Plasma haem oxygenase-1 may represent a first-in-class biomarker of oxidative stress in rheumatoid arthritis.

OBJECTIVES: This study explores the early identification of rheumatoid arthritis (RA) patients at elevated risk of progression. Haem-oxygenase-1 (HO-1) is a marker of oxidative stress in inflammation. Here, we investigate HO-1 as a biomarker of oxidative stress and its association with clinical disease activity and radiographic progression in RA. METHOD: Baseline HO-1 was measured sequentially in plasma samples from patients with early rheumatoid arthritis (eRA) (n = 80). Disease Activity Score based on 28-joint count-C-reactive protein, Clinical Disease Activity Index, and total Sharp score were used to evaluate the disease course serially over 2 years. Paired plasma and synovial fluid samples were examined for HO-1 in active established rheumatoid arthritis (esRA) (n = 20). Plasma from healthy control subjects was also included (n = 35). RESULTS: Plasma HO-1 levels were increased in eRA {1373 pg/mL [interquartile range (IQR) 1110-2050]} and esRA [2034 pg/mL (IQR 1630-2923)] compared with controls [1064 pg/mL (IQR 869.5-1378)]. HO-1 plasma levels decreased with treatment. Baseline HO-1 correlated with disease activity and radiographic progression. A strong, linear correlation was found between synovial and plasma HO-1 levels (r = 0.75, p < 0.001). CONCLUSION: In eRA, plasma levels of HO-1 were increased and correlated with disease and radiographic progression. A baseline measurement of plasma HO-1 levels demonstrated superior performance to currently used clinical and serological disease markers in the prediction of radiographic progression. Plasma HO-1 may function as a first-in-class biomarker of synovial oxidative stress in RA.

Baseline serum levels of IgA anti-cyclic citrullinated protein antibodies in early rheumatoid arthritis predict radiographic progression after 11 years of treatment: a secondary analysis of the CIMESTRA study.

OBJECTIVE: Smoking and periodontitis are risk factors for developing rheumatoid arthritis (RA), suggesting a break of tolerance on mucosal surfaces. Immunoglobulin A (IgA) antibodies are part of the mucosal immune system. The dominant autoantibodies in RA are anti-cyclic citrullinated protein antibodies (ACPAs), and IgG and IgA subclasses exist simultaneously. This study aimed to investigate the association of ACPA IgA subtypes with disease activity and long-term radiographic outcomes in RA, compared with ACPA IgG. METHOD: Total ACPA IgG, IgA, IgA1, and IgA2 were quantified in serum from patients with early RA (n = 97). Patient characteristics, IgM rheumatoid factor (IgM-RF) status, clinical and biochemical disease activity scores, and radiographic status evaluated by total Sharp score (TSS), were assessed at baseline and after 2 and 11 years of treatment. RESULTS: All patients with ACPA IgA also had ACPA IgG. ACPA IgA positivity was associated with IgM-RF and male gender. Both ACPA IgA and IgG levels at baseline were weakly associated with disease activity markers. Baseline ACPA IgA and IgG did not show a linear correlation with radiographic status after 10 years, but could predict radiographic progression (ΔTSS ≥ 5 from 0 to 11 years), with positive likelihood ratios of 3.7 and 4.0, respectively. CONCLUSION: ACPA IgA and IgG were weakly associated with disease activity in early RA. RA patients with a ΔTSS ≥ 5 after 11 years of treatment had higher ACPA IgG and ACPA IgA levels at baseline; however, none of the ACPA subtypes was superior in predicting long-term radiographic progression.

Increased synovial galectin-3 induce inflammatory fibroblast activation and osteoclastogenesis in patients with rheumatoid arthritis.

