Diagnostic Accuracy of Raman Spectroscopy Integrated With Polarized Light Microscopy for Calcium Pyrophosphate-Associated Arthritis.

OBJECTIVE: We studied the performance of integrated Raman polarized light microscopy (iRPolM) for the identification of calcium pyrophosphate (CPP)-associated arthritis (CPPD). METHODS: This is a diagnostic accuracy study including 400 consecutive synovial fluid samples from a single hospital in the Netherlands. Accuracy measures were calculated against polarized light microscopy (PLM) and the 2023 American College of Rheumatology (ACR)/EULAR criteria set for CPPD. RESULTS: The interrater reliability between iRPolM and the 2023 ACR/EULAR criteria set for CPPD was strong (κ = 0.88). The diagnostic performance of iRPolM compared to the 2023 ACR/EULAR criteria set was sensitivity 86.0% (95% confidence interval [CI] 73.3-94.2), specificity 99.1% (95% CI 97.5-99.8), positive likelihood ratio 100.33 (95% CI 32.3-311.3), negative likelihood ratio 0.14 (95% CI 0.07-0.28), positive predictive value 93.5% (95% CI 82.2-97.8), negative predictive value 98.0% (95% CI 82.2-97.8), and accuracy 97.5% (95% CI 95.5-98.8). We allowed rheumatologists to rate the certainty of their microscopic identification of CPP and found a large correspondence between iRPolM and a certain identification (κ = 0.87), whereas only 10% of the uncertain CPP identifications could be confirmed with iRPolM. We identified several novel particle types in synovial fluid analysis, including calcium carbonate crystals, deposited carotenoids, microplastics, and three types of Maltese cross birefringent objects. CONCLUSION: iRPolM can easily identify CPP crystals with a strong diagnostic performance. PLM alone is not specific enough to reliably resolve complicated cases, and the implementation of Raman spectroscopy in rheumatology practice can be of benefit to patients with suspected CPPD.

Test characteristics of Raman spectroscopy integrated with polarized light microscopy for the diagnosis of acute gouty arthritis.

OBJECTIVES: We studied the performance of Raman spectroscopy integrated with polarized light microscopy (iRPolM) as a next-generation technique for synovial fluid analysis in gout. METHODS: This is a prospective study, including consecutive synovial fluid samples drawn from any peripheral swollen joint. Diagnostic accuracy was compared to the 2015 ACR/EULAR Gout classification criteria as a reference test and to polarized light microscopy (PLM) analysis by a rheumatologist. Synovial fluid was analysed with iRPolM after unblinding the PLM results. RESULTS: Two hundred unselected consecutive patient samples were included in this study. Validation against clinical criteria: 67 patients were classified as gout according to 2015 ACR/EULAR classification criteria. Compared to the 2015 ACR/EULAR gout classification criteria, iRPolM had a sensitivity of 77.6% (95% CI: 65.8-86.9), specificity of 97.7% (95% CI: 93.5-99.5), positive predictive value (PPV) of 94.5% (95% CI: 84.9-98.2), negative predictive value (NPV) of 89.7% (95% CI: 84.7-93.1), an accuracy of 91.0% (95% CI: 86.2-94.6), a positive likelihood ratio of 34.4 (95% CI: 11.16-106.10) and a negative likelihood ratio of 0.23 (95% CI: 0.15-0.36). Validation against PLM: 55 samples were positive for MSU according to PLM. The interrater agreement between PLM and iRPolM was near perfect (к=0.90). The sensitivity of iRPolM to identify MSU in PLM-positive samples was 91.2% (95% CI: 80.7-97.1), the specificity was 97.6% (95% CI: 93.0-99.5), the PPV was 94.6% (95% CI: 85.0-98.2), NPV was 96.0% (95% CI: 91.2-98.2) and the accuracy was 95.6% (95% CI: 91.4-98.2). The positive likelihood ratio was 37.4 (95% CI: 12.20-114.71), and the negative likelihood ratio was 0.09 (95% CI: 0.04-0.21). CONCLUSION: iRPolM is a promising next-generation diagnostic tool for rheumatology by diagnosing gout with high specificity, increased objectivity, and a sensitivity comparable to PLM.

