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.

Brain-Gut and Microbiota-Gut-Brain Communication in Type-2 Diabetes Linked Alzheimer's Disease.

The gastrointestinal (GI) tract, home to the largest microbial population in the human body, plays a crucial role in overall health through various mechanisms. Recent advancements in research have revealed the potential implications of gut-brain and vice-versa communication mediated by gut-microbiota and their microbial products in various diseases including type-2 diabetes and Alzheimer's disease (AD). AD is the most common type of dementia where most of cases are sporadic with no clearly identified cause. However, multiple factors are implicated in the progression of sporadic AD which can be classified as non-modifiable (e.g., genetic) and modifiable (e.g. Type-2 diabetes, diet etc.). Present review focusses on key players particularly the modifiable factors such as Type-2 diabetes (T2D) and diet and their implications in microbiota-gut-brain (MGB) and brain-gut (BG) communication and cognitive functions of healthy brain and their dysfunction in Alzheimer's Disease. Special emphasis has been given on elucidation of the mechanistic aspects of the impact of diet on gut-microbiota and the implications of some of the gut-microbial products in T2D and AD pathology. For example, mechanistically, HFD induces gut dysbiosis with driven metabolites that in turn cause loss of integrity of intestinal barrier with concomitant colonic and systemic chronic low-grade inflammation, associated with obesity and T2D. HFD-induced obesity and T2D parallel neuroinflammation, deposition of Amyloid ß (Aß), and ultimately cognitive impairment. The review also provides a new perspective of the impact of diet on brain-gut and microbiota-gut-brain communication in terms of transcription factors as a commonly spoken language that may facilitates the interaction between gut and brain of obese diabetic patients who are at a higher risk of developing cognitive impairment and AD. Other commonality such as tyrosine kinase expression and functions maintaining intestinal integrity on one hand and the phagocytic clarence by migratory microglial functions in brain are also discussed. Lastly, the characterization of the key players future research that might shed lights on novel potential pharmacological target to impede AD progression are also discussed.

Current evidence for janus kinase inhibitors in adult and juvenile dermatomyositis and key comparisons.

INTRODUCTION: Adult dermatomyositis (DM) and juvenile dermatomyositis (JDM) are rare autoimmune diseases with characteristic skin rashes, weakness, and other systemic features. Upregulated interferon signaling has been consistently described in both adult and juvenile DM which makes janus kinase inhibitors (jakinibs) an attractive therapeutic agent that has a targeted mechanism of action. AREAS COVERED: Herein is a review of the growing literature of jakinib use in adult and juvenile DM, including reports on specific disease features and safety of jakinibs in this population and a comparison between adult and juvenile DM. We performed a literature review using PubMed including all English-language publications before 1 February 2024 and abstracts from key recent rheumatology conferences. EXPERT OPINION: Jakinibs are an exciting and promising treatment in both adult and juvenile DM. Current Phase 2 and 3 randomized placebo-controlled trials of jakinibs in both adult and JDM will provide significant insights into the efficacy of this class of medication as a potentially more mechanistically targeted treatment of both skin and muscle disease. In fact, these results will likely inform the treatment paradigm of dermatomyositis in that it may even be considered as first or second line. The next five years in the therapeutic landscape of both juvenile and adult DM is an exciting time for both patients and medical providers.

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.

Baricitinib in the treatment of systemic lupus erythematosus: a systematic review of randomized controlled trials.

Background: Baricitinib, a Janus Kinase (JAK) inhibitor, has emerged as a potential therapeutic option for systemic lupus erythematosus (SLE). This systematic review aims to synthesize evidence from randomized controlled trials (RCTs) evaluating the potential of baricitinib in treating SLE. Methods: A systematic search was conducted across electronic databases to identify relevant RCTs assessing baricitinib in patients with SLE. Studies reporting outcomes such as the Systemic Lupus Erythematosus Responder Index-4 (SRI-4), adverse events, and safety profiles were included. Data extraction and quality assessment were performed following PRISMA guidelines. Results: A total of four studies were evaluated for efficacy and safety of baricitinib therapy. Three studies reported SRI-4, British Isles Lupus Assessment Group (BILAG), and Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K), except for Dorner and colleagues Only Dorner and colleagues and Wallace and colleagues discuss the anti-dsDNA titres following treatment with baricitinib. The findings consistently demonstrated improved efficacy of baricitinib compared to placebo, particularly in terms of SRI-4 scores. Higher dosages of baricitinib showed significant improvement in disease activity and severity indices. Adverse events, including infections and gastrointestinal disturbances, were reported. Conclusion: Baricitinib holds promise for treating SLE, but caution is needed due to potential adverse events. Careful patient selection and monitoring are crucial. Future research should prioritize long-term safety and comparative effectiveness studies to better understand baricitinib's role in managing SLE.

