to the SUCRA as follows: JAK1 inhibitors > TYK2 inhibitors > combined JAK1 and JAK2 inhibitors > combined JAK1 and TYK2 inhibitors > JAK3 + TEC inhibitors > pan-JAK inhibitors. ORs were higher for longer durations of drug use and larger dosages. Subgroup analyses by disease indication revealed increased ORs for psoriasis (5.52 [95% CI, 1.39-21.88]), vitiligo (4.15 [95% CI, 1.27-13.58]), alopecia areata (3.86 [95% CI, 1.58-9.42]), and atopic dermatitis (2.82 [95% CI, 1.75-4.54]). The use of JAK inhibitors in patients with systemic lupus erythematosus (SLE) may not significantly increase the incidence of acne.Conclusions: There are higher rates of acne following treatment with JAK inhibitors for dermatologic indications, particularly with longer durations and larger dosages. Pan-JAK inhibitors exhibit the lowest incidence of acne.

Biological therapy for psoriatic arthritis: current state and future perspectives.

Psoriatic arthritis is a medical condition that lies at the intersection of various fields of medicine, and its therapy always requires a comprehensive, holistic approach. Biological disease-modifying antirheumatic drugs (bDMARDs) constitute an extremely effective treatment method for PsA, provided that appropriate principles for patient qualification for the drug are followed, along with subsequent monitoring of the response to treatment. Based on their mechanisms of action, four main groups of bDMARDs used in PsA can be distinguished (TNF inhibitors, IL-12/23 and IL-23 inhibitors, IL-17 inhibitors, CTLA4 agonists). Clinical trials are ongoing in search of registration for additional bDMARDs, and the tasks for doctors and scientists worldwide include patient education, increasing treatment accessibility, and optimizing its costs.

Advanced Systemic Treatments in Patients with Moderate-to-Severe Atopic Dermatitis: Key Learnings from Physicians Practicing in Nine Asian Countries and Territories.

INTRODUCTION: Rapid progress made in the management of atopic dermatitis (AD) in recent years and the differences in patient journey between Asian and non-Asian populations call for a review of current atopic dermatitis landscape in Asia. METHODS: A roundtable meeting with nine regional dermatological experts was held in June 2023 to discuss the optimal management approaches for moderate-to-severe AD, focusing on the use of advanced therapies. RESULTS: Disease burden on patients' quality of life, treatment adherence, and financial constraints were identified as major concerns when managing patients with moderate-to-severe AD in parts of Asia. It was agreed that the Hanifin and Rajka's criteria or the UK Working Party's Diagnostic Criteria for Atopic Dermatitis can be used to guide the clinical diagnosis of AD. Meanwhile, patient-reported outcome scales including the Dermatology Life Quality Index and Atopic Dermatitis Control Tool can be used alongside depression monitoring scales to monitor treatment outcomes in patients with AD, allowing a better understanding for individualized treatment. When managing moderate-to-severe AD, phototherapy should be attempted after failure with topical treatments, followed by conventional disease-modifying antirheumatic drugs and, subsequently, biologics or Janus kinase inhibitors. Systemic corticosteroids can be used as short-term therapy for acute flares. Although these advanced treatments are known to be effective, physicians have to take into consideration safety concerns and limitations when prescribing these treatments. CONCLUSIONS: Treatments in AD have evolved and its management varies country by country. Unique challenges across Asian countries necessitate a different management approach in Asian patients with AD.

Update of the Consensus Statement of the Spanish Society of Rheumatology on the use of biological and synthetic targeted therapies in rheumatoid arthritis.

