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Fatal Sepsis in a Patient With Rheumatoid Arthritis Treated With Etanercept

      Patients with long-standing, severe, erosive rheumatoid arthritis who have extra-articular manifestations and have undergone joint replacement surgery are at increased risk for serious infection and premature mortality. New therapies, including cytokine antagonists, hold great promise for improving the course of rheumatoid arthritis. However, they have powerful anti-inflammatory effects that may mask symptoms of serious infection. We report a case of fatal pneumococcal sepsis occurring in a 37-year-old woman with rheumatoid arthritis treated with the tumor necrosis factor antagonist etanercept and suggest management strategies for early detection and management of this complication.
      DMARD (disease-modifying antirheumatic drug), NSAID (nonsteroidal anti-inflammatory drug), RA (rheumatoid arthritis), WBC (white blood cell)
      Therapies targeting tumor necrosis factor, a proinflammatory cytokine produced by macrophages and T cells important in the inflammatory response in rheumatoid arthritis (RA), have come into widespread clinical use for the treatment of this disease. The risks of these new therapies are still incompletely understood. We report a fatal infection due to Streptococcus pneumoniae complicated by necrotizing fasciitis occurring in a patient with long-standing RA treated with prednisone and etanercept.

      REPORT OF A CASE

      A 37-year-old woman with a long-standing history of RA presented to a local emergency department with complaints of malaise, back pain, and nausea for 2 days. Examination was unrevealing except for a temperature of 39.5°C and general discomfort. Abnormal laboratory test results included a white blood cell (WBC) count of 15.1 × 10
      • Fernandez Guerrero ML
      • Martinez Quesada G
      • Bernacer Borja M
      • Sarasa Corral JL
      Streptococcal gangrene and so-called “flesh-eating bacteria disease”: a rare and devastating disease [in Spanish].
      /L and pyuria (4–10 WBCs/hpf) on urinalysis with a negative Gram stain. The result of a rapid test for streptococci was negative. The patient was admitted to the hospital and empirically started on treatment with intravenous ciprofloxacin for a presumptive diagnosis of pyelonephritis. A stress dose of 100 mg of intravenous methylprednisolone was given. Blood and urine cultures were negative. By the third hospital day she had defervesced with symptomatic improvement and was discharged without further antibiotic therapy.
      The following day she returned to the same emergency department unable to bear weight on the left lower extremity because of severe left hip and leg pain. She was afebrile, the review of systems was again noncontributory, and she was transferred to our medical center.
      Medications on admission included subcutaneous etanercept, 25 mg twice weekly (for the previous 7 months, then discontinued at the time of admission to our institution); prednisone, 5 mg once a day; sertraline, 20 mg once a day for depression; and acetaminophen, as needed. Allergies included penicillin, cephalosporins, several nonsteroidal anti-inflammatory drugs (NSAIDs), leflunomide, and tetanus toxoid. Her 6-year-old son had recently had a viral upper respiratory tract infection. She was a life-long non-smoker and rarely drank alcohol. Pneumococcal vaccine had been administered 2 years previously, and influenza vaccine was given 3 months prior to admission.
      The patient had developed seropositive RA at the age of 16 years. Despite aggressive treatment with glucocorticoids, NSAIDs, disease-modifying antirheumatic drugs (DMARDs), including gold, hydroxychloroquine, sulfasalazine, methotrexate, azathioprine, and leflunomide, often in combination, the disease course had been one of continuous disease activity and joint damage. She had taken glucocorticoids almost continuously since the onset of her RA. Because of continued active disease, etanercept, 25 mg twice a week by subcutaneous injection, was initiated as DMARD monotherapy 6 months prior to her presentation. Her medical and surgical history was contributory for multiple orthopedic procedures, including bilateral hip and knee replacements, cervical spine fusion for atlantoaxial subluxation, and numerous hand and foot surgeries. The last of the total joint replacement surgeries was performed in 1996. She was treated for a soft tissue foot abscess in 1989 and had been treated for pneumonia elsewhere in 1990. She had no history of septic arthritis. In 1991, an episode of Kikuchi necrotizing lymphadenitis was treated successfully with prednisone in doses initially of 40 mg a day. In 1993, the patient gave birth to her only child by cesarean delivery. Xerostomia and keratoconjunctivitis sicca had been present for more than 15 years.
      On admission, the patient's temperature was 36.5°C, and blood pressure was 85/50 mm Hg with a pulse of 95 beats/min and respiration of 20 breaths/min. She was in moderate generalized discomfort, but findings on head and neck, thoracic, and abdominal examinations were unremarkable. She had mild swelling of the left lower extremity extending from the groin to the ankle with severe pain on passive range of motion of the left hip, left knee, and left ankle. Neurovascular findings were intact in both lower extremities.
      Admission laboratory results included a WBC count of 3.0 × 10
