Extended exome sequencing identifies BACH2 as a novel major risk locus for Addison's disease.

BACKGROUND: Autoimmune disease is one of the leading causes of morbidity and mortality worldwide. In Addison's disease, the adrenal glands are targeted by destructive autoimmunity. Despite being the most common cause of primary adrenal failure, little is known about its aetiology. METHODS: To understand the genetic background of Addison's disease, we utilized the extensively characterized patients of the Swedish Addison Registry. We developed an extended exome capture array comprising a selected set of 1853 genes and their potential regulatory elements, for the purpose of sequencing 479 patients with Addison's disease and 1394 controls. RESULTS: We identified BACH2 (rs62408233-A, OR = 2.01 (1.71-2.37), P = 1.66 × 10-15 , MAF 0.46/0.29 in cases/controls) as a novel gene associated with Addison's disease development. We also confirmed the previously known associations with the HLA complex. CONCLUSION: Whilst BACH2 has been previously reported to associate with organ-specific autoimmune diseases co-inherited with Addison's disease, we have identified BACH2 as a major risk locus in Addison's disease, independent of concomitant autoimmune diseases. Our results may enable future research towards preventive disease treatment.

Comparison of the 1987 ACR and 2010 ACR/EULAR classification criteria for rheumatoid arthritis in clinical practice: a prospective cohort study.

OBJECTIVE: To compare application of the 1987 American College of Rheumatology (ACR) and 2010 ACR/European League Against Rheumatism (EULAR) classification criteria for diagnosing rheumatoid arthritis (RA) in clinical practice. METHOD: The medical records of patients with early arthritis attending the Rheumatology Department, Umeå University Hospital (n = 1026) were analysed. Patients with synovitis in at least one joint, no diagnosis other than RA being better for explaining the synovitis, and duration of symptoms less than 1 year at first visit, and at least 1 year of follow-up were included consecutively. Fulfilment of the 1987 and 2010 criteria at baseline was evaluated. Sensitivity and specificity for each criterion set, where estimated by using the outcome measures: initiation of methotrexate (MTX) therapy during the first year, and a clinical diagnosis of RA at the 1-year follow-up. Radiographs of hands and feet were evaluated using the Larsen score. RESULTS: The study included 313 patients, of whom 56% fulfilled the 1987 ACR criteria, 74% the 2010 ACR/EULAR criteria, and 53% both sets of criteria at baseline. The sensitivity/specificity for the 1987 and 2010 criteria with MTX within the first year as the outcome measure was 0.68/0.79 and 0.84/0.54, respectively, and with a diagnosis of RA at follow-up 0.72/0.83 and 0.91/0.65, respectively. Older patients (i.e. ≥ 60 years) more often fulfilled the 2010 criteria. Patients who fulfilled the 2010 ACR/EULAR but not the 1987 ACR criteria had a lower Larsen score at inclusion and after 2 years. CONCLUSIONS: Compared with the 1987 ACR criteria, the 2010 ACR/EULAR criteria have higher sensitivity but lower specificity, especially in patients aged ≥ 60 years. The 1987 ACR criteria are suggested to predict a more erosive disease.

Renal abnormalities in a population of patients with psoriatic arthritis.

OBJECTIVE: To investigate the prevalence of and to identify predictive factors for renal abnormalities in patients with psoriatic arthritis (PsA). METHODS: 73 patients with PsA were consecutively examined by laboratory analyses and clinically for joint manifestations. Renal function was estimated by creatinine clearance and urinary albumin. RESULTS: 17 (23.3%) of the patients had renal abnormalities as defined by creatinine clearance below the lower cut off of normal distribution (mean - 2 SD) and/or urinary excretion of albumin more than 25 mg/24 h. These patients were significantly older at the time of the study, older at joint disease onset, had longer skin disease duration, increased serum levels of beta2-microglobulin, and higher incidence of increased ESR and/or CRP levels. Increased ESR/CRP levels had significantly predictive value in multivariate analysis. CONCLUSIONS: In this study subclinical renal abnormalities was a prevalent finding. Predictive factor was inflammatory activity measured by laboratory variables. There were no predisposing effects of NSAID or DMARD therapy.

Role of adrenal medulla in development of sexual dimorphism in inflammation.

