To the Editor: We present the case of a 67-year-old woman with long-standing systemic lupus erythematosus (SLE) who developed cytomegalovirus (CMV) colitis whilst on anifrolumab, a Type 1 interferon receptor antibody, indicated for treatment of moderate to severe SLE. We believe this case is relevant to a transplant audience, as management challenges faced in transplant medicine often overlap with SLE care, particularly in patients who require renal transplantation for lupus nephritis. To our knowledge, this is the first described case of anifrolumab-induced CMV colitis, providing important context to our understanding of balanced immunosuppression in this cohort. Our patient was diagnosed with lupus nephritis in 1988, receiving high-dose corticosteroids and cyclophosphamide in early disease. Her disease manifestations have included rash, relapses of lupus nephritis leading to CKD IV nephropathy, and, most recently, active deforming arthritis. She has a prolonged immunosuppression history, with multiple prior therapies resulting in secondary treatment failure. She has remained on corticosteroids since diagnosis. At presentation, her immunosuppressive regimen included prednisolone 5 mg daily, mycophenolate mofetil 500 mg twice daily, hydroxychloroquine 200 mg alternate days, and anifrolumab 300 mg IV 4 weeks (commenced 2 months prior). Prior to this, she was on belimumab monthly infusions, which were changed to anifrolumab due to active arthritis. The patient first presented to the hospital with a 3-day history of fever and vomiting, on a background of 3 weeks of diarrhea. Examination revealed peripheral fluid overload. Laboratory investigations revealed hemoglobin 8.2 g/dL, platelets 150 × 103/µL, and white cell count 5.6 × 103/µL, with lymphopenia 0.1 × 103/µL. Renal function was abnormal: urea 22.4 mmol/L and creatinine 392 µmol/L, above the prior baseline creatinine 200 µmol/L. Blood, urine, and sputum cultures were negative, as were respiratory and fecal polymerase chain reaction (PCR) multiplex assays. Quantitative CMV PCR on peripheral blood was positive, with viral load 2865 IU/mL. Chest x-ray demonstrated small bilateral pleural effusions, right mid-zone opacification and mild cardiomegaly. CT imaging was not performed due to acute kidney injury. Given the patient's net state of immunocompromise, there was concern that CMV gastrointestinal disease may provide a unifying diagnosis. According to the 2024 Transplant-Associated Virus Infections Forum consensus definitions, proven CMV gastrointestinal disease requires symptoms, endoscopic mucosal lesions, and CMV documented in tissue. Probable CMV gastrointestinal disease is defined by compatible symptoms with CMV detected in tissue, without the need for macroscopic lesions. In this case, colonoscopy on Day 5 showed no macroscopic evidence of colitis. By Day 7, the patient's fevers had resolved, and her diarrhea was improving. Acute kidney injury persisted, with eGFR 10 mL/min. Of note, valganciclovir is not recommended at eGFR < 10 mL/min. Despite detectable CMV viremia, empiric antiviral therapy was initially withheld due to improving symptoms and severe renal impairment. The patient was discharged home with a plan to withhold anifrolumab and follow-up in the outpatient setting when colon histopathology results and repeat CMV viral load were available. The patient was seen in Infectious Diseases clinic 1 week later, where she reported recurrence of nausea and vomiting. The histopathology report was now available, revealing scattered positively stained cells on CMV immunohistochemistry, without CMV inclusion bodies. CMV viral load was 5993 IU/mL. Paired with gastrointestinal symptoms, this represented a probable diagnosis of CMV colitis. The patient was re-admitted to the hospital, where treatment was commenced with intravenous ganciclovir 60 mg daily (dose 1 mg/kg). Lower gastrointestinal symptoms improved slowly, and the patient was discharged 1 week later on renally adjusted oral valganciclovir (480 mg Q48 H). With treatment, symptoms continued to improve, and viral load was undetectable 3 weeks later. To our knowledge, we report the first case of CMV end-organ disease occurring in association with anifrolumab. As a herpesvirus, CMV-related complications are perhaps unsurprising given the recognized spectrum of infection-related complications initially described in anifrolumab clinical trials, which included varicella zoster and herpes simplex virus, in addition to influenza 1. Anifrolumab is a human monoclonal antibody targeting