Effect of glucocorticoids for the management of immune-related adverse events on outcome in melanoma patients treated with immunotherapy-a retrospective and biomarker study.

Background: Immune-related adverse events (IRAEs) during therapy with immune checkpoint inhibitors (ICIs) are common, and their management sometimes requires glucocorticoids (GCs). Predictors for development of IRAEs and data about the impact of GCs on clinical outcome are missing. We evaluated the impact of GCs to treat IRAEs on clinical outcome, and plasmatic inflammatory proteins as predictors for IRAEs. Patients and methods: Patients with melanoma (n = 98) treated with ICIs at Karolinska University Hospital were included. Clinical information and data regarding prescription of systemic GCs were collected. Baseline plasma samples (n = 57) were analyzed for expression of 92 inflammatory proteins. Results: Forty-four patients developed at least one IRAE requiring systemic GCs and the most common was hypocortisolemia (n = 11). A median overall survival of 72.8 months for patients developing IRAEs requiring GCs, 17.7 months for those who did not, and 1.4 months for individuals receiving GCs at baseline was observed in Kaplan-Meier curves (P = 0.001). In immortal time bias adjusted analysis, patients receiving steroids to treat IRAE survived slightly longer, even though this time trend was not statistically significant. The median overall survival was 29 months for those treated with GCs within 60 days after ICIs start and was not reached for patients receiving GCs later. The number of ICI cycles was higher in subjects receiving GCs after 60 days (P = 0.0053). Hypocortisolemia occurred mainly in males (10/11) and correlated with favorable outcome. Male patients with hypocortisolemia had lower expression of interleukin 8, transforming growth factor-α, and fibroblast growth factor 5 and higher expression of Delta/Notch-like epidermal growth factor-related receptor. Conclusions: GCs may be used to treat IRAEs without major concern. GCs early during ICIs may, however, impact clinical outcome negatively. The prognostic value of hypocortisolemia and inflammation proteins as biomarkers should be further investigated.

Evaluation of an individually tailored smoking-cessation intervention for patients with rheumatoid arthritis in an outpatient clinic.

OBJECTIVE: The aim of this study was to evaluate an individually tailored smoking-cessation intervention delivered in rheumatology care and compare the characteristics of patients who quit smoking with those who did not. METHOD: This was an open single-group prospective intervention study over 24 months, with assessments at baseline and at 6, 12, 18, and 24 months. Current smokers with rheumatoid arthritis (RA) were invited to a smoking-cessation programme including behavioural change support, with or without pharmacotherapy. Data on disease activity, medical treatment, and patient-reported outcomes were retrieved from the Swedish Rheumatology Quality Register. The primary outcome was the proportion of patients at month 24 who reported having quit smoking with self-reported 7 day smoking abstinence. RESULTS: In total, 99 patients participated in the study. Median age was 58 years (interquartile range 50-64); 69% were female and 88% rheumatoid factor and/or anti-cyclic citrullinated peptide positive. At 24 months, 21% of the patients had quit smoking. At 6, 12, and 18 months, 12%, 12%, and 14% of patients, respectively, had quit smoking. For patients still smoking at 24 months, the median number of cigarettes per day was significantly reduced from 12 to 6 (p ≤ 0.001). Among patients who had quit smoking at 24 months, a smaller proportion reported anxiety at baseline compared to those still smoking (28% vs 58%, p = 0.02). CONCLUSION: A smoking-cessation intervention including behavioural change support with or without pharmacotherapy can be helpful for a substantial number of RA patients. Anxiety is associated with lower smoking-cessation success rates.

Smoking and response to rituximab in rheumatoid arthritis: results from an international European collaboration.

OBJECTIVES: To investigate whether smoking habits predict response to rituximab (RTX) in rheumatoid arthritis (RA). METHOD: We included patients from the CERERRA international cohort receiving the first treatment cycle with available smoking status (n = 2481, smokers n = 528, non-current smokers n = 1953) and at least one follow-up visit. Outcome measures were change in Disease Activity Score based on 28-joint count (ΔDAS28) and European League Against Rheumatism (EULAR) good response at 6 months, with non-current smokers as the referent group. RESULTS: Compared with non-smokers at baseline, smokers were more often rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) positive and males, had shorter disease duration, lower DAS28 and Health Assessment Questionnaire (HAQ) score, a higher number of prior biological disease-modifying anti-rheumatic drugs, and were more likely to receive concomitant conventional synthetic disease-modifying anti-rheumatic drug (csDMARDs). Disease activity had decreased less in smokers at 6 months (ΔDAS28 = 1.5 vs 1.7, p = 0.006), although the difference was no longer significant after correction for baseline DAS28 (p = 0.41). EULAR good response rates did not differ between smokers and non-smokers overall or stratified by RF/ACPA status, although smokers had lower good response rates among seronegative patients (ACPA-negative: 6% vs 14%, RF-negative: 11% vs 18%). Smoking did not predict good response [odds ratio (OR) = 1.04, 95% confidence interval (CI) = 0.76-1.41], while ACPA, DAS28, HAQ, and concomitant csDMARDs were significant predictors for good response. However, when stratified by country, smokers were less likely to achieve good response in Sweden (unadjusted OR = 0.24, 95% CI = 0.07-0.89), and a trend was seen in the Czech Republic (OR = 0.45, 95% CI = 0.16-1.02). CONCLUSION: In this large, observational, multinational RA cohort, smokers starting RTX differed from non-smokers by having shorter disease duration and lower disease activity, but more previous treatments. The overall results do not support smoking as an important predictor for response to RTX in patients with RA.

