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Topical
immunomodulating drugs for alopecia areata
Immunomodulatory (capable of modifying or regulating one or
more immune functions) modalities such as anthralin, corticosteroids,
photochemotherapy (PUVA) and topical immunotherapy have long been
used to treat different alopecia areata conditions. Topical minoxidil,
a nonspecific modality used most extensively, protracts the anagen
phase and promotes the growth of longer, wider hair-strands. These
traditional therapies, however, have only limited success in the
face of the onslaught of alopecia areata, especially in cases
of severe or chronic alopecia areata. Moreover, such medications
are unfit for being used on the sensitive skin of the children.
These insights along with facts like the development of immensely
successful therapies for the treatment of other immune-mediated
inflammatory skin diseases like atopic dermatitis and psoriasis
are forcing the scientists to think in terms of trying newer topical
immunomodulating drugs and therapies for alopecia areata.
Many new immunomodulatory therapies for application to the skin
are largely based on the immunopathologic features of psoriasis
(and also atopic dermatitis) and aim to provide the following:
(i) A fall in the number of pathogenic T-cells,
(ii) Slow down T-cell activation,
(iii) Change a type 1 cytokine response to a type 2 response,
and
(iv) Impede activities of inflammatory cytokines.
The new topical immunomodulators are a relatively new class of
therapeutic agents that act locally on T cells by suppressing
cytokine transcription. Studies have enlisted tacrolimus and pimecrolimus
as the two most effective topical immunomodulators. Topical cyclosporine
(CsA) is another new entry in the rather unexplored listing of
new immunomodulatory therapies. Each one of these three drugs
acts by holding back Calcineurin, which in turn slows down IL-2
production and limits CD4 lymphocyte cell activity.
Studies on the remedial roles of the new topical immunomodulating
drugs and Therapies in alopecia areata have not achieved much
in the form of concrete results. However, the milestones achieved
in the other T-cell mediated autoimmune disorders signal a future
pregnant-with-possibilities for the treatment of alopecia areata.
Topical
tacrolimus (Protopic)
Tacrolimus given systemically has long been used to avert organ
rejection after organ transplants. Tacrolimus acts directly on
the T-cells
and
stalls the transcription or copying of the IL-2. This retards
the growth and the multiplying capacity of the T lymphocytes,
which would otherwise assume abnormal proportions in order to
counteract the foreign antigens. Tacrolimus also holds back other
cytokines (such as TNF-alpha and IFN-gamma) from activating the
T-cells.
Oral tacrolimus, like all systemic immunosuppressants, leads
to such fatal consequences as kidney and liver impairment and
high blood pressure. Topical formulations of tacrolimus in the
form of ointments have been found to be as effective as oral tacrolimus
(yet devoid of the negative side-effects). Presently, topical
tacrolimus is one of the safest and result-oriented (hence FDA-approved)
treatments for both dermatitis and psoriasis.
Clinical trials of alopecia areata patients, however, do not
present the ointment formulation in so favorable a light. A study
conducted by the Department of Dermatology, University of California,
involving alopecia areata patients highlighted the ineffectiveness
of topical tacrolimus. Seventeen alopecia areata patients with
varying percentages of scalp area affected – between 25%
and 75% – and persisting for over a period of 12 months,
were treated with 0.1% of tacrolimus ointment twice daily for
24 weeks. A six-week observation period showed no noticeable changes
in the alopecia areata condition and hair loss continued. Yet,
another study in which five patients with long-term Alopecia Universalis
were recommended a one-time application of 0.1% tacrolimus ointment
also proved the inefficacy of the treatment.
These failures, however, have not completely detered scientists
and they are continuing with their experiments with tacrolimus.
Instead, the fact that the topical application of tacrolimus induces
anagen during the telogen phase and stimulates hair growth (especially
in the absence of T-cells) has given a new impetus to their research
work.
The ongoing research studies are aimed at determining the effectiveness
of tacrolimus in treating early alopecia areata. In the early,
active phases of alopecia areata, the dermal T-cell infiltrate
is comparatively dense. It is a phase, the scholars opine, which
is more treatment-receptive. Though the results are yet awaited,
the scientists are working hard engaging in large placebo-controlled
trials. They have even come up with a far less greasy formulation
of Tacrolimus, which in itself is easy to apply and hopefully
more effective.
