Remission-inducing drugs in rheumatoid arthritis.

The administration of certain drugs to patients with established rheumatoid arthritis frequently results in improvement that is slow to appear but persists for long periods, even after the drug is discontinued. The three main drugs with this effect, whose efficacy and toxicity are reviewed in this paper, are gold salts, D-penicillamine and chloroquine. The cytotoxic agents used to treat rheumatoid arthritis, which likely have nonspecific anti-inflammatory actions and have serious long-term side effects, are also briefly reviewed. A new drug, levamisole, is currently being tested in patients with rheumatoid arthritis. It is suggested that the time for considering the introduction of a remission-inducing drug in patients with progressive rheumatoid arthritis is after an adequate trial of therapy with salicylates or other nonsteroidal anti-inflammatory agents, or both, and before the oral administration of steroids. It is difficult, however, on the basis of rigorous clinical comparisons, to recommend which of the three main remission-inducing drugs should be tried first, although gold salts have been used the most. Patients who have improved with 6 months of chrysotherapy may continue treatment for at least 3 years, during which time the frequency of mucocutaneous and renal toxic effects will steadily decrease. Some aspects of the medical economics of therapy with remission-inducing drugs for rheumatoid arthritis are discussed.     

Comparison of treatment outcome in patients with rheumatoid arthritis treated with TFX- Polfa or gold salts after a one year follow up]

Thirty five patients with rheumatoid arthritis were given TFX Polfa, initially everyday in the intramuscular injections in the dose of 10 mg TFX protein for 60 days, followed by 1 injection of 10 mg TFX protein a week for 10 months. Other 30 patients with rheumatoid arthritis treated with gold salts were used for comparison. Several clinical and laboratory tests were performed before the treatment and after 1 year. A one-year therapy significantly improved all clinical parameters in both groups. A significant increase in hemoglobin and erythrocyte count was noted in patients treated with TFX. A significant decrease in the markers of inflammation was seen. A percentage of both early and delayed E rosettes increased highly significantly. The obtained results suggest that TFX Polfa is efficient in these cases of the rheumatoid arthritis which cannot be treated with gold salts.     

Effect of gold therapy in rheumatoid arthritis on leukopoiesis and granulocyte phagocytosis]

In 12 patients with rheumatoid arthritis the investigations of leukopoiesis and granulocytic phagocytosis were carried out before and after a gold therapy. A marked reduction of granulocytic phagocytosis could be observed here which decreased after the gold therapy, yet remained below the values of a normal collective. Partly contrary informations are discussed. The disturbance of the phagocytosis capacity of granulocytes may possibly be due to a rheumatic factor.     

Modifications in alpha 2 globulins, gamma globulins and in rheumatoid factor during gold salt therapy in rheumatoid arthritis]

A total dose of g 1.071, given as hydrosoluble salts for a 12 month period, showed a significant decrease in serum gamma globulins along with clinical improvement in 17 patients affected with rheumatoid arthritis. A decrease in alpha 2 globulins and in rheumatoid factor titre was observed too, but it was not significant. The data suggest that in rheumatoid arthritis the gold therapy might also be effective on the immunological disease mechanism.     

Fibrinolysis before and after gold therapy in rheumatoid arthritis]

In 12 patients with chronic rheumatoid arthritis the immunoglobulins IgG, IgA and IgM were determined according to Mancini and the fibrinolytic split products according to Nilehn before and after a gold treatment of 3 to 6 months. The IgG values were always increased and even after the treatment there was only little regression. The fibrinolytic split products found in 5 cases speak in favour of an enhanced intravasal coagulation, which increased still further after the gold therapy. In spite of clinical improvement the immunological processes and latent actions of coagulation seem to pass almost undiminished.     

