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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, oralgold,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 hydroxychlor­oquine. 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 pre­treatment 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 andoral ulceration, and have tended to be confined to those

1

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.

Department of Der Leeds General Infirmary, Great George Street, Leeds LSI SEX, U.K.

W.W.BorroMLKYM.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 treatmentof 60 cases of chronic discoid lupus erythematosus. Hr J Dermatol1983; 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 with oral gold compound (aurauofin). Hr ƒDer : 115: 2 1 1 -3 6.

6 Thiovelt J, Nicolas JF, Kanitakis ] et al. Recombinant interferon a2a is effective in the treatment 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 Physi­cians. Methotrexate in rheumatoid arthritis. Ann Intern Med 1987; 1 0 7 :4 1 8 -1 9 .

T ran sg lu tam in ase-p ositive cells in psoriatic ep iderm is during trea tm en t w ith calcitriol ( l o t ,2 5 d ih yd roxy v itam in D j) an d tacalcitol ( l a , 2 4 d ih yd roxy v ita m in D ?)

Sir, T he 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 cross- linked 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 expres­sion 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)

we repoi that In ,2 5 jD i and In ,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

t I 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; 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

once

during differentiation of the epidermis, we used immuno-

(<"> 1995 British Association of Dermutologists, British Journal o f Denmtologu, 1 33, 65 5 -66

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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 signifi­cant 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 theinterpapillary 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

(I 0*2 in both areas). Figures 1 and 2demonstrate 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-linkedenvelopes are markedly increased in psoriatic skin and tenfold, respectively.5 Recently, we demonstrated by immunohistoehemistry that the number of transglutaminase- positive 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,

Figure 2. Plasma membrane-bound transglutaminase before treatment, and after 8 weeks of treatment with tacaleitol ointment (4/tg/g) once daily and placebo ointment once daily (n = 10). Mean ± standard error of the mean, (a) Suprapapillary distribution pattern, (b) Interpapillary distribution.

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References

1 W att I'M. Involucrin and other markers of keratlnocytc terminal differentiation. ƒ Invest Dermatol 1983; 81 (Suppl.): 100—3s.

2 Murphy GF, Flynn TC, Rice RII, Pinkus GS. Involucrin expression in normal and neoplastic hum an skin: a marker 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, Murthy S, Eckert RL. Evidence that involucrin is a covalently linked constituent of highly purified cultured kerati- nocyte cornified envelopes, ƒ Invest Dermatol 1993; 100: 3 -9 .

5 Bsmann J, Voorhees JJ, Fisher GJ. Increased membrane-associatedRestransglutaminase activity in psoriasis. Biochem

Commun 1989: 164: 2 1 9 -2 4 .6 Gerritsen MJP, Rule I-IFC, van Vlijmen-Willems IMJJ et al. Topical

treatment with 1,25 dihydroxyvitamin D3: a cell biological study. B rJ 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 D5 analogue, stimulates terminal differentiation and inhibits prolif­eration of cultured hum an keratinocytes. Arch Dermatol Res 1990: 282: 164-7 .

9 Matsunaga T, Yamamoto M, Mimura II et al. .1,24 (R) dihydroxy vitamin Dj, a novel active form of vitamin I)5 with high activity for inducing epidermal dilTerentiation but decreased hypercalce- mic 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 keratiniza- tion in psoriasis, a placebo-controlled double-blind study. Br J Derm 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. Transglutaminases in norm al and transformed hum 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 immunosorbent assay. Anal Biochem 1991; 192: 2 3 2 -6 .

14 van de Kerkhof PCM. Common pathways 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 vitamin D, increases intracellular calcium in hum an keratinocytes. Br ƒ Dermatol 1991; 124: 2 3 0 -5 .

16 Haussier MR, Donaldsen CA, Kelly MA. Functions and mechanism 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.

Treatment of recurrent aphthous stomatitis with pentoxifylline

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

I

complicating factor. Pentoxifylline (PTX) is a methylxanthine derivative with haemorrheologlcal and antithrombotic prop­erties.2 Recent experimental arid clinical observations have demonstrated that PTX also has immunomodulating and anti­inflammatory 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/1 This observation led us to speculate that PTX and thalidomide could share certain therapeutic effects, such as the prevention of RAS.7 , we six piwith RAS who were successfully treated with PTX. Oral therapy with PTX (400 mg two-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 -15 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 and mesalazine), rheumatoid arthritis (treated steroidal anti-inflammatory drugs), subacute cutaneous lupus erythematosus (treated with topical corticosteroids and sun- screening 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

non-

the drug wasmonth. The drug was well tolerated by the remaining 20pa c\ s. No

the course of treatmentwere observed in 11 patients (50%), including those caseswith anorexia nervosa, ulcerative mdcutaneous 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

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