Protocol for a systematic review and meta-analysis on Janus kinase inhibitors in the management of vitiligo.

BACKGROUND: Vitiligo is a disease that affects people of all skin shades and can impact their quality of life. Reliable evidence on the effectiveness and adverse events associated with the recent use of Janus kinase (JAK) inhibitors to treat vitiligo is needed. This protocol for a systematic review and meta-analysis seeks to collect evidence from both randomized controlled trials (RCTs) and observational studies to determine the effectiveness and patient-centered outcomes concerning treatment with JAK inhibitors. METHODS: We will conduct a systematic review of the literature for RCTs and observational studies that used upadacitinib, ritlecitinib, brepocitinib, ifidancitinib, cerdulatinib, deglocitinib, baricitinib, tofacitinib, and ruxolitinib JAK inhibitors as treatments for vitiligo compared to placebo, no treatment, or combination therapies. We will systematically search from inception in Epistemonikos, MEDLINE, Scopus, Cochrane Central Register of Controlled Trials, EMBASE, ClinicalTrials.gov, PsycINFO, Allied and Complementary Medicine Database, Latin American and Caribbean Health Sciences Literature, Web of Science Core Collection, relevant preprint servers, and the gray literature. Ethics approval was not sought as the protocol and systematic review will not involve human participants, but rather summarized and anonymous data from studies. Primary outcomes include quality of life, percentage repigmentation, decreased vitiligo within 1 year or more, lasting repigmentation after a 2-year follow-up, cosmetic acceptability of repigmentation and tolerability or burden of treatment, and adverse events. Secondary outcomes are patient and study characteristics. We will include full-text articles, preprints, and clinical trial data in any language and all geographic regions. For data sources unavailable in English, we will obtain translations from global collaborators via the Cochrane Engage network. We will exclude articles for which sufficient information cannot be obtained from the authors of articles and systematic reviews. At least two investigators will independently assess articles for inclusion and extract data; reliability will be assessed before subsequent selection and data extraction of remaining studies. The risk of bias and certainty of evidence with Grading of Recommendations Assessment, Development, and Evaluation guidelines will be assessed independently by at least two investigators. We will estimate treatment effects by random-effects meta-analyses and assess heterogeneity using I2. Data that cannot be included in the meta-analysis will be reported narratively using themes. DISCUSSION: The proposed systematic review and meta-analysis describe the methods for summarizing and synthesizing the evidence on the effectiveness and patient-centered outcomes concerning the treatment of vitiligo with JAK inhibitors that were recently approved for this indication. To disseminate further the results of our systematic review, we plan to present them at international conferences and meetings. Our findings will provide robust evidence to facilitate decision-making at the policy or practitioner level. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023383920.

Guidelines of care for the management of atopic dermatitis in adults with phototherapy and systemic therapies.

BACKGROUND: For people with atopic dermatitis (AD) refractory to topical therapies, treatment with phototherapy and systemic therapies can be considered. Multiple biologic therapies and Janus kinase (JAK)inhibitors have been approved since 2014 to treat AD. These guidelines update the 2014 recommendations for management of AD with phototherapy and systemic therapies. OBJECTIVE: To provide evidence-based recommendations on the use of phototherapy and systemic therapies for AD in adults. METHODS: A multidisciplinary workgroup conducted a systematic review and applied the GRADE approach for assessing the certainty of evidence and formulating and grading recommendations. RESULTS: The workgroup developed 11 recommendations on the management of AD in adults with phototherapy and systemic agents, including biologics, oral JAK inhibitors, and other immunomodulatory medications. LIMITATIONS: Most randomized controlled trials of phototherapy and systemic therapies for AD are of short duration with subsequent extension studies, limiting comparative long-term efficacy and safety conclusions. CONCLUSIONS: We make strong recommendations for the use of dupilumab, tralokinumab, abrocitinib, baricitinib, and upadacitinib. We make conditional recommendations in favor of using phototherapy, azathioprine, cyclosporine, methotrexate, and mycophenolate, and against the use of systemic corticosteroids.

Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations.

BACKGROUND: Guidance addressing atopic dermatitis (AD) management, last issued in 2012 by the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force, requires updating as a result of new treatments and improved guideline and evidence synthesis methodology. OBJECTIVE: To produce evidence-based guidelines that support patients, clinicians, and other decision-makers in the optimal treatment of AD. METHODS: A multidisciplinary guideline panel consisting of patients and caregivers, AD experts (dermatology and allergy/immunology), primary care practitioners (family medicine, pediatrics, internal medicine), and allied health professionals (psychology, pharmacy, nursing) convened, prioritized equity, diversity, and inclusiveness, and implemented management strategies to minimize influence of conflicts of interest. The Evidence in Allergy Group supported guideline development by performing systematic evidence reviews, facilitating guideline processes, and holding focus groups with patient and family partners. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed rating the certainty of evidence and strength of recommendations. Evidence-to-decision frameworks, subjected to public comment, translated evidence to recommendations using trustworthy guideline principles. RESULTS: The panel agreed on 25 recommendations to gain and maintain control of AD for patients with mild, moderate, and severe AD. The eAppendix provides practical information and implementation considerations in 1-2 page patient-friendly handouts. CONCLUSION: These evidence-based recommendations address optimal use of (1) topical treatments (barrier moisturization devices, corticosteroids, calcineurin inhibitors, PDE4 inhibitors [crisaborole], topical JAK inhibitors, occlusive [wet wrap] therapy, adjunctive antimicrobials, application frequency, maintenance therapy), (2) dilute bleach baths, (3) dietary avoidance/elimination, (4) allergen immunotherapy, and (5) systemic treatments (biologics/monoclonal antibodies, small molecule immunosuppressants [cyclosporine, methotrexate, azathioprine, mycophenolate, JAK inhibitors], and systemic corticosteroids) and UV phototherapy (light therapy).

Off-Label Use of Janus Kinase Inhibitors in Inflammatory Cutaneous Diseases.

Dysregulation of Janus kinase (JAK) pathways from uncontrolled cytokine signaling comprises the pathological basis for many complex inflammatory cutaneous disorders. Oral JAK inhibitors, upadacitinib, tofacitinib, and baricitinib targeting JAK 1 and JAK 1/3, respectively, are currently US Food and Drug Administration (FDA)-approved for several rheumatic conditions. However, studies have shown that JAK-mediated signaling pathways are involved in many immune-related dermatologic conditions. As a result, for recalcitrant diseases, JAK inhibitors are potential alternative therapies due to their broad targeted inhibitory mechanisms. In this case series, we present the successful off-label treatment of 6 cases across dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease, which failed conventional therapies with upadacitinib or tofacitinib. In the 3 dermatomyositis cases, use of upadacitinib or tofacitinib demonstrated positive clinical outcomes, with no recurrent symptoms in cases where upadacitinib was used. In treatment-resistant hidradenitis suppurativa, upadacitinib demonstrated reduced systemic flares and moderate cutaneous symptom improvement. In the case of cutaneous Crohn’s disease, upadacitinib resulted in reduced cutaneous symptoms without new flares. Tofacitinib resulted in completed resolution of cutaneous symptoms in our patient’s case of cutaneous lupus erythematosus. JAK inhibitors upadacitinib and tofacitinib may be potential drug candidates in patients with treatment-resistant disease, especially in cases of inflammatory cutaneous conditions such as dermatomyositis, hidradenitis suppurativa, cutaneous lupus, and cutaneous Crohn’s disease. Further studies with larger sample sizes among these conditions are warranted to assess potential broader applicability of the positive results demonstrated in our patient cases. J Drugs Dermatol. 2023;22(12):1183-1190. doi:10.36849/JDD.7500.

Vitiligo: Pathogenesis and New and Emerging Treatments.

