Clinical Review & Education
JAMA Pediatrics Clinical Challenge
Rare Adverse Effect of Treatment With Minocycline Ashika Odhav, MD; Chirag Odhav; Nimesh A. Dayal, MBBCh, MRCP, MSc
Figure 1. Ulcer with raised border and erythematous halo in distal right shin.
An 18-year-old woman presented with a 4-week history of a solitary painful bullous skin lesion over the lower right anterior tibia accompanied by generalized myalgia, polyarthalgia, joint stiffness, paraesthesia, and episodic ankle swelling. The lesion first appeared as a skin-colored papule and, within a week, developed an erythematous halo. Her medical history includes asthma and acne. To our knowledge, there is no family history of this condition. Her medications included minocycline hydrochloride (for 25 months for acne), ranitidine hydrochloride, contraceptive pills, and iron supplements. An initial physical examination revealed mild synovitis in both ankles and an erythematous, raised papule overlying the distal aspect of the right anterior tibia. Treatment with prednisone acetate (10 mg daily) was initiated. Seven weeks later, the original skin lesion evolved into an ulcer with erythematous, raised borders (Figure 1). The case patient had new erupQuiz at jamapediatrics.com tions of nonindurated, violaceous, nontender, reticulated patches overlying the skin on the bilateral anterior tibias, consistent with livedo reticularis. She denies any previous episodes, and the results of a review of mitigating factors were negative. A laboratory workup revealed a positive antinuclear antibody 1:640 nucleolar pattern, an elevated erythrocyte sedimentation rate, and elevated C-reactive protein and serum IgG levels. The results of the following laboratory studies were negative or normal: complete blood cell count, urinalysis, liver profile, Lyme disease, parvovirus B19, Monospot test, uric acid, rheumatoid factor, antistrepolysin antibody, anti-Scl70, antihepatitis C virus, hepatitis B surface antigen, hepatitis B core antibody, cytomegalovirus antibody, and human T-lymphotropic viruses 1 and 2 antibody. Culture results of the skin lesion were negative. The results from chest radiography were normal.
jamapediatrics.com
WHAT IS YOUR DIAGNOSIS?
A. Erythema nodosum B. Sarcoidosis C. Systemic lupus erythematosus D. Minocycline-induced cutaneous polyarteritis nodosa
JAMA Pediatrics March 2014 Volume 168, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Georgia User on 05/24/2015
287
Clinical Review & Education JAMA Pediatrics Clinical Challenge
Diagnosis D. Minocycline-induced cutaneous polyarteritis nodosa
Discussion The key clinical feature in this case is recognizing that this patient could have minocycline-induced cutaneous polyarteritis nodosa. Differential diagnosis includes erythema nodosum, sarcoidosis, systemic lupus erythematosus or other connective tissue disease, rheumatic fever, Lyme disease, parvovirus, minocycline-induced systemic lupus erythematosus, minocycline-induced hepatitis, lymphoma, drug reaction, and other vasculitis. To establish a definitive diagnosis requires performing a skin biopsy. The antibiotic minocycline is a semisynthetic tetracycline derivative that is widely used. Recently, attention has been paid to the rarer systemic adverse effects of minocycline-induced autoimmune disorders such as drug-induced lupus erythematosus, serum sickness, autoimmune hepatitis, polyarthritis, and vasculitis. This is a case report of minocycline-induced cutaneous polyarteritis nodosa. All reported cases1-5 described symptoms of generalized myalgia, polyarthritis, livedo reticularis, or subcutaneous nodules and histologic confirmation of vasculitis that met the American College of Rheumatology 1990 criteria for polyarteritis nodosa (at least 3 of 10 parameters).3 Idiopathic cutaneous polyarteritis nodosa is a necrotizing vasculitis of small and medium-sized arteries within the skin, without involvement of the internal organs. Culver et al1 proposed diagnostic guidelines for minocycline-induced cutaneous polyarteritis nodosa. Patients should