Development and validation of an alternative ankylosing spondylitis disease activity score when patient global assessment is unavailable.

OBJECTIVE: To develop an alternative Ankylosing Spondylitis Disease Activity Score (ASDAS) to be used in research settings in axial SpA (axSpA) when Patient Global Assessment (PGA) is unavailable in databases. METHODS: Longitudinal data from four axSpA cohorts and two randomized controlled trials were combined. Observations were randomly split in a development (N = 1026) and a validation cohort (N = 1059). Substitutes of PGA by BASDAI total score, single or combined individual BASDAI questions, and a constant value, were established in the development cohort. Conversion factors for each substitute were defined by Generalized Estimating Equations, obtaining seven 'alternative' formulae. Validation was performed in the validation cohort according to the OMERACT filter, taking into consideration: (i) truth (agreement with original-ASDAS in the continuous score, by intraclass correlation coefficient and in disease activity states, by weighted kappa); (ii) discrimination [standardized mean difference of ASDAS scores between high/low disease activity states defined by external anchors, e.g. Patient Acceptable Symptom State; agreement (kappa) in the percentage of patients reaching ASDAS improvement criteria according to alternative vs original formulae]; and (iii) feasibility. RESULTS: Comparing various options, alternative-ASDAS using BASDAI total as PGA replacement proved to be: truthful (intraclass correlation coefficient = 0.98, kappa = 0.90), discriminative [ASDAS scores between Patient Acceptable Symptom State no/yes: standardized mean difference = 1.37 (original-ASDAS standardized mean difference = 1.43); agreement with original-ASDAS in major improvement/clinically important improvement criteria: kappa = 0.93/0.88] and feasible (BASDAI total often available, as questions required for the ASDAS; conversion coefficient ≈ 1). CONCLUSION: Alternative-ASDAS using BASDAI total score as PGA replacement is the most truthful, discriminative and feasible instrument.

Therapeutic drug monitoring of infliximab compared to standard clinical treatment with infliximab: study protocol for a randomised, controlled, open, parallel-group, phase IV study (the NOR-DRUM study).

BACKGROUND: Infliximab (INX) and other tumour necrosis factor inhibitors (TNFi) have revolutionised the treatment of several immune mediated inflammatory diseases. Still, many patients do not respond sufficiently to therapy or lose efficacy over time. The large interindividual variation in serum drug concentrations on standard doses and the development of anti-drug antibodies are thought to be major reasons for treatment failures. Therapeutic drug monitoring (TDM), an individualised treatment strategy based on systematic assessments of serum drug concentrations, has been proposed as a clinical tool to optimise efficacy of INX treatment. TDM seems reasonable both from a clinical and an economical point of view, but the effectiveness of this treatment strategy has not yet been demonstrated in randomised clinical trials. The NORwegian DRUg Monitoring study (NOR-DRUM) aims to assess the effectiveness of TDM, both with regard to the achievement of remission in patients starting INX treatment (part A) as well as to maintain disease control in patients on INX treatment (part B). METHODS: The NOR-DRUM study is a randomised, open, controlled, parallel-group, comparative, multi-centre, national, superiority, phase IV study with two separate parts, NOR-DRUM A and NOR-DRUM B. Patients with rheumatoid arthritis, psoriatic arthritis, spondyloarthritis, ulcerative colitis, Crohn's disease and psoriasis are included. In both study parts participants are randomised 1:1 to either TDM of infliximab (intervention group) or to standard treatment with infliximab without knowledge of drug levels or ADAb status (control group). NOR-DRUM A will include 400 patients starting INX therapy. The primary outcome is remission at 30 weeks. In NOR-DRUM B, 450 patients on maintenance treatment with INX will be included. The primary endpoint is occurrence of disease worsening during the 52-week study period. DISCUSSION: As the first trial to assess the effectiveness, safety and cost-effectiveness of TDM in patients receiving TNFi for a range of immune mediated inflammatory diseases, we hope that the NOR-DRUM study will contribute to the advancement of evidence based personalised treatment with biological medicines. TRIAL REGISTRATION: Clinicaltrials.gov, NCT03074656. Registered on 090317.

Validity and reliability of the Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in patients with axial spondyloarthritis (axSpA) in Singapore.

INTRODUCTION: The Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) are commonly used instruments for measuring disease activity. However, few studies have assessed their psychometric properties in patients with axial spondyloarthritis (axSpA). We aimed to assess the validity and reliability of ASDAS-CRP and BASDAI in patients with axSpA in Singapore. METHODS: Cross-sectional data from 280 patients with axSpA from a dedicated axSpA clinic in a Singapore tertiary referral hospital from 2011 to 2019 were used. Internal consistency was assessed using Cronbach's alpha. Construct validity was assessed through 12 a priori hypotheses by correlation of overall ASDAS-CRP and BASDAI score with other patient-reported outcomes measures (PROMs). Structural validity was evaluated via confirmatory factor analysis using maximum-likelihood method, where Comparative Fit Index (CFI) >0.95, Tucker-Lewis Index (TLI) >0.95, Root Mean Square Error of Approximation (RMSEA) <0.06 and Standardized Root Mean Residuals (SRMR) <0.08 were indicative of good fit. RESULTS: Among 280 patients (78.2% Male; 92.5% Chinese), ASDAS-CRP showed poor internal consistency of 0.33, while BASDAI showed high internal consistency of 0.87. Convergent and divergent construct validity were demonstrated by fulfillment of 11 out of 12 a priori hypotheses when ASDAS-CRP and BASDAI were compared with other PROMs. Our proposed ASDAS-CRP and BASDAI model showed good fit for a 1-factor structure respectively (CFI = 0.993, TLI = 0.984, RMSEA = 0.036, SRMR = 0.026 for ASDAS-CRP; CFI = 0.993, TLI = 0.985, RMSEA = 0.057, SRMR = 0.022 for BASDAI), demonstrating structural validity. CONCLUSION: This study supports the use of both ASDAS-CRP and BASDAI in measuring disease activity in patients with axSpA in Singapore.

Plasma let-7i, miR-16, and miR-221 levels as candidate biomarkers for the assessment of ankylosing spondylitis in Mexican patients naïve to anti-TNF therapy.

Novel biomarkers are needed for the diagnosis and clinical assessment of ankylosing spondylitis (AS). Our objective was to investigate plasma microRNAs differentially expressed between AS patients and controls and to evaluate their potential as biomarkers in Mexican subjects. A cross-sectional study including 15 AS patients naïve to anti-TNF therapy and 13 controls was performed. Disease activity, physical function, and global well-being were evaluated by the AS Disease Activity Score (ASDAS-CRP), the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), and the AS Quality of Life Questionnaire (ASQoL), respectively. Total RNA was isolated from plasma of participants and relative expression of let-7i, miR-16, and miR-221 was evaluated. Serum levels of C-reactive protein (CRP), matrix metalloproteinase-1 (MMP-1), MMP-9, and intercellular adhesion molecule-1 (ICAM-1) were also measured. Expression of let-7i was higher in patients than in controls (1.8, 0.9 to 3.4 versus 0.6, 0.4 to 1.2; P = 0.033) with an AUC/ROC of 0.74 (0.54 to 0.93; P = 0.032). Levels of miR-16 and miR-221 were unable to discriminate between patients and controls. Notably, plasma miR-16 levels were inversely correlated with the ASDAS-CRP score (rho - 64, - 0.87 to - 0.18; P = 0.011), the BASFI score (rho - 0.78, - 0.93 to - 0.43; P = 0.001), and serum MMP-1 levels (rho - 0.59, - 0.85 to - 0.09; P = 0.022). No other associations were found. Plasma let-7i levels may serve as a biomarker for the diagnosis of AS in Mexican individuals. Additionally, plasma miR-16 levels are associated with disease activity and physical functionality in patients naïve to anti-TNF therapy.

Assessment of serum asymmetric dimethylarginine levels and left ventricular diastolic function in patients with ankylosing spondylitis.

AIM: To assess left ventricular diastolic functions and serum dimethylarginine (ADMA) concentrations, as well as the effect of different treatment strategies on ADMA concentrations and diastolic function parameters, in patients with ankylosing spondylitis (AS). METHOD: Sixty AS patients and 40 control subjects without classical cardiovascular (CV) risk factors were included in the study. Baseline clinical and echocardiographic variables were obtained. C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and ADMA levels were measured. Spinal mobility, disease activity and functional status were assessed using Bath Ankylosing Spondylitis Metrology Index, Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index. RESULTS: CRP, ESR and ADMA levels were significantly higher in the AS group as compared to the control group. Two (5%) control subjects and six (10%) AS patients met the criteria for left ventricular diastolic dysfunction (DD) on conventional Doppler echocardiography, but the difference was not statistically significant (P = 0.36). However, using tissue Doppler imaging, 12 (20%) patients in the AS group and three (8%) subjects in the control group were diagnosed with left ventricular DD (P = 0.08). The anti-tumor necrosis factor (TNF)-α group, conventional therapy group and control group were compared in terms of ADMA, CRP, ESR levels and echocardiographic parameters. ADMA levels were significantly lower in anti-TNF-α group as compared to the conventional therapy group (P < 0.001). In the control group, ADMA levels were significantly lower than both treatment groups (P < 0.001). CONCLUSION: Increased ADMA levels reveal impaired nitric oxide metabolism in a relatively young group of patients with AS, who have no classical CV risk factors. Anti-TNF-α may have beneficial effect on endothelial function in AS patients by reducing ADMA levels.

