---
title: "Mycophenolate Mofetil for Steroid-Unresponsive ICI-Associated Transverse Myelitis: Case Report and"
id: "frontiers-in-immunology-7-case-report-observational-use-of-mycophenolate-mofetil-in-probable-steroid"
canonical_url: "https://medichelpline.com/clinical-feed/frontiers-in-immunology-7-case-report-observational-use-of-mycophenolate-mofetil-in-probable-steroid"
content_type: "clinical_feed_article"
specialty: "Infectious Disease"
source_name: "Frontiers in Immunology"
source_url: "https://www.frontiersin.org/articles/10.3389/fimmu.2026.1933514"
published_at: "2026-09-21T00:00:00.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Mycophenolate Mofetil for Steroid-Unresponsive ICI-Associated Transverse Myelitis: Case Report and
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/frontiers-in-immunology-7-case-report-observational-use-of-mycophenolate-mofetil-in-probable-steroid
- **Specialty:** [Infectious Disease](https://medichelpline.com/clinical-feed/infectious-disease.md)
- **Primary Source:** Frontiers in Immunology
- **Source URL:** [Original Journal Publication](https://www.frontiersin.org/articles/10.3389/fimmu.2026.1933514)
- **Published At:** 2026-09-21T00:00:00.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- A 37-year-old man with biphasic pleural mesothelioma developed acute long-segment **immune checkpoint inhibitor (ICI)-associated transverse myelitis (TM)** after four cycles of nivolumab plus ipilimumab. - Neurologic onset occurred within one month after ICI exposure and presented with rapid bilateral lower limb weakness, sensory level (anterior waist girdle sensation), decreased deep sensation, hyperreflexia, positive Babinski signs, and loss of autonomous urination. - Cerebrospinal fluid (CSF) showed marked inflammatory changes: high protein (5.60 g/L), pleocytosis with lymphocytic predominance, positive CSF oligoclonal bands, and CSF-NGS detection of Epstein–Barr virus (EBV) reads; serum and CSF anti-AQP4, anti-MOG, and anti-GFAP were negative. Serum anti-Ri IgG was positive (1:32). - Spinal MRI demonstrated heterogeneous intramedullary T2 hyperintensity and long-segment intramedullary and meningeal contrast enhancement from T2–T10, consistent with inflammatory myelitis; follow-up MRI after treatment showed partial reduction of enhancement but new cystic/myelomalacic changes. - Initial therapy with high-dose corticosteroids and intravenous immunoglobulin (IVIg) produced limited benefit; the presentation met criteria for **steroid-unresponsive** ICI-associated TM per multidisciplinary assessment and SITC terminology. - Mycophenolate mofetil (MMF) 0.5 g twice daily was added to steroids; after one month of combination therapy the patient showed partial neurological improvement (lower limb strength from Grade I to II bilaterally, partial sensory recovery on the right), decreased intramedullary enhancement, declining ferritin levels, but persistent autonomic dysfunction and girdle sensation. - No MMF-related myelosuppression, gastrointestinal, hepatic, or renal toxicity was observed during treatment; chemotherapy (pemetrexed plus carboplatin) was safely restarted with concurrent immunosuppression and close monitoring. - Imaging evidence of cystic/myelomalacic spinal cord change suggests potential irreversible parenchymal injury and may explain incomplete recovery. The case highlights diagnostic complexity given concurrent EBV CSF reads and anti-Ri positivity, but multidisciplinary consensus favored ICI-associated TM as predominant etiology. - The report situates MMF as a second-line immunosuppressive option for steroid-unresponsive ICI-associated TM alongside IVIg, plasmapheresis, cyclophosphamide, and rituximab, while acknowledging limited evidence and the need for individualized multidisciplinary decision-making.
