Methotrexate
Methotrexate is a synthetic folic acid analogue that functions as an antimetabolite by competitively inhibiting dihydrofolate reductase (DHFR), thereby preventing the regeneration of tetrahydrofolate and disrupting the synthesis of purine and pyrimidine nucleotides essential for DNA and RNA production in rapidly dividing cells.[1][2] Developed in 1949 as a structural congener of folic acid to interfere with cellular replication, it was approved by the U.S. Food and Drug Administration in 1953 for the treatment of certain cancers.[2][3] Introduced initially for childhood leukemia following the pioneering work with related antifolates like aminopterin in 1948, methotrexate achieved a landmark success in curing choriocarcinoma, the first solid tumor demonstrated to be curable by chemotherapy alone, which established the efficacy of antimetabolites against malignancies beyond hematologic cancers.[4][5] Today, it serves as a cornerstone in regimens for acute lymphoblastic leukemia, non-Hodgkin lymphoma, osteosarcoma, and breast cancer, while low-dose applications have proven effective as a first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis, as well as for psoriasis, Crohn's disease, and ectopic pregnancies.[1][6] Its immunosuppressive effects stem from the same antifolate mechanism, reducing inflammation by limiting T-cell proliferation and cytokine production at lower doses.[1] Despite its therapeutic versatility, methotrexate's use requires careful monitoring due to dose-dependent toxicities, including hepatotoxicity manifesting as fibrosis or cirrhosis, myelosuppression leading to anemia and infection risk, gastrointestinal mucositis, and pulmonary interstitial pneumonitis.[6][7] It is strictly contraindicated in pregnancy owing to its potent teratogenic and embryocidal effects, comparable to those of thalidomide, and can exacerbate renal impairment or interact adversely with nonsteroidal anti-inflammatory drugs.[8][7] Folinic acid (leucovorin) rescue is employed in high-dose protocols to mitigate bone marrow toxicity by bypassing the DHFR block, underscoring the drug's narrow therapeutic index and the empirical basis for its clinical protocols derived from decades of pharmacokinetic and pharmacodynamic studies.[1]
Pharmacology
Chemical properties
Methotrexate, with the IUPAC name (2S)-2-[(4-{(2,4-diaminopteridin-6-yl)methylamino}benzoyl)amino]pentanedioic acid, is a synthetic antifolate analog of folic acid, also known as 4-amino-10-methylpteroylglutamic acid.[9] Its molecular formula is C_{20}H_{22}N_{8}O_{5}, and it has a molecular weight of 454.44 g/mol.[9] [10] Chemically classified as an antimetabolite, it functions as a structural derivative of pteroylglutamic acid (folic acid) modified by amination at the 4-position of the pteridine ring and N^{10}-methylation.[11] [12] The compound appears as a yellow to orange-brown crystalline powder with a melting point range of 185–204 °C.[10] [13] It exhibits low solubility in water, being practically insoluble for the base form, though the disodium salt formulation enhances solubility for pharmaceutical use; solubility increases in dilute acids and alkalis.[13] Methotrexate demonstrates stability under standard storage conditions, with noted low toxicity in certain contexts, though it requires protection from light and moisture to maintain integrity.[10] Synthesis of methotrexate involves chemical modification of pteroylglutamic acid derivatives, typically through coupling reactions that introduce the 4-amino group and the N^{10}-methyl substituent, often utilizing activated intermediates such as pteroate analogs with glutamic acid derivatives.[14] [15] In functional classifications relevant to its chemical nature, it is recognized as a disease-modifying antirheumatic drug (DMARD) due to its antimetabolite properties.[11] [16]Mechanism of action
Methotrexate exerts its primary pharmacological effect as a competitive inhibitor of dihydrofolate reductase (DHFR), the enzyme responsible for reducing dihydrofolate to tetrahydrofolate (THF). THF serves as a critical cofactor in one-carbon transfer reactions necessary for the de novo synthesis of purines, thymidylate, and other nucleotides essential for DNA and RNA production, thereby arresting the cell cycle at the S phase and inhibiting proliferation in rapidly dividing cells.[17][18][1] Upon cellular uptake via the reduced folate carrier, methotrexate undergoes polyglutamation by folylpolyglutamate synthase, forming methotrexate polyglutamates (MTX-PGs) with up to five glutamate residues. These MTX-PGs exhibit prolonged intracellular retention, higher affinity for DHFR (with Ki values 10- to 100-fold lower than the parent drug), and additional inhibition of enzymes such as thymidylate synthase, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase, and glycineamide ribonucleotide (GAR) formyltransferase, further depleting nucleotide pools and amplifying folate antagonism.