Early referral and control of disease’s flares prevent Orthopedic and Hand Surgery Indication (OHSI) in a dynamic cohort of Hispanic early rheumatoid arthritis patients

Rheumatoid arthritis (RA) patients from Latin-America present distinctive epidemiological, serological and phenotypic characteristics when compared to Caucasians patients, and these are known to impact patient outcomes [1‐3]. In addition, treating RA to target (T2T) has become an internationally agreed standard of good practice [4] although the implementation of such strategy may be restricted in developing countries and non-universal health care systems where adherence to treatment may be dramatically compromised [5, 6].

Despite early and more aggressive treatment guidelines adopted in the last decades, some patients present progressive joint destruction and eventually require a surgical solution. Joint surgery is generally considered an indicator of medical therapy failure and of poor prognosis. In addition, the appropriate orchestration and selection of joint surgical interventions are controversial and problematic for the rheumatologist [7, 8]. Recognition of predictive and reversible factors for RA patients in whom a reconstructive procedure and joint surgery may be needed seems imperative. Few studies have addressed the topic in the T2T era and in the context of early RA patients, with conflicting results. None had been performed in Latin-American patients in whom the disease has unique characteristics. Most often, studies have focused on predictors at disease presentation and identified relevant, clinical and laboratory markers of disease activity and severity [9‐12], number of copies of the shared epitope present in the patient [9, 12], radiographic damage [9, 10], demographic variables [9, 11] and short disease duration [9]. In addition, the most important time-varying factors associated with a reduced risk of joint surgery have been early treatment with conventional DMARDS during the first 2 years [10], good response to treatment during the first years of follow-up [10, 13, 14], lower annual radiographic progression rate [10, 12] and lower HAQ score at the beginning of a follow-up window [11] or in the early course of the disease [12]. Finally, the intensity of RA-specific treatment during the first year of disease diagnosis has also been associated with longer time to joint replacement surgery [13].

The objectives of the study were to describe the incidence rate of orthopedic and hand surgery indication (OHSI) in a cohort of Mexican Mestizo early RA patients treated with conventional DMARDs according to a T2T strategy (objective 1) and to investigate OHSI predictors (objective 2).

The present study was developed in a dynamic cohort of Hispanic early RA patients, in whom comprehensive rheumatologic follow-up evaluations were performed from 2004 onwards. The main purpose of the study was to prospectively assess the occurrence of and predictive factors for joint surgery indication; surgical indication (instead of surgery) was chosen due to intrinsic and extrinsic sources of vulnerability from our patients, who may delay or even halt interventions because of costs [16, 17].

We found a low incident global rate of OHSI (8/1000 patient-years) after a mean follow-up of 7 years. The OHSI annual incidental rate progressively increased after the second year. In the literature, few inception cohorts of early RA had assessed rates of orthopedic and small joint surgery, with conflicting results [9‐14, 18, 19]; prevalence ranged from 5.3% at a mean follow-up of 4.6 years [13] to 58% after a mean follow-up of 16 years [12]; variations may be explained by a lack of a uniform definition of “early disease” [9‐14, 19], a wide spectrum of follow-ups that may last up to 25 years [19], differences in the genetic background of the populations in whom surgery was assessed (from the UK [9, 11, 14], Sweden [12, 18], Canada [13], the Netherlands [10] and Finland [19]) and the year of patient’s inclusion, which may have affected the current standard of care. Our cohort had distinctive characteristics which may additionally explain our low OHSI prevalence, estimated as 2.2% at 5 years and reaching 11.7% at last follow-up (13 years); all of our patients were of Hispanic origin and there is only one study which evaluated 355 major joint surgeries performed in Brazilian patients, although only 8 patients had RA diagnosis, which precludes any comparison [20]; also, mean symptom’s duration from our patients was close to 5 months, the cohort had a limited follow-up and included patients from 2004 onwards; finally, our patients received a T2T strategy, primarily with combined traditional DMARDs meanwhile only 4 patients had access to biologics. Of note, Moura et al. [13] identified new-onset RA patients in the Québec Health Insurance Program databases from 2002 to 2011, which is close to our cohort initiation date, and described 10.9 joint replacements during 1000 person-years, similar to our finding. Published recent-onset cohorts with a higher prevalence of joint surgery included patients one or more decades previous to our inclusion date [9‐12, 14, 18, 19]. These data suggest a decline in orthopedic surgery utilization and might be explained by earlier, more aggressive and better treatment strategies [21‐24]. Nonetheless, it should be mentioned that there are conflicting results regarding benefits of biological DMARDs on the need for joint replacement surgery [25, 26].

