Clinical and Experimental Dermatology 1992; 17: 16-19.
How to improve the risk-benefit ratio of cyclosporin therapy for psoriasis M.J.KORSTANJE Department of Dermatology, Academic Hospital Maastricht, The Netherlands Accepted for publication 2 April 1991
Summary CsA therapy for psoriasis is hampered by side-effects. Topical CsA therapy is not effective. Therefore improvement of the risk-benefit ratio must be achieved by improvement of dose-regimens, combination therapy of CsA with another therapy for psoriasis or combination therapy of CsA with a therapy that may influence the pathogenesis of the most serious side-effect(s) of CsA. It seems that only therapies that influence the pathogenesis of CsA- induced acute renal-impairment, like oralfishoil or perhaps thromboxane synthesis inhibitors, may be beneficial. However, further studies are warranted to validate these findings.
Cyclosporin (CsA) is an effective drug in the treatment of psoriasis."'^ Subsequent withdrawal of the drug however, will rapidly lead to reappearance of the skin lesions to the same extent as before treatment. Treatment with CsA therefore, has to be continued according to the natural course of the disease. The safety and tolerability of CsA maintenance-therapy in psoriasis has to be established. Few studies about effectiveness and tolerability of longterm low-dose CsA maintenance-therapy (longer than 12 weeks) have been published.^"' The side-effects most frequently observed in these studies are listed in Table 1. Hypertension and renal impairment are reported frequently. Withdrawal of CsA or dose-reductions of CsA are often necessary due to side-effects. After dosereduction psoriatic skin lesions may recur^' indicating that the therapeutic window for CsA is small. So, therapy with CsA is restricted by time- and dose-related nephrotoxicity and hypertension.' Ways to improve the riskbenefit ratio of CsA therapy have to be found. As topical therapy with CsA is not effective,' improvement of the risk-benefit ratio could theoretically be achieved either by improvement of dose-regimens, combination therapy with another anti-psoriatic therapy or combination therapy with a drug that may influence the pathogenesis of the Correspondence: Dr M.J.Korstanje, 20 Alwen Drive, Thornhill, Cardiff CF4 9HD.
16
most important side-effect(s) of CsA. Each of these possibilities is discussed below. Dose-regimens Due to its lipophilicity there is a high initial uptake of CsA-related material into adipose tissue.' The mean CsA level in adipose tissue is 20-times higher than the corresponding blood-level.'" The localization of CsA in fat might be of pharmacological significance, as subcutaneous fat tissue may serve as a depot for CsA. Therefore, less frequent administration of CsA may prevent sideeffects, whilst the therapeutic effect on the skin is maintained or increased. However, in a study with alloand autotransplantation of skin in rats, in which the effectiveness of CsA administration once a day versus fractional doses was studied, renal function decreased most when CsA was given as a single daily-dose." No difference in immuno-suppressive effect was found whether CsA was given once a day or in fractional doses. This is consistent with a pilot study in patients with psoriasis, where renal function decreased more with CsA therapy given once daily, than with the same dose of CsA given twice daily.'^ Perhaps side-effects correlate more with peak blood-levels of CsA than with trough levels. This might imply that no benefit can be expected from CsA if it is administered in less than twice daily doses. CsA administration should be divided in two or even more doses a day. Larger studies are required to confirm this observation and to define the optimal regimen for administration of CsA. Combination therapy with other therapies for psoriasis Topical therapy Usually patients with severe psoriasis resistant to topical therapies are selected for CsA. Therefore, an additive effect of topical therapy in CsA treatment might not be expected. However, the addition of potent topical corticosteroids to CsA therapy clears psoriasis faster than CsA alone, while there seems to be no difference in
RISK-BENEFIT RATIO AND CSA THERAPY
17
Table 1. The most frequently observed side-effects in studies with low-dose CsA therapy for at least 12 weeks
Memardi et at. (3) (number patients 12) Fry et al. (4) (number patients 8*) Heule F et at. (5) (number patients 19) Griffiths (6) (number patients 13) de Rie et at. (7) (number patients 26)
Hypertension
Serum creatinine
6/12
7/12
4/8
3/8
9/19
8/19
6/13
12/13
8/26
18/26
Gastrointestinal complaints
Weight
Alkaline phosphatase
Hypertrichosis
Hyperkalemia
3/8 5/19
5/19
4/19
Carcinoma
1/8
3/19 7/13 4/26
3/26
11/26
1/26
*Only the patients on maintenance therapy for longer than 12 weeks have been counted.
relapse rate or side-effects.'^ Further large studies looking at the additive effects of topical therapies in CsA treatment should be carried out. PUVA therapy Combination therapy of CsA with artificially produced ultraviolet-B has, to our knowledge, not been investigated. Therapy with psoralens and artificial ultraviolet A (PUVA) has been used in combination with CsA but did not show an additive effect.'''"'^ In patients treated with immunosuppressive drugs including CsA, a high incidence of cutaneous malignancies associated with sun exposure'^'" has been reported. CsA is capable of promoting the survival and progression of UV-induced skin tumours.'^ The increased risk of cutaneous squamous-cell carcinomas in PUVA therapy'^ may be potentiated by CsA. Rapid growth of squamouscell carcinomas has been observed in patients with psoriasis treated with CsA.^"'^' Therefore, combined therapy using CsA-PUVA should be avoided. Further, CsA therapy should be avoided in patients with an increased risk of malignancies, including patients who have received a high cumulative-dose of ultraviolet radiation. Retinoids
In one case report an additive effect of etretinate to CsA therapy has been suggested.^^ However, in three small studies, etretinate did not show a clear additive effect to CsA therapy.^''-^^ Larger studies are necessary if a small additive-effect of retinoids to CsA therapy is to be detected. Methotrexate Methotrexate has no additive effect in CsA therapy,^"* and
this combination increases the risk of serious side-effects. CsA is extensively metabolized in the liver, and the metabolites are excreted mostly by the liver.^^ Drugs that inhibit hepatic metabolism raise the blood concentration of CsA. Because hepatotoxicity is a frequent side-effect of methotrexate therapy,^* it is likely that methotrexate inhibits elimination of CsA. Methotrexate is eliminated mainly by the kidneys^^ and renal clearance of methotrexate is greater than the glomerular filtration rate because of tubular secretion.^' Acute and chronic nephrotoxicity are frequent side-effects of CsA; the glomerular filtration rate is reduced,^^ and tubular function is impaired.™ CsA and methotrexate therefore decrease one another's elimination. This can increase both methotrexate and CsA bloodlevels and the risk of serious side-effects, as well. Tberapies that may influence tbe patbogenesis of CsA side-effects The pathogenesis of nearly all side-effects induced by CsA is unknown. Only the pathogenesis of acute nephrotoxicity is partly understood. Recent studies suggest that altered haemodynamics play an important role in CsAinduced renal dysfunction.^' The glomerular filtration rate is reduced both in animal experiments^^ and in man^^ following CsA-administration, probably due to an increased production of thromboxane A2 (TxA2).^^ Recently, it has been shown that fish oil, containing high concentrations of the polyunsaturated fatty-acids eicosapentaenoic acid (EPA, C20:5 omega-3) and docosahexaenoic acid (DHA, C22:6 omega-3), reduces CsA-nephrotoxicity in the rat, probably by lowering TxAZ-production.^^'^"* Two pilot-studies in man, one with patients suffering from psoriasis,^^ the other with transplant recipients,^^ strongly suggest an attenuation of CsA-induced acute renal-dysfunction by the addition of fish oil to the diet of the patient. Furthermore, CsA plus fish oil is a more potent therapeutic immunosuppressive
18
M.J.KORSTANJE
combination than CsA alone.''' However, complete protection of renal function could not be achieved. Even complete inhibition of TxA2-production in rats with a thromboxane-synthetase inhibitor^* did not return GFR to control levels, suggesting that other mechanisms are also involved in the loss of renal function induced by CsA. Further studies are warranted to validate these findings and combination therapies with CsA and thromboxane-synthetase inhibitors need to be carried out.
