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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}}</ref>
'''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>


==Introduction==
ALPS results from mutations in the human genes, Fas and FasL, which are upstream effectors of the apoptotic pathway in cells.
Autoimmune Lymphoproliferative Syndrome ([[ALPS]]) is a rare disorder of abnormal [[lymphocyte]] survival caused by defective [[Fas]] mediated [[apoptosis]].<ref name="pmid16522544">{{cite journal| author=Rao VK, Straus SE| title=Causes and consequences of the autoimmune lymphoproliferative syndrome. | journal=Hematology | year= 2006 | volume= 11 | issue= 1 | pages= 15-23 | pmid=16522544 | doi=10.1080/10245330500329094 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16522544 }} </ref> 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>


==Clinical Manifestations==
==Genetic Defect==
Lymphoproliferation: The most common clinical manifestation of ALPS is lymphoproliferation, affecting 100% of patients.
The genetic defect for this syndrome is on the tumor necrosis factor receptor gene superfamily member (TNFRSF6), this is located on chromosome 10q24.1 <ref name="titleAutoimmune Lymphoproliferative Syndrome (ALPS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)">{{cite web |url=http://www.niaid.nih.gov/publications/alps/alps.htm |title=Autoimmune Lymphoproliferative Syndrome (ALPS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH) |accessdate=2008-03-01 |work=}}</ref>. This gene encodes for cell surface receptors involved in major apoptotic pathways for lymphocytes <ref name="titleAutoimmune Lymphoproliferative Syndrome (ALPS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)"/>.
* [[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.
==Mechanism of the Type IA==
* [[Hepatomegaly]]: 30-40% of patients have enlarged livers.
The mechanism of the Fas receptor version of this syndrome has to deal with the way Fas mediated apoptosis functions works. When the Fas Ligand bonds to three Fas receptors an apoptotic signal begins. However people with a genetic defect in their Fas receptors have some receptors that do not function properly. So even if two of the receptors are normal in the complex if one has a genetic defect then the Fas ligand will be either inhibited or will work less efficiently <ref name="titleAutoimmune Lymphoproliferative Syndrome (ALPS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)"/>. Most genetic defects are merely a missence where one nucleotide is out of order, however other mutations include truncated forms which are excreted from the cell and when in the extracellular matrix can inhibit the ligands <ref name="titleAutoimmune Lymphoproliferative Syndrome (ALPS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)"/>. This inefficacy of apoptosis in lymphocytes causes an increase in the number of lymphocytes in the body, including cells that are too old and less effective. This increase in the number of lymphocytes in the body causes an increase in the size of organs(http://www.patient.co.uk/doctor/Autoimmune-Lymphoproliferative-Syndrome.htm). The enlargement of organs can cause extra pressure on unaffected organs. When organs are enlarged they tend to work either too hard, or they do not work effectively. For example, when the liver is enlarged it tends to filter the blood ineffectively, causing the premature death of red blood cells. (http://www.patient.co.uk/doctor/Autoimmune-Lymphoproliferative-Syndrome.htm)
* 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.
==Presentation==
* 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>
Among the possible symptoms are [[splenomegaly]] and [[hepatomegaly]].<ref name="titleAutoimmune Lymphoproliferative Syndrome (ALPS), National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH)"/>