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).

Systemic Lupus Erythematosus and Cytokine Storm.

Systemic lupus erythematosus (SLE) is the prototype of autoimmune diseases and can manifest with a plethora of clinical signs and symptoms associated with a myriad of laboratory abnormalities. An infrequent but potentially lethal complication of SLE is macrophage activation syndrome (MAS). The diagnosis of MAS in SLE can be very challenging due to similarities in presentation of both flares and infections, such as fever, lymphadenopathy, splenomegaly, and cytopenias. These aggravating factors contribute to the increased risk of poor outcomes in SLE-associated MAS. Indeed, at the moment MAS remains invariably lethal if untreated and still has a high mortality rate with treatment. In this chapter, we discuss several aspects of MAS in the context of SLE and in particular, the pathogenesis of MAS in SLE, how MAS presents in pediatric versus adult SLE, and, finally, MAS treatment in SLE and future directions.

JAK Inhibitors in Cytokine Storm Syndromes.

Cytokine storm syndromes (CSSs) comprise a group of severe and often fatal hyperinflammatory conditions driven by the overproduction of pro-inflammatory cytokines by activated cells of the immune system. Many of the CSS-associated cytokines mediate their downstream effects by signaling through the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In addition, several of these cytokines are produced downstream of JAK/STAT pathway activation. Therefore, targeting JAK/STAT signaling using small molecule JAK inhibitors has become an increasingly appealing therapeutic option to dampen hyperinflammation in patients with CSSs. Application of JAK inhibitors in preclinical CSS models has shown improvements in multiple sequelae of hyperinflammation, and there is growing clinical evidence supporting the efficacy of JAK inhibition in patients with these conditions. Although generally well tolerated, JAK inhibitor use is not without potential for toxicity, especially in settings like CSSs where end-organ dysfunction is common. More prospective clinical trials incorporating JAK inhibitors, alone or in combination with other immunomodulatory therapies, are necessary to determine the optimal dosing, schedule, efficacy, and tolerability of these agents for patients experiencing CSSs.

Turning the Tide against Herpes Zoster in Rheumatoid Arthritis Patients Treated with JAK Inhibitors.

Objectives: This study aimed to evaluate the incidence of Herpes Zoster (HZ) in patients with rheumatoid arthritis (RA) treated with Janus kinase inhibitors (JAKi), and to predict potential risk factors for HZ development. Methods: We retrospectively analysed medical records from RA patients at our rheumatology unit who met the 2010 ACR/EULAR criteria for RA and were receiving JAKi. The incidence and course of HZ were assessed through chart review and supplementary phone interviews. Results: A total of 198 JAKi-treated patients were monitored for an average of 18.5 months. Nine subjects experienced HZ, resulting in an incidence of 2.95 per 100 patient-years. No demographic or treatment-related differences were found among patients who developed HZ and those who did not. Disease duration (OR: 1.06, 95% CI: 1.01-1.12), time on JAKi treatment (OR: 1.04, 95% CI: 1.009-1.073), higher disease activity at JAKi initiation (OR: 4.16, 95% CI: 1.07-16.17), and at 3-month follow-up (OR: 6.0, 95% CI: 1.35-26.60) were identified as predictors of HZ occurrence. Thirty-six patients received vaccination against HZ, and none reported adverse reactions or flare-ups during a mean follow-up of 9.6 months. Conclusions: The incidence of HZ aligns with published data, suggesting that disease and treatment duration, as well as disease activity, are significant predictors of HZ in RA patients on JAKi therapy. Vaccination against HZ proved to be safe and effective, underscoring its potential protective value in this patient population.

Anterior Uveitis After Discontinuation of Janus Kinase Inhibitor, Ruxolitinib.

