6 Rheumatological symptoms due to retinoids G I~RARD KAPLAN BENEDICTE HAETTICH

'Retinoids' is a generic term that includes natural compounds of vitamin A (retinol) as well as synthetic derivatives. The clinical use of vitamin A in the treatment of cutaneous disorders of keratinization was impaired by unacceptable side-effects. The synthesis of less toxic retinoids, firstly available for topical use in the early 1960s and for oral administration in the 1970s, has been a major therapeutic trend in the dermatological field. These drugs have proved very effective in the treatment of cutaneous plagues as common as acne vulgaris or psoriasis. But their extensive use is still limited by sideeffects inherited from vitamin A. Since the daily dosage of retinoids generally ranges up to the equivalent of 250 000 iu of vitamin A, i.e. 70 mg, such treatment might be expected to produce symptoms of hypervitaminosis A. Acute intoxication with vitamin A was first observed in Arctic explorers feasting on polar bear or seal livers, which are said to contain as much as 3-13 million iu per portion (Windhorst and Nigra, 1982). It provokes vomiting, drowsiness and scaling of the skin, but no skeletal signs. Chronic hypervitaminosis A, as the result of food faddism or self-administration, produces a broad spectrum of non-specific clinical symptoms (Silverman et al, 1987), mainly dermatological and neuromuscular, but also rheumatological, including arthralgias and arthritis, bone pain, hypercalcaemia and skeletal changes. The major skeletal finding in chronic vitamin A intoxication (Frame et al, 1987) is periosteal new bone formation resulting in hyperostosis of the appendicular skeleton, especially in children, in whom premature closure of the epiphyses has also been reported. These symptoms subside when the vitamin is discontinued. Diaphyseal hyperostosis may eventually disappear. Based on knowledge of chronic vitamin A toxicity, the side-effects of retinoids are predictable, including teratogenicity (Dicken, 1984; Silverman et al, 1987). INTRODUCTION TO RETINOIDS

In the search for compounds with an acceptable risk-benefit ratio, more than 1500 derivatives were synthetized from the retinol molecule and biologically tested. Three have proved fit for clinical use (Figure 1). Isotretinoin (13-cis-retinoic acid), available under the name of Accutane or Roaccutane, Baillibre' s Clinical Rheumatology--

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was obtained by changingthe polar end group of retinol, and belongs to the first generation of retinoids. Its bioavailabilityfollowingoral administration is 25%, it is not stored in the tissues and the elimination half-lifeis 29 hours (Orfanos et al, 1987). Etretinate (Tegison or Tigason) is a secondgeneration retinoid, obtained by manipulation of the cyclic end of the molecule. Its bioavailability is better, being more than 40% after a single

~

CH2OH

Vitamin A (retinol)

~COOH lsotretinoin (13-cis-retinoic acid)

CH3OH~

C

O

O

C

2

H

5

Ertenitae t C

H

3

0

~

Acitretin Figure I. Structural configuration of the principal retinoids.

COOH

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oral dose, but etretinate has a major drawback: this lipophilic molecule is stored mainly in the subcutaneous fat, with a very slow release. After discontinuation of therapy, small quantities of etretinate are still detected in the circulation 6 to 12 months later (Orfanos et al, 1987), and perhaps even after 2 years, during which time the teratogenic risk persists. Acitretin (Ro 10-1670, NeoTigason or Soriatane) is a major metabolite of etretinate. Its principal advantage is its faster elimination; there is no tissue storage of hydrophilic acitretin, and after a long administration its elimination half-life is 2 to 3 days (Orfanos et al, 1987), but the teratogenic risk is still under scrutiny. The two compounds seem equally active, but no comparison of their side-effects is available. Owing to the known side-effects of etretinate, skeletal problems due to acitretin cannot be excluded. Arotinoids, retinoids of third generation, are under investigation. The biological activity of retinoids is mainly an inhibitory effect on cell proliferation and differentiation, particularly in keratinizing epithelia. They also inhibit sebum production, exert an immunomodulatory effect on both humoral and cellular immunity and have an anti-inflammatory activity by interfering with the arachidonic sequence (Dicken, 1984; Orfanos et al, 1987). There is some evidence that they exert their influence at the level of the nuclear DNA (Boyd, 1989). Isotretinoin is the drug of choice in the treatment of severe acne and related disorders (Perry and McEvoy, 1983). The principal indication for etretinate is pustular and erythrodermic psoriasis, but it is also effective in plaque psoriasis and palmoplantar pustulosis (Ellis and Voorhees, 1987). It has been tested in psoriatic arthritis with significant improvement (Klinkhoff et al, 1989). Etretinate is more active than isotretinoin in congenital keratinization disorders, such as ichthyosis, and is therefore prescribed to children for long periods. Both derivatives have proved beneficial in the treatment of benign or malignant cutaneous neoplasias. Table 1. The different rheumatoid symptoms associated with administration of retinoids. Skeletal symptoms Hyperostosis of the spine Hyperostosis of the appendicular bone Premature epiphyseal closure Slender long bones Osteoporosis Spontaneous fractures Calcium metabolism Hypercalcaemia Hypercalciuria Other rheumatic symptoms Musculoskeletal pain Arthralgias Arthritis Muscle damage Muscle hypertonia Necrotizing vasculitis Wegener's granulomatosis

