Vertebral abnormalities associated with synthetic retinoid use

Volume 10 Number 5, Pm't 1 May, 1984

Torre' s syndrome

tumors and visceral carcinomas. Arch Dermatol 110: 917-920, I974. 22. Tschang TP, Poulos E, Ho CK, Kuo TT: Multiple sebaceous adenomas and internal malignant disease: A case report with chromosomal analysis. Hum Pathol 7:589594, 1976.

I

I

I

I

II

I

23. Warthin AS: Heredity with reference to carcinoma. Arch Intern Med 12:546-555, 1913. 24. Lynch HT, Lynch PM, Pester J, Fusaro RM: The Cancer Family syndrome. Rare cutaneous phenotypic linkage of Torre's syndrome. Arch Intern Med 141:607-611, 1981.

III

I

Vertebral abnormalities associated with synthetic retinoid use L y n n H. Gerber, M . D . , Roberta K. Helfgott, M.D., Earl G. Gross, M . D . , Jeanne E. Hicks, M . D . , Susan S. Ellenberg, Ph.D., and G a r y L. Peck, M.D. Bethesda, MD 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 spaee 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 < 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. (J A~ ACAD DERMATOL 10:817-823, 1984.)

M a j o r advances in the treatment of several skin d i s o r d e r s have been made due to use of the synFrom the Department of RehabilitationMedicine,the Departmentof Diagnostic Radiology, Clinical Center; the DermatologyBranch. and the Biometry Branch, NationalCancerInstitute, NationalInstitutes of Health. Accepted for publicationJan 23, 1984. Reprint requests to: Dr. L. H. Gerber, Chief, Departmentof Rehabilitation Medicine, National Institutes of Health, Bldg. 10, Room 5D-37, Bethesda, MD 20205.

thetic vitamin A derivatives, etretinate and isotretinoin. Therapeutic efficacy has been established in the treatment of numerous disorders of keratinization including: ichthyoses, Dafter's disease, pityriasis rubra pilaris, and psoriasis. 1,2 Isotretinoin has been shown to be particularly effective in producing prolonged remissions in recalcitrant cystic acne.'~ While the precise mechanism of action of these compounds is not clear, several mechanisms have

817

818

Journal of the American Academy of Dermatology

Gerber et al

Table I. Description of patient population Patient group

Treated Etretinate Isotretinoin Untreated BCC BCNS Controls

patients

No. M

No. F

age

KD

DD

IC

Ps

BCC

BCNS

37 13

33 7

4 6

40.8 39.8

11 0

14 0

2 5

10 0

0 4

0 4

32 14 72

18 5 47

14 9 25

62.9 55 42

0 0 0

0 0 0

0 0 0

0 0 0

32 0 0

0 14 0

Basal cell carcinoma; BCNS: basal cell nevus syndrome;DD: Darier's disease; IC: ichthyosis;KD: other keratinizingdisorders; Ps: psoriasis. BCC:

been demonstrated in in vitro systems*: enhancement of cell differentiation, stimulation of glycoprotein synthesis, b l o c k a g e of cell cycle in G1, destabilization of cell membranes, and inhibition of prostaglandin synthesis in rheumatoid synovium. 4 This latter finding has stimulated interest in the use of these drugs in the treatment of arthritic conditions, specifically rheumatoid arthritis and psoriatic arthritis? The toxicities of the synthetic retinoids are generally similar to hypervitaminosis A and primarily involve skin and mucous membranes. Elevation of triglycerides, abnormal liver function tests, pseudotumor cerebri, and teratogenicity may occur. In addition, a pattern of axial stiffness and arthralgias has been noted. In three patients, not included in this study, peripheral reversible arthritis with effusion has been observed. Axial stiffness seems to he temporally related to drug consumption, with relief o f symptoms associated with cessation of drug. In order to better characterize the etiology of the axial stiffness, a radiographic investigation of the vertebral column in patients receiving etretinate and isotretinoin for 2 or more years was undertaken. MATERIALS AND M E T H O D S All patients currently enrolled in a protocol of the Dermatology Branch of the National Cancer Institute (NC[) for the treatment of a variety of skin disorders (Darier's disease, pityriasis rubra pilaris, nonbullous congenital ichthyosiform erythroderma, lamellar ichthyosis, erythrokeratoderma variabilis, psoriasis, basal *Peck GL: Retinoidsin clinicaldermatology.Prog Dis Skin 1:227269, 1981.

ceU nevus syndrome [BCNS], and basal cell carcinoma [BCC]) and who had received 2 or more years of treatment with isotretinoin or etretinate were eligible for study. Some patients initially received isotretinoin and were then switched to etretinate. None was initially treated with etretinate and then switched to isotretinoin. We obtained cervical, thoracic, and lumbar spine films of all consenting patients who met the eligibility criteria. All patients were receiving retinoid at the time of x-ray examination. Comparison groups were assembled from NIH patients with the diagnosis of BCC and BCNS who had spine films as part of another study but who never received etretinate or isotretinoin. We did not have comparison groups available for other skin disorders. A nonsystematic selection of age- and sex-matched controls for all treated patients was made from our x-ray file room lists of patients who did not have a diagnosis of arthritis and who had spine x-ray films as part of an evaluation for other studies, None received oral retinoids. Some received x-ray examination for metastatic workup, others, for back pain. All views of the spines and sacroiliac joints, or pelvis, were reviewed by a radiologist. All x-ray films were scored for the presence of osteophyte with designation of the vertebral level (cervical, thoracic, lumbar), bony bridge, anterior spinal ligament calcification (ASLC), and disc space narrowing. We arbitrarily defined the presence of a significant abnormality in our patient population as the presence of osteophyte at two or more vertebral levels with associated anterior spinal ligament calcification (ASLC) without degenerative disc, or vacuum phenomenon at the affected level, and without joint space narrowing. The presence of bridging osteophyte (bony bridges) was noted. When osteophyte was adjacent to either joint space narrowing or disc abnormality, it was considered evidence for degenerative joint disease, was not

Volume I0 Number 5, Part 1 May, 1984

Vertebral abnormalities associated with retinoid use

819

T a b l e II. Type and numbers of affected patients Patient group (n)

Treated Etretinate (37) Isotretinoin (13) Untreated BCC (32) BCNS (14) Controls (72)

withened I

I Aver----o'

abnormality (osteophyte > 2)

No. with bony bridge

4 5

2 6

59/40.8 54/39.8

4

4 0 3

72/62.9 -51/42

0

10

affected/average age of group

T a b l e H I . Comparison of patients with BCC and BCNS receiving treatment and those not receiving treatment No. with defined

abnormalities

BCNS + BCC Treated g isotretinoin No treatment

4 4

accepted as meeting our defined criteria, and was not included in our tabulations even if ASLC was noted. Exact methods of analysis, appropriate for use with small samples, were used to compare BCC and BCNS patients with and without treatment with isotretinoin. These methods, including estimation of odds ratios, construction of confidence limits, and testing hypotheses about the odds ratios are discussed by Thomas. 6 Comparison of a/1 retinoid-treated patients with matched controls was made using the methods of Mantel and Haenszel 7 as described for the problem of small numbers by Schlesselman. 8 RESULTS There were thirty-seven patients with various skin disorders who received > 2 years of etretinate and thirteen who received > 2 years of isotretinoin. The types of skin disorders these patients have is presented in Table I. Dosage of medication varied from patient to patient. Nine patients rec e i v e d a course of isotretinoin and subsequently r e c e i v e d etretinate. None of these nine met criteria for the defined abnormality reported in this study. D o s a g e of medication varied from patient to patient. The mean maintenance dose of isotretinoin was 2 mg/kg/day, with a range of 1.0-8.2 mg/ k g / d a y with high doses used initially and lower

I I

Total in

I

group

8 46

Odds ratio = 13.1 p < 0.01

doses for subsequent courses. Mean maintenance dose of etretinate was 0.6 mg/kg/day, with a range of 0.5-1.0 mg/kg/day. Mean total dose of isotretinoin for patients with BCNS or BCC who met criteria for the defined abnormality was 150,060 mg, and it was 204,370 mg for those with BCNS or BCC who did not meet criteria for the defined abnormality. There were thirty-two patients with the diagnosis of BCC and fourteen with the diagnosis of BCNS who had never received synthetic retinoid treatment and who had complete spine x-ray films available. We were able to obtain complete spine films on seventy-two patients, none of whom had the diagnosis of arthritis, who were then matched for age and sex with patients. None had received oral retinoids. A summary of the radiographic findings in all patients, scored for presence of osteophyte, anterior spinal ligament calcification (ASLC), and bony bridge, is presented in Table II. The age of affected patients and the mean age of each group are also presented in Table II. In patients with BCC or BCNS (Table III), the age-adjusted association between treatment with

820

Journal of the American Academy of Dermatology

Gerber et al

Table IV. Comparison o f treated and untreated controls ....

All treated (isotretinoin and etretinate) Untreated, agematched controis All isotretinoin

LNol 49 72

No. with defined abnormality

91

] ...... ~ ] 10 ]

Untreated, agematched control

Odds ratio 1.4 p = ns No. of patients with symptoms (n = 17) No. of patients without symptoms (n = 33)

12 ] ...... ~ ] 17

Table V. Comparison of patients with and without symptoms of back pain and stiffness Number with defined abnormality

No. who did not meet defined criteria

5

12

4

29

Odds ratio 2,7 p = ns

4]

vals. Typical examples of radiographic changes while on medication are shown in Figs. 1 to 4. DISCUSSION

isotretinoin and presence of the vertebral abnormality was strong and highly significant (odds r a t i o = 13.1; 90% confidence limits, 2.0-119; (p < 0.O1). When all retinoid-treated patients were compared to age- and sex-matched controls, a slightly increased risk, clinically insignificant, of having the defined abnormality of osteophyte and ASLC was identified. The odds ratio was barely greater than unity, providing little evidence for increased risk. When patients who received isotretinoin were compared with their age- and sex-matched controls, the odds ratio was 2.7, which was not statistically significant (p = 0.5) (see Table IV). When all patients receiving etretinate and isotretinoin were compared with the controls, the incidence of the defined abnormality did not significantly differ. There were noteworthy differences between the two groups that were not statistically significant. Eight of the fifty treated patients and three of the seventy-two controls had bony bridges. Eight o f the fifty treated patients and four of the seventy-two controls had osteophyte at three or more contiguous vertebrae in association with ASLC. We determined the frequency with which symptoms were associated with bony abnormalities, and there was no statistically significant correlation between symptoms and the defined abnormality (Table V). Because this was not a prospective study, x-ray films are not uniformly available on all patients prior to treatment and at subsequent fixed inter-

Patients with various skin disorders (Darier's disease, psoriasis, keratinizing disorders, ichthyosis, BCC, BCNS) have been treated with oral retinoids at the NIH for the past 8 years. Their treatment regimen consists of variable duration cycles on and off retinoid, during which time disease activity and other symptoms were monitored. Back and neck stiffness, occasionally interfering with normal function, was reported by patients, and these symptoms exacerbated with time on retinoid and abated when medication was stopped. Several patients responded to anti-inflammatory medication. Several of these skin disorders are associated with either arthritis (Ps) or skeletal anomalies (BCNS). No known association between these disorders and vertebral osteophyte or ASLC exists. We were particularly careful to determine if patients with psoriasis had arthritis. None met clinical or radiographic evidence for psoriatic arthritis. The skeletal anomalies associated with BCNS do affect the axial skeleton? Congenital anomalies were not seen in the axial skeletons of patients in this study. While our controls are not " n o r m a l s , " we are assured by chart review that they did not carry a diagnosis of arthritis. We have no information about which of these patients were symptomatic but do know that many had spine series as part of a metastatic evaluation for cancer. X-ray examination was done on others because of "back p a i n . " As a result, this control population may be biased

