Chayawee Muangchan MD. Division of Rheumatology, Department of Medicine Siriraj Hospital, Faculty of Medicine, Mahidol University

Transcription

1 Chayawee Muangchan MD. Division of Rheumatology, Department of Medicine Siriraj Hospital, Faculty of Medicine, Mahidol University

2 Systemic sclerosis: epidemiology (1) 6 5 UCTD MCTD 1 RA CTD 4 DM PM 2 3 SLE SSc o Systemic sclerosis or scleroderma (SSc) is a systemic autoimmune connective tissue disease (CTD) o It is the third prevalent among CTD o RA 1:100 o SLE 1:1,000 o SSc 1:10,000 o The hallmark features are Raynaud phenomenon & scleroderma

3 Systemic sclerosis: epidemiology (2) 6 5 UCTD MCTD 1 RA CTD 4 DM PM 2 3 SLE SSc o Age at diagnosis o Worldwide 46.79±13.42 yr. o Asian 34 [95%CI 32-36] o Siriraj o Female: Male o Worldwide 5-7:1 o Siriraj 4:1 o Subset: dcssc VS lcssc 45.33±12.67 yr. o Worldwide lcssc > dcssc (2X) o Siriraj dcssc > lcssc (4X)

4 Systemic sclerosis: pathophysiology (1) Genetic predisposition Autoimmunity Environmental triggers o HLA related gene o Non HLA related gene o Other genes o Concordance rate in dizygotic twins % o Prevalence in 1 st degree relative % o Prevalence in normal population 0.026% 15X more o Autoreactive T/B cell o Self Ag recognition o Viral infection o Toxin Microvascular endothelial cell injury Fibrosis Fibro-proliferative vasculopathy

5 Systemic sclerosis: pathophysiology (2) Immuno-modulatory, Immunosuppressive Antifibrosis Antiplatelet, Vasodilators (1) Microvascular Endothelial Injuries (2) Tissue Fibrosis (3) Fibro- Proliferative Vasculopathy Organ Ischemia Raynaud, digital ischemic complications, Scleroderma renal crisis Organ Fibrosis + Ischemia = dysfunction GERD, GI dysmotility & malabsorption, Pulmonary Hypertension, Usual interstitial pneumonia (UIP), Pulmonary restriction, Cardiomyopathy, Salt & pepper skin, Telangiectasia Organ Inflammation Puffy fingers, hands, face, Nonspecific interstitial pneumonia (NSIP)

6 Systemic sclerosis: pathophysiology (3) Organ Ischemia Organ Inflammation Organ Fibrosis + Ischemia = dysfunction

7 Primary Raynaud Normal vessels Teenage girls with family history Symmetrical attack Exaggerated response to cold Tri-phasic: Secondary Raynaud Vasculopathy Usually aged > 40 year-old Asymmetrical attack Vasodilators < Vasoconstrictors Ischemic complications D/DX of Raynaud phenomenon

8 Approach to 2 o Raynaud phenomenon Apply Virchow s triads Vessel o Atherosclerosis ±low flow/ruptured plague o Thrombo-angiitis obliterans o Exaggerated vasospasm: ergotism o Vasculopathy: SSc-RP, MCTD-RP, SLE-RP, UCTD-RP o Medium to small vessels vasculitis: o 1 o vasculitis: PAN, AAV (micro PAN, WG, CSS) o 2 o vasculitis: CTD (SLE, MCTD, DM), Behcet, IE, paraneoplastic Plasma Cellular o Hyperviscosity: 1 o VS 2 o APS o Cytosis: ALL/AML, CLL/CML, ET

9 Approach to CTD 2 o Raynaud phenomenon Early scleroderma RP + Puffy fingers Blood for ANA Anti-dsDNA Anti-Sm Anti-uRNP Anti-Scl70 Anti-centromere SSc MCTD SLE UCTD 90-95% RP, 95% ANA, 75% Anti-Scl70, 11% Anti-centromere 85-90% RP, 100% ANA>1:1600, Anti-uRNP 10-45% RP, 99% ANA, 70% Anti-dsDNA, 30% Anti-Sm 45-60% RP, % ANA, no specific serology Negative anti-dsdna/anti-sm

