Clinical findings and comparisons between atypical and classical IPEX patients.
Twelve patients with FOXP3 mutations were included in our study. Four patients (P1, P2, P3, P4) were reported previously in 2014 (33), but we provided detailed extended follow-up information regarding these patients. P8 and P9 were reported in research-based studies without clinical description (34, 35). The median age at the disease’s onset was 4 (min-max: 0–95) months, which was within the neonatal period in 4 (33.3%), between 1 and 12 months in 5 (41.6%), late-onset beyond 12 months in 3 (25%) patients. The median current age was 10 (min-max: 0.25–26.5) years, with a diagnostic delay of 1.5 (0.08–17.3) years. There was 25% kinship between the parents. The demographic and clinical features are shown in Table 1.
Table 1
The Demographic and clinical features of IPEX patients
Patient | Total (n,%) | P1 | P2 | P3 | P4 | P5 | P6 | P7 | P8 | P9 | P10 | P11 | P12 |
Clinical phenotype | Atypical (58.3%) | Atypical | Classical | Classical | Atypical | Atypical | Classical | Atypical | Classical | Atypical | Atypical | Atypical | Atypical |
Last documented age (mo) | - | 120 | 168 | 3 | 56 | 22 | 30 | 124 | 96 | 318 | 179 | 134 | 134 |
Consanguinity | 25% | - | - | - | - | - | - | + | - | - | - | + | + |
AOO (mo) | Median: 4 (min-max: 0–95) | 2 | 1 | < 1 | 1 | 3 | 5 | 84 | 6 | 8 | < 1 | 24 | 95 |
Insulin-dependent type 1 diabetes mellitus | 16.7% | - | - | + | - | + | - | - | - | - | - | - | - |
Respiratory tract infections (before IS or HSCT) | 58.3% | Pneumonia | - | Pneumonia | - | - | - | URTI and Pneumonia | Pneumonia | Pneumonia | URTI and Pneumonia | URTI | - |
Bronchiectasis | - | - | - | - | - | NA | NA | - | - | - | - | NA | - |
Eczema | 58.3% | - | + | + | - | - | + | + | + | - | - | + | + |
Other skin features | 8.3% | - | - | - | - | - | Severe diaper dermatitis | - | - | - | - | - | - |
Allergic manifestation | 50% | - | - | - | CMA | - | - | Asthma, allergic rhinitis | CMA | Asthma | - | Asthma | Asthma |
Documented bacterial infecitons | 50% | P.aeuriginosa M.gordonae | S.aureus S.epdermidis Stenotrophomonas maltophilia | NA | P.aeuriginosa | - | S.aureus Enterococcus Leuconostoc mesenteroides | - | NA | S.epidermidis non typhi- Salmonella S.enteritica | non typhi- Salmonella | NA | NA |
Documented fungal infections | 50% | - | - | C.albicans | C.albicans | - | C.albicans | C.albicans | - | C.albicans | NA | C.albicans | - |
Documented viral infections | 41.6% | CMV | - | - | CMV | - | COVID-19 | CMV | CMV | - | - | NA | NA |
Severe infections (before IS or HSCT) | 16.6% | - | - | - | - | - | Sepsis | Enterocolitis Sepsis | - | - | - | - | - |
Autoimmunity | 91.6% | + | + | + | + | + | + | + | + | + | + | + | - |
Chronic diarrhea | 75% | + | + | + | + | - | + | + | + | + | + | - | - |
Failure to thrive | 66.7% | + | + | + | + | - | + | + | - | + | - | + | - |
Organomegalies or lymphadenopathies | 41.6% | HSM | Cervical and occipital LAPs | - | - | - | - | - | - | Inguinal LAP | HSM | HSM | - |
Other features | - | Nephrotic syndrome | Focal seizure | - | - | Grade 1 left renal hydronephrosis | - | - | Bileteral hydronephrosis | Aphthous stomatitis | HT, SLE recurrent fever and abdominal pain attacks, arthritis | Esophageal varices | - |
Abbreviations: AOO: Age of onset, M.gordonae: Mycobacterium gordonae, P.aeruginosa: Pseudomonas aeruginosa, C.albicans: Candida albicans; S.aureus: Staphylococcus aureus, S.epidermidis: Staphylococcus epidermidis, CMV: Cytomegalovirus, COVID-19: Coronavirus-19, S.enterica: Salmonella enterica, URTI: Upper respiratory tract infection, SLE: Systemic lupus erythematosus, IgRT: Immunoglobulin replacement therapy, LAP: Lymphadenopathy, HSM: Hepatosplenomegaly, CMA: Cow milk allergy, HT: hypertension, M: Male, F: Female, mo: Month, IS: Immunosuppressant, HSCT: Hematopoietic stem cell transplantation, NA: Not Available. Severe infections are referred to sepsis or meningitis or osteomyelitis. |
