Introduction http://www.psoriasis-leitlinie.de 149 Background 2 3 4 5 1 Experience has shown that treatment selection for patients with psoriasis vulgaris is more commonly based on traditional concepts than on evidence-based data on the efficacy of various therapeutic options. In addition, it appears that systemic therapies are occasionally not applied in situations where they are needed due to the increased effort involved in monitoring the patients for unwanted side effects and possible interactions with other drugs. Goal of the Guidelines Physicians’ personal experiences and traditional therapeutic concepts should be supplemented and, if necessary, replaced by an evidence-based assessment of the efficacy of individual therapies in psoriasis vulgaris. The guidelines provide in-depth explanations of the available systemic and topical treatments for psoriasis, including the different photo- and photochemical therapies, and provide detailed descriptions of the administration and safety aspects. By providing background information on the profile of the available drugs, including efficacy, safety, and aspects of practicality and costs, the Guidelines should facilitate the process of selecting an appropriate treatment for each individual patient. This should help increase compliance and optimize the benefit/risk ratio of psoriasis therapies. Methods http://www.psoriasis-leitlinie.de Basis of data  Evidence assessment The efficacy and effectiveness of each intervention was evaluated using evidence-based criteria. 1 2 2 A high-quality (e.g. sample-size calculation, flow chart, intention-to-treat (ITT) analysis, sufficient size) randomized, double-blind comparative clinical study. B Randomized clinical study of lesser quality or other comparative study (non-randomized, cohort, or case-control study). C Non-comparative study. D Expert opinion. 1  2 2 Intervention is supported by studies with grade B evidence or studies with grade C evidence whose results are predominantly consistent with one another. Little or no systematic empirical evidence  Therapeutic recommendation A distinct rating of the therapeutic options or a strict clinical algorithm cannot be defined for the treatment of psoriasis vulgaris. The criteria for selecting a particular therapy are complex. The decision for a specific treatment should be based on the profile of the available drugs and the characteristics of a given patient. The decision for or against a therapy remains a case-by-case decision. These Guidelines provide a reasonable form of assistance in deciding on a suitable therapy and are an instrument for optimizing the required therapeutic process. strength of the therapeutic recommendation ↑↑ Measure is highly recommended ↑ Measure is recommended → Neutral ↓ Measure is not recommended ↓↓ Measure is highly inadvisable Results Therapeutic options are named and discussed in alphabetical order. Therapeutic strategies Fig. 1 Overview of the therapeutic options evaluated for chronic plaque psoriasis (the therapeutic options are listed alphabetically and do not represent a ranking)  Evaluation of topical and systemic therapies in tabular form These tables are intended to provide a rough orientation for evaluating the therapeutic options. Cumulative calculations of the individual aspects for the overall evaluation of the therapeutic options are not possible and cannot be drawn upon for the final analysis of a therapeutic option. The product assessment for each individual patient may deviate greatly. A direct comparison between systemic and topical therapies is not possible because of the different severity of the psoriasis lesions of patients treated with topical or systemic treatments. The evaluations reported here were made on the basis of data extracted from the literature and expert opinions. For further details refer to the Methods Report at www.psoriasis-leitlinie.de Topical monotherapy  Phototherapy and systemic monotherapy  Efficacy Scale Systemic therapy Topical therapy ++++ Approx. 90% Approx. 60% +++ Approx. 70% Approx. 45% ++ Approx. 50% Approx. 30% + Approx. 30% Approx. 15% +/− Approx. 10% Approx. 