Chronic Minocycline-Induced Autoimmunity in Children
Article Outline
Objective
To report our experience with minocycline-induced autoimmunity (MIA) in children, with an emphasis on the potential for chronicity.
Study design
Retrospective cohort study of patients with development of rheumatologic symptoms while receiving minocycline between 1996 and 2006.
Results
Twenty-seven children were diagnosed with MIA at a single pediatric rheumatology practice. The mean age at onset was 16.5 ± 1.39 years. The mean duration of minocycline use before diagnosis was 13.0 ± 10.8 months. All patients presented with constitutional symptoms. Twenty-two had polyarthralgia, and 17 had polyarthritis, mostly affecting hands and feet. On the basis of disease duration after discontinuation of minocycline, we divided subjects into 3 categories: transient, intermediate, and chronic. Seven patients had development of chronic autoimmune disease that was still active at last follow-up, a mean of 31.6 ± 13.0 (13-48) months after onset. Six patients followed an intermediate course, with resolution of symptoms within 12 months, and 14 patients had symptoms that resolved rapidly on discontinuation of minocycline. All patients with a chronic course had evidence of arthritis at presentation.
Conclusion
A substantial proportion of children with MIA had development of chronic symptoms with the potential for significant morbidity. Physicians who prescribe minocycline should be aware of its propensity for inducing potentially serious autoimmune phenomena.
Abbreviations: ANA, Anti-nuclear antibody, ANCA, Anti-neutrophil cytoplasmic antibody, DIL, Drug-induced lupus, DMARD, Disease modifying anti-rheumatic drugs, ELISA, Enzyme-linked immunosorbent assay, MIA, Minocycline induced autoimmunity, MPO, Myeloperoxidase
Minocycline was introduced in 1972 for treatment of acne vulgaris. It has become one of the most commonly used treatments for acne,1 prescribed for an estimated 15.2 million pediatric patients in the United States annually. Minocycline is a second-generation semisynthetic tetracycline derivative. It has good penetration through lipid membranes, including sebum. Once absorbed, minocycline is highly plasma protein bound, with a half-life of 16 to 18 hours. Minocycline has a large volume of distribution in tissues and fluids, with a particular affinity for tissues rich in collagen.1 All of these properties, in addition to the rare development of resistance, make minocycline a useful drug for long-term treatment of acne.
See editorial, p 303
Studies have shown that minocycline has immunomodulatory, antiinflammatory, antiangiogenic, and antiapoptotic effects. Immunomodulatory effects include decrease in polymorphonuclear chemotaxis, modification of complement pathways, inhibition of matrix metalloproteinase activity, and modulation of cytokine production.2 Because of these effects minocycline also has been used to treat autoimmune conditions, especially rheumatoid arthritis.3
The most common side effects of minocycline are gastrointestinal intolerance, vertigo, and a variety of rashes.4 Other less common but potentially more serious adverse effects include hypersensitivity reactions (serum sickness, hypersensitivity pneumonitis, pericarditis), pseudotumor cerebri, pancreatitis, and various autoimmune phenomena such as autoimmune hepatitis, drug-induced lupus (DIL), arthritis, and vasculitis.1, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14 Patients treated with minocycline might also have development of autoantibodies, including antinuclear antibody (ANA), antineutrophil cytoplasmic antibody (ANCA), and antiphospholipid antibodies, either in isolation or associated with clinical symptoms. There is significant overlap between all of these manifestations, suggesting that they represent variations of a single process.
Minocycline-associated adverse events that have been reported previously are generally transient and self-limited; autoimmune manifestations tend to resolve once the drug is stopped. In rare cases, patients have been treated with short courses of immunosuppressive therapy, most commonly systemic corticosteroids, or with long-term immunosuppression with other agents, such as azathioprine.5, 6, 7 It is not clear whether minocycline triggers an indolent autoimmune process in these patients with prolonged symptoms or merely causes a more persistent but ultimately self-limited process. The aim of this study is to report our experience with minocycline induced autoimmunity (MIA) in children, with an emphasis on the previously little-noted potential of the condition to become chronic.
