Abstract
INTRODUCTION
To determine predictors of hepatic steatosis by the computed attenuation parameter (CAP) and fibrosis via transient elastography (TE) in persons on methotrexate (MTX) therapy with rheumatologic and dermatologic diseases.
METHODS
A single-centred retrospective cohort study was performed. Patients on >6 months of MTX for a rheumatologic or dermatologic disease who had undergone TE from January 2015 to September 2019 were included. Multivariate analysis was performed to determine predictors of steatosis and fibrosis.
RESULTS
A total of 172 patients on methotrexate were included. Psoriasis was the most frequent diagnosis (n = 55), followed by rheumatoid arthritis (n = 45) and psoriatic arthritis (n = 34). Steatosis (CAP ≥245 dB/m) was present in 69.8% of patients. Multivariate regression analysis revealed that diabetes mellitus (OR 10.47, 95% CI 1.42–75.35), hypertension (OR 5.15, 95% CI 1.75–15.38), and BMI ≥30 kg/m2 (OR 16.47, 95% CI 5.56–45.56) were predictors of steatosis (CAP ≥245 dB/m). Predictors of moderate to severe fibrosis (Metavir ≥F2 = TE ≥8.0 kPa) by multivariate regression analysis included moderate to severe steatosis (CAP ≥270 dB/m) (OR 8.36, 95% CI 1.88–37.14), diabetes mellitus (OR 2.85, 95% CI 1.09–7.48), hypertension (OR 5.4, 95% CI 2.23–13.00), dyslipidemia (OR 3.71, 95% CI 1.50–9.18), and moderate alcohol use (OR 3.06, 95% CI 1.2–7.49).
CONCLUSIONS
In patients on MTX for rheumatologic and dermatologic diseases, hepatic steatosis as measured by CAP was common and moderate to severe steatosis predicted moderate to severe fibrosis.
Keywords: liver diseases, methotrexate, psoriasis, psoriatic arthritis, rheumatoid arthritis
Introduction
Low dose methotrexate (MTX) is used in the management of rheumatoid arthritis (RA), psoriatic arthritis (PsA), systemic lupus erythematosus, systemic sclerosis, inflammatory myopathies, and vasculitis (1). Non-rheumatologic indications for MTX include severe psoriasis (PsO), lichen planus, Crohn’s disease, and autoimmune hepatitis. In RA, MTX is the preferred conventional disease-modifying anti-rheumatic drug (2). MTX is an inhibitor of dihydrofolate reductase and reduces the amount of folate cofactors that are necessary for nucleic acid synthesis. The clinical benefits of MTX in RA include slowing disease progression, preventing articular, extra-articular damage, comorbidities and decreasing mortality (2).
Long-term MTX users may develop hepatic fibrosis (3). Liver histology findings in MTX use include steatosis, stellate cell hypertrophy and anisonucleosis but the exact mechanism of fibrosis remains unknown. Risk factors for fibrosis among patients on MTX include increased BMI and metabolic syndrome (4). The observation that patients with PsO also have increased rates of metabolic syndrome and NAFLD shows the potential role that steatosis may play in the pathogenesis of hepatic fibrosis in this patient population (5–7). Additionally, the severity and prognosis of NAFLD are worse in PsO compared with RA (7). Systemic inflammation has been postulated to result in steatohepatitis contributing to the development of fibrosis in patients with PsO, PsA, and RA (8).
Previously liver biopsy was used to monitor for fibrosis in patients on MTX with PsO and RA (9). Currently, transaminases, complete blood count and albumin are performed serially to monitor patients with RA for hepatotoxicity (10). Transaminase levels, however, have a poor sensitivity and specificity for the detection of hepatic fibrosis (11).
Transient elastography (TE) is a non-invasive measure of hepatic fibrosis that has been used in patients on MTX (12–14). TE measures the stiffness (or elasticity) of the hepatic parenchyma using both ultrasound and low-frequency elastic waves produced by an ultrasound vibrator applied to the right upper quadrant to measure the propagation speed of a wave using a pulse-echo ultrasound (15). An Australasian position statement has suggested that TE be considered as a routine investigation to monitor patients with PsO on MTX (16). The AAD has suggested that TE can be for patients with PsO used in two contexts: 1) screening for fibrosis prior to initiating MTX and 2) routine surveillance after a cumulative dose of 3.5–4.0 grams of MTX (17). The computed attenuation parameter (CAP) measurement, performed at the time of TE, correlates with the histological degree of steatosis. The CAP algorithm calculates the attenuation of the ultrasound signal (18).
