3.b. Treatment.pptx

DERMATOLOGICAL THERAPY Prof Andrija Stanimirović, MD, PhD TOPICAL THERAPY IN PSORIASIS TREATMENT Guidelin e Algorith m Chronic plaque-type psoriasis Calcineurin inhibitors Coaltar basic therapy Corticosteroids mild BSA < 10% PASI < 10 P Topical therapy Dithranol Laser Tazarotene Vitamin D3 moderate...

DERMATOLOGICAL THERAPY Prof Andrija Stanimirović, MD, PhD TOPICAL THERAPY IN PSORIASIS TREATMENT Guidelin e Algorith m Chronic plaque-type psoriasis Calcineurin inhibitors Coaltar basic therapy Corticosteroids mild BSA < 10% PASI < 10 P Topical therapy Dithranol Laser Tazarotene Vitamin D3 moderate BSA > 10% PASI > 10 P Calcineurin inhibitors Cyclosporin e Fumaric Acid Esters Evidence-based (S3) severe Guidelines for the Treatment of Psoriasis Vulgaris Nast et al., J Dtsch Dermatol Ges 5 (Suppl. 3), 2007 Nast et al., Arch Dermatol Res 299.111-138, 2007 (short version) Combined: Climate balneotherapy Systemic therapy Methotrexa te Retinoids UV Efalizumab Etanercept Infliximab Adalimuma b Ustekinum Keratolytics Before starting the „real” treatment Keratolytics Removal of scale or hyperkeratosis in psoriatic plaques Salicylic acid 2% to 10% Caution in children: salicylism (toxic effects - nausea, vomiting, tinnitus) Salicylic acid 5% to 10% in Vaseline - a few weeks of application Salicylic acid 20% - up to 2 weeks of administration Urea and alpha-hydroxy acids are also effective Corticosteroids and vitamin D analogues 1st therapeutic option Topical corticosteroids Most common drugs in topical therapy of psoriasis Antiinflammatory, immunosupressive and antiproliferative features Binding to receptors in cytoplasm and transporte to nucleus wher they act on gene transcription Efficacy connected with 1) potency and 2) capacity of absorption in skin Absorption can be enforced with occlusion or vehicle Topical corticosteroids CS low strength: sensitive skin-face, genital, folds CS middle strength: trunc and exstremities CS high strength: palms and soles, hands, feet Vehiculum Ointments: dry skin, hyperkeratotic lesions Lotios and gels: scalp, face, genital Creams: all regions Topical corticosteroids Tachyphylaxis-decreased CS efficacy after long-term application, exacerbation after treatment discontinuation Solution: switching to another CS decreased potency, reduced application frequency, corticoid-free applications (weekends) Side effects of CS: stretchmarks, hypertrichosis, teleangiectasia, steroid acne, systemic-suppression of pituitary-adrenal axis Topical corticosteroids Therapeutic efficiency Medium potency CS: after 4 weeks of therapy 46-56% patients in remission High potency CS: after 4 weeks of therapy 68-89% patients in remission Minimizing of systemic side effects Medium potency CS : 90-100 g per week High potency CS : 40-50 g per week Vitamin D analogues Start of application Observation: Patients with hypocalciemia often develop various forms of psoriasis, especially pustular; patients with osteoporosis and psoriasis - dramatic improvement of psoriasis after peroral vitamin D therapy Bioactive form of 1,25-dihydroxycholecalciferol inhibits keratinocyte proliferation and normalizes its differentiation Development of vitamin D analogs in psoriasis therapy Calcipotriene-vitamin D analogue Available in USA since 1993 Clinical trials: as effective as betamethasone 17valerate (CS), more effective than minute antralin therapy and 15% topical tar therapy Therapeutic response: 30-50% of patients significantly improved / remission in the first 4 weeks of therapy, effect extended for 12 months Extremely suitable for maintenance therapy Calcipotriene Included in the first line of topical psoriasis therapy (additionally with CS) The application twice daily is well tolerated, besides sensitive skin on face and groin-possible development of irritant dermatitis Avoiding hypercalciemia - Use up to 100 g of preparation per week No tachyphylaxis Not suitable for pregnant patients Synergistic combination with CS New generation of vitamin D3 analogs: calcitriol Calcitriol- topical synthetic vitamin D analog Advantage: Increased tolerance on applicaton in sensitive skin regions (face, genital region) Reduces the need for corticosteroids to a minimum Minimal systemic absorption, no hypercalcemia even when applied to 1/3 of the body's skin