Methods
Patient Population and Study Design
Because one of the characteristics of MIA is often a positive ANCA, all patients in whom this diagnosis is considered undergo ANCA testing at our program. Subjects for this study were identified from among children with samples sent for ANCA testing; those who did not receive minocycline were excluded. Of the 583 children screened for ANCA between September 1996 and September 2006, 33 met criteria for a diagnosis of MIA. These patients had a history of treatment with minocycline and clinical and laboratory findings suggestive of autoimmunity. Of the 33 patients, 6 patients were excluded because of inadequate follow-up to confirm disease course (4 patients) or age greater than 18 years (2 patients).
All medical records were reviewed, with emphasis on duration of minocycline use, dose of minocycline, presenting symptoms, findings on physical examination, laboratory data, therapies used, and outcome. The Institutional Review Board at Children's Hospital Boston approved this study.
Patients identified with apparent MIA were divided into 3 categories on the basis of disease duration after discontinuation of minocycline: transient (if they responded to minocycline withdrawal or required only a short course [<1 month] of nonsteroidal antiinflammatory drugs (NSAIDs) or corticosteroids); intermediate (if they required 1 month to 1 year of treatment NSAIDs or corticosteroids or another immunosuppressive agent, but their symptoms ultimately resolved within 1 year); or chronic (if they had active disease by clinical or laboratory criteria after the use of immunosuppressive medications for at least 1 year).
Laboratory Tests
All patients had measurements of serum transaminase levels, blood tests including routine biochemistry, erythrocyte sedimentation rate (Westergen), and C-reactive protein (nephelometry). ANA was measured by indirect immunofluorescence on Hep-2 cells at a screening dilution of 1:40. Anti-double-stranded DNA (anti ds-DNA), anti-extractable nuclear antigen panel, antihistone and antiphospholipid antibodies were measured by enzyme-linked immunosorbent assay (ELISA). ANCA testing was done with both indirect immunofluorescent staining and ELISA to myeloperoxidase (MPO) and proteinase-3.
Statistical Analysis
Categorical data and proportions were compared by use of the χ2 test or Fisher exact test, as indicated. Means were compared with the Student t test, and medians were compared by use of the Mann-Whitney U test. The Kruskal-Wallis test was applied to the ordinal variables. A value of P < .05 was considered statistically significant. SPSS software (version 11.0; SPSS, Chicago, Illinois) was used for statistical analysis.
Results
Demographic and Clinical Features
A total of 27 patients qualified for inclusion in the study. Nineteen were female (70%). The mean age (± SD) at onset of disease was 16.5 ± 1.39 years (range 13-18). All patients had used minocycline for treatment of acne.
Clinical manifestations of MIA were present for a mean of 4.33 ± 2.85 months (range 1-12) before a diagnosis of MIA was made. The mean duration of minocycline use before diagnosis was 13.0 ± 10.8 months (range 3-48). The median daily minocycline dose at onset of symptoms was 200 mg (range 150-200 mg). The median estimated cumulative dose from initiation of therapy until onset of MIA was 72.0 g (range 18-288 g). The demographic features of patients are shown in Table I. Mean follow-up duration was 22.3 ± 22.1 months (range 1-90) after the onset of symptoms. Twenty-two patients (81%) had a first-degree relative with at least 1 autoimmune disease (psoriasis, rheumatoid arthritis, systemic lupus erythematosus, thyroid disease, type 1 diabetes mellitus, multiple sclerosis, or sarcoidosis) (Table I).
