Widespread Erosions Research Articles

Successful Rituximab Treatment of Severe Pemphigus Vulgaris Resistant to Multiple Immunosuppressants

Sir, Pemphigus vulgaris (PV) is an autoimmune disease characterized by blisters and widespread erosions involving skin and mucous membranes. The disorder is mediated by antibodies, predominantly directed against the epidermal cell adhesion molecules desmoglein 1 and 3. Systemic corticosteroids are the established first-line treatment, but their use is limited due to the well known side effects, especially in long-term treatment. To reduce these side effects, several combinations with other immunosuppressive drugs have been tested in recent years, e.g. azathioprine, methotrexate, mycofenolate mofetil, cyclophosphamide, intravenous immunoglobulins, plasmapheresis and photopheresis. Unfortunately, multiresistant courses exist and present a complex therapeutic challenge. We present here the case of a 55-year-old woman suffering from PV for 13 years. She needed continuous treatment with methylprednisolone doses around 20 mg/ day to prevent widespread blistering. Treatment with azathioprine (2 mg/kg body weight/day for 1 year), cyclophosphamide (1.5 mg/kg body weight/day for 6 months), methotrexate (25 mg/week i.v. for 8 months), mycofenolate mofetil (3 g/day for 1 year) and intravenous immunoglobulins (three cycles of IntraglobinCP using 2 g/kg body weight per cycle) did not improve the clinical picture and was not able to prevent recurrences. Due to long-term steroid treatment, she had severe Cushing’s syndrome including osteoporosis leading to two vertebral fractures with a loss of about 9 cm of her body height. She suffered from steroid-induced diabetes mellitus, glaucoma and arterial hypertension, and experienced an episode of bacterial sepsis necessitating intensive care treatment. When widespread new lesions developed (Fig. 1a) we decided to treat this patient with anti-CD20 monoclonal antibody rituximab (MabThera), as successful treatment of recalcitrant PV had recently been reported (1–4). We applied four weekly cycles of 600 mg rituximab (corresponding to 375 mg/m body surface) within 5 weeks. Additional low-dose oral treatment with methylprednisolone was performed (8 mg/day). Remarkably, her skin lesion cleared up between the second and sixth weeks after the last rituximab cycle (Fig. 1b). Simultaneously, the titre of anti-epithelial antibodies, detected by indirect immunofluorescence, declined from 1:160 to 1:40. Peripheral B cells, counted by flow cytometry, decreased from normal numbers to 2 cells/ml. Severe clinical side effects were not observed. During the clinical follow-up period (now 3 months) no new lesions have appeared. Methylprednisolone dosage could be reduced to 6 mg/day. Our findings in this extremely recalcitrant patient support the clinical efficacy of rituximab for the treatment of severe PV. Further prospective controlled

Novel and recurrent mutations in the laminin-5 genes causing lethal junctional epidermolysis bullosa: molecular basis and clinical course of Herlitz disease

Herlitz disease (H-JEB), the lethal form of junctional epidermolysis bullosa, is a rare genodermatosis presenting from birth with widespread erosions and blistering of skin and mucosae because of tissue cleavage within the epidermal basement membrane. Mutations in any of the three genes encoding the alpha3, beta3 and gamma2 chains of laminin-5 underlie this recessively inherited disorder. Here, we report the molecular basis and clinical course of H-JEB in 12 patients. Two novel nonsense mutations in the gene LAMA3 (E281X and K1299X) and a novel frame-shift mutation in the gene LAMB3 (1628insG) leading to a premature termination codon were identified by DNA sequencing and confirmed by restriction fragment length polymorphism analysis. In the four patients affected, neither the resulting truncated polypeptide chains nor assembled laminin-5 protein were detectable by immunofluorescence. Three patients were found to be heterozygous for the known hotspot mutation R635X and the recurrent mutations Q373X or 29insC in the gene LAMB3, whereas five others were homozygous for R635X. Significant variations in the disease progression and survival times between 1 and 30 months in this group of H-JEB patients emphasised the impact of modifying factors and the importance of immunostaining or mRNA assessment as parallel diagnostic methods. Interestingly, the only patients who survived for longer than 6 months were four females carrying the mutation R635X homozygously. In one of them, the clinical course may have been improved by treatment with artificial skin equivalents. These data may stimulate further investigation of genotype-phenotype correlations and facilitate mutation analysis and genetic counselling of affected families.