The Relationship between Nociceptive Detection Thresholds and Pressure- and Electrical Pain Thresholds: An Explorative Study in Rheumatoid Arthritis Patients.

Recently, methods have been developed enabling the characterization of the nociceptive function at the detection threshold level by measuring nociceptive detection thresholds (NDTs), rather than at the level of the pain threshold via pain threshold (PT) measurements. Both NDT and PT measurements aim to characterize (parts of) the nociceptive system. To date it is unclear if, and if so to what extent, the two outcomes relate to one another. In this study, the primary aim is to explore the relationship between the two measures in patients with rheumatoid arthritis (RA). As secondary aim, we explore differences in NDT between these RA patients with age- and sex-matched healthy controls (HC) from a readily existing dataset. In total 46 RA patients have been recruited, whereby the pressure- (PPT; bilaterally at two locations) and electrical (EPT) pain threshold were evaluated, as well as the NDTs. Significant, positive correlations were found between the EPT and PPT (R=0.54-0.60), but not with the NDTs (R≤0.25). As compared to HC, higher NDTs were found in the RA group. As the presence of a statistically significant weak relationship can only be evaluated using a larger sample size, our results indicate that there is no moderate or stronger relation between PT and NDT outcomes. This implicates that the two outcomes are not strongly driven by the same (nociceptive) mechanism(s). Future research into NDTs and what factors and/or mechanisms affect the outcome, could yield relevant insights into how to use and interpret the results of this relatively new method.Clinical Relevance - The evaluation of nociceptive detection thresholds, in isolation or together with conventionally evaluated pain thresholds, might provide valuable and complementary insights into nociceptive (dis)function in man.

Early radiological progression remains associated with long-term joint damage in real-world rheumatoid arthritis patients treated to the target of remission.

OBJECTIVE: To evaluate radiological damage and to explore characteristics associated with radiological progression in rheumatoid arthritis (RA) treated to the target of remission in a real-world setting. METHODS: Baseline to 6 year follow-up data were used from an observational early RA cohort. Radiographs of hands and feet at baseline, 6 months, and 1, 3, and 6 years were scored using the modified Sharp/van der Heijde score (SHS). The threshold for rapid radiological progression (RRP) after 6 months was based on the calculated smallest detectable change of 3.95. Negative binomial generalized linear mixed model and logistic regression analyses were performed to examine which variables were associated with RRP and 6 year radiological progression. RESULTS: Most radiological damage occurred in the first year of treatment [median 2.0 interquartile range (IQR) 1.0-4.0 SHS points] compared to the subsequent 5 years of follow-up (median 3.0 IQR 1.0-5.0 SHS points). While low disease activity was achieved within 6 months on average, 18.8% of the patients developed RRP. Anti-cyclic citrullinated peptide (anti-CCP) positivity [incidence rate ratio (IRR) 1.42, p = 0.03], baseline erosive disease (IRR 1.60, p = 0.02), and RRP (IRR 3.28, p < 0.001) were associated with 6 year radiological progression. Erosive disease was the strongest predictor of RRP (odds ratio 8.8, p < 0.001). CONCLUSION: Long-term radiological outcome is limited in most real-world RA patients treated to the target of remission, but RRP still occurs. Anti-CCP positivity, baseline erosive disease, and RRP remain associated with long-term radiological outcome.

Association between pain phenotype and disease activity in rheumatoid arthritis patients: a non-interventional, longitudinal cohort study.

