Morbidity and mortality in rheumatoid patients during treatment with adalimumab and infliximab

E. Molloy, S. Ramakrishnan, E. Murphy and M. Barry

Department of Rheumatology, James Connolly Memorial Hospital, Blanchardstown, Dublin 15, Ireland

Correspondence to: M. Barry. E-mail: mbarry{at}ireland.com

SIR, Three anti-tumour necrosis factor (TNF) agents (infliximab, adalimumab and etanercept) have demonstrated impressive efficacy in the treatment of rheumatoid arthritis (RA). They have been remarkably safe in the clinical trials reported to date [1]. The occurrence of serious infection, some fatal, during anti-TNF therapy in three UK centres led Moots et al. [2] to advocate greater caution in the use of these agents. Others have also recently emphasized the risk of serious bacterial infection associated with anti-TNF therapy [3, 4]. As of August 2002, 574 deaths have occurred in 554 372 patient-yr of exposure to infliximab (communication from Schering-Plough). Adalimumab was licensed by the USA Food and Drug Administration in December 2002 and has been available in Ireland from the company on a named patient basis since January 2003. No deaths related to its use have been reported in the literature up to September 2003. However, three deaths possibly related to adalimumab occurred during clinical trials (communication from Abbott UK).

Fifty-three patients have been treated with anti-TNF agents in the Department of Rheumatology, JCMH (50 infliximab, four etanercept and four adalimumab) giving an approximate total of 83 patient-yr of exposure. In this group, there have been four deaths (three on infliximab and one on adalimumab). This high number of deaths is significantly at variance from the reported experience. Two deaths (one infliximab, one adalimumab) appear to be directly related to anti-TNF treatment. The other deaths (mesenteric haemorrhage in a patient taking anticoagulants and a myocardial infarction in a patient with cardiovascular risk factors) were not attributable to infliximab. A further patient recovered from Pneumocystis carinii pneumonia, which developed within 4 weeks of commencing infliximab treatment [5].

Perhaps the most striking case was that of a 70-yr-old man who was admitted in January 2003 with a 4-month history of severe seropositive RA refractory to treatment with oral and parenteral methotrexate. He had hypertension and a partial gastrectomy in 1983 for gastric cancer. There were no symptoms referable to cardiopulmonary disease. Chest radiography was normal and Mantoux testing (10 tuberculin units) was negative at 72 h. He received one intramuscular injection of 120 mg of methylprednisolone and was commenced on 40 mg of adalimumab subcutaneously fortnightly, 10 mg of methotrexate weekly and was continued on 7.5 mg of prednisolone daily. He noticed a prompt and marked clinical improvement, associated with an improvement in laboratory inflammatory indices. The patient presented to the accident and emergency department 5 weeks later, 1 week after his third dose of adalimumab, having woken that morning feeling dyspnoeic, weak and unwell. He had a 2-day history of cough. On arrival he was cyanosed, tachypnoeic, hypotensive and in uncontrolled atrial fibrillation. He was severely hypoxic and acidotic. Chest radiography revealed bilateral lung consolidation. Shortly after arrival he suffered a respiratory arrest. Despite aggressive management he died later that day. Post-mortem examination showed fulminant pneumonia with candidal colonies evident on histological examination of affected lung parenchyma.

This case is the first report in the literature of a fatality associated with adalimumab. He had a fulminant pneumonia probably secondary to candidiasis, an unusual infection in patients in the community but which is well-recognized in immunosuppressed patients. It has also been reported to occur in patients treated with infliximab and etanercept (34 and 23 cases respectively [6]). There are no previous reports of systemic candidal infections in patients treated with adalimumab, although other infections, including fungal infections such as histoplasmosis and aspergillosis, have occurred (communication from Abbott UK). A dramatic feature of this case was the rapidity with which his condition deteriorated. This would have made his death difficult to predict or prevent. Reluctance on his part to seek medical attention for the initial infective symptoms, despite being counselled in this regard, may have contributed to the final outcome.

The second death felt to be related to anti-TNF therapy was that of a 68-yr-old woman. She died 4 weeks after her third dose of infliximab from pulmonary infection on a background of pulmonary fibrosis. However, despite extensive investigation, an infective organism was not identified. Both these patients had a prompt and dramatic therapeutic response to anti-TNF agents as regards rheumatoid disease activity. It is tempting to postulate that this may perhaps indicate patients at increased risk of infectious complications as a consequence of more profound abrogation of the effects of TNF.

It is difficult to identify a common thread linking these cases that might explain why there were four deaths and one Pneumocystis carinii pneumonia in our small patient cohort receiving anti-TNF therapy. One possibility is that the administration of intramuscular methylprednisolone in close temporal proximity to the initiation of anti-TNF therapy results in potentially excessive levels of immunosuppression in susceptible patients. Age may also be a factor as all the patients who died were over 60. Although this excess of adverse events in patients receiving anti-TNF therapy may be a coincidental cluster, their occurrence has led to a re-evaluation of our practice. New departmental protocols for screening and treatment of patients with anti-TNF agents, which err on the side of caution, have been developed. These include a general screening protocol, a specific tuberculosis screening protocol and protocols for dealing with infections and comorbidities arising during treatment. Key points include: (1) the exclusion of patients with significant compromise of any organ, and the cessation of treatment in any patient who develops such compromise during treatment; (2) caution in those over the age of 60 yr; (3) delaying treatment for at least 1 month after parenteral corticosteroid treatment or in patients receiving oral prednisolone in doses in excess of 10 mg daily (or equivalent); (4) not commencing treatment with an anti-TNF agent until the patient has failed treatment with at least two disease-modifying anti-rheumatic drugs; (5) close scrutiny of patients for evidence of infection, especially those who have a prompt and significant response to therapy; and (6) a ‘biologic clinic’ has been established to facilitate close monitoring of the response to treatment and development of side-effects.

The authors have declared no conflicts of interest.

References

  1. Kalden J. Expanding role of biologic agents in rheumatoid arthritis. J Rheumatol 2002;29:27–37.
  2. Moots R, Taggart A, Walker D. Biologic therapy in clinical practice: enthusiasm must be tempered by caution. Rheumatology 2003;42:614–6.[Free Full Text]
  3. Kroesen S, Widmer AF, Tyndall A, Hasler P. Serious bacterial infections in patients with rheumatoid arthritis under anti-TNF-alpha therapy. Rheumatology 2003;42:617–21.[Abstract/Free Full Text]
  4. Netea MG, Radstake T, Joosten LA, van der Meer JW, Barrera P, Kullberg BJ. Salmonella septicemia in rheumatoid arthritis patients receiving anti-tumor necrosis factor therapy: association with decreased interferon-gamma production and Toll-like receptor 4 expression. Arthritis Rheum 2003;48:1853–7.[CrossRef][ISI][Medline]
  5. Tai TL, O'Rourke K, McWeeney M, Burke CM, Sheehan K, Barry M. Pneumocystis carinii pneumonia following a second infusion of infliximab. Rheumatology 2002;41:951–2.[Free Full Text]
  6. Ruderman JM, Markenson JA. Granulomatous infections and tumour necrosis factor antagonist therapies. Ann Rheum Dis 2003;62:172–3.[Abstract/Free Full Text]
Accepted 17 October 2003





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