Male Rheumatoid Arthritis Patients Research Articles

The hypothalamic-pituitary-adrenocortical and gonadal axis function in rheumatoid arthritis.

The altered cortisol and adrenal androgen (i.e., dehydroepiandrosterone sulfate = DHEAS) secretion, observed during testing in rheumatoid arthritis (RA) patients not treated with corticosteroids, should be clearly regarded as a "relative adrenal insufficiency" in the setting of a sustained inflammatory process, as shown by high serum IL-6 levels. Androgens seem implicated in the pathophysiology of autoimmune disorders, including RA, as natural immunosuppressors. Low plasma and synovial fluid testosterone concentrations are observed in male RA patients; low plasma DHEAS levels are mainly observed in female RA patients. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1-type immunity). Gene polymorphisms for enzymes involved in the steroidogenesis seem to further complicate the role of sex hormones in the susceptibility to autoimmunity. Acquired changes of sex steroid metabolism seem to also play a role in the peripheral sex hormone levels. In conclusion, a complex interaction between the hypothalamus-pituitary-adrenocortical and gonadal axis functions is evident in RA.

Major histocompatibility complex phenotypes influence serum testosterone concentration.

(a) To confirm our earlier observation that the phenotype HLA-DR4,7 occurs with higher frequency in male patients with rheumatoid arthritis (RA) than in female patients. (b) To test the hypothesis that DR7 is associated with low normal serum testosterone (Te) levels in healthy males; this might explain the increased frequency of DR4,7 in male patients since there appears to be a relationship between low serum Te and RA. (c) To characterize the association between HLA alleles and serum Te concentration in healthy males. An additional 82 Newfoundland (NF) RA patients were HLA-DR typed and, combined with our earlier data and data from the 11th International Histocompatibility Workshop, gave HLA-DR and sex information on 373 RA patients. Ninety-four healthy NF males were typed for HLA, the microsatellite marker TNFa (located close to the tumour necrosis factor alpha gene) and complement factor B (BF). An additional 38 males were included, selected partly based on their HLA-B type. We confirmed our earlier finding of a higher frequency of HLA-DR4,7 in male RA patients compared with female RA patients (P<0.01). Contrary to our expectations we found that DR7 was associated with higher than mean values of Te as were B5, B27, DR1, TNFa7 and BF F positivity. Conversely, low Te concentrations were found in men with B15, DR2, DR5, TNFa5 and who were BF F negative. In 28 male 'early-onset' RA patients we did not find an increased frequency of HLA alleles associated with low Te levels as compared with the frequency in 41 'late-onset' patients, suggesting that if low Te level is a risk factor and is present before onset of RA then the level cannot be explained by an association between Te level and major histocompatibility complex (MHC) phenotype. This study indicates that a man's MHC phenotype may influence his serum Te concentration, but the relationship of this, if any, to the pathogenesis of RA remains an area of speculation.

Rheumatoid arthritis associated autoantibodies in patients with synovitis of recent onset.

STATEMENT OF FINDINGS: An inception cohort of 238 patients having peripheral joint synovitis of less than 12 months duration was evaluated clinically and followed prospectively for 1 year to determine the clinical significance of a number of rheumatoid arthritis (RA) associated autoantibodies. Serum samples collected at the time of the initial evaluation were tested for rheumatoid factor (RF) and antibodies to Sa (anti-Sa), RA-33, (pro)filaggrin [antifilaggrin antibody (AFA)], cyclic citrullinated peptide (anti-CCP), calpastatin, and keratin [antikeratin antibody (AKA)]. RF had a sensitivity of 66% and a specificity of 87% for RA. Anti-Sa, AFA, and anti-CCP all had a specificity of more than 90%, but a sensitivity of less than 50% for this diagnosis. Overall, there was a high degree of correlation between AFA, AKA, anti-Sa or anti-CCP, this being highest between anti-Sa and anti-CCP (odds ratio, 13.3; P < 0.001). Of the 101 patients who were positive for at least one of these four autoantibodies, 57% were positive for only one. Finally, anti-SA identified a subset of predominantly male RA patients with severe, erosive disease. Anti-SA, AFA and anti-CCP are all specific for early RA but, overall, have little additional diagnostic value over RF alone. Although these antibodies may preferentially recognize citrullinated antigens, the modest degree of concordance between them in individual patient sera suggests that it is unlikely a single antigen is involved in generating these responses.

