Clinical evaluation of optical spectral transmission imaging for detection of disease activity in rheumatoid arthritis.

OBJECTIVE: To investigate the performance and factors of influence of optical spectral transmission (OST) imaging as a new technique for measuring joint inflammation in rheumatoid arthritis (RA). METHOD: OST was performed in 24 RA patients and 37 controls. Mann-Whitney U-test was used to assess differences in OST score between RA patients and controls. Receiver operating characteristics (ROC), linear regression and generalized estimating equations analysis were used to assess the discriminative capability of OST and the association of OST score with clinical disease parameters, ultrasound, radiographic features and cardiovascular risk parameters. RESULTS: Median OST score was higher in RA patients than in controls [16.9 (interquartile range 12.77-19.7) vs 12.11 (10.32-14.93)]. At patient level, OST score was moderately associated with ultrasound [beta 0.38 (95% CI 0.16-0.60), p = 0.001] and clinical disease activity [28-joint Disease Activity Score-C-reactive protein beta 0.30 (95% CI 0.04- 0.57), p = 0.024] in RA patients. In controls, male sex, high body mass index, and hypertension were associated with higher OST scores, while these associations were absent in RA. At joint level, the area under the ROC curve for OST score, with ultrasound or clinical swelling as reference, ranged from 0.63 to 0.70. Joint-space narrowing and malalignment were associated with higher OST joint scores, and subchondral sclerosis with lower scores. CONCLUSION: OST provides an objective measure of synovitis and correlates moderately with other examined disease activity assessment tools. Clinical patient characteristics must be considered when interpreting the results.

Disease activity in women with ankylosing spondylitis remains higher under Tumour Necrosis Factor inhibitor treatment than in men: a five-year observational study.

OBJECTIVE: To assess sex differences in response, level of disease activity, and drug survival in tumour necrosis factor inhibitor (TNFi)-naïve ankylosing spondylitis (AS) patients. METHOD: Consecutive AS patients, fulfilling the modified New York criteria, were included in a prospective cohort study at initiation of the first TNFi and followed until this medication was stopped (drug survival). Disease activity scores [AS Disease Activity Score using C-reactive protein (ASDAS-CRP), Bath AS Disease Activity Index (BASDAI), and CRP] were measured at 3, 6, and 12 months, and every subsequent year, up to 5 years. The response was defined by the ASDAS-CRP response criteria (clinically important improvement: ASDAS-CRP decrease ≥ 1.1). Analyses included regression methods for repeated measurements and survival analyses. RESULTS: Overall, 356 patients were included (34% women, mean ± sd age 46 ± 12 years), with a median disease duration of 12 (interquartile range 6;20) years. Women were less likely than men to achieve a clinically important response after 6 months of TNFi treatment (47% vs 64%; relative risk 1.4, 95% confidence interval (CI) 1.1;1.9, p = 0.02], despite a lack of sex differences in mean ASDAS-CRP levels over 5 year follow-up. Adjusted models for BASDAI over 5 years showed that women had a 0.6 point higher BASDAI score than men (ß = 0.6 0.1;1.1 <0.02). Numerically, more women than men discontinued treatment over a period of 5 years (hazard ratio = 1.5, 95% CI 0.9;2.5, p = 0.15). CONCLUSION: Female AS patients show a lower response to TNFi and a higher disease activity compared to men.

Dysregulated Fcγ receptor IIa-induced cytokine production in dendritic cells of lupus nephritis patients.

