Autoimmune lymphoproliferative syndrome
Autoimmune lymphoproliferative syndrome is a form of lymphoproliferative disorder. It affects lymphocyte apoptosis.[1] It is a RASopathy.
Introduction
Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis.[2] Normally, after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interact to trigger the caspase cascade, leading to cell apoptosis. Patients with ALPS have a defect in this apoptotic pathway, leading to chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers.[3]
Clinical manifestations
Lymphoproliferation: The most common clinical manifestation of ALPS is lymphoproliferation, affecting 100% of patients.
- Lymphadenopathy: >90% of patients present with chronic non-malignant lymphadenopathy. It can be mild to severe, affecting multiple nodal groups. Most commonly presents with massive non-painful hard cervical lymphadenopathy
- Splenomegaly: >80% of patients present with clinically identifiable splenomegaly. It can be massive.
- Hepatomegaly: 30-40% of patients have enlarged livers.
- Lymphoproliferation tends to present at a young age (median 11.5 months) and may improve with age.
Autoimmune disease: The second most common clinical manifestation and one that most often requires treatment.
- Autoimmune cytopenias: Most common. Can be mild to very severe. Can be intermittent or chronic.[4]
- Other: Can affect any organ system similar to systemic lupus erythematosis (most rare affecting <5% of patients)
- Cancer: Secondary neoplasms affect approximately 10% of patients. True prevalence unknown as <20 reported cases of cancer. Most common EBER+ Non-Hodgkin's and Hodgkin's lymphoma
- Unaffected family members with genetic mutations are also at increased risk of developing cancer
Laboratory manifestations
- Elevated peripheral blood Double Negative T cells (DNTs)[5]
- Required for diagnosis
- Immunophenotype: CD3+/CD4-/CD8-/TCRalpha/beta+
- Measured by flow cytometry: Normal values <2.5% total T cells; <1% of total lymphocytes in peripheral blood
- Marked elevations >5% virtually pathognomonic for ALPS
- Mild elevations also found in other autoimmune diseases
- Thought to be cytotoxic T lymphocytes that have lost CD8 expression
- Unknown if driver of disease or epiphenomenon
- May be falsely elevated in setting of lymphopenia or falsely decreased with immunosuppressive treatment
- Defective in vitro Fas mediated apoptosis
- Required for diagnosis under old definition. Now can be used to make diagnosis; however, not required to make diagnosis.
- Time and labor intensive assay.
- T cells from patient and normal control supported in culture for >10 days with mitogen stimulation and IL-2 expansion and then exposed to anti-Fas IgM monoclonal antibody
- ALPS patient T cells: Do not die with anti-Fas monoclonal antibody exposure. Normal T cells from unaffected patient do.
- False negative in somatic Fas variant ALPS and FasL variant ALPS
- Genetic mutations in ALPS causative genes (see below)
- Biomarkers[6][7]
- Autoantibodies: Non-specific. Can have antibodies to blood cells (DAT, anti-neutrophil, anti-platelet). Also, can have positive ANA, RF, ANCA.
Classification
Old nomenclature[9]
Revised nomenclature (2010)[10]
- ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.[11]
- ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment.[12] 10% of patients
- ALPS-FASL: Fas ligand. Germline FASL mutations. 3 reported cases
- ALPS-CASP10: Caspase 10. Germline CASP10 mutation. 2% of patients
- ALPS-U: Undefined. 20% of patients
- CEDS: Caspase 8 deficiency state. No longer considered a subtype of ALPS but distinct disorder
- RALD: NRAS, KRAS. Somatic mutations in NRAS and KRAS in lympocyte comparment. No longer considered a subtype of ALPS but distinct disesase
Diagnostic algorithm
Old criteria[9]
- Required
- Chronic non-malignant lymphoproliferation
- Elevated peripheral blood DNTs
- Defective in vitro Fas mediated apoptosis
New criteria[10]
- Required
- Chronic non-malignant lymphoproliferation (>6 months lymphadenopathy and/or splenomegaly)
- Elevated peripheral blood DNTs
- Accessory
- Primary Accessory
- Defective in vitro Fas mediated apoptosis
- Somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10)
- Secondary Accessory
- Elevated biomarkers
- Plasma sFASL >200pg/ml
- Plasma IL-10 >20pg/ml
- Plasma or serum vitamin B12 >1500ng/L
- Plasma IL-18 >500pg/ml
- Immunohistochemical findings on biopsy consistent with ALPS as determined by experienced hematopathologist
- Autoimmune cytopenias and polyclonal hypergammaglobulinemia
- Family history of ALPS or non-malignant lymphoproliferation
- Definitive diagnosis: Required plus one primary accessory criteria
- Probable diagnosis: Required plus one secondary accessory criteria
- Definitive and Probable ALPS should be TREATED THE SAME and patients counseled that they have ALPS if definitive or probable
Treatment
- Mostly commonly directed at autoimmune disease
- Maybe needed to treat bulky lymphoproliferation
- First line therapies
- Corticosteroids
- Very active but toxic with chronic use
- IVIgG
- Not as effective as in other immune cytopenia syndromes
- Second line therapies
- Mycophenolate mofetil (cellcept)[13]
- Inactivates inosine monophosphate
- Active in most patients
- Most studied medicine in clinical trials
- Some patients have complete resolution of autoimmune disease
- Some patients have partial responses
- Some patients relapse
- Does not affect lymphoproliferation or reduce DNTs
- Well-tolerated: Side effects: Diarrhea, neutropenia
- Does not require therapeutic drug monitoring
- No drug-drug interactions
- Can cause hypogammaglobulinemia (transient) requiring IVIgG replacement
- Consider PCP prophylaxis but usually not needed
- Most commonly used agent in patients who require chronic treatment based on tolerabilty and efficacy
- Sirolimus (rapamycin, rapamune)
- mTOR (mammalian target of rapamycin) inhibitor[14]
- Active in most patients
- Second most studied agent in clinical trials
- Most patients have complete resolution of autoimmune disease (>90%)[15][16]
- Most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%)
- Some patients have near complete response (disease flares with viral illness)
- Some patients have partial responses (most commonly patients with non hematologic autoimmune disease)
- Most patients have elimination of peripheral blood DNTs
- mTOR/Akt/PI3K pathway may be activated in abnormal ALPS cells: mTOR inhibitors may be targeted therapy
- May not be as immune suppressive in normal lymphocytes as other agents. Some patients have had improvement in immune function with transition from cellcept to rapamycin[17]
- Not reported to cause hypogammaglobulinemia
- Hypothetically, may have lower risk of secondary cancers as opposed to other immune suppressants
- Always a risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence
- mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. Thus, THEORETICALLY could eliminate malignant clones.