The hypothalamic-pituitary-adrenal and gonadal axes in rheumatoid arthritis.

The hypothalamic-pituitary-adrenal (HPA) and the hypothalamic-pituitary-gonadal (HPG) axes involvement or response to immune activation seems crucial for the control of excessive inflammatory and immune conditions such as autoimmune rheumatic diseases, including rheumatoid arthritis (RA). However, female patients seem to depend more on the HPA axis, whereas male patients seem to depend more on the HPG axis. In particular, hypoandrogenism may play a pathogenetic role in male RA patients because adrenal and gonadal androgens, both products of the HPA and HPG axes, are considered natural immunosuppressors. A significantly altered steroidogenesis of adrenal androgens (i.e., dehydroepiandrosterone sulfate, DHEAS and DHEA) in nonglucocorticoid-treated premenopausal RA patients has been described. The menopausal peak of RA suggests that estrogens and/or progesterone deficiency also play a role in the disease, and many data indicate that estrogens suppress cellular immunity, but stimulate humoral immunity (i.e., deficiency promotes cellular Th1-type immunity). A range of physical and psychosocial stressors are also implicated in the activation of the HPA axis and related HPG changes. Chronic and acute stressors appear to have different actions on immune mechanisms with experimental and human studies indicating that acute severe stressors may be even immunosuppressive, while chronic stress may enhance immune responses. The interactions between the immunological and neuroendocrine circuits is the subject of active and extensive ongoing research and might in the near future offer highly promising strategies for hormone-replacement therapies in RA.

Endocrine end-points in rheumatoid arthritis.

Our previous studies are reviewed and at the same time preliminary experimental observation to the topic of endocrine end-points in autoimmune disease is introduced. To this end, we have used rheumatoid arthritis (RA), including synovial fluids and primary cultures of synovial macrophages, as a model system in order to investigate (a) expression and subcellular localization of high-affinity sites of steroid binding in immune effector cells; (b) steroid metabolic profiles in both male and female RA patients, as compared to healthy subjects; and (c) activities of key steroid enzymes that govern intratissue accumulation of sex hormones. In RA tissues and cells, the concurrent evidence for (1) androgen and/or estrogen receptors, (2) high concentrations of biologically active steroids, (3) key enzymes of steroid metabolism, and (4) significant changes of estrogen to androgen ratio, all strongly suggests that individual immune cells, including synovial macrophages, may behave as steroid-sensitive cells, namely, they may represent a target for sex steroids, supporting the hypothesis of a potential endocrine regulation of the immune response also in RA disease. In this respect, definition of several endocrine end-points may have important implications for the treatment of rheumatic disease and other immunological disorders.

Body composition in rheumatoid arthritis.

The objectives were to assess bone mineral density (BMD) at different body sites in rheumatoid arthritis (RA) patients related to disease severity parameters, disease duration and corticosteroid intake, and to look for body composition measurements as lean body mass (LBM) and per cent fat as possible prognostic factors in RA. Body composition values were measured cross-sectionally in 89 RA patients and compared with 157 controls. Patients were divided into males and postmenopausal females, ever steroid treated and never steroid treated. BMD values of all body sites were significantly lower compared to normals in all subgroups, except for the lumbar spine (L2 L4) in all postmenopausal women and males never treated with steroids. There was also no clear BMD decrease in the arms of male RA patients. LBM was significantly lower in all body parts compared to controls, whereas the fat distribution ratio (FDR) showed a clear shift to abdominal in all patients. These are parameters of chronic illness and a predictor of cardiovascular disease, respectively. BMD data confirm our previous data in different patient groups (low at appendicular sites, normal lumbar BMD), but no clear influence of disease severity and steroid intake could be found. Body composition data, as LBM and FDR, are also altered in RA patients: decreased LMB and more central FDR. Their usefulness as prognostic markers in early RA patients needs to be clarified prospectively in these patient groups.

Intrusiveness of rheumatoid arthritis on sexuality in male and female patients living with a spouse.

