Predictors of quality of life, functional status, depression and fatigue in early arthritis: comparison between clinically suspect arthralgia, unclassified arthritis and rheumatoid arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is often preceded by symptomatic phases during which classification criteria are not fulfilled. The health burden of these "at-risk" stages is not well described. This study assessed health-related quality of life (HRQoL), function, fatigue and depression in newly presenting patients with clinically suspect arthralgia (CSA), unclassified arthritis (UA) or RA. METHODS: Cross-sectional analysis of baseline Patient-Reported Outcome Measures (PROMs) was conducted in patients from the Birmingham Early Arthritis Cohort. HRQoL, function, depression and fatigue at presentation were assessed using EQ-5D, HAQ-DI, PHQ-9 and FACIT-F. PROMs were compared across CSA, UA and RA and with population averages from the HSE with descriptive statistics. Multivariate linear regression assessed associations between PROMs and clinical and sociodemographic variables. RESULTS: Of 838 patients included in the analysis, 484 had RA, 200 had CSA and 154 had UA. Patients with RA reported worse outcomes for all PROMs than those with CSA or UA. However, "mean EQ-5D utilities were 0.65 (95%CI: 0.61 to 0.69) in CSA, 0.61 (0.56 to 0.66) in UA and 0.47 (0.44 to 0.50) in RA, which was lower than in general and older (≥ 65 years) background populations." In patients with CSA or UA, HRQoL was comparable to chronic conditions such as heart failure, severe COPD or mild angina. Higher BMI and older age (≥ 60 years) predicted worse depression (PHQ-9: -2.47 (-3.85 to -1.09), P < 0.001) and fatigue (FACIT-F: 5.05 (2.37 to 7.73), P < 0.001). Women were more likely to report worse function (HAQ-DI: 0.13 (0.03 to 0.21), P = 0.01) and fatigue (FACIT-F: -3.64 (-5.59 to -1.70), P < 0.001), and residents of more deprived areas experienced decreased function (HAQ-DI: 0.23 (0.10 to 0.36), P = 0.001), greater depression (PHQ-9: 1.89 (0.59 to 3.18), P = 0.004) and fatigue (FACIT-F: -2.60 (-5.11 to 0.09), P = 0.04). After adjustments for confounding factors, diagnostic category was not associated with PROMs, but disease activity and polypharmacy were associated with poorer performance across all PROMs. CONCLUSIONS: Patient-reported outcomes were associated with disease activity and sociodemographic characteristics. Patients presenting with RA reported a higher health burden than those with CSA or UA, however HRQoL in the pre-RA groups was significantly lower than population averages.

Paranasal sinus occupancy assessed from magnetic resonance images-associations with clinical indicators in patients with systemic lupus erythematosus.

OBJECTIVES: Nasal, paranasal sinus and mucosal disorders are common symptoms in autoimmune rheumatic diseases. Soft tissue changes and fluid accumulation in the osteomeatal complexes and paranasal sinuses manifest as opaqueness on radiological images which can be assessed using visual scoring and computational methods on CT scans, but their results do not always correlate. Using MRI, we investigate the applicability of different image analysis methods in SLE. METHODS: We assessed paranasal sinus opaqueness on MRI from 51 SLE patients, using three visual scoring systems and expert-delineated computational volumes, and examined their association with markers of disease activity, inflammation, endothelial dysfunction and common small vessel disease (SVD) indicators, adjusting for age and sex-at-birth. RESULTS: The average paranasal sinus volume occupation was 4.55 (6.47%) [median (interquartile range) = 0.67 (0.25-2.65) ml], mainly in the maxillary and ethmoid sinuses. It was highly correlated with Lund-Mackay (LM) scores modified at 50% opaqueness cut-off (Spearman's ρ: 0.71 maxillary and 0.618 ethmoids, P < 0.001 in all), and with more granular variations of the LM system. The modified LM scores were associated with SVD scores (0: B = 5.078, s.e. = 1.69, P = 0.0026; 2: B = -0.066, s.e. = 0.023, P = 0.0045) and disease activity (anti-dsDNA: B = 4.59, s.e. = 2.22, P = 0.045; SLEDAI 3-7: 2.86 < B < 4.30; 1.38 < s.e. < 1.63; 0.0083 ≤ P ≤ 0.0375). Computationally derived percent opaqueness yielded similar results. CONCLUSION: In patients with SLE, MRI computational assessment of sinuses opaqueness and LM scores modified at a 50% cut-off may be useful tools in understanding the relationships among paranasal sinus occupancy, disease activity and SVD markers.

The value of ultrasound-defined tenosynovitis and synovitis in the prediction of persistent arthritis.