12. Korstanje, M.J. Cyclosporin A administration in dermatology: Once a day or in fractional doses? Archives of Dermatological Research 1990; 281: 536-537. 13. Griffiths CEM, Powles AV, Baker BS et al. Combination of cyclosporine A and topical corticosteroid in the treatment of psoriasis. Transplantation Proceedings 1988; XX (Suppl. 4): 5052. 14. Korstanje MJ, Hulsmans RFHJ. Combination therapy cyclosporin A - PUVA in psoriasis. Acta Dermato-Venereologica 1990; 70: 89-90. 15. Petzelbauer P, Honigsman H, Langer K et al. Cyclosporin A in combination with photochemotherapy (PUVA) in the treatment of psoriasis. British Journal of Dermatology 1990; 123: 641-647. 16. Maize JC. Skin cancer in immunosuppressed patients. Editorial. Conclusion JAMA 1977; 237: 1857-1858. It is unlikely that an improvement in the risk-benefit ratio 17. Penn L Cancers after cyclosporin therapy. Transplantation Proceedings 1988; XX (Suppl. 1): 276-279. of CsA can be achieved by improvement of dose18. Servilla KS, Burnham DK, Daynes RA. Ability of cyclosporin to regimens, or combination therapy of CsA with other promote the growth of transplanted ultraviolet radiation-induced forms of anti-psoriatic therapy. Only fish oil in combinatumors in mice. Transplantation 1987; 44: 291-295. tion with CsA may affect the pathogenesis of the most 19. Stern RS, Lange R. Non-melanoma skin cancer occurring in serious side-effect of CsA, acute renal-impairment, in a patients treated with PUVA five to ten years after first treatment. Journal of Investigative Dermatology 1988; 91: 120-124. positive way. Better results may be obtained with combination therapy using CsA-thromboxane synthetase 20. Oxholm A, Thomsen K, Menne T. Squamous cell carcinomas in relation to cyclosporin therapy of non-malignant skin disorders. and/or receptor blockers. However, further studies are Acta Dermato-Venereologica Stockh 1989; 69: 89-90. necessary to validate these findings. 21. Korstanje MJ, van de Staak WJBM. High cumulative dose of ultraviolet radiation is a contraindication for cyclosporin therapy. Clinical and Experimental Dermatology 1990; 5: 76. 22. Korstanje MJ, Bessems PJMJ, van de Staak WJBM. CombinaReferences tion therapy cyclosporin-etretinate effective in erythrodermie 1. van Joost Th, Bos JD, Heule F, Meinardi MMHM. Low-dose psoriasis. Dermatologica 1989; 179: 94. cyclosporin A in severe psoriasis. A double-blind study. British 23. Korstanje MJ, van de Staak WJBM. Combination-therapy Journal of Dermatology 1988; 118: 183-190. cyclosporin A-etretinate for psoriasis. Clinical and Experimental 2. Ellis CN, Gorsulowsky DC, Hamilton TD et at. Cyclosporin Dermatology 1990; 15: 172-173. improves psoriasis in a double blind study. JAMA 1986; 2S6: 24. Korstanje MJ, van Breda Vriesman CJP, van de Staak WJBM. 3110-3116. Cyclosporine and methotrexate: A dangerous combination. Jour3. Meinardi MMHM, Bos JD. Cyclosporine maintenance therapy nal of the American Academy of Dermatology 1990; 23: 320-321. in psoriasis. Transplantation Proceedings 1988; XX (Suppl. 4): 42- 25. Grevel J. Significance of cyclosporine pharmacokinetics. Trans49. plantation Proceedings 1988; XX (Suppl. 2): 428-434. 4. Fry L, Griffiths CEM, Powles AV et al. Long-term cyclosporin in 26. van de Kerhof PCM, Mali JWH. Methotrexate maintenance the management of psoriasis. Transplantation Proceedings 1988; following Ingram therapy in difficult psoriasis. British Journal of XX (Suppl. 4): 23-25. Dermatology 1982; 106: 623-627. 