Effectiveness and safety of physician–pharmacist collaborative care for rheumatoid arthritis patients: The Changi General Hospital’s experience

Abstract

Background:

Increasing demand for follow-up of rheumatoid arthritis has encouraged pharmacists to collaborate with physicians to assist with patient care.

Objective:

The aim of this study was to assess the effectiveness and safety of the collaborative care model in a rheumatoid arthritis clinic.

Methods:

We performed a retrospective review of patient case notes and medication records from March 2013 to February 2016. The effectiveness and safety of collaborative care was examined in pre-implementation (standard care) versus post-implementation (collaborative care) cohorts. All patients were assessed for 12 months. Effectiveness of clinic was measured using the percentage of patients that achieved optimal doses of non-biologic disease-modifying anti-rheumatic drugs (nb-DMARDs). Clinic safety performance was evaluated based on the percentage of patients in each cohort that achieved compliance to in-house hospital guidelines on nb-DMARD monitoring. Other clinic safety factors monitored included the incidence and characteristics of nb-DMARD-associated adverse drug events.

Results:

Thirty-eight patients who had received standard care and collaborative care were reviewed. More patients receiving collaborative care achieved nb-DMARD dose optimization within a year of initiation of therapy (68.4% vs 39.5%; p-value < 0.05). Compliance to safety recommendations from hospital guidelines on nb-DMARD monitoring was significantly higher in the collaborative care group (70.6% vs 44.1%; p-value < 0.05). Collaborative care resulted in a higher incidence of nb-DMARD-associated adverse drug events being detected (26.3% vs 18.4%; p-value < 0.05). The most common adverse drug events were gastrointestinal (29.4%), dermatological (17.6%), and hematologic (17.6%), the majority being mild in severity.

Conclusion:

Collaborative rheumatoid arthritis care contributed to improvements in nb-DMARD dose optimization, compliance to hospital guidelines on monitoring, and the detection of nb-DMARD-related adverse drug events.

Keywords

Collaborative pharmacist rheumatology arthritis multi-disciplinary

Introduction

Therapeutic strategies for the treatment of rheumatoid arthritis have changed significantly over time. Tight control and rapid adjustment of non-biologic disease-modifying anti-rheumatic drugs (nb-DMARDs) therapy has been shown to be beneficial in treating patients to target (i.e. achieving disease remission or very low disease activity).¹ Disease remission refers to an absence of disease activity. Low disease activity refers to a state between high disease activity and remission.²

Clinical studies have raised concerns of nb-DMARD-associated adverse drug events, ranging from mild problems to severe and potentially fatal side effects.^3,4 An Australian study has also reported that more than one-quarter of rheumatoid arthritis patients were not able to tolerate the nb-DMARD-associated adverse drug effects and, subsequently, had to withdraw from therapy.⁵ As a result, the use of any nb-DMARD warrants regular blood tests and monitoring for adverse effects, especially during the initiation phase of therapy, as recommended by American College of Rheumatology (ACR) clinical guidelines.⁶

Findings from a systemic literature review support that quick titration of methotrexate dose to reach the highest tolerable dose was associated with increased clinical efficacy.^7,8 National Institute for Health and Care Excellence (NICE) guidelines on the management of rheumatoid arthritis in adults have placed a greater emphasis on fast escalation to a clinically effective nb-DMARD dose, rather than the choice of nb-DMARD, in people with newly diagnosed rheumatoid arthritis.⁹ Hence, rapid escalation and closer titration of nb-DMARD therapy would potentially benefit rheumatoid arthritis patients to achieve disease remission or low disease activity.

When rheumatoid arthritis is left uncontrolled, the patient may experience joint deterioration, severe disability, decreased quality of life, the onset of comorbidities, and premature mortality. The potential comorbidities include but are not limited to cardiovascular disease (CVD), cancer (specifically lymphoma and lymphoproliferative diseases, lung cancer, and melanoma), infections, depression, and gastrointestinal disease.¹⁰ Hence, if rheumatoid arthritis could be brought under control in patients more rapidly, the above complications and comorbidities could be prevented in the patient.

The growing number of patients is adding stress to crowded rheumatology clinics. Physician appointments are frequently overbooked, and it can be challenging to schedule blood tests and consultations as frequently as recommended by the hospital’s in-house rheumatology guidelines. The hospital’s in-house rheumatology guideline is broadly based on the 2008 ACR guidelines.

