Clinical trial NCT06426316: The Role of Cytokines and Regulatory T Lymphocytes in Migraine Pathophysiology.
Official title: Immune System, Inflammation, Migraine - The Role of Cytokines and Regulatory T Lymphocytes in Migraine Pathophysiology
Study type: INTERVENTIONAL
Overall status: NOT_YET_RECRUITING
Phase: NA
Conditions: Migraine Disorders
Pain
Autoimmune Diseases
Multiple Sclerosis
Endometriosis
Rheumatoid Arthritis
Crohn Disease
Lupus Erythematosus
Keywords: Migraine Disorders
Pain
Cytokines
Regulatory T cell
Lead sponsor: University Hospital, Clermont-Ferrand
Sponsor class: OTHER
First posted: 2024-05-23
Enrollment: 396
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: Migraine is a frequent and debilitating neurologic disorder. It is more frequent in women, and more prevalent in patients with autoimmune and/or inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn's disease (CD), systemic lupus erythematosus (SLE) and endometriosis, whereas patients with long standing type 1 diabetes mellitus (T1DM) - an autoimmune but non inflammatory disease - seem to be less affected compared to the general population. Despite new migraine prevention treatments, a large number of patients remain unresponsive to currently available anti-migraine therapy and migraine pathophysiology remains unclear. Several peptides (calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase activating peptide-38 (PACAP-38), vasoactive intestinal polypeptide (VIP)) and hormones (estrogens, prolactin) and the immune system play an important role in migraine pathophysiology. Among T lymphocytes, regulatory T (Treg) cells suppress inflammation. Studies have evidenced higher levels of inflammatory molecules (cytokines) in migraine patients and have suggested decreased proportions of Treg cells in migraine, as well as in MS, RA, CD and SLE, whereas inflammation declines and Treg levels seem increased in long-standing T1DM. Inflammation, which participates in migraine pain, seems to be a common factor for migraine and these diseases. However, these studies display conflicting results and further investigation is required to better understand the mechanisms behind migraine.

In this study, the investigators will compare Treg levels, as well as identify Treg subpopulations and measure cytokine levels in migraine and migraine-free participants with and without an autoimmune/inflammatory disorder (MS, RA, CD, SLE, T1DM and endometriosis).

Detailed description: Migraine is the 6th most frequent disease (14% of the population) and the second leading cause of disability worldwide. From puberty and onward, migraine is 2 to 3 times more frequent in women, which also suffer from more severe attacks. Migraine is also up to twice as prevalent in patients suffering from autoimmune or inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis (RA), Crohn disease (CD), systemic lupus erythematosus (SLE) and endometriosis, whereas patients with long standing type 1 diabetes mellitus (T1DM) - an autoimmune but non inflammatory disease - seem to be less affected compared to the general population.

Despite the identification of the role of peptides such as CGRP in migraine pathophysiology and the development of targetted anti-CGRP treatments, many patients remain unresponsive and the mechanisms behind migraine are still unclear.

The trigemino-vascular system is involved in the perception of migraine pain. Migraine occurs with trigemino-cervical neuron sensitization, leading to peptide secretion (such as CGRP, PACAP-38 and VIP), which induce neurogenic inflammation that is responsible for vasodilation, capillary leakage, oedema and further sensitization of the trigemino-vascular system, leading to amplified perception of migraine pain. CGRP, PACAP-38 and VIP infusions all induce migraine attacks in migraine patients, and only mild or no headache in healthy volunteers.

Sex hormones, prolactin and insulin are also involved in migraine pathophysiology, and the immune system, through cytokine production and immune cell dysregulations seems to also play a role in the pathogenesis of migraine. Both are closely related as sex hormone levels may have an influence on the levels of certain immune cell subtypes. Several pro-inflammatory cytokines (tumor necrosis factor (TNF)-alpha, interferon (IFN)-gamma and interleukin (IL)-6) were shown to be elevated in migraine patients but also inflammatory diseases such as MS and endometriosis compared to controls and are associated with migraine pathophysiology. Inflammation seems to be a common factor for migraine and these diseases. However, these studies provide conflicting results and further investigation is needed to better understand the role of inflammation in migraine pathophysiology.

Among T lymphocytes, regulatory T (Treg) cells regulate inflammation by suppressing effector T cells through several suppressive mechanisms such as IL-10 secretion or the hydrolysis of pro-inflammatory and nociceptive adenosine triphosphate (ATP) into anti-inflammatory and anti-nociceptive adenosine by cluster of differentiation (CD) 39 and 73 enzymes on the Treg cell surface. Recent studies have suggested decreased Treg proportions in migraine patients, particularly CD 39 and CD 73-positive Treg cells, whereas Treg cells were shown to be increased in T1DM patients. This suggests the role of Treg cells in migraine, but further studies are needed.

In this study, the investigators aim to compare Treg levels, as well as identify Treg subpopulations and measure cytokine levels in migraine and migraine-free participants with and without an autoimmune/inflammatory disorder (MS, RA, CD, SLE, T1DM and endometriosis). This will provide better understanding of migraine pathophysiology and lead to the development of targeted and personalized treatment strategies, according to the immune pain profile and associated inflammatory diseases of migraine patients.

Eligibility criteria: Inclusion Criteria:

* female
* 18 - 50 years of age
* at least 50 kg

Exclusion Criteria:

* menopause
* type 2 diabetes
* pregnancy (or delivery \< 3 months)
* breast feeding
* hysterectomy or adnexectomy
* characterized immune deficiency
* active cancer (or remission \< 1 year)
* bone marrow or solid organ transplant
* hormone therapy (other than birth control)
* migraine attack within 12 hours before or after blood test
* person under guardianship

Primary outcomes:
measure: Treg cell levels in cell/microliter (cell/µL)
timeFrame: Once, at inclusion
measure: Treg cell levels in percentage (%) of white blood cells
timeFrame: Once, at inclusion
measure: Age in years
timeFrame: Once, at inclusion
measure: Weight in kilograms (kg)
timeFrame: Once, at inclusion
measure: Score on the Hospital Anxiety and Depression Scale
timeFrame: Once, at inclusion
measure: Score on the Headache Impact Test
timeFrame: Once, at inclusion
measure: Migraine diagnostic criteria from the International Classification of Headache Disorders 3rd edition (ICHD-3)
timeFrame: Once, at inclusion
measure: Number of headache days per month in days/month
timeFrame: Once, at inclusion
measure: White blood cell count in giga/liter (G/L)
timeFrame: Once, at inclusion
measure: Sex (female, male)
timeFrame: Once, at inclusion
measure: Date of last menstrual period as a date in the form: day/month/year
timeFrame: Once, at inclusion
measure: Human chorionic gonadotropin subunit beta level in milli-international units per milliliter (mIU/mL)
timeFrame: Once, at inclusion
measure: Height in meters (m)
timeFrame: Once, at inclusion
measure: Body mass index (BMI) in kilogram per square meter (kg/m2)
timeFrame: Once, at inclusion
Secondary outcomes:
measure: Cytokine levels in picogram per milliliter (pg/mL)
timeFrame: Once, at inclusion
measure: Progesterone in nanogram per milliliter (ng/mL)
timeFrame: Once, at inclusion
measure: Estrogen in picogram per milliliter (pg/mL)
timeFrame: Once, at inclusion
measure: Follicle stimulating hormone (FSH) in milli-international units per milliliter (mIU/mL)
timeFrame: Once, at inclusion
measure: Luteinizing hormone in international units per liter (IU/L)
timeFrame: Once, at inclusion
measure: Levels of C-reactive protein (CRP) in milligram per liter (mg/L)
timeFrame: Once, at inclusion
measure: Fasting blood glucose concentration in gram per liter (g/L)
timeFrame: Once, at inclusion
measure: Insulin levels in milligram per deciliter (mg/dL)
timeFrame: Once, at inclusion
measure: Prolactin levels in nanogram per milliliter (ng/mL)
timeFrame: Once, at inclusion
measure: Calcitonin gene-related peptide (CGRP) in picogram per milliliter (pg/mL)
timeFrame: Once, at inclusion
measure: Vasoactive intestinal polypeptide (VIP) in picogram per milliliter (pg/mL)
timeFrame: Once, at inclusion
measure: Pituitary adenylate cyclase-activating polypeptide (PACAP) levels in nanogram per milliliter (ng/mL)
timeFrame: Once, at inclusion
Other outcomes:
Locations:
city: Clermont-Ferrand
country: France
facility: CHU de Clermont-Ferrand - Service de Neurologie
state: Aura
Study officials:
affiliation: University Hospital, Clermont-Ferrand
name: Xavier MOISSET
role: PRINCIPAL_INVESTIGATOR
References:
citation: Al-Hassany L, Haas J, Piccininni M, Kurth T, Maassen Van Den Brink A, Rohmann JL. Giving Researchers a Headache - Sex and Gender Differences in Migraine. Front Neurol. 2020 Oct 22;11:549038. doi: 10.3389/fneur.2020.549038. eCollection 2020.
citation: Stovner LJ, Hagen K, Linde M, Steiner TJ. The global prevalence of headache: an update, with analysis of the influences of methodological factors on prevalence estimates. J Headache Pain. 2022 Apr 12;23(1):34. doi: 10.1186/s10194-022-01402-2.
citation: Ashina M. Migraine. N Engl J Med. 2020 Nov 5;383(19):1866-1876. doi: 10.1056/NEJMra1915327. No abstract available.
citation: Pellesi L, Al-Karagholi MA, De Icco R, Coskun H, Elbahi FA, Lopez-Lopez C, Snellman J, Hannibal J, Amin FM, Ashina M. Effect of Vasoactive Intestinal Polypeptide on Development of Migraine Headaches: A Randomized Clinical Trial. JAMA Netw Open. 2021 Aug 2;4(8):e2118543. doi: 10.1001/jamanetworkopen.2021.18543.
