Necrotizing fasciitis in a patient treated with etanercept for dermatomyositis
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- Choi, K. & Yoo, W. Rheumatol Int (2009) 29: 463. doi:10.1007/s00296-008-0695-4
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We first report a case of patient with refractory dermatomyositis (DM) who successfully treated with tumor necrosis factor-α blocker, etanercept and developed necrotizing fasciitis (NF) after the use of it. NF was diagnosed early by MRI and managed with antimicrobial therapy and timely debridement of necrotic tissue with favorable outcome. We suggest that etanercept can be a useful therapeutic agent in patients with DM refractory to steroid and immunosuppressive agents and NF may occur in DM in association with etanercept therapy. We also suggest that management strategies for early diagnosis and treatment are needed for this complication.
Dermatomyositis (DM) is a systemic inflammatory disorder affecting skeletal muscles, skin and other organs [1, 2]. DM is essentially treated with glucocorticoid and cytotoxic drugs, including azathioprine, methotrexate, cyclophosphamide, chroambucil, cyclosporine and mycophenolate mofetil. There were only limited sporadic reports suggesting the addition of tumor necrosis factor-α (TNF-α) inhibitor to standard treatments have successful response in some cases of DM refractory to conventional therapies [3–6]. Although the safety of etanercept has been demonstrated in several clinical studies, the risk of infection is an area of particular interest. There were no reports about infectious complications of etanercept in patients with DM until now.
In clinical studies in patients with inflammatory myositis, infectious complications have been described in up to 26% of patients [1, 2]. Several factors may be implicated in this apparent increased frequency of infections, particularly immunosuppressive medications. In addition, immune system dysfunction may lead to elevated susceptibility to opportunistic infections [1, 2]. Necrotizing fasciitis (NF) is a serious deep-seated bacterial infection with secondary necrosis of the skin. Trauma and immune deficiency associated with connective tissue diseases or administration of immunosuppressive agents predispose to NF . Infectious side effects of etanercept have been described in the literature but there has been no mention of NF in patient with DM.
We described a 46-year-old woman with DM refractory to conventional treatments who successfully treated with etanercept and developed NF after treating with this agent. Therapies targeting TNF-α, important in the inflammatory response in DM, have suggested as a new agents for refractory case of this disease. However, the benefits and risks of these new therapies are still incompletely understood. We report a case of NF occurring in a patient with refractory DM treated with the etanercept and reviewed about the effectiveness, safety of these agents in DM, especially about NF.
A 46-year-old woman with DM presented to our outpatient clinics with erythematous swelling, tenderness and heating sense on the left thigh for 2 days. The onset of DM began 2 years ago with polyarthralgia, characteristic skin rash and proximal muscle weakness in the upper and lower extremities. A clinical diagnosis of DM was confirmed by the presence of increased muscle enzymes, skin lesions and positive findings of electromyography and muscle biopsy. Searches for an occult neoplasm were negative. Despite aggressive treatment with various immunosuppressive drugs, we failed to induce remission of DM. These included prednisolone, methotrexate, azathioprine, and cyclophosphamide, often in combination. She had taken glucocorticoids almost continuously since the onset of her DM. Because of continued active disease, etanercept, 25 mg twice a week by subcutaneous injection, was started as adjuvant therapy with steroid and methotrexate 5 months prior to her presentation. The proximal muscle weakness, arthralgia, skin rash and serum level of muscle enzyme, creatine phosphokinase (CK) were improved significantly thereafter.
On examination, she was apyrexial (temperature 36.8°C). She had a pulse of 81 beats/min and blood pressure of 120/70 mmHg. She had an erythematous, warm, swollen, indurated area at the lateral side of left thigh from near knee to just below the trochanteric area. There was no evidence for lymphangitis or lymphadenopathy. Although erythema was noted at the both elbows and hands, there was no proximal muscle weakness.
Laboratory tests revealed a leukocyte count of 9,810/mm3 with 89.7% neutrophils, 6.0% lymphocytes, hemoglobin 10.8 g/dL, hematocrit 33.7%, platelet 335,000/mm3, erythrocyte sedimentation rate 101 mm/h, and CRP 101.07 mg/L (normal value <5 mg/L). Coagulation tests were within normal range. CK (64 IU/L, normal value 50–200 IU/L) and aldolase (7.4 IU/L, normal value <7.6 IU/L) were normal range as well as aspartate aminotransferase (38 IU/L, normal value <40 IU/L), alanine aminotranferase (24 IU/L, normal value <40 IU/L). Anti-Jo-1 antibody was positive, whereas antinuclear antibody, rheumatoid factor, cryoglobulin, ANCA and anticardiolopin antibodies were all negative. Serology for antihuman immunodeficiency virus and for anti-hepatitis C and B virus antibodies were negative. Doppler ultrasonographic examination of the bilateral lower extremities was negative for deep venous thrombosis. MRI revealed that inflammation in and around psoas, iliacus, rectus femoris, adductor, vastus lateralis and hamstring muscle with fluid collection. Oxacillin resistant Staphylococcus aureus was grown from pus culture of the discharge from left thigh. Etanercept therapy was discontinued. We had incision and debridement on the left thigh and drained with saline irrigation. Histologic examination of left thigh area showed extensive necrosis of the fibroadipose tissue with mononuclear inflammatory infiltration. After the successful drainage of abscess, she was treated with intravenous vancomycin and regular dressing and markedly improved. The patient was discharged on the 32nd day on oral antibiotics for 14 additional days of therapy.
