Two Phase 3 Trials of Baricitinib for Alopecia Areata
In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks.
KEY FINDINGS: In two phase 3 trials involving patients with severe alopecia areata, oral baricitinib was superior to placebo with respect to hair regrowth at 36 weeks. Longer trials are required to assess the efficacy and safety of baricitinib for alopecia areata.
BACKGROUND: Alopecia areata is an autoimmune condition characterized by rapid hair loss in the scalp, eyebrows, and eyelashes, for which treatments are limited. Baricitinib, an oral, selective, reversible inhibitor of Janus kinases 1 and 2, may interrupt cytokine signaling implicated in the pathogenesis of alopecia areata.
DETAILS: Conducted two randomized, placebo-controlled, phase 3 trials (BRAVE-AA1 and BRAVE-AA2) involving adults with severe alopecia areata with a Severity of Alopecia Tool (SALT) score of 50 or higher (range, 0 [no scalp hair loss] to 100 [complete scalp hair loss]). Patients were randomly assigned in a 3:2:2 ratio to receive once-daily baricitinib at a dose of 4 mg, baricitinib at a dose of 2 mg, or placebo. The primary outcome was a SALT score of 20 or less at week 36. 654 patients were enrolled in the BRAVE-AA1 trial and 546 in the BRAVE-AA2 trial. The estimated percentage of patients with a SALT score of 20 or less at week 36 was 38.8% with 4-mg baricitinib, 22.8% with 2-mg baricitinib, and 6.2% with placebo in BRAVE-AA1 and 35.9%, 19.4%, and 3.3%, respectively, in BRAVE-AA2. In BRAVE-AA1, the difference between 4-mg baricitinib and placebo was 32.6 percentage points (95% confidence interval [CI], 25.6 to 39.5), and the difference between 2-mg baricitinib and placebo was 16.6 percentage points (95% CI, 9.5 to 23.8) (P0.001 for each dose vs. placebo). In BRAVE-AA2, the corresponding values were 32.6 percentage points (95% CI, 25.6 to 39.6) and 16.1 percentage points (95% CI, 9.1 to 23.2) (P<0.001 for each dose vs. placebo). Secondary outcomes for baricitinib at a dose of 4 mg but not at a dose of 2 mg generally favored baricitinib over placebo. Acne, elevated levels of creatine kinase, and increased levels of low- and high-density lipoprotein cholesterol were more common with baricitinib than with placebo.
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Source: King, B., Ohyama, M., Kwon, O., et al. (2022). Two Phase 3 Trials of Baricitinib for Alopecia Areata. N Engl J Med. 2022; 386: 1687-1699. Published: May 5, 2022. DOI: 10.1056/NEJMoa2110343.
IL-17 Inhibitors Not Associated With Increased IBD Risk in Hidradenitis Suppurativa
A systematic review and meta-analysis of 24 studies found that inflammatory bowel disease events were rare among patients with hidradenitis suppurativa receiving IL-17 inhibitors. In randomized trials, new-onset IBD occurred in 0.23% of patients receiving IL-17 inhibitors versus 0% with placebo, with no significant difference between groups. The findings are reassuring but support continued monitoring because event numbers were low and reporting was inconsistent.
KEY FINDINGS: IBD events were uncommon among patients with HS receiving IL-17 inhibitors, and randomized trial data did not demonstrate a significant increase in IBD risk compared with placebo. The higher incidence observed in nonrandomized studies may reflect differences in patient populations, follow-up, or other sources of bias and should not be interpreted as evidence of causation. Because event numbers were low and reporting of IBD outcomes was inconsistent, continued monitoring remains important, particularly in patients with existing or suspected IBD. The findings support the use of IL-17 inhibitors in HS while emphasizing the need for further prospective data on gastrointestinal outcomes.
BACKGROUND: Interleukin-17 (IL-17) inhibitors are increasingly used to treat moderate to severe hidradenitis suppurativa (HS), but concern remains about their potential relationship with inflammatory bowel disease (IBD), particularly Crohn disease and ulcerative colitis. Because patients with HS already have an elevated background risk of IBD, it can be difficult to determine whether IBD events occurring during IL-17 inhibitor therapy are treatment-related or reflect the underlying disease. This systematic review and meta-analysis evaluated the incidence of IBD among patients with HS receiving IL-17 inhibitors and compared event rates with placebo in randomized clinical trials.
