Rheumatoid arthritis patients treated in trial and real world settings: comparison of randomized trials with a registry focus on rituximab

doi:10.21203/rs.3.rs-4438439/v1

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Rheumatoid arthritis patients treated in trial and real world settings: comparison of randomized trials with a registry focus on rituximab

https://doi.org/10.21203/rs.3.rs-4438439/v1

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Objectives: To investigate whether patients with Rheumatoid Arthritis enrolled in randomized controlled trials (RCTs) and observational studies may differ in terms of characteristics that could modify treatment effects leading to effectiveness gap.

Methods: We conducted systematic literature reviews to identify RCTs with RA treated with rituximab. We compared this to data from the registry of RA cases on rituximab. We further used meta-regression analyses to assess the differences in DAS28 between RCTs and observational studies (The KRRD) by including the study design as a dichotomous covariate assessment of whether the baseline characteristics changed over time.

Results: Compared to Observational studies, the average DAS28 for RCTs are higher by 2.78 to 4.06 at baseline and 0.65 to 2.99 after baseline (P<0.001).

Furthermore, ESR and CRP declined over time in RCT patients, but not in patients participating in the registry. Overall, the patients in the registry were older than the RCT.

Conclusion: we found important differences between RA patients included in RCTs as compared with observational studies; in particular, patients with better prognostic factors were included in the RCTs, leading to a potential overestimation of the treatment effect.

randomized controlled trials

registry

rituximab

rheumatoid arthritis

Rheumatoid Arthritis (RA) is an autoimmune chronic systemic disease, characterized by symmetrical inflammation of the affected joints, with a prevalence of approximately 1% in the population [1–3]. The pathophysiology of the disease consists of synovial inflammation and hyperplasia, autoantibody production (rheumatoid factor, anti-citrullinated protein antibody (ACPA), cartilage and bone destruction, and systemic features such as cardiovascular, pulmonary, psychological, and skeletal disorders [4].

The chief biological event in rheumatoid arthritis is inflammation. The excessive production of cytokines and other cellular processes erode the cartilage and bone and are responsible for the systemic effects seen in rheumatoid arthritis. The exact cause of rheumatoid arthritis, however, remains unknown, and its prognosis is variable and is dependent on the presence of systemic manifestations [4]. The disease involves a complex combination of both genetic as well as environmental factors, for it to become established. It has been demonstrated on a molecular level that rheumatoid arthritis patients who are positive for rheumatoid factor or ACPA, have alleles that contain a common amino acid motif in the HLADRB1 region, which is called the shared epitope, and is what confirms susceptibility to the disease [5]. In twin studies it has been demonstrated that rheumatoid arthritis has a concordance rate of 9.1% among monozygotic twins, and 6.4% among dizygotic twins [6]. Psychological stressors as well as some established psychiatric illnesses such as post-traumatic stress disorder (PTSD) are thought to be risk factors that contribute to the development of RA [7–9].

Finally, some medications, such statins are thought to influence immune regulation and could eventually result in the of development of autoimmune diseases such as RA [10–11[.

After establishing the diagnosis of rheumatoid arthritis, a wide range of measures that can be used to quantify disease activity. One of the assessment scores that is widely used in practice is the DAS28 score. It is a composite score derived from four different measures, and the number 28 refers to the 28 joints that are being examined. The measures in the score include number of swollen joints, number of tender joints, ESR or CRP value, and “global assessment of health”, which is indicated by marking a 10 cm line ranging from “very good” to “very bad” [12]. These results are then fed into a complex mathematical formula to produce the overall disease activity score. A DAS28 score of greater than 5.1 implies active disease, a score of less than 3.2 implies low disease activity, and that of less than 2.6 implies disease remission.

Progressive synovitis in the setting of RA leads to joint damage and inevitably loss of function and disability; and is a clinical marker that makes initiation of treatment essential [13–17].

Treatment of RA has focused on the achievement of remission or at least a low disease activity in order to minimize and prevent joint damage and long-term disability. [18–21] The mortality rate is higher among patients with rheumatoid arthritis compared to those without the disease, and disease associated complications including cardiovascular as well as other systemic complications remain a major challenge in the overall disease management [22]. Disease-modifying antirheumatic drugs (DMARDs) are the 1st line mode of pharmacologic treatment and should ideally be started within 3 months of persistent symptoms. Options include methotrexate, sulfasalazine, hydroxychloroquine, and leflunomide. Symptomatic benefit can take 6–12 weeks following initiation of the drug [23].

Biologic agents are initiated by specialists for patients with active disease despite adequate trials of at least 2 DMARDs. These agents are diverse in the way they act on different biological pathways to influence this disease. Rituximab, for example, works as a B-cell depletion agent. This drug can be used ideally in a setting of severe active rheumatoid arthritis, where csDMARDS and TNF-α agents have failed [24]. One example of candidates for a biologic agent as part of their treatment regimen is in patients with rheumatoid arthritis who have had an inadequate response to a combination of both methotrexate and a TNF-α agent. In this case, a combination of methotrexate along with non-TNF- α agents such as abatacept, tocilizumab, sarilumab, or rituximab may be used.

Rituximab (RTX) is a monoclonal antibody that targets the CD20 antigen, thereby depleting B cells. It is used as a therapeutic biologic agent in rheumatoid arthritis (RA), as well as other autoimmune and lymphoproliferative disorders. The depletion of B cells with rituximab is achieved through several antibody-dependent mechanisms. In the case of rheumatoid arthritis, it is believed that the principal mechanism of B cell depletion is through Fc receptor gamma-mediated antibody-dependent cytotoxicity and antibody-dependent phagocytosis [25]. It is well known by now that randomized controlled trials (RCTs) are the most appropriate study methods that are used to determine the effectiveness of new treatments/drugs and interventions in healthcare [26–30].

When looking at different published RCTs worldwide, there is a lack of comparison of baseline characteristics between patients with RA receiving biological treatments. In this study, we have extracted the baseline characteristics of RA patients and their responses to RA therapy specifically, rituximab, from multiple RCTs and compared them with those of RA patients in a special registry by the name of the Kuwait Registry for Rheumatic Diseases (KRRD), from the Ministry of Health of Kuwait.

Inclusion criteria and study selection:

In our meta-analysis, we have included randomized controlled trials that recruited adult patients, regardless of age, who were previously diagnosed with RA and were treated with rituximab. Data from minors was not used in this study. The studies were conducted between 2006 and 2010. Regarding patients from the Kuwait Registry for Rheumatic Diseases (KRRD), the inclusion criteria was based on patients who were on rituximab regardless of the therapy duration, age, gender, and comorbidities. Only patients who were not on rituximab were excluded from the analysis.

The studies we included are those that reported the following: the patients’ comorbidities, medications, smoking status, current use of DMARDS, current use of steroids, DAS- 28 score, CRP, ESR levels and the HAQ-DI score. The health assessment questionnaire (HAQ) is a comprehensive measure of outcome in patients with rheumatoid arthritis. The HAQ focuses on seven categories, the patient’s ability to perform daily activity ranging from simple activities like dressing, eating, and walking; and weather or not they need assistance or devices to perform such activities. Each paper was independently assessed by three reviewers, and any disagreements were resolved by consensus, after discussion. The data compared was between the combined data from the Randomized controlled trials and that of the Registry.

Data extraction:

The data being used was collected from patients who were newly diagnosed or previously diagnosed with RA, who were attending their rheumatology clinic appointments. The patients' data was collected in a standardized sheet, which was standardized across the nation's rheumatology clinics in all governmental hospitals. All the patients diagnosed with RA in Kuwait included in this study were officially registered in the Kuwait Registry for Rheumatic Diseases (KRRD) from 2012 to 2020. The KRRD is the national registry of Kuwait, which lists all adult patients with rheumatic diseases. This study was approved by the Ethics Committees of the Faculty of Medicine at Kuwait University, the Ministry of Health, and the Kuwait Institute for medical specialization (KIMS). Informed consent was obtained from all study subjects. The collected data is entered and is secured in a computer program which is linked to all the hospitals. The use of the data from the registry was approved by the ethics committees of the Faculty of Medicine, University of Kuwait, and the Ministry of Health in Kuwait.

Informed consent

was obtained from all the represented patients enrolled in the registry. All the data of the patients in the registry who are receiving rituximab was used for comparison with the data from the patients in the RCTs who are also receiving treatment with rituximab. The data being compared from both the registry and the RCTs included the number of patients receiving rituximab, age, gender, seropositivity of RF, DAS 28 score, and prior use of DMARDS. Dichotomous data were extracted as numbers and percentages, and for continuous data, the mean and median with standard deviation was used.

