Top Dermatology Challenges in Primary Care

Update in Internal MedicineOctober 10-11, 2019

Pittsburgh, PA

Disclosures

• I am a consultant for DermTech, Eli Lilly, Janssen, Ortho, Pfizer• I am an investigator for DermTech, Eli Lilly, Janssen, Ortho, Amgen,

Abbvie, Novartis, Leo Pharma, Galderma, Boehrenger Ingelheim, Celgene

Topics to cover

• Skin cancer screening in primary care• Dermatologic effects of medications you may prescribe• Medical side effects of dermatologic medications you may encounter• Medical comorbidities of common dermatologic diseases• Easy to miss diagnoses• Common conditions and how to treat

Skin cancer screening and prevention in the primary care

setting

Source: SEER.cancer.gov

INVASIVE ONLY(40% of melanomas are in situ)

5th most common cancer in men

7th most common cancer in women

• Men > Women• Risk factors: UV exposure, + family

history, fair skin / light hair

Melanoma: clinical features

regression

Ugly ducklingEvolving

USPSTF recommendations for skin cancer screening

•“The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of visual skin examination by a clinician to screen for skin cancer in adults “

•Screening = full body visual examination of the skin

US Preventive Services Task Force. JAMA. 2016 Jul 26;316(4):429-35.

Behavioral Counseling•Updated USPSTF recommendations for counseling to prevent skin cancer

JAMA. 2018 Mar 20;319(11):1134-1142.

Melanoma screening at UPMC

§ Collaboration with primary care– QUALITY INITIATIVE§ Non-randomized, voluntary§ Use of existing health care data infrastructure and workflow§ PCPs trained to identify skin cancer using validated online training module § Patients age ≥35 offered screening annually by PCPs during routine visits§ Health maintenance module within EHR modified to identify eligible patients

and track screening activity§ Outcomes collected from EHR, cancer registry, health plan

JAMA Oncol. 2017 Aug 1;3(8):1112-1115

INFORMED training (visualdx.com)

All screen eligible

Screened Not screened

p-value

Overall patient # (n, % total eligible)

333,735 53,196

(15.9%)

280,539

(84.1%)

% Male 43.1% 43.2% 43.1% 0.49�

Median age (range) 57

(35-99)

60

(35-91)

57

(35-99)

<0.0001†

About 90% in all groups listed race as white

JAMA Oncol. 2017 Aug 1;3(8):1112-1115

Screened Unscreened p-valueAll Melanoma cases 50 (24 in situ, 26

invasive)104 (35 in situ, 69 invasive)

Median Breslow thickness of invasive melanomas with known depth ( range)

0.37 mm (0.2mm-1.5mm)

0.65 mm (0.18mm-6.5mm)

0.0006

Breslow thickness distribution• 0.01-0.50 mm 18 20• 0.51-1.00 mm 5 26• 1.01-1.50 mm 3 6• 1.51-2.00 mm 0 5• ≥2.01 mm 0 10

JAMA Oncol. 2017 Aug 1;3(8):1112-1115

Who detected melanoma in screened patients?

All cases Detected by dermatologists

Detected by trained PCP

Detected by PCP who did not train

Number cases 50 14 14 22

In situ melanoma 24 (48%) 8 (57%) 5 (36%) 11 (50%) P=0.51

Median depth of invasive melanoma (range)

0.365mm

(0.2mm-1.5mm)

0.465mm

(0.21mm-1.4mm)

0.35mm

(0.20mm-1.5mm)

0.35mm

(0.21mm-0.65mm)

P=0.49

JAMA Oncol. 2017 Aug 1;3(8):1112-1115

PCP-performed biopsies

# patients with ≥ 1 biopsy to rule out malignancy

433# patients with melanoma 15# patients with NMSC 101# patients with other malignancy 1# patients with benign biopsies 316Biopsy ratio (any malignancy) 1: 3.7Biopsy ratio (melanoma) 1: 28.9

What can I do? Basic Skin Exam“Don’t let perfect be enemy of good”

•Catching the obvious melanomas will save lives at minimum cost• Gown patients, look at skin during

the routine exam• Don’t worry about genitals, inside

the mouth, between the toes• Especially older patients (>50-60

years)

Melanoma can have many different appearances

If you are comfortable, and suspect melanoma, biopsy!

• Ideally, removal is of entire lesion and down to fat

Elliptical excision

Punch excisionSaucerization / Shave biopsy

Dermatologic effects of medications you may prescribe

• HCTZ is a photosensitizing drug• Case-control study• 1,533 case patients with BCC and 8629 case patients with SCC, matched

20:1 for sex and birth year• OR 1.29 for BCC and 3.98 for SCC among high users of HCTZ (>50,000 mg)

• Particularly high risk of SCC among patients < 50 years old• Risk increases with drug exposure

J Am Acad Derm. 2018 Apr;78(4):673-681

Thiazide diuretics and risk of skin cancer: Meta-analysis of observational studies

J Clin Med. Res. 2019; 11(4):247-255.

