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.

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.

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.

[Hyperthyroidism due to a TSH-secreting pituitary tumor].

A 28-year-old female with a 12-year history of goiter is presented. She had both clinical and laboratory evidence of hyperthyroidism, and her serum TSH was persistently and markedly elevated after treatment with antithyroid drugs. A TRH stimulation test resulted in no further rise in serum TSH after cessation of medication. Menses were regular and serum prolactin levels were normal. Serum LH and FSH responses to LHRH stimulation test were normal. No other evidence of pituitary or peripheral endocrine deficiencies existed. She underwent a subtotal thyroidectomy followed by 131I therapy three years later. A pituitary adenoma with sphenoidal and suprasellar extension was completely removed by transphenoidal approach. On light microscopy, it was mostly composed of chromophobic cells with occasional calcification showing sinusoidal pattern. On electron microscopy, most of the cells contained fine granules, which suggested thyrotroph. The immunoperoxidase technique revealed TSH beta in the cytoplasm of some adenoma cells. Three days postoperatively the patient's serum TSH levels returned to normal. TRH stimulation test produced a normal response in serum TSH. The patient was diagnosed hypothyroid by laboratory findings and is currently on thyroid replacement therapy. The patient became pregnant and delivered twice prior to the operation for pituitary adenoma. The previously reported TSH secreting adenomas associated with hyperthyroidism were reviewed.

Effects of exposure of pregnant rats to TRH on development of the pituitary-thyroid axis in their progeny.

TRH (10 and 1000 micrograms/kg body weight (BW] was injected ip into pregnant rats daily from day 0 to 20 of pregnancy, and the pituitary-thyroid axis of their pups (Mat-TRH rats) was examined on days 0, 4, 10, 21 and 90 after birth. The pituitary TSH content of male Mat-TRH rats was significantly lower on day 4, and higher on day 10 than that of control rats. The serum TSH was significantly higher on day 10 (except female 10 micrograms/kg group). An exaggerated TSH response to exogenous TRH (10 micrograms/kg BW; ip) was observed on day 10 (males, 1000 micrograms/kg group). The serum T4 level of female Mat-TRH rats was low on day 4 (1000 micrograms/kg group), and higher on day 10. On days 21 and 90, the levels of pituitary TSH, serum TSH and T4 in Mat-TRH rats were similar to those in controls, but the TSH response to TRH was still exaggerated (1000 micrograms/kg group). No significant difference between control and TRH-treated mothers was seen on days 10 and 90 postpartum except for a decreased pituitary TSH content on day 10 in the 1000 micrograms/kg group. It is concluded that repeated administration of TRH to pregnant rats shows an effect on the pituitary-thyroid axis function of their progeny in later life.

Effects of neonatal exposure to TRH on development of the pituitary-thyroid axis in rats.

TRH (10 and 1000 micrograms/kg body weight) was administered ip daily to neonatal rats from day 0 to 9 after birth (Neo-TRH rats) and their pituitary-thyroid axis was examined on days 4, 10, 21 and 90. The pituitary TSH content in Neo-TRH rats was significantly smaller than in controls on days 4 and 10. The serum TSH levels in Neo-TRH rats were significantly lower than those in controls on days 4 (male group only), 10 and 21 (only 10 micrograms/kg group). The serum T4 levels in Neo-TRH rats were lower than in controls on day 10. The reduced pituitary TSH content and serum TSH and T4 were restored to control levels on day 90. However, the response of serum TSH to exogenous TRH (10 micrograms/kg/ip) was blunted in Neo-TRH rats on days 10, 21 and 90. It is concluded that repetitive administration of TRH during the neonatal period suppresses the pituitary-thyroid axis in neonatal life, even after the basal hormone level has been restored to normal.

Thyroidal responses to human chorionic gonadotropin in the chick and rat.

The thyrotropic activity of human chorionic gonadotropin (hCG) has been examined in the chick and the rat. Uptake of 32PO4 by chick thyroid increased significantly with injection of bovine thyrotropin (bTSH) with a maximum response at 2.4 mU per chick. On the other hand, no significant stimulation of 32PO4 uptake was detected with injection of graded doses of highly purified hCG up to 0.25 mg per chick. 1 mg of partially purified hCG, equivalent in biological potency to the maximum dose of highly purified hCG used in the chick, did induce a significant increase in 32PO4 uptake. In rats, highly purified hCG stimulated a very significant release (p less than 0.001) of 125I from the thyroid and partially purified hCG had a thyrotropic activity equivalent to 0.42 microU bTSH/U hCG, identical to the value we reported in mice, 0.42 microU bTSH/U hCG. The duration of hCG action on thyroidal release of 125I in the rat was longer than that for bTSH, as it is in the mouse. hCG also induced a significant rise in the serum level of triiodothyronine in rats. We conclude that pure hCG is a weak thyrotropic substance in the rat but not in the chick. These results and other evidence suggest an inhibitory role for the densely glycosylated 30 amino acid residue C-terminal extension on the beta-subunit of hCG which limits, by steric hindrance, the interaction of the TSH-like hCG 'core' with thyrotropin receptors.

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.

Hyperalimentation in treatment of anorexia nervosa.

Ten patients with anorexia nervosa were treated with intravenous hyperalimentation (IVH) and/or psychotherapy. The five patients were treated with both IVH and psychotherapy. The five patients were treated with both IVH and psychotherapy. Their body weight rose from 66 +/- 3% (mean +/- SE) to 78 +/- 6% of their ideal weight during hospitalization, and then to 91 +/- 5% during ambulatory observation for a period of 6 to 36 months. Another group of 5 patients were treated only with psychotherapy. Their body weight increased 69 +/- 3% to 73 +/- 1% of their ideal weight during hospitalization, and then to 78 +/- 1% during during the observation period at the out-patient department during a period of 6 to 48 months. The former group gained more weight than the latter group during hospitalization (P less than 0.025) and during ambulatory observation (P less than 0.025), respectively. These results suggest that IVH is one effective remedy for anorexia nervosa and that good results can be expected from IVH and psychotherapy used in combination.

Fluctuation of the plasma TRH level in normal subjects in a 4-hour observation period.

Radioimmunoassayable TRH and TSH were measured in plasma samples taken at 5 min intervals for 4 hr (2100-0200 hr) from 4 normal male subjects. Three subjects showed a TSH surge at 2135 hr, 2455 hr and 0150 hr, respectively. The mean plasma TRH level of the 4 subjects was 10.3-11.7 pg/ml. Plasma TRH showed random fluctuation, which did not coincide with the nocturnal increase in plasma TSH.

Effect of a single dose of glucocorticoid on the diurnal variations of TSH, thyroxine, 3,5,3'-triiodothyronine, 3,3'5'-triiodothyronine and cortisol in normal men.

Plasma thyrotropin (TSH) and cortisol concentrations were suppressed immediately after an intravenous bolus dose of 8 mg betamethasone in 6 male subjects. The circadian variations of these hormones disappeared for 40 hr (TSH) and 44 hr (cortisol). Plasma thyroxine (T4), 3, 5, 3'-triiodothyronine (T3), 3,3',5'-triiodothyronine (reverse T3) levels did not show diurnal variations before betamethasone administration. Plasma T3 levels decreased to 66% of the basal levels 20 hr after batamethasone administration, whereas plasma reverse T3 levels increased to 163% of the basal levels at 24 hr. These changes were reversed by 3 to 5 days after betamethasone. The earlier recovery of the diurnal rhythm of TSH than that of cortisol suggests that the TSH rhythm is not under the direct control of circulating cortisol.

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.