Autoimmune lymphoproliferative syndrome

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Autoimmune lymphoproliferative syndrome
Other namesCanale-Smith syndrome, [1]
Specialty Immunology   OOjs UI icon edit-ltr-progressive.svg

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

Contents

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]

Signs and symptoms

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.[ citation needed ]

Autoimmune disease is the second most common clinical manifestation and one that most often requires treatment. The most common autoimmune presentations include autoimmune cytopenias, which can be mild to very severe and intermittent or chronic. [5] These include autoimmune hemolytic anemia, autoimmune neutropenia, and autoimmune thrombocytopenia. Other autoimmune manifestations can be similar to systemic lupus erythematosus (least common, affecting <5% of patients). Manifestations within the nervous system can include autoimmune cerebellar ataxia, Guillain–Barré syndrome, and transverse myelitis. Manifestations in the gastrointestinal system can include atrophic gastritis, and autoimmune hepatitis, esophagitis, colitis, and pancreatitis. Other manifestations can affect the skin (hives), lungs (bronchiolitis obliterans), or kidneys (autoimmune glomerulonephritis and 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

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] The disease is inherited in an autosomal dominant manner, but it shows incomplete penetrance with up to 40% of people with a FAS mutation not showing symptoms. [7]

Diagnosis

Diagnostic algorithm

The old diagnostic criteria for the illness included: [12] Chronic non-malignant lymphoproliferation, elevated peripheral blood DNTs and defective in vitro Fas mediated apoptosis.

The new criteria [13] 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.[ citation needed ]

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

2003 nomenclature [12]

Revised nomenclature (2010) [13]

Treatment

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.[ citation needed ]

Second line therapies include: mycophenolate mofetil (cellcept) [16] 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.[ citation needed ]

Sirolimus (rapamycin, rapamune) which is a mTOR (mammalian target of rapamycin) inhibitor [17] can be active in most patients and can in some cases lead to complete or near-complete resolution of autoimmune disease (>90%) [18] [19] 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 [20] 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, [21] [22] mercaptopurine: More commonly used in Europe. Another is rituximab but this can cause protracted hypogammaglobulinemia [23] and a splenectomy but there is a >30% risk of pneumococcal sepsis even with vaccination and antibiotic prophylaxis [24] [25]