5. Heule F, Bousema MT, Laeijendecker R, van Joost Th. Three 27. Iven H, Brasch H, Engster J. Pharmacokinetics of methotrexate long-term regimens with cyclosporin for psoriasis vulgaris. Acta and 7-hydroxy-methotrexate in rabbits. Cancer Chemotherapy and Dermato-Venereologica 1989; 69, (Suppl. 146): 171-175. Pharmacology 1985; 15: 115-120. 6. Griffiths CEM, Powles AV, McFadden J et al. Long-term 28. Iven H, Brasch H. The effects of antibiotics and uricosuric drugs cyclosporin for psoriasis. British Journal of Dermatology 1989; on the renal elimination of methotrexate and 7-hydroxymetho120: 253-260. trexate in rabbits. Cancer Chemotherapy and Pharmacology 1988; 21: 337-342. 7. de Rie MA, Meinardi MMHM, Bos JD. Analysis of side-effects of medium- and low-dose cyclosporin maintenance therapy in 29. Dieperink H, Leyssac PP, Kemp E et al. Nephrotoxicity of psoriasis. British Journal of Dermatology 1990; 123: 347-353. cyclosporin A in humans: effects on glomerular filtration and tubular reabsorption rates. European Journal of Clinical Investiga8. Bousema MT, Tank B, Heule F et al. Placebo-controlled study of tion 1987; 17: 493-496. psoriasis patients treated topically with a 10% cyclosporine gel. Journal of the American Academy of Dermatology 1990; 22: 126- 30. Versiuis DJ, Wenting GJ, Jeekel J, Weimar W. Cyclosporin A127. related proximal tubular dysfunction: impaired handling of uric 9. Backman L, Brandt I, Dallner G, Ringden O. Tissue distribution acid. Transplantation Proceedings 1987; 19: 4029-4030. of [•'H]cyclosporine A in mice. Transplantation Proceedings 1988; 31. Murray BM, Paller MS, Ferris TF. Effect of eyclosporin on renal XX (Suppl.2): 684-691. haemodynamics in conscious rats. Kidney International 1985; 28: 10. Kumar MSA, White AG, Alex G, Antos MS et al. Correlation of 767-774. blood levels and tissue levels of cyclosporine with the histologic 32. Elzinga L, Kelley VE, Houghton DC, Bennett WM. Fish oil features of cyclosporine toxicity. Transplantation Proceedings vehicle for cyclosporin lowers renal thromboxanes and reduces 1988; XX (Suppl. 2): 407-413. experimental nephrotoxicity. Transplantation Proceedings 1987; 11. Dieperink H, Leyssac PP, Starklint H, Kemp E. Cyclosporine A XIX: 1403-1406. administration: once a day or in fractional doses? Transplantation 33. Deperink H, Lessac PP, Kemp E et al. Nephrotoxicity of Proceedings 1988; XX: (Suppl. 2): 703-706. cyclosporin A in humans: effects on glomerular filtration and
RISK-BENEFIT RATIO AND CSA THERAPY
19
tubular reabsorption rates. European Journal of Clinical InvestigaOmega 3 polyunsaturated fatty acids improve renal function in tions 1987; 17: 493-496. renal transplant recipients treated with cyclosporin-A. Kidney 34. Elzinga L, Kelley VE, Houghton DC, Bennett WM. Modification International 1989; 35: 516 (A). of experimental nephrotoxicity with fish oil as the vehicle for 37. Kelley VE, MacKie J, Strom TB. Cyclosporin A plus fish oil: cyclosporin. Transplantation 1987; 43: 271-274. Accentuate the positive, eliminate the negative. Transplantation 35. Stoof TJ, Korstanje MJ, Bilo HJG et al. Doesfishoil protect renal Proceedings 1989; 21: 848-849. function in cyclosporin-treated psoriasis patients? J Internal 38. Perico N, Benigna A, Zoja C et al. Functional significance of Medicine 1989; 226: 437-441. exaggerated renal thromboxane A2 synthesis induced by cyclo36. Homan van der Heide JJ, Bilo HJG, Tegzess AM, Donker AJM. sporine A. American Journal of Physiology 1986; 251: F581-F587.
