Should the theory of methotrexate-induced liver toxicity be abandoned?

Abstract

Methotrexate (MTX) remains a cornerstone therapy for chronic inflammatory diseases (e.g., rheumatoid arthritis, psoriasis). However, long-standing concerns about MTX hepatotoxicity - especially liver fibrosis - have historically led to conservative monitoring and routine invasive liver biopsies at predefined cumulative dose thresholds. These practices often prompted early discontinuation of MTX therapy. These concerns originated from early liver biopsy studies in high-dose MTX patients that did not adequately account for metabolic risk factors. Emerging evidence indicates that advanced fibrosis is rare in MTX-treated patients and usually attributable to coexisting metabolic comorbidities (e.g., obesity, insulin resistance) rather than the cumulative MTX dose itself. Moreover, noninvasive fibrosis assessment modalities and recent large cohort studies demonstrate that MTX at standard doses with folate supplementation seldom drives fibrogenesis independently. This review reappraises MTX-related fibrosis risk in light of contemporary data and highlights a shift from dose-driven biopsy protocols to risk-based, noninvasive monitoring strategies. Recognizing that MTX is less hepatotoxic than historically assumed can prevent unnecessary drug discontinuation and refocus management on modifiable metabolic risk factors.

Key Words: Risk stratification; Noninvasive monitoring; Metabolic risk factors; Hepatotoxicity; Liver fibrosis; Methotrexate

Core Tip: Methotrexate (MTX) has long been associated with a presumed risk of hepatotoxicity and progressive liver fibrosis, largely based on early biopsy-era studies. Contemporary evidence using non-invasive fibrosis assessment shows that significant fibrosis is uncommon in MTX-treated patients and more strongly linked to metabolic dysfunction-associated steatotic liver disease and related risk factors such as obesity, diabetes, and insulin resistance. This minireview challenges the traditional perception of intrinsic MTX hepatotoxicity and argues for risk-based rather than drug-based monitoring strategies.

INTRODUCTION

Methotrexate (MTX) has been a cornerstone therapy for immune-mediated diseases such as rheumatoid arthritis and psoriasis for more than five decades. Its efficacy, durability, and low cost make it one of the most widely prescribed disease-modifying antirheumatic drugs. Alongside these benefits, however, MTX has long carried a reputation for hepatotoxicity, particularly the risk of progressive liver fibrosis. This perception was largely shaped by early biopsy studies in psoriasis cohorts treated with high cumulative doses, often without folate supplementation and with limited attention to confounding factors such as obesity, alcohol intake, and diabetes[1,2].

Concerns about “inevitable” MTX hepatotoxicity largely arose from early psoriasis cohorts exposed to prolonged, higher-intensity regimens, often without routine folate supplementation. In that era, non-specific histology (steatosis, portal inflammation, mild fibrosis) was frequently attributed to MTX, which crystallized dose-threshold biopsy policies (commonly at cumulative doses of approximately 1.5-4 g) that diffused across specialties. Over the subsequent decades, folate became standard of care, background metabolic risks were recognized, and comparative data failed to support routine, dose-driven biopsies in unselected patients. As a result, the field shifted toward selective, risk-based assessment guided by non-invasive tests (NITs), contextual liver biochemistry, and management of metabolic co-morbidities rather than cumulative dose alone.

Although routine liver biopsies were historically recommended once cumulative MTX exposure reached certain thresholds, this approach has largely disappeared in modern practice. Biopsies are invasive, prone to sampling error, and poorly tolerated, and mounting evidence has demonstrated that fibrosis detected in MTX-treated patients often reflects underlying metabolic comorbidities rather than direct drug toxicity[3,4].

The availability of non-invasive tools has transformed how hepatotoxicity is assessed. Transient elastography, shear-wave elastography, and serum fibrosis biomarkers now allow clinicians to detect and monitor fibrosis with far greater accuracy and acceptability. Application of these methods in MTX-treated cohorts consistently shows that advanced fibrosis is uncommon and that its strongest predictors are obesity, central adiposity, insulin resistance, and alcohol use, rather than cumulative MTX dose[5-7]. Large population-based studies reinforce this perspective, finding no clear dose-response association once metabolic risk factors are considered[8,9].

