NEJM This Week — July 2, 2026

The first issue of Volume 395 leads with two companion cardiology trials, but this week's best general-IM read is OVERLORD-MS — the first randomized head-to-head of two anti-CD20 antibodies, showing far-cheaper rituximab noninferior to ocrelizumab in relapsing MS (below). The paired coronary-physiology trials ALL-RISE (FFRangio) and FAST III (vessel FFR) both show angiography-derived FFR noninferior to pressure-wire FFR — important for the cath lab but a procedural decision, so flagged lower-yield. LITESPARK-022 (adjuvant belzutifan + pembrolizumab in RCC) is summarized for awareness. A high-yield Advances in Multiple Sclerosis review and a superb cobalt-toxicity teaching case round out the issue.

NeurologyOVERLORD-MS · RCTHigh yield · IM

Rituximab versus Ocrelizumab in Newly Diagnosed Relapsing Multiple Sclerosis

In newly diagnosed relapsing MS, is rituximab (a far cheaper biosimilar) noninferior to ocrelizumab for suppressing MRI disease activity?

Population: 216 treatment-naive adults (18–60 yr) in Norway/Sweden, newly diagnosed (≤12 mo) relapsing MS with recent activity, EDSS 0–4; double-blind, 3:2 allocation.
Intervention: IV rituximab (Rixathon biosimilar) 1000 mg → 500 mg every 6 months.
Comparison: IV ocrelizumab 600 mg every 6 months.
Outcome: No new/enlarging T2 lesions, mo 6→24: 92.2% vs 94.8% (difference −2.6 pp; 95% CI −9.4 to 4.3) — met the −10-pp noninferiority margin (P=0.03). Relapse/disability/cognition similar; serious AEs 8% vs 7%; infections more common with rituximab (82% vs 69%), mostly mild.

Clinical takeaway. The first randomized, double-blind head-to-head of two anti-CD20 antibodies confirms that rituximab — used off-label worldwide because biosimilars are far cheaper and it is on the WHO Essential Medicines list — is a legitimate high-efficacy option, not a compromise, at the cost of modestly more infections. Caveats: powered only for the noninferiority MRI endpoint (not superiority, not clinical/safety endpoints), short 30-month follow-up, and a homogeneous Nordic population. What this changes: supplies the randomized evidence that prior observational anti-CD20 comparisons lacked — supports rituximab as an evidence-based, low-cost alternative to ocrelizumab.

CardiologyALL-RISE · RCTLower yield · IM/ID

Angiography-Derived Fractional Flow Reserve to Guide PCI

For intermediate coronary stenoses, is FFRangio (computed from images, no wire or adenosine) noninferior to pressure-wire FFR for guiding PCI?

Population: 1930 patients at 59 international sites with ≥1 intermediate (50–90%) coronary stenosis needing physiological assessment.
Intervention: FFRangio-guided assessment (CathWorks; no pressure wire or hyperemic agent).
Comparison: Pressure-wire FFR or nonhyperemic pressure ratio.
Outcome: 1-yr death/MI/unplanned revasc 6.9% vs 7.1% (HR 0.98; 95% CI 0.70–1.39; P<0.001 noninferiority, 3.5-pp margin). FFRangio shortened procedure, fluoroscopy, and contrast but led to more PCI (44.3% vs 35.4% of lesions).

Clinical takeaway. FFRangio-guided PCI is noninferior to wire-based FFR at 1 year and simplifies the procedure. Per the editorials (Campo; Randles), the real message is a shift away from anatomy-only decisions toward physiology, with wire confirmation reserved for borderline values or complex anatomy. Platforms are not interchangeable — FAVOR III Europe’s quantitative flow ratio was NOT noninferior. What this changes: incremental for the general internist — an interventional-cardiology technique choice, not a bedside IM decision.

CardiologyFAST III · RCTLower yield · IM/ID

Angiography-Based Physiology to Guide Coronary Revascularization

Companion to ALL-RISE: is vessel FFR (3D-QCA) noninferior to pressure-wire FFR for guiding revascularization?

Population: 2211 (analysis set) at 37 European sites with intermediate (30–80%) lesions and chronic or acute coronary syndromes.
Intervention: Vessel-FFR–guided revascularization (Pie Medical 3D-QCA; no wire/adenosine).
Comparison: Pressure-wire FFR (open-label).
Outcome: 1-yr death/any MI/any revasc 7.5% vs 7.5% (difference −0.02 pp; 95% CI −2.25 to 2.21; P=0.004 noninferiority). vFFR classified more lesions significant → more revascularization (45% vs 36%), same outcomes.

