Weight of salivary gland ultrasonography compared to other items of the 2016 ACR/EULAR classification criteria for Primary Sjögren's syndrome.

OBJECTIVE: Major salivary gland ultrasonography (SGUS) is widely used for the diagnosis of primary Sjögren's syndrome (pSS). Our objective was to assess the contribution of SGUS compared to other items of the 2016 ACR/EULAR pSS classification criteria, based on expert opinion. METHODS: A secure web-based relational database was used by 24 experts from 14 countries to assess 512 realistic vignettes developed from data of patients with suspected pSS. Each vignette provided classification criteria items and information on history, clinical symptoms and SGUS findings. Each expert assessed 64 vignettes, and each vignette was assessed by 3 experts. A diagnosis of pSS was defined according to at least 2 of 3 experts. Validation was performed in the independent French DiapSS cohort of patients with suspected pSS. RESULTS: A criteria-based pSS diagnosis and SGUS findings were independently associated with an expert diagnosis of pSS (P < 0.001). The derived diagnostic weights of individual items in the 2016 ACR/EULAR criteria including SGUS were as follows: anti-SSA, 3; focus score ≥ 1, 3; SGUS score ≥ 2, 1; positive Schirmer's test, 1; dry mouth, 1; and salivary flow rate < 0.1 mL/min, 1. The corrected C statistic area under the curve for the new weighted score was 0.96. Adding SGUS improves the sensitivity from 90.2 % to 95.6% with a quite similar specificity 84.1% versus 82.6%. Results were similar in the DiapSS cohort: adding SGUS improves the sensitivity from 87% to 93%. CONCLUSION: SGUS had similar weight compared to minor items, and its addition improves the performance of the 2016 ACR/EULAR classification criteria.

Pregnancy and newborn outcomes after exposure to bisphosphonates: a case-control study.

We analyzed women and newborn outcome after maternal exposure to BPs. BPs have no teratogenic effect on the 36 analyzed pregnancies compared to unexposed controls matched on women underlying diseases (either systemic disease, either "bone" disease) but some outcome differed: neonatal complications rate in systemic diseases and live birth rate in bone diseases). INTRODUCTION: The effect of bisphosphonates (BPs) during pregnancy remains unclear. We aimed to study pregnancy outcomes in women exposed to BPs during pregnancy. METHODS: Data for cases and controls were from the French Reference Centre of Teratogenic Agents. Cases were women who received BPs in the 6 weeks before or during a pregnancy and had systemic or bone diseases. We included two respectively matched control groups: women with systemic diseases not exposed to BPs and healthy women not exposed to BPs or any teratogenic agent. Four controls were assigned to each case. RESULTS: Thirty-six women were exposed to BPs including 5 just before pregnancy and 30 during the first trimester; 23 had systemic diseases (systemic lupus erythematosus, n = 5; rheumatoid arthritis, n = 5; other, n = 13) and 13 had bone diseases. Rate of observed congenital malformations did not differ in women with a systemic or a bone disease compared to their respective controls (respectively 2/23 [8.7%] vs 2/92 [2.2%], p = 0.178 and 0/13 [0%] vs 0/52 [0%], p = 1.00). Among women with systemic diseases, non-specific neonatal complications were more frequent for cases (4/16 [25.0%] vs 4/64 [6.3%], p = 0.027). Among women with bone disorders, the live birth rate was lower for cases than healthy controls (8/10 [80%] vs 50/50 [100%], p = 0.025). CONCLUSION: We found no major teratogenic effects of BPs, but rates of neonatal complications were increased for women with systemic diseases, as were spontaneous abortions for women with bone diseases likely linked to the severity of the underlying diseases and concomitant medications.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting interleukins, immunoglobulins and complement factors and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Patients receiving interleukin-1 (IL-1) -targeted (anakinra, canakinumab or rilonacept) or IL-5-targeted (mepolizumab) agents have a moderate risk of infection and no specific prevention strategies are recommended. The use of IL-6/IL-6 receptor-targeted agents (tocilizumab and siltuximab) is associated with a risk increase similar to that observed with anti-tumour necrosis factor-α agents. IL-12/23-targeted agents (ustekinumab) do not seem to pose a meaningful risk of infection, although screening for latent tuberculosis infection may be considered and antiviral prophylaxis should be given to hepatitis B surface antigen-positive patients. Therapy with IL-17-targeted agents (secukinumab, brodalumab and ixekizumab) may result in the development of mild-to-moderate mucocutaneous candidiasis. Pre-treatment screening for Strongyloides stercoralis and other geohelminths should be considered in patients who come from areas where these are endemic who are receiving IgE-targeted agents (omalizumab). C5-targeted agents (eculizumab) are associated with a markedly increased risk of infection due to encapsulated bacteria, particularly Neisseria spp. Meningococcal vaccination and chemoprophylaxis must be administered 2-4 weeks before initiating eculizumab. Patients with high-risk behaviours and their partners should also be screened for gonococcal infection. IMPLICATIONS: Preventive strategies are particularly encouraged to minimize the occurrence of neisserial infection associated with eculizumab.

Certolizumab pegol in combination with dose-optimised methotrexate in DMARD-naïve patients with early, active rheumatoid arthritis with poor prognostic factors: 1-year results from C-EARLY, a randomised, double-blind, placebo-controlled phase III study.

OBJECTIVES: To assess the efficacy and safety of certolizumab pegol (CZP)+dose-optimised methotrexate (MTX) versus placebo (PBO)+dose-optimised MTX in inducing and sustaining clinical remission in DMARD-naïve patients with moderate-to-severe, active, progressive rheumatoid arthritis (RA), with poor prognostic factors over 52 weeks. METHODS: DMARD-naïve patients with ≤1 year of active RA were randomised (3:1) in a double-blind manner to CZP (400 mg Weeks 0, 2, 4, then 200 mg Q2W to Week 52)+MTX or PBO+MTX (the mean optimised-MTX dose=21 and 22 mg/week, respectively). Sustained remission (sREM) and sustained low disease activity (sLDA; DAS28(ESR)<2.6 and DAS28(ESR)≤3.2, respectively, at both Weeks 40 and 52) were the primary and secondary endpoints. RESULTS: Patients were randomised to CZP+MTX (n=660) and PBO+MTX (n=219). At Week 52, significantly more patients assigned to CZP+MTX compared with PBO+MTX achieved sREM (28.9% vs 15.0%, p<0.001) and sLDA (43.8% vs 28.6%, p<0.001). Inhibition of radiographic progression and improvements in physical functioning were significantly greater for CZP+MTX versus PBO+MTX (van der Heijde modified total Sharp score (mTSS) mean absolute change from baseline (CFB): 0.2 vs 1.8, p<0.001, rate of mTSS non-progressors: 70.3% vs 49.7%, p<0.001; least squares (LS) mean CFB in Health Assessment Questionnaire-Disability Index (HAQ-DI): -1.00 vs -0.82, p<0.001). Incidence of adverse events (AEs) and serious AEs was similar between treatment groups. Infection was the most frequent AE, with higher incidence for CZP+MTX (71.8/100 patient-years (PY)) versus PBO+MTX (52.7/100 PY); the rate of serious infection was similar between CZP+MTX (3.3/100 PY) and PBO+MTX (3.7/100 PY). CONCLUSIONS: CZP+dose-optimised MTX treatment of DMARD-naïve early RA resulted in significantly more patients achieving sREM and sLDA, improved physical function and inhibited structural damage compared with PBO+dose-optimised MTX. TRIAL REGISTRATION NUMBER: NCT01519791.

Rheumatoid Arthritis Patients after Initiation of a New Biologic Agent: Trajectories of Disease Activity in a Large Multinational Cohort Study.

