Validation of ACR/EULAR definition of remission in rheumatoid arthritis from RA practice: the ESPOIR cohort

Introduction

In development of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) rheumatoid arthritis (RA) remission definitions using clinical trials data, one criterion used to compare different remission definitions was whether, compared with those not in remission, those in remission had evidence of later disease stability defined by x-ray and functional status. Validation of the RA remission criteria using observational study data is necessary before recommending their use in practice.

Methods

Using data from those who met RA criteria in the ESPOIR cohort, we matched each person in remission with a person not in remission and then carried out analyses comparing later stability of x-ray and health assessment questionnaire (HAQ) between the two groups. We compared the predictive validity of the same candidate definitions of remission evaluated in the ACR/EULAR process. To minimize potential bias and produce more stable results, we used a bootstrap resampling approach to select those not in remission, repeating the sample matching analysis process 500 times.

Results

Results were similar to those of clinical trials analyzed for the ACR/EULAR remission criteria. Specifically, the ACR/EULAR remission definitions using either an simple disease activity index (SDAI) ≤ 3.3, clinical disease activity index (CDAI) ≤ 2.8 or a definition of remission requiring tender joint count, swollen joint count, patient global assessment all ≤ 1 performed as well or better than other candidate definitions of remission in terms of predicting later x-ray and function stability.

Conclusions

ACR/EULAR definitions of remission developed for trials are similarly valid in observational studies in RA and could be used in practice.     

A Systematic Review of the Screening Accuracy of the HIV Dementia Scale and International HIV Dementia Scale

Background

The HIV Dementia Scale (HDS) and International HIV Dementia Scale (IHDS) are brief tools that have been developed to screen for and aid diagnosis of HIV-associated dementia (HAD). They are increasingly being used in clinical practice for minor neurocognitive disorder (MND) as well as HAD, despite uncertainty about their accuracy.

Methods and Findings

A systematic review of the accuracy of the HDS and IHDS was conducted. Studies were assessed on Standards for Reporting Diagnostic Accuracy criteria. Pooled sensitivity, specificity, likelihood ratios (LR) and diagnostic odds ratios (DOR) were calculated for each scale as a test for HAD or MND. We retrieved 15 studies of the HDS, 10 of the IHDS, and 1 of both scales. Thirteen studies of the HDS were conducted in North America, and 7 of the IHDS studies were conducted in sub-Saharan Africa. Estimates of accuracy were highly heterogeneous between studies for the HDS but less so for the IHDS. Pooled DOR for the HDS was 7.52 (95% confidence interval 3.75–15.11), sensitivity and specificity for HAD were estimated at 68.1% and 77.9%, and sensitivity and specificity for MND were estimated at 42.0% and 91.2%. Pooled DOR for the IHDS was 3.49 (2.12–5.73), sensitivity and specificity for HAD were 74.3% and 54.7%, and sensitivity and specificity for MND were 64.3% and 66.0%.

Conclusion

Both scales were low in accuracy. The literature is limited by the lack of a gold standard, and variation in estimates of accuracy is likely to be due to differences in reference standard. There is a lack of studies comparing both scales, and they have been studied in different populations, but the IHDS may be less specific than the HDS. These rapid tests are not recommended for diagnostic use, and further research is required to inform their use in asymptomatic screening.     

Comparison of 2002 AECG and 2016 ACR/EULAR classification criteria and added value of salivary gland ultrasonography in a patient cohort with suspected primary Sjögren’s syndrome

Background

The objective was to evaluate concordance between 2002 American-European Consensus Group (AECG) and 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for primary Sjögren’s syndrome (pSS) and to assess how salivary gland ultrasonography (SGUS) might improve the classification of patients.

Methods

Patients with suspected pSS underwent a standardised evaluation, including SGUS, at inclusion into the single-centre Brittany DIApSS cohort. Agreement between the two criteria sets was assessed using Cohen’s κ coefficient. Characteristics of discordantly categorised patients were detailed.

