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Pharmacologic Treatment of Idiopathic Chilblains (Pernio): A Systematic Review

Idiopathic chilblains is a cold-induced inflammatory condition that causes significant morbidity. When preventative measures alone are inadequate, oral nifedipine is generally recommended as first-line pharmacologic therapy. Given the natural course of this spontaneously remitting/relapsing condition, controls are needed to critically appraise studies and determine the value of treatments. We report a systematic review of placebo-controlled or comparative therapeutic trials for the treatment of idiopathic chilblains. Our search of PubMed, Embase, and Cochrane databases, identified 11 studies that met our inclusion criteria for a combined study population n = 576. Therapies included nifedipine, pentoxifylline, tadalafil, topical glyceryl trinitrate (GTN), topical minoxidil, diltiazem, corticosteroids, and vitamin D. There was moderate evidence to support the use of nifedipine and pentoxifylline in the treatment of severe or refractory cases of idiopathic chilblains, while other therapies had inadequate evidence or nonsignificant results compared to placebo.


Introduction
Idiopathic chilblains (pernio) is an inflammatory condition triggered by exposure to damp-cold weather. It is observed worldwide, but more frequently in colder climates such as the UK and Northwestern Europe. 1,2 There have been cases of familial clustering, and a case-control series showed a familial relative risk of 3.6, suggesting genetic predisposition. 3,4 Chilblains-like presentations have been observed in patients testing positive for coronavirus disease 2019 (COVID- 19), although thought to occur through a different pathomechanism. 5 The typical presentation of idiopathic chilblains involves single or multiple symmetrically distributed, erythrocyanotic lesions on the distal toes and fingers, and less commonly the heels, nose, and ears. Lesions range from red-blue macules to bullae and ulcers. Symptom onset occurs in the winter, with individual episodes lasting 1-3 weeks, and spontaneous resolution in the spring. Annual recurrences are common, and elderly patients or those with venous insufficiency may experience a protracted course.
Chilblains is generally not associated with systemic involvement; however, chilblains-like presentations can be associated with cryoglobulins or cold agglutinins. Differential diagnoses include raynaud's phenomenon, cold panniculitis, and chilblain lupus.
Treatment of chilblains primarily involves preventative measures, but severe and/or persistent cases may require pharmacologic therapy. There are relatively few clinical studies to guide treatment choice, although nifedipine is considered the mainstay of systemic treatment and is widely prescribed. 1,2 Other therapies with low-level evidence or anecdotal use, include corticosteroids, topical minoxidil, topical nitroglycerin, nicotinamide, and pentoxifylline. 1,2 Given the natural course of spontaneous remission, it is difficult to assess the efficacy of treatment for chilblains without an objective control. Herein, we report a systematic review of placebo-controlled or comparative clinical trials for the treatment of chilblains.

Eligibility
Randomized controlled or comparative trials on patients with a clinical and/or histologic diagnosis of chilblains were included in our systematic review. Trials lacking a control or comparative group were excluded, as well as case series and case reports. Pharmacological therapy of chilblains was defined as those concerning the use of drugs; studies with non-drug therapies (ie, physical treatments) were excluded.

Search Strategy
PUBMED, EMBASE, and the Cochrane Database were searched for relevant studies performed in humans and published in English. No date limits were set. No limits on the total number of patients included were set. Search terms (MeSH headings) included: pernio, perniosis, chilblain; and Emtree: chilblain (pernio, perniosis). The search was conducted on March 14, 2019. Reference lists of included articles were hand-searched for any additional relevant studies. Duplicate articles were removed.

Data Extraction
Data were extracted and synthesized in tabular format, and triple checked for accuracy. The level of evidence (LOE) for each article was evaluated using the Oxford Center for Evidence-based Medicine scale. 6 Study quality was assessed using the U.S. Preventive Services Task Force quality rating criteria for randomized controlled trials (RCTs). 7

Outcomes
Outcomes were improvement in chilblains signs and symptoms, as measured by clinical assessment(s) and/or patient completed questionnaire(s), including visual analog scales (VASs).

Results
The titles and abstracts of 381 articles identified through our search strategy were screened for inclusion by M.P. using our predetermined criteria ( Figure 1). The full texts of selected articles (n = 12) were then independently assessed for inclusion in an unblinded fashion by M.P. and M.K. One article was excluded after full review, 8 since it was not an original RCT, and the results were previously published in an article already included in our analysis. 9 Thus, 11/381 articles (n = 576 recruited; n = 510 completed the studies) met eligibility criteria and were included in subsequent analysis. 9/11 studies were RCTs with LOE 1b (individual RCT) as per the Oxford scale, and 2/11 were LOE 2b (including lower quality RCTs). 9/11 studies had "good" and "fair" quality ratings as per the U.S. Preventive Services Task Force. 6/11 studies had a nifedipine treatment group, and 3/11 pentoxifylline. Additional therapies included topical glyceryl trinitrate, topical minoxidil, diltiazem, tadalafil, corticosteroids, and vitamin D. Due to heterogeneity of the designs and natures of the studies, in addition to the data, a meta-analysis was not possible. Table 1 specifies the study-type, interventions, methods,  outcomes, and limitations for the articles included in this  systematic review of chilblains treatments. Table 2 summarizes the inclusion and exclusion criteria and the primary and  secondary outcomes of the studies included in the studies,  and Table 3 specifically highlights the frequency of side effects produced by the therapies.

Nifedipine
We identified six clinical trials supporting the use of nifedipine for the treatment of chilblains, including a randomized placebo-controlled trial performed by Dowd et al. in 1986 (n = 10) which compared nifedipine to a retard preparation, 9 and several randomized trials comparing nifedipine to (i) diltiazem (n = 36), 10 (ii) topical 5% minoxidil (n = 52,84), 11,12 (iii) topical glyceryl trinitrate (n = 53). 13 Conflicting with these studies is a more recent 2016 randomized placebo-controlled trial (n = 32) that failed to show superiority to placebo. 14 Dowd et al. demonstrated that 7/10 patients treated with nifedipine experienced resolution of lesions within 7-10 days. 9 During the crossover period, 5/10 patients initially treated with nifedipine had relapses within 1 week, and 3/5 had to be restarted on nifedipine. In the remaining 2/5 patients, and the 5 patients initially treated with placebo, new lesions continued to develop and slowly resolve 20-28 days from onset. No correction was made for changes in ambient temperature. Nifedipine side effects included dizziness, flushing, occasional headaches, and hypotension.
Patra et al. compared nifedipine vs diltiazem and demonstrated that 2/12 patients on diltiazem showed complete relief in 7 days, and 3/12 patients by the 14th day. 10 However, 7/12 cases showed little or no response by 7-10 days, so they were switched to the nifedipine group. In the nifedipine group (n = 24), 21 (88%) cases showed 80% to 90% relief by the fourteenth day. The authors concluded that nifedipine is more effective than diltiazem for the treatment of chilblains.
In 2010, Kubais et al. similarly published a single blind trial in Iraq. 11 After 2 weeks, 20 (57%) patients in the nifedipine group showed "good improvement" (complete regression of erythema and partial regression of edema), and 9(26%) showed "very good improvement"(complete regression of erythema, edema, vesicles, and ulcer), P < .05. In comparison, 6 (35%) patients in the minoxidil group showed good improvement and only 1(6%) very good improvement. In the nifedipine group, 19 (54%) patients reported flushing, 3(9%) had constipation, and 2(6%) had headache. Khalid et al. (2014) further reported that 88% of patients treated with nifedipine achieved complete clearance by 6 weeks compared to 77% of patients treated with GTN 0.4% cream for 6 weeks. 13 Given the nonsignificant difference; the authors conclude GTN 0.4% cream is an effective alternative to nifedipine. However, it was noted that patients in the nifedipine group achieved earlier clearance compared to those treated with GTN cream (10.9 ± 6 days vs 16.6 ± 11.5 days, P = .05). Severe headaches experienced in the nifedipine group caused 5 patients to discontinue treatment.
Souwer et al. demonstrated that both nifedipine and placebo groups showed improvement on VAS scores after 6 weeks of treatment, but the difference between groups was nonsignificant. 14 Similarly, differences in investigatorassessed outcomes were nonsignificant. Calculations were performed with and without correction for ambient temperature, and carry-over effect was reported as negligible. The authors corrected for ambient temperature, a major confounder, by recording the daily ambient temperature and correcting for temperature changes during the study using a mixed effects model. Nifedipine was associated with significantly lower systolic blood pressure compared to placebo (134.5, 147.1 mm Hg, P = .02), and significantly higher peripheral edema score (based on patient reported VASs).
Jain et al. also reported that 10/42 patients (23.8%) in the nifedipine group vs 3/42 patients (7%) in the minoxidil group showed "very good improvement" (complete regression of erythema, edema, vesicles, and ulcer), P = .001465. 12 No side effects were experienced in either group.

Pentoxifylline
There are three studies investigating the treatment of chilblains with pentoxifylline; a placebo controlled RCT, 15 a comparative trial versus combination oral prednisolone and clobetasol ointment, 16 and a comparative trial versus tadalafil and prednisolone. 17 In 2008, Noaimi et al. conducted an open comparative study (n = 40) of oral pentoxifylline 400 mg PO three times vs oral prednisolone 0.5 mg/kg/day plus topical clobetasol ointment for 2 weeks. 16 In the prednisolone and clobetasol group, 3/11 patients who completed treatment had "good improvement" (symptoms disappeared and symptoms resolved) compared to 5/9 patients in the pentoxifylline group (P < .05). It is important to note that only 20/40 (50%) completed the study. No side effects were experienced in either group. Pentoxifylline was shown to be superior to oral and topical corticosteroids.
In 2015, Noaimi et al. further compared pentoxifylline 400 mg PO three times daily, tadalafil 5 mg PO daily, and prednisolone 15 mg PO twice daily for the treatment of idiopathic chilblains over 2 weeks. 17  Visual analog scale on disability score differences between betamethasone and placebo Table 2. Continued tadalafil, pentoxifylline, and prednisolone, respectively (ANOVA P value = .004). Mild headache was experienced by 6(40%) of patients in the tadalafil group in the first few days but did not necessitate cessation of therapy. Tadalafil has a superior effect over pentoxifylline, and that the latter is superior to prednisolone. Al-Sudany et al. also noted improvements in patients treated with 400 mg pentoxifylline within 1 week. On the Other Therapies: Topical Corticosteroids, Vitamin D Despite topical corticosteroids being prescribed frequently for the treatment of chilblains, the level of evidence is poor, with only the only supporting study being a case series of topical fluocinolone in 1973. 18 In March 2017, Souwer et al. assessed the efficacy of twice daily application of topical betamethasone valerate 0.1% cream for 6 weeks to treat chilblains, but no clinically or statistically significant differences were found when compared to the placebo. 19 In 2009, Souwer and Lagro-Janssen published a doubleblind randomized trial (n = 33) to assess the efficacy of oral vitamin D3 2000 IU daily as a treatment for chilblains. 20 Over an 8-week period, no significant differences in clinical outcomes were found between vitamin D and the placebo group once confounding factors were adjusted.

Discussion
Nifedipine is a dihydropyridine calcium channel blocker that decreases blood pressure primarily through peripheral vasodilation and is thought to alleviate cold-induced vasospasm. A 2017 Cochrane review (38 studies, n = 982 patients), concluded that calcium channel blockers "probably slightly reduce" the frequency, severity, and overall patient assessment of raynaud's attacks. 21 Importantly, while common side effects included headache, dizziness, nausea, palpitations, and ankle edema, there were no serious adverse events experienced by participants in any of these studies. Although the evidence for nifedipine use in the treatment of chilblains is less robust than that for raynaud's, it is still widely prescribed.
Raynaud's phenomenon often presents as cold digits with a demarcated white area known as a white attack. There may be a cyanotic skin change, which is blueish in color known as a blue attack. The attack begins with a single digit which then spreads to other digits symmetrically and bilaterally. The raynaud's attack is due to a transient and peripheral vasoconstrictive response to cold temperatures or emotional stress usually occurring in the digital and cutaneous arteries. This phenomenon has been shown to occur via three mechanisms including decreased blood flow, blood vessels constriction, neurogenic responses, and inflammatory and immune responses. 22 The transient receptor potential (TRPM8) ion channel is activated by the A-delta and unmyelinated C-fibers, which are activated by cold temperature. The activation for TRPM8 leads to cutaneous vasoconstriction and thermogenesis. Cold temperature also stimulates the release of vasoconstricting neuropeptides and norepinephrine, which leads to decreased blood flow to the skin. In primary raynaud's, there is an increase in alpha-2 adrenergic sensitivity in the digital and cutaneous vessels. This leads vasoconstriction in response to cold temperatures and emotional stress. In secondary raynaud's, there is an underlying condition resulting in the vasoconstriction. Often the endothelial function is impaired leading to vasoconstriction and schema in the area of skin effected. 22 Although raynaud's may be a differential diagnosis for chilblains, chilblains, in contrast, is an inflammatory condition that results from cold and damp conditions. Patients often present with multiple symmetrical erythrocyanotic lesions (ie, macule, papule, or nodules) most commonly affecting the hands or feet bilaterally. Although majority of cases are idiopathic and acute, secondary chilblain has associations with underlying conditions such as systemic lupus erythematous. This condition occurs more often in women and in patients living in colder climates. 23 Because of the rarity of chilblain, the pathogenesis is largely unknown. However, associations with vasospasm when exposed to cold and damp climates has been suggested. The most commonly reported histopathological findings include dermal infiltrate with associated edema; however, these findings are nonspecific. 23 Six of the ten studies included in our review had nifedipine as a treatment group (combined study population, n = 289), including two randomized placebo-controlled trials. 9,14 While the initial RCT in 1986 showed a very positive effect for nifedipine, the 2016 RCT, which corrected for changes in ambient temperature, reported nonsignificant differences compared to placebo. In the remaining studies, nifedipine was found to be superior to topical glyceryl trinitrate cream, minoxidil, and diltiazem. Nifedipine side effects reported in the five trials were like those observed in the raynaud's studies, and no serious adverse events were experienced. Overall nifedipine is a well-tolerated drug, and there is moderate evidence to support its use in the treatment of chilblains.
Pentoxifylline is a xanthine derivative that inhibits phosphodiesterase and increases perfusion through antiinflammatory, anti-fibrinolytic, and viscosity-lowering effects. It is only FDA approved for intermittent claudication but is frequently used off-label for a variety of dermatologic conditions. 24 Three studies included in our review showed positive efficacy for pentoxifylline in the treatment of chilblains. [15][16][17] Notably, there was a relatively large scale placebo-controlled RCT (n = 118), where 72.7% of patients in the pentoxifylline group experienced very good response, vs only 20% in the placebo group (P = .0000000). 15 Results were not corrected for ambient temperature, but the authors felt these differences were unlikely to be a major confounding factor since the study was only conducted in January and February, and an equal number of patients were included in both groups for each of the 4 years. No side effects were encountered. More common side effects of pentoxifylline reported in the literature include GI upset, dizziness, and headache. 24 Further investigations are required, but the results of the 2016 RCT are promising.
The two remaining studies included in our review were high quality placebo-controlled double-blind randomized trials of topical corticosteroids and vitamin D. 19,20 None of these treatments showed superiority compared to placebo.
It is also important to note chilblain-like eruptions in the recent context of COVID-19. According to a systematic review conducted by Conforti et al., vascular lesions associated with COVID-19 were the second most reported in the literature, majority of which were chilblain-like presentations (n = 84). Chilblain-like lesions presented commonly in patients with mild COVID-19 diseases courses and in younger populations. 25 A multi-variate logistic regression analysis recently identified chilblain-like eruption as a favorable prognostic factor for COVID-19 and less likely to be associated with severe infections. 26 It is suggested that the pathogenesis might be a protective response against COVID-19. 27 Chilblain, in the context of COVID-19 has also appeared in warm weathers as opposed to the conventional cold and damp weather, suggesting a COVID-19-related etiology. 28 In conclusion, there is moderate evidence to support the use of nifedipine and pentoxifylline as systemic treatments for idiopathic chilblains. Further studies are needed to better determine efficacy, as well as optimal dosage and duration of treatment. Both nifedipine and pentoxifylline are relatively safe and well-tolerated dugs, but not without side effects, and therefore benefits and risks must be weighed for each patient.

Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.