Monocyte chemoattractant protein 1 (MCP-1) in temporal arteritis and polymyalgia rheumatica.

OBJECTIVE: To examine the localisation of monocyte chemoattractant protein 1 (MCP-1) in the inflamed vessel wall in temporal arteritis (TA) and to measure MCP-1 in plasma both in patients with TA and patients with polymyalgia rheumatica (PMR). METHODS: By immunohistochemical techniques MCP-1 was localised to the vessel wall in patients with TA. In TA, PMR, and healthy controls MCP-1 was quantified by enzyme linked immunosorbent assay (ELISA) in plasma. RESULTS: MCP-1 was localised to the majority of mononuclear cells, some smooth muscle cells, and giant cells in the arterial biopsy specimens from 12 patients with histologically verified TA. In all sections, including the vasa vasorum, the endothelium stained positive. In the intima 73% (range 57-91%), in the media 49% (range 32-67%), and in the adventitia 74% (range of 62-91%) of all cells stained positive. In plasma MCP-1 was significantly raised in untreated TA (n=33) and untreated PMR (n=27) compared with healthy controls (n=12). Untreated TA plasma levels of MCP-1 (mean 391 pg/ml (range 82-778 pg/ml)) were similar to untreated PMR plasma levels (mean 402 pg/ml (range 29-1153 pg/ml)), and no significant difference was found between the two groups of patients. In both patients with TA and patients with PMR no correlation was found between the plasma level of MCP-1 and the erythrocyte sedimentation rate, haemoglobin concentration, and CD4/CD8 ratio. CONCLUSIONS: These results show that MCP-1 plays a part in the disease processes of TA and PMR.

Human Parvovirus and giant cell arteritis: a selective arteritic impact?

Peak incidences of giant cell arteritis (GCA) following human Parvovirus epidemics were found in 2 previous epidemiological studies. The incidence of GCA [temporal arteritis and polymyalgia rheumatica (TA + PMR)] was studied before and after a major epidemic of human Parvovirus in 1994. Clinical data from the National Patient Register showed a significant inversion of the TA/PMR ratio during a 12-month period after an HPV epidemic. The inversion of this ratio was due to an increase in TA. The change in the ratio was most pronounced in the regions with the epicenter of the epidemic.

A reduced CD8+ lymphocyte subset distinguishes patients with polymyalgia rheumatica and temporal arteritis from patients with other diseases.

OBJECTIVE: To determine the diagnostic and screening test qualities of concentrations of the CD8+ lymphocyte subset in peripheral blood to discriminate patients with giant cell arteritis (GCA) from patients with other diseases. METHODS: A CD8+ lymphocyte test was performed in 454 patients from the Department of Medicine, Randers Central Hospital. The sensitivity, specificity and predictive values of the test were calculated and presented as receiver operating characteristic (ROC) curves. RESULTS: The median percentage and numbers of CD8+ cells were significantly reduced in 227 patients with active untreated GCA compared with 227 in-patients of similar age and sex (GCA vs in-patients CD8% : 12.0 vs 20.0, CD8+ x 10(9)/l : 0.195 vs 0.374, p < 0.05). Identical ROC curves were obtained when patients with GCA were tested against various subgroups of patients. The sensitivity and specificity of the test for GCA at an optimal cutoff point were 71% and 80%, respectively, while the positive predictive value was 80%. CONCLUSION: At an optimal cutoff point, concentrations of the CD8+ lymphocyte subset in peripheral blood discriminate patients with GCA from patients with other diseases. The sensitivity and specificity of the test for GCA are equal to those of other tests used in rheumatology.

[Synchronous variations in the incidence of temporal arteritis and polymyalgia rheumatica in Danish counties. Association with epidemics of Mycoplasma pneumonia infection]. / Synkrone variationer i incidens af arteritis temporalis og polymyalgia rheumatica i danske amter. Sammenhoeng med epidemier af Mycoplasma pneumoniae-infektion.

