European S3-Guidelines on the systemic treatment of psoriasis vulgaris. Update EDF in cooperation with EADV and IPC

Transcription

1 European S3-Guidelines on the systemic treatment of psoriasis vulgaris Update 2015 EDF in cooperation with EADV and IPC

2 Table of contents List of abbreviations Introduction to the guidelines Goals of the guidelines/goals of treatment Methodology Conventional systemic therapy Acitretin Ciclosporin Fumaric acid esters Methotrexate Biological therapy Adalimumab Etanercept Infliximab Ustekinumab Biosimilars Newly approved medications and treatments in the pipeline Special considerations and special patient populations Tuberculosis (TB) screening before and during biologic treatment Hepatitis / other hepatological dysfunctions HIV Malignancies including lymphoma and skin cancer Neurological disease Ischaemic heart disease and congestive heart failure

3 5.7 Diabetes mellitus Kidney failure/renal impairment Wish for pregnancy in near future Psoriatic arthritis Vaccination References Acknowledgements Appendices

4 List of abbreviations ADA ADR AE ANA BID BIW BSA CHF CI CKD CSA DMF DLQI DMARD EDF EMA EOW FAE GRADE HAART HBV HCV HRQoL IGRA LTBI MEF MI MID MS MTX NSAID PASI PGA PIINP PsA Anti-drug antibodies Adverse drug reactions Adverse event Antinuclear antibodies Twice daily Twice weekly Body surface area Congestive heart failure Confidence interval Chronic kidney disease Ciclosporin Dimethylfumarate Dermatology Life Quality Index Disease-modifying antirheumatic drugs European Dermatology Forum European Medicines Agency Every other week Fumaric acid esters Grading of Recommendations Assessment, Development, and Evaluation Highly active antiretroviral therapy Hepatitis B virus Hepatitis C virus Health-Related Quality of Life Interferon-gamma-release assay Latent tuberculosis infection Monoethylfumarate Myocardial infarction Minimal important difference Multiple sclerosis Methotrexate Nonsteroidal anti-inflammatory drugs Psoriasis Area and Severity Index Physician s Global Assessment Procollagen type III N-terminal peptide Psoriatic arthritis 3

5 RA QD QW SAE SmPC TB TNFi Rheumatoid arthritis Once daily Once weekly Serious adverse event Summary of product characteristics Tuberculosis TNF inhibitor 4

6 1. Introduction to the guidelines 1.1 Goals of the guidelines/goals of treatment Treatment goals in psoriasis Mrowietz / Reich In recognition of the impact of psoriasis on patients the World Health Assembly (WHA) in May 2014 supported including psoriasis into the group of non-communicable diseases and requested from the World Health Organisation (WHO) beside raising awareness about the stigmatising character of psoriasis to integrate the management of psoriasis into existing services for noncommunicable diseases. According to published recommendations management of psoriasis includes multiple measures to assess the complexity of the disease before treatment decisions can be made 1. Guidelines for the treatment of psoriasis provide an overview of a variety of practical aspects relevant to selecting drugs and monitoring patients on therapy 2-6. Based on the evaluation of efficacy and safety data, as well as on the practical experience obtained with different treatment modalities, they contain a range of recommendations reached in a structured consensus process. Epidemiological studies as well as the results of patient surveys in Europe and the United States, have indicated that mean disease activity in patients with psoriasis is high and quality of life is poor, even among patients who are seen regularly by dermatologists; moreover, these findings are accompanied by data showing low treatment satisfaction and a demand for more efficacious, safe, and practical therapies Treatment goals together with the present guidelines, may help dermatologists decide when and how to progress along existing treatment algorithms, ultimately improving patient care. These concepts are based on a selected list of outcome measures that take into account not only the severity of skin symptoms but also the impact of disease on health-related quality of life (HRQoL). Although it has its drawbacks, the most established parameter to measure the severity of skin symptoms in psoriasis is the Psoriasis Area and Severity Index (PASI), which was first introduced in 1978 as an outcome measure in a retinoid trial 11. In recent clinical studies, especial- 5

7 ly those investigating biological therapies, the most commonly used primary efficacy measure has been the PASI 75 response, i. e., the percentage of patients who at a given point in time achieve a reduction of at least 75 % in their baseline PASI. Because this parameter (or an equivalent response criterion) is reported in many trials on systemic therapies for psoriasis, and because a PASI 75 response is now widely accepted as a clinically meaningful improvement, it also serves as the central evidence-based efficacy parameter in these and other psoriasis treatment guidelines. It should also be noted that a PASI 75 response, as is documented in these guidelines, can be achieved in the majority of patients with the therapeutic armamentarium presently available for the treatment of moderate-to-severe disease although the complete clearance of skin lesions may be regarded as the ultimate treatment goal for psoriasis. With the availability of new biologic agents namely the anti-il-17a, anti-il-17ra, and anti-il- 23p19 antibodies treatment efficacy can be increased in a high number of patients. For such therapies a PASI 90 response may be discussed as a new treatment goal in the future. HRQoL is an important aspect of psoriasis, not only in defining disease severity but also as an outcome measure in clinical trials. The Dermatology Life Quality Index (DLQI) is the most commonly used score for assessing the impact of psoriasis on HRQoL. It consists of a questionnaire with ten questions related to symptoms and feelings, daily activities, leisure, work and school, personal relationships, and bother with psoriasis treatment 12. The DLQI is assessed as a score ranging from 0 to 30, and the meaning of the absolute DLQI has been categorized and validated into bands 13. These bands describe the overall impact of skin disease on a person s HRQoL as follows: 0-1 = no effect ; 2-5 = small effect ; 6-10 = moderate effect ; = very large effect ; = extremely large effect. Another study demonstrated that a change of five points in the DLQI correlates with the minimum clinically meaningful change in a person s HRQoL 14. Although there is no correlation between absolute PASI and absolute DLQI scores 7, there seems to be a correlation between an improvement in PASI and an improvement in the DLQI. The drugs that produce the highest PASI reduction by the end of induction therapy are also associated with the greatest reduction in DLQI 15. In 2011 a European Consensus Programme for the first time defined treatment goals for moderate-to-severe psoriasis 16. According to the consensus programme the definition of moderate-to-severe disease was (PASI > 10 or body surface area [BSA] > 10) AND DLQI > 10 and for mild psoriasis PASI 10 AND BSA 10 AND DLQI 10. Taking into account the impact of important psoriasis characteristics from the patient's perspective criteria have been defined, which upgrade mild disease to moderate-to-severe when present. These include a 6

