Laboratory Measures Of Disease Activity Research Articles

Assessment of disease activity using a whole-body MRI derived radiological activity index in chronic nonbacterial osteomyelitis

BackgroundBased on the recently developed ChRonic nonbacterial Osteomyelitis MRI Scoring tool (CROMRIS), we developed a radiological activity index (RAI-CROMRIS) to obtain a quantification of the overall bone involvement in individual patients.MethodsWhole Body Magnetic Resonance Imaging (WB-MRI) images were scored according to parameters included in the RAI-CROMRIS: bone marrow hyperintensity, signal extension, soft tissue/periosteal hyperintensity, bony expansion, vertebral collapse. These parameters were evaluated for each bone unit yielding a score from 0 to 7 and summed up as RAI-CROMRIS including all bone units. We assessed clinical disease activity using a physician global assessment (PGA) and radiological findings in 76 treatment-naïve patients; 46 of 76 were evaluated at 6 and 12 months after initial WB-MRI. Quantitative variables were compared using the Mann-Whitney U test for unmatched groups and the Wilcoxon signed-rank test for paired groups. Correlation was evaluated using Spearman’s rank coefficient (rs).ResultsThere was a significant correlation between RAI-CROMRIS and PGA (rs = 0.32; p = 0.0055), between RAI-CROMRIS and presence of elevated erythrocyte sedimentation rate (p = 0.013) and C-reactive protein (p = 0.0001) at baseline. The RAI-CROMRIS decreased from a median of 17 at baseline to 12 at 6 months (p = 0.004) and remained stable (median 11) at 12 months. A correlation between the RAI-CROMRIS and the PGA was observed at baseline (rs = 0.41; p = 0.004) and during follow up at 6 months (rs = 0.33; p = 0.025) and 12 months (rs = 0.38; p = 0.010). The baseline RAI-CROMRIS (median 20) was significantly higher in patients who subsequently received bisphosphonates than in patients who received other treatments (median 12) and decreased significantly after bisphosphonates (p = 0.008).ConclusionsThe RAI-CROMRIS was correlated with clinical and laboratory measures of disease activity showing significant short-term changes following treatment with bisphosphonates. This tool could be used in clinical practice and clinical trials after validation.

OP0161 ASSOCIATION OF BASELINE CYTOTOXIC GENE EXPRESSION WITH USTEKINUMAB RESPONSE IN SYSTEMIC LUPUS ERYTHEMATOSUS

Background:Systemic Lupus Erythematous (SLE) is a clinically and biologically diverse disease, for which only one new therapy has been approved in the past 60 years. In a phase 2 trial on patients with mild-to-moderate SLE, ustekinumab (UST) improved clinical and laboratory measures of disease activity compared with placebo (PBO).1Objectives:We previously reported an association of IFN-γ reduction with response to UST,2suggesting an impact on the IL12/Th1 axis. To extend these findings, we performed unbiased transcriptomic analysis from baseline whole blood samples to identify genes that discriminate UST responders (UST-R) from non-responders (UST-NR) using the primary endpoint of Systemic Lupus Erythematosus Responder Index (SRI)-4 at week 24 to define response.Methods:UST was studied in a Ph2 PBO-controlled study of 102 patients with seropositive SLE and active disease despite standard therapy. Patients were randomized 3:2 to receive IV UST 6 mg/kg or placebo followed by subcutaneous injections of UST 90 mg or PBO every 8 weeks. Whole blood gene expression at baseline was measured via microarray using RNA samples from 100 patients, as samples from 2 patients failed quality control. An unbiased approach was used to identify gene signatures present at baseline that associate with UST response. Recombinant IL-12 or IL-23 was incubatedin vitrowith whole blood from 6 healthy donors for 24h and RNA-Seq was performed to determine the effect of these treatments on representative genes comprising the UST response signature.Results:A non-biased machine learning algorithm identified a 9-gene whole blood signature composed primarily of cytotoxic cell-associated transcripts (PRF1, KLRD1, GZMH, NKG7, GNLY, FGFBP2, TRGC2, TARP, TRGV2) that was enriched at baseline in UST-R vs UST-NR. By Gene Set Variation Analysis, the cytotoxic signature enrichment in UST-NR was less at baseline than both UST-R and a healthy control cohort (P=0.0087, P=0.056, respectively), whereas UST-R cytotoxic gene enrichment was similar to healthy controls (P=0.31). No significant difference in cytotoxic signature enrichment was observed at baseline between PBO responders and PBO non-responders or healthy controls (Figure). Enrichment levels of the cytotoxic gene signature remained stable over time in PBO and UST-NR groups while a trend of decreased cytotoxic signature was observed in UST-R, although never reaching levels seen in UST-NR. To begin to understand the relationship between IL-12 and IL-23, the targets of UST, and the cytotoxic signature, whole blood was stimulated with these cytokinesin vitro. Recombinant IL-12, but not IL-23, resulted in increased expression of representative members of this cytotoxic gene signature.Conclusion:We identified a novel cytotoxic signature in baseline blood samples that associated with UST response in SLE. The observation that IL-12 can increase this signaturein vitroand that IL-12 is a robust inducer of cytotoxic cell activity3as well as IFN-γ3suggests an important role of IL-12 blockade in the mechanism of action of UST in SLE.

