Different effects of thyroid disease on serum levels of procollagen III N-peptide and hyaluronic acid.

Serum levels of procollagen III N-peptide (PIIINP) and hyaluronic acid (HA) reflect secretion of procollagen III and HA from fibroblasts, a cell type sensitive to thyroid hormones. Serum PIIINP and HA concentrations were measured in different thyroid function states, the former by two different assays, one detecting intact and aggregated PIIINP (PIIINP assay) and another detecting low mol wt degradation products of PIIINP as well (Fab-PIIINP assay). Two thirds of 28 hyperthyroid patients had elevated serum PIIINP values (mean, 192% in the PIIINP assay and 243% in the Fab-PIIINP assay) compared to age- and sex-matched controls (P less than 0.001). Normalization was seen after medical treatment (n = 16). In contrast, serum HA levels increased from 49 +/- 30 to 68 +/- 37 ng/mL (P less than 0.01) when a euthyroid state was achieved. Hypothyroid patients (n = 23) had increased serum HA levels (mean, 162%; P less than 0.05), which normalized after L-T4 treatment (71 +/- 50 before and 41 +/- 20 ng/mL after treatment (n = 16; P less than 0.02). L-T4 treatment also increased serum PIIINP levels significantly. Subjects with familial dysalbuminemic hyperthyroxinemia (n = 8), representing a situation with elevated circulating levels of T4 due to enhanced protein binding, and patients with nontoxic goiter with serum TSH levels ranging from 3.6-0.05 mU/L had normal serum levels of PIIINP and HA. Our data suggest that the secretion of procollagen III and that of HA from fibroblasts are influenced differently by thyroid hormones, since the secretion of procollagen III seems enhanced by thyroid hormones, whereas the secretion of HA seems reduced. Neither euthyroidism with enhanced serum T4 levels (familial dysalbuminemic hyperthyroxinemia) nor euthyroidism with reduced serum TSH levels (nontoxic goiter) seems associated with alterations at the connective tissue level.

Serum concentrations of type I and III procollagen propeptides in healthy children and girls with central precocious puberty during treatment with gonadotropin-releasing hormone analog and cyproterone acetate.

Serum levels of type I and III procollagen propeptides (s-PICP and s-PIIINP) were measured in 466 healthy school children and in 23 girls with central precocious puberty (CPP) during GnRH analog and cyproterone acetate therapy, using two commercially available RIAs. In normal children, s-PICP and s-PIIINP changed significantly with age and pubertal development stages. For s-PIIINP, a peak was seen at 12 yr for girls and 13 yr for boys; no peak could be discerned for s-PICP. The prepubertal (Tanner stage 1) s-PICP value (mean +/- SD) for girls was 374 +/- 132 micrograms/L, the midpubertal value (stage 3) was 442 +/- 135 micrograms/L, and the postpubertal value (stage 5) was 203 +/- 103 micrograms/L. The mean s-PIIINP levels for girls were 9.1 +/- 2.4, 15.0 +/- 4.3, and 6.8 +/- 3.1 micrograms/L, respectively. For boys, levels were 362 +/- 119, 544 +/- 138, and 359 +/- 256 micrograms/L for s-PICP and 8.5 +/- 2.2, 14.5 +/- 5.0, and 8.6 +/- 3.8 micrograms/L for s-PIIINP (P < 0.001 for both propeptides in both boys and girls). There was, however, a large variation in normal values for both propeptides within the age groups and pubertal stages. There was a significant correlation of s-PICP and s-PIIINP levels to height velocity in girls (r = 0.35; P < 0.001 and r = 0.33; P < 0.001, respectively), while in boys, only s-PIIINP showed significant correlation to height velocity (r = 0.40; P < 0.001). In untreated girls with CPP, serum levels of s-PIIINP were elevated [PIIINP SD score (SDS), 2.13]. Levels of s-PICP were normal (PICP SDS, 0.39). Levels of both propeptides decreased within 2 months after initiation of therapy and remained below initial values (P < 0.01). The decrease in s-PIIINP after 2 months of therapy showed a significant correlation with the fall in height velocity SDS for chronological age after 6 months of therapy (r = 0.64; P < 0.01). We conclude that s-PIIINP and, to a lesser degree, s-PICP reflect growth in normal children, but due to the large variation, both propeptides seem unsuitable as markers for screening of growth disorders in children.

