Comparative evaluation of treatment patterns and healthcare utilization of newly-diagnosed rheumatoid arthritis patients by anti-cyclic citrullinated peptide antibody status

Abstract

Background: Anti-cyclic citrullinated peptide (CCP) antibody positivity is an established diagnostic factor for severe disease activity and joint damage and a prognostic factor for aggressive disease in rheumatoid arthritis (RA).

Objective: To compare RA-related treatment, healthcare utilization, and joint erosion between anti-CCP-positive and anti-CCP-negative RA patients.

Methods: Newly-diagnosed RA patients were identified from the Henry Ford Health System database between January 1, 2009 and December 31, 2014; the date of the first RA diagnosis within the study period was the index date. Baseline anti-CCP test was used to categorize patients as anti-CCP-positive or anti-CCP-negative, and outcomes were evaluated in the 6 months post-index.

Results: There were 217 anti-CCP-positive and 191 anti-CCP-negative RA patients included in the study. A higher proportion of anti-CCP-positive patients were initiated on RA treatment than anti-CCP-negative patients (70.5% vs 23.0%; p < .0001). More anti-CCP-positive patients received methotrexate (73.2% vs 56.8%; p = .0374), while more anti-CCP-negative patients received hydroxychloroquine (31.8% vs 13.1%; p = .0037) in first-line therapy. A higher proportion of anti-CCP-negative patients were tested for rheumatoid factor (RF) and erythrocyte sedimentation rate (ESR). Of those tested, there were more positive test results in the anti-CCP-positive cohort compared to the anti-CCP-negative cohort (RF: 84.4% vs 18.2%, p < .0001; C-reactive protein [CRP]: 69.7% vs 48.3%, p = .0008; and ESR: 89.5% vs 53.9%, p < .0001). Outpatient utilization predominated, with more anti-CCP-positive patients having any outpatient physician office visit (96.3% vs 77.5%, p < .0001) and a higher mean number of visits (5.3 vs 2.5, p < .0001) than anti-CCP-negative patients. Among anti-CCP-positive (n = 113) and anti-CCP-negative (n = 58) patients with imaging results, more anti-CCP-positive patients had joint erosion compared to anti-CCP-negative patients (18.6% vs 8.6%; p = .0858); however, statistical significance was not reached.

Conclusion: RA patients with positive anti-CCP antibodies had higher degrees of inflammation and disease activity as indicated by laboratory results, which likely contributed to their higher rates of healthcare utilization, joint erosion, and proportions of RA treatment.

Keywords:

• Rheumatoid arthritis
• healthcare utilization
• anti-cyclic citrullinated peptide
• CCP

Introduction

Rheumatoid arthritis (RA) is the most common systemic inflammatory disease and is characterized by chronic inflammation of symmetrical joints due to autoimmune disease of unknown etiology. RA affects an estimated 1% of the population globally¹. The disease can manifest at any age and is ∼3-times more common in women than men².

RA often manifests with extra-articular involvement that can include rheumatoid nodules, vasculitis, eye inflammation, neurologic dysfunction, cardiopulmonary disease, lymphadenopathy, and splenomegaly³. Bone erosions in RA, the visible loss of bone on radiographs, are a key outcome measure in RA and can be used to predict more severe courses of disease⁴. Patients with RA with bone erosions have increased mortality and morbidity in comparison to the general population due to local and systemic inflammatory processes that damage the cartilage, bone, and soft tissue, as well as blood vessels and viscera^1,4,5. Individuals with RA have decreased health-related quality-of-life (HRQoL) due to the pain, disability, and fatigue associated with the disease, which can significantly affect a person’s ability to perform normal activities of daily living (ADLs)^1,6. In order to avoid complications of RA and improve function, early diagnosis and early aggressive treatment are essential^5,7.

The American College of Rheumatology and European League Against Rheumatism (ACR/EULAR) revised the criteria for the diagnosis of RA to focus on early manifestations of disease. Rheumatoid factor (RF) is a diagnostic test that is used along with physical examination findings in the diagnosis of RA^1,7. RF is specific, but lacks sensitivity; the sensitivity ranges from 59–79%, whereas specificity ranges from 80–84%⁵. Anti-cyclic citrullinated peptide (CCP) is one of the latest markers introduced for the diagnosis of RA⁷. The sensitivity of anti-CCP antibody testing, using the second-generation assay, ranges from 64–89%, and specificity ranges from 88–99%⁵. The predictive value of anti-CCP antibodies in early arthritis for the eventual diagnosis of RA has been demonstrated⁵.

Studies have also demonstrated that anti-CCP antibodies are useful in identifying individuals who are likely to develop damage due to RA and who have clinically significant disease activity⁵. For instance, in a study that evaluated the relationship between anti-CCP antibodies and RA activities, a significant correlation was found between anti-CCP antibodies and disease activity score, which measures clinical RA activity, and also between anti-CCP antibodies and serological markers of the RA activity (C reactive protein and fibrinogen)⁸. Positive anti-CCP antibodies have also been shown to predict 1-year rapid radiographic progression in early RA, regardless of the titer⁹. A recent meta-analysis evaluated the role of anti-CCP antibodies and joint damage, and while the individual studies have conflicting results, the results of the analysis clearly showed the value of anti-CCP antibodies in predicting joint damage¹⁰. Although negative anti-CCP antibodies have been reported to be associated with milder course of progression, a recent publication reported cases of patients with seronegative RA that evolved into a severe disease with joint destructions and were refractory to treatment¹¹. Despite this finding, there appears to be strong evidence between positive anti-CCP antibodies and poor RA prognosis. The ability to identify patients who are at greatest risk for progressive and destructive arthritis is especially useful, as these individuals benefit most from early and aggressive intervention⁵.