      • Fernandez Guerrero ML
      • Martinez Quesada G
      • Bernacer Borja M
      • Sarasa Corral JL
      Streptococcal gangrene and so-called “flesh-eating bacteria disease”: a rare and devastating disease [in Spanish].
      /L with 89% neutrophils, hemoglobin of 9.7 g/dL, platelet count of 143 × 10
      • Fernandez Guerrero ML
      • Martinez Quesada G
      • Bernacer Borja M
      • Sarasa Corral JL
      Streptococcal gangrene and so-called “flesh-eating bacteria disease”: a rare and devastating disease [in Spanish].
      /L, and serum creatinine level of 1.0 mg/dL. The oxygen saturation was 100% on room air. Chest radiography revealed a diffuse right pulmonary infiltrate. Bilateral lower extremity Doppler ultrasonographic examination was negative for deep venous thrombosis. Antibiotic therapy with levofloxacin, metronidazole, and vancomycin was initiated for a presumptive diagnosis of septicemia of uncertain etiology, possibly necrotizing fasciitis. By the following morning, a fever of 39.0°C had developed, and the WBC count had decreased to 1.8 × 10
      • Fernandez Guerrero ML
      • Martinez Quesada G
      • Bernacer Borja M
      • Sarasa Corral JL
      Streptococcal gangrene and so-called “flesh-eating bacteria disease”: a rare and devastating disease [in Spanish].
      /L. The left lower extremity had developed moderate discoloration but was without crepitus, bullae, or ecchymosis. There was increased tenderness to palpation along the posterior thigh, knee, and ankle with a large effusion of the left knee. Orthopedic and infectious diseases consultations were obtained, and emergently, the patient was taken to the operating room for biopsies of the most tender areas and joint aspirations with the presumptive diagnoses of necrotizing fasciitis, left hip and knee prosthetic joint infection, and a possibly infectious arthritis in the left ankle. Intraoperative Gram stains of synovial fluid from the knee, hip, and ankle revealed gram-positive cocci resembling streptococci and few to many polymorphonuclear lymphocytes. Intravenous gammaglobulin was administered intraoperatively based on the suspicion of necrotizing fasciitis and toxic shock syndrome due to group A streptococci.
      • Perez CM
      • Kubak BM
      • Cryer HG
      • Salehmugodam S
      • Vespa P
      • Farmer D
      Adjunctive treatment of streptococcal toxic shock syndrome using intravenous immunoglobulin: case report and review.
      • Bisno AL
      • Stevens DL
      Streptococcal infections of skin and soft tissues.
      Bacterial cultures from all 3 joints and blood revealed S pneumoniae infection, which was susceptible to penicillin, levofloxacin, and vancomycin.
      Extensive involvement and degloving of the entire fascia of the posterior thigh and calf were noted, and wide débridement was undertaken. Histologic sections of left thigh and calf tissues showed acute inflammatory infiltrates involving the deep tissue and compatible with necrotizing fasciitis with no muscle involvement. Tissue Gram stain showed many cocci resembling streptococcal organisms (Figure 1).
      Figure thumbnail gr1
      Figure 1Left, The dense polymorphonuclear leukocytic infiltration of the fascia. Underlying skeletal muscle in the lower portion of the photograph is uninvolved. Right, The inflammatory reaction extended to involve subcutaneous adipose tissue in septal planes (hematoxylin-eosin, original magnification ×100 for both images).
      Resection arthroplasties of the left hip and knee were performed with insertion of antibiotic-impregnated spacers containing vancomycin and tobramycin. The left ankle was débrided through an anterior arthrotomy. Because of extensive proximal degloving, general surgeons were consulted to evaluate the retroperitoneal space and psoas fascia. There was no apparent communication with the abdominal cavity. The entire leg was irrigated with more than 20 L of sterile saline and oxychlorosene solution. The muscle and skin were loosely apposed, and the patient was transferred to the surgical intensive care unit. She remained on full ventilatory support requiring aggressive fluid resuscitation and pressor support, and intravenous clindamycin, vancomycin, and levofloxacin were continued.
      On the following day, new findings of erythema and effusion were noted in the right total knee arthroplasty, which had been previously asymptomatic. She was returned to the operating room for planned resection arthroplasty of the right knee, exploration of the right hip prostheses, and further irrigation and débridement of the left lower extremity. No further necrotic material was noted in the left lower extremity; however, aspirates of synovial fluid from the right knee and both hips revealed gram-positive cocci. The joints were again irrigated with 20 L of sterile saline solution with oxychlorosene, and the antibiotic-impregnated cement spacers were changed. The right knee prosthesis was resected, and gross purulence was found. At this point, surgery was halted because of the patient's hemodynamic instability, hypoxia, and high peak airway pressures. Subsequent evaluation in the intensive care unit revealed no evidence of pulmonary emboli or cardiogenic shock, and the patient remained hemodynamically unstable on multiple pressor agents. The patient and her family declined further operative intervention, and she died within the next few hours.