Many chronic diseases are being managed in partnership with pharmacists who assist with optimizing medication management.^11–17 For example, in a pilot study by Reid et al.,¹⁸ 242 patients attended the pharmacist-led hypertension clinic over a 10-month period. The study found that the implementation of a pharmacist-led clinic improved blood pressure control and appropriate prescribing of antiplatelet agents and statins for primary prevention of CVD and secondary prevention of artherosclerosis.¹⁸ The launch of the collaborative care rheumatology clinic at our institution aimed to ensure that nb-DMARDs such as methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide are dosed effectively and monitored closely to achieve an optimal balance between benefit and risk.

The collaborative care rheumatoid arthritis clinic started operating in March 2014, and provides the treat-to-target management of rheumatoid arthritis using a shared care model involving rheumatologists and pharmacists. Patients are referred to the collaborative care clinic by their primary rheumatologist. At the clinic, in addition to the anticipated role in providing patient education and reinforcing compliance to therapy, pharmacists use their specialized knowledge to monitor the patients’ response to their prescribed medications and make appropriate dose titration suggestions where needed (Figure 1).

Figure 1.

Overview of models of Standard Care and Collaborative Care.

Aims of the study

The primary objective of the study was as follows:

(i) To determine the effectiveness of the collaborative care model, to assess whether it improved dose optimization of nb-DMARD in rheumatoid arthritis patients compared to standard care alone.

The secondary objectives of the study were as follows:

(i) To evaluate the safety of the collaborative care model, comparing the percentage of patients in each cohort that achieved compliance to hospital guidelines on DMARDs monitoring.

(ii) To evaluate the safety of the collaborative care model, comparing the incidence of nb-DMARD-associated adverse drug events detected in each cohort.

(iii) To compare healthcare utilization costs between the two cohorts.

(iv) To look at patient’s satisfaction in the collaborative care model.

Methods

Study design

This was a real-world retrospective cohort study comparing the outcomes of rheumatoid arthritis patients who were newly started on a nb-DMARD in the 12 months prior to (standard care group) or 24 months following (collaborative care group) the implementation of the collaborative care rheumatoid arthritis clinic in March 2014. Patients of the standard care group were managed by rheumatologists and doctors only. Patients of collaborative care groups were managed by a combination of rheumatologists and pharmacists in a shared care model.

Patient population

The hospital’s electronic prescribing system was used to identify previously nb-DMARD-naïve patients who had recently been started on one or more agents for the treatment of rheumatoid arthritis. Rheumatoid arthritis was diagnosed based on ACR classification criteria. These agents included methotrexate, sulfasalazine, leflunomide, ciclosporin, mycophenolate, azathioprine, and cyclophosphamide. Hydroxychloroquine was not included due to its more benign adverse effect profile; hence, routine laboratory monitoring was unnecessary after initiation of therapy.

Eligible patients had to meet the following criteria: either the patient has a confirmed diagnosis of rheumatoid arthritis and was of stable condition that required regular blood monitoring for DMARDs; or be a newly diagnosed patient started on a new nb-DMARD that required regular monitoring and titration.

All patients aged 21 years or older who had been started on nb-DMARD therapy between March 2013 and February 2014 were assigned to the standard care group. For the collaborative care group, patients had to have started nb-DMARD therapy between March 2014 and February 2016 and been reviewed at the collaborative care rheumatoid arthritis clinic during the same time period. All patients recruited in this study were followed up for a period of 12 months.

Study end points

The primary outcome was the proportion of patients in the standard care and collaborative care groups that had reached dose optimization. The doses of nb-DMARDs that patients in both groups were taking six, nine, and 12 months after initiation of nb-DMARD therapy were noted. The optimal dose was defined as the dose at which the patient achieved therapeutic targets without experiencing adverse drug events. Therapeutic target was defined as the presence of clinical remission; however, in patients with long-standing disease, low disease activity was accepted as an alternative therapeutic target.⁶

Patients with active rheumatoid arthritis were initially started on low doses of nb-DMARDs. These doses were subsequently increased in a stepwise manner to an optimal dose. The usual target optimal doses were: methotrexate 15 to 25 mg/week, sulfasalazine 2 to 3 g/day, and leflunomide 10 to 20 mg/day. However, the true optimal dose for patients was adjusted according to both individual patient’s response and tolerance. A review panel consisting of a rheumatologist and two pharmacists reviewed both clinical and laboratory data, as well as other relevant information in manual and electronic patient records, to assess if optimal doses had been achieved and therapeutic targets met. The review panel was non-blinded, and the rheumatologist and pharmacists took charge of the management of patients’ conditions.

