Safety of biological and targeted synthetic disease-modifying antirheumatic drugs for rheumatoid arthritis as used in clinical practice: results from the ARTIS programme

Objective Longitudinal clinical registry-infrastructures such as Anti-Rheumatic Therapies in Sweden (ARTIS) allow simultaneous comparison of the safety of individual immunomodulatory drugs used in clinical practice, with consistent definitions of treatment cohorts, follow-up and outcomes. Our objective was to assess and compare incidence rates of key safety outcomes for individual targeted synthetic or biological disease-modifying antirheumatic drugs (b/ts DMARDs) in rheumatoid arthritis (RA), updating previous reports and including newer treatments including Janus Kinase inhibitors (JAKi). Methods Nationwide register-based cohort study including all patients with RA in Sweden registered as starting any b/tsDMARD 1 January 2010 through 31 December 2020, followed until 30 June 2021 (N=20 117). The incidence rates of selected outcomes, identified through national healthcare registers, were compared between individual b/tsDMARDs, adjusted for confounding by demographics, RA disease characteristics and comorbidity. Results There were marked differences in treatment discontinuations due to adverse events (rates per 1000 person-years ranged from 18 on rituximab to 57 on tofacitinib), but few significant differences were observed for the serious adverse events under study. Neither cardiovascular events nor general serious infections were more frequent on baricitinib or tofacitinib versus bDMARDs, but JAKi were associated with higher rates of hospital-treated herpes zoster (HR vs etanercept, 3.82 (95% CI 2.05 to 7.09) and 4.00 (1.59 to 10.06)). Low number of events limited some comparisons, in particular for sarilumab and tofacitinib. Conclusion Data from ARTIS supports that the b/tsDMARDs currently used to treat RA have acceptable and largely similar safety profiles, but differences exist in particular concerning tolerability and specific infection risks.


The Swedish Rheumatology Quality Register (SRQ) and ARTIS
The Swedish Rheumatology Quality Register (SRQ) was started in 1995 by the Swedish Rheumatology Society to improve the healthcare and treatment for patients with RA. SRQ followed on regional register initiatives, to enable a national real-world documentation of many different aspects of RA and developed over time into a harmonized national register. SRQ was started mainly for patients with RA, but over time it has been expanded to cover several other rheumatic diseases including ankylosing spondylitis and psoriatic arthritis, Currently, some 29,000 patients with RA initiating over 70,000 biological treatments have been registered in SRQ. The register also contains early RA patients, and increasingly, RA patients can be followed from their first RA diagnosis and onwards. In conjunction with each patient visit, the treating rheumatologist enters data on disease activity and anti-rheumatic treatment, and the patient enters data on symptoms and health-status. The coverage of the SRQ is high, and was in 2015 estimated to be about 90% for new initiations of bDMARDs among patient with RA in Sweden. 2

The National Patient Register
The Swedish National Patient Register collects information on all hospitalized (inpatient treated) patients, and all visits to physicians in non-primary outpatient care (such as a visit to a rheumatologist). 3 Diagnoses are assigned by the discharging physician, and coded according to the ICD, with version 8 used until 1986, version 9 from 1987 to 1996, and version 10 since 1997. The register also collects information of the treating hospital, medical specialty, medical procedures or interventions, and dates of hospitalization and discharge. The inpatient component was originally initiated by several counties in 1964, had 85% country-wide coverage in 1983, and is considered complete since 1987. The outpatient component of the Patient register was initiated with nationwide coverage in 2001, but the coverage was poor for several medical areas in the first years, with substantial missingness in e.g. diagnosis. This improved quickly in the first five years of the outpatient component, and since 2010, the missingness in diagnosis is stable about 1% for inpatient care and 3% for outpatient care.
Reporting data to the register is mandatory for all health care providers in Sweden, and was done on an annual basis until 2015, when the frequency increased to monthly. Data is mostly reported by Sweden's 21 Regions (the intermediate governmental level, responsible for providing public health care), who have established different local processes for extracting the mandatory information from their regional electronic medical records system, and uploading it through the National Board of Health and Welfare's secure file transfer protocol. About 1% of inpatient healthcare visits and 5% of outpatient healthcare visits are reported directly from private healthcare providers (this can be privately funded healthcare, or because the private provider for some other reason does not share electronic medical records with the healthcare Region). The local files are combined and subjected to automated and semi-automated checks of logical consistency and content deviations from e.g. expected frequency of healthcare visits.
Due to the automated processes for extracting and reporting data, the register is today expected to correspond well to the information recorded in the local medical records. Historically, validation against medical files have found an overall error rate in the main diagnoses of 4% at the ICD chapter level, and 12% at the three digit level. 4 Diagnoses recorded in the medical record can of course also be incorrect, and chart reviews and validation of the RA diagnosis based on different algorithms applied to the register data indicate a positive predictive value for a register-based diagnosis of RA around 90%. [5][6][7] The Prescribed Drug Register Started in July 2005, the National Prescribed Drug Register contains data on all dispensations of prescription medication at Swedish pharmacies. The data reporting is mandatory, and linked to the softwares used in all pharmacies that dispenses regulated (i.e., prescription) medication. Data is uploaded daily to the Swedish eHealth Agency, who sends monthly summaries to the National Board of Health and Welfare where the register is finalized. The register contains information on the prescription (who wrote it, when, who is filling it, and was there a note on dosage made) and on the dispensed item (the package ID, the number of packages). The package ID is according to a national list and can be translated to the brand name, ATC code, mode of delivery, amount of drug, and cost of drug. Due to the automated set-up, the register is considered completely accurate. The register does not capture the indication for treatment, and will not cover medications used in a hospital setting (as they are not dispensed from pharmacies) or which are bought at pharmacies without prescriptions (i.e., over the counter drugs).

