Update on cutaneous drug reactions Jennifer Madison McNiff, M.D. Professor, Dermatology and Pathology Director, Yale Dermatopathology Update on drug reactions • New drugs, new rashes • Old drugs, new concepts MABs, NIBs, and other acronyms How are generic drugs named? • USAN (United States adopted name) • 5 members (AMA, pharma, FDA) • Name all generic drugs since 1961 • Search “stem list drug names” • Http://druginfo.nlm.nih.gov/drugportal/ Molecular targeted therapy “MABs” “NIBs” • M onoclonal antibodies • Small molecule inhibitors • Target extracellular • Target intracellular receptors signaling pathways • Prevent growth, incite • Multikinase inhibitors death Molecular targeted therapy “MABs” “NIBs” CD20: Rituximab Tyrosine kinase: Imatinib EGFR: Cetuximab EGFR: Gefitinib, Erlotinib VEGF: Bevacizumab Raf kinase: Sorafinib HER2: Trastuzumab VEGF: Cediranib Block function or signaling New drugs, new rashes… Epidermal growth factor receptor inhibitors • MABs (cetuximab, panitumumab) • NIBs (gefitinib, erlotinib) • Used for lung, colon, pancreatic, head and neck cancers • EGFR on keratinocytes, side effects in skin EGFR inhibitor Suppurative folliculitis EGFR inhibitor reaction Oct 2013 Colon cancer EGFR inhibitor Rash treated Moss and Burtness with topical NEJM 353;19:2005 acne therapy (+/- oral antibiotics) Preemptive therapy may be helpful Beware superinfection EGFR inhibitor Hair abnomalities Paronychia Br J Derm 2006;155:852 PRIDE syndrome • Papulopustules/ paronychia • Regulatory abnormalities of hair growth • Itching • Dryness • Due to • EGFR inhibitors Br J Derm 2006;155:852 Squamous proliferations after cancer targeted therapies… Vismodegib and SCC BJD 2014;171:415 Voriconazole Antifungal 2 years 66-year-old-man CMML PBSCT GVHD Voriconazole Phototoxic reaction Drug discontinued Multiple SCC (24 in 18 months) Sun-exposed lesions J Am Acad Dermatol 2010;62:31-7 • 51 SCC in 8 patients on Voriconazole • Ages 9 to 54, median 34 years • Short duration immunosuppression • Hematopoietic cell transplantation 6 of 8 • Without Voriconazole, incidence of SCC only 1% over 20 years after HCT 9 yr old boy ALL V- 3 yrs AKs 22 yr HIV+ V- 15 months SCC, lentigos 46 yr man Wegener’s V- 4 yrs SCC (fatal) • Review of 8 large studies, 3710 patients • Risk of SCC on Voriconazole independent of type of transplant or sun exposure • Longer duration of Voriconazole associated with increased risk SCC • No increased risk of BCC Voriconazole • Metabolite is photoactive, causes phototoxicity • Increased risk of SCC, some aggressive • How long does this effect persist after drug is discontinued? • Are the SCC histologically unique? Ped Dermatol 2010;27:105 J Cutan Pathol 2011;38:677 39 year old woman Coccidiomycosis Arch Dermatol 2010;146(3):3000-304 Squamous proliferations on RAF inhibitors • In 131 patients: 7 SCC, 2 SCC-KA, 3 AK • Median 6.5 months after start of Rx Arch Dermatol Dec 2010 Metastatic melanoma Isolated limb perfusion Melphalan, Dactinomycin Systemic Sorafenib SCCs limited to perfused limb Arch Derm Jan 2011 59-year-old man Hepatocellular carcinoma treated with Sorafenib Sun-protected skin, no history of burn or DLE Squamous proliferations: BRAF inhibitors Vemurafenib) BRAF inhibitor for melanoma J Am Acad Dermatol 2012;67:1265 • 27 BRAF keratoses tested negative for common verruca subtypes by IHC • 27 BRAF keratoses negative for genital HPV subtypes by PCR • Most Braf keratoses are HPV negative • 13% harbor unusual HPV types Squamous lesions secondary to BRAF inhibitors • A spectrum – Warty (most show no HPV by PCR) – Acantholytic dyskeratosis – Keratoacanthoma-like (no reports of self- regression yet) – Squamous cell carcinoma (no reports of metastasis yet) – BRAF -induced verrucous keratosis Arch Dermatol 2012;148:628-33 Melanoma Treated MM Side effect of inhibitor Nature 2010;464:358 Vemurafenib-induced atypical moles/ melanoma N Eng J Med 2011;365:15 Sorafenib-induced eruptive melanocytic nevi Arch Dermatol 2008;140:820 N Eng J Med 2012;367:18 BRAF and MEK inhibition • Resistance to BRAF inhibition associated with reactivation of MAPK pathway • Dabrafenib + Trametinib (MEK inhibitor) • Improved survival • Fewer squamous proliferations • Acneiform rash with MEK inhibitor alone N Eng J Med 2015;372:30-39 JAMA Derm 2014;150:1209 Baseline Eruptive nevi BRAF inhibitor Involution MEK inhibitor + panniculitis Arch Dermatol 2012;148:357-361 Neutrophilic panniculitis Checkpoint inhibitors for melanoma, and new drug reactions Anti-PD1 lichenoid rash (nivolumab) 14 patients, 12/14 interface dermatitis, usually lichenoid H&E CD3 CD4 CD8 About 1% of patients on anti-PD1 and anti-PDL1 developed bullous disorders Vitiligo also seen in 15-20% patients on PD-1 therapy Another immunotherapy: anti-CTL4 (Ipilimumab) • Immunomodulatory