Effectiveness of Different Rituximab Doses Combined with Leflunomide in the Treatment or Retreatment of Rheumatoid Arthritis: Part 2 of a Randomized, Placebo-Controlled, Investigator-Initiated Clinical Trial (AMARA).

BACKGROUND: The optimal dose of rituximab in combination with leflunomide in patients with rheumatoid arthritis (RA) is not known. METHODS: In Part 1 (previously reported) of the investigator-initiated AMARA study (EudraCT 2009-015950-39; ClinicalTrials.gov NCT01244958), improvements at week (W)24 were observed in patients randomized to rituximab + leflunomide compared with placebo + leflunomide. In the study reported here (Part 2), Part 1 responders received rituximab 500 or 1000 mg at W24/26 plus ongoing leflunomide. Patients were randomized at baseline to their eventual W24 treatment group. The Part 2 primary outcome was the mean Disease Activity Score-28 joints (DAS28) at W52, based on the last observation carried forward (LOCF) analyses and a two-sided analysis of variance. Patient-reported outcomes (PROs) and adverse events were evaluated. RESULTS: Eighty-three patients received rituximab at W24/26 (31 rituximab→rituximab 1000 mg; 29 rituximab→rituximab 500 mg; 10 placebo→rituximab 1000 mg; 13 placebo→rituximab 500 mg). At W52, there were no significant differences in DAS28 between rituximab doses in patients originally treated with rituximab or those originally treated with placebo. In the Part 1 placebo group, the higher rituximab dose was associated with greater improvements in ACR response rates and some PROs. Adverse events were similar regardless of rituximab dose. CONCLUSIONS: Retreatment with rituximab 500 mg and 1000 mg showed comparable efficacy, whereas an initial dose of rituximab 500 mg was associated with lower response rates versus 1000 mg. Reduced treatment response with the lower dose in patients initially treated with placebo may have been influenced by small numbers and baseline disease activity.

Development of a sterile Interaction Device during Image guided minimal-invasive Interventions.

For correct setting and control of imaging during image-guided Magnetic Resonance (MR) procedures (e.g. changing the slice orientation), the radiologist currently depends heavily on the assistants in the control room. The communication between the surgeon and the assistant is difficult due to acoustic noise generated by the MR gradients. The development for a dedicated interventional interaction device is addressed in this work, which includes the development and evaluation of a sterile, MR-compatible capacitive gesture controller. The gesture controller consists of a surgical drape with four capacitive sensors, that are made of conductive fabric. These sensors are based on the principle of electrical capacitance between isolated conductive structures. Measurements of these capacitances are exploited to calculate the distance of a hand to one of the sensors. By comparing the distances of the hand to each sensor, simple swipe gestures can be detected. The sensor unit is connected to a micro-controller, which allows direct and fast processing of the incoming data. To evaluate the prototype, a user study with 25 participants took place. Each user had to perform the four swiping gestures and the hold gesture in a specific order. The gesture controller is capable of registering five different gestures (left-right, right-left, up-down, down-up, hold). A survey of the second prototype showed, that in 92,4% of cases, the correct gesture was registered. Clinical relevance This interaction device allows the practicing physician to manipulate the imaging independently and in a sterile manner, thus enabling a significant improvement in work-flow.

Rituximab plus leflunomide in rheumatoid arthritis: a randomized, placebo-controlled, investigator-initiated clinical trial (AMARA study).

