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Asta Linauskas,1,2 Kim Overvad,3 Martin Berg Johansen,4 Kristian Stengaard-Pedersen,1,5 Annette de Thurah1,5 1Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark; 2Department of Rheumatology, North Denmark Regional Hospital, Hjoerring, Denmark; 3Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, Denmark; 4Unit of Clinical Biostatistics, Aalborg University Hospital, Aalborg, Denmark; 5Department of Clinical Medicine, Aarhus University, Aarhus, Denmark Purposes: To assess whether the positive predictive value (PPV) of first-time rheumatoid arthritis (RA) diagnosis registration in the Danish National Patient Registry increases when data are linked to the RA treatment codes and to assess the PPV of first-time RA diagnoses according to RA serological subtypes.Methods: Participants from the Danish Diet, Cancer, and Health cohort with at least one RA diagnosis, registered at one of the Central Denmark Region hospitals in the Danish National Patient Registry during the period 1977–2016, were identified. Register-based RA diagnoses were verified by scrutinizing medical records against RA classification criteria or clinical case RA. PPVs for overall RA, seropositive RA, and other RA were calculated for two models: first-time RA diagnosis registration ever in the Danish National Patient Registry and first-time RA diagnosis registration ever where subsequently a prescription had been redeemed for a synthetic disease-modifying antirheumatic drug.Results: Overall, 205 of 311 first-time register-based RA diagnoses were verified (PPV: 61.9%; 95% CI: 56.9–67.0). Regarding RA serological subtypes, 93 of 150 register-based seropositive RA (PPV: 62.0; 95% CI: 53.9–69.5) and 36 of 144 other RA (PPV: 25.0; 95% CI: 18.5–32.8) were confirmed. When register-based RA diagnosis codes were linked to RA treatment codes, the PPVs increased substantially: the PPV for overall RA was 87.7% (95% CI: 82.5–91.5), the PPV for seropositive RA was 80.2% (95% CI: 71.6–86.7), and the PPV for other RA was 41.1% (95% CI: 30.2–52.9).Conclusion: The first-time RA diagnoses in the Danish National Patient Registry should be used with caution in epidemiology research. However, linking registry-based RA diagnoses to the subsequent RA treatment codes increases the probability of identifying true RA diagnoses, especially overall RA and seropositive RA. Keywords: administrative database research, Danish National Prescription Registry, Anatomical Therapeutic Chemical codes, seropositive rheumatoid arthritis, Denmark

Smoking and periodontitis are risk factors for developing rheumatoid arthritis (RA), suggesting a break of tolerance on mucosal surfaces. Immunoglobulin A (IgA) antibodies are part of the mucosal immune system. The dominant autoantibodies in RA are anti-cyclic citrullinated protein antibodies (ACPAs), and IgG and IgA subclasses exist simultaneously. This study aimed to investigate the association of ACPA IgA subtypes with disease activity and long-term radiographic outcomes in RA, compared with ACPA IgG. Total ACPA IgG, IgA, IgA1, and IgA2 were quantified in serum from patients with early RA (n = 97). Patient characteristics, IgM rheumatoid factor (IgM-RF) status, clinical and biochemical disease activity scores, and radiographic status evaluated by total Sharp score (TSS), were assessed at baseline and after 2 and 11 years of treatment. All patients with ACPA IgA also had ACPA IgG. ACPA IgA positivity was associated with IgM-RF and male gender. Both ACPA IgA and IgG levels at baseline were weakly associated with disease activity markers. Baseline ACPA IgA and IgG did not show a linear correlation with radiographic status after 10 years, but could predict radiographic progression (ΔTSS ≥ 5 from 0 to 11 years), with positive likelihood ratios of 3.7 and 4.0, respectively. ACPA IgA and IgG were weakly associated with disease activity in early RA. RA patients with a ΔTSS ≥ 5 after 11 years of treatment had higher ACPA IgG and ACPA IgA levels at baseline; however, none of the ACPA subtypes was superior in predicting long-term radiographic progression. [ABSTRACT FROM AUTHOR]

