Introduction

Rheumatoid arthritis (RA) is considered a chronic inflammatory disease characterized by progressive destruction of the synovial joints, with typical clinical signs that allow, on occasions, high suspicion based on a diligent semiological examination¹. RA is an autoimmune disease due to its pathophysiological behavior determined by autoantibodies (rheumatoid factor and anticitrulline antibodies), which have special clinical utility: they are diagnostic, preceded by more complex clinical manifestations, and have prognostic value in both treatment and disease progression.

RA is closely related to a permanent disability; the Pan American Health Organization estimates that 34 million people suffer from it², with a direct impact on work ability and functional performance; therefore, early diagnosis and timely treatment are essential pillars to improve disease prognosis and reduce severity¹. RA management can be carried out with multiple care interventions³, disease-modifying anti-rheumatic drugs or biologics, according to the treating clinical specialist criteria⁴; however, this alternative is expensive and increasingly related to effects on patients' health and adverse events (AEs), defined by the World Health Organization as any unintentional injury or damage caused by healthcare intervention, but not by the underlying disease⁵.

In addition to the clinical and public health impact, the AEs associated with the management of autoimmune diseases with biological agents represent an economic burden equivalent to 1% of the total annual cost of treatment⁶, an underestimated value, since global studies with greater accuracy are lacking⁷. In developed countries, scientific literature has reported an increase in the frequency of AEs associated with biologics in various autoimmune diseases, such as Crohn's disease and ankylosing spondylitis, and RA, especially neurological (multiple sclerosis activation), cardiovascular (heart failure flare), and increased risk of opportunistic infections (tuberculosis reactivation)⁸. This has led to the construction of consensus arguments that question the safety of these drugs in the treatment of these diseases.

In Colombia, RA has a prevalence of 0.56%; biological therapy (BT) represents an alternative for its management^6,9. The Ministry of Health and Social Protection adopts the international definition of BT as those therapeutic procedures without genetic information use¹⁰. The National Institute for Food and Drug Surveillance (Invima) regulates the use and marketing of this type of medication, which must be registered, with mandatory reporting of documented adverse events. Until 2019, Invima had approved the following biologics for the treatment of RA: infliximab, rituximab, etanercept, abatacept, certolizumab pegol, golimumab, adalimumab, and tofacitinib¹¹. The latter was included in this study after considering that it is an alternative for the management of patients with RA; however, it is not classified as a biologic, since it is part of the category of specific targeted synthetic disease-modifying antirheumatic drugs.

Even though in Colombia there is a clinical practice guideline for the management of RA with BT, the reports and evidence of AEs in RA are still limited¹², and there is no baseline that allows the follow-up of these patients. Likewise, the safety of BT and its effect on improving health, disease status, and functional disability of patients are recognized¹³. The objective of this research was to identify AEs or adverse drug reactions (ADRs) in subjects diagnosed with RA who were managed with BT, between 2000 and 2019.

Population and study area

Materials and methods

Type of study

Operational research was carried out through a descriptive, cross-sectional study, with an analytical scope, and retrospective data collection.

Source of information

The clinical records of a cohort of patients with RA under BT in a benefit plan administrator entity (BPAE) that operates nationwide, through its health service provider institutions (HPI) and a specialized HPI, were reviewed, from 2000 to 2019. The Aranson classification of severity^11,14 was used for the study of Adverse Drug Reactions (ADRs), making use of their degrees and variations according to the source of information; this is described in detail in the results.

Eligibility criteria

Inclusion: Records of users with a confirmed diagnosis of RA, who had received a single dose, several doses, dose suspension, or partial or definitive change of BT were included. There had to be at least 2 assessments in the previously defined interval.

Exclusion: Records of users with a diagnosis of psoriatic RA, juvenile RA, difficulties in drug dispensing, or incomplete medical history were excluded.

Sample size

252 medical records of patients who met the selection criteria defined above were included. These records were analyzed from 2 sources: specialized HPI and primary care HPI; Information was collected from January 1, 2000, to June 31, 2019, as shown in Fig. 1. A data collection instrument was developed that enabled the achievement of information, the construction of the studied features, and its subsequent statistical analysis. For the quality of data, double reviews of records were conducted; thirty registries already documented were taken randomly and the obtained data were audited.

RA: Rheumatoid arthritis; BT: Biological therapy; CC: Clinical chart.

Fig. 1 Diagram for the identification of the registry of patients diagnosed with RA under treatment with BT in an insurer with national coverage from 2000 to 2019. 

