What could be causing pain under areas of hyperpigmentation in a female patient with a 7-year history of Rheumatoid Arthritis (RA) who has been taking plaquenil (hydroxychloroquine)?

Pain Under Hyperpigmented Areas in RA Patient on Hydroxychloroquine

The most likely cause of pain under hyperpigmented areas in this patient is hydroxychloroquine-induced cutaneous hyperpigmentation, which can be associated with underlying dermatologic toxicity requiring immediate drug evaluation and possible discontinuation. 1, 2

Primary Differential Diagnosis

Hydroxychloroquine-Induced Cutaneous Toxicity

• Cutaneous hyperpigmentation is the second most common dermatologic adverse effect of hydroxychloroquine (116 cases in systematic review), occurring after drug eruption/rash (358 cases). 2
• Pain associated with hyperpigmented areas suggests active inflammatory or toxic dermatologic reaction rather than simple cosmetic pigmentation. 2
• The FDA label explicitly warns that serious skin reactions including DRESS syndrome and AGEP can occur with hydroxychloroquine, which may present with pain, burning, and skin changes. 1

Critical Considerations for This Patient

Immediate evaluation is required to rule out serious cutaneous adverse reactions:

• Monitor for signs of acute generalized exanthematous pustulosis (AGEP), which presents with painful pustular eruptions and can overlap with Stevens-Johnson syndrome. 1, 3
• Assess for drug eruption/rash with associated pain, pruritus, or burning—the most common dermatologic adverse effect requiring drug discontinuation. 1, 2
• The FDA label states: "Advise patients to seek medical attention promptly if they experience signs and symptoms of serious skin reactions such as blisters on the skin, eyes, lips or in the mouth, itching or burning, with or without fever." 1

Evaluation Algorithm

Step 1: Assess Severity and Characteristics

• Examine hyperpigmented areas for pustules, erosions, blistering, or mucosal involvement. 1, 3
• Document distribution pattern (limbs, trunk, face) and presence of systemic symptoms (fever, malaise). 3
• Perform Nikolsky sign testing to evaluate for Stevens-Johnson syndrome/toxic epidermal necrolysis. 3

Step 2: Rule Out Alternative Diagnoses

• Evaluate for active RA synovitis in joints underlying hyperpigmented areas, though this would be unusual presentation. 4
• Consider regional musculoskeletal pain syndromes or osteoarthritis as noninflammatory causes, though these would not explain hyperpigmentation. 4
• Assess for central pain amplification (fibromyalgia), but this does not account for localized hyperpigmentation. 4

Step 3: Determine Need for Drug Discontinuation

Discontinue hydroxychloroquine immediately if:

• Pustular eruptions, blistering, or mucosal involvement are present. 1, 3
• Progressive painful rash with systemic symptoms develops. 1, 3
• Skin biopsy confirms AGEP, DRESS, or other serious drug reaction. 1, 3

Consider dermatology consultation with skin biopsy if:

• Diagnosis remains uncertain after initial evaluation. 3
• Pain persists without clear inflammatory arthritis explanation. 2

Management Approach

If Serious Cutaneous Reaction Confirmed

• Initiate high-dose corticosteroids (methylprednisolone) as first-line treatment. 3
• Consider intravenous immunoglobulin if inadequate response to corticosteroids, particularly for Stevens-Johnson syndrome overlap. 3
• Provide aggressive supportive care with fluid/electrolyte replacement and skin barrier protection. 3

If Simple Hyperpigmentation Without Serious Features

• Hydroxychloroquine can be continued if hyperpigmentation is isolated without pain, pustules, or systemic symptoms, as cosmetic hyperpigmentation alone does not require discontinuation. 2
• However, the presence of pain suggests this is NOT simple cosmetic hyperpigmentation and warrants further investigation. 2

Critical Pitfalls to Avoid

• Do not dismiss painful hyperpigmented areas as benign cosmetic effect—pain indicates potential serious drug reaction. 1, 2
• Do not delay dermatology evaluation if diagnosis is uncertain, as AGEP and Stevens-Johnson syndrome can be life-threatening. 1, 3
• Do not attribute all symptoms to RA disease activity without considering drug-induced causes in patients on hydroxychloroquine. 4, 2
• The systematic review found dermatologic adverse effects occurred after cumulative doses ranging from as little as 3g to 2500g, meaning toxicity can occur at any point during therapy. 2

Special Consideration: Psoriasis Contraindication

If this patient has undiagnosed psoriasis, hydroxychloroquine is contraindicated as it can precipitate severe flare-ups. 5, 1

• The American College of Rheumatology explicitly recommends against hydroxychloroquine use in psoriatic arthritis. 5
• The FDA label states: "Administration of hydroxychloroquine sulfate to patients with psoriasis may precipitate a severe flare-up of psoriasis. Avoid hydroxychloroquine sulfate in patients with psoriasis." 1