Rheumatoid arthritis drug : methotrexate may elevate a risk of a variety of adverse events

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Methotrexate is a common drug with a long history; for the past 40 years, it’s been used to treat a range of diseases.

Today it is the most commonly used drug for systemic rheumatic diseases worldwide and is the first drug a physician will prescribe for a patient with rheumatoid arthritis.

But despite its use by millions of people, there is not robust data on the rates of the side effects of the drug.

Observational studies have suggested that methotrexate may elevate a person’s risk of a variety of adverse events, including liver toxicity, anemia and difficulty in breathing, but the magnitude of risk was unknown.

Taking advantage of data from the Cardiovascular Inflammation Reduction Trial (CIRT), a randomized double-blind, placebo-controlled trial, investigators from Brigham and Women’s Hospital have been able to far more accurately determine rates of adverse events for people taking methotrexate, finding small-to-moderate elevations in risks for skin cancer, gastrointestinal, infectious, lung, and blood adverse events. Results are published in Annals of Internal Medicine.

“Methotrexate is a cornerstone drug for a variety of inflammatory diseases, especially for rheumatoid arthritis,” said Daniel Solomon, MD, MPH, a rheumatologist in the Division of Rheumatology, Inflammation and Immunology at the Brigham.

“Over the decades, we’ve learned about the side effects but only from small studies. Questions for both physicians and patients have lingered about the drug’s safety.

Our study offers a detailed side-effect profile that I think will help us prescribe methotrexate in an informed way.”

Solomon and his colleagues looked at data on 4,786 participants from CIRT who were randomized to receive low-dose methotrexate with folate or a placebo.

Of 2,391 subjects who received methotrexate, 87 percent experienced an adverse event of interest compared to 81.5 percent of those who were randomized to placebo.

According to Solomon, the team’s most surprising finding was a doubling of risk of skin cancer for participants taking methotrexate (53 incidents of skin cancer versus 26 for placebo).

This result may be particularly important because patients with psoriatic arthritis – a form of arthritis that affects people with psoriasis – are already at increased risk of skin cancer.

Gastrointestinal, infectious, pulmonary and hematologic adverse events were also elevated, but the increased risk was mild to moderate.

As anticipated, the team also saw an increase in liver test abnormalities and five cases of cirrhosis in the methotrexate arm versus zero in the placebo arm.

The authors note that CIRT participants did not have rheumatoid arthritis or other rheumatic diseases and it is possible, although unlikely, that adverse event rates may vary outside of the CIRT population.

“We now have real numbers we can share with patients when talking about side effects,” said Solomon. “We definitely wouldn’t suggest this drug is too dangerous to give.

But having a clear side-effect profile allows us to give it with eyes wide open and better balances the risks and benefits of an age-old drug.”


Methotrexate (4-amino-10-methylfolic acid, MTX), an analog and antagonist of folic acid, is commonly used in the treatment of a wide range of malignant and non-malignant diseases [1].

Originally developed as an anticancer medication, MTX is currently the first-line disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA), juvenile idiopathic arthritis, and psoriasis, and is useful in inflammatory bowel diseases, multiple sclerosis, vasculitis, systemic lupus erythematosus and other connective tissue diseases, and transplantation due to its beneficial anti-inflammatory and immunomodulatory activities [1,2,3].

MTX has also prompted a growing interest in the treatment of viral mediated arthritis [4]. Many viruses—including old world alphaviruses, Parvovirus B19, hepatitis B/C virus (HBV/HBC), and human immunodeficiency virus (HIV)—are associated with arthritogenic diseases [5]. Chronic viral arthritis can clinically mimic RA and last for months to years [6]. Given pathogenic similarities with RA, MTX may provide benefits in the treatment of chronic viral associated rheumatic disorders, although the potential risk to compromise patients’ immune surveillance to prevent viral reactivation may need to be considered [7].

MTX is considered an essential medication by the World Health Organization (WHO) and is incontestably one of the pharmaceuticals greatest success stories as it found indications widely distinct from its original intention [8,9]. Despite the introduction of a number of effective biological agents for the treatment of autoimmune inflammatory diseases and mainly RA, MTX remains one of the most efficient and most commonly used therapies against which the efficacy of new DMARDs is judged [1].