How to improve the risk-benefit ratio of cyclosporin therapy for psoriasis M.J.KORSTANJE Department of Dermatology, Academic Hospital Maastricht, The Netherlands Accepted for publication 2 April 1991
Summary CsA therapy for psoriasis is hampered by side-effects. Topical CsA therapy is not effective. Therefore improvement of the risk-benefit ratio must be achieved by improvement of dose-regimens, combination therapy of CsA with another therapy for psoriasis or combination therapy of CsA with a therapy that may influence the pathogenesis of the most serious side-effect(s) of CsA. It seems that only therapies that influence the pathogenesis of CsA- induced acute renal-impairment, like oralfishoil or perhaps thromboxane synthesis inhibitors, may be beneficial. However, further studies are warranted to validate these findings.
Cyclosporin (CsA) is an effective drug in the treatment of psoriasis."'^ Subsequent withdrawal of the drug however, will rapidly lead to reappearance of the skin lesions to the same extent as before treatment. Treatment with CsA therefore, has to be continued according to the natural course of the disease. The safety and tolerability of CsA maintenance-therapy in psoriasis has to be established. Few studies about effectiveness and tolerability of longterm low-dose CsA maintenance-therapy (longer than 12 weeks) have been published.^"' The side-effects most frequently observed in these studies are listed in Table 1. Hypertension and renal impairment are reported frequently. Withdrawal of CsA or dose-reductions of CsA are often necessary due to side-effects. After dosereduction psoriatic skin lesions may recur^' indicating that the therapeutic window for CsA is small. So, therapy with CsA is restricted by time- and dose-related nephrotoxicity and hypertension.' Ways to improve the riskbenefit ratio of CsA therapy have to be found. As topical therapy with CsA is not effective,' improvement of the risk-benefit ratio could theoretically be achieved either by improvement of dose-regimens, combination therapy with another anti-psoriatic therapy or combination therapy with a drug that may influence the pathogenesis of the Correspondence: Dr M.J.Korstanje, 20 Alwen Drive, Thornhill, Cardiff CF4 9HD.
16
most important side-effect(s) of CsA. Each of these possibilities is discussed below. Dose-regimens Due to its lipophilicity there is a high initial uptake of CsA-related material into adipose tissue.' The mean CsA level in adipose tissue is 20-times higher than the corresponding blood-level.'" The localization of CsA in fat might be of pharmacological significance, as subcutaneous fat tissue may serve as a depot for CsA. Therefore, less frequent administration of CsA may prevent sideeffects, whilst the therapeutic effect on the skin is maintained or increased. However, in a study with alloand autotransplantation of skin in rats, in which the effectiveness of CsA administration once a day versus fractional doses was studied, renal function decreased most when CsA was given as a single daily-dose." No difference in immuno-suppressive effect was found whether CsA was given once a day or in fractional doses. This is consistent with a pilot study in patients with psoriasis, where renal function decreased more with CsA therapy given once daily, than with the same dose of CsA given twice daily.'^ Perhaps side-effects correlate more with peak blood-levels of CsA than with trough levels. This might imply that no benefit can be expected from CsA if it is administered in less than twice daily doses. CsA administration should be divided in two or even more doses a day. Larger studies are required to confirm this observation and to define the optimal regimen for administration of CsA. Combination therapy with other therapies for psoriasis Topical therapy Usually patients with severe psoriasis resistant to topical therapies are selected for CsA. Therefore, an additive effect of topical therapy in CsA treatment might not be expected. However, the addition of potent topical corticosteroids to CsA therapy clears psoriasis faster than CsA alone, while there seems to be no difference in
RISK-BENEFIT RATIO AND CSA THERAPY
17
Table 1. The most frequently observed side-effects in studies with low-dose CsA therapy for at least 12 weeks
Memardi et at. (3) (number patients 12) Fry et al. (4) (number patients 8*) Heule F et at. (5) (number patients 19) Griffiths (6) (number patients 13) de Rie et at. (7) (number patients 26)
Hypertension
Serum creatinine
6/12
7/12
4/8
3/8
9/19
8/19
6/13
12/13
8/26
18/26
Gastrointestinal complaints
Weight
Alkaline phosphatase
Hypertrichosis
Hyperkalemia
3/8 5/19
5/19
4/19
Carcinoma
1/8
3/19 7/13 4/26
3/26
11/26
1/26
*Only the patients on maintenance therapy for longer than 12 weeks have been counted.
