TEN, SJS, EM, BP, PV Pearls

Jacob Levitt, MD, FAAD�Professor, Vice Chair, Program Director

The Mount Sinai Medical Center, New York, NY

Disclosures

• I have served on Advisory Boards for:
• Amgen
• Janssen Biotech
• Genentech
• Medac
• Ranbaxy
• Pfizer
• Promius
• Castle Biosciences Inc.
• I have been a Consultat for:
• Novartis

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• My talk will contain off-label uses of most drugs mentioned.

Toxic Epidermal Necrolysis

SJS

TEN: natural history

• Mortality rate: 25-35%
• Fas-FasL 🡪 caspases 🡪 apoptosis
• TNF within lesional skin 🡪 activates apoptosis
• Healing within 3 weeks for untreated survivors

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Current Therapeutic Options

• STOP OFFENDING DRUG
• Supportive care
• wound dressings, ophthalmology, fluids/electrolyte balance, airway, renal function, nutrition, pain control, and prevention of infection
• Cyclosporine 3-5mg/kg/d p.o.
• IVIg 2g/kg i.v. over 3-5 days (data conflicting)
• Infliximab 5mg/kg i.v. once
• Etanercept 50mg s.c. once

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• Prednisone?
• Perhaps with liver involvement (DRESS)
• NOT thalidomide

Cyclosporine for TEN

• Open trial of ciclosporin treatment for Stevens-Johnson syndrome and toxic epidermal necrolysis.
• Valeyrie-Allanore L, et al. Br J Dermatol. 2010 Oct;163(4):847-53.

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7 TEN patients

Cyclosporine 3mg/kg x 10 days, then taper x 1 month

Re-epithelialization 7-25 days

IVIg for TEN

• High-dose intravenous immunoglobulin for severe drug reactions: efficacy in toxic epidermal necrolysis
• E. Campione, et al. Acta Derm Venereol. 2003;83(6):430–432.

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• 10 TEN patients
• IVIg 400mg/kg qd x 5 days
• Re-epithelialization: 24-40 days, 1 death
• Other studies 🡪 equipoise as to its benefit

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Infliximab for TEN

• Antitumour necrosis factor-alpha antibodies (infliximab) in the treatment of a patient with toxic epidermal necrolysis.
• Fischer M, et al. Br J Dermatol. 2002 Apr;146(4):707-9.

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• Rapid resolution of toxic epidermal necrolysis with anti-TNF-alpha treatment.
• Hunger RE, et al. J Allergy Clin Immunol. 2005 Oct;116(4):923-4.

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• Each 1 case; infliximab 5mg/kg i.v. once; re-epithelialization in 5 days

Etanercept for TEN

• Etanercept therapy for toxic epidermal necrolysis.
• Paradisi A, et al. J Am Acad Dermatol. 2014 Aug;71(2):278-83.

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• 10 TEN patients
• Treated within 72 hours
• Etanercept 50mg s.c. once
• Re-epithelialization: 8.5days (7-20 range)

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Thalidomide NOT for TEN

• Randomised comparison of thalidomide versus placebo in toxic epidermal necrolysis.
• Wolkenstein P¹, et al. Lancet. 1998 Nov 14;352(9140):1586-9.

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• Thalidomide 400mg po qd x 5 days
• 10/12 patients died in active vs. 3/10 in placebo

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Bonus: Etanercept for GVHD

• Etanercept for steroid-refractory acute graft versus host disease following allogeneic hematopoietic stem cell transplantation.
• Park JH, et al. Korean J Intern Med. 2014 Sep;29(5):630-6.

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• 18 patients
• Etanercept 25mg s.c. b.i.w. x 4 weeks
• Partial responses for GVHD in skin and gut, but not liver
• 4 patients died of infections

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Erythema Multiforme

Etiologies:

• Herpes simplex*
• Drug
• Mycoplasma
• Orf
• Histoplasma capsulatum

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*HAEM = herpes-associated EM

EM: Therapeutic Options

• Antivirals (valacyclovir, acyclovir, famciclovir)
• Prednisone
• Anti-TNF: Etanercept, Thalidomide, Adalimumab
• Cyclosporine
• Apremilast
• Dapsone, SSKI
• others

My approach:

• First Episode:
• Prednisone ~1mg/kg taper
• 60mg for 3d, taper by 10mg q2d
• Recurrent:
1. Check HSV 1 and 2 IgG titers (sensitive, not specific for HAEM)
2. Famciclovir
3. Apremilast
4. Thalidomide
5. Etanercept
• Maintenance: famciclovir
• Last resort: cyclosporine

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Famciclovir for EM

• Famciclovir for recurrent herpes-associated erythema multiforme: a series of three cases.
• J Am Acad Dermatol. 2014 Oct;71(4):e146-7.
• Routt E¹, Levitt J².

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• All failed valacyclovir but responded to famciclovir

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50 year old female with bullous erythema multiforme, �+ HSV2 IgG

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Things she tried over 15 years with HAEM

• Mycophenolate mofetil
• Cyclosporine
• Long term prednisone 🡪 Cushingoid and osteoporosis
• Methotrexate
• Adalimumab
• IVIg
• Acyclovir
• Valacyclovir
• Doxycycline
• Hydroxychloroquine
• Oxycodone
• Hydroxyzine

Patient cleared after….

• Famciclovir 500mg po tid
• Now maintenance of Famciclovir 500mg po qd

Apremilast for HAEM

• Apremilast for treatment of recurrent erythema multiforme.
• Dermatol Online J. 2017 Jan 15;23(1).
• Chen T¹, Levitt J, Geller L.

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Refractory Recurrent Erythema Multiforme Major

Failed:

• Prednisone
• IVIg
• Cyclosporine

Apremilast 45mg/day helped a lot!!! ☺

21 y.o. AA F, recurrent erosions x 10 years

• Diagnosed as Behçet’s, probably was HAEM

Within ONE WEEK of apremilast 30mg po bid!

I didn’t dose titrate – just go for it full dose and it works when you get to 1mg/kg-ish; she requires maintenance 30mg po bid

HAEM �before therapy

Four days after apremilast 30mg po bid�(no up-titration)

Another patient: Weaned off several years of prednisone, s/p rituximab and IVIg for presumed pemphigus:

Resolved with:

famciclovir 🡪 helped but recurred; �

etanercept 🡪 helped but recurred;

�thalidomide 50mg po qd 🡪 cleared her ☺

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Then wanted to get pregnant…off thalidomide flared…. ☹

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Apremilast worked!

Cyclosporine 5mg/kg/d also worked while trying to get pregnant, tapered to 2-3mg/kg/d

Hypothesis!

• Could Apremilast work for SJS/TEN?
• How could we test ethically?

Bullous Pemphigoid: �some diagnostic and therapeutic points

Do you screen for cancer in BP?

• early-onset pemphigoid
• former oncological history
• signs and symptoms of neoplasm
• BP refractory to common immunosuppressive therapy

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Ref: J Dermatol. 2016 Feb;43(2):125-33.

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BP: do we need to biopsy?

• Sensitivity and specificity of BP180 NC16A enzyme-linked immunosorbent assay for the diagnosis of pemphigoid gestationis
• J Am Acad Dermatol. 2017 Mar;76(3):560-562.
• Al Saif F¹, Jouen F², Hebert V¹, Chiavelli H², Darwish B³, Duvert-Lehembre S¹, Joly P⁴; French Study Group on Autoimmune Bullous Skin Diseases.

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• 97% sensitive
• 100% specific
• Can avoid biopsy when ruling out PUPPP vs. PG

Must we biopsy an elderly patient with blisters with (+) BP180 or BP230 serology?

• If serology is (-), biopsy for BP or LABD or EBA or MMP (among others)
• If serology is (+), treat for BP
• Specificity is 98.9%

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• BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid.

J Dermatol Sci, 30 (2002), pp. 224–232.

M. Kobayashi, M. Amagai, K. Kuroda-Kinoshita, et al.

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BP Therapy

• Prednisone taper 60mg x 3d, taper by 10mg q2d
• Doxycycline 100mg bid + niacinamide 750mg bid
• Clobetasol ointment bid to lesions

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• If that fails and it’s extensive….