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Besides musculoskeletal side-effects (Table 1), the adverse effects of retinoids are numerous (Windhorst and Nigra, 1982; Yob and Pochi, 1987; Bigby and Stern, 1988; Boyd, 1989). By far, mucocutaneous reactions are the most frequently encountered and are almost inescapable. Serum lipids, particularly triglycerides, are elevated in half of the patients, with a risk of acute pancreatitis if they rise to over 800mg/dl; cholesterol rises over 300mg/dl in 20% of patients. Hepatotoxicity has been reported witl) etretinate. Teratogenicity is of great concern: half of the infants born after exposure to retinoids during the mother's pregnancy were malformed, whatever the dose. Dosage recommendations for isotretinoin is 1 mg/kg daily for 2-3 months, then half this dose for the same time. The mean daily dose of etretinate is 0.5 mg/kg for several months, with the possibility of high initial doses over 1 mg/kg (Orfanos et al, 1987). These dosages may be exceeded depending on the clinical status or response to treatment. In as far as non-steroidal anti-inflammatory drugs and antimalarial drugs may exert an unfavourable influence on the process underlying psoriasis, their combination with etretinate may not be appropriate. Dermatologists do not agree on the safety of concomitant administration of etretinate and methotrexate; considered to be harmless under close monitoring for hepatic toxicity by Orfanos et al (1987), it is not recommended by Ellis and Voorhees (1987), who prefer a switch from one drug to the other if needed. BONE LESIONS DUE TO RETINOIDS

The usual bone lesion observed during chronic vitamin A intoxication is hyperostosis of the appendicular bone. A unique case of axial involvement was reported in 1954 by Gerber et al, in a woman after 8 years of treatment with vitamin A. Experiments in animals suggested the possibility of vertebral lesions. Seawright et al (1965), in cats fed with bovine liver containing abnormal quantities of vitamin A (up to 600 ~xg/g), described exostoses mainly confined to the cervical spine and the forelimb. In 1983, Pittsley and Yoder reported the first cases of vertebral hyperostosis related to retinoid oral administration. Since then, it is considered as the hallmark of retinoid skeletal side-effect, together with peripheral bone involvement. This vertebral hyperostosis resembles diffuse idiopathic skeletal hyperostosis (DISH); the connections between the two will be considered later. Bone lesions due to isotretinoin

The initial publication by Pittsley and Yoder (1983) is impressive: two patients treated with high doses of isotretinoin for 2 years developed an ankylosing hyperostosis of the spine, with disabling musculoskeletal pain and limitation of movement of the rachis. Widespread appendicular bone ossifications were discovered in both patients. A prospective study of bone lesions due to long-term administration of isotretinoin was undertaken by a joint team of radiologists and dermato-

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logists from the Ann Arbor Medical Centers, Michigan, USA (Ellis et al, 1984b, 1988; Pennes et al, 1984, 1988). Eight patients with diseases of keratinization, initially aged 5 to 26, received isotretinoin at a dosage ranging from 1.0 to 2.9mg/kg daily. Skeletal radiological surveys were performed before treatment and at 6 months, then at 1 year intervals after the start of therapy. Early lesions were observed at the end of the first year: six of the eight patients had developed significant skeletal hyperostosis. Subtle modifications were already demonstrable at the sixth month. All six patients had axial involvement: five in the cervical spine, with the thoracic and the lumbar segments also being affected in one case each. One case had only thoracic vertebra hyperostosis. The hyperostoses were situated at the corners of vertebra. They consisted in point-like or conical calcifications. Together with the vertebral lesions, two patients had bilateral and symmetric exostosis of the feet, and one a small hyperostose of the elbow. None had any clinical complaints. During the following years, the lesions spread and worsened, in spite of reduction of the dosage down to 1 mg/kg daily after the third year. By the end of the follow-up period (4-6 years), all six patients had involvement of the spine and the appendicular bones: the earliest lesions were the largest and the most developed. In the cervical spine, the tiny ossifications of the anterior vertebral ligament matured into corticated bony excrescences, resembling osteophytes. Two patients had also ossification of the posterior longitudinal ligament without cord compression (Pennes et al, 1985). In one case the same ossification was present at the lumbar level. The thoracic spine was involved later, but by the end of the follow-up, all six patients had thoracic lesions. The ossifications were osteophyte-like or extending and bridging over several levels as seen in DISH. The hyperostosis involved costovertebral articulations in two patients. The findings in the lumbar spine were minimal, even after 6 years, consisting of tiny calcifications pointing in the margin of the vertebra. Only one patient had ossifications of the sacroiliac ventral ligaments. In the appendicular bone, the ossifications appeared later, and were minimal, usually asymmetric or unilateral; they were found at the olecranon process of the elbow, or the acromion process of the shoulder. Tiny ossifications developed around the hip. Involvement of the feet was more prominent: it appeared earlier and four patients were affected at the end of the fourth year. Exostoses occurred at the insertion of the gastrocnemius tendon and the plantar fascia of the calcaneum, and were asymmetrical in size. It is noteworthy that, although the patients complained of vague musculoskeletal pain, it correlated poorly with the exostoses, which could be considered to be asymptomatic. There was no relation between the development of the ossification and the age of the patients, or the daily or cumulative dosage. At the time of the last publication, no patient had yet discontinued the treatment: the authors presumed that the bone lesions were permanent and would not regress after cessation of therapy (Pennes et al, 1988). These studies by Pennes et al (1984, 1988) and by Ellis et al (1984, 1988) deal with a small number of patients, treated over a long time with high dosages of isotretinoin for severe diseases of keratinization. Under these conditions, other studies yield similar results. Gross et al (1985) found bone