10 ACR / EULAR 2013 classification criteria for systemic sclerosis การตรวจพบหล ก การตรวจพบรอง คะแนนการว น จฉ ย Proximal scleroderma 9 Sclerodactyly (น บข อท ม คะแนนส งส ด) 1. Puffy fingers 2. Sclerodactyly 2 4 Fingertip lesions (น บข อท ม คะแนนส งส ด) 1. Digital tip ulcers 2. Fingertip pitting scars 2 3 Telangiectasia 2 SSc-pattern nailfold capillaroscopy 2 Pulmonary arterial hypertension and/or Interstitial lung disease (คะแนนส งส ดเท าก บ 2) 1. Pulmonary arterial hypertension 2. Interstitial lung disease 2 2 Raynaud s phenomenon 3 SSc-related autoantibody 3 (คะแนนส งส ดเท าก บ 3) 1. Anti-centromere 2. Anti-topoisomerase-I (Scl-70) 3. Anti RNA polymerase III Ann Rheum Dis. 2013; 72:

11 Progression of skin tightening from early scleroderma (1) Fingers 1 Early SSc (2) Hands (3) Forearms/Face/Feet (4) Arms/Legs (5) Trunk/Thighs 2 lcssc 3 dcssc 4 Overlap SSc 5 Sine SSc Ann Rheum Dis Jul 31. pii:annrheumdis doi: /annrheumdis

12 Clinical subsets of established SSc Siriraj SSc cohort Systemic sclerosis Early Diffuse Limited Overlap Sine Early undifferentiated SSc 10% o SSc with early disease duration from non-rp symptoms [3 (to 5) years] = SSc with high prevalence of internal organ involvements 78% 12% 43% 1% SSc-RA 25% SSc-PM 10% SSc-SLE 8% Rheumatology (Oxford). 2008;47: Ann Rheum Dis. 2007;66: Ann Rheum Dis. 2009;68: Ann Rheum Dis. 2015;74: J Rheumatol. 2014;41:

13 Imp. Scleroderma What to do next? 1. Disease duration from onset of Non-RP? 1. Early disease duration: 3(5) years o Organ = RP & digital ischemia, Scleroderma, GI, ILD, SRC 2. Late disease duration: >3(5) years o Organ = Cardiovascular (PH, PAH), digital ischemia/ contracture 2. Disease subset o Early undifferentiated, dcssc, lcssc, Overlap, Sine 3. Internal organ involvement

14 Except (95%) RP, (99%) scleroderma, (80%) GERD, (70%) digital pitting Prevalence of internal organ involvement: The 15% rule Organ involvement % 95% CI Siriraj Scleroderma renal crisis in dcssc Scleroderma renal crisis in SSc Cardiomyopathy (LVEF 45%) in SSc Clinical congestive heart failure in SSc Diastolic dysfunction (by echo) in SSc Symptomatic pericarditis or moderate-large pericardial effusion in SSc Pulmonary hypertension (by echo spap > 40 or 45 mmhg) in SSc Pulmonary arterial hypertension (by right heart catheterization) in SSc N/A Pulmonary restriction (FVC <70% predicted) in SSc Malabsorption/ intestinal pseudo-obstruction/ hyper alimentation in SSc Myositis in SSc Arthritis by swollen/ tender joint in SSc Prevalent digital ulcer in SSc Current digital gangrene in SSc Digital amputation in SSc Hospitalization due to digital vascular ischemic complication in SSc N/A Overlap Sjogren s syndrome in SSc J Rheumatol. 2013; 40:

15 Scleroderma Organ Involvement (1.1) Skin: assessment & progression Dorsum arm x 2 Dorsum forearm x 2 Dorsum hand x 2 Dorsum 2 nd or 3 rd fingers x Face Chest Abdomen Thigh x Calf x Foot x Modified Rodnan Skin Score (mrss) 0 = normal skin 1 = mild thickening 2 = moderate thickening 3 = severe thickening o Score range from 0 to 51 o mrss >20 = severe scleroderma o mrss <10 = mild scleroderma o Flare = change 25% or 5 unit o Improve = change 25% or 5 unit

16 Progression of mrss 23 mrss o Median time-to-peak mrss = 1 year o Median peak mrss for dcssc = 23 [IQR ; mean 22.8, SDD 9.6] o Median peak mrss for lcssc = 9.5 [IQR 6 14; mean 10.4, SD 6.1] *EUSTAR prospective study SSc RP within 1 year Puffy Clinical Dried (loss of sweat, sebum, hair), scleroderma Telangiectasia Median peak mrss: dcssc After a median of 1 yr. [IQR ; mean 1.9±2] dcssc 9.5 Median peak mrss: lcssc After a median of 0.9 yr. [IQR ; mean 2±2.5] lcssc edematous fibrotic atrophic Onset of RP symptom Ann Rheum Dis Jul 31. doi: /annrheumdis Yr.

