Intramuscular Gold Research Articles

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying anti-rheumatic drugs for rheumatoid arthritis: A network meta-analysis.

Methotrexate is considered the preferred disease-modifying anti-rheumatic drug (DMARD) for the treatment of rheumatoid arthritis, but controversy exists on the additional benefits and harms of combining methotrexate with other DMARDs. To compare methotrexate and methotrexate-based DMARD combinations for rheumatoid arthritis in patients naïve to or with an inadequate response (IR) to methotrexate. We systematically identified all randomised controlled trials with methotrexate monotherapy or in combination with any currently used conventional synthetic DMARD , biologic DMARDs, or tofacitinib. Three major outcomes (ACR50 response, radiographic progression and withdrawals due to adverse events) and multiple minor outcomes were evaluated. Treatment effects were summarized using Bayesian random-effects network meta-analyses, separately for methotrexate-naïve and methotrexate-IR trials. Heterogeneity was explored through meta-regression and subgroup analyses. The risk of bias of each trial was assessed using the Cochrane risk of bias tool, and trials at high risk of bias were excluded from the main analysis. The quality of evidence was evaluated using the GRADE approach. A comparison between two treatments was considered statistically significant if its credible interval excluded the null effect, indicating >97.5% probability that one treatment was superior. 158 trials with over 37,000 patients were included. Methotrexate-naïve: Several treatment combinations with methotrexate were statistically superior to oral methotrexate for ACR50 response: methotrexate + sulfasalazine + hydroxychloroquine ("triple therapy"), methotrexate + several biologics (abatacept, adalimumab, etanercept, infliximab, rituximab, tocilizumab), and tofacitinib. The estimated probability of ACR50 response was similar between these treatments (range 56-67%, moderate to high quality evidence), compared with 41% for methotrexate. Methotrexate combined with adalimumab, etanercept, certolizumab, or infliximab was statistically superior to oral methotrexate for inhibiting radiographic progression (moderate to high quality evidence) but the estimated mean change over one year with all treatments was less than the minimal clinically important difference of five units on the Sharp-van der Heijde scale. Methotrexate + azathioprine had statistically more withdrawals due to adverse events than oral methotrexate, and triple therapy had statistically fewer withdrawals due to adverse events than methotrexate + infliximab (rate ratio 0.26, 95% credible interval: 0.06 to 0.91). Methotrexate-inadequate response: In patients with an inadequate response to methotrexate, several treatments were statistically significantly superior to oral methotrexate for ACR50 response: triple therapy (moderate quality evidence), methotrexate + hydroxychloroquine (low quality evidence), methotrexate + leflunomide (moderate quality evidence), methotrexate + intramuscular gold (very low quality evidence), methotrexate + most biologics (moderate to high quality evidence), and methotrexate + tofacitinib (high quality evidence). There was a 61% probability of an ACR50 response with triple therapy, compared to a range of 27% to 64% for the combinations of methotrexate + biologic DMARDs that were statistically significantly superior to oral methotrexate. No treatment was statistically significantly superior to oral methotrexate for inhibiting radiographic progression. Methotrexate + cyclosporine and methotrexate + tocilizumab (8 mg/kg) had a statistically higher rate of withdrawals due to adverse events than oral methotrexate and methotrexate + abatacept had a statistically lower rate of withdrawals due to adverse events than several treatments. We found moderate to high quality evidence that combination therapy with methotrexate + sulfasalazine+ hydroxychloroquine (triple therapy) or methotrexate + most biologic DMARDs or tofacitinib were similarly effective in controlling disease activity and generally well tolerated in methotrexate-naïve patients or after an inadequate response to methotrexate. Methotrexate + some biologic DMARDs were superior to methotrexate in preventing joint damage in methotrexate-naïve patients, but the magnitude of these effects was small over one year.

Methotrexate monotherapy and methotrexate combination therapy with traditional and biologic disease modifying antirheumatic drugs for rheumatoid arthritis: abridged Cochrane systematic review and network meta-analysis

Objective To compare methotrexate based disease modifying antirheumatic drug (DMARD) treatments for rheumatoid arthritis in patients naive to or with an inadequate response to methotrexate.Design Systematic review and Bayesian random...

Glucocorticoids: bad or safe for the bones?

