Medrol

Abstract

The use of cyclosporine to treat psoriasis has been widely adopted since 1997, when the microemulsion form (Neoral) became available. While the causal relationship between cyclosporine and the development of malignant neoplasms has been well described in the transplant literature, it is difficult to apply this relationship to cyclosporine-treated psoriasis, since lower dosages are used (3-5 mg/kg/d vs. 7-15mg/kg/d) for a shorter duration. Current literature suggests that cancer risk is not increased when cyclosporine is used in dermatologic doses for less than 2 years in healthy patients who are not on other immunosuppressants (1). We report two patients with explosive basal cell carcinoma and keratoacanthoma development, respectively, within 3 months of initiation of cyclosporine. Neither patient had a history of skin cancer, had received PUVA therapy, or was on additional immunosuppressive therapy. To our knowledge, there have been no previous reports of the development of similar lesions in cyclosporine-treated psoriatic patients within such a short timeframe. The results of these patients may herald the need for increased awareness by dermatologists for explosively-growing neoplasms in the setting of cyclosporine-treated psoriasis.

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Case 1

A 52-year-old male with a long-term history of psoriasis (with the only treatment beyond topical therapy being methotrexate in the past) and no history of previous skin cancer presented to his primary dermatologist with a dramatic flare starting 6 weeks previously. Approximately 50% of his body surface area was covered with psoriatic plaques. The patient was prescribed cyclosporine 125 mg b.i.d and referred immediately to Baylor Dermatology. The cyclosporine dosage was continued, and triamcinolone 0.1% ointment applied b.i.d was added.

[FIGURE 1 OMITTED]

At his 2 week follow up (approximately week 8 of cyclosporine therapy), the scattered plaques were much improved, and tazarotene 0.03% gel q HS was added. Unfortunately, the patient complained of intense burning with the tazarotene gel and worsening of his psoriasis. This was discontinued and replaced with calcipotriene ointment applied b.i.d Monday through Friday and halobetasol ointment applied b.i.d. on Saturday and Sunday. In addition, the cyclosporine was increased to 250 mg every morning and 125 mg at bedtime.

Two weeks later (week 10 of cyclosporine therapy), the patient's psoriasis was nearly clear except for his hands, where small plaques continued. However, the patient complained of a rapidly growing nodule on his posterior right ear that had appeared after his last visit 2 weeks previously (Figure 1). Examination of this lesion revealed a 2-cm firm nodule with a keratotic crater. Shave biopsy revealed a nodular basal cell carcinoma. Mohs surgery was performed with successful excision of the lesion.

Case 2

A 49-year-old female was admitted to the Methodist Hospital with diffuse erythema and pustules. Two weeks prior to admission, the patient presented to her primary care physician (PCP) with a 1-week history of sore throat and fever. She also complained of a few pruritic, erythematous macules and papules over the dorsal aspect of her hands bilaterally. A rapid strep test revealed streptococcal infection, and the patient was given penicillin IM, a steroid injection, and prescribed a medrol dose pack. She returned to her PCP 1 week later with only mild improvement of her symptoms and an increased number of papules on her hands. She received a second penicillin injection. During the following week the cutaneous lesions progressed into pustules and spread rapidly to her entire body, sparing only her face and plantar surface of her feet, prompting admission to the hospital and dermatology consultation.

[FIGURE 2 OMITTED]

The patient was febrile (37.9[degrees] C) with a mild leukocytosis (15,410 cells/mm3). Physical examination revealed confluent 2-3 mm erythematous papules and pustules concentrated over the palmar and dorsal aspects of her hands and in her intertriginous areas, but also present diffusely over her body. KOH examinations and bacterial culture from two pustules were negative. Acute generalized pustular psoriasis (von Zumbusch type) was suspected and a punch biopsy performed. The patient was started on warm compresses with triamcinolone 0.1% ointment to her body and clobetasol propionate 0.05% ointment to hands and feet every 8 hours.

