Epidemiology of autoimmune hemolytic anemia: A nationwide population‐based study in <scp>F</scp> rance
Authors: Julien Maquet, Margaux Lafaurie, Ondine Walter, Laurent Sailler, Agnès Sommet, Maryse Lapeyre‐Mestre, Marc Michel, Guillaume Moulis
Journal: American Journal of Hematology (2021)

Autoimmune hemolytic anemia (AIHA) is characterized by the destruction of red blood cells by warm or cold autoantibodies. Its epidemiology is not well known. The incidence rate of AIHA has been estimated at 1.77 per 100 000 person-years between 2008 and 2016 in Denmark.1 However, these results need to be confirmed and variations by age and sex are not known. The main causes of secondary AIHA among adults are hematological malignancies and especially B-cell lymphomas, systemic autoimmune diseases and some chronic infections.2 However, their prevalences deserve to be evaluated on a large scale with recent data. Mortality has been estimated in retrospective clinical cohorts between 8 and 21% in adults, with median or mean follow-ups between 1.8 and 3.3 years.2, 3 However, mortality compared to the general population, as well as mortality over time, are not established. Moreover, AIHA has been associated with an increased risk of venous thrombosis.2, 3 The cumulative incidence of arterial thrombosis has not been measured. Infections, including opportunistic infections, are also expected to be more frequent in patients with AIHA.3 This study aimed to assess the overall incidence rate of AIHA in France, the incidence rate by age, sex and seasons, the prevalence of secondary AIHA causes, mortality and the cumulative incidence of hospitalization for thrombosis and infections compared to the general population. The data source was the French health insurance database, named Système National des Données de Santé (SNDS). This database links individualized and anonymous data covering the entire French population (>66 million inhabitants) including sociodemographics, out-hospital and hospital data.4 Data from 2010 to 2018 were available. We built the AHEAD cohort (Autoimmune HEmolytic Anemia: a population-baseD study), including all patients with an incident AIHA in France between 2012 and 2017. Patients with AIHA were identified using the international classification of disease, tenth version (ICD-10) code D59.1 as hospital discharge diagnosis or long-term disease. This code yielded a positive predictive value (PPV) of 90.0% in the SNDS.5 The date of AIHA diagnosis (index date) was defined by the first occurrence of D59.1 code after a prior observation period of at least 2 years. Warm and cold AIHA are not distinguishable in the SNDS. Each patient was matched on year of birth, sex and index date to five comparisons randomly selected from the general French population. Causes of secondary AIHA were searched during the year before the diagnosis of AIHA using specific long-term disease and hospital discharge diagnosis codes (Table S1). Evans syndrome, defined with the ICD-10 code D69.3 of immune thrombocytopenia, was described separately. The included population was subdivided into three subgroups defined at index date: primary AIHA, secondary AIHA associated with hematological malignancies and other secondary AIHAs. Death and first hospitalization for thrombosis and for infection were assessed between the index date and December 31, 2018 (end of follow-up). They were identified in the SNDS by primary hospital discharge diagnoses using appropriate ICD-10 codes (PPVs indicated in Tables S2 and S3). Statistical analyses are detailed in supplementary material. We identified 9663 patients with incident AIHA between 2012 and 2017. Patients were matched with 47 700 comparisons. Patients' and comparisons' characteristics are described in Table S4. The median age was 69.5 years and 55.6% of patients were women. Evans syndrome represented 5.8% of AIHAs. The Charlson comorbidity index score was ≥3 in 42.4% of patients with AIHA versus 13.6% of comparisons (Table S5). The overall incidence rate of AIHA was 2.44 per 100 000 person-years (95% confidence interval – 95% CI: 2.39 to 2.48). The incidence rate of AIHA was more than 10 times higher in the elderly (≥75 years) than in people aged <50 years (Figure S1). It was higher in women than in men between 15 and 45 years of age. The same pattern was observed for primary AIHAs (Figure S2). Incidence rates of AIHA by months revealed a trend for a higher incidence rate during winter (Figures S3 and S4). Note, AIHA was primary in 55.2% of the cases at the time of AIHA diagnosis. In adults, AIHA was associated with hematological malignancy in 31.9%, including lymphoma in 24.1%, B-cell chronic lymphocytic leukemia in 11.3% and myelodysplastic syndrome in 5.4%. Systemic lupus erythematosus accounted for 5.3% of AIHA in adults (Table S6). During follow-up (27 682 patient-years and 173 370 comparisons-years; median follow-up: 31 months and 43 months, respectively), 3354 patients died, 956 had a hospitalization for thrombosis and 3278 for infection. The categories of thrombosis and infection are shown in Tables S7 and S8, respectively. Infections were opportunistic in 180 patients (5.5%), including 65 Pneumocystis jirovecii pneumonias and 32 zosters. The 1-year mortality was 20.5% (95% CI: 19.7 to 21.3) in AIHA (primary AIHA: 17.9%, 95% CI: 16.8 to 18.9), versus 3.3% (95% CI: 3.1 to 3.5) in comparisons (Figure 1, Table S9 and Figure S5). The hazard ratio (HR) of death adjusted for Charlson comorbidity index score was 3.3 (95% CI: 3.1 to 3.4). It