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Real-World Analysis of Initial Clinical Response and Future Outcomes Among Patients with Rheumatoid Arthritis Initiating and Remaining on a First-Line Tumor Necrosis Factor Inhibitor in the United States
This study aimed to evaluate a subsequent treatment response among patients with rheumatoid arthritis (RA) who initiated and remained on a first-line tumor necrosis factor inhibitor (TNFi) after achieving or not achieving an initial response.
Methods
This real-world, retrospective cohort study included patients with RA in moderate/high disease activity (MDA/HDA), defined by Clinical Disease Activity Index (CDAI) score > 10, who initiated a first-line TNFi and remained on therapy for ≥ 12 months. Data were analyzed according to the time of initial evaluation: 3 months (N = 1215) or 6 months (N = 1318). Primary outcome: proportion of patients achieving low disease activity (LDA)/remission in CDAI (≤ 10) at the initial evaluation; secondary outcome: proportion of patients achieving minimal clinically important difference (MCID) in CDAI. Patients were categorized as responders or nonresponders according to outcome achievement, then analyzed for subsequent response at 12 months and maintenance of initial response through 12 months.
Results
After 3 months, 65.9% of patients were in MDA/HDA. Among these nonresponders, 73.5% remained in MDA/HDA at 12 months and 64.2% failed to improve through 12 months. Of patients in LDA/remission at 3 months, 27.0% lost their response at 12 months. Among the 59.2% of nonresponders at 6 months, 80.1% were in MDA/HDA at 12 months and 74.5% never improved through 12 months. For patients in LDA/remission at 6 months (40.8%), 23.4% subsequently lost their response at 12 months. Similar trends were observed for achievement of MCID in CDAI.
Conclusions
In patients with RA treated with a first-line TNFi, most patients who did not achieve a treatment target at an initial evaluation also failed to achieve the treatment target at 12 months. Therefore, evaluating treatment as early as 3 months after initiation may help indicate future clinical improvements and could serve as a reasonable timepoint to consider changing therapy for patients with an inadequate response.
Prior Publication: A portion of this analysis was originally presented at the American College of Rheumatology (ACR) Convergence 2024 (Washington, DC, USA; November 11–14, 2024) [1].
Key Summary Points
Why carry out this study?
Despite recommendations to switch to another tumor necrosis factor inhibitor (TNFi) or a therapy with a different mechanism of action if a treatment target is not achieved within 3 months of initiation, patients with rheumatoid arthritis (RA) prescribed a TNFi as a first-line advanced therapy often remain on treatment while failing to achieve low disease activity (LDA) or remission.
Examining the relationship between an initial treatment response with a first-line TNFi and a subsequent treatment response following continued use of the same TNFi can help to rapidly identify patients who will not respond to TNFi therapy to inform clinical decision-making.
What was learned from the study?
Among patients who did not achieve the treatment target of LDA/remission after 3 months of treatment with a first-line TNFi, 73.5% of patients did not achieve LDA/remission after 12 months. Similarly, among patients who did not achieve a treatment response after 6 months, 80.1% of patients did not achieve a treatment response after 12 months of treatment.
Approximately one in four patients who initially responded after 3 or 6 months of treatment with a first-line TNFi were no longer in LDA/remission after 12 months of treatment.
This study supports the use of a goal-directed treatment strategy to identify ineffective treatment and make timely adjustments to therapy to improve outcomes for patients with RA.
Introduction
If untreated for a prolonged period, rheumatoid arthritis (RA), a chronic inflammatory disease that causes stiffness, swelling, and pain in the joints, can result in permanent structural damage and disability [2‐6]. The American College of Rheumatology (ACR) and the European Alliance of Associations for Rheumatology (EULAR) have identified a treatment target of sustained disease remission, with low disease activity (LDA) deemed acceptable in patients for whom remission is not feasible [7, 8]. Current guidelines recommend initially treating with a conventional synthetic disease-modifying antirheumatic drug (csDMARD), such as methotrexate. Following a goal-directed treatment strategy, clinicians are recommended to evaluate achievement of LDA/remission within 3 to 6 months of initiating a new therapy. For patients who fail to achieve the treatment target, guidelines recommend re-evaluating the treatment regimen to minimize disease activity. Specifically, clinicians may consider prescribing multiple csDMARDs or adding or switching to advanced therapies like biologic disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs) for patients who fail to achieve LDA/remission with a csDMARD.