Data management and statistical analysis Univariate analysis was performed using Stata14® software (StataCorp, College Station, Texas, USA). Descriptive statistics were applied, and the Shapiro-Wilk test was used for numerical variables. The distribution and quality of data of clinical and demographic characteristics were assessed; means with their respective standard deviation were calculated, while the nominal variables were summarized using means of proportions; for all, statistically significant differences were considered with p values <0.05.

For bivariate analysis, the calculation of the odds ratio (OR) was used for those who presented and those who did not present AE or ADR. Considering that all users included in the registries were exposed to one or several biologics, significant differences were sought through the odds ratio (OR), with their respective 95% confidence intervals and their significant P values <.05, based on the Fisher's t verification test and the Shapiro-Wilk tests for the normal distribution of variables. The estimation of the prevalence ratio was also used, using 2 x 2 tables to explore the possible associations against the different types of exposure and their clinical findings. Lastly, a multivariate analysis was performed using logistic regression to review the variables that were correlated with AE or ADR through bivariate analysis.

Ethical considerations

This research was approved as risk-free research by the ethics committees of the BPAE, the specialized IPS, and Universidad Libre, according to the national regulations outlined in Resolution 8430 of 1993 of the Colombian Ministry of Health, included in Act 010-2019.

Results

Selection criteria were applied to a population of 586 users diagnosed with RA, exposed to BT, and belonging to a cohort of a BPAE with national coverage, for which medical records from 2000 to the first semester of 2019 were reviewed. According to this, 57% (334/586) of the records were excluded and the information of the remaining 43% (252/586) that fully met inclusion criteria was analyzed.

Sociodemographic characterization of the study population revealed that women constitute most users, with 91% (227/252); the median age was 57 years (IQR: 26-88). Most of them came from the Colombian Caribbean region: 44% (111/252), and 54% (136/252) of the cases were actively employed (Table 1).

RA occurs more frequently between 56 and 57 years; 54% found themselves active at jobs.

In the conducted reviews, 30 different types of clinical findings were identified and classified as ADRs, according to their literature support, clinical relevance, and their persistent reference within the group of subjects evaluated, such as adynamia and asthenia, commonly referenced by patients with several drugs and found repeatedly (Table 2).

Etanercept was the drug with the most ADRs identified (20), and infliximab had the least (eight); the average number of ADRs per patient was 1.5 (CT: 1.71; 0-10); therefore, each patient with RA exposed to BT had at least one ADR during treatment (Fig. 2).

AE: adverse event; ADR: adverse drug reaction.

Fig. 2 Percentage of ADRs per patient according to medical records between 2000 and 2019. Briefly, 37.3% of 252 patients did not register ADR. In a single patient (0.4%), 10 ADRs and a single AE were identified.  

Bivariate analysis showed a relationship between exposure to biologics and clinical findings classified in our study as ADR. In this sense, significant differences were found: male gender (OR: 2.5; 95% CI: 1.02-6.67; P = .02), time exposure to BT for more than two years (OR: 3.1; 95% CI: 1.6-5.56; P = .0001), and receiving one biologic vs. more than one (OR: 0.3; 95% CI: 0.17-0.62; P = .0002) as a protective factor (Table 3).

However, when running the logistic regression model, the adjustment of the crude ORs was achieved and two effect-modifying variables were found: exposure time to the biologic for more than two years and BT with one drug vs. more than one. This reversal of the OR values is an exotic finding that raises new questions, such as the assessment of different time ranges against the exposure proposed by each drug, which was not possible for this study because the specific duration data for each biologic could not be obtained from the source of information, but the start and ending date of BT, in general, was clear. Concerning the other effect modifier variable (BT with one medication vs. more than one), further evaluation is also required.

In this way, emphasis is placed on the need for analytical studies that evaluate these two variables with better control of information bias. Male gender was determined as a confounding variable in the adjustment with this same model. No significant differences were found between the sociodemographic characteristics and the presence of ADR. The logistic regression model used was automated (stepwise), which prevented the manual operation of these variables (Table 4).

Under the Aranson classification of severity for the study of ADRs^11,14, (grade 1:no change in dosage; grade 2: a change in dose; grade 3: suspension of treatment), the conduct taken by the treating physician was determined. Due to the limitations of the medical records, subtypes A, B or C were not used. In this way, 368 ADRs occurred in this population, of which 67.9% (250/368) were classified as grade 1 (Fig. 3).

