Disclosure. Lecture Goals. Complicated Raynaud s Phenomenon 11/6/2011

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1 Complicated Raynaud s Phenomenon Fredrick M. Wigley MD Johns Hopkins University ACR Chicago Disclosure Actelion:.Research/Lecture Amira:.Consultant/Research Kinemed: Research Medimmune:.. Research Mediquest Consultant Novartis:. Consultant/Research Orion:.. Consultant/Research Pfizer: Research Roche Consultant United Therapeutics: Research/Consultant FDA unapproved drugs and off-labeled drug use will be discussed in this lecture. Lecture Goals What is? What are some facts about its pathogenesis? How can we determine if there is critical digital ischemia? How to manage critical ischemia and complex Raynaud s Phenomenon? Cold (or emotional stress) induced sharp demarcated pallor and/or cyanosis of the distal fingers or toes. Raynaud s Phenomenon Closure of digital artery and arterioles reducing total finger blood flow Elastin with little smooth muscle Major arteries Smooth muscle Medium-Small arteries Smooth muscle Regulate regional blood flow 1

2 of the Feet What is needed to make a Diagnosis of Raynaud s Phenomenon? Ask the following questions: Study for the presence of Macro-vascular disease 1. Are your fingers unusually sensitive to cold? 2. Do your fingers change color when they are exposed to cold? 3. Do they turn white, blue or both? Confirmed if positive response to all three questions Excluded if response to 2 and 3 are negative Prevalence of Raynaud s phenomenon USA 3-5% African Americans 3% Spain 3-5% Japan 3% Netherlands 2.9% France 13-20% England 4.6% Children 15% Italy % Turkey % Greece % Estonia Slavs 11-13% Estonians 7-8% Hungary 6% 3-5% Women > Men Young > Old Variables: Gender Ethnicity Climate Occupation Review of multiple publications Terminology Raynaud Phenomenon Raynaud s Syndrome Idiopathic Raynaud s Raynaud s Disease Primary Raynaud s Phenomenon Primary RP : Abnormal Vascular Reactivity Alone Secondary Raynaud s Phenomenon Secondary RP: a variety of Insults that create abnormal Vascular Reactivity Acrocyanosis Persistent, painless, symmetric cyanosis of the hands and, less commonly, the feet, caused by vasospasm of the small vessels of the skin. Idiopathic or Secondary Hypoxemia, acrocynosis of infancy, cold agglutinins, cryoglobulinemia, APL syndrome, medications, toxins, malignancies, neuropathy, malnutrition Chilblains or Pernio Localized areas of erythema, swelling, and pruritus resulting from exposure to damp cold. emedicine. medscape 2

3 Purple Digits Normal Responses to Cold Cold Associated Independent of Temperature Injury Induced Absent Pulses Pulses Frost bite Non-freezing injury Pernio Chilblain lupus Raynaud s Acrocyanosis Cryogelling disorders cryoglobulins cryofibrinogens Secondary emboli or thrombosis Vasospasm is not always Raynaud s Phenomenon Anxiety Microemboli Microvascular occlusion Shock Hemorrhage Tissue infection Brown PJ et al Am J Clin Dermatol 2010 THERMOREGULATORY VESSELS Thermoregulatory Vessels The human skin has a unique circulation with both nutritional and temperature control functions 80-90% Cutaneous blood flow The cutaneous circulation plays a major role in maintaining normal core body temperature. Ambient temperature, Emotional state, Physical activity, Trauma to vessels or injury, Age Scleroderma: Vascular smooth muscle arterioles displayed a selective increase in a2-ar reactivity The thermoregulary vessels are primarily under sympathetic control Flavahan N. et al Arth Rheum 2000 Thompson-Tergerson et al