Two days later, after no improvement of the patient's fever or cutaneous lesions, oral cyclosporine 200 mg b.i.d. was initiated under the presumptive diagnosis of pustular psoriasis. The initial biopsy specimen did not have features of psoriasis, only spongiotic dermatitis. A second punch biopsy was immediately performed, and was consistent with pustular psoriasis.

The patient was discharged from the hospital on day 5 of cyclosporine therapy after significant improvement of the pustules and plaques. On day 14 of cyclosporine therapy, the patient was seen as an outpatient in the dermatology clinic for follow-up. There were no new pustules on her body or face and only scattered, thin plaques remained on her arms and legs. There were scattered pustules on the lateral digits, along with erythematous plaques and mild edema over the rest of her hands. The cyclosporine was continued at 200 mg b.i.d., and the Clobetasol was replaced with triamcinolone 0.1% cream for her hands.

At the next follow-up appointment, on day 29 of cyclosporine therapy, the plaques and pustules had cleared from her body. The patient's only complaint was of new lesions on her hands that had erupted since the last visit 2 weeks ago. On her hands there were eight keratotic papules and nodules ranging in size from 2-10 mm that were not present previously (Figure 2). A shave biopsy of the largest nodule revealed abundant keratin surrounded by a proliferation of stratified squamous epithelium, consistent with a keratoacanthoma. On day 49 of cyclosporine therapy, the patient was seen again. The pustules and plaques associated with the psoriasis had all cleared except for a few lesions on her palms bilaterally. The keratoacanthomas had all shown moderate spontaneous improvement. Tazarotene 0.5% gel was added to her medication regimen, and the patient was instructed to apply the gel to her hands once or twice a day.

On day 58 of cyclosporine, physical examination revealed only a few pustules remaining on her hands and only one keratoacanthoma. The keratoacanthoma had decreased by at least 50% in size since the previous visit. Oral acitretin 25 mg daily was added, and on her next visit, day 72 of cyclosporine, the remaining keratoacanthoma was no longer evident.

Discussion

We describe two patients who developed early and explosive growth of malignant and potentially malignant cutaneous neoplasms shortly after starting cyclosporine for psoriasis. In both cases, the lesions appeared rapidly within a 2-week period. Neither patient was taking any other systemic immunosuppressive medication and both were in good overall health.

A microemulsion formulation of cyclosporine (Neoral) was approved for the treatment of psoriasis in 1997. Although cyclosporine is very effective for psoriasis, there is uncertainty regarding the risk of carcinogenesis when used for relatively short periods of time. According to Comprehensive Dermatologic Drug Therapy, the increased cancer risk is not evident when cyclosporine is used in recommended dermatologic doses (5 mg/kg/day) for less than 2 years in healthy patients not on other immunosuppressants (1). In the Sandoz Pharma clinical study program of 842 patients with psoriasis receiving cyclosporine, 6 patients developed non-melanoma skin cancer (crude incidence rate 0.7%) (2). These 6 patients were on cyclosporine for an average of 11.2 months prior to detection of their malignancy. The majority of the skin cancers were described as small, non-aggressive and detected due to careful and intensive skin examination due to study participation.

The causal relationship between systemic cyclosporine therapy and malignant neoplasm development has been well described in the transplant literature. It is difficult to extrapolate the transplant data in reference to psoriasis patients as much higher doses are used (7-15 mg/kg/day vs. 5 mg/kg/day). In addition, transplant patients tend to be on cyclosporine for much longer than patients with psoriasis. In a review of all cancers found on long-term cyclosporine therapy, 22 of 141 patients post transplantation developed either basal cell or squamous cell carcinoma (3). The average latency period for cancer development in cyclosporine-treated patients was approximately 20 months. Unfortunately, there was no specific mention of the time period to develop skin cancer specifically. A recently published article focusing specifically on the risk of malignancies in psoriasis patients treated with cyclosporine. The authors, using a cohort study, found that these patients have a six-fold increase in skin malignancies compared to the general population. In addition, they found that previous exposure to methotrexate, as is found in patient two, gives a relative risk for the development of skin malignancies at 2.14.

