Abstract
Objective: To characterize the rate of healthcare resource utilization (HCRU) between anti-cyclic citrullinated peptide (CCP; a surrogate for anti-citrullinated protein antibodies [ACPAs]) positive (+) patients with rheumatoid arthritis (RA), either with or without erosions, who initiated biologic disease-modifying antirheumatic drug (bDMARD) treatment.
Methods: Data from the Corrona RA registry, a prospective registry of adult patients with RA from 177 sites across 42 states in the US, were analyzed. Annual rates of HCRU (measured based on rates of all-cause hospitalization, joint surgery, imaging procedures and use of assistive devices) were estimated in anti-CCP + patients with and without erosions following bDMARD initiation using a Poisson regression model.
Results: Among the 3333 patients with known anti-CCP and erosion status and 12-month post-bDMARD follow-up information in the Corrona registry, 2047 were anti-CCP + and included in this analysis; 868 with and 1179 without erosions. Baseline characteristics were generally well balanced between patients with and without erosions; however, those with erosions had a longer mean RA duration and a higher prior DMARD use. Over 12 months, among anti-CCP + patients, those with erosions had significantly higher rates of all HCRU, except joint surgery, than those without erosions. Age-adjusted risk ratios (95% confidence interval) were as follows: all-cause hospitalization, 1.47 (1.14, 1.90); all-cause imaging, 1.25 (1.03, 1.53); and assistive device use 1.12 (1.00, 1.25). The rate of joint surgery visits was also numerically higher in patients with versus without erosion.
Conclusions: ACPA seropositivity with erosive disease was associated with higher rates of HCRU compared with seropositivity without erosions. These findings suggest that providers may want to manage anti-CCP + patients aggressively to achieve better disease control to prevent the development of erosions and the associated increase in HCRU.
Introduction
Rheumatoid arthritis (RA) is a common destructive autoimmune disease characterized by systemic, chronic joint inflammation that leads to bone erosions and structural damageCitation1. While RA primarily affects the joints, extra-articular involvement, such as interstitial lung disease, cardiovascular disease and vasculitis, is commonCitation2. The pathology of RA is driven by persistent autoimmunity, characterized by the production of pathogenic autoantibodies and pro-inflammatory cytokinesCitation2–4, which results in increased synovitis, structural damage, functional impairment and socioeconomic costsCitation1,Citation3–5.
Citrullinated self-peptides bind to the human leukocyte antigen (HLA)-DRB1 locus of antigen-presenting cells, thereby driving the autoimmune disease process in RACitation6. Anti-citrullinated protein antibodies (ACPAs) are highly specific serological biomarkersCitation7 that predict the development of more aggressive RA, extra-articular manifestations, premature mortality and therapeutic responseCitation8–10. ACPAs have also been shown to influence the number and size of erosionsCitation8, most likely due to their ability to increase the differentiation of osteoclasts, the cells responsible for bone resorption, and to enhance bone resorption in vivoCitation11. ACPAs are estimated to be present in 60 to 80% of patients with RACitation12 and are included in American College of Rheumatology/European League Against Rheumatism (EULAR) diagnostic criteria for RACitation5. Genetic studies strongly support the notion that ACPA-positive (+) and ACPA-negative RA are distinct disease subsetsCitation13–15 with differing underlying pathologiesCitation16, and as such, these subgroups may require different treatment strategies. The EULAR recommendations for the management of RA suggest the inclusion of a biologic disease-modifying antirheumatic drug (bDMARD) into the treatment regimen of ACPA + patients who have had an inadequate response to treatment with one previous DMARDCitation17. Anti-cyclic citrullinated peptide (anti-CCP; a surrogate for ACPA) positivity is a distinct biomarker in patients with RA, and testing is readily available in clinical practice. Patients who are anti-CCP + compared with anti-CCP negative are almost three times more likely to have erosionsCitation18 and have a significantly higher 10-year probability of a major fracture or hip fractureCitation19.
