NEJM This Week — May 21, 2026

This week's issue features four randomized controlled trials across nephrology, rheumatology, infectious disease, and neurology — a telitacicept (BAFF/APRIL blockade) win in IgA nephropathy, a brepocitinib (TYK2–JAK1) breakthrough in dermatomyositis, a positive postexposure prophylaxis trial for Covid-19 (ensitrelvir), and a positive but nuanced medium-vessel-occlusion thrombectomy result. The review covers the five-subtype framework for inflammatory myopathies, and the teaching case is a classic multi-system autoimmune overlap with lupus nephritis "full house."

NephrologyTELIGAN · RCTHigh yield · IM/ID

Telitacicept in IgA Nephropathy

Population: 318 adults with biopsy-proven primary IgA nephropathy, persistent proteinuria (24-hr UPCR ≥0.8 or TP ≥1.0 g/day), eGFR ≥30 on maximum tolerated ACEi/ARB for ≥12 wk; SGLT2i permitted at stable dose; glucocorticoids/immunosuppressants prohibited (12-wk washout). Mean age 38.2 yr; 53.8% women; median UPCR 1.26; mean eGFR 75.5. Exclusively Asian population (72 sites in China).
Intervention: Telitacicept 240 mg SC once weekly × 39 weeks (dual BAFF + APRIL neutralizer via TACI–Fc fusion protein).
Comparison: Matching placebo.
Outcome: Geometric mean ratio of 24-hr UPCR at week 39 vs. baseline: −58.9% with telitacicept vs. −8.8% with placebo (relative difference −55.0%; 95% CI −61.3 to −47.6; P<0.001). eGFR change −1.0% vs. −7.7%; confirmed eGFR decline ≥30% in 6.3% vs. 27.0%. Proteinuria response (UPCR <0.8) at week 39: 61.0% vs. 19.5%. Serious AEs lower with telitacicept (2.5% vs. 8.2%).

Clinical takeaway. In a high-risk IgA nephropathy cohort already on ACEi/ARB (±SGLT2i), dual BAFF–APRIL blockade with telitacicept produced a large, sustained proteinuria reduction and preserved eGFR vs. placebo at 39 weeks. The magnitude is comparable to sparsentan, atrasentan, sibeprenlimab, and iptacopan. Limitations: interim analysis only (stage B kidney-function data pending at week 104), exclusively Asian population, and no companion editorial. Generalizability to non-Asian populations is uncertain.

RheumatologyVALOR · RCTBorderline yield · IM/ID

Brepocitinib (TYK2–JAK1 Inhibitor) in Dermatomyositis

Population: 241 adults (18–75 yr) meeting 2017 EULAR/ACR criteria for definite or probable dermatomyositis with active muscle disease (MMT-8 80–142/150) and active skin disease (CDASI-A ≥6), having failed ≥1 prior therapy (glucocorticoids, DMARDs, or IVIG). Mean age 50.6 yr; 77.6% women; 81.3% moderate-to-severe disease; 92.9% on ≥1 DM-directed therapy at baseline. 90 sites, 20 countries.
Intervention: Oral brepocitinib 30 mg once daily × 52 weeks (+ background therapy with protocol-mandated glucocorticoid taper to ≤5 mg/day by week 36).
Comparison: Placebo (same glucocorticoid taper protocol); brepocitinib 15 mg arm did not meet significance threshold.
Outcome: Total Improvement Score (TIS, 0–100) at week 52: 46.5 (30 mg) vs. 31.2 (placebo) (diff 15.3; 95% CI 6.7–24.0; P<0.001). All 9 key secondary endpoints met for 30 mg: improved CDASI-A, moderate improvement rate (68% vs. 44%), skin remission, HAQ-DI, glucocorticoid sparing. Improvement evident by week 4. Serious infections: 10% (30 mg) vs. 1% (placebo).

Clinical takeaway. In treatment-refractory dermatomyositis, brepocitinib 30 mg was superior to placebo across muscle activity, skin activity, glucocorticoid sparing, and function — the first positive phase 3 trial of a targeted agent in this disease. The editorial (Lundberg) highlights it as a precision-medicine success given dermatomyositis’s type I/II interferon-driven pathogenesis, but notes that clinically significant muscle strength improvement was not demonstrated, ILD patients were under-represented (19.5%), and autoantibody subtyping was not done. Serious infection rate (10%) warrants vigilance.

Infectious DiseaseSCORPIO-PEP · RCTHigh yield · IM/ID

Ensitrelvir for Covid-19 Postexposure Prophylaxis

Population: 2,041 household contacts (modified ITT: RT-PCR negative at baseline) of confirmed Covid-19 index patients; enrolled within 72 hr of index patient symptom onset. Mean age 42.4 yr; 59.3% female; 37.0% had ≥1 risk factor for severe Covid-19; >98% seropositive. Multi-country: US 55%, Japan 39.3%, South Africa, Argentina, Vietnam.
Intervention: Ensitrelvir 375 mg on day 1, then 125 mg daily on days 2–5 (oral SARS-CoV-2 3CL protease inhibitor); first dose directly observed.
Comparison: Matching placebo.
Outcome: RT-PCR–confirmed Covid-19 (≥1 symptom lasting ≥48 hr) by day 10: 2.9% (ensitrelvir) vs. 9.0% (placebo) (RR 0.33; 95% CI 0.22–0.49; P<0.001; 67% relative risk reduction). RT-PCR–confirmed SARS-CoV-2 infection by day 10: 14.0% vs. 21.5% (RR 0.66). Adverse events similar (15.1% vs. 15.5%); transient HDL decrease (−27% by day 6, recovering by day 15); no hospitalizations or deaths.

