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Volume 1, Number 3, January 1996

Contents: (Full text available in print editition.)

Topical Vitamin E Formulations: Not Always Benign

The apparent lack of efficacy of oral vitamin E (alpha-tocopheryl acetate) for most dermatologic disease (1) has not stopped the widespread use of vitamin E in moisturizing and anti-aging creams, lotions, oils, and ointments, based on the mistaken notion that vitamin E can somehow "improve" the skin by removing wrinkles and improving tone.

As dermatologists, we believed that even if topical vitamin E served a limited function, its use was nonetheless relatively benign. Unfortunately, this is not always the case. Although the systemic administration of vitamin E almost never produces any untoward reaction, various topical preparations can cause allergic dermatitis.

Vitamin E and Contact Dermatitis: An Epidemic in Switzerland!
In Spring 1992, an epidemic outbreak of papular and, more frequently, follicular rashes caused by a new line of cosmetics occurred throughout Switzerland. More than 900 cases were reported (263 by dermatologists plus 642 reported directly to the manufacturer), representing at least three cases of contact dermatitis per 1,000 units sold. Patch and use testing isolated vitamin E linoleate (a mixture of tocopheryl esters, mainly tocopheryl linoleate) as the causative agent. Onset of symptoms was 1-160 days (median 14 days) after first use of the cosmetics. The lesions were long lasting, widely distributed, associated with a pronounced pruritus, and frequently aggravated by sweating, solar irradiation, or heat. The rash subsided within 1-4 weeks following topical or oral corticosteroid treatment but sometimes relapsed after sun exposure. Lesions were frequently misdiagnosed as drug eruptions, viral exanthems, urticaria, polymorphous light eruption, or ectoparasitosis.(2)

Previous Reports

Thus, as well as limited utility, topical vitamin E can produce a completely opposite reaction to that intended, damaging the skin rather than "improving" it. Therefore, so-called natural vitamins are no different from many other cosmetic ingredients: they all have the potential for allergic reactions, some of which could be atypical.(4)

References (Back to vitamin E article)

  1. Pehr K, Forsey RR. "Why don't we use vitamin E in dermatology?" Can Med Assoc J1993; 149: 1247-1253.
  2. Perrenoud D, Homberger HP, Auderset PC, et al. "An epidemic outbreak of papular and follicular contact dermatitis to tocopheryl linoleate in cosmetics." Dermatology 1994; 189: 225-233.
  3. Rietschel RL, Fowler JF, eds. Fisher's Contact Dermatitis. 4th ed. Baltimore: Williams & Wilkins, 1995.
  4. Rothe MJ. "Vitamin E derivatives: `natural,' but not so innocent." Fitzpatr J Clin Derm 1995; 3: 30-31.
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Methotrexate: Still Useful After 40 Years

Methotrexate (Rheumatrex, Lederle; also sold by Mylan) is the most widely used antimetabolite in the world. Studies of the potential uses, efficacy, and toxicity of this well-established drug still continue in the field of dermatology. Some recent results are summarized below.

Approved Indications

Indications Awaiting Confirmation in Controlled Studies

Established Uses


Methotrexate's efficacy in severe psoriasis was recently confirmed in 113 patients treated for an average of nine years at a maximum weekly oral dose of 15 mg.(1) Side effects were experienced by 73% of patients, reminding us that patients on methotrexate need to be closely monitored (see below).

Psoriatic Arthritis

Almost all 28 patients receiving 15 mg oral methotrexate weekly for the treatment of psoriatic arthritis improved dramatically with regard to pain and function. However, doses below 15 mg weekly were not necessarily effective in this indication.(2)

Uses Awaiting Study and Approval

New indications for methotrexate are still being explored, and some of these are described below. Readers should be aware that the results of these uncontrolled studies need verification.

Bullous Pemphigoid

Five of eight (63%) elderly patients with refractory bullous pemphigoid who received low-dose oral methotrexate in addition to existing prednisone therapy were clear of disease one month after the start of methotrexate. The other three patients also markedly improved once their methotrexate dosage was increased. Furthermore, use of low-dose methotrexate in these patients allowed a large reduction in their daily dose of prednisone.(3)

Systemic Lupus Erythematosus

After treating 12 patients (with predominant joint manifestations) with 5-15 mg oral or I.V. methotrexate per week, Wilson and Abeles felt that methotrexate showed promise in the treatment of SLE refractory to hydroxychloroquine and corticosteroids.(4) Similarly, LeBlanc and colleagues used methotrexate, 3-10 mg/week for 3 to 14 months, to successfully treat five young women whose SLE had not responded to other treatments.(5) Furthermore, two of four patients with refractory discoid lupus erythematosus responded to 10-15 mg oral methotrexate administered weekly for 12 weeks or longer.(5a)

Other Dermatological Uses

Other dermatological conditions that may respond to methotrexate include pityriasis rubra pilaris, sarcoidosis, chronic urticaria, dermatomyositis, and lymphoproliferative diseases.6 For example, three patients with cutaneous sarcoidosis who were refractory to antimalarials and steroids significantly improved with 15-22.5 mg methotrexate weekly,(7) as did one patient with chronically debilitating corticosteroid-resistant urticaria.(8) These uses of methotrexate need to be verified and are only appropriate in patients resistant to conventional therapy.

Potential Topical Formulation

Arcturus Pharmaceutical is investigating a topical formulation that it hopes will avoid the potential liver and bone marrow toxicities (described below) associated with oral methotrexate.(9) Let's hope this topical formulation is more successful than previous such formulations.

Side Effects

Low-dose methotrexate has a number of side effects, particularly gastrointestinal and liver toxicities.


