Fatal COVID-19 Pneumonia in a Rheumatoid Arthritis Patient Receiving Long-Term Rituximab Therapy

A 58-year-old male received a diagnosis of rheumatoid arthritis (RA) in September 2011, involving shoulders, elbows, hands, knees, ankles, and feet with bony erosions. He had a pulmonary tuberculosis history (Figure 1a) complicated by restrictive pericarditis, successfully managed by antibiotics and pericardiectomy in 1995. Biweekly injection of 40 mg adalimumab, a tumor necrosis factor monoclonal antibody (mAb), was initiated in May 2014 due to refractory responses to prednisolone 10 mg/day and disease-modifying antirheumatic drugs (hydroxychloroquine, leflunomide, methotrexate, and sulfasalazine). After adalimumab therapy, there was a low disease activity (DAS28 < 3.2) with reduced medication regimen to prednisolone 5 mg/day and methotrexate 15 mg/week. ¹ Negative results of QuantiFERON test, a whole-blood interferon-γ release assay helpful for tuberculosis diagnosis, ² were obtained before and after adalimumab therapy. In September 2017, he was admitted with dyspnea and cough for 1 week. Diffuse pulmonary ground-glass infiltrations were found (Figure 1b) with negative microbiological survey. Under the suspicion of drug-induced lung injury (DILI), methotrexate use was terminated with the prescription of high-dose glucocorticoids, leading to resolved pulmonary infiltrations 1 month later (Figure 1c). There was a switch of biologics use due to a worsening activity without methotrexate therapy. Infusion of rituximab, a B-cell depleting mAb, was initiated in July 2018, 1 g every 2 weeks for two doses repeated every 6 months, together with prednisolone 10 mg/day and hydroxychloroquine 400 mg/day. There was a disease remission (DAS28 < 2.6) after rituximab therapy.

Figure 1.

Serial chest images in a rheumatoid arthritis patient under long-term rituximab therapy complicated with fatal COVID-19 pneumonia. (a) Chest X-ray (CXR) with bilateral reticulonodular lesions over upper lobes (old tuberculosis sequelae), bilateral rib fractures and sternum surgical wires (pericardiectomy) in September 2011. (b) Bilateral diffuse ground-glass infiltrations on CXR and chest computed tomography (CT) in September 2017. (c) Resolved diffuse pulmonary infiltrations on CXR and chest CT after discontinuing methotrexate use and initiating high-dose glucocorticoids therapy for 1 month in October 2017. (d) Bilateral diffuse ground-glass infiltrations related to severe acute respiratory syndrome-coronavirus 2 infection on CXR and chest CT after initiating rituximab infusion for 4 years in July 2022.

The patient received rituximab infusions on June 14 and 30, 2022. Owing to the admission for percutaneous intervention of occluded coronary arteries, nasopharyngeal SARS-CoV-2 polymerase chain reaction test was done with negative results on June 17, 2022. There was no known COVID-19 vaccination history. He visited the Emergency Department with acute onset of dyspnea and cough on July 4, 2022. There were diffuse pulmonary ground-glass infiltrations (Figure 1d) and positive results of SARS-CoV-2 test (cycle threshold 18.8), establishing a diagnosis of COVID-19 pneumonia. Despite the use of mechanical ventilation and antiviral (molnupiravir and remdesivir) and immunomodulating (dexamethasone and tocilizumab) therapy, ³ he succumbed to acute respiratory distress syndrome and multiorgan failure 15 days later.

During the COVID-19 pandemic, owing to associated comorbidities and activity/medication-related immunosuppression, inflammatory rheumatic diseases might form a vulnerable group at increased risk of severe SARS-CoV-2 infection.^4,5 Higher prescribed glucocorticoids dosages (more than 10 mg/day prednisolone-equivalent dose) in such patients have greater odds of COVID-19-related death. ⁵ Furthermore, B-cell depletion therapy can compromise humoral immune responses with difficulties in the clearance of SARS-CoV-2.^4-6 Notably, rituximab use in systemic lupus erythematosus is associated with increased hospitalization and death outcome as well as poor vaccination efficacy with lower seroconversion rates and antibody levels. ⁶ Despite the remarkable efficacy, rituximab therapy in our patient might be a COVID-19-associated death risk other than male sex, cardiovascular comorbidity, and glucocorticoids use.

Besides disease activity with lung involvement, acute diffuse pulmonary complications in RA are due to treatment-related adverse drug reaction (ADR) and infection.^7,8 DILI can occur during methotrexate therapy in RA, a reversible condition if under earlier management such as the pneumonitis episode in this case. ⁸ Indeed, COVID-19 pneumonia should be a differential diagnosis of acute diffuse pulmonary complications in RA patients receiving rituximab therapy.

Note of Authors

Increasing evidences support the association of severe SARS-CoV-2 infection in RA patients receiving rituximab therapy regardless of their vaccination status.^5,9 We reported a possible ADR of rituximab in this patient to the Food and Drug Administration through the National Adverse Drug Reaction Reporting System on August 24, 2022. ¹⁰

Chrong-Reen Wang, MD, PhD
Division of Rheumatology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan

Wei-Chieh Lin, MD, PhD
Division of Critical Care Medicine, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan