Dr John PaulingBMedSci MRCP (Rheum) PhD

Consultant Rheumatologist, Royal National Hospital for Rheumatic Diseases, Bath, UK

Visiting Senior Lecturer, University of Bath, UK

Raynaud’s phenomenon in systemic sclerosis: Why do the blood vessels stop working properly and how can we treat this?

• “What is Raynaud’s phenomenon?”

• “Why do the blood vessels stop working properly?”

• “What is the link with systemic sclerosis?”

• “Friends say they have Raynaud’s too but my

Raynaud’s seems worse. Are they the same?”

• “How can I / WE manage treat these problems?”

www.rnhrd.nhs.uk

What I will try to cover over next 30 minutes or so

Raynaud’s phenomenon

Maurice Raynaud (1834 – 1881)

De l'asphyxie locale et de la gangrène symétrique des

extrémités.

Doctoral thesis, published February 25, 1862.

Initial ischaemia

Pallor

Cyanotic phase

Blue

Hyperaemic phase

Red / purple

Clinical features of Raynaud’s phenomenon

• Usually affects fingers

• Can affect toes, thumbs, nipples, nose, earlobes

• Episodes precipitated by cold exposure and emotional stress

• Episodes accompanied by pain +/- numbness

• “Primary” in the majority of cases (excellent prognosis)

• “Secondary” forms rare e.g. systemic sclerosis but not to be missed

Causes of Raynaud’s phenomenon

Muscle in blood vessel wall

The “endothelium”

The inside of blood vessel filled with blood cells

Nerves supplying muscle

• Overactivity of nerves supplying muscle in vessel wall

• Muscles in the vessel wall contract leading to narrowing of the blood vessel or “vasoconstriction”

• Increased production of molecules which promote “vasoconstriction” by the endothelium e.g. ET-1

• Reduced production of molecules which promote relaxation of the vessel wall and “vasodilation” e.g. NO

• Production of molecules which promote “vasoconstriction” e.g. serotonin from platelets

• Activation of receptors in vessel wall which promote vasoconstriction e.g. AT II receptors

EXPOSURE TO COLD

AT II

AT II

AT II

AT IIAT II

www.rnhrd.nhs.uk

Systemic sclerosis (SSc) / Scleroderma

Blood vessel abnormalities in Systemic sclerosis

• Startin 1846Scottish girl, 18 years old “contraction of the right arm”

Ulcers formed “around the nails and joints of the fingers which healed gradually, but left the sort of contraction as existed in the right hand and arm”. “fingers contracted into the palm”

“My poor sister is now never off the sofa….so dreadfully reduced by low fainting fits… followed by hours of exhaustion; her stiffness, too, increases, so soon she will become a piece of bone”

• Thomas Barlow (1845-1945) 1888 (Royal Free Hospital)A women who for 5 years had suffered during the winter with hard yellowish patches on the extremities, which subsided on the return of spring. Ultimately the fingers were permanently altered in that the extremeties became cold, hard, somewhat unsensitive and decidedly atrophied. The last phalanges were contracted in a state of semi-flexion….The patient was liable to crises from time to time during which the finger reddened and became painful, then ulceration occurred and tardy cicatrisation with loss of substance. After each crisis the affected digit became a little more atrophied and deformed than before. There was no trace of scleroderma in other parts of the body’

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Another way of approaching systemic sclerosis

Systemic sclerosis

Blood vessel abnormalities

Fibrosis / scar tissue

Inflammation

Fatigue??

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A Simpler way of approaching scleroderma

Systemic sclerosis

Blood vessel abnormalities

Fibrosis / Scar tissueInflammation

Raynaud’s phenomenonPulmonary arterial hypertensionScleroderma renal crisis

Skin thickeningLung fibrosisGastrointestinal problemsBowel problems

Antibody formationInflammation in musclesInflammation in joints

Fatigue??

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Is Raynaud’s phenomenon in systemic sclerosis actually Raynaud’s phenomenon?

A healthy arteriole (primary RP)

Systemic sclerosis

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Evaluating Raynaud’s phenomenon (microvascular imaging)

Thermal Imaging

Healthy nailfold capillaries (as is found in primary Raynaud’s phenomenon)

Systemic sclerosis

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Theories on the link between inflammation, vascular abnormalities and fibrosis

Damage to lining of blood vessels

AntibodiesVirusesToxins e.g. solvents

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Theories on the link between inflammation, vascular abnormalities and fibrosis