8 major involvement of visible areas, major involvement of the scalp, involvement of genitals, onycholysis or onychodystrophy of at least two fingernails, presence of itch leading to scratching and the presence of recalcitrant plaques. For defining treatment goals it was consented to use PASI and DLQI in order to integrate both, the dermatologist s and the patient s judgement. In accordance to concepts of uncontrolled disease and the commonly used definition for treatment failure an algorithm was generated that can be used in daily practice to secure effective treatment (Figure 1). Treatment success was defined when a PASI 75 and above was achieved and treatment failure as not achieving PASI 50. In between PASI 50 and PASI 75 reaching a DLQI equal or below 5 was considered treatment success and a DLQI above 5 as failure. Figure 1: Treatment goal algorithm 16 A first time point to assess treatment goals for fast acting drugs (e. g., CSA, infliximab) should be at the end of induction therapy until 16 weeks after the initiation of treatment, and for drugs with a slower onset of activity (e. g., MTX, fumaric acid esters [FAE], etanercept) until 24 weeks after starting therapy. During maintenance treatment an assessment of treatment goals should be made in intervals given by the safety monitoring recommendations (usually every eight weeks). An important consideration when using treatment goals is the demand for action in case the goal is not met. In psoriasis there are a number of measures that can be applied to increase efficacy such as increasing the dose, reducing the time between applications, or adding anoth- 7

9 er drug (combination therapy). However, with certain drugs this may represent off-label therapy as such variations are not backed-up by the summary of product characteristics (SmPC). When dose adjustments are either ineffective or not appropriate changing of the drug is an important step. As there is little evidence on how to transit from one drug to another a global consensus programme provided guidance partly based on literature evidence and partly on expert opinion 17. Meanwhile treatment goals have widely been accepted as an appropriate tool to increase the quality of therapy and implemented in national guidelines Severity assessment / Quality of life Physician perspective Mrowietz / Reich Tools for assessing the severity of symptoms are available for plaque psoriasis. The most widely used measure is the PASI. According to recent guidelines, moderate-to-severe disease is defined as a PASI score > PASI 75 and PASI 90 responses are dynamic parameters that indicate the percentage of patients who have achieved an at least 75 or 90 % improvement in their baseline PASI score during treatment. Other measures frequently used to quantify disease severity in psoriasis are Physician s Global Assessment of disease severity (PGA), which is based on the measures also encompassed in the PASI; and BSA, which represents the percentage of the body surface affected by psoriasis. Different questionnaires have been developed to measure the impact of psoriasis on HRQoL; these differ from one another based on their generic (short-form (36) health survey [SF-36]), disease-specific (DLQI, Skindex), or psoriasis-related (Psoriasis Quality of Life Questionnaire [PsoQol], Psoriasis Disability Index [PDI]) approach Severity assessment / Quality of life Patients perspective Maccarone / Jobling The assessment of the severity of psoriasis has become an increasingly more formally defined and confined process in recent years. Severity has become defined technically and bureaucratically, in terms of scores derived from instruments like say, PASI, DLQI and Skindex-25. These simply fail to capture the seriousness of psoriasis as experienced by those who have the disease. They focus upon immediate, current or very recent (over the last week) acute symptoms and circumstances, when the 8

10 disease and all that it can entail is indisputably chronic. It involves long and complex experience, an organised view of the disease and its meaning for the individual, and the anticipation of its potential for future harm. The available instruments are inadequate to assessing disease impact on a patient who has had to cope with psoriasis and its treatment for not one week but possibly thousands of weeks; and who is well aware of its continuing potential for damage to future wellbeing. To suggest that someone whose scores are currently low on the basis of such measures does not have severe disease or is virtually free from psoriasis, is to be clinically insensitive. Nor do the instruments sufficiently allow for the significance of factors (not only current, but remembered and anticipated) highly salient to patients and their everyday lives - pain/irritation; bleeding - which are known to be important to self-stigmatisation; fatigue; stress; discouragement; and embarrassment. But beyond all else for a patient the disease has become serious or severe when it seems to that individual to have gone completely beyond my control in ways significant to the individual; and with all the treatments already made available proven to have failed. Only a skilful clinical assessment rather than measured scores can determine that this point in the long extended course of the disease and its treatment has been reached, and that therefore new therapeutic options are justified. The expectations and demands of payers for measurement must not over-ride the concerns and legitimate interests of patients. 9

11 1.2 Methodology Jacobs / Rosumeck / Nast These guidelines are an update of the existing European Psoriasis Guidelines published in A detailed description of the methodology used for the update can be found in the methods report (REFERENCE). In brief, available evidence of the efficacy and safety of the systemic treatments for psoriasis was summarized (end of literature search: October 12 th, 2014). Based on the evidence, recommendations were formulated and consented by an expert panel. Members of the expert group were dermatologists a rheumatologist and two patient representatives. They were officially nominated by the European Dermatology Forum (EDF), the European Association for Dermatology and Venereology (EADV) and the International Psoriasis Council (IPC). Following a systematic search and identification of literature, the quality of the included studies was assessed by using the Cochrane Risk of bias tool 25. The available evidence and its quality were summarized according to the system recommended by the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) working group 26. For the chapters of Special considerations and special patient populations, the literature was not systematically assessed and the recommendations are based on expert opinion only. All recommendations were consented using formal consensus methodologies (Delphi process and nominal group technique) 27, 28. Based on the GRADE approach, five strengths of recommendations were differentiated taking into account the quality of evidence, benefits and risks, cost, and values and preferences 29, 30. The strength is expressed by the wording and symbols as shown in Table 1. Table 1: Strength of recommendations: wording, symbols and implications 29, 30 Strength Wording Symbols Implications Strong recommendation for the use of an intervention We recommend We believe that all or almost all informed people would make that choice. Clinicians will have to spend less time on the process of decision making, and may devote that time to overcome barriers to implementation and adherence. In most clinical situations, the 10

12 recommendation may be adopted as a policy. Weak recommendation for the use of an intervention We suggest We believe that most informed people would make that choice, but a substantial number would not. Clinicians and health care providers will need to devote more time on the process of shared decision making. Policy makers will have to involve many stakeholders and policy making requires substantial debate. No recommendation with respect to an intervention We cannot make a recommendation with respect to 0 At the moment, a recommendation in favour or against an intervention cannot be made due to certain reasons (e. g., no evidence data available, conflicting outcomes, etc.) Weak recommendation against the use of an intervention We suggest not (using) We believe that most informed people would make a choice against that intervention, but a substantial number would not. Strong recommendation against the use of an intervention We recommend not (using) We believe that all or almost all informed people would make a choice against that intervention. This recommendation can be adopted as a policy in most clinical situations. For each recommendation, the strength of consensus in terms of percentage of agreement was measured and documented. Three levels of consensus were defined and distinguished. A strong consensus was generally aimed at (agreement of > 90 % of the members of the expert group). In cases where only lower values of agreement were achieved, these were defined as consensus (75 to 89 % agreement) or weak consensus (50 to 74 % agreement). All consented text passages are highlighted. The guidelines have a validity until However, an update with respect to new medications will be added before that date. The guidelines project has kindly been supported by the EDF. The financial support did not influence the guidelines development. 11

13 2. Conventional systemic therapy 2.1 Acitretin van de Kerkhof / Gisondi (based on van de Kerkhof / Girolomoni) Please compare also SmPC Instructions for use Pre-treatment Objective assessment of the disease (such as PASI/BSA/PGA; arthritis) HRQoL (such as DLQI/Skindex-29 or -17) History and clinical examination should focus on musculoskeletal problems. If patient reports complaints, further imaging investigation may be performed Exclude pregnancy/breastfeeding: patient must be informed explicitly and extensively about the teratogenic risk of the medication, the necessity of effective long-term contraception (at least two years after cessation of treatment), and the possible consequences of a pregnancy while taking retinoids; written documentation of this informational interview Note that during and up to one year after treatment, blood donation is not permitted Laboratory controls (see Table 2, page 13) During treatment Objective assessment of the disease (such as PASI/BSA/PGA; arthritis) HRQoL (such as DLQI/Skindex-29 or -17) Take capsules with a fatty meal or with whole milk Avoidance of pregnancy is mandatory. Start treatment on second or third day of the menstrual cycle, after satisfactory contraception for at least one month prior to treatment. Double contraception is recommended (e. g., condom + pill; IUD/Nuva Ring + pill; cave: no low-dosed progesterone preparations/mini-pills) during and up to two 12

14 years after end of therapy; effectiveness of oral contraceptives is reduced by acitretin Avoidance of alcohol Ask patient about spine and joint complaints at follow-up visits. If patient reports complaints, further imaging investigation may be performed Laboratory controls (see Table 2, page 13) Post-treatment Reliable contraception in women of child-bearing age for up to two years after therapy, double contraception, as described above, is recommended Patients may not donate blood for up to one year after the discontinuation of therapy Table 2: Recommended lab controls Period in weeks Parameter Pretreatment Blood count* x x x Liver enzymes** x x x Serum creatinine x Pregnancy test (urine) x Monthly up to 2 years after therapy (see national regulations) Fasting blood glucose Triglycerides, cholesterol, HDL x x x x Not all tests may be necessary for all patients. Patient history, risk exposure and patient characteristics have to be taken into account. Further specific testing may be required according to clinical signs, risk, and exposure. * Hb, Hct, leucocytes, platelets ** AST, ALT, AP, γgt Adverse drug reactions/safety Side effects that have been reported for acitretin treatment in the literature are listed in Table 3. All side effects are reversible except for hyperostosis. 13

