Biologic Therapies forHidradenitis Suppurativa

Robert G. Micheletti, MDAssistant Professor of Dermatology and MedicineCo-Director, Inpatient Dermatology Consult ServiceDirector, Hidradenitis Suppurativa Clinic, University of Pennsylvania

Learning Objectives

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• Review available evidence supporting the use of TNFα-inhibitors and other biologics for treatment of HS

• Discuss advanced treatment pearls relevant to the use of anti-TNFα therapy in HS

• Include biologic therapy as part of an algorithmic approach to HS treatment selection based on clinical severity, drug efficacy, and adverse effects

Pathogenesis

2

HS occurs due to a combination of environmental factors in a genetically susceptible individual

Exp Dermatol. 2012;21(10):735-739.

• Commensal microbes• Inflammatory peptides• Epidermal hyperplasia• Obesity / friction• Follicular occlusion• Cyst formation• Cyst rupture• Inflammation / foreign

body reaction• Bacterial colonization• Fistula tract formation• Chronic inflammation

Pathogenesis—the role of inflammation and host defenses

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• Increased production of oxygen free radicals • Enhanced expression of toll-like receptors and release

of pro-inflammatory cytokines• Increased tumor necrosis factor (TNF)-α expression• Activation of the interleukin-23 / T helper-17 pathway• Overproduction of interleukin-1β

Br J Dermatol. 2008;158(4):691-697.Br J Dermatol. 2011;164(6):1292-1298.

J Am Acad Dermatol. 2017;76(4):670-675.J Am Acad Dermatol. 2011;65(4):790-798.

Pathogenesis

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Autoimmune and autoinflammatorydisease spectrum

• Hidradenitis and pyoderma gangrenosum

Pathogenesis

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Autoimmune and autoinflammatorydisease spectrum

• Ankylosing spondylitis, hidradenitis, severe, acne, and pyoderma gangrenosum(PAPASH)

Pathogenesis

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Autoimmune and autoinflammatorydisease spectrum

• Hidradenitis and inflammatory bowel disease

Treatment—candidates for anti-TNFα therapy

An appropriate candidate for anti-TNFα therapy:• Has moderate or severe HS (Hurley II/III), AND

– Has either failed combination antibiotics (e.g., clinda/rifampin) or other therapies, OR

– Has disease which is severe or inflammatory enough to justify biologic therapy from the start

Hurley Stage II

Single or multiple separate, recurrent abscesses with sinus tract formation and scarring

28% of patients

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Hurley Stage III

Multiple interconnected tracts and abscesses in an entire anatomic area

4% of patients

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Severe inflammatory HS

A patient like this warrants biologic therapy from the start

Data Review—TNFα inhibitors

There have been many case series and studies exploring the efficacy of TNF inhibitors for HS

2013 systematic review of 65 studies (4 RCTs) suggested benefit from both infliximab and adalimumab, especially when administered in higher doses

J Dermatolog Treat. 2013 Oct;24(5):392-404.

Adalimumab 40mg• Phase II randomized, placebo-controlled trial of 154

patients with moderate to severe HS– Meaningful improvement* achieved in 17.6% (weekly) vs

9.6% (qow) vs 3.9% (placebo)

Significant improvements in HS are not seen with every other week dosing of adalimumab

Ann Intern Med. 2012 Dec 18;157(12):846-55.

Data Review—Adalimumab

Adalimumab 40mg weekly (following loading dose)• Two phase 3 RCTs (PIONEER I and II); together >600 patients

– I: Response* at 12 weeks 42% vs 26% for placebo– II: Response* at 12 weeks 59% vs 28% for placebo

Weekly adalimumab is effective, and adalimumab is now FDA-approved for HS based on these results

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Data Review—Adalimumab

Adalimumab 40mg weekly (continuation phase)

• Continued weekly adalimumab after week 12 is safe & effective

• Patients with response at week 12 may lose response by week 36 due to disease flare, though many subsequently regain it

Adalimumab is not perfect: not all respond, and those who do continue to have waxing and waning disease activity

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Data Review—Adalimumab

Adalimumab 40mg weekly (continuation phase)

• Many of those with partial response at week 12 achieve clinical response by week 36 with continued weekly adalimumab

• However, if there is no response at week 12, response is unlikely even with continued therapy

Partial improvement at week 12 justifies continued use, but if there is no improvement, it is probably time to move on

N Engl J Med 2016; 375: 422–34.