Treat-to-target in axial spondyloarthritis: an observational study in daily practice.

OBJECTIVES: To evaluate the extent to which internationally agreed treat-to-target recommendations were applied in clinical practice in patients with axial spondyloarthritis. METHODS: Data were used from a web-based patient registry for monitoring SpA in daily practice in the Netherlands. The extent to which treat-to-target was applied was evaluated through four indicators: the proportion of patients (i) with ≥1 Ankylosing Spondylitis Disease Activity Score (ASDAS) assessed during a 1-year period, (ii) having inactive disease/low disease activity (i.e. ASDAS < 2.1), (iii) in whom re-evaluation of ASDAS within recommended intervals occurred, and (iv) with high disease activity (HDA, i.e. ASDAS ≥ 2.1) in whom treatment was adapted ≤6 weeks after obtaining ASDAS ≥ 2.1. Patients with HDA with treatment adaptations were compared with patients with HDA without treatment adaptations. RESULTS: In 185 out of 219 patients (84%), disease activity was monitored with ≥1 ASDAS during a 1-year period, of whom 71 (38%) patients had a score below the target (ASDAS < 2.1) at first measurement. Re-evaluation of ASDAS ≤3 months occurred in 11% and 23% of the patients with inactive disease/low disease activity and HDA, respectively. Treatment adaptation occurred in 19 out of 114 patients (17%) with HDA. Patients in whom treatment was adapted had significantly higher ASDAS (P < 0.01), CRP levels (P < 0.05) and physician global assessment (P < 0.05) compared with patients without treatment adaptations. CONCLUSIONS: Treat-to-target was applied to a limited extent in clinical practice in patients with axial spondyloarthritis. Available disease activity scores seemed not to be used for determining the frequency of re-evaluation nor treatment adaptation.

Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial.

BACKGROUND: Gout flares are driven by interleukin (IL)-1ß. Dapansutrile inhibits the NLRP3 inflammasome and subsequent activation of IL-1ß. In this study we aimed to investigate the safety and efficacy of orally administered dapansutrile in patients with a gout flare. METHODS: In this open-label, proof-of-concept, phase 2a trial, adult patients (aged 18-80 years) with a monoarticular monosodium urate crystal-proven gout flare were enrolled at an outpatient clinic in the Netherlands and sequentially assigned using a dose-adaptive design to receive 100 mg/day, 300 mg/day, 1000 mg/day, or 2000 mg/day oral dapansutrile for 8 days. The coprimary outcomes were change in patient-reported target joint pain from baseline to day 3 and from baseline to day 7, assessed in the per-protocol population (all patients who received at least 80% of the study drug and had no major protocol deviations). Safety was assessed in the intention-to-treat population. This trial is registered with the EU Clinical Trials Register, EudraCT 2016-000943-14, and is completed. FINDINGS: Between May 18, 2017, and Jan 21, 2019, 144 patients were assessed for eligibility, of whom 34 were enrolled and 29 were included in the per-protocol population (three patients were excluded due to receiving <80% of study drug and two had major protocol deviations): eight patients received 100 mg/day, seven received 300 mg/day, six received 1000 mg/day, and eight received 2000 mg/day. Between baseline and day 3, there was a mean reduction in patient-reported target joint pain of 52·4% (SD 32·94; p=0∙016) for the 100 mg/day group, 68·4% (34·29; p=0∙016) for the 300 mg/day group, 55·8% (44·90; p=0∙063) for the 1000 mg/day group, and 57·6% (38·72; p=0∙016) for the 2000 mg/day group. At day 7, there was a mean reduction of 82·1% (22·68; p=0∙031) for the 100 mg/day group, 84·2% (16·33; p=0∙016) for the 300 mg/day group, 68·9% (34·89; p=0∙031) for the 1000 mg/day group, and 83·9% (15·44; p=0∙008) for the 2000 mg/day group, compared to baseline. 25 (73·5%) of 34 patients reported a total of 45 treatment-emergent adverse events, most of which were metabolism and nutrition disorders (17 [37·8%]) and gastrointestinal disorders (ten [22·2%]). Two serious adverse events occurred during the study, admission to hospital because of worsening of gout flare at day 3, and admission to hospital because of coronary stenosis 18 days after the patient received their last dose; these were considered moderate in severity and unrelated to the study drug. INTERPRETATION: Dapansutrile is a specific NLRP3 inflammasome inhibitor with a satisfactory safety profile and efficacy in the reduction of target joint pain in this study. Future studies are needed to confirm the clinical potential of dapansutrile.

