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The objective was to investigate the frequency of anti-cyclic citrullinated peptides (CCP) antibodies in systemic sclerosis (SSc) and primary biliary cirrhosis (PBC), utilizing a new "third generation" anti-CCP ELISA (anti-CCP3) kit and a conventional anti-CCP2 assay. Patients with PBC, SSc, RA, and normal controls were included in the study. Serum samples were screened for autoantibodies by indirect immunofluorescence (IIF), antibodies to CCP by a second- and third-generation ELISA, antibodies to "scleroderma" antigens (CENP B, Scl-70, PM/Scl and fibrillarin-Scl-34) by a line immunoassay (LIA), and IgM RF by ELISA. The frequency of anti-CCP2 antibodies in SSc and PBC samples was 14.8% (11/74) and 6.2% (5/80), respectively, and the frequency of anti-CCP3 antibodies in SSc was 13.5% (10/74) and in PBC was 3.7% (3/80). By comparison, in the RA group the frequency of anti-CCP3 and anti-CCP2 antibodies was 79.1% (38/48) and 77% (37/48), respectively. Anti-CCP3 ELISA had a sensitivity, specificity, and positive and negative likelihood ratios (LR) of 79% (95% confidence interval [CI] = 64-89%), 93% (95% CI = 88-96%), 11.8 (95% CI = 6.8-20.3), and 0.22 (95% CI = 0.12-0.38), respectively. By comparison, the anti-CCP2 assay had a sensitivity, specificity, and positive and negative LRs of 77% (95% CI = 62-87), 90% (95% CI = 85-94), 8.3 (95% CI = 5.2-13.2), and 0.25 (95% CI = 0.15-0.42), respectively. In patients with SSc, there was an association of anti-CCP2 antibodies with the presence of arthritis, but there was no association of anti-CCP2 or anti-CCP3 with anti-CENP B, anti-Scl 70, or RF. This study confirmed the high specificity and sensitivity of both anti-CCP assays for the diagnosis of RA. The presence of anti-CCP antibodies in SSc was only correlated with the presence of arthritis.

ObjectivesTo describe the baseline characteristics of SLE patients requiring biologic therapy in the UK and to explore short term efficacy and infection rates associated with rituximab (RTX) use.MethodsPatients commencing biologic therapy for refractory SLE and who consented to join BILAG-BR were analysed. Baseline characteristics, disease activity (BILAG 2004/SLEDAI-2K) and rates of infection over follow-up were analysed. Response was defined as loss of all A and B BILAG scores to ⩽ 1 B score with no new A/B scores in other organ systems at 6 months.ResultsTwo hundred and seventy SLE patients commenced biologic therapy from September 2010 to September 2015, most commonly RTX (n = 261). Two hundred and fifty (93%) patients were taking glucocorticoids at baseline at a median [interquartile range (IQR)] oral dose of 10 mg (5–20 mg) daily. Response rates at 6 months were available for 68% of patients. The median (IQR) BILAG score was 15 (10–23) at baseline and 3 (2–12) at 6 months (P < 0.0001). The median (IQR) SLEDAI-2K reduced from 8 (5–12) to 4 (0–7) (P < 0.001). Response was achieved in 49% of patients. There was also a reduction in glucocorticoid use to a median (IQR) dose of 7.5 mg (5–12 mg) at 6 months (P < 0.001). Serious infections occurred in 26 (10%) patients, being more frequent in the first 3 months post-RTX therapy. A higher proportion of early infections were non-respiratory (odds ratio = 1.98, 95% CI: 0.99, 3.9; P = 0.049).ConclusionRTX is safe and is associated with improvement in disease activity in refractory SLE patients with concomitant reductions in glucocorticoid use. Early vigilance for infection post-infusion is important to further improve treatment risks and benefits.

A role for iron in carcinogenesis is supported by evidence that iron metabolism proteins are modulated in cancer progression. To date, however, the expression of iron regulatory protein‐2 (IRP2), which is known to regulate several iron metabolism proteins, has not been assessed in colorectal cancer. Expression of IRP2 was assessed by quantitative RT‐PCR and immunohistochemistry in human colorectal cancer tissue. By interrogating The Cancer Genome Atlas (TCGA) database, expression of IRP2 and transferrin receptor‐1 (TfR1) was assessed relative to common mutations that are known to occur in cancer. The impact of suppressing IRP2 on cellular iron metabolism was also determined by using siRNA and by using the MEK inhibitor trametinib. IRP2 was overexpressed in colorectal cancer compared to normal colonic mucosa and its expression was positively correlated with TfR1 expression. In addition, IRP2 expression was associated with mutations in BRAF. The MEK inhibitor trametinib suppressed IRP2 and this was associated with a suppression in TfR1 and the labile iron pool (LIP). Moreover, epidermal growth factor stimulation resulted in decreased ferritin expression and an increase in the LIP which were independent of IRP2. Results presented here suggest that ablating IRP2 provides a therapeutic platform for intervening in colorectal tumorigenesis.

