STPR=MRSS/years since first tighteningSTPR>40units/yr for rapid; 15-40 for intermediate; <15 for slow
Shown here is a cross-section photomicrograph of a digital microartery, obtained post-mortem from a patient with chronic systemic sclerosis. The Masson-Trichrome stain used here highlights fibrosis or scar tissue in a bright blue colour. The outer lining of the microartery is clearly encased in fibrosis, which surrounds a pink layer of muscle tissue. Most strikingly, what should be a single cell layer of endothelium on the interior of the blood vessel has been replaced by well-organised scar tissue which almost completely blocks the opening in the digital artery. The red arrow shows the residual opening of the blood vessel, which occupies ~10% of a normal artery opening.The clinical situation is severe, with progressive vascular injury to the fingers, increasing risk of ischaemia and ultimately amputation. The underlying cause is a severe and obliterative fibrosis.
Vascular injury is not simply an issue of blood vessel spasm but also of irreversible blood vessel occlusion.The picture on the left is of an arteriographic study of circulation in the hand of a systemic sclerosis patient. The major blood vessels in the palm and arches are unaffected. However, circulation leading to each of the fingers is sharply cut off. The digital arteries, which are small paired arteries running up the inner and outer sides of the fingers, are the principal sites of damage in systemic sclerosis, which in turn leads to tissue injury.The photo on the right illustrates a typical problem in a patient suffering chronically from systemic sclerosis: four areas of gangrene are visible on the fingertips, and a small finger has been partially amputated after previous injury. It can be appreciated from these images that digital ulcers are a major source of morbidity, affecting hand function and quality of life, and are a consistent source of day-to-day pain.
This slide shows the pathways thought to be involved in scleroderma vascular disease and ultimately the formation of digital ulcers. First there is some injury or environmental trigger that activates the immune system, leading to inflammation, autoantibody production, and injury to the blood vessels. Capillaries get destroyed, platelets are activated to lead to clot formation, and hormones in the bloodstream that normally regulate the opening and closing of blood vessels go haywire. These include increased levels of ET1 or endothelin, which causes closing of blood vessels, and decreased levels of nitric oxide and prostaglandin, which normally keep blood vessels open. All of this leads to a decreased lumen or opening in the small blood vessels, decreased oxygen to the tissue or hypoxia, and eventually death of the cells and tissue, causing ulceration.
Skin Manifestations of Scleroderma, by Dr. Lorinda Chung MD
Skin Manifestations of Scleroderma Lorinda Chung, MD, MSStanford University School of Medicine March 9, 2013
Scleroderma=hardening of the skin• Localized Scleroderma – Morphea – Linear Scleroderma• Systemic Sclerosis – Diffuse – Limited (CREST) – Sine scleroderma – Overlap Syndrome/MCTD
Systemic Sclerosis: Subsets• Diffuse • Limited – Skin thickening: face, – Skin thickening: trunk, entire arms/legs, face, forearms, lower hands and feet; tendon legs, hands and feet friction rubs – Progressive dz following – Rapid onset following RP: onset of RP months to 3 yrs – Late internal organ dz – Early internal organ dz – Association with anti- – Association with anti-Scl-70 centromere Ab Ab – 10-yr survival >70% – 10-yr survival 40%
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 Survival In Anti-Scl-70+ SSc Patients Perera et al. Arthritis Rheum 2007;56(8):2740-6.
Potential Treatments for Skin Tightening• Anti-fibrotics: breakdown scar • Target growth factors tissue or block collagen involved in scar tissue production formation – Halofuginone – Imatinib – Antibody to Connective – Dasatinib Tissue Growth Factor • Target T Cells/Cytokines – Statins (Inflammatory cells) – Pirfenidone (in trials for IPF) – Methotrexate – Anti-transforming growth – IVIG factor-beta antibody – Mycophenolate mofetil* – LPA-1 receptor antagonist* – Cyclophosphamide – Stem cell transplant*• Target B Cells/AutoAb – Abatacept (CTLA4 Ig)** – Rituximab** – Anti-BLyS (LymphoStat-B) – Anti-Interferon antibodies – Anti-CD19 mAb (completed – Anti-IL-6 antibody** 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• 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.
Algorithm for the treatment and prevention of digital ulcers in systemic sclerosis. DU present NO YES DU in past Multiple & severe DU NO YES NO YESAvoid cold, stress, trauma* Statins Hydrocolloid occlusion Prostacyclins (IV/SQ)Smoking cessation* CCB OTC pain meds AnticoagulantsTreat RP PDE5-inhibitors Wound care Cilostazol/pentoxifylline CCB ET-receptor Treat infections Narcotics -adrenergic blockers blockers Hi dose CCB Wound care Nitrates PDE5-inhibitors Treat infections ACE-inhibitors ET-receptor blockers Consider digital or cervical ARB Cilostazol sympathectomy SSRIASA*Statins* All patients should be educated to avoid cold, stress, trauma, and nicotine. Aspirin 81mg daily should be considered for all patients who donot have a contraindication.DU=digital ulcers; RP=Raynaud’s phenomenon; CCB=calcium channel blockers; ACE=angiotensin converting enzyme; ARB=angiotensin IIreceptor blocker; SSRI=selective serotonin reuptake inhibitor; ASA=aspirin; PDE5=phosphodiesterase-5;ET=endothelin; OTC=over the counter; IV=intravenous; SQ=subcutaneous.
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 • Prevention – Acute – Minimize exposure to • Antibiotics wet environment • Possible incision/drainage – Avoid trauma to nails or – Chronic fingertips • Antifungal medication – Bring your own tools to • Topical corticosteroids 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• 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.
*12.4X increased odds of PAH for every 10-point increase in telangiectasia score (p=0.01) Shah et al. J Rheumatol 2010;37(1):98-104.
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.
BASELINE 1 MONTH Murray et al. Brit J Dermatol 2012;167:563-9.
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
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• 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 CenterFACULTY CLINICAL TRIALSDavid Fiorentino (Dermatology) • Tocilizumab for diffuse skin dzGlenn Rosen (Pulmonary) – < 5 years of skin tighteningRoham Zamanian (Pulmonary) • Macitentan for digital ulcersHoward Chang (Dermatology) – New or worsened ulcer in past monthLinda Nguyen (Gastroenterology) • Rituximab for SSc-APAHMark Nicolls (Pulmonary) – On PAH drugs for > 3 monthsWilliam Robinson (Immunology) COORDINATORS Amanda Foster: firstname.lastname@example.orgJames Chang (Hand/Vascular) 650-721-7147Francois Haddad (Cardiology) Val Scott (PAH): email@example.com 650-725-8082