Cardiopulmonary exercise testing in transthyretin amyloid cardiomyopathy patients: a long-term follow-up study.

AIMS: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) experience reduced functional capacity. We evaluated changes in functional capacity over extensive follow-up using cardiopulmonary exercise testing (CPX). METHODS: ATTR-CM patients underwent CPX and blood testing at baseline, first [V1, 8 (6-10) months] and second follow-up (V2) at 35 (26-41) months after start of disease-specific therapy. RESULTS: We included 34 ATTR-CM patients, aged 77 (±6) years (88.2% men). CPX showed two patterns with functional capacity improvement at V1 and deterioration at V2. Peak work capacity (P = 0.005) and peak oxygen consumption (VO2, P = 0.012) increased at V1 compared with baseline and decreased at V2. The ventilation to carbon dioxide relationship slope (VE/VCO2) increased at V2 compared with baseline and V1 (P = 0.044). A cut-off for peak VO2 at 14 ml/kg·min showed more events (composite of death and heart failure hospitalization): less than 14 vs. greater than 14 ml/kg·min (P = 0.013). Cut-offs for VE/VCO2 slope at 40 showed more events greater than 40 vs. less than 40 (P = 0.009). CONCLUSION: ATTR-CM patients showed an improvement and deterioration in the short-term and long-term follow-up, respectively, with a better prognosis for those with peak VO2 above 14 ml/kg·min and for a VE/VCO2 slope below 40.

American College of Rheumatology/EULAR Remission Criteria for Rheumatoid Arthritis: 2022 Revision.

OBJECTIVE: In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean- and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the 2 sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria. METHODS: We used data from 4 randomized trials comparing biologic disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared to the original threshold of 1 cm (Boolean1.0). We analyzed agreement between the Boolean- and index-based criteria (Simplified Disease Activity Index [SDAI] and Clinical Disease Activity Index [CDAI]) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire [HAQ] score ≤0.5) and radiographic nonprogression. RESULTS: Data from 2,048 trial participants, 1,101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared to Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8-4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes. CONCLUSION: Using the Boolean 2.0 criteria classifies more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardizing predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.

American College of Rheumatology/EULAR remission criteria for rheumatoid arthritis: 2022 revision.

OBJECTIVE: In 2011, the American College of Rheumatology (ACR) and EULAR endorsed provisional criteria for remission in rheumatoid arthritis (RA), both Boolean-based and index-based. Based on recent studies indicating that a higher threshold for the patient global assessment (PtGA) may improve agreement between the two sets of criteria, our goals were to externally validate a revision of the Boolean remission criteria using a higher PtGA threshold and to validate the provisionally endorsed index-based criteria. METHODS: We used data from four randomised trials comparing biological disease-modifying antirheumatic drugs to methotrexate or placebo. We tested the higher proposed PtGA threshold of 2 cm (Boolean2.0) (range 0-10 cm) compared with the original threshold of 1 cm (Boolean1.0). We analysed agreement between the Boolean-based and index-based criteria (Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)) for remission and examined how well each remission definition predicted later good physical function (Health Assessment Questionnaire (HAQ) score≤0.5) and radiographic non-progression. RESULTS: Data from 2048 trial participants, 1101 with early RA and 947 with established RA, were included. The proportion of patients with disease in remission at 6 months after treatment initiation increased when using Boolean2.0 compared with Boolean1.0, from 14.8% to 20.6% in early RA and 4.2% to 6.0% in established RA. Agreement between Boolean2.0 and the SDAI or CDAI remission criteria was better than for Boolean1.0, particularly in early disease. Boolean2.0, SDAI, and CDAI remission criteria had similar positive likelihood ratios (LRs) to predict radiographic nonprogression and a HAQ score of ≤0.5 (positive LR 3.8-4.3). The omission of PtGA (BooleanX) worsened the prediction of good functional outcomes. CONCLUSION: Using the Boolean 2.0 criteria classifies, more patients as achieving remission and increases the agreement with index-based remission criteria without jeopardising predictive value for radiographic or functional outcomes. This revised Boolean definition and the previously provisionally endorsed index-based criteria were endorsed by ACR and EULAR.

Impact of Tafamidis and Optimal Background Treatment on Physical Performance in Patients With Transthyretin Amyloid Cardiomyopathy.

BACKGROUND: In patients with transthyretin amyloid cardiomyopathy, tafamidis was shown to slow the decline in 6-minute walking distance as compared with placebo. We aimed to define the impact of tafamidis and optimal background treatment on functional capacity as determined by cardiopulmonary exercise testing (CPET). METHODS: Seventy-eight consecutive patients were enrolled in the study. They underwent CPET at baseline, and outcome defined as death or heart failure hospitalization was obtained for a time period of up to 30 months. Fifty-four patients completed a follow-up CPET at 9±3 months (range, 4-16 months). Improvement in peak VO2 at follow-up was defined as ∆peak VO2≥1.0 mL/(kg·min), stable peak VO2 was defined as 0≤∆peak VO2<1.0 mL/(kg·min), and decline in peak VO2 was defined by ∆peak VO2<0 mL/(kg·min). RESULTS: Baseline peak VO2>14 mL/(kg·min) as well as minute ventilation/carbon dioxide production slope≤34 were associated with a lower risk of death or heart failure hospitalization (P=0.002, P=0.007, respectively). In 54 patients, who received tafamidis and underwent repeat CPET testing, an improvement in physical performance (P=0.002) was observed at follow-up. When comparing pre and post-treatment parameters, 29 patients (54%) showed an increase in percent predicted peak VO2 (P<0.0001), an improvement of peak VO2 (P<0.0001), and better physical performance at follow-up (P<0.0001). Patients with stable or improved peak VO2 had less advanced heart disease at baseline (P=0.046). CONCLUSIONS: Our findings demonstrate that baseline peak VO2 and baseline minute ventilation/carbon dioxide production slope predict outcomes and an improvement in physical performance as measured by CPET was observed in patients receiving tafamidis, who had less advanced disease at baseline, emphasizing the importance of early diagnosis.

Trajectory clusters of radiographic progression in patients with rheumatoid arthritis: associations with clinical variables.

OBJECTIVES: Identification of trajectories of radiographic damage in rheumatoid arthritis (RA) by clustering patients according to the shape of their curve of Sharp-van der Heijde scores (SHSs) over time. Developing models to predict their progression cluster from baseline characteristics. METHODS: Patient-level data over a 2-year period from five large randomised controlled trials on tumour necrosis factor inhibitors in RA were used. SHSs were clustered in a shape-respecting manner to identify distinct clusters of radiographic progression. Characteristics of patients within different progression clusters were compared at baseline and over time. Logistic regression models were developed to predict trajectory of radiographic progression using information at baseline. RESULTS: In total, 1887 patients with 7738 X-rays were used for cluster analyses. We identified four distinct clusters with characteristic shapes of radiographic progression: one with a stable SHS over the whole 2-year period (C0/lowChange; 86%); one with relentless progression (C1/rise; 5.8%); one with decreasing SHS (C2/improvement; 6.9%); one going up and down (C3/bothWays; 1.4%) of the SHS. Robustness of clusters were confirmed using different clustering methods. Regression models identified disease duration, baseline C-reactive protein (CRP) and SHS and treatment status as predictors for cluster assignment. CONCLUSIONS: We were able to identify and partly characterise four different clusters of radiographic progression over time in patients with RA, most remarkably one with relentless progression and another one with amelioration of joint damage over time, suggesting the existence of distinct patterns of joint damage accrual in RA.

Role of clinical and biochemical inflammation in structural progression of patients with psoriatic arthritis.