Volume I0 Number 5, Part 1 May, 1984

Vertebral abnormalities associated with retinoid use

821

Fig. 1. Typical changes in thoracic spine seen in a 52year-old man on isotretinoin for 2 years. t o w a r d a higher frequency of radiographic back abnormalities than would be seen in an asympt o m a t i c , normal population. T h e abnormalities we observed, osteophyte, A S L C , bony bridge, without joint space narrowi n g , and disc abnormalities, resemble diffuse idiopathic skeletal hyperostosis (DISH). The dia g n o s i s of DISH is made on finding the following simultaneous radiogrphic criteria: (1)flowing ossification along the anterolateral aspect of at least f o u r contiguous vertebral bodies; (2)preservation o f the intervertebral disc space without degenerative disc disease; and (3) absence of apophyseal j o i n t ankylosis and sacroiliac erosion. Studies on the incidence of DISH in the general p o p u l a t i o n do not exist at present. In an autopsy s t u d y , the incidence was 12%. 1~ In another study o f living patients, a total age-standardized incid e n c e was 0.7% in men and 0.4% in women. ~ D I S H is a disease of the seventh decade, ~2 and the

Fig. 2. Bony bridges with intact disc spaces seen in the cervical spine in a 51-year-old man on isotretinoin for 3 years. radiographic findings are seen with increasing frequency as the population ages. 13'14 Hence, in assessing the incidence of this phenomenon in our study population, it was essential to select ageand sex-matched controls. All statistical analyses used matched pairs. Perhaps the best comparison, although the numbers are small, is that of patients with BCC and BCNS who received isotretinoin and those who did not. These patients received the highest dose of medication, 4.5 mg/kg/day of all treated. The odds of developing the defined abnormality for BCNS and BCC patients receiving isotretinoin were thirteen times those for untreated patients, a statistically significant event. In degenerative joint disease of the vertebral

822 Gerber et al

Journal of the American Academy of DermatoLogy

Fig. 3. Progression of bony bridge over 9-month period in a 61-year-old woman receiving isotretinoin.

Fig. 4. Progression of bony bridge over 9-month period in same patient as shown in Fig. 3.

column, osteophyte production occurs with or without disc disease. There does not appear to be any associated ASLC. Osteophytes take years, if not decades, to form bony bridges. Therefore, it is important to know whether our patients were well along the way to developing the radiographic changes we document prior to receiving retinoid. Because we performed a retrospective analysis, it is not possible to answer this question with data obtained from this study. We have some limited data that suggest that the process may be accelerated by the retinoids, as we have shown in Figs. 1 to 4, but we lack adequate data on the natural history of the bony bridge with which to compare our findings. The rapidity with which these findings developed and/or progressed was not evaluated in this study. We have also seen sporadic ligamentous calcification in the appen-

dicular skeleton, supporting a diffuse nature o f the hyperostosis. In our treated patients, sacroiliac joints were radiographically normal. We believe our patients are at an increased risk for developing axial hyperostosis from isotretinoin use at doses > 2 mg/kg/day for > 2 years. This study supports the observations reported by Pittsley and Yoder. TM They noted similar findings in four patients under the age of 45 who had been treated with isotretinoin for ichthyosis. While theirs was not controlled for age and sex, the fact that their patients were so young, and hence unlikely to develop skeletal hyperostosis, established the findings as significant. While several features of DISH are demonstrated in the affected population, the findings share features in common with hypervitaminosis A reported in adults, ts-t~ DISH-like findings as-

