Mechanism of action

The primary mechanism of action for LD-MTX is not completely understood versus the well-known mechanism of action as an antimetabolite of HD-MTX in oncology treatments²-⁴. There are several approaches to the mechanism of action of LD-MTX (Fig. 1), but we need more studies to explain its beneficial effect in dermatological conditions, where severe adverse effects are rarely seen²,³, in contrast with the use of higher doses.

Figure 1 Proposed mechanism of action in LD-MTX: Methotrexate inhibits aminoimidazole-4-carbox- amide ribonucleotide (AICAR) upon entering the cells, which inhibits adenosine degradation, leading to an intra and extracellular increase of adenosine concentrations. Adenosine will bind to the A2A receptor on endothelial cells, leading to an increase in anti-inflammatory modulators and a decrease in proinflammatory molecules. 

One of the main mechanisms of the action of LD-MTX includes the inhibition of dihydrofolate reductase, an essential enzyme for folate metabolism, leading to the depletion of intracellular folate with thymidine synthesis inhibition³; MTX is also an antagonist to folate metabolism, as well as it decreases the folate cofactors synthesis necessary for nucleic acid production⁴.

At lower doses, MTX increases the intracellular and extracellular adenosine concentration, suppressing pro-inflammatory molecules such as IL 12, TNFa, IL 6, IL 8, and nitric oxide, and increases anti-inflammatory mediators such as IL 10²-⁴.

Pharmacokinetics

Low-dose MTX is entirely absorbed in the gastrointestinal tract by active transport; once absorbed, it has low bioavailability (≥25%) due to intestinal tract and liver inactivation⁵. Approximately 10% of MTX is transformed to 7-OH-MTX by hepatic metabolism. It is eliminated unchanged (90%) in urine by active secretion. Peak serum levels with oral administration usually take 1-2 h and through an intramuscular injection after 30-60 min⁵. About 50% of MTX binds to serum proteins which determine the distribution in the organism. MTX is distributed in the intracellular space through the reduced folate carrier 1 receptor, and in this compartment, it is transformed into MTX polyglutamate; which accumulates intracellularly explaining why high concentrations can be maintained from weeks to months².

Supplementation

Folate supplementation is controversial since there is no established information on whether folic acid or folinic acid is the best option for LD-MTX⁵. Experts recommendations include supplementing folic acid when gastrointestinal or hematologic adverse effects occur⁶. It can be administered as 1 g daily or folinic acid 5 mg three doses every 12 h once a week⁶.

Other authors suggest folic acid 5 mg/day except for the day of MTX intake or folinic acid 15 mg/weekly⁵; in our experience, we have used folic acid 5 mg weekly without significant hematologic adverse events due to MTX (unpublished data).

Adverse effects

Few adverse effects have been reported with LD-MTX (Table 2), including abnormal liver function; gastrointestinal effects including nausea; hematopoietic suppression is often related to higher doses; subjective side effects such as fatigue and headaches; non-scarring hair loss; and in few cases, an increase in blood urea nitrogen retention, pneumonia, neoplasm, sensitivity to ultraviolet light, delay in wound healing, and cutaneous necrosis have been reported⁷,⁸. Adverse effects are more frequent in tissues with fast cellular replication such as skin and gastrointestinal system, due to MTX affinity for rapidly replicating cells. MTX is contraindicated during pregnancy and lactation (Table 3)⁷.

Monitoring

Before starting MTX, the following tests are required, including complete blood count, creatinine, liver function tests, and a pregnancy test in women with childbearing potential. In certain cases, B and C hepatitis, HIV testing, as well as the identification of latent tuberculosis might be considered⁴.

Follow-up includes a complete blood count every 2-4 weeks in the 1^st month and every 2-3 months⁴,⁶. Kalb et al.⁶ suggested monitoring liver function every month for 6 months and afterward every 2 months until normal.

In cases with a cumulative MTX dose of 3.5-4 g, liver biopsy or MTX withdrawal should be considered, although, in recent years, the use of the amino-terminal peptide of procollagen III levels may help to avoid or delay biopsy⁴,⁶.