## Clinical Analysis & Structured Key Points
Frontiers | Case Report: Observational use of mycophenolate mofetil in probable steroid-unresponsive immune checkpoint inhibitor-associated transverse myelitis CASE REPORT article Front. Immunol. , 21 September 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1933514 Published in Frontiers in Immunology Autoimmune Disorders 7 impact factor 11.3 citescore Editor & Reviewers Edited by D V Dr. Venkataramana Kandi Ph.D., MAMS, FAGE, FRCPath (London) Reviewed by T K Tomoya Kawazoe A G Ahmad Ghorbani Vanan Outline Figures and Tables Figure 1 View in article Figure 2 View in article Figure 3 View in article CASE REPORT article Front. Immunol. , 21 September 2026 Sec. Autoimmune Disorders Volume 17 - 2026 | https://doi.org/10.3389/fimmu.2026.1933514 Case Report: Observational use of mycophenolate mofetil in probable steroid-unresponsive immune checkpoint inhibitor-associated transverse myelitis L K Lingping Kong 1 X W Xin Wang 1 T Y Tao Yu 1 J W Junping Wang 2 C Y Chunsheng Yang 3 L Z Linlin Zhang 1 * D Z Diansheng Zhong 1 * 1. Department of Medical Oncology, Tianjin Medical University General Hospital, Tianjin, China 2. Department of Imaging, Tianjin Medical University General Hospital, Tianjin, China 3. Department of Neurology, Tianjin Medical University General Hospital, Tianjin, China See more Article metrics View details Abstract Immune checkpoint inhibitor (ICI)-associated transverse myelitis (TM) is a rare and severe neurological immune-related adverse event (n-irAE) with an incidence of < 0.01%, and the clinical management of steroid-unresponsive cases remains extremely challenging. This article reports the case of a 37-year-old male patient with biphasic pleural mesothelioma who developed ICI-associated TM after treatment with nivolumab combined with ipilimumab. Initial treatment with high-dose glucocorticoids plus intravenous immunoglobulin (IVIg) was ineffective. After mycophenolate mofetil (MMF) was added in combination with steroids for 1 month, the patient’s neurological function showed slight improvement, and intramedullary contrast-enhanced signals on spinal MRI showed partial reduction. However, spinal cord cystic or myelomalacic changes suggested potentially irreversible parenchymal injury. Currently, the patient has restarted pemetrexed combined with carboplatin chemotherapy, and the disease status is stable. Based on recently published case series, case reports, and systematic reviews, this article discusses the second-line treatment strategies for steroid-unresponsive ICI-associated TM, aiming to provide a reference for clinical practice in managing such rare cases. Introduction Immune checkpoint inhibitors (ICIs), including programmed death-1 (PD-1)/cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) inhibitors, have become an important treatment for various malignant tumors, such as malignant pleural mesothelioma, significantly improving the survival of patients with advanced disease. However, while ICIs remove immune checkpoint-mediated inhibition of T cells and activate systemic antitumor immune responses, they inevitably induce immune-related adverse events (irAEs) involving multiple organ systems. Among them, neurological immune-related adverse events (n-irAEs) are relatively rare but can progress rapidly and are associated with high rates of disability, making them a key focus and challenge in clinical management ( 1 ). Transverse myelitis (TM) is one of the most severe types of ICI-associated n-irAEs, accounting for only 2% of all n-irAEs ( 2 ). According to literature reports, the overall incidence of ICI-associated TM is < 0.01%, which occurs more commonly after treatment with PD-1/PD-L1 inhibitors alone or in combination with CTLA-4 inhibitors. The median time to onset is 6 weeks (range: 1–74 weeks), with 80% occurring within the first 4 months of treatment. Typical manifestations include limb weakness, abnormal sensory level, and sphincter dysfunction, which can result in permanent neurological deficits if not promptly treated ( 1 , 2 ). To date, there have been relatively few reported cases of ICI-associated TM worldwide, reported mainly as case series or individual cases, among which approximately 30% are related to combined PD-1 inhibitor and CTLA-4 inhibitor therapy ( 3 ). Currently, the first-line treatment for ICI-associated TM is high-dose glucocorticoid pulse therapy, but some patients are steroid-refractory or steroid-dependent, requiring timely initiation of second-line immunosuppressive therapy. Existing second-line treatment options include intravenous immunoglobulin (IVIg) ( 4 , 5 ), plasmapheresis, cyclophosphamide, rituximab, and other immunosuppressive therapies; however, no established standard exists ( 6 , 7 ). Mycophenolate mofetil (MMF), as a well-established immunosuppressant, has demonstrated efficacy in treating ICI-related hepatitis and nephritis ( 8 ). In addition, existing literature indicates that the pathogenesis of