19: Raynaud’s Phenomenon and Scleroderma

CHAPTER 19
Raynaud’s Phenomenon and Scleroderma

Christopher P. Denton, Carol M. Black and Voon H. Ong

Royal Free Hospital and UCL Medical School, London, UK

OVERVIEW

Survival from systemic sclerosis is improving due to earlier identification of major complications and more effective treatment of vascular complications, including scleroderma renal crisis and pulmonary arterial hypertension
Lung fibrosis is common but not always severe or progressive. Patients who are at risk of progression should be treated with intravenous cyclophosphamide.
Any of the major complications can occur in either of the two systemic sclerosis subsets, limited or diffuse, based upon the extent of skin disease. Most complications are more frequent in early diffuse systemic sclerosis.
New classification criteria have recently been developed by the ACR and EULAR and these allow cases with milder disease to be included in systemic sclerosis cohorts.
In diffuse disease, the extent of skin sclerosis may be maximal within 18–24 months of onset of disease and then plateau or improve.
Almost all patients with systemic sclerosis have Raynaud’s phenomenon but only a small proportion of patients with RP progress to connective tissue disease (and these can be identified by positive ANA and abnormal nailfold capillaroscopy).

Diagnosis, classification and epidemiology of scleroderma

Scleroderma is a collective term that applies to several related disorders that share key clinical features. It is useful to consider a spectrum of conditions that include a number of different forms of scleroderma. Localized forms of scleroderma occur most often in childhood and include morphea and linear scleroderma. In adults, these conditions may also occur. Some rare forms such as pansclerotic morphea or generalized morphea can be very severe and although not life‐threatening, warrant intensive treatment.

The systemic forms of scleroderma comprise forms of systemic sclerosis (SSc). These are autoimmune rheumatic diseases that lead to inflammation and thickening of the skin, vascular disturbance, notably Raynaud’s phenomenon, and a number of potentially lethal internal organ manifestations. It is notable that some features, such as upper gastrointestinal dysmotility or secondary Raynaud’s phenomenon, occur in all cases whereas other manifestations affect only a minority. The timing and frequency of these major complications are now well established and have recently been highlighted in a large consecutive patient series.

There are other forms of systemic sclerosis, including those cases with additional features of another autoimmune rheumatic disease such as myositis, arthritis, lupus or Sjögren’s syndrome and also a rare subset that has internal organ and vascular features but no skin sclerosis, termed systemic sclerosis sine scleroderma. It is useful to also include some cases of Raynaud’s phenomenon that have serological or other features of SSc within the scleroderma spectrum as some of these may progress to SSc.

There are newly established classification criteria for SSc that are likely to facilitate clinical care and research as they correct a number of limitations of previously developed preliminary criteria. In practice, although developed for classification, these criteria are likely to be used widely to confirm the diagnosis of cases of suspected SSc.

The prevalence of SSc has been difficult to ascertain due to the clinical heterogeneity and rarity of the condition and the spectrum of severity outlined above. Current best estimates suggest approximately 1 in 10 000 prevalence of SSc in the UK, with similar frequency in most European populations that have been examined. In the USA, it is believed that SSc is rather more common and that up to 1 in 5000 of the population may be affected.

The main focus of this chapter is on systemic sclerosis and the other forms of the condition will not be considered further as they are of less relevance to general rheumatology practice.

Raynaud’s phenomenon and connective tissue disease

Episodic cold‐induced vasospasm (Figure 19.1), triggered by cold or emotional stress, affects around 5% of the adult population, especially young females. In primary Raynaud’s (90%), there are no other clinical or investigational abnormalities. Secondary Raynaud’s (10%) implies there are other features, usually an underlying autoimmune rheumatic disease.

Hand with Raynaud’s phenomenon. — **Figure 19.1** Well‐defined blanching of skin, characteristic of Raynaud’s phenomenon

Investigation of Raynaud’s symptoms includes the identification of secondary causes (Box 19.1). Such causes of Raynaud’s, or acrocyanosis, include vibrating machine tools, thoracic outlet obstruction, drugs such as beta‐blockers and haematological abnormalities such as cryoglobulinaemia. Macrovascular arterial disease, embolization and systemic vasculitis, including Berger’s disease, are important but rare differential diagnoses. Some patients with isolated Raynaud’s phenomenon have positive antinuclear antibodies and abnormal nailfold capillaroscopy. These cases are at increased risk of developing a defined connective tissue disease, with up to 50% of such cases progressing within 10 years. The negative predictive value of normal nailfold capillaroscopy and negative autoantibody screening is powerful, allowing robust reassurance.