Is there any gender-specific difference in the cut-off values of ankylosing spondylitis disease activity score in patients with axial spondyloarthritis?

AIM: To assess the validity of Assessment in Spondyloarthritis International Society (ASAS) endorsed Ankylosing Spondylitis Disease Activity Score (ASDAS) C-reactive protein (-CRP) and ASDAS erythrocyte sedimentation rate (-ESR) in axial spondyloarthritis (axSpA) and to estimate the cut-off values for male and female patients with axSpA. METHODS: Patients with axSpA were assessed for disease activity, functions, mobility and AS Quality of Life (ASQoL) and pain. The discriminant ability of ASDAS versions was assessed using standardized mean differences. Optimal cut-off values of ASDAS versions were calculated. RESULTS: Patients with axSpA were included (196 AS, 164 non-radiographic axSpA). ASDAS versions and Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) had good correlations with patient's global (PtG) and physician's global (PhG) assessment in both groups; however, men had relatively higher coefficients. Women had significantly higher pain, ASQoL, ASDAS-ESR, BASDAI item scores, PtG, PhG and ESR. Discriminant abilities of ASDAS-CRP, ASDAS-ESR and BASDAI were similar in men and women regarding low and high disease activity. ASDAS cut-offs are quite similar in both genders and in accordance with predefined values. The cut-offs for ASDAS-ESR were relatively lower than ASDAS-CRP and women tend to have higher cut-offs than men. CONCLUSION: The construct validity of ASDAS-CRP to discriminate low and high disease activity and cut-off values are similar in male and female patients with axSpA; however, cut-offs for ASDAS-ESR need to be defined.

Assessment of semaphorin 3A and its role in bone remodelling in a group of ankylosing spondylitis patients.

OBJECTIVES: Several molecules are involved in the pathogenesis of new bone formation in ankylosing spondylitis (AS). The aim of the present study was to evaluate serum levels of semaphoring 3A in AS and to investigate any correlations with radiographic damage, disease activity, function and treatment. METHODS: AS patients who fulfilled the modified New York criteria were enrolled for this study. Healthy subjects were also enrolled as control group. BASDAI, ASDAS-CRP, BASMI, BASFI, patients and physician VAS, C-reactive protein and erythrocyte sedimentation rate were evaluated at baseline visit. Radiographs of the spine and pelvis performed within six months from the enrolment in the study were collected in all patients. Spinal damage was assessed using the mSASSS. Serum concentrations of semaphorin3A were assessed at baseline and after four months of therapy in patients who started an anti-TNF. RESULTS: Twenty healthy subjects and forty AS patients were enrolled in the study. Of these patients, 15 started anti-TNF therapy the day of baseline visit. Semaphorin3A serum concentrations [median (25th-75th)] were similar in AS patients [0.26 (0.20-0.31) ng/ml] and controls [0.28 (0.26-0.3) ng/ml; p=ns). No significant correlation was found between semaphorin 3A serum levels and radiographic damage index. Semaphorin 3A serum levels positively correlated with ESR values (rho=0.37, p=0.049) and with disease activity assessed by the physician VAS (rho=0.47, p<0.01). No differences were found in the semaphorin3A serum levels after 4 months, compared to baseline values. CONCLUSIONS: The results of the present study could contribute to the intriguing topic of bone remodelling in AS.

Assessment of relation between neutrophil lympocyte, platelet lympocyte ratios and epicardial fat thickness in patients with ankylosing spondylitis.

AIM: To investigate whether there is a relation between neutrophillymphocyte (N/L) and platelet- lymphocyte (P/L) ratios and epicardial adipose tissue (EAT) thickness in patients with ankylosing spondylitis (AS). METHODS: Thirty patients diagnosed with ankylosing spondylitis and 25 healthy people (controls) were included in the study. Age, gender, body mass index (BMI), height, hemogram, sedimentation, neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, CRP, hepatic and renal function tests, lipid profile of the all patients were recorded. Data related to duration of the disease, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI) values of the cases in the patient group were obtained. A cardiologist measured EAT thickness by ECHO in both patient and control groups. RESULTS: In the patient group, mean BASDAI and BASFI scores were 2.48±2.21 and 1.5±2.07, respectively. Age, gender, BMI values did not show statistically significant difference between the patient and the control groups. N/L and P/L ratios did not change significantly in the patient group having higher EAT, BASFI values and taking anti-TNF compared to the control group. CONCLUSION: In patients with AS, EAT measurements, which are related to inflammatory response increase, can be used for monitoring of the risk of development of cardiac disease. We could not find the relation between EAT and N/L, P/L ratios in terms of evaluation of inflammatory response.

Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index in Turkish patients with ankylosing spondylitis: relationship with disease activity and quality of life.

AIM: The aim of this study was to investigate the relationship between Spondyloarthritis Research Consortium of Canada (SPARCC) enthesitis index and disease activity and health-related quality of life in patients with ankylosing spondylitis (AS). METHODS: Eighty-six AS patients not receiving antitumour necrosis factor (TNF) therapy were included in the study. Spinal pain by visual analogue scale (pain VAS rest and activity), disease activity by Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), functional capacity by Bath Ankylosing Spondylitis Functional Index (BASFI), enthesitis severity by SPARCC index, quality of life by Short Form-36 (SF-36), and Bath Ankylosing Spondylitis Metrology Index (BASMI) were assessed in patients. In the laboratory evaluations, the erythrocyte sedimentation rates and serum C-reactive protein levels of the patients were determined. RESULTS: All participants were aged between 18 and 65 years, with a mean age of 36.9 ± 11.13 years. The most frequent region of enthesitis was Achilles tendon insertion into calcaneum (55.8%). Pain VAS rest and activity, BASFI and all parameters of SF-36 were significantly different in AS patients with and without enthesitis. SPARCC index was significantly correlated with pain VAS activity (P < 0.05), pain VAS rest, BASDAI, BASFI and all parameters of SF-36 (P < 0.001). There were no correlations between SPARCC index and BASMI, disease duration and laboratory parameters (P > 0.05). CONCLUSION: The clinical assessment of enthesitis in AS is an important outcome measure, and enthesitis indexes such as SPARCC enthesitis index can be valuable tools in the evaluation of disease activity in AS patients not receiving anti-TNF therapy.

Early diagnosis of ankylosing spondylitis: an introduction to the newly designed Iran criteria for ankylosing spondylitis.

More than 14 years of clinical practice in rheumatology led the author to develop his experience-based criteria for early ankylosing spondylitis (AS) diagnosis. This study aims to introduce this new set of criteria, Iran criteria for ankylosing spondylitis, and to assess its sensitivity in comparison with 1984 modified New York criteria. A cost-effective diagnostic approach towards AS diagnosis is also proposed. The criteria score the patients according to the findings in history and physical examination, imagings and HLA-B27 testing. Sensitivity analysis was performed in a retrospective manner after reviewing the medical records of 120 patients at the outpatient Rheumatology Clinic of the author (private sector), regarding clinical diagnosis by a single rheumatologist as the gold standard. The sensitivity was separately measured for disease durations of 2, 2-5, 5-10 and more than 10 years. Iran criteria for AS recorded a sensitivity of 100 % in all disease durations. However, the sensitivity of 1984 modified New York criteria was 48.39 % in early stages of the disease and increased to 92.10 % for disease duration of more than 10 years. Iran criteria for AS provide a highly sensitive instrument for detecting AS in its early and late, clinical and subclinical, radiographic and pre-radiographic stages as well as atypical forms.

Discrimination ability of ASDAS estimating disease activity status in patients with ankylosing spondylitis.

OBJECTIVES: To investigate discrimination ability of the Assessment of Spondyloarthritis International Society (ASAS) endorsed disease activity score (ASDAS) versions evaluating low and high disease activity in an unselected group of patients with ankylosing spondylitis (AS). METHODS: Patients consecutively included into the joint database of five university hospitals were analyzed for low or high disease activity according to different criteria. Standardized mean differences (SMD) for two ASDAS versions were evaluated. RESULTS: The ASDAS versions (back pain, morning stiffness, patient global pain, pain/swelling of peripheral joints, plus either erythrocyte sedimentation rate or C-reactive protein) discriminated high and low disease activity in subgroups according to Bath Ankylosing Spondylitis Disease Activity Score (BASDAI) and ASAS remission/partial remission criteria. ASDAS versions were also not influenced by peripheral arthritis and correlated well with other outcome measurements and acute-phase reactants. The ASDAS versions performed better than patient-reported measures or acute-phase reactants discriminating high and low disease activity status. CONCLUSION: Both ASDAS versions, consisting of both patient-reported data and acute-phase reactants, performed well in discriminating low and high disease activity. Further longitudinal data may better estimate the usefulness of ASDAS to assess disease activity subgroups and treatment response.

