No effect of intramuscular gold therapy on serological parameters of Helicobacter pylori infection in patients with rheumatoid arthritis: a 12 month prospective study.

OBJECTIVES--To assess prospectively the influence of intramuscular gold therapy on Helicobacter pylori serology in patients with rheumatoid arthritis (RA). METHODS--Fifty patients with RA were started on intramuscular gold or chloroquine, as the control group and were followed serologically for H pylori infection for 12 months. RESULTS--Twelve patients treated with gold and eight control patients treated with chloroquine, all with serological evidence for H pylori infection, showed no significant decline of IgA and IgG anti-H pylori antibody levels or serum pepsinogen A and C levels. Total serum IgA and IgG levels declined significantly during gold therapy, while they remained unchanged during chloroquine therapy. CONCLUSIONS--Intramuscular gold therapy in patients with RA does not influence the serological parameters of H pylori infection.     

Helicobacter pylori seroprevalence in patients with rheumatoid arthritis: effect of nonsteroidal anti-inflammatory drugs and gold compounds.

PURPOSE: To investigate the relationship between Helicobacter pylori infection and nonsteroidal anti-inflammatory drug (NSAID) intolerance and the effect of gold use on the seroprevalence of H. pylori. PATIENTS AND METHODS: We examined the frequency of discontinuation of NSAIDs in 132 unselected patients with rheumatoid arthritis attending an outpatient subspecialty clinic, and the effect of gold compound use on the seroprevalence (by IgG enzyme-linked immunosorbent assay) of H. pylori infection in this population. Logistic and multivariate regression analysis was performed adjusting for age, gender, ethnic origin, history of ulcer, and duration of rheumatoid arthritis. RESULTS: Fifty-four patients had a positive serology for H. pylori (41%). Twenty-seven of the seropositive patients (50%), versus 45 of the seronegative patients (57.7%), had to discontinue NSAIDs (aspirin and/or nonaspirin) at least once since their diagnosis of rheumatoid arthritis because of gastrointestinal side effects (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.63 to 1.38). Forty-one of the seropositive patients (76%) had received gold compounds as compared with 62 of the seronegative patients (79.5%) (OR: 0.96; 95% CI: 0.61 to 1.50). CONCLUSION: We did not find any relationship between H. pylori seropositivity and NSAID intolerance in patients with rheumatoid arthritis. In addition, our results do not demonstrate a reduction in H. pylori seroprevalence in rheumatoid arthritis patients treated with gold compounds.     

Hematuria in patients with rheumatoid arthritis receiving gold and D-penicillamine

We reviewed the urinalyses from 2 multicenter controlled randomized trials, one comparing moderate and low dose D-penicillamine to placebo and another comparing gold sodium thiomalate (GSTM), auranofin (AF) and placebo. In the D-penicillamine trial 30% of the 40 patients taking placebo, 34% of the 70 patients receiving 125 mg/day of D-penicillamine and 31% of the 61 patients receiving 500 mg of D-penicillamine had recurrent hematuria. In the GSTM/AF trial, 35% of the 43 placebo treated patients, 35% of the 54 GSTM treated patients and 30% of the 64 AF treated patients had hematuria. No significant difference in the frequency of hematuria between the groups in either trial was apparent. These findings suggest that the traditionally held belief that gold and D-penicillamine cause hematuria should be reconsidered.     

Gastrointestinal disorder and Helicobacter pylori infection in patients with rheumatoid arthritis

