ObjectiveSome genome-wide significant SLE risk loci associate with SLE development only while other associate with other diseases, such as type 1 diabetes (T1DM) and rheumatoid arthritis (RA). Our ...objective: to investigate what clinical phenotype associate with high polygenic scores (PRSs) for SLE-specific and multitrait-associated SLE loci.MethodsPatients with SLE (ACR-97 or SLICC-12, n=1498) and healthy controls (n=1947) were genotyped using Illumina’s Global Screening Array. SLE-associated single nucleotide variants (SNVs) (European ancestry) at GWAS significance (p<5×10–8) were identified through the GWAS catalog. After filtering 112 SNVs were identified. SNVs were considered multitrait if associated with ≥1 additional disease. Two PRSs were constructed; one including SLE specific SNVs (n=79) and one including multitrait SNVs (n=33). Groups were compared using logistic regression, adjusting for age and sex. 50% of patients with the highest SLE-specific PRS were selected and from them the 50% with the lowest multitrait PRS were selected. This group (highSLE-lowMultitrait, 25% of total) was then compared with the other patients (75% of total). The same method was used for the highMultitrait-lowSLE group.ResultsBoth PRSs were higher in patients in comparison with healthy controls, p<2×10–6. Besides SLE, the most common diseases associated with the multitrait SNVs were RA (SNV=10), T1DM (SNV=8), multiple sclerosis and ulcerative colitis (SNV=6).The highSLE-lowMultitrait group had higher prevalence of malar rash (OR 1.28(1.00–1.66), p=0.04), neurologic manifestations (OR 1.44(1.10–2.08), p=0.048), thrombocytopenia (OR 1.47(1.06–2.04), p=0.022), anti-Sm antibodies (OR 1.80(1.12–2.80), p=0.009), low complement (OR 1.70(1.25–2.30), p <0.001) and lower prevalence of hemolytic anemia (OR 0.55(0.32–0.97), p=0.038) compared with the other group.The highMultitrait-lowSLE group had higher prevalence of anti-SSA (OR 1.49 (1.14–1.94), p= 0.003) and anti-SSB antibodies (OR 1.79 (1.34–2.39), p <0.001) and lower prevalence of discoid rash (OR 0.72(0.52–1.0), p=0.038) compared with the other group.ConclusionsComparative analysis of multitrait and SLE-specific SNVs shed light on SLE heterogeneity. Leveraging data for shared genetic associations can be important for determining the genetic background influencing SLE subphenotypes, but also common disease manifestations among autoimmune diseases.AcknowledgementsSupported by the Swedish Society for Medical Research (S20–0127), the Swedish Rheumatism Association, King Gustaf V’s 80-Year Foundation, the Gustafsson Foundation.
ObjectiveGenetic contribution is crucial for SLE pathogenesis, but linking risk variants to specific mechanisms in SLE is challenging. We utilize UK Biobank data and a large well defined SLE cohort ...to investigate associations between SLE risk loci, blood biomarkers and clinical phenotype. Our objective: to study potential combinatorial effects of multiple biomarker associated SLE SNVs in clinical SLE data.MethodsWe extracted SLE associated SNVs from published European ancestry GWAS data (with p<5×10–8) and selected 112 SNVs. Associations (p<5×10–8) between these SNVs and blood biomarkers in the UK Biobank were investigated and a 17 SNV cluster associated with 38 biomarkers was identified. Patients with SLE (ACR-97 or SLICC-12, European decent, n=1498) were genotyped using Illumina’s Global Screening Array and clinical data was collected. A weighted polygenic risk score (PRS) including the 17 SNVs identified in the cluster analysis was calculated for each patient and clinical manifestations (ACR-97 criteria, antibodies) of patients with a high (50%) and low (50%) PRS were compared by logistic regression with age and sex covariates. ResultsWe identified a cluster of 17 SLE risk SNVs associated with multiple blood biomarkers in the general population. The biomarkers associated with the highest number of these SNVs include eosinophil percentage (SNV=16), aspartate aminotransferase (SNV=12), apolipoprotein A (SNV=12) and cystatin C (SNV=11). Patients with high PRS had higher total ACR -97 SLE criteria score (OR 1.35 (1.06–1.69), p=0.014) and higher prevalence of anti-SSA (OR 2.71 (2.16–3.40), p<0.001) and anti-SSB antibodies OR 4.58 (3.39–6.61) p<0.001) compared with other patients. Further, high PRS was associated with lower prevalence of thrombocytopenia (OR 0.63 (0.48–0.84), p=0.001) and anti-Sm antibodies (OR 0.59 (0.39–0.89), p=0.011).ConclusionsWe identified a cluster of SLE risk variants associated with multiple blood biomarkers in the UK Biobank. A PRS including these loci associate with an unspecific SLE phenotype including increased number of classification criteria and presence of SSA/SSB antibodies. Further studies are needed to clarify the role of these potential pleiotropic SLE risk loci in lupus pathogenesis.AcknowledgementsSupported by the Swedish Society for Medical Research(S20–0127), the Swedish Rheumatism Association, King Gustaf V’s 80-Year Foundation, the Gustafsson Foundation.
Abnormal liver function tests are frequently observed during follow-up of patients with systemic lupus erythematosus (SLE) but data on co-existence with autoimmune liver diseases (AILD) are scarce. ...This retrospective study aimed to describe the prevalence of autoimmune hepatitis (AIH) and primary biliary cholangitis (PBC) among well-characterized subjects with SLE. We also evaluated whether the presence of autoantibodies to complement protein 1q (C1q) and/or ribosomal P protein (anti-ribP) are, directly or inversely, associated with AIH, as proposed in some reports. The number of screened patients was 287 (86% females), and all cases were included in a regional Swedish cohort. Each subject of the study population met the 1982 American College of Rheumatology classification criteria and/or the Fries' diagnostic principle. By applying the simplified diagnostic AIH criteria combined with persistent transaminasemia, 40 (13.9%) cases reached at least "probable AIH". However, merely 8 of these had been diagnosed with AIH (overall AIH prevalence 2.8%). Neither anti-C1q nor anti-ribP associated significantly with AIH. By applying the recent PBC guidelines, 6 (2.1%) cases were found, but only 3 of them had actually been diagnosed with PBC and one additional subject was not identified by the guidelines (overall PBC prevalence 1.4%). Compared to prevalence data from the general Swedish population, both AIH and PBC were highly overrepresented in our study population. The sensitivity of the diagnostic AIH criteria was impeccable but the specificity was less impressive, mainly due to positive ANA and hypergammaglobulinemia. Based on our findings, among subjects with SLE, the AIH criteria are less useful and liver biopsy combined with detection of other AILD-associated autoantibodies should be performed.
ObjectiveB cell function and autoantibodies are important in SLE pathogenesis. In this work, we aimed to investigate the impact of cumulative SLE B cell genetics on SLE subphenotype and autoantibody ...profile.MethodsFemale patients with SLE (n=1248) and healthy controls (n=400) were genotyped using Illumina’s Global Screening Array. Two polygenic risk scores (PRSs), one representing B cell genes and the other B cell activation genes, were calculated for each individual using risk loci for SLE in genes assigned to B cell-related pathways according to the Kyoto Encyclopedia of Genes and Genomes, Gene Ontology and Reactome Databases.ResultsDouble-stranded DNA (dsDNA) antibodies were more prevalent among patients with a high compared with a low SLE B cell PRS (OR 1.47 (1.07 to 2.01), p=0.018), and effect sizes were augmented in patients with human leucocyte antigen (HLA) risk haplotypes HLA-DRB1*03:01 and HLA-DRB1*15:01 (DRB1*03/15 −/− (OR 0.99 (0.56 to 1.77), p=0.98; DRB1*03/15 +/− or −/+ (OR 1.64 (1.06 to 2.54), p=0.028; and DRB1*03/15 +/+ (OR 4.47 (1.21 to 16.47), p=0.024). Further, a high compared with a low B cell PRS was associated with low complement levels in DRB1*03/15 +/+ patients (OR 3.92 (1.22 to 12.64), p=0.022). The prevalence of lupus nephritis (LN) was higher in patients with a B cell activation PRS above the third quartile compared with patients below (OR 1.32 (1.00 to 1.74), p=0.048).ConclusionsHigh genetic burden related to B cell function is associated with dsDNA antibody development and LN. Assessing B cell PRSs may be important in order to determine immunological pathways influencing SLE and to predict clinical phenotype.