OBJECTIVE: To determine the contribution of clinical and biochemical inflammation to structural progression of patients with psoriatic arthritis (PsA). METHODS: We analysed patients from the Infliximab Multinational Psoriatic Arthritis Controlled Trial 2 trial (infliximab vs placebo). We obtained total modified Sharp/van-der-Heijde Scores from baseline and year one images, and swollen joint counts (SJC) and levels of C reactive protein (CRP) throughout the second half of year 1 (5 measurements) from 74 placebo-treated patients. We computed radiographic progression, time-averaged SJC (taSJC) and CRP (taCRP) values and assessed their impact on structural progression by logistic regression analysis. We further categorised patients as 'active' (+) or 'inactive' (-) based on their taSJC (cut-off point: 2/66 joints) and taCRP (cut-off point: 0.5 mg/dL) and compared radiographic progression across three groups (double inactive, single active, double active). RESULTS: ORs for progression were 1.24 (95 % CI 1.04 to 1.47; p=0.016) for taSJC and 6.08 (95 % CI 1.12 to 33.03; p=0.036) for taCRP. When predictors were dichotomised (+ vs -), differences were maintained between taSJC+ and taSJC- patients (1.05±3.21 and 0.56±2.30, respectively), as well as for taCRP+ vs taCRP- patients (1.14±3.23 and 0.05±2.37, respectively). Progression was intermediate in the presence of abnormalities of one but not the other inflammatory variable, indicating increasing radiographic progression with increasing inflammation (p=0.05). CONCLUSION: In patients with PsA, both clinical and biochemical inflammation have an impact on structural progression. Overall, progression is smallest in the absence of both clinical and biochemical inflammation, higher when either clinical or biochemical inflammation is present and highest with both clinical and biochemical inflammation.

Low serum potassium levels and diabetes - An unfavorable combination in patients with heart failure and preserved ejection fraction.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is among the most common forms of heart failure (HF). We aimed to investigate the prognostic significance of serum potassium levels and its interaction with type-2 diabetes mellitus in patients with HFpEF. METHODS: Consecutive HFpEF patients were prospectively included in a registry study. The primary endpoint was a composite of cardiac death or HF hospitalization. RESULTS: 363 HFpEF patients were enrolled (median age: 73.0 years; females: 70.3%). Median serum potassium (K+) was 4.3 mmol/L. A total of 128 (35.3%) patients had type-2 diabetes mellitus, of whom 92 were treated with oral anti-diabetic drugs and 35 with insulin. The study population was divided into two groups, according to their serum potassium levels. Significant differences between the groups were detected with regards to combined endpoint [n = 27 (61.4%) versus n = 87 (27.3%); p < 0.0001]. Lower serum potassium levels were significantly associated with adverse outcome in the Cox proportional hazard analysis [hazard ratio (HR): 1.83; 95% confidence interval (CI) 1.14-2.94; p = 0.0118]. Further independent predictors of adverse outcome were a history of HF hospitalizations (HR: 2.77; 95% CI 1.82-4.21; p < 0.0001), higher NT-pro BNP (HR: 1.93; 95% CI 1.82-4.21; p = 0.0084) as well as type-2 diabetes mellitus (HR: 1.57; 95% CI 1.05-2.34; p = 0.0027). Patients with diabetes and K+ ≤ 3.71 mmol/L faced the worst outcome as compared to the remainder of the group (p = 0.0001). CONCLUSION: In HFpEF patients, the combination of diabetes and low serum potassium levels are associated with an adverse outcome.

Implication of baseline levels and early changes of C-reactive protein for subsequent clinical outcomes of patients with rheumatoid arthritis treated with tocilizumab.

