Medication Summary
Agents used to treat autoimmune lymphoproliferative syndrome (ALPS) include immunosuppressants and immune globulins.
Immunosuppressant Agents
Class Summary
Initial therapy for autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP) includes corticosteroids. In refractory autoimmune cytopenias necessitating long-term steroid therapy, mycophenolate mofetil and tacrolimus have been shown to be effective steroid-sparing agents.
Prednisone (Deltasone, Rayos)
Prednisone is useful for treating inflammatory and allergic reactions; it may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear leukocyte (PMN) activity. It is the drug of choice for all adult patients with platelet counts below 50,000/µL. Asymptomatic patients with platelet counts higher than 20,000/µL or patients with counts of 30,000-50,000/µL with only minor purpura may not need therapy; withholding medical therapy may be appropriate for asymptomatic patients, regardless of platelet count.
Methylprednisolone (Solu-Medrol, Depo-Medrol, Medrol)
Methylprednisolone decreases inflammation by suppressing migration of PMNs and reversing increased permeability. It is used as the alternative glucocorticoid of choice for all patients with severe life-threatening bleeding or children with platelet counts below 30,000/µL. Careful observation without medical treatment may be appropriate in some asymptomatic children.
Prednisolone (Orapred, Pediapred, Millipred)
Corticosteroids act as potent inhibitors of inflammation. They may cause profound and varied metabolic effects, particularly in relation to salt, water, and glucose tolerance, in addition to their modification of the immune response of the body. Alternative corticosteroids may be used in equivalent dosage. It is used in all patients with severe life-threatening bleeding or children with platelet counts below 30,000/µL. Careful observation without medical treatment may be appropriate in some asymptomatic children.
Mycophenolate (CellCept, Myfortic)
Mycophenolate inhibits inosine monophosphate dehydrogenase (IMPDH) and suppresses de novo purine synthesis by lymphocytes, thereby inhibiting their proliferation. It inhibits antibody production. Two formulations are available; they are not interchangeable. The original formulation, mycophenolate mofetil (CellCept) is a prodrug that, once hydrolyzed in vivo, releases the active moiety, mycophenolic acid. A newer formulation, mycophenolic acid (Myfortic), is an enteric-coated product that delivers the active moiety.
Sirolimus (Rapamune)
Sirolimus inhibits a mammalian target of rapamycin (mTOR), a kinase that play a fundamental role in regulating the progression of the cell cycle and disrupts proliferation of T cells. Sirolimus monotherapy is a safe and effective steroid-sparing agent with rapid improvement of lymphoproliferation, autoimmunity and normalized biomarkers including Vit B12, IL-10, and soluble FASLG. A dose of 2.5mg/m2 daily can achieve a trough level of 5-15ng/ml. The well-known side effects are oral mucositis, hyperlipidemia, decreased renal function, myelosuppression, and drug-drug interaction.
Immune Globulin
Class Summary
High-dose (1-2 g/kg IV) immune globulin may be considered for concomitant use with pulse-dose corticosteroids in those with severe AIHA.
Immune globulin intravenous (Bivigam, Carimune NF, Octagam, Gammaplex, Gammagard, Privigen, Panzyga, Gamunex-C)
Immune globulin intravenous is given as a temporary measure to increase platelets. It neutralize circulating myelin antibodies through anti-idiotypic antibodies; down-regulates proinflammatory cytokines, including interferon gamma; blocks Fc receptors on macrophages; suppresses inducer T and B cells while augmenting suppressor T cells; blocks the complement cascade; promotes remyelination; and may increase immunoglobulin G (IgG) in cerebrospinal fluid (10% of cases).
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Examples of an autoimmune lymphoproliferative syndrome (ALPS) in a patient with grade IV (visible) lymphadenopathy.
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Autoimmune lymphoproliferative syndrome (ALPS) and ALPS-related disorders classification:
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Primary and accessory diagnostic criteria for autoimmune lymphoproliferative syndrome (ALPS).
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A patient with autoimmune lymphoproliferative syndrome (ALPS) who developed pneumococcal sepsis, a serious complication secondary to neutropenia and asplenia. Note the patient's cochlear implant; he has neurosensory hearing loss from prior episode of pneumococcal meningitis.
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Positron emission tomography (PET) superimposed over a CT scan from a patient with autoimmune lymphoproliferative syndrome (ALPS). Note the massive cervical adenopathy. PET scans may be used as a screening tool in patients with autoimmune lymphoproliferative syndrome to decrease the number of lymph node biopsies used in screening for malignancy.
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The extrinsic pathway of apoptosis. Mutations have been identified in each of the genes coding for Fas, Fas-ligand (FasL), caspase-8, and caspase-10. This figure was previously published in Rao VK, Straus SE. Autoimmune Lymphoproliferative Syndrome. Clinical Hematology. 58;759. 2006: Elsevier.
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Suggested treatment algorithm for patients with autoimmune lymphoproliferative syndrome (ALPS). This schematic diagram is included only as a suggested guideline for managing children with autoimmune lymphoproliferative syndrome–associated autoimmune multilineage cytopenias. Use of granulocyte-colony stimulating factor (G-CSF) may be warranted for severe neutropenia associated with systemic infections. Similarly, use of other chemotherapeutic and immunosuppressive agents (eg, vincristine, methotrexate, mercaptopurine, azathioprine, cyclosporine, hydroxychloroquine, tacrolimus, sirolimus) besides mycophenolate mofetil (MMF) should be considered as a steroid-sparing measure or while avoiding or postponing surgical splenectomy at the discretion of the treating clinicians based on the circumstances of a specific patient.
