Early Detection of Immune-Dysregulation Predicts a Better Response to Immunosuppressive Treatment in Chronic Immune Thrombocytopenia

Introduction Chronic immune thrombocytopenia (ITP) may represent the epiphenomenon of a complex immune-dysregulation process. Not all patients respond with equal effectiveness to different therapies as immunosuppressant (MMF and Sirolimus) or TPO-agonists, and no specific indicators at diagnosis are available to predict response. Aims To identify a group of clinical and immunological variables predictive of response to a specific second-line therapy. Methods Lymphocytes subsets including ALPS panel (double-negative T-lymphocytes—DNTs-, B220+DNTs, CD27+B cells, and CD3+CD25+/HLADR+ ratio), ALPS biomarkers (IL10, IL18, and sFAS), Ig serum levels, autoantibody screening, and Coombs test were analyzed at diagnosis, after at least 6 months, and after response to a second-line therapy. Results 72 consecutive patients with persistent/chronic ITP have been retrospectively studied. 17/72 (24%) responded to first-line therapy consisting of steroids and/or IVIG. Thirty-three of the remaining 55 responded to immunosuppressants (28) or TPO-agonists (5) given as second-line treatment. The remaining 22 patients underwent treatment with TPO-agonist after immunosuppressant failure (20) or immunosuppressant after TPO-agonist failure (2). Overall, 17 (24%) patients responded to first-line therapy, 31 (43%) and 16 (22%) patients responded to immunosuppressant and TPO-agonists, respectively, and 8 (11%) patients did not respond to any treatment. Table 1 shows patients’ demographic/clinical characteristics according to the response. Signs of immune-dysregulation in the acute phase such as DNT>1.5%, reduced in CD4 (p = 0.05) and NK cells (p = 0.05), and the simultaneous presence of ¾ positive parameters of the ALPS panel (p < 0.05) predicted a better response to immunosuppressant than to TPO-agonists. Furthermore, 51 patients were studied after the response to the treatment: in addition to platelets count, patients responding to immunosuppressants showed a statistically significant reduction of lymphoproliferation (p 0.025) and normalization of CD4+ (p 0.01), NK cells (p 0.08), (p 0.016), B220+DNTs (p 0.001), CD25/HLADR+ ratio (p 0.035), IL-18 (p 0.02), and ANA positivity compared with the others. Table 1.Demographic and clinical characteristics of the 72 patients according to the responseTotal n=72First-line th response n=17IS response n=31TPO-A response n=16Non responder n=8Overall response (P-value)IS vs tpo-A (P-value)Female, n (%)39 (54)11 (65)16 (52)9 (52)3 (37)0.6660.763Age at onset, yrs, median (IQR)9.1 (5.2-12.4)9.9 (6.8-13.5)9 (5.5-12.3)10 (6.5-14.3)4.2 (3.1-6)0.0170.296Age at onset >9.1 yrs, n (%)36 (50)10 (59)15 (48)11 (69)00.0090.183Cutaneous/mucosal diathesis, yes, n (%)651 (90)14 (82)28 (90)15 (94)8 (100.0)0.6701.000Family history,2 yes, n(%)17 (24)6 (35)9 (29)2 (12)00.1490.287Splenomegaly3/Lymphofoproliferation4, n (%)9 (12.5)09 (29)000.0040.019Low IgA, n (%)13 (18.1)1 (5.9)9 (29)2 (12.5)1 (12.5)0.2200.287Low IgG n (%)7/66 (11)0/164/31 (13)3/16 (19)0/30.3470.676Low IgM n (%)3/70 (4.3)0/173/30 (10)0/160/70.5140.542IgG subclasses abnormalities, n (%)8/60 (13)4/16 (25)3/29 (10)1/12 (8)0/30.5151.000Reduced response to vaccines6/32 (19)0/96/19 (32)0/20/20.2311.000Antinuclear antibodies, yes, n (%)17/70 (24)4/16 (25)10/31 (32)2/16 (12)1/7 (14)0.5190.176Antithyroid antibodies, yes, n (%)5/70 (7)1/16 (6)2/31 (6)2/15 (13)0/80.7680.587Anti-red blood cells antibodies, yes, n (%)8/70 (11)0/168/31 (26)0/160/70.0130.038Anti-transglutaminase antibodies, yes, n (%)1/71 (1)1/16 (6)0000.5631Exclusively cutaneous involvement, n=33;2family history of autoimmune diseases in first-degree relatives;3defined based on age-specific values of longitudinal spleen diameter, measured by abdominal ultrasound;4defined based on the presence of persistent lateral cervical and/or axillary and/or inguinal and/or intra-abdominal adenopathies identified by clinical examination or targeted ultrasound, lasting for more than 6 months and without an alternative diagnosis. Conclusions An early immunophenotypic characterization at diagnosis represents a useful tool in the choice of second-line therapy and an indicator to perform early genetic studies for a potential target therapy.