Øystein Førre

Elevated CSF levels of substance P and high incidence of Raynaud phenomenon in patients with fibromyalgia: new features for diagnosis

&NA; In 30 patients with diagnosed fibromyalgia, the CSF level of immunoreactive substance P (SP) was investigated. Compared to normal values (9.6 ± 3.2 fmol/ml), all the patients had elevated CSF levels of SP (36.1 ± 2.7 fmol/ml, range 16.5–79.1 fmol/ml). Anamnestic information from the patients revealed that 53.3% had Raynaud/Raynaud‐like phenomenon localized in the fingers, the toes or both. Although SP levels did not differ significantly in patients with or without the Raynaud phenomenon, elevated activity may be present in the peripheral branches of SP neurons which could be responsible for the last (rubor) phase of the triphasic Raynauds phenomenon. SP levels were significantly higher in patients who were smokers (40.1 ± 2.7 fmol/ml, range 25.3–64.1 fmol/ml), compared to patients who were non‐smokers (29.2 ± 5.0 fmol/ml, range 16.5–79.1 fmol/ml). We propose elevated CSF levels of SP and the Raynaud phenomenon as characteristic features for fibromyalgia with potential as diagnostic markers of the disease and further that smoking might be an aggravating factor for its pathogenesis or development.

Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci

Ankylosing spondylitis is a common, highly heritable inflammatory arthritis affecting primarily the spine and pelvis. In addition to HLA-B*27 alleles, 12 loci have previously been identified that are associated with ankylosing spondylitis in populations of European ancestry, and 2 associated loci have been identified in Asians. In this study, we used the Illumina Immunochip microarray to perform a case-control association study involving 10,619 individuals with ankylosing spondylitis (cases) and 15,145 controls. We identified 13 new risk loci and 12 additional ankylosing spondylitis–associated haplotypes at 11 loci. Two ankylosing spondylitis–associated regions have now been identified encoding four aminopeptidases that are involved in peptide processing before major histocompatibility complex (MHC) class I presentation. Protective variants at two of these loci are associated both with reduced aminopeptidase function and with MHC class I cell surface expression.

The prevalence and severity of rheumatoid arthritis in Oslo. Results from a county register and a population survey.

The objective was (1) to examine the prevalence of rheumatoid arthritis (RA) by a county patient register, (2) to cross-validate the register findings by a postal population survey, and (3) to estimate prevalences of disease subsets according to age, sex, and levels of physical disability. The study was performed within a county setting in the city of Oslo with 356,486 inhabitants between 20 and 79 years of age. Prevalence estimates were calculated from a county patient register comprising 1333 patients with RA and a population survey of 10,000 inhabitants. The overall prevalence of RA between 20 and 79 years was 0.437 (95% CI 0.413, 0.461) after adjusting for the incompleteness of the register by a factor of 1.17. Prevalences exceeding 1.0% was only found among females over 60 years. The prevalence of RA with MHAQ scores > or = 1.5 and > or = 2.0 (range 1-4) was 0.225 (95% CI 0.209, 0.243) and 0.099 (0.088, 0.111) respectively. We conclude that RA is less frequent in the city of Oslo than stated in most of the literature. The prevalence of RA with physical disability levels assumed to be associated with increased mortality is less than half of the overall prevalence of 0.4-0.5%.

Association analysis of the 1858C>T polymorphism in the PTPN22 gene in juvenile idiopathic arthritis and other autoimmune diseases.

A functional single nucleotide polymorphism, 1858C>T, in the PTPN22 gene, encoding a tyrosine phosphatase, has been reported to be associated with type I diabetes and some other autoimmune diseases. To further investigate whether this polymorphism may be a general susceptibility factor for autoimmunity, we performed an association study in five different autoimmune diseases, three previously not tested. We found an association with juvenile idiopathic arthritis (OR=1.41; P=0.04), not previously reported, and a tendency for an association with coeliac disease (OR=1.35; P=0.08). In primary sclerosing cholangitis, no association was observed (OR=0.95; P=0.8). Furthermore, we confirmed the increased risk in rheumatoid arthritis (OR=1.58; P=0.001), but could not find support for an association with systemic lupus erythematosus (OR=0.94; P=0.8). Altogether, we have provided further evidence of an association between autoimmune diseases and the 1858C>T polymorphism in PTPN22.

