British Journal of Dermatology (1990) 122, Supplement 36, 33-39.
Efficacy of low-dose cyclosporin A in psoriasis: results of dose-finding studies P.TIMONEN, D.FRIEND, K.ABEYWICKRAMA,* C.LABURTE, B.VON GRAFFENRIED AND G.FEUTREN Immunology Group and •Biostatistics Group, Department of Clinical Research, Sandoz Pharma Ltd, Basle, Switzerland
SUMMARY
The efficacy of cyclosporin A (CyA) in severe psoriasis was analysed in 457 adult patients included in five European multicentre dose-finding studies. Initial CyA doses were 1-25 mg/kg/day in 33 patients, 25-3 mg/kg/day in 285 and 5 mg/kg/day in 139. After 3 months of treatment, the reduction of the Psoriasis Area and Severity Index (PASI) score was 35 ± 6% with I 25 mg/kg/day of CyA, 57 + 2% with 2.5 mg or 3 mg/kg/day and 86 ± 2% with 5 mg/kg/day (P < o.ooi). The rates of success, defined by a PASI score reduction ^ 75% or a score ^ 8 , were 24"n, 52% and 88"/,,, respectively. There were no differences in age, initial severity or duration of psoriasis. The improvement was maintained for 9 months or more in the majority of patients receiving continuous CyA therapy.
The efficacy of cyclosporin A (CyA) in the treatment of psoriasis was recognized soon after it came into use. A dramatic improvement of skin lesions was observed in four patients in a pilot study of CyA in psoriatic arthropathy.' This effect was later confirmed in other pilot^"" and controlled"'" studies. Of major importance was the finding that low-dose CyA (less than 5 mg/kg/day) was also effective.^'''•'^ Because of the potential risk of renal impairment associated with CyA, it was essential to identify the lowest effective dose of CyA.'^ The relationship between dose and efficacy as well as the speed or duration of improvement was investigated in several multicentre studies initiated by Sandoz. This report presents the pooled analyses of these studies. In addition, this large series of patients provided the opportunity to investigate the infiuence of the patients' baseline characteristics on the clinical response. PATIENTS AND METHODS
This analysis included 457 adult patients (mean age 42 years, range 18-75) in five European multicentre dose-finding studies. All patients had severe psoriasis, defined by a PASI score ^ 18 (see below), for a mean duration of 14 years. The mean PASI score at inclusion was 25. Correspondence: Dr G.Feutren, Clinical Research/Immunology, Sandoz Pharma Lid, CH-4002 Basle, Switzerland. 33
34
P. Timonen et al.
Cyclosporin A therapy
The initial CyA doses (divided into two daily doses) were i 25 mg/kg/day in 33 patients, 25 mg or 3 mg/kg/day in 285, and 5 mg/kg/day in 139. Treatment lasted for 3 months in the five studies and, in two of them, the patients with clinical success after 3 months of treatment entered a maintenance period of continuous therapy for up to 12 months. Doses were adjusted on the basis of efficacy or renal dysfunction. In cases of inefficacy after 1-3 months treatment, the dose was increased but without exceeding 5 mg/kg/day. Whenever renal dysfunction was observed, defined as a serum creatinine increase of more than 30% over patient's own baseline, the dose was reduced by 25-50%. Patients who started on 5 mg/kg/day of CyA entered the maintenance period at that dose and began 3 months of gradual reduction of the dose to 25 mg/kg/day. Patients who initially had success on 25 mg/kg/day continued on that dose. Evaluation of severity of psoriasis
Evaluation of the severity of the disease was assessed in all studies by the Psoriasis Area and Severity Index (PASI).'* This is a clinical assessment of the area of the body affected and intensity of the three main lesions: erythema, desquamation and infiltration. Each symptom is scored as absent (= o), slight (= i), moderate (= 2) or severe (= 3). The involved area is estimated and scored within a range of 0^0 (score = o) to 9O-ioo"o (score = 6). The assessments are made separately for four different areas of the body and, using a simple mathematical procedure, a single figure emerges. Thus, a PASI score may describe either very severe lesions over a relatively small area of the body, or less severe lesions but over a larger area. To reduce the variability among the assessors, special PASI training sessions were organized in which all investigators examined the same patient, compared the results and discussed the ratings if there was a disagreement. Success was defmed as a PASI score reduction of 75 "(, or more, ora score ^ 8. A relapse was defined by an increase of 50"^ or more over the score at the time of remission. In most of the patients, global assessments were made by the investigator and by the patient, using a scale of five degrees for efficacy: none, slight, moderate, good or very good. Statistical tests Results are reported as means ± SEM. In cases of inefficacy or failure before Month 3, the last value was carried forward (intention to treat). The statistical significance of the difference between the groups was assessed by Student's r-test. The frequency of abnormalities between groups was compared using Fisher's exact test. RESULTS I
Comparison of PASI changes and global assessment
A strong correlation was found between the changes of PASI score at Month 3 and the patient's or investigator's global assessment (Fig. i). In patients who reported very good responses, the PASI score reduction was 89 ± 1% whereas, in cases of inefficacy, the PASI score was unchanged (an increase of i ± 4%). Of the patients who had PASI score reductions of 75% or more, 73'^V had a very good result, 25'\, a good result and 2",, a moderate improvement. Interestingly, of the patients who had PASI score reductions of 5O-74"(, and who were
Low-dose CyA efficacy in psoriasis
35
100' lnv«9tigator V7P\ patient
50-
2S
(52) (49)
(31)(34) slight
modaratd
good
very good
OVERALL ASSESSMENT OF EFFICACY
FIGURE I. Percentage reduction of the Psoriasis Area and Severity Index (PASI) score according to the overall assessment of efficacy by the patient or the investigator after 3 months of treatment. Means ± SEM.
considered to be 'failures', the global assessment of efficacy was very good in 14% and good in 50%. Induction of remission The percentage of PASI score reduction after 3 months of treatment was 35 ± 6% with 1-25 mg/kg/day of CyA, 57 ± 2";, with 25 mg or 3 mg/kg/day and 86 ± 2% with 5 mg/kg/day (P < 0 OOI vs all groups) (Fig. 2). Success rates at Month 3 were 24%, 52% and 88%, respectively (P ^ o 001) (Fig. 3). Patients'responses were also quicker, depending on dose, as the success rates after only 3 weeks of treatment were 6",,, 10",, and 35"o in the i 25 mg, 25 mg or 3 mg and 5 mg/kg/day CyA dose groups, respectively (P = o 001). The incidence of complete clearing of the psoriasis at 3 months was 0%, 3% and 17% for each dose group, respectively. Seventy-one patients had their CyA doses increased after 3 months from 2-5 mg to 5 mg/kg/day because of insufficient efficacy. The success rate after 3 additional months with 5 mg/kg/day was 77%. No significant difference in clinical response was detected according to age, gender, initial severity or duration of psoriasis with 25 mg (Table I) nor with 5 mg/kg/day of CyA. However, a slightly, but significantly, higher success rate was achieved in the absence of previous treatment with retinoids (P = o 047) or methotrexate (P = o 001) in the CyA 25 mg/kg/day group. No difference was seen with CyA at 5 mg/kg/day (Table 2). Maintenance therapy A subgroup of 72 patients was continuously treated with 2-5 mg/kg/day for 9 months after initial success at 3 months with that dose. Fifteen (21%) relapsed while receiving 25 mg/kg/ day of CyA after a mean treatment duration of 67 months. In a subgroup of 62 patients who
P. Timonen et al.
-25
1-25 -50-
•75.
