Johan G. Brun

Variants at multiple loci implicated in both innate and adaptive immune responses are associated with Sjögren’s syndrome

Sjögrens syndrome is a common autoimmune disease (affecting ∼0.7% of European Americans) that typically presents as keratoconjunctivitis sicca and xerostomia. Here we report results of a large-scale association study of Sjögrens syndrome. In addition to strong association within the human leukocyte antigen (HLA) region at 6p21 (Pmeta = 7.65 × 10−114), we establish associations with IRF5-TNPO3 (Pmeta = 2.73 × 10−19), STAT4 (Pmeta = 6.80 × 10−15), IL12A (Pmeta = 1.17 × 10−10), FAM167A-BLK (Pmeta = 4.97 × 10−10), DDX6-CXCR5 (Pmeta = 1.10 × 10−8) and TNIP1 (Pmeta = 3.30 × 10−8). We also observed suggestive associations (Pmeta < 5 × 10−5) with variants in 29 other regions, including TNFAIP3, PTTG1, PRDM1, DGKQ, FCGR2A, IRAK1BP1, ITSN2 and PHIP, among others. These results highlight the importance of genes that are involved in both innate and adaptive immunity in Sjögrens syndrome.

257 ankle arthroplasties performed in Norway between 1994 and 2005

Background and purpose There have been few reports on the long-term outcome of ankle replacements. The Norwegian Arthroplasty Register has been registering ankle replacements since 1994, but no analysis of these data has been published to date. Here we report data on the use of total ankle replacements and the revision rate in the Norwegian population over a 12-year period. Methods We used the Norwegian Arthroplasty Register to find ankle arthroplasties performed between 1994 and 2005. Patient demographics, diagnoses, brands of prosthesis, revisions, and time trends were investigated. Results There were 257 primary ankle replacements, 32 of which were cemented TPR prostheses and 212 of which were cementless STAR prostheses. The overall 5- year and 10-year survival was 89% and 76%, respectively. Prosthesis survival was the same for the cementless STAR prosthesis and the cemented TPR prosthesis. There was no significant influence of age, sex, type of prosthesis, diagnosis, or year of operation on the risk of revision. The incidence of ankle replacements due to osteoarthritis, but not due to inflammatory arthritis, increased over the years. Interpretation The revision rate was acceptable compared to other studies of ankle arthroplasties, but high compared to total knee and hip arthroplasties. The overall incidence of ankle replacements increased during the study period.

The complex role of vitamin D in autoimmune diseases.

Vitamin D, besides having well‐known control functions of calcium and phosphorus metabolism, bone formation and mineralization, also has a role in the maintenance of immune‐homeostasis. The immune‐regulatory role of vitamin D affects both the innate and adaptive immune system contributing to the immune‐tolerance of self‐structures. Impaired vitamin D supply/regulation, amongst other factors, leads to the development of autoimmune processes in animal models of various autoimmune diseases. The administration of vitamin D in these animals leads to improvement of immune‐mediated symptoms. Moreover, in human autoimmune diseases, such as multiple sclerosis, or rheumatoid arthritis the pathogenic role of vitamin D has been described. The review aims at describing the complex immune‐regulatory role of vitamin D from the cellular level through autoimmune animal models and depicting the known contribution of vitamin D in the pathogenesis of human autoimmune diseases.

Circulating cytokines in primary sjögren's syndrome determined by a multiplex cytokine array system

Plasma cytokines play an important role in the pathogenesis of Sjögrens syndrome (SS) by initiating and perpetuating various cellular and humoural autoimmune processes. The aim of the present study was to describe a broad spectrum of T‐cell and B‐cell cytokines, growth factors, chemokines and molecules that could contribute to cell death in SS. A novel protein array system was utilized to measure simultaneously the levels of 25 plasma cytokines of patients with primary SS and healthy individuals. Furthermore, we correlated these plasma cytokine levels with potential laboratory and clinical parameters related to disease activity in SS. A subset of plasma cytokines [e.g. interleukin‐1β (IL‐1β), IL‐6, CXCL8 (IL‐8), IL‐12 p40, IL‐15, tumour necrosis factor‐α (TNF‐α), epidermal growth factor, CCL4 (MIP‐1β), CCL2 (MCP‐1), CCL11 (Eotaxin), CCL5 (RANTES), TNF‐RI and TNF‐RII] was found to significantly differ between patients and controls. Also, distinct populations of cytokines were found to differentiate between patients with normal versus elevated ESR or IgG levels and patients with the presence or absence of extra‐glandular manifestations (EGMs). Our results support the assumption that the multiplex cytokine array system can be successfully utilized in the diagnosis and disease management of SS. Furthermore, it may provide a powerful tool in the design of individualized anticytokine therapies.

