Problem Cases of Rosacea

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Problem Cases of Rosacea
AAD 20 min

• Diane M. Thiboutot, M.D.
• Professor of Dermatology
• The Pennsylvania State University
• College of Medicine
• Hershey, PA

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Disclosure

• Clinical trials investigator and consultant
• Galderma
• Intendis

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Why is rosacea so hard to manage?

• Diagnostic challenge
• Acne, perioral dermatitis, seb derm, SLE,
  photodamage
• Childhood rosacea?
• Varied appearance
• Different subtypes
• Varying skin types
• Limited understanding of pathophysiology
• Effective therapies against some but not all
  features of the disease

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Rosacea Etiology

• Unknown, controversial aspects
• Genetics
• Helicobacter pylori
• Demodex folliculorum
• Oxygen free radicals
• P. acnes?
• Bacterial antigens (Bacillus oleronius)
• Increased activity of kallikrein 5
• Photodamage/ new vessel formation

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Altered innate immune defense in rosacea skin

• Rosacea patients have increased cathelicidin
  expression
• Increased levels of pro-inflammatory LL-37 and
  unique peptides vs. normals
• Increased activity of kallikrein 5 (SCTE) that
  processes the pro-cathelicidin
• In mice, injection of peptides, SCTE increases
  skin inflammation

Yamasaki K et al. Nature Medicine 13 975-980,
2007
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Proteolytic processing of peptides
Bevins et al. Nature Med 13904,2007

• Normal Rosacea
• Cathelicidin precursor Cathelicidin precursor

SCTE (Klk5)
SCTE (Klk5)
LL-37 and variant peptides
LL-37
Angiogenic
Proinflammatory activities
Chemotactic
Bactericidal
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Photodamage and new vessel formation

• Endothelial cells placed in a matrix of damaged
  collagen will form tubular structures
• These data suggest that damage to collagen (such
  as photodamage in rosacea) can induce new vessel
  formation (telangiectasia)

Varani, Perone, Warner, Dame, Kang, Fisher,
Voorhees. Br J Cancer 98 1646-1652, 2008
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Clinical Presentations of Rosaca
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Therapeutic Options in Rosacea
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Oral Therapies
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Oral Therapies

• Inflammatory lesions, ocular rosacea
• Tetracyclines
• Minocycline, doxycycline
• Metronidazole
• Anti-inflammatory dose doxycycline
• Flushing
• Beta blockers
• Clonidine
• Extreme or recalcitrant cases
• Isotretinoin (variable duration of effect)

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Anti-inflammatory mechanisms of tetracyclines

• Downregulate proinflammatory cytokines and
  metabolites of arachidonic acid
• Inhibit angiogenesis, reactive oxygen species,
  neutrophil chemotaxis and matrix
  metalloproteinases (tissue remodeling)

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Pharmacokinetics Anti-inflammatory dose
doxycycline
16 healthy adult subjects per arm mean weight
75 kg Measured at 7 days
Data on file, CollaGenex Pharmaceuticals, Inc.
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Isotretinoin and rosacea

• Has been used
• Results are often not long-lasting
• Beneficial in rosacea varients

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Topical therapies
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Topical Agents

• Primary1
• Metronidazole
• Azelaic acid
• Sodium sulfacetamide and sulfur
• Secondary
• Clindamycin
• Erythromycin
• Benzoyl peroxide
• Other agents (e.g., tretinoin, tacrolimus,
  pimecrolimus) have been used

Not approved for the treatment of rosacea
1. Nally JB, Berson DS. J Drugs Dermatol.
20065(1)23-26.
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Metronidazole Gel 1 Phase III Study Reduction
in Inflammatory Lesions
p.0001 vs. Vehicle
Median Reduction
10 weeks
Data on File Study Report 0215-R5.C-01-02
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Azelaic Acid (Finacea) Percent Change in
Inflammatory Lesion Count
Weeks
Thiboutot D et al. J Am Acad Dermatol.
200348836-845.
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Physical Therapies
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Therapies for Erythema/Telangiectasia

• Oral and topical medications are ineffective
• Laser/light therapies

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Light Sources in Rosacea

• Monochromatic
• KTP 532 nm
• PDL 585-595 nm
• CO2 10,600 nm
• Polychromatic
• IPL 515-1200 nm

• Rosacea features
• Telangiectasia, erythema
• Telangiectasia, erythema
• Phymas
• Telangiectasia, erythema

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Therapies for Rhinophyma

• Excision
• Carbon dioxide laser
• Cauterizing scalpel (Shaw scalpel)
• Combination

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Agents reported (off-label) in rosacea

• Oral ivermectin
• Topical permethrin
• Topical pimecrolimus
• Photodynamic therapy (methyl ALA/red light)
• Azithromycin
• Oxymetazoline (a1 adrenergic agonist)

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Managing Difficult Cases
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Possible future treatments

• Improved laser/light protocols
• Agents for erythema
• COL 118 (brimonidine)
• Topical ivermectin
• Topical dapsone
• Agents targeting cathelicidin peptides/kallikrein
  protease inhibitors

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Rosacea vs. acne
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Rosacea/seborrheic dermatitis
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Granulomatous Rosacea
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Rosacea with solid facial edema
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Two Types of Edema

• Transient, post-flushing soft edema
• Subtle
• Variable
• Over primarily inactive facial musculature
• Long-lasting, hard, non-pitting
• Solid facial edema

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Rosacea fulminans/ pyoderma faciale
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Ocular rosacea
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Ocular Rosacea (Blepharitis)

• Watery or bloodshot appearance
• Foreign body sensation
• Burning or stinging
• Dryness
• Itching
• Light sensitivity
• Blurred vision
• Telangiectases of the conjunctiva and lid margin

• Lid and periocular erythema
• Blepharitis
• Conjunctivitis
• Irregularity of eyelid margins
• Meibomian gland dysfunction
• May occur before, with, or following cutaneous
  signs and symptoms

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Ocular rosacea recommendations

• Lid hygiene
• Warm soaks
• Removal of crusts (baby shampoo)
• Artificial tears
• Ophthalmic preparations
• Cyclosporine (Restasis)

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