Radionuclide imaging with human polyclonal immunoglobulin (Tc-HIG) and bone scan in patients with rheumatoid arthritis and serum-negative polyarthritis.

BACKGROUND AND AIM: Rheumatoid arthritis (RA) is a chronic polyarthritic syndrome in which actively inflamed joints coexist with others being in remission. Compatible bone scan (BS) reveals joints with increased activity due to degenerative alterations, whilst scanning with human polyclonal immunoglobulin (HIG) is capable to show which of the joints present active inflammation of the synovial membrane. The aim of the study is to investigate the utility of molecular imaging with HIG in patients suffering from RA. PATIENTS AND METHODS: Forty patients (9 males plus 31 females), suffering from painful polyarthritic syndrome, with a mean age 45.3±7 years and a duration of disease 18.3±4.2 months were enrolled in the study. Twenty-six of the patients were serum positive to RA factor, considered as suffering from RA, whilst fourteen of them were RA factor negatives and they were considered as patients with serum-negative polyarthritis. All patients were submitted to x-rays and ultrasound examination (US) in joints of interest, plus whole body BS with (99m)Tc-MDP and finally scan with (99m)Tc-HIG. RESULTS: A total of 1680 joints have been evaluated. In 6 of the patients-two with serum negative RA (252 joints), radionuclide imaging with HIG was within normal limits, despite the fact that in compatible bone scan degenerative alterations have been mentioned in 30 joints. In all these patients disease was evaluated as inactive ("arthrotic changes"). In the remaining 34 patients-12 with serum negative RA (1428 joints), increased accumulation of HIG, concerning serum positive patients, has been mentioned to 163 joints ("arthritic changes"), whilst in the same group, BS revealed degenerative changes to 265 joints. Concerning serum negative patients, the respective results were 64 versus 190 joints. Increased uptake of HIG has been found in 189/226 swollen and painful joints (overall sensitivity according to clinical criteria 83.3%) and in 38 joints without any clinical evidence of inflammation, with clinical active inflammation presented after follow-up to 35 of them, yielding thus specificity at the level of 92%. Matched findings between these two methods have been mentioned to 185 out of 227 joints with an abnormal scan with HIG. Abnormal x-rays and US findings have been mentioned in 67 of the joints. CONCLUSIONS: According to the above mentioned, BS in RA reveals joints being actively inflamed or not, whilst radionuclide study with HIG is capable to distinguish actively inflamed joints, even in patients with serum negative RA, in a greater extent than anatomical imaging modalities.

Dissociation between circulating concentrations of immunoreactive growth hormone releasing factor and growth hormone in normal human subjects.

Using a highly specific radioimmunoassay we have measured immunoreactive human growth hormone releasing factor (ir-hGRF) concentrations in the peripheral circulation of a total of 12 normal subjects. Neither insulin-induced hypoglycaemia, intravenous arginine nor oral carbohydrate caused any change in venous plasma ir-hGRF concentrations, despite the expected stimulation and suppression respectively of growth hormone secretion. Growth hormone secretion was not increased by oral fat or protein but each of these two foods stimulated ir-hGRF concentrations two- to four-fold. Spontaneous pulses of growth hormone secretion on control days were unaccompanied by any increase in plasma ir-hGRF. The dissociation between peripheral circulating ir-hGRF and growth hormone responses demonstrated under different circumstances suggests that an important source of human growth hormone releasing factor lies outside the hypothalamus and that secretion from this source is unconnected with the normal control of pituitary growth hormone secretion.

Somatostatin octapeptide (SMS 201-995) in the medical treatment of acromegaly.

Parenteral somatostatin has been used to suppress growth hormone secretion in acromegalic patients, but long-term treatment is hampered by its short half-life of a few minutes in the circulation. An octapeptide analogue of somatostatin (SMS 201-995) has recently been developed that has greater potency and selectivity in suppressing growth hormone than the native hormone. In this study somatostatin and somatostatin octapeptide infusions were compared in 13 patients with active acromegaly. The octapeptide had a longer duration of action in the suppression of growth hormone than native somatostatin. A twice daily dose of 100 micrograms significantly suppressed growth hormone during the day. Prolactin was not suppressed, even in hyperprolactinaemic patients, and suppression of insulin was of short duration. Two patients had diarrhoea, but this disappeared when treatment with the octapeptide was stopped. Somatostatin is known to suppress pancreatic exocrine function, and it is therefore important to look for evidence of malabsorption during long-term treatment with the octapeptide. Somatostatin octapeptide is therefore useful in the treatment of acromegaly, but evidence of malabsorption should be watched for; nonparenteral routes of administration need to be assessed.

Are there genetic determinants for the glucose intolerance of acromegaly?

A genetic marker identifying the two parental insulin genes has been studied in 51 Caucasian acromegalics by Southern blot hybridization techniques using a cloned insulin gene probe. Two main DNA insertion classes were detected corresponding to the class 1 and class 3 alleles and thus the following genotypes were found: 1/1, 1/3 and 3/3. The acromegalics were subdivided depending on whether they had a normal (n = 30) or abnormal (n = 21) response to a 50 gm oral glucose tolerance test before treatment. The phenotype frequencies in the former group were 1/1, 43%; 1/3, 53%; and 3/3, 4%; and in the latter group the corresponding figures were 76%, 24% and 0%. The relative incidence of concordance of the phenotype 1/1 with abnormal glucose tolerance in acromegaly was 4.2. This phenotype is also associated with insulin dependent (Type 1) diabetes mellitus.

Evidence for the participation of endogenous opioids in the sympathoadrenal response to hypoglycaemia in man.

The effects of the long acting met-enkephalin analogue D-Ala2-MePhe4-met-enkephalin-O-ol (DAMME) and the opiate antagonist naloxone on the plasma catecholamine responses to insulin-induced hypoglycaemia have been investigated in two separate studies. DAMME depressed basal noradrenaline and adrenaline at 15 min, and blunted both the noradrenaline and adrenaline responses to hypoglycaemia. Naloxone did not alter basal plasma catecholamines, but caused a significant enhancement of the adrenaline response to hypoglycaemia. Neither DAMME nor naloxone altered the blood glucose response to insulin-induced hypoglycaemia. These data are consistent with an inhibitory modulation of endogenous opioids in the sympathoadrenal response to insulin-induced hypoglycaemia in man.

Responses to analogues of growth hormone-releasing hormone in normal subjects, and in growth-hormone deficient children and young adults.

Three analogues of growth hormone-releasing hormone (GHRH) have been compared in normal subjects. GHRH(1-29)NH2 is equipotent to GHRH(1-40); increasing doses from 10-200 micrograms per subject augments the duration of stimulated growth hormone (GH) release, but the peak serum GH shows only a poor correlation with dose. The derivative D-Ala2-GHRH(1-29)NH2 is no more potent than the unsubstituted GHRH(1-29)NH2. In 20 children and young adults with growth hormone deficiency by conventional criteria, eight showed normal or only slightly subnormal peak serum GH responses to GHRH(1-40) or GHRH(1-29)NH2. These included two patients with tumours of the hypothalamus, as well as six with idiopathic isolated growth hormone deficiency or panhypopituitarism. A poor response to GHRH was generally seen in patients on long-term GH therapy. Priming with GHRH, in either a single bolus or a continuous infusion, did not increase the GH response to GHRH. It is concluded that GHRH(1-29)NH2 is a useful analogue in the testing of GH reserve in patients with growth hormone deficiency, and has considerable potential for long-term therapy.

Measurement of immunoreactive gamma-MSH in human plasma.

A radioimmunoassay for immunoreactive gamma-MSH (IR-gamma-MSH) in human plasma has been developed. The assay is capable of detecting normal basal circulating levels which range from less than 20-100 ng/1 at 0900 h. Plasma levels are raised concomitantly with ACTH during insulin induced hypoglycaemia and CRF stimulation and suppressed with dexamethasone. Chromatographic characterisation of IR-gamma-MSH in plasma demonstrates a major peak of IR-gamma-MSH, corresponding to purified glycosylated N-terminal pro-opiomelanocortin 1-76, when IR-gamma-MSH is secreted from the pituitary. In contrast IR-gamma-MSH produced ectopically appears to be heterogeneous.

Circulating growth hormone releasing factor concentrations in normal subjects and patients with acromegaly.

A highly specific and sensitive radioimmunoassay was developed for measuring circulating growth hormone releasing factor (GRF) in human plasma. Before measuring immunoreactive GRF plasma samples were extracted on to Vycor glass. Immunoreactive GRF concentrations in plasma samples from 37 fasting normal subjects ranged from less than 10 to 60 ng/l (mean 21 ng/l). Fasting concentrations in 76 out of 80 acromegalic subjects were within the normal range, but the remaining four patients had values of 92 to 25 000 ng/l. Of these, only the patient with the highest concentration had evidence of ectopic GRF secretion from a disseminated carcinoid tumour. Two of the others had longstanding pituitary tumours, and the fourth patient had a pituitary growth hormone (GH) secreting tumour proved by its removal and subsequent remission of acromegaly. There was no correlation between serum GH and plasma immunoreactive GRF concentrations, irrespective of whether the patients were untreated or had been given radiotherapy or dopamine agonists. The assay should help elucidate the physiological role(s) of GRF and may also prove useful in differentiating between pituitary and hypothalamic defects in patients with acromegaly.

