Carpal tunnel syndrome
Associated with primary Raynaud’s phenomenon
Associated with systemic sclerosis (in particular early, rapidly progressive diffuse cutaneous disease)
Drugs and toxins
Immunosuppressive agents
Chemotherapeutic agents
Drugs used in the treatment of hypertension
Drug used in the treatment of anxiety and headache syndromes
Toxins (including occupational exposure)
Metabolic
Hypothyroidism
Carcinoid syndrome
Phaeochromocytoma
POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes) syndrome
Haematological
Abnormal cellular constituents
Leukaemia and lymphoma
Polycythaemia
Thrombocythaemia
Abnormal blood components
Paraproteinaemia
Cryoglobulins
Cryofibrinogenaemia
Cold agglutinin disease
Coagulopathy
Inherited thrombophilias
Malignancy
Solid tumours
Leukaemia, lymphoma and others
Paraneoplastic Raynaud’s phenomenon and digital ischaemia
Raynaud’s phenomenon secondary to localised radiotherapy
Carpal Tunnel
Introduction
Carpal tunnel syndrome (Fig. 10.1) may be primary (idiopathic) or secondary to a number of recognised causes, including SSc. RP and idiopathic carpal tunnel syndrome are both common conditions in the general population and may also cause similar symptoms such as painful dysthesia of the extremities [1]. An association between the two conditions has long (as early as 1957) been suspected [2, 3]; however, proving a definitive causal relationship has remained elusive.
Fig. 10.1
Note the thenar atrophy due to chronic carpal tunnel syndrome
The Association Between Idiopathic Carpal Tunnel Syndrome and Raynaud’s Phenomenon
There is a limited evidence base relating to the association between idiopathic carpal tunnel syndrome and RP. The prevalence of coexisting RP in patients with clinical and neurophysiologically proven carpal tunnel syndrome has been reported to be as high as 60 % [4]. In a recent meta-analysis of eight studies conducted between 1957 and 2006 (with a total of 675 patients), the prevalence of coexisting RP in patients with carpal tunnel syndrome, using a random effects model was 0.155 (95 % CI 0.043, 0.318); that is 15.5 % of patients with carpal tunnel syndrome also suffer with RP [5]. Of note there was a significant publication bias present and the prevalence of coexisting carpal tunnel syndrome and RP increased over time; for example, the odds ratio (of both carpal tunnel syndrome and RP coexisting) increased over the decade 1957–1967 from 1 (95 % CI 1.065, 1.112) to 2.340 (95 % CI 1.886, 2.903). The authors suggest that the increased prevalence (of both conditions coexisting) with year of publication may be due to the different characteristics of the included studies, namely, the varying climate conditions, time trend and the exact definition/diagnostic criteria of RP.
In a study of 93 patients with objectively proven idiopathic carpal tunnel syndrome and 57 control subjects, RP was observed (using a validated patient questionnaire) in 36 % of patients with idiopathic carpal tunnel syndrome and only 12 % of control subjects (P = 0.002) [1]. Chung et al. reported objective evidence of cold sensitivity as assessed by a cold provocation test with photoplethysmography in 60 % (18 out of 30) of patients with clinically and electromyographically proven idiopathic carpal tunnel syndrome [4]. The authors conducted a subsequent study on the same cohort of patients to evaluate the effect of open carpal tunnel decompression on their RP. A good improvement (improvement in both RP symptoms and normal pulse amplitude after exposure to cold) was observed in ten patients (56 %) and fair (pulse amplitude recovery by two thirds of that before cold exposure) in four patients (22 %); with a mean recovery time of 4.2 months (6 weeks to 1 year) [6].
A neuroanatomical difference in the localisation of the conduction delay between patients with idiopathic and SSc-related RP has been reported [7]. In a prospective study, nerve conduction velocity was examined in 39 patients with idiopathic RP and 18 patients with SSc-related RP, all with no symptoms of carpal tunnel syndrome [7]. Isolated conduction delay was localised in the patients with PRP to the carpal tunnel, whereas patients with SSc-related RP had slowing of both the median and ulnar nerves; the authors postulate that it is due to subclinical peripheral neuropathy.
