⚡Landmark syphilis trial

Good morning — it’s Saturday, September 20, and we’re covering a landmark syphilis trial, new TYK2 progress in psoriasis, and more.

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A landmark randomized trial in NEJM found that a single 2.4-million-unit dose of benzathine penicillin G was noninferior to a three-dose regimen for early syphilis, even in people living with HIV. The result comes amid rising syphilis cases and global shortages of the antibiotic.

Investigators enrolled 249 patients with primary (19%), secondary (47%), or early latent syphilis (33%); 61% had HIV infection, and 97% were men. The primary endpoint was serologic response at six months, defined as RPR seroreversion or a fourfold decline in titer.

At follow-up, 76% of patients in the single-dose group and 70% in the three-dose group met this endpoint, confirming noninferiority. No clinical relapses or treatment failures occurred. Among patients with HIV infection, outcomes were nearly identical (76% vs 71%)

Notably, injection-site pain was more common in the three-dose group (85% vs 76%).

Limitations included underrepresentation of women and patients with advanced or untreated HIV. The trial also excluded pregnant women and those with neurosyphilis, leaving these groups unaddressed.

According to the accompanying editorial, these findings reassure clinicians that one dose is enough for early syphilis, including in patients with HIV infection. A simplified regimen may ease pressure on drug supplies in the face of a rising disease burden.

> TYK2 field expands as D-2570 posts strong Phase 2 psoriasis results: InventisBio’s oral TYK2 inhibitor D-2570 achieved striking efficacy in a Phase 2 dose-ranging trial published in JAAD. Investigators randomized 161 adults with moderate-to-severe plaque psoriasis to D-2570 (18–36 mg daily) or placebo. At Week 12, 81%–88% of patients on D-2570 achieved clear or almost clear skin (sPGA 0/1) vs 20% on placebo (P<0.001). At the highest dose, 50% reached complete skin clearance (PASI 100) compared with only 3% on placebo (P<0.001). Responses rose steadily through Week 12 without plateauing. IL-17A levels fell by 42%–56% across active arms. The drug was generally well tolerated, with no treatment-related serious adverse events and only one discontinuation due to dermatitis. The authors noted efficacy appeared stronger than that of deucravacitinib and comparable to risankizumab, while cautioning against cross-trial comparisons. Limitations included the short duration and modest sample size. D-2570 selectively binds the TYK2 pseudokinase domain JH2 to modulate IL-23, IL-12, and type I interferon signaling. The drug joins a growing roster of TYK2 inhibitors in development, including ESK-001, zasocitinib, and ICP-488.

> First RCT shows routine high-SPF sunscreen use raises vitamin D deficiency risk: The Sun-D Trial, published in the BJD, is the first randomized controlled trial to test whether daily use of high-SPF sunscreen lowers serum 25-hydroxyvitamin D concentrations. Investigators randomized 639 adults (Fitzpatrick types I–IV) to apply SPF 50+ sunscreen daily when the UV Index was ≥3 or to continue discretionary use for about one year. After 12 months, the routine-use group had significantly lower serum 25-hydroxyvitamin D concentrations than the discretionary-use group (adjusted mean difference –5.2 nmol/L, 95% CI –7.2 to –3.2), with effects consistent across most subgroups. Importantly, vitamin D deficiency (<50 nmol/L) was more common in the routine-use group (46% vs 37%; adjusted PR 1.33, 95% CI 1.14–1.55). Rashes or acne affected 7% of routine sunscreen users, leading to six discontinuations. Sunburn, however, was far less common with routine use (43% vs 71%). Limitations included the open-label design and ongoing debate about how best to define vitamin D deficiency. These findings contrast with two earlier trials that found no effect of daily sunscreen use on vitamin D, though both studies used low-SPF (~16) sunscreens in high-UV settings. The authors conclude that while routine sunscreen use remains essential for skin cancer prevention, clinicians should identify patients at risk of vitamin D deficiency and consider supplementation.

> Oral minoxidil 2.5 mg shows similar efficacy to 5 mg in male androgenetic alopecia: A double-blind randomized trial published in JAAD found that oral minoxidil 2.5 mg offered efficacy comparable to 5 mg for male androgenetic alopecia, with fewer adverse effects. This trial is the first to directly compare different oral minoxidil doses in this population. The Brazilian study enrolled 100 men aged 25–55 years with Norwood-Hamilton stage 3V–5V androgenetic alopecia. At Week 24, non-vellus hair density at the vertex increased by 10 hairs/cm² in both groups (P=0.40). Total hair counts rose by 14 hairs/cm² with 2.5 mg and 17 hairs/cm² with 5 mg (P=0.08). Although similar proportions of patients were rated improved by dermatologists (64% vs 62%; P=0.39), patient-reported improvement favored 5 mg (92% vs 84%; P=0.009). Adverse events were more frequent with the 5mg regimen, particularly pedal edema (4% vs 0%) and hypertrichosis (78% vs 62%). The authors noted that the short follow-up may not have captured potential late-onset benefits of the higher dose. Overall, 2.5 mg daily appears to be a reasonable starting point in clinical practice, balancing efficacy with safety.

Quizzes, cases, and perspectives to sharpen your clinical eye.

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