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In the early stages of protein insertion, the protein-conducting channels of the endoplasmic reticulum have been found to be open laterally towards the lipid bilayer. The amount of opening of the channel may depend on the hydrophobicity of the signal or signal anchor sequence. The hydrophobic area is in contact with the lipids, and the translocating portion which is lipophobic is linked with the proteins.

Objective: To validate standard self-report questionnaires for depression screening in patients with rheumatoid arthritis (RA) and compare these measures to one another and to the Montgomery-Åsberg Depression Rating Scale (MADRS), a standardized structured interview.Methods: In 9 clinical centers across Germany, depressive symptomatology was assessed in 262 adult RA patients at baseline (T0) and at 12 ± 2 weeks followup (T1) using the World Health Organization 5-Item Well-Being Index (WHO-5), the Patient Health Questionnaire (PHQ-9), and the Beck Depression Inventory II (BDI-II). The construct validity of these depression questionnaires (using convergent and discriminant validity) was evaluated using Spearman's correlations at both time points. The test-retest reliability of the questionnaires was evaluated in RA patients who had not undergone a psychotherapeutic intervention or received antidepressants between T0 and T1. The sensitivity and the specificity of the questionnaires were calculated using the results of the MADRS, a structured interview, as the gold standard.Results: According to Spearman's correlation coefficients, all questionnaires met convergent validity criteria (ρ > |0.50|), with the BDI-II performing best, while correlations with age and disease activity for all questionnaires met the criteria for discriminant validity (ρ < |0.50|). The only questionnaire to meet the predefined retest reliability criterion (ρ ≥ 0.70) was the BDI-II (rs  = 0.77), which also achieved the best results for both sensitivity and specificity (>80%) when using the MADRS as the gold standard.Conclusion: The BDI-II best met the predefined criteria, and the PHQ-9 met most of the validity criteria, with lower sensitivity and specificity. [ABSTRACT FROM AUTHOR]

Objectives: To investigate long-term effectiveness and safety of subcutaneous tocilizumab (TCZ-SC) in the routine clinical care of patients with rheumatoid arthritis (RA)., Methods: ARATA (ML29087) was a prospective, multicentre, observational study of adult patients with active RA initiating therapy with TCZ-SC. The primary effectiveness outcome was the proportion of patients achieving DAS28-ESR <2.6 at week 104. Additional efficacy outcomes included individual DAS28-dcrit responses (improvement of ≥1.8 from baseline), CDAI remission (≤2.8), and patient-reported outcomes (PROs), including Work Productivity and Activity Impairment scores. Adverse event rates were used to evaluate safety and tolerability., Results: Between May 2014 and July 2018, 114 study centres in Germany enrolled 1,300 patients with RA who received at least one dose of TCZ-SC (mean age 57.3 [SD 12.5] years, mean DAS28-ESR of 4.9 [SD 1.3]). At week 104, 58.7% (365/622) patients achieved DAS28-ESR <2.6, 64.0% had an individual DAS28-dcrit response, and 31.4% (241/767) achieved CDAI remission. PROs, including patient global assessment, pain, and fatigue, showed marked improvements from baseline. Work outcomes, including absenteeism (missed work) and presenteeism (productivity while at work), also improved. Injection reactions were rare and no new safety signals occurred. Patients expressed a high level of satisfaction with treatment. Baseline patient characteristics and outcomes were similar for ARATA and ICHIBAN (an observational study of TCZ-IV in Germany), despite different formulations and time periods., Conclusions: The safety and effectiveness of TCZ-SC is maintained over 2 years during routine clinical care. TCZ-SC represents a convenient and effective option for RA patients who prefer SC administration.

Objectives: To examine the safety and effectiveness of long-term tocilizumab treatment in elderly patients with rheumatoid arthritis (RA) and patients with age-associated comorbidities., Methods: ICHIBAN (NCT01194401) was a prospective, non-interventional study that observed adult patients with active moderate-to-severe RA in German rheumatology clinics and practices for up to two years. Patients were to be treated according to the tocilizumab label. Here, we present safety and effectiveness data analysed according to patient age., Results: Of the 3,164 patients treated with at least one dose of tocilizumab, 924 patients were <50 years old, 1496 patients were 50-65 years old, and 744 patients were >65 years old at baseline. Patients >65 years had the highest baseline DAS28-ESR, CDAI, and HAQ-DI scores, along with the highest burden of comorbidities, such as diabetes, coronary heart disease, anaemia, and renal insufficiency. Under treatment with tocilizumab, patients >65 years had similar improvements in DAS28-ESR, CDAI and patient-reported outcomes (fatigue, pain, sleeplessness) with similar glucocorticoid savings compared to patient groups <65 years. Patients >65 years with late-onset RA achieved similar reductions in disease activity compared to early-onset patients. Despite numerically higher rates of adverse events (AEs), serious AEs and serious infections in patients >65 years, there were similar rates of AEs leading to withdrawal., Conclusions: Elderly patients in ICHIBAN experienced improvements similar to younger patients in most effectiveness endpoints with only slightly higher rates of AEs, indicating an overall net-positive risk-benefit ratio of tocilizumab treatment regardless of patient age.

Objectives: To assess whether tocilizumab treatment is associated with changes in depression symptoms in patients with rheumatoid arthritis (RA) during routine daily care., Methods: We retrospectively analysed data from a German non-interventional study (ARATA) of adult, tocilizumab-naïve RA patients who initiated subcutaneous tocilizumab and were followed for 52 weeks. The Beck Depression Inventory II (BDI-II) was used to assess symptoms of depression and create baseline subgroups of no (BDI-II<14), mild (14-19), moderate (20-28), and severe (≥29) depression. Other key outcomes included Disease Activity Score-28 joints (DAS28), patient-reported outcomes (PROs), and adverse events. Mixed model repeated measures (MMRM) assessed the impact of DAS28 on BDI-II over time, and Pearson correlation analyses evaluated associations between changes from baseline., Results: Of 474/1155 ARATA patients who completed the BDI-II at baseline, 47.7% had evidence of depression: 18.4% mild, 17.7% moderate, and 11.6% severe. 229 patients (48.3%) completed the BDI-II at both baseline and week 52. Two-thirds of patients with moderate or severe depression at baseline improved to a milder or no depression subgroup at week 52 (44/65 [67.7%]). Improvements in disease activity and PROs were observed in all subgroups, but patients with depression had lower response and higher adverse events rates. We observed an association between DAS28 and BDI-II over time in MMRM analyses, but the Pearson correlation for change from baseline was weak (r=0.10)., Conclusions: Depression is common in patients receiving routine care for RA. Improvements in depressive symptoms in RA during tocilizumab therapy appear to be distinct from changes in disease activity.