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Serendipity or Science; Historical Evidence Predicts Future Advances in Psoriasis Treatment
K S Leslie & N J Levell
Dermanities May 22, 2003; 1(2)
K S Leslie M.R.C.P. and N J Levell M.D.
Department of Dermatology, Norfolk & Norwich University Hospital
Colney Lane, Norwich, Norfolk. NR4 7UZ. United Kingdom
Abstract:
Most new treatments for psoriasis for more than 100 years have been discovered through serendipity and not through scientific design. Robert Willan first described psoriasis as a clinical entity almost 200 years ago1. The first scientific reference to treatment for psoriasis was made by Balmanno Squire in 1876. He described a patient who mistakenly diagnosed his own psoriasis as ring worm and used 'Goa powder' to successfully treat his psoriasis. Goa powder's active ingredient was anthralin (dithranol). By the 1950s antimetabolites were being used to treat rheumatoid arthritis and by chance patients who also had psoriasis noticed that their skin improved. This was the birth of methotrexate as a therapeutic option for psoriasis. Cyclosporin had a similar introduction when a renal transplant recipient's psoriasis melted away within a few days of starting this drug. In Japan in the 1980's researchers treating a patient for osteoporosis with vitamin D claimed they had cured his psoriasis. Topical Vitamin D analogues were quickly developed. The exception that proves the rule is the use of retinoids as it was long known that deficiency of vitamin A led to modifications to epithelial structure. Synthetic retinoids have been developed with a view to treatment of skin conditions with disordered keratinisation. Dermatology is not alone on its reliance on serendipity for treatment advancement. We contest that the art of medicine is the prime innovator for radical new therapeutic advances, whereas the science of medicine is responsible for slow incremental change.
Main Text:
Dithranol
Dithranol (anthralin) has been used for psoriasis for over a 100 years. It was originally derived from a natural product called Goa powder. The first scientific reference to its use was by Balmanno Squire in 1876. 2-3 A patient of his told him that he had used the powder to treat "ringed" psoriasis. The patient had mistook the psoriasis for ring worm. Goa powder had been used for centuries to treat fungal infections. Squire remarked on the skin irritation and skin staining. Goa powder was derived from the araroba tree which grew in the Bahia province in Brazil. The active ingredient in the powder was chrysarobine. The first related synthesised preparation anthralin was made in Germany and shown to be an effective treatment for psoriasis by Galewsky in 19164
Figure 1: 'Squame' illustration from Balmanno Squire's Book 'Photographs of Diseases of the skin' published by John Churchill and Sons, London 1865. Balmanno Squire made the first scientific reference for the use of Goa powder (the forerunner of dithranol) as a treatment for psoriasis.
Vitamin D Analogues
Topical Vitamin D analogues have been used for over a decade for psoriasis. The discovery of their usefulness as a treatment for psoriasis was by chance. Morimoto and Kumahara in 1985 described a patient whose psoriasis was 'cured' by oral administration of 1 a, 25-dihydroxyvitamin D35. They describe a 81 year old man who had been referred for treatment for osteoporosis. He was also noted to have extensive large plaque psoriasis. He was given 0.75 mg/day of 1a-hydroxyvitamin D3 orally. He was not receiving either topical or systemic treatments for psoriasis. Within 2 months his psoriasis had cleared. The same researchers published an open study in the British Journal of Dermatology a year later looking at the effects of oral and topical forms of vitamin D3 on Psoriasis6.
Figure 2: Wood engraving from Harper's Weekly 1879. Cuticura remedies have not been subject to clinical trials where as vitamin D analogues have.
Antimetabolites
Methotrexate has been used as a systemic treatment for psoriasis for about 40 years. The discovery that folate antagonists were effective treatment for psoriasis was also made by chance. Gubner et al in 1951 described a patient that was being treated with aminopterin ( closely related to methotrexate) for rheumatoid arthritis, they observed a striking remission of the patient's psoriasis7. Gubner then did a follow up study with 13 patients with psoriasis who all responded well to daily oral aminopterin, alhough all developed side effects8. Subsequently Edmundson and Guy found methotrexate to be of value for psoriasis9. The study had 24 patients treated with aminopterin and 13 treated with methotrexate. Excellent results were found in 75% of the patients and toxic effects were said to be rare.