MTX can be used both as first-line monotherapy in DMARD-naive patients [10], and as an anchor drug, in MTX-insufficient responders, in combination with other conventional or biological DMARDs to maximize therapeutic effects [11,12]. Low and more infrequent doses of MTX are used to treat inflammatory diseases and compared with the 5 g/week doses used in the treatment of malignancy, once-weekly administration of MTX at 10 to 25 mg provides optimal clinical outcomes in RA, the commonest prototype of low-dose MTX indications [13].

Fundamental mechanisms underlying the therapeutic effect of high doses MTX on malignant diseases are currently well established; MTX as a folate antagonist, competitively inhibits the activity of folate-dependent enzymes and synthesis of purine and pyrimidine required for DNA and RNA production in rapidly dividing malignant cells [14]. However, mechanisms by which low-dose MTX exerts its therapeutic effect in inflammatory disorders are not completely elucidated.

MTX is known to have highly favorable cost-effectiveness and efficacy/toxicity ratios but toxicity is still a concern. The potential adverse events associated with MTX attract considerable attention as they represent the main cause of drug withdrawal [15,16,17].

There are two broad subsets of MTX associated adverse events; Symptomatic but rarely life-threatening adverse events such as nausea, headaches, fatigue, mucositis and hair loss, and potentially life-threatening adverse events including cytopenias, interstitial lung disease (or MTX pneumonitis), and MTX related liver disease (fibrosis and cirrhosis) [8]. The precise mechanisms of MTX toxicity are still not clear. MTX mechanisms of action regarding efficacy and toxicity may be determined by either the same or different metabolic pathways.

This review will focus on the molecular mechanisms of action of MTX as an anti-inflammatory/immunomodulatory drug in order to further understand MTX therapeutic and toxic effects in inflammatory autoimmune disorders. We also review the efficacy and safety of MTX use in viral induced arthritis.

History

MTX, formerly known as amethopterin, is one of several folic acid antagonists originally synthesized in the 1940s for the treatment of malignancies and structurally designed to inhibit dihydrofolate reductase (DHFR), an essential enzyme for purine and pyrimidine synthesis in cell proliferation [18,19,20].

The rationale for the introduction of MTX for the treatment of RA was assumed on its capacity to inhibit inflammatory and proliferative response of connective tissue. The closely related antifolate aminopterin, a synthetic derivative of pterin, was shown to suppress exudative and proliferative changes in experimental formaldehyde arthritis [21]. Aminopterin was gradually replaced by MTX due to its less toxic nature and the first documented clinical use of MTX for the treatment of RA was in 1951 [22].

MTX clinical potential as a RA treatment was suggested by Gubner, after studying the effects of MTX in RA patients, and was confirmed by well designed, blinded, placebo controlled studies conducted during the 1980s [23].

RA patients treated with MTX demonstrated improved global assessments of disease activity, joint scores, and marked decreases in pain. Since then, the use of weekly low doses of MTX has expanded to involve additional inflammatory and autoimmune diseases.

In 1986, MTX was licensed by the US Food and Drug Administration (FDA) for the treatment of RA [24].The US FDA first approved the use of MTX only in life-threatening neoplastic diseases, or in patients with psoriasis or RA with severe, recalcitrant, disabling disease which is not adequately responsive to other forms of therapy [25]. Based on the American College of Rheumatology and the European League Against Rheumatism (ACR/EULAR) recommendations, MTX should be started early in recent and/or undifferentiated arthritis evocative of RA [26], in order to prevent joint destruction and disability.

Improved understanding of the pathogenesis of RA led to the introduction of biologic treatment in 1998 [27] and despite the development of several targeted biologic treatments such as TNF blockers, MTX remains the cornerstone of RA treatment, alone or in combination [28].

Continuous efforts are devoted to derivatives of MTX in order to improve the pharmacological parameters of the parent MTX. MTX derivatives bearing dihydro-2H-1,4-benzothiazine or dihydro-2H-1,4-benzoxazine applied on human synovial cells and human peripheral blood mononuclear cells (hPBMC) have been reported to have enhanced antiproliferative activity and increased DHFR binding affinity compared with MTX. In vivo, benzothiazine and benzoxazine derivatives exhibited antirheumatic activity in a rat adjuvant arthritis model [29]. Similar activities were observed with MTX derivatives containing enantiomerically pure l-erythro– or l-threo-γ-fluoroglutamic acid [30].

Didodecyl-MTX in lipid nanocarrier was found to reduce inflammation when administered via the intra-articular route into rabbits [31]. An optimized conjugate of MTX and hyaluronic acid (HA) was assessed on human fibroblast-like synoviocytes (FLS) and a synovial sarcoma cell line (SW982) and proved to be more efficient than the parent compounds to retrieve synovial inflammation in rat models [32].

MTX Adverse Effects Mechanisms of Action

Despite its widespread use in various autoimmune and inflammatory disorders, low-dose MTX is not free of drug toxicity.

The most common MTX-related adverse reactions are gastrointestinal manifestations (nausea, vomiting, stomatitis, loss of appetite) and hepatotoxicity [17]. Generally, the main cause of MTX treatment withdrawal is not the lack of efficacy but toxicity [17].

Careful and appropriate patient monitoring (blood cell counts, hepatic enzymes, creatinine) should be performed periodically and appears to significantly minimize risks associated with MTX use [142].

The mechanisms of MTX toxicity remain unclear. Some toxicities—such as cytopenia, gastrointestinal intolerance, and stomatitis—mimic the manifestations of folate deficiency and can be prevented or alleviated by folic or folinic acid supplementation [25].

Toxicities unrelated to folate deficiency include nodulosis, pulmonary fibrosis, lethargy, fatigue, and renal insufficiency [14]. The understanding of the molecular mechanisms of action of MTX may help to explain many of MTX associated toxicities [14] (Table 1).

Table 1

Major low dose MTX related adverse events.

