Association of IgE antibodies to sodium aurothiomalate and adverse reactions to chrysotherapy for rheumatoid arthritis.

The relationship between adverse reactions to chrysotherapy and specific IgE antibodies to sodium aurothiomalate (auIgE) was studied in 67 patients with rheumatoid arthritis (62) or psoriatic arthritis (5). Thirty patients (45 percent) had such antibodies versus none of the 27 control patients. Of the 34 patients in whom reactions to chrysotherapy developed, 23 (68 percent) had auIgE versus 7 (21 percent) without reactions (p less than 0.001). Mucocutaneous lesions were significantly associated with auIgE (p less than 0.001). All five patients with thrombocytopenia, but only one of five with the nephrotic syndrome, had auIgE. The patients with IgE response had higher total serum IgE levels (p less than 0.005), were more likely to be atopic (four to one), and had more recently received chrysotherapy (mean 2.8 +/- 1.95 years versus 7.0 +/- 5.75 years, p less than 0.001) than those without response, but did not differ by either the gold product or the total dose used. Chrysotherapy is associated with the production of specific IgE antibodies to a gold salt, and some mucocutaneous and hematologic reactions may be immunologically mediated.

[HLA DR7 as a protective factor against gold salt toxicity in rheumatoid arthritis]. / HLA DR7 como factor de protección frente a la toxicidad por sales de oro en la artritis reumatoide.

We performed a study of antigens HLA type I and II (specificity DR) in 90 patients with diagnosis of Rheumatoid Arthritis (RA) treated with Sodium Aurothiomalate (SATM) in order to detect the presence of an antigen HLA which could act as a protective factor against toxicity by SATM. Our results demonstrated a decrease in the frequency of the antigen DR7 in patients with toxicity by SATM, which suggests a protective factor of this antigen against the development of toxic reactions due to gold salts.

Gold causes genetically determined autoimmune and immunostimulatory responses in mice.

Natrium aurothiomaleate (GSTM) is a useful disease-modifying anti-rheumatic drug, but causes a variety of immune-mediated adverse effects in many patients. A murine model was used to study further the interaction of GSTM with the immune system, including induction of systemic autoimmunity. Mice were given weekly intramuscular injections of GSTM and controls equimolar amounts of sodium thiomaleate. The effects of gold on lymphocyte subpopulations were determined by flow cytometry. Humoral autoimmunity was measured by indirect immunofluorescence and immunoblotting, and deposition of immunoglobulin and C3 used to assess immunopathology. Gold, in the form of GSTM, stimulated the murine immune system causing strain-dependent lymphoproliferation and autoimmunity, including a major histocompatibility complex (MHC)-restricted autoantibody response against the nucleolar protein fibrillarin. GSTM did not cause glomerular or vessel wall IgG deposits. However, it did elicit a strong B cell-stimulating effect, including both T helper 1 (Th1)- and Th2-dependent isotypes. All these effects on the immune system were dependent on the MHC genotype, emphasizing the clinical observations of a strong genetic linkage for the major adverse immune reactions seen with GSTM treatment.

Interferon-gamma secreted from peripheral blood mononuclear cells as a possible diagnostic marker for allergic contact dermatitis to gold.

10% of patch-tested patients have a positive reaction to gold. Most lack clinical symptoms, but allergic contact dermatitis (ACD) to gold is increasing. In this study, 77 dermatological outpatients were divided into 3 groups depending on epicutaneous patch test outcomes: a group positive to gold (EPI+), a group negative to gold (EPI-), and a group with irritant reactions to gold (EPI-IR). Lymphocytes were stimulated in vitro with gold sodium thiosulfate. Proliferation was assessed using the lymphocyte transformation test (LTT), and cytokine secretion was assessed using a multibead array (Luminex; Linco Research Inc., St. Charles, MO, USA), in order to evaluate whether an in vitro method with high diagnostic accuracy could be devised. The EPI+ group showed a significantly increased secretion of interferon (IFN)-gamma, interleukin (IL)-2, and IL-13 and also showed a significantly higher stimulation indexes for LTT, compared to the other 2 subject groups. Sensitivity and specificity were calculated for all methods individually and combined, but IFN-gamma assessment alone was the most accurate method for identifying ACD to gold, with sensitivity and specificity of 81.8% and 82.1%, respectively. This method also identified 87.5% of the EPI-IR subjects as non-allergic. Therefore, assessment of secretion of IFN-gamma should be a valuable complement to patch test for diagnosing gold allergy.

