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Minocycline-induced Autoimmune Syndromes: Report of a Case and
Review of the Literature
Minocycline is commonly used in the treatment of acne vulgaris and rosacea. In recent years, its efficacyin rheumatoid arthritis (RA) was established. Cases of minocycline-induced autoimmune syndromes havebeen reported. We described the first report of a Chinese patient who developed minocycline-inducedvasculitis and performed a literature review on this topic. Physicians should be aware of this adverse effectof minocycline.
Anti-MPO, autoimmune syndromes, Minocycline, p-ANCA, vasculitis
Throughout years, cases of minocycline-induced autoimmunesyndromes have been reported. In this article, we reported a
Minocycline is a semi-synthetic tetracycline with improved
Chinese patient with minocycline-induced vasculitis and
anti-bacterial activity, oral availability and longer half-life. It
discussed on the various minocycline-induced autoimmune
is commonly used to treat acne vulgaris and rosacea which
often requires months to years' therapy. Apart from this, it isalso recognized as having anti-inflammatory, immuno-modulatory, and inhibitory effects on matrix metallo-
proteinases. In recent years, it has been used as a diseasemodifying agent in rheumatoid arthritis (RA). Its role is
A 47-year-old Chinese lady presented in May 2000 with
established by three randomized double-blinded placebo-
3-day history of fleeting polyarthralgia of the small and large
controlled trials.1-4 It is found to be more effective than
joints. She had a long history of rosacea with regular follow
hydroxychloroquine in early seropostive RA.5 Moreover,
up by the dermatologists and was maintained on 100 mg
it is also used in treating Lyme disease and reactive
minocycline daily for 10 years. In the recent year, she noticed
to have reticular skin rash over her limbs with Raynaud'sphenomenon and numbness over her ankles. Apart from livedo
Minocycline is generally considered a safe drug.7 Reported
reticularis (Figure 1), physical examination was unremarkable.
adverse effects include gastrointestinal toxicity, nephritis,
She was afebrile with no signs of active arthritis.
vestibular symptoms, skin hyperpigmentation, intracranialhypertension, photosensitivity, rashes, eosinophilia, fever,
Initial investigations showed normochromic normocytic
hypersensitivity pneumonitis and toxic hepatitis.7,8
anaemia with hemoglobin (Hgb) level of 10.6 g/dL anderythrocyte sedimentation rate (ESR) of 64 mm/hr. Albuminwas 33 g/dL and globulin was 57 g/dL with a polyclonal
increase in globulin. Renal and liver functions were normal.
EPARTMENT OF MEDICINE & GERIATRICS, PRINCESS MARGARET
Urine protein was negative. Rheumatoid factor was negative
OSPITAL, LAI CHI KOK, KOWLOON, HONG KONG SAR
and antinuclear antibody (ANA) was 1:160. Anti-dsDNA and
anti-extractable nuclear antigen (anti-ENA) were negative.
Complements (C3 and C4) were normal. Perinuclear-
antineutrophil cytoplasmic antibody (p-ANCA) was positive
showed demyelination and axonal degeneration with nodefinite vasculitis. She started to develop Raynaud'sphenomenon of her toes and an increase in the extent of livedoreticularis. As minocycline had been stopped for 4 monthsand there were persistent symptoms, prednisolone wascommenced at a dose of 0.5 mg/kg/day.
She responded partially to steroid treatment with animprovement in ankle movement. Steroid dose was graduallytailed down. The biochemical and serological markersgradually normalized (ESR 7 mm/hr, Hgb 12.1 g/dL, albumin/globulin 46/36 g/dL and anti-MPO turned negative). Herneuralgic pain improved slowly but numbness of the feet andlivedo reticularis persisted.
Our patient illustrates a case of minocycline-induced vasculitiswith polyarthralgia, livedo reticularis, peripheral neuropathy,positive ANA, anti-MPO and aCL antibodies.
Minocycline-induced autoimmune syndromes can becategorized into 4 types, namely minocycline-induced serumsickness, minocycline-induced lupus, minocycline-induced
autoimmune hepatitis (AIH) and minocycline-inducedvasculitis. The clinical and serological features of the separate
with elevated anti-myeloperoxidase (anti-MPO) level of 30
syndromes may overlap.8 Minocycline-induced lupus and
U/ml (normal <5). Cryoglobulin was negative. Anti-
hepatitis are the most common events. On reviewing the
cardiolipin antibodies (aCL) were elevated with IgG 34 GPL/
literature, over 60 cases of minocycline-induced lupus and
ml (normal <15) and IgM 33 MPL/ml (normal <12.5). Lupus
24 cases of minocycline-induced AIH have been reported. In
13 cases, both syndromes coexist.6 Except for serum sickness,which presents shortly (mean 16 days) after minocycline, the
Minocycline was stopped. Non-steroidal anti-inflammatory
other autoimmune syndromes manifest after prolonged use
drug was given for arthralgia. Skin biopsy performed on her
right thigh showed features of leucocytoclastic vasculitis.
