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

Abstract

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/lpr2/2 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/lpr2/2 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. Am.

FAS-L, IL-10, and double-negative CD4−CD8− TCR α/β+ T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function

“…We confirmed in this ALPS cohort that the IL-10 concentration was variably but significantly increased in the plasma of FAS-mutated patients as previously described. 11,15,16 It was only moderately elevated in some ALPS-like patients ( Figure 1C). We occasionally noticed slightly elevated plasma IL-10 values in a few healthy relatives.…”

Natural history of autoimmune lymphoproliferative syndrome associated with FAS gene mutations

“…Lymphadenopathy and splenomegaly were assessed longitudinally by physical examination and computerized tomography (CT) and scored as grade 1 to 4 using consistent in-house practices and published criteria. [34][35][36] Spleen size and volume were calculated from manually segmented axial slices from CT images. Patients developing a grade 3 or 4 cytopenia within 2 years of the onset of their symptoms were considered to have severe disease.…”

How I treat autoimmune lymphoproliferative syndrome

“…Following grading guidelines with a lymph node matrix covering all groups of nodes (eg, cervical, axillary, inguinal) are used in our clinic for longitudinal follow-up of these patients over many years: grade 1 indicates few shotty nodes; grade 2, multiple 1-to 2-cm nodes; grade 3, multiple nodes, some more than 2 cm; and grade 4, extensive visible adenopathy. 55 This grading is performed using physical examination and periodic (biannual or as necessary) CT scan evaluations of neck, chest, abdomen, and pelvis ( Figure 3). Clinically, splenomegaly is documented by consistently measuring its palpable extent below costal margin in the midclavicular line; nowadays, a more accurate serial volumetric assessment of splenomegaly can also be made from 3-dimensional reconstructions of CT scans (Figure 4).…”