BACKGROUND: In well-controlled rheumatoid arthritis (RA) without significant joint damage, a substantial proportion of patients complain of persistent pain. Previous studies have identified different pain phenotypes in RA, in which non-nociceptive pain phenotypes are associated with higher concurrent disease activity scores. In this longitudinal study, we explored associations between pain phenotypes and long-term disease activity outcome in RA patients. Secondly, we explored whether pain phenotype is associated with comorbid conditions. METHODS: One hundred eighty established RA patients were classified with a nociceptive (61%) or a non-nociceptive (39%) pain phenotype, based on their responses to the painDETECT-questionnaire. Two years of clinical follow-up data on disease activity outcomes were collected. Information on comorbid diseases was derived from electronic patient files. RESULTS: Patients with a non-nociceptive pain phenotype showed higher mean disease activity scores (DAS28, 2.57; 95% CI, 2.37-2.77 vs. 2.11; 95% CI, 1.94-2.27; p < 0.001) and a twofold lower chance of achieving sustained DAS28 remission (OR = 0.49; 95% CI, 0.26-0.92; p = 0.020). Only the tender joint count and patient global health significantly differed between the pain phenotype groups. Patients with a non-nociceptive pain phenotype had more often been diagnosed with concurrent fibromyalgia (9.9% vs. 0.9%; p = 0.007) and other pain-associated comorbid diseases (52.1% vs. 35.8%; p = 0.030) compared with patients with a nociceptive pain phenotype. CONCLUSION: This longitudinal study showed consistently worse long-term disease activity outcomes in RA patients with a non-nociceptive pain phenotype which appeared to be mainly due to differences in the subjective components of the disease activity score. TRIAL REGISTRATION: The DREAM cohort study is registered in the Netherlands Trial Register: NTR578.

Prognostic factors associated with early gout flare recurrence in patients initiating urate-lowering therapy during an acute gout flare.

Lowering serum urate levels below the threshold for crystal formation with urate-lowering therapy (ULT) has been associated with a lower risk for gout flare reoccurrences. However, gout patients on ULT still commonly suffer from recurring gout flares. The purpose of this study was to explore prognostic factors associated with gout flare recurrence within the first 3 months, in gout patients starting ULT during an acute gout flare. Post-hoc analysis of trial data on acute gout patients randomized to either gout flare standard of care or anakinra treatment were used, including baseline demographic, laboratory, clinical, and patient-reported variables, as well as 3-month follow-up data on gout flare recurrences. Only patients starting ULT at baseline were included. Using variable selection based on clinical relevance, univariate, and multivariate binary logistic regression analyses were done to examine predictors of gout flare reoccurrence. A total of 75 patients were included in this study, of which 36 (48%) experienced a gout flare ≤ 3 months post baseline. The multivariate regression analysis revealed that CRP levels > 30 mg/L (OR 9.47) and lack of prophylaxis when starting ULT (OR 11.56) were independently associated with gout flare recurrence. Similar results were found for the univariate regression analyses. Our results show that CRP levels > 30 mg/L and lack of prophylaxis when starting ULT were prognostic factors for early gout flare reoccurrence in patients starting ULT during an acute gout flare. KEY POINTS: • Gout flare recurrences were common within the first 3 months after starting urate-lowering therapy in gout patients. • Intake of prophylaxis when starting ULT had a strong protective effect on gout flare recurrences. • C-reactive protein level > 30 mg/L was an additional prognostic factor for early (≤ 3 months) gout flare reoccurrence in patients starting ULT during an acute gout flare.

Towards standardized patient reported physical function outcome reporting: linking ten commonly used questionnaires to a common metric.

OBJECTIVES: Outcomes obtained using different physical function patient reported outcome measures (PROMs) are difficult to compare. To facilitate standardization of physical function outcome measurement and reporting we developed an item response theory (IRT) based standardized physical function score metric for ten commonly used physical function PROMs. METHODS: Data of a total of 16,386 respondents from representative cohorts of patients with rheumatic diseases as well as the Dutch general population were used to map the items of ten commonly used physical function PROMs on a continuous latent physical function variable. The resulting IRT based common metric was cross-validated in an independent dataset of 243 patients with gout, osteoarthritis or polymyalgia in which four of the linked PROMs were administered. RESULTS: Our analyses supported that all 97 items of the ten included PROMs relate to a single underlying physical function variable and that responses to each item could be described by the generalized partial credit IRT model. In the cross-validation analyses we found congruent mean scores for four different PROMs when the IRT based scoring procedures were used. CONCLUSIONS: We showed that the standardized physical function score metric developed in this study can be used to facilitate standardized reporting of physical function outcomes for ten commonly used make physical function PROMs.

A retrospective analysis of medication prescription records for determining the levels of compliance and persistence to urate-lowering therapy for the treatment of gout and hyperuricemia in The Netherlands.