The incidences of temporal arteritis and polymyalgia rheumatica during a twelve year period were studied in different regions of Denmark. Data concerning the incidences of these diagnoses were obtained from two general hospitals from 1982 to 1994 and from the National Patient Register of all diagnoses from all hospitals in 13 of 16 Danish counties from 1982 til 1993. Data from all temporal artery biopsies in two counties were also obtained. Serological epidemiological surveillance data concerning infections causing epidemics in Denmark were obtained from Statens Serum Institut. Data concerning 10,818 patients from 13 counties and 2651 temporal artery biopsies from two counties were analysed. The incidence rate of temporal arteritis in the population aged 50 years and over was 20.4 per 100,000 (95% CI 19-23), and that of polymyalgia rheumatica 41.3 per 100,000 (95% CI 30-67). Significantly higher incidence rates were found in locations with a high population density. The incidence rate of histologically proven temporal arteritis in two counties was 15.1 per 100,000 > 50 years (95% CI 11-20). Pronounced quarterly and annual variations of the incidence were found, with a clustering in five peaks. These cyclic fluctuations were seen simultaneously in several regions. Two periods with an increased incidence of temporal arteritis and polymyalgia rheumatica occurred in close relation to epidemics of Mycoplasma pneumoniae infection. Two peak incidence rates were partly related to epidemics of Parvovirus B19 and one peak to an epidemic of Chlamydia pneumoniae. The synchronous variations in the incidences of temporal arteritis and polymyalgia rheumatica recorded in several regions of Denmark strongly indicate that an environmental infectious factor influences the frequencies. The close concurrence with the above-mentioned epidemics suggests that temporal arteritis and polymyalgia rheumatica may be triggered by certain viral and/or bacterial agents.

Reduced CD8+ T-cell concentration in peripheral blood of patients with carotid artery stenosis: relation to arteritis temporalis.

The percentage and numbers of CD8+ T cells are markedly decreased in peripheral blood from patients with arteritis temporalis. Transient cerebral ischaemic attacks (TIA) or brain infarctions have been frequently reported as the first and only clinical manifestation, and signs of carotid artery stenosis have been reported in 15-20% of patients with arteritis temporalis. We used a determination of the CD8+ T-cell subset to evaluate patients with TIA. Concentrations of CD8+ T cells were measured in the peripheral blood of 24 patients with TIA. The cohort investigated was consecutive, but adjusted to have a 50% a priori probability of carotid artery stenosis. An ultrasound Doppler investigation of the carotid arteries was performed in all patients. Controls were 24 healthy subjects of comparable age and sex. Median percentage and concentrations of CD8+ T cells were significantly lower in patients with TIA and carotid artery stenosis compared with (1) patients with TIA and no carotid stenosis (CD8+ %: 13.5 vs 26; CD8+ x 10(9)/1: 0.24 vs 0.44, P < 0.001) and (2) healthy controls (CD8+ %: 13.5 vs 22.5; CD8+ x 10(9)/1: 0.24 vs 0.52, P < 0.001). The prevalence of a carotid artery stenosis in the combined first and second quartile of CD8+ % (CD8+ %

Synchronous variations of the incidence of temporal arteritis and polymyalgia rheumatica in different regions of Denmark; association with epidemics of Mycoplasma pneumoniae infection.

OBJECTIVE: The etiology of temporal arteritis (TA) and polymyalgia rheumatica (PMR) is unknown, but the sudden onset and the wide variation in incidence reported from various parts of the world suggest the existence of environmental and/or genetic factors. We studied the incidence of TA and PMR during a 12 year period in different regions of Denmark. METHODS: For the period 1982 to 1994, data were obtained on the incidence of PMR and TA prospectively recorded in 2 general hospitals, and for 1982 to 1993 on the incidence reported by legal requirement to the national patient register by all hospitals in 13 of the 16 counties in Denmark. In 2 counties data on all temporal artery biopsies were obtained. Serological epidemiological surveillance data on infections causing epidemics in Denmark were obtained from the Statens Seruminstitut. RESULTS: We analyzed data on 10,818 patients from 13 counties and 2651 temporal artery biopsies from two counties. The incidence rate for TA for the population aged 50 years and older was 20.4/100,000 (95% CI, 19-23), the rate for PMR was 41.3/100,000 (95% CI, 30-67). Significantly higher incidence rates were found in locations with high population density. Median number of temporal artery biopsies performed was 109/100,000 population aged 50 years and older, and the number increased linearly with time; a positive biopsy result was observed in 15.0%; the incidence rate of histologically proven TA in 2 counties was 15.1/100,000 population aged 50 years and older (95% CI, 11-20). Pronounced quarterly and annual variations of the incidence of TA and PMR were found in each of the 13 counties, and in the 2 hospital regions, with a clustering in 5 peaks. These cyclic fluctuations were seen simultaneously in several regions irrespective of the origin (hospital based, register derived, or temporal artery biopsy) of the data. Distinct peak incidences of TA and PMR occurred in close association with 2 epidemics of Mycoplasma pneumoniae infection. Two peaks were seen, partly related to 2 epidemics of parvovirus B19 and to an epidemic of Chlamydia pneumoniae. CONCLUSION: The synchronous variations in the incidences of TA and PMR recorded in several regions of Denmark strongly indicate that an environmental infectious factor influences the frequencies. The close concurrence with epidemics of M. pneumoniae and the coincidence of 2 epidemics of parvovirus B19 and of one epidemic of C. pneumoniae in some locations with peak incidences of TA and PMR suggest that TA and PMR may be triggered by certain virus and/or bacterial agents.