Secondary outcomes evaluated were the degree of compliance to safety recommendations by the hospital’s in-house rheumatology guidelines on nb-DMARD monitoring, and the incidences and characteristics of nb-DMARD-associated adverse drug events amongst patients in the standard care and collaborative care groups. The hospital’s in-house rheumatology guidelines were broadly based on the 2008 ACR guidelines. There was an update on ACR guidelines in 2015 with no significant changes in the nb-DMARDs monitoring recommendations. The ACR guidelines⁶ recommend that the first follow-up laboratory monitoring for rheumatoid arthritis patients receiving nb-DMARDs be within two to four weeks from the date of nb-DMARD initiation. In our practice, it may be challenging for patients to get an early appointment for blood tests and physician consultation. Taking this into consideration, the first follow-up laboratory monitoring for the hospital in-house guidelines was modified to about one month of nb-DMARD initiation.

If the nb-DMARD was discontinued within one year from initiation, reasons for the discontinuation were recorded. For cases involving the withdrawal of a nb-DMARD due to an adverse event, we further compared the incidence and characteristics of the adverse event to any described in the literature (if any).

We looked at patients’ satisfaction with the collaborative care rheumatoid arthritis clinic using a questionnaire (online Supplementary Material 1).

As our collaborative care model was newly introduced at our hospital, we compared our healthcare utilization costs to a standard care model, and included costs associated with outpatient, inpatient, and emergency department (ED) visits, costs of rheumatoid arthritis-related investigations, and costs of rheumatoid arthritis-related medication. We further examined the type of specialty visited in outpatient settings as well as primary admission diagnoses (International Classification of Disease, 10th revision, Clinical Modification code). We did not include visits and admissions that were not related to rheumatoid arthritis or adverse effects to nb-DMARD. Patients who were lost to follow-up were excluded.

Statistical analysis

Descriptive statistics were calculated and presented as mean and standard deviation. Categorical variables were assessed using the χ² test or Fisher’s exact test. All statistical tests were two-tailed and statistical significance was considered when p-value < 0.05.

Results

Patient characteristics

In the standard care group, a total of 465 patients were assessed for eligibility (Figure 2). Only 38 patients were included in the study as their DMARDs were initiated during the study period of March 2013 to February 2014. In the collaborative care group, 38 rheumatoid arthritis patients were included. A total of 76 subjects (39 sulfasalazine, 29 methotrexate, six leflunomide, one ciclosporin, and one mycophenolate) were enrolled to the study. Table 1 depicts the demographic characteristics of the patients in this study. The mean age of all patients was 62 years; the study population was 64% female, 36% male. The demographic by race is 59% Chinese, 18% Malay, 10% Indian, and 13% other. The demographic makeup of the patients included in the study reflected a similar distribution of ethnic groups in Singapore, with Chinese being the majority. Overall, there was no significant difference in age, sex, and ethnicity seen between patients in the standard care and collaborative care groups (p-value > 0.05).

Figure 2.

Details of patient recruitment to standard care or collaborative care.

Table 1.

Patient characteristics.

	Standard care(n = 38)	Collaborative care(n = 38)	p-value
Age, mean (years)	63.3	61.4	0.48
Female (%)	26 (68.4)	23 (60.5)	0.47
Ethnicity
Chinese (%)	24 (63.2)	21 (55.3)	0.48
Malay (%)	6 (15.8)	8 (21.0)	0.55
Indian (%)	3 (7.8)	4 (10.5)	1.00
Others (%)	5 (13.2)	5 (13.2)	1.00

Dose optimization

During the initial phase of nb-DMARD titration, patients under collaborative care had more appointments than patients under standard care due to the need to follow the guidelines strictly. The collaborative care group were given additional pharmacist appointments for blood tests and DMARDs dose optimisation.