Data Review—Adalimumab

Data Review—Infliximab

Infliximab 5mg/kg (week 0, 2, 6, and every 8)• Double-blind prospective study of 38 patients with moderate to

severe HS– 27% versus 5% of those on placebo achieved > 50% improvement

at 8 weeks* (not statistically significant)– Moderate or significant (> 25%) improvement in 87% of treated

patients versus 11% of placebo group– DLQI, global assessment, pain, visual analog improved significantly

Evidence for efficacy despite minimal dose & duration of therapy

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Infliximab vs adalimumab:• Retrospective study of 2 cohorts of 10 patients:

– Infliximab 5mg/kg at weeks 0, 2, 6– Adalimumab 40mg every other week– Followed for one year

• Both groups improved, but the Sartorius score decreased more in the infliximab group

Note dosing issues; need comparative studies using optimal dosing regimens and the same validated outcome measures

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Data Review—Infliximab vs Adalimumab

• Adalimumab: – Need for higher dosing, at least double that for psoriasis – 160mg at week 0, 80mg at week 2, 40mg weekly beginning

at week 4

• Infliximab: – Weight-based dosing may be an advantage – In my experience, patients may respond to 5mg/kg q8

week dosing (after loading) but frequently need uptitration• Often 7.5mg/kg every 6-8 weeks, but can go up to 10mg/kg q4wConsider in the patient who flares just before infusion is due

Dosing Issues

• Infliximab– Recent abstract in fact suggests a higher starting dose

yields greater response– Dose increases generally result in improved symptoms

More often than not, I start infliximab at 7.5mg/kg for HS, if I can get it approved, especially if more severe & inflammatory

Dosing Issues

Ghias et al. Symposium on Hidradenitis Suppurativa Advances, 2018.

Other TNF Inhibitors…

Etanercept (50mg weekly or twice weekly)• Two small prospective studies vs placebo failed to

demonstrate significant improvement• Not recommended based on current evidence

Golimumab (Simponi)• Two case reports only; one positive, one negative

Certolizumab (Cimzia)• No reports; anecdotally, may have some benefit

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J Am Acad Dermatol. 2009;60:565-573.Dig Liver Dis. 2016 Dec;48(12):1511-1512.

TNF-α Inhibitors—Tips and Pearls

Special considerations:

1) Infection risk (HBV, TB, and HIV screening)2) If one TNF inhibitor fails, another might work3) Anti-drug antibody formation4) Combination therapies for added efficacy5) Work with colleagues from other specialties to address

drug choice and dosing issues6) Backing off or stopping treatment

TNF-α Inhibitors—Tips and Pearls

Anti-Drug Antibodies• Immune response stimulated by the presence of foreign

antibodies (infliximab or adalimumab) Can be responsible for waning efficacy (consider in the

patient who no longer seems to be responding)

TNF-α Inhibitors—Tips and Pearls

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1) Anti-drug antibody formation is at least somewhat common

TNF-α Inhibitors—Tips and Pearls

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2) Anti-drug antibody formation is more likely to occur when treatment is interrupted

TNF-α Inhibitors—Tips and Pearls

3) Co-administration of immunosuppressants (MTX, AZA) leads to less ADA formation and higher drug levels

Drugs. 2017 Mar;77(4):363-377.

TNF-α Inhibitors—Tips and Pearls

Anti-Drug Antibodies—treatment strategy• Attend to adherence issues and dosing frequency to minimize

risk of antibody formation• Suspect ADA formation when a biologic which was working

previously suddenly seems to stop working• Test for antibodies (provides ADA titer as well as drug level)• Add ~7.5mg/week methotrexate to counteract ADA formation

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Case Example

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60yo man

Hx severe acne, recurrent boils

Rapidly worsening, erosive lesions

Case Example

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Positive QuantiferonGold, no active TB on CXR

Rifampin + clinda

Then…Infliximab

Case Example

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Infliximab response waning

HACA positive

MTX added (7.5mg/week)

Improvement resumed

Fibrous tissue excised

24yo mother with severe, debilitating HS

Other Biologics

Ustekinumab:• 17 patient prospective study: 45 or 90 mg ustekinumab every

12 weeks (after loading)• Response by HiSCR in 47% of patients

My experience has been underwhelming; have tried dose as high as 90mg every 8 weeks (Crohn’s dosing)

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Other Biologics

Anakinra:• 20 patient randomized controlled trial• 78% response by HiSCR vs 30% placebo

I have not personally seen a significant response among the patients with severe HS I have treated with anakinra

JAMA Dermatol. 2016 Jan;152(1):52-59.