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown etiology. One of the key factors associated with SLE pathogenesis is excessive production of type I interferons (IFNs). This could result from increased activation of type I IFN-stimulating pathways, but also from decreased activation of type I IFN-inhibitory pathways. Recently, we have identified that immunoglobulin (Ig)G immune complexes strongly inhibit type I IFN production in healthy individuals by inhibitory signaling through Fcγ receptor IIa (FcγRIIa) on dendritic cells (DCs). Because, in SLE patients, immune complexes are characteristically present, we assessed whether FcγR-induced suppression of type I IFN is functional in DCs of SLE patients. We divided the SLE patients into one group without, and one group with, previous major organ involvement, for which we chose nephritis as a prototypical example. We show that DCs of lupus nephritis patients displayed impaired FcγR-mediated type I IFN inhibition compared to SLE patients without major organ involvement or healthy controls. We verified that this impaired type I IFN inhibition was not related to differences in disease activity, medication, FcγRIIa expression or expression of IFN regulatory transcription factors (IRF)1 and IRF5. In addition, we identified that DCs of lupus nephritis patients show increased FcγR-induced interleukin (IL)-1ß production, which is another important cytokine that promotes kidney inflammation. Taken together, these data indicate that DCs of lupus nephritis patients display altered FcγR-mediated regulation of cytokine production, resulting in elevated levels of type I IFN and IL-1ß. This dysregulation may contribute to the development of nephritis in SLE patients.

Serum drug concentrations to optimize switching from adalimumab to etanercept in rheumatoid arthritis.

Objectives: Inadequate response to adalimumab can be caused by insufficient blockade of the target tumour necrosis factor (TNF) at low serum concentrations. In such cases, patients may respond to another TNF inhibitor. We investigated whether the serum adalimumab concentration is related to the efficacy of a second TNF inhibitor, etanercept, in rheumatoid arthritis (RA). Methods: Patients with RA starting etanercept treatment were prospectively observed in the Reade Rheumatology Registry. In patients previously on adalimumab, serum concentrations were determined before treatment discontinuation. According to this concentration, three subgroups were formed: < 0.5 µg/mL, 0.5-5.0 µg/mL, and ≥ 5.0 µg/mL. The European League Against Rheumatism (EULAR) good/moderate response rate after 52 weeks of etanercept was compared between the switcher subgroups and biologic-naive patients. Results: In total, 449 consecutive patients were included, of whom 69 switched from adalimumab (15%) and 380 were biologic naive (85%). EULAR good or moderate response was achieved by 74% of the biologic-naive patients and by 72%, 50%, and 52% of switchers with adalimumab concentration < 0.5 µg/mL, 0.5-5.0 µg/mL, and ≥ 5.0 µg/mL, respectively (p = 0.15). Patients with an adalimumab concentration ≥ 0.5 µg/mL were significantly less likely to achieve EULAR good/moderate response on etanercept compared to biologic-naive patients, whereas patients with a concentration < 0.5 µg/mL did not significantly differ from patients starting etanercept without prior biologic treatment. Conclusion: RA patients with an inadequate response to adalimumab, in the presence of sufficient drug concentrations, benefit less from switching to another TNF inhibitor, etanercept.

Association of female sex and positive rheumatoid factor with low serum infliximab and anti-drug antibodies, related to treatment failure in early rheumatoid arthritis: results from the SWEFOT trial population.

Objective: Infliximab-treated patients with rheumatoid arthritis (RA) may respond insufficiently due to low serum infliximab (sIFX) levels, caused by anti-drug antibodies (ADAs). However, monitoring of sIFX and ADAs is not routinely implemented, and levels for optimal outcome have not been validated. We searched for predictors for sIFX < 0.2 µg/mL and ADA development in a randomized setting. Methods: In the SWEFOT trial, of 128 patients randomized to methotrexate + IFX therapy, 101 had serum samples at 3, 9, and 21 months that were analysed for sIFX [enzyme-linked immunosorbent assay (ELISA)] and ADAs [ELISA, and precipitation and acid dissociation (PandA) when sIFX > 0.2 µg/mL]. The primary and secondary outcome measures were low disease activity [LDA = 28-joint Disease Activity Score (DAS28) ≤ 3.2] and remission (DAS28 < 2.6). Baseline characteristics were assessed as potential predictors of sIFX < 0.2 µg/mL or ADA positivity, using logistic regression. Results: Categorization of sIFX levels into < 0.2, 0.2-2.9, 3.0-7.0, and > 7.0 µg/mL showed a dose-response association with LDA (30%, 64%, 67%, and 79%, respectively, p = 0.008) and remission (10%, 45%, 39%, and 66%, p = 0.004) at trial cessation (21 months). Female patients had sIFX < 0.2 µg/mL more often than males (35% vs 7%, p = 0.006), with a similar trend for rheumatoid factor (RF)-positive vs RF-negative patients (34% vs 16%, p = 0.059). ADA positivity showed similar patterns, also after adjustment for potential confounders (female sex: p = 0.050; RF positivity: p = 0.067). PandA captured four highly ADA-reactive patients with sIFX > 0.2 µg/mL, of whom three were ADA positive at other time-points, all with high DAS28 at follow-up. Conclusion: In early RA patients receiving IFX as a second-line agent, sIFX < 0.2 µg/mL and ADA development were associated with treatment failure and were more common in females, with a similar trend for RF positivity. Our findings support the use of therapeutic drug monitoring, and PandA in ADA-negative non-responders. Trial registration: SWEFOT NCT00764725 ( https://clinicaltrials.gov/ct2/show/NCT00764725 ).