Table I. Demographics, family history, minocycline exposure, duration of symptoms of patients with MIA
| Transient (n = 14) | Intermediate (n = 6) | Chronic (n = 7) | P value | |
|---|---|---|---|---|
| Female | 11 | 3 | 5 | .46 |
| Age at onset of disease (years), Mean (±SD) (range) | 16.1 ±1.14(13-18) | 17.1±1.60(14-18) | 16.5±1.13(15-18) | .33 |
| Time to clinical manifestations (mo), Mean (±SD) (range) | 3.78±2.7(1-12) | 5.33±3.82(1-12) | 4.6±2.51(1-7) | .39 |
| Duration of minocycline (mo), Mean (±SD) (range) | 13.0±9.8(3-36) | 14.6±17.3(1-48) | 11.8±7.62(4-24) | .88 |
| Estimated cumulative dose of minocycline (g), Median (range) | 72(18-216) | 72(18-288) | 72(27-108) | — |
| Family history of autoimmune disease | 12(85.7%) | 4(67%) | 6(86%).44 | |
| Psoriasis | 3 | 3 | 1 | |
| RA | 3 | 2 | 4 | |
| SLE | 1 | — | 1 | |
| Thyroid disease | 6 | 1 | 3 | |
| Type 1 DM | 2 | 1 | 2 | |
| Multiple sclerosis | 1 | 1 | — | |
| Sarcoidosis | — | 1 | — |
All patients came to medical attention with constitutional symptoms such as fever, weight loss, and malaise. Twenty-two (81.4%) patients had polyarthralgia, and 17 (62%) had polyarthritis. The joints most commonly affected were the small joints of the hands (82%), followed by the wrists (64%), ankles (35%), feet (35%), and shoulders (10%). Patients in the chronic MIA category had arthritis at presentation more frequently than did those in the other 2 groups (P = .026) (Table II). Eight (30%) patients had evidence of dermatologic manifestations including livedo reticularis. Raynaud's phenomenon was present in 6 (22%) and morning stiffness in 14 (51%) patients. In addition, most patients with chronic MIA (5/7) had development of features of nonarticular pain syndromes or fibromyalgia.
Table II. Patients' clinical manifestations at presentation
| Transient (n = 14) | Intermediate (n = 6) | Chronic (n = 7) | P value⁎ | |
|---|---|---|---|---|
| Constitutional findings† | 14 | 6 | 7 | .49 |
| Rash/Livedo reticularis | 5 | 2 | 1 | .71 |
| Arthritis | 7 | 3 | 7 | .026 |
| Arthralgia | 10 | 5 | 7 | .42 |
| Myalgia | 2 | 1 | 2 | .46 |
| Raynaud's phenomenon | 3 | 2 | 1 | .66 |
| Nail bed capillary change | — | — | 2 | .14 |
⁎A value of P < .05 was considered statistically significant. |
†Constitutional findings: fever, weight loss, malaise, oral ulcer, lymphadenopathy or headache. |
Laboratory Features
Erythrocyte sedimentation rate was increased in 12 of 24 patients (50%), and C-reactive protein was increased in 14 of 25 patients (56%). Leukopenia was present in 7 (26%) patients. Serum transaminase (AST, ALT) levels were mildly to moderately elevated (≤10 times upper limit of normal) in 11 of 27 (41%) patients. One patient had persistently elevated transaminases, leading to a liver biopsy, which was suggestive of autoimmune hepatitis (data not shown). He also had a positive ANA at a titer of 1:2560. Rheumatologic evaluation revealed that he was using minocycline for acne, and all abnormalities resolved once the minocycline was discontinued.
At least 1 ANA test result was positive in 20 of 27 (74%) patients, at titers varying from 1:40 to 1:2560; 35% were weakly positive (1:40-1:80), and 65% were positive at titers greater than 1:160 (Figure). Specific autoantibodies, including anti-dsDNA and extractable nuclear antigen panel, were negative in all patients except 1, who had a low-titer–positive anti-dsDNA antibody (patient 2). Antihistone antibodies were tested in 6 patients, and all were negative. At initial ANCA measurement, testing was positive in 18 of 27 (66.6%) patients. The pattern was perinuclear by immunofluorescent staining in 11 (61.1%) patients. ELISA testing revealed an anti-MPO specificity in all 11 patients who had perinuclear staining. The remaining 7 ANCA-positive patients (39%) had a nuclear staining pattern (atypical ANCA) with negative ELISA testing for anti-MPO antibodies. No patients had positive anti-proteinase-3 staining. There were no statistically significant differences in laboratory features among the 3 groups.
Figure.
ANA titers in patients with MIA.