This shift in evidence has important implications for both clinical practice and patient safety. Instead of rigidly focusing on cumulative exposure, clinicians are encouraged to adopt a risk-based approach that prioritizes metabolic profiling and non-invasive surveillance. Such a framework preserves access to MTX for patients who benefit from it, while ensuring those at genuine risk of liver disease are identified and managed appropriately. We also outline how these historical shifts have influenced contemporary rheumatology and hepatology guidance and day-to-day clinical practice.

This minireview summarizes current evidence on MTX-related liver fibrosis, emphasizing the dominant role of metabolic risk factors, the value of non-invasive monitoring, and the need for a more nuanced understanding of hepatic outcomes in MTX-treated patients. Details discussing the most impactful publications on this topic are summarized in Table 1.

Table 1 Published cohorts evaluating liver fibrosis in methotrexate-treated patients.

Ref.	Number of patients	Findings	Risk of fibrosis
Aithal et al[1], 2004	69	Fibrosis risk: 0% at 1500 mg, up to 32% at > 10000 mg; no correlation between cumulative dose and fibrosis progression	No; no correlation between cumulative MTX dose and fibrosis progression (r = 0.052; P = 0.65)
Zachariae et al[2], 1980	328 patients, 764 biopsies	Cirrhosis in 6.4%; 25.6% in patients treated > 5 years	Yes; strong dose-response observed; fibrosis at doses < 2 g in some cases
Roenigk et al, 1982[3]	Approximately 800 psoriasis patients (summary of multiple biopsy series)	24%-34% any fibrosis; approximately 3% cirrhosis overall (0%-6% across series); higher rates only at > 4 g	Moderate fibrosis in historical high-dose cohorts; advanced fibrosis rare and concentrated in high-dose + risk-factor patients
Chalmers et al[4], 2005	253	11 biopsied due to elevated PIIINP; 3 mild fibrosis, similar rate to routine biopsy controls	Low overall risk with once-weekly MTX regimens under PIIINP monitoring
Berends et al[5], 2007	24	Fibrosis: F0 (21%), F1 (54%), F2 (17%), F3-F4 (8%); FibroTest and FibroScan effectively identify fibrosis; no clear MTX dose association	No; no clear association between cumulative MTX dose and presence of fibrosis
Bray et al[6], 2012	21	9.5% liver fibrosis (F3); 90.5% had NAFLD/NASH	It was difficult to determine whether the fibrosis was due to MTX itself or a combination with NAFLD/metabolic syndrome
Kim et al[7], 2015	185	4.9% had liver stiffness > 8.6 kPa; no significant correlation with MTX dose, but high BMI correlated	No; only a high body mass index but not the cumulative MTX dose was associated with substantial liver fibrosis
Atallah et al[8], 2023	999	Elevated liver stiffness in 15.3%; elevated ELF in 29.4%. No significant association with cumulative MTX dose or duration. Fibrosis strongly linked to metabolic factors (BMI, diabetes), not MTX	Low (MTX risk likely overestimated)
Gelfand et al[9], 2021	40237 (PsO 5687; PsA 6520; RA 28030)	PsO/PsA MTX users had higher rates of liver disease and cirrhosis than RA MTX users; differences persisted after adjustment for MTX dose and comorbidities; RA had highest cumulative dose but lowest liver disease	Higher liver disease/cirrhosis risk in PsO/PsA vs RA, independent of MTX dose; supports role of underlying disease/metabolic factors rather than intrinsic MTX fibrogenicity
European Association for the Study of the Liver et al[12], 2016	Not applicable (clinical guideline)	MTX is not identified as a primary hepatotoxic agent in NAFLD	MTX not considered a relevant risk factor for fibrosis in this guidance
Chalasani et al[10], 2018	Not applicable (clinical guideline)	Methotrexate is not identified as a primary cause of fibrosis in NAFLD	MTX not listed among hepatotoxic agents relevant to NAFLD progression
Lertnawapan et al[13], 2019	108	Mild/moderate fibrosis in 10.3%; safe short-term MTX use	Yes; the study shows that MTX itself is an independent risk factor for liver fibrosis, but that the risks are amplified by concurrent metabolic influence (obesity, fatty liver)
Pongpit et al[14], 2016	165	Significant fibrosis in 10.9%; no correlation with cumulative MTX dose; associated with metabolic factors	No
Martyn-Simmons et al[15], 2014	27	Mild fibrosis: 63%, moderate to severe: 11%, cumulative dose (mean): 7530 mg	Methotrexate-induced liver fibrosis remains a complication that can limit the use of methotrexate for psoriasis
