Heikki Julkunen

Infliximab for 6 months added on combination therapy in early rheumatoid arthritis: 2-year results from an investigator-initiated, randomised, double-blind, placebo-controlled study (the NEO-RACo Study)

Objective Early treatment of patients with rheumatoid arthritis (RA) with combination treatment starting with methotrexate, sulfasalazine, hydroxychloroquine and prednisolone (FIN-RACo strategy) is superior to monotherapy. A study was undertaken to determine whether infliximab (INFL) added to intensified FIN-RACo treatment for the initial 6u2005months improves the 2-year outcome. Methods 99 patients with early untreated active RA were enrolled in an investigator-initiated, randomised, double-blind, multicentre, parallel-group trial. Primary outcomes were remission and radiological changes at 2u2005years. All patients started with FIN-RACo. In addition, they were randomised to receive INFL or placebo (Pla) from weeks 4 to 26. Results At 24u2005months, 66% and 53%, respectively, of the patients in the FIN-RACo+INFL and FIN-RACo+Pla groups were in remission according to the modified American College of Rheumatology (ACR) criteria (p=0.19), 26% and 10% were in sustained modified ACR remission (p=0.042) and 82% in both groups were in remission by 28-joint disease activity score (not significant). Mean changes in the total Sharp-van der Heijde score were 0.2 and 1.4, respectively (p=0.0058). Conclusions Most patients with early active RA achieve clinical remission and develop negligible joint damage with the intensified FIN-RACo regimen. Adding INFL for the first 6u2005months delays radiological progression.

Replication of GWAS-identified systemic lupus erythematosus susceptibility genes affirms B-cell receptor pathway signalling and strengthens the role of IRF5 in disease susceptibility in a Northern European population

OBJECTIVEnA large number of genes, including several not previously implicated in SLE susceptibility, have recently been identified or confirmed by genome-wide association studies (GWAS). In this study, we sought to replicate some of these results in Finnish SLE patients (nu2009=u2009275) and control individuals (nu2009=u2009356).nnnMETHODSnWe genotyped 32 single nucleotide polymorphisms (SNPs) in 12 of the best-supported GWAS-identified SLE genes and loci. We further investigated gene-gene interactions between the loci included in the study.nnnRESULTSnThe strongest evidence of association was found at the IRF5-TNPO3 locus, with the most significant P-value being 2.0u2009×u200910(-7) and an odds ratio of 1.95 (95% CI 1.51, 2.50). Association between SLE and TNFAIP3, FAM167A-BLK, BANK1 and KIAA1542 was also confirmed, although at a lower significance level and contribution to individual risk. No significant association was found with 1q25.1, PXK, ATG5, ICA1, XKR6, LYN and SCUBE1. Furthermore, no significant gene-gene interactions were detected.nnnCONCLUSIONnReplication of previous GWAS findings across diverse populations is of importance to validate these associations and to get a better understanding of potential genetic heterogeneity between populations in SLE susceptibility. Our results attest the importance of B-cell receptor pathway and IFN signalling in SLE pathogenesis.

Nonrenal and renal activity of systemic lupus erythematosus: a comparison of two anti-C1q and five anti-dsDNA assays and complement C3 and C4

Associations of different assays for antibodies to C1q (anti-C1q) and to dsDNA (anti-dsDNA) and of complements C3 and C4 with disease activity in patients with systemic lupus erythematosus (SLE) were studied. The clinical manifestations of 223 SLE patients were recorded, and the disease activity was assessed by the SLEDAI score. Anti-C1q were determined by two enzyme-linked immunosorbent assays (ELISA) and anti-dsDNA by a radioimmunoassay (RIA), a Crithidia immunofluorescence (IF) assay and three ELISA assays using human telomere DNA, plasmid DNA circles, or calf thymus DNA as antigens, respectively. Complement C3 and C4 were determined by nephelometry. Control sera were obtained from 98 blood donors. In patients with SLE, the prevalence of anti-C1q was 17–18% and that of anti-dsDNA was 36–69%. Anti-C1q, anti-dsDNA, and complement C3 and C4 correlated well with the overall activity of SLE (rxa0=xa00.323–0.351, 0.353–0.566, and −0.372–0.444, respectively; Pxa0<xa00.001). Sensitivity, specificity, positive predictive value, and negative predictive value for active lupus nephritis among SLE patients were 40–44, 92, 29, and 91–92% for anti-C1q and 48–68, 29–66, 11–16, and 86–91% for anti-dsDNA, respectively. Patients with active nephritis had higher levels of anti-C1q and lower levels of C3 and C4 than patients with inactive nephritis (Pxa0=xa00.003–0.018). The corresponding associations of anti-dsDNA were somewhat weaker (Pxa0=xa00.023–0.198). Hematological parameters reflecting disease activity correlated clearly better with anti-dsDNA and complement C3 and C4 than with anti-C1q. Anti-C1q is inferior to anti-dsDNA as a diagnostic test in SLE and in the evaluation of overall clinical activity of the disease. Anti-C1q together with complement C3 and C4 may offer useful additional information to monitor lupus nephritis activity. There are no practical differences between different assays for anti-C1q and anti-dsDNA.