Within the median follow-up period of 2.6 (min-max: 0.25–13.5) years, the most common presentations were autoimmunity (91.6%), chronic diarrhea (CD) (75%), and failure to thrive (FTT) (66.7%), followed by eczema (58.3%) and recurrent infections (RIs) (58.3%). Specifically, patients with neonatal onset (P2, P3, P4, P10) showed CD (100%), T1DM (25%), and skin manifestations (50%). These findings proportionally were 80%, 20%, and 40% in patients with disease onset between 1 and 12 months (P1, P5, P6, P8, P9). The classical triad of IPEX was observed only in one patient (P3). Significantly, patients displayed a wide array of organ involvement (Fig. 1A), with RIs and CD presenting with the most severe levels in comparison to other clinical manifestations (Fig. 1B). One patient (P12) had a narrower range of symptoms, characterized by recurrent wheezing and mild atopic dermatitis. Another case (P5) had only neonatal T1DM, controlled well with insulin infusion. Renal manifestations included nephrotic syndrome (P1) and hydronephrosis in two patients (P5, P8). The detailed course of the patients’ clinical conditions over time is described in the Supplementary file.
The presentation of IPEX can be classified as classical or atypical based on clinical findings (14). The atypical form is characterized by a late-onset (i.e., > 1 year of age), mild disease course (i.e., long-term survival without IS or with first-line IS regimens), no enteropathy and/or unusual clinical features (i.e., infrequent manifestations that go beyond the classical triad and/or involve different organs). In this study, there were four patients with classical IPEX (P2, P3, P6, P8) and eight with atypical disease (P1, P4, P5, P7, P9-12) (Fig. 1B and C). Delay in diagnosis was higher in atypical cases (median: 72 vs. 4 months, p = 0.04). The distribution of clinical findings was similar between the atypical and the classical patients. However, allergic manifestations were more pronounced in atypical patients, while skin involvement, CD, and endocrinopathy tended to be frequent in classical IPEX (Fig. 1C).
Autoimmune and allergic findings of IPEX patients.
Autoimmune findings (n = 11, 91.6%) included enteropathy (n = 7, P1, P2, P4, P6, P7, P8, P9), T1DM (n = 2, P3, P5), autoimmune hepatitis (n = 2, P1, P11), autoimmune hemolytic anemia (AIHA) (n = 2, P2, P3), immune thrombocytopenia (ITP) (n = 2, P2, P4), and systemic lupus erythematosus (SLE) (n = 1, P10). Autoantibody testing was positive for coombs test (n = 4, P2, P3, P10, P11), anti-glutamic acid decarboxylase (n = 3, P5, P6, P7), anti-thyroid peroxidase (n = 2, P3, P5), anti-enterocyte antibody (n = 2, P2, P4), antinuclear antibody (n = 2, P10, P11), anti-insulin antibody (n = 1, P5), anti-partial antibody (n = 1, P9), lupus anticoagulant antibody (n = 1, P10), and anti-smooth muscle antibody (n = 1, P11).
Allergic manifestations included asthma (n = 4, P7, P9, P11, P12), rhinitis (n = 1, P7), and cow milk allergy (n = 2, P4, P8). Severe eczema complicated with skin infections was detected in 7 patients (P2, P3, P6, P7, P8, P11, P12) (Fig. 1D).
Endoscopic biopsies with histopathology revealed celiac-like disease in two patients (P6, P9), inflammatory bowel disease (IBD)-like features in two (P7, P8), villous atrophy in three (P2, P4, P6), subtotal villous atrophy in two (P7, P9), and pancolitis accompanied by cytomegalovirus (CMV) in two patients (P1, P8). P7 had chronic inflammation and cryptitis in the ileum (Fig. 1E). P8 also exhibited eosinophilic cryptitis and cow milk allergy. P10 had mucosal congestion in the duodenum and inactive chronic gastritis. P11 had esophageal varices.
Immunological findings of IPEX patients.