Clinical reactions to systemic provocation with gold sodium thiomalate in patients with contact allergy to gold.

In a double blind experimental study, 20 patients with a contact allergy to gold sodium thiosulphate were challenged intramuscularly with the chemically similar gold sodium thiomalate and with placebo. The most spectacular clinical reaction in the 10 patients given the active agent, was an epidermal and dermal flare up of healed patch-test reactions to the gold salts, as well as a high, but transient, rise in body temperature. Previous intradermal tests were similarly reactivated. In addition, toxicoderma-like rashes were observed in several cases, but a flare up of a previous contact dermatitis site was seen in one patient only. The specificity of the positive provocations was demonstrated.

Immunomodulatory effect of gold sodium thiomalate on murine acquired immunodeficiency syndrome.

Induction of IL-2 production and increased expression of CD25 were observed in C57BL/10 mice after weekly treatment with gold sodium thiomalate (GST). LP-BM5 murine leukemia virus (MuLV) infected mice treated with GST survived longer, had less cervical lymph node swelling, lower spleen weight, and fewer abnormalities in the expression of the cell surface markers, CD4, CD8a and CD45R/B220 on spleen cells than those that were not treated with GST. Thus, GST treatment may be beneficial through a decrease in disease progression via IL-2 induction in MuLV infected mice. This may have application in human immunodeficiency virus-infected individuals.

Asthma and IgE antibodies induced by chromium and nickel salts.

Metal plating with chromium and nickel has secured an occupational relation with asthma for which an allergic basis has been postulated but not confirmed. A worker who developed de novo asthma after plating with nickel and chromium but not other metals was subjected to inhalational challenge and immunoserologic tests to evaluate this association. He developed acute asthma to chromium sulfate and a biphasic asthma-like response to nickel sulfate. Radioimmunoassays incorporating the challenge materials revealed specific IgE antibodies to the provocative agents but not to another metal, gold, which he could tolerate. The findings support the postulates that bronchial reactivity can be specifically induced by fumes of metallic salts, even in a previously nonallergic individual, and that an IgE type I immunopathogenic mechanism is involved.

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.

The pharmacological profile of auranofin, an orally active gold compound.

Auranofin (AF; ' Ridaura '), an oral chrysotherapeutic agent, parenteral gold sodium thiomalate (GST) and gold thioglucose (GTG) were evaluated in order to compare their preclinical profiles. AF was found to be more effective than GST and GTG in suppressing inflammation and stimulating cell-mediated immunity. In contrast to GST, AF inhibited cellular release of lysosomal enzymes, antibody-dependent cellular cytotoxicity, production of antibodies in adjuvant arthritic rats, and antibodies involved in cytotoxicity reactions. In pharmacokinetic studies, plasma gold in rats following AF administration, exhibited greater cell association than after GST administration. In conclusion, the pharmacological profile of AF is markedly different from those of GST and GTG and this suggests potential for improvements in chrysotherapy.

Immunosuppressive actions of gold salts.

In rheumatoid arthritis both lymphocyte-mediated and antibody-mediated immune reactions are important for the inflammatory lesions. In vivo activated B lymphocytes/plasma cells, T lymphocytes and monocytes/macrophages (Mo) are intimately involved in the disease process. Several clinical observations suggest an immunosuppressive action of gold salts. In humans, gold salts interfere with a number of Mo functions in vitro, including cellular interactions between Mo and T lymphocytes. Some workers have shown that the activation of human T lymphocytes is inhibited by gold salts, most probably secondary to an inhibition of Mo-T cell cooperation. Recent experiments indicate that gold salts also affect the in vitro differentiation of human B lymphocytes in response to polyclonal activators. Both the gold atom and the SH group seem to be important for the immunosuppressive actions of gold salts.

