Patients with rheumatoid arthritis (RA) have a high prevalence of comorbidities.1 This post-hoc analysis investigated the effect of select comorbidities (depression, osteoporosis, hepatic, cardiovascular or pulmonary disorders) on the efficacy and safety of baricitinib 4 mg once daily in patients with moderate-to-severe active RA and an inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs).
Data from the placebo-controlled periods of five baricitinib studies2–6 were pooled for baricitinib 4 mg; data for baricitinib 2 mg were not analysed due to low (n=302) patient numbers. Additional data for all baricitinib-treated patients with a median exposure of 2 years were derived from an ongoing open-label, long-term extension (LTE) study that included patients from phase II and III studies (RA-BEYOND; NCT01885078).7 Efficacy outcomes were evaluated at week 12 (vs placebo). Interaction of comorbidity-by-treatment was analysed using logistic regression or analysis of covariance. Safety observations up to week 16 (vs placebo) and during the LTE were summarised by the Medical Dictionary for Regulatory Activities preferred term.
Data from 1684 patients (803, baricitinib 4 mg; 881, placebo) from the placebo-controlled periods were analysed. The mean (SD) age was 52.7 (12.1) years, with only 38 (2.3%) patients aged ≥75 years; most patients (1506, 89.4%) were receiving background methotrexate, alone or in combination with another csDMARD. The numbers of patients receiving placebo and baricitinib 4 mg combined (with or without each comorbidity, respectively) were 133/1551 for depression, 247/1437 for osteoporosis, 424/1260 for hepatic disorders, 731/953 for cardiovascular disorders, and 166/1518 for pulmonary disorders. Demographic and clinical characteristics within each comorbidity subgroup were similar between patients randomised to baricitinib or placebo.
Higher proportions of patients achieved all clinical endpoints with baricitinib 4 mg than with placebo at week 12 across subgroups (table 1). Response rates in patients with or without each comorbidity who received baricitinib were generally close to overall response rates, with the exception of depression, where numerically lower response rates were observed in patients with versus without depression and overall (table 1). Responses to baricitinib versus placebo were similar between patients with or without comorbidity within each comorbidity subgroup, even for those with/without depression (p>0.1).
Table 1.
Efficacy and safety data reported by select comorbidities in patients treated with baricitinib or placebo*
| Depression | No depression | Osteoporosis | No osteoporosis | Hepatic disorders | No hepatic disorders | CV disorders | No CV disorders | Pulmonary disorders | No pulmonary disorders | Overall | |
| Baricitinib 4 mg | |||||||||||
| Efficacy outcomes at week 12 | |||||||||||
| Patients, N | 64 | 739 | 113 | 690 | 222 | 581 | 350 | 453 | 77 | 726 | 803 |
| ACR20 response (%)† | 59.4 | 68.2 | 65.5 | 67.8 | 67.1 | 67.6 | 68.3 | 66.9 | 66.2 | 67.6 | 67.5 |
| ACR50 response (%)† | 34.4 | 41.7 | 40.7 | 41.2 | 40.5 | 41.3 | 40.9 | 41.3 | 40.3 | 41.2 | 41.1 |
| DAS 28-hsCRP ≤3.2 response (%)† | 31.3 | 44.9 | 46.9 | 43.3 | 42.8 | 44.2 | 44.9 | 43.0 | 37.7 | 44.5 | 43.8 |
| Change in HAQ-DI‡ | −0.46 | −0.54 | −0.36 | −0.55 | −0.58 | −0.53 | −0.54 | −0.52 | −0.51 | −0.53 | −0.53 |
