Rheumatoid Arthritis Patients In Clinical Remission Research Articles

Ultrasound-detected tenosynovitis as a risk factor for flares in rheumatoid arthritis patients in clinical remission.

Our objective was to investigate the value of ultrasound (US) detected synovitis and tenosynovitis as risk factors for short term flare in rheumatoid arthritis (RA) patients in clinical remission. Consecutive RA patients in clinical remission (DAS28 ERS < 2.6) for at least 3months underwent Power Doppler ultrasound (PDUS) examination of 1st to 6th extensor compartments at the wrist, 2nd to 5th finger flexor, posterior tibial tendon, and peroneal tendons. To assess synovitis, carpal joints, 1st to 5th metacarpophalangeal (MCP) joints, and 2nd to 5th interphalangeal proximal (IPP) joints were bilaterally examined. Synovitis and tenosynovitis were defined according to OMERACT. Patients were followed for 1year. Disease flare was defined as an increase in disease activity generating the need for a change in therapy by the attending rheumatologist. Ninety patients were included. After 1year of follow-up, 26 patients (29%) experienced a flare. At baseline 39%, 23% and 8% had US-detected synovitis, tenosynovitis or both, respectively. In the 1-year period after the baseline US examination, US-detected tenosynovitis (RR: 4.9; 95% CI: 2.2-10.8) was associated with an increased risk of exacerbation. This association was not shown with US-detected synovitis (RR: 1.3; 95% CI: 0.76-2.2). In the multivariate analysis, only subclinical tenosynovitis (OR: 9.8; 95% CI: 2.5-39.1; p = 0.001) and baseline DAS28 (OR: 5.7; 95% CI: 1.1-31.6; p = 0.047) were significantly associated with an increased risk of having a flare. In our study, subclinical tenosynovitis was associated with disease flare in patients with RA in clinical remission. • Synovitis and tenosynovitis are risk factors for short term flare in RA patients in clinical remission. • Subclinical tenosynovitis, but not synovitis, was associated with disease flare in patients with unstable remission. • Ultrasound-detected tenosynovitis could be useful to predict relapses in RA patients in clinical remission.

Engineered glove to evaluate hand disability in rheumatoid arthritis: A pilot-study.

The Hand Test System (HTS) is an engineered-sensorized glove that has been originally developed in the neuroscientific field for the evaluation of hand fingers' speed movement. This pilot-study aimed to evaluate the reproducibility of HTS analysis in rheumatoid arthritis (RA), correlating glove-derived parameters with clinical disease activity indexes, self-reported disability-related questionnaires and hand strength. Fifty-five RA patients and fifty age and sex matched healthy controls (HCs) performed HTS analysis. The glove recognized the touch speed between the finger tips during standard sequences of movements, providing three quantitative parameters: touch duration (TD), inter-tapping interval (ITI) and movement rate (MR). These variables were correlated with Health Assessment Questionnaire (HAQ), Health Assessment Questionnaire-Disease Index (HAQ-DI), Hand Disability Index (HDI), Hand Grip Strength (HGS), DAS28-CRP, CDAI and SDAI. Intraclass correlation coefficient was 0.93 (CI: 0.92, 0.95). RA patients showed significantly slower TD, ITI and MR than HCs, for all classes of disease activity (P<0.001). All HTS parameters correlated significantly with HAQ, HAQ-DI, HDI, HGS, DAS28-CRP, SDAI, CDAI (between P<0.05 and P<0.001). Of note, also RA patients in clinical remission showed a significantly higher TD compared with HCs (P<0.001). HTS seems a new safe and fast tool to evaluate rheumatoid hand's functionality, measuring the speed of finger movements. Furthermore, the HTS parameters significantly correlate with quality of life, disease activity, hand strength and perceived hand disability, evaluating also potential hand motor impairment in RA clinical remission.