Statistical Analysis

Meta-analyses were performed using the meta mean function from the R package meta in R Studio [31]. For each study with more than one value of DAS28 scores for the rituximab (RTX) group after randomization, a single value was calculated using the method described in Higgins, 2008 [32]. The overall mean value of DAS28 score was quantified by pooling the means provided by the original studies using Random effect models, and the results were represented as forest plots. Statistical heterogeneity between studies was assessed using I². We further used meta-regression analyses to assess the differences in DAS28 between RCTs and observational studies (The KRRD) by including the study design as a dichotomous covariate.

We have used in our literature search, randomized controlled trials (RCTs) that included patients who are diagnosed with rheumatoid arthritis (RA) and who are specifically being treated with Rituximab as their biological therapy, as well as those patients receiving the same biologic treatment from the Kuwait Rheumatology Registry Database (KRRD). Literature review of patients revealed a total of 388 studies, following review of relevant titles and abstracts with removal of duplicates, 24 studies were included for further full text analysis. Following full text review a total of 16 were included in the final analysis. In total, eight RCTs have met our inclusion criteria that involve RA patients treated exclusively with Rituximab as their biologic therapy, with or without existing or previous DMARD therapy, which made up in total a population of 1975 patients.

In the KRRD, there was a total of 1737 patients from the studied time of the years 2012 to 2020. In the registry 63% of patients were female, and 37% were male. 22.8% of patients had a negative rheumatoid factor (RF), and 77.2% had a positive RF during diagnosis of RA. In terms of anti-cyclic citrullinated peptide antibodies (anti-CCP), 66% of patients had a positive result, and 34% had a negative result. 10.3% of patients are smokers. The average duration of illness of the patients in the registry is 9.38 years. 10% of patients had other comorbidities along with their RA, which included diabetes mellitus (DM) (20.8%), hypertension (20.2%), hyperlipidemia (10.5%) and coronary artery disease (CAD) (3.1%). Four cases of cancer were reported [33]. The average total number of DMARDs the patients were regularly taking is 1.34, the average total number of biologics the patients were on was 0.38. The percentage of patients who were on a combination of biologic and DMARD medication is 25.4%. Those on biologics only, make up 12.6%, and those on DMARDs only 62.1%. The average number of tender joints in the patients in the registry was 2.91 joints, and the average number of swollen joints was 0.78.

All the above-mentioned figures are illustrated in (Table 1), which demonstrates the demographics of the patients in the KRRD.

(Table 2) demonstrates the comparison of different variables between the patients from the KRRD and the eight different RCTs, including numerous variables which turned out to be statistically significant when comparing both populations.

For example, patients with RA in RCTs were more likely to have a higher mean DAS28 score compared to those in the KRRD prior to being started on rituximab. Figures 1 and Figs. 2 are forest plots which illustrate the comparison of DAS28 scores for users of rituximab between the observational studies (KRRD) and the RCTs at baseline and post treatment, respectively.

The overall mean scores for DAS28 are 6.31 (95% CI: 5.11–7.52) and 4.35 (95% CI: 3.66–5.05) for the studies at baseline and post baseline respectively, with substantial inconsistency of effect I² > 75% (Figs. 1 and 2).

Compared to observational studies, the average DAS28 for RCTs are significantly higher by 2.78 to 4.06 at baseline and 0.65 to 2.99 after baseline. Due to the fact of the presence of a small number of studies, assessment of and further correction for bias could not be sufficiently ascertained.

In total, there were 172 RA patients who have received Rituximab as their only biologic therapy from the study time of the years 2012 to 2020. However, only 127 patients were included in the final analysis since they had their DAS-28 figures at baseline prior to biologic therapy and post baseline after a period following initiation of therapy. The 45 patients who were excluded from the KRRD were patients who have started Rituximab but have not been followed up after a period following their treatment, thus their post treatment DAS-28 score remains unrecorded in the registry.

Meta-analyses were done using the metameanbin function from the R package meta in R Studio [34]. For each study with more than one values of DAS28 scores for the RTX post baseline after randomization, a single value was calculated using the method described in Higgins, 2008 [35], considering measures of effect were represented as RR and its corresponding 95% CIs. The overall mean value of strength of DAS28 score association for number of days and potential cofounding factor (PCF) formation was quantified by pooling the measures of effects (RRs) means provided by the original studies using the Fixed Random effect models, and the results represented as forest plots. Statistical heterogeneity between studies was assessed using the I² and Tau². We further used meta-regression analyses to assess the differences in DAS28 between RCTs and observational studies by including the study design as a dichotomous covariate.

