Introduction

Rheumatoid arthritis (RA) is a systemic and progressive disease characterized by chronic synovitis that leads to severe functional impairment. Treatment delay often impacts health-related quality of life and morbimortality [1]. Current best practices for the treatment of RA rely on early diagnosis and initiation of a disease-modifying antirheumatic drug (DMARD) until effective suppression of inflammation is achieved [2, 3]. New diagnostic tools and therapeutic advances, aligned with a “treat-to-target” strategy, have been of utmost importance for better patient outcomes [4, 5].

Extra-articular manifestations (ExtRA) are frequent findings in RA, leading to increased morbidity and mortality [6,7,8]. Rheumatoid nodules are the most common extra-articular feature and are present in up to 30% of patients. Sicca syndrome, chronic disease anaemia and pulmonary involvement are relatively common (6 to 10%). They can be present in early stages of the disease [9, 10].

Many ExtRA likely occur due to the complex chronic inflammatory and autoimmune features of RA. Persistent systemic inflammation is a well-known risk factor for ExtRA development [11, 12]. Vasculitis, neuropathy (often vasculitis-associated), serositis, interstitial lung disease, scleritis, glomerulonephritis, and Felty syndrome are often classified as severe ExtRA. These manifestations may share immunological and inflammatory disease mechanisms, although local factors may also influence organ involvement [7, 13]. All RA patients should be screened for risk factors associated with ExtRA to prevent and manage severe complications. Additionally, appropriate treatment is crucial to limit progression towards serious events [11, 12].

The general prevalence reported for ExtRA in previous cohorts varies from 8 to 40% [7]. Most cases occur with persistently high serum titres of inflammatory activity markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)] and the presence of autoantibodies [rheumatoid factor (RF) and anti-cyclic citrullinated-peptide antibodies (ACPA)]. Male sex, habitual smoking, severe joint disease, impaired functional status, and HLA-related shared epitopes have also been reported as related factors [11, 12]. So far, there is no Brazilian cohort evaluating incidence and specific ExtRA local aspects.

Most of the studies that characterise ExtRA were carried out in cohorts of patients with an RA diagnosis prior to the systematic use of the “treat to target” strategy to control the inflammatory symptoms of RA [13]. Although some subsequent studies have shown a decrease in the incidence of ExtRA over time, the real extent of its impact and incidence, particularly in the context of new treatment guidelines, is not well established. In countries where the “treat-to-target” was incorporated later, it is estimated that ExtRA occurs at a significant frequency [10, 14], representing a challenge for the proper management of the patient.

This study aims to comprehensively characterise the prevalence of ExtRA in a sample of Brazilian RA patients and assesses correlated clinical, therapeutic, and demographic characteristics.

Methods

Thirteen public healthcare centres specialising in RA management were selected to represent the five geographic regions in Brazil. Eleven centres from 4 regions enrolled in the program. The recruitment period started on August 12th, 2015, and ended on April 15th, 2016. Patients were followed for ~ 12 months, with systematic data collection at the initial visit (baseline), at the intermediate visit (6 months ± 1 month) and at the final visit (12 months ± 1 month), with additional descriptive reports of any other unscheduled visit.

The inclusion criteria were: (1) fulfilment of the 1987 American Rheumatism Association (ARA) or the 2010 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) classification criteria for rheumatoid arthritis [2, 15], (2) age ≥ 18 years, and (3) documented medical history of at least six months of treatment in their healthcare center prior to study enrollment. Erosive disease was defined according to EULAR 2013 recommendation [16]. Patients were excluded if they were unable to reliably report on the self-assessment sections of the data collection instrument. The REAL Study received ethical approval from the Universidade do Estado do Rio de Janeiro (the coordinating centre) Research Ethics Committee (registration number 45781015.8.1001.5259). Each participating site also obtained approval from their respective institution’s ethics committee. All patients consented to participation in the study. The complete study protocol was previously described [17].

The following comorbidities were considered extra-articular manifestations (ExtRA): sicca syndrome, interstitial lung disease, scleritis, episcleritis, pleuritis, pericarditis, glomerulonephritis, peripheral neuropathy, anaemia, cutaneous and systemic vasculitis, and subcutaneous nodules. The criteria for ExtRA definition was based on clinical judgement, similar to previous definitions [13] and are described in detail in Additional file 1: Table S1. According to the domain, they were based on clinical exam (nodules, ocular involvement, vasculitis) laboratory findings (chronic disease’s anaemia, after exclusion of other causes), imaging (pleuritis, pericarditis, interstitial lung disease, systemic vasculitis, visceral rheumatoid nodules) pathology (vasculitis, visceral rheumatoid nodules) and other specific diagnostic methods (such as electroneuromyography for peripheral neuropathy, Schimmer’s test and scintigraphy for sicca syndrome). Only ongoing manifestations were considered.

