Early aggressive treatment of rheumatoid arthritis is associated with improved disease control, slower radiological progression and improved functional outcomes. Tumor necrosis factor blocking therapy is effective but there remain concerns about long-term risks. Combining disease-modifying antirheumatic drugs (DMARDs) is a widely used therapeutic alternative; however, there is uncertainty surrounding the most effective regimen. A popular combination is methotrexate plus sulfasalazine, but each of these DMARDs can also be used in combination with other DMARDs and in triple therapy regimens. However, wide variations in study size, design, steroid usage and approaches to combination therapy have made it difficult to form firm conclusions regarding their efficacy. Generally, combination therapy is well tolerated and associated with no significant increase in the rate of adverse events compared with monotherapy. Methotrexate-sulfasalazine, methotrexate-chloroquine, methotrexate-cyclosporin, methotrexate-leflunomide, methotrexate-intramuscular-gold and methotrexate-doxycycline are effective combination regimens. Triple DMARD therapy is better than various DMARD monotherapy and dual therapy regimens. Methotrexate and hydroxychloroquine may have synergistic anti-inflammatory properties. Clinical trial evidence to support the use of other methotrexate and sulfasalazine combinations is often weak or lacking. Further investigation is required to determine the most effective regimen and approach to combination therapy.

Combination therapy for rheumatoid arthritis: methotrexate and sulfasalazine together or with other DMARDs

A randomized, double-blind, multicenter, controlled clinical trial of cyclosporine plus chloroquine vs. cyclosporine plus placebo in early-onset rheumatoid arthritis.

Antirheumatic drugs may lead to a number of relevant gastrointestinal complications. Symptomatical treatments with glucocorticoids and non steroidal antirheumatic drugs (NSAD) are known to induce gastric or duodenal ulcers, above all under combination therapies. Side effects of DMARD's (methotrexate, leflunomide, hydroxy/chloroquine, sulfasalazine) include unspecifical gastrointestinal symptoms like nausea, vomiting and diarrhea as well as induction of ulcerative mucosal lesions (methotrexate) and occurrence of a hepatopathy. The latter may appear as an asymptomatical elevation of liver transaminases or cholestase parameters, but can also lead, in some cases of a monothera-py (hydroxy-/chloroqine, sulfasalazine) or combination therapy (methotrexate + leflunomide) to a fulminant hepatitis. TNF-alpha-inhibiting drugs (etanercept, infliximab) as a new generation of anti-inflammatory therapeutics don't have relevant gastrointestinal side effects according recently published data.

Gastrointestinal side effects in the therapy of rheumatologic diseases

There is increasing interest in using combinations of two or more disease modifying anti-rheumatic drugs to treat rheumatoid arthritis. The use of such combinations is increasing in routine clinical practice. We have identified 18 well-conducted, randomised controlled trials of the use of combinations of disease modifying drugs, and a number of open studies that provide helpful supportive information. The 18 trials involved 2221 patients. Two trials reported strongly positive results, six reported moderately positive results and ten gave largely negative results. The combination of methotrexate, sulfasalazine and hydroxy-chloroquine appears to be effective with an acceptable level of adverse effects. There is also evidence that the combination of methotrexate and cyclosporin is advantageous. With both combinations, there appears to be further advantages from using corticosteroids in addition to the combination, although the evidence for this is incomplete. The use of other combinations is of less value, and in particular combinations involving parenteral gold, penicillamine and azathioprine are best avoided. Finally, there is growing evidence from randomised trials that the combination of anti-tumour necrosis factor (TNF) therapy with methotrexate is effective and well tolerated. We have identified four randomised controlled trials of the use of combinations of anti-TNF with methotrexate that all reported results favouring this combination. There is insufficient evidence to support the use of other combinations involving immunotherapies at the present time.

Combination therapy with disease modifying anti-rheumatic drugs in rheumatoid arthritis.

Aim. Sulfasalazine, a nonsteroidal anti-inflammatory drug, is effective in treating some autoimmune diseases, but its mechanism of action is unclear. To determine whether dendritic cells could be a possible target of the drug, we studied the effects of sulfasalazine and its metabolites, aminosalicylate and sulfapyridine, on in vitro maturation (terminal differentiation) of human myeloid dendritic cells. Methods. We prepared immature dendritic cells by incubating CD14-positive cells in the presence of granulocytemacrophage colony-stimulating factor and interleukin (IL)-4. The cells were matured by addition of tumor necrosis factor (TNF)-a, IL-1s, and prostaglandin E2 in the presence of sulfasalazine or its metabolites – aminosalicylate and sulfapyridine, or their combinations. We quantified the effect of drugs on the dendritic cell characteristics, such as stimulation of autologous and allogeneic pan-T cell proliferation, surface marker phenotype, IL-12 p40 subunit secretion, and activation of nuclear transcription factor (NF)-B. Results. Dendritic cells treated with sulfasalazine (1.25 µmol/L or 2.5 µmol/L) could not stimulate T cells (p<0.028, two-sided paired t-test). In distinction to drug-free maturing dendritic cells, 2.5 µmol/L sulfasalazine upregulated the levels of CD14 and CD68 and downregulated the levels of CD40, CD80, and CD83 (for all CD markers, p<0.03 for difference between measurements in the absence and the presence of sulfasalazine). From concentration-dependent changes in CD83 expression, we found an apparent ID50 1.5 µmol/L sulfasalazine. The apparent ID50 value for aminosalicylate-inhibited maturation was 4 µmol/L. Sulfapyridine had no effect. At 1.25 µmol/L, sulfasalazine largely inhibited NF-B activation in dendritic cells. Conclusion. Maturing human dendritic cells are hundred-fold more sensitive to sulfasalazine than T cells and NK cells and the most sensitive human cells described so far. Thus, dendritic cell maturation is an important target of sulfasalazine. Because of the role of dendritic cells in (auto)immunity, inhibition of their maturation might provide a target for further optimization of sulfasalazine therapy.

Maturation of human dendritic cells as sulfasalazine target.

The aim of the study was to assess the efficacy of a new formulation of cyclosporin-A (CyA) and sulfasalazine (SASP) combination treatment in preventing disability and reducing inflammatory disease activity in patients with early rheumatoid arthritis, as well as to assess the tolerability, safety, and suitability for long-term treatment. Forty five patients with early, active rheumatoid arthritis, (RA) were treated with CyA and SASP combination therapy for 12 months. The patients were evaluated by disease activity and radiologic measurements. The combined CyA and SASP therapy seems to be effective. Disease activity parameters improved within 3 months. The individual treatment response rate according to EULAR response criteria was 78% after a one year treatment period. Five patients were withdrawn due to gastrointestinal side effect and two patients because of lack of efficacy. CyA and SASP combination treatment seems to be effective in early severe RA, and with careful monitoring, side effects can be kept under control.

Cyclosporin and sulfasalazine combination in the treatment of early rheumatoid arthritis

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Cyclosporin and sulfasalazine combination in the treatment of early rheumatoid arthritis