15 Women of child-bearing age with a desire to conceive are excluded from acitretin treatment. Breastfeeding is also an absolute contraindication. In children treated with acitretin, it is advisable to monitor growth at regular intervals. Evidence that acitretin is associated with increased risk of infections is not available. From the mode of action an increased risk of infections is not expected. In this respect acitretin differs from other systemic treatments for psoriasis, which all have an immunosuppressive effect. Hypertriglyceridaemia, as defined by a fasting triglyceride level of 1.7 mmol/l, is a common adverse effect of acitretin use. Limited evidence exists to guide the management of acitretin-induced hypertriglyceridaemia. Dietary and lifestyle interventions are effective first-line management in reducing triglyceride levels. If dietary measures are inadequate, lipidmodifying drugs and/or referral to a lipidologist when the triglyceride level is > 5 mmol/l should be considered as well as acitretin discontinuation 31, 32. Although acitretin increases serum lipids, it has not been shown to increase cardiovascular risk. In view of the increased risk for cardiovascular diseases in patients with severe psoriasis, continuous attention for hyperlipidaemia remains indicated. However, whether a triglyceride level with acitretin use is considered acceptable in practice would depend on other factors. For example, hypertriglyceridaemia may be acceptable if the intended duration of treatment is short, or the overall cardiovascular risk is low. Dryness of skin and mucosa can be improved by lubricating the skin and using eye drops. Contact lenses should be avoided. It is important that patients be informed about the possibility of hair loss and the fact that retinoid-induced hair loss is reversible. Photosensitivity during retinoid treatment requires avoidance of excessive sun exposure and the use of sunscreens. In order to prevent elevation of serum lipids and liver enzymes, alcohol abstinence and a lowfat and low-carbohydrate diet are advised. In case of bone pain or decreased mobility, X-ray examination is indicated. In patients with muscle pain, excessive athletic activity must be avoided and nonsteroidal anti-inflammatory drugs (NSAID) are indicated. Table 3: Overview of important side effects Very frequent Frequent Vitamin A toxicity (xerosis, cheilitis) Conjunctival inflammation (cave: contact lenses), hair loss, photosensitivity, hyperlipidaemia 14

16 Occasional Rare Very rare Muscle, joint, and bone pain, retinoid dermatitis Gastrointestinal complaints, hepatitis, jaundice, bone changes with longterm therapy Idiopathic intracranial hypertension, decreased colour vision and impaired night vision Special considerations during a treatment Surgery: There is no need of acitretin discontinuation in case of elective surgery Important contraindications/restrictions on use Absolute contraindications Severe renal or hepatic dysfunction Women of child-bearing age: pregnancy, breastfeeding, desire to have children or insufficient guarantee of effective contraceptive measures up to two years after discontinuation of therapy. Alcoholism Blood donation Relative contraindications Alcohol abuse 33 Hepatitis, resulting from viral infections or drugs Diabetes mellitus Wearing contact lenses History of pancreatitis Hyperlipidaemia (particularly hypertriglyceridaemia) and drug-controlled hyperlipidaemia Drug interactions Several drugs may interfere with retinoid metabolism or retinoid effects (Table 4). Table 4: List of most important drugs with potential interactions Drug Type of interaction 15

17 Tetracycline Phenytoin Vitamin A Methotrexate Low-dose progesterone pills Lipid-lowering drugs Antifungal imidazoles Induction of idiopathic intracranial hypertension Plasma protein displacement Augmentation of retinoid effect Liver toxicity Insufficient contraceptive effect Increased risk of myotoxicity Liver toxicity Overdose/measures in case of overdose Because acitretin has low acute toxicity, adverse drug reactions (ADR) following overdose are usually reversible after discontinuation of the preparation. Headache, nausea and/or vomiting, fatigue, irritability, and pruritus are symptoms of acute overdose. Measures in case of overdose: Discontinue retinoids Monitor vital parameters, liver and renal function, electrolytes Consult other specialists to manage side effects beyond dermatological expertise Special considerations Contraception Because the effectiveness of oral contraceptives is reduced by acitretin, microdosed progestin preparations and low-dose progesterone preparations must be avoided. Double contraception is recommended (e. g., condom + pill; IUD/Nuva-Ring + pill; cave: NO low-dosed progesterone preparations/minipills). Monthly pregnancy tests are recommended in women of childbearing potential. Contraception is mandatory in women during and up to two years after discontinuation of therapy. Increase in liver enzymes under acitretin treatment Increases in liver enzymes during acitretin treatment are a challenge. Indeed, a clear upper limit for liver enzyme levels would facilitate monitoring. However, increases in liver enzymes are often transient. Therefore, in cases of increased liver enzyme levels, the blood test must be repeated. It is important to discontinue treatment if there is a trend towards increasing levels. An arbitrary, maximum acceptable level can be defined locally. 16

18 Acitretin in combination with phototherapy The combination of acitretin and phototherapy has been shown to be a beneficial combination with increased efficacy as compared to monotherapies. Low dose acitretin increases the potency of phototherapy, whilst reducing the amount of phototherapy required for clearing and the potential for acitretin adverse events Quality of evidence Jacobs/Rosumeck Five studies evaluating acitretin were included in the evidence based assessment. A summary of findings table is presented in Appendix 1 - Table 1. Acitretin vs placebo No placebo controlled studies were identified. Acitretin in different dosages 35 No statically significant difference was found for the induction therapy between 25 mg and 35 mg acitretin; between 25 mg and 50 mg actretin and between 35 mg and 50 mg acitretin once daily (QD) with respect to PASI 75, final PASI score, PGA clear (very low quality for all outcomes). Withdrawals due to adverse event (AE) did not occure in any of the groups (very low quality). Acitretin 25 mg needs the longest time until the onset of action and acitretin 35 mg seems to be slightly faster than acitretin 50 mg (very low quality). Acitretin vs etanercept 34, 36 Compared to etanercept, acitretin was shown to be inferior in the induction therapy with respect to PASI 75 (very low quality) and the final PASI score (moderate quality). Withdrawals due to AE did not occur in the induction period in either group (very low quality). No differences between acitretin and etanercept were found for long-term efficacy based on PASI 75 and for long-term safety based on patients with at least one AE (very low quality). Acitretin in combination Acitretin in combination with etanercept 36 17

