Effects of secukinumab on synovitis and enthesitis in patients with psoriatic arthritis: 52-week clinical and ultrasound results from the randomised, double-blind ULTIMATE trial with open label extension.

OBJECTIVES: In the ULTIMATE study with an open label extension, we assessed the long-term effect of secukinumab at tissue level on synovitis and enthesitis, and across all psoriatic arthritis (PsA) manifestations, using both clinical evaluations and power Doppler ultrasonography (PDUS). METHODS: This randomised, placebo-controlled, Phase 3 study (ULTIMATE) included biologic-naïve patients with PsA with active PDUS synovitis and clinical enthesitis, and inadequate response to conventional synthetic disease-modifying antirheumatic drugs. The study consisted of 3 treatment periods; in the first period (baseline to week 12) patients were randomised to receive subcutaneous secukinumab (150 mg or 300 mg according to severity of skin psoriasis) or placebo every week until week 4 and once every 4 weeks up to week 12. In the second period (weeks 12-24) all patients received open-label secukinumab with placebo patients switching to secukinumab (150 mg or 300 mg). The third period (weeks 24-52) was an extended open-label treatment period. The long-term responsiveness of the Global EULAR-OMERACT Synovitis Score (GLOESS), clinical enthesitis and global PDUS-detected enthesitis score (using two candidate definitions of activity) at patient level, together with clinical efficacy across key manifestations of PsA and safety were assessed. RESULTS: Of the 166 patients enrolled, 144 completed week 52. A significant reduction in GLOESS was demonstrated in the secukinumab group vs placebo at week 12, followed by a stable reduction of synovitis until week 52 in the secukinumab group while placebo switchers from week 12 reached a similar level of reduction at week 24 with stability thereafter. Likewise, a significant reduction in the Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index was shown in the secukinumab group vs placebo at week 12 with sustained improvement to week 52. Global OMERACT PDUS enthesitis scores were numerically lower in secukinumab vs placebo switchers in the first two treatment periods, with some stability in the third period in both groups. Improvements in clinical responses were also observed across all key domains of PsA up to week 52 in both treatment groups with no new or unexpected safety signals. CONCLUSIONS: ULTIMATE showed consistent improvements in clinically and ultrasound-assessed synovitis and enthesitis and sustained clinical efficacy through week 52 in patients with PsA treated with secukinumab and placebo switched to secukinumab.

Ultrasound in the Management of Patients With Psoriatic Arthritis: Systematic Literature Review and Novel Algorithms for Pragmatic Use.

OBJECTIVE: In 2015, the European Alliance of Associations for Rheumatology (EULAR) published recommendations for the use of imaging for the diagnosis and management of spondyloarthritis (SpA) in clinical practice. These recommendations included the use of ultrasound (US) in patients with psoriatic arthritis (PsA), but the management was not clearly distinguished from that of SpA. We aimed to systematically review the literature on the role of US for the management of PsA, and to propose pragmatic algorithms for its use in clinical practice. METHODS: A group of 10 rheumatologists, experienced in imaging and musculoskeletal US, met with the objectives of formulating key questions for a systematic literature review (SLR), appraising the available evidence, and then proposing algorithms on the application of US in suspected or established PsA, based on both the literature and experts' opinions following a Delphi process. RESULTS: The SLR included 120 articles, most of which focused on the diagnostic process. The elevated number of articles retrieved suggests the interest of rheumatologists in using US in the management of PsA. After a consensual discussion on literature data and expert opinion, the following 3 algorithms were developed to be used in practical situations: suspicion of PsA, management of PsA with good clinical response, and management of PsA with insufficient clinical response. CONCLUSION: The SLR showed interest by rheumatologists in using US to objectively evaluate PsA for diagnosis and management. We propose 3 practical algorithms to guide its use in the clinical management of patients, from diagnosis to the assessment of treatment response. Further studies are needed to define remission and to assess the ability of US to predict disease severity.

Fluorescence-optical imaging as a promising easy-to-use imaging biomarker to increase early psoriatic arthritis detection in patients with psoriasis: a cross-sectional cohort study with follow-up.