4 Adventitia Media (smooth muscle cells) Blood Flow Autonomic nervous system Intima Platelet activation Thromboxane Endothelial Injury White blood cells Neuropeptides CGRP SP NK-A NPY SOM Ach VIP NE Platelets Fibrinolysis Viscosity Platelet Activation Cytokines Endothelin Nitric Oxide Prostacyclin Constrict Dilate Dilate Alpha 2C receptor Endothelim Reversible Vasospasm Digital Ischemia Critical ischemia with vasospasm Primary involves all digits symmetrically Alone Primary Raynaud s Raynaud s disease Structural vascular disease Alone associated structural vascular disease Secondary Raynaud s syndrome In the Thumb is less often involved but not spared Pallor beyond the MCP joints is worrisome 4

5 Signs of tissue injury, ulceration or gangrene do not occur with uncomplicated vasospasm REVERSIBLE Start IN MINUTES AFTER 5 minutes REWARMING 10 minutes 15 minutes Primary Raynaud s Phenomenon Allen. E and Brown, G: 1932 Vasospastic attacks precipitated by cold or Scleroderma emotional stress Symmetric 20% if abnormal attacks nailfold in both hands Absence of tissue necrosis or gangrene 80% if abnormal nailfold and autoantibody No history or physical findings suggestive of secondary cause Normal nailfold capillaries Normal erythrocyte sedimentation rate (ESR) Negative serologic findings Reversible Vasospasm Alone Primary Raynaud s Raynaud s disease Digital Ischemia Critical ischemia with vasospasm Structural vascular disease Alone associated structural vascular disease Secondary Raynaud s syndrome Secondary Scleroderma= Immune: Reported Autoimmune 95-99% Cases Disease MCTD= Trauma: Reported Hand-Arm 95% studies of Vibration CTS with Syndrome RP Hypothyroidism and Gemcitabine RP SLE= Mechanical: 20-40% Thoracic Outlet Syndrome PM/DM= 0-60% RP of disappears Proteins: Cryoglobulins; 10% cases on Carboplatin treatment of thyroid Associated RP bilateral Cyrofibrinogens Cisplatin if CT unilateral Sjogren s= 13-33% UDCTD= Neurogenic: May not improve 50% Carpal Tunnel with release Bleomycin Syndrome of CT Batthish J Rheum 2009 Vincristine RA= Hormones: Meta-analysis % Hypothyroid; Latelwish J. Endo Invest : 15.5% of? CT Estrogens 1992 Shagan Arch Int Med 1980 have RP Toxins/Drugs/Vasoconstrictors: Smoking Hartman et al Rheumatol Int 2011 Vascular disease: Diabetes, Vasculitis, etc. Digital Ischemia Critical Ischemia with vasospasm Inflammatory Thrombotic Embolic Other: Aneurysm Atherosclerosis Arteriosclerosis Trauma Entrapment: TOS Single Digit Malignant lesion Asymmetry Absent pulses or Bruits Cutaneous signs of tissue injury 5

6 Always consider Macro-vascular disease when confronted with lower extremity digital ischemia Cold Fingers Or Critical Ischemia? 5% SYMPTOMATIC ASCVD > AGE 60 Measurement of ankle : brachial pressure index (ABPI) Is a mandatory part of clinical exam. ABPI < 0.9 demonstrates 95% sensitivity for the presence of angiographic proven disease Examination for Digital Ischemia Permanent discoloration of the digit and pain are the main symptoms of critical ischemia. Critical digital ischemia leads to signs of irreversible compromise to blood flow 6

7 Pain = continued tissue ischemia Principles to Management Vasospasm Vessel Injury Occlusion Warm Temperatures Doppler Blood Flow Keep the whole body warm Avoid rapidly shifting temperatures Avoid cold breezes Avoid cold and stress 28C. 35C. Goodfield 1988 SSC Normal Managing Scleroderma / Digital Ischemia TARGETING SMOOTH MUSCLE Oral Vasodilator Intravenous Prostaglandins Novel Preventive Therapy Endothelin-1 inhibitor Statins Anti-platelet: ASA 81 mg Anti-oxidant Therapy Surgery Sympathectomy Vascular repair Calcium Channel Blockers Dihydropyridines Nifedipine... Amlodipine... Nicardipine.. Isradipine... Felodipine... Modest Benefit 35% reduction in severity score Adalat, Procardia Norvasc, Azor Cardene DynaCirc Plendil Amlodipine 5mg: titrate to full tolerated dose (20 mg) Anti-platelet Anti-oxidant Vascular 7

