Assessment of genetic polymorphisms within nuclear factor-κB signaling pathway genes in rheumatoid arthritis: Evidence for replication and genetic interaction.

OBJECTIVE: This study was performed to replicate the associations of genetic polymorphisms within nuclear factor-κB (NF-κB) signaling pathway genes with rheumatoid arthritis (RA), and to further examine genetic interactions in a Chinese population. METHODS: A total of eleven single-nucleotide polymorphisms (SNPs) were genotyped in 594 RA patients and 604 healthy controls. RESULTS: Genetic association analysis revealed that NFKBIE rs2233434, TNIP1 rs10036748 and BLK rs13277113 were significantly associated with RA, cyclic citrullinated peptide (CCP)-positive RA and rheumatoid factor (RF)-positive RA, and TNFAIP3 rs2230926 was significantly associated with CCP-positive RA. Significant additive interaction was observed between NFKB1 rs28362491 and IKBKE rs12142086 (RERI = 0.76, 95% CI 0.13-1.38; AP = 0.57, 95% CI 0.11-1.03), NFKBIE rs2233434 and BLK rs13277113 (RERI = 1.41, 95% CI 0.88-1.94; AP = 0.85, 95% CI 0.50-1.20), NFKBIL rs2071592 and TNIP1 rs10036748 (RERI = 0.59, 95% CI 0.17-1.02; AP = 0.46, 95% CI 0.05-0.87), UBE2L3 rs5754217 and TNFSF4 rs2205960 (RERI = 0.50, 95% CI 0.16-0.84; AP = 0.57, 95% CI 0.09-1.05). Significant multiplicative interaction was detected between BLK rs13277113 and UBE2L3 rs5754217 (p = 0.02), BLK rs13277113 and TNFSF4 rs2205960 (p = 0.03). CONCLUSIONS: Our results lent further support to the role of NF-κB signaling pathway in the pathogenesis of RA from a genetic perspective.

Cost-Effectiveness Analysis of Abatacept Compared with Adalimumab on Background Methotrexate in Biologic-Naive Adult Patients with Rheumatoid Arthritis and Poor Prognosis.

OBJECTIVES: To assess cost effectiveness of abatacept versus adalimumab, each administered with methotrexate, in treating patients with rheumatoid arthritis (RA) stratified according to baseline anticitrullinated protein antibody (ACPA) levels (marker of poor prognosis in RA). METHODS: A payer-perspective cost-effectiveness model simulated disease progression in patients with RA who had previously failed conventional disease-modifying antirheumatic drugs and were starting biologic therapy. Patients commenced treatment with abatacept or adalimumab plus methotrexate and were evaluated after 6 months. Therapy continuation was based on the European League Against Rheumatism treatment response; disease progression was based on the Health Assessment Questionnaire Disability Index score. These score changes were used to estimate health state utilities and direct medical costs. Quality-adjusted life-years (QALYs) and incremental cost per QALY gained were calculated by baseline ACPA groups (Q1, 28-234 AU/ml; Q2, 235-609 AU/ml; Q3, 613-1045 AU/ml; and Q4, 1060-4894 AU/ml). Scenario analysis and one-way and probabilistic sensitivity analyses were used to evaluate robustness of model assumptions. RESULTS: Abatacept resulted in QALY gain versus adalimumab in ACPA Q1, Q3, and Q4; between-treatment difference (difference: Q1, -0.115 Q2, -0.009 Q3, 0.045; and Q4, 0.279). Total lifetime discounted cost was higher for abatacept versus adalimumab in most quartiles (Q2, £77,612 vs. £77,546; Q3, £74,441 vs. £73,263; and Q4, £78,428 vs. £76,696) because of longer time on treatment. Incremental cost per QALY for abatacept (vs. adalimumab) was the lowest in the high ACPA titer group (Q4, £6200/QALY), followed by the next lowest titer group (Q3, £26,272/QALY). CONCLUSIONS: Abatacept is a cost effective alternative to adalimumab in patients with RA with high ACPA levels.

