Nyt fra tidsskrifterne

by Thamrong Lertudomphonwanit, Chirtwut Somboonprasert, Kittiphon Lilakhunakon, Suphaneewan Jaovisidha, Thumanoon Ruangchaijatuporn, Praman Fuangfa, Sasivimol Rattanasiri, Siriorn Watcharananan, Pongsthorn Chanplakorn Background Microbiological diagnosis of tuberculous spondylodiscitis (TS) and pyogenic spontaneous spondylodiscitis (PS) is sometime difficult. This study aimed to identify the predictive factors for differentiating TS from PS using clinical characteristics, radiologic findings, and biomarkers, and to develop scoring system by using predictive factors to stratify the probability of TS. Methods A retrospective single-center study. Demographics, clinical characteristics, laboratory findings and radiographic findings of patients, confirmed causative pathogens of PS or TS, were assessed for independent factors that associated with TS. The coefficients and odds ratio (OR) of the final model were estimated and used to construct the scoring scheme to identify patients with TS. Results There were 73 patients (51.8%) with TS and 68 patients (48.2%) with PS. TS was more frequently associated with younger age, history of tuberculous infection, longer duration of symptoms, no fever, thoracic spine involvement, ≥3 vertebrae involvement, presence of paraspinal abscess in magnetic-resonance-image (MRI), well-defined thin wall abscess, anterior subligamentous abscess, and lower biomarker levels included white blood cell (WBC) counts, erythrocyte-sedimentation-rate (ESR), neutrophil fraction, and C-reactive protein (all p < 0.05). Multivariate logistic regression analysis revealed significant predictors of TS included WBC ≤9,700/mm3 (odds ratio [OR] 13.11, 95% confidence interval [CI] 4.23–40.61), neutrophil fraction ≤78% (OR 4.93, 95% CI 1.59–15.30), ESR ≤92 mm/hr (OR 4.07, 95% CI 1.24–13.36) and presence of paraspinal abscess in MRI (OR 10.25, 95% CI 3.17–33.13), with an area under the curve of 0.921. The scoring system stratified the probability of TS into three categories: low, moderate, and high with a TS prevalence of 8.1%, 29.6%, and 82.2%, respectively. Conclusions This prediction model incorporating WBC, neutrophil fraction counts, ESR and presence of paraspinal abscess accurately predicted the causative pathogens. The scoring scheme with combination of these biomarkers and radiologic features can be useful to differentiate TS from PS. …

by Hee Jung Son, Myongwhan Kim, Dong Hong Kim, Chang-Nam Kang The incidence of infectious spondylodiscitis (IS) has increased in recent years due to an increase in the numbers of older patients with chronic diseases, as well as patients with immunocompromise, steroid use, drug abuse, invasive spinal procedures, and spinal surgeries. However, research focusing on IS in the general population is lacking. This study investigated the incidence and treatment trends of IS in South Korea using data obtained from the Health Insurance Review and Assessment Service. A total of 169,244 patients (mean age: 58.0 years) diagnosed from 2010 to 2019 were included in the study. A total of 10,991 cases were reported in 2010 and 18,533 cases in 2019. Hence, there was a 1.5-fold increase in incidence rate per 100,000 people from 22.90 in 2010 to 35.79 in 2019 (P < 0.05). The incidence rate of pyogenic spondylodiscitis per 100,000 people increased from 15.35 in 2010 to 33.75 in 2019, and that of tuberculous spondylodiscitis decreased from 7.55 in 2010 to 2.04 in 2019 (P < 0.05, respectively). Elderly individuals ≥ 60 years of age accounted for 47.6% (80,578 patients) of all cases of IS. The proportion of patients who received conservative treatment increased from 82.4% in 2010 to 85.8% in 2019, while that of patients receiving surgical treatment decreased from 17.6% to 14.2% (P < 0.05, respectively). Among surgical treatments, the proportions of corpectomy and anterior fusion declined, while proportion of incision and drainage increased (P < 0.05, respectively). The total healthcare costs increased 2.9-fold from $29,821,391.65 in 2010 to $86,815,775.81 in 2019 with a significant increase in the ratio to gross domestic product. Hence, this population-based cohort study demonstrated that the incidence rate of IS has increased in South Korea. The conservative treatment has increased, while the surgical treatment has decreased. The socioeconomic burden of IS has increased rapidly.

by Carolyna Hepburn, Alexis Jones, Alan Bainbridge, Coziana Ciurtin, Juan Eugenio Iglesias, Hui Zhang, Margaret A. Hall-Craggs, Timothy J. P. Bray Qualitative visual assessment of MRI scans is a key mechanism by which inflammation is assessed in clinical practice. For example, in axial spondyloarthritis (axSpA), visual assessment focuses on the identification of regions with increased signal in the bone marrow, known as bone marrow oedema (BMO), on water-sensitive images. The identification of BMO has an important role in the diagnosis, quantification and monitoring of disease in axSpA. However, BMO evaluation depends heavily on the experience and expertise of the image reader, creating substantial imprecision. Deep learning-based segmentation is a natural approach to addressing this imprecision, but purely automated solutions require large training sets that are not currently available, and deep learning solutions with limited data may not be sufficiently trustworthy for use in clinical practice. To address this, we propose a workflow for inflammation segmentation incorporating both deep learning and human input. With this ‘human-machine cooperation’ workflow, a preliminary segmentation is generated automatically by deep learning; a human reader then ‘cleans’ the segmentation by removing extraneous segmented voxels. The final cleaned segmentation defines the volume of hyperintense inflammation (VHI), which is proposed as a quantitative imaging biomarker (QIB) of inflammation load in axSpA. We implemented and evaluated the proposed human-machine workflow in a cohort of 29 patients with axSpA who had undergone prospective MRI scans before and after starting biologic therapy. The performance of the workflow was compared against purely visual assessment in terms of inter-observer/inter-method segmentation overlap, inter-observer agreement and assessment of response to biologic therapy. The human-machine workflow showed superior inter-observer segmentation overlap than purely manual segmentation (Dice score 0.84 versus 0.56). VHI measurements produced by the workflow showed similar or better inter-observer agreement than visual scoring, with similar response assessments. We conclude that the proposed human-machine workflow offers a mechanism to improve the consistency of inflammation assessment, and that VHI could be a valuable QIB of inflammation load in axSpA, as well as offering an exemplar of human-machine cooperation more broadly.

Spondylodiscitis is an infection of vertebral body and intervertebral disc. It may be acquired by haematogenous spread of the pathogen from a distant site (most common route of infection), direct inoculation from trauma, invasive spinal diagnostic procedures or spinal surgery, or contiguous spread from adjacent soft tissue infection [1,2]. Most patients have mono-microbial infection, with Staphylococcus aureus being the most common etiological germ; other potential pathogens of spondylodiscitis include coagulase-negative staphylococci, streptococci, gram negative bacteria (such as Enterobacteriaceae and Pseudomonas aeruginosa), and rarely Mycobacterium tuberculosis and Brucella spp.

SummaryAnkylosing Spondylitis is the main entity of a family of inflammatory diseases affecting many musculoskeletal (sacroiliac joints, spine, peripheral joints) and extra-musculoskeletal sites, termed spondyloarthritis. While it is debated whether disease onset is primarily driven by autoimmune or autoinflammatory processes, what is certain is that both innate and adaptive immune responses orchestrate local and systemic inflammation, which leads to chronic pain and immobility. Immune checkpoint signals are one key player for keeping the immune system in check and in balance, but their role in disease pathogenesis is still rather elusive. Therefore, we ran a MEDLINE search utilizing the PubMed platform for a variety of immune checkpoint signals in regard to ankylosing spondylitis. In this review, we summarise the experimental and genetic data available and evaluate the relevance of immune checkpoint signalling in the pathogenesis of ankylosing spondylitis. Markers such as PD-1 and CTLA-4 have been extensively studied and facilitate the concept of an impaired negative immune regulation in ankylosing spondylitis. Other markers are either neglected completely or insufficiently examined, and the data is conflicting. Still, some of those markers remain interesting targets to decipher the pathogenesis of ankylosing spondylitis and to develop new treatment strategies.

Abstract Background Disseminated nocardiosis is a very rare disease. By now only few cases of meningitis and spondylodiscitis have been reported. To our knowledge, this is the first case of meningitis caused by Nocardia nova. Case presentation We report on a case of bacteraemia, meningitis and spondylodiscitis caused by N. nova in an immunocompetent patient. We describe the long, difficult path to diagnosis, which took two months, including all diagnostic pitfalls. After nocardiosis was diagnosed, intravenous antibiotic therapy with ceftriaxone, later switched to imipenem/cilastatin and amikacin, led to rapid clinical improvement. Intravenous therapy was followed by oral consolidation with co-trimoxazole for 9 months without any relapse within 4 years. Conclusions Establishing a diagnosis of nocardiosis is a precondition for successful antibiotic therapy. This requires close communication between clinicians and laboratory staff about the suspicion of nocardiosis, than leading to prolonged cultures and specific laboratory methods, e.g. identification by 16S rDNA PCR. …

IntroductionDuring the COVID-19 pandemic, an accelerated uptake of remote monitoring strategies, replacing traditional face-to-face care, has been observed. However, data on the effects of remote care interventions for patients with rheumatic and musculoskeletal diseases remain scarce and interpretation is hampered by study heterogeneity and research quality concerns. High-quality evidence is required to guide future implementation in clinical practice, with health economic analyses identified as an important knowledge gap. Randomised controlled trials (RCTs) comparing telemonitoring with conventional care for patients with spondyloarthritis (SpA) are currently lacking.Methods and analysisTeleSpA is a pragmatic, multicentre RCT investigating the effectiveness and cost-effectiveness of combined asynchronous telemonitoring and patient-initiated follow-up for patients with SpA, compared with conventional care. Two-hundred patients will be recruited at two hospitals and randomised (1:1) to the study intervention or standard care. The primary endpoint is a reduction in the number of follow-up visits by ≥25% in the intervention compared with standard care group, during a 1-year period. Secondary endpoints are (a) non-inferiority of the study intervention with regard to health outcomes, quality of care and patient-reported experience with care; and (b) cost-effectiveness of the intervention, evaluated through a prospective trial-based cost-utility analysis. In addition, experiences with the study intervention will be assessed among patients and healthcare providers, and factors associated with primary and secondary endpoints will be identified.Ethics and disseminationThis study was approved by the Medical Research Ethics Committee of the Academic Hospital Maastricht/Maastricht University (NL71041.068.19/METC 19-059). Results will be disseminated through publications in peer-reviewed journals and conference presentations.Trial registration numberNCT04673825.…

by Susana Aideé González-Chávez, Joan S. Salas-Leiva, Dayana E. Salas-Leiva, Salma Marcela López-Loeza, Jasanai Sausameda-García, Erasmo Orrantia-Borunda, Rubén Burgos-Vargas, Maria Fernanda Alvarado-Jáquez, Mayra Torres-Quintana, Rubén Cuevas-Martínez, Eduardo Chaparro-Barrera, Carlos Marín-Terrazas, Gerardo Pável Espino-Solís, José Pablo Romero-López, Brian de Jesús Bernal-Alferes, César Pacheco-TenaTo analyze the effect of levofloxacin-induced intestinal microbiota modifications on intestinal, joint, and systemic inflammation in the DBA/1 mice with spontaneous arthritis. The study included two groups of mice, one of which received levofloxacin. The composition and structure of the microbiota were determined in the mice’s stool using 16S rRNA sequencing; the differential taxa and metabolic pathway between mice treated with levofloxacin and control mice were also defied. The effect of levofloxacin was evaluated in the intestines, hind paws, and spines of mice through DNA microarray transcriptome and histopathological analyses; systemic inflammation was measured by flow cytometry. Levofloxacin decreased the pro-inflammatory bacteria, including Prevotellaceae, Odoribacter, and Blautia, and increased the anti-inflammatory Muribaculaceae in mice’s stool. Histological analysis confirmed the intestinal inflammation in control mice, while in levofloxacin-treated mice, inflammation was reduced; in the hind paws and spines, levofloxacin also decreased the inflammation. Microarray showed the downregulation of genes and signaling pathways relevant in spondyloarthritis, including several cytokines and chemokines. Levofloxacin-treated mice showed differential transcriptomic profiles between peripheral and axial joints and intestines. Levofloxacin decreased the expression of TNF-α, IL-23a, and JAK3 in the three tissues, but IL-17 behaved differently in the intestine and the joints. Serum TNF-α was also reduced in levofloxacin-treated mice. Our results suggest that the microbiota modification aimed at reducing pro-inflammatory and increasing anti-inflammatory bacteria could potentially be a coadjuvant in treating inflammatory arthropathies.

ObjectivesTo evaluate comanagement with rheumatology and biological prescriptions filled during pregnancy among women with axial spondyloarthritis (axSpA), rheumatoid arthritis (RA) or psoriatic arthritis (PsA) and to examine factors associated with receiving comanagement with rheumatology during pregnancy.DesignA retrospective analysis of US claims data.SettingCommercially insured enrollees using data from the 2013–2018 IBM MarketScan Commercial Claims and Encounters Database.ParticipantsWe identified 4131 pregnant women aged ≤55 years from the 2013–2018 IBM MarketScan Commercial Claims and Encounters Database with an International Classification of Disease, 9th Revision/10th Revision codes for RA, axSpA or PsA, with continuous enrolment at ≥3 months before the date of the last menstrual period (LMP) (index date) and throughout pregnancy.Primary outcomesFilled biologics (prescriptions and infusions) claims were categorised by 90 days before the LMP and trimester, as were primary care, obstetrician and rheumatological claims.ResultsThe prevalence of axSpA, RA and PsA was 0.7%, 0.2% and 0.04% among reproductive age women. The average maternal age was 32.7 years (SD 5.7). During pregnancy, 9.1% of those with axSpA (n=2,410) and 56.4% of those with RA/PsA (n=1,721) had a rheumatological claim. Biologics claims were less common among those with axSpA (90 days before LMP: 1.6%, during pregnancy: 1.1%) than those with RA/PsA (90 days before LMP: 11.9%, during pregnancy: 6.9%). Medications during pregnancy included corticosteroids (axSpA: 0.3%, RA/PsA: 2.2%), non-biological disease-modifying antirheumatic drugs (axSpA: 0.2%, RA/PsA: 1.7%), non-steroidal anti-inflammatory drugs (axSpA: 0.2%, RA/PsA: 1.3%) and opioids (axSpA: 0.2%, RA/PsA: 0.6%). Established rheumatological care and biologics claims during the 90 days before LMP showed good prediction accuracy for receiving comanagement with rheumatology during pregnancy (axSpA: area under the receiver operator curve (AUC) 0.73, RA/PsA: AUC 0.70).ConclusionComanagement with rheumatology during pregnancy occurs infrequently, especially for women with axSpA. Biologics claims during pregnancy may not align with published guidelines. Future research is warranted to improve comanagement with rheumatology during pregnancy.…

Objectives

To understand what we can learn from the impact of the COVID-19 pandemic and lockdown about what enables work participation for people with inflammatory arthritis and chronic pain conditions.

Design

Qualitative interviews embedded within an observational questionnaire study of individuals with musculoskeletal (MSK) conditions.

Setting

UK primary care (general practices), and secondary care-based rheumatology services.

Participants

Individuals with axial spondyloarthritis, psoriatic arthritis and MSK pain from three established cohorts completed an online/paper-based questionnaire (July–December 2020). A subset of respondents were selected for semistructured interviews.

Primary and secondary outcome measures

The survey quantified the effects of lockdown on work circumstances. Qualitative interviews explored the impacts of these changes and the advantages and disadvantages of changes in work circumstances.

Results

491 people (52% female, median age 49 years) who were employed at the time of lockdown responded to the questionnaire. The qualitative analysis included 157 free-text comments on work from the questionnaire and data collected within 18 interviews.

Participants reported impacts on mental and physical health, and significant financial anxieties. The impact of work changes varied depending on individual and home circumstances. Some felt forced to ignore advice to shield and continue working. The flexibility offered by home working and changes in commuting enabled greater physical activity for some, while others missed the exercise normally undertaken as part of their commute. Others reported a constant need to be ‘present’ online, which heightened anxiety and worsened MSK symptoms.