Drug interactions

Some commonly used drugs have the potential to increase MTX toxicity (Table 4), leading to pancytopenia or even death, particular care should be taken with drugs that have renal excretion which can increase adverse efects⁴,⁶. Trimethoprim-sulfamethoxazole is usually avoided in patients taking MTX due to folic acid antagonism (Fig. 2) and also sulfamethoxazole competitively inhibits renal secretion, increasing the risk for MTX toxicity⁶.

Figure 2 Comparative molecular structure of methotrexate, folic acid and trimethoprim. 

Psoriasis

Psoriasis is an inflammatory skin disease that remains one of the main indications for MTX in dermatology, with an FDA approval for severe, recalcitrant, or non-responsive psoriasis and psoriatic arthritis⁴. It is indicated as a systemic treatment when no other treatments are available, unsuccessful results with other systemic therapies or with articular involvement. It is particularly useful in patients with moderate-to-severe plaque psoriasis including nail psoriasis, generalized pustular psoriasis, psoriatic erythroderma, and palmoplantar psoriasis⁵. Studies have shown similar efficacy of MTX in stabilizing different types of psoriasis⁷.

A recent meta-analysis described a PASI₇₅ response in 40% of patients after 12 weeks with LD-MTX, but less effective compared with biologic agents⁹. In addition, MTX can be used in combination with other systemic, biologic drugs (infliximab, etanercept, and adalimumab) to increase efficacy, lowering the risk of serious adverse effects⁵,⁶.

Effective doses range between 7.5 and 25 mg weekly. Some clinicians rely on a lower “test dose” followed by laboratory tests a week or two later, but recent evidence suggests that this may not be necessary and the emphasis is made on adequate monitoring before starting and during treatment⁶,¹⁰.

Psoriasis is often related with several comorbidities, including obesity and metabolic syndrome; therefore, monitoring for hepatotoxic and hematological effects in this group of patients should be continuous⁶.

Chronic urticaria

Chronic urticaria is a frequent disease characterized by wheals for at least 6 weeks. First-line treatment for chronic urticaria includes antihistamines, but despite their efficacy, about 36.8% of patients will not have an adequate response to treatment and will require additional therapy¹¹.

LD-MTX 10-15 mg weekly has been successfully used in several case reports and case series. Sagi et al.¹² included eight patients with recalcitrant chronic urticaria using MTX with complete remission in 87% of the cases. Perez et al.¹¹ retrospectively evaluated 26 patients with steroid-dependent urticaria, 12/16 patients had a complete response, and seven patients reduce oral steroid doses and two patients suspended the treatment.

A recent systematic review and meta-analysis included two randomized controlled trials with recalcitrant urticaria and concluded that MTX did not provide any significant benefit over placebo, but the treatment was well tolerated¹³.

Atopic dermatitis

Atopic dermatitis is a chronic inflammatory disease of the skin affecting 5-20% of the pediatric population and 2-5% of the adult population¹⁴; most patients with atopic dermatitis develop a mild-to-moderate disease that is usually controlled with topical therapy or phototherapy¹⁵,¹⁶. A small subset of patients will be unresponsive to first-line treatments, often requiring systemic treatments¹⁵,¹⁷.

MTX is used as an off-label systemic alternative; few randomized controlled trials are available and most studies are retrospective in nature, showing that MTX is effective and safe for moderate-to-severe atopic dermatitis¹⁷.

Several studies have shown clinical responses ranging from 53.85% to up to 93% of patients with >75% improvement and clinical response between 4 and 12 weeks of treatment with the use of MTX¹⁸. Adverse effects were reported in 34.62% of patients; gastrointestinal and elevated transaminase levels were the most common; bone marrow suppression was rarely reported¹⁴.

