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6024 M13 Study Guide Immunomodulators and Dermatology Page 1 of 7 IMMUNOMODULATORS Disease Modifying Antirheumatic Drugs (DMARDs): Synthetic (conventional or targeted) -or- Biologic Biologic DMARDs are immunosuppressive drugs that target specific components of the inflammatory process. These drug...

6024 M13 Study Guide Immunomodulators and Dermatology Page 1 of 7 IMMUNOMODULATORS Disease Modifying Antirheumatic Drugs (DMARDs): Synthetic (conventional or targeted) -or- Biologic Biologic DMARDs are immunosuppressive drugs that target specific components of the inflammatory process. These drugs are usually combined with methotrexate. Because they suppress immune function, all biologic DMARDs pose a risk for serious infections and perhaps cancer. biologic DMARDs are so named because they are manufactured using recombinant DNA technology (p. 521). A type of biologic DMARD is monoclonal antibody drugs (MAbs), and these drugs contain the three letters mab attached to the end of each medication. A mAb is a protein (antibody) derived from a human, a mouse or similar rodent, or a combination of the two (p. 777). See image to the right (Fig. 84.1) as schematic representation of MAbs production. Name Biologics adalimumab (Humira) SubQ, IV rituximab (Rituxan) IV abatacept (Orencia) *only drug in class* SubQ, IV Interleukin Antagonists MOA Binds to and neutralizes tumor necrosis factor (TNF), an important immune mediator of joint injury in RA (p. 521). CD20 antigen exclusively on the surface of B lymphocytes. When rituximab binds with CD20, the immune system attacks the rituximab–B-cell complex, causing B-cell lysis and death (p. 523). T-cell activation inhibitor Indications Side Effects moderate to severe RA who have not responded adequately to one or more DMARDs (p. 523). Common side effects: injectionsite reactions (rash, erythema, itching, pain, swelling). May promote serious infections (e.g., bacterial sepsis, invasive fungal infections, HBV infection, TB) (p. 523) and MS Clinical Pearls Undisclosed May slow joint damage and may be used alone or in combo with methotrexate (p. 523). Fungal infection, TB, Hep B, mucocutaneous reactions B-cell labs Bactrim prophylaxis (PJP - Pneumocystis jiroveci pneumonia) RA, AS, JIA, psoriatic arthritis, psoriasis, Chron disease, ulcerative colitis Headache, upper respiratory infection, nasopharyngitis, and nausea (p. 524). Fungal infection, TB, Hep B, MS Infections: pneumonia, cellulitis, bronchitis, diverticulitis, pyelonephritis, and UTIs (p. 524). NO live-virus vaccines Auto-inflammatory disease IL-6 BBW: increased risk for serious or fatal infections Undisclosed NO live-virus vaccines AS, JIA, psoriatic arthritis, psoriasis, Chron disease, ulcerative colitis Rituximab + methotrexate is indicated for IV therapy of adults with moderate to severe RA who have not responded to one or more TNF inhibitors (p. 523). RF+ RA, JIA, SLE, nonHodgkin lymphoma, lymphocytic leukemia IL-6 blockers: tocilizumab, sarilumab IL-1 blockers: anakinra Monitoring 6024 M13 Study Guide Immunomodulators and Dermatology Page 2 of 7 Conventional DMARDs have two subclasses: major and minor. All major drugs are included below. The only minor drug included is cyclosporine. Minor drugs are not regularly used due to their severe side effects. Because of their immunosuppressant properties, DMARDs carry risk for serious infection. Conventional DMARDs tend to have delayed onset of 3-6 months for full therapeutic effect. Name Synthetic (Conventional) MOA FDA: oncology, psoriasis, juvenile idiopathic arthritis (JIA), rheumatoid arthritis (RA) methotrexate (Rheumatrex, Trexall) *first-line* Indications Folate antagonist SubQ, PO Off label: inflammatory bowel disease, atopic dermatitis, and intrauterine pregnancy and ectopic pregnancy termination sulfasalazine (Azulfidine) Undisclosed RA, JIA, ulcerative colitis, inflammatory bowel disease leflunomide (Arava) *second-line* prodrug Inhibits Tcell proliferation FDA: active RA Unknown SLE, malaria, RA As a rule, the drug is usually combined with methotrexate (p. 520). Side Effects Nausea, hair loss, mouth ulcers, hepatoxicity May be prevented with concurrent use of folic acid NO pregnancy or nursing BBW: fatal toxicities of the bone marrow, liver, lungs, and kidneys (p. 517). N, V, D, anorexia, abdominal pain, pruritis, rash, urticaria (p. 518), and headaches Diarrhea, respiratory infection, reversible alopecia, and rash (p. 518). Monitoring LFTs Q 12 weeks Synergistic when combined with targeted and biologic DMARDs Use two forms of contraception CBC, LFT, creatinine Q week for first six months Clinical Pearls Cost and clinically effective Do NOT use with Bactrim NO live-virus vaccines Limit alcohol G6PD testing Can slow joint deterioration Use two forms of contraception Slow elimination Washout required for