Patients with SLE have an increased risk of comorbidities and impaired survival. We aimed to assess whether various thresholds of oral CS (OCS) can predict development of infections, comorbidities, ...malignancies and survival in SLE using data from national health registries in Sweden.
All incident SLE cases, age >18 years, in Sweden (n = 5309) between 2005 and 2020 and matched population controls (n = 26 545) were included and followed until 2020, a total of 257 942 patient years. Data from national registers were retrieved including information from the National Prescribed Drug Register. Risk factors were analysed using time-dependent Cox regression models.
Compared with no OCS, >0 to <5.0 mg/day, 5.0-7.5 mg/day as well as >7.5 mg/day OCS predicted development of infections (pneumonia, influenza, herpes zoster and urinary tract infection), osteoporosis, osteonecrosis, gastroduodenal ulcers, cataracts, hypertension and mortality (all P < 0.05). OCS >0 to <5.0 mg/day was associated with lower hazard ratios for these comorbidities than higher doses of OCS. Fifteen years after diagnosis, 48% of patients were taking OCS at a median dose of 5.7 mg/day. A small reduction of OCS treatment 5 years after diagnosis in patients diagnosed with SLE 2006-10 compared with 2011-15 was observed, 49% vs 46% respectively (P = 0.039).
Results highlight the potential harm associated with even low OCS dose treatment in SLE and the need to judiciously use OCS at the lowest possible dose to maximize efficacy and minimize harm.
Background
Although the survival of patients with systemic lupus erythematosus (SLE) has improved, irreversible organ damage remains a critical concern. We aimed to characterize damage accrual and ...its clinical associations and causes of death in Swedish patients.
Methods
Accumulation of damage was evaluated in 543 consecutively recruited and well-characterized cases during 1998−2017. The Systemic Lupus International Collaborating Clinics (SLICC)/American College of Rheumatology damage index (SDI) was used to estimate damage.
Results
Organ damage (SDI ≥ 1) was observed in 59%, and extensive damage (SDI ≥ 3) in 25% of cases. SDI ≥ 1 was significantly associated with higher age at onset, SLE duration, the number of fulfilled SLICC criteria, neurologic disorder, antiphospholipid antibody syndrome (APS), hypertension, hyperlipidemia, depression and secondary Sjögren's syndrome (SS). In addition, SDI ≥ 3 was associated with serositis, renal and haematological disorders and interstitial lung disease. A multiple regression model identified not only well-known risk factors like APS, antihypertensives and corticosteroids, but pericarditis, haemolytic anaemia, lymphopenia and myositis as being linked to SDI. Malignancy, infection and cardiovascular disease were the leading causes of death.