BACKGROUND: Rheumatoid arthritis (RA) is characterised by clinical joint swelling and elevation of acute phase reactant levels, typically measured by the C-reactive protein (CRP). Clinical and inflammatory responses are usually concordant, except for inhibition of IL-6, which often disproportionally reduces the CRP due to direct inhibition of its hepatic production. We investigated whether pre-treatment CRP is a useful marker that can guide a preferential treatment choice towards IL-6 inhibition. METHODS: Data of 1126 treatment courses with tocilizumab (TCZ; early RA), 250 courses of rituximab (RTX; established RA) and 249 courses of methotrexate (MTX; established RA) were analysed. We compared clinical disease activity index (CDAI) values and change along 24 weeks' follow-up to CRP values at baseline or its early change. We validated the results using data from a separate TCZ trial in early RA. RESULTS: CRP levels in the TCZ group on average dropped by 74% within 4 weeks. Patients who attained CDAI remission at 24 weeks on TCZ had the highest baseline CRP levels while patients in high disease activity had the lowest; this association was reverse in the RTX and MTX groups. TCZ patients who achieved remission at 24 weeks showed the largest reductions of CRP levels by week 4 compared with those reaching higher disease activity states. Early CRP non-response was indicative of a risk of not achieving clinical treatment goals (p=0.038). CONCLUSION: Baseline CRP appears to have a positive association with reaching the therapeutic target on TCZ treatment, but is a negative predictor for RTX and MTX. Patients on TCZ without an early CRP response have a lower chance of achieving remission. CRP and its early course may inform, to some extent, the estimation of potential therapeutic success in patients with RA.

Testing different thresholds for patient global assessment in defining remission for rheumatoid arthritis: are the current ACR/EULAR Boolean criteria optimal?

OBJECTIVES: This study aimed to evaluate different patient global assessment (PGA) cut-offs required in the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean remission definition for their utility in rheumatoid arthritis (RA). METHODS: We used data from six randomised controlled trials in early and established RA. We increased the threshold for the 0-10 score for PGA gradually from 1 to 3 in steps of 0.5 (Boolean1.5 to Boolean3.0) and omitted PGA completely (BooleanX) at 6 and 12 months. Agreement with the index-based (Simplified Disease Activity Index (SDAI)) remission definition was analysed using kappa, recursive partitioning (classification and regression tree (CART)) and receiver operating characteristics. The impact of achieving each definition on functional and radiographic outcomes after 1 year was explored. RESULTS: Data from 1680 patients with early RA and 920 patients with established RA were included. The proportion of patients achieving Boolean remission increased with higher thresholds for PGA from 12.4% to 19.7% in early and 5.9% to 12.3% in established RA at 6 months. Best agreement with SDAI remission occurred at PGA cut-offs of 1.5 and 2.0, while agreement decreased with higher PGA (CART: optimal agreement at PGA≤1.6 cm; sensitivity of PGA≤1.5 95%). Changing PGA thresholds at 6 months did not affect radiographic progression at 12 months (mean ꙙsmTSS for Boolean, 1.5, 2.0, 2.5, 3.0, BooleanX: 0.35±5.4, 0.38±5.14, 0.41±5.1, 0.37±4.9, 0.34±4.9, 0.27±4.7). However, the proportion attaining HAQ≤0.5 was 90.2%, 87.9%, 85.2%, 81.1%, 80.7% and 73.1% for the respective Boolean definitions. CONCLUSION: Increasing the PGA cut-off to 1.5 cm would provide high consistency between Boolean with the index-based remission; the integer cut-off of 2.0 cm performed similarly.

Rheumatoid arthritis disease activity and the risk of aseptic arthroplasty loosening.

OBJECTIVES: To assess the influence of rheumatoid arthritis (RA) disease activity (DA) on the risk of aseptic loosening after total hip/knee arthroplasty (THA/TKA). METHODS: We identified RA patients who underwent THA/TKA and determined their DA using the simplified disease activity index (SDAI). The risk of aseptic loosening was estimated using radiographic signs of component loosening (RCL). We performed Cox regression to estimate RCL based on SDAI, adjusting for therapy. We also investigated a cohort of 2:1 matched osteoarthritis (OA) patients as a control group without systemic inflammation. RESULTS: We identified 49 RA patients with a history of THA/TKA, of whom 18 (36.7%) showed RCL. SDAI over time was significantly higher in patients with RCL (median; 25th and 75th percentile: 10.8 months; 8.6 and 15.8; vs 7.0 months; 2.7 and 15.5;p = 0.043). In the regression model, each unit of mean SDAI over time significantly increased the risk of RCL (HR 1.125, 95% CI 1.021-1.241;p = 0.018). Patients treated with biological had a lower risk of RCL than those treated with traditional DMARDs (HR 0.192, 95% CI 0.042-0.891;p = 0.035). In the 88 matched OA patients, the RCL rate was significantly lower than in the RA group (13.6%;p = 0.002). CONCLUSION: Higher inflammatory DA increases the risk for radiographic loosening after THA/TKA in patients with RA. The significantly lower risk in patients with OA further underlines the potential role of inflammatory DA. In the context of treating RA to target, the presence of an arthroplasty might be considered as an indication for more stringent control of DA.