Damage to lining of blood vessels

Intermittent Raynaud’s attacks

Destruction of blood vessels

AntibodiesVirusesToxins e.g. solvents

www.rnhrd.nhs.uk

Theories on the link between inflammation, vascular abnormalities and fibrosis

Damage to lining of blood vessels

Intermittent Raynaud’s attacks

ComplicationsDestruction of blood vessels

AntibodiesVirusesToxins e.g. solvents

Persistent Raynaud’s symptomsDigital ulcersPulmonary arterial hypertension

www.rnhrd.nhs.uk

Theories on the link between inflammation, vascular abnormalities and fibrosis

Damage to lining of blood vessels

Intermittent Raynaud’s attacks

Body recognises tissue damage

ComplicationsDestruction of blood vessels

Reduced oxygen and nutrient supply to tissues

AntibodiesVirusesToxins e.g. solvents

Persistent Raynaud’s symptomsDigital ulcersPulmonary arterial hypertension

Body attempts to make new blood vessels

www.rnhrd.nhs.uk

Theories on the link between inflammation, vascular abnormalities and fibrosis

Damage to lining of blood vessels

Tissue fibrosis

Intermittent Raynaud’s attacks

Body recognises tissue damage

Wound healing cells activated

ComplicationsDestruction of blood vessels

Reduced oxygen and nutrient supply to tissues

AntibodiesVirusesToxins e.g. solvents

Persistent Raynaud’s symptomsDigital ulcersPulmonary arterial hypertension

Skin thickeningScarring of lungsGastrointestinal dysmotility

Body attempts to make new blood vessels

www.rnhrd.nhs.uk

Theories on the link between inflammation, vascular abnormalities and fibrosis

Damage to lining of blood vessels

Tissue fibrosis

Intermittent Raynaud’s attacks

Body recognises tissue damage

Wound healing cells activated

ComplicationsDestruction of blood vessels

Reduced oxygen and nutrient supply to tissues

AntibodiesVirusesToxins e.g. solvents

Persistent Raynaud’s symptomsDigital ulcersPulmonary arterial hypertension

Skin thickeningScarring of lungsGastrointestinal dysmotility

Body attempts to make new blood vessels

A WINDOW OF OPPORTUNITY

Promote patient self-management

• Stop smoking• Keep warm (even uncomfortably so)• Be prepared• Keep skin moist and clean• Nail care• Hand exercises• Do not attempt DIY surgery• Report new ulcers on fingers and toes immediately (a

scleroderma emergency)

“Natural” remedies for Raynaud’s phenomenon

• Not strong “evidence” to support treatments• Biofeedback training• Low level laser therapy• Nutritional supplements e.g. cinnamon, vitamin

B3 (niacin)• Ginkgo biloba (Maidenhair tree)• Potential for interactions with conventional

treatments of systemic sclerosis e.g. anti-platelets, azathioprine (so bring along to clinic appointments and tell your clinician).

Drug treatment targets in Raynaud’s phenomenon

Muscle in blood vessel wall

The “endothelium”

The inside of blood vessel filled with blood cells

Nerves supplying muscle • Directly prevent vascular muscle cells contracting e.g. nifedipine, amlodipine

• Prevent nerve stimulation of vascular muscle e.g. prazosin

• Prevent stimulation of AT II receptors in vessel wall e.g. losartan

• Block action of molecules released by endothelium which promote “vasoconstriction” e.g. bosentan

• Enhance action of molecules released by endothelium which promote “vasodilation” e.g. sildenalfil (viagra)

• Block the release of molecules from blood cells which cause vasoconstriction e.g. fluoxetine (prozac)

• Inject molecules that make blood vessel muscles relax e.g. iloprost

AT II

AT II

AT II

AT IIAT II

Side effects to watch out for

• Some side effects are common to all drugs and may necessitate coming off treatment e.g. nausea, rash etc.

• Side effects generally evidence of treatment effectiveness (relating to dilated blood vessels)

• Headaches• Light-headedness if blood pressure drops too low• Side effects less of a problem if you gradually build

dose allowing body to get used to drug• Unusual not to identify treatments to suit patient and

improve symptoms

• Raynaud’s phenomenon is complex and caused by a multitude of factors

• Sometimes requires multiple treatments

• Raynaud’s even more complex in systemic sclerosis and can result in progressive damage to the blood vessels

• Early aggressive treatment might slow disease progression in systemic sclerosis

• Finger ulcers in SSc should be considered a Rheumatological Emergency and there should be an open door policy for patients for DU assessment/management

www.rnhrd.nhs.uk

Conclusions

“The captive” 1940

• Nazi’s presented his work as evidence of “Degenerate Art”

• Fled to Switzerland 1933

• Diagnosed with SSc in 1935

• Died of cardiac complications 5 years later

Paul Klee (1879-1940)

“Death and Fire” 1940

The bars are thought to represent the restrictive effect of being trapped by his cutaneous fibrosis

His face is etched with the letters “Tod” meaning death in German