January 2004

Fig2

Fig3

Diagnosis: Necrobiosis Lipoidica Diabeticorum (NLD).

Theraputic Challange: The ulcer had been present for over two years and persisted despite aggressive local wound care including surgical debridement, topical, intralesional and oral corticosteroids. She also received several courses of Trental. The goal was to heal the ulcer and then institute therapy for the NLD, her primary disease process. The mainstay of treatment of NLD has been through the use of topical, intralesional, or oral corticosteroids ironically all of which carry the inherent risk of atrophy. We sought to find a steroid sparing drug with anti inflammatory effects.

Treatment Course and Effects:

The patient was initially treated for the persistent lower leg ulcer. After 6 weeks of Unna Boot therapy, the ulcer was completely healed and the patient was switched to compression garments.
At this time the patient was enrolled in the STEPS (System for Thalidomide Education and Prescribing Safety) program and began treatment for her NLD with Thalidomide, 150 mg qhs. After one month of treatment there was significant improvement with lightening and smoothing of the borders of the lesions and a decrease in pain. After 4 months of successful therapy the thalidomide dose was decreased to 50 mg qhs because of fatigue. At this lower dose she continues to improve and has developed no new ulcers. Figures 2 & 3 show the patient's response after seven months of therapy.

Discussion: Thalidomide is currently approved for the alleviation of the symptoms of erythema nodosumm(1). However, it has been used off label for a variety of conditions from vesiculobullous dermatoses, lymphocytic and neutrophilic dermatoses and HIV related dermatoses to such conditions as graft-versus-host disease, sarcoidosis, palmar plantar pustulosis and prurigo nodularis (2).

Thalidomide has several mechanisms of action that makes it a suitaable candidate for the treatment of NLD: hypnosedative, anti-inflammatory and angiogenesis inhibition. The hypnosedative effect is thought to be beneficial in the management of NLD associated pain, especially at night. For this reason the patient was instructed to take the medication at bedtime. The initial dose of 150 mg caused excessive sedation during the day time but the lower 50 mg dose maintained clinical improvement while avoiding over sedation.

Thalomide's anti-inflammatory effect results from a variety of mechanisms including a decrease in neutrophil chemotaxis (3), a decrease in monocyte and neutrophil phaagocytosis (4) and antagonism of inflammatory mediators such as serotonin, acetylcholine, prostaglandin, and histamine (5). Because NLD is an inflammatory process associated with new vessel formation we suspected that the anti-inflammatory effects of Thalidomide would inhibit progression of the disease process in the acute phase. This was supported by the lack of inflammatory cells seen in the biopsy (Fig.5) taken at the edge of a plaque after 7 months of treatment.

NLD has been proposed to haave a vasculopahic eteology (6). Consequently we thought that te angiogenesis inhibition(7) elecited by Thalidomide might cause a decrease in the blood supply to the granulaation response leading to cessaion of disease progression and improvement in previously affected areas. Since Thalomide is a highly teratogenic drug, it is essential that ther is strict adherence to the S.T.E.P.S. prescribing guidelines (8). The fact that NLD preferentially affects women with an averaage age of onset in the third decade of life, use of Thalidomide in women of childbearing age may be prohibitive. Although our patient developed NLD in her thirties, she was 52 and post-menopausal when treatment with thalidomide was begun.

One of the most common side effects of Thalidomide is the risk for peripheral sensory neuropathy. This has been shown to abe dose-dependent with an increased risk associated with daily doses of greater than 50 mg (9). Although this patient started on a dose of 150 mg, she continued to improave clinically and improvement was maintained after the dose was decreased to 50 mg daily. Although the patient did not have a history of co-existent diabetes melitus (DM), many patients do. The fact that DM alone is associated with an increased risk for peripheral neuropathy, does not lead us to believe that treatment with Thalidomide will compound the risk for neuropathy. Likewise we do not believe that patients with pre-existing sensory neuropathy secondary to DM will have an exacerbation of their condition while on Thalidomide.

The patient presented here experienced significant improvement in symptoms related to her bilateral lower extremety NLD after being on a low dose of Thalidomide for less than one year. She has had regression of disease in previously existing plaques and has developed no new ulcers.We have treated several other patients with low dose Thalidomide (50 mg daily) with similar results.

References:

1. Stirling D, Sherman M, Strauss S: Thalidomide - a surprising recovery. J Amer Pharm Assoc NS37:306-313,1997.

2. Knable AL Jr: Miscellaneous systemic drugs. In Wolvertom, SE , editor, Comprehensive Drug Therapy. W.B.Saunders, Philadelphia 2001,pp455-464.

3. Faure M, Thivolet J, Gaucherand M: Inhibition of PMN leukocyte chemotaxis by thalidomide. Arch Dermatol Res 269:275-280, 1980.

4. Barnhill RL, Doll NJ, Milikan, LE, et al: Studies on the anti-inflammatory properties of thalidomide: effects on polymorphonuclear leukocytes and monocytes. JAAD 11:814-819, 1980.

5. Hastings RC: Kellersberger Memorial Lecture 1979: Immnosuppressive/anti-inflammatory thalidomide analogues. Ethiop Med J 18:65-71, 1980.

6. Jorizzo JL,Olansky AJ, Stanley RJ: Superficial ulcerating necrobiosis in rheumatoid arthritis. A variant of the necrobiosis lipoidica-rheumatoid nodule spectrum? Arch Derm 118:255-259, 1982.

7. D'Amato RJ, Loughnan MS, Flynn E,et al: Thalidomide is an inhibitor of angiogenesis. Proc Natl Acad Sci USA 91:4082-4085, 1984.

8. System for thalidomide education and prescibing safety: Thalomide - balancing the benefits and risks. Copyright 1998, Celgene Corporation, Warren, NJ 07059 USA (1-888-4-CELGENE).

9. Bastuji-Garin S, Ochonisky S, Revuz J, et al: Incidence and risk factors for thalidomide neuropathy: a prospective study of 135 dermatologic patients. J Invest Dermatol 119:1020-1026, 2002.

This case was submitted by Drs. Tracy Stull and Jeff Petersen.