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spurring in nine out of 11 patients (82%), the area of greatest involvement being the lower cervical and mid-thoracic spine. Di Giovanna et al (1987) focused on extraspinal calcifications; 11 out of 12 (92%) patients treated over 8 years had appendicular calcifications, involving ankle, pelvis, knee and shoulder. Ten out of 12 patients also had axial ossifications bridging at least two vertebral bodies. While patients with extensive involvement tended to have symptoms of stiffness and decreased range of movement, many of them denied any musculoskeletal symptoms. Among the 13 patients of Lawson and McGuire (1987), nine had formation of osteophytes, particularly in the cervical spine; ossifications in the suboccipital area were also found. This side-effect of isotretinoin still occurs but is less important when it is prescribed in a lower dosage for a shorter time, for instance in the treatment of severe acne. Carey et al (1988) studied 120 patients treated with 0.5 mg/kg daily for 4 months. Twelve per cent showed minor changes in the thoracic or lumbar spine, and in the tendon insertions on the calcaneum. Eleven patients were followed up: slight deterioration occurred in one, six improved and no change was seen in six. Carey et al (1988) conclude that, in these conditions, isotretinoin did not produce any significant long-term musculoskeletal change. But, unfortunately, they did not radiograph the cervical spine. Among 96 patients treated for acne with 1-2 mg/kg daily for 4-5 months, 26% had small bony spurs arising at the anterior margin of one or more vertebral bodies within 21/a years after the end of the treatment (Denman et al, 1985; Kilcoyne, 1988). Other bone lesions have been reported with isotretinoin. Of special interest is the observation of bilateral nasal bone osteophytosis in a woman who had undergone rhinoplasty and was treated 12 years later with low doses of isotretinoin. After discontinuation of treatment the new nasal bones were removed; they were made out of trabeculae of lamellar bone, covered by periosteal soft tissue. Under polarization, the osteoid seams were characteristic of mature lamellar bone (Novick et al, 1984). This observation can be considered as a clue to the nature of isotretinoin hyperostosis, which is made of regular lamellar bone. Seven patients (out of 11) were noted to have a general decrease of bone density on X-ray, but densitometry was not performed to confirm or refute the presence of osteoporosis (Lawson and McGuire, 1987). Bone lesions due to etretinate

In the main indications for etretinate--psoriasis and diseases of keratinization--the administration of the drug must be protracted. Therefore, very few available studies deal with bone side-effects in short-term treatment. Eight patients who received medium range doses for 6 to 18 months failed to exhibit any significant skeletal abnormality (Gilbert et al, 1986). In a 52year-old man, after treatment for 6 months discontinued because of severe metabolic side-effects, clinical symptoms of lumbar stenosis revealed the rapid and frank worsening of a pre-existing lumbar idiopathic hyperostosis (Bennet et al, 1985).

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Long-term administration of etretinate may be responsible for spinal hyperostosis. An extensive form, quite indistinguishable from DISH, has been observed in some patients (Burge and Ryan, 1985; Hans et al, 1988; Archer et al, 1989). Usually, the lesions are milder: 13 of 18 patients (72%) followed for 4 years had small spinal calcifications (Archer et al, 1987). In a retrospective survey of 90 patients, with a mean treatment duration of 2.4 years, 14 (15%) had hyperostosis located in the cervical, thoracic and lumbar spine (Halkier-Sorensen and Andresen, 1989). As with isotretinoin, calcification of the posterior longitudinal ligament has been reported with etretinate at the cervical level (Tosti et al, 1987). In one case its location at the thoracic level was responsible for spinal cord compression; extensive hyperostoses from the laminae and the facet joints compressing the cord were removed at laminectomy, leading to a fair clinical improvement (TfeltHansen et al, 1989). The most frequent lesions associated with long-term etretinate administration are extraspinal calcifications of tendons and ligaments. Di Giovanna et al (1986) screened prospectively 38 patients treated for psoriasis or diseases of keratinization with etretinate (mean dose 0.8 mg/kg daily) for an average duration of 60 months; 32 (84%) had radiographic evidence of extraspinal calcifications. The involvement was usually bilateral, and symmetrical in location and shape. More than one site was involved in 69% of the affected patients. The ankle (plantar aponeurosis and Achilles tendon) was the most commonly affected area (76 %), then the pelvis (53 % ), the knee, above and below the patella (42%) and, last, the shoulder and elbow. Most patients had no clinical symptoms correlated to the presence of calcifications. Besides appendicular bone, spine was involved in 29% of the patients of the total group, with at least a bony bridge between two vertebrae. All these figures were significant when compared with control groups. Extraspinal calcifications have been reported by others, the principal location being the calcanea and the pelvis (Melnik et al, 1987; Wilson et al, 1988; Wendling et al, 1990). Two locations deserve special interest. Firstly, periarticular calcifications of the hips are responsible for local pain and limitation of movement; the calcifications are usually bilateral and extensive, they rapidly arise around the capsule of the hip, at the anterosuperior margin of the acetabulum (Figure 2) and the ligamenta teres, they are associated with spinal involvement and have been described mostly in patients with psoriasis, after several months of treatment with a mediumrange dose of etretinate (Cerio et al, 1987; Martin et al, 1989; Wendling et al, 1990; L. Simon et al, personal communication). Secondly, bilateral ossification of the interosseous membrane of the forearm seems quite specific to etretinate, whatever the skin disease. The patients complain of limitation of pronation and supination, local pain, or pain in the wrist resulting from interosseous nerve compression. X-rays reveal thickening of the cortices of the radius and ulna at the attachment of the interosseous membrane, bony spicules growing from the bones into the membrane. Complete bridging between the two bones has also been described. Technetium scintigraphy shows a local increase in activity, which returns to normal after stopping therapy. These ossifications, always bilateral, may be