Vitiligo is a complex disease with a multifactorial nature and a high impact on the quality of life of patients. Although there are multiple therapeutic alternatives, there is currently no fully effective treatment for this disease. In the current era, multiple drugs are being developed for the treatment of autoimmune diseases. This review assesses the available evidence on the pathogenesis of vitiligo, and a comprehensive review of treatments available for vitiligo now and in the near future is provided. This qualitative analysis spans 116 articles. We reviewed the mechanism of action, efficacy and safety data of phototherapy, afamelanotide, cyclosporine, phosphodiesterase 4 inhibitors, trichloroacetic acid, basic fibroblast growth factor, tumor necrosis factor (TNF) inhibitors, secukinumab, pseudocatalase and janus kinase (JAK) inhibitors. At the moment, there is no clearly outstanding option or fully satisfactory treatment for vitiligo, so it is necessary to keep up the development of new drugs as well as the publication of long-term effectiveness and safety data for existing treatments.

Discovery of novel dual Bruton's tyrosine kinase (BTK) and Janus kinase 3 (JAK3) inhibitors as a promising strategy for rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronically systemic autoimmune disorder, which is related with various cellular signal pathways. Both BTK (Bruton's Tyrosine Kinase) and JAK3 (Janus Kinase 3) play important roles in the pathogenesis of rheumatoid arthritis. Herein, we reported the discovery of dual BTK/JAK3 inhibitors through bioisosterism and computer-aided drug design based on the structure of BTK inhibitor ibrutinib. We reported the discovery of dual BTK/JAK3 inhibitors which are based on the structure of BTK inhibitor ibrutinib via the method of bioisosterism and computer-aided drug design) Most of the target compounds exhibited moderate to strong inhibitory activities against BTK and JAK3. Among them, compound XL-12 stood out as the most promising candidate targeting BTK and JAK3 with potent inhibitory activities (IC50 = 2.0 nM and IC50 = 14.0 nM respectively). In the in vivo studies, compound XL-12 (40 mg/kg) exhibited more potent antiarthritic activity than ibrutinib (10 mg/kg) in adjuvant arthritis (AA) rat model. Furthermore, compound XL-12 (LD50 > 1600 mg/kg) exerted improved safety compared with ibrutinib (LD50 = 750 mg/kg). These results indicated that compound XL-12, the dual BTK/JAK3 inhibitor, might be a potent drug candidate for the treatment of RA.

Recommendations by the Spanish Society of Rheumatology on risk management of biological treatment and JAK inhibitors in patients with rheumatoid arthritis.

OBJECTIVE: To present recommendations based on the available evidence and the consensus of experts, for risk management of biological treatment and JAK inhibitors in patients with rheumatoid arthritis. METHODS: Clinical research questions relevant to the purpose of the document were identified. These questions were reformulated in PICO format (patient, intervention, comparison, outcome or outcome) by a panel of experts, selected based on their experience in the area. A systematic review of the evidence was carried out, grading according to the GRADE criteria (Grading of Recommendations Assessment, Development, and Evaluation). Specific recommendations were then formulated. RESULTS: 6 PICO questions were proposed by the panel of experts based on their clinical relevance and the existence of recent information regarding the risk of occurrence of serious infections, the risk of reactivation of the hepatitis B virus, the risk of reactivation of the virus varicella-zoster, the risk of appearance of skin (melanoma and non-melanoma) or haematological cancer, the risk of appearance of thromboembolic disease and the risk of progression of the human papilloma virus. A total of 28 recommendations were formulated, structured by question, based on the evidence found and the consensus of the experts. CONCLUSIONS: The SER recommendations on risk management of treatment with biologic therapies and JAK inhibitors in rheumatoid arthritis are presented.

Treatment options for necrobiosis lipoidica: a systematic review.

