Methotrexate is a crucial disease-modifying antirheumatic drug (DMARD) used to treat conditions such as rheumatoid arthritis, psoriasis, and certain cancers. While effective in modulating the immune system and reducing cell proliferation, it can also have a range of side effects, including effects on the skin, hair, and mucous membranes. Understanding these potential cutaneous reactions is vital for patients and healthcare providers to ensure safe and effective treatment.
How Methotrexate Affects the Skin
As an antifolate drug, methotrexate inhibits cell proliferation by interfering with the synthesis of DNA, RNA, and proteins. While this is the intended therapeutic effect for conditions like psoriasis, which involves rapid skin cell turnover, it can also harm healthy, fast-dividing cells. This includes the cells lining the mouth, the hair follicles, and the top layer of the skin, leading to a variety of dermatological side effects.
Common Dermatological Side Effects
Photosensitivity and Sun Reactions
One of the most frequently reported skin issues associated with methotrexate is photosensitivity.
- Cause: The medication makes your skin significantly more susceptible to damage from UV light.
- Symptoms: This can result in a severe, exaggerated sunburn-like reaction, even after limited sun exposure. Patients may develop rashes, redness, blisters, or swelling on sun-exposed areas. In some cases, a phenomenon called "recall" can occur, where a prior sunburn reactivates or worsens after a dose of methotrexate.
- Prevention: The NHS and other health bodies strongly recommend avoiding intense sunlight, using a high-factor sunscreen (SPF 30 or above) daily, and wearing protective clothing and a hat when outdoors. Sun lamps and sunbeds should be avoided entirely.
Mouth Sores (Stomatitis)
Oral ulcers or sores are another common side effect, particularly in the early stages of treatment. This is a sign of methotrexate's effect on the rapidly dividing cells of the oral mucosa. This side effect is often dose-related and is a key reason why patients are typically advised to take folic acid supplements, as this helps to counteract the drug's antifolate effects on healthy cells.
Hair Loss (Alopecia)
While not as common or severe as hair loss seen in high-dose chemotherapy, some patients on methotrexate may experience hair thinning or reversible alopecia. Like mouth sores, this is often linked to the drug's effect on cell turnover. Folic acid supplementation can help reduce the incidence and severity of this side effect.
Hyperpigmentation
Patients, particularly those with darker complexions, may develop hyperpigmentation (darkening) of the skin, especially in sun-exposed areas. This can occur at any point during treatment and is another reason for diligent sun protection.
Rare but Serious Skin Problems
While less common, some skin reactions can be more severe and warrant immediate medical attention.
Cutaneous Ulceration and Necrosis
This is a rare but serious sign of methotrexate toxicity, which can occur with both low and high doses.
- Presentation: Ulcerations can appear on existing psoriatic plaques, on pressure points, or on otherwise normal skin. Painful ulcerations may signal impending pancytopenia (a low blood cell count).
- Risk Factors: Inadvertent daily dosing, high dose, renal issues, and concurrent drug use increase this risk.
- Management: It is a medical emergency requiring immediate discontinuation of methotrexate and supportive care, including folinic acid rescue.
Severe Hypersensitivity Reactions
Though rare, severe allergic reactions can occur, ranging from drug rashes to life-threatening conditions like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Symptoms like blistering, peeling, or loosening of the skin, including in the mouth, require immediate emergency treatment.
Vasculitis
In some rare instances, methotrexate can cause or induce vasculitis, which is the inflammation of blood vessels. This can present as purple spots (purpura) or a rash on the legs. Cases have been reported with low-dose oral methotrexate.
Risk Factors for Increased Cutaneous Toxicity
Several factors can increase a patient's risk of experiencing severe skin problems with methotrexate:
- Renal Impairment: Because methotrexate is primarily cleared by the kidneys, impaired kidney function can lead to toxic accumulation.
- Folate Deficiency: Low folate levels can exacerbate methotrexate's effects on cell turnover, increasing the risk of side effects.
- Medication Interactions: Certain drugs, like some nonsteroidal anti-inflammatory drugs (NSAIDs) and some antibiotics, can interfere with the metabolism or excretion of methotrexate, leading to elevated levels.
- High Dosage or Incorrect Schedule: A high starting dose, or an inadvertent error resulting in daily rather than weekly dosing, can trigger acute toxicity.
- Pre-existing Skin Conditions: Patients with psoriasis are more susceptible to developing ulcerations on their existing plaques.
Comparison of Common vs. Rare Methotrexate Skin Side Effects
| Feature | Common Skin Side Effects | Rare/Severe Skin Side Effects |
|---|---|---|
| Incidence | Fairly frequent | Rare to very rare |
| Typical Cause | Direct effect on fast-dividing cells; amplified by UV light | Drug toxicity (overdose, impaired clearance, interaction) or idiosyncratic reaction |
| Examples | Photosensitivity, mouth sores, hair thinning, hyperpigmentation | Cutaneous ulceration, severe blistering rashes (SJS/TEN), vasculitis |
| Primary Management | Preventive measures (sun protection, folic acid), dose adjustment | Immediate cessation of MTX, folinic acid rescue, hospitalization for severe cases |
| Warning Signs | Mild sunburn, occasional mouth soreness, gradual hair thinning | Blistering skin, peeling, swelling, non-healing ulcers, fever, extensive rash |
Conclusion
While methotrexate is a cornerstone treatment for various inflammatory conditions, it is important for patients and healthcare providers to be aware of its potential cutaneous side effects. From the common and manageable issues like photosensitivity and mouth sores to the rare but serious risks of ulceration and severe rashes, careful monitoring and patient education are key to safe use. Regular communication with your healthcare team, strict adherence to sun protection measures, and recognizing the warning signs of more severe reactions are essential steps in mitigating the risks associated with this effective medication.
