Risk factors and outcomes of immune and non-immune causes of diffuse alveolar hemorrhage: a tertiary-care academic single-center experience.

Diffuse alveolar hemorrhage (DAH) is a rare but potentially life-threatening emergency that has both immune and non-immune etiologies. The objective of this investigation was to compare the risk factors and outcomes of immune and non-immune causes of DAH at a tertiary-care academic center. This was a retrospective observational study conducted at a University center. We reviewed all chest radiographs spanning 12 years (2007-2019) at our institute with the words "diffuse alveolar hemorrhage" in the body of their report, and ascertained cases of DAH through a detailed chart review. We used Chi-squared test to determine the differences in risk factors and outcomes between immune versus non-immune causes of DAH. We performed logistic regressions to assess whether baseline demographics and clinical features influence four critical outcomes: death, shock, renal failure, and severe anemia requiring transfusions. Over the 12-year period, there were 88 patients with DAH, 55 with non-immune and 33 with immune etiologies. Among immune causes of DAH, granulomatosis with polyangiitis (GPA) (10.2%), microscopic polyangiitis (MPA) (9%) and systemic lupus erythematosus (SLE) (9%) were most common. Among non-immune causes of DAH, coagulopathy (6.8%), decompensated heart failure (4.5%) and infection (3.4%) were most common. Patients with non-immune causes of DAH were 45.8% more likely to die and 20.7% less likely to experience sustained remission (p = 0.001). Patient with immune causes of DAH were 21% more likely to have extra-pulmonary findings and 23.7% more likely to have received hemodialysis (HD). The presence of extra-pulmonary findings was statistically significantly correlated with the number of blood products received, the need for HD and non-statistically significantly correlated with likelihood of death. Patients with immune causes of DAH were 71.5% more likely to receive multimodal therapy including corticosteroids. Immune-mediated DAH is associated with a better prognosis than non-immune DAH, despite its greater association with extra-pulmonary findings and requirement for hemodialysis.

The risk of malignancy in patients with secukinumab-treated psoriasis, psoriatic arthritis and ankylosing spondylitis: analysis of clinical trial and postmarketing surveillance data with up to five years of follow-up.

BACKGROUND: Data on the use of biologic therapy and malignancy risk are inconsistent due to limited long-term robust studies. OBJECTIVES: To assess the malignancy risk in patients with secukinumab-treated psoriasis, psoriatic arthritis (PsA) and ankylosing spondylitis (AS). METHODS: This integrated safety analysis from both the secukinumab clinical trial programme and postmarketing safety surveillance data included any patient receiving at least one approved dose of secukinumab with a maximum of 5 years of follow-up. Safety analyses evaluated the rate of malignancy using exposure-adjusted incidence rates [EAIR; incidence rates per 100 patient treatment-years (PTY)]. Standardized incidence ratios (SIRs) were reported using the Surveillance, Epidemiology, and End Results Program (SEER) database as a reference population. Crude incidence of malignancy was also reported using postmarketing surveillance data. RESULTS: Safety data from 49 clinical trials with secukinumab-treated patients were included: 10 685 patients with psoriasis, 2523 with PsA and 1311 with AS. Across indications over a 5-year period, the EAIR of malignancy was 0·85 per 100 PTY [95% confidence interval (CI) 0·74-0·98] in secukinumab-treated patients, corresponding to 204 patients per 23 908 PTY. Overall, the observed vs. expected number of malignancies from secukinumab clinical trial data were comparable, as indicated by an SIR of 0·99 (95% CI 0·82-1·19) across indications. The estimated crude cumulative incidence reporting rate per 100 PTY for malignancy was 0·27 in the postmarketing surveillance data across indications with a cumulative exposure of 285 811 PTY. CONCLUSIONS: In this large safety analysis, the risk of malignancy was low for up to 5 years of secukinumab treatment. These data support the long-term use of secukinumab in these indications.

Effect of different imputation approaches on the evaluation of radiographic progression in patients with psoriatic arthritis: results of the RAPID-PsA 24-week phase III double-blind randomised placebo-controlled study of certolizumab pegol.