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Real-world studies of patients with RA in the USA, Europe, and Japan have shown that tumor necrosis factor inhibitors (TNFis), a type of bDMARD, are the most frequently prescribed first-line advanced therapy for patients who fail to achieve a treatment target with csDMARDs [9‐13]. However, many patients still fail to achieve LDA/remission when utilizing a first-line TNFi [14‐18]. Despite the recommendation that patients with an inadequate response to a TNFi after 3 months of treatment switch to another TNFi or to an advanced therapy with a different mechanism of action, such as a Janus kinase inhibitor, interleukin-6 inhibitor, B cell inhibitor, or T cell co-stimulator [7, 8], many patients with an inadequate response to a first-line TNFi remain on treatment for 12 months or longer [14, 18]. One study found that 47.2% of patients continued the use of a first-line TNFi for 12 months without evidence of achievement of LDA/remission [18]. Furthermore, more than a third of patients remained on a first-line TNFi for 2 or 3 years (38.1% and 35.4%, respectively) without evidence of achievement of LDA/remission. An extended period without achieving a treatment goal can result in persistent pain, progressive joint damage, increased costs, and a significant decrease in a patient’s quality of life [19].
Together, these studies demonstrate a gap between the recommended goal-directed treatment strategy and the real-world practices of clinicians for patients prescribed TNFis as a first-line advanced therapy. Several studies have suggested that patients who switch to a therapy with a different mechanism of action after an inadequate response to a first-line TNFi persist on treatment longer and have a greater likelihood of being treated effectively [20‐22]. Thus, identifying patients who will not respond to treatment with a TNFi is critical to optimizing treatment outcomes through timely adjustments to therapy. However, for patients who continue to use the same TNFi despite an initial lack of response, the likelihood of later achieving a treatment target is not well understood. Furthermore, there are limited data that evaluate the likelihood that patients who initially respond to and remain on the same first-line TNFi will subsequently lose the response. Here, we sought to evaluate the subsequent treatment response among a real-world cohort of patients with RA who initiated and remained on the same first-line TNFi after achieving or not achieving an initial treatment response.
Methods
Data Source, Patients, and Study Design
This was a retrospective cohort study using data from the OM1® RA Registry (OM1, Inc.; Boston, MA, USA). The OM1 RA Registry follows patients in the USA who are managed by rheumatologists longitudinally with data derived from medical and pharmacy claims linked to electronic medical record (EMR) data. Claims include information on procedures, diagnoses, administered and dispensed medications, and patient insurance. EMR data include laboratory results and prescribing information, patient-reported outcomes, and measures of treatment response and disease activity. Patients included in the OM1 RA Registry must have multiple qualifying diagnosis codes of RA and either documented disease activity measures, joint exams, and/or patient-reported outcomes, or at least two clinical notes from a rheumatologist. The registry includes deidentified data from over 200,000 patients with RA since 2013.
Eligible patients were ≥ 18 years old and initiated a prescription for a TNFi between January 1, 2016 and March 31, 2023. The TNFis included were adalimumab (including biosimilars), infliximab (including biosimilars), golimumab, certolizumab pegol, and etanercept. To establish a baseline period and allow for follow-up, patients were required to have data available for the 12 months prior to and after initiation of the TNFi. The index date was defined as the day the TNFi prescription was initiated. To identify patients who initiated a TNFi as a first-line advanced therapy, patients were excluded if they had a prescription for a different TNFi or other advanced therapy in the 12 months prior to the index date. A prescription for the same TNFi between 9 and 12 months post-index was required to ensure patients were using the initiated first-line TNFi throughout the study. Patients were excluded if they used another advanced therapy other than the index TNFi during 12 months post-index. Additionally, eligible patients were in moderate/high disease activity (MDA/HDA) at the start of the study (1 month prior and up until the index date), as defined by a Clinical Disease Activity Index (CDAI) score > 10. To capture initial and subsequent treatment responses, an assessment of CDAI at 3 months (± 30 days) or 6 months (± 45 days) post-index plus a subsequent assessment at 12 months (± 45 days) post-index was required.
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Outcomes and Statistical Analyses
Outcomes were evaluated separately with patients included in two nonmutually exclusive cohorts based on availability of a valid CDAI assessment at either 3 months or 6 months post-index (Fig. 1). For both patient cohorts, patient demographics and clinical characteristics were reported at baseline and are presented with descriptive statistics. For each of the two independent analyses, the primary outcome was defined as the proportion of patients achieving LDA or remission in CDAI (≤ 10) at the initial visit (either 3 or 6 months post-index). For patients who achieved LDA/remission (responders) and those who did not (nonresponders), a subsequent treatment response while remaining on the same first-line TNFi was evaluated at 12 months post-index. Additionally, maintenance of the treatment response at all follow-up rheumatologist visits with a reported CDAI from the initial visit (3 or 6 months) through 12 months was evaluated separately for responders and nonresponders.
Fig. 1
Evaluation of initial treatment response to a first-line TNFi and subsequent treatment response in initial responders and nonresponders. HDA high disease activity, MDA moderate disease activity, RA rheumatoid arthritis, TNFi tumor necrosis factor inhibitor. Adult patients with RA in MDA/HDA who initiated a first-line TNFi were evaluated in nonmutually exclusive cohorts for an initial treatment response at 3 or 6 months. Initial responders and nonresponders, who remained on the same first-line TNFi for the duration of the study, were subsequently evaluated at 12 months and at all visits between the initial and subsequent measurements
A secondary outcome of the proportion of patients achieving a minimal clinically important difference (MCID) in CDAI at the initial visit (3 or 6 months post-index) was also assessed. MCID was defined as a ≥ 6-point improvement for patients in MDA at baseline and ≥ 12-point improvement for patients in HDA at baseline [23]. Patients who achieved MCID were classified as responders, while those who did not achieve MCID were classified as nonresponders. As with the primary outcome, a subsequent treatment response was evaluated at 12 months, and the maintenance of the response at all follow-up rheumatologist visits with a reported CDAI was evaluated from the initial visit through 12 months for responders and nonresponders. For both the primary and secondary outcome, all treatment response outcomes were categorical variables and thus described as counts and proportions of patients.
Additionally, two multivariable logistic regression models were developed separately to evaluate predictors of achieving LDA/remission at 12 months among patients who had not achieved LDA/remission at 3 months or at 6 months while remaining on the same TNFi. Predictors of interest included age group (< 45 years, 45 to 64 years, 65 to 74 years, and ≥ 75 years), sex, race (white, non-white, other), smoking status (nonsmoker, smoker, unknown), concomitant use of corticosteroids, statins, opioids, or methotrexate at 3 months or at 6 months, index TNFi (adalimumab, etanercept, infliximab, certolizumab, or golimumab), and CDAI score at 3 months or 6 months. Results are presented as adjusted odds ratios with 95% confidence intervals (CIs).
Ethical Approval
This was an observational research study which used a database of deidentified patient records for medical claims and electronic medical records. No interactions with patients occurred in the conduct of this study.
Results
Patient Demographics
In the cohort evaluated 3 months after initiating a first-line TNFi, a total of 1215 eligible patients were analyzed. The average age was 59.2 years, 77.1% (n/N = 937/1215) of patients were female, and 68.9% (n/N = 837/1215) of patients were reported as white (Table 1). Most patients had used csDMARDs during the 1-year baseline period (86.6%, n/N = 1052/1215) and 43.0% (n/N = 523/1215) used a concomitant csDMARD within 30 days of TNFi initiation. The most commonly prescribed TNFi was adalimumab (33.3%, n/N = 404/1215). Most patients were insured commercially (44.7%) or by Medicare (34.0%), with some patients insured by Medicaid (4.3%) or an unknown insurance type (17.0%). In the cohort evaluated 6 months after initiating a first-line TNFi, 1381 eligible patients were analyzed (Table 1). Patient demographics in the 6-month cohort were similar to those of the 3-month cohort. Additional baseline demographics and clinical characteristics for each cohort are listed in Table 1.
Table 1
Baseline demographics and clinical characteristics in patient cohorts evaluated after initiation of first-line TNFi
Parametera
3-Month cohort
6-Month cohort
N = 1215
N = 1381
Age (years), mean (SD)
59.2 (13.3)
59.0 (13.6)
Age group
18–44
171 (14.1)
207 (15.0)
45–64
594 (48.9)
653 (47.3)
65–74
294 (24.2)
353 (25.6)
75+
156 (12.8)
168 (12.1)
Sex
Female
937 (77.1)
1076 (77.9)
Male
278 (22.9)
305 (22.1)
Race
American Indian or Alaskan Native
6 (0.5)
8 (0.6)
Asian
19 (1.6)
23 (1.7)
Black
132 (10.8)
147 (10.6)
White
837 (68.9)
959 (69.4)
Native Hawaiian or Other Pacific Islander
5 (0.4)
4 (0.3)
Other
7 (0.6)
7 (0.5)
Unknown
209 (17.2)
233 (16.9)
Census region
Midwest
182 (15.0)
208 (15.1)
Northeast
119 (9.8)
125 (9.1)
South
795 (65.4)
906 (65.6)
West
118 (9.7)
140 (10.1)
Unknown
1 (0.1)
2 (0.1)
CCI,b mean (SD)
1.26 (0.7)
1.27 (0.8)
Use of csDMARDs 12 months prior to TNFi initiation
1052 (86.6)
1183 (85.7)
Concomitant csDMARD usec
523 (43.0)
601 (43.5)
Patient insurance type
Commercial
543 (44.7)
611 (44.2)
Medicaid
52 (4.3)
63 (4.6)
Medicare
413 (34.0)
470 (34.0)
Unknown insurance type
207 (17.0)
237 (17.2)
CCI Charlson comorbidity index, csDMARD conventional synthetic disease-modifying antirheumatic drug, SD standard deviation, TNFi tumor necrosis factor inhibitor
aParameters are displayed as n (%) unless indicated
bCCI measured 6 months prior to and including date of TNFi initiation
cConcomitant csDMARD use measured 30 days post-TNFi initiation
Initial and Subsequent Achievement of LDA/Remission in Patients Evaluated 3 months After Initiation of a First-Line TNFi
In the cohort of patients evaluated 3 months after initiation of a first-line TNFi, 65.9% (n/N = 801/1215) of patients were in MDA/HDA and 34.1% (n/N = 414/1215) of patients were in LDA/remission (Fig. 2a). When subsequently evaluated at 12 months post-index, the majority of nonresponders continued to be in MDA/HDA (73.5%, n/N = 589/801) (Fig. 2c). When all reported measures of CDAI between months 3 and 12 were considered, 64.2% (n/N = 514/801) of nonresponders never achieved LDA/remission, while 35.8% (n/N = 287/801) achieved LDA/remission at one or more rheumatologist visit (Fig. 2e).
Fig. 2
CDAI response 3 months after initiation of first-line TNFi and subsequent response at 12 months based on 3-month response. CDAI Clinical Disease Activity Index, HDA high disease activity, LDA low disease activity, MDA moderate disease activity, TNFi tumor necrosis factor inhibitor. a CDAI response evaluated 3 months after initiation of a first-line TNFi. CDAI score classified as LDA/remission (≤ 10) or MDA/HDA (> 10). b CDAI response at 12 months among initial responders at 3 months. c CDAI response at all visits or any visit to a rheumatologist between months 3 and 12 among initial responders at 3 months. d CDAI response at 12 months among initial nonresponders at 3 months. e CDAI response at all visits or any visit to a rheumatologist between months 3 and 12 among initial nonresponders at 3 months
For patients in LDA/remission 3 months post-index, hereafter referred to as responders, 73.0% (n/N = 302/414) of patients sustained LDA/remission at the 12-month evaluation and 27.0% (n/N = 112/414) worsened to MDA/HDA at the 12-month evaluation (Fig. 2b). When all evaluations of CDAI between months 3 and 12 were considered, 55.3% (n/N = 229/414) of initial responders maintained LDA/remission, while 44.7% (n/N = 185/414) of patients worsened to MDA/HDA at one or more visit (Fig. 2d).
Initial and Subsequent Achievement of LDA/Remission in Patients Evaluated 6 months After Initiation of First-Line TNFi
In the cohort of patients evaluated 6 months after initiation of a first-line TNFi, 59.2% (n/N = 818/1381) were in MDA/HDA (nonresponders) and 40.8% (n/N = 563/1381) were in LDA/remission (responders) at the initial visit (Fig. 3a). At the subsequent 12-month evaluation, the majority of nonresponders were in MDA/HDA (80.1%, n/N = 655/818) (Fig. 3c). When the maintenance of response through all evaluations of CDAI between 6 and 12 months was considered, 74.5% (n/N = 609/818) of nonresponders never achieved the treatment target of LDA/remission (Fig. 3e).
Fig. 3
CDAI response at 6 months after initiation of first-line TNFi and subsequent response at 12 months based on 6-month response. CDAI Clinical Disease Activity Index, HDA high disease activity, LDA low disease activity, MDA moderate disease activity, TNFi tumor necrosis factor inhibitor. a CDAI response evaluated 6 months after initiation of a first-line TNFi. CDAI score classified as LDA/remission (≤ 10), MDA/HDA (> 10). b CDAI response at 12 months among initial responders at 6 months. c CDAI response at all visits or any visit to a rheumatologist between months 6 and 12 among initial responders at 6 months. d CDAI response at 12 months among initial nonresponders at 6 months. e CDAI response at all visits or any visit to a rheumatologist between months 6 and 12 among nonresponders at 6 months
At the subsequent 12-month evaluation, 76.6% (n/N = 431/563) of responders sustained their treatment response, while 23.4% (n/N = 132/563) reported worsening to MDA/HDA (Fig. 3b). When the treatment response through all measures of CDAI between 6 and 12 months was analyzed, 66.8% (n/N = 376/563) of responders maintained their response of LDA/remission (Fig. 3d). In contrast, 33.2% (n/N = 187/563) of responders reported worsening to MDA/HDA at one or more visit between 6 and 12 months.
The outcomes of the 3-month and 6-month cohorts were generally consistent, with most patients maintaining their initial response/nonresponse at the subsequent 12-month evaluation. However, there were more patients in the 6-month cohort who maintained their initial response at 12 months post-index versus patients in the 3-month cohort.
