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Screening and follow-up of interstitial lung disease associated with rheumatoid arthritis (RA-ILD) is a challenge in clinical practice. In fact, the majority of RA-ILD patients are asymptomatic and optimal tools for early screening and regular follow-up are lacking. Furthermore, some patients may remain oligosymptomatic despite significant radiological abnormalities. In RA-ILD, usual interstitial pneumonia (UIP) is the most frequent radiological and pathological pattern, associated with a poor prognosis and a high risk to develop acute exacerbations and infections. If RA-ILD can be identified early, there may be an opportunity for an early treatment and close follow-up that might delay ILD progression and improve the long-term outcome. In connective tissue disease–associated interstitial lung disease (CTD-ILD), lung ultrasound (LUS) with the assessment of B-lines and serum Krebs von den Lungen-6 antigen (KL-6) has been recognized as sensitive biomarkers for the early detection of ILD. B-line number and serum KL-6 level were found to correlate with high-resolution computed tomography (HRCT), pulmonary function tests (PFTs), and other clinical parameters in systemic sclerosis–associated ILD (SSc-ILD). Recently, the significant correlation between B-lines and KL-6, two non-ionizing and non-invasive biomarkers, was demonstrated. Hence, the combined use of LUS and KL-6 to screen and follow up ILD in RA patients might be useful in clinical practice in addition to existing tools. Herein, we review relevant literature to support this concept, propose a preliminary screening algorithm, and present 2 cases where the algorithm was used.

Background Thickened skin is a major clinical feature in patients with systemic sclerosis (SSc). We investigated changes of skin thickness in patients with SSc using both high frequency ultrasound (HFU) and the modified Rodnan skin score (mRSS) to evaluate the feasibility of application of HFU in skin involvement and the relationship between HFU and clinical profiles. Methods We recruited 31 consecutive patients with SSc and 31 age-matched and sex-matched healthy controls in this prospective, cross-sectional study. Skin thickness was measured by an 18-MHz ultrasonic probe at five different skin sites. Total skin thickness (TST) and skin thickness using categorical mRSS scores were recorded and compared to HFU. The European Scleroderma Trial and Research (EUSTAR) group Disease Activity Index (EUSTAR-DAI) and other clinical manifestations were assessed and analyzed. Results TST in patients with SSc was thicker than in healthy controls ( P <  0.001), and correlated positively with total mRSS and the EUSTAR-DAI and correlated negatively with disease duration ( P  < 0.05). Patients with higher TST had higher EUSTAR-DAI, mRSS, C-reactive protein (CRP) and lower diffusing capacity of the lung for carbon monoxide (DLCO) ( P  < 0.05). Even in patients who on clinical assessment were assigned an mRSS that suggested the skin thickness was normal. This was also true to mRSS locally of 1 and 2 ( P  < 0.01). The area under the receiver operator characteristic (ROC) curve was 0.831 and yielded sensitivity of 77.4% and specificity of 87.1% at the predicted probability of 7.4 mm as the optimal cutoff point to access skin thickness. Conclusions In the study, HFU was able to measure skin thickness, it correlated quantitatively with a valid measure of SSc activity, and a minimal detectable difference was identified.