The goal of treatment in RA is to improve or maintain functional status, which subsequently improves HRQoL¹². Additional treatment goals include controlling disease activity and joint pain, maintaining function in ADLs or work, slowing destructive joint changes, and delaying disability¹². The RA treatment landscape has changed significantly in the past decade with the introduction of new biologic therapies and additional options for treatment administration. Consequently, newer guidelines for RA have been created to incorporate newer biologics⁶. In addition, treatment guidelines now recommend the use of biologic disease-modifying anti-rheumatic drugs (DMARDs), if warranted, early in the treatment of RA⁶ to achieve treatment goals and desired outcomes.

While anti-CCP positivity has been established as a diagnostic factor for poor prognosis, studies assessing how this translates into patient management and outcomes are limited in the US. This study sheds some light on how anti-CCP positivity affects patients’ treatment for RA and healthcare resource utilization by comparing treatment patterns with DMARDs, RA-related healthcare utilization, and joint damage between patients who were anti-CCP antibody-positive vs those who were anti-CCP antibody-negative.

Methods

Study design

We conducted a retrospective study using administrative databases and electronic medical records (EMRs) from the Henry Ford Health System (HFHS). HFHS is a large, vertically integrated healthcare system in Detroit, MI. As a non-profit corporation consisting of Henry Ford Hospital, 30 medical centers, and more than 1,000 physicians in 40 medical specialties, HFHS provides care for ∼800,000 southeastern Michigan residents. The EMR database captures inpatient and ambulatory encounters within the HFHS, allowing for patients to be tracked across the continuum of care within the HFHS. Data captured in the database include patient demographics, inpatient encounters, outpatient and emergency department (ED) encounters, procedures, prescribed or ordered medications, laboratory data, clinical data, and charge data.

As detailed clinical and treatment data are not readily available in pre-defined fields in the administrative databases, a review of patients’ EMRs was conducted. For the review of patient records, a detailed chart abstraction form was developed to support the capture of data from the medical chart needed to address the study objectives. No protected health information was collected during the review. Before the study initiation, the protocol was approved by the Institutional Review Board at HFHS.

Patient population

Patients in the HFHS database from January 1, 2009 to December 30, 2014 were identified as eligible for the study if they had evidence of being newly-diagnosed with RA. RA diagnosis was determined by the presence of at least two medical records, at least 30 days apart, with an International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM) code for RA (714.0x). Evidence of RA diagnosis was also confirmed during the review of the EMR. The date of the first record of RA diagnosis served as the index date. Data from July 1, 2008 through December 31, 2014 was used to define the baseline period for patients, which included the 6-month period prior to the index date. Data from January 1, 2009 through June 30, 2015 was used to define follow-up period for patients, which included the 6-month period following the index date.

An anti-CCP antibody test either during the 6 months before or within 30 days following the index date was required. In addition, patients had to be at least 18 years old as of the index date and have continuous activity in the HFHS in the baseline period and in the follow-up period, with continuous activity defined as having at least one visit at the HFHS in the subsequent 6–12-month period.

Patients meeting any of the following criteria were excluded from the study cohort: diagnosis for any other conditions (Crohn’s disease, ulcerative colitis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, chronic lymphocytic leukemia, juvenile idiopathic arthritis, Wegener’s granulomatosis, non-Hodgkin’s lymphoma, and polyarteritis nodosa) treated with biologic DMARDs, as indicated on the label, at any time during the study period, receipt of any biologic DMARD during the baseline period, and RA diagnosis during the baseline period.

The resulting study population was stratified as the anti-CCP-positive or anti-CCP-negative cohorts based on the anti-CCP antibody test result identified during the 6 months before or within 30 days following the index date. When multiple tests are present during this period, the test closest to the index date was used.

Baseline characteristics

Patient demographics (age, gender, race, insurance type, and index year) were measured on the index date and clinical characteristics (Charlson comorbidity index [CCI] score, specific general comorbidities, extra-articular diseases, disease-related symptoms, and concomitant medications) were measured during the baseline period.

Outcomes

Treatment patterns with conventional and biologic DMARDs and treatment outcomes were identified from the chart review during the follow-up period. Specific measures evaluated were first-line treatment regimen, time to treatment initiation, treatment changes, and response to treatment. First-line therapy was defined as the first conventional or biologic DMARD prescribed or administered for patients during follow-up. Time to first-line therapy was defined as the time from the RA diagnosis to first RA treatment. Changes to the first-line therapy were defined as discontinuation of treatment, treatment switch, or augmentation of the treatment and were captured based on evidence of a prescription or administration of a new agent that was different from the first agent or physician notes. Discontinuation was defined based on physician note indicating that the patient discontinued therapy or lack of a subsequent prescription for the index drug or other DMARDs before the end of follow-up. Discontinuation of the index drug and addition of a new drug was considered a switch, while the addition of a new drug while continuing on the index drug was considered an augmentation. Response to treatment was based on information documented in physician notes. Since this information is not readily available in pre-defined fields in the administrative data, a review of the complete EMRs was conducted. This approach is valid, as this is based directly on the information documented by the treating physicians. Response to treatment was captured as remission, partial response, no response to treatment, other, or unknown.

