Intra-articular treatment of arthritides and activated osteoarthritis with the 5-HT3 receptor antagonist tropisetron. A double-blind study compared with methylprednisolone.

BACKGROUND: Since the good effect of intra-articular injections of the 5-HT3 receptor antagonist tropisetron in patients with arthritides and activated osteoarthritis has already been demonstrated in pilot studies, the effect of tropisetron is compared with that of methylprednisolone here. OBJECTIVES: In a double-blind study, 34 patients with gonarthritides or activated osteoarthritis (18 patients with rheumatoid arthritis, 16 patients with osteoarthritis) were treated with a single intra-articular injection of 10 mg tropisetron (18 patients) or 40 mg methylprednisolone (16 patients). Before treatment as well as one and three weeks later, the intensity of rest pain and pain following exercise was measured with the visual analog scale (VAS) for pain and the clinical findings in the knee joint were recorded. RESULTS: By means of the intra-articular tropisetron treatment, the inflammatory joint process with arthritides and activated arthroses could be influenced in a similar way as with corticosteroid treatment. No significant differences were detected. CONCLUSION: According to the results presented here, the intra-articular treatment with the 5-HT3 receptor antagonist tropisetron in patients with gonarthritides and activated arthroses was about equally effective as those for treatment with corticosteroids. Therefore, it can be used as an alternative in patients for whom concomitant diseases like diabetes and hypertension make it difficult to use corticosteroids. Whether increasing the tropisetron dose may further improve the results remains to be determined in future studies.

[Bone tissue metabolism in systematic lupus erythematosus patients treated with glucocorticosteroids]. / Metabolizm tkanki kostnej u chorych na toczen rumieniowaty ukladowy leczonych glikokortykosteroidami.

The present study has been undertaken to evaluate bone turn-over in patients with systemic lupus erythematosus (SLE) treated with glucocorticosteroids. Thirty-eight patients with definite SLE has been investigated. The following parameters have been determinated. Some proinflammatory cytokine: interleukin-IL-1 alpha (IL-1 alpha), interleukin-IL-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony stimulating factor (GM-CSF) and some biochemical markers of osteoporosis: osteocalcin (BGP), alkaline phosphatase-bone formation (AP-B), procollagen type I carboxyterminal propeptide (PICP), carboxyterminal telopeptides of type I collagen (CTx) deoxypyridinoline (Dpd) and calcium/creatinin ratio have been determined. The forearm densitometry measurement was performed in all patients. We did not notice statistically significant decrease in bone mineral content and bone mineral density in spite of long term glucocorticosteroids treatment. Based on statistically significant correlation between carboxyterminal telopeptides of type I collagen (CTx) and calcium/creatinin ratio we observed increased bone resorption in analysed group of patients.

The presence of HLA-DR B1 shared motif does not influence cyclophosphamide and methotrexate cytotoxicity in rheumatoid arthritis patients.

In the present study we investigated the relation between cyclophosphamide and methotrexate toxicity and the presence of HLA- DR B1 alleles in rheumatoid arthritis patients. Seventy-eight such patients (67 women and 11 men) were observed for 12 months. Eighteen were treated with intravenous cyclophosphamide, 28 with oral methotrexate, and 32 with intramuscular gold salts. The prevalence of this shared motif was higher in the study population than in the healthy controls. However, detailed observations did not demonstrate a relation between particular genotype and drug intolerance. Based on the obtained findings we concluded that HLA-DR B1 typing cannot affect cyclophosphamide or methotrexate tolerance in rheumatoid arthritis patients. However, taking into account the relatively small number of patients expressing single genotype, further studies are recommended.

[Quantitative ultrasound densitometry (QUS) and dual X-ray densitometry (DXA) in patients with rheumatoid arthritis]. / Densytometria ultradzwiekowa (QUS) oraz densytometria klasyczna (DXA) u chorych na reumatoidalne zapalenie stawów.