Results

We prospectively included 290 patients between 2006 and 2016, among whom 125 (43%) met ACR/EULAR criteria and 114 (39%) also met AECG criteria; thus, 11 (4%) patients fulfilled only ACR/EULAR, no patients AECG only, and 165 (57%) patients neither criteria set. Concordance was excellent (κ?=?0.92). Compared to patients fulfilling both criteria sets, the 11 patients fulfilling only ACR/EULAR criteria had similar age and symptom duration but lower frequencies of xerophthalmia and xerostomia (p?<?0.01 for each) and salivary gland dysfunction (p?<?0.01); most had systemic involvement (91%), including three (27%) with no sicca symptoms; 91% had abnormal salivary gland biopsy and 46% anti-Sjögren's-syndrome-related antigen A (anti-SSA); 64% were diagnosed with pSS by the physician. SGUS was abnormal in 12% of the 165 patients fulfilling no criteria set. Including SGUS among the ACR/EULAR criteria increased sensitivity from 87.4% to 91.1% when physician diagnosis was the reference standard.

Conclusions

Agreement between AECG and ACR/EULAR criteria sets is excellent. ACR/EULAR criteria are slightly more sensitive and classified some patients without sicca symptoms as having pSS. Including SGUS in the ACR/EULAR criteria may further improve their sensitivity.

     

Confluent Granulomas and Ulcers Lined by Epithelioid Histiocytes: New Ideal Method for Differentiation of ITB and CD? A Meta Analysis

Background

There are few widely accepted criteria other than caseation, which has low sensitivity, for differentiating intestinal tuberculosis (ITB) and Crohn''s disease (CD).

Objective

We performed a meta-analysis to evaluate the use of confluent granulomas and ulcers lined by epithelioid histiocytes as histological methods for differentiating ITB and CD, compared with that of caseation.

Methods

We searched PubMed, Medline, Embase, Web of Science, the Cochrane Library and Chinese Biomedicine Database for all relevant studies on the histological differentiation of ITB and CD. Sensitivity, specificity, and diagnostic odds ratio (DOR) were calculated for each study. Study quality and heterogeneity were assessed. Meta-regression analysis and sensitivity analyses were performed.

Results

Ten randomized trials involving 316 ITB and 376 CD patients were included. The results showed that analysis of caseation showed an overall weighted area under the curve (AUC) of 0.9966, overall sensitivity and specificity were 0.21 and 1.00, respectively, with a positive likelihood ratio (+LR) of 10.79, negative likelihood ratio(-LR) of 0.82 and DOR of 13.74. Confluent granulomas had a lower overall weighted AUC of 0.9381, sensitivity and specificity were 0.38 and 0.99, respectively, with a +LR of 16.29, -LR of 0.65 and DOR of 26.52. Overall weighted AUC for ulcers lined by epithelioid histiocytes was 0.9017, sensitivity and specificity were 0.41 and 0.94, respectively, with a +LR of 6.46, -LR of 0.54 and DOR of 13.17. Significant heterogeneity was noted for the studies. Meta-regression analysis showed that study source, publication year, size, design and quality did not affect heterogeneity.

Conclusion

Confluent granulomas and ulcers lined by epithelioid histiocytes are helpful in distinguishing ITB from CD, which may provide a new method, other than caseating granulomas and acid-fast bacilli, to differentiate ITB and CD in mucosal biopsies.     

Comparison of remission criteria in a tumour necrosis factor inhibitor treated rheumatoid arthritis longitudinal cohort: patient global health is a confounder

Introduction

Our objectives were to assess the frequency and sustainability of American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) and Disease Activity Score (DAS)28(4v)–C-reactive protein (CRP) remission 12 months after the initiation of tumour necrosis factor inhibitor (TNFi) therapy in a rheumatoid arthritis (RA) cohort.

Methods

Data were collected of 273 biologic naive RA patients at baseline, then 3, 6 and 12 months post-TNFi therapy. Remission status was calculated using DAS28(4v)-CRP <2.6 and ACR/EULAR Boolean criteria. Response was scored using EULAR criteria.