** 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)<ref name="pmid12139944">{{cite journal| author=Bleesing JJ, Brown MR, Novicio C, Guarraia D, Dale JK, Straus SE et al.| title=A composite picture of TcR alpha/beta(+) CD4(-)CD8(-) T Cells (alpha/beta-DNTCs) in humans with autoimmune lymphoproliferative syndrome. | journal=Clin Immunol | year= 2002 | volume= 104 | issue= 1 | pages= 21-30 | pmid=12139944 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12139944 }} </ref>
** 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<ref name="pmid19176318">{{cite journal| author=Magerus-Chatinet A, Stolzenberg MC, Loffredo MS, Neven B, Schaffner C, Ducrot N et al.| title=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. | journal=Blood | year= 2009 | volume= 113 | issue= 13 | pages= 3027-30 | pmid=19176318 | doi=10.1182/blood-2008-09-179630 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=19176318 }} </ref> <ref name="pmid20227752">{{cite journal| author=Caminha I, Fleisher TA, Hornung RL, Dale JK, Niemela JE, Price S et al.| title=Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome. | journal=J Allergy Clin Immunol | year= 2010 | volume= 125 | issue= 4 | pages= 946-949.e6 | pmid=20227752 | doi=10.1016/j.jaci.2009.12.983 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=20227752 }} </ref>
** 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>
** 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==
==Classification==
Old nomenclature<ref name="pmid12819469">{{cite journal| author=Sneller MC, Dale JK, Straus SE| title=Autoimmune lymphoproliferative syndrome. | journal=Curr Opin Rheumatol | year= 2003 | volume= 15 | issue= 4 | pages= 417-21 | pmid=12819469 | doi= | pmc= | url= }} </ref>
[[Image:Fas signaling.jpg|thumbnail|400px|Signaling pathways of Fas. Dashed grey lines represent multiple steps in JNK signaling.]]
* IA - [[Fas]]
Types include:
* IB - [[Fas ligand]]
* I - Canale-Smith syndrome<ref>{{WhoNamedIt|synd|2128}}</ref><ref name="pmid4165068">{{cite journal |author=Canale VC, Smith CH |title=Chronic lymphadenopathy simulating malignant lymphoma |journal=J. Pediatr. |volume=70 |issue=6 |pages=891–9 |year=1967 |month=June |pmid=4165068 |doi= 10.1016/S0022-3476(67)80262-2|url=}}</ref>
* IIA - [[Caspase 10]]
** IA - [[Fas receptor]] (this form is the most common)<ref name="titleAutoimmune Lymphoproliferative Syndrome">{{cite web |url=http://www.patient.co.uk/showdoc/40002303/ |title=Autoimmune Lymphoproliferative Syndrome |accessdate=2008-03-01 |format= |work=}}</ref>
** IB - [[Fas ligand]]
* IIB - [[Caspase 8]]
* II
** IIA - [[Caspase 10]]
** IIB - [[Caspase 8]]
* III - unknown
* III - unknown
* IV - [[Neuroblastoma RAS viral oncogene homolog]]
* IV - [[Neuroblastoma RAS viral oncogene homolog]]
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>
* ALPS-FAS: [[Fas]]. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.<ref name="pmid21490157">{{cite journal| author=Kuehn HS, Caminha I, Niemela JE, Rao VK, Davis J, Fleisher TA et al.| title=FAS haploinsufficiency is a common disease mechanism in the human autoimmune lymphoproliferative syndrome. | journal=J Immunol | year= 2011 | volume= 186 | issue= 10 | pages= 6035-43 | pmid=21490157 | doi=10.4049/jimmunol.1100021 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21490157 }} </ref>
* ALPS-sFAS: [[Fas]]. Somatic FAS mutations in DNT compartment.<ref name="pmid15459302">{{cite journal| author=Holzelova E, Vonarbourg C, Stolzenberg MC, Arkwright PD, Selz F, Prieur AM et al.| title=Autoimmune lymphoproliferative syndrome with somatic Fas mutations. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 14 | pages= 1409-18 | pmid=15459302 | doi=10.1056/NEJMoa040036 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15459302 }} </ref> 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


