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- Springer Journals
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- Copyright © The Author(s) 2023
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- 2523-3106
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- 10.1186/s42358-022-00265-0
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Abstract
Background Management delays imply worse outcomes in rheumatoid arthritis (RA) and, therefore, should be mini‑ mized. We evaluated changes in diagnostic and treatment delays regarding RA in the last decades in Brazil. Methods Adults fulfilling the ACR/EULAR (2010) criteria for RA were assessed. Delays in diagnosis and treatment, and the frequencies of early management initiation within thresholds (windows of opportunity) of 3, 6, and 12 months from symptoms onset were evaluated. The Mann–Kendall trend test, chi‑squared tests with Cramer’s V effect sizes and analysis of variance were conducted. Results We included 1116 patients: 89.4% female, 56.8% white, mean (SD) age 57.1 (11.5) years. A downward trend was found in diagnostic (tau = − 0.677, p < 0.001) and treatment (tau = − 0.695, p < 0.001) delays from 1990 to 2015. The frequency of early management increased throughout the period, with ascending effect sizes across the 3‑, 6‑, and 12‑month windows ( V = 0.120, 0.200 and 0.261, respectively). Despite all improvements, even in recent years (2011–2015) the diagnostic and treatment delays still remained unacceptably high [median (IQR): 8 (4–12) and 11 (5–17) months, respectively], with only 17.2% of the patients treated within the shortest, 3‑month window. Conclusion The delays in diagnosis and treatment of RA decreased during the last decades in Brazil. Improvements (effect sizes) were greater at eliminating extreme delays (≥ 12 months) than in attaining really short management windows (≤ 3 months). Very early treatment was still an unrealistic goal for most patients with RA. Keywords Rheumatoid arthritis, Therapeutics, Epidemiology, Outcome and process assessment, Health care *Correspondence: Cleandro Pires de Albuquerque cleandro.albuquerque@gmail.com Full list of author information is available at the end of the article © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. de Albuquerque et al. Advances in Rheumatology (2023) 63:3 Page 2 of 8 Background Methods Rheumatoid arthritis (RA) is a chronic inflammatory dis - This study was conducted as part of the REAL Study, a ease associated with significant disability and an impaired multicenter observational cohort designed to assess the quality of life, with a global prevalence of approximately current patterns of RA management under real-life con- 0.5% [1]. RA represents a major public health challenge ditions [23]. From August 2015 to April 2016, patients [2], and the need for early treatment aiming at better attending outpatient clinics of eleven public hospitals in long-term outcomes is currently a well-accepted concept different regions of Brazil were included. All participants [3–8]. International efforts have aimed to increase the were 18+ years old and met the ACR/EULAR (2010) proportion of patients with RA attaining early treatment or ARA (1987) classification criteria for RA. Patients [9–12]. These initiatives were well developed in Europe underwent a structured clinical interview with physical and in some other wealthy nations (from other regions), examination, and their medical records were reviewed. leading to the establishment of “early arthritis clinics” Patients unable to complete the interview due to comor- designed to reduce delays regarding RA management bidities or cognitive impairment were excluded. The data [13–16]. reported herein were obtained from the baseline assess- However, this scenario is less clear in the developing ment of participants in the REAL Study, thus being cross- countries, where data tend to be scarce, and the health sectional in nature. The sample size was defined a priori, care resources are more limited. Regional data gaps limit aiming to achieve national representativeness, with each the understanding of early RA management status from a participating center committed to include at least 100 global perspective, thus hindering comparisons