Sacroiliac joint MRI for diagnosis of ax-SpA: algorithm to improve the specificity of the current ASAS MRI criteria.

OBJECTIVE: To compare sacroiliac joint (SIJ) lesions on MRI in women with versus without axial spondyloarthritis (ax-SpA) and establish an algorithm to determine whether such lesions are due to ax-SpA. METHODS: This retrospective comparative study assessed bone marrow edema (BME), sclerosis, erosions, osteophytes, and ankylosis at the SIJ in two groups of women, one with and another without ax-SpA. Sensitivity and specificity were calculated for combinations/characteristics of lesions, using rheumatologists' assessment with assessment of spondyloarthritis international society (ASAS) criteria as the gold standard for diagnosis of ax-SpA. RESULTS: Compared to women without ax-SpA, women with ax-SpA had more BME (61% vs 17%, p < 0.001), sclerosis (40% vs 22%, p < 0.001), erosions (35% vs 5%, p < 0.001), and ankylosis (2% vs 0%, p = 0.007), but less osteophytes (5% vs 33%, p < 0.001). The ASAS MRI criteria yielded 59% sensitivity and 88% specificity, while a new algorithm achieved 56% sensitivity and 95% specificity using the following criteria: no osteophytes at the SIJ and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. CONCLUSIONS: We recommend the following pragmatic algorithm for MRI diagnosis of ax-SpA in women: no osteophytes at the SIJ and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. The false positive rate when using the new algorithm (3.3%) is less than half than when using the ASAS MRI criteria (7.7%); thus, its application in clinical practice could reduce overdiagnosis and prevent overtreatment of ax-SpA. CLINICAL RELEVANCE STATEMENT: The developed algorithm has a false-positive rate that is less than half than when using the ASAS MRI criteria (3.3% vs 7.7%), thus its application in clinical practice could reduce overdiagnosis and prevent overtreatment of axial spondyloarthritis. KEY POINTS: • Compared to women without axial spondyloarthritis (ax-SpA), women with ax-SpA had a significantly higher prevalence of bone marrow edema (BME), sclerosis, erosions, and ankylosis, but a significantly lower prevalence of osteophytes. • A new algorithm for positive ax-SpA based on sacroiliac joint MRI was developed: no osteophytes at the sacroiliac joint (SIJ) and either (i) BME at the SIJ with at least one dimension ≥ 8 mm or (ii) at least one erosion at the SIJ. • We recommend this new algorithm for diagnosis of ax-SpA in women, as it has a significantly better specificity than the assessment of spondyloarthritis international society (ASAS) MRI criteria and less than half the false positive rate; thus, its application in clinical practice could reduce overdiagnosis and prevent overtreatment of ax-SpA.

Risk of diverticulitis and gastrointestinal perforation in rheumatoid arthritis treated with tocilizumab compared to rituximab or abatacept.

OBJECTIVE: To compare the risk of diverticulitis and gastrointestinal perforation (GIP) in RA treated with tocilizumab (TCZ) compared with rituximab (RTX) and abatacept (ABA). METHODS: We conducted a population-based study using three observational French registries on TCZ, RTX and ABA in RA. Using a propensity score approach, we compared the risk of diverticulitis or GIP in these patients. RESULTS: With inverse probability weighting, there was an increased risk of diverticulitis in TCZ-treated patients compared with RTX- or ABA-treated patients [hazard ratio (HR)=3.1 (95% CI: 1.5, 6.3), P =0.002]. Moreover, patients treated with TCZ had also an increased risk of GIP due to diverticulitis compared with those treated with RTX or ABA [HR=3.8 (1.1-13.6), P =0.04], resulting in an overall increased risk of GIP [HR=2.9 (1.1-7.8), P =0.03], while no significant increased risk of GIP due to any other aetiology was found in TCZ treated patients. Diverticulitis and GIP occurred earlier with TCZ than other drugs after the last perfusion (P =0.01), with atypical clinical presentation (slow transit in 30%, P =0.04) and lower acute-phase reactants at the time of the event (P =0.005). CONCLUSION: TCZ for RA was associated with increased odds of diverticulitis as well as GIP due to diverticulitis as compared with RTX and ABA. Our study confirms the increased odds of GIP in patients receiving TCZ, which might be explained by an increased risk of diverticulitis with misleading clinical presentation.

Rheumatoid arthritis is associated with increased gut permeability and bacterial translocation which are reversed by inflammation control.

OBJECTIVE: to assess how rheumatoid arthritis (RA) and Disease Modifying Anti Rheumatic Drugs (DMARDs) affect gut permeability. METHODS: to explore colonic mucosa integrity, tight junction proteins ZO-1, occludin and claudin 2 were quantified by immunohistochemistry on colonic biopsies in 20 RA patients and 20 age- and sex-matched controls. Staining intensity was assessed by two blinded independent readers. To explore intestinal permeability, serum concentrations of LPS-binding protein (LBP), sCD14 and zonulin-related proteins (ZRP) were evaluated by ELISA in another cohort of 59 RA: 21 patients naive of DMARDs (17 before and after introduction of a conventional synthetic (cs) DMARDs), 38 patients with severe RA (before and after introduction of a biological (b) DMARDs), and 33 healthy controls. RESULTS: Z0-1 protein was less expressed in colon of RA patients than controls (mean score ± SEM of 1.6 ± 0.56 vs 2.0 ± 0.43; p= 0.01), while no significant difference was detected for occludin and claudin-2. RA patients had higher serum LBP and sCD14 concentrations than controls. LBP and sCD14 levels were significantly correlated with DAS28 (r = 0.61, p= 0.005 and r = 0.57, p= 0.01, respectively) while ZRP did not. bDMARD responders had significantly reduced LBP and sCD14 concentrations unlike bDMARDs non-responders and patients treated with csDMARDs. CONCLUSION: RA patients have altered colonic tight junction proteins and increased serum biomarkers of intestinal permeability. There was a correlation between serological markers of intestinal permeability and disease activity as well as bDMARD response. These results suggest a link between impaired gut integrity and systemic inflammation in RA.

Rheumatoid arthritis is associated with increased gut permeability and bacterial translocation which are reversed by inflammation control.

OBJECTIVE: to assess how rheumatoid arthritis (RA) and Disease Modifying Anti Rheumatic Drugs (DMARDs) affect gut permeability. METHODS: to explore colonic mucosa integrity, tight junction proteins ZO-1, occludin and claudin 2 were quantified by immunohistochemistry on colonic biopsies in 20 RA patients and 20 age- and sex-matched controls. Staining intensity was assessed by two blinded independent readers. To explore intestinal permeability, serum concentrations of LPS-binding protein (LBP), sCD14 and zonulin-related proteins (ZRP) were evaluated by ELISA in another cohort of 59 RA: 21 patients naive of DMARDs (17 before and after introduction of a conventional synthetic (cs) DMARDs), 38 patients with severe RA (before and after introduction of a biological (b) DMARDs), and 33 healthy controls. RESULTS: Z0-1 protein was less expressed in colon of RA patients than controls (mean score ± SEM of 1.6 ± 0.56 vs 2.0 ± 0.43; p= 0.01), while no significant difference was detected for occludin and claudin-2. RA patients had higher serum LBP and sCD14 concentrations than controls. LBP and sCD14 levels were significantly correlated with DAS28 (r = 0.61, p= 0.005 and r = 0.57, p= 0.01, respectively) while ZRP did not. bDMARD responders had significantly reduced LBP and sCD14 concentrations unlike bDMARDs non-responders and patients treated with csDMARDs. CONCLUSION: RA patients have altered colonic tight junction proteins and increased serum biomarkers of intestinal permeability. There was a correlation between serological markers of intestinal permeability and disease activity as well as bDMARD response. These results suggest a link between impaired gut integrity and systemic inflammation in RA.

Trajectories in early rheumatoid arthritis related fatigue over 10 years: results from the ESPOIR cohort.

OBJECTIVES: In a cohort of early rheumatoid arthritis (RA) patients, we aimed to determine and characterise fatigue trajectories over 10 years of follow-up and identify predictors of trajectory membership. METHODS: We selected patients fulfilling the 2010 ACR/EULAR criteria for RA included in the ESPOIR cohort. We used a cluster analysis to obtain fatigue (assessed by fatigue visual analogue scale) trajectories over the course of 10 years from enrolment. Chi-square tests or ANOVA were performed to evaluate differences of baseline variables between fatigue trajectories. Using a multinomial logistic regression we were able to identify predictors of trajectory membership. RESULTS: We analysed 598 patients with mean disease duration at enrolment of 26.2±40.9 days. Cluster analysis revealed 3 trajectories: high (18%), moderate (52%) and low fatigue (30%). Compared to patients with moderate or low fatigue trajectory, patients with high fatigue trajectory were predominantly women and reported significantly higher duration and intensity of morning stiffness, HAQ score, tender joints count, levels of pain, number of awakenings due to arthritis, frequency of fibromyalgic RA, levels of physician and patient global assessment, more frequent sleep problems, and increased psychological distress. Female patients with pain, psychological distress and presence of sicca symptoms had a higher risk of being in the high trajectory group. CONCLUSIONS: These findings suggest that levels of fatigue are rather stable over time in each trajectory. Baseline clinical measures and baseline patient-reported measures of functional status better distinguished the three fatigue trajectories. We did not find any differences between trajectories in baseline laboratory measures. Inflammatory activity was not a predictor of being in the high trajectory fatigue group.

