Katie Tuckwell

Trial of Tocilizumab in Giant-Cell Arteritis

Background Giant‐cell arteritis commonly relapses when glucocorticoids are tapered, and the prolonged use of glucocorticoids is associated with side effects. The effect of the interleukin‐6 receptor alpha inhibitor tocilizumab on the rates of relapse during glucocorticoid tapering was studied in patients with giant‐cell arteritis. Methods In this 1‐year trial, we randomly assigned 251 patients, in a 2:1:1:1 ratio, to receive subcutaneous tocilizumab (at a dose of 162 mg) weekly or every other week, combined with a 26‐week prednisone taper, or placebo combined with a prednisone taper over a period of either 26 weeks or 52 weeks. The primary outcome was the rate of sustained glucocorticoid‐free remission at week 52 in each tocilizumab group as compared with the rate in the placebo group that underwent the 26‐week prednisone taper. The key secondary outcome was the rate of remission in each tocilizumab group as compared with the placebo group that underwent the 52‐week prednisone taper. Dosing of prednisone and safety were also assessed. Results Sustained remission at week 52 occurred in 56% of the patients treated with tocilizumab weekly and in 53% of those treated with tocilizumab every other week, as compared with 14% of those in the placebo group that underwent the 26‐week prednisone taper and 18% of those in the placebo group that underwent the 52‐week prednisone taper (P<0.001 for the comparisons of either active treatment with placebo). The cumulative median prednisone dose over the 52‐week period was 1862 mg in each tocilizumab group, as compared with 3296 mg in the placebo group that underwent the 26‐week taper (P<0.001 for both comparisons) and 3818 mg in the placebo group that underwent the 52‐week taper (P<0.001 for both comparisons). Serious adverse events occurred in 15% of the patients in the group that received tocilizumab weekly, 14% of those in the group that received tocilizumab every other week, 22% of those in the placebo group that underwent the 26‐week taper, and 25% of those in the placebo group that underwent the 52‐week taper. Anterior ischemic optic neuropathy developed in one patient in the group that received tocilizumab every other week. Conclusions Tocilizumab, received weekly or every other week, combined with a 26‐week prednisone taper was superior to either 26‐week or 52‐week prednisone tapering plus placebo with regard to sustained glucocorticoid‐free remission in patients with giant‐cell arteritis. Longer follow‐up is necessary to determine the durability of remission and safety of tocilizumab. (Funded by F. Hoffmann–La Roche; ClinicalTrials.gov number, NCT01791153.)

Comparison of lipid and lipid-associated cardiovascular risk marker changes after treatment with tocilizumab or adalimumab in patients with rheumatoid arthritis

Objective Compare changes in lipids and lipid-associated cardiovascular (CV) risk markers in patients with rheumatoid arthritis (RA) treated with tocilizumab or adalimumab. Methods Post-hoc analysis was performed in patients with RA who received tocilizumab intravenously every 4 weeks or adalimumab subcutaneously every 2 weeks for 24 weeks in the ADACTA trial. Lipid and lipid-associated CV risk biomarkers, including high-density lipoprotein-associated serum amyloid-A (HDL-SAA), secretory phospholipase A2 IIA (sPLA2 IIA) and lipoprotein(a) (Lp(a)), were measured at baseline and at week 8. Results The study included 162 patients treated with tocilizumab and 162 patients treated with adalimumab; HDL-SAA and sPLA2 IIA were measured in a subpopulation of 87 and 97 patients, respectively. Greater increases in mean low-density lipoprotein cholesterol (LDL-C) (0.46 mmol/L (95% CI 0.30 to 0.62)), high-density lipoprotein cholesterol (HDL-C) (0.07 mmol/L (0.001 to 0.14)), total cholesterol (TC) (0.67 mmol/L (0.47 to 0.86)), triglycerides (0.24 mmol/L (0.10 to 0.38)) and TC:HDL ratio (0.27 (0.12 to 0.42)) occurred with tocilizumab from baseline to 8 weeks. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab than adalimumab. Median changes from baseline to week 8 were –3.2 and –1.1 mg/L (p=0.0077) for HDL-SAA and –4.1 and –1.3 ng/mL (p<0.0001) for sPLA2 IIA; difference in adjusted means was –7.12 mg/dL (p<0.0001) for Lp(a). Similar results were observed in efficacy responders and non-responders per American College of Rheumatology and European League against Rheumatism criteria. Conclusion LDL-C and HDL-C increased more with tocilizumab than adalimumab. HDL-SAA, sPLA2 IIA and Lp(a) decreased more with tocilizumab. Lipid change effects of interleukin-6 and tumour necrosis factor (TNF) inhibition, manifest by their net impact on lipids and lipoproteins, are not synonymous; the clinical significance is unclear and requires further study. Trial registration number NCT01119859.; post-results

