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SSc 101 Julia Rhiannon June 2013

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1 SSc 101 Julia Rhiannon June 2013

2 outline Intro and pathogenesis Classification dcSSc ~ diffuse cutaneous systemic sclerosis –organ involvement with 2 cases –Rodnan skin scoring lcSSc ~ limited cutaneous systemic sclerosis & case Antibodies as clues to phenotype Environmental/genetic contribution and epi Therapy

3 SSc clinical manifestations result from... Autoimmunity Small vessel obliterative vasculopathy –Raynaud’s, renal crisis, PAH Pathological accumulation of collagen in skin and other organs –Sceroderma, lung parenchymal dz, GI dysmotility

4 Chicken vs Egg – Pathogenesis and autoantibodies

5 Gu, S.,, Seminars in Arthritis, 2008


7 Localized Scleroderma Morphea Linear Scleroderma Coup de Sabre

8 Case 1: Puffy Hands HPI - 45 y/o woman with 5 wks of puffy hands –recently finger turns white while grocery shopping or reaching into refrigerator. Hands feel itchy. Exam - Diffusely swollen hands and wrists. Several fingers cyanotic. Pulses intact.

9 The next step would be: 1. Check for nailfold changes 2. Doppler study 3. Order ANA panel 4. Order ANCA 5. Skin biopsy 6. Pred 60mg IM x1 7. Tell her to take her husband’s viagra Case: Puffy Hands

10 Skin: Raynaud’s Classic three color change: -pallor (vasoconstriction) -cyanosis -rubor (least frequent)Classic three color change: -pallor (vasoconstriction) -cyanosis -rubor (least frequent) Triggered by cold and emotionTriggered by cold and emotion

11 Raynaud’s Raynaud’s affects 3-5% of general population –Most are primary, usually with onset in 20s-30s Raynaud’s assoc with SSc will likely have : –Increased severity in freq/duration/morbidity –Nailfold cap abn (47% PPV) –Positive serologies (ANA 30%PPV) –With stiffness and/or pitting +/- ulcers –Age >35

12 Nailfold Capillaroscopy DilatationNormal Bizarre Loops Dilatation Dropout

13 Images in Raynaud’s Cyanosis Digital pitting

14 Treatment of Raynaud’s Central warmth, good gloves, avoid cold exposure, handwarmers Stress reduction Dihydropyridine calcium channel blockers –nifedipine 30mg ER titrate up as tolerated Phosphodiesterase 5 inhibition (sildenafil/revatio/viagra) Topical nitroglycerin for 20 minutes (or more) tid proximal to affected digit Po and IV prostanoids (alprostadil) Endothelin receptor antagonist (Bosentan) Statins Antiplatelet (ASA) and antioxidant (NAC)

15 Severe Digital Ischemia Treatment of impending digital gangrene requires hospitalization Warm room, pain meds, anxiolytics, high dose Ca channel blockers or trial of IV alprostadil (5 nanograms/kg/min for 6 hours followed by 10 nanograms/kg/min for 66 hours via PICC line), Antibiotics if infection present May try sympathetic block at the wrist; consider digital sympathectomy if successful

16 Early Skin Changes in Diffuse SSc Initially skin may be edematous Hands only early May have CTS Edema resolves; skin then indurated Extremities, face, trunk may be involved Advancing skin involvement often pruritic

17 Late Skin Changes As disease progresses, skin becomes atrophic Ulcers may develop at pressure points or with trauma Disappearance of finger tips due to resorption or gangrene Secondary joint contractures

18 Other skin changes Other –Thickened and tethered –Telangiectasia –Calcinosis –Narrowed oral aperture

19 Case 2 44 y/o male with known dcSSc admitted to MICU for –BP 210/150 –creatinine 1.5 mg/dl. –UA with +2 protein –Smear with schistocytes Next step is to give: 1. plasma exchange 2. IV Solu-Medrol & Cytoxan 3. IV nitroprusside 4. ACEi (enalaprilat or po enalapril) 5. Renal bx STAT

20 Scleroderma Renal Crisis Defined as accelerated arterial hypertension and/or rapidly progressive oliguric renal failure. Occurs in 10% of patients with scleroderma Occurs in 20-25% of pts with the RNA Pol III Ab Etiology - mimics malignant htn, 2/2 microvasc dz, vasospasm, and tissue ischemia… with elevated renin, and arteriolar fibrotic change Knowledge from clinical studies: –Must keep exquisite control of BP –When in renal crisis use ACEs before ARBs or any other –Corticosteroids thought to predispose patients to renal crisis

