Objective We aimed to investigate associations between disease manifestations of SLE and HLA risk alleles relevant to Danish subjects of European ancestry. Methods HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1 alleles were assigned from whole genome sequence data of 25,215 Scandinavian samples, called by Graphtyper, and imputed into 270,627 chiptyped Danes as described,1 including 427 SLE patients of Danish descent, previously characterized with respect to demographic, clinical and genotypic characteristics2 and controls available by collaboration with the Danish Blood Donor Study. Logistic regression was used for association testing of the imputed alleles with SLE. For SLE patients, associations between HLA risk alleles and SLE disease manifestations according to the ACR-1997 classification criteria were examined by multivariate logistic regression analyses adjusted for age and sex; one model for each disease manifestation. Results We identified eight HLA alleles that associate significantly (p<10–4, threshold for 2- and 4-digit HLA alleles) with risk of SLE: HLA-A*01:01, HLA-B*08:01, HLA-C*07:01, HLA-DPB1*01:01, HLA-DQB1*02:01, HLA-DQB1*06:02, HLA-DRB1*03:01 and HLA-DRB1*15:01, and two with protection from SLE: HLA-DQB1*05:01 and HLA-DRB1*01:01. Among the SLE patients, the most frequently observed disease manifestations were immunologic disorder (80%), non-erosive arthritis (80%), haematologic disorder (78%), malar rash (55%), photosensitivity (51%) and persistent proteinuria (37%). We further tested the association of the eight SLE associated HLA alleles, with specific disease manifestations (N=17). Nominally significant associations (OR (95%CI)) were found between HLA-A*01:01 and serositis 0.51 (0.29–0.91), pericarditis 0.40 (0.19–0.83) and leukopenia 0.46 (0.25–0.84), HLA-DPB1*01:01 and seizures 3.58 (1.12–11.47), HLA-DQB1*02:01 and pericarditis 3.78 (1.45–9.89) and between HLA-DRB1*03:01 and anti-phospholipid antibodies 0.50 (0.34–0.75), but these were not significant after multiple testing correction (p<3.7*10–4). Conclusion This study confirms the association of known SLE susceptibility HLA-A, -DPB1, DQB1 and -DRB1 alleles with SLE in Danes of European ancestry. References Eggertsson HP, Kristmundsdottir S, Beyter D, et al. GraphTyper2 enables population-scale genotyping of structural variation using pangenome graphs. Nat Commun. 2019;10(1):5402. Leffers HCB, Westergaard D, Saevarsdottir S, et al. Established risk loci for systemic lupus erythematosus at NCF2, STAT4, TNPO3, IRF5 and ITGAM associate with distinct clinical manifestations: a Danish genome-wide association study. Joint Bone Spine. 2022;89(4):105357.

ObjectivesSLE displays large clinical heterogeneity that beyond genetic factors may be determined by environmental exposures. In this Danish nationwide study, we aimed to determine if clinical subsets of SLE were associated with smoking history.MethodsAt each of six participating centres, incident or prevalent inpatients and outpatients with SLE were consecutively included. Manifestations forming the basis of SLE classification were registered in an electronic chart system. Patients also provided questionnaire-based data on environmental exposures, including smoking history. Hierarchical cluster analysis was conducted to determine and characterise subsets of patients with similar traits of disease manifestations. Levels of smoking exposure by pack-years were correlated to the identified SLE subsets, as well as discrete SLE manifestations.ResultsThe cohort consisted of 485 patients (88% women and 92% Caucasian) with SLE of which 51% were ever smokers. Common disease manifestations comprised non-erosive arthritis (81%), malar rash (57%), lymphopenia (55%), photosensitivity (50%) and persistent proteinuria (41%). We identified three distinct phenotypic clusters characterised by their preponderance of (A) neurological, serosal and mucosal involvement; (B) renal, haematological and immunological disorders; and (C) acute and chronic skin manifestations. Cluster B was the youngest and had the lowest level of smoking exposure. Age-adjusted regression analyses showed that compared with never smokers a smoking history of >20 pack-years was associated with neurological disorder (OR=3.16), discoid rash (OR=2.22), photosensitivity (OR=2.19) and inversely with haematological disorder (OR=0.40), renal disorder (OR=0.40) and non-erosive arthritis (OR=0.45), p<0.05 for all.ConclusionsOur findings support that SLE presents in varying clinical phenotypes and suggest that they may have differentiated associations with smoking history.

OBJECTIVES:To estimate the prevalence of Danish RA patients currently on biologic monotherapy and compare the effectiveness and drug adherence of biologic therapies applied as monotherapy.METHODS:All RA patients registered in the Danish biologics database (DANBIO) as receiving biologic DMARD (bDMARD) treatment as monotherapy without concomitant conventional synthetic DMARDs (csDMARDs) during the study period 1 May, 2011 through 30 April 2013 were eligible for inclusion. All patient files were checked to ensure that they were in accordance with the treatment registration in DANBIO. Descriptive statistics for prevalence, effectiveness and drug adherence of bDMARD monotherapy were calculated.RESULTS:Of the 775 patients on bDMARD monotherapy, adalimumab (21.3%), etanercept (36.6%) and tocilizumab (15.3%) were the most prevalent biologic agents administered. At the 6-month follow-up, the overall crude clinical disease activity index remission rate in patients still on a biologic drug was 22%, the 28-joint DAS remission rate was 41% and the response rate of those with a 50% improvement in ACR criteria was 28%. At the 6-month follow-up, the drug adherence rates were similar for the different bDMARDs, with the exception of infliximab, which had significantly poorer drug adherence (P < 0.001). The overall drug adherence (except for infliximab) was approximately 70% after 2 years.CONCLUSION:Nearly one in five (19%) biologic treatments for RA was prescribed in Denmark as monotherapy, of which 70% were on monotherapy from bio-initiation and 30% were on monotherapy after cessation of a concomitant csDMARD. Acceptable drug adherence and remission rates were achieved with bDMARDs. With the exception of infliximab, no statistically significant differences were observed between anti-TNFs and biologics with other modes of action.