Systemic treatment in dermatology MUDr. Eva Březinová, Ph.D. Systemic treatment - indications •Systemic diseases: •infectious, autoimmune, life-threatening diseases •single therapy in high risk groups of patients • •Skin diseases: •large area of disease •ineffectiveness of previous therapy •inability / unwillingness to apply topical treatment Systemic treatment in dermatology •Systemic treatment – classification: •Therapy of infections •Different systemic medicines •Immunomodulators and antiproliferative agents •„Biologic“ treatment 1) Systemic therapy – infectious diseases •Antibiotics •Antifungals •Antivirotics •Antiparasitics 2) Systemic therapy - different •Antihistamines •Vasoactive and antiplatelet drugs •Antiandrogens and androgens •Psychotropic drugs •Intravenous immunoglobulins (IVIG) •Systemic anticancer drugs 3) Immunomodulatory and antiproliferative treatment •Systemic corticosteroids •Methotrexate •Azathioprine •Mycophenolate mofetil •Cyclosporine A •Dapson •Antimalarials •Systemic retinoids •Interferons Glucocorticosteroids •Adrenal cortex hormones • •imunosuppressive effect •morbidistatic (suppressing symptoms and development of the disease without its cure) •antiallergic effect •anti-inflammatory effect Glucocorticosteroids - use •short-term administration of high doses applied in life-threatening conditions •pulsed corticoid therapy •prolonged glucocorticoid therapy •total administration - p.o., i. m., i. v., intranasally •local application - mucous membranes, skin (corticosteroid dermatology) Glucocorticosteroids •dosage: •according to the type of disease and the patient's weight • •monitoring: •blood count, urea, creatinine, liver tests, glycemia, ions • •systemic most common side effects: attenuation of the hypothalamic-pituitary-adrenal cortex axis Glucocorticosteroids •The half-life T1/2 of the biological effect is longer than the plasma T1/2: •- short-acting - biol. T1/2 8-12 h (hydrocortisone, cortisone) •- medium-acting - biol. T1/2 18-36 h (prednisone, prednisolone, triamcinolone, methylprednisolone) •- long-acting GCC - biol. T1/2 about 36-54 h (dexamethasone, betamethasone) Corticosteroids - long-term side effects •formation or perforation of GIT ulcer •hypertension •ACTH secretion block •mineral disorders •osteoporosis •Cushing's syndrome •acneiform rash •hypertrichosis •striae •steroid diabetes •depression •psychosis •thrombosis •activation of latent infections Corticosteroids - indications •Autoimmune bullous diseases (pemphigus, pemphigoid, scarring pemphigoid, linear IgA dermatosis, EBA, herpes gestationis) •severe allergic reactions (drug allergies, angioneurotic Quincke's edema) •Vasculitis •Connective tissue diseases (SLE, dermatomyositis, polyarteritis nodosa) •Lymphomas •Sarcoidosis •Infections with severe inflammation reactions (Jarisch-Herxheimer reaction, generalized atopic eczema) •XXX CAVE not for psoriasis !!! Dapsone (sulfone) •Antimicrobial / antiprotozoal action •Anti-inflammatory •Indications: •dermatitis herpetiformis Duhring (+ gluten-free diet) •chronic dermatoses with accumulation of neutrophils and / or eosinophils •leprosy, pneumocystis pneumonia and prevention of toxoplasmosis in AIDS Dapsone (sulfone) •Side effects: •methemoglobinemia… dyspnoea, anemia (glucose-6-phosphate dehydrogenase deficiency) - necessary controls for metHb levels •hemolysis •agranulocytosis •hepatopathy Aminoquinolones (antimalarials) •Hydroxychloroquine (Plaquenil) •It interferes with the function of lysosomes •Disrupts antigen presentation by dendritic cells •Anti-inflammatory effect •Indications: •SLE and discoid skin LE •Photodermatoses (polymorphic light eruption, porphyria cutanea tarda) •(sarcoidosis, dermatomyositis, oral lichen planus, chronic ulcerative stomatitis) •CAVE! Retinopathy, keratopathy - eye examination! Cytostatics •substances that stop the growth of tumor cells •inhibition of cell proliferation •inhibition of nucleic acid biosynthesis (antimetabolite group) •microtubule damage •inhibition of cell division •damage of the function and structure of nucleic acids Methotrexate •antimetabolite - blocking of the enzyme dihydrofolate reductase, preventing the reduction of folic acid, and thus the synthesis of RNA and DNA • •effect: •immunosuppressive •antiproliferative • •indications: •severe form of psoriasis vulgaris •neoplasia Methotrexate •dosage: •- once a week 7.5 mg in a weekly dose (approx.), ev. according to the patient's disability and weight •- concomitant administration of folic acid is necessary, due to the risk of