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Alopecia areata: Workup and treatment Carolyn Goh Assistant Clinical Professor David Geffen School of Medicine at UCLA Department of Medicine-Dermatology March 2017

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Alopecia areata: �Workup and treatment

Carolyn Goh

Assistant Clinical Professor

David Geffen School of Medicine at UCLA

Department of Medicine-Dermatology

March 2017

Introduction• Common non-scarring patchy alopecia • Lifetime risk estimated at 2.1% • Estimated to comprise 0.7-4% of all patients seen by dermatologists

• Autoimmune cell-mediated process thought to be due to loss of immune privilege of the anagen hair follicle

• Genetic polymorphisms have been identified in some populations

Overview• Epidemiology

• Burden of disease • Health-related quality of life • Comorbidities

• Treatment • JAK inhibitors – oral/topical • Other new immunomodulators • Updated information on traditional treatments

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Epidemiology• 2.1% lifetime risk of developing alopecia areata –

extrapolated from Mayo Clinic study in Olmstead County1 • Previous data 1975-1989 showed 1.7%

• Other autoimmune diseases have shown increased incidence

• Appears to be equal across ethnicities and gender • Can occur at any age, but considered less common under

age 3 and mean age of onset is in 30s for men and women Mirzoyev et al, Lifetime incidence risk of alopecia areata estimated at 2.1% by Rochester Epidemiology Project, 1990-2009. J Invest Dermatol 2014;134:1141-2.

Burden of disease is similar to psoriasis•  Disability-adjusted life year (DALY)

• Combines yrs lost to disability (morbidity) and death (mortality) • One DALY = one year of healthy life lost

•  WHO measured global DALYs lost in 2010 • AA = 1,332,800 • Psoriasis = 1,050,660 • Diabetes mellitus = 46,857,100

•  May underestimate true disease burden • Some patients with AA may not present for care • Disability imposed by emotional distress, interpersonal relationships, and financial impact were not considered

5 Villasante Fricke A and Miteva M, Clin Cosmet Invest Dermatol 2015;8:397-403.

Health-related quality of life (HRQOL)• Measure of physical, mental, emotional, and social functioning

• Rencz et al (2016) and Liu et al (2016) reviewed HRQOL studies in AA

• Overall, there is significantly reduced HRQOL in emotional, mental health, and vitality domains.

• Wearing a wig has a positive impact on HRQOL and scalp involvement, anxiety and depression have a negative impact.

• HRQOL is in AA is comparable to psoriasis and atopic derm

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Rencz F, et al, Alopecia areata and health-related quality of life: a systematic review and meta-analysis, Br J Dermatol 2016;175:561-571. Liu LY, et al, Health-related quality of life (HRQoL) among patients with alopecia areata (AA): a systematic review, J Am Acad Dermatol 2016;75:806-812.

Comorbidities•  Atopy (especially atopic dermatitis and allergic rhinitis)

•  Thyroid disease – particularly in adults

•  Autoimmune disorders • Systemic lupus – particularly in younger patients, vitiligo, psoriasis

•  Psychiatric disorders • Depression, anxiety

Chu et al, Comorbidity profiles among patients with alopecia areata: The importance of onset age, a nationwide population-based study, J Am Acad Dermatol 2011;65:949-56. Huang et al, Autoimmune, atopic, and mental health comorbid conditions associated with alopecia areata in the United States, JAMA Dermatol 2013;149:789-94.

Stroke risk and AA• Case control study from Taiwan from 2004-2011

• 3231 patients with AA compared to 16,155 matched controls • Risk of stroke within three years of AA diagnosis was increased independent of hyperlipidemia, hypertension, and heart disease (hazard ratio 1.61, 95% CI = 1.13-2.30)

• Inflammation/oxidative stress associated with AA vs. treatment effects vs. other

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Kang et al, Alopecia areata increases the risk of stroke: a 3-year follow up study, Sci Rep. 2015;5:11718.

