Real-world overall survival after alternative dosing for pembrolizumab in the treatment of non-small cell lung cancer: A nationwide retrospective cohort study with a non-inferiority primary objective.

BACKGROUND: High and increasing expenses on pembrolizumab ask for more cost-effective and sustainable treatment strategies to improve affordability of healthcare. Therefore, a part of the Dutch hospitals implemented an alternative, partially lower, weight-based dosing protocol for pembrolizumab. This provided the unique opportunity to compare the overall survival (OS) of the alternative pembrolizumab dosing protocol to standard dosing using a nationwide registry in non-small cell lung cancer (NSCLC) patients. METHODS: This is a retrospective cohort study with a non-inferiority primary objective. Forty hospitals in the Dutch Medication Audit and Dutch Lung Cancer Audit treated 1966 patients with NSCLC with first line pembrolizumab (mono- or combination therapy) between Jan 1st 2021, and Mar 31st, 2023. Alternative weight-based pembrolizumab dosing (100/150/200 mg Q3W or 200/300/400 mg Q6W) was administered to 604 patients, and 1362 patients received standard pembrolizumab dosing (200 mg Q3W or 400 mg Q6W). A Cox proportional hazard model with selected covariates was used to compare the OS between alternative and standard dosing protocols. The non-inferiority margin was set at a hazard ratio (HR) of 1.2 for OS. Non-inferiority is established by showing that the upper limit of the 95 % confidence interval (CI) of the HR of OS is smaller or equal to 1.2. RESULTS: Distribution of age (66.7 years +/-9.4), sex (45 % female) and treatment combinations were similar for both groups, comorbidity score was higher in the standard group. Median daily dose in the alternative dosing group was 22 % lower compared to the standard dosing group, 7.14 mg/day (interquartile range (IQR):5.48-8.04 mg/day) vs. 9.15 mg/day (IQR:8.33-9.52 mg/day), respectively. Alternative dosing was non-inferior to standard dosing regarding overall survival (adjusted HR 0.83, 95 %CI:0.69-1.003). CONCLUSION: This large, retrospective real-world analysis supports the hypothesis that the alternative, partially lower pembrolizumab dosing protocol in NSCLC maintains treatment effectiveness while reducing treatment costs.

Discovering novel germline genetic variants linked to severe fluoropyrimidine-related toxicity in- and outside DPYD.

BACKGROUND: The Alpe-DPD study (NCT02324452) demonstrated that prospective genotyping and dose-individualization using four alleles in DPYD (DPYD*2A/rs3918290, c.1236G > A/rs75017182, c.2846A > T/rs67376798 and c.1679 T > G/rs56038477) can mitigate the risk of severe fluoropyrimidine toxicity. However, this could not prevent all toxicities. The goal of this study was to identify additional genetic variants, both inside and outside DPYD, that may contribute to fluoropyrimidine toxicity. METHODS: Biospecimens and data from the Alpe-DPD study were used. Exon sequencing was performed to identify risk variants inside DPYD. In silico and in vitro analyses were used to classify DPYD variants. A genome-wide association study (GWAS) with severe fluoropyrimidine-related toxicity was performed to identify variants outside DPYD. Association with severe toxicity was assessed using matched-pair analyses for the exon sequencing and logistic, Cox, and ordinal regression analyses for GWAS. RESULTS: Twenty-four non-synonymous, frameshift, and splice site DPYD variants were detected in ten of 986 patients. Seven of these variants (c.1670C > T, c.1913 T > C, c.1925 T > C, c.506delC, c.731A > C, c.1740 + 1G > T, c.763 - 2A > G) were predicted to be deleterious. The carriers of either of these variants showed a trend towards a 2.14-fold (95% CI, 0.41-11.3, P = 0.388) increased risk of severe toxicity compared to matched controls (N = 30). After GWAS of 942 patients, no individual single nucleotide polymorphisms achieved genome-wide significance (P ≤ 5 × 10-8), however, five variants were suggestive of association (P < 5 × 10-6) with severe toxicity. CONCLUSIONS: Results from DPYD exon sequencing and GWAS analysis did not identify additional genetic variants associated with severe toxicity, which suggests that testing for single markers at a population level currently has limited clinical value. Identifying additional variants on an individual level is still promising to explain fluoropyrimidine-related severe toxicity. In addition, studies with larger samples sizes, in more diverse cohorts are needed to identify potential clinically relevant genetic variants related to severe fluoropyrimidine toxicity.