Risk profiling for a refractory course of rheumatoid arthritis.

BACKGROUND: Despite modern therapeutics and treatment strategies, a subset of rheumatoid arthritis (RA) patients remains insufficiently responsive to multiple therapies. Here, we identify predictors of such refractory RA ("reRA"). METHODS: Patients from a longitudinal academic clinical database with reRA (defined as failing to reach the treatment target of at least low disease activity with ≥3 DMARD courses, including ≥1 biological, over a total of ≥18 months) were compared to patients who did respond within the first two treatments (treatment amenable RA, "taRA"). We performed logistic regression analysis to identify risk factors for refractory disease, and several sensitivity analyses concerning different potential definitions for reRA to confirm the robustness of the results; key findings were also validated in an independent community cohort. RESULTS: We enrolled 412 patients, of whom 70 were reRA and 102 taRA; 240 patients fulfilled neither definition. ReRA patients were more frequently female (92.9 vs. 70.6%, p < 0.001), younger (44.37 vs. 51.14 years, p = 0.002), and had higher CDAI levels at first presentation (26.06 vs. 15.39, p < 0.001). Treatment delay was significantly longer for reRA than for taRA (3.17 vs. 1.45 years, p = 0.001). In multivariable analyses, treatment delay, female gender and higher disease activity remained as independent predictors of refractory disease. Based on the identified predictors, we developed a matrix model for risk of future reRA. CONCLUSIONS: Our data identified delay to initial treatment, female gender and higher disease activity as important predictors of a later refractory course of RA. Delay of treatment initiation is the single most important modifiable risk factor of refractory disease.

Feasibility of On-table Extubation After Cardiac Surgery with Cardiopulmonary Bypass: A Randomized Clinical Trial.

BACKGROUND: The use of short-acting anesthetics, muscle relaxation, and anesthesia depth monitoring allows maintaining sufficient anesthesia depth, fast recovery, and extubation of the patients in the operating room (OR). We evaluated the feasibility of extubation in the OR in cardiac surgery. METHODS: This clinical trial was performed on 100 adult patients who underwent elective noncomplex cardiac surgery using cardiopulmonary bypass. Additional to the routine monitoring, the patients' depth of anesthesia and neuromuscular blocked were assessed by bispectral index and nerve stimulator, respectively. In the on-table extubation (OTE) group (n = 50), a limited dose of sufentanil (0.15 µg/kg/h) and inhalational anesthetics were used for early waking. In the control group (n = 50), the same anesthesia-inducing drugs were used but the dose of sufentanil during the operation was 0.7 - 0.8 µg/kg/h. After the operation, cardiorespiratory parameters and ICU stay were documented. RESULTS: Demographic and clinical variables were comparable in both study groups. In the OTE group, we failed to extubate two patients in the OR (success rate of 96%). There were no significant differences between the two groups in terms of systolic and diastolic blood pressure at the time of entering the ICU (P > 0.05). Heart rate was lower in the OTE than in the control group at ICU admission (89.4 ± 13.1 vs. 97.6 ± 12.0 bpm; P = 0.008). The ICU stay time was lower in the OTE group (34 (21.5 - 44) vs. 48 (44 - 60) h; P = 0.001). CONCLUSIONS: Combined inhalational-intravenous anesthesia along with using multiple anesthesia monitoring systems allows reducing the dose of total anesthetics and maintaining adequate anesthesia depth during noncomplex cardiac surgery with cardiopulmonary bypass. Thus, extubation of the trachea in the OR is feasible in these patients.