Combination: vitamin D3+corticosteroid Calcipotriol + Betamethasone dipropionate cream / gel Lipophilic gel, special formulation for the scalp Calcipotriol 0.0005% and betamethasone dipropionate 0.05% Synergistic activity on molecular level Excellent cosmetic acceptability Retinoids and topical immunomodulators 2nd therapeutic option Retinoids Retinoids normalize proliferation and cell differentiation Systemic retinoids in the treatment of severe forms of psoriasis Etretinate, acitretine-serious side effects: teratogenicity, hepatotoxicity, bone changes, hair loss Need for the use of topical retinoids in the treatment of psoriasis Retinoids Available in USA since 1997 Topical psoriasis therapy with BSA≤20% It is rapidly metabolised in the skin and converted into an active metabolite, tazaroten acid Tazarotene gel 0.05% and 0.1% Clinical efficacy: 50% of patients 50% improvement after 12 weeks of therapy Long-term effects, maintenance therapy Retinoids Side effects: local skin irritation and itching Apply only to the localized skin Synergistic combination with CS Combined with CS - reduces the percentage of side effects Teratogenic, not suitable for pregnant patients, necessary contraception during therapy Topical immunomodulators Calcineurin inhibitors Tacrolimus ointment 0.03% and 0.1% Pimecrolimus cream 1% ↓ penetration through hyperkeratotic skin layer Applies on areas with thinner stratum corneum: face, flexures, genitals Topical immunomodulators-side effects LOCAL SIDE EFFECTS: Stinging Burning Itching Irritation Photosensitivity Adverse interactions with alcohol intake PREGNANCY: FDA category C Topical immunomodulators Photo/carcinogenicity ? Lerche CM et al. Exp Dermatol. 2008;17:57-62. Topical tacrolimus in combination with simulated solar radiation does not enhance photocarcinogenesis in hairless mice Topical immunomodulators Combination with UV phototherapy? Photo/carcinogenicity ? McCollum et al. Pediatr Dermatol 2010;27:425-436 Long-term topical application Tacrolimus ointment 0.03% and 0.1% on 20 000 pediatric patients with AD: no increased incidence of lymphoma/skin cancer No evidence for photocarcinogenicity in topical application Anthralin and coal tar Anthralin Inhibits cell growth and restores cell differentiation Application: once daily at night, 4-8 weeks Initial concentration: 0.5 to 0.1% gradually increased 3 do 5% Effective antipsoriatic agent without systemic side effects Synergistic effect with UVB phototherapy PREGNANCY: FDA category C Anthralin-side effects Stains hair, skin, nails, clothing brownish to purplish color Very irritating to normal skin – apply only to affected skin petroleum or zinc oxide ointment around the psoriatic lesion Avoid contact with the face, eyes or mucous membranes “Minute therapy”: application 0.5% to 1% anthralin 10 minutes, washing off with soap - as effective as the longer conventional application Coal tar Contains 10,000 different chemical compounds - precise mechanism of action is not clear Antiproliferative and anti-inflammatory actions Application: at night, should be allowed to dry on the skin for 10 to 15 minutes before the patient gets in bed, showered off in the morning 1xdaily application in conjunction with a topical corticosteroid applied 2x daily Synergistic effect with UVB phototherapy Coal tar-side effects Unpleasant odor, stains clothing Folliculitis Contact allergy (patch testing-irritant response-continue therapy, lower concentration) Bronchospasm Photosensitivity (remains active on the skin for at least 24 hours - increased risk of sunburn) Carcinogenic in animal studies, evidence in humans? FDA: concentrations between 0.5 % to 5 % are safe and effective, no scientific evidence that the tar in OTC products is carcinogenic Do not use during pregnancy/lactation Topical therapies-Summary Topical therapies for psoriasis Coal tar; dithranol; calcipotriol, calcitriol and tacalcitol (vitamin D analogues); tazarotene (vitamin A analogues); corticosteroids1 Choice of treatment depends on the extent and pattern of psoriasis, and patient preference1 Effective in short term (6–8 weeks) with a 2 point improvement on a 12 point severity scale2 Poor adherence to topical therapy in psoriasis may be common 3 1. Psoriasis - General Management. Available from: http://www.bad.org.uk/site/769/Default.aspx. Accessed 17 Feb 2010. 