RA-related healthcare utilization and laboratory testing (anti-CCP antibody, rheumatoid factor [RF], C-reactive protein [CRP], and erythrocyte sedimentation rate [ESR] tests) were evaluated during the follow-up period. Specifically, medical healthcare utilization related to RA was captured by setting of care: laboratory visits, hospitalizations, ED visits, physician office visits (rheumatologist and non-rheumatologist), and other outpatient visits. Laboratory visits for RF, CRP, and ESR testing were deemed RA-related laboratory visits. Positive or negative results for the last observed test during the follow-up period were also captured. For the RF test, 15 IU/mL was the threshold used to define a positive test and, for CRP, 0.5 mg/dL was the threshold used to define a positive test. The threshold used to define a positive test for ESR depended on the testing method and gender; for males it was >10 or >20 mm/h and for females it was >20 or >30 mm/h. Healthcare utilization in other settings of care was categorized as RA-related if an RA ICD-9-CM diagnosis code was recorded as the primary reason for the visit.

Evidence of joint erosion was identified from medical records and was determined based on physician note(s) from imaging data. Since this information is not readily available in pre-defined fields in the administrative data, a review of the complete EMRs was conducted to capture physicians’ interpretation of the imaging results. Evidence of swollen and tender joint(s) was also identified from the medical records and was determined based on physicians note(s) on patient visits.

Statistical analyses

All statistical analyses were conducted in SAS version 9.3, and 2-sided p-values <.05 were considered statistically significant.

Descriptive analyses

Descriptive statistics were presented for baseline characteristics, treatment patterns, healthcare utilization, joint erosion, and swollen and tender joints. Categorical measures were presented as the count and proportion of patients in each variable’s categories, while means, standard deviations (SDs), and medians (as appropriate) were reported for continuous variables. Statistically significant differences between the anti-CCP-positive and anti-CCP-negative patients were determined using Chi-square tests or Fisher's exact test for categorical variables and Student’s t-tests for continuous variables.

Multivariable analyses

The proportions of patients with and numbers of lab tests, outpatient physician office visits, and rheumatologist office visits were further evaluated in multivariable analyses. Since utilization in the other settings of care was not common, these outcomes were not evaluated in multivariable analyses. The multivariable analyses controlled for select patients’ demographics (age, gender, race), baseline comorbidities (CCI, joint pain, hypertension, dyslipidemia, diabetes, inflammatory back pain), and baseline medication use (glucocorticoids or analgesics).

The likelihood of having any laboratory, outpatient office, and rheumatologist visit was evaluated using multivariable logistic regression, with results presented as the adjusted proportions of patients with visits, mean differences, and 95% confidence intervals (CIs) around mean differences. The number of laboratory, outpatient office, and rheumatologist visits was evaluated using a 2-part model. The first part was a logit model estimating the probability of having ≥1 visit, and the second part was a negative binomial model estimating the number of visits among patients with ≥1 visit. Results were presented as the adjusted number of visits, mean differences, and 95% CIs around mean differences.

Results

Study population

The starting population included 7,683 patients, and a total of 1,980 patients remained after applying the study criteria. An additional 1,491 patients were excluded for not having a baseline anti-CCP antibody test. Following chart review, an additional 81 patients were excluded due to evidence of history of RA, prior treatment, and treatment outside of the study window. Ultimately, 191 (46.8%) patients who were anti-CCP-negative and 217 patients (53.2%) who were anti-CCP-positive (Figure 1) accounted for the 408 total patients with newly-diagnosed RA who were selected for the study.

Figure 1. Study attrition. Abbreviations. CCP, cyclic citrullinated peptide; DMARD, disease-modifying anti-rheumatic drug; HFHS, Henry Ford Health System; ICD-9-CM, International Classification of Diseases, 9th Revision, Clinical Modification; RA, rheumatoid arthritis.

Baseline characteristics

The mean age of the study population was 57.4 years, 79.2% were female, and the Health Alliance Plan was the health insurance payer for 35.5% of patients (Table 1). Mean CCI (SD) scores were similar between the anti-CCP-positive and anti-CCP-negative cohorts (0.5 [0.9] vs 0.3 [0.8]; p = .0790); however, there was a higher proportion of black patients in the anti-CCP-positive cohort vs the anti-CCP-negative cohort (41.9% vs 26.7%; p < .0001).

Table 1. Patient demographics and baseline clinical characteristics.