Change in MRI in patients with spondyloarthritis treated with anti-TNF agents: systematic review of the literature and meta-analysis.

OBJECTIVES: Magnetic resonance imaging (MRI) is currently the most accurate imaging tool used in axial spondyloarthritis regarding its diagnostic approach. MRI of the spine and sacroiliac joints (SIJ) might be relevant in the follow-up of axial spondyloarthritis for difficult cases, provided that its validity and correlation with clinical, biological and functional outcomes is ascertained. The aim of this study was to assess the effect of TNF alpha inhibitors (TNFi) on MRI scoring of inflammation on spine and SIJ and to evaluate their correlation with the parameters used in daily practice. METHODS: A systematic review of the literature using PUBMED and the Cochrane library was performed until January 2016. All randomised controlled trials and controlled cohorts reporting the effect of TNFi on spine and SIJ MRI scores [Ankylosing Spondylitis spine MRI (ASspiMRI), Spondyloarthritis Research Consortium of Canada (SPARCC), and Berlin] were selected. The collected outcomes were: the change in scores between baseline and follow-up in TNFi and control groups, the correlation of these changes with C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index/Functional Index (BASDAI/BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS), pain and morning stiffness. When appropriate, statistical analysis determined the pooled therapeutic effect of TNFi on MRI scores computed by meta-analysis. RESULTS: Of 39 screened references, 55 studies were included. In studies using ASspiMRI at 12-week and 2-year follow-up, and in those using SPARCC spine score at 12-week follow-up, a non-significant decrease in MRI score between the TNFi group and control group was reported (p=0.36; p=0.73; p=0.12, respectively). Only a significant decrease in the SPARCC SIJ score was reported at 12 weeks in the TNFi group versus control (p<0.0001). The correlation between MRI spine and SIJ scores on the one hand, and the clinical and biological data on the other was very heterogeneous across the different reports. However, an association was usually reported between the MRI scores and CRP, ESR and ASDAS. CONCLUSIONS: There is not sufficient evidence to distinguish the difference between changes in MRI inflammatory lesions of the spine and SIJ in patients with axial SpA related to TNF alpha inhibitor effects and those due to the natural course of the disease activity (alternating periods of flares and remission in axial SpA).

Cardiovascular events and change in cholesterol levels in patients with rheumatoid arthritis treated with tocilizumab: data from the REGATE Registry.

OBJECTIVES: Rheumatoid arthritis (RA) is responsible for excess mortality mainly due to cardiovascular disease. Studies have found elevated cholesterol levels in RA patients who received tocilizumab (TCZ). We studied the occurrence of major cardiovascular events in RA patients who received TCZ in current practice. We also analysed cholesterol level changes in these patients. METHODS: Data were collected from the French REGATE Registry, a multicentre observational study including patients with RA treated with TCZ. All cardiovascular complications were analysed. Changes in cholesterol levels were studied. Factors associated with major adverse cardiac and cerebrovascular events were analysed by multivariate analysis, estimating odds ratios and 95% confidence intervals. RESULTS: During an exposure time of 5591 patient-years (PYs), 35 cardiovascular events occurred in 33 patients, corresponding to an incidence of 0.63/100 PYs. The incidence of ischaemic stroke and cardiac ischaemia was 0.41 and 0.21/100 PYs. Age and personal history of cardiovascular events were identified as risk factors associated with cardiovascular events: OR=1.06 [95% CI 1.02-1.09] and 4.10 [1.90-8.83]. Female sex was a protective factor (OR=0.29 [95% CI 0.14-0.64]). Glucocorticoids may play a role but was not statistically significant. All cholesterol variables were increased in level after the third month of treatment with TCZ, with a 15.4%, 18.9% and 13.4% increase for total cholesterol, LDL-C and HDL-C, at 3 months. CONCLUSIONS: In current practice, cardiovascular events occurring under TCZ treatment is in the range of what is expected in RA patients despite a global increase in cholesterol levels.

Use of eHealth by Patients With Rheumatoid Arthritis: Observational, Cross-sectional, Multicenter Study.