Predictors of Achievement of LDA/Remission After Initial Nonresponse to Same TNFi
Using separate multivariable logistic regression models, we evaluated several possible predictors for subsequent achievement of LDA/remission at 12 months in patients who initially did not achieve LDA/remission at 3 or 6 months post-index. For the 3-month cohort, concomitant use of methotrexate at 3 months was a positive predictor significantly associated with achievement of LDA/remission at 12 months post-index (adjusted odds ratio [95% CIs] 1.48 [1.06, 2.07], p = 0.02). Patients with concomitant use of opioids (0.64 [0.40, 0.99], p = 0.048), smoking (0.41 [0.19, 0.82], p = 0.02), and a higher 3-month CDAI score (0.93 [0.90, 0.96], p < 0.001) were significantly less likely to achieve LDA/remission at 12 months post-index (Supplementary Fig. 1). In the 6-month cohort, only a higher 6-month CDAI score remained a significant predictor and was associated with a lower likelihood of achieving LDA/remission at 12 months post-index (0.90 [0.86, 0.94], p < 0.001) (Supplementary Fig. 2).
Initial and Subsequent Achievement of MCID in CDAI After Initiation of First-Line TNFi
A secondary analysis of both patient cohorts examined the initial and subsequent achievement of MCID in CDAI. After 3 months of treatment with a first-line TNFi, 43.7% (n/N = 531/1215) of patients achieved MCID in CDAI (Fig. 4a). Among these patients, 77.8% (n/N = 413/531) maintained MCID in CDAI at the subsequent 12-month evaluation (Fig. 4b) and 62.7% (n/N = 333/531) reported MCID in CDAI at one or more visits between 3 and 12 months (Fig. 4d). Conversely, 56.3% (n/N = 684/1215) of patients did not achieve MCID in CDAI at 3 months post-index (Fig. 4a). Among these patients, the majority (68.9%, n/N = 471/684) did not achieve MCID in CDAI at 12 months (Fig. 4c), with only 45.2% (n/N = 309/684) achieving MCID in CDAI at one or more visits between 3 and 12 months (Fig. 4e).
Fig. 4
Achievement of MCID in CDAI at 3 months after initiation of first-line TNFi and subsequent response at 12 months based on 3-month achievement. CDAI Clinical Disease Activity Index, HDA high disease activity, MCID minimal clinically important difference, MDA moderate disease activity, TNFi tumor necrosis factor inhibitor. a Achievement of MCID in CDAI score evaluated at 3 months after initiation of first-line TNFi. MCID defined as ≥ 6-point improvement from baseline for patients in MDA and ≥ 12-point improvement from baseline for patients in HDA. b Achievement of MCID in CDAI at 12 months among initial responders at 3 months. c Achievement of MCID in CDAI at all visits or any visit to a rheumatologist between months 3 and 12 among responders at 3 months. d Achievement of MCID in CDAI at 12 months among initial nonresponders at 3 months. e Achievement of MCID in CDAI at all visits or any visit to a rheumatologist between months 3 and 12 among nonresponders at 3 months
In patients evaluated 6 months after initiation of a first-line TNFi, 48.9% (n/N = 675/1381) achieved MCID in CDAI at their initial visit (Fig. 5a). Among these patients, 80.4% (n/N = 543/675) maintained MCID in CDAI at the subsequent 12-month evaluation (Fig. 5b) and 73.3% (n/N = 495/675) achieved MCID in CDAI at one or more visits between 6 and 12 months (Fig. 5d). Conversely, 51.1% (n/N = 706/1381) of patients in the 6-month cohort did not achieve MCID in CDAI at the initial visit (Fig. 5a). Among these patients, the majority (74.4%, n/N = 525/706) reported a subsequent failure to achieve MCID in CDAI at 12 months (Fig. 5c), with only 33.6% (n/N = 237/706) reporting MCID in CDAI at one or more visits between 6 and 12 months (Fig. 5e).
Fig. 5
Achievement of MCID in CDAI at 6 months after initiation of first-line TNFi and subsequent response at 12 months based on 6-month achievement. CDAI Clinical Disease Activity Index, HDA high disease activity, MCID minimal clinically important difference, MDA moderate disease activity, TNFi tumor necrosis factor inhibitor. a Achievement of MCID in CDAI score evaluated at 6 months after initiation of first-line TNFi. MCID defined as ≥ 6-point improvement from baseline for patients in MDA and ≥ 12-point improvement from baseline for patients in HDA. b Achievement of MCID in CDAI at 12 months among initial responders at 6 months. c Achievement of MCID in CDAI at all visits or any visit to a rheumatologist between months 6 and 12 among responders at 6 months. d Achievement of MCID in CDAI at 12 months among initial nonresponders at 6 months. e Achievement of MCID in CDAI at all visits or any visit to a rheumatologist between months 6 and 12 among nonresponders at 6 months
Despite guidelines that recommend re-evaluating a treatment target within 3 to 6 months of initiation [7, 8], real-world studies show that many patients with RA treated with a TNFi in the first line of advanced therapy fail to achieve the recommended treatment target of LDA/remission within this timeline [14‐18] and may remain on the same treatment for 12 months or more [14, 18]. However, the likelihood that a patient will subsequently achieve a treatment target while remaining on the same TNFi after initially not achieving a treatment target is not well understood.