OBJECTIVES: To evaluate the ability of fluorescence-optical imaging (FOI) to detect preclinical musculoskeletal inflammatory signs in patients with skin psoriasis at risk of developing psoriatic arthritis (PsA). METHODS: This investigator-initiated prospective exploratory study evaluated adult patients with psoriasis with musculoskeletal complaints and/or nail psoriasis within the last 6 months. Patients underwent a comprehensive rheumatological clinical examination (CE) along with musculoskeletal ultrasound (MSUS) and FOI of both hands at a single visit. Patients with CE-/MSUS-/FOI+ findings had MRI performed on the symptomatic or dominant hand within 7 days. If MRI was negative, the patients were followed over 2 years for the onset of clinically manifest PsA. RESULTS: A total of 389 patients were referred from dermatology centres and evaluated at 14 rheumatology sites in Germany. Seventy-seven (20%) patients with CE-/US-/FOI- were considered to have psoriasis only. PsA was diagnosed in 140/389 patients (36%) based on CE alone and in another 55 patients (14%) by additional MSUS; overall, 50% of the patient cohort was diagnosed with PsA. One hundred sixteen patients (30%) were FOI+ (CE-) of which 40 (37%) were FOI+/MRI+. In the 2-year follow-up of the FOI+/CE- patients, clinical PsA was confirmed in another 12%. CONCLUSION: FOI is a promising method for the detection of signs of musculoskeletal inflammation in hands that may serve as an early imaging biomarker for transitions from psoriasis to PsA. This imaging technique has the potential to detect PsA in at-risk patients with psoriasis, reduce time to PsA diagnosis and improve patient outcomes.

Musculoskeletal ultrasound as a screening-tool for rheumatoid arthritis: results of the "Rheuma-Truck" screening and awareness initiative

Abstract Objective: To evaluate musculoskeletal ultrasound (MSUS) as a screening tool for rheumatoid arthritis (RA) and osteoarthritis (OA) patients in a rheumatology-screening program. Patients and methods: To raise awareness for rheumatic diseases, a mobile rheumatology office was deployed in different cities of Germany ("Rheuma-Truck"). Standardized questionnaire assessment, testing for rheumatoid factor and citrullinated peptide antibodies and medical student driven MSUS of the clinically dominant hand/foot including wrist, MCP-II, -III, -V, PIP-II, -III, MTP-II and -V were offered free of charge to the population. In case of suspicious results, a rheumatologist was consulted. Results: In MSUS, 192 of 560 selected volunteers (aged 18-89, mean 52.7 years; 72.9% female) had suspicious findings including synovitis or erosions primarily affecting the MTP-II (11.8%), dorsal wrist (8.9%), and MCP-II (7%). 354 of the 560 volunteers further visited a rheumatologist of whom 76 were diagnosed with RA. According to the 'US7 Score', a sum scores ≥ 5 was significantly predictive for RA (odds ratio (OR) 5.06; confidence interval (CI) 0.83-35.32). 313 volunteers displayed signs of OA including osteophytes, while MCP-II (36.2%), MCP-III (14.8%), and the wrist (10.5%) were mostly affected. Diagnosis of RA was favoured over OA if the wrist (OR 4.2; CI 1.28-13.95), MTP-II (OR 1.62; CI 1.0-2.6), and MCP-V (OR 2.0; CI 1.0-3.8) were involved. Conclusion: Medical student driven MSUS by the 'US7 Score' can facilitate diagnosis of RA in rheumatology-screening programs due to the level of the score and the affected joints. A high rate of unknown OA signs was detected by MSUS. A mobile rheumatology office displays an opportunity to screen patients for RA and OA.

Synovial tissue transcriptomes of long-standing rheumatoid arthritis are dominated by activated macrophages that reflect microbial stimulation.