Overall, a higher percentage of patients in the collaborative care group achieved an optimized nb-DMARD dose compared to the standard care group. This observation was consistently observed across all study time points: six months (60.50% vs 36.80%; p = 0.039), nine months (63.2% vs 36.8%; p = 0.022), and one year (68.40% vs 39.5%; p = 0.011), respectively (Figure 3). The percentage of patients who achieved an optimized dose in the collaborative care group rose steadily at each interim from six months, nine months, and to one year. The percentages of patients who achieved optimized dose in standard care were the same at six months and nine months, and improved slightly at one year.

Figure 3.

Percentage of patients who achieved optimized dose in Standard Care and Collaborative Care groups.

Data on dose optimization was further analysed by drug type. Only patients receiving methotrexate and sulfasalazine were included as the small numbers of patients who received ciclosporin, mycophenolate, and leflunomide precluded them from analysis.

At the end of one year, the proportion of methotrexate recipients who were dose-optimized was 78.9% and 30.0% in the collaborative care group and standard care group, respectively (p = 0.017). Similarly, more patients in the collaborative care group who had received sulfasalazine were dose-optimized compared to those in the standard care group at one year: 60.0% versus 37.5%, respectively (p = 0.094).

Compliance to hospital in-house rheumatology guidelines on nb-DMARD monitoring

The percentage of patients who met the hospital in-house rheumatology guidelines for monitoring on initiation of therapy was significantly higher in the collaborative care group (70.6%) compared to the standard care group (44.1%; p = 0.027) (Figure 4).

Figure 4.

Compliance to guideline recommendations on laboratory monitoring at initiation of DMARD.

There were no differences in the rates of adherence to monitoring guidelines in either the collaborative care group or standard care groups based on medication received: methotrexate 78.9% versus 40.0% (p = 0.051), sulfasalazine 60.0% versus 45.8% (p = 0.39), respectively.

Incidence and characteristics of nb-DMARD-associated adverse drug events

An adverse drug event is defined as

an appreciably harmful or unpleasant reaction, resulting from an intervention related to the use of a medicinal product, which predicts hazard from future administration and warrants prevention or specific treatment, or alteration of the dosage regimen, or withdrawal of the product.¹⁹

An adverse drug event was classified as “severe” if it was life threatening or resulted in hospitalization or death in the study.

A total of 17 patients (22.4%) withdrew from nb-DMARD therapy within a year of initiation due to adverse drug events. Collaborative care more frequently detected nb-DMARD-associated adverse drug events (10 patients (26.3%) vs standard care group of seven patients (18.4%); p-value <0.05) (Table 2). The higher incidence of adverse effects detected in the collaborative group could be due to the more frequent monitoring that was possible in the group. Due to the less frequent appointments in the standard care group, some of the patient’s adverse effects may be missed out.

Table 2.

Incidences and characteristics of the adverse drug events leading to nb-DMARD withdrawal.

	All(n = 76)	Sulfasalazine(n = 39)	Methotrexate(n = 29)	Leflunomide(n = 6)
Number of adverse drug events reported	17	13	2	2
Standard care	7	7	0	0
Collaborative care	10	6	2	2
Gastrointestinal
Diarrhoea^a	2	1	-	1
Gastric discomfort^a	3	2	1	-
Dermatological
Rash	3	3	-	-
Hematologic
Leukopenia (white blood cell count <4 × 10³/uL)	2	2	-	-
Anaemia (Haemoglobin < 11.5 g/dL and drop of >2 g/dL)	1	1	-	-
Hepatic
Transaminitis (ALT and AST > 3 × ULN)	2	-	1	1
Miscellaneous
Alopecia^a	2	1^c	-	1
Ocular disorders^b	2	2	-	-
Stomatitis	1	1^c	-	-
Days to adverse drug event (number of patients, n)		1–60 days (n = 11)61–120 days (n = 0)121–180 days(n = 0)181–240 days(n = 2)	313 days (n = 1)213 days (n = 1)	101 days (n = 1)14 days (n = 1)
Dose at which adverse drug event occurred (number of patients, n)		1000 mg daily (n = 11)500 mg daily(n = 2)	7.5 mg once weekly (n = 1)12.5 mg once weekly (n = 1)	20 mg three times weekly (n = 2)

Based on patient description and willingness to continue the treatment.