Primary myelofibrosis shows widespread fibrosis in the bone marrow and is part of myeloproliferative neoplasms in which gene mutations in hematopoietic stem cells lead to abnormal clonal expansion of one or more lineage of myeloid and erythroid cells and megakaryocytes. Janus kinase (JAK) inhibitors are the main therapeutic regimen for primary myelofibrosis which harbors gene mutations, resulting in continuous activation of JAK-STAT signaling pathway. Since JAK inhibitors modulate immunological state, the administration would have a potential for uveitis. A 67-year-old patient presented with weight loss of 10 kg in the past 2 years after his retirement. He showed normocytic anemia with anisocytosis and abnormal shape, as well as hepatosplenomegaly. Suspected of hematological malignancy, bone marrow biopsy led to the diagnosis of primary myelofibrosis (grade 2) with bizarre megakaryocytes and relative maintenance of myeloid and erythroid lineage. He started to have blood transfusion. Genomic DNA analysis of the peripheral blood showed a pathogenic variant in the exon 9 of calreticulin (CALR) gene while pathogenic variants in Janus kinase-2 (JAK2), and myeloproliferative leukemia virus oncogene (MPL) were absent. He began to have oral ruxolitinib 10 mg daily at the timepoint of 5 months after the initial visit and the dose was increased to 20 mg daily 8 months later but was discontinued further 4 months later because he showed the limited effect of ruxolitinib. He had blood transfusion every week or every 2 weeks in the following 2 months until he noticed blurred vision in the right eye. The right eye showed thick fibrin membrane formation in the anterior chamber in front of the pupil which prevented the fundus from visualization. The left eye showed no inflammation and optic nerve atrophy, sequel to tuberculous meningitis in childhood. The patient started to use 0.1% betamethasone six times daily and 1% atropine once daily as eye drops. A week later, fibrin membrane disappeared and the pupillary area with total iris posterior synechia was visible in the right eye. He regained the vision in the right eye and did not show relapse of uveitis only with topical 0.1% betamethasone. Uveitis might be related with the administration and discontinuation of ruxolitinib.

Therapeutic targeting of siRNA/anti-cancer drug delivery system for non-melanoma skin cancer. Part I: Development and gene silencing of JAK1siRNA/5-FU loaded liposome nanocomplexes.

Non-melanoma skin cancer (NMSC) is one of the most prevalent cancers, leading to significant mortality rates due to limited treatment options and a lack of effective therapeutics. Janus kinase (JAK1), a non-receptor tyrosine kinase family member, is involved in various cellular processes, including differentiation, cell proliferation and survival, playing a crucial role in cancer progression. This study aims to provide a more effective treatment for NMSC by concurrently silencing the JAK1 gene and administering 5-Fluorouracil (5-FU) using liposome nanocomplexes as delivery vehicles. Utilizing RNA interference (RNAi) technology, liposome nanocomplexes modified with polyethylene imine (PEI) were conjugated with siRNA molecule targeting JAK1 and loaded with 5-FU. The prepared formulations (NL-PEI) were characterized in terms of their physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, and stability. Cell cytotoxicity, cell uptake and knockdown efficiency were evaluated in human-derived non-melanoma epidermoid carcinoma cells (A-431). High contrast transmission electron microscopy (CTEM) images and dynamic light scattering (DLS) measurements revealed that the nanocomplexes formed spherical morphology with uniform sizes ranging from 80-120 nm. The cationic NL-PEI nanocomplexes successfully internalized within the cytoplasm of A-431, delivering siRNA for specific sequence binding and JAK1 gene silencing. The encapsulation of 5-FU in the nanocomplexes was achieved at 0.2 drug/lipid ratio. Post-treatment with NL-PEI for 24, 48 and 72 h showed cell viability above 80 % at concentrations up to 8.5 × 101 µg/mL. Notably, 5-FU delivery via nanoliposome formulations significantly reduced cell viability at 5-FU concentration of 5 µM and above (p < 0.05) after 24 h of incubation. The NL-PEI nanocomplexes effectively silenced the JAK1 gene in vitro, reducing its expression by 50 %. Correspondingly, JAK1 protein level decreased after transfection with JAK1 siRNA-conjugated liposome nanocomplexes, leading to a 37 % reduction in pERK (phosphor extracellular signal-regulated kinase) protein expression. These findings suggest that the combined delivery of JAK1 siRNA and 5-FU via liposomal formulations offers a promising and novel treatment strategy for targeting genes and other identified targets in NMSC therapy.

