Translating research into clinical practice: quality improvement to halve non-adherence to methotrexate.

OBJECTIVE: MTX remains the cornerstone for therapy for RA, yet research shows that non-adherence is significant and correlates with response to therapy. This study aimed to halve self-reported non-adherence to MTX at the Kellgren Centre for Rheumatology. METHODS: An anonymous self-report adherence questionnaire was developed and data collected for 3 months prior to the introduction of interventions, and then regularly for the subsequent 2.5 years. A series of interventions were implemented, including motivational interviewing training, consistent information about MTX and development of a summary bookmark. Information on clinic times was collected for consultations with and without motivational interviewing. Surveys were conducted to ascertain consistency of messages about MTX. A biochemical assay was used to test MTX serum levels in patients at two time points: before and 2.8 years following introduction of the changes. Remission rates at 6 and 12 months post-MTX initiation were retrieved from patient notes and cost savings estimated by comparing actual numbers of new biologic starters compared with expected numbers based on the numbers of consultants employed at the two time points. RESULTS: Between June and August 2016, self-reported non-adherence to MTX was 24.7%. Following introduction of the interventions, self-reported non-adherence rates reduced to an average of 7.4% between April 2018 and August 2019. Clinic times were not significantly increased when motivational interviewing was employed. Consistency of messages by staff across three key areas (benefits of MTX, alcohol guidance and importance of adherence) improved from 64% in September 2016 to 94% in January 2018. Biochemical non-adherence reduced from 56% (September 2016) to 17% (June 2019), whilst remission rates 6 months post-initiation of MTX improved from 13% in 2014/15 to 37% in 2017/18, resulting is estimated cost savings of £30 000 per year. CONCLUSION: Non-adherence to MTX can be improved using simple measures including focussing on the adherence and the benefits of treatment, and providing consistent information across departments.

Biologic therapy for Behçet's uveitis: a systematic review.

BACKGROUND: Biologics are increasingly used in management of Behçet's Disease (BD) including ocular BD, but the evidence base is limited, mostly from studies of uveitis and BD manifestations. OBJECTIVE: To review the evidence base for biologics in the treatment of ocular BD. METHODS: Systematic literature search was made using exploded key words-Behçet's, ocular, biologics in MEDLINE, Cochrane library, Database of Abstracts Reviews and Effects, Clinical Trials.gov, Science Direct and Google Scholar. There was no limitation on region, language or date (Search updated 16th October 2018). Literature retrieval was restricted to randomised controlled trials (RCTs) of biologics. RESULTS: Of 237 papers retrieved, eight met the inclusion criteria. RCTs on interferon alpha 2a (INF-α 2a), adalimumab, secukinumab, gevokizumab, rituximab and daclizumab were retrieved (two for adalimumab and gevokizumab). The outcome measures were not met for secukinumab, daclizumab and gevokizumab. Rituximab and INF-α 2a showed promising preliminary results but sufficiently powered RCTs are needed to provide adequate evidence of efficacy. The RCTs on adalimumab did not evaluate efficacy for BD uveitis specifically, hence are of limited value for this review. CONCLUSION: Some biologics show promise in treating BD uveitis, but more RCTs are needed for firm conclusions about efficacy. A phase IV study or, registry of adalimumab could provide data on its efficacy in BD uveitis compared to other forms.

Progression of subclinical and clinical cardiovascular disease in a UK SLE cohort: the role of classic and SLE-related factors.

OBJECTIVES: We aimed to describe the rate and determinants of carotid plaque progression and the onset of clinical cardiovascular disease (CVD) in a UK SLE cohort. METHODS: Female patients with SLE of white British ancestry were recruited from clinics in the North-West of England and had a baseline clinical and CVD risk assessment including measurement of carotid intima-media thickness (CIMT) and plaque using B-mode Doppler ultrasound. Patients were followed up (>3.5 years after baseline visit) and had a repeat carotid Doppler to assess progression of plaque and CIMT. Clinical CVD events between visits were also noted. RESULTS: Of 200 patients with a baseline scan, 124 (62%) patients had a second assessment at a median (IQR) of 5.8 (5.2-6.3) years follow-up. New plaque developed in 32 (26%) (4.5% per annum) patients and plaque progression was observed in 52 (41%) patients. Factors associated with plaque progression were older age (OR 1.13; 95% CI 1.06 to 1.20), anticardiolipin (OR 3.36; 1.27 to 10.40) and anti-Ro (OR 0.31; 0.11 to 0.86) antibodies. CVD events occurred in 7.2% over 5.8 years compared with 1.0% predicted using the Framingham risk score (p<0.001). Higher triglycerides (OR 3.6; 1.23 to 10.56), cyclophosphamide exposure 'ever' (OR 16.7; 1.46 to 63.5) and baseline Systemic Lupus International Collaborating Clinics damage index score (OR 9.62; 1.46 to 123) independently predicted future CVD events. CONCLUSION: Accelerated atherosclerosis remains a major challenge in SLE disease management. A more comprehensive approach to CVD risk management taking into account disease factors such as severity and anticardiolipin antibody status may be necessary to improve CVD outcomes in this high-risk population.

