Immunodysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome (IPEX) Medication
- Author: Satyen M Gada, MD; Chief Editor: Harumi Jyonouchi, MD more...
Hematopoietic stem cell transplantation (HSCT) is the only curative therapy for immunodysregulation polyendocrinopathy enteropathy X-linked (IPEX) syndrome.[24, 25] However, numerous medications are used to treat the various disease associations.
Medications should be used on an individual basis with consideration of the particular disease targeted and individual response to therapy. Diabetes is treated with replacement insulin. Thyroid disease may be treated with either replacement thyroid hormone or antithyroid medications, depending on the underlying thyroid condition. Topical steroids and anti-inflammatory medications are used to treat the dermatitis associated with IPEX syndrome. Cytopenias can be treated with granulocyte-colony stimulating factor (G-CSF), corticosteroids, or replacement blood products in more severe cases. Infections associated with IPEX syndrome usually respond to antibiotics, antiviral, or antifungal therapy. These medications can be targeted against the specific pathogen, if known.
Immunosuppressive medications are the mainstay of treatment for the enteropathy associated with IPEX syndrome. Medications that have been reported to reduce GI symptoms include high-dose corticosteroids, cyclosporin A, tacrolimus, sirolimus, infliximab, and rituximab. None of these medications have demonstrated remission, although sirolimus has demonstrated sustained symptom reduction for as long as 5 years. The side effects of these medications include infectious complications, risk of malignancy, and end-organ toxicity. Because IPEX syndrome is rare, no large-scale comparative studies of these medications have been performed, and optimal dosing has not been established.
These agents modify immune processes that promote inflammation, without causing generalized immunosuppression.
Antibody genetically engineered. Chimeric murine/human monoclonal antibody directed against the CD20 antigen found on surface of B-lymphocytes. It eliminates circulating CD20+ B cells with resultant reduction of autoantibody production and B cell (as an antibody presenting cells) mediated immune activation.
Chimeric IgG1k monoclonal antibody that neutralizes cytokine TNF-α and inhibits its binding to TNF-α receptor. Reduces infiltration of inflammatory cells and TNF-α production in inflamed areas. Used with methotrexate in patients that have had inadequate response to methotrexate monotherapy.
Selective inhibitors of T-cell lymphocytes (eg, cyclosporine) suppress early cellular response to antigenic and regulatory stimuli.
Traditionally, high-dose steroids were thought to be lympholytic, but recent studies have suggested that steroids may inhibit T-cell proliferation and T-cell–dependent gene expression of cytokines. They produce nonspecific anti-inflammatory effects and antiadhesion effects that contribute to immune suppression.
An 11-amino acid cyclic peptide and natural product of fungi. Acts on T-cell replication and activity. Specific modulator of T-cell function and an agent that depresses cell-mediated immune responses by inhibiting T-cell function by blocking a Ca/calmodulin-NFAT mediated signaling pathway. Preferential and reversible inhibition of T lymphocytes in G0 or G1 phase of cell cycle suggested.
Binds to cyclophilin, an intracellular protein, which, in turn, prevents T-cell activation, transcription of T-cell cytokines, and the subsequent recruitment of activated T cells. Has about 30% bioavailability, but marked interindividual variability is noted. Specifically inhibits T-lymphocyte function with minimal activity against B cells. Maximum suppression of T-lymphocyte proliferation requires that drug be present during first 24 h of antigenic exposure.
Suppresses some humoral immunity and, to a greater extent, cell-mediated immune reactions (eg, delayed hypersensitivity, allograft rejection, experimental allergic encephalomyelitis, and graft versus host disease) for various organs.
Immunomodulator produced by the bacteria Streptomyces tsukubaensis. Mechanisms of action similar to cyclosporine. Primarily used in transplants but used in Behçet disease to treat uveitis.
Inhibits lymphocyte proliferation by interfering with signal transduction pathways. Binds to immunophilin FKBP12 to block action of mTOR. FDA approved for prophylaxis of organ rejection in patients receiving allogeneic renal allografts.
Prednisone or other systemic corticosteroids elicit immunosuppression for treatment of autoimmune disorders; may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Stabilizes lysosomal membranes and also suppresses lymphocyte and antibody production.
Bennett CL, Ochs HD. IPEX is a unique X-linked syndrome characterized by immune dysfunction, polyendocrinopathy, enteropathy, and a variety of autoimmune phenomena. Curr Opin Pediatr. 2001 Dec. 13(6):533-8. [Medline].
Torgerson TR, Ochs HD. Regulatory T cells in primary immunodeficiency diseases. Curr Opin Allergy Clin Immunol. 2007 Dec. 7(6):515-21. [Medline].
Wildin RS, Smyk-Pearson S, Filipovich AH. Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2002 Aug. 39(8):537-45. [Medline].
Sharma R, Ju ST. Genetic control of the inflammatory T-cell response in regulatory T-cell deficient scurfy mice. Clin Immunol. 2010 Aug. 136(2):162-9. [Medline].
Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: forkhead box protein 3 mutations and lack of regulatory T cells. J Allergy Clin Immunol. 2007 Oct. 120(4):744-50; quiz 751-2. [Medline].
van der Vliet HJ, Nieuwenhuis EE. IPEX as a result of mutations in FOXP3. Clin Dev Immunol. 2007. 2007:89017. [Medline]. [Full Text].
Su MA, Anderson MS. Monogenic autoimmune diseases: insights into self-tolerance. Pediatr Res. 2009 May. 65(5 Pt 2):20R-25R. [Medline]. [Full Text].