BP Therapy: don’t exclude rituximab!

• Think about rituximab early
• 1g on Week 0 & 2

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• First-line combination therapy with rituximab and corticosteroids provides a high complete remission rate in moderate-to-severe bullous pemphigoid.

Br J Dermatol. 2015 Jul;173(1):302-4.

Cho YT, Chu CY, Wang LF.

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Pemphigus vulgaris

Pemphigus vulgaris: what’s new?

• FDA granted breakthrough therapy status to rituximab for PV March 23, 2017

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• First-line rituximab combined with short-term prednisone versus prednisone alone for the treatment of pemphigus (Ritux 3): a prospective, multicentre, parallel-group, open-label randomised trial.

Lancet. 2017 Mar 22. pii: S0140-6736(17)30070-3.

Joly P, et al. French study group on autoimmune bullous skin diseases.

• At month 24, 41/46 (89%) R + P vs. 15/44 (34%) P alone
• Prednisone 1mg/kg x 3-6 months
• Side effects in both groups relate to steroids: diabetes, myopathy, bone disorders

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Rituximab dosing choices

• 1g at week 0 and 2 = 2.0g total

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• 375mg/m² x 4 doses = 2.8g total*

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*For 70kg male, 5’10”, BSA = 1.87m²: 375mg/m² x 1.87m² =

701.25mg x 4 = 2.8g

• Du Bois formula: BSA = 0.007184 × W^0.425 × H^0.725
• Du Bois D, Du Bois EF (Jun 1916). "A formula to estimate the approximate surface area if height and weight be known". Archives of Internal Medicine 17 (6): 863-71. PMID 2520314. Retrieved 2012-09-09.

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PV: what I do when Rituximab 1g wk 0 and 2 fails

First line for me:

• Rituximab 1g Week 0 & 2 plus Prednisone 60mg qd x 3d, taper by 10mg q2d (truly rapid taper)

If this fails:

• Repeat rapid prednisone taper +/- keep patient on 10mg until resolution
• Add IVIg 2g/kg/month

If this fails:

• Add mycophenolate mofetil 2g/d
• Prednisone 60mg for one week, taper by 10mg per week

If this fails:

• Repeat Rituximab (sometimes early at month 4) and do 375mg/m² q week x 4 weeks

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What’s in the Pemphigus Pipeline?

• Immunosuppressants
• Anti-CD20 molecules
• Novel immune targets
• CAAR T cell approach

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Sirolimus for acute pemphigus vulgaris

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• Sirolimus 2mg/d (after 6mg loading dose) and IVIg 2g/kg/months x 8 months

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• Sirolimus for acute pemphigus vulgaris: A case report and discussion of dualistic action providing for both immunosuppression and keratinocyte protection.
• Grando S, et al. J Am Acad Dermatol. Sept 2011, p.684.

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Anti-CD 20 monoclonal antibodies �(repurposing leukemia/lymphoma drugs)

• Veltuzumab: Two 320-mg subcutaneous doses 2 weeks apart; more potent than rituximab in non-Hodgkin’s lymphoma (one patient)
• Ellebrecht CT, et al. Subcutaneous veltuzumab, a humanized anti-CD20 antibody, in the treatment of refractory pemphigus vulgaris. JAMA Dermatol, 150 (2014), pp. 1331–1335.
• Ofatumumab: anti-CD20 mAb, 40mg sc q month, Phase III in PV ongoing

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• Obinutuzumab (GA-101): engineered anti-CD20 mAb with 50-fold higher binding affinity and resultant 10- to 100-fold efficacy against target B cells than nonmodified antibodies
• Ocaratuzumab (AME-133v): anti-CD20 mAb
• PRO131921: anti-CD20 mAb

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Novel Immune Targets�(initially for RA, lupus)