Other Biologics

Anti IL-17 drugs:• Single case reports of efficacy for severe HS (sekukinumab)• Now in clinical trials

Limited experience; I have treated only one HS patient with sekukinumab

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Acta Derm Venereol. 2018 Jan 12;98(1):151-152.

Other Biologics

Apremilast 30mg twice daily• 20 patients with moderate HS randomized 3:1 versus placebo• HiSCR met in 8 of 15 (53%) of treated patients compared to 0

of 5 (0%) of placebo (p=0.055) at week 16

Results not necessarily spectacular or universal, but it is helpful to have another potential option in a different class

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Other Biologics

There are now clinical trials in hidradenitis for:• IL-17 inhibitor• IL-23 inhibitor• IL-1a inhibitor• Anti-CD-40 monoclonal antibody• C5a receptor inhibitor• JAK inhibitor

clinicaltrials.gov

Combination therapies

Improvement on a biologic doesn’t necessarily mean cure, at least not yet

Avail yourself of other effective therapies in addition to the biologic to get closer to goal

Combination therapies

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55yo woman with longstanding severe HS

Severe infusion reactions on infliximab

Notably improved but still disease activity on adalimumab

Added spironolactone, then doxycycline to adalimumab

Surgical modalities, topicals, ILK, smoking cessation

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Combination therapies

Adalimumab, spironolactone, smoking cessation

Prednisone / systemic steroids:• Not a good long-term solution due to side effects• Published data are minimal and not compelling, mostly because

series report long-term response

• Might calm inflammation in the acute setting, however– Consider prednisone ~20-30mg/day tapered over 2-3 weeks for

an acute flare or overlapping with initiation of a new therapy

This is particularly relevant for patients with severe inflammatory HS, especially when switching among biologics

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Combination therapies

Work with colleagues to manage complex patients• Need to consider other disease states, comorbidities, drug-

drug interactions• As the skin expert, we are often in a position of educating

Working with colleagues

Working with colleagues

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20yo woman with severe Crohn’s and hidradenitis

If a TNF inhibitor is ineffective or poorly tolerated, what’s next?

Another anti-TNF?Ustekinumab?Anakinra?Combination antibiotics?Surgery?

Vedolizumab (Entyvio) has negligible efficacy for IBD-associated cutaneous disease

Working with colleagues

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50yo woman with end-stage renal disease, well-controlled HIV, severe HS, inflammatory arthritis, and pyoderma gangrenosum-like lesions

Care coordination:• Educating transplant team• Working with infectious

diseases, rheumatology• Making sensible drug choices

• Drug interactions• Immunosuppression

De-escalating therapy

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HS is a systemic inflammatory disease

Severe HS should be thought of like RA, IBD in this respect

We don’t stop DMARDs in these diseases as soon as we achieve disease control

Probably shouldn’t be different in severe HS

De-escalating therapy

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For milder HS, I tell patients the disease may eventually burn out

If doing well for ~6-12 months on a regimen, consider stepping back down the treatment ladder

Patients may have quit smoking or lost weight, and this also can help lessen the need for intervention

Evidence-Based Treatment Approach

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Hurley Stage I

Topical clindamycin

Benzoyl peroxide

wash

Mini Unroof,Nd:YAG

Systemic Abx(usually

doxycycline)

Evidence-Based Treatment Approach

46

Topical clindamycin

Benzoyl peroxide

wash

Systemic Abx(clinda + rifampin)

Hurley Stage II

+/- Hormonal therapies

Deroofing,CO2 Laser

Mini Unroof,Nd:YAG

Evidence-Based Treatment Approach

47

Topical clindamycin

Benzoyl peroxide

wash

Surgical excision

Infliximab orAdalimumab

+/- Hormonal therapies

Hurley Stage III

Other Abxcombinations

Systemic Abx(clinda + rifampin)

OR

Hurley Stage III

Anakinra or ustekinumab

Evidence-Based Treatment Approach

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Hurley Stage I

Lifestyle modifications

Hurley Stage IIHurley Stage II Hurley Stage III

Pain control Emotional support

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European Guidelines

Summary

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• TNFα-inhibitors are the most potent medical therapies currently available for moderate / severe hidradenitis

• Appropriate dosing of the drug and regular re-assessment and trouble-shooting are essential for success

• Other biologics may be beneficial, but more data are needed

• Despite the challenges, we should believe we can make almost any patient better there is hope

• With the current interest in HS and new clinical trials, perhaps the future will bring therapies with HiSCR 75 or 100…

The Dermatology Foundation

has supported & advanced my career

Thank you

Robert.Micheletti@uphs.upenn.eduUniversity of Pennsylvania