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656
CORRESPONDENCE
of less than 6- 5 mg per kg) is currently the drug of first choice.“
If these measures fail, a wide variety of other medications have
been advocated. These include thalidomide,3 dapsone, oral
gold,5 alpha interferon,6 and retinoids/ All have been shown,
in at least one study, to produce a good clinical response in
patients with DLE who have failed to respond to the
combination of topical steroids, sunblocks and hydroxychlor
oquine. However, in our experience, we have encountered a
number of patients with active DLE who have failed to respond
to the above treatments. In addition, the toxicity of some
treatments, such as thalidomide, oral gold or retinoids, may
limit their use. We were therefore interested to assess the
potential use of MTX in the management of DLE, which has
not been reported previously, and which might be a useful
addition to the therapeutic armamentarium for this condition.
Low-dose weekly oral MTX is a relatively safe drug and
hepatotoxicity is usually limited to psoriatics whose condition
is complicated by a secondary factor such as alcohol excess,
diabetes mellitus, arsenic ingestion, or obesity. The American
Rheumatism Association does not recommend routine pre
treatment liver biopsy for patients with uncomplicated
rheumatoid arthritis receiving MTX,8 as very few problems
have been reported with its use in this condition. Side-effects
reported in patients with SLE have included neutropenia and
oral ulceration, and have tended to be confined to those
patients with active disease with renal impairment. Thus,
short-term treatment of DLE with MTX is most unlikely to be
complicated by any significant side-effects, in the absence of
an additional factor. Possible mechanisms of action of MTX in
DLE might include inhibition of T-cell activation and the
inhibition of migration of inflammatory cells into the affected
area.
As only a small number of patients were included in this
study, the conclusions drawn must be limited. However, the
reasonable response seen in two of the four patients suggests
that MTX may be of help in patients with therapy-resistant
DLE which has failed to respond to hydroxychloroquine, and
in whom other treatments, such as thalidomide, oral gold or
retinoids, have either failed or are contraindicated.
1
Department of Der
Leeds General Infirmary,
Great George Street,
Leeds LSI SEX, U.K.
W.W.BorroMLKY
M.J.D.Gooin'iiiU)
1 Rothenberg RJ, Graziano FM, Orandone JT el til. The use of
methotrexate in steroid-resistant SLE. Arthritis Rheum 1988; 31:
6 1 2 -1 5 .
2 Goodlìeld MJ, Rowell NR. Connective tissue diseases. In: Textbook of
Dermatology (Champion RH, Burton JL, libìing FJG, eds), 5th edn.
Vol. 3. Oxford: Blackwell Scientific Publications, 1992; 2 1 8 4 -5 .
3 Knop J, Bonomann G, Ilapple R et a l Thalidomide in the treatm ent
of 60 cases of chronic discoid lupus erythematosus. Hr J Dermatol
1983; 108: 4 6 1 - 6 .
4 Lindskov R, Reumann F. Dapsone in the treatment of cutaneous
lupus erythematosus. Dermatologica 1968; 172: 2 1 4 -1 7 .
5 Dalziel K, Going G, Cartwright PH et al. Treatment of chronic discoid
lupus erythematosous w ith oral gold compound (aurauofin). Hr ƒ
: 115: 2 1 1 - 3 6.
Der
6 Thiovelt J, Nicolas JF, Kanitakis ] et al. Recombinant interferon a 2 a
is effective in the treatm ent of discoid and subacute cutaneous lupus
erythematosus. Br J Dermatol 1990; 122: 405-9.
7 Shonick JK, Formica N, Parke AL. Isotretinoin for refractory lupus
erythematosus, J Am Acad Dermatol 1986; 14: 4 9 -5 2 .
8 Health and public policy committee, American College of Physi
cians. Methotrexate in rheum atoid arthritis. Ann Intern Med 1987;
1 0 7 :4 1 8 - 1 9 .
T r a n s g lu ta m in a s e -p o s itiv e c e lls in p so ria tic ep id erm is d u r in g
tr e a tm e n t w ith calcitriol ( l o t , 2 5 d ih y d r o x y v ita m in D j ) a n d
tacalcitol ( l a , 2 4 d ih y d r o x y v ita m in D ?)
S ir , T h e keratinization process in human epidermis involves
the formation of an insoluble cross-linked protein envelope.