19 No differences were found between acitretin in combination with etanercept 25 mg once weekly (QW) and acitretin alone with respect to PASI 75 for induction and long-term therapy and patients with at least one AE for long-term therapy (very low quality for all outcomes). Withdrawals due to AE did not occur in the induction period in both groups (very low quality). Acitretin in combination with topical calcipotriol Compared to acitretin alone, acitretin in combination with topical calcipotriol was found to be superior in the induction therapy with respect to PGA clear/almost clear (low quality). Based on PGA clear for the induction and long-term treatment, it is uncertain whether there is any difference in efficacy between both groups (low quality for both outcomes). There is no difference between monotherapy and combination concerning patients with at least one AE (moderate quality) and it is uncertain whether a difference exists for withdrawal due to AE (low quality). The combination therapy seems to be faster than the monotherapy regarding an onset of action (very low quality). 37, Therapeutic recommendations Recommendation Strength of consensus Comment Based on the available evidence we cannot make a recommendation for or against the use of acitretin as a monotherapy. о Consensus Evidence and consensus based Based on clinical experience and depending on the most important outcome for the individual patient, we suggest a low dose (20 to 30 mg daily) with respect to tolerability and a high dose (> 30 mg daily) with respect to efficacy. Consensus Expert opinion Table 5: Therapeutic combinations Recommendation Strength of consensus Comments Adalimumab о Consensus No evidence available Ciclosporin Strong consensus Etanercept Consensus Expert opinion: competition cytochrome P450 inactivation Expert opinion: good safety profile assumed, possibly increased efficacy 18

20 Fumaric acid esters о Consensus No evidence available Infliximab о Consensus No evidence available Methotrexate Strong consensus Expert opinion: increased risk of hepatotoxicity possible Ustekinumab о Consensus No evidence available 19

21 2.2 Ciclosporin Reich / Yawalkar (based on Dubertret / Griffiths) Please compare also SmPC Instructions for use Pre-treatment Objective assessment of the disease (such as PASI/BSA/PGA; arthritis) HRQoL (such as DLQI/ Skindex-29 or -17) History and clinical examination should focus on previous and concomitant diseases (e. g., arterial hypertension; severe infections; malignancies, including cutaneous malignancies; renal and liver diseases) and concomitant medication (see Drug interactions) Measurement of the blood pressure on two separate occasions Laboratory controls (see Table 6, page 21) Reliable contraception (cave: reduced efficacy of progesterone-containing contraceptives) Regular gynaecologic screening according to national guidelines Consultation on vaccination; susceptibility to infections (take infections seriously, seek medical attention promptly); drug interactions (inform other treating physicians about therapy); avoidance of excessive sun exposure; use of sunscreens During treatment In uncomplicated long-term therapy with low dose ciclosporin (CSA; 2.5 to 3 mg/kg daily), follow-up intervals may be extended to two months or more. Shorter intervals may be needed in patients with risk factors, dose increases, or those who must take concomitant medications that are likely to contribute to ADR. In selected patients with intermittent and short-term treatment, less strict monitoring (regular checking of blood pressure and creatinine level) may be sufficient. 20

22 Objective assessment of the disease (such as PASI/BSA/PGA; arthritis) HRQoL (such as DLQI/Skindex-29 or -17) Clinical examination should focus on status of skin and mucous membranes (hypertrichosis, gingival changes), signs of infections, gastrointestinal or neurological symptoms (tremor, dysaesthesia), musculoskeletal/joint pain Repeat recommendation for sun avoidance and sun protection Check of concomitant medication Measurement of blood pressure Laboratory controls (see Table 6, page 21) Reliable contraception Regular gynaecologic screening according to national guidelines If creatinine is significantly elevated and/or patient on therapy for > 1 year, perform creatinine clearance (or creatinine-edta clearance where available). Determination of the CSA level is recommended in individual cases Post-treatment After discontinuation of CSA, patients should be followed up for skin cancer, especially in case of extensive prior therapeutic or natural UV exposure. Table 6: Recommended lab controls Diagnostics Pretreatment Period in weeks Full blood count* x x x x x x Liver values** x x x x x x Electrolytes*** x x x x x x Serum creatinine x x x x x x Urine status x x x Uric acid x x x x x 21

23 Pregnancy test (urine) x Cholesterol, triglycerides x**** x x Magnesium***** x x x HBV/HCV HIV x x Not all tests may be necessary for all patients. Patient history, risk exposure and patient characteristics have to be taken into account. Further specific testing may be required according to clinical signs, risk, and exposure. * Erythrocytes, leucocytes, platelets ** Transaminases, AP, γgt, bilirubin *** Sodium, potassium **** Recommended two weeks before and on the day of treatment initiation (fasting) ***** Only with indication (muscle cramps) Adverse drug reactions/safety In the included studies, adverse effects for CSA were reported primarily for short-term (i. e., induction) therapy. When several doses of CSA were studied, the rate of adverse effects generally demonstrated a clear dose dependency 39. The most frequently reported adverse effects included: Kidneys/blood pressure Increases in serum creatinine (average 5 to 30 % for entire group); in up to 20 % of patients, increases in creatinine of more than 30 % Reduced creatinine clearance (average up to 20 %) Increased blood urea nitrogen in 50 % of patients; increased uric acid in 5 % of patients Decreased Mg (average 5 to 15 %) Arterial hypertension in 2 to 15 % of patients Liver/gastrointestinal tract Gastrointestinal symptoms (nausea, diarrhoea, flatulence in 10 to 30 % of patients) Increased bilirubin in 10 to 80 % of patients Increased transglutaminases in up to 30 % of patients Gingival hyperplasia in up to 15 % of patients Other 22