[17][19][20] The drug's actions are dose-dependent, manifesting cytotoxicity at high doses (e.g., >100 mg/m²) through severe folate depletion, DNA synthesis blockade, and induction of apoptosis in malignant cells. In vitro studies demonstrate that methotrexate triggers apoptosis in transformed T lymphocytes via generation of reactive oxygen species (ROS), activation of c-Jun N-terminal kinase (JNK), and subsequent caspase-dependent pathways, with ROS scavengers mitigating these effects.[21][22][23] At low doses (e.g., 7.5-25 mg weekly), methotrexate promotes anti-inflammatory effects independent of profound folate inhibition, primarily by elevating extracellular adenosine levels through inhibition of aminoimidazole carboxamide ribonucleotide (AICAR) transformylase, leading to adenosine accumulation and its release via equilibrative nucleoside transporters. Adenosine then activates A2A and A3 receptors on leukocytes and endothelial cells, suppressing pro-inflammatory cytokine production (e.g., IL-6, TNF-α) and adhesion molecule expression while enhancing anti-inflammatory signaling.[24][25][26]Pharmacokinetics and pharmacodynamics
Methotrexate exhibits variable oral bioavailability, ranging from 60% to 90% at low doses (typically ≤30 mg/m² or ≤15 mg weekly), with peak plasma concentrations achieved within 1-2 hours post-administration; however, bioavailability decreases significantly at higher oral doses due to saturable first-pass metabolism and gastrointestinal absorption limitations.[1][27] Subcutaneous or intramuscular administration provides more consistent and higher bioavailability, approaching 100%, bypassing oral absorption variability and resulting in greater systemic exposure compared to equivalent oral doses.[28][29] The drug binds approximately 50% to plasma proteins, primarily albumin, facilitating extensive distribution into tissues including the liver, kidneys, spleen, and cerebrospinal fluid at higher doses; volume of distribution is around 0.4-0.8 L/kg, reflecting good penetration into synovial fluid and inflamed tissues relevant to its antirheumatic effects.[30][31] Intracellularly, methotrexate undergoes hepatic and peripheral polyglutamation by folylpolyglutamate synthetase (FPGS), forming methotrexate polyglutamates that enhance retention within cells and prolong inhibition of folate-dependent enzymes, thereby influencing dose-response duration.[30][32] Elimination occurs predominantly via renal excretion of unchanged drug (80-90%), with glomerular filtration and active tubular secretion mediated by organic anion transporters; a smaller portion (10-20%) undergoes enterohepatic recirculation via biliary excretion, potentially extending exposure.[33][34] The terminal elimination half-life varies with dose: 3-10 hours for low-dose regimens and 8-15 hours for high-dose infusions, influenced by renal function and polyglutamate formation.[30] Pharmacodynamic variability, including differential therapeutic responses, arises from pharmacokinetic factors such as genetic polymorphisms in transporters (e.g., reduced folate carrier 1 [RFC1]) and FPGS, which affect cellular uptake and metabolite accumulation, thereby modulating the intensity and duration of enzymatic inhibition.[35][36]Medical uses
Oncology applications
Methotrexate serves as a key component in chemotherapeutic regimens for various malignancies, leveraging its antifolate mechanism to inhibit DNA synthesis in rapidly dividing cancer cells, particularly in hematologic cancers. High-dose methotrexate (HDMTX), typically administered at doses of 3-12 g/m² intravenously, is standard in protocols for acute lymphoblastic leukemia (ALL), where it enhances systemic exposure and penetrates sanctuary sites like the central nervous system (CNS). Intrathecal methotrexate is routinely used for CNS prophylaxis in ALL and certain lymphomas to prevent meningeal involvement. HDMTX is paired with leucovorin (folinic acid) rescue, initiated 24 hours post-infusion based on serum levels, to selectively protect normal cells while preserving cytotoxicity against malignant ones.[1] In pediatric and adult ALL, HDMTX has significantly improved outcomes; randomized trials demonstrate 5-year event-free survival rates of 91.5% with HDMTX-containing regimens in T-lineage ALL, compared to 85.3% without, attributing gains to better clearance of minimal residual disease. For B-cell ALL subtypes, HDMTX integration yields disease-free survival exceeding 80% at 5 years in high-risk groups, outperforming intermediate-dose alternatives (58% vs. 32%).[37] Modern protocols, such as those from cooperative groups, report overall event-free survival approaching 90% in children, with HDMTX contributing to reduced relapse rates, though long-term neurotoxicity requires monitoring.