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 EGFR inhibitor reaction Oct 2013

Colon cancer EGFR inhibitor

Rash treated Moss and Burtness with topical NEJM 353;19:2005 therapy (+/- oral antibiotics)

Preemptive therapy may be helpful

Beware superinfection EGFR inhibitor

Hair abnomalities

Paronychia Br J Derm 2006;155:852 PRIDE syndrome

• Papulopustules/ • 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  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 , 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, 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 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 / PG Another unique Sweet’s like eruption

Child with AML treated with ATRA (all-trans retinoic acid) Neutrophilic infiltrates- may be leukemic cells undergoing maturation Old drugs, new concepts… J Am Acad Dermatol 2008;56(3):524-529 TEC

Dermatology, J. Bolognia 59 yr man on Gemcitabine for pancreatic cancer

Epidermal dysmaturation of chemotherapy Acral erythrodysesthesia, hand- foot syndrome, acral erythema

5-FU, Doxorubicin, Cytarabine

Acral erythema

Traditional chemotherapy

Nib therapy (Acral) erythrodysesthesia

Courtesy of Bolognia “Non-acral acral erythrodysesthesia” A 30-year-old woman with a recent diagnosis of breast carcinoma and joint pain developed a malar rash. Taxane chemotherapy reaction

• Interface dermatitis with arrested mitotic figures • Antimicrotubule agent, stops cell division

DDx: SLE / DM DDx: Fixed drug reaction TEC

Dermatology, J. Bolognia Eccrine squamous syringometaplasia Neutrophilic eccrine hidradenitis

Both are common in toxic erythema TEC

Dermatology, J. Bolognia Toxic erythema of chemotherapy

• EC“T ” is a useful clinical concept • Histologic terms confusing to non- dermatologists • Features may be helpful in distinguishing rash from aGVHD • The term “toxic” emphasizes risk of recurrence with same chemotherapy, worse with higher doses Summary of drug reactions

• Targeted therapies may result in the same spectrum of cutaneous reactions as other medications • Some more common reactions may inform us about other common dermatoses • As more “NIBs” and ”MABs” are developed, new patterns will likely emerge