Table 2 summarizes laboratory findings of IPEX patients at the time of the diagnosis. Mild leukocytosis and mild lymphopenia were detected in four patients each (33.3% and 33%). Remarkably, four patients (33.3%) exhibited eosinophilia, and nine (75%) showed high serum IgE levels. Low IgG, IgM, and IgA levels were detected in 41.7%, 58.3%, and 50% of the patients, respectively, but vaccine responses were intact. Most patients' T, B, and NK cells were in the normal range. In contrast, some patients revealed lower percentages of T (16.7%), B (16.7%), and NK (16.7%) cells, probably associated with the use of ISs (Table 2). Treg cell quantification, characterized by the CD4+CD25+FOXP3+ cells, revealed a reduction in percentage in only one subject (14.2%), P7, who harbored the R397Q mutation. Detailed immunological evaluations of the newly defined IPEX patients (P5-P12), including T-and B-cell subtypes, are represented in Table S1.
Table 2
The immunological and genetic findings with outcomes of IPEX patients
Patient | Total (n,%) | P1 | P2 | P3 | P4 | P5 | P6 | P7 | P8 | P9 | P10 | P11 | P12 |
Leukocytosis (mild) | 33.3% | - | - | - | - | + | + | - | + | - | + | - | - |
Lymphopenia (mild) | 33.3% | + | - | - | + | - | - | - | - | - | - | + | + |
Eosinophilia | 33.3% | - | + | + | + | + | - | - | - | - | - | - | - |
Low IgG | 41.7% | + | - | - | - | - | - | + | + | + | + | - | - |
Low IgM | 58.3% | + | - | - | - | - | + | + | + | + | + | - | + |
Low IgA | 50% | + | - | + | - | - | + | - | + | + | + | - | - |
High IgE | 75% | - | - | + | + | + | + | + | + | + | + | - | + |
Low CD3+ T cells (%) | 16.7% | + | - | - | + | - | - | - | - | - | - | - | - |
Low CD4+ T cells (%) | 33.3% | + | - | - | + | - | - | - | + | + | - | - | - |
Low CD8+ T cells (%) | 16.7% | + | - | - | + | - | - | - | - | - | - | - | - |
Low CD19+ B cells (%) | 16.7% | + | + | - | - | - | - | - | - | - | - | - | - |
Low CD16+/56+ NK cells (%) | 16.7% | + | - | - | - | - | - | - | + | - | - | - | - |
Low CD4+CD25+FOXP3+ Tregs (%) | 14.2% | - | - | NA | NA | - | - | + | - | - | NA | NA | NA |
Impaired vaccine responses | None | - | - | NA | - | - | - | - | - | - | - | - | NA |
Impaired proliferation | 33.3% | + | + | - | + | - | - | - | + | - | - | - | NA |
Mutation | - | IVS8, c.816 + 5G > A | IVS8, c.816 + 5G > A | IVS8, c.816 + 5G > A | c.751-753del, E251del | c.1117_1118delTTinsGC F373A | IVS8, c.816 + 5G > A | c.1190G > A R397Q | c.598_600del K200del | c.506G > A, C169Y | c.506G > A, C169Y | c.1040G > A R347H | c.1040G > A R347H |
Anti-microbial prophylaxis | 100% | + | + | + | + | + | + | + | + | + | + | + | + |
IgRT | 75% | + | + | - | - | + | + | + | + | - | + | + | + |
Systemic immunosuppressants | 75% | + | + | + | + | - | + | + | + | - | + | + | - |
HSCT | 50% | - | + | + | + | - | + | + | + | - | - | - | - |
Outcome | Alive (58.3%) | Dead | Alive | Dead | Dead | Alive | Alive | Dead | Alive | Alive | Dead | Alive | Alive |
Reason of death | - | Respiratory failure | | Respiratory failure, intracranial hemorrhage | Respiratory failure | - | - | GvHD, sepsis | - | - | Intracranial hemorrhage | - | - |
Abbreviations: NA: Not Available; GvHD: Graft versus host disease; HSCT: Haploidentical stem cell transplantation; IgRT: Immunoglobulin replacement therapy. The mutations are annotated according to the NM_014009.4. |
Evaluation of T-cell responses and changes with treatment.
Before HSCT, we investigated CD4+ T-cell subtypes in three patients (P5, P7, P9). These included circulating follicular helper T cells (cTFH, CD4+CXCR5+PD-1+ or CD4+CXCR5+CD45RA−), Treg cells (CD4+CD25hiFOXP3+ and CD4+CD25hiCD127lo), circulating follicular regulatory T cells (cTFR, CD4+CXCR5+CD45RA−CD25hiCD127lo). The gating strategies of these analyses are presented in Fig.S1 and Fig.S2. The cTFH cell (CD4+CXCR5+PD-1+) percentages were similar between the patients and the healthy controls; however, their PD-1 expression was significantly higher in the patients, indicating their activation status. Interestingly, the PD-1 expression was diminished following HSCT (Fig. 2A-C).
