Autoimmune lymphoproliferative syndrome

From WikiMD.com Medical Encyclopedia

Autoimmune lymphoproliferative syndrome
[[File:|250px|alt=|]]
Synonyms Canale-Smith syndrome,[1]
Pronounce
Field
Symptoms
Complications
Onset
Duration
Types
Causes
Risks
Diagnosis
Differential diagnosis
Prevention
Treatment
Medication
Prognosis
Frequency
Deaths


Autoimmune lymphoproliferative syndrome (ALPS), is a form of lymphoproliferative disorder (LPDs). It affects lymphocyte apoptosis.[2]

It is a rare genetic disorder of abnormal lymphocyte survival caused by defective Fas mediated apoptosis.[3] 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.[4]

Presentation[edit | edit source]

All people with ALPS have signs of lymphoproliferation, which makes it the most common clinical manifestation of the disease. The increased proliferation of lymphoid cells can cause the size of lymphoid organs such as the lymph nodes and spleen to increase (lymphadenopathy and splenomegaly, present in respectively over 90% and over 80% of patients). The liver is enlarged (hepatomegaly in 30 - 40% of patients).

Autoimmune disease is 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.[5] These include: Autoimmune hemolytic anemia, Autoimmune neutropenia, Autoimmune thrombocytopenia.

Other signs can affect organ systems similar to systemic lupus erythematosus (least common, affecting <5% of patients) Symptoms of the nervous system include: Autoimmune cerebellar ataxia; Guillain–Barré syndrome; transverse myelitis. Gastrointestinal signs like autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis can be found or (Dermatologic) Urticaria, (Pulmonary) bronchiolitis obliterans, (Renal) autoimmune glomerulonephritis, nephrotic syndrome.

Another sign are cancers such as Hodgkin and non-Hodgkin lymphomas which appear to be increased,[1] possibly due to Epstein–Barr virus-encoded RNA-positivity. Some carcinomas may occur. Unaffected family members with genetic mutations are also at an increased risk of developing cancer.

Genetics[edit | edit source]

This condition is usually caused by mutations in the FAS gene. Rarely cases due to mutations in other genes including the FAS ligand gene have been reported.[6]

Diagnosis[edit | edit source]

  • Elevated peripheral blood Double Negative T cells (DNTs)[7]
    • 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 pathognomonic 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
  • Biomarkers[8][9]
  • Autoantibodies: Non-specific. Can have antibodies to blood cells (DAT, anti-neutrophil, anti-platelet). Also, can have positive ANA, RF, ANCA
  • 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)


Diagnostic algorithm[edit | edit source]

The old diagnostic criteria for the illness included:[11] Chronic non-malignant lymphoproliferation, elevated peripheral blood DNTs and defective in vitro Fas mediated apoptosis.

The new criteria[12] require chronic non-malignant lymphoproliferation (over six months lymphadenopathy and/or splenomegaly), elevated peripheral blood DNTs. A primary accessory in diagnosis is defective in vitro Fas mediated apoptosis and somatic or germline mutation in ALPS causative gene (FAS, FASL, CASP10).

The secondary accessory in diagnosis are elevated biomarkers (plasma sFASL over 200 pg/ml, plasma IL-10 >20 pg/ml, plasma or serum vitamin B12 >1500 ng/L, Plasma IL-18 >500pg/ml) and immunohistochemical findings on biopsy consistent with ALPS as determined by an experienced hematopathologist. Another sign is autoimmune cytopenias and polyclonal hypergammaglobulinemia and a family history of ALPS or non-malignant lymphoproliferation.

A definitive diagnosis is chronic non-malignant lymphoproliferation and/or elevated peripheral blood DNTs plus one primary accessory criterion. A probable diagnosis is the same but with one secondary accessory criterion.

Classification[edit | edit source]

2003 nomenclature[11]

Revised nomenclature (2010)[12]

  • ALPS-FAS: Fas. Germline FAS mutations. 70% of patients. Autosomal dominant. Dominant negative and haploinsufficient mutations described.[13]
  • ALPS-sFAS: Fas. Somatic FAS mutations in DNT compartment.[14] 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 compartment. No longer considered a subtype of ALPS but distinct disesase

Treatment[edit | edit source]

Treatment is most commonly directed at autoimmune disease and may be needed to treat bulky lymphoproliferation. First line therapies include corticosteroids (very active but toxic with chronic use), and IVIgG, which are not as effective as in other immune cytopenia syndromes.

Second line therapies include: mycophenolate mofetil (cellcept)[15] which inactivates inosine monophosphate, most studied in clinical trials with responses varying (relapse, resolution, partial response). It does not affect lymphoproliferation or reduce DNTs, with no drug-drug interactions. This treatment is commonly used agent in patients who require chronic treatment based on tolerance and efficacy. It may cause hypogammaglobulinemia (transient) requiring IVIgG replacement.