Seasonal variations in the susceptibility of the aortic wall to atherosclerosis. Biochemical studies of glycosaminoglycans and collagen of rabbit atherosclerosis.

The aortic content of glycosaminoglycans and collagen as well as the uptake of [125 I] albumin were studied in 53 male albino rabbits during hair-shedding and outside the period of hair-shedding to elucidate the previously reported resistance to experimental arteriosclerosis during the shedding period [1]. The concentration of hyaluronic acid was highest during hair shedding, decreasing towards the non-shedding period. The content of dermatan sulphate, chondroitin-4, 6-sulphate and hydroxyproline was lowest during sheeding and highest outside the sheeding period. Accordingly, the incorportation of [35 S] sulphate in chondroitin -4, 6-sulphate and the dermatan plus heparan sulphate fraction was increased outside shedding, consistent with a stimulated synthesis. The concentration of hyaluronic acid was negatively correlated to the uptake of [125I] albumin, and the dermatan sulphate content was positively correlated to the content of hydroxyproline. The higher concentration of hyaluronic acid during the period of shedding may improve the elastic properties as well as the ability of the aortic wall to absorbe the haemodynamic strain involved in the vascular injury of this type of experimental arteriosclerosis [2]. The decrease in the concentration of hyaluronic acid simultaneously with an increase in the aortic content of collagen as well as of chondroitin-4, 6-sulphate and dermatan sulphate may imply a greater stiffness of the aorta resulting in a higher susceptibility to injury. The relationship between hyaluronic acid and [125 I] albumin is consistent with an importance of hyaluronic acid to the susceptibility of the arterial wall to deposition of macromolecules such as the lipids. Our observations represent an example of endogenous conditioned variations in the aortic content of glycosaminoglycans and hydroxyproline accompanied by a variation in the susceptibility to experimental arteriosclerosis.

Seasonal variations in the biophysical properties of rabbit aorta and its susceptibility to arteriosclerosis.

The physiological variations in the mechanical properties of rabbit aortae in relation to the periods of hair shedding were studied. The load-strain curves of the eight proximal thoracic segment in 15 shedding and 15 non-shedding male albino rabbits were analysed. The slope of the curves (tangent of the angle between the linear region of the load-strain curve and the strain axis) was decreased in the shedding animals compared to that of the non-shedding animals and the toe of the load-strain curves was significantly lower towards the x-axis in the shedding animals. The observations indicate a lower stiffness, that is increased elasticity, of the aortae of rabbits during hair shedding. The increased elasticity during hair shedding may explain the previously reported resistance to experimental arteriosclerosis caused by the hemodynamic strain elicited by exposure to systemic hypoxia. A decrease in the aortic content of collagen and of sulfated glycosaminoglycans, and an increase in the content of hyaluronic acid, may be of importance in the alterations of the mechanical properties of rabbit aorta during hair shedding.

Effects of intermittent and continuous hypoxia on the aortic wall in rabbits.

Male albino rabbits were exposed to intermittent nitrogen breathing every 30 sec for 5 sec, 15 min daily over a period of 3 weeks, and every 30 sec for 5 sec over a period of 10 hr. A third group of animals was exposed continuously to 8% oxygen breathing for 2 weeks. Neither intermittent not continuous hypoxia induced gross or microscopic alteration in the aorta. The effects of hypoxia upg which hypoxia was distributed than upon the total period or the degree of hypoxia. Exposure to hypoxia over a short period stimulated the synthesis of glycosaminoglycans, whereas distribution of the hypoxia over a longer period resulted in a reduction in the amount of glycosaminoglycans, probably secondary to an inhibition of the synthesis. Similarly, continuous exposure to 8% oxygen for a longer period decreased the aortic content of collagen. The alterations in the glycosaminoglycans and collagen induced by hypoxia may cause changes in the passage of macromolecules through the aortic wall. The changes may also influence the mechanical properties of the aorta and lead to impaired healing of vascular injury.

