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Objectives Explore prognostic and predictive markers of systemic sclerosis-associated interstitial lung disease (SSc-ILD) outcomes in a phase 3 trial (focuSSced) and prognostic markers in a real-world cohort (SMART). Methods The focuSSced SSc-ILD subgroup included 68 of 106 placebo-treated and 68 of 104 tocilizumab-treated patients. The SMART cohort included 505 patients with SSc-ILD. Linear mixed-effect models were used to identify factors associated with change in forced vital capacity (FVC). Kaplan-Meier estimation and Cox regression were used for time-to-event analyses. Results In placebo-treated focuSSced patients, sex was a significant prognostic factor for FVC decline; males had increased risk for absolute decline ≥10% in percent-predicted FVC (ppFVC) and 0.22% faster weekly FVC decline than females (P = 0.0001). FVC was 9.8% lower in patients with C-reactive protein >6 mg/ml versus those with C-reactive protein ≤6 mg/ml (P = 0.0059). Tocilizumab reduced the risk for ≥10% decline in ppFVC in patients who were male, had earlier disease ( Conclusion Prognostic markers in SSc-ILD were similar between focuSSced and SMART. Male sex and inflammatory markers were associated with lower FVC but interleukin-6 ≥ 10 pg/ml was not predictive of response to tocilizumab. Trial Registration ClinicalTrials.gov: NCT02453256

Rationale: Tocilizumab, an anti–interleukin-6 receptor antibody, had no statistically significant effect on skin sclerosis but preserved lung function over 48 weeks in patients with early systemic ...

Objective Tocilizumab (TCZ) has demonstrated lung function preservation in 2 randomized controlled trials in early systemic sclerosis (SSc). This effect has yet to be characterized in terms of radiographically evident quantitative lung involvement. We undertook this study to assess the impact of TCZ on lung function preservation in a post hoc analysis, stratifying treatment arms according to the degree of lung involvement. Methods The focuSSced trial was a phase III randomized placebo-controlled trial of TCZ in patients with SSc and progressive skin disease. Participants underwent baseline and serial spirometry along with high-resolution chest computed tomography at baseline and at week 48. Quantitative interstitial lung disease (QILD) and fibrosis scores were assessed by computer software. We classified QILD into the following categories of lung involvement: mild (>5-10%), moderate (>10-20%), and severe (>20%). Results Of 210 participants recruited for the trial, 136 patients (65%) had ILD. The majority of these patients (77%) had moderate-to-severe involvement (defined as >10% lung involvement). The TCZ arm demonstrated preservation of forced vital capacity percent predicted (FVC%) over 48 weeks (least squares mean change in FVC% = -0.1) compared to placebo (-6.3%). For mild, moderate, and severe QILD, the mean ± SD change in FVC% in the TCZ arm at 48 weeks were -4.1 ± 2.5% (n = 11), 0.7 ± 1.9% (n =19), and 2.1 ± 1.6% (n = 26), respectively, and in the placebo group were -10.0 ± 2.6% (n = 11), -5.7 ± 1.6% (n = 26), and -6.7 ± 2.0% (n = 16), respectively. Similar treatment-related preservation findings were seen independent of fibrosis severity. Conclusion TCZ in early SSc-associated ILD with progressive skin disease stabilized FVC% over 48 weeks, independent of the extent of radiographically evident QILD.

ObjectivesAmerican College of Rheumatology Composite Response Index in Systemic Sclerosis (ACR-CRISS) is a composite endpoint to assess the likelihood of improvement in diffuse systemic sclerosis. ACR-CRISS is a weighted score and includes five core set measures: modified Rodnan skin score, FVC% predicted, health assessment questionnaire–disability index, and patient and clinician global assessments.MethodsWe analysed core set measures from 354 participants who participated in three placebo-controlled trials. We generated 10 development datasets, randomly selected from 2/3 of the participants, stratified by study and treatment group. The remaining participants (1/3 of the participants) formed the validation sets. Risk differences (RDs) between active and placebo treatments were calculated by averaging over the replicate datasets; bootstrap 95% CIs for the RDs to estimate the magnitude of treatment effects.ResultsIn the development sets (n=237), the proportion of participants in the active group had statistically higher improvement in >1 of 5 core set measures versus the placebo group. For example, the proportion who improved by ≥20% in ≥3 core set measures was 49.4% in the active versus338.9% in the placebo; RD: 10.5%, 95% CI4.9 % to 16.1%. In the validation sets (n=117), the proportion who improved by ≥20% in ≥3 core set measures was 50.3% in the active versus35.63% in the placebo (RD:114.8%, 95% CI 3.1% to225.7%). Similar trends were seen with larger percentage cut-offs.ConclusionRevised CRISS, as assessed by the proportion of participants who improved by a certain percentage in ≥3 of 5 core set measures, is a potential new composite outcome measure.