Assessment of local carotid stiffness in seronegative and seropositive rheumatoid arthritis.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic, inflammatory disease associated with increased risk of cardiovascular (CV) disease. Arterial stiffness (AS) is an independent predictor of CV events. This study aimed to analyse local carotid AS parameters in seronegative and seropositive RA patients. DESIGN: Of 347 consecutive RA patients, we selected specifically those who were free of established CV diseases and risk factors. As a result, 140 patients (126 women, 52.2 ± 10 years) and 140 healthy controls (122 women, 52.7 ± 8.0 years) were enrolled into this study. The common carotid AS was evaluated using radio frequency echo-tracking system to determine the local carotid pulse wave velocity (cPWV) and carotid intima-media thickness (cIMT). Based on rheumatoid factor (RF) and/or anti-citrullinated protein antibody (ACPA) positivity, RA patients were categorized into seronegative and seropositive subgroups. RESULTS: Carotid PWV was determined to be significantly higher in all patients and subgroups than controls (p < .001 for all). Although cIMT was similar between the patients, controls and seropositive subgroup, seronegative patients had significantly higher cIMT compared to controls (p = .035) and seropositive group (p = .010). Moreover, a significant positive correlation was found between cPWV and age (r: 0.603, p < .001), ESR (r: 0.297, p = .004), ACPA (r: 0.346, p = .001) and cIMT (r: 0.290, p = .005) in seropositive patients. CONCLUSIONS: RA per se is sufficient to cause arteriosclerosis in the absence of classical CV risk factors. However, arterial hypertrophy is only increased in seronegative patients but not in seropositive group.

HLA-DRB1 Amino Acid Positions 11/13, 71, and 74 Are Associated With Inflammation Level, Disease Activity, and the Health Assessment Questionnaire Score in Patients With Inflammatory Polyarthritis.

OBJECTIVE: Rheumatoid arthritis (RA) susceptibility HLA-DRB1 haplotypes based on amino acid positions 11/13, 71, and 74 predict radiographic damage. The mechanism of action is unknown, but it may be mediated by inflammation. We undertook this study to systematically investigate the effect of these amino acids on nonradiographic measures of disease activity/outcomes. METHODS: We tested the association of RA susceptibility HLA-DRB1 amino acids with the C-reactive protein (CRP) level, the tender joint count (TJC), the swollen joint count (SJC), the Disease Activity Score in 28 joints (DAS28), and the Health Assessment Questionnaire (HAQ) score in the Norfolk Arthritis Register (NOAR) and Early Rheumatoid Arthritis Study (ERAS) cohorts. Longitudinal modeling of disease activity/outcomes was performed using generalized linear latent and mixed models. Mediation analysis was performed using directed acyclic graphs to investigate the paths from genetic factors to outcome. RESULTS: A total of 2,158 patients were available for analysis in the NOAR cohort. Valine at position 11 showed the strongest association with the CRP level (P = 2.21 × 10-6 ), the SJC (P = 7.51 × 10-6 ), and the DAS28 (P = 0.002); it was marginally associated with the HAQ score (P = 0.044) but not with the TJC. The same amino acid and haplotype risk hierarchy observed for susceptibility and radiographic severity was observed for the CRP level and nonradiographic measures of disease activity/outcome, apart from the TJC. The results were replicated in the ERAS cohort. The effect of valine at position 11 on the SJC was mainly mediated by anti-citrullinated protein antibody status, the effect of which was mainly mediated by inflammation; however, the effect of valine at position 11 was also independent of the CRP level (P = 1.6 × 10-4 ). CONCLUSION: Genetic markers of RA susceptibility located within HLA-DRB1 determine the levels of clinical and systemic inflammation independently, and also determine all objective measures of disease activity and outcome.

Reliable and cost-effective serodiagnosis of rheumatoid arthritis.

Early diagnosis of patients with rheumatoid arthritis (RA) optimises therapeutic benefit and the probability of achieving disease remission. Notwithstanding clinical acumen, early diagnosis is dependent on access to reliable serodiagnostic procedures, as well as on the discerning application and interpretation of these. In the case of RA, however, no disease-specific serodiagnostic procedure is available due to the multi-factorial and polygenic nature of this autoimmune disorder. This has resulted in the development of an array of serodiagnostic procedures based on the detection of autoantibodies reactive with various putative autoantigens. Other procedures based on measurement of elevations in the concentrations of systemic biomarkers of inflammation, most commonly acute phase reactants and cytokines/chemokines, are used as objective indices of disease activity. Following a brief overview of RA research in African populations, the current review is focused on those autoantibodies/biomarkers, specifically rheumatoid factor, anti-citrullinated peptide antibodies and C-reactive protein, which are currently recognised as being the most reliable and cost-effective with respect to disease prediction and diagnosis, as well as in monitoring activity and outcome.