The National Cancer Register.
The Swedish National Cancer Register was established in 1958 and contains information on date of cancer (and some selected pre-cancers) onset, and type of cancer according to the ICD classification and morphology/histology. About 99% of cancers have been morphologically verified. Reporting of incident cancers (including invasive malignancies as well as selected types of cancer in situ) is mandatory and semiautomated, resulting in an estimated coverage greater than 95%. 8,9 In practice, reporting to the Cancer register often required two complementary reports: a pathologists report of morphological characteristics and a clinican's report of clinical stage and ICDO-coded diagnosis. As soon as one of these reports is sent to the Cancer register's regional center, it will start a process of investigation with reminders sent out until the report can be completed, and only then is it formally recorded in the register. The pathology reports are sent directly from the medical records system used at clinical laboratories, and have little lag time and high degree of completeness, while the clinical report can have substantial lag. For cancers which are never biopsied, this means that the coverage is much less complete. This is known to lead to underestimates of internal cancers with poor prognosis, in particular in older patients, and as much as 30% of pancreatic cancer has been estimated to be missing from the Cancer register. 10,11 For such types of cancer, it is recommended to also use data from the Cause of Death register.

The Cause of Death Register
The National Cause of Death Register contains information on date and cause of death (underlying and contributory) for all deceased residents, including deaths among Swedish residents who died abroad. The register was started in 1952, and the data is considered complete since 1961. 12 From that year and onward, cause of death is missing for less than 0.5% of deceased individuals, and in 2002, a validation study estimated that only 3.3% had any errors at the three-digit level of the ICD-coded underlying cause of death. The register depends on a semi-manual process of data collection, where the medical doctor who signs the death certificate is responsible for uploading the causal chain leading to the death directly to the National Board of Health and Welfare, where coding consistency is checked and follow-up questions can be sent out to confirm or complete records. The high completeness of the register is possible since the Board have access to the quickly updated census information, and send out reminders and follow-up questions for each recorded death lacking a valid cause of death certificate.

The Tuberculosis Register
The Public Health Agency maintains a register of certain communicable diseases, including a sub register on tuberculosis. This Tuberculosis (TB) Register started in 1969 on a national level and contains data on active TB diagnoses. Reporting incident TB cases to this register is done in parallel by both the microbiological laboratories and clinicians when a patient is culture-positive. In addition, any individual BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) clinically diagnosed with TB is reported to the TB register's web-based reporting system by the clinician. Completeness and quality of the data retrieved is monitored weekly, resulting in 100% coverage of all cases verified by culture. 13,14 The Total Population Register The Total Population Register is maintained by Statistics Sweden as the backbone of the Swedish system of national register. 15 Derived from the continuously updated census data at the Swedish Taxation Office, the register lists data on residency at a given point in time since it was founded in 1961, and dates of emigration/immigration for all subjects ever resident in Sweden since 1961. This register is used to identify the general population comparison cohorts, and to censor subjects who die or emigrate during follow-up.

Malignancy
The Cancer register All except benign tumors 10 yrs

Infection
As the outcome As the outcome 5 yr

Herpes zoster
As the outcome As the outcome 5 yr  Notes: a) Medical history in five years before treatment start, except serious infection (one year before start) and malignancy or joint surgery (ten years before). Standardized bias larger than 0.1 was considered indicative of poor balance, marked in red.

Knee or hip prosthesis
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)  Figure S1. MACE component outcomes among all Swedish RA patients who started b/tsDMARD 2010-2020.
Crude and weighted incidence rate per 1000 person-years of cardiovascular outcomes by b/tsDMARD, and adjusted hazard ratios versus etanercept. wIR, inverse probability of treatment weighted incidence rate per 1000 person-years, adjusted for demographics, RA clinical characteristics, and comorbidity; wHR, weighted hazard ratio from Cox regression.
BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s)  Figure S2. Incidence rate of safety outcomes comparing Swedish RA patients who started b/tsDMARD 2010-2020 to b/tsDMARD-naive patients with RA.
IR: age and sex-standardized incidence rate per 1000 person-years, and age-sex adjusted hazard ratios from Cox regression.