Pulmonary Medicine

Approach to tapering antisarcoidosis therapy Purpose of review Sarcoidosis is a multisystemic granulomatous disease, which commonly affects the lung. The natural course of the disease and prognosis are variable from asymptomatic, spontaneous remission to progressive disease, which requires treatment. Once treatment is initiated, tapering therapy can be problematic. Recent findings Corticosteroids are recommended as first-line therapy, but optimal regimen and duration of treatment is not well established. Treatment may differ based on severity of disease, extrapulmonary involvement, physician and patient preferences. We reviewed currently recommended regimens, particularly, in pulmonary sarcoidosis and the use of alternative treatments as corticosteroid-sparing agents. Summary Corticosteroid use is quite effective as initial therapy but is associated with significant side effects. An approach to tapering sarcoidosis therapy is not standardized, given the lack of evidence-based data. This review provides guidance based on the current literature. Correspondence to Kamonpun Ussavarungsi, MD, Division of Pulmonary and Critical Care, Department of Internal Medicine, 200 Hawkins Drive, C33 GH, Iowa City, IA 52242, USA. Tel: +1 319 384 9832; e-mail: kamonpun-ussavarungsi@uiowa.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Noninvasive volume-assured pressure support for chronic respiratory failure: a review Purpose of review Noninvasive ventilation (NIV) is an established treatment for chronic hypercapnic respiratory failure (CRF). Volume-assured pressure support (VAPS) is a mode of NIV that automatically adjusts inspiratory pressure in order to maintain a constant respiratory volume. We aim to discuss the role and application of VAPS in CRF. Recent findings Recently published meta-analyses and reviews fail to demonstrate a significant difference in gas exchange, sleep, or quality-of-life improvement in patients with CRF between VAPS and bilevel positive airway pressure (BPAP). A recent manuscript suggests that VAPS therapy in chronic obstructive pulmonary disease patients may reduce the number of exacerbations. It has been shown that with a protocol-driven approach BPAP and VAPS can both be successfully titrated during a single split-night polysomnography. Summary VAPS is as effective as other modes of NIV at improving ventilation and sleep in CRF. The potential advantage is a more consistent ventilatory support through daytime–nighttime variations and progression of disease over time. However, the impact on long-term outcomes, such as survival, has not been studied. Correspondence to Timothy I. Morgenthaler, MD, Department of Pulmonary and Critical Care Medicine and the Center for Sleep Medicine, Mayo Clinic, Rochester, MN 55905, USA. Tel: +507 266 6880; e-mail: TMorgenthaler@mayo.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Indications for treatment of sarcoidosis Purpose of review To describe the current knowledge on indications for sarcoidosis treatment. Recent findings Despite the lack of evidence-based recommendations, the sarcoidosis community has adopted the concept of starting systemic anti-inflammatory treatment because of potential danger (risk of severe dysfunction on major organs or death) or unacceptable impaired quality of life (QoL). On the contrary, while QoL and functionality are patients’ priorities, few studies have evaluated treatment effect on patient-reported outcomes. The awareness of long-term corticosteroids toxicities and consequences on QoL and the emergence of novel drugs have changed therapeutic management. Second-line therapy, mainly methotrexate and azathioprine, are indicated for corticosteroids sparing or corticosteroids-resistant sarcoidosis. TNF-α inhibitors are a useful third-line therapy in chronic refractory disease. In addition to organ-targeted treatment, efforts should also be taken for treating nonorgan-specific symptoms, such as physical training for fatigue, and various disease complications. Summary Clinicians should offer a tailored treatment for each patient and ensure a holistic multidisciplinary approach, including pharmacological and nonpharmacological interventions. Patient-centered communication is critical to drive shared decisions, in particular for the tricky situation of isolated impaired QoL as the unique therapeutic indication. Once treatment is decided, clinicians should define a clear therapeutic plan, including goals and instruments to assess response. Correspondence to Hilario Nunes, MD, PhD, Service de Pneumologie, Hôpital Avicenne, Assistance Publique Hôpitaux de Paris, 125 route de Stalingrad, Bobigny, Paris 93009, France. Tel: +33 1 48 95 51 21; fax: +33 1 48 95 51 26; e-mail: hilario.nunes@aphp.fr Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