Cardiovascular risk and AA• Retrospective study from Boston, MA (2000-2010)

• Decreased odds for developing ischemic stroke (odds ratio 0.39, 95% CI 0.18-0.87) and a trend toward decreased risk of acute myocardial infarction (odds ratio 0.91, 95% CI 0.59-1.39)

• 1377 patients with AA compared to 4131 matched controls

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Huang et al, Cardiovascular risk in patients with alopecia areata (AA): a propensity-matched retrospective analysis, J Am Acad Dermatol. 2016;75:151-4.

Vitamin D in AA• Some retrospective analyses have shown an association between low vitamin D (25OH) levels and alopecia areata, some showing an association with severity.

• Evaluation of 133 patients with AA out of 55,929 over 12 years in the Nurses’ Health Study showed no significant association with predicted vitamin D status.

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Aksu Cerman et al, Vitamin D deficiency in alopecia areata, Br J Dermatol 2014;170:1299-304. Mahamid et al, Association between vitamin D levels and alopecia areata, Isr Med Assoc J 2014;16:367-70. d’Ovidio et al, Reduced level of 25-hydroxyvitamin D in chronic/relapsing alopecia areata, Dermatoendocrinol 2013;5:271-3. Thompson et al, Estimated serum vitamin D status, vitamin D intake, and risk of incident alopecia areata among US women. Arch Dermatol Res 2016;308: 671-676

Skin cancer risk reduced in AA• Negative association with squamous cell carcinoma and basal cell carcinoma

• Trend for melanoma, but not significant • Possibly related to genetics that may confer immunologic advantage

• Of note, the costimulatory pathway which has been identified in GWAS studies for AA has been targeted to treat melanoma

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Mostaghimi et al, Cancer Epidemiol (2016) 41, 129-31. Miller et al, J Investig Dermatol Symp (2015) 17, 61–62.

Summary of epidemiology studies• Consider screening for lupus in younger patients, thyroid disease in older patients, and psychiatric comorbidities (referral to psychologist or psychiatrist)

• Consider screening for vitamin D deficiency • new definitions for vitamin D deficiency (<20 ng/ml considered inadequate and 20-50 ng/ml considered adequate)

• There may be surprising associations – clinical observation and continued epidemiological studies are important

Treatment and management• JAK inhibitors • Other biologics (ustekinumab, apremilast, abatacept) • Simvastatin/ezetimibe – mixed results • Hydroxychloroquine – not effective • Platelet rich plasma • Contact immunotherapy and anthralin

Janus kinase inhibitors• Ruxolitinib = Jakafi (~$11,000 for 30-day supply) = JAK1/JAK2 inhibitor

• Approved for use in myelofibrosis in 2011

• 20 mg twice daily

•  Tofacitinib = Xeljanz (~$4,000 for 30-day supply) = pan-JAK inhibitor • Approved for use in rheumatoid arthritis in 2012

• 5 mg twice daily, increase to 10 mg qAM, 5 mg qPM

• Extended release now available – 11 mg daily

•  At least 7 others in clinical trials, and 1 approved for use in dogs for eczema

Janus kinase inhibitors•  Topical ruxolitinib in trials for alopecia areata

•  Topical tofacitinib s/p trials for psoriasis • Both available through compounding pharmacies as cream or solution; some

anecdotal improvement.

•  Oral: open-label clinical trials done, but no randomized controlled trials

•  Case report of baricitinib

•  Adverse effects: diarrhea, headaches, other GI side effects. Liver function

abnormalities, infection, possible malignancy, bowel perforation. Long term risk

largely unknown.

JAK inhibitors in AA• Ruxolitinib (20 mg twice daily) – 9/12 (75%) patients SALT

30-70% with >50% regrowth after 4-6 months. +relapse over 3-6 months.