Organ SystemMTX Related Adverse EventsToxic Mechanism of Action
GastrointestinalNausea;
Vomiting;
Diarrhea;
Mucositis and stomatitis
Gastrointestinal toxicities and bone marrow suppression seem to be directly related to folate antagonism, because these tissues have high cell turnover with a high requirement for purines, thymidine, and pyrimidine [37,143,144]. Supplementation of folic or folinic acid may diminish toxicity.
Gastrointestinal symptoms of nausea and diarrhea may be more frequent with oral MTX [145]. Switching from oral to parental administration was shown to significantly decrease the frequency of adverse gastrointestinal events in patients with RA [146,147], suggesting that other mechanisms may account for MTX induced gastrointestinal toxicity.
The pathogenic mechanism underlying gastrointestinal side effects may also be related to the change of plasma homocysteine [148].
HematologicalAnaemia;
Leucopenia;
Thrombopenia;
Pancytopenia
Recently, MTX-induced thrombocytopenia was shown to be mediated by MTX-induced activation of platelet apoptosis via JNK and oxidative stress [149].
HepaticElevated liver enzymesLong-term MTX administration can cause accumulation of MTX polyglutamates in the liver and decreased folate levels. The depletion of hepatic folate stores by accumulated MTX poly glutamates is one possible toxic effect of MTX on the liver [150]. Folate supplementation has been associated with a reduced incidence of elevated transaminases induced by MTX treatment [15].
Steatosis, fibrosis, cirrhosisMTX-related hepatic fibrosis may be mediated through an adenosine pathway. MTX was shown to enhance adenosine release from cultured hepatoma (HepG2) cells. Adenosine A2A receptor occupancy stimulates collagen production by hepatic stellate cell lines [151,152]. Unlike wild-type mice, mice deficient for the adenosine A2A receptor or treated with an adenosine A2A receptor antagonist (ZM241385) were protected from developing liver fibrosis when challenged by hepatotoxin (carbon tetrachloride or thiocetamide) [151].
MTX-related liver fibrosis may also be mediated by its capacity to interfere with the generation of methionine from homocysteine. Excess of homocysteine induces endoplasmic reticulum stress promoting fat accumulation in the liver. Homocysteine can also activate hepatic stellate cells and proinflammatory cytokines, leading to liver fibrosis [153,154].
MTX-induced hepatic damage may be related to the generation of reactive oxygen species (ROS). MTX was shown to cause oxidative tissue damage by increasing lipid peroxidation in the liver tissue and decreasing the level of antioxidant enzymes in rats [155].
PulmonaryInterstitial pneumonitis; Pneumocystis carinii pneumonia; Pulmonary fibrosisPulmonary toxicity has been shown to occur at both high- and low-dose MTX treatment, suggesting an idiosyncratic reaction not linked to folate antagonism [49].
Several mechanisms for the pathogenesis of MTX-induced pneumonitis have been suggested including hypersensitivity, direct drug toxicity to the lung tissue, immunosuppression or altered cytokine expression contributing to the pulmonary inflammatory response and tissue damage [156].
Typical bronchoalveolar lavage and histological findings support the concept that MTX-induced pneumonitis represents a hypersensitivity reaction [157,158,159]. MTX also induces injury to alveolar epithelial walls and pulmonary fibrosis, suggesting a direct drug toxicity route [160].
MTX pulmonary toxicity may be mediated by mitogen-activated protein kinase (MAPK) pathways activation and cytokine release [156].
MTX can compromise the immune response and increase the risk for opportunistic infections due to Pneumocystis carinii [161].
RenalA decrease in glomerular filtration rate; Renal insufficiency (only in pre-existing, severely impaired renal function)In contrast to high-dose MTX, which can lead to direct tubulus toxicity and subsequent renal failure, renal toxicities induced by low-dose MTX are rare.
Low dose MTX has been associated with decrease in glomerular filtration rate (GFR) [162,163,164]. MTX and its major metabolite 7-OH-MTX are relatively insoluble in acid urine and may act as a direct toxin on the tubular epithelium, or precipitate within the tubular lumen, which can lead to intratubular obstruction resulting in a decrease in GFR (particularly at high doses) [49,165].
Evidence for a direct toxic effect of MTX on renal tubular cells has been demonstrated [166]; Low doses MTX can induce cell swelling and necrosis in renal tubular cells, which may lead to permanent tubular damage [166].
MTX associated renal toxicity may be explained by an increase in plasma adenosine concentration in extracellular fluid and subsequent activation of A1 receptors in renal tissue, reducing renal blood flow and salt and water excretion [167].
Long duration of low dose MTX administration caused severe kidney injury and renal MTX accumulation in a rat model. 4-hydroxynonenal (4-HNE) and malondialdehyde (MDA), which are reliable oxidative stress markers, were significantly increased in Long-MTX treated rats suggesting that MTX-induced kidney injury may be mediated through an increase in oxidative stress [168].
DermatologicNodulosis (rare); Alopecia; Rash; Anaphylactic reactionsMTX-induced nodulosis may be mediated by adenosine through the adenosine A1 receptor [169]. MTX was shown to induce the generation of multinucleated giant cells, as does adenosine A1 receptor occupancy. This effect of MTX was reversed by a specific adenosine A1 receptor antagonist.
Alopecia related to MTX treatment seems to be related to folate antagonism. In low dose MTX treatment, alopecia is rare and generally resolves several months after discontinuation [17,170].
Central nervous system (CNS)Lethargy and fatigue; Headache, vertigo (less frequent)Neurotoxicity of MTX may be related to MTX induced adenosine release and accumulation in the CNS. By acting at the A1 receptor on the perifornical lateral hypothalamus, adenosine may regulate wakefulness and somnolence and so potentially explaining asthenia and sleepiness experienced by some patients after MTX intake [171,172].
Other possible mechanisms of MTX-induced neurotoxicity are increased homocysteine levels and their excitatory amino acid neurotransmitter metabolites as homocysteic acid and cysteinesulfinic acid [173] and impairment of biopterin regerenating system in the brain, resulting in a reduced monoamine neurotransmitters availability [174].
UrogenitalTeratogenecity; oligospermia; gynecomastia (rare)Use of MTX should be avoided before or during pregnancy because of its documented embryotoxicity and teratogenicity [175].
MusculoskeletalOsteopathy; OsteoporosisThe effect of low dose MTX on bone was described in rats. Prolonged administration of low dose MTX in rats caused significant osteopenia with reduced osteoblast activity and increased osteoclast recruitment, which results in increased bone resorption [176]. However, no detrimental impact of MTX on the skeleton has been reported in patients treated with low dose MTX. MTX seems to have no clinically significant effect on bone mineral density (BMD) or on the osteoblast lineage [177,178].
ImmunologicOpportunistic infectionsThere is a belief amongst rheumatologists that MTX, as an immunosuppressant drug, is asssociated with the development of opportunistic infections. Weekly low-doses MTX can affect T cell activity [58], and cases of Pneumocystis pneumonia, nocardiosis, aspergillum, cryptococcosis, herpes zoster, herpes simplex and listeria-meningitis have been reported [170,179].
Despite some studies suggesting an increased risk of infection with MTX [180,181], several other studies have found that low-dose MTX does not appear to significantly increase the risk of infections in RA patients [182,183,184,185]. This risk appears to be associated with disease activity, comorbidities (diabetes, alcoholism) and the use of glucocorticoids, but not directly with MTX treatment [182]. It is well recognized that RA patients have significant increased risk of infection possibly due to chronic immune activation and inflammation which may impair immune function [185]. An increased risk of infection associated with MTX is possibly offset by the improvement of the immunological function secondary to the control of inflammation [185].
OthersLymphoproliferative disordersLymphoproliferative disorders occur with increased frequency in RA patients compared to the general population, especially in the setting of high disease activity [170,184,186,187]. A relationship between MTX treatment and the occurrence of lymphoproliferative disorders in RA has been suggested. Long-term MTX therapy was associated with Epstein–Barr virus-related lymphoproliferative disorders with spontaneous regression after MTX withdrawal [188]. Despite its association with Epstein–Barr-associated lymphomas, there is currently no clear evidence that MTX provides additional risk of lymphoproliferative disorders to that of RA itself [184,189].

One of the major adverse effects of MTX is hepatotoxicity. Minor elevations in aminotransferases are common, but hepatic steatosis, fibrosis, and cirrhosis occur infrequently during low-dose MTX therapy [8]. The mechanism by which MTX adversely affects the liver remains unclear.

It was suggested that MTX hepatotoxicity may result from a depletion of hepatic folate stores and the accumulation of MTX poly glutamates in the liver [150]. A definitive relationship between folate deficiency and hepatotoxicity has not been experimentally confirmed. However, folate supplementation has been associated with a reduced incidence of hepatic adverse effects (elevated transaminases) induced by MTX treatment [8,15].

MTX-related hepatic fibrosis was found to be mediated through an adenosine pathway. MTX was shown to enhance the release of adenosine from cultured hepatoma cells [151]. Ethanol, which is one of the most important causes of hepatic cirrhosis, has the same effect on hepatocyte release of adenosine [190].

Adenosine, in turn, binds to the adenosine A2A receptor on hepatic stellate cells, the principal fibrogenic cell type in the liver, and promotes collagen production [151,152]. Unlike wild-type mice, mice deficient for the adenosine A2A receptor were protected from developing liver fibrosis when challenged by hepatotoxin (carbon tetrachloride or thiocetamide) demonstrating the key role of adenosine A2A receptors in the pathogenesis of hepatic fibrosis [151].

Moreover, MTX is known to interfere with the generation of methionine from homocysteine (Figure 2). Excess homocysteine can induce endoplasmic reticulum stress and promote fat accumulation in the liver. Homocysteine can also activate proinflammatory cytokines and hepatic stellate cells, leading to liver fibrosis [153,154].

MTX demonstrates important toxic effects on the pulmonary system. The pathogenesis of MTX associated pulmonary toxicity has not been elucidated fully.

Acute pneumonitis is the most common type of pulmonary toxicity associated with MTX. Most researchers suggest that MTX pneumonitis is a form of hypersensitivity lung disease because of the presence of fever, peripheral eosinophilia, an increase in CD4+ (T-helper) cells in bronchoalveolar lavage fluid, as well as a mononuclear cell infiltration of the lungs and granulomatous inflammation [157,158,159].