Smoking and response to rituximab in rheumatoid arthritis: results from an international European collaboration.

OBJECTIVES: To investigate whether smoking habits predict response to rituximab (RTX) in rheumatoid arthritis (RA). METHOD: We included patients from the CERERRA international cohort receiving the first treatment cycle with available smoking status (n = 2481, smokers n = 528, non-current smokers n = 1953) and at least one follow-up visit. Outcome measures were change in Disease Activity Score based on 28-joint count (ΔDAS28) and European League Against Rheumatism (EULAR) good response at 6 months, with non-current smokers as the referent group. RESULTS: Compared with non-smokers at baseline, smokers were more often rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) positive and males, had shorter disease duration, lower DAS28 and Health Assessment Questionnaire (HAQ) score, a higher number of prior biological disease-modifying anti-rheumatic drugs, and were more likely to receive concomitant conventional synthetic disease-modifying anti-rheumatic drug (csDMARDs). Disease activity had decreased less in smokers at 6 months (ΔDAS28 = 1.5 vs 1.7, p = 0.006), although the difference was no longer significant after correction for baseline DAS28 (p = 0.41). EULAR good response rates did not differ between smokers and non-smokers overall or stratified by RF/ACPA status, although smokers had lower good response rates among seronegative patients (ACPA-negative: 6% vs 14%, RF-negative: 11% vs 18%). Smoking did not predict good response [odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.76-1.41], while ACPA, DAS28, HAQ, and concomitant csDMARDs were significant predictors for good response. However, when stratified by country, smokers were less likely to achieve good response in Sweden (unadjusted OR = 0.24, 95% CI = 0.07-0.89), and a trend was seen in the Czech Republic (OR = 0.45, 95% CI = 0.16-1.02). CONCLUSION: In this large, observational, multinational RA cohort, smokers starting RTX differed from non-smokers by having shorter disease duration and lower disease activity, but more previous treatments. The overall results do not support smoking as an important predictor for response to RTX in patients with RA.

Genotypes, phenotypes and treatment with immunomodulators in the rheumatic diseases.

The autoimmune rheumatological diseases rheumatoid arthritis (RA), spondyloarthritis (SpA) and systemic lupus erythematosus (SLE) are treated with conventional immunosuppressive agents and with modern biological immunomodulators. The latter group of medications have brought about a major change in our ability to control RA and SpA, with more modest results for SLE. The biologicals are very specific in their mechanisms of action, targeting one specific cytokine or one particular cellular marker. Because of this, their efficacy can readily be linked to a single immunomodulatory mechanism. This observation has fuelled hopes that the efficacy of these agents can be predicted at the individual level based on the patient's genetic predisposition, immunological profile or disease phenotype. Whilst the biologic therapies have improved the prospects for patients with these diseases very significantly, the hope that they could be targeted to the patient in an individualized manner has not completely born fruit. In this review, I will argue that we are witnessing important progress in this field, and that justified hope exists for true advances in precision medicine in the autoimmune diseases in the coming years.

Rituximab-mediated late-onset neutropenia in systemic lupus erythematosus - distinct roles of BAFF and APRIL.

