Principal component analysis reveals disconnect between regulatory cytokines and disease activity in Systemic Lupus Erythematosus.

OBJECTIVE: Cytokine dysregulation contributes to inflammation and organ damage in Systemic Lupus Erythematosus (SLE). Principle Component Analysis (PCA) can determine which groups of cytokines have the most influence across disease activity states. MATERIAL AND METHOD: A cross-sectional study of age- and gender-matched SLE patients (n = 100) and controls (n = 31). SLE patients had a median Systemic Lupus Erythematosus Disease Activity Index - 2000 (SLEDAI-2K) score of 6 (IQR 2, 11). IFN-γ, interleukin (IL)-1ß, IL-4, IL-6, IL-10, IL-12, IL-17, BAFF, TNF-α, TGF-ß1, MIP-1α, MIP-1ß and MCP-1 levels were quantified by sandwich ELISA, and compared non-parametrically between groups. PCA was used to determine the principal components across controls, SLE patients in states of remission (SLEDAI-2K = 0), low disease activity (LDA = SLEDAI-2K from 1 ≤ x ≤ 4) or high disease activity (HDA = SLEDAI-2K > 4). RESULTS: TGF-ß1 (Rs -0.266, p = 0.005) and IL-1ß (Rs -0.199, p = 0.004) inversely correlated, whereas BAFF correlated with increasing disease activity (Rs 0.465, p < 0.001). IL-1ß, IL-4, IL-10, IL-12, IL-17, IFN-γ, MCP-1, and TNF-α were featured consistently in the PC1 of all study groups. PC1 changes from controls to SLE-HDA patients, included: the increased impact of IL-1ß (from 0.58 to >0.95); increased impact of IL-6 in HDA (0.76); increased influence of MIP-1α (0.60) and MIP-1ß (0.85); and the uncoupling of TGF-ß1 (0.14). PC2 changes from healthy controls to the HDA state, included: the increased influence of BAFF (from -0.18 to 0.88); the oppositional effect of TGF-ß1 (-0.36); and, the inclusion of MCP-1 (0.65). Levels of cytokine profiles were equivalent between controls and SLE patients (p > 0.18). BAFF was not associated with the cytokine profiles. TGF-ß1 associated with Th1 (Rs 0.36), Th1 + Th17 (Rs 0.22), and inversely with Th17/Th2 (Rs -0.23) profiles. IL-1ß associated with the proinflammatory (Rs 0.47), Th1 (Rs 0.55), Th2 (Rs 0.55), Th17 (Rs 0.51), Th1 + Th17 (Rs 0.56), Th2 + Treg (Rs 0.45), and inversely with the (Th1 + Th17 / Th2 + Treg) (Rs -0.22) and Th17/Th2 (Rs -0.27) profiles (all, p < 0.05). CONCLUSION: Principal component analysis helped to describe the influence of complex cytokine interactions in SLE in a manner congruent with the wider literature. The typical univariate changes in BAFF and TGF-ß1 levels with increasing levels of disease activity, were not the dominant factors (in PC1) in the PCA. The PCA demonstrated that IL-1ß did not seem to change its regulatory function in SLE.

Medication selection and patient compliance in the clinical management of osteoporosis.

BACKGROUND: Osteoporosis contributes significantly to morbidity and mortality. Antiresorptive therapy is effective in primary and secondary fracture prevention, but compliance with bisphosphonate therapy is poor, resulting in poorer patient outcomes. OBJECTIVE: The objectives of this article are to aid clinicians' treatment selection and improve patient adherence. DISCUSSION: A literature review of treatment options and factors contributing to poor patient treatment adherence was conducted for this article. The effectiveness of osteoporosis treatment is reduced because of poor adherence. This is associated with a lack of patient understanding of their condition, perception of fracture risk and concerns about adverse events. Appropriate treatment selection and novel oral and parenteral options may help improve compliance. Increasing treatment adherence requires clinicians to improve patient education. Discussion around patient preferences, implications of fragility fractures, minimising side effects and efficacy of treatment is essential despite the lack of any tangible 'symptom' benefit.