•100
12 WEEKS
FIGURE 2. Percentage PASI score reduction according to dose in the first 3 months of treatment (intention to treai). Means + SEM; SIM = CyA.
had success with an initial dose of 5 mg/kg/day, CyA was gradually reduced over 3 months to 25 mg/kg/day. Twenty (ag'^o) of these 62 patients had a relapse at a mean dose of 3-5 mg/kg/day after a mean duration of 7 months of CyA treatment. DISCUSSION
In the present study, the analysis of the efficacy was based on the changes of the PASI, a clinical Sandimmun dose
100%'
• 5.0 mg/kg/d
r
50%-
2.5 mg/kg/d
r
1.25 mg/kg/d
25%-
6 WEEKS
12
FIGURE 3. Cumulative success rate in the first 3 months of treatment according to Sandimmun* (CyA) dose. Success was defined as a PASI score reduction ^ 7 5 % or a score of ^ 8 .
Low-dose CyA efficacy in psoriasis
37
TABLE 1. Clinical response of psoriasis with CyA ( 2 5 mg/kg/day) according to baseline characteristics
n i%)
% PASI reduction
51/129 (40) 57/120(47)
55 ± 3 60 ± 3
74/173(43) 34/68 (50)
58 + 3 55 ± 6
54/151 (36) 44/90 (49)
57 ± 3 59 ± 4
55/123(45) 53/116(46)
58 ± 3 58 ± 3
Success rate
Age
^ 40 years >4O Male Female
Gender PASI score Psoriasis duration
^15 years > 15 years
Means + SEM after first 3 months of treatment. Success = PASI score reduction ^75''-,j or a score
score. Changes in this score correlated very well with the global evaluation of efficacy by the patient or the investigator. The PASI score reduction ^ 75%, used in the protocols to define a success, was equivalent to a good or very good response in 98",, of the patients. On the other hand, the PASI score underestimated the improvement in some patients, which is easily understandable as some particularly disabling sites, such as the face or palms, have only a limited contribution to the PASI score. Furthermore, in some cases of chronic and resistant psoriasis, a limited improvement may have been considered a very good response. Indeed, among the patients who were considered failures but who had a PASI reduction of 50-74%, the overall patients' evaluation was good to very good in 64",!. This pooled analysis confirmed the dose-response relationship with CyA doses at 125 mg, 25 mg or 3 mg, and 5 mg/kg/day which was significant after only 3 weeks of treatment. Only
TABLE 2, Clinical response of psoriasis according to previous therapy CyA(:2 5 mg/kg/day)
CyA (5 mg/kg/day)
n k ,'oi
% PASI reduction
19/59 (32) 108/182 (59)
38 ± 5 64 ± 2
27/31(87) 70/81 (86)
84 + 2 87 ± 3
62/131 (47) 65/108 (60)
53 ± 3 63 ± 3
51/58 (8g) 46/54 (85)
87 + 2 86 ± 3
Success rate
Success rate «(%)
% PAS! reduction
Methotrexate Yes
No Retinoids Yes No
Means ± SEM after first 3 months of treatment. Success = PASI score reduction ^ 75";, or a score of ^ 8.