      DISCUSSION

      Anticytokine therapy for RA shows remarkable promise for ameliorating the clinical symptoms and perhaps halting the disease progression.
      • O'Dell JR
      Anticytokine therapy—a new era in the treatment of rheumatoid arthritis? [editorial].
      Etanercept and infliximab, both now approved for the treatment of RA, are effective antagonists of tumor necrosis factor α. These agents, used alone or in combination with other DMARDs such as methotrexate, demonstrate powerful anti-inflammatory activity and may slow progression of the disease.
      • O'Dell JR
      Anticytokine therapy—a new era in the treatment of rheumatoid arthritis? [editorial].
      • Weinblatt ME
      • Kremer JM
      • Bankurst AD
      • et al.
      A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.
      • Bathon JM
      • Martin RW
      • Fleischmann RM
      • et al.
      A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
      • Moreland LW
      • Schiff MH
      • Baumgartner SW
      • et al.
      Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial.
      • Lipsky PE
      • van der Heijde DM
      • St Clair EW
      • Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis With Concomitant Therapy Study Group
      • et al.
      Infliximab and methotrexate in the treatment of rheumatoid arthritis.
      Clinical trials with etanercept indicate that serious adverse events occur with a frequency of approximately 4% (compared with approximately 5% with placebo) and suggest good efficacy, tolerability, and safety profile for this drug during the course of trials with up to 1 year of follow-up.
      • Weinblatt ME
      • Kremer JM
      • Bankurst AD
      • et al.
      A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.
      • Bathon JM
      • Martin RW
      • Fleischmann RM
      • et al.
      A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
      • Moreland LW
      • Schiff MH
      • Baumgartner SW
      • et al.
      Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial.
      Longer-term follow-up safety and tolerability information is limited. In short-term trials, the incidence of upper respiratory tract infections was 16% in patients receiving placebo and 29% in patients treated with etanercept, although this difference is no longer present with longer follow-up.
      • Weinblatt ME
      • Kremer JM
      • Bankurst AD
      • et al.
      A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.
      • Bathon JM
      • Martin RW
      • Fleischmann RM
      • et al.
      A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
      • Moreland LW
      • Schiff MH
      • Baumgartner SW
      • et al.
      Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial.
      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 may be about 3% in open and placebo-controlled trials and in a trial comparing etanercept with methotrexate in early RA.
      • Weinblatt ME
      • Kremer JM
      • Bankurst AD
      • et al.
      A trial of etanercept, a recombinant tumor necrosis factor receptor: Fc fusion protein, in patients with rheumatoid arthritis receiving methotrexate.
      • Bathon JM
      • Martin RW
      • Fleischmann RM
      • et al.
      A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
      • Moreland LW
      • Schiff MH
      • Baumgartner SW
      • et al.
      Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial.
      Infections with S pneumoniae are commonly associated with predisposing factors, including RA. An unusual manifestation of S pneumoniae infection is necrotizing fasciitis.
      • Choudhri SHR
      • Brownstone R
      • Hashem F
      • Magro CM
      • Crowson AN
      A case of necrotizing fasciitis due to Streptococcus pneumoniae.
      • Fernandez Guerrero ML
      • Martinez Quesada G
      • Bernacer Borja M
      • Sarasa Corral JL
      Streptococcal gangrene and so-called “flesh-eating bacteria disease”: a rare and devastating disease [in Spanish].
      • Taylor SN
      • Sanders CV
      Unusual manifestations of invasive pneumococcal infection.
      • Ruoff KL
      • Whiley RA
      • Beighton D
      Streptococcus.
      Our patient had received etanercept with excellent clinical response for 6 months prior to her death. At the time of death, she was also receiving prednisone, 5 mg a day. Long-standing, deforming, erosive, seropositive RA with extra-articular disease manifestations (including rheumatoid nodules, sicca complex, and a history of Kikuchi syndrome) such as this patient had are well-recognized risk factors for premature death from this disease.