As we mentioned previously,127 patients from KRRD were included in our comparison study for the period from 2012–2020. Those patients were on rituximab as their only biological treatment. The goal of the study is to compare the characteristics of RA patients receiving rituximab from the KRRD with that of patients from RCTs. We have found clinically relevant differences between RCTs and observational studies in RA. There are different elements that account for the differences between RCTs and our KRRD registry patients, of which include the characteristics of the person such as age, sex, body weight, and baseline severity of disease.

Compared with RCTs, RA patients in our registry were older, by an average difference in age of 3 years (P value < 0.001, shown in Table 2). Like the patients making up the KRRD, the patients we included in our metanalysis were patients diagnosed with RA who are being treated with rituximab regardless of their age. Both the RCT and KRRD were representative of the real-life gender distribution of the disease as female participants were more than the male participants by a ratio of almost 4:1 and 3:1 respectively.

The disease activity of RA has always been recorded in KRRD using the number of swollen and tender joints in addition to the ESR level. This is calculated collectively in the disease activity score for RA (DAS-28). In the context of the tender joints, it has been shown in our analysis that the mean number of tender joints was thirty-two in the RCTs compared to around four joints in the KRRD which was statistically significant (P value < 0.001, shown in Table 2). For the number of swollen joints, the mean number was twenty-one in the RCTs and almost none in the KRRD. In the RCTs, only patients with active disease were included, but in the registry, the patients who had mild to moderate disease were also included, which closely resembles real life patient encounters.

This highlights the heterogenicity of the two populations, as in the RCTs only the severely affected patients with a high tender and swollen joint count made up the study population. Whereas the patients in the registry were more representative of a wider severity spectrum of RA disease activity. There is also a significant difference in the mean DAS-28 scores between the two patient populations (Table 2).

One of the RCTs called the Image Trial recruited the patients with highest DAS28 score with almost three times the value classified as active disease, demonstrating an overestimation of disease improvement. The erythrocyte sedimentation rate also showed a statistically signification difference between the RCTs and the registry patients (RCTs: a mean ESR of 46 mm/hr and KRRD mean ESR: 26 mm/hr) (Table 2). The RCTs also demonstrated an HAQ mean that was higher than that of the registry.

In conclusion, from all the previously mentioned parameters it has become obvious that the patients included in the RCTs are those with a more active disease when compared with those same RA patients making up the registry; therefore, the response to the treatment with rituximab with the patients in the RCTs was seen to be more dramatic when compared to those patients receiving the same treatment in the registry.

There are few points that we believe have strengthened our analysis. One being the search for studies that was done independently by three different authors. We reviewed the literature systematically and choose the studies that included RA patients being treated with rituximab. Data inclusion and extraction criteria was discussed and agreed upon between the authors and was individually checked by each one of us.

The limitations encountered while applying this comparison between the registry and RCTs, included some characteristics that were not reported accurately although had they been more appropriately reported, could have significantly contributed to our analysis. These characteristics included, concomitant MTX use, concomitant DMARD use, and the percentage of smokers.

In summary, we found important differences between RA patients included in RCTs as compared with observational studies; in particular, patients with better prognostic factors were included in the RCTs, which lead to a potential overestimation of the treatment effect. More research is needed to overcome this efficacy gap in the treatment of RA to generate real-world evidence that reflects real world patient encounters.

a) Ethics and consent to participate: Informed consent was taken from all patients prior to the publication of the data.

b) Consent for publication: Not applicable.

c) Availability of data and materials: Data in the forest plots of Figures 1 and 2, in the results section, which demonstrate comparison between RA patients in the KRRD and the RCTs prior to and after treatment with rituximab respectively is not available publicly, however it can be provided upon direct request from author Ahmad Al Saber,<[email protected]>.

Data in the Table 1 in the results section which shows the demographics of patients included in the Kuwait Registry for Rheumatic Diseases (KRRD) is not available publicly, however it can be provided upon direct request from author Ahmad Al Saber, <[email protected]>.