| Safety outcomes at week 16 | |||||||||||
| Patients, N | 64 | 738 | 113 | 689 | 222 | 580 | 350 | 452 | 77 | 725 | 802 |
| Any TEAE, n (%), (EAIR) | 45 (70.3), (246) |
450 (61.0), (208) |
70 (61.9), (216) |
425 (61.7), (210) |
152 (68.5), (232) |
343 (59.1), (202) |
227 (64.9), (221) |
268 (59.3), (202) |
62 (80.5), (284) |
433 (59.7), (203) |
495 (61.7), (210) |
| SAE, n (%), (EAIR) | 0, (0.0) |
25 (3.4), (11.5) |
9 (8.0), (27.8) |
16 (2.3), (7.9) |
8 (3.6), (12.2) |
17 (2.9), (10.0) |
14 (4.0), (13.6) |
11 (2.4), (8.3) |
4 (5.2), (18.3) |
21 (2.9), (9.8) |
25 (3.1), (10.6) |
| Discontinuation due to AEs, n (%), (EAIR) | 1 (1.6), (5.5) |
24 (3.3), (11.1) |
7 (6.2), (21.6) |
18 (2.6), (8.9) |
9 (4.1), (13.7) |
16 (2.8), (9.4) |
14 (4.0), (13.6) |
11 (2.4), (8.3) |
3 (3.9), (13.8) |
22 (3.0), (10.3) |
25 (3.1), (10.6) |
| Deaths, n (%), (EAIR) | 0, (0.0) |
0, (0.0) |
0, (0.0) |
0, (0.0) |
0, (0.0) |
0, (0.0) |
0, (0.0) |
0, (0.0) |
0, (0.0) |
0, (0.0) |
0, (0.0) |
| Placebo | |||||||||||
| Patients, N | 69 | 812 | 134 | 747 | 202 | 679 | 381 | 500 | 89 | 792 | 881 |
| Efficacy outcomes at week 12 | |||||||||||
| ACR20 response (%)† | 31.9 | 39.8 | 32.1 | 40.4 | 37.1 | 39.8 | 40.7 | 38.0 | 32.6 | 39.9 | 39.2 |
| ACR50 response (%)† | 8.7 | 14.9 | 11.9 | 14.9 | 11.4 | 15.3 | 14.4 | 14.4 | 12.4 | 14.6 | 14.4 |
| DAS 28-hsCRP ≤3.2 response (%)† | 13.0 | 16.9 | 12.7 | 17.3 | 12.9 | 17.7 | 15.7 | 17.2 | 16.9 | 16.5 | 16.6 |
| Change in HAQ-DI§ | −0.20 | −0.26 | −0.08 | −0.27 | −0.28 | −0.26 | −0.27 | −0.23 | −0.17 | −0.26 | −0.25 |
| Safety outcomes at week 16 | |||||||||||
| Any TEAE, n (%), (EAIR) | 57 (82.6), (301) |
437 (53.8), (192) |
91 (67.9), (251) |
403 (53.9), (191) |
119 (58.9), (207) |
375 (55.2), (198) |
228 (59.8), (212) |
266 (53.2), (191) |
59 (66.3), (238) |
435 (54.9), (196) |
494 (56.1), (200) |
| SAE, n (%), (EAIR) |
6 (8.7), (31.7) |
25 (3.1), (11.0) |
9 (6.7), (24.9) |
22 (2.9), (10.4) |
5 (2.5), (8.7) |
26 (3.8), (13.7) |
16 (4.2), (14.9) |
15 (3.0), (10.8) |
2 (2.2), (8.1) |
29 (3.7), (13.1) |
31 (3.5), (12.6) |
| Discontinuation due to AEs, n (%), (EAIR) | 3 (4.3), (15.9) |
21 (2.6), (9.2) |
9 (6.7), (24.9) |
15 (2.0), (7.1) |
6 (3.0), (10.4) |
18 (2.7), (9.5) |
12 (3.1), (11.1) |
12 (2.4), (8.6) |
4 (4.5), (16.1) |
20 (2.5), (9.0) |
24 (2.7), (9.7) |
| Deaths, n (%), (EAIR) | 1 (1.4), (5.3) |
0, (0.0) |
1 (0.7), (2.8) |
0, (0.0) |
0, (0.0) |
1 (0.1), (0.5) |
1 (0.3), (0.9) |
0, (0.0) |
0, (0.0) |
1 (0.1), (0.5) |
1 (0.1)§, (0.4) |
| Baricitinib safety outcomes after median exposure of 2 years | |||||||||||
| Patients, N | 342 | 3097 | 500 | 2939 | 810 | 2629 | 1535 | 1904 | 373 | 3066 | 3439 |
| Any TEAE, n (%), (EAIR) | 318 (93.0), (51.4) |
2592 (83.7), (43.1) |
444 (88.8), (45.9) |
2466 (83.9), (43.5) |
711 (87.8), (45.1) |
2199 (83.6), (43.5) |
1351 (88.0), (44.8) |
1559 (81.9), (43.1) |
343 (92.0), (45.7) |
2567 (83.7), (43.6) |
2910 (84.6), (43.9) |
| SAE, n (%), (EAIR) | 73 (21.3), (11.8) |
489 (15.8), (8.1) |
132 (26.4), (13.7) |
430 (14.6), (7.6) |
168 (20.7), (10.7) |
394 (15.0), (7.8) |
348 (22.7), (11.5) |
214 (11.2), (5.9) |
102 (27.3), (13.6) |
460 (15.0), (7.8) |
562 (16.3), (8.5) |
| Discontinuation due to AEs, n (%), (EAIR) | 36 (10.5), (5.8) |
283 (9.1), (4.7) |
71 (14.2), (7.3) |
248 (8.4), (4.4) |
93 (11.5), (5.9) |
