In a rheumatoid arthritis patient on disease-modifying antirheumatic drugs who has had a week-long fever with an elevated procalcitonin, should the DMARDs be temporarily discontinued?

Should DMARDs Be Temporarily Discontinued in an RA Patient with Week-Long Fever and Elevated Procalcitonin?

Yes, temporarily withhold DMARDs (except glucocorticoids) in this patient with confirmed bacterial infection, as indicated by elevated procalcitonin, while initiating appropriate antibiotic therapy and close monitoring for disease flare.

Rationale for DMARD Discontinuation

Procalcitonin as a Specific Marker for Bacterial Infection

• Elevated procalcitonin (≥0.5 ng/ml) is highly specific (98.2%) for bacterial infection in RA patients, with a positive likelihood ratio of 14.33, making it far superior to CRP, ESR, or WBC count for distinguishing bacterial infection from disease flare. 1

• Procalcitonin levels ≥0.5 ng/ml strongly suggest bacterial infection and warrant treatment modification, though levels <0.5 ng/ml do not rule out infection. 1

• All patients experiencing an RA flare without infection showed negative PCT levels (≤0.1 ng/ml), whereas 25.8% of those with bacterial infection had levels ≥0.5 ng/ml. 1

Evidence Supporting Temporary DMARD Discontinuation During Serious Infection

• The 2023 Australian recommendations conditionally recommend against routinely discontinuing DMARDs perioperatively, but explicitly state to consider temporary discontinuation of biologic DMARDs in individuals with high risk of infection or where the impact of infection would be severe. 2

• A week-long fever with elevated procalcitonin represents a serious bacterial infection where the impact would be severe, meeting criteria for temporary discontinuation. 2

• Targeted synthetic DMARDs (JAK inhibitors) should be temporarily discontinued during serious infections based on conditional recommendations. 2

Critical Exception: Continue Glucocorticoids

• If this patient is on chronic glucocorticoid therapy, continue glucocorticoids and potentially increase the dose using a "stress-scheme" during severe infection. 3

• Glucocorticoids cannot be stopped abruptly due to risk of adrenal suppression, and patients on long-term therapy may require supplementation during significant intercurrent infection. 3

Specific Management Algorithm

Step 1: Immediate Actions

• Initiate appropriate broad-spectrum antibiotic therapy based on suspected source of infection
• Continue glucocorticoids at current dose or increase if clinically indicated 3
• Temporarily hold conventional synthetic DMARDs (methotrexate, leflunomide, sulfasalazine) 2
• Temporarily hold biologic DMARDs (TNF inhibitors, IL-6 inhibitors, abatacept, rituximab) 2
• Temporarily hold targeted synthetic DMARDs (JAK inhibitors) 2

Step 2: Monitoring During Infection Treatment

• Monitor for clinical response to antibiotics over 48-72 hours
• Assess for signs of RA disease flare (joint swelling, morning stiffness >1 hour, elevated inflammatory markers beyond infection)
• Serial procalcitonin measurements can guide response to antibiotic therapy 1

Step 3: Criteria for DMARD Resumption

• Resolution of fever for at least 48 hours
• Clinical improvement of infection source
• Normalization or significant decline in procalcitonin levels
• Completion of appropriate antibiotic course or near-completion with clear clinical improvement

Step 4: Restarting DMARDs

• Resume conventional synthetic DMARDs first (methotrexate has a long half-life, so brief interruption is less impactful) 3
• Resume biologic DMARDs once infection is clearly resolving and patient is clinically stable 2
• Resume targeted synthetic DMARDs last, given their broader immunosuppressive effects 2

Important Caveats and Pitfalls

Common Pitfalls to Avoid

• Do not assume elevated inflammatory markers represent only RA flare in a patient with prolonged fever—procalcitonin is essential to distinguish bacterial infection from disease activity. 1

• Do not abruptly discontinue glucocorticoids even during serious infection, as this can precipitate adrenal crisis. 3

• Do not delay antibiotic therapy while waiting for DMARD washout—start antibiotics immediately. 1

• Be aware that IL-6 inhibitors and JAK inhibitors can mask fever and suppress acute phase reactants (including potentially procalcitonin), making infection harder to detect. 3

Nuanced Considerations

• While some evidence suggests biologic DMARDs may actually reduce sepsis risk and mortality after serious infection (OR 0.56 for sepsis development), this protective effect is likely due to preventing unregulated inflammatory host response in patients with well-controlled disease—not during active untreated infection. 4

• The protective effect of biologics on sepsis outcomes 4 applies to patients already on stable therapy who develop infection, not to the decision of whether to continue during active serious infection with elevated procalcitonin.

• Methotrexate has a long half-life and pausing for a short period may be "futile" from a pharmacokinetic standpoint, but the clinical principle of reducing immunosuppression during serious bacterial infection still applies. 3

Risk of Disease Flare

• The risk of RA flare during temporary DMARD discontinuation must be weighed against mortality risk from uncontrolled bacterial infection—in this scenario with confirmed bacterial infection (elevated procalcitonin), infection control takes priority. 1

• Most patients can tolerate 1-2 weeks of DMARD interruption without irreversible joint damage, especially if glucocorticoids are continued. 3

• If significant disease flare occurs during infection treatment, consider low-dose glucocorticoid increase rather than restarting DMARDs until infection is controlled. 3