Progressive Systemic Sclerosis an overview

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Progressive systemic sclerosis is a systemic pathology caused by the excessive accumulation of collagen that can infiltrate all organs, especially the lungs and the digestive tract. Its evolution is unpredictable and its objective evaluation difficult.

Despite diverse investigations, no specific, effective therapeutic agent has been identified. Because it is able to block the synthesis of collagen and stimulates the in vitro activity of collagenases, colchicine was prescribed to counter the functional anomalies of fibroblasts and collagen synthesis suspected in this disease. Other pathophysiological mechanisms are at play (autoimmunity, endothelial cell involvement). Findings have differed according to the study considered, but all had low enrollment, various stages of evolution, and short follow-up periods. In light of the complex pathogenesis of this disease, numerous other molecules have been tested, sometimes successfully:penicillamine D,platelet-aggregation inhibitors,immunosuppressants, interferon-γ…

The first publication dates from 1967. Using trimethyl-colchicinic acid, Housset (190) described the clear attenuation of skin infiltration in three patients with sclerodermal plaques as of the 15th day of treatment and in nine subjects with recent- onset acrosclerosis at the end of the first month of therapy. This attenuation and healing of cutaneous ulcers occurred in five of the 13 individuals with advanced acrosclerosis and in two of the nine patients with generalized progressive systemic sclerosis. This analogue allowed the administration of higher doses, compared to those tolerated for colchicine.

In a small, double-blind, randomized, cross-over trial, including 14 patients for 6 months, then open for 6 months, that tested colchicine (1 mg, 6/7 days) versus placebo, nine patients improved under treatment as assessed by clinical criteria, and continued to do so during the open period. The skin collagen content, evaluated histologically, decreased in six patients. Serum proline concentrations decreased, and those of hydroxyproline increased, in eight cases, findings suggesting the enhanced degradation of collagen (191). The long-term outcome of these patients, with a mean treatment duration of 39 months, was reported in 1979. Based on clinical criteria of skin elasticity, improvement was noted for 17 of the 19 with generalized progressive systemic sclerosis, and three of the four with localized forms. The results were significantly better when the progressive systemic sclerosis had been evolving for <5> 1.43 mg/day (192). Diffuse cutaneous scleroderma regressed in 2 months in a young girl taking 1 mg of colchicine daily after the failure of penicillamine D that had been administered for 5 months. A relapse occurred rapidly after the discontinuation of colchicine which was successfully reintroduced (193). This drug can also be active against the subcutaneous calcifications secondary to progressive systemic sclerosis (194). Thus, this molecule might slow the progression of systemic scleroderma before the appearance of visceral localizations and improve the quality of life of a certain number of patients.

Colchicine was not effective in other patients. With treatment durations varying from 2 to 12 months, no significant effect on skin elasticity, as assessed with a Petechiometer, was observed for four non-treated and seven treated (daily dose of 1 mg of colchicine) patients. It should be kept in mind that the daily dose was only 1 mg, and the time since the onset of the disease was not mentioned (195). No improvement was recorded for ten subjects with advanced progressive systemic sclerosis (including six with esophageal involvement and five with pulmonary fibrosis), a mean of 9 years of evolution since onset and a mean weekly dose of 10.6 mg for 1 year. The disease continued to progress in some patients: two of them already had pulmonary fibrosis and disease progressing for <5> mg) (196). No clinical improvement was observed in eight patients treated with 2 mg/day for 8–24 months (197). A double-blind, cross-over study of twelve patients that lasted 12 months and compared colchicine (1.2 mg/day) to a placebo did not detect any difference in skin elasticity, as assessed clinically (198).

Among the other molecules evaluated, penicillamine D gave the best results with a prolongation of survival (199) In a retrospective series of 118 patients with progressive systemic sclerosis evolving for <3> months was longer than that of those who were not taking the drug (P <0.05)>(200). Furthermore, the speed with which visceral localization(s) appeared was significantly slower (P= 0.01) in this group. None of these improvements was observed under immunosuppressive therapy (200). Carbon monoxide diffusion was retrospectively found to be significantly improved in the 44 patients on penicillamine D, as compared to the 48 not taking the drug (201), with a mean treatment duration of 2.3 years. This significant improvement (P <0.005)>(202). Penicillamine D is thus preferred over colchicine, despite its frequent side effects that can necessitate its discontinuation.

The hope invested in platelet-aggregation inhibitors dissipated quickly. The combination of dipyridamole (225 mg/day) and salicylic acid (975 mg/day) given for 1–2 years to 28 patients with progressive systemic sclerosis of recent onset failed in a double-blind, randomized trial versus placebo (203). Other than isolated successes reportedly obtained with methotrexate (204), immunosuppressants seem to have little impact (199, 205, 206). Cyclosporine, after initial promising results, is being investigated (199, 206-208). The same can be said for interferon-y, for which a first open, non-controlled trial showed significant attenuation of skin involvement, but no improvement of pulmonary function, after 6 months of treatment in ten patients (209).

Colchicine can be used for patients with skin lesions, but not systemic involvement, before prescribing penicillamine D, which is responsible for a certain number of side effects. However, prospective randomized trials including patients in the early stages of progressive systemic sclerosis are needed to determine the factors of disease progression, and to compare these different therapeutic agents.

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