Additive effects of the major risk alleles of IRF5 and STAT4 in primary Sjogren's syndrome

Primary Sjögrens syndrome (SS) shares many features with systemic lupus erythematosus (SLE). Here we investigated the association of the three major polymorphisms in IRF5 and STAT4 found to be associated with SLE, in patients from Sweden and Norway with primary SS. These polymorphisms are a 5-bp CGGGG indel in the promoter of IRF5, the single nucleotide polymorphism (SNP) rs10488631 downstream of IRF5 and the STAT4 SNP rs7582694, which tags the major risk haplotype of STAT4. We observed strong signals for association between all three polymorphisms and primary SS, with odds ratios (ORs) >1.4 and P-values <0.01. We also found a strong additive effect of the three risk alleles of IRF5 and STAT4 with an overall significance between the number of risk alleles and primary SS of P=2.5 × 10−9. The OR for primary SS increased in an additive manner, with an average increase in OR of 1.78. For carriers of two risk alleles, the OR for primary SS is 1.43, whereas carriers of five risk alleles have an OR of 6.78. IRF5 and STAT4 are components of the type I IFN system, and our findings emphasize the importance of this system in the etiopathogenesis of primary SS.

Association of EBF1 , FAM167A(C8orf13)-BLK and TNFSF4 gene variants with primary Sjögren's syndrome

We performed a candidate gene association study in 540 patients with primary Sjögrens Syndrome (SS) from Sweden (n=344) and Norway (n=196) and 532 controls (n=319 Swedish, n=213 Norwegian). A total of 1139 single-nucleotide polymorphisms (SNPs) in 84 genes were analyzed. In the meta-analysis of the Swedish and Norwegian cohorts, we found high signals for association between primary SS and SNPs in three gene loci, not previously associated with primary SS. These are the early B-cell factor 1 (EBF1) gene, P=9.9 × 10−5, OR 1.68, the family with sequence similarity 167 member A–B-lymphoid tyrosine kinase (FAM167A–BLK) locus, P=4.7 × 10−4, OR 1.37 and the tumor necrosis factor superfamily (TNFSF4=Ox40L) gene, P=7.4 × 10−4, OR 1.34. We also confirmed the association between primary SS and the IRF5/TNPO3 locus and the STAT4 gene. We found no association between the SNPs in these five genes and the presence of anti-SSA/anti-SSB antibodies. EBF1, BLK and TNFSF4 are all involved in B-cell differentiation and activation, and we conclude that polymorphisms in several susceptibility genes in the immune system contribute to the pathogenesis of primary SS.

Immunoglobulin G and A Antibody Responses to Bacteroides forsythus and Prevotella intermedia in Sera and Synovial Fluids of Arthritis Patients

ABSTRACT The objective of the present study was to investigate immunoglobulin G (IgG) and IgA antibody immune responses to Porphyromonas gingivalis, Prevotella intermedia, Bacteroides forsythus, and Candida albicans in the sera of patients with rheumatoid arthritis (RA), the synovial fluid (SF) of patients with RA (RA-SF samples), and the SF of patients without RA (non-RA-SF samples). An enzyme-linked immunosorbent assay was used to determine IgG and IgA antibody levels in 116 serum samples from patients with RA, 52 RA-SF samples, and 43 non-RA-SF samples; and these were compared with those in SF samples from 9 patients with osteoarthritis (OA-SF samples) and the blood from 100 donors (the control [CTR] group). Higher levels of IgG antibodies against B. forsythus (P < 0.0001) and P. intermedia (P < 0.0001) were found in non-RA-SF samples than in OA-SF samples, and higher levels of IgG antibodies against B. forsythus (P = 0.003) and P. intermedia (P = 0.024) were found in RA-SF samples than in OA-SF samples. Significantly higher levels of IgA antibodies against B. forsythus were demonstrated in both RA-SF and non-RA-SF samples than in OA-SF samples. When corrected for total Ig levels, levels of IgG antibody against B. forsythus were elevated in RA-SF and non-RA-SF samples compared to those in OA-SF samples. Lower levels of Ig antibodies against B. forsythus were found in the sera of patients with RA than in the plasma of the CTR group for both IgG (P = 0.003) and IgA (P < 0.0001). When corrected for total Ig levels, the levels of IgG and IgA antibodies against B. forsythus were still found to be lower in the sera from patients with RA than in the plasma of the CTR group (P < 0.0001). The levels of antibodies against P. gingivalis and C. albicans in the sera and SF of RA and non-RA patients were comparable to those found in the respective controls. The levels of IgG and IgA antibodies against B. forsythus were elevated in SF from patients with RA and non-RA-SF samples compared to those in OA-SF samples. Significantly lower levels of IgG and IgA antibodies against B. forsythus were found in the sera of patients with RA than in the plasma of the CTR group. This indicates the presence of an active antibody response in synovial tissue and illustrates a potential connection between periodontal and joint diseases.

