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.

9. 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.

11. 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.

12. 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

15. 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.

16. Scleroderma Vascular Disease

17. Scleroderma Vascular Disease

18. Digital vascular injury in SSc

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

20. 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

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

22. 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.

24. 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.

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

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

27. ET
ET-1
AT1
Local Cooling
Botulinum
Toxin?
ARBs
ETR
Antagonists
ETR
a2-AR
Antagonists
CCBs
NO
Donors
PDE5
Inhibitors
Statins
ANGII
PGI2
Wigley FM and Flavahan NA
Systemic Cooling

28. 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

29. 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:

30. 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.

31. 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.

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

33. 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

34. 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.

35. Periarterial Sympathectomy
James Chang, Hand Surgeon, Stanford

36. Vascular Bypass
James Chang, Hand Surgeon, Stanford

37. 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.

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

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

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

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

42. 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)
• a2C-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.

43. 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

44. 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