Clinical Markers Of Disease Activity Research Articles

EHealth mindfulness-based music therapy for patients undergoing allogeneic hematopoietic stem cell transplantation: A pilot randomized controlled trial protocol

BackgroundAllogeneic stem cell transplantation (allo-SCT) is the preferred therapy for patients with high-risk or relapsed hematologic malignancies, but may be complicated by psychological distress (e.g., depression, anxiety) and symptom burden (e.g., fatigue, pain). Mindfulness-based music therapy (MBMT), a relatively novel integrative medicine intervention that draws from mindfulness and music therapy principles, has shown promise in improving psychosocial outcomes and symptom burden in cancer patients. We outline an eHealth-based MBMT (eMBMT) intervention protocol examining: (1) feasibility, acceptability, and intended effects of eMBMT in improving HRQOL, symptom burden, and clinical markers of disease activity (e.g., infections), and (2) the extent to which eMBMT music therapy component-associated improvements in HRQOL, symptom burden, and disease activity are mediated by improvements in psychosocial and physiological (e.g., systemic inflammation, immune recovery) adaptation. MethodsParticipants (n = 60) with a hematologic malignancy undergoing allo-SCT will be randomized to receive eMBMT or an eHealth-based mindfulness meditation (eMM) intervention. eMBMT includes eight 60-min sessions facilitated by a music therapist focusing on mindfulness and music therapy. eMM includes eight 60-min self-led MM practices. ResultsFeasibility, acceptability, HRQOL, symptom burden, disease activity, and mediation effects of psychosocial and physiological adaptation will be assessed at baseline, pre-infusion, and post-engraftment with blood collection at baseline and post-engraftment. ConclusionThe current pilot RCT is the first eMBMT intervention to address the HRQOL and symptom burden of patients who are undergoing allo-SCT. Results will inform a fully powered RCT to establish preliminary efficacy of eMBMT on improvements in HRQOL, symptom burden, and disease activity.

Smartphone-based cough monitoring as a near real-time digital pneumonia biomarker.

Cough represents a cardinal symptom of acute respiratory tract infections. Generally associated with disease activity, cough holds biomarker potential and might be harnessed for prognosis and personalised treatment decisions. Here, we tested the suitability of cough as a digital biomarker for disease activity in coronavirus disease 2019 (COVID-19) and other lower respiratory tract infections. We conducted a single-centre, exploratory, observational cohort study on automated cough detection in patients hospitalised for COVID-19 (n=32) and non-COVID-19 pneumonia (n=14) between April and November 2020 at the Cantonal Hospital St Gallen, Switzerland. Cough detection was achieved using smartphone-based audio recordings coupled to an ensemble of convolutional neural networks. Cough levels were correlated to established markers of inflammation and oxygenation. Cough frequency was highest upon hospital admission and declined steadily with recovery. There was a characteristic pattern of daily cough fluctuations, with little activity during the night and two coughing peaks during the day. Hourly cough counts were strongly correlated with clinical markers of disease activity and laboratory markers of inflammation, suggesting cough as a surrogate of disease in acute respiratory tract infections. No apparent differences in cough evolution were observed between COVID-19 and non-COVID-19 pneumonia. Automated, quantitative, smartphone-based detection of cough is feasible in hospitalised patients and correlates with disease activity in lower respiratory tract infections. Our approach allows for near real-time telemonitoring of individuals in aerosol isolation. Larger trials are warranted to decipher the use of cough as a digital biomarker for prognosis and tailored treatment in lower respiratory tract infections.

Nuclear Magnetic Resonance Spectroscopy Metabolomics in Idiopathic Intracranial Hypertension to Identify Markers of Disease and Headache.