24 Paresthesias in up to 40 % of patients Muscle aches in 10 to 40 % of patients Headache in 10 to 30 % of patients Tremor in 2 to 20 % of patients Hypertrichosis in < 5% of patients Adverse effects have also been reported in long-term studies (i. e., up to two years). In one study with 251 randomized patients receiving CSA 2.5 mg or 5 mg/kg daily for up to 21 months, AEs were observed in 54 % of the patients taking the drug; 8 % of these AEs were classified as severe 40. In about every fifth patient (18 %), therapy was discontinued as a result of AEs. Therapy was discontinued as a result of an increase in serum creatinine of > 30 % in 24 patients (10 %) and as a result of arterial hypertension in 6 % of patients. While the latter was not dose dependent, the former was in a total of 46 % of patients in this long-term study (compared with up to 20 % in the short-term studies) 41. A recent Cochrane review confirmed a statistically significant increase in blood pressure with CSA and indicates a dose-related effect with lower doses (1-4 mg/kg daily) increasing mean blood pressure by an average of 5 mmhg and higher doses (> 10 mg/kg daily) increasing mean blood pressure by 11 mmhg on average 42. As shown in one long-term study with 220 patients, the incidence of side effects is correlated with dose, duration of treatment, age, diastolic blood pressure, and serum creatinine 43. Kidney abnormalities In a recent review Maza et al. 44 reported that kidney abnormalities follow a pattern of increasing severity from elevation of serum creatinine, reduction of the GFR to structural damage. According to this overview, an increase of serum creatinine above 30 % from baseline is found in 10 to 40 % of patients after three to six months and 20 to 70 % after two years. It is a predictor of structural damage if not reversible. The GFR is decreased by 10 % four months after cessation of therapy. Mild kidney interstitial fibrosis after one year of therapy is found in 30 to 50 % of patients, more moderate-to-severe fibrosis after three to four years. In addition, tubular atrophy occurs in 30 % and glomerular sclerosis in 12 % after three years, but up to 26 % after ten years. Malignancies 23

25 As with other immunosuppressive therapies, CSA carries an increased risk of developing lymphoproliferative disorders and other malignant tumours, especially of the skin. The incidence of malignancies appears to be dependent primarily on the degree and duration of immunosuppression and on other preceding or concomitant therapies, such as photochemotherapy or MTX. Patients must be monitored especially carefully following long-term therapy with CSA. An increased risk of skin cancer, especially squamous cell carcinomas, has been observed in patients with psoriasis vulgaris who have received long-term photochemotherapy (especially high cumulative doses of PUVA, > 1000 J/cm²). In one study of patients who had previously received PUVA, the risk of squamous cell carcinoma was seven times greater after first CSA use than in the previous five years (i. e., prior to CSA treatment) after adjusting for PUVA and MTX exposure 45. For the total cohort any use of CSA was associated with a three-fold increase, i. e., comparable to that for at least 200 PUVA treatments. In another cohort study over five years (average duration of CSA treatment 1.9 years), the incidence of malignancies was twice as high as in the general population 46. This was attributable to a sixfold greater risk of skin cancer, the majority of cases being squamous cell carcinomas. Significant effects on the incidence of non-melanoma skin cancers were demonstrated in these studies based on duration of therapy with CSA and previous therapy with PUVA, MTX, or other immunosuppressive agents. Because squamous cell carcinomas can be difficult to diagnose in active psoriasis, a biopsy should be performed if there is any suspicion. There are case reports where therapy with acitretin demonstrated a beneficial effect in psoriasis patients with multiple squamous cell carcinomas as a consequence of immunosuppressive therapy, for example with CSA 47, 48. In some psoriasis patients treated with CSA, benign lymphoproliferative changes, as well as B- and T-cell lymphomas, occurred but receded when the drug was immediately discontinued. In the literature there are at least 20 single case publications on malignancies in CSA-treated patients with psoriasis vulgaris. Among these there are at least seven cases with nodal or cutaneous lymphomas and several cases with HPV-associated carcinoma. Infections As with other immunosuppressive therapies, CSA may increase the general risk of various bacterial, parasitic, viral, and fungal infections, as well as the risk of infections with opportunistic pathogens. As a rule, however, this increased risk of infections plays only a minor role when treating psoriasis vulgaris with CSA. Although CSA even has some inhibitory effects on HCV and HBV, it should be considered with caution in patients with HCV and especially 24