Results

Mean (range) patient age was 59.9 (7.2-85.4) years with disease duration of 13.4 (1.0-52.0) years. Responder status maintained from 3–12 months (86%, 82.4%), laboratory/clinical parameters (erythrocyte sedimentation rate (ESR), CRP, patient global health (PGH), DAS28(4v)-CRP) also showed sustained improvement (P < 0.05). DAS28 remission was reached by 102 subjects at 1 year, 27 patients were in Boolean remission, but 75 missed it from the DAS28 remission group. Patients in remission were younger (P = 0.041) with lower baseline tender joint count (TJC)28 and PGH than those not in remission (P = 0.001, P = 0.047). DAS28 remission patients were older (P = 0.026) with higher 12 months PGH and subsequently higher DAS28 than Boolean remission patients (P < 0.0001). Patients not achieving Boolean remission due to missing one subcriteria most frequently missed PGH ≤1 criteria (79.8%).

Conclusions

Only 10% of this TNFi treated cohort achieved remission according to the new ACR/EULAR criteria, which requires lower disease activity. More stringent criteria may ensure further resolution of disease activity and better longterm radiographic outcome, which supports earlier intervention with biologic therapy in RA.     

Comparative Effectiveness of Tocilizumab with either Methotrexate or Leflunomide in the Treatment of Rheumatoid Arthritis

Objective

In agreement with EULAR recommendations, a DMARD in combination with a biotherapy is the reference treatment because of the superior long-term clinical and radiographic outcomes. Methotrexate (MTX) is the cornerstone of combination therapy but is in some cases contra-indicated or poorly tolerated. This observational study aimed to compare the effectiveness and safety of TCZ in combination with either MTX or leflunomide (LEF) in the treatment of patients with active rheumatoid arthritis (RA) and an inadequate response to one or more DMARDs and/or biological agents in a real-world setting.

Methods

We performed an ambispective review of 91 patients with active RA who were routinely treated with TCZ plus MTX or LEF. A comparative study between the two combinations of treatment was performed at 6 months of follow-up considering 3 outcomes: improvement of RA disease activity, evolution of functional disability, and tolerability and side effect profile.

Results

Of the 91 patients, 62 received TCZ with MTX and 29 received TCZ with LEF. Eighty-one patients were followed for 6 months, and the remaining 10 patients discontinued treatment due to serious adverse events. At baseline, there were no significant differences between the groups in terms of the main clinical and laboratory data or in the number of previous DMARDs and biological agents used. At 6 months, there were no significant differences between the combinations in terms of disease activity and functional disability. Serious adverse events occurred in 11% and 10% of the patients treated in combination with MTX and LEF, respectively.

Conclusion

Our preliminary data support the argument that LEF is an effective and safe (equivalent) alternative to MTX for combination treatment with TCZ.     

Sustained rheumatoid arthritis remission is uncommon in clinical practice

Introduction

Remission is an important goal of therapy in rheumatoid arthritis (RA), but data on duration of remission are lacking. Our objective was to describe the duration of remission in RA, assessed by different criteria.

Methods

We evaluated patients from the Brigham and Women''s Rheumatoid Arthritis Sequential Study (BRASS) not in remission at baseline with at least 2 years of follow-up. Remission was assessed according to the Disease Activity Score 28-C-reactive protein (DAS28-CRP4), Simplified Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI) scores, and the recently proposed American College of Rheumatology (ACR)/European League against Rheumatism (EULAR) criteria for remission. Analyses were performed by using Kaplan-Meier survival curves.

Results

We identified 871 subjects with ≥2 years of follow-up. Of these subjects, 394 were in remission at one or more time-points and not in remission at baseline, according to at least one of the following criteria: DAS28-CRP < 2.6 (n = 309), DAS28-CRP < 2.3 (n = 275), SDAI (n = 168), CDAI (n = 170), and 2010 ACR/EULAR (n = 158). The median age for the 394 subjects at entrance to BRASS was 56 years; median disease duration was 8 years; 81% were female patients; and 72% were seropositive. Survival analysis performed separately for each remission criterion demonstrated that < 50% of subjects remained in remission 1 year later. Median remission survival time was 1 year. Kaplan-Meier curves of the various remission criteria did not significantly differ (P = 0.29 according to the log-rank test).

Conclusions

This study shows that in clinical practice, a minority of RA patients are in sustained remission.     

