Autoimmune lymphoproliferative syndrome: A disorder of immune dysregulation.

Autoimmune Lymphoproliferative Syndrome (ALPS) is an autoimmune disease that has been reported in over 2200 patients. It is a rare, genetic disease where pathogenic variants occur in the extrinsic pathway of apoptosis. Various mutations in different genes, such as FAS, FASL, and CASP10, can result in ALPS. Most commonly, pathogenic variants occur in the FAS receptor. This malfunctioning pathway allows for the abnormal accumulation of lymphocytes, namely CD3 + TCRαß+CD4 - CD8- (double negative (DN) T) cells, which are a hallmark of the disease. This disease usually presents in childhood with lymphadenopathy and splenomegaly as a result of lymphoproliferation. Over time, these patients may develop cytopenias or lymphomas because of irregularities in the immune system. Current treatments include glucocorticoids, mycophenolate mofetil, sirolimus, immunoglobulin G, and rituximab. These medications serve to manage the symptoms and there are no standardized recommendations for the management of ALPS. The only curative therapy is a bone marrow transplant, but this is rarely done because of the complications. This review serves to broaden the understanding of ALPS by discussing the mechanism of immune dysregulation, how the symptoms manifest, and the mechanisms of treatment. Additionally, we discuss the epidemiology, comorbidities, and medications relating to ALPS patients across the United States using data from Cosmos.

Ankle-Brachial Index and Subsequent Risk of Severe Ischemic Leg Outcomes: The ARIC Study.

Background Ankle-brachial index (ABI) is used to identify lower-extremity peripheral artery disease (PAD). However, its association with severe ischemic leg outcomes (eg, amputation) has not been investigated in the general population. Methods and Results Among 13 735 ARIC (Atherosclerosis Risk in Communities) study participants without clinical manifestations of PAD (mean age, 54 [SD, 5.8] years; 44.4% men; and 73.6% White) at baseline (1987-1989), we quantified the prospective association between ABI and subsequent severe ischemic leg outcomes, critical limb ischemia (PAD with rest pain or tissue loss) and ischemic leg amputation (PAD requiring amputation) according to discharge diagnosis. Over a median follow-up of ≈28 years, there were 221 and 129 events of critical limb ischemia and ischemic leg amputation, respectively. After adjusting for demographics, ABI ≤0.90 versus 1.11 to 1.20 had a ≈4-fold higher risk of critical limb ischemia and ischemic leg amputation (hazard ratios, 3.85 [95% CI, 2.09-7.11] and 4.39 [95% CI, 2.08-9.27]). The magnitude of the association was modestly attenuated after multivariable adjustment (hazard ratios, 2.44 [95% CI, 1.29-4.61] and 2.72 [95% CI, 1.25-5.91], respectively). ABI 0.91 to 1.00 and 1.01 to 1.10 were also associated with these severe leg outcomes, with hazard ratios ranging from 1.7 to 2.0 after accounting for potential clinical and demographic confounders. The associations were largely consistent across various subgroups. Conclusions In a middle-aged community-based cohort, lower ABI was independently and robustly associated with increased risk of severe ischemic leg outcomes. Our results further support ABI ≤0.90 as a threshold diagnosing PAD and also suggest the importance of recognizing the prognostic value of ABI 0.91 to 1.10 for limb prognosis.