Maybury et al[16], 2014	429 patients (from 8 biopsy-based studies)	Pooled RD: 22% for any fibrosis, 9% for significant fibrosis, 4% for cirrhosis	Yes - increased fibrosis risk; no clear dose-effect; limited by study heterogeneity
Weinblatt et al[17], 1992	26	0% fibrosis at 24 months; mild fibrosis in 1 patient at 48 months and 72 months	No, low; “there have been no cases of either moderate fibrosis or cirrhosis in this cohort”. “Results from the liver biopsies are reassuring”
Arias et al[18], 1993	16	Fibrosis in 9.1% biopsies; 1 mild, 1 moderate-severe	No, “those patients with the shortest duration of therapy were actually those with the most severe liver abnormalities on biopsy, although this inverse relationship was not statistically significant”
Boffa et al[19], 1996	87	21% fibrosis, 4% cirrhosis, 30% inflammation at initial biopsy	Low, “the risk of significant liver damage from low-dose, once-weekly MTX therapy for psoriasis is low”
Richard et al[20], 2000	57	33.8% mild fibrosis by Roenigk; 94.6% fibrosis (48.6% mild, 41.8% moderate, 4% severe) by SSS. No progression at 2 g cumulative MTX dose	No, “neither the Roenigk score nor the SSS demonstrated any progression of hepatic fibrosis in patients having received 2 g of MTX, or showing abnormal levels of transaminases”
Lémann et al[21], 2000	49	11 biopsied; 3 normal, 5 mild steatosis, 1 mild portal fibrosis, no advanced fibrosis over median 18 months	No, MTX-related liver fibrosis was rare and mild in this cohort. No progressive or advanced fibrosis was reported, despite MTX use over a median of 18 months (range 7-59 months)
Maurice et al[22], 2005	38	Fibrosis in 13% patients; progression in 16% paired biopsies at median dose of 5960 mg	Low overall fibrosis risk under modern weekly low-dose regimens: Median cumulative MTX dose at time of fibrotic biopsy: 5960 mg; whole cohort median: 2740 mg; advanced fibrosis was more likely in patients with: Higher cumulative MTX dose
Laharie et al[23], 2006	62	1 cirrhosis, 3 mild fibrosis; no difference by MTX dose	No, “there was no significant difference between patients in group 1 (high dose) and group 2 (naive) and the two groups were comparable according to the CDAI”
Halonen et al[24], 2006	16	19% mild fibrosis; no dose-response relationship with MTX	No, “no minimum cumulative MTX dose as a potential indicator for liver fibrosis was detected”. “MTX or its metabolites did not predict histological liver disease”
Carneiro et al[25], 2008	13	Minimal fibrosis < 2 g cumulative MTX; increased fibrosis ≥ 3 g cumulative dose	Yes, low risk up to 2 g cumulative MTX dose - no clear signs of new or advanced fibrosis. Increased risk at ≥ 3 g - several patients developed portal fibrosis, fibrous septa, and regenerative nodules
Arena et al[26], 2012	100	Liver stiffness strongly correlated with cumulative MTX dose; fibrosis observed with doses > 4000 mg and LS > 9 kPa	Yes, increased liver stiffness was clearly correlated with higher cumulative MTX dose, even after adjustment for other factors. Fibrosis was only detected in patients with LS > 9 kPa and high MTX dose (> 4000 mg)
Barbero-Villares et al[27], 2012	49	Advanced fibrosis in 7.5%; no association with MTX duration or cumulative dose	No, “regarding LF development, MTX therapy is safe”
Dubey et al[28], 2016	204	Biopsy-confirmed fibrosis in 2 patients (1%); no correlation with cumulative MTX dose up to 8 g	No, no statistical association between MTX dose and liver damage, even at doses up to approximately 8 g
Bordbar et al[29], 2018	78	MTX use not associated with increased fibrosis risk; no difference with chronic hepatitis	No
Cervoni et al[30], 2020	131	Higher cumulative MTX dose independently associated with fibrosis; amplified risk with obesity/fatty liver	Yes
Rivera et al[31], 2022	457	Hepatic steatosis in 64.1%; advanced fibrosis risk in 26.2%-37.2%, significantly correlated with longer MTX exposure, metabolic syndrome, and alcohol use	Moderate (increases with treatment duration)
Wong et al[32], 2024	228	Significant fibrosis in 26.5%; correlated with obesity and diabetes, not MTX dose/duration	No, “liver fibrosis was not correlated with the total cumulative dose of MTX or duration of MTX use, but was significantly correlated with obesity and diabetes status”