A TH2 (CXCR3−CCR6−) skewing and reduced TH17 (CXCR3−CCR6+) responses were observed in cTFH (CD4+CXCR5+CD45RA−) and Treg (CD4+CD25hiCD127lo) cells without significant differences between the pre-HSCT samples vs. healthy controls. These abnormal responses were corrected after HSCT (Fig. 2D-G).
We further quantified the percentage of natural Treg cells (CD4+CD25hiFOXP3+) and found comparable results between the patients (P2, P5, P6, P7, P8, P9) and healthy controls. However, the canonical markers of Tregs, including CD25 (IL-2RA), FOXP3, and CTLA-4, were lower in the patients pre-HSCT than in healthy controls and increased from baseline after successful transplantation (Fig. 3A-C). Furthermore, we also evaluated the cTFR cell population within the cTFH cell. The frequency of these cells before and after HSCT was similar to that of healthy control subjects (Fig. 3D). T-cell activation and proliferation responses were similar in the tested patients to healthy controls (Fig.S3).
Genetic variants of IPEX patients.
Twelve patients in the study harbored seven previously reported mutations (33, 36–44). There were missense (n = 4; P5, P7, P9, P10, P11, P12), inframe deletions (n = 2; P4, P8), and splice site (n = 1; P1, P2, P3, P6) mutations (Table 2). Overall, three mutations were located at the FKH domain (P5, P7, P11, P12), one at the N-terminal (P9, P10), one (P8) at the ZF domain, one at the LZ domain (P4), and one (P1, P2, P3, P6) between the LZ and FKH domains, close to the LZ domain. The overall structure of FOXP3 and localization of variants with atypical and classical presentations is depicted in Fig. 4A. The K200del variant results in a 53% loss of FOXP3 protein, while the E251del variant leads to a 43% loss. Deletion-causing variants can significantly reduce protein levels and contribute to folding defects, impacting protein function. The potential effects of missense variants (C169Y, R347H, F373A, and R397Q) on protein structure were investigated based on the predicted unfolding free energy change (31). As shown in Table S2, all of the detected missense variants destabilize the FOXP3, supporting the potential pathogenicity of the variants. The C169Y variant can interfere with the physical interaction between the FOXP3 protein and IKZF4 and ZFP90 proteins (Fig. 4A and B). Following the C169Y variant, a new intramolecular hydrophobic interaction occurs with the F171 amino acid (Fig. 4C, Table S3). The R347H, F373A, and R397Q variants are located in the FKH at the protein's C-terminal, crucial for DNA interaction (Fig. 4B). These variants destabilize the protein structure by leading to the loss of intramolecular interactions (Fig. 4C, Table S3) and may disrupt nuclear localization and hinder the formation of the necessary head-to-head dimer structure for DNA binding (45). All the described mutations were conserved among the species (Fig.S4).
Interestingly, P1, P2, P3, and P6 were from the same family and had a mutation that caused a defective splice site, leading to exon 8 skipping (33). While P1 showed atypical presentation characterized by colitis and autoimmune hepatitis, P2, P3, and P6 presented with early onset classical phenotype. Mutations associated with IPEX phenotypes (classical or atypical) in our cohort and comparison with previously reported patients with the same mutations displayed divergent presentations (Table S4), and the clinical and immunological comparisons between all our variant types and involved domains did not reveal any differences and were not associated with survival. Therefore, we concluded that no strong genotype–phenotype relationship governed the manifestations of IPEX syndrome.
Treatment and disease course during the follow-up of IPEX patients.
All patients received antimicrobial prophylaxis (100%), nine patients (75%) received IS, and six patients (50%) underwent HSCT (Fig. 5A, Table 2, Table S1). At the end of the study, seven (58.3%) patients are still surviving. P1, P3, and P4 died due to respiratory failure, and P7 because of CMV sepsis in the 4th month of HSCT. P10 died from intracranial hemorrhage secondary to trauma while receiving only immunoglobulin replacement therapy without IS or HSCT.