Until recently, patients with rheumatoid arthritis (RA) were treated with monotherapy using conventional drugs such as sulfasalazine, antimalarials, intramuscular gold and methotrexate, which often leads to persistent arthritis, loss of...

Are glucocorticoids harmful to bone in early rheumatoid arthritis?

In the past, patients with rheumatoid arthritis (RA) were treated with monotherapy with conventional drugs, such as sulfasalazine, methotrexate, and intramuscular gold, which often leads to persistent arthritis, loss of functional capacity, and decreased quality of life. Both active RA and the use of high-dose glucocorticoids (GCs) are associated with generalized bone loss and fractures, but it is well known that GCs have a strong immunosuppressive effect. With the introduction of tumor necrosis factor (TNF-α)-blockers and other biologics, clinical remission is a realistic target in approximately half of the early RA patients; the same seems to be true for the use of methotrexate with chronic low-dose or initially high-dose GCs. With the use of a treat-to-target strategy focusing on clinical remission or low disease activity in early RA patients, the negative effects of systemic inflammation on bone can be arrested, and both local bone loss (in the joints) and generalized bone loss at the spine and hips can be prevented.

Corneal chrysiasis. Gold salt deposits in the cornea in a patient with rheumatoid arthritis. An analysis with confocal microscopy

Case reportA 60-year-old woman with rheumatoid arthritis of 20 years onset, on treatment with monthly intramuscular gold salts (GS) for the last 7 years. She complained of suffering from halo vision, and the examination showed a visual acuity of 0.6 in both eyes (BE). The slit lamp showed some deposits in the stroma with scattered golden granulated, without any further inflammatory reaction. DiscussionGS deposits are dose-dependent and reversible, although very slowly. In this article, we introduce, for the first time, evidence of deposits of GS in all layers of the cornea, predominantly in the corneal stroma and in the endothelium.

Crisiasis corneal. Depósitos corneales de sales de oro en paciente con artritis reumatoide. Análisis con microscopía confocal

Case reportA 60-year-old woman with rheumatoid arthritis of 20 years onset, on treatment with monthly intramuscular gold salts (GS) for the last 7 years. She complained of suffering from halo vision, and the examination showed a visual acuity of 0.6 in both eyes (BE). The slit lamp showed some deposits in the stroma with scattered golden granulated, without any further inflammatory reaction. DiscussionGS deposits are dose-dependent and reversible, although very slowly. In this article, we introduce, for the first time, evidence of deposits of GS in all layers of the cornea, predominantly in the corneal stroma and in the endothelium.

Research allocations: Subjective factors often influence outlays

Intramuscular gold therapy is a widely accepted form of treatment for active rheumatoid arthritis which fails to respond to salicylates or nonsteroidal anti-inflammatory agents. However, logistical concerns, uncommon but potentially serious renal and hematologic toxicity, and the relatively high long-term dropout rate mitigate against this form of therapy. Auranofin is an orally absorbed gold compound which differs significantly from intramuscular gold in terms of both pharmacokinetics and potential mechanisms of action. Clinical experience with auranofin is reviewed both at the Cleveland Clinic and worldwide. Therapeutic efficacy compares favorably with intramuscular gold and D-penicillamine, while significantly fewer patients are withdrawn from therapy due to toxicity (most commonly, diarrhea) than with intramuscular gold. Proteinuria and thrombocytopenia are considerably less common. Auranofin may prove to be valuable in the management of severe rheumatoid arthritis and offers several potential advantages over intramuscular gold therapy.

Intramuscular gold for the treatment of seronegative spondyloarthropathy associated with familial Mediterranean fever

Articular attack is a common feature of familial Mediterranean fever (FMF). FMF arthritis commonly resolves without any sequale within a few weeks. However, approximately 10% of the patients develop protracted arthritis persisting for months to years. Treatment with colchicine may not be effective and nonsteroidal antiinflammatory drugs or second line agents may be needed for the management of protracted arthritis. In this paper, we describe a 22-year-old patient with FMF who was complicated with protracted arthritis in the knee and shoulder joints and bilateral sacroiliitis. He was successfully treated by intramuscular gold 50 mg weekly. However, gold treatment was discontinued 8 months later because of the development of asymptomatic proteinuria. In conclusion, FMF should be considered in the evaluation of peripheric oligoarthritis, particularly in patients with Mediterranean origin. Intramuscular gold might be an effective agent. However, care should be taken regarding the development of proteinuria.

