Studies of drug safety in the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting mainly smaller joints. Patients are at risk for complications as joint destruction, but starting treatment soon after onset of disease, has reduced the risk for complications. Methotrexate (MTX) is the anchor drug in the treatment of RA and has proven effects on both inflammatory symptoms and joint destruction. apy. Identifying patients at risk for MTX-induced hepatotoxicity before treatment could be a way to minimize the risk for Adverese effects.Following the introduction of pre-treatment screening, the risk of tuberculosis (TB) among patients with RA starting biologic treatment has decreased. By contrast, the risk remains several-fold increased in RA patients non-exposed to biological treatment. Knowledge about risk factors for TB and TB characteristics in this group of patients, and thus optimal clinical risk stratification and preven-tion, is still limited.In Paper I, only a small number of ALT tests (7%) performed during MTX therapy in RA patients, capture an elevation of ALT > upper limit of normal (ULN). ALT >1.5 × ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT. Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions. The results support a more individualized approach to monitoring and handling of ALT elevations during MTX therapy. In Paper II MTHFR A1298C (rs1801131) was nominally associated with ALT >1.5 x ULN within 6 months after the start of MTX (OR=1.7 [95% CI 1.04-2.9], p=0.03). In a multi-ple regression analysis for ALT >1.5 X ULN within 6 months of treatment start, including known risk factors for ALT elevation and MTHFR A1298C, the C-statistic was 0.734. A mod-el containing clinical risk factors and MTHFR A1298C might be used for prediction of ALT elevation in MTX treated patients. In Paper III a Genome-Wide Association Study (GWAS) and analysis of candidate Single Nucleotide Polymorphisms (SNPs) were performed. Four SNPs in and upstream of the ribonucleoprotein, PTB Binding 2 gene on chromosome 1 were associated with max ALT within 6 months on a genome wide level (p<5x10-8). Our results indicate that the RAVER2 and/or JAK1 genes might play a role in MTX- induced hepatotoxici-ty, but further studies are necessary for confirmation of the results. In Paper IV, we performed a population based case-control study. Several RA-associated risk factors (treatment with leflunomide, azathioprine or prednisolone and concomitant obstructive lung disease) may contribute to the increased TB risk in biologics-naïve RA patients. We could not confirm previous findings of an association with the use of moderate to high doses of prednisolone (≥15 mg). TB risk seems difficult to predict with precision in the individual biologics-naïve patient based on RA-associated risk factors. This suggests TB screening should be considered in biologics-naïve patients. In conclusion, results from these studies suggest that several factors could increase the risk of AEs in RA patients. The risk might be reduced by utilizing prediction models that include knowledge about the medical history of the individual patient and genetic data in combination with screening for TB