BACKGROUND: Necrobiosis lipoidica (NL) is a rare, idiopathic, and recalcitrant disease of collagen degeneration for which treatment options have been poorly studied. Due to its recurring nature, risk for ulceration, and high morbidity, there is a need to understand existing treatment modalities to better inform clinical care. OBJECTIVE: This review aims to describe the therapeutic modalities reported in the literature for the treatment of NL. METHODS: A literature search of treatments was performed by searching for publications between January 2016 and May 2022 on PubMed and Scopus. Given the limited high-quality evidence, case reports and series were included. Only publications presenting information on both attempted treatments and outcomes were included. RESULTS: A total of 60 novel articles were identified (54 case reports, two case series, and four retrospective cohort studies). These studies cumulatively reported on 274 patients and covered treatments including phototherapy, topical corticosteroids, topical calcineurin inhibitors, biologics, immunosuppressants, JAK inhibitors, combination therapies, and several others. The greatest amount of evidence was found for photodynamic therapy (improvement in 72 of 80 patients), UVA-based phototherapy (12 of 33), topical corticosteroids (21 of 46), compression therapy (15 of 20), and topical calcineurin inhibitors (11 of 17). Several newer treatments were also described, including ustekinumab and JAK inhibitors. CONCLUSIONS: This systematic review provides a comprehensive summary of recently published treatments for NL. As the existing data comes predominantly from case reports and series, statistical conclusions are not assessed. A greater number of randomized controlled trials with standardized endpoints are necessary to compare treatment efficacy.

Efficacy and Safety of Biological Therapies and JAK Inhibitors in Older Patients with Inflammatory Bowel Disease.

With the introduction of more and more monoclonal antibodies selectively targeting various mediators of the immune system, together with Janus-Kinase (JAK)-inhibitors with variable affinities towards different JAK subtypes, the available therapeutic options for the treatment of inflammatory bowel diseases (IBD) have undergone an acceleration in the last five years. On the other hand, the prevalence of IBD patients over 65-years-old is steadily increasing, and, with this, there is a large population of patients that presents more comorbidities, polypharmacy, and, more frequently, frailty compared to younger patients, exposing them to potentially major risks for adverse events deriving from newer therapies, e.g., infections, cardiovascular risks, and malignancies. Unfortunately, pivotal trials for the commercialization of new therapies rarely include older IBD patients, and those with serious comorbidities are virtually excluded. In the present review, we focus on existing literature from pivotal trials and real-world studies, analyzing data on efficacy/effectiveness and safety of newer therapies in older IBD patients with special emphasis on comorbidities and frailty, two distinct but intercorrelated aspects of the older population since age by itself seems to be of minor importance.

Biological and JAK inhibitor therapy outcomes for severe psoriasis in trisomy 21.

Little is known about biological outcomes for severe psoriasis in trisomy 21 (T21). Our aim was to review outcomes of patients with T21 and severe psoriasis treated with biologic or Janus kinase inhibitors (JAKi). Information on demographics, co-morbidities, and therapeutic responses was retrospectively collated. Twenty-one patients were identified (mean age 24.7 years). Ninety percent (18/20) of TNFα inhibitor trials failed. Almost two-thirds (7/11) of patients achieved an adequate response with ustekinumab. All three patients treated with tofacitinib achieved an adequate response following at least three biologic failures. The mean number of biologic/JAKi therapies received was 2.1 with overall survival of 36%. Eighty-one percent (17/21) of patients required conversion from their index biologic treatment due to failure. In patients with T21 and severe psoriasis, failure of TNFα inhibition is common and ustekinumab therapy should be considered as first-line therapy. The role of JAKi is emerging.

New molecules for atopic dermatitis treatment beyond biological therapy.

PURPOSE OF REVIEW: This review aims to provide a summary of current knowledge on new topical and oral non-biological therapies recently approved for Atopic Dermatitis (AD) treatment. RECENT FINDINGS: The immense research carried out in the last decade has focused on understanding the molecular basis underlying AD and has allowed the development of new targeted drugs. Despite several biologic therapies are approved or in development, other non-biologic targeted therapies (small molecules) have emerged, such as the Janus kinase (JAK) inhibitors baricitinib, upadacitinib and abrocitinib, expanding the range of therapeutic options. Based on recent available data from head-to-head comparisons and meta-analysis studies, JAK inhibitors showed a faster onset of action and slightly higher efficacy at 16 weeks compared with biologic agents. Concerning topical treatment, presently, corticosteroids and calcineurin inhibitors are the main therapeutic options, but are not recommended for long-term management due to potential safety issues. Currently, two topical JAK inhibitors (ruxolitinib and delgocitinib) and one phosphodiesterase 4 (PDE4) inhibitor (difamilast) are approved and have shown good efficacy results and a favorable safety profile. SUMMARY: These new drugs (systemic and topical) are needed to increase the success of AD treatment, particularly for patients who do not or no longer respond to treatment.