Urate-lowering therapy (ULT) is a recommended life-long treatment for gout patients. However, despite these recommendations, recurrent gout attacks are commonly observed in clinical practice. The purpose of this study was to assess the levels of compliance and persistence to ULT in The Netherlands, in order to reflect on the current gout care delivered by health professionals. Anonymous prescription records were obtained from IQVIA's Dutch retrospective longitudinal prescription database, containing ULT dispensing data for allopurinol, febuxostat, and benzbromarone from November 2013 to July 2017. Compliance to ULT was determined by calculating the proportion of days covered (PDC) over 12 months. Persistence over 12 months was evaluated by determining the time to discontinuation, without surpassing a refill gap of > 30 days. Association of PDC and persistence with age, gender, and first prescriber were examined using beta regression- and cox-regression models, respectively. There were 45,654 patients who met the inclusion criteria. Overall, 51.7% of the patients had a ULT coverage of ≥ 80% of the days in 1 year (PDC ≥ 0.80), and 42.7% of the patients were still persistent after 1 year. Men, older patients, and patients whose first prescriber was a rheumatologist were more persistent and had a higher PDC. Our results show that medication adherence to ULT after 1 year is suboptimal, considering that current guidelines recommend ULT as a life-long treatment. Future studies addressing the reasons for treatment cessation and improving treatment adherence seem warranted.

Long-term disease and patient-reported outcomes of a continuous treat-to-target approach in patients with early rheumatoid arthritis in daily clinical practice.

Patients in real life may differ from those in clinical trials. The aim of this study is to report 5-year outcomes of a continuous treat-to-target (T2T) approach in patients with rheumatoid arthritis (RA) in daily clinical practice. In the Dutch RhEumatoid Arthritis Monitoring cohort, all patients with a clinical diagnosis of RA were treated according to a protocolled T2T strategy, aimed at 28-joint Disease Activity Score (DAS28) < 2.6. Outcomes were percentages of patients in distinct levels of disease activity, mean course of DAS28 and prevalence of sustained (drug-free) remission. Also, data on functional disability (Health Assessment Questionnaire) and health-related quality of life (Short-Form 36) were examined. Mean DAS28 improved from 4.93 (95% CI 4.81-5.05) at baseline to 2.49 (95% CI 2.35-2.63) after 12 months and remained stable thereafter. Percentages of patients at 12 months with DAS28 < 2.6 (remission), DAS28 ≥ 2.6 and ≤ 3.2 (low disease activity), DAS28 > 3.2 and ≤ 5.1 (moderate disease activity) and DAS28 > 5.1 (high disease activity) were 63, 16, 18 and 3%, respectively. Sustained remission (DAS28 < 2.6 during ≥ 6 months) was observed at least once in 84% of the patients and drug-free remission (DAS28 < 2.6 during ≥ 6 months after withdrawal of all disease-modifying anti-rheumatic drugs) in 36% of the patients. Functional disability and health-related quality of life significantly improved during the first 24 weeks. Continuous application of T2T in real-life RA patients leads to favourable disease- and patient-related outcomes.

Determinants of Perceived Health Nonimprovement in Early Rheumatoid Arthritis Patients With Favorable Treatment Outcomes.

OBJECTIVE: To explore the association between achieving favorable clinical outcomes and patients' perceived change in overall health status after 12 months of treat-to-target in patients with early rheumatoid arthritis (RA) and to identify determinants of subjective nonimprovement. METHODS: Baseline and 12-month data of patients included in the Dutch Rheumatoid Arthritis Monitoring remission induction cohort study with at least a moderate response (by European League Against Rheumatism criteria) after 1 year were selected for analysis. Logistic regression analysis was used to identify factors associated with nonimproved perceived overall health status at 12 months. RESULTS: At 12 months, 75 of 210 patients (35%) did not consider their health to have improved despite having achieved favorable clinical outcomes. Relative change from baseline in pain (Wald = 20.20; P < 0.01) and fatigue (Wald = 5.58; P = 0.02) was independently associated with nonimproved perceived overall health status. The results were similar when only patients with ≤1 swollen joint were analyzed. An improvement of 55% in pain measured on a visual analog scale was found to discriminate reasonably well between patients who considered their health to have improved versus patients who did not, with an area under the receiver operating characteristic curve of 0.70 (95% confidence interval 0.61-0.78). CONCLUSION: These results demonstrate that clinical improvements do not equate with improved subjective health for all patients. The association of nonimprovement with changes in pain and fatigue suggest that it might be worthwhile to monitor and address pain and fatigue in addition to and independently of disease activity in early RA.