Studies of drug safety in the treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting mainly smaller joints. Patients are at risk for complications as joint destruction, but starting treatment soon after onset of disease, has reduced the risk for complications. Methotrexate (MTX) is the anchor drug in the treatment of RA and has proven effects on both inflammatory symptoms and joint destruction. apy. Identifying patients at risk for MTX-induced hepatotoxicity before treatment could be a way to minimize the risk for Adverese effects.Following the introduction of pre-treatment screening, the risk of tuberculosis (TB) among patients with RA starting biologic treatment has decreased. By contrast, the risk remains several-fold increased in RA patients non-exposed to biological treatment. Knowledge about risk factors for TB and TB characteristics in this group of patients, and thus optimal clinical risk stratification and preven-tion, is still limited.In Paper I, only a small number of ALT tests (7%) performed during MTX therapy in RA patients, capture an elevation of ALT > upper limit of normal (ULN). ALT >1.5 × ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT. Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions. The results support a more individualized approach to monitoring and handling of ALT elevations during MTX therapy. In Paper II MTHFR A1298C (rs1801131) was nominally associated with ALT >1.5 x ULN within 6 months after the start of MTX (OR=1.7 [95% CI 1.04-2.9], p=0.03). In a multi-ple regression analysis for ALT >1.5 X ULN within 6 months of treatment start, including known risk factors for ALT elevation and MTHFR A1298C, the C-statistic was 0.734. A mod-el containing clinical risk factors and MTHFR A1298C might be used for prediction of ALT elevation in MTX treated patients. In Paper III a Genome-Wide Association Study (GWAS) and analysis of candidate Single Nucleotide Polymorphisms (SNPs) were performed. Four SNPs in and upstream of the ribonucleoprotein, PTB Binding 2 gene on chromosome 1 were associated with max ALT within 6 months on a genome wide level (p<5x10-8). Our results indicate that the RAVER2 and/or JAK1 genes might play a role in MTX- induced hepatotoxici-ty, but further studies are necessary for confirmation of the results. In Paper IV, we performed a population based case-control study. Several RA-associated risk factors (treatment with leflunomide, azathioprine or prednisolone and concomitant obstructive lung disease) may contribute to the increased TB risk in biologics-naïve RA patients. We could not confirm previous findings of an association with the use of moderate to high doses of prednisolone (≥15 mg). TB risk seems difficult to predict with precision in the individual biologics-naïve patient based on RA-associated risk factors. This suggests TB screening should be considered in biologics-naïve patients. In conclusion, results from these studies suggest that several factors could increase the risk of AEs in RA patients. The risk might be reduced by utilizing prediction models that include knowledge about the medical history of the individual patient and genetic data in combination with screening for TB

Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes : A long-term follow-up of predictors, surveillance, and outcome in clinical practice

Aim: To assess predictors of alanine aminotransferase (ALT) elevation in methotrexate (MTX) treated rheumatoid arthritis (RA) patients, and to describe the monitoring of liver enzymes, including handling and outcome of elevated ALT. Methods: All RA patients starting MTX in January, 2005 to April, 2013 at a rheumatology clinic, (Uppsala University Hospital, Sweden) were identified from electronic medical records. Clinical and laboratory data were obtained from medical records, supplemented by telephone interviews. Predictors for ALT >1.5x over the upper limit of normal (ULN) were identified by multiple regression analysis. Results: The study comprised 213 RA patients starting MTX. During a mean follow-up of 4.3 years, 6288 ALT tests were performed; 7% of tests with ALT were >ULN. ALT >1.5x ULN was observed in 44 (21%) patients and the strongest predictor was a pre-treatment elevation of ALT (adjusted odds ratio = 6.8, 95% CI 2.2-20.5). Recurrent elevations occurred in 70% of patients who continued treatment, and the proportion was similar in those with and without interventions, for example MTX dose reduction (67% vs 73%, P = 0.43). Seven patients (3%) permanently stopped MTX due to ALT elevation, and two were eventually diagnosed with non-alcoholic fatty liver disease. No patient developed hepatic failure. Conclusion: Only a small number of ALT tests performed during MTX therapy in RA capture an elevation. A pre-treatment elevation of ALT was the strongest predictor for early and recurrent ALT elevations during therapy. This study supports a more individualized approach to monitoring and handling of ALT elevations during MTX therapy in RA than recommended in current guidelines

Treatable traits and exacerbation risk in patients with uncontrolled asthma prescribed GINA step 1–3 treatment : a nationwide asthma cohort study