Although the presence of steatosis correlates with the extent of fibrosis in NAFLD, this could be different in patients receiving MTX (19,20). First, MTX independently stimulates hepatic stellate cells and myofibroblasts; therefore, there could be a discordance between the extent of steatosis and fibrosis in these patients. Second, immune-mediated disorders may attenuate the extent of hepatic fibrosis in NAFLD (21). Therefore, this patient population may have more extensive steatosis but less fibrosis.
To our knowledge, no studies have evaluated steatosis utilizing CAP in chronic MTX users. Our primary aim was to identify predictors of hepatic steatosis, as measured by CAP, and fibrosis, as measured by TE, in patients on MTX. Additionally, we assessed for a correlation between cumulative MTX dosing and the presence of steatosis and fibrosis.
Materials and Methods
Study design
We performed a retrospective study of patients on MTX for rheumatologic or dermatologic conditions and who underwent TE (FibroScan, Echosens, Paris, France) from January 2015 to September 2019 at an academic tertiary care centre. Demographic and clinical data were collected from the electronic medical records. The study was approved by the University of British Columbia Providence Health Care Research Institute Research Ethics Boards (H19–02689). We included adults (>18 years old) diagnosed with RA, PsO, PsA, eczema, lichen planus, mixed connective tissue disease, systemic lupus erythematosus, and ankylosing spondylitis who underwent transient elastography. Patients with active hepatitis B (surface antigen positivity) and patients with excessive alcohol use (more than 15 standard drinks per week for men and more than 10 standard drinks per week for women) were excluded.
Assessment of transient elastography and computed attenuation parameter
Patients on chronic methotrexate therapy were referred to an academic hepatology centre in Vancouver, British Columbia, Canada. TE and CAP are measured using FibroScan operated by a certified technician who had performed at least 100 prior scans. Patients fasted for more than 2 hours prior to TE and CAP measurement. For patients with a body mass index (BMI) above 30 kg/m2, the XL probe was used. For all other patients, the M probe was used. Those with a TE score greater than 8.0 kPa were considered to have at least moderate fibrosis (≥F2) by the meta-analysis of histological data in viral hepatitis (Metavir) score. Patients with CAP ≥245 dB/m and CAP ≥270 dB/m were considered to have at least mild (≥S1) and moderate (≥S2) steatosis, respectively.
Demographics and clinical variables
For eligible patients, the following demographic and clinical variables were collected: age, gender, rheumatologic or dermatologic diagnosis, BMI, comorbidities (diabetes mellitus, hypertension, dyslipidemia, and viral hepatitis), moderate alcohol use, MTX lifetime exposure, TE, CAP scores, probe type, and interquartile range. Liver enzymes, function and routine biochemistry were collected within 3 months preceding or following TE and CAP assessment. The Fibrosis-4 (FIB-4) index was calculated using the following formula: age (years) × AST [U/L]/(platelets [109/L] × (ALT [U/L])1/2). The aspartate aminotransferase to platelet ratio (APRI) was calculated using the formula AST/upper limit of normal]/ platelet count [109/L] × 100.
Statistical analysis
The IBM SPSS Statistics package, version 25 (IBM Corporation, Armonk, New York, USA), was used for analysis. The mean (SD) was used for descriptive quantitative variables. Two-sided t-tests were performed to determine significant between group differences between patients with and without steatosis. The Pearson correlation test was used to determine statistical association between cumulative MTX dose, steatosis, and fibrosis. Multivariate logistic regression analysis was used to determine predictors of steatosis and fibrosis.
