Minocycline-associated rimmed vacuolar myopathy in a patient with rheumatoid arthritis
© Bokuda et al.; licensee BioMed Central Ltd. 2012
Received: 8 September 2012
Accepted: 20 November 2012
Published: 21 November 2012
The autophagic vacuolar myopathies (AVM) are a group of inherited myopathies defined by the presence of autophagic vacuoles in pathological muscle specimens. AVM can be categorized into three groups: acid maltase deficiency, myopathies characterized by autophagic vacuoles with unique sarcolemmal features, and rimmed vacuolar myopathies (RVM). While the pathogeneses of these conditions are still being elucidated, some drugs (e.g., chloroquine, its analog, hydroxychloroquine, and colchicine) can also cause AVM. Minocycline is a disease-modifying anti-rheumatic drug that may be used in the treatment of rheumatoid arthritis (RA). Here, we describe the first case of minocycline-associated AVM with rimmed vacuole formation.
A 75-year-old woman suffering from RA has been continuously treated with minocycline (200 mg/day) for the past 7 years. During this time, she developed a myopathy that predominantly affected her lower limbs. Histological studies of biopsied muscle revealed scattered atrophic myofibers with rimmed vacuoles that contained pigment granules. Histochemical staining revealed that the pigment comprised both iron and melanin, which is consistent with type II minocycline-induced cutaneous pigmentation. Under electron microscopy, autophagic vacuoles were consistently observed in association with numerous collections of pigment granules.
This is the first report of minocycline-induced pigmentation in skeletal muscle. The strong association between autophagic vacuoles and the accumulation of minocycline-induced pigments suggest that long-term minocycline treatment induced pigment accumulation, leading to elevation of autophagic activity and RVM. It might also be possible that minocycline directly activated autophagy, as the observed pigments are known to form complexes containing minocycline and/or its metabolites. As long-term minocycline treatment is expected to be used more widely in the future, we must draw attention to this adverse effect.
KeywordsMinocycline Autophagic vacuole Rimmed vacuolar myopathy Minocycline-induced pigmentation Rheumatoid arthritis
Autophagy, which is a lysosomal degradation pathway that is essential for cell survival , plays a key role in the pathogenesis of several inherited myopathies; these include autophagic vacuolar myopathies (AVM)  as well as the drug-induced AVM caused by chloroquine, hydroxychloroquine and colchicine [3, 4]. Both inhibition and activation of autophagy can lead to the appearance of autophagic vacuoles in pathological muscle specimens [1, 2]. In addition to the best characterized AVM, Pompe disease, two other categories of AVM have recently emerged. One is Danon disease and its related disorders, which are characterized by autophagic vacuoles with unique sarcolemmal features . The other is typified by the presence of rimmed vacuoles (vacuoles within myofibers that are lined with blue granular material following hematoxylin-eosin staining or with red material following modified Gomori trichrome staining); electron microscopy has revealed that these are actually clusters of autophagic vacuoles .
Minocycline is a semi-synthetic derivative of tetracycline that functions as a broad-spectrum antimicrobial agent and has proven to be a moderately effective disease-modifying anti-rheumatic drug in the treatment of rheumatoid arthritis (RA) . The drug is generally well tolerated, but long-term use of minocycline (100 to 200 mg/day), especially in the management of acne vulgaris or RA, can be associated with a number of side effects. The most common adverse drug reactions are photosensitivity and esophagitis, while the rarer adverse events include severe allergic reactions, such as Stevens-Johnson syndrome, systemic lupus erythematosus, serum sickness, autoimmune hepatitis, vasculitis and dermatomyositis [7, 8]. Long-term use of minocycline can also cause pigmentation, which is a well-recognized adverse effect that affects the skin and other organs . To our knowledge, this is the first report of rimmed vacuolar myopathy (RVM) associated with long-term minocycline treatment, wherein cluster of autophagic vacuoles are associated with the accumulation of minocycline-induced pigmentation.