OBJECTIVE: To investigate the efficacy and safety of rituximab + LEF in patients with RA. METHODS: In this investigator-initiated, randomized, double-blind, placebo-controlled phase 3 trial, patients with an inadequate response to LEF who had failed one or more DMARD were randomly assigned 2:1 to i.v. rituximab 1000 mg or placebo on day 1 and 15 plus ongoing oral LEF. The primary efficacy outcome was the difference between ≥50% improvement in ACR criteria (ACR50 response) rates at week 24 (P ≤ 0.025). Secondary endpoints included ACR20/70 responses, ACR50 responses at earlier timepoints and adverse event (AE) rates. The planned sample size was not achieved due to events beyond the investigators' control. RESULTS: Between 13 August 2010 and 28 January 2015, 140 patients received rituximab (n = 93) or placebo (n = 47) plus ongoing LEF. Rituximab + LEF resulted in an increase in the ACR50 response rate that was significant at week 16 (32 vs 15%; P = 0.020), but not week 24 (27 vs 15%; P = 0.081), the primary endpoint. Significant differences favouring the rituximab + LEF arm were observed in some secondary endpoints, including ACR20 rates from weeks 12 to 24. The rituximab and placebo arms had similar AE rates (71 vs 70%), but the rituximab arm had a higher rate of serious AEs (SAEs 20 vs 2%), primarily infections and musculoskeletal disorders. CONCLUSION: The primary endpoint was not reached, but rituximab + LEF demonstrated clinical benefits vs LEF in secondary endpoints. Although generally well tolerated, the combination was associated with additional SAEs and requires monitoring. TRIAL REGISTRATION: EudraCT: 2009-015950-39; ClinicalTrials.gov: NCT01244958.

Golimumab improves patient-reported outcomes in daily practice of inflammatory rheumatic diseases in Germany.

Aim: To analyze the quality of life (QoL), work productivity and activity impairment (WPAI) and healthcare resource utilization (HCRU) in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients receiving golimumab under routine clinical settings in Germany. Materials & methods: Prospective observational study, GO-ART, analyzed changes in WPAI, QoL and HCRU during 24 months of golimumab therapy. Results: Seven hundred and forty-eight patients (RA = 250, PsA = 249 and AS = 249) were enrolled. Substantial improvements in WPAI scores presenteeism, activity impairment and total work productivity impairment and QoL were observed at month three and were maintained through month 24. Fewer patients had disease-related hospitalizations and consulted physician at month 24 than at the baseline. Conclusion: Golimumab induces sustained improvements in WPAI and QoL and reduces healthcare resource utilization in RA, PsA and AS.

Antimodified protein antibody response pattern influences the risk for disease relapse in patients with rheumatoid arthritis tapering disease modifying antirheumatic drugs.

OBJECTIVE: To perform a detailed analysis of the autoantibody response against post-translationally modified proteins in patients with rheumatoid arthritis (RA) in sustained remission and to explore whether its composition influences the risk for disease relapse when tapering disease modifying antirheumatic drug (DMARD) therapy. METHODS: Immune responses against 10 citrullinated, homocitrullinated/carbamylated and acetylated peptides, as well as unmodified vimentin (control) and cyclic citrullinated peptide 2 (CCP2) were tested in baseline serum samples from 94 patients of the RETRO study. Patients were classified according to the number of autoantibody reactivities (0-1/10, 2-5/10 and >5/10) or specificity groups (citrullination, carbamylation and acetylation; 0-3) and tested for their risk to develop relapses after DMARD tapering. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining the role of autoantibodies in predicting relapse. RESULTS: Patients varied in their antimodified protein antibody response with the extremes from recognition of no (0/10) to all antigens (10/10). Antibodies against citrullinated vimentin (51%), acetylated ornithine (46%) and acetylated lysine (37%) were the most frequently observed subspecificities. Relapse risk significantly (p=0.011) increased from 18% (0-1/10 reactivities) to 34% (2-5/10) and 55% (>5/10). With respect to specificity groups (0-3), relapse risk significantly (p=0.021) increased from 18% (no reactivity) to 28%, 36% and finally to 52% with one, two or three antibody specificity groups, respectively. CONCLUSIONS: The data suggest that the pattern of antimodified protein antibody response determines the risk of disease relapse in patients with RA tapering DMARD therapy. TRIAL REGISTRATION NUMBER: 2009-015740-42; Results.