3o
P. Timonen et al.
a small number of the patients had a complete clearing ofpsoriasis but, as recently suggested,''^ this should not be the goal of the treatment. The response rate was quicker and higher with CyA 5 mg than with 2-5 mg/kg/day. However, with this latter dose, 52",, of the patients had success by the third month. With CyA at r 25 mg/kg/day, the improvement was very slow. The very significant response rate observed with 25 mg/kg/day indicates that this should be the standard starting CyA dose as it is accompanied by a low incidence ofrenal dysfunction." In addition, 77"(, of the failures with 25 mg/kg/day showed success after increasing the CyA dose to 5 mg/kg/day. Hence, no tachyphylaxis was observed in patients who started with low doses of CyA which were increased because of insufficient efficacy. The rate of success with CyA at 5 mg/kg/day did not differ according to the patients' baseline characteristics or previous therapies for psoriasis. However, a slightly lower rate of remission was observed with 25 mg/kg/day in patients previously treated with methotrexate or retinoids. These patients may have been particularly severely affected or resistant to treatment as no relationship between CyA blood trough levels and previous therapies was detected.*" Improvement of the psoriasis was maintained in the majority of patients taking a stable CyA dose. In the 5 mg/kg/day group, the attempt to reduce the dose to 25 mg/kg/day resulted in a relapse in 39*^0 of patients. This relatively high incidence may be explained, at least in part, by the definition of relapse, which was an increase in PASI score of 5o'lo over that at the time of success. In the patients with complete (or nearly) clearing, a minimal recurrence was considered a relapse. However, it is very likely that the maintenance dose is very close to the minimum effective dose for inducing an improvement. It is known from the early experience with CyA in severe psoriasis''' that a relapse occurs within weeks after stopping treatment, and that continuous therapy for as long as 3 years is required to maintain a response.^'" Thus, it is essential to remain at the lowest effective dose for a given patient which, for the majority, should be 2-5-3 mg/kg/day of CyA. REFERENCES 1 Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med 1979; 301: 555. 2 Harper Jl, Keat ACS, Staughton RCD. Cyclosporin for psoriasis. Lancet 1984; ii: 981-2. 3 Griffiths CEM, Powles AV, Leonard JN et al. Clearance of psoriasis with low-dose cyclosporin. Br MedJ 1986; 293: 731-24 Van Joost T, Heule F, Stolz E, Beukers R. Short- term use of cyclosporin A in severe psoriasis. Br J Dermatol 1986; 114: 615-20. 5 Wentzell JM, Baughman RD, O'Connor GT, Bemier GM. Cyclosporine in the treatment of psoriasis. Arch Dermatol 1987; 123: 163-5. 6 Picascia DD, Garden JM, Freinkel RK, Roenigk HH. Treatment of resistant severe psoriasis with systemic cyclosporine. J Am Acad Dertnatol 1987; 17: 408-14. 7 Sasaki T, Ikezawa Z, Nakajima H. Treatment of severe psoriasis with low-dose cydosporin A and the effect on the helper-suppressor T-cell ratio in peripheral blood. J Dertnatol (Tokyo J 1988; 15: 480-6. 8 BonifatiCClericoRjPotenzaCM, CarlesimoM. Cyclosporin A; preliminary results in the treatment of psoriasis. Acta Derm Venereol (Stockh) 1989; Suppl 146: 151-4. 9 Higgins E, Munro C, Marks J et al. Relapse rates in moderately severe chronic psoriasis treated with cyclosporin A. Br y Dertnatol 1989; 121: 71-4. 10 Cimitan A, Fantini F, Giannetti A. CUnical trial with cyclosporin A. Acta Derm Venereol (Stockh) 1989; Suppl 146: 159-63. 11 Finzi AF, Mozzanica N, Cattaneo A ef a/. Effectiveness of cyclosporine treatment in severe psoriasis: a clinical and immunologic study. J Am Acad Dermatol 1989; 21: 91-7. 12 Ellis CN, Gorsulowski DC, Hamilton TA et al. Cyclosporine improves psoriasis in a double-blind study. JAMA 1986; 256: 3110-6.
Low-dose CyA efficacy in psoriasis
39
13 Van Joost T, Bos JD, Heule F, Meinardi MMHM. Low- dose cyclosporin A in severe psoriasis. A double- blind study. Br y Dermatot 1988; 118: 183-90. 14 De Rie MA, Tegelberg MJAM, Meinardi MMHM et al. Low-dose cyclosporin A in a large series of moderate psoriasis patients: preliminary results. J Invest Dermatol 1989; 93: 307. 15 Dubertret L, Perussel M, Robioia O, Feutren G. Cyclosporin in psoriasis: a long-term randomized study on 37 patients. Acta Derm Vetiereol (Stockh) 1989; Suppl 146: 136. 16 Frappaz A, Haftek H, Thivoiet J. Long-term treatment of severe psoriasis with low-dose cyclosporin (25 mg/kg/day to 5 mg/kg/day), Acta Derm Venereol (Stockh) 1989; Suppl 146: 147. 17 Feutren G, Abeywickrama K, Friend D, Von Graffenried B. Renal function and blood pressure in psoriatic patients treated with cyclosporin A. Br y Dermatot 1990; 122: Suppl 36: 57-69. 18 Fredriksson T, Pettersson U. Severe psoriasis: oral therapy with a new retinoid. Dermatologica 1978; 157: 238-44. 19 Bos JD, Meinardi MMHM, Van Joost T et al. Use of cyclosporine in psoriasis. Laticel 1989; U: 1500- 2. 20 Feutren G, Friend D, Timonen P et al. Predictive value of cyclosporin A level for efficacy or renal dysfunction in psoriasis. Br y Dermatol 1990; 122: Suppl 36: 85-93. 21 Griffiths CEM, Powles AV, McFadden J et at. Long- term cyclosporin for psoriasis. Br y Dermaiol 1989; 120: 253-60. 22 Powles AV, McFadden J, Fry L. Three-year follow-up of patients with psoriasis treated with cycJosporin. J Invest Dermatol 1989; 93: 306.
