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| | {{Autoimmune lymphoproliferative syndrome}} |
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| '''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}} |
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| {{EH}} | | {{SK}} Canale-Smith syndrome; ALPS |
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| '''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]]== |
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| ==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.<ref name="pmid19930184">{{cite journal| author=Teachey DT, Seif AE, Grupp SA| title=Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS). | journal=Br J Haematol | year= 2010 | volume= 148 | issue= 2 | pages= 205-16 | pmid=19930184 | doi=10.1111/j.1365-2141.2009.07991.x | pmc=PMC2929682 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19930184 }} </ref>
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| ==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.
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| Autoimmune disease: The second most common clinical manifestation and one that most often requires treatment.
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| * Autoimmune cytopenias: Most common. Can be mild to very severe. Can be intermittent or chronic.<ref name="pmid15542578">{{cite journal| author=Teachey DT, Manno CS, Axsom KM, Andrews T, Choi JK, Greenbaum BH et al.| title=Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS). | journal=Blood | year= 2005 | volume= 105 | issue= 6 | pages= 2443-8 | pmid=15542578 | doi=10.1182/blood-2004-09-3542 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15542578 }} </ref>
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| ** Autoimmune [[Hemolytic Anemia]]
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| ** Autoimmune [[Neutropenia]]
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| ** Autoimmune [[Thrombocytopenia]]
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| * Other: Can affect any organ system similar to [[systemic lupus erythematosis]] (most rare affecting <5% of patients)
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| ** Nervous: Autoimmune cerebellar [[ataxia]]; [[Guillain-Barre]]; [[Transverse myelitis]]
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| ** GI: Autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis
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| ** Derm: Urticaria
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| ** Pulmonary: [[Bronchiolitis obliterans]]
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| ** Renal: Autoimmune glomerulonephritis, nephrotic syndrome
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| * 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
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| ** Unaffected family members with genetic mutations are also at increased risk of developing cancer
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| ==Laboratory Manifestations== | | ==[[Autoimmune lymphoproliferative syndrome risk factors|Risk Factors]]== |
| * Elevated peripheral blood Double Negative T cells (DNTs)
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| ** Required for diagnosis
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| ** Immunophenotype: CD3+/CD4-/CD8-/TCRalpha/beta+
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| ** Measured by [[flow cytometry]]: Normal values <2.5% total T cells; <1% of total lymphocytes in peripheral blood
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| ** Marked elevations >5% virtually pathognomic for ALPS
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| ** Mild elevations also found in other autoimmune diseases
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| ** Thought to be cytotoxic T lymphocytes that have lost CD8 expression
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| ** ?Unknown if driver of disease or epiphenomenon
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| ** May be falsely elevated in setting of lymphopenia or falsely decreased with immunosuppressive treatment
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| * Defective in vitro Fas mediated apoptosis
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| ** Required for diagnosis under old definition. Now can be used to make diagnosis; however, not required to make diagnosis.
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| ** Time and labor intensive assay.
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| ** 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
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| ** ALPS patient T cells: Do not die with anti-Fas monoclonal antibody exposure. Normal T cells from unaffected patient do.
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| ** False negative in somatic Fas variant ALPS and FasL variant ALPS
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| * Genetic mutations in ALPS causative genes (see below)
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| * Biomarkers
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| ** Polyclonal [[hypergammaglobulinemia]]<ref name="pmid20068224">{{cite journal| author=Seif AE, Manno CS, Sheen C, Grupp SA, Teachey DT| title=Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: a multi-institutional study. | journal=Blood | year= 2010 | volume= 115 | issue= 11 | pages= 2142-5 | pmid=20068224 | doi=10.1182/blood-2009-08-239525 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20068224 }} </ref>
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| ** Elevated serum FASL
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| ** Elevated plasma [[IL-10]] and/or IL-18
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| ** Elevated plasma or serum [[vitamin B12]]
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| * [[Autoantibodies]]: Non-specific. Can have antibodies to blood cells (DAT, anti-neutrophil, anti-platelet). Also, can have positive ANA, RF, ANCA.