BACKGROUND: The use of eHealth tools (eg, the internet, mobile apps, and connected devices) in the management of chronic diseases and for rheumatoid arthritis is growing. eHealth may improve the overall quality of care provided to patients with chronic diseases. OBJECTIVE: The primary objective of this study was to describe eHealth use by patients with rheumatoid arthritis in France. The secondary objectives were to identify associations between patient demographics and disease characteristics and the use of eHealth tools, and assess their expectations of eHealth. METHODS: In this cross-sectional, multicenter study, patients with rheumatoid arthritis, according to the 2010 ACR/EULAR classification criteria, were recruited from 5 university hospitals (Bordeaux, Clermont-Ferrand, Limoges, Montpellier, and Toulouse). Patients completed an anonymous self-questionnaire, including demographic data, evaluating their eHealth use (ie, access, support, frequency of use, type of use, and reason for use). The rheumatologist in charge of each patient completed an independent medical questionnaire on disease characteristics, activity of rheumatoid arthritis, and treatments. Data were collected between December 2018 and July 2019. RESULTS: Questionnaires were completed by 575 participants, with a mean age of 62 (SD 13) years, 447 (77.7%) of whom were female. Overall, 82.2% (473/575) of the participants had access to eHealth through a computer (402/467, 86.1%), tablet (188/467, 40.2%), or smartphone (221/467, 47.3%). Of these, 36.4% (170/467) of the participants used the internet for health in general, and 28.7% (134/467) used it specifically for rheumatoid arthritis-related reasons. All these 134 patients used eHealth to learn about disease pathology, and 66.4% (89/134) of them used it as a tool to help monitor rheumatoid arthritis. Most patients (87/125, 69.6%) had a paper file, 19.2% (24/125) used a digital tool (spreadsheets, 10/125, 8%; mobile app, 9/125, 7.2%; or website, 5/125, 4%), and 24.8% (31/125) did not use any tools for monitoring. Few patients (16/125, 12.8%) used tools for treatment reminders. About 21.6% (27/125) of the patients using eHealth used a specific app for rheumatoid arthritis. Univariate analysis showed that age, education level, employment status, treatment, comorbidities, membership of a patient association, and patient education program were associated with eHealth use for rheumatoid arthritis. Multivariate analysis showed that membership of a patient association (odds ratio [OR] 5.8, 95% CI 3.0-11.2), use of biologic disease-modifying antirheumatic drugs (OR 0.6, 95% CI 0.4-1.0), and comorbidities (OR 0.7, 95% CI 0.6-0.8) remained associated with eHealth use for rheumatoid arthritis. Recommendation by a doctor (225/330, 68.2%), ease of use (105/330, 31.8%), and data security (69/330, 20.9%) were factors favoring the use of eHealth. CONCLUSIONS: To date, few patients have used eHealth for disease management. The use of a reliable and validated eHealth tool for rheumatoid arthritis could therefore be promoted by rheumatologists and could optimize therapeutic adherence.

MRI of sacroiliac joints for the diagnosis of axial SpA: prevalence of inflammatory and structural lesions in nulliparous, early postpartum and late postpartum women.

OBJECTIVES: To determine the prevalence of bone marrow oedema (BME) at the sacroiliac joint (SIJ) in early postpartum (EPP), nulliparous (NP) and late postpartum (LPP) women, and to identify factors associated with BME presence at the SIJ. METHODS: Three groups were obtained: NP (never given birth), EPP (given birth within 12 months) and LPP (given birth more than 24 months). The primary outcome was the presence of BME and/or structural lesions (erosions, osteophytes, ankylosis and sclerosis) at the SIJ MRI. RESULTS: BME prevalence was greater among EPP (33%) than NP (14%, p=0.001), but was not different to LPP (21%, p=0.071). The Assessment of SpondyloArthritis international Society (ASAS) MRI criteria for sacroiliitis were positive in 75%, 71% and 80%, respectively, of EPP, NP and LPP women with BME. EPP (38%) had similar prevalence of sclerosis than LPP (28%, p=0.135), but greater than NP (18%, p=0.001). Lastly, EPP (28%) had similar prevalence of osteophytes than LPP (42%) and NP (27%), although there was a difference between LPP and NP (p=0.006). CONCLUSIONS: EPP have higher BME prevalence at the SIJ than NP, EPP tend to have higher BME prevalence compared with LPP and BME presence decreases with time from delivery. Three-quarters of women with BME at the SIJ had a positive ASAS MRI criteria for sacroiliitis, indicating that BME presence as the main criterion for a positive diagnosis can lead to false-positive results. SIJ MRIs should not be interpreted in isolation, since age, time from delivery and other factors may outweigh the pertinence of MRI findings. Trial registration number NCT02956824.