Limited value for ultrasonography in predicting flare in rheumatoid arthritis patients with low disease activity stopping TNF inhibitors.

Objective: Ultrasonography (US) can be used for treatment decisions in RA patients. This study investigated the added value of US to clinical variables in predicting flare in RA patients with longstanding low disease activity when stopping TNF inhibitors (TNFi). Methods: Cox models with and without using US added to clinical variables were developed in the Potential Optimization of Expediency of TNFi-UltraSonography study. RA patients (n = 259), using >1 year TNFi and csDMARD with DAS28 < 3.2 for 6 months prior to inclusion, were followed for 52 weeks after stopping TNFi. The added value of US was assessed in two ways: first, by the extent to which individual predictions for flare at 52 weeks with and without US differed; and second, by comparing how US information improved the prediction to classify patients at 52 weeks in the low risk (<33% flare), intermediate risk (33-50%) and high risk (50-100%) groups. Results: Although US was predictive of flare at group level (multivariate hazard ratio = 1.7; 95% CI: 1.1, 2.5), individual predictions for flare at 52 weeks with and without US differed little (median difference 3.7%; interquartile range: -7.8 to 6.5%). With US, 15.9% of patients were designated low risk; without US, 14.6%. In fact, 12.0% of patients were US-classified as low risk with/without knowing US. Conclusion: In RA patients with longstanding low disease activity, at time of stopping TNFi, US is a predictor for flare at group level, but at the patient level, US has limited added value when common clinical parameters are used already, though the predictive value of clinical predictors is modest as well.

Reduction in Spinal Radiographic Progression in Ankylosing Spondylitis Patients Receiving Prolonged Treatment With Tumor Necrosis Factor Inhibitors.

OBJECTIVE: To evaluate the course of spinal radiographic progression for up to 8 years of followup in a large cohort of ankylosing spondylitis (AS) patients treated with tumor necrosis factor (TNF) inhibitors. METHODS: Consecutive patients from the Groningen Leeuwarden AS cohort starting TNF inhibitors between 2004 and 2012 were included. Baseline and biannual radiographs were randomized with radiographs of TNF-naive AS patients and scored in chronologic order according to modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The course of radiographic progression (linear or nonlinear) was investigated using generalized estimating equations. Primary analysis was performed in patients with complete data over 4, 6, and 8 years of followup. Sensitivity analysis was performed after single linear imputation of missing radiographic data and after adjusting for patient characteristics with possible influence on radiographic progression. RESULTS: At baseline, median mSASSS of 210 included AS patients was 2.8 (interquartile range 0.0-12.0), mean ± SD mSASSS 10.0 ± 15.5. During the first 4 years, radiographic progression followed a linear course (estimated mean progression rate was 1.7 for 0-2 and 2-4 years). A deflection from a linear course was found in patients with complete and imputed data over 6 and 8 years. The estimated mean 2-year progression rate reduced from 2.3 to 0.8 in patients with complete 8-year data. The same pattern was found after adjustment for baseline mSASSS scores, presence of syndesmophytes, sex, HLA-B27 status, age, symptom duration, smoking duration, body mass index, disease activity, and nonsteroidal antiinflammatory drug use. CONCLUSION: This observational cohort study in AS patients receiving long-term TNF inhibitors showed a reduction in spinal radiographic progression after more than 4 years of followup.

