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Pediatric-onset Evans syndrome outcomes
relation coefficient. Survival and cumulative incidence estimates were based on the Kaplan–Meier method and compared using log-rank test. Patients of OBS’CEREVANCE cohort with isolated cITP or AIHA were used for comparison in survival analyses (unpublished data). The Cox proportional hazards method was used to analyze factors associated with time-dependent variables (i.e., time to CR, AIN, cIM, and second-line treatment, as well as survival). The potential cumulative and/or time-dependent nature of variables was taken in account. Proportionality of hazard was assessed for each variable. Logistic regression was used to analyze factors associated with severe or recurrent infections. Variables that were statistically significant in the univariate analyses were included in the multivariate analyses. We investigated associations with the following characteristics and events: sex, consanguinity, cIM/cancer in a first-degree relative, age at first and second cytopenia, sequence of cytopenia, AIN, hypogammaglobulinemia, time to ITP/AIHA CR, severe/recurrent infections, number of cIM, number of second-line treatments. The 95% Confidence Intervals (CI) for hazard ratios (HR) and odds ratios (OR) were not adjusted for multiple testing and should not be used to infer definitive effects. All tests were two-sided and a P-value <0.05 was consid- ered statistically significant. Statistical analyses were performed using R (ver. 4.0; R Development Core Team) and GraphPad Prism (ver. 8; GraphPad Software, Inc., San Diego, CA, USA) software.
Results
Population
Of the 216 patients with pES, 151 were included in this study (Online Supplementary Figure S1). They were fol- lowed from 25 different centers. Patient characteristics are shown in Table 1. The median (min–max) follow-up time from the first cytopenia diagnosis was 11.3 years (range, 5.1–38.0 years). Median age at final follow-up was 18.5 years (range, 6.8–50.0 years). In 20 cases (15%), follow-up was discontinued because the patient was considered cured (n=11) or lost to follow-up (n=9). Median age at loss to follow-up was 18.4 years (range, 6.8-25.1 years).
Hematological outcomes
AIN developed in 43 patients (28.5%). It was diagnosed within 1 month before or after first cytopenia onset in 23 of 43 cases (53.5%), more than 1 month before in two cases (4.7%), and more than 1 month after in 18 cases (41.9%; maximal delay, 12.4 years). In all cases, the diag- nosis was made before the age of 18 years (median age, 6.8 years; range, 0.6–16.2 years).
ITP and AIHA flare rates at 5 years of follow-up were calculated for the 61 alive patients who did not receive a second-line treatment during this period. Forty-eight patients (79%) had experienced an ITP flare and seven (11%) an AIHA flare.
The proportion of patients achieving sustained CR for ITP and AIHA steadily increased after cytopenia onset (Figure 1A). At 5 and 10 years, ITP was in sustained CR in 40.5% and 62.3% of patients (P=0.02) and AIHA was in sustained CR in 54.5% and 74.1% of patients (P=0.001), respectively. Sustained CR was achieved earlier for AIHA than ITP (median time to CR, 4.0 years vs. 7.0 years; P=0.01). At the final follow-up of the 135 surviving patients, the numbers of patients in CR, partial remission, and no remission were 126 (83%), five (3%), and one (1%) for AIHA and 119 (79%), eight (5%), and five (3%) for ITP, respectively (missing data in three cases). Forty-six
Table 1. Patient characteristics. Number of patients
Sex ratio (male/female)
Consanguinity, n (%)
cIM/cancer in first-degree relative, n (%) Median age (years) at
First cytopenia (min-max) ITP diagnosis (min-max) AIHA diagnosis (min-max) ES diagnosis (min-max)
Sequence of ES Simultaneous, n (%) ITP then AIHA, n (%) AIHA then ITP, n (%)
Time between first and second cytopenia (years) Median (min-max)**
Direct antiglobulin test at AIHA diagnosis IgG, n (%)
IgG + C3, n (%)
Unspecified, n (%)
C3, n (%)
IgA + C3, n (%) IgM then IgG, n (%)
Duration of follow-up after first cytopenia (years) Median (min-max)
Mean ± SD
Age at last follow-up (years)
Median (min-max)
Mean ± SD
151
1.40 (88/63) 12 (7.9) 43 (28)
5.4 (0.2-16.0) 6.7 (0.2-17.1)* 7.8 (0.2-21.5)* 8.9 (0.2-21.5)
52 (34.4) 62 (41.1) 37 (24.5)
2.5 (0.1-15.8)
73 (48.3) 61 (40.4) 11 (7.3) 4 (2.6) 1 (0.7) 1 (0.7)
11.3 (5.1-38.0) 12.5 ± 6.0
18.5 (6.8-50.0) 19.1 ± 6.8
*P=0.0076. **Considering the 99 patients with sequential cytopenias. CIM: clinical immunopathological manifestation; Ig: immunoglobulin; SD: standard deviation; ITP: immune thrombocytopenic purpura; AIHA: autoimmune hemolytic anemia; ES: Evans syndrome.
patients (34%) had no treatment ongoing at last follow- up. No particular characteristic was associated with AIHA or ITP CR, including cIM and bIM.
Over the first three decades, the proportions of patients achieving sustained CR increased with age (Figure 1B). ITP and AIHA were in CR in 26% and 30% of cases at 10 years compared to 50% and 72% at 20 years, respectively (P<0.001 for both comparisons).
Immunopathological manifestations
A total of 122 of 151 patients (81%) had at least one IM. The data for each category and specific diagnosis are shown in the Online Supplementary Table S2.
cIM developed in 100 of 151 patients (66%). A total of 47 patients (31%) had two or more IM and 22 (15%) patients had three or more IM (Online Supplementary Figure S2A). Patients with no cIM had shorter median follow-up times (9.7 years vs. 13 years; P=0.0002) and were younger when data were collected (15 years vs. 20 years; P<0.0001). A cIM was diagnosed before the first cytopenia in 21 of 100, simultaneously in 13, and after in 66 cases (median delay, 3.7 years [range, 0.2–20.5 years]; Figure 2A). Among the 185 cIM, 29 (16%) were diagnosed before any second-line treatment. No cIM category had a statisti- cally significant difference in frequency before and after first second-line treatment. The number of cIM increased
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