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- Karlsson Sundbaum, Johanna, 1969-
(författare)
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Studies of drug safety in the treatment of rheumatoid arthritis
- 2020
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- 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.
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| 4. |
- Wallman, J. K., et al.
(författare)
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High degree of classification criteria fulfillment among patients with clinical psoriatic arthritis diagnoses in Sweden
- 2020
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Ingår i: Annals of the Rheumatic Diseases. - : BMJ Publishing Group Ltd. - 0003-4967 .- 1468-2060. ; 79, s. 1725-1726
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- The clinical diagnosis of psoriatic arthritis (PsA) may be challenging. In Sweden, the vast majority of PsA cases are diagnosed within rheumatology or internal medicine (IM). Knowledge of the correspondence between clinical ICD diagnoses and classification criteria fulfillment is crucial to interpret studies identifying cases based on ICD codes.Objectives:To assess the degree to which patients with clinical PsA diagnoses in Sweden fulfill established PsA classification criteria.Methods:Four hundred patients with ≥1 outpatient physician visit to one of five rheumatology or IM departments (3 university/2 county departments, spread across Sweden) 2013-2015 with a main ICD-10 diagnosis of PsA (L40.5/M07.0-M07.3), were randomly selected from the Swedish National Patient Register (80 cases/site). Based on a structured medical record review, positive predictive values (PPV) of a clinical PsA diagnosis (i.e. ≥1 visit with a PsA ICD-10 code) for fulfillment of the following classification criteria were assessed: CASPAR,[1] Moll & Wright,[2] Vasey & Espinoza,[3] and Modified ESSG criteria for PsA,[4] respectively (as well as for any of these); ASAS criteria for peripheral or axial spondyloarthritis (SpA) [5]; and the 1987 ACR criteria for rheumatoid arthritis (RA).[6] Subanalyses regarding CASPAR fulfillment were also performed restricted to patients with available rheumatoid factor and peripheral X-ray status (central CASPAR items; n=227), and among patients with ≥2 ICD codes for PsA, of which ≥1 from a rheumatology/IM department (n=353).Results:Out of 400 clinically diagnosed PsA patients, 343 (86%) fulfilled any of the 4 PsA classification criteria, with a PPV for CASPAR fulfillment of 69% (rising to 73-82% in the subanalyses;Figure 1). Substantial overlap was seen regarding fulfillment of the 4 PsA criteria (Figure 2A). Moreover, 86% fulfilled the ASAS peripheral or axial SpA criteria, while the 1987 ACR definition of RA was met by 27% – in both cases with the great majority also classifiable as PsA (Figure 2B). Most patients not fulfilling any PsA criteria had either no verified arthritis or polyarticular disease (Table). Overall, only 6.5% of the clinical PsA diagnoses were judged as clearly wrong by the rheumatologists performing the medical record assessments.Conclusion:The validity of clinical ICD-10 diagnoses for PsA in the Swedish National Patient Register is good, with a PPV of 86% for the fulfillment of established PsA classification criteria.References:[1]Arthritis Rheum2006;54:2665-73[2]Semin Arthritis Rheum 1973;3:55-78[3]In: Calin A, editor. Spondyloarthropathies. Orlando: Grune & Stratton; 1984:151-85[4]Ann Rheum Dis2005;64(Suppl II):ii3–ii8[5]Ann Rheum Dis2011;70:25-31[6]Arthritis Rheum1988;31:315-24Patient characteristics (n=400), stratified by classification criteria fulfillmentFulfilling anyPsA criterian=343Not fulfilling anyPsA criterian=57Male sex, %4644Age, yrs; mean (SD)59 (14)62 (15)Symptom duration, yrs; mean (SD)18 (12)16 (13)Psoriasis, %8947Nail psoriasis, %3811Arthritis, %9358 Monoarthritis, %*7.90 Oligoarthritis, %*4522 Polyarthritis, %*4778DIP-joint arthritis, %287.0Dactylitis, %281.8Enthesitis, %4219Inflammatory back pain, %275.3RF positive, %5.814ACPA positive, %4.43.5Arthritic X-ray changes in hands/feet, %3321* % of patients with arthritis of known distribution. Missing data: 0-4%, except forRF (33%), ACPA (37%) and X-ray changes (20%).Acknowledgments:This work was supported by Celgene, Novartis, Pfizer, Reumatikerförbundet and Psoriasisförbundet.Disclosure of Interests:Johan K Wallman Consultant of: AbbVie, Celgene, Eli Lilly, Novartis and UCB Pharma, Gerd-Marie Alenius: None declared, Eva Klingberg Grant/research support from: Roche, Consultant of: Novartis, Speakers bureau: Eli Lilly, Valgerdur Sigurdardottir Consultant of: Novartis, Sara Wedrén: None declared, Sofia Exarchou: None declared, Ulf Lindström: None declared, Daniela Di Giuseppe: None declared, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma, Lennart T.H. Jacobsson Consultant of: AbbVie, Eli Lilly, Janssen, Novartis and Pfizer
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