Although the EULAR treatment guidelines highlight the importance of the stratification of patients with RA based on the presence of poor prognostic factorsCitation17, little is known regarding the impact of these factors, such as ACPA seropositivity and erosive disease, on healthcare resource utilization (HCRU). The Brigham and Women’s Hospital Rheumatoid Arthritis Sequential Study (BRASS) demonstrated that anti-CCP + and erosions were significantly associated with greater adverse clinical outcomes and HCRU compared with those seen in patients lacking one or more of these poor prognostic factors (anti-CCP+/erosion−, anti-CCP−/erosion + or anti-CCP−/erosion−), despite the use of bDMARDs by many patientsCitation18. In this study, we sought to understand the relationship between ACPA positivity, erosion status (presence/absence) and HCRU as a marker of the impact of disease in a national sample of patients. There was particular interest in evaluating the impact of bone erosions on HCRU as bone erosions are readily detected using common imaging techniques and are a marker of irreversible end organ damageCitation20.
Methods
Patient population
The Corrona RA registry is an independent, prospective, national, observational cohort containing information on patients recruited from 177 private and academic practice sites across 42 states in the US, with 745 participating rheumatologists. As of September 2018, the Corrona database included information on 49,888 patients with RA. The Corrona registry was established in 2001; as such, eligible patients had a diagnosis of RA according to either the 1987 American College of Rheumatology (ACR) Classification CriteriaCitation21 or the 2010 ACR/EULAR Classification CriteriaCitation5. Data on 378,530 patient visits and 177,754 patient-years of follow-up time have been collected, with a mean patient follow-up of 4.4 (median 3.3) years. The Corrona RA registry was established, and this study carried out, in accordance with the Declaration of Helsinki. All participating investigators were required to obtain Institutional Review Board approval for the conduct of non-interventional research involving human patients with a limited dataset. Sponsor approval and continuing review was obtained through a central Institutional Review Board (IRB; New England Independent Review Board, NEIRB No. 120160610). For academic investigative sites that did not receive a waiver to use the central IRB, full board approval was obtained from the respective governing IRBs and documentation of approval was submitted to Corrona, LLC prior to initiating any study procedures. All patients in the Corrona registry were required to provide written informed consent and authorization prior to participating.
Study population
This analysis included patients aged ≥18 years at the time of enrolment (between October 2001 and August 2017), with RA, who initiated a bDMARD (tumor necrosis factor inhibitors [TNFi]: adalimumab, certolizumab pegol, etanercept, golimumab or infliximab, and non-TNFi: abatacept, rituximab or tocilizumab). Patients had known erosion status, as measured by radiography, magnetic resonance imaging (MRI) or ultrasound and reported by the treating rheumatologist, and were anti-CCP + at or prior to the bDMARD initiation visit and at the 12-month (±3 month) follow-up visit. Patients were classified as having erosive disease if erosions were ever reported (any joint) prior to index visit.
Study outcomes
HCRU was measured over 12 months from the initiation visit. HCRU included all-cause hospitalizations, all-site joint surgeries, imaging procedures (joint radiographs, MRIs or ultrasounds) and use of assistive devices (devices used for dressing, built-up or special utensils, jar openers, crutches, cane, built-up or special chair, wheelchair, walker, raised toilet seat, bathtub bar, long-handled appliances for reach, bathtub seat and long-handled appliances in bathroom). Outcomes were captured using physician/laboratory follow-up forms.
Statistical analysis
Patients discontinuing or switching bDMARD during the 12-month follow-up were included in this analysis. Anti-CCP positivity was defined as having a blood anti-CCP level ≥20 units/mL. Owing to the nature of the outcomes, which only involved positive counts, it was possible to approximate HCRU using a Poisson distribution. As such, rates of HCRU per 100 patient-years and risk ratios, adjusted by baseline age, were estimated with 95% confidence intervals (CIs) using a Poisson regression model.
Results
Patient disposition and baseline characteristics
Of 13,914 biologic initiators included in the Corrona RA database, 3333 had known anti-CCP and erosion status and 12-month follow-up information. Of these patients, 2047 were anti-CCP + and were included in this analysis: 868 with and 1179 without erosions (). At bDMARD initiation visit, anti-CCP + patients with and without erosions had a mean (standard deviation [SD]) age of 58.9 (12.5) and 55.9 (12.5) years and a mean (SD) disease duration of 11.7 (10.1) and 6.4 (7.5) years, respectively (). Baseline characteristics were generally well balanced between anti-CCP + patients with and without erosions, except that patients with erosions had a longer RA duration and had higher prior conventional synthetic DMARD and prior b/targeted synthetic DMARD use compared with those without erosions ().