26 49, 50 HBV infections and consultation with a hepatologist prior to therapy is recommended. Infections deserve special attention as possible trigger factors for relapse. Patients in whom an infection-triggered exacerbation of psoriasis vulgaris is probable should first be treated with appropriate therapy for the infection, followed by a re-examination of the indication for CSA. An increased tendency to infection has been observed in patients with psoriatic arthritis, who under certain circumstances are treated with various immunosuppressive agents in addition to CSA. Pregnancy/birth defects/nursing The data available on the safety of CSA use in pregnant women are scarce. Animal studies have shown no relationship between CSA and birth defects. CSA has also proved not to be teratogenic with successful pregnancy outcomes in transplantation medicine. However, experience in patients who have undergone transplantation suggests that CSA increases the probability of pregnancy-related complications such as pre-eclampsia and premature birth with low birth weight. Thus CSA should only be used during pregnancy if the benefits outweigh the potential risks, which is rarely not the case in psoriasis vulgaris. Pregnant women who take the drug should be carefully monitored. Women of childbearing age who have psoriasis should only be given CSA after a negative pregnancy test. Adequate contraception must be ensured during therapy. It should be noted that CSA can reduce the efficacy of progesteronecontaining contraceptives. In psoriasis patients who become pregnant while taking CSA, the risks and benefits of continuing therapy should be carefully weighted. Ciclosporin and alcohol (capsules contain 12.7 % vol. alcohol) enter breast milk. Breastfeeding should be avoided while using CSA. Nursing mothers with psoriasis vulgaris should be given an alternative therapy. Ciclosporin in elderly persons There is only limited experience available on the use of CSA in elderly persons. There are no specific problems when CSA is used according to the recommendations. However, it should be used with more caution in obese elderly persons. The risk of developing renal failure after the age of 50 increases greatly under therapy with CSA. For this reason, laboratory monitoring should be stricter in this age group. The presence/occurrence of (UV-related) skin tumours should be given special attention. Measures in case of ADR 25

27 The adverse drug effects of CSA therapy are generally dose-dependent and respond to dose reduction. Special methods/measures are recommended for some of the adverse effects occurring with CSA. With an increase in serum creatinine of 30 % compared to the baseline mean value, an initial check of fluid intake should be performed. If serum creatinine increases by 30 to 50 % (even if within normal limits), a reduction in the dose of CSA of at least 25 % and another check within 30 days is recommended. If an increase in creatinine of 30 % is still present, CSA should be discontinued. If a 50 % increase of serum creatinine occurs, the CSA dose should be reduced by at least 50 %. In these cases, patients should be re-examined within 30 days and, if creatinine is still 30 % above baseline, CSA should be discontinued. If hypertension develops (systolic 160 mmhg or diastolic 90 mmhg in two consecutive measurements), antihypertensive therapy should be initiated or an existing antihypertensive therapy intensified. Appropriate agents include calcium channel blockers, such as amlodipine (5 to 10 mg daily), nifedipine (cave: gingival hyperplasia) or isradipine (2.5 to 5 mg daily). However, calcium antagonists themselves may increase CSA blood levels. This is the case for diltiazem, nicardipine, and verapamil. With the use of beta-blockers there might be the risk of triggering psoriasis. Therapy with ACE inhibitors or ATII receptor antagonists increases the risk of a hyperkalaemia. If, despite calcium channel blockers, a patient s blood pressure remains above the aforementioned limits, the CSA dosage should be reduced by 25 %. If this does not result in a normalization of blood pressure, therapy with CSA should be discontinued. Hypomagnesaemia should be treated with magnesium supplements (begin with 200 mg magnesium daily), which may be increased if needed. If the tolerance and efficacy of CSA are otherwise good and there are no neurological disturbances associated with the decreased magnesium levels, no further measures are required. With hyperkalaemia, a low potassium diet and sufficient fluid intake (2-3 L daily) should be recommended to the patient. If the response is not satisfactory, the CSA dose should be reduced by 25 %. The possible occurrence of arrhythmia with hyperkalaemia and the possible need for acute intervention should be kept in mind. Changes in serum potassium and magnesium levels have been observed in particular in patients with pronounced renal failure. With hyperuricaemia, a low purine diet and sufficient volume of liquids is recommended (2-3 L daily). If there is a lack of improvement and the situation appears to be threatening for the patient, the dosage should be reduced by 25 %. If no improvement is achieved, the medication should be discontinued. With regard to comedication with allopurinol, please refer to the subchapter on drug interactions. 26

28 With an increase in transaminases or total bilirubin to more than twice the normal value, a reduction in the dose of CSA by 25 % and subsequent reassessment within 30 days is recommended. If the laboratory values continue to deviate, CSA should be discontinued. With an increase in blood lipids (fasting values for cholesterol and/or triglycerides), a low-cholesterol, low-fat diet should be recommended. If no improvement is achieved, a reduction in dose or discontinuation of therapy with CSA should be considered, depending on the degree of hyperlipidaemia and the patient s risk profile. Isolated cases of serious, but reversible, impairment of renal function with a corresponding increase of serum creatinine has been observed in organ-transplant patients with the simultaneous use of fibrate-containing drugs (bezafibrate, fenofibrate). Ciclosporin may reduce the clearance of some HMG-CoA reductase inhibitors (lovastatin); as a result, their plasma levels and toxicity may be increased (muscle aches, myasthenia, myositis, and rhabdomyolysis). A corresponding warning in the expert information recommends close monitoring of patients in whom CSA and statins are used together (determination of the serum creatinine phosphokinase values) so as to detect myopathy at an early stage followed by a dosage reduction or, if needed, discontinuation of the statin. Simultaneous use of ezetimibe (Ezetrol ) is possible; however, interactions have been described (increase of the mean area under the curve of total ezetimibe). If gingival hyperplasia develops, optimal dental hygiene must be insured. Depending on the degree and progress of the findings, a dose reduction or discontinuation of CSA is recommended. Table 7: Overview of important side effects Very frequent Frequent Occasional Rare Very rare None Renal failure (dose-dependent); danger of irreversible renal damage (longterm therapy); hypertension; gingival hyperplasia; reversible hepatogastric complaints (dose dependent); tremor; weariness; headache; burning sensation in hands and feet; reversible elevated blood lipids (especially in combination with corticosteroids); hypertrichosis Seizures, gastrointestinal ulcerations, weight gain, hyperglycaemia, hyperuricaemia, hyperkalaemia, hypomagnesaemia, acne, anaemia Ischemic heart disease, pancreatitis, motor polyneuropathy, impaired vision, defective hearing, central ataxia, myopathy, erythema, itching, leucopoenia, thrombocytopenia Microangiopathic haemolytic anaemia, haemolytic uremic syndrome, colitis (isolated cases), papillary oedema (isolated cases), idiopathic intracranial hypertension (isolated cases) 27

