British jourtial of Dertnatology (1992) 126, 621-623.
REPORT OF A MEETING
Consensus Conference on cyclosporin A for psoriasis February 1992 M.J.MIHATSCH AND K.WOLFF* Department of Dermatology I, University of Vienna Medical School Vienna, Austria * Institut fiir Pathologic Kantonsspital Basel, Switzerland
Summary
Human studies using oral cyclosporin A (CyA; Sandimmun®) therapy for psoriasis have been in progress for nearly 9 years. Cumulative data of the clinical effects ofthis therapy in 1000 patients have been collected, and are derived from multiple open and controlled studies. The efficacy of this treatment in psoriasis is well recognized, and the relative safety of up to 2 years of therapy is also established, provided that the guidelines are observed. However, there is concern regarding the longterm safety of CyA treatment of psoriasis as experience is still limited. Careful monitoring of all CyAtreated patients is therefore tnandatory, and CyA should only be used by dermatologists who have expertise in its use. During treatment, co-operation with an experienced nephrologist is strongly recommended.
Who should be treated.' Psoriatic patients who have failed with topical and ultraviolet radiation (UVL) treatments may be considered for CyA therapy. The psoriasis should be of such severity that the risks inherent in this treatment are justified for that patient.
Patients who have the following conditions should, in general, not be considered for treatment: previous or concomitant malignancies; infections of any type; primary or secondary immunodeficiency; severe chronic organ dysfunction; drug or alcohol abuse. Patients with abnormal renal function or uncontrolled hypertension, as well as those who are uncooperative, should be considered unsuitable for CyA therapy.
Who should not be treated? Psoriatic patients who have other systemic disorders and who are taking additional medication should be carefully assessed before prescribing CyA because of possible drug interactions and other adverse effects. This applies, in particular, to concomitant therapy with potentially nephrotoxic and cytotoxic agents. Patients receiving concomitant immunosuppressive or radiation therapy (including PUVA and UVL) should not receive CyA because of the risk of malignancy. Patients should also be warned of the risks of overexposure to solar radiation. Drugs which interfere with the bioavailability or metabolism of CyA, and drugs known to be nephrotoxic, especially non-steroidal anti-inflammatory agents, should be avoided. Correspondence: Professor Dr M.J.Mihatsch. Institut fiir Pathologie, Kantonsspital Basel, Universitatskliniken. Schonbeinstrasse 40, CH-4()()3 Basel. Switzerland.
How should the treatment be administered.' The patient should be carefully instructed concerning the nature of the treatment. The starting dose should range from 3 (up to 4) mg/kg body weight/day, taken as a single dose or divided into two doses. If improvement in psoriasis does not occur within 1 month, the CyA dose can be increased, but should not exceed 5 mg/kg body weight/day orally. As the skin lesions improve, the dose should be reduced in steps of 0-5-1 mg/kg body weight to the minimum maintenance dose; if clinical improvement continues, CyA treatment should be discontinued to determine if therapy is still required. If adverse effects arise and depending on their severity, either the daily dose should be reduced in steps or, if necessary, treatment should be discontinued. Special attention should be paid to serum creatinine increases of more than 30% over the patient's own pretreatment 621
622
M.J.MIHATSCH AND K.WOLFF
values as confirmed on two or more occasions within 2 weeks. Hypertension (diastolic blood pressure over 105 mmHg or a sustained diastolic blood pressure over 95 mmHg) should be treated. Diuretics should not be used. Treatment should be discontinued in cases where there is an insufficient response of the psoriatic lesions to CyA at a dose of 5 mg/kg body weight within 6 weeks, or if the effective dose is not compatible with the safety guidelines. Present experience indicates that severe psoriasis recurs when CyA treatment is stopped, as is the case with other therapies. In severe psoriasis, the aim of maintenance therapy is to maintain substantial clinical improvement with the lowest possible dose of CyA. A total clearing of the skin should not be attempted, as indicator lesions are needed to guide future dose adjustments. After reaching a relatively disease-free state, the patient should be given the minimum effective maintenance dose. Intermittent therapy is to be encouraged whenever possible. If patients have been successfully treated for 2 years, the decision whether or not to extend therapy should be based upon the most recent information regarding the long-term use of CyA in psoriasis, as this data is still being accumulated. If a patient experiences a serious exacerbation during the maintenance treatment, therapy can be changed to a dose that is sufficient to control psoriasis while remaining compatible with the safety guidelines. Every attempt should then be made to reduce the dose to the lowest effective level.
three separate occasions to ensure accurate baseline values. The variability of these creatinine levels should be kept below 10 /imol/1. Ideally, a direct assessment of renal function, for example, glomerular filtration rate (GFR), should be made before therapy. During therapy, it is mandatory that the serum creatinine is measured frequently and carefully monitored for any increase, Cyclosporin A dosage should be lowered or the therapy discontinued if the serum creatinine rises to more than 30% above the patient's own pretreatment values. Initial investigations of bilirubin, liver enzymes, serum potassium, magnesium, uric acid, fasting lipids and urinary protein are also required. Regular clinical and laboratory examinations are essential. Follow-up assessment, especially of blood pressure and serum creatinine, should be performed every 2 weeks during the initial 3 months, and then monthly throughout therapy if the patient's serum creatinine is stable. If the dose is increased, or if either serum creatinine or blood pressure rises, more frequent controls are necessary. If hypertension develops, it should be treated with calcium antagonists such as nifedipine or isradipine, but not diltiazem or verapamil because of their interference with CyA blood levels. If creatinine is persistently raised by more than 30% of pretreatment values, the following algorithm should be followed to avoid renal damage (Fig, 1). Any adverse effects, such as tremor, hypertrichosis, gingival hyperplasia and nausea, which may arise should be recorded. Because of its poor predictive value
Serum creatinine rises > 3 0 %
How should the patient be monitored during therapy? Psoriasis is not a life-threatening disease, and the use of CyA must be carefully monitored and controlled. Thus, careful dermatological and physical examinations, including blood pressure measurements (on at least two occasions before initiating therapy) should be undertaken. As CyA is an immunosuppressive drug, physical examination for tumours, including those of the skin and cervix, should be performed. In order to limit nephrotoxicity, control must be directed towards the exclusion of patients with potential risk factors, limiting the dose to a maximum of 5 mg/kg body weight and adhering to the lowest possible maintenance dose, and ensuring that there is frequent and careful monitoring of renal function. Prior to therapy, a 12-h fasting serum creatinine (and all other laboratory tests) should be obtained on at least
Reduce CyA dose
(for I month)
Creatinine decreases to < 30%
Creatinine remains > 3 0 %
CyA treatment can be continued
Stop CyA treatment
Creatinine returns to within 10% of prefreatment value
CyA treatment can be resumed Figure 1 .