Corticotrophin releasing factor: effects on circulating gut and pancreatic peptides in man.

As a CRF-like peptide has been isolated from human gut, we investigated the effect of synthetic CRF-41 100 micrograms on gut and pancreatic peptides in six normal subjects. There was a significant rise in pancreatic polypeptide compared to a control infusion, but no change in plasma insulin, pancreatic glucagon, gastrin, somatostatin, motilin, neurotensin, gastric inhibitory peptide, or cholecystokinin was seen. In addition, there was no change in circulating met-enkephalin. We conclude that the rise in pancreatic polypeptide seen after CRF administration may suggest a role for a CRF-like peptide in the control of pancreatic function.

Growth hormone releasing factor: comparison of two analogues and demonstration of hypothalamic defect in growth hormone release after radiotherapy.

Human pancreatic growth hormone releasing factor (hpGHRF(1-40] stimulates the release of growth hormone in normal subjects and some patients with growth hormone deficiency. A study comparing the shorter chain amidated analogue hpGHRF(1-29) with an equivalent dose of hpGHRF(1-40) in seven normal subjects showed no significant difference in growth hormone response between the two preparations. Six patients with prolactinomas were also tested; these patients had received megavoltage radiotherapy previously but had developed growth hormone deficiency as shown by insulin induced hypoglycaemia. In all six patients 200 micrograms hpGHRF(1-40) or hpGHRF(1-29)NH2 produced an increase in the serum growth hormone concentration. These data suggest that hpGHRF(1-29)NH2 may be useful for testing the readily releasable pool of growth hormone in the pituitary and that cases of hypothalamo-pituitary irradiation resulting in growth hormone deficiency may be due to failure of synthesis or delivery of endogenous GHRF from the hypothalamus to pituitary cells.

CRF-41 stimulates the release of beta-lipotrophin and beta-endorphin in normal human subjects.

A prompt rise in circulating immunoreactive N- and C-terminal lipotrophin (LPH) accompanied the increase in ACTH when 100 micrograms CRF-41 was given to 6 normal male subjects. Chromatography of the basal and peak 15-min values showed that there was an equimolar increase in beta-LPH and beta-endorphin, to cause parallel release of ACTH, beta-endorphin and beta-LPH from the pro-opiocortin precursor.

Corticotrophin releasing factor: responses in normal subjects and patients with disorders of the hypothalamus and pituitary.

Synthetic CRF-41 has been given to 43 patients with hypothalamic, pituitary or adrenal diseases and contrasted with the responses in 20 normal subjects. In the normal subjects the mean increment in serum cortisol (+/- SE) was 276 +/- 38 nmol/l; the increments showed a significant negative correlation with the basal serum cortisol levels (r = -0.56; P less than 0.02). The mean peak serum cortisol was 662 +/- 34 nmol/l and the mean peak corticosterone was 28.6 +/- 3.8 nmol/l. There was a significant positive correlation between the peak serum corticosterone and cortisol concentrations (r = 0.84; P less than 0.0001). Dexamethasone pretreatment abolished the rise in cortisol in response to CRF-41. The peak serum cortisol following CRF-41 was not significantly different between the normal subjects and those patients with pituitary disease who had normal cortisol responses to insulin-induced hypoglycaemia. However, in individual patients the peak cortisol levels induced by hypoglycaemia were greater than, but significantly correlated with, those induced by 100 micrograms of CRF-41. Seven patients were ACTH deficient in response to hypoglycaemia, and of these six responded normally to CRF-41. Only one of these patients had a lesion clearly originating in the hypothalamus; four had pituitary tumours with suprasellar extensions and the remaining patient had idiopathic GH and ACTH deficiency. Our data suggest that these patients have a functional defect of ACTH secretion due to the failure of CRF to reach the corticotroph. Of the four patients with pituitary-dependent Cushing's disease who were on no treatment at the time of testing, three showed an exaggerated and one a normal response to CRF-41. These normal or enhanced responses of hypercortisolaemic patients with Cushing's syndrome contrast with the complete inhibition of the responses to CRF-41 in normal subjects given dexamethasone. In the treated patients with Cushing's syndrome and normal serum cortisol levels, those with pituitary-dependent disease showed an enhanced ACTH response to CRF-41 as compared with the ectopic ACTH group, but there was some overlap between the two groups. Acromegalic patients did not show a GH response to CRF-41. We conclude that administration of CRF-41 is a safe new method for investigating disorders of the hypothalamo-pituitary axis.

Growth-hormone-releasing factor in growth hormone deficiency: demonstration of a hypothalamic defect in growth hormone release.

Four patients with hypothalamic tumours or idiopathic growth hormone (GH) deficiency, who were GH deficient by conventional criteria, responded to 200 micrograms synthetic hpGRF-40 with a clear rise in circulating GH.