BACKGROUND: Response to disease modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (RA) is often heterogeneous. We aimed to identify types of disease activity trajectories following the initiation of a new biologic DMARD (bDMARD). METHODS: Pooled analysis of nine national registries of patients with diagnosis of RA, who initiated Abatacept and had at least two measures of disease activity (DAS28). We used growth mixture models to identify groups of patients with similar courses of treatment response, and examined these patients' characteristics and effectiveness outcomes. FINDINGS: We identified three types of treatment response trajectories: 'gradual responders' (GR; 3576 patients, 91·7%) had a baseline mean DAS28 of 4·1 and progressive improvement over time; 'rapid responders' (RR; 219 patients, 5·6%) had higher baseline DAS28 and rapid improvement in disease activity; 'inadequate responders' (IR; 103 patients, 2·6%) had high DAS28 at baseline (5·1) and progressive worsening in disease activity. They were similar in baseline characteristics. Drug discontinuation for ineffectiveness was shorter among inadequate responders (p=0.03), and EULAR good or moderate responses at 1year was much higher among 'rapid responders' (p<0.001). INTERPRETATION: Clinical information and baseline clinical characteristics do not allow a reliable prediction of which trajectory the patients will follow after bDMARD initiation.

Efficacy of abatacept in systemic lupus erythematosus: a retrospective analysis of 11 patients with refractory disease.

Objective The objective of this study was to assess the safety and efficacy of abatacept in patients with SLE refractory to conventional treatment in routine clinical practice. Methods This retrospective study included 11 SLE patients treated with abatacept for an active and refractory disease. The primary endpoint was the change in SLE Disease Activity Index (SLEDAI) score at six months. Response was defined as a decrease of SLEDAI ≥4 in a patient continuing abatacept. Results Indications of abatacept treatment were articular ( n=8), renal ( n=1) and cutaneous ( n=1) involvement and autoimmune thrombocytopenia ( n=1). Abatacept was discontinued before six months in two patients, because of adverse event ( n=1) and/or lupus flare ( n=2). The median SLEDAI decreased from 6 (2-20) to 4 (0-20) ( p=0.031). Decrease of SLEDAI ≥4 was observed in 6/11 patients (55%) and response to treatment according to the physician's judgement in 8/11 (73%) patients. Improvement of articular involvement was observed in 7/8 (87.5%) patients. Four adverse events were observed in three patients, but no severe infection occurred. Conclusion This study suggests some efficacy of abatacept in patients with refractory disease in routine clinical practice, particularly in the case of articular manifestations, with an acceptable safety profile. These data support conducting new controlled trials of abatacept in SLE patients.

Brief Report: Association of Rheumatoid Factor and Anti-Citrullinated Protein Antibody Positivity With Better Effectiveness of Abatacept: Results From the Pan-European Registry Analysis.

OBJECTIVE: To investigate the role of rheumatoid factor (RF) status and anti-citrullinated peptide antibody (ACPA) status as predictors of abatacept (ABA) effectiveness in patients with rheumatoid arthritis (RA). METHODS: We conducted a pooled analysis of data from 9 observational RA registries in Europe (ARTIS [Sweden], ATTRA [Czech Republic], BIOBADASER [Spain], DANBIO [Denmark], GISEA [Italy], NOR-DMARD [Norway], ORA [France], Reuma.pt [Portugal], and SCQM-RA [Switzerland]). Inclusion criteria were a diagnosis of RA, initiation of ABA treatment, and available information on RF and/or ACPA status. The primary end point was continuation of ABA treatment. Secondary end points were ABA discontinuation for ineffectiveness or adverse events and response rates at 1 year (good or moderate response according to the European League Against Rheumatism criteria with LUNDEX adjustment for treatment continuation). Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the study end points in relation to RF and ACPA status were calculated. RESULTS: We identified 2,942 patients with available data on RA-associated autoantibodies; data on RF status were available for 2,787 patients (77.0% of whom were RF positive), and data on ACPA status were available for 1,903 patients (71.3% of whom were ACPA positive). Even after adjustment for sociodemographic and disease- and treatment-related confounders, RF and ACPA positivity were each associated with a lower risk of ABA discontinuation for any reason (HR 0.79 [95% CI 0.69-0.90], P < 0.001 and HR 0.78 [95% CI 0.68-0.90], P < 0.001, respectively), compared to RF-negative and ACPA-negative patients. Similar associations with RF and ACPA were observed for discontinuation of ABA treatment due to ineffectiveness, with HRs of 0.72 (95% CI 0.61-0.84) and 0.74 (95% CI 0.62-0.88), respectively (both P < 0.001). CONCLUSION: Our results strongly suggest that positivity for RF or ACPA is associated with better effectiveness of ABA therapy.

