The role of tender and swollen joints for the assessment of inflammation in PsA using ultrasound.

OBJECTIVE: To evaluate tender joints (TJ) and swollen joints (SJ) for the assessment of ultrasound (US) defined inflammation in PsA. METHODS: Eighty-three PsA patients underwent clinical and US examinations at two scheduled study visits 12 months apart. Tenderness and swelling were assessed at 68 and 66 joints, respectively, and US examinations were conducted at all 68 joints. At patient level, associations with clinical composites and US scores were performed using correlations and by analysing patients with predominantly tender (pTender) or swollen joints (pSwollen). At joint level, a Power Doppler (PD) value ≥ 1 was defined as active synovitis. A generalized linear mixed model was created to assess the predictive value of TJ and SJ for active synovitis after 12 months. RESULTS: SJC showed better correlations with GS/PD scores (r = 0.37/0.47) than with TJC (PD: r = 0.33), while TJC correlated better with patient reported outcomes (PROMs) like patient global assessment (TJC: r = 0.57; SJC r = 0.39). Patients with pTender showed poorer results for PROMs and disease activity scores than patients with pSwollen, but not for laboratory or US markers of inflammation. Swollen joints showed active synovitis in 35% of cases, while only 16% of tender joints were active according to US. Swelling at baseline better predicted active synovitis at the same joint after 12 months [odds ratio (OR) 6.33, P <0.001] as compared with tenderness (OR 3.58, P <0.001). CONCLUSIONS: SJ are more closely linked with US signs of inflammation as compared with TJ in PsA. Joint swelling is a better predictor for signs of US inflammation than tenderness after one year of follow-up.

Ultrasound verified enthesophytes are associated with radiographic progression at entheses in psoriatic arthritis.

OBJECTIVES: The aim of this prospective study was to examine whether ultrasound or clinical abnormalities at enthesal sites predict radiographic progression at entheses in psoriatic arthritis (PsA). METHODS: Consecutive PsA patients were included and subjected to clinical and ultrasound assessments at 14 entheses at baseline, 6 and 12 months. Radiographs were performed at 0 and 12 months. By US, we investigated structural (erosions, osteophytes) and inflammatory changes [grey scale (0-32) and power Doppler (0-14, range global ultrasound score 0-140)], and radiographs were evaluated for enthesophytes and erosions (score range 0-56). Multivariate regression models were conducted to identify the possible association of clinical and ultrasound findings with radiographic progression. RESULTS: We examined 83 patients at baseline, of whom 43 (51.8%) had complete clinical, ultrasound and X-ray data. Twenty-four of 43 patients (55.8%) developed radiographic progression of entheses. These patients were younger (49.6 vs 59.3, P =0.005), had shorter disease duration (9.7 vs 17.9 years, P=0.015) and lower clinical disease activity at 6-months [disease activity in psoriatic arthritis (DAPSA) 6.7 vs 17.0, P=0.018] as compared with patients without progression. Non-progressors had higher ultrasound enthesophyte scores at baseline than progressors (20 vs 15, P<0.05). The multivariate regression analysis revealed that 48.6% of the variance of the X-ray score at 12-months follow-up (RegcoeffB = 0.827, P=0.000) could be explained by the baseline US enthesophyte score. CONCLUSION: Our data indicate that radiographic progression at entheses is linked with age, disease duration and ultrasound verified enthesophytes at baseline. No other ultrasound parameter predicted radiographic progression at entheses.

Evaluating current definitions of low disease activity in psoriatic arthritis using ultrasound.

