Title: Injection Site Reaction and Leukocytoclastic Vasculitis Associated with Adalimumab Therapy for Rheumatoid Arthritis

Biography:

Abstract

Tumor necrosis factor (TNF)-α inhibitors, including adalimumab (Humira; AbbVie, IL) have been shown to be effective in controlling chronic inflammatory diseases.

Injection site reactions (ISRs) are the most common adverse events associated with TNF-α inhibitors such as adalimumab, but systemic effects are rarely described.³We report the case of a woman who developed marked ISR and systemic leukocytoclastic vasculitis (LCV) after initiating adalimumab for rheumatoid arthritis (RA).

Case

The patient is a 75-year-old woman with seropositive RA with polyarthropathy, who had recently started adalimumab presented with a diffuse skin eruption. She had been previously treated with tocilizumab (4mg/kg monthly), methotrexate (10 mg weekly), and prednisone (5 mg weekly), with declining therapeutic effect. She was to undergo treatment with adalimumab (40 mg / 2 weeks). The patient reported that she administered a first adalimumab injection in the right lower abdominal quadrant two weeks prior to dermatologic evaluation. One day prior to dermatologic evaluation, she noted a round rash at the injection site and then overnight developed multiple skin lesions. She reported pruritus but otherwise felt well. Of note, she had taken 2 g of amoxicillin four days prior for a dental procedure. She had no additional medications. Physical examination revealed an 8 cm round erythematous patch with central, dusky hyperpigmentation over the right abdomen. There were numerous 3-8 mm urticarial macules and papules scattered over the legs, trunk, and arms, some with dusky centers. Urticarial patches were present on the palms. Oral mucosa and conjunctivae were unremarkable.

A punch biopsy of the abdominal injection site showed perivascular lymphocytes and eosinophils, indicative of a drug eruption. Punch biopsy of an urticarial papule on the left thigh showed LCV, characterized by fibrinoid degeneration of small blood vessels and a mixed infiltrate, with abundant neutrophils and prominent nuclear dust.

Discussion

Various adverse events have been reported in clinical trials of subcutaneous TNF-α inhibitors, most commonly ISRs. ISR, by definition, includes any of: erythema, pruritus, hemorrhage, pain, or swelling at the site of injection.

LCV is a small vessel vasculitis involving dermal postcapillary venules. Drugs cause roughly 10% of LCV, which generally manifest between 7 and 21 days following treatment.⁶Numerous studies have associated anti-TNF-α therapy with vasculitis,^7-10most commonly cutaneous vasculitis (most prevalent in patients with RA).⁸During RA clinical trials using adalimumab, the incidence of LCV was 0.01 events per 100 person-years of exposure.⁴The pathogenesis of anti-TNF-α associated vasculitis remains unclear. One hypothesis is that anti-drug host antibodies initiate an immune-complex mediated hypersensitivity reaction. Another theory suggests that TNF-α antagonists induce a switch from the predominant T helper 1 (Th1) profile of RA to a Th2 response.^11,12

In our patient, the skin lesions began at the injection site and subsequently spread. Given the injection site localization and the time course, adalimumab was presumed to be causative. It is possible that amoxicillin could also have caused the diffuse eruption. Our patient was successfully treated with discontinuation of adalimumab and initiation of corticosteroid therapy, with antihistamines as needed.