Number of individual ACPA reactivities in synovial fluid immune complexes, but not serum anti-CCP2 levels, associate with inflammation and joint destruction in rheumatoid arthritis

IntroductionIndividual patients with rheumatoid arthritis (RA) show divergent specific anti-citrullinated protein/peptide antibodies (ACPA) patterns, but hitherto no individual ACPA specificity has consistently been linked to RA pathogenesis. ACPA are also...

EFFICACY OF ADALIMUMAB IN EARLY RHEUMATOID ARTHRITIS IN RELATION TO ITS SERUM LEVEL AND THE PRESENCE OF ANTI-DRUG ANTIBODY

Objective: to assess the relationship of the efficiency of adalimumab (ADA) therapy in early rheumatoid arthritis (RA) with the serum level of the drug and with the presence of antibody (Ab) to it. Subjects and methods. Serum concentration of ADA and Ab against it (μg/ml) were measured using an enzyme immunoassay in 25 patients with early RA before, 12 and 24 weeks after beginning of the therapy. All patients received the disease-modifying antirheumatic drug methotrexate and ADA 40 mg subcutaneously every other week. ADA was the first biological agent for all patients. Results . The patients were divided into the following groups: those with a serum ADA level of <2.85 (Group 1, n=7) and ≥2.85 (Group 2, n=13). After 24 weeks of treatment, Group 1 showed higher disease activity (DAS was 4.5 [3.3; 4.9]) and levels of acute-phase reactants (ESR, 44 [18; 57] mm/hr; C-reactive protein (CRP), 10.1 [4.9; 34.5] mg/ml) than Group 2 (3.5 [2.9; 3.9], 15.0 [6.0; 17.0] mm/hr, 1.9 [0.75; 6.7] mg/ml, respectively; p<0.05). Also, after 24 weeks of therapy, there was a negative correlation of ADA level and DAS28 (r=-0.46; p=0.04), CRP (r=-0.54;p=0.02) and ESR (r=-0.5; p=0.02). Anti-ADA Ab were found in 3 and 2 patients after 12 and 24 weeks, respectively. After 24 weeks of therapy, all patients with anti-ADA Ab exhibited no clinical effect. There were few unresponsive patients (11%) among those without anti-ADA Ab. Conclusion. In patients with early RA treated with ADA, its low serum level (<2.85 μg/ml) is associated with the higher clinical and laboratory measures of disease activity. After 12–24 weeks of ADA therapy, 10–12.5% of patients are found to have Ab to the drug and its production is associated with lower efficacy.

AB0620 B lymphocyte stimulator(BLYS) levels are higher in younger caucasian patients with SLE

BackgroundElevated levels of B Lymphocyte Stimulator(BLyS) play an important role in the pathogenesis of Systemic Lupus Erythematosus. Although anti BLyS-targeted therapies have shown promise in the treatment of SLE, results...