	All patients		Positive anti-CCP test		Negative anti-CCP test		p-value
	(n = 408)		(n = 217)		(n = 191)
Demographic characteristics
Age in years, mean (SD)	57.4	(15.8)	59.1	(14.8)	55.5	(16.7)	.0232*
Age group in years, n (%)
18–34	39	(9.6)	16	(7.4)	23	(12.0)	.2247
35–44	46	(11.3)	20	(9.2)	26	(13.6)
45–54	80	(19.6)	42	(19.4)	38	(19.9)
55–64	102	(25.0)	59	(27.2)	43	(22.5)
65+	141	(34.6)	80	(36.9)	61	(31.9)
Gender, n (%)
Female	323	(79.2)	166	(76.5)	157	(82.2)	.1571
Race, n (%)
White	198	(48.5)	89	(41.0)	109	(57.1)	<.0001*
Black	142	(34.8)	91	(41.9)	51	(26.7)
Hispanic	17	(4.2)	7	(3.2)	10	(5.2)
Asian	4	(1.0)	3	(1.4)	1	(0.5)
Other	4	(1.0)	2	(0.9)	2	(1.0)
Unknown	43	(10.5)	25	(11.5)	18	(9.4)
HAP insurance, n (%)
Yes	145	(35.5)	84	(38.7)	61	31.9)	.1538
No	263	(64.5)	133	(61.3)	130	68.1)
Index year, n (%)
2011	92	(22.5)	42	(19.4)	50	(26.2)	.0552
2012	98	(24.0)	55	(25.3)	43	(22.5)
2013	82	(20.1)	53	(24.4)	29	(15.2)
2014	136	(33.3)	67	(30.9)	69	(36.1)
Deyo-CCI score, mean (SD)	0.4	(0.9)	0.5	(0.9)	0.3	(0.8)	.0790
Deyo-CCI score, n (%)
0	311	(76.2)	157	(72.4)	154	(80.6)	.1161
1	64	(15.7)	38	(17.5)	26	(13.6)
≥2	33	(8.1)	22	(10.1)	11	(5.8)
Specific comorbidities and RA-related conditions
Joint pain	150	(36.8)	95	(43.8)	55	(28.8)	.0017*
Hypertension	107	(26.2)	55	(25.3)	52	(27.2)	.6667
Dyslipidemia	58	(14.2)	28	(12.9)	30	(15.7)	.4184
Diabetes	41	(10.0)	23	(10.6)	18	(9.4)	.6937
Inflammatory back pain	38	(9.3)	16	(7.4)	22	(11.5)	.1506
Chronic obstructive pulmonary disease/asthma	20	(4.9)	12	(5.5)	8	(4.2)	.5312
Joint swelling	11	(2.7)	9	(4.1)	2	(1.0)	.0537
Weakness	4	(1.0)	1	(0.5)	3	(1.6)	.2180
Enthesopathy	4	(1.0)	3	(1.4)	1	(0.5)	.2820
Pulmonary nodule	3	(0.7)	2	(0.9)	1	(0.5)	.3984
Vasculitis, other	2	(0.5)	2	(0.9)	0	(0.0)	.2823
Rheumatoid lung	1	(0.2)	0	(0.0)	1	(0.5)	.4681
Sjögren’s syndrome	1	(0.2)	0	(0.0)	1	(0.5)	.4681
Joint stiffness	1	(0.2)	1	(0.5)	0	(0.0)	.5319
Baseline medications
Glucocorticoids	170	(41.7)	111	(51.2)	59	(30.9)	<.0001*
NSAIDs	235	(57.6)	161	(74.2)	74	(38.7)	<.0001*
Other analgesics	197	(48.3)	125	(57.6)	72	(37.7)	<.0001*

Abbreviations. CCP, cyclic citrullinated peptide; CCI, Charlson comorbidity index; HFHS, Henry Ford Health System; NSAID, non-steroidal anti-inflammatory drug; SD, standard deviation.

* Statistical significance.

The most common comorbidities across both cohorts included joint pain (36.8%), hypertension (26.2%), dyslipidemia (14.2%), diabetes (10.0%), and inflammatory back pain (9.3%). Notably, the prevalence of joint pain was higher in the anti-CCP-positive cohort in comparison to the anti-CCP-negative cohort (43.8% vs 28.8%; p = .0017), although all other comorbidity prevalence rates were similar between cohorts.

More anti-CCP-positive patients used non-steroidal anti-inflammatory drugs, glucocorticoids, and other analgesics than anti-CCP-negative patients (74.2% vs 38.7%, p < .0001; 51.2% vs 30.9%, p < .0001; and 57.6% vs 37.7%, p < .0001, respectively).

Treatment patterns

A statistically significantly higher proportion of the anti-CCP-positive patients compared to the anti-CCP-negative patients was initiated on RA treatment (70.5% vs 23.0%; p < .0001) (Table 2). On average, patients initiated treatment within 1 month following diagnosis (anti-CCP-positive, mean SD: 31.1 [42.1] and anti-CCP-negative, 28.1 [37.4]; p = .6538).

Table 2. Treatment patterns.

	Total	Positive anti-CCP test	Negative anti-CCP test	p-value
	(n = 408)	(n = 217)	(n = 191)
First-line therapy
Proportion of treated patients, n (%)	97 (48.3)	153 (70.5)	44 (23.0)	<.0001*
Agents in the regimen, n (%)
Non-biologic DMARDs	94 (98.5)	150 (98.0)	44 (100.0)	.4664
Hydroxychloroquine	34 (17.3)	20 (13.1)	14 (31.8)	.0037*
Leflunomide	5 (2.5)	5 (3.3)	0 (0.0)	.2784
Methotrexate	137 (69.5)	112 (73.2)	25 (56.8)	.0374*
Minocycline	1 (0.5)	0 (0.0)	1 (2.3)	.2234
Sulfasalazine	11 (5.6)	7 (4.6)	4 (9.1)	.1407
Azathioprine	1 (0.5)	1 (0.7)	0 (0.0)	.7766
Hydroxychloroquine, methotrexate	3 (1.5)	3 (2.0)	0 (0.0)	.4664
Hydroxychloroquine, sulfasalazine	2 (1.0)	2 (1.3)	0 (0.0)	.6023
Biologic DMARDs	3 (1.5)	3 (2.0)	0 (0.0)
Adalimumab	1 (0.5)	1 (0.7)	0 (0.0)	.7766
Etanercept	1 (0.5)	1 (0.7)	0 (0.0)	.7766
Etanercept, methotrexate	1 (0.5)	1 (0.7)	0 (0.0)	.7766
Time to first-line treatment, days, mean (SD)	28.8 (38.4)	28.1 (37.4)	31.1 (42.1)	.6538
Type of treatment change^a, n (%)
Continuation/unknown	47 (74.6)	115 (75.2)	32 (72.7)	.0058*
Discontinuation	21 (10.7)	17 (11.1)	4 (9.1)
Switch	19 (9.6)	15 (9.8)	4 (9.1)
Augmentation	10 (5.1)	6 (3.9)	4 (9.1)
Time to treatment change, days, mean (SD)	83.4 (51.5)	83.8 (52.7)	82.0 (49.7)	.9178
Response to treatment, n (%)
Remission	43 (21.8)	35 (22.9)	8 (18.2)	.2444
Partial response	62 (31.5)	51 (33.3)	11 (25.0)
No response	25 (12.7)	21 (13.7)	4 (9.1)
Other/unknown	67 (34.0)	46 (30.1)	21 (47.7)