Long-term drug survival and clinical effectiveness of etanercept treatment in patients with ankylosing spondylitis in daily clinical practice.

OBJECTIVES: Randomised controlled trials and open-label extension studies have demonstrated the clinical efficacy and safety of tumour necrosis factor-alpha (TNF-α) blocking therapy in pre-selected study patients with ankylosing spondylitis (AS). Our aim was to investigate the 7-year drug survival and clinical effectiveness of etanercept treatment in AS patients in daily clinical practice. METHODS: Consecutive AS patients from the prospective observational GLAS cohort who started etanercept because of active disease were included and evaluated over 7 years according to a fixed protocol. Continuation of treatment was based on BASDAI improvement and/or expert opinion. RESULTS: Of the 89 included AS patients, 45 (51%) were still using etanercept at 7 years of follow-up. Reasons for treatment discontinuation were adverse events (n=22), inefficacy (n=13), or other reasons although good clinical response (n=9). Etanercept treatment resulted in a rapid (after 6 weeks) and sustained improvement in disease activity (BASDAI, ASDAS, CRP, physician GDA), spinal mobility, physical function (BASFI), quality of life (ASQoL), and extra-spinal manifestations (swollen joints, tender joints and tender entheses). Furthermore, concomitant NSAID or DMARD use decreased significantly during follow-up. At 7 years, low disease activity and remission were present in 67-73% and 29-30% of the 45 patients, respectively. Of the patients who discontinued etanercept, 18 switched successfully to a second or third TNF-α blocker during follow-up. CONCLUSIONS: In a large cohort of AS patients treated with etanercept, approximately 50% continued this treatment for 7 years. Our broad evaluation of clinical endpoints proves the long-term effectiveness of etanercept treatment in daily clinical practice.

Obesity Is Common in Axial Spondyloarthritis and Is Associated with Poor Clinical Outcome.

OBJECTIVE: To assess the prevalence of overweight and obesity in a large cohort of patients with axial spondyloarthritis (axSpA) in comparison with the general population. To explore the relationship of body mass index (BMI) with clinical outcome in axSpA. METHODS: Patients from the Groningen Leeuwarden Axial SpA cohort who visited the outpatient clinic in 2011/2012 were included in this cross-sectional analysis. Body weight, height, disease activity, physical function, and quality of life (QoL) were assessed. Patients were divided into normal weight (BMI < 25 kg/m(2)), overweight (BMI ≥ 25 to < 30 kg/m(2)), and obese (BMI ≥ 30 kg/m(2)). BMI data for the general population in the same demographic region, matched for age and sex, were obtained from the LifeLines Cohort Study. RESULTS: Of the 461 patients with axSpA, 37% were overweight and 22% were obese. In the LifeLines cohort (n = 136,577), 43% were overweight and 15% were obese. Overweight and obese patients were older, had longer symptom duration, and had more comorbidities, especially hypertension. Further, obese patients had significantly higher disease activity, worse physical function, and worse QoL than overweight and normal weight patients (mean Bath Ankylosing Spondylitis Disease Activity Index 4.5, 3.5, 3.8; mean Ankylosing Spondylitis Disease Activity Score 2.8, 2.2, 2.3; median C-reactive protein 5, 3, 3 mg/l; median erythrocyte sedimentation rate 13, 8, 8 mm/h; median Bath Ankylosing Spondylitis Functional Index 5.2, 2.9, 2.9; median Ankylosing Spondylitis QoL Questionnaire 8, 4, 5, respectively). After adjustment for potential confounders, obesity proved to be an independent predictor of worse clinical outcome. CONCLUSION: In this large observational cohort study, obesity is more common in axSpA than in the general population and it is associated with worse clinical outcome.

Spinal radiographic progression in patients with ankylosing spondylitis treated with TNF-α blocking therapy: a prospective longitudinal observational cohort study.