Nine patients (75%) received immunoglobulin replacement therapy (IgRT) for 20 months (min-max:3–48 months). The ISs included prednisolone (n = 8, P1, P2, P3, P4, P7, P8, P10, P11), sirolimus (n = 6, P2, P3, P4, P6, P10, P11), azathioprine (n = 5, P1, P7, P8, P10, P11), cyclosporine A (n = 2, P2, P3), mycophenolate mofetil (MMF) (n = 2, P2, P11), infliximab (n = 1, P8), hydroxychloroquine (n = 1, P10), and cyclophosphamide (n = 1, P10) (Fig. 5B, Table S1). Three patients were receiving quadruple, 2 patients were receiving triple, and 3 patients were receiving dual ISs to control disease activity (Fig. 5C). Severe side effects of ISs were observed during the follow-up, leading to caseation of therapies (Fig. 5D). In a more comprehensive breakdown, P1 exhibited myeloid aplasia and bicytopenia, P2 presented with Perthes disease and genu valgum, P9 experienced an allergic skin reaction, P10 demonstrated proteinuria, and P11 grappled with severe aphthous stomatitis alongside nasal bleeding. Overall, there was only PR (n = 5, 55%) or NR (n = 4, 45%) with ISs, but 33.3% of the patients showed CR to HSCT (Fig. 5E). The detailed clinical courses and treatment options are provided in the Supplementary file; however, essential therapeutic steps are mentioned as follows:
P1 exhibited complex findings, including nephrotic syndrome, autoimmune hepatitis, and enteropathy. Despite receiving azathioprine and prednisolone, there was only a partial response. At age 9, he developed neutropenia, potentially linked to prolonged azathioprine use, partially improved upon discontinuation of the drug and use of high-dose corticosteroids and colony-stimulating factor. Unfortunately, he succumbed to severe respiratory distress at age 9. P2 presented at 6 months with eczematous skin rash, diarrhea, vomiting, and protein-losing enteropathy. Corticosteroids and cyclosporine improved symptoms until HSCT at 8 months. Following a period of stability, he developed ITP at 3 years and responded to prednisolone, but later experienced AIHA attacks treated with sirolimus for 5 years. However, he showed difficulty walking and hip pain; he developed avascular necrosis and was diagnosed with Perthes disease and genu valgum, possibly related to a side effect of sirolimus, leading to drug withdrawal. Subsequently, he started MMF to control his hemolysis. P3, who had neonatal T1DM, dermatitis, and respiratory distress syndrome right after birth, needed ventilatory support and developed AIHA during follow-up. He was treated with surfactant, antibiotics, corticosteroids, and cyclosporine A with no significant improvement. On day 43, sirolimus was initiated, which led to successful weaning off mechanical ventilation five days later. P4, diagnosed with IPEX at 48 months due to early-onset diarrhea without other autoimmunities, showed no response to corticosteroids and sirolimus. P5 had T1DM without other symptoms, waiting for HSCT. P6 received sirolimus for diarrhea and eczematous lesions, resulting in a successful control. P7, who had late-onset CD, showed partial improvement to prednisolone. Therefore, azathioprine was added for 5 months without responsiveness.
P8 presented atopic dermatitis and CD before 12 months of age and was diagnosed with CMV colitis and IBD at 13 months of age. He received ganciclovir, intermittent prednisolone, and azathioprine treatments for approximately 1.5 years. Additionally, he received infliximab treatment once a month, 4 times in total. He did not benefit from any therapy until HSCT. P9 started IgRT but discontinued due to an allergic reaction. P10 was diagnosed with SLE at 11 years and experienced splenomegaly and thrombocytopenia despite azathioprine, hydroxychloroquine, and prednisolone treatments. After IPEX diagnosis, sirolimus was started, which improved lymphoproliferation but led to proteinuria, ultimately resulting in drug discontinuation. He died due to intracranial hemorrhage while awaiting HSCT. P11 was diagnosed with autoimmune hepatitis at the age of 6 and was first treated with systemic corticosteroids and then sequentially with azathioprine and MMF for approximately 3 years. After diagnosis with IPEX, he started to receive sirolimus. However, within 3 months, his symptoms did not regress. He experienced severe aphthous stomatitis and fatigue, leading to drug discontinuation. His family objects to HSCT, and he is followed in poor condition. P12, a twin of P11, only had asthma and mild atopic dermatitis and never received IS therapy.