17 Predictor for rapid progressive skin sclerosis** mrss 1. Arthritis (swollen & tender joint) 2. Tendon friction rub 3. Digital ulcer 4. Anti Scl-70 positivity Ann Rheum Dis. 2016;75: Median peak mrss: dcssc Development of internal organ involvement 1. GERD 2. digital ischemic vascular complications 3. Interstitial lung disease 4. scleroderma renal crisis dcssc 9.5 Median peak mrss: lcssc edematous fibrotic atrophic lcssc Onset of RP symptom Ann Rheum Dis Jul 31. doi: /annrheumdis Yr.

18 Predictor for rapid progressive skin sclerosis** mrss 1. Arthritis (swollen & tender joint) 2. Tendon friction rub 3. Digital ulcer 4. Anti Scl-70 positivity Ann Rheum Dis. 2016;75: Median peak mrss: dcssc Screening for internal organ involvement 1. Survey questioning for GERD symptoms 2. Exam for digital ischemia: RP, pitting scar, ulcer, resorption 3. Interstitial lung disease: Fc/DOE, crackles, CXR, PFT ±HRCT 4. scleroderma renal crisis: BP, Creatinine dcssc 9.5 Median peak mrss: lcssc edematous fibrotic atrophic lcssc Onset of RP symptom Ann Rheum Dis Jul 31. doi: /annrheumdis Yr.

19 Predictor for development of dcssc** mrss 1. Male gender 2. Anti RNA polymerase III 3. Anti Scl-70 positivity Ann Rheum Dis Jul 31. doi: /annrheumdis Median peak mrss: dcssc dcssc 9.5 Median peak mrss: lcssc edematous fibrotic atrophic Onset of RP symptom lcssc Yr.

20 Predictor for progression of scleroderma in dcssc mrss 1. Arthritis 2. Disease duration 15 months 3. mrss 22/51 Ann Rheum Dis. 2015;74: Median peak mrss: dcssc 9.5 Pts. who have mrss 22 & disease duration 15 mo. are apt to be progressive scleroderma Threshold for treatment of skin sclerosis Median peak mrss: lcssc dcssc lcssc edematous fibrotic atrophic Onset of RP symptom Ann Rheum Dis Jul 31. doi: /annrheumdis Yr.

21 Scleroderma Organ Involvement (1.2) Skin: Salt and Pepper appearance

22 1. General management 1. Moisturizer, sun screen, avoid rubbing 2. Anti histamine for itching skin 3. Range of motion exercise to prevent joint contracture 2. Specific treatment (DMARDs) 1. Methotrexate mg/wk months (FVC >70% predicted) (B) 2. Cyclophosphamide 2 MKD 12 months (A) 3. Mycophenolate mofetil (cellcept ) 3 g/day months (B) 4. Colchicine (C) 5. Chloroquine (C) Scleroderma Organ Involvement (1.3) Skin: Treatment Ann Rheum Dis. 2009; 68: Semin Arthritis Rheum. 2012; 42: Br J Rheumatol. 1996; 35: Arthritis Rheum. 2001; 44: N Engl J Med. 2006; 354: Am J Respir Crit Care Med. 2007; 176: Aim at mrss = 0 No tendon friction rub Save skin appendages & skin pigment Rheumatology (Oxford). 2007; 46: Ann Rheum Dis. 2011; 70: Rheumatology (Oxford). 2009; 48: J Rheumatol. 2012; 39: J Rheumatol. 1979; 6: J Rheumatol. 1977; 4:272-6.

23 mrss plot over 1 year stratified by skin sclerosis burden group (AUC of mrss x 1 yr.) High skin burden Overall Moderate skin burden Low skin burden -5

24 Scleroderma Organ Involvement (2.1) Lungs: Interstitial lung disease (ILD) Siriraj: symptomatic SSc-ILD 39% SSc ILD o o After Dx SSc 6 mo. o Before Dx SSc 3.6 mo. 46% NSIP Nonspecific interstitial pneumonia 14% UIP Usual interstitial pneumonia o After Dx SSc 5 yr. C NSIP Cellular NSIP F NSIP Fibrotic NSIP HRCT chest o NSIP: ground glass opacity o UIP: reticular/interlobular/interstitial thickening, traction bronchiectasis/bronchiolectasis, honey-comb appearance