immune checkpoint inhibitor-associated TM is complex, involving abnormal T-cell activation, autoantibody production, and cytokine storms. For example, elevated interleukin-6 (IL-6) levels in the cerebrospinal fluid of some patients suggest a strong inflammatory response and cytokine-mediated tissue injury ( 9 ). In other cases, increased levels of chemokines such as C-X-C motif chemokine ligand 13 (CXCL13) in the cerebrospinal fluid indicate the involvement of B-cell-mediated immune responses. At the same time, some reported cases have a history of spinal radiotherapy, suggesting that radiotherapy may increase the risk of ICI-associated TM by damaging the blood-brain barrier and enhancing immune cell infiltration ( 7 ). In the present case, the patient exhibited a suboptimal response to high-dose corticosteroid monotherapy. To address this therapeutic challenge, we added MMF as a second-line immunosuppressive agent. Mechanistically, MMF exerts its therapeutic effect by inhibiting inosine monophosphate dehydrogenase (IMPDH), thereby suppressing T and B lymphocyte proliferation, reducing cytokine production, and mitigating immune-mediated tissue injury within the spinal cord. By integrating the diagnostic and treatment course of this case with evidence from recently published case reports and reviews, this article analyzes the therapeutic strategies for steroid-unresponsive ICI-associated TM, providing a clinical basis and novel insights for the diagnosis and treatment of similar cases. Case General information and clinical background A 37-year-old male patient with no previous medical history, no history of smoking or alcohol use, and no significant family history was admitted. In November 2022, the patient underwent a chest CT due to cough, which revealed small nodules in the upper lobe of the right lung and the dorsal segment of the lower lobe of the left lung (size approximately 9.6 mm × 6.2 mm × 5.6 mm), accompanied by calcification and interlobar pleural adhesion along the left oblique fissure. The nodules were considered benign calcified nodules. On 8 July 2025, the patient was admitted to the cardiology department of our hospital due to worsening chest pain. PET-CT showed an irregular soft tissue nodule in the subpleural area of the dorsal segment of the left lower lung, multiple enlarged lymph nodes in the left hilum and mediastinum (SUV = 11.0SUV), diffuse thickening of the left pleura (SUV = 7.9), and a large amount of left pleural effusion. On 23 July 2025, thoracoscopic pleural lesion resection was performed. The pathological diagnosis was a malignant tumor of the left parietal and visceral pleura, with biphasic mesothelioma (epithelioid-predominant) considered based on clinical and immunohistochemical findings. Tumor treatment and onset of irAE ICI treatment phase From 5 August to 21 October 2025, the patient received first-line treatment with nivolumab 360 mg d1 Q3W + ipilimumab 50 mg d1 Q6W, completing a total of four cycles. After three cycles, efficacy evaluation showed stable disease (SD), but left thoracoabdominal pain continued to worsen. Pain treatment and chemotherapy On 27 October 2025, intrathecal injection + spinal nerve root radiofrequency ablation was performed, but the analgesic effect was poor. On 14 November 2025, the patient received one cycle of pemetrexed combined with carboplatin chemotherapy at an outside institution. Onset of neurological symptoms On 20 November 2025, the patient suddenly developed bilateral lower limb weakness accompanied by sensory abnormalities and was unable to stand. On 24 November, the symptoms worsened, with the development of anterior waist girdle sensation. On 26 November, he was admitted to the neurology department. Clinical manifestations and specialist examination On admission, specialist examination showed clear consciousness, normal articulation, and no abnormalities in cranial nerve examination. Limb muscle strength was Grade V in both upper limbs and Grade I in both lower limbs. Muscle tone was normal on the left side and decreased on the right side. There was abnormal superficial pain sensation in the left lower limb, decreased superficial pain sensation in the right lower limb, decreased sensation in the saddle area and posterior waist, and an obvious anterior waist girdle sensation. Deep sensation was decreased in both lower limbs. Bilateral hyperreflexia and a positive Babinski sign were present. Meningeal irritation signs were negative, and autonomous urination function was completely lost. Auxiliary examinations Cerebrospinal fluid and serological examinations (27 November 2025) Opening intracranial pressure was 122 mmH 2 O. Gross appearance of cerebrospinal fluid (CSF) was yellowish, with positive Pandy’s test (3+). Routine CSF showed a red blood cell count of 2 × 10 6 /L and a white blood cell count of 100 × 10 6 /L, with a lymphocyte predominance (mononuclear cells, 97%; multinuclear cells, 3%). CSF biochemistry showed a total protein level of 5.60 