Gastrointestinal disorders such as gastritis and peptic ulceration are very common in patients with rheumatoid arthritis. Helicobacter pylori appeared to be a high risk factor for the development of peptic ulcers or chronic active gastritis. Thus, the objective of this study is to elucidate gastrointestinal findings and the prevalence of H. pylori in patients with rheumatoid arthritis. Consecutive RA patients were recruited for this study, irrespective of gastrointestinal symptoms. Routine endoscopy was performed and mucosal specimens were analyzed according to the Sydney system. H. pylori infection was determined histologically using H–E staining, Wartin Starry silver staining, and immunohistochemistry. Of 97 patients, only 16 had gastrointestinal symptoms. By endoscopic examination, gastritis was observed in 39 patients (40.2%), gastric ulcers in 24 patients (24.7%), and duodenal ulcers in 7 patients (7.2%). The histological results analyzed by the Sydney system showed "inflammation," "active," and "atrophy" for 71.1%, 58.5%, and 54.6% of samples, respectively. Sixty patients (61.9%) were infected by H. pylori, but the presence of H. pylori did not increase the chance of endoscopic gastrointestinal disorders. The presence of a rheumatoid factor was inversely related to H. pylori infection, and the value of the rheumatoid factor was lower in patients with the infection. In conclusion, it was found that H. pylori infection was not a major cause of gastrointestinal disorders in RA, and that the presence of rheumatoid factor significantly reduces the chance of H. pylori infection. Received: January 22, 2000 / Accepted: October 31, 2000     

Decreased plasma fibrinolysis in patients with rheumatoid arthritis.

We have investigated the fibrinolytic status of 56 patients with rheumatoid arthritis (RA). Plasma fibrinogen and plasminogen were significantly elevated. Levels of these two substrates, along with alpha 2 macroglobulin and antithrombin III correlated with disease activity. Plasminogen activator (PA) activity was decreased in patients with severe disease. Twelve patients were given stanozolol, a fibrinolytic enhancing agent, for two months as a test for endothelial production of plasminogen activator. This caused a significant increase in blood plasminogen and PA activity. Five patients received a two-week course of stanozolol with joint aspiration before and after. Joint plasminogen levels were increased. We suggest that inadequate fibrinolysis occurs in RA, and that this may contribute to some of the pathological features of the disease. It is possible to stimulate both blood and joint fibrinolysis by stanozolol. A more prolonged increase in plasminogen activator activity might decrease joint fibrin deposition, and stanozolol should be investigated as a therapeutic agent in RA.     

Elevated level of IgA gliadin antibodies in patients with rheumatoid arthritis

The possibility that dietary antigens contribute to the pathogenesis of rheumatoid arthritis (RA) has been proposed. Moreover, occasional patients have been described in whom coeliac disease and RA coincide. Furthermore, most RA patients are treated with non-steroidal anti-inflammatory drugs (NSAIDs), which are known to increase gut permeability. For these reasons antibodies against gliadin were measured in a group of 43 patients with rheumatoid arthritis (RA) and a group of 43 age- and sex-matched controls. The median IgA antigliadin ELISA index was 7.1 (range 2.1-22.4) for the RA group and 3.1 (range 0.3-34.9) for the controls (p = 0.0001). The median IgG and IgM antigliadin indexes for the RA group didn't differ significantly from those of the controls. In the RA group, the level of antigliadin antibodies did not correlate with the daily dose of NSAIDs. The elevated IgA antigliadin titre in the RA group might be ascribed to the use of NSAIDs, which are harmful to the gut, but the immunological trigger effect of gluten cannot be ruled out.     

Prediction of progressive joint damage in patients with rheumatoid arthritis receiving gold or D-penicillamine therapy.

Seventy two patients with classical or definite rheumatoid arthritis (RA) were randomly allocated to receive gold or D-penicillamine therapy (DPA) in a prospective study designed to evaluate whether it is possible to predict which patients will show radiological progression despite therapy. Forty five patients completed 12 months' treatment. There were no significant demographic or clinical differences between them and the 27 drop outs. Twenty of the 45 patients showed no radiological progression between six and 12 months. These patients had less severe initial radiological damage, lower levels of serum aspartate transaminase (serum AST) and lactic dehydrogenase (LDH), but higher levels of serum cholesterol. Twenty five patients did show progression during the six to 12 month period. This group included all the men with nodules. Of the 43 pretreatment clinical and laboratory variables examined, however, the majority failed to predict whether or not progression would subsequently occur. This included the acute phase response and seropositivity.     