DETAILS: The investigators searched PubMed, Embase, and the Cochrane CENTRAL database from inception through November 2025. Twenty-four studies met the inclusion criteria, comprising 10 randomized clinical trials, 11 nonrandomized studies, and 3 case reports. Overall, the analysis included 3,015 patients with HS treated with an IL-17 inhibitor. Outcomes included new-onset IBD, worsening of preexisting IBD, IBD subtype, clinical features, and time to IBD onset.
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Across the 10 randomized clinical trials, new-onset IBD occurred in 6 of 2,572 patients receiving IL-17 inhibitors (0.23%) compared with 0 of 1,066 patients receiving placebo through week 16. The pooled risk difference was 0.002 (95% CI, -0.003 to 0.007), indicating no statistically significant difference between treatment and placebo groups.
In the nonrandomized studies, 7 new-onset IBD events were reported among 469 patients, corresponding to a crude incidence of 1.49%. The pooled incidence was 3.90% (95% CI, 2.30%-6.50%). Across randomized trials, long-term extension studies, and nonrandomized studies, 17 new-onset IBD cases and 4 IBD flares were reported.
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Source: Cutrona, M., Jolkovsky, E. L., Romanelli, S., et al. Inflammatory Bowel Disease and Interleukin-17 Inhibitors in Hidradenitis Suppurativa: A Systematic Review and Meta-Analysis. JAMA Dermatology. 2026; Published: September 9, 2026. DOI: 10.1001/jamadermatol.2026.3373.
Formononetin May Protect Against Anthracycline Cardiotoxicity Through Cardiac Metabolic Improvement
A preclinical study identified ERRa as an early metabolic regulator of anthracycline-induced cardiotoxicity, with its reduction occurring before overt cardiac dysfunction. Formononetin, an ERRa activator, improved cardiac metabolism and function in mouse and pig models while also enhancing doxorubicin's anticancer activity in breast cancer organoids. The findings suggest a potential dual-action strategy for protecting the heart during anthracycline therapy, but clinical studies are still needed.
KEY FINDINGS: The findings identify ERRα downregulation as an early and potentially causal component of anthracycline-induced cardiac injury. Formononetin improved cardiac energy metabolism and function in experimental models while retaining, and potentially enhancing, doxorubicin's anticancer activity in breast cancer organoids. The study therefore suggests that pharmacologic activation of ERRα could represent a future strategy for simultaneously addressing anthracycline cardiotoxicity and cancer treatment. However, the evidence remains preclinical, and clinical studies are required to determine whether these findings translate into cardioprotection in patients receiving anthracycline chemotherapy.
BACKGROUND: Anthracyclines such as doxorubicin are effective anticancer agents, but their use can be limited by anthracycline-induced cardiotoxicity (AIC). Early metabolic disturbances in cardiac muscle may contribute to the development of cardiac dysfunction. This study investigated the role of estrogen-related receptor α (ERRα), a regulator of cardiac energy metabolism, in AIC and evaluated whether pharmacologic activation of ERRα with formononetin could provide cardiac protection while maintaining anticancer activity.
DETAILS: The investigators used a porcine model of anthracycline cardiotoxicity to examine changes in ERRα over time and cardiomyocyte-specific gain- and loss-of-function mouse models to assess its functional role. Mechanistic experiments, including ChIP-qPCR, reporter assays, and microscale thermophoresis, were used to investigate how formononetin interacts with the ERRα pathway. Cardiac tissue from patients who had received chemotherapy was also examined, while human breast cancer patient-derived organoids were used to evaluate potential effects on tumor activity. ERRα expression was reduced in hearts from the porcine AIC model and in cardiac tissue from patients treated with chemotherapy. In pigs, the reduction occurred at the 6-week subclinical stage, before overt cardiac dysfunction developed. Increasing ERRα expression specifically in cardiomyocytes enhanced mitochondrial metabolic programs and fatty-acid oxidation and preserved systolic function after doxorubicin exposure, whereas ERRα reduction worsened metabolic dysfunction and cardiac impairment.