Erythrocyte Membrane Gold Levels After Treatment with Auranofin and Sodium Aurothiomalate

Triethylphosphine gold-2,3,4,6-tetra-o-acetyl-L-thio-D-glucopyranoside (auranofin and sodium aurothiomalate; Myocrisin are two chemically different gold compounds used to treat rheumatoid arthritis. This study highlights the interaction, in vivo, of these drugs with erythrocyte membrane in patients with rheumatoid arthritis. Fifty-eight patients with definite or classical rheumatoid arthritis were included in this study and randomly allocated to three groups as 18 patients in the Myocrisin group, 20 patients in the auranofin group, and 20 patients in the placebo group. The drugs appeared to react, in vivo, in different ways. With Myocrisin, the level of gold in erythrocyte membrane was, initially, very high and decayed exponentially afterwards, whereas auranofin produced a constant high level up to 36 weeks. The erythrocyte membrane gold level in nonsmokers was higher than that in smokers in the auranofin group, and it decreased with an increase in the number of cigarettes smoked (r = 0.836 P < 0.01); no such correlation was observed in the Myocrisin group. In a changeover study, auranofin appeared to change the nature of erythrocyte membrane after reacting with it and rendering it incapable of picking up any gold from Myocrisin. In the case of auranofin, the hemolysate membrane gold level was found to correlate with clinical improvement.     

Immunological Studies on the Mechanism of Gold Hypersensitivity Reactions

Immunological studies were performed on 12 patients with rheumatoid arthritis who developed reactions to gold. IgE levels were found to be raised in 10 of 11 patients tested at the time of the gold reaction, returning to normal on stopping therapy. Two of 12 patients with gold reactions had positive in-vitro lymphocyte transformation responses to gold.It is suggested that dermatological side effects in particular are mediated by a type I hypersensitivity response.     

Behavior of the heparinocytes after gold therapy]

A reduction of the total leukocytes as well as a significant decrease of heparinocytes and BAI (basophilic age index) can be observed in rheumatoid arthritis in the course of a gold therapy. As some coagulation parameters simultaneously speak in favour of an enhancement of the intravasal coagulation, a partial blocking of the endogenous heparin caused by gold may be supposed. A combined heparin or heparinoid therapy in a low dosage is being recommended for risk patients of the vascular and coagulation system.     

Gene therapy for arthritis – where do we stand?

The successful use of biologicals in the treatment of rheumatoid arthritis, psoriatic arthritis and spondyloarthritis has had a major impact on the management of these conditions. The challenge in the development of gene therapy as an alternative to these current treatments is to demonstrate that such therapy is more advantageous for patients from the therapeutic and safety points of view. Also, it will need to be demonstrated that gene therapy for the arthritides is economically feasible and that patient populations worldwide will be able to access these treatments.     

Gene therapy for arthritis--where do we stand?

The successful use of biologicals in the treatment of rheumatoid arthritis, psoriatic arthritis and spondyloarthritis has had a major impact on the management of these conditions. The challenge in the development of gene therapy as an alternative to these current treatments is to demonstrate that such therapy is more advantageous for patients from the therapeutic and safety points of view. Also, it will need to be demonstrated that gene therapy for the arthritides is economically feasible and that patient populations worldwide will be able to access these treatments.     

Gold and palladium burden from dental restoration materials.

From 81 volunteers (16 without dental restorations, 65 with gold crowns or inlays) samples of saliva before and after chewing gum, blood, serum, urine and faeces were taken and analysed for gold (Au) and palladium (Pd). The Au concentration in all analysed biomonitors correlates significantly to the number of teeth with gold restorations. For Pd the correlations were still significant, but weaker than for Au. Persons with gold restorations show maximal Au and Pd concentrations, 10(2)-10(3) higher than the background burden. The calculated maximal daily Au load in saliva (1.38 mg Au per day) reaches the range of an oral Au therapy for rheumatoid arthritis with 6 mg Auranofin (= 1.74 mg Au per day). During this therapy severe and frequent side effects are reported. In contrast, the Au concentration in serum maximally reached from Au restorations, amounts to only approximately 1/20 of the Au level during arthritis therapy. But even under subtherapeutic doses of 1 mg Auranofin/day severe side effects have been reported (4 out of 56 cases). The mean Au blood concentration from 1 mg Auranofin daily was only 3 times higher than our maximum value. A toxicological classification of the Pd values is difficult, because no toxicological threshold limit has been established, especially for the low-level long-term burden with Pd.     