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(a)

(b)

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(c) Figure 2. Ossifications in a patient treated with etretinate. This 58-year-old patient with psoriatic arthritis had been treated with etretinate for 30 months (0.6mg/kg daily; total dose 30g). Occurrence of pain and limitation of movement in the hips improved after discontinuation of treatment. These X-rays show enthesopathies of the hip and the spine that did not exist when the treatment was started. (a) Paravertebral ossification. (b) Bilateral ossifications of the margin of the acetabula. (e) Computed tomography of the hip, showing calcification of the acetabulum and capsule. With kind permission of Prof. L. Simon.

isolated or part of a diffuse hyperostosis (Smitt and De Mari, 1984; Guit et al, 1986; Dodd et al, 1988; Wilson et al, 1988; Krause et al, 1989). The hyperostosis of etretinate seems to be independent of the total dose or total duration of treatment, but the longer the treatment, the more widespread and prominent the lesions. Other skeletal lesions have been reported: periosteal thickening of the ulna and fibular, disc degeneration, osteoporosis (without densitometry) and slender long bones (Halkier-Sorensen and Andresen, 1989). Bone toxicity of acitretin

One report of the skeletal side-effects of acitretin is available (Kilcoyne, 1988). [n this study, 241 patients had been treated for psoriasis with acitretin for 6 months. Some had DISH or age-related vertebral pathology, and 5% of them showed radiological progression of their abnormalities, Skeletal toxicity of retinoids in children

Growth retardation and premature closure of epiphyseal plates have been associated with chronic hypervitaminosis A in children (Pease, 1962). That is why the consequences of retinoid administration for the child skeleton are of great concern. Despite careful screening and radiological surveys, only five cases of premature epiphyseal closure have been reported, a very low

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figure in comparison with the number of treated children (Milstone et al, 1982; Prendiville et al, 1986; Marini et al, 1988; Cuny et al, 1989). It occurs with long-term treatment (median 5 years) or with a very high dose, and with either isotretinoin (2 cases) or etretinate (3 cases). It was detected by routine radiographic skeletal survey, but with isotretinoin, some children complained of local pain on movement. Radiographic examinations demonstrated dense metaphyseal bands at the level of the zone of provisional calcification, and asymmetric closure of the epiphyses of the tibiae, femurs or elbows. These changes, often unilateral, involved a knee (2 cases), an ankle (1 case), the two elbows (1 case), and were widespread in the last case, resulting in growth arrest and small stature. Discontinuance of therapy was followed by a gradual decrease in the metaphyseal bands and resumption of clinical growth (Marini et al, 1988). The toxicity of retinoic acid can be explained by its action as a modulator of chondrocyte phenotype and gene expression (Marini et al, 1988). In culture, the synthesis of type II collagen and cartilage-specific proteoglycan is suppressed; there is no induction of type I collagen (Benya and Padilla, 1986). Marini et al (1988) suggested that the metaphyseal chondrocyte dysfunction due to retinoic acid produces an abnormal matrix which is not well resorbed. To detect early epiphyseal changes, the performance of a baseline radiographic skeletal survey followed by X-ray examination of the long bone epiphyses at yearly intervals for the duration of treatment is recommended (Prendiville et al, 1986). The most important precaution to take to avoid skeletal toxicity is the use of the lowest maintenance dose level for the shortest possible time in children requiring retinoids. As for other bone abnormalities, isotretinoin is a cause of hyperostosis in children as well as in adults; five of the eight patients reported by Ellis et al (1984a) were under 15 when the treatment with isotretinoin was started. Three children out of 14 treated with isotretinoin had abnormal bone modelling in the femur and the tibia, consisting of narrowing of the diaphysis and flaring of the metaphysis (Lawson and McGuire, 1987). Etretinate seems less toxic: there is no clear evidence of spinal or extraspinal calcifications in children on etretinate, except for a 14-year-old patient with bilateral ossification of the interosseous membrane of the forearm (Smitt and De Marl, 1984). Nineteen young patients on long-term treatment with this drug were screened by scintigraphy and X-rays and did not show any abnormalities (Glover et al, 1987). Halkier-Sorensen and Andresen (1988) performed radiographic surveys at various stages during or after treatment with etretinate in ten children (mean age 10.8 years) with disorders of keratinization. In eight affected children they found periosteal thickening (6 cases), periosteal bone resorption (2 cases), osteoporosis (2 cases), disc narrowing (3 cases), and slender long bones and obvious risk of spontaneous fractures (1 case). Compared with age- and sex-matched normal controls, the children had a decrease in the total width and marrow cavity width of the second left metacarpal bone. As two spontaneous fractures have been observed in a child with radiological osteopenia (Prendiville et al, 1986), one must be aware of the possibility of bone fragility induced by retinoids in children (Glover and Atherton, 1987).

