biologic therapies for hidradenitis suppurativa...1) infection risk (hbv, tb, and hiv screening) 2)...
TRANSCRIPT
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
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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
J Am Acad Dermatol. 2009;61(1):51-57.
Hurley Stage III
Multiple interconnected tracts and abscesses in an entire anatomic area
4% of patients
J Am Acad Dermatol. 2009;61(1):51-57.
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
N Engl J Med 2016; 375: 422–34.
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
N Engl J Med 2016; 375: 422–34.
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
J Am Acad Dermatol. 2010 Feb;62(2):205-17
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
J Dermatolog Treat. 2012;23:284-9.
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
Dermatology. 2013;226(2):97-100.Arch Dermatol. 2010;146;501-504.
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
BioDrugs. 2015 Aug;29(4):241-58.
1) Anti-drug antibody formation is at least somewhat common
TNF-α Inhibitors—Tips and Pearls
Drugs. 2017 Mar;77(4):363-377.
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
J Dermatol. 2010 Aug;37(8):708-13.
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)
Br J Dermatol 2016; 174: 839–46.
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
Br J Dermatol. 2018 Jul;179(1):182-185.Ann Dermatol. 2018 Aug;30(4):462-464.
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
J Am Acad Dermatol. 2019 Jan;80(1):80-88.
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
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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
49J Eur Acad Dermatol Venereol. 2015 Apr;29(4):619-44.
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
[email protected] of Pennsylvania