Background Tocilizumab, an interleukin 6 receptor (IL-6R) antagonist monoclonal antibody, has shown efficacy in patients with coronavirus disease 2019 (COVID-19) pneumonia, but the optimal dose is unknown. Methods Patients hospitalized for moderate to severe COVID-19 pneumonia were randomized 1:1 to receive standard of care treatment and 1–2 doses of intravenous tocilizumab 4 mg/kg or 8 mg/kg (open-label). Primary pharmacokinetic and pharmacodynamic end points were serum concentrations of tocilizumab and soluble interleukin 6 receptor (sIL-6R), IL-6, ferritin, and C-reactive protein (CRP), from baseline to day 60. The secondary end point was safety. Key exploratory efficacy end points included clinical status, time to discharge, mortality rate, and incidence of mechanical ventilation. Results Of 100 patients randomized, 49 received tocilizumab 4 mg/kg and 48 received 8 mg/kg. In pharmacokinetic and sIL-6R assessments, dose-dependent differences were seen in patients who received 1 or 2 doses of 4 or 8 mg/kg. Serum concentrations of IL-6, ferritin, and CRP and safety outcomes were comparable between groups. Through day 60, serious adverse events were reported in 30.6% and 25.0% of patients in the 4- and 8-mg/kg groups, respectively. Eight patients (16.3%) in the 4-mg/kg group and 6 (12.5%) in the 8-mg/kg group died. Exploratory time-to-event outcomes favored 8 mg/kg within the first 2 weeks. Conclusions In patients with moderate to severe COVID-19 pneumonia who received tocilizumab 4 or 8 mg/kg, pharmacokinetic and sIL-6R assessments showed expected dose-dependent effects; pharmacodynamic assessments and safety were comparable, with no new safety signals. Further study is required before a lower dose of tocilizumab can be recommended in patients with COVID-19 pneumonia. Clinical Trials Registration NCT04363736.

OBJECTIVES: To explore candidate prognostic and predictive biomarkers identified in retrospective observational studies (interleukin-6, C-reactive protein, lactate dehydrogenase, ferritin, lymphocytes, monocytes, neutrophils, d-dimer, and platelets) in patients with coronavirus disease 2019 pneumonia after treatment with tocilizumab, an anti-interleukin-6 receptor antibody, using data from the COVACTA trial in patients hospitalized with severe coronavirus disease 2019 pneumonia. DESIGN: Exploratory analysis from a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. SETTING: Hospitals in North America and Europe. PATIENTS: Adults hospitalized with severe coronavirus disease 2019 pneumonia receiving standard care. INTERVENTION: Randomly assigned 2:1 to IV tocilizumab 8 mg/kg or placebo. MEASUREMENTS AND MAIN RESULTS: Candidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomization) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses. Modeling in the placebo arm showed all candidate biomarkers except lactate dehydrogenase and d-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modeling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction, p = 0.03), mechanical ventilation (predictive interaction, p = 0.01), and clinical status (predictive interaction, p = 0.02) compared with placebo. CONCLUSIONS: Multiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.

Introduction Real-world use of immunomodulating therapy (IMT) in patients with systemic sclerosis (SSc) was investigated for the first time in a descriptive, retrospective cohort analysis of claims made in a healthcare insurance database to characterize treatment patterns and their alignment with SSc disease manifestations. Methods Treatment patterns and disease manifestations, symptoms, complications, and comorbidities were assessed in patients with SSc enrolled in a US healthcare claims database who received treatment between January 2006 and December 2013 and for whom data were available 6 months before and 12 months after SSc diagnosis. Results Among 7812 eligible patients, 6852 received treatments of interest for SSc and 2404 (30.8%) received IMT during the first year after SSc diagnosis. In the first year after diagnosis, the most common claims were for antibiotics (61.7%), opioids (50.6%), glucocorticoids (46.5%), and proton pump inhibitors (35.4%); the most common organs involved with complications among patients with SSc were lung (30.5%), heart (17.4%), and gastrointestinal tract (22.4%); the most common signs or symptoms were musculoskeletal (16.1%) and fatigue (10.5%); 1035 patients (15.1%) had infections and 14 (0.2%) had malignancies. Among patients who received IMT, 43.8% received at least hydroxychloroquine and 21.1% received at least methotrexate; 460 patients switched to a second IMT, 23.0% to at least methotrexate and 22.8% to at least mycophenolate mofetil. The most common comorbidities reported with first IMT were in lung (11.8%), overlap syndrome (8.4%), heart (5.3%), and gastrointestinal (6.8%) categories. Conclusion One-third of patients with SSc in the healthcare claims population received IMTs during the first year after diagnosis. However, patients who received IMTs had disease manifestations similar to those of the overall SSc healthcare claims population. Electronic Supplementary Material The online version of this article (10.1007/s40744-019-00181-8) contains supplementary material, which is available to authorized users.