OBJECTIVES: To report the effect of different imputation methodologies on the assessment of radiographic progression in clinical trials. METHODS: The 216-week RAPID-psoriatic arthritis (PsA) (NCT01087788) trial of certolizumab pegol (CZP) in patients with active PsA was double-blind and placebo-controlled until week 24. A primary end point was change from baseline in modified Total Sharp Score(s) (mTSS). Prespecified imputation methodology in patients with fewer than two analysable mTSS used minimum observed baseline score for missing baseline values and maximum observed week 24 score for missing week 24 values. Post hoc analyses used alternative methods of imputation in patients with fewer than two analysable mTSS. mTSS non-progressors were defined as patients with ≤0 (predefined) or ≤0.5 (post hoc) change in mTSS from baseline to week 24. Baseline mTSS and C-reactive protein levels as predictors of radiographic progression were investigated. RESULTS: 409 patients were randomised. Baseline demographics were similar between groups. Prespecified imputation analysis inappropriately overestimated radiographic progression (least squares mean placebo, 28.9; CZP, 18.3; p≥0.05). Multiple post hoc analyses demonstrated that CZP inhibited radiographic progression compared with placebo, particularly in patients with high baseline mTSS and C-reactive protein levels. mTSS non-progression rate was higher in CZP than placebo groups in all analyses. CONCLUSIONS: Inappropriate prespecified imputation methodology resulted in an unrealistic assessment of progression in all arms. Methodologies for imputing missing radiographic data can greatly affect assessment and reporting of mTSS progression.

Effect of certolizumab pegol on signs and symptoms in patients with psoriatic arthritis: 24-week results of a Phase 3 double-blind randomised placebo-controlled study (RAPID-PsA).

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-PsA (NCT01087788), an ongoing Phase 3 trial in patients with psoriatic arthritis (PsA). METHODS: Patients were randomised 1:1:1 to placebo, 200 mg CZP every 2 weeks (Q2W) or 400 mg CZP every 4 weeks (Q4W). Patients could have had exposure to one previous tumour necrosis factor (TNF) inhibitor therapy. Primary endpoints were American College of Rheumatology 20% (ACR20) response at week 12 and modified Total Sharp Score change from baseline at week 24. Secondary endpoints included; Psoriatic Arthritis Response Criteria (PsARC) score, Health Assessment Questionnaire Disability Index (HAQ-DI), Psoriasis Area and Severity Index, Leeds Enthesitis Index, Leeds Dactylitis Index, and Modified Nail Psoriasis Severity Index. RESULTS: Of 409 patients randomised, 368 completed 24 weeks of treatment. ACR20 response was significantly greater in CZP 200 mg Q2W and 400 mg Q4W-treated patients than placebo (58.0% and 51.9% vs 24.3% (p<0.001)) at week 12, with improvements observed by week 1. There was a statistically significant improvement in physical function from baseline, measured by HAQ-DI in CZP patients compared with placebo (-0.50 vs -0.19, p<0.001) and more patients treated with CZP 200 mg Q2W and CZP 400 mg achieved an improvement in PsARC at week 24 than placebo (78.3% and 77.0% vs 33.1% (p<0.001)). Sustained improvements were observed in psoriatic skin involvement, enthesitis, dactylitis and nail disease. Higher ACR20 response with CZP was independent of prior TNF inhibitor exposure. No new safety signals were observed. CONCLUSIONS: Rapid improvements in the signs and symptoms of PsA, including joints, skin, enthesitis, dactylitis and nail disease were observed across both CZP dosing regimens.

Efficacy of certolizumab pegol on signs and symptoms of axial spondyloarthritis including ankylosing spondylitis: 24-week results of a double-blind randomised placebo-controlled Phase 3 study.

OBJECTIVES: To evaluate the efficacy and safety of certolizumab pegol (CZP) after 24 weeks in RAPID-axSpA (NCT01087762), an ongoing Phase 3 trial in patients with axial spondyloarthritis (axSpA), including patients with ankylosing spondylitis (AS) and non-radiographic axSpA (nr-axSpA). METHODS: Patients with active axSpA were randomised 1:1:1 to placebo, CZP 200 mg every 2 weeks (Q2W) or CZP 400 mg every 4 weeks (Q4W). In total 325 patients were randomised. Primary endpoint was ASAS20 (Assessment of SpondyloArthritis international Society 20) response at week 12. Secondary outcomes included change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and Bath Ankylosing Spondylitis Metrology Index (BASMI) linear. RESULTS: Baseline disease activity was similar between AS and nr-axSpA. At week 12, ASAS20 response rates were significantly higher in CZP 200 mg Q2W and CZP 400 mg Q4W arms versus placebo (57.7 and 63.6 vs 38.3, p≤0.004). At week 24, combined CZP arms showed significant (p<0.001) differences in change from baseline versus placebo in BASFI (-2.28 vs -0.40), BASDAI (-3.05 vs -1.05), and BASMI (-0.52 vs -0.07). Improvements were observed as early as week 1. Similar improvements were reported with CZP versus placebo in both AS and nr-axSpA subpopulations. Adverse events were reported in 70.4% vs 62.6%, and serious adverse events in 4.7% vs 4.7% of All CZP versus placebo groups. No deaths or malignancies were reported. CONCLUSIONS: CZP rapidly reduced the signs and symptoms of axSpA, with no new safety signals observed compared to the safety profile of CZP in RA. Similar improvements were observed across CZP dosing regimens, and in AS and nr-axSpA patients.

Investigating diagnosis, treatment, and burden of disease in patients with ankylosing spondylitis in Central Eastern Europe and the United States: a real-world study.

INTRODUCTION/OBJECTIVES: Ankylosing spondylitis (AS) is a chronic inflammatory immune-mediated condition. We compared AS diagnosis, treatment, and burden in Central Eastern European countries (CEE), where this has been less researched, and the United States (US) from a real-world perspective. METHODS: Point-in-time survey of rheumatologists and their AS patients was conducted in the US (Apr-Oct 2018) and CEE (Aug-Nov 2019) via physician- and patient-completed record forms, including clinical and patient-reported outcomes. Statistical analysis included descriptive statistics, t-tests, Fisher's exact tests, and generalized linear models. RESULTS: In total, 487 patients were recruited from 88 rheumatologists in the US and 922 patients from 126 rheumatologists in CEE. Time from onset of symptoms to final AS diagnosis was longer in CEE than the US (4.2 vs 2.7 years, p < 0.05). At diagnosis, a greater use of conventional synthetic disease-modifying antirheumatic drugs (DMARDs) and injected steroids was reported in CEE vs the US (43.7% vs 27.6%, p < 0.05; 19.3% vs 8.7%, p < 0.05). 22.9% of US patients received a biologic DMARD at diagnosis vs 10% of CEE patients (p < 0.05). At current consultation, biologic DMARD use in CEE was lower vs the US (27.9% vs 71.0%, p < 0.05). CEE vs US patients had greater disease activity (mean Bath Ankylosing Spondylitis Disease Activity Index 4.2 vs 3.1, p < 0.05) and worse quality of life (QoL; mean Ankylosing Spondylitis Quality of Life Questionnaire score 6.2 vs 8.4, p < 0.05). CONCLUSIONS: AS patients in CEE vs the US faced slower diagnosis and worse access to biologics, disease activity, and QoL. Whether early access to biologics can improve symptoms, QoL, and daily activities in AS patients in CEE remains to be seen. Key Points • The study provided evidence on the real-world approach to the diagnosis, treatment, and burden of axSpA (axial spondyloarthritis) in CEE compared with the US. • The study reported patients in CEE experienced longer delays in diagnosis and poorer access to biologics than in the US. • This may have resulted in higher disease activity, greater levels of pain, and poorer outcomes, as reported by patients with axSpA in CEE.

Efficacy and safety of different doses and retreatment of rituximab: a randomised, placebo-controlled trial in patients who are biological naive with active rheumatoid arthritis and an inadequate response to methotrexate (Study Evaluating Rituximab's Efficacy in MTX iNadequate rEsponders (SERENE)).