Results
A total of 172 patients on MTX were enrolled, of whom 82 were male (Table 1). PsO was the most frequent diagnosis (n = 55), followed by RA (n = 45) and PsA (n = 34). Steatosis (CAP ≥245 dB/m) was noted in 120 patients compared with 52 who did not have steatosis (CAP <245 kPa). TE score (7.67 kPa [SD 2.8] versus 4.6 kPa [SD 2.2]; p <0.05) and BMI (28.9 kg/m2 [SD 6.2] versus 24.1 kg/m2 [SD 3.4]; p <0.05) were higher in the steatosis group compared with the group without steatosis. The prevalence of steatosis was 69.8% in this population of patients on MTX. Most patients with PsA (85%), PsO (80%), and lupus (71%) had CAP evidence of steatosis.
Table 1:
Demographic parameters of patients on methotrexate with CAP evidence of steatosis compared with no evidence of steatosis (N = 172)
| Variable | CAP <245 dB/m (n = 52) | CAP ≥245 dB/m (n = 120) | p-value | ||||
|---|---|---|---|---|---|---|---|
| Age, y, mean (SD) | 59.7 (13.5) | 60.6 (12.5) | >0.05 | ||||
| Sex (male/female) | 22/30 | 60/60 | >0.05 | Diagnosis, no. (%) | |||
| PsA | 5 (10) | 29 (24) | <0.05* | ||||
| PsO | 11 (21) | 44 (37) | |||||
| RA | 23 (44) | 22 (18) | |||||
| Eczema | 5 (10) | 5 (4) | |||||
| Lupus | 8 (15) | 20 (17) | |||||
| Past HBV/HCV, no. (%)† | 19 (36.5) | 29 (24.1) | >0.05 | ||||
| AST, U/L, mean (SD) | 27.4 (3.5) | 34.3 (4.5) | <0.05* | ||||
| ALT, U/L, mean (SD) | 26.7 (2.8) | 37.8 (4.2) | <0.05* | ||||
| Platelets per mm3, mean (SD) | 270 (12.5) | 274 (13.7) | >0.05 | ||||
| Albumin, g/L, mean (SD) | 43.6 (3.6) | 43.4 (4.2) | >0.05 | ||||
| Cumulative methotrexate dose, g, mean (SD) | 3.2 (1.4) | 5.6 (2.1) | <0.05* | ||||
| Diabetes mellitus, no. (%) | 2 (4) | 42 (35) | <0.05* | ||||
| Hypertension, no. (%) | 4 (7.6) | 55 (46) | <0.05* | ||||
| Dyslipidemia, no. (%) | 4 (7.6) | 46 (38) | <0.05* | ||||
| Moderate alcohol use, no. (%) | 13 (25) | 77 (64) | <0.05* | ||||
| TE, kPa, mean (SD) | 4.6 (2.2) | 7.67 (2.8) | <0.05* | ||||
| BMI, kg/m2, mean (SD) | 24.1 (3.4) | 28.9 (6.2) | <0.05* | ||||
| APRI, mean (SD) | 0.32 (0.25) | 0.45 (0.58) | >0.05 | ||||
| FIB-4, mean (SD) | 1.28 (0.74) | 1.47 (1.49) | >0.05 |
* Statistically significant
† Hepatitis C post sustained virologic response or past hepatitis B infection (surface antigen negative and core antibody positive) CAP = Computed attenuation parameter;
PsA = Psoriatic arthritis; PsO = Psoriasis; RA = Rheumatoid arthritis; HBV = Hepatitis B virus; HCV = Hepatitis C virus; AST = Aspartate aminotransferase; ALT = Alanine aminotransferase; TE = Transient elastography; APRI = Aspartate aminotransferase to platelet ratio index; FIB-4 = Fibrosis-4 index
Moderate to severe steatosis (CAP ≥270 dB/m) was identified in 48.3% of patients (n = 89) (Table 2). When compared with patients without moderate or severe steatosis, this group also had higher TE scores (8.3 kPa [SD 2.9] versus 4.6 kPa [SD 1.9]; p <0.05) and a higher mean BMI (29.8 kg/m2 [SD 6.7] versus 24.7 kg/m2 [SD 3.8]; p <0.05). Most patients with PsA (67%), PsO (66%), and lupus (52%) had CAP evidence of at least moderate steatosis. Conversely, only a minority of patients with RA had CAP evidence of at least moderate steatosis.