5% – Not defined Not defined The evidence level applies only to the estimate of efficacy. Safety/tolerance in induction therapy or maintenance therapy  Practicality (Patient) Practicality (Physician) Cost/benefit  The evaluations of safety/tolerance in induction therapy or maintenance therapy as well as practicality for the physician or patient and the cost/benefit were performed using a scale ranging from poor (–) to good (++++). The gradation between these two extremes was made based on expert opinion and unsystematic literature search. A level of evidence was not given for these evaluations since no systematic literature review was performed. Evaluation of topical therapies Calcineurin inhibitors Table 1 Tabular summary Calcineurin inhibitors First approved in Germany ® 2002 (Atopic dermatitis, not approved for psoriasis vulgaris) ® 2002 (Atopic dermatitis, not approved for psoriasis vulgaris) Recommended initial dosage  Recommended maintenance dosage Individual therapeutic adjustment Expected beginning of clinical effect After approximately 2 weeks Response rate No data available Important contraindications Pregnancy and nursing (due to lack of experience) skin infections, immune suppression Important adverse drug reactions (ADRs) Burning sensation on skin, skin infections Important drug interactions None known Other Cave: Do not combine with phototherapy! Photoprotection!   Corticosteroids Table 2 Tabular summary Corticosteroids First approved in Germany 1956 (Psoriasis vulgaris) Recommended control parameters None Recommended initial dosage One to two times daily Recommended maintenance dosage Gradual reduction following onset of effect Expected beginning of clinical effect After 1–2 weeks Response rate Betamethasone dipropionate, two times daily: marked improvement or clearance of the skin lesions in 46–56% patients after 4 weeks (LE 1) Important contraindications Skin infections, rosacea, perioral dermatitis Important ADRs Skin infections, perioral dermatitis, skin atrophy, hypertrichosis, striae Important drug interactions None Other –   Coal tar Table 3 Tabular summary Coal tar First approved in Germany Listed active ingredient since 2000 (DAC on page 170), historical application, various tar-containing externals are licensed as drugs, application of tar as anti-psoriatic following publication by Goeckermann in 1925 Recommended control parameters After long-term application/application on large areas: if needed clinical controls for potential development of skin carcinoma Recommended initial dosage 5–20% salve preparations or gels for local therapy, 1× daily Recommended maintenance dosage No long-term application (max. 4 weeks, DAC 2000) Expected beginning of clinical effect After 4–8 weeks, efficacy improves in combination with UV application Response rate There is insufficient data available on the response rate as a monotherapy (LE 4) Important contraindications Pregnancy and nursing Important ADRs Color, odor, carcinogenic risk, phototoxicity—which is part of the desired effect Important drug interactions Not known with topical use Other DAC 2000 (on page 170), Hazardous Goods Directive Appendix 4 No. 13   Dithranol Table 4 Tabular summary Dithranol First approved in Germany Psoralon 1983 (Psoriasis vulgaris) Psoradexan 1994 (Psoriasis vulgaris) Micanol 1997 (Psoriasis vulgaris) Recommended control parameters Intensity of irritation Recommended initial dosage Begin with 0.5% preparation for long-term therapy or 1% for short-contact therapy, then increase if tolerated Recommended maintenance dosage Not recommended for maintenance therapy  Expected beginning of clinical effect After 2–3 weeks Response rate  Marked improvement or clearance of skin lesions in 30–50% of the patients (LE 2) Important contraindications Acute, erythrodermic forms of psoriasis vulgaris; pustular psoriasis Important ADRs Burning and reddening of the skin in >10% Important drug interactions – Other –   Tazarotene Table 5 Tabular summary Tazarotene First approved in Germany 1997 (psoriasis vulgaris) Recommended control parameters Check development of skin irritations Recommended initial dosage Begin with one treatment daily of tazarotene gel 0.05% in the evening for approximately 1–2 weeks Recommended maintenance dosage If necessary continue for 1–2 weeks with tazarotene gel 0.1% Expected beginning of clinical effect After 1–2 weeks Response rate After 12 weeks therapy with 0.1% tazarotene gel improved findings of at least 50% in approximately 50% of the patients (LE 2) Important contraindications Pregnancy, nursing Important ADRs Pruritus, burning sensation of skin, erythema, irritation Important drug interactions Avoid concomitant use of preparations with irritating and drying properties  Other –   3 Table 6 Tabular summary 3 First approved in Germany  Calcipotriol 1992 (Psoriasis vulgaris)  Tacalcitol 1994 (Psoriasis vulgaris)  Calcitriol 1999 (Psoriasis vulgaris)  Calcipotriol/Betamethasone  2002 (Psoriasis vulgaris) Recommended control parameters Monitor for skin irritations  Recommended initial dosage Calcipotriol: 1× to 2× daily to affected locations, up to a maximum of 30% of the body surface Tacalcitol: 1× daily to affected locations, up to a maximum of 20% of the body surface Calcitriol: 2× daily to affected locations, up to a maximum of 35% of the body surface Recommended maintenance dosage Calcipotriol: 1× to 2× daily, up to 100 g/week for up