Validation of the Ulcerative Colitis Colonoscopic Index of Severity and Its Correlation With Disease Activity Measures

Endoscopic healing is likely to become an important goal for treatment of patients with ulcerative colitis (UC). A simple validated endoscopic index is needed. We validated the previously developed UC Colonoscopic Index of Severity (UCCIS). In a prospective study, 50 patients with UC were examined by colonoscopy; we analyzed videos of rectum and sigmoid, descending, transverse, and cecum/ascending colon. Eight gastroenterologists blindly rated 4 mucosal lesions (for vascular pattern, granularity, friability, ulceration) and severity of damage to each segment and overall. The global assessment of endoscopic severity (GAES) was based on a 4-point scale and 10-cm visual analogue scale. Correlation of the UCCIS score with clinical indexes (clinical activity index and simple clinical colitis activity index), patient-defined remission, and laboratory measures of disease activity (levels of C-reactive protein, albumin, and hemoglobin and platelet counts) were estimated by using the Pearson (r) or Spearman (r(s)) method. Interobserver agreement was good to excellent for the 4 mucosal lesions evaluated by endoscopy and the GAES. The UCCIS calculated for our data accounted for 74% (R(2) = 0.74) and 80% (R(2) = 0.80) of the variation in the GAES and visual analogue scores, respectively (P < .0001). The UCCIS also correlated with clinical activity index (r = 0.52, P < .001), simple clinical colitis activity index (r = 0.62, P < .0001), and patient-defined remission (r = 0.43, P < .01). The UCCIS also correlated with levels of C-reactive protein (r(s) = 0.56, P < .001), albumin (r = -0.55, P < .001), and hemoglobin (r = -0.39, P < .01). A rederivation of the equation for the UCCIS by using the data from a previous study combined with those of the current study (n = 101) yielded similar results. The UCCIS is a simple tool that provides reproducible results in endoscopic scoring of patients with UC.

Validation of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and Its Correlation With Clinical Indices and Laboratory Measures of Disease Activity

Validation of the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and Its Correlation With Clinical Indices and Laboratory Measures of Disease Activity Sunil Samuel, Edward V. Loftus, David H. Bruining, Kelvin T. Thia, William J. Tremaine, Kenneth W. Schroeder, William A. Faubion, Sunanda V. Kane, Darrell S. Pardi, Piet C. de Groen, William S. Harmsen, Alan R. Zinsmeister, William J. Sandborn

Potential Effect of Anti-Tumour Necrosis Factor-Alpha Treatment on Reducing the Cardiovascular Risk Related to Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects about 1% of the adult population. RA sufferers not only have a high chronic disease burden, but may also experience increased cardiovascular disease (CVD) and mortality as the prevalence of myocardial infarction (MI) is 4 times higher in RA patients than in general population, and there is ample evidence showing that coagulation processes are active in RA. Fibrin accumulation in the synovium is one of the most striking pathological features of rheumatoid synovitis and characteristic RA antibodies such as anti-citrullinated protein antibodies (ACPA) can cross-react with epitopes exposed on fibrin and fibrinogen molecules, and thus impair fibrinolysis. The inflammation, coagulation and fibrinolytic systems are modulated by a common mechanism that includes the involvement of proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). It has long been recognised that extensive cross-talk takes place between the coagulation pathway and the inflammatory process at various levels, and there is growing evidence that this interaction may be relevant to arthritis. Large-scale, long-term studies have shown that anti-TNF-alpha treatment improves the clinical and laboratory measures of disease activity, and reduces local and systemic inflammation. TNF-alpha blockade may therefore also reduce the impaired coagulation and cardiovascular risk associated with RA. This review provides an overview of the pathophysiological role of TNF-alpha in thrombotic mechanisms and the evidence so far available indicating that anti-TNF-alpha treatment can modify cardiovascular risk in RA.

Significance of magnetic resonance imaging for early rheumatoid arthritis activity

Система комплексной поддержки и сопровождения научного журнала Elpub позволяет запустить двуязычный сайт журнала со встроенной системой электронной редакции в соответствии с лучшими издательскими практиками, а так же предусматривает техническую и методическую поддержку со стороны специалистов НЭИКОН.

