Adverse Dermatological Reaction to Mycophenolate Mofetil in a Patient with Systemic Lupus Erythematosus: A Case Report

Introduction

Mycophenolate mofetil (MMF) is an immunosuppressive agent that inhibits inosine monophosphate dehydrogenase. T lymphocytes and B lymphocytes are more dependent on this pathway, so MMF can selectively inhibit their proliferation [1]. MMF is widely used to prevent rejection in solid-organ transplantation and to treat autoimmune diseases, including systemic lupus erythematosus (SLE). It is generally considered to have a good safety profile, with common adverse effects including gastrointestinal reactions, bone marrow suppression, and infections [2–4]. However, MMF-induced drug eruptions are rarely reported.

About 70–85% of SLE patients will have skin manifestations, presenting as malar rash in the zygomatic region; symmetrical papular psoriatic rashes affecting the trunk and upper limbs can also be seen, and acute episodes often predominate in sun-exposed areas [5]. Due to the diversity of SLE skin lesions, the differential diagnosis of drug-induced dermatitis is more complicated.

This report describes the case of a 50-year-old woman with a 6-year history of SLE, presenting with a 6-day history of fever and skin rash after starting treatment with MMF. The report follows the CARE guidelines. The patient gave informed consent for publication of the case and the Hospital Ethics Committee approved the reporting.

Case Report

A 50-year-old female patient was admitted to the Rheumatology Department of Changji Prefecture People’s Hospital in Xinjiang on July 18, 2024, with the chief concern of intermittent polyarthritis for over 6 years and fever for 6 days. She had a confirmed history of SLE, lupus nephritis, lupus arthritis, and primary biliary cholangitis. She had been on long-term treatment with methylprednisolone, cyclosporine, ursodeoxycholic acid, calcium carbonate, and calcitriol.

In February 2024, she adjusted her cyclosporine dosage to 50 mg every 2 weeks due to elevated blood pressure, but did not inform her physician of this change during follow-up visits. SLE flare was suspected, and Tripterygium wilfordii glycoside tablets, 20 mg, twice daily were prescribed. On July 2, MMF 0.5 g, twice daily, was added to the treatment regimen due to uncontrolled SLE. On July 18, she had fever (39–40°C), chills, cough, and occasional white sticky sputum. Physical examination revealed facial flushing but no rash, and auscultation of the lungs revealed coarse breath sounds and scattered moist rales at the lung bases. On July 18, laboratory tests showed leukopenia (2.80×109/L), elevated C-reactive protein (20.80 mg/L), positive influenza A virus IgM antibodies (194.69 AU/ml), complement C3 0.53 g/L, complement C4 0.09 g/L, and 24-hour urine protein quantitative 0.31 g/24 h. Chest CT scan showed a small amount of right-sided pleural effusion. On July 18, she was treated with oseltamivir phosphate and levofloxacin, and MMF was discontinued. Methylprednisolone, ursodeoxycholic acid, cyclosporine, and Tripterygium wilfordii glycosides were continued. On July 20, her fever resolved, and she was afebrile for 2 days.

On July 24, laboratory tests showed white blood cell count was 2.37×109/L and C-reactive protein level was 11.30 mg/L. Due to persistent SLE activity and cyclosporine intolerance due to hypertension, treatment was switched to methylprednisolone 28 mg daily and MMF 0.75 g twice daily, as MMF is a first-line therapeutic drug for lupus nephritis. She developed nausea, vomiting, fever (39°C), and a diffuse erythematous rash on the face, trunk, and upper limbs after taking MMF. The rash was characterized by ill-defined, coalescing patches, with normal skin temperature and blanching on pressure, accompanied by itching. It was diagnosed by the Dermatology Department as drug-induced dermatitis-exanthematous drug eruption (Figures 1–3). Levofloxacin and MMF were discontinued, and the patient was treated with intravenous methylprednisolone 60 mg and antihistamines. The fever resolved within 2 days, and the rash began to fade after 8 days of treatment. In August 2024, she was given MMF again. She developed nausea, vomiting, fever (38.4°C), and a recurrence of the rash within 1 hour of taking MMF. The rash was similar in appearance to the previous episode, with additional conjunctival edema and congestion on the next day. MMF was then discontinued. Her fever resolved within 1 day, and the rash disappeared after 5 days. She was discharged from the hospital and followed up for 2 months, without recurrence of the rash.

