British Journal of Dermatology (1990) 122, Supplement 36, 41-45.
Cyclosporin A in atopic dermatitis J.S.ROSS AND R.D.R.CAMP St John's Hospital for Diseases of the Skin and St Thomas's Hospital, London, U.K.
SUMMARY
Over the past 10 years, oral cyclosporin A (CyA) has been used to treat a range of inflammatory and immunologically mediated dermatological conditions, but only psoriasis has been shown to be responsive in double-blind, controlled trials. Thirteen patients with severe atopic dermatitis were treated for up to 31 months. Ten patients had a good response, one patient a moderate response and two a slight response. In two of these patients, CyA was withdrawn after more than 2 years of continuous treatment because of increasing plasma creatinine levels. Cyclosporin A appears to be useful in the treatment of severe, therapy-resistant atopic dermatitis, but careful monitoring of side-effects and dose adjustments are required.
Cyclosporin A (CyA) has been used to treat a range of infiammatory and immunologically mediated skin diseases.' However, double-blind placebo-controlled trials^' have confirmed that only in psoriasis is orally administered CyA therapeutically effective. There is now increasing uncontrolled evidence suggesting that CyA is useful in atopic dermatitis. In 1987, Van Joost ei al.-* reported favourable responses in two patients given low-dose CyA for 6-8 weeks. Subsequently, Logan and Camp' found CyA to be helpful in two patients treated for 5 and II months, respectively. In 1989, Taylor et al.^ described six patients with atopic dermatitis given CyA 6 mg/kg/day for 8 weeks. Five patients responded, four experiencing greater than 5O"o improvement within 4 weeks. One patient failed to respond and, of the initial responders, three flared during treatment. The authors concluded that CyA may be beneficial in some patients with atopic dermatitis. Two descriptions of the effectiveness of CyA in single cases of atopic dermatitis have also been reported.''^ The experience in Newcastle-upon-Tyne in the U.K. is that CyA is highly effective in the majority of patients who have atopic dermatitis treated with oral CyA (S. Shuster, personal communication), although such findings have not been universal (K. Wolff, personal communication). This is a report of uncontrolled observations in 13 patients who had severe, therapeutically unresponsive, atopic dermatitis treated with CyA for r-31 months.
Correspondence: Dr R.Camp, Institute of Dennatology, St Thomas's Hospital, Lambeth Palace Road, London SEl 7EH, U.K.
41
y.S.Ross and R.D.R.Camp TABLE I. Clinical data of 13 patients given CyA for severe atopic dermatitis
Age
Gender
Treatment duration (months)
I 2
40 64
F F
9 9
3
38
4
30 60
F M M M M
26 31 25
Patient number
5 6 7 8
39 36 x8
9 10
II 12
13
20 26 25 31 37
F
F F M M M
6 3 5 7 8 I 2 I
Previous treatment
Global respome
SS
Good Good Good Good Good Good Good Slight
SS, AZ, PUVA PUVA SS, AZ, PUVA SS, AZ, PUVA —
SS, AZ, PUVA UVB
SS, PUVA PUVA SS, PUVA — SS
SUght Moderate
Good Good Good
SS, systemic steroids; AZ, azathioprine. PATIENTS
Over the past 4 years, 13 adult patients (six females and seven males; age range 18-64 years) have been treated with low-dose CyA (2-6 mg/kg/day). All patients fulfilled the diagnostic criteria of Hanifin and Rajka for atopic dermatitis.** All patients had failed to respond to conventional treatment with emollients, topical steroids and oral antihistamines, and all but one had been admitted on at least one occasion for intensive topical therapy. All were judged to have sufficiently severe disease to justify treatment with CyA. Eight patients had received at least one course of systemic corticosteroids, four had received oral azathioprine, and eight had undergone PUVA photochemotherapy (Table I). This treatment was not continued because of unsatisfactory clinical responses or, in a minority, because of the occurrence of side-effects. With one exception, none of the patients had a history of hypertension, or renal, liver or malignant disease, and none was receiving drugs considered to interfere with the pharmacokinetics of CyA. The exception was a 65-year-old female with severe atopic dermatitis who had, 20 years previously, undergone cone biopsy followed by hysterectomy for apparent intraepithelial cervical neoplasia. Gynaecological examination had, however, revealed that she was free of genital disease. MANAGEMENT
Cyclosporin A treatment was begun in eight patients in the outpatients' clinic and these patients were seen at i- to 2-week intervals for 4-6 weeks. In the remaining five patients, CyA treatment was begun during a period of admission to hospital. Once stabilized, patients were seen at 4-week intervals. Starting doses of CyA varied from 2 to 5 mg/kg/day and were given in divided doses except for three patients who took once-daily doses. Maintenance doses ranged between 25-6 mg/kg/day (average 4 mg/kg/day) and were the lowest dosages able to maintain adequate disease control. Most patients, therefore, had some residual degree of dermatitis because of this therapeutic principle of using the lowest possible maintenance dose.
