Sirolimus (rapamycin) is a Federal Drug Administration-approved immunosuppressant that targets mTOR. Sirolimus has been in clinical use for over 20 years and its toxicities are well-described (Abdel-Karim & Giles, 2008
). We hypothesized that mTOR inhibitors would be effective in patients with ALPS for three compelling reasons: (i) mTOR inhibitors induce cell death and apoptosis in abnormal lymphocytes; (ii) mTOR inhibitors, unlike most other immunosuppressive medications, increase peripheral blood regulatory T cells (Tregs) and (iii) mTOR inhibitors are safe and well-tolerated.
Common toxicities found in patients taking sirolimus include hypercholesterolemia, hypertension and mucositis (Abdel-Karim & Giles, 2008
). An increased risk of infections is very rare when used as a single agent; however, when combined with other immunosuppressive agents the risk increases. Sirolimus requires therapeutic drug monitoring to maximize effect and avoid toxicity.
Treatment for patients with refractory ALPS is challenging. Many patients do not require chronic treatment, but for those patients who do there are only a few effective and tolerable agents. Currently a number of more targeted therapies are undergoing preclinical testing and clinical trials. Pyrimethamine and sulphadoxine were shown to reduce lymphoproliferation and autoimmune cytopenias significantly in a small series of patients with ALPS; however, this combination failed to show any response in a different larger clinical trial (Ferrer et al, 2007
). We have also recently shown that targeting the Notch signaling pathway may be beneficial in preclinical models of ALPS (Teachey et al, 2008
), while other groups have shown that arsenic and histone deacetylase-inhibitors may be effective in preclinical models of ALPS (Ferrer et al, 2007
). As with many autoimmune diseases, rituximab has been shown to be effective in a subset of ALPS patients; however, 5–10% of ALPS patients eventually develop common variable immunodeficiency (CVID) and our group (unpublished observations) and others have seen an association between rituximab use and the development of CVID in ALPS patients (Dale et al, 2007
). Moreover, the effects of rituximab are generally relatively transient; patients that do respond will probably relapse and with the potential risk of CVID, we recommend avoiding use of rituximab in ALPS patients. MMF was found to be effective in another series (Koneti Rao et al, 2005
). While we have had less success overall with this drug, we have also seen good responses in a few children with ALPS treated with MMF (unpublished data).
MMF inhibits lymphocyte proliferation but does not cause lymphocyte death and does not appear to increase Tregs (Noris et al, 2007
). Tregs are a subset of T lymphocytes that suppress the activation of the immune system and increasing Treg numbers may improve autoimmune diseases (Brusko et al, 2008
). Interestingly, some evidence suggests that peripheral blood DNTs may be dysregulated Tregs, while other evidence suggests they are cytotoxic T lymphocytes that have lost CD8 expression (Bleesing et al, 2001
; Fischer et al, 2005
). We have found mTOR inhibition decreases these abnormal DNTs in ALPS patients. Sirolimus has been shown to increase Tregs in healthy volunteers and patients with other autoimmune diseases (Battaglia et al, 2006
). These observations, taken together, suggest the possibility that the improved responses with sirolimus seen here compared to other immunosuppressive agents, both in preclinical models and in patients, may be attributable to both induction of apoptosis in the abnormal lymphocytes and increases in normal Tregs. In subsequent patients, we plan to measure Tregs before and after initiating treatment with sirolimus. Unfortunately, as DNTs do not survive in culture, we could not directly test the in-vitro
sensitivity of ALPS-patient’s DNTs to sirolimus.
As sirolimus can cause lymphocyte apoptosis and increase Tregs, it may also have activity in non-ALPS patients with autoimmune cytopenias, including patients with immune thrombocytopenia purpura (ITP), autoimmune hemolytic anemia (AIHA) and autoimmune neutropenia, either as isolated idiopathic conditions or when associated with other autoimmune syndromes, including lupus or Evans syndrome. Our findings suggest that sirolimus may be superior to other agents currently used for or being investigated in these syndromes, including mercaptopurine, MMF, cyclosporine and tacrolimus. None of these agents are both lymphotoxic to both B and T cells while simultaneously increasing Tregs. Accordingly, we plan to open a clinical trial investigating the efficacy of sirolimus in patients with chronic ITP and chronic AIHA.
We found sirolimus was very effective in ameliorating autoimmune disease and lymphoproliferation in patients with ALPS, corroborating our previous preclinical work. Based on these results, we plan to continue to treat patients with ALPS and either steroid-refractory disease or who are steroid-intolerant with sirolimus and we have initiated a phase II efficacy trial of sirolimus in ALPS. Based on this trial, we anticipate that sirolimus may move to the frontline of therapy for patients with ALPS.