The patient had been on MMF for approximately 10 days before admission with a rash. After admission, the fever was considered to be related to infection, and MMF was discontinued. She received antiviral and antibacterial therapy, and her fever resolved. During subsequent treatment, MMF was reintroduced twice, and each time she developed fever, nausea, vomiting, and a rash with the same characteristics. Based on the temporal relationship and the clinical presentation, it was concluded that the drug-induced dermatitis was likely caused by MMF.

The differential diagnoses included SLE disease activity, infectious rash, and other drug allergies. First, the absence of characteristic skin manifestations of SLE (such as malar rash, photosensitivity), and the lack of improvement in the rash after increasing the dosage of methylprednisolone, were inconsistent with the characteristics of lupus rash. Second, although she tested positive for influenza A IgM, viral rashes are mostly self-limiting and should not reappear after re-exposure to MMF. Third, although levofloxacin and Tripterygium glycosides tablets can cause drug eruptions, the former had been discontinued before the first rash occurred, and the latter had been taken by the patient for a long time without skin adverse reactions. Although she did not undergo a skin biopsy, the characteristic clinical features and the recurrence of the second rash after re-exposure to MMF strongly support the diagnosis of MMF allergy rather than other etiologies (Table 1).

Discussion

Our patient developed dermatitis after MMF treatment, which was rare and characterized by fever, nausea, vomiting, and a diffuse erythematous rash. Her symptoms resolved after discontinuation of MMF and treatment with corticosteroids and antihistamines. Early recognition and discontinuation of MMF are crucial to managing MMF-induced dermatitis and preventing long-term complications.

Our patient with SLE developed drug-induced rash after receiving MMF, highlighting a rare adverse reaction with non-negligible clinical risks. Mild drug-induced dermatitis can present as self-limiting symptoms such as maculopapules and pruritus, but in severe cases it can progress to Stevens-Johnson syndrome or toxic epidermal necrolysis. The latter has a mortality rate of up to 30%, and milder reactions (such as maculopapular rashes) may be the initial manifestation of more severe drug adverse reactions [6,7].

MMF is metabolized into mycophenolic acid in the body, which selectively inhibits lymphocyte proliferation by suppressing inosine monophosphate dehydrogenase. It is a first-line treatment for lupus nephritis. Common adverse effects of MMF include gastrointestinal reactions, bone marrow suppression, diarrhea, and infections, with drug eruptions being rarely reported [1,2,8]. The mechanisms underlying MMF-induced dermatitis may involve multiple aspects. Severe cutaneous drug reactions are characterized as drug-specific T cell-mediated diseases, where immune receptors and mediators play a crucial role in their development [9]. Studies have shown that CD4+ T cell activation leads to maculopapular reactions, while CD8+ T cell activation is more commonly associated with bullous skin reactions such as Stevens-Johnson syndrome/toxic epidermal necrolysis [10]. Levin reported a case of papulosquamous psoriasiform rash following MMF use in a patient with myasthenia gravis, with pathological findings of lymphocytic infiltration and clinical manifestations/lesion distribution similar to psoriasiform dermatitis, suggesting an immune-mediated mechanism [11]. Additionally, individual genetic predisposition such as specific HLA alleles [12], and impaired skin barrier function and dysbiosis of the skin microbiota may contribute to the development of MMF-related drug-induced dermatitis [13].

This patient presented with macules and pruritus, consistent with the milder reaction patterns described in the literature [14]. Georgesen et al reported a case of a generalized fixed drug eruption associated with MMF. The patient developed a widespread, erythematous rash that was temporally related to MMF administration. The rash resolved upon discontinuation of the drug and reappeared upon rechallenge, confirming the causality [15]. Avoiding rechallenge is recommended following a fixed drug eruption, as subsequent exposure carries the risk of inducing serious skin reactions. Chen et al reported a case of acute generalized exanthematous pustulosis induced by MMF in a patient with pemphigus foliaceus. The patient developed widespread pustular lesions shortly after starting MMF, which resolved upon discontinuation of the drug [16]. This case is notable for the severity of the reaction and the rapid onset.

Conclusions

Although MMF-induced dermatitis is a rare adverse effect, the present case and other reports highlight the potential for MMF to cause severe skin reactions, which clinicians should be aware of to ensure patient safety. The underlying mechanisms are complex and diverse. Early recognition and discontinuation of MMF are crucial to managing these adverse events and preventing long-term complications.