      • Turesson C
      • Jacobsson L
      • Bergström U
      Extra-articular rheumatoid arthritis: prevalence and mortality.
      The contribution of etanercept to the fatal infection suffered by our patient remains speculative and unknown. Causation can neither be asserted nor ruled out with certainty. In the setting of sepsis, abrogation of the inflammatory response by an anti-inflammatory agent and, as suggested by this case, anticytokine therapies may obscure the signs and symptoms of severe infections. The events argue that etanercept should have been discontinued when serious infection was recognized at the time of initial hospitalization, although it is uncertain whether this measure would have affected the eventual outcome. The precipitous decline in the WBC count from 15.1 to 3.0 × 10
      • Fernandez Guerrero ML
      • Martinez Quesada G
      • Bernacer Borja M
      • Sarasa Corral JL
      Streptococcal gangrene and so-called “flesh-eating bacteria disease”: a rare and devastating disease [in Spanish].
      /L in 4 days was likely due to overwhelming sepsis, although sporadic nonrecurrent neutropenia was reported in 16% of patients with early RA treated with etanercept, 25 mg twice weekly.
      • Bathon JM
      • Martin RW
      • Fleischmann RM
      • et al.
      A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
      A clinical trial of non-RA patients with established sepsis treated with etanercept demonstrated increased mortality in such patients.
      • Fisher Jr, CJ
      • Agosti JM
      • Opal SM
      • Soluble TNF Receptor Sepsis Study Group
      • et al.
      Treatment of septic shock with the tumor necrosis factor receptor: Fc fusion protein.
      High-risk patients with RA, such as those with extra-articular disease, joint prostheses, and comorbid conditions (eg, diabetes and heart failure), who are placed on anticytokine therapy should be monitored for early signs and symptoms of infection warranting early and aggressive intervention. While we cannot be certain that the course of the fatal sepsis in our patient could have been altered, we believe early intervention to treat potentially serious adverse effects, including infection, begins with education of the patient, who must contact his or her physician immediately to be promptly evaluated at any sign of an untoward event. It would seem prudent to discontinue use of these therapies, at least temporarily, if serious infection is suspected, particularly since the powerful anti-inflammatory effects of anticytokine therapy can mask symptoms of infection and potentially delay institution of appropriate therapy as suggested by our case. We agree with the manufacturer's recommendation that etanercept should be discontinued in patients with serious infections. Because of the increased susceptibility of patients with severe, longstanding RA to infection by common and more unusual organisms, hospitalization for observation and treatment with fluids and broad-spectrum antibiotics should be initiated, adjusting antibiotic therapy when the causative pathogen is identified.

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        A comparison of etanercept and methotrexate in patients with early rheumatoid arthritis.
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        Infliximab and methotrexate in the treatment of rheumatoid arthritis.
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        Unusual manifestations of invasive pneumococcal infection.
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      Linked Article

      • TNF-α Inhibition: The Need for a Tumor Necrosis Factor Thermostat
        Mayo Clinic ProceedingsVol. 76Issue 6
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          With the approval of etanercept for the treatment of rheumatoid arthritis (RA) in 1998 and infliximab a year later, a new era in the treatment of RA began.1 Clinicians now have the ability to inhibit the effects of tumor necrosis factor α (TNF-α) by 2 different approaches: the administration of either soluble TNF receptors (etanercept) or anti–TNF-α antibodies (infliximab). These biological agents allow us, for the first time, to target a specific cytokine, TNF-α. The clinical efficacy of these 2 new approaches has been impressive.
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