Periarticular osteoporosis of the forearm correlated with joint destruction and functional impairment in patients with rheumatoid arthritis.

UNLABELLED: The relationship between periarticular osteoporosis in the distal forearm and joint destruction or functional impairment in patients with rheumatoid arthritis (RA) is not sufficiently elucidated. From a single institutional cohort study, we found a strong correlation between periarticular forearm bone mineral density (BMD) and joint destruction or functional impairment. INTRODUCTION: This study was conducted to investigate (1) the difference between various periarticular regions of interest (ROIs) of BMD of the forearm, (2) the correlation between periarticular forearm BMD and joint destruction and physical function, (3) the independent variables for predicting BMD of the forearm, and (4) the forearm BMD of different ROIs in the early stage of RA. METHODS: We conducted a cross-sectional study in an RA cohort. Measurements included BMD of the distal forearm, joint destruction of the hands assessed by modified total Sharp score (mTSS), functional impairment assessed by a health assessment questionnaire (HAQ), and other clinical data. Variables affecting the forearm BMD values were analyzed by correlation and stepwise regression analyses. RESULTS: Of the 405 patients enrolled in the present study, 370 (average age; 62.9 years) were identified as having definite RA with a complete set of data. BMD in the distal end of the forearm (BMDud) was significantly reduced compared with that in the distal third of the forearm (BMD1/3). In a stepwise regression analysis, the mTSS in BMD1/3 was an independent predicting variable, while age and partial HAQ scores associated with the upper extremity were common independent variables in BMDud and BMD1/3. BMDud was significantly less than BMD1/3, even in patients with a short duration of the disease. BMD1/3 was significantly less in non-remission group compared with that in remission group in patients with a short duration of the disease. CONCLUSION: Periarticular BMD in the distal forearm is closely correlated with joint destruction and functional impairment in RA. Periarticular BMD in the distal forearm may be already reduced at the clinical manifestation of the disease.

Systemic effects of surgical intervention on disease activity, daily function, and medication in patients with rheumatoid arthritis.

OBJECTIVES: Although tight control of rheumatoid arthritis (RA) has been achieved through the development of effective medication, surgical intervention is still required for a certain subpopulation of patients. To examine the systemic effects of orthopaedic surgery, we evaluated improvements in disease activity, daily function, and medication after surgery. METHOD: A prospective cohort study was conducted in 196 cases of elective orthopaedic surgery in 150 patients with RA from January 2011 to March 2014 in our institution. The 28-joint count Disease Activity Score based on erythrocyte sedimentation rate (DAS28-ESR) and modified Health Assessment Questionnaire (mHAQ) scores just before surgery and at 6 and 12 months after surgery were examined prospectively. Concomitant medications were also investigated. RESULTS: Significant improvement was seen in the DAS28-ESR and mHAQ scores for replacement surgery in both the upper and lower extremities, and for arthroplasty/arthrodesis in the upper extremities at the 12-month follow-up. Partial mHAQ scores for the lower extremities were significantly reduced in lower replacement surgery, and partial mHAQ scores for the upper extremities were significantly reduced in upper arthroplasty/arthrodesis surgery. Although the use of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) did not decrease after surgery, the dose of prednisolone (PSL) decreased significantly at 12 months after surgery, especially in the well-controlled group and in surgical procedures in the lower extremities. CONCLUSIONS: Elective orthopaedic surgery improves both systemic disease activity and general functional impairment. Orthopaedic surgery is effective in reducing the amount of medication required postoperatively.

Oral steroid decreases the progression of joint destruction of large joints in the lower extremities in rheumatoid arthritis.

To identify the risk factors for destruction of large joints in the lower extremities in patients with rheumatoid arthritis (RA) during a 4-year follow-up period in a prospective study.We enrolled consecutive patients who participated in both 2012 and 2016. Clinical data, disease activity, and types of medication were collected in 2012. Standard anteroposterior radiographs of weight-bearing joints (hips, knees, and ankles) were taken in 2012 and 2016. Radiographic progression was defined as progression in the Larsen grade or the need for joint arthroplasty or arthrodesis. The association between baseline characteristics and the incidence of radiographic progression was statistically assessed.A total of 213 patient were enrolled, and, after exclusion, 186 patients were analyzed. Sixty 9 patients (37.1%) showed radiographic progression in 1 of the large joints in the lower extremities. Multivariate regression analysis showed that radiographic progression was associated with older age, higher disease activity, and the presence of radiographic destruction at the baseline. The lower dosage of oral prednisolone was a significant risk factor compared with higher dosage when used.Patients with the risk factors should be followed closely to limit the progression of large joint destruction in the lower extremities.

