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%.

[Methotrexate therapy of rheumatoid arthritis. An open observation study of 110 patients with median length of treatment of 17.8 month]. / Metotrexatbehandling af arthritis rheumatoides. En åben observationsundersøgelse af 110 patienter behandlet i mediant 17.8 måneder.

Effects and side-effects of treating patients with rheumatoid arthritis with methotrexate given as weekly pulse-treatment are examined in an open observation study. One hundred and ten consecutive patients with active rheumatoid arthritis entered the study. Six criteria of remission were registered as effect variables. Median length of treatment at the time of investigation was 17.8 months. At this point, 34 patients were in complete remission, with a median effect score of five point five out of six possible points. Twenty-nine were in partial remission and 47 (42.7%) had not improved. The median effect score for all patients was three point 6 (95% confidence limits (2-4). Methotrexate treatment was stopped in 24 patients, in 15 of these because of a combination of side-effects and lack of therapeutic response. Prednisone treatment could be discontinued in 20 out of 57 patients during the course of methotrexate treatment. Side-effects were registered in 67 cases (62.7%), and led to treatment being discontinued in 21 cases. Nearly half the side-effects consisted of dyspepsia and rises in amino-transferase levels (48 of 67 patients). Consistently raised amino-transferase levels were found in five cases, all returned to normal after methotrexate was stopped. Serious side-effect were registered in four cases, consisting of two cases of short-term pancytopenia following overdosage and two cases of severe hypoxia following methotrexate-induced alveolitis.

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.

CD8+ lymphocyte subset in polymyalgia rheumatica and arteritis temporalis. Inverse relationship between the acute hepatic phase reactants and the CD8+ T-cell subset.

Laboratory hallmarks of giant cell arteritis (GCA) are mainly an elevated ESR and a decreased level of the CD8+ T-lymphocyte subset. Because a normal or minimally raised ESR is found in 10-20% of patients with an active GCA, we assessed the role of the CD8+ T-cell subset in patients with high and low acute hepatic phase response. Fifty-five patients with active, untreated disease were studied. The median ESR was 85 mm/h and the median CRP was 57 mg/l (normal controls less than 10 mg/l). The median CD8+T-cell reading was 0.197 X 10(9)/l and the median CD8% was 10.0 (3.8 - 23), which was significantly different from normal controls (CD8+ T-cells 0.511 X 10(9)/l, CD8+% 22 (12 - 32] (p less than 0.05). A low acute phase response (median ESR 41 mm/h, range 12-47) was identified in 11 patients or 20%. In these patients the median CD8+ T-cell reading was 0.176 x 10(9)/l and the median CD8+% 8.5 (4.3 - 15). These CD8+ values were significantly lower than values for the CD8+ T-cells (0.209 x 10(9)/l) and CD8+% (10.0), found in patients with a high acute phase response (median ESR 90 mm/h, range 50 - 145) (p less than 0.01). Our study confirms the presence of a subgroup of patients with PMR/AT who, despite active disease, exhibit a low acute phase response, and further indicates that this subgroup is characterized by a marked depletion of CD8+ T-cells in peripheral blood.

HLA-DR expression and disease activity in ulcerative colitis.

In 12 patients with active ulcerative colitis (UC) the rectal epithelial cells were analyzed for HLA-DR antigens by an immunohistochemical technique. The clinical, rectoscopic, and histologic stages were also determined. The investigations were carried out at the beginning of the study and 2 weeks and 3 months later. The rectal epithelial cells were HLA-DR-positive in all patients at the first two examinations. After 3 months five patients had changed to an HLA-DR-negative stage, whereas the other seven patients remained HLA-DR-positive. Closer analyses showed that expression/nonexpression of HLA-DR antigens on rectal epithelial cells of patients with UC could not be predicted from the clinical, rectoscopic, or histologic findings. HLA-DR expression is normally restricted to immunocompetent cells. The presence of HLA-DR antigens on epithelial cells may be a consequence of immunological reactions. Whether HLA-DR-positive cells have a specific function is unknown.

Decreased level of suppressor/cytotoxic T cells (OKT8+) in polymyalgia rheumatica and temporal arteritis: relation to disease activity.

Separated peripheral blood mononuclear cells were analyzed by fluorescent microscopy with monoclonal antisera for T cells (OKT3+), helper/inducer T cells (OKT4+) and suppressor/cytotoxic T cells (OKT8+). Thirty-seven patients with polymyalgia rheumatica (PMR), 13 of whom had positive biopsies for arteritis, were studied and compared with 25 age and sex matched normal subjects. The percentages of OKT3+ and OKT4+ T cells were similar in the PMR group and controls, but percentage of OKT8+ T cells was significantly reduced in patients (14.8 +/- 6.8) compared with controls (22.1 +/- 6.3). Values of OKT8+ T cells were extremely low in untreated patients with active, acute disease (7.8 +/- 4.4%) and significantly lower than in prednisone treated patients with inactive disease (17.3 +/- 5.9). These findings indicate that low values of circulating OKT8+ T cells is a feature of PMR and is related to disease activity.

C3 nephritic factor in a patient with recurrent Neisseria meningitidis infections.

A 15-year-old female experienced two systemic infections with N.meningitidis (group C and B) within a two months period. Classical as well as alternative pathway CH50 determinations on the patients serum showed no lysis. All individual complement factor concentrations, except for C3, were found to be within the reference area. Crossed immunoelectrophoretic analysis of C3 revealed no demonstrable native C3. The patient had normal levels of C3c and a markedly elevated C3d concentration. Serum from the patient was found to convert all native C3 in normal sera within 10 minutes at 37 degrees C. The active converting principle, present in the IgG fraction activated C3 in C4-depleted serum, and had a dose dependent stabilizing effect on the EA-C3bBb complex. The isolated factor showing the characteristics of C3 nephritic factor (C3 NeF), was unchanged in the patients serum over a ten months observation period. Circulating immune complexes (IC) could not be demonstrated by a C1q-dependent assay but the patients capacity to solubilize preformed IC in vitro was virtually abolished. The patient had no signs of renal disease or lipodystrophy.