Geissal, Erik D. MD; Wernick, Richard MD
The overlap of relapsing polychondritis (RP) and Behcet disease was dubbed MAGIC syndrome by Firestein et al in 1985 as an acronym for mouth and genital ulcerations with inflamed cartilage.1 RP itself is a multisystem autoimmune disorder with protean manifestations. Its hallmark is cartilaginous inflammation that typically involves the ears, nose, eyes, peripheral joints, and tracheobronchial tree; it can coexist with a systemic vasculitis. RP, as its name suggests, progresses in a fluctuating manner, and without treatment can result in permanent destruction of the affected body part.2
Dramatic resolution of RP symptoms can often be achieved with corticosteroids, but not all patients respond adequately. In the absence of randomized trials, clinicians have used nonsteroidal anti-inflammatory drugs, colchicine, hydroxychloroquine, dapsone, methotrexate, azathioprine, cyclophosphamide, and cyclosporine to control the disease, but response is variable.3
In this report, we describe a challenging case of treatment-resistant MAGIC syndrome that responded completely to infliximab therapy.
A 34-year-old male taxi driver with a history of asthma suddenly developed nasal swelling and pain in October 2004. He also experienced epistaxis, headaches, maxillary tooth pain, mouth sores, and a hoarse voice. Ibuprofen partially relieved his symptoms. Two months later, he experienced severe cough productive of thick mucus. In December 2004, he presented to his primary care physician with these symptoms as well as sinus pain, low-grade fever, headaches, hemoptysis, and drenching night sweats. He was diagnosed with a sinus infection and given 3 weeks of antibiotics and antitussives, with no relief. Prednisone 50 mg daily for 5 days led to dramatic resolution of his symptoms.
One week after the prednisone course ended, symptoms recurred, accompanied by new right earache. He also noticed blistering at the fingernail edges of 7 of his digits; these blisters exuded a purulent material. A complete blood count, complete metabolic panel, and urinalysis were normal. Erythrocyte sedimentation rate was 67 mm/h. A chest radiograph revealed no abnormalities. Two weeks into a course of amoxicillin, he developed right eye pain, tinnitus in both ears, and worsening night sweats.
In February 2005, he was evaluated by a pulmonologist. Pulmonary function tests were normal. Chest computed tomography was normal; sinus computed tomography showed maxillary sinusitis. Amoxicillin-clavulanate and a prednisone taper resolved his symptoms. A month later, he developed a painful, bleeding penile ulcer (Fig. 1). A dermatologist noted small oral ulcers. A biopsy of the penile lesion was reported as ulceration with diffuse suppurative granulomatous vasculitis. A nasal mucosal biopsy revealed nonspecific inflammation. Antinuclear antibody, antineutrophil cytoplasmic antibody (ANCA), rheumatoid factor, and hepatitis C antibody were all negative.
Because Wegener granulomatosis (WG) was suspected based on the penile biopsy report, methotrexate 15 mg weekly and prednisone 10 mg daily were started with subsequent improvement in symptoms. After 3 months, methotrexate was discontinued and prednisone tapered, resulting in recurrence of his nasal pain and swelling, epistaxis, headaches, night sweats and pain, swelling, and photophobia of the right eye. An ophthalmologist diagnosed scleritis. Prednisone 80 mg daily was begun and he was referred to our rheumatology department in September 2005.
He admitted to prior use of intranasal cocaine every few months, but none since 1 month before the onset of illness. He denied intravenous drug use but smoked marijuana 2 to 4 times per week. Ocular examination revealed marked scleral erythema of the right eye. He had a prominent saddle-nose deformity. There were no nasal nor oral ulcerations. Lungs were clear to auscultation. Genitalia were normal as was the remainder of his examination.
ANCA assays, both by indirect immunofluorescence and enzyme immunoassay, at 2 different laboratories were negative. Methotrexate 20 mg/wk was restarted. His scleritis worsened, prompting an increase of prednisone to 100 mg daily and methotrexate to 30 mg/wk. Over the next few months, his scleritis improved but flared when prednisone was tapered to less than 15 mg daily. He developed new infrapatellar and foot redness and swelling as well as painful subcutaneous nodules on the ventral aspect of his penis leading to penile curvature. Urinalysis, complete blood count, and complete metabolic panel remained normal.
