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While novel therapeutic agents for rheumatoid arthritis are emerging with considerable success in clinical trials, it is still widely recognized that an evidence‑practice gap exists, in that the real‑life effectiveness is not synonymous with the trial efficacy. Prior studies adopting stringent protocol criteria of patient management showed success in achieving more optimal outcomes by following a more strict control of the disease activity, intensifying therapy, and more frequent, regular monitoring. This is a prospective, observational study that evaluates the achievement of therapeutic goals in routine rheumatoid arthritis care. Moreover, clinical characteristics are analyzed as potential predictors of achieving the optimal target. Suprisingly, the rate of remission and adequate disease control is very low, despite several years having passed since the introduction of this therapeutic paradigm. These data indicate an urgent need for an educational intervention or structured approaches to implement treat‑to‑target strategy in daily care.

Introduction

Rheumatoid arthritis (RA) is an autoimmune disease with a chronic and progressive course characterized by systemic inflammation and multiorgan involvement. Pathogenesis of the disease is complex and seems to combine genetic susceptibility and environmental factors that contribute to polyarthritis through mechanisms involving post‑transcriptional gene regulation, protein citrullination, and loss of immune tolerance.¹ Early recognition of RA is crucial to capture the “window of opportunity” (variably defined across studies from the first 12 weeks up to 2 years) and promptly initiate antirheumatic disease‑modifying drug (DMARD) therapy.^2,3 Maintaining remission or at least low disease activity (LDA) through stringent monitoring and therapy escalation (if indicated and tolerated) prevents structural damage and functional disability.^4-6 It should be kept in mind that following a treat‑to‑target (T2T) strategy improves remission rates,⁷ quality of life (QoL) and cost‑efficiency over usual care.^8-10

In internal medicine, there seems to be a degree of clinical inertia in daily care, as can be suspected based on reports on the control of hypertension and hyperlipidemia in the general population.¹¹ Reports from other common, chronic conditions show that in prospective analyses of the effectiveness of maintenance treatment, therapeutic success is not uniform. For example, patient and physician‑rated asthma control increases from approximately one‑fourth to two‑thirds of cases by 6 months.¹² Similarly, uncertainty remains over whether the T2T strategy is feasible for routine care. Even in protocol‑based studies, the level of physician adherence to T2T varies.^13,14 Daily practice is a substantially different environment due to multiple physician (eg, lack of confidence in composite indices), patient (eg, illness beliefs, preference), and health care barriers (eg, time constraints, reimbursement).^14-16 Studies have shown that in daily care only a minority of patients achieve or remain in remission.¹⁷ Findings appear to differ by country, welfare, and health care. A considerable geographical variation in assessing quality indicators (eg, the disease activity, function, remission) has been observed in the international METEOR database.¹⁸ It has further been shown that the disease activity and biological DMARD (bDMARD) usage varies worldwide.¹⁹ Geographical differences in national income level affect the access to conventional synthetic DMARD (csDMARD) and bDMARD, which can be particularly striking. Novel targeted synthetic DMARDs (tsDMARDs) are emerging,²⁰ but their accessibility across lower welfare countries is not fully known. Moreover, financial and administrative barriers are identified among chief restrictions to bDMARD access.²¹ We conducted an in‑depth examination to assess the real‑world situation regarding T2T and RA care in Poland, which is a Central Eastern European country (consequently, limited data are available at present). In our prior nationwide analyses, bDMARD access was estimated at only 3% of the RA patient population.²² These findings point toward the need for population‑specific real‑world evidence with regard to T2T strategy implementation, its effectiveness, and potential barriers to widespread uptake. The rationale for the present study was drawn from a prior survey in a nationwide, representative sample of Polish rheumatologists,²³ which suggested disparities between some practice patterns and the European League Against Rheumatism (EULAR) guidelines. For example, nearly two‑thirds of patients are estimated to never achieve remission.²³

We aimed to examine implementation of selected aspects of T2T strategy in a cohort of RA patients without “adequate” disease control (ie, at least moderate disease activity according to the disease activity score using 28‑joint count [DAS28]).

Patients and methods

Results

In the present cohort of RA patients treated in routine care, only 9% achieved LDA or remission by 3 months, and 35% achieved the target at 6 months. The patients were stratified by their status of achieving the target at 3 and 6 months. We examined clinical characteristics across the groups to identify the factors associated with worse disease control at a given timepoint (Tables 1 and 2). The achievement of treatment targets is reflected in both clinical and objective (ie, levels of acute phase reactants) measures of inflammation and inflammatory activity. At both timepoints, younger age and a higher degree of education were demographic factors positively associated with achieving LDA and / or remission. A higher body mass index (BMI) was negatively linked with achieving T2T goals, and its effect was stronger at 6 months. The patients failing to achieve the target at both the 3- and 6‑month mark had a higher median duration of sick leave than the individuals meeting T2T goals, but the difference was insignificant for both timepoints.

Self‑reported impairment at work was substantially less frequent in the treatment goal‑achieving groups at both 3 and 6 months. This finding is reflected in the observation that the patients achieving RA treatment targets were more often employed full‑time. Although the proportion of part‑time workers was similar initially, the patients achieving the treatment targets were less frequently working part‑time in the long‑term. Combined with a greater proportion of participants working full‑time, this suggest that their work capacity may have improved. By 6 months, RA duration alone had a negative impact on the target goals. However, our study may be insufficiently powered to identify this relationship, as the majority of patients had an established disease.