between participants. regions and countries. Moreover, all efforts and initiatives The participants were stratified according to the year to reduce RA management delays should be assessed reg- their articular symptoms began. Comparisons were ularly to allow for adjustments whenever required. Brazil then made between these ordered strata. Trend analyses is one of the largest countries in Latin America, a region were primarily conducted on a year-to-year basis. Other where robust data on the status of early RA management assessments and comparisons were conducted consider- is lacking [17]. ing the following time intervals (for the year of articular Accruing evidence supports the concept of a window symptoms onset): before 1990, 1991–1995, 1996–2000, of opportunity regarding RA management: an early and 2001–2005, 2006–2010, and 2011–2015. limited period in the beginning of the disease when the Participants were inquired regarding the delays treatment benefits are the best possible, as opposed to between the articular symptoms onset, RA diagnosis, the concept of a smooth continuum where the sooner the and treatment initiation, i.e., the use of the first disease- treatment is started, the better the outcomes regardless modifying anti-rheumatic drug (DMARD). The delays of the disease duration [18–21]. The width of that win - were ascertained using medical records whenever possi- dow is not precisely defined, but most studies now iden - ble. The proportions of patients receiving early RA diag - tify an upper limit of approximately 3–6 months after nosis and treatment were assessed across the successive symptoms onset [4, 18, 19, 22]. time intervals using 3 different cutoff points to define an The existence of such a window of opportunity implies early diagnosis or treatment: ≤ 3 months, ≤ 6 months, that monitoring only the changes in mean delays could be and ≤ 12 months from symptoms onset. This approach misleading when assessing the effectiveness of initiatives accounted for the current uncertainty as to when the to achieve early RA management. The mean delay could window of opportunity precisely closes [19, 24]. More decrease simply by gradually eliminating extreme delays, importantly, this triple cutoff provided insight on the without necessarily guaranteeing that most patients will consistency of the results (sensitivity analysis), while also fall within some targeted window. Thus, the attainment allowing for the identification of non-uniform changes in of early RA management should rather be measured magnitude across the different windows. directly, through the proportion of patients initiating Trends in the median diagnostic and treatment delays treatment within predefined time limits. from 1990 to 2015 (on a year-to-year basis) were assessed In this study, we evaluated changes in the mean diag- with the Mann–Kendall trend test. Associations between nostic and treatment delay concerning RA, in the last 3 unordered categorical variables were verified using the decades in Brazil. However, more importantly, we also Pearson’s chi-squared test; for ordered categorical varia- investigated changes in the proportions of patients that bles, the Mantel–Haenszel “linear-by-linear” chi-squared initiated treatment within predefined windows of oppor - test was used instead. Effect sizes for associations based tunity for early RA management in the same period. on chi-squared tests were calculated using Cramer’s V. Odds ratios (OR) were also computed when 2 × 2 tables were applicable. Comparisons between multiple groups de A lbuquerque et al. Advances in Rheumatology (2023) 63:3 Page 3 of 8 regarding continuous variables were made by one-way symptoms onset from 1990 to 2015 are shown in Figs. 1 analysis of variance (ANOVA) with Welch’s correction and 2, respectively. Downward trends were found in (homogeneous variance not assumed) and Games-How- the delays for RA diagnosis (S = − 183, tau = − 0.677, ell post-hoc tests. No data imputation was conducted. p < 0.001; Mann–Kendall test) and treatment (S = − 197, The significance level was set at 0.05. Statistical analyses tau = − 0.695, p < 0.001; Mann–Kendall test) between were performed using SPSS 25 and R 3.6.2. 