Sirolimus (rapamycin, rapamune) which is a mTOR (mammalian target of rapamycin) inhibitor[16] can be active in most patients and can in some cases lead to complete or near-complete resolution of autoimmune disease (>90%)[17][18] With this treatment most patients have complete resolution of lymphoproliferation, including lymphadenopathy and splenomegaly (>90%) and have elimination of peripheral blood DNTs. Sirolimus 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[19] and it has not been reported to cause hypogammaglobulinemia. Hypothetically, Sirolimus may have lower risk of secondary cancers as opposed to other immune suppressants and requires therapeutic drug monitoring. It is the second most commonly used agent in patients that require chronic therapy. It is mostly well tolerated (though side effects include mucositis, diarrhea, hyperlipidemia, delayed wound healing) with drug-drug interactions. It has better activity against autoimmune disease and lymphoproliferation than mycophenolate mofetil and other drugs; however, sirolimus requires therapeutic drug monitoring and can cause mucositis. A risk with any agent in pre-cancerous syndrome as immune suppression can decreased tumor immunosurvellence. Its mTOR inhibitors active against lymphomas, especially EBV+ lymphomas. The Goal serum trough is 5-15 ng/ml and can consider PCP prophylaxis but usually not needed.

Other treatments may include drugs like Fansidar,[20][21] mercaptopurine: More commonly used in Europe. Another is rituximab but this can cause protracted hypogammaglobulinemia[22] and a splenectomy but there is a >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis[23][24]

References[edit | edit source]

  1. ↑ 1.0 1.1 Straus SE, Jaffe ES, Puck JM, The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis, Blood, Vol. 98(Issue: 1), pp. 194–200, PMID: 11418480,
  2. ↑ , The autoimmune lymphoproliferative syndrome: An experiment of nature involving lymphocyte apoptosis, Immunologic Research, 2007, Vol. 40(Issue: 1), pp. 87–92, DOI: 10.1007/s12026-007-8001-1, PMID: 18193364, Full text, [unreliable medical source?]
  3. ↑ , Causes and consequences of the autoimmune lymphoproliferative syndrome, Hematology, 2006, Vol. 11(Issue: 1), pp. 15–23, DOI: 10.1080/10245330500329094, PMID: 16522544, Full text,
  4. ↑ , Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS), British Journal of Haematology, 2010, Vol. 148(Issue: 2), pp. 205–16, DOI: 10.1111/j.1365-2141.2009.07991.x, PMID: 19930184, PMC: 2929682,
  5. ↑ , Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS), Blood, 2005, Vol. 105(Issue: 6), pp. 2443–8, DOI: 10.1182/blood-2004-09-3542, PMID: 15542578, [unreliable medical source?]
  6. ↑ Magerus-Chatinet A, Stolzenberg MC, Lanzarotti N, Neven B, Daussy C, Picard C, Neveux N, Desai M, Rao M, Ghosh K, Madkaikar M, Fischer A, Rieux-Laucat F (2012) Autoimmune lymphoproliferative syndrome caused by a homozygous null FAS ligand (FASLG) mutation. J Allergy Clin Immunol
  7. ↑ , A Composite Picture of TcRα/β+ CD4−CD8− T Cells (α/β-DNTCs) in Humans with Autoimmune Lymphoproliferative Syndrome, Clinical Immunology, 2002, Vol. 104(Issue: 1), pp. 21–30, DOI: 10.1006/clim.2002.5225, PMID: 12139944, [unreliable medical source?]
  8. ↑ , FAS-L, IL-10, and double-negative CD4−CD8− TCR α/β+ T cells are reliable markers of autoimmune lymphoproliferative syndrome (ALPS) associated with FAS loss of function, Blood, 2009, Vol. 113(Issue: 13), pp. 3027–30, DOI: 10.1182/blood-2008-09-179630, PMID: 19176318, Full text, [unreliable medical source?]
  9. ↑ , Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome, Journal of Allergy and Clinical Immunology, 2010, Vol. 125(Issue: 4), pp. 946–949.e6, DOI: 10.1016/j.jaci.2009.12.983, PMID: 20227752, PMC: 3412519, [unreliable medical source?]
  10. ↑ , Identifying autoimmune lymphoproliferative syndrome in children with Evans syndrome: A multi-institutional study, Blood, 2010, Vol. 115(Issue: 11), pp. 2142–5, DOI: 10.1182/blood-2009-08-239525, PMID: 20068224, [unreliable medical source?]
  11. ↑ 11.0 11.1 , Autoimmune lymphoproliferative syndrome, Current Opinion in Rheumatology, 2003, Vol. 15(Issue: 4), pp. 417–21, DOI: 10.1097/00002281-200307000-00008, PMID: 12819469, Full text,
  12. ↑ 12.0 12.1 , Revised diagnostic criteria and classification for the autoimmune lymphoproliferative syndrome (ALPS): Report from the 2009 NIH International Workshop, Blood, 2010, Vol. 116(Issue: 14), pp. e35–40, DOI: 10.1182/blood-2010-04-280347, PMID: 20538792, PMC: 2953894,
  13. ↑ , FAS Haploinsufficiency is a Common Disease Mechanism in the Human Autoimmune Lymphoproliferative Syndrome, The Journal of Immunology, 2011, Vol. 186(Issue: 10), pp. 6035–43, DOI: 10.4049/jimmunol.1100021, PMID: 21490157, PMC: 3725553, [unreliable medical source?]
  14. ↑ , Autoimmune Lymphoproliferative Syndrome with SomaticFasMutations, New England Journal of Medicine, 2004, Vol. 351(Issue: 14), pp. 1409–18, DOI: 10.1056/NEJMoa040036, PMID: 15459302, [unreliable medical source?]
  15. ↑ , Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome, British Journal of Haematology, 2005, Vol. 129(Issue: 4), pp. 534–8, DOI: 10.1111/j.1365-2141.2005.05496.x, PMID: 15877736, [unreliable medical source?]
  16. ↑ , Rapamycin improves lymphoproliferative disease in murine autoimmune lymphoproliferative syndrome (ALPS), Blood, 2006, Vol. 108(Issue: 6), pp. 1965–71, DOI: 10.1182/blood-2006-01-010124, PMID: 16757690, PMC: 1895548, [unreliable medical source?]
  17. ↑ , Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome, British Journal of Haematology, 2009, Vol. 145(Issue: 1), pp. 101–6, DOI: 10.1111/j.1365-2141.2009.07595.x, PMID: 19208097, PMC: 2819393, [unreliable medical source?]
  18. ↑ , Rapid regression of lymphadenopathy upon rapamycin treatment in a child with autoimmune lymphoproliferative syndrome, Pediatric Blood & Cancer, 2009, Vol. 53(Issue: 6), pp. 1117–9, DOI: 10.1002/pbc.22151, PMID: 19588524, [unreliable medical source?]
  19. ↑ , Autoimmune Lymphoproliferative Syndrome: New Approaches to Diagnosis and Management, Clinical Advances in Hematology & Oncology, 2011, Vol. 9(Issue: 3), pp. 233–5, PMID: 21475130, Full text, [unreliable medical source?]
  20. ↑ , Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: Preliminary results of a clinical cohort study and molecular observations, British Journal of Haematology, 2002, Vol. 117(Issue: 1), pp. 176–88, DOI: 10.1046/j.1365-2141.2002.03357.x, PMID: 11918552, [unreliable medical source?]
  21. ↑ , Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr-/- mice or in patients with autoimmune lymphoproliferative syndrome, American Journal of Hematology, 2007, Vol. 82(Issue: 12), pp. 1049–55, DOI: 10.1002/ajh.21007, PMID: 17674358,
  22. ↑ , Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS), Pediatric Blood & Cancer, 2009, Vol. 52(Issue: 7), pp. 847–52, DOI: 10.1002/pbc.21965, PMID: 19214977, PMC: 2774763,
  23. ↑ , How I treat autoimmune lymphoproliferative syndrome, Blood, 2011, Vol. 118(Issue: 22), pp. 5741–51, DOI: 10.1182/blood-2011-07-325217, PMID: 21885601, PMC: 3228494,
  24. ↑ , A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation, Blood, 2011, Vol. 118(Issue: 18), pp. 4798–807, DOI: 10.1182/blood-2011-04-347641, PMID: 21885602,


