Tetracycline and Epidermolysis Bullosa Simplex: Title and subTitle BreakA New Indication for One of the Oldest and Most Widely Used Drugs in Dermatology?

WITHIN THE PAST 15 years, remarkable advances have been made in our understanding of each of the major types and subtypes of inherited epidermolysis bullosa (EB). These have included the more complete characterization of the breadth, severity, and relative frequency of cutaneous¹ and extracutaneous² manifestations within each EB type and subtype, estimations of the cumulative and interval risks for each known outcome or complication of the disease,^{3 - 5} determination of the prevalence and incidence of each major and minor phenotype within several geographically and ethnically distinct populations,⁶ and the elucidation of the molecular basis of most EB subtypes.⁷ Although eventually some of this knowledge may result in the successful development of beneficial gene therapies, at present there are no treatments available that appear to result in long-term reductions in blister counts or improvement in skin mechanical fragility in any form of this disease, despite numerous attempts with a variety of topical and systemically administered medications. This is particularly disappointing, since even those patients with the most localized forms of EB experience tremendous alterations in lifestyle and quality of life, and patients with some of the more generalized forms of EB are also at increased risk of early mortality.

The most promising therapy described for EB to date—systemic phenytoin in recessive dystrophic EB⁸ —led to a randomized, double-blind, placebo-controlled, multicenter trial. This study unfortunately did not confirm any lasting benefit of this therapy within the patient population studied.⁹ A similarly designed trial was performed in EB simplex using the topical anti-inflammatory agent parfenac, based on large numbers of anecdotal reports of its benefit in patients with localized forms of this disease.¹⁰ Disappointingly, no difference was observed between the inert vehicle and the active drug, although a considerable placebo effect was still observed in several patients. Indeed, the placebo effect was so strong that some of the latter patients continued to seek this drug in Europe after being shown that they were unable to distinguish active drug from vehicle.

In 1997,¹¹ investigators reported on the results of an unblinded, noncrossover-designed, nonplacebo-controlled study involving systemic cyproheptadine in a small cohort of patients with Dowling-Meara EB simplex, based on the findings by Tadini et al¹² in one kindred and on the use of another serotonin antagonist¹³ in this disease. Its beneficial results were attributed to cyprohepatidine acting as an antagonist to the H₁ histamine receptor and serotonin-2 and serotonin-1C receptors. Although a minority (n=4) of patients reportedly experienced some reduction in blister formation and symptoms, there were a number of potentially major methodological problems in study design, including a very small number (n=13) of subjects, marked patient dropout rate (9 of 13), and limited time of observation (6 weeks).¹¹ Based on these findings, it is impossible to know whether this medication has any long-term therapeutic role in the management of even a minority of patients with Dowling-Meara EB simplex.

Many other drugs have been tried in inherited EB. Other systemic therapies have included corticosteroids,¹⁴ vitamin E,^{14 - 16} retinoids,^{17 - 18} cyclosporin,¹⁹ other immunosuppressant agents, psoralen (in combination with UV-A irradiation),²⁰ minocycline,²¹ and antimalarial agents.²² Topical therapies have included high-potency corticosteroids, aluminum chloride,^{23 - 25} and numerous antibiotic preparations.^{26 - 28} Although some of these interventions have been reported to result in temporary symptomatic benefit, none (with the possible exception of topical antibiotic therapy) has been shown to have lasting value in the long-term management of any type of inherited EB when rigorously assessed in double-blind, randomized clinical trials.

In this issue of the ARCHIVES, Malkinson et al²⁹ describe their experience with oral tetracycline treatment of a father and son affected with the Dowling-Meara subtype of EB simplex. The tetracycline was initially given to the son for acne, and the authors noted dramatic reduction in both blister counts and skin mechanical fragility. A dose-dependent response was observed, with the best response noted at a dosage of 1500 mg/d. An identical response was observed in the affected parent. Of importance, a long-standing benefit was observed, with recurrence of disease activity as the dosage of tetracycline was reduced.

Epidermolysis bullosa simplex is the most common form of inherited EB. Based on data collected by the National EB Registry, for example, it is estimated that the prevalence of EB simplex in the United States in 1990 was 4.60 per million.⁶ Assuming that this project was able to identify only 5% of all patients with EB simplex, this number translates to nearly 23,000 affected individuals within the United States.⁶ Similar incidence and prevalence rates have been reported in other geographic areas worldwide, suggesting that any therapy of benefit in this major type of EB would affect a sizable patient population.

It is quite unclear how tetracycline might affect blister formation in a disorder of keratin mutations, such as EB simplex, although its modulating action might be the result of an anti-inflammatory effect, as has been suggested in a host of other otherwise unrelated skin diseases that clearly benefit from its use. Of note, the Dowling-Meara subtype of EB simplex is characterized by the presence of inflammatory blisters. The findings reported in 2 patients with Dowling-Meara disease in this issue of the ARCHIVES are therefore very exciting for several reasons. First, tetracycline is among the most studied and prescribed drug in dermatological practice. Experience in millions of patients worldwide has demonstrated its remarkable safety and the very limited number of adverse effects that may occur following its administration. As such, tetracycline would certainly be among the safest of any drugs that might be systemically used in EB. Second, this drug is exceedingly inexpensive, making its use practical in virtually every patient in whom it is indicated. Third, rather than requiring tapering, its use can be discontinued immediately, should adverse effects occur. It is unknown whether long-term use of tetracycline at the dosage found to be beneficial in the 2 patients described in this issue of the ARCHIVES might be associated with a higher risk of adverse effects. Fourth, serial laboratory studies are not routinely required in otherwise healthy individuals who are treated continuously for many months with tetracycline, based on exhaustive data in patients with acne. Fifth, although tetracycline is not to be prescribed for children younger than 11 or 12 years, owing to the risk of permanent yellowing of teeth, or to pregnant women, owing to discoloration of primary teeth in the developing fetus, it does not cause major birth defects, making its use in women of child-bearing age far less problematic than the use of many other systemic agents.

Unfortunately, observations on therapeutic responses made in case reports and small case series are not always borne out when larger, more controlled studies are performed. The multicenter phenytoin trial in recessive dystrophic EB is a good example of how divergent such findings can occasionally be. Similarly, findings observed within a single kindred, such as those reported in this month's issue of the ARCHIVES, may represent a response that, for unexplained reasons, cannot be generalized to others outside that particular family. Despite these caveats, the intriguing findings described by Malkinson et al²⁹ merit the performance of a large, randomized, placebo-controlled, double-blind study to test the validity of their observations. If, indeed, high-dosage tetracycline therapy has a long-term modulating effect on disease activity in EB, then this observation may result in the most important therapeutic intervention yet described in EB, translating into markedly enhanced quality of life at little or no risk of adverse effects from its long-term use.