Rheumatoid arthritis "in the buff": erosive arthritis in defleshed bones

Examination of isolated bones from patients with unequivocal rheumatoid arthritis provides only a glimpse of the disease but has been the only "gold standard" for recognition of osseous lesions as compatible with the diagnosis of rheumatoid arthritis. Documentation of skeletal pathologic changes in confidently diagnosed individuals has been a major missing link in the transition from clinical to skeletal analysis. Availability of appropriate skeletal material from two patients with long-standing, well-documented rheumatoid arthritis provided the opportunity for acquiring such information. The osseous appearance, skeletal distribution, and distinguishing features of rheumatoid arthritis "in the buff" were delineated in two contemporary patients and in a skeletal population of 2,906 individuals. The preconceived notion of anticipated severity of disease has hereby been tested and found wanting. Severe lesions are not recognizable or distinguishable from artifact in relatively fragile rheumatoid arthritis-affected bones, whether freshly prepared or remotely sampled. Characterization of the nature and epidemiology of osseous alterations in two contemporary skeletal populations permitted the development of a standard for recognition of the disease in skeletal populations.     

Effects of disease-modifying anti-rheumatic drugs (DMARDs) on the activities of rheumatoid arthritis-associated cathepsins K and S

Rheumatoid arthritis is an inflammatory and disabling joint disease affecting 0.5-1.5% of the population. Although various anti-inflammatory (NSAIDs) and disease-modifying (DMARDs) drugs are in clinical use, their precise mechanisms of action are not always defined. In this report, we discuss the effects of widely used DMARDs such as gold derivatives and chloroquine on cathepsins K and S, which have been implicated as critical mediators of inflammation and joint erosion in rheumatoid arthritis. We demonstrate that clinically potent gold derivatives inhibit cathepsins K and S in in vitro and cell-based assays. An X-ray analysis of the gold thiomalate/cathepsin K complex reveals that the inhibitor is bound to the active-site cysteine residue of the protease. Chloroquine, a lysosomotropic agent of lower clinical potency than gold derivatives, inhibits neutral pH-labile cathepsins intracellularly, but does not affect the neutral pH-stable cathepsin S. The potent inhibition of cathepsins implicated in the pathogenesis of rheumatoid arthritis by gold derivatives may explain the therapeutic efficacy of these drugs.     

Role of glutathione peroxidase in rheumatoid arthritis: analysis of enzyme activity and DNA polymorphism.

Aberrant expression of the antioxidant enzyme glutathione peroxidase (GPx) could contribute to the etiology of rheumatoid arthritis (RA). However, previous enzyme activity studies examining this relationship were inconclusive. Indirect evidence for this relationship derives from the known efficacy of gold therapy in RA, since gold compounds specifically inhibit GPx. The hypothesis that variants of GPx are associated with RA was examined by two approaches: enzyme activity analysis and restriction fragment length polymorphism (RFLP) association analysis. No significant difference was found in whole blood GPx activity between 28 RA patients and 36 controls. GPx activity appeared to be independent of sex, race, or type of drug treatment. However, a statistically significant difference was found with respect to treatment responsiveness. RA patients classified as good responders to gold therapy, but who were no longer taking gold, had a significantly higher GPx activity compared to both the controls and good responders currently on gold therapy. Aberrantly high GPx activity could contribute to RA by generating excess oxidized glutathione, a potent collagenase activator. Gold therapy would reduce GPx activity to normal levels. The restriction enzyme Pvu II in conjunction with a GPx gene probe identified a useful RFLP (Al, 22 kbp; A2, 15 kbp) with allelic frequencies of A1 and A2 equal to 0.11 and 0.89, respectively, in the control population. No statistically significant association, however, could be demonstrated between this allelic variant of the GPx gene and RA.     