UNLABELLED: The aim of this study was to assess of bone mineral content (BMC) and bone mineral density (BMD) of the forearm using DXA technique (DTX-200) and to evaluate broadband ultrasound attenuation (BUA) and speed of sound (SOS) of the heel using QUS technique (DTU-ONE). We examined 83 RA patients: 73 women and 10 men, at average age (55.0 +/- 12.2 yrs), ranging from 29 to 85 yrs. Average disease duration was 112.6 +/- 98.1 months. Disease activity was assessed according to Mallya and Mace index and radiological stage of the disease according to Steinbrocker index. We found significant correlation between BMC, BMD and BUA (r = 0.6572, r = 0.6081, respectively) and between BMC, BMD and SOS (r = 0.4704, r = 0.4723, respectively). IN CONCLUSION: quantitative ultrasound parameters (BUA and SOS) significant correlate with BMC and BMD values of the forearm assessed by DXA technique in rheumatoid arthritis patients.

[Glucocorticosteroid induced osteoporosis in patients with rheumatoid arthritis]. / Osteoporoza posteroidowa u chorych na reumatoidalne zapalenie stawów.

Glucocorticosteroids have been recognized as a well known risk factor for drug induced osteoporosis. Many studies have shown a decrease in bone mass, bone quality disorders and an increase in the risk of fractures in patients with long-term corticosteroid therapy. Rheumatic patients, particular with rheumatoid arthritis, who are usually chronic steroid users are at the highest risk. On the other hand uncontrolled active inflammatory process is also a main factor for rapid bone loss. Some studies suggest that patients with low dose corticosteroid therapy (prednisone 5 to 7.5 mg per day) are not at increased risk of osteoporosis. Our study of 36 rheumatoid arthritis women treated with daily prednisone doses between 5 to 7.5 mg in comparison with non-steroid control group confirmed the above suggestion.

TNF-alpha gene polymorphism does not affect the clinical and radiological outcome of rheumatoid arthritis.

The present study was undertaken in order to investigate the relationship between tumor necrosis factor-alpha (TNF-alpha) gene polymorphism and the radiological progression of rheumatoid arthritis (RA) within the first 3-years of the disease. Sixty-eight RA patients (59 women and nine men) were observed for 3-years. TNF-alpha polymorphism analysis was performed in all patients. Radiographs of the hands were taken at the onset of study and after 3-years of follow-up. Radiographs were assessed according to the Larsen index (damage score and progression of damage score). We did not observe any correlation between TNF gene polymorphism and damage score or progression of damage score. The obtained data suggests that TNF-308 polymorphism cannot serve as an indicator of the disease course in RA patients.

Does the presence of HLA-DR B1 shared motif affect progression of the disease in rheumatoid arthritis patients?

The present study was undertaken in order to evaluate role of HLA DR Bl shared motif in prognosis of development of erosions in rheumatoid arthritis (RA). HLA genotyping was carried out in a retrospective analysis of 73 RA patients and 87 healthy controls using polymerase chain reaction. The assessment of disease activity was performed according to Mallya-Mace Index, whereas radiographs of hands were assessed according to the Larsen Index. HLA-DR4 and DR10 were significantly increased among RA patients. Relative risk was 7.540 and 4.646, respectively. Interestingly, the presence of DRl and DR14 did not enhance the relative risk in our group of patients. Determination of HLA-DR B1 alleles showed that among RA patients the most frequent was HLA-DR Bl*0401, *0404, and *0408. They gave a rise to a relative risk of 4.010, 7.540, and 3.686 respectively. For the purpose of analysis the patients were divided into three groups. The first group comprised 14 patients with two high-risk alleles (HLA DR B1 *01, *0401, *0404, *0408, *14). The second group gathered 35 patients with one high-risk allele. Twenty-four patients with no high-risk alleles were designated to the third group. We did not notice any differences in damage score and progression of damage score in rheumatoid arthritis patients with different number of high risk motifs. In conclusion, HLA-DR B1 shared motif was found to be significantly more frequent among analyzed erosive rheumatoid arthritis as compared to matched healthy controls. We did not observe any relation between the presence of shared motifs and outcome of the disease. Therefore, it seems that HLA DR B1 determination may very helpful in diagnosing or in establishing groups of risk but it is not likely to have a role in predicting development aggressive forms of RA.

