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Objective: Biologic agents with different mechanisms of action [inhibitors of tumor necrosis factor-α (TNF-α), interleukin (IL)-12/23, and IL-17] showed efficacy in randomized controlled trials (RCT) in the treatment of psoriatic arthritis. We conducted a pooled metaanalysis of these agents for treatment of dactylitis and enthesitis and compared results with the American College of Rheumatology 20 (ACR20) response and Health Assessment Questionnaire-Disability Index (HAQ-DI) scores., Methods: A systematic literature search was performed and a pooled metaanalysis of RCT with anti-TNF-α (infliximab, golimumab, adalimumab), anti-IL-12/23 (ustekinumab), and anti-IL-17 (secu kinumab, ixekizumab) was conducted using the random-effects model. Bias was assessed using the Cochrane risk-of-bias tool., Results: Eighteen RCT were included in the pooled analysis (n = 6981). Both TNF-α inhibitors and novel biologics (ustekinumab, secukinumab, ixekizumab) demonstrated significant resolution of dactylitis at Week 24 with pooled risk ratios (RR) versus placebo of 2.57 (95% CI 1.36-4.84) and 1.88 (95% CI 1.33-2.65), respectively. For resolution of enthesitis at Week 24, RR for TNF-α inhibitors was 1.93 (95% CI 1.33-2.79) versus 1.95 (95% CI 1.60-2.38) for novel biologics. Both biologic categories showed overlapping ranges of ACR20 responses (TNF-α inhibitors: RR = 2.23, 95% CI 1.60-3.11; pooled IL-12/23 and -17: RR = 2.30, 95% CI 1.94-2.72) and similar quality of life improvement scores with mean HAQ-DI score changes of -0.29 (95% CI -0.39 to -0.19) and -0.26 (95% CI -0.31 to -0.22), respectively., Conclusion: The pooled analysis demonstrated that anti-TNF-α agents have the same efficacy as novel agents (ustekinumab, secukinumab, and ixekizumab) in dactylitis and enthesitis.

Objective: Evaluate enthesitis, physical function, and health-related quality of life (HRQOL) among patients with psoriatic arthritis (PsA) who are naive to anti-tumor necrosis factor agents., Methods: In PSUMMIT 1 and 2, patients with PsA were randomized to placebo or ustekinumab 45 mg or 90 mg. Enthesitis was assessed at weeks 0 and 24 (Maastricht Ankylosing Spondylitis Enthesitis Score). Assessments included Health Assessment Questionnaire-Disability Index (HAQ-DI), Medical Outcomes Study Short Form-36 (SF-36) physical component summary/mental component summary (PCS/MCS), and American College of Rheumatology 20 (ACR20)., Results: At Week 24, 21 had worsened enthesitis, 158 had improved enthesitis, and 412 had unchanged enthesitis. Improved enthesitis was associated with improvements in HAQ-DI and SF-36 MCS. Results were similar for ACR20 responders and nonresponders., Conclusion: Improvement in enthesitis at Week 24 was associated with improvements in physical function/HRQOL regardless of ACR20 response.

Objective: Guidelines suggest that rheumatoid arthritis (RA) patients with previously treated solid malignancy may be treated as patients without such history. The recommendation is based on limited evidence, and rheumatologists and patients are frequently hesitant to start or continue biologic therapy after a cancer diagnosis. The objective of this study was to describe biologic use in real-world patients with RA following a malignancy diagnosis., Methods: RA patients enrolled in the Corrona registry and diagnosed with solid malignancy with at least 1 followup visit within 12 months after diagnosis were included in this analysis. The proportion of patients continuing or initiating biological/targeted synthetic disease-modifying antirheumatic drug (bDMARD/tsDMARD) after diagnosis was estimated. Median time to initiation of bDMARD/tsDMARD after diagnosis was calculated using the Kaplan-Meier method and the proportion initiating biologic treatment in 6-month time intervals was estimated using the life-table method., Results: There were 880 patients who met inclusion criteria with 2585 person-years total followup time postdiagnosis. Of those, 367 (41.7%) were treated with bDMARD/tsDMARD within 12 months preceding malignancy, of whom 270 (30.7%) were taking such agents at first postdiagnosis visit. Forty-four (5%) switched biologic agents within 36 months and an additional 90 patients (10.2%) started a biologic. The majority of bDMARD/tsDMARD initiations during followup was a tumor necrosis factor inhibitor (TNFi; 53.5%)., Conclusion: In real-world practice, nearly one-third of RA patients with a cancer diagnosis were treated with systemic therapy in the immediate visit after malignancy diagnosis and a considerable percentage of malignancy survivors initiated biologic therapy within 3 years. The majority of bDMARD/tsDMARD initiations post-malignancy diagnosis was a TNFi.

Objective: Multidrug resistance (MDR) transporters may be used as biomarkers to monitor disease progression in RA and as a predictive tool to establish responsiveness to biological therapy. In this multicenter clinical trial, we aimed to assess the predictive value of activity measurement of transporters MDR1, MD resistance protein (MRP)1, and breast cancer resistance protein (BCRP) for biological therapeutic response in RA before the initiation of biological therapy as well as 4 to 6 and 12 weeks after., Methods: Peripheral blood samples were collected from 27 responders and 12 nonresponders to biological disease-modifying antirheumatic drugs (bDMARD) at the indicated timepoints as well as from 35 healthy controls. MDR activity factor (MAF) of MDR1, MRP1, and BCRP was measured in CD3+ and CD19+ cells using the Solvo MDQ Kit and cell surface staining by flow cytometry following peripheral blood mononuclear cells isolation., Results: At the start of therapy, MAFC (composite MAF of MRP1 and MDR1) and MAFMDR values, and at 4 to 6 weeks of treatment, MAFC, MAFMRP, and MAFMDR values of CD3 cells were higher in nonresponders compared to responders. Receiver-operation characteristic curve analysis revealed that RA patients with MAFC values above 21.3 in CD3 cells at the start of bDMARD therapy are likely to be nonresponders. At 4 to 6 weeks of treatment, these also predict unfavorable response: MAFC values above 20.3, MAFMRP values above 6.0, and MAFMDR values above 13.9 in CD3 cells., Conclusion: Our results indicate that the determination of MAFC values in CD3 cells of patients with RA may be of predictive value prior to the initiation of biological therapy, to establish whether the patient will demonstrate sufficient therapeutic response.

Objective: Acute anterior uveitis (AAU) is common in ankylosing spondylitis (AS). Golimumab (GOL), a tumor necrosis factor-α inhibitor (TNFi), has proven to be effective in the treatment of AS. To date, the effect of GOL on the incidence of AAU in AS is unknown. The objective was to study the AAU occurrence rate in patients with AS during GOL treatment and secondarily, the efficacy of GOL in daily clinical practice., Methods: The study was a multicenter prospective study in a real-world setting in patients with AS who were treated with GOL for 12 months. The occurrence of AAU was assessed in the year before the initial TNFi treatment and during GOL treatment and calculated for the period at risk for a new AAU. Measures for disease activity [Ankylosing Spondylitis Disease Activity Score (ASDAS)] and treatment response [Assessment of Spondyloarthritis international Society (ASAS20 score)] were collected., Results: In total, 93 patients (65% male, 55% TNFi-naive, 27% history of AAU) were included, with a median disease duration of 7 years and ASDAS score of 3.1. During GOL treatment, the AAU occurrence rate was reduced from 11.1 to 2.2 per 100 patient-years (rate-ratio 0.20, 95% CI 0.04-0.91). After 3 months of treatment, 41% of the patients experienced a clinically important improvement of the ASDAS score (p < 0.001) and 36% an ASDAS20 response (p < 0.001). At month 12, 49% had achieved an ASAS20 response (p < 0.001)., Conclusion: In AS, the AAU occurrence rate and disease activity decreased significantly during GOL treatment. Therefore, GOL can be considered a good choice in patients with AS who need a TNFi, especially in cases of recurrent AAU. (EudraCT number: 2012-002458-21).

