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• W2116847416 abstract "To the Editor: The autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic lymphadenopathy, splenomegaly, autoimmune cytopenias, and expansion of T cell receptor (TCR) αβ+ CD3+CD4–CD8– (αβ-double-negative [DNT]) cells (see this article's Table E1 in the Online Repository at www.jacionline.org). Approximately two thirds of the patients with ALPS symptoms are genetically characterized, and most have germline (ALPS Ia) or somatic (ALPS Ia-s) TNFRSF6 (FAS) mutations. A small number of patients have defects in genes encoding Fas ligand (ALPS Ib), caspase-10 (ALPS II), or neuroblatoma-RAS (NRAS) viral oncogene homolog (ALPS IV). In addition, a large group of patients with ALPS findings remain genetically uncharacterized (ALPS III), and yet another has an undefined ALPS-like syndrome (ALPS-phenotype; Table I).1Bidere N. Su H.C. Lenardo M.J. Genetic disorders of programmed cell death in the immune system.Annu Rev Immunol. 2006; 24: 321-352Crossref PubMed Scopus (163) Google Scholar, 2Oliveira J.B. Bidere N. Niemela J.E. Zheng L. Sakai K. Nix C.P. et al.NRAS mutation causes a human autoimmune lymphoproliferative syndrome.Proc Natl Acad Sci U S A. 2007; 104: 8953-8958Crossref PubMed Scopus (79) Google Scholar Given the clinical similarities among all these groups, we sought to develop a biomarkers-based algorithm to predict the presence or absence of FAS mutations in this setting.Table IDescription of patients with ALPS and control groups included in the studyClassificationDescriptionNo. of subjectsALPS IaPatients with ALPS and germline FAS mutations162ALPS Ia-sPatients with ALPS and somatic FAS mutations9Healthy mutation-positive relativesHealthy relatives of patients with ALPS Ia who carry a FAS mutation115Mutation negative relativesHealthy relatives of patients with ALPS Ia who do not carry a FAS mutation179ALPS IIIPatients who fulfill criteria for ALPS but have no causative mutation identified52ALPS-phenotypePatients with autoimmune cytopenias, lymphadenopathy/splenomegaly, and αβ-DNT cells >1%, without genetic abnormalities or lymphocyte defective apoptosis40 Open table in a new tab To this end, we investigated 26 parameters including immunophenotyping, eosinophil and monocyte counts, serum or plasma vitamin B12 (B12), soluble FAS ligand (sFASL), immunoglobulins, and levels of 14 cytokines in 562 subjects classified into 6 categories (Tables I and E1). The number of measurements, medians, and first and third quartiles are presented in this article's Tables E2 and E3 in the Online Repository at www.jacionline.org. A full description of the Methods can be found in the Online Repository at www.jacionline.org. Elevated αβ-DNT cells are a hallmark of ALPS, but their utility for predicting FAS mutations had not been previously evaluated.3Sneller M.C. Straus S.E. Jaffe E.S. Jaffe J.S. Fleisher T.A. Stetler-Stevenson M. et al.A novel lymphoproliferative/autoimmune syndrome resembling murine lpr/gld disease.J Clin Invest. 1992; 90: 334-341Crossref PubMed Scopus (255) Google Scholar Patients with ALPS Ia and Ia-s had a high percentage of αβ-DNT cells, with median values 5.1% and 7.7%, respectively, compared with 0.5% for control mutation-negative relatives (MNRs; P < .0001; Fig 1, A; Table E2). The αβ-DNT level was predictive of FAS mutations, with values >4% found in 60% (90/152) of patients with type Ia and in the majority of patients with type Ia-s (7/9), but in only 13% (11/85) of patients with ALPS type III and ALPS-phenotype (Fig 1, A). This value was associated with a positive likelihood ratio (LR) of 5.0 and a posttest probability of 89.3% for harboring FAS mutations. Conversely, the presence of αβ-DNT cells in the 1% to 2% range decreased the posttest probability to 25%, with a LR of 0.19 (Fig 2, B and C; see this