What is the diagnosis for a patient with a history of arthritis, currently on disease-modifying antirheumatic drugs (DMARDs), who presents with a painful red macular rash on the palms one month after starting treatment?

DRESS Syndrome (Drug Reaction with Eosinophilia and Systemic Symptoms)

The most likely diagnosis is DRESS syndrome, a severe hypersensitivity reaction to one of the DMARDs (most commonly sulfasalazine), presenting with the characteristic painful erythematous macular rash on the palms, occurring approximately one month after treatment initiation. 1, 2

Clinical Presentation and Diagnosis

DRESS syndrome typically manifests 2-8 weeks after drug initiation and is characterized by: 2, 3

• Painful erythematous macular or maculopapular rash affecting palms, soles, and other body areas 2, 4
• Fever (often high-grade) 2, 3
• Lymphadenopathy 2, 3
• Eosinophilia (peripheral blood eosinophil count >1,000/μL or >10%) 2, 3
• Internal organ involvement including hepatitis (elevated transaminases), nephritis, pneumonitis, or myocarditis 1, 3
• Atypical lymphocytes on blood smear 2

The timing (one month after DMARD initiation) and location (palms) are highly characteristic of DRESS syndrome rather than a simple drug eruption. 2, 4

Most Likely Causative Agent

Sulfasalazine is the most common DMARD associated with DRESS syndrome, though methotrexate, leflunomide, and hydroxychloroquine have also been implicated. 1, 2, 4

The FDA label for sulfasalazine explicitly warns: "Severe, life-threatening, systemic hypersensitivity reactions such as drug rash with eosinophilia and systemic symptoms have been reported in patients taking sulfasalazine. Early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident." 1

Critical Diagnostic Workup Required Immediately

Obtain the following laboratory tests urgently: 2, 4, 3

• Complete blood count with differential (looking for eosinophilia >1,000/μL and atypical lymphocytes)
• Comprehensive metabolic panel (hepatic transaminases, creatinine, BUN for organ involvement)
• Urinalysis (for nephritis)
• Chest X-ray (if respiratory symptoms present, to evaluate for pneumonitis)
• Troponin and ECG (if cardiac symptoms, to rule out myocarditis)

Immediate Management Algorithm

Step 1: Discontinue All Suspect DMARDs Immediately

Stop all recently initiated DMARDs (sulfasalazine, methotrexate, leflunomide, or hydroxychloroquine) immediately without waiting for laboratory confirmation. 1, 2, 4 The FDA label states: "Sulfasalazine should be discontinued at the first appearance of skin rash, mucosal lesions, or any other sign of hypersensitivity." 1

Step 2: Assess Disease Severity

• Mild DRESS (rash without systemic symptoms or organ involvement): Supportive care with close monitoring may suffice 2
• Moderate to Severe DRESS (fever, lymphadenopathy, eosinophilia >1,500/μL, or any organ involvement): Requires systemic corticosteroid therapy 2, 4

Step 3: Initiate Corticosteroid Therapy

For moderate to severe DRESS, start prednisone 0.5-1.0 mg/kg/day (typically 40-60 mg daily for adults) immediately. 2, 4 One case report documented that a patient "only improved after treatment with prednisone" despite drug discontinuation. 2

Continue corticosteroids for 4-6 weeks minimum, then taper slowly over 2-3 months to prevent rebound. 2, 4

Step 4: Monitor for Complications

DRESS syndrome carries a 10% mortality rate primarily from: 2, 4

• Hepatic failure (most common cause of death)
• Neutropenic sepsis and secondary infections 4
• Multiple organ dysfunction syndrome 4
• Myocarditis 3

Monitor liver function tests, complete blood counts, and renal function weekly during the acute phase. 4

Critical Pitfalls to Avoid

Do not rechallenge with the same DMARD or structurally related drugs. One fatal case report documented a patient who initially developed a rash with sulfasalazine, improved after discontinuation, but was later rechallenged with hydroxychloroquine (which had also been given initially), leading to fatal TEN/DRESS overlap syndrome. 4

Do not mistake DRESS for a viral infection. DRESS syndrome is "commonly mistaken for a viral infection" due to fever, lymphadenopathy, and atypical lymphocytes, but this delay in recognition increases morbidity and mortality. 2

Do not wait for eosinophilia to appear before acting. Early DRESS may present with rash and fever before eosinophilia develops; the FDA label notes "early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident." 1

Future DMARD Selection After Recovery

Once DRESS syndrome resolves completely (typically 6-12 weeks): 5, 6

• Avoid the causative DMARD permanently and document the severe drug allergy 4
• Consider patch testing 4-6 weeks after resolution to identify the specific culprit drug 3
• Switch to an alternative DMARD with different chemical structure: If sulfasalazine caused DRESS, consider methotrexate monotherapy or biologic DMARDs (TNF inhibitors, abatacept, tocilizumab) combined with methotrexate 5, 6
• Screen for tuberculosis and hepatitis B before initiating biologic therapy 6