Objective Rituximab-mediated late-onset neutropenia (LON) has been described in various diseases. We investigated its occurrence, consequences and contributing factors in patients with systemic lupus erythematosus (SLE). Methods Rituximab-treated patients from the Karolinska University Hospital ( n = 107) were surveyed. LON was defined as an absolute neutrophil count <1500 cells/µl, occurring four weeks to two years following rituximab treatment, or later during sustained B-cell depletion. Serum levels of B-cell-related cytokines and growth factors of the myeloid lineage were determined using enzyme-linked immunosorbent assay. Results Thirty-two patients (29.9%) developed LON after a median time of 201.5 days. Thirteen patients were admitted to the hospital; 10 due to fever. Three patients developed critical conditions. BAFF levels increased from baseline (median: 0.62 ng/ml) to the post-treatment evaluation (median: 1.16 ng/ml; p < 0.001); post-treatment levels were higher in the LON group ( p = 0.021). APRIL levels were higher in the LON group both at baseline (median: 1.54 versus 1.15 ng/ml; p = 0.027) and post-treatment (median: 2.39 versus 1.11 ng/ml; p = 0.011). IL-6 and GM-CSF levels decreased in the non-LON group ( p < 0.001), but not in LON patients. High baseline disease activity predicted LON development (OR: 4.1; 95% CI: 1.1-15.2 for SLEDAI-2K > 8). No association with neutropenia prior to rituximab treatment was documented. Conclusion Post-rituximab LON was a common complication. Although the phenomenon was predominantly self-limiting, several patients developed severe conditions. Distinct roles of BAFF and APRIL are implicated: BAFF may contribute to LON development, whereas high APRIL levels may be predictive. Rituximab-treated SLE patients should be monitored for neutrophil counts, fever and infections.

Relationship between glucocorticoid dose and adverse events in systemic lupus erythematosus: data from a randomized clinical trial.

OBJECTIVE: The aim was to obtain a better understanding of the relationship between exposure to glucocorticoids (GCs) and adverse events (AEs) reported in a randomized controlled trial (RCT) in systemic lupus erythematosus (SLE) patients. METHOD: We used data from the BLISS-76 trial on belimumab. The data were accessed through an agreement under the SHARE mechanism. AEs were grouped according to medical relevance, i.e. based on similarity of symptoms and pathophysiology. We studied the relationship between AEs and exposure to GCs at baseline and at any time-point, and compared the frequencies of each AE and groups of AEs between tertiles of cumulative GC dose. RESULTS: In total, 991 AEs were reported in the 819 patients of the trial. The frequencies of anaemia, pyrexia, oral herpes, and malaise were significantly higher (p < 0.05) in patients who were on GCs at baseline than in those who were not. The frequencies of several other AEs, including nausea, seasonal allergy, bacterial sinusitis, and viral upper respiratory infection, were significantly higher in patients without GCs. For cumulative GCs, tachycardia and proteinuria were significantly more frequent in the highest tertile than in the lowest tertile, but other AEs and groups of AEs were significantly more frequent in the lowest tertile. CONCLUSION: This study highlights the feasibility of post-hoc analyses of RCTs using the SHARE mechanism and demonstrates the association of GCs with various AEs. Contrary to expectations, there were also associations between lower cumulative GC dose and several other AEs.

Gender Differences in Axial Spondyloarthritis: Women Are Not So Lucky.

PURPOSE OF REVIEW: Ankylosing spondylitis (AS) was historically seen as a predominantly male disease. However, more recent data showed a more homogenous sex prevalence. Unfortunately, in many studies in axial spondyloarthritis (axSpA), the number of women included is low and the analyses are often not stratified for gender distribution. The purpose of this review is to aggregate the existing data on gender differences in axSpA in order to increase the awareness that female axSpA patients are still under-recognized. RECENT FINDINGS: Several studies considering gender differences revealed that female axSpA patients had different disease manifestations due to different immunological, hormonal, and genetic responses. For instance, allelic frequencies of the AHNK-gene and tissue non-specific alkaline phosphatase (TNAP) haplotypes differed between men and women with ankylosing spondylitis (AS). In addition, different levels of tumor necrosis factor (TNF), interleukins IL-6, IL-17, and IL-18, were found between the two sexes. Furthermore, female patients show a higher diagnostic delay compared to males. Several studies indicate a higher frequency of extra-articular manifestations (EAM) in female axSpA patients, such as enthesitis, psoriasis, and inflammatory bowel disease (IBD), whereas acute anterior uveitis is more prevalent in male patients. Male AS patients more frequently show a higher Bath Ankylosing Spondylitis Radiology Index (BASRI) scores and modified Stoke Ankylosing Spondylitis Spine Scores (mSASSS) than females, which indicates that males have higher radiological damage and radiographic progression. However, disease activity (BASDAI) and quality of life (AsQol) scores are significantly higher in women, and more importantly, they have significantly lower response rates to treatment with TNF inhibitors (TNFi) and a significantly lower drug adherence. Despite the fact that men with axial SpA have a worse radiologic prognosis, women have a high disease burden, in part because they have a longer delay in diagnosis, higher disease activity, and significantly less responsiveness to treatment with TNFi.