article's Table E4 in the Online Repository at www.jacionline.org).Fig 2sFASL levels and combinations of biomarkers accurately predict FAS mutations. A, Scatter plot showing sFASL levels. Increasing (B) and decreasing (C) probabilities for having a FAS mutation according to the percentage of αβ-DNT cells, levels of vitamin B12, IL-10, IL-18, sFASL, and results of FAS-induced apoptosis assay. Bars denote median values. P values for the differences between groups were obtained by Mann-Whitney test and are shown above each graph (∗∗∗P < .0001; ∗∗P < .001; ∗P < .05; NS, no significant difference). HMPR, Healthy mutation-positive relative.View Large Image Figure ViewerDownload Hi-res image Download (PPT) In line with previous reports, patients with ALPS, regardless of mutation status, had <16% of circulating B cells expressing the memory marker CD27 (Fig 1, B) 4Bleesing J.J. Brown M.R. Straus S.E. Dale J.K. Siegel R.M. Johnson M. et al.Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome.Blood. 2001; 98: 2466-2473Crossref PubMed Scopus (79) Google Scholar. Finding memory B cells >16% made the diagnosis of ALPS very unlikely (LR = 0.17). Other described abnormalities including increased CD3+HLA-DR+ to CD3+CD25+ ratio and high number of B cells had no additional diagnostic utility.4Bleesing J.J. Brown M.R. Straus S.E. Dale J.K. Siegel R.M. Johnson M. et al.Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome.Blood. 2001; 98: 2466-2473Crossref PubMed Scopus (79) Google Scholar We also evaluated serum B12 levels in patients with ALPS and found very elevated median levels in ALPS Ia and Ia-s (2259 ng/L; 1653 ng/L) compared with control MNRs (474 ng/L; P < .0001) and healthy mutation-positive relatives (570 ng/L; P < .0001). A modest but statistically significant increase was also noted in ALPS III and ALPS-phenotype, with medians of 759 ng/L and 943 ng/L, respectively (Fig 1, C). Levels above 1500 ng/L were observed in only 15% (4/28) of the patients with ALPS type III and ALPS-phenotype, contrasting with 63% (72/114) of patients with ALPS Ia. The LR for a FAS mutation with B12 levels >1500 ng/L was 4.0, with a posttest probability of 87%. In contrast, having B12 levels <1000 ng/L diminished the posttest probability to 35% (Fig 2, B and C; Table E4). Analysis of plasma cytokines revealed 2 additional biomarkers for ALPS: IL-18 and TNF-α. Median plasma IL-18 levels were elevated in patients with ALPS Ia and Ia-s compared with control MNRs (1041 pg/mL, 1526 pg/mL, and 208 pg/mL, respectively; P < .0001). Patients with ALPS III and ALPS-phenotype had median values of 521 pg/mL and 702 pg/mL, respectively (P < .001 compared with MNRs; Fig 1, D). Furthermore, IL-18 <500 pg/mL was rarely seen in patients with ALPS and FAS mutations (7/56), with an associated negative LR of 0.19. TNF-α levels were higher in all ALPS groups with median values of 5 pg/mL for ALPS Ia (P < .0001), 9 pg/mL for ALPS Ia-s (P < .05), 8 pg/mL for ALPS III (P < .0001), and 7 pg/mL for ALPS-phenotype (P < .0001) compared with 1.3 pg/mL for MNRs (Fig 1, E). As previously reported, IL-10 was markedly elevated in ALPS Ia and Ia-s compared with MNRs (P < .0001) and patients with ALPS III and ALPS-phenotype (P < .0001)5Lopatin U. Yao X. Williams R.K. Bleesing J.J. Dale J.K. Wong D. et al.Increases in circulating and lymphoid tissue interleukin-10 in autoimmune lymphoproliferative syndrome are associated with disease expression.Blood. 2001; 97: 3161-3170Crossref PubMed Scopus (86) Google Scholar, 6Fuss I.J. Strober W. Dale J.K. Fritz S. Pearlstein G.R. Puck J.M. et al.Characteristic T helper 2 T cell cytokine abnormalities in autoimmune lymphoproliferative syndrome, a syndrome marked by defective apoptosis and humoral autoimmunity.J Immunol. 