and Lindsay Muir2
(1)
Centre for Musculoskeletal Research, The University of Manchester and Salford Royal NHS Foundation Trust, Stopford Building, Oxford Road, Manchester, M13 9PT, UK
(2)
Hand Surgery, Salford Royal NHS Foundation Trust, Salford, Lancashire, M6 8HD, UK
Keywords
Raynaud’s phenomenonCritical Digital IschemiaSystemic sclerosisSclerodermaTreatmentHand surgerySympathectomyBotulinum toxinIntroduction
Raynaud’s phenomenon (RP) is an episodic phenomenon in which the skin of the extremities undergoes a classical color change of white (the physiological basis for which is ischemia), blue (cyanosis), and red (hyperemia). The condition may be associated with significant discomfort and pain [1, 2]. RP is usually idiopathic (primary RP), but may occur due to a driving etiology (secondary RP). Primary RP does not progress to digital ulceration or critical ischemia . Classification criteria for primary RP have been proposed and are widely used by clinicians [3, 4]. There is a wide range of causes of secondary RP, which may (albeit rarely) progress to critical digital ischemia with potential gangrenous progression requiring amputation. The distinction between primary and secondary RP is important as both the prognosis and management may differ significantly. The aim of this chapter is to describe the background, clinical evaluation, and treatment of the patient with RP who then presents with critical digital ischemia. Most of our review applies especially to patients with systemic sclerosis (SSc) because this is where the (limited) evidence base is the strongest.
The first section of the chapter deals with general principles of assessment and treatment, initially in the patient in whom the cause of secondary RP is unknown, and then in the patient with a known diagnosis of SSc. Although critical ischemia is a relatively rare complication of RP, nonetheless a significant proportion of affected patients require surgery: the surgical approach to management is described in the second section.
General Approach to the Patient with RP and Critical Ischemia
Classification criteria for primary RP (listed below) have been proposed (adapted from the proposed LeRoy and Medsger criteria [3]). Patients who have abnormality in any one of these domains require further investigation.
Episodic attacks of acral pallor or cyanosis
Strong and symmetrical peripheral pulses
Absence of ischemic tissue loss (digital pitting, ulceration, or gangrene)
Negative anti-nuclear antibody
Normal ESR
The Patient Presenting with RP and Critical Ischemia in Whom the Diagnosis is Unknown
The clinician must perform a comprehensive clinical assessment in patients with RP presenting with critical ischemia without a known diagnosis in order to identify any of the secondary causes of RP (Table 24.1). It is important to recognize that many of the secondary causes of RP, in particular SSc [5] and cancer-associated [6], are not uncommonly associated with severe digital vascular disease, including critical digital ischemia and necrosis . Establishing the diagnosis is of upmost importance as treating the underlying cause of patient’s secondary RP may improve critical digital ischemia.
Table 24.1
The secondary causes of Raynaud’s phenomenon, many of these can be associated with critical digital ischemia (note this is not an exhaustive list)
Rheumatological | Connective tissue diseases: Systemic sclerosis and systemic sclerosis–spectrum disorders, systemic lupus erythematous, Sjogren’s syndrome, idiopathic inflammatory myopathies (dermatomyositis and polymyositis), mixed connective tissue disease, overlap conditions |
Vasculitis | |
Hand arm vibration syndrome (vibration white finger) | Developing in (some) individuals who have been exposed to vibrating tools |
Drugs and toxins | Immunosuppressive agents (e.g., cyclosporine A and interferons) |
Chemotherapeutic agents (e.g., bleomycin and cisplatin) | |
Drugs used in the treatment of hypertension (e.g., beta blockers and clonidine) | |
Drug used in the treatment of anxiety and headache syndromes (e.g., ergots and methysergide) | |
Toxins including occupational exposure (e.g., cocaine and vinyl chloride) | |
Endocrine/metabolic | Hypothyroidism |
Rarer endocrinological conditions: Carcinoid syndrome, pheochromocytoma and POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) syndrome | |
Hematological | Abnormal blood components: Cold agglutinin disease, cryoglobulinemia, cryofibrinogenemia, and paraproteinemia |
Abnormal cellular constituents: Leukemia and lymphoma, polycythemia, and thrombocythemia | |
Coagulopathy: Inherited and acquired (e.g., anti-phospholipid [Hughes] syndrome | |
Malignancy | Solid tumors: Most tumors have been implicated (in particular: lung, ovary, stomach, breast, and uterus) |
Hematological (e.g., leukemia and lymphoma) | |
Paraneoplastic |
History and Physical Examination
Because the differential diagnosis of secondary RP is so diverse, a detailed medical history with full review of systems should be undertaken, including asking about symptoms suggestive of a connective tissue disease, in particular of SSc (e.g., skin changes and gastrointestinal motility issues). The duration of the patient’s RP should be ascertained and whether this has historically proceeded to digital ulceration and/or critical ischemia. The patient’s current drug treatments (both prescribed and “over the counter”) should be scrutinized to detect any of the medications associated with secondary RP (as described in Table 24.1). In addition, the patient’s family and occupational histories should be documented. For example, is there a history of vinyl chloride exposure?
Investigations
Initial blood investigations in all patients include routine hematology and biochemistry (± thyroid function) and coagulation studies (e.g., internal normalized ratio [INR] and activated partial thromboplastin time [APTT]). Doppler ultrasound examination of the vascular tree of the upper limbs should be obtained early to exclude significant large (proximal) obstructive disease, in particular when symptoms are asymmetric.
Additional coagulation studies may be indicated (e.g., testing for the presence of the lupus anticoagulant and anti-phospholipid serology) in patients with a suspected connective tissue disease or a history suggestive of anti-phospholipid (Hughes) syndrome (e.g., previous thrombotic events and/or pregnancy morbidity/mortality) [7]. Immunology should be performed where there is a clinical suspicion of an underlying autoimmune disease: anti-nuclear antibody, complements and also anti-neutrophilic cytoplasmic antibody (ANCA) if the clinical features are suggestive of a vasculitic illness. The urine should be examined (in particular if there is a clinical suspicion of systemic vasculitis or a connective tissue disease) to exclude an active renal sediment, initially by dipstick. If positive for blood and/or protein, then microscopy (e.g., to detect red cell casts indicative of glomerulonephritis) and/or the quantification of proteinuria are indicated. Blood cultures should be performed if there is concern as to systemic infection. Other blood investigations (e.g., cryoglobulins) should be performed if clinically indicated.
A chest radiograph/thoracic outlet view should be performed to exclude a cervical obstructive lesion (i.e., a bony cervical rib). Other investigations (where indicated) include angiography (either magnetic resonance or conventional digital subtraction X-ray angiography) and transthoracic echocardiography (if there is a clinical suspicion of a central embolic source from infective endocarditis).
Specialist investigations for RP include capillaroscopy (a non-invasive microscope examination of the nailfold capillaries in situ) and thermography (cold challenge testing with examination of temperature response using a thermal camera), in particular in the assessment of patients with possible SSc (Fig. 24.1).
Fig. 24.1
Nailfold capillaroscopy and thermography . Capillaroscopy. (a) Normal nailfold capillaroscopy. The capillaries are regular in appearance (albeit slightly tortuous) and capillary density is preserved. (b) Capillaroscopy from a patient with systemic sclerosis. Several capillaries are grossly enlarged, and the capillaries are disordered in shape and arrangement. Thermography (measure of skin temperature) after cold challenge testing. (c) Healthy control. Normal thermographic appearance at 23 °C with no significant temperature gradient between the distal fingers and the dorsum of the hand. (d) Secondary Raynaud’s phenomenon (in a patient with systemic sclerosis). Temperature gradient persists even after warming at a room temperature of 30 °C
Management
Irrespective of the cause of RP, critical ischemia in RP is always a medical emergency and the patient requires urgent hospitalization as the critical ischemia may rapidly progress to irreversible gangrene, with potential loss of the digit. The aim of treatment is to improve perfusion to the ischemic digit and to identify and treat (if appropriate) any underlying secondary cause of RP (Table 24.1) and/or potentially modifiable factors (Table 24.2).
Table 24.2
Contributory (and potentially modifiable) causes to the development and/or progression of critical digital ischemia
In all patients | Smoking |
Drug treatment that reduces digital perfusion, e.g., beta blockers | |
Large (proximal) vessel disease | |
Pro-thrombotic coagulopathy, e.g., anti-phospholipid syndrome | |
Thromboembolic disease | |
Mainly in patients with SSc or other connective tissue diseases | Cryoglobulinemia |
Vasculitis |
Patients who smoke should be counseled as to the upmost importance of smoking cessation and given all possible support in their efforts to stop smoking. Analgesia must be optimized early, as critical ischemia is very often excruciatingly painful. Patients should receive intravenous prostanoid therapy (e.g., iloprost) unless contraindicated; however, it is often poorly tolerated (due to systemic vasodilation) and/or not effective. Critically ischemic digits are often secondarily infected and require treatment with appropriate intravenous antibiotic therapy. As described below under “surgical management ” vascular intervention may be required (e.g., angioplasty) if there is a significant large (proximal) vascular disease. Many clinicians will also prescribe anti-platelet therapy and/or short-term anticoagulation in an attempt to save the digit; however, there is no good evidence base to support either of these interventions. Short-term statin therapy may also be considered (the rationale being that statin therapy is often used in the management of patients with acute coronary syndromes) [8] but again there is no good evidence base for this approach.
Once critical ischemia is established it is often too late to save the digit, and therefore debridement and/or amputation of necrotic tissue (including the whole of the digit) may be indicated, in particular, if the area of necrosis has become established. The gangrenous tissue may autoamputate spontaneously. Digital (palmar) sympathectomy should also be considered, especially if the critical ischemia is progressing and/or involving the other digits. These surgical options are described in detail below.
The Patient Presenting with Known SSc and Critical Ischemia
Systemic Sclerosis
SSc is a complex autoimmune connective tissue disease that is characterized by vascular abnormalities, immune system activation, and a dramatic fibrotic response [9–11]. Vascular abnormalities (often referred to as the “vasculopathy”) are postulated to have a key role in the pathogenesis of SSc (including the earliest events in the initiation of disease) and are responsible for many of the later complications of the disease (e.g., digital ulceration/critical ischemia and pulmonary arterial hypertension) [9–11]. An increased risk of macrovascular (including myocardial infarction, stroke, and peripheral vascular) disease has been reported in patients with SSc [12, 13] including at the level of the digital artery [14, 15] and with selective involvement of the ulnar artery [14, 16–18] which is associated with more severe digital vascular disease, including digital ulceration [18].
There is an increasing emphasis internationally toward the earlier diagnosis of SSc, in part, due to the number of effective treatments that are available for the internal organ involvement (e.g., phosphodiesterase inhibition and endothelin receptor antagonism for pulmonary hypertension as well as for digital ulceration) [19–21]. The American College of Rheumatology and the European League Against Rheumatism classification criteria for SSc (although not intended for diagnostic purposes) are a useful clinical tool when assessing patients with possible SSc [22, 23].
Critical Digital Ischemia in Patients with SSc
Critical digital ischemia although uncommon represents the most severe end of the spectrum of digital vascular disease in patients with SSc. In a large (n = 1168) prospective cohort study from the United Kingdom, the authors reported that 1.4 % of patients with SSc developed critical digital ischemia within an 18-month period [5]. Critical ischemia may involve multiple digits and/or require amputation [24]. Positive associations with severe digital ischemia and anti-centromere antibody [24, 25] and anti-beta2-glycoprotein I [26] have been reported.
The management of critical digital ischemia in patients with SSc is very similar to those patients in whom the underlying diagnosis is unknown, with a few caveats to the approach to treatment. Again, critical digital ischemia is a medical emergency and requires prompt clinical assessment and hospitalization. All patients with SSc should be counseled to seek urgent medical device if any of the digits becomes permanently discolored. Smoking cessation is again of upmost importance. In a retrospective study that included 101 patients with SSc, those who were current smokers were more likely than never smokers to require debridement (odds ratio 4.5, 95 % confidence interval 1.1, 18.3) [27]. Any co-existing secondary causes of RP (Table 24.1) and/or contributory cause/s, although rare (e.g., cryoglobulins, systemic vasculitis, and anti-phospholipid syndrome) (Table 24.2) should be identified early and treated appropriately. Figs. 24.2 and 24.3 describe two cases of critical digital ischemia in patients with SSc.
Fig. 24.2
A 59-year-old male with limited cutaneous SSc presented with a progressive area of ischemia and infection of the left middle terminal phalanx and was promptly admitted for intravenous antibiotic therapy. Despite intervention, he developed critical digital ischemia with a well-demarcated area of necrosis at the fingertip (a, b). He was known to have circulating cryoglobulins but this had never necessitated treatment (e.g., preserved complements with no features of cryoglobulinemic vasculitis). Urgent sympathectomy, botulinum injection (at the level of the digital nerve), and amputation of the tip of the digit was performed. Subsequently he required further surgery (c) to extend the level of his amputation due to progressive necrosis. He subsequently made a good recovery (d) and his hand function has been maintained. Copyright Salford Royal NHS Foundation Trust. Reproduced with permission
Fig. 24.3
A 37-year-old female with SSc/systemic lupus erythematosus overlap (anti-RNP antibody positive) with pulmonary hypertension and pulmonary fibrosis presented with a several month history of critical ischemia of multiple digits of the hands and feet (a–c) and areas of digital ulceration (over the small joints of the hands). She was thought to have a vasculitic component to her illness because of a large vasculitic looking ankle ulcer (d), and had previously received steroid therapy, cyclophosphamide, and rituximab (therapies used in the treatment of systemic vasculitis). There was no evidence of an associated coagulopathy (in particular secondary anti-phospholipid syndrome). Surprisingly, she only reported minimal associated pain with the areas of critical ischemia (and digital ulceration). She had previously been treated with intravenous (IV) prostanoid therapy, but there were concerns about giving further IV prostanoid prior to further investigation of her pulmonary hypertension. Surgical debridement is planned, but it is likely that her hand function will remain severely compromised. Copyright Salford Royal NHS Foundation Trust. Reproduced with permission
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