To determine whether physical disability, pain, depressive mood, and criticism by the spouse are differentially related to intrusiveness of rheumatoid arthritis (RA) on sexuality in male and female patients. Physical and psychological aspects of health were assessed in 102 male and 118 female RA patients who were living with a spouse. Patients were classified into 3 levels of intrusiveness of RA on sexuality. The data were analyzed by means of analysis of covariance and multiple regression analysis. Greater intrusiveness of RA on sexuality was related to greater physical disability, pain, and depression in male and female RA patients. Female patients, compared with male patients, appeared to have lower levels of mobility and self-care. Male and female patients did not differ in their level of intrusiveness of RA on sexuality. Physical disability, pain, and, to a lesser extent, depression were found to contribute to intrusiveness of RA on sexuality. It is suggested that differences in sexual motivation between men and women might have been influential in the absence of gender differences in intrusiveness.

Arthritis and perceptions of quality of life: an examination of positive and negative affect in rheumatoid arthritis patients.

The utility of measuring both positive and negative affective states for assessing rheumatoid arthritis (RA) patients was examined in 3 independent samples of male and female RA patients (Sample A: 179 women, 48 men; Sample B: 177 women, 24 men; Sample C: 134 women, 38 men). Confirmatory factor analyses of each sample indicated that positive and negative affect constituted separate, negatively correlated factors. The relations among disease variables, coping, and affects were consistent with a model in which coping mediates the relationship between disease variables and positive and negative affect. Patients with higher pain and limitation from RA had higher levels of maladaptive coping, and maladaptive coping was associated with lower positive affect and higher negative affect. Those RAs with higher activity limitation also reported less adaptive coping, which was associated with less positive affect.

Klinefelter's syndrome and rheumatoid arthritis report of a case and review of the literature

Our case report describes a patient with Klinefelter's syndrome (KFS) associated with rheumatoid arthritis (RA). He had active RA in 1985 but his arthritis almost subsided in 1993 without intensive treatments for RA as well as KFS. Recently, the lower levels of testosterone in male RA patients, especially at the active phase has been reported. However, it is still questionable whether hypogonadism is a predisposing factor or just a consequence of disease. Since our case had a mild clinical course, and since the incidence of RA associated with KFS is very rare in comparison with other rheumatic diseases, may suggest that the low levels of testosterone are not a predisposing factor to the activity of RA.

Relationship of pain behavior to disease activity and health status in rheumatoid arthritis.

The purpose of the study was to investigate the contributions of disease activity, health status, and self-efficacy to the pain behavior exhibited by patients with rheumatoid arthritis. Measures included the Arthritis Impact Measurement Scales, the Arthritis Self-Efficacy Scale, a visual analogue scale for pain, and the McGill Pain Questionnaire. Joint counts and ratings of pain behavior also were obtained. All measures were collected at both baseline and 6 months. Hierarchical multiple regression analyses revealed that disease activity, as measured by joint count, was significantly related to a modified pain behavior index at both time intervals. With joint count entered into the regression model, no other variable consistently increased the predictive accuracy of the model. There were no significant correlations between the modified pain behavior index and either the visual analogue scale for pain or the McGill Pain Questionnaire scores. The results suggest that pain behavior in male rheumatoid arthritis patients is more closely related to disease activity than to self-reported pain, health status, or perceived self-efficacy.

Rheumatoid arthritis, the contraceptive pill, and androgens.

Evidence is accumulating that low androgen concentrations are a cause of rheumatoid arthritis. This would explain a number of established features of the epidemiology of the disease. These include: (a) the variation of disease activity with pregnancy; (b) the variation of age at onset by sex; (c) the variation by sex with HLA-B15; (d) the association with bone mineral density; and (e) the differing time trends in incidence rates by sex. It is argued, moreover, that if one makes a plausible assumption--namely, that women who choose oral contraceptives have high androgen concentrations at the time they first make this choice--then an explanation becomes available for the confusion about the relation between rheumatoid arthritis and oral contraception. Grounds are adduced for that assumption. If this line of reasoning is substantially correct it also has implications for the relations between rheumatoid arthritis and smoking and consumption of alcohol.

Evidence for the presence of androgen receptors in the synovial tissue of rheumatoid arthritis patients and healthy controls.