The added value of synovial fluid centrifugation for monosodium urate and calcium pyrophosphate crystal detection.

The aim of the study was to assess the added value of synovial fluid (SF) centrifugation for microscopic monosodium urate (MSU) and calcium pyrophosphate (CPP) crystal detection in patients with arthritis. This is a prospective observational study using SF samples from joints of patients undergoing joint arthrocentesis. Two blinded observers assessed the SF smears by polarized light microscopy for the presence of crystals before as well as after centrifugation. SF samples were collected from 98 patients with arthritis. After exclusion, 87 samples were eligible for inclusion. Of each sample, 2 smears before and after centrifugation were prepared and microscopically examined, resulting in 348 smears per observer. Observer 1 identified MSU crystals in 18.4% and CPP in 9.2% of the smears before as well as after centrifugation. No extra MSU crystal-positive smears were identified after centrifugation. However, centrifugation yielded 4 additional CPP crystal-positive smears. Observer 2 identified MSU crystals in 15.5% and CPP crystals in 6.3% of the smears before as well as after centrifugation. Centrifugation yielded 2 additional MSU crystal-positive smears and 4 CPP crystal-positive smears. Monosodium urate crystals were well recognized without centrifugation. Centrifugation of SF had limited additional value for increasing the amount of MSU-positive smears. However, CPP crystals were identified in a higher number of smears after centrifugation than before. Therefore, centrifugation may be of additional value in selected patients with suspected calcium pyrophosphate deposition disease and to a lesser extent for gout.

Initial combination therapy versus step-up therapy in treatment to the target of remission in daily clinical practice in early rheumatoid arthritis patients: results from the DREAM registry.

BACKGROUND: Treat to target (T2T) is widely accepted as the standard of care for patients with rheumatoid arthritis (RA) and has been shown to be more effective than traditional routine care. The objective of this study was to compare the effectiveness of two T2T strategies in patients with early RA: a step-up approach starting with methotrexate (MTX) monotherapy (cohort I) versus an initial disease-modifying antirheumatic drug combination approach (cohort II). METHODS: A total of 128 patients from cohort II were case-control-matched with 128 patients from cohort I on gender, age, and baseline disease activity. Twelve-month follow-up data were available for 121 patients in both cohorts. The primary outcome was the proportion of patients having reached at least one 28-joint Disease Activity Score (DAS28) score <2.6 (remission) during 12 months of follow-up. Secondary outcomes were time until remission was achieved and mean DAS28 scores at 6- and 12-month follow-up. RESULTS: After 12 months of follow-up, remission was reached at least once in 77.3 % of the patients in cohort II versus 71.9 % in cohort I (P = 0.31). Median time until first remission was 17 weeks in cohort II versus 27 weeks in cohort I (P = 0.04). A significant time by strategy interaction was found in mean DAS28 scores. Post hoc analysis revealed a significant difference in mean DAS28 scores between both cohorts at 6 months (P = 0.04), but not at 12 months (P = 0.36). CONCLUSIONS: The initial combination strategy resulted in a comparable remission rate after 1 year but a significantly shorter time until remission. At 6 months, mean DAS28 scores were lower in patients with initial combination treatment than in those with step-up therapy. At 12 months, no significant differences remained in mean DAS28 scores or the proportion of patients in remission.

Interference of NSAIDs with the thrombocyte inhibitory effect of aspirin: a placebo-controlled, ex vivo, serial placebo-controlled serial crossover study.