Objective: Individuals with rheumatoid arthritis (RA) are at a heightened risk of sudden cardiac death, an outcome increased in those with prolongation of the corrected electrocardiographic QT interval (QTc). We compared QTc between patients with RA and demographically matched controls and studied the change in QTc after treatment with the interleukin 6 inhibitor tocilizumab (TCZ)., Methods: Standard 12-lead electrocardiograms were obtained and QTc was measured in patients with RA at baseline and after 24 weeks of TCZ treatment, then compared with non-RA controls who were frequency-matched on age and sex. Indicators of the baseline QTc and predictors of change in QTc were studied using multivariable linear regression., Results: A total of 94 RA and 42 non-RA controls were studied. The average baseline QTc was 10 ms longer in the RA group vs controls (422 vs 412 ms, respectively; p < 0.001) and decreased to an average of 406 ms with treatment (p < 0.001). Baseline QTc was significantly and independently higher among those with anticyclic citrullinated peptide antibodies seropositivity, higher swollen joint counts, and higher levels of C-reactive protein (CRP) and matrix metalloproteinase 3. Each log unit decrease in CRP with treatment was associated with an average reduction in QTc of 2.9 ms (p = 0.002) after adjusting for age and baseline QTc. Clinical response measures were not associated with the change in QTc., Conclusion: The marked normalization of QTc observed with TCZ treatment, and its close parallel with CRP reduction, support the premise that systemic inflammation contributes to cardiac repolarization abnormalities in RA that may be amenable to treatment.

Objective: Obese patients with rheumatoid arthritis (RA) report more joint swelling and tenderness and often have poorer responses to therapy than nonobese patients. The aim of this posthoc analysis of the MUSICA trial was to compare imaging and clinical disease activity measures in obese and nonobese patients with RA., Methods: MUSICA evaluated methotrexate (MTX) 20 mg/week versus 7.5 mg/week in combination with adalimumab (ADA) in RA patients with an inadequate response to MTX. Patients were categorized by baseline body mass index as normal (< 25), overweight (≥ 25 to < 30), or obese (≥ 30). Synovial vascularity and hypertrophy, swollen and tender joint counts (SJC and TJC), American College of Rheumatology (ACR) responses, and low disease activity (LDA), defined as Clinical Disease Activity Index < 10 and 28-joint count Disease Activity Score using C-reactive protein (DAS28-CRP) < 3.2, were assessed at weeks 12 and 24., Results: Patient characteristics were similar among groups at baseline. Obese patients had numerically smaller changes from baseline to weeks 12/24 in SJC, TJC, DAS28-CRP, and synovial hypertrophy and vascularity versus nonobese patients. Significantly fewer obese patients reached ACR20/50 at weeks 12 and 24, and LDA at Week 12; this difference was especially apparent in patients receiving 7.5 mg/week MTX but was no longer significant at Week 24., Conclusion: Obese patients with RA had worse clinical and ultrasonographic responses than nonobese patients, which were partly overcome with time. Obese patients may experience better and faster clinical improvements if ADA is initiated with high-dose (20 mg/week) rather than low-dose MTX. [ClinicalTrials.gov: NCT01185288].

Objective: To determine the efficacy of 2 tight control treatment strategies aiming at Simplified Disease Activity Score (SDAI) remission (SDAI ≤ 3.3) compared to 28-joint count Disease Activity Score (DAS28) remission (DAS28 < 2.6) in the prevention of arterial stiffness in patients with early rheumatoid arthritis (RA)., Methods: This was an open-label study in which 120 patients with early RA were randomized to receive 1 year of tight control treatment. Group 1 (n = 60) aimed to achieve SDAI ≤ 3.3 and Group 2 (n = 60), DAS28 < 2.6. Pulse wave velocity (PWV) and augmentation index (AIx) were measured at baseline and 12 months. A posthoc analysis was also performed to ascertain whether achieving sustained remission could prevent progression in arterial stiffness., Results: The proportions of patients receiving methotrexate monotherapy were significantly lower in Group 1 throughout the study period. At 12 months, the proportions of patients achieving DAS28 and SDAI remission, and the change in PWV and AIx, were comparable between the 2 groups. In view of the lack of differences between the 2 groups, a posthoc analysis was performed at Month 12, including all 110 patients with PWV, to elucidate the independent predictors associated with the change in PWV. Multivariate analysis revealed that achieving sustained DAS28 remission at months 6, 9, and 12 and a shorter disease duration were independent explanatory variables associated with less progression of PWV., Conclusion: With limited access to biologic disease-modifying antirheumatic drugs, treatment efforts toward DAS28 and SDAI remission had similar effects in preventing the progression of arterial stiffness at 1 year. However, achieving sustained DAS28 remission was associated with a significantly greater improvement in PWV. [Clinical Trial registration: Clinicaltrial.gov NCT01768923.].

Objective: Hydroxychloroquine (HCQ) is a commonly used medicine for the treatment of systemic lupus erythematosus (SLE), and Th17 cells are closely related to the pathogenesis of SLE. However, the role and mechanism of HCQ on Th17 cell differentiation in SLE is not clearly understood. Here, we investigate the effect of HCQ on Th17 cell differentiation both in vitro and in patients with SLE., Methods: Twenty-five patients with SLE were divided into 2 treatment groups: prednisone alone and HCQ plus prednisone. Interleukin 17 (IL-17) expression was analyzed by ELISA and real-time (RT)-PCR. Th17 were measured in patients with SLE by flow cytometry before and after HCQ treatment. In vitro , naive T cells were cultured in Th17-inducing conditions with or without HCQ. Cell differentiation and IL-17 expression were analyzed. Finally, transcriptome sequencing identified differential gene expression between naive T cells and induced Th17 cells., Results: In patients, HCQ plus prednisone treatment inhibited IL-17 production, gene expression, and Th17 cell differentiation. In vitro , HCQ inhibited Th17 cell proliferation and differentiation, as well as IL-17 production. Five microRNA were significantly different in Th17 cells compared with naive T cells, and HCQ treatment reversed this effect. In vivo , microRNA-590 (miR-590) was verified and was significantly decreased in Th17 cells, compared with naive T cells from lupus-prone mice. Moreover, miR-590 was increased in patients treated with HCQ plus prednisone., Conclusion: HCQ inhibited Th17 cell differentiation and IL-17 production both in vitro and in patients with SLE. Our study provides additional evidence for HCQ as a treatment for SLE.

Objective: We examined agreement between the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) response criteria in rheumatoid arthritis (RA) and tested whether discordant responses were associated with patients' baseline characteristics or changes in RA activity encapsulated by the different criteria., Methods: In a prospective longitudinal study, we examined responses of 243 patients with active RA to escalation of antirheumatic treatment. We computed agreement between pairs of response criteria using κ coefficients and identified patient characteristics associated with unique responses to individual criteria., Results: We found that 110 patients (45.3%) had an ACR 20% improvement (ACR20) response, 135 (55.5%) had a EULAR moderate/good response, and 83 (34.1%) had an SDAI50 response. Agreement was moderate to good (ACR20/EULAR κ 0.57; ACR20/SDAI50 κ 0.64; EULAR/SDAI50 κ 0.59). All who had SDAI50 response also had a EULAR response. Patient characteristics at baseline generally did not distinguish those who responded to both, 1, or neither criterion. Discordance was most often because of improvements in the erythrocyte sedimentation rate or C-reactive protein level among EULAR and SDAI50 responders, which were not as common among ACR20 responders. Based on receiver-operating characteristic curves, SDAI35 response had a better balance of sensitivity and specificity relative to ACR20 and EULAR moderate/good responses than SDAI50., Conclusion: Discordant responses to RA improvement criteria are most often because of differences in responses of acute-phase reactants. SDAI35 response had higher sensitivity for improvement, as reflected by other response criteria, than SDAI50 response.