OBJECTIVE: Galectin-3 (Gal-3) has been suggested as a proinflammatory mediator in rheumatoid arthritis (RA). We aimed to study clinical and pathogenic aspects of Gal-3 in RA. METHOD: Plasma samples from healthy controls (n = 48) and patients with newly diagnosed, early RA were assayed for soluble Gal-3. In patients with chronic RA (n = 18), Gal-3 was measured in both plasma and synovial fluid. Synovial fluid mononuclear cells were used to purify fibroblast-like synoviocytes (FLSs) and osteoclasts. Monocultures of FLSs and autologous co-cultures of FLSs and peripheral blood mononuclear cells were established and co-incubated with a Gal-3 inhibitor. RESULTS: Patients with early and chronic RA had persistently increased plasma levels of Gal-3 compared with controls. However, changes in plasma Gal-3 at the level of individuals were associated with long-term disease activity. In seropositive early RA patients, all patients with decreasing plasma Gal-3 from 0 to 3 months had low disease activity after 2 years (p < 0.05). Gal-3 levels in synovial fluid were markedly elevated. In vitro, co-incubation with a Gal-3 inhibitor (GB1107, 10 µM) led to a significant reduction in both interleukin-1ß and tumour necrosis factor-α secretion from FLS monocultures (both p < 0.05) and decreased monocyte-derived osteoclastogenesis compared with controls (both p < 0.05). CONCLUSIONS: Our findings underscore the role of Gal-3 regarding disease activity and tissue destruction in RA. An initial decrease in plasma Gal-3 levels predicted decreased long-term disease activity. Correspondingly, a Gal-3 inhibitor decreased the activity of inflammatory FLSs and osteoclastogenesis in patients with RA.

Pelvic organ function before and after laparoscopic bowel resection for rectosigmoid endometriosis: a prospective, observational study.

OBJECTIVE: To assess urinary, sexual, and bowel function before and after laparoscopic bowel resection for rectosigmoid endometriosis. DESIGN: Prospectively collected data regarding the function of the pelvic organs. SETTING: Tertiary endometriosis referral unit, Aarhus University Hospital. SAMPLE: A cohort of 128 patients who underwent laparoscopic bowel resection for endometriosis. METHODS: The International Consultation on Incontinence Questionnaire (ICIQ), Sexual Function-Vaginal Changes Questionnaire (SVQ), and the Low Anterior Resection Syndrome (LARS) questionnaire were answered before and after surgery. Non-invasive urodynamic testing was performed. MAIN OUTCOME MEASURES: Pre- and postoperative function of the pelvic organs was compared, and risk factors for improved/impaired function were identified. RESULTS: A total of 96.1% of the women completed the 1-year follow-up. A significant decrease (P = 0.002) in bladder filling problems (F-score) was observed 1 year after surgery, primarily caused by a significant decrease in bladder pain (P = 0.0001). No change for urodynamic parameters was observed. A significant increase in overall sexual satisfaction (P = 0.0001) and decrease in worries about sexual life (P = 0.001) was seen 1 year after surgery. Frequency of defecation was significantly increased 1 year after surgery (P = 0.0001), but the overall bowel function measured by LARS score was unchanged. Patients with anastomotic leakage had a significantly higher risk (odds ratio, OR 5.40; P = 0.002) of increased incontinence problems (I-score) 1 year after surgery. CONCLUSION: A significant and clinically relevant improvement in urinary and sexual function 1 year after laparoscopic bowel resection for endometriosis was found. Except for anastomotic leakage, this could be observed independent of any patient- or treatment-related factor. Apprehension about impairment of urinary and sexual function should not be a contraindication for bowel resection in endometriosis patients. TWEETABLE ABSTRACT: Rectal resection for endometriosis does not impair urinary and sexual function 1 year after surgery.

Increased soluble programmed death-1 (sPD-1) is associated with disease activity and radiographic progression in early rheumatoid arthritis.

OBJECTIVES: Programmed death-1 (PD-1) is an immunoregulatory molecule functioning by down-regulating immune responses. PD-1 is present on follicular helper T cells (TFH) and is important in the formation of plasma cells. PD-1 exists in a bioactive soluble form (sPD-1) and is thought to be implicated in disease activity in chronic rheumatoid arthritis (RA). METHOD: We measured sPD-1 at baseline and 9 months after treatment initiation in plasma from early RA patients (n = 34). We tested for correlations with the Disease Activity Score using 28 joint counts (DAS28), the Health Assessment Questionnaire (HAQ) score, immunoglobulin M rheumatoid factor (IgM-RF), anti-cyclic citrullinated peptide (anti-CCP) antibodies, C-reactive protein (CRP), interleukin-21 (IL-21), and total Sharp score (TSS). We also measured sPD-1 in plasma from healthy volunteers (HV) (n = 20) and in plasma and synovial fluid (SF) from patients with chronic RA (> 8 years of disease, n = 30). We further investigated the cellular expression of PD-1 and its ligand PD-L1. RESULTS: sPD-1 concentrations in early [median 0.421 ng/mL, interquartile range (IQR) 0.04-2.560 ng/mL] and chronic (median 0.239 ng/mL, IQR 0.184-0.584 ng/mL) RA were increased compared with HV (median 0.04 ng/mL, IQR 0.04-0.04 ng/mL) (all p < 0.005). In early RA the change in sPD-1 was associated with DAS28 (r = 0.363, p < 0.05) and HAQ score (r = 0.554, p < 0.05) and inversely with TSS at 3-5 years (r = -0.468, p < 0.05). sPD-1 concentration correlated with IgM-RF, anti-CCP antibodies, and IL-21 (all p < 0.05). PD-1 was primarily expressed by synovial memory T cells whereas PD-L1 was mainly expressed by synovial monocytes. CONCLUSIONS: The significantly elevated plasma levels of sPD-1 in early RA, the association with core disease parameters, and the inverse correlation with TSS suggest that sPD-1 is an important mediator in inflammatory and radiographic disease progression.

