The patient with a painful knee.

Knee pain encompasses a wide array of differential diagnoses and can often pose a diagnostic challenge, as it can have traumatic or non-traumatic causes. A good clinical history, assessment and anatomical knowledge gives a strong foundation to narrow down the diagnosis, and understanding the correct imaging modality and findings further informs correct and timely management. This article reviews various disease processes including fractures, inflammatory, infective and neoplastic causes, and discusses the assessment and various imaging modalities to aid diagnosis in both primary and secondary care.

A novel treatment to enhance survival for end stage triple negative breast cancer using repurposed veterinary anthelmintics combined with gut­supporting/immune enhancing molecules.

Patients with end­stage metastatic disease have limited treatment options and those diagnosed with triple negative breast cancer (Her2, Estrogen receptor, Progesterone receptor) have a poor prognosis. Using a triple negative mammary tumor model selected for brain metastasis (4T1Br4) in the mouse, treatment options that may increase survival when therapeutics are applied at post­metastasis were assessed. Anti­parasitic benzimidazoles (BZs) destabilize microtubules, inhibit metabolic pathways, reduce cell proliferation, and induce apoptosis in tumor cells. Co­administration of two BZs was selected, oxfendazole (OFZ) and parbendazole (PBZ), shown to overcome resistance development in anthelmintic effects by imposing metabolic delay to assess if multiple BZ approach is also suitable to enhance anticancer effects. It has been previously reported that treatment of mammary tumor­bearing mice at an early stage with chitin microparticles (CMPs) decreased tumor growth and metastases by enhancing both innate M1 macrophage and TH1 adaptive immune response. Oral administration of CMPs was previously revealed to affect the gut in intestinal inflammation. A combination BZ (OFZ/PBZ) and CMP treatment was tested to target tumor development and metastasis and effects were compared in response to monotherapies of the same compounds or to untreated mice. The results demonstrated increased survival, decreased tumor cell proliferation, decreased metastasis in lungs and brain, increased levels of fecal SCFAs butyric, acetic, propionic and valeric acids with increased butyric and propionic acid levels in brain biopsies in combination treated compared with untreated mice. At the primary tumor, SCFA receptor FFAR2 expression was increased in combination treatment compared with untreated mice, suggestive of a non­invasive cancer phenotype. The superior cytotoxic effects of OFZ/PBZ were confirmed as opposed to single treatment with OFZ or PBZ using 3D spheroids generated from a human breast cancer cell line, MDA­MB­468. These data are compelling for treatment option possibility even at late stages of metastasized breast cancer.

Soft tissue tumor imaging in adults: European Society of Musculoskeletal Radiology-Guidelines 2023-overview, and primary local imaging: how and where?

OBJECTIVES: Early, accurate diagnosis is crucial for the prognosis of patients with soft tissue sarcomas. To this end, standardization of imaging algorithms, technical requirements, and reporting is therefore a prerequisite. Since the first European Society of Musculoskeletal Radiology (ESSR) consensus in 2015, technical achievements, further insights into specific entities, and the revised WHO-classification (2020) and AJCC staging system (2017) made an update necessary. The guidelines are intended to support radiologists in their decision-making and contribute to interdisciplinary tumor board discussions. MATERIALS AND METHODS: A validated Delphi method based on peer-reviewed literature was used to derive consensus among a panel of 46 specialized musculoskeletal radiologists from 12 European countries. Statements were scored online by level of agreement (0 to 10) during two iterative rounds. Either "group consensus," "group agreement," or "lack of agreement" was achieved. RESULTS: Eight sections were defined that finally contained 145 statements with comments. Overall, group consensus was reached in 95.9%, and group agreement in 4.1%. This communication contains the first part consisting of the imaging algorithm for suspected soft tissue tumors, methods for local imaging, and the role of tumor centers. CONCLUSION: Ultrasound represents the initial triage imaging modality for accessible and small tumors. MRI is the modality of choice for the characterization and local staging of most soft tissue tumors. CT is indicated in special situations. In suspicious or likely malignant tumors, a specialist tumor center should be contacted for referral or teleradiologic second opinion. This should be done before performing a biopsy, without exception. CLINICAL RELEVANCE: The updated ESSR soft tissue tumor imaging guidelines aim to provide best practice expert consensus for standardized imaging, to support radiologists in their decision-making, and to improve examination comparability both in individual patients and in future studies on individualized strategies. KEY POINTS: • Ultrasound remains the best initial triage imaging modality for accessible and small suspected soft tissue tumors. • MRI is the modality of choice for the characterization and local staging of soft tissue tumors in most cases; CT is indicated in special situations. Suspicious or likely malignant tumors should undergo biopsy. • In patients with large, indeterminate or suspicious tumors, a tumor reference center should be contacted for referral or teleradiologic second opinion; this must be done before a biopsy.

