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  • Burman, Janne; Palosuo, Kati; Kukkonen, Kaarina; Pelkonen, Anna; Makela, Mika J. (2019)
  • Yeo, L.; Pujol-Autonell, I.; Baptista, R.; Eichmann, M.; Kronenberg-Versteeg, D.; Heck, S.; Dolton, G.; Sewell, A. K.; Härkönen, T.; Mikk, M. -L.; Toppari, J.; Veijola, R.; Knip, M.; Ilonen, J.; Peakman, M. (2020)
    In type 1 diabetes (T1D), autoreactive cytotoxic CD8(+) T cells are implicated in the destruction of insulin-producing beta cells. The HLA-B*3906 and HLA-A*2402 class I genes confer increased risk and promote early disease onset, suggesting that CD8(+) T cells that recognize peptides presented by these class I molecules on pancreatic beta cells play a pivotal role in the autoimmune response. We examined the frequency and phenotype of circulating preproinsulin (PPI)-specific and insulin B (InsB)-specific CD8(+) T cells in HLA-B*3906(+) children newly diagnosed with T1D and in high-risk HLA-A*2402(+) children before the appearance of disease-specific autoantibodies and before diagnosis of T1D. Antigen-specific CD8(+) T cells were detected using human leucocyte antigen (HLA) class I tetramers and flow cytometry was used to assess memory status. In HLA-B*3906(+) children with T1D, we observed an increase in PPI5-12-specific transitional memory CD8(+) T cells compared to non-diabetic, age- and HLA-matched subjects. Furthermore, PPI5-12-specific CD8(+) T cells in HLA-B*3906(+) children with T1D showed a significantly more antigen-experienced phenotype compared to polyclonal CD8(+) T cells. In longitudinal samples from high-risk HLA-A*2402(+) children, the percentage of terminal effector cells within the InsB(15-24)-specific CD8(+) T cells was increased before diagnosis relative to samples taken before the appearance of autoantibodies. This is the first study, to our knowledge, to report HLA-B*3906-restricted autoreactive CD8(+) T cells in T1D. Collectively, our results provide evidence that beta cell-reactive CD8(+) T cells restricted by disease-associated HLA class I molecules display an antigen-experienced phenotype and acquire enhanced effector function during the period leading to clinical diagnosis, implicating these cells in driving disease.
  • Turunen, Katri; Antikainen, Jenni; Lääveri, Tinja; Kirveskari, Juha; Svennerholm, Ann-Mari; Kantele, Anu (2020)
    Background: Enterotoxigenic Escherichia coli (ETEC) is a major pathogen causing travellers' diarrhoea (TD) among visitors to low- and middle-income countries (LMIC). Scant data are available on rates of travel-acquired ETEC producing heat-labile (LT) and/or heat-stable (ST) toxin or its subtypes, STh (human) and STp (porcine) in various geographic regions, and on clinical pictures associated with each toxin. Methods: Using qPCR, we analysed LT, STh, and STp in stools positive for ETEC in a prospective study among 103 Finnish travellers visiting LMIC. They filled in questionnaires and provided stool samples before and after travel. We scrutinized geographic distribution of LT, STh, and STp ETEC findings, and association between these different ETEC subtypes and moderate/severe TD. Results: Among the 103 stool samples positive for ETEC toxins, the rate for LT was 76%, for STh 26%, and STp 41%. The rate for LT-only was 44%, for 5Th-only 6%, STp-only 16%, LT + STh 10%, LT + STp 15%, STh + STp 3%, and LT + STh + STp 8%. Findings varied by destination; the rates of LT, STh, and STp were 79%, 21%, and 57%, respectively, in Southern Asia (n = 14); 85%, 10%, and 20% in South-eastern Asia (n = 20); 84%, 13%, and 29% in Eastern Africa (n = 31); and 56%, 50%, and 63% in Western Africa (n = 32), respectively. Of travellers positive for LT, STh, and STp, 83%, 100%, and 88%, encountered TD; 35%, 55%, and 41% reported moderate/severe TD. STh was associated with moderate/severe TD. Conclusions: Toxin findings varied by destination; multiple toxins were commonly detected. Moderate/severe TD was reported most frequently by subjects with STh-ETEC.
