Abstract
Objective:
To assess changes in the cumulative incidence of extraarticular manifestations of rheumatoid arthritis (ExRA) and associated mortality risk.
Methods:
This study evaluated trends in occurrence of ExRA using a population-based inception cohort that included all adult patients with incident RA from 1985 through 2014 meeting the 1987 American College of Rheumatology criteria. Patients were divided into two cohorts based on the incidence date of RA, 1985-1999 and 2000-2014. The occurrence of ExRA was determined by manual chart review, and the 10-year cumulative incidence was estimated for each ExRA in both cohorts. Cox proportional hazard models were used to determine associations between specific demographic and RA disease characteristics and ExRA and between ExRA and mortality.
Results:
There were 907 patients included, 296 in the 1985-1999 cohort and 611 in the 2000-2014 cohort. The 10-year cumulative incidence of any ExRA decreased significantly between the earlier and later cohorts (45.1% vs 31.6%, p<0.001). This was largely driven by significant declines in subcutaneous rheumatoid nodules (30.9% vs 15.8%, p<0.001) and non-severe ExRA (41.4% vs 28.8%, p=0.001). Identified risk factors for the development of any ExRA include RF positivity (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.43-2.86) and current smoking (HR 1.61, 95% CI 1.10-2.34). Mortality was increased in patients with either non-severe (HR 1.83, 95% CI 1.18-2.85) or severe ExRA (HR 3.05, 95% CI 1.44-6.49).
Conclusions:
The incidence of ExRA have decreased over time. Mortality remains increased in patients with ExRA.
INTRODUCTION
Rheumatoid arthritis (RA) is a systemic inflammatory disease that can manifest as both inflammatory arthritis and extraarticular organ involvement. Extraarticular manifestations of RA (ExRA) historically occur in over 50% of patients and include both non-severe manifestations like rheumatoid nodules, as well as severe manifestations, such as rheumatoid vasculitis [1–3]. The development of ExRA is of significant concern for healthcare providers due to the resulting morbidity and association with premature mortality [1,4–6].
The development of ExRA is classically associated with seropositive status and high disease activity [1,7–9]. Notable changes have occurred in both the epidemiology and management of RA in recent years that may directly affect the incidence of ExRA. First, there has been a significant decrease in the incidence of seropositive RA with a concomitant increase in seronegative RA [10–11]. Second, over the last two and a half decades, several novel therapies have been introduced into routine clinical practice. Third, clinical guidelines have shifted recommendations encouraging clinicians to incorporate a “treat-to-target” strategy utilizing clinical disease activity measures to monitor response to treatment [12–14]. Fourth, guidelines have recommended treating RA at an earlier stage with disease-modifying antirheumatic drugs (DMARDs) to prevent permanent joint damage and alter the course of the disease to increase rates of remission and low disease activity [15–16]. Fifth, the use of advanced imaging has become increasingly common in early diagnosis and management [17–18]. Overall, these major advances in management of RA have resulted in improved control of RA disease activity.
It is unknown how the incidence of ExRA have changed given the new landscape of RA epidemiology and shifting management paradigms. The most recent epidemiology study of ExRA to analyze changes in incidence over time included patient follow up until 2008 [1]. Although this study did not reveal significant changes in overall ExRA incidence, this study and others have indicated that the incidence of some severe ExRA appear to be declining in recent decades [1,19,24–25].
Patients with RA have a higher mortality rate compared to those without RA [26–28]. This disparity is further accentuated among those with ExRA [1,4]. Given the epidemiologic and management changes in RA, it is unclear if the mortality gap between those with and without ExRA remains, especially considering the potentially shrinking gap in mortality rates as assessed between RA and non-RA matched cohorts [28].
The primary objective of this study was to determine changes in ExRA incidence over time using a population-based inception cohort. We also sought to determine if patients with ExRA are at increased risk of mortality compared to patients without ExRA. We hypothesized that the incidence of ExRA is declining in recent years, while mortality rates remain elevated in those with ExRA.
PATIENTS AND METHODS
Study Setting
This was a retrospective, observational, population-based cohort study that utilized an inception cohort of patients with RA who have lived in Olmsted County, Minnesota. Due to the availability of outpatient and inpatient medical records for several decades through the Rochester Epidemiology Project (REP), Olmsted County is well positioned for epidemiologic studies [29–30]. The REP is a medical record linkage system that incorporates medical records from varying healthcare providers throughout Olmsted County. Because of the comprehensive nature of the REP, there is almost complete ascertainment of incident cases of RA in Olmsted County. Additionally, through the resources of the REP, an inception cohort of patients with RA has been created and continually updated. This is the only such population-based, longitudinal RA inception cohort in the USA. The methods of inclusion and review of this inception cohort have been reviewed elsewhere [10].