We evaluated the metabolomic profile in the CSF, serum, and urine of participants with idiopathic intracranial hypertension (IIH) compared with that in controls and measured changes in metabolism associated with clinical markers of disease activity and treatment. A case-control study compared women aged 18-55 years with active IIH (Friedman diagnostic criteria) with a sex-matched, age-matched, and body mass index-matched control group. IIH participants were identified from neurology and ophthalmology clinics from National Health Service hospitals and underwent a prospective intervention to induce disease remission through weight loss with reevaluation at 12 months. Clinical assessments included lumbar puncture, headache, papilledema, and visual measurements. Spectra of the CSF, serum, and urine metabolites were acquired using proton nuclear magnetic resonance spectroscopy. Urea was lower in IIH participants (CSF, controls median ± IQR 0.196 ± 0.008, IIH 0.058 ± 0.059, p < 0.001; urine, controls 5971.370 ± 3021.831, IIH 4691.363 ± 1955.774, p = 0.009), correlated with ICP (urine p = 0.019) and headache severity (CSF p = 0.031), and increased by 12 months (CSF 12 months; 0.175 ± 0.043, p = 0.004, urine; 5210.874 ± 1825.302, p = 0.043). The lactate:pyruvate ratio was increased in IIH participants compared with that in controls (CSF, controls 49.739 ± 19.523, IIH 113.114 ± 117.298, p = 0.023; serum, controls 38.187 ± 13.392, IIH 54.547 ± 18.471, p = 0.004) and decreased at 12 months (CSF, 113.114 ± 117.298, p < 0.001). Baseline acetate was higher in IIH participants (CSF, controls 0.128 ± 0.041, IIH 0.192 ± 0.151, p = 0.008), correlated with headache severity (p = 0.030) and headache disability (p = 0.003), and was reduced at 12 months (0.160 ± 0.060, p = 0.007). Ketones, 3-hydroxybutyrate and acetoacetate, were altered in the CSF at baseline in IIH participants (3-hydroxybutyrate, controls 0.074 ± 0.063, IIH 0.049 ± 0.055, p = 0.019; acetoacetate, controls 0.013 ± 0.007, IIH 0.017 ± 0.010, p = 0.013) and normalized at 12 months (0.112 ± 0.114, p = 0.019, 0.029 ± 0.017, p = 0.015, respectively). We observed metabolic disturbances that are evident in the CSF, serum, and urine of IIH participants, suggesting global metabolic dysregulation. Altered ketone body metabolites normalized after therapeutic weight loss. CSF:serum urea ratio was altered, which may influence ICP dynamics and headache. Elevated CSF acetate, known to stimulate trigeminal sensitization, was associated with headache morbidity. These alterations of metabolic pathways specific to IIH provide biological insight and warrant mechanistic evaluation. Registered on ClinicalTrials.gov, NCT02124486 (submitted April 22, 2014) and NCT02017444 (submitted December 16, 2013).

MCTR3 reprograms arthritic monocytes to upregulate Arginase-1 and exert pro-resolving and tissue-protective functions in experimental arthritis.

SummaryBackgroundRheumatoid arthritis (RA) is a progressive degenerative disorder that leads to joint destruction. Available treatments only target the inflammatory component with minimal impact on joint repair. We recently uncovered a previously unappreciated family of pro-resolving mediators, the maresin conjugate in tissue regeneration (MCTR), that display both immunoregulatory and tissue-protective activities. Thus, we queried whether the production of these autacoids is disrupted in RA patients and whether they can be useful in treating joint inflammation and promoting joint repair.MethodsUsing a highly phenotyped RA cohort we evaluated plasma MCTR concentrations and correlated these to clinical markers of disease activity. To evaluate the immunoregulatory and tissue reparative activities we employed both in vivo models of arthritis and organ culture models.FindingsHerein, we observed that plasma MCTR3 concentrations were negatively correlated with joint disease activity and severity in RA patients. Evaluation of the mechanisms engaged by this mediator in arthritic mice demonstrated that MCTR3 reprograms monocytes to confer enduring joint protective properties. Single cell transcriptomic profiling and flow cytometric evaluation of macrophages from mice treated with MCTR3-reprogrammed monocytes revealed a role for Arginase-1 (Arg-1) in mediating their joint reparative and pro-resolving activities. Arg-1 inhibition reversed both the anti-arthritic and tissue reparative actions of MCTR3-reprogrammed monocytes.InterpretationOur findings demonstrate that circulating MCTR3 levels are negatively correlated with disease in RA. When administered to mice in vivo, MCTR3 displayed both anti-inflammatory and joint reparative activities, protecting both cartilage and bone in murine arthritis. These activities were, at least in part, mediated via the reprogramming of mononuclear phagocyte responses.FundingThis work was supported by funding from the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation programme (grant no: 677542) and the Barts Charity (grant no: MGU0343) to J.D. J.D. is also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant 107613/Z/15/Z).

Oral cyclosporine is effective in stabilizing active vitiligo: Results of a randomized controlled trial.

Oral dexamethasone mini pulse (OMP) is an established treatment modality for active vitiligo. Cyclosporine may have therapeutic role in active vitiligo but current evidence supporting its role is scarce. The objective of study was to compare the efficacy and safety of oral cyclosporine with OMP in patients of active vitiligo. Fifty patients with active vitiligo were randomized into two groups of 25 patients. Group 1 was treated with OMP (2.5mg dexamethasone) on two consecutive days/week for 4months while group 2 was treated with cyclosporine (3mg/kg/day) for 4months. Laboratory monitoring was performed as per the prevalent protocol. The patients were followed up for another 2months after stopping treatment. Arrest of disease progression (ADP) was defined as change of vitiligo disease activity score from 4+ to 3+ (time elapsed since last disease activity being more than 6 weeks upto 3months) during the study period (6months). ADP was attained in 21 patients in group 1 and 22 patients in group 2 (84% vs. 88%, p=1.00) at the end of 6months. However, mean time to achieve ADP was significantly lower in group 2 as compared to group 1 (10.92 [4.12] weeks vs. 13.90 [3.92] weeks, p=0.01). Extent of repigmentation, improvement in patient assessment score, vitiligo quality of life and clinical markers of disease activity were marginal and comparable in both groups. Cyclosporine leads to earlier disease stabilization in active vitiligo as compared to OMP. Although considered a rescue drug in dermatology, low dose cyclosporine can be an effective therapeutic alternative in vitiligo patients.