Gold: an old drug still working in refractory pemphigus

The mainstay of treatment for pemphigus is systemic corticosteroids. Different adjuvants have been used to reduce side-effects of long-term corticotherapy. Gold is an anti-inflammatory drug used in autoimmune diseases, whose use has waned with the advent of new immunosuppressive agents. To study the outcome of the use of intramuscular gold treatment of pemphigus vulgaris refractory to previous therapies. Thirteen patients with pemphigus vulgaris who had failed to respond to several prior therapies were treated with aurothiomalate, as a steroid-sparing agent. Patients were monitored to assess disease activity and gold toxicity. Seven patients achieved complete remission. Four patients were able to taper prednisone doses, although pemphigus flared when prednisone was discontinued or reduced. Toxicity was observed in the other two patients. In 53.4% of the patients, the use of chrysotherapy resulted in the complete clearing of the disease, discontinuation of all systemic therapies and induced a long-term clinical remission. Prednisone doses were able to be reduced in the remaining 46.6%. Any side-effects were reversible with drug discontinuation. Gold therapy showed efficacy as a secondary line treatment in refractory pemphigus vulgaris.

Gold

High-dose steroids in combination with other immunosuppressant substances, usually azathioprine, are the therapy of choice in pemphigus vulgaris. Complete remission can be difficult to achieve, with mucosal lesions often recalcitrant. We describe two patients in whom gold in the form of sodium aurothiomalate was effective in resolving mucosal lesions. Initially both patients were treated with high-dose corticosteroids, one in combination with mycophenolate mofetil. Their oral lesions proved to be stubborn but responded well to intramuscular gold, which also showed a steroid-sparing effect, so that the dosage of corticosteroids could be reduced to a minimum. Sodium aurothiomalate was continued until both patients were in remission without any side effects.

Pathogenesis and Management of Adult-Onset Still’s Disease

To review recent literature regarding the pathogenesis and treatment of adult-onset Still's disease (AOSD). We searched MEDLINE and PUBMED from 1971 to present using the following terms: adult-onset Still's disease, AOSD, or adult Still's disease. In addition we manually retrieved relevant abstracts from recent American College of Rheumatology and European League Against Rheumatism meetings. The etiology of AOSD, a rare, immune-mediated, multisystem inflammatory disorder characterized by quotidian spiking fevers, evanescent rash, and arthritis, remains unknown. An infectious etiology has been postulated, although a definitive agent has yet to be identified. Cytokines, such as interleukin (IL)-1, IL-6, interferon (IFN)-gamma, and tumor necrosis factor-alpha, are elevated in patients with AOSD. IL-18 and macrophage-colony stimulating factor also seem to play a role. Treatment historically consisted of nonsteroidal antiinflammatory drugs, often in combination with low-dose corticosteroids. Immunosuppressants (mainly methotrexate, but also intramuscular gold, azathioprine, cyclosporine A, leflunomide, and cyclophosphamide) and intravenous gamma-globulin are efficacious and have been used as steroid-sparing drugs. The recently reported use of anticytokine (anti-TNF-alpha, anti-IL-1, and anti-IL-6) agents in refractory cases has opened new horizons in the treatment of AOSD and provided important clues for its pathophysiology. Advances in immunology have enhanced our understanding of the role of cytokines in AOSD pathogenesis. Early, promising studies of anticytokine agents in AOSD may provide further insight into the pathogenetic mechanisms of this complex disease.

Is combination therapy with methotrexate and intramuscular gold an efficacious method of treatment for RA?

Is combination therapy with methotrexate and intramuscular gold an efficacious method of treatment for RA?

