Autoimmunity in Children Associated with Chronic Minocycline Treatment

Abstract & Commentary

By Hal B. Jenson, MD, FAAP, Professor of Pediatrics, Tufts University School of Medicine, and Chief Academic Officer, Baystate Medical Center, Springfield, MA, is Associate Editor for Infectious Disease Alert

Synopsis: Chronic minocycline treatment for acne can result in autoimmune phenomenon with constitutional symptoms, polyarthralgia and polyarthritis, and rash. Although symptoms usually resolve with cessation of minocycline, sometimes requiring non-steroidal anti-inflammatory drugs, approximately one-quarter of children develop chronic autoimmune disease.

Source: El-Hallak M, et al. Chronic minocycline-induced autoimmunity in children. J Pediatr. 2008;153:314-319.

Of 583 children < 18 years of age tested for anti-neutrophil cytoplasmic antibody (ANCA) at Boston Children's Hospital from 1996 to 2006, 27 children had a history of minocycline administration, with clinical and laboratory findings of autoimmunity. Of these 27 children, 19 were female (70%). All patients had minocycline prescribed for treatment of acne, with a mean duration of 13 months.

Clinical manifestations included fever, weight loss, and malaise in all 27 (100%), polyarthralgia in 22 (81%), and frank polyarthritis in 17 (62%). The small joints of the hands were most commonly affected (82%), followed by the wrists (64%), ankles (35%), feet (35%), and shoulders (10%). Rash, including livedo reticularis, was present in 8 (30%), Raynaud's phenomenon in 6 (22%), and morning stiffness in 14 (51%).

Leukopenia was present in 7 (26%), and serum transaminases (AST, ALT) were mildly-to-moderately elevated in 11 (41%). The erythrocyte sedimentation rate was increased in 12 of 24 patients (50%), and the C-reactive protein was increased in 14 of 25 patients (56%). The anti-nuclear antibody (ANA) test was positive in 20 of 27 (74%), with titers from 1:40 to 1:2560. Specific autoantibodies, including anti-dsDNA, Sm, and RNP, were negative in all patients except one, and antihistone antibodies were negative in all six children tested. The ANCA was positive in 18 (67%), with perinuclear fluorescent staining and a positive anti-myeloperoxidase (anti-MPO) specificity in 11, and a nuclear staining pattern (atypical ANCA) and negative anti-MPO in seven.

The clinical outcome was highly variable after cessation of minocycline: in 14 children (52%), the symptoms resolved upon cessation, or required only a short course of non-steroidal anti-inflammatory drugs (NSAIDs); six (22%) had eventual resolution within one year, requiring treatment with either NSAIDs or corticosteroids; and seven (26%) had chronic autoimmune disease, primarily manifesting as persistent arthritis, with a mean follow-up of 31.2 ± 13.5 (range, 13-48) months after onset. These patients required long-term treatment that included corticosteroids, methotrexate, and anti-tumor necrosis factor alpha agents. There was no correlation of the clinical course with the cumulative dose or duration of minocycline administration.

Commentary

The principal adverse events associated with minocycline include gastrointestinal intolerance, vertigo, and various rashes. There is much overlap of minocycline-induced autoimmunity with the less common adverse events of minocycline, including hypersensitivity reactions (eg, serum sickness, hypersensitivity pneumonitis, pericarditis), pseudotumor cerebri, autoimmune hepatitis, drug-induced lupus, arthritis, and vasculitis. The pathogenesis of minocycline-induced autoimmunity is unknown. Unlike other drugs that cause drug-induced lupus with equal distribution between males and females, 70% of these cases of minocycline-induced autoimmunity were females.

This report suggests that minocycline-induced autoimmunity is a rare condition; during this 10-year period, it was diagnosed in only 0.05% of all children referred to this clinic. It is possible that the incidence is greater, given the usual resolution in most children with cessation of minocycline and the widespread use of chronic minocycline for treatment of acne. Minocycline is one of the most prescribed treatments for acne, with more than 15 million pediatric patients taking minocycline each year. Physicians should be aware of this association and consider this in children taking minocycline with constitutional or musculoskeletal symptoms.