Hemoglobin A1c for Diagnosis of Postpartum Abnormal Glucose Tolerance among Women with Gestational Diabetes Mellitus: Diagnostic Meta-Analysis

Objective

To evaluate the accuracy of glycosylated hemoglobin A1c (HbA1c) for the diagnosis of postpartum abnormal glucose tolerance among women with gestational diabetes mellitus (GDM).

Methods

After a systematic review of related studies, the sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and other measures about the accuracy of HbA1c in the diagnosis of postpartum abnormal glucose tolerance were pooled using random-effects models. The summary receiver operating characteristic (SROC) curve was used to summarize the overall test performance.

Results

Six studies met our inclusion criteria. The pooled results on SEN, SPE, PLR, NLR, and DOR were 0.36 (95% CI 0.23–0.52), 0.85 (95% CI 0.73–0.92), 2.4 (95% CI 1.6–3.6), 0.75 (95% CI 0.63–0.88) and 3 (95% CI 2–5). The area under the summary receiver operating characteristic (SROC) curve was 0.67 with a Q value of 0.63.

Conclusions

Measurement of HbA1c alone is not a sensitive test to detect abnormal glucose tolerance in women with prior GDM.     

The effect of smoking and alcohol consumption on markers of systemic inflammation,immunoglobulin levels and immune response following pneumococcal vaccination in patients with arthritis

Introduction

The purpose of this research was to study the influence of cigarette smoking and alcohol consumption on immune response to heptavalent pneumococcal conjugate vaccine, immunoglobulin levels (Ig) and markers of systemic inflammation in patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA).

Methods

In total, 505 patients were vaccinated. Six pre-specified groups were enrolled: RA on methotrexate (MTX) treatment in some cases other disease-modifying antirheumatic drugs (DMARDs) (I); RA on anti-tumour necrosis factor (TNF) as monotherapy (II); RA on anti-TNF+MTX+ possibly other DMARDs (III); SpA on anti-TNF as monotherapy (IV); SpA on anti-TNF+MTX+ possibly other DMARDs (V); and SpA on nonsteroidal anti-inflammatory drugs (NSAIDs) and/or analgesics (VI). Smoking (pack-years) and alcohol consumption (g/week) were calculated from patient questionnaires. Ig, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined at vaccination. IgG antibodies against serotypes 23F and 6B were measured at vaccination and after four to six weeks using standard ELISA. Immune response (ratio between post- and pre-vaccination antibodies; immune response (IR)) and positive immune response (≥2-fold increase in pre-vaccination antibodies; posIR) were calculated.

Results

Eighty-eight patients (17.4%) were current smokers. Smokers had higher CRP and ESR, lower IgG and lower IR for both serotypes (P between 0.012 and 0.045). RA patients on MTX who smoked ≥1pack-year had lower posIR for both serotypes (P = 0.021; OR 0.29; CI 0.1 to 0.7) compared to never-smokers. Alcohol consumption was associated with lower CRP (P = 0.05) and ESR (P = 0.003) but did not influence IR or Ig levels.

Conclusion

Smoking predicted impaired immune response to pneumococcal conjugate vaccine in RA patients on MTX. Smokers with arthritis had higher inflammatory markers and lower IgG regardless of diagnosis and treatment. Low to moderate alcohol consumption was related to lower levels of inflammation markers but had no impact on immune response.

Trial registration

EudraCT EU 2007-006539-29 and NCT00828997     

A multicenter,double-blind,randomized, controlled phase III clinical trial of chicken type II collagen in rheumatoid arthritis

Introduction

Chicken type II collagen (CCII) is a protein extracted from the cartilage of chicken breast and exhibits intriguing possibilities for the treatment of autoimmune diseases by inducing oral tolerance. A 24-week, double-blind, double-dummy, randomized, methotrexate (MTX)-controlled study was conducted to evaluate the efficacy and safety of CCII in the treatment of rheumatoid arthritis (RA).