Exploring the contribution of genetic variants to high sunitinib exposure in patients with cancer.

AIMS: Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50-87.5 ng/mL for the intermittent dosing schedule, ~10-21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib. METHODS: This was a genome-wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose-normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P-value ≤5 × 10-8 was considered significant and a P-value between 5 × 10-8 and 5 × 10-6 was considered suggestive. RESULTS: Sixty-nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon-like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10-19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10-6). CONCLUSIONS: While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity.

A Genome-Wide Association Study of Endoxifen Serum Concentrations and Adjuvant Tamoxifen Efficacy in Early-Stage Breast Cancer Patients.

Tamoxifen is part of the standard of care of endocrine therapy for adjuvant treatment of breast cancer. However, survival outcomes with tamoxifen are highly variable. The concentration of endoxifen, the 30-100 times more potent metabolite of tamoxifen and bioactivated by the CYP2D6 enzyme, has been described as the most relevant metabolite of tamoxifen metabolism. A genome-wide association study (GWAS) was performed with the objective to identify genetic polymorphisms associated with endoxifen serum concentration levels and clinical outcome in early-stage breast cancer patients receiving tamoxifen. A GWAS was conducted in 608 women of the CYPTAM study (NTR1509/PMID: 30120701). Germline DNA and clinical and survival characteristics were readily available. Genotyping was performed on Infinium Global Screening Array (686,082 markers) and single nucleotide polymorphism (SNP) imputation by using 1000 Genomes. Relapse-free survival during tamoxifen (RFSt) was defined the primary clinical outcome. Endoxifen serum concentration was analyzed as a continuous variable. Several genetic variants reached genome-wide significance (P value: ≤5 × 10-8). Endoxifen concentrations analysis identified 430 variants, located in TCF20 and WBP2NL genes (chromosome 22), which are in strong linkage disequilibrium with CYP2D6 variants. In the RFSt analysis, several SNP were identified (LPP gene: rs77693286, HR 18.3, 95% CI: 15.2-21.1; rs6790761, OR 18.2, 95% CI: 15.5-21.1). Endoxifen concentrations have a strong association with the chromosome 22, which contains the CYP2D6 gene.

The impact of autoantibodies on the efficacy of biological disease-modifying anti-rheumatic drugs in rheumatoid arthritis: meta-analysis of randomized controlled trials.

OBJECTIVE: To investigate the efficacy of bDMARDs in patients with RA with RF/ACPA compared with patients without these autoantibodies. METHODS: Previous systematic literature reviews performed by EULAR RA management task forces were searched for qualifying RCTs. RCTs investigating the efficacy of bDMARDs and including both autoantibody-positive (≤80% of total population) and -negative RA patients were eligible. For trials comparing bDMARD+csDMARD vs csDMARD, relative risks (RR) comparing two groups (RF + vs RF-, ACPA+ vs ACPA-) were calculated for efficacy outcomes for each arm. Subsequently, relative risk ratios (RRRs) were computed, as the ratio of RR of the bDMARD-arm and the RR from the non-bDMARD-arm. Pooled effects were obtained with random effect meta-analyses. RESULTS: Data from 28 eligible RCTs were analyzed, pooling 23 studies in three subgroups: 6 including csDMARD-naïve patients, 14 csDMARD-IR, and 3 TNFi-IR patients. In csDMARD-naïve and csDMARD-IR patients, seropositivity was not associated with a better response to bDMARDs: pooled 6-month ACR20 RRRs 1.02 (0.88-1.18) and 1.09 (0.90-1.32), respectively. Other outcomes showed no difference between groups either. In TNFi-IR patients, based on 3 trials, the 6-month ACR20 RRR was 2.28 (1.31-3.95), favoring efficacy in seropositive patients. Other outcomes mostly showed no significant difference between the groups. Based on the mode of action, efficacy was comparable between RF-positive and RF-negative patients for both TNFi and non-TNFi treatment and also for the individual bDMARDs. CONCLUSION: The effect of bDMARDs is generally comparable in patients with and without RF/ACPA, regardless of the patient population, the mechanism of action or individual drug used.

Haplotype reconstruction for genetically complex regions with ambiguous genotype calls: Illustration by the KIR gene region.

Advances in DNA sequencing technologies have enabled genotyping of complex genetic regions exhibiting copy number variation and high allelic diversity, yet it is impossible to derive exact genotypes in all cases, often resulting in ambiguous genotype calls, that is, partially missing data. An example of such a gene region is the killer-cell immunoglobulin-like receptor (KIR) genes. These genes are of special interest in the context of allogeneic hematopoietic stem cell transplantation. For such complex gene regions, current haplotype reconstruction methods are not feasible as they cannot cope with the complexity of the data. We present an expectation-maximization (EM)-algorithm to estimate haplotype frequencies (HTFs) which deals with the missing data components, and takes into account linkage disequilibrium (LD) between genes. To cope with the exponential increase in the number of haplotypes as genes are added, we add three components to a standard EM-algorithm implementation. First, reconstruction is performed iteratively, adding one gene at a time. Second, after each step, haplotypes with frequencies below a threshold are collapsed in a rare haplotype group. Third, the HTF of the rare haplotype group is profiled in subsequent iterations to improve estimates. A simulation study evaluates the effect of combining information of multiple genes on the estimates of these frequencies. We show that estimated HTFs are approximately unbiased. Our simulation study shows that the EM-algorithm is able to combine information from multiple genes when LD is high, whereas increased ambiguity levels increase bias. Linear regression models based on this EM, show that a large number of haplotypes can be problematic for unbiased effect size estimation and that models need to be sparse. In a real data analysis of KIR genotypes, we compare HTFs to those obtained in an independent study. Our new EM-algorithm-based method is the first to account for the full genetic architecture of complex gene regions, such as the KIR gene region. This algorithm can handle the numerous observed ambiguities, and allows for the collapsing of haplotypes to perform implicit dimension reduction. Combining information from multiple genes improves haplotype reconstruction.

IGF1 and Insulin Receptor Single Nucleotide Variants Associated with Response in HER2-Negative Breast Cancer Patients Treated with Neoadjuvant Chemotherapy with or without a Fasting Mimicking Diet (BOOG 2013-04 DIRECT Trial).

AIM: We aimed to investigate associations between IGF1R and INSR single nucleotide variants (SNVs) and clinical response in patients with breast cancer treated with neoadjuvant chemotherapy with or without a fasting mimicking diet (FMD) from the DIRECT trial (NCT02126449), since insulin-like growth factor 1 (IGF1) and the insulin pathway are heavily involved in tumor growth and progression. METHODS: Germline DNA from 113 patients was tested for 17 systematically selected candidate SNVs in IGF1R and INSR with pathological and radiological response. RESULTS: IGF1R variants A > G (rs3743259) and G > A (rs3743258) are associated with worse pathological response compared to reference alleles p = 0.002, OR = 0.42 (95%CI: 0.24; 0.73); p = 0.0016; OR = 0.40 (95%CI: 0.23; 0.70). INSR T > C (rs1051690) may be associated with worse radiological response p = 0.02, OR = 2.92 (95%CI: 1.16; 7.36), although not significant after Bonferroni correction. Exploratory interaction analysis suggests that IGF1R SNVs rs2684787 and rs2654980 interact negatively with the FMD group regarding radiological response p = 0.036, OR = 5.13 (95%CI: 1.12; 23.63); p = 0.024, OR = 5.71 (95%CI: 1.26; 25.85). CONCLUSIONS: The IGF1R variants rs3743259 and rs3743258 are negatively associated with pathological response in this cohort, suggesting potential relevance as a predictive biomarker. Further research is needed to validate these findings and elucidate the underlying mechanisms and interaction with FMD.

AAV-mediated gene augmentation therapy of CRB1 patient-derived retinal organoids restores the histological and transcriptional retinal phenotype.

Retinitis pigmentosa and Leber congenital amaurosis are inherited retinal dystrophies that can be caused by mutations in the Crumbs homolog 1 (CRB1) gene. CRB1 is required for organizing apical-basal polarity and adhesion between photoreceptors and Müller glial cells. CRB1 patient-derived induced pluripotent stem cells were differentiated into CRB1 retinal organoids that showed diminished expression of variant CRB1 protein observed by immunohistochemical analysis. Single-cell RNA sequencing revealed impact on, among others, the endosomal pathway and cell adhesion and migration in CRB1 patient-derived retinal organoids compared with isogenic controls. Adeno-associated viral (AAV) vector-mediated hCRB2 or hCRB1 gene augmentation in Müller glial and photoreceptor cells partially restored the histological phenotype and transcriptomic profile of CRB1 patient-derived retinal organoids. Altogether, we show proof-of-concept that AAV.hCRB1 or AAV.hCRB2 treatment improved the phenotype of CRB1 patient-derived retinal organoids, providing essential information for future gene therapy approaches for patients with mutations in the CRB1 gene.

A 12-gene pharmacogenetic panel to prevent adverse drug reactions: an open-label, multicentre, controlled, cluster-randomised crossover implementation study.

BACKGROUND: The benefit of pharmacogenetic testing before starting drug therapy has been well documented for several single gene-drug combinations. However, the clinical utility of a pre-emptive genotyping strategy using a pharmacogenetic panel has not been rigorously assessed. METHODS: We conducted an open-label, multicentre, controlled, cluster-randomised, crossover implementation study of a 12-gene pharmacogenetic panel in 18 hospitals, nine community health centres, and 28 community pharmacies in seven European countries (Austria, Greece, Italy, the Netherlands, Slovenia, Spain, and the UK). Patients aged 18 years or older receiving a first prescription for a drug clinically recommended in the guidelines of the Dutch Pharmacogenetics Working Group (ie, the index drug) as part of routine care were eligible for inclusion. Exclusion criteria included previous genetic testing for a gene relevant to the index drug, a planned duration of treatment of less than 7 consecutive days, and severe renal or liver insufficiency. All patients gave written informed consent before taking part in the study. Participants were genotyped for 50 germline variants in 12 genes, and those with an actionable variant (ie, a drug-gene interaction test result for which the Dutch Pharmacogenetics Working Group [DPWG] recommended a change to standard-of-care drug treatment) were treated according to DPWG recommendations. Patients in the control group received standard treatment. To prepare clinicians for pre-emptive pharmacogenetic testing, local teams were educated during a site-initiation visit and online educational material was made available. The primary outcome was the occurrence of clinically relevant adverse drug reactions within the 12-week follow-up period. Analyses were irrespective of patient adherence to the DPWG guidelines. The primary analysis was done using a gatekeeping analysis, in which outcomes in people with an actionable drug-gene interaction in the study group versus the control group were compared, and only if the difference was statistically significant was an analysis done that included all of the patients in the study. Outcomes were compared between the study and control groups, both for patients with an actionable drug-gene interaction test result (ie, a result for which the DPWG recommended a change to standard-of-care drug treatment) and for all patients who received at least one dose of index drug. The safety analysis included all participants who received at least one dose of a study drug. This study is registered with ClinicalTrials.gov, NCT03093818 and is closed to new participants. FINDINGS: Between March 7, 2017, and June 30, 2020, 41 696 patients were assessed for eligibility and 6944 (51·4 % female, 48·6% male; 97·7% self-reported European, Mediterranean, or Middle Eastern ethnicity) were enrolled and assigned to receive genotype-guided drug treatment (n=3342) or standard care (n=3602). 99 patients (52 [1·6%] of the study group and 47 [1·3%] of the control group) withdrew consent after group assignment. 652 participants (367 [11·0%] in the study group and 285 [7·9%] in the control group) were lost to follow-up. In patients with an actionable test result for the index drug (n=1558), a clinically relevant adverse drug reaction occurred in 152 (21·0%) of 725 patients in the study group and 231 (27·7%) of 833 patients in the control group (odds ratio [OR] 0·70 [95% CI 0·54-0·91]; p=0·0075), whereas for all patients, the incidence was 628 (21·5%) of 2923 patients in the study group and 934 (28·6%) of 3270 patients in the control group (OR 0·70 [95% CI 0·61-0·79]; p <0·0001). INTERPRETATION: Genotype-guided treatment using a 12-gene pharmacogenetic panel significantly reduced the incidence of clinically relevant adverse drug reactions and was feasible across diverse European health-care system organisations and settings. Large-scale implementation could help to make drug therapy increasingly safe. FUNDING: European Union Horizon 2020.