Study population and data collection
For inclusion into the study, patients were required to meet the 1987 American College of Rheumatology (ACR) criteria for RA and were ≥18 years of age [31]. The incidence date of RA was defined as the date at which ≥4 of the 1987 ACR criteria for RA were met. Patients living in Rochester, Minnesota, between 1/1/1985 and 12/31/1994, and patients living in Olmsted County between 1/1/1995 and 12/31/2014 who met these criteria were included in this study. About 65-70% of the Olmsted County population during the 1985-1994 period lived in the city of Rochester.
Patients were then grouped into two cohorts based on the incidence date of RA, an earlier cohort between 1985-1999 and a later cohort between 2000-2014. The year 2000 was chosen a priori as the transition point between cohorts given the significant management and epidemiologic changes occurring in RA around that time and the hypothesized reduction in ExRA that would result. Patients were followed until the earlier of death, migration from the region, or 12/31/2000 (for patients with incident RA from 1985-1994), 12/31/2008 (for patients with incident RA from 1995-2007), or 10/15/2022 (for patients with incident RA from 2008-2014).
Individual patient data were obtained through manual chart review for the presence of 19 individual ExRA. Inclusion criteria for ExRA remain unchanged from our prior ExRA epidemiologic studies (supplemental table 1) [1–2,23]. Each was classified as either severe or non-severe based on the Malmö Criteria.[2] The incidence date of each ExRA was abstracted manually from patient medical records. Data on ExRA incidence among patients with RA between 1985-2007 were previously collected and included in prior ExRA epidemiology publications [1–2,23]. All chart abstraction data included in this study utilized the same comprehensive ExRA list and criteria. To ensure consistency in data collection across the study period, 25 incident cases between 2008-2014 were reviewed simultaneously by BK and the principal investigator (EM), who previously collected the 1995-2007 incident RA data. An additional 25 cases from the previously published data (1985-2007) were reviewed again by BK to further ensure consistency in data collection over time. All questions regarding patient data collection were reviewed by EM.
Demographic, laboratory, and RA specific data is updated continuously by nurse abstractors for all patients with RA in the inception cohort. RA disease specific data includes seropositivity, medications stratified by class, and the absence or presence of periarticular erosions. Vital status is routinely collected by the REP. This study was approved by the institutional review boards of Mayo Clinic (IRB #17-002593) and Olmsted Medical Center (IRB #017-OMC-17). The need for informed consent was waived. Patients who declined the use of their medical records for research purposes were not included in the study, per Minnesota law. This manuscript follows the Strengthening the Reporting of Observational studies in Epidemiology (STROBE) reporting guidelines for observational studies [32].
Statistical methods
Descriptive statistics were used to summarize demographic and basic RA data. Chi-square and rank sum tests were used to compare demographic and RA specific disease characteristics between the cohorts. The cumulative incidence of any ExRA, adjusted for the competing risk of death, was estimated in each cohort (1985-1999 and 2000-2014) using Aalen-Johansen methods. The cumulative incidence of severe and non-severe ExRA as well as specific ExRA in each cohort were also assessed by this method. Non-linear time trends were examined using smoothing splines. Associations between specific demographic and RA disease data with severe ExRA, non-severe ExRA, and rheumatoid nodules were determined in the 2000-2014 time period using Cox proportional hazard models adjusting for age and sex. Models for the maximum erythrocyte sedimentation rate (ESR) in the first year and erosions in the first year were performed using the time since 1 year after RA incidence. Medications were modeled using time-dependent covariates for exposure that counted patients as unexposed prior to first medication exposure and as exposed thereafter.
Associations between ExRA and mortality were examined using Cox models with time-dependent covariates. The two-way interaction between ExRA and time period was used to assess the diminishing effect of ExRA on mortality over time. Analyses were performed using SAS version 9.4 (SAS Institute, Cary, NC, USA) and R 4.1.2 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
Patient characteristics
This study included 907 patients, 296 patients (67% female) with incident RA between 1985-1999 and 611 patients (70% female) from 2000-2014. The earlier cohort had an average age of 57.6 years at diagnosis with a median follow up of 9.5 years (interquartile range [IQR] 6.7-12.0) compared with the later cohort that had an average age of 55.3 years with a median follow up of 7.4 years (IQR 4-10.3 years). Rheumatoid factor (RF) was present in 70% of patients in the earlier cohort and 58% in the later cohort. The percentage of patients treated with a biologic DMARD (bDMARD) within the first year of RA diagnosis increased from 1% to 11% in the later cohort. The baseline characteristics of each cohort are shown in table 1.