To study the presence of androgen receptors in the synovial tissue of male and female patients with rheumatoid arthritis (RA) and matched healthy controls. Both site I (high affinity, low binding capacity) and site II (reduced affinity, higher binding capacity) androgen receptors were investigated in soluble and nuclear fractions of homogenized synovial samples, using the dextran-coated charcoal method. The finding of pure, high-affinity site I receptors in both fractions was considered indicative of androgen receptor positivity. In order to determine what type of synovial cell was positive for androgen receptors, cryosections of synovial tissues were immunostained with a specific monoclonal anti-androgen receptor antibody (MAb), using both immunofluorescence and immunoperoxidase techniques. Double immunostaining with this MAb and specific MAb directed toward different macrophage/granulocyte antigens was also performed. Remarkable differences were found between male and female controls: Most males were positive for androgen receptors, and most females were negative. The fetomolar content of androgen receptor in the nuclear fraction was fairly constant, but the soluble fraction showed a higher femtomolar concentration in female RA patients than in controls of either sex, as well as in male RA patients compared with female RA patients. The androgen receptor-positive cells in both RA and control synovial cryosections were found by immunostaining to be macrophage-like synoviocytes, and were also found to be HLA-DR positive. The immunosuppressive action exerted by androgens might, at least in part, be mediated through their interaction with macrophage-like synoviocytes functioning as antigen-processing and antigen-presenting cells in rheumatoid synovia.

Case report: Interleukin‐6 positive follicular hyperplasia in the lymph node of a patient with rheumatoid arthritis

We examined interleukin-6 production in the hyperplastic lymph node of a 77-year-old male rheumatoid arthritis patient with lymphadenopathy. The interleukin-6 production of the lymph node was observed by both immunohistological staining and in vitro culture. The results suggest that interleukin-6 plays a significant pathogenic role in the etiology of the lymphadenopathy seen in many rheumatoid arthritis patients.

Sex hormone status of male patients with rheumatoid arthritis: evidence of low serum concentrations of testosterone at baseline and after human chorionic gonadotropin stimulation.

Serum concentrations of luteinizing hormone, follicle-stimulating hormone, prolactin, 17 beta-estradiol, testosterone, androstenedione, dehydrotestosterone, dehydroepiandrosterone sulfate, and cortisol were examined in 14 men with rheumatoid arthritis (RA) and in age-matched osteoarthritis controls. Hypophyseal, adrenal, and testicular responses to stimulation with luteinizing hormone-releasing hormone, adrenocorticotropin, and human chorionic gonadotropin, respectively, were evaluated in 8 RA patients and in 8 age-matched healthy volunteers. Basal serum testosterone concentrations were significantly lower in male RA patients than in the osteoarthritis control subjects (P less than 0.01). After human chorionic gonadotropin stimulation, serum concentrations of testosterone were also lower in the RA patients than in normal healthy controls (P less than 0.05). These findings suggest that diminished testicular steroid biosynthesis might contribute to the serum testosterone deficiency observed in male RA patients.

Pain management in rheumatoid arthritis: Cognitive behavior modification and transcutaneous neural stimulation

In order to assess the combined effects of cognitive-behavior modification (CBM) and transcutaneous neural stimulation (TNS) on patients with rheumatoid arthritis, a pilot research project was conducted. An interrupted time-series design was utilized with subjects serving as their own controls. Eight male rheumatoid arthritis patients were randomly assigned, two subjects each, to one of the following treatment conditions: (1) Cognitive Behavior Modification (CBM); (2) Transcutaneous Neural Stimulation (TNS); (3) CBM followed by a CBM/TNS combination; or (4) TNS followed by a CBM/TNS combination. The dependent measures included a visual analogue scale, grip strength, McGill Pain Questionnaire, and joint evaluations by a rheumatologist blind to the treatment conditions. Regarding self-reported pain, this study found a slight superiority for the combined TNS/CBM treatments, particularly when the TNS procedures were introduced first. Further research on strategies for maximizing nonpharmacological pain management is recommended.

The influence of HLA phenotypes on the response to parenteral gold in rheumatoid arthritis.