Induction of sustained remission in early inflammatory arthritis with the combination of infliximab plus methotrexate: the DINORA trial.

BACKGROUND: In the present study, we explored the effects of immediate induction therapy with the anti-tumour necrosis factor (TNF)α antibody infliximab (IFX) plus methotrexate (MTX) compared with MTX alone and with placebo (PL) in patients with very early inflammatory arthritis. METHODS: In an investigator-initiated, double-blind, randomised, placebo-controlled, multi-centre trial (ISRCTN21272423, http://www.isrctn.com/ISRCTN21272423 ), patients with synovitis of 12 weeks duration in at least two joints underwent 1 year of treatment with IFX in combination with MTX, MTX monotherapy, or PL randomised in a 2:2:1 ratio. The primary endpoint was clinical remission after 1 year (sustained for at least two consecutive visits 8 weeks apart) with remission defined as no swollen joints, 0-2 tender joints, and an acute-phase reactant within the normal range. RESULTS: Ninety patients participated in the present study. At week 54 (primary endpoint), 32% of the patients in the IFX + MTX group achieved sustained remission compared with 14% on MTX alone and 0% on PL. This difference (p < 0.05 over all three groups) was statistically significant for IFX + MTX vs PL (p < 0.05), but not for IFX + MTX vs MTX (p = 0.10), nor for MTX vs PL (p = 0.31). Remission was maintained during the second year on no therapy in 75% of the IFX + MTX patients compared with 20% of the MTX-only patients. CONCLUSIONS: These results indicate that patients with early arthritis can benefit from induction therapy with anti-TNF plus MTX compared with MTX alone, suggesting that intensive treatment can alter the disease evolution. TRIAL REGISTRATION: The trial was registered at http://www.isrctn.com/ISRCTN21272423 on 4 October 2007 (date applied)/12 December 2007 (date assigned). The first patient was included on 24 October 2007.

Determination of Autoantibody Isotypes Increases the Sensitivity of Serodiagnostics in Rheumatoid Arthritis.

Anti-citrullinated protein antibodies (ACPA) and rheumatoid factor (RF) are the most commonly used diagnostic markers of rheumatoid arthritis (RA). These antibodies are predominantly of the immunoglobulin (Ig) M (RF) or IgG (ACPA) isotype. Other subtypes of both antibodies-particularly IgA isotypes and other autoantibodies-such as RA33 antibodies-have been repeatedly reported but their diagnostic value has still not been fully elucidated. Here, we investigated the prevalence of IgA, IgG, and IgM subtypes of RF, ACPA, and RA33 antibodies in patients with RA. To determine the diagnostic specificity and sensitivity sera from 290 RA patients (165 early and 125 established disease), 261 disease controls and 100 healthy subjects were tested for the presence of IgA, IgG, and IgM isotypes of RF, ACPA, and RA33 by EliA™ platform (Phadia AB, Uppsala, Sweden). The most specific antibodies were IgG-ACPA, IgA-ACPA, and IgG-RF showing specificities >98%, closely followed by IgG- and IgA-RA33 while IgM subtypes were somewhat less specific, ranging from 95.8% (RA33) to 90% (RF). On the other hand, IgM-RF was the most sensitive subtype (65%) followed by IgG-ACPA (59.5%) and IgA-RF (50.7%). Other subtypes were less sensitive ranging from 35 (IgA-ACPA) to 6% (IgA-RA33). RA33 antibodies as well as IgA-RF and IgA-ACPA were found to increase the diagnostic sensitivity of serological testing since they were detected also in seronegative patients reducing their number from 109 to 85. Moreover, analyzing IgM-RF by EliA™ proved more sensitive than measuring RF by nephelometry and further reduced the number of seronegative patients to 76 individuals. Importantly, among antibody positive individuals, RA patients were found having significantly more antibodies (≥3) than disease controls which generally showed one or two antibody species. Thus, increasing the number of autoantibodies in serological routine testing provides valuable additional information allowing to better distinguish between RA and other rheumatic disorders, also in patients not showing antibodies in current routine diagnostics. In conclusion, testing for multiple autoantibody specificities increases the diagnostic power of autoimmune diagnostics and could further support physicians in clinical decision-making.