Table 1.
Baseline demographics, clinical characteristics, and comorbidities
| Period of RA Incidence | |||
|---|---|---|---|
|
| |||
| Variable | 1985-1999 (N=296) |
2000-2014 (N=611) |
Total (N=907) |
| Age (mean ± SD), years | 57.6 ± 16.03 | 55.3 ± 15.27 | 56.1 ± 15.55 |
| Female sex, n (%) | 198 (67%) | 430 (70%) | 628 (69%) |
| Follow up, years (SD) | 9.1 (3.61) | 7.4 (4.06) | 7.9 (4.00) |
| RF positive, n (%) | 208 (70%) | 349 (58%) | 557 (62%) |
| Percent tested for RF | 100% | 98% | 99% |
| Cigarette smoking, n (%) | |||
| Never | 127 (43%) | 326 (53%) | 453 (50%) |
| Former | 113 (38%) | 187 (31%) | 300 (33%) |
| Current | 56 (19%) | 98 (16%) | 154 (17%) |
| Obesity (body mass index ≥30 kg/m2), n (%) | 76 (26%) | 247 (40%) | 323 (36%) |
| Periarticular erosions, n (%) | |||
| In the 1st year after RA diagnosis | 70 (24%) | 175 (29%) | 245 (27%) |
| Percent with radiographs | 93% | 95% | 94% |
| Highest ESR in the 1st year after RA incidence, mm/h (SD) | 32.9 (25.2) | 30.1 (24.7) | 31.0 (24.9) |
| Medication exposure in the first year after RA incidence, n (%) | |||
| Methotrexate | 73 (25%) | 319 (52%) | 392 (43%) |
| Other DMARDs | 173 (58%) | 286 (47%) | 459 (51%) |
| Gold | 30 (10%) | 0 | 30 (3%) |
| Sulfasalazine | 23 (8%) | 43 (7%) | 66 (7%) |
| Hydroxychloroquine | 116 (39%) | 248 (41%) | 364 (40%) |
| Azathioprine | 4 (1%) | 4 (1%) | 8 (1%) |
| Cyclophosphamide | 0 | 2 (1%) | 2(1%) |
| Leflunomide | 3 (1%) | 23 (4%) | 26 (3%) |
| bDMARD | 4 (1%) | 68 (11%) | 72 (8%) |
| Glucocorticoids | 161 (54%) | 328 (54%) | 489 (54%) |
Abbreviations: RA = rheumatoid arthritis; SD = standard deviation; RF = rheumatoid factor; ESR = erythrocyte sedimentation rate; DMARDs = disease modifying antirheumatic drugs; bDMARDs = biologic disease modifying antirheumatic drugs
Incidence of ExRA
Table 2 shows the 10-year cumulative incidence of ExRA. The 10-year cumulative incidence of developing any ExRA decreased between the 1985-1999 and the 2000-2014 cohorts (45.1% vs. 31.6%). This represents a 35% reduction (age- and sex-adjusted hazard ratio [HR]: 0.65; 95% confidence interval [CI]: 0.51-0.82). Additional adjustment for RF and current smoking had little impact on this association (HR: 0.69; 95% CI: 0.52-0.91). This coincided with a reduction in non-severe ExRA in the later cohort (10-year cumulative incidence 41.4% vs. 28.8%). The 10-year cumulative incidence of severe ExRA was 7.1% in the earlier cohort and 6.0% in the later cohort, though this 28% reduction was not statistically significant (age- and sex-adjusted HR: 0.72; 95% CI: 0.40-1.29; age-, sex-, RF- and current smoking-adjusted HR: 0.83;95% CI: 0.39-1.76). Figure 1 demonstrates the changing risk of developing any ExRA over time and shows a precipitous decline in risk among patients with incident RA starting in 2005.
Table 2.