Polymorphisms of the ITGAM Gene Confer Higher Risk of Discoid Cutaneous than of Systemic Lupus Erythematosus

Background Lupus erythematosus (LE) is a heterogeneous disease ranging from mainly skin-restricted manifestations (discoid LE [DLE] and subacute cutaneous LE) to a progressive multisystem disease (systemic LE [SLE]). Genetic association studies have recently identified several strong susceptibility genes for SLE, including integrin alpha M (ITGAM), also known as CD11b, whereas the genetic background of DLE is less clear. Principal Findings To specifically investigate whether ITGAM is a susceptibility gene not only for SLE, but also for cutaneous DLE, we genotyped 177 patients with DLE, 85 patients with sporadic SLE, 190 index cases from SLE families and 395 population control individuals from Finland for nine genetic markers at the ITGAM locus. SLE patients were further subdivided by the presence or absence of discoid rash and renal involvement. In addition, 235 Finnish and Swedish patients positive for Ro/SSA-autoantibodies were included in a subphenotype analysis. Analysis of the ITGAM coding variant rs1143679 showed highly significant association to DLE in patients without signs of systemic disease (P-value u200a=u200a4.73×10−11, OR u200a=u200a3.20, 95% CI u200a=u200a2.23–4.57). Significant association was also detected to SLE patients (P-value u200a=u200a8.29×10−6, OR u200a=u200a2.14, 95% CI u200a=u200a1.52–3.00), and even stronger association was found when stratifying SLE patients by presence of discoid rash (P-value u200a=u200a3.59×10−8, OR u200a=u200a3.76, 95% CI u200a=u200a2.29–6.18). Significance We propose ITGAM as a novel susceptibility gene for cutaneous DLE. The risk effect is independent of systemic involvement and has an even stronger genetic influence on the risk of DLE than of SLE.

Linkage mapping of systemic lupus erythematosus (SLE) in Finnish families multiply affected by SLE

Systemic lupus erythematosus (SLE) is an autoimmune disease with diverse and variable clinical manifestations and unknown aetiology. Epidemiological and animal studies indicate that environmental and genetic factors are involved in the development of the disease. Several candidate gene loci (including the human leucocyte antigen ( HLA ) region, Fcγ receptors, and complement components) have been implicated through association studies, and multiple susceptibility loci have been detected in inbred mouse models of SLE.1,2 Until now, six groups have published genomewide scans with SLE as a phenotype in different ethnic groups.3–8 Recently, linkage to chromosome 2q37 (logarithm of odds (LOD) 4.24) in a Swedish population resulted in the identification of a new susceptibility gene PDCD1 in a large multinational study by Prokunina et al .8,9 The SLE associated allele of this immunoreceptor gene alters a binding site for the runt related transcription factor 1 ( RUNX1 ), which is found in an intronic enhancer.nnStratification of pedigrees based on clinical manifestations has been used in recent studies that involved genomewide scans.10–16 The aim was to achieve genetically and clinically homogeneous sets of families and to increase the power to detect susceptibility genes for different subphenotypes of SLE. Altogether, 17 regions have been linked significantly to SLE with model based and non-parametric approaches; 11 of these in stratified studies. In addition, several other regions with suggestive linkage have been identified, but only some of those loci have been implicated in more than one study.6,18 The data suggest that multiple genes are involved in conferring susceptibility to SLE.nnIn our study, we conducted a nationwide and genomewide scan for SLE susceptibility loci in Finnish families multiply affected by SLE. The extensive hospital registration system in Finland allowed us to identify and recruit approximately 85% of all patients with …

The association of antibodies to cardiolipin, beta 2-glycoprotein I, prothrombin, and oxidized low-density lipoprotein with thrombosis in 292 patients with familial and sporadic systemic lupus erythematosus.

Objective: To determine the prevalence of antibodies to phospholipid‐binding plasma proteins (aPL) and to oxidized low‐density lipoprotein (OX‐LDL), and to study the association of these antibodies with thrombosis and coronary heart disease (CHD) in patients with systemic lupus erythematosus (SLE). Methods: Clinical data and sera from 89 Finnish patients with familial and 203 with sporadic SLE were available for the study. Enzyme‐linked immunosorbent assays (ELISA) were used for antibody determination. Results: The occurrence of thrombosis in our SLE patients was 13.7% (40/292) and of clinically diagnosed CHD was 1.4% (4/292). All antibody assays, except IgM‐aCL, were significantly associated with thrombosis. IgG‐aCL alone or in combination with anti β2‐GPI or with anti OX‐LDL were reasonably sensitive (38%, 48%, and 58%, respectively) and specific (87%, 80% and 72%, respectively) for a history of thrombosis. A high risk of arterial thrombosis (TIA or stroke) was associated with positivity of IgG‐aCL, anti β2‐GPI, and anti‐prothrombin. Venous thrombosis was significantly associated with all other assays except IgM‐aCL and anti‐prothrombin. No test correlated with CHD, but the number of affected patients was small. There were three multiplex SLE families with two patients having a history of thrombosis: no consistent pattern of aPL or anti OX‐LDL was found in these patients. Conclusion: IgG‐aCL alone or in combination with anti β2‐GPI or anti OX‐LDL are sensitive and specific tests for detecting SLE patients at increased risk of thrombosis. The aetiopathogenesis of thrombosis in familial SLE appears to be multifactorial.