Cancer development in patients hospitalized with systemic lupus erythematosus: A population-level data linkage study.

AIM: To explore the association between systemic lupus erythematosus (SLE) with the risk of cancer development and subsequent 5-year mortality in Western Australia (WA). METHODS: Population-level, data linkage study of SLE patients (n = 2111) and general population comparators (n = 21 110) hospitalized between 1980 and 2014. SLE patients (identified by ICD-9-CM: 695.4, 710.0, and ICD-10-AM: L93.0, M32.0) were nearest matched (10:1) for age, sex, Aboriginality, and temporality. Follow up was from time zero (index SLE hospitalization) to cancer development, death or 31 December 2014. We assessed the risk of cancer development and subsequent 5-year mortality between SLE patients and comparators with univariate and multivariate-adjusted Cox proportional hazards regression models. RESULTS: SLE patients had similar multivariate-adjusted risk (adjusted hazard ratio [aHR] 1.03, 95% confidence interval [CI] 0.93-1.15; p = .583) of cancer development. Cancer development risk was higher in SLE patients <40 years old (aHR 1.58, 95% CI 1.29-1.94; p < .001), and from 1980 to 1999 (aHR 1.16, 95% CI 1.02-1.31; p < .001). SLE patients had higher risk of developing cancer of the oropharynx (aHR 2.13, 95% CI 1.30-3.50), vulvo-vagina (aHR 3.22, 95% CI 1.34-7.75), skin (aHR 1.20, 95% CI 1.01-1.43), musculoskeletal tissues (aHR 2.26, 95% CI 1.16-4.40), and hematological tissues (aHR 1.78 95% CI 1.25-2.53), all p < .05. After cancer development, SLE patients had increased risk of 5-year mortality (aHR 1.31, 95% CI 1.06-1.61); highest in patients <50 years old (aHR 2.03, 95% CI 1.03-4.00), and in those with reproductive system and skin cancers. CONCLUSIONS: Hospitalized SLE patients had increased risk of multiple cancer sub-types. Following cancer development, SLE patients had increased risk of 5-year mortality. There is scope to improve cancer prevention and surveillance in SLE patients. TRIAL REGISTRATION: Not applicable. This low-risk risk study used de-identified administrative linked health data.

Smoking associates with increased BAFF and decreased interferon-γ levels in patients with systemic lupus erythematosus.

OBJECTIVE: In SLE, smoking increases the burden of cutaneous disease and organ damage, and leads to premature mortality. However, the effect of smoking on disease manifestations and cytokine levels of patients with SLE is unclear. This study compared characteristics of patients with SLE across smoking status, and determined the association of smoking with serum cytokine levels. METHOD: A cross-sectional study of patients with SLE (n=99) during a research visit in which smoking status was ascertained. Smoking status was compared across classification criteria (American College of Rheumatology Classification Criteria for SLE (ACR97)), disease activity (SLE Disease Activity Index), autoantibody levels, accrued damage (Systemic Lupus International Collaborating Clinics/ACR Damage Index), and circulating concentrations of serum interferon-gamma (IFN-γ), interleukin (IL)-1ß, IL-4, IL-6, IL-10, IL-12, IL-17, B cell-activating factor (BAFF), tumour necrosis factor-alpha, transforming growth factor beta 1 (TGF-ß1), macrophage inflammatory protein 1 alpha (MIP-1α), MIP-1ß and monocyte chemoattractant protein 1. Linear regression models determined the association between smoking and cytokine levels, adjusting for age and sex, clinical characteristics (model 1), and anti-inflammatory (IL-4, IL-10 and TGF- ß1) and regulatory (IL-1ß) cytokines (model 2). RESULTS: Among patients with SLE (97.9% ANA+; mean 48.48 years old; 86.9% female; mean 10 years of disease duration), 35.4% (n=35 of 99) were smoking (an average of 7 cigarettes/day for 24 years). Smokers had increased odds of prevalent ACR97 malar rash (OR 3.40, 95% CI 1.23 to 9.34) and mucosal ulcers (OR 3.31, 95% CI 1.36 to 8.05). Smokers had more arthritis (OR 3.19, 95% CI 1.19 to 8.60), migraine (OR 2.82, 95% CI 1.07 to 7.44), Raynaud's phenomenon (OR 5.15, 95% CI 1.95 to 13.56) and increased non-steroidal anti-inflammatory drug use (OR 6.88, 95% CI 1.99 to 23.72). Smoking associated with 27% increased BAFF levels (95% CI 6% to 48%) and 42% decreased IFN-γ levels (95% CI -79% to -5%) in model 2. CONCLUSION: In patients with SLE, smoking independently associated with increased BAFF and decreased IFN-γ levels, and an increased frequency of arthritis, migraine and Raynaud's phenomenon. Smoking cessation is advisable to reduce systemic inflammation, reduce disease activity and improve host defence.