[Bone tissue metabolism in patients with rheumatoid arthritis treated with glucocorticosteroids]. / Metabolizm tkanki kostnej u chorych na reumatoidalne zapalenie stawów leczonych glikokortykosteroidami.

The present study has been undertaken to evaluate bone turn-over in rheumatoid arthritis (RA) patients as well as the influence of low dose glucocorticosteroids (gcs) on bone mass loss. Ninety patients with establish RA has been investigated. The patients have been divided into two groups: 44 patients treated with gcs (age 52.5 +/- 12.4 years, disease duration 122 +/- 102 months, total dose of GCS, equivalent to prednisone -7.4 +/- 8.3 g) and 46 patients who were not treated with gcs (age 54.3 +/- 9.7 years, disease duration 134 +/- 120 month). Fifty patients have been assessed twice (after 12 month). Bone mineral content and bone mineral density have been determined in all patients in distal forearm. Additionally, some biochemical markers of osteoporosis: osteocalcin, alkaline phosphatase-bone formation, carboxyterminal telopeptides of type I collagen (CTx), procollagen type I carboxyterminal propeptide (PICP), deoxypyridynoline and some proinflammatory cytokine: IL-1 alpha, IL-6, TNF-alpha, GM-CSF has been determined. No difference in bone metabolism between RA patients receiving gcs treatment and those treated without gcs was shown. It is concluded that anti-inflammatory effect of gcs may balance the direct effect of gcs on bone mineral content in RA patients, particularly those with short term treatment.

Nabumetone induces less gastrointestinal mucosal changes than diclofenac retard.

The aim of the study was to compare the efficacy and the effects on the mucosa of the gastrointestinal tract (GIT) of nabumetone and diclofenac retard in patients with osteoarthritis (OA). An open, multicentre, randomised, comparative, endoscopy-blind parallel group study included 201 patients with nabumetone and 193 patients with diclofenac retard suffering from moderate to severe OA of the knee or hip joint. Twelve clinical efficacy variables were assessed and a portion of the population underwent gastroduodenoscopy. All patients exhibited significant improvement in pain severity and pain relief (p < 0.001 and p < 0.0001, respectively) but there were no differences between the groups for all the efficacy variables. Eleven per cent of patients on nabumetone and 19% on diclofenac experienced GIT side-effects. Sixty-nine patients with nabumetone and 61 with diclofenac underwent gastroduodenoscopy. The differences in the mucosal grade for the oesophagus, stomach and duodenum at baseline were not significant. In the oesophagus there were significantly less changes after treatment with nabumetone (p = 0.007) than with diclofenac; there were similar findings in the stomach (p < 0.001) but the difference in the duodenum was not significant. This study indicates that nabumetone and diclofenac retard have similar efficacy in the treatment of OA, but nabumetone has significantly fewer GIT side-effects.

Quantitative changes in peripheral blood lymphocytes in erosive rheumatoid arthritis patients treated with methotrexate. Correlation with disease activity.

In order to better understand the immunological mechanisms involved in the pathogenesis of rheumatoid arthritis (RA), the level of various lymphocyte subsets in the peripheral blood of 29 patients with erosive RA was determined. All the patients were treated with methotrexate for 2 years. The total number and the proportion of CD3 cells, CD3+CD4+ and CD3+CD8+ cells did not change during the study. The initially increased level of CD19+ B-cells and CD19+CD5+ cells decreased during the treatment. The percentage of CD3-CD16+ natural killer cells was not affected by the treatment. At the inception of the study, we observed a deficiency of CD4+ CD45RA+ cells and the level of CD3+CD29+ cells was slightly increased. During the treatment we noticed significant elevation of CD45RA cells. Consequently, the CD29/CD45RA ratio significantly decreased. We showed significant correlation between changes in disease activity and changes in the level of CD19+ cells and CD4+CD29+ cells. Our results suggest that low-dose methotrexate may affect immunocompetent cells. The lowering in the CD29+ subset population associated with depletion of CD19 B-cells after methotrexate therapy may limit abnormal CD4+ cell activation and reduce the migration of lymphocytes into inflamed synovium.