OBJECTIVES: This phase III study evaluated the efficacy and safety of rituximab plus methotrexate (MTX) in patients with active rheumatoid arthritis (RA) who had an inadequate response to MTX and who were naïve to prior biological treatment. METHODS: Patients with active disease on stable MTX (10-25 mg/week) were randomised to rituximab 2 x 500 mg (n=168), rituximab 2 x 1000 mg (n=172), or placebo (n=172). From week 24, patients not in remission (Disease Activity Score (28 joints) > or =2.6) received a second course of rituximab; patients initially assigned to placebo switched to rituximab 2 x 500 mg. The primary end point was American College of Rheumatology 20 (ACR20) response at week 24. All patients were followed until week 48. RESULTS: At week 24, both doses of rituximab showed statistically superior efficacy (p<0.0001) to placebo (ACR20: 54%, 51% and 23%; rituximab (2 x 500 mg) + MTX, rituximab (2 x 1000 mg) + MTX and placebo + MTX, respectively). Secondary end points were also significantly improved for both rituximab groups compared with placebo. Further improvements in both rituximab arms were observed from week 24 to week 48. Rituximab + MTX was well tolerated, demonstrating comparable safety to placebo + MTX through to week 24, and between rituximab doses through to week 48. CONCLUSIONS: Rituximab (at 2 x 500 mg and 2 x 1000 mg) plus MTX significantly improved clinical outcomes at week 24, which were further improved by week 48. No significant differences in either clinical or safety outcomes were apparent between the rituximab doses.

Unmet needs in ankylosing spondylitis patients receiving tumour necrosis factor inhibitor therapy; results from a large multinational real-world study.

BACKGROUND: Symptoms and comorbidities of ankylosing spondylitis (AS) considerably reduce health-related quality of life (HRQoL) and ability to work. This real-world study assessed rates of tumour necrosis factor inhibitor (TNFi) use and switching, treatment failure, and associations between failing TNFi and HRQoL, work productivity and activity impairment (WPAI). METHODS: AS patients and their treating physicians completed questionnaires capturing patient demographics, clinical status, TNFi treatment history, reasons for switching TNFi, HRQoL and WPAI. Current TNFi was determined as "failing" if, after ≥3 months, physician-rated disease severity had worsened, remained severe, was "unstable/deteriorating", physicians were dissatisfied with disease control and/or did not consider treatment a "success". RESULTS: The analysis included 2866 AS patients from 18 countries. Of 2795 patients with complete treatment data, 916 (32.8%) patients had never received TNFi therapy, 1623 (58.1%) patients were receiving their 1st TNFi and 200 (7.2%) patients had ever received ≥2 TNFi (treatment switch). Primary or secondary lack of efficacy were the commonest reasons for switching, and the mean delay in switching after primary lack of efficacy was 11.1 months. 232 (15.4%) patients on TNFi were currently "failing" who, compared to those with treatment success, reported poorer HRQoL: 5-dimension EuroQoL (EQ-5D-3 L): 0.63 vs. 0.78; Medical Outcomes Study Short-Form Health Survey version 2 (SF-36v2) mental component summary (MCS): 41.8 vs. 46.3; physical component summary (PCS): 40.2 vs. 45.1; impaired work productivity: 46.4% vs. 25.0%; and activity: 44.5% vs. 29.6%; all P < 0.001. CONCLUSIONS: Among AS patients, switching TNFi is uncommon and delayed by nearly 1 year despite primary lack of efficacy. Patients currently failing TNFi experience worse physical function, HRQoL and work productivity.

Propensity score matching/reweighting analysis comparing intravenous golimumab to infliximab for ankylosing spondylitis using data from the GO-ALIVE and ASSERT trials.