D-penicillamine-induced angiopathy in rats. Changes in aortic collagen, glycosaminoglycans, DNA and RNA in rats treated with D-penicillamine.

Male Sprague-Dawley rats were treated with D-penicillamine (D-pen) in doses of 100, 250 or 500 mg/kg per day for 10, 32, 42 or 70 days. In addition animals were examined 28 days after withdrawal from 42 day's treatment with D-pen at 100 or 500 mg/kg per day. Pair-fed rats served as controls. The changes in aortic collagen, glycosaminoglycans (GAGs), DNA and RNA were studied. D-Pen had a dose- and time-related solubilizing effect on aortic collagen, which regained normal resistance to extraction within 28 days after cessation of the treatment. In contrast, D-pen caused a progressive accumulation of hydroxyproline (Hyp) in the aortic wall during and after treatment, probably mediated by an increased number of matrix synthesizing cells, as judged by augmentation of the DNA content in the presence of unaltered Hyp/DNA and RNA/DNA ratios. The relative amount of type III collagen was increased after 500 mg/kg per day D-pen for 10 and 42 days. High doses of D-pen increased the percentage of water in the aortic wall and reduced the ratio of Hyp to total tissue protein, suggesting an increased content of water-binding substances. This was confirmed by GAG accumulation. Hyaluronic acid (HA) and chondroitin 4,6-sulphate (CHS) were predominant after 32 and 42 days, whereas CHS, heparan sulphate (HS) and dermatan sulphate (DS) prevailed after 70 days of treatment. These observations suggest that processes of repair and regeneration are elicited secondary to the inhibitory effect of D-pen on aortic collagen and elastin crosslinking. Hypertrophy of the vessel wall may imply an increased rigidity, resulting in further increase of the susceptibility to haemodynamic injury.

Increased collagen prolyl hydroxylase activity in the aortic wall of rabbits exposed to chronic hypoxia.

The activity of collagen prolyl hydroxylase in aortic wall was studied in rabbits exposed to chronic 10% ambient oxygen tension for 30 days. Prolyl hydroxylase in rabbit aorta was shown to be similar to the enzyme from other sources in that it required molecular oxygen, alpha-ketoglutarate, ferrous iron and ascorbate for its activity. The activity of prolyl hydroxylase was increased to 180% of controls in the intima-media samples from rabbits exposed to hypoxia. No atherosclerotic lesions could be seen in arteries of animals kept in chronic hypoxia. If the arteries of rabbits were injured with a single mechanical dilatation, the activity of prolyl hydroxylase increased more than 2-fold, as reported previously. The exposure of these animals to chronic hypoxia further elevated the prolyl hydroxylase activity.

Effect of D-penicillamine on the mechanical properties of aorta, muscle tendon and skin in rats.

The biomechanical properties of rat aorta, muscle tendon and skin were studied after daily D-penicillamine treatment (500 mg/kg) for 5, 10 and 42 days. D-Penicillamine treatment for 5 days resulted in increased aortic extensibility. After long-term treatment the aorta exhibited a shift towards decreased extensibility and increased stiffness at small 'stress' values. Simultaneously the dry weight and diameter of the aortic samples were increased after D-penicillamine treatment for 42 days. After correction of the mechanical parameters for the increased amount of tissue of the samples, the stiffness at small 'stress' values was still increased and the mechanical stability at high 'stress' values retained. This is in contrast to the marked reduction in the strength of muscle tendon and skin of the same animals after D-penicillamine treatment for 42 days. This study demonstrates that a primary increase in the extensibility of aorta may elicit a reactive formation of vascular connective tissue. It is proposed that aortic smooth muscle cells are activated by an increased pulsatile distension of the vessel wall secondary to the early effect of D-penicillamine on collagen and elastin. The resulting excess deposition of collagen and elastin leads to increased stiffness, which may in turn increase the susceptibility of the aortic wall to hemodynamic injury. Consequently D-penicillamine may not as proposed counteract the development of atherosclerosis.