The adult with low back pain: causes, diagnosis, imaging features and management.

Low back pain is the leading cause of disability worldwide. This article highlights the importance of succinct history taking and a thorough clinical examination when managing a patient with lower back pain in hospital. Furthermore, it encourages the clinician to consider the pertinent causes of low back pain such as age-related degeneration, malignancy, trauma, infection and seronegative inflammatory spondyloarthropathies, and looks at the diagnosis, imaging features and key management options which are available in secondary care.

Otolaryngological burden of disease in children with primary ciliary dyskinesia in Victoria, Australia.

OBJECTIVES: The aim of this study was to summarize the otolaryngological manifestations amongst children with primary ciliary dyskinesia (cwPCD) to improve diagnosis, investigations and management amongst otolaryngologists. METHODS: A retrospective review of primary ciliary dyskinesia (PCD) diagnoses at our institution over an 8-year period between January 2014 and October 2022 was conducted. Patient characteristics, diagnosis, otolaryngological symptomatology, treatment and outcomes were recorded. RESULTS: 24 patients were identified. Thirteen patients (54%) had documented conductive hearing loss on audiological evaluation; with 11 (85%) requiring hearing aids. Six patients (25%) underwent middle ear ventilation tube (MEVT) insertion with 67% experiencing post-MEVT otorrhoea. Twenty children (83%) reported chronic nasal discharge however only 3 (13%) reported nasal obstruction. Nine patients (38%) had symptoms consistent with sleep disordered breathing with 79% of them requiring operative management with adenotonsillectomy. CONCLUSION: Middle ear effusion is common amongst cwPCD and should be managed with conservative measures due to the significant burden of post-MEVT otorrhoea. Sinonasal symptoms rarely need surgical intervention. Many otolaryngological symptoms of PCD are often underreported, particularly sleep-disordered breathing. Paediatric PCD patients should be managed in a multidisciplinary team with routine and tailored therapies to manage all aspects of the condition.

Managing Cardiovascular and Cancer Risk Associated with JAK Inhibitors.

Janus kinase inhibitors (JAKi) have enormous appeal as immune-modulating therapies across many chronic inflammatory diseases, but recently this promise has been overshadowed by questions regarding associated cardiovascular and cancer risk emerging from the ORAL Surveillance phase 3b/4 post-marketing requirement randomized controlled trial. In that study of patients with rheumatoid arthritis with existing cardiovascular risk, tofacitinib, the first JAKi registered for chronic inflammatory disease, failed to meet non-inferiority thresholds when compared with tumor necrosis factor inhibitors for both incident major adverse cardiovascular events and incident cancer. While this result was unexpected by many, subsequently published observational data have also supported this finding. Notably, however, such a risk has largely not yet been demonstrated in patients outside the specific clinical situation examined in the trial, even in the face of many studies examining this. Nevertheless, this signal has practically re-aligned approaches to both tofacitinib and other JAKi to varying extents, in other patient populations and contexts: within rheumatoid arthritis, but also in psoriatic arthritis, axial spondyloarthritis, inflammatory bowel disease, atopic dermatitis, and beyond. Application to individual patients can be more challenging but remains important to harness the substantive potential of JAKi to the maximum extent safely possible. This review not only explores the evolution of the regulatory response to the signal, its informing data, biological plausibility, and its impact on guidelines, but also the many factors that clinicians must consider in navigating cardiovascular and cancer risk for their patients considering JAKi as immune-modulating therapy.