pregnancy Toxic retinopathy QT prolongation Routine eye screens Get baseline eye exam Kidney damage In patients with an inadequate response to methotrexate, adding cyclosporine may produce significant improvement (p. 521). Cyclosporine should be reserved for severe, progressive RA that has not responded to safer DMARDs (p. 521). NO pregnancy hydroxychloroquine (Plaquenil) cyclosporine (Gengraf) *last choice* Undisclosed Rejection of transplanted organs May reduce RA symptoms 6024 M13 Study Guide Immunomodulators and Dermatology Page 3 of 7 Targeted DMARDs are janus kinase (JAK) inhibitors. JAKs are intracellular enzymes that have a role in initiating cytokine signaling as part of the signal transducer and activation of transcription (STAT) pathway. This pathway is involved in inflammatory and immune responses; therefore, by inhibiting JAKs, these DMARDs reduce immune and inflammatory responses that underlie the pathology of RA (pp. 525-526). Name Synthetic (Targeted) Indications Tofacitinib (Xeljanz) PO RA, psoriatic arthritis, ankylosing spondylitis (AS), polyarticular (5+ joint) JIA, ulcerative colitis Baricitinib (Olumiant) Other RA Drugs: Side Effects Heart-related events, cancer, blood clots, death BBW: serious or fatal infection risk Monitoring Clinical Pearls 20% of patients develop infection Undisclosed 16% of patients develop infection NSAIDS – aspirin, celecoxib Glucocorticoids – prednisone (often used as bridge considering long time to full effect of conventional DMARDs; multiple side effects; if high-dose → Ca++ supplementation; if long-term → annual DEXA scans) GOUT Gout is a rheumatic disease associated with severe joint pain due to uric acid crystals. Drugs to manage inflammation can significantly reduce pain (p. 528). Principles for initiating therapy include treat to target (serum urate level <6 mg/dL -or- <5 mg/dL if tophi present), timing the initiation of urate-lowering medication, and understanding treatment is usually long-term. Acute Episode of Gout In patients with infrequent flareups (less than three per year), treatment of symptoms may be all that is needed. Nonsteroidal anti-inflammatory drugs (NSAIDs) are considered first-line agents for relieving the pain of an acute gouty attack. Glucocorticoids are an acceptable option. Colchicine is generally reserved for patients who are unresponsive to or intolerant of safer agents (p. 528). NSAIDS Indomethacin: 50 mg TID initially until pain is tolerable, then reduce dosage and continue dosing for 3–5 days (p. 528). Naproxen (Naprosyn ER): one tablet initially, then one tablet daily until attack subsides (p. 528). Glucocorticoids Prednisone: 30–50 mg once daily or in two divided doses until pain is tolerable; then gradually tapered over 7–10 days (p. 528). Intra-articular glucocorticoids: ideal if 1 to 2 joints are involved. Colchicine Colcrys only: Day 1 = 1.2 mg at first sign of the flare, followed by 0.6 mg 1 h later (maximum, 1.8 mg/24 h) (p. 528). Day 2 = Day 2 through 48 hours after flare resolution, 0.6mg PO BID (PPT) Prophylaxis for Gout Allopurinol Allopurinol 100mg daily (starting dose) titrate up by 100mg every two to four weeks to reach urate goal <6mg/dL Colchicine (Colcrys, Mitigare): 0.6 mg once or twice daily (maximum, 1.2 mg/24 h) (p. 528) for three to six months (PPT). 6024 M13 Study Guide Immunomodulators and Dermatology Page 4 of 7 DERMATOLOGY Exemplar Drugs Name Indication tretinoin cream (Retin-A) Acne vulgaris adapalene (Differin) Acne vulgaris topical benzoyl peroxide Acne vulgaris topical clindamycin Acne vulgaris spironolactone Acne oral isotretinoin (Accutane) Acne ethinyl estradiol + drospirenone (Yaz) Acne Oral contraceptive ethinyl estradiol + norgestimate (Orthotricyclen) Acne Oral contraceptive topical triamcinolone (Kenalog) Various skin conditions with itching, redness, dryness, crusting, scaling, inflammation, and discomfort Side Effect peeling, dry skin, burning and stinging, erythema, itching, photosensitivity peeling, dry skin, burning and stinging, erythema, itching, photosensitivity dry skin, burning, erythema, photosensitivity burning, dryness, erythema hyperkalemia, avoid in pregnancy, menstrual irregularities, breast tenderness, anorexia, N/V/D, orthostatic hypotension, HA, dizziness, fatigue, gynecomastia dry skin and mucous membranes, visual changes, hyperlipidemia, elevation of hepatic transaminase levels, myalgias, teratogenic nausea, vomiting, breast tenderness, headache, mood changes, feeling tired or irritable, weight gain, skin darkening or pigmentation changes, changes in menstrual periods, decreased libido stomach pain, gas, nausea, vomiting, breast tenderness, acne, darkening of facial skin, headache, nervousness, mood changes, changes in weight, breakthrough bleeding, vaginal itching or discharge, rash burning, itching, irritation, stinging, redness, dry skin, change in skin color, hair