Внеклеточные ловушки нейтрофилов: динамика образования, ассоциированная с переходом от ремиссии к активному ревматоидному артриту

Tne aim of the research. To evaluate the main parameters of neutrophil extracellular traps formation (NETosis) and their dynamics in rheumatoid arthritis (RA) patients associated with the transition from remission to active autoimmune infl ammation. Material and methods. A total of 37 patients (6 males and 31 females) with verifi ed RA according to the ACR/EULAR 2010 criteria were enrolled in the study and formed the main group. Th e comparison group was constituted by 30 healthy volunteers. Circulating neutrophils were isolated with one-step density gradient centrifugation using double layers of iohexol gradient in the original modifi cation. Th e quantitative composition of neutrophils was assessed through microscopy of smears stained according to May-Grunwald. Cell viability as well as non-specifi c activation were evaluated microscopically using trypan blue exclusion assay and nitroblue tetrazolium test, respectively. Neutrophil extracellular trap (NETs) formation was induced by 50 nM phorbol-12-myristate-13- acetate and assessed using fl uorescence microscopy. Results. Neutrophils isolated from RA patients in clinical remission have been revealed to have a higher ability for spontaneous and induced NETs formation than neutrophils from the comparison group. Th e transition from remission to active RA was characterised by a signifi cant increase in induced and, especially, spontaneous formation of NETs. Th e growth rate of spontaneous NET formation was 3.9-fold higher than the induced NETs formation. Spontaneous formation of NETs above 16.4 % may serve as a possible RA activation indicator. Neutrophils from ACPA-positive RA patients were found to have increased spontaneous and induced NETs formation compared to ACPA-negative RA patients. Conclusion. We have studied the main parameters of NETs formation and their dynamics associated with the transition from remission to active autoimmune infl ammation in RA patients. Th e activity of RA has a more pronounced eff ect on the intensity of NETs formation than the presence of ACPA. NETs may be considered a new potential diagnostic and prognostic biomarker

Effect of initiating biologics compared to intensifying conventional DMARDs on clinical and MRI outcomes in established rheumatoid arthritis patients in clinical remission: Secondary analyses of the IMAGINE-RA trial

Objectives: 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. Method: 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. Trial registration: Clinicaltrials.gov identifier: NCT01656278

A nomogram to predict recurrence of RA patients in clinical remission within one year.

Some patients with rheumatoid arthritis (RA) will recur despite they have achieved clinical remission after treatment. The subclinical synovitis detected by ultrasonography (US) may be one of the main causes of the RA recurrence. The aim of this study is to establish a nomogram for predicting the outcome of RA patients with disease in clinical remission. One hundred and sixty-seven RA patients who achieved clinical remission and were willing to receive a 1-year follow-up were included in this study. Their demographic, clinical, and laboratory characteristics were recorded at baseline. 7-joints ultrasound (US7) synovitis score (simplified from US7 score) were evaluated at baseline and at the end of follow-up (or when RA recurrence confirmed). All patients were divided into recurrence group and non-recurrence group after the follow-up. Multivariable regression was applied to link the predictors that were significant at p < 0.05 in the univariate analysis and the recurrence of RA patients in clinical remission, which was served as the basis of the nomogram. Fifty-one RA patients were included in the recurrence group and 116 patients in the non-recurrence group. All US7 synovitis scores in this study showed excellent reproducibility. Multivariable analysis revealed that high-titer positive anti-cyclic citrullinated peptide (anti-CCP), simplified clinical disease activity index (SDAI), baseline grayscale ultrasound (GSUS) score, and baseline power Doppler ultrasound (PDUS) score were the independent predictors for RA recurrence within 1 year. A nomogram incorporating the independent predictors was constructed to predict the risk of RA recurrence. The nomogram showed good discrimination (C-index=0.826) and good calibration. The nomogram incorporating anti-CCP, SDAI, and subclinical synovitis helps to achieve complete remission and reduces the risk of short-term recurrence of RA patients.

Role of 7-Joint Ultrasonic Score in Predicting the Prognosis of Rheumatoid Arthritis

Background: There is a higher possibility for rheumatoid arthritis (RA) recurrence if patients have subclinical synovitis. Seven-joint ultrasonic score (US7 score) allows an accurate detection of subclinical synovitis, but its predictive role in the recurrence of RA patients in remission is uncertain. Objectives: The goal of this study was to explore the role of US7 score in predicting the recurrence of RA patients with disease in clinical remission. Patients and Methods: Totally, 186 RA patients in clinical remission were recruited and their demographic and clinicobiologic characteristics were collected. The US7 score and disease activity score in 28 joints (DAS28) were recorded as baseline indicators for a 1-year follow-up. Patients were divided into the recurrence group and non-recurrence group according to their recurrent results. The clinical indicators and US7 scores before the follow-up were compared and analyzed between the two groups. Kaplan-Meier and univariate COX regression analysis were used to analyze the effect of US7 score on the recurrence of RA. Receiver-operating characteristics (ROC) curves were established to evaluate the predictive accuracy of DAS 28 and US7 score for the outcome of RA. Results: Of the 186 RA patients, 55.9% received conventional disease-modifying antirheumatic drugs (cDMARDs) and 44.1% received biologic disease-modifying antirheumatic drugs (bDMARDs). Totally, 60 patients (32.3%) suffered from recurrence and were included in the recurrence group, and the remaining 126 patients were included in the non-recurrence group. The recurrence rate of patients without subclinical synovitis (10.26%) was lower than that of patients with subclinical synovitis (48.15%, χ2 = 27.556, P &lt; 0.001). US7 score was associated with an increased risk of recurrence in RA patients after successful treatment (P &lt; 0.001, hazard ratio = 1.363, 95% CI = 1.247 - 1.488). The area under the curve of the prediction model with combined US7 score and DAS 28 was higher (0.904) compared to that of US7 score or DAS 28 (P &lt; 0.05). Conclusion: The US7 score is capable of predicting the recurrence of RA patients because of its advantages in identifying subclinical synovitis. The combined model of DAS28 and US7 score was accurate for predicting the recurrence of RA patients in clinical remission.

Treat-to-target strategies aiming at additional ultrasound remission is associated with better control of disease activity and less flare in rheumatoid arthritis.

Treat-to-target (T2T) strategy has greatly improved the prognosis of rheumatoid arthritis (RA). However, the additional benefit of targeting ultrasound (US) remission in addition to clinical remission has been debated. RA patients in clinical remission or low disease activity were enrolled. They were assorted into two groups according to the principle of T2T strategy adopted. In clinical group, treatment decision was made with the aim of maintaining DAS28(ESR) ≤ 3.2 only, while in clinical US group, the aim was to attain total power Doppler (PD) US score = 0 in addition to DAS28(ESR) ≤ 3.2. The time-averaged DAS28, flare, and changes of treatment strategy were compared. One hundred ninety-four patients completed 1-year follow-up, with 100 in clinical US and 94 in clinical group. Compared to clinical group, time-averaged DAS28 in clinical US group was significantly lower (1.89 ± 0.51 vs. 2.33 ± 0.71, P < 0.01) with less flare (20.0% vs. 36.2%, P < 0.05). Furthermore, at the end of 1year, significantly more patients successfully achieved step-down therapy (66.0% vs. 44.7%, P < 0.01) and dramatically fewer patients with step-up therapy in the clinical US group (13.0% vs. 25.5%, P < 0.05) compared to clinical group. In clinical US group, baseline DAS28(ESR) > 2.29, presence of subclinical synovitis, and step-down strategy were independent risk factors for relapse after clinical remission or low disease activity was achieved. An US-driven T2T in addition to current clinical remission strategy is associated with better control of the disease activity, reduction of relapse, as well as long-term step-down therapy. Step-down strategy should be carefully applied to the patients with baseline DAS28(ESR) over 2.29 and presence of subclinical synovitis even after they have achieved clinical remission or low disease activity. Key Points • Targeting ultrasound remission in addition to current T2T strategy is associated with a better control of RA. • Step-down strategy should be cautiously considered in those with DAS28(ESR) > 2.29 and baseline subclinical synovitis after they have achieved clinical remission or low disease activity.

Association between MRI findings and patient‐reported outcomes in patients with rheumatoid arthritis in clinical remission and at relapse

To investigate whether magnetic resonance imaging (MRI) pathologies in the wrist/hand of rheumatoid arthritis (RA) patients are associated with patient-reported outcomes (PROs) at clinical remission and relapse. Wrist/hand MRIs and wrists/hands/feet radiographs were obtained in 114 established RA patients in clinical remission, before tapering their biologic disease-modifying antirheumatic drugs. MRIs were assessed according to the Outcome Measures in Rheumatology (OMERACT) RA MRI score (RAMRIS) for inflammation (synovitis/tenosynovitis/bone marrow edema) and damage (bone erosion/joint space narrowing) at baseline (ie remission) and in case of a relapse (n=70). Radiographs were assessed according to the Sharp/van der Heijde (SvH) method at baseline. These scores were assessed for associations with health assessment questionnaires (HAQ), visual analog scales (VAS global/pain), EuroQol-5 dimensions and Short-Form 36 physical and mental component summary (SF-36 PCS/MCS) using Spearman correlations, univariate/multivariable linear regression analyses and generalized estimating equations. Furthermore, MRI pathologies were assessed for association with specific hand-related HAQ items using Jonckheere trend tests. Magnetic resonance imaging-assessed damage was associated with impaired HAQ and SF-36 PCS at remission and relapse (P<.01), independent of clinical and radiographic measures, and was also associated with most of the hand-related HAQ items (P<.03). In multivariate models including MRI, SvH scores were not associated with PROs. MRI-assessed inflammation was not associated with PROs at remission or relapse. Magnetic resonance imaging-assessed wrist/hand damage, but not inflammation, in patients with established RA is associated with patient-reported physical impairment at remission and relapse. The amount of damage in the wrist/hand is associated with reduced hand function.

Lack of association between clinical and ultrasound measures of disease activity in rheumatoid arthritis remission.

Objectives:The objective of this study was to assess the prevalence of ultrasound (US) abnormalities and association with clinical parameters in rheumatoid arthritis (RA) clinical remission.Methods:Patients with established RA in clinical remission (DAS28-CRP < 2.4) taking conventional synthetic disease-modifying anti-rheumatic drugs were recruited as part of the Biomarkers of Remission in Rheumatoid Arthritis (BioRRA) Study. In addition, patients from the Newcastle Early Arthritis Clinic (NEAC) with early active RA (DAS28-CRP > 2.4) or seronegative non-inflammatory arthralgia (NIA) were studied as positive and negative controls, respectively. The association between individual dependent variables (synovial power Doppler and greyscale, tenosynovial greyscale, and erosions) and clinical parameters was assessed by multivariate ordinal logistic regression, with adjustment for multiple testing.Results:A total of 294 patients were included: 66 RA in remission, 146 active RA, and 82 NIA. Within the active RA group, significant associations were observed between swollen joint count and higher total synovial greyscale score (OR 1.17 95% CI 1.08–1.26, p < 0.001) and higher total synovial power Doppler score (OR 1.20, 95% CI 1.12–1.30, p < 0.001). No significant associations were observed for the NIA group. In the RA remission group, US abnormalities were frequently observed and comparable for both DAS28-CRP and 2011 ACR/EULAR Boolean remission, with no significant association with clinical parameters identified.Conclusion:We observed widespread subclinical US findings in RA patients in clinical remission, even when remission is defined using the stringent ACR/EULAR Boolean criteria. In contrast to active disease, synovial power Doppler failed to show significant association with any of the clinical parameters in RA remission. Our results suggest that clinical and US examinations are non-overlapping in evaluating RA remission, challenging the proposition of US-driven management strategies in this setting.

Power Doppler ultrasound in the evaluation of hand joints in rheumatoid arthritis patients in clinical remission: Association with composite index scores and functional status

BackgroundEvaluation of remission in Rheumatoid Arthritis (RA) largely relies on composite scores based on clinical and laboratory assessments however, patients can fulfill clinical remission criteria as defined by composite scores, yet still have evidence of synovitis detectable on imaging. Aim of the workTo evaluate hand and wrist joints in patients with RA in clinical remission using power Doppler (PD) ultrasonography and to study the association between ultrasonographic findings and composite index scores. Patients and methodsThis study was conducted on 50 RA patients in clinical remission. Ten matched healthy subjects were included as control. The modified health assessment questionnaire (MHAQ) was assessed in the patients; disease activity was calculated using a composite index score including disease activity score (DAS28) and clinical disease activity index (CDAI). Ultrasonographic assessment of the hand and wrist joints was performed. ResultsThe mean age of the patients was 50.9 ± 9.2 years, disease duration was 10.6 ± 5.5 years and were 38 females and 12 males. The mean DAS28 was 2.3 ± 0.3. On ultrasonographic examination, 14 (28%) patients had normal synovium, while 18 (36%) showed synovial hypertrophy without evidence of inflammation and 18 (36%) had PD signals. DAS28 was higher in patients with PD signals (2.36 ± 0.3) compared to those without synovitis (2.3 ± 0.28). There was a significant correlation between PD activity and CDAI (p = 0.005), MHAQ (p = 0.002) and disease duration (p = 0.023). ConclusionPower Doppler ultrasound can detect residual inflammation in RA patients in clinical remission and its scores were signficantly associated with the clinical disease activity index and functional status.

Remaining local subclinical joint inflammation is associated with deteriorated metacarpeal head bone microarchitecture in rheumatoid arthritis patients low disease activity

ObjectivesBone alterations at the subchondral level during rheumatoid arthritis (RA) remain under investigation. It remains unknown whether subchondral bone damage might still occur in RA patients in clinical remission, which could then infer suggesting that even minor subclinical inflammatory changes in the joint can induce local bone loss. MethodsThirty-two RA patients treated with biological disease-modifying anti-rheumatic drugs (bDMARDs) with low disease activity since at least 6 months and having erosion on the second or third metacarpeal head were enrolled in this pilot cross-sectional study. They were divided in two groups according to local inflammation assessed by Doppler-ultrasound exam surrounding the site of erosion. Cortical and trabecular parameters of the metacarpeal head were then assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) and compared in both groups. ResultsTwenty and twelve RA patients were enrolled in the “Doppler positive erosion” (DE+) group and Doppler negative erosion (DE−) group, respectively. No difference was observed in their clinical or biological RA characteristics. Both cortical density and thickness were similar among groups. Within the trabecular network, while no difference in bone volume was observed, trabecular density as well as trabecular number were decreased (P<0.001 and P<0.05 respectively), whereas trabecular separation and distribution of trabecular separation were increased in DE+ compared to DE− (P<0.05). ConclusionIn RA patients in low disease activity under bDMARDs, persistence of local inflammation was associated with alteration of the trabecular compartment. Trabecular density was the most strongly altered parameter and could be a candidate to assess drug effect on periarticular bone damage.

Clinical and sonographic biomarkers of structural damage progression in RA patients in clinical remission: A prospective study with 12 months follow-up.

To determine clinical and sonographic biomarkers predicting structural damage progression at 12 months of follow-up as measured by magnetic resonance imaging (MRI) in rheumatoid arthritis (RA) patients in clinical remission. We included patients with RA in clinical remission, defined as 28-joint disease activity score (DAS28)-erythrocyte sedimentation rate (ESR) <2.6 for >6 months. Ultrasound scans of both hands and knees and MRI of the dominant hand were performed at baseline and at 12 months. Out of 55 patients, 42 completed the follow-up. Among them, 78% were female, aged (median) 54 years; disease duration was 93 months. In total, 12 (28%) patients were taking oral prednisone, 34 (81%) conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), and 20 (47%) biological therapies. At baseline, 45% fulfilled criteria previously defined for ultrasound-defined active synovitis (UdAS) [PD (power Doppler) signal + synovial hyperplasia ≥2]. Multivariate analysis showed significant associations between baseline MRI erosion score, body mass index (BMI), disease duration, prednisone treatment, absence of biologic and csDMARDs, UdAS, and MRI erosion score progression after 12 months. In an exploratory analysis, serum levels of calprotectin correlated significantly with bone edema progression. We identified clinical and sonographic markers of structural damage progression after 12 months follow-up in patients with RA in clinical remission. Meeting the criteria of ultrasound active synovitis, defined as simultaneous relevant synovial hyperplasia and PD, was associated with erosion progression after 12 months. Calprotectin was associated with bone edema, in an exploratory analysis.

Ultrasound-defined remission for good functional status in rheumatoid arthritis

Background & objectives:It has been shown that joint damage due to subclinical synovitis progresses despite apparent clinical remission in rheumatoid arthritis (RA). Hence, finding more objective methods to investigate subclinical synovitis has become a current issue. Ultrasonography (US) has been among the most investigated methods. This study was conducted to detect whether there was subclinical inflammation in RA patients in clinical remission by power Doppler ultrasonography (PDUS) and to evaluate the effects of this inflammation on upper extremity function.Methods:Forty five RA patients fulfilled the remission criteria of disease activity score 28 using erythrocyte sedimentation rate (DAS28-ESR), were enrolled in the study. Bilateral wrist, 2nd and 3th metacarpophalangeal and proximal interphalangeal joints and 2nd and 5th metatarsophalangeal joints were examined by PDUS. Upper extremity function was assessed with Michigan Hand Outcomes Questionnaire (MHQ) and handgrip strength. The pain was evaluated by visual analogue scale (VAS).Results:In 29 of 45 RA patients in clinical remission, synovitis was detected by PDUS at least in one joint. VAS and DAS28-ESR scores were significantly lower and total MHQ, some subgroup scores of MHQ (overall hand function, activity of daily living and work performance) and grip strength of the dominant hand were higher in patients with PD signal negativity.Interpretation & conclusions:PDUS showed a crucial role in determining the subclinical synovitis. Subclinical synovitis negatively affects the upper extremity function. Ultrasound-defined remission may be considered for good functional status and real remission in patients with RA.

Musculoskeletal Ultrasound in the Treat-to-Target Treatment Strategies in Rheumatoid Arthritis

Treat-to-target (T2T) strategy, aiming at clinical remission or low disease activity, has greatly improved the prognosis of rheumatoid arthritis (RA) since its institution in clinical practice in 2010. However, with the widespread application of ultrasound, the subclinical synovitis has been observed to be commonly present in RA patients in clinical remission. A systematic literature search and meta-analysis elated revealed an association between Power Doppler positivity and the risk of flare (OR 4.52, 95% CI 2.61-7.84, P<0.00001, I2=21%), the risk of progressive bone erosion on patient level (OR 12.80, 95% CI 1.29-126.81, P=0.03, I2=52%) and risk of progressive bone erosion on joint level (OR 11.85, 95% CI 5.01-28.03, P<0.00001, I2=0%). Furthermore, the treatment strategies targeting ultrasound remission in addition to clinical remission better controlled disease activity of RA patients and reduced flare during follow-up comparted to the treatment with clinical remission as the only target. Deeper clinical remission reflects the better control of subclinical synovitis under the ultrasound and could be an optimized treatment target in RA management.

Serum Calprotectin Discriminates Subclinical Disease Activity from Ultrasound-Defined Remission in Patients with Rheumatoid Arthritis in Clinical Remission.

ObjectiveClinical remission in some patients with rheumatoid arthritis (RA) may be associated with ongoing synovial inflammation that is not always detectable on clinical examination or reflected by laboratory tests but can be visualized by musculoskeletal ultrasound. The goal of our study was to determine the levels of serum calprotectin, a major leukocyte protein, in patients with RA in clinical remission and to investigate the ability of serum calprotectin levels to distinguish patients in ultrasound-defined remission from those with residual ultrasound subclinical inflammation.MethodsSeventy RA patients in clinical remission underwent clinical and ultrasound examination. Ultrasound examination was performed according to the German US7 score. Ultrasound remission was defined as grey scale (GS) range 0–1 and power Doppler (PD) range 0. The levels of serum calprotectin and C-reactive protein (CRP) were determined. The discriminatory capacity of calprotectin and CRP in detecting residual ultrasound inflammation was assessed using ROC curves.ResultsThe total number of patients fulfilling the DAS28-ESR, DAS28-CRP, SDAI and CDAI remission criteria was 58, 67, 32 and 31, respectively. Residual synovial inflammation was found in 58–67% of the patients who fulfilled at least one set of clinical remission criteria. Calprotectin levels were significantly higher in patients with residual synovial inflammation than in those with ultrasound-defined remission (mean 2.5±1.3 vs. 1.7±0.8 μg/mL, p<0.005). Using ultrasound-defined remission criteria, calprotectin had an AUC of 0.692, p<0.05 using DAS28-ESR remission criteria and an AUC of 0.712, p<0.005 using DAS28-CRP remission criteria. Calprotectin correctly distinguished ultrasound remission from subclinical activity in 70% of patients. CRP (AUC DAS28-ESR = 0.494, p = NS; AUC DAS28-CRP = 0.498, p = NS) had lower and insignificant discriminatory capacity.ConclusionThe present study demonstrates the potential of calprotectin to distinguish RA patients in both clinical and ultrasound-defined remission from patients in clinical remission but with residual subclinical disease activity.

El papel de la ultrasonografía para la evaluación subclínica de la artritis reumatoide en remisión. Revisión sistemática de la literatura

There is an interest in the role of ultrasound (US), particularly the presence of power Doppler (PD) signal and synovial hypertrophy in the evaluation of subclinical activity in rheumatoid arthritis patients (RA) on remission. ObjectiveExamine the evidence to determine the usefulness of US and PD in the evaluation of patients with RA in remission using clinimetric properties. Materials and methodsA systematic literature search was performed using electronic databases PubMed, EMBASE, BioMed Central, Cochrane registry of clinical trials and secondary reference sources of articles published up to 2 March 2014, with the key terms “arthritis, rheumatoid” or “arthritis” and “ultrasonography” or “ultrasonography, Doppler, pulsed” and “remission induction” were used until March 2, of the 2014, without language restriction. Observational cohort studies that assessed the prevalence of subclinical activity by US and PD in adult patients with RA in clinical remission were included. Methodological quality of the articles was verified and relevant information extracted from each one. ResultsA total of 13 studies were identified for analysis. RA activity using these imaging techniques was observed in 14.6 to 95% for US synovial hypertrophy and 1.2 to 64.5% for PD in remission patients using clinimetry. ConclusionsIn RA patients with clinical remission, variable subclinical activity was observed with ultrasound detected by synovial hypertrophy and a positive intra-articular PD signal. The latter enables residual from inflammatory pannus to be differentiated, and to also predict relapse and correlate with disease progression, allowing therapeutic changes. More studies evaluating treatment and prognostic outcomes are required.

Antibodies to infliximab and adalimumab in patients with rheumatoid arthritis in clinical remission: a cross-sectional study.

Objective. To investigate if antibodies towards biological TNF-α inhibitors (anti-TNFi Abs) are present in patients with rheumatoid arthritis (RA) in clinical remission and to relate any anti-TNFi Abs to circulating level of TNF-α inhibitor (TNFi). Methods. Patients with RA, treated with infliximab or adalimumab, and in clinical remission (DAS28(CRP) < 2.6) were included from 6 out-patient clinics. In blood samples, presence of anti-TNFi Abs was determined by radioimmunoassay, and concentration of bioactive TNFi was measured by a cell-based reporter gene assay. Results. Anti-TNFi Abs were present in 8/44 patients (18%) treated with infliximab and 1/49 patients (2%) treated with adalimumab (p = 0.012). In the former group, anti-TNFi Abs corresponded with low levels of TNFi (p = 0.048). Anti-TNFi Ab-positive patients had shorter disease duration at initiation of TNFi therapy (p = 0.023) but were similar for the rest of the compared parameters. Conclusions. In RA patients in clinical remission, anti-TNFi Abs occur frequently in patients treated with infliximab, while they occur rarely in patients treated with adalimumab. Presence of anti-infliximab Abs is accompanied by low or undetectable levels of infliximab. These data suggest that continued infliximab treatment may be redundant in a proportion of RA patients treated with infliximab and in clinical remission.

Modulation of peripheral T-cell function by interleukin-7 in rheumatoid arthritis.