Conclusion

Lockdown showed that flexible working arrangements, which consider the positive and negative aspects of commuting, posture, movement, and work environment matter for work participation, and can have wider benefits in terms of health and well-being for those with long-term MSK conditions. Incorporating these into new models of work will help make the workplace more equitable and inclusive for people with long-term MSK conditions.

…

Ankylosing spondylitis (AS) belongs to a group of diseases, called spondyloarthropathies (SpA), that are strongly associated with the genetic marker HLA-B27. AS is characterized by inflammation of joints and primarily affects the spine. Over 160 subtypes of HLA-B27 are known, owing to high polymorphism. Some are strongly associated with disease (e.g., B*2704), whereas others are not (e.g., B*2709). Misfolding of HLA-B27 molecules [as dimers, or as high-molecular-weight (HMW) oligomers] is one of several hypotheses proposed to explain the link between HLA-B27 and AS. Our group has previously established the existence of HMW species of HLA-B27 in AS patients. Still, very little is known about the mechanisms underlying differences in pathogenic outcomes of different HLA-B27 subtypes. We conducted a proteomics-based evaluation of the differential disease association of HLA B*2704 and B*2709, using stable transfectants of genes encoding the two proteins. A clear difference was observed in protein clearance mechanisms: whereas unfolded protein response (UPR), autophagy, and aggresomes were involved in the degradation of B*2704, the endosome–lysosome machinery was primarily involved in B*2709 degradation. These differences offer insights into the differential disease association of B*2704 and B*2709.…

Introduction

Psoriatic arthritis (PsA) is an inflammatory disease characterised by synovitis, enthesitis, dactylitis and axial involvement. The prevalence of axial involvement ranges from 25% to 70% in this patient group. Treatment recommendations for axial PsA were mainly extrapolated from guidelines for axial spondyloarthritis, and the main treatment options are non-steroidal anti-inflammatory drugs and biological disease-modifying antirheumatic drugs (tumour necrosis factor, IL-17 and IL-23 inhibitors). Tofacitinib was approved for the treatment of PsA and its efficacy on axial inflammation has been demonstrated in a phase II study of ankylosing spondylitis (AS). This prospective study aims to evaluate the efficacy of tofacitinib in reducing inflammation in the sacroiliac joints (SIJs) and spine on MRI in patients with axial disease of their PsA presenting with active axial involvement compatible with axial PsA.

Methods and analyses

This is a randomised, double-blind, placebo-controlled, multicentre clinical trial in patients with axial PsA who have evidence of axial involvement, active disease as defined by a Bath AS Disease Activity Index score of ≥4 and active inflammation on MRI of the SIJs and/or spine as assessed by and independent central reader. The study includes a 6-week screening period, a 24-week treatment period, which consist of a 12-week placebo-controlled double-blind treatment period followed by a 12-week active treatment period with tofacitinib for all participants, and a safety follow-up period of 4 weeks. At baseline, 80 subjects shall be randomised (1:1) to receive either tofacitinib or matching placebo for a 12-week double-blind treatment period. At week 12, an MRI of the whole spine and SIJs will be performed to evaluate the primary study endpoint.

Ethics and dissemination

The study will be performed according to the ethical principles of the Declaration of Helsinki and the German drug law. The independent ethics committees of each centre approved the ethical, scientific and medical appropriateness of the study before it was conducted.

Trial registration number

NCT04062695; ClinicalTrials.gov and EudraCT No: 2018-004254-22; European Union Clinical Trials Register.

Abstract

Background

Only three other cases of rat bite fever caused by Streptobacillus notomytis in humans have been reported since this species was identified in 2015. Data specific to the differences in clinical features and geographic distribution between S. notomytis infection and S. moniliformis infection are scarce. All previous cases of human S. notomytis infection were reported from Japan. This is the first case of S. notomytis infection reported from outside of Japan.