In July 2006, methotrexate was discontinued and cyclophosphamide was begun at 100 mg daily and gradually increased to 175 mg. Nevertheless, penile pain increased, scleritis worsened, and his left knee became warm and swollen. Magnetic resonance imaging of the knee showed thickening of the patellar tendon with subcutaneous edema and a small joint effusion. Methylprednisolone 1 g intravenously was administered daily for 3 days with resolution of symptoms.
Two weeks later, the patient's right ear pinna became swollen for the first time and RP was suspected. Prednisone dosage was increased from 40 to 60 mg daily with improvement. A second pathologist at a vasculitis referral center reviewed the penile biopsy and found “vascular inflammation with fibrinoid deposition, consistent with necrotizing vasculitis; significant granulomatous inflammation was not identified.” Cyclophosphamide was discontinued and a 10-week course of mycophenolate mofetil 1 g twice daily was begun in addition to prednisone 50 mg daily; symptoms continued unabated. In January 2007, infliximab 5 mg/kg i.v. with concomitant methotrexate 25 mg/wk was substituted for mycophenolate, with infusions at weeks 0, 2, 6, and then every 8 weeks; prednisone was tapered gradually over the ensuing 8 months. The patient improved dramatically within 2 weeks of starting infliximab. Arthritis, scleritis, penile ulcerations, and lower-extremity lesions resolved. As the prednisone was tapered, the patient had 4 different episodes of painful mouth ulcers, which tested negative for herpes simplex virus and resolved spontaneously. The patient has continued to be in remission, as of December 2009, on infliximab 5 mg/kg every 8 weeks and methotrexate 15 mg weekly.
Although WG was initially suspected, the addition of cartilaginous inflammation to a negative ANCA, failure to respond to WG therapy, and nonconfirmation of granulomatous disease on biopsy led to a diagnosis of MAGIC. The bulk of our patient's clinical findings suggested RP: nasal chondritis, ocular inflammation, respiratory tract chondritis (hoarseness), and cochlear inflammation (tinnitus).4 Our patient also had features which suggested Behcet disease: recurrent oral ulcers, a penile ulcer, and papulopustular fingertip lesions. The overlap of RP and Behcet disease was dubbed MAGIC syndrome in 1985,1 and since then 10 additional cases have been reported in the English literature.5–13 None of these cases was treated with a TNF-alpha inhibitor.
Infliximab is an inhibitor of TNF-alpha, a cytokine involved in systemic inflammation. Produced predominantly by activated macrophages, it augments activation of T helper cells, which in turn promotes cellular and humoral immune function.14,15 Blocking the function of TNF-alpha has led to successful treatment of inflammatory disorders such as rheumatoid arthritis and Crohn disease. Although the pathogenesis of RP is unknown, it is generally believed to be an autoimmune disease resulting from circulating antibodies against type II collagen in cartilage.3 RP is associated with human leukocyte antigen-DR4, suggesting immune-mediated pathophysiology. RP may be a TH1-mediated process, as levels of interferon-gamma and interleukin-12 correlate with clinical disease activity.16 Our patient's dramatic and sustained response suggests a prominent role for TNF-alpha in the pathogenesis of RP.
We were able to find 9 previously reported cases of RP treated with tumor necrosis factor (TNF)-alpha inhibitors, summarized in Table 1.15–22 Five patients had ocular involvement, which is often resistant to treatment.3 Eight of the 9 patients experienced complete remission of their RP and 7 of the 8 received infliximab.15,17–21 One patient's disease failed to respond to either infliximab or etanercept.16 Time from treatment to remission onset varied from 4 days to 2 weeks, and duration of remission from 6 to 18 months. All reported remissions were ongoing at the time of publication. No flares were reported except in the case of a 14-year-old girl who experienced 1 episode of nasal chondritis.22 One patient dramatically improved after 2 doses of infliximab 3 mg/kg, but then died of multiorgan failure because of Staphylococcus aureus septicemia.21
It should be noted that our patient also reported using cocaine before his disease presentation. Cocaine abuse has been linked to vasculitic syndromes.23 However, our patient's cocaine use ceased 1 month before the onset of symptoms, and he repeatedly denied use of the drug as his disease progressed. Furthermore, the systemic nature of his syndrome is not consistent with cocaine use, which is generally limited to facial midline destructive lesions.24 We therefore believe that his previous drug habit did not contribute significantly to the signs and symptoms of his disease.
