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Autoimmune lymphoproliferative syndrome

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Autoimmune lymphoproliferative syndrome
SpecialtyImmunology Edit this on Wikidata

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 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[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

  1. ^ 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.
  2. ^ 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. ^ 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.{{cite journal}}: CS1 maint: PMC format (link) CS1 maint: multiple names: authors list (link)
  4. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  5. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  6. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  7. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  8. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ a b Sneller MC, Dale JK, Straus SE (2003). "Autoimmune lymphoproliferative syndrome". Curr Opin Rheumatol. 15 (4): 417–21. PMID 12819469.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  10. ^ a b 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: PMC format (link) CS1 maint: multiple names: authors list (link)
  11. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  12. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  13. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  14. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: PMC format (link) CS1 maint: multiple names: authors list (link)
  15. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: PMC format (link) CS1 maint: multiple names: authors list (link)
  16. ^ 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.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Teachey DT (2011). "Autoimmune lymphoproliferative syndrome: new approaches to diagnosis and management". Clin Adv Hematol Oncol. 9 (3): 233–5. PMID 21475130.
  18. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  19. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)
  20. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: PMC format (link) CS1 maint: multiple names: authors list (link)
  21. ^ Rao VK, Oliveira JB (2011). "How I treat autoimmune lymphoproliferative syndrome". Blood. doi:10.1182/blood-2011-07-325217. PMID 21885601.
  22. ^ 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. {{cite journal}}: Explicit use of et al. in: |author= (help)CS1 maint: multiple names: authors list (link)

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