Regarding the pediatric population, there are no guidelines for immunosuppressive drugs, leading to uncertainty of the efficacy and safety of these drugs. Anderson et al.¹⁷ conducted a retrospective study in 55 pediatric patients with atopic dermatitis, treated with LD-MTX (median dose: 0.45 mg/kg weekly) during 15.3 months, showing 76.4% improvement; gastrointestinal symptoms, acquired skin infections, and blood count abnormalities were the most common side effects.

Pemphigus vulgaris

Pemphigus is an autoimmune blistering disease that affects skin and mucosa, mortality decreased importantly since the introduction of systemic steroids, remaining the first line of treatment¹⁹, however, significant long-term side effects limit their extensive use, and thus, other immunomodulatory drugs are required²⁰.

A 2009 meta-analysis included 136 pemphigus patients treated with systemic glucocorticoids and MTX, showing clinical improvement in 82% of cases²⁰. Baum et al.²¹ included 30 patients with pemphigus vulgaris treated with prednisone and MTX 15 mg/weekly; prednisone tapering was possible in 76.6% of patients even in recalcitrant cases, highlighting a steroid-sparing effect.

Tran et al.¹⁹ presented 23 patients treated with prednisone and MTX with a maximum dose of 20 mg/week; improvement of blistering was seen in 91.3% after initiation of MTX and 69.6% discontinue prednisone in a mean of 18 months.

Bullous pemphigoid

Bullous pemphigoid is an autoimmune subepidermal blistering disease, presenting as tense blisters, that may last from months to years and usually affecting older individuals that, if left untreated, may last from several months to years to control²². Oral and topical corticosteroids continue to be one of the mainstay therapies despite their numerous side effects²³. LD-MTX has been proposed for the treatment of bullous pemphigoid as monotherapy or as adjunctive management with topical corticosteroids to reduce treatment periods²²,²³.

Considering patients with bullous pemphigoid tend to be older, concerns have been raised regarding the use of MTX and decreased renal function, but observations have shown no correlation with the increased risk of mortality²³. Dosage in this subgroup of patients tends to be lower, up to 12.5 mg/week, with median doses of 5 mg that could be explained by the physiological decrease in renal function²².

Retrospective studies have shown complete response after 1 month in 90% of patients who initially did not respond to topical clobetasol propionate²³ and its usefulness as a steroid-sparing agent with successful prednisone tapering²².

Evidence of MTX use in bullous pemphigoid is scarce and low quality. Some authors suggest that MTX should be reserved for the unresponsive disease²²,²³.

Dermatomyositis

Dermatomyositis is a multisystemic disorder, classified as a subtype of idiopathic inflammatory myopathies, and characterized by proximal muscle weakness and classic cutaneous lesions²⁴,²⁵. Glucocorticoids are considered the first-line therapy and the only Food and Drug Administration approved treatment for dermatomyositis, however, in many cases, additional immunosuppressants and immunomodulatory are required to achieve adequate control, and few studies on these medications have been conducted²⁴.

In dermatomyositis, patients often require higher MTX doses than the previous dermatoses (up to 25 mg weekly)²⁶, with a significant reduction in the severity of cutaneous signs and symptoms, and better outcomes on 5-year survival. Lung involvement in this group of patients plays a fundamental role in the treatment selection since MTX may lead to lung injury²⁵,²⁶.

Ruperto et al.²⁷ conducted a randomized trial in patients with newly diagnosed juvenile dermatomyositis that included 139 patients and were split into prednisone, prednisone plus cyclosporine, or prednisone plus MTX. Improvement at 24 months follow-up favored the combined treatment versus prednisone alone. The safety analysis seemed to favor MTX over cyclosporine as a combination therapy. Infections were more frequent with the combined treatment and adverse effects included the increase in liver enzymes, nausea, hepatitis, and lung disorder.

Localized and systemic sclerosis

Alopecia areata

Alopecia areata is a cause of non-scaring hair loss with an estimated lifetime prevalence of approximately 2%³⁵. Alopecia areata exerts a significant impact on morbidity and patient's quality of life³⁶. In the pediatric population, it is associated with a poorer prognosis than adults³⁷, as the treatment frequently presents low tolerability of therapy and the need for continuing blood testing³⁶.