CyA in atopic dermatitis 43 Patients were encouraged to use emollients and topical steroids, and oral antihistamines and antibiotics were prescribed when necessary. Monitoring of side-effects was carried out at each visit and comprised blood pressure estimation, urinalysis, full plasma biochemical screening including creatinine, urea, electrolytes, uric acid, alkaline phosphatase and alanine transaminase. Creatinine clearance measurements have been performed at intervals of approximately 3 months in the last 18 months. Whole blood trough CyA levels were determined regularly at the outset, but were subsequently carried out infrequently as the dosage of CyA was determined by clinical response and monitoring of side-effects. These studies were not company-sponsored, but were funded by the National Health Service as part of normal patient care.
CLINICAL RESPONSES AND SIDE-EFFECTS
Within 1-4 weeks of starting CyA treatment, all patients showed some improvement in the extent and severity of disease and degree of pruritus. On global assessment, this improvement was judged to be good in 10 patients, moderate in one and slight in two (Table I). Nine patients responded dramatically with substantial improvement noted within i week of starting treatment. In the remaining four patients, improvement (although only slight in two cases) was noted after 2-4 weeks. Whenever possible, the dose of CyA was reduced to the minimum effective level. In rwo patients (numbers 8 and 9 in Table I), the response to treatment was only slight in spite of an increase in CyA dose to 6 mg/kg/day. In both patients, 12-hour trough blood levels of CyA were low with this dose (54-87 ng/ml, monoclonal antibody radioimmunoassay). These observations were inexplicableas neither patient was receiving drug treatment known to interfere with the pharmacokinetics of CyA. In view of their only slight responses to treatment, CyA was stopped after 5 and 7 months in these two patients, respectively. One patient subsequently improved while receivingtraditional Chinese herbal remedies, but the other was lost to follow-up. CyA was stopped in two patients (numbers 4 and 5 in Table I) after 25 and 31 months, respectively, because of progressive increases in plasma creatinine. Plasma creatinine levels did not fall substantially following reduction of CyA dose (Figs 1 and 2), and the lower doses were associated with worsening of the dermatitis. Patient number 4 (Table I) was subsequently controlled with oral prednisolone (maximum dose 15 mg/day). The prednisolone was gradually tapered and stopped after 7 months. The patient then remained in remission without treatment other than emollients, and was discharged from follow-up. The other patient (number 5 in Table I) required re-admission to hospital for intensive topical treatment because of an erythrodermic fiare. PUVA photochemotherapy was successfully reintroduced and, at the time of writing, has provided adequate control for 6 months. In both of these patients, plasma creatinine levels returned to baseline within 4-5 months of stopping CyA. One patient (number I in Table I) stopped CyA treatment after 9 months during a period of disease quiescence while on holiday and, since then, has been able to maintain adequate disease control with topical steroids. At present, the remaining eight patients are continuing with CyA therapy. Seven have been considered to be well controlled, and one (number io in Table I) moderately so. Three patients have required treatment with oral nifedipine for CyA-induced hypertension. In one case, this was changed to atenolol because of side-effects and insufficient control. Significant infection was encountered in only one patient (number 5 in Table I), who developed a low-grade
44
J.S.Ross and R.D.R.Camp 12
ftonths 18
2(1
30
50 18 2U Months FIGURE I. CyA dose, plasma creatinine and diastolic blood pressure levels in patient number 4 during 31 months of CyA treatment. 12
Staphylococcal folliculitis of both forearms which was unresponsive to repeated courses of fiucloxacillin. This problem was present both before and during CyA therapy, but cleared after CyA was stopped. No cases of herpes simplex infection were encountered. COMMENT
Low-doseoral CyA appears to have been effective in inducing clinically useful improvement in 11 out of 13 patients with atopic dermatitis. These patients all had severe disease, and CyA appeared to be more beneficial than previous regimes in all but two cases. Cyclosporin A was subjectively well tolerated and, in the majority, was associated with substantial improvement within 1 week. These results are encouraging and, in the U.K., a multicentre randomized, double-blind, placebo-controlled, cross-over study of CyA in atopic dermatitis is nearing completion. The safety of short- and long-term CyA in atopic dermatitis also requires further assessment. At present, its use should be restricted to patients with severe disease unresponsive to conventional treatment and for whom PUVA photochemotherapy is unsuccessful, contraindicated or not possible. To our knowledge, CyA has not been used in the treatment of children with severe atopic dermatitis. Careful monitoring and adjustment of dosage to the lowest effective level are
CyA in atopic dermatitis
45
Honths 6
02
18
J
T3 0)
3
a.