1997; 158: 1912-1918PubMed Google Scholar (Fig 1, F). Sixty percent (83/139) of the patients with ALPS Ia and all patients with ALPS Ia-s exhibited values >40 pg/mL, contrasting with 26% (10/38) of patients with ALPS III and ALPS-phenotype. For levels of IL-10 >40 ng/mL, the positive LR was 3.8, with a posttest probability of 85% for having a FAS mutation. Notably, only 20% (29/141) of patients with ALPS Ia and no patients with ALPS Ia-s had IL-10 values <20 pg/mL, giving a negative LR of 0.31 and a posttest probability of 33% for FAS mutations (Fig 2, B and C; Table E4). A recent report documented high levels of sFASL in patients with ALPS.7Magerus-Chatinet A. Stolzenberg M.C. Loffredo M.S. Neven B. Schaffner C. Ducrot N. et al.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. 2009; 113: 3027-3030Crossref PubMed Scopus (106) Google Scholar We expanded these findings analyzing more than 200 patients and controls. Ninety-seven percent of patients with ALPS Ia (136/140) and all patients with ALPS Ia-s had plasma sFASL >200 pg/mL, with median values of 1114 pg/mL and 1329 pg/mL, respectively, compared with control MNR levels of 104 pg/mL (P < .0001 for both groups). Only modest elevations of sFASL were seen in patients with ALPS III and ALPS-phenotype, as well as healthy mutation-positive relatives, with median values of 208 pg/mL, 174 pg/mL, and 207 pg/mL, respectively (Fig 2, A). These findings make sFASL the most sensitive biomarker to rule out a FAS mutation, with values <200 pg/mL associated with a negative LR of 0.05 and a posttest probability of 7.7% (Fig 2, C; Table E4). Soluble FASL also showed a strong positive correlation with IL-10 (r = 0.8; P < .0001) and a moderate correlation with αβ-DNT cells (r = 0.6; P < .0001) and B12 levels (r = 0.69; P < .0001; see this article's Fig E1, A, in the Online Repository at www.jacionline.org). The area under the ROC curve for sFASL, αβ-DNT cells, B12, and IL-10 levels were calculated to evaluate how well they discriminate patients with a FAS mutation from those without (Fig E1, B). The area under the curve for sFASL was 0.9 (defines an excellent test) and for αβ-DNT cells was 0.81. B12 and IL-10 exhibited areas significantly less than sFASL (P < .05), with values of 0.76 and 0.77. We next evaluated whether combinations of αβ-DNT cells, B12, IL-10, IL-18, and sFASL would have increased power to predict or exclude FAS mutations in patients suspected of ALPS (Fig 2, B; Table E4). The combination of αβ-DNT cells >4% with B12 >1500 ng/L or IL-10 >40 pg/mL or IL-18 >500 ng/mL or sFASL >300 pg/mL was associated with >95% probability of having a FAS mutation. Conversely, having αβ-DNT cells <2% in combination with IL-10 <20 pg/mL or B12 <1000 ng/L or IL-18 <500 ng/mL decreased the probability of a FAS mutation to less than 10% (Fig 2, C; Table E4). Finally, finding αβ-DNT cells <2% and sFASL <200 pg/mL resulted in <2% probability for a FAS mutation. In conclusion, the biomarkers described should aid in the selection of patients with findings of ALPS for further diagnostic workup. In addition, the presence of a combination of markers strongly suggestive of a FAS mutation in the setting of a negative genetic test should prompt a search for somatic mutations in sorted αβ-DNT cells. Five hundred sixty-two subjects studied at the National Institutes of Health under an Institutional Review Board–approved protocol were included in this study. All patients presented with lymphadenopathy and/or splenomegaly and αβ-DNT cells above 1% of the total lymphocytes, typically associated with autoimmune cytopenias. Immunophenotyping, mutation analysis, and apoptosis assays were performed as previously described.E1Jackson C.E. Fischer R.E. Hsu A.P. Anderson S.M. Choi Y. Wang J. et al.Autoimmune lymphoproliferative syndrome with defective Fas: genotype influences penetrance.Am J Hum Genet. 