One hundred and ten patients with rheumatoid arthritis (RA) were studied for a possible influence of HLA phenotypes on the reaction to parenteral gold in the first 6 months of treatment, in terms of both clinical response and toxicity. Frequencies of HLA-B8 and -DR3 were significantly increased in patients who responded excellently to gold treatment as compared with non-responders (p = 0.04 for both antigens). On the other hand, for HLA-DR7 there was a tendency for increased frequency in non-responders versus excellent and moderate responders (p less than 0.03; Pc = n.s.). Drug toxicity was higher in excellent than in non-responders (p less than 0.04), being exceptionally high in male excellent responders (85% versus 33% in females, p less than 0.01), probably due to the increased frequency in B8 and DR3 in the excellent responder group as a whole and in the excellent responder males in particular. We conclude that HLA antigens B8 and DR3 co-determine both toxicity and excellent clinical response to parenteral gold, whereas the presence of DR7 is possibly associated with non-response. In addition, we found sex differences in reaction to parenteral gold, which may be related to an increased frequency of HLA-B8 and -DR3 in male RA patients.

Diffuse interstitial lung disease in rheumatoid arthritis. Views on immunological and HLA findings.

Immunological parameters including HLA typing were studied in 32 patients with rheumatoid arthritis (RA) associated diffuse interstitial lung disease (DILD) and in 32 age- and sex-matched RA control patients. The male RA patient group with DILD also included patients with other intrathoracic manifestations and had a higher prevalence of HLA-B8 and Dw3 than did healthy controls, thus agreeing with our earlier results that RA patients with this antigen combination are prone to multiple intrathoracic complications. Patients with DILD had higher titres of rheumatoid factor (RF) and lower complement (C4) levels than matched RA controls. The RF titre was in inverse correlation with C3 and C4 levels, suggesting that RF immune complexes may also promote rheumatoid lung disease via activation of the classical pathway of complement.

Rheumatoid arthritis with pleural effusion includes a subgroup with autoimmune features and HLA-B8, Dw3 association.

Twenty-eight patients with rheumatoid pleural effusion were investigated to examine the frequency of HLA antigens as compared with 56 rheumatoid arthritis (RA) patients without this intrathoracic manifestation of RA and with 283 healthy controls. HLA-B8 was strongly associated with the presence of pleural effusion (PE) in RA patients. A high prevalence (71%) of B8/Dw3 was found among male RA patients of the PE group in whom the joint disease had begun at an age over 50 years and who also had besides pleuritis other intrathoracic manifestations of RA associated with high rheumatoid factor titres and low complement (C4) levels in sera. Actually, the HLA-B8 association was not seen in the rest of the PE group. The finding may be related to the heterogeneity of RA, a male subgroup of the disease being characterized by multiple intrathoracic manifestations and genetically associated with the large group of autoimmune disorders, such as SLE, characterized by high prevalences of HLA-B8 and D(R)3.

HLA DR antigens in rheumatoid arthritis.

The prevalence and possible prognostic significance of HLA-DR antigens have been studied in 129 patients with seropositive (RF-positive) classical rheumatoid arthritis (RA). HLA-DR4 was increased in RA, whilst HLA-DR2 was decreased, though it was not associated with either low titres of RF or with good prognosis. HLA-DR3-positive patients had the highest prevalence of antibodies to nuclear antigens, and the antigen correlated negatively to the presence of subcutaneous nodules, bony erosions and familial RA. RA patients possessing DR3 thus had some of the characteristics of SLE. HLA-DR5 was not present in male RA patients. An absence of familial RA was observed among DRw8-positive patients.

Acid Glycosaminoglycans in Plasma: II. Findings in Rheumatoid Arthritis

The glycosaminoglycans (GAG) directly adsorbable from undiluted plasma on DE-52 anion-exchange cellulose (free GAG) and the GAG adsorbable on AG 1 X 2 anion exchange resin after papain proteolysis (bound GAG) were determined in 35 patients suffering from active erosive rheumatoid arthritis (RA) and in 50 control subjects. Free GAG levels were significantly elevated in both female (p less than 0.001) and male (p less than 0.05) RA patients. Bound GAG levels were significantly depressed in female (p less than 0.02) but not in male RA patients. Total GAG concentrations in RA patients and in controls were fairly similar. No consistent differences in the electrophoretic patterns of the plasma GAG from RA patients and controls were discernible. The free GAG concentrations in RA plasma samples did not correlate with seropositivity or ESR.