[Personalised medicine in rheumatology]. / Personalised medicine in de reumatologie.

BACKGROUND: An important goal in medicine is to provide patients with individualised and personalised treatment. Personalised medicine is making an important contribution. AIM: To summarise developments in the field of personalised medicine in rheumatology. METHOD: We review the results so far and discuss what developments we can expect in the future. RESULTS: In rheumatology there have been advances in three main areas: 1. therapeutic drug monitoring (measuring medication levels and using the results as a guide for further treatment); 2. the use of biomarkers to determine which drugs should be selected or which should be stopped; 3. involvement of the patient's own observations concerning treatment options. CONCLUSION: Personalised medicine is being used increasingly in rheumatology.

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.

Economic considerations and patients' preferences affect treatment selection for patients with rheumatoid arthritis: a discrete choice experiment among European rheumatologists.

OBJECTIVE: To compare the value that rheumatologists across Europe attach to patients' preferences and economic aspects when choosing treatments for patients with rheumatoid arthritis. METHODS: In a discrete choice experiment, European rheumatologists chose between two hypothetical drug treatments for a patient with moderate disease activity. Treatments differed in five attributes: efficacy (improvement and achieved state on disease activity), safety (probability of serious adverse events), patient's preference (level of agreement), medication costs and cost-effectiveness (incremental cost-effectiveness ratio (ICER)). A Bayesian efficient design defined 14 choice sets, and a random parameter logit model was used to estimate relative preferences for rheumatologists across countries. Cluster analyses and latent class models were applied to understand preference patterns across countries and among individual rheumatologists. RESULTS: Responses of 559 rheumatologists from 12 European countries were included in the analysis (49% females, mean age 48 years). In all countries, efficacy dominated treatment decisions followed by economic considerations and patients' preferences. Across countries, rheumatologists avoided selecting a treatment that patients disliked. Latent class models revealed four respondent profiles: one traded off all attributes except safety, and the remaining three classes disregarded ICER. Among individual rheumatologists, 57% disregarded ICER and these were more likely from Italy, Romania, Portugal or France, whereas 43% disregarded uncommon/rare side effects and were more likely from Belgium, Germany, Hungary, the Netherlands, Norway, Spain, Sweden or UK. CONCLUSIONS: Overall, European rheumatologists are willing to trade between treatment efficacy, patients' treatment preferences and economic considerations. However, the degree of trade-off differs between countries and among individuals.

The prevalence and determinants of anti-DFS70 autoantibodies in an international inception cohort of systemic lupus erythematosus patients.

