Vascular endothelial growth factor in patients with psoriatic arthritis.

OBJECTIVE: To determine the levels of vascular endothelial growth factor (VEGF) in patients with active psoriatic arthritis, patients with inactive psoriatic arthritis, and healthy controls. Serum VEGF levels were correlated with clinical and laboratory features in patients with active psoriasis arthritis. METHODS: Serum samples from 14 patients with active psoriatic arthritis, 14 patients with inactive psoriatic arthritis, and 9 healthy controls were investigated. VEGF levels in the serum were measured using a sensitive sandwich ELISA. RESULTS: The mean serum VEGF concentration in patients with active PA was 394.4 pg/ml (394 +/- 171.8), in patients with inactive PA 200.4 pg/ml (200.4 +/- 115.7), and in healthy subjects 214.3 pg/ml (214.3 +/- 162.1). Patients with active psoriasis arthritis had significantly higher levels of VEGF compared to patients with inactive psoriasis arthritis and healthy individuals (p > 0.001). In contrast, VEGF levels were comparable in patients with inactive psoriatic arthritis and controls (p =0.659). Furthermore, in patients with psoriatic arthritis, VEGF levels were positively correlated with ESR, HAQ, PASI and VAS. CONCLUSION: VEGF levels may be regarded as a good indicator of active psoriasis arthritis.

HFE genotyping demonstrates a significant incidence of hemochromatosis in undifferentiated arthritis.

OBJECTIVE: Hereditary hemochromatosis is a common autosomal recessive disorder of iron metabolism. Among Northern Europeans the carrier frequency is estimated to be 1 in 10, while up to 1 in 200 is affected by the disease. Arthropathy is one early clinical manifestation of this disease, but the articular features are often misdiagnosed. In this study the two frequent mutations of the HLA-linked hemochromatosis gene (HFE) were investigated in a rheumatology clinic population. METHODS: Two hundred and six consecutive patients (mean age 57.7 years; 38 male/168 female) attending a rheumatology clinic over a period of 14 months were screened for HFE mutations (C282Y and H63D). All standard diagnostic procedures were used to identify the aetiology of the arthropathy. Mutations were evaluated by separation on PAGE of digested PCR amplificates of DNA (by SnapI and Bcl-I, for C282Y and H63D, respectively) obtained from PBMCs. RESULTS: The C282Y and H63D allele frequencies were 4.5 and 12.8 in patients with rheumatic diseases. Five patients were homozygote for H63D (2.4%), and one for C282Y (0.5%). Five patients were compound heterozygous (2.4%). The observed C282Y allele frequency in rheumatic patients with undifferentiated arthritis was 12.9 and exceeded that of healthy subjects (p = 0.01). CONCLUSIONS: Determination of the HFE genotype is clinically useful in patients with arthritis of unknown origin, to allow early diagnosis of hemochromatosis.

Inhibition of complement activation in aged individuals due to increased plasma fibronectin concentration.

The influence of fibronectin levels on complement activation by immune complexes and non-immune activators in elderly humans was investigated. The present study demonstrates for the first time a shift in complement activation from the classical to the alternative pathway, if the fibronectin concentration rises above a certain level (near 1 mg/ml). Plasma of elderly individuals often contains large amounts of fibronectin, the reason for which is unknown. While C1 consumption is inhibited under these conditions, C3 depletion remains largely unaffected. This could be due to a compensatory triggering of the alternative reaction sequence caused by fibronectin deposition at and blockade of C1-activating sites. Probable physiologic implications of this changed complement activation pattern are discussed.

Effects of pirazolac on arachidonic acid metabolism in the human synovial system.

Six patients suffering from rheumatoid arthritis with massive knee joint effusions were treated with single daily doses of 600 mg pirazolac, a novel non-steroidal anti-inflammatory drug, for 3 days. Before the first dose, 3 hours after the second and the third dose, specimens of plasma and synovial fluid were drawn simultaneously. Plasma and synovial fluid concentrations of pirazolac, as determined by HPLC, amounted to 47.9 micrograms/ml and 19.8 micrograms/ml (Day 2) and 55.5 micrograms/ml and 18.7 micrograms/ml (Day 3), respectively. The samples were analyzed for PGE2, LTB4, LTC4 and LTD4 applying various extraction procedures and subsequent radioimmunoassays. PGE2 levels decreased during treatment from 928 pg/ml to 443 pg/ml after the third dose of pirazolac. LTB4 levels were slightly but insignificantly augmented. LTC4 and LTD4 concentrations were below the detection limit prior to and after administration of the drug.

Decisive diagnosis of seronegative polyarthritis by 3-phase bone scintigraphy.