Efficacy of low-dose cyclosporin A in psoriasis: results of dose-finding studies P.TIMONEN, D.FRIEND, K.ABEYWICKRAMA,* C.LABURTE, B.VON GRAFFENRIED AND G.FEUTREN Immunology Group and •Biostatistics Group, Department of Clinical Research, Sandoz Pharma Ltd, Basle, Switzerland
SUMMARY
The efficacy of cyclosporin A (CyA) in severe psoriasis was analysed in 457 adult patients included in five European multicentre dose-finding studies. Initial CyA doses were 1-25 mg/kg/day in 33 patients, 25-3 mg/kg/day in 285 and 5 mg/kg/day in 139. After 3 months of treatment, the reduction of the Psoriasis Area and Severity Index (PASI) score was 35 ± 6% with I 25 mg/kg/day of CyA, 57 + 2% with 2.5 mg or 3 mg/kg/day and 86 ± 2% with 5 mg/kg/day (P < o.ooi). The rates of success, defined by a PASI score reduction ^ 75% or a score ^ 8 , were 24"n, 52% and 88"/,,, respectively. There were no differences in age, initial severity or duration of psoriasis. The improvement was maintained for 9 months or more in the majority of patients receiving continuous CyA therapy.
The efficacy of cyclosporin A (CyA) in the treatment of psoriasis was recognized soon after it came into use. A dramatic improvement of skin lesions was observed in four patients in a pilot study of CyA in psoriatic arthropathy.' This effect was later confirmed in other pilot^"" and controlled"'" studies. Of major importance was the finding that low-dose CyA (less than 5 mg/kg/day) was also effective.^'''•'^ Because of the potential risk of renal impairment associated with CyA, it was essential to identify the lowest effective dose of CyA.'^ The relationship between dose and efficacy as well as the speed or duration of improvement was investigated in several multicentre studies initiated by Sandoz. This report presents the pooled analyses of these studies. In addition, this large series of patients provided the opportunity to investigate the infiuence of the patients' baseline characteristics on the clinical response. PATIENTS AND METHODS
This analysis included 457 adult patients (mean age 42 years, range 18-75) in five European multicentre dose-finding studies. All patients had severe psoriasis, defined by a PASI score ^ 18 (see below), for a mean duration of 14 years. The mean PASI score at inclusion was 25. Correspondence: Dr G.Feutren, Clinical Research/Immunology, Sandoz Pharma Lid, CH-4002 Basle, Switzerland. 33