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Drug screening identified formononetin as a selective ERRα activator. In mouse and pig models, formononetin increased ERRα activity, improved cardiac mitochondrial metabolism, and reduced anthracycline-associated cardiac injury. Mechanistic experiments indicated that formononetin interacts with the ERRα/PGC-1α complex and promotes its stability, supporting activation of downstream metabolic pathways.
Importantly, formononetin also demonstrated anticancer activity in human breast cancer patient-derived organoids. Treatment with formononetin alone reduced organoid viability and proliferation, while combining formononetin with doxorubicin produced greater antitumor effects.
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Source: Wang, X., Ling, G., Wei, Y., et al. Natural ERRα Activator Formononetin Ameliorates Anthracycline Cardiotoxicity via Metabolic Improvement. Circulation Research. 2026; 139(7): e329042. Published: September 11, 2026. DOI: 10.1161/CIRCRESAHA.126.329042.
Accounting for Long-Term Consequences of Tuberculosis Strengthens the Case for Preventive Screening in New Immigrants
A Canadian modeling study found that including long-term illness and mortality after tuberculosis more than doubled the estimated health benefits of postarrival TB screening and preventive treatment among new immigrants. Incorporating these consequences reduced the projected cost from $235,088 to $100,742 CAD per QALY gained. The findings highlight the importance of considering the long-term burden of TB when evaluating prevention strategies.
KEY FINDINGS: The analysis suggests that excluding long-term illness, mortality, and healthcare costs after TB treatment can substantially underestimate the health value of TB prevention. In the modeled Canadian immigrant population, incorporating these consequences more than doubled the estimated QALY benefit of postarrival TB infection screening and preventive treatment and reduced the estimated cost per QALY by more than half. However, the findings depend on assumptions about the long-term effects of TB, and the investigators noted that some underlying associations may include residual confounding and that post-TB illness estimates are less certain.
BACKGROUND: Tuberculosis prevention strategies are commonly evaluated by considering acute TB disease and death, while longer-term consequences after successful treatment may be overlooked. These consequences can include persistent illness, increased mortality, and additional healthcare utilization. This study assessed how incorporating these longer-term effects would change estimates of the health benefits and cost-effectiveness of postarrival TB infection screening and preventive treatment among people newly immigrating to Canada.
DETAILS: The investigators developed a Markov microsimulation model representing a hypothetical cohort of 400,000 people immigrating permanently to Canada in 2025. The analysis compared the existing postarrival TB infection screening level of 0.5% with a modeled screening strategy reaching 68% of eligible new immigrants. The intervention targeted new permanent residents from countries with annual TB incidence >50/100,000 persons; individuals testing positive for TB infection were assumed to receive 4 months of daily rifampin as preventive treatment. Outcomes were projected over 25 years and included TB episodes, TB deaths, quality-adjusted life-years (QALYs), and TB-related healthcare costs. The model incorporated three post-TB consequences: increased mortality after TB treatment, persistent illness or disability, and excess healthcare costs. A total of 2,000 probabilistic simulations were performed to account for uncertainty in model parameters.
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When only acute TB consequences were considered under the current screening scenario, the model projected 927 (95% UR 764-1,123) TB cases, 30 (95% UR 24-36) TB deaths, and 312 (95% UR 241-386) QALYs lost over 25 years. Adding post-TB death increased estimated QALYs lost by 1.6-fold, while including post-TB illness increased them by 1.5-fold. When all three long-term consequences were incorporated, TB was projected to account for 657 (95% UR 479-876) QALYs lost, a 2.1-fold increase compared with considering acute consequences alone.
The expanded screening and preventive-treatment strategy produced 2.4-fold greater estimated QALY gains (95% UR 1.6-4.4-fold) and 2.2-fold more TB deaths averted (95% UR 1.6-3.0-fold) when all post-TB consequences were included. The estimated incremental cost-effectiveness ratio decreased from $235,088 to $100,742 CAD per QALY gained. In the model incorporating all post-TB consequences, 53% of simulations fell below a willingness-to-pay threshold of $100,000 per QALY, compared with 8% when only acute TB consequences were considered.