A 75-year-old woman was admitted to our hospital due to a 2-year history of gradually progressive gait disturbance. She had suffered from RA since the age of 25. Because of an exacerbation of this disease, she started taking prednisolone (5 mg/day) and sulfasalazine at 67 years, and had been continuously treated with minocycline (200 mg/day) since the age of 68. She noticed a gradual increase in blue-black skin pigmentation on both legs at 72 years. Thereafter, she began to have difficulty walking, and would frequently catch the tip of her foot on the ground. No exposure to other drugs known to cause pigmentary changes was recorded.
In addition to the standard battery of histological stains, the sural nerve biopsy specimen was embedded in epoxy resin and examined by light and electron microscopy. Light microscopy of the sural nerve showed a reduction in the number of large diameter myelinated fibers, but no other specific features (Figure 3F). However, Prussian blue and Masson Fontana staining revealed perivascular deposits of iron and melanin in the epineurial blood vessels. Electron microscopy revealed a few highly electron-dense granules in the cytoplasm of Schwann cells, where the myelin sheath was disrupted (Figure 3G).
The incidences of minocycline-induced cutaneous pigmentation have been reported in up to 41% of patients with RA who take minocycline . Histochemical staining for pigmented substances (e.g., iron, melanin) has shown that minocycline-induced cutaneous pigmentation can be classified into three or four distinct types . In the present study, histochemical staining of the biopsied muscle demonstrated that the pigments comprised iron and melanin, which is consistent with type II minocycline-induced cutaneous pigmentation . Iron deposition in skeletal muscle has rarely been described in some disorders, including idiopathic hemochromatosis, transfusion induced hemosiderosis, diabetic neuropathy, Waldenstrom’s macroglobulinemia, and AIDS patients [12–14]. Laboratory investigations of our patient showed no evidence of these conditions. No previous study has reported melanin deposition in human skeletal muscle, except for cases of melanoma invasion. Here, we report the first identification of minocycline-induced pigmentation (comprising iron and melanin) in skeletal muscle.
The sural nerve biopsy demonstrated the features of a chronic axonal neuropathy, with minimal pigment observed in the cytoplasm of Schwann cells. Only a few cases of minocycline-associated sensory neuropathy have been reported, and axonal-type sensory neuropathy is a common complication in RA . Thus, it is unclear whether or not the sensory neuropathy observed in our patient is related to minocycline therapy.
One year after the cessation of minocycline therapy, our patient exhibited no worsening of gait disturbance. There was little improvement in muscle weakness, however, perhaps because she had taken minocycline for an extremely long duration even after the appearance of skin pigmentation. This is an unusual condition. However, long-term minocycline treatment may be used more widely in the future, as on-going clinical trials are assessing the therapeutic use of minocycline as an anti-inflammatory agent in a broad range of disorders. Thus, we must draw attention to this adverse effect because its insidious onset, slowly progressive course, and lack of creatine kinase elevation could complicate its prompt identification in patients.
Chloroquine and hydroxychloroquine are anti-malarial drugs that are also used to treat RA and systemic lupus erythematosus. Hydroxychloroquine is used much more frequently than chloroquine, as the latter is more likely to cause irreversible retinal damage. Long-term hydroxychloroquine treatment rarely causes myopathy and sensory neuropathy; the former typically manifests with an insidious onset and normal-to-mildly-elevated creatine kinase levels, and muscle biopsy consistently reveals curvilinear bodies and muscle fiber atrophy with vacuolar changes [3, 22]. After the therapy is discontinued, the resolution of symptoms is slow and may be incomplete. In rare cases, long-term hydroxychloroquine treatment can also cause skin pigmentation . In all reported cases, the main histological feature of hydroxychloroquine-induced pigmentation was the presence of iron and melanin deposits in the dermis . These features are very similar to those observed in our patient, who had never taken the anti-malarial drugs, suggesting that there may be a common pathogenic mechanism underlying these conditions. Hydroxychloroquine myopathy is usually of mild to moderate severity, but a few case of severe hydroxychloroquine myopathy, involving respiratory muscles and/or cardiac myocytes, have been reported [24, 25]. However, our patient did not have any symptoms related to respiratory or cardiac dysfunction. Chloroquine and hydroxychloroquine accumulate within lysosomes and are thought to block autophagy by elevating intralysosomal pH and inhibiting lysosomal enzymes [26, 27]. However, the exact mechanism underlying myocyte toxicity is unclear. In the future, it will be particularly interesting to examine whether iron and melanin are deposited in the muscles of hydroxychloroquine myopathy patients.
