Concurrent use of methotrexate and celecoxib increases risk of silent liver fibrosis in rheumatoid arthritis patients with subclinical reduced kidney function

Abstract

We evaluated the effects of concurrent use of methotrexate and celecoxib on silent liver and kidney damages in rheumatoid arthritis (RA) patients. We enrolled 92 RA patients with normal laboratory results related to liver and kidney functions, who had received methotrexate and celecoxib concurrently over 6 months. Liver stiffness measurement (LSM) using transient elastography and ultrasonography were performed along with blood and urine tests. Estimated glomerular filtration rate (eGFR) was calculated by both the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and the Modification of Diet in Renal Disease (MDRD) equations. Initial eGFR represented kidney function at the time of the initiation of celecoxib. The cutoff for abnormal LSM values was adopted as 5.3 kPa. The optimal cutoff of each eGFR for abnormal LSM values was also calculated. The median age of patients was 55 years old (74 women). The median LSM was 4.4 kPa and the median eGFRs and median initial eGFRs ranged from 89 to 99 mL/min/1.73 m(2). The cumulative doses of methotrexate and celecoxib and their concurrent administration duration did not affect LSM values and eGFRs. Both eGFRs were significantly associated with LSM values. Patients with initial eGFR(CKD-EPI), initial eGFR(MDRD), and eGFR(CKD-EPI) below each optimal cutoff had significantly high risks for silent liver fibrosis (RR 9.4, 10.3, and 4.4, p < 0.001, respectively). Both initial eGFRs (CKD-EPI and MDRD) and eGFR (CKD-EPI) were significant predictors for the development of silent liver fibrosis in RA patients who had received methotrexate and celecoxib concurrently for at least 6 months.

Methotrexate Promotes Platelet Apoptosis via JNK-Mediated Mitochondrial Damage: Alleviation by N-Acetylcysteine and N-Acetylcysteine Amide

“…However, several studies have demonstrated the adverse effects of MTX in long term or high dose treatment; one of the major concerns being its pro-oxidant and non-specific action [5]. The average MTX levels in cerebrospinal fluid and serum is reported to be 17.1 μM and 779 μM respectively in various cancer patients treated with high-dose MTX [6].…”

Usefulness of noninvasive diagnostic procedures for assessment of methotrexate hepatotoxicity in patients with rheumatoid arthritis

“…However, due to a lack of precise recommendations, most physicians only monitor the aminotransferase level in serum, which may but does not always correspond to the extent of liver damage. Liver fibrosis might progress silently without an apparent elevation of the aminotransferase serum level [ 11 , 12 , 15 , 16 ]. Liver biopsy, on the other hand, carries the risk of morbidity and even mortality, which highlights the need for new, less invasive methods.…”

“…In most studies, an interconnection between the cumulative dose of MTX and the TE result was not observed [3,10,12,[14][15][16][17][18][19][20]. Only two studies reported the opposite result [11,13].…”

Transient Elastography for Monitoring for Hepatotoxicity in Rheumatoid Arthritis Patients on Long-term Methotrexate

“…They recommended TE as an added diagnostic option 7 . A second Korean study assessed celecoxib with MTX and postulated that low estimated glomerular filtration rate may predict the development of silent liver fibrosis 8 . They recommended TE to monitor for MTX toxicity in patients with chronic kidney disease with low estimated glomerular filtration rate.…”

“…7 A second Korean study assessed celecoxib with MTX and postulated that low estimated glomerular filtration rate may predict the development of silent liver fibrosis. 8 They recommended TE to monitor for MTX toxicity in patients with chronic kidney disease with low estimated glomerular filtration rate. A 2012 prospective Korean trial found leflunomide use was an independent predictor of abnormal LSM values in MTX-exposed individuals.…”