Validity aspects of erythrocyte sedimentation rate and C-reactive protein in ankylosing spondylitis: a literature review.

The preliminary core set for endpoints in disease controlling antirheumatic therapy includes acute phase reactants. The objective of this clinically oriented literature review was to examine and compare the validity of erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) in ankylosing spondylitis (AS) clinical trials. A MEDLINE search was performed covering the years 1967 through April 1998. AS studies were identified and selected if they included ESR and/or CRP and either presented data about their relation with disease activity or were designed as longitudinal clinical trials. Additional studies were identified by scrutinizing references cited in the retrieved studies. The selected studies were examined for truth (association with disease activity), discriminative power (sensitivity to change and discrimination between active and inactive treatment in longitudinal clinical trials), and feasibility (e.g., applicability and costs) of ESR and CRP in AS. We identified 12 articles on the association of ESR and/or CRP with disease activity and 13 longitudinal clinical trials reporting ESR and/or CRP data. Although the applied definitions or disease activity proved very inhomogenous, there was some evidence that both acute phase reactants are correlated with disease activity. In terms of discriminative capacity the available data are inconclusive. Relevant feasibility aspects are general availability, technically simple measurement, and an advantage in the cost of ESR and central laboratory facilities for CRP. Acute phase reactants do not comprehensively represent the disease process in AS. Their worth in AS clinical trials is limited. Based on the currently existing data neither measure is clearly superior in terms of validity. When selecting an acute phase reactant, feasibility aspects may be most relevant in choice of measure.

Relative value of erythrocyte sedimentation rate and C-reactive protein in assessment of disease activity in ankylosing spondylitis.

Our aim was to determine whether C-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) is more appropriate in measuring disease activity in ankylosing spondylitis (AS). We studied 191 consecutive outpatients with AS in The Netherlands, France, and Belgium. Patients were attending secondary and tertiary referral centers. The external criterion for disease activity was: physician and patient assessment of disease activity on a visual analog scale (VAS) and the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). In each measure we defined 3 levels of disease activity: no activity, ambiguous activity, and definite disease activity. The patients with AS (modified New York criteria) were divided into 2 groups: those with spinal involvement only (n=149) and those who also had peripheral arthritis and/or inflammatory bowel disease (IBD) (n=42). For each criterion of disease activity, the patients with no activity and with definite activity were included in receiver operator curves and used to determine cutoff values with the highest sensitivity and specificity. We also calculated Spearman correlations. The median CRP and ESR were 16 mg/l and 13 mm/h, respectively, in the spinal group and 25 mg/l and 21 mm/h, respectively, in the peripheral/IBD group. In both groups the Spearman correlation coefficients between CRP and ESR were around 0.50. There was moderate to poor correlation between CRP, ESR, and the 3 disease activity variables (0.06-0.48). Sensitivity for both ESR and CRP was 100% for physician assessment and between 44 and 78% for patient assessment of disease activity and the BASDAI, while specificity was between 44 and 84% for all disease activity measures. The positive predictive values of CRP and ESR in our setting were low (0.15-0.69). We conclude that neither CRP nor ESR is superior to assess disease activity.

C-reactive protein in the assessment of disease activity in juvenile rheumatoid arthritis and juvenile spondyloarthritis.

Disease activity in 31 children with JRA and 12 with JSA was investigated clinically and by serial measurements of serum CRP and ESR over a one-year period. Prior mean duration of disease was 4.3 years. There was a significant correlation of CRP with ESR and both parameters correlated significantly with clinical disease activity. CRP concentrations and ESR in active disease were significantly higher than in moderately active and inactive disease, though neither parameter showed any significant difference between moderately active and inactive disease. Clinical scoring was more sensitive in detection of moderate disease activity than were CRP and ESR. However, in systemic JRA without articular involvement, laboratory parameters were more useful for assessing disease activity.

Problems in the assessment of disease activity in ankylosing spondylitis.

Serial assessments of disease activity using clinical, laboratory and thermographic indices were made on 20 patients with ankylosing spondylitis (AS) before and after active in-patient exercise classes and two months after discharge. Clinical measurements and the erythrocyte sedimentation rate suggested decreased activity by the time of the final assessment but plasma viscosity and thermography suggested increased activity and levels of C-reactive protein were unchanged. Functional improvements occurred mostly during the in-patient period. A wide range of complement levels was found but did not change, and IgG rheumatoid factor levels were negative throughout. The problems of laboratory assessment in AS are stressed.