OBJECTIVE: To update the consensus document of the Spanish Society of Rheumatology (SER) regarding the use of targeted biological and synthetic therapies in rheumatoid arthritis (RA) with the aim of assisting clinicians in their therapeutic decisions. METHODS: A panel of 13 experts was assembled through an open call by SER. We employed a mixed adaptation-elaboration-update methodology starting from the 2015 Consensus Document of the Spanish Society of Rheumatology on the use of biological therapies in RA. Starting with systematic reviews (SR) of recommendations from EULAR 2019, American College of Rheumatology 2021, and GUIPCAR 2017, we updated the search strategies for the PICO questions of GUIPCAR. An additional SR was conducted on demyelinating disease in relation to targeted biological and synthetic therapies. Following the analysis of evidence by different panelists, consensus on the wording and level of agreement for each recommendation was reached in a face-to-face meeting. RESULTS: The panel established 5 general principles and 15 recommendations on the management of RA. These encompassed crucial aspects such as the importance of early treatment, therapeutic goals in RA, monitoring frequency, the use of glucocorticoids, the application of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), biological DMARDs (bDMARDs), and targeted synthetic DMARDs. Additionally, recommendations on dose reduction of these drugs in stable patients were included. This update also features recommendations on the use of bDMARDs and Janus Kinase inhibitors in some specific clinical situations, such as patients with lung disease, a history of cancer, heart failure, or demyelinating disease. CONCLUSIONS: This update provides recommendations on key aspects in the management of RA using targeted biological and synthetic therapies.

Pharmacological Trends in the Management of Atopic Dermatitis: A Comprehensive Review.

Atopic dermatitis (AD) is a prevalent, chronic inflammatory skin condition characterized by pruritus, erythema, and impaired skin barrier function. AD management presents significant challenges due to its complex pathophysiology involving immune dysregulation and genetic predispositions. While traditional therapies, such as topical corticosteroids and emollients, remain foundational, their limitations have spurred the development of novel pharmacological approaches. This comprehensive review explores current pharmacological trends in the management of AD, focusing on emerging therapies that target specific immunological pathways. Biologic agents, including monoclonal antibodies against interleukin (IL)-4, IL-13, and IL-31 receptors, offer targeted mechanisms to modulate immune responses implicated in AD pathogenesis. Janus kinase (JAK) and phosphodiesterase-4 (PDE-4) inhibitors represent another class of promising therapies, providing alternatives for patients resistant to conventional treatments. The review synthesizes evidence from clinical trials and studies to evaluate these pharmacological agents' efficacy and safety profiles. Considerations for personalized medicine approaches, including biomarkers for treatment response prediction and genotype-based therapies, are discussed to highlight the potential for tailored treatment strategies in AD management. In conclusion, this review underscores the evolving landscape of pharmacological interventions for AD, emphasizing the need for continued research to address unmet clinical needs and optimize patient outcomes. By delineating current advancements and future directions, this review aims to inform clinical practice and guide future research endeavours in dermatology.

Safety of baricitinib in Japanese patients with rheumatoid arthritis in clinical use: 3-year data of all-case post-marketing surveillance study.

OBJECTIVE: To assess safety of baricitinib in Japanese patients with rheumatoid arthritis in real-world clinical practice. METHODS: This all-case post-marketing surveillance study included patients initiating baricitinib for rheumatoid arthritis from September 2017 to April 2019. Treatment duration was recorded. Safety data were collected for up to 3 years from baricitinib initiation (up to 4 weeks post discontinuation in discontinuing patients). RESULTS: Safety analyses included 4720 patients; 2580 (54.7%) were ≥65 years old. Baricitinib persistence rate was 45.4% (3 year Kaplan-Meier analysis); the most common discontinuation reason was insufficient effectiveness (n = 1005, 21.3%). Serious adverse events occurred in 600 patients (incidence rate 10.42/100 patient-years; 95% confidence interval, 9.76-11.09). There were 39 deaths (incidence rate 0.43 [0.30-0.57]/100 patient-years). Incidence rate per 100 patient-years for adverse events of special interest were herpes zoster 4.68 (4.22-5.14), serious infection 3.05 (2.68-3.41), malignancy 1.09 (0.87-1.30), major adverse cardiovascular events 0.35 (0.23-0.48) and venous thromboembolism 0.25 (0.15-0.36). Incidence rates did not increase with prolonged exposure. CONCLUSIONS: No new safety concerns were identified during this 3 year post-marketing surveillance study of baricitinib in Japanese patients with rheumatoid arthritis. Patients and clinicians should be cognizant of herpes zoster and other serious infection risks during baricitinib treatment, especially in the first 6 months.