growth, rash Notes First-line therapy First-line therapy Pair with ABX to avoid resistance Pair with benzoyl peroxide to avoid ABX resistence Diuretic used for aldosterone antagonist properties iPledge: Participation in Risk Evaluation and Mitigation Strategy (REMS) program is required for isotretinoin therapy in the United States Consider contraindications, cautions, and potential adverse effects such as risk of blood clots Consider contraindications, cautions, and potential adverse effects such as risk of blood clots Corticosteroid cream 6024 M13 Study Guide Immunomodulators and Dermatology Page 5 of 7 Acne Vulgaris Acne vulgaris is a common skin condition that occurs when the hair follicles get clogged with oil, skin cells, and bacteria. Symptoms include blackheads, whiteheads, pimples, and painful nodules under the skin. What is a first line treatment for mild and moderate Acne Vulgaris? ▪ First-line o Topical retinoids ▪ Alternative o Salicylic acid o Azelaic acid What were some ways mentioned in the lecture to reduce antibiotic resistance when treating Acne Vulgaris? ▪ Use topical clindamycin with benzoyl peroxide to reduce risk of ABX resistance ▪ Use oral ABX with benzoyl peroxide to reduce risk of ABX resistance What are potential adverse effects of: ▪ topical retinoids: peeling, dry skin, burning and stinging, erythema, itching, photosensitivity ▪ benzoyl peroxide: dry skin, burning, erythema, photosensitivity ▪ topical antibiotics: o topical clindamycin: burning, dryness, erythema o topical erythromycin: alternative but resistance exists, so clindamycin is preferred ▪ spironolactone: hyperkalemia, avoid in pregnancy, menstrual irregularities, breast tenderness, anorexia, N/V/D, orthostatic hypotension, HA, dizziness, fatigue, gynecomastia ▪ oral antibiotics: o doxycycline: hepatic toxicity, renal toxicity, depression of skeletal growth, dental staining o minocycline: hepatic toxicity, renal toxicity, depression of skeletal growth, dental staining ▪ oral retinoid – isotretinoin (Accutane): dry skin and mucous membranes, visual changes, hyperlipidemia, elevation of hepatic transaminase levels, myalgias, teratogenic 6024 M13 Study Guide Immunomodulators and Dermatology Page 6 of 7 Topical corticosteroids Match vehicle (ointment, cream, lotion, solution, gel, foam) to lesion and consider location. What are potential adverse effects? ▪ Local effects: burning, pruritis, erythema ▪ Skin changes: atrophy, shiny and wrinkled skin with telangiectasias (spider veins), striae, acneiform eruption (dermatoses that resemble acne vulgaris), hypo/hyperpigmentation, hypertrichosis (excessive hair growth), hypersensitivity reaction ▪ Other: photosensitization, fungal growth ▪ System: HPA axis suppression, hyperglycemia, cataracts, glaucoma ▪ Risk of side effects increase with duration > 3 weeks What do classes I-VII mean, and which are low, moderate, and high potency? Which classes could be considered/avoided for various parts of the body? NOTE: You do not have to memorize which specific topical steroids are in the classes I-VII.) 6024 M13 Study Guide Immunomodulators and Dermatology Page 7 of 7 Adverse Cutaneous Drug Reactions (ACDRs) • What are some adverse cutaneous drug reactions (ACDRs) discussed in the lecture? o Exanthematous reactions ▪ Type IV allergic reaction ▪ Usually occurs 3-10 days after taking Rx ▪ Erythematous macules and/or papules that predominantly involve the trunk and proximal extremities. Can be associated with significant pruritis. o Urticaria ▪ Type I allergic reaction ▪ Usually occurs over minutes to hours after taking Rx ▪ Urticaria can also be associated with angioedema and anaphylaxis o Fixed drug eruption ▪ Type IV allergic reaction ▪ Usually occurs within hours of taking Rx ▪ Single or few dusky red round or oval lesions o Photosensitive reactions ▪ Type IV allergic reaction ▪ Usually occurs within minutes to hours of sun exposure (particularly UVA) ▪ Exaggerated sunburn o Steven-Johnson Syndrome/toxic epidermal necrolysis (SJS/TEN) ▪ Type IV allergic reaction ▪ Usually occurs 1 week to 1 month after taking Rx ▪ Malaise, fever, blistering of mucous membranes, progressive rash to epidermal necrosis and sloughing ▪ Many experts consider TEN to be severe variant of SJS o Drug reaction with eosinophilia and systemic symptoms (DRESS) ▪ Type IV allergic reaction ▪ Usually occurs 2-8 weeks after taking Rx (UpToDate) ▪ Extensive skin rash (such as morbilliform eruption, erythroderma) in association with visceral organ involvement (liver most common, but can involve other organs) • Are ACDRs always immediate? o No. See timing per reaction above. • What are initial considerations for the provider if they suspect a patient has one of the ACDRs discussed? o DC offending drug o Consult dermatologist or allergist for next steps o Reaction prevention if patient needs to stay on medication