Autoantibodies to dense fine speckles 70 (DFS70) are purported to rule out the diagnosis of SLE when they occur in the absence of other SLE-related autoantibodies. This study is the first to report the prevalence of anti-DFS70 in an early, multinational inception SLE cohort and examine demographic, clinical, and autoantibody associations. Patients were enrolled in the Systemic Lupus International Collaborating Clinics (SLICC) inception cohort within 15 months of diagnosis. The association between anti-DFS70 and multiple parameters in 1137 patients was assessed using univariate and multivariate logistic regression. The frequency of anti-DFS70 was 7.1% (95% CI: 5.7-8.8%), while only 1.1% (95% CI: 0.6-1.9%) were monospecific for anti-DFS70. In multivariate analysis, patients with musculoskeletal activity (Odds Ratio (OR) 1.24 [95% CI: 1.10, 1.41]) or with anti-ß2 glycoprotein 1 (OR 2.17 [95% CI: 1.22, 3.87]) were more likely and patients with anti-dsDNA (OR 0.53 [95% CI: 0.31, 0.92]) or anti-SSB/La (OR 0.25 [95% CI: 0.08, 0.81]) were less likely to have anti-DFS70. In this study, the prevalence of anti-DFS70 was higher than the range previously published for adult SLE (7.1 versus 0-2.8%) and was associated with musculoskeletal activity and anti-ß2 glycoprotein 1 autoantibodies. However, 'monospecific' anti-DFS70 autoantibodies were rare (1.1%) and therefore may be helpful to discriminate between ANA-positive healthy individuals and SLE.

Choosing wisely in daily practice: a mixed methods study on determinants of antinuclear antibody testing by rheumatologists.

OBJECTIVES: To explore the relationship between antinuclear antibody (ANA) overuse and rheumatologist-related factors before and after an intervention aimed at reducing ANA overuse. METHOD: In this mixed methods study we performed surveys among rheumatologists (n = 20) before and after the ANA intervention (education and feedback). We identified clinician-related determinants of ANA overuse (demographic characteristics, cognitive bias, numeracy, personality, thinking styles, and knowledge) by multivariate analysis. Two focus group meetings with rheumatologists were held 6 months after the intervention to explore self-reported determinants. RESULTS: Questionnaires were completed by all rheumatologists and eight participated in the focus groups. Rheumatologists with more work experience and a less extravert personality ordered more ANA tests before the intervention [ß = 0.01, 95% confidence interval (CI) 0.003 to 0.02, p = 0.01 and ß = -0.11, 95% CI -0.21 to -0.01, p = 0.04, respectively; R2 = 47%]. After the intervention, female rheumatologists changed less than their male colleagues with regard to the number of ANA tests ordered (ß = 0.15, 95% CI 0.03-0.26, p = 0.02; R2 = 25%). During the focus groups, seven themes were identified that influenced improvement in ANA overuse: determinants related to the intervention and the study, individual health professionals, patients, professional interactions, incentives and resources, capacity for organizational change, and social, political, and legal factors. CONCLUSIONS: We identified several determinants that together explained a sizable part of the variance observed in the ANA outcomes at baseline and in the change in ANA outcomes afterwards. Furthermore, the focus groups yielded additional factors suggesting a complex interplay of determinants influencing rheumatologists' ANA ordering behaviour.

Implementation of protocolized tight control and biological dose optimization in daily clinical practice: results of a pilot study.

OBJECTIVES: To assess the effects of education, guideline development, and individualized treatment advice on rheumatologist adherence to tight control-based treatment and biological dose optimization in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and spondyloarthropathy (SpA) patients. METHOD: This pilot study, among two rheumatologists and two specialized nurses in a general hospital, combined education, feedback, local guideline development, and individualized treatment advice. Outcomes (baseline and 1 year post-intervention) were the percentage of patients with a Disease Activity Score in 28 joints (DAS28) or Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) measured during the visit, mean DAS28/BASDAI, and the percentage of patients using a reduced biological dose. DAS28 outcomes only applied to RA and PsA patients, BASDAI outcomes only applied to SpA patients whereas outcomes on biological dose applied to all patients. RESULTS: A total of 232 patients (67% RA, 15% PsA, 18% SpA; 58% female, mean age 56 ± 15 years) were included in the study. The percentage of DAS28 and BASDAI measurements performed increased after the intervention [DAS28 15-51%, odds ratio (OR) 3.3, 95% confidence interval (CI) 2.1-5.5; BASDAI 23-50%, OR 2.2, 95% CI 1.0-5.5], with mean DAS28 and BASDAI scores remaining similar (DAS28: mean difference 0.1, 95% CI -0.3 to 0.5; BASDAI: mean difference 0.03, 95% CI -1.8 to 1.9). Use of a reduced biological dose increased from 10% to 61% (OR 3.9, 95% CI 2.4-6.5). CONCLUSIONS: A multicomponent intervention strategy aimed at rheumatologists can lead to improved adherence to tight control-based treatment and a reduction in the use of biologicals in RA, SpA, and PsA patients.