NF is a rapidly progressive infection of the subcutaneous tissue, associated with substantial mortality and long-term morbidity. A recent history of trauma can often be elicited, and many have an underlying disease that impairs the normal immune response to infection. Although there were very rare case reports of NF in patients with connective tissue disorders, including rheumatoid arthritis (RA)  and systemic lupus erythematosus , NF was not reported in patient with DM until now. We here report a case of NF occurring in a patient with DM treated with the etanercept and suggest that NF may be a very rare complicating infectious disease in DM.
DM is considered to be associated with high morbidity and mortality rates, in some cases as high as 50%, primarily related to life-threatening cardiac and lung impairment, as well as infectious manifestations [1, 2]. In clinical series of patients with DM, infectious complications have been described in up to 26% of patients [1, 2]. Both lung and digestive tract are the predominant sites of related opportunistic infections (89% of cases) . Although there were no cases of NF in patient with DM until now, NF may be a very rare accompanying infectious disease in DM. Patients with DM have predisposing risk factors for developing infections, including esophageal involvement, thoracic muscle myopathy, and the use of cytotoxic drugs. In addition, immune system dysfunction, due to DM itself, may lead to elevated susceptibility to opportunistic infections [1, 2]. Lymphocytopenia and lower serum total protein levels has been further known as a contributing factor for the development of infection in DM .
Several studies suggested that TNF-α may play an important role in the pathogenesis of DM. It was overexpressed in muscle from patients with DM 11] and polymorphism in TNF-α-308 promoter region has been found in juvenile DM . Abnormally high levels of TNF-α may be toxic to myofibrils and simultaneously prevent the formation of new ones . Therefore, TNF-α may be an attractive therapeutic target, especially in DM resistant to conventional treatments. Several sporadic case reports and small series [3–6] suggest that the addition of TNF-α inhibitor to standard treatment may be useful in refractory DM, which can be proved only with randomized controlled studies using standardized efficacy measures . Our patient had received etanercept with excellent clinical response for 5 months prior to the development of NF.
Anticytokine therapy for RA shows remarkable promise for ameliorating the clinical symptoms and perhaps halting the disease progression. However, the roles of TNF-α inhibitors are only justified by case reports and are not widespread clinical use for the treatment of DM. In RA, information from placebo-controlled trials suggests that the incidence of serious infections in patients receiving either etanercept or placebo is 1%, while the overall rate of serious infections in RA patients requiring hospitalization was about 3% in open and placebo-controlled trials and in a trial comparing etanercept with methotrexate in early RA [15, 16]. Infections with Streptococcus pneumoniae are commonly associated with use of etanercept in RA. Although infective side effects of biologic agents have been described in several literatures, there was only one case of NF occurred in patient with RA treated with infliximab until now 17].
The infectious side effects by this agent in DM are impossible to know exactly. And, thus the contribution of etanercept to the fatal infection suffered by our patient remains speculative. In our patient, prolonged steroid administration might have increased the risk of infection and caused the fragility of skin tissue, which in turn allowed easy access of bacteria into the circulation. The use of cytotoxic drugs, including methotrexate, cyclophosphamide and azathioprine for long duration, and lymphocytopenia may be contributing factors developing NF in this case. High-risk DM patients with above described predisposing factors and who are placed on therapy with TNF-α inhibitors should be monitored for early symptoms and signs of infection warranting early and aggressive intervention.
Mortality rates due to infection in three studies that included patients with PM/DM were 7.0, 4.3, and 6.5% [10, 18]. The mortality rate of NF was much higher than general infectious diseases, about 35–60% . Administration of antibiotics and early management especially aggressive surgical debridement can prevent mortality . In the setting of serious infections, abrogation of the inflammatory response by an anti-inflammatory agent and anticytokine therapies, as suggested by this case, may obscure the signs and symptoms of severe infections. This indicates that etanercept should have been discontinued when serious infection was recognized, although it is uncertain whether this measure would have affected the eventual outcome.
In conclusion, the case presented here shows that TNF-α inhibitors may be useful in some cases of refractory DM and NF might be rare infectious complication of DM in association with or without etanercept therapy. More information is required to assess the efficacy and risks of infection particularly as TNF-α inhibitor will be used more frequently in the future.