SummaryBackgroundRetrospective observational studies suggest that interleukin-6 (IL-6), C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, lymphocytes, monocytes, neutrophils, D-dimer, and platelets are associated with disease progression, treatment outcomes, or both, in patients with COVID-19 pneumonia. We explored these candidate prognostic and predictive biomarkers with efficacy outcomes after treatment with tocilizumab, an anti–IL-6 receptor antibody using data from the COVACTA trial for patients hospitalised with severe COVID-19 pneumonia.MethodsCandidate biomarkers were measured in 295 patients in the tocilizumab arm and 142 patients in the placebo arm. Efficacy outcomes assessed were clinical status on a seven-category ordinal scale (1, discharge; 7, death), mortality, time to hospital discharge, and mechanical ventilation (if not receiving it at randomisation) through day 28. Prognostic and predictive biomarkers were evaluated continuously with proportional odds, binomial or Fine-Gray models, and additional sensitivity analyses.FindingsModelling in the placebo arm showed all candidate biomarkers except LDH and D-dimer were strongly prognostic for day 28 clinical outcomes of mortality, mechanical ventilation, clinical status, and time to hospital discharge. Modelling in the tocilizumab arm showed a predictive value of ferritin for day 28 clinical outcomes of mortality (predictive interaction p=0.03), mechanical ventilation (predictive interaction p=0.01), and clinical status (predictive interaction p=0.02) compared with placebo.InterpretationMultiple biomarkers prognostic for clinical outcomes were confirmed in COVACTA. Ferritin was identified as a predictive biomarker for the effects of tocilizumab in the COVACTA patient population; high ferritin levels were associated with better clinical outcomes for tocilizumab compared with placebo at day 28.RESEARCH IN CONTEXTEvidence before this studyThe efficacy and safety of the anti–interleukin-6 receptor antibody tocilizumab in the treatment of patients hospitalised with COVID-19 pneumonia was investigated in COVACTA, a double-blind, randomised, placebo-controlled trial. The primary endpoint of improved clinical status on a seven-category ordinal scale (1, discharged/ready for discharge; 7, death) at day 28 was not met in this trial. Among the secondary endpoints, no difference in mortality at day 28 was observed, but time to hospital discharge was shorter in the tocilizumab group. Subgroup analysis suggested there might be a treatment benefit in patients grouped according to their ordinal scale category at baseline.We searched PubMed on September 14, 2020, using the terms “tocilizumab AND (COVID-19 OR coronavirus) AND biomarker” with no language or date restrictions. The search retrieved 18 articles, four of which identified laboratory measures as potential biomarkers in patients who received tocilizumab for the treatment of COVID-19 pneumonia. The biomarkers reported in these studies include interleukin-6, C-reactive protein, ferritin, fibrinogen, liver transaminases, lymphocytes, platelets, and D-dimer. However, these previous studies were single-centre, retrospective, observational studies. Larger, prospective, controlled trials are needed to investigate potential prognostic and predictive biomarkers to assess the outcomes and response to treatments for COVID-19.Added value of this studyThis exploratory analysis of data from COVACTA demonstrated interleukin-6, C-reactive protein, ferritin, neutrophils (percentage and absolute count), neutrophil-to-lymphocyte ratio, lymphocytes (percentage and absolute count), monocytes (percentage), and platelets as strong prognostic biomarkers in patients hospitalised with severe COVID-19 pneumonia. More important, ferritin showed predictive value for tocilizumab treatment effects on day 28 clinical outcomes of mortality, mechanical ventilation (among the subgroup of patients not receiving mechanical ventilation at randomisation), and clinical status compared with placebo.Implications of all the available evidenceIn patients with elevated levels of ferritin at baseline, tocilizumab decreased the probability of death, mechanical ventilation, and worsening clinical status at day 28 compared with placebo, suggesting that ferritin might be useful as a predictive biomarker of efficacy outcomes for tocilizumab in patients with severe COVID-19 pneumonia.

ObjectivesAssess the efficacy and safety of tocilizumab in patients with systemic sclerosis (SSc) in a phase II study.MethodsPatients with SSc were treated for 48 weeks in an open-label extension phase of the faSScinate study with weekly 162 mg subcutaneous tocilizumab. Exploratory end points included modified Rodnan Skin Score (mRSS) and per cent predicted forced vital capacity (%pFVC) through week 96.ResultsOverall, 24/44 (55%) placebo-tocilizumab and 27/43 (63%) continuous-tocilizumab patients completed week 96. Observed mean (SD (95% CI)) change from baseline in mRSS was –3.1 (6.3 (–5.4 to –0.9)) for placebo and –5.6 (9.1 (–8.9 to–2.4)) for tocilizumab at week 48 and –9.4 (5.6 (–8.9 to –2.4)) for placebo-tocilizumab and –9.1 (8.7 (–12.5 to –5.6)) for continuous-tocilizumab at week 96. Of patients who completed week 96, any decline in %pFVC was observed for 10/24 (42% (95% CI 22% to 63%)) placebo-tocilizumab and 12/26 (46% (95% CI 27% to 67%)) continuous-tocilizumab patients in the open-label period; no patients had >10% absolute decline in %pFVC. Serious infection rates/100 patient-years (95% CI) were 10.9 (3.0 to 27.9) with placebo and 34.8 (18.0 to 60.8) with tocilizumab during the double-blind period by week 48 and 19.6 (7.2 to 42.7) with placebo-tocilizumab and 0.0 (0.0 to 12.2) with continuous-tocilizumab during the open-label period.ConclusionsSkin score improvement and FVC stabilisation in the double-blind period were observed in placebo-treated patients who transitioned to tocilizumab and were maintained in the open-label period. Safety data indicated increased serious infections in patients with SSc but no new safety signals with tocilizumab.Trial registration numberNCT01532869; Results.