2. Mason J, et al. Br J Dermatol 2002;146:351-64. 3. Richards HL, et al. J Am Acad Dermatol. 1999;41(4):581-3. Indications for systemic therapy of psoriasis Failure of adequate trial of topical therapy Repeated hospital admissions for topical therapy Extensive chronic plaque psoriasis in the elderly or infirm Generalised pustular or erythrodermic psoriasis Severe psoriatic arthropathy Rule of tens Body surface area affected (BSA) >10%, or PASI score >10, or DLQI >10 Psoriasis - General Management. Available from: http://www.bad.org.uk/site/769/Default.aspx. Accessed 17 Feb 2010. Severity of Psoriasis and Prevalence “Ideal Therapy” for Psoriasis Effective, long-term control Safe Minimal monitoring Patient acceptance Selective/targeted therapy Principles of psoriasis treatment Sinergistic effect and added efficacy + dosage & toxicity decreasing 1.Combined Topical and sistemic therapy Sistemic and phototherapy Topical and phototherapy PUVA 2.Rotational Decreasing the possibility of side-effects 3.Sequential- MTX (CyA) Acitretin point to maximmize initial effect and diminish longlasting toxicity – Phase of clearing – Transitional phase – Maintenance phase UVB TAR Oral systemic therapies Methotrexate – a folic acid antagonist that interferes with purine synthesis and thus inhibits DNA synthesis and cell replication; it also has specific T-cell suppressive activities Ciclosporin – an immunosuppressant that inhibits the activation of T cells and may also exert a direct effect on epidermal keratinocytes Oral retinoids – vitamin A analogues (acitretin is the principal licensed product in this class) which reduce epidermal proliferation and differentiation Fumaric acid esters – non-specific T cell inhibitors producing changes in cytokine production that are beneficial in psoriasis (used mainly in Germany, for severe psoriasis) Menter A, Griffiths CEM. Lancet. 2007; 370:272-84. Methotrexate Proposed mechanisms of action Immunomodulatory effects1 Inhibition of proliferating lymphoid tissue Inhibition of IL-1 activity and IL-6 production Structure of methotrexate2 Anti-inflammatory effects1 Reduced neutrophil and monocyte chemotaxis Inhibition of leucocyte accumulation at sites of inflammation Inhibition of epidermal proliferation1 Interference with cell kinetics via temporary reduction on DNA synthesis 1. Zachariae H. Methotrexate. In: van de Kerkhof P, editor. Textbook of Psoriasis, 2ed. Oxford: Blackwell Publishing; 2003. 2. Methotrexate - Compound Summary. Available at: http://pubchem.ncbi.nlm.nih.gov. Accessed: 17 Feb 2010. Methotrexate Long-term treatment up to 26 years Majority of patients responded well to treatment – One or more side-effects were observed in 61% of patients – Therapy was discontinued in 20% of patients Patients should be regularly monitored in particular for liver and bone marrow toxicity. n=157 76 80 Patients (%) No obvious relation between cumulative dose or duration of methotrexate therapy and frequency or severity of side effects 100 60 40 18 20 6 0 Poor Moderate Good Treatment response MTX dose regimen: 15-20 mg/wk Mean cumulative dose: 3394 mg Mean treatment duration: 237 weeks Haustein UF, Rytter M. J Eur Acad Dermatol Venereol. 2000;14(5):382-8. MTX- EADV RECOMMENDATION Efficaceous for moderate to severe psoriasis Regular laboratory controls necessary Not convenient for induction therapy as it has slow mode of action Methotrexate Safety considerations Absolute contraindications Severe infections, severe liver or kidney disorders, bone marrow dysfunction, pregnancy or breastfeeding, impaired lung function or pulmonary fibrosis, alcohol abuse, immunodeficiency, acute peptic ulcer Important side effects Bone marrow depression, liver toxicity, pneumonia, and alveolitis Important drug interactions Trimethoprim, probenecid, retinoids, NSAIDs Special considerations Dosage only once weekly; overdose may lead to leucopenia/pancytopenia and thus be life-threatening "Its clinical application is restricted by severe adverse drug reactions [...]. However, with precise patient selection, thorough patient information, strict monitoring, use of the lowest effective dose, and the additional administration of folic acid, an acceptable safety profile can also be attained for methotrexate therapy." Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009;23 Suppl 2:1-70. ACITRETIN – EADV RECOMMENDATION Monotherapy only in generalized pustular psoriasis (first choice) Combinations /Re-UVB, Re-PUVA/ Women of childbearing age– NO! Side-effects (skin, hyperlipidemia,liver function) Acitretin Long-term efficacy and safety PASI scores for patients who completed the study PASI reduced by 76% in patients reaching Week 52 – Side-effects were common, including cheilitis (78%), hair loss (52%) and pruritis (51%) – 14 patients withdrew due to adverse reactions 20 Absolute PASI score Open-label study: optimal doses of acitretin (10-70 mg) administered to patients with severe psoriasis (n=63) for 12 months 30 15 10 5 0 0 4 8 12 26 Time (weeks) Murray HE, et al. J Am Acad Dermatol. 1991;24(4):598-602. 35 43 52 Ciclosporin Proposed mechanism of action Ciclosporin forms complex with cyclophilin (isomerase) Structure of ciclosporin2 Complex inhibits calcineurin Signal transduction from T cell receptor to cytokine promotors is blocked Inhibition of IL-2, IL-3, IL-4, IL-5, GM-CSF and TNF-a 1. de Rie MA, Bos JD. Cyclic Immunosupressive Drugs. In: van de Kerkhof P, editor. Textbook of Psoriasis, 2ed. Oxford: Blackwell Publishing; 2003. 2. Cyclosporine - Compound Summary. Available at: http://pubchem.ncbi.nlm.nih.gov. Accessed: 17 Feb 2010. Ciclosporin Intermittent therapy in patients non-responsive to topicals Ciclosporin courses required during the study Cumulative remission rates for each treatment period 1.0 400 Patients 300 Cumulative remission rate 400 259 200 117 100 0.8 0.6 Period 1 Period 2 Period 3 Period 4 0.4 0.2 26 0 1 2 3 4 Patients (%) Ho VC, et al. The PISCES Study Group. Br J Dermatol. 1999;141(2):283-91. 0 0 14 28 42 56 70 84 98 112 126 140 Time (days) Ciclosporin – EADV recommendation Induction therapy for moderate to severe psoriasis in adults with failure of phototherapy Long therm therapy in selected patients (BUT no longer than 2 years because of efficacy decreasing and toxicity increasing ) with regular controles Ideal patient for therapy with ciclosporin Erythrodermic and generalized pustular psoriasis Accute flares of chronic plaque psoriasis Psoriais with unadequate response to other modalities of systemic therapy Ciclosporin Safety considerations Impaired renal function; uncontrolled hypertension; uncontrolled infections; Absolute disease (current or previous, in particular haematologic diseases contraindications malignant or cutaneous malignancies, with the exception of basal cell carcinoma) Important side effects Renal failure, hypertension, liver failure, nausea, anorexia, vomiting, diarrhoea, hypertrichosis, gingival hyperplasia, tremor, malaise, paresthesias Important drug interactions Many different interactions – the metabolism of ciclosporin is dependent on the hepatic enzyme cytochrome P450-3A4 Special issues Increased risk of lymphoproliferative disease in transplant patients. Increased risk of squamous cell carcinoma in psoriasis patients following excessive photochemotherapy "Ciclosporin can be considered for long-term therapy (up to 2 years) in individual cases, but patients should be monitored closely for signs of increasing toxicity, especially for decreases in renal function or the efficacy of treatment." Pathirana D, et al. J Eur Acad Dermatol Venereol. 2009;23 Suppl 2:1-70. Fumaric acid esters (FAE) Long-term safety in severe psoriasis Review of patients (n=66) with severe psoriasis receiving long-term FAE therapy (up to 14 years) Adverse events (73% of patients) were usually mild 55 50 42 Patients (%) Relative lymphocytopenia (76% of patients) led to permanent discontinuation of FAE therapy in four cases A transient eosinophilia and moderate liver enzyme elevations were observed in 14% and 25% of patients, respectively 60 40 30 20 14 12 14 10 2 5 2 Fl us hi ng D ia rrh oe St a om ac Nau h se co a m pl ai nt Ti s re dn es D s iz zin es s Itc hi ng Fe ve r 0 Hoefnagel JJ, et al. Br J Dermatol. 