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Screening for bone lesions in retinoid-treated patients Detection of hyperostosis, both axial and appendicular, relies on two methods: technetium scintigraphy and radiological survey. Technetium scintiscans have been done in symptomatic patients. Local abnormal isotope uptake was present in patients with ossification of the interosseous membrane of the forearm. A patient who complained of diffuse musculoskeletal pain had multiple sites of hyperfixation; the radiographs were initially normal, but hyperostoses appeared on these very sites 3 years later (Hans et al, 1988). In two other cases, abnormal isotope uptake was coincident with radiological hyperostoses, especially around the hip (Martin et al, 1989); the fixation faded when etretinate was stopped (Wendling et al, 1990). Technetium scintigraphy has been used for systematic screening of patients receiving etretinate (Wilson et al, 1988). There was an important discrepancy between isotope uptake, musculoskeletal complaints and X-rays: several sites of hyperfixation did not correlate with any radiological abnormality. Whole body scintiscans were used in children treated with etretinate, and failed to reveal any pathological fixation (Glover et al, 1987). T6r~k et al (1989) observed slightly increased uptakes in patients with etretinate or isotretinoin, but no radiographs were available. Thus, scintigraphy may be useful to investigate a symptomatic patient, but it cannot be relied on for regular screening of patients under treatment (Wilson et al, 1988). Periodical X-rays have been used to detect axial and appendicular hyperostosis; in prospective studies, multiple radiographs have been taken of the cervical, thoracic and lumbar spine, and of the pelvis, knees, ankles and forearms, before starting the treatment, then at yearly intervals. This method is too costly and too hazardous to be recommended for all patients. Since the commonest locations of hyperostosis are the cervical and thoracic spine and the calcanea, monitoring of patients taking retinoids should be restricted to annual lateral films of these areas, or at least of the ankle (Ellis and Voorhees, 1987). Additional film should be taken of any symptomatic site. Interpretation by an expert radiologist should be mandatory. In children, the sensitivity of technetium bone scanning for assessment of early abnormalities of the growth plates is a moot point (Prendiville et al, 1986; Glover et al, 1987). Prendiville et al (1986) recommends X-ray examination of the long bone epiphyses at yearly intervals for the duration of treatment. One must keep in mind that premature epiphyseal closure is excessively rare. Retinoids and calcium metabolism Hypervitaminosis A is known to be associated with hypercalcaemia (Katz and Tzagournis, 1972; Frame et al, 1974). Because of the structural similarity of retinoids, one could be anxious about abnormalities in calcium metabolism induced by these drugs. In many studies, parameters of calcium metabolism were sharply scrutinized: no abnormality has ever been detected in blood calcium, phosphorus, alkaline phosphatase, vitamin D and its metabolites, parathormone and urinary excretion of calcium, with two exceptions:

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1.

Hypercalcaemia was found in a 19-year-old man who had been taking isotretinoin for 10 weeks, at 0.9 mg/kg daily for the first month, then at 1.6mg/kg daily. The serum calcium level reached a peak value of 12.3 mg/dl and returned to normal within 36 hours after cessation of therapy (Valentic et al, 1983). Two patients with psoriasis and receiving long-term etretinate had significantly elevated 24-hour urinary calcium levels (Wilson et al, 1988).

2.

Save for these three cases, retinoids have not been shown to have an adverse effect on calcium metabolism. Discussion

Isotretinoin as well as etretinate are responsible for skeletal side-effects, mainly hyperostosis. This affects the axial skeleton, and prevails in the cervical and thoracic spine. Usually mild, the hyperostoses are tiny, pointing ossifications at the edge of the vertebra. But they can develop as osteophytes, bridging over more than three vertebral bodies, and the widespread calcification of the common anterior vertebral ligament has been reported, resulting in ankylosis of the spine. Limitation of movement is the only clinical symptom referred to by the patients. Appendicular bone hyperostosis frequently accompanies the spinal involvement. The commonest location is the foot, especially the calcaneum, then the pelvis, the knee, and less often the elbow and shoulder. The hyperostoses start at the bone insertion of a tendon, for instance the Achilles tendon or the plantar aponeurosis, and thus it can be considered as an enthesopathy. Peripheral hyperostosis is asymptomatic. Other bone side-effects are uncommon. Premature epiphyseal closure in children is very rare, and augmentation of bone transparency on radiographs has been considered as osteoporosis, but never confirmed by a reliable absorptiometry. On the whole, the adverse reactions of retinoids on bone are benign. We do not know about the long-term evolution of bone lesions when the treatment is stopped: most arguments are in favour of irreversibility (White and MacKie, 1989). It seems also that the enthesopathies may progress in spite of discontinuation of etretinate, which is stored in the tissue for several months. Several aetiological factors can be considered. The adverse effects are partially dose- and time-related. With short treatments and low doses, the incidence of vertebral abnormalities does not differ significantly from ageand sex-matched controls (Gerber et al, 1984). But incidence is very high and statistically significant (more than 80% of the cases) with high dosages and long-term administration. Location of the hyperostosis slightly differs, depending on the drug: axial involvement is more common with isotretinoin, while appendicular hyperostosis is more often caused by etretinate. As for the patient background, age does not seem to play a role, nor does the HLA-B27 status: in DiGiovanna's study (DiGiovanna et al, 1987), among eight patients with peripheral hyperostosis who were typed for HLA-B27, only one was positive. The underlying dermatological conditions may be congenital diseases of keratinization, which are never associated with skeletal abhor-