Data in Table 2 in the results section which compares different characteristics in rheumatoid arthritis patients between those included in the RCTS and those from the Kuwait Registry for Rheumatic Diseases (KRRD) is not available publicly, however can be provided upon direct request from author Ahmad Al Saber, <[email protected]>

d) Competing interests: Not applicable.

e) Funding: Not applicable.

f) Authors’ contributions:

Ahmad Al Shami: writing of results and discussion parts of manuscript.

Mohammad Al Mousa: writing of introduction and methods, as well as providing references and proofreading/editing of manuscript.

Fahad Al Muhanna: writing of results and discussion parts of manuscript.

Ahmad Al Saber: Provided statistical analysis for results as well as providing information for tables 1 and 2, in addition to the forest plots of figures 1 and 2.

Yaser M. Ali: Overall supervision and structure of the study.

g) Acknowledgments: Not applicable.

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Table (1): Demographics of the Kuwait Registry for Rheumatic Diseases (KRRD) Summary descriptive table

	[ALL]
	N = 1737
Gender:
Female	1094 (63.0%)
Male	643 (37.0%)
Age at Diagnosis	9.38 )6.75)
RF:
Negative	364 (22.8%)
Positive	1229 (77.2%)
ANTI.CCP:
Negative	467 (34.0%)
Positive	905 (66.0%)
on_comobination therapy	928 (53.4%)
Smoking	132 (10.3%)
TDMARD	1.34 (0.87)
Total biological therapy	0.38 (0.49)
Treatment:
Combination (at least one DMARD and at least one Biologic)	441 (25.4%)
Monotherapy (only biologics)	218 (12.6%)
Not on biologic therapy	1078 (62.1%)
Tender	2.91 (5.76)
Swollen	0.78 (2.54)

Table (2): (characteristic comparison table between the randomized controlled trials and Kuwait Registry for Rheumatic Diseases)

	Dancer	Mirror	Sunrise	Image	Reflex	keystone	Serene	Strand	RCT	KRRD	P-value
Female, n (%)	257 (81.3%)	277 (80.1%)	257 (80.8%)	415 (83.2%)	251 (81.5%)	242 (81.2%)	271 (80.4%)	91 (75.2%)	2061 (81.0%)	129 (75%)
Age, mean (SD)	51.1 (11.2)	52.4 (12.3)	54 (11.0)		52.2 (12.2)	52.2 (12.2)	51 (12.6)	53.3 (10.6)	52.31 (1.79)	55 (11.1)	< 0.001
RF (negative), n (%)		100 (28.9%)	74 (23.3%)	70 (14.0%)	66 (21.5%)	64 (21.5%)	86 (25.5%)		460 (18.1%)	43 (25.0%)	0.065
Tender, mean (SD)	33 (14.4)	32.3 (14.0)	32 (15.6)	33.6 (15.35)	33.9 (15.1)	33.8 (15.2)	28.7 (14.9)	32.9 (14.8)	32.53 (2.41)	3.51 (8.4)	< 0.001
Swollen, mean (SD)	22	19.3 (10)	22 (11.5)	22 (11.9)	23.4 (11.8)	23.3 (11.5)	19.5 (10.3)	20.8 (11.3)	21.54 (1.80)	0.48 (2.02)	< 0.001
DAS28, mean (SD)	6.75 (0.85)	6.73 (0.9)	6.7 (1.2)	7.05 (1.00)	6.9 (1.00)	6.8 (1.00)	6.5 (1.06)	6.8 (0.9)	6.78 (0.155)	2.69 (1.28)	< 0.001
ESR (mean)	43 (25.1)	46.5 (25.7)	42.4 (26.1)		48 (25.5)	47.8 (25.6)		51.7 (24.9)	46.57 (3.672)	26.7 (20.5)	< 0.001
CRP (mean)	3.1	2.3	1.9	3.2	3.7	3.7		3.1	3	6.38	-
VAS (mean)					3.8	3.8		3.1	3.57	1.81	-
HAQ, mean (SD)	1.75 (0.6)	1.69 (0.55)	1.5 (0.57)		1.9 (0.6)	1.8 (0.5)		1.8 (0.63)	1.74 (0.056)	1.06 (0.73)	< 0.001

Statistical descriptive presented as frequency (%, (SD))

No competing interests reported.

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Rheumatoid arthritis patients treated in trial and real world settings: comparison of randomized trials with a registry focus on rituximab

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