Figure 1. Patient disposition. Abbreviation. CCP+, cyclic citrullinated peptide positive. This figure was originally published on poster 2500, “Association Between Anti-Citrullinated Protein Antibody Status, Erosive Disease and Healthcare Resource Utilization in Patients With RA”; Leslie R. Harrold”, presented at the 2018 Annual Meeting of the American College of Rheumatology held in Chicago, IL, USA.
Table 1. Patient demographics and disease characteristics at first biologic initiation visit.
Healthcare resource utilization
Over 12 months of follow-up, among anti-CCP + patients, the rates of HCRU were higher for patients with versus without erosions at the baseline bDMARD initiation visit (). Adjusted risk rates per 100 person-years were significantly higher in patients with versus without erosions (95% CIs of age-adjusted risk ratios did not cross 1; ) for all-cause hospitalization (15.2 vs. 9.4), all-cause imaging (22.2 vs. 18.1) and assistive device use (73.0 vs. 60.6). While not significant, the rate of joint surgeries (5.3 vs. 3.7) was numerically higher in patients with versus without erosions (age-adjusted risk ratio [95% CI]: 1.31 [0.86, 1.98]).
Figure 2. Rates of HCRU in anti-CCP + patients with RA, with and without erosions. *Rates per 100 patient-years with 95% CI based on Poisson distributed counts. †Reference group: anti-CCP + patients without erosions. Abbreviations. CCP+, cyclic citrullinated peptide positive; CI, confidence interval; HCRU, healthcare resource utilization; RA, rheumatoid arthritis.
Discussion
Using data from the Corrona RA registry, a large US-based registry containing long-term data, we compared the rates of HCRU in patients with RA who initiated bDMARD treatment and who were anti-CCP+, either with or without erosions. Our results showed that, among anti-CCP + patients, those with erosions had higher rates of HCRU (all-cause hospitalizations, joint-surgery visits, all-cause imaging and assistive device use) over 12 months than those without erosions.
Our findings of increased HCRU in patients who were anti-CCP + with erosions were consistent with the findings of the smaller, single, tertiary-care center BRASS, which demonstrated that patients who are anti-CCP + and have erosions are significantly more likely to be hospitalized or use durable medical equipment (stands, walkers and wheelchairs) than those lacking one or more of these poor prognostic factors (anti-CCP+/erosion−, anti-CCP−/erosion + or anti-CCP−/erosion−)Citation18. A separate analysis of the Corrona RA database also showed that patients with higher disease activity have higher rates of HCRU than patients in sustained remissionCitation22. The increased HCRU seen in anti-CCP + patients with erosions, therefore, likely reflects overall higher RA disease activity, suggesting that achieving good disease control could reduce healthcare expense.
Treat-to-target is a broad concept in RA in which a treatment target, typically remission or low disease activityCitation23, is set and response is frequently monitoredCitation24. If improvements are not seen within 3 months of treatment initiation, or if the target is not achieved within 6 months, therapy should be adjustedCitation24. While a treat-to-target approach is recommended in RACitation25,Citation26, it can be hard to implement in everyday practice, and many patients do not receive care consistent with these guidelinesCitation27,Citation28. As such, identifying factors predictive of more severe disease and increased HCRU would be of use in identifying which patients will derive the most benefit from early intensive therapy. The anti-CCP + testing and imaging used in this study are techniques that are widely used in practice. Given our results and those from previous analysesCitation18,Citation22, patients with RA who are anti-CCP + are a population at high risk of poor outcomes and thus should be targeted for early and more aggressive management, consistent with treatment guidelinesCitation17. Early intensive treatment has been shown to reduce the progression of RA to an erosive disease stateCitation29, thereby improving outcomes for the patient but also reducing HCRU and costs.