A genetic approach to the aetiology of giant cell arteritis: depletion of the CD8+ T-lymphocyte subset in relatives of patients with polymyalgia rheumatica and arteritis temporalis.

OBJECTIVE: To investigate the CD8+ T-cell concentrations in first degree relatives of patients with giant cell arteritis (GCA) in order to evaluate whether the low CD8+ T-cell values found in most patients with GCA are acquired or hereditary. METHODS: Probands were 5 patients with arteritis temporalis (TA) and 15 with polymyalgia rheumatica (PMR). Forty of 60 available relatives participated in the study. They were all interviewed concerning signs of previous illness. A blood sample screening was performed, including IgM-RF and ANA on Hep-2 cells. Age- and sex-matched controls consisted of 29 persons with no history of inflammatory or malignant diseases. Measurements of the T-lymphocyte subsets CD3+, CD4+ and CD8+ were made after Ficoll-Hypaque separation. RESULTS: Healthy relatives disclosed a significantly decreased CD8+ percentage in their peripheral blood compared with controls. The median CD8+% in relatives was 17% (C1 95% 15-20%) and in controls it was 23% (C1 95% 20-28%). Twelve relatives had a decreased concentration of CD8+ T-cells and 10 showed an elevated CD4+/CD8+ ratio. Two relatives had GCA and 3 had rheumatoid arthritis (RA). In one family 3 healthy siblings participated and showed extremely low CD8+ percentages (2.5%, 6.5%, 3.4%) and absolute values (0.042, 0.102, 0.035 x 10(9)/l) CONCLUSION: TA, PMR and RA are frequently (12.5%) found in the first degree relatives of patients with GCA. The finding of extremely low CD8+ T-cell values in completely healthy relatives indicates that the CD8+ T-cell depletion seen in patients with GCA is a hereditary characteristic.

[CD8+ T-lymphocytes. Evaluation of the diagnostic value in patients with giant cell arteritis]. / CD8+ T-lymfocytter. Vurdering af den diagnostiske voerdi hos patienter med koempecellearteritis.

In patients with temporal arteritis and polymyalgia rheumatica, a marked depletion of percentage and number of circulating CD8+ T-lymphocytes are found in most cases. We assessed the diagnostic value of CD8+ levels in a larger group of patients with temporal arteritis and polymyalgia rheumatica before and after treatment with prednisolone and in relation to patients with other medical and rheumatic diseases. Median percentage and number of CD8+ cells in patients with polymyalgia rheumatica were significantly decreased (CD8+% 12.0, CD8+ cells 0.192 x 10(9)/l) compared with 1) controls (CD8+% 23.0, CD8+ cells 0.51 x 10(9)/l), 2) patients with other rheumatic diseases (CD8+% 20.8, CD8+ cells 0.39 x 10(9)/l), 3) patients with other medical diseases (CD8+% 20.6, CD8+ cells 0.46 x 10(9)/l). After 600 days of prednisolone treatment CD8+ values increased significantly (CD8+% 14.5, CD8+ cells 0.324 x 10(9)/l). In a cohort of patients with a low a priori probability of giant cell arteritis (39%), the positive predictive value of a significantly low CD8+ concentration was 51% while the likelihood of no disease with a normal CD8+ value was 71%.