The global view Purpose of review To understand the global distribution of different forms of pulmonary hypertension. Recent findings Different registries have explored the epidemiological characteristics of pulmonary hypertension. Interestingly, there is a clear difference in the prevalence of different forms of pulmonary hypertension in developed regions in comparison with less developed countries. This finding suggests not only that extrapolation of data should be avoided but also that the known prevalence of pulmonary hypertension might be underestimated. Summary Pulmonary hypertension might be more prevalent than what is currently believed. Specific forms of pulmonary hypertension distributed worldwide might characterize an unrecognized burden that still have to be properly approached. This highlights the heterogeneity of pulmonary hypertension around the world. It is clear that more epidemiological data are still needed as well as studies addressing management alternatives in these specific regions. Correspondence to Rogerio Souza, Pulmonary Circulation Unit, Pulmonary Division, Heart Institute, University of Sao Paulo Medical School, Av. Dr Eneas de Carvalho Aguiar, 44 – 5 and – Bl 2, São Paulo, SP 05400-900, Brazil. Tel: +55 11 26 61 56 95; e-mail: rogerio.souza@fm.usp.br Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Shaping the future of an ultra-rare disease: unmet needs in the diagnosis and treatment of pulmonary alveolar proteinosis Purpose of review Pulmonary alveolar proteinosis (PAP) can be considered the archetype of ultra-rare diseases with a prevalence of under 10 cases per million. We discuss the classification of PAP, the current diagnostic practice and the supplementary role of genetic testing and granulocyte–macrophage colony-stimulating factor (GM-CSF) signalling in the diagnosis of congenital and hereditary PAP. We report on novel therapeutic approaches such as GM-CSF substitution, stem cell transplantation, pioglitazone, statins and immunomodulation. Recent findings The discovery of new genetic mutations underlying this syndrome raises the question whether the classification should be radically revised in the future. Serum GM-CSF autoantibody is the best diagnostic marker for autoimmune PAP, the most common form, but does not correlate with disease severity. Several circulating biomarkers have been investigated to assess disease activity and predict outcome. Imaging techniques have also enormously evolved and offer new tools to quantify disease burden and possibly drive therapeutic decisions. Promising clinical trials are ongoing and will generate new treatment strategies besides or in addition to whole lung lavage in the next future. Summary Despite impressive advances in understanding pathogenesis, PAP remains a rare syndrome with several unanswered questions impacting diagnosis, management and treatment, and, as a result, patients’ quality of life. Correspondence to Francesco Bonella, Ruhrlandklinik, Universitätsmedizin Essen, Tüschener Weg 40, 45239 Essen, Germany. Tel: +49 201 433 4502; fax: +49 201 433 4029; e-mail: francesco.bonella@rlk.uk-essen.de Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

New trajectories in the treatment of interstitial lung disease: treat the disease or treat the underlying pattern? Purpose of review A subset of patients with interstitial lung diseases (ILDs), such as rheumatoid arthritis (RA)-associated ILD and chronic hypersensitivity pneumonitis, will experience a disease course similar to patients with idiopathic pulmonary fibrosis (IPF). They also often have a usual interstitial pneumonia (UIP) pattern of fibrosis. Although the standard of care for patients with RA-ILD and chronic hypersensitivity pneumonitis is immunosuppression, the optimal treatment for patients with progressive disease and a UIP pattern remains unknown. Recent findings Recent research has highlighted shared risk factors, disease behavior and pathobiology between RA-ILD, chronic hypersensitivity pneumonitis and IPF. The presence of a UIP pattern, in both RA-ILD and chronic hypersensitivity pneumonitis, is associated with a worse prognosis. Moreover, genetic risk factors, previously well characterized in IPF, are increasingly being linked to RA-ILD and chronic hypersensitivity pneumonitis. The MUC5B promoter variant rs5705950, telomerase complex mutations and short telomere lengths are also linked to an increased susceptibility to pulmonary fibrosis in RA and chronic hypersensitivity pneumonitis. Summary IPF shares several clinical, genetic and biological features with other ILDs exhibiting the UIP pattern. The optimal pharmacologic management of these patients remains uncertain. Several ongoing trials are evaluating the efficacy of antifibrotic medications in these other diagnoses and may change how we approach ILD treatment. Correspondence to Joyce S. Lee, Department of Medicine, University of Colorado, 1635 Aurora Ct, Aurora, CO 80045, USA. Tel: +1 855 586 4824; e-mail: joyce.lee@ucdenver.edu Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Patient perspectives in sarcoidosis Purpose of review The review presents an overview of the scientific publications about patient perspectives in sarcoidosis. Recent findings The literature on patient perspectives in sarcoidosis is limited. Patient perspectives in sarcoidosis encompass a myriad of topics that have been addressed to some degree in the literature: patient needs and perceptions, patient-reported burden of sarcoidosis, and patient treatment priorities. Similar findings across studies were high levels of reported fatigue, a need to incorporate psychological support into the treatment plan and easy access to sarcoidosis expert centers. Furthermore, largely similar results were found across countries. Summary There is a growing focus in patient perspectives in terms of sarcoidosis treatment. A multidisciplinary approach including psychological support and attention to fatigue, may better reflect the needs of sarcoidosis patients. Further research on sarcoidosis patient perspectives in sarcoidosis is needed to optimize care. Correspondence to Sanne J. van Helmondt, MSc, Department of Pulmonology, ILD Center of Excellence, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands. Tel: +31 883201572; e-mail: s.van.helmondt@antoniusziekenhuis.