8 Topical Nitrates BEFORE DIRECT VASODILATORS ACE inhibitors do not benefit Treated with topical glyceryl trinitrate Low Perfusion= Blue High Perfusion= Red AFTER Calcium Channel Blockers Dihydropyridines Nitrates Topical Quinapril did not affect the occurrence of digital ulcers or the frequency or severity of RP episodes. Vascular Gliddon et al Arthritis&Rheum 2007 No treatment ACE inhibitors/arb Captopril, Enalapril, Quinapril / Losartan Angiotensin Placebo Anderson et al 2002 Niacin Hydralazine Angiotensin Receptor Blocker Primary RP= 25 Secondary RP= weeks Losartan 50 mg RP severity (0-10): 5.50 to 2.84 RP frequency (daily): 3.52 to 1.96 Nifedipine 40 mg RP severity (0-10) : 4.48 to 3.90 RP frequency (daily): 3.65 to 4.4 DIRECT VASODILATORS Endothelial Cell Phosphodiesterase Inhibitors Sildenafil, Vardenafil, Tadalafil Endothelin Inhibitors Bosentan, Ambristatin, Sitaxsentan NO substrates L-arginine Prostaglandins Vascular Dziadzio et al Arth Rheum 2001 Sildenafil vs. Placebo Modified release Sildenafil 50 mg bid N= 57 Limited scleroderma 3 days 100 mg then 200 mg for 25 days Outcomes: Change in RP RCS Duration of attacks Pain score Biomarkers Fries, R. et al. Circulation 2005;112: Copyright 2005 American Heart Association Phosphodiesterase Inhibitor Herrick et al Arth Rheum

9 Phosphodiesterase Inhibitors Based Sildenafil on current : data from small clinical trials, open-label Benefit pilot : Fries studies et al Circulation and 2005 case series and reports, phosphodiesterase 5 inhibitors may help some No Benefit: Zamiri et al Ann Rheum Dis 2004 patients with very serious Raynaud s. Tadalafil: A large, well-conducted multicenter, 20 mg for 4 weeks: No Benefit Schiopu et al J Rheum 2009 double-blind study is needed to determine the benefit and risk 20 mg of these as add agents on (CCB): in Raynaud s Benefit phenomenon. Shenoy et al Rheumatology 2011 Alfonso et al Expert Opin Invest Drugs 2009 Vardenafil Open-labeled study: improved digital blood flow» Caglayan et al Arch Intern Med 2006 Adrenergic Nerves Blockers Sympathetic Nervous System Direct Vasodilators Endothelial Cell Endothelin Inhibitors Bosentan, Sitaxsentan Prostanoids NO substrates Direct Vasodilators Phosphodiesterase Inhibitors Sildenafil, Vardenafil, Tadalafil Vascular Bosentan Rapids Double-blind, 2 placebo controlled trial 122 patients; randomized 2:1 to receive Mean bosentan new ulcers (62.5 mg po No bid benefit then to for 125 Severity mg po bid) or placebo for 16 of weeks. Raynauds attacks: Bosentan. 1.9 Fewer Placebo new. digital 2.7 ulcers Recommended only for Placebo mean 2.7 ulcers (p=.0083) Scleroderma patients Matucci-Cerinic Bosentan Ann mean Rheum 1.4 Dis ulcers 2011 with recurrent digital Improved hand function ulcers Korn JH et al. Arth Rheum Prostaglandins Intravenous Prostaglandins PGE 1 Alprostadil PGI 2 Epoprostenol Iloprost, Treprostinil Subcutaneous PGI 2 Treprostinil Oral Prostaglandins PGE 1 Misoprostol PGI 2 Iloprost, Cisaprost, Beraprost, Treprostinil 40.00% 35.00% 30.00% 25.00% 20.00% 15.00% 10.00% 5.00% 0.00% IV Iloprost : Multi-center Study Attacks RP Score Percent Improvement from Baseline N =131 Iloprost Placebo Wigley: Annals Intern Med