Dosing of tumour necrosis factor-α inhibitors (TNFis) is not personalized causing interindividual variation in serum drug levels; however, dose optimization is not widely implemented. We hypothesized that some patients are overdosed; thus, drug prescription could be reduced by therapeutic drug monitoring (TDM). Independent of disease activity, 239 adults treated for rheumatoid arthritis (n = 99), psoriatic arthritis 15 (n = 48), or spondyloarthritis (n = 92) were recruited for a 48-week prospective, randomized open-label trial. Standard care alone or plus TDM was applied in chronic arthritis patients treated with infliximab (IFX), (n = 81), etanercept (ETN) (n = 79), or adalimumab (ADA) (n = 79). Serum TNFi trough levels assessed at inclusion and every 4 months determined patients within/outside predefined therapeutic intervals, supporting change in prescription or drug switch. The primary endpoint was reduced drug prescription. Compared to standard care, TDM reduced prescribed IFX [−12% (95% confidence interval −20, −3); p = 0.001] and ETN (−15% (−29, 1); p = 0.01], and prolonged the interdosing intervals of ETN [+235% (38, 432); p = 0.02] and ADA [+28% (6, 51); p = 0.04]. Time to drug switch was accelerated (χ2 = 6.03, p = 0.01). No group differences in adverse events, disease activity, or self-reported outcomes were shown, indicating equally sustained remission. TDM reduced prescription of IFX, ETN, and ADA and identified patients benefiting from accelerated drug switch, thereby minimizing treatment failure, risk of toxicity, and unnecessary adverse events. [ABSTRACT FROM AUTHOR]

14-3-3η is a proinflammatory mediator critical to joint destruction in rheumatoid arthritis (RA). We aimed to evaluate serum 14-3-3η for predicting disease activity and radiographic progression in patients with early RA in the double-blinded, randomized OPERA trial. 180 patients with early RA were randomized to receive methotrexate (MTX) + adalimumab or MTX + placebo in combination with glucocorticoid injections into swollen joints. Disease activity was measured using the 28-joint Disease Activity Score–C-reactive protein (DAS28-CRP). Clinical remission was defined as DAS28-CRP < 2.6. X-rays of hands and feet were evaluated by the Total Sharp van der Heijde score (TSS). Radiographic progression was defined as exceeding the smallest detectable change (1.8 TSS-units). Serum 14-3-3η was determined by enzyme-linked immunosorbent assay. Multivariate logistic regression models were used to identify predictors of DAS28-CRP remission at 6 months and radiographic progression at 12 months. Baseline 14-3-3η was a borderline significant independent predictor of radiographic progression at 12 months (odds radio = 1.02, 95% confidence interval 1.00–1.03, p = 0.05). In anti-cyclic citrullinated peptide antibody (ACPA)-negative patients, a moderate/high baseline 14-3-3η concentration increased the risk of radiographic progression at 12 months [4/51 (8%) vs 3/9 (33%), χ2 = 4.823, p = 0.028]. No value of 14-3-3η for predicting achievement of clinical remission was found. Serum 14-3-3η was a borderline significant predictor of radiographic progression, particularly in ACPA-negative patients, but not of predicting achievement of clinical remission. Optimal cut-off levels of 14-3-3η for predicting radiographic progression in RA need further clarification. [ABSTRACT FROM AUTHOR]

Galectin-3 (Gal-3) has been suggested as a proinflammatory mediator in rheumatoid arthritis (RA). We aimed to study clinical and pathogenic aspects of Gal-3 in RA. Plasma samples from healthy controls (n = 48) and patients with newly diagnosed, early RA were assayed for soluble Gal-3. In patients with chronic RA (n = 18), Gal-3 was measured in both plasma and synovial fluid. Synovial fluid mononuclear cells were used to purify fibroblast-like synoviocytes (FLSs) and osteoclasts. Monocultures of FLSs and autologous co-cultures of FLSs and peripheral blood mononuclear cells were established and co-incubated with a Gal-3 inhibitor. Patients with early and chronic RA had persistently increased plasma levels of Gal-3 compared with controls. However, changes in plasma Gal-3 at the level of individuals were associated with long-term disease activity. In seropositive early RA patients, all patients with decreasing plasma Gal-3 from 0 to 3 months had low disease activity after 2 years (p < 0.05). Gal-3 levels in synovial fluid were markedly elevated. In vitro, co-incubation with a Gal-3 inhibitor (GB1107, 10 µM) led to a significant reduction in both interleukin-1β and tumour necrosis factor-α secretion from FLS monocultures (both p < 0.05) and decreased monocyte-derived osteoclastogenesis compared with controls (both p < 0.05). Our findings underscore the role of Gal-3 regarding disease activity and tissue destruction in RA. An initial decrease in plasma Gal-3 levels predicted decreased long-term disease activity. Correspondingly, a Gal-3 inhibitor decreased the activity of inflammatory FLSs and osteoclastogenesis in patients with RA. [ABSTRACT FROM AUTHOR]