34
P. Timonen et al.
Cyclosporin A therapy
The initial CyA doses (divided into two daily doses) were i 25 mg/kg/day in 33 patients, 25 mg or 3 mg/kg/day in 285, and 5 mg/kg/day in 139. Treatment lasted for 3 months in the five studies and, in two of them, the patients with clinical success after 3 months of treatment entered a maintenance period of continuous therapy for up to 12 months. Doses were adjusted on the basis of efficacy or renal dysfunction. In cases of inefficacy after 1-3 months treatment, the dose was increased but without exceeding 5 mg/kg/day. Whenever renal dysfunction was observed, defined as a serum creatinine increase of more than 30% over patient's own baseline, the dose was reduced by 25-50%. Patients who started on 5 mg/kg/day of CyA entered the maintenance period at that dose and began 3 months of gradual reduction of the dose to 25 mg/kg/day. Patients who initially had success on 25 mg/kg/day continued on that dose. Evaluation of severity of psoriasis
Evaluation of the severity of the disease was assessed in all studies by the Psoriasis Area and Severity Index (PASI).'* This is a clinical assessment of the area of the body affected and intensity of the three main lesions: erythema, desquamation and infiltration. Each symptom is scored as absent (= o), slight (= i), moderate (= 2) or severe (= 3). The involved area is estimated and scored within a range of 0^0 (score = o) to 9O-ioo"o (score = 6). The assessments are made separately for four different areas of the body and, using a simple mathematical procedure, a single figure emerges. Thus, a PASI score may describe either very severe lesions over a relatively small area of the body, or less severe lesions but over a larger area. To reduce the variability among the assessors, special PASI training sessions were organized in which all investigators examined the same patient, compared the results and discussed the ratings if there was a disagreement. Success was defmed as a PASI score reduction of 75 "(, or more, ora score ^ 8. A relapse was defined by an increase of 50"^ or more over the score at the time of remission. In most of the patients, global assessments were made by the investigator and by the patient, using a scale of five degrees for efficacy: none, slight, moderate, good or very good. Statistical tests Results are reported as means ± SEM. In cases of inefficacy or failure before Month 3, the last value was carried forward (intention to treat). The statistical significance of the difference between the groups was assessed by Student's r-test. The frequency of abnormalities between groups was compared using Fisher's exact test. RESULTS I
Comparison of PASI changes and global assessment
A strong correlation was found between the changes of PASI score at Month 3 and the patient's or investigator's global assessment (Fig. i). In patients who reported very good responses, the PASI score reduction was 89 ± 1% whereas, in cases of inefficacy, the PASI score was unchanged (an increase of i ± 4%). Of the patients who had PASI score reductions of 75% or more, 73'^V had a very good result, 25'\, a good result and 2",, a moderate improvement. Interestingly, of the patients who had PASI score reductions of 5O-74"(, and who were
Low-dose CyA efficacy in psoriasis
35
100' lnv«9tigator V7P\ patient
50-
2S
(52) (49)
(31)(34) slight
modaratd
good
very good
OVERALL ASSESSMENT OF EFFICACY
FIGURE I. Percentage reduction of the Psoriasis Area and Severity Index (PASI) score according to the overall assessment of efficacy by the patient or the investigator after 3 months of treatment. Means ± SEM.
considered to be 'failures', the global assessment of efficacy was very good in 14% and good in 50%. Induction of remission The percentage of PASI score reduction after 3 months of treatment was 35 ± 6% with 1-25 mg/kg/day of CyA, 57 ± 2";, with 25 mg or 3 mg/kg/day and 86 ± 2% with 5 mg/kg/day (P < 0 OOI vs all groups) (Fig. 2). Success rates at Month 3 were 24%, 52% and 88%, respectively (P ^ o 001) (Fig. 3). Patients'responses were also quicker, depending on dose, as the success rates after only 3 weeks of treatment were 6",,, 10",, and 35"o in the i 25 mg, 25 mg or 3 mg and 5 mg/kg/day CyA dose groups, respectively (P = o 001). The incidence of complete clearing of the psoriasis at 3 months was 0%, 3% and 17% for each dose group, respectively. Seventy-one patients had their CyA doses increased after 3 months from 2-5 mg to 5 mg/kg/day because of insufficient efficacy. The success rate after 3 additional months with 5 mg/kg/day was 77%. No significant difference in clinical response was detected according to age, gender, initial severity or duration of psoriasis with 25 mg (Table I) nor with 5 mg/kg/day of CyA. However, a slightly, but significantly, higher success rate was achieved in the absence of previous treatment with retinoids (P = o 047) or methotrexate (P = o 001) in the CyA 25 mg/kg/day group. No difference was seen with CyA at 5 mg/kg/day (Table 2). Maintenance therapy A subgroup of 72 patients was continuously treated with 2-5 mg/kg/day for 9 months after initial success at 3 months with that dose. Fifteen (21%) relapsed while receiving 25 mg/kg/ day of CyA after a mean treatment duration of 67 months. In a subgroup of 62 patients who
P. Timonen et al.
-25
1-25 -50-
•75.