In conclusion, we present the first case of MAGIC syndrome with a response to a TNF-alpha inhibitor, specifically infliximab. Although there may be publication bias toward more favorable responses to therapy, our patient's dramatic resolution of all RP activity—previously refractory to potent immunosuppressive drugs—suggests that TNF-alpha plays a fundamental role in this disease. In the absence of a randomized trial, this case report supports the consideration of infliximab in treating MAGIC syndrome or severe RP itself.
1. Firestein GS, Gruber HE, Weisman MH, et al. Mouth and genital ulcers with inflamed cartilage: MAGIC syndrome. Five patients with features of relapsing polychondritis and Behcet disease. Am J Med
2. Trentham DE, Le CH. Relapsing polychondritis. Ann Intern Med
3. Molina JF, Espinoza LR. Relapsing polychondritis. Baillieres Clin Rheumatol
4. McAdam LP, O'Hanlan MA, Bluestone R, et al. Relapsing polychondritis: prospective study of 23 patients and a review of the literature. Medicine (Baltimore)
5. Ng CS, Hogan P, McKenzie S, et al. Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome complicated by aneurysmal aortitis. J Clin Rheumatol
6. Caceres M, Estrera AL, Buja LM, et al. Transverse aortic arch replacement associated with MAGIC syndrome: case report and literature review. Ann Vasc Surg
7. Gertner E. Severe recurrent neurological disease in the MAGIC syndrome. J Rheumatol
8. Nanke Y, Kamatani N, Kobashigawa T, et al. Two Japanese cases with MAGIC syndrome (mouth and genital ulcers with inflamed cartilage). Clin Exp Rheumatol
. 2006;24(5 suppl 42):S113–S114.
9. Kim M, Park K, Min J, et al. A case of polychondritis in a patient with Behcet disease. Korean J Intern Med
10. Kotter I, Deuter C, Gunaydin I, et al. MAGIC or not MAGIC—–does the MAGIC (mouth and genital ulcers with inflamed cartilage) syndrome really exist? A case report and review of the literature. Clin Exp Rheumatol
. 2006;24(5 suppl 42):S108–S112.
11. Imai H, Motegi M, Mizuki N, et al. Mouth and genital ulcers with inflamed cartilage (MAGIC syndrome): a case report and literature review. Am J Med Sci
12. Le TD, Wechsler B, Piette JC, et al. Aortic insufficiency and recurrent valve prosthesis dehiscence in MAGIC syndrome. J Rheumatol
13. Orme RL, Nordlund JJ, Barich L, et al. The MAGIC syndrome (mouth and genital ulcers with inflamed cartilage). Arch Dermatol
14. Dinarello CA. Proinflammatory cytokines. Chest
15. Cazabon S, Over K, Butcher J. The successful use of infliximab in resistant relapsing polychondritis and associated scleritis. Eye
16. Kraus VB, Stabler T, Le E, et al. Urinary type II collagen neoepitope as an outcome measure for relapsing polychondritis. Arthritis Rheum
17. Carter JD. Treatment of relapsing polychondritis with a TNF antagonist. J Rheumatol
18. Richez C, Dumoulin C, Coutouly X, et al. Successful treatment of relapsing polychondritis with infliximab. Clin Exp Rheumatol
19. Mpofu S, Estrach C, Curtis J, et al. Treatment of respiratory complications in recalcitrant relapsing polychondritis with infliximab. Rheumatology
20. Saadoun D, Deslandre CJ, Allanore Y, et al. Sustained response to infliximab in 2 patients with refractory relapsing polychondritis. J Rheumatol
21. Matzies FG, Manger B, Schmitt-Haendle M, et al. Severe septicaemia in a patient with polychondritis and Sweet's syndrome after initiation of treatment with infliximab. Ann Rheum Dis
22. Bell D, Wright D, Witt PD. Durability of nasal reconstruction in an adolescent with relapsing polychondritis treated with infliximab. Plast Reconstr Surg
23. Brust J. Vasculitis owing to substance abuse. Neurol Clin
24. Trimarchi M, Gregorini G, Facchetti F, et al. Cocaine-induced midline destructive lesions: clinical, radiographic, histopathologic, and serologic features and their differentiation from Wegener's granulomatosis. Medicine (Baltimore)
© 2010 Lippincott Williams & Wilkins, Inc.