In this real-world, retrospective cohort study of patients with RA, between 50% and 65% of patients failed to achieve an initial treatment target after 3 or 6 months of treatment with a first-line TNFi. Among these patients, between 73% and 80% also failed to achieve a treatment target after 12 months. For patients who achieved a treatment target at either 3 or 6 months after initiating a first-line TNFi, most patients were able to maintain this response at 12 months. However, between 16% and 22% of these initially responsive patients reported a loss of treatment response at 12 months, with even more patients reporting a loss of treatment response at one or more visits between the initial assessment and 12 months. Together, these results show that an initial response to treatment may serve as a reliable indicator of whether a patient will subsequently achieve a treatment target while remaining on the same therapy.
For patients with RA, quickly achieving remission or LDA can greatly improve their quality of life, decrease healthcare costs, and reduce pain levels [24, 25]. Thus, following the recommended goal-directed treatment strategy is critical to optimize therapy [5, 7, 8, 26, 27]. To minimize joint damage and severe symptoms, clinicians may set a less stringent target of LDA for patients with severe, highly active, and/or polyrefractory disease versus remission for patients with MDA [27]. This study assessed two different treatment targets: achievement of LDA/remission in CDAI and achievement of a MCID in CDAI. Including an assessment of MCID in CDAI provided the opportunity to assess the likelihood of subsequently achieving and maintaining a less stringent treatment response. However, more than half of all patients failed to achieve MCID in CDAI at the initial assessment 3 or 6 months post-index. Furthermore, among initial nonresponders, the majority of patients did not achieve MCID in CDAI at 12 months. These results suggest that even modest improvements in clinical outcomes, which will typically be gained early in the course of therapy, such as achievement of MCID in CDAI, may not be achieved by all patients who initiate a first-line TNFi. Furthermore, failure to initially achieve even a modest treatment target while utilizing a first-line TNFi may reliably indicate an inability to achieve a target in the future. Together, these results provide evidence that clinicians should consider switching therapies sooner if a patient fails to achieve a low-level treatment response at an initial assessment.
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In addition to choosing an appropriate treatment target, clinicians must also determine the treatment interval for assessing achievement of the target [27]. In this study, the rate of initially achieving a treatment target was similar between patients evaluated at 3 months after initiating a first-line TNFi and patients evaluated 6 months after initiating a first-line TNFi. Likewise, the subsequent response rates at 12 months for initial responders and nonresponders were similar between the 3-month and 6-month cohorts. While clinicians may choose to follow the recommended 3- to 6-month timeline or tailor their treatment strategy for each patient, these results show that assessing a treatment target 3 months after initiation appears to be sufficient time to predict if a first-line TNFi will be effective.
Despite evidence-based recommendations from ACR and EULAR to follow a goal-directed treatment strategy [7, 8], this and other real-world studies reveal that patients are remaining on treatment with first-line TNFis despite failing to achieve a treatment target [14, 18]. Several studies have offered reasons for the gap between these guidelines and real-world clinical practice, such as clinical inertia, patient preference, a fear of worsening symptoms or side effects, and barriers in healthcare and/or insurance structure [26‐30]. Still, some have suggested that outside of the EMR or survey data analyzed, physicians may follow a goal-directed treatment strategy while incorporating patient preference [27]. One study found that engaging patients in the decision to set a treatment target and the strategy to modify treatment as needed led to greater success in achieving a target and higher rates of satisfaction [26]. By informing patients of the effectiveness of a goal-directed treatment regimen, as evidenced by this study, both clinicians and patients may be better at weighing the risks and benefits of a given treatment.
For patients who did not achieve LDA/remission after 3 months of treatment with a first-line TNFi, those with concomitant use of methotrexate at 3 months were significantly more likely to achieve LDA/remission at 12 months. Conversely, patients who were smokers, those with concomitant use of opioids at 3 months, and those with a higher 3-month CDAI score were significantly less likely to achieve LDA/remission at 12 months. However, for patients who did not achieve LDA/remission after 6 months of treatment with a first-line TNFi, the 6-month CDAI score was the only predictor significantly associated with achieving LDA/remission at 12 months. While this analysis was exploratory, the results suggest that some factors earlier in the course of treatment may influence a future treatment response. However, after 6 months of treatment without achieving a response, there is less opportunity to modify the response trajectory. Future research into factors that can predict a subsequent treatment response after an initial lack of response, such as seropositivity and the dosage of concomitant medications, could lead to earlier intervention and reduce the burden of disease.