Advances in microbiome research suggest involvement in chronic inflammatory diseases such as rheumatoid arthritis (RA). Searching for initial trigger(s) in RA, we compared transcriptome profiles of highly inflamed RA synovial tissue (RA-ST) and osteoarthritis (OA)-ST with 182 selected reference transcriptomes of defined cell types and their activation by exogenous (microbial) and endogenous inflammatory stimuli. Screening for dominant changes in RA-ST demonstrated activation of monocytes/macrophages with gene-patterns induced by bacterial and fungal triggers. Gene-patterns of activated B- or T-cells in RA-ST reflected a response to activated monocytes/macrophages rather than inducing their activation. In contrast, OA-ST was dominated by gene-patterns of non-activated macrophages and fibroblasts. The difference between RA and OA was more prominent in transcripts of secreted proteins and was confirmed by protein quantification in synovial fluid (SF) and serum. In total, 24 proteins of activated cells were confirmed in RA-SF compared to OA-SF and some like CXCL13, CCL18, S100A8/A9, sCD14, LBP reflected this increase even in RA serum. Consequently, pathogen-like response patterns in RA suggest that direct microbial influences exist. This challenges the current concept of autoimmunity and immunosuppressive treatment and advocates new diagnostic and therapeutic strategies that consider microbial persistence as important trigger(s) in the etiopathogenesis of RA.

Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM).

OBJECTIVES: To investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target. METHODS: RA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models. RESULTS: In total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52). CONCLUSION: In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.

Adherence to Treat-to-target Management in Rheumatoid Arthritis and Associated Factors: Data from the International RA BIODAM Cohort.

OBJECTIVE: Compelling evidence supports a treat-to-target (T2T) strategy for optimal outcomes in rheumatoid arthritis (RA). There is limited knowledge regarding the factors that impede implementation of T2T, particularly in a setting where adherence to T2T is protocol-specified. We aimed to assess clinical factors that associate with failure to adhere to T2T. METHODS: Patients with RA from 10 countries who were starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required per protocol to adhere to the T2T strategy. Factors influencing adherence to T2T low disease activity (T2T-LDA; 44-joint count Disease Activity Score ≤ 2.4) were analyzed in 2 types of binomial generalized estimating equations models: (1) including only baseline features (baseline model); and (2) modeling variables that inherently vary over time as such (longitudinal model). RESULTS: A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. Failure of adherence to T2T-LDA was noted in 1765 visits (40.5%). In the baseline multivariable model, a high number of comorbidities (OR 1.10, 95% CI 1.02-1.19), smoking (OR 1.32, 95% CI 1.08-1.63) and high number of tender joints (OR 1.03, 95% CI 1.02-1.04) were independently associated with failure to implement T2T, while anticitrullinated protein antibody/rheumatoid factor positivity (OR 0.63, 95% CI 0.50-0.80) was a significant facilitator of T2T. Results were similar in the longitudinal model. CONCLUSION: Lack of adherence to T2T in the RA BIODAM cohort was evident in a substantial proportion despite being a protocol requirement, and this could be predicted by clinical features. [Rheumatoid Arthritis (RA) BIODAM cohort; ClinicalTrials.gov: NCT01476956].

Outcomes and Findings of the International Rheumatoid Arthritis (RA) BIODAM Cohort for Validation of Soluble Biomarkers in RA.

OBJECTIVE: The Outcome Measures in Rheumatology Soluble Biomarker Working Group initiated an international, multicenter, prospective study, the Rheumatoid Arthritis (RA) BIODAM cohort, to generate resources for the clinical validation of candidate biomarkers predictive of radiographic progression. This first report describes the cohort, clinical outcomes, and radiographic findings. METHODS: Patients with RA from 38 sites in 10 countries starting or changing conventional synthetic disease-modifying antirheumatic drugs and/or starting tumor necrosis factor inhibitors were followed for 2 years. Participating physicians were required to adhere to a treat-to-target strategy. Biosamples (serum, urine) were acquired every 3 months, radiography of hands and feet every 6 months, and ultrasound of hands and feet every 3 months in a subset. Primary endpoint was radiographic progression by the Sharp/van der Heijde score. RESULTS: A total of 571 patients were recruited and 439 (76.9%) completed 2-year followup. At baseline, the majority was female (76%), mean age 55.7 years, and mean disease duration 6.5 years. Patients had a mean of 8.4 swollen and 13.6 tender joints, 44-joint count Disease Activity Score (DAS44) 3.8, 77.7% rheumatoid factor-positive or anticitrullinated protein antibody-positive. Percentage of patients in DAS and American College of Rheumatology remission at 2 years was 52.2% and 27.1%, respectively. Percentage of patients with radiographic progression (> 0.5) at 1 and 2 years was 38.2% and 59.9%, respectively. CONCLUSION: The RA BIODAM prospective study succeeded in generating an extensive list of clinical, imaging (2343 radiographs), and biosample (4638 sera) resources that will be made available to expedite the identification and validation of biomarkers for radiographic damage endpoints. (Clinicaltrials.gov: NCT01476956, clinicaltrials.gov/ct2/show/NCT01476956).