fulfill 6 of the following 7 criteria: (1) minocycline use for more than 12 months; (2) skin manifestations, including livedo reticularis and/or subcutaneous nodules; (3) arthritis and/or myalgia and/or neuropathy in the distribution of the rash; (4) lack of systemic organ involvement; (5) skin biopsy sample showing necrotizing vasculitis of small and/or medium-sized vessels; (6) evidence of perinuclear antineutrophilic cytoplasmic antibodies; and (7) improvement after discontinuation of minocycline.1 Polyarteritis nodosa is usually self-limited, once minocycline is discontinued. In several cases,2,3 the syndrome will reoccur if rechallenged with minocycline. Previous case reports and case series1,3-5 have shown initial symptomatic improvement with short courses of prednisone. It is contraindicated to restart minocycline after this adverse effect has occurred. ARTICLE INFORMATION Author Affiliations: Department of Pediatrics, Children’s Mercy Hospital, Kansas City, Missouri (A. Odhav); College of Letters and Science, University of California, Berkeley (C. Odhav); Arthritis Center of Orlando, Orlando Health Central Hospital, Orlando, Florida (Dayal). Corresponding Author: Ashika Odhav, MD, Department of Pediatrics, Children’s Mercy Hospital, 4949 Wornall Rd, Unit 309, Kansas City, MO 64112 ([email protected]). Section Editor: Samir S. Shah, MD, MSCE Accepted for Publication: July 29, 2013.
288
Figure 2. Medium-sized vessel with neutrophilic vasculitis (hematoxylin-eosin, original magnification ×100).
For this patient, the results of a further workup for systemic lupus erythematosus, including anti–Sjögren syndrome antigen A, anti– Sjögren syndrome antigen B, antiribonucleoprotein, anti-Sm, and anti–double-stranded DNA antibodies, were negative. A histologic examination of the skin biopsy sample of the lesion over the right anterior tibia revealed inflammation of medium-sized vessels in the subcutis with minimal associated panniculitis (Figure 2). Neutrophils and fibrin are present in the vessel wall. A biopsy of the skin over the left anterior tibia revealed a mixed inflammatory infiltrate composed of lymphocytes and histiocytes in the deep dermis and subcutaneous tissue; the epidermis was unremarkable. The infiltrate is predominantly perivascular, although no distinct damage and no small vessels were noted. These findings were diagnostic of polyarteritis nodosa. Sarcoidosis is unlikely with a normal chest radiograph and with no histological evidence of granulomas. Initially, the patient was treated with intermittent short courses of prednisone for symptom control. Minocycline therapy was discontinued. She had complete resolution of her symptoms, and her laboratory test results returned to normal. She continues to be asymptomatic 18 months after cessation of minocycline. Physicians should be aware of this serious but reversible adverse effect of this commonly used antibiotic. Early recognition and discontinuation results in a favorable outcome with complete resolution of the lesions.
Conflict of Interest Disclosures: Dr Dayal has served as a consultant and was on the speaker’s bureau for Abbott and Warner Chilcott. No other disclosures were reported.
2. Katada Y, Harada Y, Azuma N, et al. Minocycline-induced vasculitis fulfilling the criteria of polyarteritis nodosa. Mod Rheumatol. 2006;16(4):256-259.
Previous Presentation: The paper was presented at the American College of Physicians Internal Medicine 2012 Conference; April 20, 2012; New Orleans, Louisiana.
3. Schrodt BJ, Callen JP. Polyarteritis nodosa attributable to minocycline treatment for acne vulgaris. Pediatrics. 1999;103(2):503-504.
REFERENCES 1. Culver B, Itkin A, Pischel K. Case report and review of minocycline-induced cutaneous polyarteritis nodosa. Arthritis Rheum. 2005;53(3):468-470.
4. Schaffer JV, Davidson DM, McNiff JM, Bolognia JL. Perinuclear antineutrophilic cytoplasmic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris. J Am Acad Dermatol. 2001;44(2):198-206. 5. 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(4):396-398.