Derivatives of bis-aldonic acid amides and their anticoagulant and antithrombotic properties.

Aprosulate sodium was the first representative of a new class of synthetic polyanions showing antithrombotic efficacy in different animal models. In several clinical trails (Phase I) in human volunteers aprosulate demonstrated anticoagulant properties, too. Searching for other active substances of similar structure, a series of bis-aldonic acid amides were synthesized. These compounds exhibited interesting antithrombotic and anticoagulant activities. The pharmacodynamic activities of the compounds LW 10121, LW 10125, LW 10114, 10244, and LW 10168 are summarized in this article. These substances prolonged the APTT to 150% of the blank values at concentrations of 1.5 to 13.5 micrograms/mL. The thrombin time and anti-Xa test were only slightly influenced by concentrations up to 100 micrograms/mL. All compounds were investigated in a jugular vein hemostasis model in rats to examine their antithrombotic potential. They all had an antithrombotic activity lower than aprosulate, except compound LW 10121, which seemed to be a little more active. The subcutaneous injection of 10 mg/kg LW 10121 resulted in a longer duration of action than aprosulate and heparin. On the basis of the chemical structure and the profile of action, it is assumed that the new compounds may possess the same mode of action as aprosulate, but the mechanism of action may be different from heparin and low molecular weight heparins.

Demonstration of flufenamic acid in histological sections.

A simple method is described to show the transdermal penetration of flufenamic acid (CAS 530-78-9) into the skin of laboratory animals. After topical application of gels and creams containing flufenamic acid the substance exerts a fluorescent painting in corium and subcutis of histological slides. This effect needs the chemical reaction between the test substance and sulphuric acid in synthetic resin sections.

Pharmacologic profile of the antithrombotic and bleeding actions of sulfated lactobionic acid amides.

1. The introduced bis-lactobionic acid amides represent a new group of synthetic polyanions with a molecular weight of 2387 to 2514d. The compounds are homogeneous and chemically defined. 2. The in vitro blood coagulation parameters (APTT, Heptest, anti-Xa, thrombin time, and anti-IIa) are only marginally altered by these compounds. 3. In a rat model of venous thrombosis using endothelial damage as the thrombogenic stimulus, the antithrombotic activity of the bis-lactobionic acid amides was shown in a dose- and time-dependent manner. 4. LW 10082 and LW 10121 prolong the bleeding time at dosages about 10 times less than that of heparin. The safety/efficacy index appears to be wider for these compounds than for heparin. 5. In subchronic toxicologic studies in rats, LW 10082 was well tolerated up to a dosage of 100 mg/kg body weight. 6. The anticoagulant and antithrombotic activities of the bis-lactobionic acid amides decrease gradually with the increasing number of methylene groups in the alkylene chain.

Antithrombotic action of recombinant hirudin in a venous thrombosis model.

The dose- and time-dependent antithrombotic activity of recombinant hirudin (r-hirudin) was examined in a new animal model of venous thrombosis. For the evaluation of the antithrombotic activity of r-hirudin, an occluding thrombus was produced by repeated clamping of the rat jugular vein. The number of clampings necessary to induce thrombosis served as a measure of antithrombotic activity. The gradual reduction of blood flow was registered by Doppler sonography. In order to estimate the relative antithrombotic activity of r-hirudin, its potency in this model was compared with other antithrombotic substances. r-Hirudin proved to be less potent than heparin after intravenous administration. Its half-life after subcutaneous administration was relatively short; however, the antithrombotic potency after subcutaneous administration was comparable to that of heparin.

Double blind placebo controlled trial of pulse treatment with methylprednisolone combined with disease modifying drugs in rheumatoid arthritis.