A simplified radiographic score effectively predicts radiographic progression of early arthritis in a large nationwide French cohort.

OBJECTIVE: Evaluating radiographic progression is a key component of the follow-up of patients with RA. Existing scores are ill-suited to everyday clinical practice. The objective here was to validate a new simplified radiographic score (SRS) for evaluating radiographic progression in patients with early arthritis. METHODS: Patients with arthritis of <6 months' duration were included in the large, prospective, nationwide, French ESPOIR cohort. Radiographs of the hands and feet were obtained at inclusion then 1 and 5 years later. The modified Sharp scores and SRS were determined by blinded readers. Interobserver reliability and intraobserver repeatability of each score, as well as agreement between the two scores, were assessed by computing the intraclass correlation coefficients. The rates of progression over the first year and the next 4 years were determined. RESULTS: The 506 patients with complete data for the first 5 years were included. At inclusion, the intraclass correlation coefficient between the two scores was good for erosions (0.715, P < 0.001), joint space narrowing (0.892, P < 0.001) and the total score (0.896, P < 0.001). Agreement between the two scores was also good for radiographic progression after 1 year (0.781, P < 0.001). The SRS had good positive and negative predictive values for slow and for rapid progression. SRS determination was less time consuming. CONCLUSION: The SRS is effective for monitoring radiographic progression in early arthritis and is easier to use and less time-consuming than the Sharp score. The usefulness of the SRS in clinical practice deserves further evaluation.

Safety of surgery in patients with rheumatoid arthritis treated with tocilizumab: data from the French (REGistry -RoAcTEmra) Regate registry.

OBJECTIVES: To investigate the frequency and risk factors of postoperative complications in RA patients treated with tocilizumab (TCZ). METHODS: The French registry REGATE recruited 1496 RA patients receiving TCZ in routine care. Data from patients treated with TCZ who underwent surgery were reviewed. Frequency of post-surgery complications was collected and compared in patients with and without complications in order to identify factors associated with complications. Similar analysis was performed in patients with postoperative infection. RESULTS: We identified 167 patients who underwent 175 surgical procedures including 103 orthopaedic surgeries (58.9%). The patients were mainly women (84%) with a mean disease duration of 14.96±11.29 years. The mean delay between surgery and the last TCZ infusion was 4.94±1.74 weeks. Fifteen patients experienced 15 complications (8.6%) with 10 severe infections including 5 surgical site infections (33.3%). There was no significant difference between patients with and without complications. In multivariate analysis, previous treatment with rituximab in the previous year tended to be associated with postoperative complications (OR: 3.27, IC95% 0.92-11.49, p=0.06). Concerning postoperative infections, diabetes mellitus tended to be associated with this complication (OR: 3.73, IC95% 0.88-15.79, p=0.06) in multivariate analysis. CONCLUSIONS: In RA patients treated with TCZ in perfusion, the rate of surgical complications was low: 8.6%. The median time between surgery and last infusion was relatively short according to half-life of TCZ but did not influence the rate of postoperative complications.

Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis.

OBJECTIVE: Cardiovascular disease (CVD) is the leading cause of mortality in patients with rheumatoid arthritis (RA). Hydroxychloroquine (HCQ) has been shown to improve survival rates in other inflammatory diseases. We aimed to assess the available literature on the cardiovascular impact of HCQ in patients with RA. METHODS: We systematically searched for studies evaluating the effects of HCQ on cardiovascular outcomes of known risk factors for CVD in patients with RA. Databases searched were MEDLINE (via PubMed), EMBase, Cochrane Library and the American College of Rheumatology and European League Against Rheumatism annual meetings. A meta-analysis was performed with a random-effects model, estimating mean differences (MDs), HRs and 95% CIs. Data were extracted by one investigator and independently checked by another. RESULTS: The literature search revealed 185 articles and abstracts of interest; further examination resulted in 16 studies fulfilling the criteria. The MDs between HCQ users and non-users in levels of total, low-density and high-density cholesterol and triglycerides were -9.8 (95% CI -14.0 to -5.6), -10.6 (95% CI -14.2 to -7.0), +4.1 (95% CI 2.2 to 6.0) and -19.2 (95% CI -27.2 to -11.1), respectively. Diabetes incidence was lower for HCQ ever users than never users (HR 0.59 (95% CI 0.49 to 0.70)). HCQ seemed to decrease insulin resistance and incidence of CVD, but data were too few for meta-analysis. CONCLUSION: Besides its limited efficacy for disease activity and progression, HCQ may benefit the metabolic profile and to a lesser extent cardiovascular events in patients with RA, which suggests its usefulness combined with other conventional synthetic disease-modifying antirheumatic drugs.

