Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr-/- mice or in patients with autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder of lymphocyte apoptosis leading to childhood onset of marked lymphadenopathy, hepatosplenomegaly, autoimmune cytopenias, and increased risk of lymphoma. Most cases are associated with heterozygous mutations in the gene encoding Fas protein. Prolonged use of immunosuppressive drugs that do ameliorate its autoimmune complications fail to consistently lessen lymphoproliferation in ALPS. A case series had described children with ALPS, whose spleens (SPL) and lymph nodes decreased in size when treated weekly with pyrimethamine and sulfadoxine; parallel in vitro studies showed only pyrimethamine to promote apoptosis. On the basis of that experience, we undertook additional in vitro lymphocyte apoptosis assays, and measured SPL weights, lymphocyte numbers, and immunophenotypes in Fas-deficient MRL/lpr-/- mice to gain further insights into the utility of combined pyrimethamine/sulfadoxine or pyrimethamine alone. Moreover, seven children with ALPS enrolled in a study of escalating dose of pyrimethamine alone given twice weekly for 12 weeks to determine if their lymphadenopathy and/or splenomegaly would diminish, as assessed by standardized computerized tomography. Neither pyrimethamine alone or with sulfadoxine in the MRL/lpr-/- mice, nor pyrimethamine alone in ALPS patients proved efficacious. We conclude that these drugs do not warrant further use empirically or as part of clinical trials in ALPS Type Ia as a lympholytic agent.

Fluorodeoxyglucose positron emission tomography (FDG-PET) for monitoring lymphadenopathy in the autoimmune lymphoproliferative syndrome (ALPS).

Autoimmune lymphoproliferative syndrome (ALPS) is associated with mutations that impair the activity of lymphocyte apoptosis proteins, leading to chronic lymphadenopathy, hepatosplenomegaly, autoimmunity, and an increased risk of lymphoma. We investigated the utility of fluorodeoxyglucose positron emission tomography (FDG-PET) in discriminating benign from malignant lymphadenopathy in ALPS. We report that FDG avidity of benign lymph nodes in ALPS can be high and, hence, by itself does not imply presence of lymphoma; but FDG-PET can help guide the decision for selecting which of many enlarged nodes in ALPS patients to biopsy when lymphoma is suspected.

Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome.

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of apoptosis associated most often with heritable FAS mutations leading to lymphadenopathy, hypersplenism and chronic refractory autoimmune cytopenias. Mycophenolate mofetil (MMF) was used to treat cytopenias in 13 ALPS patients aged 9 months to 17 years from a cohort of 118 children (aged < 18 years) and 82 adults. Twelve responded for a median follow-up of 49 weeks (range 38-240 weeks), defined by maintenance of adequate blood counts and reduction in dosage or cessation of other immunosuppressive agents. This preliminary experience suggests that MMF may spare steroid usage in patients with ALPS-associated cytopenias.

Bilateral uveitis in a patient with autoimmune lymphoproliferative syndrome.

PURPOSE: We report a case of autoimmune lymphoproliferative syndrome (ALPS) presenting with bilateral uveitis. DESIGN: Observational case report. METHODS: Review of case record, serum and aqueous IL-10 and IL-6 cytokine results, and immunosuppressive treatment of a patient with a mutation in the gene encoding Fas. RESULTS: Control of the intermediate uveitis required sustained doses of topical and periocular corticosteroids as well as systemic cyclosporine. The serum IL-10 level was elevated, as commonly seen in ALPS, but the aqueous IL-10 was not. CONCLUSIONS: Despite a Th2 immune predominance in ALPS, uveitis, a Th1-mediated disease, may still manifest in these patients. The pathogenesis of uveitis in ALPS may differ from that of the systemic disease overall. Long-term follow-up is required for patients with uveitis associated with ALPS.