Adalimumab-induced asthma

A. N. Bennett, M. Wong, A. Zain, G. Panayi1 and B. Kirkham1

Guy's and St Thomas' Foundation Hospital NHS Trust and 1 GKT School of Medicine, London, UK

Correspondence to: B. W. Kirkham, Department of Rheumatology, Thomas Guy House, Guy's Hospital, St Thomas St, London SE1 9RT, UK. E-mail: bruce.kirkham{at}gstt.sthames.nhs.uk

SIR, A 51-yr-old lady with a 15-yr history of erosive seropositive rheumatoid arthritis (RA) was treated with adalimumab, having failed multiple DMARDs. Prior to this she had no personal or family history of asthma or atopy and had never smoked.

Within 2 weeks of starting adalimumab she developed a diurnal bronchial wheeze with shortness of breath. This persisted and was reported at review 8 weeks later. Pulmonary function tests (PFT) showed an obstructive pattern, forced expiratory volume in 1 s (FEV1) reduced by 49% of predicted and a significant bronchodilator response of 25% improvement in FEV1 (15% improvement indicates reversible airways disease) (Table 1). A raised transfer coefficient (KCo) of 1.88 mmol/kPa/min/l (117% predicted) was also noted, which is typical of asthma. A full blood count showed a new eosinophilia of 1.0 x 109/l (normal range 0.0–0.4) and a raised immunoglobulin E of 384 kU/l (normal range 0–81).


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TABLE 1. Pulmonary function test before and after bronchodilator

 
The chronology of events and absence of previous respiratory disease suggested an adverse reaction to adalimumab. Introducing methotrexate was considered to suppress this presumed immunological side-effect, but due to previous severe rashes with methotrexate this was not pursued. Therefore inhaled beclomethasone 200 µg twice daily was added.

Within 3 days her symptoms had improved and within 2 weeks they were completely controlled by beclomethasone. Subsequent PFT on beclomethasone whilst still on adalimumab were much improved, with a FEV1 of 2.02 l and a FEV1/forced vital capacity (FVC) ratio of 81.8%.

Unfortunately, after an initial good response to adalimumab with a greater than 50% reduction in swollen and tender joint count, the RA persistently flared. Adalimumab was stopped after 5 months of treatment. The patient subsequently stopped the beclomethasone inhaler with no return of symptoms. PFT 3 months after stopping all medication had returned to normal (Table 1). Eosinophils also returned to normal within 3 weeks of stopping the drug.

Adalimumab is a fully human recombinant monoclonal anti-tumour necrosis factor-{alpha} (anti-TNF-{alpha}) antibody recently licensed for the treatment of moderate to severely active RA. Like all anti-TNF-{alpha} drugs, adalimumab has recognized side-effects, increased susceptibility to infection being the most worrying.

This is the only Committee on Safety of Medicines (CSM)-reported adverse event of asthma with adalimumab to date in the UK. Further information from Abbott Laboratories revealed that in the pivotal trials of adalimumab asthma has been reported as an adverse event in 0.3% of adalimumab-treated patients compared with 0.1% of placebo-treated patients. Neither treatment nor the pre-existence of asthma was recorded; however, no patient had to stop adalimumab.

A possible explanation of the new onset of asthma in these patients lies in the contrasting inflammatory responses in RA compared with asthma and other allergic diseases. Among T-helper cells (Th), two opposite poles of immune responses can be distinguished based on secretion of cytokines: the Th1 cytokine pattern, with predominant secretion of interferon {gamma} (IFN-{gamma}) and TNF-{alpha}, and induction of a cellular immune response. In contrast, the Th2 cytokine pattern has predominant secretion of interleukin (IL)-4, IL-5 and IL-13 and induction of the humoral immune response. Atopic disorders show a raised level of IgE and a Th2 cytokine response [1], whilst RA is considered to be a Th1-polarized disease [1–5].

The generation of a Th2 immune response is inhibited in the presence of Th1 cytokines and vice versa [6]. Based on reciprocal inhibition of the development of Th1 and Th2 responses, it has been suggested that Th1- and Th2-polarized diseases mutually exclude one another. We hypothesize that active RA in this case produced a Th1 cytokine response, which suppressed the clinical expression of asthma. However, once the TNF-{alpha} blocking drug was introduced, the Th1 response was suppressed, allowing the Th2-activated pathway to express itself clinically as asthma.

This hypothesis would suggest a class effect. Indeed, asthma has been reported as an adverse event to the CSM for both infliximab and etanercept. There have been two reported cases of new onset asthma with etanercept and two exacerbations of asthma, one with each of etanercept and infliximab. Additionally, there have been another 25 cases of reported bronchospasm or wheezing, although most of these have been related to anaphylaxis.

Asthma appears to be a definite but rare side-effect of anti-TNF blockade. In all the adalimumab reported cases the asthma has been mild and adalimumab has not needed to be withdrawn. The details of the asthma adverse events to infliximab and etanercept are not available. In the absence of other guidelines, we followed the British Thoracic Society (BTS) guidelines for asthma [7] and added an inhaled steroid, which completely resolved the patient's mild symptoms.

We conclude that asthma in this patient was precipitated by the anti-TNF-{alpha} drug adalimumab. Although at no stage was the asthma severe enough for the drug to be stopped, we would recommend careful observation, particularly in patients with a personal or family history of asthma or atopy, and adherence to the BTS guidelines for asthma [7] if symptoms occur.

B.W.K. has received research support from Abbot Ltd and Centocor Inc. G.P. has received sponsorship to attend meetings and research funding from and/or acted in an advisory capacity to a number of pharmaceutical and biotechnology companies involved in the development or manufacture of anti-rheumatic therapies. The other authors have declared no conflicts of interest.

References

  1. Del Prete G. Human Th1 and Th2 lymphocytes: their role in the pathophysiology of atopy. Allergy 1992;47:450–5.[ISI][Medline]
  2. Simon AK, Seipelt E, Sieper J. Divergent T-cell cytokine patterns in inflammatory arthritis. Proc Natl Acad Sci USA 1994;91:8562–6.[Abstract/Free Full Text]
  3. Liblau RS, Singer SM, McDevitt HO. Th1 and Th2 CD4+ T cells in the pathogenesis of organ-specific autoimmune diseases. Immunol Today 1995;35:34–8.[CrossRef]
  4. Schulze-Koops H, Lipsky PE, Kavanaugh AF, Davis LS. Elevated Th1 or Th0-like cytokine mRNA in peripheral circulations of patients with rheumatoid arthritis. Modulation by treatment with anti-ICAM-1 correlates with clinical benefit. J Immunol 1995;155:5029–37.[Abstract]
  5. Dolhain RJEM, van der Heiden AN, ter Haar NT, Breedveld FC, Miltenburg AMM. Shift toward T lymphocytes with a T helper 1 cytokine-secretion profile in the joints of patients with rheumatoid arthritis. Arthritis Rheum 1996;39:1961–9.[ISI][Medline]
  6. Abbas AK, Murphy KM, Sher A. Functional diversity of helper T lymphocytes. Nature 1996;383:787–93.[CrossRef][ISI][Medline]
  7. Higgins BG, Douglas JG. The new BTS/SIGN asthma guidelines: where evidence leads the way. Thorax 2003;58:98–9.[Free Full Text]
Accepted 1 April 2005





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