This study describes the association between RPF and asbestos-related lung diseases. We hope that our results help to identify persons who have developed RPF through occupational exposure to asbestos. Even though the findings of the current study alone are not enough to declare a causal association between asbestos exposure and RPF, they strengthen the validity of the results of our earlier case-control study and clarify the phenotype of asbestos-related RPF.
To our knowledge, the literature contains only three reports describing asbestos-related pleural findings in altogether five RPF patients [14–16]. In our study 16 out of 22 (73%) asbestos-exposed RPF patients had asbestos-related pleural pathology in their chest HRCT. The prevalence of pleural plaques, DPT and lung fibrosis found in the asbestos-exposed RPF patients was similar to that determined for the asbestos-exposed controls, but DPT was clearly more extensive in the asbestos-exposed RPF patients. Only a few RPF patients and controls with more than 10 fiber-years of asbestos exposure had asbestosis. It seems that the exposure level associated with the development of RPF is comparable to that associated with the development of pleural fibrosis rather than to the high level of exposure that induces asbestosis.
On the basis of our results, it can be argued that RPF is an independent risk factor for pleural fibrosis. The results of the case-control setting (ordinal regression analysis, additional file 3) indicate that RPF patients are more prone towards the development of severe DPT than exposed control subjects. The small number of cases did not allow us to evaluate the interactions between asbestos and RPF. Pleural fibrosis was evident at the time of the RPF diagnosis in most of the cases. Asbestos exposure occurs mainly via the respiratory system, and pleural fibrosis is far more common than RPF. It has been estimated that there are approximately 200 000 asbestos-exposed people , 80 000 men with bilateral pleural plaques, and even more with DPT  and, according to our estimations, 70–100 patients with RPF in Finland. Taking into consideration these findings, we suggest that asbestos-exposed subjects with RPF develop concomitant pleural fibrosis because of their higher individual susceptibility for asbestos-induced fibrosis.
Parietal pleural plaques are considered pathognomonic for asbestos exposure, and hence they also serve as an indicator of past exposure . The clear difference between the unexposed and exposed groups with a positive trend in the RPF subgroups with slight and moderate exposure strengthens the validity of the results of our previous exposure risk assessment .
The percentage of bilateral pleural plaques in the asbestos-exposed groups was similar to those in previous studies, in which similar asbestos-exposed cohorts in Finland have been studied with CT scanning or autopsy [20, 21]. Two of the eighteen patients with RPF but assumed to have had no asbestos exposure, had some bilateral plaques but no other evaluated abnormalities. This finding probably reflects a high urban background of amphibole asbestos anthophyllite, which was previously widely used in Finland and results in a relatively high prevalence of PPP in the Finnish urban population .
DPT was the most frequent among the asbestos-exposed RPF patients and it was thicker than in the asbestos-exposed controls or in the unexposed RPF patients. DPT is thought to be a consequence of acute asbestos-related pleurisy . However, DPT is not specific to asbestos exposure and may also result from other inflammatory conditions, such as infections, trauma, surgery and drug reactions (eg to ergot derivates) . Crocidolite-related DPT has been shown to progress in the first 15 years after its diagnosis , and this progression concurs with our clinical experience in Finland with the past use of amphibole asbestos. We think that the thinner DPT seen in unexposed RPF patients may be the result of short-lasting injury such as surgery or infection, and the thicker DPT found in asbestos-exposed persons is probably related to continuous irritation caused by bioresistant amphibole fibers.
Available CT scans of RPF tissue in asbestos-exposed patients show large unresolved masses that are probably, for the most part, acellular fibrous tissue resembling the one found in DPT.
DPT, unlike parietal pleural plaques, causes significant restrictive impairment of lung function [25, 26]. The latency time for DPT is typically over 20 years from the beginning of asbestos exposure, although benign asbestos pleurisy can occur earlier . DPT can be induced by moderate asbestos exposure, and the amount of exposure required for the development of DPT is probably higher than for parietal pleural plaques . Nine out of the eleven asbestos-exposed patients with RPF and bilateral DPT also had bilateral pleural plaques (class ≥ 2). Marked DPT masks parietal plaques, and some patients with class 2 plaques and thick DPT may, in fact, have had bilateral plaques of class 3.