JAMA Pediatrics March 2014 Volume 168, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Georgia User on 05/24/2015
jamapediatrics.com
JAMA Pediatrics Clinical Challenge
Rare Adverse Effect of Treatment With Minocycline Ashika Odhav, MD; Chirag Odhav; Nimesh A. Dayal, MBBCh, MRCP, MSc
Figure 1. Ulcer with raised border and erythematous halo in distal right shin.
An 18-year-old woman presented with a 4-week history of a solitary painful bullous skin lesion over the lower right anterior tibia accompanied by generalized myalgia, polyarthalgia, joint stiffness, paraesthesia, and episodic ankle swelling. The lesion first appeared as a skin-colored papule and, within a week, developed an erythematous halo. Her medical history includes asthma and acne. To our knowledge, there is no family history of this condition. Her medications included minocycline hydrochloride (for 25 months for acne), ranitidine hydrochloride, contraceptive pills, and iron supplements. An initial physical examination revealed mild synovitis in both ankles and an erythematous, raised papule overlying the distal aspect of the right anterior tibia. Treatment with prednisone acetate (10 mg daily) was initiated. Seven weeks later, the original skin lesion evolved into an ulcer with erythematous, raised borders (Figure 1). The case patient had new erupQuiz at jamapediatrics.com tions of nonindurated, violaceous, nontender, reticulated patches overlying the skin on the bilateral anterior tibias, consistent with livedo reticularis. She denies any previous episodes, and the results of a review of mitigating factors were negative. A laboratory workup revealed a positive antinuclear antibody 1:640 nucleolar pattern, an elevated erythrocyte sedimentation rate, and elevated C-reactive protein and serum IgG levels. The results of the following laboratory studies were negative or normal: complete blood cell count, urinalysis, liver profile, Lyme disease, parvovirus B19, Monospot test, uric acid, rheumatoid factor, antistrepolysin antibody, anti-Scl70, antihepatitis C virus, hepatitis B surface antigen, hepatitis B core antibody, cytomegalovirus antibody, and human T-lymphotropic viruses 1 and 2 antibody. Culture results of the skin lesion were negative. The results from chest radiography were normal.
jamapediatrics.com
WHAT IS YOUR DIAGNOSIS?
A. Erythema nodosum B. Sarcoidosis C. Systemic lupus erythematosus D. Minocycline-induced cutaneous polyarteritis nodosa
JAMA Pediatrics March 2014 Volume 168, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Georgia User on 05/24/2015
287
Clinical Review & Education JAMA Pediatrics Clinical Challenge
Diagnosis D. Minocycline-induced cutaneous polyarteritis nodosa
Discussion The key clinical feature in this case is recognizing that this patient could have minocycline-induced cutaneous polyarteritis nodosa. Differential diagnosis includes erythema nodosum, sarcoidosis, systemic lupus erythematosus or other connective tissue disease, rheumatic fever, Lyme disease, parvovirus, minocycline-induced systemic lupus erythematosus, minocycline-induced hepatitis, lymphoma, drug reaction, and other vasculitis. To establish a definitive diagnosis requires performing a skin biopsy. The antibiotic minocycline is a semisynthetic tetracycline derivative that is widely used. Recently, attention has been paid to the rarer systemic adverse effects of minocycline-induced autoimmune disorders such as drug-induced lupus erythematosus, serum sickness, autoimmune hepatitis, polyarthritis, and vasculitis. This is a case report of minocycline-induced cutaneous polyarteritis nodosa. All reported cases1-5 described symptoms of generalized myalgia, polyarthritis, livedo reticularis, or subcutaneous nodules and histologic confirmation of vasculitis that met the American College of Rheumatology 1990 criteria for polyarteritis nodosa (at least 3 of 10 parameters).3 Idiopathic cutaneous polyarteritis nodosa is a necrotizing vasculitis of small and medium-sized arteries within the skin, without involvement of the internal organs. Culver et al1 proposed diagnostic guidelines for minocycline-induced cutaneous polyarteritis nodosa. Patients should fulfill 6 of the following 7 criteria: (1) minocycline use for more than 12 months; (2) skin manifestations, including livedo reticularis and/or subcutaneous nodules; (3) arthritis and/or myalgia and/or neuropathy in the distribution of the rash; (4) lack of systemic organ involvement; (5) skin biopsy sample showing necrotizing vasculitis of small and/or medium-sized vessels; (6) evidence of perinuclear antineutrophilic cytoplasmic antibodies; and (7) improvement after discontinuation of minocycline.1 Polyarteritis nodosa is usually self-limited, once minocycline is discontinued. In several cases,2,3 the syndrome will reoccur if rechallenged with minocycline. Previous case reports and case series1,3-5 have shown initial symptomatic improvement with short courses of prednisone. It is contraindicated to restart minocycline after this adverse effect has occurred. ARTICLE INFORMATION Author Affiliations: Department of Pediatrics, Children’s Mercy Hospital, Kansas City, Missouri (A. Odhav); College of Letters and Science, University of California, Berkeley (C. Odhav); Arthritis Center of Orlando, Orlando Health Central Hospital, Orlando, Florida (Dayal). Corresponding Author: Ashika Odhav, MD, Department of Pediatrics, Children’s Mercy Hospital, 4949 Wornall Rd, Unit 309, Kansas City, MO 64112 ([email protected]). Section Editor: Samir S. Shah, MD, MSCE Accepted for Publication: July 29, 2013.