Early response to therapy predicts 6-month and 1-year disease activity outcomes in psoriatic arthritis patients.

Objectives: In PsA management, remission and low disease activity represent preferential treatment targets. We aimed at evaluating the predictive value and clinical use of initial therapeutic response for subsequent achievement of these targets. Methods: Based on data of 216 patients enrolled in a randomized controlled trial of golimumab (GO-REVEAL), we performed diagnostic testing analyses using 3- and 6-month disease activity as tests for treatment outcomes to understand the implications of early response. In regression analyses, we estimated the probabilities for achieving at least LDA. Disease activity was measured by the disease activity index for PsA (DAPSA). Results: Three-month DAPSA levels were excellent tests for disease activity at 6 months (and at 1 year), with areas under the receiver operating characteristic curves of 0.92 (and 0.88, respectively). The estimated probability for 6-month LDA could be quantified as <22% if patients did not reach at least moderate disease activity after 3 months on golimumab. Similar data were seen for early DAPSA response: patients achieving a DAPSA 85% at 3 months had an 84% probability for 6-month LDA or REM. All results were validated in an independent trial cohort of patients treated with infliximab (IMPACT 2). Conclusion: Three months after implementation of therapy in PsA, it is already possible to evaluate the potential for accomplishing therapeutic goals. This substantiates the choice of the 3-month assessment as essential for treatment adaptations.

Epidemiology of Multiple Sclerosis in Austria.

BACKGROUND: To assess the incidence rate and prevalence ratio of multiple sclerosis (MS) in Austria. METHODS: Hospital discharge diagnosis and MS-specific immunomodulatory treatment prescriptions from public health insurances, covering 98% of Austrian citizens with health insurance were used to extrapolate incidence and prevalence numbers based on the capture-recapture method. RESULTS: A total of 1,392,629 medication prescriptions and 40,956 hospitalizations were extracted from 2 data sources, leading to a total of 13,205 patients. The incidence rate and prevalence ratio of MS in Austria based on the capture-recapture method were 19.5/100,000 person-years (95% CI 14.3-24.7) and 158.9/100,000 (95% CI 141.2-175.9), respectively. Female to male ratio was 1.6 for incidence and 2.2 for prevalence. CONCLUSIONS: Incidence rates and prevalence ratios of MS in our study are within the upper range of comparable studies across many European countries as well as the United States.

Cartilage damage and bone erosion are more prominent determinants of functional impairment in longstanding experimental arthritis than synovial inflammation.

Chronic inflammation of articular joints causing bone and cartilage destruction consequently leads to functional impairment or loss of mobility in affected joints from individuals affected by rheumatoid arthritis (RA). Even successful treatment with complete resolution of synovial inflammatory processes does not lead to full reversal of joint functionality, pointing to the crucial contribution of irreversibly damaged structural components, such as bone and cartilage, to restricted joint mobility. In this context, we investigated the impact of the distinct components, including synovial inflammation, bone erosion or cartilage damage, as well as the effect of blocking tumor necrosis factor (TNF) on functional impairment in human-TNF transgenic (hTNFtg) mice, a chronic inflammatory erosive animal model of RA. We determined CatWalk-assisted gait profiles as objective quantitative measurements of functional impairment. We first determined body-weight-independent gait parameters, including maximum intensity, print length, print width and print area in wild-type mice. We observed early changes in those gait parameters in hTNFtg mice at week 5 - the first clinical signs of arthritis. Moreover, we found further gait changes during chronic disease development, indicating progressive functional impairment in hTNFtg mice. By investigating the association of gait parameters with inflammation-mediated joint pathologies at different time points of the disease course, we found a relationship between gait parameters and the extent of cartilage damage and bone erosions, but not with the extent of synovitis in this chronic model. Next, we observed a significant improvement of functional impairment upon blocking TNF, even at progressed stages of disease. However, blocking TNF did not restore full functionality owing to remaining subclinical inflammation and structural microdamage. In conclusion, CatWalk gait analysis provides a useful tool for quantitative assessment of functional impairment in inflammatory destructive arthritis. Our findings indicate that cartilage damage and bone erosion, but not synovial inflammation, are the most important determinants for progressive functional impairment in this chronic erosive arthritis model.

