Global improvement of systemic scleroderma under long-term administration of octreotide

ARTICLE

Although a large number of treatments have been proposed for scleroderma, there is still no drug available to cure this disorder. Octreotide (Sandostatine^®) has proven to be effective for the treatment of intestinal dysmotility in patients with scleroderma [1]. For short-term administration, the somatostatin analogue octreotide reduces bacterial overgrowth, stimulates intestinal motility and improves abdominal symptoms [1, 2]. To date no data have reported a possible global improvement of scleroderma manifestations with long-term administration of octreotide.

Case report

A 53-year-old black woman was admitted in 1993 to our hospital for recurrent acute intestinal pseudo-obstruction. She was diagnosed with a four-year history of progressive and severe systemic scleroderma. The condition started in 1989 with a Raynaud phenomenon rapidly followed by cutaneous changes. On admission, physical examination showed a diffuse skin sclerosis with the unpigmented area predominant on the arms, the face and the chest. The skin was thickened preventing any venous blood puncture. The fingers held in semiflexion. Myositic involvement was noted with proximal muscle weakness and elevation of serum creatine phosphokinase. Lung functions were abnormal with an impaired carbon monoxide transfer factor (57% of the predicted normal value). Digestive involvement was severe with complaints of dysphagia, vomiting and recurrent intestinal pseudo-obstruction. The total weight loss was 18 kg. She had manometric evidence of abnormal esophageal motility, with aperistalsis and decreased gastroesophageal-sphincter pressure. Antinucleolar antibodies were present (1/1,000) whereas anticentromere, anti-Scl 70, anti-Jo-I, and anti-DNA were not found. Prednisone was started in November 1993 (1 mg/kg) and only provided relief of muscle symptoms. Volvulus of the small intestine occurred in May 1994 for which the patient underwent emergency surgery. Thereafter intestinal manifestations persisted unchanged. Breath tests revealed bacterial overgrowth into the intestinal lumen. The patient was placed under parenteral renutrition.

Octreotide (Sandostatine^®, 75 µg/d) was initiated in November 1994. Prednisone was initially dosed at 20 mg per day and progressively tapered. After one month of treatment, oral feeding was restarted and weight gain of 6.5 kg was achieved. After 8 months of treatment, normal weight was obtained. On examination skin induration was spectacularly reduced and pigmentation returned to a normal state (Figs. 1 and 2). Venous blood puncture was possible and the ability to straighten the fingers was restored. Dyspnea disappeared and physical activity was quite normal. Octreotide was stopped in November 1996. In October 1997, one year after the discontinuation of octreotide, carbon monoxide transfer factor increased to 70% of that predicted for age and sex. In February 1999, the skin involvement remained very limited.

Discussion

Effects of octreotide on intestinal motility in scleroderma are well known and were rapidly observed in our case [1, 2]. Because of severe intestinal manifestations, long-term administration of octreotide was undertaken and induced an unexpected skin, muscle and respiratory improvement. No side-effect was observed despite long-term administration. Octreotide is a long-acting somatostatin analogue, principally used in the treatment of endocrine tumors. Somatostatin elicits a wide range of biological effects which may modulate inflammation. It inhibits the activity of immunocompetent cells, including T lymphocyte proliferation and immunoglobulin production by B lymphocytes [3, 4]. It modifies the secretory activity of neurons and neuroendocrine cells [3, 4]. Octreotide effects on intestinal transit are unclear and may be secondary to immunomodulation or neurotransmission effects [5].

To our knowledge, extradigestive effects of octreotide in scleroderma have not been studied. It is unlikely that the relief of symtoms in this patient are strictly due to the increase of the diet, and such improvement has not been described after parenteral renutrition. Regression of sclerodermatous skin manifestations were reported in acromegaly and in a patient with carcinoid syndrome treated by octreotide [6, 7]. It is speculated that somatostatin has a direct action on dermal fibroblasts and may act as a negative autocrine/paracrine factor [8].

This report suggests that long-term administration of octreotide may be beneficial in the treatment of patients with systemic scleroderma. Long-term trials are required to confirm these preliminary results.

REFERENCES

1. Soudah HC, Hasler WL, Owyang C. Effect of octreotide on intestinal motility and bacterial overgrowth in scleroderma. N Engl J Med 1991; 325: 1461-7.

2. Kobayashi T, Kobayashi M, Naka M, Nakajima K, Momose A, Toi M. Response to octreotide of intestinal pseudoobstruction and pneumatosis cystoides intestinalis associated with progressive systemic sclerosis. Intern Med 1993; 32: 607-9.

3. Kolasinski SI, Haines KA, Shegel EL, Cronstein BN, Abramson SB. Neuropeptides and inflammation. A somatostatin analog as a selective antagonist of neutrophil activation by substance P. Arthritis Rheum 1992; 35: 369-75.

4. Van Hagen PM, Krenning EP, Kwekkeboom DJ, Reubi JC, Anker-Lugtenburg PJ, Löwenberg B, Lamberts WJ. Somatostatin and the immune and haematopoietic system: a review. Eur J Clin Invest 1994; 24: 91-9.

5. Greydanus MP, Camilleri M. Abnormal postcibal antral and small bowel motility due to neuropathy or myopathy in systemic sclerosis. Gastroenterology 1989; 96: 110-5.

6. Sassolas G, Harris AG, Deidier-James A, and the French Sms 201-995. Acromegaly Study Group. Long-term effect of incremental doses of the somatostatin analog Sms 201-995 in 58 acromegalic patients. J Clin Endocinol Metabol 1990; 71: 391-7.

7. Pavlovic M, Saiag P, Lotz JP, Marinho E, Clerici T, Izrael V. Regression of sclerodermatous skin lesions in a patient with carcinoid syndrome treated by octreotide. Arch Dermatol 1995; 131: 1207-9.

8. Rauly I, Saint-Laurent N, Delesque N, Buscail L, Estève JP, Vaysse N, Susini C. Induction of a negative autocrine loop by expression of Sst2 somatostatin receptor in NIH 3T3 cells. J Clin Invest 1996; 97: 1874-83.