Microvascular Response in Patients with Complex Regional Pain Syndrome as Measured by Laser Doppler Imaging.

OBJECTIVES: Our aim was to investigate the hypothesis that microvascular dysfunction occurs in patients with CRPS. Specifically, whether there were functional differences in either deeper cutaneous blood vessels or more superficial nutritive vessels between the affected and unaffected limb in patients with CRPS, and between CRPS patients and healthy control subjects. METHODS: Twenty-two patients with CRPS (five male; mean age 45 years; eight upper limb involvement, 14 lower limb) and 23 healthy control subjects (one male; 43 years) were recruited. Microvascular flow at affected and unaffected contralateral sites was measured, following local heating, using laser Doppler imaging (red/green wavelengths). Corresponding sites were imaged in healthy controls. Maximum flux level and area under the curve (first 20 scans, AUC20) were measured. RESULTS: Vasodilator responses to heat were similar in affected and unaffected limbs, and in healthy controls. For example, median (IQR) "red" AUC20 in CRPS was 138.6 (120.0-152.9)% change from baseline in affected limb and 135.0 (120.7-166.8)% in unaffected limb, and (in healthy controls) 133.1 (117.2-145.9)% and 139.1% (126.0-162.1) in limb 1 and 2. CONCLUSIONS: We found no impairment of vasodilation in cutaneous microvessels in CRPS. The vasomotor changes in CRPS may relate to larger vessel dysfunction.

Interventions for the management of oral ulcers in Behçet's disease.

BACKGROUND: Behçet's disease is a chronic inflammatory vasculitis that can affect multiple systems. Mucocutaneous involvement is common, as is the involvement of many other systems such as the central nervous system and skin. Behç̧et's disease can cause significant morbidity, such as loss of sight, and can be life threatening. The frequency of oral ulceration in Behçet's disease is thought to be 97% to 100%. The presence of mouth ulcers can cause difficulties in eating, drinking, and speaking leading to a reduction in quality of life. There is no cure for Behçet's disease and therefore treatment of the oral ulcers that are associated with Behçet's disease is palliative. OBJECTIVES: To determine the clinical effectiveness and safety of interventions on the pain, episode duration, and episode frequency of oral ulcers and on quality of life for patients with recurrent aphthous stomatitis (RAS)-type ulceration associated with Behçet's disease. SEARCH METHODS: We undertook electronic searches of the Cochrane Oral Health Group Trials Register (to 4 October 2013); the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2013, Issue 9); MEDLINE via Ovid (1946 to 4 October 2013); EMBASE via Ovid (1980 to 4 October 2013); CINAHL via EBSCO (1980 to 4 October 2013); and AMED via Ovid (1985 to 4 October 2013). We searched the US National Institutes of Health trials register (http://clinicaltrials.gov) and the World Health Organization (WHO) Clinical Trials Registry Platform for ongoing trials. There were no restrictions on language or date of publication in the searches of the electronic databases. We contacted authors when necessary to obtain additional information. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that looked at pre-specified oral outcome measures to assess the efficacy of interventions for mouth ulcers in Behçet's disease. The oral outcome measures included pain, episode duration, episode frequency, safety, and quality of life. Trials were not restricted by outcomes alone. DATA COLLECTION AND ANALYSIS: All studies meeting the inclusion criteria underwent data extraction and an assessment of risk of bias, independently by two review authors and using a pre-standardised data extraction form. We used standard methodological procedures expected by The Cochrane Collaboration. MAIN RESULTS: A total of 15 trials (n = 888 randomised participants) were included, 13 were placebo controlled and three were head to head (two trials had more than two treatment arms). Eleven of the trials were conducted in Turkey, two in Japan, one in Iran and one in the UK. Most trials used the International Study Group criteria for Behçet's disease. Eleven different interventions were assessed. The interventions were grouped into two categories, topical and systemic. Only one study was assessed as being at low risk of bias. It was not possible to carry out a meta-analysis. The quality of the evidence ranged from moderate to very low and there was insufficient evidence to support or refute the use of any included intervention with regard to pain, episode duration, or episode frequency associated with oral ulcers, or safety of the interventions. AUTHORS' CONCLUSIONS: Due to the heterogeneity of trials including trial design, choice of intervention, choice and timing of outcome measures, it was not possible to carry out a meta-analysis. Several interventions show promise and future trials should be planned and reported according to the CONSORT guidelines. Whilst the primary aim of many trials for Behç̧et's disease is not necessarily reduction of oral ulceration, reporting of oral ulcers in these studies should be standardised and pre-specified in the methodology. The use of a core outcome set for oral ulcer trials would be beneficial.