29 Special considerations during a treatment Surgery: Consider discontinuing CSA for one week prior to elective surgery Important contraindications/restrictions on use Absolute contraindications Impaired renal function Insufficiently controlled arterial hypertension Severe infectious disease History of malignancy (possible exceptions: treated basal cell carcinoma, history of squamous carcinoma in situ) Current malignancy Simultaneous PUVA therapy Relative contraindications Previous potential carcinogenic therapies (e. g., arsenic, PUVA > 1000 J/cm²) Psoriasis triggered by severe infection or drugs (beta-blockers, lithium, anti-malarial drugs) Significant hepatic diseases Hyperuricaemia Hyperkalaemia Simultaneous therapy with nephrotoxic drugs (see drug interactions) Simultaneous phototherapy (SUP, for PUVA see above) Simultaneous use of other systemic immunosuppressive agents Simultaneous use of systemic retinoids or therapy with retinoids in the last four weeks prior to planned onset of therapy with CSA Drug or alcohol-related diseases Long-term previous treatment with MTX Pregnancy/breastfeeding 28

30 Vaccination with live vaccines Epilepsy Current treatment with castor oil preparations Drug interactions The availability of CSA depends primarily on the activity of two molecules the hepatic enzyme cytochrome P450-3A4 (CYP3A4), which is involved in its metabolism, and the intestinal P-glycoprotein, an ATP-dependent transporter protein that transports various drugs, among them CSA, from the enterocytes back into the intestinal lumen. The activities of these molecules may both vary for genetic reasons and be influenced by drugs and herbal substances 51. Above all, modulators and substrates of CYP3A4 are relevant for therapeutic practice. The calcium-antagonist diltiazem, the antimycotics ketoconazole and itraconazole, the macrolide antibiotics (with the exception of azithromycin), and grapefruit juice are strong inhibitors of the CYP3A4 with the risk of CSA overdosing, while the phytopharmaceutical agent St John s wort is a CYP3A4 inductor, with the risk of sub-therapeutic CSA levels. Because a worsening of myopathy due to the simultaneous intake of HMG-CoA reductase inhibitors (statins) is possible, the risks of concomitant statin therapy should be weighed carefully. In addition, interactions that could exacerbate ADR such as nephrotoxicity must be considered. Ciclosporin levels are increased by (CYP3A inhibition): Calcium antagonists (diltiazem, nicardipine, nifedipine, verapamil, mibefradil), amiodarone, macrolide antibiotics (erythromycin, clarithromycin, josamycin, posinomycin, pristinamycin), doxycycline, gentamicin, tobramycin, ticarcillin, quinolones (such as ciprofloxacin), ketoconazole and less pronounced fluconazole and itraconazole, oral contraceptives, androgenic steroids (norethisterone, levonorgestrel, methyl testosterone, ethinyl estradiol), danazol, allopurinol, bromocriptine, methylprednisolone (high doses), ranitidine, cimetidine, metoclopramide, propafenone, protease inhibitors (e. g., saquinavir), acetazolamide, amikacin, statins (above all atorvastin and simvastatin), cholic acids and derivatives (ursodeoxycholic acids), grapefruit juice. Ciclosporin levels are decreased by (CYP3A induction): 29

31 Carbamazepine, phenytoin, barbiturates, metamizole, rifampicin, octreotide, ticlopidine, nafcillin, probucol, troglitazone, intravenously administered sulfadimidine and trimethoprim, St John s wort. Possible reinforcement of nephrotoxic ADR through: Aminoglycoside (e. g., gentamicin, tobramycin), amphotericin B, trimethoprim and sulfamethoxazole, vancomycin, ciprofloxacin, aciclovir, melphalan, NSAID (diclofenac, naproxen, sulindac). It is recommended that the creatinine values be determined more frequently with these preparations; if necessary, reduce the dosage of the comedication. A considerable (reversible) impairment of renal function is possible with fibrates (bezafibrate and fenofibrate). On the other hand, during CSA therapy, an increased plasma level of some drugs occurs as a result of reduced clearance. This is true for digoxin, colchicine, prednisolone, some HMG-CoA reductase inhibitors (e. g., lovastatin), and diclofenac. The cause is probably a reduced first-pass effect (increased danger of renal damage). Other interactions: Increased risk of a gingival hyperplasia with the simultaneous intake of nifedipine; increased immunosuppression/tumour risk with simultaneous treatment with other immunosuppressive agents or tumour-inducing substances; vaccination may be less effective; CSA may reduce the effect of progesterone-containing contraceptives; with high doses of prednisone, prednisolone, or methylprednisolone, the risk of cerebral convulsions is increased. As a result of the disulfiram-like effect that has been observed following the administration of N-methylthiotetrazole cephalosporin (cefotetan), the simultaneous administration of CSA (alcoholcontaining drug) should be performed with care Overdose/measures in case of overdose If overdose is suspected, the following approach is recommended: Determine CSA blood level Interrupt CSA Determine vital parameters, liver, renal values, electrolytes If needed, introduce additional measures (including consultation with other specialists) 30