Long-Term Outcomes
Seven (26%) patients had development of chronic autoimmune disease, primarily manifesting as persistent arthritis. At a mean of 31.2 ± 13.5 (13-48) months after onset, most of these patients continued to have active autoimmune disease at last follow-up (Table III). These patients required long-term immunosuppressive therapy with numerous agents in addition to corticosteroids, including methotrexate and anti-tumor necrosis factor–α agents. One of the patients (no. 2) in this group presented with small-joint arthritis, positive rheumatoid factor, ANA, ANCA, and anti-ds-DNA (low titer), but negative anti-Sm, anti-RNP and antihistone antibodies. She was initially treated with oral corticosteroids and methotrexate for presumed seropositive arthritis. However, her syndrome evolved into more of a lupuslike condition with development of diffuse proliferative glomerulonephritis (World Health Organization Class IV lupus nephritis) 4 years after diagnosis of MIA. She was treated with pulse methylprednisolone and mycophenolate mofetil.
Table III. Clinical and laboratory features, and their disease evolution and condition at last follow-up for patients with chronic MIA
| Patient | Symptoms | ANA titer/Pattern | ds-DNA | ENA | ANCA pattern | Therapy | Follow-up (mos) | Course |
|---|---|---|---|---|---|---|---|---|
| 1 | Arthritis Weight loss Fatigue | − | − | − | − | NSAID Corticosteroid Methotrexate Etanercept | 48 | Laboratory findings normalized in 27 mos. Remained symptomatic at last follow-up |
| 2 | Arthritis Fatigue | 1:160 homogeneous | + | − | Nuclear | NSAID Corticosteroid Methotrexate MMF | 43 | Lupuslike syndrome and DPGN developed at 42nd month |
| 3 | Arthritis Fever Weight lossFatigue | 1:640 homogeneous | − | − | Perinuclear | NSAID Corticosteroid Methotrexate Etanercept | 34 | Clinical and laboratory findings resolved in 20 months |
| 4 | Arthritis Fever | 1:320 homogeneous | − | − | Nuclear | Corticosteroid | 26 | Clinical and laboratory findings resolved in 15 mo except features of PAS |
| 5 | Arthritis Fatigue Raynaud's phenomenon | 1:320 nucleolar | − | − | − | Corticosteroid | 13 | Remained symptomatic at last follow-up |
| 6 | Arthritis Rash Weight loss | − | − | − | − | Corticosteroid Methotrexate | 36 | Remained symptomatic at last follow-up |
| 7 | Arthritis | 1:40 homogeneous | − | − | − | Corticosteroid Methotrexate | 13 | Remained symptomatic at last follow-up |
Six (22%) patients followed an intermediate course with eventual resolution of symptoms in less than 1 year. Most of these subjects required therapy with corticosteroids and NSAIDs. The remaining 14 (51.8%) patients had symptoms only transiently. They either responded to cessation of minocycline or required only a short therapeutic course of NSAIDs or corticosteroids (less than 30 days).
Discussion
The first cases of MIA appeared in the literature in the early 1990s. In 1 nested case control study, an 8.5-fold increased risk for development of DIL was found in patients using minocycline compared with nonusers and tetracycline users combined.15 We report 27 pediatric patients in whom autoimmunity developed after minocycline use. About one-fourth of these patients continued to have evidence of ongoing disease at last follow-up, an average of 32 months after minocycline was discontinued. This represents the largest cohort of children with chronic sequelae of minocycline use reported to date. There was no association between the duration of minocycline use, estimated cumulative dose of minocycline, and clinical course. The higher percentage of chronicity in our patients compared with previous reports cannot be explained by longer exposure to minocycline. The mean time that our patients received minocycline before disease onset was about 13 months, slightly shorter than the 18 to 25 months previously reported.1, 16 This is also a shorter duration of exposure than that reported in adults in whom autoimmune disorders developed after minocycline use.6
Patients with MIA typically present with constitutional symptoms such as fever, malaise, and decreased appetite, in addition to arthralgia and myalgia.7, 8, 10, 11, 12, 13, 16, 17, 18 All of our patients with a chronic course had arthritis at presentation, suggesting that it may be a predictor of the disease course (Table II). Further studies with larger patient numbers are needed to better delineate this possibility. Most of our patients with a chronic course (71.2%) also had development of features of pain amplification/fibromyalgia. In addition to musculoskeletal complaints, our patients also had a variety of features such as myalgia, Raynaud's phenomenon, and livedo reticularis, suggesting that the spectrum of MIA might be broader than recognized previously.