Risk of losing remission, low disease activity or radiographic progression in case of bDMARD discontinuation or tapering in rheumatoid arthritis: systematic analysis of the literature and meta-analysis.

OBJECTIVES: To assess the risk of losing remission, low disease activity (LDA) or radiographic progression in the case of (1) discontinuing or (2) tapering doses of biological disease-modifying antirheumatic drugs (bDMARDs) compared with continuation of the initial treatment regimen in rheumatoid arthritis (RA) patients with remission or LDA. MATERIALS AND METHODS: A systematic literature analysis was carried out through May 2017 on the PubMed, Embase, Cochrane and international congress databases, selecting controlled trials comparing bDMARDs discontinuation/tapering versus continuation in RA patients with remission or LDA. The meta-analysis assessed the risk ratio (RR) and 95% CI of losing remission or LDA and the risk of radiographic progression after (1) discontinuing and (2) tapering doses of bDMARDs versus continuing the initial treatment. RESULTS: The meta-analysis comparing bDMARDs discontinuation versus continuation performed on nine trials showed an increased risk of losing remission (RR (95% CI)=1.97(1.43 to 2.73), P<0.0001) or LDA (RR (95% CI)=2.24(1.52 to 3.30), P<0.0001) and an increased risk of radiographic progression (RR (95% CI)=1.09(1.02 to 1.17), P=0.01) in case of bDMARD discontinuation. The meta-analysis comparing bDMARDs tapering versus continuation performed on 11 trials showed an increased risk of losing remission (RR (95% CI)=1.23(1.06 to 1.42), P=0.006) but no increased risk of losing LDA (RR (95% CI)=1.02 (0.85 to 1.23), P=0.81) nor any increased risk of radiographic progression (RR (95% CI)=1.09(0.94 to 1.26), P=0.26) in case of bDMARD tapering. CONCLUSION: Discontinuation of bDMARDs leads to an increased risk of losing remission or LDA and radiographic progression, while tapering doses of bDMARDs does not increase the risk of relapse (LDA) or radiographic progression, even though there is an increased risk of losing remission.

Genetic analysis of adults heterozygous for ALPL mutations.

Hypophosphatasia (HPP) is a rare inherited metabolic bone disease due to a deficiency of the tissue nonspecific alkaline phosphatase isoenzyme (TNSALP) encoded by the ALPL gene. Patients have consistently low serum alkaline phosphatase (AP), so that this parameter is a good hallmark of the disease. Adult HPP is heterogeneous, and some patients present only mild nonpathognomonic symptoms which are also common in the general population such as joint pain, osteomalacia and osteopenia, chondrocalcinosis, arthropathy and musculoskeletal pain. Adult HPP may be recessively or dominantly inherited; the latter case is assumed to be due to the dominant negative effect (DNE) of missense mutations derived from the functional homodimeric structure of TNSALP. However, there is no biological argument excluding the possibility of other causes of dominant HPP. Rheumatologists and endocrinologists are increasingly solicited for patients with low AP and nonpathognomonic symptoms of HPP. Many of these patients are heterozygous for an ALPL mutation and a challenging question is to determine if these symptoms, which are also common in the general population, are attributable to their heterozygous ALPL mutation or not. In an attempt to address this question, we reviewed a cohort of 61 adult patients heterozygous for an ALPL mutation. Mutations were distinguished according to their statistical likelihood to show a DNE. One-half of the patients carried mutations predicted with no DNE and were slightly less severely affected by the age of onset, serum AP activity and history of fractures. We hypothesized that these mutations result in another mechanism of dominance or are recessive alleles. To identify other genetic factors that could trigger the disease phenotype in heterozygotes for potential recessive mutations, we examined the next-generation sequencing results of 32 of these patients for a panel of 12 genes involved in the differential diagnosis of HPP or candidate modifier genes of HPP. The heterozygous genotype G/C of the COL1A2 coding SNP rs42524 c.1645C > G (p.Pro549Ala) was associated with the severity of the phenotype in patients carrying mutations with a DNE whereas the homozygous genotype G/G was over-represented in patients carrying mutations without a DNE, suggesting a possible role of this variant in the disease phenotype. These preliminary results support COL1A2 as a modifier gene of HPP and suggest that a significant proportion of adult heterozygotes for ALPL mutations may have unspecific symptoms not attributable to their heterozygosity.