OBJECTIVES: The value of US-defined tenosynovitis in predicting the persistence of inflammatory arthritis is not well described. In particular, the predictive utility of US-defined tenosynovitis of larger tendons is yet to be reported. We assessed the value of US-defined tenosynovitis alongside US-defined synovitis and clinical and serological variables in predicting persistent arthritis in an inception cohort of DMARD-naïve patients with early arthritis. METHODS: One hundred and fifty DMARD-naïve patients with clinically apparent synovitis of one or more joints and a symptom duration of ≤3 months underwent baseline clinical, laboratory and US (of 19 bilateral joints and 16 bilateral tendon compartments) assessments. Outcomes were classified as persistent or resolving arthritis after 18 months' follow-up. The predictive value of US-defined tenosynovitis for persistent arthritis was compared with those of US-defined synovitis, and clinical and serological variables. RESULTS: At 18 months, 99 patients (66%) had developed persistent arthritis and 51 patients (34%) had resolving disease. Multivariate logistic regression analysis showed that US-detected digit flexor tenosynovitis [odds ratio (OR): 6.6, 95% CI: 2.0 , 22.1, P = 0.002] provided independent predictive data for persistence over and above the presence of US-detected joint synovitis and RF antibodies. In the RF/ACPA-negative subcohort, US-defined digit flexor tenosynovitis remained a significant predictive variable (OR: 4.7, 95% CI: 1.4, 15.8, P = 0.012), even after adjusting for US-defined joint synovitis. CONCLUSION: US-defined tenosynovitis provided independent predictive data for the development of persistent arthritis. The predictive role of US-defined digit flexor tenosynovitis should be further assessed; investigators should consider including this tendon site as a candidate variable when designing imaging-based predictive algorithms for persistent inflammatory arthritis development.

Multimorbidity in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results From a Longitudinal, Multicenter Data Linkage Study.

OBJECTIVE: Antineutrophil cytoplasmic antibody-associated vasculitis (AAV) is considered a chronic, relapsing condition. To date, no studies have investigated multimorbidity in AAV nationally. This study was undertaken to characterize temporal trends in multimorbidity and report excess health care expenditures associated with multimorbidities in a national AAV cohort from Scotland. METHODS: Eligible patients with AAV were diagnosed between 1997 and 2017. Each patient was matched with up to 5 general population controls. Linked morbidity and health care expenditure data were retrieved from a Scottish national hospitalization repository and from published national cost data. Multimorbidity was defined as the development of ≥2 disorders. Prespecified morbidities, individually and together, were analyzed for risks and associations over time using modified Poisson regression, discrete interval analysis, and chi-square test for trend. The relationship between multimorbidities and health care expenditure was investigated using multivariate linear regression. RESULTS: In total, 543 patients with AAV (median age 58.7 years [range 48.9-68.0 years]; 53.6% male) and 2,672 general population controls (median age 58.7 years [range 48.9-68.0 years]; 53.7% male) were matched and followed up for a median of 5.1 years. AAV patients were more likely to develop individual morbidities at all time points, but especially <2 years after diagnosis. The highest proportional risk observed was for osteoporosis (adjusted incidence rate ratio 8.0, 95% confidence interval [95% CI] 4.5-14.2). After 1 year, 23.0% of AAV patients and 9.3% of controls had developed multimorbidity (P < 0.0001). After 10 years, 37.0% of AAV patients and 17.3% of controls were reported to have multimorbidity (P < 0.0001). Multimorbidity was associated with disproportionate increases in health care expenditures in AAV patients. Health care expenditure was highest for AAV patients with ≥3 morbidities (3.89-fold increase in costs, 95% CI 2.83-5.31; P < 0.001 versus no morbidities). CONCLUSION: These findings emphasize the importance of holistic care in patients with AAV, and may identify a potentially critical opportunity to consider early screening.

Characterizing infection in anti-neutrophil cytoplasmic antibody-associated vasculitis: results from a longitudinal, matched-cohort data linkage study.

OBJECTIVES: Infection exerts a major burden in ANCA-associated vasculitis (AAV), however, its precise extent and nature remains unclear. In this national study we aimed to longitudinally quantify, characterize and contextualize infection risk in AAV. METHODS: We conducted a multicentre matched cohort study of AAV. Complementary data on infections were retrieved via data linkage with the population-based Scottish microbiological laboratory, hospitalization and primary care prescribing registries. RESULTS: A total of 379 AAV patients and 1859 controls were followed up for a median of 3.5 years (interquartile range 1.9-5.7). During follow-up, the proportions of AAV patients with at least one laboratory-confirmed infection, severe infection and primary care antibiotic prescription were 55.4%, 35.6% and 74.6%, respectively. The risk of infection was higher in AAV than in matched controls {laboratory-confirmed infections: incidence rate ratio [IRR] 7.3 [95% confidence interval (CI) 5.6, 9.6]; severe infections: IRR 4.4 [95% CI 3.3, 5.7]; antibiotic prescriptions: IRR 2.2 [95% CI 1.9, 2.6]}. Temporal trend analysis showed that AAV patients remained at a higher risk of infections throughout the follow-up period, especially year 1. Although the Escherichia genus was the most commonly identified pathogen (16.6% of AAV, 5.5% of controls; P < 0.0001), AAV patients had the highest risk for Herpes [IRR 12.5 (95% CI 3.7, 42.6)] and Candida [IRR 11.4 (95% CI 2.4, 55.4)]. CONCLUSION: AAV patients have up to seven times higher risk of infection than the general population and the overall risk remains significant after 8 years of follow-up. The testing of enhanced short- to medium-term prophylactic antibiotic regimes should be considered.

