Are CGRP monoclonal antibodies immunosuppressive? Are there any particular infections associated with their use?

Comment by InpharmD Researcher

CGRP is known to downregulate pro-inflammatory cytokines such as TNF-α, IL-12, and IFN-γ while promoting IL-10 and IL-4; inhibition may inadvertently promote a pro-inflammatory state, leading to immune-mediated conditions. However, immune suppression and infections do not appear to be significant risks of CGRP inhibitor (including the monoclonal antibodies) use, and they are not discussed in any of their prescribing labels (package inserts).

Background

Targeting calcitonin gene-related peptide (CGRP) and its receptor (CGRPR) have been acclaimed as pivotal breakthroughs in migraine treatment, but they may have immunological implications. CGRP has been shown to influence immune cell function, including dendritic cells, macrophages, mast cells, and lymphocytes, through mechanisms involving antigen presentation, cytokine modulation, and chemotaxis. Notably, CGRP is implicated in antiviral immunity by enhancing macrophage-mediated responses against herpes simplex virus-1 and suppressing HIV-1 infectivity in Langerhans cells. Additionally, CGRP played a role in bacterial homeostasis by regulating commensal bacterial virulence and promoting antimicrobial peptide secretion. It has the ability to shift immune responses towards a Th2-skewed profile, as observed in helminthic infections where CGRP downregulated interferon-gamma while promoting interleukin-4 expression. CGRP is known to downregulate pro-inflammatory cytokines such as TNF-α, IL-12, and IFN-γ while promoting IL-10 and IL-4, thereby maintaining immune tolerance. Inhibition of this neuropeptide may inadvertently promote a pro-inflammatory state, leading to immune-mediated conditions as demonstrated by a 2021 case series [Table 1]. A pharmacokinetic analysis of anti-CGRP monoclonal antibodies, including erenumab, fremanezumab, and galcanezumab, raised concerns regarding the systemic blockade of CGRP due to their prolonged half-lives and supraphysiological plasma concentrations. According to European public assessment reports, post-administration serum concentrations of these therapies were significantly higher (up to 10^6-fold) than endogenous CGRP levels, raising concerns about long-term immunological consequences. Careful patient monitoring, particularly in individuals with underlying infectious or inflammatory conditions, and dose titration strategies may be prudent to mitigate potential adverse effects; however, there is no standardized protocol for dose titrations. Moreover, limitations in current preclinical models for studying CGRP inhibitors were discussed, emphasizing the need for in-depth investigations using relevant immunological and infectious disease frameworks. [1], [2], [3]

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Are CGRP monoclonal antibodies immunosuppressive? Are there any particular infections associated with their use?

Level of evidence

D - Case reports or unreliable data  Read more→


Please see Tables 1-2 for your response.

 

 

Inflammatory complications of CGRP monoclonal antibodies: a case series

Design

Case series

N= 8

Objective

To present a case series of eight patients with new or significantly worsened inflammatory pathology in close temporal association with the commencement of calcitonin gene-related peptide (CGRP) monoclonal antibody (mAb) therapy

Inclusion Criteria

Patients with new or significantly worsened inflammatory pathology after starting CGRP mAb therapy

Exclusion Criteria

None specified

Methods

This was a retrospective chart review and case series of patients (7 women, 1 man) from tertiary care and private headache clinics in Australia and Ireland between 2019-2020. Six cases developed a de novo inflammatory condition post exposure (median 88 days, IQR 71–105) to a CGRP mAb, while the remaining two patients had a significant and unexpected exacerbation of their previously very well controlled immune-mediated disease.
Patient Comorbidities Concomitant medications CGRP mAb treatment Response to CGRP mAb Complication (time to onset) Diagnosis of complication Management of complications
Case 1 56M

BMI 28.4 kg/m2, Rheumatoid arthritis (quiescent), anxiety, dyslipidaemia, pulmonary fibrosis

 Rosuvastatin, atenolol, fenofibrate Erenumab, single dose - Autoimmune hepatitis (D14 of Rx) Specialist diagnosis, biopsy proven CGRP agent ceased. Stabilised with steroid and azathioprine
Case 2 67F

BMI 23.5 kg/m2, Chronic fatigue syndrome, fibromyalgia, hypertension, constipation

 Candesartan, pregabalin, esomeprazole, clomipramine, naratriptan Erenumab, 15 months >75% reduction MMD Ocular Susac's syndrome (12 months of Rx) Specialist diagnosis

CGRP agent ceased. No further flares, or progression to brain/ auditory involvement with IVIg, aspirin, prednisolone, mycophenolate.
Case 3 44F BMI 20.8 kg/m2 Zolmitriptan Erenumab, single dose >75% reduction MMD DRESS Syndrome (D26 of Rx) Specialist diagnosis, biopsy proven

CGRP agent ceased. Resolved within four weeks tapering 1 mg/kg prednisolone.
Case 4 32F BMI 35 kg/m2 Topiramate Erenumab, 6 months transitioned to Fremanezumab, 5 months >75% reduction MMD Granulomatosis with polyangiitis (5 months of Rx) Specialist diagnosis, biopsy proven

CGRP agent ceased. Complication ongoing with prednisolone and methotrexate.
Case 5 20F BMI 18,9 kg/m2, lgG4 disease, GORD, osteoporosis, adrenal insufficiency

10 mg Prednisolone, gabapentin, calcitriol, propranolol, tapentadol, nortriptyline, CBD oil, omeprazole

 Galcanezumab, single dose - Severe polyarthralgia (D4 of Rx) Specialist diagnosis CGRP agent ceased. Complication improved 30% but ongoing
Case 6 45F BMI 32.3 kg/m2, Psoriasis, chronic fatigue syndrome, Lyme disease

Roxithromycin, tinidazole, minocycline, N-acetylcysteine, naratriptan, botulinum toxin, rosuvastatin

 Galcanezumab, single dose None Severe exacerbation of psoriasis (PASI score 16) (D2 of Rx) Specialist diagnosis, biopsy proven CGRP agent ceased. Complication improved (PASI 2) with steroid cream and methotrexate.
Case 7 41F BMI 25.6kg/m2, Psoriatic arthritis (previously controlled > 5 years on adalimumab), osteopenia

Adalimumab, pantoprazole, gabapentin, verapamil, amitriptyline, fenofibrate, naratriptan

 Erenumab, single dose >50% reduction MMD Flare of psoriatic arthritis (5 months of Rx) Specialist diagnosis CGRP agent ceased. Complication improving with steroids and change in biological therapy.
Case 8 46F EH BMI 31 kg/m2 2 Asthma

Propranolol, microgynon, Symbicort, PRN rizatriptan

 Erenumab, 18 months >50% reduction MMD Urticarial eczema (16 months of Rx) Specialist diagnosis CGRP agent ceased. Complication improving with topical steroids, emollients, UVB therapy
BMI; Body mass index, CM: chronic migraine, CBD: cannabidiol, CGRP: Calcitonin Gene Related Peptide, DRESS: Drug reaction with eosinophilia and systemic symptoms, GORD: Gastro-oesophageal reflux disease, IVIg: intravenous immunoglobulin, MMD: monthly migraine days, PASI: Psoriasis area and severity index, UVB: ultraviolet-B
Study Author Conclusions/Discussion

This case series provides novel insights on the potential molecular mechanisms and side-effects of CGRP antagonism in migraine and supports clinical vigilance in patient care going forward.

The findings suggest that CGRP inhibition may disrupt immune homeostasis, given CGRP’s established role in modulating both innate and adaptive immune responses. CGRP is known to downregulate pro-inflammatory cytokines such as TNF-α, IL-12, and IFN-γ while promoting IL-10 and IL-4, thereby maintaining immune tolerance. Inhibition of this neuropeptide may inadvertently promote a pro-inflammatory state, leading to immune-mediated conditions. The authors proposed that patients with pre-existing or latent autoimmune disease may be at higher risk for these adverse effects, though further investigation is warranted to establish definitive causality.
Critique

The study highlights potential inflammatory complications associated with CGRP mAb therapy, but is limited by its small sample size and lack of a control group. The temporal association and biological plausibility support the findings, but further research is needed to establish causation and identify at-risk populations.