Minocycline has proven to be an effective disease-modifying anti-rheumatic drug. However, we herein report for the first time that long-term minocycline treatment may cause RVM via the accumulation of minocycline-induced pigmentation in skeletal muscle. The clinical features of minocycline-associated RVM are very similar to those observed in hydroxychloroquine myopathy, suggesting that there may be a common pathogenic mechanism underlying these conditions. As long-term minocycline treatment may be used more widely in the future, we must draw attention to this adverse effect.
Written informed consent was obtained from the patient for publication of this case report. A copy of the written consent is available for review by the Editor-In-Chief of this journal.
Autophagic vacuolar myopathy
Rimmed vacuolar myopathy
TAR-DNA binding protein-43
Distal myopathy with rimmed vacuoles.
This study was funded by the Tokyo Metropolitan Government.
- Levine B, Kroemer G: Autophagy in the pathogenesis of disease. Cell. 2008, 132: 27-42. 10.1016/j.cell.2007.12.018.PubMed CentralView ArticlePubMed
- Nishino I: Autophagic vacuolar myopathy. Semin Pediatr Neurol. 2006, 13: 90-95. 10.1016/j.spen.2006.06.004.View ArticlePubMed
- Casado E, Gratacos J, Tolosa C, Martinez JM, Ojanguren I, Ariza A, Real J, Sanjuán A, Larrosa M: Antimalarial myopathy: an underdiagnosed complication? Prospective longitudinal study of 119 patients. Ann Rheum Dis. 2006, 65: 385-390. 10.1136/ard.2004.023200.PubMed CentralView ArticlePubMed
- Kuncl RW, Duncan G, Watson D, Alderson K, Rogawski MA, Peper M: Colchicine myopathy and neuropathy. N Engl J Med. 1987, 316: 1562-1568. 10.1056/NEJM198706183162502.View ArticlePubMed
- Nishino I: Eludication of pathomechanism of and development of therapy for autophagic vacuolar myopathy. Rinsho Shinkeigaku. 2010, 50: 1-6. 10.5692/clinicalneurol.50.1.View ArticlePubMed
- Smith CJ, Sayles H, Mikuls TR, Michaud K: Minocycline and doxycycline therapy in community patients with rheumatoid arthritis: prescribing patterns, patient-level determinants of use, and patient-reported side effects. Arthritis Res Ther. 2011, 13: R168-10.1186/ar3491.PubMed CentralView ArticlePubMed
- Joshi H, Chhikara V, Arya K, Pathak R: Some undesirable effects reported in past five years related to minocycline therapy: a review. Ann Biol Res. 2010, 1: 64-71.
- Geddes MR, Sinnreich M, Chalk C: Minocycline-induced dermatomyositis. Muscle Nerve. 2010, 41: 547-549. 10.1002/mus.21487.View ArticlePubMed
- Eisen D, Hakim MD: Minocycline-induced pigmentation. Incidence, prevention and management. Drug Saf. 1998, 18: 431-440. 10.2165/00002018-199818060-00004.View ArticlePubMed
- Roberts G, Capell HA: The frequency and distribution of minocycline induced hyperpigmentation in a rheumatoid arthritis population. J Rheumatol. 2006, 33: 1254-1257.PubMed
- Mouton RW, Jordaan HF, Schneider JW: A new type of minocycline-induced cutaneous hyperpigmentation. Clin Exp Dermatol. 2004, 29: 8-14. 10.1111/j.1365-2230.2004.01421.x.View ArticlePubMed
- Griggs RC, Markesbery WR, Bauman AW, Callerame ML: Perivascular hemosiderin deposition in muscle in Waldenstrom’s macroglobulinemia. J Neurol Sci. 1975, 25: 153-163. 10.1016/0022-510X(75)90137-9.View ArticlePubMed