Many inflammatory diseases show a female predilection in adults, but not prepubertally. Because sex differences in the inflammatory response in the adult rat are mediated, in part, by sexual dimorphism in adrenal medullary function, we investigated the contribution of the adrenal medulla to the ontogeny of sexual dimorphism in inflammation. Whilst there was no sex difference in the magnitude of the plasma extravasation (PE) induced by the potent inflammatory mediator bradykinin (BK) in prepubertal rats, in adult rats BK-induced PE was markedly greater in males. Also, adult male rats, gonadectomized prior to puberty, had a lower magnitude of BK-induced PE than did adult male controls, whilst adult females gonadectomized prepubertally had higher BK-induced PE than did controls. In rats gonadectomized after puberty, the magnitude of BK-induced PE in adult males was not affected, whilst in females it resulted in significantly higher BK-induced PE, similar to the effect of prepubertal gonadectomy. When tested prepubertally, adrenal denervation increased the magnitude of BK-induced PE in females, but not in males. In contrast, in both males and females tested as adults, but castrated prepubertally, and in gonad-intact adult females, adrenal denervation significantly increased the magnitude of BK-induced PE. Adrenal denervation in prepubertal females given adult levels of 17beta-oestradiol produced a marked enhancement in the denervation-induced increase in magnitude of BK-induced PE compared to females not exposed prematurely to sex hormones. These studies suggest that an adrenal medulla-dependent inhibition of BK-induced PE is present in female but not male rats, and is enhanced by oestrogen but suppressed by testosterone.

Increased prevalence of atherosclerosis in patients with medium term rheumatoid arthritis.

OBJECTIVE: To measure the extent of atherosclerosis in patients with rheumatoid arthritis (RA) with a disease duration of considerable length, and in age and sex matched individuals. METHODS: Thirty-nine patients with RA (30 women, 9 men) with disease onset occurring between 1974 and 1978, and less than 65 years of age at the time of investigation, were enrolled together with 39 sex and age matched controls. Quantitative measurement of intima-media thickness (IMT) and semiquantitative assessment of the presence of plaque were undertaken by B-mode ultrasound of the common carotid artery (CCA-IMT) and the common femoral artery on the right-hand side. Echo Doppler cardiography was performed with an Accuson Aspen. The results were related to disease activity variables and accumulated disease activity, to lipid levels [i.e., cholesterol, high density lipoproteins, low density lipoproteins, triglycerides (TG)], to hemostatic factors [tissue plasminogen activator antigen (tPAag), plasminogen activator inhibitor-1 (PAI-1), von Willebrand factor (vWF)], and to soluble adhesion molecules (sICAM-1 and sE-selectin). RESULTS: Patients with RA had higher maximal and mean IMT values compared with controls. The difference concerning mean CCA-IMT reached statistical significance in patients with RA and correlated significantly with lipids (cholesterol, LDL, LDL/HDL ratio, TG) and tPAag. The prevalence of plaques, as well as of aortic cusp sclerosis, was higher in RA but only the difference in aortic cusp sclerosis was statistically significant. Patients with plaques had significantly higher levels of lipids (cholesterol, LDL, LDL/HDL ratio) than patients without plaques, while patients with cusp sclerosis had significantly higher cholesterol and TG levels. sICAM-1 was significantly higher both in patients with plaques and in those with aortic cusp sclerosis compared to patients without. CONCLUSION: Our results suggest an accelerated atherosclerosis in patients with RA that is related mainly to lipid levels.

Sex steroid regulation of the inflammatory response: sympathoadrenal dependence in the female rat.

To investigate the role of sex steroids in sex differences in the response of rats to the potent inflammatory mediator bradykinin (BK), we evaluated the effect of sex steroid manipulation on the magnitude of BK-induced synovial plasma extravasation (PE). The magnitude of BK-induced PE is markedly less in females. Ovariectomy of female rats increased BK-induced PE, and administration of 17beta-estradiol to ovariectomized female rats reconstituted the female phenotype. Castration in male rats decreased BK-induced PE, and administration of testosterone or its nonmetabolizable analog dihydrotestosterone reconstituted the male phenotype. The results of these experiments strongly support the role of both male and female sex steroids in sex differences in the inflammatory response. Because the stress axes are sexually dimorphic and are important in the regulation of the inflammatory response, we evaluated the contribution of the hypothalamic-pituitary-adrenal and the sympathoadrenal axes to sex differences in BK-induced PE. Neither hypophysectomy nor inhibition of corticosteroid synthesis affected BK-induced PE in female or male rats. Adrenal denervation in females produced the same magnitude increase in BK-induced PE as adrenalectomy or ovariectomy, suggesting that the adrenal medullary factor(s) in females may account for the female sex steroid effect on BK-induced PE. Furthermore, we have demonstrated that in female but not male rats, estrogen receptor alpha immunoreactivity is present on medullary but not cortical cells in the adrenal gland. These data suggest that regulation of the inflammatory response by female sex steroids is strongly dependent on the sympathoadrenal axis, possibly by its action on estrogen receptors on adrenal medullary cells.

Cardiovascular morbidity and mortality in patients with seropositive rheumatoid arthritis in Northern Sweden.