g/L (significantly elevated), chloride of 105 mmol/L (decreased), and glucose of 2.5 mmol/L (reference, 2.5–4.4 mmol/L). CSF oligoclonal bands were positive, while serum oligoclonal bands were negative. CSF cytology showed no malignant tumor cells. CSF-NGS detected 57 Epstein–Barr-virus-4 reads with a relative abundance of 99.1%; blood-NGS returned negative. No clinical or laboratory evidence supported overt acute central nervous system infection. Serological testing showed that anti-AQP4, anti-MOG, and anti-GFAP antibodies were negative in both serum and CSF. The paraneoplastic antibody panel showed serum anti-Ri immunoglobulin G (anti-Ri-IgG) positivity (1:32), and the remaining paraneoplastic antibodies were negative. No obvious abnormalities were observed in the autoantibody profile, thyroid function, or serum tumor markers. Imaging examinations Initial thoracic spinal MRI (27 November 2025) Heterogeneous signals within the spinal canal at T2 to T10 levels, with linear prominent enhancement of the dura mater and arachnoid mater, irregular morphology of the spinal cord, and heterogeneous enhancement, consistent with TM inflammatory changes ( Figures 1A, C ). Figure 1 MRI progression. At diagnosis (A, C) , 1 month after combined steroid and MMF therapy (B, D) . (A) Sagittal contrast-enhanced T2-TSE sequence. Note that CSF demonstrates low signal intensity on this contrast-enhanced T2-TSE acquisition, with intramedullary inflammatory hyperintensity (red arrows). (B) Sagittal noncontrast T2-weighted TSE image showing partial reduction of intramedullary inflammatory signal abnormalities. (C) Axial postcontrast T1-weighted image demonstrating intramedullary inflammatory enhancement (red arrow). (D) Follow-up axial postcontrast T1-weighted image showing partial reduction of intramedullary enhancement. Diagnosis Following a multidisciplinary consultation involving oncologists, neurologists, and radiologists, the radiologist pointed out that imaging studies after immune checkpoint inhibitor (ICI) therapy showed long-segment enhancement of the spinal meninges (dura mater and leptomeninges) and spinal cord, which made tumor metastasis less likely. Isolated Epstein-Barr virus (EBV) myelitis is rare and usually involves short segments when present, and imaging cannot reliably distinguish it from paraneoplastic lesions. The neurologist noted that cerebrospinal fluid examination showed markedly elevated protein, with glucose within the normal reference range. CSF cytology showed no malignant tumor cells, which makes malignant and infectious etiologies clinically less likely. Negative demyelinating antibodies ruled out autoimmune demyelinating diseases. The clinical presentation of long-segment myelitis accompanied by girdle-like pain and paralysis was consistent with typical immune-mediated injury. Although EBV infection and positive Ri antibody may act as triggering factors, the main pathogenic mechanism was ICI-induced immune dysfunction. Moreover, the treatment approach for TM is consistent across these three etiologies. The oncologist stated that, given the clear use of ICI therapy within 1 month before symptom onset and the atypical manifestation associated with Ri antibody positivity (which typically involves the brainstem and cerebellum), this case was diagnosed as ICI-associated TM, and a mixed multifactorial etiology could not be excluded. Multidisciplinary consultation favored ICI-associated TM as the predominant etiology, while mixed multifactorial contributions could not be fully ruled out. Treatment course and symptom changes From 29 November to 3 December, the patient was treated with intravenous immunoglobulin (25 g daily for 5 days), which resulted in limited clinical response. From 5 to 9 December, methylprednisolone was administered at 500 mg daily for 5 days, leading to partial relief of abdominal and subcutaneous pain. On 10 and 11 December, methylprednisolone 80 mg was given daily for 2 days, and the muscle strength of the right lower limb improved from Grade I to Grade II. On 11 December, methylprednisolone 40 mg was administered for 1 day, with no change in symptoms. On 12 December, the patient was switched to oral prednisone 30 mg daily, with a rapid tapering schedule that reduced the dose to two tablets every other day at the patient’s request. Symptoms remained unchanged during this period. Subsequently, the patient was transferred to the Department of Medical Oncology for further treatment. On 15 December, serum cytokine levels were normal, while ferritin was elevated at 1,708.93 ng/ml. Sensory, motor, and autonomic nerve dysfunction persisted, indicating that there was no improvement in TM. From 15 to 21 December, the patient received methylprednisolone 80 mg daily for 7 days combined with MMF 0.5 g twice daily. This resulted in partial recovery of the sensory deficit in the right lower limb. From 22 to 29 December, oral prednisone 50 mg daily was administered for 7 days in combination with MMF 0.5 g