Systemic Sclerosis - Boca Raton Regional...

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Systemic Sclerosis Ronald R. Butendieck, M.D. Division of Rheumatology Mayo Clinic, FL


Conflict of interest

• None


Outline

• Background

• Classification criteria

• Clinical manifestations by organ system

• Treatment


Systemic Sclerosis (SSc): Background

• Rare, but potentially devastating connective tissue disease characterized by autoimmunity, vasculopathy, and fibrosis

• Prevalence between 7-489 cases per million

• Higher prevalence in US and Australia compared to Japan and Europe

• Female/male 4:1

Chifflot H, Arthritis Rheum. 2008


2013 ACR/EULAR Classification Criteria for Systemic Sclerosis

ITEMS SUBITEMS WEIGHT

Bilateral skin

thickening fingers

extending to MCPs

9

Skin thickening Puffy fingers

Whole finger

2

4

Fingertip lesions Digital tip ulcers

Pitting scars

2

3

Telangiectasia 2

Abnormal nailfold

capillaries

2

PAH and/or ILD 2

Raynaud’s 3

Specific abs 3

van den Hoogen F, Arthritis Rheum. 2013 ≥9 Classified with definite SSc Se 91%

Sp 92%


SSc Specific Autoantibodies: Clinical Features

ACA U1-RNP PmScl U3-RNP Scl-70 RNA Pol3

SSc subset

(% of pts)

Limited

(50-90%)

Limited

(100%

MCTD)

Limited

(3%)

Diffuse

(7%)

Diffuse

(20-30%)

Diffuse

(25%)

Lungs PAH PAH ILD

Myositis

ILD +

PAH

ILD

Kidneys SRC SRC SRC

Steen VD, J Rheumatol. 2007

ACA: Anticentromere ab; PAH: Pulmonary arterial hypertension; ILD: Interstitial

lung disease; SRC: Scleroderma renal crisis


Diffuse vs Limited Scleroderma: Comparison by Organ System

ORGAN SYSTEM DIFFUSE (%) LIMITED (%)

Skin thickening 100 95

Telangiectasias 30 80

Calcinosis 5 45

Raynaud’s 85-95 95

Arthralgias and/or

arthritis

80 60

Tendon friction rub 65 10

Myopathy 20 10

Esophageal

hypermotility

75 75

Pulmonary fibrosis 35-59 25-35

CHF 10 1

Renal crisis 15 1


Sclero-Derma (Skin Thickening)

• Excessive production of type 1 collagen with accumulation of glycosaminoglycan and fibronectin

• Loss of sweat glands/hair

• Rodnan skin score

• May soften over 3-10 years

Copyright 2015 ACR


Slero-Derma: Treatment

• Methotrexate: 2 RCTs

• Improvement in Rodnan scores, but not statistically significant

• Endorsed by EULAR for early progressive disease

• Mycophenolate mofetil: observational studies

• Suggestive improvement in Rodnan scores

• No RTCs

• Cyclophosphamide: 1 RTCs (Scleroderma Lung Study)

• Efficacy during treatment lost after discontinuation

Nihtyanova SI, Clin Exp Rheumatol., 2014


Telangiectasias

• Dilated venules, capillaries, and arterioles

• More common in limited SSc

• Cosmetic issue

• Makeup

• Laser therapy for face

Copyright 2015 ACR


Calcinosis cutis

• Basic calcium phosphate

• Typically over periarticular surfaces

• Firm, irregular, nontender

• May recur after surgical removal

• Complications: ulcerations, infections, functional

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Calcinosis cutis: Treatment

• Extremely challenging

• Minocycline 50-100 mg daily

• 1 case series: 8/9 pts with improvement

• No improvement in multicenter open-label trial

• Infliximab or rituximab

• Case reports only

Mayes MD, Arthritis Rheum. 2004

Tosounidou S, Rheumatology (Oxford). 2014

de Paula DR, Clin Rheumatol. 2013

Daoussis D, Arthritis Rheum. 2012

Robertson LP, Ann Rheum Dis. 2003

Copyright 2015 ACR


Nailfold capillaries

• Microscopy

• Independent predictor for development of definitive SSc

• Capillary enlargement capillary loss capillary telangiectases

Koenig M, Arthritis Rheum. 2008

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Raynaud's phenomenon (RP)