Outcomes of COVID-19 in people with rheumatic and musculoskeletal disease in Ireland over the first 2 years of the pandemic.

BACKGROUND: Poor COVID-19 outcomes occur with higher frequency in people with rheumatic and musculoskeletal diseases (RMD). Better understanding of the factors involved is crucial to informing patients and clinicians regarding risk mitigation. AIM: To describe COVID-19 outcomes for people with RMD in Ireland over the first 2 years of the pandemic. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24th March 2020 and 31st March 2022 were analysed. Differences in the likelihood of hospitalisation and mortality according to demographic and clinical variables were investigated. RESULTS: Of 237 cases included, 59.9% were female, 95 (41.3%) were hospitalised, and 22 (9.3%) died. Hospitalisation was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular and pulmonary disease, and cancer. Hospitalisation was less frequent in people with inflammatory arthritis and conventional synthetic or biologic disease-modifying antirheumatic drug use. Hospitalisation had a U-shaped relationship with disease activity, being more common in both high disease activity and remission. Mortality was more common with increasing age, gout, smoking, long-term glucocorticoid use, comorbidities, and specific comorbidities of cardiovascular disease, pulmonary disease, and obesity. Inflammatory arthritis was less frequent in those who died. CONCLUSION: Hospitalisation or death were more frequently experienced by RMD patients with increasing age, certain comorbidities including potentially modifiable ones, and certain medications and diagnoses amongst other factors. These are important 'indicators' that can help risk-stratify and inform the management of RMD patients.

APOBEC mutagenesis is a common process in normal human small intestine.

APOBEC mutational signatures SBS2 and SBS13 are common in many human cancer types. However, there is an incomplete understanding of its stimulus, when it occurs in the progression from normal to cancer cell and the APOBEC enzymes responsible. Here we whole-genome sequenced 342 microdissected normal epithelial crypts from the small intestines of 39 individuals and found that SBS2/SBS13 mutations were present in 17% of crypts, more frequent than most other normal tissues. Crypts with SBS2/SBS13 often had immediate crypt neighbors without SBS2/SBS13, suggesting that the underlying cause of SBS2/SBS13 is cell-intrinsic. APOBEC mutagenesis occurred in an episodic manner throughout the human lifespan, including in young children. APOBEC1 mRNA levels were very high in the small intestine epithelium, but low in the large intestine epithelium and other tissues. The results suggest that the high levels of SBS2/SBS13 in the small intestine are collateral damage from APOBEC1 fulfilling its physiological function of editing APOB mRNA.

Examining the Characteristics of Colchicine-Induced Myelosuppression in Clinical Cases: A Systematic Review.

OBJECTIVE: The use of colchicine has been associated with varying degrees of myelosuppression. Despite expanded use in cardiovascular and inflammatory conditions, there remains clinician concern because of potential myelosuppressive side effects. A systematic review was conducted to explore the reported myelosuppressive events of colchicine. METHODS: A systematic review was conducted using the MeSH terms ("colchicine") AND ("myelosuppression," "bone*," "marrow," "suppression," "aplasia," "leukopenia/leucopenia," "lymphopenia," "neutropenia") on September 1, 2020, and was updated on November 30, 2021. The search was conducted in PubMed, ScienceDirect, Scopus, Embase, and Cochrane Library. The search included references published from 1978 to 2020 and was limited to English-language observational studies (ie, case reports, case series, case control studies, and cohort studies) or trial data. RESULTS: In total, 3233 articles were screened, with 30 studies of 47 patients with myelosuppression from colchicine identified. Most patients with myelosuppression had comorbidities, including renal impairment (21/47, 44.7%). Out of 47 patients, 15 (31.9%) and 13 (27.7%) were reported to be concurrently taking cytochrome P450 3A4 (CYP3A4) inhibitors and P-glycoprotein (P-gp) efflux transporter inhibitors, respectively. Patients with renal impairment accounted for the majority of overall patients taking these CYP3A4 and P-gp inhibitors (8/15, 53.3%, and 8/13, 61.5%, respectively). Out of 21 patients with renal impairment, 13 had worsening cytopenia during colchicine use. The presentations ranged from moderate anemia (grade 2) to severe thrombocytopenia, neutropenia, and leukopenia (grade 4). CONCLUSION: Colchicine has few reports of myelosuppression. The majority of patients with myelosuppression had preexisting renal impairment or concomitant CYP3A4 or P-gp inhibitor use. Caution should be taken in this subset of patients with increased monitoring.

Certolizumab Pegol Treatment in Patients with Axial-Spondyloarthritis-Associated Acute Anterior Uveitis: a Narrative Review.

BACKGROUND: Acute anterior uveitis (AAU) affects up to 40% of patients with axial spondyloarthritis (axSpA). An effective treatment for patients with axSpA that reduces the risk of AAU flares while also targeting axial symptoms is therefore highly desirable. Tumor necrosis factor inhibitors (TNFis) have been shown effective for treatment of axSpA and AAU occurrence, with guidelines conditionally recommending treating patients with axSpA and associated AAU with TNFi monoclonal antibodies. To date, most available data on the impact of TNFis on AAU in axSpA are from observational, open-label studies without parallel comparator arms. However, there is a growing body of evidence describing the impact of the TNFi certolizumab pegol (CZP) on the incidence of axSpA-associated AAU. OBJECTIVE: Our objective was to collate data pertaining to the impact of CZP in axSpA-associated AAU in patients across the full axSpA spectrum. METHODS: Data were obtained from four industry-supported phase 3 and 4 clinical trials (C-VIEW, C-axSpAnd, C-OPTIMISE, and RAPID-axSpA). To supplement these data, a targeted literature review was performed through searches of MEDLINE, Embase, and reference lists. RESULTS: Available data from 1467 patients from the C-VIEW, C-axSpAnd, C-OPTIMISE, and RAPID-axSpA trials show CZP to be effective in AAU in patients across the full axSpA spectrum, reducing AAU flares when compared with placebo or pretreatment period. No differences in AAU outcomes were reported when stratified by axSpA subgroup age or sex. The targeted literature review identified six further studies of CZP in spondyloarthritis-associated AAU, only one of which was specific to axSpA. CONCLUSION: CZP was effective in reducing AAU incidence in clinical trials with patients with axSpA. The targeted literature review, however, highlighted that there remains a paucity of data beyond these trials. Data from comparative studies would further enhance the body of evidence on the effects of CZP in patients with axSpA who develop AAU.

Folic acid and methotrexate use and their association with COVID-19 diagnosis and mortality: a case-control analysis from the UK Biobank.

OBJECTIVE: To determine if methotrexate or folic acid prescription was associated with differential risk for COVID-19 diagnosis or mortality. DESIGN: Case-control analysis. SETTING: The population-based UK Biobank (UKBB) cohort. PARTICIPANTS: Data from 380 380 UKBB participants with general practice prescription data for 2019-2021. Updated medical information was retrieved on 13 December 2021. PRIMARY AND SECONDARY OUTCOME MEASURES: The outcomes of COVID-19 diagnosis and COVID-19-related mortality were analysed by multivariable logistic regression. Exposures evaluated were prescription of folic acid and/or methotrexate. Criteria for COVID-19 diagnosis were (1) a positive SARS-CoV-2 test or (2) ICD-10 code for confirmed COVID-19 (U07.1) or probable COVID-19 (U07.2) in hospital records, or death records. By these criteria, 26 003 individuals were identified with COVID-19 of whom 820 were known to have died from COVID-19. Logistic regression statistical models were adjusted for age sex, ethnicity, Townsend deprivation index, body mass index, smoking status, presence of rheumatoid arthritis, sickle cell disease, use of anticonvulsants, statins and iron supplements. RESULTS: Compared with people prescribed neither folic acid nor methotrexate, people prescribed folic acid supplementation had increased risk of diagnosis of COVID-19 (OR 1.51 (1.42-1.61)). The prescription of methotrexate with or without folic acid was not associated with COVID-19 diagnosis (p≥0.18). People prescribed folic acid supplementation had positive association with death after a diagnosis of COVID-19 (OR 2.64 (2.15-3.24)) in a fully adjusted model. The prescription of methotrexate in combination with folic acid was not associated with an increased risk for COVID-19-related death (1.07 (0.57-1.98)). CONCLUSIONS: We report an association of increased risk for COVID-19 diagnosis and COVID-19-related death in people prescribed folic acid supplementation. Our results also suggest that methotrexate might attenuate these associations.

Inherited MUTYH mutations cause elevated somatic mutation rates and distinctive mutational signatures in normal human cells.

Cellular DNA damage caused by reactive oxygen species is repaired by the base excision repair (BER) pathway which includes the DNA glycosylase MUTYH. Inherited biallelic MUTYH mutations cause predisposition to colorectal adenomas and carcinoma. However, the mechanistic progression from germline MUTYH mutations to MUTYH-Associated Polyposis (MAP) is incompletely understood. Here, we sequence normal tissue DNAs from 10 individuals with MAP. Somatic base substitution mutation rates in intestinal epithelial cells were elevated 2 to 4-fold in all individuals, except for one showing a 31-fold increase, and were also increased in other tissues. The increased mutation burdens were of multiple mutational signatures characterised by C > A changes. Different mutation rates and signatures between individuals are likely due to different MUTYH mutations or additional inherited mutations in other BER pathway genes. The elevated base substitution rate in normal cells likely accounts for the predisposition to neoplasia in MAP. Despite ubiquitously elevated mutation rates, individuals with MAP do not display overt evidence of premature ageing. Thus, accumulation of somatic mutations may not be sufficient to cause the global organismal functional decline of ageing.

Clinical Utility of Bronchoalveolar Lavage in Pediatric Oncology Patients.

BACKGROUND: Lower airway sampling is important in the assessment of lower respiratory tract infection in children with cancer or posthematopoietic stem cell transplant and can be done via bronchoalveolar lavage (BAL). Clinicians can struggle with balancing the benefits of BAL against the risks. This study aimed to define the diagnostic and clinical utility of BAL in this population. METHODS: A single-center retrospective review of BAL performed in children with cancer or posthematopoietic stem cell transplant. Data extracted included demographics, BAL method and results and antimicrobial treatment. Variables significantly associated with diagnostic yield, diagnostic impact (confirmation or exclusion of infection), and clinical impact (any change in antimicrobial or nonantimicrobial therapy) were assessed in both univariate and multivariate analysis. RESULTS: Seventy-three BAL episodes were included. In 26 (35.6%) episodes, a pathogen was identified on BAL. Forty-nine (67%) BAL episodes had a diagnostic impact and 15 (21%) had a clinical impact. Late BAL (>72 hours) compared with early BAL (odds ratio 3.27; 95% CI: 1.03-10.86), and flexible bronchoscopy compared with nonbronchoscopic lavage (odds ratio 6.10; 95% CI: 1.90-24.0), were more likely to have a diagnostic impact on multivariate analysis. No associations were found for clinical impact. CONCLUSIONS: One-third of BAL episodes identified a pathogen, two-thirds had a diagnostic impact, and almost a quarter of episodes impacted antimicrobial prescribing. The method and timing of BAL may be important, with flexible bronchoscopy 6-fold more likely and late BAL 3-fold more likely to have a diagnostic impact.

The effect of azithromycin on structural lung disease in infants with cystic fibrosis (COMBAT CF): a phase 3, randomised, double-blind, placebo-controlled clinical trial.

BACKGROUND: Structural lung disease and neutrophil-dominated airway inflammation is present from 3 months of age in children diagnosed with cystic fibrosis after newborn screening. We hypothesised that azithromycin, given three times weekly to infants with cystic fibrosis from diagnosis until age 36 months, would reduce the extent of structural lung disease as captured on chest CT scans. METHODS: A phase three, randomised, double-blind, placebo-controlled trial was done at eight paediatric cystic fibrosis centres in Australia and New Zealand. Infants (aged 3-6 months) diagnosed with cystic fibrosis following newborn screening were eligible. Exclusion criteria included prolonged mechanical ventilation in the first 3 months of life, clinically significant medical disease or comorbidities other than cystic fibrosis, or macrolide hypersensitivity. Participants were randomly assigned (1:1) to receive either azithromycin (10 mg/kg bodyweight orally three times per week) or matched placebo until age 36 months. Randomisation was done with a permuted block strategy and an interactive web-based response system, stratified by study site. Unblinding was done once all participants completed the trial. The two primary outcomes were the proportion of children with radiologically defined bronchiectasis, and the percentage of total lung volume affected by disease. Secondary outcomes included clinical outcomes and exploratory outcomes were inflammatory markers. Analyses were done with the intention-to-treat principle. This study is registered at ClinicalTrials.gov (NCT01270074). FINDINGS: Between June 15, 2012, and July 10, 2017, 281 patients were screened, of whom 130 were enrolled, randomly assigned, and received first study dose. 68 participants received azithromycin and 62 received placebo. At 36 months, 88% (n=50) of the azithromycin group and 94% (n=44) of the placebo group had bronchiectasis (odds ratio 0·49, 95% CI 0·12 to 2·00; p=0·32), and total airways disease did not differ between groups (median difference -0·02%, 95% CI -0·59 to 0·56; p=0·96). Secondary outcome results included fewer days in hospital for pulmonary exacerbations (mean difference -6·3, 95% CI -10·5 to -2·1; p=0·0037) and fewer courses of inhaled or oral antibiotics (incidence rate ratio 0·88, 95% CI 0·81 to 0·97; p=0·0088) for those in the azithromycin group. For the preplanned, exploratory analysis, concentrations of airway inflammation were lower for participants receiving azithromycin, including interleukin-8 (median difference -1·2 pg/mL, 95% CI -1·9 to -0·5; p=0·0012) and neutrophil elastase activity (-0·6 µg/mL, -1·1 to -0·2; p=0·0087) at age 36 months, although no difference was noted between the groups for interleukin-8 or neutrophil elastase activity at 12 months. There was no effect of azithromycin on body-mass index at age 36 months (mean difference 0·4, 95% CI -0·1 to 0·9; p=0·12), nor any evidence of pathogen emergence with the use of azithromycin. There were few adverse outcomes with no differences between the treatment groups. INTERPRETATION: Azithromycin treatment from diagnosis of cystic fibrosis did not reduce the extent of structural lung disease at 36 months of age; however, it did reduce airway inflammation, morbidity including pulmonary exacerbations in the first year of life and hospitalisations, and improved some clinical outcomes associated with cystic fibrosis lung disease. Therefore we suggest thrice-weekly azithromycin is a strategy that could be considered for the routine early management of paediatric patients with cystic fibrosis. FUNDING: Cystic Fibrosis Foundation.

Drivers and hazards of consumption of unpasteurised bovine milk and milk products in high-income countries.