Comparative safety of oral Janus kinase inhibitors and dupilumab in patients with atopic dermatitis: a population-based cohort study.

BACKGROUND: Systemic Janus kinase inhibitors (JAKi) and dupilumab both have emerged as promising therapeutics for atopic dermatitis (AD). While dupilumab has a favorable safety profile, use of oral JAKi has been established in other diseases that carry potential comorbid susceptibilities that influence safety. OBJECTIVE: To provide real-world evidence of the safety of oral JAKi in AD patients. METHODS: The study used observational data from TriNetX (Cambridge, Massachusetts). Patients with AD treated with either oral JAKi (upadacitinib, abrocitinib, and baricitinib) or dupilumab were enrolled. The two treatment groups were propensity-score matched 1:1 based on demographics, comorbidities, and prior medications. Safety outcomes within two years after the initiation of medications were measured by hazard ratios with 95% confidence intervals. RESULTS: A total of 14,716 patients were included, with 942 patients treated with oral JAKi and 13,774 with dupilumab. The two treatment groups included 938 patients after matching. Treatment with oral JAKi was not associated with increased risks of mortality, malignancies, major adverse cardiovascular events, venous thromboembolism, renal events, or serious gastrointestinal events. However, patients receiving oral JAKi showed significantly higher risks of skin and subcutaneous tissue infection, herpes infection, acne, cytopenia, and hyperlipidemia, whereas the risk of ophthalmic complications was higher in those receiving dupilumab. CONCLUSION: This study found that oral JAKi did not exhibit concerning safety issues in treating patients with AD but increased the risk of infections and laboratory abnormalities. Long-term follow-up data are required to validate these findings.

Myelofibrosis and anemia: A German claims data analysis to describe epidemiology and current treatment.

OBJECTIVES: There is limited data on the incidence, prevalence, and treatments for myelofibrosis (MF) in Germany. This retrospective study examined claims data from 3.3 million insured individuals, spanning from 2010 to 2021. METHODS: Four sensitivity scenarios were explored to identify cases of MF. Point prevalence and cumulative incidence of MF were determined as of December 31, 2021, and within 2021, respectively. A cross-sectional analysis used the main scenario definition of MF to identify cases and evaluate the period prevalence of patients receiving treatment for symptoms and/or splenomegaly, including first-line (1L) Janus kinase inhibitor (JAKi), second-line, or further (2L+) MF-related treatment therapies during 2021. The prevalence of anemia treatment was also reported. RESULTS: The estimated standardized point prevalence of MF on December 31, 2021, was 9.9-12.4 cases per 100 000 persons, and cumulative incidence in 2021 was 1.2-1.8 cases per 100 000 persons. Standardized period prevalence in 2021 for MF patients receiving 1L JAKi and/or 2L+ MF-related treatment was 4.0 cases per 100 000. Among these patients, 47.1%-53.7% required treatment for anemia, resulting in a period prevalence of 1.9-2.2 cases per 100 000 individuals. CONCLUSION: The data reveal gaps in MF treatments and the need to improve patient quality of life.

Unraveling the diagnostic odyssey: stimulator of interferon gene-associated vasculopathy with onset in infancy in a 30-year-old female.

Stimulator of interferon gene (STING)-associated vasculopathy with onset in infancy (SAVI) is an extremely rare autoinflammatory disease. We present the case of a female Korean patient with early-onset interstitial lung disease who was initially suspected to have systemic lupus erythematosus (SLE) but was ultimately diagnosed with SAVI. The patient exhibited signs of interstitial lung disease and cutaneous manifestations before the age of 1 year and continued to have recurrent fever accompanied by pulmonary infiltrates. Based on positive findings for antibodies associated with SLE, such as antinuclear antibodies and anti-double-stranded DNA, the pulmonary involvement was considered a manifestation of SLE. Another significant symptom was recurrent skin ulceration, which led to partial spontaneous amputation of most of the toes due to inflammation. Given the early onset of interstitial lung disease, severe skin ulcers, and symptoms resembling SLE, autoinflammatory syndrome, especially SAVI was suspected. Following confirmation by genetic testing at age 29 years, the patient was started on tofacitinib, a Janus kinase inhibitor. Despite the prolonged use of multiple immunosuppressive therapies, the patient's lung condition continued to worsen, ultimately requiring lung transplantation. This observational report highlights the importance of considering SAVI as a potential diagnosis when manifestations of interstitial lung disease are observed during infancy. Early proactive treatment is crucial for lung involvement, as this can have long-term effects on patient's prognosis.