OBJECTIVE: To assess whether monthly treatment with intravenous methylprednisolone enhances or accelerates the effect of disease modifying drugs in patients with rheumatoid arthritis. DESIGN: A 12 month double blind, placebo controlled, multicentre trial in which patients with active rheumatoid arthritis were randomly allocated to receive pulses of either methylprednisolone or saline every four weeks for six months. At the start of the pulse treatment all patients were started on penicillamine or azathioprine. SETTING: Four rheumatology departments in Denmark. PATIENTS: 97 Patients (71 women, 26 men) aged 23-84 (mean 60) who had active rheumatoid arthritis of at least four weeks' duration despite treatment with non-steroidal anti-inflammatory drugs. MAIN OUTCOME MEASURES: Monthly clinical recording of morning stiffness, number of tender and swollen joints, blinded observers' evaluation of therapeutic effect, and patients' self assessed condition. Concomitant laboratory measurements of erythrocyte sedimentation rate and concentrations of C reactive protein and haemoglobin. Radiography to determine the number of erosions at the start of treatment and after 12 months. RESULTS: 57 Patients completed the trial, taking the same disease modifying drug throughout. Evaluation four weeks after each pulse treatment and at 12 month follow up showed no significant differences between the methylprednisolone and placebo groups in any of the clinical or laboratory variables. Radiography showed the same degree of progression of erosions in both groups. Evaluation of the total data on 97 patients and on the 57 who completed the trial showed the same lack of significance between the treatment groups. CONCLUSIONS: Intravenous pulse treatment with steroids can be recommended only for rapid temporary relief of flares of disease in patients with rheumatoid arthritis. The response is short lived. Repeated pulses of methylprednisolone at four week intervals do not improve the results of treatment with drugs that induce remission such as penicillamine and azathioprine.

CD8+ T lymphocyte subset in giant cell arteritis and related disorders.

Median percentage and number of circulating CD8+ T lymphocytes (suppressor/cytotoxic T lymphocytes) are markedly decreased in patients with giant cell arteritis (GCA). We assessed the diagnostic usefulness of CD8+ T cell values, in 108 patients who had a temporal artery biopsy during a 3 year period. Histologic evidence of GCA was found in 26 patients. Negative biopsy patients were divided into 2 groups, one with 49 patients and a probable GCA syndrome (polymyalgia rheumatica with a negative biopsy) and a group with non-GCA (33 patients). Median percentage and number of CD8+ T cells were significantly decreased with definite GCA (CD8+% 10.0, CD8+ cells 0.221 x 10(9)/l), and probable GCA syndrome (CD8+% 10.0, CD8+ cells 0.197 x 10(9)/l) compared with non-GCA (CD8+% 22.0, CD8+ cells 0.527 x 10(9)/l) and controls (CD8% 21, CD8+ cells 0.518 x 10(9)/l). Significantly low CD8+ T cell values were found in nearly 80% of patients with active untreated GCA or GCA syndrome and in 15% of patients with non-GCA. Positive predictive value of a significant low CD8+ T cell value is 85% while the likelihood of no GCA or GCA syndrome with normal CD8+ T cell values is 60%.

Serological and immunohistochemical determination of von Willebrand factor antigen in serum and biopsy specimens from patients with arteritis temporalis and polymyalgia rheumatica.

Von Willebrand factor antigen (vWF-Ag) levels in serum from patients with untreated polymyalgia rheumatica (PMR) and arteritis temporalis (AT) were measured using an ELISA technique. The level in patients with AT was significantly higher (median 229%, range 182-358%) than in patients with PMR (median 190%, range 131-390%) and in controls (median 179%, range 65-296%). Using an immunoperoxidase technique and biopsy specimens from 21 temporal arteries (7 patients with AT, 7 with PMR and 7 with other diseases), vWF-Ag was localized in the luminal endothelium in all cases. VWF-Ag was also present in many new vessels along the lamina elastica of the artery wall in all patients with AT, but not in patients with PMR. We relate the higher vWF-Ag level in these patients to an increased vWF-Ag production by endothelian cells in new, proliferating vessels in the artery wall.

[The effect on wound healing of glycosaminoglycan polysulfate]. / Experimentelle Untersuchungen zur Beeinflussung der Wundheilung mit Glycosaminoglycanpolysulphat.

Experimental Investigations on the Influence of Glycosaminoglycan Polysulfate on Wound Healing. The effect of glycosaminoglycan polysulfate (GAGPS) on wound healing has been studied using two different animal models. In the first model the treatment with GAGPS significantly reduced the area of skin lesions on irradiated rats. In a second animal model, the healing of perforating wounds on rabbit ears was measured. In this case, a deleterious effect of irradiation was not visible after treatment with GAGPS.