anemia and reduction of gastrointestinal and hepatic toxicity •monitoring: •- control of hematological functions (at least once a month) •- liver and kidney function (once every 1-3 months) Methotrexate •side effects: •- hepatotoxicity •- myelotoxicity •- methotrexate pneumonitis •- nausea •- stomatitis •- diarrhea •- defluvium •- excessive fatigue •- chills and fever •- dizziness •- reduced resistance to infections Cyclophosphamide •indications: •- neoplasia •- psoriasis vulgaris severe forms •- autoimmune diseases •- vasculitis • •dosage: •- the average dose is between 50 and 100 mg a day, early in the morning and the bladder should be emptied often •- sufficient hydration of the patient is necessary, maintaining fluid balance to prevent the development of cystitis Cyclophosphamide •monitoring: •- control of hematological functions (at least once a month) •- liver and kidney function (once every 1-3 months) • •side effects: •- nausea and vomiting •- anorexia and uncommon abdominal discomfort, abdominal pain and diarrhea •- haemorrhagic colitis, ulceration of the oral mucosa •- headache •- disorders of gonadal function (azoospermia, amenorrhea) Azathioprine •imidazole derivative of 6-mercaptopurine (6-MP) •the effect of the therapy is not apparent until several weeks or months of treatment •immunosuppressive antimetabolite alone or in combination with other medicinal products (corticosteroids) Azathioprine •Indication: •severe rheumatoid arthritis •systemic lupus erythematosus •dermatomyositis and polymyositis •autoimmune chronic active hepatitis •pemphigus vulgaris •polyarteriitis nodosa •autoimmune hemolytic anemia •chronic refractory idiopathic thrombocytopenic purpura •relapsing multiple sclerosis •transplanted •intestinal inflammation Azathioprine •dosage: •- 1 to 3 mg / kg body weight / day • •monitoring: •- once a week blood count and differential (8 weeks), then once a month (bone marrow suppression) •- urea, creatinine, liver tests Azathioprine •side effects: •- infectious and parasitic diseases •- benign and malignant neoplasms (including cysts and polyps) •- blood and lymphatic system disorders - bone marrow suppression •- immune system disorders •- respiratory, thoracic and mediastinal disorders •- very rare: reversible pneumonitis •- skin disorders and subcutaneous tissue •- alopecia • •CAVE: live vaccine must not be given - atypical potentially harmful reactions! Cyclosporine A •cyclic polypeptide •suppresses the body's natural immune response •suppresses the body's inappropriate response to its own cells and tissues Cyclosporine A •indications: •- prevention and treatment of immune reactions to transplanted organs and tissues •- autoimmune diseases •- intraocular inflammation (endogenous uveitis) •- nephrotic syndrome •- rheumatoid arthritis •- psoriasis vulgaris •- atopic dermatitis Cyclosporine A •Dosage: •- total dose 2.5-5 mg / kg body weight per day divided into two doses •Monitoring: •- level of cyclosporine in the blood •- blood pressure - regularly during treatment •- liver and kidney function, blood lipid level Cyclosporine A •side effects: •- manifestations of temporary damage to the nervous system - tingling in the hands and feet, headache - migraine, limb tremor •- formation of fine hairs or highlighting of existing hair - hypertrichosis •- damage to kidney function and high blood pressure •- growth of breasts and mammary glands Retinoids •vitamin A analogues •normalization of proliferation, differentiation and keratinization of epidermal cells • •CAVE: •- co-administration of tetracycline antibiotics increases the risk of intracranial hypertension •- reduces the effect of low doses of progestins used as contraceptives Acitretin •synthetic aromatic analog of retinoic acid • •indications: •- severe forms of psoriasis •- palmoplantar keratoderma •- congenital ichthyosis •- lichen ruber planus •- follicular keratosis •- pityriasis rubra pilaris •- palmoplantar pustulosis Acitretin •dosage: •- start of therapy 25 mg daily, further depending on the condition •- the maximum recommended daily dose is 75 mg •monitoring: •- liver tests, lipids, glycaemia Acitretin •side effects: •- severe headache •- inflammation of the lining of the mouth, abdominal pain, diarrhea, nausea, vomiting •- fragility of the skin, feeling sticky skin or rash, inflammation of the skin, changes in hair structure, brittle nails, skin infections around the nails, reddening of the skin •- joint, muscle, swelling of the ankles •- blurred vision •- increased sensitivity of the skin to