PURPOSE: Nonsteroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA) are often prescribed concurrently in patients with nociceptive pain and cardiovascular comorbidity. NSAIDs and ASA inhibit the same COX-enzymes, and thus may interact. ASA's cardioprotective antiplatelet effect is entirely COX-1 dependent. NSAIDs can be either non-COX-1 and COX-2 selective or COX-2 selective. The aim of this study was to examine the interaction between ASA and different selective and nonselective NSAIDs on thrombocyte function. METHODS: Single-blind, prospective, placebo-controlled, ex vivo, serial crossover trial of 3-day cycles separated by washout periods of at least 12 days in 30 healthy volunteers, evaluating interaction on ASA's antithrombocyte effect by naproxen, ibuprofen, meloxicam, or etoricoxib taken 2 h before ASA. Ex vivo thrombocyte function, closure time (CT) in seconds, was measured using the Platelet Function Analyzer 100 (PFA-100). CT prolongation during a cycle reflects thrombocyte inhibitory effect. ASA nonresponse was defined as CT prolongation <40 % in the placebo cycle. ASA nonresponders were excluded. Wilcoxon signed-rank was used to evaluate NSAID effect on ASA-induced CT prolongation. RESULTS: Ibuprofen and naproxen inhibit ASA's antithrombocyte effect below the nonresponse threshold. Etoricoxib and meloxicam do not cause relevant change in ASA thrombocyte inhibition. Naproxen has an inherent weak thrombocyte inhibitory action below the ASA response threshold. CONCLUSIONS: COX-1 affinity determines the interaction between NSAIDs and ASA on thrombocyte adhesion and aggregation. Ibuprofen and naproxen, but not etoricoxib or meloxicam, taken 2 h before ASA, significantly inhibit ASA's antithrombocyte effect.

Under-utilization of gastroprotective drugs in patients with NSAID-related ulcers.

OBJECTIVE: To determine the proportion of patients with a risk of NSAID gastropathy receiving adequate gastroprotection. METHODS: This observational study was performed between November 2001 and December 2003. We selected patients who were hospitalized with perforated and bleeding gastroduodenal ulcers attributable to NSAID use and controls without ulcers. Data were collected on their sociodemographic characteristics, actual and recent medication, comorbidity and medical history. For each patient and control the number of different risk factors associated with NSAID gastropathy was calculated. A composite risk factor (CRF) was obtained from the sum of all separate risk factors. RESULTS: During the observational period a total of 388 patients using NSAID were included in the study, 104 patient cases and 284 matched community-based controls. The mean CRF was significantly higher in patient cases than in controls (cases mean CRF 3.31 (SD 1.67) and controls mean CRF 2.76 (SD 1.45), p = 0.002). A total of 148 (38%) patients used an adequate preventive strategy. Significant variables for using a preventive strategy were concomitant use of steroids (corrected odds ratio 4.22, 95% CI 2.11 8.47, p < 0.001), a history of gastroduodenal ulcers (corrected odds ratio 2.90, 95% CI 1.51 - 5.56, p = 0.001) and concomitant use of low-dose aspirin (corrected odds ratio 1.96,95% CI 1.18 3.25, p= 0.01). Among patients with 4 or more risk factors associated with NSAID gastropathy, 47% still did not use adequate gastroprotection. CONCLUSION: Gastroprotective drugs are greatly under-utilized in patients with a risk of NSAID gastropathy.

[Fatal miliary tuberculosis during treatment with infliximab]. / Fatale miliaire tuberculose tijdens behandeling met infliximab.

A 73-year-old woman was admitted to hospital with fever whilst under treatment with infliximab for rheumatoid arthritis. Despite repeated and specific testing, tuberculosis was only diagnosed post mortem. During infliximab therapy, latent tuberculosis can reactivate in subacute form with a possible fatal outcome. For infliximab therapy to be administered safely, the risk that the patient concerned is latently infected with tuberculosis has to be estimated beforehand; if necessary a prophylactic anti-tuberculosis treatment may be given.

Beta 3-adrenergic receptor gene polymorphism and type 2 diabetes in a Caucasian population.