•100
12 WEEKS
FIGURE 2. Percentage PASI score reduction according to dose in the first 3 months of treatment (intention to treai). Means + SEM; SIM = CyA.
had success with an initial dose of 5 mg/kg/day, CyA was gradually reduced over 3 months to 25 mg/kg/day. Twenty (ag'^o) of these 62 patients had a relapse at a mean dose of 3-5 mg/kg/day after a mean duration of 7 months of CyA treatment. DISCUSSION
In the present study, the analysis of the efficacy was based on the changes of the PASI, a clinical Sandimmun dose
100%'
• 5.0 mg/kg/d
r
50%-
2.5 mg/kg/d
r
1.25 mg/kg/d
25%-
6 WEEKS
12
FIGURE 3. Cumulative success rate in the first 3 months of treatment according to Sandimmun* (CyA) dose. Success was defined as a PASI score reduction ^ 7 5 % or a score of ^ 8 .
Low-dose CyA efficacy in psoriasis
37
TABLE 1. Clinical response of psoriasis with CyA ( 2 5 mg/kg/day) according to baseline characteristics
n i%)
% PASI reduction
51/129 (40) 57/120(47)
55 ± 3 60 ± 3
74/173(43) 34/68 (50)
58 + 3 55 ± 6
54/151 (36) 44/90 (49)
57 ± 3 59 ± 4
55/123(45) 53/116(46)
58 ± 3 58 ± 3
Success rate
Age
^ 40 years >4O Male Female
Gender PASI score Psoriasis duration
^15 years > 15 years
Means + SEM after first 3 months of treatment. Success = PASI score reduction ^75''-,j or a score
score. Changes in this score correlated very well with the global evaluation of efficacy by the patient or the investigator. The PASI score reduction ^ 75%, used in the protocols to define a success, was equivalent to a good or very good response in 98",, of the patients. On the other hand, the PASI score underestimated the improvement in some patients, which is easily understandable as some particularly disabling sites, such as the face or palms, have only a limited contribution to the PASI score. Furthermore, in some cases of chronic and resistant psoriasis, a limited improvement may have been considered a very good response. Indeed, among the patients who were considered failures but who had a PASI reduction of 50-74%, the overall patients' evaluation was good to very good in 64",!. This pooled analysis confirmed the dose-response relationship with CyA doses at 125 mg, 25 mg or 3 mg, and 5 mg/kg/day which was significant after only 3 weeks of treatment. Only
TABLE 2, Clinical response of psoriasis according to previous therapy CyA(:2 5 mg/kg/day)
CyA (5 mg/kg/day)
n k ,'oi
% PASI reduction
19/59 (32) 108/182 (59)
38 ± 5 64 ± 2
27/31(87) 70/81 (86)
84 + 2 87 ± 3
62/131 (47) 65/108 (60)
53 ± 3 63 ± 3
51/58 (8g) 46/54 (85)
87 + 2 86 ± 3
Success rate
Success rate «(%)
% PAS! reduction
Methotrexate Yes
No Retinoids Yes No
Means ± SEM after first 3 months of treatment. Success = PASI score reduction ^ 75";, or a score of ^ 8.
