Aetiopathogenesis and Treatment of Vitiligo

THE NATIONAL MEDICAL JOURNAL OF INDIA
VOL. 8, NO.1,
3
1995
prices for pharmaceutical products, especially patented ones, are so severely
controlled that production is scarcely profitable, there will be little incentive
to engage in research and development and little money to finance it. This
then reverts to the point made earlier: the extent to which prices for patented
products will be allowed to rise above those that would prevail in a non-patent
situation is essentially related to the incentives that the government wishes
to provide for research aimed at the development of new drugs.
REFERENCES
1 GAIT secretariat. The results of the Uruguay round of multilateral trade negotiations: The legal texts.
Marrakesh agreement establishing the World Trade Organization. Geneva. June 1994.
2 Suchy H. Patentrestlaufzeit neuerer pharmazeutischer Wirkstoffe. Pharma dialog 96. Bundesverband der
Pharmazeutischen Industrie e. V .• Frankfurt. 1987.
3 Lis Y. Walker SR. The erosion of effective patent life-an international comparison. Carshalton, United
Kingdom:Centre for Medicines Research. 1989.
4 Redwood H. Pharmaceutical patent term restoration for the I990s. Felixstowe, United Kingdom:Oldwicks
Press. 1990.
5 Redwood H. New horizons in India: The consequences of pharmaceutical patent protection. Felixstowe,
United Kingdom:Oldwicks Press. 1994.
6 Operations Research Group. Drugs under patent-The Indian scenario. Bombay. 1993.
7 European Report. Brussels:Europe Information Service. 1 March 1994.
ADRIAN
OTTEN
Intellectual Property and Investment Division
General Agreement on Tariffs and Trade
Geneva
Switzerland
The author has asked that it be made explicit that this editorial was invited by
The National Medical Journal of India
Aetiopathogenesis
and Treatment of Vitiligo
Vitiligo, also known as leukoderma, is an acquired disorder characterized by
patchy progressive depigmentation of the skin. It affects 1% of the world's
population with the incidence in India ranging from 6% in Calcutta to 1.~5%
in Delhi. As there have been good reviews on this subject recently'+ where
the neural, autoimmune and free radical hypotheses were discussed, I will
only deal with areas which have been left largely uncovered, i.e. its
aetiopathogenesis and treatment.
It is generally agreed that there are no functional melanocytes in the vitiligo
maculev' but none of the many theories put forward explain the causes for
their 10SS.1-4 After methods for getting pure cultures of melanocytes from
baby foreskin and other sites became established.! attempts to study the
abnormality responsible for the premature loss or destruction of the melanocytes
were made by Purl et al.6 To do this they examined the epidermis from three
different regions of untreated vitiligo subjects, namely uninvolved skin,
perilesional skin and the vitiligo patch.
Melanocytes from uninvolved skin of untreated vitiligo subjects in culture
manifest a lag period in the onset of their growth of about 6 to 11 days while
the melanocytes from normal adult humans do not show any such lag. Also
the number of melanocytes observed 48 hours after plating 1()6 epidermal
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cells from the uninvolved area was only half the number observed after plating
the same number of cells from normal adults. This was in spite of the fact
that the melanocyte cell number in uninvolved, untreated vitiligo epidermis
was the same as that in normal humans. The melanocytes from an uninvolved
area of untreated vitiligo subjects can also not be passaged, i.e. they do not
survive detachment by trypsinization, while melanocytes from normal humans
survive many such detachments from culture dishes."
The melanocytes from perilesional areas of untreated vitiligo patients do
not grow at all in culture and show an abnormal morphology compared to
cells from an uninvolved area."
If these abnormal growth characteristics were related to the disease, one
would expect that they would be corrected once the individual was treated
successfully. In fact they were corrected using psoralens, ultraviolet A (PUV A)
therapy." That repigmentation by PUV A therapy might have been a result
of increased growth factors for melanocytes in the circulation is indicated by
the fact that serum from repigmenting vitiligo subjects increases the proliferation
rate of melanocytes from normal human beings and that the serum from
normal adults is more stimulatory to the growth of melanocytes from normal
or treated vitiligo subjects than the serum from untreated vitiligo subjects."