Smoking and the risk of systemic lupus erythematosus

This study aims to study the association of smoking with the development of systemic lupus erythematosus (SLE). The study included 223 SLE patients (92xa0% women, mean age 47xa0years) and 1,538 population controls of similar age and socioeconomic status living in the metropolitan area of Finland. The history of smoking in patients and controls was obtained by personal interview. The prevalence of current and past smoking was more common in patients with SLE than in controls. In women with a history of daily smoking for more than 1xa0year, the odds ratio (OR) for SLE was 1.45 (95xa0% CI 1.07–1.97), in current daily smokers as compared to never smokers, the OR was 1.55 (1.00–2.40), and in ex-smokers versus never smokers 1.80 (1.15–2.83). The number of men with SLE, who had smoked more than 100 cigarettes during their lifetime was higher than in male controls (pu2009=u20090.026). A history of smoking is significantly though modestly associated with the development of SLE.

Smoking, disease activity, permanent damage and dsDNA autoantibody production in patients with systemic lupus erythematosus

AbstractThe aim was to study the association of smoking with the activity and severity of systemic lupus erythematosus (SLE) and the production of antibodies to dsDNA. The study included 223 SLE patients attending the outpatient clinics at Helsinki University Central Hospital. The history of smoking was obtained by personal interview, and clinical data related to SLE by interview, clinical examination and chart review. The activity of SLE was assessed by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score and permanent damage by the SLICC/ACR score. Antibodies to dsDNA were determined by three ELISA assays, by the indirect immunofluorescence technique using Crithidia luciliae cells as substrates and by the Farr assay. There were no significant differences in the SLEDAI scores between current smokers (73 patients), ex-smokers (59) and never-smokers (91), though current smokers tended to have lower disease activity. The SLICC/ACR scores between the groups were practically equal. Current smokers had significantly lower levels of antibodies to dsDNA than ex- and never-smokers (pxa0=xa00.025). Our study suggests that cigarette smoke may have immunosuppressive effect on autoantibody production in patients with SLE. Permanent damage was not found to be associated with smoking.n

Variation in STAT4 is associated with systemic lupus erythematosus in a Finnish family cohort

Objectives To investigate whether 10 single nucleotide polymorphisms (SNPs) and haplotypes in the STAT4 gene, previously associated with systemic lupus erythematosus (SLE) in a Swedish case–control cohort, are also associated with SLE risk in a Finnish SLE family cohort. Method Genotyping was performed in 192 Finnish families, with 237 affected subjects and their healthy relatives, using the SNPstream genotyping system. Results Transmission disequilibrium test analysis provided the strongest signal of association for two linked SNPs: rs7582694 (p=0.002, OR=2.57) and rs10181656 (p=0.001, OR=2.53). Haplotype association analysis using a sliding window approach was also performed and showed that the strongest association signal originates from SNPs in intron 3 of STAT4. Conclusion The main association signal for STAT4 with SLE previously reported in Caucasians is the same in the Finnish population. This is the first study that confirms the association of STAT4 with SLE in a family cohort.

Frequency of and risk factors for symptomatic bone fractures in patients with systemic lupus erythematosus

Objectives: To study risk factors for symptomatic bone fractures in patients with systemic lupus erythematosus (SLE) and to compare the frequency of fractures between SLE patients and population controls. Method: The study included 222 SLE patients [mean age 47.0 years, disease duration 13.1 years, 204 (92%) women] and 720 population controls living in the metropolitan area of Helsinki. The history of symptomatic bone fractures in SLE patients and controls was recorded by interview, and demographic and clinical data of SLE patients were obtained by interview, clinical examination, and chart review. Results: A history of at least one symptomatic bone fracture was recorded in 93 (42%) of all 222 patients with SLE. The risk of any fracture in 204 women with SLE compared to controls was 1.8 [95% confidence interval (CI) 1.3–2.4] and fractures in the ankle, hip, and vertebral column were more common than in female controls, with odds ratios (ORs) of 2.0 (95% CI 1.1–3.7), 5.1 (95% CI 1.2–21.5), and 4.0 (95% CI 1.8–8.6), respectively. In 18 men with SLE, compared to male controls, no difference in the frequency of fractures was observed (OR 0.7, 95% CI 0.3–2.0). Risk factors for bone fractures in women with SLE were age (p = 0.008), comorbidity (p = 0.050), and the duration of corticosteroid use (p = 0.025). Conclusions: Symptomatic bone fractures, especially in the ankle, hip, and vertebral column, are common in women with SLE. Special attention should be paid to preventing fractures in elderly female patients with comorbidities and a long duration of corticosteroid use.