Overview of alopecia areata for managed care and payer stakeholders in the United States.

Alopecia areata (AA) is an autoimmune disease with a complex pathophysiology resulting in nonscarring hair loss in genetically susceptible individuals. We aim to provide health care decision makers an overview of the pathophysiology of AA, its causes and diagnosis, disease burden, costs, comorbidities, and information on current and emerging treatment options to help inform payer benefit design and prior authorization decisions. Literature searches for AA were conducted using PubMed between 2016 and 2022 inclusive, using search terms covering the causes and diagnosis of AA, pathophysiology, comorbidities, disease management, costs, and impact on quality of life (QoL). AA is a polygenic autoimmune disease that significantly impacts QoL. Patients with AA face economic burden and an increased prevalence of psychiatric disease, as well as numerous systemic comorbidities. AA is predominantly treated using corticosteroids, systemic immunosuppressants, and topical immunotherapy. Currently, there are limited data to reliably inform effective treatment decisions, particularly for patients with extensive disease. However, several novel therapies that specifically target the immunopathology of AA have emerged, including Janus kinase (JAK) 1/2 inhibitors such as baricitinib and deuruxolitinib, and the JAK3/tyrosine kinase expressed in hepatocellular carcinoma (TEC) family kinase inhibitor ritlecitinib. To support disease management, a disease severity classification tool, the Alopecia Areata Severity Scale, was recently developed that evaluates patients with AA holistically (extent of hair loss and other factors). AA is an autoimmune disease often associated with comorbidities and poor QoL, which poses a significant economic burden for payers and patients. Better treatments are needed for patients, and JAK inhibitors, among other approaches, may address this tremendous unmet medical need. DISCLOSURES: Dr King reports seats on advisory boards for and/or is a consultant and/or clinical trial investigator for AbbVie, Aclaris Therapeutics Inc, AltruBio Inc, Almirall, Arena Pharmaceuticals, Bioniz Therapeutics, Bristol Meyers Squibb, Concert Pharmaceuticals Inc, Dermavant Sciences Inc, Eli Lilly and Company, Equillium, Incyte Corp, Janssen Pharmaceuticals, LEO Pharma, Otsuka/Visterra Inc, Pfizer, Regeneron, Sanofi Genzyme, TWi Biotechnology Inc, and Viela Bio; and speakers bureaus for AbbVie, Incyte, LEO Pharma, Pfizer, Regeneron, and Sanofi Genzyme. Pezalla is a paid consultant to Pfizer for market access and payer strategy concerns; Fung, Tran, Bourret, Takiya, Peeples-Lamirande, and Napatalung are employees of Pfizer and hold stock in Pfizer. This article was funded by Pfizer.

Deucravacitinib is an allosteric TYK2 protein kinase inhibitor FDA-approved for the treatment of psoriasis.