Table 2:
Demographic parameters of patients on methotrexate with CAP evidence of moderate to severe steatosis (N = 172)
| Variable | CAP <270 dB/m (n = 83) | CAP ≥270 dB/m (n = 89) | p-value | ||||
|---|---|---|---|---|---|---|---|
| Age, y, mean (SD) | 60.6 (13.3) | 60.4 (13.2) | >0.05 | ||||
| Sex (male/female) | 33/50 | 38/51 | >0.05 | ||||
| Diagnosis no. (%) | |||||||
| PsA | 12 (14) | 25 (28) | <0.05* | ||||
| PsO | 18 (22) | 35 (40) | |||||
| RA | 33 (40) | 12 (13) | |||||
| Eczema | 8 (10) | 4 (4) | |||||
| Lupus | 12 (14) | 13 (15) | |||||
| Past HBV/HCV, no. (%)† | 25 (30) | 23 (25) | >0.05 | AST, U/L, mean (SD) | 26.5 (4.2) | 37.6 (5.5) | <0.05* |
| ALT, U/L, mean (SD) | 26.3 (3.6) | 38.5 (5.3) | <0.05* | ||||
| Platelets per mm3, mean (SD) | 275 (13.6) | 276 (15.5) | >0.05 | ||||
| Albumin, g/L, mean (SD) | 43.3 (4.4) | 43.2 (3.8) | >0.05 | ||||
| Cumulative methotrexate dose, g, mean (SD) | 2.8 (1.6) | 6.4 (2.7) | <0.05* | ||||
| Diabetes mellitus, no. (%) | 8 (9) | 35 (40) | <0.05* | ||||
| Hypertension, no. (%) | 15 (18) | 44 (50) | <0.05* | ||||
| Dyslipidemia, no. (%) | 11 (13) | 39 (44) | <0.05* | ||||
| Moderate alcohol use, no. (%) | 30 (36) | 60 (68) | <0.05* | ||||
| TE, kPa, mean (SD) | 4.6 (1.9) | 8.3 (2.9) | <0.05* | ||||
| BMI, kg/m2, mean (SD) | 24.7 (3.8) | 29.8 (6.7) | <0.05* | ||||
| APRI, mean (SD) | 0.68 (0.24) | 0.65 (0.28) | >0.05 | ||||
| FIB-4, mean (SD) | 1.3 (0.75) | 1.5 (1.7) | >0.05 |
* Statistically significant
† Hepatitis C post sustained virologic response or past hepatitis B infection (surface antigen negative and core antibody positive) CAP: Computed attenuation parameter;
PsA = Psoriatic arthritis; PsO = Psoriasis; RA = Rheumatoid arthritis; HBV = Hepatitis B virus; HCV = Hepatitis C virus; AST = Aspartate aminotransferase; ALT = Alanine aminotransferase; TE = Transient elastography; APRI = Aspartate aminotransferase to platelet ratio index; FIB-4 = Fibrosis-4 index
To analyze the correlation between steatosis as measured by CAP and lifetime MTX dose, we used Pearson correlation analysis (Figure 1). Higher CAP score was correlated with increased lifetime dose of MTX (r = 0.48, p = 0.001) (n = 85 patients).
Figure 1:
Correlation between steatosis as measured by CAP and lifetime MTX dose
CAP = Computed attenuated parameter (dB/m); MTX = Methotrexate lifetime dosing (g)
Multivariate logistic regression analysis was used to determine clinical and demographic predictors of steatosis (Table 3). Predictors of steatosis (CAP ≥245 dB/m) included hypertension (OR 5.15, 95% CI 1.75–15.38), diabetes mellitus (OR 10.47, 95% CI 1.42–75.35), BMI ≥25 kg/m2 (OR 10.1, 95% CI 1.88–37.14) and BMI ≥30 kg/m2 (OR 16.47, 95% CI 5.56–45.56). Moderate alcohol use (OR 1.36, 95% CI 0.65–2.89), dyslipidemia (OR 2.25, 95% CI 0.70–6.65), male sex (OR 0.69, 95% CI 0.39–1.87), and past viral hepatitis (B or C) (OR 0.78, 95% CI 0.58–1.29) were not predictive of steatosis. Predictors of moderate to severe steatosis (CAP ≥270 dB/m) (shown in Table 4) included hypertension (OR 4.40, 95% CI 1.94–9.97), dyslipidemia (OR 3.75, 95% CI 1.48–9.50), diabetes mellitus (OR 4.60, 95% CI 1.47–14.49), and BMI ≥25 kg/m2 (OR 1.98, 95% CI 1.45–3.22) in patients treated with MTX. Moderate alcohol use (OR 1.41, 95% CI 0.54–2.4), male sex (OR 1.02, 95% CI 0.54–1.92), and past viral hepatitis (OR 0.19, 95% CI 0.19–0.79) were not predictive of a higher risk of severe steatosis.