Reversibility of D-penicillamine induced collagen alterations in rat skin and granulation tissue.

Granulation tissue was produced in rats by subcutaneous implantation of Visella sponges. D-penicillamine (D-pen) 100 or 500 mg/kg was administered daily for 42 days by gastric tubing. Pairfed, placebo treated animals were included as controls. Half of the groups were kept for additionally 28 days without medication. The inhibitory effect of D-pen on cross-link formation in newly synthesized collagen was readily reversible. By contrast, cross-link deficiency lasting beyond the observation period was observed in the higher polymeric collagen variants released by dilute acid, heat exposure or limited pepsin proteolysis as estimated by solubility, alpha/beta chain ratio and/or aldehyde content. By SDS-polyacrylamide gel electrophoresis on gels containing 3.6 M urea it was shown that purified dermal acid soluble collagen from treated animals consisted of a mixture of type I and III collagen, whereas only type I collagen was detected in controls. The band pattern was identical in reduced and unreduced collagen samples. Four weeks after D-pen discontinuance type III collagen had disappeared from the acid extract. Moreover, the ratio of type III to type I collagen in the pepsin digest from both granulation tissue and skin showed a persistent rise with D-pen. These observations indicate that D-pen destabilized type III collagen in particular by interference with its disulfide linkages. The amount of granulation tissue remained unaffected throughout the experiment, whereas the skin collagen content decreased at the higher dose level. The regeneration was not completed by the end of the observation period. Modulation of the molecular stability of granuloma collagens may be of relevance for the antirheumatoid effect of D-pen, but the sustained effect on normal tissues may imply a long standing impairment of their supportive capacity.

Collagen distribution in developing experimentally induced granulation tissue. A morphometric study.

Viscose cellulose sponges were implanted subcutaneously on the back of full-grown Sprague-Dawley rats. Seven, 14, 21, 28, 42, 60 and 90 days after implantation, groups of 12 animals decapitated and the sponges were removed and processed for light microscopy. Five microns sections were stained with Picro-Sirius Red. Morphometry was performed on the zone of ingrowth and the collagen. The intersectional variation in the morphometrically determined collagen density within the sponges was below 20%. The hydroxyproline content was determined biochemically in 5 microns sections of sponges implanted for 14, 42, 60 and 90 days. A positive correlation (rho = 0.79, p less than 0.0001) was observed between the biochemically and morphometrically determined collagen contents. The morphometric determinations showed a steady increase in the granulation tissue ingrowth. At day 60 the ingrowth was complete. There was an increasing collagen density from days 7 and 14 through days 21 and 28, followed by a nearly steady state up to day 90 and a significantly higher collagen density peripherally than centrally in the day 42 sponges. The study has shown that morphometric collagen determination at light microscopical level using Sirius Red-stained sections may add quantitative data describing the dynamic changes in collagen content and distribution within developing granulation tissue.

Collagen metabolism during wound healing in rats. The aminoterminal propeptide of type III procollagen in serum and wound fluid in relation to formation of granulation tissue.

The aminoterminal propeptide of type III procollagen (PIIINP) in serum has been shown to correlate with fibrillogenesis, and thus to be a potential direct marker of type III collagen deposition. The aim of the study was to investigate the correlation between changes in serum PIIINP and formation of granulation tissue during pharmacological suppression. Granulation tissue was induced in rats by the implantation of viscose cellulose sponges. Pharmacological suppression was achieved by cyclophosphamide treatment. To distinguish between the isolated effect of cyclophosphamide and the influence of the weight loss caused by treatment, weight loss caused by starvation was investigated. In untreated rats, serum PIIINP and wound fluid PIIINP were related to formation of granulation tissue (serum: r = 0.58, p < 0.05; wound fluid: r = 0.56, p < 0.05). In rats treated with cyclophosphamide, collagen deposition and formation of granulation tissue were markedly reduced, as compared within the untreated rats (6% vs 33%, p = 0.01). Wound fluid PIIINP reflected the sparse collagen deposition (r = 0.48, p < 0.05), whereas serum PIIINP decreased (-35%, p < 0.01) and was not correlated with the formation of granulation tissue. In starved rats, with a weight loss of 8%, formation of granulation tissue, vascular density, and collagen deposition were not reduced. Wound fluid PIIINP reflected the formation of granulation tissue (r = 0.52, p < 0.05), whereas serum PIIINP remained unchanged despite normal formation of granulation tissue. Starvation of rats without implants caused a decrease in serum PIIINP (-33%(-)-48%, p < 0.01). We conclude that during cyclophosphamide treatment and after a moderate weight loss, serum PIIINP is not a valid marker of fibrillogenesis. However, in normal rats with free access to food, changes in serum PIIINP mirror fibrillogenesis. Furthermore, our study provides experimental evidence consistent with the hypothesis that wound fluid PIIINP directly mirrors the local formation of granulation tissue, independent of weight loss and cyclophosphamide treatment.