• Episodic, self-limiting and reversible vasomotor disturbance

• Triggers: environmental cold, emotional stress, or spontaneous

• Color changes: pallor, cyanosis, and then erythema on rewarming

• May experience numbness, tingling, or pain

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Raynaud’s phenomenon: Flags

• Later age of onset (>40 years)

• History of a known precipitant

• Male gender

• Development of ulcerations

• Asymmetric attacks

• RP associated with signs or symptoms of another disease

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Raynaud’s phenomenon:

• Red flags to suggest early SSc

• Positive ANA, anti-Scl-70, or ACA

• Nailfold capillary abnormalities

• Tendon friction rubs

• Digital edema or puffy hands

• Dilated, patulous esophagus

Koenig M, Arthritis Rheum. 2008

Spencer-Green G, Arch Intern Med.1998

Kallenberg CG, Ann Rheum Dis. 1988


Raynaud’s phenomenon: Pearls

• RP precedes skin changes by >1 year

• Limited scleroderma

• RP develops simultaneously with skin changes

• Systemic scleroderma


Raynaud’s phenomenon: Nonpharmacologic Treatment

• Keep extremities AND core warm

• Smoking cessation

• Avoid certain drugs • Sympathomimetics • ADHD medications • Serotonin agonists

• Avoid repeated trauma to fingertips

• Control or limitation of emotional stress

• Relationship to estrogens and caffeine not clear

Hudson M, Arthritis Rheum. 2011

Goldman W, Arthritis Rheum. 2008

Freedman RR, Br Med J (Clin Res Ed). 1983


Raynaud’s phenomenon: Nonpharmacologic Treatment

• Complementary and alternative medicine

• Behavioral feedback ineffective

• ? Therapeutic gloves helpful

• Laser may be helpful, but not clinically relevant

• Acupuncture may help primary Raynaud's, need more evidence however

Malenfant D, Rheumatology (Oxford. 2009


Raynaud’s phenomenon: Pharmacologic Treatment

• Calcium channel blockers

• Nifedipine 30-180 mg/day

• Amlodipine 5-20 mg/day

• NOT verapamil (Kinney EL, J Clin Pharmacol. 1982)

• Start with low-dose, slowly titrate to maximum

• Watch for side effects

Huisstede BM, Arch Phys Med Rehabil. 2011

Thompson AE, Rheumatology (Oxford). 2005



• Losartan 50 mg/day vs nifedipine 40 mg/day

• Statistically significant decrease in severity/frequency of attacks with losartan

• Fluoxetine 20 mg/day vs nifedipine 40 mg/day

• Statistically significant decrease in severity/frequency of attacks with fluoxetine

Coleiro B, Rheumatology (Oxford). 2001

Dziadzio M, Arthritis Rheum. 1999



• Phosphodiesterase type 5 inhibitors

• Systemic review/meta-analysis of 5 RTCs

• Efficacy of sildenafil, tadalafil, and vardenafil

• Topical nitrates

• Multiple formulations tested in RTCs noting efficacy

• Apply proximal

Roustit M, Ann Rheum Dis. 2013

Herrick AL, Curr Opin rheumatol. 2011

Chung L, Arthritis Rheum. 2009


Raynaud’s phenomenon: Advanced Treatments

• Endothelin-1 antagonists: bosentan

• IV prostaglandins

• Iloprost, epoprostenol, treprostinil

• Hold other therapy while receiving infusions

• Chemical/surgical sympathectomy

• Intra-digital and palmar botulism toxin injection

Iorio ML, Semin Arthritis Rheum. 2012

Huisstede BM, Arch Phys Med Rehabil. 2011

Wasserman A, Semin Arthritis Rheum. 2010

Pope J, Cochrane Database Syst Rev. 2000


Systemic Sclerosis: GI manifestations overview

• Upper GI • Decreased oral aperture • Sicca symptoms • Hypomotility/Dysphagia • Reflux esophagitis • Stricture

• Lower GI • Hypomotility • Small bowel bacterial overgrowth

(constipation/diarrhea) • Malabsorption • Loss of rectal sphincter tone with

fecal incontinence

Copyright 2015 ACR


Systemic Sclerosis: Esophageal dysfunction

• Symptoms

• Reflux • Dysphagia

• Cough

• Causes

• LES incompetence

• Stricture formation • Abnormal motility

• Investigations • Manometry

• Barium swallow

• Esophagoscopy

Turner R, Am J Med Sci, 1973

Akesson A, Br J Rheumatol, 1989


Systemic Sclerosis: Esophageal dysfunction: Treatment

• Lifestyle changes • Establishment of normal weight • Head of bed elevation • Multiple small meals • Allow 3 hours before laying down after meals • Cessation of smoking and reduction of alcohol intake

