Primary pernio, also known as chilblains, is a cold-induced vasculopathy that is more commonly seen in damp climates and not associated with an underlying disease state [21, 22]. It primarily affects the hands and feet and is more commonly seen in young women in a bilateral, symmetric distribution [23]. Lesions may also affect the pinnae of the ear, nose, and thighs [22]. Inflammatory red to purple macules are characteristically seen on the distal ends of the affected area and usually appear within hours following cold exposure (Fig. 11.2) [22]. Lesions are often associated with burning, pain, and/or pruritis. Small joint enlargement may be seen in the involved areas, and ulceration of lesions is occasionally noted [24].

Chilblains is idiopathic and not usually indicative of a more serious underlying condition [24]. The etiology is not well defined, but is thought to be related to abnormal vascular responses to cold exposure [25, 26].

Chilblains may be confused with Raynaud’s as both conditions occur after exposure to cold, affect acral areas, and may cause associated pain and red or purple discoloration of the skin. Chilblains tends to present with more discrete acral lesions rather than the more even discoloration seen in Raynaud’s [27, 28].

Differences between chilblains and Raynaud’s in the acute setting include an absence of the early pallor in chilblains, which is often present in Raynaud’s. In addition, persistence of cold or purple hands despite rewarming is more commonly seen in chilblains than Raynaud’s [28, 29]. As a result, symptoms of chilblains are less likely to recede in the summer months [30].

Prompt recognition through a careful history and physical exam can avoid excessive investigation and anxiety, allowing appropriate simple advice and treatment [24]. Laboratory studies from patients with chilblains usually do not demonstrate evidence of cryoglobulins, cryofibrinogens, or cold agglutinins [23]. In an initial evaluation, however, these studies, in addition to complete blood count, comprehensive metabolic panel, erythrocyte sedimentation rate, c-reactive protein, serum protein electrophoresis, complement, rheumatoid factor, antiphospholipid antibodies, and ANA should be evaluated to look for secondary causes, but are usually normal in primary chilblains [23, 26, 28]. Evaluation for cryoglobulins in the initial evaluation remains an area of debate [26, 31]. Biopsies are not routinely recommended, but when performed, are done to distinguish between chilblains and the skin lesions of SLE. The lesions are thought to be inflammatory with a variety of histopathological changes described. A mononuclear vascular infiltrate and variable papillary dermal edema are described but are not specific enough to be diagnostic of chilblains [24]. Findings that are not specific for lupus but that suggest chilblains lupus over primary chilblains include the combination of edema and reticular dermis infiltrate with a perieccrine reinforcement, differences in spongiosis, vacuolation of basal layer, edema of the dermis, and deep perieccrine inflammation [32].

Chilblains is generally benign without systemic complications [24]. Most cases will resolve in 1–2 weeks, with modification of cold exposure and avoidance of acute temperature changes [23]. Early recognition can avoid excessive diagnostic testing, alleviate anxiety, and allow appropriate simple lifestyle modification and management as indicated [23]. Avoidance of extended cold exposure through proper attire and limiting the time of exposure to cold temperatures minimize risk of future attacks. In an Australian review, most patients improved with the warmer weather or responded to cold protection with all cases resolving by late spring [24]. However, most were also treated with nonsteroidal anti-inflammatory drugs, prednisone or calcium channel blockers and therefore distinguishing the effects of the drug from the effects of environmental changes is challenging [24].

In situations where repeated cold exposure is likely and lesions are persistent or recurrent, we recommend a short course of pharmacologic therapy. While several treatment options exist, we recommend calcium channel blockers, as first line therapy in such cases. This class of medications has been studied in two small placebo-controlled trials in patients with chilblains [33, 34]. Both studies supported the use of this class of medications over placebo in the treatment of chilblains. Short courses of oral prednisone (3–5 days), topical steroids, prazosin, or NSAIDS prescribed for 1–2 weeks would be the alternative therapies to calcium channel blockers [21, 24, 35]. As data for using these drugs for treating chilblains is limited, we recommend selecting the therapeutic agent based on the risk–benefit ratio for the patient and their comorbidities.

Chilblain lupus, or Hutchinson lupus, was first described in 1888 by Jonathan Hutchinson. It is a rare and chronic form of cutaneous LE characterized by erythematosus-purple plaques located in the distal extremities, often also affecting the nose and ears. These lesions are induced by exposure to cold or a drop in temperature. Lesions may be associated with mild pain, pruritis, or hyperhidrosis. In addition, pigmentary changes and atrophic scarring may also be seen (Fig. 11.3). Chilblain lupus and primary pernio/chilblains may be confused, but other coexisting features of systemic lupus suggest chilblain lupus over primary pernio/chilblains [36, 37]. At times, chilblains lupus may be associated with other forms of cutaneous lupus and may progress to systemic disease (Fig. 11.3).

The etiology of chilblain lupus may be sporadic or familial. The pathogenesis of the sporadic variant remains unknown, but is thought to involve reduced digital perfusion resulting from reversible vasoconstriction or microvascular injury provoked by cold exposure [38]. Sporadic chilblain lupus usually presents in adulthood with symptoms occurring during cold or damp periods.

The familial form usually presents early in childhood and is attributed to autosomal dominant inheritance of missense mutations in TREX1 [38, 39]. TREX1 encodes the most abundant exonuclease in mammals and functions to degrade single stranded DNA [40, 41]. It is hypothesized that the buildup of intracellular nucleic acids in the setting of decreased TREX1 initiates an IFN-mediated immune response resulting in inflammation and autoimmunity [38, 42].

Chilblain lupus, like Raynaud’s, predominantly affects acral areas that are more susceptible to the cold. They can present together or independently. Chilblain lupus presents with painful discolorations of the skin after cold exposure or with relative changes in temperature. Like patients with Raynaud’s, secondary to an autoimmune disease, patients with chilblain lupus may have associated autoantibodies, including ANA, anti-DNA, and anti-nucleosome, but generally do not progress to systemic lupus.

The history is the most critical factor in making the diagnosis of chilblain lupus. Although not widely used, the “Mayo Clinic Diagnostic Criteria” were proposed by one group of authors to standardize the diagnosis of chilblain lupus [43]. Two major and three minor criteria were proposed. The major criteria included (1) skin lesions in acral locations induced by exposure to cold or a drop in temperature, and (2) evidence of lupus erythematosus in the skin lesions by results of histopathologic examination or direct immunofluorescence study. The three minor criteria include (1) coexistence of systemic lupus erythematosus or other skin lesions of discoid lupus erythematosus, (2) response to anti-lupus erythematosus therapy, and (3) negative results of cryoglobulin and cold agglutinin studies. For diagnosis of chilblain lupus, both major criteria and one minor criterion must to be present [43].

Additional confirmatory studies may include findings on pathology, although biopsy is not necessary to confirm the diagnosis. Such findings include epidermal atrophy, basal layer degeneration, and periadnexal and perivascular inflammatory infiltrates. Additional, less common findings include dyskeratosis, dermal mucin deposition, deposition of granular Ig deposits and complement in the basement membrane [30].

If uncomplicated, chilblain lupus should initially be managed with lifestyle modification, including minimizing cold exposure and enhancing protective clothing when cold exposure is necessary. Topical or oral antibiotics may be used if secondary wound infection is suspected. If lifestyle modification is inadequate as manifested by recurrence of the lesions, systemic corticosteroids and/or mycophenolate may be used [44, 45].

First described by Crocq in 1896, acrocyanosis is a persistent, symmetric, painless, cyanotic discoloration of the digits and face that is characterized by persistent color changes and exacerbated by exposure to cold temperatures [46]. It is often associated with local hyperhidrosis of hands and feet. Acrocyanosis can present as a primary or idiopathic condition or as a secondary manifestation of another disease.

The etiology of primary acrocyanosis is not well understood, and it has been suggested that pathologically different mechanisms may underlie this condition [46]. Primary acrocyanosis is usually a benign condition that predominantly affects young women in the second and third decades of life that may spontaneously resolve [46]. Secondary acrocyanosis, on the other hand, is seen in association with a variety of conditions including but not limited to malignant and hematologic disorders, drug and toxin exposures, infections, and others [47–54]. Secondary acrocyanosis often correlates with disease severity and may resolve with treatment or removal of the underlying cause and thus may be a clue to the underlying diagnosis [47–54].

Acrocyanosis and Raynaud’s are similar conditions and may be confused in the clinical setting. Both conditions are cold-sensitive and may result in a cyanotic discoloration of the affected areas, with most prominent manifestations occurring in the hands and feet. Acrocyanosis differs from Raynaud’s in that it involves persistent digital discoloration while Raynaud’s is reversible. In addition, acrocyanosis lacks the initial phase of pallor that often precedes the bluish discoloration in Raynaud’s. Finally, Raynaud’s may be associated with pain whereas acrocyanosis is typically painless.

Acrocyanosis is less common than Raynaud’s, and contrary to the latter, is characterized by nonparoxysmal, in most cases persistent, painless bluish-red symmetrical discolorations of the hands, feet, and knees. Like Raynaud’s, it is more frequent in women than in men. With both Raynaud’s and acrocyanosis, a distinction is made between primary and secondary forms [55].

Diagnosis of acrocyanosis depends largely on the history and physical examination. The diagnostic value of pathology is limited as the tissue findings are often nonspecific. Findings generally include local edema and fibrosis with superficial capillary dilation with or without evidence of new vessel formation. Mild perivascular lymphocytic infiltrates may also be seen [46].

The management of acrocyanosis involves avoidance of environmental triggers, such as cold exposure, and enhancing local circulation [46]. Data regarding the efficacy of medications for the treatment of acrocyanosis lacking as definitions of acrocyanosis vary widely across the literature (Fig. 11.4) [46].

Livedo reticularis was first described in 1860 by Ferdinand von Hebra, an Austrian dermatologist who was describing the skin discoloration as “pale blue” or lividus in Latin [56]. It is an erythematous to violaceous netlike vascular pattern on the skin that blanches with applied pressure [57, 58]. It predominantly affects young women and is most frequently observed in the lower extremities [58]. Livedo reticularis is usually a normal physiologic finding that resolves with warming, but it can also be suggestive of an underlying hypercoagulable state [57–59].

Livedo racemosa, or “broken pattern livedo,” is distinguishable from livedo reticularis [57]. There is a widespread form which can sometimes be confused with livedo reticularis, but it is generally distinguishable by its asymmetry, lack of blanching, and irreversibility with warming [60]. It is important to make a distinction between the two conditions because livedo racemosa is usually associated with underlying vascular disease (e.g., anti-phospholipid syndrome), while this is only sometimes true for livedo reticularis (Fig. 11.5) [58]. In addition, the long term cutaneous complications of livedo racemosa may be more severe, as the clinical course can result in retiform pigmentation and ulceration [56].

The cutaneous vascular anatomy contributes to the pattern seen clinically in livedo reticularis [59]. Central blanching at the center of arterial hexagons and/or a blanchable cyanotic venous congestion along the venous rims are the typical cutaneous patterns seen in livedo reticularis [56]. As blood flow through these vessels is impaired (e.g., vasoconstriction from exposure to cold), cyanotic discoloration occurs in the anastamotic areas where blood flow is slowed and the characteristic net-like pattern is seen [58].

Livedo racemosa, or “broken pattern livedo,” is thought to result from an underlying inflammatory and/or occlusive pathology leading to irregular and persistent impairments in blood flow and a branching pattern of blueish discoloration of the skin [60]. There are many causes of livedo racemosa and they include a variety of connective tissue disorders (e.g., polyarteritis nodosa, systemic lupus erythematosus with or without APS), infections (e.g., syphilis, tuberculosis), drugs, hematological disorders (e.g., APS, polycythemia rubra vera, essential thrombocythemia, cryoglobulinemia, cold agglutinins), and cholesterol embolization syndrome [56, 58, 59]. Antiphospholipid syndrome is a particularly strong concern as the association with livedo is strong and it may be the only clue to an early diagnosis [57, 61–67].

Raynaud’s and both forms of livedo are associated with cyanotic color changes in the skin and can be associated with exposure to cold. Raynaud’s and livedo reticularis, however, may completely reverse with warming, whereas livedo racemosa does not (Fig. 11.6) [59]. The distribution of the two conditions is quite different with Raynaud’s predominantly affecting acral areas and livedoid vasculopathy predominantly affecting skin in a more proximal distribution (e.g., skin on the thighs and knees). Both Raynaud’s and livedo racemosa may be associated with some cutaneous ulceration resulting from ischemia of the affected area.

The diagnosis of livedo reticularis and livedo racemosa is based on clinical context and findings on physical examination [59]. As both forms of livedo may be associated with other systemic diseases, a careful and thorough history should be taken to evaluate for relevant signs and symptoms [58]. Particular attention should be paid to personal or family history of autoimmunity and/or thrombosis. A detailed personal history of medications changes, recent vascular procedures, and history of relevant complicating factors such as renal failure or hepatitis C should also be acquired [59].

On physical examination, a thorough review of the patient, particularly evaluating the skin pattern, color, and distribution of the lesions is essential. While laboratory testing in patients with livedo reticularis should be guided by findings in the history and physical examination that cause suspicion for underlying systemic conditions, in livedo racemosa, extensive laboratory testing is required given its more frequent association with a variety of other systemic illnesses [58, 59]. Skin biopsies are generally low yield in patients with livedo reticularis although they may help distinguish vasculitis from vasculopathy and normal skin. When skin is obtained, several punch biopsies are recommended from varying locations, including from the central blanched area and peripheral blue areas [59]. If fixed purpuric areas or subcutaneous nodules are present, these should be biopsied as well. As the purpose of such biopsies is to obtain tissue from medium blood vessels which are present in the deep reticular dermis and subcutaneous fat, large punch biopsies or wedge biopsies are recommended [59].

Other than cold avoidance, no treatment is indicated for primary livedo reticularis [59]. Treatment of the underlying cause in either livedo reticularis or livedo racemosa should be the aim of medical management of the underlying disease state.

Erythromelalgia was first described in 1878 by an American neurologist, Dr. Silas Weir Mitchell, and is thus also known as Weir Mitchell’s disease [68]. In the literature, erythromelalgia is also referred to by a variety of other names, including acromelalgia, erythralgia, erythermalgia, erythermomelalgia, and erythroprosopalgia [69].

Erythromelalgia is a condition in which patients experience attacks of burning or piercing pain and erythema of the skin of the extremities upon exposure to mild warmth (32–36 °C) (Fig. 11.7). The attacks are generally alleviated by cooling [70]. In some patients symptoms are constant, varying only in intensity, while in others they are episodic, sometimes occurring several times a day [69, 71]. It is most commonly reported in the lower extremities, but involvement of the hands, ears, and face has been described [71]. Symptoms are most common in the warm summer months and can be exacerbated by ambulation, physical activity, leg dependence, shoes, and gloves [68, 69, 72]. Immersion of the affected area in ice or cold water, exposure to air currents, or elevation have all been reported to provide some relief [69]. It is thought that women are more frequently affected than men [55, 73]. The average age of onset is reported as 40–55 years of age, but children and elderly persons may also be affected [55, 72, 74]. A patient’s quality of life can be significantly impacted by the disease, with depression and even suicide reported as outcomes [71, 75].

Erythromelalgia can be classified either as a primary (inherited) or secondary (sporadic) disorder. The primary form of erythromelalgia in some families, is inherited in an autosomal dominant pattern and is caused by a gain-of-function mutation in the SCN9A gene on chromosome 2q31-32 encoding the Na(v) 1.7 sodium channel while at other times it is sporadic, possibly caused by acquired mutations [68–70]. The Na(v) 1.7 sodium channel is mainly expressed in the sympathetic and nociceptive small-diameter sensory neurons of the dorsal root ganglion. This mutation causes a hyperpolarizing shift in activation and slow deactivation, resulting in hyperexcitability of the cells containing these channels [68, 69]. It is hypothesized that the connection between the pain and temperature related symptoms in erythromelalgia may be related to the co-expression of Na(v)1.7 channels in neurons with temperature sensitive transient receptor vanilloid channels (TRPV) although more data is needed [70].

Secondary erythromelalgia is not well understood, but some suggest that it is a consequence of neuropathic and microvascular complications related to one or more drugs or underlying disorders [70, 76]. Withdrawal of the precipitating medication or treatment of the underlying disorder usually results in eventual resolution of the symptoms.

Both Raynaud’s and erythromelalgia are temperature sensitive conditions. Pain is often experienced with relative changes in temperature, and in both conditions symptoms are primarily localized to the hands and feet. Both conditions may involve an erythematous flush of the skin during episodes and they may coexist [77].

Erythromelalgia and Raynaud’s differ in several ways. First, the ischemic phase that defines Raynaud’s is absent in erythromelalgia. Erythromelalgia also may improve with elevation of the extremity, while this is uncharacteristic of Raynaud’s. Erythromelalgia also usually improves or resolves with cold exposure, and digital ulcers are not seen. Finally, in contrast to Raynaud’s, erythromelalgia is more common in lower extremities than the upper extremities, but can affect both.

The diagnosis of erythromelalgia is clinical, requiring a strong history and physical exam, as no objective laboratory criteria are available [69, 76]. During the initial evaluation, it is important to consider an evaluation for other associated conditions to differentiate between its primary and secondary forms. Several sets of criteria have been proposed to make the diagnosis of erythromelalgia, although consensus on the “standard” criteria is lacking [71, 78, 79].