Pernio (chilblains)

INTRODUCTION — Pernio (also known as chilblains or perniosis) is a condition characterized by the development of cold-induced erythrocyanotic skin lesions. The word "chilblains" may be derived from the Old English words "chill" and "blegen" (sore) [1].

Pernio manifests as erythematous to violaceous macules, papules, plaques, or nodules in sites of cold exposure. The most common sites for involvement are the fingers and toes (picture 1A-E). Symptoms of pruritus, pain, or burning often accompany the skin lesions, and complications of blistering, ulceration, or secondary infection can occur.

In many patients, pernio presents as an acute eruption that begins 12 to 24 hours after cold exposure and resolves within a few weeks. However, pernio may also follow a chronic or recurrent course. Treatment primarily involves protection of affected areas from cold environments.

The clinical features, diagnosis, and management of pernio will be reviewed here. Pernio is distinct from lupus pernio, a form of cutaneous sarcoidosis. Lupus pernio is discussed separately. (See "Cutaneous manifestations of sarcoidosis", section on 'Lupus pernio'.)

EPIDEMIOLOGY — Data on the epidemiology of pernio are limited. Pernio usually occurs following exposure to cold, damp environments, and thus is most common among individuals who live in cold climates. Symptoms commonly begin in early winter and resolve by spring as cold exposure decreases. However, patients may develop recurrences during subsequent winters or persistent disease [2-4].  

Young and middle-aged women are the most common populations affected by pernio [5,6]. However, children, older adults, and males may also develop this condition [4,5,7,8]. Low body mass index has been proposed as a potential risk factor for pernio based upon several reports documenting the occurrence of pernio in women with low body mass indexes [6,8,9].

PATHOGENESIS — The pathogenesis of pernio is unclear. It is postulated that pernio results from an abnormal vascular response to cold exposure. Cold-induced vasoconstriction or vasospasm resulting in hypoxemia that stimulates an inflammatory response is a potential mechanism for the formation of skin lesions. A role for hyperviscosity or endothelial damage in the microvasculature associated with the presence of autoantibodies also has been considered [10,11].

ASSOCIATED DISORDERS — The term "secondary pernio" is sometimes used to refer to pernio that occurs in patients with hematologic disorders (eg, paraproteinemia), autoimmune disease, viral hepatitis, or malignancy. Although multiple reports document such occurrences [3,5,7,12,13], data are insufficient to confirm a causative relationship between pernio and most of these systemic diseases. The significance of certain laboratory abnormalities (eg, cold agglutinins or antiphospholipid antibodies) identified in subsets of patients with pernio is also unclear [5,14]. One report documents the detection of cryoglobulins in three children with pernio [15]; however, cryoglobulins have not been detected among patients with pernio in several larger series [3,5,16].  

The most frequently reported and most studied relationship between pernio and another disease is the relationship between pernio and lupus erythematosus. Multiple reports describe the development of skin lesions that are clinically consistent with pernio in patients with clinical or laboratory evidence of cutaneous lupus erythematosus or systemic lupus erythematosus [1,11,12]. The term "chilblain lupus erythematosus" is used to refer to this presentation. (See 'Chilblain lupus erythematosus' below.)

CLINICAL MANIFESTATIONS — Pernio usually manifests as single or multiple, symmetrically distributed, edematous, erythematous to violaceous macules, papules, plaques, or nodules (picture 1A-F). The dorsal fingers or toes are classic sites for involvement. Less frequently, pernio involves the nose, ears, soles of feet, calves, thighs, or buttocks (picture 1G) [3,17]. Blisters or ulceration may develop, and symptoms of burning, tenderness, or pruritus are often present. Secondary infection is a potential complication of pernio in patients who develop blistering or ulceration.

Pernio may run an acute or chronic course. In acute idiopathic cases, the skin lesions usually appear within 12 to 24 hours of cold exposure and resolve within one to three weeks [3]. Chronic pernio may manifest as recurrent acute episodes or episodes that persist for longer than several weeks. Although symptoms of chronic pernio often improve during warm months of the year, persistence of chronic pernio beyond the cold seasons occasionally occurs.

Patients who develop pernio in association with a systemic disease may be more likely to experience disease persistence. A prospective study of 51 patients evaluated for pernio in a dermatology department found that persistence beyond the cold seasons was significantly more common in patients with underlying systemic disease [3]. In the study, four of seven patients with secondary pernio (pernio associated with hepatitis B infection, cutaneous lupus erythematosus, an undifferentiated connective tissue disease, antiphospholipid antibody syndrome, or rheumatoid arthritis) had persistence of pernio beyond the cold seasons compared with only 1 of 44 patients classified as having idiopathic disease.

