Extraspinal tendon and ligament calcification associated with long-term therapy with etretinate.

Isotretinoin, a synthetic retinoid that has been prescribed for over 500,000 patients with cystic acne, has been associated with both spinal hyperostosis and a disorder similar to diffuse idiopathic skeletal hyperostosis. We describe a syndrome of tendon and ligament calcification, primarily in extraspinal locations, that we have observed after long-term therapy for psoriasis and disorders of keratinization with etretinate, another synthetic retinoid. Of 38 patients who had received etretinate (average dose, 0.8 mg per kilogram of body weight per day; average duration, 60 months), 32 (84 percent) had radiographic evidence of extraspinal tendon and ligament calcification. The most common sites of involvement were the ankles (29 patients [76 percent]), pelvis (20 patients [53 percent]), and knees (16 patients [42 percent]); spine involvement was uncommon in this group of etretinate-treated patients. Involvement tended to be bilateral and multifocal. Fifteen (47 percent) of the 32 affected patients had no bone or joint symptoms at the sites of radiographic abnormality. Thus, tendon and ligament calcification can occur without vertebral involvement as well as in association with it (for example, as part of the spectrum of diffuse idiopathic skeletal hyperostosis). We have identified extraspinal tendon and ligament calcification as a toxic effect that is commonly associated with long-term etretinate therapy.

Dose-dependent suppression by the synthetic retinoid, 4-hydroxyphenyl retinamide, of streptococcal cell wall-induced arthritis in rats.

We studied the effects of oral administration of the retinoid, 4-hydroxyphenyl retinamide (4-HPR), on group A streptococcal cell wall-induced polyarthritis in the rat, a model characterized initially by exudative inflammation of peripheral joints followed by chronic proliferative/erosive synovitis. Experimental arthritis was induced in female LEW/N rats by i.p. injection of streptococcal cell walls in saline (15 micrograms/g body weight). Depending upon the experiment, continuous daily oral administration of the retinoid was begun either 14 days prior to induction of the disease, at the time of cell wall administration and/or 11 days and 31 days after cell wall injection. Dosage was either 1 or 2 mmol 4-HPR/kg of chow. During the course of the disease, severity of clinical illness was assessed by determination of clinical severity index, by histological or radiologic examination, and by measurement of production in vitro of collagenase and prostaglandin E2 by excised synovial tissue. In rats fed the retinoid prior to cell wall injection, both the acute and the chronic responses were suppressed. In rats given the retinoid at the time of cell wall injection, the acute inflammatory response was only partially suppressed on the diet containing 2 mmol 4-HPR/kg chow, but the chronic disease was impressively inhibited in a dose dependent manner. Similarly, in animals with established disease, the drug was also effective; however, the more advanced the illness, the less effective the drug. Clinical observations were paralleled by the histological, radiographical and biochemical analyses. Treated animals showed far less synovial proliferation and joint destruction, and synovial tissues taken from these rats produced lesser amounts of collagenase and prostaglandin E2. No significant toxicity of the retinoid was noted. We conclude that oral administration of 4-HPR suppresses, in a dose and time dependent manner, both the acute and chronic stages of streptococcal cell wall-induced arthritis in rats without apparent significant toxicity. Our data suggest that studies of the effects of this retinoid on patients with chronic inflammatory synovitis are warranted.

Vertebral abnormalities associated with synthetic retinoid use.

Frequent symptoms of back and neck stiffness led to a radiographic investigation of the vertebral spine in patients receiving synthetic retinoids, isotretinoin and etretinate. X-ray examination of fifty patients with various skin disorders who received retinoids for at least 2 years were compared with seventy-two age- and sex-matched untreated patients. Differences in frequencies of defined abnormalities, which included anterior spinal ligament calcification and presence of osteophyte at two or more vertebral levels in the absence of joint space narrowing, were determined for treated and untreated patients. When the entire group of treated patients was compared with the entire group of those untreated, no statistically significant differences were observed. When only patients with basal cell nevus syndrome ( BCNS ) or basal cell carcinoma (BCC) who had never received retinoid were compared with those who received isotretinoin, the frequency of the defined abnormalities was significantly higher in the treated group (P less than 0.01). This study suggests that the ingestion of isotretinoin at mean total dose of 150,060 mg for an average of 2.9 years is associated with a statistically significant increase in developing an associated ossifying diathesis in patients with BCNS or BCC, when compared with matched, untreated controls.