Figure 3: Folic Acid studies in rats in a laboratory in Bethesda, Maryland, USA 1954.
Cyclosporin A
Sandoz Laboratories discovered and isolated cyclosporin A (CSA) from the soil fungi Trichoderma polysporum and cyclindrocarbon lucidum in 197310. Although CSA had only weak antibiotic activity it was found to have immunosuppressive properties. It was initially licensed for organ transplantation after successful trials in patients receiving renal allografts11. In a pilot study to investigate the effect of CSA in patients with rheumatoid arthritis, four patients with psoriatic arthritis were also treated12. All four patients had almost total clearance of their psoriasis within one week of CSA orally. The psoriatic lesions gradually returned in all patients to their previous severity about two weeks after stopping CSA. The study showed only a moderate effect of CSA when treating the patients with rheumatoid arthritis.
Figure 4: Joseph Stalin 1879-1953. Had cyclosporine A been available to treat Stalin's psoriasis, would he have been such a homicidal maniac?
Retinoids:
Animals deprived of vitamin A were shown to have modifications of the epithelial structure with increased epidermal keratinisation and squamous metaplasia of the mucous membranes13. In humans, vitamin A deficiency manifests itself with dry skin and follicular hyperkeratosis14. This observation led researchers to postulate a role for vitamin A in the pathogenesis of Darier's disease15. In 1949, Studer and Frey16 observed that sub-toxic doses of vitamin A could induce 'peeling' of the horny layer and it was then thought that it could be of use as a treatment for psoriasis. Initial therapeutic trials with mega-doses of vitamin A were found to have a slight improvement in psoriasis but unfortunately the subjects developed Hypervitaminosis A syndrome with dryness of mucous membranes, desquamation of healthy skin and neurological problems17. During the 1960's and 70's new synthetic vitamin A analogues, such as isotretinoin were found to be very effective treatment for acne. By 1975, a new aromatic retinoid, etretinate was tested in patients with psoriasis. This compound had a therapeutic index ten times more favourable that all- trans-retinoic acid and very encouraging clinical results were reported18. The use of retinoids and their development as a treatment for psoriasis is the only group that bucks the trend closer to science than serendipity.
Other Treatments
Topical corticosteroids were developed in the 1950's and were tried as treatment for many different inflammatory dermatoses. Initial results were disappointing as the early preparations of topical corticosteroids were of a low potency. In the early 1960's topical corticosteroids were being used under occlusive dressings as a treatment for psoriasis19. The subsequent development of more potent topical steroids lessened the need for occlusion. The initial use of coal tar and ultraviolet light is hidden in the past but their use was surely serendipitous.
Figure 5: Use the supreme skin remedy, Sulphide of arsenicum, M Buffords sons 1876. Not all treatments for skin diseases have stood the test of time.
Conclusions
Dermatology is not alone in its reliance on serendipity for advancement of treatments, this can broadly be said of all medical science. Surely the greatest advancement in medicine in the twentieth century was the discovery of antibiotics, that would not have occurred if Fleming had been more meticulous in laboratory cleanliness. That is not to underestimate the genius of many of medicine's forefathers but to celebrate their exploitation of serendipity. In the future should we invest in specific drug development programs or just give the money to various scientists and clinicians to allow them to satisfy their own curiosity. History would suggest that the latter option may be more rewarding!
Figure 6: Alexander Fleming 1881-1955. Inspired Genius or dirty chemist?
Acknowledgements
All figures are Courtesy of the National Library of Medicine Maryland, USA.
