Raynaud Phenomenon and Digital Ulcers in Scleroderma

Presented by Lorinda Chung, MD of Stanford University School of Medicine.

1. Raynaud Phenomenon and Digital Ulcers in Systemic Sclerosis Lorinda Chung, MD, MS Associate Professor of Medicine and Dermatology Division of Immunology and Rheumatology Stanford University School of Medicine October 20, 2018

2. Raynaud Phenomenon and Digital Ulcers in Systemic Sclerosis Definitions Pathophysiology Current Management Strategies Potential Novel Treatments

3. What is Raynaud phenomenon? Cold or stress-induced episodic spasm of blood vessels leading to decreased blood flow to the fingers, toes, and sometimes ears and nose Characterized by typical color changes: White Blue Red with rewarming Associated symptoms: Numbness Pain Tingling Block et al. Lancet 2001;357:2042-8.

4. Maverakis et al. J Autoimmun 2014;48-49:60-5.

5. Subtypes of Raynaud phenomenon Primary RP Not associated with another disease Usually mild symptoms Risk Factors: Living in cold climate Female sex Smoking Family history of RP Secondary RP Associated with underlying disease such as scleroderma More severe symptoms related to damaged blood vessels Block et al. Lancet 2001;357:2042-8.

6. Nailfold Capillaroscopy Hand-held microscope used to look at capillaries (small blood vessels) at the proximal nailfold .

7. Nailfold Capillaroscopy Changes seen in Scleroderma and related diseases Enlarged or giant capillaries Capillary hemorrhages Loss of capillaries Disorganized or bushy capillaries One study showed that 82% of patients who presented with RP and these nailfold changes developed a connective tissue disease within 6.5 years. Scleroderma pattern on NC and RP are part of revised 2013 ACR/EULAR classification criteria. Cutolo et al. Rheumatology 2006;45S:43-6. Meli et al. Clin Rheumtol 2006;25:153-8. Van den Hoogan et al. Arthritis Rheum 2013;65:2737-47.

8. Nailfold Capillaroscopy: Scleroderma Stages Early Few enlarged capillaries Few capillary hemorrhages Active Frequent enlarged capillaries and hemorrhages Moderate loss of capillaries Mild disorganization Late Few giant capillaries or hemorrhages Severe loss of capillaries ( avascular areas) Severe disorganization with bushy capillaries Cutolo et al. Rheumatology 2006;45S:43-6.

9. Scleroderma Digital Ulcers Occur in up to 50% of patients with limited or diffuse scleroderma Can occur at tips of digits or overlying joints Painful and heal slowly Complications include: Functional disability and immobility Scarring and loss of distal tissue ( ie . fingertip) Infection (osteomyelitis) Can progress to gangrene Chung et al. Autoimmun Rev 2006;5:125-8.

10. Digital Ischemic Ulcers Definition: Denuded area with defined border and loss of epithelialization, loss of epidermis and dermis (top two layers of skin) but can be covered with crust Does not include fissures, paronychia (inflammation around nail), or ulcers that extrude calcium

11. Pathophysiology of SSc -RP Abnormal sympathetic nerve signaling in response to stimuli (cold) NORMAL SYSTEMIC SCLEROSIS Flavahan . Raynaud Phenomenon: A Guide to Pathogenesis and Treatment. 2015.

12. Scleroderma Vascular Disease

13. Scleroderma Vascular Disease

14. Digital vascular injury in SSc

15. Kahaleh Rheum Dis Clin N Am 2008;34:57-71.

16. Current Management Strategies for RP AVOID TRIGGERS (COLD AND STRESS) Keep EXTREMITIES AND CORE BODY temperature warm DO NOT SMOKE OR USE OTHER FORMS OF NICOTINE AVOID TRAUMA GOOD SKIN CARE AVOID MEDICATIONS THAT VASOCONSTRICT BLOOD VESSELS

17. Medications that can worsen RP : Decongestants Amphetamines Cocaine Clonidine Narcotics Bleomycin, cisplatin, or vinblastine/vincristine Cyclosporine Interferons Estrogens Current Management Strategies for RP

18. Current Management Strategies for DU Supportive Therapies Antibiotics for infections Staph (most common), strep, and gut bacteria Cephalexin or clindamycin If purulence, cover MRSA with trimethoprim/sulfamethoxazole or clindamycin Pain medications Wound care Keep clean: soap and water 2x/day Mupirocin 2% or silver nitrate topical antibiotics while moist Hydrocolloid dressing: polyurethane film coated with a strong adhesive Protects skin from bacteria Serves as a barrier against further injury Cappelli and Wigley . Rheum Dis Clin N Am 2015;41:419-38.

19. Wound Care for DU Application Instructions: Cleanse the ulcer or wound site with hydrogen peroxide 3% or an antibacterial soap. Dry the area completely. Apply antibiotic ointment only to the wound site, being careful not to get the greasy ointment where the adhesive of the hydrocolloid dressing is to be placed. Cut the hydrocolloid dressing approximately 1/2 to 1 inch beyond the wound’ s margin. After peeling off the adhesive backing on the hydrocolloid dressing, apply the sticky side of the dressing to the wound. Tape may be used around the edges of the dressing to aid in keeping the hydrocolloid dressing in place. The hydrocolloid dressing should be changed and cleaned according to the above instructions about every third day, or sooner if the dressing is oozing a lot of fluid.

20. Medication Options for RP/DU Cappelli and Wigley . Rheum Dis Clin N Am 2015;41:419-38.

21. Cappelli and Wigley . Rheum Dis Clin N Am 2015;41:419-38. Medication Options for RP/DU

22. ET ET-1 AT1 Local Cooling Botulinum Toxin? ARBs ETR Antagonists ETR a 2-AR Antagonists CCBs NO Donors PDE5 Inhibitors Statins ANGII PGI2 Wigley FM and Flavahan NA Systemic Cooling

23. Procedures for RP/DU Botulinum toxin injections Inhibits release of acetylcholine and norepinephrine in the nerves inhibits smooth muscle cell and blood vessel constriction Inhibits release of endothelin-1 (powerful vasoconstrictor) Sympathectomy Chemical Cervical Localized digital Vascular reconstruction

24. Botulinum Toxin for Raynaud Phenomenon Review of literature 10 of 29 studies from 2004-2014 reviewed 129 patients with primary and secondary RP 75-100% experienced reduction in pain and healing of ulcers Most common complication was transient hand weakness in 14% Segreto et al. Ann Plast Surg 2016;77:318-323. Neumeister et al. J Hand Surg Am 2010;35:

25. Botulinum Toxin for RP: Systematic Review 11 studies with 125 patients with primary and secondary RP Small studies with no standardization in injection sites or outcomes Level of evidence ranges from very low to moderate Need large randomized controlled trials Zebryk et al. Arch Med Sci 2016;12(4):864-70.

26. Botulinum toxin for SSc -RP: Randomized Double-blind Placebo-controlled Trial 40 SSc patients received 50 units Btx -A in 2.5 mL saline in one randomly selected hand 2.5 mL saline injection in opposite hand Doppler laser imaging at 1 and 4 months Patient report of Raynaud severity at 1 and 4 months Bello et al. Arthritis Rheumatol.  2017;69(8):1661-1669. 

27. Botulinum toxin for SSc-RP: Randomized Double-blind Placebo-controlled Trial Bello et al. Arthritis Rheumatol.  2017;69(8):1661-1669. 

28. Sympathectomy for RP and/or DU Chemical Injection of lidocaine or bupivicaine in the digital or wrist area to temporarily reduce vasoconstriction Temporary chemical sympathectomy can be done for critical digital ischemia Cervical Surgical procedure to decrease the activity of sympathetic nerves May be more effective in primary RP Only ~20% have lasting benefit Risk of nerve damage resulting in pain and loss of localized sweating

29. Sympathectomy for RP/DU Localized digital Surgical procedure removing sympathetic nerves and scar tissue around blood vessels to improve blood flow. Especially useful for severe DU affecting 1 or 2 fingers. Earlier intervention may result in better outcomes. Vascular reconstruction Surgery to remove blocked areas of digital arteries to improve blood flow. Especially useful if a major hand artery is blocked.

30. Periarterial Sympathectomy James Chang, Hand Surgeon, Stanford

31. Vascular Bypass James Chang , Hand Surgeon, Stanford

32. Digital Sympathectomy Experience: Stanford 17 SSc patients (26 hands) Peripheral digital sympathectomy between January 2003 and September 2013 Pain improvement/resolution in 24 (92%) hands post-operatively DU healed in all patients Recurrence of DU requiring surgical intervention at 6 months and 4.5 years in 2 hands Minor infection, wound opening, or abscess occurred in seven hands (27%) Momeni et al. Microsurgery 2015;35:441-6.

33. UK Scleroderma Study Group Algorithm for RP Management Hughes et al. Rheumatology 2015;54:2015-24.

34. UK Scleroderma Study Group Algorithm for DU Management Hughes et al. Rheumatology 2015;54:2015-24.

35. UK Scleroderma Study Group Algorithm for Critical Digital Ischemia Management Hughes et al. Rheumatology 2015;54:2015-24.

36. Cappelli and Wigley . Rheum Dis Clin N Am 2015;41:419-38. JHU Algorithm for RP/DU Management

37. Potential Novel Treatments for RP/DU Phosphodiesterase-5 inhibitors Sildenafil, tadalafil, vardenafil, udenafil Oral prostacyclin ( treprostinil ) sGC stimulator ( riociguat ) Prostacyclin receptor agonist ( selexipag ) Phosphodiesterase-3 inhibitor (cilostazol) a 2C-adenoreceptor antagonists (ORM-12741) Rho-kinase inhibitor ( fasudil ) Injection of autologous adipose-derived stromal vascular fraction in fingers Cells with regenerative capacity (mesenchymal stem cells, EPCs, hematopoietic cells) Guillaume-Jugnot et al. Rheumatology 2016;55:301-6.

38. Summary RP and DU in SSc are related to abnormal blood flow from dysregulated signaling in the nerves and due to underlying vascular disease Medications for RP and DU with RCT evidence to support their use include calcium channel blockers, PDE-5 inhibitors, ETRAs, IV prostacyclins , statins, SSRIs, and ARBs There is currently not enough evidence to support use of botox in the treatment of RP and DU, but digital sympathectomy is an important modality to improve blood flow Several novel therapies and procedures are currently being evaluated in RCT

39. Stanford Scleroderma Center Rheumatology: Lorinda Chung Tamiko Katsumoto Jison Hong Janice Lin William Robinson PJ Utz Dermatology: David Fiorentino Matthew Lewis Howard Chang Endocrinology Joy Wu Pulmonary: Mark Nicolls Tushar Desai Rishi Raj Joshua Mooney Roham Zamanian Gastroenterology: John Clarke Nielsen Fernandez-Becker Laren Becker Linda Nguyen Hand/Vascular: James Chang Cardiology: Francois Haddad