Efficacy and Safety of Upadacitinib for Axial Spondyloarthritis: A Systematic Review and Meta-Analysis.

INTRODUCTION: Upadacitinib, a selective JAK1 inhibitor, has demonstrated promising results in the treatment of axial Spondyloarthritis (AxSpA). AxSpA management remains challenging since there is a gap in knowledge regarding the potential effect of upadacitinib in axSpA patients. Exploring novel therapeutic options is crucial. Therefore, we performed this systematic review and meta-analysis to summarize and synthesize results collected from available randomized-- controlled trials (RCTs) about the efficacy and safety of upadacitinib for patients with axSpA. METHODS: A systematic literature search of Medline via PubMed, Web of Science, Scopus, EBSCO, and Cochrane Central was conducted in October 2023. Relevant RCTs were selected, and their data were extracted and analyzed using the RevMan 5.4 software. The main outcomes were assessment in Spondylarthritis International Society (ASAS) 20, ASAS40, SPARCC MRI sacroiliac joint, and Bath Ankylosing Spondylitis disease activity index (BASDAI) 50. RESULTS: Three RCTs with a total of 920 participants were included in this study. Upadacitinib showed significant improvement in the ASAS40 response, ASAS20 response, BASDAI50 response, and SPARCC MRI Sacroiliac Joint change from baseline compared to placebo at 14-week duration (RR 2.19, 95% CI (1.79 to 2.68), P < 0.00001), (RR 1.62, 95% CI [1.42 to 1.84), P < 0.00001), (RR 2.16, 95% CI (1.75 to 2.67), P < 0.00001), and (MD -3.32 points, 95% CI (-3.96 to -2.68), P < 0.00001) respectively. However, this efficacy decreased after the 52-week duration in terms of ASAS40 RR 2.19 vs. 1.02, ASAS20 RR 1.62 vs. 0.98, BASDAI 50 RR 2.16 vs. 1.05, and ASAS Partial Remission RR 3.82 vs. 1.07. CONCLUSION: Upadacitinib 15 mg showed satisfactory and promising efficacy in the treatment of AxSpA, with no difference in safety profile compared to the placebo.

Restoration of Skin Barrier Abnormalities with IL4/13 Inhibitors and Jak Inhibitors in Atopic Dermatitis: A Systematic Review.

Background and Objectives: Atopic dermatitis is a chronic inflammatory skin disorder with a significant burden on patients' quality of life. This systematic review aims to evaluate the restoration of skin barrier abnormalities with interleukin-4/interleukin-13 (IL-4/IL-13) inhibitors and Janus kinase (JAK) inhibitors in atopic dermatitis. Materials and Methods: A comprehensive review of the literature was conducted, focusing on studies that assess the use of IL-4/IL-13 inhibitors and JAK inhibitors for atopic dermatitis. We identified eligible studies by searching Medline via PubMed with a special focus on their effect on the restoration of the epidermal barrier. Included studies evaluated the transepidermal water loss (TEWL), the reduction in epidermal thickness (ET), the improvement in ceramide synthesis, and the increase in stratum corneum hydration (SCH) with IL-4/IL-13 inhibitors and JAK inhibitors. The quality of included studies was assessed using the ROBINS-I and the RoB 2.0 tool for assessing the risk of bias. Results: Ten of the included studies concern dupilumab, while two concern JAK inhibitors. Ten were observational studies and two were randomized controlled trials (RCTs). The total number of included participants was 378 concerning dupilumab and 38 concerning JAK inhibitors. Five studies did not include any comparison group, three included healthy volunteers, two were conducted versus placebo, and two compared dupilumab with other treatments. The follow-up period ranged between 29 days and 32 weeks. The results demonstrated a significant decrease in transepidermal water loss (TEWL) and an increase in SCH on eczematous lesions for patients with sustained response to dupilumab treatment and observed improvements in ET and filaggrin (FLG) staining, which further support the efficacy of JAK inhibitors in enhancing skin barrier function. Conclusions: This review underscores the efficacy of IL-4/IL-13 inhibitors in improving skin barrier function. However, the limited number of studies focusing on JAK inhibitors and the overall lack of RCTs highlight the need for further research to establish the definitive role of IL-4/IL-13 inhibitors and JAK inhibitors in the restoration of the skin barrier.