Cumulative incidence of extraarticular rheumatoid arthritis at 10-year follow up
| Period of RA Incidence | |||||
|---|---|---|---|---|---|
|
| |||||
| 1985-1999 (n = 296) | 2000-2014 (n = 611) | ||||
|
| |||||
| Extraarticular Manifestations* | Number of Events | 10-year Cumulative Incidence %, (95% CI) | Number of Events | 10-year Cumulative Incidence %, (95% CI) | HR for time period (95% CI)** |
| Any ExRA | 138 | 45.1 (39.4, 51.6) | 201 | 31.6 (27.3, 36.5) | 0.65 (0.51, 0.82) |
| Severe ExRA | 23 | 7.1 (4.7, 10.9) | 33 | 6 (3.8, 9.3) | 0.72 (0.40, 1.29) |
| Pericarditis | 5 | 2 (0.8, 4.7) | 10 | 2.2 (1.0, 4.6) | 1.09 (0.36, 3.29) |
| Pleuritis | 7 | 2.1 (1.0, 4.8) | 7 | 0.7 (0.03, 1.9) | 0.51 (0.15, 1.68) |
| Felty’s syndrome | 2 | 0.7 (0.2, 2.7) | 0 | 0 | -- |
| Vasculitis¥ | 5 | 1.8 (0.7, 4.2) | 2 | 0.4 (0.1, 1.8) | -- |
| Neuropathy | 5 | 1.4 (0.5, 3.6) | 8 | 0.8 (0.3, 2.4) | 0.65 (0.19, 2.28) |
| Scleritis | 0 | 0 | 3 | 1.4 (0.5, 4.5) | -- |
| Episcleritis | 2 | 0.3 (0.05, 2.4) | 6 | 0.6 (0.1, 2.4) | -- |
| Other ExRA | 119 | 41.4 (35.9, 47.9) | 151 | 28.8 (24.8, 33.5) | 0.67 (0.53, 0.86) |
| Keratoconjunctivitis sicca | 49 | 15.8 (11.9, 20.9) | 86 | 14.8 (11.5, 19.1) | 0.90 (0.62, 1.31) |
| Xerostomia | 1 | 0.3 (0.05, 2.4) | 19 | 3.6 (2.1, 6.3) | -- |
| Sjogren’s syndrome | 32 | 10.1 (7.1, 14.3) | 47 | 8.2 (5.7, 11.7) | 0.70 (0.44, 1.13) |
| Pulmonary fibrosis | 15 | 5.2 (3.1, 8.7) | 20 | 2.8 (1.7, 4.8) | 0.62 (0.30, 1.31) |
| Bronchiolitis obliterans | 2 | 0.7 (0.2, 3.0) | 1 | 0.2 (0.02, 1.2) | -- |
| Organizing pneumonia | 2 | 0.3 (0.05, 2.4) | 2 | 0.3 (0.09, 1.4) | -- |
| Cervical myelopathy | 4 | 1.4 (0.5, 3.8) | 1 | 0.2 (0.03, 1.6) | -- |
| Subcutaneous nodules | 90 | 30.9 (25.8, 37.1) | 94 | 15.8 (12.9, 19.4) | 0.52 (0.39, 0.70) |
| Other nodules | 0 | 0 | 9 | 1.2 (0.5, 3.0) | -- |
Abbreviations: ExRA = extraarticular manifestation of rheumatoid arthritis, HR = hazard ratio; RA = rheumatoid arthritis, CI = confidence interval.
HR reaching statistical significance in bold.
There were no cases of retinal vasculitis, glomerulonephritis, or amyloidosis in either cohort;
Adjusted for age and sex. Must have at least 5 events in each group;
Included major cutaneous and internal organ vasculitis
Figure 1. Risk of developing any extraarticular manifestation of rheumatoid arthritis based on year of rheumatoid arthritis incidence.
Figure demonstrating the changing hazard ratios (solid black line) and associated 95% confidence intervals (dotted lines) for the development of any extraarticular manifestation of rheumatoid arthritis as a linear trend based on year of rheumatoid arthritis incidence.
The most common ExRA was the subcutaneous rheumatoid nodule, which substantially decreased over time. The 10-year cumulative incidence of subcutaneous rheumatoid nodules in the first cohort was 30.9% compared to 15.8% in the second cohort (age- and sex-adjusted HR: 0.52, 95% CI: 0.39-0.70). Additionally, adjusting for RF and current smoking slightly attenuated this result (HR: 0.60; 95% CI: 0.42-0.86). There was a general trend of decline in several ExRA that were not statistically significant. No ExRA had a statistically significant increase over time. There were no cases of retinal vasculitis, glomerulonephritis, or amyloidosis in either cohort.