Statistical analysis

Results are presented as mean (± standard deviation) and number (%) for continuous and categorical variables, respectively. Continuous variables were compared using Mann–Whitney U-test, since most distributions failed in normality tests. For categorical variables, differences were assessed using Fisher’s exact test or chi-square test, as appropriate. A multivariate logistic regression analysis was performed using as dependent variable the presence of extra-articular manifestations, and the variables with p < 0.2 in each univariate analysis as the independent ones.

In all the statistical tests, the level of significance was set at 5% (p < 0.05). Licensed Stata/SE 14 was used as software.

Results

A total of 1115 patients were enrolled in the study. Demographic and clinical data at the time of the initial evaluation are described elsewhere [15]. Approximately 90% were female, with a mean age of 56.7 (22.1–88.8) years and median disease duration of 12.7 (0.7–56.9) years. Most subjects were white (56.8%). Almost 80% of patients belonged to low or low-middle socioeconomic classes.

ExtRA occurred in 261 patients (23.4%). As many patients presented more than one ExtRA (Figs. 1 and 2), the total number of events was 334. The most common ExtRA was subcutaneous nodules (n = 92, 35.2% in the ExtRA group and 8% of the total 1,115 patients), followed by anaemia (n = 78, 29.8% in the ExtRA group and 7% of the entire cohort), and sicca syndrome (n = 65, 24.9% in the ExtRA group and 5.8% of the entire cohort). Interstitial lung disease occurred in 45 patients, corresponding to 17.2% of ExtRA patients and 4% of the entire cohort.

Fig. 1
figure 1

ExtRA distribution by site and/or type among 334 occurrences in 261 patients. Graphic shows the absolute number and percentage (n = 1115 patients) from each of the patient cohorts. Additionally, the number of patients presenting with the coexistence of ExtRA is shown in the connecting lines. *SC: subcutaneous, SS: sicca syndrome, ILD: interstitial lung disease

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Fig. 2
figure 2

Number of cumulative ExtRA in 261 patients. As shown below, most patients (77%) presented a single ExtRA, while 33% had two or more manifestations

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Demographic and clinical data from the ExtRA and non-ExtRA groups are summarized in Table 1. Comparison among the ExtRA and non-ExtRA groups showed significantly higher age (60.4 ± 10.1 vs. 57.5 ± 11.8 years, p = 0.0003), disease duration (17.5 ± 10.3 vs. 13.7 ± 9.1 years, p = 0.0001), Clinical Disease Activity Index (CDAI) (18.2 ± 16 vs. 11.5 ± 10.6, p < 0.0001), Disease Activity Score 28 (DAS 28) (4.3 ± 1.6 vs. 3.4 ± 1.4 p < 0.0001), and Health Assessment Questionnaire-Disability Index (HAQ-DI) (1.15 ± 0.8 vs. 0.87 ± 0.7, p < 0.0001) in the ExtRA group. Additionally, high titres of RF (≥ 3 × the upper limit) were significantly more prevalent in the ExtRA group (62.8% vs. 54.1%, p = 0.018).

Table 1 Extra and no-extra groups clinical data
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Treatment with azathioprine (2.7% vs. 0.4%, p = 0.002), etanercept (8.4% vs. 5%, p = 0.041), glucocorticoids (GC) (52.4% vs. 43%, p = 0.0002), and nonsteroidal anti-inflammatory drugs (NSAIDs) (14.6% vs. 7.4%, p = 0004) were also more frequent in the ExtRA group (Table 2). The multivariate logistic regression showed that the independent factors associated to the presence of extra-articular RA were erosive disease (OR 1.657 [95% CI 1.154–2.380] p = 0.006), longer disease duration (OR 1.097 for each 5 years of disease [95% CI 1.002–1.200] p = 0.044), and higher CDAI (OR 1.026 [95% CI 1.010–1.042] p = 0.001).

Table 2 Current pharmacological treatment, according to the presence of extra-articular symptoms
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Subgroup analyses for special interest manifestations were performed: sicca syndrome, vasculitis/neuropathy, rheumatoid nodules, and interstitial lung disease (ILD). The results were similar to the overall group (Additional file 1: Tables S2–S4), except for patients in the ILD group (Table 3) who presented differences regarding the pharmacological treatment: fewer patients in the ILD group used methotrexate (p = 0.010), whereas more ILD patients used azathioprine (p < 0.001), infliximab (p = 0.010), and GC (p < 0.001). The analysis of the non-ILD manifestations together was more similar to the overall group (Table 4), regarding the influence of age (p = 0.016), disease duration (p < 0.001), erosive disease (< 0.001) and disease activity (< 0.001), use of NSAID (p < 0.001) and glucocorticoids (p = 0.003). These patients also used more etanecerpt (p = 0.027), but not more azathioprine (p = 0.103), with a lower frequency of leflunomide (p = 0.039).