MTX has been used both as monotherapy and as an adjunct to corticosteroids, however, there is insufficient evidence regarding low-dose MTX is useful for maintaining hair growth in extensive disease³⁸. The available evidence suggests that it is well-tolerated and may offer a useful treatment alternative³⁵, but there remains a lack of clear definitive evidence or guidelines³⁶.

In the pediatric population, it should be considered the use of MTX in severe and resistant cases, having the advantage that it can be maintained for several years, in contrast with other treatments with a high rate of relapse or no data in long-term effects such as methylprednisolone or diphencyprone³⁶,³⁷.

Phan et al.³⁸ performed a systematic review and meta-analysis in patients with alopecia areata treated with corticosteroid and MTX, showing a complete response (100% regrowth of hair) in 35.8% (adults: 44.7% and pediatric: 11.6%) and good response (50-100% regrowth of hair) in 63.2% (adult: 69.3% and pediatric: 46.5%) with an average time of regrowth of 3.125 months and complete regrowth in 9.9 months.

Pityriasis rubra pilaris

Pityriasis rubra pilaris is an uncommon papulosquamous inflammatory disease of the skin, which may progress to erythroderma³⁹. Some authors state that after 3 years, up to 80% of these cases may develop spontaneous remission, therefore, treatment efficacy is difficult to assess, however, non-remitting pityriasis rubra pilaris has been described³⁹. The use of MTX is strongly supported and its mechanism of action is presumed as an antiproliferative and anti-inflammatory agent³⁹.

A literature review including 116 cases reported complete clearance in 23.3% and excellent clinical response in 17.2% of the patients³⁹.

Malignancy

Keratoacanthoma

Keratoacanthoma is considered well-differentiated squamous cell carcinoma with a low malignancy potential due to their tendency to present involution. Clinically, these tumors are characterized by an initial rapid growth rate followed by the aforementioned involution⁴². Keratoacanthoma has distinct clinical features, and histopathological confirmation is advised to rule out squamous cell carcinoma⁴², before starting intralesional treatment and a repeat biopsy in case of failure to respond after two intralesional MTX treatment with low recurrence rate (1-8%)⁴³. Several intralesional therapies have emerged in recent years providing advantages such as avoidance or delaying surgery in high-risk groups, better cosmetic results, or decreasing tumor size⁴³,⁴⁴. Due to the capacity of inhibiting growth in fast-growing tumors, MTX has shown good efficacy in managing keratoacanthomas⁴².

Moss et al.⁴³ included 157 tumors treated with intralesional MTX, with a resolution of 88% with 1-4 doses (average total dose: 8.12 mg). In non-responding cases, 8/9 presented an average decrease in size of 3.2 × 4.4 mm, none of the tumors showed an increase in size after the intralesional MTX⁴³.

Basal cell carcinoma

Basal cell carcinoma accounts for almost 80% of the cases of skin cancer, occurring more frequently in the head⁴⁵, and usually had a slow growth rate with extremely rare metastasis capacity. Simple surgical excision and Mohs surgery are the gold standards⁴⁵; but in patients who are not good candidates for surgical treatment, therapeutic alternatives are needed; intralesional MTX has been studied as an option in the treatment of basal cell carcinoma with no efficacy⁴⁵.

MTX acts by suppressing mitosis that inhibits DNA synthesis during cell replication in rapidly growing tumor, however, since basal cell carcinoma is a slow-growing tumor, MTX is not recommended. Balighi et al.⁴⁵ reported 40 nodular basal cell carcinoma in 11 patients treated with intralesional MTX in three different schemes: 2.5 mg/ml in 10 lesions, 10 mg/ml in 21 lesions, and 25 mg/ml in 9 lesions. No significant changes in the shape or the tumor size were observed, concluding in the lack of efficacy of MTX in the treatment of basal cell carcinoma.