Fluorescence optical imaging for the detection of potential psoriatic arthritis in comparison to musculoskeletal ultrasound.

OBJECTIVE: Comparison of fluorescence optical imaging (FOI) with grayscale (GS) and power Doppler ultrasound (PDUS) to detect joint inflammation in patients with confirmed or suspected psoriatic arthritis (PsA). METHODS: Patients (n = 60) with psoriasis and tenderness and/or swelling of joints were separated into two groups: diagnosis confirmed by the treating dermatologist before the start of the study (n = 26), and suspected PsA (n = 34). GS/PDUS of the hand most clinically affected was performed with a dorsal/palmar view (wrist, MCP, PIP, DIP2-5). FOI examination was carried out in a standardized manner by analyzing the predefined Phases 1-3. RESULTS: FOI was found to be more sensitive than ultrasound (US) for detection of inflammation in PIP/DIP joints (p = 0.035). Confirmed PsA patients showed more findings in FOI P2 and P3, while suspected PsA patients showed more findings in P1. In the confirmed PsA group, most involved joints were MCP joints, while in the suspected PsA group, more involved wrist joints and DIP joints (p = 0.006) were detected with FOI. CONCLUSIONS: The differences between the confirmed and suspected groups indicate that FOI is helpful in the detection of early PsA since P1 may correspond to acute inflammation, whereas P2 and P3 enhancement reflect chronic inflammation. Fluorescence optical imaging might therefore be a novel diagnostic tool for early PsA diagnosis.

Monocyte alterations in rheumatoid arthritis are dominated by preterm release from bone marrow and prominent triggering in the joint.

OBJECTIVE: Rheumatoid arthritis (RA) accompanies infiltration and activation of monocytes in inflamed joints. We investigated dominant alterations of RA monocytes in bone marrow (BM), blood and inflamed joints. METHODS: CD14+ cells from BM and peripheral blood (PB) of patients with RA and osteoarthritis (OA) were profiled with GeneChip microarrays. Detailed functional analysis was performed with reference transcriptomes of BM precursors, monocyte blood subsets, monocyte activation and mobilisation. Cytometric profiling determined monocyte subsets of CD14++CD16-, CD14++CD16+ and CD14+CD16+ cells in BM, PB and synovial fluid (SF) and ELISAs quantified the release of activation markers into SF and serum. RESULTS: Investigation of genes differentially expressed between RA and OA monocytes with reference transcriptomes revealed gene patterns of early myeloid precursors in RA-BM and late myeloid precursors along with reduced terminal differentiation to CD14+CD16+monocytes in RA-PB. Patterns associated with tumor necrosis factor/lipopolysaccharide (TNF/LPS) stimulation were weak and more pronounced in RA-PB than RA-BM. Cytometric phenotyping of cells in BM, blood and SF disclosed differences related to monocyte subsets and confirmed the reduced frequency of terminally differentiated CD14+CD16+monocytes in RA-PB. Monocyte activation in SF was characterised by the predominance of CD14++CD16++CD163+HLA-DR+ cells and elevated concentrations of sCD14, sCD163 and S100P. CONCLUSION: Patterns of less mature and less differentiated RA-BM and RA-PB monocytes suggest increased turnover with accelerated monocytopoiesis, BM egress and migration into inflamed joints. Predominant activation in the joint indicates the action of local and primary stimuli, which may also promote adaptive immune triggering through monocytes, potentially leading to new diagnostic and therapeutic strategies.