Methods

Five hundred three RA patients were included in the study. Patients received either 0.1 mg daily of CCII (n = 326) or 10 mg once a week of MTX (n = 177) for 24 weeks. Each patient was evaluated for pain, morning stiffness, tender joint count, swollen joint count, health assessment questionnaire (HAQ), assessments by investigator and patient, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) by using the standard tools at baseline (week 0) and at weeks 12 and 24. Additionally, rheumatoid factor (RF) was evaluated at weeks 0 and 24. Measurement of a battery of biochemical parameters in serum, hematological parameters, and urine analysis was performed to evaluate the safety of CCII.

Results

Four hundred fifty-four patients (94.43%) completed the 24-week follow-up. In both groups, there were decreases in pain, morning stiffness, tender joint count, swollen joint count, HAQ, and assessments by investigator and patient, and all differences were statistically significant. In the MTX group, ESR and CRP decreased. RF did not change in either group. At 24 weeks, 41.55% of patients in the CCII group and 57.86% in the MTX group met the American College of Rheumatology 20% improvement criteria (ACR-20) and 16.89% and 30.82%, respectively, met the ACR 50% improvement criteria (ACR-50). Both response rates for ACR-20 and ACR-50 in the CCII group were lower than those of the MTX group, and this difference was statistically significant (P < 0.05). The DAS28 (disease activity score using 28 joint counts) values of the two treatment groups were calculated, and there was a statistically significant difference between the two treatment groups (P < 0.05). Gastrointestinal complaints were common in both groups, but there were fewer and milder side effects in the CCII group than in the MTX group. The incidence of adverse events between the two groups was statistically significant (P < 0.05).

Conclusions

CCII is effective in the treatment of RA and is safe for human consumption. CCII exerts its beneficial effects by controlling inflammatory responses through inducing oral tolerance in RA patients.

Trials Registration

Clinical trial registration number: ChiCTR-TRC-00000093.     

Evolution of Direct Costs in the First Years of Rheumatoid Arthritis: Impact of Early versus Late Biologic Initiation - An Economic Analysis Based on the ESPOIR Cohort

Objectives

To estimate annual direct costs of early RA by resource component in an inception cohort, with reference to four distinct treatment strategies: no disease modifying antirheumatic drugs (DMARDs), synthetic DMARDs only, biologic DMARDs in the first year (‘first-year biologic’, FYB), and biologic DMARDs from the second year after inclusion (‘later-year biologic’, LYB); to determine predictors of total and non-DMARD related costs.

Methods

The ESPOIR cohort is a French multicentric, prospective study of 813 patients with early arthritis. Data assessing RA-related resource utilisation and disease characteristics were collected at baseline, biannually during the first two years and annually thereafter. Costs predictors were determined by generalised linear mixed analyses.

Results

Over the 4-year follow-up, mean annual direct total costs per treatment strategy group were €3,612 for all patients and €998, €1,922, €14,791, €8,477 respectively for no DMARDs, synthetic DMARDs only, FYB and LYB users. The main predictors of higher costs were biologic use and higher Health Assessment Questionnaire (HAQ) scores at baseline. Being a biologic user led to a higher total cost (FYB Rate Ratio (RR) 7.22, [95% CI 5.59–9.31]; LYB RR 4.39, [95% CI 3.58–5.39]) compared to non-biologic users. Only LYB increased non-DMARD related costs compared to all other patients by 60%.

Conclusions

FYB users incurred the highest levels of total costs, while their non-DMARD related costs remained similar to non-biologic users, possibly reflecting better RA control.     

Level of agreement between 2002 American–European Consensus Group and 2012 American College of Rheumatology classification criteria for Sjögren’s syndrome and reasons for discrepancies

Introduction

The aims of this study were to assess agreement between the currently used 2002 American–European Consensus Group (AECG) classification criteria and the new 2012 American College of Rheumatology (ACR) criteria for Sjögren’s syndrome (SS) and to identify potential sources of disagreement.

Methods

We studied 105 patients between 2006 and 2013 from the Brittany cohort of patients with suspected SS. AECG criteria were applied using only Schimer’s test and unstimulated whole salivary flow (UWSF) to assess objective ocular and oral involvement, since these are the tests most physicians use in clinical practice. Agreement between the two sets of criteria was assessed using Cohen’s κ coefficient.

