Data from the romanian registry of rheumatic Diseases (rrBr) for patients with axial sponDyloarthritis treateD with Biologic Disease-moDifying anti-rheumatic Drugs (bDmarDs) During 2019

The Romanian Registry of Rheumatic Diseases (RRBR, in Romanian) is an electronic application that includes data of all patients with inflammatory rheumatic diseases treated with biologics in Romania. First patients with axial spondyloarthritis (axSpA) were included in 2015 and the registry collected multiple variables like demographics, axSpA therapies, disease activity, adverse events, in order to provide data for patients in our country. The number of axSpA patients introduced in RRBR has been steadily increasing within the last 3 years. The patients included in the registry are with the two types of ax SpA (non-radiographic and radiographic spondyloarthritis) with a relatively high prevalence of extra-scheletal manifestations and a lot of comorbidities. Data regarding treatment showed a prevalence of monotherapy with biologic disease-modifying anti rheumatic drugs (bDMARDs), TNF-alpha inhibitors being used by 91% of the patients. 41% of the patients started bDMARD-therapy early during disease course (under 2 years from diagnosis). The most frequent prescribed bDMARDs was adalimumab, followed by etanercept. Treatment decisions trends in 2019 showed that some molecules present a positive balance such as bDMARD biosimilars and secukinumab. Overall, bDMARDs achieved treatment target (ASDAS defined remission and LDA) within the first 6 months of treatment in 87.6% 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 axial spondyloarthrits management in a real-life national setting of rheumatology healthcare.


INTRODUCTION
Axial spondyloarthritis (axSpA) is a disabling inflammatory arthritis of the spine, presenting frequently as chronic back pain, typically before the age of 45. It is associated with one or more of several articular features, including synovitis, enthesitis, and dactylitis. It may also be associated with uveitis, psoriasis, and inflammatory bowel diseases. Axial SpA includes non-radiographic axial SpA (nr-ax-SpA), without plain radiographic changes on sacroiliac joints and ankylosing spondylitis with radiographic changes of sacroiliitis (1).
The Romanian Registry of Rheumatic Diseases (RRBR) is a national electronic database comprising all patients with axial spondyloarthritis (axSpA) treated with reimbursed biological (bDMARDs) [1]. RRBR was launched in February 2013 as a prospective observational study for patients with rheumatoid arthritis and in 2015 were included for observational study patients with axSpA. 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 bDMARD therapy and scientific use of Ref: Ro J Rheumatol. 2020;29(1) DOI: 10.37897/RJR.2020. 1.5 their RRBR. Long-term efficacy, safety, drug survival and switch were evaluated and presented every year.
The guidelines for biological treatment in axSpA are represented by inclusion criteria: -Confirmed axial SpA diagnosis according to ASAS/EULAR (2009) criteria; -Active disease: ASDAS > 2.5 or BASDAI > 6; for patients with extrascheletal manifestations or coxitis ASDAS > 2.1, BASDAI> 4, elevated C-reactive protein (CRP) > 3xN or erytrocyte sedimentation rate (ESR) > 28 mm/1 h -Failure to standard treatment (2 NSAIDs > 6 weeks, Sulphasalazine (SSZ) for peripheral involvement, local steroid injection -Second opinion The RRBR can capture several types of treatment decisions: -initiations (ax SpA) patients naïve to b DMARDs who fulfill the above criteria and who will henceforth receive bDMARDs with classical posology, reimbursed by the National Health Insurance House, -initial monitoring (axSpA patients currently treated with bDMARDs not reimbursed by the National Health Insurance House, for example patients from clinical trials or patient initiated on bDMARDs in other countries, using classical or tapered regimens, who will henceforth receive reimbursed bDMARDs -continuations (visits at every 6 months of ax-SpA patients from the first categories who will continue their previous reimbursed bD-MARD either with classical regime, tapered regime or revert levels of tapering) -switches (axSpA patients with adverse events, primary or secondary non-responders who will not continue with their previous reimbursed bDMARD, but with another).

AXSPA CHARACTERISTICS OF 2019 PATIENTS
The number of axSpA patients with visits introduced in the RRBR has been increasing within the last 3 years ( Figure 1): 3,187 patients in 2017, 3,417 patients in 2018 (7.2% increase compared to 2017) and 3,651 patients in 2019 (6.9% increase compared to 2018). In 2019, there were 417 cases (11.4%) without RRBR data for more 12 months and 137 cases (3.8%%) were lost to follow-up. Demographically, the predominant patient profile was that of urban-dwelling overweight young non-smoking man, with a mean age of 46.8 years and with established axSpA (mean disease duration of 12.23 years - Table 1). Of note, 967 patients were retired because of axSpA meaning 26% the entire sample. Regarding age distribution, patients form 2019 showed a very low prevalence of patients below 25 years of age (%), with a predominance of patients aged 46-65 years (%), followed by patients aged above 65 years (%) and patients aged 26-45 years ( Figure 2). HLA-B27 was tested in 2,160 patients (59%) and 1,992 patients (92%) were HLA-B27 positive.
According to ASAS/EULAR 2009 classification criteria for axial SpA, of the 3,651 patients in 2019 RRBR database, 335 patients (9%) were without plain radiographic changes, but with bone edema on MRI and they were classified as non-radiographic axial SpA (nr-axSpA), while 3,316 patients (91%) were with radiographic changes of sacroiliitis (sacroiliitis fulfilling the New York criteria). Surprisingly, 407 patients reported with axSpA (12.3%) had no RRBR records of imaging sacroiliitis ( Figure 3).

