Objective. Generalized DNA hypomethylation contributes to altered T cell function and gene expression in systemic lupus erythematosus (SLE). Some of the overexpressed genes participate in the disease process, but the full repertoire of genes affected is unknown. Methylation-sensitive T cell genes were identified by treating T cells with the DNA methyltransferase inhibitor 5-azacytidine and comparing gene expression with oligonucleotide arrays. CD70, a costimulatory ligand for B cell CD27, was one gene that reproducibly increased. We then determined whether CD70 is overexpressed on T cells treated with other DNA methylation inhibitors and on SLE T cells, and determined its functional significance.Methods. Oligonucleotide arrays, real-time reverse transcription-polymerase chain reaction, and flow cytometry were used to compare CD70 expression in T cells treated with 2 DNA methyltransferase inhibitors (5-azacytidine and procainamide) and 3 ERK pathway inhibitors known to decrease DNA methyltransferase expression (U0126, PD98059, and hydralazine). The consequences of CD70 overexpression were tested by coculture of autologous T and B cells with and without anti-CD70 and measuring IgG production by enzymelinked immunosorbent assay. The results were compared with those of T cells from lupus patients. Results. SLE T cells and T cells treated with

Objective. To evaluate the efficacy and safety of treatment with ocrelizumab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) and an inadequate response to MTX.Methods. STAGE was a phase III randomized, double-blind, parallel-group international study to eval- Results. The ACR20 response rates were 35.7% in the placebo group, 56.9% in the ocrelizumab 200 mg group, and 54.5% in the ocrelizumab 500 mg group at 24 weeks, and 27.6%, 58.3%, and 62.1%, respectively, at 48 weeks (P < 0.0001 versus placebo for each dose at both time points). At week 48, both of the ocrelizumab doses improved the ACR50 and ACR70 response rates 3-fold as compared with placebo and showed a statistically significant (P < 0.0001) reduction in joint damage progression relative to placebo (mean change in SHS reduced by 85% and 100% for the 200-mg and 500-mg doses, respectively). Rates of serious infection were comparable in the placebo (3.48 per 100 patient-years) and ocrelizumab 200 mg (3.54 per 100 patient-years) groups but were elevated in the ocrelizumab 500 mg group (8.66 per 100 patient-years).Conclusion. With both ocrelizumab doses, the primary end point was met, and the signs and symptoms of RA were significantly improved at weeks 24 and 48. Ocrelizumab also significantly inhibited the progression ClinicalTrials.gov identifier: NCT00406419.

Aim: To evaluate the persistence and adherence of subcutaneous biologics in patients with psoriatic arthritis (PsA). Patients & methods: Psoriatic arthritis patients who initiated adalimumab, certolizumab pegol, etanercept, golimumab or secukinumab between 15 January 2016 and 31 July 2017 were identified in the Truven Databases. Outcomes included discontinuation rate, persistence and adherence over 12 months. Results: Of 1558 patients included, the 12-month discontinuation rate was lowest with secukinumab (36.5%), followed by adalimumab, golimumab, etanercept and certolizumab pegol (42.6–51.6%). Mean persistence ranged from 240.7 (certolizumab pegol) to 282.8 days (secukinumab). The mean proportion of days covered was highest with secukinumab (0.67) and lowest with certolizumab pegol (0.49). Conclusion: Patients who initiated secukinumab had the lowest discontinuation rate and highest persistence and adherence over 12 months.

Objective. To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy.Methods. This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti-abatacept antibody-positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20. Results. Ninety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were ؊1.67 (95% confidence interval [95% CI] ؊2.06, ؊1.28; combination) and ؊1.94 (95% CI ؊2.46, ؊1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were ؊1.84 (95% CI ؊2.23, ؊1.34; combination) and ؊2.86 (95% CI ؊3.46, ؊2.27; monotherapy) at month 18. Conclusion. SC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX.

T cells from patients with active lupus have multiple biochemical abnormalities. One of these is DNA hypomethylation, which in model systems alters gene expression and induces lupus-like autoimmunity. Recent reports indicate that DNA methylation is regulated in part by the ERK pathway, and that ERK pathway signaling is diminished in lupus T cells. This suggests a model in which defective T cell ERK pathway signaling contributes to the development of autoimmunity by decreasing DNA methyltransferase expression, modifying DNA methylation patterns and altering gene expression. This mechanism could contribute to idiopathic and drug-induced lupus.