• Low IFN and cytotoxic lymphocyte signatures on gene expression profiles associated with lack of response

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Mackay-Wiggan, J., et al. (2016). "Oral ruxolitinib induces hair regrowth in patients with moderate-to-severe alopecia areata." JCI Insight 1(15): e89790.

Tofacitinib• Tofacitinib (5 mg twice daily) 66 pts, SALT 50-100% – 32% with >50% regrowth within 3 months, 32% with 5-50% regrowth. + relapse ~8.5 weeks

• Tofacitinib (5-10 mg twice daily) +/- pulsed oral corticosteroid (300 mg monthly x 3 mos) – 65 pts, SALT >40%, 58% with >50% change in SALT score in 4-18 mos.

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Kennedy Crispin, M., et al. (2016). "Safety and efficacy of the JAK inhibitor tofacitinib citrate in patients with alopecia areata." JCI Insight 1(15): e89776. Liu, L. Y., et al. (2017). "Tofacitinib for the treatment of severe alopecia areata and variants: A study of 90 patients." Journal of the American Academy of Dermatology 76(1): 22-28.

Tofacitinib (cont.)• Tofacitinib in adolescents ages 12-17

• 10/14 patients with SALT 20-100% with mean SALT improvement of 88% over 2-16 months

• Dose 5 mg twice daily except one on 10 mg qam, 5 mg qpm • Mild adverse effects, no treatment interruptions

• Anecdotally – intralesional corticosteroid injections seem to help as well.

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Craiglow, B. G., et al. (2017). "Tofacitinib for the treatment of alopecia areata and variants in adolescents." Journal of the American Academy of Dermatology 76(1): 29-32.

Off-label use• CBC, CMP, Hep B, Hep C, HIV, Quantiferon gold (or PPD), lipids, CXR possibly

• CBC, CMP, lipids 4-6 weeks after first dose, then q3 months

• 5-10 mg twice daily, or extended release 11 mg 1-2 times daily

• Photos at baseline and each follow up; SALT score • Consider intralesional, intramuscular, or oral corticosteroids

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Considerations•  Very difficult to obtain coverage from insurance, though new data

may be helpful

• Rheumatology referral may be helpful • Familiarity with drug, adverse effects, and alternatives

• More time for appointments to discuss risks

• Samples – but may not be reliable source.

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Other targeted therapies• Ustekinumab (IL12-23/p40 inhibitor)

• 90 mg q12 wks; 1/3 with complete response after 12 months, others with moderate response, but AA has developed in pts on ustekinumab

• Apremilast (PDE4 inhibitor) • prevents AA in human skin grafts on mouse model

• Abatacept (CTLA4 agonist) - 125 mg SC weekly • SALT 30-100% 1/15 patients with 98% regrowth after 6 months, 2/15 with 23% regrowth

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Guttman-Yassky, E., et al. (2016). "Extensive alopecia areata is reversed by IL-12/IL-23p40 cytokine antagonism." J Allergy Clin Immunol 137(1): 301-304. Mackay-Wiggan, J., et al. (2015). "Subcutaneous abatacept in the treatment of moderate to severe alopecia areata." Journal of Investigative Dermatology 135: S41. Keren, A., et al. (2015). "The PDE4 inhibitor, apremilast, suppresses experimentally induced alopecia areata in human skin in vivo." J Dermatol Sci 77(1): 74-76.

Simvastatin/ezetimibe – 40/10 mg daily• Lattouf et al (2015) - Pilot study of 29 patients

• 40-70% SALT score, 73% responded after 16-24 wks (>20% regrowth), +relapse, No adverse effects

• Loi et al (2016) – 20 patients • >70% SALT, no patients with >20% regrowth. • Simvastatin with JAK inhibition, modulates lymphocyte activity, ezetimibe antioxidant effects and possible role in autophagy

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Lattouf, C., et al. (2015). "Treatment of alopecia areata with simvastatin/ezetimibe." Journal of the American Academy of Dermatology 72(2): 359-361. Loi, C., et al. (2016). "Alopecia areata (AA) and treatment with simvastatin/ezetimibe: experience of 20 patients." Journal of the American Academy of Dermatology 74(5): e99-e100.