Immunofluorescence was negative. She was put on aspirin
Minocycline-induced Serum Sickness
and persantin as suggested by the dermatologist.
Clinical features include fever, arthralgia, lymphadenopathyand urticarial rash a few days after starting minocycline. This
On follow up 4 weeks later, she had no more arthralgia but
condition is self-limiting and symptoms subside soon after
still complained of numbness of her feet. Physical examination
reviewed loss of pinprick sensation on the dorsum of her feet.
Propioception was intact. Diminished muscle power was noted
on dorsiflexion and plantar flexion of both feet.
This is the commonest entity. It is defined as a syndrome withat least one clinical feature of systemic lupus erythematosus
Nerve conduction study showed combined motor and sensory
(SLE), positive ANA together with circumstantial association
peripheral neuropathy. Sural nerve biopsy was performed and
between the use of drug and development of clinical and
serological features. It has been estimated that minocycline is
persistent decline in p-ANCA and anti-MPO supported a
associated with an 8.5 fold increased risk of developing a
cause-effect relation.14 In 2 case series, patients developed
lupus-like syndrome.9 It can cause disease exacerbation in
recurrence of symptoms soon after rechallenge with
cases of probable SLE. It occurs more frequently in female
(female to male ratio = 8:1) suggesting that male sex mightpossess protective factor.10 Most patients remit within few
Diagnosis of the condition is difficult. There is a great
days after drug withdrawal, a few need a short course of
variability in time course of development among reported
corticosteroid. There was a case report of death from
cases, and there are no confirmatory test. Clues to diagnosis
rely on a temporal association between the use of drug andthe development of clinical/serological features supported by
Minocycline-induced Autolimmune Hepatitis (AIH)
resolution upon drug cessation. Relapse on rechallenge further
Patients develop variable degree of elevated serum
transaminases (2-10 fold) which usually normalize within 3months after drug cessation.9 Serum level of alkaline
Elkayam et al. confirmed that p-ANCA characterized
phosphatase is usually normal. In the literature, one patient
minocycline-induced vasculitis syndrome and seemed to be
died with severe hepatitis and another required liver
more common than ANA.9 Association of ANCA with drug-
induced diseases has been reported for procainamide,hydralazine, anti-thyroid drug and penicillamine.15 These
Thirteen cases have been reported to have coexisting
drugs share a common metabolic transformation to cytotoxic
minocycline-induced lupus and minocycline-induced AIH.6
metabolites that depends on exposure to myeloperoxidase
They all presented with symmetrical polyarthralgia/
activity of activated neutrophils.16 The cytotoxic capacity
polyarthritis. More than half had fever, weight loss, malaise
gained by the reactive intermediate leads to immune
and rash. Two had extra-articular/extra-hepatic involvement
dysregulation that may eventually culminate in an
with Hashimoto thyroiditis and peripheral neuropathy. All
autoimmune syndrome. Minocycline shares the capacity to
patients had positive ANA predominantly homogenous
pattern. Acute phase reactants were elevated. Majority of themhad rapid remission after drug cessation but one patient
Genetic factors have also been postulated for the development
required a 2-year course of immunosuppressive therapy.
of p-ANCA associated immune phenomenon. Four out of 6patients in a Israel series had HLA-DRB1*1104 as compared
to a frequency of 12% in general Israel population. It may
Common presentations include fever, arthralgia, symmetrical
represent a genetic susceptibility marker of minocycline
polyarthritis, cutaneous (livedo reticularis and subcutaneous
associated immune phenomenon in Israel patients.9 Recent
nodules), renal and hepatic involvement. A common
studies have reported an association with HLA-DR4.18
serological marker is high titer of p-ANCA and the presenceof anti-MPO.
In contrast to 'classic drug-induced lupus' in which antihistoneantibodies are present in more than 95% of patients,19 this
Thirteen cases (3 male and 10 female) have been reported.12
antibody is seldom reported in minocycline-induced
There was no mortality. Their age ranged from 15 to 35 with
autoimmune disease. On the other hand, elevated levels of
duration of drug exposure ranging from 9 days to 9 months.
anti-cardiolipin antibodies have been reported.9,13
Average daily dose was 100 mg. In 3 cases, vasculitis occurredafter minocycline was renewed with previous uneventful
Use of minocycline for treatment of RA was established
course. A 15-year-old girl developed polyarteritis nodosa
in randomized controlled trials.1-4 There was no report of
(PAN) with livedo reticularis, diffuse myalgia and arthralgia.
