IMPORTANCE Atopic dermatitis is associated with substantial patient and caregiver burden. Currently available treatments for atopic dermatitis are inadequate or contraindicated for some patients. Abrocitinib (PF-04965842) is an oral Janus kinase 1 selective inhibitor under investigation for the treatment of atopic dermatitis. OBJECTIVE To investigate the efficacy and safety of abrocitinib for patients with moderate to severe atopic dermatitis. DESIGN, SETTING, AND PARTICIPANTS A phase 2b, randomized, double-blinded, placebo-controlled, parallel-group trial was conducted from April 15, 2016, to April 4, 2017, at 58 centers in Australia, Canada, Germany, Hungary, and the United States among 267 patients 18 to 75 years of age with a clinical diagnosis of moderate to severe atopic dermatitis for 1 year or more and inadequate response or contraindication to topical medications for 4 weeks or more within 12 months. Efficacy was assessed in the full analysis set, which was a modified intention-to-treat population that included all patients who received 1 dose or more of the study drug except for 4 patients from 1 site. INTERVENTIONS Participants were randomly assigned 1:1:1:1:1 to receive abrocitinib (200 mg, 100 mg, 30 mg, or 10 mg) or placebo once daily for 12 weeks. MAIN OUTCOMES AND MEASURES The primary outcome was the proportion of patients achieving an Investigator's Global Assessment of clear (0) or almost clear (1) with an improvement from baseline of 2 grades or more at week 12. The secondary outcome was the percentage change from baseline in the Eczema Area and Severity Index at week 12. RESULTS Of the 267 participants, 144 were women (mean [SD] age, 40.8 [16.1] years). At week 12, 21 of 48 patients receiving 200 mg of abrocitinib (43.8%; P < .001, 2-sided), 16 of 54 patients receiving 100 mg of abrocitinib (29.6%; P < .001), and 3 of 52 patients receiving placebo (5.8%) achieved grades of clear or almost clear on the Investigator's Global Assessment scale with improvement of 2 grades or more; these rates correspond to maximum effect model-based estimates of 44.5% (95% CI, 26.7%-62.3%) for those receiving 200 mg of abrocitinib, 27.8% (95% CI, 14.8%-40.9%) for those receiving 100 mg of abrocitinib, and 6.3% (95% CI, −0.2% to 12.9%) for those receiving placebo. Reductions in the Eczema Area and Severity Index were 82.6% (90% CI, 72.4%-92.8%; P < .001) for those receiving 200 mg of abrocitinib, 59.0% (90% CI, 48.8%-69.3%; P = .009) for those receiving 100 mg of abrocitinib, and 35.2% (90% CI, 24.4%-46.1%) for those receiving placebo. Adverse events were observed in 184 of 267 patients (68.9%); the most frequently reported adverse events (in Ն3 patients in any group) were dermatitis atopic, upper respiratory tract infection, headache, nausea, and diarrhea. Dose-dependent decreases in platelet count were observed but trended upward toward baseline levels after week 4. CONCLUSIONS AND RELEVANCE Once-daily oral abrocitinib was effective and well tolerated for short-term use in adults with moderate to severe atopic de...

The design and conduct of clinical trials for new OA treatments should address the heterogeneity of the disease, treatment-associated structural changes in target joints and patient-reported outcomes.

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Background: Alopecia areata (AA) is an autoimmune form of hair loss with limited treatments.Objective: To evaluate the efficacy and safety of the Janus kinase inhibitors ritlecitinib and brepocitinib in patients who have AA with $ 50% scalp hair loss.Methods: Patients were randomized to once-daily ritlecitinib, brepocitinib, or placebo. The primary efficacy endpoint was a 24-week change from baseline in the Severity of Alopecia Tool (SALT) score. The key secondary efficacy endpoint was the proportion of patients achieving 30% improvement in SALT score (SALT 30 ).Results: The ritlecitinib, brepocitinib, and placebo groups included 48, 47, and 47 patients, respectively. At week 24, least-squares mean difference from placebo in SALT score change from baseline was 31.1 (95% confidence interval [CI], 18.8-43.5) for ritlecitinib and 49.2 (95% CI, 36.6-61.7) for brepocitinib (P \.0001 for both comparisons with placebo). SALT 30 was achieved by 50% (90% CI, 38%-62%) of patients receiving ritlecitinib, 64% (90% CI, 51%-75%) receiving brepocitinib, and 2% (90% CI, 0%-9%) receiving placebo. Two patients experienced a serious adverse event (rhabdomyolysis) in the brepocitinib group only.Limitations: Only a single-dosage regimen of each study drug was included. Conclusion:Treatment with ritlecitinib or brepocitinib for 24 weeks was efficacious and generally well tolerated.