Case presentation

A 72-year-old Thai woman was admitted to Siriraj Hospital (Bangkok, Thailand)—Thailand’s largest university-based national tertiary referral center—in August 2020 with fever, myalgia, and polyarthralgia for 3 days, and gradually decreased consciousness for the past 1 day. Physical examination and laboratory investigations revealed septic arthritis of both knee joints, meningitis, and hepatitis. She was initially misdiagnosed as rheumatoid arthritis in the elderly since the initial investigations were unable to detect a causative pathogen. However, S. notomytis infection was later confirmed by polymerase chain reaction amplification of a part of the 16S rRNA gene and sequencing from synovial fluid. Her clinical course was also complicated by spondylodiscitis and epidural abscess caused by S. notomytis, which was detected from tissue biopsy. Therefore, rat bite fever in this patient manifested as meningitis, septic polyarthritis, hepatitis, and spondylodiscitis. The patient was treated with intravenous ceftriaxone then switched to oral amoxicillin with complete recovery.

Conclusions

The clinical manifestations of S. notomytis infection are similar to those demonstrated in S. moniliformis infection. This case also showed that arthritis caused by S. notomytis mimics rheumatoid arthritis, and that meningitis and spondylodiscitis are potential coexisting complications that can be found in S. notomytis infection.

Introduction

Inflammatory arthritis (IA) conditions, including rheumatoid arthritis, psoriatic arthritis and axial spondyloarthritis, are characterised by inflammatory infiltration of the joints. Biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs), respectively, reduce the effects of proinflammatory cytokines and immune cells to ameliorate disease. However, immunosuppression can be associated with high rates of serious adverse events (SAEs), including serious infections, and maybe an increased risk of malignancies and cardiovascular events. Currently, there is no empirical evidence on the extent to which contextual factors and risk of bias (RoB) domains may modify these harm signals in randomised trials.

Methods and analysis

We will search MEDLINE (via PubMed) for systematic reviews published since April 2015 and all Cochrane reviews. From these reviews, randomised trials will be eligible if they include patients with an IA condition with at least one group randomly allocated to bDMARD and/or tsDMARD treatments. A predefined form will be used for extracting data on population characteristics (eg, baseline characteristics or eligibility criteria, such as medication background) and specific harm outcome measures, such as number of withdrawals, numbers of patients discontinuing due to adverse events and number of patients having SAEs. RoB in individual trials will be assessed using a modified Cochrane RoB tool. We will estimate the potentially causal harm effects related to the experimental intervention compared with control comparator as risk ratios, and heterogeneity across randomised comparisons will be assessed statistically and evaluated as inconsistency using the I2 Index. Our metaregression analyses will designate population and trial characteristics and each RoB domain as independent variables, whereas the three harm domains will serve as dependent variables.

Ethics and dissemination

Ethics approval is not required for this study. Results will be disseminated through publication in international peer-reviewed journals.

PROSPERO registration number

CRD42020171124.

Abstract

Purpose

This study sought to recognize differences in clinical disease manifestations of spondylodiscitis depending on the causative bacterial species.

Methods

We performed an evaluation of all spondylodiscitis cases in our clinic from 2013–2018. 211 patients were included, in whom a causative bacterial pathogen was identified in 80.6% (170/211). We collected the following data; disease complications, comorbidities, laboratory parameters, abscess occurrence, localization of the infection (cervical, thoracic, lumbar, disseminated), length of hospital stay and 30-day mortality rates depending on the causative bacterial species. Differences between bacterial detection in blood culture and intraoperative samples were also recorded.

Results

The detection rate of bacterial pathogens through intraoperative sampling was 66.3% and could be increased by the results of the blood cultures to a total of 80.6% (n = 170/211). S. aureus was the most frequently detected pathogen in blood culture and intraoperative specimens and and was isolated in a higher percentage cervically than in other locations of the spine. Bacteremic S. aureus infections were associated with an increased mortality (31.4% vs. overall mortality of 13.7%, p = 0.001), more frequently developing complications, such as shock, pneumonia, and myocardial infarction. Comorbidities, abscesses, length of stay, sex, and laboratory parameters all showed no differences depending on the bacterial species.

Conclusion

Blood culture significantly improved the diagnostic yield, thus underscoring the need for a structured diagnostic approach. MSSA spondylodiscitis was associated with increased mortality and a higher incidence of complications.