Longer symptom duration at referral and a higher number of flares/patient during follow-up were the only predictors of incidental OHSI. Early RA cohorts identified additional predictors, and the variability of the results may be explained by the cohort’s heterogeneity (as previously described), the selection of variables to be included and how the models were built. Baseline and comprehensive cumulative variables related to disease activity, to treatment and to adherence were both included in the model as a unique characteristics of our study design. Two groups of investigators, Gwinnith et al. [11] and Kapetanovic et al. [12], also assessed baseline and time varying predictors of orthopedic surgery in recent-onset RA cohorts; the former found that functional disability at time-points was the strongest predictor of future major surgery while acute reactant-phase determinations, baseline HAQ, and early radiological changes were identified as predictors of future need for large joint replacements in the second cohort. In addition, disease activity, radiographic damage, acute reactant-phase determinations, female sex and genotyping were identified as predictors of joint surgery in recent-onset RA, when only baseline variables were considered [9, 11].

In our study, the disease activity construct was extensively assessed during follow-up. Our results highlight that in order to prevent joint surgery, the number of flares must be controlled. Interestingly, we also found differences between patients with/without OHSI in the distribution of category-1 and -6 flares. The former represents a surrogate of adequate disease activity control and mild flares and was the predominant category of flares in patients without OHSI; meanwhile, category-6 flares indicate unsatisfactory disease activity control and were predominant in patients who ultimately received OHSI. Markusse et al. [27] followed up 508 RA patients from the BeSt study, who were T2T for 10 years. The authors formulated 3 definitions of disease flare based on the original DAS; patients who suffered a minor flare B showed more joint damage progression when compared with their counterpart. A higher number of flares was associated with higher disease activity [28] that, if uncontrolled, may progress to severe joint destruction, unremitting pain and joint deformity; in such clinical context, joint arthroplasty has proven to be a successful intervention to improve physical function [29‐31].

In addition to flare control, symptom duration at referral was also found to prevent joint surgery and could be considered a surrogate of early use of DMARDs. Moura et al. [13] found that longer exposure to methotrexate or DMARDs during the first year of follow-up after RA diagnosis was associated with longer time to joint replacement surgery, in a new-onset cohort of 11,333 RA patients. Our patients were indicated DMARDs at first evaluation and symptom duration at referral cut-off of 6 months may be considered an early referral, which is an evidence-based recommendation in newly diagnosed RA patients who improves long-term outcomes and patient quality of life [32].

The study has limitations that must be addressed. First, the study was conducted at a single center which limits the generalization of the results. Second, it was also conducted in an observational cohort and therefore has the limitations of such cohorts, particularly follow-up losses and lack of standardization and control with respect to certain variables and outcomes [33]. Third, we arbitrarily defined and classified flares into 6 categories; it should be emphasized that at the patient level, the six categories may be present and it is unknown if a predominant category may eventually have the greatest impact; also, flare was arbitrarily defined based on a change in EULAR categories, although there is no consensus on flare’s definition, as recently published [34]; nonetheless, we performed a sensitivity analysis defining flare as DAS28 > 3.2 [34] and same patients were identified. Fourth, access to biologics was restricted and it may have impacted disease activity control. Finally, the number of OHSI patients was limited and results should be interpreted with caution.

Our study complements the existing literature related to predictors of joint surgery in real world early RA patients. A delay/prevention of joint surgery may be added to the list of benefits when patients are referred early to a rheumatologist. In addition, flare attenuation should also be considered a target to impact joint interventions, particularly those flares that translate into high disease activity.