the Type I interferon receptor subunit (IFNAR1), thereby inhibiting the IFN-α/β signaling pathway 2. Type I interferon signaling is central to antiviral immunity, promoting dendritic cell maturation and downstream B-cell and T-cell activation. Inter also amplifies self-reactive responses that contribute to end-organ injury in SLE 3. Interferon blockade reduces autoimmune injury, at the cost of impaired immune control of virus invasion and replication. Concurrent lymphopenia, corticosteroid use, and use of T-cell agents such as mycophenolate amplify viral vulnerability. This was likely the case in our patient, in whom multiple therapies may have synergized to increase infection risk. In keeping with this underlying immunological mechanism, pooled clinical trial data demonstrated significant risk of herpes zoster reactivation in patients on anifrolumab, with an incidence of 6.1% versus 1.3% in placebo group 4. Immunization against herpes zoster is recommended in all SLE patients 5. Of note, live vaccines should be avoided whilst on immunosuppression, including anifrolumab. Administration of the inactivated Shingrix vaccine is preferred, ideally prior to commencement of anti-IFN therapy or other immunosuppressive therapy. Clinical trial safety outcomes reflect up to 52 weeks of follow-up, and longer-term or cumulative viral risks beyond one year, including CMV reactivation risk, remain under-characterized 1. Determining whether to initiate antiviral therapy in the case of our patient was particularly challenging, as contribution of CMV to the patient's presentation was initially uncertain, and had to be weighed against the substantial risk of ganciclovir-associated nephrotoxicity. Following the index episode of CMV colitis, the patient remained vulnerable to future disease reactivation in the setting of persistent immunosuppression for escalating SLE activity. Secondary CMV prophylaxis was considered, but was avoided in the setting of persistent renal impairment. Without secondary prophylaxis, a return to her previous level of immunosuppression was deemed unsafe. At initial presentation, renal physicians assessed the patient's lupus nephritis to be in clinical remission, raising concern that CMV gastrointestinal disease and associated systemic inflammation contributed to irreversible loss of residual renal function. Her renal function subsequently declined, ultimately necessitating dialysis and assessment of transplant eligibility. Her mycophenolate was ceased, and anifrolumab was recommenced at a reduced dose, for ongoing management of active arthritis. This case highlights the difficulty of quantifying CMV risk in treatment-experienced lupus patients, a highly heterogeneous population in whom cumulative immunosuppression, immune dysregulation, and end-organ involvement vary widely. Trial-derived safety data may be insufficient to predict individual infection risk in this cohort, necessitating a personalized approach to risk assessment and prophylaxis, particularly in patients with advanced renal disease and evolving transplant candidacy. Management in such cases is complex and requires close multidisciplinary collaboration between rheumatology, infectious diseases, nephrology, and transplant services. Lupus nephritis affects approximately 50% of SLE patients, with 30% of those progressing to end-stage kidney disease, many requiring renal transplantation. Following FDA approval in 2021, anifrolumab has been established as an effective SLE therapy with corticosteroid-sparing effects and meaningful improvements in skin and joint disease activity. Its role in lupus nephritis remains unproven; however, early-phase studies suggest possible renal benefit, albeit at higher than currently approved doses. The ongoing Phase III, double-blind, placebo-controlled IRIS trial is expected to clarify its role and safety in proliferative nephritis 6. In summary, interferon-alpha-receptor blockade should be recognized as a novel immunosuppressive agent with potential to induce CMV disease. This case highlights several management challenges, including prophylaxis decisions in the absence of formal guidelines for non-transplant patients, and the need to balance infection risk with renal toxicity in patients with progressive kidney disease. We would like to thank our patient for graciously allowing her story to be shared for educational purposes. The authors have nothing to report. Written informed consent for the publication of this article was provided by the patient.
Spear et al. (2026) studied this question.