|
|
| (47 intermediate revisions by 6 users not shown) |
| Line 1: |
Line 1: |
| | __NOTOC__ |
| {{Infobox_Disease | | {{Infobox_Disease |
| | Name = {{PAGENAME}} | | | Name = {{PAGENAME}} |
| Line 15: |
Line 16: |
| | MeshID = | | | MeshID = |
| }} | | }} |
| | {{Autoimmune lymphoproliferative syndrome}} |
|
| |
|
| '''Editor-In-Chief:''' David Teachey, MD [mailto:TEACHEYD@email.chop.edu] | | '''Editor-In-Chief:''' David Teachey, MD [mailto:TEACHEYD@email.chop.edu] '''Associate editor in chief''': {{SharmiB}} |
|
| |
|
| {{EH}} | | {{SK}} Canale-Smith syndrome; ALPS |
|
| |
|
| '''Autoimmune lymphoproliferative syndrome''' is a form of [[lymphoproliferative disorder]]. It affects [[lymphocyte]] [[apoptosis]].<ref name="pmid18193364">{{cite journal |author=Fleisher TA |title=The autoimmune lymphoproliferative syndrome: an experiment of nature involving lymphocyte apoptosis |journal=Immunol. Res. |volume=40 |issue=1 |pages=87–92 |year=2008 |pmid=18193364 |doi=10.1007/s12026-007-8001-1 |url=http://dx.doi.org/10.1007/s12026-007-8001-1}}</ref>
| | ==[[Autoimmune lymphoproliferative syndrome overview|Overview]]== |
|
| |
|
| ==Introduction== | | ==[[Autoimmune lymphoproliferative syndrome historical perspective|Historical Perspective]]== |
| 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== | | ==[[Autoimmune lymphoproliferative syndrome classification|Classification]]== |
| Lymphoproliferation: The most common clinical manifestation of ALPS is lymphoproliferation, affecting 100% of patients.
| | ==[[Autoimmune lymphoproliferative syndrome pathophysiology|Pathophysiology]]== |
| * [[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
| | ==[[Autoimmune lymphoproliferative syndrome causes|Causes]]== |
| * [[Splenomegaly]]: >80% of patients present with clinically identifiable splenomegaly. It can be massive.
| | ==[[Autoimmune lymphoproliferative syndrome differential diagnosis|Differentiating Autoimmune lymphoproliferative syndrome from other Diseases]]== |
| * [[Hepatomegaly]]: 30-40% of patients have enlarged livers.
| | ==[[Autoimmune lymphoproliferative syndrome epidemiology and demographics|Epidemiology and Demographics]]== |
| * 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 prevalance unknown as <20 reported cases of cancer. Most common EBER+ non-hodgkins and hodgkins lymphoma
| |
| ** Unaffected family members with genetic mutations are also at increased risk of developing cancer
| |
|
| |
|
| ==Laboratory Manifestations== | | ==[[Autoimmune lymphoproliferative syndrome risk factors|Risk Factors]]== |
| * 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== | | ==[[Autoimmune lymphoproliferative syndrome screening|Screening]]== |
| Old criteria
| |
| * Required
| |
| ** Chronic non-malignant lymphoproliferation
| |
| ** Elevated peripheral blood DNTs
| |
| ** Defective in vitro Fas mediated apoptosis
| |
|
| |
|
| New criteria
| | ==[[Autoimmune lymphoproliferative syndrome natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| *Required
| | |
| ** Chronic non-malignant lymphoproliferation (>6 months lymphadenopathy and/or splenomegaly)
| | ==References== |
| ** Elevated peripheral blood DNTs
| | |
| *Accessory
| | ==Diagnosis== |
| ** Primary Accessory
| | |
| *** Defective in vitro Fas mediated apoptosis
| | [[Autoimmune lymphoproliferative syndrome criteria|Diagnostic Criteria]] | [[Autoimmune lymphoproliferative syndrome history and symptoms|History and Symptoms]] | [[ Autoimmune lymphoproliferative syndrome physical examination|Physical Examination]] | [[Autoimmune lymphoproliferative syndrome laboratory findings|Laboratory Findings]] | [[Autoimmune lymphoproliferative syndrome electrocardiogram|Electrocardiogram]] | [[Autoimmune lymphoproliferative syndrome chest x ray|Chest X Ray]] | [[Autoimmune lymphoproliferative syndrome CT|CT]] | [[Autoimmune lymphoproliferative syndrome MRI|MRI]] | [[Autoimmune lymphoproliferative syndrome echocardiography or ultrasound|Echocardiography or Ultrasound]] | [[Autoimmune lymphoproliferative syndrome other imaging findings|Other Imaging Findings]] | [[Autoimmune lymphoproliferative syndrome other diagnostic studies|Other Diagnostic Studies]] |
| *** 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== | | ==Treatment== |
| * Mostly commonly directed at autoimmune disease
| | [[Autoimmune lymphoproliferative syndrome medical therapy|Medical Therapy]] | [[Autoimmune lymphoproliferative syndrome surgery |Surgery]] | [[Autoimmune lymphoproliferative syndrome primary prevention|Primary Prevention]] | [[Autoimmune lymphoproliferative syndrome secondary prevention|Secondary Prevention]] | [[Autoimmune lymphoproliferative syndrome cost-effectiveness of therapy|Cost-Effectiveness of Therapy]] | [[Autoimmune lymphoproliferative syndrome future or investigational therapies|Future or Investigational Therapies]] |
| * 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]] 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
| |
| | |
|
| |
|
| | ==Case Studies== |
|
| |
|
| ==References==
| | [[Autoimmune lymphoproliferative syndrome case study one|Case #1]] |
| {{reflist}}
| | |
| | [[Category:Disease]] |
| | [[Category:Hematology]] |
|
| |
|
| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |