A validation of register-derived diagnoses of interstitial lung disease in patients with inflammatory arthritis: data from the NOR-DMARD study.

OBJECTIVE: There is a lack of knowledge concerning the validity of the interstitial lung disease (ILD) diagnoses used in epidemiological studies on rheumatic diseases. This paper seeks to verify register-derived ILD diagnoses using chest computed tomography (CT) and medical records as a gold standard. METHOD: The Norwegian Anti-Rheumatic Drug Register (NOR-DMARD) is a multicentre prospective observational study of patients with inflammatory arthritis who start treatment with disease-modifying anti-rheumatic drugs. NOR-DMARD is linked to the Norwegian Patient Registry (NPR) and Cause of Death Registry. We searched registers for ILD coded by ICD-10 J84 or J99 among patients with rheumatoid arthritis, psoriatic arthritis, or spondyloarthritis. We extracted chest CT reports and medical records from participating hospitals. Two expert thoracic radiologists scored examinations to confirm the ILD diagnosis. We also searched medical records to find justifications for the diagnosis following multidisciplinary evaluations. We calculated the positive predictive values (PPVs) for ILD across subsets. RESULTS: We identified 71 cases with an ILD diagnosis. CT examinations were available in 65/71 patients (91.5%), of whom ILD was confirmed on CT in 29/65 (44.6%). In a further 10 patients, medical records confirmed the diagnosis, giving a total of 39/71 verified cases. The PPV of a register-derived ILD diagnosis was thus 54.9%. In a subset of patients who had received an ILD code at two or more time-points and had a CT scan taken within a relevant period, the PPV was 72.2%. CONCLUSION: The validity of register-based diagnoses of ILD must be carefully considered in epidemiological studies.

SARS-CoV-2 Positivity in Asymptomatic-Screened Dental Patients.

Enhanced community surveillance is a key pillar of the public health response to coronavirus disease 2019 (COVID-19). Asymptomatic carriage of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a potentially significant source of transmission, yet remains relatively poorly understood. Disruption of dental services continues with significantly reduced capacity. Ongoing precautions include preappointment and/or at appointment COVID-19 symptom screening and use of enhanced personal protective equipment (PPE). This study aimed to investigate SARS-CoV-2 infection in dental patients to inform community surveillance and improve understanding of risks in the dental setting. Thirty-one dental care centers across Scotland invited asymptomatic-screened patients aged over 5 y to participate. Following verbal consent and completion of sociodemographic and symptom history questionnaire, trained dental teams took a combined oropharyngeal and nasal swab sample using standardized Viral Transport Medium-containing test kits. Samples were processed by the Lighthouse Lab and patients informed of their results by SMS/email with appropriate self-isolation guidance in the event of a positive test. All positive cases were successfully followed up by the national contact tracing program. Over a 13-wk period (from August 3, 2020, to October 31, 2020), 4,032 patients, largely representative of the population, were tested. Of these, 22 (0.5%; 95% CI, 0.5%-0.8%) tested positive for SARS-CoV-2. The positivity rate increased over the period, commensurate with uptick in community prevalence identified across all national testing monitoring data streams. To our knowledge, this is the first report of a COVID-19 testing survey in asymptomatic-screened patients presenting in a dental setting. The positivity rate in this patient group reflects the underlying prevalence in community at the time. These data are a salient reminder, particularly when community infection levels are rising, of the importance of appropriate ongoing infection prevention control and PPE vigilance, which is relevant as health care team fatigue increases as the pandemic continues. Dental settings are a valuable location for public health surveillance.

Biomarkers of cardiovascular risk across phenotypes of osteoarthritis.

BACKGROUND: The objective of this study was to explore the associations between ultrasonographic and radiographic joint scores and levels of arterial CVD risk markers in patients with osteoarthritis (OA). Secondly, to compare the levels of arterial CVD risk markers between OA phenotypes and controls. METHOD: The "Musculoskeletal pain in Ullensaker" Study (MUST) invited residents of Ullensaker municipality with self-reported OA to a medical examination. OA was defined according to the American College of Rheumatology (ACR) criteria and phenotyped based on joint distribution. Joints of the hands, hips and knees were examined by ultrasonography and conventional radiography, and scored for osteosteophytes. Hands were also scored for inflammation by grey scale (GS) synovitis and power Doppler (PD) signal. Control populations were a cohort of inhabitants of Oslo (OCP), and for external validation, a UK community-based register (UKPC).Pulse pressure augmentation index (AIx) and pulse wave velocity (PWV) were measured using the Sphygmocor apparatus (Atcor®). Ankel-brachial index (ABI) was estimated in a subset of patients. In separate adjusted regression models we explored the associations between ultrasonography and radiograph joint scores and AIx, PWV and ABI. CVD risk markers were also compared between phenotypes of OA and controls in adjusted analyses. RESULTS: Three hundred and sixty six persons with OA were included (mean age (range); 63.0 (42.0-75.0)), (females (%); 264 (72)). Of these, 155 (42.3%) had isolated hand OA, 111 (30.3%) had isolated lower limb OA and 100 (27.3%) had generalized OA. 108 persons were included in the OCP and 963 persons in the UKPC; (mean age (range); OCP: 57.2 (40.4-70.4), UKPC: 63.9 (40.0-75.0), females (%); OCP: 47 (43.5), UKPC: 543 (56.4%). Hand osteophytes were associated with AIx while GS and PD scores were not related to CVD risk markers. All OA phenotypes had higher levels of AIx compared to OCP in adjusted analyses. External validation against UKPC confirmed these findings. CONCLUSIONS: Hand osteophytes might be related to higher risk of CVD. People with OA had higher augmented central pressure compared to controls.Words 330.

Biological treatment in ankylosing spondylitis in the Nordic countries during 2010-2016: a collaboration between five biological registries.

OBJECTIVES: Large-scale observational cohorts may be used to study the effectiveness and rare side effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) in ankylosing spondylitis (AS), but may be hampered by differences in baseline characteristics and disease activity across countries. We aimed to explore the research infrastructure in the five Nordic countries regarding bDMARD treatment in AS. METHOD: This observational cohort study was based on data from biological registries in Denmark (DANBIO), Sweden (SRQ/ARTIS), Finland (ROB-FIN), Norway (NOR-DMARD), and Iceland (ICEBIO). Data were collected for the years 2010-2016. Registry coverage, registry inventory (patient characteristics, disease activity measures), and national guidelines for bDMARD prescription in AS were described per country. Incident (first line) and prevalent bDMARD use per capita, country, and year were calculated. In AS patients who started first line bDMARDs during 2010-2016 (n = 4392), baseline characteristics and disease activity measures were retrieved. RESULTS: Registry coverage of bDMARD-treated patients ranged from 60% to 95%. All registries included extensive prospectively collected data at patient level. Guidelines regarding choice of first line drug and prescription patterns varied across countries. During the period 2010-2016 prevalent bDMARD use increased (p < 0.001), whereas incident use tended to decrease (p for trend < 0.004), with large national variations (e.g. 2016 incidence: Iceland 10.7/100 000, Finland 1.7/100 000). Baseline characteristics were similar regarding C-reactive protein, but differed for other variables, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (range 3.5-6.3) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (2.7-3.8) (both p < 0.0001). CONCLUSION: Collaboration across the five Nordic biological registries regarding bDMARD use in AS is feasible but national differences in coverage, prescription patterns, and patient characteristics must be taken into account depending on the scientific question.

High-intensity cardiorespiratory and strength exercises reduced emotional distress and fatigue in patients with axial spondyloarthritis: a randomized controlled pilot study.

OBJECTIVE: To investigate the effect of high-intensity exercise on emotional distress, fatigue, and ability to do a full day's activities in patients with axial spondyloarthritis (axSpA). METHOD: A total of 28 physically inactive axSpA patients were randomized to either an exercise group (EG), which performed 12 weeks of cardiorespiratory and strength exercises, or a control group (CG), which received treatment as usual. The outcomes reported in this paper are secondary outcomes in the trial and included emotional distress (General Health Questionnaire-12, 0-36, 36 = worst), fatigue [numeric rating scale (NRS), 0-10, 10 = worst], and ability to do a full day's activities (NRS, 0-10, 10 = worst). Post-intervention differences were assessed by analysis of covariance with baseline values as covariates. RESULTS: Twenty-four patients were included in the analyses. All patients in the EG followed the exercise protocol. The EG had a statistically significant beneficial effect [mean group differences (95% confidence interval)] on emotional distress [-5.8, (-9.7, -1.9), p < 0.01], fatigue [-2.4, (-4.3, -0.4), p = 0.02], and ability to do a full day's work [-2.2, (-3.9, -0.4), p = 0.02] compared to the CG. CONCLUSION: This pilot study showed promising effects of cardiorespiratory and strength exercises on emotional distress, fatigue, and ability to do a full day's activities in patients with axSpA. The findings need to be confirmed in a larger trial.

Circulating levels of inflammatory cytokines and cytokine receptors in patients with ankylosing spondylitis: a cross-sectional comparative study.

OBJECTIVES: Insight into the most important inflammatory pathways in ankylosing spondylitis (AS) could be of importance in risk stratification and the development of treatment strategies. Therefore, we aimed to compare circulating levels of inflammatory biomarkers between AS patients and controls, and explore associations between these biomarkers and clinical measures of disease activity. METHOD: In a cross-sectional study, 143 AS patients were compared with 124 population controls. Blood samples were analysed by immunoassays for interleukin (IL)-6, IL-17a, IL-23, soluble tumour necrosis factor receptor 1 (sTNF-R1) and 2 (sTNF-R2), and osteoprotegerin (OPG). Disease activity was measured by the AS Disease Activity Score (ASDAS) and the Bath AS Disease Activity Index (BASDAI). RESULTS: Analysis of covariance (ANCOVA) demonstrated elevated plasma levels of sTNF-R1 [geometrical mean 0.94 (95% CI 0.88-1.00) vs. 0.83 (95% CI 0.78-0.89) ng/mL, p < 0.01] and OPG (2.3, 95% CI 2.1-2.4 vs. 2.0, 95% CI 1.9-2.2 ng/mL, p = 0.02) and, although not significant, of IL-23 (122, 95% CI 108-139 vs. 106, 95% CI 93-120 pg/mL, p = 0.07) in AS patients vs. CONTROLS: More AS patients had a high level of sTNF-R2 than controls (22 vs. 1, p < 0.01). No differences between the groups were seen for IL-6 and IL-17a. In patients, no significant associations were seen between inflammatory markers and disease activity measures after adjusting for personal characteristics. CONCLUSION: Significantly higher plasma levels of sTNF-R1, sTNF-R2, and OPG and numerically but non-significantly higher levels of IL-23 were found in AS patients compared to controls, indicating that these cytokines and cytokine receptors are important inflammatory pathways. Clinical measures of disease activity were not significantly correlated with circulating inflammatory markers.

EULAR evidence-based recommendations for cardiovascular risk management in patients with rheumatoid arthritis and other forms of inflammatory arthritis.

OBJECTIVES: To develop evidence-based EULAR recommendations for cardiovascular (CV) risk management in patients with rheumatoid arthritis (RA), ankylosing spondylitis (AS) and psoriatic arthritis (PsA). METHODS: A multidisciplinary expert committee was convened as a task force of the EULAR Standing Committee for Clinical Affairs (ESCCA), comprising 18 members including rheumatologists, cardiologists, internists and epidemiologists, representing nine European countries. Problem areas and related keywords for systematic literature research were identified. A systematic literature research was performed using MedLine, Embase and the Cochrane library through to May 2008. Based on this literature review and in accordance with the EULAR's "standardised operating procedures", the multidisciplinary steering committee formulated evidence-based and expert opinion-based recommendations for CV risk screening and management in patients with inflammatory arthritis. RESULTS: Annual CV risk assessment using national guidelines is recommended for all patients with RA and should be considered for all patients with AS and PsA. Any CV risk factors identified should be managed according to local guidelines. If no local guidelines are available, CV risk management should be carried out according to the SCORE function. In addition to appropriate CV risk management, aggressive suppression of the inflammatory process is recommended to further lower the CV risk. CONCLUSIONS: Ten recommendations were made for CV risk management in patients with RA, AS and PsA. The strength of the recommendations differed between RA on the one hand, and AS and PsA, on the other, as evidence for an increased CV risk is most compelling for RA.

Real-time detection of mitochondrial inhibition at frog motor nerve terminals using increases in the spatial variance in probability of transmitter release.

The effects of Hg2+, methyl mercury, and flufenamic acid, all of which inhibit mitochondria, were examined at frog motor nerve terminals. Unbiased estimates of m (no. of transmitter quanta released), n (no. of functional release sites), p (probability of release), and vars p (spatial variance in p) were obtained using K(+)-induced asynchronous neurosecretion (m, n and p not having the same definitions as with nerve-evoked release). Transient but significant increases in m, n, p and vars p were found with all three agents. These findings indicate that mitochondrial inhibition and release of sequestered Ca2+ can be detected as a real-time increase in vars p. The results also suggest that changes in vars p might be used to differentiate between cellular (membrane) and subcellular (organellar) actions of drugs at the nerve terminal.

Effect of the putative cognitive enhancer, linopirdine (DuP 996), on quantal parameters of acetylcholine release at the frog neuromuscular junction.

1. The subcellular mechanism and site of action of linopirdine or DuP 996 (3,3-bis(4-pyridinylmethyl)-1-phenylindolin-2-one) was investigated at the frog neuromuscular junction, using miniature endplate potential (m.e.p.p.) counts and a new method for obtaining unbiased estimates of n (number of functional release sites), p (probability of release), and varsp (spatial variance in p). 2. DuP 996 produced an increase in m (no. of quanta released), which was due to an increase in n and p. The increase in m was concentration-dependent over a range of 0.1-100 microM and completely reversible with 15 min of wash. There was a saturation in the increase in p, but not in the increase in m and n, for [DuP 996] > 10 microM. By contrast, there was no major change in varsp. 3. Block of presynaptic Na(+)- and Ca(2+)-channels with 3 microM tetrodoxin and 1.8 mM Co2+ prevented the m.e.p.p. frequency increase to DuP996, and this effect was completely reversed by washing. 4. Application of the neuronal Ca(2+)-channel blocker, omega-conotoxin GVIA (1 microM) brought about a rapid and profound decrease in the m.e.p.p. frequency increased produced by DuP996. The effect of the toxin was not reversed by prolonged washing. 5. Block of voltage-gated K(+)-channels with 100 microM 4-aminopyridine (4-AP) resulted in only a small (28%) increase in m. The combination of 4-AP (100 microM) and DuP996 (10 microM) produced an increase in m (189%) which was much greater than the sum of the responses to each agent alone. This increase in m was due solely to an increase in n, as p and varsp were unchanged.6. For [DuP 996] up to 100 gM, there was no apparent change in the mean size, amplitude distribution,or time course of m.e.p.ps, signifying that it had no anticholinesterase activity.7. It is concluded that DuP 996 increases the release of quantal transmitter but not the postsynaptic response to the quanta. This appears to involve an effect at the nerve terminal membrane, most likely an increase in Ca2+-conductance, and not an action to block K+-conductance or to release Ca2+ from intraterminal organelles.

Unbiased estimates of quantal release parameters and spatial variation in the probability of neurosecretion.

A procedure was developed for dealing with two problems that have impeded the use of quantal parameters in studies of transmitter release. The first, involving temporal and spatial biasing in the estimates for the number of functional release sites (n) and probability of release (p), was addressed by reducing temporal variance experimentally and calculating the bias produced by spatial variance in p (var(s)p). The second, involving inaccuracies in the use of nerve-evoked endplate potentials (EPPs), was circumvented by using only miniature EPPs (MEPPs). Intracellular recordings were made from isolated frog cutaneous pectoris, after decapitation and pithing of the animals, and the concentration of K+ ([K+]) was raised to 10 mM to increase the level of transmitter release. The number of quanta released (m) by the EPP was replaced by the number of MEPPs in a fixed time interval (bin), and 500 sequential bins used for each quantal estimate. With the use of 50-ms bins, estimates for var(s)p were consistently negative. This was due to too large a bin (and introduction of undetected temporal variance) because the use of smaller bins (5 ms) produced positive estimates of var(s)p. Increases in m, n, and p but not var(s)p were found in response to increases in [K+] or [Ca2+]/[Co2+]. La3+ (20 microM) produced increases in m and n, which peaked after 20 min and declined toward zero. There were also large increases in p and var(s)p, which peaked and declined only to initial control values. The increase in var(s)p was presumed to reflect La(3+)-induced release of Ca2+ from intracellular organelles. The results suggest that this approach may be used to obtain unbiased estimates of n and p and that the estimates of var(s)p may be useful for studying Ca2+ release from intraterminal organelles.