Topical
pimecrolimus (Elidel)
A very successful inflammatory skin disease curing agent, pimecrolimus
has been derived from Ascomycin. Being a cell-selective cytokine
inhibitor, pimecrolimus gets lodged into macrophilin-12 and holds
back Calcineurin. This, in turn, hinders the synthesis of the
inflammatory cytokines IL-2 and IFN-gamma and hence, neither the
mast cells nor the T-cells are activated.
Properties of pimecrolimus such as its being a highly skin specific
anti-inflammatory agent yet not triggering any systemic immune
response have made it the best option for curing inflammatory
skin diseases. Studies have shown that the 1% cream formulation
greatly improves atopic dermatitis, yet it does not set off any
skin atrophy, pigmentation or telangiectasia.
The viscous, heavy formulation of the cream cuts back on its
success in alopecia areata. Owing to its thick, greasy quality,
the cream fails to penetrate deeper into the inner layers of skin
and thus, fails to target the T-cells involved in alopecia areata.
Clinical trials of oral pimecrolimus (in psoriasis) have suggested
that, like the cream formulation, it initiates no systemic immunosuppression
and remains inactive in transplantations as well. So far, scientists
have not ventured into clinical trials on alopecia areata with
oral pimecrolimus.
Topical
cyclosporin A (PsorBan)
The most successful among the new topical immunomodulating drugs
is perhaps Cyclosporin A (CsA). The efficacy of oral CsA in treating
acute forms of inflammatory skin diseases (and that too comparatively
instantaneously) needs no ascertaining. Yet, scientists have ruled
out the use of oral CsA on account of the toxic effects.
Owing to their poor skin penetration, topical formulations of
CsA were once disregarded as a cure for inflammatory disorders.
This hurdle has been crossed and a heptamer of arginine-conjugated
formulation of CsA (joined with a pH-sensitive linker) with an
enhanced power to penetrate the skin has been developed of late.
This hyperactive form of CsA penetrates full skin thickness (even
subcutaneous fat) and
puts a full stop to the long continuing process of skin inflammation.
Topical CsA preparations have cleared all clinical safety tests
and scientists have issued a clean chit in relation to its toxicity
profile. Much is happening on the exploration front – a
research on phase II multicenter psoriasis is currently in
progress. Clinical trials in alopecia areata are yet to be attempted,
but given the positive aspects of CsA there may be a favorable
outcome.
Topical
immunomodulating drugs for alopecia areata references
- Rallis E, Nasiopoulou A, Kouskoukis C, Roussaki-Schulze
A, Koumantaki E, Karpouzis A, Arvanitis A. Oral administration
of cyclosporin A in patients with severe alopecia areata. Int
J Tissue React. 2005;27(3):107-10. PMID: 16372476
- Price VH, Willey A, Chen BK. Topical tacrolimus in alopecia
areata. J Am Acad Dermatol. 2005 Jan;52(1):138-9. PMID: 15627095
- Feldmann KA, Kunte C, Wollenberg A, Wolfe H. Is topical tacrolimus
effective in alopecia areata universalis? Br J Dermatol. 2002
Nov;147(5):1031-2. PMID: 12410729
- Freyschmidt-Paul P, Hoffmann R, Levine E, Sundberg JP, Happle
R, McElwee KJ. Current and potential agents for the treatment
of alopecia areata. Curr Pharm Des. 2001 Feb;7(3):213-30. PMID:
11311114
- Thiers BH. Topical tacrolimus: treatment failure in a patient
with alopecia areata. Arch Dermatol. 2000 Jan;136(1):124. PMID:
10632221
- Ferrando J, Grimalt R. Partial response of severe alopecia
areata to cyclosporine A. Dermatology. 1999;199(1):67-9. PMID:
10449964
- Yamamoto S, Kato R. Hair growth-stimulating effects of cyclosporin
A and FK506, potent immunosuppressants. J Dermatol Sci. 1994
Jul;7 Suppl:S47-54. PMID: 7528050
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