Serum aminoterminal type III procollagen peptide. Relation to biosynthesis of collagen type III in experimentally induced granulation tissue in rats.

Serum aminoterminal type III procollagen peptide was measured in rats during the development of granulation tissue induced by subcutaneous implantation of viscose cellulose sponges. Active collagen type III synthesis in granulation tissue during the first three weeks was accompanied by an increase in serum propeptide level. A positive correlation was observed between the increase in serum propeptide level on the one hand and the increase in granulation tissue collagen type III content and the in vitro formation of tissue 3H-hydroxyproline on the other hand. In some animals the serum propeptide level remained low, despite biochemical signs of collagen synthesis, indicating variations in the release into serum and/or the metabolism of circulating propeptide. The increase in propeptide antigen concentration was mainly due to an elevated content of material with molecular weight equal to or twice that of the propeptide. A minor fraction of the propeptide remained attached to the interstitial collagen fibres in the granulation tissue. The correlation between the serum propeptide level and the biosynthesis of collagen at the site of the focal fibroproliferative process suggests that the serum propeptide level may be a valuable indicator of fibrogenesis and thereby of disease activity in fibrotic conditions.

Serum aminoterminal type III procollagen peptide in early rheumatoid arthritis: relation to disease activity and progression of joint damage.

Serum levels of the aminoterminal type III procollagen peptide (S-PIIINP) have been used as markers of proliferative inflammation in rheumatoid arthritis (RA) and a prognostic significance has been suggested. To test this further we have measured S-PIIINP longitudinally for 2 years in 66 patients with definite RA and a disease duration of less than 2 years, and related the levels to clinical, biochemical, and radiographic findings. In this patient group the correlations between S-PIIINP and ESR and CRP, respectively, were higher than those obtained between S-PIIINP and articular indices, and markedly higher than in patients with RA of longer duration. Patients with normal mean levels of S-PIIINP during the study period had a significantly slower rate of radiographic progression than patients with elevated mean levels of S-PIIINP. ESR yielded in general higher correlations with the joint damage process than did S-PIIINP. The correlations between S-PIIINP and the joint damage scores increased with time. A multiple regression analysis showed that ESR explained most of the variance in joint damage progression over 2 years, but S-PIIINP added independent information. About one third of the variance could be explained by the two variables.

Connective tissue metabolites in serum as markers of disease activity in patients with rheumatoid arthritis.

The serum levels of aminoterminal type III procollagen peptide (S-PIIINP), immunoreactive prolyl 4-hydroxylase protein (S-IRPH), 7S domain of collagen type IV (S-Col IV, 7S), and fragment P1 of laminin (S-Lam), which are associated with the metabolism of extracellular interstitial collagens and basement membranes, were measured sequentially for two years in 14 rheumatoid arthritis (RA) patients undergoing disease modifying antirheumatic drug treatment. Elevated S-PIIINP, S-IRPH, and S-Col IV, 7S levels were demonstrated in active RA. In active disease the metabolites showed some correlation with clinical and serological signs of disease activity. A high average synovial fluid/serum concentration ratio of PIIINP and of Col IV, 7S supports the concept that the increased serum levels of PIIINP and Col IV, 7S originated from the diseased joints. After 2 years of treatment a decline was observed in S-PIIINP and S-Col IV, 7S in treatment responders. However, the median levels of S-PIIINP and S-IRPH were still above the upper limit of normal, suggesting smouldering, subclinical inflammatory processes. S-Lam remained within the normal range in active and inactive disease.