ObjectiveTo quantify how well phase III randomised clinical trials in both SLE and lupus nephritis (LN) represents a real-world SLE cohort.MethodsLiterature reviews were performed of major published phase III SLE (n=12) and LN (n=6) clinical trials (ClinicalTrials.gov). Inclusion and exclusion criteria common across these trials were collated for non-renal SLE or LN trials, and applied to patients recruited to the British Isles Lupus Assessment Group-Biologics Register (BILAG-BR) starting either biological or standard-of-care (SOC) therapies.ResultsWe recruited 837 patients to the BILAG-BR from September 2010 to June 2018, starting either SOC (n=125, 15%) or a biological medication (n=712, 85%). Active LN, defined as a BILAG A in the renal domain occurred in 20% (n=166). Overall, 530 (63%) patients were ineligible to participate in non-renal SLE clinical trials and 72 (43%) patients with active LN would be ineligible for LN trials. The most common reasons for ineligibility from the non-renal lupus trials included active renal involvement (n=166, 20%) and low disease activity (n=114, 15%). For LN trials, the most common exclusion met was pre-existing renal impairment (n=15, 9%). Patients with fewer comorbidities were more likely to be eligible to participate in non-renal SLE trials.ConclusionsIn this national register of patients with moderate-to-severe SLE, nearly two-thirds would not be eligible for recruitment to key SLE clinical trials nor would almost half of those with active LN. Eligibility criteria may excessively constrain enrolment and thus, how we can generalise trial results in a real-world setting.

Objective. Gene expression profiles are associated with the clinical heterogeneity of systemic lupus erythematosus (SLE) but are not well studied as biomarkers for therapy. We studied gene expression and response to rituximab in a multiethnic UK cohort who were refractory to standard therapy.Methods. We evaluated baseline expression levels of transcripts known to associate with clinical features of SLE using a 96-probe TaqMan array and whole blood samples from 213 patients with active SLE who had been prospectively enrolled in the British Isles Lupus Assessment Group (BILAG) Biologics Register. We measured autoantibodies using immunoprecipitation and enzyme-linked immunosorbent assays. We determined responses to first-cycle rituximab at 6 months from treatment start in 110 SLE patients by assessing BILAG 2004 disease activity.Results. Interferon gene expression scores were lower in patients of European ancestry than in all other ancestry groups. The relationship between blood interferon gene expression scores and scores annotated to plasmablasts, neutrophils, myeloid lineage, inflammation, and erythropoiesis differed between patients of European and non-European ancestries. Hierarchical clustering revealed 3 distinct non-European ancestry patient subsets with stratified responses to rituximab that were not explained by sociodemographic and clinical variables, with responses lowest in an interferon-low, neutrophil-high cluster and highest in a cluster with high expression levels across all signatures (P < 0.001). Clusters in European ancestry patients did not predict response to rituximab but segregated patients by global disease activity and renal involvement. In both ancestral groups, interferon-high clusters were associated with U1 RNP/Sm antibodies.Conclusion. Ancestry appears central to the immunologic and clinical heterogeneity in SLE. These results suggest that ancestry, disease activity, and transcriptional signatures could each assist in predicting the effectiveness of B cell depletion therapies.

Running Title Belimumab use in Refractory SLEKey Words Systemic Lupus Erythematosus, Biologic Therapy, Rituximab, Belimumab, Register. We sought to investigate the number of patients and the clinical characteristics of patients treated with a biologic in the BILAG-BR who would potentially have been eligible for belimumab using this guidance [5] Of the 270 patients registered for biologic use to Nov 2015, 82 (33%) had evidence of both low complement and elevated anti-dsDNA antibodies at enrolment. Of these, 46 (56.1%) patients had a BILAG A in the renal (n=29) or neuropsychiatric system (n=17) making them ineligible for therapy. An additional 4 (4.9%) had a SLEDAI score < 10. Thus from 2010-2015 32 patients (13%) enrolled in the BILAG-BR would have been eligible for belimumab.Amongst these 32 patients the BILAG mucocutaneous (MUC) and musculoskeletal (MSK) systems had the most frequent A (MSK=7, MUC=6) and B scores (MSK=11 ,MUC=8) ( Figure 1). 17 (53%) patients had a history of renal disease. The median (IQR) baseline SLEDAI was 12.5 (12 -15.75).Regarding medication use 28 (87.5%) and 27 (84.4%) patients were on an anti-malarial or oral prednisolone respectively. The median (IQR) baseline prednisolone dose was 15mg (10mg-20mg). The median (IQR) number of prior standard immunosupressant agents was 2 (1-3). Mycophenolate mofetil was the most frequently prescribed therapy (n=23) followed by azathioprine (n=15) and cyclophosphamide (n=11).When we assessed response to RTX in this cohort who would now be eligible for belimumab, the median (IQR) SLEDAI improved from 12.5 (12-15.75) at baseline to 4 (0-8) at 6 months (p < 0.0001). The total number of BILAG A scores reduced from 16 to 2 and B scores from 33 to 9. A corresponding reduction in corticosteroid dose was also noted from 15mg (10mg-20mg) to 6mg (5mg-10mg) at 6 months (p < 0.001).Improved access to biologic therapies will enhance physician's ability to control disease activity whilst facilitating corticosteroid tapering and preventing damage [6]. Given the response rate to most biologic therapies in SLE is approximately 50%, the addition of belimumab to UK physicians' armamentarium is to be welcomed, especially for those patients who have not responded to conventional therapy. Our data will help inform clinicians and planners about the expected rates of usage and the clinical characteristics of patients requiring belimumab in the UK. Mucocutaneous and musculoskeletal were the systems most likely to have active disease requiring belimumab. A history of renal involvement was however noted in approximately 50% of cases, emphasising that previous renal involvement does not exclude patients from belimumab, indeed both the BLISS-52 and 76 trials included patients with active renal disease and a post hoc analysis suggested favourable renal outcomes in this population [7]. Our data also suggests that RTX remains a realistic therapeutic option for patients who fail to respond to belimumab.In summary, between 2010 and 2015 13% of patients who commenced biologic therapy f...

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