Peripheral (digital) vasculopathy in systemic sclerosis Ariane Herrick
Raynaud s phenomenon VASOPASM DEOXYGENATION REPERFUSION
Main causes of RP Primary (idiopathic) Connective tissue diseases, including SScspectrum disorders Hand-arm-vibration syndrome Extrinsic vascular compression Other causes of large vessel disease Intravascular disease/hyperviscosity syndromes Drugs, chemicals Other
Primary versus secondary RP In primary Raynaud s: Episodic attacks of acral pallor or cyanosis Strong and symmetrical peripheral pulses No evidence of digital pitting, ulceration or gangrene Normal nailfold capillaries Negative ANA (< 1/100) Normal ESR LeRoy & Medsger. Clin Exp Rheumatol 1992
Recently proposed diagnostic criteria for primary RP Maverakis et al. J Autoimmunity 2014
SSc-related digital vasculopathy Background: the scale of the problem Pathogenesis 4 case histories Current clinical practice Recent clinical trials The challenges
The scale of the problem 96.3% of patients with SSc experience RP Meier et al. Ann Rheum Dis 2012 Of 2080 patients with SSc, 58% reported a history of digital ulcers (DUs) Steen et al. Rheumatology 2009 Of 1168 patients with SSc, 17% developed at least one DU over an 18 month period Nihtyanova et al. Ann Rheum Dis 2008 DU often occur early in the course of SSc Hachulla et al. J Rheumatol 2007 Point-prevalence of DU in patients was 10% in a study of 148 patients Ennis et al. Scand J Rheumatol 2014
SSc-related digital vasculopathy Background: the scale of the problem Pathogenesis Case histories Current clinical practice Recent clinical trials The challenges
Pathogenesis of SSc-related RP l l l Vascular (functional and structural) Neural Intra-vascular
Functional vascular abnormalities l l l Imbalance between vasoconstriction and vasodilation Impaired vasodilation and/or Increased vasoconstriction
In SSc, digital vasculopathy is structural as well as functional Herrick. Nature Reviews Rheumatol 2012 Digital artery Nailfold capillaries
Analogies with PAH. Humbert et al. N Eng J Med 2004
Figure 1 Schematic representation of some of the key elements and mechanisms contributing to the pathogenesis of Raynaud phenomenon Herrick, A. L. (2012) The pathogenesis, diagnosis and treatment of Raynaud phenomenon Nat. Rev. Rheumatol. doi:10.1038/nrrheum.2012.96
SSc-related digital vasculopathy Background: the scale of the problem Pathogenesis 4 case histories Current clinical practice Recent clinical trials The challenges
How strongly does abnormal capillaroscopy predict SSc? In 586 patients with RP followed for 3197 person years, abnormal capillaroscopy and SSc-specifc antibodies were independent predictors of SSc SSc developed in: 1.8% with neither 25.8% with abnormal capillary pattern 35.4% with a specific autoantibody 79.5% with both Koenig et al. Arthritis Rheum 2008
New ACR/EULAR criteria for the classification of systemic sclerosis Criteria Sub-criteria Weight/score Skin thickening of the fingers of both hands extending proximal to MCP joints 9 Skin thickening of the fingers (count the higher of the two) Fingertip lesions (count the higher of the two) Puffy fingers Whole Finger, distal to MCP Digital Tip Ulcers Pitting Scars Telangiectasia 2 2 4 2 3 Abnormal nailfold capillaries Lung Involvement Pulmonary arterial hypertension (on RHC) and/or Interstitial lung disease (on HRCT) 2 2 Raynaud s phenomenon Scleroderma related antibodies Any of anti-centromere, anti-topoisomerase I (anti-scl 70), anti-rna polymerase III 3 3 ** Total score of 9 is classified as SSc Van den Hoogen et al 2013
SSc-related digital vasculopathy Background: the scale of the problem Pathogenesis 4 case histories Current clinical practice (including UK consensus best practice pathways) Recent clinical trials The challenges
EULAR recommendations for SScrelated digital vasculopathy l l l Calcium channel blockers are first-line IV iloprost or other IV prostanoids for: Severe RP Digital ulcers Bosentan for prevention of digital ulcers in patients with diffuse cutaneous SSc and multiple ulcers Kowal-Bielecka et al. Ann Rheum Dis 2009
1. Management of Raynaud s Phenomenon Establish diagnosis and identify any underlying cause amenable to treatment No underlying cause amenable to treatment Treat underlying cause e.g. cryoglobulinaemia 2. General/lifestyle measures: Patient education - Avoid cold, keep warm - Stop smoking (Complementary therapies) Ineffective 3. Drug therapy: first line 4. CCB, ARB, SSRI, alpha blockers, ACE inhibitors, topical nitrates + Antiplatelet and /or statin therapy Effective Ineffective oral therapies/refractory disease 5. Drug therapy: refractory IV prostanoid Effective 6. Ineffective PDE5 inhibitor Effective Progression to digital ulceration and/or critical ischaemia
Remember general/lifestyle measures l l l Keep warm! Stop smoking Remember the feet