Ruxolitinib Cream in Adolescents/Adults with Atopic Dermatitis Meeting Severity Thresholds for Systemic Therapy: Exploratory Analysis of Pooled Results from Two Phase 3 Studies.

INTRODUCTION: Standard therapy for patients with mild to moderate atopic dermatitis (AD) typically includes topical therapies; however, patients with more extensive AD and/or AD refractory to topical therapy may benefit from systemic treatment. Ruxolitinib cream monotherapy has demonstrated superior antipruritic and anti-inflammatory effects versus vehicle in patients with mild to moderate AD, and long-term disease control with as-needed use. Here, efficacy/safety of 1.5% ruxolitinib cream through 52 weeks was assessed in a subset of patients with moderate and/or more extensive disease. METHODS: This post hoc analysis of TRuE-AD1/TRuE-AD2 included patients who, at baseline, had Investigator's Global Assessment (IGA) score of 3, Eczema Area and Severity Index (EASI) ≥ 16, and affected body surface area (BSA) ≥ 10% (higher severity of disease threshold subgroup). Disease control and safety were assessed. RESULTS: Of 1249 patients in the overall population, 78 (6.2%) met all higher severity of disease threshold criteria (continuous-use vehicle-controlled period: 1.5% ruxolitinib cream, n = 32; vehicle, n = 13); 28 and 4 of these patients, respectively, continued as-needed 1.5% ruxolitinib cream during the long-term safety (LTS) period. At week 8 (continuous-use), IGA-treatment success (IGA 0/1, with ≥ 2-grade improvement from baseline) was achieved by 19/32 (59.4%) patients applying 1.5% ruxolitinib cream versus no patients applying vehicle. In the LTS period, those achieving clear/almost clear skin increased from 19/28 patients (67.9%; continuous-use: week 8) to 18/23 patients (78.3%; as-needed use: week 52) in patients applying ruxolitinib cream from day 1. Ruxolitinib cream was well tolerated, with few application site reactions, regardless of disease severity threshold. Efficacy and safety results were similar to the overall study population. CONCLUSION: Patients with AD who meet standard disease severity eligibility criteria for systemic therapy may achieve IGA-treatment success with clear/almost clear skin with continuous-use ruxolitinib cream, and maintain long term-disease control with as-needed ruxolitinib cream monotherapy. TRIAL REGISTRATION NUMBER: NCT03745638/NCT03745651.

Atopic dermatitis (AD) is a skin condition that causes itchy, dry, and inflamed skin. For many people AD is controlled with medication that is applied to the skin. However, for some people medication that is taken orally or injected (i.e., systemic treatment) may be needed. Systemic treatment can sometimes be challenging. Doctors use a variety of tools to measure AD severity and apply standard criteria to help determine if a person should receive systemic treatment. In the TRuE-AD1/TRuE-AD2 clinical trials, itch and inflammation improved in people with mild to moderate AD after they applied ruxolitinib cream twice daily for 8 weeks. When people then applied ruxolitinib cream to areas of AD only when it was needed for another 44 weeks, ruxolitinib cream provided long-term control of their AD. The aim of this analysis was to assess disease control with ruxolitinib cream in people with AD severe enough to meet the standard criteria indicating a need for systemic treatment. In this group, the majority had clear or almost clear skin after applying ruxolitinib cream twice daily for 8 weeks. After 44 weeks of as-needed application of ruxolitinib cream, most people still had clear or almost clear skin. In this group of people who may have otherwise needed treatment with systemic therapy, ruxolitinib cream twice daily for 8 weeks and then as-needed was generally well tolerated. These results show that as-needed ruxolitinib cream may provide long-term control of AD in people who may otherwise have needed systemic therapy.

Re-evaluating Methods for Assessing Differences in Response in Ileal vs. Colonic Crohn's Disease: A Post-hoc Analysis of the FITZROY Trial.

