Abstract
Raynaud’s phenomenon (RP) is a major cause of pain and disability in patients with autoimmune connective tissue diseases (CTDs), particularly systemic sclerosis (SSc). The clinician must perform a comprehensive clinical assessment in patients with RP to differentiate between primary (idiopathic) and secondary RP, in particular (for rheumatologists), secondary to an autoimmune CTD, as both the prognosis and treatment may differ significantly. Key investigations are nailfold capillaroscopy and testing for autoantibodies (in particular, those associated with SSc). Patients with RP and either abnormal nailfold capillaroscopy or an SSc-specific antibody (and especially with both) have a high risk of transitioning to an autoimmune CTD. Both nailfold capillaroscopy and autoantibody specificity may help the clinician in predicting organ-based complications. The management of CTD-associated RP requires a multifaceted approach to treatment, including patient education and conservative (‘non-drug’) measures. Patients with CTD-associated RP often require pharmacological treatment, which in the first instance is usually a calcium channel blocker, although other agents can be used. There is an increasing tendency to use phosphodiesterase type 5 inhibitors early in the treatment of CTD-associated RP. Oral therapies are commonly associated with side effects (often due to systemic vasodilation) that may result in failure of dose escalation and/or permanent discontinuation. Intravenous prostanoid therapy and surgery (e.g., botulinum toxin injection and digital sympathectomy) can be considered in severe RP. Patients with CTD-associated RP can develop a number of ischaemic digital complications (primarily ulcers and critical ischaemia), which may be associated with significant tissue loss. Future research is required to increase the understanding of the pathogenesis and natural history of RP (to drive therapeutic advances), and to explore/develop drug therapies, including those that target the mechanisms mediating cold-induced vasoconstriction, and locally acting therapies free of systemic side effects.
Introduction
Raynaud’s phenomenon (RP) is common in patients with autoimmune connective tissue diseases (CTDs) having a significant impact on patients’ perceived quality of life . RP manifests as an episodic colour change of the extremities, triggered by cold exposure and/or emotional stress. RP is often one of the earliest clinical manifestations observed in patients with CTDs; thus, it presents an early opportunity to identify patients likely to develop a CTD, in particular, systemic sclerosis (SSc). The aim of this review is to provide an update on the assessment of patients with RP, the natural history of CTD-associated RP and advances in therapies (including structured protocols) for RP and for the most severe ischaemic complication critical digital ischaemia (treatment of SSc-related digital ulceration is discussed in Chapter 1).
Assessment of the patient with RP
RP ( Fig. 1 ) is common. The prevalence estimates vary, most likely reflecting differences in definition of RP between studies as well as geographic variations. One UK study suggested that the prevalence could be as high as 19% , although most studies have suggested lower prevalences of 3–5% in the general population .
The vast majority of patients presenting with RP will have primary (idiopathic) RP (PRP), which is ‘benign’, in that it is entirely reversible and does not progress to irreversible tissue injury. However, the clinician must bear in mind that RP has a differential diagnosis ( Table 1 ). Although this includes a large number of different conditions including hand–arm vibration syndrome, extrinsic vascular compression, ‘intravascular’ diseases including paraproteinaemia and certain drug treatments including beta-blockers , RP secondary to CTD is of utmost interest to the rheumatologist, which can be very severe and difficult to treat. As already stated, RP is often one of the most visible and distressing aspects of CTD, and can be the presenting feature.
| Primary (idiopathic) RP | ||
|---|---|---|
| Secondary RP | Vascular (usually proximal large vessel disease, often unilateral symptoms) | Compressive (e.g., cervical rib) Obstructive: non-inflammatory (i.e., atherosclerosis) Inflammatory vascular disease (e.g., thromboangiitis obliterans (Buerger’s disease)) |
| Hand–arm vibration syndrome (vibration white finger) | ||
| Autoimmune conditions | SSc Systemic lupus erythematosus Sjögren’s syndrome Mixed connective tissue disease/overlap syndromes Undifferentiated connective tissue disease Idiopathic inflammatory myopathies | |
| Drug-related | Amphetamines Beta blockers Bleomycin Cisplatin Clonidine Cyclosporine Interferon a and b Methysergide Polyvinyl chloride | |
| Conditions associated with increased plasma viscosity and reduced digital perfusion | Cryoglobulinaemia Cryofibrinogenaemia Paraproteinaemia Malignancy (including as a paraneoplastic phenomenon) | |
| Other causes and associations | Carpal tunnel syndrome Frostbite Hypothyroidism | |
When assessing a patient with RP, the key questions for the rheumatologist are as follows:
- 1.
Why does this patient have RP? Could s/he have an underlying CTD?
- 2.
How severe is the RP? This will dictate management. For example, mild RP may respond to conservative (non-drug) measures, whereas severe RP progressing to finger ulceration will require a very aggressive approach.
As in most areas of medicine, a full assessment requires a detailed history and examination, complemented by targeted investigations. During the initial assessment, the clinician must be aware of the proposed criteria for PRP , which have recently been revisited by Maverakis et al. LeRoy and Medger proposed that for RP to be primary the following criteria must be met: the attacks of acral pallor or cyanosis should be episodic; the peripheral pulses should be strong and symmetrical; there should be no evidence of digital pitting, ulceration or gangrene; the nailfold capillaries should be normal; and antinuclear antibody (ANA) should be negative/low titre and the erythrocyte sedimentation rate (ESR) normal. The criteria of Maverakis et al. do not require a normal ESR .
History and examination
Key points in the history are the presence of any symptoms pointing to an underlying CTD (e.g., photosensitivity or mouth ulcers) and/or symptoms indicating severe disease (e.g., interference with activities of daily living or a history of digital ulcers). A full systems enquiry must therefore be taken, including a drug history, an occupational history (with particular reference to vibratory tool use or chemical exposures) and a family history (specifically of CTD).
Similarly, a full examination must be performed, but focussing specifically on the fingers and toes, for signs of digital ulceration, pitting scars, puffy fingers, sclerodactyly or any nailfold changes visible to the naked eye. The peripheral pulses must be checked, to indicate proximal large vessel disease.
Investigations
The basic set of investigations comprises a blood count, ESR, ANA and nailfold capillaroscopy (discussed below). The results of all tests should be normal/negative in PRP. Many clinicians consider a blood biochemical profile with thyroid function tests and a thoracic outlet radiograph (looking for a cervical rib) a part of the ‘routine’ assessment. When the history and examination indicate an underlying CTD, tests for other autoantibodies (including disease-specific autoantibodies) should be requested (the associations of RP with the different CTDs are discussed later). Other investigations should be requested as clinically indicated . For example, if large (proximal) vessel disease is suspected, then vascular investigations are indicated, initially with arterial Doppler studies.
SSc is the CTD most likely to be associated with the most severe RP, and most of the studies into predictors of development of underlying CTD in patients with RP have been in the context of SSc. SSc-specific autoantibodies (including anti-centromere and anti-topoisomerase (anti-Scl-70)) and nailfold capillaroscopic abnormalities are now well recognised as independent risk factors for SSc .
Nailfold capillaroscopy
Normal nailfold capillaries ( Fig. 2 ) are reassuring in patients with RP. Conversely, dilated loops, areas of avascularity, distortion of the normal capillary architecture and multiple haemorrhages indicate an underlying SSc-spectrum disorder . The development and increasing availability of high-magnification videocapillarosopy (200–600×), among other factors, have led to increased interest in capillaroscopy in recent years . Cutolo et al. described a method of scoring the ‘scleroderma pattern’ (‘early’, ‘active’ and ‘late’) : the early pattern (especially relevant to an early diagnosis of an SSc-spectrum disorder in the patient presenting with RP) is characterised by the presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss. Although nailfold capillary abnormalities have been described in CTDs other than SSc, the changes tend to be non-specific, other than in inflammatory muscle disease (especially dermatomyositis (DM)), in which ‘scleroderma-pattern’ abnormalities are well described .
For clinicians without access to standard wide-field microscopy or to videocapillaroscopy, capillaries may be visualised using a dermatoscope (magnification in the order of 10×) or with an ophthalmoscope , although a disadvantage of the ophthalmoscope is the narrower field of view. A recent study suggested that dermoscopy compared favourably to videocapillaroscopy; however, videocapillaroscopy images were more likely to be classifiable (and were graded more severely) than dermoscopy images. It is likely that the USB microscope, a low-powered digital microscope that connects to any computer via a USB port, will also be used in the future.
Although the main clinical indication for nailfold capillaroscopy is the diagnosis of underlying CTD, recently, there has been considerable interest in capillaroscopy as a predictor of RP severity (specifically of digital ulceration) in patients with SSc .
Other vascular investigations
Infrared thermography measures surface temperature and can help differentiate between patients with PRP and SSc ( Fig. 3 ). However, this is a relatively expensive technique available only in specialist centres. Dynamic imaging, most commonly with a cold challenge test , is generally incorporated into thermography protocols. The persistence of a temperature gradient along a finger of >1 °C (fingertip colder) at a room temperature of 30 °C also helps differentiate PRP from SSc-related RP .
A number of other methods have been applied in studies to differentiate between primary and SSc-related RP . These include laser Doppler flowmetry, laser Doppler imaging and laser speckle contrast imaging , plethysmography and finger systolic pressure measurements . These methods have the potential to measure disease severity, but further validation is required before they can become adopted as outcome measures.
Assessment of the patient with RP
RP ( Fig. 1 ) is common. The prevalence estimates vary, most likely reflecting differences in definition of RP between studies as well as geographic variations. One UK study suggested that the prevalence could be as high as 19% , although most studies have suggested lower prevalences of 3–5% in the general population .
The vast majority of patients presenting with RP will have primary (idiopathic) RP (PRP), which is ‘benign’, in that it is entirely reversible and does not progress to irreversible tissue injury. However, the clinician must bear in mind that RP has a differential diagnosis ( Table 1 ). Although this includes a large number of different conditions including hand–arm vibration syndrome, extrinsic vascular compression, ‘intravascular’ diseases including paraproteinaemia and certain drug treatments including beta-blockers , RP secondary to CTD is of utmost interest to the rheumatologist, which can be very severe and difficult to treat. As already stated, RP is often one of the most visible and distressing aspects of CTD, and can be the presenting feature.
| Primary (idiopathic) RP | ||
|---|---|---|
| Secondary RP | Vascular (usually proximal large vessel disease, often unilateral symptoms) | Compressive (e.g., cervical rib) Obstructive: non-inflammatory (i.e., atherosclerosis) Inflammatory vascular disease (e.g., thromboangiitis obliterans (Buerger’s disease)) |
| Hand–arm vibration syndrome (vibration white finger) | ||
| Autoimmune conditions | SSc Systemic lupus erythematosus Sjögren’s syndrome Mixed connective tissue disease/overlap syndromes Undifferentiated connective tissue disease Idiopathic inflammatory myopathies | |
| Drug-related | Amphetamines Beta blockers Bleomycin Cisplatin Clonidine Cyclosporine Interferon a and b Methysergide Polyvinyl chloride | |
| Conditions associated with increased plasma viscosity and reduced digital perfusion | Cryoglobulinaemia Cryofibrinogenaemia Paraproteinaemia Malignancy (including as a paraneoplastic phenomenon) | |
| Other causes and associations | Carpal tunnel syndrome Frostbite Hypothyroidism | |
When assessing a patient with RP, the key questions for the rheumatologist are as follows:
- 1.
Why does this patient have RP? Could s/he have an underlying CTD?
- 2.
How severe is the RP? This will dictate management. For example, mild RP may respond to conservative (non-drug) measures, whereas severe RP progressing to finger ulceration will require a very aggressive approach.
As in most areas of medicine, a full assessment requires a detailed history and examination, complemented by targeted investigations. During the initial assessment, the clinician must be aware of the proposed criteria for PRP , which have recently been revisited by Maverakis et al. LeRoy and Medger proposed that for RP to be primary the following criteria must be met: the attacks of acral pallor or cyanosis should be episodic; the peripheral pulses should be strong and symmetrical; there should be no evidence of digital pitting, ulceration or gangrene; the nailfold capillaries should be normal; and antinuclear antibody (ANA) should be negative/low titre and the erythrocyte sedimentation rate (ESR) normal. The criteria of Maverakis et al. do not require a normal ESR .
History and examination
Key points in the history are the presence of any symptoms pointing to an underlying CTD (e.g., photosensitivity or mouth ulcers) and/or symptoms indicating severe disease (e.g., interference with activities of daily living or a history of digital ulcers). A full systems enquiry must therefore be taken, including a drug history, an occupational history (with particular reference to vibratory tool use or chemical exposures) and a family history (specifically of CTD).
Similarly, a full examination must be performed, but focussing specifically on the fingers and toes, for signs of digital ulceration, pitting scars, puffy fingers, sclerodactyly or any nailfold changes visible to the naked eye. The peripheral pulses must be checked, to indicate proximal large vessel disease.
Investigations
The basic set of investigations comprises a blood count, ESR, ANA and nailfold capillaroscopy (discussed below). The results of all tests should be normal/negative in PRP. Many clinicians consider a blood biochemical profile with thyroid function tests and a thoracic outlet radiograph (looking for a cervical rib) a part of the ‘routine’ assessment. When the history and examination indicate an underlying CTD, tests for other autoantibodies (including disease-specific autoantibodies) should be requested (the associations of RP with the different CTDs are discussed later). Other investigations should be requested as clinically indicated . For example, if large (proximal) vessel disease is suspected, then vascular investigations are indicated, initially with arterial Doppler studies.
SSc is the CTD most likely to be associated with the most severe RP, and most of the studies into predictors of development of underlying CTD in patients with RP have been in the context of SSc. SSc-specific autoantibodies (including anti-centromere and anti-topoisomerase (anti-Scl-70)) and nailfold capillaroscopic abnormalities are now well recognised as independent risk factors for SSc .
Nailfold capillaroscopy
Normal nailfold capillaries ( Fig. 2 ) are reassuring in patients with RP. Conversely, dilated loops, areas of avascularity, distortion of the normal capillary architecture and multiple haemorrhages indicate an underlying SSc-spectrum disorder . The development and increasing availability of high-magnification videocapillarosopy (200–600×), among other factors, have led to increased interest in capillaroscopy in recent years . Cutolo et al. described a method of scoring the ‘scleroderma pattern’ (‘early’, ‘active’ and ‘late’) : the early pattern (especially relevant to an early diagnosis of an SSc-spectrum disorder in the patient presenting with RP) is characterised by the presence of a small number of giant capillaries and of microhaemorrhages, without obvious capillary loss. Although nailfold capillary abnormalities have been described in CTDs other than SSc, the changes tend to be non-specific, other than in inflammatory muscle disease (especially dermatomyositis (DM)), in which ‘scleroderma-pattern’ abnormalities are well described .
For clinicians without access to standard wide-field microscopy or to videocapillaroscopy, capillaries may be visualised using a dermatoscope (magnification in the order of 10×) or with an ophthalmoscope , although a disadvantage of the ophthalmoscope is the narrower field of view. A recent study suggested that dermoscopy compared favourably to videocapillaroscopy; however, videocapillaroscopy images were more likely to be classifiable (and were graded more severely) than dermoscopy images. It is likely that the USB microscope, a low-powered digital microscope that connects to any computer via a USB port, will also be used in the future.
Although the main clinical indication for nailfold capillaroscopy is the diagnosis of underlying CTD, recently, there has been considerable interest in capillaroscopy as a predictor of RP severity (specifically of digital ulceration) in patients with SSc .
Other vascular investigations
Infrared thermography measures surface temperature and can help differentiate between patients with PRP and SSc ( Fig. 3 ). However, this is a relatively expensive technique available only in specialist centres. Dynamic imaging, most commonly with a cold challenge test , is generally incorporated into thermography protocols. The persistence of a temperature gradient along a finger of >1 °C (fingertip colder) at a room temperature of 30 °C also helps differentiate PRP from SSc-related RP .
A number of other methods have been applied in studies to differentiate between primary and SSc-related RP . These include laser Doppler flowmetry, laser Doppler imaging and laser speckle contrast imaging , plethysmography and finger systolic pressure measurements . These methods have the potential to measure disease severity, but further validation is required before they can become adopted as outcome measures.
RP in CTDs
RP is common in patients with autoimmune CTDs. In this section, we review the evidence relating to the occurrence and clinical associates of RP in patients with CTDs, including the occurrence of digital ischaemic complications, which, in part, inform the treatment of CTD-associated RP (discussed in the third part of this review).
Systemic sclerosis
Almost all patients with SSc have RP, which is often the presenting feature. In an analysis of patients from the European Scleroderma Trials and Research (EUSTAR) group, which included 7655 patients with SSc, >95% of patients presented with a history of RP, with no difference observed between patients with limited cutaneous (lcSSc) and diffuse cutaneous (dcSSc) disease subtypes (96.6% and 96.1%, respectively) . Patients with lcSSc often present with a long history (often decades) of RP. In patients with dcSSc, however, the onset of RP typically occurs within a year (either before or after) of the onset of skin sclerosis . The importance of RP in patients with SSc is reflected by its inclusion in the 2013 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for SSc (scoring three points out of the nine required for the classification of SSc) . In addition, RP is one of only three key features or ‘red flags’ (along with puffy fingers and ANA positivity) that should alert the clinician to the Very Early Diagnosis of Systemic Sclerosis (VEDOSS) cohort, requiring the presence of the SSc pattern on nailfold capillaroscopy or SSc-specific autoantibodies . In an analysis of 469 patients with RP enrolled in the VEDOSS cohort , patients who were ANA positive (compared to ANA negative) were more likely to show an SSc pattern on capillaroscopy (53.6% and 13.4%, respectively); in addition, vascular complications (telangiectasias, current digital ulcers and pitting scars) were more common in ANA-positive RP patients. In patients with SSc, RP is often very severe, which can progress to digital ulceration and sometimes to gangrene.
Mixed connective tissue disease
Similar to SSc, RP is very common in patients with mixed connective tissue disease (MCTD), the vast majority of whom (in excess of 90%) will develop RP during the course of their disease . In a study of 25 patients with MCTD, Sharp et al. reported that RP was present in 84% of patients . A long history of RP is often reported in patients with MCTD, and RP is often the only or one of few symptoms of a CTD at the time of diagnosis . In a longitudinal study, which included 47 patients with MCTD with a mean follow-up period of 3–29 years, RP was present at the time of initial presentation, diagnosis and cumulatively during follow-up in 74%, 89% and 96% of patients, respectively . Digital ischaemic complications including ulceration of the fingers are relatively rare compared to SSc . More than half of patients with MCTD may demonstrate a ‘scleroderma pattern’ on nailfold capillaroscopy , which has been reported to be associated with the development of internal organ complications .
Undifferentiated connective tissue disease
RP occurs in around half of patients with undifferentiated connective tissue disease (UCTD) . In a retrospective study, which included 91 patients with a follow-up period of 1 year, the prevalence of RP was reported to be 46% (second only to arthralgias at 80%) . Similarly, De Angelis et al. reported the prevalence of RP to be 52.5% in a study investigating the clinical and serological associates of RP in patients with UCTD . The patients with (vs. without) RP had a higher frequency of oesophageal dysmotility and of anti-ribonucleoprotein antibodies. In addition, the authors reported that capillaroscopic abnormalities (in particular, widened and irregularly enlarged capillary loops) were more often found in these patients with RP. The development of digital ischaemic lesions including ulceration of the fingers should prompt the clinician to reassess the patient and consider the evolution into a defined CTD, in particular SSc.
Sjögren’s syndrome
RP is commonly observed in patients with primary Sjögren’s syndrome (SS), and up to one-third of patients may develop RP during the course of their disease . In approximately half of patients who develop RP, the onset of RP is reported before the onset of sicca symptoms, and often the frequency of RP attacks either remains the same or decreases over the course of time . Although an initial association between HLA-DR3/4 and the presence of RP in patients with SS was reported , subsequent studies have not confirmed such an association . Skopouli et al. reported that patients with SS with (vs. without) RP were more likely to develop glomerulonephritis, peripheral neuropathy and myositis, although this did not reach statistical significance . No association between SS-associated autoantibody profile and RP has been reported . Of mechanistic interest, an association between the presence of anti-centromere antibody and RP has been reported in patients with SS . In a retrospective study, which included 535 patients with SS, the prevalence of anti-centromere antibody was 3.7% . Patients with SS and anti-centromere antibody positivity had a higher prevalence of RP, but a lower prevalence of ocular dryness, hypergammaglobulinaemia and anti-Ro and anti-La antibodies than those who were anti-centromere negative. Patients commonly require pharmacological treatment for their RP, but digital ischaemic complications are rare. In a cross-sectional study of 40 patients with SS-related RP, 15 (38%) patients required pharmacological treatment for their RP, most commonly with calcium channel blockers, and one patient required intravenous prostanoid therapy for digital ulcers and distal gangrene .
Systemic lupus erythematosus
The prevalence of RP in patients with systemic lupus erythematosus (SLE) has been reported to be 18–40% . RP may develop prior to the diagnosis of SLE or during the course of the disease . A lower prevalence of RP has been reported in males and in patients with late-onset SLE . The presence of RP in patients with SLE is a potential clinical biomarker of internal organ complications. In a study including 79 patients with SLE and RP, patients with (compared to those without) RP were significantly more likely to show central nervous system involvement and peripheral neuropathy, whereas (secondary) SS was less common . In their prospective study including 77 patients with SLE, Kamel et al. reported that RP was associated with an increased risk of pulmonary hypertension (relative risk 4.44), although this did not reach statistical significance . Although Vayssairat et al. report an association between RP and anti-cardiolipin (IgG) antibody positivity in patients with SLE , other authors have reported either a negative or no association with antiphospholipid (IgG and IgM anti-cardiolipin and anti-beta 2 glycoprotein) antibodies . A positive association between RP and anti-RNP antibody in patients with SLE has been reported . Rodriguez et al. report that patients with SLE and RP are likely to develop both arterial and venous thromboses in the presence of anti-cardiolipin antibodies, although this did not reach statistical significance . SSc-like nailfold capillaroscopic abnormalities have been associated with RP in patients with SLE .
Idiopathic inflammatory myopathies
RP is not uncommon in patients with idiopathic inflammatory myopathies (IIMs), particularly in patients with anti-synthetase syndrome. In a study from a large, unselected Norwegian cohort of 230 patients with IIMs, the frequency of RP was found to be around 20% in polymyositis and 40% in DM . The anti-synthetase syndrome is a clinical subset of IIMs including interstitial lung disease (ILD), cutaneous features, RP and the presence of autoantibodies directed towards aminoacyl-transfer RNA (tRNA) synthetases . In their review on the anti-synthetase syndrome, Katzap et al. reported the incidence of RP to be as high as 62% . In a study including 41 patients with IIMs, only patients with (vs. without) anti-Jo-1 antibodies had RP (42% and 0%, respectively) . Anti-melanoma differentiation-associated gene-5 (MDA5) antibody is significantly associated with the development of cutaneous ulceration (and also ILD) in patients with DM . In a retrospective study, which included 152 patients with DM, 43 patients (28%) presented with cutaneous ulcers . The pathophysiology of cutaneous ulceration in IIMs warrants further investigation.
Transition from primary to secondary RD
As previously described, the distinction between primary and secondary RP (PRP and SRP) is of great importance, as both the prognosis and treatment can differ significantly. In the literature, between 1% and 3% of patients with ‘isolated’ PRP have been reported to evolve into SRP every year , often within 5 years from the first assessment .
As highlighted in the assessment of RP, nailfold capillaroscopy and testing for autoantibodies – in particular, SSc-associated autoantibodies – are key investigations in patients with RP. In a large, prospective study that included 586 patients who were followed up for 3197 person-years, 12.6% of patients progressed to SSc . The time to develop SSc after the first evaluation and the first onset of RP was 1.95 and 4.56 years, respectively. In the patients who developed SSc, the frequency of nailfold capillary abnormalities and SSc autoantibodies was 58% and 78.4%, respectively, and the presence of both was associated with a 60-fold increased risk of developing SSc. Of interest, a different temporal relationship for the development of microvascular damage (as assessed by capillary enlargement on capillaroscopy) was observed between different autoantibodies (earliest with anti-RNA polymerase, intermediate with anti-topoisomerase and latest with anti-centromere). In a systematic review and meta-analysis, which included 639 patients with PRP (with a follow-up period of 2531 patient-years), 12.6% of patients developed SRP over an average follow-up duration of 4 years . The adjusted odds ratio (OR) of predictors of progression to SRP included the presence of abnormal nailfold capillaries (14.6) and ANA positivity (3.0). Ingegnoli et al. proposed a simple prognostic algorithm to predict the probability (≤10%, 10–50% and ≥50%) of patients with ‘isolated’ RP developing SSc based on the number of nailfold capillaries, presence of giant loops and ANA positivity, with good reported prognostic discriminatory ability (Harrell’s C -index = 0.86) . Furthermore, in a prospective study including 307 consecutive patients with RP, in addition to ANA positivity, other predictors (hazard ratio) of transition to SRP were older age at the time of RP onset (2.59), shorter RP duration (0.87) and abnormal ‘thoracic outlet testing’ .
Just as in adults, nailfold capillaroscopy is a very useful prognostic tool for the development of an autoimmune CTD in the juvenile population as well. In a prospective study that included 250 children and adolescents (with a mean age of 15 years) with RP, 23.6% had developed a CTD at the end of follow-up (ranging between 1 and 6 years) . Although most individuals who developed a CTD showed normal capillaries or non-specific abnormalities on capillaroscopy, the presence of the scleroderma pattern on capillaroscopy was found in more than half (61%) of the individuals who developed an SSc spectrum disorder 6 months before the full expression of their CTD.
Another key issue operationally is the definition of the transition from PRP to SRP, including the development of autoimmune CTDs, in particular SSc, in their earliest forms. In a study including 129 patients referred with PRP, Cutolo et al. reported that 14.7% (19 patients) developed SRP, defined by the presence of abnormal nailfold capillaroscopy, over a mean follow-up period of 29.4 months . The importance of nailfold capillaroscopy and SSc-associated autoantibodies in the early diagnosis of SSc is reflected in the inclusion of these investigations in the 2013 ACR/EULAR classification criteria for SSc , as well as the VEDOSS criteria . When the presence of an underlying CTD in the patient presenting with RP is uncertain, many clinicians will adopt a pragmatic approach if there are any abnormalities suggestive (but not diagnostic) of an underlying CTD (e.g., a weakly positive ANA and borderline widened capillaries) and repeat the capillaroscopy in 6–12 months. Cutolo et al. proposed twice-yearly capillaroscopic examination of patients with PRP in order to detect the transition to SRP at the earliest opportunity . From the available data, it would seem reasonable to keep particularly patients at the highest risk of developing SRP under (at least) annual review for up to 5 years (as the majority of patients could be expected to transition to SRP during this time period).
Future prospective, longitudinal studies are required to further understand the transition from PRP to SRP, with a view to devising possible early intervention strategies (e.g., vascular remodelling agents) and to informing the optimal treatment of RP at different stages of the disease process. A key issue in future studies is how RP attacks (both frequency and severity) are measured. The current methods are subjective and are often based on successful patient diary completion and return (these diaries are not always returned). Possible approaches to overcome these issues would be developing a ‘uniform’ definition of RP and developing novel methods of measuring RP (e.g., objective vascular imaging and mobile smartphone technology).
Related posts:
Improving care of autoimmune connective tissue diseases: Lessons from longitudinal cohorts
Connective tissue disease-related interstitial lung disease
Pregnancy and autoimmune connective tissue diseases
Cardiovascular risk and its modification in patients with connective tissue diseases
Antiphospholipid syndrome
Primary Sjögren’s syndrome
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