^a The response to treatment was defined based on physicians notes in the patients’ medical records.

Abbreviations. CCP, cyclic citrullinated peptide; DMARD, disease-modifying antirheumatic drug; SD, standard deviation.

* Statistical significance.

In first-line therapy, non-biologic DMARDs, predominantly methotrexate, were the most commonly used treatment. More anti-CCP-positive patients were prescribed methotrexate (73.2% vs 56.8%; p = .0374), while more anti-CCP-negative patients were prescribed hydroxychloroquine (31.8% vs 13.1%; p = .0037). Three anti-CCP-positive patients and no anti-CCP-negative patients were prescribed a biologic DMARD. Response to treatment did not differ significantly (p = .2444): 22.9% of anti-CCP-positive and 18.2% of anti-CCP-negative patients had a complete response to first-line therapy, and 33.3% of anti-CCP-positive and 25.0% of anti-CCP-negative patients had a partial response to first-line therapy. Treatment change significantly differed between the two cohorts (p = .0058): 11.1% and 9.1% discontinued and 13.7% and 18.2% switched/augmented in the anti-CCP-positive and anti-CCP-negative cohorts, respectively. Treatment changes occurred ∼3 months following treatment initiation (anti-CCP-positive, 83.8 [52.7] and anti-CCP-negative, 82.0 [49.7]; p = .9178).

RA-related healthcare utilization

Laboratory utilization differed between anti-CCP-positive and anti-CCP-negative cohorts (Table 3). Anti-CCP-positive patients were less likely to have laboratory testing performed compared to anti-CCP-negative patients (64.5% vs 78.0%; p = .0028). This was also indicated by the lower mean (SD) number of laboratory visits for anti-CCP-positive patients when compared to the anti-CCP-negative patients (3.5 [2.2] vs 4.2 [2.7]; p = .0140). After adjusting for baseline characteristics, overall laboratory utilizations were similar to the unadjusted results (Tables 4 and 5).

Table 3. RA-related healthcare utilization.

	All patients	Positive anti-CCP test	Negative anti-CCP test	p-value
	(n = 408)	(n = 217)	(n = 191)
Laboratory visits
Any RA-related tests
n (%) patients	289 (70.8)	140 (64.5)	149 (78.0)	.0028*
Mean (SD) # of tests	3.9 (2.5)	3.5 (2.2)	4.2 (2.7)	.0140*
RF
n (%) patients	131 (32.1)	32 (14.7)	99 (51.8)	<.0001*
Mean (SD) # of tests	1.1 (0.3)	1.0 (0.2)	1.1 (0.4)	.3092
CRP
n (%) patients	235 (57.6)	119 (54.8)	116 (60.7)	.2293
Mean (SD) # of tests	1.7 (1.2)	1.7 (1.1)	1.7 (1.3)	.9565
ESR
n (%) patients	220 (53.9)	105 (48.4)	115 (60.2)	.0168*
Mean (SD) # of tests	1.7 (1.1)	1.7 (1.0)	1.7 (1.2)	.8682
Outpatient physician office visits
n (%) patients	357 (87.5)	209 (96.3)	148 (77.5)	<.0001*
Mean (SD) # of visits	4.1 (3.2)	5.3 (3.2)	2.5 (2.4)	<.0001*
Outpatient rheumatologist office visits
n (%) patients	315 (77.2)	203 (93.5)	112 (58.6)	<.0001*
Mean (SD) # of visits	3.7 (2.7)	4.5 (2.6)	2.3 (2.1)	<.0001*
Outpatient non-rheumatologist office visits
n (%) patients	152 (37.3)	91 (41.9)	61 (31.9)	.0371*
Mean (SD) # of visits	2.1 (1.6)	2.2 (1.2)	1.9 (2.0)	.1799
Outpatient primary care physician office visits
n (%) patients	52 (12.7)	35 (16.1)	17 (8.9)	.0289*
Mean (SD) # of visits	1.6 (0.9)	1.6 (1.0)	1.5 (0.7)	.7922
Occupational therapist/physiotherapist visits
n (%) patients	0 (0.0)	0 (0.0)	0 (0.0)	NA
Mean (SD) # of visits	0 (0.0)	0 (0.0)	0 (0.0)	NA
Other specialist visits
n (%) patients	115 (28.2)	71 (32.7)	44 (23.0)	.0301*
Mean (SD) # of visits	2.0 (1.7)	2.1 (1.1)	2.0 (2.3)	.7743
RA-related surgery
n (%) patients	0 (0.0)	0 (0.0)	0 (0.0)	NA
Mean (SD) # of visits	0 (0.0)	0 (0.0)	0 (0.0)	NA
Other outpatient services visits
n (%) patients	11 (2.7)	6 (2.8)	5 (2.6)	.9270
Mean (SD) # of visits	3.1 (3.3)	4.5 (4.0)	1.4 (0.5)	.1195
Hospitalization
n (%) of patients	2 (0.5)	1 (0.5)	1 (0.5)	.4992
Mean (SD) # of visits	1 (NA)	1.0 (NA)	1.0 (NA)	NA
Mean (SD) length of stay	3.5 (2.1)	5.0 (NA)	2.0 (NA)	NA
ED visits
n (%) of patients	4 (1.0)	3 (1.4)	1 (0.5)	.2820
Mean (SD) # of visits	1.3 (0.5)	1.3 (0.6)	1.0 (NA)	.6667