Optimisation of a treat-to-target approach in rheumatoid arthritis: strategies for the 3-month time point.

BACKGROUND: Treat-to-target (T2T) is a widely accepted management strategy for rheumatoid arthritis (RA) with a key decision point at 3 months after treatment initiation. At this time point, it remains unclear which patients will benefit from treatment adaptation or from continuation of existing treatment. METHODS: We performed a pooled analysis of patient-level clinical trial data of patients with RA. We used a diagnostic testing methodology and a probabilistic approach employing logistic regression to investigate which levels of response at 3 months can inform treatment decisions in regard to achieving the target at 6 months. RESULTS: To be at least 80% sensitive for achieving the low disease activity (LDA) target at 6 months, a change at 3 months in Simplified Disease Activity Index/Clinical Disease Activity Index (SDAI or CDAI) of 58% needs to be observed at 3 months. Higher changes are needed to sensitively predict remission (REM). Not reaching the (minor) SDAI 50% response level is afflicted with very low negative likelihood ratios (LRs) (0.28 for LDA and 0.07 for REM at 6 months). Experiencing (major) SDAI 85% response has substantial positive LRs of 9.2 for reaching LDA and 6.2 for reaching REM at 6 months. In logistic regression, the change at 3 months is significantly associated with reaching of the target at 6 months. CONCLUSIONS: The 3-month time point is a critical decision point. Not achieving minor responses at 3 months makes reaching of the treatment target at 6 months highly unlikely, while reaching major responses is highly predictive of reaching the treatment target.

Disease activity in psoriatic arthritis (PsA): defining remission and treatment success using the DAPSA score.

BACKGROUND: The Disease Activity Index for Psoriatic Arthritis (DAPSA) is a valid and discriminative tool. Definitions of disease activity states and therapeutic response are still missing. We derived such criteria for the DAPSA. METHODS: We retrieved 30 patient profiles from an observational database including joint counts, patient pain and global activity ratings and C-reactive protein (CRP) and carried out a survey among experts to classify patients into remission (REM), low (LDA), moderate (MDA) or high (HDA) disease activity. Based on the distributions of DAPSA in each of these expert-assigned states we defined the cutpoints between groups. We performed similar analyses evaluating a clinical score (cDAPSA), omitting CRP. To define minor, moderate and major treatment response, we used Cohen's Kappa statistics and analysed agreement of DAPSA percentage change with ACR20/50/70-response in three randomised controlled trials. RESULTS: Our survey yielded a response rate of 75% (n=33). Mean DAPSA differed significantly between patients classified as REM, LDA, MDA or HDA (p<0.001). Based on the distributions of DAPSA in these groups, we propose cut-off values of ≤4 for REM, >4 and ≤14 for LDA, >14 and ≤28 for MDA and >28 for HDA. We observed best agreement with ACR20/50/70-response at DAPSA changes of 50/75/85%, reflecting minor, moderate and major improvement. CONCLUSIONS: The DAPSA constitutes a disease-specific, validated and feasible tool for PsA assessment. In this study, we provide criteria for disease activity states and treatment response. They are based on an international expert survey, and show good performance in clinical trials and observational data.