Still's disease in children and adults: a distinct pattern of acute-phase proteins.

Crossed affinoimmunoelectrophoresis with Con A as a ligand was used to examine the microheterogeneity of alpha1-acid glycoprotein (AGP) and alpha1-antichymotrypsin (ACT) in sera of patients with child-onset and adult-onset Still's disease. The reactivity of both proteins was increased in sera of adults and decreased in sera of children with active disease, when compared with normal values. We also found statistically significant differences in serum concentration of ACT and ferritin in both diseases. This result suggests different pathogenic mechanisms of Still's disease in children and adults. Serum concentration of ferritin and ACT could be of value as a combined marker for the adult, but not the juvenile form of Still's disease.

[The role of MHC class II genes in the etiopathogenesis of rheumatoid arthritis]. / Rola genów MHC klasy II w etiopatogenezie reumatoidalnego zapalenia stawów.

Rheumatoid arthritis (RA) is associated with HLA-DR4 and DR1 antigens. HLA-DRB1 gene sequences analysis demonstrated that only a limited set of alleles is positively associated with RA. Third hypervariable region sequences (70-74, 86) Q(R)R(K)RAA, G(V) are found in up to 95% of erosive RA. The presence of disease-associated allels may predict severe outcome of the disease. Therefore, their presence may allow us to start aggressive therapy in early stage of the disease.

[Echocardiographic heart assessment in systemic lupus erythematosus]. / Echokardiograficzny obraz serca w toczniu ukladowym.

A prospective two dimensional and Doppler echocardiographic studies were performed in 41 patients to assess the incidence and spectrum of cardiac abnormalities. All patients included in the study fulfilled the 1982 revised criteria of the American Rheumatism Association for classification of SLE. There were 37 women and 4 men with average age of 38 years. Average duration of SLE was 6.5 years (range 6 months to 20 years). Nineteen patients (46.3%) with SLE had cardiac abnormalities. Valvular abnormalities were found in 14 patients (34.1%). Mitral valve abnormalities were the most common findings-in 7 patients (17.1%). There were 6 patients with aortic (14.6%), and 3 patients with tricuspid valve abnormalities (7.3%). One patient had morphological echocardiographic pattern suggesting noninfective verrucous vegetations affecting the tricuspid valve. Pericardial effusion was identified in 5 patients (12.2%). We found no correlation between the prevalence of cardiac abnormalities and duration, age and disease activity in SLE patients.

The effect of methotrexate and azathioprine on the serum levels of IgA-alpha 1-antitrypsin complex in juvenile chronic arthritis.

In the present study we investigated the influence of methotrexate (MTX) and azathioprine (AZA) on the serum levels of the IgA-alpha 1-antitrypsin (IgA-AT) complex in patients with the systemic form of juvenile chronic arthritis (JCA). Fifty-six JCA patients (22 treated with MTX, 18 treated with AZA, and 16 not treated with any immunosuppressive agent) were enrolled in the study. MTX dosage ranged from 0.3 to 0.5 mg/kg-1 week-1, while AZA was given daily at an average dose of 1 mg/kg. MTX was given for 13 months (SD = 7 months) whereas AZA for 11 months (SD = 6 months). The average value of the complex was higher in JCA patients than in both control groups (0.74 +/- 0.73 U vs 0.37 +/- 0.13 U (control children), P < 0.001 and vs 0.23 +/- 0.12 U (control adults), P < 0.001). Values exceeding the normal range were found in twenty-two JCA patients (39.4%). Serum IgA-AT level was lowest in the MTX group compared to AZA and non-treated patients (0.56 +/- 0.24 U, 0.76 = 0.43 U, 0.95 +/- 0.52 U, respectively, P < 0.05). IgA values exceeding normal levels for age were found in 14% of the patients. A correlation between the levels of the IgA-AT complex and C-reactive protein (r = 0.43, P < 0.01), alpha 1-acid-glycoprotein (r = 0.45, P < 0.01), alpha 1-antichymotrypsin (r = 0.52, P < 0.01), alpha 1-antitrypsin (r = 0.40, P < 0.01) and IgA (r = 0.56, P < 0.01) was established.