OBJECTIVE: To evaluate low disease activity (LDA) cut-offs in psoriatic arthritis (PsA) using ultrasound. METHODS: Eighty-three PsA patients underwent clinical and ultrasound examinations at two visits. LDA was assessed using the Disease Activity index for Psoriatic Arthritis (DAPSA ⩽ 14), the Psoriatic ArthritiS Disease Activity Score (PASDAS ⩽ 3.2), the Composite Psoriatic Disease Activity Index ⩽ 4, the DAS28-CRP ⩽ 2.8 and the minimal disease activity criteria. Ultrasound was performed at 68 joints and 14 entheses. Minimal ultrasound disease activity (MUDA-j/e) was defined as a Power Doppler score ⩽ 1, respectively at joints, paratendinous tissue, tendons and entheses. A global ultrasound score was calculated by summing Grey Scale and Power Doppler information (GUIS-j/e). RESULTS: LDA was present in 33.7-65.0% at baseline and in 44.3-80.6% at follow-up, depending on the criteria used. MUDA-j/e was observed in 16.9% at baseline and in 30% at follow-up. GUIS-j/e was significantly higher in patients with moderate/high disease activity vs LDA according to DAPSA and PASDAS at baseline and DAPSA, PASDAS, Composite Psoriatic Disease Activity Index and minimal disease activity at follow-up. Patients in moderate/high disease activity had MUDA-j/e in 8.1-21.4% at baseline and in 8.3-20.0% at follow-up, depending on the applied clinical composite. MUDA-j/e patients with moderate/high disease activity had higher levels of pain and pain-related items than those with LDA. CONCLUSION: The LDA cut-offs of DAPSA, PASDAS, Composite Psoriatic Disease Activity Index, minimal disease activity, but not DAS28-CRP are capable of distinguishing between high and low ultrasound activity. Pain and pain-related items are the main reason why PsA patients without signs of ultrasound inflammation are classified with higher disease activity.

Senescent T-Cells Promote Bone Loss in Rheumatoid Arthritis.

Objective: T-cells are critical players in the pathogenesis of osteoporosis in patients with rheumatoid arthritis (RA). Premature senescence of lymphocytes including the accumulation of senescent CD4+ T-cells is a hallmark feature of RA. Whether T-cell senescence is associated with bone loss in RA patients is elusive so far. Methods: This includes a prospective study of consecutive patients with RA (n = 107), patients with primary osteopenia/-porosis (n = 75), and healthy individuals (n = 38). Bone mineral density (BMD) was determined by dual-energy X-ray absorptiometry scan. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed to analyze the pro-osteoclastic phenotype and the function of senescent CD4+CD28- T-cells. Results: Patients with osteopenia/-porosis yielded a higher prevalence of senescent CD4+CD28- T-cells than individuals with normal BMD, in the RA, as well as in the non-RA cohort. Receptor activator of nuclear factor kappa-B ligand (RANKL) was expressed at higher levels on CD4+CD28- T-cells as compared to CD28+ T-cells. Stimulation with interleukin-15 led to an up-regulation of RANKL expression, particularly on CD28- T-cells. CD4+CD28- T-cells induced osteoclastogenesis more efficiently than CD28+ T-cells. Conclusion: Our data indicate that senescent T-cells promote osteoclastogenesis more efficiently than conventional CD28+ T-cells, which might contribute to the pathogenesis of systemic bone loss in RA and primary osteoporosis.

Ultrasound verified inflammation and structural damage in patients with hereditary haemochromatosis-related arthropathy.