Inflammatory joint disease is mainly diagnosed on grounds of clinical investigation, laboratory testing (acute phase reactants), and radiography. Radionuclide imaging has recently been added to the armamentarium of clinician. This case report points out the role of three-phase bone scan and HIG (human immunoglobulin) scan in the discovery of the inflammatory nature of polyarthralgia in a young woman with equivocal clinical and laboratory results. In the aim of diagnosing arthritis early in its course scintigraphy proved to be superior to conventional radiography. It also allows more discriminating selection of subsequent X-ray examination to limit radiation exposure.

Pharmacokinetic studies on diponium bromide.

The body elimination kinetics and the metabolic pathway of intravenously administered diponium bromide ((2-[alpha,alpha-dicyclopentylacetoxy)- ethyl] triethylammonium bromide) were studied. The rapid alpha- distribution phase had a t 1/2 of 4 to 11 minutes. The elimination rate varied between 2.3 and 7.7 hours. The distribution volume was 29.64 +/- 15.03 l, the total body clearance was 72.99 +/- 28.52 ml/min, and the renal clearance showed a mean value of 45.03 +/- 12.51 ml/minute. Thin layer chromatography of extracts derived from urine and faeces showed unchanged DB and a metabolite in urine; in the faeces of some volunteers three metabolites were detected, which were characterized by their Rf-values. DB does not bind to erythrocytes but to plasma proteins.

Methotrexate serum-level determinations during low-dose therapy of rheumatoid and psoriatic arthritis.

In 29 patients, 21 suffering from psoriatic arthritis and eight patients suffering from rheumatoid arthritis, methotrexate serum-levels were determined by means of radioimmunoassay. The aim of the investigation was to recognize an eventual dependence of the serum level of methotrexate on the total cumulative dose and to test the possibility of a concomitant therapy control. Beside the determinations of the serum levels of methotrexate, clinical examinations and laboratory tests were done at regular intervals. The values obtained showed no significant increase during the course of therapy compared to the values at the beginning of the treatment. Likewise no correlation to the total cumulative dose, the clinical picture or to the occurrence of side-effects could be found. Nor could any relationship between the changing of laboratory parameters and the methotrexate serum-levels be observed. No differences appeared in the methotrexate serum-levels during therapy of either rheumatoid or psoriatic arthritis patients. In conclusion it seems impossible to monitor a low-dose methotrexate therapy by continuous determinations of the serum levels of the drug.

Autoimmunity and T-cell subpopulations in old age.

To investigate the interrelationship between T-cell-dependent immune functions and autoimmune phenomena in old age we determined T-cell subpopulations in 20 aged healthy individuals (80-96 years old) using monoclonal antibodies. These persons were also investigated as to humoral parameters such as antinuclear antibodies, rheumatoid factors (IgG-, IgA-, IgM-RF), antibodies to collagen types I-IV as well as autoantibodies to organ-specific antigens. In addition, immune complexes were determined. We found that aged individuals have an increased frequency of autoantibodies as compared to a young control population, each aged subject presenting with at least one autoantibody species. Immune complexes, however, were only rarely detected. Three individuals showed a slightly increased T-helper/T-suppressor cell ratio, four had a decreased ratio. An increased number of T-suppressor cells was significantly correlated with a lowered incidence of anticollagen antibodies. Other parameters tested by us: fibronectin, laminin, procollagen type III, C3 and C4 complement components, immunoglobulins and acid alpha 1-glycoprotein. Aged individuals have significantly higher serum levels of fibronectin, while laminin and procollagen concentrations are in the normal range. A large percentage of old individuals had increased serum levels of C3 and/or C4. The acute phase protein orosomucoid, however, was in the normal range.

[Oligoarthritic joint symptoms of the hands in metastasizing bronchial carcinoma]. / Oligarthrikuläre Gelenkssymptomatik der Hände bei metastasierendem Bronchuskarzinom.

Bronchial carcinomata very frequently metastasize to bony tissue. The most common sites are generally known, but metastases can also occur in atypical locations where they then simulate other clinical syndromes. The present paper describes the clinical picture of a patient with small-cell bronchial carcinoma metastasizing to the finger joints. The frequency of this manifestation is investigated on the basis of the literature.

[Therapeutic efficacy of slow-release allopurinol in gout and hyperuricaemia (author's transl)]. / Zur Frage der therapeutischen Wirksamkeit von Allopurinol in retardform bei Gicht und Hyperurikämie.

The efficacy of a retard preparation of allopurinol is verified by biochemical, pharmacological and clinical investigations. The action of a 300 mg allopurinol tablet, with normal release and absorption parameters, is based on the specific activity of oxypurinol, a metabolite which is formed from allopurinol according to a biotransformation process. The inhibitory action of oxypurinol on xanthine oxidase amounts to only 1/5th of that of allopurinol. On the other hand allopurinol shows an extremely short half life, so that a slow-release preparation of allopurinol seems the better way of administration to get adequate uricostatic efficacy by a single dose over a 24-hour period.