The following preferred terms were reported: blurred vision, watery/irritating eyes.

One patient reported to have both alopecia and stomatitis.

Specifically, adverse drug events leading to nb-DMARD withdrawal were seen in 13 (33.3%) patients started with sulfasalazine, two (6.9%) patients receiving methotrexate and two (33.3%) patients treated with leflunomide. The most common adverse drug events were gastrointestinal (29.4%), dermatological (17.6%), hematologic (17.6%), and hepatic (11.8%).

The majority of sulfasalazine adverse drug events occurred at doses of 1000 mg daily (n = 11), except two patients at doses of 500 mg daily. Methotrexate adverse drug events occurred at low doses: 7.5–12.5 mg once weekly (n = 2). Similarly, leflunomide adverse drug events had occurred at low doses too: 20 mg three times weekly (n = 2).

Two patients suffered a methotrexate-related adverse drug event at 213 and 313 days after the initiation of therapy, respectively. Sulfasalazine-related adverse drug events generally occurred within less than 60 days from the start of treatment (n = 11), although two patients had sulfasalazine-related adverse drug events occur after six months at 199 and 231 days. The number of days to leflunomide-associated adverse drug events varied, from as early as 14 days (n = 1) to as late as 101 days (n = 1). No patients passed away during the review period.

Healthcare utilization costs: comparing the standard care and collaborative care models

The healthcare utilization costs were calculated for each patient in both groups. These costs included those associated with outpatient, inpatient, and ED visits, rheumatoid arthritis-related investigations and rheumatoid arthritis-related medication. There was no statistically significant difference (p > 0.05) for healthcare cost utilization between the two groups: SGD$489.5 (±268.1) (collaborative care), as compared with SGD$407.6 (±255.4) (standard care). Although the healthcare cost is slightly higher in the collaborative care group, there was better detection of adverse events in the collaborative care group as compared to the standard care group.

Patients’ experience with the collaborative care rheumatoid arthritis clinic

The survey results revealed that collaborative care rheumatoid arthritis clinic received positive feedback from patients, with an overall high degree of satisfaction (mean score of 4.45/5 overall). All the patients felt that the pharmacists provided clear and detailed information about their disease and medication (mean score of 4.34), and they were confident that they knew what side-effects were possible (mean score of 4.45). Most patients expressed that they were more likely to adhere to treatment (mean score of 4.45), and the majority of patients were willing to come back for follow-up at the collaborative care rheumatoid arthritis clinic (mean score of 4.55). This patient satisfaction survey reflected the acceptability of a non-physician-led clinic in our local setting and highlighted the usefulness of having a regular clinic for monitoring medication toxicity and for patient education. These findings were consistent with other studies, which evaluated the acceptability and impact of collaborative care clinics.

Discussion

The study demonstrated that a greater proportion of patients under the collaborative care model achieved optimal dose of DMARD at six months, nine months, and one year from initiation. Early treatment and rapid dose escalation to optimize nb-DMARD treatment has been shown to be beneficial in achieving disease remission.²⁰

We observed that the hospital in-house rheumatology guideline recommendations on laboratory monitoring in rheumatoid arthritis patients receiving nb-DMARDs were more consistently implemented in the group of patients under collaborative care than the standard care group. Studies showed that the majority of adverse effects developed within the first three months of treatment with nb-DMARDs.²¹ Hence, ACR recommends full blood counts, liver transaminase levels, and serum creatinine levels to be monitored more frequently, every two to four weeks, during this induction phase. Performing these blood tests promptly would help early detection of potentially adverse, or even life-threatening, drug-related complications.

In order to quickly escalate the dose of nb-DMARD and dutifully perform guideline-directed laboratory monitoring, patients would require frequent hospital appointments with rheumatologists. In a busy tertiary hospital, there is always a high patient-to-specialist doctor ratio. Appointments to rheumatologists are usually fully booked for three to four months. Our study results support the usefulness of the collaborative care model, where pharmacists practise at the top of their license and promote the accessibility and affordability of care, which is beneficial to patients.