Conclusions
After a mean SLE duration of 17 years, the majority of today's Swedish SLE patients have accrued damage. We confirm previous observations and report some novel findings regarding disease phenotypes and damage accrual.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Summary
Serum immunoglobulin (Ig)G anti‐nuclear antibodies (ANA) detected by indirect immunofluorescence (IF) microscopy remains a hallmark of systemic lupus erythematosus (SLE). Whether or not ...IF‐ANA status varies over time is controversial. We therefore designed a prospective study with longitudinal follow‐up of patients with recent‐onset SLE. The study population consisted of 54 recently diagnosed SLE cases, all meeting the 1982 American College of Rheumatology (ACR) and/or the 2012 Systemic Lupus International Collaborating Clinics (SLICC) criteria. Clinical follow‐up data, including disease activity, organ damage and sera, were collected from clinical onset of SLE and onwards, in most cases yearly (0‒96 months). IF‐ANA was analysed on human epithelial cells‐2 (HEp‐2) cells and categorized regarding staining patterns. Using an addressable laser bead assay (FIDIS™ Connective profile), we measured IgG‐ANA fine specificities against Ro52/SSA, Ro60/SSA, Sjögren’s syndrome type B antigen (La/SSB), Smith antigen (Sm), Smith antigen/ribonucleoprotein (Sm/RNP), U1 RNP (U1RNP), dsDNA, ribosomal‐P protein and histone. At baseline, all patients were judged ANA‐positive at an abnormal titre corresponding to the 95th percentile of healthy blood donors, but seven of 54 patients (13%) lost ANA‐positivity over time. Homogeneous (AC‐1; 46%) and speckled (AC‐4 or 5; 31%) were the most frequently observed patterns at inclusion, whereas 7% switched pattern at least once during follow‐up. Established associations between ANA fine specificities and clinical data were confirmed. Levels of anti‐Sm/RNP, but not of anti‐dsDNA, correlated with clinical disease activity modified SLE disease activity 2000 (mSLEDAI‐2K). Our data indicate that a considerable proportion of Swedish patients with SLE lose ANA‐positivity over time, whereas consistent staining patterns were frequent. The clinical and mechanistic relevance of ANA seroconversion remains uncertain. Further prospective evaluations in larger SLE populations with more diverse ethnicities are warranted.
This prospective study, which includes patients with recent‐onset systemic lupus erythematosus, shows that a considerable proportion of Swedish cases lose IgG anti‐nuclear antibody (ANA) positivity detected by indirect immunofluorescence over time.
To investigate associations between a high genetic disease risk and disease severity in patients with systemic lupus erythematosus (SLE).
Patients with SLE (n=1001, discovery cohort and n=5524, ...replication cohort) and healthy controls (n=2802 and n=9859) were genotyped using a 200K Immunochip single nucleotide polymorphism array. A genetic risk score (GRS) was assigned to each individual based on 57 SLE risk loci.
SLE was more prevalent in the high, compared with the low, GRS-quartile (OR 12.32 (9.53 to 15.71), p=7.9×10
and OR 7.48 (6.73 to 8.32), p=2.2×10
for the discovery and the replication cohorts, respectively). In the discovery cohort, patients in the high GRS-quartile had a 6-year earlier mean disease onset (HR 1.47 (1.22 to 1.75), p=4.3×10
), displayed higher prevalence of damage accrual (OR 1.47 (1.06 to 2.04), p=2.0×10
), renal disorder (OR 2.22 (1.50 to 3.27), p=5.9×10
), anti-dsDNA (OR 1.83 (1.19 to 2.81), p=6.1×10
), end-stage renal disease (ESRD) (OR 5.58 (1.50 to 20.79), p=1.0×10
), proliferative nephritis (OR 2.42 (1.30 to 4.49), p=5.1×10
), anti-cardiolipin-IgG (OR 1.89 (1.13 to 3.18), p=1.6×10
), anti-β
-glycoprotein-I-IgG (OR 2.29 (1.29 to 4.06), p=4.8×10
) and positive lupus anticoagulant test (OR 2.12 (1.16 to 3.89), p=1.5×10
) compared with patients in the low GRS-quartile. Survival analysis showed earlier onset of the first organ damage (HR 1.51 (1.04 to 2.25), p=3.7×10
), first cardiovascular event (HR 1.65 (1.03 to 2.64), p=2.6×10
), nephritis (HR 2.53 (1.72 to 3.71), p=9.6×10
), ESRD (HR 6.78 (1.78 to 26.86), p=6.5×10
) and decreased overall survival (HR 1.83 (1.02 to 3.30), p=4.3×10
) in high to low quartile comparison.