J
I
ex
•
o ».* CO
110 100
/\
90 SO 70
/
•^
\
V
60
50 105
A
100
90 85 80
/
A rt V \ i i \
/ .
5—a.
12
18
; topped
95
30
Months
HGURE 2. CyA dose, plasma creatinine and diastolic blood pressure levels in patient number 5 during 26 months of CyA treatment.
essential in all cases. The exclusion criteria and other guidelines outlined elsewhere in this supplement regarding the use of CyA in psoriasis should, as far as possible, be strictly followed. REFERENCES 1 Gupta AK, Brown MD, Ellis CN et al. Cyclosporine in dermatology. J Am Acad Dermatol 1989; 21: 1245-56. 2 Ellis CN, Gorsulowsky DC, Hamilton TA et al. Cyclosporine improves psoriasis in a double-blind study. yAMA 1986; 256: 3110-6. 3 Van Joosi T, Bos JD, Heule F et al. Low-dose cyclosporin A In severe psoriasis. Br y Dertnatol 1988; 118: 183-90. 4 Van Joost T, Stolz E, Heule F. Efficacy of low-dose cyclosporine in severe atopic skin disease. Arch Dermatol 1987; 123; 166-7. 5 Logan RA, Camp RDR. Severe atopic eczema: Response to oral cyclosporin A. y Roy Soc Med 1988; 81: 417-8. 6 Taylor RS III, Cooper KD, Headington JT et al. Cyclospodne therapy for severe atopic dermatitis. 7 Am Acad Dermatol 1989; 21: 580-3. 7 Motley RJ, Whittaker JA, Holt PJA. Resolution of atopic dermatitis in a patient treated with cyclosporin. Clin Exp Dertnatol 1989; 14: 243-4. 8 Gould MH, Picascia DD, Roenigk HH. Treatment-resistant atopic dermatitis controlled with cyclosporin A. Im y Dermatol 1989; 28: 481-2. 9 Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980; Suppi 92: 44-7.
Cyclosporin A in atopic dermatitis J.S.ROSS AND R.D.R.CAMP St John's Hospital for Diseases of the Skin and St Thomas's Hospital, London, U.K.
SUMMARY
Over the past 10 years, oral cyclosporin A (CyA) has been used to treat a range of inflammatory and immunologically mediated dermatological conditions, but only psoriasis has been shown to be responsive in double-blind, controlled trials. Thirteen patients with severe atopic dermatitis were treated for up to 31 months. Ten patients had a good response, one patient a moderate response and two a slight response. In two of these patients, CyA was withdrawn after more than 2 years of continuous treatment because of increasing plasma creatinine levels. Cyclosporin A appears to be useful in the treatment of severe, therapy-resistant atopic dermatitis, but careful monitoring of side-effects and dose adjustments are required.
Cyclosporin A (CyA) has been used to treat a range of infiammatory and immunologically mediated skin diseases.' However, double-blind placebo-controlled trials^' have confirmed that only in psoriasis is orally administered CyA therapeutically effective. There is now increasing uncontrolled evidence suggesting that CyA is useful in atopic dermatitis. In 1987, Van Joost ei al.-* reported favourable responses in two patients given low-dose CyA for 6-8 weeks. Subsequently, Logan and Camp' found CyA to be helpful in two patients treated for 5 and II months, respectively. In 1989, Taylor et al.^ described six patients with atopic dermatitis given CyA 6 mg/kg/day for 8 weeks. Five patients responded, four experiencing greater than 5O"o improvement within 4 weeks. One patient failed to respond and, of the initial responders, three flared during treatment. The authors concluded that CyA may be beneficial in some patients with atopic dermatitis. Two descriptions of the effectiveness of CyA in single cases of atopic dermatitis have also been reported.''^ The experience in Newcastle-upon-Tyne in the U.K. is that CyA is highly effective in the majority of patients who have atopic dermatitis treated with oral CyA (S. Shuster, personal communication), although such findings have not been universal (K. Wolff, personal communication). This is a report of uncontrolled observations in 13 patients who had severe, therapeutically unresponsive, atopic dermatitis treated with CyA for r-31 months.
Correspondence: Dr R.Camp, Institute of Dennatology, St Thomas's Hospital, Lambeth Palace Road, London SEl 7EH, U.K.