Visual Assessment of Chest Computed Tomography Findings in Anti-cyclic Citrullinated Peptide Antibody Positive Rheumatoid Arthritis: Is it Associated with Airway Abnormalities?

INTRODUCTION: We aimed to evaluate the association between specific anti-cyclic citrullinated peptide antibody (ACCPA) and pulmonary abnormalities in rheumatoid arthritis (RA) subjects. METHODS: Computed tomography (CT) images of 83 subjects with RA were evaluated in a blind fashion. Enrolled subjects underwent autoantibody testing to determinate titer of ACCPA and rheumatoid factor, and pulmonary function testing. Visual CT assessment included lobar analysis for extent of semi-quantitative total interstitial lung disease score (ILDS) and each airway abnormality score (bronchiectasis, bronchial wall thickening, centrilobular nodules, and expiratory air trapping). Correlation tests, and simple and multiple regression analyses were performed to determine the relationship between the visual CT abnormalities, physiologic parameters, and autoantibody titers. RESULTS: ACCPA-positive subjects had a greater extent and higher prevalence of small airway abnormalities including centrilobular nodules and air trapping compared to ACCPA-negative subjects (all p < 0.05). Bronchiectasis and bronchial wall thickening correlated with the ratio of forced expiratory volume in 1 s and forced vital capacity (FVC) (r = -0.236 and r = -0.329, all p < 0.05), and ILDS correlated with FVC and the diffusing capacity of the lung for carbon monoxide (r = -0.218 and r = -0.366, all p < 0.05). Bronchial wall thickening and air trapping correlated with ACCPA titers (r = 0.235 and r = 0.264, all p < 0.05). Air trapping and bronchial wall thickening were significantly associated with ACCPA titers. CONCLUSION: In ACCPA (+) RA, visual CT assessment of large and small airways beyond RA-ILD, which is attributable to RA-related autoimmunity, can provide valuable information regarding airway abnormalities, regardless of the patients' physiologic airflow limitations.

Resting energy expenditure is not associated with disease activity in women with rheumatoid arthritis: cross-sectional study.

BACKGROUND/AIMS: Increased resting energy expenditure (REE) in rheumatoid arthritis (RA) patients is thought to be caused by hypermetabolism associated with production of proinflammatory cytokines. Our aim in the present study was to explore the possible association between REE and disease activity in females with RA. METHODS: A total of 499 female RA patients were recruited to this cross-sectional study assessing REE scores on disease activity indices (the routine assessment of patient index data 3 [RAPID3], the disease activity score 28, and the clinical/simplified disease activity index [CDAI/SDAI]) and the levels of RA-associated autoantibodies (rheumatoid factor and anticyclic citrullinated peptide [anti-CCP] antibodies). Age-matched healthy female controls (n = 131) were also enrolled. RESULTS: REE did not differ between RA patients (all patients, and those in remission or not) and controls, or between RA patients in remission or not (p > 0.05 for all comparisons). Increased REE in total RA patients was associated with younger age and a higher body mass index (BMI) (p < 0.001 and p < 0.001, respectively), but not with disease activity index scores on any of RAPID3, CDAI, or SDAI. BMI was the only clinical parameter exhibiting a significant relationship with REE quartiles (Q1 to Q4; p < 0.001); none of disease duration, functional status, or anti-CCP antibody titer in RA patients was significantly related to REE, based on analysis of covariance. CONCLUSIONS: We found no association between REE and disease activity in RA patients, implying that energy metabolism in RA patients might be independent of RA-associated systemic inflammation.

Anti-citrullinated peptide antibodies and rheumatoid factor isotypes in the diagnosis of rheumatoid arthritis: an assessment of combined tests.