Corticosteroid-related adverse events in patients with giant cell arteritis: A claims-based analysis ☆☆

OBJECTIVE Corticosteroids (CS) are standard treatment for giant cell arteritis (GCA), but concerns persist over toxicities associated with long-term use. In this retrospective study of medical claims data, we estimated risks for adverse events (AEs) in CS-treated GCA patients. METHODS Cox regression analyses with CS use as a time-dependent variable were conducted on data from the 2003 to 2012 Truven Health Analytics MarketScan Database. Patients 50 years of age and older who had ≥2 claims of newly diagnosed GCA, ≥1 filled oral CS prescription, and no AEs before GCA diagnosis were included. The primary outcome was presence of a new CS-related AE. RESULTS In total, 2497 patients were included. Their mean age was 71.0 years, and 71% were women. Follow-up was 9680 patient-years (PY). CS treatment continued for a mean (SD) of 1.196 (729.2) days; mean (SD) prescribed cumulative CS dose was 6983.3mg (6519.9). The overall AE rate was 0.43 events/PY; the most frequent AEs were cataract and bone disease. For each 1000-mg increase in CS exposure, the hazard ratio (HR) increased by 3% (HR = 1.03; 95% CI: 1.02-1.05; P < 0.001). Additionally, statistically significant individual associations between increased CS exposure and AE risk were observed for bone-related AEs (P < 0.001), cataract (P < 0.001), glaucoma (P = 0.005), pneumonia (P = 0.003), and diabetes mellitus (P < 0.001 in a subset of patients with no previous history of diabetes). CONCLUSION CS exposure significantly increased risk for potentially serious AEs, emphasizing a need for new treatment options for GCA patients.

Newly diagnosed vs. relapsing giant cell arteritis : Baseline data from the GiACTA trial

OBJECTIVE To report entry criteria and clinical features of patients with newly diagnosed and relapsing giant cell arteritis (GCA) enrolled in a randomized trial of tocilizumab, an interleukin-6 receptor-alpha inhibitor. METHODS Newly diagnosed GCA was defined as diagnosis ≤6 weeks before baseline. Relapsing GCA was defined as diagnosis >6 weeks before baseline with ≥2 consecutive weeks of prednisone ≥40mg/day. All patients had active GCA within 6 weeks of baseline. All statistical results are exploratory. RESULTS Of 251 patients, 119 (47%) had newly diagnosed and 132 (53%) had relapsing GCA. Mean age was 69 years in both subsets; 75% were women. Relapsing patients were heavier [difference in means (95% CI): women, 4.18kg (0.49-7.87, P = 0.027); men, 8.25kg (1.42-15.09, P = 0.019)] and had higher mean body mass index [difference in means (95% CI): women, 1.72kg/m2 (0.44-2.99, P = 0.009); men, 2.85kg/m2 (0.32-5.37, P = 0.028)]. Relapsers had higher baseline prevalence of depression (16% vs. 4%) and osteopenia/osteoporosis (33% vs. 23%, P = 0.002 and P = 0.062, respectively). At diagnosis, 67% had new-onset headaches; 34% had mouth pain/jaw claudication. One-fifth had polymyalgia rheumatica symptoms but no cranial manifestations; 62% had positive temporal artery biopsy findings; 37% were enrolled on the basis of cross-sectional imaging study findings. CONCLUSIONS Demographics of the GiACTA population reflect the epidemiologic profile of GCA. Baseline comorbidities associated with glucocorticoids were more prevalent among relapsing patients than among those with newly diagnosed disease, highlighting the need for new GCA treatment options. More than one-third of patients were enrolled based on large-vessel imaging.

