Patients’ and rheumatologists’ perspectives on the efficacy and safety of low-dose glucocorticoids in rheumatoid arthritis—an international survey within the GLORIA study

Abstract

Objective

To evaluate the current perspectives of patients and health professionals regarding the efficacy and safety of low-dose glucocorticoids (GCs) in RA.

Methods

Two online surveys were disseminated to patients and health professionals, in their native language, through national patient organizations and national rheumatology medical societies, respectively. SurveyMonkey^®, MediGuard.org and the Glucocorticoid Low-dose Outcome in RA Study (GLORIA) website were used to offer and deliver these surveys.

Results

A total of 1221 RA patients with exposure to GCs, and 414 rheumatologists completed the surveys. Patients and rheumatologists reported high levels of agreement regarding the efficacy of low-dose GCs: at least 70% considered that they are very rapid and effective in the control of signs and symptoms of RA. However, half of the patients also reported having suffered serious adverse events with GCs, and 83% described concerns about safety. The majority of rheumatologists estimated that endocrine, ophthalmologic and cutaneous adverse events affect >4% of all patients treated with low-dose GCs for 2 years, based on a heat map.

Conclusions

RA patients with self-reported exposure to GCs express high levels of satisfaction with low-dose GCs efficacy, as do rheumatologists. However, both expressed excessive concerns regarding the safety of GCs (greatly exceeding the published evidence data), which may compromise the optimal use of this medication. This study indicates that there is an unmet need for appropriately designed prospective trials that shed light on the real risk associated with low-dose GCs, as well as a need for renovated educational programs on the real benefits and harms of low-dose GCs, for both patients and physicians.

Introduction

Seventy years after their discovery, glucocorticoids (GCs) still play a crucial role in the management of RA [1–3]. Their clinical (and structural) efficacy is well demonstrated, even at low doses [4]. Low-dose GCs (defined as a daily dose of 7.5 mg prednisolone-equivalent or less) [4] are mainly recommended (on the basis of demonstrated efficacy) as bridging therapy, combined with conventional synthetic DMARDs (csDMARDs), in patients with early RA [3]. They are also useful for controlling flares in established RA [5]. Apart from their clinical effects, GCs in combination with csDMARDs can reduce or delay the use of biologics [6].

However, the longstanding debate about the balance between the efficacy and safety of treatment with GCs does not seem to cease, despite recent developments towards converging views [7]. Recent trials have suggested that this balance can be favourable, particularly if GCs are kept at low doses [8, 9]. A recent updated review of randomized controlled trials (RCTs) concluded that the toxicity of low-dose GCs used for 2 years is mild and not statistically different from that of a placebo [10]. Conversely, observational studies generally report significantly more adverse events (AEs) in RA patients taking GCs than in those not taking GCs, regarding cardiovascular events [11], infections [12], diabetes [13, 14] and osteoporosis [15], even at low doses [10]. These differences are likely related to study design.

Observational studies are often of lower quality than RCTs due to: higher risk of bias (namely confounding by indication), poorer documentation of GC exposure and different models of risk attribution [10]. These caveats cannot be fully resolved by statistical corrections. RCTs have potential limitations of their own, namely those related to insufficient sample size and duration, focus on effectiveness with limited assessment of AEs and, often, poor representation of clinical practice due to inclusion criteria. Interestingly, a recent meta-analysis suggests that, by and large, populations included in GC trials provide a fair representation of real-world RA patients [16]. Thus, real scientific progress can only be made by large pragmatic randomized double-blind trials, such as the Glucocorticoid Low-dose Outcome in RA (GLORIA) Trial [17]. This study was designed to consider the safety and effectiveness of adding low-dose GCs to the standard treatment for 2 years in elderly (≥65 years old) patients with RA. Safety of treatment with GCs is based on spontaneous reports and on a 57-item symptom list completed by the patients at the start and the end of the trial [17].