The role of leukocyte-stromal interactions in chronic inflammatory joint disease.

Rheumatoid arthritis (RA) is a debilitating, chronic, persistent inflammatory disease that is characterised by painful and swollen joints. The aetiology of RA is unknown, however whereas past research has concentrated on the role of immune or inflammatory infiltrating cells in inflammation, it is becoming clear that stromal cells play a critical part in regulating the quality and duration of an inflammatory response. In this review we assess the role of fibroblasts within the inflamed synovium in modulating immune responses; in particular we examine the role of stromal cells in the switch from resolving to persistent inflammation as is found in the rheumatoid synovium.

Topical glucocorticoid therapy directly induces up-regulation of functional CXCR4 on primed T lymphocytes in the aqueous humor of patients with uveitis.

Overexpression of the constitutive chemokine receptor CXCR4 has been shown to contribute to the accumulation of leukocytes at sites of chronic inflammation. Glucocorticoids are widely used to treat inflammatory disorders such as uveitis to considerable effect, yet paradoxically have been reported to increase CXCR4 expression in vitro. We show here that ocular lymphocytes isolated from patients with uveitis who had been treated with topical glucocorticoids expressed highly elevated levels of CXCR4. The up-regulation of CXCR4 could be reproduced in vitro by culture of CD4(+) T cells with aqueous humor (AqH), indicating a role for the ocular microenvironment rather than preferential recruitment of CXCR4(+) cells. Untreated uveitis and noninflammatory AqH up-regulated CXCR4 to a limited extent; this was dependent on TGF-beta2. However, the highest levels of CXCR4 both in vivo and in vitro were found in the glucocorticoid-treated patients. Glucocorticoids appeared to be directly responsible for the induction of CXCR4 in treated patients, as the glucocorticoid receptor antagonist RU38486 inhibited the in vitro up-regulation by AqH from these patients. Dexamethasone selectively up-regulated CXCR4 in vitro, but not any of a wide range of other chemokine receptors. CXCL12, the ligand for CXCR4, was present in AqH under noninflammatory conditions, but the levels were low in untreated uveitis and undetectable in treated uveitis AqH. The importance of these results for the treatment of HIV patients with glucocorticoids is discussed as well as a role for glucocorticoid-induced CXCR4 up-regulation and CXCL12 down-regulation in controlling the migration of lymphocyte populations, resulting in resolution of inflammation.

Rheumatoid fibroblast-like synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4+ and CD8+ T cell migration within synovial tissue.

OBJECTIVE: A characteristic feature of the inflammatory infiltrate in rheumatoid arthritis is the segregation of CD4 and CD8 T lymphocyte subsets into distinct microdomains within the inflamed synovium. The aim of this study was to test the hypothesis that chemokines in general and stromal cell-derived factor 1 (SDF-1; CXCL12) in particular are responsible for generating this distinctive microcompartmentalization. METHODS: We examined how synovial CD4/CD8 T cell subsets interacted in coculture assays with fibroblasts derived from chronic inflammatory synovial lesions and normal synovial tissue as well as from fetal lung and adult skin. We used the ability of T cells to migrate beneath fibroblasts (a process called pseudoemperipolesis) as an in vitro marker of T cell accumulation within synovial tissue. RESULTS: Rheumatoid fibroblast-like synoviocytes (FLS) displayed a unique ability to support high levels of CD4 and CD8 T cell pseudoemperipolesis. Nonrheumatoid FLS as well as fetal lung fibroblasts supported low levels of pseudoemperipolesis, while skin-derived fibroblasts were unable to do so. CD8 T cells migrated under fibroblasts more efficiently and at a higher velocity than CD4 T cells, a feature that was intrinsic to CD8 T cells. Rheumatoid fibroblasts constitutively produced high levels of SDF-1 (CXCL12), which was functionally important, since blocking studies showed reductions in T cell pseudoemperipolesis to levels seen in nonrheumatoid FLS. Rheumatoid fibroblasts also constitutively produced high levels of vascular cell adhesion molecule 1 (VCAM-1; CD106), but this did not contribute to T cell pseudoemperipolesis, unlike the case for B cells, which require SDF-1 (CXCL12)-CXCR4 and CD49d-VCAM-1 (CD106) interactions. Importantly, only combinations of rheumatoid FLS and rheumatoid-derived synovial fluid T cells supported pseudoemperipolesis when examined ex vivo, confirming the in vivo relevance of these findings. CONCLUSION: These studies demonstrate that features intrinsic to both fibroblasts (the production of SDF-1) and CD8/CD4 T cells (the expression of CXCR4) are responsible for the characteristic pattern of T lymphocyte accumulation seen in the rheumatoid synovium. These findings suggest that the SDF-1/CXCR4 ligand/receptor pair is likely to play an important functional role in T lymphocyte accumulation and positioning within the rheumatoid synovium.