Efficacy and safety of subcutaneous tabalumab, a monoclonal antibody to B-cell activating factor, in patients with systemic lupus erythematosus: results from ILLUMINATE-2, a 52-week, phase III, multicentre, randomised, double-blind, placebo-controlled study.

OBJECTIVES: To evaluate the efficacy and safety of tabalumab, a human IgG4 monoclonal antibody that neutralises membrane and soluble B-cell activating factor (BAFF). METHODS: This randomised, placebo-controlled study enrolled 1124 patients with moderate-to-severe systemic lupus erythematosus (SLE) (Safety of Estrogens in Lupus Erythematosus National Assessment- SLE Disease Activity Index ≥6 at baseline). Patients received standard of care plus subcutaneous study drug, starting with a loading dose (240 mg) at week 0 and followed by 120 mg every 2 weeks (120 Q2W), 120 mg every 4 weeks (120 Q4W) or placebo. Primary endpoint was proportion achieving SLE Responder Index 5 (SRI-5) improvement at week 52. RESULTS: Clinical characteristics were balanced across groups. The primary endpoint was met with 120 Q2W (38.4% vs 27.7%, placebo; p=0.002), but not with the less frequent 120 Q4W regimen (34.8%, p=0.051). Although key secondary endpoints (time to severe flare, corticosteroid sparing and fatigue) were not met, patients treated with tabalumab had greater SRI-5 response rates in a serologically active subset and improvements in more stringent SRI cut-offs, SELENA-SLEDAI, Physician's Global Assessment, anti-double-stranded DNA antibodies, complement, total B cells and immunoglobulins. The incidences of deaths, serious adverse events (AEs), and treatment-emergent AEs were similar in the 120 Q2W, 120 Q4W and placebo groups, but depression and suicidal ideation, albeit rare events, were more commonly reported with tabalumab. CONCLUSION: SRI-5 was met with 120 Q2W and although key secondary endpoints were not met, numerous other secondary endpoints significantly improved in addition to pharmacodynamic evidence of BAFF pathway blockade. The safety profile for tabalumab was similar to placebo, except for depression and suicidality, which were uncommon. TRIAL REGISTRATION NUMBER: NCT01205438.

Dietary micronutrient intake and atherosclerosis in systemic lupus erythematosus.

OBJECTIVE: The aim of this study was to investigate the role of dietary micronutrient intake in systemic lupus erythematosus (SLE). METHODS: This study included 111 SLE patients and 118 age and gender-matched controls. Data on diet (food frequency questionnaires) were linked with data on Systemic Lupus Activity Measure, Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and carotid atherosclerotic/echolucent plaque (B-mode ultrasound). Dietary micronutrient intake were compared between SLE patients and controls and in relation to lupus activity and atherosclerosis in SLE. Associations between micronutrient intake and plaque were analyzed through logistic regression, adjusted for potential confounders. RESULTS: Micronutrient intake did not differ between patients and controls, and between lower and higher lupus activity, apart from the fact that phosphorus was associated with SLEDAI > 6. In SLE patients, some micronutrients were associated with atherosclerotic plaque, left side. Lower intake of riboflavin and phosphorus was associated with atherosclerotic plaque, left side (odds ratio (OR) 3.06, 95% confidence interval (CI) 1.12-8.40 and OR 4.36, 95% CI 1.53-12.39, respectively). Higher intake of selenium and thiamin was inversely associated with atherosclerotic plaque, left side (OR 0.28, 95% CI 0.09-0.89 and OR 0.26, 95% CI 0.08-0.80, respectively). In addition, higher intake of thiamin was inversely associated with echolucent plaque, left side (OR 0.22, 95% CI 0.06-0.84). Lower intake of folate was inversely associated with bilateral echolucent plaque (OR 0.36, 95% CI 0.13-0.99). CONCLUSIONS: SLE patients did not have different dietary micronutrient intake compared to controls. Phosphorus was associated with lupus activity. Riboflavin, phosphorus, selenium and thiamin were inversely associated with atherosclerotic plaque, left side in SLE patients, but not in controls. Dietary micronutrients may play a role in atherosclerosis in SLE.