Psoriasis is a heterogeneous, inflammatory, autoimmune skin disease that affects up to 2% of the world's population. There are many treatment modalities including topical medicines, ultraviolet light therapy, monoclonal antibodies, and several oral medications. Cytokines play a central role in the pathogenesis of this disorder including TNF-α, (tumor necrosis factor-α) IL-17A (interleukin-17A), IL-17F, IL-22, and IL-23. Cytokine signaling involves transduction mediated by the JAK-STAT pathway. There are four JAKS (JAK1/2/3 and TYK2) and six STATS (signal transducer and activators of transcription). Janus kinases contain an inactive JH2 domain that is aminoterminal to the active JH1 domain. Under basal conditions, the JH2 domain inhibits the activity of the JH1 domain. Deucravacitinib is an orally effective N-trideuteromethyl-pyridazine derivative that targets and stabilizes the TYK2 JH2 domain and thereby blocks TYK2 JH1 activity. Seven other JAK inhibitors, which target the JAK family JH1 domain, are prescribed for the treatment of neoplastic and other inflammatory diseases. The use of deuterium in the trimethylamide decreases the rate of demethylation and slows the production of a metabolite that is active against a variety of targets in addition to TYK2. A second unique aspect in the development of deucravacitinib is the targeting of a pseudokinase domain. Deucravacitinib is rather specific for TYK2 and its toxic effects are much less than those of the other FDA-approved JAK inhibitors. The successful development of deucravacitinib may stimulate the development of additional pseudokinase ligands for the JAK family and for other kinase families as well.

Comparison of the effects of peficitinib and tofacitinib in the adjuvant-induced arthritis rat model.

We investigated and compared the pharmacologic properties of two Janus kinase (JAK) inhibitors, peficitinib and tofacitinib, in an adjuvant-induced arthritis rat model. Repeated administration of peficitinib (3 - 30 mg/kg) or tofacitinib (1 - 10 mg/kg) exhibited a dose-related and significant attenuation of arthritis score, paw swelling, pain threshold, grip strength and histopathologic injuries in the model; peficitinib 10 mg/kg and tofacitinib 3 mg/kg demonstrated comparable efficacy. Equivalent Cmax and AUC0-12h values were observed with peficitinib 10 mg/kg and tofacitinib 3 mg/kg, suggesting that the two drugs may demonstrate comparable efficacy on arthritis-associated symptoms at comparable plasma concentration levels. However, peficitinib 10 mg/kg had greater efficacy than tofacitinib 3 mg/kg on some inflammation- and bone destruction-associated parameters in the paw fluid, including the production of vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF), receptor activator of nuclear factor kappa-B ligand, and matrix metalloproteinase-3, which are associated with arthritis exacerbation. Peficitinib 10 mg/kg also showed significantly greater inhibitory effects than tofacitinib 3 mg/kg on loss of bone mineral density and synovial thickening score, which might be a result of the VEGF and PDGF receptor kinase inhibitory effects of peficitinib, in addition to JAK inhibition. In conclusion, both tofacitinib and peficitinib potently improved arthritis and associated symptoms in adjuvant-induced arthritis rats; moreover, owing to possible differences in the mechanism of action of the two drugs, peficitinib may have exerted its effects through JAK inhibition and additional unique off-target properties.

Vitiligo Treatments: Review of Current Therapeutic Modalities and JAK Inhibitors.

Vitiligo is a chronic autoimmune disease characterized by loss of pigment of the skin, affecting 0.5-2% of the population worldwide. It can have a significant impact on patients' quality of life. In recent years, there has been significant progress in our understanding of the pathogenesis of vitiligo. It is believed that vitiligo develops due to a complex combination of genetics, oxidative stress, inflammation, and environmental triggers. Conventional treatments include camouflage, topical corticosteroids, topical calcineurin inhibitors, oral corticosteroids, phototherapy, and surgical procedures, with the treatment regimen dependent on the patient's preferences and characteristics. With increased understanding of the importance of the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in the pathogenesis of vitiligo, treatment has expanded to include the first US FDA-approved cream to repigment patients with vitiligo. This review summarizes our understanding of the major mechanisms involved in the pathogenesis of vitiligo and its most common available treatments.

Treatment of in vitro generated Langerhans cells with JAK-STAT inhibitor reduces their inflammatory potential.

