Methotrexate for rheumatoid arthritis: what should the patient be told?

A. J. K. Ostor, D. R. O'Gradaigh and J. R. Jenner

Addenbrookes Hospital, Rheumatology, Cambridge, UK

Correspondence to: A. J. K. Ostor. E-mail: andrew.ostor{at}addenbrookes.nhs.uk

SIR, Methotrexate (MTX) has become the disease-modifying anti-rheumatic drug (DMARD) of choice in treating rheumatoid arthritis (RA). Side-effects, however, are the major reason for cessation of therapy. The most serious complication is MTX pneumonitis (MTX-p), which is both unpredictable and poorly understood. We present a case highlighting the need for vigilance in all patients treated with MTX and explore the degree to which patients should be informed of possible adverse events.

A previously fit, 72-yr-old retired air force officer suffered from progressive seropositive erosive RA for a period of 7 months despite non-steroidal anti-inflammatory drugs (NSAIDs) and prednisolone at 10 mg daily. Owing to disabling disease the patient was given the Arthritis Research Council leaflet on MTX and was counselled regarding the risks and benefits of the medication. He was then commenced on MTX at 7.5 mg weekly with excellent symptomatic relief. Three months after the introduction of MTX he presented with a 3-day history of shortness of breath, dry cough and night sweats. On examination he had a respiratory rate of 24 breaths per minute, was cyanosed and febrile (38°C) with coarse crackles bilaterally. Full blood examination was normal, inflammatory markers were significantly raised and arterial blood gas analysis revealed hypoxaemia and hypocapnoea. A septic work-up prior to antibiotics was negative, as were viral antibody titres. Chest radiography showed a diffuse interstitial and alveolar infiltrate as did high-resolution computed tomography, with no evidence of granulomas or micronodules (Fig. 1). A baseline chest radiograph was normal. Transbronchial lung biopsy showed a mixed inflammatory cell infiltrate with foamy macrophages consistent with non-specific interstitial pneumonitis. Biopsies and bronchial fluid were negative for Pneumocystis carinii pneumonia and Cytomegalovirus. A diagnosis of MTX-p was made in the light of the clinical picture and lack of evidence of an infective cause. MTX was discontinued at the onset of symptoms and intravenous methylprednisolone and broad-spectrum antibiotics including co-trimoxazole were commenced. Despite this the patient required artificial ventilation and subsequently died 11 days after admission, an autopsy was not performed. His relatives wrote after his death questioning whether he had been given enough information concerning the complications of MTX prior to treatment.



View larger version (100K):
[in this window]
[in a new window]
 
FIG. 1. High-resolution CT showing a diffuse interstitial and alveolar infiltrate.

 
Over 120 cases of MTX-p have been described [1] and the estimated prevalence varies between 0.3 and 18.1% [2, 3] with a mean of 3.3% [4]. The case fatality rate has previously been shown to be 17.2% of all patients developing this complication [5], with the most recent series reporting a rate of 22% [1]. These figures are surprisingly high and are based on small series. Larger studies of the incidence, morbidity and mortality of MTX-p are needed and mandatory reporting should be considered. Unfortunately there is no pathognomonic feature of MTX-p and the clinical picture may mimic an infective cause; it therefore remains a diagnosis of exclusion.

The decision to commence a patient on MTX is multifactorial and the risk of potentially fatal pneumonitis is undoubtedly its ‘Achilles' heel’. Thorough discussion of the risk versus benefit of MTX needs addressing prior to its institution. In the light of the reported incidence of MTX-p and its fatality rate, how much information should the patient receive? Knowing alternatives are available, should patients be told that MTX use is potentially fatal?