minocycline-induced autoimmune syndrome among the
Skin biopsy demonstrated small and medium sized vasculitis
345 RA patients in the trials. In a small study, two out of
30 RA patients developed unexplained hepatitis thatresolved on withdrawal of treatment.11 There was one case
Eleven patients had complete resolution of symptom after drug
report of minocycline-induced lupus-like syndrome in RA
cessation while 2 required a course of prednisone. Slow but
It is difficult to diagnose drug-induced autoimmune
Gordon MM, Porter D. Minocycline induced lupus: case
phenomenon in RA patients as elevated ESR and
series in the West of Scotland. J Rheumatol 2001;28:
polyarthralgia/polyarthritis may reflect disease activity. New
Elkayam O, Yaron M, Caspi D. Minocycline-induced
rheumatic symptoms, newly emerged ANA and the absence
autoimmune syndromes: an overview. Semin Arthritis Rheum
of elevated C-reactive protein warrant a high suspicion for
patients taking long-term minocycline. To make the issue more
Elkayam O, Levartovsky D, Brautbar C, et al. Clinical and
complicated, minocycline was found to be effective in treating
immunological study of 7 patients with minocycline-induced
RA-related leucocytoclastic vasculitis.21 Additional clinical
autoimmune phenomena. Am J Med 1998;105:484-7.
research is needed to document the long-term efficacy: toxicity
Masson C, Chevailler A, Pascaretti C, Legrand E, Bregeon C,Audran M. Minocycline related lupus. J Rheumatol 1996;23:
Gough A, Chapman S, Wagstaff K, Emery P, Elias E.
Minocycline induced autoimmune hepatitis and systemic lupus
erythematosus-like syndrome. BMJ 1996;312:169-72.
ten Holder SM, Joy MS, Falk RJ. Cutaneous and systemic
Minocycline is increasingly used in the treatment of rheumatic
manifestations of drug-induced vasculitis. Ann Pharmacother
diseases and side effects are going to be encountered more
Schrodt BJ, Callen JP. Polyarteritis nodosa attributable to
frequently. It is advisable to perform periodic liver function
minocycline treatment for acne vulgaris. Pediatrics 1999;103:
tests and ANA accompanied with clinical surveillance for
patients on long-term minocycline.23 Patients should be
Elkayam O, Yaron M, Caspi D. Minocycline induced arthritis
informed of these rare but potentially serious adverse effects,
associated with fever, livedo reticularis, and pANCA. Ann
and if happen, they should be advised to avoid all tetracycline
since information on potential cross-reactivity is not available.24
Merkel PA. Drug associated with vasculitis. Curr Opin
Rechallenge of the drug is not recommended given a large
Jiang X, Khursigara G, Rubin RL. Transformation of lupus-
number of alternative treatment options available.
inducing drugs to cytotoxic products by activated neutrophils.
McHugh NJ, Dunphy J, Rands A, Hill C. Antimyeloperoxidase
antibodies in minocycline induced lupus syndrome andmyeloperoxidase independent drug toxicity. Arthritis Rheum
Kloppenburg M, Breedveld FC, Terwiel JP, Mallee C,
Dijkmans BA. Minocycline in active rheumatoid arthritis. A
Dunphy J, Oliver M, Rands AL, Lovell CR, McHugh NJ.
double-blind, placebo-controlled trial. Arthritis Rheum 1994;
Antineutrophil cytoplasmic antibodies and HLA class II alleles
in minocycline-induced lupus-like syndrome. Br J Dermatol
Tilley BC, Alarcon GS, Heyse SP, et al. Minocycline in
rheumatoid arthritis. A 48-week, double-blind, placebo-
Dubois EL, Wallace DJ. Drugs that exacerbate and induce
controlled trial. MIRA Trial Group. Ann Intern Med 1995;
systemic lupus erythematosus. Lea and Febiger, 5th ed.
O'Dell JR, Haire CE, Palmer W, et al. Treatment of early
Marzo-Ortega H, Misbah S, Emery P. Minocycline induced
rheumatoid arthritis with minocycline or placebo: results of a
autoimmune disease in rheumatoid arthritis: a missed
randomized, double-blind, placebo-controlled trial. Arthritis
diagnosis? J Rheumatol 2001;28:377-8.
Houck HE, Kauffman CL, Casey DL. Minocycline treatment
O'Dell JR, Paulsen G, Haire CE, et al. Treatment of early
for leukocytoclastic vasculitis associated with rheumatoid
seropositive rheumatoid arthritis with minocycline: four-year
arthritis. Arch Dermatol 1997;133:15-6.
followup of a double-blind, placebo-controlled trial. Arthritis
Griffiths B, Gough A, Emery P. Minocycline-induced
autoimmune disease: comment on the editorial by Breedveld.
O'Dell JR, Blakely KW, Mallek JA, et al. Treatment of early
seropositive rheumatoid arthritis: a two-year, double-blind
Angulo JM, Sigal LH, Espinoza LR. Minocycline induced
comparison of minocycline and hydroxychloroquine. Arthritis
lupus and autoimmune hepatitis. J Rheumatol 1999;26:
Angulo JM, Sigal LH, Espinoza LR. Coexistent minocycline-
Knowles SR, Shapiro L, Shear NH. Serious adverse reactions
induced systemic lupus erythematosus and autoimmune
induced by minocycline. Report of 13 patients and review of
hepatitis. Semin Arthritis Rheum 1998;28:187-92.
the literature. Arch Dermatol 1996;132:934-9.
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