A high GRS is associated with increased risk of organ damage, renal dysfunction and all-cause mortality. Our results indicate that genetic profiling may be useful for predicting outcomes in patients with SLE.
To elucidate antibody responses after the second and third dose of COVID-19 vaccine in patients with inflammatory rheumatic diseases (IRD) treated with biologic/targeted disease modifying ...anti-rheumatic drugs (b/ts DMARDs).
Antibody levels to antigens representing spike full length protein and spike S1 were measured before vaccination, 2–12 weeks after the second dose, before and after the third dose using multiplex bead-based serology assay. Positive antibody response was defined as antibody levels over cut off (seropositivity) in seronegative individuals or ≥ 4-fold increase in antibodies in individuals seropositive for both spike proteins.
Patients (n = 414) receiving b/ts DMARDs (283 had arthritis, 75 systemic vasculitis and 56 other autoimmune diseases) and controls (n = 61) from five Swedish regions participated. Treatments groups were: rituximab (n = 145); abatacept (n = 22); Interleukin 6 receptor inhibitors IL6i (n = 79); JAnus Kinase Inhibitors JAKi (n = 58), Tumour Necrosis Factor inhibitor TNFi (n = 68) and Interleukin12/23/17 inhibitors IL12/23/17i (n = 42). Percentage of patients with positive antibody response after two doses was significantly lower in rituximab (33,8%) and abatacept (40,9%) (p < 0,001) but not in IL12/23/17i, TNFi or JAKi groups compared to controls (80,3%). Higher age, rituximab treatment and shorter time between last rituximab course and vaccination predicted impaired antibody response. Antibody levels collected 21–40 weeks after second dose decreased significantly (IL6i: p = 0,02; other groups: p < 0,001) compared to levels at 2–12 week but most participants remained seropositive. Proportion of patients with positive antibody response increased after third dose but was still significantly lower in rituximab (p < 0,001).
Older individuals and patients on maintenance rituximab have an impaired response after two doses of COVID-19 vaccine which improves if the time between last rituximab course and vaccination extends and also after an additional vaccine dose. Rituximab patients should be prioritized for booster vaccine doses. TNFi, JAKi and IL12/23/17i does not diminished humoral response to primary and an additional vaccination.
Abstract Objectives Belimumab is the first biologic drug approved for Systemic Lupus Erythematosus (SLE). Here, we aimed to investigate the effects of belimumab on clinical and serologic outcomes, ...and sought to identify predictors of treatment response in three Swedish real-life settings. Methods Fifty-eight patients were enrolled at initiation of belimumab and followed longitudinally for up to 53 months. Surveillance outcomes included the SLE Disease Activity Index 2000 (SLEDAI-2K), 100 mm Visual Analogue Scales for Physician's Global Assessment (PGA), fatigue, pain and general health, and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). Assessment of treatment response included the SLE responder index (SRI). B lymphocyte stimulator (BLyS) levels were determined using ELISA. Results SLEDAI-2K (median baseline score: 8.0; IQR: 4.0–13.8), PGA and corticosteroid use decreased during therapy, and patients reported improvements on fatigue, pain, and general health ( p < 0.0001 for all). SDI scores remained stable ( p = 0.08). Patients with baseline SDI scores > 1 showed decreased probability and prolonged time to attain SRI response (HR: 0.449; 95% CI: 0.208–0.967), as did current smokers compared with non-smokers (HR: 0.103; 95% CI: 0.025–0.427). In contrast, baseline BLyS levels ≥ 1.2 ng/mL predicted increased probability and shorter time to attain SRI response (HR: 2.566; 95% CI: 1.222–5.387). Conclusions Disease activity and corticosteroid usage decreased, patient-reported outcomes improved, and no significant organ damage was accrued during follow-up. Smoking and organ damage predicted reduced treatment efficacy. These findings might contribute to a better selection of patients who are likely to benefit from belimumab.
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