Objective: To investigate whether adalimumab (ADA) reduces whole-body (WB-) magnetic resonance imaging (MRI) indices for inflammation in the entheses, peripheral joints, sacroiliac joints, spine, and the entire body in patients with axial spondyloarthritis (axSpA)., Methods: An investigator-initiated, randomized, placebo-controlled, double-blinded 48-week followup trial included 49 patients with axSpA, who had Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) ≥ 4.0 despite treatment with nonsteroidal antiinflammatory drugs and a clinical indication for tumor necrosis factor inhibitor treatment. Patients were randomized to subcutaneous ADA 40 mg or placebo every other week for 6 weeks; thereafter, all patients received ADA. Conventional MRI and WBMRI were performed at weeks 0, 6, 24, and 48. The primary WBMRI endpoint was the proportion of patients with an improvement in WBMRI total inflammation index above the smallest detectable change (SDC) at Week 6., Results: The primary WBMRI endpoint (improvement of SDC > 2.3) was met in 11 (44%) patients in the ADA group and 3 (13%) patients in the placebo group (p = 0.025, Fisher's exact test). The primary conventional MRI endpoint, the minimally important change in Spondyloarthritis Research Consortium of Canada Spine MRI Inflammation Index at Week 6, was achieved by 9 (36%) patients in the ADA group and 4 (17%) patients in the placebo group (p = 0.20). The primary clinical endpoint, BASDAI reduction > 50% or 2.0 at Week 24, was attained by 32 (65%) patients., Conclusion: ADA provided significant reductions in WBMRI indices of peripheral, axial, and whole-body inflammation in patients with axSpA. WBMRI is promising for objective assessment and monitoring of peripheral and axial disease activity in future clinical trials.

Objective: Around one-third of patients with juvenile idiopathic arthritis (JIA) fail to respond to first-line methotrexate (MTX) or anti-tumor necrosis factor (TNF) therapy, with even fewer achieving ≥ American College of Rheumatology Pediatric 70% criteria for response (ACRpedi70), though individual responses cannot yet be accurately predicted. Because change in serum S100-protein myeloid-related protein complex 8/14 (MRP8/14) is associated with therapeutic response, we tested granulocyte-specific S100-protein S100A12 as a potential biomarker for treatment response., Methods: S100A12 serum concentration was determined by ELISA in patients treated with MTX (n = 75) and anti-TNF (n = 88) at baseline and followup. Treatment response (≥ ACRpedi50 score), achievement of inactive disease, and improvement in Juvenile Arthritis Disease Activity Score (JADAS)-10 score were recorded., Results: Baseline S100A12 concentration was measured in patients treated with anti-TNF [etanercept n = 81, adalimumab n = 7; median 200, interquartile range (IQR) 133-440 ng/ml] and MTX (median 220, IQR 100-440 ng/ml). Of the patients in the anti-TNF therapy group, 74 (84%) were also receiving MTX. Responders to MTX (n = 57/75) and anti-TNF (n = 66/88) therapy had higher baseline S100A12 concentration compared to nonresponders: median 240 (IQR 125-615) ng/ml versus 150 (IQR 87-233) ng/ml, p = 0.021 for MTX, and median 308 (IQR 150-624) ng/ml versus 151 (IQR 83-201) ng/ml, p = 0.002, for anti-TNF therapy. Followup S100A12 could be measured in 44/75 MTX-treated patients (34/44 responders) and 39/88 anti-TNF-treated patients (26/39 responders). Responders had significantly reduced S100A12 concentration (MTX: p = 0.031, anti-TNF: p < 0.001) at followup versus baseline. Baseline serum S100A12 in both univariate and multivariate regression models for anti-TNF therapy and univariate analysis alone for MTX therapy was significantly associated with change in JADAS-10., Conclusion: Responders to MTX or anti-TNF treatment can be identified by higher pretreatment S100A12 serum concentration levels.

Objective: To assess the implementation of European recommendations for use of TNF inhibitors for spondyloarthritis (SpA), rheumatologists' level of knowledge of and adherence to the recommendations, and potential barriers to the application of recommendations., Methods: We conducted a retrospective study among 42 rheumatologists who initiated a first subcutaneous TNF inhibitor for SpA in 2013 or 2014. Thirty items from national and international recommendations were separated into 3 domains: indication, pretherapeutic monitoring, and management under TNF inhibitors. A standardized data collection procedure was used to gather data from medical files to assess the application of each recommendation. Questionnaires assessing the knowledge, level of adherence to each recommendation, and potential barriers to their implementation were sent to rheumatologists., Results: Rheumatologists applied a mean of 60% of items from domains A and B, but less than 50% from domain C items. Recommendations regarding the search for previous infection and the prevention of future infections were the ones most often applied. However, < 60% of rheumatologists assessed cancer and other diseases before TNF inhibitor initiation. More than 95% of rheumatologists knew of the recommendations and had a high level of adherence. Lack of time, difficulties accessing specialized consultations, and lack of flexibility in the recommendations explained rheumatologists' difficulties in applying the recommendations., Conclusion: Despite high levels of knowledge of, and adherence to, recommendations for using TNF inhibitors for SpA, rheumatologists' application was limited because of a lack of human and material resources.

Objective: To compare the efficacy of 6 tumor necrosis factor-α inhibitors (TNFi) in treatment of ankylosing spondylitis (AS) at 12 weeks and 24 weeks., Methods: We performed a systematic literature review of randomized controlled trials of TNFi in patients with active AS. We included trials that reported efficacy at 10 to 14 weeks (12-week analysis) and at 24 to 30 weeks (24-week analysis). We used Bayesian network metaanalysis (NMA) to compare their relative efficacy to improve the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), and C-reactive protein (CRP) level., Results: We included 20 trials of 6 TNFi, with 43 treatment arms and 3220 participants. All TNFi were significantly better than placebo in reducing BASDAI and BASFI at 12 weeks and 24 weeks; all but certolizumab pegol (CZP) were statistically better than placebo in reducing CRP at 12 weeks; all but CZP and infliximab-dyyb (IFX biosimilar) were significantly better than placebo in reducing CRP at 24 weeks. IFX was superior to the other TNFi in decreasing BASDAI at 12 weeks, but not at 24 weeks. Excluding 1 open-label trial, there were no differences among TNFi., Conclusion: Based on this NMA of clinical trials, IFX was superior to other TNFi in reducing BASDAI at 12 weeks, but sensitive to inclusion of an open-label trial, and its efficacy was diminished at 24 weeks. The analysis was limited by few direct comparison trials. Further study of relative safety and longterm effectiveness will help inform the choice of TNFi in treating active AS.

Objective: To investigate sex differences in connection with the effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with ankylosing spondylitis (AS)., Methods: A total of 440 patients with AS (294 men; 146 women) initiating a first TNFi in the prospective Swiss Clinical Quality Management Cohort were included. We evaluated the proportion of patients achieving the 20% and 40% improvement in the Assessment of Spondyloarthritis international Society criteria (ASAS20 and ASAS40) as well as Ankylosing Spondylitis Disease Activity Score (ASDAS) improvement and status scores at 1 year. Patients having discontinued TNFi were considered nonresponders. Logistic regression analyses were performed to adjust for important predictors of response., Results: Compared to men, female patients had lower mean C-reactive protein levels, better spinal mobility, and more peripheral disease at the start. There was no sex disparity with regard to the ASDAS, the Bath Ankylosing Spondylitis Disease Activity and Functional indices, and the quality of life. At 1 year, 52% of women and 63% of men achieved an ASAS20 response (OR 0.63, 95% CI 0.37-1.07, p = 0.09). An inactive disease status (ASDAS < 1.3) was reached by 18% of women and 26% of men (OR 0.65, 95% CI 0.32-1.27, p = 0.22). These sex differences in response to TNFi were more pronounced in adjusted analyses (OR 0.34, 95% CI 0.16-0.71, p = 0.005 for ASAS20 and OR 0.10, 95% CI 0.03-0.31, p < 0.001 for ASDAS < 1.3) and confirmed for all the other outcomes assessed., Conclusion: In AS, fewer women respond to TNFi and women show a reduced response in comparison to men.

