MS Drug Ocrelizumab Linked to Rare Lung Disease in New Case Series

A widely used multiple sclerosis drug may, in a small but meaningful number of patients, trigger a little-known inflammatory lung condition that doctors can easily mistake for a stubborn infection. In a study published in the Journal of Neurology, a team at IRCCS San Raffaele Scientific Institute in Milan reports five cases of organizing pneumonia among 626 people with multiple sclerosis treated with ocrelizumab, a frequency of roughly 0.8 percent. The finding, which the researchers set against a careful review of previously published cases, adds weight to a growing suspicion that anti-CD20 antibody therapies, which deliberately deplete a class of immune cells called B lymphocytes, can occasionally provoke interstitial lung disease. For a drug taken by tens of thousands of patients worldwide, even a rare side effect deserves close attention, particularly one whose symptoms so closely mimic pneumonia that diagnosis is often delayed for weeks.

Ocrelizumab is a humanized monoclonal antibody that binds to the CD20 protein found on the surface of B cells, marking them for destruction and dramatically reducing the immune attacks on the nervous system that drive multiple sclerosis. Approved after landmark trials showed clear benefits in both relapsing and primary progressive forms of the disease, it has become one of the most prescribed high-efficacy therapies in neurology. Like all immunotherapies, however, it reshapes the immune system in ways that are still being mapped. Infections, infusion reactions, and a theoretical concern about certain malignancies have long been part of its safety profile. The new study suggests that the lung, an organ densely populated by immune surveillance cells, may occasionally become collateral damage in the altered immunological landscape that follows B-cell depletion.

Organizing pneumonia is not an infection at all, despite its name. It is a form of interstitial lung disease in which the tiny air sacs of the lung and their surrounding tissue become inflamed and then filled with plugs of loose connective tissue, a process pathologists describe as granulation tissue extending into the alveolar spaces. It can arise without any identifiable cause, in which case it is called cryptogenic, or it can be secondary to drugs, infections, radiation, or autoimmune disease. Patients typically develop a persistent fever, a dry cough, and breathlessness that fail to respond to antibiotics, which is precisely the pattern that should alert clinicians to look for something other than bacterial pneumonia. On chest computed tomography, the signature findings are patchy ground-glass opacities, areas of consolidation, and sometimes the striking reversed halo sign, in which a ring of denser tissue surrounds a clearer center.

The Milanese team, led by Enrico Petza and senior author Massimo Filippi, retrospectively collected clinical, radiological, laboratory, treatment, and outcome data from multiple sclerosis patients at their center who developed organizing pneumonia while on ocrelizumab. The five identified patients, three of them women, had a median age of 54 years, with ages ranging from 27 to 64. The condition did not appear early in treatment. On average, patients had been receiving ocrelizumab for about 5.1 years before symptoms emerged, with a standard deviation of 2.9 years, and the lung disease declared itself a mean of 10.8 weeks, with a standard deviation of 10.4 weeks, after the most recent infusion. That long latency is clinically important, because it means neither patient nor physician is likely to connect a fever appearing months after a routine infusion with the drug that caused it.

The clinical picture in all five cases was strikingly uniform. Each patient presented with a persistent fever that refused to yield to antibiotics, and some also had a nonproductive cough. Chest CT scans consistently revealed patchy ground-glass opacities and consolidations, the radiological hallmarks of organizing pneumonia. Treatment followed the standard approach for the condition: all patients received prednisone at doses of 0.5 to 1 milligram per kilogram of body weight per day, continued for a median of 30 days with a range of 15 to 60 days, followed by a gradual tapering of the dose. Corticosteroids suppress the inflammatory process and usually produce a prompt clinical response, and indeed the patients initially improved. Ocrelizumab was discontinued in every case, a decision that reflects the seriousness with which the treating neurologists viewed the association.

The follow-up data, however, reveal a more troubling story than the initial recovery might suggest. Over a median follow-up of 29 months, ranging from 4 to 47 months, four of the five patients experienced respiratory relapses, and residual radiological abnormalities persisted in their lungs despite treatment. Only one patient eventually restarted a disease-modifying therapy, beginning ozanimod, a sphingosine-1-phosphate receptor modulator, two years after the onset of the lung disease. The reluctance to re-expose these patients to immunotherapy is understandable, but it leaves them vulnerable to renewed multiple sclerosis activity, creating a genuine therapeutic dilemma. The persistence of lung changes on imaging also raises questions about whether organizing pneumonia associated with B-cell depletion follows a more indolent course than the idiopathic form of the disease.