citation: Al-Karagholi MA, Kalatharan V, Ghanizada H, Gram C, Dussor G, Ashina M. Prolactin in headache and migraine: A systematic review of clinical studies. Cephalalgia. 2023 Feb;43(2):3331024221136286. doi: 10.1177/03331024221136286.
citation: Bhoi SK, Kalita J, Misra UK. Metabolic syndrome and insulin resistance in migraine. J Headache Pain. 2012 Jun;13(4):321-6. doi: 10.1007/s10194-012-0416-y. Epub 2012 Jan 26.
citation: Schetters STT, Gomez-Nicola D, Garcia-Vallejo JJ, Van Kooyk Y. Neuroinflammation: Microglia and T Cells Get Ready to Tango. Front Immunol. 2018 Jan 25;8:1905. doi: 10.3389/fimmu.2017.01905. eCollection 2017.
citation: Watkins LR, Maier SF. Glia: a novel drug discovery target for clinical pain. Nat Rev Drug Discov. 2003 Dec;2(12):973-85. doi: 10.1038/nrd1251. No abstract available.
citation: Perini F, D'Andrea G, Galloni E, Pignatelli F, Billo G, Alba S, Bussone G, Toso V. Plasma cytokine levels in migraineurs and controls. Headache. 2005 Jul-Aug;45(7):926-31. doi: 10.1111/j.1526-4610.2005.05135.x.
citation: Vignali DA, Collison LW, Workman CJ. How regulatory T cells work. Nat Rev Immunol. 2008 Jul;8(7):523-32. doi: 10.1038/nri2343.
citation: Arumugam M, Parthasarathy V. Reduction of CD4(+)CD25(+) regulatory T-cells in migraine: Is migraine an autoimmune disorder? J Neuroimmunol. 2016 Jan 15;290:54-9. doi: 10.1016/j.jneuroim.2015.11.015. Epub 2015 Nov 28.
citation: Faraji F, Shojapour M, Farahani I, Ganji A, Mosayebi G. Reduced regulatory T lymphocytes in migraine patients. Neurol Res. 2021 Aug;43(8):677-682. doi: 10.1080/01616412.2021.1915077. Epub 2021 Apr 14.
citation: Okimura H, Tanaka Y, Fujii M, Shimura K, Maeda E, Ito F, Khan KN, Nakamura Y, Mori T, Kitawaki J. Changes in the proportion of regulatory T cell subpopulations during menstrual cycle and early pregnancy. Am J Reprod Immunol. 2022 Dec;88(6):e13636. doi: 10.1111/aji.13636. Epub 2022 Oct 21.
citation: Moisset X, Bommelaer G, Boube M, Ouchchane L, Goutte M, Dapoigny M, Dallel R, Guttmann A, Clavelou P, Buisson A. Migraine prevalence in inflammatory bowel disease patients: A tertiary-care centre cross-sectional study. Eur J Pain. 2017 Oct;21(9):1550-1560. doi: 10.1002/ejp.1056. Epub 2017 May 16.
citation: Moisset X, Giraud P, Dallel R. Migraine in multiple sclerosis and other chronic inflammatory diseases. Rev Neurol (Paris). 2021 Sep;177(7):816-820. doi: 10.1016/j.neurol.2021.07.005. Epub 2021 Jul 27.
citation: Yang MH, Wang PH, Wang SJ, Sun WZ, Oyang YJ, Fuh JL. Women with endometriosis are more likely to suffer from migraines: a population-based study. PLoS One. 2012;7(3):e33941. doi: 10.1371/journal.pone.0033941. Epub 2012 Mar 19.
citation: Hagen K, Asvold BO, Midthjell K, Stovner LJ, Zwart JA, Linde M. Inverse relationship between type 1 diabetes mellitus and migraine. Data from the Nord-Trondelag Health Surveys 1995-1997 and 2006-2008. Cephalalgia. 2018 Mar;38(3):417-426. doi: 10.1177/0333102417690488. Epub 2017 Jan 23.
citation: Malutan AM, Drugan T, Costin N, Ciortea R, Bucuri C, Rada MP, Mihu D. Pro-inflammatory cytokines for evaluation of inflammatory status in endometriosis. Cent Eur J Immunol. 2015;40(1):96-102. doi: 10.5114/ceji.2015.50840. Epub 2015 Apr 22.
citation: Gobel K, Ruck T, Meuth SG. Cytokine signaling in multiple sclerosis: Lost in translation. Mult Scler. 2018 Apr;24(4):432-439. doi: 10.1177/1352458518763094. Epub 2018 Mar 7.
citation: Shi JL, Zheng ZM, Chen M, Shen HH, Li MQ, Shao J. IL-17: an important pathogenic factor in endometriosis. Int J Med Sci. 2022 Apr 11;19(4):769-778. doi: 10.7150/ijms.71972. eCollection 2022.
citation: Viisanen T, Gazali AM, Ihantola EL, Ekman I, Nanto-Salonen K, Veijola R, Toppari J, Knip M, Ilonen J, Kinnunen T. FOXP3+ Regulatory T Cell Compartment Is Altered in Children With Newly Diagnosed Type 1 Diabetes but Not in Autoantibody-Positive at-Risk Children. Front Immunol. 2019 Jan 22;10:19. doi: 10.3389/fimmu.2019.00019. eCollection 2019.