Background: Anti–interleukin-6 receptor antibody TCZ showed clinically relevant lung function preservation (forced vital capacity [FVC]) in SSc patients (pts) in a phase 2 trial. Objective: Investigate TCZ vs placebo (PBO) in SSc in a phase 3 trial. Methods: Pts were randomized 1:1 to double-blind subcutaneous TCZ 162 mg or PBO per week (wk) for 48 wks. Primary endpoint: difference (TCZ vs PBO) in modified Rodnan skin score (mRSS) change from baseline (∆BL). Secondary endpoints: percent-predicted (pp)FVC; time to treatment failure (TTF; time from first study treatment to first occurrence of death, FVC decline >10%, mRSS increase ≥20% and mRSS ≥5, or occurrence of SSc complications); Health Assessment Questionnaire–Disability Index (HAQ-DI); pt/physician global assessment (Pt/PhGA) visual analog scale. Results: Of 106 PBO and 104 TCZ pts, 31% had previous/current interstitial lung disease based on their history. At wk 48, adjusted least-squares mean difference ∆BL mRSS PBO vs TCZ was –1.7 [95% CI: –3.8, 0.3], p=0.098). Cumulative distribution of ∆BL ppFVC (median [IQR] PBO –3.9 [–7.2, 0.6]; TCZ –0.6 [–5.3, 3.9] van Elteren nominal p=0.0015) and difference in mean ∆BL FVC at wk 48 (167 mL [95% CI: 83, 250]) favored TCZ. TTF hazard ratio (95% CI) was 0.6 (0.4, 1.1) numerically favoring TCZ (Cox proportional hazards p=0.082). No clinically meaningful difference was seen in mean (95% CI) difference ∆BL HAQ-DI –0.1 (–0.2, 0.1), PtGA –2.4 (–8.6, 3.7), PhGA –2.5 (–8.7, 3.8). Safety profile was consistent with SSc complications and TCZ treatment. Conclusion: The primary mRSS endpoint was not met. A clinically relevant difference in FVC was seen for TCZ vs PBO, with preservation of lung function.