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Source: Ainiwaer, A., Uppal, A., Schwartzman, K., et al. Posttuberculosis Consequences on Tuberculosis Prevention Effectiveness and Cost-effectiveness among New Immigrants, Canada. Emerging Infectious Diseases. 2026; 32(9): 1421-1429. Published: September, 2026. DOI: 10.3201/eid3209.260473.
A Pragmatic SMART Study of Medication and CBT Sequencing in Pediatric Anxiety Disorders
Fluoxetine and exposure-based CBT showed broadly comparable improvement over 24 weeks. Among those remaining symptomatic, CBT followed by combination therapy showed the strongest overall improvement pattern.
KEY FINDINGS: In this pragmatic study of clinically complex and demographically diverse youths, fluoxetine and exposure-based CBT produced broadly comparable improvement in anxiety symptoms over 24 weeks. For patients who remained symptomatic after 12 weeks, adding the alternate treatment generally showed a tendency toward greater improvement than optimizing monotherapy, although the overall differences were small and did not establish combination therapy as superior on the primary outcome. The CBT→combination sequence produced the strongest overall pattern of improvement across anxiety severity and functional impairment measures. Treatment response also varied across racial and ethnic groups, with Non-Hispanic White youths showing greater benefit from fluoxetine-based treatment sequences on some parent- and youth-reported secondary outcomes, whereas racial and ethnic minority youths showed greater benefit from transition to combination therapy on selected measures.
BACKGROUND: Choosing between medication and cognitive-behavioral therapy (CBT) as the initial treatment for pediatric anxiety disorders, and determining how to proceed when symptoms persist, remains clinically challenging. This pragmatic randomized trial evaluated whether initiating treatment with fluoxetine or exposure-based CBT produced better outcomes and whether adding the alternate treatment was more effective than continuing the initial therapy when remission was not achieved after 12 weeks.
DETAILS: This 24-week, single-blind sequential multiple assignment randomized trial included 316 youths aged 8-17 years with DSM-5 anxiety disorders, significant anxiety symptoms, and functional impairment. Participants were initially randomized to 12 weeks of fluoxetine or weekly exposure-based "Coping Cat" CBT. Fluoxetine dosing ranged from 10 to 80 mg/day. Youths who did not achieve remission after 12 weeks were subsequently randomized to either optimization of their initial treatment or optimization plus addition of the other modality. Outcomes included youth- and parent-reported 41-item Screen for Child Anxiety Related Emotional Disorders (SCARED) scores and Childhood Anxiety Impact Scale (CAIS) scores. The study was conducted in primary care and community mental health settings and included youths with substantial sociodemographic disadvantage and co-occurring mental health conditions.
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Youth-reported SCARED scores decreased by 31.7% over 24 weeks, from 42.9 at baseline to 29.31 at study endpoint. Improvement did not differ significantly between initial fluoxetine and CBT, although CBT showed a nonsignificant numerical advantage, with a 24-week difference in mean group change of 1.45 (95% CI=-2.25, 5.16). Among participants who did not remit by week 12, combination treatment was not significantly superior to continued optimized monotherapy for youth-reported anxiety at week 24 (group difference in mean change from baseline: -2.74, 95% CI=-6.53, 1.05).
Exploratory analyses of treatment sequences found that CBT followed by combination therapy produced the greatest overall improvement across the primary and secondary outcomes, although youth-reported SCARED scores did not differ significantly between individual sequences at week 24. Parent-reported SCARED scores declined by 37.8%, from 38.9 to 24.2, over 24 weeks. Parent ratings showed faster improvement with initial fluoxetine at weeks 6 and 12, while youth-reported CAIS scores favored initial CBT by week 24. Reduced appetite was more frequent with medication during both treatment stages, occurring in 43.7% versus 32.3% during stage 1 (p<0.05) and in 17.3% with med→med, 3.6% with CBT→CBT, and 12.1% with combination treatment during stage 2 (p=0.013). Serious or unexpected adverse events were rare.
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Source: Peterson, B. S., West, A. E., Weersing, V. R., et al. A Pragmatic SMART Study of Medication and CBT Sequencing in Pediatric Anxiety Disorders: A Randomized Clinical Trial. American Journal of Psychiatry. 2026; 183(9): 668-681. Published: September, 2026. DOI: 10.1176/appi.ajp.20251037.
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