Conflict of interest
None
Source of Funding
None
REFERENCES
1 Willan, R. On Cutaneous Disease, Vol 1. Philadelphia 1808, Kimber and Conrad, p. 115
2 Squire B: Chrysophanic acid ointment. Pharm J & Trans 1876; 36:489-490
3 Squire B Treatment of psoriasis by an ointment of chrysophanic acid. Br Med J 1876; 2: 819-820
4 Galewsky E. Uber Cignolin, ein Ersatzpraparat des Chrysarobins. Dermatol Wochenschr 1910; 62:113-115
5 Morimoto,S & Kumahara,Y. A patient with psoriasis cured by 1α-hydroxyvitamin D3. Medical Journal of Osaka University 1985; 35: 51-54
6 Morimoto,S.,Yoshikawa,K., Kozuka,T.,Kitano,Y., Imanaka,S., Fukuo,K., Koh,E. & Kumahara, Y. An open study of vitamin D3 treatment in psoriasis vulgaris. British Journal of Dermatology 1986; 115:421-429
7 Gubner, R., August, S. & Ginsberg, V. Effect of Aminopterin in Rheumatoid Arthritis and Psoriasis. Amer J Med Sci 1951;220:176-182
8 Gubner, R. Effect of "Aminopterin" on epithelial tissues. AMA Arch Derm Syph 1951; 64: 688-699
9 Edmundson, W F & Guy, W B. Treatment of psoriasis with folic acid antagonists. AMA Arch Derm 1958; 78: 200-203
10 Borel JF. The history of cyclosporin A and its significance, in White DJG, editor. Cyclosporin A . Amsterdam, 1982, Elsevier Biomedical Press, p 5-17
11 Calne RY, White DJG, Thiru S et al. Cyclosporin A in patients receiving renal allografts from cadaveric donors. Lancet 1978; 2: 1323-1327
12 Mueller W & Herrmann B. Cyclosporin A for psoriasis. New England Journal of Medicine 1979; 301:555
13 Wolbach, S B and Howe, P R. Tissue changes following deprivation of fat soluble A-vitamin. J Exp. Med 1925; 42: 753
14 Frazier, C N and Hu, CK. Cutaneous lesions associated with a deficiency in vitamin A in Man. Arch. Intern. Med 1931; 48: 507
15 Peck, S M, Chargin, L, and Sobotka, H. Keratosis follicularis (Darier's disease), a vitamin A deficiency disease. Arch. Derm. Syph 1941; 43: 223
16 Studer, A and Frey, J R. Über hautveränderungen der ratte nach grossen oralen dosen von vitamin A. Schweiz. Med. Wochenschr 1949; 17: 382-384
17 Frey, J R and Schoch, M A. Therapeutische versuche bei psoriasis mit Vitamin A, zugleich ein Beitrag zur A-Hypervitaminose. Dermatologica 1952; 104 : 80
18 Ott, F and Bollag, W. Therapie der psoriasis mit einem oral wirksamen neuen Vitamin A-Saure-Derivat. Schweiz. Med. Wochenschr 1975; 105: 439-441
19 Stevenson, C J and Whittingham, G E. Psoriasis treated with topical fluocinolone acetonide and occlusive dressings. Br Med J 1963; 3: 1450-1451
Kieron Leslie MB BS BMedSCi MRCP is a specialist registrar in dermatology at the Norfolk & Norwich University hospital. Research interests include HIV dermatology as well as the history of medicine. When not rectifying the cutaneous abnormalities of the people of Norfolk, Kieron can be found cooking up a storm in the kitchen or singing along to recordings of Maria Callas.
Nick Levell MD FRCP MBA is a Yorkshireman working as a Consultant Dermatologist to the Norfolk and Norwich University Hospital and Senior Lecturer to the University of East Anglia in the UK. He is a member of the hospital art committee and curator of the hospital heritage collection which contains thousands of artifacts dating back to the 18th century. He is secretary and a founder member of the British Association of Dermatologists historical committee and is coordinating
the first historical symposium of this group at the BAD 2003 summer
meeting in Brighton UK.
email: kieronleslie@yahoo.com