Clinical takeaway. A second platform reaching the same conclusion as ALL-RISE. Per the editorial (Chatzizisis), the concordant results support angiography-derived FFR as a class, while invasive wire testing stays necessary for aorto-ostial/left-main/complex anatomy; the higher revascularization rate without better outcomes is an unresolved question. What this changes: reinforces the physiology-over-anatomy shift in the cath lab — awareness, not a general-IM decision.

Heme / OncologyLITESPARK-022 · RCTLower yield · IM/ID

Adjuvant Pembrolizumab plus Belzutifan for Renal-Cell Carcinoma

After nephrectomy for clear-cell RCC at increased recurrence risk, does adding the HIF-2α inhibitor belzutifan to adjuvant pembrolizumab improve disease-free survival?

Population: 1841 patients with resected clear-cell RCC at intermediate-high/high recurrence risk or M1 with no evidence of disease.
Intervention: Pembrolizumab 400 mg q6wk (≤1 yr) + belzutifan 120 mg daily.
Comparison: Pembrolizumab + placebo (double-blind).
Outcome: Disease-free survival HR 0.72 (95% CI 0.59–0.87; P<0.001); 24-mo DFS 80.7% vs 73.7%. Overall survival immature (HR 0.78; P=0.24). Grade ≥3 AEs 52.1% vs 30.2% — anemia and hypoxia (HIF-2α class effect).

Clinical takeaway. Adding belzutifan improves disease-free survival but with substantially more toxicity and, so far, no survival benefit — a subspecialty adjuvant-oncology decision. The anemia/hypoxia/polycythemia signature reflects HIF-2α biology (mechanistically the mirror image of this issue’s cobalt-toxicity teaching case). What this changes: incremental adjuvant option; not a general-IM decision.

NeurologyReview · High yield · IM

Advances in Multiple Sclerosis

What is first-line disease-modifying therapy for relapsing MS, and what is the leading environmental cause?

•Anti-CD20 B-cell–depleting mAbs (ocrelizumab, ublituximab, ofatumumab, rituximab) are now first-line for relapsing MS — they cut new MRI lesion formation by ~99%, but benefit against progression is only partial. "Progression independent of relapse activity" is now the main driver of long-term disability. •Epstein–Barr virus is a necessary (not sufficient) cause — MS is very rare in EBV-naive persons; EBV persists in memory B cells, helping explain why B-cell depletion works. •Early high-efficacy therapy (vs step-up) gives the best long-term control; anti-CD20 agents are favored peri-pregnancy and show no rebound on stopping (unlike natalizumab/fingolimod).

Teaching Case · Clinical Problem-Solving

The Daily Grind · Toxicology / Neurology

High yield · IM

Key learning point. Final diagnosis: systemic cobalt toxicity (metallosis). A 56-year-old developed subacute sensory ataxia, cognitive decline, hypothyroidism, hyperglycemia, and unexplained rising hemoglobin (to 19 g/dL) after a fractured ceramic hip liner/head was revised to a cobalt–chromium head — retained ceramic microdebris ground the new head (“third-body wear”), releasing cobalt (serum 592 ng/mL; normal <10). Think cobalt toxicity when a metal-bearing prosthesis is joined by sensory neuropathy + encephalopathy + cardiomyopathy/arrhythmia + hypothyroidism + polycythemia (cobalt stabilizes HIF → EPO) ± tinnitus/sensorineural hearing loss. Diagnose with the serum cobalt level; treat by removing the source (revision + débridement) ± chelation — recovery tracks hardware removal, not chelation, and is often incomplete.

Also in this issue (not randomized trials / out of scope, so not summarized as such): Clinical Decisions — operative vs nonoperative management for appendicitis (point–counterpoint); Images in Clinical Medicine — Cat Scratch Disease; Trampoline Fracture; Perspectives — physicians in the American Revolution; combating the chronic pain–opioid use disorder syndemic; the invisible load of cognitive symptoms; Medicine and Society — Latino contributions to U.S. population health; plus Correspondence (WHIM syndrome somatic genetic rescue; AI detection of Hirschsprung disease; hypertension control in low-income patients; ianalumab + eltrombopag in ITP).

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: OVERLORD-MS (NCT04578639), ALL-RISE (NCT05893498), FAST III (NCT04931771), LITESPARK-022 (NCT05239728). Citations: N Engl J Med 2026; Vol. 395, No. 1. DOIs: 10.1056/NEJMoa2600993, 10.1056/NEJMoa2600949 (editorials 10.1056/NEJMe2603396, 10.1056/NEJMe2602134), 10.1056/NEJMoa2601841 (editorial 10.1056/NEJMe2603714), 10.1056/NEJMoa2518245, 10.1056/NEJMra2501195, 10.1056/NEJMcps2517160.