Genome-wide Association Study of Methotrexate-Induced Liver Injury in Rheumatoid Arthritis Patients.

Hepatotoxicity is a serious adverse drug reaction related to methotrexate (MTX). However, the cause of drug-induced liver injury (DILI) is still unclear and unpredictable. Genetic risk factors may predispose for MTX-DILI. Therefore, we conducted a nested case-control genome-wide association study to explore genetic risk factors associated with MTX-DILI. Seven international groups contributed blood samples and data of patients with rheumatoid arthritis who used MTX. MTX-DILI was defined as an alanine aminotransferase (ALT) level of at least three times the upper limit of normal (ULN), to increase contrast controls ALT levels did not raise above two times the ULN. Per study site, control subjects and patients with MTX-DILI (ratio 3:1) were matched for age, gender, and duration of MTX use. Patients were genotyped using Illumina GSA MD-24v1-0 and data were imputed using the 1000 Genomes reference panel. Single-nucleotide polymorphisms (SNPs) were analyzed using an additive genetic model, corrected for sex, country, and age. A P-value of ≤ 5 × 10-8 was considered significant, whereas a  P-value of ≤ 5 × 10-6 was considered suggestive. A total of 108 MTX-DILI cases and 311 controls were included for association analysis. None of the SNPs were significantly associated with MTX-DILI. However, we found seven suggestive genetic variants associated with MTX-DILI (P-values 7.43 × 10-8 to 4.86 × 10-6 ). Of those, five SNPs were in the intronic protein-coding regions of FTCDNL1, BCOR, FGF14, RBMS3, and PFDN4/DOK5. Investigation of candidates SPATA9 (rs72783407), PLCG2 (rs60427389), RAVER2 (rs72675408), JAK1 (rs72675451), PTPN2 (rs2476601), MTHFR C677T (rs1801133), and into the HLA region did not show significant findings. No genetic variants associated with MTX-DILI were found, whereas suggestive SNPs need further investigation.

Nationwide inventory on retinopathy of prematurity screening in the Netherlands.

PURPOSE: Provide up-to-date insight in incidence of retinopathy of prematurity (ROP), logistics of screening and treatment in the Netherlands and influence of the new national ROP guideline in which more stringent screening criteria were implemented and the early treatment for ROP criteria (ETROP) were emphasised. METHODS: Multicentre prospective nationwide study including all preterm infants, born in the Netherlands in 2017, and considered eligible for ROP screening. Anonymised data from ophthalmologists and paediatricians were merged. Outcome data were compared with the first national ROP inventory (NEDROP-1, 2009). RESULTS: In 2017, 1492 infants were live born with gestational age (GA) <32 weeks (2009: 1662); 1287 infants were eligible for screening (2009: 2033). Ophthalmologists screened 1085 infants, versus 1688 in 2009, corrected with factor 1.114 for the difference in number of live births, a 28.4% (479/1688) decrease in screened infants was seen. Among surviving infants with GA <32 week, ROP was found in 305/1492 babies, 20.4% (2009: 324/1662, 19.5%) of which 49/1492 stage ≥3, 3.3% (2009: 30/1662, 1.8%). In all infants, report on presence or absence of plus disease was provided, according to the ETROP criteria. Treatment was performed in 39 infants. Of infants with ROP stage ≥3, 3/49 (6.1%) progressed to retinal detachment (2009: 6/30, 20.0%). CONCLUSION: The overall ROP incidence expressed as a percentage, remained stable but the number of infants that developed severe ROP nearly doubled. A near one-third reduction in screened infants shows satisfactory implementation of the new screening criteria. A notable decrease in retinal detachment delineates improved treatment outcome.

Validation of transcriptome signature reversion for drug repurposing in oncology.

Transcriptome signature reversion (TSR) has been extensively proposed and used to discover new indications for existing drugs (i.e. drug repositioning, drug repurposing) for various cancer types. TSR relies on the assumption that a drug that can revert gene expression changes induced by a disease back to original, i.e. healthy, levels is likely to be therapeutically active in treating the disease. Here, we aimed to validate the concept of TSR using the PRISM repurposing data set, which is-as of writing-the largest pharmacogenomic data set. The predictive utility of the TSR approach as it has currently been used appears to be much lower than previously reported and is completely nullified after the drug gene expression signatures are adjusted for the general anti-proliferative downstream effects of drug-induced decreased cell viability. Therefore, TSR mainly relies on generic anti-proliferative drug effects rather than on targeting cancer pathways specifically upregulated in tumor types.

Genotyping for HLA risk alleles versus patch tests to diagnose anti-seizure medication induced cutaneous adverse drug reactions.

Aim: To provide a comparison of genotyping for HLA risk alleles versus patch testing to determine which of these two tests is a better diagnostic tool for cutaneous hypersensitivity reactions caused by anti-seizure medication. Methods: A literature study was performed in PubMed to assess the sensitivity and specificity of HLA genotyping and patch tests for identifying anti-seizure medication induced cutaneous hypersensitivity reactions. Results: This study shows that HLA-B*15:02 genotyping shows high sensitivity for carbamazepine-induced SJS/TEN, especially in Han Chinese and Southeast Asian patients (66.7-100.0%) whereas the sensitivity of patch tests (0.0-62,5%), HLA-A*31:01 (0-50%) and HLA-B*15:11 (18.2-42.9%) are lower. On the contrary, for carbamazepine and phenytoin induced DRESS, patch tests (respectively 70.0-88.9% and 14.3-70.0%) show higher sensitivity than HLA tests (0-66.7% and 0-12.7%). Also for lamotrigine-induced DRESS patch tests perform better than HLA-B*15:02 (33.3-40.0 versus 0%). For anti-seizure medication induced MPE and for oxcarbazepine-induced SCARs more studies are needed. Conclusion: Use of HLA-B genotyping may aid clinicians in the diagnosis of carbamazepine, phenytoin, lamotrigine and oxcarbazepine induced SJS/TEN, particularly in Han Chinese and Southeast Asian patients. On the other hand, patch tests seem to perform better in the diagnosis of carbamazepine and phenytoin induced DRESS.

Intervention with methotrexate in patients with arthralgia at risk of rheumatoid arthritis to reduce the development of persistent arthritis and its disease burden (TREAT EARLIER): a randomised, double-blind, placebo-controlled, proof-of-concept trial.

BACKGROUND: Rheumatoid arthritis is the most common autoimmune disease worldwide and requires long-term treatment to suppress inflammation. Currently, treatment is started when arthritis is clinically apparent. We aimed to evaluate whether earlier intervention, in the preceding phase of arthralgia and subclinical joint inflammation, could prevent the development of clinical arthritis or reduce the disease burden. METHODS: We conducted a randomised, double-blind, placebo-controlled, proof-of-concept-trial at the Leiden University Medical Centre, Leiden, Netherlands. Adults aged 18 years or older with arthralgia clinically suspected of progressing to rheumatoid arthritis and MRI-detected subclinical joint inflammation were eligible for enrolment across 13 rheumatology outpatient clinics in the southwest region of the Netherlands and randomly assigned (1:1) to a single intramuscular glucocorticoid injection (120 mg) and a 1-year course of oral methotrexate (up to 25 mg/week), or placebo (single injection and tablets for 1 year). Participants and investigators were masked to group assignment. Follow-up continued for 1 year after the end of the 1-year treatment period. The primary endpoint was development of clinical arthritis (fulfilling the 2010 rheumatoid arthritis classification criteria or involving two or more joints) that persisted for at least 2 weeks. Patient-reported physical functioning, symptoms, and work productivity were secondary endpoints, which were measured every 4 months. Additionally, the course of MRI-detected inflammation was studied. All participants entered the intention-to-treat analysis. This trial is registered with EudraCT, 2014-004472-35, and the Netherlands Trial Register, NTR4853-trial-NL4599. FINDINGS: Between April 16, 2015, and Sept 11, 2019, 901 patients were assessed for eligibility and 236 were enrolled and randomly assigned to active treatment (n=119) or placebo (n=117). At 2 years, the frequency of the primary endpoint was similar between the groups (23 [19%] of 119 participants in the treatment group vs 21 [18%] of 117 in the placebo group; hazard ratio 0·81, 95% CI 0·45 to 1·48). Physical functioning improved more in the treatment group during the first 4 months and remained better than in the placebo group (mean between-group difference in Health Assessment Questionnaire disability index over 2 years: -0·09, 95% CI -0·16 to -0·03; p=0·0042). Similarly, pain (on scale 0-100, mean between-group difference: -8, 95% CI -12 to -4; p<0·0001), morning stiffness of joints (-12, -16 to -8; p<0·0001), presenteeism (-8%, -13 to -3; p=0·0007), and MRI-detected joint inflammation (-1·4 points, -2·0 to -0·9; p<0·0001) showed sustained improvement in the treatment group compared with the placebo group. The number of serious adverse events was equal in both groups; adverse events were consistent with the known safety profile for methotrexate. INTERPRETATION: Methotrexate, the cornerstone treatment of rheumatoid arthritis, initiated at the pre-arthritis stage of symptoms and subclinical inflammation, did not prevent the development of clinical arthritis, but modified the disease course as shown by sustained improvement in MRI-detected inflammation, related symptoms, and impairments compared with placebo. FUNDING: Dutch Research Council (NWO; Dutch Arthritis Society).

Neuropathic-like pain symptoms in inflammatory hand osteoarthritis lower quality of life and may not decrease under prednisolone treatment.

BACKGROUND: Pain is common in hand osteoarthritis (OA) and multiple types may occur. We investigated the prevalence, associated patient characteristics, influence on health-related quality of life (HR-QoL) and response to anti-inflammatory treatment of neuropathic-like pain in inflammatory hand OA. METHODS: Data were analysed from a 6-week, randomized, double-blind, placebo-controlled trial investigating prednisolone treatment in 92 patients with painful inflammatory hand OA. Neuropathic-like pain was measured with the painDETECT questionnaire. Associations between baseline characteristics and baseline neuropathic-like pain were analysed with ordinal logistic regression, association of baseline neuropathic-like pain symptoms with baseline HR-QoL with linear regression, painDETECT and visual analogue scale (VAS) change from baseline to week 6 and interaction of painDETECT with prednisolone efficacy on VAS pain change from baseline to week 6 with generalized estimating equations (GEE). RESULTS: Of 91 patients (79% female, mean age 64) with complete painDETECT data at baseline, 53% were unlikely to have neuropathic-like pain, 31% were indeterminate and 16% were likely to have neuropathic-like pain. Neuropathic-like pain was associated with female sex, less radiographic damage and more comorbidities. Patients with neuropathic-like pain had lower HR-QoL (PCS-6.5 [95% CI -10.4 to -2.6]) than those without. Neuropathic-like pain symptoms remained under prednisolone treatment and no interaction was seen between painDETECT and prednisolone efficacy on VAS pain. CONCLUSIONS: In this study, 16% of inflammatory hand OA patients had neuropathic-like pain. They were more often female, had more comorbidities and had lower QoL than those without. Neuropathic-like pain symptoms remained despite prednisolone treatment and did not seem to affect the outcome of prednisolone treatment. SIGNIFICANCE: Pain is the dominant symptom in hand OA, with an unclear aetiology. In this study, we found that neuropathic-like pain may play a role in hand OA, that it showed associations with female sex, younger age and more comorbidities and that it lowered health-related quality of life in hand OA. Neuropathic-like pain in hand OA seems resistant to prednisolone therapy but did not seem to interfere with the treatment of inflammatory pain with prednisolone.

Genome-Wide Meta-Analysis Identifies Variants in DSCAM and PDLIM3 That Correlate with Efficacy Outcomes in Metastatic Renal Cell Carcinoma Patients Treated with Sunitinib.

