Associations Between Safety of Certolizumab Pegol, Disease Activity, and Patient Characteristics, Including Corticosteroid Use and Body Mass Index
Abstract
Objective
To examine relationships between knee osteoarthritis (KOA) and obesity, diabetes mellitus (DM), and cardiovascular disease (CVD).
Methods
Associations of time-dependent obesity, DM, and CVD with KOA transition states over approximately 18 years were examined among 4093 participants from a community-based cohort. Transition states were 1) no knee symptoms and no radiographic KOA (rKOA; Kellgren-Lawrence grade ≥2 in at least one knee), 2) asymptomatic rKOA, 3) knee symptoms only, 4) symptomatic rKOA (sxKOA; rKOA and symptoms in same knee). Markov multistate models estimated adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for associations between comorbid conditions and transitions across states, adjusting for baseline age, sex, race, education, enrollment cohort, birth year, and time-dependent knee injury history.
Results
At baseline, 40% of participants had obesity, 13% had DM, and 22% had CVD (mean age = 61 years; 34% Black; 37% male). Compared with those without obesity, those with obesity had a higher hazard of worsening from no rKOA/no symptoms to asymptomatic rKOA (aHR = 1.7; 95% CI = 1.3-2.2) and from knee symptoms to sxKOA (aHR = 1.7; 95% CI = 1.3-2.3), as well as a lower hazard of symptom resolution from sxKOA to asymptomatic rKOA (aHR = 0.5 [95% = CI 0.4-0.7]). Compared with those without CVD, those with CVD had a higher hazard of worsening from no rKOA/symptoms to knee symptoms (aHR = 1.5; 95% CI = 1.1-2.1). DM was not associated with transitions of rKOA.
Conclusion
Prevention of obesity and CVD may limit the development or worsening of rKOA and symptoms.
Introduction
Abstract Objective To investigate the impact of baseline and time-varying factors on the risk of serious adverse events (SAEs) in patients during long-term certolizumab pegol (CZP) treatment. Methods Safety data were pooled across 34 CZP clinical trials in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and plaque psoriasis (PSO). Cox proportional hazards modeling was used to investigate the association of baseline patient characteristics with risk of serious infectious events (SIEs), malignancies, and major adverse cardiac events (MACEs). Cox modeling for recurrent events assessed the impact of time-varying body mass index (BMI), systemic corticosteroid (CS) use, and disease activity on SIE risk in RA and SAE risk in PSO. Results Data were pooled from 8747 CZP-treated patients across indications. Cox models reported a 44% increase in SIE risk associated with a baseline BMI of 35 kg/m2 or more versus a baseline BMI of 18.5 kg/m2 to less than 25 kg/m2. Baseline systemic CS use, age of 65 years or more, and disease duration of 10 years or longer also increased SIE risk. Older age was the only identified risk factor for malignancies. The risk of MACEs increased 107% for BMI of 35 kg/m2 or more versus BMI of 18.5 kg/m2 to less than 25 kg/m2 and increased 51% for men versus women. Higher disease activity, older age, systemic CS use, BMI of 35 kg/m2 or more, and baseline comorbidities were SIE risk factors in RA. Age and systemic CS use were risk factors for SAEs in PSO. Conclusion Age, BMI, systemic CS use, and disease activity were identified as SIE risk factors in CZP-treated patients. Risk of malignancies was greater in older patients, whereas obesity and male sex were MACE risk factors.