Occurrence and correlates of fatigue in psoriatic arthritis

Objective:To determine the relationship between fatigue and disease-related and psychosocial variables in psoriatic arthritis (PsA).Method:499 patients attending the University of Toronto PsA Clinic were administered the modified fatigue severity scale...

Reduction in Tγδcell numbers and alteration in subset distribution in systemic lupus erythematosus

We have studied the distribution of T gamma delta cells in the peripheral blood of 35 patients with systemic lupus erythematosus (SLE) and 36 age-matched controls. The monoclonal antibodies A13, BB3 and Ti gamma A, which are specific for the V delta 1, V delta 2 and V delta 9 gene products respectively, were used to define T gamma delta cell subsets. A significantly lower frequency of T gamma delta cells was found in peripheral blood lymphocytes of SLE patients compared with normal subjects (3.2% versus 5.9%). There was a marked reduction in the V delta 2+ subset of T gamma delta cells, which resulted in a reversal of the ratio of V delta 2+/V delta 1+ cells from 4.34 to 0.56. No correlation was found with either clinical or laboratory measures of disease activity. These results suggest that the observed changed in T gamma delta subset distribution are related to the SLE itself, and not secondary to changes in disease activity.

Serum pro-matrix metalloproteinase-3 as an indicator of disease activity and severity in rheumatoid arthritis: comparison with traditional markers

Matrix metalloproteinase-3 (MMP-3) production increases in rheumatoid arthritis (RA) and has been proposed as a marker of disease activity and joint damage. The aim of this cross-sectional study is to examine the usefulness of serum proMMP-3 as an indicator of disease activity and severity in comparison with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). Serum proMMP-3 was measured by a quantitative ELISA in 85 RA patients and 70 healthy subjects. Clinical and laboratory measures of disease activity and severity were obtained. Radiological joint damage was assessed by the method of Larsen. Serum proMMP-3 was significantly higher in RA patients than that in the healthy subjects. The active RA patients had significantly higher serum proMMP-3 than the inactive patients. Serum proMMP-3 was significantly correlated with some parameters of disease activity including swollen joints count, proximal interphalangeal joint score, morning stiffness, and Health Assessment Questionnaire; however, ESR and serum CRP were better correlated with all indicators of the disease activity than proMMP-3. The analysis of receiver operating characteristic supported that ESR and CRP had higher performance for reflection of activity compared to proMMP-3. There were no significant associations among Larsen score and proMMP-3, ESR, and CRP. Our results suggest that the cross-sectional measurement of serum proMMP-3 could not give additional information about RA disease activity compared to ESR and CRP, and could not give any information about joint damage.

A longitudinal study of the effect of disease activity and clinical damage on physical function over the course of psoriatic arthritis: Does the effect change over time?

To investigate whether there are differential effects of disease activity and damage on physical functioning as measured by the Health Assessment Questionnaire (HAQ) over the course of psoriatic arthritis (PsA). Between June 1993 and March 2005, 382 patients attending the University of Toronto PsA clinic had completed > or =2 HAQs on an annual basis. At the time of each HAQ assessment, clinical and laboratory measures of disease activity and damage were recorded. Generalized linear mixed-effects models were used to investigate the longitudinal relationship between disease activity, damage, and the HAQ score. To avoid floor effects that would arise in a single mixed-effects model, we adopted a 2-part model. The number of actively inflamed joints (measure of disease activity) and the number of clinically deformed joints (measure of damage) were positively and significantly related to the HAQ score. Furthermore, interaction terms for illness duration with the number of actively inflamed joints were statistically significant, with or without inclusion of the erythrocyte sedimentation rate and morning stiffness in the model (P = 0.029 and P < 0.001, respectively). The positive effects of actively inflamed joints on the level of the HAQ score decreased over increasing duration of PsA. There was less evidence to suggest that the positive effect of joint damage on the HAQ score increased over time. Our results support the view that the influence of disease activity on HAQ scores declines with increased disease duration. We could not demonstrate strong evidence that the effect of clinical damage increases over the course of illness.

The use of the British Isles Lupus Assessment Group (BILAG) index as a valid tool in assessing disease activity in childhood-onset systemic lupus erythematosus.