therapy, alone or combined with anti-PD1 agents • Improved survival • Rash common, usually morbilliform • Unusual cutaneous reactions may be instructive about other cutaneous diseases J Am Acad Dermatol 2013;69:5 Ipilimumab (anti-CTL4) J Cutan Pathol 2018;45:636 Granulomatous dermatitis also seen with BRAF inhibitors, patients sometimes exposed to both Tumor necrosis factor inhibitors • Infliximab (Remicade) • Adalimumab (Humira) • Certolizumab (Cimzia) • Etanercept (Enbrel, recombinant DNA) • Indications: Inflammatory bowel disease, rheumatoid arthritis, psoriasis Tumor necrosis factor inhibitors ~ 25% patients have skin reactions ~ • Injection site reactions • Infections (7%): HSV, bacteria, fungal • Paradoxic psoriasis (5%) and sarcoidal granulomas • Uncommon to rare: – LCV, EM, EN, LE Patient with rheumatoid arthritis on Adalimumab Patient with rheumatoid arthritis on Adalimumab Gram AFB Eczema vs. Psoriasis Patient with Crohn’s disease TNF inhibitor-induced psoriatic skin lesions New rash on feet of 26 yr woman with Crohn’s disease on Certolizumab TNF inhibitor-induced psoriatic lesions • Typically pustular and palmar-plantar • Class effect, not drug specific • TNF blockade results in increased secretion of interferon-α, which predisposes to or exacerbates psoriasis 13 year-old girl with Crohn’s disease on infliximab (TNF-αI), 1 month of hair loss Resembles “psoriatic alopecia”….. Psoriasiform changes Areata-like features Absent sebaceous lobules Catagen shift Follicular miniaturization Atlas of Hair Pathology with Clinical Correlations Sperling, Cowper, Knopp 61 year old female on Etanercept (anti- TNF) for rheumatoid arthritis for four years developed plaque on the arm ASDP ESS 2010 Sarcoid-like granulomas after anti-TNFα therapy • Reported in skin and lung • Paradoxic- anti-TNFα used for sarcoid • Resolves after d/c drug, +/- steroids • Beware infectious granulomatous diseases, occur at higher incidence after anti-TNFα therapy Another TNFα inhibitor reaction TNFα inhibitor-related lupus erythematosus • Positive ANA and other autoantibodies more frequent after TNFα inhibitor therapy • Autoantibodies and clinical LE more common with infliximab than etanercept • Compared to traditional drug induced LE, higher incidence of rash and anti-dsDNA antibodies with anti-TNFα LE • 14 patients with lupus-like reaction to TNFα inhibitor therapy • Mean treatment 16 months • ANA + 100%, dsDNA 71% • Arthritis 93% • Cutaneous findings 29% • Often tolerate different TNF inhibitor TNF inhibitor-related lymphoid lesions TNFα inhibitor-related lymphoid lesions • Patients with RA or PS already at increased risk for lymphoma • Cases after TNFα Rx are CTCL, not CBCL • Cautionary note: confirm original diagnosis of psoriasis, not patch MF, prior to anti-TNFα therapy! Patient with Crohn’s disease Numerous ulcers developed on infliximab Resolved after drug removed Other neutrophilic reactions… A 70-year-old woman hospitalized for a cardiac procedure developed a fever and widespread sterile pinpoint pustular rash. Acute generalized exanthematous pustulosis (AGEP) • Reaction pattern • Drug – majority of cases – B-lactam antibiotics most common – Calcium channel blockers (Diltiazem) – Antimalarials • Acute viral infection • Hypersensitivity to mercury Acute generalized exanthematous pustulosis • Onset < 24 hours after drug • Fever, pustules of face and intertriginous areas, disseminate in a few hours • Desquamation without scar or sequelae • No certain correlation with psoriasis AGEP AJD 2005 Up to 80% of AGEP patients patch test positive DDx: Linear IgA dermatosis s/p Vancomycin Drug induced linear IgA dermatosis IgA Widespread pustules 1 day after Vancomycin and Tramadone, with facial swelling and transaminitis Epidermal acantholysis, DIF negative ? Patient with Hailey Hailey disease, AGEP, and systemic symptoms! B J Derm 2013;169:1223 Drug reaction with systemic symptoms and eosinophilia • DRESS = Severe adverse drug reaction • High fever, facial edema, erythroderma, exfoliation, lymphadenopathy, eosinophilia, abnormal liver function tests • Antiepileptics, minocycline, allopurinol, dapsone, sulfonamides most common DRESS Allopurinol Ceftriaxone Vemurafenib causes DRESS too… Eosinophils and lymphocytes DRESS and HHV6 • Reactivation of viruses common in DRESS • HHV6, HHV7, CMV, EBV • Might predict high risk patients • Antiviral response may contribute to clinical symptoms January ‘09 Also HHV6, HHV7, CMV, VZV Other unique reactions… A 50-year-old man with advanced lung cancer developed a papular nonpruritic eruption on his trunk. GMCSF • Cytokine to stimulate marrow stem cells • Distinct diffuse skin reactions with increased dermal macrophages GMCSF • Cytokine to stimulate marrow stem cells • Neutrophilic reactions – Sweet’s