Involucrln, filaggrin and other major precursor proteins of the
corniiied cell envelope are expressed late during epidermal
differentiation.1 Involucrin expression starts in the upper
spinous cell layers in normal human skin. Filaggrin
expression is restricted to the granular layer and the stratum
corneum.3 These and other precursor proteins become crosslinked by the activity of transglutaminase K, the rate limiting
enzyme in the formation of the corniiied envelope, via e-(7 ~
glutamyl) lysine isopeptide bonds.4
It has been demonstrated that membrane-associated
transglutaminase activity and the number of cross-linked
envelopes are markedly increased in psoriatic skin. It is also
well established that in psoriatic epidermis involucrin expres
sion is significantly increased, whereas filaggrin expression is
decreased or even absent.
In keratinocytes in vitro, it has been demonstrated that
corniiied envelope formation and transglutaminase activity
are enhanced by calcitriol (la-,25 dihydroxy vitamin I)().
tacalcitol (Irv,24 dihydroxy vitamin Dj), and calcipotriol.'l)
that In ,2 5
we repoi
j D i and I n ,24
(OI'DiDj reduce the expression of involucrin and increase
filaggrin expression in psoriatic skin.(>’10
A mouse monoclonal antibody (Igt52a) against human
keratinocyte transglutaminase (BTT) has become available for
tI I!
j
|*
i
,ec
e.
the present investigation was to examine the effect of l« ,2 5
2 D) and of l a , 24 (Oil)_> l)5 on the expression of human
keratinocyte transglutaminase in vivo during treatment of
psoriatic plaques with these, derivatives.
Twenty patients with stable psoriasis vulgaris were included
in this study. Ten patients were treated with calcitriol in
petrolatum (3 /¿g/g) twice daily. Before treatment, and after I ,
2 and 4 weeks of treatment, punch biopsies ( J rnm) were
taken from the psoriatic lesions. Calcitriol was obtained from
Solvay Duphar, Amsterdam, the Netherlands. The other 10
patients were Ire;
once
daily on one half of the body, and the ointment base alone
on the other half, for 8 weeks. Before treatment, and after 8
weeks of treatment, punch biopsies (3 mm) were taken from
both body halves.
To visualize transglutaminase type 1, which is expressed
during differentiation of the epidermis, we used immuno*
(<"> 1995 British Association of Dermutologists, British Journal o f D enm tologu, 1 33, 65 5 -6 6
0
>/c
0 80
70
60
50
40
30
20
10
0
Wk 0
Wk 4
Wk 4
Wk 0
Interpapillary
Tip
Figure 1. Plasma m em brane-bound transglutam inase before treat
ment, and after 4 weeks of treatm ent with calcitrici 3
petrolatum, twice daily (n = 10). Mean ± standard error of the mean,
peroxidase staining
glut a m in a se (m o u se
an anti-human keratinocyte trans
is
m
was
glutaminase expression was assessed by calculating the ratio
positive cell layers/total cell layers of the living epidermis. This
procedure was performed at two sites: at: the tip of a dermal
papilla, and in the interpapillary region. On every slide, two
representative areas were examined, and the mean of these
observations was assessed. The Wilcoxon ranking test for
matched pairs was used for statistical analysis.
The calcitriol-treated lesions showed a statistically signifi
cant reduction of transglutaminase expression at the tip of a
dermal papilla after 4 weeks of treatment (P < 0*03).
ary region, the transgluti
tendency to decrease after 4 weeks
(P < 0-075).
The tacalcitol-treated lesions also showed a statistically
significant decrease of transglutaminase expression at the tip
of a dermal papilla (P < 0*03), whereas the expression in the
interpapillary zone was not significantly a fleeted by
treatment ( P < 0*125). The transglutaminase expression in
the biopsies of the lesions treated with placebo did not change
0*2 in both areas). Figures 1 and 2
(I
demonstrate the mean values ± the standard error of the
mean. Figure 3 shows the distribution of transglutaminase
before and after 4 weeks of treatment with calcitriol.