Improvement of fatigue in patients with rheumatoid arthritis treated with biologics: relationship with sleep disorders, depression and clinical efficacy. A prospective, multicentre study.

OBJECTIVES: To assess predictive factors of improvement in related fatigue in rheumatoid arthritis (RA) patients newly receiving biologic therapy, and specifically the influence of the improvement of the quality of sleep. METHODS: We conducted a multicentre prospective study in RA patients requiring initiation or change of biologic therapy. The improvement in fatigue, sleep disorders and depression was assessed respectively by the FACIT fatigue scale, Spiegel scale and Beck Depression Inventory at inclusion (M0) and 3 months (M3) after the beginning of treatment. Potential confounders were assessed and adjusted for. The association between evolution of fatigue and other characteristics were evaluated by univariate (χ2) then multivariate (logistic regression) analyses. RESULTS: We followed-up 99 patients. FACIT scores at M0 revealed frequently reported fatigue: 89%, high prevalence of sleep disorders: 95% and depression: 67%. Improvement of fatigue, sleep quality and depression was observed in 58.6%, 26.3% and 34.3% of cases, respectively. Significant factors associated with an improvement in fatigue at M3 were an elevated sedimentation rate at M0 (OR=5.7[2.0-16.0], p=0.001) and a favourable EULAR response at M3 (OR=4.8[1.6-14.8], p=0.006). Furthermore, a number of swollen joints > 5 at baseline (OR=0.3 [0.1-0.8]) and the use of psychotropic drugs (OR=0.2[0.04-0.9]) were predictive of an absence of improvement in fatigue. No significant association with the improvement in sleep disorders could be demonstrated. CONCLUSIONS: Fatigue in RA is improved by effective treatment, via decreasing disease activity. Improvement of sleep disorders is more likely a surrogate of therapeutic efficiency rather than an independent outcome.

Performance of patient-reported outcomes in the assessment of rheumatoid arthritis disease activity:the experience of the ESPOIR cohort.

OBJECTIVES: Rheumatoid arthritis (RA) activity can be assessed by several outcome measures. The importance of patient-reported outcomes (PROs) has recently been advocated. Our objective was to determine whether patient self-assessment can reflect RA disease activity. METHODS: Data from patients included in the early arthritis ESPOIR cohort and fulfilling 2010 ACR/EULAR criteria for RA at month 12 were used. Data for several PROs (visual analogue scale for fatigue, pain, patient assessment of disease activity; Health Assessment Questionnaire [HAQ]; Medical Outcomes Study Short Form 36 [SF36]; Echelle de Mesure de l'Impact de la polyarthrite Rhumatoïde-court [EMIR-court] and Routine Assessment of Patient Index Data 3 [RAPID3]) were collected and their association with disease activity measured by Disease Activity Score in 28 joints-3 variables (DAS28-3v) was assessed. The association of PROs and disease activity was assessed by explained variance, Pearson correlation and performance of each PRO in differentiating low versus high disease activity states. RESULTS: We evaluated data for 677 patients. Whatever the disease activity, less impaired PROs was associated with the lowest disease activity. All PROs were moderately correlated with RA disease activity. The RAPID3 had the best association with DAS28-3v in determining RA disease activity state (r=0.45-0.55, explained variance 30-45%, sensitivity 69-100% and specificity 55-78%). Global PROs (RAPID3, EMIR-court) had the highest association with disease activity, followed by PROs assessing physical function. CONCLUSIONS: The association of PROs and RA disease activity (DAS28-3v) remains moderate. RAPID3, a global PRO, had the best association with disease activity as compared with other analysed PROs.

MRI and serum biomarkers correlate with radiographic features in painful hand osteoarthritis.