Systemic Inflammatory Parameters in Patients with Elderly-Onset Rheumatoid Arthritis (EORA) and Young-Onset Rheumatoid Arthritis (YORA)-An Observational Study.

Background: Rheumatoid arthritis (RA) occurs more often in elderly individuals. Elderly onset RA (EORA) (onset > 60 years) encompasses a specific subset of patients if compared with young onset RA (YORA) (onset at a younger age). There is a need to define reliable, simple markers to properly assess the inflammatory activity of RA. Hematological markers of systemic inflammation (Platelet-To-Lymphocyte (PLR) and Neutrophil-To-Lymphocyte (NLR) ratios) are novel measures of the inflammatory response. The goal of the study was to analyze the course of EORA vs. YORA patients and to assess associations between systemic and clinical disease activity markers, including PLR and NLR, in different subsets of patients. PLR and NLR have not previously been assessed in EORA and YORA. Methods: The study group consisted of 113 consecutive patients (63 EORA and 50 YORA). The following assessments were performed: joint counts, Disease Activity Score (DAS28), complete blood cell counts, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP). Results: EORA was characterized by significantly higher disease activity markers (conventional inflammatory and clinical), a lower rate of remission or low disease activity, and less frequent use of biological drugs and glucocorticoids. The NLR and PLR were positively correlated with disease activity markers. The PLR was significantly lower in EORA compared with in YORA. Conclusion: EORA and YORA patients differed significantly. In EORA, conventional disease activity markers were higher, the PLR was significantly lower.

Crohn's Disease Activity Quantified by Iodine Density Obtained From Dual-Energy Computed Tomography Enterography.

The objective of this study was to assess if bowel wall iodine density obtained from dual-source, dual-energy computed tomography enterography (DECTE) could be a biomarker of Crohn's disease activity. Twenty-two patients with Crohn's disease imaged with DECTE from February 2016 to May 2018 were retrospectively identified by departmental report search. Iodine maps were created with commercial software (Syngovia). Iodine content was normalized to the aorta, and then manual dual-energy region-of-interest cursors were placed over the visibly assessed maximal and minimal iodine density within segments of involved as well as unaffected small bowel. The mixed Hounsfield unit value, maximum iodine density (Imax), and minimum iodine density (Imin) were recorded. The length of affected bowel demonstrating maximum disease activity as a percentage of overall involvement was subjectively assessed. A weighted iodine density (Iweighted) was calculated. The clinical assessment of disease activity using erythrocyte sedimentation rate, C-reactive protein, fecal calprotectin, colonoscopy/endoscopy, and surgery, if available, served as the reference standard. The Crohn's disease activity index was also used as a separate additional reference standard. Significant heterogeneity within the affected segments was present. The average Imax and Imin of affected bowel was 4.27 ± 1.11 (2.4-7.4) mg/mL and 2.71 ± 0.51 (2.2-3.9) mg/mL, respectively. Iodine density of normal-appearing small bowel was 1.40 ± 0.26 (0.9-1.9) mg/mL. The Imax and Imin of affected bowel differed significantly from normal bowel (P < 0.0001). Mixed Hounsfield unit (101.82 ± 27.5) also statistically differed (46.33 ± 19.62) (P < 0.0001). Using overall clinical assessment as the reference standard, all patients with Imin of greater than 2.6 mg/mL, Iweighted of greater than 3.3 mg/mL, or Imax of greater than 4.7 mg/mL had clinically active disease. Sixteen of 17 patients with Imin of greater than 2.2 mg/mL and 14/15 with Iweighted of greater than 3 mg/mL had clinically active disease. Using Crohn's disease activity index as the reference standard, all patients with Imin of greater than 2.7 mg/mL, Iweighted of greater than 3.6 mg/mL, or Imax of greater than 5.4 mg/mL had clinically active disease. The median effective dose was 4.64 ± 1.68 mSv (range, 2.03-8.12 mSv). Iodine density obtained from DECTE highlights regions of maximal activity within affected bowel segments. An iodine density of 2 mg/mL appears to be a threshold between normal bowel segments and those with active Crohn's disease. Iodine density measurement thresholds Imin of greater than 2.6 mg/mL, Iweighted of greater than 3.3 mg/mL, and Imax of greater than 4.7 mg/mL correlate with established clinical markers of disease activity, with Imin seemingly most useful in daily clinical practice.

