Higher Prevalence of Autoimmune Diseases in Patients with Sickle Cell Disease
Authors: Tang Man Wai , Nur Erfan , Van Tuijn Charlotte F.J. , Biemond Bart J. 
Published: November 2021

Abstract
Introduction
Sickle cell disease (SCD) affects millions of people throughout the world. This is caused by a mutation in the hemoglobin gene resulting in abnormal red blood cells. Patients with SCD are in a state of chronic inflammation that is driven by ongoing hemolysis and ischemia-reperfusion injury due to recurrent vaso-occlusions.(1) It is also known that infections occur more frequently in patients with SCD. Abundant literature support the role of infections, interacting with the immune system as the so-called second hit in the cascade towards development of autoimmune diseases.(2) The chronic inflammation together with genetic predisposition and environmental factors can potentially lead to an auto-inflammatory state and/or disease. Recently, a study has shown a prevalence of autoimmune diseases (AID) of 1,3% in SCD patients between 7 and 17 years of age, although not compared to the general population.(3) Our hypothesis is that due to the chronic inflammation the prevalence of autoimmune diseases in adult patients with SCD are much higher compared to the general population. The aim of the study was to evaluate the proportion of patients with and without an AID.
Methods
Between 2004 and 2021, patients with SCD aged above 18 were seen at the outpatient clinic at the Amsterdam University Medical Center in Amsterdam. We performed a retrospective study in adult SCD patients to assess the prevalence of AID in SCD. AID was defined as: disease with the presence of autoantibodies and/or auto-reactive lymphocytes becoming involved in inflammation, which develop pathological autoimmunity and finally leads to tissue damage. We have selected 35 most common autoimmune diseases. A total of 338 patients with SCD were eligible and included in the study. The patient characteristics were summarized in Table 1. The previously reported prevalence of the AID in the African-American population was used to compare the prevalence in our study cohort. In addition, risk factors for AID and relation with organ damage was analyzed.

Results
AID was diagnosed in 36/338 patients with SCD. The prevalence of AID in this cohort is 10,7% compared to 4.7% in the general population (see table 2). There was no difference in patient characteristics (age, sex, genotype) between the SCD patients with or without AID. The BMI was higher in the group of patients with autoimmune diseases, although not statistically significant. In patients with SCD, the most frequent (&gt;1%) diagnosed AID were: sudden deafness (1.8%), hyper- and hypothyroidism (3%) and sarcoidosis (1.2%). With respect to organ damage, a significantly high rate of retinopathy was observed in SCD patients with AID as compared to SCD patients without AID (53% and 29% respectively, p=0.005). Furthermore, a trend towards more frequently microalbuminuria was found in SCD patients with AID 14/36 (39%) as compared to patients without AID 69/302 (23%).
Conclusions
This study showed for the first time a higher prevalence of autoimmune diseases in adult patients with SCD compared to previous reported in the general population. In patients with AID, a trend towards more microalbuminuria and significantly higher rate of retinopathy were observed. These findings support the hypothesis that the chronic inflammatory state in SCD patients may be related to the development of AID. Further research is needed to find strategies to target the chronic inflammatory state in order to prevent the development of AID.
References
1. Nader E, Romana M, Connes P. The Red Blood Cell-Inflammation Vicious Circle in Sickle Cell Disease. Front Immunol. 2020;11:454.
2. Ercolini AM, Miller SD. The role of infections in autoimmune disease. Clin Exp Immunol. 2009;155(1):1-15.
3. Li-Thiao-Te V, Uettwiller F, Quartier P, Lacaille F, Bader-Meunier B, Brousse V, et al. Coexistent sickle-cell anemia and autoimmune disease in eight children: pitfalls and challenges. Pediatr Rheumatol Online J. 2018;16(1):5.
Figure 1 Figure 1.

Disclosures
Nur: Celgene: Speakers Bureau; Roche: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Biemond: Global Blood Therapeutics: Honoraria, Research Funding, Speakers Bureau; Sanquin: Research Funding; CSL Behring: Honoraria; Novo Nordisk: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding, Speakers Bureau.