Background and Objective: Uncontrolled asthma in patients treated for mild/moderate disease could be caused by non-pulmonary treatable traits (TTs) that affect asthma control negatively. We aimed to identify demographic characteristics, behavioural (smoking) and extrapulmonary (obesity, comorbidities) TTs and the risk for future exacerbations among patients with uncontrolled asthma prescribed step 1–3 treatment according to the Global Initiative for Asthma (GINA). Methods: Twenty-eight thousand five hundred eighty-four asthma patients (≥18 y) with a registration in the Swedish National Airway Register between 2017 and 2019 were included (index-date). The database was linked to other national registers to obtain information on prescribed drugs 2-years pre-index and exacerbations 1-year post-index. Asthma treatment was classified into step 1–3 or 4–5, and uncontrolled asthma was defined based on symptom control, exacerbations and lung function. Results: GINA step 1–3 included 17,318 patients, of which 9586 (55%) were uncontrolled (UCA 1–3). In adjusted analyses, UCA 1–3 was associated with female sex (OR 1.34, 95% CI 1.27–1.41), older age (1.00, 1.00–1.00), primary education (1.30, 1.20–1.40) and secondary education (1.19, 1.12–1.26), and TTs such as smoking (1.25, 1.15–1.36), obesity (1.23, 1.15–1.32), cardiovascular disease (1.12, 1.06–1.20) and depression/anxiety (1.13, 1.06–1.21). Furthermore, UCA 1–3 was associated with future exacerbations; oral corticosteroids (1.90, 1.74–2.09) and asthma hospitalization (2.55, 2.17–3.00), respectively, also when adjusted for treatment step 4–5. Conclusion: Over 50% of patients treated for mild/moderate asthma had an uncontrolled disease. Assessing and managing of TTs such as smoking, obesity and comorbidities should be conducted in a holistic manner, as these patients have an increased risk for future exacerbations

Severe COVID-19 among patients with asthma and COPD : a report from the Swedish National Airway Register

Background: Patients with obstructive lung diseases may be at risk of hospitalization and/or death due to COVID-19. Aim: To estimate the frequency of severe COVID-19, and COVID-19-related mortality in a well-defined large population of patients with asthma and chronic inflammatory lung disease (COPD). Further to assess the frequency of asthma and COPD as registered comorbidities at discharge from hospital, and in death certificates. Methods: At the start of the pandemic, the Swedish National Airway Register (SNAR) included 271,404 patients with a physician diagnosis of asthma and/or COPD. In September 2020, after the first COVID-19 wave in Sweden, the database was linked with the National Patient Register (NPR), the Swedish Intensive Care Register and the Swedish Cause of Death Register, which all provide data about COVID-19 based on International Classification of Diseases (ICD-10) codes. Severe COVID-19 was defined as hospitalization and/or intensive care or death due to COVID-19. Results: Among patients in SNAR, 0.5% with asthma, and 1.2% with COPD were identified with severe COVID-19. Among patients  < 18 years with asthma, only 0.02% were severely infected. Of hospitalized adults, 14% with asthma and 29% with COPD died. Further, of patients in SNAR, 56% with asthma and 81% with COPD were also registered in the NPR, while on death certificates the agreement was lower (asthma 24% and COPD 71%). Conclusion: The frequency of severe COVID-19 in asthma and COPD was relative low. Mortality for those hospitalized was double as high in COPD compared to asthma. Comorbid asthma and COPD were not always identified among patients with severe COVID-19

Multiple manifestations of uncontrolled asthma increase the risk of severe COVID-19

Objective: Asthma control is of importance when assessing the risk of severe outcomes of COVID-19. The aim of this study was to explore associations of clinical characteristics and the effect of multiple manifestations of uncontrolled asthma with severe COVID-19. Methods: In 2014–2020, adult patients with uncontrolled asthma, defined as Asthma Control Test (ACT) ≤19 were identified in the Swedish National Airway Register (SNAR) (n = 24533). The SNAR database, including clinical data, was linked with national registers to identify patients with severe COVID-19 (n = 221). The effect of multiple manifestations of uncontrolled asthma was based on: 1) ACT ≤15, 2) frequent exacerbations and 3) previous asthma inpatient/secondary care and evaluated stepwise. Poisson regression analyses were conducted with severe COVID-19 as the dependent variable. Results: In this cohort with uncontrolled asthma, obesity was the strongest independent risk factor for severe COVID-19 in both sexes, but even greater in men. Multiple manifestations of uncontrolled asthma were more common among those with severe COVID-19 vs. without: one, 45.7 vs. 42.3%, two, 18.1 vs. 9.1% and three, 5.0 vs. 2.1%. The risk ratio (RR) of severe COVID-19 increased with an increasing number of manifestations of uncontrolled asthma: one, RR 1.49 (95% CI 1.09–2.02), two, RR 2.42 (95% CI 1.64–3.57) and three, RR 2.96 (95% CI 1.57–5.60), when adjusted for sex, age, and BMI. Conclusions: It is important to consider the effect of multiple manifestations of uncontrolled asthma and obesity when assessing patients with COVID-19, as this increases the risk of severe outcomes substantially