relapse rate or side-effects.'^ Further large studies looking at the additive effects of topical therapies in CsA treatment should be carried out. PUVA therapy Combination therapy of CsA with artificially produced ultraviolet-B has, to our knowledge, not been investigated. Therapy with psoralens and artificial ultraviolet A (PUVA) has been used in combination with CsA but did not show an additive effect.'''"'^ In patients treated with immunosuppressive drugs including CsA, a high incidence of cutaneous malignancies associated with sun exposure'^'" has been reported. CsA is capable of promoting the survival and progression of UV-induced skin tumours.'^ The increased risk of cutaneous squamous-cell carcinomas in PUVA therapy'^ may be potentiated by CsA. Rapid growth of squamouscell carcinomas has been observed in patients with psoriasis treated with CsA.^"'^' Therefore, combined therapy using CsA-PUVA should be avoided. Further, CsA therapy should be avoided in patients with an increased risk of malignancies, including patients who have received a high cumulative-dose of ultraviolet radiation. Retinoids
In one case report an additive effect of etretinate to CsA therapy has been suggested.^^ However, in three small studies, etretinate did not show a clear additive effect to CsA therapy.^''-^^ Larger studies are necessary if a small additive-effect of retinoids to CsA therapy is to be detected. Methotrexate Methotrexate has no additive effect in CsA therapy,^"* and
this combination increases the risk of serious side-effects. CsA is extensively metabolized in the liver, and the metabolites are excreted mostly by the liver.^^ Drugs that inhibit hepatic metabolism raise the blood concentration of CsA. Because hepatotoxicity is a frequent side-effect of methotrexate therapy,^* it is likely that methotrexate inhibits elimination of CsA. Methotrexate is eliminated mainly by the kidneys^^ and renal clearance of methotrexate is greater than the glomerular filtration rate because of tubular secretion.^' Acute and chronic nephrotoxicity are frequent side-effects of CsA; the glomerular filtration rate is reduced,^^ and tubular function is impaired.™ CsA and methotrexate therefore decrease one another's elimination. This can increase both methotrexate and CsA bloodlevels and the risk of serious side-effects, as well. Tberapies that may influence tbe patbogenesis of CsA side-effects The pathogenesis of nearly all side-effects induced by CsA is unknown. Only the pathogenesis of acute nephrotoxicity is partly understood. Recent studies suggest that altered haemodynamics play an important role in CsAinduced renal dysfunction.^' The glomerular filtration rate is reduced both in animal experiments^^ and in man^^ following CsA-administration, probably due to an increased production of thromboxane A2 (TxA2).^^ Recently, it has been shown that fish oil, containing high concentrations of the polyunsaturated fatty-acids eicosapentaenoic acid (EPA, C20:5 omega-3) and docosahexaenoic acid (DHA, C22:6 omega-3), reduces CsA-nephrotoxicity in the rat, probably by lowering TxAZ-production.^^'^"* Two pilot-studies in man, one with patients suffering from psoriasis,^^ the other with transplant recipients,^^ strongly suggest an attenuation of CsA-induced acute renal-dysfunction by the addition of fish oil to the diet of the patient. Furthermore, CsA plus fish oil is a more potent therapeutic immunosuppressive
18
M.J.KORSTANJE
combination than CsA alone.''' However, complete protection of renal function could not be achieved. Even complete inhibition of TxA2-production in rats with a thromboxane-synthetase inhibitor^* did not return GFR to control levels, suggesting that other mechanisms are also involved in the loss of renal function induced by CsA. Further studies are warranted to validate these findings and combination therapies with CsA and thromboxane-synthetase inhibitors need to be carried out.