• Pharmacologic therapy • PPI/H2 blocker • Prokinetic agents (metoclopramide, erythromycin) • Dilatation

Emmanuel AV, Aliment Pharmacol Ther. 2004

Hendel L, Aliment Pharmacol Ther. 1992


Systemic Sclerosis: Gastric involvement

• Delayed gastric emptying • Increased esophageal sx • Radionuclide gastric

emptying study • Lifestyle

changes/prokinetics

• GI bleed (GAVE) • Iron deficiency anemia • Gastroscopy • Endoscopic coagulation

• Pulsed dye laser • Argon plasma

coagulation

Duchini A, Am J Gastroenterol. 1998

Watson M, Arthritis Rheum. 1996

Maddern GJ, Gastroenterology. 1984

Blackwell JN, Gut. 1983

Copyright 2015 ACR


Systemic Sclerosis: Small intestine

• Reduced peristalsis stasis intestinal dilation

• Bacterial overgrowth (glucose hydrogen breath test)

• Pain, bloating, pseudoobstruction

• Constipation to diarrhea/steatorrhea/malabsorption

• Weight loss

• Treatment for bacterial overgrowth options

• Tetracycline or trimethoprim • Ciprofloxacin

• Amoxicillin-clavulanate

• Metronidazole in addition for 5-7 days if breakthrough

• May need rotational abx

• Probiotics in for mild sx

Fretch TM, Clin Exp Rheumatol. 2011

Kaye SA, Br J Rheumatol. 1995

Reinhardt JF, Am J Roentgenol Radium Ther Nucl Med. 1962


Systemic Sclerosis: Large intestine

• Decreased peristalsis constipation

• Atrophy/thinning ”wide-mouthed” diverticula

• Ano-rectal dysfunction fecal incontinence

• Tx of bacterial overgrowth

• Biofeedback

• Surgical options

• Sacral n. stimulator Leighton JA, Dis Colon Rectum. 1993

Chiou AW, Dis Colon Rectum. 1989

Cohen S, Gastroenterology.1980

Meszaros WT, Am J Roentgenol Radium Ther Nucl Med. 1959

Copyright 2015 ACR


Systemic Sclerosis: Hepatobiliary

• Primary biliary sclerosis

• Chronic cholestatic liver disease with inflammatory infiltrates within portal tracts resulting in fibrosis

• Anti-mitochondrial-abs (AMA)

• Treatment

• Pruritis: cholestyramine, colestipol, or rifampin

• PBC: ursodiol

• Vitamin E supplementation

• Liver transplant for advanced cirrhosis


Systemic Sclerosis: Interstitial Lung Disease (ILD)

• Nonspecific interstitial pneumonitis (NSIP) or usual interstitial pneumonitis (UIP)

• Pts with SSc higher risk of earlier onset

• ACA protective

• Anti-Scl-70 higher risk

Gilson M, Eur Respir J. 2010

Fischer A, Chest. 2008

Reveille JD, Arthritis Rheum. 2003

Copyright 2015 ACR


• In the office

• Cough

• Dyspnea

• Bibasilar fine inspiratory crackles “Velcro” rales

• Workup

• Complete PFTs

• HRCT

Systemic Sclerosis: ILD

Copyright 2015 ACR


Systemic Sclerosis: ILD Workup

• PFTs: decreased DLCO

• Correlates with HRCT chest findings

• Predictor of poor outcome

• HRCT: extent of ILD

• Negatively correlated with FVC

• Predicts mortality

• Biopsy typically not indicated unless atypical HRCT findings

Goldin JG, Chest. 2008

Goh NS, Am J Respir Crit Care Med. 2008

Bouros D, Am J Respir Crit Care Med. 2002

Wells AU, Arthritis Rheum. 1997


Systemic Sclerosis: ILD Treatment

• Cyclophosphamide • 2 RTC trials over 12 months in early disease

• Scleroderma Lung Study (SLS) and FAST Trial • Statistically significant benefit in FVC • Not clinically significant

• Mycophenolate mofetil • No RTCs, one currently ongoing (SLS II) • Several prospective and retrospective studies noting

benefit

• Rituximab: case studies only

Nihtyanova SI, Clin Exp Rheumatol. 2014

Tashkin DP, J Med. 2006

Hoyles RK, Arthritis Rheum. 2006


Systemic Sclerosis ILD Treatment

• High dose immunosuppression with autologous hematopoietic stem cell transplantation (HSCT)