Genome-wide association study of liver enzyme elevation in an extended cohort of rheumatoid arthritis patients starting low-dose methotrexate

Aim: A follow-up genome-wide association study (GWAS) in an extended cohort of rheumatoid arthritis (RA) patients starting low-dose methotrexate (MTX) treatment was performed to identify further genetic variants associated with alanine aminotransferase (ALT) elevation. Patients & methods: A GWAS was performed on 346 RA patients. Two outcomes within the first 6 months of MTX treatment were assessed: ALT >1.5-times the upper level of normal (ULN) and maximum level of ALT. Results: SPATA9 (rs72783407) was significantly associated with maximum level of ALT (p = 2.58 x 10(-8)) and PLCG2 (rs60427389) was tentatively associated with ALT >1.5 x ULN. Conclusion: Associations with SNPs in genes related to male fertility (SPATA9) and inflammatory processes (PLCG2) were identified

Genome-wide association study of liver enzyme elevation in rheumatoid arthritis patients starting methotrexate

Aim: To identify novel genetic variants predisposing to elevation of Alanine aminotransferase (ALT) in rheumatoid arthritis (RA) patients after initiation of methotrexate (MTX) treatment. Patients & methods: We performed genome-wide association studies in 198 RA patients starting MTX. Outcomes were maximum level of ALT and ALT >1.5-times the upper level of normal within the first 6 months of treatment. Results: RAVER2 (rs72675408) was significantly associated with maximum level of ALT (p = 4.36 × 10-8). This variant is in linkage disequilibrium with rs72675451, which is associated with differential expression of JAK1 and RAVER2. Conclusion: We found an association between ALT elevation and genetic variants that may regulate the expression of JAK1 and RAVER2. JAK1 encodes a janus kinase involved in the pathogenesis of RA

Uncontrolled asthma predicts severe COVID-19: a report from the Swedish National Airway Register

Background: Severe asthma increases the risk of severe COVID-19 outcomes such as hospitalization and death. However, more studies are needed to understand the association between asthma and severe COVID-19. Methods: A cohort of 150,430 adult asthma patients were identified in the Swedish National Airway Register (SNAR) from 2013 to December 2020. Data on body mass index, smoking habits, lung function, and asthma control test (ACT) were obtained from SNAR, and uncontrolled asthma was defined as ACT ⩽19. Patients with severe COVID-19 were identified following hospitalization or in death certificates based on ICD-10 codes U07.1 and U07.2. The Swedish Prescribed Drug register was used to identify comorbidities and data from Statistics Sweden for educational level. Multivariate logistic regression analyses were used to estimate associations with severe COVID-19. Results: Severe COVID-19 was identified in 1067 patients (0.7%). Older age (OR = 1.04, 95% CI = 1.03–1.04), male sex (1.42, 1.25–1.61), overweight (1.56, 1.27–1.91), obesity (2.12, 1.73–2.60), high-dose inhaled corticosteroids in combination with long-acting β-agonists (1.40, 1.22–1.60), dispensed oral corticosteroids ⩾2 (1.48, 1.25–1.75), uncontrolled asthma (1.64, 1.35–2.00), cardiovascular disease (1.20, 1.03–1.40), depression (1.47, 1.28–1.68), and diabetes (1.52, 1.29–1.78) were associated with severe COVID-19, while current smoking was inversely associated (0.63, 0.47–0.85). When comparing patients who died from COVID-19 with those discharged alive from hospital until 31 December 2020, older age, male sex, and current smoking were associated with COVID-19 death. Conclusion: Patients with uncontrolled asthma and high disease burden, including increased asthma medication intensity, should be identified as risk patients for severe COVID-19. Furthermore, current smoking is strongly associated with COVID-19 death in asthma