  • Lauper, Kim; Mongin, Denis; Iannone, Florenzo; Kristianslund, Eirik K.; Kvien, Tore K.; Nordström, Dan C.; Pavelka, Karel; Pombo-Suarez, Manuel; Rotar, Ziga; Santos, Maria J.; Codreanu, Catalin; Lukina, Galina; Gale, Sara L.; John, Markus; Luder, Yves; Courvoisier, Delphine S.; Gabay, Cem (2020)
    Objectives To compare treatment effectiveness in rheumatoid arthritis (RA) patients naïve to biological disease-modifying antirheumatic drugs (bDMARDs) treated with tocilizumab (TCZ) or TNF-inhibitor (TNFi) with (-combo) or without (-mono) conventional synthetic DMARDs (csDMARDs). Methods Patients with RA across 7 European registries, naïve to bDMARDs who initiated treatment with TCZ or TNFi from 2009 to 2016 were included. Drug retention rate was analyzed using Kaplan–Meier and Cox models, and CDAI over time by mixed models. The proportions of patients reaching CDAI low disease activity (LDA) and remission after one year were corrected for attrition. Results 6713 TNFi-combo, 3762 TNFi-mono, 646 TCZ-combo and 384 TCZ-mono were eligible. Crude median retention was 3.67 years (95%CI 3.41-3.83) for TNFi-combo, 4.14 (3.77-4.62) for TNFi-mono, 2.98 (2.76-3.34) for TCZ-combo and 3.63 years (3.34-5.03) for TCZ-mono. After adjustment for covariates, country and year of treatment initiation stratification, hazards of discontinuation were lower for TCZ-mono (0.60, 95% CI 0.52-0.69) and TCZ-combo (0.66, 95% CI 0.54-0.81) compared to TNFi-combo. Adjusted CDAI evolution was not significantly different between groups. CDAI LDA and remission corrected for attrition were similar between TCZ with or without csDMARDs and TNFi-combo. Conclusion In routine care across 7 European countries, the adjusted drug retention, adjusted CDAI over time and attrition-corrected response proportion for RA patients were similar for bio-naïve patients if treated with TNFi-combo, TCZ-combo or TCZ-mono.
  • Swann, J. R.; Rajilic-Stojanovic, M.; Salonen, A.; Sakwinska, O.; Gill, C.; Meynier, A.; Fanca-Berthon, P.; Schelkle, B.; Segata, N.; Shortt, C.; Tuohy, K.; Hasselwander, O. (2020)
    With the growing appreciation for the influence of the intestinal microbiota on human health, there is increasing motivation to design and refine interventions to promote favorable shifts in the microbiota and their interactions with the host. Technological advances have improved our understanding and ability to measure this indigenous population and the impact of such interventions. However, the rapid growth and evolution of the field, as well as the diversity of methods used, parameters measured and populations studied, make it difficult to interpret the significance of the findings and translate their outcomes to the wider population. This can prevent comparisons across studies and hinder the drawing of appropriate conclusions. This review outlines considerations to facilitate the design, implementation and interpretation of human gut microbiota intervention studies relating to foods based upon our current understanding of the intestinal microbiota, its functionality and interactions with the human host. This includes parameters associated with study design, eligibility criteria, statistical considerations, characterization of products and the measurement of compliance. Methodologies and markers to assess compositional and functional changes in the microbiota, following interventions are discussed in addition to approaches to assess changes in microbiota-host interactions and host responses. Last, EU legislative aspects in relation to foods and health claims are presented. While it is appreciated that the field of gastrointestinal microbiology is rapidly evolving, such guidance will assist in the design and interpretation of human gut microbiota interventional studies relating to foods.
