“Systemic Sclerosis: Recognition of Systemic and multisystem ”

November 15, 2017

Patrick Cronin, DO,FACR Clinical Instructor Cooper Medical School of Rowan University Cooper University Bone & Joint Institute Division of Rheumatology

American College of Rheumatology Systemic Sclerosis (1980): Classification criteria

Diagnosis: 1 major (or) 2 minor

Major criterion Proximal scleroderma (proximal to the MCP joints)

Minor criteria Sclerodactyly Digital pitting or scars or loss substance finger pad Bibasilar pulmonary fibrosis Classification: Scleroderma

Systemic Sclerosis

Diffuse cutaneous Progressive Systemic Sclerosis

Limited cutaneous C.R.E.S.T. (calcinosis, Raynaud’s, esophageal dysmotility, sclerodactyly, atelectasis) Syndrome

Scleroderma sine scleroderma

Scleroderma-Like Syndromes

 Scleredema — Scleredema is characterized by prominent symmetrical skin thickening predominantly on the trunk, particularly the shoulders and back. The face may also be affected. In severe cases, mobility of the shoulders and chest is markedly impaired. Patients with insulin-dependent diabetes mellitus may develop a type of scleredema called scleredema of Buschke(Raynaud phenomenon and autoantibodies are not present in these patients, and internal organ involvement is rare)

 Scleromyxedema — Scleromyxedema (papular mucinosis) is characterized by waxy yellow-red papules on the head, neck, arms, and upper trunk, commonly occurring over thickened and indurated skin. Middle-aged adults are most commonly affected. The presence of a monoclonal protein, often IgG lambda, detected by immunofixation on samples of serum and/or urine supports the diagnosis of scleromyxedema. Skin biopsy is valuable. Scleromyxedema may be associated with AL amyloidosis and .

 Diabetes mellitus and myxedema due to hypothyroidism can be accompanied by skin induration. Endocrine disorders may also occur in some patients with monoclonal gammopathies, for example, in the POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal gammopathy, and Skin changes)

Scleromyxedema/myxedema

Epidemiology: Scleroderma

 Female : Male = 3:1 (Greater in African-American women)  Age: Peak 35-65 years  Incidence: 19 cases/million/year  Prevalence: 19-75 cases/100,000 Scleroderma: Proposed Pathophysiology

Cytokines  Transforming Growth Factor β (TGF- β)  Platelet Derived Growth Factor (PDGF)

Endothelial damage – releases endothelin – increase fibroblast function  Collagen I   Glycosaminoglycans

Endothelial injury Vasoconstriction/Fibroblast↑ Hypoxia -- ↑ TGF β Fibroblast ↑ Scleroderma Scleroderma: ANA

Centromere Homogenous

Speckled Nucleolar Scleroderma: Skin “Raynaud’s”

 Maurice Raynaud in 1862 stated that "local asphyxia of the extremities“ – loss of oxygen to the tissue.

“Raynaud’s” http://www.nhlbi.nih.gov/health/health-topics/topics/raynaud

Scleroderma: Digital Artery Thermography: Raynaud’s

Control 1 Raynaud’s Scleroderma

15 c

23 c Scleroderma: Raynaud’s Raynaud’s

 Episodic  Reversible digital color change  White to blue to red  Well-demarcated

 Due to vasospasm

 Usually cold-induced

 Primary & secondary

forms Raynaud’s Scleroderma: Raynaud’s, Scleroderma: Capillary Microscopy

Causes of Secondary Raynaud’s

 Connective tissue diseases

Scleroderma, systemic erythematosus, MCTD, undifferentiated CTD, Sjogren’s syndrome, , others

 Occlusive arterial disease Atherosclerosis, anti-phospholipid syndrome, Buerger’s disease

 Vascular injury Frostbite, vibratory trauma

 Drugs and toxins Beta blockers, vinyl chloride, bleomycin, ergot, amphetamines, cocaine

 Hyperviscosity/cold-reacting proteins Paraproteinemia, polycythemia, , cryofibrinogenemia, cold agglutinins Raynaud’s

Scleroderma: Edematous Changes, Hands Scleroderma: Puffy Phase, Hand Scleroderma: Hands Scleroderma: Skin Induration Scleroderma: Acrosclerosis Scleroderma: Acrolysis Scleroderma: Acro-sclerosis & Terminal Digit Resorption Scleroderma: Digital Pitting Scars Limited Systemic Sclerosis: Calcinosis

•Calcinosis (Hydroxyapatite) •Colchicine •Calcium Channel Blockers

Arthritis Rheum. 1995 Nov;38(11):1646-54. Treatment of calcinosis with diltiazem. Palmieri GM, Sebes JI, Aelion JA, Moinuddin M, Ray MW, Wood GC, Leventhal MR. Source University of Tennessee at Memphis 38163, USA. Scleroderma: Calcinosis Cutis Scleroderma: Calcinosis and Acrolysis Limited Systemic Sclerosis: Calcinosis: Arm Scleroderma: Calcinosis Scleroderma: Facial Changes Scleroderma: Facial Changes Scleroderma: Facial Changes Scleroderma: Watermelon Stomach Scleroderma: Dysmotility and Esophagus

 Upper GI tract  GERD Proton Pump Inhibitor  Aspiration Pneumonia PPI vs. Carafate  Esophagitis/Barrett’s Scleroderma: Bowel Dilatation

 GI  Malabsorption  Vitamin D  Difficult to treat  Bacterial Overgrowth  Metronidazole  Tetracycline  Ciprofloxacin  Weight Loss/Cachexia  TPN  Pseudo-obstruction  Non-surgical  General Measures  Octreotide, erythromycin Scleroderma: Wide-Mouth Diverticula

 Diverticula  Wide mouth  Rare diverticulitis  Pneumatosis Cystoides Intestinalis Non-Surgical Scleroderma: Pulmonary, Cardiac

Pulmonary Pulmonary: ILD/HTN - Rule out – Embolic disease (APL), CHF, OSA 6 minute walk Echocardiogram – yr’ly: PAP PFT with DLCO – yr’ly: compare DLCO Cardiac Contraction band necrosis - arrhythmias Pericardial effusion – large, non-tamp. Myocarditis

Scleroderma: Pulmonary HTN

 PHTN – Echocardiogram or Right Heart Cath.

