What is the step‑by‑step graded oral challenge protocol for sulfasalazine in a patient with a remote mild sulfonamide reaction more than five years ago without anaphylaxis, Stevens‑Johnson syndrome, toxic epidermal necrolysis, or DRESS?

Graded Challenge Protocol for Sulfasalazine

For a patient with a remote mild sulfonamide reaction more than five years ago without severe cutaneous adverse reactions (SCARs), a 1-step full-dose challenge with sulfasalazine is the appropriate approach, administered in a monitored clinical setting. 1

Rationale for 1-Step Challenge

The 2022 Joint Task Force on Practice Parameters for Drug Allergy establishes that a 1-step full-dose challenge is appropriate for patients with non-anaphylactic, benign cutaneous reactions that occurred >5 years ago. 1 This recommendation is based on data showing:

• 95% success rate with 1-step full-dose challenges in patients without anaphylactic histories 1
• Higher likelihood of passing the challenge with more remote histories and vague "sulfa" allergy labels 1
• Studies demonstrating that full-dose challenge appears equally efficacious to multi-step "desensitization" protocols in non-anaphylactic patients 1

Step-by-Step Protocol

Pre-Challenge Assessment

Confirm the patient meets criteria for 1-step challenge: 1

• Nonsevere delayed reactions without multiple features consistent with IgE-mediated reaction
• Nonsevere immediate reaction (e.g., isolated urticaria, maculopapular exanthem, or gastrointestinal symptoms with onset <1 hour) that occurred ≥5 years ago
• Nonsevere accelerated reaction (onset >1 hour to 36 hours) that occurred ≥5 years ago
• Unknown, remote history

Absolute exclusions: 1

• History of Stevens-Johnson syndrome (SJS)
• History of toxic epidermal necrolysis (TEN)
• History of drug reaction with eosinophilia and systemic symptoms (DRESS)
• History of anaphylaxis at any time point

Challenge Procedure

Administer full therapeutic dose of sulfasalazine (typically 500 mg to 1000 mg depending on indication) in a single dose 1

Observe in clinic for 2 hours after administration 1

Provide 24-hour phone call follow-up after the full dose 1

Monitoring During Challenge

Watch for signs of:

• Immediate reactions: urticaria, angioedema, bronchospasm, hypotension 1
• Delayed reactions: maculopapular rash, fever, malaise 1
• Early warning signs of SCARs: fever, influenza-like symptoms, dysphagia, burning eyes (though these should not occur with appropriate patient selection) 2

Alternative: 2-Step Challenge (If Needed)

If there is significant patient anxiety or the history suggests slightly higher risk while still meeting challenge criteria, a 2-step approach may be considered: 1

Step 1: Administer 1/10th of the therapeutic dose (e.g., 50-100 mg sulfasalazine)

• Observe for 1 hour in clinic 1

Step 2: If Step 1 is tolerated, administer full therapeutic dose

• Observe for 2 hours in clinic 1
• Provide 24-hour phone call follow-up 1

Important Caveats

Desensitization protocols should be relegated primarily to those with convincing histories of anaphylaxis and are not indicated for this patient population. 1

The FDA label for sulfasalazine mentions desensitization-like regimens starting with 50-250 mg daily and doubling every 4-7 days, but explicitly states desensitization should not be attempted in patients with history of anaphylactoid reactions. 3 Given the evidence showing equal efficacy of direct challenge versus gradual protocols in non-anaphylactic patients, the simpler 1-step approach is preferred. 1

Cross-reactivity between sulfonamide antimicrobials and sulfasalazine (a sulfonamide non-antimicrobial) is minimal due to structural differences, specifically the aromatic amine group at the N4 position present in antimicrobial sulfonamides. 1, 4 However, sulfasalazine itself contains a sulfonamide moiety and can cause reactions independent of antimicrobial sulfonamide allergy.

If the patient develops symptoms during challenge, immediately discontinue the medication and treat appropriately with antihistamines, corticosteroids, or epinephrine depending on severity. 1