A new hypothesis for the aetiology of vitiligo was thus postulated, that a
deficiency of growth factor for melanocytes, locally or in the circulation could
result in their premature loss.?
It is also commonly believed that vitiligo is transmitted as an autosomal
dominant trait with incomplete penetrance. For example, in a border area of
Gujarat and Maharashtra there is a community known as Somavamsha
Sahasarjuna Kshatriya (SSK) , some of them migrated to Bangalore many
centuries ago. This community has a number of parallel relationships with
the Khatri community of South Gujarat which has a high incidence (3.6%)
of vitiligo in this country. 8 Both these communities belong to the Kshatriya
caste and work in the silk industry. The small number of SSKs in Bangalore
have been marrying within their community for centuries. At the request of
their leaders who felt that the high incidence of vitiligo should be investigated,
we took detailed histories and examined 52 cases. The onset of vitiligo in this
community was earlier than in the general population? and 47 (90%) of the
patients had close relatives with the condition." This suggests a genetic predisposition.!" Others too, in this country!' and in the USA,12 have found that
there is a familial basis for vitiligo.
These observations are further strengthened by a report that 7 twins out
of 10 genetically identical pairs were affected by vitiligo while only 1 was
affected in 11 fraternal pairs." The age of onset and in some cases the areas
of skin involved were remarkably similar in the genetically identical pairs.'?
Further evidence on the genetic predisposition for vitiligo comes from
studies on the depigmenting mouse labelled the vitlvit mouse by Lerner. 14
This is one of the most promising animal models for human vitiligo, and it
has been found that the vit gene of the vitlvit mouse maps to the mi locus of
the laboratory mouse. IS The human homologue of the rni gene of the mouse
has now been cloned.I" It now remains to be seen whether mutations in the
,human homologue of this gene are related to the pathology of vitiligo.
The standard treatment of vitiligo is PUV A which is the most effective
therapy available for repigmentation of vitiliginous patches. This has its roots
in the original description of the disease in the Atharva Veda where the oral
intake of an oily extract of the seeds of the psoralen containing Psoralia
corylifolia (Bouchi, Bavachi and Vasuchika) was advocated followed by
exposure to sun. PUV A helps about 50% of patients.
Other treatments include melagenina, an alcoholic extract of human
placenta, which has been advocated by Cuban dermatologists. Unfortunately
there is not much scientific evidence to support this treatment because
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THE NATIONAL MEDICAL JOURNAL OF INDIA
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experimentally melagenina, with or without exposure to ultraviolet light for
periods up to 6-8 weeks, produces no effects on melanocytes.I? The addition
of melagenina to cultures of human or murine melanocytes also does not
affect growth rates or tyrosinase activity.'? Finally, double-blind placebocontrolled studies done in Venezuela, Mexico and India do not confirm the
claims of Cuban investigators.!?
Recently, mini pulse therapy with betamethasone was tried on vitiligo
patients who have extensive or fast spreading disease with a 40% success rate. 18
Surgical methods have been developed in the last few years in cases where
vitiligo is stable, limited to a few patches and unresponsive to other treatments.
The techniques range from autologous epidermal punch grafts, epidermal
grafts obtained from suction blisters and autologous melanocyte transplants.
The transplants are performed after culturing melanocytes alone or with
keratinocytes from the uninvolved epidermis of patients, expanding the cell
numbers in culture and when their growth reaches confluency, adding calcium
chloride to the culture medium resulting in differentiation of the keratinocytes.
The multi-layered cell sheet thus obtained is detached from the culture dishes
by sterile petrolatum gauze and transplanted on to dermabraded vitiligo
macules under local anaesthesia.'?
I have little doubt that the genes responsible for vitiligo and the triggering
factors are likely to be identified soon and more efficient methods of treatment
will be available within the next 4 to 5 years.
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A. RAMAIAH
Department of Biochemistry
All India Institute of Medical Sciences
New Delhi