Predictive risk factors of serious infections in patients with rheumatoid arthritis treated with abatacept in common practice: results from the Orencia and Rheumatoid Arthritis (ORA) registry.

OBJECTIVES: Little data are available regarding the rate and predicting factors of serious infections in patients with rheumatoid arthritis (RA) treated with abatacept (ABA) in daily practice. We therefore addressed this issue using real-life data from the Orencia and Rheumatoid Arthritis (ORA) registry. METHODS: ORA is an independent 5-year prospective registry promoted by the French Society of Rheumatology that includes patients with RA treated with ABA. At baseline, 3 months, 6 months and every 6 months or at disease relapse, during 5 years, standardised information is prospectively collected by trained clinical nurses. A serious infection was defined as an infection occurring during treatment with ABA or during the 3 months following withdrawal of ABA without any initiation of a new biologic and requiring hospitalisation and/or intravenous antibiotics and/or resulting in death. RESULTS: Baseline characteristics and comorbidities: among the 976 patients included with a follow-up of at least 3 months (total follow-up of 1903 patient-years), 78 serious infections occurred in 69 patients (4.1/100 patient-years). Predicting factors of serious infections: on univariate analysis, an older age, history of previous serious or recurrent infections, diabetes and a lower number of previous anti-tumour necrosis factor were associated with a higher risk of serious infections. On multivariate analysis, only age (HR per 10-year increase 1.44, 95% CI 1.17 to 1.76, p=0.001) and history of previous serious or recurrent infections (HR 1.94, 95% CI 1.18 to 3.20, p=0.009) were significantly associated with a higher risk of serious infections. CONCLUSIONS: In common practice, patients treated with ABA had more comorbidities than in clinical trials and serious infections were slightly more frequently observed. In the ORA registry, predictive risk factors of serious infections include age and history of serious infections.

Rheumatoid Factor and Disease Activity Are Independent Predictors of Lymphoma in Primary Sjögren's Syndrome.

OBJECTIVE: To define parameters predictive of lymphoma development in patients with primary Sjögren's syndrome (SS). METHODS: A multicenter case-control survey was performed to identify predictors of lymphoma. Cases were patients who developed lymphoma after diagnosis of primary SS and were mainly recruited through the Club Rhumatismes et Inflammation network. For each case, 2 controls (matched for disease duration and age) were randomly selected among patients with primary SS and without lymphoma. Cases and controls were compared using univariate analysis and then using multivariate analysis to identify independent predictors of lymphoma. RESULTS: One hundred one patients with primary SS and lymphoma were included. Eighty-seven patients were women (86.1%), and the mean ± SD age at lymphoma diagnosis was 57.4 ± 12.6 years. The most frequent histologic type was B cell non-Hodgkin's lymphoma (NHL) in 99 of 101 patients, with marginal-zone lymphoma in 76 of the 99 patients (76.8%) including 58 (58.6%) with lymphoma of the mucosa-associated lymphoid tissue type. Lymphomas were most frequently located in the salivary glands (43 patients). A specific treatment was initiated at diagnosis in 87 patients with B cell NHL, and 61 patients (61.6%) achieved complete sustained remission after the first line of treatment. In the multivariate analysis, salivary gland enlargement, the presence of rheumatoid factor (RF), low C4, cryoglobulinemia, lymphopenia, and disease activity according to the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (excluding the lymphoma domain) were found to be predictors of lymphoma. No previous treatment for primary SS was associated with any effect on lymphoma occurrence. CONCLUSION: In addition to previously known factors predictive of lymphoma occurrence, the independent roles of RF and disease activity were demonstrated in this case-control study of primary SS-associated lymphoma. Our findings highlight the roles of chronic antigenic stimulation and disease activity in the development of this severe complication.