Abbreviations. CCP, cyclic citrullinated peptide; CRP, C-reactive protein; ED, emergency department; ESR, erythrocyte sedimentation rate; NA, not applicable; RA, rheumatoid arthritis; RF, rheumatoid factor; SD, standard deviation.

* Statistical significance.

Table 4. Adjusted^a proportion of visits.

	Positive anti-CCP test	Negative anti-CCP test	Difference	95% LCI	95% UCI
Lab visits, %	66.36	76.39	–10.03	–21.40	–0.23
Outpatient office visits, %	95.48	81.01	14.47	9.17	17.01
Outpatient rheumatologist office visits, %	91.87	64.10	27.77	21.58	31.47

^a The logistic regression model controlled for age, gender, race, Deyo-Charlson comorbidity index, joint pain, hypertension, dyslipidemia, diabetes, inflammatory back pain, glucocorticoid use, and analgesic use.

Abbreviations. CCP, cyclic citrullinated peptide; LCI, lower confidence interval; UCI, upper confidence interval.

Table 5. Adjusted^a mean number of visits.

	Positive anti-CCP test	Negative anti-CCP test	Difference	95% LCI	95% UCI
Lab visits	2.30	3.28	–0.99	–1.31	–0.61
Outpatient office visits	4.86	2.15	2.70	1.99	3.54
Outpatient rheumatologist office visits	3.96	1.56	2.40	1.79	3.12

^a The zero-inflated negative binomial model controlled for age, gender, race, Deyo-Charlson comorbidity index, joint pain, hypertension, dyslipidemia, diabetes, inflammatory back pain, glucocorticoid use, and analgesic use.

Abbreviations. CCP, cyclic citrullinated peptide; LCI, lower confidence interval; UCI, upper confidence interval.

Overall, the anti-CCP-negative cohort had a higher proportion of patients tested for RF (51.8% vs 14.7%; p < .0001) and ESR (60.2% vs 48.4%; p = .0168), although the proportion tested for CRP was similar between cohorts (60.7% vs 54.8%, p = .2293) (Table 2). The mean (SD) numbers of RF (1.1 [0.4] vs 1.0 [0.2]; p = .3092), CRP (1.7 [1.3] vs 1.7 [1.1]; p = .9565), and ESR (1.7 [1.2] vs 1.7 [1.0]; p = .8682) tests were similar between the cohorts. Of the patients tested for RF, anti-CCP-positive patients were significantly more likely to test positive for RF (84.4% vs 18.2%, p < .0001) (Figure 2). Of the patients tested for CRP and ESR, anti-CCP-positive patients were more likely to have positive test results (69.7% vs 48.3%, p = .0008 and 89.5% vs 53.9%, p < .0001, respectively) (Figure 2).

Figure 2. RA-related laboratory test results. Abbreviations. CCP, cyclic citrullinated peptide; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate; RA, rheumatoid arthritis; RF, rheumatoid factor.

Healthcare visits associated with RA occurred primarily in the outpatient setting, and differences were observed between the cohorts (Table 3). The proportion of patients with any outpatient physician office visit and the mean (SD) number of visits were higher in the anti-CCP-positive cohort compared with the anti-CCP-negative cohort (96.3% vs 77.5%, p < .0001 and 5.3 [3.2] vs 2.5 [2.4], p < .0001, respectively). After adjusting for baseline characteristics, utilization in the outpatient physician office was similar to the unadjusted results (Tables 4 and 5).

Most outpatient visits were to a rheumatologist. The proportion of patients with a rheumatologist visit and the mean (SD) number of visits to a rheumatologist were significantly higher in the anti-CCP-positive cohort compared with the anti-CCP-negative cohort (93.5% vs 58.6%, p < .0001 and 4.5 [2.6] vs 2.3 [2.1], p < .0001, respectively) (Table 3). The adjusted proportion of anti-CCP-positive patients with a rheumatologist visit and the adjusted mean number of visits to a rheumatologist maintained a similar trend, with the anti-CCP-positive cohort having greater utilization than the anti-CCP-negative cohort (Tables 4 and 5).

