Uncomplementary

A 26-year-old woman presented to the emergency department with a 3-day history of fatigue, myalgias, and pain and swelling of the right knee and ankle, and both wrists. Her medical history was significant for hypertension as a complication of a childhood diagnosis of atypical hemolytic uremic syndrome, which was stabilized with eculizumab treatment. She had no history of connective tissue disease. Aside from the eculizumab, her medications included fosinopril and amlodipine for hypertension, and ferrous fumarate. She had no history of recent travel or intravenous drug use, and no ill contacts. She was in a monogamous relationship with a male partner and denied ever being sexually active. On examination, the patient was afebrile with a blood pressure of 154/102 mm Hg and a heart rate of 110/min (regular). She had swelling and tenderness of multiple large joints, including the right and left knees and right ankle, as well as bilateral tenosynovitis of the wrists. She had widespread 5–10 mm pustules as well as nonblanchable purpuric skin lesions (Figure 1). Pustular skin lesion on the volar aspect of the patient's right wrist. Initial investigations revealed a hemoglobin concentration of 113 g/L (normal, 120–160 g/L), a white blood cell count of 14.4 × 109/L (normal, 4.0–11.0 × 109/L), a neutrophil count of 12.5 × 109/L (normal, 2.00–7.5 × 109/L) and a platelet count of 149 × 109/L (normal, 150–400 × 109/L). The patient’s creatinine level was 139 µmol/L (normal, 50–98 µmol/L), which was her baseline. Urinalysis was positive for microscopic hematuria. Blood cultures obtained on admission were negative. Plain radiography of the patient’s right knee demonstrated an effusion. We performed arthrocentesis of the right knee. Gram staining of the synovial fluid culture is presented in Figure 2. Gram stain of the synovial fluid culture from the patient's right knee. What is your diagnosis? Diagnosis: disseminated gonococcal infection in the setting of eculizumab therapy. Additional history revealed that the patient had had recent unprotected intercourse with her male partner, prompting testing for sexually transmitted infections. Result of urine nucleic acid amplification testing was positive for Neisseria gonorrhoeae, which also grew from the right knee synovial fluid (Figure 2), confirming a diagnosis of disseminated gonococcal infection (DGI). Results of testing for human immunodeficiency virus (HIV), syphilis, Chlamydia trachomatis, and hepatitis A, B, and C viruses were negative. The hepatitis B surface antibody result was positive, consistent with immunity from prior vaccination. We treated the patient with ceftriaxone (1 g daily for 7 days, administered intravenously) and a 1-time dose of azithromycin (1 g, taken orally). Given the slow resolution of her joint swelling and the resultant limitation in mobility, we administered adjuvant prednisone on the third day of antibiotic therapy (20 mg/d for 14 days, taken orally), resulting in rapid resolution of her symptoms. When prednisone was discontinued, the patient experienced a flare of her symptoms; she was then treated with a prednisone taper over a 20-day period, with complete resolution of symptoms. This case provided an opportunity to consider the differential diagnosis for a 26-year-old woman presenting with arthritis and skin rash while receiving therapy with eculizumab. Eculizumab is a engineered humanized anti–complement C5 monoclonal antibody used to treat paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome. Through its mechanism of action, eculizumab inhibits complement-mediated serum bactericidal activity that requires formation of the membrane attack complex. Thereby, it increases the risk of infection with neisserial species, including Neisseria meningitidis and N. gonorrhoeae, owing to impaired opsonophagocytic destruction of these bacteria [1]. The rate of invasive meningococcal disease in persons receiving eculizumab is approximately 1000–2000-fold the population-based rate [2]. Twelve cases of DGI related to complement-inhibiting monoclonal antibody therapy have been reported in the literature, including 11 patients receiving eculizumab and 1 patient receiving ravulizumab. The clinical presentation and severity of DGI varied between patients. Manifestations ranged from fever, rigors, arthralgia, and skin lesions to septic shock, organ failure, and death. Only 2 of the 12 patients presented with arthritis. Eleven cases resolved with antibiotic therapy, and 1 patient died [3–6]. The first-line treatment for DGI is ceftriaxone (1 g given daily for 7 days, intramuscularly or intravenously) plus either oral azithromycin (a single 1 g dose given orally) or doxycycline (100 mg given orally, twice daily for 7 days) to provide additional coverage for N. gonorrhoeae as well as coverage of C. trachomatis, if present [7]. While the immunopathogenesis of DGI is not fully elucidated, it is hypothesized that inflammation due to circulating immune complexes contributes to the disease presentation, including immune complex rheumatologic manifestations [8]. Therefore, it follows that treatment with adjunctive anti-inflammatory therapy, such as corticosteroid therapy, could help modulate the immunologic response to infection in patients receiving targeted antimicrobial therapy. This was the rationale for administering prednisone to our patient. To our knowledge, no randomized controlled clinical trials have evaluated this approach. Our patient was born outside North America, and she had not received a primary meningococcal vaccination series in childhood. There is a black box warning for treatment with eculizumab, stating that patients should receive meningococcal vaccines ≥2 weeks before administration of the first dose, unless the risks of delaying therapy outweigh the risk of meningococcal infection [9]. In follow-up, we prescribed penicillin prophylaxis (500 mg twice daily, taken orally) and initiated vaccination with meningococcal conjugate vaccine (MenACWY) at 0 and 2 months and a serogroup B meningococcal vaccine (Men4B) series at 0 and 2 months, per Centers for Disease Control and Prevention recommendations [10]. The penicillin prophylaxis was continued until 2 months after the last vaccination. This case provides several key learning points. First, complement plays an important role in host protection again neisserial infections and iatrogenic manipulation of the complement system, in this case with eculizumab, is a risk factor for neisserial disease. Our patient's presentation with a syndrome of dermatitis and arthritis in the context of receiving eculizumab alerted us to the possibility of neisserial infection and prompted testing for gonococcal disease when further history was available. Second, immune-mediated mechanisms contribute to the skin and joint manifestations of DGI, which prompted us to administer adjuvant corticosteroid therapy concurrent with targeted antimicrobial therapy. Finally, this patient's presentation with DGI allowed us to identify a gap in disease prevention and an opportunity to administer meningococcal vaccination, which should be a standard of care before patients receive anticomplement therapies, such as eculizumab.

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