How to manage methotrexate (MTX) in patients with active infection?

Management of Methotrexate in Patients with Active Infection

Methotrexate should be temporarily discontinued during severe infection or when infection is not responding to standard treatment, and can be restarted when the infection has cleared. 1

Infection Risk with Methotrexate

• Low-dose methotrexate (MTX) is associated with an increased risk of infection, particularly pneumonia, skin/soft tissue infections, and urinary tract infections, with most infections occurring within the first 18 months of treatment 1, 2
• MTX is considered a relative contraindication in patients with active infectious disease, particularly chronic infections that are likely to be worsened by immunosuppressive effects 1
• Opportunistic infections have been reported in patients taking MTX, usually within the first 12 weeks of treatment, but the risk remains throughout the treatment course 1, 3
• Even with normal leukocyte counts, patients on low-dose MTX remain at risk for opportunistic infections 3

Management Algorithm for MTX in Active Infection

Severe or Non-Responsive Infections

• Immediately discontinue MTX in patients with severe infection or infection not responding to standard treatment 1
• MTX should be permanently discontinued in patients who develop opportunistic infections 1, 2
• Monitor patients carefully for signs of sepsis and treat accordingly during infection 1

Mild to Moderate Infections

• For mild infections responding to standard treatment, MTX can often be continued with close monitoring 1
• Consider more frequent blood count monitoring during antibiotic treatment for infections 1
• If antibiotics are given for a severe infection, MTX should be stopped until the patient recovers and the antibiotic course is complete 1

Special Considerations

• Avoid co-trimoxazole, trimethoprim, and other antifolate drugs in patients taking MTX due to risk of bone marrow suppression 1
• Be particularly cautious with MTX in patients with comorbidities that increase infection risk (e.g., diabetes) 1, 4
• For patients with HIV or hepatitis, MTX should be used with extreme caution and only with specialist involvement 1, 5

Monitoring During Infection

• Obtain complete blood count with differential to assess for neutropenia or other cytopenias when infection develops 2, 5
• Monitor renal function closely as decreased renal function can lead to increased MTX levels and toxicity 5
• Check liver function tests as both infection and MTX can affect liver function 1, 5

Restarting MTX After Infection

• MTX can be restarted when the infection has cleared 1
• Consider a lower initial dose when restarting after a severe infection, with gradual dose escalation 5
• Resume regular monitoring schedule after restarting therapy 1, 5

Perioperative Considerations

• When MTX is controlling skin disease, it can generally be continued during the perioperative period 1
• For major surgery in patients with comorbidities like diabetes that increase infection risk, the decision to continue MTX must be made on a case-by-case basis 1
• Evidence from rheumatology studies shows mixed results regarding perioperative MTX use and infection risk 4, 6

Common Pitfalls and Caveats

• Do not restart MTX too early before infection has fully resolved, as this may lead to recurrence or worsening of infection 1
• Be aware that MTX can mask signs of infection such as fever and inflammation 2
• Remember that opportunistic infections can occur at any time during MTX treatment, not just at the beginning 1, 3
• Consider prophylactic measures for patients at high risk of opportunistic infections, such as those with low immune cell counts or on concomitant high-dose corticosteroids 2
• Drug interactions with antibiotics can increase MTX toxicity through reduced protein binding or decreased renal elimination 1