Emerging treatments for moderate-to-severe atopic dermatitis (AD) may provide greater and faster improvement in AD signs and symptoms than current therapies.To examine JADE COMPARE (NCT03720470) data using stringent efficacy end points.Adults with moderate-to-severe AD were randomly assigned 2:2:2:1 to receive oral abrocitinib 200 or 100 mg once daily, subcutaneous dupilumab 300 mg every 2 weeks (600-mg loading dose), or placebo, with medicated topical therapy for 16 weeks. Stringent response thresholds were applied for Eczema Area and Severity Index (EASI), Investigator's Global Assessment, Dermatology Life Quality Index, Peak Pruritus Numerical Rating Scale, and Night Time Itch Scale severity.At week 16, 48.9%, 38.0%, and 38.8% of the abrocitinib 200-mg, 100-mg, and dupilumab groups, respectively, achieved greater than or equal to 90% improvement from baseline in EASI versus 11.3% placebo; 14.9%, 12.6%, and 6.5% achieved Investigator's Global Assessment 0 (clear) versus 4.8% placebo; 29.7%, 21.6%, and 24.0% achieved Dermatology Life Quality Index 0/1 (no/minimal impact on quality of life) versus 10.6% placebo; and 57.1%, 44.5%, and 46.1% achieved Night Time Itch Scale severity 0/1 (no/minimal night-time itch) versus 31.9% placebo. Kaplan-Meier median time to greater than or equal to 90% improvement from baseline in EASI was 59, 113, and 114 days in the abrocitinib 200-mg, 100-mg, and dupilumab groups, respectively, and was not evaluable for placebo; median time to Peak Pruritus Numerical Rating Scale 0/1 (no/very minimal itch) was 86 and 116 days for abrocitinib 200-mg and dupilumab groups, respectively, and was not evaluable for abrocitinib 100-mg and placebo groups.A greater proportion of patients treated with abrocitinib than placebo had almost complete control of AD signs and symptoms.
Human immunodeficiency virus (HIV) infection is associated with progressive loss of circulating CD4+ lymphocytes. Treatment with highly active antiretroviral therapy (HAART) has led to increases in CD4+ T lymphocytes of naive (CD45RA+62L+) and memory (CD45R0+RA−) phenotypes. Thymic computerized tomography scans were obtained on 30 individuals with HIV disease to investigate the role of the thymus in cellular restoration after 48 weeks of HAART. Individuals with abundant thymic tissue had higher naive CD4+ T lymphocyte counts at weeks 2–24 after therapy than individuals with minimal thymic tissue. Individuals with abundant thymic tissue had significantly larger increases in naive CD4+ cells during the first 4 weeks of therapy. These individuals were also more likely to experience viral rebound despite comparable initial declines in plasma HIV-1 RNA. These findings suggest that there is a complex relationship among the thymus, viral replication, and lymphocyte restoration after application of HAART in HIV disease.
Background. A tropism test is required before administration of the antiretroviral drug maraviroc. However, plasma RNA testing is not possible in patients with undetectable plasma viral loads. Here we assess genotypic testing of cellular human immunodeficiency virus (HIV) DNA from peripheral blood mononuclear cells (PBMCs) to predict virologic responses in treatment-experienced patients beginning maraviroc-containing regimens.
Patients (pts) with RA have increased risk of myocardial infarction (MI) and stroke that cannot be completely explained by traditional cardiovascular (CV) risk factors. Tofacitinib is an oral JAK inhibitor for the treatment of RA. Treatment with tofacitinib may increase total cholesterol (TC), low-density lipoprotein-cholesterol (LDL-c) and high-density lipoprotein-cholesterol (HDL-c), without affecting TC/HDL-c ratio.
Objectives
To evaluate major adverse CV event (MACE) risk factors in tofacitinib-treated pts with RA in the clinical development programme.
Methods
Data were pooled from pts with moderately to severely active RA receiving ≥1 tofacitinib dose in 6 Phase 3 and 2 long-term extension (LTE) studies (1 LTE study ongoing, data cut-off: April 2015). MACE was any MI, stroke or CV death (coronary, cerebrovascular, cardiac). Cox regression models evaluated associations between baseline (BL) values and time (BL to first tofacitinib dose) to first MACE. Changes (BL to Week [wk] 24) in MACE predictors and time to future MACE (first occurrence after 24 wks) were evaluated after adjusting for age, BL values and time-varying tofacitinib dose. Hazard ratios (HR) and 95% confidence intervals (CI) were calculated.
Results
52 MACE cases occurred over 12,873 pt-years (py) of exposure in 4076 pts (incidence rate: 0.4 pts with events/100 py). At BL, compared with pts without MACE, pts with MACE were older (mean age 60.2 vs 52.7 years) with a higher mean BMI (29.2 vs 27.0 kg/m2) and longer mean RA disease duration (10.1 vs 7.7 years), and were more likely to have a history of diabetes (15.4% vs 7.6%) and hypertension (57.7% vs 33.7%). Pts with MACE had higher mean TC (208.2 vs 198.3 mg/dL), LDL-c (123.3 vs 114.0 mg/dL), TC/HDL-c ratio (4.0 vs 3.5) and triglycerides (152.1 vs 125.3 mg/dL) at BL, and lower HDL-c (55.3 vs 59.4 mg/dL) vs pts without MACE. In univariate analyses, traditional CV risk factors and corticosteroid and statin use at BL were associated with MACE risk (Table). BL disease activity and inflammation measures were not associated with MACE risk (Table). In multivariate analysis, BL age, hypertension and the TC/HDL-c ratio were significantly associated with MACE risk. Increases in HDL-c (p<0.001) and decreases in TC/HDL-c ratio (p<0.05) after 24 wks of tofacitinib therapy were significantly associated with decreased risk of future MACE (Figure). Increases in erythrocyte sedimentation rate (ESR; p=0.09) may be associated with increased future MACE risk. Changes in TC, LDL-c or other disease activity measures were not associated with future MACE risk.