Metformin to reduce metabolic complications and inflammation in patients on systemic glucocorticoid therapy: a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial

An urgent need to reduce the metabolic side-effects of glucocorticoid overexposure has been recognised, as glucocorticoid excess can lead to Cushing's syndrome, which is associated with high morbidity. We aimed to evaluate the potential of metformin to reverse such effects while sparing the anti-inflammatory benefits of glucocorticoids. We did a randomised, double-blind, placebo-controlled, proof-of-concept, phase 2 trial involving four hospitals in the UK. Patients without diabetes were eligible if they were between the ages of 18 and 75 years with an inflammatory disease treated with continuous prednisolone (≥20 mg/day for ≥4 weeks and remaining on ≥10 mg/day for the subsequent 12 weeks, or its cumulative dose-equivalent). Eligible patients were randomly allocated (1:1) to either the metformin or placebo groups, using a computer-generated randomisation table stratified according to age and BMI. Metformin and placebo were administered orally for 12 weeks in escalating doses: 850 mg/day for the first 5 days, 850 mg twice a day for the next 5 days, and 850 mg three times a day subsequently. The primary outcome was the between-group difference in visceral-to-subcutaneous fat area ratio over 12 weeks, assessed by CT. Secondary outcomes included changes in metabolic, bone, cardiovascular, and inflammatory parameters over 12 weeks. Our analysis followed a modified intention-to-treat principle for the primary outcome. This study is registered with ClinicalTrials.gov, NCT01319994. Between July 17, 2012, and Jan 14, 2014, 849 patients were assessed for study eligibility, of which 53 were randomly assigned to receive either metformin (n=26) or placebo (n=27) for 12 weeks. 19 patients in the metformin group and 21 in the placebo group were eligible for the primary outcome analysis. Both groups received an equivalent cumulative dose of glucocorticoids (1860 mg prednisolone-equivalent [IQR 1060-2810] in the metformin group vs 1770 mg [1020-2356] in the placebo group); p=0·76). No change in the visceral-to-subcutaneous fat area ratio between the treatment groups was observed (0·11, 95% CI -0·02 to 0·24; p=0·09), but patients in the metformin group lost truncal subcutaneous fat compared with the placebo group (-3835 mm2, 95% CI -6781 to -888; p=0·01). Improvements in markers of carbohydrate, lipid, liver, and bone metabolism were observed in the metformin group compared with the placebo group. Additionally, those in the metformin group had improved fibrinolysis, carotid intima-media thickness, inflammatory parameters, and clinical markers of disease activity. The frequency of pneumonia (one event in the metformin group vs seven in the placebo group; p=0·01), overall rate of moderate-to-severe infections (two vs 11; p=0·001), and all-cause hospital admissions due to adverse events (one vs nine; p=0·001) were lower in the metformin group than in the placebo group. Patients in the metformin group had more events of diarrhoea than the placebo group (18 events vs eight; p=0·01). No significant changes in the visceral-to-subcutaneous fat area ratio between the treatment groups were observed; however, metformin administration did improve some of the metabolic profile and clinical outcomes for glucocorticoid-treated patients with inflammatory disease, which warrants further investigation. Barts Charity and Merck Serono.

Activated T-Follicular Helper 2 Cells Are Associated With Disease Activity in IgG4-Related Sclerosing Cholangitis and Pancreatitis.

OBJECTIVES:Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) and autoimmune pancreatitis (AIP) are characterized by an abundance of circulating and tissue IgG4-positive plasma cells. T-follicular helper (Tfh) cells are necessary for B-cell differentiation into plasma cells. We aimed at elucidating the presence and phenotype of Tfh cells and their relationship with disease activity in IgG4-SC/AIP.METHODS:Circulating Tfh-cell subsets were characterized by multiparametric flow cytometry in IgG4-SC/AIP (n = 18), disease controls with primary sclerosing cholangitis (n = 8), and healthy controls (HCs, n = 9). Tissue Tfh cells were characterized in IgG4-SC/AIP (n = 12) and disease control (n = 10) specimens. Activated PD1+ Tfh cells were cocultured with CD27+ memory B cells to assess their capacity to support B-cell differentiation. Disease activity was assessed using the IgG4–responder index and clinical parameters.RESULTS:Activated circulating PD-1+CXCR5+ Tfh cells were expanded in active vs inactive IgG4-SC/AIP, primary sclerosing cholangitis, and HC (P < 0.01), with enhanced PD-1 expression on all Tfh-cell subsets (Tfh1, P = 0.003; Tfh2, P = 0.0006; Th17, P = 0.003). Expansion of CD27+CD38+CD19lo plasmablasts in active disease vs HC (P = 0.01) correlated with the PD-1+ Tfh2 subset (r = 0.69, P = 0.03). Increased IL-4 and IL-21 cytokine production from stimulated cells of IgG4-SC/AIP, important in IgG4 class switch and proliferation, correlated with PD-1+ Tfh2 (r = 0.89, P = 0.02) and PD-1+ Tfh17 (r = 0.83, P = 0.03) subsets. Coculture of PD1+ Tfh with CD27+ B cells induced higher IgG4 expression than with PD1− Tfh (P = 0.008). PD-1+ Tfh2 cells were strongly associated with clinical markers of disease activity: sIgG4 (r = 0.70, P = 0.002), sIgE (r = 0.66, P = 0.006), and IgG4–responder index (r = 0.60, P = 0.006). Activated CXCR5+ Tfh cells homed to lymphoid follicles in IgG4-SC/AIP tissues.CONCLUSIONS:Circulating and tissue-activated Tfh cells are expanded in IgG4-SC/AIP, correlate with disease activity, and can drive class switch and proliferation of IgG4-committed B cells. PD1+ Tfh2 cells may be a biomarker of active disease and a potential target for immunotherapy.