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malities. However, retinoids are also widely used for diseases like acne and palmoplantar pustulosis, which can be responsible for hyperostosis: for example, the SAPHO syndrome includes synovitis, hyperostosis and osteitis in association with ache and pustulosis (Chamot et al, 1987). In such cases the hyperostosis is different: the location is axial, involving the anterior thorax and the vertebra, the process is osseous, resulting in hypertrophy and condensation of the bone (rib, clavicle or vertebra), and there is no enthesopathy. Patients with psoriasis are prone to bony proliferation, which occurs at sites where tendons and ligaments insert on bone, especially the calcaneum and the pelvis; in the spine, besides the p aravertebral ossification, extensive proliferation occurs all along the anterior surface of the cervical spine (Resnick and Niwayama, 1981). These lesions are in some way similar to those initiated by retinoids, but the hyperostosis of psoriatic patients treated with etretinate seems to be related to the drug rather than the disease for the following reasons: it occurs in patients without psoriatic arthritis, it grows and matures very fast, and it is more widespread than in psoriasis. Nevertheless, it is not impossible that retinoid-induced hyperostosis might be more prominent in patients already prone to bony proliferation; for instance, it is noteworthy that the hyperostoses round the hip occur quite exclusively in psoriatic patients, and we have also quoted the case of a patient whose lumbar localization of DISH dramatically worsened after a short treatment with etretinate (Bennet et al, 1985). The radiological similarities between retinoid-induced hyperostosis and DISH have been underlined by most of the reports. The lesions of the spine in DISH are made of flowing calcifications and ossifications; at least four contiguous vertebral bodies must be involved (Resnick and Niwayama, 1981). It can spread more widely, there is no disc narrowing in the involved area, and sacroiliac joint disease and apophyseal joint bony ankylosis are absent. The appendicular bone involvement of DISH is a genuine enthesopathy, and it occurs in the same locations as retinoid hyperostosis--the foot, pelvis and shoulder. Involvement of the hip is less frequent and less severe. DISH is generally asymptomatic, except for limitation of movement. There are slight differences between the two diseases: retinoid hyperostoses predominate in the cervical spine, whereas DISH occurs mainly in the thoracic level, and DISH is usually asymmetric, being more prominent on the right side of the column. It is uncommon in young people, and there is an increasing incidence with age. It is more frequent in males. But both diseases are so alike that these differences seem to be a matter of aetiology rather than of pathogenesis. Several clues are in favour of a linked pathogenesis for DISH and retinoid hyperostosis. We have already focused on animal pathology, and on the cervical spine hyperostosis in cats fed with a diet rich in vitamin A. A raised blood level of vitamin A has been reported in patients with DISH. Arlet et al (1983) compared the level of vitamin A and 13-carotene in the blood of two groups of patients: one group with DISH and a control group. The blood level of vitamin A was higher in DISH patients than in controls, whereas the level of 13-carotene was reduced. In another study, 23 patients had an elevation of vitamin A in the blood (about 20%), but the retinol-binding protein (RBP) level was not modified, explaining the

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high retinol/RBP ratio (Abiteboul and Arlet, 1985). A high free vitamin A fraction in the plasma of DISH patients may perhaps be responsible for their bone lesions. In the same way, a high level of retinoid in the plasma of treated patients may be the cause of hyperostosis. But whatever the pathogenic linkage, the mechanism of action of vitamin A and retinoids on bone remains unknown or merely speculative. OTHER RHEUMATIC SYNDROMES Musculoskeletal pain and arthralgias

These side-effects are common and occur in approximately 20% of patients (Auffret and Binet, 1986). The symptoms are more frequent with isotretinoin, and affect rather older patients. The muscular pain involves mainly the upper trunk, middle and lower part of the spine, and the muscles of the legs (Orfanos et al, 1987). It is sometimes related to hyperostosis. Transient arthralgia is present in about 16% of the patients treated with isotretinoin (Matsuoka et al, 1984; Camisa, 1986). Usually mild, the symptoms may disappear even if the treatment is continued (Orfanos et al, 1987). However, in rare cases the musculoskeletal pain is generalized, severe and disabling (Pittsley and Yoder, 1983), requiring discontinuation of treatment, which leads to prompt improvement of the symptoms (Papasavvas et al, 1987). Arthritis