The British Isles Lupus Assessment Group (BILAG) index is a standardized systemic lupus erythematosus (SLE) disease activity assessment. The main aim of this study was to correlate the BILAG index with laboratory measures of disease activity in childhood-onset SLE with and without biopsy-proven lupus nephritis. Prospective observational comparison study of the BILAG index in 21 SLE patients under 18 yr of age over a 12-month period in a tertiary referral paediatric outpatient clinic. Eleven patients with lupus non-nephritis and 10 patients with lupus nephritis were reviewed. The lupus nephritis patients had significantly (P<0.001) more admissions over a similar time interval since diagnosis. The renal BILAG disease activity scores were significantly greater (P = 0.013) in the lupus nephritis group (range 1-9, median 3.0, compared with 0-3 and 1.0 in the lupus non-nephritis group). The total BILAG scores and patient visual analogue scores (VAS) were higher in the lupus nephritis groups, unlike the lower physician VAS, but these differences were not statistically significant compared with other laboratory indices of disease activity. The BILAG index is a useful tool in monitoring disease activity in children and adolescents with SLE. The data collected for the BILAG index can be used serially and effectively by different clinicians over time to enable recording of disease status at sequential assessments. The lower patient VAS in the lupus non-nephritis group was not significant and may reflect the patients' own perception of lethargy at times of increased disease activity.

Does active treatment of rheumatoid arthritis limit disease-associated bone loss?

Generalized bone loss in rheumatoid arthritis (RA) is multi-factorial, with the inflammatory disease itself thought to contribute to bone loss. To study the extent to which control of disease activity affects bone turnover in RA and whether treatment with disease-modifying anti-rheumatic drugs (DMARDs) reduces bone turnover and loss of bone mass, we measured bone density and biochemical markers of bone resorption in a group of patients with active RA starting on DMARDS. Patients with active RA were enrolled on starting a new DMARD. Patients were mobile and none took steroids or any treatment for osteoporosis. Clinical and laboratory measures of disease activity were made at 3-monthly intervals and an index of disease activity (DAS) calculated. Bone density was assessed at 0, 1 and 2 yr (Hologic QDR 4500c). Urinary deoxypyridinoline (D-PYR) and pyridinoline (PYR) were measured by ELISA at 0, 3, 6, 9 and 12 months. Forty patients were enrolled, mean age 59.5 (range 31-76), 26 female, 14 male, 25 had established RA, 15 had RA for <2 yr. Baseline D-PYR was elevated (8.4+/-4.55 nmol/mmol creatinine) and correlated with ESR (r=0.6, P<0.01) and DAS (r=0.4, P<0.05). On treatment ESR and DAS fell by 38.5 and 29.3%, respectively. D-PYR was reduced by 12.3% by 9 months (P<0.01). Spearman rank order correlation showed ESR to be the most significant determinant of D-PYR over 1 yr (r=0.43, P<0.001). Serial bone density was available on 21 patients. There was no significant change in BMD over the 2 yr. The change in DAS over 0-3 months showed an inverse relationship with the percent change in spine over 1 yr (r=-0.5, P=0.05). The change in D-PYR over 0-3 months was not closely related to the change in BMD at hip or spine at 1 yr. Disease activity is a significant determinant of bone turnover in RA. Bone resorption markers fall on treatment of RA with DMARDs and no change in BMD was demonstrated at 2 yr. This study suggests the need to control disease activity in RA in order to prevent systemic bone loss.

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Nonstandard and adjunctive medical therapies for systemic lupus erythematosus

Clinical improvement and radiological deterioration in rheumatoid arthritis: evidence that the pathogenesis of synovial inflammation and articular erosion may differ.

The contrast between clinical improvement and radiological deterioration in rheumatoid arthritis (RA) is striking. We characterized this relationship using serial disease activity measures and radiographs of hands and feet in 40 RA patients observed over 6 yr. All disease activity measures improved, including grip strength, Ritchie index (RI), haemoglobin and erythrocyte sedimentation rate (ESR) (all P < 0.0001). In contrast, articular erosion increased (P < 0.0001). Radiological change during the study correlated with RI (r = 0.49), haemoglobin (r = -0.56) and ESR (r = 0.53). Radiological status at review also correlated with these variables (r = 0.36, -0.44 and 0.36, respectively). Articular erosion continues in RA despite clinical improvement and is accelerated in those with evidence of continuing synovial inflammation, reflected in clinical and laboratory measures of disease activity. Since many therapies in RA suppress inflammation, but not erosion, these findings suggest that the pathogenesis of articular erosion may differ from that of synovial inflammation.