to 1 year Tacalcitol: 1× daily for 8 weeks, for up to 18 months, on a maximum of 15% of the body surface with up to 3.5 g daily Calcitriol: insufficient experience with the application for more than 6 weeks  Expected beginning of clinical effect After 1–2 weeks Response rate  Between 30 and 50% of the patients demonstrated a marked improvement or clearance of the lesions after 4–6 weeks (LE 1) Important contraindications Diseases with abnormal calcium metabolism, severe liver and renal diseases Important ADRs Skin irritation (reddening, itching, burning) Important drug interactions Drugs which elevate the calcium levels, (e.g. thiazide diuretics), no concomitant application of topical salicylic acid preparations (inactivation) Other 3   Phototherapy Table 7 Tabular summary Phototherapy First approved in Germany Clinical experience, depending on the modality for >50 years Recommended control parameters Regular skin inspection (UV erythema) Recommended initial dosage Individual dose depends on skin type; options: • UVB: 70% of minimum erythema dose (MED) • Oral PUVA (photochemotherapy): 75% of the minimum phototoxic dose (MPD) – Recommended maintenance dosage Increase according to degree of UV erythema Expected beginning of clinical effect After 1–2 weeks  Response rate In >75% of the patients PASI, 75 after 4–6 weeks (LE 2) Important contraindications  Important ADRs  Important drug interactions Drugs causing phototoxicity or photoallergy Other Combination with topical preparations acts synergistically, PUVA may not be combined with cyclosporine   Evaluation of systemic therapies Efalizumab Table 8 Tabular summary Efalizumab First approved in Germany September 2004 (psoriasis vulgaris) Recommended control parameters Prior to therapy exclusion of significant infections, complete blood count, liver values  Recommended initial dosage 0.7 mg/kg body weight (BW) per week Recommended maintenance dosage 1 mg/kg BW per week Expected beginning of clinical effect  After 4–8 weeks Response rate PASI 75 for approximately 30% of the patients after 12 weeks (LE 1) Important contraindications (limited selection) Chronic or acute infections, pregnancy, malignant diseases, immune deficiencies, no vaccinations before or during treatment Important ADRs (limited selection) Flu-like injection reactions, leukocytosis and lymphocytosis, rebound, exacerbation and arthralgia, thrombocytopenia Important drug interactions Not known  Other Stop therapy due to the risk of exacerbation and rebound if a PASI reduction of 50% is not achieved after 12 weeks  Table 9 Laboratory controls during treatment with efalizumab  a b   Etanercept Table 10 Tabular summary Etanercept First approved in Germany 2002 (Psoriasis arthritis )/2004 (psoriasis vulgaris) Recommended control parameters Prior to therapy exclusion of tuberculosis, complete blood count, liver and renal values, urinanalysis  Recommended initial dosage Twice 25 mg per week or 2× 50 mg/week Recommended maintenance dosage Twice 25 mg per week Expected beginning of clinical effect  After 4–8 weeks, at the latest after 12 weeks Response rate PASI 75 in 34% (2 × 25 mg) or 49% (2 × 50 mg) of the patients at the end of the induction phase (12 weeks) (LE 1) Important contraindications (limited selection) Infections, pregnancy, nursing, heart failure NYHA III–IV Important ADRs (limited selection) Local reactions, infections  Important drug interactions (limited selection) Anakinra (IL-1 receptor antagonist) Other –  Table 11 Laboratory controls during treatment with etanercept   Infliximab Table 12 Tabular summary Infliximab First approved in Germany 2004 (Psoriasis arthritis)/2005 (psoriasis vulgaris) Recommended control parameters Prior to therapy exclusion of tuberculosis, during therapy: leukocyte and platelet counts, liver value controls, signs of clinical infection Recommended initial dosage 5 mg/kg BW at week 0, 2, 6 Recommended maintenance dosage 5 mg/kg BW in dosage intervals of 8 weeks Expected beginning of clinical effect  After 1–2 weeks Response rate PASI 75 in ≥80% of the patients with moderate to severe psoriasis vulgaris (LE 1) Important contraindications (limited selection) Acute or chronic infections, tuberculosis, cardiac failure NYHA III–IV, pregnancy and nursing Important ADRs (limited selection) Infusion reactions, severe infections, progression of heart failure NYHA III–IV, very rare liver failure, autoimmune phenomena Important drug interactions (limited selection) Anakinra (IL-1 receptor antagonist) Other –  Table 13 Laboratory controls during treatment with infliximab  a  Cyclosporine Table 14 Tabular summary Cyclosporine First approved in Germany 1983 (Transplantation medicine) 1993 (Psoriasis vulgaris) Recommended control parameters Interview/examination:  • Status