12. Korstanje, M.J. Cyclosporin A administration in dermatology: Once a day or in fractional doses? Archives of Dermatological Research 1990; 281: 536-537. 13. Griffiths CEM, Powles AV, Baker BS et al. Combination of cyclosporine A and topical corticosteroid in the treatment of psoriasis. Transplantation Proceedings 1988; XX (Suppl. 4): 5052. 14. Korstanje MJ, Hulsmans RFHJ. Combination therapy cyclosporin A - PUVA in psoriasis. Acta Dermato-Venereologica 1990; 70: 89-90. 15. Petzelbauer P, Honigsman H, Langer K et al. Cyclosporin A in combination with photochemotherapy (PUVA) in the treatment of psoriasis. British Journal of Dermatology 1990; 123: 641-647. 16. Maize JC. Skin cancer in immunosuppressed patients. Editorial. Conclusion JAMA 1977; 237: 1857-1858. It is unlikely that an improvement in the risk-benefit ratio 17. Penn L Cancers after cyclosporin therapy. Transplantation Proceedings 1988; XX (Suppl. 1): 276-279. of CsA can be achieved by improvement of dose18. Servilla KS, Burnham DK, Daynes RA. Ability of cyclosporin to regimens, or combination therapy of CsA with other promote the growth of transplanted ultraviolet radiation-induced forms of anti-psoriatic therapy. Only fish oil in combinatumors in mice. Transplantation 1987; 44: 291-295. tion with CsA may affect the pathogenesis of the most 19. Stern RS, Lange R. Non-melanoma skin cancer occurring in serious side-effect of CsA, acute renal-impairment, in a patients treated with PUVA five to ten years after first treatment. Journal of Investigative Dermatology 1988; 91: 120-124. positive way. Better results may be obtained with combination therapy using CsA-thromboxane synthetase 20. Oxholm A, Thomsen K, Menne T. Squamous cell carcinomas in relation to cyclosporin therapy of non-malignant skin disorders. and/or receptor blockers. However, further studies are Acta Dermato-Venereologica Stockh 1989; 69: 89-90. necessary to validate these findings. 21. Korstanje MJ, van de Staak WJBM. High cumulative dose of ultraviolet radiation is a contraindication for cyclosporin therapy. Clinical and Experimental Dermatology 1990; 5: 76. 22. Korstanje MJ, Bessems PJMJ, van de Staak WJBM. CombinaReferences tion therapy cyclosporin-etretinate effective in erythrodermie 1. van Joost Th, Bos JD, Heule F, Meinardi MMHM. Low-dose psoriasis. Dermatologica 1989; 179: 94. cyclosporin A in severe psoriasis. A double-blind study. British 23. Korstanje MJ, van de Staak WJBM. Combination-therapy Journal of Dermatology 1988; 118: 183-190. cyclosporin A-etretinate for psoriasis. Clinical and Experimental 2. Ellis CN, Gorsulowsky DC, Hamilton TD et at. Cyclosporin Dermatology 1990; 15: 172-173. improves psoriasis in a double blind study. JAMA 1986; 2S6: 24. Korstanje MJ, van Breda Vriesman CJP, van de Staak WJBM. 3110-3116. Cyclosporine and methotrexate: A dangerous combination. Jour3. Meinardi MMHM, Bos JD. Cyclosporine maintenance therapy nal of the American Academy of Dermatology 1990; 23: 320-321. in psoriasis. Transplantation Proceedings 1988; XX (Suppl. 4): 42- 25. Grevel J. Significance of cyclosporine pharmacokinetics. Trans49. plantation Proceedings 1988; XX (Suppl. 2): 428-434. 4. Fry L, Griffiths CEM, Powles AV et al. Long-term cyclosporin in 26. van de Kerhof PCM, Mali JWH. Methotrexate maintenance the management of psoriasis. Transplantation Proceedings 1988; following Ingram therapy in difficult psoriasis. British Journal of XX (Suppl. 4): 23-25. Dermatology 1982; 106: 623-627. 