Efficacy and safety of Janus kinase inhibitors in patients with difficult-to-treat rheumatoid arthritis.

OBJECTIVES: This study evaluated the effectiveness of Janus kinase inhibitors (JAKi) in patients with difficult-to-treat rheumatoid arthritis (D2T RA). METHODS: This study included 220 patients with RA who were treated with JAKi. Sixty-two patients were naïve to biological disease-modifying anti-rheumatic drugs (bDMARDs)/JAKi (1st group), 57 patients were failure to one bDMARDs/JAKi (2nd group), and 101 patients were failure to ≥ 2 bDMARDs/JAKi. Of these 101 patients, 25 did not meet the D2T RA criteria (non-D2T RA group) and 76 met the D2T RA criteria (D2T RA group). RESULTS: : DAS28-ESR was improved in all groups at 24 weeks (1st: p<0.01, 2nd: p<0.01, non-D2T RA: p=0.01, D2TRA: p=0.02), and improvement ratio of DAS28-ESR was not different between DT2RA group and 2nd (p=0.73) or non-D2T RA group (p=0.68). Glucocorticoid use (odds ratios: 8.67; 95% CI: 1.23-60.90; P=0.03) and number of past bDMARD/JAKi uses ≥ 3 (odds ratios: 10.55; 95% CI: 1.39-80.30; P=0.02) were risk factors for DAS28-ESR ≥ 3.2 at 24 weeks in the D2T RA group. CONCLUSIONS: Clinical efficacy of JAKi in D2T RA group did not differ from that in 2nd and non-D2T RA groups. Glucocorticoid use and multiple bDMARD/JAKi failure were poor prognostic factors for D2T RA.

Biologic and Small Molecule Therapy in Atopic Dermatitis.

Atopic dermatitis is a chronic inflammatory dermatosis characterized by pruritic, scaly, erythematous lesions. Its incidence varies but is estimated to be approximately 20% in children and between 7 and 14% in adults, with variation amongst countries. It is a multifactorial condition, with a complex interplay between genetic, immunological, and environmental factors. Research into the inflammatory response has identified new therapeutic targets that work to reduce inflammation and subsequently reduce flares. This study explores existing therapeutic agents for atopic dermatitis as well as newer therapies such as biologics and small molecules, drawing upon each agent's mechanism of action, relevant landmark clinical trials, efficacy, and safety profile. Current therapies include emollients, corticosteroids, cyclosporine A, calcineurin inhibitors, phototherapy, and methotrexate. Biologics described include dupilumab, tralokinumab, lebrikizumab, nemolizumab, and rocatinlimab. Small molecules inhibitors include Janus kinase inhibitors, phosphodiesterase 4 inhibitors, transient receptor potential vanilloid subfamily V member 1 antagonist, and aryl hydrocarbon receptor antagonist.

Role of Cytokines and Chemokines in Vitiligo and Their Therapeutic Implications.