Serious adverse effects associated with glucocorticoid therapy in patients with giant cell arteritis (GCA): A nested case–control analysis ☆

OBJECTIVE Giant cell arteritis (GCA) is an inflammatory vasculitis preferentially affecting large and medium-sized arteries. High-dose oral glucocorticoids (GCs) are the mainstay of GCA therapy. Using data from the UK Clinical Practice Research Datalink (CPRD), we examined the risk of oral GC-related serious adverse events (SAEs) in a UK population of patients with giant cell arteritis (GCA). METHODS We conducted a series of nested case-control analyses in GCA patients to examine the effect of increasing dose of prednisolone on the risk of developing diabetes, glaucoma, osteoporosis, fractures, serious infection requiring hospitalization, and death. We used conditional logistic regression to calculate the unadjusted and multivariate odds ratios (ORs) with 95% CIs for the associations between prednisolone use and the risks of all outcomes of interest. We stratified the analyses by increasing cumulative prednisolone use and average daily dose. RESULTS In the multivariate analyses, we observed a trend of increasing risk of diabetes and osteoporosis with increasing cumulative dose of oral prednisolone (ptrend < 0.05). GCA patients in the highest daily dose category (30mg/d) had an increased risk of diabetes (adjusted OR, 95% CI) (4.7, 2.8-7.8), osteoporosis (1.9, 1.2-2.9), fractures (2.6, 1.6-4.3), glaucoma (3.5, 2.0-6.1), serious infection (3.3, 2.2-5.2), and death (2.1, 1.3-3.5) compared to those with lower average daily prednisolone doses (5mg/d). CONCLUSION Compared to lower average daily prednisolone doses, high average daily doses were associated with an increased risk of serious adverse effects.

Development and Implementation of a Double-Blind Corticosteroid-Tapering Regimen for a Clinical Trial

We describe the design and operationalization of a blinded corticosteroid-tapering regimen for a randomized trial of tocilizumab in giant cell arteritis (GCA). To our knowledge, no clinical trial in any disease has ever employed a blinded corticosteroid-tapering regimen, but this was necessary to the design of our trial which is likely to be relevant to other investigations of steroid-sparing regimens. Two standardized corticosteroid-tapering regimens are required for this GCA trial: a 6-month regimen in 3 arms (taken with tocilizumab 162 mg subcutaneously weekly or every other week or with placebo) and a 12-month regimen with placebo (fourth arm). Investigators select initial prednisone doses, tapered in an open-label fashion until 20 mg/day. Doses <20 mg/day are blinded. At least 27 blinded blister packs are required to ensure blinding and encourage compliance. This permits all possible daily doses but requires ≤5 capsules/day. The number of capsules taken at any point during tapering is identical across groups. Our approach may be extrapolated to trials beyond GCA.

Incidence of outcomes potentially associated with corticosteroid therapy in patients with giant cell arteritis.