10 Cyclic Iloprost Oral Prostaglandins Repeated exposure Weekly during winter Every 3-4 or 6 weeks Every 3 months Continuous for 8-21 days Cordioli et al Minerva Med 1992 Zachariae et al Acta Derm Venerol 1996 Scorza et al Clin Exp Rheuamtol 2001 Bettoni et al Clin Rheumatol 2002 Garcia Hernandez et al Med Clin 2004 Milio et al Rheumatology 2006 More oral prostacyclin (Treprostinil) Freedom-M 12 week trial (n=228) BID drug versus Placebo Class II-III, CTD (19%) Median walk improved 25.5 meters vs. -5 meters (p=0.0125) 183 now on open labeled (up to 3 years followup) More new stable Epoprostenol Prostaglandin Receptor Agonist Adrenergic Nerves Blockers Sympathetic Nervous System Circulating Modulators Endothelial/VSM Cells Direct Vasodilators Direct Vasodilators Endothelial Cell Prostacyclin receptor (IP)Agonist (Selexipeg) N=43 in placebo controlled trial on ERA or PDE Primary outcome: PVR treatment effect 30.3% at 17 weeks (p=0.0045) Secondary outcome: 6MWT improved Tolerated well with expected side effects Simonneau et al Abstract ATS 2010 Serotonin Inhibitors (SSRIs) Fluoxetine Anti-oxidants Probucol, NAC, Statins Aspirin Thromboxane Inhibitors Vascular Smooth Muscle Fluoxetine (Prozac) Patients n=53 (26 PRP, 27 SRP) randomized Fluoxetine 20 mg daily vs. Nifedipine 40 mg daily BOTOX Coleiro B et al. Rheumatology 2001;40(9):

11 Complementary Medicine Acupuncture (n=2) Anti-oxidants (n=2) Biofeedback (n=5) Essential Fatty Acids (n=3) Ginkgo Biloba (n=1) L-arginine (n=2) Laser (n=3) Glucoaminogylcans (n=1) Therapeutic gloves (n=1) Malenfant et al Rheumtology 2009 Vasodilator Options Calcium Channel Blocker: Nifedipine; Amlodipine Nitric oxide: Topical Nitrates Phosphodiesterase inhibitors: Cilostazol Pentoxifylline Sildenafil Tadalafil Selective Serotonin Reuptake inhibitors: Fluoxetine Angiotensin receptor inhibitor: Lorsartan Alpha-adrenergic blockers: Prazosin Prostaglandins: Prostacyclin (PGI2) Rho-Kinase inhibitor: Fasudil Other: Botulium toxin; alpha 2c receptor antagonist Address Underlying disease process Avoid cold, stress and aggravating factors Calcium Channel Blocker alone Add ARB, alpha blocker, PDE inhibitor or nitrate, SSRI Intravenous Prostaglandins Add Statin and/or ET-1 inhibitor Digital sympathectomy Surgical correction Vascular Protection Vasospasm: Vasodilators Vasculopathy: Statins? Prostaglandins: PGI2? Angiotensin II type I RB: Losartan? Tyrosine Kinase inhibitors: Gleevic? Endothelin inhibitors: Bosentan? Rho Kinase Inhibitors: Fasudil? Anti-oxidants: Probucol; N-acetylcysteine Vascular occlusion: Anti-platelet? Anti-coagulation? STATINS 84 scleroderma patients for 4 months Atorvastatin 40mg/day (n=56) Placebo (n=28) Number of New Ulcers (mean) Active Drug=1.6 versus Placebo= 2.5 Persistent Pain is a medical emergency indicating urgent care SHAQ-DI, VAS for RP, DU severity, and pain scales favored STATIN group Endothelial markers improved. Abou-Raya et al J Rheumatol