Distinct biomarkers for different bones in osteoporosis with rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is known to cause secondary osteoporosis and fragility fractures. This study aimed to identify biomarkers predictive of bone mineral density (BMD) change at three anatomical sites in patients with RA. METHODS: We conducted a prospective longitudinal study in patients with RA. In 2012, we recruited 379 patients from an RA cohort, 329 of whom underwent evaluation of blood and urine biomarkers together with measurement of BMD in the lumbar spine, proximal femur, and distal forearm. The BMD in these three regions was reassessed in 2014. We performed multivariate linear regression analysis to identify those factors associated with BMD change. RESULTS: The averages of age, body mass index, and disease activity score in 28 joints (DAS28) at baseline were 63.2 (minimum to maximum, 32-85), 21.3 (12.3-30.0), and 3.2 (0.1-5.9), respectively. Univariate analysis showed that the annual BMD change was significantly associated with the use of steroid, bisphosphonate (BP) or vitamin D (VitD), and serum homocysteine in the lumber spine; DAS28, the use of BP or VitD, CRP, and anti-cyclic citrullinated peptide antibody (ACPA) in the proximal femur; and the dosage of MTX, the use of BP or VitD, and serum tartrate-resistant acid phosphatase 5b (TRACP-5b) in the distal forearm, respectively. CONCLUSIONS: Predictive biomarkers for BMD change in RA patients differ at each anatomical site. Practitioners should treat each anatomical site with different markers and prescribe osteoporosis drugs to prevent fractures for RA patients.

Propylthiouracil blocks extrathyroidal conversion of thyroxine to triiodothyronine and augments thyrotropin secretion in man.

Propylthiouracil (PTU) inhibits peripheral deiodination of thyroxine (T4) and triiodothyronine (T3) and decreases the metabolic effectiveness of T4 in animals. To assess the effect of PTU on extrathyroidal conversion of T4 to T3 in man, 15 studies were performed in athyreotic patients treated with 100 or 200 mug of L-T4 daily for 1 mo before the addition of PTU, 250 mg every 6 h for 8 days. serum T3, T4, and thyrotropin (TSH) were measured daily by radioimmunoassay; serum TSH response to 500-mug thyrotropin-releasing hormone (TRH) was measured before and on the last day of giving PTU. On the 100-mug LT4 dose, serum T3 fell from 120 plus or minus 5 (SE) to 83 plus or minus 6 ng/dl (P less than 0.005) with return to 113 plus or minus 5 ng/dl after stopping PTU; serum T4 (4.5 plus or minus 0.3 mug/dl) did not change. Similar results were seen in patients taking 200 mug of L-T4 daily. On the 100-mug dose of L-T4 the fall in T3 was accompanied by a reciprocal rise in serum TSH to 195 plus or minus 33% of initial concentration (P less than 0.01) with return to 104 plus or minus 8% after PTU. The serum TSH response to TRH (DELTAMUU/ml over base line) was greater during PTU therapy than during the control period. On 100-mug L-T4 DELTA TSH rose from 64 plus or minus 19 to 101 plus or minus 23 muU/ml (P less than 0.005). Expressed as percent of base-line TSH concentration, TSH rose from 140 plus or minus 52 to 280 plus or minus 44% (control vs. PTU) at 15 min, 265 plus or minus 72 to 367 plus or minus 63% at 30 min, 223 plus or minus 54 to 313 plus or minus 54% at 45 min, 187 plus or minus 45 to 287 plus or minus 51% at 60 min, and 145 plus or minus 22 to 210 plus or minus 28% at 120 min after TRH. The data suggest that PTU blocks extrathyroidal conversion of T4 to T3, thus increasing pituitary TSH secretion and augmenting the TSH response to TRH.

Serum thyroid hormones and thyrotropin in anorexia nervosa.

