Department of Rheumatology, Whipps Cross University Hospital, Whipps Cross Road, London E11 1NR, UK
SIR, The increased risk of tuberculosis (TB) in patients receiving anti-tumour necrosis factor (TNF) therapy is of great concern. A recent case of ours raises a further worry that patients on anti-TNF may be particularly refractory to treatment. Our patient was a 65-yr-old man, born in Calcutta and resident in the UK for over 30 yr, with seropositive erosive rheumatoid arthritis as well as psoriasis. His disease, of 10 yr duration, had failed to respond to methotrexate, sulphasalazine and oral prednisolone alone and in combination at full doses. He had never had symptomatic TB nor received BCG vaccination. His chest X-ray was normal and a Heaf test was grade 1 (considered negative). He was treated with infliximab infusions, with marked improvement of his disease, and he was able to return to work. After a year without problems he experienced a minor allergic reaction during an infusion and his treatment was stopped. His disease relapsed after 6 weeks without therapy, and at his request further treatment was agreed, which was provided under cover of antihistamines and methylprednisolone prior to the infusion of infliximab. Two weeks after this infusion, he developed a dry cough and fevers that were treated by his general practitioner with antibiotics. He failed to respond and became generally unwell with persisting fevers, rigors, daily sweats and weight loss. A chest X-ray and CT scan of the chest revealed miliary shadowing throughout the lung fields, and a diagnosis of TB was made. He was commenced on quadruple therapy (rifampicin, isoniazid, pyrazinamide and ethambutol) but a week later his condition deteriorated with episodic fever spikes of 42°C and associated rigors, sweats and transient confusion. Further broad-spectrum antibiotic agents were added [ceftazidime, levofloxacin, amikacin, Augmentin (co-amoxiclav)] with no response in his symptoms. Microscopy and culture of sputum and bronchoalveolar lavage specimens were repeatedly negative for any organism, including TB and fungi. After 3 weeks of anti-TB therapy, he had an open-lung biopsy that revealed caseating granulomata typical of TB. It was only by the end of the fourth week of anti-TB therapy that his fever resolved. He is now well, although his rheumatoid arthritis and psoriasis have relapsed and remain steroid dependant.
TNF is required for the formation of effective granulomas, which limit tissue damage and mycobacterial dissemination [1]. Experimentally induced mycobacterial infection in animals deficient in TNF is lethal as the disease becomes quickly disseminated [2]. A recent review of TB cases associated with infliximab therapy reports 70 cases of TB notified to the FDA in the United States [3]. Unlike our patient, the majority of patients presented early in the course of treatment. Forty patients had extrapulmonary disease (17 disseminated) and 12 died despite treatment for the disease. It is of interest that the number of reported cases of TB with etanercept are far fewer and may reflect differences in their half-lives or differing modes of TNF inhibition.
In our case, the prolonged time to respond to therapy caused considerable concern regarding the underlying diagnosis and led to two fibre-optic bronchoscopies and ultimately an open-lung biopsy to confirm the diagnosis. In the absence of any measurement for TNF levels in our patient, we hypothesize that TNF inhibition led to rapidly disseminated disease and that the response to anti-TB therapy was delayed, and perhaps only became effective as the TNF inhibition began to fade 67 weeks after his last infusion of infliximab. In conclusion, biological therapy with infliximab seems to confer an increased risk of TB. Presentations are often atypical, which may delay diagnosis and lead to a worse prognosis, particularly if presenting with disseminated disease. Our experience also highlights that the response to therapy may be delayed, which in itself could further place the patient at risk.
Notes
Correspondence to: J. C. Taylor or J. Lanham. E-mail: jaime{at}doctors.org.uk
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