Tables
| Disease | Mutation | Clinical Features |
|---|---|---|
| Caspase-8 deficiency state (CEDS) | Autosomal recessive/ LOF mutation in CASP8 gene (2q33.1) | Recurrent sinopulmonary infections, severe mucocutaneous herpes simplex viral infection with defects in activation of T, B and NK cells, hypogammaglobulinemia, low pneumococcal antibodies, low T cell function (lymphocyte mitogen stimulation), low NK function [18] |
| FADD deficiency | Autosomal recessive/ LOF mutation in FADD gene (11q13.3) | Susceptibility to bacterial and viral infections related to functional hyposplenism and impaired interferon immunity, congenital heart disease, recurrent fever, liver dysfunction, seizures [19] |
| Ras-associated autoimmune leukoproliferative disorder | Germline or somatic mutations/ GOF mutation in NRAS gene (1p13.2) and KRAS gene (12p12.1) | Lymphadenopathy, massive splenomegaly, increased circulating B cells, hypergammaglobulinemia, autoimmunity [20, 21, 22] |
| Dianzani autoimmune lymphoproliferative disease | N252S and A91B perforin gene variations, osteopontin polymorphism | No increased DNT, defective Fas, lymphadenopathy, splenomegaly, autoimmunity [23, 24] |
| Activated phosphoinositide 3-kinase δ syndrome (APDS) | Autosomal dominant/ gain of function mutations in PIK3CD (1p36.22), PIK3R1(5q13.1) | Combined immunodeficiency with recurrent sinopulmonary infections, lymphadenopathy, herpesvirus infection, autoinflammatory disease, lymphoma and neurodevelopmental delay [25] |
| Protein kinase C delta (PRKCD) deficiency | Autosomal recessive/ loss of function mutation in PRKCD gene (3p21.1) | Hypogammaglobinemia, recurrent infections, lymphadenopathy, hepatosplenomegaly, autoimmunity and NK cell dysfunction [26, 27] |
| Lipopolysaccharide responsive and beige like anchor protein (LABA) deficiency with autoantibodies, regulatory T cell defects, autoimmune infiltration and enteropathy (LATAIE) | Autosomal recessive/ loss of function mutation in LPS-responsive and beige-like anchor protein (LABA) gene (4q31.3) | Autoimmunity, chronic diarrhea, enteropathy or IBD–like disease, splenomegaly, pneumonia, reduction in number of regulatory T cell, CD4 T cells, class-switched memory B cell and hypogammaglobinemia [28] |
| CTLA4 haloinsufficiency with autoimmune infiltration (CHAI) | Autosomal dominant/ LOF in CTLA4 gene (2q33.2) | Hypogammaglobulinemia, lymphoproliferation, autoimmune cytopenia, and respiratory, gastrointestinal, or neurological symptoms [29] |
| GOF mutations in STAT1 | Autosomal dominant/ GOF mutation in STAT1 gene (2q32.2) | Recurrent infections including chronic mucocutaneous candidiasis (CMC), recurrent Staphylococcus aureus, recurrent herpes, Mycobacterium, autoimmunity, cytopenia and aneurysm [30] |
| GOF mutations in STAT3 | Autosomal dominant/ GOF mutation in STAT3 gene (17q21.2) |
Hypogammaglobulinemia, autoimmunity, cytopenia, lymphadenopathy, splenomegaly, enteropathy, interstitial lung disease, endocrinopathy, postnatal growth failure [31, 32] |
Deficiency of adenosine deaminase 2 (DADA2) |
Autosomal recessive adenosine deaminase-2 (ADA2) gene (22q11.1) | Recurrent fever, vasculitis, aneurysms, hypertension, ischemic or hemorrhagic stroke, livedo reticularis, lymphadenopathy, hepatosplenomegaly,hypogammaglobulinemia, cytopenia, lymphopenia [33, 34] |
| B cell expansion with NF-B and T cell anergy disease (BENTA) | Autosomal dominant, GOF mutation in CARD11 gene (7p22.2) | Lymphadenopathy, splenomegaly, autoimmunity, cytopenia, low antibodies, recurrent bacterial infections, chronic viral (EBV, molluscum) infections, B cell lymphoma [35, 36] |
Deregulation of Fas ligand expression caused by IL-12RB1 mutation |
Autosomal recess, LOF mutation in IL12RB1 gene (19p13.11) | Lymphadenopathy, splenomegaly, hepatomegaly, elevated numbers of double-negative T cells, autoimmune cytopenias, and increased levels of vitamin B12 and interleukin-10 [37] |
| X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia” (XMEN) | LOF mutation in MAGT1 gene (Xq21.1) | Persistent Epstein–Barr virus (EBV) viremia, history of EBV+ lymphoma, a CD4:CD8 T-cell ratio of 1 or less with a normal lymphocyte count or mild to moderate lymphopenia, recurrent sinopulmonary and viral infections, hypogammaglobulinemia, variable antibody response to vaccinations, neutropenia, autoimmunity [38, 39] |