Introduction: The consumption of dairy products contributes to health, nutrition, and livelihoods globally. However, dairy products do not come without microbiological food safety risks for consumers. Despite this risk, common hygiene measures in high-income countries, particularly pasteurisation, ensures that milk is safe, and is indeed frequently mandated by law. Nevertheless, over the past two decades, there has been a global increase in the number of consumers in high-income developed countries actively seeking out unpasteurised milk in liquid and product forms for perceived nutritional and health benefits, and improved taste. The often-anecdotal claims upon which consumers make such choices are not all supported by scientific evidence; however, some recent research studies have investigated (and in some cases demonstrated) the positive impact of unpasteurised milk consumption on the prevalence of asthma, atopy, rectal cancer and respiratory illness. Methods: To investigate the significance of unpasteurised milk and milk product consumption for human health in high-income countries, outbreak data between the years 2000 and 2018 were obtained for the United States of America, Canada, the European Union, the United Kingdom, Japan, New Zealand and Australia, which were then categorized into three World Health Organisation subregions: AMR A, EUR A and WPR A. Outbreak dynamic variables such as pathogens, the place of consumption, numbers of outbreaks and deaths per million capita, the average number of cases per outbreak and regulations were described and analysed using R Studio. To provide an overview of unpasteurised milk-related disease outbreaks, a rapid evidence review was also undertaken to establish an overview of what is known in the current literature about hazards and drivers of consumption. Results: Foodborne outbreaks associated with unpasteurised dairy consumption have risen in high-income countries over the period 2000 to 2018, with Campylobacter spp. being the most common aetiological agent responsible, followed by Escherichia coli and Salmonella spp. The most common places of consumption are on farms or in households, indicating individuals choose to drink unpasteurised milk, rather than a widespread distribution of the product, for example, at social events and in schools. Further study is needed to better understand contributing factors, such as cultural differences in the consumption of dairy products. Conclusion: There are several observable health benefits linked to consuming raw milk, but outbreaks associated with unpasteurised milk and milk products are on the rise. It cannot be definitively concluded whether the benefits outweigh the risks, and ultimately the decision lies with the individual consumer. Nevertheless, many countries have regulations in place to protect consumer health, acknowledging the definite risks to human health that unpasteurised dairy foods may pose, particularly from microbial hazards.

Certolizumab Pegol Efficacy in Patients With Non-Radiographic Axial Spondyloarthritis Stratified by Baseline MRI and C-Reactive Protein Status: An Analysis From the C-axSpAnd Study.

OBJECTIVE: Tumor necrosis factor inhibitors (TNFi) are an effective treatment for non-radiographic axial spondyloarthritis (nr-axSpA). To be eligible, however, many authorities require patients with nr-axSpA to show active sacroiliitis on magnetic resonance imaging (MRI) and/or an elevated C-reactive protein (CRP) level, possibly resulting in a perception that patients with nr-axSpA without both factors have only low responses to TNFi treatment. We evaluated clinical responses to certolizumab pegol (CZP) in patients with nr-axSpA stratified by baseline MRI/CRP status. METHODS: C-axSpAnd was a phase 3, multicenter study on CZP in adult patients with active nr-axSpA and objective signs of inflammation. This analysis assessed efficacy of CZP over the 52-week randomized, double-blind, placebo-controlled period in patients stratified into subgroups based on the presence of active sacroiliitis on MRI and CRP level at baseline. RESULTS: CZP-treated patients across all MRI/CRP subgroups achieved clinical responses greater than placebo. Across outcome measures, CZP-treated MRI+/CRP+ patients demonstrated the greatest clinical responses, but substantial improvements were also observed in CZP-treated MRI+/CRP- and MRI-/CRP+ patients. Ankylosing Spondylitis Disease Activity Score Major Improvement response rates at week 52 among CZP-treated patients (75.6% MRI+/CRP+; 47.5% MRI-/CRP+; and 29.7% MRI+/CRP-) were higher than rates in placebo groups (range: 3.9%-12.5%). Assessment of SpondyloArthritis international Society 40% response, Bath Ankylosing Spondylitis Disease Activity Index, and Bath Ankylosing Spondyloarthritis Functional Index had similar response patterns, although differences between the CZP-treated MRI/CRP subgroups were smaller. Clinical responses among CZP-treated patients were also observed in additional subgroups, including those with low Spondyloarthritis Research Consortium of Canada MRI sacroiliac joint inflammation scores and those with normal baseline CRP levels. CONCLUSION: Our findings indicate that CZP treatment benefits patients with nr-axSpA across MRI+/CRP+, MRI-/CRP+, and MRI+/CRP- subgroups.

Mutational landscape of normal epithelial cells in Lynch Syndrome patients.

