Introduction

Brief overview of chilblains (also known as pernio)

Chilblains, or pernio, are a type of inflammatory skin response to cold, damp, non-freezing conditions. These typically occur on extremities, including the fingers, toes, and ears, as a result of abnormal responses of blood vessels. Chilblains typically resolve on their own, but may require medical evaluation in cases that are severe or persistent.¹

• Common symptoms:
  • Itching, burning, or pain in the affected area
  • Red, purple, or blue discolouration of the skin
  • Swelling, raised bumps (papules or nodules), blistering, or ulceration if severe¹

How medications affect chilblains

The impact of circulation on the development of chilblains

Chilblains (pernio) are superficial inflammatory skin lesions due to exposure to cold, and both impaired circulation and vasoconstriction have a significant role in their aetiology. Exposure to cold can induce rapid vasospasm, the narrowing of blood vessels and blood flow, leading to localised hypoxia and inflammation of the skin of the extremities. Endothelial dysfunction may only serve to exacerbate this process and can further impede circulation.³

Medication and increased susceptibility

Certain medications, including, more specifically, vasoconstricting agents (such as adrenergic or serotonergic agents), can lead to impaired peripheral circulation and thus increase the risk of chilblains. Other medications that may have an effect on vascular tone, not limited to certain antidepressants and antimalarials, may contribute to impaired vascularisation. On the contrary, vasodilators such as nifedipine or topical nitroglycerin may be used, especially in attempts to counteract vasoconstriction or improve circulation in peripheral or extremity use of these agents, therefore supporting the role of circulation in both the development of chilblains and their treatment.⁴

Medications that can worsen or trigger chilblains

Marginal toxicity of agents occurs when a medication induces or aggravates chilblains, which are erosive inflammatory dermatoses resulting from cold weather exposure. Knowledge about drug-induced etiologies is essential for clinicians and practitioners caring for patients with primary and secondary conditions, including chilblains, autoimmune conditions, migraine, and cancers. The monoclonal antibodies targeting the calcitonin gene-related peptide (CGRP; such as erenumab and galcanezumab) have been reported in relation to chilblains in the scientific literature. 

While reports indicate a specific risk for chilblains related to monoclonal antibodies targeting CGRP, it is important to note that an array of migraine treatments is available that do not have the same risks. It is of note that switching to an oral CGRP antagonist (rimegepant) did not lead to reexposure to chilblain symptoms, supporting the risk associated with monoclonal antibodies. 

Immune checkpoint inhibitors (ICIs) such as pembrolizumab, which are regularly used as cancer therapy, have also been related to extremely rare chilblain-like eruptions and overlap syndromes resembling systemic lupus erythematosus (SLE). The eruptions can occur soon after treatment initiation, and continued treatment would be complicated by immunosuppression and vasodilation potential from medication, requiring careful patient assessment and care considerations. Several other medications (listed within) are not and cannot be identified as safe and effective for chilblains. Assessment of reexposure to chilblains will require careful consideration. 

Understanding and documenting the elevated risk for chilblains associated with several treatment types may allow for improved access to care for each patient who utilises and stimulates access to therapeutics.^5,6

How to manage or prevent chilblains while on these medications

Chilblains are inflammatory skin lesions that result from cold and damp conditions, and effective management is especially important for patients on medications that might hurt peripheral circulation. It is best to combine lifestyle changes along with medication management, individualised to the patient’s clinical status.

• General preventive strategies:
  • Avoid cold and damp areas: Cold and damp conditions, especially affecting the toes, fingers, and ears, need to be avoided, and/or those areas kept warm
  • Smoking cessation: Smoking worsens peripheral circulation and should be avoided at all times¹
• Medical treatments:
  • Nifedipine: Nifedipine is moderately effective for treatment and also preventative; however, there may be side effects (e.g., edema and hypotension)²
  • Pentoxifylline: Pentoxifylline is effective for cases that are otherwise refractory to other measures and has an excellent safety profile²
  • Topical nitroglycerin: There has not been a lot of strong evidence regarding using topical nitroglycerin, but it has been deemed effective in some cases²
  • Corticosteroids: Corticosteroids have not been demonstrated to be more effective than placebo in this context relating to persistence of symptoms/chilblains²
  • Other medications: SSRIs, antimalarials, or antithrombotic strategies may also be of consideration based on an individualised plan⁴
• Medication-induced chilblains:

CGRP monoclonal antibodies (generally for migraines) could infrequently induce chilblains. When that happens, switching to alternatives (such as rimegepant) has been shown to lessen symptoms⁷

• Specific considerations:

Monitor drug-drug interaction: looking for medicines that will worsen peripheral circulation, such as vasoconstrictors, all while looking at whether it will affect any substances used for symptomatic treatment of chilblains⁷

Summary

Chilblains, or pernio, are inflammatory skin lesions caused by cold and damp conditions, and their presentation depends on compromised circulation capability, especially vasoconstriction, which decreases blood flow to the distal extremities. Nifedipine and pentoxifylline are examples of medications used for lesions that are severe or persisting in nature, as they are considered to enhance blood circulation and reduce inflammation. Other therapies, such as nitroglycerin topical ointment and corticosteroids, have limited efficacy in treatment. Some medications, particularly ones that induce vasoconstriction (such as these CGRP monoclonal antibodies for migraine headaches), could also create chilblains or exacerbate existing chilblains because they diminish an already diminished flow. 

Prevention measures include a series of lifestyle changes, such as limiting exposure to cool or cold temperatures, stopping smoking habits, and medicinal use (for example, nifedipine) would also potentially be helpful. Drug discontinuation (such as medications that induce vasoconstriction) or utilising an alternative medication would be another approach to ameliorate symptoms. 

Overall management of chilblains while taking any of these prior medications would require a complete portfolio of management that includes behavioural changes directed at lifestyle, pharmacologic treatment, and the need for continued surveillance for medication interactions or adverse effects from his pharmacologic treatment on circulation.