Individual response to sunitinib in metastatic renal cell carcinoma (mRCC) patients is highly variable. Earlier, sunitinib outcome was related to single nucleotide polymorphisms (SNPs) in CYP3A5 and ABCB1. Our aim is to provide novel insights into biological mechanisms underlying sunitinib action. We included mRCC patients from the European EuroTARGET consortium (n = 550) and the RIKEN cohort in Japan (n = 204) which were analysed separately and in a meta-analysis of genome-wide association studies (GWAS). SNPs were tested for association with progression-free survival (PFS) and overall survival (OS) using Cox regression. Summary statistics were combined using a fixed effect meta-analysis. SNP rs28520013 in PDLIM3 and the correlated SNPs rs2205096 and rs111356738 both in DSCAM, showed genome-wide significance (p < 5 × 10−8) with PFS and OS in the meta-analysis. The variant T-allele of rs28520013 associated with an inferior PFS of 5.1 months compared to 12.5 months in non-carriers (p = 4.02 × 10−10, HR = 7.26). T-allele carriers of rs28520013 showed an inferior OS of 6.9 months versus 30.2 months in non-carriers (p = 1.62 × 10−8, HR = 5.96). In this GWAS we identified novel genetic variants in PDLIM3 and DSCAM that impact PFS and OS in mRCC patients receiving sunitinib. The underlying link between the identified genes and the molecular mechanisms of sunitinib action needs to be elucidated.

Time to Functional Recovery After Laser Tonsillotomy Performed Under Local Anesthesia vs Conventional Tonsillectomy With General Anesthesia Among Adults: A Randomized Clinical Trial.

Importance: Carbon dioxide laser tonsillotomy performed under local anesthesia may be an effective and less invasive alternative than dissection tonsillectomy for treatment of tonsil-related afflictions. Objective: To compare functional recovery and symptom relief among adults undergoing tonsillectomy or tonsillotomy. Design, Setting, and Participants: This randomized clinical trial was conducted at 5 secondary and tertiary hospitals in the Netherlands from January 2018 to December 2019. Participants were 199 adult patients with an indication for surgical tonsil removal randomly assigned to either the tonsillectomy or tonsillotomy group. Interventions: For tonsillotomy, the crypts of the palatine tonsil were evaporated using a carbon dioxide laser under local anesthesia, whereas tonsillectomy consisted of total tonsil removal performed under general anesthesia. Main Outcomes and Measures: The primary outcome was time to functional recovery measured within 2 weeks after surgery assessed for a modified intention-to-treat population. Secondary outcomes were time to return to work after surgery, resolution of primary symptoms, severity of remaining symptoms, surgical complications, postoperative pain and analgesics use, and overall patient satisfaction assessed for the intention-to-treat population. Results: Of 199 patients (139 [70%] female; mean [SD] age, 29 [9] years), 98 were randomly assigned to tonsillotomy and 101 were randomly assigned to tonsillectomy. Recovery within 2 weeks after surgery was significantly shorter after tonsillotomy than after tonsillectomy (hazard ratio for recovery after tonsillectomy vs tonsillotomy, 0.3; 95% CI, 0.2-0.5). Two weeks after surgery, 72 (77%) patients in the tonsillotomy group were fully recovered compared with 26 (57%) patients in the tonsillectomy group. Time until return to work within 2 weeks was also shorter after tonsillotomy (median [IQR], 4.5 [3.0-7.0] days vs 12.0 [9.0-14.0] days; hazard ratio for return after tonsillectomy vs tonsillotomy, 0.3; 95% CI, 0.2-0.4.). Postoperative hemorrhage occurred in 2 patients (2%) in the tonsillotomy group and 8 patients (12%) in the tonsillectomy group. At 6 months after surgery, fewer patients in the tonsillectomy group (25; 35%) than in the tonsillotomy group (54; 57%) experienced persistent symptoms (difference of 22%; 95% CI, 7%-37%). Most patients with persistent symptoms in both the tonsillotomy (32 of 54; 59%) and tonsillectomy (16 of 25; 64%) groups reported mild symptoms 6 months after surgery. Conclusions and Relevance: This randomized clinical trial found that compared with tonsillectomy performed under general anesthesia, laser tonsillotomy performed under local anesthesia had a significantly shorter and less painful recovery period. A higher percentage of patients had persistent symptoms after tonsillotomy, although the intensity of these symptoms was lower than before surgery. These results suggest that laser tonsillotomy performed under local anesthesia may be a feasible alternative to conventional tonsillectomy in this population. Trial Registration: Netherlands Trial Register Identifier: NL6866 (NTR7044).