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BackgroundAs of January 15, 2016, secukinumab became the first fully human anti–interleukin-17 monoclonal antibody approved for the treatment of patients with psoriatic arthritis (PsA) in the United States. Secukinumab may be administered with or without loading of 150 mg or 300 mg (patients with concomitant moderate to severe psoriasis only) at weeks 0, 1, 2, 3 and 4 followed by maintenance dosing every 4 weeks. The use of a loading regimen of secukinumab in a real-world setting of patients with PsA has not been evaluated since its approval in the United States.ObjectivesTo better understand the real-world use of secukinumab by describing the demographic, clinical and treatment characteristics (loading vs no loading) of secukinumab-treated patients with PsA.MethodsRetrospective data from the Symphony Health Solutions Lx commercial claims database were used to identify patients who had ≥1 secukinumab claim between 01/15/2016 and 06/30/2016. Patients who were included in the analysis were aged ≥18 years, had ≥1 ICD-9 code of 696.0 or ICD-10 code of L40.5 for PsA and had ≥1 pharmacy or medical claim in the 12 months prior to their first secukinumab claim (index date). Patient demographics and secukinumab dosage were examined at the index date. Clinical characteristics, comorbidities and treatment history in the 12 months prior to the index date were identified and presented by use vs no use of loading.ResultsA total of 764 patients met the inclusion criteria. The mean (SD) age was 50.7 (11.6) years, 58.5% of patients were female and 39.8% of patients were from the south. The most common specialties prescribing secukinumab to patients with PsA were rheumatologists (52.1%) and dermatologists (30.0%). A total of 608 patients (79.6%) received loading and 156 (20.4%) did not; at the index date, the majority of patients received secukinumab at the 300-mg dose in the loading (73.2%) and no loading (84.6%) groups. Patient demographics, clinical characteristics and treatment history were generally comparable between groups (Table 1). However, more patients with loading had prior oral corticosteroid (OCS; 30.9% vs 20.5%), targeted synthetic disease-modifying antirheumatic drug (tsDMARD; 24.7% vs 17.3%) and biologic (64.3% vs 59.6%) use compared with those without loading. The most prevalent comorbidities were psoriasis (58.8%), hypertension (34.4%) and hyperlipidemia (26.8%). A higher proportion of patients with loading had hypertension (35.2% vs 31.2%), rheumatoid arthritis (RA; 15.3% vs 10.9%), fatigue (13.5% vs 9.0%) and anxiety (13.3% vs 8.3%) and a lower proportion had psoriasis (57.4% vs 64.1%) compared with those without loading.ConclusionsThis US claims-based study found the majority ($≈ $ 73%) of secukinumab-treated patients with PsA were initiated with a loading regimen. Most patients initiated the 300-mg dose regardless of loading. A higher proportion of patients with loading had prior OCS, tsDMARD and biologic use, as well as hypertension, RA, fatigue and anxiety compared with those without loading, suggesting pat...

BackgroundSecukinumab is a fully human anti–interleukin-17 monoclonal antibody approved for the treatment of patients with moderate to severe plaque psoriasis, psoriatic arthritis and ankylosing spondylitis (AS), and may be administered with or without a loading regimen of 150 mg at weeks 0, 1, 2, 3 and 4 followed by maintenance dosing every 4 weeks. The dosing pattern of secukinumab in a real-world setting of patients with AS has not been evaluated since its approval in the United States on January 15, 2016.ObjectivesTo describe the demographic, clinical and treatment characteristics (loading, dose) of patients with AS who were treated with secukinumab in routine clinical practice in the United States.MethodsRetrospective data from the Symphony Health Solutions Lx commercial claims database were used to identify AS patients who had ≥1 secukinumab treatment between January 15, 2016 and June 30, 2016. Patients eligible for inclusion were ≥18 years of age who had the diagnosis of AS and ≥1 pharmacy or medical claim in the 12 months prior to their first secukinumab treatment (index date). Patient demographics and secukinumab dosage were examined at the index date. Clinical characteristics, comorbidities and treatment history in the 12 months prior to the index date were identified and presented by use versus no use of a loading regimen of secukinumab.ResultsA total of 152 patients who initiated secukinumab were included in this study; the mean (SD) age of included patients was 45.3 (11.1) years and 53.9% were female. Of the 152 patients, 119 patients (78.3%) received a loading regimen and 33 (21.7%) did not. Patient demographics, clinical characteristics and treatment history were not significantly different between the two cohorts (Table 1). The majority of patients (65.5%) with loading initiated secukinumab with the 150-mg dose, whereas the majority of patients (60.6%) without loading initiated with the 300-mg dose. More than half of the patients in each cohort received a biologic therapy during the 12-month baseline period (loading, 65.5%; no loading, 51.5%). Other prior treatments included oral corticosteroids (30.3% for both), conventional synthetic disease-modifying antirheumatic drugs (DMARDs) (loading, 31.9%; no loading, 21.2%) and targeted synthetic DMARDs (loading, 4.2%; no loading, 12.1%). The prevalence of comorbidities was similar between the two cohorts, with the most prevalent comorbidities being hypertension (19.1%), rheumatoid arthritis (19.1%) and other skin diseases (18.4%).ConclusionsIn this retrospective, administrative claims-based study, the majority of patients with AS initiated secukinumab treatment with a loading regimen. Although only the 150-mg dose of secukinumab is approved for the treatment of AS, almost 40% of patients received the 300-mg dose, indicating a need to better understand patient and treatment characteristics for secukinumab in patients with AS. The results of this study provide early insights into real-world use of secukinumab with and without a loading regimen in patients ...