Ergot drugs have been shown to cause pleural effusion and DPT . This finding is particularly interesting because the use of ergotamine derivates is also a well known risk factor for RPF . In our study, however, the persons having RPF in relation to the use of ergoline medication had no signs of DPT. The pleural effusion and DPT induced by asbestos and ergot drugs share common features, and the etiological diagnosis is difficult for persons with both exposures .
Three asbestos-exposed RPF patients had exceptionally large anterior pleural masses extending into the anterior mediastinum. All of them also had typical asbestos-related findings: widespread bilateral plaques in all three; dorsal DPT in two cases (Figure 3A and 3B) and fibrotic lesions fulfilling the criteria for asbestosis in one case (Figure 3C, not shown with the parenchymal settings). In all of these cases the pleural masses were visible in the chest X-rays taken at the time of the diagnosis of RPF. The coexistence of large masses in the pleural and retroperitoneal space suggests a common etiology, although there was no continuity between the mediastinal and retroperitoneal masses. In our experience, such changes are rarely found even in asbestos-exposed persons having other marked pleural pathology. Two similar cases having slight asbestos exposure and no other known risk factors for RPF have been recently reported in France . It seems that asbestos can induce unusually severe fibrotic reaction in some susceptible individuals.
Our study showed that the frequency of asbestos-related lung fibrosis in RPF patients was not higher than that of the asbestos-exposed controls. It has been widely accepted that the development of asbestosis requires high-level asbestos exposure, a minimum of 20–25 fiber-years . Most of our patients and the controls had exposure of <20 fiber-years, and, therefore, the proportion of persons with asbestosis was low.
Although we propose that pleural and retroperitoneal fibrosis may both be caused by asbestos fibers, there are certain differences in the clinical picture of pleural fibrosis and RPF. RPF is usually symptomatic, causing poorly localized pain in the abdominal, flank, or back region. Symptoms and laboratory findings suggesting systemic inflammation–weight loss, fever and nausea, a clearly elevated erythrocyte sedimentation rate and anaemia–are frequently present . DPT usually progresses slowly and is asymptomatic in many cases, and parietal plaques cause no symptoms. Only patients with acute asbestos pleurisy may have local and systemic symptoms and a moderately elevated erythrocyte sedimentation rate . Corticosteroids usually have a dramatic effect on inflammation in RPF, and together with surgical management of ureteric obstruction are the mainstay treatment for RPF . Corticosteroids have no role in the management of DPT, but may alleviate the symptoms of acute asbestos pleurisy.
Albeit our study population is one of the largest published sets of RPF patients in the literature, the numbers of participants in our study was still rather small. Therefore we combined the groups of RPF patients with slight and moderate-to-high asbestos exposure. This combined group of RPF patients had, on the average, less asbestos exposure than the control group with exposure of ≥ 10 fiber-years in all cases. The ordinal logistic regression modeling may, therefore, have underestimated the risk of pleural fibrosis in association with RPF.
On the basis of our epidemiologic work and our current study we propose the following criteria for the classification of RPF as an occupational disease: (i) occupational asbestos exposure of ≥ 10 fiber-years (OR 8.8) or (ii) occupational asbestos exposure of <10 fiber-years (OR 5.5) combined with bilateral pleural plaques or DPT or both pleural plaques and DPT. The presence of asbestosis (parenchymal fibrosis) should not to be required for the diagnosis of asbestos-related RPF. Asbestos-related RPF, like asbestos-related pleurisy, should be a diagnosis of exclusion. Nevertheless, asbestos-related pleural findings should be taken into account also in the presence of other risk factors, such as ergotamine medication or abdominal aortic aneurysm.