External links[edit | edit source]

Classification
External resources
Medicine-stub.png
This article is a stub related to medicine. You can help WikiMD by expanding it!
WikiMD
Navigation: Wellness - Encyclopedia - Health topics - Disease Index‏‎ - Drugs - World Directory - Gray's Anatomy - Keto diet - Recipes

Search WikiMD

Ad.Tired of being Overweight? Try W8MD's physician weight loss program.
Semaglutide (Ozempic / Wegovy and Tirzepatide (Mounjaro / Zepbound) available.
Advertise on WikiMD

WikiMD's Wellness Encyclopedia

Let Food Be Thy Medicine
Medicine Thy Food - Hippocrates

Medical Disclaimer: WikiMD is not a substitute for professional medical advice. The information on WikiMD is provided as an information resource only, may be incorrect, outdated or misleading, and is not to be used or relied on for any diagnostic or treatment purposes. Please consult your health care provider before making any healthcare decisions or for guidance about a specific medical condition. WikiMD expressly disclaims responsibility, and shall have no liability, for any damages, loss, injury, or liability whatsoever suffered as a result of your reliance on the information contained in this site. By visiting this site you agree to the foregoing terms and conditions, which may from time to time be changed or supplemented by WikiMD. If you do not agree to the foregoing terms and conditions, you should not enter or use this site. See full disclaimer.
Credits:Most images are courtesy of Wikimedia commons, and templates, categories Wikipedia, licensed under CC BY SA or similar.

Retrieved from "https://wikimd.com/w/index.php?title=Autoimmune_lymphoproliferative_syndrome&oldid=5181016"

Contributors: Prab R. Tumpati, MD