Until we have conclusive evidence, the perceptions and preconceptions of both rheumatologists and RA patients on GCs can jeopardize the optimum use of this therapy. RA patients may be exposed to excessive risk by overconfident physicians, but they may also choose not to take beneficial dosages of GCs based on concerns and prior (negative) experiences of AEs [18]. In this environment, assessing the perspectives of both rheumatologists and patients regarding low-dose GCs is important for promotion of the best possible use of GCs once proper evidence is obtained. The aim of this work was to evaluate the current perspectives of patients and rheumatologists regarding the efficacy and safety of treatment of RA with low-dose GCs.

Methods

The present work was performed within GLORIA (www.gloriatrial.org), briefly described above [17]. The research team is committed to promoting a better understanding among health professionals (HPs) and RA patients of the efficacy and safety of treatment with low-dose GCs.

Online surveys

Patients with RA and HPs with experience in the management of GC treatment in these patients were invited to complete an online survey during a 14-month period (September 2018–October 2019). These surveys were designed by the GLORIA research team and were translated into Portuguese, Dutch, English, German, Spanish, Italian, French and Russian languages. Patients’ surveys were written in lay language and fine-tuned by patient research partners (M.V. and M.d.W.).

SurveyMonkey^®, MediGuard.org and the GLORIA website (http://www.gloriatrial.org/page/surveys) were used to offer the online surveys. Patients and HPs were informed that their responses would be anonymous and would be used solely for scientific purposes. The patient survey was disseminated with the assistance of members of EULAR People with Arthritis and Rheumatism in Europe (PARE) and patients’ national organizations. The HPs survey was disseminated through GLORIA team members and national scientific societies of rheumatology.

Patients

The patient survey included 17 questions with single or multiple choices, divided in two parts (Supplementary File 1, available at Rheumatology online). The first included patient characteristics (i.e. age, sex, country, years in school), disease duration, and GC therapy (i.e. name of the prescribed GC, treatment duration, average daily dose).

In the second part, patients were questioned about their beliefs regarding efficacy (three questions) and AEs of low-dose GCs (two questions). Due to regulatory issues, the first of these two questions was phrased differently for patients residing in the USA (‘If I take glucocorticoids, I am concerned that I may suffer a serious adverse event’) and elsewhere: ‘I have suffered very serious adverse events due to glucocorticoids.’ Patients were asked to agree or disagree with statements on a five-point scale (Agree/Slightly agree/Neutral/Slight disagree/Disagree).

The second question was: ‘How serious did you consider these events to be?’ and was rated using a different scale (Life threatening/Serious impact in my quality of life/Minor impact in my quality of life/Most of them mild and well tolerated). Mistakenly, this question was not incorporated in the Portuguese, German or Dutch translated versions. Patients were not given a formal definition of ‘serious adverse event’ – understanding of this concept was left to patients.

Health professionals

The HPs’ survey included 38 questions with single or multiple choices. The survey was divided into three parts (Supplementary File 2, available at Rheumatology online). The first part investigated the HPs’ characteristics (i.e. age, sex, country, speciality). In the second part, HPs were asked to estimate the frequency and seriousness of AEs as a consequence of the use of low-dose GCs for 2 years, in the following system/organ classes: general, dermatological, psychiatric, endocrine, gastrointestinal, cardiovascular, ophthalmological, musculoskeletal, wounds/infection and others. HPs were asked to respond according to a 7-point scale [I dońt know/None/Very rare (<1%)/Rather rare (1–3%)/Rather frequent (4–10%)/Frequent (11–20%)/Very frequent (>21%)].

The third part (17 questions) questioned HPs about their beliefs regarding efficacy of low-dose GCs. Here, HPs could signal agreement or disagreement on a 5-point scale: disagree, slightly disagree, neutral, slightly agree and agree.

Although the original intention was to include different categories of HPs, the very low response rate of non-rheumatologists (nurses/physiotherapists 4.3%, n = 19; internists/other specialties 2.5%, n = 11) led us to analyse only the results of surveys answered by rheumatologists. The characterization of participating non-rheumatologists and their responses are presented in Supplementary File 3, available at Rheumatology online.

