To the Editor: The study by Krueger et al
1
presented the combination of anthralin and calcipotriene in the treatment of alopecia
areata (AA), and the result was impressive. It may provide us with an alternative
approach to tackle treatment-resistant AA when conventional treatments fail. However,
the rationale of combination treatment and the underlying mechanisms are interesting
and worth further discussion.
The authors mentioned the possible mechanisms of calcipotriene in AA, which may be
related to irritant dermatitis or allergic contact dermatitis. Although topical vitamin
D analogues do cause irritant dermatitis, the reported percentage of skin irritation
is only 10% to 15% according to the product label.
2
Besides, it is commonly believed that topical calcipotriene–induced allergic contact
dermatitis is rare considering the widespread usage of the drugs.
3
Although the data from psoriatic subjects may not be accurately extrapolated to other
populations, a study of calcipotriol patch tests in healthy volunteers may provide
us with some information.
4
The results showed that score 1/2 (doubtful reaction) is common on day 2 in all groups
including vehicle control, so this reaction type may not be a reliable indicator.
Score 1 reaction was present in slightly more than 10% of the subjects who received
50 μg/mL concentration on day 2. On day 3, less than 5% of this group showed score
1 or score 2 reactions. That is to say, the percentage of irritation after patch testing
using the calcipotriol solution is not much different from that in psoriatic subjects
(10% to 15%). Although the methods of application (patch test vs topical) and preparations
(50 μg/mL solution vs 50 μg/g cream) were different, the study results may be useful
to estimate the irritation potential of calcipotriol in subjects with normal skin
turnover. Therefore, the rationale to use topical vitamin D analogues as a method
to “bolster the resultant dermatitis” is not convincing given the less than 15% chance
to elicit this irritant effect. Whether the reported case had irritant or allergic
reaction to calcipotriene was not known, as combination treatment with anthralin was
used, and no patch test result of calcipotriene was provided. The idea of combining
2 contact sensitizers, which included diphenylcyclopropenone (DPCP) and anthralin,
as a contact immunotherapy regimen was tried by some researchers, but the results
were conflicting and may increase the severity of adverse effects.
5
The more commonly postulated mechanisms of vitamin D analogues in the treatment of
AA are related to its immunomodulatory effects, such as enhancement of regulatory
T cells, inhibition of CD8+ T-cell activation, and mitigated interferon-γ–induced
loss of immune privilege of the hair bulb.
6
However, the mechanisms of anthralin or DPCP in the management of AA are not fully
understood. Some evidence shows that DPCP treatment is associated with altered peribulbar
CD4+/CD8+ ratio and inflammatory cytokine profiles.
5
Whether combining topical calcipotriene and anthralin exerts a synergistic effect
remains to be studied. The reason for the potential synergy might be explained with
the effects of the anti-inflammatory cytokine interleukin (IL)-10. Evidence showed
that anthralin stimulated the production of IL-10 in a rat model of AA
7
and upregulated IL-10 receptors on a human keratinocyte cell line.
8
As mentioned earlier, calcipotriol induces regulatory T cells, and regulatory T cells
are known to produce IL-10. In addition, some experiments revealed that calcipotriol
enhanced IL-10 secretion in human psoriatic skin
9
and also increased IL-10 receptor gene expression in human epidermal cells.
10
Combining these 2 agents might further increase the activity of IL-10, thus mitigating
the effects of other proinflammatory cytokines in AA lesions.
In addition, the authors stated that “calcipotriene causes allergic contact dermatitis,
likely via thymic stromal lymphopoietin (TSLP), which adds an additional mechanism
of immunomodulation.” This hypothesis is also intriguing, and further discussion is
necessary. Evidence showed that the expression of TSLP may be differently affected
by topical calcipotriol in different species. TSLP was increased in keratinocytes
after topical calcipotriol in a mouse model, but another study showed that a similar
effect was not observed in normal human or monkey skin.
11
On the other hand, topical calcipotriol was shown to induce the expression of TSLP
in human psoriatic skin lesions.
12
Whether TSLP is inducible by calcipotriol in AA is still unknown. However, even if
AA lesions show increased production of TSLP after topical calcipotriol, whether TSLP
poses a positive or negative effect is still uncertain. A genetic study of AA lesions
found increased expression of T helper cell (Th)2, Th1, IL-23, and IL-9/Th9 pathway
genes, including the TSLP gene.
13
Therefore, the complex pathophysiology of AA may not be fully explained by the theory
of Th1/Th2 balance. The authors of the previous case report developed a combination
regimen that may potentially be valuable in treatment-resistant AA, and further research
is needed to delineate the possible mechanisms of action.