Autoimmune hepatitis of varying severities induced by minocycline has been reported.8, 16 In most of our patients hepatic abnormalities were mild and transient, except in 1 patient who required liver biopsy. The paucity of severe hepatitis in our cohort may represent improved recognition of this entity, and rapid discontinuation of minocycline in such children. Alternatively, if patients were evaluated in the gastroenterology clinic without ANCA testing, we might not have identified them for inclusion in our study. A limitation of our study is the restrictive method of case finding. It is not possible to comment on the rate or spectrum of MIA.
The pathogenesis of MIA remains unclear. The process may share some mechanisms with other triggers of drug-induced autoimmunity, including binding of intermediate metabolites to enzymes, hapten formation, unmasking of neoantigens, molecular mimicry, and cross-reactivity with self antigens such as microsomal cytochromes.19 Host susceptibility factors such as slow acetylator status, latent viral infections, and human leukocyte antigen (HLA) haplotypes most likely play a role in the pathogenesis of MIA as well.19 Possible associations with certain major histocompatibility complex genes (HLA-DR4, HLA-DR2, and HLA-DQB1) have already been shown, but definitive studies are lacking.20 Recent findings implicating a role of minocycline in caspase-dependent and -independent pathways of apoptosis, one of the mechanisms potentially responsible for autoimmune conditions such as systemic lupus erythematosus, suggest yet another possible mechanism for development of MIA.21
Unlike other drugs that cause DIL in proportions of males and females equal to the proportion taking the causative medication, the overwhelming majority of MIA cases involve females.2 Seventy percent of our cases were female. This is similar to the female preponderance in spontaneously occurring autoimmunity, despite the fact that 60% of minocycline prescriptions are given to males.5 Thus minocycline may differ fundamentally from other drugs that can trigger autoimmune syndromes, perhaps by unmasking an underlying predisposition to autoimmunity. The strong family histories of autoimmune conditions among subjects support this possibility. Although it is possible that patients had autoimmune diseases before starting minocycline and were merely discovered after its initiation, the resolution of findings within 1 year in 74% of our patients makes this hypothesis unlikely.
A unique panoply of autoantibodies also characterizes MIA, including positive ANA and ANCA. Marzo-Ortega et al9 showed high titer ANA positivity in 30% of their patients with MIA. In our study, high-titer ANA was found in about two thirds of patients. We did not see any tendency to higher titers in the chronic group. ANCA, too, may be integrally involved in the pathogenesis of the MIA syndrome.22 We observed that 18 (66.1%) patients had positive ANCA, most with anti-MPO specificity. This is similar to the percentage of patients in an earlier report.23 Other autoantibodies, such as anti-dsDNA and antiphospholipid antibodies, were rarely positive in our patients, similar to previous reports.16 In addition, antihistone antibodies are found less often in minocycline-induced autoimmunity than in other forms of DIL.1, 6, 19 This is consistent with our results: none of our patients who were tested had positive antihistone antibodies.
MIA is a rare condition. During a 10-year period, about 0.05% of all the children referred to the rheumatology clinic at a large tertiary care children's hospital had apparent autoimmune sequelae related to minocycline use.
In view of the widespread use of minocycline, particularly for treatment of acne in adolescents, MIA might well be more common than has been reported to date. The typically benign and self-limited nature of the phenomenon, as well as failure to consider a potential link between minocycline and constitutional or musculoskeletal symptoms, could lead to substantial underdiagnosis. It is important for physicians to be aware of the association between minocycline and development of chronic autoimmune conditions. The drug should be promptly discontinued in children with development of symptoms consistent with MIA. Additional data are needed to determine whether the risk/benefit ratio of minocycline justifies its continued use for the treatment of acne.
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PII: S0022-3476(08)00204-7
doi:10.1016/j.jpeds.2008.03.013
© 2008 Mosby, Inc. All rights reserved.
Refers to article:
- Autoimmunity and Minocycline