Results

Of those studied, 42 patients fulfilled AECG and 35 ACR criteria. Agreement between the two sets was moderate (κ = 0.53). Patients fulfilling ACR but not AECG criteria (n = 8) were significantly younger and had shorter symptom durations, but only three of them had SS in the opinion of the evaluating physician. Xerostomia and xerophthalmia (AECG set only) did not discriminate between patients with and without SS. The use of UWSF in the AECG but not the ACR criteria explained part of the disagreement. The serological item in the ACR set (positive rheumatoid factor and antinuclear antibody ≥1:320 or anti-SSA/SSB positivity) did not result in classification differences compared to anti-SSA/SSB antibody alone (AECG set). Agreement between ocular staining score ≥3 (ACR set) and Schirmer’s test ≤5 mm/5 min (AECG set) was very low (κ = 0.14).

Conclusions

Agreement was only moderate between ACR and AECG criteria, suggesting these two sets would not select comparable patient populations. An international consensus about which classification criteria should be used in clinical studies is needed.     

Meta-Analysis Assessment of GP210 and SP100 for the Diagnosis of Primary Biliary Cirrhosis

Purpose

To conduct a systematic review of included studies assessing the association of GP210 and SP100 with the risk of primary biliary cirrhosis (PBC) using meta-analysis.

Methods

Five databases, the Cochrane Library, MEDLINE, VIP, CNKI, WANFANG were used to detect the role of GP210 and SP100 in diagnosis of PBC. Approximately 13,000 participants from several countries were included in this analysis. Meta-DiSc statistical software was used for analysis.

Results

25 studies on GP210 and 21 studies on SP100 were included in the meta-analysis. The DOR, sensitivity, specificity of GP210 in diagnosis of PBC were 24.854 (11.957–51.660), 0.272 (0.257–0.288), 0.985 (0.982–0.988), respectively, and they were 9.133 (4.739–17.600), 0.231 (0.213–0.249), 0.977 (0.973–0.981) for SP100.

Conclusion

Our meta-analysis indicated both GP210 and SP100 had high specificity but low sensitivity in diagnosis of PBC.     

Efficacy and safety of pateclizumab (anti-lymphotoxin-α) compared to adalimumab in rheumatoid arthritis: a head-to-head phase 2 randomized controlled study (The ALTARA Study)

Introduction

Tumor necrosis factor (TNF) and, possibly, lymphotoxin alpha (LTα) signaling contribute to inflammation and rheumatoid arthritis (RA) pathogenesis. Pateclizumab (anti-lymphotoxin- alpha; MLTA3698A) is a humanized monoclonal antibody that blocks and depletes anti-LTα. This phase 2, randomized, head-to-head, active- and placebo-controlled trial examined the safety and efficacy of pateclizumab compared to adalimumab in RA patients with an inadequate response to disease-modifying antirheumatic drugs (DMARD-IR).

Methods

Patients (n = 214) with active RA (≥6 swollen and tender joints, C-reactive protein ≥10 mg/L) on oral DMARDs were randomized (2:2:1) to receive pateclizumab 360 mg, adalimumab 40 mg, or placebo subcutaneously every 2 weeks. The primary endpoint, 4-variable, 28-joint disease activity score erythrocyte sedimentation rate (DAS28(4)-ESR) response, was evaluated at 12 weeks using an analysis of covariance (ANCOVA) model with adjustments for concomitant DMARD use and geographic region. Secondary efficacy endpoints included American College of Rheumatology (ACR) 20, ACR50, and ACR70 responses at Day 85. Pharmacokinetics, pharmacodynamics, and immunogenicity of pateclizumab were assessed.

Results

Pateclizumab reduced the DAS28(4)-ESR response (−1.89) at 12 weeks, however, this did not reach statistical significance compared to placebo (−1.54), while adalimumab (−2.52) differed significantly from both placebo and pateclizumab. Pateclizumab 12-week ACR20, ACR50 and ACR70 response rates (64%, 33%, and 14%) suggested clinical activity but were not statistically significant compared to placebo rates (46%, 24%, and 8%, respectively). CXCL13 serum levels decreased significantly following pateclizumab and adalimumab administration, demonstrating pharmacological target engagement by both drugs. Overall, adverse events (AEs) were comparable among all cohorts. Infections were the most common AE, occurring with comparable frequency in all groups. Serious AEs occurred in 0% of pateclizumab, 5.9% of adalimumab, and 2.3% of placebo patients, with serious infection in 2.3% of adalimumab patients and none in pateclizumab and placebo patients.

