- Letter to the Editor
- Open Access
Rituximab and bilateral HSV epithelial keratitis in a patient with mucous membrane pemphigoid
© The Author(s). 2018
- Received: 26 March 2018
- Accepted: 4 July 2018
- Published: 23 August 2018
B cell depleting therapy is widely used for lymphoproliferative diseases and immune-mediated disorders, including mucous membrane pemphigoid. The latter is an autoimmune blistering disease affecting predominantly the mucosae potentially associated with devastating complications.
A 71-year-old patient with severe mucous membrane pemphigoid involving ocular, oral pharyngeal and laryngeal involvement is described. To control the disease, the patient was given rituximab therapy in combination with oral corticosteroids. He subsequently experienced an epithelial herpes simplex virus keratitis in one eye and 3 months later in his fellow eye. Topical treatment with ganciclovir resulted in prompt recovery.
For the first time, a correlation between rituximab and bilateral epithelial herpes simplex virus keratitis is described.
Although rituximab is a promising biologic agent for the treatment of autoimmune diseases, it bears the risk of reactivation of viral infections, including the onset of herpes simplex virus keratitis.
- Epithelial keratitis
- Herpes simplex virus
- Mucous membrane pemphigoid
- Ocular inflammation
Rituximab is a B cell depleting anti-CD20 monoclonal antibody that is increasingly used to treat autoimmune disorders and B cell non-Hodgkin lymphoma. It has become an important therapeutic option for the treatment of refractory mucous membrane pemphigoid [1, 2]. As with other immunosuppressive agents, there is the risk of opportunistic infections or reactivations, including hepatitis B virus and herpes viruses (HSV) [3–5]. Here, we report a potential association between rituximab and de novo corneal infection with HSV.
The clinical diagnosis of mucous membrane pemphigoid was confirmed based on the characteristic clinical features, consistent light microscopy findings and positive immunopathological findings. The direct immunofluorescence microscopy studies showed linear IgG and C3 deposits along the epidermal basement membrane. By indirect immunofluorescence microscopy using saline-split normal human skin as substrate, the patient had circulating autoantibodies reacting against the epidermal side of the split, while the ELISA-BP180 (MBL International, Japan) was positive (49.4 U/mL; normal value < 9 U/L). The lymphocyte count was reduced to 0.8 × 109/L 6 months after the intensification of the immunosuppressive therapy, i.e. 2 months after the onset of HSV keratitis in the right eye.
For the diagnosis of the ocular surface changes, an impression cytology technique was used as described elsewhere (Fig. 2c) . The impressions were processed, using monoclonal antibodies to assess the presence of HSV (fluorescein isothiocyanate-labelled mouse monoclonal antibodies to HSV-1 antigen, Evans Blue counterstain; MicroTrak HSV-1 Culture Identification/Typing Reagent, Trinity Biotech). The impressions were tested positive for HSV-1 in both eyes (Fig. 2d). Ganciclovir gel 1.5 mg/g was applied topically 4×/24 h to treat the superficial HSV keratitis for 10 days. Once the epithelial changes had resolved, a maintenance therapy with ganciclovir gel 1×/24 h was established. No topical steroids were applied.
This is the first report on bilateral epithelial HSV-1 keratitis in a patient with progressive severe mucous membrane pemphigoid. The keratitis first developed in one eye, and 3 months later in the fellow eye. HSV keratitis is usually regarded as a recurrence of a primary infection during childhood. In most cases, it presents as an unilateral condition [7, 8]. A compromised immune system, however, is a well-recognised risk factor for bilateral HSV keratitis [7, 8]. Therefore, patients with autoimmune disorders are at risk while on anti-inflammatory medication. Various immunosuppressive drugs have been linked to the reactivation of viral infections. They have also been reported for rituximab, including reactivations of polyomaviruses, hepatitis B virus and viruses of the herpes group (cytomegalovirus and Epstein-Barr virus) [3, 4]. However, there is no previous report on reactivation of HSV-1 keratitis or de novo corneal infection with HSV-1.
The sequence of therapy change in our patient strongly suggests a causal relation between rituximab use and the development of a first episode of HSV-1 keratitis in one eye, and later in the fellow eye. It is also conceivable that the previous immunosuppressive regimen with steroids and azathioprine has put our patient at additional risk for herpes infection.
Special clinical and laboratory monitoring of patients on immunosuppressive medications including rituximab, a highly effective biologic agent, is mandatory to exclude the development for severe infectious complications, such as in our patient.
The authors thank Dr. Patrick Redli, Institute of Medical Virology, University Zürich, for the immunofluorescence imaging.
BW, main author, conceived the case report and coordinated the manuscript. SS helped in the literature research and helped to draft the manuscript. BL, supervisor, helped to draft the manuscript. All the authors read and approved the final manuscript.
Ethics approval and consent to participate
Consent for publication
The patient has consented to the submission of the case report to the journal.
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
- Le Roux-Villet C, Prost-Squarcioni C, Alexandre M, Caux F, Pascal F, Doan S, Brette MD, Soued I, Gabison É, Letestu R, Laroche L, Bachelez H (2011) Rituximab for patients with refractory mucous membrane pemphigoid. Arch Dermatol 147:843–849View ArticlePubMedGoogle Scholar
- Dart JK (2017) The 2016 Bowman lecture conjunctival curses: scarring conjunctivitis 30 years on. Eye 31:301–332View ArticlePubMedPubMed CentralGoogle Scholar
- Kroll JL, Beam C, Li S et al (2013) Reactivation of latent viruses in individuals receiving rituximab for new onset type 1 diabetes. J Clin Virol 57:115–119View ArticlePubMedPubMed CentralGoogle Scholar
- Aksoy S, Harputluoglu H, Kilickap S et al (2007) Rituximab-related viral infections in lymphoma patients. Leuk Lymphoma 48(7):1307–1312View ArticlePubMedGoogle Scholar
- Schuler S, Brunner M, Bernauer W (2016) Rituximab and acute retinal necrosis in a patient with scleromalacia and rheumatoid arthritis. Ocul Immunol Inflamm 2:96–98View ArticleGoogle Scholar
- Thiel MA, Bossart W, Bernauer W (1997) Improved impression cytology techniques for the immunopathological diagnosis of superficial viral infections. Br J Ophthalmol 81:984–988View ArticlePubMedPubMed CentralGoogle Scholar
- Wilhelmus KR, Falcon MG, Jones BR (1981) Bilateral herpetic keratitis. Br J Ophthalmol 65:385–387View ArticlePubMedPubMed CentralGoogle Scholar
- Souza P Má F, Holland EJ, AJW H (2003) Bilateral herpetic keratoconjunctivitis. Ophthalmology 110:493–496View ArticlePubMedGoogle Scholar