Vitiligo is a persistent autoimmune disease characterized by progressive depigmentation of the skin caused by the selective destruction of melanocytes. Although its etiopathogenesis remains unclear, multiple factors are involved in the development of this disease, from genetic and metabolic factors to cellular oxidative stress, melanocyte adhesion defects, and innate and adaptive immunity. This review presents a comprehensive summary of the existing knowledge on the role of different cellular mechanisms, including cytokines and chemokines interactions, in the pathogenesis of vitiligo. Although there is no definitive cure for vitiligo, notable progress has been made, and several treatments have shown favorable results. A thorough understanding of the basis of the disease uncovers promising drug targets for future research, providing clinical researchers with valuable insights for developing improved treatment options.

[Small Molecule Therapy for Inflammatory Bowel Disease: JAK Inhibitors and S1PR Modulators].

Small molecules, including Janus kinase (JAK) inhibitors and sphingosine-1-phosphate receptor modulators (S1PRMs), are promising new treatments for inflammatory bowel disease (IBD). Small molecules exhibit more predictable pharmacokinetics than biologics, are less likely to induce immune responses, and can be administered orally. JAK inhibitors function by blocking the activity of JAK enzymes, which prevents the subsequent phosphorylation and activation of signal transducer and activator of transcription (STAT) proteins. Tofacitinib and filgotinib are approved for treating ulcerative colitis (UC), while upadacitinib is approved for UC and Crohn's disease. Nevertheless, JAK inhibitors can increase the risk of herpes zoster, cancer, major adverse cardiovascular events, and venous thromboembolism. S1PRMs bind to S1PRs, particularly S1PR1, on lymphocytes. This interaction inhibits lymphocytes from exiting the lymph nodes and migrating to the gut, thereby reducing inflammation and the immune response in the intestinal mucosa. Ozanimod and etrasimod are S1PRMs approved for the treatment of UC, but they can cause side effects such as bradycardia, conduction disorder, and macular edema. Overall, JAK inhibitors and S1PRMs offer significant benefits in managing IBD, although their potential side effects require careful monitoring.

More Time Spent with Clear Skin and No Itch with Upadacitinib versus Dupilumab for Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD), with its hallmark symptoms of pruritus and skin lesions, often impairs patients' quality of life. We assessed time spent with clear/almost clear skin and no/minimal itch during upadacitinib treatment versus placebo or dupilumab among patients with moderate-to-severe AD. METHODS: This analysis consisted of a post hoc analysis of Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 were replicate, randomized, double-blind, placebo-controlled phase 3 studies with patients randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 16 weeks. Heads Up was a head-to-head, randomized, double-blind, double-dummy, phase 3b study with patients randomized (1:1) to upadacitinib 30 mg or subcutaneous dupilumab 300 mg for 24 weeks. Skin clearance was assessed with the Eczema Area and Severity Index (EASI) at baseline, weeks 1, 2, and 4, and every 4 weeks thereafter. Itch was assessed using the Worst Pruritus Numerical Rating Scale (WP-NRS) daily over 16 weeks and every 2 weeks thereafter to week 24 in Heads Up. RESULTS: This analysis included 1683 patients in Measure Up 1 and 2 and 673 patients in Heads Up. Through 16 weeks in Measure Up 1 and 2, patients receiving upadacitinib spent 9.8-13.4 times as many days with an EASI 90 response and 7.0-10.3 times as many days with a WP-NRS 0/1 response versus placebo. In Heads Up, patients receiving upadacitinib spent 2.0 and 1.7 times as many days through 16 and 24 weeks, respectively, with an EASI 90 response versus dupilumab. Through 16 and 24 weeks, patients receiving upadacitinib spent 3.0 and 2.6 times as many days, respectively, with a WP-NRS 0/1 response versus dupilumab. CONCLUSIONS: Patients with moderate-to-severe AD spent more time with clear/almost clear skin and no/minimal itch with upadacitinib versus placebo or dupilumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), Heads Up (NCT03738397).