To compare the effect of treat-to-target-based escalations in conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) and biologics on clinical disease activity and magnetic resonance imaging (MRI) inflammation in a rheumatoid arthritis (RA) cohort in clinical remission. One-hundred patients with established RA, Disease Activity Score based on 28-joint count–C-reactive protein (DAS28-CRP) < 3.2, and no swollen joints (hereafter referred to as 'in clinical remission') who received csDMARDs underwent clinical evaluation and MRI of the wrist and second to fifth metacarpophalangeal joints every 4 months. They followed a 2 year MRI treatment strategy targeting DAS28-CRP ≤ 3.2, no swollen joints, and absence of MRI osteitis, with predefined algorithmic treatment escalation: first: increase in csDMARDs; second: adding a biologic; third: switch biologic. MRI osteitis and Health Assessment Questionnaire (HAQ) (co-primary outcomes) and MRI combined inflammation and Simplified Disease Activity Index (SDAI) (key secondary outcomes) were assessed 4 months after treatment change and expressed as estimates of group differences. Statistical analyses were based on the intention-to-treat population analysed using repeated-measures mixed models. Escalation to first biologic compared to csDMARD escalation more effectively reduced MRI osteitis (difference between least squares means 1.8, 95% confidence interval 1.0–2.6), HAQ score (0.08, 0.03–0.1), MRI combined inflammation (2.5, 0.9–4.1), and SDAI scores (2.7, 1.9–3.5). Treat-to-target-based treatment escalations to biologics compared to escalation in csDMARDs more effectively improved MRI inflammation, physical function, and clinical disease activity in patients with established RA in clinical remission. Treatment escalation in RA patients in clinical remission reduces clinical and MRI-assessed disease activity. Clinicaltrials.gov identifier: NCT01656278 [ABSTRACT FROM AUTHOR]

Summary: Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that primarily affects the axial skeleton. A predominance of innate versus adaptive immune responses have been reported in axSpA, indicating a prominent autoinflammatory component of the disease. Little is known about the lectin pathway proteins (LPPs) of the complement system in relation to axSpA. We have investigated LPPs in patients with axSpA and control individuals. Plasma samples were obtained from a cross‐sectional cohort of 120 patients with a clinical diagnosis of axSpA and from 144 age‐ and gender‐matched controls. The plasma concentrations of 11 LPPs were measured, using sandwich‐type time‐resolved immunofluorometric assays in patients and controls, and related to clinical diagnosis and disease activity. Three LPPs [H‐ficolin (ficolin‐3), L‐ficolin (ficolin‐2) and collectin liver 1 (CL‐L1)] were significantly higher in axSpA patients than in controls (P < 0·0001) and one LPP, collectin kidney 1 (CL‐K1), was significantly lower (P < 0·0001). Further, combining H‐ or L‐ficolin concentrations above the 75th percentile of the respective H‐ or L‐ficolin concentration measured in controls with human leucocyte antigen (HLA)‐B27 positivity yielded axSpA diagnostic specificities of 99/99% and positive likelihood ratios of 68/62, respectively. H‐ficolin and L‐ficolin plasma concentrations were found to be elevated in axSpA patients regardless of time since diagnosis. H‐ficolin and L‐ficolin may represent diagnostic biomarkers for patients with axSpA and should be further evaluated. Our results showed no association between disease activity and the measured LPP concentrations. This result might be due to the cross‐sectional design, and should be further investigated. [ABSTRACT FROM AUTHOR]

ObjectivesMethodResultsConclusionThis study explores the early identification of rheumatoid arthritis (RA) patients at elevated risk of progression. Haem-oxygenase-1 (HO-1) is a marker of oxidative stress in inflammation. Here, we investigate HO-1 as a biomarker of oxidative stress and its association with clinical disease activity and radiographic progression in RA.Baseline HO-1 was measured sequentially in plasma samples from patients with early rheumatoid arthritis (eRA) (n = 80). Disease Activity Score based on 28-joint count–C-reactive protein, Clinical Disease Activity Index, and total Sharp score were used to evaluate the disease course serially over 2 years. Paired plasma and synovial fluid samples were examined for HO-1 in active established rheumatoid arthritis (esRA) (n = 20). Plasma from healthy control subjects was also included (n = 35).Plasma HO-1 levels were increased in eRA {1373 pg/mL [interquartile range (IQR) 1110–2050]} and esRA [2034 pg/mL (IQR 1630–2923)] compared with controls [1064 pg/mL (IQR 869.5–1378)]. HO-1 plasma levels decreased with treatment. Baseline HO-1 correlated with disease activity and radiographic progression. A strong, linear correlation was found between synovial and plasma HO-1 levels (r = 0.75, p < 0.001).In eRA, plasma levels of HO-1 were increased and correlated with disease and radiographic progression. A baseline measurement of plasma HO-1 levels demonstrated superior performance to currently used clinical and serological disease markers in the prediction of radiographic progression. Plasma HO-1 may function as a first-in-class biomarker of synovial oxidative stress in RA. [ABSTRACT FROM AUTHOR]