Detection of severe digital vasculopathy in systemic sclerosis by colour Doppler sonography is associated with digital ulcers.

Objective: Colour Doppler ultrasonography (CDUS) is very important in general vascular diagnostic procedures. Its role in determining the extent of vasculopathy in Systemic Sclerosis (SSc) needs further investigation. The aim of this study was to compare the presence of altered arteries with nailfold capillaroscopy and clinical signs of ischaemia, that is, digital ulcers or pitting scars (DU/PS). A feasible CDUS protocol is provided. Methods: Two thousand five hundred and twenty-eight arteries of the fingers, palms and wrists from 79 SSc patients (32 arteries per patient) were examined using CDUS. Furthermore, nailfold capillaroscopy, clinical and laboratory data were evaluated. Results: Narrowed or occluded lumens were seen in 39.8% of all assessable arteries (n = 2489) and 48.9% of all proper palmar digital arteries (n = 1564) but only 15.6% (P < 0.0001) of proximal arteries (n = 924). Fingerwise analyses presented significant coincidence of pathological CDUS findings and DU/PS (P = 0.0009). Pathological CDUS findings were also associated with elevated CRP concentrations, current or past smoking with ⩾20 pack-years, male gender and present or past DU/PS. Receiver operating characteristic curve analysis (area under the curve = 0.727) suggested a cut-off value of ⩾20% pathological vessels (sensitivity: 90.7%; specificity: 47.8%) for the presence of DU/PS. An examination protocol focusing on the right-hand digits II-V (proper palmar digital arteries) revealed similar results (area under the curve = 0.751; sensitivity: 93.0%; specificity: 43.5%). Conclusion: CDUS of hand and finger arteries allows measurement of the extent of SSc vasculopathy, which is associated with clinical signs of chronic malperfusion. A shortened examination protocol of CDUS (right-hand digits II-V; 15 min instead of 45 min examination time) could complement vascular diagnostics in SSc.

Comparison of tocilizumab and tumour necrosis factor inhibitors in rheumatoid arthritis: a retrospective analysis of 1603 patients managed in routine clinical practice.

Tocilizumab (TCZ) and tumour necrosis factor inhibitors (TNFi) are recommended for the treatment of rheumatoid arthritis (RA) in patients with inadequate response (IR) to prior disease-modifying antirheumatic drugs (DMARDs). This retrospective analysis assessed the efficacy of TCZ and TNFi, alone or in combination with DMARDs, in 1603 patients with IR to previous treatment with either DMARDs (DMARD-IR) and/or TNFi (TNFi-IR), initiating treatment with TCZ or a TNFi, managed in routine clinical practice. Patients were grouped according to treatment history and treatment initiated: DMARD-IR patients initiating treatment with TCZ + DMARD (DMARD-IR TCZ) or TNFi + DMARD (DMARD-IR TNFi), DMARD-IR and/or TNFi-IR patients initiating treatment with TCZ monotherapy (TCZ mono) or TNFi monotherapy (TNFi mono), and TNFi-IR patients initiating treatment with TCZ + DMARD (TNFi-IR TCZ) or TNFi + DMARD (TNFi-IR TNFi). Patients initiating treatment with TCZ generally had more severe disease and longer disease duration compared with the corresponding TNFi group. Significantly more patients achieved remission (DAS28 ESR <2.6) in the TCZ groups compared with corresponding TNFi groups (DMARD-IR, TCZ 44.0 % vs. TNFi 29.6 %; monotherapy, TCZ 37.2 % vs. TNFi 30.2 %; TNF-IR, TCZ 41.3 % vs. TNFi 19.2 %; p < 0.001 for all comparisons). More patients achieved moderate-good responses (EULAR criteria) in the TCZ treatment groups (79-85 %) compared with TNFi treatment groups (65-81 %). Patient-reported outcomes showed greater improvements in TCZ compared with TNFi groups. In patients with inadequate response to DMARDs and/or TNFi treated in routine clinical practice, TCZ in combination with DMARDs or as monotherapy resulted in significantly more patients achieving remission and more marked improvements in patient-reported outcomes compared with TNF inhibitors.

miR-148a is upregulated by Twist1 and T-bet and promotes Th1-cell survival by regulating the proapoptotic gene Bim.