At both timepoints, pain and physical disability were significantly higher among the patients failing to achieve the target. Interestingly, although smoking status was negatively associated with the disease control at 3 months, this was not reflected in the analysis for 6 months, which could be due to other confounding factors.

The variables significantly associated with treatment target achievement at 6 months were somewhat different than their 3‑month counterparts (see Table 3 and 4). Male sex, younger age, and lower BMI appeared as factors of significance positively associated with LDA and / or remission in the long‑term. Meanwhile, smoking status and lower prednisone dosage remained significant predictors of T2T status at both 3 and 6 months.

Discussion

Achieving the treatment target is of high importance for optimizing patient outcomes in RA. Multinational studies have indicated that a sustained T2T strategy (which encompasses a wide range of treatment and management‑related decisions) leads to improved outcomes and a higher likelihood of remission.⁷ On the other hand, while achieving sustained remission is possible, it is viewed as a realistic target only for a proportion of patients.²⁸ Studies have shown that the disease control rates vary substantially across Europe.²⁹ In the present cohort of RA patients treated in routine care, only 9% achieved LDA or remission by 3 months, and 35% of patients achieved the target at 6 months. In comparison, in a Dutch cohort of very early RA, 47% achieved DAS28 remission by 6 months.³⁰ In randomized trials prior to the era of T2T, achieving remission in usual care was estimated at 16%, while 31% remission rate was achieved in centers with stringent monitoring by 6 months.³¹ More recently, real‑life cohorts with established RA have shown that LDA is achievable by half of the patients after 1 year.³² Our data may fall into the lower‑bound estimates for achieving T2T goals, however, it should be noted that our study was nested in routine care, rather than specialized, tertiary centers.

For early RA, 3 months are an important timepoint of clinical significance, which is tied to future likelihood of achieving the remission.³³ Considering that the majority of the patients recruited in this study had an established disease, by the time they had come into contact with a rheumatologist, they may have missed the window of opportunity. Earlier studies have suggested that achieving treatment targets for RA is suboptimal in Poland; 64% of patients are estimated to never achieve remission, while only 21% of bDMARD‑naïve (of note, bDMARD accessibility is estimated at 3% in Poland) patients are reported with “adequate” RA control.²³ Similarly, only 26% of patients in a cross‑sectional sample from a national Polish RA study were reported with the disease remission.²² Our study extended these earlier findings and provided a prospective overview on the real‑world achievement of treatment targets. It should also be noted that DAS28 is considered a less stringent measure for remission due to high weight of acute phase reactants, which may reflect an even lower rate of “true” remissions than currently observed.³⁴ Our data suggest that in routine RA care, achieving LDA or remission is not common. Whether T2T is feasible for routine care is debatable^35,36; it is a set of principles for best practice that clinicians should strive to adhere to but nonmedical factors are likely to hamper the actual practice.^37,38 It is difficult to identify the main culprit for low rates of treatment success. Studies have shown a discrepancy between provider‑reported adherence to guidelines and the actual practice.³⁹ This may account, to some extent, for the unsatisfactory rates of adequate disease control observed at present.

Despite achieving the treatment targets, at present, 20% of patients with RA control required steroid use, albeit in small doses. Patient characteristics that are associated with treatment targets are different at 3 and 6 months, which suggests that “early” and “long‑term” improvement in RA control is affected by multiple factors to a different extent. However, smoking status and steroids remained significant predictors of achieving treatment targets throughout the timeframe, which points to their importance in therapeutic strategy at any given time. Both these findings confirm data from earlier reports.^40-42 Steroids still remain a mainstay of the combination treatment in ambulatory care, which may be due to their effectiveness, low cost, clinician familiarity with them, and difficulty of initiating a more specialized drug programme referral. Low‑dose GCs have been shown to provide favorable clinical and radiological benefits without compromising safety in early RA.⁴³ However, their long‑term use at moderate to high doses is associated with a plethora of toxic side effects and should be applied with great care. Recent reports have shown that switching the target therapy if its goals are not reached by 6 months yields favorable results.⁴⁴In prior analyses examining routine RA care, maintenance of GC use (>6 months) was estimated for 25% of Polish patients. For over one‑third of the patients, despite the failure of treatment schemes comprising at least 2 csDMARDs, a second‑line therapy (bDMARDs) was not planned in the therapeutic strategy.²³ These findings indicate that a considerable degree of undertreatment or clinical inertia may occur in routine RA care, specifically with regard to second‑line treatment options. Even in cohorts that reported favorable T2T results, the provider’s discordance with the disease activity measures was noted as a justification for the treatment inertia.⁴⁵ A recently published analysis on a cohort of RA patients implies a degree of clinical inertia; observations show a prevalence of low treatment satisfaction and poor disease control, despite claims of adherence.⁴⁶ Most patients appear to trust their providers and hold preference for the physicians’ treatment goals over their own.⁴⁷ Therefore, convincing physicians of the importance of achieving the treatment goals and adequate control of RA activity is of paramount importance.

We found that the provider’s opinion of satisfactory adherence was more common regarding patients who failed to reach their treatment goals. This may indicate that the rheumatologists do not always accurately identify and predict the patients’ treatment‑related behaviors. We remain optimistic that with the advent of biosimilars and greater availability of biological agents, the preferences of clinicians will shift from clinical inertia to implementation of the emerging treatment options such as biosimilars, tsDMARDs, and Janus kinase inhibitors.