2003;149(2):363-9. Phototherapy UVA and UVB (nb-UV 311nm) psoriasis vulgaris, atopic dermatitis, vitiligo lymphoma, alopecia, photodermatoses UVA + psoralens = PUVA therapy retinoids + UVA + psoralens = RePUVA therapy UVB Burn / Bad UVB UVB- lentigo, actinic keratosis, carcinoma, melanoma UVA Aging UVA UVA – photoaging, photosensibilisation, carcinoma, melanoma Phototherapy... calculations based on skin type starting dose Phototherapy... inside insidepart partofoflight lightsource source Phototherapy Broadband and narrowband UVB phototherapy Effective treatments for guttate or plaque psoriasis resistant to topical therapy Requirement to visit clinic may limit use for some patients Combination with other anti-psoriasis treatments (tars, topical calcipotriol, oral retinoids) have proved effective Photochemotherapy (PUVA) Combination with other anti-psoriasis treatments (vitamin D analogue preparations, retinoids) have proved effective. Potential adverse effects include itch, burning, risk of cataracts (eye protection required for 24 hours post therapy) and risk of skin cancer with chronic UV exposure Phototherapy requires good metering, equipment monitoring and maintenance of patient records to track UV exposure Psoriasis - General Management. Available from: http://www.bad.org.uk/site/769/Default.aspx. Accessed 9 Mar 2009. History of psoriasis phototherapy Heliothera py Carbon arc lamp 1923 – Goeckerman BB– UVB + coal tar 1953 – Ingram BB–UVB + dithranol 1974 – development of high intensity UVA lamp UVA + psoralens = PUVA 1981 – the action spectrum for UV phototherapy of psoriasis was determined by Parrish and Jaenicke 1984 –Philips developed NB–UVB fluorescent lamp (TL– 01, 311 nm) Phototherapy Traditionally means the use of artificial UVB irradiation delivered by fluorescent lamps without the addition of an exogenous photosensitizer – Narrowband UVB (NB–UVB, TL–01) – Broadband UVB (BB–UVB) Photochemotherapy with psoralens PUVA = combined use of the furocoumarin drug psoralen (P) + ultraviolet A (UVA) Wholebody (oral, bath) Local (oral, paint, bath) Phototherapy Mechanism of action UV radiation is absorbed by endogenous chromophores – nuclear DNA Immunosuppression Alteration of cytokine expression Cell cycle arrest Phototherapy of psoriasis Safety Efficacy Combination therapy Risks Future Dosimetry and calibration Constancy of lamp output should be checked weekly using an independent hand–held dose meter Calibration of a UV dosimeter – on an annual basis BAD Working Party report on minimum standards for phototherapy services (www.bad.org.uk) Minimal erythema dose (MED) and minimal phototoxic dose (MPD) The MED/MPD is the dose that provokes a just perceptible erythema Establishing MED/MPD – safe practice Skin type assessment – risk of burning Phototherapy of psoriasis Protocol for oral PUVA With MPD testing (preferred) 8–methoxypsoralen (MOP) or 5–MOP Frequency of treatment: twice per week Initial dose: 70% MPD Increment: 20% Maximum single dose: 15 J/cm² Psoriasis before and after PUVA Patient with PASI 30 before PUVA Patient clear after 27 treatments Bath PUVA Bath PUVA preferred to oral PUVA: – – – – in children significant hepatic dysfunction in patients with cataracts where psoralen–drug interaction anticipated i.e. warfarin No need for eye protection after therapy Phototherapy of psoriasis Protocol for bath PUVA With MPD testing (preferred) 8–MOP preferred to 5–MOP and TMP (increased risk of a blistering phototoxic reaction) Frequency of treatment: twice per week Initial dose: 50% MPD Increments: 20% Maximum single dose: 8 J/cm² Hand and foot PUVA Frequency of treatment: twice per week Maximum single dose: 15 J/cm² Phototherapy of psoriasis Protocol for NB–UVB With MED testing (preferred) Frequency of treatment: three times per week (preferred) Initial dose: 70% of MED Increments: 20% Maximum single dose: 5 J/cm² Psoriasis before and after NB-UVB Patient with PASI 9 before NB-UVB Patient almost clear after 30 treatments Psoriasis NB–UVB is superior to BB-UVB Almost 30 years of clinical experience and data from several controlled studies have demonstrated that NB– UVB is more effective for psoriasis than NB–UVB Randomized double–blind trial of the treatment of chronic plaque psoriasis: efficacy of PUVA vs NB–UVB therapy PUVA is significantly more effective than NB–UVB, requiring significantly fewer treatments for clearance, giving significantly longer remissions, and having a similar low incidence of shortterm adverse effects However, because of better long–term safety of NB–UVB than PUVA, it should be preferred as a first choice, until disease response noted, PUVA being kept in reserve for NB–UVB failures Yones SS et al. Arch Dermatol 2006; 142(7): 836–42. Efficacy of PUVA therapy vs NB–UVB in chronic plaque psoriasis: a systematic literature review (conclusion) PUVA and NB–UVB are both effective PUVA tends to clear psoriasis more reliably, with fewer sessions, and provides with longer lasting clearance NB–UVB is preferred as first line phototherapy option because of long–term risks of PUVA Archier E et al.. J Eur Acad Dermatol Venereol. 