Conclusions
In pooled analyses of tofacitinib-treated pts (age and BL value adjusted), increases in LDL-c and TC after 24 wks of tofacitinib therapy were not associated with future MACE risk. Increases in HDL-c and decreases in the TC/HDL-c ratio after 24 wks of tofacitinib therapy were associated with reduced future MACE risk. Increases in ESR after 24 wks may be associated with increased future MACE risk. More data are needed to confirm these findings.
Acknowledgements
Previously presented at ACR 2016 and reproduced with permission. This study was sponsored by Pfizer Inc. Editorial support was provided by C Viegelmann of CMC and was funded by Pfizer Inc.
Disclosure of Interest
C. Charles-Schoeman Grant/research support from: AbbVie, Bristol-Myers Squibb, Pfizer Inc, Consultant for: Amgen, Pfizer Inc, Regeneron-Sanofi, H. Valdez Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, K. Soma Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, L. Hwang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. DeMasi Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, M. Boy Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, I. McInnes Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Janssen, Merck, Novartis, Pfizer Inc, Roche
Objective Patients with rheumatoid arthritis (RA) are at increased risk for herpes zoster (HZ) (i.e., shingles). The aim of this study was to determine whether treatment with tofacitinib increases the risk of HZ in patients with RA. Methods HZ cases were identified as those reported by trial investigators from the databases of the phase II, phase III, and long‐term extension (LTE) clinical trials in the Tofacitinib RA Development Program. Crude incidence rates (IRs) of HZ per 100 patient‐years (with 95% confidence intervals [95% CIs]) were calculated by exposure group. Logistic regression analyses were performed to evaluate potential risk factors for HZ (e.g., age, prednisone use). Results Among 4,789 participants, 239 were identified as having tofacitinib‐associated HZ during the phase II, phase III, and LTE trials, of whom 208 (87%) were female and whose median age was 57 years (range 21–75 years). One HZ case (0.4%) was multidermatomal; none of the cases involved visceral dissemination or death. Twenty‐four patients with HZ (10%) permanently discontinued treatment with tofacitinib, and 16 (7%) were either hospitalized or received intravenous antiviral drugs. The crude HZ IR across the development program was 4.4 per 100 patient‐years (95% CI 3.8–4.9), but the IR was substantially higher within Asia (7.7 per 100 patient‐years, 95% CI 6.4–9.3). Older age was associated with HZ (odds ratio 1.9, 95% CI 1.5–2.6), and IRs for HZ were similar between patients receiving 5 mg tofacitinib twice daily (4.4 per 100 patient‐years, 95% CI 3.2–6.0) and those receiving 10 mg twice daily (4.2 per 100 patient‐years, 95% CI 3.1–5.8). In the phase III trials among placebo recipients, the incidence of HZ was 1.5 per 100 patient‐years (95% CI 0.5–4.6). Conclusion In the Tofacitinib RA Development Program, increased rates of HZ were observed in patients treated with tofacitinib compared with those receiving placebo, particularly among patients within Asia. Complicated HZ among tofacitinib‐treated patients was rare.
We compared immune phenotypes, lymphocyte proliferation (LP), and delayed type hypersensitivity (DTH) responses in 28 male antiretroviral treatmentnaive and experienced HIV-1-infected patients, matched pair-wise according to age and CD4+ T-lymphocyte count. Median CD4+ T-lymphocyte counts were 441 cells/μL and 483 cells/μL and median CD4+ T-lymphocyte nadirs were 435 cells/μL and 150 cells/μL in both groups, respectively. Absolute numbers of circulating T-lymphocyte subpopulations and proportions of naive and memory T-lymphocytes were comparable in the two groups. Untreated patients had greater proportions of activated CD4+ (p < .05) and CD8+ (p < .01) T-cells expressing human leukocyte antigen (HLA)DR and CD38 and fewer CD8+ cells expressing CD28 (p < .05). DTH and LP responses were comparable in both groups except for HIVp24, LP responses, and mumps DTH responses, which were of greater magnitude in the group treated with highly active antiretroviral therapy (HAART) (p < .05). Thus, HIV-1-infected patients who experienced substantial increases in CD4+ T-lymphocyte counts after suppression of viral replication on HAART had fewer activated lymphocytes and similar immune function when compared with findings in untreated patients with similar CD4+ T-cell counts. HIV replication has minimal real time effect on CD4+ T-cell function in response to non-HIV antigens but helper T-cell responses to HIV-gag antigen are impaired during ongoing viral replication and may be restored by antiretroviral therapy.
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