“Number of patients” refers to the analysed cohort size. “Findings” summarize the main liver assessment results. “Risk of fibrosis” is reported as defined in each study (biopsy stage or non-invasive thresholds). MTX: Methotrexate; PIIINP: Procollagen III aminoterminal propeptide; NAFLD: Non-alcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; BMI: Body mass index; ELF: Enhanced liver fibrosis; PsO: Psoriasis; PsA: Psoriatic arthritis; RA: Rheumatoid arthritis; CI: Confidence interval; RD: Risk difference; SSS: Scheuer scoring system; CDAI: Clinical disease activity index; LS: Liver stiffness; LF: Liver fibrosis.

OLD APPROACHES: INVASIVE MONITORING

For decades, the assessment of MTX-related hepatotoxicity relied heavily on invasive methods, particularly liver biopsy. This practice stemmed from early reports describing structural changes in the liver of patients receiving long-term MTX, particularly those with psoriasis[1,2]. At the time, biopsy was considered the gold standard for evaluating liver fibrosis and was recommended at predetermined cumulative dose thresholds. Some protocols suggested routine biopsies after 1.5 g of MTX exposure, later extending to 3-4 g, regardless of clinical or biochemical findings[3]. While this strategy reflected the best available evidence of its era, it carried several limitations. Liver biopsy is invasive, carries risk of complications, and is poorly tolerated by patients, especially when repeated for surveillance[4]. Sampling error and inter-observer variability are well-recognized problems, raising concerns about reliability when small samples are extrapolated to represent the entire organ[4]. Furthermore, many of the histological abnormalities attributed to MTX exposure were non-specific, such as steatosis or mild portal inflammation, and could equally reflect metabolic conditions or alcohol use[2,4].

Over time, it became clear that routine biopsy surveillance often failed to provide actionable information. In many cases, patients with normal biochemical profiles underwent invasive procedures without evidence of significant pathology. Conversely, fibrosis when detected was frequently associated with established risk factors for liver disease rather than with MTX itself[1,2]. As understanding of the metabolic drivers of liver injury evolved, the rationale for universal biopsy-based monitoring weakened. By the early 2000s, hepatology and rheumatology guidelines had begun to move away from routine surveillance biopsies in favor of more selective, individualized approaches[3,4]. Although biopsy retains a role in selected clinical scenarios - such as unexplained advanced liver disease or discordant non-invasive findings - it is no longer regarded as a necessary component of routine MTX monitoring[4]. Accordingly, formerly standard dose-threshold biopsy policies have been progressively de-emphasized in favor of selective, risk-based assessment[10,11]. The subsequent sections detail modern, non-invasive strategies and how to operationalize them pragmatically in clinic.