The number of patients with an outpatient non-rheumatologist office visit was higher in the anti-CCP-positive cohort than the anti-CCP-negative cohort (41.9% vs 31.9%, p = .0371); however, the mean number of outpatient non-rheumatologist visits was similar between cohorts (2.2 [1.2] vs 1.9 [2.0], p = .1799) (Table 3). Of the non-rheumatologist office visits, a higher number of anti-CCP-positive patients had outpatient primary care physician office visits and other specialist visits than anti-CCP-negative patients (16.1% vs 8.9%, p = .0289 and 32.7% vs 23.0%, p = .0301, respectively) (Table 3). The mean number of visits to outpatient primary care physicians and other specialists, however, did not differ between anti-CCP-positive and anti-CCP-negative cohorts (1.6 [1.0] vs 1.5 [0.7], p = .7922 and 2.1 [1.1] vs 2.0 [2.3], p = .7743, respectively) (Table 3). Almost none of the anti-CCP-positive and anti-CCP-negative patients had a hospitalization or ED visit related to RA (Table 3).

Disease-related outcomes

Imaging results were available for 52.1% of the anti-CCP-positive cohort and 30.4% of the anti-CCP-negative cohort (p < .0001) (Table 6). Among those with imaging results, a higher proportion of anti-CCP-positive patients had evidence of erosion compared to anti-CCP-negative patients (18.6% vs 8.6%, p = .0858), but statistical significance was not reached. Also, a higher proportion of anti-CCP-positive patients compared to anti-CCP-negative patients reported tender joints (61.3% vs 24.6%, p < .0001) and swollen joints (62.7% vs 26.2%, p < .0001) (Table 6). In both cohorts, the finger and wrist joints were the most commonly affected joints.

Table 6. Disease activity and joint erosion.

	Total		Positive anti-CCP test		Negative anti-CCP test		p-value
	(n = 408)		(n = 217)		(n = 191)
w/imaging results	171	(41.9)	113	(52.1)	58	(30.4)	<.0001*
w/erosion	26	(15.2)	21	(18.6)	5	(8.6)	.0858
w/tender joint
Any	180	(44.1)	133	(61.3)	47	(24.6)	<.0001*
Joint, finger	106	(26.0)	85	(39.2)	21	(11.0)
Wrist, right	63	(15.4)	48	(22.1)	15	(7.9)
Wrist, left	58	(14.2)	46	(21.2)	12	(6.3)
Joint, toe	35	(8.6)	32	(14.7)	3	(1.6)
Ankle, right	30	(7.4)	22	(10.1)	8	(4.2)
Ankle, left	28	(6.9)	22	(10.1)	6	(3.1)
Knee, left	22	(5.4)	16	(7.4)	6	(3.1)
Elbow, right	19	(4.7)	16	(7.4)	3	(1.6)
Knee, right	19	(4.7)	14	(6.5)	5	(2.6)
Elbow, left	17	(4.2)	13	(6.0)	4	(2.1)
Shoulder, right	17	(4.2)	12	(5.5)	5	(2.6)
Shoulder, left	16	(3.9)	11	(5.1)	5	(2.6)
Spine	14	(3.4)	9	(4.1)	5	(2.6)
Hip, left	5	(1.2)	3	(1.4)	2	(1.0)
Hip, right	5	(1.2)	2	(0.9)	3	(1.6)
w/swollen joint
Any	186	(45.6)	136	(62.7)	50	(26.2)	<.0001*
Joint, finger	119	(29.2)	90	(41.5)	29	(15.2)
Wrist, left	75	(18.4)	60	(27.6)	15	(7.9)
Wrist, right	70	(17.2)	55	(25.3)	15	(7.9)
Ankle, right	40	(9.8)	26	(12.0)	14	(7.3)
Ankle, left	38	(9.3)	26	(12.0)	12	(6.3)
Knee, left	25	(6.1)	19	(8.8)	6	(3.1)
Knee, right	24	(5.9)	18	(8.3)	6	(3.1)
Elbow, left	21	(5.1)	19	(8.8)	2	(1.0)
Elbow, right	17	(4.2)	11	(5.1)	6	(3.1)
Joint, toe	14	(3.4)	11	(5.1)	3	(1.6)
Shoulder, right	2	(0.5)	2	(0.9)	0	(0.0)
Shoulder, left	1	(0.2)	1	(0.5)	0	(0.0)
Hip, left	0	(0.0)	0	(0.0)	0	(0.0)
Hip, right	0	(0.0)	0	(0.0)	0	(0.0)
Spine	0	(0.0)	0	(0.0)	0	(0.0)

Abbreviations. CCP, cyclic citrullinated peptide.

* Statistical significance.

Discussion

Our findings reveal differences in treatment and healthcare utilization patterns for RA management between anti-CCP-positive and anti-CCP-negative patients. A significantly higher proportion of anti-CCP-positive patients initiated treatment compared to anti-CCP-negative patients, likely indicating a higher severity of disease in these patients. This shows that physicians are more aggressive in their management of anti-CCP-positive patients as it relates to treatment initiation. It is also interesting to note that anti-CCP-positive patients were significantly older and race also differed significantly when compared to the anti-CCP-negative patients. To the best of our knowledge, no US study has evaluated the association between age or race and anti-CCP antibodies. One study in Chinese rheumatoid arthritis patients evaluated differences in age and anti-CCP antibody status. In this study, similar proportions of patients in the 16–40, 41–60, and >60-year age groups had positive anti-CCP antibodies¹³.