3o
P. Timonen et al.
a small number of the patients had a complete clearing ofpsoriasis but, as recently suggested,''^ this should not be the goal of the treatment. The response rate was quicker and higher with CyA 5 mg than with 2-5 mg/kg/day. However, with this latter dose, 52",, of the patients had success by the third month. With CyA at r 25 mg/kg/day, the improvement was very slow. The very significant response rate observed with 25 mg/kg/day indicates that this should be the standard starting CyA dose as it is accompanied by a low incidence ofrenal dysfunction." In addition, 77"(, of the failures with 25 mg/kg/day showed success after increasing the CyA dose to 5 mg/kg/day. Hence, no tachyphylaxis was observed in patients who started with low doses of CyA which were increased because of insufficient efficacy. The rate of success with CyA at 5 mg/kg/day did not differ according to the patients' baseline characteristics or previous therapies for psoriasis. However, a slightly lower rate of remission was observed with 25 mg/kg/day in patients previously treated with methotrexate or retinoids. These patients may have been particularly severely affected or resistant to treatment as no relationship between CyA blood trough levels and previous therapies was detected.*" Improvement of the psoriasis was maintained in the majority of patients taking a stable CyA dose. In the 5 mg/kg/day group, the attempt to reduce the dose to 25 mg/kg/day resulted in a relapse in 39*^0 of patients. This relatively high incidence may be explained, at least in part, by the definition of relapse, which was an increase in PASI score of 5o'lo over that at the time of success. In the patients with complete (or nearly) clearing, a minimal recurrence was considered a relapse. However, it is very likely that the maintenance dose is very close to the minimum effective dose for inducing an improvement. It is known from the early experience with CyA in severe psoriasis''' that a relapse occurs within weeks after stopping treatment, and that continuous therapy for as long as 3 years is required to maintain a response.^'" Thus, it is essential to remain at the lowest effective dose for a given patient which, for the majority, should be 2-5-3 mg/kg/day of CyA. REFERENCES 1 Mueller W, Herrmann B. Cyclosporin A for psoriasis. N Engl J Med 1979; 301: 555. 2 Harper Jl, Keat ACS, Staughton RCD. Cyclosporin for psoriasis. Lancet 1984; ii: 981-2. 3 Griffiths CEM, Powles AV, Leonard JN et al. Clearance of psoriasis with low-dose cyclosporin. Br MedJ 1986; 293: 731-24 Van Joost T, Heule F, Stolz E, Beukers R. Short- term use of cyclosporin A in severe psoriasis. Br J Dermatol 1986; 114: 615-20. 5 Wentzell JM, Baughman RD, O'Connor GT, Bemier GM. Cyclosporine in the treatment of psoriasis. Arch Dermatol 1987; 123: 163-5. 6 Picascia DD, Garden JM, Freinkel RK, Roenigk HH. Treatment of resistant severe psoriasis with systemic cyclosporine. J Am Acad Dertnatol 1987; 17: 408-14. 7 Sasaki T, Ikezawa Z, Nakajima H. Treatment of severe psoriasis with low-dose cydosporin A and the effect on the helper-suppressor T-cell ratio in peripheral blood. J Dertnatol (Tokyo J 1988; 15: 480-6. 8 BonifatiCClericoRjPotenzaCM, CarlesimoM. Cyclosporin A; preliminary results in the treatment of psoriasis. Acta Derm Venereol (Stockh) 1989; Suppl 146: 151-4. 9 Higgins E, Munro C, Marks J et al. Relapse rates in moderately severe chronic psoriasis treated with cyclosporin A. Br y Dertnatol 1989; 121: 71-4. 10 Cimitan A, Fantini F, Giannetti A. CUnical trial with cyclosporin A. Acta Derm Venereol (Stockh) 1989; Suppl 146: 159-63. 11 Finzi AF, Mozzanica N, Cattaneo A ef a/. Effectiveness of cyclosporine treatment in severe psoriasis: a clinical and immunologic study. J Am Acad Dermatol 1989; 21: 91-7. 12 Ellis CN, Gorsulowski DC, Hamilton TA et al. Cyclosporine improves psoriasis in a double-blind study. JAMA 1986; 256: 3110-6.
Low-dose CyA efficacy in psoriasis
39
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