25 Pure GGO: Lung attenuation Any GGO: Interstitial thickening

26 UIP: interstitial thickening, traction bronchiectasis UIP: end-stage lung disease Honey-comb appearance

27 Level1 origin of great vessel

28 Level② tracheal carina

29 Level3 pulmonary veins

30 Level4 between 3 & 5

31 Level5 1cm above Rt. hemi diaphragm

32 Scleroderma Organ Involvement (2.2) Lungs: Interstitial lung disease (ILD) % predicted Normal Defect in SSc Pathology in SSc FVC 80 Restriction UIP FEV1/FVC 80 Large airways FEF 25-75% 80 Small airways TLC 80 Restriction UIP DLCO/VA 80 Gas exchange NSIP or PH/PAH 6MWD 380 CV/RS reserve UIP, NSIP, or PH/PAH Induction Cyclophosphamide oral 2 MKD 12 months (B) - Cyclophosphamide IV 600 mg/m 2 q mo. x 6 mo. + prednisolone 20 mg AD (B) Mycophenolate mofetil G/D 12 months (B) Predictor of progression 1. Early disease (<5 yr.) 2. Anti-Scl-70 (+) 3. HRCT>20% lung-fields 4. Declines over a year 1. Absolute FVC 10% 2. Absolute corrected DLCO 15% Maintenance Azathioprine 2.5 MKD x 6 mo. N Engl J Med. 2006; 354: Arthritis Rheum. 2006; 54: Rheumatol Int. 2012; 32: Lung. 2013; 191: Pulm Med. 2012; 2012:

33 Scleroderma Organ Involvement (3.1) CVS: pulmonary hypertension RHC The 5th world PH symposium Pulmonary arterial hypertension (PAH) 2. Pulmonary hypertension left sided heart disease 3. Pulmonary hypertension lung disease (ILD) 4. Chronic thromboembolic PH (CTHEP) 5. PH multifactorial mechanisms Normal cardiac output PAH = mpap > 25 mmhg at rest PCWP 15 mmhg

34 Scleroderma Organ Involvement (3.2) CVS: pulmonary hypertension RHC Medial hyperplasia Intimal proliferation Normal cardiac output PAH = mpap > 25 mmhg at rest PCWP 15 mmhg o The pathologic changes in SSc-PH involve small- to medium-sized pulmonary a. o The obliterative pulmonary vasculopathy is characterized by 1. Intimal proliferation and fibrosis 2. Medial hyperplasia 3. Adventitial fibrosis 4. ± in situ thrombosis

35 Scleroderma Organ Involvement (3.3) CVS: pulmonary hypertension 1) SSc-PAH (vasculopathy) lcssc mpap > 25 mmhg; PCWP 15 mmhg 2) SSc-PH due to left sided heart disease dcssc mpap > 25 mmhg; PCWP > 15 mmhg 3) SSc-ILD-PH (PH due to chronic lung disease / hypoxia) mpap > 25 mmhg; PCWP 15 mmhg; FVC < 60% or FVC 60-70% + HRCT-chest moderate-severe ILD Diffusion defect, V/Q mismatch and Entrapment of pulmonary capillaries/ arterioles SSc-CTEPH is only 0.1% (worldwide) SSc-APS is 2% (Siriraj), SSc-CTEPH is 0.5% (Siriraj) Need a long period of time to cause obliterative pulmonary vasculopathy dcssc PH-ILD happened earlier relatively to PAH and PH-LHD Simonneau G, et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2009;54(1 Suppl):S43-54.

36 Scleroderma Organ Involvement (3.4) CVS: pulmonary hypertension o Incidence: /100/year (White) o Prevalence: 15% (worldwide = Siriraj) o Late complication 9-10 yr. (White); 6 yr. (Siriraj) o Worldwide lcssc > dcssc SSc-PAH > SSc-PH-ILD/SSc-PH-LHD o Siriraj (Thai) dcssc > lcssc SSc-PH-ILD > SSc-PH-LHD > SSc-PAH o Siriraj SSc-PH: 94% dcssc, +NSIP 50%, +UIP 17%

37 Scleroderma Organ Involvement (3.5) CVS: pulmonary hypertension surveillance Echocardiography (TTE) (1) RVSP (mmhg) <36 mmhg 36 X <50 50 mmhg mpap 25 mpap >25 No PAH Suspected PAH RHC Pulmonary function test DLCO/VA <60 or FVC/DLCO >1.6 (S&S) DLCO/VA <60 or FVC/DLCO >1.6 and NT probnp >2X UL DLCO/VA <60 or FVC/DLCO >1.6 (S&S) FVC < 60% or FVC 60-70% + HRCT-chest moderate-severe ILD > (S&S) >2.8 (3) RA dimension >53 mm (2) TRV max (m/s) And RV midcavity dimension >35 mm

38 Scleroderma Organ Involvement (3.6) CVS: pulmonary hypertension treatment o 2015 ESC ERS guideline general measures (PAH) 1. Activity active within symptom limits 2. Avoid pregnancy (barrier) 3. Influenza & Pneumococcal vaccination 4. Supportive Px 1. Diuretics (RV failure + fluid retention) 2. O2 therapy in PaO2 <60 mmhg/ <91% SPaO2 3. Oral anticoagulant in CTHEP 4. Correction of IDA o Specific treatment: Fc III Sildenafil (10) mg q 8 hr.