twice daily. The sensory level on the right lower limb shifted caudally, and the muscle strength of the left lower limb improved from Grade I to Grade II. During the follow-up period after discharge, prednisone was tapered by one tablet weekly, while MMF 0.5 g twice daily was continued. Symptoms did not improve further, and the abdominal band-like sensation persisted. Serum ferritin levels gradually decreased during treatment ( Figure 2 ). Figure 2 Trend of serum ferritin levels before and after treatment. Restart of tumor treatment On 29 December, the patient received the second cycle of pemetrexed plus carboplatin chemotherapy. After evaluation, the patient’s neurological symptoms were stable, immunosuppressive treatment had not caused severe infection, spinal inflammatory lesions were controlled, and there was no evidence of tumor progression. Therefore, on the basis of continuing maintenance treatment with MMF + low-dose steroids, pemetrexed combined with carboplatin chemotherapy was restarted. During chemotherapy, neurological function, blood counts, liver and kidney function were closely monitored, and no severe chemotherapy-related adverse reactions occurred. Rechecked thoracic spinal MRI (19 January 2026, 1 month after treatment) The intramedullary abnormal enhancement signals from T2 to T10 showed partial reduction in extent and intensity ( Figures 1B, D ); cystic or myelomalacic changes were observed within the previously affected spinal cord ( Figure 3 ). Figure 3 MRI demonstrated cystic or myelomalacic foci within the spinal cord. Chest CT (dynamic reexamination during treatment) Nodular thickening of the left pleura and left pleural effusion showed no significant progression compared with the previous assessment; recent reexamination following the restart of chemotherapy (January 2026) showed stable tumor lesions with no new lesions. Outcome and prognosis Neurological function outcome (1 month after treatment) After 1 month of MMF combined with steroid treatment, the patient’s neurological function showed a partial recovery pattern: bilateral lower limb muscle strength recovered from Grade I to Grade II; superficial sensation in the right lower limb partially recovered, while the anterior waist girdle sensation did not improve; the area of decreased sensation in the saddle area and posterior waist decreased; autonomous urination function did not recover. Follow-up thoracic spine MRI demonstrated partial reduction of intramedullary inflammatory enhancement; these imaging changes occurred during combined immunosuppressive therapy and cannot be solely attributed to MMF. The presence of spinal cord cystic or myelomalacic changes suggests potentially irreversible parenchymal injury, which may underlie the patient’s incomplete neurological recovery. Tumor outcome After restarting pemetrexed combined with carboplatin chemotherapy, the patient completed two cycles of chemotherapy. Recent evaluation showed SD, with no enlargement of left pleural lesions, no significant increase in pleural effusion, and no new lesions. Drug safety and long-term prognosis During treatment, the patient had no MMF-related gastrointestinal discomfort, myelosuppression, or liver and kidney function damage, and steroid adverse reactions were mild. Currently, he is still receiving maintenance treatment with MMF 0.5 g PO BID + prednisone 20 mg PO QD. It is planned to gradually reduce the steroid dose according to the recovery of neurological function and maintain MMF for a long time to prevent recurrence of inflammation; at the same time, chemotherapy will be continued to control the tumor, thoracic spinal MR and tumor imaging will be repeated regularly, and neurological function and tumor progression will be followed up long-term. Discussion This case illustrates a diagnostically complex presentation of probable immune checkpoint inhibitor-associated TM. In accordance with the 2023 SITC consensus terminology for irAEs, we define this presentation as steroid-unresponsive ( 10 ). Several overlapping potential contributing factors were identified, including serum anti-Ri paraneoplastic antibody positivity and Epstein–Barr virus sequences detected within the cerebrospinal fluid. Alternative etiologies, including leptomeningeal malignancy, postprocedural inflammatory myelopathy, EBV-driven primary CNS infection, and paraneoplastic-mediated myelitis, were comprehensively evaluated. Leptomeningeal malignancy is clinically very unlikely, supported by negative CSF cytology for malignant tumor cells and the absence of leptomeningeal enhancement on serial gadolinium-enhanced brain-spine MRI. Postprocedural inflammatory myelopathy is also improbable, given that intrathecal pain-relieving intervention was performed approximately 1 month before symptom onset, inconsistent with the typical time course of procedure-related spinal injury. Although EBV sequences were detected in CSF-NGS, there was no clinical
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