MODERN APPROACHES: NON-INVASIVE MONITORING

The landscape of MTX hepatotoxicity assessment has been transformed by the emergence of non-invasive tools for evaluating liver fibrosis[5]. These methods, including transient elastography, shear-wave elastography, magnetic resonance elastography, and serum-based fibrosis panels, provide reproducible, patient-friendly alternatives to biopsy. Their adoption has enabled a more nuanced understanding of hepatic outcomes in MTX-treated populations.

Transient elastography (e.g., FibroScan) is the most widely used modality. It measures liver stiffness as a surrogate for fibrosis and is quick, painless, and well validated in chronic liver diseases such as viral hepatitis and non-alcoholic fatty liver disease[1]. In MTX cohorts, elastography has consistently shown that significant fibrosis is uncommon, even among long-term users[6,7]. Importantly, elevated stiffness values often correlate with features of metabolic dysfunction - such as obesity, insulin resistance, and hepatic steatosis - rather than with cumulative MTX exposure[6,7]. Similar findings have been reported with real-time shear-wave elastography, which provides quantitative and region-specific stiffness measurements[7].

Serum-based biomarkers and fibrosis scores also offer valuable insights. Markers such as procollagen III peptide, FibroTest, aspartate aminotransferase/platelet ratio index, and fibrosis-4 index (FIB-4) have been evaluated in MTX-treated patients, demonstrating utility in ruling out advanced fibrosis with high negative predictive value[5,7]. When used in conjunction with imaging-based elastography, these tools enhance diagnostic confidence and reduce the need for invasive testing[5,8].

The broader use of non-invasive methods has also clarified the role of MTX in the context of metabolic liver disease. Patients with psoriasis or rheumatoid arthritis often carry a high burden of obesity, type 2 diabetes, and dyslipidemia - factors strongly associated with steatosis and fibrosis independent of MTX[8,9]. By disentangling drug exposure from metabolic risk, non-invasive studies have reinforced the view that MTX alone is rarely the dominant driver of fibrogenesis[7-9].

Collectively, these advances support a shift toward risk-based monitoring strategies. Rather than focusing on cumulative dose thresholds, clinicians can now tailor surveillance according to metabolic profile, alcohol use, and non-invasive fibrosis findings[8,9]. This approach aligns MTX hepatotoxicity monitoring with broader hepatology practice and avoids unnecessary treatment discontinuation in patients who derive substantial benefit from the drug.

Limitations and pitfalls of noninvasive methods

Despite clear advantages, noninvasive tools have contextspecific limitations clinicians should anticipate. We highlight those in Table 2.

Table 2 Non-invasive monitoring: How to deal with common pitfalls.

Tool/scenario	Common pitfalls	What to do (mitigation)	When to escalate
Transient elastography/shearwave elastography	False-highs with acute inflammation, cholestasis, or postprandial state; obesity/central adiposity lowers reliability; device/probe cut-off variability; suboptimal IQR/median	Repeat in fasting state; use correct probe (XL if BMI/skin-capsule distance warrants); ensure quality metrics (e.g., IQR/median ≤ 30%, ≥ 10 valid shots); standardize device/protocol; interpret with ALT, platelets, clinical context	If kPa remains high on repeat under proper conditions and discordant with labs/clinical picture - consider turnover panel or specialist review
Serum scores (FIB-4, APRI, ELF, PIIINP)	Age-dependence; low PPV for moderate fibrosis in low-prevalence settings; systemic inflammation elevates components and may over-call risk	Use rule-out/rule-in bands; re-test when disease activity is quiescent; combine with elastography for concordance	Concordant high risk across two modalities or rising trend despite risk optimization, escalate work-up or therapy discussion
Discordance management	Enzymes high but TE low; TE high with normal labs	Consider MASLD activity, extrahepatic drivers, transient flares. Confirm fasting/probe; repeat TE; consider turnover markers before biopsy	Persisting discordance after optimized repeats, and where biopsy would change management
Follow-up cadence/interpretation	Over-reliance on single thresholds during changing clinical status	Prefer trendbased interpretation (bi-directional movement over time) with standardized timing/conditions	Escalate if sustained upward trends in TE and/or serum scores occur despite riskfactor optimization