Statistical analysis

A descriptive analysis was performed: categorical variables were presented using absolute and relative frequencies; continuous data were presented as mean (s.d.) or median and interquartile range, as appropriate. Doses of different GC preparations were converted into milligrams prednisolone-equivalent. To test for differences in response between countries, an overall χ² test was performed per questionnaire item; where significant, post-hoc explorative pairwise comparisons were made (a detailed description of this statistical analysis and the results are presented in Supplementary File 4, available at Rheumatology online). The data was analysed using SPSS version 25.0 (SPSS, Inc., Chicago, IL, USA).

Results

Patients

A total of 1221 RA patients with exposure to GCs, from 31 countries, completed the survey. Table 1 summarizes the socio-demographic, disease and treatment characteristics of all patients, presented as combined results and also as results for each country. Most patients resided in Brazil (32%), USA (20%), UK (15%), Germany (9%), Portugal (8%) and the Netherlands (7%). Overall, 89% were female, with a median age (Q1–Q3) of 52 (41–62) years and disease duration of 10 (4–18) years. The majority of patients (∼70%) had read articles or pamphlets on the benefits or harms of treatment with GCs. The median duration of GC exposure was 3 (1–10) years, with an average daily dose during the last year of treatment of 5 (4–10) mg per day of prednisolone-equivalent.

Rheumatologists

A total of 414 rheumatologists, mostly from Brazil (27%), Italy (19%), the Netherlands (13%), France (12%), Spain (9%) and Portugal (9%) completed the survey. About half of the respondents were female, and their median age (Q1–Q3) was 49 (38–59) (Table 2). All responding rheumatologists were directly involved in the care or education of RA patients.

Efficacy

Regarding the patient perspective on efficacy, high levels of satisfaction were reported in response to the three questions asked: 86% considered that low-dose GCs were very useful in their case (Table 3), and the majority of patients considered that GCs were very effective in the control of symptoms and that they produced this benefit within days, even in low doses (73% and 71%, respectively). Rates of approval were very similar across different countries.

Similarity, 75% of the rheumatologists considered low-dose GCs to be very effective in the control of signs and symptoms of RA, and 71% agreed that GCs improve RA symptoms within days (Table 4). Regarding articular damage, 61% agreed that low-dose GCs have disease-modifying antirheumatic effects, whereas 28% disagreed with this view. The efficacy of GCs was estimated to wane after a few months or years by 33% of rheumatologists, while 46 and 45% expressed the opposite view.

In addition, high percentages of rheumatologists considered that treatment with low-dose GCs is effective in improving most symptoms of RA, including pain (92%), severity of morning stiffness (88%) and function (78%) (Table 4). Additionally, 70, 64 and 44% of the rheumatologists considered that low-dose GCs improve fatigue, emotional well-being and sleep, respectively. Disagreement with efficacy statements was most frequently expressed regarding benefits upon sleep (22% of respondents).

Safety

Of the 1080 patients, 47% (503) reported having suffered serious AEs (SAEs) due to GCs (Table 5), according to the definitions described above. In addition, 396 of these patients answered the question concerning the impact of SAEs on their lives: 36% reported that these events had a serious impact on their quality of life, and a further 9% perceived these events as ‘life-threatening’ (Supplementary File 6 – Table S7, available at Rheumatology online). Importantly, 83% of the American patients (116 of 140) were concerned that they might suffer an SAE.

Rheumatologists were asked to estimate the frequency of a variety of putative AEs that would be associated with treatment with low-dose prednisolone (≤7.5 mg prednisolone-equivalent/day) for 2 years. Remarkable differences of opinion were expressed regarding the likely prevalence of some AEs, namely dermatological and ophthalmological. The percentage of rheumatologists that acknowledged knowing too little to make an estimate was very small (mostly ≤3%). The AEs considered appear more frequently according to the rheumatologists were the endocrine (63%), the ophthalmologic (51%) and the cutaneous (42%) abnormalities, and AEs were estimated to affect >4% of all patients under that treatment regime. Emphasis was put on AEs on diabetic control (81%), weight gain (82%) and fat redistribution (63%) being estimated to affect ≥4% of individuals. Cataracts (61%) and glaucoma (42%) were also signalled. Skin atrophy and easy bruising were considered the most common cutaneous AEs according to this survey.

