Polygenic risk provides biological validity for the ICHD-3 criteria among Finnish migraine families.

BACKGROUND: Migraine is diagnosed using the extensively field-tested International Classification of Headache Disorders (ICHD-3) consensus criteria derived by the International Headache Society. To evaluate the criteria in respect to a measurable biomarker, we studied the relationship between the main ICHD-3 criteria and the polygenic risk score, a measure of common variant burden in migraine. METHODS: We used linear mixed models to study the correlation of ICHD-3 diagnostic criteria, underlying symptoms, and main diagnoses with the polygenic risk score of migraine in a cohort of 8602 individuals from the Finnish Migraine Genome Project. RESULTS: Main diagnostic categories and all underlying diagnostic criteria formed a consistent continuum along the increasing polygenic burden. Polygenic risk was associated with the heterogeneous clinical picture starting from the non-migraine headache (mean 0.07; 95% CI 0.02-0.12; p = 0.008 compared to the non-headache group), to probable migraine (mean 0.13; 95% CI 0.08-0.18; p < 0.001), migraine headache (mean 0.17; 95% CI 0.14-0.21; p < 0.001) and migraine with typical visual aura (mean 0.29; 95% CI 0.26-0.33; p < 0.001), all the way to the hemiplegic aura (mean 0.37; 95% CI 0.31-0.43; p < 0.001). All individual ICHD-3 symptoms and the total number of reported symptoms, a surrogate of migraine complexity, demonstrated a clear inclination with an increasing polygenic risk. CONCLUSIONS: The complex migraine phenotype progressively follows the polygenic burden from individuals with no headache to non-migrainous headache and up to patients with attacks manifesting all the features of the ICHD-3 headache and aura. Results provide further biological support for the ICHD-3 diagnostic criteria.

Enhanced passive safety surveillance of a quadrivalent inactivated split virion influenza vaccine in Finland during the influenza season 2020/21.

BACKGROUND: The European Medicines Agency (EMA) requires enhanced safety surveillance to be conducted for annual seasonal influenza vaccines with the aim of rapidly detecting any potential new safety concerns before the peak immunisation period of the vaccine in any given year. The aim of this study was to detect any clinically significant change in the frequency or severity of expected reactogenicity of the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunisation in Finland for the 2020/21 season. The primary objective was to investigate the frequency of suspected adverse drug reactions (ADRs) occurring within 7 days following vaccination. METHODS: Enhanced passive safety surveillance of individuals vaccinated with IIV4 was conducted from October 9, 2020 to November 30, 2020 across seven sites in Finland. The vaccinee reporting rate and ADR reporting rate were calculated and compared with known or expected safety data in order to identify any clinically significant changes. RESULTS: Data were collected from 1008 individuals with 29 vaccinees reporting 82 suspected ADRs. Of these, 28 people reported 79 suspected ADRs within 7 days following vaccination, corresponding to a vaccinee reporting rate of 2.78% (95% CI: 1.85, 3.99) (ADR reporting rate, 7.84% [95% CI: 6.25, 9.67%]). The most frequently reported ADRs were injection site reactions (vaccination site pain, vaccination site erythema and vaccination site swelling) (n = 46, 2.28%), myalgia (n = 9, 0.89%) and headache (n = 8, 0.79%). No serious suspected adverse events were reported at any point post-vaccination and ADR reporting rates were in general lower compared to those reported for IIV4 in the 2019/20 surveillance study. CONCLUSION: No clinically significant changes in what is known or expected for IIV4 were reported for the 2020/21 season which supports the safety profile of this vaccine and will help maintain public confidence in influenza vaccination.

Enhanced passive safety surveillance of the quadrivalent inactivated split-virion influenza vaccine (IIV4) in Finland during the 2019/20 influenza season.

BACKGROUND AND AIMS: The Enhanced Passive Safety Surveillance is a requirement of the European Medicines Agency (EMA) for seasonal influenza vaccines, aiming to rapidly detect any significant change in frequency or severity of expected reactogenicity or allergic events prior to widespread use of a vaccine in any particular year. The aim of this surveillance was to assess the quadrivalent inactivated split-virion influenza vaccine (IIV4) during routine immunization in Finland, as per the national immunization program for 2019/20. The primary objective was to investigate the suspected adverse drug reactions (ADR) occurring within 7 days following vaccination. METHODS: Passive surveillance of individuals vaccinated with IIV4 was conducted within the first 4 to 6 weeks of the influenza season in Finland. Potential ADRs were reported via phone or posted adverse event forms. The vaccinee reporting rate and ADR reporting rate were calculated and compared with the known or expected safety data in order to identify any change which was clinically significant. RESULTS: Data were collected from 939 individuals, with 56 reports received for 163 suspected ADRs. Of these, 38 individuals reported 117 suspected ADRs within 7 days following vaccination, corresponding to an ADR reporting rate of 12.46% (95% CI: 10.41, 14.74%); vaccination-site pain, vaccination-site reaction, and pyrexia were the most frequently reported ADRs. The 18-to-65 years of age category had an ADR reporting rate of 12.56%, the over-65 years of age category had an ADR reporting rate of 16.22%, and no ADRs were reported for individuals aged 6 months to 18 years. No serious suspected ADRs were reported at any time post-vaccination, and the ADR rates were comparable to those reported for IIV4 in the 2018/19 seasonal assessment. The frequency of suspected ADRs was generally aligned with those reported in the Summary of Product Characteristics (SmPC), with the exception of asthenia, somnolence, and erythema, which were slightly higher. No reporting pattern by type, frequency, or severity was identified for the suspected ADRs. CONCLUSIONS: No clinically significant changes in what is known or expected for IIV4 was reported for the 2019/20 season, which supports the overall safety profile.

Burden of migraine in Finland: multimorbidity and phenotypic disease networks in occupational healthcare.

BACKGROUND: Migraine is a complex neurological disorder with high co-existing morbidity burden. The aim of our study was to examine the overall morbidity and phenotypic diseasome for migraine among people of working age using real world data collected as a part of routine clinical practice. METHODS: Electronic medical records (EMR) of patients with migraine (n = 17,623) and age- and gender matched controls (n = 17,623) were included in this retrospective analysis. EMRs were assessed for the prevalence of ICD-10 codes, those with at least two significant phi correlations, and a prevalence >2.5% in migraine patients were included to phenotypic disease networks (PDN) for further analysis. An automatic subnetwork detection algorithm was applied in order to cluster the diagnoses within the PDNs. The diagnosis-wise connectivity based on the PDNs was compared between migraine patients and controls to assess differences in morbidity patterns. RESULTS: The mean number of diagnoses per patient was increased 1.7-fold in migraine compared to controls. Altogether 1337 different ICD-10 codes were detected in EMRs of migraine patients. Monodiagnosis was present in 1% and 13%, and the median number of diagnoses was 12 and 6 in migraine patients and controls. The number of significant phi-correlations was 2.3-fold increased, and cluster analysis showed more clusters in those with migraine vs. controls (9 vs. 6). For migraine, the PDN was larger and denser and exhibited one large cluster containing fatigue, respiratory, sympathetic nervous system, gastrointestinal, infection, mental and mood disorder diagnoses. Migraine patients were more likely affected by multiple conditions compared to controls, even if no notable differences in morbidity patterns were identified through connectivity measures. Frequencies of ICD-10 codes on a three character and block level were increased across the whole diagnostic spectrum in migraine. CONCLUSIONS: Migraine was associated with an increased multimorbidity, evidenced by multiple different approaches in the study. A systematic increase in the morbidity across the whole spectrum of ICD-10 coded diagnoses, and when interpreting PDNs, were detected in migraine patients. However, no specific diagnoses explained the morbidity. The results reflect clinical praxis, but also undoubtedly, the pathophysiological phenotypes related to migraine, and emphasize the importance of better understanding migraine-related morbidity.

Burden of migraine in Finland: health care resource use, sick-leaves and comorbidities in occupational health care.

BACKGROUND: The highest prevalence of migraine is detected among people who are of working age. The aim of this study was to assess the burden of migraine in an occupational health care setting using real world data collected as a part of routine clinical practice. METHODS: This retrospective register study included migraineurs using occupational health care at the private health care provider Terveystalo. An age and gender matched control population was established for comparison. Electronic medical records were assessed for overall and migraine related health care visits, sick-leaves and comorbidities. Stratification to acute and prophylactic treatment groups along with prophylactic treatment lines was based on prescriptions. RESULTS: Among the 369,383 individuals in the study cohort, 7.4% women and 2.1% men were identified having a diagnosis of migraine. Prophylactic medication was prescribed to 13% of migraine patients and exclusively acute medication to 37%. Although migraine related visits and sick-leave days were significantly lower than overall visits or sick-leave days, both increased by prophylactic treatment line. The number of visits rose from 13.8 to 26.2 and sick-leave days from 16.8 to 30.4 per patient-year, in those without prophylaxis vs. ≥3 prophylactic treatments. Moreover, migraine patients had 1.7-fold increase in visits and 1.8-fold increase in sick leave days on average per patient-year, when compared to the control population. Depression and anxiety were 1.8-fold more common among patients with migraine, and the frequency also increase by treatment line. CONCLUSIONS: Migraine burden increased by each failed treatment line and was associated with increased comorbidity. In addition, migraine patients had significantly higher extent of visits and sick-leave days as well as extent of comorbidities when compared to their age- and gender-matched counterparts.

The contribution of CACNA1A, ATP1A2 and SCN1A mutations in hemiplegic migraine: A clinical and genetic study in Finnish migraine families.

Objective To study the position of hemiplegic migraine in the clinical spectrum of migraine with aura and to reveal the importance of CACNA1A, ATP1A2 and SCN1A in the development of hemiplegic migraine in Finnish migraine families. Methods The International Classification of Headache Disorders 3rd edition criteria were used to determine clinical characteristics and occurrence of hemiplegic migraine, based on detailed questionnaires, in a Finnish migraine family collection consisting of 9087 subjects. Involvement of CACNA1A, ATP1A2 and SCN1A was studied using whole exome sequencing data from 293 patients with hemiplegic migraine. Results Overall, hemiplegic migraine patients reported clinically more severe headache and aura episodes than non-hemiplegic migraine with aura patients. We identified two mutations, c.1816G>A (p.Ala606Thr) and c.1148G>A (p.Arg383His), in ATP1A2 and one mutation, c.1994C>T (p.Thr665Met) in CACNA1A. Conclusions The results highlight hemiplegic migraine as a clinically and genetically heterogeneous disease. Hemiplegic migraine patients do not form a clearly separate group with distinct symptoms, but rather have an extreme phenotype in the migraine with aura continuum. We have shown that mutations in CACNA1A, ATP1A2 and SCN1A are not the major cause of the disease in Finnish hemiplegic migraine patients, suggesting that there are additional genetic factors contributing to the phenotype.

Enhanced passive safety surveillance of high-dose and standard-dose quadrivalent inactivated split-virion influenza vaccines in Germany and Finland during the 2022/23 influenza season.

Enhanced Passive Safety Surveillance (EPSS) was conducted for quadrivalent inactivated split-virion influenza vaccines (IIV4) in Germany (high dose [HD]) and Finland (standard dose [SD]) for the northern hemisphere (NH) 2022/23 influenza season. The primary objective was to assess adverse events following immunization (AEFI) occurring ≤7 days post-vaccination. In each country, the EPSS was conducted at the beginning of the NH influenza season. Exposure information was documented using vaccination cards (VC), and AEFI were reported via an electronic data collection system or telephone. AEFI were assessed by seriousness and age group (Finland only). The vaccinee reporting rate (RR) was calculated as the number of vaccinees reporting ≥ 1 AEFI divided by the total vaccinees. In Germany, among 1041 vaccinees, there were 31 AEFI (ten vaccinees) during follow-up, including one serious AEFI. Of 16 AEFI (six vaccinees) with reported time of onset, 15 occurred ≤7 days post-vaccination (RR 0.58%, 95% confidence interval [CI] 0.21, 1.25), which was lower than the 2021/22 season (RR 1.88%, 95% CI: 1.10, 3.00). In Finland, among 1001 vaccinees, there were 142 AEFI (51 vaccinees) during follow-up, none of which were serious. Of 133 AEFI (48 vaccinees) with time of onset reported, all occurred ≤7 days post-vaccination (RR 4.80%, 95% CI: 3.56, 6.31), which was similar to the 2021/22 season (RR 4.90%, 95% CI: 3.65, 6.43). The EPSS for HD-IIV4 and for SD-IIV4 in the 2022/23 influenza season did not suggest any clinically relevant changes in safety beyond what is known/expected for IIV4s.

Enhanced passive safety surveillance of high-dose and standard-dose quadrivalent inactivated split-virion influenza vaccines in Germany and Finland during the influenza season 2021/22.