Apart from the effects of cyclosporine, psoriasis itself may increase a patient's risk for developing a malignant neoplasm. It is difficult, however, to distinguish the risk associated with the disease from the risk associated with the treatment for the disease. One study in Denmark, for example, reported the cancer incidence in 6,910 psoriasis patients (5). The authors found that the relative risk of malignancy in the setting of psoriasis is 1.35. The relative risk of non-melanoma skin cancers in these patients was more substantial at 2.5. However, the authors could not account for the prior therapies, including UV therapy and PUVA, both of which increase the risk for skin malignancies.

What is unusual about the patients described above, therefore, is the very rapid development of the cutaneous neoplasms after the initiation of cyclosporine therapy, especially given the absence of previous PUVA therapy. The first patient had an explosively growing BCC after being on cyclosporine for approximately 2 months; the second patient developed keratoacanthomas after being on cyclosporine for approximately 1 month. To the best of our knowledge, these are the first reported cases of the development of (potential) cutaneous malignancies within such a short time span after the initiation of cyclosporine therapy. One published report is of a patient developing squamous cell carcinomas at 6 and 18 m of maintenance cyclosporine therapy (6). Another is of a patient

developing nodular cutaneous T-lymphocytic infiltrates within 14 days of the initiation of therapy (7). This is not a comparable case, however, because the patient was started on a very high dose of cyclosporine (14 mg/kg/day).

The nephrotoxic and hypertensive side effects of cyclosporine make it a complex therapy for psoriasis patients (8). However, given its rapid onset of action, it remains a first-line therapy for severe plaque or pustular psoriasis that necessitates quick amelioration. Whereas the abundance of literature points to 2 years as the cutoff for a greatly increased risk of malignancy in continuous cyclosporine therapy, our experience points to the possibility of much earlier cancer development.

References

1. Koo JY, Lee CS, Maloney JE. Cyclosporine and Related Drugs. In: Wolverton SE (ed.), Comprehensive Dermatologic Drug Therapy. Philadelphia: W.B. Saunders Company. 2001; 205-29.

2. Krupp P, Monka C. Side-Effect Profile of Cyclosporine A in Patients Treated for Psoriasis. Br J Dermatol. 1990; 122:47-56.

3. Penn I. Cancers Following Cyclosporine Therapy. Transplantation 1987; 42:32-5.

4. Paul CF, et al. Risk of Malignancies in Psoriasis Patients Treated with Cyclosporine: a 5 y Cohort Study. J Inv Dermatol. 2003; 120:211-6.

5. Olsen JH, Moller H, Frentz G. Malignant Tumors in Patients with Psoriasis. J Am Acad Dermatol. 1992;27:716-22.

6. Bos JD, Meinardi MMHM. Two Distinct Squamous Cell Carcinomas in a Psoriasis Patient Receiving Low-Dose Cyclosporine Maintenance Treatment [Letter]. J Am Acad Dermatol. 1989; 21:1305-6.

7. Brown MD, et al. Rapid Occurrence of Nodular Cutaneous T-lymphocyte Infiltrates with Cyclosporine Therapy. Arch Dermatol. 1988; 124:1097-100.

8. Fradin MS, et al. Management of Patients and Side Effects During Cyclosporine Therapy for Cutaneous Disorders. J Am Acad Dermatol. 1990; 23:1265-75.

EDWARD L LAIN MDMBA (1), RAMSEY F MARKUS MD (2)

1. DEPARTMENT OF DERMATOLOGY, UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES, LITTLE ROCK, AK. DEPARTMENT OF DERMATOLOGY, BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX

2. DEPARTMENT OF DERMATOLOGY, BAYLOR COLLEGE OF MEDICINE, HOUSTON, TX

ADDRESS FOR CORRESPONDENCE:

Ramsey F. Markus MD

Assistant Professor, Department of Dermatology

Baylor College of Medicine

1 Baylor Plaza, F 840

Houston TX 77030

Phone: (713) 798-6925

Fax: (713) 798-6923

E-mail: rmarkus@bcm.tmc.edu

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