Repeatedly activated T helper 1 (Th1) cells present during chronic inflammation can efficiently adapt to the inflammatory milieu, for example, by expressing the transcription factor Twist1, which limits the immunopathology caused by Th1 cells. Here, we show that in repeatedly activated murine Th1 cells, Twist1 and T-bet induce expression of microRNA-148a (miR-148a). miR-148a regulates expression of the proapoptotic gene Bim, resulting in a decreased Bim/Bcl2 ratio. Inhibition of miR-148a by antagomirs in repeatedly activated Th1 cells increases the expression of Bim, leading to enhanced apoptosis. Knockdown of Bim expression by siRNA in miR-148a antagomir-treated cells restores viability of the Th1 cells, demonstrating that miR-148a controls survival by regulating Bim expression. Thus, Twist1 and T-bet not only control the differentiation and function of Th1 cells, but also their persistence in chronic inflammation.

Urinary CD4 T cells identify SLE patients with proliferative lupus nephritis and can be used to monitor treatment response.

OBJECTIVES: Proliferative lupus nephritis (LN) is one of the major concerns in the treatment of systemic lupus erythematosus (SLE). Here we evaluate urinary CD4 T cells as a biomarker of active LN and indicator of treatment response. METHODS: Urinary CD3CD4 T cells were quantified using flow cytometry in 186 urine samples from 147 patients with SLE. Fourteen patients were monitored as follow-up. Thirty-one patients with other nephropathies and 20 healthy volunteers were included as controls. RESULTS: In SLE, urinary CD4 T cell counts ≥800/100 ml were observed exclusively in patients with active LN. Receiver operator characteristic analysis documented clear separation of SLE patients with active and non-active LN (area under the curve 0.9969). All patients with up-to-date kidney biopsy results showing proliferative LN had high urinary CD4 T cell numbers. In patients monitored under therapy, normalisation of urinary CD4 T cell counts indicated lower disease activity and better renal function. In contrast, patients with persistence of, or increase in, urinary T cells displayed worse outcomes. CONCLUSIONS: Urinary CD4 T cells are a highly sensitive and specific marker for detecting proliferative LN in patients with SLE. Furthermore, monitoring urinary CD4 T cells may help to identify treatment responders and treatment failure and enable patient-tailored therapy in the future.

Evaluation of the novel ultrasound score for large joints in psoriatic arthritis and ankylosing spondylitis: six month experience in daily clinical practice.

BACKGROUND: To evaluate the utility of the recently introduced SOLAR score (sonography of large joints in Rheumatology), which has been validated in RA patients, in a cohort of patients with Psoriatic Arthritis (PsA) and Ankylosing Spondylitis (AS) presenting with involvement of large peripheral joints. METHODS: The recently established SOLAR score has been designed to determine the degree of inflammation in the shoulder, the elbow, the hip and the knee joint in patients suffering from RA. Since large joints are frequently involved in PsA and AS, synovitis and synovial vascularity were scored semiquantitatively (grade 0-3) by grey scale (GSUS) and power Doppler ultrasound (PDUS) utilizing the validated scoring system. Each joint was scanned from different angles, the knee joint for example was divided into four areas to score for synovitis: the suprapatellar longitudinal, the medial longitudinal, the lateral longitudinal, and the posterior region. Each area was scored from 0-3, so a maximum score of 12 could be achieved. PsA and AS patients presenting with peripheral joint disease involving large joints were examined at baseline, 3 and 6 months after initiation of local or systemic therapy (DMARDs/Biologics). For evaluation of the inflammatory status, the erythrocyte sedimentation rate (ESR) was determined. RESULTS: A cohort of 126 patients were enclosed, and 83 of these were followed for 6 months. At baseline before modification of the therapy, patients received DMARDs (n = 83), DMARDs plus biologics (n = 30), or biologic monotherapy (n = 29). Following intervention, all US scores demonstrated a marked improvement. The GSUS and the PDUS scores for all joint areas, except the PDUS score of the hip, exhibited a significant improvement (p < 0.05), while the GSUS of the knee showed even a highly significant (p < 0.001) change. The ESR displayed a significant decrease from 27 to 19 mm (p < 0.002) representing good treatment response. CONCLUSION: The SOLAR score, which has been recently introduced for RA patients, is a very suitable instrument for the qualitative and quantitative evaluation of large joint involvement in PsA and AS patients and allows for treatment monitoring.