One study reported that gastrointestinal symptoms occurred in 32% of patients receiving once weekly low-dose oral methotrexate therapy for psoriasis. These symptoms could be adequately controlled by folic acid supplementation, apparently without compromising the therapeutic efficacy of methotrexate.(10)


A meta-analysis of 15 studies comprising 636 patients using low-dose methotrexate showed a 28% incidence of histological progression of liver disease.(11) Conversely, a study in 49 similarly-dosed psoriasis patients showed histological deterioration in only 18% of livers and an improvement in 24%, neither of which correlated to cumulative methotrexate dosing.(11a) Nonetheless, severe hepatitis may be more common in patients concurrently receiving etretinate, in those with heavy alcohol consumption, or in those with a higher total cumulative dose of methotrexate. Furthermore, patients with rheumatoid arthritis experience far less hepatotoxicity than those with psoriasis.(13)

In treating rheumatic diseases, liver biopsies have been recommended but are not without risk. Newly revised guidelines on the use of methotrexate in rheumatic disease have dropped the pre-treatment recommendation for a liver biopsy, as long as patients have normal liver function, have no adverse history or risk factors, and will only be receiving the drug for a few months.(12) According to existing guidelines in dermatology, a liver biopsy is recommended within the first two to four months of starting methotrexate, with a repeat biopsy after each additional 1.5 gm of cumulative methotrexate (usually every two years). Liver enzymes should also be frequently monitored.(13) Boffa and colleagues performed 182 liver biopsies over a 10-year period on patients receiving long-term, low-dose, once-weekly oral methotrexate for severe psoriasis. Their results suggest that, with careful follow-up, the risk of development or progression of liver disease is modest and that the requirement for performing routine liver biopsies in these patients needs to be reconsidered.(11a) A concerted effort is needed to develop up-to-date guidelines based on current practice in dermatology.


Headaches, dizziness, fatigue, mood alterations, pulmonary toxicity, and skin cancer have all been reported in patients receiving methotrexate. Hematologic toxicity, the major side effect of high dose methotrexate, is reversible by the folic acid analog, leucovorin, and is uncommon with low-dose therapy. Methotrexate is also teratogenic and is not recommended for use in women likely to become pregnant.

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References (Return to methotrexate article)

1. Van Dooren-Greebe RJ, Kuijpers ALA, Mulder J, et al. "Methotrexate revisited: effects of longterm treatment in psoriasis." Br J Dermatol 1994;130:204-210.

2. Greaves MW, Weinstein GD. "Treatment of psoriasis." N Eng J Med 1995; 332:581-588.

3. Paul MA, Jorizzo JL, Fleischer AB Jr, et al. "Low-dose methotrexate treatment in elderly patients with bullous pemphigoid." J Am Acad Dermatol 1994; 31:620-625.

4. Wilson K, Abeles M. "A 2-year open ended trial of methotrexate in systemic lupus erythematosus." J Rheumatol 1994; 21:1674-1676.

5. LeBlanc BAGW, Dagenais P, Urowitz MB, et al. "Methotrexate in systemic lupus erythematosus." J Rheumatol 1994; 21:836-838.

5a. Bottomley WW, Goodfield MJD. "Methotrexate for the treatment of discoid lupus erythematosus." Br J Dermatol 1995; 133:655-656.

6. Olsen EA. "The pharmacology of methotrexate." J Am Acad Dermatol 1991; 25:306-318.

7. Webster GF, Razsi LK, Sanchez M, et al. "Methotrexate therapy in sarcoidosis." Annals Intern Med 1989; 111: 538 - 539.

8. Weiner MJ. "Methotrexate in cortico-resistant urticaria." Annals Intern Med 1989; 110:848.

9. Hwang GC, Lin AY, Chen W, et al. "Development and optimization of methotrexate topical formulation." Drug Devel and Ind Pharmacy 1995; 21:1941-1945.

10. Duhra P. "Treatment of gastrointestinal symptoms associated with methotrexate therapy for psoriasis." J Am Acad of Dermatol 1993; 28:466-469.

11. Whiting-O'Keefe QE, Fye KH, Sack KD. "Methotrexate and histologic abnormalities: a meta-analysis." Am J Med 1991; 90:711-716.

11a. Boffa MJ, Chalmers RJG, Haboubi NY, et al. "Sequential liver biopsies during long-term methotrexate treatment for psoriasis: a reappraisal." Br J Dermatol 1995; 133:774-778.

12. Kremer JM, Alarcon GS, Lightfoot RW Jr, et al. "Methotrexate for rheumatoid arthritis: suggested guidelines for monitoring liver toxicity." Arthritis Rheum 1994; 37:316- 328.

13. Petrazzuoli M, Rothe MJ, Grin-Jorgensen C, et al. "Monitoring patients taking methotrexate for hepatotoxicity." J Am Acad Dermatol 1994; 31:969-977.

Minoxidil update

A joint meeting of American non-prescription drugs and dermatological and ophthalmological drugs advisory committees (FDA) has recommended that minoxidil 2% be switched from prescription only to OTC status.

Minoxidil was first made available OTC in the UK in September 1995. Prior to that, New Zealand, Guatemala, Denmark, and the Netherlands granted similar status for the treatment of hair re-growth for androgenetic alopecia. Canada is still awaiting OTC approval.

The USA FDA Advisory Committee has recently approved the use of minoxidil 5% for the treatment of male pattern hair loss. Regulatory authorities in New Zealand and Denmark have approved the use of minoxidil 5%.

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Skin Therapy Letter. (ISSN 1201-5989) Copyright 1995 by International Skin Therapy Newsletter Inc. All rights reserved. Reproduction in whole or in part by any process in whole or in part is strictly forbidden without prior consent of the publisher in writing.

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