Quality criteria for transient elastography commonly include interquartile range/median ≤ 30% and ≥ 10 valid measurements; thresholds vary by device/probe and clinical context. IQR: Interquartile range; BMI: Body mass index; ALT: Alanine aminotransferase; FIB-4: Fibrosis-4 index; APRI: Aspartate aminotransferase/platelet ratio index; ELF: Enhanced liver fibrosis test; PIIINP: Procollagen III aminoterminal propeptide; PPV: Positive predictive value; TE: Transient elastography; MASLD: Metabolic dysfunction-associated steatotic liver disease.

ROLE OF METABOLIC RISK

The strongest determinant of liver fibrosis in MTX-treated patients is not the drug itself but the metabolic environment in which it is prescribed. Patients with rheumatoid arthritis, psoriasis, and psoriatic arthritis often have an increased prevalence of obesity, insulin resistance, dyslipidemia, and type 2 diabetes, conditions that are well recognized as central drivers of metabolic dysfunction-associated steatotic liver disease and progressive fibrosis[10,12]. These comorbidities, rather than cumulative MTX dose, consistently emerge as the dominant predictors of hepatic injury.

Non-invasive studies reinforce this perspective. When liver stiffness is elevated in MTX cohorts, it typically parallels markers of metabolic dysfunction - higher body mass index, central adiposity, and metabolic syndrome components - rather than duration of therapy or total MTX exposure[13,14]. Similarly, serum fibrosis indices such as FIB-4 and aspartate aminotransferase/platelet ratio index frequently reflect the background burden of steatosis and insulin resistance[15]. This suggests that MTX may act more as a co-factor in already vulnerable livers rather than as an independent hepatotoxin.

Alcohol consumption further amplifies this risk, compounding metabolic stress and synergizing with other hepatotoxic pathways[16]. Distinguishing alcohol-related injury from drug-induced changes is often challenging, and failure to account for this factor in early MTX studies likely inflated estimates of drug-related toxicity. Recognizing the primacy of metabolic risk has major clinical implications. It reframes MTX hepatotoxicity as part of the broader spectrum of fatty liver disease and supports a management paradigm focused on weight control, glycemic regulation, and reduction of alcohol intake. Rather than discontinuing MTX based on cumulative dose alone, clinicians are encouraged to assess and modify these risk factors. Such an approach not only ensures hepatic safety but also preserves access to one of the most effective and affordable disease-modifying therapies.

CONCLUSION

Reassessing MTX hepatotoxicity means letting contemporary evidence, rather than legacy habits, guide decisions. In routine low-dose, folate-supplemented use, clinically meaningful fibrosis is uncommon, and where it appears it tracks far more closely with metabolic risk than with cumulative exposure[4-9]. Population analyses reach the same conclusion once obesity, insulin resistance, steatosis and alcohol are considered, with dose contributing little on its own[9,10,12]. Our clinical experience is consistent with this pattern; in a Swedish rheumatoid and psoriatic arthritis cohort assessed with elastography, liver stiffness rose with body mass index, glycaemia and triglycerides rather than with cumulative MTX (in review).

What helps clinicians the most is knowing what to do when tests are abnormal. When alanine aminotransferase is persistently raised but elastography is low or normal, the working diagnosis is usually active steatotic liver disease or an extrahepatic source rather than drug toxicity[5-7,10,12,13]. The pragmatic course is to intensify weight, glycaemic and alcohol management, review other hepatotoxins, adjust MTX only if enzymes continue to climb, and repeat biochemistry in four to eight weeks. If results improve or stabilise, continue MTX and reassess elastography, including steatosis quantification where available, in six to twelve months.