ACPA (anti-citrullinated protein antibody) tests are today systematically added to clinical and radiological investigations when diagnosing rheumatoid arthritis (RA), and the inclusion of ACPA positivity in the new 2010 RA criteria underlines their importance. The aim of this study was to determine the sensitivity and specificity of different ACPA assays and IgA, IgG and IgM isotypes of rheumatoid factor (RF) in a cohort of patients with early RA in order to assess the value of combining the tests. The serum samples were obtained from 46 RA patients, 80 patients with systemic rheumatic disease, and 20 blood donors. ACPAs were measured using five different commercial kits. The receiver operating characteristic (ROC) curves of the anti-ACPA tests had area under the curve (AUC) values of 0.60-0.83. The diagnostic accuracy of the Bio-Rad multiplex flow immunoassay, a new technology for ACPA testing, was very similar to that of the other widely used commercial immunoassays. The EliA CCP-Phadia test was the most specific, and had the best positive likelihood ratio and positive predictive values, whereas the anti-CCP Inova 3.1 test was the most sensitive, and had the best negative likelihood ratio and negative predictive values. The best combination to use for early RA screening was an ACPA test together with IgM and IgA RF.

Repeated anticitrullinated protein antibody and rheumatoid factor assessment is not necessary in early arthritis: results from the ESPOIR cohort.

OBJECTIVE: Presence and levels of anticyclic citrullinated peptide antibodies (anti-CCP) and rheumatoid factor (RF) contribute to the classification and prognosis of rheumatoid arthritis (RA). The objective was to determine the usefulness of repeating anti-CCP/RF measurements during the first 2 years of followup in patients with early arthritis. METHODS: In patients with early undifferentiated arthritis, serial anti-CCP and RF were measured using automated second-generation assays every 6 months for 2 years. Frequencies of seroconversions (from negative to positive or the reverse) and changes in antibody levels during followup were determined. RESULTS: In all, 775 patients, mean (SD) age 48.2 (12.5) years, mean symptom duration 3.4 (1.7) months, 76.6% female, were analyzed; 614 (79.2%) satisfied the American College of Rheumatology/European League Against Rheumatism 2010 classification criteria for RA at baseline. At baseline, respectively for anti-CCP and RF, 318 (41.0%) and 181 (23.4%) patients were positive, of whom 298 (93.7% of the positive) and 111 (61.3% of the positive) were highly positive (above 3 × upper limit of the norm). There were only 12 anti-CCP seroconversions toward the positive (i.e., 2.6% of the anti-CCP-negative), 21 seroconversions toward the negative (6.6% of the anti-CCP-positive), and 8 (1.0%) changes to a higher anti-CCP level category during the 2-year followup; respectively for RF, 27 (4.6%), 95 (52.5%), and 13 (1.7%). CONCLUSION: In this cohort of patients with early arthritis, including in the subset of patients who did not fulfill the RA criteria, antibody status showed little increase over a 2-year period. Repeated measurements of anti-CCP/RF very infrequently offer significant additional information.

Predictive value of autoantibody testing for validating self-reported diagnoses of rheumatoid arthritis in the Women's Health Initiative.

Rheumatoid arthritis (RA) research using large databases is limited by insufficient case validity. Of 161,808 postmenopausal women in the Women's Health Initiative, 15,691 (10.2%) reported having RA, far higher than the expected 1% population prevalence. Since chart review for confirmation of an RA diagnosis is impractical in large cohort studies, the current study (2009-2011) tested the ability of baseline serum measurements of rheumatoid factor and anti-cyclic citrullinated peptide antibodies, second-generation assay (anti-CCP2), to identify physician-validated RA among the chart-review study participants with self-reported RA (n = 286). Anti-CCP2 positivity had the highest positive predictive value (PPV) (80.0%), and rheumatoid factor positivity the lowest (44.6%). Together, use of disease-modifying antirheumatic drugs and anti-CCP2 positivity increased PPV to 100% but excluded all seronegative cases (approximately 15% of all RA cases). Case definitions inclusive of seronegative cases had PPVs between 59.6% and 63.6%. False-negative results were minimized in these test definitions, as evidenced by negative predictive values of approximately 90%. Serological measurements, particularly measurement of anti-CCP2, improved the test characteristics of RA case definitions in the Women's Health Initiative.