Platelet rich plasma (PRP)• Few studies, but many patients inquire about it • El Taieb et al (2017)

• Significant improvement monthly PRP vs. placebo and minoxidil 5%, patchy better than AT or AU. (x 3 months)

• Singh (2015) – 19/20 with regrowth, monthly x 6 months

• Trink et al (2013) – double blind, placebo, half head x 3 months

• Significant improvement monthly PRP (60% complete) vs. ILK (27%) vs. placebo, even after 1 year; baseline SALT ~32-36%

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El Taieb et al, Platelets rich plasma versus minoxidil 5% in treatment of alopecia areata: A trichoscopic evaluation. Dermatol Ther. 2017 Jan;30(1) Singh, Role of platelet-rich plasma in chronic alopecia areata: Our centre experience. Indian J Plast Surg. 2015 Jan-Apr;48(1):57-9. Trink et al, A randomized, double-blind, placebo- and active-controlled, half-head study to evaluate the effects of platelet-rich plasma on alopecia areata. Br J Dermatol. 2013 Sep;169(3):690-4.

Hydroxychloroquine• Case reports and anecdotally associated with regrowth

• 200 mg twice daily

• Nissen et al (2016) • Series of 8 patients, 1 with extensive regrowth, but relapsed while on medication.

• Only use if possible connective tissue disease

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Nissen et al, Hydroxychloroquine is ineffective in treatment of alopecia totalis and extensive alopecia areata: A case series of 8 patients. JAAD Case Rep. 2016 Mar 4;2(2):117-8.

Contact immunotherapy• Chiang et al (2014) reviewed 50 cases using DPCP

• 71% of AT and 56% of AU patients >50% regrowth • 15% of responders did not respond until 1-2 years

• DPCP + anthralin 0.5% ointment • 88% (n=22) vs. 54.5% (n=12) had 50% or greater terminal hair regrowth after 30 weeks

• Prior sensitization may not be necessary • 4/6 patients who either were not sensitized or failed to develop a reaction eventually had regrowth

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Chiang et al, J Am Acad Dermatol, 2014;71:595. Durdu et al, J Am Acad Dermatol, 2015;72:640. Vedak and Kroshinsky, J Am Acad Dermatol, 2015;73:471.

Reviews• Pulsed corticosteroid therapy (Shreberk-Hassidim et al, 2016)

• 41 studies, various protocols (IV, IM, PO; once monthly or once weekly), only one randomized controlled trial

• Complete response in 40% of patients in the RCT (0% in placebo group), 43% in the study population, 51% in pediatric-only studies.

• DPCP (Kuin et al, 2015) • 11 studies with 500 patients, no RCTs, 10 half head studies with no treatment, variety of AA severity.

• ~50% response rate overall, remission tended to last > 1 year

• High dropout rates, level of evidence poor.

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Treatment summary• JAK inhibitors seem to be most promising

• Higher doses – unknown safety • Combination therapy may be necessary – is effectiveness as great, then?

• Topical route likely better safety profile, but unknown benefit • Long term use likely necessary • Patients with longer duration of disease and more extensive disease still have poorer response

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Treatment summary• Other biologics may be helpful, but minimal data • Traditional therapies still reliable

• May take longer than many studies (>3 months)

• Camouflage options and support helpful either when treatments fail or while undergoing treatment

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Future

• Randomized controlled trials are needed. • Continue to improve studies on “old” treatments. • Clinical observation in conjunction with translational research can continue to help us better understand this disease.

• Patient-centered outcomes will be a focus.

Patient centered outcomes/research

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Macbeth et al, Establishing and Prioritising Research Questions for the Treatment of Alopecia Areata: The Alopecia Areata Priority Setting Partnership. Br J Dermatol 2016 [Epub ahead of print]