BACKGROUND: Enhanced passive safety surveillance (EPSS) was conducted for quadrivalent inactivated split-virion influenza vaccines (IIV4) in Germany (high dose [HD], aged ≥60 years) and in Finland (standard dose [SD], aged ≥6 months) at the beginning of the northern hemisphere 2021/22 influenza season. The primary objective was to assess adverse drug reactions (ADRs) occurring ≤7 days post-vaccination. METHODS: Vaccinees were issued vaccination cards (VC) and were encouraged to report ADRs via an electronic data collection system or by telephone. ADRs were assessed by frequency, time to onset, intensity and by age group. The vaccinee reporting rate (RR) was calculated as the number of vaccinees reporting ≥1 ADR divided by total vaccinees. Reactogenicity was compared with previous experiences with each vaccine. RESULTS: Among 903 HD-IIV4 vaccinees in Germany, 17 reported ≥1 ADR within ≤7 days post-vaccination: RR, 1.88% (95% CI: 1.10, 3.00). Time to onset was known for 53/65 ADRs, all of which occurred ≤7 days post-vaccination. In Germany, seven ADRs were reported that were not listed previously. Among the 1000 SD-IIV4 vaccinees in Finland, 49 reported ≥1 ADR within ≤7 days post-vaccination: RR, 4.90% (95% CI: 3.65, 6.43). Time to onset was known for 126/134 ADRs, of which 125 occurred ≤7 days post-vaccination. In Finland, 21 ADRs were reported that were not listed previously. No ADRs reported during follow-up were serious. CONCLUSIONS: The EPSS for HD-IIV4 and for SD-IIV4 in the 2021/22 influenza season did not suggest any clinically relevant changes in safety beyond what is known/expected for IIV4s.

Erenumab Decreases Headache-Related Sick Leave Days and Health Care Visits: A Retrospective Real-World Study in Working Patients with Migraine.

INTRODUCTION: The prevalence of migraine is highest among working age individuals, and this disease is associated with an increased number of sick leaves and health care visits, as well as lost productivity. Erenumab, the first monoclonal antibody targeting the calcitonin gene-related peptide (CGRP) pathway, is effective in decreasing the monthly number of migraine days, but evidence of its impact on the number of sick leave days and health care visits in patients with migraine is limited. METHODS: This retrospective registry study focused on occupationally active patients with migraine treated with erenumab at a Finnish private health care provider, Terveystalo. Erenumab responders, defined as patients who had at least two unique prescriptions of erenumab and no prescription of other CGRP inhibitor (CGRPi), were followed for 12 months prior to and after erenumab treatment initiation (index), and the change in the number of headache-related and all-cause sick leave days, health care visits and prescriptions for other medications during this period were assessed from the registry data. The same outcomes were assessed in an age- and sex-matched control group of migraine patients not receiving CGRPi to control for potential changes in patient behavior and health care practices during the COVID-19 pandemic. RESULTS: Altogether, 162 patients who were entitled to employer-sponsored health care received erenumab and met the 12-month follow-up requirements. In the responder group (n = 82; 50.1%) headache-related sick leave days were reduced by 73.9% (p = 0.035) and health care visits by 44.6% (p < 0.001) in the 12 months following treatment initiation compared to the period of 12 months prior to treatment. All-cause sick leave days were reduced by 19.4% and all-cause health care visits by 13.5%, but these changes were not statistically significant. Triptan prescriptions decreased by 30.4% (p = 0.012) and other prophylactic treatments by 31.5% (p = 0.004). No significant changes were observed in the corresponding outcomes in the migraine control group during the same period. CONCLUSIONS: The results of this registry study suggest that in addition to the effect on the monthly number of migraine days documented in clinical trials, erenumab can significantly reduce the number of headache-related sick leave days and health care visits in employed patients with migraine managed in routine clinical practice.

Enhanced passive safety surveillance of a trivalent and a quadrivalent influenza vaccine in Denmark and Finland during the 2018/2019 season.

The European Medicines Agency requires Enhanced Passive Safety Surveillance (EPSS) for all seasonal influenza vaccines. Here, we report the EPSS results for the trivalent inactivated influenza vaccine (IIV3; Vaxigrip®) and the quadrivalent inactivated influenza vaccine (IIV4; VaxigripTetraTM) during the 2018/19 influenza season in Denmark and Finland. The primary objective was to estimate the rates of suspected adverse reactions (ARs) occurring within 7 days following routine vaccination. Between October and November 2018, 1000 safety report cards (SRCs) for IIV3 were distributed in Denmark, and 996 SRCs for IIV4 were distributed in Finland. Participants were instructed to report any ARs by telephone or e-mail using the information provided on the SRC. All participants vaccinated with IIV3 were aged ≥18 years. Most participants vaccinated with IIV4 (95.5%) were aged 18 - 65 years, 2.2% were aged 6 months to 17 years, and 2.3% were aged >65 years. Fifty-five ARs were reported by 12 participants (1.2%) vaccinated with IIV3 and 162 ARs were reported by 53 participants (5.3%) vaccinated with IIV4. The most frequent ARs were vaccination site pain and fever for IIV3, and vaccination site pain, vaccination site inflammation, myalgia, and headache for IIV4. The 2018/19 AR rates for IIV3 were comparable to 2017/18 rates. The 2018/19 AR rates for IIV4 were higher than those in 2017/18 but were still lower than the expected AR rates listed in the IIV4 Summary of Product Characteristics. In conclusion, the 2018/19 EPSS showed no clinically significant change from the expected safety profiles of IIV3 and IIV4 vaccines.

[Cluster headache]. / Sarjoittainen päänsärky.

Cluster headache is a condition of extremely intense unilateral pain in the ocular or temporal region. Most patients are male. The condition occurs in clusters lasting from weeks to months. In some patients the clusters occur in seasonal periods. Prophylaxis of the bouts is based on verapamil and therapy is based on subcutaneous sumatriptan, intranasally sprayable zolmitriptan, or oxygen. In addition, corticosteroids and a short course of treatment with an ergotamine product can be used, if the bouts cannot be otherwise treated.

Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families.

Complex traits, including migraine, often aggregate in families, but the underlying genetic architecture behind this is not well understood. The aggregation could be explained by rare, penetrant variants that segregate according to Mendelian inheritance or by the sufficient polygenic accumulation of common variants, each with an individually small effect, or a combination of the two hypotheses. In 8,319 individuals across 1,589 migraine families, we calculated migraine polygenic risk scores (PRS) and found a significantly higher common variant burden in familial cases (n = 5,317, OR = 1.76, 95% CI = 1.71-1.81, p = 1.7 × 10-109) compared to population cases from the FINRISK cohort (n = 1,101, OR = 1.32, 95% CI = 1.25-1.38, p = 7.2 × 10-17). The PRS explained 1.6% of the phenotypic variance in the population cases and 3.5% in the familial cases (including 2.9% for migraine without aura, 5.5% for migraine with typical aura, and 8.2% for hemiplegic migraine). The results demonstrate a significant contribution of common polygenic variation to the familial aggregation of migraine.

Comorbidity in Finnish migraine families.

The objective of the study was to investigate comorbidity of migraine in Finnish migraine families. One thousand consecutive participants in the Finnish Migraine Gene Project reported their medical illnesses in addition to migraine and headache. Migraine patients (n=678) reported significantly more hypotension (OR 1.43, CI 95% 1.02-2.01), allergy (OR 1.83, CI 95% 1.34-2.51) and psychiatric disorders (OR 4.09, CI 95% 2.11-7.92) compared to their family members without migraine (n=322). Subgroup analyses demonstrated that especially women and the group fulfilling the criteria for both migraine with and without aura were likely to have additional disorders besides their migraine. Interestingly, male migraineurs with aura reported a significant association with stroke and epilepsy. Familial migraine is comorbid with hypotension, allergy and psychiatric disorders. The association between migraine with aura and stroke and epilepsy among men of the studied families warrants further study. Clinical, pathophysiological and genetic implications of these results are discussed.

Chromosome 19p13 loci in Finnish migraine with aura families.

Chromosomal area 19p13 contains two migraine associated genes: a Ca(v)2.1 (P/Q-type) calcium channel alpha(1) subunit gene, CACNA1A, and an insulin receptor gene, INSR. Missense mutations in CACNA1A cause a rare Mendelian form of migraine, familial hemiplegic migraine type 1 (FHM1). Contribution of CACNA1A locus has also been studied in the common forms of migraine, migraine with (MA) and without aura (MO), but the results have been contradictory. The role of INSR is less well established: A region on 19p13 separate from CACNA1A was recently reported to be a major locus for migraine and subsequently, the INSR gene was associated with MA and MO. Our aim was to clarify the role of these loci in MA families by analyzing 72 multigenerational Finnish MA families, the largest family sample so far. We hypothesized that the potential major contribution of the 19p13 loci should be detected in a family sample of this size, and this was confirmed by simulations. We genotyped eight polymorphic microsatellite markers surrounding the INSR and CACNA1A genes on 757 individuals. Using parametric and non-parametric linkage analysis, none of the studied markers showed any evidence of linkage to MA either under locus homogeneity or heterogeneity. However, marginally positive lod scores were observed in three families, and thus for these families the results remain inconclusive. The overall conclusion is that our study did not provide evidence of a major MA susceptibility region on 19p13 and thus we were not able to replicate the INSR locus finding.