Late-onset neutropenia after treatment with rituximab for rheumatoid arthritis and other autoimmune diseases: data from the AutoImmunity and Rituximab registry.

OBJECTIVES: To evaluate the prevalence of late-onset neutropenia and its complications in patients treated with rituximab (RTX) for rheumatoid arthritis (RA) and other autoimmune diseases (AIDs) in a prospective registry. METHODS: The AutoImmunity and Rituximab registry is an independent 7-year prospective registry promoted by the French Society of Rheumatology. For each episode of neutropenia, data were validated by the clinician in charge of the patient. RESULTS: Among 2624 patients treated with RTX for refractory AIDs, and at least 1 follow-up visit (a total follow-up of 4179 patient-years in RA and 987 patient-years in AIDs), late-onset neutropenia was observed in 40 patients (25 RA (1.3% of patients with RA, 0.6/100 patient-years), and AIDs in 15 (2.3% of patients with AIDs, 1.5/100 patient-years)). 6 patients (15%) had neutrophils <500/mm(3), 8 (20%) had neutrophils between 500 and 1000/mm(3), and 26 (65%) had neutrophils between 1000 and 1500/mm(3). Neutropenia occurred after a median period of 4.5 (3-6.5) months after the last RTX infusion in patients with RA, and 5 (3-6.5) months in patients with AIDs. 5 patients (12.5%), 4 of them with neutrophils lower than 500/mm(3), developed a non-opportunistic serious infection and required antibiotics and granulocyte colony-stimulating factor injections, with a favourable outcome. After resolution of their RTX-related neutropenia, 19 patients (47.5%) were re-treated, and neutropenia reoccurred in 3 of them. CONCLUSIONS: Late-onset neutropenia might occur after RTX and may result in serious infections. Thus, monitoring of white cell count should be performed after RTX. However, in this large registry of patients with AIDs, the frequency of RTX-induced neutropenia was much lower than that previously reported in patients treated for blood malignancies or AIDs.

The impact of patient heterogeneity and socioeconomic factors on abatacept retention in rheumatoid arthritis across nine European countries.

BACKGROUND: There are substantial differences in accessibility to biological disease modifying antirheumatic drugs (bDMARDs) across countries. The objective of this study was to analyse the impact of patient demographics, disease characteristics and gross domestic product (GDP) on abatacept (ABA) retention in patients with rheumatoid arthritis (RA) treated in clinical practice. METHODS: Data from nine European observational RA cohorts of patients treated with ABA were pooled. Kaplan-Meier analysis was used to compare drug retention across registries. Specific causes of drug retention were investigated using competing risks multivariate Cox regression. RESULTS: A total of 3961 patients treated with ABA, with 6188 patient-years of follow-up, were included. Patients in the different national registries had similar demographic features, but varied in baseline disease characteristics. ABA drug retention differed between countries, with median drug retention rates ranging from 1.2 to more than 6 years. The differences in drug retention were marginally explained by disparities in disease characteristics, while the national GDP per capita was strongly associated with drug retention (correlation coefficient -0.74; p=0.02). CONCLUSIONS: Patient characteristics at ABA initiation vary across Europe, probably reflecting differences in eligibility criteria and prescription patterns. However, the difference in ABA drug retention between countries was not primarily explained by disparities in patient characteristics. Lower ABA retention was observed in countries with a more liberal access to bDMARDs and higher GDP. National differences need to be accounted for when pooling data on treatment with bDMARDs from various countries.

The incidence of tuberculosis in patients treated with certolizumab pegol across indications: impact of baseline skin test results, more stringent screening criteria and geographic region.