Fig. 3 Distribution of the severity of the total ADRs reported in the medical records of patients with RA between 2000 and 2019. In summary, 27.2% of ADRs were classified with the most severe grade according to Aranson's classification. Clinical records prevented establishing a trend in the number of ADRs per year. RA: Rheumatoid arthritis; ADR: adverse drug reaction. 

The most frequent ADRs were myalgia/arthralgia in 24.2% (89/368), headache (migraine) in 14.4% (53/368), and recurrent flu syndromes in 13.9% (51/368).

The ADRs that occurred with all biologics included Sjögren’s syndrome, migraine, myalgia/arthralgia, and recurrent flu syndromes. Regarding the ADR prevalence ratio (PR) compared between drugs, it was found that psoriasis is five times more prevalent in rituximab (PR = 5.0); chronic obstructive pulmonary disease flare was 4.2 times more prevalent with infliximab (PR = 4.2), and elevation of transaminases was 3.6 times more prevalent with tocilizumab (Table 5).

Discussion

In Colombia, the prevalence of RA and its sociodemographic characteristics have been established⁹; however, evidence regarding patient safety with therapeutic options, including BT, is still scarce¹⁵. This research revealed a situational and contextual scenario in an BPAE with national coverage of ADRs related to biologics for the management of this disease.

The considerations analyzed are based on the study of other sociodemographic aspects such as age, territorial location, health system affiliation, and work activity, which did not show any link with the effect on the user's health during exposure to BT¹⁶.

Among the clinical features, it was found that 37.5% of the ADRs were related to the application of etanercept, which despite being the most frequent, did not establish a trend concerning severe ADRs; this finding was also referenced in the literature when compared with other drugs within the analyzed sample⁷.

Determining the most frequent ADRs disputes the true impact of the use of BT for treatment of RA, since myalgia and arthralgia were the most frequent in this study, considering that it could be an important determinant for users' quality of life and their work potential, in terms of temporary and permanent disability, which is associated with the numbers mentioned by health organizations on an international scale^2,17.

Another relevant ADR after BT was tuberculosis^18,19, with a proportion of 5.2% (252/19), which, although rare, should have control and surveillance by the treating physicians, due to a high impact on public health in Colombia; these findings were also reported in Canada and European countries^18,19.

Among the ADRs with low statistical impact, but with clinical relevance in this study, we mention the case of demyelination of the upper limbs²⁰, like one reported in Ireland, where the relationship between rituximab and demyelinating diseases is suggested²¹. In addition, a single case of thyroid cancer was described²², which may be related to immune response alteration that may favor activation of oncogenesis.

ADRs described in this research considerably impact the quality of life and well-being of BT users, considering that 63% of them presented at least one that compromised their safety under the application of this technology. Review of evidence is controversial regarding the presence of ADRs and the use of BT since the conflicts of interest mediate in showing objective and impartial results; even in ADR reviews in other diseases susceptible to being treated with this therapy, precise data on different outcomes were not found.

On the other hand, a relationship between the time of exposure to BT and receiving one or more biologics and the presence of ADRs may be feasible; the statistical analyses obtained only allow us to propose these relationships as new hypotheses that must be verified with future studies. In the literature reviewed, no follow-up of complete cohorts of patients with all types of BT was evidenced; mainly isolated case reports²³ or economic evaluations of up to 3 drugs⁷ were found, which strengthened the need for this study.

Grade-3 severity in the ADR classification had a significant proportion (27%), which may influence the safety outlook of these medications; therefore, these results are an initial approximation for patient safety adjustments in healthcare institutions, as recommended by the Ministry of Health guidelines²⁴.

Conclusions

ADRs produced by exposure to BT in RA are frequent and severe; this study achieved the projection of a previously unknown scenario, inquiring about the readjustment of the well-known concept of risk-benefit in clinical practice. Going deeper into the investigation on patient safety will allow warnings for early detection by medical specialists and experts, given that the current ignorance of the subject may be part of the problem since the patient is not investigated clinically searching for possible negative effects on their biopsy-chosocial well-being derived directly and indirectly from therapy.

The fact of highlighting the most serious degree of severity (which implies the suspension of the drug due to ADRs), as a large proportion within the classified groups, confirms the previously stated importance of delving into the issue of patient safety about BT of the therapy for RA, considering that the patient exposed to this indication during his treatment must be assessed in a routine, systematic, and diligent manner to timely identify the presence of ADRs.