1990 and 2015. The study was approved by a central ethics review The year of symptoms onset (as arranged in time board and by institutional boards in each participating intervals: ≤ 1990, 1991–1995, 1996–2000, 2001– center (https:// plata forma brasil. saude. gov. br/, protocol 2005, 2006–2010, and 2011–2015) was associated to number CAAE 45781015.8.1001.5259) and was con- the percentages (relative frequencies) of individuals ducted in accordance with the 1964 Declaration of Hel- attaining early RA diagnosis, considering all defined sinki and its later amendments. All patients provided cutoff points: ≤ 3 months (χ (1) = 9.76, V = 0.113, written informed consent prior to inclusion in the study. p = 0.002), ≤ 6 months (χ (1) = 24.2, V = 0.162, p < 0.001), and ≤ 12 months (χ (1) = 57.61, V = 0.237, p < 0.001); Results p-values computed from the Mantel-Haenzel linear- The current study included 1116 participants from the by-linear chi-squared test. The more recent the period REAL cohort, whose detailed characteristics have already of disease onset, the higher the percentage of individu- been published [23]. Patients were predominantly female als being diagnosed within each of these thresholds (89.4%), white (56.8%), seropositive for the rheumatoid (Table 1). factor (78.6%), and had a high prevalence of erosive joint Likewise, the year of symptoms onset (in time inter- disease (54.9%); their mean (standard deviation [SD]) age vals: ≤ 1990, 1991–1995, 1996–2000, 2001–2005, was 57.1 (11.5) years and the mean (SD) disease duration 2006–2010, and 2011–2015) was associated with the was 174.9 (115) months. percentages (relative frequencies) of participants receiv- The mean delays with 95% confidence intervals (CI) ing their first DMARD within 3 months (χ (1) = 11.25, for RA diagnosis and treatment according to the year of V = 0.120, p = 0.001), 6 months (χ (1) = 34.84, V = 0.200, Fig. 1 Rheumatoid arthritis diagnostic delay (months) according to the year of symptoms onset in Brazil. Note: The dots and bars represent the point estimates and 95% confidence intervals for the means, respectively de Albuquerque et al. Advances in Rheumatology (2023) 63:3 Page 4 of 8 Fig. 2 Rheumatoid arthritis treatment delay (months) according to the year of symptoms onset in Brazil. Note: The dots and bars represent the point estimates and 95% confidence intervals for the means, respectively Table 2 Frequency of early RA treatment in Brazil according to Table 1 Frequencies of early RA diagnosis in Brazil according to the year of disease onset the year of disease onset Disease onset Delay from symptoms onset to the first N* [a],[b] Disease onset Delay from symptoms onset to RA N* (year) DMARD [a], [b] (year) diagnosis ≤ 3 months ≤ 6 months ≤ 12 months ≤ 3 months ≤ 6 months ≤ 12 months ≤ 1990 8.5% 14.9% 33.3% 141 ≤ 1990 12.4% 23.6% 41.6% 161 1991–1995 5.3% 15.8% 34.7% 95 1991–1995 10.7% 24.3% 44.7% 103 1996–2000 12.3% 24.7% 44.5% 146 1996–2000 10.5% 25.3% 48.1% 162 2001–2005 11.5% 26.3% 49.8% 217 2001–2005 13.9% 29.1% 57.4% 237 2006–2010 17.2% 38.9% 61.1% 239 2006–2010 19.9% 39.1% 65.6% 256 2011–2015 17.2% 36.3% 72.0% 157 2011–2015 20.6% 43.8% 76.9% 160 RA, rheumatoid arthritis; DMARD, disease-modifying anti-rheumatic drug RA: rheumatoid arthritis *Numbers of participants with data available for the analyses [a] *Numbers of participants with data available for the analyses The table shows the frequencies (%) of early RA treatment (early initiation [a] of the first DMARD) considering different delay thresholds (windows of The table shows the frequencies (%) of early diagnoses considering different delay thresholds (windows of opportunity) opportunity) [b] [b] A significant association (p < 0,001) was found between the year of disease A significant association between the year (period) of disease onset and the frequency of early RA diagnoses was observed within all considered windows, onset and the frequency of early RA treatment within all considered windows (delay thresholds); the Mantel–Haenszel linear-by-linear chi-squared test i.e., for the 3-month (p = 0.002), 6-month (p < 0.001) and 12-month (p < 0.001) delay thresholds; the Mantel–Haenszel linear-by-linear chi-squared test percentages of patients being treated within each of these predefined windows (Table 2). p < 0.001), and 