  • Murtojärvi, Mika; Halkola, Anni S.; Airola, Antti; Laajala, Teemu D.; Mirtti, Tuomas; Aittokallio, Tero; Pahikkala, Tapio (2020)
    Introduction Predictive survival modeling offers systematic tools for clinical decision-making and individualized tailoring of treatment strategies to improve patient outcomes while reducing overall healthcare costs. In 2015, a number of machine learning and statistical models were benchmarked in the DREAM 9.5 Prostate Cancer Challenge, based on open clinical trial data for metastatic castration resistant prostate cancer (mCRPC). However, applying these models into clinical practice poses a practical challenge due to the inclusion of a large number of model variables, some of which are not routinely monitored or are expensive to measure. Objectives To develop cost-specified variable selection algorithms for constructing cost-effective prognostic models of overall survival that still preserve sufficient model performance for clinical decision making. Methods Penalized Cox regression models were used for the survival prediction. For the variable selection, we implemented two algorithms: (i) LASSO regularization approach; and (ii) a greedy cost-specified variable selection algorithm. The models were compared in three cohorts of mCRPC patients from randomized clinical trials (RCT), as well as in a real-world cohort (RWC) of advanced prostate cancer patients treated at the Turku University Hospital. Hospital laboratory expenses were utilized as a reference for computing the costs of introducing new variables into the models. Results Compared to measuring the full set of clinical variables, economic costs could be reduced by half without a significant loss of model performance. The greedy algorithm outperformed the LASSO-based variable selection with the lowest tested budgets. The overall top performance was higher with the LASSO algorithm. Conclusion The cost-specified variable selection offers significant budget optimization capability for the real-world survival prediction without compromising the predictive power of the model.
  • Purmonen, Timo; Puolakka, Kari; Bhattacharyya, Devarshi; Jain, Minal; Martikainen, Janne (2018)
    ObjectiveTo study cost-effectiveness of an interleukin (IL)-17A inhibitor secukinumab, with other biologics and apremilast in patients with Psoriatic arthritis (PsA) from payer perspective in Finland.MethodsIn this semi-Markov model, subcutaneous (SC) secukinumab was compared with SC treatments etanercept and its biosimilar, certolizumab pegol, adalimumab and its biosimilar, golimumab, ustekinumab, intravenous (IV) treatment infliximab, as well as oral non-biologic apremilast. Patients without prior exposure (naive) to biologics and without moderate to severe psoriasis were considered for secukinumab 150mg group. Secukinumab 300mg group included naive patients with moderate to severe psoriasis and all patients with prior biologic exposure. The PsA Response Criteria (PsARC) at 12-week was primary criteria for treatment response. Other clinical as well as cost related model inputs were derived from relevant clinical trials as well as Finnish publications. The key model outcomes were quality-adjusted life years and incremental cost-effectiveness ratio. An annual 3% discount rate was applied to all future costs and benefits. Model input variations were assessed through sensitivity analyses and alternative scenario analyses.ResultsFor a lifetime horizon (60years), secukinumab 150mg dominated all branded SC biologics and apremilast with highest QALY of 8.01 and lowest lifetime cost of Euro187,776, while it was cost-effective against IV infliximab among biologic-naive patients without moderate to severe psoriasis. Secukinumab 300mg was cost-effective against all branded SC biologics and apremilast and dominated IV infliximab among biologic-naive patients with moderate to severe psoriasis, while it was cost-effective in biologic experienced patients. With the one-way sensitivity analysis, PsARC response, drug acquisition cost, and health assessment questionnaire score were the most important parameters affecting the outcomes. Across all treatment groups, patients on secukinumab were most likely to achieve highest net monetary benefit than other competitors in probabilistic sensitivity analysis. With alternative scenario analysis, results largely remained unchanged.ConclusionsSecukinumab is a cost-effective treatment for PsA patients from a Finnish payer's perspective.
  • EFSA Panel Dietetic Prod Nutr; Heinonen, Marina (2017)
    Following an application from Suomen Terveysravinto Oy, submitted for authorisation of a health claim pursuant to Article 13(5) of Regulation (EC) No 1924/2006 via the Competent Authority of Finland, the EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA) was asked to deliver an opinion on the scientific substantiation of a health claim related to curcumin and normal functioning of joints. The food that is proposed as the subject of the health claim is curcumin. The Panel considers that curcumin is sufficiently characterised. The claimed effect proposed by the applicant is 'normal functioning of joints by reducing the biomarkers of inflammation'. The target population proposed by the applicant is the general population. Upon a request from EFSA to clarify whether the claimed effect is related to the normal function of joints or rather to the reduction of inflammation, the applicant did not address this issue in the reply. The Panel assumes that the claimed effect refers to the maintenance of joint function. The Panel considers that maintenance of joint function is a beneficial physiological effect. The Panel considers that no conclusions can be drawn from 15 human intervention studies conducted in patients with osteoarthritis or rheumatoid arthritis and from one study in obese subjects on serum cytokines for the scientific substantiation of the claim. In the absence of evidence for an effect of curcumin on the normal function of joints in humans, the results of the human studies on curcumin pharmacokinetics, safety and mechanistic studies, the animal studies and the in vitro studies submitted by the applicant cannot be used as a source of data for the scientific substantiation of the claim. The Panel concludes that a cause and effect relationship has not been established between the consumption of curcumin and maintenance of joint function. (C) 2017 European Food Safety Authority.
  • Pett, Helmi; Bradley, John; Okebe, Joseph; Dicko, Alassane; Tiono, Alfred B.; Goncalves, Bronner P.; Stone, Will; Chen, Ingrid; Lanke, Kjerstin; Neuvonen, Mikko; Mustaniemi, Anna-Liina; Eziefula, Alice C.; Gosling, Roly; D'Alessandro, Umberto; Drakeley, Chris; Niemi, Mikko; Bousema, Teun (2019)
    Single-dose primaquine (PQ) clears mature gametocytes and reduces the transmission of Plasmodium fakiparurn after artemisinin combination therapy. Genetic variation in CYP2D6, the gene producing the drug-metabolizing enzyme cytochrome P450 2D6 (CYP2D6), influences plasma concentrations of PQ and its metabolites and is associated with PQ treatment failure in Plasmodium vivax malaria. Using blood and saliva samples of varying quantity and quality from 8 clinical trials across Africa (n = 1,076), we were able to genotype CYP2D6 for 774 samples (72%). We determined whether genetic variation in CYP2D6 has implications for PQ efficacy in individuals with gametocytes at the time of PQ administration (n = 554) and for safety in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals treated with PQ (n = 110). Individuals with a genetically inferred CYP2D6 poor/intermediate metabolizer status had a higher gametocyte prevalence on day 7 or 10 after PQ than those with an extensive/ultrarapid CYP2D6 metabolizer status (odds ratio [OR] = 1.79 [95% confidence interval {CI}, 1.10, 2.90]; P = 0.018). The mean minimum hemoglobin concentrations during follow-up for G6PD-deficient individuals were 11.8 g/dl for CYP2D6 extensive/ultrarapid metabolizers and 12.1 g/dl for CYP2D6 poor/intermediate metabolizers (P = 0. 803). CYP2D6 genetically inferred metabolizer status was also not associated with anemia following PQ treatment (P = 0.331). We conclude that CYP2D6 poor/intermediate metabolizer status may be associated with prolonged gametocyte carriage after treatment with single-low-dose PQ but not with treatment safety.
  • Lääveri, Tinja; Vilkman, Katri; Pakkanen, Sari; Kirveskari, Juha; Kantele, Anu (2018)
    Background: Among visitors to the (sub)tropics, 20-50% contract travellers' diarrhoea (TD) and 5-30% take antibiotics. While shortening the duration of illness, antimicrobials predispose to acquisition of multi-drug resistant bacteria. Therefore, liberal use is no longer advocated. Although antibiotics kill pathogens, no data support the view that they could prevent post-infectious sequelae. We investigated how antibiotic use for TD abroad impacts the pathogen findings at return. Materials and methods: We revisited 456 travellers' clinical data and stool pathogens examined by qPCR for Salmonella, Yersinia, Campylobacter, Shigella, Vibrio cholerae and enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enterohaemorrhagic (EHEC) and enteroinvasive (EIEC) Escherichia coli. Results: Among travellers with TD, antibiotic users had pathogen-positive samples less frequently than non-users (50% versus 83%). The difference was significant for EPEC (23% versus 47%) and EAEC (27% versus 54%), but not ETEC (17% versus 26%) or the other pathogens. Shigella/EIEC was found more often among antibiotic users than non-users (4% versus 1%). Conclusion: Despite antibiotic treatment of TD, half of the users still had stool pathogens at return, reflecting either antibiotic resistance of pathogens or recolonisation/reinfection while abroad. Treatment of TD with antibiotics during travel should not be interpreted to indicate eradication of pathogens.
  • Malm, Maria; Hyoty, Heikki; Knip, Mikael; Vesikari, Timo; Blazevic, Vesna (2019)
    Most of the research effort to understand protective immunity against norovirus (NoV) has focused on humoral immunity, whereas immunity against another major pediatric enteric virus, rotavirus (RV), has been studied more thoroughly. The aim of this study was to investigate development of cell-mediated immunity to NoV in early childhood. Immune responses to NoV GI.3 and GII. 4 virus-like particles and RV VP6 were determined in longitudinal blood samples of 10 healthy children from three months to four years of age. Serum IgG antibodies were measured using enzyme-linked immunosorbent assay and production of interferon-gamma by peripheral blood T cells was analyzed by enzyme-linked immunospot assay. NoV-specific T cells were detected in eight of 10 children by the age of four, with some individual variation. T cell responses to NoV GII.4 were higher than those to GI.3, but these responses were generally lower than responses to RV VP6. In contrast to NoV-specific antibodies, T cell responses were transient in nature. No correlation between cell-mediated and antibody responses was observed. NoV exposure induces vigorous T cell responses in children under five years of age, similar to RV. A role of T cells in protection from NoV infection in early childhood warrants further investigation.
  • Kankaanranta, Hannu; Harju, Terttu; Kilpelainen, Maritta; Mazur, Witold; Lehto, Juho T.; Katajisto, Milla; Peisa, Timo; Meinander, Tuula; Lehtimeki, Lauri (2015)
  • Hemilä, Harri (2017)
    Background: The relative scale has been used for decades in analysing binary data in epidemiology. In contrast, there has been a long tradition of carrying out meta-analyses of continuous outcomes on the absolute, original measurement, scale. The biological rationale for using the relative scale in the analysis of binary outcomes is that it adjusts for baseline variations; however, similar baseline variations can occur in continuous outcomes and relative effect scale may therefore be often useful also for continuous outcomes. The aim of this study was to determine whether the relative scale is more consistent with empirical data on treating the common cold than the absolute scale. Methods: Individual patient data was available for 2 randomized trials on zinc lozenges for the treatment of the common cold. Mossad (Ann Intern Med 125:81-8, 1996) found 4.0 days and 43% reduction, and Petrus (Curr Ther Res 59:595-607, 1998) found 1.77 days and 25% reduction, in the duration of colds. In both trials, variance in the placebo group was significantly greater than in the zinc lozenge group. The effect estimates were applied to the common cold distributions of the placebo groups, and the resulting distributions were compared with the actual zinc lozenge group distributions. Results: When the absolute effect estimates, 4.0 and 1.77 days, were applied to the placebo group common cold distributions, negative and zero (i.e., impossible) cold durations were predicted, and the high level variance remained. In contrast, when the relative effect estimates, 43 and 25%, were applied, impossible common cold durations were not predicted in the placebo groups, and the cold distributions became similar to those of the zinc lozenge groups. Conclusions: For some continuous outcomes, such as the duration of illness and the duration of hospital stay, the relative scale leads to a more informative statistical analysis and more effective communication of the study findings. The transformation of continuous data to the relative scale is simple with a spreadsheet program, after which the relative scale data can be analysed using standard meta-analysis software. The option for the analysis of relative effects of continuous outcomes directly from the original data should be implemented in standard meta-analysis programs.
  • Reinders, Ilse; Wijnhoven, Hanneke A. H.; Jyväkorpi, Satu K.; Suominen, Merja H.; Niskanen, Riikka; Bosmans, Judith E.; Brouwer, Ingeborg A.; Fluitman, Kristien S.; Klein, Michel C. A.; Kuijper, Lothar D.; van der Lubbe, Laura M.; Olthof, Margreet R.; Pitkälä, Kaisu H.; Vijlbrief, Rachel; Visser, Marjolein (2020)
    Introduction Short-term metabolic and observational studies suggest that protein intake above the recommended dietary allowance of 0.83 g/kg body weight (BW)/day may support preservation of lean body mass and physical function in old age, but evidence from randomised controlled trials is inconclusive. Methods and analysis The PRevention Of Malnutrition In Senior Subjects in the EU (PROMISS) trial examines the effect of personalised dietary advice aiming at increasing protein intake with or without advice regarding timing of protein intake to close proximity of usual physical activity, on change in physical functioning after 6 months among community-dwelling older adults (>= 65 years) with a habitual protein intake of Discussion The PROMISS trial will provide evidence whether increasing protein intake, and additionally optimising the timing of protein intake, has a positive effect on the course of physical functioning after 6 months among community-dwelling older adults with a habitual protein intake of Ethics and dissemination The study has been approved by the Ethics Committee of the Helsinki University Central Hospital, Finland (ID of the approval: HUS/1530/2018) and The Medical Ethical Committee of the Amsterdam UMC, location VUmc, Amsterdam, the Netherlands (ID of the approval: 2018.399). All participants provided written informed consent prior to being enrolled onto the study. Results will be submitted for publication in peer-reviewed journals and will be made available to stakeholders (ie, older adults, healthcare professionals and industry).
  • Lindström, Ulf; Di Giuseppe, Daniela; Delcoigne, Benedicte; Glintborg, Bente; Moller, Burkhard; Ciurea, Adrian; Pombo-Suarez, Manuel; Sanchez-Piedra, Carlos; Eklund, Kari; Relas, Heikki; Gudbjornsson, Bjorn; Love, Thorvardur Jon; Jones, Gareth T.; Codreanu, Catalin; Ionescu, Ruxandra; Nekvindova, Lucie; Zavada, Jakub; Atas, Nuh; Yolbas, Servet; Fagerli, Karen Minde; Michelsen, Brigitte; Rotar, Ziga; Tomsic, Matija; Iannone, Florenzo; Santos, Maria Jose; Avila-Ribeiro, Pedro; Ornbjerg, Lykke Midtboll; Ostergaard, Mikkel; Jacobsson, Lennart T. H.; Askling, Johan; Nissen, Michael J. (2021)
    Background Comedication with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) during treatment with tumour necrosis factor inhibitors (TNFi) is extensively used in psoriatic arthritis (PsA), although the additive benefit remains unclear. We aimed to compare treatment outcomes in patients with PsA treated with TNFi and csDMARD comedication versus TNFi monotherapy. Methods Patients with PsA from 13 European countries who initiated a first TNFi in 2006-2017 were included. Country-specific comparisons of 1 year TNFi retention were performed by csDMARD comedication status, together with HRs for TNFi discontinuation (comedication vs monotherapy), adjusted for age, sex, calendar year, disease duration and Disease Activity Score with 28 joints (DAS28). Adjusted ORs of clinical remission (based on DAS28) at 12 months were calculated. Between-country heterogeneity was assessed using random-effect meta-analyses, combined results were presented when heterogeneity was not significant. Secondary analyses stratified according to TNFi subtype (adalimumab/infliximab/etanercept) and restricted to methotrexate as comedication were performed. Results In total, 15 332 patients were included (62% comedication, 38% monotherapy). TNFi retention varied across countries, with significant heterogeneity precluding a combined estimate. Comedication was associated with better remission rates, pooled OR 1.25 (1.12-1.41). Methotrexate comedication was associated with improved remission for adalimumab (OR 1.45 (1.23-1.72)) and infliximab (OR 1.55 (1.21-1.98)) and improved retention for infliximab. No effect of comedication was demonstrated for etanercept. Conclusion This large observational study suggests that, as used in clinical practice, csDMARD and TNFi comedication are associated with improved remission rates, and specifically, comedication with methotrexate increases remission rates for both adalimumab and infliximab.