Quantification of synovistis by MRI: correlation between dynamic and static gadolinium-enhanced magnetic resonance imaging and microscopic and macroscopic signs of synovial inflammation.

Dynamic and static gadolinium-diethylenetriaminepentaacetic acid(Gd-DTPA)-enhanced magnetic resonance imaging (MRI) were evaluated as measures of joint inflammation in arthritis, by a comparison with macroscopic and microscopic signs of synovitis. Furthermore, the importance of the size of the evaluated synovial areas was investigated, as was the optimal time for enhancement measurements. Seventeen rheumatoid arthritis knees and 25 osteoarthritis knees, scheduled for arthroscopy or arthrotomy, were included. Macroscopic and microscopic synovial inflammation as well as nine histologic tissue characteristics were graded at four preselected biopsy sites. Preoperative T1-weighted dynamic fast low angle shot and static spin-echo Gd-enhanced MRI were performed. The dynamic enhancement rate and the static enhancement were measured in the entire synovial membrane of a preselected slice as well as at the four biopsy sites, and compared to synovial pathology. The rate of early enhancement of the total synovial membrane of the preselected slice, determined by dynamic MRI, was highly correlated with microscopic evidence of active inflammation (Spearman p = 0.73; p < 10(-7). Dynamic MRI could distinguish knees with and without synovial inflammation with a high predictive value (0.81-0.90). Moderate and severe inflammation could not be differentiated. The early enhancement rate was correlated with histologic features of active inflammation, particularly vessel proliferation and mononuclear leucocyte infiltration. Dynamic evaluation of small synovial sections at the biopsy sites and static spin-echo MRI resulted in considerably weaker correlations to histologic inflammation than dynamic evaluation of the total synovium. The optimal time for enhancement measurements was one-half to one minute after Gd injection, as the highest correlation coefficients to histologic inflammation were observed in this interval. Dynamic MRI can be used to determine synovial inflammation. Evaluation of large synovial areas one-half to one minute after Gd injection best reflects joint inflammation.

Acute phase proteins and clinical synovitis activity in patients with rheumatoid arthritis.

A number of laboratory variables, including Hb., ESR and several phase proteins, fluctuated in concord with the clinical signs of synovitis activity in patients with rheumatoid arthritis during a controlled study of 3 disease-modifying anti-rheumatic drugs (DMARD). The correlation between laboratory variables and clinical synovitis was significant in a large patient population but the correlation coefficients were not of such magnitude that any of the laboratory variables reflected clinical synovitis activity in a reliable manner in the individual patients. In patients treated with azathioprine, the response of the Hb, (and consequently of the ESR), was reduced compared to patients given other DMARD. This phenomenon was caused by the bone marrow suppressing effect of azathioprine. However, the effect of azathioprine on the clinical synovitis activity did not differ from that of the 2 other drugs. Similar results were found by reviewing the literature about controlled trials of DMARD. In the present trial the clinical evaluation was performed under optimal conditions. In daily clinical practice the evaluations of the joints may be less than optimal since they may be performed by different rheumatologists with varying experience. Consequently, it may be difficult to do without the unreliable laboratory variables mentioned in the routine assessments of disease activity, unless the quality of routine evaluations of synovitis activity is improved considerably.

Systemic lupus erythematosus: follow-up study of 148 patients. I: Classification, clinical and laboratory findings, course and outcome.

