Multiple autoimmune syndrome: Clinical, immunological and genotypic characterization

Mariana Fidalgo; Raquel Faria; Cláudia Carvalho; Graziela Carvalheiras; Denisa Mendonça; Fátima Farinha; Berta Martins da Silva; Carlos Vasconcelos

doi:10.1016/j.ejim.2023.06.020

Multiple autoimmune syndrome: Clinical, immunological and genotypic characterization

Eur J Intern Med. 2023 Oct:116:119-130. doi: 10.1016/j.ejim.2023.06.020. Epub 2023 Jun 28.

Authors

Mariana Fidalgo¹, Raquel Faria², Cláudia Carvalho³, Graziela Carvalheiras⁴, Denisa Mendonça⁵, Fátima Farinha², Berta Martins da Silva³, Carlos Vasconcelos²

Affiliations

¹ Internal Medicine Resident, Clinical Internship at Unidade de Imunologia Clínica (2), Portugal. Electronic address: marianafidalgo@gmail.com.
² Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Portugal; Unit for Multidisciplinary Research in Biomedicine, Portugal.
³ Unit for Multidisciplinary Research in Biomedicine, Portugal; Laboratório de Imunogenética, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal.
⁴ Unidade de Imunologia Clínica, Centro Hospitalar do Porto, Portugal.
⁵ Departamento de Estudos de Populações, Instituto de Ciências Biomédicas Abel Salazar, Universidade do Porto, Portugal; EpiUnit, Instituto de Saúde Pública, Universidade do Porto, Portugal.

PMID: 37385917
DOI: 10.1016/j.ejim.2023.06.020

Abstract

Introduction: The existence of subphenotypes common to several autoimmune diseases (AIDs) suggests a shared physiopathology - autoimmune tautology. Multiple Autoimmune Syndrome (MAS) - the coexistence of three or more AIDs in one person-, best illustrates that polyautoimmunity is more than a coincidence.

Objectives: Characterize and compare the monoautoimmune and MAS patients. Understand if clustering of AIDs leads to differences in disease severity, autoantibodies expression or genetic polymorphisms that could be markers for polyautoimmunity.

Methods: Currently adult patients were selected from unit cohort. MAS was assumed when ≥3 AIDs were present. 343 patients were included after exclusion criteria: having two AIDs or undetermined diagnosis. Clinical and immunological data were collected from medical files. HLA-DRB1 was genotyped by PCR-SSP methodology and PTPN22(rs2476601) polymorphisms by TaqMan Real Time PCR. Data were analysed using Chi-Square, Fisher's exact tests and logistic regression. Odds ratios (OR) and 95% confidence intervals were calculated.

Results: In comparison with control population: ELEVATED FREQUENCIES: HLA-DRB1*03 in study cohort (OR=3.68,p<0.001) and in monoautoimmune SLE (OR=2.79,p<0.001) and SjS (OR=8.27,p<0.001); HLA-DRB1*15 in monoautoimmune SjS (OR=2.39,p = 0.011); HLA-DRB1*16 in MAS SLE (OR=2.67,p = 0.031); PTPN22_T in all groups except monoautoimmune SjS and triple positive systemic MAS.

Diminished frequencies: HLA-DRB1*11 in study cohort (OR=0.57,p = 0.013), in MAS SLE (OR=0.39,p = 0.031) and monoautoimmune SjS (OR=0.10,p = 0.005); HLA-DRB1*13 in study cohort (OR=0.52,p = 0.001) and in monoautoimmune SLE (OR=0.53,p = 0.009) and SjS (OR=0.38,p = 0.031); HLA-DRB1*14 in study cohort (OR=0.32,p = 0.013) and monoautoimmune SLE (OR=0.21,p = 0.021); SLE group: HLA-DRB1*07 frequency was higher in monoautoimmune patients (OR=0.43,p = 0.023). MAS patients had significantly more NPSLE (OR=2.99,p<0.001), subacute cutaneous lesions (OR=2.30,p = 0.037), muscle&tendon (OR=2.00,p = 0.045), and haematological (OR=3.18,p = 0.006) involvement and Raynaud's (OR=2.94,p<0.001). SjS group: MAS patients had more frequently cryoglobulins (OR=2.96,p = 0.030), low complement (OR=2.43,p = 0.030) and Raynaud's (OR=4.38,p<0.001); monoautoimmune patients had more parotid enlargement (OR=0.12,p<0.001). APS group: MAS patients had more non-thrombotic manifestations (OR=4.69,p = 0.020) and Raynaud's (OR=9.12,p<0.001). Triple positive systemic MAS (SLE+SjS+APS) had more frequently severe kidney involvement (OR=11.67,p = 0.021) and CNS thrombosis (OR=4.44,p = 0.009). Anti-U1RNP increased frequency was transversally attributable to MAS.

Conclusions: The coexistence of AIDs contributes to a more severe disease course. We confirmed previously established genetic risk and protection factors and suggest a new protective one - HLA-DRB1*14. HLA-DRB1*07 and anti-U1RNP could be markers for mono and polyautoimmunity, respectively; HLA-DRB1*13 could be a predictor for vascular risk in patients with multiple AIDs. PTPN22(rs2476601) polymorphism could be associated with less severe disease.

Keywords: Antiphospholipid syndrome; HLA-DRB1; Multiple autoimmune syndrome; PTPN22; Polyautoimmunity; Sjögren's syndrome; Systemic lupus erythematosus; Triple positive systemic MAS.