39 Scleroderma Organ Involvement (4) GI tract Purse lips Oral aperture (<3 cm) 2 nd Sjogren syndrome Esophageal dysphagia (Oropharyngeal PM) GERD GAVE IDA Dysmotility malnutrition Constipation Bacterial overgrowth Pseudo diverticulosis Treatment 1. PPI / antacids 2. Prokinetics 3. Laxatives 4. Antibiotics

40 Scleroderma Organ Involvement (5.1) Vessels: RP & digital ischemia Digital ischemic complications 1.Raynaud phenomenon 2.Digital pitting scar 3.Digital tip/finger ulcer 4.Digital gangrene/auto amputation 5.Digital fat pad loss/shortening

41 Scleroderma Organ Involvement (5.2) Vessels: RP & digital ischemia Treatment RP & Primary prevention for digital ischemic complications o Nifedipine sustained/controlled release mg/day o + alpha blocker, ACEI, ARB o ± Low dose ASA, chloroquine o Change to Sildenafil mg/day Treatment for digital ischemic complications o Nifedipine sustained/controlled release mg/day o Or Sildenafil mg/day o Or Iloprost nanogram/bw 1 kg/minute 3 5 days

42 Scleroderma Organ Involvement (6) Musculoskeletal o RA overlap Px as RA o Swollen & Tender joint: 15% o PM overlap Px as PM but caution for steroids o Proximal muscle weakness + CPK ± EMG/NCV ± M. biopsy: 15% o Bland myopathy: o Mild proximal muscle weakness + mildly elevated CPK o Without EMG/NVC + M. biopsy evidence of myositis

43 Scleroderma Organ Involvement (7) Kidney: Scleroderma renal crisis 1. Rapidly progressive skin sclerosis (first 4 year) 2. Tendon friction rub 3. Prednisolone 15 mg/day (last 6 months) 4. Anti RNA polymerase III o10% normotensive o previous ACEI, CCB o cardiomyopathy o No prophylactic ACEI o Cannot SRC o Worse outcome o likelihood of permanent dialysis o Proliferative obliterative vasculopathy without inflammation or immune deposition o Accelerated HT, oliguric ARF, TMA, MAHA, CHF, encephalopathy, retinopathy o Captopril SBP 20 / DBP 10 mmhg 1 st 24 hr. 2 nd line: CCB, α blocker Shanmugam VK, Steen VD. Curr Opin Rheumatol. 2012;24:

44 Scleroderma OPD service (1) 1.1 Scleroderma worsening? 1.2 Raynaud worsening? 1.3 Dyspnea (Fc) worsening? 2 BW/ GI symptoms? 2.1 Dysphagia 2.2 Acid in mouth 2.3 Night regurgitate 2.4 Heartburn 2.5 Early satiety 2.6 Constipation Physical Exam 3.1 Inter incisor distance 3.2 Salivary pooling/oral thrush 4 CVS: BP, loud P2 5 RA: crackles 6 mrss, tendon friction rub, salt pepper 7 Digital ischemic complications o Raynaud phenomenon o Digital pitting scars/ tip ulcer/ gangrene 8 Proximal muscle weakness (PM) 9 Swollen/Tender joint (RA) Lab: CBC, ESR/CRP, Cr, CPK, AST, ALT, albumin, UA/UPCR Annually CXR, ECG, Echo, PFT+DLCO/VA If DOE: HRCT chest

45 Scleroderma OPD service (2) 1.1 ASA (81) 1x1 1.2 Nifedipine (20)SR 1x1 2.1 Chloroquine (250) ½ x1 2.2 Colchicine (0.6) 1x2 2.3 DMARDs: Skin: MTX, CyC, MMF NSIP: CyC, MMF PM: MTX, AZA, CyC, MMF RA: MTX 3.1 Omeprazole (20) 1x2 ac 3.2 Domperidone (10) 1x3 ac 4 Moisturizers, Sunscreen 5 Antihistamine 6 Laxatives 7 if MTX Folic (5) 1x1 8 if CYC Bactrim DS 1x1 M,W,F 9 if ILD Influenza vaccination