[38] For non-Hodgkin lymphoma, particularly diffuse large B-cell lymphoma (DLBCL) and Burkitt lymphoma, HDMTX augments R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) in high-risk cases for CNS prophylaxis, with feasible integration on day 1 of cycles improving regimen deliverability without excess toxicity.[39] However, evidence on survival benefit is mixed, as prophylactic HDMTX reduces but does not eliminate CNS relapse risk, conferring no clear overall survival advantage in some analyses.[40] In osteosarcoma, HDMTX forms the backbone of multi-agent therapy like the MAP regimen (high-dose methotrexate, doxorubicin, cisplatin), administered neoadjuvantly and adjunctively to improve histologic response and long-term survival, with studies confirming its role in achieving event-free survival rates of 60-70% in localized disease when combined appropriately.[41] Applications in breast cancer have historically included moderate-dose methotrexate in regimens like CMF (cyclophosphamide, methotrexate, fluorouracil) for adjuvant therapy, yielding relapse-free survival benefits in node-positive cases, though high-dose variants show limited added efficacy and are rarely used today due to comparable alternatives.[42] Resistance in solid tumors, including osteosarcoma and breast cancer, often arises via dihydrofolate reductase (DHFR) gene amplification, enabling cells to overcome inhibition and necessitating combination strategies or novel antifolates.[43]Autoimmune and inflammatory disorders
Methotrexate serves as a first-line disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis (RA), recommended by the American College of Rheumatology (ACR) for its ability to reduce disease activity, inhibit radiographic joint damage progression, and improve physical function when administered weekly at low doses starting from 7.5–15 mg, titrated up to a maximum of 25 mg.[44][45] European League Against Rheumatism (EULAR) guidelines endorse rapid escalation to 25 mg weekly with folic acid supplementation to optimize efficacy while minimizing toxicity.[46] Randomized trials support monotherapy success rates of approximately 59% in achieving low disease activity or remission at one year, with predictors including lower baseline disease activity and fewer tender joints.[47] Subcutaneous methotrexate demonstrates superior bioavailability and clinical outcomes compared to oral administration, particularly at doses exceeding 15 mg weekly, due to avoidance of first-pass metabolism and reduced gastrointestinal variability.[48] In combination with biologics like etanercept, as evaluated in the TEMPO trial, remission rates reached 37% at one year versus lower rates with methotrexate alone, highlighting additive benefits for non-responders while affirming methotrexate's foundational role.[49] Long-term persistence in RA averages 60% at 24 months and declines to 40% at 48 months, influenced by factors such as seropositivity and early response, with discontinuation often linked to adverse effects rather than inefficacy.[50] In Crohn's disease, methotrexate functions as a steroid-sparing agent for maintenance of remission in steroid-dependent patients, with intramuscular or subcutaneous doses of 25 mg weekly inducing remission in controlled trials involving 30–50% of participants.[51] American Gastroenterological Association (AGA) guidelines advise against its use for induction in moderate-to-severe cases, citing insufficient evidence from randomized trials where oral formulations at 12.5 mg weekly failed to outperform placebo.[52][53] For psoriatic arthritis, methotrexate is used off-label at similar low weekly doses despite only weak-to-moderate evidence; a Cochrane review of randomized trials found it marginally superior to placebo for joint and skin outcomes, with ACR20 response rates around 40–50% at 6 months, though biologics often supplant it in refractory cases.[54][55] Real-world data indicate combination with tumor necrosis factor inhibitors enhances persistence and efficacy over monotherapy.[56]Dermatological conditions
Methotrexate is utilized for the management of severe, recalcitrant plaque psoriasis, administered at low weekly oral doses of 10-25 mg, which inhibits excessive keratinocyte proliferation through dihydrofolate reductase antagonism in the folate pathway. Clinical trials have reported PASI-75 response rates (75% improvement in Psoriasis Area and Severity Index) of 50-60% after 12-16 weeks of such therapy, with sustained skin clearance in long-term maintenance.[57][58][59] In moderate-to-severe atopic dermatitis, methotrexate serves as an off-label systemic option, particularly when topical therapies fail, with retrospective and controlled studies demonstrating marked reductions in disease severity scores; for instance, one cohort achieved >75% improvement in 93% of adult patients after 6-12 months at doses of 10-20 mg weekly. Pediatric trials further indicate superior sustained remission compared to cyclosporine, with efficacy persisting beyond 36 weeks in severe cases.