Table 1. Population baseline characteristics for CZP-treated patients
| Name | HR Information | Contact | |||
|---|---|---|---|---|---|
| Position | Salary | Office | Extn. | ||
| Tiger Nixon | System Architect | Edinburgh | 61 | 2011/04/25 | $320,800 |
| Garrett Winters | Accountant | Tokyo | 63 | 2011/07/25 | $170,750 |
| Ashton Cox | Junior Technical Author | San Francisco | 66 | 2009/01/12 | $86,000 |
| Cedric Kelly | Senior Javascript Developer | Edinburgh | 22 | 2012/03/29 | $433,060 |
| Airi Satou | Accountant | Tokyo | 33 | 2008/11/28 | $162,700 |
| Brielle Williamson | Integration Specialist | New York | 61 | 2012/12/02 | $372,000 |
| Herrod Chandler | Sales Assistant | San Francisco | 59 | 2012/08/06 | $137,500 |
| Rhona Davidson | Integration Specialist | Tokyo | 55 | 2010/10/14 | $327,900 |
| Colleen Hurst | Javascript Developer | San Francisco | 39 | 2009/09/15 | $205,500 |
| Sonya Frost | Software Engineer | Edinburgh | 23 | 2008/12/13 | $103,600 |
| Jena Gaines | Office Manager | London | 30 | 2008/12/19 | $90,560 |
| Quinn Flynn | Support Lead | Edinburgh | 22 | 2013/03/03 | $342,000 |
| Charde Marshall | Regional Director | San Francisco | 36 | 2008/10/16 | $470,600 |
| Haley Kennedy | Senior Marketing Designer | London | 43 | 2012/12/18 | $313,500 |
| Tatyana Fitzpatrick | Regional Director | London | 19 | 2010/03/17 | $385,750 |
| Michael Silva | Marketing Designer | London | 66 | 2012/11/27 | $198,500 |
| Paul Byrd | Chief Financial Officer (CFO) | New York | 64 | 2010/06/09 | $725,000 |
| Gloria Little | Systems Administrator | New York | 59 | 2009/04/10 | $237,500 |
| Bradley Greer | Software Engineer | London | 41 | 2012/10/13 | $132,000 |
| Dai Rios | Personnel Lead | Edinburgh | 35 | 2012/09/26 | $217,500 |
| Jenette Caldwell | Development Lead | New York | 30 | 2011/09/03 | $345,000 |
| Yuri Berry | Chief Marketing Officer (CMO) | New York | 40 | 2009/06/25 | $675,000 |
| Caesar Vance | Pre-Sales Support | New York | 21 | 2011/12/12 | $106,450 |
| Doris Wilder | Sales Assistant | Sydney | 23 | 2010/09/20 | $85,600 |
| Angelica Ramos | Chief Executive Officer (CEO) | London | 47 | 2009/10/09 | $1,200,000 |
| Gavin Joyce | Developer | Edinburgh | 42 | 2010/12/22 | $92,575 |
| Jennifer Chang | Regional Director | Singapore | 28 | 2010/11/14 | $357,650 |
| Brenden Wagner | Software Engineer | San Francisco | 28 | 2011/06/07 | $206,850 |
| Fiona Green | Chief Operating Officer (COO) | San Francisco | 48 | 2010/03/11 | $850,000 |
| Shou Itou | Regional Marketing | Tokyo | 20 | 2011/08/14 | $163,000 |
| Michelle House | Integration Specialist | Sydney | 37 | 2011/06/02 | $95,400 |
| Suki Burks | Developer | London | 53 | 2009/10/22 | $114,500 |
| Prescott Bartlett | Technical Author | London | 27 | 2011/05/07 | $145,000 |
| Gavin Cortez | Team Leader | San Francisco | 22 | 2008/10/26 | $235,500 |
| Martena Mccray | Post-Sales support | Edinburgh | 46 | 2011/03/09 | $324,050 |
| Unity Butler | Marketing Designer | San Francisco | 47 | 2009/12/09 | $85,675 |
| Howard Hatfield | Office Manager | San Francisco | 51 | 2008/12/16 | $164,500 |
| Hope Fuentes | Secretary | San Francisco | 41 | 2010/02/12 | $109,850 |
| Vivian Harrell | Financial Controller | San Francisco | 62 | 2009/02/14 | $452,500 |
| Timothy Mooney | Office Manager | London | 37 | 2008/12/11 | $136,200 |
| Jackson Bradshaw | Director | New York | 65 | 2008/09/26 | $645,750 |
| Olivia Liang | Support Engineer | Singapore | 64 | 2011/02/03 | $234,500 |
| Bruno Nash | Software Engineer | London | 38 | 2011/05/03 | $163,500 |
| Donna Snider | Customer Support | New York | 27 | 2011/01/25 | $112,000 |
Abbreviation: HDI, human development index (2019); MTX, methotrexate.
Categorical data are n (%); continuous data are median (25th percentile-75th percentile).
a Years in practice were available for 11 low HDI countries and 12 medium/high HDI countries.
b Prescriber status was missing for one low HDI country and one medium/high HDI country; total is greater than 27 as it includes countries with multiple prescriber categories (internal medicine + orthopedics [two medium/high HDI], orthopedics + generalists/house officers [one medium/high HDI], and other specialists + generalists/house officers [one low HDI]).