BACKGROUND AND AIMS: The ileum is the most commonly affected segment of the gastrointestinal tract in Crohn's disease (CD). We aimed to determine whether disease location affects response to filgotinib, a Janus kinase (JAK) inhibitor, in patients with moderate-to-severely active Crohn's disease (CD) and applying appropriate methods to account for differences in measuring disease activity in the ileum compared to the colon. METHODS: This post-hoc analysis of data from the FITZROY phase 2 trial (NCT02048618) compared changes in the Crohn's Disease Activity Index (CDAI) and Simple Endoscopic Score for Crohn's Disease (SES-CD) amongst patients with ileal-dominant and isolated colonic CD treated with 10 weeks of filgotinib 200 mg daily or placebo. A mixed effects model for repeated measures was used to test whether ileal disease responded differently than colonic disease, by evaluating for effect modification using the interaction term of treatment assignment-by-disease location. RESULTS: Numerically greater proportions of patients with isolated colonic disease compared to ileal-dominant CD achieved clinical remission (CDAI <150, 75.9% vs. 41.6%) and endoscopic response (SES-CD reduction by 50%, 52.5% vs. 15.5%) at Week 10. However, after adjusting for baseline disease activity by disease location and within-patient clustering effects, there was no significant difference in treatment response by disease location (mean difference in ΔCDAI between ileal-dominant vs. isolated colonic disease +9.24 [95% CI: -87.19, +105.67], p=0.85; mean difference in ΔSES-CD -1.93 [95% CI: -7.03, +3.44], p=0.48). CONCLUSIONS: Filgotinib demonstrated similar efficacy in ileal-dominant and isolated colonic CD when controlling for baseline disease activity and clustering effects.

Successful treatment of infantile refractory bullous pemphigoid with baricitinib.

Infantile bullous pemphigoid (BP) is a rare autoantibody-mediated skin disorder. We report the effective treatment of a 6-month-old infant with BP using baricitinib, a Janus kinase (JAK) inhibitor, after failure with steroids and intravenous immunoglobulin. The patient achieved full remission and discontinued all medications without any relapses. To our knowledge, this is the first case of baricitinib used in an infant with BP.

Safety and Efficacy of Upadacitinib in Patients with Rheumatoid Arthritis Refractory to Biologic DMARDs: Results Through Week 216 from the SELECT-CHOICE Study.

INTRODUCTION: The safety and efficacy of upadacitinib 15 mg (UPA15) through week 216 was evaluated in patients with rheumatoid arthritis (RA) from the long-term extension (LTE) of the phase 3 SELECT-CHOICE study. METHODS: Patients with RA refractory to biologic disease-modifying antirheumatic drugs (bDMARDs) were randomized to UPA15 or abatacept (ABA) for 24 weeks. During the open-label LTE, patients on ABA switched to UPA15 at week 24, and those on UPA15 continued treatment. The safety and efficacy of continuous UPA15, and ABA to UPA15, are summarized through week 216. RESULTS: The LTE was comprised of 91.4% (n = 277/303) of patients that initially received UPA15, and 89.6% (n = 277/309) that initially received ABA. Of patients on UPA15 in the LTE (n = 547), 28.3% (n = 155/547) discontinued the study drug by week 216. Relative to other adverse events of special interest, and largely consistent with previous findings at week 24, higher rates of serious infection, COVID-19, herpes zoster, and elevated creatine phosphokinase were reported, while rates of malignancy excluding nonmelanoma skin cancer (NMSC), NMSC, major adverse cardiovascular event (MACE), and venous thromboembolism (VTE) were low. Long-term safety data with UPA through week 216 aligned with previous observations and no new safety risks were identified, including in patients who switched from ABA to UPA15. Proportions of patients achieving 28-joint disease activity score based on C-reactive protein (DAS28[CRP]) < 2.6/ ≤ 3.2, clinical disease activity index (CDAI) and simple disease activity index (SDAI) low disease activity/remission, ≥ 20%/50%/70% improvement in the American College of Rheumatology (ACR20/50/70) response criteria, and Boolean remission were maintained or improved with UPA15 through week 216. Improvements in the Health Assessment Questionnaire-Disability Index (HAQ-DI), patient's assessment of pain, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were also maintained or improved with UPA15 through week 216. Across all efficacy endpoints, similar results were observed in patients who switched from ABA to UPA15 versus continuous UPA15. Patients with an inadequate response to ≥ 1 prior tumor necrosis factor (TNF) inhibitor (UPA15: n = 263/303, 86.8%; ABA to UPA15: n = 273/309, 88.3%) showed similar responses to the total population. CONCLUSIONS: The long-term safety profile of UPA was consistent with previous findings and the broader RA clinical program. Compared to the primary analyses at week 24, efficacy responses were maintained or further improved with UPA15 through week 216 in patients with RA. Trial registration, ClinicalTrials.gov identifier: NCT03086343.