Sixteen patients with typical signs and symptoms of anorexia nervosa were studied with measurement of serum thyroxine (T4), triiodothyronine (T3) and thyrotropin (TSH), both baseline and stimulated by thyrotropin-releasing hormone (TRH). The results of the patients were compared with those of 16 normal control subjects. Serum T4 (5.8 plus or minus 0.26 mug/100 ml, mean plus or minus SE) and T3 (82 plus or minus 5.7 ng/100 ml) of patients with anorexia nervosa were significantly (P less than 0.001) lower than those of control subjects (T4 7.7 plus or minus 0.32 mug/100 ml and T3 158 plus or minus 4.7 ng/100 ml respectively). Furthermore, the ratio of T3/T4 (1.48 plus or minus 0.243 x 10(-2)) in anorexia nervosa was also lower than that of control subjects (2.21 plus or minus 0.093 x 10(-2)) (P less than 0.001). Basal serum TSH was within normal or below the limits of detection. TSH and T3 rose after administration of TRH. The peak values of TSH were observed after 60 to 12o min, instead of 30 min normally seen after TRH injection.

Plasma thyrotropin, thyroxine, and triiodothyronine relationships in man.

The physiologic relationships of plasma TSH, T4 and T3 levels measured every 20 min in seven healthy young men and one healthy young woman have been investigated. A nocturnal TSH surge was observed in all subjects on both nights of the 36-48 h baseline observation period. In males the maximum plasma TSH value occurred at 2300 h. The mean peak TSH level was 2.0 +/- 0.3 (se) muU/ml compared with a mean of 1.3 +/- 0.9 muU/ml for the entire baseline records of the 8 subjects. The effect of iv infusion of 32-1000 mug of somatostatin (SRIF) for 1 1/2-3 h was investigated in four of the male subjects during 2 or 4 consecutive nights following the control period. Temporal relationships between the hormonal fluctuations observed throughout the control period and during the nights of SRIF infusion were investigated using time series analysis and Student's t test. Rapid fluctuations of plasma T4 and T3 concentration were noted, even when corrected for changes in total protein concentration, with an average coefficient of variation of 10% for T3 and 12% for T4. No increment of plasma T4 or T3 followed the nocturnal TSH surge nor were the rapid fluctuations of the thyroid hormones altered by the TSH surge. SRIF infusion commencing at 2300 h suppressed the elevated TSH levels (P is less than 0.01) while similar infusions begun at 2100 h blocked the expected nocturnal TSH rise observed during control periods in male subjects. Plasma T4 and T3 levels were not significantly affected by the administration of SRIF. The relationship of the rapid plasma T4 and T3 variations to postural changes was investigated in four euthyroid male subjects. Serum levels of TSH, T4 and T3 and total protein were determined at 15 min intervals while postural changes were carefully monitored. The ratios of T4 and T3 to total protein were relatively stable (3-4% coefficient of variation) when the subjects were kept in a supine and motionless position. A 50 mug bolus infusion of T4 raised the basal T4 level by only 1-2 mug/dl. The data suggest that short-term fluctuation of plasma T4 and T3 result from changes in protein concentration due to hemodynamic responses to alteration of posture and physical activity and not to pulsatile secretion of T4 and T3.

Pituitary-thyroid function in trophoblastic disease.

Pituitary-thyroid function was assessed in 12 patients with trophoblastic disease (4 hydatidiform mole, 3 invasive mole, and 5 choriocarcinoma). Thyroid-stimulating activity was detectable, by means of the McKenzie bioassay, in 6 patients (Group 1) but not in the other 6 patients (Group 2). In Group 1 serum thyrotropin (TSH) determined by radioimmunoassay was mostly undetectable and did not respond to the administration of thyrotropin-releasing hormone (TRH) determined by radioimmunoassay was mostly undetectable and did not respond to the administration of thyrotropin-releasing hormone (TRH), while in Group 2 basal TSH was detectable in half of the patients and responded to TRH in all cases. Serum concentrations of total thyroxine (T4) (18.7 +/- 2.0 mug/100 ml, mean +/- SE), free T4 (4.9 +/- 0.04 ng/100 ml), total triiodothyronine (T3) (352 +/- 72 ng/100 ml), and free T3 (0.57 +/- 0.11 ng/100 ml) in Group 1 were statistically greater than those in Group 2 (total T4, 9.2 +/- 1.0 mug/100 ml, free T4, 2.0 +/- 0.2 ng/100 ml; total T3 156 +/- 20 ng/100 ml, and free T3 0.23 +/- 0.03 ng/100 ml). Free T4 and T3 fractions were within normal limits in both groups. After treatment of 5 patients in Group 1, the thyroid stimulating activity determined by bioassay dropped to undetectable levels, the serum concentrations of thyroid hormones decreased to normal limits, and TSH response to TRH became positive. These findings indicate that an abnormal thyroid stimulator, derived from the trophoblastic tissue, stimulated the thyroid hormone secretion from the thyroid gland and in turn suppressed TSH response to TRH in some patients with trophoblastic disease.