Long-term organ damage accrual and safety in patients with SLE treated with belimumab plus standard of care.

OBJECTIVE: To examine long-term organ damage and safety following treatment with belimumab plus standard of care (SoC) in patients with systemic lupus erythematosus (SLE). METHODS: Pooled data were examined from two ongoing open-label studies that enrolled patients who completed BLISS-52 or BLISS-76. Patients received belimumab every four weeks plus SoC. SLICC Damage Index (SDI) values were assessed every 48 weeks (study years) following belimumab initiation (baseline). The primary endpoint was change in SDI from baseline at study years 5-6. Incidences of adverse events (AEs) were reported for the entire study period. RESULTS: The modified intent-to-treat (MITT) population comprised 998 patients. At baseline, 940 (94.2%) were female, mean (SD) age was 38.7 (11.49) years, and disease duration was 6.7 (6.24) years. The mean (SD) SELENA-SLEDAI and SDI scores were 8.2 (4.18) and 0.7 (1.19), respectively; 411 (41.2%) patients had organ damage (SDI = 1: 235 (23.5%); SDI ≥ 2: 176 (17.6%)) prior to belimumab. A total of 427 (42.8%) patients withdrew overall; the most common reasons were patient request (16.8%) and AEs (8.5%).The mean (SD) change in SDI was +0.2 (0.48) at study years 5-6 (n = 403); 343 (85.1%) patients had no change from baseline in SDI score (SDI +1: 46 (11.4%), SDI +2: 13 (3.2%), SDI +3: 1 (0.2%)). Of patients without organ damage at baseline, 211/241 (87.6%) had no change in SDI and the mean change (SD) in SDI was +0.2 (0.44). Of patients with organ damage at baseline, 132/162 (81.5%) had no change in SDI and the mean (SD) change in SDI was +0.2 (0.53). The probability of not having a worsening in SDI score was 0.88 (95% CI: 0.85, 0.91) and 0.75 (0.67, 0.81) in those without and with baseline damage, respectively (post hoc analysis).Drug-related AEs were reported for 433 (43.4%) patients; infections/infestations (282, 28.3%) and gastrointestinal disorders (139, 13.9%) were the most common. CONCLUSION: Patients with SLE treated with long-term belimumab plus SoC had a low incidence of organ damage accrual and no unexpected AEs. High-risk patients with pre-existing organ damage also had low accrual, suggesting a favorable effect on future damage development.

Safety, tolerability, efficacy and pharmacodynamics of the selective JAK1 inhibitor GSK2586184 in patients with systemic lupus erythematosus.

We aimed to evaluate the pharmacodynamics, efficacy, safety and tolerability of the JAK1 inhibitor GSK2586184 in adults with systemic lupus erythematosus (SLE). In this adaptive, randomized, double-blind, placebo-controlled study, patients received oral GSK2586184 50-400 mg, or placebo twice daily for 12 weeks. Primary endpoints included interferon-mediated messenger RNA transcription over time, changes in Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index score, and number/severity of adverse events. A pre-specified interim analysis was performed when ≥ 5 patients per group completed 2 weeks of treatment. In total, 84-92% of patients were high baseline expressors of the interferon transcriptional biomarkers evaluated. At interim analysis, GSK2586184 showed no significant effect on mean interferon transcriptional biomarker expression (all panels). The study was declared futile and recruitment was halted at 50 patients. Shortly thereafter, significant safety data were identified, including elevated liver enzymes in six patients (one confirmed and one suspected case of Drug Reaction with Eosinophilia and Systemic Symptoms), leading to immediate dosing cessation. Safety of Estrogen in Lupus National Assessment-SLE Disease Activity Index scores were not analysed due to the small number of patients completing the study. The study futility and safety data described for GSK2586184 do not support further evaluation in patients with SLE. Study identifiers: GSK Study JAK115919; ClinicalTrials.gov identifier: NCT01777256.