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Dr. Efferen is a member of the Division of Pulmonary and Critical Care Medicine, State University of New York, Downstate and Kings County Hospital Center, Brooklyn, NY.
Correspondence: Linda S. Efferen, MD, FCCP, State University of New York, Downstate Box 19, 450 Clarkson Ave, Brooklyn, NY 11203; e-mail: lefferen{at}dnamail.com
It is well-recognized that sarcoidosis is a multisystemic disorder of unknown etiology that can present with a myriad of signs and symptoms, but most commonly presents with pulmonary, ocular, or cutaneous involvement. Nonetheless, well over 100 years since its first description, unanswered questions about sarcoidosis abound. That is not to say that great strides have not been made in understanding the underlying pathogenesis and pathophysiology of the disease. However, with respect to clinical management, we remain at a point at which significant breakthroughs appear as a distant goal on the horizon, with no guarantee of attainment.
In addition to being of unknown etiology, predicting who will get sarcoidosis or who is destined to experience a "bad" clinical course has proven elusive. While a genetic predisposition or susceptibility to disease appears to be certain, with an impact on the clinical manifestations and outcome, the ability to predict an individual’s clinical course is limited. In the area of treatment, significant controversy and uncertainty remain. Relatively recently we have moved away from a position of treating all patients with sarcoid to, perhaps, a period of expectant observation in anticipation of spontaneous remission when possible.1 2 However, a role for long-term treatment, even in the absence of symptoms or deterioration, has been advocated3 and continues to be debated.
What makes sarcoidosis so challenging? There is a multitude of possible answers. Let us take the numerical problem. Perceived as a rare disease (which it is not), sarcoidosis tends to follow a generally benign clinical course in the majority of patients. Although reports vary, it is estimated that approximately half of all patients have no or minimal symptoms or signs, approximately 40% have moderate disease, and < 10% have severe disease. Sarcoidosis suffers from a set of unfortunate perceptions. Who can get excited about a disease considered "usually a self-limited disease"?4 In addition, the very nature of the disease, its ability to affect literally any organ or body part, the highly variable nature of the clinical course, and the varied symptoms and signs emanating from specific organ involvement all contribute to the fragmentation of our clinical experience and the data in the published literature. Clinical sarcoidosis is a difficult disease to study. Definitions of disease, organ involvement, severity of disease, and treatment strategies remain highly varied and as individualized as the number of investigators reporting their experience.
Some of these difficulties are being addressed. A Case Control Etiologic Study (ACCESS) group proposed an instrument for defining organ involvement in patients with sarcoidosis.5 It is hoped that this instrument will lead to an improvement in the standardization of the definition of organ involvement in sarcoidosis, eliminating some of the confusion encountered by clinicians and researchers when they attempt to characterize or classify a patient. Unfortunately, it does not address the degree or severity of involvement or the activity of disease. The joint statement6 on sarcoidosis from the American Thoracic Society, the European Respiratory Society, and the World Association of Sarcoidosis and Other Granulomatous Disorders (WASOG) is an invaluable reference for clinicians and investigators. Periodic updates to the statement as new information becomes available would allow leaders in the field to continue to provide a much-needed consensus statement that remains current and timely.
Pulmonary hypertension, also a problematic disease, is estimated to occur in 1 to 4% of patients with sarcoidosis.7 The prevalence is likely to be higher in patients with more severe disease.8 9 Most commonly ascribed to long-standing parenchymal lung disease with fibrosis and hypoxia, granulomatous involvement of pulmonary arterioles,10 severe obliteration of pulmonary veins by noncaseating granulomas,11 and proximal pulmonary artery stenosis secondary to enlarged hilar nodes12 have also been described. Despite the varied mechanisms underlying the pathogenesis of pulmonary hypertension, it appears that pulmonary vasodilatation may be effective in a wide range of underlying pathologic abnormalities.13
In this issue of CHEST, Preston et al (see page 866) report their experience with eight patients with moderate-to-severe sarcoidosis related pulmonary hypertension. As with most articles delineating therapeutic trials in sarcoid, this article suffers from its unavoidable design (a prospective observational study) and its small sample size. Nevertheless, despite these limitations the authors should be commended for their significant contribution to our knowledge on this specific issue.