Lynch Syndrome (LS) is an autosomal dominant disease conferring a high risk of colorectal cancer due to germline heterozygous mutations in a DNA mismatch repair (MMR) gene. Although cancers in LS patients show elevated somatic mutation burdens, information on mutation rates in normal tissues and understanding of the trajectory from normal to cancer cell is limited. Here we whole genome sequence 152 crypts from normal and neoplastic epithelial tissues from 10 LS patients. In normal tissues the repertoire of mutational processes and mutation rates is similar to that found in wild type individuals. A morphologically normal colonic crypt with an increased mutation burden and MMR deficiency-associated mutational signatures is identified, which may represent a very early stage of LS pathogenesis. Phylogenetic trees of tumour crypts indicate that the most recent ancestor cell of each tumour is already MMR deficient and has experienced multiple cycles of clonal evolution. This study demonstrates the genomic stability of epithelial cells with heterozygous germline MMR gene mutations and highlights important differences in the pathogenesis of LS from other colorectal cancer predisposition syndromes.

Temporal trends in COVID-19 outcomes in people with rheumatic diseases in Ireland: data from the COVID-19 Global Rheumatology Alliance registry.

OBJECTIVES: Although evidence is accumulating globally, data on outcomes in rheumatic disease and COVID-19 in Ireland are limited. We used data from the COVID-19 Global Rheumatology Alliance (C19-GRA) to describe time-varying COVID-19 outcomes for people with rheumatic disease in Ireland. METHODS: Data entered into the C19-GRA provider registry from Ireland between 24 March 2020 and 9 July 2021 were analysed. Differences in the likelihood of hospitalization and mortality according to demographic and clinical variables were investigated using Chi-squared test or Fisher's exact test, as appropriate. Trends in odds of hospitalization and mortality over time were investigated using logistic regression with the time period as a categorical variable. RESULTS: Of 212 cases included, 59.4% were female and median age was 58.0 years (range 13-96). Of the 212 cases, 92 (43%) were hospitalized and 22 (10.4%) died. Increasing age, a diagnosis of gout, ever smoking, glucocorticoid use, having comorbidities and specific comorbidities of cancer, cardiovascular and pulmonary disease were more common in those hospitalized. A diagnosis of inflammatory arthritis, csDMARD and/or b/tsDMARD use were less frequent in those hospitalized. Increasing age, a diagnosis of gout, ever smoking, having comorbidities and specific comorbidities of obesity, cardiovascular and pulmonary disease were more common in those who died. Odds of hospitalization or mortality did not change over time. CONCLUSION: No temporal trend was observed in either COVID-19-related hospitalization or mortality outcomes for people with rheumatic disease in Ireland.

Waiting for JAK inhibitor safety data.

The US Food and Drug Administration (FDA) has recently added a new 'black box warning' on all currently approved Janus kinase (JAK) inhibitors indicated for the treatment of arthritis and other inflammatory conditions based on results from the ORAL Surveillance study of tofacitinib versus tumour necrosis factor alpha inhibitors in rheumatoid arthritis. This is a warning difficult to ignore because the data, being from a randomised controlled trial, are of high fidelity and hard to reproach. It is especially problematic because safety data for all the other JAK inhibitors will be pending for several years. So how might we proceed, without being bound by our stasis? The lack of absolute certainty seems to require a pragmatic approach to the routine care use of JAK inhibitors. The patients who were at greatest risk were older and had other risk factors for the corresponding adverse events, in keeping with effect modification. This highlights the need to focus on risk stratification when tailoring therapy. In this viewpoint, we propose a simple illustration to guide clinical decision-making. First, identify general risk factors for venous thromboembolic event (VTE), major adverse cardiac event (MACE) and cancer (age>65 years and smoking) and whether there is a previous history of VTE, MACE or cancer. Then, evaluate risk based on the number of other risk factors for VTE and the number of other risk factors for MACE. Ultimately, 'treat-to-target' will in the end always be 'treat-to-agreement'. As we have done in the past, and will do in the future, the optimal treatment strategy will have to be tailored based on individual patient risk factors and preferences in a shared-decision process.