Ultrasound imaging for the rheumatologist XL. Sonographic assessment of the hip in rheumatoid arthritis patients.

OBJECTIVES: The aim of the present study was to correlate clinical and laboratory data with those obtained by ultrasound (US) evaluation of the hip in a cohort of patients with rheumatoid arthritis (RA). METHODS: Fifty-two RA patients attending the Rheumatology Departments involved in the present study were enrolled. Demographic (age, gender), clinical (body mass index, disease duration, treatments, history or current hip pain, tenderness by internal or external hip rotation or palpation of the greater trochanteric region), laboratory (erythrosedimentation rate, C-reactive protein, rheumatoid factor and antibodies anti-citrullinated peptides) and clinimetric data (disease activity score 28 - DAS28, Health Assessment Questionnaire - HAQ, Lequesne index) were collected. All patients underwent an US examination of both hips according to international guidelines. RESULTS: A total of 100 hips were scanned in 52 patients with RA. Approximately half of the patients reported a history of hip pain, one fourth complained of current pain, and the physical examination (internal and/or external rotation and palpation of the greater trochanteric region) evocated pain up to 19% and 22% of the patients, respectively. US examination found signs of hip joint abnormalities in 42% of the patients; US changes indicative of hip joint inflammation and damage were detected respectively in 24% and 32% of the cases. No patient presented power Doppler signal in the hip joint. A significant correlation between US pathological findings at hip level was found with clinical data (current pain and evocated pain by internal or external hip rotation). Furthermore, US cartilage lesion correlated with age of the patient, and US bone erosions with the disease duration. No correlation was found between the sonographic assessment and laboratory data, DAS 28, and Lequesne index. CONCLUSIONS: US abnormalities at hip joint level obtained in the present study correlated with clinical findings, while no correlation was found with DAS28 or laboratory data. Further investigations are encouraged to clarify the US additional value at hip level in patients with RA.

Should rheumatoid factor in rheumatoid arthritis be sent to Davy Jones's Locker?

This article reviews the characteristics and weaknesses of the rheumatoid factor (RF) assay compared with anti-citrullinated peptide antibody (ACPA) testing in the work-up of patients with synovitis. This should lead physicians to change their ordering habits and replace RF by ACPA. For RA diagnosis, good clinical judgement based on clinical history, physical examination and routine laboratory work exceeds the value of RF and ACPA assays. In settings of both low and high pretest probability, the added value of each of these assays is low. In cases with intermediate probability, ACPA assays are superior to immunoglobulin (Ig)M-RF because of their higher specificity, and they should be the first choice in a RA diagnostic work-up. Dual testing brings few additional advantages and increases costs significantly. ACPA and IgM-RF are both imperfect tests; around 30% of patients with manifest RA will test negative in both assays and therefore caution needs to be exercised when interpreting negative results. Since 2009, the anti-cyclic citrullinated peptide (anti-CCP) antibody assay has been the only assay available at our institution for RA work-up, with IgM-RF available on a case-by-case basis for non-RA diseases. This has led to a 70% reduction in RF assays performed annually.

Remission is the goal for cardiovascular risk management in patients with rheumatoid arthritis: a cross-sectional comparative study.

OBJECTIVES: To compare markers of cardiovascular disease (CVD) risk between patients with rheumatoid arthritis (RA) in an active disease state and those with RA in remission, and to compare both groups with community controls. METHODS: 113 patients with RA and 86 community controls were assessed across a panel of biomarkers for CVD. RA in remission was defined as Clinical Disease Activity Index ≤2.8. Community controls were selected at random by Statistics Norway, and controls were matched with patients in the cohorts in strata using details of age, sex and residential area. A panel of biomarkers (N-terminal pro-brain natriuretic peptide (NT-proBNP), total cholesterol, reactive hyperaemia index (RHI), pressure measurements, measures of arterial stiffness and intima-media thickness) were compared between patients with active RA and those with RA in remission. Both groups were compared with controls. In addition, biomarker levels were compared across subgroups based on anticyclic citrullinated peptide status, level of joint destruction and presence of extra-articular manifestations. RESULTS: Patients with active RA had significantly higher levels of NT-proBNP, brachial systolic pressure, augmentation index and central systolic pressure but lower cholesterol than patients in remission and controls. In addition, patients with active RA had significantly higher levels of pulse wave velocity and worse RHI than patients in remission. Comparison across other subgroups gave less consistent differentiations in levels of CVD risk markers. CONCLUSION: Patients with active RA, but not those in remission, had significantly increased levels of CVD risk markers. These results link inflammatory activity to markers of CVD risk in patients with RA and may indirectly support the notion that remission in RA confers diminished cardiovascular morbidity.