1. Management of Raynaud s Phenomenon Establish diagnosis and identify any underlying cause amenable to treatment No underlying cause amenable to treatment Treat underlying cause e.g. cryoglobulinaemia 2. General/lifestyle measures: Patient education - Avoid cold, keep warm - Stop smoking (Complementary therapies) Ineffective 3. Drug therapy: first line 4. CCB, ARB, SSRI, alpha blockers, ACE inhibitors, topical nitrates + Antiplatelet and /or statin therapy Effective Ineffective oral therapies/refractory disease 5. Drug therapy: refractory IV prostanoid Effective 6. Ineffective PDE5 inhibitor Effective Progression to digital ulceration and/or critical ischaemia
Management of Digital Ulceration 1. Establish diagnosis early 2. Treat any contributory cause e.g. infection, large vessel disease 3. Optimal wound care and analgesia 4. 5. 6. Optimise oral vasodilators or IV prostanoids Consider surgical debridement in patients with necrotic tissue or underlying calcinosis + + Antiplatelet and/or statin therapy Ineffective/recurrent ulceration 7. Repeat IV prostanoids or PDE5 inhibitor or ERA Ineffective 8. Consider digital sympathectomy
Treat any contributory cause Infection (there may be underlying osteomyelitis) Underlying calcinosis Large (proximal) vessel problems Vasculitis/coagulopathy Smoking Exacerbating therapies
Management of Digital Ulceration 1. Establish diagnosis early 2. Treat any contributory cause e.g. infection, large vessel disease 3. Optimal wound care and analgesia 4. 5. 6. Optimise oral vasodilators or IV prostanoids Consider surgical debridement in patients with necrotic tissue or underlying calcinosis + + Antiplatelet and/or statin therapy Ineffective/recurrent ulceration 7. Repeat IV prostanoids or PDE5 inhibitor or ERA Ineffective 8. Consider digital sympathectomy
Management of Critical Digital Ischaemia 1. Establish diagnosis and identify any treatable contributory cause No contributory cause 2. Treat any contributory cause - Large (proximal) vessel disease -Vasculitis -Coagulopathy -Thromboembolism - Smoking 3. 4. 5. Admit for IV Antiplatelet therapy Consider statin 6. + + prostanoid and + analgesia Antibiotic if any possibility of infection Ineffective Effective 7. Optimise oral vasodilator therapy (consider PDE5 inhibitor) 8. Consider digital 9. Surgical debridement if necrotic 10. sympathectomy + tissue + Short term anticoagulation
SSc-related digital vasculopathy Background: the scale of the problem Pathogenesis 4 case histories Current clinical practice Recent clinical trials The challenges
Recent studies of PDE inhibitors Placebo controlled cross-over of tadalafil. No benefit Schiopu et al. J Rheumatol 2009 Placebo controlled cross-over of tadalafil. Improvement in RP symptoms Shenoy et al. Rheumatol 2010 Placebo controlled parallel group of modified release sildenafil. Reduction in RP attacks Herrick et al. Arthritis Rheum 2011 Placebo controlled cross-over of vardenafil. Improvement in RP symptoms Caglayan et al. Arch Int Med 2012 Udenafil 100mg/day of comparable efficacy to amlodipine 10mg/day in improving RP attacks Lee et al. Rheumatology 2014
Recent clinical trials of SSc-related DU RAPIDS-1 (bosentan) recruited 122 patients Korn et al. Arthritis Rheum 2004 RAPIDs-2 (bosentan) recruited 188 patients Matucci-Cerinic et al. Ann Rheum Dis 2011 Quinapril study recruited 210 patients (186 with SSc) Gliddon et al. Arthritis Rheum 2007 DISTOL (oral treprostinil) recruited 148 patients Seibold et al. Arthritis Rheum (abstract) 2011
New DU New DU RAPIDS-1 and RAPIDS-2 studies RAPIDS-1: Occurrence of new DU at week 16 1-48% p = 0.008* RAPIDS-2: Occurrence of new DU at week 24 2-30% p = 0.035** 3 2.5 2 1.5 1 0.5 0 *Poisson regression analysis **Pitman permutation test 2.7 n = 43 1.4 n = 78 Week 16 Placebo Bosentan 3 2.5 2 1.5 1 0.5 0 2.7 1.9 n = 89 n = 95 Week 24 Placebo Bosentan 1. Korn JH et al Arthritis Rheum 2004 2. Matucci-Cerinic et al Ann Rheum Dis 2011
SSc-related digital vasculopathy Background: the scale of the problem Pathogenesis 4 case histories Current clinical practice Recent clinical trials The challenges
The challenges l l l Developing new therapies Early diagnosis (capillaroscopy) Validating new outcome measures for use in clinical trials
Herrick. Rheumatol 2005
SSc-related digital vasculopathy Background: the scale of the problem Pathogenesis 4 case histories Current clinical practice Recent clinical trials The challenges
Conclusions SSc-related digital vasculopathy carries a huge burden of pain and morbidity Not all digital ischaemia in patients with SSc is due to microangiopathy alone Optimal implementation of the current recommendations requires: Rapid access clinics/ open door policy Availability of drug treatment Availability of multidiscipinary team support Current treatments are not ideal, indicating the need for clinical trials of new therapies