Thiazide diuretics and skin cancer: Clinical considerations

ØData most concerning for increased risk of SCC; less so for melanoma and BCC

ØCounsel patients on HCTZ about risk of photosensitivity and sun protection

ØConsider alternative antihypertensive drugs for patients with >1 non-melanoma skin cancer, fair skin/ easy burning, high sun exposure

ØLimit cumulative dose of HCTZ if possible

Propranolol may reduce the risk of melanoma recurrence

JAMA Oncol. 2018 Feb 8;4(2):e172908.

Clinical case• Tense pruritic bullae appearing in an 81

year old man 8 months after starting linagliptin

• Resolution with discontinuation of linagliptin

J Diabetes Investig. 2018 Mar;9(2):445-447.

Dipeptidyl-peptidase 4 inhibitor- associate bullous pemphigoid • Rare autoimmune bullous disease • Generalized pruritic tense blisters, mainly in

elderly patients.• Characterized by autoantibodies directed against

hemidesmosomal proteins (BP180 and BP230)

• Retrospective case-control study in

diabetic patients with BP and age/sex/yr

of diagnosis –matched controls

• Association of DPP-4 inhibitor use (not

other diabetic medications) with risk of

BP

• Supported by other studies

• Highest risk with Vildagliptin

• Several cases of resolution with stopping

DPP-4 inhibitor

JAMA Dermatol. 2019;155(2):172-177.

Medical side effects of dermatologic medications you

may encounter

Plaque type psoriasisThere are now 10 biologics

FDA-approved for the treatment of psoriasis!

TNF antagonistsEtanercept• Fusion of 2 human TNF-a receptors

and Fc portion of human IgG1

Adalimumab• Fully human IgG1 monoclonal

antibody to TNF-a

Infliximab• Chimeric (75% human,

25% mouse) antibody to TNF-a

Certolizumab Pegol• PEGylated Fc portion of anti- TNF-a

All FDA-approved to treat psoriasis and psoriatic arthritis

IL-12/23 antagonist p35p19

p40p40

• Ustekinumab: mAb to IL-12/23

IL-23 antagonists

p40

p19 p19

p403 now available:• Guselkumab• Tildrakizumab• Risankizumab

IL-17 antagonistsIL17A IL17A Ixekizumab and Secukinumab

• Fully human mAb to IL-17A• FDA approved for psoriasis

and psoriatic arthritis

BrodalumabFully human mAB to IL-RAFDA approved for psoriasis

Class-specific safety concernsTNF antagonists

• Lupus-like syndrome• Demyelinating disease• Congestive heart failure

exacerbation• Reactivation of Hepatitis B• Small increase in risk of non-

melanoma skin cancer• Salmonella / listeria infection• Melanoma metastasis in

patients with invasive melanoma

IL-17 antagonists• Inflammatory bowel disease• Non-invasive candida / fungal

infection• Suicide (brodalumab)

Inflammatory bowel disease and IL-17 inhibition• In phase 3 clinical trials:• Secukinumab: exposure adjusted incidence rates of 0.11 and 0.15

per 100 patient-years for CD and UC, respectively• Ixekizumab:

• 6480 patient-exposure years• CD: incidence rate = 1.1/1000 patient-exposure years; • UC, incidence rate = 1.9/1000 patient-exposure years).

• Brodalumab: 1 case of CD

J Am Acad Dermatol. 2017 Mar;76(3):441-448. J Dermatolog Treat. 2018 Feb;29(1):13-18.

Candidiasis and tinea infections

• Incidence of mucocutaneous candidiasis is 3-4% for patients on anti-IL-17 antagonists• No evidence of systemic / disseminated candida• Treatable infections

Br J Dermatol. 2017 Jul;177(1):47-62.

Suicide and Brodalumab: 4 cases in psoriasis

J Am Acad Dermatol. 2018 Jan;78(1):81-89. Skin Therapy Lett. 2018 Mar;23(2):1-3.

• Also one in the rheumatoid arthritis trial, and one in a psoriatic arthritis study.

• The FDA analyzed the data available in 2015 and determined no established drug-related risk of suicide or suicidal ideation.

• To date, no additional data correlating brodalumab use and suicide

Screening for tuberculosis

• Recommended prior to starting any biologic• Highest risk of TB reactivation with TNF antagonists• Screening for latent TB- QuantiFERON gold, T spot, or PPD

• PPD not good option if prior BCG vaccination• CXR normal in latent TB

• Patients with latent TB can start biologics once they start on treatment, but need to ensure they complete the course

• TB reactivation is EXTRAPULMONARY in about 2/3 of cases so look beyond the chest x ray

Dixon et al Arthritis Rheum 2006;54:2368-76.

Beyond TB: other infectious concerns with TNF antagonist

• Also consider legionella, histoplasmosis

• Listeria and salmonella are also intracellular bacteria and

TNF antagonists reduce immunity to these food-borne

illnesses

– After warning labels introduced in UK to avoid undercooked

eggs, poultry, and meats, incidence of listeria and salmonella

in users of TNF antagonists decreased by about 73%

Ann Rheum Dis. 2013 Mar;72(3):461-2.