BACKGROUND: Chronic arthropathy occurs in approximately two thirds of patients with hereditary haemochromatosis (HH). The aim was to study inflammatory and structural lesions in patients with HH with (HH-A) and without arthropathy (HH-WA) using ultrasonography. METHODS: This was a cross-sectional study of 26 patients with HH-A, 24 with HH-WA and 37 with hand osteoarthritis (HOA). Clinical examination was performed in 68 joints, and we retrieved data on hand function, pain and global disease activity (all using a visual analogue scale (VAS)), morning stiffness and ferritin levels. Standard x-ray and ultrasound were conducted in 36 joints (hands, hips, knees and ankles), and we graded grey scale synovitis (GSS), power Doppler ultrasound (PD), osteophytes, erosions, tenosynovitis and cartilage damage semi-quantitatively in accordance with prior publications. RESULTS: Ultrasound revealed a high proportion of inflammatory changes in HH-A; GSS was found in 96.2% and PD signals in 80.8% of patients (median GSS score 9, PD score 2.5). The frequency of these findings was similar in HOA. Inflammation was also common in HH-WA, yielding GSS in 83.3% and PD signals in 50.0% of patients. Cartilage damage was most prominent in HH-A as compared to HH-WA and HOA (median scores 11.0, 2.5 and 2.0, respectively). The prevalence and extent of erosions and osteophytes were similar in all groups. None of the ultrasound scores was associated with pain or function; GSS, PD, osteophyte and cartilage scores correlated with x-ray-verified structural damage. CONCLUSION: A high prevalence of ultrasound-verified inflammation and cartilage damage was found in HH-A, and to a lesser extent in HH-WA. These findings were associated with x-ray-verified damage but not with clinical scores of pain and function.

Novel Senescent Regulatory T-Cell Subset with Impaired Suppressive Function in Rheumatoid Arthritis.

OBJECTIVE: Premature senescence of lymphocytes is a hallmark of inflammatory rheumatic diseases such as rheumatoid arthritis (RA). Early T-cell aging affects conventional T-cells but is presumably not limited to this cell population; rather it might also occur in the regulatory T-cells (Tregs) compartment. In RA, Tregs fail to halt aberrant immune reactions and disease progression. Whether this is associated with early Treg senescence leading to phenotypic and functional changes of this subset is elusive so far. METHODS: Eighty-four RA patients and 75 healthy controls were prospectively enrolled into the study. Flow cytometry, magnetic-associated cell sorting, and cell culture experiments were performed for phenotypic and functional analyses of Treg subsets. T-cell receptor excision circle (TREC) levels and telomere lengths were determined using RT-PCR. RESULTS: In this paper, we describe the novel CD4+FoxP3+CD28- T-cell subset (CD28- Treg-like cells) in RA patients revealing features of both Tregs and senescent T-cells: Treg surface/intracellular markers such as CD25, CTLA-4, and PD-1 as well as FOXP3 were all expressed by CD28- Treg-like cells, and they yielded signs of premature senescence including reduced TREC levels and an accumulation of γH2AX. CD28- Treg-like could be generated in vitro by stimulation of (CD28+) Tregs with TNF-α. CD28- Treg-like cells insufficiently suppressed the proliferation of effector T-cells and yielded a pro-inflammatory cytokine profile. CONCLUSION: In conclusion, we describe a novel T-cell subset with features of Tregs and senescent non-Tregs. These cells may be linked to an aberrant balance between regulatory and effector functions in RA.

It's more than dryness and fatigue: The patient perspective on health-related quality of life in Primary Sjögren's Syndrome - A qualitative study.

OBJECTIVES: In Primary Sjögren's Syndrome (PSS), there is an apparent lack of data concerning the perspectives of patients, their needs, preferences and difficulties of daily life. This qualitative study was conducted to explore perspectives and needs of patients with PSS that influence health related quality of life (HRQL). METHODS: We recruited 20 PSS patients fulfilling the American-European consensus classification criteria out of the PSS cohort of the Medical University Graz, Austria. In total, 6 focus group sessions (with three to four patients per group) were performed. A modified meaning condensation procedure was used to analyse the data. RESULTS: The interview analysis resulted in 484 meaning units, 254 subconcepts and 86 concepts. The identified concepts were grouped into three dimensions: physical dimension, psychological & emotional challenges and social life & daily living. A dependency between the three categories was identified. The concepts most commonly reported by patients were related to the physical dimension: pain and dryness as well as complaints associated with/provoked by these symptoms. Patients also reported shortness of breath, fatigue und constipation. CONCLUSIONS: This qualitative study underpins that HRQL in PSS patients is affected by several factors. The problems are not limited to dryness, pain and fatigue while the complaints secondary to these symptoms are important to patients with PSS significantly affecting physical, psychological and social life components of HRQL. A disease-specific patient related outcome measures for clinical practice and trials should be developed considering the different aspects of HRQL in PSS.