was 2.9 (95% CI: 2.7 to 3.1) in primary AIHA. We observed a higher mortality in all categories of age. The 5-year mortality was 18.2% (95% CI: 16.7 to 19.7) in patients with AIHA between 15 and 65 years old versus 2.4% (95% CI: 2.1 to 2.7) in comparisons of the same age (Figure S6). The 1-year cumulative incidence of hospitalization for thrombosis was 6.0% (95% CI: 5.6 to 6.5) in AIHA (in primary AIHA: 5.7%, 95% CI: 5.1 to 6.4) versus 1.8% (95% CI: 1.7 to 1.9) in comparisons (Figure S7 and Table S10). The subdistribution HR (sHR) of hospitalization for thrombosis was 1.9 (95% CI: 1.8 to 2.0). The increased risk of hospitalization for thrombosis was observed for both arterial and venous events (Figure S8), in all categories of age (Figures S5 and S6). The risk increased with higher age, more for arterial thrombosis than for venous thrombosis. The 1-year cumulative incidence of hospitalization for infection was 22.9% (95% CI: 22.1 to 23.8) in AIHA (in primary AIHA: 20.9%, 95% CI: 19.8 to 22.0) versus 3.5% (95% CI: 3.3 to 3.6) in comparisons (Figure S7 and Table S11). The sHR of hospitalization for infection was 4.1 (95% CI: 3.9 to 4.3). The cumulative incidences of hospitalization for infection in patients were similar across age groups, and higher than in comparisons in all categories of age (Figures S5 and S6). This nationwide study with recent data (2012–2017) consisted in the largest cohort of patients with incident AIHA to date (9663 patients). The incidence rate of AIHA was estimated at 2.4 per 100 000 person-years (95% CI: 2.4 to 2.5) and was more than 10 times higher in the elderly and the very elderly compared to people under 50 years of age. The size of the cohort allowed incidence rate calculations by months and age subgroups. In addition, this study confirmed that AIHA patients have a high risk of death, hospitalization for thrombosis and for infection compared to the general population. The overall incidence rate was slightly higher in our study than in Denmark between 2008 and 2016 (1.8 per 100 000 person-years, 95% CI: 1.7 to 1.9).1 Of note, patients with a diagnosis of Evans syndrome were excluded in this Danish study.1 The all-cause mortality was high in our study (40% at 5 years; 15% in patients with primary AIHA patients aged between 15 and 64 years). French and Italian retrospective series, with younger patients, reported 8 and 21% of death with a mean follow-up of 3.8 and a median follow-up 2.8 years, respectively2, 3 versus 50% at 6.3 years in the population-based Danish study.1 Interestingly, hospitalization for thrombosis mostly occurred during the first year after AIHA diagnosis, suggesting that thrombosis occurs mostly during active hemolysis, as previously reported.2, 3 It is noteworthy that the risks of hospitalization for thrombosis and for infection had similar magnitudes in both primary and secondary AIHA, indicating the high severity of AIHA regardless of associated diseases. Our study has some limitations. Although PPVs of ICD-10 diagnosis codes for AIHA, thrombosis and infections have been validated in the SNDS with values mostly greater than 90%,5 we cannot exclude some misclassifications. The SNDS could not distinguish warm AIHA from cold AIHA. Of note, a recent Danish study found very close estimates of mortality and thrombosis at 5 years in a population of 72 patients with cold agglutinin disease, suggesting similar risks in both subtypes of AIHA.6 Because laboratory findings such as hemolysis parameters, blood cell counts, reticulocytosis and characteristics of direct antiglobulin tests were not available in the SNDS, we were unable to stratify our analyses by severity of AIHA, although it may impact the prognosis.3 In conclusion, the incidence rate of AIHA was more than 10 times higher in the elderly and very elderly compared to people under 50 years of age, suggesting a potential role for immunosenescence. Secondary AIHAs were frequent in adults. Mortality, hospitalizations for infection and for thrombosis were very frequent in both primary and secondary AIHAs. The authors thank Marjorie Boussac and the Caisse Nationale de l'Assurance maladie des Travailleurs Salariés engineers who performed raw data extraction from the SNDS database. This study was academic, funded by Société nationale française de médecine interne (SNFMI) and the University hospital of Toulouse. This study was academic. M.M. participated to educational sessions and boards for Amgen, Novartis, UCB, Argenx. G.M. received meeting attendance grants from Amgen and Novartis, is coordinator of research studies granted by Amgen, CSL Behring, Grifols and Novartis. He participated to educational sessions funded by Amgen and Novartis, and to boards for Amgen, Novartis and Sobi. All other authors declare having no competing interest. Julien Maquet, Margaux Lafaurie, Ondine Walter, Agnès Sommet, Maryse Lapeyre-Mestre and Guillaume Moulis designed the study. Julien Maquet conducted the statistical analyses. Julien Maquet, Margaux Lafaurie and Guillaume Moulis wrote the paper; all other authors critically reviewed the manuscript and gave final approval for publication. The data that support the findings of this study are available from the Health-Data-hub. Restrictions apply to the availability of these data, which were used under license for this study. Data are available by submitting a request to the Health-Data-Hub at: https://www.health-data-hub.fr/depot. All the data were anonymous. Appendix S1. Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.