Conclusions

Pateclizumab had a good safety profile in patients inadequately responsive to DMARDs, but no statistically significant improvement in RA signs and symptoms after 12 weeks of treatment. Adalimumab demonstrated efficacy and safety comparable to published results in this head-to-head comparison in DMARD-IR RA patients.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01225393","term_id":"NCT01225393"}}NCT01225393, Registered 18 October 2010.     

Masitinib in the treatment of active rheumatoid arthritis: results of a multicentre,open-label,dose-ranging,phase 2a study

Introduction

Since current treatment options for patients suffering from active rheumatoid arthritis (RA) remain inadequate, especially for those unresponsive to disease-modifying antirheumatic drugs (DMARDs), new and improved medication is needed. This study evaluates the safety and efficacy of masitinib (AB1010), a potent and selective protein tyrosine kinase inhibitor of c-KIT, in the monotherapy treatment of DMARD-refractory RA.

Methods

This was a multicentre, uncontrolled, open-label, randomised, dose-ranging, phase 2a trial. Masitinib was administered orally to 43 patients who had inadequate response to DMARDs, at initial randomised dosing levels of 3 and 6 mg/kg per day over a 12-week period. Dose adjustment was permitted based upon tolerability and response criteria. Efficacy was assessed via American College of Rheumatology 20%/50%/70% improvement criteria (ACR20/50/70) responses, disease activity score using 28 joint counts (DAS28), index of improvement in RA (ACRn) and C-reactive protein (CRP) improvement, relative to baseline at week 12.

Results

Improvement was observed in all efficacy endpoints, including ACR20/50/70 scores of 54%, 26% and 8%, respectively, and a reduction in CRP level by greater than 50% for approximately half the population. This improvement was sustainable throughout an extension phase (> 84 weeks) and was also independent of initial DMARD resistance (anti-tumour necrosis factor-alpha and/or methotrexate). A relatively high patient withdrawal rate (37%) required the use of last observation carried forward (LOCF) data imputation. Incidence of adverse events was high (95%), although the majority were of mild or moderate severity with a considerable decline in frequency observed after 12 weeks of treatment. Two nonfatal serious adverse events were reported. Dose-response analyses tentatively indicate that an initial dosing level of 6.0 mg/kg per day administered orally in two daily intakes is the most appropriate, based upon potency and tolerability trends.

Conclusions

Treatment with masitinib improved DMARD-refractory active RA. Following an initial high incidence of mostly mild to moderate side effects during the first 12 weeks of treatment, masitinib appears to be generally well tolerated. This, together with evidence of a sustainable efficacy response, suggests that masitinib is suitable for long-term treatment regimens. Since this was the first study of masitinib in a nononcologic pathology, the relatively high patient withdrawal rate observed can be partly attributed to a highly cautious response to adverse events. There is sufficient compelling evidence to warrant further placebo-controlled investigation.

Trial registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00831922","term_id":"NCT00831922"}}NCT00831922.     

Diagnostic accuracy of blood B-cell subset profiling and autoimmunity markers in Sj?gren’s syndrome

Introduction

The aims of this study were to evaluate the diagnostic accuracy of blood B-cell subset profiling and immune-system activation marker assays in primary Sjögren’s syndrome (pSS) and to assess whether adding these tools to the current laboratory item would improve the American-European Consensus Group (AECG) criteria.

Methods

In a single-center cohort of patients with suspected pSS, we tested the diagnostic performance of anti-SSA, antinuclear antibody (ANA), rheumatoid factor (RF), gammaglobulins, IgG titers, and B-cell ratio defined as (Bm2 + Bm2′)/(eBm5 + Bm5), determined using flow cytometry. The reference standard was a clinical diagnosis of pSS established by a panel of experts.