OBJECTIVES: We report the incidence of tuberculosis (TB) across certolizumab pegol (CZP) clinical trials in rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), before and after the introduction of stricter TB screening. METHODS: TB incidence rates (IRs) were assessed and stratified according to screening guidelines used at the time of CZP trials. Before 2007 (original trials), purified protein derivative (PPD) tuberculin skin test positivity varied according to local standards (induration ≥5 up to ≥20 mm). Since 2007, all CZP trial protocols have been amended, including trials spanning (intermediate) and initiated after 2007 (current), mandating that any patient with PPD≥5 mm receives treatment for latent TB infection (LTBI). All cases of suspected TB or PPD≥5 mm, in pooled data from 5402 CZP patients across all CZP trials up to 2012, underwent blinded central review by independent experts. RESULTS: 44 TB cases were confirmed in pooled CZP RA trials (IR 0.47/100PY, patient-years) with no cases in Japanese RA trials (J-RAPID, HIKARI). Single TB cases were confirmed in psoriasis and axSpA trials (RAPID-axSpA), and no cases in the PsA trial (RAPID-PsA). IR of TB was 0.51/100PY across original or intermediate RA trials and 0.18/100PY in current trials. The majority of TB cases in RA occurred in Eastern (IR 1.02/100PY) and Central Europe (IR 0.58/100PY). Of 242/370 PPD≥5 mm patients who received 9 months isoniazid (INH) treatment for latent TB infection (LTBI), none developed TB, versus 7.8% of 128 untreated PPD≥5 mm patients. CONCLUSIONS: Implementation of more stringent LTBI screening, plus treatment for LTBI, reduced the IR of TB, even when INH was administered after starting CZP therapy.

ACPA-positive primary Sjögren's syndrome: true primary or rheumatoid arthritis-associated Sjögren's syndrome?

OBJECTIVES: Anticyclic citrullinated protein antibodies (ACPA) are highly specific of rheumatoid arthritis (RA). However, they have also been detected in 5-10% of primary Sjögren's syndrome (pSS). We compared ACPA-positive and negative patients with pSS and assessed the risk of evolution to RA. PATIENTS AND METHODS: ACPA-positive and negative patients with pSS were included in this study. For ACPA-positive patients, clinical and radiological re-evaluation was systematically performed after at least 5 years of follow-up. Diagnosis was reassessed at the end of the follow-up to identify patients that developed RA according to the American College of Rheumatology 1987 classification criteria. RESULTS: At inclusion in the cohort 16 patients with pSS were ACPA positive and 278 were ACPA negative. ACPA-positive patients, had more frequently arthritis (43.7% vs 12.2%; p=0.003) but not arthralgias. They also had more frequent lung involvement (25% vs 8.1%; p=0.05). After median follow-up of 8 (5-10) years, 7/16 (43.8%) patients developed RA including 5 (31.25%) with typical RA erosions. Elevation of acute phase reactants at inclusion was the only parameter associated with progression to erosive RA. CONCLUSIONS: Median term follow-up of ACPA-positive patients with pSS showed that almost half of them developed RA, particularly in the presence of elevation of acute phase reactants. These results support the usefulness of a close radiological monitoring of these patients for early detection of erosive change not to delay initiation of effective treatment. Indeed, number of these patients with ACPA-positive pSS may actually have RA and associated SS.

CXCL13 and CCL11 Serum Levels and Lymphoma and Disease Activity in Primary Sjögren's Syndrome.

OBJECTIVE: Non-Hodgkin's lymphoma (NHL) is a severe complication of primary Sjögren's syndrome (SS). Ectopic germinal centers (GCs) in the salivary glands are predictors of the occurrence of NHL. Given the association between CCL11 and CXCL13 and ectopic GCs, we assessed the link between these chemokines and NHL, as well as the association between these chemokines and disease activity, in patients with primary SS. METHODS: Serum levels of CCL11 and CXCL13 were evaluated by multiplex assay in 385 patients included in the Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. The association between chemokine levels, B cell biomarkers, and patient subsets was assessed using Spearman's test for continuous data and the nonparametric Mann-Whitney U test for categorical data. Multivariate analyses were performed to identify parameters associated with lymphoma and disease activity. RESULTS: Seventeen patients had a history of lymphoma, and 5 of them had developed NHL during followup. The median serum levels of CCL11 and CXCL13 in the total cohort were 106.48 pg/ml (interquartile range 69.33-149.85) and 108.31 pg/ml (interquartile range 58.88-200.13), respectively. Patients with lymphoma had higher levels of CXCL13 than did patients without lymphoma (P = 0.006) and a trend toward a higher level of CCL11 (P = 0.056). Low C4 and high BAFF levels were associated with NHL on multivariate analysis (P = 0.01 and P = 0.0002, respectively). CCL11 and CXCL13 levels correlated positively with the rheumatoid factor titer, the κ-to-λ free light chain ratio, and the ß2 -microglubulin level. CXCL13 was the only parameter associated with disease activity on multivariate analysis. CONCLUSION: These findings demonstrate a link between CXCL13 and CCL11 and disease activity and lymphoma. This highlights the continuum between chronic B cell activation, disease activity, and lymphomagenesis in patients with primary SS.