Aurosomes produced in the synovial membrane by the oral administration of a gold compound SK & F 36914.

Chlorotriethylphosphine gold (SK & F 36914) administered orally to rabbits produced aurosomes in the synovial membrane. These aurosomes were similar to aurosomes produced by parenteral or intra-articular injections of soluble gold salts such as sodium aurothiomalate and aurothioglucose. This study shows, (1) that an orally administered gold compound is capable of producing gold deposits in the synovial membrane, and (2) that such compounds may have a future in the treatment of rheumatoid arthritis.     

Adverse reactions to D-penicillamine after gold toxicity.

The incidence of adverse reactions to D-penicillamine in 155 patients with rheumatoid arthritis was analysed and compared with their history of adverse reactions to gold. Out of 125 patients who took only D-penicillamine, 45 developed side effects from the drug, whereas of 27 patients with a history of gold toxicity, 18 also reacted adversely to D-penicillamine. All patients who took D-penicillamine within six months after an adverse reaction to gold developed side effects from D-penicillamine. Fourteen patients developed similar adverse reactions to D-penicillamine and gold, and the interval between treatments in this group was significantly shorter (p less than 0.01) than in those who developed either differing adverse reactions to both drugs or no reaction to D-penicillamine after treatment with gold. An interval exceeding six months between treatment with gold and treatment with D-penicillamine in patients who have developed adverse reactions to gold apparently reduces the risk of adverse reactions to D-penicillamine.     

Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis.

Synovial tissue affected by rheumatoid arthritis is characterized by proliferation, which leads to irreversible cartilage and bone destruction. Current and experimental treatments have been aimed mainly at correcting the underlying immune abnormalities, but these treatments often prove ineffective in preventing the invasive destruction. We studied the expression of cyclin-dependent kinase inhibitors in rheumatoid synovial cells as a means of suppressing synovial cell proliferation. Synovial cells derived from hypertrophic synovial tissue readily expressed p16INK4a when they were growth-inhibited. This was not seen in other fibroblasts, including those derived from normal and osteoarthritis-affected synovial tissues. In vivo adenoviral gene therapy with the p16INK4a gene efficiently inhibited the pathology in an animal model of rheumatoid arthritis. Thus, the induction of p16INK4a may provide a new approach to the effective treatment of rheumatoid arthritis.     

CD8+ T Cells Specific to Apoptosis-Associated Antigens Predict the Response to Tumor Necrosis Factor Inhibitor Therapy in Rheumatoid Arthritis

CD8⁺ T cells specific to caspase-cleaved antigens derived from apoptotic T cells (apoptotic epitopes) represent a principal player in chronic immune activation, which is known to amplify immunopathology in various inflammatory diseases. The purpose of the present study was to investigate the relationship involving these autoreactive T cells, the rheumatoid arthritis immunopathology, and the response to tumor necrosis factor-α inhibitor therapy. The frequency of autoreactive CD8⁺ T cells specific to various apoptotic epitopes, as detected by both enzyme-linked immunospot assay and dextramers of major histocompatibility complex class I molecules complexed with relevant apoptotic epitopes, was longitudinally analyzed in the peripheral blood of rheumatoid arthritis patients who were submitted to etanercept treatment (or other tumor necrosis factor inhibitors as a control). The percentage of apoptotic epitope-specific CD8⁺ T cells was significantly higher in rheumatoid arthritis patients than in healthy donors, and correlated with the disease activity. More important, it was significantly more elevated in responders to tumor necrosis factor-α inhibitor therapy than in non-responders before the start of therapy; it significantly dropped only in the former following therapy. These data indicate that apoptotic epitope-specific CD8⁺ T cells may be involved in rheumatoid arthritis immunopathology through the production of inflammatory cytokines and that they may potentially represent a predictive biomarker of response to tumor necrosis factor-α inhibitor therapy to validate in a larger cohort of patients.