• ASSIST • 19 pts randomize to IV CYC or HSCT x 12

months • Improvement in skin and ILD • No deaths

• ASTIS • 156 pts randomized to IV CYC or HSCT • Improvement in skin and ILD • 10% pts died from HSCT at 2 years


Van Laar JM. 2012

Burt RK, Lancet. 2011


Systemic Sclerosis Pulmonary arterial hypertension

• Leading cause of death in SSc

• Typically PAH Type 1

• Found in about 10-15% pts with SSc

• 2-year mortality 74-89%

• Up to 22% asymptomatic at diagnosis

• Need to screen patients

Coghlan JG, Ann Rheum Dis. 2014

Chung L, Arthritis Care Res (Hoboken). 2014

Yang X, Clin Rheumatol. 2013

Muangchan C, J Rheumatol. 2013

Lefèvre G, Arthritis Rheum. 2013

Hinchcliff M, J Rheumatol. 2011


Systemic Sclerosis PAH: Risk factors

• Positive antibodies

• Anti-centromere-ab

• RNP

• “Isolated“ ANA

• DLCO low (<60 % predicted) or progressive decline

• FVC/DLCO ratio >1.6

• Longstanding disease

• Increased age and male gender Steen V, Arthritis Rheum. 2003

Avouac J, J Rheumatol. 2010

Aggarwal R, Arthritis Rheum. 2009

Allanore Y, Arthritis Rheum. 2008

Kampolis C, Scand J Rheumatol. 2008

Steen VD, J Rheumatol. 2007


Systemic Sclerosis PAH: Screening

• No agreed upon consensus

• Symptoms

• Baseline PFTs and echo

• Right heart cath “gold standard”

• In those with symptoms highly suspicious

• Positive echo

• Mean pulmonary artery pressure ≥25 mmHg and pulmonary capillary wedge pressure ≤15 mmHg

Coghlan JG, Ann Rheum Dis. 2014


Systemic Sclerosis PAH: Treatment

• Prostanoid therapy

• Epoprostenol, treprostinil and iloprost

• Endothelin receptor antagonists

• Bosentan and ambrisentan

• Nitric oxide pathway stimulation

• Sildenafil, tadalafil, riociguat



Systemic Sclerosis Scleroderma Renal Crisis

• 3 Major Features

• Acute onset renal failure

• Abrupt onset moderate to marked hypertension (>150/90)

• Urine sediment typically normal with few cells or casts. Proteinuria, if present, is usually mild

• Up to 10% may be NORMOTENSIVE

• Typically occurs within first 3-5 years

• 5-20% patients Guillevin L, Rheumatology (Oxford). 2012

Denton CP, Rheumatology (Oxford). 2009

Teixeira L, Ann Rheum Dis. 2008

Penn H, QJM. 2007

Helfrich DJ, Arthritis Rheum. 1989


Systemic Sclerosis SRC: Risk factors

• Diffuse skin involvement, especially if rapidly progressive

• Tendon friction rubs

• Use of glucocorticoids (≥15 mg/day in last 6 mo)

• Presence of antiRNA-polymerase III-ab

• Cyclosporin Nguyen B, J Rheumatol. 2010

Teixeira L, Ann Rheum Dis. 2008

Penn H, QJM. 2007

Steen VD, Arthritis Rheum. 1998

Copyright 2015 ACR


Systemic scleroderma SRC: Treatment

• Goal: Reach baseline BP in 72 hrs

• Angiotensin-converting enzyme inhibitors

• Captopril 6.25 mg or 12.5 mg with titration

• Switch to long-acting (enalapril, ramipril)

• Indefinite treatment

• ESRD: Hemodialysis

• Cont. ACE (may still improve after 6-12 mo)

• Poorer outcomes then non-SSc patients

Penn H, QJM. 2007

Steen VD, Ann Intern Med. 2000

Steen VD, Ann Intern Med. 1990


Systemic scleroderma Take home points

• Potentially devastating connective tissue disease characterized by autoimmunity, vasculopathy, and fibrosis that can affect multiple organ systems

• Important clinical manifestations include Raynaud’s, scleroderma, gastrointestinal dysmotility, ILD, PAH, and SRC

• Key serology including ANA, anti-Scl70, and anti-centromere-ab have clinical and prognostic value

• Screening for ILD and PAH is strongly recommended


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