Table 3 Interstitial lung disease (ILD) patients: clinical data and current pharmacological treatment
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Table 4 No-ILD extra and no-extra groups clinical data and current pharmacological treatment
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Discussion

In the present cohort, extRA manifestations had a considerable prevalence in RA patients. Persistently active and severe disease with high RF titres and established sequelae are risk factors for extRA. These findings are similar to previously reported data [6, 11,12,13]. However, unlike previous findings, we did not observe a correlation with ACPA positivity, probably due to the test’s unavailability to almost half of the patients studied. Likewise, there was no significant correlation with smoking status, except for rheumatoid nodules [13, 14]. In this specific group, smoking habit (current and ever, summed up) was more prevalent in comparison to the overall ExtRA patients (66.3 vs. 51.7%).

Although smoking is a known risk factor for extra-articular manifestations, the role of active smoking is more pronounced for this outcome than previous smoking, as demonstrated by Turesson [13], who found a relative risk of 1.52 for the development of ExtRA in active smokers at RA diagnosis. The role of ever-smoking (not at RA diagnosis) was not so well defined for ExtRA. In our cohort, the prevalence of ever-smokers was much higher than active smokers (42.1% vs. 9.6% in ExtRA patients), which can partially explain our findings. We did not specify in our questionnaire if smoking habit was present at RA diagnosis, what could be a bias. Additionally, our cohort mainly consists of older patients presenting long-term, RF-positive, erosive disease, and we believe that these other risk factors overcame smoking risk itself.

Regarding pharmacological treatment, the higher use of glucocorticoids in patients with extRA can be explained both by the greater inflammatory activity and severity of joint disease, as well as by the extRA treatment itself. Additionally, the greater use of NSAIDs is also justified by articular activity, chronic pain and damage.

Interestingly, a trend towards greater use of anti-tumour necrosis factor (TNF) drugs in the extRA group was observed, with statistical significance in favour of etanercept. One hypothesis for this finding is disease severity, which requires biological treatment for inflammatory control. In addition, when the cohort was initiated, anti-TNF drugs had a greater availability in Brazil compared to other biologics. Factors that could favour etanercept could include safety concerns, such as the lower risk for certain infections [18] (herpes zoster [19] and tuberculosis [18]) and the shorter half-life, considering the extRA patient’s profile (older, disabled, with more severe disease and more comorbidities).

When we examined the use of conventional synthetic DMARD treatment, there was a greater proportion of patients using azathioprine (AZA) in the extRA group. Presumably, this drug was chosen for extRA control, because the effectiveness of AZA for inflammatory articular activity is limited [20]. Considering the widespread AZA use for RA-ILD in Brazil, a comparison between the non-ILD ExtRA summed up, versus no-ExtRA, failed to show significant difference regarding AZA use, what may imply a preference for AZA in RA-ILD clinical management (influenced also by the drug wide availability in Brazil). On the other hand, a lower LEF use was detected in the non-ILD extRA group, probably because this csDMARD is usually avoided in the presence of neuropathy and vasculitis.

Further subgroup analysis regarding the most frequent and/or clinically significant manifestations (sicca syndrome, subcutaneous nodules, vasculitis) did not reveal differences between the extRA and control groups. However, patients with ILD presented a relevant difference that should be explored: the lower use of MTX.

ILD is a topic of growing interest because it currently represents the second leading cause of death among patients with RA and because of its novel antifibrotic therapeutic effects [21, 22]. The incidence and morbimortality of RA-ILD have grown over the years [22, 23]. Clinically significant ILD occurs in up to 10% of RA cases [23, 24]. In our cohort, ILD occurrence was lower, reported in 4% of the patients. Considering that access to diagnostic tools (such as high-resolution chest tomography) varies significantly between different regions of the country, underdiagnosis and heterogeneous data may explain this finding. Another contributing factor for this scenario is the lack of specific guidelines for ILD detection and treatment in RA patients [25].

We found that the use of MTX was less frequent in patients with ILD in Brazil. This finding is similar to a recent multicentre study [26]. Avoiding MTX in ILD has been a widespread practice for many years in rheumatology, as it is believed that MTX could exacerbate ILD. Currently, this misconception has been elucidated: MTX probably has a protective role against RA-ILD development, either by a direct immunosuppressive effect targeting the lung or by an MTX-driven decrease in systemic inflammation [26].

The REAL study [17], an observational multicentre cohort, has a limitation in its design. All enrolled sites are tertiary centres, presenting a severe disease profile predominance, and probably not fully representative of the broader management of RA across the country. Additionally, the cross-sectional nature of the study design precludes establishing causal association between variables and outcomes.

Conclusion

Our results suggest that extRA is an actual challenge in the management of RA patients in Brazil. Its high prevalence calls attention to the need for further studies, evaluating the potential effect of treatment strategies using longitudinal design. It is possible that early and rigorous medical management with effective therapies could help lower the risk and severity of ExtRA.