Sarcoidosis: Evolving Concepts

Jan C. Grutters, MD, PhD

Despite a history of more than 100 years and a huge amount of scientific effort sarcoidosis still remains an enigmatic disorder of unknown etiology. The disease challenges many health care professionals, researchers, and in the first place patients, who suffer most from its consequences, every day.

A regular update of our understanding of the disease, including new insights from recent clinical and/or fundamental studies, is therefore of the utmost importance. It helps to maintain the highest quality of care given to sarcoidosis patients, and to facilitate researchers in their search of the unknown that could ultimately lead to a cure for the disease.

It is therefore that I present with great pleasure the current issue of Seminars in Respiratory and Critical Care Medicine (SRCCM) which is entirely dedicated to sarcoidosis. “Sarcoidosis: Evolving Concepts” is written by an outstanding group of clinicians and scientists. Many of them are world renowned and very experienced in the care of sarcoidosis; others are more at the beginning of their career but already highly dedicated to the unraveling of its mysteries.

The issue starts off with an interesting article by Mateyo and Thomeer giving a global perspective on the epidemiology of sarcoidosis, and especially recognizing the understudied but yet susceptible African population. It is, in particular, this population with a relatively unmixed genetic background that can provide us with a unique opportunity for unraveling the complex genetic basis of sarcoidosis.

After that, Beijer et al give a very detailed overview of our current understanding of the etiology and immunopathogenesis of sarcoidosis. Besides long suspected exogenous triggers, such as mycobacterial and Propionibacterium antigens, also self-antigens, such as vimentin and serum amyloid A, have recently been found to play a role in the development of sarcoidosis, supporting autoimmunity as a cause of the disease.

The next article by Calandriello and Walsh describes the significant advances that have been made in the imaging of sarcoidosis over the last decade. They present to us an integrated clinicoradiological staging algorithm for stratifying risk in patients with pulmonary sarcoidosis in clinical practice (combining key lung function parameters and high-resolution computed tomography (HRCT) findings). Further, they highlight the emerging role of ¹⁸F-fluorodeoxyglucose positron emission tomography (FDG-PET) in diagnosis and management of sarcoidosis.

The six following articles deal with significant clinical manifestations of sarcoidosis. Karakaya et al give an articulate review on the acute type sarcoidosis, also referred to as the Löfgren's syndrome. This phenotype is of great scientific interest as it has the strongest genotype–phenotype associations so far reported in sarcoidosis, and shows a remarkable seasonal clustering during the spring months. Up-to-date and very useful reviews on pulmonary sarcoidosis and sarcoidosis-associated pulmonary hypertension are provided by Bonifazi et al, and by Shlobin and Baughman, respectively. The other three articles deal with important clinical topics, all necessitating specific expertise, and ideally a multidisciplinary collaboration. (1) The article by Sayah et al on cardiac sarcoidosis (CS) emphasizing the need for a thorough diagnostic process and aggressive management strategy in this condition, including immunosuppressive medication and/or placement of implantable cardioverter defibrillator, especially in cases with serious ventricular arrhythmias and/or diminished cardiac function. Despite the lack of evidence from randomized controlled trials, it is clear that mortality rates of untreated CS are high. The role of FDG-PET is evolving in the follow-up of CS, especially to ascertain the effect of immunosuppressive therapy in the organ at danger. (2) The article by Culver et al on neurosarcoidosis makes it very clear that neurosarcoidosis has a wide variety of clinical manifestations with broad differential diagnosis. Specialized multidisciplinary teams are, therefore, indispensable for optimal care, which also accounts for the management of small fiber neuropathy, a recently recognized nongranulomatous parasarcoidosis syndrome with a high impact on the quality of life. (3) Finally, the article by Groen and Rothova gives us an extensive overview of the ocular involvement of sarcoidosis, which may occur in a substantial subset of patients, and can be sight threatening, often requiring systemic treatment. According to these experts, the visual outcome of sarcoidosis-associated uveitis is, however, fairly good if therapy has started on time.

Subsequently, the current medical therapy for sarcoidosis is reviewed by Valeyre et al. Although, there have been no major breakthroughs from randomized controlled trials, like for example in idiopathic pulmonary fibrosis (IPF), the role of tumor necrosis factor alpha (TNF-α) inhibitors has further crystallized. Currently, they are used in many centers around the world, especially in severe refractory cases. Importantly, in pulmonary sarcoidosis, it was recently demonstrated that response to infliximab depends upon the intensity of the inflammatory process in the lung parenchyma measured by FDG-PET. Together with the experience of FDG-PET in CS, this finding gives rise to the concept of FDG-PET being a valuable tool for precision medicine in sarcoidosis, that is, to estimate the potential benefit and/or to ascertain the effect of immunosuppressive therapy in vital organs, such as heart and lungs, on an individual basis. Also, Schupp et al provide us with a detailed overview of current ongoing studies in sarcoidosis which will hopefully lead to novel therapies in the near future. Further, Yserbyt et al carefully describe the role of solid organ transplantation in sarcoidosis. For selected patients, overall survival after lung as well as heart transplantation is reported to be comparable to other indications. An important message in their article is that although sarcoidosis may recur after transplantation, currently no reason withholds this chance of surviving from otherwise eligible patients.

The last article by Judson presents a comprehensive state-of-the-art overview of the quality of life in sarcoidosis. Although well aware of their core task to save sarcoidosis patient from the dangerous manifestation of the disease, clinicians in real life are much more confronted by patients that suffer from chronic debilitating symptoms without having a life- and/or organ-threatening disease. Optimal management usually starts with proper assessment. Therefore, it is estimated that in the near future health-related quality of life assessment will become more important in everyday sarcoidosis care. Nevertheless, some hurdles are to be taken care of which are nicely discussed in this contribution of Judson.

In summary, this issue of SRCCM will hopefully serve as a valuable update for those involved in the care for sarcoidosis, and might inspire researchers in their work toward a better understanding of this extraordinary disease.

Last but not the least I would like to thank all the authors for their outstanding contribution to this remarkable issue.