  • Gabay, Cem; Riek, Myriam; Hetland, Merete Lund; Hauge, Ellen-Margrethe; Pavelka, Karel; Tomsic, Matija; Canhao, Helena; Chatzidionysiou, Katerina; Lukina, Galina; Nordstrom, Dan C.; Lie, Elisabeth; Ancuta, Ioan; Victoria Hernandez, M.; van Riel, Piet L. M. C.; van Vollenhoven, Ronald; Kvien, Tore K. (2016)
    Objectives To examine the effectiveness of tocilizumab (TCZ) with and without synthetic disease-modifying antirheumatic drugs (sDMARDs) in a large observational study. Methods Patients with rheumatoid arthritis treated with TCZ who had a baseline visit and information on concomitant sDMARDs were included. According to baseline data, patients were considered as taking TCZ as monotherapy or combination with sDMARDs. Main study outcomes were the change of Clinical Disease Activity Index (CDAI) and TCZ retention. The prescription of TCZ as monotherapy was analysed using logistic regression. CDAI change was analysed with a mixed-effects model for longitudinal data. TCZ retention was analysed with a stratified extended Cox model. Results Multiple-adjusted analysis suggests that prescription of TCZ as monotherapy varied according to age, corticosteroid use, country of the registry and year of treatment initiation. The change of disease activity assessed by CDAI as well as the likelihood to be in remission were not significantly different whether TCZ was used as monotherapy or in combination with sDMARDs in a covariate-adjusted analysis. Estimates for unadjusted median TCZ retention were 2.3 years (95% CI 1.8 to 2.7) for monotherapy and 3.7 years (lower 95% CI limit 3.1, upper limit not estimable) for combination therapies. In a covariate-adjusted analysis, TCZ retention was also reduced when used as monotherapy, with an increasing difference between mono and combination therapy over time after 1.5 years (p=0.002). Conclusions TCZ with or without concomitant sDMARDs resulted in comparable clinical response as assessed by CDAI change, but TCZ retention was shorter under monotherapy of TCZ.
  • Chatzidionysiou, Katerina; Lie, Elisabeth; Nasonov, Evgeny; Lukina, Galina; Hetland, Merete Lund; Tarp, Ulrik; Ancuta, Ioan; Pavelka, Karel; Nordstrom, Dan C.; Gabay, Cem; Canhao, Helene; Tomsic, Matija; van Riel, Piet L. C. M.; Gomez-Reino, Juan; Kvien, Tore K.; van Vollenhoven, Ronald F.; Rheumatic Dis Portuguese Register (2016)
    Background: The approved dose of rituximab (RTX) in rheumatoid arthritis is 1000 mg x 2, but some data have suggested similar clinical efficacy with 500 mg x 2. The purpose of this study was to compare the effectiveness of the regular and low doses given as first treatment course. Methods: Twelve European registries participating in the CERERRA collaboration (The European Collaborative Registries for the Evaluation of Rituximab in Rheumatoid Arthritis) submitted anonymized datasets with demographic, efficacy and treatment data for patients who had started RTX. Treatment effectiveness was assessed by DAS28 reductions and EULAR responses after 6 months. Results: Data on RTX dose were available for 2,873 patients, of whom 2,625 (91.4 %) and 248 (8.6 %) received 1000 mg x 2 and 500 mg x 2, respectively. Patients treated with 500 mg x 2 were significantly older, had longer disease duration, higher number of prior DMARDs, but lower number of prior biologics and lower baseline DAS28 than those treated with 1000 mg x 2. Fewer patients in the low-dose group received concomitant DMARDs but more frequently received concomitant corticosteroids. Both doses led to significant clinical improvements at 6 months. DAS28 reductions at 6 months were comparable in the 2 dose regimens [mean DeltaDAS28 +/- SD -2.0 +/- 1.3 (high dose) vs. -1.7 +/- 1.4 (low dose), p = 0.23 adjusted for baseline differences]. Similar percentages of patients achieved EULAR good response in the two dose groups, 18.4 % vs. 17.3 %, respectively (p = 0.36). Conclusions: In this large observational cohort initial treatment with RTX at 500 mg x 2 and 1000 mg x 2 led to comparable clinical outcomes at 6 months.