Unmasking of autoreactive CD4 T cells by depletion of CD25 regulatory T cells in systemic lupus erythematosus.

OBJECTIVE: Autoreactive CD4 T cells specific for nuclear peptide antigens play an important role in tolerance breakdown during the course of systemic lupus erythematosus (SLE). However, reliable detection of these cells is limited due to their low frequency in peripheral blood. The authors assess autoreactive CD4 T cells in a representative SLE collective (n=38) by flow cytometry and study the influence of regulatory T cells (Treg) on their antigenic challenge. METHODS: CD4 T-cell responses were determined according to intracellular CD154 expression induced after 6-h short-term in-vitro stimulation with the SLE-associated autoantigen SmD1(83-119). To clarify the influence of Treg on the activation of autoreactive CD4 T cells, CD25 Treg were depleted by magnetic activated cell sorting before antigen-specific stimulation in selected experiments. RESULTS: In the presence of Treg, autoreactive CD4 T-cell responses to SmD1(83-119) were hardly observable. However, Treg removal significantly increased the frequency of detectable SmD1(83-119)-specific CD4 T cells in SLE patients but not in healthy individuals. Consequently, by depleting Treg the percentage of SmD1(83-119)-reactive SLE patients increased from 18.2% to 63.6%. This unmasked autoreactivity of CD4 T cells correlated with the disease activity as determined by the SLE disease activity index (p=0.005*, r=0.779). CONCLUSIONS: These data highlight the pivotal role of the balance between autoreactive CD4 T cells and CD25 Treg in the dynamic course of human SLE. Analysing CD154 expression in combination with a depletion of CD25 Treg, as shown here, may be of further use in approaching autoantigen-specific CD4 T cells in SLE and other autoimmune diseases.

Evaluation of several ultrasonography scoring systems for synovitis and comparison to clinical examination: results from a prospective multicentre study of rheumatoid arthritis.

OBJECTIVES: To evaluate different global ultrasonographic (US) synovitis scoring systems as potential outcome measures of rheumatoid arthritis (RA) according to the Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) filter. METHODS: To study selected global scoring systems, for the clinical, B mode and power Doppler techniques, the following joints were evaluated: 28 joints (28-joint Disease Activity Score (DAS28)), 20 joints (metacarpophalangeals (MCPs) + metatarsophalangeals (MTPs)) and 38 joints (28 joints + MTPs) using either a binary (yes/no) or a 0-3 grade. The study was a prospective, 4-month duration follow-up of 76 patients with RA requiring anti-tumour necrosis factor (TNF) therapy (complete follow-up data: 66 patients). Intraobserver reliability was evaluated using the intraclass correlation coefficient (ICC), construct validity was evaluated using the Cronbach alpha test and external validity was evaluated using level of correlation between scoring system and C reactive protein (CRP). Sensitivity to change was evaluated using the standardised response mean. Discriminating capacity was evaluated using the standardised mean differences in patients considered by the doctor as significantly improved or not at the end of the study. RESULTS: Different clinimetric properties of various US scoring systems were at least as good as the clinical scores with, for example, intraobserver reliability ranging from 0.61 to 0.97 versus from 0.53 to 0.82, construct validity ranging from 0.76 to 0.89 versus from 0.76 to 0.88, correlation with CRP ranging from 0.28 to 0.34 versus from 0.28 to 0.35 and sensitivity to change ranging from 0.60 to 1.21 versus from 0.96 to 1.36 for US versus clinical scoring systems, respectively. CONCLUSION: This study suggests that US evaluation of synovitis is an outcome measure at least as relevant as physical examination. Further studies are required in order to achieve optimal US scoring systems for monitoring patients with RA in clinical trials and in clinical practice.