The vast majority of patients with RP have isolated symptoms that typically develop in the teenage years and become more troublesome in adulthood. These cases are female predominant and often run in families. These include the majority of cases of primary Raynaud’s phenomenon in which there are no clinical features of an associated condition and, more specifically, no alteration in microvascular structure, evidenced by normal nailfold video‐capillaroscopy and absence of antinuclear autoantibodies. Thus, patients with possible RP need to be carefully and appropriately evaluated. Some cases of isolated RP are identified in which there are features that point to the development of a connective tissue disease, in particular, altered nailfold capillaries and positive ANA. The pattern of capillaroscopy can be helpful in determining significance and likely associated or future connective tissue disease and ANA patterns can be similarly informative. A landmark study has shown that up to 50% of cases develop SSc if they have an SSc hallmark ANA and scleroderma pattern capillary alterations. This forms an important group of cases that may facilitate very early diagnosis of SSc (VEDOSS).

It is helpful to perform systematic assessment in all cases to determine any underlying cause or associated condition (summarized in Figure 19.2).

Diagram illustrating investigation of cases of Raynaud’s phenomenon with downward arrow from primary to tertiary care then arrows pointing to connective tissue disease diagnosis and UCTD, MCTD, SLE, SSc, myositis. — **Figure 19.2** Schematic summarizing investigation of cases of Raynaud’s phenomenon to identify those with an associated connective tissue disease

In addition to defined autoimmune rheumatic diseases, there are many patients with overlap syndromes or undifferentiated connective tissue disease who have Raynaud’s and also features such as arthralgia, malaise or photosensitivity but who do not fulfil classification criteria for a defined disease. These may later evolve into more significant diseases (see also Chapters 18 and 20).

Systemic sclerosis

The most important disease within the scleroderma spectrum is SSc (Table 19.1). This has high mortality, and approximately 60% of patients diagnosed with SSc will ultimately die from the disease. Most often, this is due to cardiorespiratory complications. Nevertheless, there has been significant improvement in survival recently due to better treatment of organ‐based complications, and the overall 5‐year survival now approaches 80%. Cardinal features of SSc are the association of skin sclerosis with Raynaud’s phenomenon, which is almost always present, and with internal organ involvement, which varies in extent between patients. The majority of cases fall into one of two major subsets. The characteristics of patients with each subset at different times in their disease are summarized in Boxes 19.2 and 19.3.

Table 19.1 The spectrum of scleroderma and scleroderma‐like disorders

Localised scleroderma (morphoea)	Dermal inflammation and fibrosis. No visceral disease, few vascular symptoms
Plaque morphoea	Fewer than four localised areas of involvement
Generalised morphoea	More than four localized areas of involvement
Linear morphoea	Skin sclerosis follows a dermatomal distribution; commonest form of childhood onset scleroderma
En coup de sabre	Scalp and facial linear lesion often with underlying bone changes
Systemic sclerosis
Diffuse cutaneous systemic sclerosis	Skin involvement proximal to elbows or knees, short history of Raynaud’s phenomenon associated with anti‐topoisomerase‐1 (Scle‐70) or anti‐RNA polymerase III antibodies
Limited cutaneous systemic sclerosis	Skin thickening affects extremities only, long history of Raynaud’s phenomenon, associated with anti‐centromere antibodies
Overlap syndromes	Clinical features of systemic sclerosis associated with those of another autoimmune rheumatic disease (SLE, myositis, arthritis
Systemic sclerosis sine scleroderma	Serological, vascular and visceral features of SSc without detectable skin sclerosis
Isolated Raynaud’s phenomenon
Primary	Common, onset in adolescence, female predominance, normal nailfold capillaroscopy and negative autoantibody profile
Secondary	Raynaud’s with abnormal nailfold capillaries and/or positive antinuclear autoantibody testing

Box 19.2 Characteristic findings and management approach for limited cutaneous systemic sclerosis

Long‐standing Raynaud’s phenomenon is common and may be the presenting feature together with dysphagia or gastro‐oesophageal reflux. These are treated symptomatically
All patients should be screened at diagnosis for organ‐based disease, including lung fibrosis and pulmonary hypertension. Regular assessment should be long term as complications, especially pulmonary hypertension, may occur at any stage of follow‐up
Constitutional symptoms including fatigue are common but associated diagnoses such as hypothyroidism or consequences of malnutrition should be excluded
Skin involvement is generally mild but vascular complications can be severe and may require intravenous prostacyclin or other advanced therapies

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