Objective: To report efficacy and tolerance of interleukin 1 blockade in adult patients with mevalonate kinase deficiency (MKD)., Methods: We retrospectively collected data on 13 patients with MKD who had received anakinra (n = 10) and canakinumab (n = 7)., Results: Anakinra resulted in complete or partial remission in 3/10 and 5/10 patients, respectively, and no efficacy in 2/10, but a switch to canakinumab led to partial remission. Canakinumab resulted in complete or partial remission in 3/7 and 4/7 patients, respectively., Conclusion: These data support frequent partial responses, showing a better response with canakinumab. The genotype and therapeutic outcomes correlation should help in the personalization of treatment.

Objective: The aim of this study was to evaluate the influence of sex on response to treatment and disease remission in patients with axial spondyloarthritis (axSpA)., Methods: In this retrospective multicenter study, patients with axSpA, according to the Assessment of Spondyloarthritis international Society (ASAS) criteria for axSpA, and treated with adalimumab, etanercept, golimumab, or infliximab, were studied. We compared clinical characteristics, patient-reported outcomes, disease activity, function, and response to treatment in male and female patients with this disease., Results: Three hundred forty patients with axSpA (270 with ankylosing spondylitis, 19 with psoriatic arthritis with axial involvement, and 51 with nonradiographic axSpA) were studied. Male subjects had a significantly higher prevalence of grade IV sacroiliitis, higher levels of serum C-reactive protein, lower Maastricht Ankylosing Spondylitis Enthesitis Score, and fatigue when compared with females. Further, Kaplan-Meier survival curves showed that the rate of partial remission, ASAS40 response, and Ankylosing Spondylitis Disease Activity Score (ASDAS) major improvement, but not ASDAS inactive disease, were significantly lower in female patients., Conclusion: Our data suggest that female sex was associated with a lower rate of response to treatment and of disease remission in patients with axSpA treated with antitumor necrosis factor-α drugs.

As in other inflammatory rheumatic diseases, the objective of psoriatic arthritis (PsA) treatment is the achievement of a defined target. Recent recommendations propose aiming for remission or low disease activity; however, a consensual definition of remission is lacking. A state of minimal disease activity (MDA) has been established and is defined by low activity assessed by tender/swollen joint counts, tender entheseal points, Psoriasis Area and Severity Index or body surface area, patient pain and global activity visual analog scale, and functional evaluation by Health Assessment Questionnaire. Since its development, MDA has been used increasingly in studies and clinical trials. In this article, the potential use of MDA as a treatment target in PsA is reviewed. The frequencies of MDA achievement with biologic disease-modifying antirheumatic drugs are summarized based on data from registries, observational studies, and clinical trials. Predictors and the prognostic effect of attaining MDA are also evaluated.

Objective: Rebound may occur in patients with psoriatic arthritis (PsA) who discontinue TNF inhibitor (TNFi) therapy in low disease activity (LDA)., Methods: Using physician and patient reports, we quantified rebound following TNFi discontinuation [defined as Clinical Disease Activity Index (CDAI) score > 10 or TNFi restart] and time to rebound in adults with PsA in LDA (CDAI score ≤ 10) at TNFi discontinuation., Results: Rebound occurred in 73% (69/94) of patients soon after discontinuation (median time to rebound 8.0 mos, 95% CI 6.0-12.0)., Conclusion: Rebound occurred frequently in patients with PsA after TNFi discontinuation. TNFi discontinuation after achieving LDA should be carefully considered.

Objective: To determine whether levels of plasma n-3 polyunsaturated fatty acids are associated with response to antitumor necrosis factor (anti-TNF) agents in rheumatoid arthritis (RA), and whether this putative effect may have its basis in altering anti-TNF-driven Th17 cell differentiation., Methods: Plasma was collected at baseline and after 3 months of anti-TNF treatment in 22 patients with established RA, and fatty acid composition of the phosphatidylcholine (PC) component was measured. CD4+CD25- T cells and monocytes were purified from the blood of healthy donors and cocultured in the presence of anti-CD3, with or without etanercept (ETN), eicosapentaenoic acid (EPA), or the control fatty acid, linoleic acid (LA). Expression of interleukin 17 and interferon-γ was measured by intracellular staining and flow cytometry., Results: Plasma PC EPA levels and the EPA/arachidonic acid ratio correlated inversely with change in the Disease Activity Score at 28 joints (DAS28) at 3 months (-0.51, p = 0.007 and -0.48, p = 0.01, respectively), indicating that higher plasma EPA was associated with a greater reduction in DAS28. Plasma PC EPA was positively associated with European League Against Rheumatism response (p = 0.02). An increase in Th17 cells post-therapy has been associated with nonresponse to anti-TNF. ETN increased Th17 frequencies in vitro . Physiological concentrations of EPA, but not LA, prevented this., Conclusion: EPA status was associated with clinical improvements to anti-TNF therapy in vivo and prevented the effect of ETN on Th17 cells in vitro . EPA supplementation might be a simple way to improve anti-TNF outcomes in patients with RA by suppressing Th17 frequencies.

Objective: Patients with resolved hepatitis B virus (HBV) infection, i.e., hepatitis B surface antigen (HBsAg)-negative/antihepatitis B core antigen (anti-HBc)-positive, undergoing rituximab (RTX)-based chemotherapy for hematological malignancies without anti-HBV prophylaxis are at risk of HBV reactivation, but the risk in such patients receiving RTX for rheumatological disorders is not clear. We evaluated this risk in HBsAg-negative/anti-HBc-positive patients with rheumatoid arthritis (RA) undergoing RTX without prophylaxis., Methods: Thirty-three HBsAg-negative/anti-HBc-positive outpatients with RA with undetectable HBV DNA by sensitive PCR assay [73% women, median age 60 years, 85% with HBsAg antibodies (anti-HBs), 37% with antihepatitis B envelope antigen] received a median of 3 cycles of RTX (range 1-8) over 34 months (range 0-80) combined with disease-modifying antirheumatic drugs (DMARD) without prophylaxis. All underwent clinical and laboratory monitoring during and after RTX administration, including serum HBsAg and HBV DNA measurements every 6 months or whenever clinically indicated., Results: None of the patients seroreverted to HBsAg during RTX treatment, but 6/28 (21%) showed a > 50% decrease in protective anti-HBs levels, including 2 who became anti-HBs-negative. One patient (3%) who became HBV DNA-positive (44 IU/ml) after 6 months of RTX treatment was effectively rescued with lamivudine before any hepatitis flare occurred. Among the 14 patients monitored for 18 months (range 0-70) after RTX discontinuation, no HBV reactivation was observed., Conclusion: The administration of RTX + DMARD in patients with RA with resolved HBV infection leads to a negligible risk of HBV reactivation, thus suggesting that serum HBsAg and/or HBV DNA monitoring but not universal anti-HBV prophylaxis is justified.