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Nonorgan manifestations of sarcoidosis Purpose of review The current review discusses the diagnosis and management of nonorgan-related symptoms that commonly arise in the setting of systemic sarcoidosis. Fatigue, small fiber neuropathy (SFN) and neuropsychological symptoms are highlighted. Recent findings The debilitating effects of chronic nonorgan-based symptoms in sarcoidosis have led to recent studies focusing on incidence rates, contributing factors and potential therapeutic strategies. In a web-based survey of over 1000 sarcoidosis patients, the most common symptom was fatigue, which was reported by over 90% of participants, whereas memory loss and concentration problems were reported in 50%. SFN was also common, and may be diagnosed with tools such as skin biopsy measurement of intraepidermal nerve fibers and corneal confocal microscopy. In a recent cohort study of SFN patients, serologic evaluation demonstrated other contributing causes such as diabetes and vitamin B12 deficiency, which warrant-specific treatment. Finally, physical inactivity in patients with sarcoidosis correlated with lower quality-of-life (QOL) scores and possibly fatigue. Multidisciplinary programs that include physical therapy, patient education and psychological support were found to improve fatigue and mood disorders. Summary Recognition of nonorgan-related symptoms and their impact on patient QOL is essential to optimal treatment of the sarcoidosis patient. Correspondence to Jinny Tavee, MD, Department of Neurology, Northwestern University Feinberg School of Medicine, 259 E Erie St. 19th Floor, Chicago IL 60611, USA. Tel: +1 312 695 7950; fax: +1 312 695 5747; e-mail: jinny.tavee@nm.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Clustering of immune-mediated diseases in sarcoidosis Purpose of review Sarcoidosis is an immune-mediated disease of unknown cause. Immune-mediated diseases appear to cluster in patients and in families. We review what is known on this topic for sarcoidosis, and what factors may underlie disease clustering. Recent findings In populations of patients with sarcoidosis, relative risk estimates of Sjögren's syndrome, systemic lupus erythematosus, autoimmune hepatitis, ankylosing spondylitis, multiple sclerosis (MS), celiac disease, autoimmune thyroid disease, and ulcerative colitis, varied between 2.1 and 11.6. In relatives of patients with sarcoidosis, relative risk estimates varied between 1.3 and 5.8 for sarcoidosis, MS, celiac disease, type 1 diabetes, Graves’ disease, rheumatoid arthritis, Crohn's disease, and ulcerative colitis. Shared risk loci in key immunological pathways provide evidence for a contribution to development of multiple diseases. Identical changes in the immune status, epigenetic alterations, and environmental triggers have been detected in several diseases, and drug-induced disease is likely responsible for a small portion of co-occurring disease. Summary Clustering of sarcoidosis and other immune-mediated diseases in patients and in their relatives occurs for sarcoidosis, MS, celiac disease, Graves’ disease, and ulcerative colitis. Further research is needed to substantiate causal links and risk estimates in patients and their relatives. Correspondence to Jan C. Grutters, MD, PhD, Department of Pulmonology, Interstitial Lung Diseases Centre of Excellence, St. Antonius Hospital, Koekoekslaan 1, 3435 CM Nieuwegein, The Netherlands. E-mail: j.grutters@antoniusziekenhuis.nl Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.

Pulmonary hypertension due to interstitial lung disease Purpose of review Pulmonary hypertension has been reported to complicate the course of a number of fibrotic lung diseases, including idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis and nonspecific interstitial pneumonitis. Most commonly, mild elevations in the mean pulmonary artery pressure are seen in patients with advanced pulmonary fibrosis. However, some patients may develop severe pulmonary hypertension, which appears out of proportion to the degree of their restrictive lung disease. Recent findings The benefits of pulmonary vasodilator therapy have yet to be established in pulmonary hypertension complicating fibrotic lung disease. In fact, one recent clinical trial examining riociguat in patients with pulmonary hypertension complicating idiopathic interstitial pneumonias was terminated early for an increased risk of death or hospitalization. Multiple clinical trials on this topic are currently ongoing, including studies examining inhaled pulmonary vasodilator therapies. Summary The development of pulmonary hypertension is associated with increased exertional oxygen requirements, worsened functional capacity and attenuated life expectancy. It is hoped that continued research will find an effective therapy for this condition, which will improve quality of life and extend life expectancy in patients with this condition. Correspondence to Christopher S. King, MD, FCCP, Inova Fairfax Advanced Lung Disease and Transplant Clinic, 3300 Gallows Rd, Falls Church, VA 22042, USA. Tel: +1 703 776 4979; fax: +1 703 776 3515; e-mail: Christopher.king@inova.org Copyright © 2019 Wolters Kluwer Health, Inc. All rights reserved.