There were 6 out of 12 patients who underwent HSCT. The overall survey after transplantation was 50% (Table 2). P2, now 14 years old, was transplanted from his HLA-identical sister at the age of 8 months. He engrafted well and showed an almost full donor cell chimerism 4 weeks after HSCT. He had ITP at the age of 3 years and recurrent AIHA attacks between the age of 4.5-6 years. In the current situation, his last chimerism was 88%, and he has received IgRT and MMF to control his hemolysis. P3 and P4 were transplanted from HLA-identical umbilical cord blood. However, they died early due to the ARDS after the procedure, and P4 chimerism was only 6% and failed to engraft (33). P6 and P8 were successfully transplanted. Their chimerism levels were 100% in the 2nd and 3rd months of HSCT. P6 is doing well within 2 years of transplantation, with 100% chimerism and free of eczema and diarrhea. P8 had received bone marrow stem cells from a 10/10 HLA-compatible sibling donor. His symptoms improved, and he has been followed up without medication for the last 5 years post-HSCT. P7 had received peripheric blood stem cells from an unrelated 10/10 HLA-compatible donor. While chimerism was 99% in the 1st and 2nd months of HSCT, he developed steroid-resistant grade 4 gastrointestinal GvHD. He received tacrolimus, MMF, corticosteroids, and ruxolitinib for 4 months. Extracorporeal photopheresis was applied, and mesenchymal stem cells were given 2 times due to resistant GvHD. The patient developed BK virus hemorrhagic cystitis and CMV reactivation, complicated with pneumonia, resistant to ganciclovir and foscarnet treatments. He showed respiratory failure and died due to CMV sepsis at the age of 10 years, 4 months after HSCT. In total, 3 patients' families (P9, P11, P12) objected to the HSCT. The details of the indication and course of HSCT in IPEX patients are presented in Table 3.
Table 3
Indication and course of hematopoietic stem cell transplantation in IPEX patients
Patient's code | Indication of transplantation | Age of transplantation (years) | Graft source | HLA-match | Conditioning regimens | GvHD prophylaxis | Post-HSCT infections | Post-HSCT complications | GvHD (grade) | Post-HSCT IgRT | Post-HSCT last donor chimerism | Outcome | Post-HSCT follow-up period (months) |
P2 | Uncontrolled CD, eczema | 0.8 | BM | MSD-10/10 | TREO/FLU/ATG | CsA, MTX | - | - | - | - | 88% | Alive, AIHA and ITP attacks | 158 |
P3 | Severe respiratory distress, neonatal DM, eczema, AIHA | 0.1 | UCBSC | MUD-10/10 | BU/FLU/ATG | CsA, MTX | Candida | Intracranial hemorrhage, respiratory failure | - | No | - | Deceased (ARDS and intracranial hemorrhage) | 0.8 |
P4 | Uncontrolled CD | 4 | UCBSC | MUD-10/10 | BU/FLU/ATG | CsA, MTX | CMV | Failed to engraft | - | No | 6% | Deceased (ARDS and sepsis) | 8 |
P6 | Uncontrolled CD, eczema | 1.3 | PBSC | MUD-10/10 | TREO/FLU/Cy | CsA, MTX | - | - | - | No | 100% | Alive and well | 15 |
P7 | Uncontrolled CD | 10 | PBSC | MUD-10/10 | TREO/FLU/THIO | CsA, MTX | CMV, BK virus | GI GvHD, hemorrhagic cystitis | IV | No | 99% | Deceased (sepsis) | 4 |
P8 | Uncontrolled CD, eczema | 2.5 | BM | MSD-10/10 | BU/FLU/Cy | CsA, ATG | - | - | - | No | 100% | Alive and well | 66 |
Abbreviations: AIHA: Autoimmune hemolytic anemia; ATG: Anti-thymoglobulin; ARDS: Acute respiratory distress syndrome; BM: Bone marrow; Bu: Busulfan; CD: Chronic diarrhea; CsA: Cyclosporine A; Cy: cyclophosphamide; DM: Diabetes Mellitus; Flu: Fludarabine; GvHD: Graft versus host disease; ITP: Immune thrombocytopenia; MUD: Matched unrelated donor; MSD: Matched sibling donor; MTX: Methotrexate; THIO: Thiotepa; UCBSC: Umbilical cord blood stem cell; PBSC: Peripheral blood stem cell. |
There were no significant differences in the probability of OS between patients who received or did not receive transplantation. However, the estimated OS post-HSCT exhibited a favorable trend compared to patients treated with ISs, as depicted in Fig.S5A and B. Furthermore, individuals with autoimmunities, CD, FTT, LRTI, and skin manifestations demonstrated a better probability of OS. However, statistical significance was not achieved, likely attributed to the limited number of patients in these subgroups (Fig.S5C and D, FigS6A-C).