No adjustments were made for the differences in baseline demographics and disease characteristics between patients with and without erosions as these characteristics are an important part of the typical profile of a patient with erosions. Imbalances seen between patients with and without erosions may be associated with the development of erosions. We show the differences between the two cohorts to characterize the two distinct patient populations and demonstrate the covariates and disease characteristics seen in patients who develop erosions, as well as to demonstrate the importance of early and intensive treatment for anti-CCP + patients who have erosions.
The limitations of this study should be considered. As in any observational study, treatment selection is not random and bias is a concern because physicians prescribe therapies based on the patient’s profile. Although patients enrolled in Corrona are somewhat more likely to be prescribed bDMARDs than comparable patients receiving treatment through Medicare, patients were similar in terms of demographics and burden of comorbiditiesCitation30. While results of registry cohorts are dependent on the characteristics of enrolled patients and the clinical and laboratory information that is available, there is no reason to believe that systematic bias exists between patients enrolled in Corrona with and without laboratory results, according to treatments. It should also be noted that the database does not capture all HCRU, but only that reported by the patient or other providers to the treating rheumatologist at routine clinical visits. However, this is unlikely to affect the difference in outcomes between patients with and without bone erosions. Costs of prescribed medications were not included in this analysis, and healthcare costs have been shown to vary by bDMARDCitation31,Citation32. In addition, the cost-effectiveness of early therapeutic intervention was not considered in this study; however, previous research suggests early intervention is associated with lower costs in the long termCitation33–35. Finally, this study was not designed to determine the impact of ACPA on HCRU, as all patients were anti-CCP+.
Conclusions
In patients with RA, erosive disease predicts high HCRU, suggesting that early therapeutic intervention may be warranted in anti-CCP + patients to achieve better disease control, prevent the development of erosions and reduce complications from RA and associated costly HCRU.
Transparency
Declaration of funding
This study is sponsored by Corrona, LLC and funded by Bristol-Myers Squibb. The design and study conduct were a collaborative effort between Corrona and Bristol-Myers Squibb, and financial support for the study was provided by Bristol-Myers Squibb.
Declaration of financial/other relationships
L.R.H. is an employee of Corrona, LLC, has stock options in Corrona, LLC, has received grant funding from Pfizer and is a consultant to AbbVie, Bristol-Myers Squibb and Roche. S.E.C. and E.A. have stock options/bond holdings in, and are employees of, Bristol-Myers Squibb. Y.S., S.R. and L.G. are employees of Corrona, LLC. J.M.K. has stock options/bond holdings in, and is an employee of, Corrona, LLC; is a consultant for AbbVie, Amgen, Bristol-Myers Squibb, Genentech, Lilly, Pfizer Inc., Regeneron and Sanofi; and has received research grants from AbbVie, Genentech, Lilly, Novartis and Pfizer. Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Author contributions
All authors made a substantial contribution to the conception and design, execution, or analysis and interpretation of data for this study. All authors were involved in writing and critically drafting the article or revising it critically for important intellectual content. All authors approved the final version to be submitted for publication and agree to be accountable for all aspects of the work. All authors had full access to all data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.
Acknowledgements
The authors would like to thank all of the patients and providers who have participated in the Corrona RA registry. This study was sponsored by Corrona, LLC. Corrona has been supported through contracted subscriptions in the last 2 years by AbbVie, Amgen, Boehringer Ingelheim, Bristol-Myers Squibb, Celgene, Crescendo, Eli Lilly and Company, Genentech, Gilead, GlaxoSmithKline, Janssen, Merck, Momenta Pharmaceuticals, Novartis, Pfizer Inc., Regeneron, Roche, Sun, UCB and Valeant. Professional medical writing and editorial assistance was provided by Lola Parfitt, MRes, at Caudex and was funded by Bristol-Myers Squibb.
Data availability statement
Bristol-Myers Squibb policy on data sharing may be found at https://www.bms.com/researchers-and-partners/independent-research/data-sharing-request-process.html.
The Corrona dataset is based on a large US multicenter study adhering to a number of institutional review boards, with complex logistics. Patients did not provide consent to raw data sharing during the data collection for this purpose, and the Corrona data sharing policies do not permit raw data sharing for this purpose. An aggregated limited dataset from the current analyses is available to qualified investigators with an approved protocol. Data requests may be sent to Corrona, represented by Dr. Jeff Greenberg, e-mail [email protected].
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