Other specific AEs that emerged as a special cause of concern included minor infection, loss of bone density, fragility fractures, hypertension and dyslipidaemia.

Psychological AEs were expected to affect ≥4% of all RA patients exposed to the low-dose GC treatment regime by 33% of all rheumatologists, with an emphasis on mood disturbances and insomnia (Fig. 1 and Supplementary File 5 – Table S6, available at Rheumatology online).

Fig. 1 is a heat map of the prevalence of AEs expected during treatment with low-dose GCs per system/organ class, as estimated by rheumatologists. The numbers in each cell indicate the percentages of rheumatologists estimating a certain prevalence, and each row adds up to 100%.

Differences in rheumatologist’s perspectives across countries

We found statistically significant international differences in the rheumatologists’ perspectives regarding the efficacy and safety of low-dose GCs (Supplementary File 4 – Tables S4 and S5, available at Rheumatology online).

Discussion

In this large international survey of patients and rheumatologists, we found overall high levels of satisfaction with the efficacy of low-dose GCs and their rapid onset of action in RA. Not all rheumatologists were convinced that low-dose GCs are efficacious in reducing structural damage, and only about half believe they maintain their long-term effectiveness. These findings are mostly concordant with the published literature, in which clinical and structural efficacy of GCs is widely acknowledged by experts [8, 9, 19] and patients [20, 21].

Regarding safety, about half of RA patients exposed to GCs in this study reported having suffered SAEs, and the majority expressed concerns about safety. One might query whether the reported frequency of SAEs as perceived by the patient is reasonable, based on the findings of RCTs and observational studies. Taking as an example serious infections, long-term outcomes of the CAMERA-II trial showed that these were higher in the former MTX-placebo group (13%) than in the MTX-PDN group (9%), although this difference was not statistically significant [22]. This result is in line with the findings of the BARFOT study [23]. In a large nested case–control study, serious infections were reported in 10.2% of ≤5mg/day GC users, versus 2.4% in non-GC users [24]. Based on these data, the percentage of SAEs perceived by our RA patients far exceeds the data reported in the literature. Also, and in line with our findings, previous studies have reported that 47–90% of patients consider GCs unsafe [21, 25–27]. In our study, approximately half of the responding patients had >3 years of GC treatment, and 25% had been treated with GCs for >10 years. This long-term exposition to GCs and associated cumulative doses may contribute to the reported prevalence and fear of AEs. It is also possible that patients attribute negative health impacts to GCs that are due to other concomitant medications, to RA itself or to comorbidities [28]. Whatever their origin, these numbers deserve the clinician’s attention as they will certainly influence the shared decision-making process and subsequently the adherent behaviour.

About half of the rheumatologists estimated that >4% of all patients exposed to ≤7.5 mg/day of prednisolone equivalent for 2 years would experience endocrine, ophthalmologic or cutaneous AEs. Similar results were obtained regarding bone mass loss, fragility fractures, cardiovascular events, hypertension and dyslipidaemia [29]. There was considerable variability in the estimated prevalence of specific types of AEs, namely concerning dermatological and ophthalmological effects.

Again, the question can be posed whether the above-mentioned rates, fears and estimates of AEs are reasonable, taking into account available evidence from published RCTs and observational studies. We must acknowledge, that these two sources of evidence are highly contradictory, as highlighted below, taking new-onset of diabetes, cataracts and glaucoma as leading examples.

Taking the same prototypical case as used in our survey, RA patients under doses of ≤7.5 mg/day prednisolone or equivalent for 2 years of treatment, data from RCTs indicates 0.78% would develop new-onset diabetes, which is similar to the percentage observed in non-exposed patients, 0.56% [10]. In contrast, observational studies suggest that this occurs in ∼4% of patients treated with low-to-medium doses of GCs over 2 years [14] or 5% of patients receiving ≤10mg/day prednisolone for a median 4.6 (2.5–8.8) years of follow-up [13]. The responding rheumatologists’ estimates of 81% and 45% for patients receiving these doses of GCs, respectively, are thus far greater than the data from published RCTs and observational studies.

Regarding ophthalmologic AEs, data from a few RCTs suggest that cataracts may occur in ∼2.8% of patients exposed to prednisolone 5–10 mg/day for 2 years vs 2.3% in unexposed people, for 2 years of treatment [8, 30–32]. More than half of our responding rheumatologists expected this to happen to >4% of the patients.

The incidence of glaucoma in the abovementioned RCTs was 1.6% vs 0.4%, respectively [8, 31, 32]. Based on the two observational studies, the incidence of glaucoma was 2.9% (17/584) in users of GCs (≤7.5 mg/day) for at least 12 months vs 2.1% (9/419) in non-GC users [33, 34]. Our results indicate that almost half of the rheumatologists expected this to affect >4% of all exposed patients. In all, fear of AEs among rheumatologists is obviously greater than is justified by even the most negative evidence-based estimates.

Strengths of this study include the large number of respondents, which greatly exceeds that of previous studies. We also believe that the extensive list of AEs rated by the rheumatologists and the request of an estimate for their prevalence was very useful for acquiring more comprehensive representations of rheumatologists’ perspectives on GC safety than has previously been available.

This study also has weaknesses. The rate of AEs reported by patients is, by definition, the rate according to their perception; we sought no confirmation of these events, and we did not account for the potential effects of comorbidities and comedications. The question about the impact of the SAEs on patients’ lives was responded to by only one-third of all patients. Similar considerations apply to the estimates provided by rheumatologists. Also, a selection bias cannot be ignored, i.e. all responding RA patients had used GCs, were members or followers of patient organizations and probably had higher education on GCs than those not responding. In addition, the large differences between countries in the number of respondents naturally skew the aggregate results towards the perspectives of patients and rheumatologists from countries with larger numbers. Our results suggest the existence of international differences in the rheumatologists’ perspectives regarding the efficacy and safety of low-dose GCs, but this study was not designed to allow a detailed discussion of this.

In summary, this report highlights that both patients and rheumatologists have excessive concerns about AEs associated with low-dose GCs, which probably leads to suboptimal use of this medication, compromising treatment efficacy, worsening clinical outcomes and increasing healthcare costs [35].

This indicates an unmet need for definitive evidence on the actual efficacy and safety of the use of low-dose GCs in RA. The issue of whether the best representation of clinical reality is provided by RCTs or observational studies is a complex one [10, 28, 36], but it has become clear that firm conclusions about safety cannot be provided by either the available RCTs or observational studies.

This imposes the need for trials that are simultaneously focused on safety, randomized (to avoid bias by indication), pragmatic (to allow for naturally occurring comorbidities and comedications), and large enough to assure statistical power and ability to correct for co-factors.

One such trial is currently underway – The GLORIA Trial (www.gloriatrial.org). It is hoped that its results will provide the clarity needed to shed light on these important issues.

Acknowledgements

The authors would like to thank the national organizations of PARE that supported this initiative and contributed to the dissemination of the surveys, in particular the Italian Rheumatism Association, the French Rheumatism Association, the Portuguese League Against Rheumatism, the Romanian League Against Rheumatism and the Russian Rheumatism Association. Also, we would like to thank the National Scientific Rheumatological Societies, namely the Brazilian Society of Rheumatology, the Portuguese Society of Rheumatology, the Italian Society for Rheumatology, the French Society for Rheumatology and the South African Rheumatism and Arthritis Association.

Finally, we are grateful to all health professionals who collaborated in the dissemination of the surveys, in particular Dr Francisca Sivera, Jenny de La Torre, Dr Ruxandra Ionescu, Dr Thierry Thomas, Dr Pavol Masaryk, and to the team involved in the survey’s translation: Dr Andrea Di Matteo (Italy), Suzette Fernandes (France) and Polina Pchelnikova (Russia).

Funding: This project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No. 634886.

Disclosure statement: The authors have declared no conflicts of interest.

Data availability statement

Data are available upon reasonable request by any qualified researchers who engage in rigorous, independent scientific research, and will be provided following review and approval of a research proposal and Statistical Analysis Plan (SAP) and execution of a Data Sharing Agreement (DSA). All data relevant to the study are included in the article.

Supplementary data

Supplementary data are available at Rheumatology online.

References