AIM: The beta 3-adrenergic receptor (beta 3-AR) is suspected to play a key role in the regulation of energy balance by increasing lipolysis and thermogenesis. A mutation in the beta 3-AR gene (Trp64Arg) has been associated with the capacity of weight gain and with early onset of noninsulin dependent diabetes mellitus (type 2 diabetes). In this study we investigated the prevalence of the two beta 3-AR alleles in a Caucasian population and studied the association between the beta 3-AR genotype and metabolic disorders (obesity and type 2 diabetes). METHODS: Genomic DNA extracted from peripheral blood leucocytes of 200 Caucasian subjects (137 subjects with and 63 subjects without type 2 diabetes). The MvaI polymorphism of beta 3-AR, which detects the Trp64Arg mutation, was determined by polymerase chain reaction (PCR). We studied the correlation between the Trp64Arg mutation and the body mass index (b.m.i. kg/m2). RESULTS: There was no significant difference between the patients with type 2 diabetes and control subjects in the frequency of the Arg64 allele (5.5% and 4.8%, respectively). Within the group of type 2 diabetes patients were 14 subjects with the Trp64Arg mutation (b.m.i., mean +/- s.d.: 31 +/- 8.5 kg/m2) and 123 without the mutation (b.m.i. 29 +/- 4.8). There was no association between the beta 3-AR gene polymorphism and sex, obesity, blood pressure, glycohaemoglobin concentration, proteinuria. CONCLUSION: Our results suggest that the Trp64Arg mutation is not a major determinant of metabolic disorders (type 2 diabetes, obesity) and chronic complications of type 2 diabetes in a Dutch population.

Opioid receptor ligand binding in the human striatum: II. Heterogeneous distribution of kappa opioid receptor labeled with [3H]bremazocine.

Selective kappa opioid receptor autoradiography with [3H]bremazocine (BRM) was used to examine regional and subregional kappa receptor distribution patterns at five rostrocaudal levels through the human striatum. [3H]BRM binding densities were measured in the individual striatal nuclei and in subregions therein. The distribution of [3H]BRM binding sites was found to have a strongly heterogeneous character. At the regional level a rostral-to-caudal decrease in [3H]BRM binding densities was observed. Also, a dorsal-to-ventral differentiation was seen, with higher values in the ventral striatum, especially in the nucleus accumbens, and lower values in the dorsal parts of the caudate nucleus and putamen. These findings suggest an association of kappa receptor function with limbic-related processes in the ventral striatum. Along the ventral edge of the nucleus accumbens and putamen, specific domains with extremely high [3H]BRM binding values were identified.

Preferential loss of preproenkephalin versus preprotachykinin neurons from the striatum of Huntington's disease patients.

Preferential loss of basal ganglia neurons and terminals occurs in Huntington's disease (HD). Terminals of preproenkephalin medium-size spiny neurons are more vulnerable than terminals of preprotachykinin neurons, but the peptidergic neurons of origin have not yet been shown to die preferentially. We sought to determine, in the striatum, whether preproenkephalin neurons were lost to a greater extent than preprotachykinin neurons and to determine whether there were decreases in specific messenger RNA (mRNA) levels of preproenkephalin, preprotachykinin, and calbindin D28k. We found a grade-related decrease in the number of preprotachykinin- and calbindin D28k-labeled neurons per measuring field in the caudate nucleus of patients with HD. Three measures of the neuronal level of preprotachykinin mRNA were all significantly reduced (6-65% of control values) in HD caudate nucleus. No decline in calbindin D28k mRNA levels per neuron were found in HD striata compared to control striata. We found a greater loss of preproenkephalin neurons per field than preprotachyknin neurons per field in the caudate nucleus of HD brains compared to control brains. Preprotachykinin neurons are lost in HD in a grade-related manner and surviving preprotachykinin neurons are impaired in function. However, preproenkephalin neurons are lost to a greater extent than preprotachykinin neurons, which may explain preferential changes found in projection regions of the striatum. Declines in neuropeptide mRNA may be specific in HD, since calbindin D28k mRNA levels were unchanged. Alterations in the levels of expression of preproenkephalin and preprotachykinin mRNA may be direct or indirect effects of the HD mutation.