The Journal of Pediatrics
Volume 153, Issue 3 , Pages 303-304, September 2008

Autoimmunity and Minocycline

  • Terry L. Moore, MD

      Affiliations

    • Corresponding Author InformationReprint requests: Terry L. Moore, MD, Professor of Internal Medicine, Pediatrics, and Molecular Microbiology and Immunology, Director, Division of Rheumatology and Pediatric Rheumatology, Saint Louis University School of Medicine, 1402 S Grand Blvd, Room 211A Doisy Hall, St. Louis, MO 63104

Professor of Internal Medicine, Pediatrics, and Molecular Microbiology and Immunology, Director, Division of Rheumatology and Pediatric Rheumatology, Saint Louis University School of Medicine, St. Louis, Missouri

Article Outline

Abbreviations: ANA, Antinuclear antibodies, ANCA, Antineutrophil cytoplasmic antibodies, ds, Double-stranded, MPO, Myeloperoxidase

 

Drug-induced antinuclear antibodies (ANA) and other autoantibodies and drug-induced lupus syndromes can occur after the use of certain medications. Various autoantibodies develop in many patients because of medications, but clinical disease with lupus-like features develops in only a few patients.1 The antibodies are usually ANA or antihistone antibodies,2 but other antibodies, such as antineutrophil cytoplasmic antibodies (ANCA), specifically antibodies to myeloperoxidase (MPO), have been reported in association with certain medications.3

See related article, p 314

In this issue of The Journal, El-Hallak et al4 report on their experience with minocycline-induced autoimmunity in children, with an emphasis on the potential for chronicity. They reviewed the cases of all children examined in the Division of Immunology, Program in Rheumatology at the Children's Hospital Boston and Harvard Medical School between 1997 and 2006. They noted that minocycline-induced autoimmunity was diagnosed in 27 children. All patients had constitutional symptoms, 22 with polyarthralgia and 17 with frank polyarthritis, mostly affecting hands and feet. They found that chronic autoimmune disease, still active at their last follow-up at a mean of 32 months, developed in 7 patients. Six patients had an intermediate course, with resolution of symptoms within 12 months, and 14 patients had symptoms that resolved with the discontinuation of minocycline. All patients with a chronic course had evidence of arthritis. On the basis of their study, they concluded that chronic symptoms with a potential for significant morbidity develops in a substantial proportion of children with minocycline-induced autoimmunity.4 They emphasized that physicians who prescribe minocycline should be aware of its propensity for inducing potential serious autoimmune phenomena.

Minocycline has become 1 of the most commonly used treatments for acne vulgaris, prescribed for almost 15.2 million pediatric patients in the United States annually.5 It is a second generation semisynthetic tetracycline derivative.5 Minocycline was first thought to be a causative agent of possible drug-related connective tissue disease in 1992, and >50 other cases have been reported in literature.1 Most cases occur in young women being treated for acne. Earlier studies have shown earlier and current exposure of doses >100 mg per day increased the risk of possible drug-induced autoimmunity.6 Most studies have reported that the main symptoms were constitutional, including rash, polyarthralgia, frank inflammatory arthritis, and autoimmune hepatitis.7 Pulmonary and cutaneous manifestations also have been noted.7, 8 Laboratory study results show ANA vary in titer in these patients. Antibodies to cardiolipin and double-stranded (ds) DNA occur less frequently, but the patients often had positive test results for perinuclear ANCA at titers >1:160, with antibodies directed to MPO being noted.1, 3, 8, 9 El-Hallak et al4 found similar findings in their patients, with skin rashes and even hypersensitivity reactions noted. The erythrocyte sedimentation rate was increased in 50% of patients, and C-reactive protein levels were increased in 56% of patients, with leukopenia present in 26% of patients. Serum transaminase levels were elevated in 41% of patients. ANA were positive in 74% of patients, with titers varying from 1:40 to 1:2560, of which 65% were positive at titers >1:160. In their study, all patients had negative test results for antibodies to dsDNA, Sm, and RNP, except for 1 patient with a low titer. Antihistone antibodies were tested in 6 patients, and all results were negative. ANCAs were positive in 67% (18/27) of patients, with perinuclear immunofluorescence in 61% of patients, and 11 patients had antibodies to MPO. Chronic autoimmune disease developed in 7 of the patients (26%), primarily manifesting as persistent arthritis. These patients required long-term treatment with numerous agents, including corticosteroids, methotrexate, and anti-tumor necrosis factor alpha agents. Six of the patients (22%) had an intermediate course, with eventual resolution of symptoms in <1 year. In some cases, however, these patients did require corticosteroids and non-steroidal anti-inflammatory agents to control their arthritic complaints.