[Use of the proteinase inhibitor alpha 2-macroglobulin in synovial fluids of arthritis of different origins and its relation to serologic parameters]. / Die Utilisation des Proteinaseinhibitors alpha 2-Makroglobulin in Synovialflüssigkeiten von Arthritiden verschiedener Genese und dessen Beziehung zu serologischen Parametern.

Collagen and proteoglycan are major constituents of the articular cartilage. In rheumatic disorders joint damage is attributed to the excessive action of proteoglycan degrading proteinases (P) and specific collagenases, which are released by connective tissue- and inflammatory cells in the synovial compartment. Collagenase is secreted in a latent form, which requires activation by a variety of serine-proteinases. Thus, several different proteinases are involved in pathogenesis of joint disease. alpha 2-macroglobulin was shown to be the major inhibitor of proteinases in complex biological fluids. To assess the utilization of alpha 2M by proteinases in synovial fluids (SF) from different arthritides we have employed a newly introduced solid phase immuno-sorbent assay, which allows concentration of alpha 2M and its proteinase-complexes from biological fluids. Most pronounced utilization of alpha 2M (up to 50% of total SF alpha 2M) was found in marked joint inflammation as judged from RF, immunocomplexes, C3 complement activation and acute phase reactants. Supported by animal experiments, which revealed that alpha 2M.P complexes but not native alpha 2M induce synovitis in rabbits after repeated intra-articular administration, it is suggested that pathophysiological rise of alpha 2M.P may impair cellular functions in inflammatory connective tissue, e.g. synovial tissue.

[Cellular and humoral immune phenomena in psoriatic arthritis]. / Untersuchungen über zelluläre und humorale Immunphänomene bei der Arthritis psoriatica.

The function of cellular immunity factors (lymphocyte transformation and phagocytosis by polymorphonuclear leucocytes [PMN] and monocytes in connection with the concentration of intracellular ATP) and humoral immunity factors (serum concentration of immunoglobulin and complement factors C'3 and C'4) was investigated in 16 controls, 21 patients with psoriatic arthritis and 19 with psoriasis vulgaris. The results were compared with the clinical and anamnestic data of the patients. PMN phagocytosis of zymosan opsonized with rabbit standard serum was decreased in psoriasis vulgaris in comparison with the controls. Also, monocyte phagocytosis of non-opsonized zymosan was decreased in psoriatic arthritis, as compared with psoriasis vulgaris. Furthermore, in PMNs intracellular ATP was elevated in psoriatic arthritis as compared with the controls, but decreased in comparison with patients with psoriasis vulgaris. The intracellular ATP in monocytes was decreased in psoriasis vulgaris as compared with the controls. Humoral immunological findings: serum IgG concentration was higher in psoriatic arthritis than in controls and in psoriasis vulgaris. Elevated C'3 and decreased C'4 serum concentrations in psoriatic arthritis indicate an activation of the complement system.

The influence of synovial fluids from patients with rheumatic diseases on chick embryo fibroblasts.

Primary chick-embryo fibroblasts (PCEF) were used as target cells to measure the influence of synovial fluids of patients suffering from osteoarthritis (OA; n = 5), rheumatoid arthritis (RA; n = 12) and psoriatic arthritis (PA; n = 2). The following metabolic cell products were measured: DNA, RNA, glycosaminoglycans (GAG), sulfated glycosaminoglycans, protein and collagen, with the same joint effusions being used in each test. Since it is not a single substance that provokes a stimulating or inhibiting effect in the joint, the crude synovial fluids were applied in these preliminary experiments. It was found that each type of synovial fluid showed an influence on the biological processes in the PCEF. The DNA, RNA and GAG syntheses were strongly influenced by the joint effusions, in contrast to the protein, collagen and sulfated glycosaminoglycan syntheses which were less affected. Generally, the nucleic acid synthesis differed significantly between the OA, RA and PA synovial fluids. The addition of heparin to the synovial fluids caused an additive inhibiting effect on the DNA synthesis but did not influence the other biochemical parameters. The synovial fluids of RA patients, and to a much greater extent those of PA patients, inhibited the thymidine incorporation whereas OA synovial fluids had a less pronounced effect. This result indicates a disease-dependent composition of the synovial fluids. RNA synthesis was diminished in all three groups, but again this effect was strongest in the case of the PA synovial fluids. GAG synthesis was markedly stimulated by the PA synovial fluids and somewhat, though to a lesser extent, by the OA and RA synovial fluids. The sulfated glycosaminoglycan synthesis in the PCEF, as revealed by 35S incorporation into the GAG, was less influenced and on the whole stimulated by the OA and RA synovial fluids. The same trend could be observed with regard to the collagen synthesis. The intracellular protein synthesis was less influenced by the OA (91.9%) and more strongly suppressed by the RA (78.7%) and the PA (76.7%) synovial fluids. PCEF therefore appear to be a convenient and sensitive target cell system to study alterations of biochemical processes caused by crude synovial fluids and also of different origin by individual factors isolated from synovial fluids.