OBJECTIVE: To compare the relative efficacy of intravenous golimumab (GOL IV) and infliximab (IFX) for active ankylosing spondylitis (AS). METHODS: Propensity score (PS) methods were used to compare the efficacy of GOL IV 2 mg/kg and IFX 5 mg/kg using individual patient data (IPD) from the active arms of the phase 3 GO-ALIVE and ASSERT studies. Outcomes included the proportion of patients with a ≥ 20% improvement in the Assessment of Spondyloarthritis International Society Criteria (ASAS20), change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) score, and change from baseline in C-reactive protein (CRP) levels from weeks 4-52. RESULTS: Before matching, 105 patients were treated with GOL IV and 201 patients were treated with IFX. After matching on all covariates, 118 patients were included in the ASAS20 analysis, 96 in the BASFI analysis, and 160 in the CRP analysis. After matching, GOL IV showed significantly greater improvement in ASAS20 response than IFX for weeks 28-44 (e.g., OR = 9.05 [95% CI 1.62-50.4] at week 44) and was comparable in change from baseline in BASFI scores and CRP levels to IFX at all time points. Results were robust for inclusion of different sets of covariates in scenario analyses. CONCLUSIONS: This is the first analysis of its kind to leverage clinical trial data to compare two biologics using PS methods in the treatment of active AS. Overall, GOL IV was associated with greater improvement in ASAS20 response than IFX in patients with AS at 28, 36, and 44 weeks of follow-up. Key Points • Although intravenous golimumab (GOL IV) and infliximab (IFX) are the only two IV-based tumor necrosis factor (TNF) inhibitors with demonstrated phase 3 clinical efficacy in patients with ankylosing spondylitis (AS), no study has evaluated their comparative efficacy in a head-to-head trial. • Propensity score matching was used to derive indirect treatment comparisons of GOL IV and IFX for ≥ 20% in the Assessment of Spondyloarthritis International Society Criteria (ASAS20), change in Bath Ankylosing Spondylitis Functional Index (BASFI), and change in C-reactive protein (CRP) using individual patient data from the GO-ALIVE and ASSERT phase 3 trials. • Propensity score matched indirect comparisons showed improved relative efficacy of GOL IV compared to IFX; after matching for up to 16 baseline covariates, GOL IV was associated with significantly greater odds of ASAS20 response at weeks 28, 36, and 44 than IFX as well as equivalent changes from baseline in BASFI and CRP. • This novel application of propensity score matching using data from phase 3 trials, the first analysis of its kind in AS, allowed adjustment for important imbalances in prognostic factors between trials to generate estimates of comparative efficacy between GOL IV and IFX in the absence of a head-to-head trial between these treatments.

A systematic review and network meta-analysis of current and investigational treatments for active ankylosing spondylitis.

OBJECTIVE: To compare the relative efficacy of current and investigational biologic and oral small molecule (OSM) treatments for active ankylosing spondylitis (AS). METHODS: A systematic literature review was conducted to identify all phase 2/3 randomized trials of interest in patients with AS. Outcomes assessed were ≥ 20% improvement in the Assessment of Spondyloarthritis International Society Criteria (ASAS20) and change from baseline in Bath Ankylosing Spondylitis Functional Index (BASFI) and C-reactive protein (CRP) at weeks 12-16. Bayesian network meta-analyses were conducted for outcomes using a random effects model. Baseline-risk adjustment was also conducted to account for differences in placebo response across studies. Surface Under the Cumulative Ranking curve (SUCRA) values are reported, reflecting the relative probability that intervention was the best of all interventions. RESULTS: The investigational agent tofacitinib 5 mg was the top-ranked treatment (SUCRA, 93%) for ASAS20 response, followed by intravenous (IV) golimumab 2 mg/kg (90%). Golimumab IV 2 mg/kg and infliximab 5 mg/kg were the top two ranked treatments for change from baseline in BASFI (golimumab IV, 81%; infliximab, 80%) and change from baseline in CRP (infliximab, 90%; golimumab IV, 82%). CONCLUSIONS: Two approved therapies (golimumab IV, infliximab) and one investigational product ranked highest for efficacy in AS. Key Points • Although golimumab IV, infliximab, and tofacitinib ranked highest for efficacy in AS, differences in efficacy between approved and investigational therapies were not statistically significant.

Effects of infliximab on markers of inflammation and bone turnover and associations with bone mineral density in patients with ankylosing spondylitis.

