Dialogues in Dermatology Commentaries - November 2005
Volume 57, No. 2
Pharmacoepidemiology
Joel M. Gelfand, M.D. intervie...
Dr. Gelfand surveys controversial topics in dermatology including the risk of developing lymphoma in patients
using the ne...
Boehm and Bieber, in the article “Chilblain lupus erythematosus Hutchinson: successful treatment with
mycophenolate mofeti...
venous insufficiency. Other approaches to management include the use of topical recombinant growth factors, skin
equivalen...
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Dialogues in Dermatology Commentaries - November 2005

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Dialogues in Dermatology Commentaries - November 2005

  1. 1. Dialogues in Dermatology Commentaries - November 2005 Volume 57, No. 2 Pharmacoepidemiology Joel M. Gelfand, M.D. interviewed by Jacqueline Junkins-Hopkins, M.D. “Dr. Heymann, I’m terribly embarrassed by my toenails. I saw this ad on TV that said I can get rid of those nasty little creatures making a home in nails” “I suppose you are referring to terbinafine, Mrs. Rubrum” “Is the medicine safe?” “As far as medicines go, yes, it’s safe, but not without potential risks. For example, there is a very rare chance that it could damage your liver” “What are the odds?” “According to Dr.Wolverton’s text, Comprehensive Dermatologic Drug Therapy, “the estimated incidence of terbinafine inducing clinically significant symptoms and signs for which no other cause was apparent is 1:45,000 to 1:120,000”. “That high! I can’t take that chance! Isn’t there anything I can put on the nail?” “Of course. It’s topical ciclopirox. It’s not nearly as effective, but you don’t have to worry at all about your liver.” “I cannot take such a chance with the pill. Whenever anything bad can happen, it will always happen to me.” “You do realize, Mrs. Rubrum, you took a greater risk coming to the office to discuss this than you would to take the medicine. According to the National Safety Council, in 2002 the risk of dying in a car accident was 1:17,625, with the lifetime risk being 1:228.” “I’m asking for advice, Dr. Heymann. What should I do?” “It’s really up to you. You have to believe that the benefit of taking the medicine is worth the potential risk.” “Oh forget it. By the way did I tell you I stopped using the cream you gave me for Ellie’s eczema? I really don’t want her getting cancer.” “Do you want to hear why that cream is safe? The data for that conclusion is based more on theoretical speculation rather than fact.” “I’d love to Dr. Heymann, but I must get to the store before 8 o’clock – the Powerball jackpot is going to be at least 278 million and I’m getting 100 tickets. You never know!” “No Mrs. Rubrum, you never know, but you can sure make an educated guess.” In this outstanding dialogue, Dr. Gelfand defines pharmacoepidemiology as the discipline that examines the safety of medicines in large populations. He states that more than half of all drugs demonstrate serious side effects that were not appreciated prior to their approval. In the phased studies used to bring these drugs to market , only a small number of patients participate, exclusion criteria are utilized with relatively healthy patients entering the study, and the duration of use of the drug is for weeks or months, rather than years. Once the drug is on the market, more patients in various states of health use these drugs for longer periods of time, and adverse reactions that were not apparent during the initial trials are revealed.
  2. 2. Dr. Gelfand surveys controversial topics in dermatology including the risk of developing lymphoma in patients using the new biologics, the risk of lymphoma with the use of topical immunomodulators, and the risk of suicide in patients receiving isotretinoin. It is human nature to feel that the only number that matters is one. The spouse of the unfortunate person who died of hepatic failure after exposure to terbinafine would not be comforted by the data referred to earlier. Without diminishing the tragedy of individual circumstances, we must help guide our patients by putting these remote risks in perspective, and trying to help them make informed decisions that they are comfortable with, especially when the benefit far exceeds the risk. There is another aspect to this discussion which deserves mention. There is a very real risk in our litigious society of being sued should these adverse reactions occur. I do not know the true statistical risks of litigation, but I would be willing to bet that when there is a knock on the door following a severe adverse drug reaction, the odds are you are receiving a subpoena rather than a check for a million dollars from Publisher’s Clearinghouse. Discussing major risks with the patient, and documenting this conversation in the chart, will simultaneously help protect the physician while ensuring that the patient is well informed. Mycophenolate Mofetil J. Mark Jackson, M.D. interviewed by Joel Barkoff, M.D. Mycophenolate mofetil (MMF, CellCept) has experienced a meteoric rise in the dermatologic therapeutic ladder during the past decade as a steroid-sparing immunosuppressive agent. According to Frieling and Luger in the article “Mycophenolate mofetil and leflunomide: promising compounds for the treatment of skin diseases”, published in the October 2002 issue of Clinical and Experimental Dermatology, MMF is the ester of mycophenolic acid (MPA), which was introduced in the early 1970’s for the treatment of psoriasis. The use of MPA was hindered by adverse gastrointestinal symptoms and possible carcinogenicity. MMF is superior to MPA by providing increased bioavailability with fewer adverse reactions. After absorption, MMF is converted to the active metabolite, MPA which inhibits the enzyme inosine monophosphate dehydrogenase, thereby blocking the production of guanosine nucleotides necessary for DNA and RNA synthesis. MPA is five times more potent in inhibiting the type II isoform of the enzyme, which is expressed in activated T and B lymphocytes, compared to the type I isoform, which is expressed in most mammalian cells. This allows MPA to serve as an inhibitor of T and B lymphocyte activation and proliferation. Other mechanisms contributing to immunosuppression may include the induction of apoptosis of activated T cells, the recruitment of lymphocytes and monocytes to sites of inflammation, or by impairing the maturation of dendritic cells, thereby inducing immunotolerance. According to Stern et al, in the article “The use of systemic immune modulators in dermatology: an update”, published in the April 2005 issue of Dermatologic Clinics, the most common side effects of MMF are gastrointestinal and hematologic, including nausea, vomiting, diarrhea, and abdominal cramps. The overall incidence of gastrointestinal side effects ranges from 12% to 36%. Severe leukopenia has been reported in 0.5% to 2.0% of patients. There may be a slightly increased risk in the development of lymphoproliferative malignancies, and there appears to be a two to three times higher relative risk of herpetic viral infections. MMF has been reported to be valuable in the treatment of immunobullous disorders including pemphigus vulgaris, pemphigus foliaceous, linear IgA dermatosis, cicatricial pemphigoid, paraneoplastic pemphigus, and epidermolysis bullosa acquisita. Other conditions in which the use of MMF has been reported include psoriasis, pyoderma gangrenosum, atopic dermatitis, dyshidrotic eczema, sarcoidosis, vasculitis, necrobiosis lipoidica, dermatomyositis, and lupus erythematosus. This commentary will focus on the use of MMF in cutaneous lupus erythematosus. There appears to be a growing consensus that MMF soon may be playing a vital role in patients with lupus nephritis. McCune and Riskala, in the article “Mycophenolate mofetil: A magic bullet for lupus?” published in the June 2005 issue of the Journal of Rheumatology, report that MMF as a first-line therapy of lupus nephritis has thus far been equivalent to bolus cyclophosphamide in relatively short-term trials. MMF is a candidate to become first-line therapy for lupus nephritis on the basis of additional studies and sufficient long-term data for comparison. These authors report that studies in mouse models of lupus nephritis suggest that a decrease in nitric oxide production may underlie the effectiveness of MMF in lupus nephritis, perhaps independent of its immunosuppressive properties.
  3. 3. Boehm and Bieber, in the article “Chilblain lupus erythematosus Hutchinson: successful treatment with mycophenolate mofetil”, published in the February 2001 issue of Archives of Dermatology, reported the case of a 75 year old woman with Raynaud’s syndrome associated with painful acral papulosquamous plaques, fissures and ulcers, demonstrating histologic features of lupus. She was minimally responsive to oral steroids, antimalarials, azathioprine, and pentoxifylline. After six weeks of MMF there was substantial improvement, and by week 14, near complete clearing was achieved. Goyal and Nousari, in the article “Treatment of resistant discoid lupus erythematosus of the palms and soles”, from the July 2001 issue of the Journal of the Academy of Dermatology, reported two cases, 42 and 43 year old women, respectively, with refractory discoid lesions (DLE) of the palms and soles, both of whom responded to MMF within four months. Schanz et al, in the July 2002 issue of the British Journal of Dermatology, reported complete clearing of lesions of subacute cutaneous lupus erythematosus (SCLE) in a 53 year old woman and a 60 year old man, both of whom had extensive annular lesions on the trunk unresponsive to azathioprine, antimalarials, and glucocorticoids. In both patients, the administration of MMF caused the skin manifestations to disappear within weeks. In the December 2002 issue of Archives of Dermatology, in the article “Mycophenolate mofetil for the treatment of cutaneous lupus erythematosus with smoldering systemic involvement”, Hanjani and Nousari detail the rapid improvement of lupus profundus, with MMF in a 58 year old woman. The patient was in remission after three months of therapy, without evidence of disease flare after eight months. This article reports three other patients successfully treated with MMF, two of whom achieved remission within six weeks, with the third in remission within three months. These patients carried diagnoses of tumid lupus, discoid lupus and lupus perniosis, and SCLE. MMF is not universally