Autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome
OMIM	601859 603909
DiseasesDB	33425 Template:DiseasesDB2

Editor-In-Chief: David Teachey, MD [1]

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Autoimmune lymphoproliferative syndrome is a form of lymphoproliferative disorder. It affects lymphocyte apoptosis.

Introduction

Autoimmune Lymphoproliferative Syndrome (ALPS) is a rare disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis. 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.

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.
  • 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)
  • 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
  • Polyclonal hypergammaglobulinemia
  • 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.

Classification

Old nomenclature:

• IA - Fas
• IB - Fas ligand
• IIA - Caspase 10
• IIB - Caspase 8
• III - unknown
• IV - Neuroblastoma RAS viral oncogene homolog

Revised nomenclature (2010)

• ALPS-FAS: Fas. Germline FAS mutations. 70% of patients
• ALPS-sFAS:Fas. Somatic FAS mutations in DNT compartment. 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

• Required
  • Chronic non-malignant lymphoproliferation
  • Elevated peripheral blood DNTs
  • Defective in vitro Fas mediated apoptosis

New criteria

• 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)
    • Inactivates inosine monophosphate
    • Active in most patients
    • Most studied medicine in clinical trials
    • Some patients have complete resolution of autoimmune disease
    • Many 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
    • Active in most patients
    • Second most studied agent in clinical trials
    • Most patients have complete resolution of autoimmune disease (>90%)
    • 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
    • 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:
    • Fansidar, mercaptopurine: More commonly used in Europe. Good ancedotal data
    • Rituximab: AVOID. Can cause life long hypogammaglobulinemia
    • Splenectomy: AVOID. >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis