FormalPara Key Summary Points

Why carry out this study?

Glucocorticoids (GCs) remain the mainstay of treatment for various rheumatic diseases, but inappropriate use can worsen GC-related problems, besides the complex treatment regimens and well-established side effects.

There has been no previous research on the identification and management of GC-related problems in patients with rheumatic diseases despite the existence of several guidelines and reviews on the management of systemic GC treatment.

The objective of this study was to identify and manage GC-related problems in patients using GCs in a rheumatology outpatient clinic.

What was learned from this study?

This study revealed a high prevalence of GC-related problems in patients with rheumatic diseases, predominantly related to treatment safety.

The clinical pharmacist's involvement in the healthcare team has had a positive impact on identifying and resolving GC-related problems.

Detecting GC-related problems at an early stage and managing them appropriately provides an opportunity to minimize possible side effects.

Introduction

Glucocorticoids (GCs) are highly effective anti-inflammatory and immunosuppressive agents that have been used in the treatment of various rheumatic diseases such as rheumatoid arthritis, vasculitis, connective tissue diseases, and polymyalgia rheumatica. Despite the established efficacy of GCs, their long-term use is associated with well-known adverse events such as hyperglycemia and diabetes mellitus, cardiovascular diseases, osteoporosis, dyslipidemia, ophthalmological, dermatological and gastrointestinal problems, and infections [1, 2]. Depending on investigated adverse events and study design, a prevalence of adverse events has been reported as 10–80% in patients using glucocorticoids. Those troublesome and sometimes severe side effects frequently contribute to drug non-adherence, resulting in treatment failure and disease flares. On the other hand, adverse events, such as weight gain or skin toxicity, can be important for patients and have a negative impact on treatment compliance [3,4,5,6]. A recent study of patients with rheumatoid arthritis on GCs found that 25% of the patients discontinued glucocorticoids due to adverse events [5]. Various glucocorticoid regimens with different tapering instructions for patients with rheumatic diseases are another matter of concern and leads to inappropriate use of glucocorticoids in patients who already receive complex therapies [7].

Evidence-based recommendations have been developed and published for the rational use of systemic GC treatment in rheumatic diseases [8,9,10,11,12,13,14], which emphasize close monitoring and appropriate preventive strategies. In line with these guidelines, it is critical to assess individual risk factors to inform patients about adverse events in order to manage GC-related issues effectively.

Drug-related problems (DRPs) are defined as events or circumstances involving drug therapy that actually or potentially interfere with desired health outcomes that occur at any stage of the treatment [15]. The prevalence of DRPs in the rheumatology population has been reported to be 78–88%, and the majority of these problems are associated with the use of disease-modifying antirheumatic drugs (DMARDs) [16,17,18]. Several studies have shown that medication use in inflammatory rheumatic diseases is suboptimal. A considerable proportion of patients do not take their medication regimen as prescribed, due to adverse effects, concerns about the medication itself, and a lack of information about the disease and the medication [19, 20]. These DRPs can have serious consequences, such as increased disease activity and side effects, which can ultimately lead to increased morbidity, mortality, and healthcare costs [21,22,23]. In addition to DMARDs, glucocorticoids can also cause DRPs; these problems include adverse drug reactions, additional treatment needed, dosing problems, drug use problems, compliance, and unnecessary treatment. Therefore, in order to enhance patient outcomes, the timely identification and resolution of DRPs is critical.

Clinical pharmacists can identify and prevent DRPs to improve health outcomes and reduce treatment-related risks. It has previously been demonstrated that integrating clinical pharmacists into multidisciplinary teams facilitates advanced care provision in primary care and various specialties [24]. In addition, the involvement of pharmacists/clinical pharmacists in rheumatology outpatient clinics have been shown to prevent medication errors [25], detect drug–drug interactions [26], reduce DRPs [16], improve patient compliance, knowledge of disease and medication, and health-related quality of life [27,28,29,30,31,32]. However, only a few studies have focused on the management of GC-related problems in rheumatology settings. Therefore, this study aims to quantify and characterize GC-related problems and present interventions for managing these problems in patients with inflammatory rheumatic diseases who receive GC treatment.

Methods

Study Design and Setting

This prospective study was carried out between January 2021 and June 2022 in the rheumatology outpatient clinic of a tertiary university hospital. Patients aged > 18 years with a diagnosis of inflammatory arthritis, connective tissue disease (CTD) and vasculitides, newly prescribed or currently using GC treatment, were included in the study after informed patient consent was obtained. To ensure accurate medical history, the treatment period with GCs was restricted to a maximum of 2 years. Patients visiting the outpatient clinic for routine follow-up were referred to the clinical pharmacist at baseline (t0), 3 (t3), and 6 (t6) months to be evaluated regarding GC-related problems after consultation by the physician. The clinical pharmacist planned interventions to resolve the identified problems. The interventions that may influence the physician’s treatment decision, such as the requests for laboratory monitoring, adding a new drug to the treatment regimen, or adjusting the dose of an existing drug, were discussed with the physician. In addition, patients were directly provided with interventions, such as counseling for newly prescribed drugs and lifestyle changes. The acceptance rate of the interventions was recorded and the resolution of the problems was assessed at the following outpatient visits. Since the identified adverse events may not be directly related to GCs, all adverse events were considered as potential. Clinical pharmacists are not allowed to make any changes in the prescribing process in Turkey. Thus, in this study, planned interventions were recommended to physicians, even if it was related to drug treatment.

Ethical Approval

The study was approved by the University Clinical Trials Ethics Committee (KA-21026). All patients provided written informed consent to participate in the study. The study was conducted according to the Declaration of Helsinki and the Harmonization of Good Clinical Practice Guidelines.

Data Collection

Patients’ data were collected prospectively by two rheumatologists and a clinical pharmacist at baseline and subsequent visits. Data included demographics (age, sex, weight, height); clinical characteristics; diagnosis of the rheumatic diseases and disease duration, comorbidities; medical treatments including conventional and biologic DMARDs, GCs, time of initiation of GC treatment, and other drugs used for comorbidities. Low-dose GC therapy < 7.5 mg/day; medium dose, 7.5–30 mg/day; high dose was defined as 30–100 mg/day of prednisone equivalent.

To identify GC-related problems, patients’ weight, blood pressure, and muscle strength of both upper and lower extremities were measured, skin and neuropsychiatric toxicity, and possible infections were evaluated at each visit. If the laboratory parameters, such as fasting blood glucose, hemoglobin A1C (HbA1c) and lipid profile, had not been studied within the last 3 months, the physician was consulted to order routine blood tests. Drugs used for comorbidities were recorded, including any changes in drug and/or dosage at each visit. Similarly, if the bone mineral density (BMD) assessment for osteoporosis was not performed within the last year, the physician was consulted, and a BMD assessment was subsequently ordered. If a BMD assessment was performed within the last 2–3 years in patients who were already receiving osteoporosis treatment, they were not ordered for BMD assessment. At each clinical visit, patients were re-evaluated by the clinical pharmacists to ensure whether they were using medical treatments accordingly and adherently.

Classification and Assessment of Glucocorticoid-Related Problems

During the study period, GC-related problems were identified by the clinical pharmacist, and a consensus on the problems was reached in collaboration with a rheumatologist. The GC-related problems were categorized by the Pharmaceutical Care Network Europe (PCNE) classification system version 9.1 [15]. This classification system categorizes GC-related problems as in problem (six subdomains), its causes (38 subdomains), the planned interventions (17 subdomains), acceptance of the intervention proposal (ten subdomains) and outcomes of the intervention (seven subdomains). GC-related problems were considered completely resolved once the physician accepted the pharmacist’s recommendation and implemented the changes for GC treatment before any adverse effects occurred.

Statistical Analysis

Data were analyzed with IBM Statistics SPSS for Windows v23.0 software. The prevalence and types of DRPs are reported as a percentage. Categorical variables were presented as frequency and percentage, and continuous variables were presented as mean and standard deviation (SD) or median and interquartile range (IQR) based on the distribution of the data. The normality of the quantitative variables was assessed using Kolmogorov–Smirnov normality test. The t test for parametric variables and the Mann–Whitney U test for non-parametric variables were used to evaluate the association between continuous variables. Categorical variables were compared with the Pearson chi-square or Fisher’s exact tests. All statistical tests were performed at the statistical significance level of 5%.

Results

Demographics and Clinical Characteristics

A total of 156 patients (57.7% female) were included, with a mean age (± SD) of 49.1 ± 17.1 years. More than half of the patients (62.2%) had primary systemic vasculitides following chronic inflammatory arthritis. A total of 95 (60.9%) patients had at least one comorbidity, the most common ones being hypertension (34.6%) and diabetes mellitus (19.2%), followed by hypothyroidism (14.1%) and hyperlipidemia (10.9%) (Table 1).

Table 1 Demographics, clinical characteristics, and glucocorticoid usage of the patients
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Glucocorticoid Use

At baseline (t0), 38.5% of patients were on low-dose (≤ 7.5 mg/day) GCs. Prednisolone was used in 53.2% of patients, and the remaining were using methylprednisolone. Intravenous pulsed methylprednisolone was given for 27.6% of patients during the disease duration and the most common dose regimen was 1000 mg/day for 3 days. At the end of 6 months, patients have received a median (IQR) cumulative prednisolone dose of 4930 mg (7237.5 mg) (Table 1).

Medications Used in the Study Population

Half of the patients were on conventional synthetic DMARDs, the most being methotrexate (38.5%, n = 60), followed by hydroxychloroquine (30.8%, n = 48). Biological DMARDs were only prescribed in 16.7% of patients. Thirteen patients (8.3%) were only on GCs with no additional immunosuppressive therapy (Fig. 1).

Fig. 1
figure 1

Disease-modifying anti-rheumatic drugs, immunosuppressives and biologic agents used in patients (n = 156). Patients may have had more than one immunosuppressive. *Others: Sulfasalazine, cyclosporine, tocilizumab, tofacitinib, mepolizumab, infliximab, etanercept, and adalimumab

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Besides immunosuppressive treatments, most of the patients (96.8%) were also taking additional medications for comorbid conditions at baseline (t0) (Table 1). The most commonly used drugs were gastroprotective agents and calcium/vitamin D supplements, which were used in 78.2% (n = 122) and 71.2% (n = 111) of patients, respectively (Fig. 2).

Fig. 2
figure 2

Classes of drugs commonly used for comorbidities (n = 156). Patients may have had more than one drug for comorbidities. ACE angiotensin-converting enzyme, ARBs angiotensin-receptor blockers, CCBs calcium channel blockers

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Glucocorticoid-Related Problems

Overall, 236 GC-related problems were identified in 103 (66%) patients, with a median of 1 (minimum–maximum: 0–5) problems per patient. Among 103 patients, 25.2% had one, 40.8% had two, and 34% had three or more GC-related problems. The incidence of GC-related problems did not differ between the low (66.7%), medium (64.7%), and high dose (66.7%) of GC using patients (p = 0.97) at the time of enrolment. However, the median cumulative prednisolone dose was higher in patients with GC-related problems (3115 vs. 5455 mg, p = 0.01) (Table 1). The ‘adverse event (possibly) occurring’ was the most common subdomain of problems (n = 222) as ‘treatment safety’, and the remaining (n = 14) were related to ‘treatment effectiveness’.

Among the causes of 236 identified problems, ‘no or inappropriate monitoring’ (fasting blood glucose, HbA1c, lipid profile, BMD measurement for monitoring adverse events of GCs) was the most common (n = 98) and followed by ‘no or incomplete drug treatment despite existing indication’ (lipid-lowering drugs, antihypertensive and antidiabetic drugs, bisphosphonates, calcium/vitamin D supplement) (n = 94) (Table 2).

Table 2 Identified causes of glucocorticoid-related problems (n = 236)
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The most common cause (n = 7) of GC treatment being not optimal was the patient’s inappropriate use of drugs unintentionally. Furthermore, inadequate (wrong, unclear, or missing) instructions for timing of drug usage, patients using the drug less than the prescribed dosage or not taking the drug intentionally and frequent dosage regimens than the intended dose were the other causes identified for suboptimal GC treatment.

Planned Interventions

Amongst identified problems, 381 planned interventions were suggested for 224 problems: 47.7% (n = 182) at the ‘prescriber level’, 31.8% (n = 121) at the ‘patient level’ and 20.5% (n = 78) at the ‘drug level’ and 373 (98%) of them were accepted (Table 3). As a result of those recommendations, drug treatments were initiated (n = 60) (including calcium supplements, bisphosphonates, antihypertensives, lipid-lowering agents, and vitamin D), the dose was changed (n = 9), drug treatments were discontinued (n = 3), drug treatments were changed to alternatives (n = 3) and the instructions for the use of GC were changed (n = 3). No intervention was proposed for 12 out of 236 (5.1%) GC-related problems; all of these were associated with increased lipid levels that did not require treatment.

Table 3 Planned interventions to solve problems
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Outcomes of the Interventions

In total, 182 out of 236 GC-related problems (77.1%) were totally solved, seven (3.0%) were partially solved after the implementation of planned interventions, whereas 20 (8.4%) could not be solved despite the intervention due to patient/physician being non-adhere to the recommended intervention (Table 3). The outcome of the interventions could not be determined in 15 (6.4%) problems due to lost to follow-up.

Discussion

This is the first study particularly to evaluate GC-related problems and their management in patients with rheumatic diseases. In this study, we have shown that although patients experience GC-related problems, these problems can be solved by the interventions of a clinical pharmacist before they cause any harm to the patients. In patients receiving GC therapy, it is important to consider individual risk factors and/or preventive measures and to optimize treatment.

A study conducted in medical wards demonstrated that 71% of patients had GC-related problems [33], which is consistent with the findings of our study. In addition, studies evaluating DRPs in patients with rheumatoid arthritis reported that more than two-thirds of patients had a mean of 1.5 and 1.6 DRP per patient, respectively [16, 17].

According to the classification of the problems, the most common GC-related problems observed were related to treatment safety (94.1%), which can be considered as potential adverse drug events. It can be acknowledged that adverse events cannot only be attributed to glucocorticoids because of pre-existing comorbidities (such as hypertension and diabetes), which can be worsened with concurrent GC treatment. It is difficult to establish causality with GCs alone and to distinguish adverse events attributable to GCs from those that occur as a result of the underlying disease, comorbidities or comedications [34].

Although the rate of adverse drug reactions associated with GC treatment was found high in this study (94.1%) compared to the rate found by Chepkonga et al. (39.4%) [33], this difference can be explained by the use of different categorization for DRPs. The PCNE classification system is designed to capture possible adverse drug events, which may increase the rate of adverse drug events (possibly) occurring in this study. Adverse drug events were also found to be the most common DRPs both in rheumatology [16, 17, 35] and other settings [33, 36, 37] in previous studies. This indicates the need for patients to be adequately screened by pharmacists and physicians for the potential risk of adverse events.

Many factors could explain why patients with GC-related problems had higher cumulative doses of prednisolone in this study. Cumulative prednisolone exposure is related to the type, duration, severity and nature of the rheumatic disease. These factors and a higher cumulative dose of prednisolone increase the risk of complications, comorbidities, comedications, adverse events and the need for routine monitoring. This may lead to an increased risk of GC-related problems [38]. However, no difference was found in the incidence of GC-related problems between the patients receiving the low, medium and high doses of glucocorticoids at the time of the enrolment. This finding can be explained by having a significant proportion of the identified problems being related to the lack of laboratory monitoring (such as HbA1c and BMD measurements), and patients did not receive a constant dose of GCs (which was adjusted by the physician according to the disease activation, remission or adverse events) throughout the study. It is important to note that the lack of monitoring can lead to serious consequences for patients. Therefore, regular laboratory monitoring is crucial for patients using GC to detect and manage GC-related problems at an early stage in order to ensure patient safety.

Even though only a small proportion of the problems identified in this study were related to ‘treatment effectiveness’, many of those problems were patient-originated. The complexity of rheumatic diseases and their management strategies (including GCs tapering) and concerns about adverse events may have led to intentional or unintentional inappropriate use of GCs in rheumatology practice. This can result in ineffective treatment, treatment failure, lack of patient adherence and reduced patients’ quality of life. Therefore, interventions that address the educational needs of patients with rheumatic diseases, with a focus on GC treatment, may increase patient’s awareness and improve adherence.

The main causes of the GC-related problems identified in this study were lack of laboratory monitoring for conditions that may have developed by long-term GC use (41.5%) and no drug treatment despite existing indications (mainly for lipid-lowering agents) (39.8%). It has been reported that untreated conditions often occur due to rheumatologists not addressing the patient’s minor conditions, such as anemia, constipation, and diarrhea [37]. Likewise, rheumatologists have primarily concentrated on treating patients' rheumatic diseases rather than monitoring drug side effects. This is due to the high patient load of the outpatient clinic and the time constraints of their practice in this study. It has been known that failure to treat these conditions in patients using GCs can increase the risk of cardiovascular disease and fractures, reduce patients’ quality of life and affect treatment compliance [2].

Almost all interventions proposed by clinical pharmacists were accepted (98%) and 80.1% of problems were solved. This finding was comparable with the results of a similar study conducted in patients with rheumatoid arthritis by Sah SK et al., which found the acceptance rate as 91.3% [17]. This demonstrated that the clinical pharmacist’s recommendations to resolve DRPs were highly appreciated and accepted by the rheumatologists. However, it should be noted that a small number of recommendations were not accepted or accepted but not implemented in this study. The reasons for this may include the patient's clinical condition not allowing the recommendation to be implemented, the patient's or physician's lack of cooperation and the physician postponing the implementation to the next follow-up visit.

In regards to the interventions, the initiation of lipid-lowering agents was the main recommendation, which was not implemented. This can be attributed to the factors of; conservative approaches of the rheumatologists in this study, an asymptomatic nature of dyslipidemia [39] and atherosclerotic cardiovascular disease being developed slowly over time [40, 41]. Therefore, physicians may be reluctant to add a new drug to a patient's already complex treatment, which may have led them to prioritize dyslipidemia as later in the list of problems [42, 43].

It is important to highlight the strengths of this study. Firstly, to the best of our knowledge, there has been no previous research on the identification and management of GC-related problems in the rheumatology setting, despite the availability of therapeutic guidelines. The study's prospective nature has provided an opportunity to demonstrate the clinical impact of interventions following the identification of GC-related problems. Despite its strengths, this study has some limitations. As the patient’s comorbidities and heterogeneity of rheumatic diseases may contribute to the development of identified adverse events, it cannot be fully regarded as GCs-related. The outcomes of the interventions could not be determined in 15 problems due to patients being lost to follow-up. Finally, the study was conducted in a single outpatient clinic, which may limit the generalizability of study findings.

Conclusions

This study showed that GC-related problems are common in patients with rheumatic diseases, and the integration of a clinical pharmacist into the routine clinic plays an important role in facilitating the identification of GC-related problems and assisting physicians to resolve these problems. Given the fact that most common problems were related to inadequate monitoring or GC-induced untreated indications, pharmacists can be well-positioned to support individualized patient care by reviewing patients' medications, identifying DRPs, and providing safe and effective medication use.