OBJECTIVE: To investigate the overall and the cardiovascular mortality in rheumatoid arthritis (RA) in Northern Sweden. To analyze the effect of traditional risk factors and factors associated with rheumatoid disease and its treatment on the progression of cardiovascular disease (CVD) and on mortality by all causes. METHODS: A cohort of 606 patients with seropositive RA were followed from 1979 to the end of 1994 or to the death of the patient. Standardized mortality ratio and survival curves were estimated with the population of Vasterbotten as reference. Sex, age at disease onset, treatment with corticosteroids, use of disease modifying antirheumatic drugs (DMARD) and hormone replacement therapy (HRT), hypertension, diabetes mellitus, HLA types, and cause of death were recorded from disease onset. Cox's proportional hazards regression was used to identify important predictors for death and cardiovascular event during followup. RESULTS: The standardized mortality ratio in both sexes was significantly higher (1.57) for all underlying causes together, for CVD (1.46) and for ischemic heart disease (IHD) (1.54) compared to the reference population. The death rate increased over time. In multiple Cox regression analyses, male sex, higher age at disease onset, and former cardiovascular event increased the death rate. Male sex, high age at disease onset, and hypertension increased the risk of cardiovascular event. Diabetes mellitus, treatment with corticosteroids, DMARD, or HRT did not influence the risks of death or first cardiovascular event. CONCLUSION: The overall mortality and death due to CVD and IHD were in both sexes increased in seropositive RA. Male sex and high age at disease onset predicted death and cardiovascular event. Except for hypertension, which increased the risk for cardiovascular event, neither of these traditional cardiovascular risk factors nor corticosteroid treatment influenced mortality by all causes or by cardiovascular event.

Peripheral blood lymphocyte subsets in polymyalgia rheumatica.

Peripheral blood lymphocytes from 23 patients with polymyalgia rheumatica (PMR) were characterized using monoclonal antibodies and flow cytometry in a two-year prospective study. There were no significant differences in absolute numbers or relative percentages of lymphocytes or CD3+, CD4+, CD8+ T cells or the CD4+ T cell functional subsets, virgin (CD4+CD45RA+) and memory (CD4+CD29+) T cells, in patients before or during corticosteroid treatment compared to controls. Previous reports on decreased levels of CD8+ T cells as a characteristic of PMR/giant cell arteritis was not confirmed. The absolute number and relative percentage of lymphocytes with natural killer cell activity, CD16+ CD56+ cells, were significantly lower in patients with active untreated PMR as well as during corticosteroid treatment compared to controls, but at the two-year follow-up the difference was less marked.

Interference with the cortisol axis by the microtubule antagonist, CPH82.

Treatment with CPH 82, a mixture of two benzylidated podophyllotoxin glycosides, has been shown to improve inflammatory activity in patients with RA. The drug has few side effects but some patients have developed clinical features of Cushing's syndrome. We studied the hypothalamic-pituitary-adrenocortical axis in two female patients before and during treatment with CPH82. The results clearly demonstrate that CPH82 was associated with suppression of the endogeneous production of ACTH and cortisol with a concomitant paradoxical picture of clinical hypercortisolism. These observations suggest that CPH82 has glucocorticoid receptor agonistic effects.

Muscle endurance, muscle tension and personality traits in patients with muscle or joint pain--a pilot study.

OBJECTIVE: To investigate the relationships between personality traits, depressive symptomatology and continuous muscle tension. METHODS: These were investigated by means of a visual analog scale and the presence of continuous muscle tension during repeated isokinetic shoulder flexions in patients with muscle or joint pain and controls. RESULTS: A significantly higher level of muscle tension between contractions was found in the patient groups in painful muscles. The patients with primary fibromyalgia and trapezius myalgia differed in degree of depressive symptomatology compared to controls. CONCLUSION: Inhibition of aggression correlated significantly with the tension level between contractions during the isokinetic test indicating interaction between psychological and somatic factors.

Trichorhinophalangeal syndrome type I and systemic lupus erythematosus with complement C4A homozygous null alleles in the same family.

A three generation family from northern Sweden with both trichorhinophalangeal syndrome type I (TRP I) and systemic lupus erythematosus (SLE)-like syndrome with complement C4 homozygous null alleles is described. Five family members in three generations were affected by the TRP I syndrome, indicating autosomal dominant inheritance. Two members had clinical and laboratory signs of SLE and two other members SLE-like syndrome. All living family members in the first and second generation had homozygous C4A null alleles. In three of the adults the two syndromes occurred simultaneously, probably in this family by coincidence.

Thrombocytosis in active rheumatoid arthritis. Relation to other parameters of inflammatory activity and confounding effect of automated cell counting.