226 (8.6), (4.5) |
173 (11.3), (5.7) |
146 (7.7), (4.0) |
35 (9.4), (4.7) |
284 (9.3), (4.8) |
319 (9.3), (4.8) |
| Deaths, n (%), (EAIR) | 3 (0.9), (0.5) |
10 (0.3), (0.2) |
7 (1.4), (0.7) |
6 (0.2), (0.1) |
1 (0.1), (0.1) |
12 (0.5), (0.2) |
9 (0.6), (0.3) |
4 (0.2), (0.1) |
4 (1.0), (0.5) |
9 (0.3), (0.2) |
13 (0.4), (0.2) |
Comorbidities and associated terms are based on the Medical Dictionary for Regulatory Activities classification system. Terms for depression included depressed mood, depression postoperative, depression, depressive symptoms, dysthymic disorder, major depression, suicidal ideation and suicide attempt. Terms for osteoporosis included low bone density (bone density decreased), non-traumatic bone fracture (osteoporotic fracture), osteopaenia, osteoporosis postmenopausal, osteoporosis and senile osteoporosis. Terms for hepatic disorders included alanine aminotransferase increased, aspartate aminotransferase increased, biliary cirrhosis primary, blood alkaline phosphatase increased, cholestasis, chronic hepatitis, drug-induced liver injury, gamma-glutamyltransferase increased, hepatic enzyme abnormal, hepatic enzyme increased, hepatic function abnormal, hepatic lesion, hepatic steatosis, hepatitis, hepatitis acute, hepatitis toxic, hepatomegaly, hypertransaminasaemia, hypoalbuminaemia, jaundice, liver disorder, liver function test abnormal, liver injury, liver operation, non-alcoholic steatohepatitis, serum hepatitis B virus core antibody positive, serum hepatitis B virus surface antibody positive, spider nevus, transaminases increased and varices oesophageal. Terms for cardiovascular disorders included acute myocardial infarction, blood cholesterol increased, blood glucose abnormal, blood glucose increased, cerebral infarction, cerebrovascular accident, coronary artery bypass, diabetes mellitus, diabetes mellitus inadequate control, diabetic ketoacidosis, essential hypertension, gestational diabetes, glucose tolerance impaired, hypercholesterolaemia, hyperglycaemia, hyperlipidaemia, hypertension, hypertensive cardiomyopathy, hypertensive heart disease, intermittent claudication, ischaemic stroke, labile hypertension, lacunar infarction, low-density lipoprotein increased, myocardial infarction, peripheral arterial occlusive disease, peripheral artery stenosis, subarachnoid haemorrhage, subdural haematoma, systolic hypertension and transient ischaemic attack. Terms for pulmonary disorders included allergic bronchitis, apnoea, asbestosis, aspirin-exacerbated respiratory disease, asthma, asthma exercise-induced, atelectasis, bronchial hyper-reactivity, bronchiectasis, bronchiolitis, bronchitis chronic, bronchospasm, bullous lung disease, chronic obstructive pulmonary disease, cor pulmonale chronic, diffuse panbronchiolitis, dyspnoea, dyspnoea exertional, emphysema, idiopathic pulmonary disease, infantile asthma, interstitial lung disease, Langerhans cell histiocytosis, lung consolidation, lung cyst, obstructive airways disorder, pneumoconiosis, pneumonitis, pulmonary bulla and pulmonary fibrosis. The number of patients with idiopathic pulmonary disease, interstitial lung disease or pulmonary fibrosis was low (6 and 8 patients for baricitinib 4 mg and placebo, respectively); thus, the impact of these conditions on baricitinib treatment outcomes cannot be concluded with certainty.