OBJECTIVE Giant cell arteritis (GCA) is an inflammatory disorder of blood vessels that preferentially affects large- and medium-sized arteries. High-dose oral corticosteroids (CS) are the mainstay of GCA therapy. Using data from the UK Clinical Practice Research Datalink, we quantified and compared the incidence of selected potentially CS-associated adverse outcomes in patients with and without GCA. METHODS We conducted a retrospective follow-up study of GCA and non-GCA patients to examine the incidence of adverse outcomes attributable to CS use. Eligibility criteria for the GCA group included a first-time diagnosis of GCA at age 50 years or older with receipt of ≥1 prescription(s) for prednisolone. GCA patients were matched to a GCA-free comparison group of equal size on age, sex, general practice, and calendar time. We estimated incidence rates and incidence rate ratios (IRRs) for diabetes, osteoporosis, glaucoma, fractures, serious infection requiring hospitalization, and death for GCA and non-GCA patients and compared all-cause hospitalizations between the two groups. RESULTS The cohort consisted of 5011 GCA and 5011 matched non-GCA patients. Approximately 74% were women, and mean age at GCA diagnosis was 72.9 years. The IR for all outcomes was greater in the GCA group than the non-GCA group. IRRs [95% confidence intervals (CIs)] were as follows: diabetes 1.4 (1.2-1.7), osteoporosis 2.4 (2.1-2.8), fractures 1.4 (1.2-1.6), glaucoma 2.0 (1.6-2.5), serious infection requiring hospitalization 1.5 (1.3-1.7), and death 1.2 (1.0-1.3). CONCLUSION Compared with age- and sex-matched non-GCA patients, patients with GCA were at increased risk for diabetes, osteoporosis, fracture, and glaucoma and at a marginally increased risk for death.

Effect of IL-6 receptor blockade on high-sensitivity troponin T and NT-proBNP in rheumatoid arthritis

Background and aims Observational associations between inflammation and cardiovascular disease are interesting, but randomised experimental data are lacking. We investigated the effect of the IL-6 receptor blocker tocilizumab on N terminal pro B type natriuretic peptide (NT-proBNP) and high sensitivity troponin T (hsTnT) in rheumatoid arthritis (RA) patients. Methods A post-hoc study was performed in a subset of patients with moderate to severe RA participating in a randomised controlled trial. The effect of tocilizumab on cardiac biomarkers was determined using stored serum (baseline and 24 weeks) in recipients of tocilizumab (8 mg/kg every 4 weeks plus DMARDs; n = 225) or placebo (every 4 weeks plus DMARDs; n = 132). Results Median NT-proBNP and hsTnT concentrations at baseline were 100 pg/ml and 5.7 pg/ml, respectively. NT-proBNP decreased in both study arms (median at 24 weeks 77 pg/ml in the placebo arm, 79 pg/ml in the tocilizumab arm; p<0.001 for the decrease in both arms), and decreased to a similar extent comparing study arms (tocilizumab effect: −5.5%, p=0.55). hsTnT also decreased in both study arms (median at 24 weeks 3.1 pg/ml in the placebo arm, 4.4 pg/ml in the tocilizumab arm; p<0.001 for the decrease in both arms). The extent of the reduction in hsTnT was greater in the placebo group (tocilizumab effect: +23.3%, p=0.002). Change in NT-proBNP, but not hsTnT, correlated modestly with change in CRP (r = 0.17, p=0.013). Conclusions These data argue against a rapid preferential benefit of IL-6 blockade on these specific surrogate markers of cardiovascular risk, but may be consistent with a general cardiovascular benefit of improved RA treatment. Clinical trials.gov identifier NCT00106574.

OP0131 Optimal dose of tocilizumab for the treatment of giant cell arteritis: efficacy, safety, and exposure-efficacy analysis from giacta

