BACKGROUND. Monogenic IFN–mediated autoinflammatory diseases present in infancy with systemic inflammation, an IFN response gene signature, inflammatory organ damage, and high mortality. We used the JAK inhibitor baricitinib, with IFN-blocking activity in vitro, to ameliorate disease.METHODS. Between October 2011 and February 2017, 10 patients with CANDLE (chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperatures), 4 patients with SAVI (stimulator of IFN genes–associated [STING-associated] vasculopathy with onset in infancy), and 4 patients with other interferonopathies were enrolled in an expanded access program. The patients underwent dose escalation, and the benefit was assessed by reductions in daily disease symptoms and corticosteroid requirement. Quality of life, organ inflammation, changes in IFN-induced biomarkers, and safety were longitudinally assessed.RESULTS. Eighteen patients were treated for a mean duration of 3.0 years (1.5–4.9 years). The median daily symptom score decreased from 1.3 (interquartile range [IQR], 0.93–1.78) to 0.25 (IQR, 0.1–0.63) (P < 0.0001). In 14 patients receiving corticosteroids at baseline, daily prednisone doses decreased from 0.44 mg/kg/day (IQR, 0.31–1.09) to 0.11 mg/kg/day (IQR, 0.02–0.24) (P < 0.01), and 5 of 10 patients with CANDLE achieved lasting clinical remission. The patients’ quality of life and height and bone mineral density Z-scores significantly improved, and their IFN biomarkers decreased. Three patients, two of whom had genetically undefined conditions, discontinued treatment because of lack of efficacy, and one CANDLE patient discontinued treatment because of BK viremia and azotemia. The most common adverse events were upper respiratory infections, gastroenteritis, and BK viruria and viremia.CONCLUSION. Upon baricitinib treatment, clinical manifestations and inflammatory and IFN biomarkers improved in patients with the monogenic interferonopathies CANDLE, SAVI, and other interferonopathies. Monitoring safety and efficacy is important in benefit-risk assessment.TRIAL REGISTRATION. ClinicalTrials.gov NCT01724580 and NCT02974595.FUNDING. This research was supported by the Intramural Research Program of the NIH, NIAID, and NIAMS. Baricitinib was provided by Eli Lilly and Company, which is the sponsor of the expanded access program for this drug.

Aims Clinical trials test the safety and efficacy of behavioral and pharmacological interventions in drug-dependent individuals. However, there is no consensus about the most appropriate outcome(s) to consider in determining treatment efficacy or on the most appropriate methods for assessing selected outcome(s). We summarize the discussion and recommendations of treatment and research experts, convened by the US National Institute on Drug Abuse, to select appropriate primary outcomes for drug dependence treatment clinical trials, and in particular the feasibility of selecting a common outcome to be included in all or most trials. Methods A brief history of outcomes employed in prior drug dependence treatment research, incorporating perspectives from tobacco and alcohol research, is included. The relative merits and limitations of focusing on drug-taking behavior, as measured by self-report and qualitative or quantitative biological markers, are evaluated. Results Drug-taking behavior, measured ideally by a combination of self-report and biological indicators, is seen as the most appropriate proximal primary outcome in drug dependence treatment clinical trials. Conclusions We conclude that the most appropriate outcome will vary as a function of salient variables inherent in the clinical trial, such as the type of intervention, its target, treatment goals (e.g. abstinence or reduction of use) and the perspective being taken (e.g. researcher, clinical program, patient, society). It is recommended that a decision process, based on such trial variables, be developed to guide the selection of primary and secondary outcomes as well as the methods to assess them.