Validation of Standardized Questionnaires Evaluating Symptoms of Depression in Rheumatoid Arthritis Patients: Approaches to Screening for a Frequent Yet Underrated Challenge.

OBJECTIVE: To validate standard self-report questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to one another and to the Montgomery-Åsberg Depression Rating Scale (MADRS), a standardized structured interview. METHODS: In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks followup (T1) using the World Health Organization 5-Item Well-Being Index (WHO-5), the Patient Health Questionnaire (PHQ-9), and the Beck Depression Inventory II (BDI-II). The construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman's correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone a psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as the gold standard. RESULTS: According to Spearman's correlation coefficients, all questionnaires met convergent validity criteria (ρ > |0.50|), with the BDI-II performing best, while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (ρ < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (ρ ≥ 0.70) was the BDI-II (rs = 0.77), which also achieved the best results for both sensitivity and specificity (>80%) when using the MADRS as the gold standard. CONCLUSION: The BDI-II best met the predefined criteria, and the PHQ-9 met most of the validity criteria, with lower sensitivity and specificity.

Prediction of disease relapses by multibiomarker disease activity and autoantibody status in patients with rheumatoid arthritis on tapering DMARD treatment.

OBJECTIVE: To analyse the role of multibiomarker disease activity (MBDA) score in predicting disease relapses in patients with rheumatoid arthritis (RA) in sustained remission who tapered disease modifying antirheumatic drug (DMARD) therapy in RETRO, a prospective randomised controlled trial. METHODS: MBDA scores (scale 1-100) were determined based on 12 inflammation markers in baseline serum samples from 94 patients of the RETRO study. MBDA scores were compared between patients relapsing or remaining in remission when tapering DMARDs. Demographic and disease-specific parameters were included in multivariate logistic regression analysis for defining predictors of relapse. RESULTS: Moderate-to-high MBDA scores were found in 33% of patients with RA overall. Twice as many patients who relapsed (58%) had moderate/high MBDA compared with patients who remained in remission (21%). Baseline MBDA scores were significantly higher in patients with RA who were relapsing than those remaining in stable remission (N=94; p=0.0001) and those tapering/stopping (N=59; p=0.0001). Multivariate regression analysis identified MBDA scores as independent predictor for relapses in addition to anticitrullinated protein antibody (ACPA) status. Relapse rates were low (13%) in patients who were MBDA-/ACPA-, moderate in patients who were MBDA+/ACPA- (33.3%) and MBDA-ACPA+ (31.8%) and high in patients who were MBDA+/ACPA+ (76.4%). CONCLUSIONS: MBDA improved the prediction of relapses in patients with RA in stable remission undergoing DMARD tapering. If combined with ACPA testing, MBDA allowed prediction of relapse in more than 80% of the patients. TRIAL REGISTRATION NUMBER: EudraCT 2009-015740-42.

Investigation on the comparability of the light spot hydrophone and the fiber optic hydrophone in lithotripter field measurements.

Optical hydrophones are optimized pressure-pulse-sensors used for high-power shockwave sources, such as lithotripters. Recent investigation of Smith et al. ["A Comparison of light spot hydrophone and fiber optic probe hydrophone for lithotripter field characterization," Rev. Sci. Instrum. 83, 014301 (2012)] show discrepancies in the negative pressure peak and tensile pulse duration regarding measurements carried out with two optical hydrophones: the Light Spot Hydrophone (LSHD) and the fiber optic hydro-phone. It was assumed that the differences arise from cavitation effects at the end-face of the LSHD glass-block and filter characteristics of the trans-impedance amplifier of the LSHD. The present study investigates the transfer-function of the LSHD. It is shown that the filter characteristics of the amplifier cause discrepancies in the rarefaction pressure pulse fraction (depending on the energy settings of the source 15 ± 2%).

Targeting pathophysiological rhythms: prednisone chronotherapy shows sustained efficacy in rheumatoid arthritis.