Volume 10 Number 5, Part 1 May, 1984

Vertebral abnormalities associated with retinoid use

sociated with hypervitaminosis A is a rarely rep o r t e d e v e n t , probably because headache, irritability, l i v e r toxicity, and insomnia usually limit the a m o u n t o f vitamin A ingested. In the reports of adults with hypervitaminosis A , s y m p t o m s of stiffness and tenderness upon c o m p r e s s i o n of the long bones were noted. 1~-'8 X - r a y examination of the spine revealed calcification o f ligamenta flava and calcification of the inf r a p a t e l l e r ligament of the knee and iliolumbar liga m e n t s associated with periosteal elevation along the ischial ramus. S o m e of the findings and the c o m p l a i n t s of stiffness are similar to those obs e r v e d with synthetic retinoids described in this r e p o r t . It should be noted that patients receiving oral synthetic retinoids do not have elevated levels o f v i t a m i n A. P a t i e n t s with DISH are frequently asymptomatic. Patients in this study were more frequently a s y m p t o m a t i c than symptomatic, but those who w e r e s y m p t o m a t i c noted improvement when off r e t i n o i d therapy. Symptomatology did not predict r a d i o g r a p h i c abnormalities; of those who met x - r a y criteria for bony abnormalities, five were s y m p t o m a t i c and four were not. In s u m m a r y , this study demonstrates an inc r e a s e d incidence of hyperostosis of the vertebral b o d i e s that is characterized by osteophyte, ASLC, a n d o c c a s i o n a l bony bridge in patients receiving i s o t r e t i n o i n and etretinate. Patients treated with i s o t r e t i n o i n for BCNS and BCC had statistically s i g n i f i c a n t l y more vertebral abnormalities than u n t r e a t e d patients with BCNS and BCC. The obs e r v e d abnormalities have features in common w i t h D I S H , degenerative arthritis, and hypervit a m i n o s i s A. REFERENCES

1. Peck GL, O/sen TG, Yoder FW, et al: Prolonged remissions of cystic and conglobate acne with 13 cis retinoic acid. N Engl J Med 300:329-333, 1979.

823

2. Peck GL, Yoder FW, Olsen TG, et al: Treatment of Darier's disease, lamellar ichthyosis, pityriasis rubra pilaris, cystic ache and basal cell carcinoma with oral 13 cis retinoic acid. Dermatologica 157(suppl 1):11-12, 1978. 3. Peck GL: Retinoids in dermatology: An interim report. Arch Dermatol 116:283-294, 1980. 4. Brinckerhoff CE, McMillan RM, Dayer JM, Harris ED Jr: Inhibition by retinoic acid of collagenase production in rheumatoid synovial cells. N Engl J Med 303:432436, 1980. 5. Rosenthal M: Retinoid in der Behandlung yon psoriasis-arthritis. Schweiz Med Wochenschr 109:1912-1914, 1979. 6. Thomas DG: Exact and asymptotic methods for the combination of 2x2 tables. Comput Biomed Res 8:423-446, 1975. 7. Mantel N, Haenszel W: Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 22:719-748, 1959. 8. Schlesselman JJ: Case control studies. New York, 1982, Oxford University Press. 9. Dunnick NR, Head GL, Peck GL, Yoder FW: Nevoid basal cell carcinoma syndrome: Radiographic manifestations including cyst-like lesions of the phalanges. Radiology 127:331-334, 1978. 10. Resnick D, Niwayama G: Diagnosis of bone and joint disorders. Philadelphia, 1982, W. B. Saunders Co., p. 1420. 11. Julkunen H, Knekt P, Aromata A: Spondylosis deforroans and diffuse idiopathic skeletal hyperostosis (DISH) in Finland. Scand J Rheumatol 10:193-203, 1981. 12. Forestier J, Lagier R: Ankylosing hyperostosis of the spine. Clin Orthop 74:65-83, 1971. 13. Ritchie JH, Fahrni WH: Age changes in lumbar intervertebral discs. Can J Surg 13:65-71, 1970. 14. Smith CF, Pugh DG, Polley HF: Physiologic vertebral ligamentous calcification: An aging process. Am J Roentgenol 74:1049-1058, 1955. 15. Pittsley RA, Yoder FW: Retinoid hyperostosis. Skeletal toxicity associated with long term administration of 13-cis retinoic acid for refractory ichthyosis. N Engl J Med 308:1012-1014, 1983. 16. Gerber A, Rabb AP, Sobel AE: Vitamin A poisoning in adults. Am J Med 16:729-745, 1954. 17. Bifulco E: Vitamin A intoxication. Report of a case in an adult. N Engl J Med 248:690-692, 1953. 18. Sulzberger MB, Lazar MP: Hypervitaminosis A: Report of a case in an adult. JAMA 146:788-793, 1951.