Long-term low-dose methotrexate (MTX) has a proven beneficial effect in patients with rheumatoid arthritis; the main drawback being the risk of interstitial pneumonia. Although estimations have varied, in our recent prospective analysis we observed 4 cases among 124 receiving MTX for rheumatological disorders, i.e. a risk rate of 3.2% Age, sex, disease duration, administration route and daily or cumulative dose do not appear to affect risk, but recent work suggest that renal failure, concomitent use of nonsteroid anti-inflammatory drugs, smoking, past pulmonary history or radiographic anomalies as well as recent withdrawal of corticosteroids are risk factors. Pulmonary function tests can be used to detect acute disorders and regular testing has been proposed to help predicted pulmonary complications in patients receiving long-term MTX. Unfortunately, minimal variations observed to date, for example in forced vital capacity or expiratory volume, do not appear to occur prior to clinical manifestations and may be due to normal aging processes or the pathological effect of the rheumatoid disease itself. In addition, due to the proven efficacy of MTX, randomized trials against a control group not given MTX would be ethically unacceptable. We are thus still unable to predict development of secondary pulmonary complications to long-term low-dose MTX. We therefore recommend testing pulmonary function at treatment onset to establish a reference for subsequent tests performed in case of clinical manifestations during MTX therapy. Patients should be counselled to consult in case of pulmonary symptoms in order to allow diagnosis as early as possible. The most recent data also would suggest that MTX may induce infraclinical alterations of pulmonary function although their significance remains to be clarified.

STUDY OBJECTIVE Acute interstitial pneumonitis is the main pulmonary side effect during methotrexate (MTX) treatment for rheumatoid arthritis. The aim of the study was to determine the following: (1) the incidence of MTX-induced pneumonitis during low-dose long-term MTX treatment for chronic arthritis; (2) whether periodic pulmonary function tests were useful for detecting MTX pneumonitis before clinical symptoms; and (3) whether any subclinical abnormality of pulmonary function was present in asymptomatic patients receiving MTX treatment. DESIGN Pulmonary function tests, including diffusing capacity for carbon monoxide (DCO) measurements, were performed in 124 patients receiving low-dose MTX for rheumatologic diseases at the time of initiating treatment, and then at 3 months, 6 months, and at 6-month intervals thereafter. Mean duration of treatment was 23 months. RESULTS MTX treatment was interrupted in six patients for acute onset of clinical symptoms; criteria for diagnosis of MTX pneumonitis were fullfilled in four cases (incidence: 3.2%); no risk factor could be identified. No significant decrease in pulmonary function parameters could be observed before the onset of clinical symptoms of MTX pneumonitis, and this adverse effect could not be predicted by periodic function tests. A statistically significant decrease was found in FVC (-2.2%, p=0.04), FEV1 (-5.0%, p<0.001), and diffusing capacity per alveolar volume, DCO/VA (-4.8%, p=0.03), but not DCO (-1.3%, p>0.05), in the 118 other asymptomatic patients during MTX treatment. CONCLUSION We found minor subclinical alterations in pulmonary function in asymptomatic patients receiving low-dose long-term MTX treatment, but periodic pulmonary function tests did not allow us to detect MTX-induced pneumonitis before clinical symptoms. Therefore, we recommend that these tests should not be systematically performed while patients are receiving treatment.

Bi-apical pulmonary fibrosis particular to ankylosing spondylitis is found in 1 to 10% of cases. The non-specific fibrosis or fibrosis of a more specific character such as iritis or the aortic disease are discussed. The fibrosis may be provoked by repeated infections which would favour an eventual hypoventilation at the apices secondary to the rigidity of the thoracic cage. To test this hypothesis we have studied muco-ciliary clearance in 10 subjects presenting with ankylosing spondylitis without any pulmonary radiological lesion and have compared these to 7 control subjects. No statistical difference was found in the clearance rate between the control subjects and the patients on the one hand (whether or not they had extra articular manifestations) and between the different areas of the lung (notably superior and inferior) in patients on the other hand. Thus this bi-apical fibrosis does not seem to explain the phenomena repeated infections at the apices which might have been favoured by any secondary deficiency in muco-ciliary clearance and hypoventilation of the apices. It seems most likely that the fibrosis has a specific origin related to the nature of the disease.

Tracheo-bronchial clearance in the hyper-secreting asthmatic patient was studied by observing the elimination over a period of time of a tracer placed on the bronchial wall over time. The authors describe the method used. The analysis of the results enables two purification processes to be distinguished: muco-ciliary activity and cough. The reliability of the method enabled comparison of the results obtained in 7 healthy subjects and 11 hyper-secreting asthmatics. In the healthy subjects, clearance is carried out by the muco-ciliary activity. In the asthmatics, global clearance is normal, but the cough plays an essential role as the muco-ciliary activity is decreased. The question then arises as to whether the decreased muco-ciliary activity in asthmatic patients is due to failure of the bronchial cilia or to the mucus.

Though the same symptoms are observed in either hyper- or hypothermia, the etiology may be of four different types: 1) the thermoregulatory mechanisms may be insufficient to adapt to temperature extremes in normal subjects; 2) there may be modifications in peripheral thermoregulatory responses, when the patient compensates for the deficiency or excess by other thermoregulatory responses: the internal temperature is then not distrubed but is not stable; 3) a central lesion causing loss of ability to oppose low temperatures results in hypothermia with coma as soon as the subject is exposed to cold. Loss of ability to oppose heat is not encountered: it is superimposable on the hyperexcitation of the centers that oppose heat; 4) modifications in thermoregulatory responses are mainly evident as fever, a protective defense reaction of the organism wich should be supported rather than fought. The inverse syndrome, if it exists, is difficult to distinguish from the loss of ability to oppose cold. The term of "anapyrexia" is suggested for this latter condition. Whatever the diagnosis, measurment of rectal temperature is insufficient for diagnosis, and thermoregulatory responses have to be evaluated. Therapy for the same symptom may, in fact, be inversed depending on the etiology. It may well be that thermoregulatory function is poorly understood because of its true importance. Possessing no specific organs, it uses the various reactions that have appeared during phytogenetic development to ensure thermal homeostasis. It acts permanently through multiple, independent, regulatory loops allowing many compensatory mechanisms. This underlines, in an indirect manner, the need for the organism to maintain at all costs a constant temperature. This permanent thermal homeostasis implies that only severe disorders result in hyper- or hypothermia, that major disturbances are rapidly fatal, which emphasizes the fundamental importance of thermorgulation.

In numerous species, saliva secretion is an important thermolytic response to hyperthermia. The aim of the present work was to look for a thermolytic saliva secretion in human beings. Saliva collected by cannulation was not secreted more during active or passive hyperthermia than during control periods. Therefore, it can be concluded that saliva secretion has no thermoregulatory role in human beings.