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- Lundtoft, Christian, et al.
(författare)
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Combined genetic deficiencies of the classical complement pathway are strongly associated with both systemic lupus erythematosus and primary Sjögren's syndrome
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5205 .- 2326-5191. ; 74:11, s. 1842-1850
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Tidskriftsartikel (refereegranskat)abstract
- ObjectiveComplete genetic deficiency of the complement component C2 is a strong risk factor for monogenic systemic lupus erythematosus (SLE), but whether heterozygous C2 deficiency adds to the risk of SLE or primary Sjögren's syndrome (pSS) has not been studied systematically. Here we investigated heterozygous C2 deficiency and C4 copy number variation in relation to clinical manifestations in SLE and pSS.MethodsThe presence of the common 28-bp C2 deletion rs9332736 and C4 copy number variation was examined in Scandinavian patients diagnosed with SLE (n=958) or pSS (n=911), and 2,262 controls using DNA sequencing. Plasma concentration of complement proteins and classical complement function was analysed in a subgroup of patients.ResultsHeterozygous C2 deficiency – when present in combination with a low C4A copy number – substantially increased the risk of SLE (OR=10.2, CI95%: 3.5-37.0) and pSS (OR=13.0, CI95%: 4.5-48.4) when compared to individuals with two C4A copies and normal C2. For patients heterozygous for rs9332736 with one C4A copy, the median age of diagnosis was 7 years and 12 years earlier in SLE and pSS, respectively. Reduced plasma C2 (p=2x10-9) and impaired function of the classical complement pathway (p=0.03) was detected in SLE patients with heterozygous C2 deficiency. Finally, we describe a pSS patient with homozygous C2 deficiency.ConclusionWe demonstrate that the combination of partial deficiencies of C2 and C4A in the classical complement pathway is a strong risk factor for SLE and pSS. Our results emphasise the central role of the complement system in the pathogenesis of both diseases.
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| 2. |
- Lundtoft, Christian, et al.
(författare)
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Complement C4 Copy Number Variation is Linked to SSA/Ro and SSB/La Autoantibodies in Systemic Inflammatory Autoimmune Diseases
- 2022
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Ingår i: Arthritis & Rheumatology. - : Wiley. - 2326-5191 .- 2326-5205. ; 74:8, s. 1440-1450
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Tidskriftsartikel (refereegranskat)abstract
- Objective Copy number variation of the C4 complement components, C4A and C4B, has been associated with systemic inflammatory autoimmune diseases. This study was undertaken to investigate whether C4 copy number variation is connected to the autoimmune repertoire in systemic lupus erythematosus (SLE), primary Sjogrens syndrome (SS), or myositis. Methods Using targeted DNA sequencing, we determined the copy number and genetic variants of C4 in 2,290 well-characterized Scandinavian patients with SLE, primary SS, or myositis and 1,251 healthy controls. Results A prominent relationship was observed between C4A copy number and the presence of SSA/SSB autoantibodies, which was shared between the 3 diseases. The strongest association was detected in patients with autoantibodies against both SSA and SSB and 0 C4A copies when compared to healthy controls (odds ratio [OR] 18.0 [95% confidence interval (95% CI) 10.2-33.3]), whereas a weaker association was seen in patients without SSA/SSB autoantibodies (OR 3.1 [95% CI 1.7-5.5]). The copy number of C4 correlated positively with C4 plasma levels. Further, a common loss-of-function variant in C4A leading to reduced plasma C4 was more prevalent in SLE patients with a low copy number of C4A. Functionally, we showed that absence of C4A reduced the individuals capacity to deposit C4b on immune complexes. Conclusion We show that a low C4A copy number is more strongly associated with the autoantibody repertoire than with the clinically defined disease entities. These findings may have implications for understanding the etiopathogenetic mechanisms of systemic inflammatory autoimmune diseases and for patient stratification when taking the genetic profile into account.
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| 4. |
- Ramirez, Jorge, et al.
(författare)
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Difference in Clinical Presentation between Female and Male Patients with Primary Sjogren's Syndrome at Diagnosis and in Long-Term Follow-up
- 2017
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Ingår i: Arthritis & Rheumatology. - : Wiley-Blackwell. - 2326-5191 .- 2326-5205. ; 69
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Background/Purpose: Despite men being less prone to develop autoimmune diseases, male sex has been associated with a more severe disease course in several systemic autoimmune diseases. In the present study, we aimed to identify differences in clinical presentation between the sexes at the time of diagnosis and during long-term follow-up of primary Sjögren's syndrome (pSS), and to establish whether male sex is associated with a more severe form of pSS. Methods: Incident, treatment naïve patients (n=199, 186 females and 13 males) from Stockholm, Sweden were prospectively included during a 5-year period and examined for items of classification criteria for pSS as well as extraglandular manifestations (EGM). Serum was sampled at the time of diagnosis and anti-Ro52/SSA levels measured by ELISA. Replication of significant findings was confirmed in an independent cohort of incident pSS patients from Pisa, Italy (n=377, 368 females and 9 males), and meta-analysis performed. We further studied a cohort of 967 patients with prevalent pSS (899 females and 68 males) from Scandinavian clinical centers. The mean follow-up time (years) was 8.8 ± 7.6 for women and 8.5 ± 6.2 for men (ns). Clinical data including serological and hematological parameters, glandular, EGM and comorbidities were compared between men and women. Results: An increased frequency of EGM in men at diagnosis was observed and replicated (p=0.05, p=0.0003, and pmeta=0.002, respectively). This related to pulmonary involvement, vasculitis and lymphadenopathy being more common in men, for whom a lower age at diagnosis was observed in the exploratory cohort. Additionally, SSA positive male patients had significantly higher levels of anti-Ro52 levels than their female counterparts (p=0.02). After long-term follow-up, male patient serology was characterized by more frequent positivity for anti-SSA and anti-SSB (p=0.02), and ANA (p=0.02). Also, men with pSS were more frequently diagnosed with interstitial lung disease (p=0.008), lymphadenopathy (p=0.04) and lymphoma (p=0.007). Conversely, concomitant hypothyroidism was more common among female patients (p=0.009). Conclusion: Our analysis of two independent cohorts of incident pSS and a large cohort of prevalent pSS demonstrates significant differences between women and men with pSS. Notably, men present with more EGM, enhanced serological profile and a higher frequency of lymphoma development.
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