CYCLOSPORIN A FOR PSORIASIS
in psoriatic patients, routine measurement of drug blood levels is not essential, but may be useful for detecting possible drug interactions or non-compliance of the patient. This Consensus Conference took place in Morocco, 8-11 February 1992, under the sponsorship of Sandoz Pharma Ltd (Basel, Switzerland). The co-chairmen were M.J.Mihatsch, Pathology Institute, Cantonal Hospital, University of Basel, Basel, Switzerland, and K.Wolff, Department of Dermatology I, University of Vienna Medical School, Vienna, Austria, The other participants were: F.Arellano, Drug Monitoring Centre, Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland; F.VV.Ballardie, The Renal Unit, Manchester Royal Infirmary, Manchester, U.K.: S.S.Bleehen, Department of Dermatology, Royal Hallamshire Hospital, Sheffield, U.K.: J.D.Bos, Department of Dermatology, University of Amsterdam, Academisch Medisch Centrum, Amsterdam, The Netherlands; A.J.M.Donker, Department of Nephrology, Free University Hospital, Amsterdam, The Netherlands; D.Dunsire, Sandoz Pharma Ltd, Basel, Switzerland; G.Feutren, Immunology Group, Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland; L.Fry, Department of Dermatology, St Mary's Hospital, London, U.K.; R.Grossman, Department of Dermatology, St Louis Hospital, Paris, France; B.Hulme, Department of
623
Renal Medicine, St Mary's Hospital, London, U.K.; P.Krupp, Drug Monitoring Centre, Department of Clinical Research. Sandoz Pharma Ltd, Basel, Switzerland; C. Laburte, Immunology Group, Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland; J.Mason, Renal Research, Clinical and Preclinical Pharmacology, Sandoz Pharma Ltd, Basel, Switzerland; D.O'Sullivan, Clinical Research (Immunology and Dermatology), Sandoz Pharmaceuticals, Camberley, Surrey, U.K.; P.Petzelbauer, Department of Dermatology I, University of Vienna Medical School, Vienna, Austria; S.Reitamo, Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland; H.Rorsman. Department of Dermatology, University Hospital, University of Lund, Lund, Sweden; D.Salomon, Dermatology Clinic, Cantonal Hospital, University of Geneva, Geneva, Switzerland; S,Shuster, Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, U.K.; G.Thiel. Department of Nephrology, Cantonal Hospital, University of Basel, Basel, Switzerland; R.Till, Allergy-Dermatology, Sandoz Pharma Ltd, Basel, Switzerland; J.J.Voorhees, Department of Dermatology, University of Michigan Medical Centre, Ann Arbor, Michigan, U.S.A.; H.Zachariae, Department of Dermatology, Marselisborg Hospital, University of Aarhus, Aarhus, Denmark.
REPORT OF A MEETING
Consensus Conference on cyclosporin A for psoriasis February 1992 M.J.MIHATSCH AND K.WOLFF* Department of Dermatology I, University of Vienna Medical School Vienna, Austria * Institut fiir Pathologic Kantonsspital Basel, Switzerland
Summary
Human studies using oral cyclosporin A (CyA; Sandimmun®) therapy for psoriasis have been in progress for nearly 9 years. Cumulative data of the clinical effects ofthis therapy in 1000 patients have been collected, and are derived from multiple open and controlled studies. The efficacy of this treatment in psoriasis is well recognized, and the relative safety of up to 2 years of therapy is also established, provided that the guidelines are observed. However, there is concern regarding the longterm safety of CyA treatment of psoriasis as experience is still limited. Careful monitoring of all CyAtreated patients is therefore tnandatory, and CyA should only be used by dermatologists who have expertise in its use. During treatment, co-operation with an experienced nephrologist is strongly recommended.
Who should be treated.' Psoriatic patients who have failed with topical and ultraviolet radiation (UVL) treatments may be considered for CyA therapy. The psoriasis should be of such severity that the risks inherent in this treatment are justified for that patient.
Patients who have the following conditions should, in general, not be considered for treatment: previous or concomitant malignancies; infections of any type; primary or secondary immunodeficiency; severe chronic organ dysfunction; drug or alcohol abuse. Patients with abnormal renal function or uncontrolled hypertension, as well as those who are uncooperative, should be considered unsuitable for CyA therapy.
Who should not be treated? Psoriatic patients who have other systemic disorders and who are taking additional medication should be carefully assessed before prescribing CyA because of possible drug interactions and other adverse effects. This applies, in particular, to concomitant therapy with potentially nephrotoxic and cytotoxic agents. Patients receiving concomitant immunosuppressive or radiation therapy (including PUVA and UVL) should not receive CyA because of the risk of malignancy. Patients should also be warned of the risks of overexposure to solar radiation. Drugs which interfere with the bioavailability or metabolism of CyA, and drugs known to be nephrotoxic, especially non-steroidal anti-inflammatory agents, should be avoided. Correspondence: Professor Dr M.J.Mihatsch. Institut fiir Pathologie, Kantonsspital Basel, Universitatskliniken. Schonbeinstrasse 40, CH-4()()3 Basel. Switzerland.
