Data from the romanian registry of rheumatic Diseases for patients with rheumatoiD arthritis treateD with biologic anD targeteD synthetic Disease-moDifying anti-rheumatic Drugs During 2019

The number of rheumatoid arthritis (RA) patients with visits introduced in the Romanian Registry of Rheumatic Diseases (RRBR) has been steadily increasing within the last 3 years. Included patients display the classical phenotype of established RA, with a relatively high prevalence of extra-articular manifestations, cardiovascular comorbidity and a high burden regarding early retirement due to RA. Data regarding treatment showed a very low prevalence of monotherapy with biologic and targeted synthetic disease-modifying drugs (b/tsDMARD) and a low prevalence of glucocorticoid-therapy. Approximately a fifth of the patients started b/tsDMARD-therapy early during disease course (under 2 years from diagnosis). The most frequent prescribed bDMARD was etanercept, followed by adalimumab and rituximab. Treatment decisions trends in 2019 showed that some molecules present a negative balance, such as abatacept and rituximab, while others present a positive balance such as bDMARD biosimilars and tsDMARDs. Overall, b/tsDMARD achieved treatment target (DAS28-defined remission and LDA) within the first 6 months of treatment in 81.4% of treated patients. Also, RRBR data indicate a slow but significant increase in tapered regimens. Thus, the RRBR has proved to be a very valuable tool in capturing data regarding RA management in a real-life national setting of rheumatology healthcare.


INTRODUCTION
The Romanian Registry of Rheumatic Diseases (in Romanian, RRBR) is a national electronic database comprising all rheumatoid arthritis (RA) patients treated with reimbursed biological and targeted synthetic disease-modifying anti-rheumatic drugs (bDMARDs, tsDMARDs) [1]. RRBR was launched in February 2013 and it was designed as a prospective observational study. Efficacy and safety data are uploaded for each patient usually every 6 months by attending physicians. Prior to treatment and inclusion in the RRBR, all patients give written informed consent for both b/tsDMARD therapy and scientific use of their RRBR data. A consenting patient is included in the RRBR and begins treatment with b/ tsDMARDs if all of the following 4 criteria are fulfilled: • their RA diagnosis fulfills the 2010 RA classification criteria [2]; • there is significant RA activity according to DAS28 [3], defined simultaneously as: -DAS28 above 5.1, irrespective of disease duration, or DAS28 above 3.2 in early RA (defined as a disease duration shorter than 2 years) with at least 5 poor prognosis factors from the following: age below 45 years; rheumatoid factor (RF) and/or anti-citrullinated protein antibodies (ACPA) more than 10 times the upper limit of normal; erythrocyte sedimentation rate (ESR) above 50 mm/h or C-reactive protein (CRP) more than 5 times the upper limit of normal; erosions on conventional radiographs of hand and feet, ultrasound or magnetic resonance imaging; a score of 1.5 or above on the health assessment questionnaire (HAQ); the presence extra-articular manifestations; -5 or more tender/swollen joints from the DAS28 count; -at least 2 of the following 3 supplementary criteria: morning stiffness above 60 minutes, ESR above 28 mm/h, CRP more than 3 times the upper limit of normal, according to each local laboratory. -failure to achieve DAS28 remission or low disease activity with at least 2 conventional synthetic DMARDs (csDMARDs, usually methotrexate, leflunomide, sulfasalazine and hydroxychloroquine, alone or in combinations), used for at least 12 weeks each at maximum indicated or tolerated doses; -there are no contraindications according to summaries of product characteristics and physician evaluations. The RRBR can capture several types of treatment decisions: initiations (RA patients naïve to b/tsDMARDs who fulfill the above criteria and who will henceforth receive b/tsDMARDs with classical posology, reimbursed by the National Health Insurance House), initial monitoring (RA patients currently treated with b/tsDMARDs not reimbursed by the National Health Insurance House, for example patients from clinical trials or patient initiated on b/ tsDMARDs in other countries, using classical or tapered regimens, who will henceforth receive reimbursed b/tsDMARDs), continuations (visits at every 6 months of RA patients from the first categories who will continue their previous reimbursed b/tsDMARD either with classical regime, tapered regime or revert levels of tapering) and switches (RA patients with adverse events, primary or secondary non-responders who will not continue with their previous reimbursed b/tsDMARD, but with another).

RA CHARACTERISTICS OF 2019 RRBR PATIENTS
The number of RA patients with visits introduced in the RRBR has been increasing within the last 3 years ( Figure 1): starting from 4,171 patients in 2017, increasing with 5.7% in 2018 and reaching 4,755 patients in 2019 (14.0% increase compared to 2017 and 7.9% increase compared to 2018). In 2019, there were 752 cases (15.8%) without RRBR data for more 12 months and 404 cases (8.5%) were lost to follow-up.

FIGURE 1. Number of RA patients with visits introduced in the RRBR in the last 3 years
Demographically, the predominant patient profile was that of urban-dwelling overweight retired non-smoking women, with a mean age of 59.4 years and with established RA (mean disease duration of 13.7 years - Table 1). Of note, 1,756 patients were retired because of RA, meaning more than a third from the entire sample (36.9%) and more than half of the retired RA patients (51.3%). Regarding age distribution, the 2019 showed a very low prevalence of patients below 25 years of age (1.22%), with a predominance of patients aged 46-65 years (54.4%), followed by patients aged above 65 years (33.1%) and patients aged 26-45 years (11.2%) ( Figure 2).
From the total 4,755 RA patients in 2019, 4,604 (96.8%) had reports of RF tests, which were positive in 3,959 patients (86.0% from the subgroup with reported RF tests; Figure 3), according to each local laboratory. Similarly, 3,414 (71.8%) patients had reports of ACPA tests, which were positive in 2,853 patients (83.6% from the subgroup with reported ACPA tests). Overall, 2,719 patients were both RF and ACPA positive (76.6% of tested patients).

