The Era of Cooperation

This issue of the ARCHIVES is the second entirely dedicated to Medical Dermatology. It is easy to see from the articles in this issue that Callen and Robinson¹ are right to assert that “Medical Dermatology Is Alive and Well.” This issue also proves that a lot of patients are Alive and Well, thanks to the care of Medical Dermatologists. In this issue, Medical Dermatologists report on better treatments for patients afflicted with dermatomyositis, necrobiosis lipoidica, and livedoid vasculopathy. There are studies on cutaneous diseases that are associated with arthritis, breast cancer, and leukemia. There are also reports on identifying and preventing adverse reactions to prednisone and mycophenolate mofetil. Even a cursory review of this issue reveals that Medical Dermatologists are on the front lines of identifying and treating diseases with important systemic implications.

As the president of the Medical Dermatology Society (MDS) (http://www.meddermsociety.org), I am happy to proclaim that this is a great time to be a Medical Dermatologist. In the last few years, the MDS has seen an explosion in membership and sponsorship. We have also seen a marked increase in the number of resident physicians and dermatology applicants interested in careers in Medical Dermatology. This is best evidenced by the interest in the MDS Mentorship awards, the Dermatology Foundation Career Development Awards in Medical Dermatology, and the combined Internal Medicine–Dermatology residencies. Medical Dermatologists have never had better access to information, diagnostic tests, or therapeutic options. And we are certainly not lacking for patients in need of our expertise.

Each study in this journal reflects a labor of love, and many represent a decade or more of work. But if we want to improve dermatology, we can and we must do more. Across dermatology, our literature reflects the hard work of individuals and single institutions. The only entities that appear capable of producing cooperation in dermatology are the large pharmaceutical companies. Unfortunately, many dermatologic diseases are rare and therefore not profitable to study. The pharmaceutical companies have brought dermatologists together to conduct studies to bring their drugs to market. When studied, the questions answered only serve a narrow interest and rarely answer meaningful questions for the practicing dermatologist. Is it useful to know that a drug is better than placebo when you want to know what is the best, the safest, and the most cost-effective treatment? Studies to answer these questions can and will be done if we demand it.

It is well past time that we move beyond the eras of the individual and the corporation and into an Era of Cooperation. With cooperation, we will create national study groups and databases for serious cutaneous diseases. Databases that might take 1 investigator a lifetime might take 10 to 20 investigators just a few years. The drive to create databases will require the development of validated clinically meaningful outcomes measures. A collaborative effort is already under way to develop a Cutaneous Lupus Severity Index (CLASI), and the same efforts can be made in other diseases. Databases will lead to more useful clinical information on these diseases and their treatments for practicing dermatologists. They will also provide better clinical material for basic investigations and hopefully a better understanding of these diseases.

What the practicing dermatologist needs the most are therapeutic trials to create gold standard therapies for our most difficult diseases. To this end, we have created the MDS Cooperative Group to develop and conduct therapeutic trials in serious skin diseases. Our goal is to conduct an annual therapeutic trial that will create a gold standard treatment for skin diseases for which none currently exist. The MDS recently completed a trial of a steroid-sparing agent in pemphigus vulgaris, and we are about to start a study in generalized lichen planus. We plan to collaborate with industry, government, and patient advocacy groups to identify future studies. We hope that other like-minded dermatologists will join us in these efforts.

When I pick up a dermatology journal, I am always thrilled to see that there are new dermatologic diseases and new versions of old diseases to report. In this issue, Brey et al² describe 4 patients who presented with acute-onset, painful acral granuloma annulare. Interestingly, the authors state that

[t]wo of our patients had arthritic complaints, and another had an elevated serum rheumatoid factor, but neither met the criteria defined by the American College of Rheumatology for rheumatoid arthritis.^{2 (p53)}

This article also contains an excellent review of the differential diagnosis for tender hand nodules and palisading granulomas.