41
y.S.Ross and R.D.R.Camp TABLE I. Clinical data of 13 patients given CyA for severe atopic dermatitis
Age
Gender
Treatment duration (months)
I 2
40 64
F F
9 9
3
38
4
30 60
F M M M M
26 31 25
Patient number
5 6 7 8
39 36 x8
9 10
II 12
13
20 26 25 31 37
F
F F M M M
6 3 5 7 8 I 2 I
Previous treatment
Global respome
SS
Good Good Good Good Good Good Good Slight
SS, AZ, PUVA PUVA SS, AZ, PUVA SS, AZ, PUVA —
SS, AZ, PUVA UVB
SS, PUVA PUVA SS, PUVA — SS
SUght Moderate
Good Good Good
SS, systemic steroids; AZ, azathioprine. PATIENTS
Over the past 4 years, 13 adult patients (six females and seven males; age range 18-64 years) have been treated with low-dose CyA (2-6 mg/kg/day). All patients fulfilled the diagnostic criteria of Hanifin and Rajka for atopic dermatitis.** All patients had failed to respond to conventional treatment with emollients, topical steroids and oral antihistamines, and all but one had been admitted on at least one occasion for intensive topical therapy. All were judged to have sufficiently severe disease to justify treatment with CyA. Eight patients had received at least one course of systemic corticosteroids, four had received oral azathioprine, and eight had undergone PUVA photochemotherapy (Table I). This treatment was not continued because of unsatisfactory clinical responses or, in a minority, because of the occurrence of side-effects. With one exception, none of the patients had a history of hypertension, or renal, liver or malignant disease, and none was receiving drugs considered to interfere with the pharmacokinetics of CyA. The exception was a 65-year-old female with severe atopic dermatitis who had, 20 years previously, undergone cone biopsy followed by hysterectomy for apparent intraepithelial cervical neoplasia. Gynaecological examination had, however, revealed that she was free of genital disease. MANAGEMENT
Cyclosporin A treatment was begun in eight patients in the outpatients' clinic and these patients were seen at i- to 2-week intervals for 4-6 weeks. In the remaining five patients, CyA treatment was begun during a period of admission to hospital. Once stabilized, patients were seen at 4-week intervals. Starting doses of CyA varied from 2 to 5 mg/kg/day and were given in divided doses except for three patients who took once-daily doses. Maintenance doses ranged between 25-6 mg/kg/day (average 4 mg/kg/day) and were the lowest dosages able to maintain adequate disease control. Most patients, therefore, had some residual degree of dermatitis because of this therapeutic principle of using the lowest possible maintenance dose.
CyA in atopic dermatitis 43 Patients were encouraged to use emollients and topical steroids, and oral antihistamines and antibiotics were prescribed when necessary. Monitoring of side-effects was carried out at each visit and comprised blood pressure estimation, urinalysis, full plasma biochemical screening including creatinine, urea, electrolytes, uric acid, alkaline phosphatase and alanine transaminase. Creatinine clearance measurements have been performed at intervals of approximately 3 months in the last 18 months. Whole blood trough CyA levels were determined regularly at the outset, but were subsequently carried out infrequently as the dosage of CyA was determined by clinical response and monitoring of side-effects. These studies were not company-sponsored, but were funded by the National Health Service as part of normal patient care.