To place their five cases in context, the researchers conducted a literature review and identified 17 previously reported cases of organizing pneumonia in ocrelizumab-treated patients. Descriptive comparison showed substantial consistency between the Milanese cohort and the published cases, in terms of timing, presentation, imaging findings, and response to corticosteroids. Earlier reports included patients whose lung disease followed COVID-19 infection during anti-CD20 therapy, complicating the picture, since viral infection itself can trigger secondary organizing pneumonia. But the accumulation of cases without any infectious trigger, occurring years into treatment and weeks after infusions, strengthens the argument that ocrelizumab itself can be the inciting agent. The pattern also echoes what has been described with rituximab, an older anti-CD20 antibody used in lymphoma and rheumatoid arthritis, which has been linked to organizing pneumonia in multiple published reports.

Why would depleting B cells inflame the lung? The authors point out that the mechanism remains unclear and call for further studies to clarify the potential role of CD20-positive lymphocyte depletion in the pathogenesis of organizing pneumonia. Several hypotheses are plausible. B cells are not merely antibody producers; they regulate other immune cells, present antigens, and secrete cytokines that maintain immune homeostasis in tissues. Removing them may disturb the delicate balance of immune surveillance in the lung, allowing aberrant repair processes to take hold. Alternatively, the timing of the lung injury weeks after infusion could reflect the repopulation phase, when immature B cells return and the immune system recalibrates. It is also possible that a subclinical infection, undetected in an immunologically altered host, seeds the inflammatory cascade. Disentangling these possibilities will require immunological studies of affected lung tissue and longitudinal immune monitoring of treated patients.

For clinicians, the practical message is vigilance. A multiple sclerosis patient on ocrelizumab who develops weeks of unexplained fever with a dry cough, especially when antibiotics fail, should undergo chest imaging, and the radiologist should be told to consider organizing pneumonia among the differential diagnoses. Early recognition matters because corticosteroids are effective and because continuing the offending drug may prolong or worsen the lung injury. The authors note that the condition remained rare, affecting fewer than one in a hundred patients at their center, and nothing in the study undermines the substantial efficacy that ocrelizumab has demonstrated in randomized trials. But rare complications of very common drugs translate into real numbers of affected people, and the long latency between treatment and disease makes spontaneous reporting and pooled surveillance essential.

The study also highlights a broader theme in modern neuroimmunology: as high-efficacy immunotherapies transform the prognosis of multiple sclerosis, the frontier of care is shifting toward the fine print of long-term safety. Interstitial lung disease has now been reported as a late occurrence in ocrelizumab-treated patients in other journals as well, suggesting that the signal is no longer anecdotal. Larger registries, systematic pulmonary follow-up, and mechanistic research into how B-cell depletion reshapes lung immunity will be needed to identify who is at risk and whether monitoring or prophylactic strategies can prevent the disease. For now, the Milanese case series offers clinicians a clear template of what to watch for, and it offers patients the reassurance that when the condition is caught, effective treatment exists, even if the road to full recovery can be longer than anyone would like.

Subject of Research: Organizing pneumonia associated with ocrelizumab treatment in multiple sclerosis patients

Article Title: Ocrelizumab-related organizing pneumonia in multiple sclerosis: insights from a case series and literature review

Article References: Petza, E., Guerrieri, S., Marino, V., Gattuso, I., Rubin, M., Nozzolillo, A., Rocca, M. A., Moiola, L., & Filippi, M. (2026). Ocrelizumab-related organizing pneumonia in multiple sclerosis: insights from a case series and literature review. Journal of Neurology, 273(10), Article 600. https://doi.org/10.1007/s00415-026-14130-3

Image Credits: AI Generated

DOI: 10.1007/s00415-026-14130-3

Keywords: multiple sclerosis, ocrelizumab, organizing pneumonia, interstitial lung disease, anti-CD20 therapy, B-cell depletion, corticosteroids, chest CT, drug safety, neuroimmunology, case series, Journal of Neurology