When enzymes are normal but elastography is high, the first step is to confirm the signal. Repeat the measurement with the appropriate probe, review the steatosis readout and routine labs, and consider a collagen-turnover panel to adjudicate[5-7,10,12,13]. If stiffness compatible with at least moderate fibrosis persists despite risk-factor optimisation, refer to hepatology and consider biopsy only when the result will change management, for example to exclude an alternative diagnosis or to stage before a major therapeutic change[1,4-6,13]. Biopsy now has a focused role and is not required for routine surveillance. Therefore, we suggest a pragmatic pathway to harmonize rheumatology, dermatology, and hepatology practice[10,11] (Table 3). This algorithm reflects contemporary guidance showing high negative predictive value for FIB-4 < 1.3 and vibration-controlled transient elastography < 8 kPa, the age-adjusted FIB-4 threshold (> 2.0 if > 65 years), and the superior rule-in performance of enhanced liver fibrosis score/magnetic resonance elastography for advanced disease; it also accounts for NIT pitfalls (fasting, obesity, inflammation), emphasizing repeat qualityassured testing before changing therapy.

Table 3 Stepwise algorithm for liver fibrosis risk stratification and monitoring in methotrexate-treated patients.

Step	Criteria and interpretation (key thresholds)	Actions and followup
Baseline risk	Alcohol intake; metabolic risk: BMI/waist, diabetes, lipids, blood pressure. Review co-medications (polypharmacy); check ALT/AST, platelets, eGFR. Known chronic liver disease (viral hepatitis, cholestatic/autoimmune), significant alcohol use, or CKD start in a higher-risk lane	Place the patient in the appropriate risk lane before NITs
Primary triage (FIB-4)	Calculate FIB-4 for steatosis risk or unexplained enzyme elevation. Interpretation: FIB-4 < 1.3 (low risk). If age > 65: < 2.0 (low risk). FIB-4 ≥ 1.3 (or ≥ 2.0 if > 65 years) proceed to secondary assessment	Low risk: Continue MTX and risk-factor optimization; repeat FIB-4 every 2-3 years (every 1-2 years with diabetes or > 2 metabolic risk factors)
Secondary assessment	Use VCTE first (fast ≥ 3 hours; correct probe; document IQR/median). VCTE: < 8 kPa (low risk); 8-12 kPa (indeterminate); > 12 kPa (high likelihood of advanced fibrosis). Alternatives/complements: ELF (rule-out < 9.8; consider cirrhosis risk if ≥ 11.3), MRE (≥ 3.63 kPa suggests advanced fibrosis)	Repeat if suboptimal conditions; if uncertainty persists, consider hepatology consultation
Follow-up - low risk	FIB-4 < 1.3 and VCTE < 8 kPa	Continue MTX; optimize metabolic risk. Recheck FIB-4 in 1-3 years; repeat VCTE if clinical status changes
Follow-up - intermediate risk	FIB-4 ≥ 1.3 or VCTE 8-12 kPa or ELF 9.8-11.2	Continue MTX; intensify metabolic management. Repeat NITs in 6-12 months
Follow-up - high risk	VCTE > 12 kPa, or ELF ≥ 11.3, or MRE ≥ 3.63 kPa, or falling platelets	Discuss with hepatology. Consider dose reduction/alternative therapy; evaluate for portal hypertension. Initiate HCC surveillance if cirrhosis is suspected
Switch therapy despite mild fibrosis	Consider switching from MTX (or reducing dose) if either of the following occurs despite optimized metabolic care: ≥ 20% increase in VCTE/MRE with the final value in or approaching the indeterminate band (e.g., 6.5-8.0 kPa), confirmed on repeat testing in strict fasting; persistent ALT/AST elevations ≥ 2 × ULN on ≥ 2 tests ≥ 4 weeks apart without another cause	Switch or reduce MTX after risk-benefit discussion
Biopsy and referral triggers	Non-invasive tests discordant (e.g., FIB-4 high but VCTE low). Confirmed VCTE ≥ 12 kPa or ELF ≥ 11.3. New cytopenias or synthetic dysfunction; persistent clinical suspicion despite equivocal NITs	Refer to hepatology; consider liver biopsy