Biological treatment in ankylosing spondylitis in the Nordic countries during 2010-2016: a collaboration between five biological registries.

OBJECTIVES: Large-scale observational cohorts may be used to study the effectiveness and rare side effects of biological disease-modifying anti-rheumatic drugs (bDMARDs) in ankylosing spondylitis (AS), but may be hampered by differences in baseline characteristics and disease activity across countries. We aimed to explore the research infrastructure in the five Nordic countries regarding bDMARD treatment in AS. METHOD: This observational cohort study was based on data from biological registries in Denmark (DANBIO), Sweden (SRQ/ARTIS), Finland (ROB-FIN), Norway (NOR-DMARD), and Iceland (ICEBIO). Data were collected for the years 2010-2016. Registry coverage, registry inventory (patient characteristics, disease activity measures), and national guidelines for bDMARD prescription in AS were described per country. Incident (first line) and prevalent bDMARD use per capita, country, and year were calculated. In AS patients who started first line bDMARDs during 2010-2016 (n = 4392), baseline characteristics and disease activity measures were retrieved. RESULTS: Registry coverage of bDMARD-treated patients ranged from 60% to 95%. All registries included extensive prospectively collected data at patient level. Guidelines regarding choice of first line drug and prescription patterns varied across countries. During the period 2010-2016 prevalent bDMARD use increased (p < 0.001), whereas incident use tended to decrease (p for trend < 0.004), with large national variations (e.g. 2016 incidence: Iceland 10.7/100 000, Finland 1.7/100 000). Baseline characteristics were similar regarding C-reactive protein, but differed for other variables, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (range 3.5-6.3) and Ankylosing Spondylitis Disease Activity Score (ASDAS) (2.7-3.8) (both p < 0.0001). CONCLUSION: Collaboration across the five Nordic biological registries regarding bDMARD use in AS is feasible but national differences in coverage, prescription patterns, and patient characteristics must be taken into account depending on the scientific question.

Relationship between glucocorticoid dose and adverse events in systemic lupus erythematosus: data from a randomized clinical trial.

OBJECTIVE: The aim was to obtain a better understanding of the relationship between exposure to glucocorticoids (GCs) and adverse events (AEs) reported in a randomized controlled trial (RCT) in systemic lupus erythematosus (SLE) patients. METHOD: We used data from the BLISS-76 trial on belimumab. The data were accessed through an agreement under the SHARE mechanism. AEs were grouped according to medical relevance, i.e. based on similarity of symptoms and pathophysiology. We studied the relationship between AEs and exposure to GCs at baseline and at any time-point, and compared the frequencies of each AE and groups of AEs between tertiles of cumulative GC dose. RESULTS: In total, 991 AEs were reported in the 819 patients of the trial. The frequencies of anaemia, pyrexia, oral herpes, and malaise were significantly higher (p < 0.05) in patients who were on GCs at baseline than in those who were not. The frequencies of several other AEs, including nausea, seasonal allergy, bacterial sinusitis, and viral upper respiratory infection, were significantly higher in patients without GCs. For cumulative GCs, tachycardia and proteinuria were significantly more frequent in the highest tertile than in the lowest tertile, but other AEs and groups of AEs were significantly more frequent in the lowest tertile. CONCLUSION: This study highlights the feasibility of post-hoc analyses of RCTs using the SHARE mechanism and demonstrates the association of GCs with various AEs. Contrary to expectations, there were also associations between lower cumulative GC dose and several other AEs.

Optimizing biological treatments for rheumatoid arthritis.