[60][61][62] For localized scleroderma, methotrexate is recommended off-label as first-line systemic therapy in cases with extensive skin or musculoskeletal involvement, showing improvements in lesion activity and range of motion in pediatric patients treated with 15 mg/m² weekly alongside corticosteroids. Empirical benefits stem from its antifibrotic effects via reduced cellular proliferation, though evidence derives primarily from small observational studies rather than large randomized trials.[63][64] In refractory psoriasis, low-dose methotrexate is often combined with biologic agents such as TNF inhibitors or IL-17 antagonists, yielding higher PASI-75 rates (up to 70-80% in some cohorts) than biologics alone, without increased serious adverse events in short-term use. Clinicians must monitor for methotrexate-specific cutaneous toxicities, such as accelerated nodulosis or mucositis, which can mimic psoriatic flares and necessitate dose adjustment or discontinuation.[65][66]Reproductive and obstetric uses
Methotrexate is employed in the medical management of unruptured ectopic pregnancies in hemodynamically stable patients, offering a non-surgical alternative that preserves fertility. The American College of Obstetricians and Gynecologists (ACOG) recommends systemic methotrexate for cases with initial serum β-hCG levels below 5,000 mIU/mL, gestational age under 3.5 cm, and absence of fetal cardiac activity, achieving success rates of 85-95% in appropriately selected patients.[67] Single-dose protocols involve intramuscular administration of 50 mg/m², followed by serial β-hCG monitoring on days 4 and 7 post-injection; a decline of at least 15% between these days predicts treatment success with high reliability.[68] Multi-dose regimens (e.g., 1 mg/kg on alternating days with leucovorin rescue) are reserved for higher-risk cases, though they carry increased toxicity without superior efficacy in most scenarios.[69] Failure rates range from 5-15% for single-dose therapy in low-β-hCG cases, rising to 20-30% with levels exceeding 5,000 mIU/mL or larger adnexal masses, often necessitating surgical intervention such as salpingostomy or salpingectomy.[70] Close follow-up mitigates rupture risk (approximately 6-7% overall), with ectopic pregnancies being non-viable and potentially life-threatening due to tubal rupture and hemorrhage if untreated.[71] This approach avoids operative risks but requires patient compliance and excludes those with renal impairment, active peptic ulcers, or breastfeeding status. Methotrexate is contraindicated in viable intrauterine pregnancies owing to its potent teratogenicity, which disrupts folate metabolism and DNA synthesis during embryogenesis, leading to neural tube defects, craniofacial dysmorphism, limb reductions, and cardiac anomalies in exposures during the first trimester.[72] The critical window for malformations spans 6-8 weeks post-conception, with case series documenting fetal methotrexate syndrome in unintended exposures, including anencephaly and hydrocephalus.[73] Off-label use in early induced abortion (typically <7 weeks gestation, combined with misoprostol) achieves efficacy comparable to mifepristone regimens but is less common due to slower action and higher side effects; the FDA has not approved it for this purpose, classifying it as abortifacient only in non-FDA contexts.[74] Debates persist on its classification: while essential for ectopic treatment (preserving maternal life without viable fetal outcome), elective abortifacient applications terminate developing pregnancies, raising ethical distinctions between therapeutic necessity and intentional interruption, though empirical data affirm its causal role in fetal demise via antiproliferative effects.[75] Post-treatment contraception is advised for 3 months due to gametogenic risks, with no evidence of increased infertility from ectopic management doses.[76]Other indications
Methotrexate has demonstrated efficacy in treating sarcoidosis, particularly as a second-line or steroid-sparing agent for pulmonary and refractory forms, with response rates approaching 80% in observational studies of patients unresponsive to corticosteroids.[77] A randomized trial published in May 2025 showed methotrexate to be comparable to prednisone in improving pulmonary function over 24 months, though with a slower onset of action and reduced incidence of steroid-related adverse effects such as weight gain and hyperglycemia.[78] In vasculitis, methotrexate serves as a maintenance therapy for nonsevere forms, including granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA), where guidelines from 2021 recommend it over cyclophosphamide to minimize toxicity while achieving remission in active disease.