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References

  1. 1 2 Straus SE, Jaffe ES, Puck JM; et al. (Jul 2001). "The development of lymphomas in families with autoimmune lymphoproliferative syndrome with germline Fas mutations and defective lymphocyte apoptosis". Blood. 98 (1): 194–200. doi:10.1182/blood.v98.1.194. PMID   11418480.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  2. ↑ Fleisher, Thomas A. (2007). "The autoimmune lymphoproliferative syndrome: An experiment of nature involving lymphocyte apoptosis". Immunologic Research. 40 (1): 87–92. doi:10.1007/s12026-007-8001-1. PMID   18193364. S2CID   34565602.[ unreliable medical source? ]
  3. ↑ Rao, V. Koneti; Straus, Stephen E. (2006). "Causes and consequences of the autoimmune lymphoproliferative syndrome". Hematology. 11 (1): 15–23. doi: 10.1080/10245330500329094 . PMID   16522544. S2CID   21782729.
  4. ↑ Teachey, David T.; Seif, Alix E.; Grupp, Stephan A. (2010). "Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)". British Journal of Haematology. 148 (2): 205–16. doi:10.1111/j.1365-2141.2009.07991.x. PMC   2929682 . PMID   19930184.
  5. ↑ Teachey, David T.; Manno, Catherine S.; Axsom, Kelly M.; Andrews, Timothy; Choi, John K.; Greenbaum, Barbara H.; McMann, Joseph M.; Sullivan, Kathleen E.; 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.[ 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. ↑ Autoimmune Lymphoproliferative Syndrome (ALPS) Causes. (2019, April 19). NIH: National Institute of Allergy and Infectious Diseases. https://www.niaid.nih.gov/diseases-conditions/autoimmune-lymphoproliferative-syndrome-causes
  8. ↑ Bleesing, Jack J.H.; Brown, Margaret R.; Novicio, Cynthia; Guarraia, David; Dale, Janet K.; Straus, Stephen E.; Fleisher, Thomas A. (2002). "A Composite Picture of TcRα/β+ CD4−CD8− T Cells (α/β-DNTCs) in Humans with Autoimmune Lymphoproliferative Syndrome". Clinical Immunology. 104 (1): 21–30. doi:10.1006/clim.2002.5225. PMID   12139944.[ unreliable medical source? ]
  9. ↑ Magerus-Chatinet, Aude; Stolzenberg, Marie-Claude; Loffredo, Maria S.; Neven, Bénédicte; Schaffner, Catherine; Ducrot, Nicolas; Arkwright, Peter D.; Bader-Meunier, Brigitte; et al. (2009). "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. 113 (13): 3027–30. doi: 10.1182/blood-2008-09-179630 . PMID   19176318.[ unreliable medical source? ]
  10. ↑ Caminha, Iusta; Fleisher, Thomas A.; Hornung, Ronald L.; Dale, Janet K.; Niemela, Julie E.; Price, Susan; Davis, Joie; Perkins, Katie; et al. (2010). "Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome". Journal of Allergy and Clinical Immunology. 125 (4): 946–949.e6. doi:10.1016/j.jaci.2009.12.983. PMC   3412519 . PMID   20227752.[ unreliable medical source? ]
  11. ↑ Seif, A. E.; Manno, C. S.; Sheen, C.; Grupp, S. A.; Teachey, D. T. (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.[ unreliable medical source? ]
  12. 1 2 Sneller, Michael C.; Dale, Janet K.; Straus, Stephen E. (2003). "Autoimmune lymphoproliferative syndrome". Current Opinion in Rheumatology. 15 (4): 417–21. doi:10.1097/00002281-200307000-00008. PMID   12819469. S2CID   21295897.
  13. 1 2 Oliveira, J. B.; Bleesing, J. J.; Dianzani, U.; Fleisher, T. A.; Jaffe, E. S.; Lenardo, M. J.; Rieux-Laucat, F.; Siegel, R. M.; 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.
  14. ↑ Kuehn, H. S.; Caminha, I.; Niemela, J. E.; Rao, V. K.; Davis, J.; Fleisher, T. A.; Oliveira, J. B. (2011). "FAS Haploinsufficiency is a Common Disease Mechanism in the Human Autoimmune Lymphoproliferative Syndrome". The Journal of Immunology. 186 (10): 6035–43. doi:10.4049/jimmunol.1100021. PMC   3725553 . PMID   21490157.[ unreliable medical source? ]
  15. ↑ Holzelova, Eliska; Vonarbourg, Cédric; Stolzenberg, Marie-Claude; Arkwright, Peter D.; Selz, Françoise; Prieur, Anne-Marie; Blanche, Stéphane; Bartunkova, Jirina; et al. (2004). "Autoimmune Lymphoproliferative Syndrome with SomaticFasMutations". New England Journal of Medicine. 351 (14): 1409–18. doi: 10.1056/NEJMoa040036 . PMID   15459302.[ unreliable medical source? ]
  16. ↑ Koneti Rao, V.; Dugan, Faith; Dale, Janet K.; Davis, Joie; Tretler, Jean; Hurley, John K.; Fleisher, Thomas; Puck, Jennifer; Straus, Stephen E. (2005). "Use of mycophenolate mofetil for chronic, refractory immune cytopenias in children with autoimmune lymphoproliferative syndrome". British Journal of Haematology. 129 (4): 534–8. doi: 10.1111/j.1365-2141.2005.05496.x . PMID   15877736.[ unreliable medical source? ]
  17. ↑ Teachey, D. T.; Obzut, DA; Axsom, K; Choi, JK; Goldsmith, KC; Hall, J; Hulitt, J; Manno, CS; 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.[ unreliable medical source? ]
  18. ↑ Teachey, David T.; Greiner, Robert; Seif, Alix; Attiyeh, Edward; Bleesing, Jack; Choi, John; Manno, Catherine; Rappaport, Eric; et al. (2009). "Treatment with sirolimus results in complete responses in patients with autoimmune lymphoproliferative syndrome". British Journal of Haematology. 145 (1): 101–6. doi:10.1111/j.1365-2141.2009.07595.x. PMC   2819393 . PMID   19208097.[ unreliable medical source? ]
  19. ↑ 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". Pediatric Blood & Cancer. 53 (6): 1117–9. doi: 10.1002/pbc.22151 . PMID   19588524.[ unreliable medical source? ]
  20. ↑ Teachey, David T. (2011). "Autoimmune Lymphoproliferative Syndrome: New Approaches to Diagnosis and Management". Clinical Advances in Hematology & Oncology. 9 (3): 233–5. PMID   21475130. Archived from the original on 2012-04-26.[ unreliable medical source? ]
  21. ↑ Van Der Werff Ten Bosch, Jutte; Schotte, Peter; Ferster, Alice; Azzi, Nadira; Boehler, Thomas; Laurey, Genevieve; Arola, Mikko; Demanet, Christian; et al. (2002). "Reversion of autoimmune lymphoproliferative syndrome with an antimalarial drug: Preliminary results of a clinical cohort study and molecular observations". British Journal of Haematology. 117 (1): 176–88. doi: 10.1046/j.1365-2141.2002.03357.x . PMID   11918552.[ unreliable medical source? ]
  22. ↑ Rao, V. Koneti; Dowdell, Kennichi C.; Dale, Janet K.; Dugan, Faith; Pesnicak, Lesley; Bi, Lilia L.; Hoffmann, Victoria; Penzak, Scott; et al. (2007). "Pyrimethamine treatment does not ameliorate lymphoproliferation or autoimmune disease in MRL/lpr-/- mice or in patients with autoimmune lymphoproliferative syndrome". American Journal of Hematology. 82 (12): 1049–55. doi:10.1002/ajh.21007. PMID   17674358. S2CID   35312783.
  23. ↑ Rao, V. Koneti; Price, Susan; Perkins, Katie; Aldridge, Patricia; Tretler, Jean; Davis, Joie; Dale, Janet K.; Gill, Fred; et al. (2009). "Use of rituximab for refractory cytopenias associated with autoimmune lymphoproliferative syndrome (ALPS)". Pediatric Blood & Cancer. 52 (7): 847–52. doi:10.1002/pbc.21965. PMC   2774763 . PMID   19214977.
  24. ↑ Rao, V. K.; Oliveira, J. B. (2011). "How I treat autoimmune lymphoproliferative syndrome". Blood. 118 (22): 5741–51. doi:10.1182/blood-2011-07-325217. PMC   3228494 . PMID   21885601.
  25. ↑ Neven, Bénédicte; Magerus-Chatinet, Aude; Florkin, Benoit; Gobert, Delphine; Lambotte, Olivier; De Somer, Lien; Lanzarotti, Nina; Stolzenberg, Marie-Claude; et al. (2011). "A survey of 90 patients with autoimmune lymphoproliferative syndrome related to TNFRSF6 mutation". Blood. 118 (18): 4798–807. doi: 10.1182/blood-2011-04-347641 . PMID   21885602.
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