How should the treatment be administered.' The patient should be carefully instructed concerning the nature of the treatment. The starting dose should range from 3 (up to 4) mg/kg body weight/day, taken as a single dose or divided into two doses. If improvement in psoriasis does not occur within 1 month, the CyA dose can be increased, but should not exceed 5 mg/kg body weight/day orally. As the skin lesions improve, the dose should be reduced in steps of 0-5-1 mg/kg body weight to the minimum maintenance dose; if clinical improvement continues, CyA treatment should be discontinued to determine if therapy is still required. If adverse effects arise and depending on their severity, either the daily dose should be reduced in steps or, if necessary, treatment should be discontinued. Special attention should be paid to serum creatinine increases of more than 30% over the patient's own pretreatment 621
622
M.J.MIHATSCH AND K.WOLFF
values as confirmed on two or more occasions within 2 weeks. Hypertension (diastolic blood pressure over 105 mmHg or a sustained diastolic blood pressure over 95 mmHg) should be treated. Diuretics should not be used. Treatment should be discontinued in cases where there is an insufficient response of the psoriatic lesions to CyA at a dose of 5 mg/kg body weight within 6 weeks, or if the effective dose is not compatible with the safety guidelines. Present experience indicates that severe psoriasis recurs when CyA treatment is stopped, as is the case with other therapies. In severe psoriasis, the aim of maintenance therapy is to maintain substantial clinical improvement with the lowest possible dose of CyA. A total clearing of the skin should not be attempted, as indicator lesions are needed to guide future dose adjustments. After reaching a relatively disease-free state, the patient should be given the minimum effective maintenance dose. Intermittent therapy is to be encouraged whenever possible. If patients have been successfully treated for 2 years, the decision whether or not to extend therapy should be based upon the most recent information regarding the long-term use of CyA in psoriasis, as this data is still being accumulated. If a patient experiences a serious exacerbation during the maintenance treatment, therapy can be changed to a dose that is sufficient to control psoriasis while remaining compatible with the safety guidelines. Every attempt should then be made to reduce the dose to the lowest effective level.
three separate occasions to ensure accurate baseline values. The variability of these creatinine levels should be kept below 10 /imol/1. Ideally, a direct assessment of renal function, for example, glomerular filtration rate (GFR), should be made before therapy. During therapy, it is mandatory that the serum creatinine is measured frequently and carefully monitored for any increase, Cyclosporin A dosage should be lowered or the therapy discontinued if the serum creatinine rises to more than 30% above the patient's own pretreatment values. Initial investigations of bilirubin, liver enzymes, serum potassium, magnesium, uric acid, fasting lipids and urinary protein are also required. Regular clinical and laboratory examinations are essential. Follow-up assessment, especially of blood pressure and serum creatinine, should be performed every 2 weeks during the initial 3 months, and then monthly throughout therapy if the patient's serum creatinine is stable. If the dose is increased, or if either serum creatinine or blood pressure rises, more frequent controls are necessary. If hypertension develops, it should be treated with calcium antagonists such as nifedipine or isradipine, but not diltiazem or verapamil because of their interference with CyA blood levels. If creatinine is persistently raised by more than 30% of pretreatment values, the following algorithm should be followed to avoid renal damage (Fig, 1). Any adverse effects, such as tremor, hypertrichosis, gingival hyperplasia and nausea, which may arise should be recorded. Because of its poor predictive value
Serum creatinine rises > 3 0 %
How should the patient be monitored during therapy? Psoriasis is not a life-threatening disease, and the use of CyA must be carefully monitored and controlled. Thus, careful dermatological and physical examinations, including blood pressure measurements (on at least two occasions before initiating therapy) should be undertaken. As CyA is an immunosuppressive drug, physical examination for tumours, including those of the skin and cervix, should be performed. In order to limit nephrotoxicity, control must be directed towards the exclusion of patients with potential risk factors, limiting the dose to a maximum of 5 mg/kg body weight and adhering to the lowest possible maintenance dose, and ensuring that there is frequent and careful monitoring of renal function. Prior to therapy, a 12-h fasting serum creatinine (and all other laboratory tests) should be obtained on at least
Reduce CyA dose
(for I month)
Creatinine decreases to < 30%
Creatinine remains > 3 0 %
CyA treatment can be continued
Stop CyA treatment
Creatinine returns to within 10% of prefreatment value
CyA treatment can be resumed Figure 1 .