A 48‐week, randomized, double‐blind, double‐observer, placebo‐controlled multicenter trial of combination methotrexate and intramuscular gold therapy in rheumatoid arthritis: Results of the METGO study

To evaluate the efficacy and safety of adding intramuscular (IM) gold to the treatment regimen of patients with rheumatoid arthritis (RA) who have a suboptimal response to methotrexate (MTX). A randomized, double-blind, double-observer, placebo-controlled multicenter trial of 48 weeks was conducted. Sixty-five RA patients who had a suboptimal response to >/=12 weeks of MTX therapy were randomly assigned to receive weekly IM gold or placebo in addition to MTX. Gold was administered according to a standard protocol developed for the study. The primary outcome measure was the percentage of patients who met the American College of Rheumatology (ACR) 20% improvement criteria (achieved an ACR20 response) at week 48. Secondary outcomes included the percentages of patients achieving ACR50 and ACR70 responses, the individual criteria that make up the primary outcome, quality of life, direct and indirect health care costs, intraarticular steroid use, and adverse events, among other measures. Statistical analyses were based on an intent-to-treat strategy. Sixty-one percent of patients receiving gold achieved an ACR20 response compared with 30% of patients receiving placebo (chi(2) = 6.04, P = 0.014; logistic regression odds ratio 3.64 [95% confidence interval 1.3, 10.4], P = 0.016). Twenty-six percent of patients receiving gold achieved an ACR50 response compared with 4% of patients receiving placebo (P = 0.017), and 21% of patients receiving gold achieved an ACR70 response compared with 0% of patients receiving placebo (P = 0.011). From both clinical and cost-effectiveness perspectives, gold was the preferred and dominant strategy. Study treatment was discontinued in 23 patients (14 in the placebo group compared with 9 in the gold group; P = 0.022) due to loss to followup, adverse events, or lack of efficacy. In RA patients with a suboptimal response to MTX, adding weekly IM gold causes significant clinical improvement. Adverse events were minor, and IM gold-related adverse events led to discontinuation in only 11% of the gold group over 48 weeks.

Modelling cost effectiveness and cost utility of sequential DMARD therapy including leflunomide in rheumatoid arthritis in Germany

To quantify direct costs of medication and cost of illness (according to functional capacity) for patients with rheumatoid arthritis (RA) in Germany, allowing further use in a health economic evaluation of sequential therapy with disease-modifying antirheumatic drugs (DMARDs) in specialised, i.e. rheumatological, care in Germany. The analysis was conducted from the societal perspective in Germany using a modelling approach, which was based on secondary analysis of existing data and on data from a sample of 583 patients from the German rheumatological database of 1998. Functional capacity was defined by the Hannover Functional Ability Questionnaire (HFAQ) scores. Costs were calculated from resources utilised and patients' work capacity. Direct costs consisted of outpatient medical services, inpatient treatment, long-term care and rehabilitation treatment. Indirect costs incurred by sick leave and premature retirement were quantified according to the human-capital approach. Average total direct costs (year 1998-2001 values) per patient per year for continuous treatment with the selected DMARDs comprising costs for drugs, monitoring and treatment of adverse drug reactions (ADRs) were highest for intramuscular gold (sodium aurothiomalate) [euro 2106 (euro 1 approximately equal to $US 0.91; average of the period from 2000 through 2001)] followed by leflunomide (euro 2010), azathioprine (euro 1878), sulfasalazine (euro 1190), oral methotrexate (euro 708), and lowest for the antimalarials chloroquine/hydroxychloroquine (euro 684). There were additional yearly costs for RA-related non-DMARD medication of euro 554 per patient, including management of ADRs. Mean cost of illness (year 1998 values) excluding medication cost amounted to euro 17,868 per RA patient per year. Annual costs increased with increasing disability, i.e. decreasing functional capacity, of RA patients from euro 6029 per patient with more than 94% of functional capacity to euro 28,509 per patient with <20% of functional capacity. In general, there was a predominance of indirect costs in each of the categories of functional capacity, ranging between 74% and 87% of total (direct and indirect) annual costs per RA patient. Annual direct costs increased from euro 811 to euro 7438 per patient with increasing disability. Inpatient treatment was the predominant component of direct costs. Patients in the worst category (<20%) of function experienced hospital costs that were 6.5 times higher than those of patients in the best category (>94%). On the basis of the data presented it can be concluded that the results of this investigation are typical for patients in rheumatological care in Germany and can therefore be used in a health economic analysis of different DMARD sequences aimed at changing disease progression over time.

A survey of British rheumatologists' DMARD preferences for rheumatoid arthritis.