OBJECTIVES: To evaluate spinal radiographic damage over time and to explore the associations of radiographic progression with patient characteristics and clinical assessments including disease activity in ankylosing spondylitis (AS) patients treated with tumor necrosis factor-alpha (TNF-α) blocking therapy in daily clinical practice. METHODS: Consecutive outpatients from the Groningen Leeuwarden AS (GLAS) cohort were included based on the availability of cervical and lumbar radiographs before start of TNF-α blocking therapy and after 2, 4, and/or 6 years of follow-up. Clinical data were assessed at the same time points. Radiographs were scored by two independent readers using the modified Stoke AS Spine Score (mSASSS). Spinal radiographic progression in relation to clinical assessments was analyzed using generalized estimating equations. RESULTS: 176 AS patients were included, 58% had syndesmophytes at baseline. Median mSASSS increased significantly from 10.7 (IQR: 4.6-24.0) at baseline to 14.8 (IQR: 7.9-32.8) at 6 years. At the group level, spinal radiographic progression was linear with a mean progression rate of 1.3 mSASSS units per 2 years. Both spinal radiographic damage at baseline and radiographic progression were highly variable between AS patients. Male gender, older age, longer disease duration, higher BMI, longer smoking duration, high CRP, and high ASDAS were significantly associated with syndesmophytes at baseline. Significantly more radiographic progression was seen in patients with versus without syndesmophytes (2.0 vs. 0.5 mSASSS units per 2 years) and in patients >40 versus ≤40 years of age (1.8 vs. 0.7 mSASSS units per 2 years). No longitudinal associations between radiographic progression and clinical assessments were found. CONCLUSIONS: This prospective longitudinal observational cohort study in daily clinical practice shows overall slow and linear spinal radiographic progression in AS patients treated with TNF-α blocking therapy. At the individual level, progression was highly variable. Patients with syndesmophytes at baseline showed a 4-fold higher radiographic progression rate than patients without syndesmophytes.

Higher bone turnover is related to spinal radiographic damage and low bone mineral density in ankylosing spondylitis patients with active disease: a cross-sectional analysis.

INTRODUCTION: Ankylosing spondylitis (AS) is characterized by excessive bone formation and bone loss. Our aim was to investigate the association of bone turnover markers (BTM) with spinal radiographic damage and bone mineral density (BMD) in AS patients with active disease. METHODS: 201 consecutive AS outpatients of the Groningen Leeuwarden AS (GLAS) cohort were included. Serum markers of bone resorption (C-telopeptides of type-I collagen, sCTX) and bone formation (procollagen type-I N-terminal peptide, PINP; bone-specific alkaline phosphatase, BALP) were measured. Z-scores were used to correct for the normal influence that age and gender have on bone turnover. Radiographs were scored by two independent readers according to modified Stoke AS Spinal Score (mSASSS). The presence of complete bridging (ankylosis of at least two vertebrae) was considered as measure of more advanced radiographic damage. Low BMD was defined as lumbar spine and/or hip BMD Z-score ≤ -1. RESULTS: Of the 151 patients with complete data, 52 (34%) had ≥ 1 complete bridge, 49 (33%) had ≥ 1 syndesmophyte (non-bridging), and 50 (33%) had no syndesmophytes. 66 (44%) had low BMD. Patients with bridging had significantly higher sCTX and PINP Z-scores than patients without bridging (0.43 vs. -0.55 and 0.55 vs. 0.04, respectively). Patients with low BMD had significantly higher sCTX Z-score than patients with normal BMD (-0.08 vs. -0.61). After correcting for gender, symptom duration, and CRP, sCTX Z-score remained significantly related to the presence of low BMD alone (OR: 1.60), bridging alone (OR: 1.82), and bridging in combination with low BMD (OR: 2.26). CONCLUSIONS: This cross-sectional study in AS patients with active and relatively long-standing disease demonstrated that higher serum levels of sCTX, and to a lesser extent PINP, are associated with the presence of complete bridging. sCTX was also associated with low BMD. Longitudinal studies are needed to confirm that serum levels of sCTX can serve as objective marker for bone-related outcome in AS.