In two recent articles [6, 7] the authors emphasize the issue of communicating risk of harm from interventions and caution against ‘manipulations’ of information to achieve professionally determined goals. It could be argued, however, that the clinician's responsibility is to communicate information about the risks of both the intervention and of not intervening. In the context of rheumatoid arthritis, early introduction of DMARDs improves prognosis and rheumatologists therefore recommend therapy before the potential harm of RA is manifest. Lloyd [6] describes a number of simplifying heuristics used by patients, including the ability to imagine the adverse outcome, its immediacy and severity and the extent to which the risk can be controlled. Patients struggle to comprehend and retain the numerical data that evidence-based medicine provides, with many preferring qualitative terms such as rare, possible and probable.

An article by Fraenkel et al. [8] highlighted the unwillingness of RA patients to accept side-effects commonly associated with anti-rheumatic medications. Thirty-three per cent of the patients would not commence therapy due to the risk of even minor adverse events. The side-effects studied ranged from minor cosmetic changes to the development of malignancy. In bivariate analysis, the lack of acceptability of adverse events was not associated with patient demographics including education level, arthritis-related health status and preference for disclosure of information. The patients did, however, wish to be fully informed of the risks of therapy.

How is the clinician to inform the patient responsibly yet without bias? Patients should be informed of the possiblity of lung disease prior to MTX introduction and of the urgent need to report new respiratory symptoms. In those already taking MTX the development of pneumonitis is unpredictable and physicians should remain vigilant when respiratory symptoms develop to avoid future fatalities.

What we must put first in all the practice of our art, is how to make the patient well. (Hippocrates 460–377 BC)

The authors have declared no conflicts of interest.

References

  1. Imokawa S, Colby TV, Leslie KO, Helmers RA. Methotrexate pneumonitis: review of the literature and histopathological findings in nine patients. Eur Respir J 2000;15:373–81.[Abstract/Free Full Text]
  2. Buchbinder R, Hall S, Sambrook PN et al. Methotrexate therapy in rheumatoid arthritis: a life table review of 587 patients treated in community practice. J Rheumatol 1993;20:639–44.[ISI][Medline]
  3. Bell MJ, Geddie WR, Gordon DA, Reynolds WJ. Pre-existing lung disease in patients with rheumatoid arthritis may predispose to methotrexate lung. Arthritis Rheum 1987;29:S75.
  4. Salaffi F, Manganelli P, Carotti M, Subiaco S, Lamanna G, Cervini C. Methotrexate-induced pneumonitis in patients with rheumatoid arthritis and psoriatic arthritis: report of five cases and review of the literature. Clin Rheumatol 1997;16:296–304.[ISI][Medline]
  5. Kremer JM, Alarcon GS, Weinblatt ME et al. Clinical, laboratory, radiographic, and histopathologic features of methotrexate-associated lung injury in patients with rheumatoid arthritis. A multicenter study with literature review. Arthritis Rheum 1997;40:1829–37.[ISI][Medline]
  6. Lloyd AJ. The extent of patients' understanding of the risk of treatments. Qual Health Care 2001;10(Suppl. 1):i14–i18.[Abstract/Free Full Text]
  7. Edwards A, Elwyn G, Mulley A. Explaining risks: turning numerical data into meaningful pictures. Br Med J 2002;324:827–30.[Free Full Text]
  8. Fraenkel L, Bogardus S, Concato J, Felson D. Unwillingness of rheumatoid arthritis patients to risk adverse effects. Rheumatol 2002;41:253–61[Abstract/Free Full Text]
Accepted 22 April 2003





This Article
Full Text (PDF)
Alert me when this article is cited
Alert me if a correction is posted
Services
Email this article to a friend
Similar articles in this journal
Similar articles in ISI Web of Science
Similar articles in PubMed
Alert me to new issues of the journal
Add to My Personal Archive
Download to citation manager
Search for citing articles in:
ISI Web of Science (1)
Disclaimer
Request Permissions
Google Scholar
Articles by Ostor, A. J. K.
Articles by Jenner, J. R.
PubMed
PubMed Citation
Articles by Ostor, A. J. K.
Articles by Jenner, J. R.