To determine the current disease-modifying anti-rheumatic drug (DMARD) preferences of UK consultant rheumatologists. A questionnaire was sent in May 2002. We asked which DMARD(s) was most frequently preferred first and sought the most typical sequence of DMARDs, including DMARD combinations. Also we determined the extent to which prognostic and other factors influenced treatment choices. Comments were invited, written responses abstracted and key themes identified. After two mailings, 331 (of 460; 72%) suitable questionnaires were returned. Ninety-five per cent (315/331) preferred methotrexate (154, 46.5%) or sulphasalazine (144, 43.5%) or either of these two (17, 5%) as first-choice agent. Of those who chose methotrexate first, 80% (123/154) ranked sulphasalazine second, 45% (55/123) combined sulphasalazine and methotrexate and 49% (27/55) then added hydroxychloroquine to this combination, in active disease. Of those who chose sulphasalazine first, 95% (137/144) ranked methotrexate second, 75% (113/150) preferring methotrexate monotherapy and 12% (18/150) the combination with sulphasalazine. Rheumatologists who preferred sulphasalazine first more commonly used subsequent DMARDs singly than those who started with methotrexate (P < 0.0001). Leflunomide was more commonly preferred than intramuscular gold as third choice (52/145 vs 29/145; P < 0.003). The most popular sequence of DMARDs was methotrexate or sulphasalazine, singly or in combination, leflunomide, intramuscular gold and anti-tumour necrosis factor therapy. Poor prognostic factors influenced DMARD choice, but patient occupation and drug costs did not. Methotrexate has displaced other DMARDs, especially sulphasalazine, as agent of first choice and newer agents have displaced older DMARDs. Whether the expressed preference for particular DMARDs accurately reflects actual use, and is optimal in rheumatoid arthritis, remains to be determined.

Evaluation and management of psoriatic arthritis: the role of biologic therapy

Clinicians often view psoriatic arthritis (PsA) as a rather minor arthritic disorder because many are unaware of the substantial damage, disability, and reduced quality of life that patients with this disease can suffer. Compared with better-studied arthritic conditions, such as rheumatoid arthritis (RA) with well-known consequences of disease progression, PsA does not elicit the same urgency to treat early and aggressively. This is largely owing to the lack of predictive epidemiologic data regarding disease progression in PsA. However, numerous studies indicate that PsA and RA are comparable in terms of overall severity of joint involvement and disability over equivalent disease duration. Many of the drugs traditionally used for PsA therapy are also used to treat RA, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, methotrexate (MTX), sulfasalazine, cyclosporine, etretinate, auranofin, intramuscular gold, and azathioprine. All of these drugs have significant risk of toxicity over long-term use, and all provide variable efficacy. This makes it difficult for clinicians to make sound risk-benefit assessments regarding treatment or nontreatment of PsA, because the risks of disease progression cannot be weighed against the risks of therapy. The newer biologic antirheumatic drugs appear to combine greater efficacy of treatment with significantly less toxicity by targeting specific mediators involved in the pathogenesis of PsA.

Pemphigus vulgaris: a review of treatment over a 19-year period.

Pemphigus vulgaris is an autoimmune blistering disease of the skin and mucous membranes with a high mortality if left untreated. We present a retrospective analysis of 159 patients with pemphigus vulgaris and pemphigus vegetans who were admitted to the Department of Dermatology and Venereology, Zagreb University Hospital Center (Zagreb, Croatia) from 1980 to 1998. Female to male ratio was approximately 2:1. The mean age was 53 years. During the war years in Croatia (1991-95) we noticed a low incidence of pemphigus vulgaris, and from 1996 to 1998 the incidence almost doubled. Diagnosis was based on histopathology [showing typical pemphigus vulgaris changes in 156 (98%) patients], indirect immunofluorescence [positive in 122 (77%) patients], direct immunofluorescence [positive in 141 (89%) patients], and blister smear cytology (Tzanck test) [positive in 115 (72%) patients]. High dosages of prednisone (100-150 mg) were given to 129 patients, which was combined with azathioprine. Patients with refractory pemphigus vulgaris were treated with intramuscular gold (14 patients) and plasmapheresis (five patients). All patients were treated with local ointments. The prolonged use of high doses of corticosteroids and immunosuppressants caused several complications, in particular, steroid diabetes (37 patients), skin infections (26 patients), arterial hypertension (23 patients), cardiorespiratory diseases (22 patients), sepsis (nine patients), etc. During the hospital treatment, 14 patients died, 10 during 1980-89 and only four during the 1990-98 period. The main causes of death were cardiorespiratory failure (six patients) and sepsis (five patients). Although pemphigus vulgaris is still a life-threatening disease, today it can be successfully treated with a combination of immunosuppressive agents. Early diagnosis and treatment of pemphigus vulgaris allow a better prognosis with lower mortality rates.