Opportunistic infections and biologic therapies in immune-mediated inflammatory diseases: consensus recommendations for infection reporting during clinical trials and postmarketing surveillance.

No consensus has previously been formed regarding the types and presentations of infectious pathogens to be considered as 'opportunistic infections' (OIs) within the setting of biologic therapy. We systematically reviewed published literature reporting OIs in the setting of biologic therapy for inflammatory diseases. The review sought to describe the OI definitions used within these studies and the types of OIs reported. These findings informed a consensus committee (infectious diseases and rheumatology specialists) in deliberations regarding the development of a candidate list of infections that should be considered as OIs in the setting of biologic therapy. We reviewed 368 clinical trials (randomised controlled/long-term extension), 195 observational studies and numerous case reports/series. Only 11 observational studies defined OIs within their methods; no consistent OI definition was identified across studies. Across all study formats, the most numerous OIs reported were granulomatous infections. The consensus group developed a working definition for OIs as 'indicator' infections, defined as specific pathogens or presentations of pathogens that 'indicate' the likelihood of an alteration in host immunity in the setting of biologic therapy. Using this framework, consensus was reached upon a list of OIs and case-definitions for their reporting during clinical trials and other studies. Prior studies of OIs in the setting of biologic therapy have used inconsistent definitions. The consensus committee reached agreement upon an OI definition, developed case definitions for reporting of each pathogen, and recommended these be used in future studies to facilitate comparison of infection risk between biologic therapies.

Efficacy of anti-TNF alpha in severe and/or refractory Behçet's disease: Multicenter study of 124 patients.

OBJECTIVE: To report the efficacy and safety of anti-TNF agents in patients with severe and/or refractory manifestations of Behçet's disease (BD). METHODS: We performed a multicenter study of main characteristics and outcomes of anti-TNF alpha treatments [mainly infliximab (62%), and adalimumab (30%)] in 124 BD patients [48% of men; median age of 33.5 (28-40) years]. RESULTS: Overall response (i.e. complete and partial) rate was 90.4%. Clinical responses were observed in 96.3%, 88%, 70%, 77.8%, 92.3% and 66.7% of patients with severe and/or refractory ocular, mucocutaneous, joint, gastro-intestinal manifestations, central nervous system manifestations and cardiovascular manifestations, respectively. No significant difference was found with respect to the efficacy of anti-TNF used as monotherapy or in association with an immunosuppressive agent. The incidence of BD flares/patient/year was significantly lower during anti-TNF treatment (0.2 ± 0.5 vs 1.7 ± 2.4 before the use of anti-TNF, p < 0.0001). The prednisone dose was significantly reduced at 6 and 12 months (p < 0.0001). In multivariate analysis, retinal vasculitis was negatively associated with complete response to anti-TNF (OR = 0.33 [0.12-0.89]; p = 0.03). The efficacy and relapse free survival were similar regardless of the type of anti-TNF agent used. After a median follow-up of 21 [7-36] months, side effects were reported in 28% of patients, including infections (16.3%) and hypersensitivity reactions (4.1%). Serious adverse events were reported in 13% of cases. CONCLUSION: Anti-TNF alpha therapy is efficient in all severe and refractory BD manifestations. Efficacy appears to be similar regardless of the anti-TNF agent used (infliximab or adalimumab).