P551 Use of preoperative total parenteral nutrition is associated with clinical and laboratory remission in severe active Crohn’s disease

Crohn’s disease (CD) patients with active penetrating and stricturing disease have a high prevalence of malnutrition that has been shown to increase post-operative complications. The effect of 1–3 months of pre-operative exclusive total parental nutrition (TPN) in active CD patients is not well established. We investigated the efficacy of exclusive TPN in active CD patients. From our IBD Centre database (prospectively collected data) we identified all patients with complicated, active CD who were candidates for bowel resection between January 2016 and October 2018. CD location and activity were recorded based on the modified Montreal classification. Inclusion required exclusive preoperative home TPN without additional oral intake for the 1–3 months prior to surgery. The Harvey–Bradshaw Index (HBI), body mass index (BMI), C-reactive protein (CRP) and albumin levels were recorded at baseline and at the end of TPN therapy. Seventeen pre-operative CD patients (58.8% male, 41.2% female) on exclusive TPN were identified. The mean age of the cohort was 31.5 ± 11.8 years with median disease duration of 8 years (IQR 3–12). Mean duration of pre-operative TPN treatment was 69 days (range 24–110). Most patients had ileocolonic (35.3%) or terminal ileal CD (23.5%), and the stricturing and/or stenotic (B2) phenotype (94.1%) was the most common. During TPN treatment, 70.6% were on stable doses of medication (immunomodulators and/or biologics) and 29.4% had no medical treatment. All 17 patients had significant clinical improvement in all disease activity indices at the end of preoperative TPN (baseline vs. post TPN): HBI 16.3 ± 7 vs. 6.1 ± 6.1 (p = 0.001); BMI 19.7 ± 3.3 vs. 20.8 ± 3.2 (p = 0.017); CRP 58.5 (IQR 33–149) vs. 12.5 (IQR 6–30) (p = 0.001); and albumin 2.8 ± 0.6 vs. 3.7 ± 0.5 (p = 0.001). Two patients (11.7%) no longer required bowel resections after completion of exclusive TPN. Exclusive pre-operative TPN was associated with weight gain, decreased inflammatory biomarkers, and improved clinical disease activity markers and nutrition. While these initial results are encouraging, additional studies are needed before a recommendation can be made regarding longer duration of exclusive pre-operative TPN for severe, refractory CD to decrease disease activity and improve nutritional status before elective surgery.

Identification and clinical role of choroidal neovascularization characteristics based on optical coherence tomography angiography.

To suggest a novel classification of neovascular age-related macular degeneration (AMD) based on optical coherence tomography angiography (OCTA) and to correlate morphological characteristics based on optical coherence tomography (OCT)/OCTA with clinical criteria of disease activity. A total of 88 eyes with neovascular AMD (14 treatment-naïve, 74 eyes following anti-vascular endothelial growth factor treatment (VEGF)) were examined using the AngioVue OCTA system (Optovue, Inc., Fremont, CA, USA) and evaluated based on vascular morphology. Choroidal neovascularization (CNV)-vessel morphology based on OCTA and associations with retinal layers were described and correlated with clinical markers of disease activity. In treatment-naïve CNV, CNV-vessel morphology based on OCTA showed a dense-net configuration (DN) in 12 of 14 eyes, a loose-net configuration (LN) in one of 14 eyes and an unidentifiable CNV pattern in one of 14 eyes, whereas in treated CNV, DN was registered in 43.2% (32/74), LN in 27% (20/74), DN with additional LN (mixed type) in 14.9% (11/74) and an unidentifiable CNV pattern in 14.9% (11/74). Clinical correlations revealed a significantly longer disease duration for LN with a median value of 4.3years compared to DN with 2.0years (p=0.009) and for CNV involving the outer retina with 3.1years compared to CNV not involving the outer retina with 1.9years (p=0.051). Optical coherence tomography angiography (OCTA) allows identification of distinct CNV-specific vascular patterns at the level of the outer retinal layer and choriocapillaris. Correlation with clinical and functional parameters may be useful to better understand pathophysiological mechanisms and guide efficient therapeutic strategies.

