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Studies of drug safety in the treatment of rheumatoid arthritis
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Rheumatology.ORCID iD: 0000-0001-5313-7981
2020 (English)Doctoral thesis, comprehensive summary (Other academic)
Description
Abstract [en]

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.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2020. , p. 71
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1659
Keywords [en]
Drug safety, Rheumatoid arthritis, Hepatotoxicity, Methotrexate, MTHFR, GWAS, tuberculosis, screening
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-407866ISBN: 978-91-513-0925-5 (print)OAI: oai:DiVA.org:uu-407866DiVA, id: diva2:1417745
Public defence
2020-05-25, H:son Holmdahlsalen, Akademiska sjukhuset, ingång 100/101, 2 tr, Uppsala, 13:00 (Swedish)
Opponent
Supervisors
Available from: 2020-05-04 Created: 2020-03-30 Last updated: 2020-05-04
List of papers
1. Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice
Open this publication in new window or tab >>Methotrexate treatment in rheumatoid arthritis and elevated liver enzymes: A long-term follow-up of predictors, surveillance, and outcome in clinical practice
Show others...
2019 (English)In: INTERNATIONAL JOURNAL OF RHEUMATIC DISEASES, ISSN 1756-1841, Vol. 22, no 7, p. 1226-1232Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
WILEY, 2019
Keywords
liver toxicity, liver transaminases, methotrexate, non-alcoholic fatty liver disease, rheumatoid arthritis
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:uu:diva-391959 (URN)10.1111/1756-185X.13576 (DOI)000476560400008 ()31012257 (PubMedID)
Funder
Swedish Research CouncilSwedish Heart Lung Foundation
Available from: 2019-08-27 Created: 2019-08-27 Last updated: 2020-03-30Bibliographically approved
2. MTHFR, TYMS and SLCO1B1 polymorphisms and adverse liver effects of methotrexate in rheumatoid arthritis
Open this publication in new window or tab >>MTHFR, TYMS and SLCO1B1 polymorphisms and adverse liver effects of methotrexate in rheumatoid arthritis
(English)In: Article in journal (Refereed) Epub ahead of print
Abstract [en]

Aims: To investigate whether variants of MTHFR, TYMS and SLCO1B1 are associated with alanine aminotransferase (ALT) elevation in rheumatoid arthritis patients starting methotrexate (MTX). Patients & Methods: Clinical and laboratory data were collected from the start of MTX treatment. Genotyping of MTHFR, TYMS and SLCO1B1 was performed. Univariate and multiple logistic regression were used for statistical analysis. Results: 34 out of 369 patients experienced ALT >1.5xULN less than 6 months from start. MTHFR A1298C (rs1801131) was nominally associated with an ALT > 1.5 xULN within 6 months after the start of MTX (OR = 1.7 [95% CI: 1.04-2.9]; p = 0.03), but did not pass correction for multiple testing. A multiple model containing MTHFR 1298C and clinical factors predicted the outcome (C-statistic 0.735). TYMS and SLCO1B1 were not associated with the outcome. Conclusions: A model containing MTHFR 1298C and clinical factors might predict risk of early ALT elevation.

Keywords
MTHFR; TYMS and SLCO1B1; liver toxicity; methotrexate; rheumatoid arthritis; transaminases
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-407857 (URN)10.2217/pgs-2019-0186 (DOI)
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-03-30
3. A genome-wide association study of elevation of alanine aminotransferase in patients with rheumatoid arthritis starting therapy with methotrexate
Open this publication in new window or tab >>A genome-wide association study of elevation of alanine aminotransferase in patients with rheumatoid arthritis starting therapy with methotrexate
(English)Manuscript (preprint) (Other academic)
Keywords
liver toxicity, methotrexate, rheumatoid arthritis, transaminases, GWAS and RAVER2
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-407858 (URN)
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-03-30Bibliographically approved
4. Tuberculosis in biologic-naïve patients with rheumatoid arthritis - risk factors and tuberculosis characteristics
Open this publication in new window or tab >>Tuberculosis in biologic-naïve patients with rheumatoid arthritis - risk factors and tuberculosis characteristics
(English)Manuscript (preprint) (Other academic)
Keywords
rheumatoid arthritis, tuberculosis, biologic–naïve, risk factors
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-407859 (URN)
Available from: 2020-03-30 Created: 2020-03-30 Last updated: 2020-03-30Bibliographically approved

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