Objective: We evaluated the synovial effects of 2 potent biologic rheumatoid arthritis (RA) therapies, focusing on their effect on the expression level of carboxypeptidase B (CPB) and its substrates., Methods: Patients with RA receiving infliximab (IFX; n = 9) or rituximab (RTX; n = 5) had an arthroscopic synovial biopsy at baseline and 16 weeks posttherapy. Expression of CPB, C5a, osteopontin (OPN), CD3, CD20, CD55, and CD68 was assessed by immunohistochemistry and image analysis, and compared with OA synovium. RA disease activity score was assessed at multiple timepoints. Serial serum samples were analyzed for soluble CPB and C5a levels., Results: The baseline clinical characteristics of patients receiving IFX and RTX were similar. At the time of the second biopsy, 50% of patients had achieved a European League Against Rheumatism good or moderate response. At baseline, expression of CPB, C5a, and OPN was markedly higher in RA compared with OA synovium and correlated with mononuclear cell infiltration. There was an overall reduction in synovial expression of CPB, C5a, and OPN paralleling a reduction in mononuclear cell infiltration, but these changes were not associated with clinical response. After an early reduction in serum C5a levels, these returned to baseline levels at later timepoints., Conclusion: In response to IFX and RTX treatment, RA synovial expression of CPB, C5a, and OPN decrease independently of the clinical response, reflecting the complex proinflammatory and antiinflammatory effects of this pathway.

Objective: Ankylosing spondylitis (AS) is characterized by chronic inflammation leading to ankylosis, but also to low bone mineral density (BMD) and vertebral fractures (VFx). Treatment with tumor necrosis factor-α blockers decreases inflammation and has shown to be effective in increasing BMD. We studied the effects of etanercept (ETN) on BMD and VFx in patients with AS after 2 years of treatment. Further, we studied changes in bone turnover markers and radiological damage., Methods: Patients with active AS, treated with ETN for 2 years, were included. BMD lumbar spine and hip were measured at baseline and after 2 years, as well as radiological damage (modified Stoke Ankylosing Spondylitis Spinal Score with the addition of the thoracic spine), VFx (Genant method), and change in bone turnover markers., Results: Forty-nine patients with AS were included. After 2 years of ETN, hip BMD increased by 2.2% (p = 0.014) and lumbar spine BMD by 7.0% (p < 0.001). The Bath Ankylosing Spondylitis Disease Activity Index decreased significantly (p < 0.001), as well as C-reactive protein and erythrocyte sedimentation rate (p < 0.001). Despite ETN therapy, the number of patients with VFx more than doubled (from 6 to 15 patients, p = 0.003). Also, the radiological damage increased significantly over time (from 12.1 to 18.5, p < 0.001); however, no significant change in bone turnover markers was found., Conclusion: This prospective longitudinal observational cohort study showed that after 2 years of ETN, BMD of the hip and spine increased significantly, but the number of patients with VFx and the severity of VFx increased as well. Besides that, radiological progression, including the thoracic spine, increased significantly. Thus, the favorable bone-preserving effect is accompanied by unfavorable outcomes on VFx and radiological damage.

Psoriatic arthritis (PsA) is a chronic systemic inflammatory disorder characterized by the association of arthritis and periarticular inflammation in patients with psoriasis. In addition to a heterogeneous and variable clinical course, PsA is complex and multifaceted and may include prominent involvement in the peripheral and axial diarthrodial joints, the skin and nails, and in periarticular structures such as entheses. Simultaneous inflammation in the skin and musculoskeletal structures in a single patient, a relatively common scenario, often leads to marked decrease in function and quality of life. Thus, it is essential for the clinician to document the extent of disease involvement and craft a therapeutic plan that addresses the different domains of disease. In an effort to update previous treatment recommendations developed by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA), several evidence-based, systemic reviews of therapies for PsA were completed, analyzed, and circulated for consensus.

Objective: The aim of our pilot study was to prospectively evaluate the effect of inhibiting interleukin 6 on the left ventricular (LV) structure and function in patients with rheumatoid arthritis (RA) without cardiac symptoms, using cardiac magnetic resonance (CMR)., Methods: Female patients with RA with active disease and healthy controls were enrolled. Cardiac symptoms were absent in all subjects. Tocilizumab (TCZ; 8 mg/kg IV every 4 weeks) was prescribed for patients with RA with an inadequate clinical response to methotrexate. All subjects underwent baseline evaluation of LV function and structure measured by CMR. We compared measures of LV geometry and function between patients with RA and patients without RA controls at baseline, and changes in the same variables between baseline and after 52 weeks of treatment among the group with RA., Results: Twenty women with RA were compared with 20 women without RA of similar mean age. In patients with RA at baseline, ejection fraction (EF) was significantly lower (-3.7%) and LV mass index (LVMI) significantly higher (+9.2%) compared with controls. TCZ treatment resulted in a significant decrease in the Simplified Disease Activity Index (SDAI) after 52 weeks of treatment, paralleling a significant increase in EF (+8.2%) and a significant decrease in LVMI (-24.4%) over the same period. The percentage change in LVMI correlated strongly with the percentage change in SDAI (r = -0.63, p = 0.0028). LV geometry in the group with RA at baseline showed eccentric hyper-trophy compared with the group without RA, a condition that normalized after TCZ treatment., Conclusion: TCZ treatment significantly increased EF and decreased LVMI associated with disease activity.

Objective: Randomized controlled studies have demonstrated protective advantages of biologic therapies over the synthetic disease-modifying antirheumatic drugs (DMARD) in slowing joint damage progression in patients with rheumatoid arthritis (RA). This effect appears to be largely independent of the clinical disease control. We measured the rate of radiographic progression in patients with RA in clinical remission treated with synthetic versus biologic DMARD., Methods: This is an observational cohort study of patients with RA in clinical remission, nested within the Swiss Clinical Quality Management in Rheumatoid Arthritis (SCQM-RA) Registry. The primary study outcome was the rate of radiographic progression (Ratingen erosion score), and a secondary outcome was functional disability [Health Assessment Questionnaire-Disability Index (HAQ-DI)] progression. We compared the rate of progression between synthetic and biologic DMARD using a multivariate regression model for longitudinal data, adjusting for potential confounders., Results: A total of 2055 patients in the SCQM-RA registry were in remission at least once from 1999 to 2012 and met the study inclusion criteria. Baseline characteristics of patients in remission receiving synthetic and biologic DMARD were not significantly different in terms of prognostic factors for joint damage progression. During followup, erosion progression differed significantly between the 2 groups [1.4% (95% CI: 1.1-1.6) vs 0.9% (95% CI: 0.5-1.2) of progression over 3 years, respectively, p < 0.001], with less damage progression in patients treated with biologic DMARD than with synthetic DMARD. This difference remained significant after adjusting for confounding factors. The evolution of the HAQ-DI score was also statistically better in the biologic group (p < 0.001)., Conclusion: This observational study confirms that the rate of structural damage progression in clinical remission is decreased taking biologics compared to synthetic DMARD. However, while the difference is statistically significant it is probably not relevant from a clinical perspective.

Objective: Patients with spondyloarthritis (SpA) receiving anti-TNF-α treatment have an increase in fat mass. This may be relevant to cardiovascular risk. The aim of this study was to estimate visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) changes by dual-energy x-ray absorptiometry (DEXA) in patients with SpA under anti-TNF-α therapy., Methods: We used an ancillary protocol to an open, prospective 2-year followup study of patients with SpA. Waist circumference (WC), body weight, body mass index, VAT, and SAT were measured at baseline, 6 months, and 1 and 2 years. Univariate and multivariate analyses were performed to assess variables associated with VAT and SAT changes., Results: A total of 85 patients were analyzed. Patients were 39.3 ± 11.4 years old and mean baseline Bath Ankylosing Spondylitis Disease Activity Index was 55.0 ± 20.2. Treatment was effective according to clinical and biological variables, and body weight increased by 0.9 ± 1.7 kg over 2 years. There was a significant gain in VAT after 6 months (13.7 ± 20.6 cm(2), p < 0.0001), 1 year (21.0 ± 26.6 cm(2), p < 0.0001), and after 2 years (29.1 ± 33.4 cm(2), p < 0.0001); and in SAT after 6 months (12.5 ± 27.4 cm(2), p < 0.0001), 1 year (27.1 ± 38.2 cm(2), p < 0.0001), and after 2 years (31.9 ± 53.2 cm(2), p < 0.0001). We could not find any determinant of these changes by multivariate analysis., Conclusion: In patients with SpA receiving anti-TNF-α therapy, there is an early significant increase in abdominal obesity with significant increase in both VAT and SAT after 1 and 2 years of treatment. Prospective studies are required to investigate the relationship between these changes and cardiovascular risk.