Validation of a phospholipase A2 receptor antibody ELISA in an Australian cohort with membranous glomerulonephritis

A commercial PLA2R Ab ELISA was validated by examining its ability to distinguish primary from secondary membranous nephropathy, correlating results with clinical markers of disease activity, and comparing its performance with an indirect immunofluorescence test (IIFT). PLA2R Ab levels were measured in 77 patients with biopsy proven membranous nephropathy, divided into either idiopathic (n=61) or secondary groups (n=6). In the idiopathic group, measures of contemporaneous disease activity (proteinuria, serum creatinine) were compared between seropositive and seronegative subjects. ELISA values were then compared with semi-quantitative results from an IIFT using PLA2R transfected HEK293 cells as substrate. The PLA2R Ab ELISA was positive in only 15 of 61 (25%) patients with idiopathic membranous nephropathy (IMN), but there was a significant negative relationship with time since diagnosis. Thus, in a subgroup of patients diagnosed within 6 months of analysis, the sensitivity was 6/15 (55%), rising to 6/8 (75%) in those recently-diagnosed patients who had not been treated. In the entire cohort, there was a significant positive correlation between ELISA values and degree of proteinuria, but our analysis did not control for variation of both variables with time. The PLA2R Ab ELISA also showed very high agreement with IIFT (96%). Therefore, the PLA2R Ab ELISA is a highly specific test for distinguishing primary from secondary membranous nephropathy that is most sensitive in newly diagnosed patients who have not received immunosuppression. Antibody levels correlated with degree of proteinuria, but this relationship was not shown to be independent of time. Both IIFT and ELISA platforms performed comparably.

Serum carcinoembryonic antigen (CEA) as a clinical marker in acquired idiopathic generalized anhidrosis: a close correlation between serum CEA level and disease activity

Hypohidrosis/anhidrosis are congenital or acquired sweating impairments. Among them, acquired idiopathic generalized anhidrosis/hypohidrosis (AIGA) is the most common, and characterized by favourable response to systemic corticosteroid, however, no clinical markers for disease severity or activity have been developed. Our aim was to verify the usefulness of serum carcinoembryonic antigen (CEA) level monitoring as a clinical marker for disease activity of AIGA. Ten cases of AIGA diagnosed at Asahikawa Medical University, from 1980 to 2014 were included in the study. CEA and/or CEACAM1 expression level was analysed using immunohistochemistry and enzyme-linked immunosorbent assay. CEA expression was restricted to the apical membrane of glandular cells in eccrine sweat glands in most of the three types of cases we examined [healthy control, patients with atopic dermatitis (AD) or urticaria]. However, CEA expression was detected diffusely and much more intensively in eight of the 10 AIGA cases included in this study. CEACAM1-expression was much more restricted on the apical membrane of glandular cells of both the AIGA cases and the other control subjects. While serum CEA levels increased in all five AIGA cases examined (5.8-43.2 ng/mL), it remained within normal limits in all control subjects: nine healthy individuals; 10 cases of AD; 10 cases of idiopathic urticaria; four cases of normohidrotic cholinergic urticaria (Mann-Whitney's U-test, P < 0.05). The increased serum CEA levels in AIGA decreased in conjunction with improved sweating during methyl prednisolone pulse therapy or repeated bathing. Serum CEA level may serve as a clinical marker for AIGA activity.

PTU-071 Impact of body mass index (BMI) upon anti-tnf trough and anti-drug antibody levels

<h3>Introduction</h3> The anti-tumour necrosis factor (TNF) agents, infliximab and adalimumab, are effective in treating inflammatory bowel diseases (IBD). Response is better in patients with detectable levels of circulating drug prior to the next administration (trough level). Some patients fail to respond to these drugs initially or lose response over time. Factors which influence loss of response are poorly defined but body mass index (BMI), prior surgery and smoking status have been reported to influence outcomes. In particular, BMI adversely affect outcomes with both infliximab and adalimumab, but the relationship of BMI to trough levels has not been reported previously. <h3>Method</h3> We conducted a single centre prospective cross-sectional study. All IBD patients treated with infliximab or adalimumab were eligible. Trough levels and anti-drug antibodies were obtained concurrently with routine clinical data, clinical markers of disease activity, faecal calprotectin (FC), C-reactive protein (CRP) and BMI. Variables including BMI that may predict trough levels and anti-drug antibodies were then assessed. Therapeutic infliximab was defined as trough level &gt;2 mcg/ml (need units and adalimumab as &gt;5.5 microgram/ml. <h3>Results</h3> 87 patients were included in the study; 69 had CD (44 IFX, 25 ADA) and 18 had UC (9 each on IFX and ADA). Of the total cohort, 12 had undetectable trough levels (&lt;0.1) and 22 had supra-therapeutic levels (&gt;8). A higher percentage of patients with undetectable trough levels were on infliximab (92% vs 8%, p &lt; 0.01). Supra-therapeutic levels were noted in 55% and 45% of infliximab and adalimumab patients respectively. In the infliximab group, the median BMI was 24.9 (range 17.23–42.28), and 26 had aBMI &gt;25 (49%). For adalimumab the median BMI was 22.92 (range 16.14–37.64), and 13 had a BMI &gt;25 (38%). Those with sub-therapeutic trough levels had a higher BMI, which is most prominent in the adalimumab group. Patients with sub-therapeutic levels of infliximab had a median BMI of 25.3 (IQR: 22.6–30.5) compared to those with therapeutic levels 23.8 (IQR: 19.9–29.6). For adalimumab the median BMI was 22.8 (IQR: 20.5–25.6) in therapeutic and 27.4 (IQR: 21.9–32.9) in the sub-therapeutic group but this did not reach statistical significance. <h3>Conclusion</h3> There does appear to be a correlation between BMI and trough levels, particularly in patients receiving adalimumab. Therefore trough level measurement and dose adjustment, particularly in those taking adalimumab with a BMI &gt;25, should be considered to optimise therapy and clinical outcomes. <h3>Disclosure of interest</h3> None Declared.