Results

Of 181 patients included in the study, 77 had pSS. By logistic regression analysis, only ANA ≥1:640 (sensitivity, 70.4%; specificity 83.2%) and B-cell ratio ≥5 (sensitivity, 52.1%; specificity, 83.2%) showed independent associations with pSS of similar strength. In anti-SSA-negative patients, presence of either of these two criteria had 71.0% sensitivity but only 67.3% specificity for pSS; whereas combining both criteria had 96.2% specificity but only 12.9% sensitivity. Adding either of these two criteria to the AECG criteria set increased sensitivity from 83.1% to 90.9% but decreased specificity from 97.1% to 85.6%, whereas adding both criteria in combination did not substantially modify the diagnostic performance of the criteria set. The adjunction of RF + ANA ≥1:320, as proposed in the new American College of Rheumatology (ACR) criteria, did not improve the diagnostic value of anti-SSA.

Conclusions

Blood B-cell subset profiling is a simple test that has good diagnostic properties for pSS. However, adding this test, with or without ANA positivity, does not improve current classification criteria.     

Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis

Introduction

The aim of this study was to determine the prevalence of gastrointestinal and behavioural symptoms occurring before (anticipatory/associative) and after methotrexate (MTX) administration, termed MTX intolerance, in rheumatoid (RA) and psoriatic arthritis (PsA).

Methods

Methotrexate Intolerance Severity Score (MISS), previously validated in juvenile idiopathic arthritis patients, was used to determine MTX intolerance prevalence in 291 RA/PsA patients. The MISS consisted of four domains: abdominal pain, nausea, vomiting and behavioural symptoms, occurring upon, prior to (anticipatory) and when thinking of MTX (associative). MTX intolerance was defined as ≥6 on the MISS with ≥1 point on anticipatory and/or associative and/or behavioural items.

Results

A total of 123 patients (42.3%) experienced at least one gastrointestinal adverse effect. The prevalence of MTX intolerance was 11%. MTX intolerance prevalence was higher in patients on parenteral (20.6%) than on oral MTX (6.2%) (p < 0.001).

Conclusion

Besides well-known gastrointestinal symptoms after MTX, RA and PsA patients experienced these symptoms also before MTX intake. RA and PsA patients on MTX should be closely monitored with the MISS for early detection of MTX intolerance, in order to intervene timely and avoid discontinuation of an effective treatment.     

Diagnostic Value of Mutation-Specific Antibodies for Immunohistochemical Detection of Epidermal Growth Factor Receptor Mutations in Non-Small Cell Lung Cancer: A Meta-Analysis

Background

Various studies have assessed the diagnostic accuracy of EGFR mutation-specific antibodies in non-small cell lung cancer (NSCLC). We performed a meta-analysis of existing data to investigate the diagnostic value of mutation-specific antibodies for detection of EGFR mutations in NSCLC.

Methods

We systematically retrieved relevant studies from PubMed, Web of Knowledge, and Google Scholar. Data from studies that met the inclusion criteria were extracted for further exploration of heterogeneity, including calculation of the average sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and analysis of SROC(summary receiver operating characteristic) curves.

Results

Fifteen studies met our inclusion criteria. A summary of the meta-analysis of the efficacy of the anti-E746-A750 antibody was as follows: sensitivity, 0.60 (95% CI, 0.55–0.64); specificity, 0.98 (95% CI, 0.97–0.98); PLR, 33.50 (95% CI, 13.96–80.39); NLR, 0.39 (95% CI, 0.30–0.51) and DOR, 111.17 (95% CI, 62.22–198.63). A similar meta-analysis was performed for the anti-L858R antibody with results as follows: sensitivity, 0.76 (95% CI, 0.71–0.79); specificity, 0.96 (95% CI, 0.95–0.97); PLR, 24.42 (95% CI, 11.66–51.17); NLR, 0.22 (95% CI, 0.12–0.39) and DOR, 126.66 (95% CI, 54.60–293.82).

Conclusion

Immunohistochemistry alone is sufficient for the detection of EGFR mutations if the result is positive. Molecular-based analyses are necessary only if the anti-E746-A750 antibody results are negative. Immunohistochemistry seems more suitable for clinical screening for EGFR mutations prior to molecular-based analysis.