Figure 3. Proportion of patients with axSpA and nr-axSpA
AxSpA is more common among men, but the frequencies among women are higher in nr-axSpA with male/female ratio 2/1. There are also some other characteristics of patients with nr-axSpA. They are younger than patients with AS with a mean age of disease 42.3 and with a mean disease duration 7.2 years, lower as compared with all patients with ax-SpA (table 2).
The cohort exhibited a high prevalence of early bDMARDs treatment: 41.5% of patients started bDMARDs within the first 2 years of disease evolution, while 25% had a disease duration of over 10 years when starting bDMARDs ( figure 7).
The number of initiations, continuations and switches in 2019 were quite similar to 2018 (table 3).  From the total of 2,823 axSpA patients on molecules with available biosimilars in 2019 in Romania (namely adalimumab, for which biosimilars became available later in the year, and etanercept and infliximab, for which biosimilar were already available from the start of the year), 85.7% were on originator molecules and 14.3% on biosimilars. 91% of the patients treated with biologics were on TNF-alpha inhibitors and only 9% on Secukinumab (table 4).
Of note, the most frequently prescribed bDMARD was adalimumab, received by 1,199 patients (meaning 33% from the 3,651 patients on active bDMARD treatment), followed by etanercept received by 1,182 patients (32.5%) and infliximab (12%). TNF-alpha inhibitors were used to treat 91% of the patients and 9% of the patients were treated with the only non-TNF inhibitor approved in Romania, secukinumab, a human IgG1k monoclonal antibody that binds to the protein interleukin (IL)-17A. Treatment decisions trends in 2019 is showed in Table 5.

AXSPA TREATMENT EFFICACY IN 2019 IN THE RRBR DATABASE
The primary goals of management for patients with axial spondyloarthritis (AxSpA) are to optimize short-and long-term health-related quality of life. The available data suggest that therapy should be commenced at an early stage of the disease, when the process of bone repair expected to occur after an inflammatory phase has not yet started. The 2016 update of the Assessment of Spondyloarthritis International Society (ASAS) and the EULAR guidelines included a new recommendation supporting the T2T paradigm in axSpA (2). Clinical assessment should include a focused history and examination directed at the patient's known manifestations and screening for other features associated with axial spondyloarthritis (axSpA). The adequacy of the response is  (2). Clinically significant improvement is defined as either a 50 percent improvement of the BASDAI score (BASDAI 50) or an absolute change of ≥ 2 on a scale of 0 to 10 and a clinical "expert" opinion that a particular patient has improved. The ASDAS categorizes the disease activity as inactive, low, high, or very high. A change of ≥ 1.1 in the ASDAS score is considered a significant improvement, while a change of ≥ 2.0 is a major improve-ment (3). ASDAS has been shown to have good discriminatory capacity and sensitivity to change because incorporates an objective measure of disease activity such as CRP or ESR. ASDAS inactive disease (< 1.3) can be considered a possible target and remission criterion in axSpA (4).
In 2019 in RRBR there were 383 initiations with monitoring visits at 6 months: for these patients, the average BASDAI decreased with 4.92 and the average ASDAS decreased with 2.72 (figure 8).
There were 2,922 continuations in the cohort: for these patients, compared to 6 months prior, the current evaluation showed that the average BASDAI  Achieving inactive disease may improve structural and functional outcomes and stop the development of radiographic spine damage. Data from RRBR demonstrated that 1,439 patients (49.6%) for 2,922 continuations in the cohort achieved remission according to ASDAS and 1,108 patients (38%) achieved a low disease activity with ASDAS between 1.3 and 2.1.
As of 2019, from the patients which continue the biological treatment, 2,613 axSpA patients (89.4%) were exposed to a single bDMARD and 725 (24.81%) patients received 2 consecutive bDMARDs and 10.71% received 3 or more bDMARDs (Table 6). When investigating efficacy in patients who continued the bDMARD (n = 2,922), according to the history of bDMARDs exposure, the mean ASDAS revealed that patients with 1 biological exposure tended to be in remission and those with 2 or more different bDMARDs exposures were in LDA (Table 6), suggesting the need of dynamic treatment in more severe cases in order to reach the therapeutic target.
Tapering strategy for anti-TNF therapy is successful in maintaining remission or LDA in most patients with axial spondyloarthritis (5). The bDMARD dosage tapering had been made in patients with a maintained remission more than 12 months and consisted of the following: increase the interval between doses for subcutaneous bDMARDs or reduction of the dose for intravenous bDMARDs. Compared to the end 2018, when 305 (8.9%) patients were receiving tapered bDMARDs and 27 patients returned from tapered doses to the classical frequency of bDMARD administration, at the end of 2019 a total of 351 (9.6%) patients were receiving tapered bDMARDs and 42 patients reverted their tapered bDMARD regimen (Tabel 7).

CONCLUSIONS
The number of axSpA patients with visits introduced in the Romanian Registry of Rheumatic Diseases has been steadily increasing within the last 3 years. Patients included in RRBR display are with a relatively high prevalence of extra-articular mani- Figure 9. The variation of mean BASDAI and ASDAS for 2,922 continuations in the cohort festations, cardiovascular comorbidity. Data regarding treatment showed a prevalence of bDMARD-monotherapy. Approximately 41% of the patients started bDMARD-therapy early during disease course (under 2 years from diagnosis). The most frequent prescribed bDMARD was adalimumab, followed by etanercept and infliximab. Treatment decisions trends in 2019 showed that some molecules present a positive balance such as bDMARD biosimilars. Overall, bDMARDs achieved treatment target (ASDAS-defined remission and LDA) within the first 6 months of treatment in 87.6% 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 axSpA management in a real-life national setting of rheumatology healthcare.