accepted as a panacea in the treatment of lupus. Pisoni et al, in the article “Skin manifestations of systemic lupus erythematosus refractory to multiple treatment modalities: poor results with mycophenolate mofetil” studied seven patients with systemic lupus erythematosus (SLE) and skin involvement (including acute cutaneous lupus, SCLE, DLE, vascultis, urticarial rash, and chilblain lupus). The authors found no response in five patients, a partial response in one, and an initial response with a subsequent flare while on MMF in one patient. The authors concluded that MMF is not particularly effective for the cutaneous manifestations of SLE. They also acknowledge that these patients were also recalcitrant to other therapies, placing them at the severe and most difficult to treat end of the lupus spectrum. MMF appears to be a promising immunosuppressive agent for the treatment of cutaneous lupus erythematosus. Controlled, randomized, blinded studies would be optimal in establishing the true efficacy of MMF, but such trials have yet to be reported. Pentoxifylline is an example of a medication on my list of “wonder drugs”, meaning that I wonder why these agents seem so spectacular in the literature and so disappointing when I prescribe them for my patients. I am sanguine that MMF may be an exception – I anticipate utilizing it successfully in my patients with intractable cutaneous lupus erythematosus. Leg Ulcers Mark D.P. Davis, MD interviewed by Joel Barkoff, MD This expansive dialogue offers Dr. Davis’ thoughts on the pathogensis of leg ulcers and his approach to their management. He offers his insights on dressings, growth factors, skin grafts, artificial skin, control of leg edema, hyperbaric oxygen, vacuum-assisted closure, and pain control. For another perspective, this commentary will be the management strategy section from the chapter on leg ulcers, by Drs. Jonathan Kantor and David J. Margolis, in the second edition of Treatment of Skin Disease, to be published early in 2006. I am a coeditor of this textbook along with Drs Mark Lebwohl, Ian Coulson, and John Berth-Jones. Accurate diagnosis is key in the management of these wounds, and therapy is aimed at both mitigating any anatomic abnormalities and optimizing the wound healing environment. When approaching a leg ulcer, it is important to keep a broad differential diagnosis in mind; although the majority may be classified as venous leg ulcers, these wounds may be due to arterial insufficiency, pressure, or diabetic neuropathy. Venous ulcers are caused indirectly by ambulatory venous hypertension, most often due to the failure of the calf pump muscle system. Therefore, management hinges on lower limb compression and moist wound dressings. Elevation of the leg at night and, when necessary, weight reduction, are additional strategies to reduce the impact of
  4. 4. venous insufficiency. Other approaches to management include the use of topical recombinant growth factors, skin equivalents (or cell-based therapies) and oral pentoxifylline. Most patients will improve with conservative management (compression and dressings), although compliance with compression therapy (e.g. compression stockings, compression bandages, etc.) may be a challenge. Most of these wounds heal in less than 6 months. Patients with diabetes mellitus may develop lower extremity wounds. The diabetic neuropathic foot ulcer, which is likely the only wound that is really a direct complication of diabetes, stems from the lower extremity neuropathy that is associated with diabetes. Unperceived repetitive trauma and pressure from walking that leads to neuropathic ulcers. Management depends on optimal control of diabetes, offloading of the affected limb, and moist wound dressings. Other treatment options include recombinant growth factors like recombinant human platelet-derived growth factor (rh-PDGF), and skin equivalents including Apligraf and Graftskin, which may be necessary in order to achieve optimal results. However, recurrent ulcerations and ensuing amputations are a real and serious complication. Drs. Kantor and Margolis recommend the following specific investigations evaluating leg ulcers: 1) a hemoglobin A1c level; 2) clinical testing for neuropathy 3) lower extremity vascular studies, including the ankle-brachial index, and 4) skin biopsies to rule out cutaneous malignancies. Recommendations for first-line therapeutic interventions include compression for venous ulcers and offloading for diabetic neuropathic ulcers. A second-line approach is the utilization of topical rh-PDAGF (becaplermin), applying skin equivalent dressings such as Graftskin and Apligraf, and oral pentoxyfilline. Third line therapies include intermittent pneumatic compression, oral antibiotic therapy, laser, therapeutic ultrasound, and possibly vitamins and minerals such as zinc. There are diverse approaches in the management of wounds. In the words of Ralph Waldo Emerson (from the “Musketaquid” Poems – [1847]): I am a willow of the wilderness Loving the wind that bent me. All my hurts My garden spade can heal. A woodland walk A quest of river-grapes, a mocking thrush, A wild-rose, or rock-loving columbine, Salve my worst wounds.

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