Objective: Tocilizumab (TCZ), an antiinterleukin-6 receptor monoclonal antibody, is clinically beneficial in patients with systemic-onset juvenile idiopathic arthritis (sJIA). We investigated the clinical and radiological outcomes of TCZ therapy in patients with sJIA., Methods: We retrospectively evaluated 2 clinical trials (NCT00144599 and NCT00144612) involving 40 patients with sJIA who received intravenous TCZ (8 mg/kg) every 2 weeks. Clinical data and radiographs of the hands and large joints were assessed before and during TCZ treatment. The Poznanski score, modified Larsen scores of the hands and large joints, and Childhood Arthritis Radiographic Score of the Hip (CARSH) were recorded., Results: After a mean duration of 4.5 years of TCZ treatment, clinical data had improved significantly, the mean Poznanski score improved from -1.5 to -1.1, the mean Larsen score of the hands deteriorated from 7.0 to 10.0, the mean Larsen score for the large joints deteriorated from 5.9 to 6.8, and the CARSH worsened from 3.9 to 6.2. The Larsen score for the large joints improved in 11 cases (28%), remained unchanged in 8 cases (20%), and worsened in 21 cases (52%). Matrix metalloproteinase 3 (MMP-3) levels remained significantly higher (278 mg/dl) in patients with worsened Larsen scores than in patients with improved or unchanged scores (65 mg/dl). Logistic regression analysis showed that older age at disease onset was a significant risk factor for radiographic progression., Conclusion: The modified Larsen score of the large joints deteriorated in half the patients who had high MMP-3 levels during TCZ treatment and who were significantly older at disease onset.

Objective: Evaluate the safety and efficacy of longterm abatacept (ABA) treatment over 5 years in methotrexate (MTX)-refractory patients with rheumatoid arthritis (RA)., Methods: Patients from the 1-year, double-blind Abatacept in Inadequate Responders to Methotrexate (AIM) study (NCT00048568) received open-label ABA (∼10 mg/kg) in the longterm extension (LTE). Safety was assessed for patients who received ≥ 1 ABA dose, and efficacy for patients randomized to ABA and treated in the LTE. Radiographs were evaluated for changes in Genant-modified Sharp scores., Results: Out of 652 patients, 539 entered the LTE (ABA, n = 378; placebo, n = 161). At Year 5, 72.4% were ongoing; discontinuation rates declined over time. Incidence rates of serious adverse events, serious infections, malignancies, and autoimmune events were 13.87, 2.84, 1.45, and 0.99 events/100 patient-years exposure, respectively. American College of Rheumatology 20 response was 82.3% (n = 373) and 83.6% (n = 268) at years 1 and 5, respectively. Disease Activity Score 28 C-reactive protein (DAS28-CRP) < 2.6 and ≤ 3.2 were achieved by 25.4% and 44.1% of patients at Year 1 (n = 370), and 33.7% and 54.7% at Year 5 (n = 267), respectively. Mean changes in DAS28-CRP and Health Assessment Questionnaire-Disability Index at Year 1 [-2.83 (n = 365) and -0.68 (n = 369)] were maintained at Year 5 [-3.14 (n = 264) and -0.77 (n = 271)] for patients continuing treatment. Of them, 59.5% (n = 291) and 45.1% (n = 235) remained free from radiographic progression at years 1 and 5, respectively., Conclusion: In MTX-refractory patients with RA, longterm ABA treatment was well tolerated and provided consistent safety and sustained efficacy, with high patient retention. Radiographic progression continued to be inhibited with ongoing treatment.

Objective: Growth retardation is a frequent complication of severe juvenile idiopathic arthritis (JIA). Biologic treatments may improve growth velocity by controlling systemic inflammation and reducing corticosteroids. Our goals were to compare growth velocity before and after the onset of biologic therapy and to determine whether the JIA subtype, the use of steroids, the requirement of one or several biologic agents, or the disease activity influenced growth velocity., Methods: We retrospectively analyzed the growth of children with JIA who never received growth hormone treatment, who started biologic treatment before puberty, and who were followed for at least 6 months afterward., Results: We included 100 children (33 boys). Median patient age was 7.1 years (range: 1.6-15.7) at the onset of biologic treatment and 11.0 years (range: 2.3-19.5) at the latest followup. Forty-six patients had received corticosteroid and 34 had received more than 1 biologic agent. Patient median height expressed as SD score (SDS) was 0.31 (range: -2.47 to 5.46) at disease onset, -0.24 (-3.63 to 2.90) at biologic therapy onset (p < 0.0001), and -0.15 (-4.95 to 3.52) at the latest followup (p = 0.171 compared to biologic treatment onset). Patients who required several biologics and systemic patients had a significantly lower growth velocity after the onset of biologic treatment. At the latest followup, 18% of our study group had low growth velocities and 19% were below -2SD or shorter than genetically programmed., Conclusion: In a subset of patients, particularly systemic JIA patients and patients who required more than 1 biologic, biologic therapy may be insufficient to restore normal growth velocity.

Objective: To evaluate changes in body mass index (BMI) among cohorts of children with juvenile idiopathic arthritis (JIA) with and without tumor necrosis factor (TNF) inhibitor therapy., Methods: We performed a retrospective chart review of children with JIA who newly initiated TNF inhibitor therapy and had at least 1 year of subsequent followup (TNF cohort). We also included children with JIA and at least 1 year of followup without any TNF inhibitor therapy (comparator cohort). Children with systemic arthritis were excluded. Age and sex specific BMI z-scores and their corresponding categories (normal, overweight, obese) were determined. We compared changes from a baseline visit to the last followup visit using t-test for BMI z-scores and chi square and Kruskal-Wallis tests for BMI categories., Results: The TNF cohort had 167 patients; the comparator cohort had 37. The median study followup was 2.8 and 2.2 years, respectively. The cohorts had similar age, sex, race, weight, and height distributions. The TNF cohort had a statistically significant increase in BMI z-score from baseline (+0.15; p = 0.02) that was not significantly different from the increase (+0.09) observed in the comparator cohort (p = 0.5). There was no significant change in the proportions of overweight and obese children in the TNF cohort compared to baseline (p = 0.6) or compared to the change in the comparator cohort (p = 0.2)., Conclusion: Over more than 2 years of followup, we did not observe a significant increase in BMI among children with JIA receiving TNF inhibitor compared to those not receiving it.

Objective: Spinal inflammation and erosions have been described in magnetic resonance imaging (MRI) examinations of patients with ankylosing spondylitis (AS). MRI scoring systems have implemented these observations., Methods: MRI scans (T1 or short-tau inversion recovery) from tumor necrosis factor-α blocker (anti-TNF) trials with patients with active AS (n = 22) were analyzed at baseline and after 2 years based on vertebral units (VU). The analysis was based on the prevalence of spinal erosions in relation to inflammation (active erosions) or without it (inactive erosions) as an outcome measure on MRI and their course under anti-TNF therapy. The results of MRI scoring systems that include (ASspiMRI) or exclude (Berlin score) erosions were also compared., Results: At baseline, there were more VU with inflammation (33.7%) than with erosions irrespective of activity (10.6%). After 2 years, active erosions decreased to 3.7% while inflammation was seen in a total of 12% of VU - a reduction of 58.9% and 64.5%, respectively (both p < 0.02). The overall extent of erosions decreased from 10.6% at baseline to 5.6% at 2 years. At the patient level, 73% and 32% of patients showed active erosions (p = 0.002), while 100% and 64% of patients showed inflammation (p = 0.029) at baseline and 2 years, respectively. Both scoring systems showed similar improvement, independent of inclusion or exclusion of erosions., Conclusion: Inflammation with erosions was observed in the spine of most patients with AS but their contribution to changes observed upon anti-TNF therapy was small, indicating that erosions do not need to be included in quantitative scoring systems of inflammation. Spinal inflammation was still present after 2 years of anti-TNF therapy in two-thirds of patients.

