Long-term follow-up of IPEX syndrome patients after different therapeutic strategies: An international multicenter retrospective study

Abstract

Background: Immunodysregulation polyendocrinopathy enteropathy x-linked (IPEX) syndrome is a monogenic autoimmune disease caused by FOXP3 mutations. Because it is a rare disease, the natural history and response to treatments, including allogeneic hematopoietic stem cell transplantation (HSCT) and immunosuppression (IS), have not been thoroughly examined.

Objective: This analysis sought to evaluate disease onset, progression, and long-term outcome of the 2 main treatments in long-term IPEX survivors.

Methods: Clinical histories of 96 patients with a genetically proven IPEX syndrome were collected from 38 institutions worldwide and retrospectively analyzed. To investigate possible factors suitable to predict the outcome, an organ involvement (OI) scoring system was developed.

Results: We confirm neonatal onset with enteropathy, type 1 diabetes, and eczema. In addition, we found less common manifestations in delayed onset patients or during disease evolution. There is no correlation between the site of mutation and the disease course or outcome, and the same genotype can present with variable phenotypes. HSCT patients (n = 58) had a median follow-up of 2.7 years (range, 1 week-15 years). Patients receiving chronic IS (n = 34) had a median follow-up of 4 years (range, 2 months-25 years). The overall survival after HSCT was 73.2% (95% CI, 59.4-83.0) and after IS was 65.1% (95% CI, 62.8-95.8). The pretreatment OI score was the only significant predictor of overall survival after transplant (P = .035) but not under IS.

Conclusions: Patients receiving chronic IS were hampered by disease recurrence or complications, impacting long-term disease-free survival. When performed in patients with a low OI score, HSCT resulted in disease resolution with better quality of life, independent of age, donor source, or conditioning regimen.

Keywords: FOXP3; IPEX; Treg cells; enteropathy; genetic autoimmunity; hematopoietic stem cell transplantation; immunosuppression; neonatal diabetes; primary immune deficiency; rapamycin.

FIG 1

Patients’ demographics and disease-related characteristics. A, Diagnostic delay scatter plot displaying correlation between age at diagnosis and age at onset (n = 96). Spearman’s rank correlation ρ = 0.456, P < .001. B, Histogram distribution of number of patients diagnosed between 2001 and 2015. Overlaid density distribution showed in blue. C, Heat map of number of symptoms at onset grouped by age at onset. Symptoms present in each age group (indicated by rows) were scaled (z-score or standardized score) and then converted to colors from yellow (low = less frequent) to red (high = highly frequent). Data were not available (NA) for 3 patients; 1 patient has the mutation but has not yet experienced the onset; and for 2 patients, the first symptom is unknown. D, Bar graph comparing frequency of symptoms at onset and later during disease evolution. Every bar indicates number of patients presenting each symptom. However, each patient can exhibit >1 symptom at once. E, Uncommon manifestations. Every bar indicates number of patients presenting each symptom. F, Scatter plot of FOXP3 gene mutations grouped by domain, indicating age at onset (circles) and number of symptoms at onset (asterisks), with median (n = 87; for 10 patients, cDNA FOXP3 mutations were not specified). Gene structure: N-terminal proline-rich (PRR) domain (orange), zinc-finger (ZF) domain (green), leucine-zipper (LZ) domain (blue), LZ-FKH loop (yellow), and FKH domain (red). Mutations were grouped as follows: <c.1 to c.570> 5 E1-5 N-terminal domain, <c.591 to c.666> = E5-6 ZF domain, <c.717 to c.780> = E6-7 LZ domain, <c.781 to c.1010> = E7-9 LZ-FKH loop domain, <c.1011 to c.1251> = E9-11 FKH domain. AIHA, Autoimmune hemolytic anemia; AIN, autoimmune neutropenia; AT, autoimmune thyroiditis; FTT, failure to thrive; ITP, idiopathic thrombocytopenic purpura; Neph, nephropathy; LN, lymphadenopathy; PRR, proline-rich region; UTR, untranslated region.

FIG 2

Timeline of natural history and disease evolution. Patients undergoing HSCT (A) and IS (B). Each line represents a patient identified by his FOXP3 mutation in order of localization on the gene. The end on the line represents the last day of follow-up, and different symbols represent age at onset (circles) and age at HSCT (triangles) or the beginning of IS. An X at the end of the line indicates the age of death. The color of the line indicates the disease status after treatment, whether the patient went into remission (blue), was still diabetic (gray) or not cured (red). NA, Not available.

FIG 3

Immunosuppressive therapy. A, Bar graph indicating numbers of patients exhibiting response, partial benefit, or no response according to a specific immunosuppressive drug administered (n = 34; however, each patient received >1 drug). B, Bar graph indicating each patient’s outcome after treatment with a combination of drugs, as last treatment. Each bar represents the number of patients receiving the treatment, distinguishing those in remission from those with additional or persistent autoimmunity (n = 34). C, Pre- and post-IS patients’ conditions, each bar represents the number of patients presenting each condition. On the right side, the relative percentage is reported (n = 34; however, each patient could present with >1 condition at once). D, Percentage of survival for patients undergoing IS (n = 34) according to score post-IS (P = .0444). AZA, Azathioprine; Ca Inhib, calcineurin inhibitors; CTLA, cytotoxic T lymphocyte–associated antigen; MTX, methotrexate; MMF, mycophenolate mofetil; “others”, any different IS (eg, 6-mercaptopurina, mesalazine); RAPA, rapamycin.

FIG 4

Survival analysis of patients undergoing HSCT. Percentage of survival of patients undergoing HSCT (n = 58) according to conditioning (log-rank test, P = .234) (A), donor type (P = .886) (B), age at HSCT (P = .359) (C), score pre-HSCT (P = .003) (D), score and conditioning (P = .010) (E), and score and age at HSCT (P = .019) (F). A survival probability table accompanies those plots that show significant differences (time points: 6 months, and 1, 3, 5, and 10 years). Full C, Full conditioning regimen; MMRD, mismatched related donor; MMUCB, mismatched unrelated cord blood; MMUD, mismatched unrelated donor; MSD, matched sibling donor; MUD, matched unrelated donor.

FIG 5

Probability of survival and disease status after treatment. A, Survival analysis of IPEX patients undergoing HSCT or IS (n = 92, P = .055). B, Disease-free survival analysis of IPEX patients undergoing IS or HSCT censored for deaths (n = 81, P = .419).