==External links==
==Diagnostic Algorithm==
Old criteria<ref name="pmid12819469">{{cite journal| author=Sneller MC, Dale JK, Straus SE| title=Autoimmune lymphoproliferative syndrome. | journal=Curr Opin Rheumatol | year= 2003 | volume= 15 | issue= 4 | pages= 417-21 | pmid=12819469 | doi= | pmc= | url= }} </ref>
*[http://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=alps GeneReviews/NCBI/NIH/UW entry on Autoimmune Lymphoproliferative Syndrome]
* Required
** Chronic non-malignant lymphoproliferation
** Elevated peripheral blood DNTs
** Defective in vitro Fas mediated apoptosis


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>
==References==
*Required
{{reflist}}
** 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==
{{Lymphoid malignancy}}
* Mostly commonly directed at autoimmune disease
{{Extracellular ligand disorders}}
* Maybe needed to treat bulky lymphoproliferation
{{Cell surface receptor deficiencies}}
* First line therapies
{{DEFAULTSORT:Autoimmune Lymphoproliferative Syndrome}}
** [[Corticosteroids]]
[[Category:Diseases of immune dysregulaton]]
*** Very active but toxic with chronic use
** [[IVIgG]]
*** Not as effective as in other immune cytopenia syndromes
* Second line therapies
** [[Mycophenolate mofetil]] (cellcept)<ref name="pmid15877736">{{cite journal| author=Rao VK, Dugan F, Dale JK, Davis J, Tretler J, Hurley JK et al.| title=Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome. | journal=Br J Haematol | year= 2005 | volume= 129 | issue= 4 | pages= 534-8 | pmid=15877736 | doi=10.1111/j.1365-2141.2005.05496.x | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15877736 }} </ref>
*** 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<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>
*** Active in most patients
*** Second most studied agent in clinical trials
*** 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> <ref name="pmid19588524">{{cite journal| author=Janić MD, Brasanac CD, Janković JS, Dokmanović BL, Krstovski RN, Kraguljac Kurtović JN| title=Rapid regression of lymphadenopathy upon rapamycin treatment in a child with autoimmune lymphoproliferative syndrome. | journal=Pediatr Blood Cancer | year= 2009 | volume= 53 | issue= 6 | pages= 1117-9 | pmid=19588524 | doi=10.1002/pbc.22151 | pmc= | url= }} </ref>
*** 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<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>
*** 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,<ref name="pmid11918552">{{cite journal| author=van der Werff Ten Bosch J, Schotte P, Ferster A, Azzi N, Boehler T, Laurey G et al.| title=Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: preliminary results of a clinical cohort study and molecular observations. | journal=Br J Haematol | year= 2002 | volume= 117 | issue= 1 | pages= 176-88 | pmid=11918552 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11918552 }} </ref> <ref name="pmid17674358">{{cite journal| author=Rao VK, Dowdell KC, Dale JK, Dugan F, Pesnicak L, Bi LL et al.| title=Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr-/- mice or in patients with autoimmune lymphoproliferative syndrome. | journal=Am J Hematol | year= 2007 | volume= 82 | issue= 12 | pages= 1049-55 | pmid=17674358 | doi=10.1002/ajh.21007 | pmc= | url= }} </ref> mercaptopurine: More commonly used in Europe. Good ancedotal data
*** Rituximab: AVOID. Can cause life long hypogammaglobulinemia<ref name="pmid19214977">{{cite journal| author=Rao VK, Price S, Perkins K, Aldridge P, Tretler J, Davis J et al.| title=Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS). | journal=Pediatr Blood Cancer | year= 2009 | volume= 52 | issue= 7 | pages= 847-52 | pmid=19214977 | doi=10.1002/pbc.21965 | pmc=PMC2774763 | url= }} </ref>
*** Splenectomy: AVOID. >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis<ref name="pmid21885601">{{cite journal| author=Rao VK, Oliveira JB| title=How I treat autoimmune lymphoproliferative syndrome. | journal=Blood | year= 2011 | volume= | issue= | pages= | pmid=21885601 | doi=10.1182/blood-2011-07-325217 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21885601 }} </ref> <ref name="pmid21885602">{{cite journal| author=Neven B, Magerus-Chatinet A, Florkin B, Gobert D, Lambotte O, De Somer L et al.| title=A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation. | journal=Blood | year= 2011 | volume= | issue= | pages= | pmid=21885602 | doi=10.1182/blood-2011-04-347641 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21885602 }} </ref>




==References==
{{immunology-stub}}
{{reflist}}


{{WH}}
[[id:Sindrom limfoproliferatif autoimun]]
{{WS}}
[[nl:Auto-immuun lymfoproliferatief syndroom]]

Revision as of 17:56, 14 October 2011

Autoimmune lymphoproliferative syndrome
SpecialtyImmunology Edit this on Wikidata

Autoimmune lymphoproliferative syndrome is a form of lymphoproliferative disorder. It affects lymphocyte apoptosis.[1]

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
      • 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[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:
      • 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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