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| ==Classification==
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| Old nomenclature:
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| * IA - [[Fas]]
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| * IB - [[Fas ligand]]
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| * IIA - [[Caspase 10]]
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| * IIB - [[Caspase 8]]
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| * III - unknown
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| * IV - [[Neuroblastoma RAS viral oncogene homolog]]
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| Revised nomenclature (2010)<ref name="pmid20538792">{{cite journal| author=Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ et al.| title=Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. | journal=Blood | year= 2010 | volume= 116 | issue= 14 | pages= e35-40 | pmid=20538792 | doi=10.1182/blood-2010-04-280347 | pmc=PMC2953894 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20538792 }} </ref>
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| * ALPS-FAS: [[Fas]]. Germline FAS mutations. 70% of patients
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| * ALPS-sFAS:[[Fas]]. Somatic FAS mutations in DNT compartment. 10% of patients
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| * ALPS-FASL: [[Fas ligand]]. Germline FASL mutations. 3 reported cases
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| * ALPS-CASP10: [[Caspase 10]]. Germline CASP10 mutation. 2% of patients
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| * ALPS-U: Undefined. 20% of patients
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| * CEDS: Caspase 8 deficiency state. No longer considered a subtype of ALPS but distinct disorder
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| * RALD: [[NRAS]] , [[KRAS]]. Somatic mutations in NRAS and KRAS in lympocyte comparment. No longer considered a subtype of ALPS but distinct disesase
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| ==Diagnostic Algorithm== | | ==[[Autoimmune lymphoproliferative syndrome screening|Screening]]== |
| Old criteria
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| * Required
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| ** Chronic non-malignant lymphoproliferation
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| ** Elevated peripheral blood DNTs
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| ** Defective in vitro Fas mediated apoptosis
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| New criteria<ref name="pmid20538792">{{cite journal| author=Oliveira JB, Bleesing JJ, Dianzani U, Fleisher TA, Jaffe ES, Lenardo MJ et al.| title=Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): report from the 2009 NIH International Workshop. | journal=Blood | year= 2010 | volume= 116 | issue= 14 | pages= e35-40 | pmid=20538792 | doi=10.1182/blood-2010-04-280347 | pmc=PMC2953894 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20538792 }} </ref>
| | ==[[Autoimmune lymphoproliferative syndrome natural history, complications and prognosis|Natural History, Complications and Prognosis]]== |
| *Required
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| ** Chronic non-malignant lymphoproliferation (>6 months lymphadenopathy and/or splenomegaly)
| | ==References== |
| ** Elevated peripheral blood DNTs
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| *Accessory
| | ==Diagnosis== |
| ** Primary Accessory
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| *** 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)
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| ** Secondary Accessory
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| *** Elevated biomarkers
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| **** Plasma sFASL >200pg/ml
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| **** Plasma IL-10 >20pg/ml
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| **** Plasma or serum vitamin B12 >1500ng/L
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| **** Plasma IL-18 >500pg/ml
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| *** Immunohistochemical findings on biopsy consistent with ALPS as determined by experienced hematopathologist
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| *** Autoimmune cytopenias and polyclonal hypergammaglobulinemia
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| *** Family history of ALPS or non-malignant lymphoproliferation
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| * Definitive diagnosis: Required plus one primary accessory criteria
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| * Probable diagnosis: Required plus one secondary accessory criteria
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| * Definitive and Probable ALPS should be TREATED THE SAME and patients counseled that they have ALPS if definitive or probable
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| ==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
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| * First line therapies
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| ** [[Corticosteroids]]
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| *** Very active but toxic with chronic use
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| ** [[IVIgG]]
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| *** Not as effective as in other immune cytopenia syndromes
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| * Second line therapies
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| ** [[Mycophenolate mofetil]] (cellcept)
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| *** Inactivates inosine monophosphate
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| *** Active in most patients
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| *** Most studied medicine in clinical trials
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| *** Some patients have complete resolution of autoimmune disease
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| *** Many patients have partial responses
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| *** Some patients relapse
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| *** Does not affect lymphoproliferation or reduce DNTs
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| *** Well-tolerated: Side effects: Diarrhea, neutropenia
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| *** Does not require therapeutic drug monitoring
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| *** No drug-drug interactions
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| *** Can cause hypogammaglobulinemia (transient) requiring IVIgG replacement
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| *** Consider PCP prophylaxis but usually not needed
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| ** [[Sirolimus]] (rapamycin, rapamune)
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| *** mTOR ([[mammalian target of rapamycin]]) inhibitor<ref name="pmid16757690">{{cite journal| author=Teachey DT, Obzut DA, Axsom K, Choi JK, Goldsmith KC, Hall J et al.| title=Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS). | journal=Blood | year= 2006 | volume= 108 | issue= 6 | pages= 1965-71 | pmid=16757690 | doi=10.1182/blood-2006-01-010124 | pmc=PMC1895548 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16757690 }} </ref>
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| *** Active in most patients
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| *** Second most studied agent in clinical trials
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| *** Most patients have complete resolution of autoimmune disease (>90%)<ref name="pmid19208097">{{cite journal| author=Teachey DT, Greiner R, Seif A, Attiyeh E, Bleesing J, Choi J et al.| title=Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome. | journal=Br J Haematol | year= 2009 | volume= 145 | issue= 1 | pages= 101-6 | pmid=19208097 | doi=10.1111/j.1365-2141.2009.07595.x | pmc=PMC2819393 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19208097 }} </ref>
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| *** Most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%)
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| *** Some patients have near complete response (disease flares with viral illness)
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| *** A few patients have had partial responses (most commonly patient with non-cytopenia autoimmune disease)
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| *** Most patients have elimination of peripheral blood DNTs
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| *** mTOR/Akt/PI3K pathway may be activated in abnormal ALPS cells: mTOR inhibitors may be targeted therapy
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| *** 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<ref name="pmid21475130">{{cite journal| author=Teachey DT| title=Autoimmune lymphoproliferative syndrome: new approaches to diagnosis and management. | journal=Clin Adv Hematol Oncol | year= 2011 | volume= 9 | issue= 3 | pages= 233-5 | pmid=21475130 | doi= | pmc= | url= }} </ref>
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| *** Not reported to cause hypogammaglobulinemia
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| *** Hypothetically, may have lower risk of secondary cancers as opposed to other immune suppressants
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| **** Always a risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence
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| **** mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. Thus, THEORETICALLY could eliminate malignant clones.
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| *** Requires therapeutic drug monitoring
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| **** Goal serum trough 5-15ng/ml
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| *** Drug-drug interactions
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| *** Well tolerated: Side effects: mucositis, diarrhea, hyperlipidemia, delayed wound healing
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| *** Consider PCP prophylaxis but usually not needed
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| ** Other agents:
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| *** Fansidar, mercaptopurine: More commonly used in Europe. Good ancedotal data
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| *** Rituximab: AVOID. Can cause life long hypogammaglobulinemia
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| *** Splenectomy: AVOID. >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis
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| | ==Case Studies== |
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| ==References==
| | [[Autoimmune lymphoproliferative syndrome case study one|Case #1]] |
| {{reflist}}
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| | [[Category:Disease]] |
| | [[Category:Hematology]] |
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| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |