Chilblains after galcanezumab for chronic migraine prevention: A case report

Abstract

Background

Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are effective migraine prophylactics but real-world safety data is still emerging. This is the first case of chilblains associated with galcanezumab.

Case

A 50-year-old female commenced galcanezumab for migraine prophylaxis. She tolerated the loading dose well. Ten days after her second dose, she developed multiple skin lesions, fluctuating distal cyanosis and polyarthralgia in both hands. Rheumatologists confirmed a diagnosis of chilblains temporally related to the CGRP mAb. Galcanezumab was subsequently ceased with full clinical recovery. There was no clinical or serological evidence of an underlying autoimmune condition.

Conclusion

This case demonstrates a previously unreported reaction temporally associated with galcanezumab. We hypothesise herein a mechanism of biological plausibility for this reaction based on the drug's mechanism of action. Vigilance is required in monitoring for potential adverse events. Further research is required into risk factors for such presentations.

Graphical abstract

This is a visual representation of the abstract.

Background of CGRP therapy

Calcitonin gene-related peptide monoclonal antibodies (CGRP mAbs) are effective migraine prophylactics with excellent tolerance and minimal side effects. ¹ Post-marketing surveillance data has shown that these medications most commonly cause side effects of local injection site reactions or constipation.^2,3 Due to the widespread distribution of CGRP within the body, there are many theoretical off-target effects of these blocking agents, which have not been borne out conclusively in clinical trials or post marketing surveillance studies. ⁴ Of relevance to this case report, this drug class has been associated with Raynaud phenomenon – most likely due to the inhibition of CGRP's vasodilatory action. ⁵ No prior cases of chilblains associated with this drug class have been reported.

Case presentation including outcome and follow-up

A 50-year old female was seen in the Headache clinic of a tertiary referral centre for management of chronic migraine, diagnosed by a headache neurologist. Other past history was significant for endometriosis and anxiety. Her regular medications included propranolol 40 mg twice per day for anxiety, which she had been on for over a decade without side effects, and an oestrogen patch for menopausal symptoms. Socially, she was living independently at home with her husband, did not smoke, drink or use recreational substances. There was no personal or family history of autoimmune disease, vascular disease or rheumatological disease. She has never had any previous similar symptoms such as colour changes to skin, cold-induced skin or joint changes, Raynaud's phenomenon or joint pathologies. She did not have any risk factors for vascular disease such as hypertension or diabetes.

Migraine started in her early 30s. Magnetic resonance imaging of the brain was normal. At baseline she had 15 monthly headache days, 8 monthly migraine days and the rest of the month was crystal clear. Prior to our review she had failed three oral preventers – propranolol, topiramate and sandomigran. Of note, propranolol 40 mg twice daily had been used for 10 years for symptoms of anxiety with no impact on headaches and no cardiovascular side effects.

The patient was commenced on galcanezumab in accordance with local regulatory guidelines. ⁶ The patient tolerated the 240 mg loading dose, and her headache frequency improved to 0 monthly headache days, however developed an adverse event 38 days following commencement. The patient developed pain in all joints of both hands. Within 24 h, she had significant pain throughout the right upper limb with swelling, erythema and pain in all metacarpophalangeal (MCP), proximal and distal interphalangeal (PIP and DIP) joints. Two weeks later, she noticed similar swelling, erythema and pain in the left hand MCP, DIP and PIP joints. In cold weather there was cyanosis in all fingers. Unfortunately, the issue was not raised with her treating team until the subsequent clinical appointment 77 days following commencement of the medication.

On clinical review, the patient reported pain and was found to have oedema, erythema in all MCP, PIP and DIP joints bilaterally (Figure 1). There was nailbed discolouration in digits one, three and four bilaterally. Mild livedo reticularis was noted throughout the upper limbs. She also reported some discrete lesions between joints which were erythematous, flat and pruritic. They were not blisters or vesicles. There were no ragged cuticles. There were no rashes elsewhere in the body. Upper limb pulses and capillary refill were normal. There was no tenderness or boggy swelling. She had full range of movement in all upper limb joints. Upper limb functional tasks were normal.

Figure 1.

Patient commenced galcanezumab for chronic migraine prevention and reported bilateral hand symptoms 38 days after commencement. Chilblains was clinically diagnosed 103 days after treatment onset, after specialist rheumatologist review. Interval changes are shown relative to days since first dose at day. (a) 42, (b) day 78, (c) and (d) day 85 and (d) day 103, (e) day 120. Full symptom resolution occurred 140 days after treatment cessation.

She had no constitutional symptoms, uveitis or iritis, dysphagia, alopecia, respiratory symptoms or genital ulcers. She did complain of occasional xerostomia and associated intermittent mouth ulcers but these were attributed to multiple antihistamines. There were no systemic signs to suggest autoimmune or inflammatory aetiologies such as systemic lupus erythematosus, dermatomyositis or scleroderma. She was up to date with bowel, breast and cervical cancer screening.

The following blood tests were negative: full blood count, renal function, liver function, ferritin, electrolytes, glucose, uric acid, C reactive protein, folate, vitamin B12, erythrocyte sedimentation rate, antinuclear antibodies and extractable nuclear antigen antibodies, creatinine kinase, hepatitis B and C serology, anti-Jo1 antibodies, rheumatoid factor, anti-cyclic citrullinated peptide and full inflammatory myositis workup.

Due to concerns about a drug reaction the patient was advised to cease galcanezumab, and referred for rheumatologist evaluation who confirmed a diagnosis of chilblains. Though she had been on propranolol for over 10 years with no side effects or distal extremity cyanosis, we were concerned about it worsening her current symptoms, so we advised her to slowly wean off. Systemic steroids and calcium channel blockers were considered for symptomatic relief, but the patient declined as she felt the symptoms were manageable. She was seen regularly until full resolution of her symptoms roughly 193 days since the second dose. The patient expressed gratitude that the reaction was reversible yet was understandably upset about needing to stop the medication when it had been a very effective headache preventer.

Discussion

To our knowledge, this is the first case in the world of chilblains (pernio) in association with galcanezumab. While Raynaud's phenomenon and inflammatory pathologies have been previously described as a potential complication of anti-CGRP therapy, concurrent chilblains has not been previously reported.^7,8 Recognition of possible off-target effects of CGRP inhibition is critical to ensure appropriate counselling, and safe use of this medication class.

While chilblains (pernio) is incompletely understood, there are several relevant aspects to the pathophysiology of Chilblains that are of relevance to our case. Cold-induced vasospasm leads to local ischaemia which triggers a local inflammatory reaction, and ultimately skin breakdown. ⁹ This process leads to the classical appearance of chilblains, of erythematous or cyanotic distal extremities, with lesions that start as macules and can progress to bullae or ulcers. ⁹ Idiopathic chilblains is a clinical diagnosis, however serology can be helpful to exclude secondary causes such as systemic lupus erythematosus, Raynaud's disease, cryoglobulinemia and cold panniculitis. ¹⁰ Chilblains is distinct from Raynaud's phenomena, and can be differentiated by the lack of classic triphasic colour changes, and the presence of both pain and pruritus in response to cold weather. ⁹

The development of chilblains in this case was temporally related to the commencement of a CGRP monoclonal antibody. The inhibition of the CGRP ligand, which has a compensatory vasodilatory action in the body ⁴ provides a biologically plausible explanation for this association. Rare reports of inflammatory complications ⁸ provide a further speculative interaction between CGRP inhibition and the pathophysiology of chilblains.

There are several limitations to this case that should be highlighted. Firstly, the patient was on a second vasoactive medication (propranolol); however, the dose was stable and the patient had tolerated the medication for over a decade without complication. Secondly, due to the novelty of this report, coincidence cannot be excluded. Further prospective studies are required.

Clinical implications

Chilblains may be a spontaneous, monophasic reaction triggered by galcanezumab.

Prescribers should be aware of this potential side effect in the post-marketing phase of this medication.