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

IntroductionThis study was performed to develop ultrasound composite scores for the assessment of inflammatory and structural lesions in Psoriatic Arthritis (PsA).MethodsWe 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.ResultsThe 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.ConclusionBoth new PsA ultrasound composite scores (PsASon22 and PsASon13) revealed sufficient convergent construct validity, sensitivity to change, reliability and feasibility.Electronic supplementary materialThe online version of this article (doi:10.1186/s13075-014-0476-2) contains supplementary material, which is available to authorized users.

Correlation between clinical signs and optical coherence tomography with enhanced depth imaging findings in patients with birdshot chorioretinopathy.

Birdshot chorioretinopathy (BCR) is a bilateral posterior uveitis that typically requires aggressive therapy to prevent loss of vision. Clinical signs of disease activity may be subtle and visual acuity is often preserved despite significant loss of visual function. Optical coherence tomography with enhanced depth imaging (OCT-EDI), a new technology that allows visualization of structures posterior to the retinal pigment epithelium, may be a useful tool to monitor disease activity in these patients. To determine the correlation between symptoms and signs of disease activity in BCR and specific findings on OCT-EDI. Retrospective medical record review of 14 patients treated for BCR in the uveitis clinic at Northwestern University. All patients underwent OCT-EDI (58 scans). Clinical symptoms of photopsias/vibrating vision and signs of macular edema, vitreous haze, and retinal vasculitis were graded; a second grading scale was developed for the evaluation of OCT-EDI. Individual scans of each eye of each patient at each point were graded in a masked fashion. Optical coherence tomography with EDI in BCR. Spearman rank correlation of clinical measures to OCT-EDI measures. The most frequent score in each clinical category was 0 (inactive). In those BCR patients with symptoms (21 eye examinations), the subjective complaint of photopsias/vibrating vision was associated with the objective finding of suprachoroidal fluid on OCT-EDI (P = .003), and the frequency and severity of photopsias correlated with the thickness of the fluid band (Pearson product moment correlation, 0.39). Two of the clinical markers of disease activity measured in this study (vasculitis and vitreous haze) also showed a significant Spearman rank correlation with the presence and amount of suprachoroidal fluid on OCT-EDI (vasculitis, 0.45 [P < .001]; vitreous haze, 0.59 [P < .001]). The presence of suprachoroidal fluid on OCT-EDI appears to correlate with the subjective complaints of photopsias in patients with BCR and other more easily assessed clinical features such as vasculitis and vitreous haze. Optical coherence tomography with EDI may be a useful tool for objective monitoring of BCR.

Prognostic Significance Of Parameters Of Dynamic Contrast-Enhanced MRI Detecting Increased Bone Marrow Microcirculation In Monoclonal Plasma Cell Disorders