Aluminum inhibits glutamate release from transverse rat hippocampal slices: role of G proteins, Ca channels and protein kinase C.

Aluminum (Al) has been shown to produce deficits in learning and memory. The present experiments tested the hypothesis that Al-induced inhibition of learning may be due to its effect on glutamate release secondary to changes in calcium channel function and/or intracellular events triggering glutamate release. Calcium-dependent potassium (K)-evoked [14C]-glutamate release from 400 microns transverse rat hippocampal slices was inhibited by Al in a concentration dependent manner (IC50 = 40 microM). Aluminum (30, 100 microM) noncompetitively inhibited Bay K 8644-evoked glutamate release. 4-Aminopyridine (30, 1000 microM) noncompetitively attenuated the Al inhibition of glutamate release, suggesting an Al-induced alteration of Ca channel function. Activation of the Gi protein by R(-)phenylisopropyladenosine (PIA; 1 microM) reduced K-evoked glutamate release 69%, whereas 300 microM Al produced an 84% reduction. These effects were prevented by the Gi protein inhibitor N-ethylmaleimide (NEM; 100 microM), suggesting an effect of Al on the Gi protein to inhibit glutamate release. Phorbol myristate acetate (0.16 microM)-induced glutamate release was inhibited by 300 microM Al and 80 microM polymyxin B, suggesting an Al modulation of protein kinase C (PKC)-evoked glutamate release. These results demonstrate an Al inhibition of glutamate release that may be mediated by multiple, but interconnected mechanisms (e.g., via interactions with Ca systems), providing multiple targets for an Al-induced alteration of neuronal function.

Subcellular mechanism and site of action of ionic lanthanum at the motor nerve terminal.

The mechanism by which ionic lanthanum (La3+) increases and subsequently decreases spontaneous transmitter release was investigated by recording miniature endplate potentials (MEPPs) at frog neuromuscular junctions. Addition of tetrodotoxin and Co2+ delayed the onset of MEPP frequency increase but did not otherwise prevent the response. Dinitrophenol substantially reduced but did not eliminate the increase, whereas 3,4,5-trimethoxybenzoic acid 8-(diethylamino) octyl ester (TMB-8) completely abolished it. Thus, La3+ does not act by depolarizing the terminal or by substituting for Ca2+ at transmitter release sites. Instead, it appears to enter the terminal through Na+ channels and promote Ca2+ release from intracellular organelles. The profound depletion of transmitter with time may be due to the high turnover of transmitter coupled with the inhibition of metabolic processes by La3+.

Tetrahydroaminoacridine and physostigmine have opposing effects on probability of transmitter release at the frog neuromuscular junction.

The effect of 1,2,3,4-tetrahydro-9-aminoacridine (THA) on quantal transmitter release was examined at the frog neuromuscular junction. THA (3 microM) caused an increase in m (no. of quanta released) as measured by K(+)-evoked miniature endplate potential (MEPP) frequency. This was due to an increase in p (probability of release), as n (no. of functional release sites) was unchanged. The increase in p was dose-dependent over a range of 0.3-10 microM. By contrast, physostigmine (3 microM) caused a decrease in p, and neostigmine, which does not cross the nerve membrane, had no consistent effect on p. At the postsynaptic site, neostigmine produced the largest increase in MEPP size (79.2%), and THA produced the smallest (17.5%). The divergent effects of THA and physostigmine on p indicate a fundamental difference in their actions at the nerve terminal.

Reduced intestinal calcium and dietary calcium intake, increased aluminum absorption, and tissue concentration in the rat.