A coding polymorphism in NALP1 confers risk for autoimmune Addison's disease and type 1 diabetes.

Variants in the gene encoding NACHT leucine-rich-repeat protein 1 (NALP1), an important molecule in innate immunity, have recently been shown to confer risk for vitiligo and associated autoimmunity. We hypothesized that sequence variants in this gene may be involved in susceptibility to a wider spectrum of autoimmune diseases. Investigating large patient cohorts from six different autoimmune diseases, that is autoimmune Addisons disease (n=333), type 1 diabetes (n=1086), multiple sclerosis (n=502), rheumatoid arthritis (n=945), systemic lupus erythematosus (n=156) and juvenile idiopathic arthritis (n=505), against 3273 healthy controls, we analyzed four single nucleotide polymorphisms (SNPs) in NALP1. The major allele of the coding SNP rs12150220 revealed significant association with autoimmune Addisons disease compared with controls (OR=1.25, 95% CI: 1.06–1.49, P=0.007), and with type 1 diabetes (OR=1.15, 95% CI: 1.04–1.27, P=0.005). Trends toward the same associations were seen in rheumatoid arthritis, systemic lupus erythematosus and, although less obvious, multiple sclerosis. Patients with juvenile idiopathic arthritis did not show association with NALP1 gene variants. The results indicate that NALP1 and the innate immune system may be implicated in the pathogenesis of many autoimmune disorders, particularly organ-specific autoimmune diseases.

Rheumatoid Inflammatory T‐Cell Clones express mostly Th1 but also Th2 and Mixed (Th0‐Like) Cytokine Patterns

This study was performed in order to characterize whether T cells from rheumatoid synovial inflammation belong to the Th1‐ or Th2‐like functional subsets. Cytokine production was studied in 26 CD4+αβ+ and 2 CD8+αβ T‐cell clones from the synovial fluid, the synovial membrane and peripheral blood of 5 patients. Fifteen of the CD4+ clones were raised against various mycobacterial antigens and 11 CD4+ clones and 2 CD8+ clones were raised unspecifically using PHA and/or IL‐2. The specificities of these clones are not known. In the mycobacterial antigen‐specific group, all CD4+’αβ T‐cell clones produced IFN‐γ at high levels, while the production of IL‐4 was generally absent or low (< 1 ng/ml), consistent with a Thl‐like profile. Some of these clones, however, also produced various amounts of IL‐10 which has been regarded as a Th2 product but can be produced also in lower amounts by Thi cells. One HSP‐65‐specific clone produced levels of IL‐4 and IL‐10 in the same order as that of IFN‐γ, thus appearing to be Th0‐like. Among the 11 unspecific CD4+ clones, 7 showed a Thl‐like pattern but with lower levels of IFN‐γ than the antigen‐specific clones. However, three clones did not produce any IFN‐γ activity but produced IL‐4 and one of them also produced distinct amounts of IL‐10, compatible with a Th2‐like pattern. In addition, one of the clones also showed an almost equally strong IFN‐γ and IL‐4 production, thus most likely representing a Th0‐like clone.

Decreased CD4+ Lymphocyte Activation and Increased Interleukin-4 Production in Peripheral Blood of Rheumatoid Arthritis Patients After Acute Starvation

Abstract: We investigated the effects of acute starvation on mitogen-induced T-cell activation and Th1/Th2 cytokine responses in rheumatoid arthritis (RA) patients. Ten RA patients with active disease underwent a 7-day fast followed by a 2-week refeeding period. Immunological, hormonal, laboratory and clinical evaluations were carried out on days 0, 7 and 21. Using flow cytometry, mitogen-stimulated T-cell activation was assessed in fresh heparinised blood via analysis of CD69 expression. Production of Th1 (interferon-γ) and Th2 (interleukin-4, IL-4) cytokines was also assessed by ELISA. The 7-day fast significantly decreased the erythrocyte sedimentation rate, C-reactive protein level, joint count, morning stiffness, body weight, CD4+ and CD8+ counts and CD69+ expression on mitogen stimulated CD4+ lymphocytes. A significant increase in mitogen-induced IL-4 production after fasting was found. The fast markedly reduced serum leptin and insulin-like growth factor-1 concentrations. No significant differences occurred in serum cortisol or prolactin before and after fasting. Decreases in CD4+ lymphocyte activation during fasting correlated with decreases in body weight. Our results suggest that the clinical and laboratory improvements in fasting RA patients may be attributed to decreased CD4+ T-cell activation and an increase in the number and/or function of IL-4-producing Th2 cells. Factors associated with loss of body weight during acute starvation appear to have an inhibitory effect on CD4+ lymphocyte activation.