The effect of methotrexate and azathioprine on the serum levels of IgA-alfa1-antitrypsin complex in juvenile chronic arthritis

In the present study we investigated the influence of methotrexate (MTX) and azathioprine (AZA) on the serum levels of the IgA-alpha1-antitypsin (IgA-AT) complex in patients with the systemic form of juvenile chronic arthritis (JCA). Fifty-six JCA patients (22 treated with MTX, 18 treated with AZA, and 16 not treated with any immuno-suppressive agent) were enrolled in the study. MTX dosage ranged from 0.3 to 0.5 mg kg(-1) week(-1) while AZA was given daily at an average dose of 1 mg/kg. MTX was given for 13 months (SD = 7 months) whereas AZA for 11 months (SD = 6 months). The average value of the complex was higher in JCA patients than in both control groups (0.74 + 0.73 U vs 0.37 + 0.13 U (control children), P<0.001 and vs 0.23 + 0.12 U (control adults), P<0.001). Values exceeding the normal range were found in twenty-two JCA patients (39.4 percent). Serum IgA-AT level was lowest in the MTX group compared to AZA and non-treated patients (0.56 + 0.24 U, 0.76 + 0.43 U, 0.95 + 0.52 U, respectively, P<0.05). IgA values exceeding normal levels for age were found in 14 percent of the patients. A correlation between the levels of the IgA-AT complex and C-reactive protein (r = 0.43, P<0.01), alpha1-acid-glycoprotein (r = 0.45, P<0.01), alpha1-antichymotrypsin (r = 0.52, P<0.01), alpha1-antitrypsin (r = 0.40, P<0.01) and IgA (r = 0.56, P<0.01) was established.

Interleukin-10 and interleukin-6 in lupus erythematosus and rheumatoid arthritis, correlations with acute phase proteins.

We sought to investigate the influence of interleukin-10 (IL-10) and IL-6 on the acute phase proteins (APP) in systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). IL-10, IL-6, Creactive protein (CRP), alpha-1-acid glycoprotein (AGP), and alpha1 antichymotrypsin (ACT) serum levels were determined in one hundred-eight patients (71 with SLE, 37 with RA). Quantification of the serum IL-10 level showed increased levels in SLE and RA patients as compared to healthy controls. Serum IL-6 level was found to be elevated in SLE and RA patients. A correlation between IL-10 and IL-6 serum level was found only in SLE. CRP and AGP serum levels were increased in RA as compared to controls, whereas in SLE only AGP was found elevated. A statistically significant correlation between IL-6 serum level and CRP, AGP and ACT was found only in RA. No correlation between IL-10 and serum level of CRP, AGP and ACT was established. Since IL-10 has a potent immunosuppressive activity, we expected it to be negatively correlated with APP levels. Surprisingly, IL-10 did not correlate with APP either in SLE or RA patients. However, the elevation of IL-10 serum levels in SLE and RA and the correlation between IL-10 and IL-6 in SLE may suggest that IL-10 may play a central role in inflammatory connective tissue diseases.

Relations between absolute number of CD4 + CD29+ memory cells and levels of interleukin-6, rheumatoid factors, and acute phase proteins in rheumatoid synovial fluid.