Objective: To assess the effects on bone mineral density (BMD) of prolonged anti-tumor necrosis factor (anti-TNF) therapy in patients with spondyloarthritis (SpA); to compare the BMD changes to those observed in SpA patients not treated with anti-TNF; and to identify the predictors of these changes., Methods: Fifty-nine patients with SpA according to the European Spondylarthropathy Study Group criteria who were treated with anti-TNF therapy for at least 4 years were included. Thirty-four patients with SpA from an international longitudinal observational study (OASIS cohort) were used as a control group. Lumbar spine and hip BMD were measured by dual-energy x-ray absorptiometry at baseline, after 1 year, and after at least 4 years., Results: Over an average 6.5 years' followup, the increase in BMD was 11.8% (± 12.8%) at the lumbar spine (p < 0.0001) and 3.6% (± 9.3%) at the great trochanter (p = 0.0001) in patients treated with anti-TNF. At the lumbar spine, the increase was similar in patients with and those without syndesmophytes. BMD changes were significantly higher in the anti-TNF group than in the control group at lumbar spine (p < 0.0001), at femoral neck (p = 0.002), and at trochanter (p = 0.011), but not at total hip (p = 0.062). Multivariate analysis showed that the predictors of lumbar spine BMD changes in the total population were the use of anti-TNF (p < 0.0001) and, in the anti-TNF therapy group, the 1-year lumbar spine BMD change (p = 0.007)., Conclusion: This study shows that prolonged anti-TNF therapy increases lumbar spine and trochanter BMD. This effect should be taken into account before introducing antiosteoporotic treatment in these patients.

Objective: To determine whether methotrexate (MTX) affects the expression of genes involved in the transport [SLC19A1 (RFC1), ABCB1 (MDR1), ABCC1 (multidrug resistance proteins 1), ABCG2 (BCRP)], metabolism [γ-glutamyl hydrolase (GGH), folylpolyglutamate synthetase (FPGS)], and mechanism of action of MTX [thymidylate synthase, MTR, MTRR] in rheumatoid synovium., Methods: Synovial tissue samples were obtained from 20 patients with rheumatoid arthritis (RA). Gene expression was undertaken using quantitative real-time PCR., Results: All the genes examined were expressed in all samples. Expression of SLC19A1, GGH, FPGS, ABCC1, and MTRR was significantly higher in patients receiving MTX compared to those not receiving MTX (p < 0.05). The ratio of FPGS:GGH gene expression was 2.7 ± 0.51 ng/ml GAPDH (range 0.67-9.58)., Conclusion: Genes involved in the transport, metabolism, and mechanism of action of MTX are expressed in rheumatoid joint synovium. These data provide evidence that MTX has the potential to be polyglutamated within the joint. The higher expression of FPGS compared to GGH in synovial tissue might favor production of long-chain MTX polyglutamates. Thus MTX has the potential to exert its therapeutic effects at the primary site of the inflammatory process in RA.

Objective: In rheumatoid arthritis (RA), anti-tumor necrosis factor (anti-TNF) treatment is shown to reduce but not to arrest the rate of hand bone loss. This has not been assessed in psoriatic arthritis (PsA). Our objective was to examine changes in cortical hand bone density in patients with PsA treated with placebo or infliximab (IFX)., Methods: Patients in IMPACT II (Induction and Maintenance Psoriatic Arthritis Clinical Trial 2) were randomized to placebo or IFX. After Week 24, all received IFX. In a subset of 120 patients, cortical hand bone density was assessed at Weeks 0, 24, and 54 by digital X-ray radiogrammetry (dxr-BMD) on the same radiographs scored for joint damage., Results: Changes from baseline to 24 weeks in dxr-BMD were -0.30% (SD 1.1%) in the placebo group and -0.08% (SD 1.4%) in the IFX group (p = 0.63). Between baseline and 54 weeks the changes were -0.71% (SD 2.1%) in the placebo group and 0.15% (SD 1.7%) in the IFX group (p = 0.07), and between 24 and 54 weeks -0.41% (SD 1.4%) and 0.23% (SD 0.8%), respectively (p = 0.05). No significant correlation was found between change in dxr-BMD and radiographic damage., Conclusion: This pilot study indicates that hand bone loss in PsA patients treated with anti-TNF can be arrested. Assessment of hand bone density may thus be a potential outcome measure for bone involvement and a response variable to treatment in PsA.

Objective: To investigate the effect of 1-year treatment with the anti-tumor necrosis factor-α (TNF-α) drug etanercept on lipid profile and oxidative stress in children and adolescents with juvenile idiopathic arthritis (JIA)., Methods: Thirty children with JIA (22 females; mean age 12.3 ± SD 5.7 yrs), all eligible for anti-TNF-α treatment, were assessed at baseline and after 6- and 12-month treatment with etanercept. Disease activity was determined using the Juvenile Arthritis Disease Activity Score (JADAS). Blood samples were drawn to measure the acute-phase reactants C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), lipids, and the proinflammatory cytokines TNF-α, interleukin-1β (IL-1β), IL-6 and interferon-γ. To measure the oxidative stress marker 8-iso-prostaglandin F2α, 24-h urine samples were collected., Results: Inflammatory indicators (CRP and ESR) and JADAS scores improved significantly after 1 year of etanercept treatment (all p < 0.001). Proinflammatory cytokines showed significant reduction during the study period (all p < 0.001). Similar reductions were detected in total cholesterol (p < 0.001), low-density lipoprotein cholesterol (p = 0.04), and triglycerides (p < 0.001), whereas no significant change was found in high-density lipoprotein cholesterol. No side effects were observed during the treatment period., Conclusion: This study shows for the first time that anti-TNF-α therapy for JIA is associated not only with a beneficial effect on clinical disease activity and inflammatory indexes, but also with improved lipid profile and oxidative stress. These findings suggest that TNF-α blockers might reduce atherosclerotic risk in children with JIA.

Objective: To study safety and potential efficacy of a 2-treatment course (month 0/6) with rituximab (RTX) in early diffuse systemic sclerosis (dcSSc)., Methods: Two years' followup (open-label study) was done of 8 patients with early dcSSc. Patients received an infusion of 1000 mg RTX 2 times at months 0 and 6, with 100 mg methylprednisolone. Clinical measurements, Disease Activity Score, functional status, and CD19+ peripheral blood count were performed at months 0, 3, 6, 12, 15, 18, and 24 and histopathological evaluation of the skin at months 0, 3, 12, and 24., Results: There was a clinically significant change in skin score, with a mean Modified Rodnan skin score of 24.8 at baseline (SD 3.4) and 13.6 at Month 24 [SD 5.6; mixed models analyses (MMA) p < 0.0001] and a significant decrease in Disease Activity Score (DAS), with a median of 4.5 at baseline (range 1.5-7.5) and 0.5 at Month 24 (range 0.0-5.5; MMA p < 0.0001). Indices of internal organ involvement remained stable throughout the study. RTX induced effective B cell depletion at baseline and Month 6 (< 5 CD19+ cells/μl blood). The blindly assessed hyalinized collagen score changed significantly over time (MMA p = 0.009), with a mean of 69.3 at baseline (SD 22.8) and 33.1 at 24 months (SD 27.0). Five serious adverse events were considered unrelated to the RTX treatment., Conclusion: A 2-treatment course (months 0/6) with RTX appears to be well tolerated and may have potential efficacy for skin disease and stabilization of internal organ status in early dcSSc. Clinical Trials Registration NCT00379431.

