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Ulcerating necrobiosis lipoidica resolving in response to cyclosporine-A

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https://doi.org/10.5070/D36f7981ks
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Ulcerating necrobiosis lipoidica resolving in response to cyclosporine-A
Kevin Smith, M.D.
Dermatology Online Journal: 3(1): 2

Abstract

Necrobiosis lipoidica often fails to respond adequately to therapy with topical and intralesional corticosteroids, or to systemic medications like niacinamide and pentoxifylline (Trental). On the basis of unpublished work which showed a predominance of T helper cells in lesions of necrobiosis lipoidica, and recalling the case of a woman whose necrobiosis lipoidica improved after she was started on cyclosporine for a renal transplant, systemic cyclosporine was successfully used in the cases of two young women who had insulin-dependent diabetes and were disfigured by severe, ulcerating necrobiosis lipoidica on the anterior lower legs. Response to treatment was monitored with photographs. In both cases the ulcers resolved, and remained in remission after cyclosporine was stopped.

Introduction

Necrobiosis lipoidica (NL) is closely associated with diabetes. About 660f patients with NL have overt diabetes, and additional 4% have an abnormal glucose tolerance test, and 110f those with a normal glucose tolerance test have a family history of diabetes. NL occurs in about 0.30f patients with diabetes, with a female:male ratio of 3:1. NL can occur simultaneously with granuloma annulare (GA), which has a similar histology to NL and which is occasionally associated with diabetes. Many patients with NL may demonstrate diabetic end organ damage, including nephropathy, neuropathy and retinopathy.(1)

NL often fails to respond adequately to conventional therapy with topical and intralesional corticosteroids, or to systemic medications like niacinamide and pentoxifylline (Trental). On the basis of unpublished work with Arnold Schroeter and Richard Winkelmann which showed a predominance of T-helper cells in lesions of necrobiosis lipoidica, and recalling the case of a woman whose necrobiosis lipoidica improved after she was started on cyclosporine for a renal transplant, I suggested a trial of treatment with cyclosporine to two young women who had insulin-dependent diabetes and were disfigured by severe, ulcerating necrobiosis lipoidica on the anterior lower legs.

Methods

Response to therapy was monitored by serial photographs of the involved areas. Both the patients and myself knew that active cyclosporine was being administered (there was no placebo control). Patients were given printed instructions on the correct use of cyclosporine. Patients were instructed to monitor blood glucose daily, and they reported that there were no changes from usual while taking cyclosporine. Creatinine and blood pressure were monitored once a week for the first month, then twice a month while the patients were taking cyclosporine.

Case 1: Female with insulin dependent diabetes diagnosed at the age of 14 in 1987, and biopsy proven NL on the lower legs since 1990. The lesions on the lower legs did not respond adequately to trials of treatment with:

  • niacinamide 1.5 grams bid from May 1991 until November 1993.
  • psoralen plus ultraviolet-A light (PUVA), stopped in June 1992 after 26 treatments.
  • intralesional injections of triamcinolone acetonide (Kenalog)
    • right lower leg: 3 ml of 5 mg/ml in September 1991 and 3 ml of 3 mg/ml in January 1994.
    • left lower leg: 3 ml of 3mg/ml in December 1993 and 1.5 ml of 6 mg/ml in November 1994.
  • pentoxifylline (Trental) 400 mg tid - from February 1992 until April 1992, and again for 6 weeks from November until December 1994.
  • flurandrenolide 4 ug/cm2 tape (Drenison) - from November 1993 until January of 1994.
Ulceration of the lesions of NL on the lower legs developed in October 1994. These did not respond adequately to the addition of a hydrocolloid dressing (Duoderm-CGF) to her treatment program, and cyclosporine-A (Sandimmune) 100 mg tid (~ 5 mg/kg/day) was started on 15 February 1995 (image 1). This was well tolerated and the ulcers started to resolve within 4 weeks (image 2, image 3). Sandimmune was stopped 23 May 1995 (image 4), and the ulcers remained in remission without any treatment until late March 1996 (image 5, image 6) when two 1 cm erosions developed in the NL on the left anterior lower leg. Sandimmune 100 mg bid was resumed in late April 1995 and discontinued in 1 month when the ulcers resolved.
FIGURE 1 FIGURE 2
Figure 1 (left): Case 1: start of cyclosporine.
Figure 2 (right): Case 1: day 34 of cyclosporine
FIGURE 3 FIGURE 4
Figure 3 (left): Case 1: day 64 of cyclosporine
Figure 4 (right): Case 1: day 97 - final day of cyclosporine
FIGURE 5 FIGURE 6
Figure 5 (left):Case 1: 15 days after stopping cyclosporine
Figure 6 (right): Case 1: 142 days after stopping cyclosporine
Case 2: Female with insulin-dependent diabetes diagnosed at the age of 13 in 1977, and NL on the lower legs since 1983. Ulceration in the lesions of NL started in 1989, and did not respond adequately to:
  • niacinamide 1.5 grams bid for several months - stopped in 1989.
  • intralesional injections by another physician with triamcinolone acetonide (Kenalog)5 mg/ml, stopped in 1989. The total number of injections and the total amount of Kenalog injected is not known.
Her NL responded partially to:
  • 205 treatments with psoralen plus ultraviolet-A light (PUVA) between April 1994 and July 1995.
  • pentoxifylline (Trental) 400 mg tid started in 1993 and continued to the present time.
1 - 2 cm ulcers in the lesions of NL on the lower legs continued to develop, and on 19 July 1995 cyclosporine-A (Sandimmune Neoral) 100 mg bid (~3mg/kg/day) was started. She was also taking erythromycin (ERYC) 250 mg bid for diabetic gastroparesis. Trental 800 mg tid and PUVA were continued. Apart from occasional mild nausea Sandimmune Neoral was well tolerated and the ulcerated areas resolved over a period of 2 months.