  • Lehtinen, Matti; Apter, Dan; Eriksson, Tiina; Harjula, Katja; Hokkanen, Mari; Natunen, Kari; Nieminen, Pekka; Paavonen, Jorma; Palmroth, Johanna; Petaja, Tiina; Pukkala, Eero; Vänskä, Simopekka; Cheuvart, Brigitte; Soila, Maaria; Bi, Dan; Struyf, Frank (2021)
    Introduction We conducted a community-randomized trial (NCTBLINDED) in Finland to assess gender-neutral and girls-only vaccination strategies with the AS04-adjuvanted human papillomavirus (HPV)-16/18 (AS04-HPV-16/18)vaccine. Methods Girls and boys (12-15 years) were invited. We randomized 33 communities (1:1:1 ratio): Arm A: 90% of randomly selected girls and boys received AS04-HPV-16/18 vaccine and 10% received hepatitis B vaccine (HBV); Arm B: 90% of randomly selected girls received AS04-HPV-16/18 vaccine, 10% of girls received HBV, and all boys received HBV; Arm C: all participants received HBV. Effectiveness measurements against prevalence of HPV-16/18 cervical infection were estimated in girls at 18.5 years. The main measures were: (1) overall effectiveness comparing Arms A or B, regardless of vaccination status, vs Arm C; (2) total effectiveness comparing AS04-HPV-16/18 vaccinated girls in pooled Arms A/B vs Arm C; (3) indirect effectiveness (herd effect) comparing girls receiving HBV or unvaccinated in Arm A vs Arm C. Co-primary objectives were overall effectiveness following gender-neutral or girls-only vaccination. Results Of 80,272 adolescents invited, 34,412 were enrolled. Overall effectiveness was 23.8% (95% confidence interval: -19.0, 51.1; P = 0.232) with gender-neutral vaccination. Following girls-only vaccination, overall effectiveness was 49.6% (20.1, 68.2; P = 0.004). Total effectiveness was over 90% regardless of vaccination strategy. No herd effect was found. Immunogenicity of the AS04-HPV-16/18 vaccine was high in both sexes. Conclusions This study illustrates the difficulty in conducting community randomized trials. It is not plausible that vaccinating boys would reduce overall effectiveness, and the apparent lack of herd effect was unexpected given findings from other studies. This analysis was likely confounded by several factors but confirms the vaccine's high total effectiveness as in clinical trials.
  • Wardlaw, Joanna M; Debette, Stephanie; Jokinen, Hanna; De Leeuw, Frank-Erik; Pantoni, Leonardo; Chabriat, Hugues; Staals, Julie; Doubal, Fergus; Rudilosso, Salvatore; Eppinger, Sebastian; Schilling, Sabrina; Ornello, Raffaele; Enzinger, Christian; Cordonnier, Charlotte; Taylor-Rowan, Martin; Lindgren, Arne G. (2021)
    'Covert' cerebral small vessel disease (ccSVD) is common on neuroimaging in persons without overt neurological manifestations, and increases the risk of future stroke, cognitive impairment, dependency, and death. These European Stroke Organisation (ESO) guidelines provide evidence-based recommendations to assist with clinical decisions about management of ccSVD, specifically white matter hyperintensities and lacunes, to prevent adverse clinical outcomes. The guidelines were developed according to ESO standard operating procedures and Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. We prioritised the clinical outcomes of stroke, cognitive decline or dementia, dependency, death, mobility and mood disorders, and interventions of blood pressure lowering, antiplatelet drugs, lipid lowering, lifestyle modifications, glucose lowering and conventional treatments for dementia. We systematically reviewed the literature, assessed the evidence, formulated evidence-based recommendations where feasible, and expert consensus statements. We found little direct evidence, mostly of low quality. We recommend patients with ccSVD and hypertension to have their blood pressure well controlled; lower blood pressure targets may reduce ccSVD progression. We do not recommend antiplatelet drugs such as aspirin in ccSVD. We found little evidence on lipid lowering in ccSVD. Smoking cessation is a health priority. We recommend regular exercise which may benefit cognition, and a healthy diet, good sleep habits, avoiding obesity and stress for general health reasons. In ccSVD, we found no evidence for glucose control in the absence of diabetes or for conventional Alzheimer dementia treatments. Randomised controlled trials with clinical endpoints are a priority for ccSVD.
  • Bassetti, Claudio L. A.; Kallweit, Ulf; Vignatelli, Luca; Plazzi, Giuseppe; Lecendreux, Michel; Baldin, Elisa; Dolenc-Groselj, Leja; Jennum, Poul; Khatami, Ramin; Manconi, Mauro; Mayer, Geert; Partinen, Markku; Pollmaecher, Thomas; Reading, Paul; Santamaria, Joan; Sonka, Karel; Dauvilliers, Yves; Lammers, Gert J. (2021)
    Background and purpose Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. Methods The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. Results A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. Conclusion The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.