Table 3:
Predictors of steatosis (CAP ≥245 dB/m) by multivariate logistic regression analysis
| Variable | Odds ratio (95% CI) | p-value |
|---|---|---|
| Moderate alcohol use | 1.36 (0.65–2.89) | >0.05 |
| Past HBV/HCV† | 0.78 (0.58–1.29) | >0.05 |
| Dyslipidemia | 2.25 (0.70–6.65) | >0.05 |
| Diabetes mellitus | 10.47 (1.42–75.35) | <0.05* |
| Hypertension | 5.15 (1.75–15.38) | <0.05* |
| BMI ≥30, kg/m2 | 16.47 (5.56–45.56) | <0.05* |
| BMI ≥25, kg/m2 | 10.1 (1.88–37.14) | <0.05* |
| Male | 0.69 (0.39–1.87) | >0.05 |
| APRI ≥0.7 | 1.07 (0.26–4.27) | >0.05 |
| FIB-4 ≥1.45 | 1.80 (0.79–4.10) | >0.05 |
* Statistically significant
† Hepatitis C post sustained virologic response or past hepatitis B infection (surface antigen negative and core antibody positive) CAP = Computed attenuation parameter;
HBV = Hepatitis B virus; HCV = Hepatitis C virus; APRI = Aspartate aminotransferase to platelet ratio index; FIB-4 = Fibrosis-4 index
Table 4:
Predictors of moderate to severe steatosis (CAP ≥270 dB/m) by multivariate logistic regression analysis
| Variable | Odds ratio (95% CI) | p-value |
|---|---|---|
| Moderate alcohol use | 1.41 (0.54–2.4) | >0.05 |
| Past HBV/HCV† | 0.19 (0.19–0.79) | <0.05* |
| Dyslipidemia | 3.75 (1.48–9.50) | <0.05* |
| Diabetes mellitus | 4.6 (1.47–14.49) | <0.05* |
| Hypertension | 4.40 (1.94–9.97) | <0.05* |
| BMI ≥30, kg/m2 | 7.75 (4.43–10.87) | <0.05* |
| BMI ≥25, kg/m2 | 1.98 (1.45–3.22) | <0.05* |
| Male | 1.02 (0.54–1.92) | >0.05 |
* Statistically significant
† Hepatitis C post sustained virologic response or past hepatitis B infection (surface antigen negative and core antibody positive) CAP = Computed attenuation parameter;
HBV = Hepatitis B virus; HCV = Hepatitis C virus
Multivariate logistic regression analysis revealed that predictors of moderate to severe fibrosis (Metavir ≥F2 = TE ≥8.0 kPa) among patients on MTX included moderate to severe steatosis (CAP ≥270 dB/m) (OR 8.36, 95% CI 1.88–37.14), diabetes mellitus (OR 2.85, 95% CI 1.09–7.48), hypertension (OR 5.40, 95% CI 2.23–13.00), dyslipidemia (OR 3.71, 95% CI 1.50–9.18), moderate alcohol use (OR 3.06, 95% CI 1.20–7.49), FIB-4 >1.45 (OR 2.68, 95% CI 1.49–5.33), and APRI >0.7 (OR 2.27, 95% 1.32–4.74) (Table 5). Past viral hepatitis (OR 0.36, 95% CI 0.12–1.05) and steatosis (CAP ≥245 dB/m) (OR 4.94, 95% CI 0.63–38.76) were not predictors of moderate to severe fibrosis (Metavir ≥F2).