Otsubo, K, H Kanegane, Y Kamachi, I Kobayashi, I Tsuge, et al. Identification of FOXP3-negative regulatory T-like (CD4+CD25+CD127low) cells in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Clinical Immunology. 2011. 141:111-120.
Passerini L, Di Nunzio S, Gregori S, et al. Functional type 1 regulatory T cells develop regardless of FOXP3 mutations in patients with IPEX syndrome. Eur J Immunol. 2011 Apr. 41(4):1120-31. [Medline]. [Full Text].
d'Hennezel E, Bin Dhuban K, Torgerson T, Piccirillo CA, Piccirillo C. The immunogenetics of immune dysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet. 2012 May. 49(5):291-302. [Medline].
Kinnunen T, Chamberlain N, Morbach H, Choi J, Kim S, Craft J. Accumulation of peripheral autoreactive B cells in the absence of functional human regulatory T cells. Blood. 2013 Feb 28. 121(9):1595-603. [Medline].
Moraes-Vasconcelos D, Costa-Carvalho BT, Torgerson TR, Ochs HD. Primary immune deficiency disorders presenting as autoimmune diseases: IPEX and APECED. J Clin Immunol. 2008 May. 28 Suppl 1:S11-9. [Medline].
Patey-Mariaud de Serre N, Canioni D, Ganousse S, Rieux-Laucat F, Goulet O, Ruemmele F, et al. Digestive histopathological presentation of IPEX syndrome. Mod Pathol. 2009 Jan. 22(1):95-102. [Medline].
Nieves DS, Phipps RP, Pollock SJ, Ochs HD, Zhu Q, Scott GA, et al. Dermatologic and immunologic findings in the immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Arch Dermatol. 2004 Apr. 140(4):466-72. [Medline].
Myers AK, Perroni L, Costigan C, Reardon W. Clinical and molecular findings in IPEX syndrome. Arch Dis Child. 2006 Jan. 91(1):63-4. [Medline]. [Full Text].
Gambineri E, Perroni L, Passerini L, Bianchi L, Doglioni C, Meschi F, et al. Clinical and molecular profile of a new series of patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: inconsistent correlation between forkhead box protein 3 expression and disease severity. J Allergy Clin Immunol. 2008 Dec. 122(6):1105-1112.e1. [Medline].
Barzaghi F, Passerini L, Gambineri E, Ciullini Mannurita S, Cornu T, Kang ES, et al. Demethylation analysis of the FOXP3 locus shows quantitative defects of regulatory T cells in IPEX-like syndrome. J Autoimmun. 2012 Feb. 38(1):49-58. [Medline]. [Full Text].
Ochs HD, Gambineri E, Torgerson TR. IPEX, FOXP3 and regulatory T-cells: a model for autoimmunity. Immunol Res. 2007. 38(1-3):112-21. [Medline].
Verbsky JW, Chatila TA. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) and IPEX-related disorders: an evolving web of heritable autoimmune diseases. Curr Opin Pediatr. 2013 Dec. 25(6):708-14. [Medline].
Lampasona V, Passerini L, Barzaghi F, Lombardoni C, Bazzigaluppi E, Brigatti C, et al. Autoantibodies to harmonin and villin are diagnostic markers in children with IPEX syndrome. PLoS One. 2013. 8(11):e78664. [Medline]. [Full Text].
Le Bras S, Geha RS. IPEX and the role of Foxp3 in the development and function of human Tregs. J Clin Invest. 2006 Jun. 116(6):1473-5. [Medline]. [Full Text].
Halabi-Tawil M, Ruemmele FM, Fraitag S, Rieux-Laucat F, Neven B, Brousse N, et al. Cutaneous manifestations of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Br J Dermatol. 2009 Mar. 160(3):645-51. [Medline].
Zennaro D, Scala E, Pomponi D, Caprini E, Arcelli D, Gambineri E, et al. Proteomics plus genomics approaches in primary immunodeficiency: the case of immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Clin Exp Immunol. 2012 Jan. 167(1):120-8. [Medline]. [Full Text].
Bae KW, Kim BE, Choi JH, Lee JH, Park YS, Kim GH, et al. A novel mutation and unusual clinical features in a patient with immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. Eur J Pediatr. 2011 Dec. 170(12):1611-5. [Medline].
Kasow KA, Morales-Tirado VM, Wichlan D, Shurtleff SA, Abraham A, Persons DA, et al. Therapeutic in vivo selection of thymic-derived natural T regulatory cells following non-myeloablative hematopoietic stem cell transplant for IPEX. Clin Immunol. 2011 Nov. 141(2):169-76. [Medline]. [Full Text].
Rao A, Kamani N, Filipovich A, Lee SM, Davies SM, Dalal J, et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007 Jan 1. 109(1):383-5. [Medline].
Passerini L, Mel ER, Sartirana C, Fousteri G, Bondanza A, Naldini L, et al. CD4+ T cells from IPEX patients convert into functional and stable regulatory T cells by FOXP3 gene transfer. Sci Transl Med. 2013 Dec 11. 5(215):215ra174. [Medline].
Gambarara M, Bracci F, Diamanti A, Ambrosini MI, Pietrobattista A, Knafelz D, et al. Long-term parenteral nutrition in pediatric autoimmune enteropathies. Transplant Proc. 2005 Jun. 37(5):2270-1. [Medline].
Harbuz R, Lespinasse J, Boulet S, Francannet C, Creveaux I, Benkhelifa M, et al. Identification of new FOXP3 mutations and prenatal diagnosis of IPEX syndrome. Prenat Diagn. 2010 Nov. 30(11):1072-8. [Medline].