Carpal Tunnel Syndrome Secondary to Systemic Sclerosis
Carpal tunnel syndrome is a well-recognised early complication in the disease course of patients with systemic sclerosis (SSc) [8, 9], in particular progressive disease [10] and the diffuse cutaneous subtype. During the oedematous phase, there may be compression of the median nerve in the carpal tunnel, which may regress as the fibrotic phase progresses. Often surgical decompression of the carpal tunnel syndrome can be avoided and symptoms may improve spontaneously as the oedema resolves.
Expert Opinion
Many clinicians have long suspected an association between carpal tunnel syndrome and RP. Both conditions are common in the general population and may present with similar symptomology; however, a causal relationship has yet to be established. In early SSc (in particular rapidly progressive, diffuse cutaneous SSc), carpal tunnel syndrome commonly occurs, but may spontaneously improve as the oedematous phase resolves with the onset of skin fibrosis. Lack of validated measures of RP in studies of patients with carpal tunnel syndrome makes it difficult to tease out whether some symptoms are related to carpal tunnel syndrome or to RP. Of clinical relevance to the rheumatologist, only one small study has suggested that the (surgical) treatment of carpal tunnel syndrome may significantly improve patients’ symptoms of RP,
Drug and Toxins
Introduction
A considerable list of drugs and toxins (Table 10.2) can alter peripheral blood flow: some of these agents may cause vasoconstriction that can either aggravate existing RP or precipitate acute vasospasm mimicking RP.
Table 10.2
The secondary drug and toxin causes of Raynaud’s phenomenon
Immunosuppressive agents | Cyclosporine A |
Interferons | |
Chemotherapeutic agents | Bleomycin |
Vinblastine | |
Cisplatin | |
Other agents, e.g. tegafur, gemcitabine/S-1 | |
Drugs used in the treatment of hypertension | Beta-blockers |
Clonidine | |
Drug used in the treatment of anxiety and headache syndromes, and amphetamines | Ergots |
Methysergide | |
Amphetamines | |
Toxins (including occupational exposure) | Cocaine |
Cannabis | |
Vinyl chloride |
When assessing the patient with RP a thorough drug, occupational and social history is essential to ascertain if there are any putative agents causing peripheral vasospasm. If potential causative agents are identified, these drugs/toxins should be stopped or avoided if at all possible. For example, the patient presenting with RP after starting a beta-blocker for hypertension should be changed to another class of suitable antihypertensive. However, there will be instances when the drug causing or worsening RP cannot be stopped, in which case appropriate management of the resultant RP will need to be instituted.
It is also important to be aware that the drugs and toxins presented in this section may cause SRP, and this should be considered on regular review of medication after initiation of the therapy.
Immunosuppressive Agents
Cyclosporine A
Since approval in the early 1980s, cyclosporine A (CsA) has become a widely used immunosuppressive agent, preventing rejection of organs following transplantation surgery and treating a range of autoimmune diseases. Amongst potential side effects, case reports since the earliest years of its use have suggested that CsA can precipitate RP [11–14]. In vitro study suggests that the mechanism of this drug-induced peripheral vasospasm may be endothelial cell synthesis and release of endothelin (ET) on CsA exposure [15]. However, interrogation of clinical, therapeutic and hormonal characteristics of organ transplant patients in clinical study by Piquard et al. questions the link between CsA and high levels of ET in this patient group [16] and non-invasive measures of finger blood flow fail to exhibit vasoconstriction on low maintenance CsA following heart transplant [17]. Indeed it has been suggested that CsA may even augment skin vasodilation [18].
Interestingly, CsA has been proposed and investigated as a potential therapy for patients with SSc, most of whom experience severe RP. Whereas there has been suggestion of the potential therapeutic benefits of CsA for non-Raynaud’s aspects of disease in small open-label studies of SSc [19, 20], there have been concerns about other side effects, particularly renal toxicity [21].
Interferons
Interferon-alpha (IFN-α), with its broad range of effects on various biological pathways, is an attractive therapeutic option for a number of clinical indications: IFN-α induced RP, usually with associated catastrophic digital ischaemia resulting in peripheral tissue infarction, has subsequently been described in patients treated for hepatitis B [22], hepatitis C [23] and several malignancies, such as chronic myeloid leukaemia [24–26] and melanoma [27].
Less commonly, RP has been linked with interferon-beta (IFN-β) therapy. Induction of RP has been reported in a patient with multiple sclerosis (MS) treated with IFN-β [28]. SSc (almost invariably associated with significant RP) has developed in some IFN-β treated cases of MS [29, 30].
Data on interferon-gamma (IFN-γ) is limited and conflicting, with report of treatment exacerbating RP in patients with SSc [31], whilst an in vitro study has suggested that a population of CD4+ T cells produces high levels of IFN-γ, which may be protective in RP [32]. IFN-γ and IFN-α have been studied in SSc patients by a numbers of investigators, but initial promise [33] has not translated to a useful therapy.
Mohokum et al. [34] conducted a meta-analysis assessing the prevalence of RP in patients treated with interferons in published data. Their conclusion was that, despite heterogeneity, there was a possible association between RP and IFN therapy, but the caveat was that there were only six eligible studies for inclusion.
Chemotherapeutic Agents
Bleomycin, Vinblastine, Cisplatin and Other Agents
The development of RP on chemotherapy has been well documented, particularly for testicular neoplasms. A steady stream of reports, from the late 1970s onwards, links bleomycin alone or in combination with vinblastine and/or cisplatin with onset or significant worsening of RP in this group [35–40]. Vogelzang et al. [41] found 22 of 60 men (37 %) treated with bleomycin and vinblastine, with or without cisplatin, for testicular cancer developed RP. Even without RP there is evidence of exaggerated cold response on non-invasive testing of vascular function in patients treated with this chemotherapy regime [42, 43]. RP occurring following these three agents has been linked, potentially, to hypomagnesaemia [44] as well as being reported in combination with cryoglobulinaemia [45]. Bleomycin-induced RP has even been associated with acral sclerosis in one case report [46].
Precipitation of digital gangrene in a patient with coexisting RP treated for non-Hodgkin lymphoma with bleomycin and vincristine has also been described [47] as well as RP after a single dose of bleomycin in Hodgkin Disease [48].
Bleomycin for acquired immune deficiency syndrome-related Kaposi’s sarcoma has also been linked to induction of RP and severe peripheral ischaemia in numerous cases, either alone [49–52] or in combination with vinblastine [53], vincristine/vinblastine [54] or vincristine and doxorubicin [55]. Decreased capillary density has been found on nailfold capillary microscopy on bleomycin treatment in this group of patients [51]. Local intradermal bleomycin treatment for warts can also initiate RP [56–58].
The various contributions of the individual agents to peripheral vasospasm in chemotherapy regimens are not clear. Hladunewich et al.[53] found that bleomycin or vinblastine alone was not associated with RP but sequential vinblastine followed by bleomycin was. McGuire et al. [59] found a 2-year-old treated for a vaginal tumour developed RP after bleomycin, with resolution of her vasospasm despite continued vinblastine. Mohokum et al. [60] conducted a meta-analysis to tease out the prevalence of RP in patients receiving cisplatin-based therapy and found some indication of an association in the 24 eligible studies, although results were confounded by heterogeneity of studies.
Other chemotherapy agents have been linked with RP and RP-associated disorders. RP, severe digital ischaemia and SSc have been triggered by tegafur, the pro-drug of 5-fluorouracil, [61] as well as with gemcitabine/S-1 for pancreatic metastatic pancreatic cancer [62] and gemcitabine/carboplatin in an SSc patient treated for lung cancer [63].
Drugs Used in the Treatment of Hypertension
Beta-Blockers
Beta-adrenergic blockade is an established treatment for the extremely common problem of essential hypertension, and is proven to prevent many of the damaging sequelae of uncontrolled high blood pressure. Beta-blockers have a number of other therapeutic indications, such as treatment of cardiac failure, protection of the myocardium post-myocardial infarction, arrhythmia control and reduction of tremor/anxiety. A recent meta-analysis interrogated the published evidence behind the generally accepted paradigm of beta-blocker association with RP [64]. Of 13 eligible, but heterogeneous, studies and 1,012 individuals, the pooled prevalence of RP in patients receiving beta-blockers was 14.7 %, indicating only a possible association between RP and beta-blocker therapy.
Clonidine
Clonidine is a preferential alpha-2 adrenergic agonist (see Chaps. 4 and 5). It can be used to treat essential hypertension, although it is infrequently used for this indication currently. Clonidine may also be used for attention deficit hyperactivity disorder (ADHD) or anxiety. In a double-blind study of 60 forest workers with hand-arm vibration syndrome, clonidine was studied, with the hypothesis that it would attenuate peripheral sympathetic activity and alleviate RP. However, clonidine showed no difference to placebo in length or frequency of RP attacks, and indeed two subjects had apparent clonidine-provoked RP [65]. Coffman and Cohen [66, 67] confirmed that both alpha-1 and alpha-2 adrenoreceptor subtypes were present in the digital vasculature, with the alpha-2 receptors being the more important in sympathetic neural vasoconstriction at this site (see Chaps. 4 and 5). In PRP subjects, Freedman et al. [68] found increased peripheral vascular adrenergic receptor sensitivity compared to controls, with clonidine, like phenylephrine, resulting in greater digital blood flow reduction in the PRP group (see Chaps. 4 and 5). The same group then established that cooling augmented the alpha-2 adrenergic vasoconstriction produced by clonidine in controls [69], and subsequently that cooling increased the alpha-2 adrenergic vasoconstriction produced by clonidine in PRP [70] and SSc-related RP [71] but not in the control group on this occasion.
Phenylephrine is commonly used in over-the-counter decongestants. Although it can cause powerful vasoconstriction of digital arteries (see Chaps. 4 and 5), it is extensively but variably metabolised in the gut and it is unclear if it can attain sufficient blood levels to cause clinically significant vasoconstriction (see Chap. 18).
Drugs Used in the Treatment of Anxiety and Headache Syndromes, and Amphetamines
Ergots
Ergot alkaloids are used in the management of migrainous headache. They can initiate vasoconstriction through multiple mechanisms including activation of alpha-adrenergic and serotonergic receptors. In migraine, they are assumed to function by vasoconstriction of cranial blood vessels [72]. The first published description of the use of “ergot of rye” was in the British Medical Journal in 1868 [73]. Vascular toxicity from ergots is well- and long-recognised, with descriptions of peripheral gangrene being recorded in the medical literature through the decades, back to 1930, although historical references to ergotism predate even this [74].
Bromocriptine is also an ergoline but is used for its dopamine agonist effects to treat pituitary tumours, hyperprolactinaemia, Parkinson’s disease and type II diabetes mellitus, rather than headaches. Via the same sympatholytic, vasoconstrictor mechanisms it can also precipitate RP.
Methysergide
Methysergide is a serotonin (5-HT) inhibitor initially synthesised from lysergic acid. It was developed to treat migraine but it has been limited therapeutically because it causes retroperitoneal fibrosis with chronic use. It is a proven vasoconstrictor with effects on peripheral vasculature [72, 73].
Amphetamines
Amphetamines are central nervous system stimulants, affecting dopaminergic and noradrenergic systems. They result in the release of catecholamines from synapses, and theoretically can cause peripheral vasospasm. The main clinical use for the amphetamine class is treatment of ADHD. Goldman et al. [75] set out to investigate whether RP was associated with use of these amphetamine-based medications in children with ADHD, and found a significant association in their case–control study of 64 patients.
Toxins (Including Occupational Exposure)
Cocaine and Cannabis
Both vasoconstriction, via blocking of presynaptic uptake of norepinephrine and dopamine, and thrombosis contribute to cocaine-induced arterial compromise in a number of vascular beds. Although ischaemic myocardial events are well described in cocaine users, RP is surprisingly rarely reported in association with cocaine consumption [76]. Short duration of cocaine use is postulated as a possible reason behind the lack of RP reports in cocaine abuse [77]. There have been a number of reported cases of RP associated with SSc developing in individuals abusing cocaine [78].
Vinyl Chloride
Vinyl chloride monomer (VCM) is an aliphatic hydrocarbon, used as the base material in the synthesis of the commonly used synthetic resin polyvinyl chloride (commonly referred to as the abbreviation “PVC”) [80]. Although working with PVC is completely harmless, exposure to VCM, e.g. during the manual descaling of autoclaves, is potentially hazardous [80]. Occupational exposure to VCM has been associated with a scleroderma-like syndrome, including extensive skin [81] and lung fibrosis [81], acro-osteolysis [82, 83] and RP [80, 84, 85]. A similar genetic susceptibility to both SSc and the scleroderma-like syndrome associated with VCM exposure has been reported [86]. SSc-like nailfold capillary changes have been described in patients with previous VCM exposure [80, 84, 85, 87, 88]. However from the published literature, a causal relationship between microvascular abnormalities (as assessed by capillaroscopy) and the development of RP in this patient group is far from certain [80, 85]. In a recent study that included 21 patients exposed to VCM (and 40 controls), capillaroscopic abnormalities were still present on average 15 years after retirement [80]. Although, the patients who were exposed to VCM had a statistically significantly higher reported prevalence of RP (19 % vs. 0 % respectively), this was not associated with the presence of capillaroscopic abnormalities [80].
Expert Statement
A number of prescription, non-prescription drugs and toxins (including occupation related) may precipitate or exacerbate RP. When these agents are initiated, care should be exercised in individuals with pre-existing RP, and, if possible, alternative therapies, which do not compromise peripheral blood flow, should be used instead. Patients started on therapies, which can trigger RP, should have medication review at appropriate intervals to ensure that medication does not have to be stopped or treatment added for associated RP. In the patient presenting with RP, particularly of “late onset”, a careful drug and social history is imperative to identify any potential causative agents.
Metabolic
Introduction
There is interplay of endocrine control with vasomotor tone. Disturbance of endocrine systems may result in RP. This is most commonly recognised in hypothyroidism, and, when taking a clinical history, examining and ordering laboratory investigations in the person presenting with RP, this possibility should be considered.
Thyroid Disorders
Both primary and central hypothyroidisms are commonly associated with a number of general symptoms including feeling cold, and hypothermia is a feature of myxoedema coma. Therefore, as thyroid disease results in impaired thermoregulation, in routine clinical practice, hypothyroidism might be a potential cause of or exacerbating factor for RP.
However, there is limited hard evidence in the literature for a link between hypothyroidism and isolated RP. In 1976, Shagan and Friedman presented two cases of patients with RP who were found to be hypothyroid, and whose symptoms abated with thyroid replacement therapy [89]. They postulated that altered autonomic function in hypothyroidism resulted in RP. The same authors published a case report of a patient with panhypopituitarism whose only clinical symptom was RP, advocating that the diagnosis of hypothyroidism should be considered in the individual presenting with RP [90]. A later case report suggested the same consideration should be made in paediatric populations [91]. Nielsen et al. reported that 15 of 17 untreated patients with hypothyroidism had cold hands, with 4 having true RP, and confirmed digital artery closure on local finger cooling in the 4 RP sufferers [92]. Treatment with l-thyroxine significantly attenuated the cold sensitivity [92] and a further case report has described resolution of severe RP on adequate l-thyroxine treatment of hypothyroidism [93]. One case report of a 29-year-old woman linked her hypothyroidism presenting with acute myocardial infarction to her background history of several years of antecedent RP, suggesting that vasospasm of the peripheral and coronary arteries may both be linked to thyroid inactivity [94]. However, there have been no further suggestions of such an association in the subsequent 30 years.
Thyroid disorders are well described in autoimmune diseases that have an association with RP [95]. In particular, SSc, which is associated with severe RP in most cases, has been associated with subclinical/clinical hypothyroidism and hyperthyroidism in a large number of case reports and series [96–108]. Antonelli et al. set out to evaluate the prevalence of thyroid disorders by studying 202 consecutive SSc patients and comparing to a matched control group of 404 subjects: the odds ratio (OR) for female SSc versus controls was 14.5 for clinical hypothyroidism, and there were three cases of Grave’s disease and two cases of papillary thyroid cancer in the SSc group compared to zero cases in the control group [109].
Neuroendocrine Tumours: Carcinoid and Phaeochromocytoma
Carcinoid syndrome occurs in less than 10 % of patients with the rare neuroendocrine tumour, carcinoid. Circulating neuroendocrine mediators (serotonin) result in vasomotor disturbance, most commonly resulting in facial flushing and peripheral oedema, with RP being less frequently reported. However, even in 1963, in a clinico-pathological conference of carcinoid occurring in a woman with a background of RP, the discussants question the association of the RP with carcinoid and describe clinical and pathological features suggestive of concurrent SSc [110]. A number of cases have been published of SSc occurring in carcinoid: in some cases the carcinoid occurs in patients with established SSc and associated RP, and in other cases sclerodermatous skin involvement alone develops in advanced carcinoid [111–113].
Phaeochromocytoma is a neuroendocrine tumour of the adrenal medulla that secretes catecholamines, and is associated with symptoms of sympathetic overactivity: hence, RP has been associated with the list of possible symptoms [114]. The finding of phaeochromocytoma has also been reported in patients with RP and SSc [115].
POEMS Syndrome
RP has been associated with the rare multisystem disorder POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy and skin changes) [116, 117], which is a paraneoplastic syndrome associated with plasma cell dyscrasia [117]. The skin changes in POEMS syndrome may mimic SSc [118] and (reversible) pulmonary hypertension has been described [119, 120], that has been reported to be steroid responsive [121]. There are several case reports [122–124] in the published literature reporting an association between RP and POEMS syndrome. In a single centre review of patients with confirmed POEMS syndrome, 20 % of patients had coexisting RP [118]. Of interest, in a study that included 9 patients with POEMS syndrome (4 had RP) who received an autologous haematopoietic stem cell transplant, three patients’ RP improved and the other patient stabilised [125].
Expert Statement
When there is endocrine imbalance, disturbance of vasomotor tone may occur. Hypothyroidism is common and may present as or exacerbate existing RP. On assessing the patient with RP, one should consider thyroid or other endocrine disease. Treatment of hypothyroidism may also treat associated RP.
Haematological
The physician must perform a comprehensive clinical assessment and maintain a high index of suspicion to identify those patients with SRP due to an underlying haematological abnormality. In general, these may be considered within three groups (Fig. 10.2), that may overlap: (1) abnormal cellular components, (2) abnormal blood components and (3) a pro-thrombotic tendency (coagulopathy).
Fig. 10.2
The haematological causes of Raynaud’s phenomenon
Abnormal Cellular Components
Both quantitative (e.g. an increased cellular count and haematocrit) and functional abnormalities (including a propensity towards intravascular thrombosis) are recognised causes of RP and also erythomelalagia. Malignant transformation of myeloid lineage cells (polycythaemia and essential thrombocythaemia) is considered here, whereas leukaemia, lymphoma and related conditions are discussed in section “Malignancy”.
Polycythaemia and Thrombocythaemia
Although polycythaemia and thrombocythaemia are generally considered by many to be recognised causes of SRP, there is a lack of a robust evidence base to support this. Polycythaemia (or more accurately speaking “erythrocytosis”) may be defined as an increase in the circulating red blood cells with a persistently elevated haematocrit [126]. It may be primary (polycythaemia vera) or secondary to hypoxemia (chronic lung disease, smoking, right to left cardiopulmonary vascular shunts and hypoventilation syndromes), renal disease (polycystic kidney disease and hypernephroma) and miscellaneous causes (including raised oxygen affinity haemoglobin, hepatoma and cerebellar haemangioma) [126, 127]. Thrombocythaemia (thrombocytosis) is usually a reactive process (e.g. to an underlying infection, chronic inflammation, cancer or major trauma); however, in a small number of patients it may be due to a clonal proliferation of hematopoietic stem cells (essential thrombocythaemia) [128].
Polycythaemia and Thrombocythaemia Due to Myeloproliferative Neoplasms, Including a Propensity Toward Thrombotic Disease and Erythromelalgia
The myeloproliferative neoplasms are a group of related clonal disorders that arise from haematopoietic progenitor cells, including polycythaemia vera and essential thrombocythaemia [129]. An activating mutation in the tyrosine kinase JAK2 has been well described in both of these conditions [129]. In both polycythaemia vera and essential thrombocytaemia, an increased propensity towards thrombosis has been observed. Large vessel (arterial) thrombosis occurs most frequently, however microcirculatory occlusive disease is also seen, manifesting as (but not limited to) Raynaud’s-like phenomenon [130, 131], which may result in critical digital ischaemia [132]. Myeloproliferative neoplasms are also a secondary cause of erythromelalgia; that may mimic RP [130, 131, 133]. Erythomelalgia is characterised by severe burning pain and skin erythema (akin to the hyperaemic phase in a Raynaud’s attack), but is quite dissimilar through a notable improvement in cold ambient environments; again, stressing the paramount importance of eliciting a comprehensive history of cold sensitivity [134] (Chap. 11).
Abnormal Blood Components
RP and digital ischaemia have been associated with various abnormal blood constituents. This may occur due to the physical obstruction of the microcirculation or as an immunologically mediated phenomenon.
Paraproteinaemia
A paraprotein is the protein product (monoclonal immunoglobulin or immunoglobulin light chain [Bence Jones protein]) of the clonal proliferation of mature B-lymphocyte lineage cells (including plasma cells) that may be detected in the blood and urine [135]. Paraproteinaemia and cryoglobulins (a type of paraprotein with unique physical properties) have been associated with RP [136] and in particular cryoglobulins with digital ischaemia.
Cryoglobulins
Cryoglobulins (cryoglobulinaemia) (Fig. 10.3) denotes the presence in the serum of single or mixed immunoglobulin chains [137] that precipitate at temperatures below 37 °C and dissolve upon rewarming [138]. Type 1 cryoglobulins are single monoclonal immunoglobulin (usually IgM) and account for approximately 10 % of patients with cryoglobulinaemia [137]. Mixed cryoglobulins are immune complexes that contain either monoclonal (type 2) or polyclonal (type 3) immunoglobulins [139]. Essential cryoglobulinaemia is a rare systemic vasculitis due to immune complex deposition in the wall of small and medium blood vessels [138]. In a small case series of three patients with essential cryoglobulinaemia, disease was characterised by RP, arthralgia-arthritis and skin lesions [140]. Monoclonal cryoglobulins are often associated with haematological conditions (including lymphoproliferative disorders and B-cell dysplasias) [137–140], whereas mixed cryoglobulins are associated with a number of systemic conditions (including autoimmune diseases, e.g. Sjögren’s syndrome and systemic lupus erythematous [SLE]) [141] and infections (classically hepatitis C infection) [138, 141].
Fig. 10.3
Cryoglobulinaemia: Cutaneous infarction on hand due to type 1 cryoglobulins
In a multi-centre retrospective study of 891 patients with cryoglobulinaemia, at the time of diagnosis, overall 19.5 % of patients reported symptoms of RP; however, this was almost twice as frequent in patients with cryoglobulinaemias secondary to an underlying connective tissue disease [142]. Ferri et al. reported RP in patients with mixed cryoglobuinaemia in 36 % (79/220 patients) at baseline and 48 % (91/190) at the end of follow-up between 1972 and 2001 (mean duration of follow-up 6.7 years) [143].
Considering the SSc population, in a study of 246 patients with SSc, circulating cryoglobulins were detected in 7 (2.8 %); 2 patients had trace amounts, whereas 5 (4 limited cutaneous SSc: 1 diffuse cutaneous SSc) had mixed cryoglobulins [144]. All five patients were positive for hepatitis C infection and four developed a clinically apparent cryoglobulinaemic vasculitis. These patients had a severe vascular syndrome (including necrotic skin ulcers and one patient required bilateral below knee amputation). The authors propose the severe vascular disease observed in these patients may be due the additive effect of their underlying SSc-related microvascular disease and cryoglobulinaemic vasculitis [144]. There is no evidence available to suggest that treating a patient’s cryoglobulinaemia improves their coexisting RP.
Cryofibrinogenaemia
Cryofibrinogenemia is a much rarer condition that cryoglobulinaemia. Cryoprecipitate (formed of fibrinogen, fibrin, fibronectin and other smaller proteins) is formed as the plasma (note, not the serum as in cryoglobulinaemia) is cooled at 4 °C, and becomes resoluble again as the temperature of the sample is rewarmed towards 37 °C [145]. Similar to cryoglobulinaemia, it may be primary (essential) or secondary to a range of conditions, including systemic autoimmune conditions, infections and malignancy [146]. The frequency of RP in the literature in essential cryofibrinogenemia ranges between 16.6 % [147] and 53.7 % [145] and secondary cryofibrinogenaemia between 0 % [148] and 24 % [145]. Again, there is no evidence available to suggest that treating a patient’s cryofibrinogaemia improves coexisting RP.
Cold Agglutinin Disease
Cold agglutinin disease is a cold-induced autoimmune haemolytic anaemia due to pathological reactive antibodies that are directed towards antigens present on the surface of red blood cells [149, 150]. In cold agglutinin disease, the antibodies are usually of the IgM class (monoclonal IgM kappa paraproteins) [151] and exhibit reactivity at body temperature (37 °C), with maximal biological activity at 4 °C [149]. Cold agglutinin disease may occur as a primary or secondary phenomenon to a range of infections, including bacterial (Mycoplasma pneumonia and Chlamydia psittaci) [151] and various viruses (Cytomegalovirus, Epstein–Barr, Parvovirus B19, Rubella and Varicella zoster) [151]. In the few published case reports [151, 152], cold agglutinin disease is associated with severe RP that often occurs bilaterally and involves all the digits and not uncommonly progresses to critical digital ischaemia [151, 152]. Kröger et al. found in their study of 306 patients with RP, that the detection of low titres of cold agglutinins in 49 patients was not associated with significant symptoms, or definite abnormalities on nailfold capillaroscopy after 3 years of follow-up [153]. In one case report, treatment of the patient’s cold agglutinin disease (monoclonal IgM band) with chemotherapy was not associated with an improvement in their RP (with digital ischaemia and ulceration); subsequently requiring intra-arterial reserpine [152].
Coagulopathy
Inherited Thrombophilias (Antiphospholipid Syndrome and Protein C, Protein S, Antithrombin III, Factor V Leiden Deficiencies)
The antiphospholipid (Hughes) syndrome is characterised by recurrent (and potentially catastrophic) thrombosis (arterial or venous) and obstetric morbidity, in the presence of characteristic antiphospholipid autoantibodies (anticardiolipin antibody, the lupus anticoagulant and antibodies toward β2-glycoprotein I) [154, 155].
Despite a strong theoretical rationale (thrombotic occlusion of the microcirculation) for the digital microcirculation to be compromised in the inherited thrombophilias (Protein C, protein S, antithrombin III and factor V Leiden deficiencies), there is a lack of a robust evidence base to support this. In a study of 200 patients with PRP and 200 healthy controls, the prevalence of thrombosis associated alleles (including the factor V Leiden mutation) did not differ significantly between the two groups [156].
The evidence for an association between anticardiolipin antibodies and RP is conflicting, with some studies reporting a positive association [157, 158] and others reporting no association [159–161]. Lupus anticoagulant positivity has been associated with RP in patients with SLE [157]. However, paradoxically in a study of 93 patients with SLE (40 with and 53 without RP), the prevalence of all antiphospholipid antibodies (including anticardiolipin and β2-glycoprotein I) was higher in those patients without RP, and a negative association between RP and the IgG subtype of anticardiolipin autoantibody was reported [161]. An association between IgG anticardiolipin antibody and digital necrosis has been described [158].
Antiphospholipid antibodies are not uncommonly seen in patients with SSc; although characteristic thrombotic complications are uncommon [162]. While an association between antiphospholipid antibodies and macrovascular disease (including pulmonary hypertension) in patients with SSc has been described [163, 164]; the association with RP and in particular, critical digital ischaemia is conflicting. Several studies have reported an association between antiphospholipid antibodies and digital infarcts [163, 164], whereas one study has found no association between anticardiolipin antibodies and severe digital ischaemia [165]. Antiphospholipid antibodies have also been described with internal malignancy, including in the context of co-existent digital ischaemia [166]; however, it is not clear if they play a pathological role in thrombosis or are an epiphenomenon [167].
Expert Opinion
A wide range of haematological abnormalities has been associated with RP, although the evidence base for some haematological causes is equivocal or contradictory. Mechanistically there is a strong theoretical rational for how the haematological causes may compromise digital vascular blood flow. The association with RP is more likely caused by occlusive vascular disease or hypoperfusion due to RP attacks, rather than isolated vascular compromise. Haematological causes of RP may broadly be considered under the following three headings: abnormal cellular and blood components as well as a propensity towards intravascular thrombosis. All may be malignancy driven. The identification of the haematological causes of RP requires a high index of clinical suspicion to ensure optimal management. Firstly, many of the haematological causes may well be treatable and secondly, they are not uncommonly associated with severe digital vascular disease, e.g. gangrene.
Malignancy
The association between RP and (often) critical digital ischaemia with internal malignancy has been informed by a limited number of case reports and series in the published literature. Digital ischaemia may occur as a direct result of the neoplastic process, e.g. occlusion of the microcirculation through malignant cells or as a true paraneoplastic effect independent of the direct effect of the underlying neoplasm. Of caution to the clinician, this may predate the diagnosis of the underlying malignancy and inform the diagnostic process, through the course of investigation to exclude a secondary cause for the patient’s RP. Malignancy may also drive the production of cryoproteins (cryofibrinogen and cryoglobulins) and antiphospholipid antibodies. The association between radiotherapy and the development of RP including digital ischaemia is also discussed here, whereas therapeutics used in the treatment of malignancy have been discussed earlier in this chapter. Of note to the clinician in the assessment of patients with RP, ANA positivity (often in very high titre) may long predate the diagnosis of the malignancy [168, 169].
Related posts:
Stay updated, free articles. Join our Telegram channel
Full access? Get Clinical Tree