Hospitalisation for systemic lupus erythematosus associates with an increased risk of mortality in Australian patients from 1980 to 2014: a longitudinal, population-level, data linkage, cohort study.

OBJECTIVE: Mortality rates for patients with SLE have not been reported in Australia. This study determined the association between a hospitalisation for SLE with mortality. METHODS: Population-level cohort study of patients with SLE (n=2112; 25 710 person-years) and general population comparators (controls) (n=21, 120; 280 637 person-years) identified from hospital records contained within the WA Rheumatic Disease Epidemiological Registry from 1980 to 2013. SLE was identified by ICD-9-CM: 695.4, 710.0, ICD-10-AM: L93.0, M32.0. Controls were nearest matched (10:1) for age, sex, Aboriginality and temporality. Using longitudinal linked health data, we assessed the association between a hospitalisation for SLE mortality and mortality with univariate and multivariate Cox proportional hazards and competing risks regression models. RESULTS: At timezero, patients with SLE were similar in age (43.96 years), with higher representation of females (85.1% vs 83.4%, p=0.038), Aboriginal Australians (7.8% vs 6.0%) and smokers (20.5% vs 13.2%). Before study entry, patients with SLE (mean lookback 9 years) had higher comorbidity accrual (Charlson Comorbidity Index ≥1 item (42.0% vs 20.5%)), especially cardiovascular disease (CVD) (44.7% vs 21.0%) and nephritis (16.4% vs 0.5%), all p<0.001. During follow-up (mean 12.5 years), 548 (26.0%) patients with SLE and 2450 (11.6%) comparators died. A hospitalisation for SLE increased the unadjusted (HR 2.42, 95% CI 2.20 to 2.65) and multivariate-adjusted risk of mortality (aHR 2.03, 95% CI 1.84 to 2.23), which reduced from 1980 to 1999 (aHR 1.42) to 2000-2014 (aHR 1.27). Females (aHR 2.11), Aboriginal Australians (aHR 3.32), socioeconomically disadvantaged (aHR 2.49), and those <40 years old (aHR 7.46) were most vulnerable. At death, patients with SLE had a higher burden of infection (aHR 4.38), CVD (aHR 2.09) and renal disease (aHR 3.43), all p<0.001. CONCLUSIONS: A hospitalisation for SLE associated with an increased risk of mortality over the 1980-2014 period compared with the general population. The risk was especially high in younger (<40 years old), socioeconomically disadvantaged and Aboriginal Australians.

The burden of subclinical intra-articular inflammation in gout.

OBJECTIVE: To assess the burden of subclinical intra-articular inflammation using ultrasound in people with gout. METHODS: A pilot, prospective longitudinal cohort of 28 participants with gout were examined twice, once during a gout flare (n = 25) and then during an inter-critical phase (n = 27). At each visit, a 52 joint count was done followed by ultrasound examination for detection of intra-articular power Doppler (PD) signal. Clinically active joints were defined as tender and swollen. Data was collected on patient reported gout pain - visual analog scale (VAS) (painVAS), physician global VAS (physicianVAS), Health Assessment Questionnaire (HAQ), serum uric acid, erythrocyte sedimentation rate (ESR), and high-sensitivity C-reactive protein (HsCRP). RESULTS: At the flare visit, participants had a median of 1 clinically active joint (interquartile range [IQR] 1-2), and a median of 5 joints with a PD score ≥ 2 (IQR 4-10, P < .001). At the inter-critical visit, participants reported an median of 0 clinically active joints (IQR 0-0), and a median of 4 joints with a PD score ≥ 2 (IQR 3-7, P < .001). Physician VAS (5.69 vs 3.40, P < .001), painVAS (6 vs 0, P < .001), HAQ (0.75 vs 0.12, P = .032), and ESR (29 vs 13.5 mm/h, P = .02) were higher at the acute visit, but HsCRP levels were similar (8.88 vs 5.15 mg/L, P = .062). CONCLUSION: This pilot study established the presence of subclinical intra-articular inflammation in gout at both acute and inter-critical phases. Despite the apparent resolution of symptoms after an acute flare, a relatively high proportion of joints had subclinical inflammation in the inter-critical visit. The long-term implications of untreated subclinical joint inflammation are not clear.