Determinants of hydroxychloroquine blood concentration variations in systemic lupus erythematosus.

OBJECTIVE: Blood concentrations of hydroxychloroquine (HCQ) vary widely among patients with systemic lupus erythematosus (SLE). A pharmacokinetic/pharmacodynamic relationship has been found in different situations, and a very low blood concentration of HCQ is a simple marker of nonadherence to treatment. Therefore, interest in blood HCQ concentration measurement has increased, but little is known about factors that influence blood HCQ concentration variability. This study was undertaken to analyze determinants of blood HCQ concentrations. METHODS: We conducted a retrospective analysis of patient data, including data from the Plaquenil Lupus Systemic (PLUS) study, to determine the association of epidemiologic, clinical, and biologic factors with blood HCQ concentrations. Data for nonadherent patients (blood HCQ concentration <200 ng/ml) were excluded. RESULTS: To examine homogeneous pharmacologic data, we restricted the analyses of the PLUS data to the 509 SLE patients receiving 400 mg/day. We found no association of ethnicity or smoking with blood HCQ concentrations and no pharmacokinetic drug-drug interaction with antacids or with inhibitors or inducers of cytochrome P450 enzymes. On multivariate analysis, high body mass index (P = 0.008), no treatment with corticosteroids (P = 0.04), increased time between the last tablet intake and measurement of blood HCQ concentrations (P = 0.017), low platelet count (P < 0.001), low neutrophil count (P < 0.001), and high estimated creatinine clearance (P < 0.001) were associated with low blood HCQ concentrations. In 22 SLE patients with chronic renal insufficiency (median serum creatinine clearance 52 ml/minute [range 23-58 ml/minute]) who received 400 mg/day HCQ, the median blood HCQ concentration was significantly higher than that in the 509 patients from the PLUS study (1,338 ng/ml [range 504-2,229 ng/ml] versus 917 ng/ml [range 208-3316 ng/ml]) (P < 0.001). CONCLUSION: We provide a comprehensive analysis of determinants of blood HCQ concentrations. Because this measurement is increasingly being used, these data might be useful for clinicians.

Standardizing terms, definitions and concepts for describing and interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the Innovative Medicines Initiative ABIRISK consortium.

Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

Update on the safety profile of certolizumab pegol in rheumatoid arthritis: an integrated analysis from clinical trials.

OBJECTIVE: To report the long-term safety data of certolizumab pegol (CZP) in rheumatoid arthritis (RA) accumulated as of 30 November 2011. DESIGN: Data from 10 completed randomised controlled trials (RCT) of CZP in RA and several open-label extensions (OLE) were pooled across all doses. Reported adverse events (AE) occurred between the first dose and 84 days after the last dose. All deaths, serious infectious events (SIE) and malignancies were reviewed by external experts, classified according to predefined rules, and validated by an external steering committee. Incidence rates (IR) and event rates (ER) per 100 patient-years (PY) are presented. RESULTS: 4049 RA patients who received CZP were included in the safety pooling; total exposure 9277 PY, mean exposure 2.1 years (range 0.04-7.6). SIE, most frequently pneumonia (IR 0.73/100 PY), were the most common serious AE, occurring more frequently in CZP compared to placebo-treated patients in RCT (IR 5.61/100 PY vs 1.35/100 PY, odds ratio (OR) 4.35, 95% CI 0.65 to 29.30). SIE rates were lower in the CZP-treated population including OLE (ER 4.33/100 PY). 44 patients developed tuberculosis (IR 0.47/100 PY), 39 from high endemic regions. 58 deaths occurred in CZP-exposed patients (IR 0.63/100 PY) and 70 developed malignancies excluding non-melanoma skin cancer (IR 0.76/100 PY), including five lymphomas (IR 0.05/100 PY). CONCLUSIONS: No new or unexpected safety signals associated with CZP emerged in this updated long-term safety analysis. While SIE rates were higher for CZP than for placebo in RCT, the rate decreased with continued exposure to CZP. These rates are consistent with data previously reported for CZP and other tumour necrosis factor inhibitors.