• Naïve B cell --//🡪 plasma cell
• Belimumab (GSK): anti-BAFF
• Blocks the cytokine
• BAFF = B cell activation factor; aka B Lymphocyte Stimulator (BLyS)
• VAY-736 (MorphoSys; Novartis): anti-BAFF-R
• Blocks the receptor
• BAFF-R = B cell activation factor receptor; aka B Lymphocyte Stimulator) mAb
• Block B cell receptor signaling
• PRN1008 (Principia Biopharma): oral, reversible covalent Bruton’s Tyrosine Kinase (BTK) inhibitor
• Involved in B cell receptor signaling during normal B-cell development and activation
• Block FcRn function
• SYNT001 (Syntimmune): blocks neonatal Fc receptor (FcRn) function
• FcRn prolongs half-lives of IgG
• Allows accelerated catabolism of pathogenic anti-dsg IgG

BAFF / BAFF-R inhibition

• Apoptosis of autoreactive B cells
• ↓ B cell differentiation

Novel Immune Targets�(initially for RA, lupus)

• Naïve B cell --//🡪 plasma cell
• Belimumab (GSK): anti-BAFF
• Blocks the cytokine
• BAFF = B cell activation factor; aka B Lymphocyte Stimulator (BLyS)
• VAY-736 (MorphoSys; Novartis): anti-BAFF-R
• Blocks the receptor
• BAFF-R = B cell activation factor receptor; aka B Lymphocyte Stimulator) mAb
• Block B cell receptor signaling
• PRN1008 (Principia Biopharma): oral, reversible covalent Bruton’s Tyrosine Kinase (BTK) inhibitor
• Involved in B cell receptor signaling during normal B-cell development and activation
• Block FcRn function
• SYNT001 (Syntimmune): blocks neonatal Fc receptor (FcRn) function
• FcRn prolongs half-lives of IgG
• Allows accelerated catabolism of pathogenic anti-dsg IgG

Bruton’s Tyrosine Kinase (BTK) inhibitor

Accessed from: https://healthunlocked.com/cllsupport/posts/130023667/novel-bruton’s-tyrosine-kinase-btk-inhibitor-ono-4059-enters-uk-cll-clinical-trial [May 28, 2017]

• Block BCR signaling
• Induce B-cell apoptosis

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Novel Immune Targets�(initially for RA, lupus)

• Naïve B cell --//🡪 plasma cell
• Belimumab (GSK): anti-BAFF
• Blocks the cytokine
• BAFF = B cell activation factor; aka B Lymphocyte Stimulator (BLyS)
• VAY-736 (MorphoSys; Novartis): anti-BAFF-R
• Blocks the receptor
• BAFF-R = B cell activation factor receptor; aka B Lymphocyte Stimulator) mAb
• Block B cell receptor signaling
• PRN1008 (Principia Biopharma): oral, reversible covalent Bruton’s Tyrosine Kinase (BTK) inhibitor
• Involved in B cell receptor signaling during normal B-cell development and activation
• Block FcRn function
• SYNT001 (Syntimmune): blocks neonatal Fc receptor (FcRn) function
• FcRn prolongs half-lives of IgG
• Allows accelerated catabolism of pathogenic anti-dsg IgG

Neonatal Fc receptor (FcRn) �Prevents Degradation of IgG:

• Found in endothelial cell membranes
• Responsible for IgG recycling
• Binds Fc portion of:
• Anti Dsg 3 IgG
• IVIG

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Pemphigus autoantibodies

P

P

P

P

P

Ig

Ig

Ig

Ig

P

P

P

P

Ig

P

P

🡻 [P]

Competitive binding at FcRn

P

P

P

Chimeric Antigen Receptor T cells �(CAR T Cells)

• Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease.
• Science. 2016 Jul 8;353(6295):179-84.
• Ellebrecht CT¹, Bhoj VG², Nace A¹, Choi EJ¹, Mao X¹, Cho MJ¹, Di Zenzo G³, Lanzavecchia A⁴, Seykora JT¹, Cotsarelis G¹, Milone MC⁵, Payne AS⁶.

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• Manipulate T cells that kill B cells
• Engineered human T cells to express a chimeric autoantibody receptor (CAAR)
• Dsg 3 fused to CD137-CD3ζ signaling domains
• Dsg3 CAAR-T cells kill cells expressing anti-Dsg3 B-cell receptors

CAAR T cells for PV

His Name is Hazel ☺