2012; 26( Suppl 3): 11-21 Combination therapy Topicals: tar, dithranol, calcipotriol; corticosteroids Retinoids (Re–PUVA, Re–NB–UVB) Methotrexate Biologics – main concern is potentially increased risk of skin cancer Acute side effects of phototherapy Similar to sunburn Clinical features: erythema, edema, vesiculation and necrosis Peak before 24 hours – UVB Peak at about 72–96 hours – PUVA, related to psoralen phototoxicity More likely with topical PUVA Oral 8–MOP may cause nausea/vomiting Some patients may develop PLE Long–term side effects of phototherapy UVB is known carcinogen No significant association between NB–UVB and BCC, SCC or melanoma in 3867 patients treated with NB–UVB in Tayside, Scotland These reassuring results do not demonstrate the early increase in skin cancers that was found associated with PUVA However, cautious interpretation is required – relatively few patients who had a high treatment number and because the slow evolution of skin cancers may result in a delayed incidence peak Ongoing risk assessment is therefore essential Hearn RM et al. Br J Dermatol 2008; 159: 931–5. Long–term side effects of PUVA Premature photoageing Risk of cataracts PUVA lentigines Increased number of actinic keratoses SCC incidence in PUVA–treated psoriasis correlates with cumulative UVA dose Slightly increased risk of melanoma (Stern RS and the PUVA Follow-Up Study, 2001); cumulative dose or number of phototoxic episodes Minimising a risk Keep cumulative doses low Do not exceed a total number of sessions over 150 for PUVA and 200–300 for NB–UVB Regularly update and improve protocols Audit Life–long monitoring of patients who received excessive PUVA Phototherapy of psoriasis Conclusion Phototherapy, in its different forms has proved itself to be well–established, safe, effective and reliable in the treatment of psoriasis NB–UVB should be preferred as a first choice, because of better long–term safety PUVA is more effective than NB–UVB for psoriasis Combination with other treatment modalities should be considered in unresponsive patients Therefore, the future seems bright for light! PHOTOTHERAPY – EADV RECOMMENDATIONS Induction therapy Not suitable for longlasting treatment because of cummulative toxicity and time-consuming mode Dear God when will this presentatio n end!? DEATH BY Breakdown of usage of therapeutic modalities according to psoriasis severity Melnikova Nat Rev Drug Discovery 2009;8:767-8 Patient with severe disease and where standard therapy cannot be used or continued Psoriasis Area Severity Index (PASI) 0-72;  >10 = severe psoriasis Measurement of disease severity and response to treatment will become part of everyday practice  Dermatology Life Quality Index (DLQI) 030; > 10 = significant detriment Guidelin e Algorith m Chronic plaque-type psoriasis Calcineurin inhibitors Coaltar basic therapy Corticosteroids mild BSA < 10% PASI < 10 P Topical therapy Dithranol Laser Tazarotene Vitamin D3 moderate BSA > 10% PASI > 10 P Calcineurin inhibitors Cyclosporin e Fumaric Acid Esters Evidence-based (S3) severe Guidelines for the Treatment of Psoriasis Vulgaris Nast et al., J Dtsch Dermatol Ges 5 (Suppl. 3), 2007 Nast et al., Arch Dermatol Res 299.111-138, 2007 (short version) Combined: Climate balneotherapy Systemic therapy Methotrexa te Retinoids UV Efalizumab Etanercept Infliximab Adalimuma b Ustekinum The March of Psoriasis Modifier genes Disease mechanisms Genetic susceptibility Innate Adaptive vascular effects Environmental factors Disease prevention measures Epidermal/ Barrier effects Disease treatment PSORIASIS (Clinical disease) Co-morbidities including Cardiovascular & Psoriatic arthritis Phenotypes Outcome measures, Biomarkers Griffiths & Barker Lancet 2007; 370: 263 Can Biologics Prevent? Treating the Systemic Disease: Comorbidities in Psoriasis Patients Psychosocial