This issue also helps to clarify a confusing diagnosis. Walling et al³ report 9 new cases and review 52 cases of neutrophilic dermatosis of the dorsal hands. Of the patients, 21% had leukemia, myelodysplasia, or other hematologic disease. Unfortunately, this disease has suffered from being named and renamed in report after report. This entity has been called atypical or bullous Sweet syndrome, atypical or bullous pyoderma gangrenosa, pyoderma gangrenosa/Sweet syndrome overlap, pustular vasculitis of the hands, and neutrophilic dermatosis of the dorsal hands. It does neither our patients nor our physicians any good to have duplicate names for the same disease. This review helps to clarify the confusing nosology of this disorder. The authors are correct to assert that this entity is a variant of Sweet syndrome, and I wish that we would all agree to call it Sweet syndrome.

This issue offers 3 therapeutic reports in notoriously hard to treat diseases. Kukreja and Petersen⁴ report a patient with necrobiosis lipoidica successfully treated with thalidomide. Browning and Callen⁵ report a patient with livedoid vasculopathy in association with cryofibrinogenemia and hyperhomocysteinemia responding to warfarin. Sereda and Werth⁶ report 2 female patients with breast cancer who experienced an improvement in their cutaneous dermatomyositis while taking the antiestrogen medications tamoxifen or anastrozole. It is interesting to ponder how we will incorporate these treatments into our therapeutic ladders and what they will teach us about the pathophysiology of the underlying diseases.

The unifying theme of this issue is minimizing adverse effects from systemic corticosteroids. Even with an ever-expanding armamentarium of therapeutic options, long-term systemic corticosteroid therapy remains the undisputed choice for our most serious inflammatory dermatologic disorders.

The largest reductions in bone mass occur in the first 6 months of treatment, with a rapid increase of risk of fracture within the first 3 months of glucocorticoid therapy [J Bone Miner Res. 2000;15:993-1000; Med Pediatr Oncol. 2003;41:212-216; Osteoporos Int. 2002;13:777-787]. In glucocorticoid-induced osteoporosis (GIOP), the risk of fractures exceeds the risk of reduced BMD [bone mineral density]. Thus, for a given BMD, the risk of fracture may be greater in GIOP than in postmenopausal osteoporosis [Thorax. 1991;46:803-806]. The magnitude of this problem has been demonstrated by cross-sectional studies, which suggest that most patients receiving long-term glucocorticoid therapy have low BMD and that more than one fourth sustain osteoporotic fractures [Arthritis Rheum. 1996;39:1791-1801].^{7 (p37)}

Medical Dermatologists have long been aware of the severe consequences of long-term systemic corticosteroid use and have worked to minimize these risks.

One approach has been the use of steroid-sparing agents. This is best exemplified by the report by Edge et al⁸ on the use of mycophenolate mofetil in 12 patients with dermatomyositis. The good news is that 10 of 12 patients had a rapid response in their strength and skin disease within 8 weeks. Each of the patients had been treatment failures to prednisone and/or methotrexate sodium as well as a number of other medications. Fortunately, most of these patients were able to be weaned off of prednisone and methotrexate. Unfortunately, their care was complicated by 1 case of breast cancer, 1 case of Epstein-Barr virus–induced central nervous system lymphoma, and 2 cases of mild hematologic abnormalities. Hantash and Fiorentino⁹ also report on 2 patients who developed increased levels of serum hepatic transaminases (liver function tests) while being treated with mycophenolate mofetil as a steroid-sparing agent for severe atopic dermatitis. These are important reminders that emphasize the need for vigilant surveillance for opportunistic infections, end-organ toxic effects, and malignancies in all patients treated with immunosuppressive agents.