21 Renal Involvement in diffuse scleroderma Renal Crisis –rapidly progressive azotemia –malignant hypertension –microangiopathic hemolytic anemia –thrombocytopenia –proteinuria, hematuria arteriolar fibrinoid necrosis Scleroderma renal crisis/malignant Htn

22 Syndromes in Systemic Sclerosis Vascular –Raynaud’s Phenomenon –Renal Crisis –Pulmonary Hypertension –Myocardial Change +/- sudden death –Visceral Raynaud’s Fibrotic –Skin Involvement –Interstitial Lung Disease –Intimal Hyperplasia Immunologic –Alveolitis –Myositis –Tendonitis –Synovitis

23 Other Organ Involvement Muscle –Inflammatory (overlap with polymyositis) –Type 2 fiber atrophy Joint –Arthralgias (rarely arthritis) –Acrosclerosis calcinosis and acrolysis –Tendon fibrosis Nerve –Compressive neuropathy –Autonomic dysfunction

24 Gastrointestinal Involvement Esophageal dysmotility (90%) Gastroparesis Small bowel dysmotility Large bowel –Diarrhea (bacterial overgrowth  malabsorption) –Large mouth diverticuli GAVE/Watermelon Stomach

25 Lung Involvement Pulmonary hypertension Interstitial lung disease Diaphragmatic dysfunction

26 Active ILD in SSc likely to be NSIP Depressed FVC or declining FVC by >10% in 4-6mo Bilateral Basal predominant Confluent Ground glass Reticular lines Traction bronchiectasis Will progress to PF without treatment

27 Cardiac Involvement Myocardial fibrosis –most common manifestation Coronary Artery Disease Conduction System Disease and Arrhythmias Pericardial Disease

28 Diffuse disease, assessment over time Skin involvement reflects relative risk of new internal organ involvement –Pace –Progression –Extent Must be able to track extent and severity of skin changes Classification and prognosis depends on these determinations in addition to antibodies Rodnan skin score is qualitative –0 normal; 1 mild; 2 moderate; 3 severe thickening –summation of 17 body areas

29 Face Upper arm Anterior chest Forearm Hand Fingers Thigh Leg Foot Upper arm Abdomen Forearm Hand Fingers Thigh Leg Foot Uninvolved Mild thickening Moderate thickening Severe thickening 0 1 2 3 Clinical Assessment of Skin Thickening-Modified Rodnan Skin Score (MRSS)

30 Clinical Meaningfulness of Change in MRSS Increase predicts worsening of SScIncrease predicts worsening of SSc Stability predicts reduced new internal involvementStability predicts reduced new internal involvement Improvement predicts improved 5 and 10 year survivalImprovement predicts improved 5 and 10 year survival High scores (>20) predict renal crisis (OR 6.64)High scores (>20) predict renal crisis (OR 6.64) High scores (>20) predict mortality (OR 3.39)High scores (>20) predict mortality (OR 3.39) Improved score correlates with HAQ-DI, hemoglobinImproved score correlates with HAQ-DI, hemoglobin

31 lcSSc (limited cutaneous systemic sclerosis) C alcinosis, R aynaud’s, E sophageal dysmotility, S clerodactly, T elangiectasia Raynaud’s often present for years prior to skin edema/thickening Skin involvement limited (fingers distal to MCPs) PAH > ILD Digital infarcts seen CREST associated with PBC, occasionally also with Sjogren’s Calcinosis

32 Case 3 HPI - A 52 y/o women with 10 yrs of Raynaud’s here w/ recently increasing problems with hands as well as dysphagia. She has also noted small red dots on her face and hands appearing over the last 6 months. Exam - In the office she has active Raynaud’s and has multiple small red lesions on face, hands, and tongue.

33 1. Homogeneous 2. Nucleolar 3. Peripheral 4. Centromere 5. Speckled Case 3 What pattern would you expect to see on ANA testing?