Alteration of a model antigen by Au(III) leads to T cell sensitization to cryptic peptides.

Certain metal ions are known to be potent sensitizers, but the self proteins modified by metal ions and the self peptides recognized by 'metal-specific' T cells are unknown. In humans and mice treatment with gold anti-rheumatic drugs, containing Au(I), may lead to allergic and autoimmune side effects. Human and murine T cells do not react to Au(I), however, but to the reactive metabolite Au(III). Here we show that alteration by Au(III) of a model antigen, bovine ribonuclease (RNase)A, results in T cell sensitization to cryptic peptides of this protein. Upon immunization of mice with Au(III)-pretreated RNase [RNase/Au(III)], CD4+ T cell hybridomas specific for RNase/Au(III) were obtained in addition to those recognizing the immunodominant peptide RNase 74-88; the latter also were obtained after immunization with native RNase. RNase/Au(III)-specific T cell hybridomas reacted against RNase/Au(III) and RNase denatured by S-sulfonation of cysteine residues, but not against native RNase, or RNase pretreated with Au(I), A1(III), Cu(II), Fe(II), Fe(III), Ni(II), Mn(II), or Zn(II). Using a panel of overlapping, synthetic RNase peptides which were devoid of gold or gold-induced modifications, epitope mapping revealed that RNase/Au(III)-specific T cell hybridomas recognized the cryptic peptides 7-21 and 94-108, respectively. Comparison of the proliferative response of bulk CD4+ T cells, prepared from splenocytes after immunization with either RNase/Au(III) or native RNase, revealed that Au(III) pretreatment of RNase led to a markedly enhanced response to the two cryptic peptides while it did not influence the response to the immunodominant peptide. The cryptic peptides were also presented after preincubation of bone marrow-derived macrophages with RNase and Au(I), but not with RNase alone, suggesting that oxidation of Au(I) to Au(III) and subsequent protein alteration by Au(III) can happen in mononuclear phagocytes. We conclude that Au(III) alteration of proteins alters antigen processing and, thus leads to presentation of cryptic peptides. This mechanism may shed light on the development of allergic and autoimmune side effects of Au(I) anti-rheumatic drugs. In addition, it might provide a general mechanism of how metal ions act as T cell sensitizers.

Phagocytes render chemicals immunogenic: oxidation of gold(I) to the T cell-sensitizing gold(III) metabolite generated by mononuclear phagocytes.

The oxidizing capacity of phagocytic cells is suspected to play a major role in the generation of immunogenic drug metabolites, in particular those that cause extrahepatic immunopathological lesions. In the case of the antirheumatic drug gold(I) disodium thiomalate (Na2Au(I)TM), oxidation of the Au(I) ion to Au(III) appears to be responsible for the adverse immune reactions which may develop during gold therapy. Here, we show that the reactive metabolite Au(III) may be generated by mononuclear phagocytes (M phi) exposed to Au(I). The generation of Au(III) was analyzed by means of the adoptive transfer popliteal lymph node assay (PLNA) in mice, using T lymphocytes previously sensitized to Au(III) as a detection probe. Donors of the Au(III)-primed T cells were either directly sensitized to Au(III) by injection of tetrachloroauric acid (HAu(III)Cl4), or indirectly via chronic treatment with Na2Au(I)TM. As donors of peritoneal cells (PC), we used mice which had received weekly i.m. injections of Na2Au(I)TM for 12 weeks and contained increased numbers of activated B cells. The PC of these mice were found to elicit a significant secondary response when used as antigenic material for the restimulation of Au(III)-primed T cells. The immunogenicity of PC obtained from Na2Au(I)TM-treated mice paralleled the total gold content of these cells. Noteworthily, M phi exposed to Au(I) in vitro also proved capable of eliciting a specific secondary response of Au(III)-primed T cells. Hence, M phi exposed to Au(I) generate the reactive intermediate Au(III) which, apparently via oxidation of self proteins, sensitizes T cells. As M phi are constituents of many different organs and, moreover, communicate with T cells, their capacity to generate Au(III) may account for the various extrahepatic adverse immune reactions induced by Au(I) drugs.