Arthritis is uncommon and only three cases of acute, aseptic arthritis in patients receiving isotretinoin for acne have been reported in the literature (Matsuoka et al, 1984; Camisa, 1986). They developed between the third week and third month of therapy, in the knee or ankle. A non-inflammatory synovial fluid was present in one case. Articular swelling and effusion resolved without sequelae in a few days under non-steroidal antiinflammatory treatment, and the isotretinoin was either continued or not. One case of chondrocostal arthritis (Tietze's syndrome) was reported (Grob and Bonerandi, 1986) in a 17-year-old patient with cystic ache, 6 weeks after initiation of isotretinoin at a dosage of 1 mg/kg daily. The swelling of the two involved joints disappeared with discontinuation of the drug and administration of a non-steroidal anti-inflammatory agent. The role of retinoids in arthritis is debatable since severe ache is associated with inflammatory arthropathy (Kaplan et al, 1983), but imputation was thought to be plausible; in the case reported by Camisa (1986), rechallenge with isotretinoin resulted in a relapse of the arthritis. Retinoid-induced skeletal muscle damage

Isotretinoin and etretinate induce reversible clinical and electromyographic signs of muscle injury (Hodak et al, 1986, 1987). Patients complain of muscle pain and tenderness on palpation of thighs, shoulders and arms; moderate weakness of the shoulder and pelvic girdle musculature can be observed.

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These muscular signs take place a few days after starting treatment with isotretinoin (0.5 mg/kg daily), but they appear later, between the third and seventh month, when etretinate is given (mean dosage 0.7 mg/kg daily). Serum creatine kinase and aldolase levels are raised in most cases. Electromyographic study shows a non-specific myopathy, mainly in the proximal muscles. A biopsy sample of deltoid muscle in a patient treated with isotretinoin showed slight variations in the size of muscle fibres; elongated, elliptical, non-membrane bound bodies between the muscle fibrils were seen using electron microscopy (Hodak et al, 1986). In patients treated with etretinate, light microscopy of a biopsy sample of the quadriceps showed loss of striation with homogenization of all cytoplasmic elements and enhanced eosinophilia in a few segments of several muscle fibres, without any inflammatory reaction (Hodak et al, 1987). Withdrawal of the drug leads to normalization of muscle enzyme activities in 3-4 days, and clinical recovery in the next few weeks. Severe myalgias associated with muscle spasms have been reported after a few days of treatment with isotretinoin (Huston and Mules, 1985). The erythrocyte sedimentation rate was increased, but creatine kinase activity was not. Symptoms improved with discontinuation of the drug and nonsteroidal anti-inflammatory treatment. With etretinate, a syndrome of axial muscle rigidity has been described in three patients (Ellis et al, 1986; Albin et al, 1988). Within 2-3 months after the initiation of etretinate therapy with doses ranging from 0.5 to 1 mg/kg daily, the patients noted painless muscle stiffness involving their back, neck and proximal lower extremities. On physical examination, tone was increased in the thighs and had a plastic quality. The paraspinal muscles were firm. Gait was broad-based, slow and the patients had a stooped posture. Extension of the neck, anteflexion of the waist and lateral flexion of both were limited. Electromyography revealed persistent activation of motor units during attempted relaxation. A percutaneous femoral nerve block extinguished the lower extremity rigidity in one patient. The stiffness symptoms remitted when the dose was reduced or discontinued and worsened with each new course of etretinate, but persistence of symptoms and findings 2 years after discontinuation of etretinate was observed in one case (perhaps due to the low rate of elimination of the drug). Levodopa improved the clinical status (Albin et al, 1988). This syndrome differs from the stiff-man syndrome in that intermittent spasms are absent, the extremities are spared, the patients have a stooped posture and the electromyographical abnormality is restricted to an abnormal relaxation pattern. The lack of other abnormalities on electroneuromyography and the results of the peripheral nerve block argue against a muscle disease and are in favour of a neurogenic process involving the central nervous system (Albin et al, 1988). The symptomatic relief obtained with levodopa suggests a deficiency of dopamine or another catecholamine. Vasculitis and retinoids