Suppression of inflammation reduces endothelial microparticles in active systemic lupus erythematosus.

BACKGROUND: In a prospective observational study, we investigated whether patients with active systemic lupus erythematosus (SLE) had higher indices of endothelial damage and dysfunction than healthy controls and whether improved disease control was associated with improvement in these indices. METHODS: Twenty-seven patients with active SLE (four or more American College of Rheumatology (ACR) criteria) and 22 age-matched controls were assessed. Endothelial microparticles (EMPs; CD31+/annexin V+/CD42b-) were quantified using flow cytometry. Brachial artery flow-mediated dilatation (FMD) was measured using automated edge-tracking software. Twenty-two patients had a second assessment at a median (IQR) of 20 (16, 22) weeks after initiating new immunosuppressive therapy. RESULTS: SLE patients had a median (IQR) baseline global British Isles Lupus Assessment Group Disease Activity Index (BILAG-2004) score of 14 (12, 22). CD31+/annexin V+/CD42b- EMPs were higher (157 548/ml (59 906, 272 643) vs 41 025(30 179, 98 082); p=0.003) and endothelial-dependent FMD was lower (1.63% (-1.22, 5.32) vs 5.40% (3.02, 8.57); p=0.05) in SLE patients than controls. CD31+/annexin V+/CD42b- EMPs correlated inversely with FMD (%) (r(2) -0.40; p=0.006). At follow-up, the median (IQR) change in global BILAG-2004 score was -11 (-18, -3). CD31+/annexin V+/CD42b- EMP levels were reduced (166 982/ml (59 906, 278 775 vs 55 655(29 475, 188 659; p=0.02) and FMD had improved (0.33% (-2.31, 4.1) vs 3.19% (0.98, 5.09); p=0.1) at the second visit. CONCLUSIONS: Active SLE is associated with evidence of increased endothelial damage and endothelial dysfunction, which improved with suppression of inflammation. Better control of active inflammatory disease may contribute to improved cardiovascular risk in patients with SLE.

Shortened telomere length in patients with systemic lupus erythematosus.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) have a higher rate of premature death compared to the general population, suggesting a phenotype of premature senescence in SLE. Telomere length can be used to assess overall biologic aging. This study was undertaken to address the hypothesis that patients with SLE have reduced telomere length. METHODS: Telomere length was measured cross-sectionally in whole blood from SLE patients and age-matched healthy female controls, using real-time quantitative polymerase chain reaction. SLE-related and cardiovascular risk factors were assessed. RESULTS: We compared telomere length in 63 SLE patients and 63 matched controls with a median age of 50.8 years (interquartile range [IQR] 37-59 years) and 49.9 years (IQR 32-60 years), respectively. The median relative telomere length in SLE patients was 0.97 (IQR 0.47-1.57), compared to 1.53 (IQR 0.82-2.29) in controls (P = 0.0008). We then extended our cohort to measure telomere length in 164 SLE patients. Shorter telomere length was associated with Ro antibodies (ß ± SE -0.36 ± 0.16; P = 0.023), and longer telomere length was associated with steroid therapy (0.29 ± 0.14; P = 0.046). We also noted an association of longer telomere length with increasing body mass index (ß ± SE 0.07 ± 0.01; P < 0.0001) and tobacco smoking (0.64 ± 0.26; P = 0.016), as well as with the presence of carotid plaque (0.203 ± 0.177; P = 0.032). CONCLUSION: Telomere length is shortened in SLE patients compared to controls and does not appear to be a reflection of disease activity or immune cell turnover. Subsets of patients such as those positive for Ro antibodies may be particularly susceptible to premature biologic aging. The predictive value of telomere length as a biomarker of future risk of damage/mortality in SLE requires longitudinal evaluation.

Construct and criterion validity of the short form-6D utility measure in patients with systemic lupus erythematosus.

OBJECTIVE: Preference-based measures, such as the Short Form-6D (SF-6D), allow quality-adjusted life-years, used in cost-utility evaluations, to be calculated. We investigated the construct and criterion validity of the SF-6D in patients with systemic lupus erythematosus (SLE). METHODS: Female patients with SLE were recruited from outpatient clinics at 2 timepoints, 5 years apart. Cross-sectional correlation of the SF-6D with domains of the disease-specific LupusQol health-related quality of life (HRQOL) measure, the Systemic Lupus International Collaborating Clinics Damage Index (SDI; for damage) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI; for activity) measures, and patient characteristics was tested. The ability to discriminate between groups defined by smoking status, presence/absence of carotid plaque, depression, and fatigue was tested using the t-test. RESULTS: In total 181 patients were recruited at baseline. The SF-6D correlated moderately to strongly with all domains of the LupusQoL (0.6-0.8) apart from intimate relationships (0.42) and body image (0.34). Correlations of the SF-6D with the demographic and disease-specific measures at baseline were small for the SDI score (-0.23) and age (-0.19) and in the expected direction. The SF-6D did not correlate with disease activity (SLEDAI -0.08). The SF-6D could distinguish those who smoked, had carotid plaque, had depression, and reported fatigue from those who did not, with the largest effect size being for depression (0.75). CONCLUSION: The SF-6D displays construct and criterion validity for use in patients with SLE, but the low correlation with aspects of intimate relationships and body image represents a concern and reinforces the need to collect disease-specific measures of HRQOL alongside generic preference-based instruments.