In accordance with ACR guidelines for RA¹⁴, first-line treatments for patients with RA in this study were mostly non-biologic DMARDs. The findings of this study also revealed that treatment with methotrexate was more common among anti-CCP-positive patients, while hydroxychloroquine was more common among anti-CCP-negative patients. In patients who have never taken a DMARD, methotrexate is preferred as DMARD monotherapy¹², thus it is not surprising that the majority of patients were treated with methotrexate as first-line therapy. Further, hydroxychloroquine requires less monitoring after baseline than methotrexate; thus, clinicians may have chosen hydroxychloroquine as first-line therapy in anti-CCP-negative patients for monitoring convenience and better adverse event profiles than methotrexate¹².

In first-line therapy, response to treatment did not differ significantly between the anti-CCP-positive and anti-CCP-negative patients, although about half of treated patients had either recorded complete or partial responses. However, treatment change following first-line therapy differed between the two cohorts, with a higher proportion of anti-CCP-positive patients discontinuing their treatment and a higher proportion of anti-CCP-negative patients augmenting their treatment. Studies evaluating treatment patterns and treatment response by anti-CCP serostatus have mainly focused on treatment with biologics. Since early treatment was captured in the current study, only a few patients initiated treatment with biologic DMARDs. In studies evaluating response to treatment with biologic DMARDs, some biologics have been reported to be more effective in patients with positive anti-CCP antibodies. In a recent exploratory analysis, both adalimumab and abatacept were more effective in patients who were anti-CCP2-positive than in those who were anti-CCP2-negative at baseline¹⁵. However, differences were observed in the response patterns to both treatments when assessed by baseline antibody concentration. The effect of abatacept treatment was more notable in the higher anti-CCP2 quartile than in lower quartiles, while the effect of adalimumab was similar across all anti-CCP2 quartiles¹⁵. A real-world study also reported that anti-CCP positivity predicted better efficacy with abatacept, independent from disease activity¹⁶. Similar results have also been observed in other studies, which identified positive anti-CCP antibodies or RF as predictors for EULAR response following treatment with rituximab^17,18.

More patients in the anti-CCP-negative cohort had RA-related laboratory tests compared to the anti-CCP-positive cohort. Since positive anti-CCP antibodies are highly predictive of a poor RA prognosis, other RA-related tests that can indicate inflammation and disease activity level are likely not performed as frequently in patients with positive anti-CCP antibodies. Physicians might repeat RA-related laboratory measures more frequently in those with negative anti-CCP antibodies to identify other indications of an aggressive disease being present. This premise is supported by our results indicating that anti-CCP-negative patients averaged significantly more RA-related laboratory measures over their follow-up than anti-CCP-positive patients.

Among the anti-CCP-positive patients tested for RA-related laboratory measures, the rates of positive RF, ESR, and CRP results were significantly higher than the anti-CCP-negative cohort. This indicates a higher degree of inflammation and disease activity among patients in the anti-CCP-positive cohort, which likely contributed to the higher RA-related healthcare utilization observed in other settings of care. The anti-CCP-positive cohort also had more patients with outpatient visits in general, and also outpatient visits to rheumatologists, and at a greater frequency than the anti-CCP-negative cohort.

Anti-CCP-positive patients had a higher proportion of patients with joint erosion, although statistical significance was not reached, likely due to the sample size. In addition, rates of tender and swollen joints were significantly higher in anti-CCP-positive patients. Joint damage, especially articular erosion, is an important outcome in RA¹⁰. Studies have evaluated the association between anti-CCP antibodies and joint erosion, and a recent meta-analysis showed antibodies to citrullinated peptide antigens to be a strong predictor of joint erosion in RA¹⁰. Another study reported that the presence of anti-CCP antibodies and RF shows an additive effect on erosion number and erosion size¹⁹.

Some study limitations should be noted. The data were collected only from the HFHS, and services provided outside of the HFHS are not captured. Clinical practice within the HFHS may not be generalizable to that of other health systems or providers. The population was not geographically diverse, as the HFHS EMR database captures data on patients in the Detroit area only; as a result, findings may not be generalizable to other populations. The post-index period for the outcome assessment was 6 months; therefore, outcomes that will likely become more prevalent later in the disease were not observed. Also, a follow-up period of 6 months may not be long enough to assess response to treatment(s) and progression(s) to subsequent lines of therapy.

Conclusion

As noted previously, positive anti-CCP antibodies appear to correlate with greater damage due to RA⁵. Consistently, our study showed that patients with positive anti-CCP antibodies had laboratory results indicative of higher inflammation and disease activity, imaging results demonstrating increased proportions of joint erosion, and increased documentation of joint swelling and tenderness. Anti-CCP-positive patients were more likely to be initiated on treatment following RA diagnosis, indicating that physicians are more aggressive in treating this cohort. The severity of disease, symptoms, and early initiation of treatment that requires more monitoring likely contributed to the higher healthcare utilization in the outpatient office setting among patients with positive anti-CCP antibodies.

Transparency

Declaration of funding

This study was funded by Bristol-Myers Squibb. Xcenda, LLC received funding from Bristol-Myers Squibb to conduct this study and develop the manuscript. Henry Ford Health System received research funding from Xcenda, LLC.

Declaration of financial/other relationships

KP, AS, and HA are employees of Bristol-Myers Squibb. AO, HCS, and ME are employees of Xcenda, LLC. LL is an employee of Henry Ford Health System and the University of Michigan-Dearborn and received research funding from Xcenda, LLC. Peer reviewers on this manuscript have received an honorarium from JME for their review work, but have no other relevant financial relationships to disclose.

Acknowledgments

Kimberly Gittings of Xcenda, LLC, assisted in the preparation of this manuscript.