12 Platelet activation Fibrin deposition Fibrinolysis Persistent widespread ischemic pain heralds tissue infarction and gangrene. Acute Digital Ischemia Acute Digital Ischemia Rest and warm Control Pain Local digital block Start Vasodilator: Calcium Channel Blocker Prostaglandins Digital block. 2% Lidocaine 0.5% Bupivacaine 1% Mepivacaine Continuous Regional Anesthesia O.2% ropivacaine (Greengrass et al 2003) Copyright 1996 Acute Digital Ischemia Start Vasodilator: Short acting CCB Titrate to maximum tolerated dose If non-responding or severe event start IV prostaglandins Prostaglandins Intravenous Prostaglandins Peripheral PGE 1 Alprostadil vein at ng/kg/min continuous PGI 2 Epoprostenol for 3-plus days Iloprost Treprostinil Consider Inhaled prostaglandins 12

13 Iloprost in the treatment of ischemic digits in pediatric CTD 15 patients Juvenile scleroderma (6) Systemic lupus erythematosus (5) Mixed connective tissue disease (3) Cutaneous polyarteritis nodosa (1) All improved signs of digital ischemia Normal digital flow in 74% Six (3 with gangrene) failed therapy Only minor side effects Zulian et al Rheumatology 2004 Anticoagulation Unfractionated Heparin (UFH) Low Molecular Weight Heparin Synthetic Although Heparin no studies Pentasacchride are available (?) when acute rapid advancing ischemia Direct Thrombin inhibitors (?) Is present, short term anti-coagulation makes sense Precaution: GI bleeding Anti-fibrinolytic therapy is not recommended Anti-platelet Therapy Surgical Options Aspirin 81 mg daily Vasodilator therapy Calcium Channel blockers Prostaglandins Other Options Ticlopidine, Clopidogrel Cilostazol, Pentoxifylline Sympathectomy Microsurgical revascularization If no response to medical therapy then Digital Move to arterial Surgical reconstruction options Wound Care Bogoch et al J of Rheum 2005 Sympathectomy Proximal Sympathectomy Uncontrolled data in 580 patients suggest 89% benefit Coveliers et al J Vasc Surgery 2011 Digital Sympathectomy 15/20 autoimmune patients had complete healing and or decrease of ulcers A sympathectomy can reverse an acute ischemic crisis but may not cure the problem. Hartzell et al J Hand Surg

14 Vascular Surgery Ulnar artery Digital artery Combined surgery: Microsurgical revascualrization Arterial reconstruction Sympathectomy Allen s Test Amputation Fredrick M. Wigley, M.D., Professor of Medicine, Johns Hopkins University, and Director of the Johns Hopkins Scleroderma Center Consequences of Vascular Injury Some fingers are worse than others. Index, Middle: worse Thumb: least White attacks lead to critical ischemia. Blue attacks are mainly thermoregulatory vasospasm. Low blood flow usually last 15 minutes after rewarming. Painful attacks are a symptom of ischemia. Vasospasm Ischemia- reperfusion Vasculopathy Intimal Fibrosis Vessel loss Ischemia-Reperfusion injury Tissue Hypoxia Superoxide Radicals Coagulation Platelet activation Fibrinolysis Vasodilators Protective agents Immunosuppression Stem cells Anti-oxidants Nitric Oxide Inhibit Platelets Acute anticoagulation 14

15 Nutritional Blood Flow: The capillaries α2c-adrenergic blockers Adventitia Media (smooth muscle cells) Thermoregulatory Blood Flow: The AV shunts Autonomic nervous system CCBs Intima COLD FINGERS versus ISCHEMIC FINGERS NO PDE inhibitors WARM TEMPERATURES PGI White blood cells 2 Neuropeptides CGRP SP NK-A NPY SOM Ach VIP NE Nitrates ET-1 Prostaglandins ACE inhibitors Platelets 5-HT TXA ET-1 inhibitors SSRIs aspirin Rho-kinase inhibitors Thanks All members of the team at the JOHNS HOPKINS SCLERODERMA CENTER Thanks All members of the team at the JOHNS HOPKINS SCLERODERMA CENTER Phone: Fax: Phone: Fax: Managing Scleroderma Digital Ischemia RP with No Ulcers Stop Aggravating Factors Cold Trauma Stress Smoking Severe Ischemia Ulcers Start Calcium Channel Blocker Plus Aspirin Titrate CCB to maximum tolerated Dose Add Second vasodilator agent: PDE-5 Inhibitor Nitrates Prostacyclins Protective Agents 15

