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CASE BASED REVIEW
Ahead of print publication  

Minocycline-induced antineutrophil cytoplasmic antibody-associated vasculitis in children


 Department of Pediatrics, Bharati Vidyapeeth University Medical College Hospital and Research Centre, Pune, Maharashtra, India

Correspondence Address:
Sunil Kapur,
Department of Pediatrics, Bharati Vidyapeeth University Medical College Hospital and Research Centre, Apollo Spectra Hospital, Pune, Maharashtra
India
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/injr.injr_33_20

  Abstract 


Chronic exposure to minocycline, a commonly used anti-acne medication, results in a variety of autoimmune syndromes. Minocycline-induced vasculitis often associated with the presence of antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA) has been reported in Western literature, mainly in adults. Herein, we report a rare case of a 15-year-old male child on minocycline treatment for 1 year, who presented with fever, skin rash, and polyarthralgia for 4 months. His erythrocyte sedimentation rate (ESR) level was elevated, ANA and myeloperoxidase ANCA were positive, and skin biopsy revealed leukocytoclastic vasculitis. Upon discontinuation of minocycline and prescribing a short course of oral steroids, all his symptoms resolved and ESR normalized within 2 weeks. The child remained asymptomatic with normal acute-phase reactants at 2-month follow-up. This outcome suggested that minocycline was the main cause of ANCA-associated vasculitis.

Keywords: Antineutrophil cytoplasmic antibodies, drug-induced vasculitis, leukocytoclastic vasculitis, minocycline



How to cite this URL:
Kapur S, Oswal J. Minocycline-induced antineutrophil cytoplasmic antibody-associated vasculitis in children. Indian J Rheumatol [Epub ahead of print] [cited 2020 Oct 29]. Available from: https://www.indianjrheumatol.com/preprintarticle.asp?id=289179




  Introduction Top


Minocycline, a commonly used anti-acne drug, is a long-acting tetracycline antibiotic that binds to 30S bacterial ribosomal subunit inhibiting protein synthesis.[1] Various autoimmune manifestations associated with chronic minocycline intake include drug-induced lupus, vasculitis, serum-sickness-like disease, autoimmune hepatitis, eosinophilic pneumonia, and Sweet's syndrome.[2] Drugs usually implicated in inducing antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) are antithyroid drugs, cocaine, levamisole, and hydralazine.[3] Medium-vessel vasculitis syndrome similar to polyarteritis nodosa (PAN) with ANCA positivity has been reported with minocycline usage.[2],[4],[5] Herein, we report a rare case of AAV induced by minocycline in a young male during the treatment of acne vulgaris.


  Case Based Review Top


A 15-year-old male child presented with fever, rash, and polyarthralgia for the last 4 months. He was on tablet minocycline 100 mg once a day for the last 1 year for his acne vulgaris. There was no history of weight loss, bleeding manifestations, hair fall, oral ulcers, abdominal pain, myalgia, hematuria, paresthesia, and dyspnea. His blood pressure was normal. Systemic examination was within normal limits. Musculoskeletal examination revealed mild right wrist swelling. On local examination, the rash was maculopapular, and erythematous, mainly on the medial aspect of the right forearm [Figure 1]. Investigations revealed hemoglobin of 8.9 g/dl, white blood cell count of 15,400/mm3, and a platelet count of 3.9 lakhs/mm3 with raised erythrocyte sedimentation rate (ESR) (48 mm/h). X-ray chest and nasal sinuses, urine routine, renal and liver function tests, viral serology (HIV, hepatitis B surface antigen, and hepatitis C virus), Mantoux test, and cultures (blood and urine) were negative with normal ophthalmology examination. Ultrasonography right wrist revealed synovitis, and skin biopsy was suggestive of leukocytoclastic vasculitis [Figure 2]. Antinuclear antibody (ANA) (immunofluorescence) was positive (1:160 titer, nucleolar pattern). Anti-double-stranded DNA antibody (anti-dsDNA), anti-Smith, anti-histone, anti-phospholipid antibodies, complement levels (C3, C4), rheumatoid factor, and serum cryoglobulins were negative. Perinuclear ANCA (p-ANCA) staining pattern was detected by immunofluorescence with positive myeloperoxidase (MPO)-reactive antibodies (enzyme-linked immunosorbent assay; significantly elevated at >200 IU/ml). Suspecting drug-induced AAV, minocycline was stopped, and the child was given a short course (2 weeks) of low-dose oral steroids (0.5 mg/kg/day). This resulted in prompt resolution of his clinical symptoms and normalization of his inflammatory markers within 2 weeks of stoppage of minocycline. At 2-month follow-up of steroids, the child was asymptomatic with normal ESR.
Figure 1: Maculopapular, erythematous rash mainly on the medial aspect of the right forearm

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Figure 2: Skin histopathologic analysis (hematoxylin-eosin) showing leukocytoclastic vasculitis. Perivascular infiltrates with neutrophils and nuclear dust were identified