We also found that between 19% and 27% of patients who initially responded to treatment were unable to maintain this response through 12 months. This finding is consistent with clinical and real-world studies of patients that report a secondary loss of response in patients treated with TNFis [31, 32]. The cause of the secondary loss of response can vary and may depend on patient demographic factors, like a history of smoking and body mass index. Additionally, immunogenicity to TNFis can induce anti-drug antibodies (ADAs), which in complex with TNF inhibitors can impact circulating drug levels. Prior research has shown that patients treated with adalimumab who develop ADAs were less likely to achieve minimal disease activity or remission [33]. Furthermore, studies have shown that the use of concomitant csDMARDs may decrease the formation of ADAs and is associated with improved clinical outcomes [34].
While the pattern of treatment responses observed in the current study is informative, the study design poses some limitations. It is possible that clinicians continued to prescribe the same TNFi for reasons other than effectiveness, including contraindications for other medications, concerns about side effects, or challenges with cost and insurance reimbursement [26, 35]. This study specifically examined the treatment responses of patients who used the same first-line TNFi for 12 months, which inherently restricts the patient population and potentially limits the comparability of this study with other real-world or clinical data that followed patients after a treatment switch. By excluding patients who switched therapy within a 12-month period, this study cannot report on any subsequent treatment responses for these patients, nor the reason(s) for discontinuing a first-line TNFi. However, it is reasonable to assume that patients and their prescribing physician could also choose to switch from a first-line TNFi to another therapy for causes beyond effectiveness.
Additionally, this study specifically analyzed CDAI as the treatment response, which does not require a laboratory test and could therefore be quickly and simply assessed [36, 37]. Our results were consistent with another study of patients treated with a TNFi that found that approximately 60% of patients who did not achieve a response in CDAI at 6 months also did not achieve a response at 12 months [14]. This study also found that patients with an inadequate response at 12 months also reported numerically smaller improvements in patient-reported outcomes compared to patients who were able to achieve a response by 12 months. However, not all physicians use CDAI as a measure of disease activity, which may have limited the availability of patients for this study and impact the applicability and generalizability of these results. Certain types of patients, such as those with high levels of disease activity who require frequent monitoring, may receive CDAI assessments more frequently, which could bias the study population. While we note that the comparability of CDAI to other measurements of disease activity such as Disease Activity Score using 28 joint counts (DAS28) and Simplified Disease Activity Index (SDAI) has been shown in previous research, future work could replicate the structure of this study to examine the subsequent achievement of treatment targets in patients according to an initial response in other routinely collected measures of disease activity [36, 37].
While the OM1 RA Registry follows over 200,000 patients longitudinally with clinical, laboratory, and other linked data, the use of a single registry may have introduced selection bias into our patient cohorts. Furthermore, as with other studies utilizing real-world data, the variables available for analysis were collected during the course of routine clinical practice and may be incomplete or inconsistent between healthcare encounters. While this study reported that some patients were using medications like csDMARDs, steroids, statins, and opioids concomitantly with the first-line TNFi, the data did not indicate the type, start date of the medication, or dosage, all of which could impact treatment response. In fact, because the majority of medication information in the OM1 RA Registry is based on prescriptions entered into EMRs, rather than pharmacy claims, the prescribed medications in the EMR may not mean that the medication was filled and/or taken by patients as directed. Furthermore, this study was not designed to capture safety events from the EMR. However, it is reasonable to conclude that any treatment-emergent safety events that did occur, whether in initial responders or nonresponders, were not serious enough to warrant discontinuation of treatment with the first-line TNFi, as all patients in the study were required to remain on the same first-line TNFi for 12 months. By limiting our study population in this way, it is possible that we have biased the population to include only patients for whom TNFis are well tolerated.
With the availability of other advanced therapies, clinicians are now able to consider other options, including other bDMARDs and tsDMARDs, after an initial failure to achieve a treatment target with a TNFi. Given this choice, particular attention has been given to evaluating the effectiveness of cycling within the TNFi class or switching to a therapy with a different mechanism of action. There is a growing body of evidence from clinical and real-world studies that suggests switching to a different mechanism of action may result in better clinical outcomes for patients with an inadequate response after treatment with a TNFi [35, 38‐43]. These results, along with those from this study, emphasize that early evaluation of a treatment target after initiating a first-line TNFi can allow for timely adjustments to the individualized treatment strategy required for a patient with RA.
Conclusions
This retrospective, real-world study of patients with RA treated with the same first-line TNFi for at least 12 months evaluated the achievement of a treatment target at 12 months according to an initial assessment of response at 3 or 6 months. Overall, a large majority of patients who did not achieve an initial treatment target were unable to achieve the target at a subsequent visit when remaining on the same TNFi. With many options for advanced treatment now available, clinicians must decide at what timepoint a patient who fails to achieve a treatment target should continue the same treatment or switch to another therapy. These results demonstrate that evaluation of treatment response as early as 3 months after initiating a first-line TNFi may serve as a useful indicator of future clinical improvements on this treatment.