Table 5:
Predictors of moderate to severe fibrosis (Metavir* ≥F2) by multivariate logistic regression analysis
| Variable | Odds ratio (95% CI) | p-value |
|---|---|---|
| Moderate alcohol use | 3.06 (1.2–7.49) | <0.05† |
| Past HBV/HCV‡ | 0.36 (0.12–1.05) | >0.05 |
| Dyslipidemia | 3.71 (1.50–9.18) | <0.05† |
| Diabetes mellitus | 2.85 (1.09–7.48) | <0.05† |
| Hypertension | 5.40 (2.23–13.0) | <0.05† |
| BMI ≥30, kg/m2 | 3.38 (1.86–5.65) | <0.05† |
| BMI ≥25, kg/m2 | 2.50 (1.58–4.51) | <0.05† |
| Steatosis (CAP§ ≥245 dB/m) | 4.94 (0.63–38.76) | >0.05 |
| Moderate to severe steatosis (CAP ≥270 dB/m) | 8.36 (1.88–37.14) | <0.05† |
| APRI >0.7 | 2.27 (1.32–4.74) | <0.05† |
| FIB-4 >1.45 | 2.68 (1.49–5.33) | <0.05† |
* Meta-analysis of histological data in viral hepatitis
† Statistically significant
‡ Hepatitis C post sustained virologic response or past hepatitis B infection (surface antigen negative and core antibody positive) CAP = Computed attenuation parameter;
HBV = Hepatitis B virus; HCV = Hepatitis C virus; APRI = Aspartate aminotransferase to platelet ratio index; FIB-4 = Fibrosis-4 index
Pearson correlation analysis determined no correlation between TE and cumulative MTX dose (r = 0.12, p = 0.21).
Discussion
Our study highlights the importance of metabolic syndrome and hepatic steatosis in the development of hepatic fibrosis. Steatosis was present in a large proportion of patients with rheumatologic and dermatologic diseases on MTX. Population estimates reveal a 5%–30% prevalence of steatosis worldwide with locoregional variation (22,23). Previous studies have noted an increased prevalence of NAFLD in patients with PsO, as high as 59% (7,24). In our study, 80% of patients with PsO had evidence of steatosis. The risk of NAFLD appears to be even higher in patients with PsA and moderate to severe PsO compared with mild PsO (5). In our study, 85% of patients with PsA had evidence of steatosis. Chronic low-grade inflammation is postulated to play a role in the development of NAFLD in these patients (25). Conversely, NAFLD could be a driver for inflammation in keratinocytes and joints in PsO and PsA (8). Primary care data from the United Kingdom assessed the role of treatment of PsO, PsA and RA on the risk of NAFLD. When compared with the general population, treated and untreated patients with PsO had a higher risk of NAFLD. Patients treated for PsA had a higher risk for NAFLD, whereas those who were untreated did not. However, previous studies have not detected increased rates of NAFLD in RA patients regardless of treatment (8). Concordantly in our study, moderate steatosis was only found in 27% of patients with RA, compared with 67% of PsA patients and 66% of PsO patients.
In our study, the mean BMI, rates of diabetes mellitus, hypertension and dyslipidemia were significantly higher among patients with steatosis. These observations could be related to the metabolic syndrome, the underlying inflammatory condition, MTX use or a combination of these. PsA is associated with a metabolic phenotype including dyslipidemia, hypertension, impaired fasting glucose, diabetes mellitus, and obesity (26). PsA patients have increased triglyceride levels and decreased high-density lipoprotein, which is consistent with dyslipidemia. Unexpectedly, their low-density lipoprotein-C levels are lower, but this is likely a result of systemic inflammation (27). Obesity is associated with a higher risk of developing PsA. Weight loss improved disease activity in patients with PsA and obesity (28). An increased risk of diabetes mellitus was noted in patients with PsO and PsA (29). Hypertension is more prevalent among patients with PsO and PsA (30). It is less certain whether there is a link between metabolic syndrome and RA. The data supporting a link between obesity and RA are mixed (26,31). Increased abdominal girth, independent of BMI, has been associated with RA (32). It remains unclear whether patients with RA are at increased risk of diabetes mellitus (29). RA patients, however, have a higher baseline blood pressure compared with the general population (33). Previous studies have demonstrated that patients with PsO on MTX develop more hepatic fibrosis than patients with RA (34). Concordantly, patients with PsO have higher rates of NAFLD than patients with RA. This observation has generated the hypothesis of the importance of metabolic syndrome and steatosis in the pathogenesis of hepatic fibrosis.