Reduction of peripheral blood lymphocytes in patients receiving gold therapy for rheumatoid arthritis.

Peripheral blood lymphocytes were monitored prospectively in 10 patients with rheumatoid arthritis (RA) receiving up to 1 g of sodium aurothiomalate. There was a significant fall in the absolute lymphocyte count from a mean +/- SEM of 1956 +/- 190/mm3 (1.956 +/- 0.19 X 10(9)/l) to 1232 +/- 210/mm3 (1.232 +/- 0.21 X 10(9)/l) (p less than 0.01). The number of of circulating lymphocytes fell in all patients by an amount which ranged between 108/mm3 (0.108 X 10(9)/l) and 1394/mm3 (1.394 X 10(9)/l), with a mean fall of 727/mm3 (0.727 X 10(9)/l). No significant change was noted in the total white cell count or total polymorphonuclear cell count over the same period. In contrast there was no change in the total lymphocyte count in an age and sex matched group of RA patients treated with penicillamine. This previously unreported observation may give new insight into the mechanism of action of gold salts in RA.     

Association of HLA-B35 with mucocutaneous lesions in Israeli patients with rheumatoid arthritis receiving gold treatment.

Seventy-four Israeli patients with rheumatoid arthritis (RA) were studied for possible association between HLA antigens and adverse reactions to gold treatment (aurothioglucose). HLA-B35 was significantly increased in patients who developed gold induced mucocutaneous lesions. These results are in accord with earlier reports, despite the different genetic background of the Israeli RA population and the different type of gold compound used.     

Changes in Helicobacter pylori status in patients with rheumatoid arthritis under non-steroidal anti-inflammatory drugs

BACKGROUND: The role of Helicobacter pylori infection in rheumatoid arthritis (RA) patients during treatment with non-steroidal anti-inflammatory drugs (NSAID) is still unclear. METHODS: By means of endoscopy and biopsy, gastroduodenal lesions and H. pylori status were repeatedly examined in 88 RA patients at intervals ranging from 26 to 49 months. Histology and culture were applied to determine H. pylori status. Serial changes in gastroduodenal lesions and histologic score for mucosal atrophy were compared among groups classified by initial and second H. pylori status. RESULTS: There were 28 patients with continuously positive H. pylori infection (CP group), 33 patients with continuously negative H. pylori infection (CN group), 7 patients in whom H. pylori status became negative (PN group), and 20 patients in whom H. pylori status could not be determined (UD group). Age, duration and species of NSAID, disease activity of RA, gastroprotective drugs applied and the prevalence of gastroduodenal mucosal lesions were not different among the groups at either the initial or the second examination. In the PN group, the score for mucosal atrophy at the second examination was significantly lower than at the initial examination, whereas no difference was found for the CP, CN and UD groups. Overall, histologic score for mucosal atrophy was higher in H. pylori-positive patients than in H. pylori-negative patients at both initial and second examination. CONCLUSIONS: In RA patients using NSAIDs, H. pylori infection may not affect the course of gastroduodenal lesions and activity of RA, but the infection contributes to mucosal atrophy.     

Induction of antinuclear antibodies in patients with rheumatoid arthritis receiving treatment with human recombinant interferon gamma.

Of six patients with rheumatoid arthritis (RA) treated with human recombinant interferon gamma for two to eight months, three developed antinuclear antibodies (ANAs). This was accompanied by a simultaneous clinical exacerbation of the disease activity. In this study both anti-inflammatory and immunostimulatory effects of human recombinant interferon gamma in patients with RA were observed.     