The association of clinical parameters and ultrasound verified inflammation with patients' and physicians' global assessments in psoriatic arthritis.

OBJECTIVES: To study the association of clinical and/or ultrasound variables with patients' (PGA) and physicians' (EGA) global assessment of disease activity in psoriatic arthritis (PsA). The correlation of these parameters with the discordance between PGA and EGA, as well as with PGA/EGA changes over 6 months was also investigated. METHODS: Prospective study of 83 consecutive PsA patients with 2 visits scheduled 6 months apart. All patients underwent the following assessments: tender (TJC) and swollen joint count (SJC), PASI, dactylitis and Leeds enthesitis index. PGA, patients' level of pain (pain VAS), EGA, and HAQ were also recorded. Grey scale (GS) and power Doppler (PD) ultrasound were performed at 68 joints (evaluating synovia and tendons) and 14 entheses. Regression analyses were performed to assess the association of these variables with PGA and EGA. Two new variables "PGAminusEGA" and "PGAchange - EGAchange" were developed to explore the discrepancy between PGA and EGA and the consistency of PGA/EGA changes over time, respectively. RESULTS: The parameters explaining most of PGA and EGA variability were pain VAS (30.5%) and SJC (48.5%), respectively. The correlation between EGA and joint counts was stronger in patients with high vs. low levels of ultrasound verified inflammation. PGAminusEGA was mainly explained by pain and SJC. Pain was the most important predictor of PGA change whereas TJC and HAQ were more closely associated with EGA changes. "PGAchange-EGAchange" was linked to pain and SJC. Ultrasound scores were not linked with either of these variables. CONCLUSIONS: Pain VAS and joint counts are the most important clinical parameters explaining patients' and physicians' perception of disease activity, whereas the correlation of active inflammation as verified by sonography with these factors is limited.

Premature senescence of T-cell subsets in axial spondyloarthritis.

OBJECTIVE: To investigate the possible occurrence of early thymic failure and premature senescence of naïve and memory T-cells in patients with axial spondyloarthritis (aSpA). METHODS: Prospective, cross-sectional study of consecutive patients with aSpA (n=51), rheumatoid arthritis (RA, n=51) and healthy controls (HCs, n=50). Demographic, clinical and laboratory parameters were collected in all patients and we isolated naïve (CD45RA(+)) and memory (CD45RO(+)) CD4(+) and CD8(+) T-cell subsets by MACS technology. T-cell receptor rearrangement excision circle (TREC) and telomere length were measured by real-time PCR. We used TRECs as a surrogate for thymus function and telomere length as an indicator of cellular senescence. Telomerase activity was analysed with the Telomeric Repeat Amplification Protocols. RESULTS: We observed a premature decline of thymic output in patients with aSpA and patients with RA compared with HCs as indicated by a reduction of TREC levels in naive T-cells (aSpA: age adjusted regression coefficient (regcoeff) for CD4(+)CD45RA(+) T-cells -2.566, p=0.023; RA regcoeff=-2.844, p=0.008). Telomere length of all CD4(+) and CD8(+) T-cell subsets was reduced in young patients with aSpA compared with HCs, whereas data for patients with RA were comparable with HCs. Telomerase activity was inversely correlated with telomere length in HCs (correlation coefficient (corcoeff)=-0.532, p<0.001) but not in patients with aSpA (corcoeff=-0.056, p=0.697) and RA (corcoeff=-0.003, p=0.982). CONCLUSIONS: Our data indicate an age-inappropriate shrinkage of thymic output, an inappropriate shortening of telomeres in young patients with aSpA and an impaired telomerase enzyme in patients with aSpA and RA.

Ultrasound composite scores for the assessment of inflammatory and structural pathologies in Psoriatic Arthritis (PsASon-Score).