Effect of thyrotropin-releasing hormone on secretion of thyrotropin, prolactin, thyroxine, and triiodothyronine in pregnant and fetal rhesus monkeys.

The effect of thyrotropin-releasing hormone (TRH) on the pituitary-thyroid axis and on prolactin secretion was studied in pregnant Rhesus monkeys during the latter period of gestation and in non-pregnant female controls. The baseline plasma concentrations of TSH, T3, T4, and prolactin (PRL) of pregnant monkeys did not differ from those of non-pregnant monkeys. After administration of TRH, plasma prolactin rose to higher levels in pregnant monkeys than in non-pregnant monkeys whereas there was a similar response of plasma TSH, T4 and T3 in both groups. The baseline plasma TSH was elevated and plasma T3 was decreased in the fetus compared with the mother. Administration of TRH iv to the maternal monkey caused a larger response in the fetal plasma TSH than in that of the mother and was followed by larger increments in plasma T4 and T3 concentrations in the fetuses than in the mothers. The larger increments of plasma TSH and thyroid hormones in the fetus compared with the mother also occurred when TRH was given iv to the fetus. There was a significant rise of plasma prolactin in both mother and fetus after administration of TRH to mother or fetus; the increase of plasma PRL was much higher in the mother than in the fetus. The data show that TRH can cross the primate placenta in either the maternal to fetal or fetal to maternal direction. The fetal thyroid of the Rhesus monkey during the latter period of gestation can release both T4 and T3 in response to TSH.

A new method of paired thyrotropin assay as a screening test for neonatal hypothyroidism.

A simple and reliable method of paired TSH assay was developed and used in screening for neonatal primary hypothyroidism. In this method, a paired assay is first done. Equal parts of the extracts of dried blood spots on filter paper (9 mm diameter) from two infants 4-7 days old are combined and assayed for TSH by double antibody RIA. If the value obtained is over the cut-off point, the extracts are assayed separately for TSH in a second assay to identify the abnormal sample. Two systems, A and B, with different cut-off points were tested. On the basis of reference blood samples (serum levels of TSH, 80 microU/ml in system A and 40 microU/ml in system B), the cut-off point was selected as follows: upper 5 (A) or 4 (B) percentile in the paired assay and values of reference blood samples in the second individual assay. Four cases (2 in A and 2 in B) of neonatal primary hypothyroidism were found among 25 infants (23 in A and 2 in B) who were recalled from a general population 41,400 infants (24,200 in A and 17,200 in B) by 22,700 assays. This paired TSH neonatal hypothyroidism.

A case of pituitary adenoma with possible simultaneous secretion of thyrotropin and follicle-stimulating hormone.

A TSH- and FSH-screening pituitary adenoma was demonstrated in a 23-yr-old man who presented with bitemporal hemianopsia, but without clinical or laboratory evidences of hyper- or hypothyroidism or hypogonadism. Basal TSH (29-45 microunits/ml) and FSH (44-63 mIU/ml) were moderately elevated. GH and ACTH secretion were impaired, and basal PRL and testosterone were normal. TRH and LRH elicited a significant increase in TSH and FSH, respectively. The plasma glycoprotein alpha-subunit concentration was normal, and its response to simultaneous administration of TRH and LRH was low. Plasma TSH was not suppressed completely by exogenous T3. After operation and radiotherapy, elevated TSH and FSH as well as failure of T3 to suppress TSH were corrected. No significant changes in thyroid hormone concentration in the blood were detected in spite of the reduction of TSH. TSH and FSH concentrations in the tumor extract were lower than those in normal pituitaries. Histologically, the tumor was very vascular and consisted mostly of a single type of cell. The tumor cells were positively stained for FSH beta-subunit by immunohistochemical study, but for none of other pituitary hormones or subunits examined. Electron microscopic examination revealed relatively abundant single type secretory granules of high electron density. It is possible that the tumor simultaneously secreted TSH and FSH, the former possibly being immunologically active, but biologically inactive.

Thyroid function in patients undergoing maintenance hemodialysis: unexplained low serum thyroxine concentration.