Urticarial venulitis

ABSTRACT: Episodes of recurrent urticaria and angioedema may be a clinical manifestation of cutaneous necrotizing venulitis. Known as urticarial vasculitis, this edematous form of necrotizing venulitis occurs in patients with serum sickness, connective tissue disorders, hematologic malignant conditions, an IgMKM component, infections, or physical urticarias after the administration of therapeutic agents, and as an idiopathic disorder. The skin lesions appear as erythematous, occasionally indurated wheals which may contain foci of purpura. Although the individual urticarial lesions may last for less than 24 hours, they often persist up to 3–5 days. The episodes of urticaria are chronic; approximately 70% of the afflicted individuals are women. General features include fever, malaise, and myalgia. Specific organ involvement includes enlargement of the lymph nodes, liver, and spleen and involvement of the synovia, kidneys, gastrointestinal tract, respiratory tract, eyes, and central nervous system. In the treatment of urticarial vasculitis there are no double-blind, placebo-controlled trials. Reports exist of the treatment of patients with H1 antihistamines, nonsteroidal anti-inflammatory agents, colchicine, hydroxychloroquine, dapsone, prednisone, azathioprine, methotrexate, cyclophosphamide, and intramuscular gold therapy.

A survey of United States rheumatologists concerning effectiveness of disease-modifying antirheumatic drugs and prednisone in the treatment of rheumatoid arthritis.

To collect the ratings of American rheumatologists regarding relative short-term and long-term effectiveness of disease-modifying antirheumatic drug (DMARD) therapy in the treatment of rheumatoid arthritis and to compare these data with results of a meta-analysis of randomized, controlled clinical trials (RCTs) of these drugs. A survey was mailed to 3,200 United States rheumatologists who were members of the American College of Rheumatology during the summer of 1996. The survey was completed by 645 rheumatologists. Methotrexate (MTX) was rated as substantially more effective than any other DMARD after both 1 year and 4 years of therapy. At 1 year, more than 90% of rheumatologists rated MTX as "good or excellent," compared with 35% giving a similar rating to intramuscular (IM) gold, the second-ranked DMARD. At 4 years, MTX was rated as "good or excellent" by 65%, compared with 53% for combinations, 30% for prednisone, and 11% for hydroxychloroquine, the second-ranked single DMARD. These ratings reflect results of long-term observational studies, but differ considerably from a meta-analysis of results of short-term RCTs, in which the efficacy of MTX, sulfasalazine, penicillamine, and IM gold were indistinguishable. The ratings of US rheumatologists regarding effectiveness of DMARD therapies are in agreement with observational data, but differ substantially from results of RCTs. These findings suggest that observational studies may yield useful and important information about treatment results, which are complementary to, but not available from, the RCT model. Regulatory agencies should consider long-term observational studies as a part of the evaluation of drugs.

Treatment of pemphigus with gold.

Although gold has been reported to be useful in treating pemphigus vulgaris, its use has waned in recent years because of concerns regarding efficacy and toxicity. To review 26 patients with pemphigus who were treated with intramuscular gold over a 10-year period. Gold was effective in 62% of patients as a primary treatment for pemphigus or as a steroid-sparing agent. An average of 3 months of therapy was required before the daily prednisone dosage could be halved. Four patients were free of disease and stopped receiving all therapy at the conclusion of the study. Toxic effects due to gold therapy developed in 42% of patients and all adverse effects resolved with its cessation. While toxic effects limit the use of gold in many patients with pemphigus, it may be effective in treating a large percentage of patients who otherwise are unable to reduce their steroid requirement. Because of its delayed onset of action, patients treated with gold usually require systemic steroids when therapy is initiated. Controlled, prospective trials are needed to further evaluate the efficacy of gold and its potential steroid-sparing effects.