Background Tumor necrosis factor (TNF) inhibitors are a mainstay in the treatment of rheumatoid arthritis (RA), as well as in the management of spondyloarthritis (SpA) and inflammatory bowel diseases (IBD). Unfortunately, a portion of patients taking these drugs require escalating doses within the approved label to achieve response, while others lose response altogether. This may be due to the development of antibodies against TNFi agents. Objectives Our objective was to examine the immunogenicity of TNF inhibitors (adalimumab, infliximab, etanercept, golimumab, and certolizumab) in RA, SpA, and IBD, and to examine the potential effect of anti-drug antibodies (ADABs) on the loss of clinical response through a systematic literature review and meta-analysis. Methods We conducted a comprehensive literature search using three databases (PubMed, Web of Science, and the Cochrane library) to identify studies examining the immunogenicity of TNF inhibitors in autoimmune diseases between 1966 and 31 December 2013. Inclusion criteria required that studies be in English, be randomized controlled trials, observational studies, or case reports involving more than five patients, and that the patients be aged 18 years or older. Studies were excluded if they were strictly genetic with no clinical correlate, if the patients had concomitant cancer within 5 years of the study, or if the patients had a renal disease requiring dialysis. Double extraction was followed by a third extraction if needed. Consensus was reached by discussion when disagreements occurred. Random-effect models were generated for the meta-analysis of 68 studies to estimate the odds ratio (OR) of the ADAB effects on TNF inhibitor response. Regression analysis was used to compare among the drugs and diseases. Results A total of 68 studies (14,651 patients) matched the inclusion/exclusion criteria. Overall, the cumulative incidence of ADABs was 12.7 % [95 % confidence interval (CI) 9.5–16.7]. Of the patients using infliximab, 25.3 % (95 % CI 19.5–32.3) developed ADABs compared with 14.1 % (95 % CI 8.6–22.3) using adalimumab, 6.9 % (95 % CI 3.4–13.5) for certolizumab, 3.8 % (95 % CI 2.1–6.6) for golimumab, and 1.2 % (95 % CI 0.4–3.8) for etanercept. ADABs reduced the odds of clinical response by 67 % overall, although most of the data were derived from articles involving infliximab (nine) and adalimumab (eight). The summary effect for infliximab yielded an estimated OR (with ADABs vs. without) of 0.42 (95 % CI 0.30–0.58); the summary effect for adalimumab yielded an estimated OR (as above) of 0.13 (95 % CI 0.08–0.22); and the OR (as above) for golimumab was 0.42 (95 % CI 0.22–0.81). All figures were statistically significant. ADABS decreased response by 27 % in RA and 18 % in SpA, both of which were statistically significant. However, the effect of ADABS on response was not statistically significant for IBD when we only included the studies that reported the duration of exposure in the regression analysis. The use of concomitant immunosuppressives (methotrexate, 6-mercaptopurine, azathioprine, and others) reduced the odds of ADAB formation in all patients by 74 %. The OR for risk with immunosuppressives versus without was 0.26 (95 % CI 0.21–0.32). Conclusion ADABs developed in 13 % of patients. All five TNF inhibitors were associated with ADABs, but to varying degrees depending on the specific TNF inhibitor and the disease. ADABs are associated with reduced clinical response and an increased incidence of infusion reactions and injection site reactions. Concomitant use of immunosuppressives can reduce ADAB formation.

The early phase of systemic sclerosis (SSc) presents edema as one of the main features: this is clinically evident in the digital swelling (puffy fingers) as well as in the edematous skin infiltration of the early active diffuse subset. Other organs could be affected by this same disease process, such as the lung (with the appearance of ground glass opacities) and the heart (with edematous changes on cardiac magnetic resonance imaging). The genesis of tissue edema is tightly linked to pathological changes in the endothelium: various reports demonstrated the effect of transforming growth factor β, vascular endothelial growth factor and hypoxia-reperfusion damage with reactive oxygen species generation in altering vascular permeability and extravasation, in particular in SSc. This condition has an alteration in the glycocalyx thickness, reducing the protection of the vessel wall and causing non-fibrotic interstitial edema, a marker of vascular leak. Moreover, changes in the junctional adhesion molecule family and other adhesion molecules, such as ICAM and VCAM, are associated with an increased myeloid cells' extravasation in the skin and increased myofibroblasts transformation with further vascular leak and cellular migration. This mini-review examines current knowledge on determinants of vascular leak in SSc, shedding light on the role of vascular protection. This could enhance further studies in the light of drug development for early treatment, suggesting that the control of vascular leakage should be considered in the same way that vasodilation and inflammation reduction, as potential therapeutic targets.

Background The extent of lung involvement visualized by high-resolution computed tomography (HRCT) is a predictor of decline in forced vital capacity (FVC) in scleroderma–interstitial lung disease. Our objective was to evaluate the performance of three different HRCT-defined staging systems in the Scleroderma Lung Study I (SLS I) over a 1-year period. Methods We assessed two visual semiquantitative scores: the maximum fibrosis score (MaxFib, the fibrosis score in the zone of maximal lung involvement) and visual assessment of total lung involvement (TLI) as proposed by Goh and Wells. In addition, we evaluated the computer-aided diagnosis and calculated the quantitative percentage with fibrosis (QLF) and TLI. Results The mean duration of the disease was 3.2 years, and the mean FVC was 67.7 %. Regardless of the staging system used, a greater degree of fibrosis/TLI on HRCT scans was associated with a greater decline in FVC in the placebo group. Using the MaxFib and QLF, the mean absolute changes in FVC from baseline were 0.1 % and −1.4 %, respectively, in <25 % lung involvement vs. a change of −6.2 % and −6.9 %, respectively, with >25 % involvement (negative score denotes worsening in FVC). Conversely, cyclophosphamide was able to stabilize decline in FVC in subjects with greater degree of involvement detected by HRCT. Using the visual MaxFib and QLF, the mean absolute improvements in FVC were 1.2 and 1.1, respectively, with >25 % involvement. Conclusions HRCT-defined lung involvement was a predictor of decline in FVC in SLS I. The choice of staging system for cohort enrichment in a clinical trial depends on feasibility. Trial registration ClinicalTrials.gov identifier: NCT00004563 (Scleroderma Lung Study I) ISRCTN15982171. Registered 19 Aug 2015.