It has been demonstrated that membrane-associated
transglutaminase activity and the number of cross-linked
envelopes are markedly increased in psoriatic skin
and tenfold, respectively.5 Recently, we demonstrated by
immunohistoehemistry that the number of transglutaminasepositive cells is markedly increased in lesional skin compared
with the clinically uninvolved skin of psoriatic patients. The
distribution pattern of transglutaminase comprised relatively
more cell layers compared with the distribution pattern of
involucrin. To date, the trigger for
transglutaminase in psoriatic skin has still to be Identified. It is
at involucrin expression stimulates the
expression of its cross-linking enzyme directly. Alternatively,
(a)
(b)
100
ao
60
%
40
Figure 2. Plasma m em brane-bound
transglutaminase before treatm ent, and after
8 weeks of treatm ent with tacaleitol ointm ent
(4/tg/g) once daily and placebo ointm ent
once daily (n = 10). Mean ± standard error
of the mean, (a) Suprapapillary distribution
pattern, (b) Interpapillary distribution.
20
0
Wk 0
Wk 8
Tacalcitol
(( ’> 1 9 9 5 British Association of Dermatologists, British Immuti o f Dei
Wk o
Wk 8
Placebo
, 13?, 6 5 3 - M 7
Wk 0
Wk B
Tacalcitol
Wk o
Wk a
Placebo
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D e p a r tm e n t o f D e rm a to lo g y ,
U n iv e r s ity H ospital N ijm eg en
PO Box 9 101,
M.J.P.GlïRRITSKN
P .E .J.van E rp
Treatment of recurrent aphthous stomatitis with
pentoxifylline
P . C . M . v a n de K urkhof
6 5 0 0 H B N ijm e g e n ,
The N e th e rla n d s
References
1 W att I'M. Involucrin and other markers of keratlnocytc terminal
differentiation. ƒ Invest Dermatol 1983; 81 (Suppl.): 1 0 0 —3s.
2 M urphy GF, Flynn TC, Rice RII, Pinkus GS. Involucrin expression
in normal and neoplastic hu m an skin: a m arker for keratinocyte
dilTerentiation. J Invest Dermatol 1984: 82: 4 5 3 - 7 .
i Kanitakis J, Ramirez-Bosca A, Reano A et a l Filaggrin expression
in normal and pathological skin. Virchows Archiv A Pathol Anal
Histopathol 1988; 412: 3 7 5 - 8 2 .
4 YalTe MB, M urthy S, Eckert RL. Evidence th at involucrin is a
covalently linked constituent of highly purified cultured keratinocyte cornified envelopes, ƒ Invest Dermatol 1993; 100: 3 -9 .
5 Bsmann J, Voorhees JJ, Fisher GJ. Increased membrane-associated
transglutam inase activity in psoriasis. Biochem
Res
Commun 1989: 164: 2 1 9 - 2 4 .
6 Gerritsen MJP, Rule I-IFC, van Vlijmen-Willems IMJJ et al. Topical
treatm ent with 1,25 dihydroxyvitamin D3: a cell biological study.
B r J Dermatol 1993; 128: 6 6 6 - 7 3 .
7 Binderup L, Bramm E. Effects of a novel vitamin D j analogue MC
903 on cell proliferation and differentiation in vitro and on calcium
metabolism in vivo. Biochem Pharmacol 1988; 37: 8 8 9 -9 5 .
8 Kragballe K, Wildfang IL. Calcipotriol MC 903, a novel vitamin D 5
analogue, stimulates terminal differentiation and inhibits prolif
eration of cultured h u m an keratinocytes. Arch Dermatol Res 1990:
2 8 2 : 1 6 4 -7 .
9 M atsunaga T, Yamamoto M, Mimura II et al. .1,24 (R) dihydroxy
vitamin Dj, a novel active form of vitam in I)5 with high activity
for inducing epidermal dilTerentiation but decreased hypercalcemic activity. J Dermatol 1990; 17: 1 3 5 -4 2 .
10 Gerritsen MJP, Boezeman JBM, van Vlijmen-Willems IM]f. van de
Kerkhof PCM. The effect of tacalcitol (1,24 (OH)) 0 j ) on
cutaneous inllammation, epidermal proliferation and keratinization in psoriasis, a placebo-controlled double-blind study. Br J
D erm atol} 994; 131: 5 7 - 6 3 .
11 Phillips MA, Stewart BE, Qin Q et al. Primary structure of
keratinocyte transglutaminase. Proc Natl Acad Sei USA 1990; 87:
9 3 3 3 -7 .