The authors provide a well-constructed overview of the current understanding and experience of pulmonary hypertension and sarcoidosis. As they point out, the short-term and long-term responses to vasodilators in patients with sarcoidosis and pulmonary hypertension have not been studied extensively, with few prior cases having been reported in the literature.13 14 15 Based on referral patterns, the authors were able to accumulate what is now the largest published experience evaluating the vasoresponsiveness of patients with sarcoidosis-associated pulmonary hypertension. They demonstrated that the administration of both inhaled nitric oxide (iNO) and IV epoprostenol resulted in a favorable acute response in the majority of their patients. Acutely, seven of eight patients responded to iNO vs four of the six patients who were given epoprostenol. While the authors state that two of five patients given calcium channel blockers responded, this response was limited to a decrease in systemic vascular resistance. The severity of disease in their patients can be appreciated by the fact that six of the eight patients died an average of 7 months after the acute trial. Of interest, the average survival time for the five patients treated with iNO was 15.4 months, and the only two "long-term" survivors currently still alive were treated with iNO.
While acknowledging the inherent bias in the literature against the publication of "negative" studies, the authors’ ability to demonstrate physiologic and perhaps survival benefit is intriguing and encouraging. Given the small number of patients in their series, one should not leap to conclusions, and this cannot be considered a definitive study. On the other hand, there is a strong suggestion of possible, if not probable, benefit. For once, the possibility of therapeutic benefit for patients experiencing recalcitrant disease seems possible, if transient.
But there is another issue to be considered. The authors note that long-term iNO therapy was not initiated for study patients after January 1999 due to increased costs and lack of funding. They also note that long-term treatment with epoprostenol was not studied, even though it may be as effective as long-term iNO treatment, since treatment in secondary pulmonary hypertension is usually not covered under current Medicare reimbursement guidelines, although compassionate-use protocols may be approved by some insurance carriers.14 So where do we go from here?
Sarcoidosis is not a rare disease. While the clinical course may be considered to be generally benign, it is highly variable. A significant proportion of patients have severe, unremitting, or progressive disease. Sarcoidosis is estimated to have an incidence of 21 cases per 1 million persons, exceeding that of idiopathic pulmonary fibrosis, lymphangioleiomyomatosis, and other rare interstitial lung disorders.16 Yet, sarcoidosis lags behind these other diseases when it comes to recognition and research funding.
There are many investigators who have made the study of sarcoidosis a personal priority. There are many patients with sarcoidosis who urgently need us to move the field forward. There is no paucity of sarcoidosis groups or registries that are sponsored by patients with the disease or individuals or institutions with an interest in the disease. These registries have done much to disseminate information and to promote awareness of the disease, but they are neither uniform nor unified.
I would like to use this editorial platform to exhort those with an interest in sarcoidosis who have access to patients with sarcoidosis to generate the momentum necessary to establish an organized method to share data, experiences, and expertise. The need for this can be no more clearly exemplified than by the plight delineated by the current authors.
The ACCESS group and the recently established North American chapter of WASOG are the most readily identifiable groups that could help spearhead the initiative that I would like to propose: to establish a national or international registry and database of sarcoidosis patients and a research consortium. This could serve as a potential resource to all investigators and clinicians, fostering participation in the development or utilization of treatment and research protocols and guidelines. In turn, this would greatly expand the ability to accumulate important information and would allow us to more rapidly develop new protocols and, ultimately, to better serve the unfortunate patient with severe debilitating sarcoidosis who may not have direct access to centers with significant expertise.
The suggestion to establish a registry and research initiative is not novel. But neither has it yet been done for sarcoidosis. We have a specific issue presented by Preston and coworkers: should iNO and epoprostenol be approved for use in patients with secondary pulmonary hypertension that is associated with sarcoidosis? I believe we would all respond that more data are necessary and that better designed trials are required. Yet, it is likely that attempts to reproduce the experience of Preston et al will be forthcoming as patient care dictates, even in the absence of the organized collaborative effort that is required to come to some firm conclusions.
Will this require a lot of hard work and planning? Without a doubt. But, it is time to move the field forward. In addition to this particular question, many other perplexing issues and problems emanating from this fascinating and challenging disorder could be addressed. Let’s get the ball rolling!
References
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