OBJECTIVES: To evaluate the relationship between bone mineral density (BMD) and biomarkers of bone turnover and inflammation in patients with ankylosing spondylitis (AS) treated with infliximab. METHODS: Patients (n = 279) were randomly assigned (3:8) to receive placebo or 5 mg/kg infliximab every 6 weeks through week 96. At week 24, placebo-treated patients crossed over to infliximab 5 mg/kg. Starting at week 36, patients treated with infliximab received dose escalations to 7.5 mg/kg. Hip and spine BMD were measured (baseline, week 24, week 102) using dual-energy x-ray absorptiometry. Sera were analysed (baseline, week 24, week 102) for levels of bone alkaline phosphatase (BAP), osteocalcin, C-terminal cross-linking telopeptide of type I collagen (CTX), interleukin-6 (IL-6), vascular endothelial growth factor (VEGF) and transforming growth factor-beta. RESULTS: Patients treated with infliximab showed significantly greater median increases in BMD of the spine (2.5%, p<0.001) and hip (0.5%, p = 0.033) at week 24 than those who received placebo (0.5% and 0.2% respectively). Baseline levels of IL-6, VEGF, osteocalcin, BAP and CTX were significantly correlated with increases in spinal BMD at weeks 24 and 102 in the infliximab group. In a multiple regression analysis, high baseline osteocalcin levels and early increases in BAP at week 2 were significantly associated with increases in BMD scores of the spine (week 102) and hip (weeks 24 and 102) in the infliximab group. CONCLUSIONS: Patients with AS who received infliximab showed significant increases in BMD scores over 2 years. While many significant correlations were observed between BMD scores of the hip and spine and biomarker levels, high baseline osteocalcin levels and early increases in BAP were consistently associated with increases in BMD scores.

Unmet needs in psoriatic arthritis patients receiving immunomodulatory therapy: results from a large multinational real-world study.

OBJECTIVE: There are limited data on therapy selection and switching in psoriatic arthritis (PsA). This 18 country, real-world study assessed use and switching of immunomodulatory therapy (biologic/apremilast), the extent of treatment failure and its association with reduced physical functioning, health-related quality of life (HRQoL), and work productivity and activity impairment (WPAI). METHODS: PsA patients under routine care and their treating physicians provided demographics, current therapy, reasons for switching, duration of first therapy, HRQoL, HAQ-DI, and WPAI. Current immunomodulatory therapy was determined as "failing" if, after ≥ 3 months, physician-rated disease severity had worsened, remained severe, was "unstable/deteriorating," or they were dissatisfied with disease control and/or did not consider treatment a "success." RESULTS: Included were 3714 PsA patients; 1455 (40.6%) had never received immunomodulatory therapy; 1796 (50.1%) had ever received 1 immunomodulatory therapy and 331 (9.2%) ≥ 1. Lack of efficacy with first immunomodulatory therapy was the most common reason for switching; patients whose physicians indicated "primary lack of efficacy" as the reason, switched after a mean of 9.4 months. Patients currently failing immunomodulator therapies (n = 246) had poorer HRQoL compared with treatment success (n = 1472) measured by EQ-5D-3L (0.60 vs 0.77%; P < 0.0001); SF-36 PCS (40.8% vs 46.1%; P < 0.0001) MCS (41.1% vs 45.3%; P < 0.0001). Physical functioning, activity, and work productivity were also more impaired (HAQ-DI: 0.88 vs 0.56; activity impairment: 46.7% vs 29.7%; overall work impairment: 35.4% vs 26.1%; all P < 0.0001). CONCLUSIONS: Poor treatment response in PsA is associated with substantial negative patient impact. In cases of primary treatment failure, timely switching is needed.

Long-term safety of secukinumab in patients with moderate-to-severe plaque psoriasis, psoriatic arthritis, and ankylosing spondylitis: integrated pooled clinical trial and post-marketing surveillance data.