288
Figure 2. Medium-sized vessel with neutrophilic vasculitis (hematoxylin-eosin, original magnification ×100).
For this patient, the results of a further workup for systemic lupus erythematosus, including anti–Sjögren syndrome antigen A, anti– Sjögren syndrome antigen B, antiribonucleoprotein, anti-Sm, and anti–double-stranded DNA antibodies, were negative. A histologic examination of the skin biopsy sample of the lesion over the right anterior tibia revealed inflammation of medium-sized vessels in the subcutis with minimal associated panniculitis (Figure 2). Neutrophils and fibrin are present in the vessel wall. A biopsy of the skin over the left anterior tibia revealed a mixed inflammatory infiltrate composed of lymphocytes and histiocytes in the deep dermis and subcutaneous tissue; the epidermis was unremarkable. The infiltrate is predominantly perivascular, although no distinct damage and no small vessels were noted. These findings were diagnostic of polyarteritis nodosa. Sarcoidosis is unlikely with a normal chest radiograph and with no histological evidence of granulomas. Initially, the patient was treated with intermittent short courses of prednisone for symptom control. Minocycline therapy was discontinued. She had complete resolution of her symptoms, and her laboratory test results returned to normal. She continues to be asymptomatic 18 months after cessation of minocycline. Physicians should be aware of this serious but reversible adverse effect of this commonly used antibiotic. Early recognition and discontinuation results in a favorable outcome with complete resolution of the lesions.
Conflict of Interest Disclosures: Dr Dayal has served as a consultant and was on the speaker’s bureau for Abbott and Warner Chilcott. No other disclosures were reported.
2. Katada Y, Harada Y, Azuma N, et al. Minocycline-induced vasculitis fulfilling the criteria of polyarteritis nodosa. Mod Rheumatol. 2006;16(4):256-259.
Previous Presentation: The paper was presented at the American College of Physicians Internal Medicine 2012 Conference; April 20, 2012; New Orleans, Louisiana.
3. Schrodt BJ, Callen JP. Polyarteritis nodosa attributable to minocycline treatment for acne vulgaris. Pediatrics. 1999;103(2):503-504.
REFERENCES 1. Culver B, Itkin A, Pischel K. Case report and review of minocycline-induced cutaneous polyarteritis nodosa. Arthritis Rheum. 2005;53(3):468-470.
4. Schaffer JV, Davidson DM, McNiff JM, Bolognia JL. Perinuclear antineutrophilic cytoplasmic antibody-positive cutaneous polyarteritis nodosa associated with minocycline therapy for acne vulgaris. J Am Acad Dermatol. 2001;44(2):198-206. 5. 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(4):396-398.
JAMA Pediatrics March 2014 Volume 168, Number 3
Copyright 2014 American Medical Association. All rights reserved.
Downloaded From: http://archpedi.jamanetwork.com/ by a University of Georgia User on 05/24/2015
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