Case Report: A 40-Year-Old Man with Vasculitic Neuropathy

Discussion

Minocycline is a synthetic, tetracycline-derived, broad-spectrum antibiotic that has been used for more than 30 years. It is active against a wide range of aerobic and anaerobic gram-positive and gram-negative bacteria, and against other microorganisms, including Rickettsia, Chlamydia, Plasmodium and Mycoplasma pneumoniae. Minocycline also has anti-inflammatory properties that have been studied, with variable success, for the treatment of rosacea, bullous and neutrophilic dermatoses, pyoderma gangrenosum, sarcoidosis, aortic aneurysms, cancer metastasis, periodontitis and auto­immune disorders, such as rheumatoid arthritis and scleroderma.⁴

Proposed mechanisms of immune modulation include inhibition of enzymes (e.g., metalloproteinases and nitrous oxide synthetase); inhibition of neutrophil apoptosis; immune cell activation, proliferation and chemotaxis; and abnormal production of reactive metabolites.⁴

Our case & those reviewed underscore the importance of recognizing the association of positive ANA & P-ANCA  tests with long-term minocycline use.

Rarely, minocycline has also been reported to trigger various autoimmune diseases. Drug-induced lupus stemming from minocycline use has been well documented in dermatology and rheumatology literature since the first case reports in 1992, almost 20 years after the drug became available on the market.⁵ Clinical manifestations develop, on average, around two years after initial exposure to the drug and are usually limited to dermatologic and musculoskeletal systems.⁶ All patients have positive ANA tests, but anti-histone antibodies are uncommon. Minocycline is the only antibiotic in the tetracycline class associated with drug-induced lupus.

An association between minocycline and autoimmune hepatitis is also well recognized. Liver injury typically occurs within two years after starting the drug.¹ Laboratory abnormalities typically include high-titer ANA, peripheral ANCA (P-ANCA) and polyclonal gammopathies. Disease manifestations resolve shortly after minocycline discontinuation. Minocycline has also been associated with eosinophilic pneumonitis, serum-sickness and Sweet’s syndrome.¹

Vasculitic neuropathies are well described in the literature and have numerous secondary causes, mainly related to other diseases.⁷ Medication-associated vasculitic neuropathy is not well represented in the literature. A case-based review in 2013 described 15 patients with minocycline-induced vasculitis.⁸ Ten patients had ANA, eight patients had P-ANCA, and four had MPO-ANCA. Most patients had skin involvement, with livedo reticularis and/or subcutaneous nodules. Seven patients had musculoskeletal symptoms (arthralgias and myalgias). One patient had testicular involvement. One patient had a sural nerve biopsy that showed vasculitis with thrombosis in a medium-sized artery.

In 2012, a group from the Mayo Clinic described nine patients with minocycline-associated polyarteritis nodosa-like vasculitis and reviewed 12 other cases in the literature.⁹ Patient ages in the Mayo series ranged from 18–55 years.

Four patients in the Mayo series had skin involvement, and four patients had other organs that were pathologically shown to be sites of active vasculitis, including gallbladder (one patient), renal artery (one patient) and testicle (one patient). Two patients had mononeuritis multiplex (one associated with the gallbladder and one with isolated peripheral nerve disease). Constitutional symptoms (fever, malaise, arthralgias, myalgias) were present in eight patients. Three patients were ANA positive and nine patients were P-ANCA positive (MPO-ANCA in two and PR3-ANCA in one).

Patients were excluded from the series if they were found to meet criteria for ANCA-associated vasculitis or ANA-associated connective tissue diseases. The median duration of minocycline use in this series was two years (range: one to four years). Three patients were treated only by minocycline withdrawal. Six patients required additional treatment with immunosuppressants (e.g., prednisone, cyclophosphamide, mycophenolate mofetil, azathioprine, sulfasalazine and dapsone).

In the other 12 cases, the patients’ ages ranged from 18–70 years. Ten had skin involvement, one had testicular pain (presumed to be from vasculitis), and one had isolated mononeuritis multiplex. Eight patients were ANCA positive (six were P-ANCA positive, of whom two were MPO positive), four had borderline ANCA “type unknown.” The median duration of minocycline use was 2.5 years, and all cases were reported as resolved by stopping the minocycline therapy.

We identified and reviewed 11 additional cases of vasculitic neuropathy presenting with primary neurologic involvement (see Table 2, p. 30).^10–17 Ages ranged from 17–70 years. Six cases involved women, and five involved men. Eight patients presented with mononeuritis multiplex (seven cases involved lower extremities and one involved an upper extremity). Three patients presented with midbrain strokes (one with concomitant mononeuritis multiplex). One patient presented with transient hemi­paresis and was found to have vertebral branch arteritis. Only one patient had skin involvement. Six patients experienced constitutional symptoms, including fevers, chills, fatigue and arthralgias. The average time of exposure to minocycline before symptoms developed was a little less than two years. Eight patients were ANA positive (one was anti-Ro positive, and one had anti-histone antibody). Four were P-ANCA positive (of whom, two were MPO positive). Eight patients were treated with immunosuppressant medications (including corticosteroids, azathioprine, methotrexate and cyclophosphamide). Resolution of active disease occurred in all patients after minocycline was discontinued, with an average response time of 10 weeks.

Table 2: Summary of Cases of Minocycline-Associated Isolated Vasculitic Neuropathy & Response Time After Discontinuing Minocycline

Key: ANCA: anti-neutrophil cytoplasmic antibody; P-ANCA: perinuclear ANCA; ANA: anti-nuclear antibody; ENA: extactable nuclear antigen; MPO: myeloperoxidase; PR3: proteinase 3;

In a 2007 dermatology cross-sectional study, ANCA was found in 7% of minocycline-exposed acne patients compared with none in the unexposed cohort group.¹⁸ In this study, no statistical difference in the prevalence of ANA positivity between patients exposed (13%) or not exposed (11%) to minocycline was found. However, higher titers of ANA (1:160 or higher) were found in the minocycline-exposed group (45%) than in the unexposed group (12%).