Background:The anti–interleukin-6 (IL-6) receptor-α antibody tocilizumab (TCZ) demonstrated skin score improvement and forced vital capacity (FVC) preservation in patients with systemic sclerosis (SSc) in a phase 2 randomized controlled trial.1,2Data from the 48-week, double-blind (DB), placebo (PBO)-controlled period of the focuSSced phase 3 trial were previously presented,3and open-label (OL) data up to week 96 are presented herein.Objectives:To assess the long-term safety and efficacy of TCZ in SSc patients.Methods:Adult patients with active SSc (≤60-month duration, modified Rodnan skin score [mRSS] 10-35, and elevated acute-phase reactants) treated with PBO or TCZ in the DB period received OL TCZ 162 mg SC weekly from weeks 48 to 96 in the OL period (PBO→OL TCZ and TCZ→OL TCZ, respectively). Exploratory analysis of data up to week 96 included no formal statistical analyses. Changes in mRSS and percent predicted FVC (ppFVC) were assessed.Results:Overall, 92/105 TCZ (88%) and 89/107 PBO (83%) patients entered the OL TCZ treatment period at week 48, and 85/105 TCZ→OL TCZ (81%) and 82/107 PBO→OL TCZ (77%) patients completed treatment up to week 96. Continued decline in mRSS was observed in the OL period for PBO→OL TCZ and TCZ→OL TCZ patients (Table). Change in ppFVC for patients who switched from PBO to TCZ (PBO→OL TCZ) was comparable between weeks 48 and 96 (OL period) to the change in patients who received TCZ from BL to week 48 in the DB period (Table). Rates (95% CI) of serious adverse events from weeks 48 to 96 were 15.8 (8.6, 26.5) per 100 PY for TCZ→OL TCZ patients, 14.8 (7.9, 25.3) per 100 PY for PBO→OL TCZ patients, and 15.4 (11.0, 20.9) for all TCZ exposure over 96 weeks (n = 193). Rates (95% CI) of serious infections were 2.3 (0.3, 8.1) per 100 PY for TCZ→OL TCZ patients, 3.4 (0.7, 10.0) per 100 PY for PBO→OL TCZ patients, and 3.0 (1.3, 5.9) for all TCZ exposure over 96 weeks. One death occurred during the OL period in each arm.Conclusion:Although OL data have to be interpreted with caution, results from OL TCZ treatment show numeric improvements in mRSS and FVC preservation similar to those of the DB period, with a beneficial effect on trajectory of FVC decline in patients who switched from PBO to TCZ. Long-term safety results were consistent with the known safety profile of TCZ, and no new or unexpected events were observed.References:[1]Khanna D et al.Lancet2016;387:2630-40.[2]Khanna D et al.Ann Rheum Dis.2018;77:212-20.[3]Khanna D et al.Arthritis Rheumatol2018;70(suppl 10):abst 898.Table.Change in Efficacy From BaselineBaseline to Week 48Baseline to Week 96Week 48 to Week 96PBOTCZPBO→OL TCZTCZ→OL TCZPBO→OL TCZTCZ→OL TCZmRSS, mean (95% CI)a–5.3 (–6.9, –3.7)n = 92–6.7 (–8.0, –5.4)n = 97–8.4 (–10.0, –6.8)n = 83–9.6 (–10.9, –8.4)n = 85–2.5(–3.3, –1.6)n = 82–2.3(–3.2, –1.5)n = 85ppFVC, mean (95% CI) [median]–4.1 (–5.8, –2.4) [–3.9]n = 92–0.2 (–1.6, 1.2) [–0.7]n = 94–3.3 (–5.1, –1.5) [–3.1]n = 79–0.5 (–2.4, 1.3) [–1.4]n = 840.6 (–0.7, 1.9) [0.3]n = 78–0.3 (–1.7, 1.1) [0.0]n = 82Decline in ppFVC ≥10%, n/N (%)a15/91(16.5)5/93(5.4)14/79 (17.7)11/84 (13.1)NANAImprovement in ppFVC, n/N (%)a26/91(28.6)43/93(46.2)22/79(27.8)35/84(41.7)NANAaObserved data. NA, not assessed.Disclosure of Interests:Dinesh Khanna Shareholder of: Eicos, Grant/research support from: NIH NIAID, NIH NIAMS, Consultant of: Acceleron, Actelion, Bayer, BMS, Boehringer-Ingelheim, Corbus, Galapagos, Genentech/Roche, GSK, Mitsubishi Tanabi, Sanofi-Aventis/Genzyme, UCB Pharma, Celia J. F. Lin Employee of: Genentech, Helen Spotswood Shareholder of: Roche Products Ltd, Employee of: Roche Products Ltd, Jeff Siegel Employee of: Genentech, Daniel Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS, Corbus Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech, Consultant of: AbbVie, Actelion, Amgen, BMS, Cytori Therapeutics, Corbus Pharmaceuticals, the National Institutes of Health, Novartis, Pfizer, and Roche/Genentech, Speakers bureau: CMC Connect (McCann Health Company), Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer

We read the intriguing findings by Narvaez1 about the effect of tocilizumab (TCZ) in patients with established systemic sclerosis-associated interstitial lung disease (SSc-ILD) with great interest. In the double-blind, randomised, placebo-controlled faSScinate study2 and open-label extension,3 we assessed the efficacy and safety of TCZ in patients with systemic sclerosis. There were important differences between our trial and the data presented by Narvaez1. In the faSScinate study, the patient population shown to benefit from TCZ had shorter duration of disease (mean disease duration of 1.6 years in faSScinate vs 6.9 years in Narvaez), increased serum acute phase reactants, …

Objective.Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone.Methods.A chart review of patients with RA from 2 Canadian rheumatology practices between July 1, 2010, and July 31, 2014, identified 2 groups of patients: those taking denosumab and a bDMARD concurrently (concurrent group) and those taking only a bDMARD (biologic-alone group). Patients were followed from the time of initiation of denosumab, or a matched index date for the biologic-alone group, to the end of the study or loss to followup. Instances of serious or opportunistic infections were recorded.Results.A total of 308 patients (n = 102 for the concurrent group and n = 206 for the biologic-alone group) were evaluated. Within the concurrent group, 3 serious infection events occurred. Within the biologic-alone group, 4 serious infection events and 1 opportunistic infection event occurred. In both groups, all patients with serious or opportunistic infection recovered, and there were no instances of death during the study period.Conclusion.This study demonstrated a low occurrence of serious and opportunistic infections in patients with RA taking bDMARD, including patients with concurrent denosumab use.