The present paper is a description of 148 patients with circulating antinuclear antibodies and multisystemic disease filed during 18 years by one of the authors and followed up to date in 1981-83. Seventy-eight per cent of the patients satisfied the 1971 ARA criteria for the classification of systemic lupus erythematosus and 92 per cent fulfilled the 1982 ARA criteria. Eighty-five per cent were women, the mean age at onset of SLE was 32 years. Malar rash and arthritis were early manifestations in 80 per cent of the patients whereas the onset of nephropathy, CNS manifestations, serositis, and peripheral cytopenia was delayed in about half of the patients. Nephropathy and thrombocytopenia were observed particularly in the youngest patients. The mean duration of the observation period was 8 years. The 10-year-survival was 80 per cent. Half of the deaths were presumably unrelated to SLE. The mean ages at entry of patients who died of SLE and of unrelated causes were 30 and 52 years respectively. Eighteen per cent of the deaths were caused by uremia and 18 per cent by infections. The total and the SLE related mortalities were evenly distributed throughout the observation period. The morbidity (incidence of new ARA criteria and other findings indicating active disease) decreased during the first year of observation but rarely subsided completely during the following years. All patients observed for more than 10 years showed evidence of active disease during the rest of the observation period and most showed evidence of renal disease.

Systemic lupus erythematosus. Follow-up study of 148 patients. II: Predictive factors of importance for course and outcome.

The predictive value of a number of clinical and laboratory variables for the mortality of 148 patients with systemic lupus erythematosus (SLE) with a mean observation period of 8 years and a 10-year-survival of 80 per cent was calculated by means of differentiated survival rate analyses and stepwise regression analyses. The predictive power of several variables increased if the calculations were based on deaths caused by SLE rather than on the total mortality rate. The survival rate decreased after 1973 because a diagnosis of SLE was made in some patients with terminal disease who would have remained without a diagnosis before that time. The causes of death and the treatment were identical before and after 1973. The presence of a high number of diagnostic ARA criteria within the first year of observation was a predictor of decreased survival. Severe but non-fatal infections (meningitis, septicemia, pneumonia) significantly reduced the survival rate. Patients with proteinuria and azotemia, within the first 2 years of observation, had a 10-year-survival of 70 per cent. The survival of patients with CNS manifestations was not significantly reduced. The butterfly rash and the presence of lymphopenia were predictors of decreased survival, whereas the presence of DNA antibodies had no predictive value for survival.

Serum aminoterminal type III procollagen peptide in inflammatory and degenerative rheumatic disorders.

Measurement of the aminoterminal type III procollagen peptide in serum has been suggested as a marker of the biosynthesis of collagen type III, a major connective tissue component in repair processes. In the present study the propeptide level correlated with the inflammatory synovial mass in rheumatoid arthritis and osteoarthritis. This implies that the propeptide level reflects the collagen type III synthesis occurring in the synovial repair processes, whether they were caused by inflammatory or degenerative rheumatic disorders. Physical activity did not enhance the transition of the propeptide from the synovial fluid or the inflamed synovial membrane to the blood. Normal serum propeptide values were observed in most patients with ankylosing spondylitis and degenerative diseases of the spine. This may reflect the lower amount of inflammatory tissue in these diseases and hence the sensitivity of the assays.

Influence of previous gold treatment and other patient variables on outcome of treatment with disease modifying anti-rheumatic drugs (DMARD) in patients with rheumatoid arthritis.

Based on a 2-year controlled double-blind trial of levamisole, penicillamine, and azathioprine (L, P, and A), a computer aided search for predictive factors of outcome was instituted. Already at month 4 several indicators of synovitis activity were able to discriminate between patients staying in the trial for 24 months and patients whose treatment was discontinued before that time. Patients who had previously received gold therapy responded less favourably to L, P, and A than those who had not received gold. This reduction of response was more pronounced in gold resistant patients than in patients whose gold treatment had been discontinued for other reasons. The only phase protein (of several) with a predictive value was haptoglobin. If, after 4 months of treatment, haptoglobin did not normalize, this finding indicated a lack of response to treatment or a deterioration of synovitis activity during the following 4 months. The response to treatment was not influenced by HLA-types, sex, age, or clinical synovitis, disease duration, functional or anatomical aberrations at the start of treatment. The shape of the response curve as reflected by means of monthly measurements of serum-albumin and ESR was not related to disease duration, HLA-types, or previous gold treatment.