[79] For juvenile idiopathic arthritis (JIA), low-dose methotrexate at 8.5–15 mg/m² weekly remains a cornerstone for polyarticular subtypes, with a 2024 Cochrane review confirming improved treatment response rates up to six months compared to placebo, though evidence for long-term pain reduction is limited.[80] Investigational applications include relapse prevention in multiple sclerosis, where low-dose oral methotrexate in pilot trials reduced relapse rates and stabilized disability progression over 18 months, but larger randomized data indicate only trends toward benefit without establishing it as standard therapy.[81] In chronic noninfectious uveitis, methotrexate achieves inflammation control in 70–90% of steroid-refractory cases, with long-term studies reporting sustained visual acuity preservation and steroid-sparing effects in up to 56% of patients over multiple years.[82] For graft-versus-host disease (GVHD) post-allogeneic hematopoietic stem cell transplantation, methotrexate contributes to overall response rates of 70–78% in both acute and chronic forms when used in combination regimens.[83] Off-label use in sickle cell disease for vaso-occlusive crises shows preliminary promise from a 2017 pilot study, where low-dose methotrexate reduced crisis frequency and inflammatory markers, though randomized evidence remains scarce and larger trials are needed to confirm efficacy and safety.[84]Administration and dosing
Routes of administration
Methotrexate is administered through multiple routes, including oral, subcutaneous, intramuscular, intravenous, and intrathecal, with selection influenced by the clinical indication, required systemic exposure, and patient-specific factors such as gastrointestinal tolerance or need for central nervous system penetration.[1] Oral tablets provide convenient weekly low-dose therapy for conditions like rheumatoid arthritis, but exhibit dose-dependent bioavailability averaging 60-70% at doses below 15 mg, with absorption saturation leading to reduced and highly variable uptake at higher oral doses due to limited gastrointestinal transporter capacity.[85][86] In contrast, subcutaneous administration achieves nearly complete bioavailability with lower interpatient variability, resulting in approximately 30% greater area under the curve compared to equivalent oral doses in rheumatoid arthritis patients, which supports its preference for consistent efficacy in autoimmune disorders where oral absorption may falter.[86][87] Parenteral routes bypass gastrointestinal limitations, ensuring predictable pharmacokinetics essential for oncology applications; intravenous infusions enable high-dose delivery for tumor treatment, while intramuscular injections are commonly used for single-dose regimens in ectopic pregnancy management to achieve rapid systemic levels without vascular access.[1][88] Intrathecal administration, via lumbar puncture, delivers the drug directly into cerebrospinal fluid for prophylaxis or treatment of meningeal involvement in leukemias and lymphomas, circumventing the blood-brain barrier.[89][90] Recent shortages of injectable formulations, driven by manufacturing constraints and surging demand since 2023, have intermittently disrupted access to subcutaneous, intramuscular, and intravenous options, prompting reliance on oral alternatives where clinically feasible despite their bioavailability drawbacks.[91][92] Bioavailability considerations guide route selection, favoring parenteral methods for patients with absorption variability or high-dose needs to optimize therapeutic outcomes.[93][94]Dosing guidelines
Methotrexate dosing regimens are tailored to the specific indication, with low doses typically administered weekly for autoimmune and inflammatory conditions and higher bolus doses for oncology applications, often requiring supportive therapies like leucovorin rescue in the latter.[95] For rheumatoid arthritis, the initial dose is 7.5 mg orally once weekly, with gradual titration by 2.5 to 5 mg increments every 2 to 4 weeks up to a maximum of 25 mg weekly based on clinical response and tolerability.[1] Similar protocols apply to psoriasis, starting at 10 to 15 mg weekly and escalating to 25 to 30 mg weekly as needed.[95] In oncology, particularly for acute lymphoblastic leukemia or osteosarcoma, high-dose methotrexate is given intravenously at 1 to 12 g/m² over 4 to 36 hours, followed by leucovorin rescue starting 24 hours post-infusion at 10 to 15 mg/m² every 6 hours until serum methotrexate levels fall below 0.2 micromolar, ensuring rapid reversal of toxicity while preserving antitumor efficacy.[96] Lower oncology doses, such as 20 to 30 mg/m² weekly intramuscularly, may be used for maintenance in certain regimens.[95] Dose adjustments are essential for renal impairment; for creatinine clearance below 60 mL/min, reduce the dose by 50% or more, with further reductions or discontinuation if clearance is under 30 mL/min to prevent accumulation and toxicity.