BACKGROUND: Secukinumab, a fully human immunoglobulin G1-kappa monoclonal antibody that directly inhibits interleukin (IL)-17A, has been shown to have robust efficacy in the treatment of moderate-to-severe psoriasis (PsO), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) demonstrating a rapid onset of action and sustained long-term clinical responses with a consistently favorable safety profile in multiple Phase 2 and 3 trials. Here, we report longer-term pooled safety and tolerability data for secukinumab across three indications (up to 5 years of treatment in PsO and PsA; up to 4 years in AS). METHODS: The integrated clinical trial safety dataset included data pooled from 21 randomized controlled clinical trials of secukinumab 300 or 150 or 75 mg in PsO (14 Phase 3 trials and 1 Phase 4 trial), PsA (3 Phase 3 trials), and AS (3 Phase 3 trials), along with post-marketing safety surveillance data with a cut-off date of June 25, 2017. Adverse events (AEs) were reported as exposure-adjusted incident rates (EAIRs) per 100 patient-years. Analyses included all patients who received ≥ 1 dose of secukinumab. RESULTS: A total of 5181, 1380, and 794 patients from PsO, PsA, and AS clinical trials representing secukinumab exposures of 10,416.9, 3866.9, and 1943.1 patient-years, respectively, and post-marketing data from patients with a cumulative exposure to secukinumab of ~ 96,054 patient-years were included in the analysis. The most frequent AE was upper respiratory tract infection. EAIRs across PsO, PsA, and AS indications were generally low for serious infections (1.4, 1.9, and 1.2, respectively), Candida infections (2.2, 1.5, and 0.7, respectively), inflammatory bowel disease (0.01, 0.05, and 0.1, respectively), and major adverse cardiac events (0.3, 0.4, and 0.6, respectively). No cases of tuberculosis reactivation were reported. The incidence of treatment-emergent anti-drug antibodies was low with secukinumab across all studies, with no discernible loss of efficacy, unexpected alterations in pharmacokinetics, or association with immunogenicity-related AEs. CONCLUSIONS: Secukinumab demonstrated a favorable safety profile over long-term treatment in patients with PsO, PsA, and AS. This comprehensive assessment demonstrated that the safety profile of secukinumab was consistent with previous reports in patients with PsO, PsA, and AS, supporting its long-term use in these chronic conditions.

Reactive arthritis following culture-confirmed infections with bacterial enteric pathogens in Minnesota and Oregon: a population-based study.

OBJECTIVE: To describe the epidemiology and clinical spectrum of reactive arthritis (ReA) following culture-confirmed infection with bacterial enteric pathogens in a population-based study in the USA. METHODS: We conducted telephone interviews of persons age>1 year with culture confirmed Campylobacter, Escherichia coli O157, Salmonella, Shigella and Yersinia infections reported to FoodNet (http://www.cdc.gov/FoodNet/) in Minnesota, USA and Oregon, USA between 2002 and 2004. SUBJECTS: with new onset joint pain, joint swelling, back pain, heel pain and morning stiffness lasting >or=3 days within 8 weeks of culture (possible ReA) were invited to complete a detailed questionnaire and physical examination. RESULTS: A total of 6379 culture-confirmed infections were reported; 70% completed screening interviews. Of these, 575 (13%) developed possible ReA; incidence was highest following Campylobacter (2.1/100,000) and Salmonella (1.4/100,000) infections. Risk was greater for females (relative risk (RR) 1.5, 95% CI, 1.3 to 1.7), adults (RR 2.5, 95% CI, 2.0 to 3.1) and subjects with severe acute illness (eg, fever, chills, headache, persistent diarrhoea). Risk was not associated with antibiotic use or human leukocyte antigen (HLA)-B27. A total of 54 (66%) of 82 subjects examined had confirmed ReA. Enthesitis was the most frequent finding; arthritis was less common. The estimated incidence of ReA following culture-confirmed Campylobacter, E coli O157, Salmonella, Shigella and Yersinia infections in Oregon was 0.6-3.1 cases/100,000. CONCLUSIONS: This is the first population-based study of ReA following infections due to bacterial enteric pathogens in the USA. These data will help determine the burden of illness due to these pathogens and inform clinicians about potential sequelae of these infections.

Early Disease Activity or Clinical Response as Predictors of Long-Term Outcomes With Certolizumab Pegol in Axial Spondyloarthritis or Psoriatic Arthritis.