Background GiACTA, a randomized, double-blind, placebo-controlled trial, evaluated the efficacy and safety of tocilizumab (TCZ), an IL-6 receptor-α inhibitor, in patients with giant cell arteritis (GCA).1,2 Objectives Secondary analyses to evaluate the differential efficacy and safety of TCZ between patients with new-onset and relapsing GCA and to evaluate the TCZ exposure-efficacy relationship at week 52 of the trial. Methods Patients aged ≥50 years with active GCA were randomly assigned 1:1:2:1 to short-course prednisone (PBO+26), long-course prednisone (PBO+52) (26-week or 52-week prednisone taper + weekly subcutaneous [SC] placebo, respectively), weekly (TCZ-QW) or every-other-week (TCZ-Q2W) SC TCZ 162 mg + 26-week prednisone taper. Subgroup analysis was performed by disease-onset status (new-onset vs relapsing) to evaluate the proportions of patients in sustained remission at week 52 and time to flare. The impact of TCZ exposure, categorized into high, medium and low tertiles, on time to flare was evaluated across all patients in all treatment arms. Results Randomization included 251 patients, 119 (47%) with new-onset and 132 (53%) with relapsing GCA, distributed evenly across groups. Higher proportions of patients achieved sustained remission in the TCZ vs placebo groups regardless of disease onset (new-onset, relapsing–TCZ-QW: 59.6%, 52.8%; TCZ-Q2W: 57.7%, 47.8%; PBO+26: 21.7%, 7.4%; PBO+52: 21.7%, 14.3%, respectively). Patients with relapsing disease at baseline were in relapse-free remission longer and thus had lower risk for flare (hazard ratio) when treated with TCZ-QW than TCZ-Q2W. Hazard ratio (99% CI) for flare vs PBO+26 was 0.23 (0.09–0.61) for TCZ-QW and 0.42 (0.14–1.28) for TCZ-Q2W; vs PBO+52 it was 0.36 (0.13–1.00) for TCZ-QW and 0.67 (0.21–2.10) for TCZ-Q2W. TCZ exposure-efficacy analysis showed that most patients in the low exposure tertile had been treated with TCZ-Q2W (80%) whereas those with medium and high exposure primarily received TCZ-QW (84% and 98%, respectively). Kaplan-Meier analysis demonstrated that patients with higher exposure benefited from a longer time to flare (Figure). Adverse events (AEs) were similar across groups. Serious AEs were reported in 15.0% TCZ-QW, 14.3% TCZ-Q2W, 22.0% PBO+26 and 25.5% PBO+52 patients; rates were similar between new-onset and relapsing patients. Conclusions The compelling treatment effect of TCZ in GCA patients as measured by sustained remission to 52 weeks was consistent regardless of disease-onset status. Duration of relapse-free remission until flare was longer in patients with higher TCZ exposure, most notably in relapsing patients treated with TCZ-QW. References Unizony SH et al. Int J Rheumatol. 2013;2013:912562. Stone JH et al. 2016 ACR/ARHP Annual Mtg; Washington, DC; A911. Disclosure of Interest J. Stone Grant/research support from: Roche, Genentech, Xencor, Consultant for: Roche, Genentech, Xencor, K. Tuckwell Shareholder of: Roche, Employee of: Roche, S. Dimonaco Employee of: Roche Products Ltd., M. Klearman Employee of: Genentech, N. Mallalieu Shareholder of: Roche, Employee of: Roche, M. Aringer Speakers bureau: Roche, Chugai, D. Blockmans: None declared, E. Brouwer Consultant for: Roche, M. Cid Speakers bureau: Roche, Novartis, B. Dasgupta Speakers bureau: Roche, GlaxoSmithKline, J. Rech: None declared, C. Salvarani: None declared, G. Schett Speakers bureau: AbbVie, Bristol-Myers Squibb, Celgene, Chugai, GlaxoSmithKline, Lilly, Novartis, Roche, Sanofi, UCB, H. Schulze-Koops: None declared, R. Spiera Grant/research support from: Roche, Genentech, Consultant for: Roche, Genentech, S. Unizony: None declared, N. Collinson Employee of: Roche Products Ltd.