A diagnostic algorithm for persistence of very early inflammatory arthritis: the utility of power Doppler ultrasound when added to conventional assessment tools.

OBJECTIVES: The aim of this study was to assess the value of power Doppler ultrasound (PDUS) in combination with routine management in a cohort of patients with very early inflammatory arthritis (IA). METHODS: 50 patients with < or =12 weeks of inflammatory symptoms with or without signs had clinical, laboratory and imaging assessments. Diagnosis was recorded at 12 months. Assuming a 15% pre-test probability of IA, post-test probabilities for various assessments were calculated and used to develop a diagnostic algorithm. RESULTS: All patients positive for rheumatoid factor (RF) and/or cyclic citrullinated peptide (CCP) developed persistent IA, so the added value of PDUS was assessed in the seronegative (RF and CCP negative) group. The probability of IA in a seronegative patient was 6%. The addition of clinical and radiographic features raised the probability of IA to 30% and, with certain ultrasound features, this rose to 94%. CONCLUSIONS: In seronegative patients with early IA, combining PDUS with routine assessment can have a major impact on the certainty of diagnosis.

[Assessment of serum IgG activity correlation against cyclic citrullinated peptide antibodies, topoisomerase I and centromere proteins in Mexican patients with progressive systemic sclerosis]. / Evaluación de la correlación de la actividad de IgG sérica contra péptido citrulinado cíclico, topoisomerasa I y proteínas de centrómero en pacientes mexicanos con esclerosis sistémica progresiva.

OBJECTIVE: To evaluate sera titers for antibodies anti-cyclic citrullinated peptide and their correlation against sera levels of anti-topoisomerase I and anti-centromere antibodies in Mexican patients with systemic sclerosis. PATIENTS AND METHODS: Consecutive outpatients with systemic sclerosis who attending to rheumatology clinic at a second level hospital facility. The antibodies anti-cyclic citrullinated peptide, anti-topoisomerase I and anti-centromere were determined by enzymatic immunoassay (ELISA). STATISTICAL ANALYSIS: Spearman for correlation between numerical variables with nonparametric distribution. Fisher exact test or chi2 to compare proportions and Student t test for dimensional variables. RESULTS: Thirty female patients were included; aged 53 +/- 13, the disease duration at the time of the study was 10 +/- 9. Twenty-three patients (77%) exhibited diffuse disease. Anti-centromere, anti-topoisomerase I, and anti-cyclic citrullinated peptide were detected in nine, nine and three patients respectively. The correlation analysis showed the independence of autoantibodies anti-centromere and anti-topoisomerase I with respect to the levels of anti-cyclic citrullinated peptide. CONCLUSIONS: This study confirms the low frequency of anti-cyclic citrullinated peptide antibodies in patients with systemic sclerosis. A lack of correlation between autoantibodies considered as "mutually excluded" anti-topoisomerase I and anti-centromere, indicating that the analysis of the relevance for anti-cyclic citrullinated peptide in systemic sclerosis must include other clinical and serological variables.

Investigating the viability of genetic screening/testing for RA susceptibility using combinations of five confirmed risk loci.

OBJECTIVE: Five loci-the shared epitope (SE) of HLA--DRB1, the PTPN22 gene, a locus on 6q23, the STAT4 gene and a locus mapping to the TRAF1/C5 genetic region--have now been unequivocally confirmed as conferring susceptibility to RA. The largest single effect is conferred by SE. We hypothesized that combinations of susceptibility alleles may increase risk over and above that of any individual locus alone. METHODS: We analysed data from 4238 RA cases and 1811 controls, for which genotypes were available at all five loci. RESULTS: Statistical analysis identified eight high-risk combinations conferring an odds ratio >6 compared with carriage of no susceptibility variants and, interestingly, 10% population controls carried a combination conferring high risk. All high-risk combinations included SE, and all but one contained PTPN22. Statistical modelling showed that a model containing only these two loci could achieve comparable sensitivity and specificity to a model including all five. Furthermore, replacing SE (which requires full subtyping at the HLA-DRB1 gene) with DRB1*1/4/10 carriage resulted in little further loss of information (correlation coefficient between models = 0.93). CONCLUSIONS: This represents the first exploration of the viability of population screening for RA and identifies several high-risk genetic combinations. However, given the population incidence of RA, genetic screening based on these loci alone is neither sufficiently sensitive nor specific at the current time.