Aims To compare long-term outcomes among participants randomized to buprenorphine or methadone. Design/Setting/Participants Follow-up was conducted in 2011–2014 of 1,080 opioid-dependent participants entering 7 opioid treatment programs in the USA between 2006 and 2009 and randomized (within each program) to receive open-label buprenorphine/naloxone or methadone for up to 24 weeks; 795 participants completed in-person interviews (~74% follow-up interview rate) covering on average 4.5 years. Measurements Outcomes were indicated by mortality and opioid use. Covariates included demographics, site, cocaine use, and treatment experiences. Findings Mortality was not different between the two randomized conditions with 23 (3.6%) of 630 participants randomized to buprenorphine having died, versus 26 (5.8%) of 450 participants randomized to methadone. Opioid use at follow-up was higher among participants randomized to buprenorphine relative to methadone (42.8% vs. 31.7% positive opioid urine specimens, p< .01, effect size (h)=0.23 [0.09, 0.38]; 5.8 days vs. 4.4 days of past 30-day heroin use, p< .05, effect size (d)=0.14 [0.00, 0.28]). Opioid use over the follow-up period by randomization condition was also significant (F(7,39600)=3.16; p < .001) mostly due to less treatment participation among participants randomized to buprenorphine than methadone. Less opioid use was associated with both buprenorphine and methadone treatment (relative to no treatment); no difference was found between the two treatments. Individuals who are white or used cocaine at baseline responded better to methadone than to buprenorphine. Conclusions There are few differences in long-term outcomes between buprenorphine and methadone treatment for opioid dependence, and treatment with each medication is associated with a strong reduction in opioid use.

Premenstrual dysphoric disorder (PMDD) symptoms are eliminated by ovarian suppression, stimulated by administration of ovarian steroids, yet appear in the context of levels of ovarian steroids indistinguishable from those in women without PMDD. Thus PMDD symptoms could be precipitated by either an acute change in the levels of ovarian steroids, or that stable levels of ovarian steroids above a critical threshold play a permissive role in the expression of an underlying infradian affective “pacemaker.” In this study, we attempted to define the kinetics of the ovarian steroid event relevant to triggering of PMDD symptoms. We studied 22 women with PMDD, aged 30 to 50 years. Twelve women who experienced symptom remission after 2–3 months of GnRH agonist-induced ovarian suppression (leuprolide) then received one month of single-blind(participant only) placebo and then three months of continuous combined estradiol/progesterone. Primary outcome measure was the Rating for Premenstrual Tension observer rater- and self-ratings completed every two weeks during clinic visits. Multivariate repeated measure ANOVA for mixed models was employed. Both Premenstrual Tension -self and –rater scores were significantly increased (more symptomatic) during the first month of combined estradiol/progesterone compared with all other months (i.e., last month of leuprolide alone (p=.0003,p<.0001, respectively), placebo(p=.0015,p=.0013, respectively), and 2nd month of estradiol/progesterone (p=.0014,p<.0001, respectively), and 3rd month of estradiol/progesterone (p=.0006,p<.0001, respectively). There were no significant differences in symptom severity scores (Premenstrual Tension -self, –rater)between the last month of leuprolide alone and the placebo month(p=.609, p=.106, respectively), 2nd month of estradiol/progesterone (p=.639, p=.524, respectively) and 3rd month of estradiol/progesterone (p=.99, p=.812, respectively). Finally, Premenstrual Tension scores in the 2nd and 3rd estradiol/progesterone months did not significantly differ. We demonstrated that the change in levels of estradiol/progesterone from low to high, and not the steady state levels, was associated with the onset of PMDD symptoms. Therapeutic efforts to modulate the change in steroid levels proximate to ovulation merit further study.

Population pharmacokinetic (popPK) modeling was used to characterize the PK profile of the oral Janus kinase (JAK)1/JAK2 inhibitor, baricitinib, in 18 patients with Mendelian interferonopathies who are enrolled in a compassionate use program. Patients received doses between 0.1 to 17 mg per day. Covariates of weight and renal function significantly influenced volume-of-distribution and clearance, respectively. The half-life of baricitinib in patients less than 40 kg was substantially shorter than in adult populations, requiring the need for dosing up to 4 times daily. On therapeutic doses, the mean area-under-the-concentration-vs.-time curve was 2,388 nM*hr, which is 1.83-fold higher than mean baricitinib exposures in adult patients with rheumatoid arthritis receiving doses of 4 mg once-daily. Dose-dependent decreases in interferon (IFN) biomarkers confirmed an in vivo effect of baricitinib on type-1 IFN signaling. PopPK and pharmacodynamic data support a proposal for a weight- and estimated glomerular filtration rate-based dosing regimen in guiding baricitinib dosing in patients with rare interferonopathies.