Alopecia areata (AA) is a condition in which hair is lost in small regions or over the entire body. It has a prevalence of 1 in 1000 and has a great impact on psychological wellbeing. AA is generally considered an autoimmune disease in which a collapse of the immune privilege system of the hair follicle has shown to play an important role, potentially driven by interferon gamma (IFN-γ). The most prominent cells located in or around the hair follicle in AA are Langerhans cells, CD4+ or CD8+ T cells, macrophages and mast cells. Langerhans cells, specialized dendritic cells, are resident in the epidermis and are known to associate with hair follicles. Therefore, we aimed to develop in vitro generated Langerhans cells contributing as an in vitro model of disease. In vitro models provide insight into the behaviour of cells and are a valuable tool before being in need of an animal model or patient samples. For this, Langerhans-like cells were generated from CD14+ monocytes in the presence of GM-CSF and TGF-ß. After 10 days of cell culture, Langerhans-like cells express CD207 and CD1a but lack CD209 expression as well as Birbeck granules. Next, Langerhans-like cells were exposed to inflammatory conditions and the effect of different AA treatments was investigated. All treatments-diphencyprone contact immunotherapy, UV-B light therapy and JAK-STAT inhibition-affect the expression of costimulatory and skin-homing markers on Langerhans-like cells. Importantly, also the T cell stimulatory capacity of Langerhans-like cells was significantly reduced following treatment under inflammatory conditions. Noteworthy, JAK-STAT inhibition outperformed conventional AA treatments. In conclusion, our findings demonstrate that in vitro generated Langerhans-like cells can be used as a model of disease. Moreover, JAK-STAT inhibition may become a valuable new approach for the treatment of AA.

Systematic review with network meta-analysis: Risk of Herpes zoster with biological therapies and small molecules in inflammatory bowel disease.

BACKGROUND: Biologics and small molecules for inflammatory bowel disease (IBD) may increase infection risk. Herpes zoster causes acute and long-term symptoms, but vaccination is not recommended in patients with IBD, unless >50 years of age. AIMS: To examine risk of Herpes zoster infection with all licensed biologics and small molecules for IBD using network meta-analysis. METHODS: We searched the literature to 4th October 2022, for randomised controlled trials of these drugs in luminal Crohn's disease or ulcerative colitis reporting data on occurrence of Herpes zoster infection during follow-up. We used a frequentist approach and a random effects model, pooling data as relative risks (RRs) with 95% confidence intervals (CIs). RESULTS: We identified 25 trials (9935 patients). Only tofacitinib 10 mg b.d. (RR = 6.90; 95% CI 1.56-30.63, number needed to harm (NNH) = 97; 95% CI 19-1022) and upadacitinib 45 mg o.d. (RR = 7.89; 95% CI 1.04-59.59, NNH = 83; 95% CI 10-14,305) were significantly more likely to increase risk of Herpes zoster infection. Janus kinase inhibitors were the most likely drug class to increase risk of infection, and risk increased with higher doses (RR with lowest dose = 3.16; 95% CI 1.02-9.84, NNH = 265; 95% CI 65-28,610, RR with higher dose = 5.91; 95% CI 2.21-15.82, NNH = 117; 95% CI 39-473). CONCLUSIONS: In a network meta-analysis, the janus kinase inhibitor tofacitinib, and all janus kinase inhibitors considered as a class, were most likely to increase risk of Herpes zoster infection. Risk increased with higher doses.

The use of Janus kinase inhibitors and narrowband ultraviolet B combination therapy in non-segmental vitiligo.

Vitiligo is a depigmentation disorder of the skin that occurs secondary to the destruction of melanocytes by an immune-mediated process. Vitiligo clinically presents with depigmented macules and patches, most commonly on the face, acral sites, and genitalia. It can be characterized as generalized or localized based on distribution. The localized form can be further divided into segmental (linear, band-like, or Blaschkoid) and non-segmental vitiligo. The classical treatment of vitiligo includes topical steroids, pulsed oral steroids in unstable vitiligo, phototherapy, a combination of steroid therapy and phototherapy, surgical grafting, as well as intentional depigmentation therapy in severe cases. However, recent advances in understanding the immune mechanisms implicated in the pathogenesis of vitiligo have led to the use of an FDA-approved topical Janus kinase (JAK) inhibitors for vitiligo. Despite this novel therapy advancement, we recommend the addition of narrowband ultraviolet B (NB-UVB) to JAK inhibitors in patients with extensive and progressive lesions, or those not fully responsive to JAK inhibitor monotherapy.