burden Ocular inflammation (Iritis/Uveitis/ Episcleritis) Crohn‘s Disease Ulcerative Colitis Psoriatic Arthritis 730% Spondyloarthropathies Nail psoriasis 4050%  Metabolic Syndrome CVD Diabetes Stroke Obesity Plaque Psoriasis and other forms Biologic therapy Today... Biological drugs Biologics Drugs which alter the immune response RHEUMATOID ARTHRITIS SARCOIDOSIS PSORIATIC ARTHRITIS ULCERATIVE COLITIS CROHN DISEASE PRIMARY BILIARY CIRRHOSIS INDICATIO NS PLAQUE PSORIASIS ANKYLOSING SPONDYLITIS IDIOPATHIC PULMONARY FIBROSIS DM TYPE I Psoriasis is an immune-mediated disease It was initially thought that psoriasis was purely a disease associated with increased proliferation of keratinocytes Evidence now supports the hypothesis that psoriasis is an immune-mediated disease1,2 T cells are activated in the skin by an as yet unidentified “trigger” Activated T cells release inflammatory cytokines Inflammation causes keratinocyte activation and proliferation Activated keratinocytes drive further T cell activation The antigen (or autoantigen) that drives the initial immune response in psoriasis has not yet been identified 1. Nickoloff BJ, Nestle FO. J Clin Invest. 2004;113(12):1664-75. 2. Griffiths CE, Barker JN. Lancet. 2007;370(9583):263-71. S1/38 Th17 cytokines drive inflammation and keratinocyte hyperplasia in psoriatic plaque1 Activation Th17 Cytokine Release IL-17 IL-22 TNF-a 1. Aggarwal S, Gurney AL. J Leukoc Biol. 2002;71(1):1-8. Inflammation MCP-1 Groa IL-8 G-CSF GM-CSF IL-6 PGE2 ICAM-1 VCAM-1 Monocyte and neutrophil recruitment Neovascularisation Vasodilatation T cell influx Keratinocyte hyperplasia S1/41 IL-12 and IL-23: central cytokines in psoriasis Psoriasis is an inflammatory disease in which different elements of the immune system interact to produce the classic psoriatic plaque in individuals with a genetic predisposition Recent findings indicate that IL-12 and IL-23 produced by dendritic cells are key cytokines in the disease process IL-12 and IL-23 drive the differentiation and expansion of T cell populations of the Th1 and Th17 subtype Th1 and Th17 cells promote the formation of psoriatic skin lesions by the production of cytokines such as IL-17, IL-22, IFN-g, and TNF-a IL-12 and IL-23 are heterodimers with a common subunit (known as p40) that is a potential target for therapeutic intervention in psoriasis S1/42 The central role of IL-12 and IL-23 in the development of Th1 and Th17 cells DC DC Naïve T cell Naïve T cell IL-23 Cytokines including IL-17 IL-22 TNF-α IL-12 Th17 Th1 Cytokines including IFN-g TNF-a IL-2 Inflammation, keratinocyte hyperplasia, neovascularisation, vasodilatation, T cell/neutrophil influx Plaque formation S1/43 Pathophysiology of psoriasis Adapted from: Nickoloff BJ, Nestle FO. J Clin Invest. 2004; 113:166475. Trigger/ initiation Genetic predisposition Chemokines, cytokines Dendriti c cell T cell Keratinocyte activation Inflammatory cytokines IL-12/ IL-23 T cell White blood cell recruitment, angiogenesis T cell T cell T cell Dendritic cell and T cell activation, cytokines T cell FOR INTERNAL TRAINING USE ONLY SUBJECT TO LOCAL HCC AND REGULATORY APPROVAL S1/46 Pathophysiology of psoriasis – summary The clinical characteristics of psoriasis follow activation of T cells by dendritic cells T cells undergo differentiation and proliferation The release of IL-12 and IL-23 from dendritic cells results in the differentiation of T cells into Th1 and Th17 cells, which are the principal “effector” T cells in psoriatic plaques S1/44 Biologics: Maintenance of Psoriasis Remission “Marathon” Comparative Trial of Adalimumab vs Methotrexate (CHAMPION) 100 80 Patients (%) PASI 75 80*† 77*† 62*† 60 36 40 25 23*‡ 20 13 4 0 3 Week 4 Placebo (n=53) 9 Week 8 MTX (n=110) 15 Week 12 19 Week 16 Adalimumab (n =108) *p10, BSA >10, DLQL >10) Psoriatic arthritis Frequent relapses Special locations Contraindications for biologics: guttata; /pustular/ psoriasis active TB immunosupressed patients pregnancy malignancy within 5 years longlasting PUVA allergy to biologics anamnesis of demyelinanting disease autoimmune diseases infections congestive heart failure Involvement of patients 1. Anamnesis and physical examination Medicamments Heart diseases Malignancy Previous therapy Other types of psoriasis (arhtritis, pustular, nails, inverse, erythrodermia) Infections