25-Hydroxyvitamin D deficiency is associated with increased aortic stiffness in patients with systemic lupus erythematosus.

OBJECTIVE: To determine the relationship between serum vitamin D and markers of subclinical cardiovascular disease (CVD) in patients with SLE. METHODS: We recruited SLE patients (≥ 4 ACR 1997 criteria) from outpatient clinics between January 2007 and January 2009. Vitamin D deficiency was defined as serum 25(OH)D <20 ng/ml measured by ELISA. Disease activity was measured using the SLEDAI-2K score. Aortic pulse wave velocity (aPWV) was measured using PulseTrace 3600 (Micromedical) and carotid plaque (CP) and intima-media thickness (IMT) assessed using B-mode Doppler US. RESULTS: Seventy-five women with SLE were recruited with a median (interquartile range) disease duration of 16 (8-27) years. Patients with vitamin D deficiency had higher BMI (P = 0.014) and insulin resistance (P = 0.023) than those with 25(OH)D >20 ng/ml. Subjects with SLEDAI-2K ≥ 4 had lower 25(OH)D than those with SLEDAI-2K <4 (median 12.9 vs 20.3 ng/ml, P = 0.031). Aortic stiffness was significantly associated with serum 25(OH)D [log(aPWV) ß (95% CI) -0.0217 (-0.038, -0.005), P = 0.010] independently of BMI, CVD risk factors and serum insulin. Adjustment for disease activity reduced the strength of the association. There was no association between 25(OH)D and CP or IMT. CONCLUSIONS: Vitamin D deficiency is associated with increased aortic stiffness in SLE, independent of CVD risk factors and insulin. Increased inflammatory disease activity may be the mechanism by which vitamin D deficiency mediates vascular stiffness in this patient group.

Possible therapeutic use of vasodilator iontophoresis.

BACKGROUND: Investigation into the effects of a novel vasodilator delivery method (for the eventual treatment of scleroderma related digital ulceration) on healthy controls is reported. When Raynaud's phenomenon (episodic cold-induced colour changes of the fingers) occurs in the context of scleroderma, it can be extremely severe, leading to ulceration and sometimes gangrene. The current treatment of choice for scleroderma-related critical digital ischaemia and/or ulceration is intravenous prostanoid therapy, necessitating hospitalisation. However, iloprost is often poorly tolerated and may be ineffective. METHODS: This study utilises a newly designed iontophoresis chamber which has the potential to allow a therapeutic, rather than diagnostic application for vasodilatory iontophoresis. Ten healthy controls underwent whole finger iontophoresis with 1% acetylcholine chloride for 2 min at 100 microA. Iontophoresis with varying treatment times and currents was carried out on a subset of subjects to determine the effect on perfusion increase. RESULTS: A significant increase in perfusion following iontophoresis was found, compared to the adjacent, untreated finger (P < 0.001). Maximum increase as a percentage from baseline, mean [SD] = 100 [66]%. Both treatment time and current have an approximately linear relationship with perfusion increase. CONCLUSIONS: Iontophoresis of the whole finger administers drugs locally with no systemic effects and warrants further investigation as a therapy.

Comparison of red and green laser doppler imaging of blood flow.

BACKGROUND AND OBJECTIVES: Laser Doppler imaging (LDI) of perfusion has been performed with a novel green wavelength (532 nm) for comparison with a HeNe laser (633 nm), the aim being validation of the green laser wavelength as a research tool. STUDY DESIGN/MATERIALS AND METHODS: The effect of wavelength and power on images was investigated and perfusion response following both finger occlusion and local heating of the dorsum were examined as reproducible stimuli for clinical studies. RESULTS: The most striking difference between red and green LDI is the absence of veins on green LDI, which are seen with red LDI. Differences have been quantified using vein LDI profiles. Differences were found between blood flow responses imaged by red and green LDI (3 and 5 mW, respectively) for occlusion and heat stimuli. Results are discussed in the context of light penetration. CONCLUSIONS: Red and green wavelengths appear to image different components of the microcirculation.