Erythema multiforme (EM) is an immune-mediated hypersensitivity reaction with ‘target lesions’ and, in severe cases, mucosal involvement, distinguishing EM major from minor. It is typically self-limiting, resolving in 7–21 days.1 Severe cases can be life-threatening, with mucosal involvement in 2–10% of patients.1 Infections account for 90% of cases, with herpes simplex virus (HSV)-1 being the most common cause, followed by HSV-2 and Mycoplasma pneumoniae, particularly in children.2 Management focuses on treating the underlying cause, such as antiviral prophylaxis for HSV-associated cases. If antivirals fail or HSV is absent, thalidomide may be effective but has neurological side effects.3 Dapsone has shown efficacy in refractory cases.4 Severe, treatment-resistant EM may require immunosuppressive therapy, including rituximab.3 We present a patient with chronic, refractory EM achieving complete resolution with rituximab after failing multiple therapies, highlighting its potential efficacy in challenging cases.
Case report
A 37-year-old man with chronic, long-standing EM presented to our clinic in February 2017 with recurrent painful ulcers papules and nodules on his bilateral upper and lower extremities after hospital discharge on prednisone taper (Figure 1). His treatment history included dapsone, methotrexate and apremilast, which were all ineffective, while previously effective therapies – doxycycline 100 mg twice daily and hydroxychloroquine 200 mg twice daily – had been discontinued. At the initial visit, he was restarted on these agents and prednisone 50 mg daily with a tapering plan.
Examination revealed active lesions on his right knee and left forearm. The risks of prolonged steroid use and the need for ophthalmological evaluation were discussed. By March 2017, despite prednisone (50 mg daily), persistent flares led to discontinuation of doxycycline and the initiation of ciclosporin (100 mg daily).
Serological studies (anti-neutrophil cytoplasmic antibody, complement levels, antinuclear antibody, anti-dsDNA) were unremarkable, supporting the exclusion of vasculitis, lupus and blistering disorders. Serum protein electrophoresis, cryoglobulins and peripheral flow cytometry for CD19 and CD20 were negative. Elevated Mycoplasma IgG, IgM and anti-streptolysin-O antibody titres warranted further evaluation.
Direct immunofluorescence was positive for scattered IgA and IgM in the epidermis and papillary dermis. Left knee punch biopsy revealed vacuolar interface dermatitis with dyskeratosis and necrosis, consistent with a diagnosis of. Ciclosporin provided partial improvement, allowing prednisone tapering to 40 mg daily by April 2017.
New lesions on the left dorsal hand and forearm in July 2017 prompted the initiation of thalidomide (50 mg nightly) and the discontinuation of hydroxychloroquine and doxycycline. Mycoplasma species infection was ruled out during an infectious disease consultation, although IgG and IgM remained elevated. By September 2017, the patient was only on thalidomide and tapered prednisone.
In November 2017, new outbreaks occurred, despite the tapering regimen. Targetoid papules and plaques on his forearms and hyperpigmented macules on his dorsal hands and legs were noted. Prednisone tapering and thalidomide continued.
By March 2018, active lesions persisted only on his forearms and left knee. Rituximab therapy was considered following negative evidence of haematological malignancies if disease remission failed on the current regimen. In September 2018, further improvement was noted with thalidomide 50 mg nightly and self-tapered prednisone (20 mg daily), although occasional outbreaks persisted.
Intravenous immunoglobulin (IVIg; 1 g−1 kg−1 daily for 2 days every 6 weeks) was initiated until rituximab approval could be acquired, and baby aspirin (81 mg daily) was added for the prevention of thrombosis. Rituximab (1000 mg intravenously) was initiated in June 2019 after hepatitis serology confirmed negative hepatitis B surface antigen and core antibody (anti-HBc). The patient reported no flares right after two infusions 2 weeks apart, allowing for the discontinuation of prednisone and thalidomide.
In December 2019, the patient remained lesion-free without ongoing medications (Figure 2). At a follow-up in December 2024, he continued to be lesion-free and off medications. Laboratory findings showed elevated Mycoplasma species IgG but negative IgM levels, confirming rituximab’s sustained efficacy.
Ongoing monitoring focuses on maintaining remission and assessing laboratory parameters.
Discussion
This case highlights rituximab’s efficacy in chronic, refractory EM after multiple therapies fail. Despite treatment with prednisone, hydroxychloroquine, doxycycline, ciclosporin, thalidomide and IVIg, the patient experienced persistent lesions and recurrent flares. Rituximab infusions led to complete, sustained remission for over 5 years, enabling discontinuation of systemic immunosuppressants.
These findings reinforce rituximab as a viable option in treatment-resistant EM.5 Increasing evidence suggests that B-cell activation and subsequent autoantibody production may play a role in the pathology of EM.3 Rituximab, a monoclonal antibody, works mechanistically by targeting the CD20 antigen on B lymphocytes. This leads to the depletion of B cells, thereby modulating aberrant immune responses.6 In refractory EM, rituximab’s efficacy is hypothesized to result from the reduction of pathogenic antibody production. This mechanism supports its use in EM resistant to conventional therapies.
Although not the first report of rituximab’s utility in EM, this case aligns with Hirsch et al.,3 who documented successful outcomes in five patients with chronic EM that was unresponsive to standard treatments. Our case substantiates these findings, demonstrating rituximab’s role in durable remission. This supports the hypothesis that targeting CD20-mediated immune dysregulation may effectively manage severe EM where conventional interventions fail.5
This case report highlights rituximab’s pivotal role in the treatment of chronic, refractory EM by achieving long-term remission through the reduction of Mycoplasma species IgM antibody levels. These findings add to the growing evidence supporting rituximab’s efficacy and emphasize its consideration in cases unresponsive to mainstream therapies. Further studies are essential to develop standardized treatment protocols and identify the patient populations most likely to benefit from this approach.