- Requires therapeutic drug monitoring
- Goal serum trough 5-15ng/ml
- Drug-drug interactions
- Well tolerated: Side effects: mucositis, diarrhea, hyperlipidemia, delayed wound healing
- Consider PCP prophylaxis but usually not needed
- Second most commonly used agent in patients that require chronic therapy.
- Better activity against autoimmune disease and lymphoproliferation than mycophenolate mofetil and other drugs; however, sirolimus requires therapeutic drug monitoring and can cause mucositis
- Other agents:
- Fansidar,[18][19] mercaptopurine: More commonly used in Europe. Good ancedotal data
- Rituximab: AVOID. Can cause life long hypogammaglobulinemia[20]
- Splenectomy: AVOID. >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis[21][22]
References
- ^ Fleisher, Thomas A. (2007). "The autoimmune lymphoproliferative syndrome: An experiment of nature involving lymphocyte apoptosis". Immunologic Research 40 (1): 87–92. doi:10.1007/s12026-007-8001-1. PMID 18193364.
- ^ Rao, V. Koneti; Straus, Stephen E. (2006). "Causes and consequences of the autoimmune lymphoproliferative syndrome". Hematology 11 (1): 15–23. doi:10.1080/10245330500329094. PMID 16522544.
- ^ Teachey, David T.; Seif, Alix E.; Grupp, Stephan A. (2010). "Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)". British Journal of Haematology 148 (2): 205–16. doi:10.1111/j.1365-2141.2009.07991.x. PMC 2929682. PMID 19930184. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2929682.
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- ^ Bleesing, Jack J.H.; Brown, Margaret R.; Novicio, Cynthia; Guarraia, David; Dale, Janet K.; Straus, Stephen E.; Fleisher, Thomas A. (2002). "A Composite Picture of TcRα/β+ CD4−CD8− T Cells (α/β-DNTCs) in Humans with Autoimmune Lymphoproliferative Syndrome". Clinical Immunology 104 (1): 21–30. doi:10.1006/clim.2002.5225. PMID 12139944.
- ^ Magerus-Chatinet, Aude; Stolzenberg, Marie-Claude; Loffredo, Maria S.; Neven, Bénédicte; Schaffner, Catherine; Ducrot, Nicolas; Arkwright, Peter D.; Bader-Meunier, Brigitte et al. (2009). "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". Blood 113 (13): 3027–30. doi:10.1182/blood-2008-09-179630. PMID 19176318.
- ^ Caminha, Iusta; Fleisher, Thomas A.; Hornung, Ronald L.; Dale, Janet K.; Niemela, Julie E.; Price, Susan; Davis, Joie; Perkins, Katie et al. (2010). "Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome". Journal of Allergy and Clinical Immunology 125 (4): 946–949.e6. doi:10.1016/j.jaci.2009.12.983. PMID 20227752.
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- ^ a b Sneller, Michael C.; Dale, Janet K.; Straus, Stephen E. (2003). "Autoimmune lymphoproliferative syndrome". Current Opinion in Rheumatology 15 (4): 417–21. doi:10.1097/00002281-200307000-00008. PMID 12819469.
- ^ a b Oliveira, J. B.; Bleesing, J. J.; Dianzani, U.; Fleisher, T. A.; Jaffe, E. S.; Lenardo, M. J.; Rieux-Laucat, F.; Siegel, R. M. et al. (2010). "Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): Report from the 2009 NIH International Workshop". Blood 116 (14): e35–40. doi:10.1182/blood-2010-04-280347. PMC 2953894. PMID 20538792. http://www.pubmedcentral.nih.gov/articlerender.fcgi?tool=pmcentrez&artid=2953894.
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- ^ Holzelova, Eliska; Vonarbourg, Cédric; Stolzenberg, Marie-Claude; Arkwright, Peter D.; Selz, Françoise; Prieur, Anne-Marie; Blanche, Stéphane; Bartunkova, Jirina et al. (2004). "Autoimmune Lymphoproliferative Syndrome with SomaticFasMutations". New England Journal of Medicine 351 (14): 1409–18. doi:10.1056/NEJMoa040036. PMID 15459302.
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