The magnitude of thrombocytosis and the possible confounding effect of platelet clumping, an in vitro artifact resulting in spuriously low platelet counts, in active rheumatoid arthritis (RA) was evaluated by a prospective survey of 57 consecutive patients, 60% of whom had thrombocytosis. Five cases (9%) of platelet clumping, assessed by H6000 pictures, were found. A low-grade platelet loss in many of the samples anticoagulated by EDTA was suggested by comparison with platelet counts obtained in parallel blood samples anticoagulated by citrate. Thus, the possibility of spuriously low platelet counts due to laboratory artifacts must always be taken into consideration in RA patients. The relation between thrombocytosis and other estimates of disease activity was also studied. The platelet count in citrated blood in active RA was significantly correlated with ESR, acute phase plasma proteins, and neutrophil, basophil and monocyte counts. In a multivariate regression model, however, only the correlation with haptoglobin (p = 0.06) approached significance.

HLA genotypes in two three-generation families with rheumatoid arthritis.

Two three-generation families from Northern Sweden with rheumatoid arthritis (RA) were clinically examined. Tissue typing was performed for HLA-A, -B, -C, and -DR antigens. No disease-associated haplotype could be defined within these families. Six of nine members with RA were HLA-DR4 positive. Both families had a HLA-DR4 containing haplotype in the first generation and second-generation members married DR4 positive individuals, which probably increased the risk to develop RA in the third-generation members.

HLA antigens in patients with otosclerosis.

Seventy-four (50 females and 24 males) consecutively sampled patients with otosclerosis were tissue typed for HLA A and B antigens. There was no significant increase in any A or B antigen, but the frequency of B40 was significantly lower (p less than 0.05) in patients than in blood donors. No significant difference in HLA antigen frequencies was found between men and women, or in patients with vs. without a family history of otosclerosis.

HLA antigens and adverse drug reactions to sodium aurothiomalate and D-penicillamine in patients with rheumatoid arthritis.

The association between HLA antigens and adverse drug reactions (ADR), (e.g. proteinuria, haematological abnormalities, stomatitis, diarrhoea and dermatitis) in rheumatoid arthritis (RA) to sodium aurothiomalate (gold) and to D-penicillamine (PA) were studied in 32 patients. Thirty-eight RA patients treated with gold and PA, and with no ADR to these drugs, were used as controls. The frequency of HLA B8 was significantly (p less than 0.05) increased among RA patients with ADR compared to plasma donors. DR3 was also significantly increased (p less than 0.05) in RA patients with haematological ADR compared to plasma donors. Haematological ADR occurred significantly (p less than 0.05) more often in DR3 positive patients (55%) than among DR3 negative RA patients (27%).

Bf and C3 complement types in rheumatoid arthritis.

Bf and C3 complement types were studied in 100 male and 100 females patients from northern Sweden with erosive rheumatoid arthritis (RA) and compared with population controls. A significantly decreased frequency of the Bf FS phenotype was found particularly in males and in patients with a family history of polyarthritis. Significant Bf associations were also found with a more severe form of RA (functional classes III and IV) and with high titers of the rheumatoid factor. No significant difference with respect to C3 phenotype and gene frequencies was found between RA patients and controls. Thus, the association between RA and C3F found in some previous investigations was not confirmed.

Haptoglobin groups and rheumatoid arthritis.

Haptoglobin types were determined in 200 patients with rheumatoid arthritis (RA) subdivided according to sex and familial occurrence of polyarthritis. A highly significant excess of the Hp2 gene was found among patients with a family history of polyarthritis, more pronounced among males. The possible association between Hp2 and predisposition for increased immune reactivity is discussed.

Alpha-1-antitrypsin types and rheumatoid arthritis.

Frequencies of alpha-1-antitrypsin (Pi) phenotypes were studied in 100 female and 100 male Swedish patients with classical rheumatoid arthritis and compared with the population frequencies. A significant increase of rare Pi types (MS, MZ, MF and SZ) was found among the patients. However, the increase concerned mainly Z heterozygotes and was more strongly pronounced in male patients. The M-subtypes showed no association with rheumatoid arthritis. Previous investigations of Pi types in rheumatoid arthritis have shown somewhat variable results. The results so far indicate, however, that an association between the Z allele and rheumatoid arthritis is likely to exist, while the evidence for a relationship between rheumatoid arthritis and other Pi alleles is considerably weaker.

HLA B27 in the population of northern Sweden.

The frequency of HLA B27 in blood donors born in northern Sweden was found to be 16.6%. This was significantly higher than in southern Sweden or in caucasians generally, with the exception of Finland. A close genetic relationship has been found between the population of northern Sweden and the Finnish. The higher frequency of HLA B27 is particularly interesting in view of the finding of a higher incidence of rheumatic diseases in northern than in southern Sweden. We also found a surprisingly large number of patients with reactive arthritides and ankylosing spondylitis in the patient registers of the rheumatology department, which further indicated a genetic influence on rheumatic disorders in northern Sweden.