Prognostication accuracy of final destination in poststroke patients requiring transitional care.

OBJECTIVES: Transitional care program in Australia targets older patients in hospitals requiring ongoing slow-stream restorative care prior to discharge. Poststroke patients often require extended care and are transferred to these facilities. Transitional care providers require a predicted discharge destination. The aim of this study was to assess the accuracy of this prediction. METHODOLOGY: This study included all patients transferred to transitional care from a stroke rehabilitation unit over eight years. Information regarding the predicted final discharge destination was collected from medical records, and the actual discharge destination was obtained from the transitional care registry. RESULTS: Final destination prediction was equivalent between medical and multidisciplinary teams (κ = 0.87). However, only 60% of the predictions were accurate. Subgroup analysis, as measured by the Modified Barthel Index, suggested that functional gain was a better predictor of final destination. Other characteristics, such as age, sex and type of stroke, did not demonstrate good correlation with the final destination. CONCLUSION: Functional improvement, that is the Modified Barthel Index, is the best predictor of final destination after transitional care.

The Impact of Cytokines on the Health-Related Quality of Life in Patients with Systemic Lupus Erythematosus.

INTRODUCTION: Systemic lupus erythematosus (SLE) reduces the health-related quality of life (HRQoL), even during periods of disease quiescence. We investigated whether subclinical inflammation as reflected by cytokine levels is linked with reduced HRQoL. METHODS: A cross-sectional study of SLE patients (n = 52, mean age 47.3, 86.5% female) who completed a Short Form Health Survey-36 (SF-36) questionnaire. The clinical and demographic data, scores for the disease activity (SLEDAI-2K), organ damage (SDI), and laboratory data were collected simultaneously. The autoantibody and cytokine levels (IFN-γ, IL-1ß, IL-4, IL-6, IL-10, IL-12, IL-17, BAFF, TNF-α, TGF-ß1, MIP-1α, MIP-1ß and MCP-1 (levels in pg/mL) were quantified by sandwich ELISA. The comparisons and associations were assessed non-parametrically, and a multiple regression determined the effect sizes (ES) of the variables on the SF-36 domain and summary scores. RESULTS: The SF-36 summary and domain scores for SLE patients were significantly (20-40%) lower than in a comparable control group, with the exception of the Mental Health scores (p = 0.06). SLE patients had a normal body mass index (BMI) (median, 24.2 kg/m2), a high rate of smoking (69.2%), and usage of social security benefits (90.4%). TGF-ß1 (ES 0.06), IL-12 (ES -0.11), IFN-γ (ES 0.07) and MCP-1 (ES 0.06) influenced the SF-36 domain scores; and MCP-1 (ES 0.04) influenced the Mental Health Summary Score (MCS). Obvious manifestations, including patient visual analogue scale (VAS) (ES -2.84 to -6.29), alopecia (ES -14.89), malar rash (ES -14.26), and analgesic requirement (ES -19.38), independently influenced the SF-36 items; however, the SF-36 scores were not reflected by the physician VAS or disease activity (SLEDAI-2K). CONCLUSIONS: Cytokines had a minimal impact on HRQoL in SLE patients, especially compared to visible skin manifestations, central nervous system (CNS) damage, and pain. Better tools are needed to capture HRQoL in measures of disease activity.