DIAGNOSIS — Pernio should be suspected in patients who develop edematous, erythematous to violaceous skin lesions in association with cold exposure, particularly when located on acral sites. The diagnosis is based upon a consistent clinical history and consistent physical findings. We reserve skin biopsies for assistance with the diagnosis of clinically atypical cases and reserve further laboratory workup for patients in whom the clinical presentation suggests the possibility of a concomitant systemic disease.

History and physical examination — The history and physical examination are the mainstays for diagnosis. Findings that support a diagnosis of pernio include:

●Edematous, erythematous to violaceous macules, papules, plaques, or nodules, particularly when located on acral sites (picture 1A-E, 1G)

●Onset associated with cold exposure

●Greatest severity of symptoms during cold months of the year

●Improvement with elimination of cold exposure (however, chronic disease courses do not rule out pernio)

In addition to an interview of the patient to determine whether cold exposure is a precipitating factor for skin lesions and an examination of the affected areas, a review of systems should be performed to identify signs or symptoms of an underlying disease (particularly hematologic disorders, autoimmune disease, or malignancy). A full skin examination is also recommended to identify skin abnormalities suggestive of underlying medical disorders [5]. In particular, the possibility of chilblains lupus erythematosus should be considered if cutaneous manifestations of lupus erythematosus (eg, discoid lupus erythematosus, malar erythema) are seen. (See 'Associated disorders' above and 'Chilblain lupus erythematosus' below.)

Although not typically used for diagnosis, capillaroscopic abnormalities may be present in patients with pernio. Increased nailfold capillary tortuosity and diameter as well as increased apical capillary diameter have been reported in patients with idiopathic pernio [18].

Skin biopsy — A biopsy is not necessary for the diagnosis of most cases of pernio. A biopsy primarily serves to confirm the presence of features consistent with pernio or to detect histologic evidence that suggests a different disorder (eg, vasculitis or cutaneous thrombosis). There are no pathognomonic histopathologic findings of pernio.

Histopathology — A diagnosis of pernio is supported by the detection of the following features [19-21]:

●Papillary dermal edema (amount of edema is variable)

●Superficial and deep, moderate to dense lymphocytic infiltrate surrounding blood vessels and eccrine glands

In addition, necrotic keratinocytes and lymphocytic vasculitis (edema of vessel walls and lymphocytic infiltration of vessel walls) may be present [19].

The possibility of chilblain lupus erythematosus is suggested by the detection of vacuolization of the basal layer of the epidermis in addition to the typical findings of pernio [19,20]. However, the absence of this finding does not rule out chilblain lupus erythematosus, and vacuolization of the basal layer has been reported in a small proportion of patients perceived to have idiopathic pernio [19,20]. (See 'Chilblain lupus erythematosus' below.)

Additional evaluation — There are no serologic tests that confirm a diagnosis of pernio. Laboratory investigations are reserved for the evaluation for concomitant medical disorders. Thus, we reserve laboratory studies for patients with chronic (lasting more than several weeks) or recurrent pernio and patients with other signs or symptoms that suggest the possibility of an underlying systemic disease [12].

Further evaluation of older adult individuals with new-onset pernio also may be prudent. A study of seven consecutive patients over the age of 65 with pernio found underlying diseases in six patients (myelodysplastic disease, chronic myelomonocytic leukemia, colorectal adenocarcinoma, and Sjögren syndrome) [7].

Our initial laboratory work-up typically includes tests for hematologic abnormalities and lupus erythematosus:

●Complete blood count

●Serum protein electrophoresis with immunofixation (to evaluate for an associated paraproteinemia)

●Antinuclear antibody

We perform further laboratory tests if further workup is required based upon the results of the tests above or if specific abnormalities are suggested by the physical examination or review of symptoms. Examples of laboratory tests that may be added include extractable nuclear antigen antibodies, rheumatoid factor, antiphospholipid antibodies, and cryoglobulins [5]. In particular, as cryoglobulins have only rarely been reported in association with pernio [15], routine testing is not necessary [3,5,16].

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of pernio includes other cold-induced disorders that have a predilection for acral areas. One of the disorders that should be distinguished from idiopathic pernio is chilblain lupus erythematosus.

Chilblain lupus erythematosus — Chilblain lupus erythematosus is an uncommon disorder that is diagnosed in patients who have both skin lesions that are clinically consistent with pernio and clinical or laboratory features of cutaneous or systemic lupus erythematosus. Chilblain lupus erythematosus is often considered a form of chronic cutaneous lupus erythematosus.

Additional study is necessary to clarify the clinical and histopathologic features that distinguish chilblain lupus erythematosus from idiopathic pernio. Observations from a series of 33 patients with pernio that included patients with chilblain lupus erythematosus suggest that persistence of skin lesions beyond cold seasons may be more frequent in patients with chilblain lupus erythematosus [12]. In addition, pathologic examination of chilblain lupus erythematosus often demonstrates vacuolization of the basal layer of the epidermis (a common finding in other forms of cutaneous lupus erythematosus) and direct immunofluorescence of lesional skin may reveal a positive lupus band (linear deposition of immunoglobulins or complement at the dermal-epidermal junction) [22]. However, basal layer vacuolization and a lupus band are not always present in patients with consistent skin lesions and lupus erythematosus [12,19,20]. Moreover, basal layer vacuolization has been detected in patients with pernio who had no other evidence for lupus erythematosus [12,19,20].

Familial chilblain lupus erythematosus is a rare presentation of chilblain lupus erythematosus that is caused by heterozygous mutations in the genes encoding 3’ repair endonuclease (TREX1) or the phosphohydrolase sterile alfa motif domain and HD domain-containing protein (SAMHD1) [23]. Familial chilblain lupus typically begins in early childhood. TREX1 mutations have also been associated with increased risk for systemic lupus erythematosus. (See "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Genetic factors'.)

Other disorders — Examples of disorders that may be mistaken for pernio include cold panniculitis, acrocyanosis, Raynaud phenomenon, and cold-induced vascular occlusion syndromes. The development of pernio-like, acral skin lesions (colloquially referred to as "COVID toes") has also been reported in patients with coronavirus disease 2019 (COVID-19) [24-27]. The relationship between these findings and COVID-19 is under investigation. (See "COVID-19: Cutaneous manifestations and issues related to dermatologic care", section on 'Cutaneous manifestations of COVID-19'.)

●Cold panniculitis – Cold panniculitis (also known as popsicle panniculitis) is a form of lobular panniculitis that results from direct cold exposure. Typically, erythematous, indurated plaques develop at the sites of cold exposure and resolve within a few weeks (picture 2) [28]. Cold panniculitis is most common in very young children and the cheeks and chin are common sites for involvement. Contact with popsicles or ice cubes may induce the lesions. Unlike pernio, biopsy of an affected area demonstrates lobular panniculitis in addition to a superficial and deep perivascular lymphohistiocytic infiltrate [28]. (See "Panniculitis: Recognition and diagnosis", section on 'Trauma'.)

●Acrocyanosis – Acrocyanosis presents with chronic coolness and violaceous discoloration of the hands and feet, rather than the papular eruption of pernio. Other sites, such as the nose, ears, lips, and nipples, may be affected. Exposure to cold temperatures exacerbates the clinical findings. Acrocyanosis is usually asymptomatic [29].

●Raynaud phenomenon – Raynaud phenomenon is an exaggerated vascular response to cold or emotional stress that produces abnormal vasoconstriction of the digital arteries and cutaneous arterioles, resulting in the sharply demarcated, characteristic skin pallor on the digits followed by blue and then red color changes of the digital skin (picture 3) [2,18]. The changes are transient, with the skin pallor and blue phases lasting for 15 to 20 minutes. The papules, plaques, and nodular lesions of pernio are absent. (See "Clinical manifestations and diagnosis of Raynaud phenomenon".)

●Cryoglobulinemia and cryofibrinogenemia – Vascular occlusion secondary to type I cryoglobulinemia or cryofibrinogenemia may result in the development of purpura or skin necrosis in acral areas (picture 4). Purpura is not a typical feature of pernio. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Type I cryoglobulinemia' and "Disorders of fibrinogen", section on 'Cryofibrinogenemia'.)

●Aicardi-Goutières syndrome – Skin lesions consistent with pernio may occur in up to 40 percent of children with Aicardi-Goutières syndrome, a rare genetic encephalopathic and immunologic disorder that results from mutations in TREX1 or other genes [30]. Aicardi-Goutières syndrome presents in infancy with basal ganglia calcification, white matter abnormalities, chronic lymphocytosis in the cerebrospinal fluid, and increased serum levels of interferon-alfa [30]. TREX1 mutations have also been associated with familial chilblain lupus and systemic lupus erythematosus. (See 'Chilblain lupus erythematosus' above and "Epidemiology and pathogenesis of systemic lupus erythematosus", section on 'Genetic factors'.)

MANAGEMENT — The management of pernio focuses primarily on measures to minimize cold exposure. We reserve pharmacologic therapy for patients who do not improve sufficiently with these interventions.

First-line therapy — Patients with pernio should be instructed to keep the affected area warm by wearing appropriately insulated clothing, gloves, and footwear. Unprotected exposure to cold conditions should be avoided.

We also encourage patients who smoke to discontinue smoking, based upon knowledge of the detrimental effect of smoking on vascular disease and wound healing. However, the impact of smoking cessation on the clinical course of pernio has not been studied. (See "Benefits and consequences of smoking cessation", section on 'Cardiovascular disease' and "Benefits and consequences of smoking cessation", section on 'Postoperative complications'.)

Other interventions — Data are limited on the efficacy of other interventions for pernio. Topical corticosteroids and oral nifedipine are among the most commonly used pharmacologic therapies.

In clinical practice, medium to high potency topical corticosteroids are sometimes prescribed in an attempt to hasten resolution of pernio lesions [5,31,32]. Randomized trials to confirm the efficacy of local corticosteroid therapy are lacking. In our experience, topical corticosteroids have sometimes seemed helpful, but it is possible that the clinical manifestations would have resolved at a similar pace without them. Cutaneous atrophy is a potential adverse effect of prolonged used of this treatment. (See "Topical corticosteroids: Use and adverse effects", section on 'Adverse effects'.)

Limited data suggest patients who do not improve with conservative measures may benefit from treatment with nifedipine:

●Nifedipine – Nifedipine is a calcium channel blocker with vasodilatory properties. The findings of a small randomized trial suggest the drug may be beneficial for pernio [33,34].

In a crossover trial in which 10 patients with idiopathic pernio that had persisted for a minimum of five months per year for the preceding three years were randomly assigned to treatment with nifedipine retard (20 mg three times daily) or placebo for six weeks and switched to the other agent for the subsequent six weeks, 7 of the 10 patients had resolution of established lesions within 7 to 10 days after starting nifedipine [33,34]. Although no patients developed new lesions during nifedipine therapy, new lesion development continued during placebo treatment.

Potential adverse effects of nifedipine include flushing, peripheral edema, nausea or heartburn, and dizziness or lightheadedness.

There are anecdotal reports of the use of other therapies, such as intralesional corticosteroid injection, oral prednisone, prazosin, weight gain in underweight patients, pentoxifylline, nicotinamide, topical minoxidil, nitroglycerin paste, and topical tacrolimus [5,6,10,35]. Additional study is necessary to determine the efficacy of these therapies.

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Pernio (also known as chilblains or perniosis) is a cutaneous disorder characterized by the development of cold-induced erythrocyanotic skin lesions (picture 1A-E). Young and middle-aged women are most commonly affected by pernio; however, children, males, and older adults may also develop this condition. (See 'Epidemiology' above.)

●Pathogenesis – The pathophysiology of pernio is not known. Pernio is thought to result from an abnormal vascular response to cold exposure. (See 'Pathogenesis' above.)

●Associated disorders – Pernio may occur independently (idiopathic pernio) or in patients with other diseases. The development of pernio has been reported in patients with hematologic disorders, autoimmune diseases, viral hepatitis, and malignancy. The strength of the relationship between pernio and many of the reported disease associations is unclear. (See 'Associated disorders' above.)

●Clinical manifestations – Pernio classically presents as erythematous to violaceous macules, papules, plaques, or nodules on the hands or feet (picture 1A-E). Less commonly, the nose, ears, soles of the feet, calves, thighs, or buttocks are affected (picture 1G). Blistering or ulceration may be present. (See 'Clinical manifestations' above.)

●Clinical course – The clinical course of pernio varies. Given the association with cold exposure, symptoms most commonly develop during the cold months of the year. Acute, idiopathic cases of pernio typically resolve within one to three weeks. Pernio may also follow a chronic or recurrent course. (See 'Clinical manifestations' above.)

●Diagnosis – The diagnosis of pernio can usually be made based upon the patient history and clinical examination. Skin biopsies are reserved for atypical cases. (See 'Diagnosis' above.)

●Additional evaluation – The possibility of an underlying systemic disease should be considered in patients with pernio. Laboratory evaluation to detect another disease is appropriate when the clinical evaluation suggests an underlying disorder or when pernio is recurrent or chronic. (See 'Additional evaluation' above.)

●Management – The management of pernio primarily consists of avoidance of precipitating conditions. Patients should be instructed to keep the affected areas warm by wearing appropriately insulated clothing and avoiding unprotected exposure to cold conditions. For adults with refractory pernio, we suggest treatment with nifedipine (Grade 2B). (See 'Management' above.)