Skin Manifestations of Scleroderma

Lorinda Chung, MD, MSStanford University School of Medicine

March 9, 2013

Overview

• Skin tightening• Digital ulcers• Paronychia• Calcinosis• Telangiectasias• Hypo-/hyperpigmentation• Lipodermatosclerosis

Scleroderma=hardening of the skin

• Localized Scleroderma– Morphea– Linear Scleroderma

• Systemic Sclerosis– Diffuse– Limited (CREST)– Sine scleroderma– Overlap Syndrome/MCTD

Systemic Sclerosis: Subsets

• Diffuse– Skin thickening: face, trunk, entire arms/legs, hands and

feet; tendon friction rubs– Rapid onset following RP: months to 3 yrs– Early internal organ dz– Association with anti-Scl-70 Ab– 10-yr survival 40%

• Limited– Skin thickening: face, forearms, lower legs, hands and

feet– Progressive dz following onset of RP– Late internal organ dz– Association with anti-centromere Ab– 10-yr survival >70%

Systemic Sclerosis: CREST

• Calcinosis• Raynaud’s• Esophageal

Dysmotility• Sclerodactyly• Telangiectasias

Skin Thickening in Systemic Sclerosis

• Modified Rodnan Skin Score– Validated measure of skin thickening used in clinical trials– Correlates with internal organ involvement and survival in

diffuse patients– Thickening assessed in 17 body areas: face/neck, anterior

chest, abdomen and bilateral fingers, dorsal hands, forearms, upper arms, feet, lower legs, and thighs

– Each area scored and summed for total score (0-51):• 0=normal• 1=mild thickening• 2=moderate thickening, unable to move• 3=hidebound, unable to pinch

Natural History of Skin Tightening in Systemic Sclerosis

Medsger Rheum Dis N Am 2003;29(2):255-73.

Different Rates of Skin Thickness Progression in Anti-Scl70+ SSc Patients

Perera et al. Arthritis Rheum 2007;56(8):2740-6.

Rapid Skin Thickness Progression Associated with Poorer SurvivalIn Anti-Scl-70+ SSc Patients

Perera et al. Arthritis Rheum 2007;56(8):2740-6.

Potential Treatments for Skin Tightening

• Target growth factors involved in scar tissue formation– Imatinib– Dasatinib

• Target T Cells/Cytokines (Inflammatory cells)– Methotrexate– IVIG– Mycophenolate mofetil*– Cyclophosphamide– Stem cell transplant*– Abatacept (CTLA4 Ig)**– Anti-Interferon antibodies– Anti-IL-6 antibody**

• Anti-fibrotics: breakdown scar tissue or block collagen production– Halofuginone– Antibody to Connective Tissue

Growth Factor– Statins– Pirfenidone (in trials for IPF)– Anti-transforming growth

factor-beta antibody– LPA-1 receptor antagonist*

• Target B Cells/AutoAb– Rituximab**– Anti-BLyS (LymphoStat-B)– Anti-CD19 mAb (completed trial)

*Ongoing clinical trials**Clinical trials available or soon to be available at Stanford

Scleroderma Digital Ulcers• Occur in up to 50% of patients with limited or

diffuse scleroderma.• Can occur at tips of digits or overlying joints.• Painful and heal slowly.• Complications include:

– Functional disability and immobility– Scarring and loss of distal tissue (ie. fingertip)– Infection (osteomyelitis)– Can progress to gangrene (dead tissue)

Chung and Fiorentino. Autoimmun Rev 2006;5:125-8.

Scleroderma Digital Ulcers

Causes• Vasospasm (RP)• Vasculopathy• Thrombosis (Clot)• Calcinosis (Limited)• Repeated trauma• Tight skin overlying

joints

Scleroderma Vascular Disease

Scleroderma Digital Ulcers

• Risk Factors– Male sex– Presence of pulmonary arterial hypertension– Severe involvement of the esophagus– Diffuse skin involvement (only when PAH present)– Young age at onset of RP– Elevated sedimentation rate

Sunderkotter et al. Br J Dermatol 2009;160:835-43.

Scleroderma Digital Ulcers

Kahaleh Rheum Dis Clin N Am 2008;34:57-71.

DU present

DU in past Multiple & severe DU

YESNO

Avoid cold, stress, trauma*Smoking cessation*Treat RP CCB a-adrenergic blockers Nitrates ACE-inhibitors ARB SSRIASA*Statins

StatinsCCBPDE5-inhibitorsET-receptor blockers

NO NOYES YES

Hydrocolloid occlusionOTC pain medsWound careTreat infectionsHi dose CCBPDE5-inhibitorsET-receptor blockersCilostazol

Prostacyclins (IV/SQ)AnticoagulantsCilostazol/pentoxifyllineNarcoticsWound careTreat infectionsConsider digital or cervical sympathectomy

* All patients should be educated to avoid cold, stress, trauma, and nicotine. Aspirin 81mg daily should be considered for all patients who do not have a contraindication.DU=digital ulcers; RP=Raynaud’s phenomenon; CCB=calcium channel blockers; ACE=angiotensin converting enzyme; ARB=angiotensin II receptor blocker; SSRI=selective serotonin reuptake inhibitor; ASA=aspirin; PDE5=phosphodiesterase-5;ET=endothelin; OTC=over the counter; IV=intravenous; SQ=subcutaneous.

Algorithm for the treatment and prevention of digital ulcers in systemic sclerosis.

Paronychia• Skin infection that occurs

around the nails, presenting as painful, red, swollen area around the nail.