Mortality and ExRA
Patients with ExRA were noted to have an increased risk of premature mortality compared to patients with RA without ExRA (HR 2.0, 95% CI 1.32-3.02). Increased risk of mortality was seen in patients with both severe ExRA (HR 3.05, 95% CI 1.44-6.49) and nonsevere ExRA (HR 1.83, 95% CI 1.18-2.85) compared to patients with RA without ExRA. There was no evidence of a change in the association between ExRA and mortality over time (interaction p=0.60). Rheumatoid nodules were likewise associated with increased risk of mortality (HR 1.94, 95% CI 1.15-3.28). Figure 2 demonstrates the Kaplan-Meier survival curves among those with ExRA between the earlier and later cohorts. Mortality risk of those with ExRA was not different between the cohorts (HR 0.98, 95% CI 0.65-1.50).
Figure 2. Mortality after developing any extraarticular manifestation of rheumatoid arthritis.
Kaplan-Meier curve depicting survival trends after the development of any extraarticular manifestation of rheumatoid arthritis between the two rheumatoid arthritis incident cohorts.
Risk factors associated with ExRA
Several features were associated with increased risk of developing ExRA in the 2000-2014 time period (table 3). The strongest risk factor for the development of any ExRA and rheumatoid nodules was RF positivity (HR 2.02, 95% CI 1.43-2.86 and HR 4.45, 95% CI 2.41-8.23, respectively). Current smoking was associated with the development of any ExRA (HR 1.61, 95% CI 1.10-2.34), severe ExRA (HR 2.98, 95% CI 1.30-6.84), and subcutaneous rheumatoid nodules (HR 2.09, 95% CI 1.30-3.37). Calendar year was negatively associated with any ExRA (HR 0.93, 95% CI 0.90-0.97) and subcutaneous rheumatoid nodules (HR 0.88, 95% CI 0.84-0.93).
Table 3.
Risk factors associated with occurrence of extraarticular rheumatoid arthritis in the 2000-2014 cohort.
| Variable | Any ExRA | Severe ExRA | Rheumatoid Nodules |
|---|---|---|---|
| HR (95% CI)* | HR (95% CI)* | HR (95% CI)* | |
| Age (per 10-year increase) | 1.06 (0.96, 1.18) | 1.05 (0.80, 1.39) | 0.95 (0.82, 1.09) |
| Male sex | 1.01 (0.71, 1.42) | 1.44 (0.63, 3.28) | 1.77 (1.14, 2.73) |
| Calendar year | 0.93 (0.90, 0.97) | 0.93 (0.84, 1.03) | 0.88 (0.84, 0.93) |
| Cigarette smoking at RA incidence | |||
| Ever | 0.94 (0.69, 1.28) | 1.38 (0.62, 3.08) | 1.38 (0.90, 2.13) |
| Current | 1.61 (1.10, 2.34) | 2.98 (1.30, 6.84) | 2.09 (1.30, 3.37) |
| BMI (per 1 kg/m2 increase) at RA incidence | 0.99 (0.97, 1.02) | 0.97 (0.91, 1.03) | 1.00 (0.97, 1.04) |
| RF positivity at RA incidence | 2.02 (1.43, 2.86) | 1.03 (0.45, 2.36) | 4.45 (2.41, 8.23) |
| Highest ESR in the 1st year of RA | 1.02 (0.93, 1.11) | 1.02 (0.86, 1.21) | 1.03 (0.91, 1.17) |
| Erosions on radiographs in the 1st year of RA | 0.93 (0.51, 1.71) | 1.76 (0.67, 4.59) | 1.05 (0.51, 2.19) |
| Medication usage | |||
| Methotrexate | 1.16 (0.83, 1.63) | 0.67 (0.29, 1.53) | 1.77 (1.09, 2.86) |
| Other DMARD | 1.23 (0.88, 1.71) | 1.18 (0.51, 2.71) | 1.24 (0.79, 1.94) |
| bDMARDs | 1.54 (0.95, 2.49) | 3.20 (1.37, 7.48) | 1.64 (0.87, 3.11) |
| Glucocorticoids (systemic) | 1.07 (0.76, 1.50) | 1.82 (0.62, 5.40) | 1.11 (0.69, 1.77) |
Adjusted for age, sex, and calendar year
Abbreviations: BMI = body mass index, CI = confidence interval, DMARDs = disease modifying antirheumatic drugs; bDMARDs = biologic disease modifying antirheumatic drugs, ESR = erythrocyte sedimentation rate, HR = hazard ratio, RA= rheumatoid arthritis, RF = rheumatoid factor, RA = rheumatoid arthritis; SD = standard deviation.