RA TREATMENT CHARACTERISTICS OF 2019 RRBR PATIENTS
All 4,755 RA patients received one current bDMARD or tsDMARD, with 1.6% of patients on bDMARD or tsDMARD monotherapy and 98.4% of them with at least one current associated csDMARD ( Figure 6), namely 76.7% on one current csDMARD, 20.7% on 2 current csDMARDs and 1.0% on 3 current csDMARDs.
As expected, methotrexate was the most frequent associated csDMARD (2,332 patients, 49.0% of total), with a mean weekly dose of 15 mg (45.8% of patients on methotrexate had 20 mg/week, 17.0% had 15 mg/week and 34.3% had 10 mg/week).
In the entire sample (n = 4,755), only 6.9% of patients were reported to use current oral glucocorticoids (prednisone of methylprednisolone), with 54.5% of them on low doses (7.5 mg/day prednisone equivalent or lower).
The mean RA duration at bDMARD and tsDMARD start was 8.2 years, with an approximately even distribution on disease duration categories (Figure 7), noting that 21.2% had early RA (defined as a disease duration under 2 years) when starting b/tsDMARDs, while 31.7% had a disease duration of over 10 years when starting b/tsDMARDs.
Treatment decisions trends in 2019 showed that some molecules present a negative balance (Table  3)

RA TREATMENT EFFICACY IN 2019 IN THE RRBR DATABASE
The therapeutic objective in RA is to achieve a state of remission of the disease, whenever possible (most commonly in early RA, with the early initiation of treatment), or a state of low disease activity (LDA), in cases where remission cannot be obtained (most commonly in established or severe forms of RA) [4]. The national guidelines for RA treatment and consequently the RRBR use DAS28-defined categories of disease activity (DAS28 up to 2.6 for remission and up to 3.2 for LDA), with additional information regarding SDAI-defined categories of disease activity (SDAI up to 3.3 for remission and up to 11.0 for LDA) [5].
In this sense, efficacy data for patients who were initiated on b/tsDMARDs in 2019 and who had their first 6-month evaluation in 2019 (n = 259), excluding switches, showed a significant variation of mean DAS28 (from 6.35 at initiation to 3.19 after the first 6 months) and of mean SDAI (from 42.3 at initiation to 10.7 after the first 6 months), both scores barely reaching the LDA target overall (Figure 9).
Of the 3,546 patients who continued the same b/ tsDMARD in 2019, there were 706 patients on rituximab which were excluded because of the particular re-administration strategy for this molecule accord- ing to the national protocol: repeated treatment will be administered after at least 24 weeks from the previous treatment cycle, only to responses (patients who previously achieved treatment target of remission/LDA) and only when one of the following conditions of disease activity is met: there is a residual active disease (DAS28 ≥ 3.2) or there is a reactivation of the disease with an increase in DAS28 with 1.2 or more, provided the disease activity class changes to the next higher activity level (from remission to LDA or from LDA to MDA). Excluding patients on rituximab leaved 2840 patients who continued with the same b/tsDMARD treatment in 2019 ( Figure 10) which revealed that 2,312 patients where within DAS28-defined treatment target of remission/LDA (representing 81.4% of treated patients) and 2,530 patients were within SDAI-defined treatment target of remission/LDA (representing 89.1% of treated patients).
As of 2019, from the entire sample, 57.7% of RA patients were exposed to a single b/tsDMARD, 26.2% received 2 consecutive b/tsDMARDs and 16.1% received 3 or more b/tsDMARDs (Table 4). When investigating efficacy in patients who continued the same b/tsDMARD (n = 2,840, excluding rituximab) according to the history of b/tsDMARD exposure, the mean DAS28 revealed that patients with up to 2 different b/tsDMARD exposures tended to be in remission, while patients with 3 or more b/ tsDMARD exposures were in LDA (Table 4), suggesting the need of dynamic treatment in more severe cases in order to reach the therapeutic target.
Compared to the end 2018, when 181 (4.11%) patients were receiving tapered bDMARDs and 17 patients returned from tapered doses to the classical frequency of bDMARD administration, at the end of 2019 a total of 216 (4.54%) patients were receiving tapered bDMARDs and 19 patients reverted their tapered bDMARD regimen (Figure 11).

CONCLUSIONS
The number of RA patients with visits introduced in the Romanian Registry of Rheumatic Diseases has been steadily increasing within the last 3 years. Included patients display the classical phenotype of established RA, with a relatively high prevalence of extra-articular manifestations, cardiovascular comorbidity and a high burden regarding early retirement due to RA. Data regarding treatment showed a very low prevalence of b/tsDMARD-monotherapy and a low prevalence of glucocorticoid-therapy. Approximately a fifth of the patients started b/tsDMARD-therapy early during disease course (under 2 years from diagnosis). The most frequent prescribed bDMARD was etanercept, followed by adalimumab and rituximab. Treatment decisions trends in 2019 showed that some molecules present a negative balance, such as abatacept and rituximab, while others present a positive balance such as bDMARD biosimilars and tsDMARDs. Overall, b/tsDMARD achieved treatment target (DAS28-defined remission and LDA) within the first 6 months of treatment in 81.4% of treated patients. Also, RRBR data indicate a slow but significant increase in tapered regimens. Thus, the RRBR has proved to be a very valuable tool in capturing data regarding RA management in a real-life national setting of rheumatology healthcare.