Clinical manifestations of lupus are encountered in a variety of disease entities, including isolated cutaneous lupus, undifferentiated connective tissue disease, mixed connective tissue disease, drug-induced lupus, overlap syndrome, and systemic lupus erythematosus (SLE). While each entity has been recognized as a specific disease with its own diverse clinical and serological pattern, one could argue that many findings are common. Could it be that all of these entities actually represent a spectrum of one disease? Could it be that rather than the genetic predisposition and hence controlled factors that govern this spectrum of diseases, that environmental factors associated with SLE could also play a role in the different entities of this spectrum? The traditional environmental triggers in SLE include sunlight and ultraviolet (UV) light, infections, smoking, and medications including biologics such as tumor necrosis factor alpha (TNF-a) blockers. In this review, we update and further substantiate these traditional factors in the various lupus-related syndromes. We will also discuss the association with vaccine exposure, industrial estrogens, and other factors.

Autoantibody production and immune complex deposition within the kidney promote renal disease in patients with lupus nephritis. Thus, therapeutics that inhibit these pathways may be efficacious in the treatment of systemic lupus erythematosus. Bruton’s tyrosine kinase (BTK) is a critical signaling component of both BCR and FcR signaling. We sought to assess the efficacy of inhibiting BTK in the development of lupus-like disease, and in this article describe (R)-5-amino-1-(1-cyanopiperidin-3-yl)-3-(4-[2,4-difluorophenoxy]phenyl)-1H-pyrazole-4-carboxamide (PF-06250112), a novel highly selective and potent BTK inhibitor. We demonstrate in vitro that PF-06250112 inhibits both BCR-mediated signaling and proliferation, as well as FcR-mediated activation. To assess the therapeutic impact of BTK inhibition, we treated aged NZBxW_F1 mice with PF-06250112 and demonstrate that PF-06250112 significantly limits the spontaneous accumulation of splenic germinal center B cells and plasma cells. Correspondingly, anti-dsDNA and autoantibody levels were reduced in a dose-dependent manner. Moreover, administration of PF-06250112 prevented the development of proteinuria and improved glomerular pathology scores in all treatment groups. Strikingly, this therapeutic effect could occur with only a modest reduction observed in anti-dsDNA titers, implying a critical role for BTK signaling in disease pathogenesis beyond inhibition of autoantibody production. We subsequently demonstrate that PF-06250112 prevents proteinuria in an FcR-dependent, Ab-mediated model of glomerulonephritis. Importantly, these results highlight that BTK inhibition potently limits the development of glomerulonephritis by impacting both cell- and effector molecule-mediated pathways. These data provide support for evaluating the efficacy of BTK inhibition in systemic lupus erythematosus patients.

The safety, tolerability, pharmacokinetics, and pharmacodynamics of PF-06700841 were assessed in a randomized, double-blind, placebo-controlled, single- and multiple-dose escalation, parallel-group study in healthy subjects and patients with plaque psoriasis. The single ascending dose (1, 3, 10, 30, 100, or 200 mg) and multiple ascending dose (MAD; PF-06700841; up to 175 mg once daily or 50 mg twice daily for 10 days) periods included 54 healthy participants. In addition, 30 patients with psoriasis received PF-06700841 30 or 100 mg or placebo once daily for 28 days. Single PF-06700841 doses were rapidly absorbed, with peak plasma concentrations ≤ 1 hour, proportional exposure up to 100 mg, and mean half-life 3.8-7.5 hours. On day 10 of MAD, plasma concentrations peaked at ≤1.5 hours postdose (10-175 mg once daily). Elimination half-life was 4.9-10.7 hours; steady state was reached by day 8. In psoriasis patients on day 28, peak plasma concentrations occurred at 1-2 hours. Biomarkers IP-10 and high-sensitivity C-reactive protein were reduced and returned to near baseline levels after dosing. Maximal mean percent change from baseline in the Psoriasis Area and Severity Index scores for PF-06700841 30 mg once daily and 100 mg once daily were -67.92% and -96.31%, respectively, in week 4. All adverse events were mild/moderate. PF-06700841 was safe and well tolerated up to 200 mg once daily in healthy subjects and 100 mg once daily in patients with psoriasis, suggesting potential therapeutic utility in plaque psoriasis and other inflammatory diseases.

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