Subjective and objective results of anterior vaginal wall repair in an outpatient clinic: a 5-year follow-up.

INTRODUCTION AND HYPOTHESIS: This prospective follow-up study evaluates long-term subjective and objective outcome of conventional anterior vaginal wall repair in an outpatient setting. METHODS: Eighty-two women were operated. At 5-year follow-up anatomical results were evaluated by clinical examination. Furthermore, the women filled in a validated symptom and quality of life questionnaire. RESULTS: Seventy (85%) women attended the follow-up visit. Eleven percent of these had been reoperated for anterior vaginal wall prolapse and was considered a separate group in the analysis. Thirty-four percent had no pelvic organ prolapse (POP). Twenty-nine percent had stage 1 POP whereas 24% had stage 2 and 2% stage 3 at follow-up. Seventy-eight percent of the women had no bulge symptoms, and 73%of the women considered their condition improved. CONCLUSIONS: At 5-year follow-up 78 % was relieved from their bulge symptoms by an operation using local anesthesia. Eleven percent of the women had been reoperated.

Soluble macrophage-derived CD163 is a marker of disease activity and progression in early rheumatoid arthritis.

OBJECTIVES: To investigate the expression of the soluble form of the resident macrophage marker CD163 (sCD163) and its association with core parameters for disease activity, including radiographic progression in early rheumatoid arthritis (RA). METHODS: In a longitudinal sample set from early RA patients (n=34) we measured plasma levels of sCD163 at initiation of treatment and after 9 months of treatment and correlated levels with disease activity in 28 joints (DAS28), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and total Sharp score (TSS). We also measured plasma levels of sCD163 in 55 healthy volunteers (HV) and in a transverse sample set of chronic (>8 years of disease) RA patients (n=24) and OA patients (n=24) with paired plasma and joint fluid. RESULTS: Early RA patients had significantly higher plasma levels of sCD163 (1.69mg/l (1.42-2.10)) (median (IQR)) at baseline than after 9 months of treatment (1.28mg/l (0.963-1.66), p=0.001), but not significantly changed compared with HV (1.66mg/l (1.22-2.02)). In early RA patients, baseline levels of sCD163, correlated with DAS28, CRP and ESR. Interestingly, sCD163 at 9 months was associated with radiographic progression (TSS) between year 0 and 5 (r=0.468, p=0.02). Levels of sCD163 were higher in RA patients, than in OA patients and higher in SF than in plasma. CONCLUSIONS: Plasma levels of macrophage derived sCD163 are associated with disease activity and predict radiographic progression in early RA patients, supporting that sCD163 may have a role as a biomarker of disease activity and that resident macrophages are important for joint destruction.

Effects of androstenedione, insulin and luteinizing hormone on steroidogenesis in human granulosa luteal cells.