12 months (χ (1) = 64.79, V = 0.261, Compared to participants whose symptoms began p < 0.001) of symptoms onset; p-values based on the before 1990, patients whose symptoms started between Mantel-Haenzel linear-by-linear chi-squared test. The 2011 and 2015 showed higher odds of receiving a more recent the period of disease onset, the higher the diagnosis within 3 months (OR 1.83; 95% confidence de A lbuquerque et al. Advances in Rheumatology (2023) 63:3 Page 5 of 8 Table 3 Delays in RA management in Brazil according to the year of disease onset Disease onset (year) Diagnostic delay (months) N* Treatment delay (months) N* Mean (SD) Median [IQR] Mean (SD) Median [IQR] ≤ 1990 71.2 (92.6) 24 [8–120] 161 101.7 (118.5) 60 [12–163] 141 1991–1995 47.8 (56.2) 24 [8–72] 103 52.5 (1.3) 36 [12–82] 95 1996–2000 35.3 (44.3) 21 [6–48] 162 40.0 (53.3) 24 [6.75–49] 146 2001–2005 28.2 (38.3) 12 [6–36] 237 32.5 (41.5) 13 [6–37.5] 217 2006–2010 17.8 (19.8) 12 [5–24] 256 17.8 (19.0) 12 [5–24] 239 2011–2015 11.1 (9.4) 8 [4–12] 160 12.2 (9.8) 11 [5–17] 157 RA, rheumatoid arthritis; SD, standard deviation; IQR, interquartile range *Numbers of participants with data available for the assessments interval [CI] 1.00–3.35), 6 months (OR 2.52; 95% CI existence of a window of opportunity for better treat- 1.56–4.07), and 12 months (OR 4.66; 95% CI 2.88–7.56) ment outcomes with an upper limit situated between 3 of symptoms onset. Similarly, patients whose symptoms to 6 months after disease onset is now widely accepted initiated between 2011 and 2015 had higher odds of [4, 18, 21]. Widespread efforts to reduce delays in RA receiving their first DMARD within 3 months (OR 2.23, diagnosis and treatment are needed, but the accomplish- 95%CI [1.08–4.50]), 6 months (OR 3.26, 95%CI [1.85– ments of such initiatives in developing countries remain 5.74]), and 12 months (OR 5.14, 95%CI [3.14–8.42]) of unclear due to scarcity of data. symptoms onset when compared to those whose symp- We observed a significant decrease in diagnostic and toms began before 1990. treatment delays in the last decades in Brazil (Figs. 1, 2), Diagnostic and treatment delays decreased along the such as reported in other nations [26–28]. Before 1990, successive time intervals for the year of symptoms onset the median delay to RA diagnosis in Brazil was 24 months (Table 3). Groups stratified according to these intervals and to receive the first DMARD was 60 months. These differed as to the mean delay (in months) to RA diag - delays have decreased ever since and converged to a nosis [F(5, 411.3) = 37.6; p < 0.001] and treatment [F(5, median of 8 months for diagnosis and 11 months for 372.8) = 41.9; p < 0.001]. Post-hoc analyses revealed that treatment in the period 2011–2015 (Table 3). Despite all participants whose symptoms began between 2011 and the improvements, these numbers were still higher than 2015 had significantly lower diagnostic and treatment those reported in developed countries, where treatment delays when compared to all other groups (Table 4). delay has mostly been situated around 4–8 months from disease onset [28–30]. This finding reinforces the need Discussion for regional data in order to understand the status of Rheumatoid arthritis is a major global health problem, early RA management from a global perspective; gener- associated with a high burden of disease from both indi- alizations are not warranted. vidual and societal perspectives [2]. Early RA treatment The proportion of patients receiving early RA diagnosis provides the best opportunities to achieve disease remis- and treatment increased along the studied period con- sion and long-term damage prevention [6, 7, 25]. The sidering all defined windows (Tables 1, 2). In 2011–2015, Table 4 Changes in delays for RA management in Brazil across periods Reference period Comparison period Mean difference [95% CI] (months) For diagnostic delay For treatment delay 2011–2015 ≤ 1990 − 60,2 [− 81.3, − 39.0] − 89,6 [− 118.5, − 60.6] 1991–1995 − 36,7 [− 52.9, − 20.5] − 40,4 [− 55.9, − 24.8] 1996–2000 − 24,2 [− 34.5, − 13.9] − 27,8 [− 40.7, − 14.9] 2001–2005 − 17,1 [− 24.6, − 9.7] − 20,3 [− 28.7, − 11.9] 2006–2010 − 6,7 [− 10.8, − 2.6]* − 5,7 [− 9.8, − 1.5] RA, rheumatoid arthritis; CI, confidence interval *p = 0.002; all other differences shown in the table were significant at p < 0.001 on Games-Howell post-hoc tests following one-way ANOVA de Albuquerque et al. Advances in Rheumatology (2023) 63:3 Page 6 of 8 more than 70% of the patients with RA were diagnosed diagnostic and treatment delays were ascertained using and treated within 12 months of symptoms onset. Nev- medical records, but for most participants these data ertheless, in the same period, only 36.3% received treat- were not retrievable from previous records. Confidence ment within 6 months and 17.2% within 3 months of intervals (CI) for the mean delays were computed on a symptoms onset (Table 2). This shorter (3-month) win - year-to-year basis (Figs. 1, 2), revealing greater impreci- dow has been associated with the best outcomes [4, sion (larger CI), as expected, around the older point esti- 31, 32]. Therefore, despite all the improvements, even mates in comparison to the more recent ones. Despite recently a very early beginning of RA treatment (where this limitation, our findings of decreasing delays in RA the most promising results are expected) was still diffi - management are consistent with those reported in other cult to achieve in Brazil. countries [26–28]. We noted increasing effect sizes (V values) for the asso - ciation between the year of symptoms onset (arranged Conclusions in time intervals) and the proportions of patients receiv- Delays in the diagnosis and treatment of RA decreased ing early RA management across the 3, 6, and 12-month progressively, and more patients could receive early treat- thresholds. This indicated that the magnitude of changes ment in the last decades in Brazil. Nevertheless, even in diagnostic and treatment delays was not the same in in recent years (2011–2015), the median delay to treat- these 3 windows. Instead, changes were greater around ment remained unacceptably high (11 months). Improve- the 12-month threshold. This phenomenon can also ments were greater in the elimination of very large delays be perceived with the increasing odds ratios for early (≥ 12 months) than in the attainment of really short (and treatment across the 3, 6, and 12-month windows when desirable) management windows (≤ 3 months). Very early comparing patients whose symptoms initiated in the treatment of RA remained difficult to achieve. Additional 2011–2015 period and those with symptoms onset efforts are clearly needed in pursuit of that goal in Brazil, before 1990. In other words, large delays (of more than which might also be the case in other developing nations 12 months) were more easily reduced, whereas achieving where robust data tend to be scarce. Country-level data delays of less than 3–6 months (which are the ideal goals as we provided herein are essential for a proper under- of early management) proved to be more difficult. standing of the status of early RA treatment from a global The mean diagnostic and treatment delay decreased perspective. progressively across the studied periods. Patients whose symptoms initiated in 2011–2015 (reference group) had Abbreviations significantly shorter delays in both diagnosis and treat - ACR American College of Rheumatology ment when compared to all other groups; the further ANOVA Analysis of variance removed into the past the period of symptoms onset, ARA American Rheumatism Association CI Confidence interval the greater the differences in comparison to the refer - DMARD Disease‑modifying anti‑rheumatic drugs ence group (Table 4). These findings suggest a sustained EULAR European League Against Rheumatism decrease in mean delays throughout the assessed period, IQR Interquartile range OR Odds ratio rather than a transient phenomenon at some particular RA Rheumatoid arthritis occasion. SD Standard deviation However, as noticed before, the sustained decrease in Acknowledgements mean diagnostic and treatment delays in the last decades We thank the Brazilian Society of Rheumatology and the Rheumatology Ser‑ did not imply a uniform change across the different win - vice of the University Hospital of Brasilia (HUB/UnB) for supporting this project. dow thresholds. Rather, the decreases were influenced Author contributions more by the progressive elimination of very large delays All