The pathophysiologic mechanism of minocycline-induced autoimmune syndrome remains unknown. Studies speculated on hapten formation, unmasking of neoantigens, molecular mimicry, cross reactivity with self-antigens such as microsomal cytochromes, or unmasking an underlying lupus diathesis.4, 8 Factors such as low acetylator status also may play a role in the pathogenesis.8 Overall, El-Hallak et al4 pointed out that the drug-induced syndrome caused by minocycline was a rare condition. In a 10-year period, only 0.5% of all children who were referred to the clinic had apparent autoimmune sequela related to minocycline. However, in view of the wide spread use of minocycline, particularly for treatment of acne in adolescence, it may be under-reported. Patients re-challenged with minocylcine have redeveloped symptoms within a few hours to a few days after restarting the medication.3, 8 Therefore, re-challenge usually is contraindicated, but supervised re-challenge might be helpful for confirming the diagnosis in the future.1 Overall, the report makes pediatricians, family practitioners, internists, and dermatologists aware of the possible link between minocycline and constitutional musculoskeletal symptoms. Earlier mild symptomatology could have led to substantial under-diagnosis. This report will help in making more physicians aware of the potential autoimmune stimulus of minocycline in patients and the possible chronic ramifications.

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References 

  1. Mongey AB, Hess EV. Drug insight: autoimmune effects of medications—what's new?. Nat Clin Rheumatol. 2008;4:136–144
  2. Burlingame RW, Rubin RL. Drug-induced anti-histone autoantibodies display two patterns of reactivity with substructures of chromatin. J Clin Invest. 1991;88:680–690
  3. Lawson TM, Amos N, Bulger D, Williams BD. Minocycline-induced lupus: clinical features and response to rechallenge. Rheumatology (Oxford). 2001;40:329–335
  4. El-Hallak M, Giani T, Yeniay BS, Jacobs KE, Kim S, Sundel RP, et al. Chronic minocycline induced autoimmunity in children. J Pediatr. 2008;153:314–319
  5. Eichenfield AH. Minocyline and autoimmunity. Curr Opin Pediatr. 1999;11:447–456
  6. Sturkenboom MCJM, Meier CR, Jick H, Strickler BHC. Minocycline and lupus like syndrome in acne patients. Arch Intern Med. 1999;159:484–490
  7. Tournigand C, Genereau T, Prudent M, Piermord MC, Hernson S, Chosidow O. Minocyline-induced clinical and biological lupus-like disease. Lupus. 1999;8:773–774
  8. Elkayam O, Levartovsky D, Brautbon C, Yaron M, Burke M, Vardinon N, et al. Clinical and immunological study of 7 patients with minocycline-induced autoimmune phenomena. Am J Med. 1998;105:484–487
  9. Dunphy J, Oliver M, Rands Al, Lovell CR, McHugh NJ. Anti-neutrophil cytoplasmic antibodies and HLA class II alleles in minocycline-induced lupus-like syndrome. Br J Dermatol. 2000;142:461–467

PII: S0022-3476(08)00395-8

doi:10.1016/j.jpeds.2008.05.011

Refers to article:

  • Chronic Minocycline-Induced Autoimmunity in Children , 28 April 2008

    Moussa El-Hallak, Teresa Giani, Betul Sozeri Yeniay, Kathleen E. Jacobs, Susan Kim, Robert P. Sundel, Fatma Dedeoglu
    The Journal of Pediatrics September 2008 (Vol. 153, Issue 3, Pages 314-319)

The Journal of Pediatrics
Volume 153, Issue 3 , Pages 303-304, September 2008

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