BACKGROUND: The present study was conducted to investigate the effect of androstenedione, insulin and LH on human granulosa cell oestrogen and progesterone production. We postulated that elevated concentrations of androstenedione, insulin and LH may be important modulators of granulosa cell steroidogenesis. METHODS: Granulosa cells obtained in connection with IVF procedures were cultured for a total of 4 days in serum-free medium containing androstenedione (10(-6) mol/l). We tested the effect of androstenedione (10(-5) mol/l) on insulin (0-800 microIU/ml), LH (1-10 ng/ml) as well as on insulin + LH-stimulated oestrogen and progesterone production. RESULTS: Insulin increased the basal secretion of steroid hormones, and furthermore augmented LH-stimulated oestrogen and progesterone accumulation in granulosa cell cultures. Androstenedione (10(-5) mol/l) stimulated basal oestrogen production, but significantly reduced (32-58%) insulin + LH-stimulated oestrogen and progesterone secretion (P < 0.05). CONCLUSION: These results suggest that high androstenedione concentrations may act directly to impair insulin augmentation of LH-stimulated oestradiol and progesterone production in cultured human granulosa luteal cells. This is compatible with the hypothesis that high androgen levels may inhibit oestrogen production in polycystic ovary follicles, and as such may contribute to anovulation and infertility in women with polycystic ovary syndrome.

Effects of leptin on basal and FSH stimulated steroidogenesis in human granulosa luteal cells.

BACKGROUND: Body weight influences fertility and studies in mice have indicated that leptin is one of the mediators of this effect. Leptin is believed to centrally stimulate the hypothalamic-pituitary axis resulting in increased gonadotropin release. Moreover, leptin is present in follicular fluid and the receptor is expressed in the human ovary. The aim of this study was to evaluate the direct effect of leptin on cultured human granulosa cell steroidogenesis. METHODS: Granulosa cells were obtained in connection with IVF procedures, and then cultured in a serum-free medium containing androstenedione (1 microM) for a total of 4 days. After 2 days of culture the medium was changed and the hormones under study were added. We tested the effect of leptin (1, 20, 100 ng/ml) on basal, FSH (10-100 ng/ml), and FSH (10-100 ng/ml)+IGF-I (30 ng/ml) stimulated steroidogenesis. RESULTS: Leptin (20 ng/ml and 100 ng/ml) significantly reduced basal and FSH-stimulated estradiol secretion (p<0.05). Basal and FSH (10 and 30 ng/ml) stimulated progesterone production was significantly inhibited by leptin 20 ng/ml, whereas leptin 100 ng/ml significantly reduced basal but not FSH stimulated progesterone production. Finally, steroidogenesis stimulated by IGF-I alone and in combination with FSH was not influenced by leptin. CONCLUSION: These results suggest that leptin acts directly to inhibit basal and FSH stimulated estradiol and progesterone production in cultured human granulosa cells. This raises the possibility that high circulating leptin levels as seen in obese women may compromise fertility through peripheral mechanisms.

[Polycystic ovary syndrome I. Clinical presentation and treatment]. / Polycystisk ovarie-syndrome I. Klinisk billede og behandling.

Polycystic ovary syndrome (PCOS) is probably the most prevalent endocrinopathy in women and the most common cause of menstrual disturbances during the reproductive age. It is characterised by the presence of polycystic ovaries on ultrasound examination together with clinical and biochemical signs of hyperandrogenaemia. The majority of patients will seek medical advice because of menstrual disturbances, infertility or signs of hyperandrogeneamia (hirsutism, acne, alopecia). In obese patients the therapeutic mainstay is weight reduction. Anovulatory infertility is treated by stimulation of ovulation, laparoscopic electrocautery or IVF, while patients with menstrual disturbances without a wish to conceive should be treated with cyclic gestagen therapy or oral contraceptives in order to reduce the increased life-long risk of endometrial cancer. Additionally, hirsutism may be treated by epilation or antiandrogen therapy. PCOS is a common disease with an increased risk of NIDDM, hypertension, cardiovascular disease and endometrial cancer. Polycystic ovary syndrome is thus a disease which needs attention from the health system.

[Polycystic ovary syndrome II. Endocrinology and metabolism]. / Polycystisk ovarie-syndrome II. Endokrinologi og metabolisme.

The polycystic ovary syndrome (PCOS) is diagnosed by the simultaneous presence of polycystic ovaries by ultrasound together with clinical and biochemical signs of hyperandrogenaemia. Recently, it has been shown that a majority of PCO patients exhibit metabolic abnormalities, i.e. android obesity, insulin resistance and dyslipidaemia, all of which dispose to "civilized" life-style diseases such as cardiovascular disease and non-insulin dependent diabetes. PCOS is therefore not merely a gynaecological curiosity, but an endocrinopathy with multisystem sequelae. The endocrinological and metabolic aspects of the disease are discussed.