 

References:

Ray JC, Allen P, Bacsi A, et al. Inflammatory complications of CGRP monoclonal antibodies: a case series. J Headache Pain. 2021;22(1):121. Published 2021 Oct 9. doi:10.1186/s10194-021-01330-7

 

Calcitonin Gene–Related Peptide Monoclonal Antibodies and Risk of SARS-CoV-2 Infection and Severe COVID-19 Outcomes Among Veterans With Migraine Disorder
Design

Retrospective cohort study

N= 354,294
Objective

To evaluate the association between CGRP monoclonal antibody (mAb) treatment and risk of SARS-CoV-2 infection and sequela hospitalization, requiring supplemental oxygen, use of mechanical ventilation, or death
Study Groups

CGRP mAb initiators (n= 9992)

Noninitiators (n= 8,168,660)
Inclusion Criteria

Aged 18-65 years with a 12-month history of migraine, no previous SARS-CoV-2 infection, no contraindication or recent prescription of CGRP mAb (>5 months), no prior use of CGRP receptor antagonists, regular health care system contact, not residing in long-term care facilities
Exclusion Criteria

Serious hypersensitivity to CGRP mAbs, concurrent cluster headache, received galcanezumab
Methods

This was a retrospective analysis of electronic health records of US veterans from the VHA Headache Centers of Excellence administrative data cohort. CGRP mAb prescriptions identified using outpatient pharmacy records.
Duration

January 20, 2020, to May 19, 2022
Outcome Measures

Primary: Cumulative incidence of SARS-CoV-2 infection

Secondary: Hospitalization, requiring supplemental oxygen, use of mechanical ventilation, death within 30 days of positive test result
Baseline Characteristics  

Initiators (n = 9992)

   Noninitiators (n = 8,168,660)
Age, years

46.0 ± 9.5

   46.6 ± 10.2
Men

53.9%

   65.7%
White

63.4%

   61.8%
Chronic migraine

29.7%

   7.0%
Prescribed triptans

83.7%

   58.5%
Results  

Events/person-trials

 HR or OR (95% CI) p-value

Initiators

 Noninitiators
SARS-CoV-2 infection

1247/9992 (12.5%)

9.6%

 0.95 (0.89 to 1.01) 0.08
Hospitalization

55/1247 (4.4%)

4.8%

 0.89 (0.66 to 1.20) 0.45
Supplemental oxygen

36/1247 (2.9%)

3.4%

 0.81 (0.57 to 1.17) 0.27
Mechanical ventilation

8/1247 (0.6%)

0.6%

 1.02 (0.50 to 2.09) 0.96
Death

2/1247 (0.2%)

0.5%

 0.53 (0.13 to 2.13) 0.37
Adverse Events

No significant differences in the likelihood of hospitalization, requiring supplemental oxygen, use of mechanical ventilation, or death between CGRP mAb initiators and noninitiators who tested positive for SARS-CoV-2
Study Author Conclusions

CGRP mAb treatment was not associated with positive SARS-CoV-2 test results or risk of severe COVID-19 outcomes, suggesting that CGRP mAbs may be used for migraine prevention during the COVID-19 pandemic.
Critique

The study's large sample size and use of a national integrated health care system are strengths, minimizing misclassification bias. However, the retrospective design and potential for unmeasured confounders limit causal inference. The short median duration of CGRP mAb treatment (5 months) restricts long-term outcome analysis. The small number of severe COVID-19 events limits the power to detect differences in severe outcomes. The study population of relatively young and healthy veterans may not generalize to older or more comorbid populations.

 

References:

Wang K, Fenton BT, Deng Y, et al. Calcitonin Gene-Related Peptide Monoclonal Antibodies and Risk of SARS-CoV-2 Infection and Severe COVID-19 Outcomes Among Veterans With Migraine Disorder. JAMA Netw Open. 2023;6(7):e2326371. Published 2023 Jul 3. doi:10.1001/jamanetworkopen.2023.26371