IntroductionInterleukin-7 (IL-7) is a cytokine essential for T-cell lymphopoiesis, survival and polarization with an emerging role in autoimmunity. We previously demonstrated reduced levels of circulating IL-7 in rheumatoid arthritis (RA), although high amounts are expressed in joints, suggesting differences between systemic and synovial effects. We observed healthy levels of IL-7 in 48% of RA patients in clinical remission (CR) and aimed to investigate the consequences of IL-7 deficiency on T-cell responses.MethodsWe used RA patients with active disease and in CR presenting various levels of IL-7, to investigate its modulatory effects on T cells by analysing responses to phyto-haemagglutinin (PHA), expression of polarization or survival factors, or suppression by regulatory T cells (Tregs).ResultsIL-7 levels were normal (>10 pg/ml) in 48% of RA patients in CR. Amongst 63 CR patients followed up for 18 months, lack of IL-7 recovery was observed in 13 out of 15 (86%) patients experiencing relapse but only 11 out of 48 (23%) of those who did not (P = 0.0002). Binary regressions showed high significance for below normal IL-7 levels for self-reported maternal family history of arthritis (odds ratio (OR): 7.66, P = 0.006) and a trend for smoking (OR: 3.33, P = 0.068) with no further demographic or clinical associations. Serum IL-7 correlated with restored CD4+T-cell response to PHA (rho = 0.879); this was not related to an increase in T-cell proliferation capacity or expression of survival factors B-cell lymphoma 2 (BCL2) and BCL2-associated protein X (BAX). Expression of Th1 polarization factor (TBET) was also dependent on exposure to IL-7 in vivo (rho = 0.600). In contrast CD25highTregs’ response to PHA was not affected by in vivo IL-7, but their suppression capabilities were related to circulating IL-7 (rho = 0.589). Co-stimulation with IL-7 (mimicking the joint environment) increased responsiveness of CD4+T-cells to PHA, lowering the ability of CD25highTregs to suppress them.ConclusionsOur data demonstrate that IL-7 has a critical role in modulating T-cell function in vivo, possibly explaining opposing effects observed systemically and in the joint. Lack of IL-7 recovery in CR by maintaining a suppressed immune system may be a determinant factor in the occurrence of relapse.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0511-3) contains supplementary material, which is available to authorized users.

Prediction of Relapse After Discontinuation of Biologic Agents by Ultrasonographic Assessment in Patients With Rheumatoid Arthritis in Clinical Remission: High Predictive Values of Total Gray‐Scale and Power Doppler Scores That Represent Residual Synovial Inflammation Before Discontinuation

This prospective study aimed to determine whether the comprehensive ultrasonographic assessment of synovial inflammation predicts relapse after discontinuation of treatment with a biologic agent in patients with rheumatoid arthritis (RA) in clinical remission. RA patients in clinical remission (Disease Activity Score in 28 joints [DAS28] <2.6) receiving treatment with a biologic agent who agreed to discontinue the treatment were recruited. Patients underwent a comprehensive ultrasound scan on 134 synovial sites in 40 joints and were prospectively followed up for 6 months. Physicians who evaluated the patients during the study period were blinded to the baseline ultrasound findings. Forty-two patients receiving either a tumor necrosis factor antagonist or tocilizumab were enrolled. Using the optimal cutoff values determined by receiver operating characteristic curve analysis, relapse rates were significantly higher in patients whose total ultrasound scores at discontinuation were high than in those whose total ultrasound scores were low (P < 0.001 for both total gray-scale and power Doppler scores), whereas the difference between high and low DAS28 was not statistically significant (P = 0.158 by log rank test). Positive and negative predictive values were 80.0% and 73.3% for the total gray-scale score and 88.9% and 74.2% for the total power Doppler score, respectively. In RA patients in clinical remission receiving treatment with a biologic agent, residual synovial inflammation determined by comprehensive ultrasound assessment predicted relapse within a short term after discontinuation of the treatment. Our data provide a rationale and groundwork to conduct a large-scale study for establishment of ultrasound-based strategies to optimize the period of treatment with a biologic agent.

FRI0276 Ultrasonography as Useful Tool to Identify Rheumatoid Arthritis Patients in Clinical Remission for Tapering or Withdrawal TNFA Blockers without Disease Relapse

BackgroundUltrasonography (US) has superior sensitivity in detecting the presence of synovial hypertrophy (SH) and its activity by Power Doppler (PD) in Rheumatoid Arthritis (RA). The relapse rate is nearly 50%...