INTRODUCTION: This study was performed to develop ultrasound composite scores for the assessment of inflammatory and structural lesions in Psoriatic Arthritis (PsA). METHODS: We performed a prospective study on 83 PsA patients undergoing two study visits scheduled 6 months apart. B-mode and Power Doppler (PD) findings were semi-quantitatively scored at 68 joints (evaluating synovia, perisynovial tissue, tendons and bone) and 14 entheses. We constructed bilateral and unilateral (focusing the dominant site) ultrasound composite scores selecting relevant sites by a hierarchical approach. We tested convergent construct validity, reliability and feasibility of inflammatory and structural elements of the scores as well as sensitivity to change for inflammatory items. RESULTS: The bilateral score (termed PsASon22) included 22 joints (6 metacarpophalangeal joints (MCPs), 4 proximal interphalangeal joints (PIPs) of hands (H-PIPs), 2 metatarsophalangeal joints (MTPs), 4 distal interphalangeal joints (DIPs) of hands (H-DIPs), 2 DIPs of feet (F-DIPs), 4 large joints) and 4 entheses (bilateral assessment of lateral epicondyle and distal patellar tendon). The unilateral score (PsASon13) compromised 13 joints (2 MCPs, 3 H-PIPs, 1 PIP of feet (F-PIP), 2 MTPs, 1 H-DIP and 2 F-DIPs and 2 large joints) and 2 entheses (unilateral lateral epicondyle and distal patellar tendon). Both composite scores revealed a moderate to high sensitivity (bilateral composite score 43% to 100%, unilateral 36% to 100%) to detect inflammatory and structural lesions compared to the 68-joint/14-entheses score. The inflammatory and structural components of the composite scores correlated weakly with clinical markers of disease activity (corrcoeffs 0 to 0.40) and the health assessment questionnaire (HAQ, corrcoeffs 0 to 0.39), respectively. Patients with active disease achieving remission at follow-up yielded greater reductions of ultrasound inflammatory scores than those with stable clinical activity (Cohen's d effect size ranging from 0 to 0.79). Inter-rater reliability of bi- and unilateral composite scores was moderate to good with ICCs ranging from 0.42 to 0.96 and from 0.36 to 0.71, respectively for inflammatory and structural sub-scores. The PsASon22 and PsASon13 required 16 to 26 and 9 to 13 minutes, respectively to be completed. CONCLUSION: Both new PsA ultrasound composite scores (PsASon22 and PsASon13) revealed sufficient convergent construct validity, sensitivity to change, reliability and feasibility.

The impact of aging on regulatory T-cells.

Age-related deviations of the immune system contribute to a higher likelihood of infections, cancer, and autoimmunity in the elderly. Senescence of T-lymphocytes is characterized by phenotypical and functional changes including the loss of characteristic T-cell surface markers, while an increase of stimulatory receptors, cytotoxicity as well as resistance against apoptosis is observed. One of the key mediators of immune regulation are naturally occurring regulatory T-cells (Tregs). Tregs express high levels of CD25 and the intracellular protein forkhead box P3; they exert their suppressive functions in contact-dependent as well as contact-independent manners. Quantitative and qualitative defects of Tregs were observed in patients with autoimmune diseases. Increased Treg activity was shown to suppress anti-tumor and anti-infection immunity. The effect of aging on Tregs, and the possible contribution of age-related changes of the Treg pool to the pathophysiology of diseases in the elderly are still poorly understood. Treg homeostasis depends on an intact thymic function and current data suggest that conversion of non-regulatory T-cells into Tregs as well as peripheral expansion of existing Tregs compensates for thymic involution after puberty to maintain constant Treg numbers. In the conventional T-cell subset, peripheral proliferation of T-cells is associated with replicative senescence leading to phenotypical and functional changes. For Tregs, different developmental stages were also described; however, replicative senescence of Tregs has not been observed yet.