Treat-to-target is a highly accepted treatment approach for people with rheumatoid arthritis, but the risk of adverse drug events following the intensified treatment has never been assessed.²² It seems a higher rate of nb-DMARD-associated adverse drug events was detected in the collaborative care group compared to the standard care group. This is not surprising because with an intensive dose escalation, more adverse drug events may occur. It is important to note that most of the adverse drug events detected were only mild. Collaborative care is a safe approach, carefully balancing the benefit of earlier attainment of disease remission and mitigating the risk of severe adverse drug events.

In addition, there may be an under-detection of adverse drug reactions in the standard care group due to infrequent monitoring. Less than half of the patients in the standard care group (44.1%) versus collaborative care group (70.6%) (p = 0.027) were monitored according to guidelines. It is postulated that the collaborative care group patients were seen by healthcare providers more regularly and, therefore, detected more adverse drug events.

Overall, tolerance toward nb-DMARDs in our study population appeared comparable to the literature reports. About 22.4% of patients withdrew from nb-DMARD therapy due to adverse drug events, consistent with other studies; cessation of nb-DMARD treatment occurred because of an adverse event in 25% to 42% of patients.⁵ Time from nb-DMARD initiation to adverse events varied widely, from two weeks to nine months, emphasizing the necessity for continued vigilance even after the induction phase of the therapy.

In the collaborative care model, the pharmacist supplemented the physician consultations (about two follow-up visits within a year). This new care model did not demonstrate any deleterious effect on patient care.

Integrating pharmacists into outpatient rheumatoid arthritis clinics did not statistically increase healthcare utilization costs. The collaborative care model optimized manpower resources and contributed to a sustainable healthcare system, as well as leading to better and more prompt detection of any adverse effects of nb-DMARDs on patients.

One of the limitations of our study is that the sample size was small, making it challenging to interpret and generalize the results. The retrospective collection of some data from the case notes can also be criticized for its subjective, selective, and potentially inconsistent nature. It was not possible to collect information about the number of swollen joints or tender joints, or patient’s global assessments of health, as these were not available electronically and often not documented consistently in paper case notes. As a result, we did not include disease activity such as the DAS 28 score as one of the study outcomes. In future studies, prospective design should be employed to allow collection of such information.

The results from the analysis of healthcare utilization cost should be interpreted with caution. There are limitations related to the retrospective observational study design, small sample size, and short duration of follow-up. Future studies focusing on cost-effectiveness should be conducted to allow a better comparison of the healthcare utilization costs between the standard care and collaborative care model in rheumatoid arthritis management.

Conclusion

Implementing the collaborative care rheumatoid arthritis clinic in our hospital meets the demand for greater healthcare provision in the rheumatology field. Our research has highlighted the importance of a shared care model of physicians and pharmacists in improving nb-DMARD dose optimization, adherence to safety recommendations from hospital in-house rheumatology guidelines on nb-DMARD monitoring, and detection of adverse drug events in rheumatoid arthritis patients.

Supplemental Material

Supplementary_Effectiveness_and_safety – Supplemental material for Effectiveness and safety of physician–pharmacist collaborative care for rheumatoid arthritis patients: The Changi General Hospital’s experience

Supplemental material, Supplementary_Effectiveness_and_safety for Effectiveness and safety of physician–pharmacist collaborative care for rheumatoid arthritis patients: The Changi General Hospital’s experience by Elena Meishan Lee, Archana Ramaswamy Vasudevan, Ian Yew Jin Wee, Serene Dingju Yeow and Vinh Thuc Uyen Dinh in Proceedings of Singapore Healthcare

Footnotes

Acknowledgements

The authors thank Ms Carmen Kam (Research Unit, Changi General Hospital) for her assistance in the statistical analysis.

Author contributions

EML and SDY researched the literature, conceived the study, and were involved in protocol development. EML gained ethical approval. EML and VTUD were involved in patient recruitment, collection of data, and data analysis. VTUD wrote the first draft of the manuscript; EML revised it critically. All authors reviewed and edited the manuscript and approved the final version of the manuscript

Availability of data and materials

The datasets were generated from the pharmacy dispensing system (Pharmacy Management System), and analysed based on information from electronic medical records (Sunrise Care Manager).

Declaration of conflicting interests

None declared.

Ethical approval

Ethical approval for this study was obtained from the SingHealth Centralised Institutional Review Board (CIRB ref: 2014/861/F). Informed consent was waived based on ethical consideration.

Funding

This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Supplementary material

Supplemental material for this article is available online.

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Supplementary Material

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