Acknowledgements
Medical Writing/Editorial Assistance
Medical writing support was provided by Kathleen E. Gordon, PhD, of AbbVie Inc and funded by AbbVie Inc. Editorial support was provided by S. Michael Austin of AbbVie Inc and funded by AbbVie Inc. During the preparation of this manuscript, the authors and/or medical writer used AbbVie’s Generative Artificial Intelligence to create the first draft of the Plain Language Summary (PLS). After using this tool/service, the authors and/or medical writer reviewed and edited the PLS, as needed, and take full responsibility for the content of the publication.
Declarations
Conflict of Interest
During the completion of the manuscript, the affiliation of Dr. Manish Jain changed to Flourish Research, Chicago, IL, USA and Ravenswood Rheumatology, Chicago, IL, USA. Financial arrangements of the authors with companies whose products may be related to the present manuscript are listed, as declared by the authors. Christina Charles-Schoeman: has received grant support from Priovant, CSL Behring, Janssen; grant support and consultant for Octapharma, Pfizer, AbbVie Inc., Bristol Myers Squibb; consultant for Boehringer Ingelheim, Recludix. Patrick Zueger: Employee of AbbVie Inc. and may hold stock or options. Erin McDearmon-Blondell: Employee of AbbVie Inc. and may hold stock or options. Siran Fang: Employee of AbbVie Inc. and may hold stock or options. Yi Peng: Employee of AbbVie Inc. and may hold stock or options. Tanjinatus Oishi: Employee of AbbVie Inc. and may hold stock or options. Manish Jain: has received grant/research support from AbbVie Inc., Amgen, AnaptysBio, AstraZeneca, Bristol Myers Squibb, Celgene, Eli Lilly, Horizon, Janssen, Kolon TissueGene, LG Chem, Merck, Moderna, Novartis, Olatec, NIH, Pfizer, Selecta, and Shionogi. John Tesser: has received grant/research support from AbbVie Inc., Alpine, Amgen, Arthrosi Therapeutics, Bendcare, Biogen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, CorEvitas, CSL Behring, DRL, Eli Lilly, Emerald, Exagen, Genentech, Gilead, Global Health Living Foundation, Horizon, Janssen, Kolon TissueGene, Mitsubishi, Organogenesis, Pfizer, Samumed/Biosplice, Selecta, SetPoint, Sun Pharma, Takeda, and Vorso; served on advisory boards or as a consultant for AbbVie Inc., Amgen, AstraZeneca, Aurinia, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Pfizer, Samumed/Biosplice, Sanofi/Genzyme, and UCB; speaker fees from AbbVie Inc., Amgen, Aurinia, AstraZeneca, Bristol Myers Squibb (through 2021), Eli Lilly, GlaxoSmithKline, Janssen, Pfizer, Sanofi/Genzyme, and UCB.
Ethical Approval
This was an observational research study which used a database of deidentified patient records for medical claims and electronic medical records. No interactions with patients occurred in the conduct of this study.
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Real-World Analysis of Initial Clinical Response and Future Outcomes Among Patients with Rheumatoid Arthritis Initiating and Remaining on a First-Line Tumor Necrosis Factor Inhibitor in the United States
Verfasst von
Christina Charles-Schoeman
Patrick Zueger
Erin McDearmon-Blondell
Siran Fang
Yi Peng
Tanjinatus Oishi
Manish Jain
John Tesser
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Die Ingestion von Fischgräten kann schwerwiegende abdominale Komplikationen verursachen. Die vorliegende Kohortenanalyse liefert umfassende Daten zu Lokalisationen, CT-Befunden und Behandlungsstrategien über einen Zeitraum von fast zehn Jahren.
Erwachsene mit Covid-19 erhielten in den Monaten nach einem PCR-Nachweis deutlich häufiger eine neue CRS-Diagnose als Personen mit negativem PCR-Test. Der Risikoanstieg zeigte sich unter allen Varianten, am stärksten in der Omikron-Periode.
In der nicht-interventionellen Real-World-Studie HANNA wurde Nivolumab bei Menschen mit rezidiviertem oder metastasiertem Plattenepithelkarzinom der Kopf-Hals-Region in verschiedenen Therapielinien geprüft. Ein Kollege präsentierte auf dem diesjährigen Krebskongress in Berlin die finalen Daten.
Die Effektivität von Checkpoint-Inhibitoren wird unter anderem durch das Mikrobiom und Komedikationen beeinflusst. Wie Ballaststoffe wirken und welche Medikamente man nicht zusammen mit der Immuntherapie geben sollte, zeigten eine Kollegin und ein Kollege auf dem DKK in Berlin auf.