authors made substantial contributions to the acquisition of data, have (greater effect sizes around the 12-month windows) than been involved in drafting the manuscript or revising it critically for important by the increments in frequency of short delays (smaller intellectual content, gave final approval of the version to be published and have participated sufficiently in the work to take public responsibility for effect sizes around the 3-month widows). This find - appropriate portions of the content; and agreed to be accountable for all ing indicates that measuring the proportions of patients aspects of the work in ensuring that questions related to the accuracy or being treated within the targeted windows could be more integrity of any part of the work are appropriately investigated and resolved. In addition, GRCP, ABVS, and LMHM made substantial contributions to study con‑ useful for policy adjustments than simply measuring ception and design, and CPA made substantial contributions to data analysis changes in mean delays. and interpretation. All authors read and approved the final manuscript. The main limitation of this study was that it relied to a Funding great extent on the information provided directly by par- The study was supported by the Brazilian Society of Rheumatology. The ticipants regarding the delays between symptoms onset funder had no participation in the study design, data collection, analysis or and the diagnosis and treatment of RA. When feasible, interpretation, nor in the writing of the manuscript. de A lbuquerque et al. Advances in Rheumatology (2023) 63:3 Page 7 of 8 Availability of data and materials References The datasets used and/or analyzed during the current study are available from 1. Almutairi KB, Nossent JC, Preen DB, et al. The prevalence of rheumatoid the corresponding author on reasonable request. Not applicable for materials. arthritis: a systematic review of population‑based studies. J Rheumatol. 2021;48:669–76. 2. Safiri S, Kolahi AA, Hoy D, et al. Global, regional and national burden Declarations of rheumatoid arthritis 1990–2017: a systematic analysis of the Global Burden of Disease study 2017. Ann Rheum Dis. 2019;78:1463–71. Ethics approval and consent to participate 3. Lard LR, Visser H, Speyer I, et al. 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Evaluating relationships ogy, Universidade do Estado do Rio de Janeiro (UERJ ), Rio de Janeiro, RJ, Brazil. between symptoms duration and persistence of rheumatoid arthritis: Medical Sciences, Universidade Estadual de Campinas (UNICAMP), Campinas, does a window of opportunity exist? Results on the Leiden early arthri‑ SP, Brazil. School of Medicine, Universidade de Ribeirão Preto, Universidade de tis clinic and ESPOIR cohorts. Ann Rheum Dis. 2015;74:806–12. São Paulo (USP), Ribeirão Preto, SP, Brazil. Instituto de Assistência Médica ao 19. Raza K, Filer A. The therapeutic window of opportunity in rheumatoid Servidor Público Estadual, Hospital do Servidor Público Estadual de São Paulo arthritis: does it ever close? Ann Rheum Dis. 2015;74:793–4. (IAMSPE), São Paulo, SP, Brazil. Department of Internal Medicine, Universidade 20. Cush JJ. Early rheumatoid arthritis—is there a window of opportunity? Federal do Paraná (UFPR), Curitiba, PR, Brazil. 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Ann Rheum Dis. 2012;71:989–92. 32. Gremese E, Salaffi F, Bosello SL, et al. Very early rheumatoid arthritis as a predictor of remission: a multicentre real life prospective study. Ann Rheum Dis. 2013;72:858–62. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub‑ lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : fast, convenient online submission thorough peer review by experienced researchers in your field rapid publication on acceptance support for research data, including large and complex data types • gold Open Access which fosters wider collaboration and increased citations maximum visibility for your research: over 100M website views per year At BMC, research is always in progress. Learn more biomedcentral.com/submissions
Journal
Advances in Rheumatology – Springer Journals
Published: Feb 6, 2023
Keywords: Rheumatoid arthritis; Therapeutics; Epidemiology; Outcome and process assessment; Health care