Objective: Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) are proinflammatory cytokines involved in inflammatory response. Effective TNF-α blocker treatment is associated with an increase in circulating myeloid dendritic cells (mDC), suggesting their release from inflamed synovium. Currently, in vivo effects of IL-6 inhibition on DC are unknown. We monitored the changes in circulating mDC and plasmacytoid DC (pDC) during tocilizumab (TCZ) therapy in patients with rheumatoid arthritis (RA)., Methods: DC subset levels were evaluated by flow cytometry in patients with RA (n = 43) and in healthy volunteers (n = 20). In patients with RA, these levels were measured before and during TCZ therapy (8 mg/kg every 4 weeks). Response to TCZ therapy was evaluated at 12 weeks. Statistical analysis was based on Mann-Whitney U tests or Wilcoxon signed-rank tests., Results: At baseline, patients with active RA were characterized by a significantly lower level of circulating mDC and pDC compared to healthy donors. However, this difference did not correlate with any disease activity score. TCZ-treated patients who met the European League Against Rheumatism (EULAR) improvement criteria at Week 12 had significant reductions in mDC and monocyte levels as compared with EULAR nonresponders. Levels of pDC, CD4+ T cells, and CD8+ T cells remained stable during the TCZ courses, regardless of treatment response., Conclusion: Our study reveals an unexpected reduction of circulating mDC and monocytes in patients with RA in response to TCZ therapy. In accord with reports on neutrophils and platelets decreasing during TCZ therapy, our data suggest an effect of IL-6 inhibition on cells from myeloid lineage.

Tumor necrosis factor (TNF) antagonists are drugs developed to block endogenous TNF, an essential proinflammatory molecule with a central role in the pathogenesis of rheumatoid arthritis (RA). Although extensive studies have been performed concerning the mode of action of TNF-blocking agents, there are still many unresolved questions and potential differences between different TNF-blocking drugs. One unresolved issue is to what extent apoptosis is affected by TNF blockade in RA. We provide an overview of studies that have investigated the proapoptotic effect of different anti-TNF drugs in RA, searching for a unified interpretation of somewhat contradictory data.

Objective: To study the influence of anti-tumor necrosis factor-α (TNF-α) treatment on echocardiographic measures and concentrations of endothelin 1 (ET-1), interleukin 6 (IL-6), and amino-terminal fragment of pro-brain natriuretic peptide (NT-proBNP) in a cohort of 23 female patients with rheumatoid arthritis (RA)., Methods: We recruited 23 patients (mean age 51.3 ± 1.55 yrs) with RA resistant to treatment with disease-modifying antirheumatic drugs and average disease duration of 7.1 ± 1.0 years who had been selected to start treatment with the anti-TNF-α antagonist infliximab. Transthoracic echocardiographic examinations were performed before the first infusion and repeated after 1 year of treatment. Data for age, sex, RA disease activity by Disease Activity Score (DAS28) and echocardiographic data, NT-proBNP, IL-6, ET-1, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and other routine laboratory data were collected before treatment and after 1 year., Results: Twelve months of treatment with infliximab resulted in reduction of RA activity (i.e., reduction of DAS and acute-phase reactants). There was increased left ventricle ejection fraction, from 58.5% before treatment to 63% after. Treatment with infliximab also resulted in significant reduction of ET-1 (1.26 fmol/ml before treatment vs 0.43 fmol/ml after), IL-6 (58.46 pg/ml vs 3.46 pg/ml), and NT-proBNP (43.06 fmol/ml vs 14.78 fmol/ml). These reductions were observed after just 4 months of treatment and remained significant until the termination of the study., Conclusion: In patients with RA, treatment with infliximab contributed significantly to increase in left ventricular ejection fraction. Improvement of cardiac function was shown by conventional echocardiography; there was reduction of biochemical markers of heart failure.

Objective: Tumor necrosis factor-α (TNF-α) antagonists bring about significant improvement in chronic inflammatory diseases such as rheumatoid arthritis (RA) and spondyloarthritis (SpA). There is some evidence that they can also have negative myocardial effects, but to date this issue has not been clarified. We evaluated changes in electrocardiographic measures [QT interval, corrected, dispersion, and dispersion corrected (QT, QTc, QTd, QTdc, respectively)] in patients with RA or SpA treated with anti-TNF agents (infliximab and etanercept), those treated with other biological agents (rituximab), and with methotrexate., Methods: We studied 38 consecutive patients with RA (21 patients) or SpA (19 patients) being treated with TNF-α antagonists, 8 patients with RA being treated with rituximab, and 13 patients (8 with RA and 5 with SpA) taking methotrexate. Electrocardiographs (ECG) were performed on all participants at baseline and 12 months after initiation of treatment, and the QT, QTc, and QTd were calculated with standard procedures., Results: After 12 months of treatment, significant increases over baseline values were observed in the mean QT (p < 0.009), QTd (p < 0.0001), and QTdc (p < 0.0001) of the anti-TNF group, but no significant changes were observed in those taking rituximab. QT changes in the anti-TNF group were unrelated to the disease (RA vs SpA) or drug (infliximab vs etanercept), and none were associated with clinical manifestations of cardiac disease., Conclusion: In patients with RA and SpA, TNF-α antagonists seem to increase the QT and QTd measures. Although these changes were completely asymptomatic, ECG may be indicated in patients being considered for anti-TNF therapy to identify those at risk for cardiac complications.

Objective: To compare the respective effects of tocilizumab (TCZ) monotherapy, etanercept (ETN) monotherapy, and adalimumab (ADA) monotherapy on arterial stiffness in patients with rheumatoid arthritis (RA) in an open-label, randomized controlled trial., Methods: Patients with RA were eligible if they had active disease (28-joint Disease Activity Score > 3.2) and no prior treatment with methotrexate or biologics. All 64 patients had no history of cardiovascular disease or steroid treatment. Patients were randomly assigned to receive TCZ alone (n = 22), ETN alone (n = 21), or ADA alone (n = 21). Arterial stiffness was assessed with cardio-ankle vascular index (CAVI) and aortic augmentation index normalized to a fixed heart rate of 75 bpm (AIx@75) at baseline and 24 weeks' followup. Clinical data were collected at regular visits., Results: The characteristics of each group at baseline were not significantly different. In all groups there was significant attenuation from baseline to 24 weeks in CAVI (Week 0-Week 24, TCZ: 0.85 ± 0.15 m/s, p = 0.02; ETN: 0.81 ± 0.18 m/s, p = 0.03; ADA: 0.90 ± 0.21 m/s, p = 0.02) and in AIx@75. There were no significant differences among the groups in measures of CAVI or AIx@75. The 3 therapies made no difference to carotid intima-media thickness and carotid artery plaque. Only TCZ increased fasting serum total cholesterol from baseline to 24 weeks., Conclusion: The 3 types of monotherapy limited arterial stiffness in patients with RA to a similar extent.

Objective: To assess whether blockade of tumor necrosis factor-alpha (TNF-alpha) influences surgical wound healing in a normal mouse experimental model., Methods: Wound healing time course and degree of surgical wound collagenization were measured by morphological techniques and digital image analysis in 80 male SWISS-OF1 mice (40 received subcutaneous etanercept at a dose of 0.1 mg/25 g/ at -7, 0, 7, and 14 days)., Results: No significant differences were observed between treated and untreated animals in wound healing, re-epithelialization, or formation of inflammatory infiltrate or granulation tissue at days 7, 15, or 20 after surgery. At 20 days, the collagen area was larger in treated versus untreated mice (109,029 +/- 28,489 microm(2) vs 79,305 +/- 19,798 microm(2), p = 0.026, Mann-Whitney U test)., Conclusion: Surgical wounds showed a higher degree of collagenization at 20 days in etanercept-treated versus untreated mice, with no differences in the time course of wound healing. These data suggest that biological therapies to block TNF-alpha do not affect wound healing and do not need to be suspended during the perioperative period.