*Efficacy outcomes were assessed at week 12 for baricitinib and placebo; safety outcomes were recorded from baseline to week 16 for baricitinib and placeboin the randomised controlled trials and for all patients receiving baricitinib after a median exposure of 2 years in the long-term extension study.
†Percentage of patients achieving ACR20, ACR50 and DAS 28-hsCRP ≤3.2.
‡Least squares mean changes in HAQ-DI scores from baseline to week 12; negative changes indicate improvement from baseline.
§One death occurred in a patient receiving placebo; this patient had depression, osteoporosis and a cardiovascular disorder.
ACR, American College of Rheumatology;ACR20, 20% improvement from baseline in ACR criteria;ACR50, 50% improvement from baseline in ACR criteria;AE, adverse event;CV, cardiovascular;DAS28-hsCRP, Disease Activity Score for 28-joints based on the level of high-sensitivity C reactive protein;EAIR, exposure-adjusted incidence rate;HAQ-DI, Health Assessment Questionnaire–Disability Index;N, number of patients randomised and treated in each comorbidity subgroup; n, number of patients with event; SAE, serious adverse event;TEAE, treatment-emergent adverse event.
The safety analysis set from the placebo-controlled periods included 1683 patients (802, baricitinib; 881, placebo) with 235.2 and 246.9 patient-years of exposure (PYE) to baricitinib 4 mg or placebo, respectively. Similar proportions of patients experienced ≥1 treatment-emergent adverse events (TEAEs) between baricitinib and placebo across comorbidity subgroups (table 1). The most common TEAEs for the overall population were nasopharyngitis (5.6%, baricitinib vs 5.2%, placebo), upper respiratory tract infections (4.5% vs 3.5%), urinary tract infections (3.5% vs 2.6%) and bronchitis (2.9% vs 2.6%). Serious adverse events (SAEs) and discontinuations were infrequent, occurring at similar rates across subgroups for baricitinib and placebo. SAE and discontinuation rates for baricitinib-treated patients with/without each comorbidity were generally close to overall rates, although numerical differences were observed between patients with depression (lower rates), osteoporosis (higher rates) or pulmonary disorders (higher rates) and those without these comorbidities.
In the LTE study, safety data were available from 3439 patients with a total of 6633 PYE to baricitinib. Overall, the incidence of TEAEs, SAEs, discontinuations and reported deaths was similar between patients with or without comorbidity within each comorbidity subgroup (table 1). Further, the exposure-adjusted incidence rates for all patients were lower in the LTE than during the placebo-controlled period for all safety outcomes assessed. The numerical differences between patients with/without each comorbidity observed after 16 weeks (see above) were not observed in the LTE study.
This is the first analysis assessing the impact of select comorbidities on the efficacy and safety of baricitinib 4 mg. Limitations of this post-hoc analysis include the analysis of patient data derived from randomised clinical trials rather than real-world patient data, such that patients with certain acute or historical conditions, unstable illness, or certain laboratory abnormalities were excluded from the trials (see online supplementary text); the limited number of patients in each comorbidity subgroup and the limited duration of analyses; the non-inclusion of all known comorbidities in RA; the mix of comorbidities included in each subgroup, which could vary in severity and overall impact on patients; the inability to assess adverse events of specific interest and whether comorbidity severity improved or worsened following baricitinib treatment; and the inability to conclude on the efficacy and safety of baricitinib in patients aged ≥75 years and/or exposed to baricitinib 2 mg due to low patient numbers. Planned analyses of safety data from registries or healthcare databases in the USA and Europe are expected to address many of the current limitations.
annrheumdis-2018-214261supp001.docx (20.5KB, docx)
Baricitinib 4 mg showed similar efficacy and safety during placebo-controlled and LTE observation periods regardless of the presence or absence of select comorbidities in patients with moderate-to-severe active RA and an inadequate response to csDMARDs. No trends for increased risk of safety events related to comorbidity were observed across comorbidity subgroups for baricitinib during a median exposure of 2 years. Further studies are needed to confirm the data presented, which provide a hypothesis only.