HR reaching statistical significance in bold.
DISCUSSION
The epidemiology of ExRA is changing. The main finding of our study is that ExRA incidence is declining. This is the first study to demonstrate a decline when incorporating a comprehensive list of severe and non-severe ExRA. The decrease in overall ExRA by about a third is particularly driven by a reduction in the occurrence of subcutaneous rheumatoid nodules, the most common ExRA, in which the 10-year cumulative incidence nearly halved between the earlier cohort (incident RA between 1985-1999) and later cohort (incident RA between 2000-2014). Most individual ExRA demonstrated trends toward a decline in 10-year cumulative incidence. Importantly, no ExRA showed a statistically significant increase over time, and some ExRA (e.g., amyloidosis) are extinct in the studied population.
The handful of prior epidemiologic studies assessing the frequency of multiple ExRA over time have either revealed a decline in individual severe ExRA or no significant changes (supplemental table 2) [1,4,19,23,33–34]. Utilizing data from the United States Veteran’s Health Administration (VHA) database, Bartels et al assessed the prevalence of outpatient and inpatient visits for severe ExRA [19,33]. They demonstrated a significant decline in severe ExRA over time with this decline centered around year 2000. Additionally, Ward et al compared rates of hospitalization in California for rheumatoid vasculitis and splenectomy for Felty’s syndrome and noted significant declines between the time frames 1983-1987 and 1998-2001 of 33% and 71%, respectively [34]. Lastly, studies by Myasoedova et al and Turesson et al utilizing Olmsted County epidemiologic data, as in our current study, assessed both severe and non-severe ExRA covering incident RA cases from 1955-2007 with follow up until 2008 [1,4,23]. These studies did not reveal a significant decline in ExRA incidence except for rheumatoid vasculitis. Our current study demonstrated a marked numerical decline in the occurrence of ExRA in recent years, although the decline in the 10-year cumulative incidence of severe ExRA or rheumatoid vasculitis did not reach statistical significance, likely due to the relatively small number of cases of severe ExRA and rheumatoid vasculitis limiting statistical power, especially when compared to the larger VHA database or California hospitalization records.
The underpinning reasons for the decline in severe ExRA incidence in the former studies are likely multifactorial. One interesting finding is the shift in severe ExRA frequency in the early 2000s. This is especially noted by Bartels et al in their study of patients in the VHA system [19,33]. In this context, it is also interesting to note the differing results between our current study and Myasoedova et al regarding ExRA risk, as both utilized epidemiologic data from Olmsted County but chose differing transition points for the comparison cohorts: year 1995 for Myasoedova et al and year 2000 for our current study [1]. Unlike our current study, this previous study from our group did not show a change in rheumatoid nodules (10-year cumulative incidence 31.2% in both incident cohorts), and there was even a slight trend towards increasing non-severe ExRA and overall ExRA incidence. The reason for this difference in ExRA incidence over time between our studies can be visualized by figure 1, which demonstrates the marked decline in ExRA risk starting in patients with incident RA in 2005. As the study by Myasoedova et al contained cases of incident RA only until 2007, it did not fully capture the decline in ExRA that was subsequently seen [10]. This again highlights the shifting RA epidemiology occurring in the early 2000s.
Changes in ExRA incidence are likely reflective of differences in ExRA risk factors over time. Our study identified several risk factors for the development of ExRA (table 3) and are mostly consistent with prior studies (supplemental tables 2 and 3). Risk factors for the development of any ExRA include RF positivity and current smoking. The most important risk factor for the development of ExRA is RF positivity. Patients with RF positive RA were twice as likely to develop any ExRA and more than 4 times as likely to develop rheumatoid nodules. Interestingly, the incidence of seropositive RA has decreased over time while the incidence of seronegative RA has increased over time. This study demonstrated RF positivity to be present in 70% of patients in the earlier cohort and 58% in the later cohort. This decline in seropositivity has been demonstrated in other studies from the US and European populations [10–11]. Our recent study demonstrated a decline in RF positive RA from 69% to 51% when comparing incident RA from 1995-2004 and 2005-2014 [10]. This was subsequently shown in a Dutch RA cohort when assessing anti-citrullinated protein antibody positive RA incidence over time [11]. Given the importance of antibody positivity as a risk factor for ExRA, it is likely that this change in seropositivity is playing an important role in the ExRA decline seen in our current study.