IntroductionDynamic contrast enhanced magnetic resonance imaging (DCE-MRI) is a non-invasive imaging technique allowing the detection of changes in local microcirculation reflecting increased angiogenesis. DCE-MRI parameters Amplitude A (reflecting blood volume) and exchange rate constant kep (reflecting vascular permeability) are increased in bone marrow exams of patients with active multiple myeloma (MM) compared to healthy controls. In the current prospective study we analyzed the prognostic significance of the DCE-MRI parameters in 289 patients with monoclonal plasma cell disorders and 33 healthy controls. MethodsThe patient group consisted of 68 individuals with monoclonal gammopathy of undetermined significance (MGUS), 90 patients with smoldering MM (sMM) and 131 patients with symptomatic MM according to IMWG criteria. All patients and controls underwent standardized DCE-MRI with high temporal resolution (T1w-turboFLASH) of the lumbar spine (symptomatic patients before start of therapy). Regions of interest were drawn manually on T1-weighted images encompassing the bone marrow of each of the 5 lumbar vertebrae sparing the vertebral vessel. Values of the DCE-MRI parameters of the 5 lumbar vertebrae were summarized per patient in median values. Log transformation was used for median kep values. ResultsSignificant differences in Amplitude A were found between sMM and controls (P=0.004), sMM and MGUS (P=0.01), and MM and all other groups (P<0.001 respectively). For exchange rate constant kep differences were significant between sMM and controls (P=0.01), sMM and MGUS (P=0.01) and MM and all other groups (P<0.001 respectively). P-values were adjusted for multiple testing by Holm's method. Comparison of DCE-MRI- and clinical parameters revealed a significant positive correlation of Amplitude A with beta2-microglobulin (P<0.001), high risk cytogenetics (P=0.009), immunoparesis (P<0.001) and a negative correlation with albumin, hemoglobin and age (P<0.001, respectively). For exchange rate constant kep the following significant correlation were found: positive correlation with beta2-microglobulin (P<0.001), LDH (P=0.03), immunoparesis (P<0.001) and negative correlation with albumin (P=0.03), hemoglobin (P<0.001) and age (P=0.03). Application of univariate and multivariate Cox models revealed a significant prognostic impact for median of DCE-MRI parameter Amplitude A for progression free survival of patients with MGUS (univariate P=0.02), sMM (univariate P=0.002; multivariate P=0.03) and for overall survival of MM patients (multivariate P=0.05). Log transformed arameter kep showed prognostic significance for PFS of MM patients (univariate P=0.04). The multivariate Cox model was adjusted for the following additional factors: plasma cells in bone marrow, M-Protein, IgG-subtype, presence of immunoparesis and age. M-protein (P=0.004), age (P=0.03) and a non-IgG-type (P=0.006) also were revealed as significant prognostic factors. ConclusionDCE-MRI is a non-invasive imaging tool delivering parameters on bone marrow microcirculation which are correlated to clinical markers of disease activity as well stage of disease. In all groups of patients especially DCE-MRI parameter Amplitude A is of significant prognostic value for progression free and in symptomatic patients also for overall survival. Disclosures:No relevant conflicts of interest to declare.

Long term cholesterol lowering therapy does not interfere with clinical response to anti CD20 therapy in patients with rheumatoid arthritis

Objective: Cholesterol lowering therapy was reported to inhibit rituximab (RTX) clinical efficacy in lymphoma and rheumatoid arthritis (RA). For a short period of treatment (6 months), this effect has not been proved. The objective of our study was to asses if long term cholesterol lowering therapy with statins, which may influence long time (18 months) clinical response in patients with RA treated with RTX. Methods: Starting from February 2010, all patients initiating RTX treatment in Sfanta Maria Hospital, Bucharest, were included in this prospective cohort study (total number 82). All patients had high disease activity RA, failure to at least one anti TNF and consecutively switched to anti CD20 therapy with RTX associated with Disease Modifying Antirheumatic Drugs (DMARD) (i.e. methotrexat, sulfasalasine, hidroxichloroquine). RTX was administered intravenously as two 1 g infusions given with standardized premedication, separated by an interval of two weeks. Biological tests [i.e. erythrocyte sedimentation rate (ESR), C reactive protein (CRP)], clinical disease activity markers (i.e. number of swollen and tender joints) and composite scores [i.e. Disease Activity Score based on 28 joints counts (DAS28) visual analogue scale, and European League Against Rheumatism (EULAR) response criteria] were provided at every 3 months. Total cholesterol level and statin treatment were monitored. The statin treatment was initiated according to national guideline. For the final analysis, we excluded patients that discontinued statin treatment or had associated statin after RTX was initiated. Results: 45 patients fulfilled criteria for the final analysis: 20 patients had statin associated to RTX. DAS 28 scores, CRP levels and ESR levels of both groups were similar at baseline. Patients exposed to statins were significantly older than unexposed patients (p = 0.017). Clinical outcome was evaluated using DAS28 and EULAR response, both measured at 6, 12 and 18 months. A tendency of increasing in DAS28 score was observed in the statin-exposed group, but statistical tests (Student t-test) showed no significant difference for DAS28 score on follow up, with p values N0.05 (at 6 months p = 0.777, at 12 months p = 0.303 and at 18 months p = 0.136). The statin-exposed status was negatively correlated to EULAR response at 6 months (r =−0.073, p = 0.661) and 18 months (r =−0.197, p = 0.244), but the correlation was very weak and with no statistical significance. Conclusions: Even though cholesterol depletion may influence the integrity of lipid rafts in the cell membrane, consecutively inhibiting hypercrosslinking of CD20 molecules with RTX, long term inhibitory effects of statins on RTX treatment in RA patients have not been proven. As far as we know, long term impact has not previously been studied. More studies are required regarding this possibility.

AB1471-HPR The reliability and validity of a novel MRI-based tool for the evaluation of forefoot bursae in patients with rheumatoid arthritis: The “FFB-score”

BackgroundWe recently demonstrated forefoot bursae (FFB) are a clinically important feature in patients with rheumatoid arthritis (RA)1. However, there is a need for an observer-independent, reliable and valid method of...

SAT0412 Prediction of erosive disease in rheumatoid arthritis: Utility of ultrasound joint score in patients with a short disease duration

BackgroundTo optimize therapy in rheumatoid arthritis (RA) patients (pts), it would be beneficial to identify those pts who are going to suffer joint damage before X-ray - erosions occur, to...