OBJECTIVE: This 9-month open-label extension of the Circadian Administration of Prednisone in Rheumatoid Arthritis Study (CAPRA 1) investigated the long-term safety and efficacy of prednisone chronotherapy with a novel modified-release (MR) prednisone for up to 12 months. METHODS: Of 288 patients with rheumatoid arthritis originally randomised to MR or immediate-release (IR) prednisone, 249 continued with prednisone chronotherapy (2-10 mg/day) in the 9-month open-label extension. Duration of morning stiffness of the joints (MS), disease activity scores (DAS28), American College of Rheumatology (ACR20) responses and plasma levels of interleukin 6 (IL-6) were assessed. Safety was analysed from adverse event reports and laboratory investigations. RESULTS: During the 3-month double-blind phase, patients in the MR group achieved a reduction in MS of 33.1% while no change was observed in the IR group. After 6 months of treatment, MS was reduced in the IR/MR group by 54% and in the MR/MR group by 56%. MS reduction after 12 months was 45% (IR/MR group) and 55% (MR/MR group). Plasma levels of IL-6 declined on MR treatment. DAS28 was reduced from 5.8 to 4.8 (MR/MR group) and 4.9 (IR/MR group), respectively. 37% of the 219 patients who completed the 12-month study achieved improvement according to the ACR20 criteria. Adverse events did not differ from the known profile of low-dose prednisone. CONCLUSIONS: Prednisone chronotherapy with the MR tablet was safe and well tolerated and provided a sustained improvement which resulted in a better benefit to risk ratio of low-dose glucocorticoid treatment for at least 12 months.

Efficacy of modified-release versus standard prednisone to reduce duration of morning stiffness of the joints in rheumatoid arthritis (CAPRA-1): a double-blind, randomised controlled trial.

BACKGROUND: Circadian rhythms are changed in patients with rheumatoid arthritis. A new modified-release delivery system has been developed which adapts the release of the administered glucocorticoid to the circadian rhythms of endogenous cortisol and disease symptoms to improve the benefit-risk ratio of glucocorticoid therapy in rheumatoid arthritis. We aimed to assess the efficacy and safety of a new modified-release prednisone tablet compared with immediate-release prednisone in patients with this disease. METHODS: In a 12-week, multicentre, randomised, double-blind trial, 288 patients with active rheumatoid arthritis were randomly assigned to either a modified-release prednisone tablet (n=144) or to an immediate-release prednisone tablet (n=144). The modified-release tablet was taken at bedtime and prednisone was released with a delay of 4 h after ingestion. This treatment was compared with morning administration of immediate-release prednisone as an active comparator. The primary outcome measure was duration of morning stiffness of the joints. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00146640. FINDINGS: The mean relative change in duration of morning stiffness of the joints from baseline to end of treatment was significantly higher with modified-release prednisone than with immediate-release prednisone (-22.7%vs -0.4%; difference=22.4% [95% CI 0.49-44.30]; p=0.045). Patients in the prednisone modified-release group achieved a mean reduction of 44.0 (SD 136.6) min compared with baseline. The absolute difference between the treatment groups was 29.2 min (95% CI -2.59 to 61.9) in favour of modified-release prednisone (p=0.072). The safety profile did not differ between treatments. INTERPRETATION: Modified-release prednisone is well tolerated, convenient to administer, and produces a clinically relevant reduction of morning stiffness of the joints in addition to all known therapeutic effects of immediate-release prednisone.

[Care of a patient with an implant-borne, bar-retained prosthesis in the maxilla. Case report]. / Die Versorgung eines Patienten mit einer implantatgetragenen Stegprothese im Oberkiefer. Ein Fallbericht.

A case presentation documents the prosthetic treatment of a denture in the upper jaw, and a conventional tooth--supported as well as a combined tooth--implant--supported fixed partial denture in the lower jaw.