To test the influence of calcium (Ca) on aluminum (Al) absorption, Ca was withheld from or added (1mM) to the perfusate of the in situ rat gut. The rats had been maintained on Purina Rat Chow. Ca addition significantly decreased (to 70%) the rate of Al disappearance from the gut and decreased (to 55%) the area under the curve of Al appearance in portal blood. To test the influence of Ca deficiency on Al absorption, rats were maintained on a low-Ca (0.008%) or a Ca-replete (0.5%) diet for 1-4 wk. The in situ gut was prepared, and a perfusate containing approximately 1 microM Ca was used. The rate of Al disappearance from the gut of low-Ca diet rats was significantly faster than from the gut of rats maintained on the Ca-replete diet, averaging 156% of the latter. Al appearance in portal blood was significantly greater (averaging 38%) in rats maintained on the low-Ca diet than in controls. To determine if Ca deficiency influences Al tissue distribution independent of gastrointestinal Al absorption, rats maintained on a low-Ca or a Ca-replete diet received 20 ip Al injections over 1 mo. Rats eating the low-Ca diet demonstrated enhanced tissue Al accumulation in all tissues studied, except for muscle and cerebral cortex. These results demonstrate enhanced Al absorption and tissue retention in the presence of reduced intestinal Ca concentration and reduced Ca intake.

Aluminum uptake by the in situ rat gut preparation.

An in situ rat gut preparation was used to elucidate the mechanisms of gastrointestinal aluminum (Al) absorption. Al uptake rate at the mucosal surface was decreased by the paracellular pathway blockers kinetin (1 mM) and 2,4,6-triaminopyrimidinium (10 mM), by sodium removal with choline substitution and by treatment with amiloride (1 mM), an epithelial sodium transport blocker. The rate of Al uptake was unchanged by 2,4-dinitrophenol (0.1 mM), 4-aminopyridine (0.1 mM, 0.5 mM) and verapamil (0.1 mM). The rate of Al uptake was increased from a medium containing no added calcium, a treatment which decreases resistance to flux in the paracellular pathway. These results suggest that gastrointestinal Al uptake occurs by an energy-independent, sodium-dependent, paracellular pathway-mediated process.

Influence of calcium on aluminum accumulation by the rat jejunal slice.

The isolated rat jejunal slice was used to determine if aluminum (Al) interacts with the gastrointestinal (GI) calcium (Ca) transporting system. Al uptake by the rat jejunal slice was reduced by Ca channel blockers (verapamil, nifedipine, diltiazem-10 microM) and a medium containing no added Ca. Conversely, Al uptake was increased by Ca channel activators (4-aminopyridine, .05mM, .1mM; Bay k 8644, 1, 10 microM) and by 5mM Ca. Al uptake was saturable and energy dependent but yielded a low activation energy (Ea = 3.9 +/- 0.3 kcal/mole). Al uptake was increased by vanadate (100 microM), an inhibitor of both the active Ca pump and Na/K-ATPase. These results suggest that Al does interact with the GI Ca transporting system. This interaction may form the basis for its accumulation and toxicity in different tissues which contain similar processes for handling Ca.

Aluminum intoxication and the victim of Alzheimer's disease: similarities and differences.

Aluminum (Al) has been implicated in the pathogenesis and may produce a model of senile dementia of the Alzheimer's type (SDAT). To better understand the effects of Al on the mammalian brain, Al was studied in rabbits and rats using several experimental approaches. Similar behavioral toxicity and site and degree of neurofibrillary tangle (NFT) development were obtained after intracerebroventricular (icv) or repeated sc Al, although a more protracted time course after the latter. SDAT victims demonstrate some similar behavioral signs but a different type of NFT. A classically conditioned, defensive reflex (nictitating membrane extension) was used to compare response acquisition, retention, and extinction in Al-exposed and control rabbits of various ages. Both increasing age and Al exposure attenuated these measures, suggesting that advanced age and Al intoxication provide behavioral models of SDAT. A deficit in acquisition of a classically conditioned response (eyeblink) in senile-demented patients has been reported. These cognitive deficits in rabbits occurred after a less than two-fold increase in brain Al. Brain Al in SDAT victims has been reported to be unchanged or slightly increased. Further similarity to SDAT was obtained with 4-aminopyridine (4-AP) which attenuated Al-induced behavioral deficits in rabbits and the Al inhibition of glutamate release from rat hippocampal slices. 4-Aminopyridine has been reported to attenuate behavioral deficits in SDAT patients. A tubulin, GTP binding site was blocked in SDAT victim brain but not in control or Al-intoxicated rabbit brain, indicating a biochemical dissimilarity. In summary, Al-intoxication produces a model of SDAT with many similarities but significant differences.