A long-term study looked at a drug named upadacitinib to treat people with rheumatoid arthritis (RA), a disease that causes joint pain and damage. The study included patients whose RA was not improved by other injectable medicines. The study compared upadacitinib with another drug called abatacept. After 24 weeks, patients who were taking abatacept switched to upadacitinib, and patients taking upadacitinib continued on upadacitinib treatment for over 4 years. The researchers looked at how well the treatments worked over the long-term and if there were any side effects. The side effects with upadacitinib treatment in this long-term study were similar to side effects reported in previous studies with upadacitinib. The researchers also found that upadacitinib helped to lessen the symptoms of RA over time and helped patients complete their daily activities and reduced their pain and tiredness. This was true for patients who switched from abatacept to upadacitinib after 24 weeks and for patients who took upadacitinib from the start of the study. Patients who had not responded to other medicines also had similar improvements with upadacitinib. In conclusion, upadacitinib can help people with RA over the long term and no new safety risks were found.

A double-blind pilot study of oral baricitinib in adult patients with lupus erythematosus panniculitis.

Lupus erythematosus panniculitis (LEP) is a chronic inflammatory skin disease with a significant impact on the overall well-being of patients. The safety and efficacy of oral baricitinib for the treatment of LEP have not been studied. This study aimed to explore the efficacy of oral baricitinib in patients with LEP who are recalcitrant or intolerant to conventional therapies. Patients (aged ≥18 years) with active LEP (with a revised cutaneous lupus erythematosus disease area and severity index [RCLASI]-active score ≥4] were randomly assigned 2:1 to baricitinib (4 mg) or placebo (once daily for 20 weeks). The placebo group was switched to baricitinib (4 mg) at week 13, and the final evaluation was conducted at week 24. The primary endpoint was the proportion of patients with an RCLASI-A score decreased by 20% at week 12. The secondary endpoints included the changes in the Cutaneous Lupus Erythematosus Disease Area and Severity Index active-(CLASI-A) score, the Dermatology Life Quality Index (DLQI), the Physician's Global Assessment (PGA) score, and safety. Five patients were enrolled. Three patients received baricitinib (4 mg), and two patients were treated with placebo. Two patients in the baricitinib treatment group showed a significant RCLASI-A decrease at week 12 and week 24. Two patients in the placebo group had no change in RCLASI-A at week 12 and a significant decrease at week 24. No new safety events were observed. Treatment with baricitinib was effective and well tolerated in patients with LEP.

JAK inhibitors attenuate hyperactivation of nonswitched memory B cells in rheumatoid arthritis patients in remission.

OBJECTIVE: To investigate the distribution and activation of B-cell subpopulations in rheumatoid arthritis (RA) patients treated with Janus kinase inhibitors (JAKis) and to analyze their correlation with disease remission. METHODS: Peripheral blood samples were collected from 23 adult healthy controls and 58 RA patients, 31 of whom were treated with JAKis and assessed during a 24-month follow-up. The number of peripheral B-cell subpopulations (including naive B cells, nonswitched memory B (NSMB) cells, switched memory B cells, and double-negative B cells), their activation, and phosphorylation of SYK and AKT upon B-cell receptor (BCR) stimulation in each population were analyzed by flow cytometry. RESULTS: Compared with that in healthy controls, the frequency of NSMB cells was significantly lower in new-onset untreated RA patients. However, expression of CD40, CD80, CD95, CD21low and pAKT significantly increased in these NSMB cells. Additionally, the number of NSMB cells correlated negatively with DAS28-ESR and IgG and IgA levels in these patients; expression of CD80, CD95 and CD21low on NSMB cells correlated positively with DAS28-ESR and IgG and IgA levels. After treatment with JAKis, the serum IgG concentration significantly decreased in RA patients in remission, but CD40, CD95 and pAKT levels in NSMB cells significantly decreased. CONCLUSION: RA patients present different B-cell subpopulations, in which the frequency of NSMB cells is negatively associated with disease activity. However, treatment with JAKis can inhibit activation of NSMB cells, restore the balance of kinase phosphorylation, and facilitate disease remission in RA patients.