CYCLOSPORIN A FOR PSORIASIS
in psoriatic patients, routine measurement of drug blood levels is not essential, but may be useful for detecting possible drug interactions or non-compliance of the patient. This Consensus Conference took place in Morocco, 8-11 February 1992, under the sponsorship of Sandoz Pharma Ltd (Basel, Switzerland). The co-chairmen were M.J.Mihatsch, Pathology Institute, Cantonal Hospital, University of Basel, Basel, Switzerland, and K.Wolff, Department of Dermatology I, University of Vienna Medical School, Vienna, Austria, The other participants were: F.Arellano, Drug Monitoring Centre, Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland; F.VV.Ballardie, The Renal Unit, Manchester Royal Infirmary, Manchester, U.K.: S.S.Bleehen, Department of Dermatology, Royal Hallamshire Hospital, Sheffield, U.K.: J.D.Bos, Department of Dermatology, University of Amsterdam, Academisch Medisch Centrum, Amsterdam, The Netherlands; A.J.M.Donker, Department of Nephrology, Free University Hospital, Amsterdam, The Netherlands; D.Dunsire, Sandoz Pharma Ltd, Basel, Switzerland; G.Feutren, Immunology Group, Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland; L.Fry, Department of Dermatology, St Mary's Hospital, London, U.K.; R.Grossman, Department of Dermatology, St Louis Hospital, Paris, France; B.Hulme, Department of
623
Renal Medicine, St Mary's Hospital, London, U.K.; P.Krupp, Drug Monitoring Centre, Department of Clinical Research. Sandoz Pharma Ltd, Basel, Switzerland; C. Laburte, Immunology Group, Department of Clinical Research, Sandoz Pharma Ltd, Basel, Switzerland; J.Mason, Renal Research, Clinical and Preclinical Pharmacology, Sandoz Pharma Ltd, Basel, Switzerland; D.O'Sullivan, Clinical Research (Immunology and Dermatology), Sandoz Pharmaceuticals, Camberley, Surrey, U.K.; P.Petzelbauer, Department of Dermatology I, University of Vienna Medical School, Vienna, Austria; S.Reitamo, Department of Dermatology, Helsinki University Central Hospital, Helsinki, Finland; H.Rorsman. Department of Dermatology, University Hospital, University of Lund, Lund, Sweden; D.Salomon, Dermatology Clinic, Cantonal Hospital, University of Geneva, Geneva, Switzerland; S,Shuster, Department of Dermatology, Royal Victoria Infirmary, Newcastle upon Tyne, U.K.; G.Thiel. Department of Nephrology, Cantonal Hospital, University of Basel, Basel, Switzerland; R.Till, Allergy-Dermatology, Sandoz Pharma Ltd, Basel, Switzerland; J.J.Voorhees, Department of Dermatology, University of Michigan Medical Centre, Ann Arbor, Michigan, U.S.A.; H.Zachariae, Department of Dermatology, Marselisborg Hospital, University of Aarhus, Aarhus, Denmark.