1999; 64: 1002-1014Abstract Full Text Full Text PDF PubMed Scopus (181) Google Scholar, E2Oliveira J.B. Bidere N. Niemela J.E. Zheng L. Sakai K. Nix C.P. et al.NRAS mutation causes a human autoimmune lymphoproliferative syndrome.Proc Natl Acad Sci U S A. 2007; 104: 8953-8958Crossref PubMed Scopus (173) Google Scholar, E3Bleesing J.J. Brown M.R. Straus S.E. Dale J.K. Siegel R.M. Johnson M. et al.Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome.Blood. 2001; 98: 2466-2473Crossref PubMed Scopus (121) Google Scholar Vitamin B12 levels, immunoglobulin measurements, and monocyte and eosinophil counts were obtained by reviewing medical and laboratory records of all participants. For patients with repeated measurements, the first available result was used, regardless of the clinical status or ongoing therapy. The quantification of plasma ILs was performed by ELISA following the manufacturer's instructions. sFASL, TNF-α, IL-2, IL-7, IL-13, and IL-15 kits were from R&D Systems (Minneapolis, Minn); IL-18 was from MBL Co, Ltd (Naku-ku Nagoya, Japan); IL-10, IL-1b, IL-4, IL-5, IL-6, and IFN-γ kits were from Endogen; IL-12 was from Biosource International (Camarillo, Calif); and IL-23 from Bender Medsystems (Vienna, Austria). The measurements were performed on frozen plasma samples, and for patients with more than 1 sample available, the first collected sample was used for testing. One technical aspect worth noting is that IL-18 levels are spuriously increased in blood samples shipped overnight, especially in the warm summer months, so that only fresh samples (<8h post drawing time) should be used for analysis. Statistical analysis was performed by using Prism (Graphpad Software, San Diego, Calif), JMP-7 (SAS, Cary, NC) and the statistical and graphics language R version 2.9.0 (http://www.R-project.org). The Wilcoxon-Mann-Whitney test was used to compare groups. Sensitivity and specificity of each biomarker to detect ALPS and FAS mutations were obtained, and LRs (LR+ = sensitivity/100 – specificity; LR– = 100 – sensitivity/specificity), odds ratios (odds posttest = odds pretest × LR), and probabilities ([odd/1 + odd] × 100) were calculated. Pretest odds and probability for having a FAS mutation were obtained by calculating the prevalence of FAS mutations on our whole cohort of patients and were found to be 1.7 and 63%, respectively. When associating more than 1 biomarker, the posttest odds were calculated by multiplying the pretest odds by the combination of LRs (odds posttest = odds pretest × LR1 × LR2 × … × LRn). Receiver operating characteristic curves were used to evaluate the best levels of vitamin B12, IL-10, sFASL, and αβ-DNT able to differentiate FAS mutants from no mutants and to evaluate the accuracy of the biomarkers. Tabled 1National Institutes of Health diagnostic criteria for ALPSRequired criteriaChronic nonmalignant lymphadenopathy and/or splenomegalyCD3+TCRαβ+CD4–CD8– (DNT) cells above 1% of the total lymphocytesLymphocyte apoptosis defectSupporting criteriaFamily history of ALPSCharacteristic histopathologyAutoimmune manifestations Open table in a new tab Tabled 1Medians and first and third quartiles of the biomarkers evaluatedALPS IaALPS Ia-sALPS IIIALPS-phenotypeHMPRMNRBiomarkerNMedian1st/3rd quartileNMedian1st/3rd quartileNMedian1st/3rd quartileNMedian1st/3rd quartileNMedian1st/3rd quartileNMedian1st/3rd quartileDNT (no.)16210148/23999444/212493020/61383920/64106168/29134106/17DNT (%)1625.12.6/8.497.74.8/10.6491.61.1/2.4381.71.5/2.31090.80.5/1.71380.50.3/0.77CD20+ (%)149158.5/20.6818.411.9/27.645158.4/213517.57.9/24.210810.157.4/14.613810.87.9/14CD20+CD27+/CD20+1210.060.03/0.160.0550.052/0.07350.100.05/0.15310.090.04/0.15660.170.13/0.22790.250.18/0.31CD3+CD25+ (%)14716.210.2/23.9811.98.6/16.64612.68.9/18.33613.69.8/22.810624.417.2/33.813125.816.3/32.4CD3+HLA-DR+ (%)1472013.9/27.981511.7/214614.310.5/28.93614.77.8/26.810611.67.9/16.113196.5/13.5B12 (ng/L)11522591151//5216816531154/215316759561/118513943590/116346570338/102252474321/709sFasL (pg/mL)1421114476/189281329608/173239208125/31231174104/25674207132/3544410479/139IL-10 (pg/mL)1465825/1268187104.5/246.243179/35.535116/24.510073/1614641/8IL-1β (pg/mL)4800/1200/01300/1710/1.74310/2.36700/1.9IL-2 (pg/mL)14300/5.5800/0.54300/23510/610200/16.714100/23IL-4 (pg/mL)3700/0200/0800/0400/02500/04100/0IL-5 (pg/mL)3300/2100/0900/1.6500/03900/07100/0IL-6 (pg/mL)14000/280.50/1.254200/2340.50/2.7510200/114200/2IL-7 (pg/mL)2421/410.8910/2.8521/143120.6/43711/3IL-12 (pg/mL)100.290/0.90ND310.5/2.5273.5/10.51400/03400/0IL-13 (pg/mL)3800/8.25100/0700/31.5700/71400/10.53200/0IL-15 (pg/mL)7310/2511/12710.5/2221.51/24520/24710/2IL-18 (pg/mL)591041684/1495615261031/180613521249/155817702399/11736530295/99835208168/355IL-23 (pg/mL)3218392/439.71891211663.5/325.214343299/5262415158.7/280.71320869/445TNF-α (pg/mL)13350/11897.5/9.74183/183471.8/24.59520/51291.30/3IFN-γ (pg/mL)14200/483.51.5/6.254300/33510/4.510100/314200/2IgG (mg/dL)10914801070/1930819001260/2475151040803/1490131190827/205046121510.2/1350541010907/1187IgE (IU/mL)916411/4247298.5/8311195/37.5955/1833207/59473219/66Eosinophils (K/uL)1230.240.12/0.4380.150.06/0.23310.150.1/0.36270.140.08/0.35670.130.07/0.21830.170.1/0.22Monocytes (K/uL)1180.60.4/180.430.34/0.65310.550.44/1.09280.620.51/0.85690.440.35/0.54870.450.36/0.56HMPR, Healthy mutation-positive relative; MNR, mutation negative relative; N, number of subjects studied; ND, not determined. Open table in a new tab HMPR, Healthy mutation-positive relative; MNR, mutation negative relative; N, number of subjects studied; ND, not determined. Tabled 1Biomarkers in patients with ALPS types Ib, II, and IVBiomarkerALPS IbALPS IIALPS IVNo. of patients111DNT (no.)6683888DNT (%)1.5272.2CD20+ (%)1714.149CD20+CD27+/CD20+ND0.20.03CD3+CD25+ (%)6.65.818.7CD3+HLA-DR+ (%)36.758.94.9B12 (ng/L)14574086392sFASL (pg/mL)86165104IL-10 (pg/mL)273539IL-1b (pg/mL)150IL-2 (pg/mL)11015IL-4 (pg/mL)100NDIL-5 (pg/mL)NDND0IL-6 (pg/mL)0ND6IL-7 (pg/mL)NDND4IL-12 (pg/mL)NDNDNDIL-13 (pg/mL)350NDNDIL-15 (pg/mL)NDNDNDIL-18 (pg/mL)NDND2678IL-23 (pg/mL)NDNDNDTNF-α (pg/mL)156.56IFN-γ (pg/mL)553.60IgG (mg/dL)41727101750IgE (IU/mL)10ND5Eosinophils (K/uL)0.70.660.08Monocytes (K/uL)1.41.0592.1ND, Not determined. Open table in a new tab ND, Not determined. Tabled 1Probabilities, likelihood ratios, and odds ratios for having a FAS mutation associated with different biomarker levelsBiomarker(s)FAS mutation probability (%)Likelihood ratioOdds ratioDNT >1% and clinical findings631.7Abnormal apoptosis assay711.462.5IL-10 >40 pg/mL853.285.6IL-10 <20 pg/mL330.310.49B12 >1500 ng/L873.996.8B12 <1000 ng/L350.310.54DNT >4%895.008.5DNT <2%240.190.32IL-18 >500 ng/L772.053.48IL-18 <500 ng/L250.190.33sFASL >300 pg/mL884.57.7sFASL <200 pg/mL7.70.050.08DNT >2% and IL-10 >20 pg/mL88.44.57.62DNT >2% and IL-10 >40 pg/mL93.28.0613.7DNT >4% and IL-10 >20 pg/mL93.99.1615.58DNT >4% and IL-10 >40 pg/mL9716.4727.9DNT >2% and B12 >1000 ng/L89.44.98.40DNT >2% and B12 >1500 ng/L94.39.816.65DNT >4% and B12 >1000 ng/L94.510.117.19DNT >4% and B12 >1500 ng/L972033.9DNT >2% and IL-18 >500 pg/mL89.525.028.54DNT >4% and IL-18 >500 pg/mL9410.2817.47DNT >2% and sFasL >200 pg/mL89.34.918.36DNT >2% and sFasL >300 pg/mL9511.0918.9DNT >4% and sFASL >200 pg/mL94.710.0517.09DNT >4% and sFASL >300 pg/mL9722.738.59DNT <2% and IL-10 <20 pg/mL90.060.10DNT <2% and B12 <1000 ng/L90.060.10DNT <2% and IL-18 <500 ng/L6.00.0370.06DNT <2% and sFASL <200 pg/mL1.60.0090.016 Open table in a new tab" @default.
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• W2116847416 title "Using biomarkers to predict the presence of FAS mutations in patients with features of the autoimmune lymphoproliferative syndrome" @default.
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