Necrotizing fasciitis (NF) is a rare severe infection affecting subcutaneous tissue and superficial fascia associated with considerable mortality (70–80%).1–3 The infections are the most feared adverse events of tocilizumab (TOC); there are few published pos-marketing data.

A case report of NF is presented with a published cases review through PubMed database and several European Biologics Registers.

A 66-year-old Caucasian woman with a seropositive RA presented with sudden onset of severe and progressive forearm and elbow pain with 3 days of evolution. She denied fever and history of trauma or animal bite. Since fourteen years ago, she has been consecutively treated with methotrexate (up to 20mg/week), etanercept (50mg weekly) and adalimumab (40mg fortnightly), which were discontinued owing to lack of efficacy. For three years, she has been treated with prednisolone (7.5mg/day), leflunomide (LEF) (10mg/day) and TOC (8mg/kg intravenous (iv) every 4 weeks). The prior medical history was significant for bacterial osteomyelitis (foot fifth digit) under TOC monotherapy for a year. Vital signs were as follow: pulse, 86beats/min; blood pressure, 135/72mmHg; body temperature, 36.8°C. Had active synovitis in metacarpophalangeal, interphalangeal and wrist joints. Left upper limb presented diffusely oedematous with a slight erythematous rash and increased temperature. Laboratory tests were as follow: hemoglobin 12.3g/dl; white blood cell (WBC) count 11.8×109/l (neutrophils 10.6×109/l); platelets 149×109/l; C-reactive protein (CRP) 74.6mg/L; creatinine 1.51mg/dl; sodium 138mEq/l and glucose 91mg/dl. Arteriovenous Doppler ultrasound excluded venous thrombosis.

Three days later, erythrocyte sedimentation rate was 58mm and CRP 188.3mg/L. Differential diagnosis included cellulitis and septic arthritis. Immunosuppressants drugs were discontinued, cholestyramine and empiric antibiotic therapy (vancomycin and imipenem) were initiated. Magnetic resonance showed peri-aponeurosis and muscle edema (especially deltoid muscle), signs of cellulitis, without organized collections. At day 5 of treatment, lesions rapidly progressed to extensive areas of skin detachment and necrosis with severe exudation (Fig. 1). She had now periodic fever. Enterobacter aerogenes, Pseudomonas aeruginosa and Stenotrophomonas maltophilia were identified in the skin; blood cultures were negative. Surgical debridement with subsequent partial skin graft and a twenty-days period of antibiotics led to progressive improvement. She was discharged at day 39.

Figure 1.

Evolution of skin lesions at first five days of internment: áreas of extensive skin detachment in the context of ruptura of blisters and severe exudation and necrotic áreas.

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After one-year follow-up there was no recurrence of infections. She is under hydroxychloroquine (400mg/day) and prednisolone (7.5mg/day). Methotrexate was added but soon discontinued due to oral mucositis. TOC was permanently withdrawn.

We identified three case reports of NF in RA patients receiving TOC3–5 and three under TNF antagonists6–8 (Table 1). Published rates of serious skin and soft tissue infections in RA patients vary widely between different European Biologics Registers, from 12–18 per 1000 patient-years in the British register to 37–76 per 1000 patient-years in German register.9 Results from British register showed that the majority were cellulitis (227/309; 73%) and only four cases were NF (all with anti-TNF).10

A German cohort study concluded that longer disease duration, history of severe infections, previous exposure to multiple DMARDs and concomitant treatments with LEF, prednisone or proton-pump inhibitor increase the risk of infections under TOC. This is our patient profile. In the TOWARD study, infections were more prevalent among patients receiving TOC and DMARDs simultaneously; however, there was no explicitly assigned association to LEF.11 Thus, we cannot overlooked that our patient was under LEF and glucocorticoids and we should attribute the adverse event to their association with TOC rather than to TOC alone. TOC contribution remains speculative and causality can neither be asserted nor ruled out with certainty. So, we believe that is important to report such infections in the post-marketing surveillance.

In conclusion, physician should keep in mind that infections may mimic a disease flare and the absence of fever does not exclude serious infections in RA patients under biologics.

All authors declare no conflicts of interest.