Biologic and targeted therapeutics in vitiligo.

BACKGROUND: Vitiligo is a long-standing progressive autoimmune disease with depigmented macules/patches with significant psychological morbidity to the patients. From being one of the most poorly understood diseases in the past, there has been a rampant advance in determining the molecular and genetic factors influencing the disease process. More light has been shed on the complex intracellular environment and interplay between innate and adaptive immunity. Numerous cytokines and signaling pathways have been associated with disease pathogenesis in the recent past. OBJECTIVE: The aim of this review the efficacy of biologic and targeted therapeutics in vitiligo. METHODS: A detailed literature search was conducted on databases like PubMed, COCHRANE Central, EMBASE and Google Scholar using keywords-"biologics," "vitiligo," "treatment," "repigmentation," "JAK inhibitors,", "TNF-ê­¤ inhibitors," and "IL17/23 inhibitors," Relevant studies and review articles in English were analyzed in detail and report was written. This article aimed at a comprehensive review of all the biologicals and newer targeted therapeutics tried in vitiligo and their efficacy with an insight into the potential complications arising as a result of the therapy. RESULTS: Most conventional vitiligo treatment modalities are restricted to generalized nonspecific immunosuppressants like topical and oral corticosteroids, calcineurin inhibitors, phototherapy, and surgical modalities. There have been reports and studies on the usage of biologicals in treating vitiligo. JAK inhibitors have shown good efficacy in vitiligo; however, it lacks substantial evidence in the form of randomized control trials. Similarly, the use of targeted therapeutics in treating vitiligo is substantiated by limited evidence and requires more randomized trials for further evidence. CONCLUSION: JAK inhibitors have shown promising results and good tolerability; Adjuvant phototherapy can achieve a superior response compared to monotherapy. Though TNF-ê­¤ has been tried in a few cases, it is best used if vitiligo is present in association with other chronic autoimmune diseases for which it is indicated. More in vitro studies and clinical research are required to understand the pathogenesis clearly, and therapy has to be targeted at specific pathways for a better approach toward vitiligo. Treatment aimed at induction and differentiation of melanocytes may be added to achieve faster repigmentation.

JAK Inhibitor Safety Compared to Traditional Systemic Immunosuppressive Therapies.

Dermatologists treating atopic dermatitis are interested in the safety profile of the recently available JAK inhibitors, upadacitinib and abrocitinib, especially after they received boxed safety warnings. Long-term clinical trial data using these JAK inhibitors for the treatment of atopic dermatitis suggest that they are associated with very low incidence rates of malignancy, major adverse cardiac events, and thromboembolic events. However, a knowledge gap exists regarding the incidence of adverse events for JAK inhibitors compared to traditional systemic therapies used to treat poorly controlled atopic dermatitis as well as baseline rates in both atopic dermatitis and reference control populations. To address this gap, we analyzed data regarding adverse events of special interest for methotrexate, cyclosporine, and systemic corticosteroids and calculated the incidence of adverse events per 100 patient-years for these drugs. We also examined data regarding baseline incidence of adverse events in atopic dermatitis and control patients. We found that compared to upadacitinib and abrocitinib, traditional systemic therapies for atopic dermatitis demonstrated equal or higher incidence rates for malignancy (excluding non-melanoma skin cancer), non-melanoma skin cancer, major adverse cardiac events, and venous thromboembolism. Moreover, the use of upadacitinib and abrocitinib also exhibited either comparable or lower incidence of malignancy (excluding non-melanoma skin cancer), major adverse cardiac events, and venous thromboembolism, but higher rates of non-melanoma skin cancer, in comparison to baseline rates in atopic dermatitis or control patients. These findings indicate that JAK inhibitors should be positioned, at least based on safety, ahead of traditional systemic therapies for atopic dermatitis treatment.J Drugs Dermatol. 2022;21(12):1298-1303. doi:10.36849/JDD.7187.