Neil Collinson

Long-term safety of rituximab in rheumatoid arthritis: 9.5-year follow-up of the global clinical trial programme with a focus on adverse events of interest in RA patients.

Objectives Evaluation of long-term safety of rituximab in rheumatoid arthritis (RA). Methods Pooled observed case analysis of data from patients with moderate-to-severe, active RA treated with rituximab in a global clinical trial programme. Results As of September 2010, 3194 patients had received up to 17 rituximab courses over 9.5 years (11 962 patient-years). Of these, 627 had >5 years’ follow-up (4418 patient-years). A pooled placebo population (n=818) (placebo+methotrexate (MTX)) was also analysed. Serious adverse event and infection rates generally remained stable over time and multiple courses. The overall serious infection event (SIE) rate was 3.94/100 patient-years (3.26/100 patient-years in patients observed for >5 years) and was comparable with placebo+MTX (3.79/100 patient-years). Serious opportunistic infections were rare. Overall, 22.4% (n=717) of rituximab-treated patients developed low immunoglobulin (Ig)M and 3.5% (n=112) low IgG levels for ≥4 months after ≥1 course. SIE rates were similar before and during/after development of low Ig levels; however, in patients with low IgG, rates were higher than in patients who never developed low IgG. Rates of myocardial infarction and stroke were consistent with rates in the general RA population. No increased risk of malignancy over time was observed. Conclusions This analysis demonstrates that rituximab remains generally well tolerated over time and multiple courses, with a safety profile consistent with published data and clinical trial experience. Overall, the findings indicate that there was no evidence of an increased safety risk or increased reporting rates of any types of adverse events with prolonged exposure to rituximab during the 9.5 years of observation.

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.)

Incidence of Giant Cell Arteritis and Characteristics of Patients: Data-Driven Analysis of Comorbidities

To establish the incidence of giant cell arteritis (GCA), cumulative use of prednisolone, and comorbidities most associated with GCA.

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.

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.

SAT0531 Acute phase reactant levels and prednisone doses at disease flare in patients with giant cell arteritis: prospective data from the giacta trial

Background The relationship between acute phase reactant levels and giant cell arteritis (GCA) disease flares is not known, particularly in the era of interleukin-6 receptor blockade with tocilizumab (TCZ). Prednisone doses at which GCA flares can occur have not been studied thoroughly in prospective clinical trials. Objectives Investigate prednisone doses and acute phase reactant levels at the time of disease flare in patients with GCA. Methods Secondary analyses of prednisone doses, C-reactive protein (CRP) levels, and erythrocyte sedimentation rate (ESR) were performed for patients who experienced GCA flare after achieving remission during 52 weeks of treatment with TCZ-weekly or -every-other-week+26 week prednisone taper (TCZ-QW or TCZ-Q2W) or placebo +26 week or 52 week prednisone taper (PBO+26 or PBO+52). The last CRP and ESR values before first disease flare were used if values on the day of first flare were missing. Analyses are descriptive and were performed post hoc. Results GCA flare after remission was reported in 23% (23/100) of TCZ-QW patients, 26% (13/50) of TCZ-Q2W patients, 68% (34/50) of PBO +26 patients, and 49% (25/51) of PBO +52 patients.1 Median CRP levels and ESR at the time of flare were lower in the TCZ groups than in the PBO groups (Table). In the TCZ groups, 92% (33/36) of flares were associated with normal CRP levels (≤1 mg/dL) and 89% (32/36) were associated with normal ESR values (<30 mm/h). In the PBO groups, 34% (20/59) of flares were associated with normal CRP values and 31% (18/59) with normal ESR. Median (min–max) prednisone doses at the time of disease flare in the combined TCZ and combined PBO groups were 5.5 (0.0–310.0) and 9.0 (0.0–55.0) mg/day, respectively. Among 149 patients in the TCZ groups, 10 (7%) had disease flares while receiving prednisone doses greater than 10 mg/day, accounting for 28% of all disease flares in the TCZ groups. Among 101 patients in the PBO groups, 23 (23%) had disease flares while receiving prednisone doses>10 mg/day, accounting for 39% of all disease flares in the PBO groups. Thus, 33 of the 95 disease flares in GiACTA (35%) occurred while the patient was receiving ≥10 mg/day prednisone.Abstract SAT0531 – Table 1 Prednisone doses and acute phase reactants at GCA flare Conclusions Acute phase reactants are not reliable correlates of disease flare in TCZ-treated patients, but approximately one-third of all PBO +prednisone patients also had normal acute phase reactants at the time of disease flare. Median prednisone dose at the time of disease flare for TCZ-treated patients was numerically lower than that of patients treated with PBO +prednisone. One-third of all disease flares in GiACTA occurred while the patient was receiving >10 mg/day prednisone. Reference [1] Stone JH, et al. N Engl J Med2017;377:317–328. Acknowledgements This study was sponsored by F. Hoffmann-La Roche Ltd. Disclosure of Interest J. Stone Grant/research support from: Roche, Genentech, Xencor, Consultant for: Roche, Genentech, Xencor, K. Tuckwell Shareholder of: Roche, Employee of: Genentech, S. Dimonaco Employee of: Roche, M. Klearman Employee of: Genentech, M. Aringer Consultant for: Chugai, Roche, Speakers bureau: Chugai, Roche, D. Blockmans: None declared, E. Brouwer Grant/research support from: Roche, M. C. Cid Consultant for: Roche, Novartis, Boehringer-Ingelheim, B. Dasgupta Consultant for: Roche, GlaxoSmithKline, J. Rech: None declared, C. Salvarani: None declared, H. Schulze-Koops: None declared, G. Schett Grant/research support from: AbbVie, BMS, Celgene, Chugai, GSK, Lilly, Novartis, Roche, Sanofi, UCB, Consultant for: AbbVie, BMS, Celgene, Chugai, GSK, Lilly, Novartis, Roche, Sanofi, UCB, R. Spiera Grant/research support from: Roche/Genentech, Consultant for: Roche/Genentech, S. H. Unizony: None declared, N. Collinson Employee of: Roche