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  Discussion Top


In this case, the diagnosis of minocycline-induced vasculitis was substantiated by our patient's young age; the presence of p-ANCA with MPO specificity; and the rapid improvement of skin rash, arthralgia, fever, and ESR after drug discontinuation. Most of the cases of drug-induced vasculitis mainly affect medium- and small-sized blood vessels, which was also seen in our patient.[6] In the largest case series of minocycline-induced PAN, Kermani et al. reported nine patients, out of which six patients had histopathological evidence and three patients had angiographic evidence of vasculitis.[4] The authors reported four patients with cutaneous disease and five cases with target organ involvement (mainly kidney and central nervous system); all the nine patients were positive for p-ANCA, two patients were positive for MPO ANCA, and three patients were with positive ANA. Symptomatic resolution following drug discontinuation was seen in all patients, with six patients requiring additional immunosuppression. A small subgroup of minocycline-induced vasculitis patients are positive for both antinuclear antibodies and ANCAs, which was also noticed in our patient.[2] Schrodt and Callen presented a case report of a 15-year-old female with minocycline-induced biopsy-proven vasculitis with livedo reticularis and myalgias, consistent with PAN.[7] Tabriziani et al. have reported the case of a 21-year-old female with minocycline-induced renal PAN with positive p-ANCA with MPO specificity and renal angiography suggestive of aneurysms.[8] Our patient did not have any evidence of target organ involvement. Additional cases of minocycline-induced ANCA vasculitis (biopsy proven) have been reported mainly in adults.[9],[10],[11] MPO involvement in minocycline metabolism leads to novel haptens for autoantibody creation (anti-MPO and p-ANCA), which could be a potential mechanism in minocycline-induced vasculitis.[12] Marzo-Ortega et al. have reported 5% ANCA positivity in 252 acne vulgaris patients on minocycline treatment, with the most common pattern being p-ANCA (67%) with MPO positivity (87%).[13] Abnormal ANCA normalization can take almost a full year after minocycline stoppage.[2] Whether ANCA titers could be an indicator of disease activity and disease monitoring is disputable.[14] Probably, we report the first case of minocycline-induced AAV in a child from India. [Table 1] presents the case reports of biopsy-proven minocycline-induced vasculitis in children (≤18 years). Patients who develop drug-induced vasculitis should never be rechallenged with the same drug.
Table 1: Biopsy-proven cases of minocycline-induced vasculitis in children (≤18 years)

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  Conclusion Top


Our case demonstrates the potential role of minocycline, a commonly used anti-acne drug, in children in the induction of AAV. Pediatricians should be aware of the propensity of drugs to cause vasculitis, which requires withdrawal of the culprit drug and additional immunosuppression in selected cases.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Kircik LH. Doxycycline and minocycline for the management of acne: A review of efficacy and safety with emphasis on clinical implications. J Drugs Dermatol 2010;9:1407-11.  Back to cited text no. 1
    
2.
Lenert P, Icardi M, Dahmoush L. ANA (+) ANCA (+) systemic vasculitis associated with the use of minocycline: Case-based review. Clin Rheumatol 2013;32:1099-106.  Back to cited text no. 2
    
3.
Pendergraft WF 3rd, Niles JL. Trojan horses: Drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Curr Opin Rheumatol 2014;26:42-9.  Back to cited text no. 3
    
4.
Kermani TA, Ham EK, Camilleri MJ, Warrington KJ. Polyarteritis nodosalike vasculitis in association with minocycline use: A singlecenter case series. Semin Arthritis Rheum 2012;42:21321.  Back to cited text no. 4
    
5.
Kang MK, Gupta RK, Srinivasan J. Peripheral vasculitic neuropathy associated with minocycline use. J Clin Neuromuscul Dis 2018;19:138-41.  Back to cited text no. 5
    
6.
Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am 2001;27:849-62.  Back to cited text no. 6
    
7.
Schrodt BJ, Callen JP. Polyarteritis nodosa attributable to minocycline treatment for acne vulgaris. Pediatrics 1999;103:503-4.  Back to cited text no. 7
    
8.
Tabriziani H, Wilcox CS, Gilbert ON, Lipkowitz MS. Minocycline-induced renal polyarteritis nodosa. Case Rep 2012;2012:bcr2012006503.  Back to cited text no. 8
    
9.
Pelletier F, Puzenat E, Blanc D, Faivre B, Humbert P, Aubin F. Minocycline- induced cutaneous polyarteritis nodosa with antineutrophil cytoplasmic antibodies. Eur J Dermatol 2003;13:396-8.  Back to cited text no. 9
    
10.
Culver B, Itkin A, Pischel K. Case report and review of minocycline-induced cutaneous polyarteritis nodosa. Arthritis Rheum 2005;53:468-70.  Back to cited text no. 10
    
11.
Tehrani R, Nash-Goelitz A, Adams E, Dahiya M, Eilers D. Minocycline- induced cutaneous polyarteritis nodosa. J Clin Rheumatol 2007;13:146-9.  Back to cited text no. 11
    
12.
Gao Y, Zhao MH. Drug-induced anti-neutrophil cytoplasmic antibody-associated vasculitis [Review]. Nephrology 2009;14:33-41.  Back to cited text no. 12
    
13.
Marzo-Ortega H, Baxter K, Strauss RM, Drysdale S, Griffiths B, Misbah SA, et al. Is minocycline therapy in acne associated with antineutrophil cytoplasmic antibody positivity? A cross sectional study. Br J Dermatol 2007;156:1005-9.  Back to cited text no. 13
    
14.
Fujieda M, Hattori M, Kurayama H, Koitabashi Y; Members and Coworkers of the Japanese Society for Pediatric Nephrology. Clinical features and outcomes in children with antineutrophil cytoplasmic autoantibody-positive glomerulonephritis associated with propylthiouracil treatment. J Am Soc Nephrol 2002;13:437-45.  Back to cited text no. 14
    


    Figures

  [Figure 1], [Figure 2]
 
 
    Tables

  [Table 1]



 

 
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