Vibration-controlled transient elastography quality: Interquartile range/median < 30%, ≥ 10 valid shots; correct probe (XL for high body mass index). Prefer fasting when possible; standardize timing and conditions between measurements. Interpret results with clinical context (alanine aminotransferase, platelets). BMI: Body mass index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; eGFR: Estimated glomerular filtration rate; CKD: Chronic kidney disease; NIT: Non-invasive test; FIB-4: Fibrosis-4 index; MTX: Methotrexate; VCTE: Vibration-controlled transient elastography; IQR: Interquartile range; ELF: Enhanced liver fibrosis; MRE: Magnetic resonance elastography; HCC: Hepatocellular carcinoma; ULN: Upper limit of normal.

Patients who already have low-grade fibrosis or who newly cross into that range while receiving MTX need individualised plans. Randomised trials of continuation in established fibrosis are scarce and unlikely for practical and ethical reasons, so shared decisions should weigh disease control against hepatic trajectory. When fibrosis is compensated and clearly driven by metabolic risk, continuing MTX is often reasonable if weight, glycaemia and alcohol are actively managed, enzymes are tracked every one to three months and elastography is repeated at six to twelve months; progression despite optimisation should prompt a switch. Alternatives are not uniformly hepatosafe and are seldom studied in fibrotic livers, so automatic discontinuation for mild fibrosis may be unnecessarily cautious[8-10,12].

Beyond low-grade fibrosis, closer long-term surveillance is prudent in patients with pre-existing chronic liver disease (viral, autoimmune, cholestatic), metabolic dysfunction-associated steatotic liver disease with diabetes or recent weight gain, sustained alcohol risk, long-term MTX users with new enzyme rises or upward non-invasive fibrosis signals, and those with prior unexplained liver function tests flares. This specifies who needs tighter follow-up while keeping our monitoring cadence unchanged.

Important uncertainties remain. Elastography thresholds vary with device, probe and body habitus, stiffness can rise transiently with inflammation or cholestasis, and serum panels may over-call fibrosis in active inflammatory disease[5-7,10,12,13]. Harmonised cut-offs by probe and body mass, validation of trend-based algorithms that combine elastography with selective biomarkers, and prospective evaluation of continuation strategies in compensated metabolic fibrosis are sensible next steps.

Co-medications and drug-drug interactions in MTX-treated patients is another important issue. Several commonly encountered agents can add hepatic risk or interact with MTX. Key considerations include alcohol, leflunomide (hepatotoxicity), isoniazid, azole antifungals and some macrolides (cytochrome P450 and transporter interactions), chronically high-dose acetaminophen, and certain herbal supplements. Statin-associated transaminitis is usually co-manageable and not an automatic reason to stop MTX if benefits outweigh risks. Practical steps are: (1) Reconcile medications at MTX initiation and whenever adding/removing potential hepatotoxins; (2) Adjust laboratory cadence for several weeks after such changes; and (3) Treat metabolic risks (weight, diabetes, alcohol) as first-line “hepatoprotection”. This approach complements NIT-guided monitoring without reverting to legacy cumulative-dose approaches.

Taken together, the contemporary picture is consistent and practical. Advanced fibrosis during low-dose, folate-supplemented MTX is uncommon and usually reflects the patient’s metabolic milieu rather than a cumulative drug effect. A pathway that begins with metabolic profiling and alcohol history, uses folate routinely, interprets enzymes in context, employs elastography with selective biomarkers, and reserves biopsy for clearly defined situations allows patients to retain access to an effective, inexpensive therapy while maintaining hepatic safety.