The area of rheumatoid arthritis (RA) treatment has been revolutionized during the last decades with the development of biological therapies and their introduction into daily clinical practice contributing greatly to this dramatic change. However, several aspects of the use of these highly effective but expensive therapies remain far from optimal. To date, there is no clear evidence for the optimal sequence of biological agents, and the choice of a second- or third-line biologic is random. The effect of drug levels and the presence of neutralizing anti-drug antibodies remain unclear. In addition, the identification of prognostic factors of response, both clinical and histopathological, is crucial for a more individualized treatment approach.

Effectiveness and survival-on-drug of certolizumab pegol in rheumatoid arthritis in clinical practice: results from the national Swedish register.

OBJECTIVES: Evidence regarding the efficacy and effectiveness of certolizumab pegol (CZP) in rheumatoid arthritis (RA) patients who have failed to respond to treatment with a tumour necrosis factor inhibitor (TNFi) is limited. The aim of this study was to describe the effectiveness and survival-on-drug of CZP in a real-life setting, both in TNFi-naïve patients and in patients who had previously failed TNFis, and in relation to disease activity at baseline. METHOD: The national Swedish Rheumatology Quality Register (SRQ) was used to identify patients with RA starting treatment with CZP between 2009 and 2013. The effectiveness of treatment was assessed using the 28-joint Disease Activity Score (DAS28), the Health Assessment Questionnaire (HAQ), measures of remission, the European League Against Rheumatism (EULAR) response during 0-6 months from start of treatment, and survival-on-drug during the first 30 months. RESULTS: A total of 945 RA patients started treatment with CZP. Of these, 540 (57.1%) received CZP as the first biological treatment, 215 (23%) had failed one previous TNFi, and 190 (20%) had failed at least two TNFis. Overall, 71% achieved at least a EULAR moderate response and 38% had a EULAR good response at 6 months from baseline. TNFi-naïve patients achieved significantly better results and had better survival-on-drug compared to patients who had failed previous TNFis. Around 20% of patients who had not responded to two or more prior TNFis achieved EULAR good response to therapy and a similar percentage achieved remission. Patients who had high baseline disease activity had a higher risk of discontinuing treatment compared to those without high disease activity. CONCLUSIONS: In this real-life RA cohort, CZP was associated with significant clinical improvement. The effectiveness and survival-on-drug vary markedly depending on the line of treatment.

Rituximab versus anti-TNF in patients who previously failed one TNF inhibitor in an observational cohort.

OBJECTIVE: The purpose of this study was to characterize and compare responses in patients who had failed one tumour necrosis factor (TNF) inhibitor when switching to another TNF inhibitor or rituximab (RTX). METHODS: The Stockholm TNF follow-up registry (STURE) was used. Treatment results at 6 months were analysed by (i) the biologic used, (ii) the type of anti-TNF switch, and (iii) the reason for discontinuation (inefficacy or intolerance). RESULTS: A total of 328 patients who failed an anti-TNF switched to an alternative biologic, 69 to RTX, 161 to an anti-TNF monoclonal antibody (mAb), and 98 to etanercept (ETA). Significant reductions in the 28-joint Disease Activity Score (DAS28) at 6 months were observed for all groups. The mean ± SD reduction in DAS28 was 1.70 ± 1.18 for RTX, 1.40 ± 1.51 for ETA, and 0.67 ± 1.36 for mAb, the difference being statistically significant between RTX and mAb (p < 0.0001). For patients who had failed ETA, RTX led to significantly greater DAS28 reductions than mAb (p = 0.01). When the reason for discontinuation of the previous anti-TNF was intolerance or secondary inefficacy, RTX led to significantly greater DAS28 reduction compared to mAb and ETA (p = 0.01 and p = 0.03, respectively). CONCLUSIONS: In this observational cohort, patients who failed one anti-TNF had better overall results when treated with RTX than with a subsequent anti-TNF mAb. Having failed ETA, RTX yielded greater DAS28 reductions and European League Against Rheumatism (EULAR) responses than mAb. The advantage of RTX was most clearly seen in patients who had failed anti-TNF because of intolerance or secondary inefficacy.

When to initiate and discontinue biologic treatments for rheumatoid arthritis?

The introduction of biologic therapies heralded a new era in the treatment for chronic inflammatory autoimmune diseases of which rheumatoid arthritis is one of the most prevalent. From a scientific point of view, these therapies demonstrated that the targeting of individual cytokines or cell-surface markers is a very effective approach. For the physician, the appropriate selection of patients in whom these therapies should be initiated is critical, as is the even more contentious issue of whether these therapies can or should be discontinued in selected patients with excellent clinical responses. Whereas the former issue has been addressed in a large number of clinical trials and observational studies, the latter remains poorly investigated and is currently the subject of further study.