Autoimmune and Inflammatory Diseases in Children with Sickle Cell Disease: A French Multicenter Observational Study on Diagnostic and Therapeutic Issues
Authors: Vinit Caroline , Guitton Corinne , de Montalembert Mariane , Benhaim Patricia , Amor-Chelihi Lahoueri , Bader-Meunier Brigitte , Missud Florence , Melki Isabelle , Gajdos Vincent , Arnaud Cecile , Kamden Annie , Charara Oussama , Hentgen Véronique , Nathanson Sylvie , Bloch Coralie , Meinzer Ulrich , Quartier Pierre , Kone-Paut Isabelle , De Pontual Loïc , Pham Luu-Ly 
Published: December 2024

Autoimmune and inflammatory diseases (AIIDs) encompass a spectrum of systemic or organ-specific conditions, wherein the immune system is compromised due to a loss of self-tolerance. AIIDs have been reported in both adults and children with sickle cell disease (SCD), but clinical data are still scarce, particularly in children.
To identify clinical and paraclinical patterns at diagnosis of AIIDs in children with SCD and to describe their evolution, we performed an observational study among a cohort of 3,800 children with SCD, in a French multicenter study from 1991 to 2018. The inclusion criteria were i) children with SCD, ii) one or more concomitant AIIDs confirmed according to the diagnostic criteria published by the American College of Rheumatology and the European League Against Rheumatism, iii) AIID diagnosis before the age of 18 years-old. Children with isolated positive autoantibodies or autoimmune-like manifestations without a definitive diagnosis were excluded. Data from SCD children with AIIDs were retrospectively collected and included clinical characteristics, inflammatory markers (at diagnosis and after treatment), auto-antibodies patterns, evolution during follow-up (treatment, remission and occurrence of complications).
Thirty-five children with SCD reported 44 AIIDs (0.9%, 95%CI [0.6-1.3]). Sex ratio was 0.84 and the median age was 10 [IQR 7-13] years-old at AIID diagnosis. The median length of follow-up was 13.5 [IQR 10-19] years. Thirty patients (86%, 95%CI [70-95]) had the S/S genotype, four (11%) the S/C genotype, and one (3%) the S/beta0 thalassemic genotype. AIIDs diagnosed were: auto-immune liver disease (AILD, n=13) including autoimmune hepatitis (AIH, n=8) and autoimmune sclerosing cholangitis (AISC, n=8), inflammatory bowel disease (IBD, n=7), juvenile idiopathic arthritis (JIA, n=6), systemic lupus erythematosus (SLE, n=5), autoimmune hemolytic anemia (AIHA, n=3), Sjögren syndrome (n=2), histiocytic necrotizing lymphadenitis (n=2), vasculitis (n=2), myasthenia gravis (MG, n=2), sarcoidosis (n=2), inflammatory uveitis (n=1), sclerodermia/juvenile dermatomyositis (JDM, n=1). Eight patients (23%, 95%CI[10-40]) had two or more concomitant AIIDs, including mixed connective tissue diseases (n=2, with SLE + Sjögren's syndrome, and scleroderma + JDM), SLE-associated MG (n=1), AISC with IBD (n=3), AISC with sarcoidosis (n=1), and concomitant AISC with AIH, IBD, and AIHA (n=1).
The mean time between the first symptoms and AIID diagnosis was 15.5 (± 29) months, with longer durations for JIA, IBD and Sjögren's syndrome. Two patients (6%, 95%CI [0.7-19]) required intensive care at AIID diagnosis: one patient with MG for extracorporeal membrane oxygenation, and one with acute liver failure.
Children diagnosed with AILD had highest hypergammaglobulinemia level at diagnosis (31 ± 8.6 g/L), which significantly decreased at last follow-up (18 ± 4.9 g/L; p=0.003). At AIID diagnosis, antinuclear antibody (ANA) titers were weakly positive (1:160) in five patients (14%, 95%CI [4.8-3]), moderately positive (1:320 to 1:800) in nine patients (26%, 95%CI[12-43]), and strongly positive (≥1:1280) in six patients (17%, 95%CI [7-34]).
Of the 21 children (60%) treated with systemic steroids, 14 (67%) experienced vaso-occlusive crisis. Thirteen patients (37%, 95%CI [21-55]) received biological therapy, including anti-interleukin IL-1 (n=2, 6%), anti-IL-6 (n=2, 6%), anti-CD20 (n=6, 17%), anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA4; n=4, 11%), and anti-tumor necrosis factor (TNF)α (n=11, 31%). A complete remission of AIID was observed in 26% (95%CI [12-43], n=9/35) of the patients.Nine patients (26%, 95%CI [12-43]) had severe infections. Three children (9%) underwent hematopoietic stem cell transplantation, one died of steroid-resistant multipolar graft-versus-host reaction.
Prevalence of AIID was 0.9% in our cohort of 3800 children with SCD, which is one of the largest pediatric series to date, among this specific population. Delayed diagnosis was frequent due to intricated clinical patterns between AIID and SCD. Clinicians must be aware of warning signs associated with elevated inflammatory markers, hypergammaglobulinemia or specific antibodies. Therapeutic strategies remain challenging for those vulnerable children.