 High mortality – 52% at 3 years survival (*) Bosentan (next slide)

Sildenafil – SUPER-1 trial (1)

(*) Survival and prognostic factors in systemic sclerosis-associated pulmonary hypertension: a systematic review and meta-analysis. Lefèvre G, Dauchet L, Hachulla E, Montani D, Sobanski V, Lambert M, Hatron PY, Humbert M, Launay D Arthritis Rheum. 2013;65(9):2412.

(1)Sildenafil citrate therapy for pulmonary arterial hypertension. Galiè N, Ghofrani HA, Torbicki A, Barst RJ, Rubin LJ, Badesch D, Fleming T, Parpia T, Burgess G, Branzi A, Grimminger F, Kurzyna M, Simonneau G; Sildenafil Use in Pulmonary Arterial Hypertension (SUPER) Study Group. N Engl J Med. 2005 Nov 17;353(20):2148-57

Scleroderma: Kidney

 Scleroderma Renal Crisis  High Renin State  Microangiopathic Hemolytic Anemia  HTN and active urine sediment  may play a role (*), anti-RNA polymerase III autoantibody was detected in 52 percent of SRC or fine speckled immunofluorescence pattern  Treatment  ACE inhibitor – Calcium Channel Blocker  Minimize steroids

(*)Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Steen VD, Medsger TA Jr. Arthritis Rheum. 1998 Sep;41(9):1613-9.

Reversal of Vascular and Renal Crises of Scleroderma by Oral Angiotensin-Converting-Enzyme Blockade Jorge A. Lopez-Ovejero, M.D., Stuart D. Saal, M.D., William A. D'Angelo, M.D., Jhoong S. Cheigh, M.D., Kurt H. Stenzel, M.D., and John H. Laragh, M.D. N Engl J Med 1979; 300:1417-1419 Scleroderma: Kidney

One year survival, 15% without and 76% with ACE inhibitors (P < 0.001).

Courtesy of Helmut Rennke, Courtesy of Carol Black, MD. MD. Graphic 78330 Version 6.0 Graphic 70213 Version 2.0

Scleroderma Renal Crisis: renal biopsy with fibrinoid deposition, “onion-ring” muscular hyperplasia

Outcome of renal crisis in systemic sclerosis: relation to availability of angiotensin converting enzyme (ACE) inhibitors. Steen VD, Costantino JP, Shapiro AP, Medsger TA Jr Ann Intern Med. 1990;113(5):352. Raynaud’s: Hands

 Raynaud’s  Longer term use  Aspirin or pentoxifylline  Calcium Channel Blockers  Bosentan (PAH)  Short term use  Topical NTG  Prostacyclin IV  Phosphodiesterase Inhibitor  Others – SSRI, ARB/ACE, ect.

Arthritis Rheum. 2004 Dec;50(12):3985-93. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Korn JH, Mayes M, Matucci Cerinic M, Rainisio M, Pope J, Hachulla E, Rich E, Carpentier P, Molitor J, Seibold JR, Hsu V, Guillevin L, Chatterjee S, Peter HH, Coppock J, Herrick A, Merkel PA, Simms R, Denton CP, Furst D, Nguyen N, Gaitonde M, Black C. Raynaud’s: Homeostasis/Prevention

Life-Style Changes  Dry hands and feet  Avoid convection currents Wool socks and mittens  Layer chest wall for heat trapping.  Quit tobacco; limit caffeine and alcohol Queen Elisa: Raynaud’s patient and spokesperson Scleroderma: Treatment

Immunosuppression (Diffuse Disease only)  Traditional immunotherapy and antifibrotics  Methotrexate  D-penicillamine  Cyclophosphamide  Current clinical immunotherapy treatments  Mycophenolate mofatil  Abatacept*  Tocilizumab*  Rituximab *

Mycophenolate mofetil versus oral cyclophosphamide in scleroderma-related interstitial lung disease (SLS II): a randomised controlled, double-blind, parallel group trial. Tashkin DP, Roth MD, Clements PJ, Furst DE, Khanna D, Kleerup EC, Goldin J, Arriola E, Volkmann ER, Kafaja S, Silver R, Steen V, Strange C, Wise R, Wigley F, Mayes M, Riley DJ, Hussain S, Assassi S, Hsu VM, Patel B, Phillips K, Martinez F, Golden J, Connolly MK, Varga J, Dematte J, Hinchcliff ME, Fischer A, Swigris J, Meehan R, Theodore A, Simms R, Volkov S, Schraufnagel DE, Scholand MB, Frech T, Molitor JA, Highland K, Read CA, Fritzler MJ, Kim GH, Tseng CH, Elashoff RM, Sclerodema Lung Study II Investigators Lancet Respir Med. 2016;4(9):708. Epub 2016 Jul 25. Thank You. Questions?