Thyroid function was studied in 55 patients undergoing maintenance hemodialysis who were all judged to be clinically euthyroid. The dialysis patients, in comparison to normal control subjects, had significantly lower mean values for serum T4 (4.0 +/- 1.4 [SD] microgram/dl versus 7.9 +/- 1.5 microgram/dl, p less than 0.001), T3 (118 +/- 31 ng/dl versus 147 +/- 28 ng/dl, p less than 0.001), free T4 measured by equilibrium dialysis (1.22 +/- 0.38 ng/dl versus 2.15 +/- 0.67 ng/dl, p less than 0.001), free T3, free T4 index, and free T3 index. Serum TBG, measured by radioimmunoassay, was similar to that of the controls and serum TSH, 2.2 +/- 1.3 micromicron/ml, was also similar to that of control values, 2.0 +/- 1.1 micromicron/ml. The serum PBI did not change during the dialysis procedure, but serum inorganic iodine fell slightly from 2.1 +/- 1.1 microgram/dl before dialysis to 1.2 +/- 0.6 microgram/dl after dialysis (p less than 0.05). The marked reduction in serum total T4 and free T4 concentrations and the moderate reduction in serum total T3 and free T3 levels in apparently euthyroid patients undergoing hemodialysis has not been explained. The normal serum TSH levels in the face of these low concentrations of thyroid hormone suggests an abnormality in the control of TSH secretion in these patients.

Failure of triiodothyronine to prevent propylthiouracil-induced hypothyroidism and goiter in fetal sheep.

Administration of propylthiouracil (PTU) to pregnant, third trimester sheep led to decreasing serum thyroxine and increasing serum thyroid-stimulating hormone in both mothers and fetuses. Hypothyroidism appeared more pronounced in the fetuses than in the ewes, and goiter formation was observed in all fetuses exposed to PTU. Concomitant administration of triiodothyronine failed to protect the fetuses from the effects of PTU.

Kinetic aspects of the antigen-antibody reaction in various radioimmunoassays: effect of delayed addition of labeled or unlabeled antigens on sensitivity of assay.

The kinetics of the antigen-antibody reaction were examined systematically in four kinds of double-antibody radioimmunoassay (RIA). In all the RIAs, the dose-response curves obtained on delayed addition by 24 to 48 h of labeled antigens (curves B), were shifted downwards and to the left of those obtained on simultaneous addition of the reagents (curves A), resulting in improved sensitivity of the assay. On the contrary, the dose-response curves obtained on delayed addition of unlabeled antigens (curves C), were shifted upwards and to the right of curves A, resulting in reduced sensitivity. In human thyrotropin (hTSH) RIA, curves B and C approached curves A very little, even after 168 h of incubation. A similar phenomenon was observed with anti-hTSH antisera from five different sources at two incubation temperatures, and the dilution curves of 125I-labeled hTSH and unlabeled hTSH appeared to be parallel. Therefore, the phenomenon observed with hTSH RIA could not be attributed to the assay conditions or to peculiar properties of the reagents used. In insulin RIA, the reversibilities of the shifts of curves B and C were slight but comparable to those observed in hTSH RIA. In 1-3,5,3'-triiodothyronine RIA, curves B and C gradually approached curves A on prolonged incubation and curves B became nearly identical with curves A after 98 h of incubation. On the other hand, in alpha-fetoprotein (AFP) RIA, curves B and C did not approach curves A, even on prolonged incubation for up to 288 h. The "equilibrium affinity constants" of the antibodies were of the same order of magnitude, thus it is unlikely that differences in the constants can account for the differences in the reversibility of these RIAs. In APF RIA, a significant amount of the antigen-antibody complex was precipitated without second antibody after centrifugation at 3000 X g. These findings suggest that the extent of dissociation of the immune complexes depends on their size, which in turn is related to the molecular weight of the antigen.

Radioimmunoassay for human pancreatic amylase: comparison of human serum amylase by measurement of enzymatic activity and by radioimmunoassay.

A radioimmunoassay (RIA) for human pancreatic amylase has been developed for the determination of human serum amylase content. The assay was shown to be sensitive (7 ng/ml), reproducible and specific, but human pancreatic amylase and salivary amylase could not be distinguished by the antiserum used. In normal subjects, the mean concentration of amylase determined by the RIA was found to be 122.1 ng/ml (range: 55--250 ng/ml). A good correlation was observed between the concentration of amylase and its enzymatic activity in normal subjects. In some instances with high amylase activity, however, the rise in enzymatic activity was not accompanied by increasing amount of amylase content.