The reasons for declining seropositivity are not fully elucidated but one contributing factor is likely the decline in smoking. Smoking not only is associated with increased risk of seropositive RA but has been associated with ExRA development in prior studies even after adjusting for seropositivity [1,7,23,35]. A history of ever smoking in the early cohort was 57% compared to 47% in the later cohort, likely contributing to the decreasing ExRA incidence noted in our study.
Improvements in the early diagnosis and management of RA may play an important role in declining ExRA. Although disease activity scores were not available for this study, we could use other measures of disease severity such as the presence of joint erosions and inflammatory markers, which have been noted to be risk factors for ExRA in other studies [1,7,22,36]. Counterintuitively, there was a greater cumulative incidence of erosive changes in the 1st year of RA diagnosis in the later cohort (29%) compared to the earlier cohort (24%), with almost universal radiographic imaging available. Notably, most erosive changes were seen at time of diagnosis. This may reflect a combination of the increasing incidence of seronegative RA, its associated delay in diagnosis, and the increasing rates of erosive disease in seronegative RA which have been previously noted in this study population [10]. Additionally, the mean highest ESR within the first year of diagnosis was not substantially different between the cohorts and was not found to be a risk factor for the presence ExRA. Lastly, the effect of novel therapies is difficult to assess, as patients who are treated with these medications generally have higher disease activity and longer disease duration, confounding the benefit or risk of these medications regarding ExRA development. Severe ExRA but not any ExRA or rheumatoid nodules were associated with the use of bDMARDs. Thus, our data is conflicting regarding our hypotheses that improved early detection and effective control of RA are playing a significant role in the decline of ExRA incidence as several confounding factors are likely influencing these results.
Although not assessed in the current study, racial background and nationality, as well as the potentially linked socioeconomic, genetic, and exposure differences, contribute significantly to ExRA variability. This is particularly highlighted by nation-specific studies examining rheumatoid nodules (supplemental tables 2 and 3). Rheumatoid nodule prevalence is highest in White North America and northern European populations (around 30%), like the predominant racial background in our current study. An intermediate prevalence of nodules is usually found in Mediterranean populations (estimates about 15%) and low prevalence in Asian and African countries (estimates <5%) [1,5,22–23,36–45]. A single rheumatology center in San Francisco demonstrated this variability persists among racially and ethnically different patients in a single locality, as the odds for developing ExRA among Hispanic patients were 2.5 times higher compared to Asian patients [36].
The variable incidence of ExRA among different racial and ethnic groups is likely related at least in part to differing frequencies of genetic variants which are known to be linked to ExRA. One example is the association of the gain of function MUC5B promoter variant with RA-associated interstitial lung disease. This variant is more common in North American and European countries compared to Asian countries [46–47]. Additionally, variations in particular genotypes associated with severe ExRA may also be contributing, such as DRB1*0401 and 0401/0401 homozygosity with Felty’s syndrome and the HLA-C3 allele and two HLA-DRB1*04 alleles with rheumatoid vasculitis [48–49].
Substantial differences are also seen based on duration of RA [21–22,35,37,41,50]. The French multisite ESPOIR cohort, a cohort of patients with early onset arthritis, reported on patients with 2-3 months of follow up after initial diagnosis of RA [21]. Only 1.2% of patients had developed rheumatoid nodules. Additional studies by Korkmaz et al in Turkey and Carmona et al in Spain likewise demonstrate significant variability in ExRA incidence based on disease duration (supplemental table 3) [41,50].
The decline of ExRA is of great importance clinically as ExRA are linked to morbidity and mortality [1–2,4,36]. We demonstrated that patients with ExRA continue to have heightened risk for premature mortality, and that this risk is present whether a patient has severe or nonsevere ExRA. Patients with severe ExRA had more than a 3-fold increased mortality risk compared to those without ExRA, and patients with non-severe ExRA had a 1.8-fold increased mortality risk. We also demonstrated that patients with rheumatoid nodules have almost a two-fold increased risk for mortality compared to patients without rheumatoid nodules. Mortality in patients with rheumatoid nodules has not been recently assessed in the literature.
There are several strengths to this study. Through our medical records linkage system in combination with the longitudinal and standardized approach utilized for inclusion in our RA inception cohort, we were able to obtain virtually complete ascertainment of patients with RA fulfilling the 1987 ACR classification criteria and living in the study region. The medical records linkage system also allows us to combine both outpatient and inpatient data, which is infrequent in the ExRA literature. To allow for comparison of prior ExRA studies in Olmsted County, consistent criteria were used for the assessment of ExRA. Manual medical records review is likely superior to diagnostic code-based estimates of ExRA given the variability in applying diagnostic codes to specific ExRA and uncertainty surrounding whether specific presentations that may be ExRA (e.g., sicca symptoms) are secondary to RA or to another etiology (e.g., medications). Additionally, the positive predictive value for assessing ExRA using specific diagnostic codes has not been assessed in database-wide analyses.