sunlight (photosensitivity reactions) •- fetal malformations (necessary protection against pregnancy during therapy and 2 years after termination) Isotretinoin •13-cis-retinoic acid •the ability to bind to a retinoic acid binding protein Isotretinoin •effect: •- direct inhibitory effect on sebaceous gland and sebocyte maturation •- specific action on proliferating sebaceous epithelium •- reduces keratinization in follicles •- indirectly reduces bacterial flora •- ability to inhibit neutrophils and monocytes •- fatty food, milk - increased bioavailability •- main metabolic product 4-oxo-isotretinoin Isotretinoin •indications: •- cystic forms of acne unresponsive to adequate treatment with systemic antibiotics and topical drugs •dosage: •- 0.5–1 to 2 mg / kg / day •- once or twice a day with food •- to the cumulative dose (120–150 mg / kg / therapy, exceptionally up to 180 mg) •- cumulative dose over 180 mg / kg / therapy has no better a therapeutic effect Isotretinoin •monitoring: •- liver enzymes and fats (CHOL, TAG) before the start of treatment, after 1 month of treatment and then every 3 months, ev. according to results Isotretinoin •side effects: •- teratogenicity (not transmitted by ejaculate or sperm) embryotoxicity •- dryness of the lips (almost 100% of patients - indicator of correct absorption of the drug), dryness of the skin, mucous membranes, burning of the eyes •- increased sensitivity to UV radiation (thinning of the skin not photosensitivity) •- pain of muscles, joints •- increased fatigue •- night vision disorders •- increased serum lipids, liver enzymes •- depression - no direct link Bexarotene •3rd generation retinoid - "rexinoid" •activator of RXR receptors •it affects the gene expression of premalignant and malignant cells • •Indications: advanced T-cell lymphomas Antihistamines •In dermatology H1 antihistamines •1st generation - lower selectivity to H1 rec, penetrate through HEB •- sedative effect, cardiotoxicity, mucosal dryness •- bisulepin (Dithiaden) •- dimethindene (Fenistil) •- promethazine (Prothazine) Antihistamines •2nd generation - selective, do not penetrate HEB - non-sedative, safe •- cetirizine (Alerid, Analergin, Cetirizin, Zodac, Zyrtec) •- desloratadine (Aerius, Dasselta, Desloratadine) •- fexofenadine (Ewofex, Fexigra) •- levocetirizine (Analergin, Cezera, Xyzal, Zenaro) •- loratadine (Clarinase, Claritine, Flonidan) •- rupatadine (Tamalis) •- bilastine (Xados) Antiandrogens •effects: blocking the effects of androgens in the target tissue •indications: •- treatment and control of benign prostatic hyperplasia (BPH) in patients with an enlarged prostate •- treatment of androgenetic alopecia in men (young) Finasteride •competitive inhibitor of human 5-alpha-reductase type II, formation of a stable enzyme complex •- reduction of dihydrotestosterone production • •dosage: - 1 mg daily • •monitoring: - fPSA Finasteride •systemic most common side effects: •- sexual dysfunction •- breast tenderness to touch or breast enlargement, rash, breast discharge •- testicular pain, allergic reactions Antibiotics •Penicillins •Indications: •Syphilis and other treponematoses •Inflammation of the skin and soft tissues caused by Streptococcus sp. - impetigo, erysipelas •Lyme disease •Actinomycosis •Listeriosis •Insect sting infections Antibiotics •Cephalosporins: •Broad spectrum, 1.-4. generation (the higher the generation, the lower the efficiency on G + and increases on G-) •Indications: •Uncomplicated inflammation of the skin and subcutaneous tissue caused by Staph. aureus and Streptococcus sp. - impetigo, erysipelas •Gonorea •Lyme disease •Bacterial meningitis • Antibiotics •Tetracyclines •Indication: •- actinomycosis •- morsus insecti •- anthrax •- Lyme disease •- chlamydial infections •- MRSA •- syphilis •- tularemia •- acne vulgaris Antibiotics •Clindamycin (lincosamides) •Good permeability to tissues and body fluids •Indications: •Staphylococcal and streptococcal infections •Anaerobes •Hidradenitis suppurativa Antibiotics •Macrolides •- in case of hypersensitivity to beta-lactams •Indications: •Uncomplicated skin inflammations (folliculitis, erysipelas, cellulitis) •Bartonellosis •Morsus insecti •Lyme disease •Chlamydial infections •Infection with atypical mycobacteria Antibiotics •Fluoroquinolones •Indications: •1st choice: anthrax, complicated skin inflammation (G-bacteria), Pseudomonas aeruginosa infection (otitis externa, ecthyma gangraenosum) •2nd choice: bartonellosis, chlamydial infections, erysipelas, gonorrhea, granuloma inguinale Antibiotics •Sulfonamides: trimethoprim/sulfamethoxazole •Indications: •Community MRSA infection •Uncomplicated inflammation of the skin and subcutaneous tissue •Granuloma inguinale, ulcus molle •Urinary tract infections Antivirotics •Acyclovir •p.o., i.v., locally •Control of renal function (dose reduction) •Indications: •Symptomatic primary or recurrent mucocutaneous HSV-1 or HSV-2 infection •Suppression of recurrent HSV-1/2 infections •Perinatal prevention and treatment of neonatal HSV infection •Treatment of VZV in adults and immunocompromised Antivirotics •Valacyclovir •Indications: •Treatment of primary or recurrent genital HSV infection •Prevention of recurrent genital HSV infection •Treatment of VZV infection • • Interferons •Proteins - cytokines of non-specific immunity, acting in antiviral defense, act paracrine, increase cellular toxicity against viruses and malignancies •Interferon α - adjuvant therapy in malignant melanoma, therapy of mycosis fungoides, granulomatous inflammation •Interferon γ - is not registered in the Czech Republic •Adverse reactions: flu-like symptoms, leukopenia Antifungals •Extensive fungal infections of the skin, skin adnexa, mucous membranes •Prophylactically in immunocompromised •p.o., i.v. •1. polyenes •2. azoles •3. allylamines • •Itraconazole, fluconazole, terbinafine Antifungals •Itraconazole: •Against dermatophytes, yeasts, saprophytic and dimorphic fungi •Dosage: •Onychomycosis: •200 mg daily for 12 weeks •or pulse regimen 2x200 mg 1 week, then 3 weeks without therapy and then another pulse, repeated 2x to 3x Antifungals •Fluconazole: •Dermatophytes and yeasts except Candida Krusei •The first choice for mucocutaneous candidiasis •150 mg once, for chron. infections once a week for up to 6 months •More serious infections: Day 1 200-400 mg / d, then 100-200 mg / d for 2-3 weeks •Onychomycosis: 150 mg once a week until the nail grows up (up to 12 months) Antifungals •Terbinafine: •Lipophilic, keratophilic •After absorption it is distributed in the skin and adipose tissue •Onychomycosis, tinea capitis, refractory tinea corporis, tinea pedis •CAVE hepatopathy, renal dysfunction •250 mg / d 6 weeks (tinea capitis) to 12 weeks (onychomycosis) Targeted anti-inflammatory and anti-tumor drugs (immunobiology) •They interfere with the pathogenetic process in cells at the molecular level •The target is both tumor cells and non-tumor cells •Targeted drugs can be used in such pathogen. states where it is known: •Specific biomarker (cytokine, cytokine receptor, growth factor) •Aberrant ligand or signaling pathway Targeted anti-inflammatory and anti-tumor drugs (immunobiology) •Classification by structure: •Recombinant cytokines and growth factors •Monoclonal antibodies •Fusion proteins •Small molecules • •Classification according to effects on biomarkers: •Inhibitors of TNF-α, interleukins, enzymes, receptors, lymphocyte surface antigens, T-cell immunomodulatory receptors and transduction signals Targeted anti-inflammatory and anti-tumor drugs (immunobiology) •Indications: Psoriasis •TNF α inhibitors (etanercept, adalimumab, infliximab, certulizumab pegol) •Inhibitor IL-12/23 (ustekinumab) •Inhibitor IL -17A (secukinumab, ixekizumab) •Inhibitor IL-17-AR (brodalumab) •Inhibitor IL-23 (guselkumab) •Inhibitor IL-23p19 (tildrakizumab, risankizumab) •Phosphodiesterase (PDE4) inhibitor (apremilast) Targeted anti-inflammatory and anti-tumor drugs (immunobiology) •Atopic dermatitis •IL-4R inhibitor (dupilumab) • •Lupus erythematodes •IL-6 inhibitor (tocilizumab) • •Hidradenitis suppurativa •TNF α inhibitors (adalimumab) • •Chronic spontaneous urticaria •IgE receptor inhibitor (omalizumab) Targeted anti-inflammatory and anti-tumor drugs (immunobiology) •Pemphigus vulgaris, Wegener's granulomatosis, microscopic polyangiitis •Anti-CD20 (rituximab) • •Acute SLE •anti- B-lymphocyte activating protein (belimumab) Targeted anti-inflammatory and anti-tumor drugs (immunobiology) •CD30 + cutaneous lymphoma •Anti CD30 (brentuximab vedotin) • •Malignant melanoma •Anti CTLA-4 (ipilimumab), anti PD-1 (pembrolizumab, nivolumab) •BRAF and MEK tyrosine kinase inhibitors (vemurafenib, dabrafenib, trametinib, cobimetinib) Targeted anti-inflammatory and anti-tumor drugs (immunobiology) •Dermatofibrosarcoma protuberans •Bcr-Abl tyrosinase inhibitors (imatinib) • •Metastatic BCC, locally advanced BCC •Inhibitor of hedgehog pathway (vismodegib), inhibitor of signaling pathway (sonidegib) • •Metastatic Merkel cell carcinoma •Inhibitor of PD-L1 T-cell immunomodulatory receptor (avelumab)