[1] Folic acid supplementation, at 1 mg daily or 5 mg weekly on a non-methotrexate day, is recommended alongside low-dose regimens for autoimmune indications to mitigate gastrointestinal and hematologic toxicities without compromising therapeutic effectiveness, though it is contraindicated during high-dose oncology cycles where leucovorin is preferred.[97] Emerging evidence from studies between 2023 and 2025 indicates that MTHFR gene polymorphisms, such as C677T, may predict delayed methotrexate clearance and heightened toxicity risk, particularly in high-dose settings, prompting consideration of preemptive dose reductions or enhanced rescue in genetically susceptible patients, though routine pharmacogenetic testing is not yet standard and requires further validation for dosing optimization.[98][99]Monitoring requirements
Baseline assessments prior to initiating methotrexate therapy include a complete blood count (CBC) to evaluate for baseline hematologic abnormalities, liver function tests (LFTs) such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST) to screen for hepatotoxicity risk, and renal function tests including serum creatinine to assess glomerular filtration rate, as methotrexate is primarily renally excreted.[100] [1] Additional baseline evaluations may encompass serum albumin levels, which correlate with hepatic synthetic function, and a chest X-ray in patients with pulmonary risk factors.[100] [101] Ongoing monitoring for chronic low-dose regimens, such as in rheumatoid arthritis, typically involves CBC to detect myelosuppression, LFTs (ALT/AST) every 1-3 months after initial stabilization, and renal function assessments at similar intervals to identify early toxicity.[102] [101] For higher-risk patients or during dose escalation, testing frequency increases to every 1-2 weeks initially, then extends to every 2-3 months once stable.[101] Pulmonary function tests or high-resolution CT are recommended only if respiratory symptoms arise, given the risk of methotrexate-induced pneumonitis.[1] In long-term users, supplemental monitoring may include homocysteine levels to assess folate status, particularly if folic acid supplementation is inadequate, though routine folic acid level measurement is not standard.[103] Annual dermatologic examinations are advised for patients on extended therapy, especially those with psoriasis, due to elevated non-melanoma skin cancer risk.[104] Empirical thresholds for intervention include temporary discontinuation and specialist consultation if LFT elevations exceed 3 times the upper limit of normal (ULN) on two consecutive tests, or permanent cessation if sustained beyond 3x ULN, as per rheumatology consensus to mitigate fibrosis progression.[100] [105] Myelosuppression thresholds prompt dose reduction or withholding if absolute neutrophil count falls below 1,000/μL or platelets below 75,000/μL.[1] These strategies, derived from observational cohorts and society guidelines, aim to balance efficacy against cumulative toxicity without relying on invasive procedures like routine liver biopsy in low-dose settings.[103]Adverse effects and toxicity
Common and gastrointestinal effects
Gastrointestinal disturbances represent the most frequent adverse effects associated with methotrexate, particularly in patients treated for rheumatoid arthritis, with a pooled prevalence of 32.7% upon initiation of monotherapy.[106] Nausea and vomiting occur in 20-65% of rheumatoid arthritis patients, manifesting as dose-related symptoms that often peak shortly after administration.[107] These effects are more pronounced with oral dosing compared to subcutaneous administration, where nausea rates are reported at 63% for oral versus 37% for subcutaneous, vomiting at 30% versus 11%, and dyspepsia at 48% versus 29%.[108] Other common gastrointestinal issues include stomatitis and mucositis, with stomatitis prevalence ranging from 6-8% in low-dose regimens for rheumatic diseases.[109] These mucosal irritations typically present as painful oral ulcers or inflammation, correlating with peak drug levels and resolving upon dose reduction in empirical observations.[100] Non-gastrointestinal common effects encompass fatigue, affecting approximately 29.4% of early rheumatoid arthritis patients, and alopecia, with rates of 1-5% or up to 9.2% in cohort studies.[110][109] Alopecia is generally mild and reversible, often linked to cumulative dosing rather than acute exposure.[111] Such effects underscore methotrexate's tolerability profile at low doses, where incidence diminishes with route optimization or divided dosing to blunt peak concentrations.[112]| Adverse Effect | Oral Incidence (%) | Subcutaneous Incidence (%) | Source |
|---|---|---|---|
| Nausea | 63 | 37 | BMC Rheumatol |
| Vomiting | 30 | 11 | BMC Rheumatol |
| Dyspepsia | 48 | 29 | BMC Rheumatol |