There are several potential limitations to this study. First, generalizability is limited given our data is from a single region in the US and is demographically about 90% white. Second, the retrospective nature of our study can lead to falsely low detection rates of ExRA, especially for less symptomatic ExRA, as only those rising to clinical attention and recorded in the medical record were included. Additionally, in the setting of improved therapeutics and management strategies, we cannot rule out the possibility of declining vigilance in routine clinical assessment of ExRA over the study period. Rheumatologists, however, consistently assess for ExRA during visits and given the long follow-up for both cohorts, this concern is substantially mitigated. Third, new and increased availability of specific testing may increase detection of specific ExRA over time (e.g., advanced cardiac imaging for detection of pericarditis). Fourth, difficulty remains in assessing whether specific signs or symptoms (e.g., sicca symptoms) are secondary to RA or another etiology. This limitation, as mentioned above, is partially mitigated by manually chart review and assessing clinical circumstances longitudinally. Fifth, the lack of disease activity scores weakens our ability to assess the potential link between improved disease activity and the decline in ExRA over time. Sixth, our study does not include information regarding the timing of implementation of specific therapies and the potential impact on future occurrence of ExRA individually or cumulatively (e.g., the effect of early bDMARD use on ExRA incidence). Seventh, for consistency in comparing ExRA data across studies in our study population, the same criteria for ExRA have been maintained, though changes have occurred in the classification of some of these conditions (e.g., secondary Sjogren’s syndrome, pulmonary fibrosis). Lastly, some ExRA, particularly severe ExRA, were noted to be rare and thus limited our power to assess for changes in the cumulative incidence of all individual ExRA. Notwithstanding this limitation, this study did show the near absence of cervical myelopathy and Felty’s syndrome in the recent decades.
In summary, there has been a significant decline in ExRA over time that is driven in part by the declining incidence of the subcutaneous rheumatoid nodule. Though there are trends of reduction in most individual ExRA, rheumatoid nodule incidence almost halved. These findings are clinically important as ExRA continue to be linked with increased mortality risk. The decline in ExRA incidence may be related to other epidemiologic shifts in the primary risk factors, such as the decline in seropositive RA and smoking and secular trends in use of antirheumatic therapies, however, more research is needed to further elucidate why ExRA incidence is declining and if this decline is seen in other populations.
Supplementary Material
SIGNIFICANCE AND INNOVATIONS:
Non-severe ExRA incidence is declining, primarily due to a reduction in the cumulative incidence of rheumatoid nodules by almost 50%.
Both severe and non-severe ExRA continue to pose increased mortality risk compared to patients with RA who do not have ExRA.
ACKNOWLEDGEMENTS
The authors wish to thank Hannah E. Langenfeld for assistance with data analysis.
Funding:
This work was supported by grants from the National Institutes of Health, NIAMS (R01 AR46849) and NIA (R01 AG068192, R01 AG034676, K24 AG078179-02). This study was made possible by Grant Number UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The funders had no role in study design; collection, analysis, or interpretation of data; or writing or submitting the manuscript.
Conflicts of Interest:
Dr. Davis declares research funding from Pfizer and has submitted a provisional U.S. patent application no. 63/243,933 entitled, “Methods and Materials for Assessing and Treating Arthritis,” unrelated to the current study. Dr. Matteson has received grants from AbbVie, consulting fees from Boehringer Ingelheim GmBH and Alvotech, honoraria from Boehringer Ingelheim GmBH and Novartis, and has participated on a data safety monitoring board or advisory boards for Horizon Therapeutics and the NIH.
DATA AVAILABILITY STATEMENT
Mayo Clinic Institutional Review Board (IRB) policy does not allow full access of patient information to be provided to a third party without prior approval from the IRB committee overseeing this study. However, access to the complete de-identified data can be made available following approval. Requests for additional study related data can be sent to Cynthia S. Crowson at crowson@mayo.edu.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data Availability Statement
Mayo Clinic Institutional Review Board (IRB) policy does not allow full access of patient information to be provided to a third party without prior approval from the IRB committee overseeing this study. However, access to the complete de-identified data can be made available following approval. Requests for additional study related data can be sent to Cynthia S. Crowson at crowson@mayo.edu.