Our study noted a correlation between an increased total lifetime dose of MTX and increased steatosis by CAP score, which highlights the potential role of MTX in the development of steatosis. Liver biopsy has previously identified a non-alcoholic steatohepatitis (NASH)-like pattern of injury in 17 of 24 patients treated with MTX at a total cumulative dose of 5 g. Most of the patients who developed NASH-like changes had a feature of the metabolic syndrome. A positive correlation between MTX dose and NASH stage on biopsy was also noted (35). Our study provides further evidence supporting MTX’s potential role in the pathogenesis of steatosis in a dose-dependent fashion. Further studies should attempt to determine whether withdrawing MTX plays a role in reversing steatosis as measured by CAP.
We did not note a correlation between cumulative MTX dose and fibrosis as measured by TE. This is consistent with another study that has shown that cumulative MTX dose is not a predictor of fibrosis in the context of PsO (36). However, two further studies have identified that the duration of MTX exposure and higher cumulative MTX dose were correlated with fibrosis (37,38). High-quality prospective studies with sequential TE measurements are still lacking and would help determine whether cumulative MTX dose is associated with fibrosis.
We demonstrated that patients on MTX have significantly higher rates of fibrosis if they are known to have metabolic syndrome and moderate to severe steatosis. Understanding that MTX cumulative dose was not associated with increased fibrosis suggests that patient and disease factors may have a more significant role than MTX exposure alone in causing fibrosis. Fibrosis surveillance should be intensified in patients on MTX with known diabetes mellitus, hypertension, dyslipidemia, obesity, or hepatic steatosis.
We present further convincing data supporting the use of non-invasive markers of fibrosis and steatosis to guide the treatment of rheumatologic and dermatologic diseases. TE has been used to advise which patients on MTX have already developed fibrosis (12–14). However, our study shows that an increased CAP score can advise which patients are at increased risk of fibrosis. Moderate and severe steatosis were predictors of moderate and severe fibrosis. This is in support of steatosis playing a role in the development of fibrosis. Previous studies have identified that co-existent risk factors such as diabetes mellitus and obesity decrease the threshold at which patients on MTX develop severe fibrosis (39).
TE is thought to be limited by the presence of obesity. This is relevant to our study with high rates of metabolic syndrome and obesity. The XL probe can be used in the obese patient population and provides more reliable results than the standard M probe (40). The optimal CAP and histopathologic cut-offs for grading steatosis require further study and have not been fully validated (41,42). As a result, the optimal CAP cut-offs for steatosis grading provided in this study may change with further research. More importantly, the absolute CAP values ≥270 dB/m seen here have been shown to be a predictor of moderate to severe fibrosis. The CAP measurement can be easily obtained at the time of TE measurement and should be used to determine which patients on MTX are at increased risk of developing fibrosis.
The limitations of our study include its retrospective nature, which relies on the accuracy of medical records documentation. Patients had been referred to an academic tertiary care hepatology centre, and selection bias may have occurred for patients more likely to have hepatotoxicity. It was not possible to account for the use of corticosteroid medication which has previously been associated with NAFLD.
In summary, moderate to severe steatosis as measured by CAP (≥270 dB/m) and metabolic syndrome are predictors of moderate to severe fibrosis in patients on MTX. Patients known for the metabolic syndrome would likely benefit from a more intensive evaluation for fibrosis. Future studies should determine the optimal role of other non-invasive markers of fibrosis in screening patients prior to initiating MTX therapy as well as in surveillance.
Acknowledgements:
The authors wish to thank Miroslaw Tomaszewski for his contribution in proofreading the manuscript.
Ethics Approval:
The study was approved by the University of British Columbia Providence Health Care Research Institute Research Ethics Boards (H19–02689).
Informed Consent:
N/A
Registry and Registration No. of the Study/Trial:
N/A
Funding:
No funding was received for this work.
Disclosures:
The authors have nothing to disclose.
Peer Review:
This article has been peer reviewed.
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