© 2006 American Thoracic Society doi: 10.1164/rccm.2509010
LymphangioleiomyomatosisA National Registry for a Rare DiseaseNottingham University, Nottingham City Hospital, Nottingham, United Kingdom
Miller School of Medicine, University of Miami, Miami, Florida Lymphangioleiomyomatosis (LAM), like other rare diseases, raises particular problems for patients, physicians, and those involved in research. Patients are frustrated by the fact that their family doctor and friends have not heard of the condition, and their specialist may or may not have seen a case previously. Finding that little research is being performed into their disease only compounds this frustration since it removes the hope that often sustains patients with such an illness—that an effective treatment may appear in their lifetime. This was the situation in which patients with LAM found themselves 10 to 15 years ago, when the medical literature was essentially limited to a few reviews and case reports (1, 2). LAM was seen as a cystic lung disease, associated in approximately half the patients with renal angiomyolipomas (3, 4). Patients were often treated with hormonal therapies, for which there was, and still is, little evidence of efficacy (5). Within the last decade, however, the situation has changed remarkably, mainly due to three interrelated developments. The LAM Foundation, founded in 1995 by the mother of a patient with LAM, has provided patient support and advocacy for patients with LAM with great effectiveness, in addition to raising considerable funds for research. Support groups in other countries provide similar benefits. A second factor has been the fact that LAM- like lung disease is also found in some patients with tuberous sclerosis complex (TSC) (6, 7), and much progress has been made in identifying the genes responsible for TSC, the proteins they code for, and the pathways concerned with the disease. The mammalian target for rapamycin, mTor, appears to be involved in sporadic LAM as well as TSC (8, 9), and clinical trials of rapamycin in patients with LAM and TSC are now underway. A third factor has been the establishment in 1997 of a national U.S. LAM registry by the National Heart, Lung, and Blood Institute. Any patient with LAM who wishes to be seen at one of six participating centers and is able to attend annually can enroll. The registry is designed to further characterize the clinical and laboratory features and natural history of LAM, and to be a resource for research and clinical trials. It is clear from the registry and previous work that LAM may occur sporadically or as part of TSC; an important difference is that TSC can be inherited, whereas sporadic LAM can not. Patients with sporadic LAM may have renal angiomyolipomas, axial lymphadenopathy, or abdominal lymphangiomyomas, but no other features of TSC. Whether there is benefit in dividing patients with sporadic LAM into those with and without extrapulmonary manifestations is uncertain. (10). In this issue of the Journal (pp. 105–111), Ryu and colleagues (11) describe the clinical characteristics of 230 patients with LAM enrolled in the U.S. national registry between 1998 and 2001. Most patients had sporadic LAM and 15% had TSC. At the time they were enrolled, some patients had newly diagnosed LAM, whereas others had been diagnosed some years previously and were therefore likely to have more severe disease. This is by far the largest database of patients with LAM, and the authors are to be congratulated on collecting data on so many patients. Their findings confirm in most respects those reported in previous studies (1, 2, 12, 13), including the high incidence of pneumothorax and recurrent pneumothoraces. There are some differences, however; patients in the current series covered a wider age range and presented with their first symptom at an older age, 39 years compared with 32 to 34 years in three previous series (1, 2, 13). Whether this difference reflects a change in the disease over time, differences in subject selection, or geographical differences in age of onset is not clear, but the finding is intriguing and merits further investigation. Increased recognition of LAM, and more widespread availability of imaging techniques, should ensure the disease is diagnosed earlier, and indeed a third of the patients had normal lung function at enrollment. Some data from the registry have been reported previously, including information on bone density, lung function, and meningiomas (14–16). Data on quality-of-life measurements have been collected for the first time for patients with LAM, and are compared here with the findings from patients with chronic obstructive pulmonary disease, although interpretation is difficult in view of the marked differences in age, sex, and lung function. One of the main values of this registry will be for follow-up studies, to see, for example, whether patients with sporadic LAM and extrapulmonary features have a different prognosis from those without these characteristics. It should be recognized, however, that patients who enroll in the registry are unlikely to be representative of all patients with LAM. Selection bias is suggested by the high proportion of college graduates, and patients with more severe disease may not wish to travel to a distant center on a regular basis, particularly if it involves air travel and they have had one or more pneumothoraces. LAM is a progressive disease, so measures of severity, such as lung function, will depend on how advanced the disease is, and mean figures will reflect the ratio of prevalent to incident cases, which may be higher when a registry is new. The authors have included data on sporadic LAM and LAM associated with TSC separately in most tables, but the combined figures may reflect the relative numbers in each category because patients with TSC appear to have milder lung problems in general (7). Finally, it is difficult for the reader to determine whether some outcomes, such as the number of pregnancies or miscarriages, differ from those expected among women of a similar age without a matched control group. This may be worth considering in the future. Having a national registry should help overcome some of the problems experienced by patients with a rare disease. It will help develop centers with expertise, provide a critical mass of patients to be studied over time, and should facilitate research. Time will tell whether the national LAM registry will show the way forward for other rare diseases. FOOTNOTES Conflict of Interest Statement: Neither of the authors has a financial relationship with a commercial entity that has an interest in the subject matter of this manuscript. REFERENCES
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