Apremilast• Inhibits PDE4• FDA approved for

psoriasis and psoriatic arthritis•Modest efficacy

• Side Effects• GI primarily- diarrhea• Often reason for

stopping• Depression•Weight loss in about

20%

Biochemical Pharmacology. Volume 83, Issue 12, 15 June 2012, Pages 1583–1590

Easy to miss/ mistreat

Diagnosis: Acute Urticaria

24 y.o. female with rash• Started 3 days ago• No new medications or foods• No joint pain, GI symptoms, fevers• Lesions come and go each dayà resolve

completely, new ones appear

Urticaria

• Presentation: pruritic wheals, single lesions last < 24 hours• Cause• Usually idiopathic• Consider other causes

• Drug• Dermatographism (can induce urticaria by scratching on skin)• Physical urticaria – induced by pressure, vibration, heat or cold• Allergy testing not warranted!• If negative ROS, don’t need lab work

• If lesions last >24 hours, burn more than itch, associated with joint pain, heal with bruising, consider urticarial vasculitis- refer to dermatology

Classifying urticaria

Duration: •Acute (< 6 weeks)•Chronic (>6 weeks)

Allergy. 2018 Jul;73(7):1393-1414

Work up• If angioedema, is patient on ACE-I? If so stop and re-evaluate• Acute Urticaria

• Take a history, but no routine testing unless suspect a particular food as a cause

• Chronic• Good history• Determine if inducible à identify cause• Other associated symptoms?• Routine monitoring (consider):

• CBC with differential• ESR and/ or CRP

“Intensive and costly general screening programs for causes of urticaria are strongly advised against”

Allergy. 2018 Jul;73(7):1393-1414

Hives: induced by

cold

3 min exposure to ice cube

Cold urticaria

Scratch test: Dermatographism

Allergy. 2018 Jul;73(7):1393-1414

Urticaria

• What about oral steroids?• They will make urticaria go away in most cases while on high-dose

steroids• Urticaria will return with dose tapering/ cessation• Rarely indicated, particularly for chronic urticaria!

Hives, every night

• Hives, onset in the "tingling" symptoms – minimal pruritus

• The rash will fade somewhat throughout the following day to where it almost disappears, only to become red again at the end of the day

• Associated with fevers and joint pain/swelling

• Labs

• CRP 6.1• ESR: 54• Ferritin: 2378

When it may be more than just urticaria

• Adult Onset Still’s Disease• Fever, arthritis, nonpruritic urticaria-like lesions• Classically appear nightly, improve during day• Characterized by markedly elevated ESR, CRP, ferritin• Striking response to NSAIDs

• Consider other causes if• Fever• Unexplained lymphadenopathy• Arthralgias• Lymphadenopathy• Non-pruritic lesions

When wound care continues to fail

•78 year old woman•Healthy• Spontaneously developed open wounds on arms,

trunk•No response to wound care, oral antibiotics• Serial debridement did not improve and actually

worsened disease

Pyoderma gangrenosum

Pyoderma gangrenosum

• Autoinflammatory neutrophilic dermatosis• Non-healing, ulcerated lesions• Exhibit pathergy (worsen with mechanical trauma)• Associated with other neutrophilic or inflammatory disorders • inflammatory bowel disease • rheumatoid arthritis• seronegative arthritis• hematologic disorders, including paraproteninemia, especially Ig A • neutrophilic malignancies such as acute myelogenous leukemia (AML)

DIAGNOSIS OF EXCLUSION!

Topical Therapy• Potent topical steroids• Intralesional steroids• Topical dapsone• Topical tacrolimus

Systemic Therapy• Prednisone (0.5-1 mg/ kg / d)• Cyclosporine (3-5 mg/ kg/d)• Colchicine (0.6-1.2 mg/ d)• Dapsone (50-100 mg / d)• Azathioprine (50-1000 mg BID)• Mycophenolate mofetil (1-1.5 g BID)• Minocycline (100 mg / d)

Biologic Therapy• Anti TNF alpha

§ Infliximab§ Adalimumba

• Anti IL-1§ Anakinra§ Canakinumab§ Gevokizuma

• Anti IL-12/23§ Ustekinumab

Pyoderma gangrenosum therapy

Therapies: cyclosporine, adalimumab, topical clobetasol, topical dapsone, gentle wound care, lots of hand holding over 5 years

Surgical therapy is not the answer!

Initial presentation After surgical re-excision After topical steroids

Take-home points• Skin exam during routine physical can improve early detection of

skin cancer

• Consider stopping thiazide diuretics in patients with skin cancer

• Risk of bullous pemphigoid with DPP4 inhibitors

• Patients on biologics:

• Risk of IBD with IL-17 inhibitors

• Risk of TB is low, but consider extrapulmonary TB in patients on TNF

antagonists

• Urticaria: think before you give a steroid taper

• Non-healing wound: consider pyoderma gangrenosum