Trial registration numbers: NCT01185353, NCT01469013, NCT00902486, NCT01710358 and NCT01721057.
Acknowledgments
The authors would like to acknowledge Ioannis Nikas, PhD, and Sue Chambers, PhD (Rx Communications, Mold, UK) for medical writing assistance during the preparation of this research letter, funded by Eli Lilly and Company.
Footnotes
Handling editor: Josef S Smolen
Contributors: All authors contributed substantially to the conception or design of the work, or the acquisition, analysis or interpretation of data for the work; drafted the work or revised it critically for important intellectual content; gave their final approval of the version to be published; and agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Funding: This study was funded by Eli Lilly and Company and Incyte Corporation. IdlT, VR, FD and SW are employees of Eli Lilly and Company and, together with the other authors, were involved in the study design; in the collection, analysis and interpretation of the data; in the writing of the report; and in the decision to submit the paper for publication.
Competing interests: BC reports grants and personal fees from Merck and Pfizer, and personal fees from AbbVie, BMS, Janssen, Eli Lilly, Roche Chugai, Sanofi and UCB, outside the submitted work. AB reports grants and personal fees from Eli Lilly, during the conduct of the study, and grants from Pfizer, AbbVie, MSD and BMS, grants and personal fees from Novartis and Nordic, and personal fees from UCB, Celltrion, Kern Pharma, Sanofi and Sandoz, outside the submitted work. H-PT reports personal fees from AbbVie, Chugai, Janssen Cilag, Eli Lilly, Novartis, Roche, Sandoz Hexal and Sanofi Aventis, outside the submitted work. MD reports grants and personal fees from Eli Lilly, Pfizer, AbbVie and UCB, during the conduct of the study. VR is a minor shareholder of Eli Lilly and Company. PSP, JZ, IdlT, FD and SW report no conflicts of interest.
Patient consent: Obtained.
Ethics approval: All studies were conducted in accordance with the ethical principles of the Declaration of Helsinki and Good Clinical Practice guidelines. Studies were approved by the following review boards: NCT01469013: Parexel #205204; NCT01185353: Schulman Associates IRB, IRB #10-5255-0; NCT00902486: Copernicus Group IRB #PAR1-09-143; NCT01710358 (RA-BEAM): Quorum Review IRB #27257; NCT01721057 (RA-BUILD): Quorum Review IRB #27258. In addition, studies were approved by each participating centre’s institutional review board or ethics committee.
Provenance and peer review: Not commissioned; externally peer reviewed.
Data sharing statement: The data will not be shared as they are proprietary information.
References
- 1. Dougados M, Soubrier M, Antunez A, et al. . Prevalence of comorbidities in rheumatoid arthritis and evaluation of their monitoring: results of an international, cross-sectional study (COMORA). Ann Rheum Dis 2014;73:62–8. 10.1136/annrheumdis-2013-204223 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. Keystone EC, Taylor PC, Drescher E, et al. . Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis 2015;74:333–40. 10.1136/annrheumdis-2014-206478 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Tanaka Y, Emoto K, Cai Z, et al. . Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis receiving background methotrexate therapy: a 12-week, double-blind, randomized placebo-controlled study. J Rheumatol 2016;43:504–11. 10.3899/jrheum.150613 [DOI] [PubMed] [Google Scholar]
- 4. ClinicalTrials.gov INCB028050 compared to background therapy in patients with active rheumatoid arthritis (RA) with inadequate response to disease modifying anti-rheumatic drugs, 2009. Available: https://clinicaltrials.gov/ct2/show/NCT00902486 [Accessed 18 Mar 2018].
- 5. Dougados M, van der Heijde D, Chen Y-C, et al. . Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 2017;76:88–95. 10.1136/annrheumdis-2016-210094 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Taylor PC, Keystone EC, van der Heijde D, et al. . Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 2017;376:652–62. 10.1056/NEJMoa1608345 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
annrheumdis-2018-214261supp001.docx (20.5KB, docx)