• Usually caused by breach in skin barrier.

• Infection can be due to bacteria, yeast, or fungus.

• Prevalence and incidence in scleroderma patients unknown.

Paronychia

• Treatment– Acute

• Antibiotics• Possible incision/drainage

– Chronic• Antifungal medication• Topical corticosteroids

• Prevention– Minimize exposure to

wet environment– Avoid trauma to nails or

fingertips– Bring your own tools to

nail salons– Do not trim cuticles or

use cuticle removers– Use aquaphor or

vaseline around cuticles

Calcinosis

• Calcium deposits under the skin.• Can occur in limited or diffuse skin disease, usually a sign of damage.• Common locations: hands, arms, elbows, knees, trunk• Can be nodular or plaque-like

Calcinosis

• Assessment of calcinosis:• X-rays: lesions on extremities• CT: lesions on trunk/plaque-like lesions• Ultrasound: experimental

Calcinosis: Treatments

• Not very effective: warfarin, probenecid, colchicine, alendronate

• Some efficacy: calcium channel blockers, minocycline (especially if inflammation present)

• Often successful: surgical removal– Not all lesions are accessible for surgery– Can recur

Telangiectasias

• Small dilated blood vessels near the surface of the skin.• Matted or square-like appearance in patients with scleroderma.• Can be seen in limited or diffuse disease, usually a sign of damage.• Common locations: hands/fingers, oral mucosa, face, chest, arms

• Others: over joints, periungual (around nail)

Telangiectasias

Telangiectasias

• Clinical Associations:– Older age– African-Americans less likely to develop– Former or current smoking– Longer disease duration– Increased risk for pulmonary arterial hypertension

Shah et al. J Rheumatol 2010;37(1):98-104.

Shah et al. J Rheumatol 2010;37(1):98-104.

Shah et al. J Rheumatol 2010;37(1):98-104.

*12.4X increased odds of PAH for every 10-point increase in telangiectasia score (p=0.01)

Telangiectasias: Treatment

• 585 nm flashlamp pulsed dye laser– 1-4 treatments in 8 scleroderma patients– No scarring or pigmentary changes post-treatment– Did not recur during follow-up of 6 months to 2

years

Ciatti et al. J Am Acad Dermatol 1996;35:487-8.

Ciatti et al. J Am Acad Dermatol 1996;35:487-8.

Telangiectasias: Treatment

• Intense pulsed light– 17 patients underwent 3 monthly treatments

• 3 patients withdrew: hyperpigmentation, facial edema, hand blistering

– Follow-up at 1, 6, and 12 months after last treatment– Perfusion as measured by laser doppler imaging was

decreased at 1 and 6 months, but not maintained to 12 months.

– 12/16 patients with follow-up photographs were improved or much improved at 1 and 6 months.

Murray et al. Brit J Dermatol 2012;167:563-9.

Murray et al. Brit J Dermatol 2012;167:563-9.

1 MONTHBASELINE

Hypo-/Hyperpigmentation

• Change in the pigment of skin due to unknown cause– Salt and pepper appearance

• Common locations: chest, lower extremities, back, hands, arms, face

Salt and Pepper

Lipodermatosclerosis

• Fat inflammation that can be seen with chronic leg edema and autoimmune diseases

• Cause in scleroderma is unknown

LIPODERMATOSCLEROSIS• Chronic inflammation and

fibrosis of skin and SQ tissue of the lower legs causing a bound-down appearance.

• Can be plaque or surrounding entire lower leg.

• Also known as hypodermitis sclerodermaformis and sclerosis panniculitis.

Lipodermatosclerosis: Inverted champange bottle appearance

Lipodermatosclerosis

• Prevalence in SSc unknown and may be associated with anti-phospholipid antibodies

• Related to venous insufficiency—71% with associated edema

• Obese, middle-aged women• Initially painful and redhyperpigmented,

bound-down skin• ~13% associated with ulceration

Miteva et al. Dermatol Ther 2010;23(4):375-88.

Lipodermatosclerosis: Treatments

• Compression stockings• Stanozolol/Danazol

– Synthetic/modified testosterone derivative that breaks up scar tissue

• Intralesional steroids• Pentoxifylline

– Decreases sludging of blood• Excision

– For non-healing ulcers• Topical capsaicin

Miteva et al. Dermatol Ther 2010;23(4):375-88.

Summary

• Scleroderma is characterized by skin tightening but the extent and rate differs among patients.

• Digital ulcers and paronychia are related to the abnormal blood vessels in patients with scleroderma and poor wound healing.

• Calcinosis, telangiectasias, and hypo-/hyperpigmentation in scleroderma are signs of damage in the skin that need further study and better treatments.

Stanford Scleroderma Center

FACULTY CLINICAL TRIALS• Tocilizumab for diffuse skin dz

– < 5 years of skin tightening• Macitentan for digital ulcers

– New or worsened ulcer in past month

• Rituximab for SSc-APAH– On PAH drugs for > 3 months

David Fiorentino (Dermatology)

Glenn Rosen (Pulmonary)

Roham Zamanian (Pulmonary)

Howard Chang (Dermatology)

Linda Nguyen (Gastroenterology)

Mark Nicolls (Pulmonary)

William Robinson (Immunology)

James Chang (Hand/Vascular)

Francois Haddad (Cardiology)

COORDINATORSAmanda Foster: amfoster@stanford.edu

650-721-7147Val Scott (PAH): valval@stanford.edu

650-725-8082