- Gherardi RK, Mhiri C, Baudrimont M, Roullet E, Berry JP, Poirier J: Iron pigment deposits, small vessel vasculitis, and erythrophagocytosis in the muscle of human immunodeficiency virus-infected patients. Hum Pathol. 1991, 22: 1187-1194. 10.1016/0046-8177(91)90100-4.View ArticlePubMed
- Davis DG, Markesbery WR: Perivascular siderophages in skeletal muscle from a patient with diabetic neuropathy. Acta Neuropathol. 1992, 84: 216-220. 10.1007/BF00311399.View ArticlePubMed
- Agarwal V, Singh WR, Chauhan S, Tahlan A, Ahuja CK, Goel D, Pal L: A clinical, electrophysiological, and pathological study of neuropathy in rheumatoid arthritis. Clin Rheumatol. 2008, 27: 841-844. 10.1007/s10067-007-0804-x.View ArticlePubMed
- Lee HS, Daniels BH, Salas E, Bollen AW, Debnath J, Margeta M: Clinical utility of LC3 and p62 immunohistochemistry in diagnosis of drug-induced autophagic vacuolar myopathies: a case–control study. PLoS One. 2012, 7: e36221-10.1371/journal.pone.0036221.PubMed CentralView ArticlePubMed
- Küsters B, van Hoeve BJ, Schelhaas HJ, Ter Laak H, van Engelen BG, Lammens M: TDP-43 accumulation is common in myopathies with rimmed vacuoles. Acta Neuropathol. 2009, 117: 209-211. 10.1007/s00401-008-0471-2.View ArticlePubMed
- Liu WT, Lin CH, Hsiao M, Gean PW: Minocycline inhibits the growth of glioma by inducing autophagy. Autophagy. 2011, 7: 166-175. 10.4161/auto.7.2.14043.View ArticlePubMed
- Du B, Zhang Y, Tang Y, Wang P: Minocycline attenuates ototoxicity and enhances antitumor activity of cisplatin treatment in vitro. Otolaryngol Head Neck Surg. 2011, 144: 719-725. 10.1177/0194599810395090.View ArticlePubMed
- Okada N, Moriya K, Nishida K, Kitano Y, Kobayashi T, Nishimura H, Aoyama M, Yoshikawa K: Skin pigmentation associated with minocycline therapy. Br J Dermatol. 1989, 121: 247-254. 10.1111/j.1365-2133.1989.tb01807.x.View ArticlePubMed
- Nathaniel ST, Daniel M, Sook-Bin W: Oral mucosal pigmentation secondary to minocycline therapy: report of two cases and a review of the literature. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2004, 97: 718-725. 10.1016/j.tripleo.2003.11.006.View Article
- Stein M, Bell MJ, Ang LC: Hydroxychloroquine neuromyotoxicity. J Rheumatol. 2000, 27: 2927-2931.PubMed
- Puri PK, Lountzis NI, Tyler W, Ferringer T: Hydroxychloroquine-induced hyperpigmentation: the staining pattern. J Cutan Pathol. 2008, 35: 1134-1137. 10.1111/j.1600-0560.2008.01004.x.View ArticlePubMed
- Siddiqui AK, Huberfeld SI, Weidenheim KM, Einberg KR, Efferen LS: Hydroxychloroquine-induced toxic myopathy causing respiratory failure. Chest. 2007, 131: 588-590. 10.1378/chest.06-1146.View ArticlePubMed
- Abdel-Hamid H, Oddis CV, Lacomis D: Severe hydroxychloroquine myopathy. Muscle Nerve. 2008, 38: 1206-1210. 10.1002/mus.21091.View ArticlePubMed
- de Duve C, de Barsy T, Poole B, Trouet A, Tulkens P, Van Hoof F: Commentary: lysosomotropic agents. Biochem Pharmacol. 1974, 23: 2495-2531. 10.1016/0006-2952(74)90174-9.View ArticlePubMed
- Stauber WT, Hedge AM, Trout JJ, Schottelius BA: Inhibition of lysosomal function in red and white skeletal muscles by chloroquine. Exp Neurol. 1981, 71: 295-306. 10.1016/0014-4886(81)90090-X.View ArticlePubMed
- The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/12/140/prepub
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