However, others suggest that injury may result from a direct toxic effect of MTX on the lung [191]. Evidence for MTX direct pulmonary toxicity has been proposed by Ohbayashi and colleagues; MTX was shown to induce alveolar epithelial injury and pulmonary fibrosis with a decrease of alveolar epithelial cells and an increase of fibroblast cells in mouse lung tissues [160].

Other researchers speculate that the immunosuppressive effects of MTX impair the host immune response and increase the susceptibility of the patient to acquired or latent viral infections (e.g., cytomegalovirus or Epstein–Barr virus) [161]. Moreover, MTX was found to induce MAPK pathways activation and to modulate cytokine expression which may contribute to the pulmonary inflammatory response [156].

Interestingly, MTX was reported to be associated with marked asthenia in patients [171]. This is possibly due to the release of adenosine in the CNS. Adenosine is known to have neuromodulatory properties and its accumulation in the CNS is associated with headache, nausea, and somnolence [192].

By acting at the A1 receptor on the perifornical lateral hypothalamus, adenosine may regulate wakefulness and somnolence, so potentially explaining the sleepiness experienced by some patients after MTX intake [171]. In children receiving high doses of MTX, severe sleepiness and coma have been described [172]. Bernini and colleagues reported that theophylline, a non-selective adenosine receptor antagonist, could reverse the CNS toxicity of MTX in children treated with high doses of MTX [172].

MTX-induced neurotoxicity may also be mediated by elevated homocysteine levels and their excitatory amino acid neurotransmitter metabolites, such as homocysteic acid and cysteine sulfinic acid, which may cause excitotoxic neural death [173].

An impairment of biopterin metabolism, leading to decreased monoamine neurotransmitters synthesis was also suggested as a possible mechanism of MTX associated neurotoxicity [174].

MTX treatment is known to induce the formation of subcutaneous nodules, an accumulation of multinucleated giant cells derived from mononuclear cells [169,170,193]. Using an in vitro model of giant cell formation, Merrill and colleagues investigated MTX-induced nodulosis. They demonstrated that MTX enhances the generation of multinucleated giant cells, as does adenosine A1 receptor occupancy. This effect of MTX is reversed by a specific adenosine A1 receptor antagonist. Thus, MTX-induced nodulosis may be mediated by adenosine through the adenosine A1 receptor [169].

It is well-documented that low-dose MTX can exhibit kidney damage [162,163,164,194]. However, the mechanism underlying MTX-induced kidney injury remains unknown. It has been reported that high dose MTX can cause kidney damage by the precipitation of MTX and its major metabolite, 7-OH MTX, in acid urine which may contribute to intratubular obstruction and impaired renal function [37,49,165].

Kidney damage due to precipitation of MTX and tubular injury may occur with high dose MTX; but it is very rare with chronic low dose therapy. It was also suggested that MTX-associated renal injury may by mediated through the induction of adenosine plasma concentration and subsequent activation of A1 receptors in renal parenchyma, reducing renal blood flow and thereby diminishing renal function [167].

Recently, using a rat model with renal failure caused by low-dose MTX administration, Li et al. demonstrated that long-MTX administration caused MTX accumulation in renal tissue and severe glomerular and tubular injury through an increase in oxidative stress [168].

MTX is largely excreted into urine. Impaired renal excretion of MTX and its accumulation in serum may lead to the enhancement of MTX toxicities and primarily bone marrow depression [195]. For this reason, low dose MTX is contraindicated if the glomerular filtration rate (GFR) is less than 30 mL/min [196].

MTX should also not be delivered to pregnant women, due to risks of fetal death or malformations [49]. Some cases of MTX-induced lymphomas have also been reported, potentially related to EBV. MTX may also induce severe skin reactions and opportunistic infections such as Pneumocystis carinii pneumonia [25,159].


More information: Solomon, DH et al. “Adverse Effects of Low Dose Methotrexate in a Randomized Double-Blind Placebo-Controlled Trial: Adjudicated Results from the Cardiovascular Inflammation Reduction Trial” Annals of Internal MedicineDOI: 10.7326/M19-3369

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