Cold or Methotrexate Toxicity? Warning Signs to Know

When you take weekly low-dose methotrexate for an autoimmune condition like rheumatoid arthritis, it is completely normal to worry about catching infections. Because methotrexate affects your immune system, you are susceptible to everyday viruses. However, it is also important to know the difference between a typical infection and methotrexate toxicity—a condition where the drug causes harm to your body, such as dangerous drops in blood cells, severe mouth sores, or kidney and liver issues ^[1][2].

While symptoms can overlap, understanding the red flags of toxicity and having a clear action plan can help you stay safe and get the right care at the right time.

Understanding Bone Marrow Toxicity (Myelosuppression)

One of the most serious forms of methotrexate toxicity is myelosuppression, where the bone marrow stops producing enough new blood cells ^[3]. If all three main types of blood cells—white blood cells, red blood cells, and platelets—drop to low levels, it is called pancytopenia ^[1].

While routine blood monitoring helps lower your risk of toxicity, it does not eliminate it. Blood counts can drop between tests due to dehydration, kidney changes, missing your folic acid, or taking interacting medications (like certain antibiotics such as trimethoprim-sulfamethoxazole) ^[3][4]. Note: Methotrexate for autoimmune conditions is typically taken once a week. Taking it daily by accident is a medical emergency and requires immediate poison control or emergency advice ^[5].

How to Tell the Difference

A viral infection like a cold, influenza, or COVID-19 might start with a runny nose, mild congestion, or a cough. While you should monitor these and consider testing for common viruses, you must also watch for systemic red flags that suggest methotrexate toxicity:

• Signs of low platelets (thrombocytopenia): Unusual bruising, bleeding gums, nosebleeds, or petechiae (tiny, pinpoint red or purple spots on the skin that do not fade when pressed) ^[6][7].
• Signs of low red blood cells (anemia): Unexplained, severe fatigue or weakness that feels much heavier than being tired from a cold ^[1][8].
• Signs of mucosal damage: Painful mouth ulcers or severe sores in your mouth and throat that make it hard to eat or drink. This can happen with or without low blood counts and requires prompt evaluation ^[1][9].
• Persistent cough or shortness of breath: While a cough can be a cold, a persistent cough or breathlessness can sometimes indicate methotrexate-related lung issues or a serious infection like pneumonia ^[10].

Why Fevers Require Prompt Attention

Methotrexate can cause a specific drop in neutrophils, which are the infection-fighting cells of your immune system. A low neutrophil count is called neutropenia ^[11].

When your neutrophils are dangerously low, your body may not be able to produce typical signs of an infection, like localized swelling or pus. Often, the only warning sign of a severe, potentially life-threatening infection (sepsis) is a new fever ^[11][12]. Because you cannot check your neutrophil count at home, a fever while taking methotrexate requires prompt medical assessment.

Your clinician will likely order a Complete Blood Count (CBC) to check your blood cells, alongside other assessments like kidney and liver tests, viral testing, or a medication review to determine the exact cause of your symptoms ^[13][14]. A CBC alone does not prove an illness is harmless, but it is a critical piece of the puzzle.

Your Action Plan

When to seek same-day advice:
Contact your prescribing clinician promptly if you develop a measured fever, chills, painful mouth ulcers, or new bruising and petechiae ^[6][1]. Do not wait for your next routine appointment. Do not take your next dose of methotrexate until you have spoken with your prescriber or an urgent care clinician ^[15].

When to seek emergency care:
Do not wait for an outpatient blood test if you are seriously ill. Call emergency services or go to the nearest emergency room if you experience:

• Severe shortness of breath or chest pain
• Confusion, fainting, or severe weakness
• Uncontrolled bleeding, black or bloody stools, or vomiting blood ^[7]
• Inability to swallow or keep fluids down
• Rapidly worsening illness or signs of sepsis ^[16]