Long-term treatment with ocrelizumab may be associated with interstitial lung disease (ILD), according to a research letter published in JAMA Neurology.¹ In a retrospective, single-center cohort of 67 patients with relapsing-remitting multiple sclerosis (MS), investigators identified 6 cases (9.0%) of ILD—specifically organizing pneumonia (OP)—occurring after prolonged exposure to therapy.1
These events occurred after a mean of 22.8 infusion cycles and a mean treatment duration of 10.5 years, suggesting a potential cumulative risk not captured in shorter-term clinical trials. All patients were neurologically stable prior to onset, and infectious etiologies, including SARS-CoV-2, were excluded.
The authors, led by Krzysztof W. Selmaj, MD, PhD, of the Center of Neurology in Lodz, and Anne H. Cross, MD, PhD, of Washington University School of Medicine, proposed that hypogammaglobulinemia may contribute to the immune dysregulation underlying ILD in these patients, drawing an analogy to pulmonary involvement observed in primary immunodeficiency disorders.¹ They also noted that the affected patients are among those with the longest cumulative exposure to ocrelizumab in the OPERA trial program—a cohort uniquely positioned to reveal late-onset effects not observable in the original 96- to 120-week controlled trials.
The retrospective analysis was conducted by investigators at the Center of Neurology in Lodz, Poland, in collaboration with researchers from the University of Warmia and Mazury, Washington University School of Medicine, and affiliated pulmonary and radiology centers.¹ In the analysis, all patients received standard intravenous ocrelizumab 600 mg every 24 weeks and underwent regular neurological assessments, laboratory monitoring, and annual MRI. Informed consent was obtained from patients who survived; personal data were fully deidentified.
Overall, all 6 patients who developed ILD were neurologically stable prior to symptom onset. Their mean age was 51.8 years (SD, 6.0), and Expanded Disability Status Scale (EDSS) scores before ILD ranged from 2.0 to 6.0 (mean, 4.25 [SD, 1.67]). Symptom onset occurred a mean of 14.5 weeks after the last ocrelizumab infusion, though timing varied considerably—from 3 to 35 weeks—across cases. Presenting symptoms included persistent cough, dyspnea, fever, generalized weakness, and reduced exercise tolerance.
High-resolution computed tomography (HRCT) showed ground-glass opacities with peripheral and migratory consolidations consistent with OP in all 6 patients. Bronchoalveolar lavage (BAL), performed in 5 of 6 cases, demonstrated lymphocytic predominance—a pattern atypical for infectious pneumonia and consistent with immune-mediated lung injury. Cryobiopsy was performed in three patients and confirmed OP histologically in all three.
Key Takeaways
- Drug name and class: Ocrelizumab (Ocrevus); humanized anti-CD20 monoclonal antibody
- Indication(s): Relapsing forms of MS (including relapsing-remitting MS, clinically isolated syndrome, and active secondary progressive MS); primary progressive MS (PPMS)
- Study type: Retrospective cohort study; single-center OPERA I follow-up site; data analysis March 2023–June 2025
- Key efficacy/safety finding: 6 of 67 patients (9.0%) developed ILD (organizing pneumonia) after a mean ocrelizumab exposure of 10.5 years (mean 22.8 infusion cycles); all had complete CD19 B-cell depletion; 5 of 6 had IgG below the lower limit of normal at ILD onset
- Clinical outcomes: 4 patients recovered with corticosteroids (mean ~7 weeks); 2 patients died; 3 patients resumed ocrelizumab (mean delay 9.1 months)
- Key safety signal: Late-emerging organizing pneumonia; antibiotic-refractory; characterized by lymphocytic BAL and migratory ground-glass opacities on HRCT; associated with hypogammaglobulinemia
- Regulatory status: Ocrelizumab approved by FDA (March 2017) for RMS and PPMS; subcutaneous formulation (Ocrevus Zunovo) approved September 2024; ILD/OP not currently listed as a labeled warning in prescribing information
In the analysis, all 6 patients had complete CD19 B-cell depletion at symptom onset. Immunoglobulin levels had declined substantially over the treatment course; at the time of ILD presentation, IgG was below the lower limit of normal in five of six patients, and IgA and IgM were below normal in four of six patients each.
A wide range of antibiotics was empirically administered in all cases and proved ineffective. Four patients responded to corticosteroid therapy, achieving clinical and radiological resolution after a mean of approximately seven weeks. Two cases were fatal. Three patients ultimately resumed ocrelizumab treatment after a mean delay of 9.1 months (SD, 3.2 months).
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Originally approved in 2017 as the first disease-modifying therapy for both relapsing forms of MS and primary progressive MS, ocrelizumab is a humanized anti-CD20 monoclonal antibody that targets CD20-positive B and pre-B lymphocytes, inducing their depletion through antibody-dependent cellular cytolysis and complement-dependent cytotoxicity.2 Although its mechanism in MS is not fully elucidated, B-cell depletion is presumed to reduce inflammatory myelin and axonal damage driven by autoreactive B cells.
What does appear clinically actionable is the diagnostic pattern: OP in ocrelizumab-treated patients consistently presented with antibiotic-refractory respiratory symptoms, characteristic HRCT findings, and lymphocytic predominance on BAL—and responded to corticosteroids when identified promptly. According to the study authors, the two fatalities in this series underscore the risk of delayed recognition or misattribution to infectious etiology.
REFERENCES
1. Zurawska AE, Cross AH, Rzeszutek K, et al. Interstitial Lung Disease as a Late Occurrence in Ocrelizumab-Treated Patients With Multiple Sclerosis. JAMA Neurol. Published online April 6, 2026. doi:10.1001/jamaneurol.2026.0548
2. FDA approves OCREVUS (ocrelizumab) for treatment of adult patients with relapsing or primary progressive forms of multiple sclerosis. US Food and Drug Administration. March 28, 2017. Accessed April 7, 2026. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761371s000lbl.pdf