Abstract Objective To investigate the impact of baseline and time-varying factors on the risk of serious adverse events (SAEs) in patients during long-term certolizumab pegol (CZP) treatment. Methods Safety data were pooled across 34 CZP clinical trials in rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), psoriatic arthritis (PsA), and plaque psoriasis (PSO). Cox proportional hazards modeling was used to investigate the association of baseline patient characteristics with risk of serious infectious events (SIEs), malignancies, and major adverse cardiac events (MACEs). Cox modeling for recurrent events assessed the impact of time-varying body mass index (BMI), systemic corticosteroid (CS) use, and disease activity on SIE risk in RA and SAE risk in PSO. Results Data were pooled from 8747 CZP-treated patients across indications. Cox models reported a 44% increase in SIE risk associated with a baseline BMI of 35 kg/m2 or more versus a baseline BMI of 18.5 kg/m2 to less than 25 kg/m2. Baseline systemic CS use, age of 65 years or more, and disease duration of 10 years or longer also increased SIE risk. Older age was the only identified risk factor for malignancies. The risk of MACEs increased 107% for BMI of 35 kg/m2 or more versus BMI of 18.5 kg/m2 to less than 25 kg/m2 and increased 51% for men versus women. Higher disease activity, older age, systemic CS use, BMI of 35 kg/m2 or more, and baseline comorbidities were SIE risk factors in RA. Age and systemic CS use were risk factors for SAEs in PSO. Conclusion Age, BMI, systemic CS use, and disease activity were identified as SIE risk factors in CZP-treated patients. Risk of malignancies was greater in older patients, whereas obesity and male sex were MACE risk factors.
Table 1. Population baseline characteristics for CZP-treated patients
| Overall (N = 8747; 17 317 PY) | RA (n = 6927; 13 542 PY) | axSpA (n = 315; 978 PY) | PsA (n = 393; 1316 PY) | PSO (n = 1112; 1481 PY) | |
|---|---|---|---|---|---|
| Mean age, years (SD) | 51.3 (12.7) | 53.0 (12.2) | 39.8 (11.9) | 47.7 (11.3) | 45.4 (13.0) |
| ≥18 yr to 45 yr | 2495 (28.5) | 1609 (23.2) | 203 (64.4) | 154 (39.2) | 529 (47.6) |
| Wide column | |||||
| ≥45 yr to 65 yr | 4954 (56.6) | 4131 (59.6) | 104 (33.0) | 214 (54.5) | 505 (45.4) |
| ≥65 yr | 1298 (14.8) | 1187 (17.1) | 8 (2.5) | 25 (6.4) | 78 (7.0) |
| Female sex, n (%) | 6201 (70.9) | 5491 (79.3) | 119 (37.8) | 218 (55.5) | 373 (33.5) |
| BMI, mean (SD), kg/m2 | 28.2 (6.7) | 27.8 (6.6) | 27.6 (5.9) | 29.8 (6.5) | 30.1 (6.9) |
| 18.5 kg/m2 | 219 (2.5) | 196 (2.8) | 7 (2.2) | 4 (1.0) | 12 (1.1) |
| ≥18.5 kg/m2 to 25 kg/m2 | 2881 (32.9) | 2465 (35.6) | 105 (33.3) | 86 (21.9) | 225 (20.2) |
| ≥25 kg/m2 to 30 kg/m2 | 2806 (32.1) | 2149 (31.0) | 105 (33.3) | 144 (36.6) | 408 (36.7) |
| ≥30 kg/m2 to 35 kg/m2 | 1578 (18.0) | 1180 (17.0) | 57 (18.1) | 88 (22.4) | 253 (22.8) |
| ≥35 kg/m2 | 1236 (14.1) | 916 (13.2) | 36 (11.4) | 70 (17.8) | 214 (19.2) |
| Disease duration, mean (SD), yr | 8.0 (8.8) | 6.4 (6.9) | 6.8 (7.5) | 8.6 (8.3) | 18.4 (12.3) |
| 1 yr | 1730 (19.8) | 1591 (23.0) | 80 (25.4) | 39 (9.9) | 20 (1.8) |
| ≥1 yr to 5 yr | 2529 (28.9) | 2161 (31.2) | 92 (29.2) | 135 (34.4) | 141 (12.7) |
| ≥5 yr to 10 yr | 1913 (21.9) | 1585 (22.9) | 61 (19.4) | 90 (22.9) | 177 (15.9) |
| ≥10 yr | 2575 (29.4) | 1590 (23.0) | 82 (26.0) | 129 (32.8) | 774 (69.6) |
| Systemic CS use, n (%) | 3496 (40.0) | 3200 (46.2) | 160 (50.8) | 99 (25.2) | 37 (3.3) |
| MTX use, n (%) | 5741 (65.6) | 5435 (78.5) | 55 (17.5) | 250 (63.6) | 1 (0.1) |
| Prior anti-TNF drug use, n (%) | 1555 (17.8) | 1283 (18.5) | 49 (15.6) | 75 (19.1) | 148 (13.3) |
Abbreviation: HDI, human development index (2019); MTX, methotrexate.
Categorical data are n (%); continuous data are median (25th percentile-75th percentile).
a Years in practice were available for 11 low HDI countries and 12 medium/high HDI countries.
b Prescriber status was missing for one low HDI country and one medium/high HDI country; total is greater than 27 as it includes countries with multiple prescriber categories (internal medicine + orthopedics [two medium/high HDI], orthopedics + generalists/house officers [one medium/high HDI], and other specialists + generalists/house officers [one low HDI]).