CLINICAL RESPONSES AND SIDE-EFFECTS
Within 1-4 weeks of starting CyA treatment, all patients showed some improvement in the extent and severity of disease and degree of pruritus. On global assessment, this improvement was judged to be good in 10 patients, moderate in one and slight in two (Table I). Nine patients responded dramatically with substantial improvement noted within i week of starting treatment. In the remaining four patients, improvement (although only slight in two cases) was noted after 2-4 weeks. Whenever possible, the dose of CyA was reduced to the minimum effective level. In rwo patients (numbers 8 and 9 in Table I), the response to treatment was only slight in spite of an increase in CyA dose to 6 mg/kg/day. In both patients, 12-hour trough blood levels of CyA were low with this dose (54-87 ng/ml, monoclonal antibody radioimmunoassay). These observations were inexplicableas neither patient was receiving drug treatment known to interfere with the pharmacokinetics of CyA. In view of their only slight responses to treatment, CyA was stopped after 5 and 7 months in these two patients, respectively. One patient subsequently improved while receivingtraditional Chinese herbal remedies, but the other was lost to follow-up. CyA was stopped in two patients (numbers 4 and 5 in Table I) after 25 and 31 months, respectively, because of progressive increases in plasma creatinine. Plasma creatinine levels did not fall substantially following reduction of CyA dose (Figs 1 and 2), and the lower doses were associated with worsening of the dermatitis. Patient number 4 (Table I) was subsequently controlled with oral prednisolone (maximum dose 15 mg/day). The prednisolone was gradually tapered and stopped after 7 months. The patient then remained in remission without treatment other than emollients, and was discharged from follow-up. The other patient (number 5 in Table I) required re-admission to hospital for intensive topical treatment because of an erythrodermic fiare. PUVA photochemotherapy was successfully reintroduced and, at the time of writing, has provided adequate control for 6 months. In both of these patients, plasma creatinine levels returned to baseline within 4-5 months of stopping CyA. One patient (number I in Table I) stopped CyA treatment after 9 months during a period of disease quiescence while on holiday and, since then, has been able to maintain adequate disease control with topical steroids. At present, the remaining eight patients are continuing with CyA therapy. Seven have been considered to be well controlled, and one (number io in Table I) moderately so. Three patients have required treatment with oral nifedipine for CyA-induced hypertension. In one case, this was changed to atenolol because of side-effects and insufficient control. Significant infection was encountered in only one patient (number 5 in Table I), who developed a low-grade
44
J.S.Ross and R.D.R.Camp 12
ftonths 18
2(1
30
50 18 2U Months FIGURE I. CyA dose, plasma creatinine and diastolic blood pressure levels in patient number 4 during 31 months of CyA treatment. 12
Staphylococcal folliculitis of both forearms which was unresponsive to repeated courses of fiucloxacillin. This problem was present both before and during CyA therapy, but cleared after CyA was stopped. No cases of herpes simplex infection were encountered. COMMENT
Low-doseoral CyA appears to have been effective in inducing clinically useful improvement in 11 out of 13 patients with atopic dermatitis. These patients all had severe disease, and CyA appeared to be more beneficial than previous regimes in all but two cases. Cyclosporin A was subjectively well tolerated and, in the majority, was associated with substantial improvement within 1 week. These results are encouraging and, in the U.K., a multicentre randomized, double-blind, placebo-controlled, cross-over study of CyA in atopic dermatitis is nearing completion. The safety of short- and long-term CyA in atopic dermatitis also requires further assessment. At present, its use should be restricted to patients with severe disease unresponsive to conventional treatment and for whom PUVA photochemotherapy is unsuccessful, contraindicated or not possible. To our knowledge, CyA has not been used in the treatment of children with severe atopic dermatitis. Careful monitoring and adjustment of dosage to the lowest effective level are
CyA in atopic dermatitis
45
Honths 6
02
18
J
T3 0)
3
a.
J
I
ex
•
o ».* CO
110 100
/\
90 SO 70
/
•^
\
V
60
50 105
A
100
90 85 80
/
A rt V \ i i \
/ .
5—a.
12
18
; topped
95
30
Months
HGURE 2. CyA dose, plasma creatinine and diastolic blood pressure levels in patient number 5 during 26 months of CyA treatment.
essential in all cases. The exclusion criteria and other guidelines outlined elsewhere in this supplement regarding the use of CyA in psoriasis should, as far as possible, be strictly followed. REFERENCES 1 Gupta AK, Brown MD, Ellis CN et al. Cyclosporine in dermatology. J Am Acad Dermatol 1989; 21: 1245-56. 2 Ellis CN, Gorsulowsky DC, Hamilton TA et al. Cyclosporine improves psoriasis in a double-blind study. yAMA 1986; 256: 3110-6. 3 Van Joosi T, Bos JD, Heule F et al. Low-dose cyclosporin A In severe psoriasis. Br y Dertnatol 1988; 118: 183-90. 4 Van Joost T, Stolz E, Heule F. Efficacy of low-dose cyclosporine in severe atopic skin disease. Arch Dermatol 1987; 123; 166-7. 5 Logan RA, Camp RDR. Severe atopic eczema: Response to oral cyclosporin A. y Roy Soc Med 1988; 81: 417-8. 6 Taylor RS III, Cooper KD, Headington JT et al. Cyclospodne therapy for severe atopic dermatitis. 7 Am Acad Dermatol 1989; 21: 580-3. 7 Motley RJ, Whittaker JA, Holt PJA. Resolution of atopic dermatitis in a patient treated with cyclosporin. Clin Exp Dertnatol 1989; 14: 243-4. 8 Gould MH, Picascia DD, Roenigk HH. Treatment-resistant atopic dermatitis controlled with cyclosporin A. Im y Dermatol 1989; 28: 481-2. 9 Hanifin JM, Rajka G. Diagnostic features of atopic dermatitis. Acta Derm Venereol (Stockh) 1980; Suppi 92: 44-7.