OBJECTIVE: Early identification of patients unlikely to achieve good long-term disease control with anti-tumor necrosis factor therapy in axial spondyloarthritis (SpA) and psoriatic arthritis (PsA) is important for physicians following treat-to-target recommendations. Here we assess associations between disease activity or clinical response during the first 12 weeks of treatment and attainment of treatment targets at week 48 in axial SpA and PsA patients receiving certolizumab pegol. METHODS: The relationship between disease activity or clinical response during the first 12 weeks of treatment and achievement of week-48 targets (for axial SpA: inactive disease based on Ankylosing Spondylitis Disease Activity Score [ASDAS] using the C-reactive protein [CRP] level, or Bath Ankylosing Spondylitis Disease Activity Index <2 with normal CRP level; and for PsA: minimal disease activity) was assessed post hoc using RAPID-axSpA and RAPID-PsA trial data. RESULTS: A clear relationship between disease activity from week 2 to 12 and achievement of week-48 treatment targets was observed in both axial SpA and PsA populations. In axial SpA, week-48 ASDAS inactive disease was achieved by 0% of patients (0 of 21) with ASDAS very high disease activity at week 12, compared to 68% of patients (34 of 50) with week-12 ASDAS inactive disease. For PsA, week-48 minimal disease activity was achieved by 0% of patients (0 of 26) with Disease Activity Score in 28 joints (DAS28) using the CRP level >5.1 at week 12, compared to 73% of patients (57 of 78) with DAS28-CRP <2.6. Similar results were observed regardless of the disease activity measure used. Clinical response at week 12 also predicted week-48 outcomes, though to a lesser extent than disease activity. CONCLUSION: Using disease activity and the clinical response state during the first 12 weeks of certolizumab pegol treatment, it was possible to identify a subset of axial SpA and PsA patients unlikely to achieve long-term treatment goals.

Observed Incidence of Uveitis Following Certolizumab Pegol Treatment in Patients With Axial Spondyloarthritis.

OBJECTIVE: Axial spondyloarthritis (axial SpA) is characterized by inflammation of the spine and sacroiliac joints and can also affect extraarticular sites, with the most common manifestation being uveitis. Here we report the incidence of uveitis flares in axial SpA patients from the RAPID-axSpA trial, including ankylosing spondylitis (AS) and nonradiographic (nr) axial SpA. METHODS: The RAPID-axSpA (NCT01087762) trial is double-blind and placebo-controlled to week 24, dose-blind to week 48, and open-label to week 204. Patients were randomized to certolizumab pegol (CZP) or placebo. Placebo patients entering the dose-blind phase were re-randomized to CZP. Uveitis events were recorded on extraarticular manifestation or adverse event forms. Events were analyzed in patients with/without history of uveitis, and rates reported per 100 patient-years. RESULTS: At baseline, 38 of 218 CZP-randomized patients (17.4%) and 31 of 107 placebo-randomized patients (29.0%) had past uveitis history. During the 24-week double-blind phase, the rate of uveitis flares was lower in CZP (3.0 [95% confidence interval (95% CI) 0.6-8.8] per 100 patient-years) than in placebo (10.3 [95% CI 2.8-26.3] per 100 patient-years). All cases observed during the 24-week double-blind phase were in patients with a history of uveitis; in these patients, rates were similarly lower for CZP (17.1 [95% CI 3.5-50.1] per 100 patient-years) than placebo (38.5 [95% CI 10.5-98.5] per 100 patient-years). Rates of uveitis flares remained low up to week 96 (4.9 [95% CI 3.2-7.4] per 100 patient-years) and were similar between AS (4.4 [95% CI 2.3-7.7] per 100 patient-years) and nr-axial SpA (5.6 [95% CI 2.9-9.8] per 100 patient-years). CONCLUSION: The rate of uveitis flares was lower for axial SpA patients treated with CZP than placebo during the randomized controlled phase. Incidence of uveitis flares remained low to week 96 and was comparable to rates reported for AS patients receiving other anti-tumor necrosis factor antibodies.