16 Transient Receptor Potential Channel Melastatin member 8 (TRPM 8) Preoptical : Anterior Hypothalamus Thermostat Patapoutlan et al 2003 A decrease of calcitonin gene-related peptide Whole-Body (CGRP) Cooling immunoreactive nerves in the epidermis and around capillaries in the dermal papillae (P = 0.005). Bunker et al Lancet 1990; Terenghi et al J. Path 1991 Neuropeptides CGRP SP NK-A NPY SOM Ach VIP NE Cutaneous vasoconstriction through the sympathetic nervous system is the initial response to cold exposure minimizing heat loss Thompson-Torgerson et al 2009 Lecture Goals Digital Ischemia Reversible Vasospasm Critical ischemia with vasospasm Alone Primary Raynaud s Raynaud s disease Structural vascular disease Alone associated structural vascular disease Secondary Raynaud s syndrome 16

17 Anti-oxidants Probucol: Twelve weeks' treatment with 500 mg (n=40; 20 with scleroderma) a reduction in the frequency and severity of Raynaud s attacks and a rise in oxidation LDL lag time (Denton et al 1999) A combination of micronutrient antioxidants and allopurinol No benefit: vwf factor or response to cold or RP (Herrick et al 2000). Vitamin E ( mg daily) vs placebo No difference in whole body cooling and urinary F(2)- isoprostane (Cracowski et al 2005) N-acetylcysteine (NAC) Failed Clinical Trial (Furst et al : 1979) IV therapy for RP (Sambo et al: 2001; Rosato et el 2009) Scleroderma Macro-vascular disease Calcium Channel Angiotensin Autonomic nervous system Adventitia Media (smooth muscle cells) Intima White blood cells Blood Vessel Circulating Factors Neuropeptides CGRP SP NK-A NPY SOM Ach VIP NE Platelets Nitric Oxide: Prostaglandin: PGI2 Serotonin Thromboxane Neural Control Alpha 2C receptor Endothelin-1 ACE inhibitors Quinapril did not affect the occurrence of digital ulcers or the frequency or severity of RP episodes. CCB alone Add ARB, alpha blocker, PDE inhibitor or nitrate SSRI Administration of quinapril for up to 3 years had no demonstrable effects on the occurrence of upper limb digital ulcers or on other vascular manifestations of lcssc in this patient population. Gliddon et al Arthritis&Rheum 2007 Intravenous Prostaglandins Add Statin and/or ET-1 inhibitor Digital sympathectomy Surgical correction 17

18 Digital Sympathectomy A systematic Review of the Outcomes of Digital Sympathectomy for Treatment of Chronic Digital Ischemia. 251 digits with avg. follow-up 0.5 to 4.7 years 14 % required amputation 18% had recurrence of ulcers Scleroderma: Complications in 37%. Kotis and Chung. J Rheum 2003 Prostacyclin analogs The Cochrane review of 7 clinical trials using prostacyclin analogs in RP secondary to scleroderma found similar results, with the analysis favoring drug with respect to attack frequency and severity, physician assessment of treatment, and improvement in digital lesions. Pope J et al The Cochrane Library 2009 Blood vessels Cutaneous sensory nerves Decreased vasodilatation Increased reactivity : Alpha 2C Structural Disease Vasospasm Consider: Larger vessel disease, Vasculitis, Coagulopathy Smooth muscle Endo Endo Smooth Muscle Endothelin-1 Nitric Oxide Prostaglandins Damaging oxidative stress Vascular Lumen Platelet activation Viscosity Fibrinolysis Intimal fibrosis CLOT DIRECT VASODILATORS Calcium Channel Blockers Dihydropyridines Nitrates Topical Vascular ACE inhibitors/arb Captopril, Enalapril, Losartan, Quinapril Niacin Hydralazine 18