There was a transient elevation of the serum creatinin to 189 µmol/L in October 1995 and Sandimmune Neoral was stopped, with return of the serum creatinin to normal over a period of several months. Several 1 cm erosions developed in the lesions of NL in December 1995, perhaps because the patient had started to smoke in December. Smoking was stopped, and the NL has been kept in remission since December 1995 with PUVA twice a week and Trental 800 mg tid.

Discussion

The following lines of evidence led to this trial of treatment with cyclosporine-A in the cases presented here:
  • Cell marker studies on biopsy specimens from lesions of NL and GA demonstrated a predominance of T-helper cells (unpublished data: Smith KC, Winkelmann RK & Schroeter AL).
  • A diabetic patient with necrobiosis lipoidica noted improvement of her necrobiosis lipoidica after starting cyclosporine-A as part of a renal transplant protocol (unpublished data: Smith KC, Winkelmann RK & Schroeter AL).
  • NL has been reported to respond to anti-inflammatory treatments, including PUVA(2), niacinamide(3), and topical(4), intralesional(5) and systemic(6) corticosteroids. Cyclosporine acts as a very specific anti- inflammatory agent, selectively inhibiting T-cell proliferation in response to mitogens or alloantigens. It is most effective early in the immune response, and is thought to act mainly by selectively inhibiting the expression of some genes, in particular the IL-2 gene. IL-2 plays a critical role the commitment to growth and development of helper / inducer T cells and helper / inducer T cell-induced maturation of cytotoxic T cells . It may also dampen IL-1 release from some macrophages and antagonize IL-2 driven DNA synthesis.

Because of the potential for nephrotoxicity, in particular in diabetics who may already have poor renal function secondary to diabetic nephropathy , close monitoring of serum creatinin is essential, in particular when the patient is taking medications such as erythromycin (Case Two) which may increase the blood level of cyclosporine.

Conclusion

Cyclosporine-A is useful in the management of severe ulcerating NL, and long-term treatment with cyclosporine was not needed in these cases.

Acknowledgement: Sandimmune Neoral was provided by Sandoz Canada. The author has acted as a speaker for Sandox (Novartis) Corporation.

References

1. Demis: Clinical Dermatology; Volume 1, Unit 4-8:1-7, revision CD-94.Lippincott-Raven, Philadelphia, 1997.

2. Honig B, Morrison WL, Karp D: Photochemotherapy beyond psoriasis. J Am Acad Dermatol 31:775-790, 1994.

3. Handfield-Jones S, Jones S, Peachey R: High-dose nicotinamide in the treatment of necrobiosis lipoidica. Br J Dermatol 118:693-696, 1988.

4. Goette DK: Resolution of necrobiosis lipoidica with exclusive clobetasol propionate treatment. J Am Acad Dermatol 22:855-856, 1990.

5. Sparrow G, Abell E: Granuloma annulare and necrobiosis lipoidica treated by jet injector. Br J Dermatol 93:85-89, 1975.

6. Petzelbauer P, Wolff K Tappeiner G: Necrobiosis lipoidica: Treatment with systemic corticosteroids. Br J Dermatol 126 :542-545, 1992. 


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