Choice of second-line disease-modifying antirheumatic drugs after failure of methotrexate therapy for rheumatoid arthritis: a decision tree for clinical practice based on rheumatologists' preferences.

OBJECTIVE: To survey rheumatologists' preferences for the choice of a second-line disease-modifying antirheumatic drug (DMARD) after inadequate response with methotrexate (MTX) therapy in rheumatoid arthritis (RA). METHODS: Thirty-six rheumatologists stated their preferences for RA treatment after inadequate response with MTX therapy (optimal dose at least 6 months). From the initial scenario, we derived 54 vignettes varying by rheumatoid factor or anti-cyclic citrullinated peptide antibody presence, swollen joint count, Disease Activity Score in 28 joints, and structural damage. Respondents stated their preference among 5 therapeutic options: MTX continuation, switch to another conventional DMARD, addition of another conventional DMARD, addition of anakinra, or addition of a tumor necrosis factor (TNF) blocker. Presentation by pairs yielded 10 combinations of strategies for each variant, totaling 540 vignettes; participants evaluated a random sample of 180 vignettes. Determinants of each top-ranked option were analyzed by logistic regression. The compilation of these data served to define a therapeutic algorithm. RESULTS: The responses of 33 rheumatologists were analyzable. Therapeutic preferences corresponded to the top-ranked options. For patients with mild or moderately active RA, either a switch or step-up strategy to another conventional DMARD was top ranked. TNF blockers were preferred for RA patients with high disease activity or progressive structural damage. On the basis of these preferences, we developed a simple decision tree for use in daily clinical practice. CONCLUSION: Our simple, easy-to-use decision tree developed from rheumatologists' preferences for therapy after failure of MTX therapy in RA treatment may guide rheumatologists in daily practice to choose a second-line DMARD.

Cost effectiveness of the determination of autoantibodies against cyclic citrullinated peptide in the early diagnosis of rheumatoid arthritis.

OBJECTIVE: To estimate the incremental cost-effectiveness ratio (ICER) of antibodies against cyclic citrullinated peptides (aCCP) in the early diagnosis of rheumatoid arthritis (RA). METHODS: A Markov model was used to model 10-year progression of RA in patients first diagnosed with undifferentiated arthritis (UA) and to estimate the incremental costs and quality-adjusted life years (QALYs) of using aCCP additionally to American College of Rheumatology (ACR) criteria. The impact of later diagnosis and treatment due to non-use of aCCP was modelled as increased Health Assessment Questionnaire (HAQ) progression. Utilities were assigned to HAQ states for calculating QALYs. Uncertainty was analysed using univariate and probabilistic sensitivity analyses (Monte Carlo simulation). RESULTS: Baseline ICER was euro 930/QALY. Univariate sensitivity analyses identified the impact of later diagnosis on HAQ progression as a major source of uncertainty, resulting in an ICER range from "dominance" to euro 153 092/QALY, compared with a maximum ICER of euro4870/QALY for other variables. Monte Carlo simulation resulted in a 95% uncertainty interval from euro 3537/QALY (dominance) to euro 5429/QALY; when indirect costs were considered, Monte Carlo simulation resulted in a 95% uncertainty interval from euro 78 115/QALY (dominance) to -euro 23 444/QALY (dominance). CONCLUSIONS: Using aCCP in the diagnosis of RA in patients with UA is likely to be cost effective compared with using ACR criteria alone. When indirect costs are incorporated, aCCP seems to save costs. Clearly, more research is needed relating the effects of diagnosis and treatment on the long-term course and the resulting functional impairment of RA as measured by the HAQ.