Cross-reactive antiidiotypic antibodies against human rheumatoid factors from patients with juvenile rheumatoid arthritis

We prepared antiidiotypic (anti-Id) antibody to 2 polyclonal IgM rheumatoid factors (IgM-RF) and 2 polyclonal "hidden" IgM-RF. The anti-Id antibodies were isolated by chromatography on Sepharose 4B, to which was bound rabbit anti-human IgG Fc fragments. F(ab')2 fragments from the anti-Id antibodies were generated by pepsin digestion and isolated by gel filtration. The anti-Id antibodies directed against RF from 4 patients with juvenile rheumatoid arthritis (JRA) were tested by an inhibition hemolytic assay for cross-reactivity with IgM-RF from 4 adult patients with rheumatoid arthritis, 6 patients with JRA, and 13 JRA patients with hidden RF. The 4 anti-Id antibodies had variable cross-reactivity with the isolated adult RA RF, JRA RF, and JRA hidden RF. Similar results were obtained by a direct-binding enzyme-linked immunosorbent assay for the anti-Id antibodies. The broad pattern of cross-reactivity was apparently unrelated to a particular amino acid sequence, but was associated with the antigen-binding site of IgM-RF. These results suggest the possibility that the anti-Id antibodies prepared against isolated RF obtained from JRA patients bear the "internal image" of antigen; that is, the Fc region of human IgG. These anti-Id antibodies may be generated in JRA patients and may possess specific immunomodulatory properties.     

Evidence for immunostimulatory effects of intramuscular gold in patients with rheumatoid arthritis: correlation with skin reactions

OBJECTIVE: Intramuscular gold is a well documented treatment in rheumatoid arthritis (RA), but its mechanism of action is still poorly understood. From an observation that gold sodium thiomalate (GSTM) induces monocyte-derived interleukin 6 (IL-6) and IL-10 production in vitro, a hypothesis has been proposed that gold exerts its action mainly as a selective immunostimulator rather than as a general immunosuppressant. In this prospective study we investigated cytokine production in peripheral blood from patients with RA during treatment with GSTM. METHODS: A total of 20 patients with RA were treated with GSTM for at least 3 months. Disease activity was recorded at baseline, 12, 20, and 28 weeks. The ELISPOT method was used to measure spontaneous production of IL-6, IL-10, and interferon-g (IFN-g) from peripheral blood mononuclear cells (PBMC) at baseline and 4 and 12 weeks and production after incubation with GSTM in vitro, at different concentrations (0, 3, 12.5, 40 micro g/ml) at baseline. IL-6 and IL-10 concentrations in serum were measured with ELISA. RESULTS: The numbers of IL-10-producing cells were increased after 4 weeks' treatment with GSTM (p < 0.01). The numbers of cells spontaneously producing IL-6 were increased after 4 weeks (p < 0.01) and 12 weeks (p < 0.01). The numbers of IFN-g-producing cells were increased after 4 weeks (p < 0.01). Serum concentrations of IL-10 were increased after 4 weeks (p < 0.01). Serum concentrations of IL-6 were not changed at any timepoint. The in vitro effect of GSTM on IL-10 production from PBMC at baseline predicted development of skin reactions during GSTM treatment, with lack of skin reactions being associated with high gold induced IL-10 production (p < 0.05). There was no correlation between clinical response and cytokine production. CONCLUSION: This study indicates an immunostimulatory effect of GSTM treatment in patients with RA. The increase in IL-10 production during GSTM treatment may contribute to the positive effects of gold in RA.     

Anticardiolipin antibodies in patients with rheumatoid arthritis

Summary Anticardiolipin antibodies (ACA) were assayed by ELISA in 73 patients with rheumatoid arthritis. Twelve (16.48%) patients showed levels of ACA three standard deviations above the value of the control group and were considered positive; these patients were compared to the group with ACA within the normal levels regarding the following clinical and laboratorial characteristics: spontaneous abortions, central nervous system involvement, systematization and activity of disease, alterations in platelet counts, presence of antinuclear antibodies and rheumatoid factor. Significant statistical association could be demonstrated between systematization and presence of antinuclear antibodies (ANA) and positiveness to ACA (IgG, IgM or both). These findings might indicate that ACA in patients with RA could have relevance to morbidity of disease or perhaps to its pathogenesis.