Tocilizumab (TCZ) is the first humanized anti-interleukin-6 (IL-6) receptor monoclonal antibody approved for the treatment of patients with rheumatoid arthritis (RA), Castleman’s disease, polyarticular and systemic juvenile idiopathic arthritis, and, most recently, giant cell arteritis as well as for the treatment of chimeric antigen receptor T cell therapy-induced cytokine release syndrome. The global clinical development program for TCZ provides a wealth of clinical data on intravenous TCZ, and more recent studies in patients with RA have provided evidence characterizing the role of intravenous TCZ as monotherapy in early disease and led to the introduction of a subcutaneous formulation of TCZ. In addition, recently published open-label extension and observational studies continue to support the long-term efficacy and safety of TCZ in both clinical trial and real-world settings. Given the involvement of IL-6-mediated signaling in inflammatory disorders, TCZ is also being investigated in other immunological diseases. In particular, a phase 2 trial on the safety and efficacy of subcutaneous TCZ in adults with systemic sclerosis shows clinically relevant improvements in skin sclerosis and lung function in these patients. Another anti-IL-6 receptor agent, sarilumab, targeting the IL6 receptor alpha subunit, was recently approved for the treatment of patients with RA, although long-term data for this biologic are not yet published. In this article we review the placement of TCZ in current treatment guidelines; recent clinical trial data, including quality of life in patients with RA; recent updates to the TCZ safety profile; recent investigations of TCZ in other immunological diseases; and the clinical development of other novel IL-6-targeted agents.

Background To investigate the diagnostic accuracy of lung ultrasound (LUS) for interstitial lung disease (ILD) in patients with rheumatoid arthritis (RA). Methods This retrospective study included patients over 18 years with RA evaluated at the Department of Rheumatology and Immunology of Shantou Central Hospital. All patients underwent chest high-resolution computed tomography (HRCT) and LUS within one month. The LUS was performed in a total of 50 scanning sites (ScS), and the number of B-lines present in each ScS was counted and summed up as B-lines score. A positive judgement was given on LUS when the B-lines score exceeded 10. The presence and patterns of ILD were defined by HRCT findings. ROC curve analysis was used to calculate the accuracy of LUS to detect ILD. Results A total of 120 RA patients (86 women, with a median age of 56.0 [50.0–64.0] years) were enrolled. Based on the HRCT, 76 patients were found to have radiographic ILD, with 63 exhibiting nonspecific interstitial pneumonia (NSIP) and 13 showing usual interstitial pneumonia (UIP). Sonographic ILD was detected in 76 patients who underwent LUS examination. The concordance rate between two modalities was 83.33% (Kappa value = 0.64, 95% CI 0.50–0.78). The diagnostic sensitivity and specificity of LUS were 86.84% and 77.27%, respectively. The positive predictive value, negative predictive value, a positive likelihood ratio and a negative likelihood ratio were 86.84%, 77.27%, 3.82, and 0.17, respectively. The number of B-lines in RA with ILD and without ILD on HRCT showed a significant difference (34.0 [15.0–96.5] vs. 6.5 [2.5–10.0], P  < 0.001). The presence of 12 B-lines on 50 ScS was the optimal cutoff value for detecting RA-ILD (AUC = 0.89, 95% CI 0.82–0.94, sensitivity of 85.53%, specificity of 81.82%, P  < 0.001). Conclusions Lung ultrasound is a valuable diagnostic tool for RA-ILD and can be used as a screening method to identify patients who require further evaluation with chest HRCT.