FRI0253 Patient-reported outcomes in patients with rheumatoid arthritis treated with subcutaneous tocilizumab compared with placebo or intravenous tocilizumab in combination with csdmards

Background Two previous randomized, controlled trials (RCTs), BREVACTA and SUMMACTA, showed subcutaneous tocilizumab (TCZ-SC) was superior to placebo (PBO) and comparable to intravenous TCZ (TCZ-IV) in combination with csDMARDs for improving RA disease activity.1,2 Objectives To compare the efficacy of TCZ-SC with PBO or TCZ-IV + csDMARDs for improvement in patient-reported outcomes (PROs) in 2 RCT populations. Methods Both RCTs enrolled patients (pts) with inadequate responses to DMARDs; up to 20% had inadequate responses to tumor necrosis factor inhibitors. In BREVACTA, pts received blinded TCZ-SC 162 mg or PBO every 2 weeks (q2w) + csDMARDs for 24 weeks. In SUMMACTA, pts received TCZ-SC 162 mg weekly or TCZ-IV 8 mg/kg q4w + csDMARDs for the 24-week double-blind period. PROs, assessed at 12 weeks (prior to rescue) in BREVACTA and 24 weeks in SUMMACTA, included patient global assessment (PtGA; visual analog score [VAS], 0–100 mm), pain (VAS), Health Assessment Questionnaire Disability Index (HAQ-DI, 0–3) and Short Form-36 (SF-36) physical and mental component summary (PCS, MCS: 0–50) and domain (0–100) scores. The proportions of pts reporting scores ≥ minimum clinically important differences (MCID) and ≥ age/gender-matched normative values were assessed for each treatment group. Results Baseline PRO scores were mostly comparable between treatment groups in each study and between study populations. In BREVACTA, significantly more pts who received TCZ-SC reported scores ≥ MCID for all PROs at week 12 compared with PBO (54% to 73% vs 42% to 55%, respectively; number needed to treat [NNT], 5.2 to 13.0). Compared with 1% to 20% at baseline, 8% to 34% of pts who received TCZ-SC and 4% to 25% of PBO pts reported scores ≥ normative values in all PROs at week 12 (Table). In SUMMACTA, similar proportions of pts who received TCZ-SC and TCZ-IV reported scores ≥ MCID in all PROs at week 24 (61% to 84% vs 64% to 84%, respectively). The proportion of patients who reported scores ≥ normative values was comparable between the TCZ-SC and TCZ-IV groups across all PROs; compared with 0.2% to 23% at baseline, 14% to 41% of pts who received TCZ-SC and 15% to 42% of pts who received TCZ-IV reported scores ≥ normative values at week 24 (Table). Conclusions In BREVACTA, TCZ-SC + csDMARDs resulted in significantly greater improvements across all PROs and significantly more pts reporting scores ≥ MCID at week 12 compared with PBO. Similarly, more pts receiving TCZ-SC reported scores ≥ normative values at week 12 compared with PBO, despite few pts with such scores at baseline. Responses were similar between pts treated with TCZ-SC and TCZ-IV + csDMARDs in SUMMACTA at week 24. These data show TCZ treatment resulted in clinically meaningful improvements in PROs and indicate that attainment of normative scores is a realistic goal in treatment of pts with active RA. References Kivitz A, et al. Arthritis Care Res (Hoboken). 2014;66:1653–61. Burmester G, et al. Ann Rheum Dis. 2014;73:69–74. Acknowledgements This study was funded by F. Hoffmann-La Roche/Genentech. Disclosure of Interest V. Strand Consultant for: Abbvie; Amgen; AstraZeneca; Biogen Idec; Boehringer Ingelheim; Celltrion; Crescendo; Genentech/Roche; GlaxoSmithKline; Janssen; Lilly; Merck; Novartis; Pfizer; Regeneron; Samsung; Sanofi; UCB, K. Lampl Employee of: Genentech, Inc, C. Birchwood Employee of: Genentech, Inc, J. Pei Employee of: Genentech, Inc, K. Tuckwell Shareholder of: Roche, Employee of: Roche, R. Finch Shareholder of: Roche, Employee of: Roche, A. Kivitz Consultant for: Genentech; Novartis; Pfizer; Sanofi-Regeneron; UCB, G. Burmester Grant/research support from: Roche, Consultant for: Roche