Erythema nodosum and acne fulminans (including severe ulcerating cystic

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acne, fever and arthralgia) have been reported to be triggered 3 weeks after starting isotretinoin (1 mg/kg daily) in two patients with acne (Kellet et al, 2985). Evidence of circulating immune complexes was demonstrated in these two patients. In both cases, symptoms responded to prednisolone (25-30 mg daily) and the level of circulating immune complexes returned to normal values within 4 weeks. Isotretinoin was continued at the same dosage and achieved excellent results in 3-4 months. This syndrome may have been a manifestation of leukocytoclastic vasculitis (Dwyer et al, 1989). Leukocytoclastic vasculitis has been associated with retinoid therapy, and most of the cases have been reviewed by Dwyer et al (1989). Six patients were taking isotretinoin (Epstein et al, 1987; Dwyer et al, 2989; Reynolds et al, 1989) and three etretinate (Dwyer et al, 2989; Harrison, 1989). The vasculitis developed while the patients were receiving isotretinoin (mean dosage 50 mg daily) for a mean duration of 89 days (range 45 to 133 days), but one case occurred within 6 weeks after completion of treatment (Reynolds et al, 1989). The dose and duration of treatment with etretinate seemed to be lower. The course and severity of the vasculitis were variable. The patients complained of fever, myalgia, arthralgia and purpura, and the vasculitis may involve the skin, gut, kidneys and lungs. The cutaneous rash was extensive. Involvement of the gut was very frequently responsible for generalized abdominal pain, haematemesis and rectal bleeding. Urine analysis showed proteinuria and haematuria in half of the cases. One patient had pulmonary lesions, but no details are available. Skin biopsy demonstrated leukocytoclastic vasculitis, with deposits of vascular immunoglobulin A and C3 seen using immunofluorescence (Dwyer et al, 1989). In one case, muscle biopsy demonstrated a necrotizing vasculitis with fibrinoid necrosis affecting the small arteries (Reynolds et al, 1989). Cessation of etretinate was associated with improvement of the vasculitis in one case (Harrison, 1989). In the other cases, high dosages of prednisone were prescribed, and usually cyclophosphamide had to be added to control the signs (Epstein et al, 1987; Dwyer et al, 1989; Reynolds et al, 1989). Wegener's granulomatosis has been reported in association with isotretinoin treatment in three patients with acne (Scully et al, 1986; Epstein et al, 1987; Dwyer et al, 1989). While taking isotretinoin (1.1 mg/kg daily) for 14 weeks, a 18-year-old patient complained of fever, cough and weight loss (Epstein et al, 1987). Examination showed otitis media, sinusitis and a right-lung infiltrate. Renal insufficiency, haematuria and proteinuria developed during the next week. A biopsy of lung tissue revealed granulomatous inflammation with focal clusters of neutrophils, irregular zones of necrosis and extensive intra-alveolar haemorrhage. Histological examination of the kidney demonstrated diffuse segmental necrotizing and crescenting glomerulonephritis involving 50% of the glomeruli. With prednisone and cyclophosphamide, the symptoms resolved gradually, except for the renal function, which deteriorated, necessitating long-term haemodialysis and a renal transplant. Another 20-year-old patient who was taking isotretinoin 0.5 and 1.1mg/kg on alternate days for 16 weeks experienced muscle aches, arthralgias, haemoptysis, diarrhoea, purpuric papules on the skin, fever and weight loss (Epstein et al, 1987). Bilateral

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perihilar infiltrates, parenchymal lung nodules and microscopic haematuria were present. The pathological findings were extensive intra-alveolar haemorrhage in the lungs, leukocytoclastic vasculitis in the skin and diffuse proliferative glomerulonephritis in the kidney. Prednisone and cyclophosphamide were able to control the symptoms. The third patient was 18 years old when he developed Wegener's granulomatosis while receiving isotretinoin 80 mg daily for 7 weeks (Scully et al, 1986). The coexistence of Wegener's granulomatosis and administration of isotretinoin may be a mere coincidence (Scully et al, 1986). One cannot rule out the possibility that the dermatoses being treated, instead of being ache, were actually ulcerative lesions of Wegener's disease (Dwyer et al, 1989). It is noteworthy that all three patients, plus two with leukocytoclastic vasculitis, had otitis media or nasal mucosal inflammation for a year before starting isotretinoin therapy, but became severely ill only when treatment was started (Dwyer et al, 1989). This finding suggests that patients with 'a stuffy nose and ears' are perhaps at risk for the development of vasculitis and should be monitored with special care for pulmonary and renal complications while receiving isotretinoin (Epstein et al, 1987). CONCLUSION Retinoids belong to a pharmaceutical class with a brilliant future: they are a basic treatment for a lot of severe skin diseases, and their astonishing efficiency can entirely change the life of a patient with an otherwise untreatable dermatosis. The musculoskeletal side-effects, which are only part of the numerous adverse reactions to these drugs, are not very severe. Most of them are asymptomatic, and when, by chance, they are the cause of clinical symptoms, they are very seldom disabling. Often a patient who experiences a musculoskeletal side-effect, should it be muscular pain, arthralgias or limitation of movement of the spine or the hip, prefers to endure it rather than stop the only medication able to suspend his agony. That is why one should quietly observe a patient taking retinoids and avoid bothering him with inopportune skeletal screenings or unjustified ominous warnings. SUMMARY

Isotretinoin and etretinate are synthetic derivatives of vitamin A widely used in the treatment of dermatological diseases, mainly those affecting keratinization. They have numerous side-effects, among which the rheumatic symptoms are not the most common or the most severe. The main skeletal adverse reaction of retinoids is hyperostosis. It mainly occurs with protracted treatments and high dosages, and its incidence may exceed 80% after a few years of administration. Hyperostosis is axial, located in the cervical and thoracic spine, and may be responsible for limitation of movement; in the appendicular bone, enthesopathies occur at the foot, pelvis, hip, and less commonly the shoulder and elbow. They are usually mild and asymptomatic.

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The radiological appearance is very similar to diffuse idiopathic skeletal hyperostosis. Isotretinoin tends to be responsible for axial involvement, etretinate for peripheral locations. The other skeletal side-effects are uncommon and include periostealproliferation, calcification of the interosseous membrane of the forearm and diffuse radiological bone hyperlucency. In children, premature epiphyseal closure is very rare. About 20% of patients complain of musculoskeletal pain and arthralgias. A few cases of true arthritis have been reported. Retinoids may be responsible for muscular damage and an abnormality of muscular tone resembling the stiff-man syndrome. Some cases of necrotizing vasculitis and three cases of Wegener's granulomatosis have been observed in patients treated with retinoids. Except for these latter arguable cases, rheumatoid syndromes due to retinoids are rather benign, and should not be an obstacle to the future development of their therapeutic utilization.

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