of skin and mucous membranes • Signs of infection • Neurological, gastrointestinal symptoms • Blood pressure 14 Recommended initial dosage 2.5–3 (max. 5) mg/kg BW Recommended maintenance dosage Interval therapy (between 8 and 16 weeks) with dosage reduction at the end of the induction therapy (e.g., 0.5 mg/kg BW every 14 days) or Continuous long-term therapy with dosage reduction (e.g. by 50 mg every 4 weeks after week 12) and a dosage increase by 50 mg with relapse Maximum total duration of therapy: 2 years Expected beginning of clinical effect After approximately 4 weeks Response rate Dose-dependent: after 8–16 weeks with 3 mg/kg BW; PASI 90 in approximately 30–50% of patient and PASI 75 in approximately 50–70% of patients (LE 1) Important contraindications (limited selection) Absolute Reduced renal function, insufficiently controlled arterial hypertension, uncontrolled infections, relevant malignancies (current or previous, in particular hematologic diseases and cutaneous malignancies with the exception of basal cell carcinoma) Relative: Relevant hepatic dysfunction, pregnancy and nursing, concomitant use of substance which interacts with cyclosporine, concomitant UV-therapy or prior PUVA-pre-therapy with cumulative dosage >1000 J/cm², concomitant application of other immunosuppressives, retinoids or long-term prior-therapy with methotrexate (MTX) Important ADRs (limited selection) Renal failure, increase of blood pressure, liver failure, nausea, anorexia, vomiting, diarrhea, hypertrichosis, gingival hyperplasia, tremor, weariness, parasthesia, hyperlipidemia Important drug interactions (limited selection) Increase of the cyclosporine level (CYP3A inhibition) through: Allopurinol, calcium antagonists, amiodarone, antibiotics (macrolides, clarithromycin, josamycin, ponsinomycin, pristinamycin, doxycycline, gentamicin, tobramycin, ticarcillin, quinolones), ketoconazole, oral contraceptives, methylprednisolone (high dosages), ranitidine, cimetidine, grapefruit juice Decrease of the cyclosporine level (CYP3A induction) through: Carbamazepine, phenytoin, barbiturates, metamizole, St. John’s wort  Possible reinforcement of nephrotoxic adverse drug reactions through: Aminoglycosides, amphotericin B, ciprofloxacin, acyclovir, non-steroidal antiphlogistics Specific interactions: Potassium-saving substances: increased risk of hyperpotassemia Reduced clearance of: Digoxin, colchicine, prednisolone, HMG-CoA reductase inhibitors (e.g. lovastatin), diclofenac Other Increased risk of lympho-proliferative diseases in transplant patients. Increased risk of squamous cell carcinoma in psoriasis patients following excessive phototherapy. Only moderately effective in and not approved for psoriatic arthritis  Also used successfully in the therapy of chronic-inflammatory diseases in children  Table 15 Laboratory controls during treatment with cyclosporine  a b c d e  Fumaric acid esters Table 16 Tabular summary Fumaric acid esters First approved in Germany 1995 (Psoriasis vulgaris)  Recommended control parameters Serum creatinine, transaminases/γGT, complete blood count including differential blood count, urinanalysis Recommended initial dosage 17 Recommended maintenance dosage Individually adapted dosage Expected beginning of clinical effect After approximately 6 weeks Response rate PASI 75 in 50–70% of the patients at the end of the induction phase after 16 weeks (LE 2) Important contraindications (limited selection) Chronic diseases of the gastrointestinal tract and/or the kidneys and chronic diseases, which are accompanied by an impairment of the leukocyte count or functions, malignant diseases, pregnancy and nursing  Important ADRs (limited selection) Gastrointestinal complaints, flush, lymphopenia, eosinophilia Important drug interactions None known Other – Table 17 Dosage regimen for Fumaderm therapy  Fumaderm initial Fumaderm Week 1 1-0-0  Week 2 1-0-1  Week 3 1-1-1  Week 4  1-0-0 Week 5  1-0-1 Week 6  1-1-1 Week 7  2-1-1 Week 8  2-1-2 Week 9  2-2-2  Table 18 Laboratory controls during treatment with fumaric acid esters  a  Methotrexate Table 19 Tabular summary Methotrexate First approved in Germany ® 1991 (Psoriasis vulgaris) ® 1992 (Psoriasis vulgaris) ® 2004 (Psoriasis vulgaris) Recommended control parameters Complete blood count (Hb, HCT, differential blood count, platelets), renal function (serum creatinine, urea, urine sediment), liver values (serum transaminases), III-procollagen amino terminal propeptides  Recommended initial dosage 5–15 mg per week Recommended maintenance dosage 5–22.5 mg per week depending on effect Expected beginning of clinical effect After 4–8 weeks Response rate PASI 75 in approximately 60% of the patients at the end of the induction phase of 16 weeks (LE 3) Important contraindications (limited selection) Absolute contraindications Desire to have children (for both men and women), pregnancy and nursing, inadequate contraception, drug consumption, alcoholism, known sensitivity to active ingredient methotrexate (e.g. pulmonary toxicity), bone marrow dysfunction, severe liver disease, severe infections, immunodeficiency, active peptic ulcers, hematologic changes (leucopenia, thrombocytopenia, anemia), renal failure Relative contraindications Kidney disorders, liver disorders, history of arsenic consumption , chronic congestive cardio-myopathy, adiposity, old age, diabetes mellitus, history of hepatitis, lack of patient compliance, ulcerative colitis, diarrhea, NSAID use, gastritis Important ADRs (limited selection) Liver fibrosis/cirrhosis, pneumonia/alveolitis, bone marrow depression, renal damage, alopecia (reversible), nausea, weariness, vomiting, elevated transaminases, infection, gastrointestinal ulcerations, nephrotoxicity Important drug interactions (limited selection) Cyclosporine, salicylates, sulfonamides, probenecide, penicillin, colchicin, NSAIDs (naproxene, ibuprofene, etc.), ethanol, co-trimoxazole, pyrimethamine, chloramphenicol, sulfonamides, prostaglandin synthesis inhibitors, cytostatics, probenecide, barbiturates, phenytoin, retinoids, sulfonamides, sulfonylurea, tetracyclines, co-trimoxazol, chloramphenicol, dipyridamole, retinoids, ethanol, leflunomide Other Consistent avoidance of alcohol, X-ray of the lungs prior to beginning therapy   Table 20 137  a b c  Retinoids Table 21 Tabular summary Acitretin First approved in Germany 1992 (Psoriasis vulgaris) Recommended control parameters Erythrocyte sedimentation rate (ESR), complete blood count, liver values, renal values, blood lipid values, pregnancy test, x-ray control of the bones in case of long-term therapy Recommended initial dosage 0.3–0.5 mg/kg BW per day for approximately 4 weeks, then 0.5–0.8 mg/kg BW Recommended maintenance dosage Individual dosaging dependent on the results and tolerance  Expected beginning of clinical effect After 4–8 weeks Response rate Widely variable and dose-dependent, no definite statement possible, partial remission (PASI 75) in 25–75% of the patients (30–40 mg per day) (LE 3) in studies Important contraindications (limited selection) Renal and liver damage, desire to have children in female patients of child-bearing age, pregnancy, nursing, alcohol abuse, manifest diabetes mellitus, wearing of contact lenses, history of pancreatitis, hyperlipidemia requiring drug treatment Important ADRs (limited selection) Hypervitaminosis A (e.g., cheilitis, xerosis, nose-bleeding, alopecia, increased skin fragility)  Important drug interactions (limited selection) Phenytoin, tetracyclines, methotrexate, alcohol, mini-pill Other Contraception up to 2 years after discontinuation in female patients of child-bearing age  a Table 22 Laboratory controls during treatment with Acitretin  a b  Other therapies Climate/balneotherapy Table 23 Tabular summary Climate/balneotherapy First approved in Germany Clinical experience with balneotherapy has existed for more than 200 years  Recommended control parameters Regular skin inspection Recommended initial dosage Therapy regimens vary depending on the institution/location Recommended maintenance dosage Therapy regimens vary depending on the institution/location Expected beginning of clinical effect Varies greatly Response rate Varies greatly (LE 4) Important contraindications Dependent on modality selected Important ADRs Dependent on modality selected Important drug interactions Not applicable Other Balneotherapy and climate therapy are frequently combined   Psychosocial therapy   Notes on the use of the Guidelines The presentation of the therapies deliberately focused on those aspects deemed particularly relevant by a panel of experts. Aspects which are not of specific importance for a certain intervention, but which are part of the physician’s general obligations to the patient, such as the investigation of intolerance and allergies toward certain drugs or the exclusion of contraindications, are not individually listed, but it is nevertheless taken for granted that these are part of the physician’s duty to provide care. It is recommended that each and every user carefully reads and follows the product information and compare it with the recommendations in the Guidelines on dosaging, contraindications, and drug interactions for completeness and currentness. Every dose or application is administered at the user’s own risk. The authors and the publishers kindly request that users inform them of any inaccuracies that they might notice. The users are requested to keep themselves constantly informed of any new findings subsequent to the publication of the Guidelines.