Radiological outcome in ankylosing spondylitis: use of the Stoke Ankylosing Spondylitis Spine Score (SASSS).

We investigated the role of the Stoke Ankylosing Spondylitis Spine Score (SASSS) in a longitudinal cohort study of 53 patients with AS, assessed 9 yr apart, and its relation to clinical, functional and laboratory measures of disease activity and outcome. We also examined the long-term predictive value of quantitative sacroiliac scintigraphy (QSS). SASSS correlated closely with clinical measures, including occiput-wall distance (OWD) (P < 0.001) and modified Schober (P < 0.001). QSS was significantly correlated with final X-ray score (P < 0.05). SASSS changed significantly (P < 0.001) over the study period; two patterns of change in spine score were discernible, one with little change in radiological score and the other showing marked progression. The SASSS is a useful, valid score, which correlates with clinical outcomes measures and which has identified specific patterns of radiographic progression in AS.

Prevalence of metacarpal osteopenia in young rheumatoid arthritis patients.

The aim of this study was to assess the prevalence of and diagnostic role of metacarpal osteopenia in rheumatoid arthritis (RA) and to evaluate its detectability using receiver operating characteristic (ROC) analysis. Metacarpal bone mineral density was measured in 98 patients with classical RA using a computer-assisted measure of 6 metacarpal diameters (radiogrammetry) in patients aged less than 50 years. Sensitivity and specificity of the technique in discriminating the RA patients from 85 normal controls and osteopenic RA subjects from their normopenic counterparts, was determined by standard statistical techniques. Clinical, laboratory and radiological variables were compared in their ability to explain the variance of metacarpal bone density. The prevalence of metacarpal osteopenia in RA was 55%. Prolonged disease and reduced function significantly differentiated osteopenic from non-osteopenic RA patients. Discriminant analysis of RA and control groups showed that measurement of 6 metacarpals was more accurate than the 2nd metacarpal measurement alone in predicting the RA patients. The sum of 6 metacarpal combined cortical width (CCW) had a sensitivity of 61% and specificity of 68% in discriminating the RA patients from the controls. Receiver operating characteristics curves showed, not surprisingly, that objective measurement of bone diameters was superior to clinical or laboratory measures of disease activity in correctly classifying a randomly chosen RA patient as osteopenic or not. Metacarpal osteopenia is common in RA and it may be a useful measure of the disease in young patients.

Significance of systemic endotoxaemia in inflammatory bowel disease.

Quantitative and qualitative disturbances in faecal flora suggest a role for enteric bacteria and their products in the pathogenesis of inflammatory bowel disease (IBD). This study investigated the hypothesis that systemically circulating endotoxins are of pathogenic significance in IBD by measuring antibody, cytokine, and acute phase protein responses. Systemic endotoxaemia was found in 88% patients with ulcerative colitis (n = 25) and 94% with Crohn's disease (n = 31) during clinical relapse. Systemic endotoxaemia correlated positively with anatomic extent and clinical activity of ulcerative colitis. Circulating tumour necrosis factor (TNF) was detected in 40% of patients with ulcerative colitis and 45% with Crohn's disease. Plasma TNF concentrations correlated with clinical and laboratory measures of disease activity and were associated with a surgical outcome to the disease episode. Plasma soluble TNF receptor p55 concentration correlated positively with disease activity and endotoxin core antibody concentrations. Plasma IgG endotoxin core antibody concentrations were significantly increased in patients with Crohn's disease and correlated with systemic endotoxaemia. The presence of systemic endotoxaemia, its correlation with disease activity, disease extent, and endotoxin core antibody concentration and the detection of circulating TNF and soluble TNF receptors all support a pathogenic role for endotoxins in IBD.