OBJECTIVES: To explore the relationship between clinical findings, biologic biomarkers, conventional radiography and MRI in patients with painful hand OA. METHODS: The following patient baseline data from the DORA study (evaluating anti-TNF-α agents against painful hand OA) were used: clinical assessment (pain, swelling, stiffness and function: Dreiser functional hand index [FIHOA] and Cochin hand functional scale [CHFS]); measurement of biomarkers (cartilage oligomeric matrix protein (COMP), type IIA collagen N-propeptid (PIINP), hyaluronic acid (HA), ultrasensitive C-reactive protein (usCRP), tumour necrosis factor (TNF), interleukin (IL)-6, IL-1ß and urinary CTXII); radiological staging (Verbruggen, Kallman, Kellgren-Lawrence); anatomical evaluation by contrast-enhanced MRI of proximal and distal interphalangeal joints of dominant hand. Associations between clinical, biomarker and imaging findings were assessed using the Spearman correlation coefficient and test. RESULTS: 18 patients were recruited, and 144 joints studied. A correlation was found between clinical features (pain, FIHOA, CHFS) and the Verbruggen score (respectively: p=0.05, r=0.47; p=0.05, r=0.48; p=0.05, r=0.48). Serum IL-1 level was strongly associated with loss of function (FIHOA: p=0.02, r=-0.73; CHFS: p=0.01, r=-0.76) and radiological erosions (p=0.03, r=0.7) as with urinary CTX2. A significant association was found between MRI osteophytes and usCRP (p=0.0026). MRI and radiological features were significantly correlated except for synovitis and bone marrow lesions. CONCLUSIONS: MRI synovitis was not correlated with radiological scores, clinical or biologic markers of inflammation. There was a strong correlation between other MRI features and radiological scores. Serum IL-1 level was associated with structural damage and function.

Effect of tumour necrosis factor blockers on radiographic progression of psoriatic arthritis: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVES: We performed a systematic review and meta-analysis of randomised controlled trials (RCTs) of psoriatic arthritis (PsA) to examine the effect of tumour necrosis factor (TNF) blockers on radiographic progression, and to determine whether treatment combining TNF blocker with methotrexate (MTX) was superior to TNF-blocker monotherapy. METHODS: We systematically reviewed articles published up to December 2012 in Embase and Medline, and from the two last EUropean League Against Rheumatism (EULAR) and American College or Rheumatology (ACR) meetings. The primary endpoint was the proportion of patients with no radiographic progression (non-progressors) at treatment week 24 (defined by change in modified total Sharp score (mTSS) ≤0.5). The Mantel-Haenszel method was used to estimate ORs and 95% CIs of the effect of TNF blockers (with or without MTX) versus placebo (with or without MTX). Statistical heterogeneity was assessed by χ² test. RESULTS: The search retrieved 207 articles; 5 (1110 patients) met the meta-analysis criteria. For patients receiving TNF blockers, 494/584 (84.5%) were considered non-progressors at treatment week 24 vs 362/526 (68.8%) receiving placebo (OR 2.68 (95% CI 1.99 to 3.60) p<0.001), without significant heterogeneity (I(2)=3%; p=0.39). Only three RCTs provided data on potential additional efficacy of MTX: two did not find significant difference, one suggested a benefit of combined therapy. CONCLUSIONS: For patients with PsA, control of structural damage is better at week 24 with TNF blockers than placebo. Due to the limited data, we were unable to conclude on the potential additional effect of MTX on structural damages.

Assessment of MRI abnormalities of the sacroiliac joints and their ability to predict axial spondyloarthritis: a retrospective pilot study on 110 patients.

OBJECTIVE: To assess sacroiliac joint (SIJ) modifications on MRI and their ability to predict axial spondyloarthritis (SpA) with the purpose of identifying parameters for future prospective studies. METHODS: Retrospective study was carried out of 110 consecutive patients referred for SIJ MRI with coronal, axial short TI inversion recovery (STIR), and axial T1 sequences over 6 months. Factors associated with SpA, including MRI SIJ modifications (fat deposition, structural abnormalities on T1-weighted images, and bone marrow edema [BME] on STIR sequences) and age were explored using multivariate logistic regression. The reference diagnosis was made 1-1.5 years later based on clinical, radiological, and biological findings, according to Assessment of SpondyloArthritis International Society (ASAS) criteria. RESULTS: Twenty-eight patients were diagnosed with SpA (female/male: 19/9, age 41 ± 13 years). Abnormal findings were found in up to 21 % of patients without SpA (including 11 % with BME), versus 64 % of SpA patients (50 % with BME). A threshold age of 42.6 years was found to discriminate SpA patients (ROC AUC: 0.71, 95 % CI: 0.59-0.81). BME location in the sacral (OR: 7.07 [1.05, 47.6], p = 0.044) and both sacral and iliac areas (OR: 36.0 [5.61, 231], p = 0.0002), as well as age (OR: 0.95 [0.92, 0.98], p = 0.0019) were found to be independent predictors of SpA. 83.6 % of patients were effectively diagnosed using BME location and patient age in a classification and regression tree (CART) algorithm (sensitivity: 61 %, specificity: 91 %, PPV: 71 %, NPV: 87 %). CONCLUSION: The BME location combined with the patient's age (threshold 42.6 years) could help predict SpA. Further studies are required before these features can be used by radiologists to boost their confidence in reporting SIJ MRI.