34 Classification of Systemic Sclerosis and Organ Involvement All systemic sclerosis –Raynaud’s –Esophageal dysmotility –Telangiectasias dcSSc –Interstitial Lung disease –Renal Crisis –Cardiac Involvement –GI involvement lcSSc –Pulmonary hypertension –Calcinosis –Overlap syndromes-Sjogren’s, RA, SLE, MCTD, PBC

35 homogenous (diffuse) speckled nucleolar ANA pattern matters centromere PAH risk ILD risk

36 Antibodies as clues to phenotype, organ involvement, prognosis dcSScdcSSc –ANA positive 40-90% with nucleolar pattern on ANA –Scl-70 (anti-topoisomerase 1) with low sensitivity / high specificity for diffuse disease –RNA Polymerase III - most severe skin involv., highest freq of renal crisis, best overall prognosis –U3 RNP - diffuse but with PAH +/- ILD, skeletal and cardiac muscle inv lcSSclcSSc –centromere ANA very specific for CREST/limited disease in up to 90% of pts; PAH –U1 RNP – MCTD with SSc phenotype, risk of PAH –Th/To - PAH +/- ILD; more pulm fibrosis and renal crisis than anti-centromere+ pts Arthritis Rheum. 2009 Apr;60(4):1112-28.

37 Predominant Features Associated with Scleroderma-Specific Autoantibodies ACATh/ToU1- RNP PmSclU3-RNPTopo1Pol 3 SSc Subset LLLLDDD LungPHILD & PHPHILD & PH ILD Renal---- +++ Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35:35-42, 2005.

38 Survival according to antibody

39 Env/Occup Genetics Polyvinylchloride - 1930s Toxic oil syndrome- Spain - rapeseed oil contaminated with aniline dye  SScl like disease contaminated L-tryprophan - 1989 – “eosinophilia myalgia syndrome” Silica dust - case reports in miners Organic solvents - textile industry / paint thinners and removers Epoxy resins Pesticides Hand/arm vibration Arch Occup Environ Health 2004; 77:10-16 1.6% of Ssc pts have a 1 st degree relative with SSc (RR=13) 5.9% concordance in identical twins (300 times higher than chance) Strong associations with HLA-A1, -B8, -DR3 haplotype and with DR3/DR52 Strong associations with C4AQ0 and DQA2 Well-defined cluster of Choctaw Indians with diffuse phenotype

40 Epidemiology Prevalence: 276-300 cases per million Incidence: 20 cases per million/year F:M = 4.6:1 Shows relative phenotypic severity in African Americans and Native Americans. Onset peaks between 45-60 yrs of age. Prognosis worsens with increasing age of onset.

41 Treatment overview Htn –ACEi, CCB Raynaud’s –CCB –PDE5 inhibition –nitrates GI –Cholinergic agonists –PPI, H2B –antibiotics for bowel overgrowth –Reglan/domperidone –Argon coag for GAVE Doxepin for itching Treat depression, anxiety, sleeplessness PAH –Bosentan –Epoprostenol –PDE5 inhibition DMARDS –methotrexate –MMF (CellCept/Myfortic) –Cyclophosphamide –Steroids, LD(<15mg) –N-acetylcysteine –Rituximab –Stem cell transplant –Tyr-kinase inhibition –Anti-CTGF

42 “No drug has been shown to be completely worthless until tried in Scleroderma” –Eric Bywaters

43 Scleroderma 3K/5K walk June is SSc awareness month Walk is this coming Sat, June 15 th, 2013

44 References Shah, A and F. Wigley, Mayo Clin Proc. 2013 Apr; 88(4):377-393. Klippel, John,, Primer on the Rheumatic Diseases, 13 th ed. Springer, 2008. Hochberg, Marc,, Rheumatology, 4 th ed., Mosby Elsevier, 2007. Steen VD. Autoantibodies in systemic sclerosis. Semin Arthritis Rheum 35:35-42, 2005. Arch Occup Environ Health 2004; 77:10-16 Gu, S.,, Seminars in Arthritis, 2008 Arthritis Rheum. 2009 Apr;60(4):1112-28.


46 Organ Involvement and Survival Organ Involvement –L: Lung; H: Heart, K: Kidney Medicine 81:139,2002 (1012 Italian patients)

47 Therapy of localized scleroderma UVA Topical steroids Calcipotriol (Vit D analog) Methotrexate Experimental: –Anti-TGF  MAb –Halofuginone (interferes w/ TGFb induced collagen synth) –Topical TGFb1 binding peptides –thalidomide

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