12 Schmidt R, Michel S, Shroot B, Reichert U. Transglutam inases in
norm al and transformed h u m an keratinocytes in culture. ƒ Invest
Dermatol 1988; 90: 4 7 5 - 9 .
13 Michel S, Courseaux A, Miguel C et al. Determination of retinoid
activity by an enzyme-linked im m unosorbent assay. Anal Biochem
1991; 192: 2 3 2 - 6 .
14 v an de Kerkhof PCM. Common pathw ays for epidermal growth
and inflammation and their relevance in the pathogenesis of
psoriasis. Int J Dermatol 1991; 30: 7 5 5 - 6 2 .
15 Bittiner B, Bleehen SS, MacNeil S. l a , 2 5 (OH)2 vitam in D,
increases intracellular calcium in h u m a n keratinocytes. Br ƒ
Dermatol 1991; 124: 2 3 0 - 5 .
16 Haussier MR, Donaldsen CA, Kelly MA. Functions and m echanism
of action of the 1,25-dihydroxy-vitamin D 5 receptor. In: Vitamin
D: a Chemical, Biochemical and Clinical Update (Norman AW,
Schaefer K, Grigoleit 1-I-G, eds). Berlin: de Gruyter, 1985; 8 3 - 9 2 .
17 Bauer FW. Cell kinetics. In: Textbook of Psoriasis (Mier PD, van de
Kerkhof PCM, eds). Edinburgh: Churchill Livingstone, 1986;
100 - 12 .
Sir, Recurrent aphthous stomatitis (RAS) is one of the most
common diseases affecting the oral mucosa. Many drugs,
including analgesics, antibiotics, topical and systemic corti
costeroids, dapsone, colchicine and thalidomide, have been
used to relieve pain and to reduce the frequency of relapse.
They are not always effective, and side-effects are a
complicating factor. Pentoxifylline (PTX) is a methylxanthine
derivative with haemorrheologlcal and antithrombotic prop
erties.2 Recent experimental arid clinical observations have
demonstrated that PTX also has immunomodulating and anti
inflammatory activities,3 which seem to be related, at least in
part, to the inhibitory effect of PTX on tumour necrosis factor
(TNF)-alpha production.4 Thalidomide, which is one of the
treatments of choice for severe RAS,15 also inhibits TNF-alpha
production/1This observation led us to speculate that PTX and
thalidomide could share certain therapeutic effects, such as
, we
the prevention of RAS.7
six pi
with RAS who were successfully treated with PTX. Oral
therapy with PTX (400 mg tw o-three times daily) suppressed
the recurrence of aphthae in five patients, and led to a
reduction in the number and duration of ulcers, with
symptomatic improvement, in one patient.8 We now report
22 additional cases.
Twenty-two patients (14 women and eight men) between
19 and 75 years of age (mean 34 years), were enrolled in this
open study. All the patients were diagnosed as having minor
RAS, and had a disease duration of 2 -8 years (mean 3*5
years). They all had multiple oral aphthous ulcers
lasted for 7 -1 5 days, and experienced recurrences at
every 2 months. Seventeen patients had neither clinical nor
analytical evidence of any underlying systemic or cutaneous
disease. The remaining five patients suffered from
itis (which was treated with low-dose oral corticosteroids
nonand mesalazine), rheumatoid arthritis (treated
steroidal anti-inflammatory drugs), subacute cutaneous lupus
erythematosus (treated with topical corticosteroids and sunscreening cream), anorexia nervosa and Parkinson's disease.
All the patients received oral therapy with PTX at a dose of
400 mg three times daily. Patients were studied monthly for a
6-month oerlod. Two
the drug was
month. The drug was well tolerated by the remaining 20
p a c\
s. No
the course of treatment
were observed in 11 patients (50%), including those cases
with anorexia nervosa, ulcerative
md
cutaneous lupus erythematosus. Six patients (27%) showed
recurrence of the lesions during the period of the study, but
there was a reduction in the number and duration of ulcers, as
well as in the pain and difficulty with eating. Recurrence of
aphthous ulcers without symptomatic improvement was
I
The present study, and our
that continuous PTX treatment can
or
reduce its severity, In most patients. In addition,
© 1995 British Association of Dermatologists, British Journal of Dermatology, 133, 6 5 3 - 6 6 7
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