Risk contacts Family planning Profession (frequent traveller) 2. Screening before therapy PASI score LFT complete Urin and renal function PPD/Quantiferon, pulmologist Hepatitis B and C markers HIV Psoriatic arthritis Heart and neurological diseases Pregnancy test BIOLOGICALS AND TB Increased susceptibility to TB or reactivation of latent TB is the characteristic of the application of biologics Before therapy with biologics all patients : screening for TB, active and non-active (“latentn”) Screening of patients descreased risk of TB Clinical examination Detalied personal history with data concerning TB or previous/current immunosupresive therapy RTG chest PPD/Quantiferon Pulmologist Quantiferon gold (ELISA) INF-γ based assay – protein which codes only M. TBC and is present in blood PREGNANCY AND BREASTFEEDING Antagonists TNF-α – Women in fertile age should take adjusted contraception during the therapy and 6 months after tha last administration of drug Antagonist IL 12/23 – contraception during therapy and 15 weeks after therapy Vaccination Recommendation: live viruse or live bacterial vaccines should not be given together with biologics Patients on biologics can in the same time receive inactive or non-live vaccine Therapy interruption with TNFα antagonists: pregnancy surgery diagnosis of malignancy or neurological disease (PML) severe infection (TB, bacteria, fungi) LE-like symptoms patient’s decision loss of eficaccy MOST COMMON SIDE EFFECTS of TNF-α antagonists TB Infections of upper respiratoty tract Lymphoma Hepatotoxicity Antibodies Infusion reactions Mode of application Infliximab Adalimumab Etanercept Ustekinumab Secukinumab Otezla peroral infusion subcutaneous injections DOSAGE: adalimumab 80 mg s.c./ every 2 weeks 40 mg etanercept 2xweekly 25 mg s.c./ 24 weeks ustekinumab 45 mg s.c. 0, 4, every 12 weeks Infliximab i.v. 5 mg/kg 0,2,6 week, then every 8 weeks Apremilast 30 mg bid peroral TNFα blockers: ETANERCEPT TNF alpha promotes inflammation and its associated fever and signs (pain, tenderness, and swelling) in several inflammatory conditions-rheumatoid arthritis and ankylosing spondylitis Synthetic protein that binds to TNF alpha and removes most of the TNF alpha from the joints and blood ETANERCEPT-contraindications Active serious infections Sepsis Concurrent cyclophosphamide therapy or patients with Wegener granulomatosis receiving immunosuppressive therapy Hypersensitivity Concomitant use of live vaccines Breastfeeding PREGNANCY: FDA category B ETANERCEPT-side effects >10% Non-upper respiratory tract infection Injection-site reaction Upper respiratory tract infection Headache Rhinitis 1-10% Nausea Dizziness Pharyngitis Abdominal pain Vomiting Hematologic disorders (thrombocytopenia, aplastic anemia, leukopenia) ADALIMUMAB-contraindications PREGNANCY: FDA category B Lactation: present in low levels in human milk and is not likely to be absorbed by a breastfed infant ADALIMUMAB-side effects >10% 1-10% Injection site pain Upper respiratory tract infection ↑ creatine phosphokinase Headache Rash Sinusitis Nausea Urinary tract infection Abdominal pain Flu-like syndrome Hyperlipidemia Back pain Hypercholesterolemia Hematuria Hypertension ↑alkaline phosphatase ADALIMUMAB-side effects 10% Antinuclear antibodies dev Infection Upper resp tract infection Abdominal pain Nausea Infusion reactions Headache Development of antibodies to double stranded DNA Sinusitis, cough Diarrhea ↑ ALT INFLIXIMAB-side effects 1-10% Bronchitis Dyspepsia Rash Fatigue Back pain Rhinitis Urinary tract infections Arthralgia Fever Hypertension Pruritus Dyspnea Candidiasis ANA Lupus-like symptoms IL-12/23 blocker: USTEKINUMAB Fully human monoclonal antibody that antagonizes interleukin12 and -23 Plaque Psoriasis:for the treatment of adults (18 years or older) with moderate-to-severe plaque psoriasis who are candidates for phototherapy or systemic therapy USTEKINUMAB-contraindications Hypersensitivity Active serious infection Concomitant live vaccines: Discontinue at least 15 weeks before live Resume at least 2 weeks later vaccines USTEKINUMAB-side effects Nasopharyngitis Back pain Cellulitis Depression Diarrhea Fatigue Headache Injection site erythema Myalgia Fatigue Nasal congestion Urticaria Rash Pruritus Antibody formation USTEKINUMAB-side effects >10%