5. Heule F, Bousema MT, Laeijendecker R, van Joost Th. Three 27. Iven H, Brasch H, Engster J. Pharmacokinetics of methotrexate long-term regimens with cyclosporin for psoriasis vulgaris. Acta and 7-hydroxy-methotrexate in rabbits. Cancer Chemotherapy and Dermato-Venereologica 1989; 69, (Suppl. 146): 171-175. Pharmacology 1985; 15: 115-120. 6. Griffiths CEM, Powles AV, McFadden J et al. Long-term 28. Iven H, Brasch H. The effects of antibiotics and uricosuric drugs cyclosporin for psoriasis. British Journal of Dermatology 1989; on the renal elimination of methotrexate and 7-hydroxymetho120: 253-260. trexate in rabbits. Cancer Chemotherapy and Pharmacology 1988; 21: 337-342. 7. de Rie MA, Meinardi MMHM, Bos JD. Analysis of side-effects of medium- and low-dose cyclosporin maintenance therapy in 29. Dieperink H, Leyssac PP, Kemp E et al. Nephrotoxicity of psoriasis. British Journal of Dermatology 1990; 123: 347-353. cyclosporin A in humans: effects on glomerular filtration and tubular reabsorption rates. European Journal of Clinical Investiga8. Bousema MT, Tank B, Heule F et al. Placebo-controlled study of tion 1987; 17: 493-496. psoriasis patients treated topically with a 10% cyclosporine gel. Journal of the American Academy of Dermatology 1990; 22: 126- 30. Versiuis DJ, Wenting GJ, Jeekel J, Weimar W. Cyclosporin A127. related proximal tubular dysfunction: impaired handling of uric 9. Backman L, Brandt I, Dallner G, Ringden O. Tissue distribution acid. Transplantation Proceedings 1987; 19: 4029-4030. of [•'H]cyclosporine A in mice. Transplantation Proceedings 1988; 31. Murray BM, Paller MS, Ferris TF. Effect of eyclosporin on renal XX (Suppl.2): 684-691. haemodynamics in conscious rats. Kidney International 1985; 28: 10. Kumar MSA, White AG, Alex G, Antos MS et al. Correlation of 767-774. blood levels and tissue levels of cyclosporine with the histologic 32. Elzinga L, Kelley VE, Houghton DC, Bennett WM. Fish oil features of cyclosporine toxicity. Transplantation Proceedings vehicle for cyclosporin lowers renal thromboxanes and reduces 1988; XX (Suppl. 2): 407-413. experimental nephrotoxicity. Transplantation Proceedings 1987; 11. Dieperink H, Leyssac PP, Starklint H, Kemp E. Cyclosporine A XIX: 1403-1406. administration: once a day or in fractional doses? Transplantation 33. Deperink H, Lessac PP, Kemp E et al. Nephrotoxicity of Proceedings 1988; XX: (Suppl. 2): 703-706. cyclosporin A in humans: effects on glomerular filtration and
RISK-BENEFIT RATIO AND CSA THERAPY
19
tubular reabsorption rates. European Journal of Clinical InvestigaOmega 3 polyunsaturated fatty acids improve renal function in tions 1987; 17: 493-496. renal transplant recipients treated with cyclosporin-A. Kidney 34. Elzinga L, Kelley VE, Houghton DC, Bennett WM. Modification International 1989; 35: 516 (A). of experimental nephrotoxicity with fish oil as the vehicle for 37. Kelley VE, MacKie J, Strom TB. Cyclosporin A plus fish oil: cyclosporin. Transplantation 1987; 43: 271-274. Accentuate the positive, eliminate the negative. Transplantation 35. Stoof TJ, Korstanje MJ, Bilo HJG et al. Doesfishoil protect renal Proceedings 1989; 21: 848-849. function in cyclosporin-treated psoriasis patients? J Internal 38. Perico N, Benigna A, Zoja C et al. Functional significance of Medicine 1989; 226: 437-441. exaggerated renal thromboxane A2 synthesis induced by cyclo36. Homan van der Heide JJ, Bilo HJG, Tegzess AM, Donker AJM. sporine A. American Journal of Physiology 1986; 251: F581-F587.