Clinical takeaway. Ensitrelvir as 5-day postexposure prophylaxis reduced symptomatic Covid-19 by 67% in household contacts when started within 72 hr of index patient symptom onset — the first antiviral to demonstrate this efficacy, outperforming nirmatrelvir–ritonavir (29–36%) and molnupiravir (24%) in prior PEP trials. Ensitrelvir is approved in Japan for this indication; US approval is pending. ID/ID-fellow pearl: ensitrelvir is a moderate CYP3A inhibitor (screen drug interactions); the HDL reduction is reversible; no ritonavir boosting required. No companion editorial published.

NeurologyORIENTAL-MeVO · RCTLower yield · IM/ID

Thrombectomy in Medium-Vessel-Occlusion Stroke

Population: 563 adults (≥18 yr) with pre-stroke mRS 0–2, acute ischemic stroke due to medium-vessel occlusion (M2/M3 MCA, A1–3 ACA, P1–3 PCA; M2 ≤2.0 mm), NIHSS ≥6, within 24 hr of last-known-well. Median age 71 yr; median NIHSS 10; 42.8% women; 36.6% received IV thrombolysis. 48 centers in China.
Intervention: Endovascular thrombectomy + standard medical management within 24 hr (stent retriever, aspiration, IA thrombolysis, or combinations at operator discretion).
Comparison: Standard medical management alone (antiplatelet therapy; IV thrombolysis if eligible).
Outcome: Functional independence (mRS 0–2) at 90 days: 58.6% vs. 46.6% (adjusted RR 1.24; 95% CI 1.07–1.44; P=0.004). Symptomatic intracranial hemorrhage 4.7% vs. 2.2%. 90-day mortality 11.1% vs. 10.2% (NS). No benefit in subgroups: NIHSS <8, M3 occlusion, or randomization ≥8 hr.

Clinical takeaway. In contrast to three prior neutral trials (ESCAPE-MeVO, DISTAL, DISCOUNT), ORIENTAL-MeVO showed a benefit for thrombectomy in medium-vessel occlusion. The editorial (Ospel, Hill) attributes the divergent result to higher baseline NIHSS, younger age, and lower thrombolysis use — patients with more severe deficits have less spontaneous recovery and more room for benefit. The editorial cautions that the narrower target population is younger age + NIHSS ≥8 + early presentation; most patients with MeVO will NOT benefit. All patients enrolled in China (higher intracranial atherosclerosis prevalence). Open-label.

RheumatologyReview · Lower/Borderline yield · IM/ID

Inflammatory Myopathies

Comprehensive subspecialty reference. Two pearls relevant to the knowledgeable internist:

•Five-subtype framework: inclusion-body myositis (IBM), immune-mediated necrotizing myopathy (IMNM), antisynthetase syndrome, overlapping myositis, and dermatomyositis — each with a distinct myositis-specific autoantibody, pathomechanism, and prognosis. •Red-flag antibody — anti-MDA5: dermatomyositis subtype; carries >50% mortality from rapidly progressive interstitial lung disease in ~30% of cases. IBM is unique: does not respond to glucocorticoids, predominates in men >60 yr (quadriceps + finger flexors), and combines inflammatory and degenerative pathology.

Teaching Case · Case Records of the MGH

Case 14-2026: A 50-Year-Old Woman with Vaginal Bleeding and Anemia · Rheumatology / Immunology

High yield · IM/ID

Key learning point. Final diagnosis: overlap syndrome of SLE and idiopathic inflammatory myopathy (lupus nephritis class V/III). Diagnostic pearls: (1) “Full house” immunofluorescence on kidney biopsy (IgG, IgM, IgA, C3, C1q) is diagnostic of lupus nephritis. (2) Strongly positive non–glycoprotein-specific platelet-associated IgM can be a false positive in high-RF-IgM states — a glycoprotein-specific direct platelet autoantibody test is required to confirm ITP. (3) When a patient meets classification criteria for two rheumatic diseases simultaneously, “overlap syndrome” is the more precise diagnosis than mixed connective-tissue disease (even when anti-RNP is positive). Treatment: hydroxychloroquine + mycophenolate mofetil + glucocorticoids + belimumab for lupus nephritis; IVIG for acute myositis; PCP prophylaxis with TMP-SMX.

Also in this issue: All original articles in this issue were randomized controlled trials; no additional non-RCT original papers (brief reports, single-arm, or observational studies) were identified beyond those summarized above.

Summaries are original paraphrases prepared for educational use; figures are drawn from the published full text. Read the full articles at NEJM.org (subscription required). Trial registrations: TELIGAN (NCT05799287), VALOR (NCT05437263), SCORPIO-PEP (NCT05897541 & jRCT2031230124), ORIENTAL-MeVO (NCT06146790). Citations: N Engl J Med 2026; Vol. 394, No. 19. DOIs: 10.1056/NEJMoa2514415, 10.1056/NEJMoa2503531, 10.1056/NEJMoa2509306, 10.1056/NEJMoa2514120, 10.1056/NEJMra2415426, 10.1056/NEJMcpc2517864.