Background Treatment with tocilizumab (TCZ) in early systemic sclerosis (SSc; FaSScinate trial) resulted in consistent, but not statistically significant, improvements in skin sclerosis (mRSS) at wks 24 and 481. The CRISS index has been proposed as a composite index for trials in SSc2. CRISS is a 2-step process that assigns a probability of improvement for each subject ranging from 0.0 [no improvement] to 1.0 [marked improvement]. Step 1 assesses clinically meaningful decline in cardio-pulmonary-renal involvement and assigns a probability of 0.0. For remaining subjects, 5 variables are used to calculate probability of improvement. These are: FVC%, mRSS, patient (PT GA) and physician globals (MD GA), and HAQ-DI. Objectives To assess the performance of CRISS index in the FaSScinate trial. Methods In FaSScinate, pts ≥18 y with active SSc were randomized 1:1 to TCZ or placebo (PLA) for 48 wks. Step 1 CRISS was captured using review of serious adverse event data. Non-parametric Wilcoxon test was used to assess significant differences between the CRISS scores in both arms. Analyses were carried out for subject who had complete data at baseline and 24 weeks and at baseline and 48 weeks. Results 87 pts (43 TCZ, 44 PBO) were enrolled. Baseline characteristics were similar between arms. 4 subjects in the PBO group and none in TCZ met the pre-defined definition of worsening in Step 1 and were given a score of 0.0. For remaining subjects, we calculated probability score for each subject. Using CRISS as a continuous measure, the median score was statistically significant and favored TCZ compared to PBO at wks 24 and 48 (p=0.04 and 0.01; Table). Table also presents the individual components of Step 2 where only FVC% was statistically significant favoring TCZ at wk 48. Conclusions In this post-hoc analysis, CRISS index was able to discriminate TCZ from PBO, supporting its validity in an independent cohort. References Khanna D. Lancet. 2016. Khanna D. Arthritis Rheum. 2016. Disclosure of Interest D. Khanna Grant/research support from: NIH/NIAMS and NIH/NIAID, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer Ingelheim, Genentech/Roche, Sanofi-aventis, GSK, Corbus, Cytori, EMD Serono, V. Berrocal: None declared, C. Denton Consultant for: Actelion, Bayer, GSK, CSL Behring, Merck-Serono, Genentech-Roche, Inventiva, Sanofi-Aventis, Boehringer Ingelheim, A. Jaheris Shareholder of: Roche stock and options, Employee of: Genentech, H. Spotwood Employee of: Roche, C. Lin Employee of: Genentech, J. Siegel Employee of: Genentech, D. Furst Grant/research support from: Amgen, BMS, NIH, Novartis, Pfizer, Roche/Genentech, Consultant for: AbbVie, Amgen, BMS, Cytori, Novartis, Pfizer, Roche/Genentech, UCB

Background Denosumab treatment for up to 8 years in the FREEDOM study and Extension was associated with low fracture incidence. It was not clear whether subjects who discontinued during the study conduct had a higher risk of fracture than those who remained enrolled, thereby underestimating the true fracture risk for the entire trial cohort. Thus, we explored the influence of early withdrawals on nonvertebral fracture incidence during the Extension study. Methods To understand the potential effect of depletion of susceptible subjects on fracture incidence, we first evaluated subject characteristics in patients who were enrolled in the Extension vs those who were not. We subsequently employed a Kaplan-Meier multiple imputation (KMMI) approach to consider subjects who discontinued as if they remained enrolled with a 0%, 20%, 50%, and 100% increase in fracture risk compared with participants remaining on study. Results Extension enrollees were generally similar to nonparticipants in median age (71.9 and 73.1 years, respectively), mean total hip bone mineral density T-score (–1.9 and –2.0, respectively), and probability of fracture risk by Fracture Risk Assessment Tool (FRAX®) at FREEDOM baseline (16.9% and 17.7% for major osteoporotic fracture and 6.7% and 7.4% for hip fracture, respectively). When we assumed a doubled fracture risk (100% increase) after discontinuation in KMMI analyses, nonvertebral fracture rate estimates were only marginally higher than the observed rates for both the crossover group (10.32% vs 9.16%, respectively) and the long-term group (7.63% vs 6.63%, respectively). Conclusion The observation of continued denosumab efficacy over 8 years of treatment was robust and does not seem to be explained by depletion of susceptible subjects. Trial registration ClincalTrials.gov registration number NCT00523341; registered August 30, 2007 Electronic supplementary material The online version of this article (doi:10.1186/s12891-017-1520-6) contains supplementary material, which is available to authorized users.

