Autoimmune lymphoproliferative syndrome
| Autoimmune lymphoproliferative syndrome | |
| OMIM | 601859 603909 |
|---|---|
| DiseasesDB | 33425 Template:DiseasesDB2 |
Editor-In-Chief: David Teachey, MD [1]
Synonyms and keywords: Canale-Smith syndrome
Overview
Autoimmune lymphoproliferative syndrome is a form of lymphoproliferative disorder. It affects lymphocyte apoptosis.[1] Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis.[2]
Classification
Old nomenclature[3]
- IA - Fas
- IB - Fas ligand
- IIA - Caspase 10
- IIB - Caspase 8
- III - unknown
- IV - Neuroblastoma RAS viral oncogene homolog
Revised nomenclature (2010)[4]
- ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.[5]
- ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment.[6] 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
Pathophysiology
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.[7]
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.[8]
- Autoimmune Hemolytic Anemia
- Autoimmune Neutropenia
- Autoimmune Thrombocytopenia
- Other: Can affect any organ system similar to systemic lupus erythematosis (most rare affecting <5% of patients)
- Nervous: Autoimmune cerebellar ataxia; Guillain-Barre; Transverse myelitis
- GI: Autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis
- Derm: Urticaria
- Pulmonary: Bronchiolitis obliterans
- Renal: Autoimmune glomerulonephritis, nephrotic syndrome
- 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)[9]
- 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 pathognomic 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[10] [11]
- Polyclonal hypergammaglobulinemia[12]
- Elevated serum FASL
- Elevated plasma IL-10 and/or IL-18
- Elevated plasma or serum vitamin B12
- Autoantibodies: Non-specific. Can have antibodies to blood cells (DAT, anti-neutrophil, anti-platelet). Also, can have positive ANA, RF, ANCA.
Diagnostic Algorithm
Old criteria[3]
- Required
- Chronic non-malignant lymphoproliferation
- Elevated peripheral blood DNTs
- Defective in vitro Fas mediated apoptosis
New criteria[4]
- 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
- Elevated biomarkers
- Primary Accessory
- 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
- Corticosteroids
- 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
- 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)
- A few patients have had partial responses (most commonly patient with non-cytopenia 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
- Other agents:
- Mycophenolate mofetil (cellcept)[13]
References
- ↑ Fleisher TA (2008). "The autoimmune lymphoproliferative syndrome: an experiment of nature involving lymphocyte apoptosis". Immunol. Res. 40 (1): 87–92. doi:10.1007/s12026-007-8001-1. PMID 18193364.
- ↑ Rao VK, Straus SE (2006). "Causes and consequences of the autoimmune lymphoproliferative syndrome". Hematology. 11 (1): 15–23. doi:10.1080/10245330500329094. PMID 16522544.
- ↑ 3.0 3.1 Sneller MC, Dale JK, Straus SE (2003). "Autoimmune lymphoproliferative syndrome". Curr Opin Rheumatol. 15 (4): 417–21. PMID 12819469.
- ↑ 4.0 4.1 Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ; 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.
- ↑ Kuehn HS, Caminha I, Niemela JE, Rao VK, Davis J, Fleisher TA; et al. (2011). "FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome". J Immunol. 186 (10): 6035–43. doi:10.4049/jimmunol.1100021. PMID 21490157.
- ↑ Holzelova E, Vonarbourg C, Stolzenberg MC, Arkwright PD, Selz F, Prieur AM; et al. (2004). "Autoimmune lymphoproliferative syndrome with somatic Fas mutations". N Engl J Med. 351 (14): 1409–18. doi:10.1056/NEJMoa040036. PMID 15459302.
- ↑ Teachey DT, Seif AE, Grupp SA (2010). "Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)". Br J Haematol. 148 (2): 205–16. doi:10.1111/j.1365-2141.2009.07991.x. PMC 2929682. PMID 19930184.
- ↑ Teachey DT, Manno CS, Axsom KM, Andrews T, Choi JK, Greenbaum BH; et al. (2005). "Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS)". Blood. 105 (6): 2443–8. doi:10.1182/blood-2004-09-3542. PMID 15542578.
- ↑ Bleesing JJ, Brown MR, Novicio C, Guarraia D, Dale JK, Straus SE; et al. (2002). "A composite picture of TcR alpha/beta(+) CD4(-)CD8(-) T Cells (alpha/beta-DNTCs) in humans with autoimmune lymphoproliferative syndrome". Clin Immunol. 104 (1): 21–30. PMID 12139944.
- ↑ Magerus-Chatinet A, Stolzenberg MC, Loffredo MS, Neven B, Schaffner C, Ducrot N; et al. (2009). "FAS-L, IL-10, and double-negative CD4- CD8- TCR alpha/beta+ 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 I, Fleisher TA, Hornung RL, Dale JK, Niemela JE, Price S; et al. (2010). "Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome". J Allergy Clin Immunol. 125 (4): 946–949.e6. doi:10.1016/j.jaci.2009.12.983. PMID 20227752.
- ↑ Seif AE, Manno CS, Sheen C, Grupp SA, Teachey DT (2010). "Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study". Blood. 115 (11): 2142–5. doi:10.1182/blood-2009-08-239525. PMID 20068224.
- ↑ Rao VK, Dugan F, Dale JK, Davis J, Tretler J, Hurley JK; et al. (2005). "Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome". Br J Haematol. 129 (4): 534–8. doi:10.1111/j.1365-2141.2005.05496.x. PMID 15877736.
- ↑ Teachey DT, Obzut DA, Axsom K, Choi JK, Goldsmith KC, Hall J; et al. (2006). "Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS)". Blood. 108 (6): 1965–71. doi:10.1182/blood-2006-01-010124. PMC 1895548. PMID 16757690.
- ↑ Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J; et al. (2009). "Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome". Br J Haematol. 145 (1): 101–6. doi:10.1111/j.1365-2141.2009.07595.x. PMC 2819393. PMID 19208097.
- ↑ Janić MD, Brasanac CD, Janković JS, Dokmanović BL, Krstovski RN, Kraguljac Kurtović JN (2009). "Rapid regression of lymphadenopathy upon rapamycin treatment in a child with autoimmune lymphoproliferative syndrome". Pediatr Blood Cancer. 53 (6): 1117–9. doi:10.1002/pbc.22151. PMID 19588524.
- ↑ Teachey DT (2011). "Autoimmune lymphoproliferative syndrome: new approaches to diagnosis and management". Clin Adv Hematol Oncol. 9 (3): 233–5. PMID 21475130.
- ↑ van der Werff Ten Bosch J, Schotte P, Ferster A, Azzi N, Boehler T, Laurey G; et al. (2002). "Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations". Br J Haematol. 117 (1): 176–88. PMID 11918552.
- ↑ Rao VK, Dowdell KC, Dale JK, Dugan F, Pesnicak L, Bi LL; et al. (2007). "Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr-/- mice or in patients with autoimmune lymphoproliferative syndrome". Am J Hematol. 82 (12): 1049–55. doi:10.1002/ajh.21007. PMID 17674358.
- ↑ Rao VK, Price S, Perkins K, Aldridge P, Tretler J, Davis J; et al. (2009). "Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS)". Pediatr Blood Cancer. 52 (7): 847–52. doi:10.1002/pbc.21965. PMC 2774763. PMID 19214977.
- ↑ Rao VK, Oliveira JB (2011). "How I treat autoimmune lymphoproliferative syndrome". Blood. doi:10.1182/blood-2011-07-325217. PMID 21885601.
- ↑ Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L; et al. (2011). "A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation". Blood. doi:10.1182/blood-2011-04-347641. PMID 21885602.