“Sarcoidosis: Recent Advances”

In this issue of Seminars in Respiratory and Critical Care Medicine, leading researchers from around the world provide state-of-the-art reviews on sarcoidosis with updates from the last issue on sarcoidosis from 2010. Since then, the etiology of sarcoidosis is still elusive, diagnosis of sarcoidosis remains more and more a complex process of exclusion, and therapy beyond corticosteroids is problematic and debated. Within this broad scope of basic and clinical science, there has been considerable progress over the past several years in each of these areas. These fields are reviewed by researchers that have contributed in those areas and by experienced clinicians to provide a comprehensive overview for both clinicians and translational researchers.

There is compelling evidence that infectious agents play a major etiologic role in sarcoidosis with most studies focused on the role of Mycobacteria and/or Propionibacteria. The conundrum in sarcoidosis is how infectious agents induce chronic sarcoidosis without evidence of an active, viable replicating tissue microbial infection. Chen et al (see Etiologic Role of Infectious Agents, on page 285) elaborate a concept of chronic stimulation of the innate immune system by disaggregated host protein serum amyloid A within granulomas following a microbial infection that induces a hyperimmune Th1 immune response to microbial antigens associated with successful immune control.[1] In many interstitial lung diseases, including sarcoidosis, a distortion of the immune system with autoaggression and impaired wound healing can be observed. The balance of classically and alternatively activated macrophages has a great influence on the course of inflammation and wound repair also in sarcoidosis.[2] In the article of Zissel, the imbalances of the cytokine network, the T cell and the macrophage subsets are reviewed and discussed as the consequence of binding of a nominal antigen by T-lymphocytes.

The genetic background of sarcoidosis has been scrutinized in recent years without identifying clear genetic risk profiles useful to the practicing clinician. Many susceptibility genes have been identified and a recent study by Fischer et al highlights the overlap between sarcoidosis and another granulomatous disorder, Crohn disease.[3] They discuss in their article on the genetics of sarcoidosis that these findings give rise to new views on the genetics of granulomatous disorders which share genetic background and pathogenetic mechanisms.

Making the diagnosis of sarcoidosis requires the exclusion of other granulomatous disorders with similar clinical phenotypes. In this context, two disorders of particular interest are chronic beryllium disease and common variable immunodeficiency because they share many clinical features and pathogenic pathways. Importantly, these disorders need to be distinguished from sarcoidosis cohorts because the therapeutic approaches are fundamentally different.[4] [5] [6] Chronic beryllium disease and its similarities with sarcoidosis are reviewed by Maier (see Sarcoidosis and Chronic Beryllium Disease: Similarities and Differences, page 316) to guide the practicing clinician through this complex differential diagnosis. Common variable immunodeficiency and its overlap with sarcoidosis are reviewed by Verbsky and Routes (see Sarcoidosis and Common Variable Immunodeficiency: Similarities and Differences, page 330) and in the article on clinical evaluation of sarcoidosis by Valeyre.

After establishing the diagnosis of sarcoidosis, an estimation of its inflammatory activity is mandatory to help guide therapeutic decisions. Since sarcoidosis inflammation is compartmentalized to the organs manifesting with disease, gauging this local inflammatory activity by biomarkers of the peripheral blood may be difficult and of limited value. Imaging techniques have recently been shown to capture inflammatory activity causing progressive pulmonary organ damage.[7] Adams and colleagues (see FDG-PET for Gauging of Sarcoid Disease Activity, on page 352) present in their article a comprehensive overview of the development of gauging sarcoidosis activity by fluorine-18 labeled fluorodeoxyglucose positron emission tomography.

Biological drugs can be used to manipulate the cytokine network in chronic inflammatory disorders. In Crohn disease and many collagen vascular diseases, effective biologic treatment regimens have been developed. In sarcoidosis, however, development of effective biologic treatments is making only slow progress and all current consensus therapies lack regulatory approval. In their review, Baughman and colleagues review the therapeutic options employing classical immunosuppressive drugs and biologicals that have been the focus of multiple studies in the treatment of sarcoidosis. These investigators also identify some promising biologicals and other therapies with potential for therapeutic use in sarcoidosis but that have not yet been the focus of large clinical trials.[8]

The protean manifestations of cardiac sarcoidosis pose a diagnostic dilemma since they may take place without further organ manifestations pointing toward the diagnosis of multisystem sarcoidosis. A systematic clinical approach employing new diagnostic and therapeutic concepts is given by Lynch and colleagues. Advanced interstitial lung diseases may cause pulmonary hypertension and right heart disease.[9] In their article, Shino and colleagues review studies that indicate this is also the case for sarcoidosis in which medical therapy of pulmonary hypertension is limited and lung transplantation is the last resort.

In summary, this issue of Seminars in Respiratory and Critical Care Medicine will hopefully illustrate the scientific and clinical progress of the past 4 years in the broad spectrum of basis science and clinical activities in sarcoidosis. The articles highlight the difficulties encountered when rare disorders are in the focus of basic science and clinical researchers. Despite these considerable challenges, this issue shows progress has been made that can help guide clinical decisions. We thank all the contributors of this issue for sharing their specific insight and experience, which we hope will enhance the readers' interest and understanding of sarcoidosis.

• References

• 1 Chen ES, Song Z, Willett MH , et al. Serum amyloid A regulates granulomatous inflammation in sarcoidosis through Toll-like receptor-2. Am J Respir Crit Care Med 2010; 181 (4) 360-373
• 2 Pechkovsky DV, Prasse A, Kollert F , et al. Alternatively activated alveolar macrophages in pulmonary fibrosis-mediator production and intracellular signal transduction. Clin Immunol 2010; 137 (1) 89-101
• 3 Fischer A, Nothnagel M, Franke A , et al. Association of inflammatory bowel disease risk loci with sarcoidosis, and its acute and chronic subphenotypes. Eur Respir J 2011; 37 (3) 610-616
• 4 Bouvry D, Mouthon L, Brillet PY , et al; Groupe Sarcoïdose Francophone. Granulomatosis-associated common variable immunodeficiency disorder: a case-control study versus sarcoidosis. Eur Respir J 2013; 41 (1) 115-122
• 5 Chase NM, Verbsky JW, Hintermeyer MK , et al. Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID). J Clin Immunol 2013; 33 (1) 30-39
• 6 Ribeiro M, Fritscher LG, Al-Musaed AM , et al. Search for chronic beryllium disease among sarcoidosis patients in Ontario, Canada. Lung 2011; 189 (3) 233-241
• 7 Keijsers RG, Verzijlbergen EJ, van den Bosch JM , et al. 18F-FDG PET as a predictor of pulmonary function in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 2011; 28 (2) 123-129
• 8 Sweiss NJ, Lower EE, Mirsaeidi M , et al. Rituximab in the treatment of refractory pulmonary sarcoidosis. Eur Respir J 2014;
• 9 Saggar R, Khanna D, Vaidya A , et al. Changes in right heart haemodynamics and echocardiographic function in an advanced phenotype of pulmonary hypertension and right heart dysfunction associated with pulmonary fibrosis. Thorax 2014; 69 (2) 123-129