Background Systemic sclerosis (SSc) is a debilitating disease with few treatment options. Interleukin-6 (IL-6) appears to play a role in SSc pathogenesis. 1,2 Data from the 48-week, double-blind (DB), placebo (PBO)-controlled period of the faSScinate trial were previously presented, 3 and open-label (OL) data are presented herein. Objectives To assess safety and efficacy of tocilizumab (TCZ) in SSc patients during 48 weeks of OL TCZ treatment. Methods Patients ≥18 y with active SSc (≤5-year duration, modified Rodnan skin score [mRSS] 15–40, and elevated acute-phase reactants) received OL TCZ 162 mg SC weekly from week 48 to week 96. Change from baseline in mRSS, patient-reported outcomes (PROs), and FVC at week 96 were exploratory measures. Observed means used all available data. Results In total, 27/43 (63%) TCZ and 24/44 (55%) PBO patients completed week 96. Baseline (BL) characteristics were similar at BL and at entry into the OL period. Patients who switched from PBO→OL TCZ showed improvement in observed mean change from BL in mRSS at week 96 (–9.4) relative to the end of the 48-week DB period (–3.1). In patients initially randomized to TCZ (TCZ→OL TCZ), mean change in mRSS was –5.6 at week 48 and –9.1 at week 96. In the OL period, improvements in PROs were noted at week 96 vs week 48 in the PBO→OL TCZ group (mean [SD] change from BL at week 96 vs week 48 in HAQ-DI: –0.3 [0.4] vs 0.2 [0.4]; Patient Global VAS: –23.8 [36.0] vs –4.0 [24.0]; FACIT-Fatigue:11.3 [12.8] vs 1.4 [7.6]). In patients who completed the study, none experienced a >10% decline in % predicted FVC during the OL period on TCZ therapy. Rates (95% CI) of serious adverse events/100 patient-years (PY) in the DB period were 76.1 (50.6, 110.0) in PBO patients and 66.7 (42.3, 100.1) in TCZ patients and were 36.0 (18.0, 64.4) in PBO→OL TCZ patients and 16.5 (5.4, 38.5) in TCZ→OL TCZ patients in the OL period. Rates (95% CI)/100PY of serious infections in the DB period were 10.9 (3.0, 27.9) in PBO patients and 34.8 (18.0, 60.8) in TCZ patients. In the OL period they were 19.6 (7.2, 42.7) in PBO→OL TCZ patients and 0.0 (0.0, 12.2) in TCZ→OL TCZ patients. No deaths occurred in the OL period (deaths in DB period: 3 TCZ, 1 PBO). Conclusions Although OL data have to be interpreted with caution, efficacy and safety in PBO-treated patients who switched to OL TCZ were generally similar to those observed in patients randomized to TCZ in the DB period. Results over 96 weeks of TCZ treatment suggest maintenance of the clinical response for mRSS in SSc patients. Serious infection rates increased in PBO patients after they switched to OL TCZ. Long-term safety was consistent with the natural history of SSc and the safety profile of TCZ. References J Rheumatol 1998;25:308. Pathobiology 1993;61:239. Ann Rheum Dis 2015;74(suppl 2):87. Disclosure of Interest D. Khanna Grant/research support from: NIH/NIAMS, NIH/ NIAID, Bayer, BMS, Consultant for: Bayer, BMS, Genetech/Roche, GSK, Genkyotex, Sanofi-Aventis, Actelion, Gilead, C. Denton Grant/research support from: GSK, Actelion, CSL Behring, Consultant for: GSK, Bayer, Actelion, Roche, Merck-Serono, MedImmune, A. Jahreis Shareholder of: Roche, Employee of: Genentech, J. van Laar Grant/research support from: MSD, Consultant for: MSD, Roche, Pfizer, BMS, Eli Lilly, L. Burke Employee of: Roche Products Ltd., H. Spotswood Shareholder of: Roche, Employee of: Roche Products Ltd., C. Lin Shareholder of: Amgen, Roche/Genentech, Employee of: Genentech, J. Pope Grant/research support from: Roche, Bayer, BMS, Consultant for: Roche, Actelion, Bayer, BMS, Y. Allanore Grant/research support from: Bristol-Myers Squibb, Roche/Genentech, Inventiva, Pfizer, Sanofi, and Servier, Consultant for: Actelion, Bayer, Roche/Genentech, Inventiva, Medac, Pfizer, Sanofi, Servier, and UCB, U. Muller-Ladner Consultant for: Roche, Chugai Pharma, Speakers bureau: Roche, Chugai Pharma, J. Siegel Shareholder of: Roche, Employee of: Genentech, D. Furst Grant/research support from: AbbVie, Actelion, Amgen, BMS, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB, Consultant for: AbbVie, Actelion, Amgen, BMS, Cytori, Janssen, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB

Background Studies combining immunosuppressive biologics have shown an increased risk of infections. Objectives Examine the occurrence of serious and opportunistic infections in RA patients treated concurrently with DMAb and an immunosuppressive biologic, and those treated with only an immunosuppressive biologic. Methods We reviewed RA patients from two rheumatology practices in Ontario (Canada) between 01July2010 and 31July2014. Eligible patients were ≥18 years of age with RA, registered in the practice ≥3 months before and after the index date, and received ≥1 injection/infusion or filled a prescription for an immunosuppressive biologic therapy for RA. Patients with HIV or AIDS, or who were receiving cancer treatment or immunosuppressive therapies for conditions other than RA or living in a nursing home were excluded. The incidence of serious infections was counted for two different groups: 1) those who had used DMAb and an immunosuppressive biologic concurrently and 2) those who had used an immunosuppressive biologic alone. Serious infection was defined as resulting in hospitalization or an emergency room (ER) visit with associated use of IV antibiotics and a primary diagnosis of infection. The observational period was from the index date to 31July2014 or loss to follow-up, whichever came first. For the concurrent group, index date was defined as their first DMAb injection. A frequency-matching technique utilizing the index date of the concurrent group was used to select the index date of the biologic-alone group. Results 308 patients met the eligibility criteria; patient characteristics (± 6 months of index event) are shown below. Three events of serious infection occurred in three patients in the concurrent group (all three were cases of pneumonia); four events of serious infection occurred in four patients in the biologic-alone group (three cases of pneumonia, one upper respiratory tract infection, all resulting in hospitalization). One event of opportunistic infection ( mycobacterium avium complex and pleural infection) occurred in the biologic-alone group. All patients recovered, with no instances of death. Conclusions RA patients may require treatment for bone loss due to intrinsic disease, steroid use, and advancing age. This study demonstrates a low occurrence of serious infections in biologically-treated RA patients, including patients with concurrent DMAb use. Acknowledgement Study funded by Amgen Inc; Claire Desborough, an Amgen employee, provided writing assistance. Disclosure of Interest M. Wong-Pack: None declared, R. Rodjanapiches: None declared, A. Lau Consultant for: Amgen, Abbvie, Celgene, Roche, UCB, Speakers bureau: Amgen, Abbvie, G. Ioannidis: None declared, S. Wade Consultant for: Amgen, A. Balasubramanian Shareholder of: Amgen, Employee of: Amgen, C. Lin Shareholder of: Amgen, Employee of: Amgen, P. Roy-Gayos: None declared, W. Bensen Grant/research support from: Amgen, Abbvie, Roche, Janssen, Consultant for: Eli Lilly, Amgen, UCB, Abbvie, BMS, Janssen, Pfizer, Roche, AstraZeneca, R. Bensen: None declared, J. Adachi Grant/research support from: Amgen, Eli Lilly, Marck, Consultant for: Activas, Amgen, Eli Lilly, Merck, Speakers bureau: Amgen, Eli Lilly, Merck

Background In the United States, systemic sclerosis (SSc) develops in adults at an annual estimated incidence rate of 20 cases per million, and the estimated prevalence is 240 cases per million. 1 Published research on the epidemiology of SSc and common treatments for US SSc patient cohorts is limited. In general, SSc patients are treated based on their specific organ involvement; patients with diffuse skin involvement or severe organ involvement, or both, are treated with systemic immunosuppressive therapy. Objectives To understand the treatment patterns for and the real-world use of immunosuppressive drugs in adults with SSc using data from a large US healthcare claims database. Methods The analysis is a retrospective cohort study of patients with SSc diagnosed from 2006 to 2012 using data from Truven Health MarketScan® Research Databases, a medical insurance claims database of insured active employees and their dependents, early retirees, Medicare-eligible retirees, and Medicaid recipients. An SSc diagnosis was determined by ≥1 inpatient claim for an SSc diagnosis ( ICD-9 710.1) or ≥2 outpatient claims for an SSc diagnosis. During the study time period, patients were allowed enrollment gaps of ≤30 days but had to have enrollment data 6 months before and 12 months after the SSc diagnosis. Results The prevalence of SSc in the MarketScan database from 2006 to 2013 ranged from 204 to 247 cases per million adults who were actively enrolled in health insurance plans. There were 6872 patients ≥18 years of age diagnosed with and treated for SSc during the study time period. Eighty-six percent of the treated SSc population were female, and the average age of the cohort was 54 years. The most common medication claims among patients in the first year after an SSc diagnosis were for antibiotics (54%), opioids (44%), corticosteroids (40%), and proton pump inhibitors (PPIs) (31%). Approximately 30% of SSc patients initiated ≥1 of the following disease-modifying antirheumatic drugs (DMARDs), alone or in combination, in the first year after the SSc index, with a median time to initiation of 70 days: methotrexate (21%), mycophenolate mofetil (17%), biologics (3%), cyclophosphamide (2%), or other DMARDs (62% of which included azathioprine, chloroquine, cyclosporine, hydroxychloroquine, penicillamine, quinacrine, and sulfasalazine). Among patients who filled a DMARD prescription in the first year, 15% switched to a second type of DMARD. Of the 70% of patients who did not fill a prescription for DMARD in the first year after the SSc index, 63% filled prescriptions for antibiotics, 56% opioids, 33% corticosteroids, 26% PPIs, 20% NSAIDs, 10% ACE inhibitors, 10% calcium antagonists, 5% prokinetics, 1% ERA, and Conclusions These data show that the prevalence of SSc among adults in a US healthcare claims population is consistent with the estimated US prevalence. Most SSc patients do not initiate DMARD treatment in the first year after diagnosis, and most SSc patients have received antibiotics, opioids, and systemic corticosteroids. References Mayes MD et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003;48:2246–2255. Disclosure of Interest S. Gale Shareholder of: Roche, Employee of: Roche, N. Mathew: None declared, C. Lin: None declared, A. Jahreis: None declared, K. Sarsour Shareholder of: Roche, Employee of: Roche