Liu et al⁷ report on 35 dermatology patients receiving 10 mg/d of prednisone or greater for their autoimmune skin diseases. At the time of referral, 80% of patients were not receiving osteoporosis prophylaxis with a bisphosphonate. This report shows that bisphosphonate use for dermatology patients was not affected by the 2001 American College of Rheumatology guidelines that recommended bisphosphonates for all patients without contraindications, beginning long-term oral corticosteroid therapy, 5 mg/d of prednisone or greater. “At the time of the first available DEXA [dual energy x-ray absorptiometry] scan, 7 patients still had T-score values within the normal range, 8 were osteopenic, and 3 were osteoporotic.”^{7 (p39)}

Summey and Yosipovitch¹⁰ provide an excellent practical update on the prevention of GIOP. This should be required reading because dermatologists are among the leading prescribers of high-dose oral corticosteroids. The take-home message is simple: Patients receiving high-dose (≥5 mg/d) chronic (anticipated, ≥3 months) prednisone should be started on 1500 mg/d of calcium and 800 IU/d of vitamin D and an oral bisphosphonate on the day they start therapy. These patients should also receive a baseline DEXA scan, with follow-up every 6 to 12 months.

The first choice for prevention and treatment of glucocorticoid-induced osteoporosis should be a potent oral bisphosphonate such as alendronate sodium (70 mg/wk) or risedronate sodium (35mg/wk). Patients who are unable to sit upright for 60 minutes after taking oral bisphosphonate or who have esophagitis should be treated with an intravenous bisphosphonate such as pamidronate disodium or zolendronate (zolendronic acid). Premenopausal women interested in becoming pregnant should not receive bisphosphonates. Options for this group include vitamin D metabolites or calcium and plain vitamin D. If bisphosphonates are used, strict contraceptive measures should be addressed and documented. In patients with severely diminished bone density (T score <−3.5) or patients with active osteoporotic fractures, the anabolic agent teriparatide should be considered as a first-line option for up to 2 years.^{10 (p88)}

Bisphosphonate use for GIOP prevention is low in studies of primary care physicians and specialists in this country and abroad.

[s]tudies have shown that less than 50% of patients receiving long-term treatment with oral steroids have been evaluated for osteoporosis, and less than 25% have been treated [BMJ. 1996;313:344-346; Chest. 1994;105:1722-1727].^{10 (p83)}

Multifaceted interventions have since been developed to improve the management of GIOP in patients who receive long-term glucocorticoid therapy [Arthritis Rheum. 2004;51:383-387; J Rheumatol. 2004;31:550-556]. The results have so far been mixed. Solomon et al [Arthritis Rheum. 2004;51:383-387] designed a 3-part intervention that was specifically targeted toward practicing rheumatologists. The intervention failed to result in any differences in treatment or bone densitometry use even after a 6-month follow-up period. Unlike the study by Solomon et al [Arthritis Rheum. 2004;51:383-387], a comprehensive educational program involving general practitioners and community pharmacies was implemented in Tasmania, Australia, and led to greater use of osteoporosis preventive therapies [J Rheumatol. 2004;31:550-556]. Bisphosphonate use, for example, increased from 6% before intervention to 24% after intervention.^{7 (p39)}

It would be interesting to know how many of the patients in the study by Liu et al⁷ were managed solely by a dermatologist and how many were comanaged with a primary care physician. Most Medical Dermatologists try to work in partnership with a patient's primary care physician. Unfortunately, studies indicate that primary care physicians infrequently practice appropriate GIOP prevention. As Medical Dermatologists, we need to do a better job of not just treating disease but of preventing it. To do this, Medical Dermatologists need to make GIOP prevention the standard of care for all of our patients and initiate it the day the steroid therapy starts.

By any measure, dermatologists are in demand. The demand among medical students to become a dermatologist is unbelievable. The demand of patients to be cared for by a dermatologist is high across the country. Dermatology has expanded to bring our expertise into the care of children, into procedures, into pathology, into cosmesis, and into the care of the Medical Dermatology patient. The use of biologic drugs for psoriasis by over half of American dermatologists reveals that dermatologists have expanded their use of systemic medications to treat skin disease. Also, I believe that dermatologic patients who were previously untreated or undertreated have benefited from more aggressive care. We have developed a new generation of dermatologists who are comfortable and skilled in all aspects of dermatology, especially the care of the Medical Dermatology patient. The future of dermatology in general and Medical Dermatology in particular is bright.

Correspondence: Dr Heffernan, Division of Dermatology, Wright State University, 1 Elizabeth Pl, Dayton, OH 45408 (michael.heffernan@wright.edu).

Financial Disclosure: None.