Association analysis of the interleukin 17A gene in Caucasian rheumatoid arthritis patients from Norway and New Zealand

OBJECTIVE Elevated levels of IL-17A have been detected in the inflamed synovium of RA patients, and murine arthritis models deficient in IL17A have shown reduced inflammation. Our aim was to investigate IL17A as a candidate gene for RA, and to assess correlations between risk variants and disease phenotypes. METHODS Five single nucleotide polymorphisms (SNPs) were selected to tag the genetic variability of the IL17A region and were genotyped by TaqMan technology on 950 RA cases and 933 random controls from Norway. Associations to progression of radiographic damage and presence of autoantibodies were examined in a 10-yr follow-up cohort of early RA. In addition, 580 RA patients and 504 controls from New Zealand were used as a replication data set. RESULTS A weak association between RA and the promoter SNP rs2275913 [odds ratio (OR) = 1.17; 95% CI 1.02, 1.34; P = 0.02] was found in the Norwegian population. The association was also evident at the genotype level where it indicated a recessive model. The allelic association was not replicated in the RA cohort from New Zealand (OR = 0.96; 95% CI 0.81, 1.16; P = 0.69). However, combined analysis suggested a weak recessive association (OR = 1.19; 95% CI 1.02, 1.37; P = 0.02). No significant associations were observed with radiographic progression, anti-cyclic citrullinated peptide or IgM-RF. CONCLUSIONS Modest evidence of an association with IL17A in Norwegian RA patients was observed. Although, our findings were not replicated in an independent RA material from New Zealand, a significant common risk estimate indicated that IL17A warrants further investigation in RA.

Rheumatoid arthritis and metal compounds—perspectives on the role of oxygen radical detoxification†

Rheumatoid arthritis (RA) is characterised by migration of activated phagocytes and other leukocytes into synovial and periarticular tissue. Activated oxygen species and other mediating substances from triggered phagocytes appear to exacerbate and perpetuate the rheumatoid condition. Iron excesses are capable of aggravating the arthritic inflammation, probably through their pro-oxidant potentials. In contrast, therapeutically given gold salts, through a lysosomal loading of the metal, inhibit the triggered cells, thereby reducing the toxic oxygen production. Pharmacological doses of zinc also may immobilise macrophages. Furthermore, the copper-zinc-containing enzyme SOD (superoxide dismutase) can act as a scavenger of toxic oxygen in the tissues. Therapeutic remission of RA has been obtained following intraarticular administration of SOD. Intramuscular administration of copper complexes has induced remission in about 60% of RA patients in open studies. Another drug, penicillamine, that protects cellular membranes against toxic oxygen in vitro, is presumed to act as an antirheumatic via the SOD mimetic activity of its copper complex. Thiomalate and other thiols may possess similar activities. Selenium compounds also may act as oxygen radical scavengers. A significant alleviation of articular pain and morning stiffness was obtained following selenium and vitamin E supplementation in a double-blind study on RA patients. The observations reviewed here indicate that metal compounds and other antioxidants can reduce the rheumatic inflammation by reducing the cellular production and/or concentration of toxic oxygen species.

Augmented numbers of HLA-DR-positive T lymphocytes in the synovial fluid and synovial tissue of patients with rheumatoid arthritis and juvenile rheumatoid arthritis: in vivo-activated T lymphocytes are potent stimulators in the mixed lymphocyte reaction.

Twenty to 40 % of T cells from synovial fluid and synovial tissue and 3–11 % of the peripheral blood T lymphocytes from patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) expressed HLA‐DR antigens as detected by monoclonal anti‐HLA‐DR antibodies in direct immunofluorescence. Synovial fluid and synovial tissue T lymphocytes had a stimulating capacity comparable to that of non‐T cells in the allogeneic primary mixed lymphocyte reaction (MLR). The MLR was inhibited by monoclonal anti‐HLA‐DR antibodies. This is, to our knowledge, the first report on in‐vivo‐activated T lymphocytes as stimulator cells in MLR. The results suggest that T cells from synovial fluid and synovial tissue are locally activated by stimuli so far unidentified.