Objective This study aimed to assess the minimal clinically important differences (MCIDs) for the modified Rodnan skin score (mRSS) using combined data from the Scleroderma Lung Studies (I and II). Methods MCID estimates for the mRSS at 12 months were calculated using three anchors: change in scores on the Health Assessment Questionnaire- Disability Index from baseline to 12 months, change in scores on the Patient Global Assessment from baseline to 12 months, and answer at 12 month for the Short Form-36 health transition question “Compared to one year ago, how would you rate your health in general now?” We determined the mRSS MCID estimates for all participants and for those with diffuse cutaneous systemic sclerosis (dcSSc). We then assessed associations between MCID estimates of mRSS improvement and patient-reported outcomes, using Student’s t test to compare the mean differences in patient outcomes between those who met the MCID improvement criteria versus those who did not meet the improvement criteria. Results The mean (SD) mRSS at baseline was 14.75 (10.72) for all participants and 20.93 (9.61) for those with dcSSc. The MCID estimate for mRSS improvement at 12 months ranged from 3 to 4 units for the overall group (improvement of 20–27% from baseline) and was 5 units for those with dcSSc (improvement of 24% from baseline). Those who met the mRSS MCID improvement criteria had statistically significant improvements in scores on the Short Form-36 Physical Component Summary, the Transition Dyspnea Index, and joint contractures at 12 months. Conclusion MCID estimates for the mRSS were 3–4 units for all participants and 5 units for those with dcSSc. These findings are consistent with previously reported MCID estimates for systemic sclerosis.

Background To demonstrate equivalent efficacy of the proposed high-concentration (100 mg/ml), citrate-free adalimumab biosimilar CT-P17 to European Union-approved adalimumab (EU-adalimumab) in subjects with active rheumatoid arthritis (RA). Methods This randomized, double-blind phase III study ( ClinicalTrials.gov , NCT03789292) randomized (1:1) subjects with active RA at 52 centers to receive CT-P17 or EU-adalimumab 40 mg subcutaneously every 2 weeks until week 52. Results to week 24 are reported here. The primary endpoint was 20% improvement by American College of Rheumatology criteria (ACR20) response rate at week 24. Equivalence was concluded if the corresponding confidence intervals (CIs) for the estimate of treatment difference were within predefined equivalence margins: − 15 to 15% (95% CI; European Medicines Agency assumption); − 12 to 15% (90% CI; Food and Drug Administration assumption). Additional efficacy, pharmacokinetic, usability, safety, and immunogenicity endpoints were evaluated. Results 648 subjects were randomized (324 CT-P17; 324 EU-adalimumab). The ACR20 response rate at week 24 was 82.7% ( n  = 268/324) in both groups (intention-to-treat population). The 95% CI (− 5.94 to 5.94) and 90% CI (− 4.98 to 4.98) were within predefined equivalence margins for both assumptions and equivalent efficacy was concluded. Additional endpoints and overall safety were comparable between groups. Mean trough serum concentrations of CT-P17 were slightly higher than those of EU-adalimumab. Immunogenicity was slightly lower numerically for the CT-P17 group than for the EU-adalimumab group. Conclusions CT-P17 and EU-adalimumab have equivalent efficacy and comparable safety and immunogenicity in subjects with active RA. Overall safety of CT-P17 is consistent with the known safety profile of reference adalimumab. Trial registration ClinicalTrials.gov, NCT03789292 . Registered 28 December 2018—retrospectively registered.

Interleukin-1 (IL-1) plays an important role in the pathophysiology and progression of rheumatoid arthritis (RA) by contributing to destruction of cartilage, bone, and periarticular tissues. Inhibiting IL-1 synthesis or activity with the use of recombinant human IL-1 receptor antagonist (anakinra) may prove to be an effective approach to the treatment of RA. The purpose of this article is to review the effects of anakinra in the treatment of RA. A MEDLINE search from 1982 to 2003 was used to identify animal studies and randomized clinical trials of anakinra and other therapies that target IL-1. Clinical trials of anakinra have shown that it reduces the signs and symptoms of active disease and slows the rate of radiographic destruction in adults with RA. With anakinra 150 mg/d, 43% of patients achieved an American College of Rheumatology (ACR) 20% response, compared with 27% with placebo ( P = 0.014). The ACR20 score indicates at least 20% improvement in the ACR composite score, which includes assessment of tender and swollen joint count, and other clinical end points such as pain and disability assessment. Patients treated with anakinra also experienced a 59% reduction in new bony erosion compared with controls ( P < 0.001) and a 65% reduction in joint space narrowing as measured by the modified Sharp score ( P = 0.020). Injection-site reactions were the most commonly reported adverse event, occurring in 50%, 73%, and 81% of patients receiving anakinra 30, 75, and 150 mg/d, respectively, compared with 25% of patients receiving placebo. Few serious adverse events were reported, and they typically occurred in patients receiving the highest daily dosage. IL-1 is an important cytokine in promoting the damage associated with RA. Anakinra is mildly to moderately effective and well tolerated in patients with active RA when used as monotherapy or in combination with methotrexate.