Effect of Methotrexate Alone or in Combination With Sulphasalazine on the Production and Circulating Concentrations of Cytokines and Their Antagonists. Longitudinal Evaluation in Patients With Rheumatoid Arthritis

Abstract

S U M M A R YIn a recent study from our group, the combination of methotrexate and sulphasalazine (MTX + SASP) seemed superior to MTX alone in the treatment of rheumatoid arthritis (RA). To assess the impact of these therapies on the cytokine cascade, the in vitro production and circulating concentrations of several cytokines and endogenous cytokine antagonists were measured in 30 healthy controls and longitudinally in a subset of 26 patients enrolled in this study. Compared to controls, RA patients had significantly higher circulating concentrations of interleukin-6 (IL-6), soluble receptors for tumour necrosis factor (sTNFR), soluble receptors for interleukin-2 (sIL-2R) and interleukin-1 receptor antagonists (IL-1RA), and their peripheral blood mononuclear cells (PBMNC) showed a higher spontaneous production of interleukin-1/i (IL-l/i), tumour necrosis factor a (TNFa) and IL-1RA (both secreted and cell-associated) and a higher stimulated production of cell-associated TNFa, IL-1RA and (to a lesser extent) IL-l/i. Treatment with MTX alone (n = 12) or combined with SASP (n = 14), resulted in significant reductions of circulating IL -6 and sIL-2R but did not alter IL-l/i, TNFa or IL-1RA concentrations. Decreases in circulating levels of sTNFR and in the in vitro production of cell-associated IL-l/i and IL-1RA after stimulation were only observed in patients treated with MTX + SASP. The concentrations of IL-1RA and sTNFR in the circulation exceeded moderately those of IL-l/i and TNFa but this is probably insufficient to block IL-1 and TNFa activity. In conclusion, therapy with MTX alone or with SASP modulates IL -6 and sIL-2R concentrations in RA. Decreased production of IL-l/i and IL-1RA and circulating sTNFR levels were only observed during therapy with MTX -f SASP. Whether this relates to the better clinical effect observed with the combination therapy remains to be investigated. Circulating levels of IL-6, sIL-2R and sTNFR seem useful markers of disease activity in RA.K ey w o r d s : Cytokines, Methotrexate, Sulphasalazine, Combination therapy.

Plasma levels of lipid and cholesterol oxidation products and cytokines in diabetes mellitus and cigarette smoking: effects of vitamin E treatment

“…and TNFa, whereas there was an increased LPS-stimulated level of IL-1RA in both patients with diabetes and smokers versus con trols. Increased levels of the cytokine IL-1RA have been observed in the acute phase of meningococcal disease and in rheumatoid arthritis, and is supposed to reflect an antiinflammatory reaction [66,67]. Thus, the results of IL-1RA levels in our study would indicate an increased inflammation in patients with diabetes mellitus and in smokers.…”

Methotrexate treatment in juvenile localized scleroderma: A randomized, double-blind, placebo-controlled trial

“…In patients with morphea and systemic sclerosis (SSc), an increase in serum levels of IL-2, IL-4, and IL-6 has been demonstrated, and declines in these levels paralleled improvement in cutaneous sclerosis (10). Decreased levels of circulating IL-6 and soluble IL-2 with MTX treatment, both in adults and in children with rheumatoid arthritis, have been reported (11,12). Indeed, MTX has been shown to induce a significant reduction in the number of mast cells and of tenascin, a component of the extracellular matrix strongly represented in the epidermal proliferation process and dermal sclerosis, in tissue samples from patients with localized scleroderma (13).…”

Rheumatoid Art hritis: Monotherapy versus Combination Therapy

“…In a assessment the impact of these therapies on the cytokine cascade, the in vitro production and circulating concentrations of several cytokines and endogenous cytokine antagonists were measured in 30 healthy controls and longitudinally in a subset of 26 patients enrolled in this study 18 . Compared to controls, RA patients had significantly higher circulating concentrations of interleukin-6 (IL-6), soluble receptors for tumour necrosis factor (sTNFR), soluble receptors for interleukin-2 (sIL-2R) and interleukin-1 receptor antagonists (IL-1RA), and their peripheral blood mononuclear cells (PBMNC) showed a higher spontaneous production of interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF alpha) and IL-1RA (both secreted and cell-associated) and a higher stimulated production of cell-associated TNF alpha, IL-1RA and (to a lesser extent) IL-1 beta.…”

“…MTX and SSZ are used as monotherapy and in combination 5 . Although their mechanism of action remains unclear, several reports suggest that these drugs may differ in their effects on circulating cytokines and cytokine production 6 . Two studies using the combination of drugs used in this study 7 .…”