Impact of lean mass and fat mass on bone mineral density: The Hordaland Health Study

OBJECTIVES To examine the relationship between soft tissue composition and bone mineral density (BMD) of the hip and whether these relationships differ by gender and age. METHODS Femoral neck BMD and total body soft tissue composition were measured by dual X-ray absorptiometry in a population-based sample of 5205 men and women 47-50 and 71-75 years old. Analysis of covariance was used to explore possible modifying effects of sex and gender on the impact of fat and lean mass on BMD. RESULTS The difference in BMD per kilo lean mass (LM) was larger than the difference per kilo fat mass (FM). The effect of FM on BMD was significantly greater among women than among men. In multivariate adjusted analyses, 10kg increase in LM was associated with a 0.083 (95% confidence interval [CI]: 0.075, 0.092)g/cm(2) increase in BMD. A 10kg increase in FM was associated with 0.013 (0.007, 0.019)g/cm(2) increase in BMD among men and 0.021 (0.017, 0.026)g/cm(2) among women. There was indication of a steeper dose-response relationship at lower levels of FM among women. CONCLUSIONS Compared to FM, LM was generally more strongly related to BMD of the femoral neck in middle-aged and elderly men and women. FM was a significantly stronger predictor of BMD among women than among men, particularly at lower levels of FM.

Sjögren's Syndrome—A Plethora of Clinical and Immunological Phenotypes with a Complex Genetic Background

Abstract:  Primary Sjögrens syndrome is a complex autoimmune disorder, considered to represent an ideal disease with which to study the mechanisms underlying autoimmunity because its manifestations are both organ specific and systemic in nature. The characteristic histologic finding in target organs is a progressive focal infiltration of mononuclear lymphoid cells, replacing glandular epithelium (lymphoepithelial lesion). This involvement has been re‐emphasized in the 2002 revised EU criteria for Sjögrens syndrome. Moreover, ectopic secondary lymphoid follicles in Sjögrens syndrome contain all elements of relevance for driving an autoimmune response. A number of cytokines and chemokines are involved and particularly B cell activating factor seems to direct the lifespan of infiltrating B cells by enhancing their proliferation and maturation. The recent discovery of clinical benefit after B cell depletion also highlights the pivotal role of B cells in Sjögrens syndrome. A major challenge in Sjögrens syndrome will be to stratify the disease process including genetic and environmental triggers. Identification of novel genetic and molecular markers may lead to the development of better diagnostic and prognostic tools in Sjögrens syndrome including its systemic complications. This minor review will cover the current knowledge on classification, pathogenesis, multiplex findings, potential candidate genes, gene profiling results, and novel therapy approaches. New hypotheses behind the complexity of Sjögrens syndrome are expected to follow.

Calprotectin in patients with systemic lupus erythematosus: relation to clinical and laboratory parameters of disease activity.

Calprotectin (L1) is a granulocyte and monocyte cytosolic protein released during activation of these cells. The plasma level of L1 has been shown to be a good marker of disease activity in rheumatoid arthritis. In this cross-sectional study of 100 patients with systemic lupus erythematosus (SLE), the serum level of L1 was found to be higher in patients than in matched controls (3661 μg/l versus 1051 μg/l; P < 0.001). The serum level of L1 was the only laboratory parameter with significant association to the disease activity index SLEDAI (r = 0.28; P < 0.01). Furthermore, the serum level of L1 was significantly higher in SLE patients with anti-DNA antibodies compared to patients without anti-DNA antibodies (4501 μg/l versus 3279 μg/l; P = 0.01). SLE patients with arthritis had higher serum levels of L1 than patients without arthritis (7652 μg/l versus 2811 μg/l; P < 0.01), indicating that the serum level of L1 also reflects arthritis activity in SLE.