Synovial fluid samples from 21 rheumatoid arthritis patients were analyzed for lymphocyte subsets using flow cytometry and antibodies to the lymphocyte surface antigens CD3, CD4, CD8, CD16, CD19, CD29, and CD45RA. Synovial fluid levels of interleukin-6, rheumatoid factors and acute phase proteins were also measured. Depletion of CD45RA+ cells and predominance of CD29+ cells were found. Interleukin-6 levels were markedly elevated (1155 pg/ml; range, 24-3875 pg/ml), as were levels of IgM, IgG and IgA rheumatoid factors and of acute phase proteins. CD4 + CD29+ counts were significantly correlated with interleukin-6 levels. Interleukin-6 levels were significantly correlated with levels of all three rheumatoid factor classes but not with levels of acute phase proteins. Significant correlations were also found between CD19+ B counts and levels of all three rheumatoid factor classes. These data suggest that synovial fluid CD4 + CD29+ cells may be involved in the immune dysregulation characteristic of rheumatoid arthritis. The correlation between CD4 + CD29+ counts and interleukin-6 levels is consistent with the recent hypothesis that, together with monocytes, CD4 + CD29+ cells are an important source of the elevated levels of interleukin-6 seen in rheumatoid synovial fluid.

[The effect of immunosuppressive drugs on expression of surface antigens of lymphocytes in patients with rheumatoid arthritis]. / Wplyw zwiazków immunosupresyjnych na ekspresje powierzchniowych antygenów limfocytów u chorych na reumatoidalne zapalenie stawów.

One hundred and fifty patients with rheumatoid arthritis (RA) were treated with immunosuppressive drugs for 12 months. Fifty nine patients were treated with methotrexate (MTX), 15 with cyclophosphamide (CTX), 30 with prednisone (PRE) and 46 with non steroidal antiinflammatory drugs (NSAID). The cell surface phenotype of lymphocyte was analyzed using immunofluorescence methods ans a variety of monoclonal antibodies. The studies were performed using fluorescence activated cell scanner (FACScan) and epifluorescence microscope. No changes in the percentage of CD3, CD4, CD8 were observed. However, in the MTX treated group the percentage of CD19+ (15.1% before treatment vs 10.2% after 12 months MTX treatment (p < 0.05) and CD5+CD19+ B-cells was decreased. In CTX treated group the percentage of both B cells (17.4% vs 11.0% (p < 0.5)) and activated T cells was decreased (CD25+: 2.8% vs 1.1%, p < 0.05 and HLA-DR+: 22.1% vs 12.7%, p < 0.01). Patients treated with prednisone expressed several changes in lymphocyte phenotype i.e. decreasing of activated T cells (CD3+CD25+: 6.9% vs 3.6%, p < 0.01), B cells (CD5+CD19+: 3.4% vs 0.8%, p < 0.001), and NK cells (CD16+: 14.8% vs 8.5, p < 0.01 and CD56+: 16.3% vs 10.7%, p < 0.01). Analyzing immunosuppressive drugs appeared to be very sufficient in the RA treatment. Moreover, the correlation between percentage of both B lymphocytes and activated T cells, and activity of disease were shown.

Cytokine concentration in serum of lupus erythematosus patients: the effect on acute phase response.

In order to get a better insight into cytokine network regulation in systemic lupus erythematosus (SLE), we analyzed levels of interleukin-10 (IL-10), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and interferon-gamma (IFN-gamma) in the sera from 36 SLE patients. Moreover, C-reactive protein (CRP), alpha-1-acid-glycoprotein (AGP), and alpha-1-antichymotripsin (ACT) serum levels were evaluated. Serum levels of IL-10 and IL-6 were significantly increased when compared with healthy controls. TNF-alpha and IFN-gamma did not differ from normal values. We established the relationship between IL-10 and IL-6 as well as between IL-10 and TNF-alpha. None of the analyzed cytokines correlated with the acute phase protein levels. Based on the obtained data, we conclude that IL-10 may play the superior regulating role in SLE. A lack of correlation between the cytokines and acute phase proteins suggests their independence from cytokine regulation.