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Sarcoidosis New Concepts in Cause and Treatment

PCCSU Volume 25, Lesson 14

PCCSU

The American College of Chest Physicians offers this lesson as a review of a previously offered self-study program. The program provides information on pulmonary, critical care, and sleep medicine issues. CME is no longer available for the PCCSU program.

Objectives

  • Update your knowledge and understanding of pulmonary medicine topics.
  • Update your knowledge and understanding of critical care medicine topics.
  • Update your knowledge and understanding of sleep medicine topics.
  • Learn clinically useful practice procedures.

CME Availability

Effective July 1, 2013, PCCSU Volume 25 is available for review purposes only.

Effective December 31, 2012, PCCSU Volume 24 is available for review purposes only.

Effective December 31, 2011, PCCU Volume 23 is available for review purposes only. CME credit for this volume is no longer being offered

Effective December 31, 2010, PCCU Volume 22 is available for review purposes only. CME credit for this volume is no longer being offered.

Accreditation Statement

The American College of Chest Physicians is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

CME Statement

Credit no longer available as of July 1, 2013.

Disclosure Statement

The American College of Chest Physicians (CHEST) remains strongly committed to providing the best available evidence-based clinical information to participants of this educational activity and requires an open disclosure of any potential conflict of interest identified by our faculty members. It is not the intent of CHEST to eliminate all situations of potential conflict of interest, but rather to enable those who are working with CHEST to recognize situations that may be subject to question by others. All disclosed conflicts of interest are reviewed by the educational activity course director/chair, the Education Committee, or the Conflict of Interest Review Committee to ensure that such situations are properly evaluated and, if necessary, resolved. The CHEST educational standards pertaining to conflict of interest are intended to maintain the professional autonomy of the clinical experts inherent in promoting a balanced presentation of science. Through our review process, all CHEST CME activities are ensured of independent, objective, scientifically balanced presentations of information. Disclosure of any or no relationships will be made available for all educational activities.

CME Availability

Volume 25 Through June 30, 2013
Volume 24 Through December 31, 2012
Volume 23 Through December 31, 2011
Volume 22 Through December 31, 2010

Hardware/software requirements: Web browsing device with working Web browser.

PCCSU Volume 25 Editorial Board

Editor-in-Chief
Steven A. Sahn, MD, FCCP

Director, Division of Pulmonary and Critical Care Medicine, Allergy, and Clinical Immunology
Medical University of South Carolina
Charleston, SC

Dr. Sahn has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Deputy Editor
Richard A. Matthay, MD, FCCP

Professor of Medicine
Section of Pulmonary and Critical Care Medicine
Yale University School of Medicine
New Haven, CT

Dr. Matthay has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Alejandro C. Arroliga, MD, FCCP
Professor of Medicine
Texas A&M Health Science Center
College of Medicine
Temple, TX

Dr. Arroliga has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Paul D. Blanc, MD, FCCP
Professor of Medicine
University of California, San Francisco
San Francisco, CA

Dr. Blanc has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health, Flight Attendants Medical Research Institute – university grant monies
University of California San Francisco, US Environmental Protection Agency, California Environmental Protection Agency Air Resources Board – consultant fee
Habonim-Dror Foundation Board of Trustees – fiduciary position

Guillermo A. do Pico, MD, FCCP
Professor of Medicine
University of Wisconsin Medical School
Madison, WI

Dr. do Pico has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Ware G. Kuschner, MD, FCCP
Associate Professor of Medicine
Stanford University School of Medicine
Palo Alto, CA

Dr. Kuschner has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Teofilo Lee-Chiong, MD, FCCP
Associate Professor of Medicine
National Jewish Medical Center
Denver, CO

Dr. Lee-Chiong has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

National Institutes of Health – grant monies (from sources other than industry)
Covidien, Respironics, Inc. – grant monies (from industry-related sources)
Elsevier – consultant fee

Margaret Pisani, MD, MPH, FCCP
Assistant Professor of Medicine
Yale University School of Medicine
New Haven, CT

Dr. Pisani has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Stephen I. Rennard, MD, FCCP
Professor of Medicine
University of Nebraska Medical Center
Omaha, NE

Dr. Rennard has disclosed significant relationships with the following companies/organizations whose products or services may be discussed within Volume 25:

AstraZeneca, Biomark, Centocor, Novartis – grant monies (from industry-related sources)

Almirall, Aradigm, AstraZeneca, Boehringer Ingelheim, Defined Health, Dey Pharma, Eaton Associates, GlaxoSmithKline, Medacrop, Mpex, Novartis, Nycomed, Otsuka, Pfizer, Pulmatrix, Theravance, United Biosource, Uptake Medical, VantagePoint – consultant fee/advisory committee

AstraZeneca, Network for Continuing Medical Education, Novartis, Pfizer, SOMA – speaker bureau

Ex Officio
Gary R. Epler, MD, FCCP

Clinical Associate Professor of Medicine
Harvard Medical School
Brigham & Women's Hospital
Boston, MA

Dr. Epler has disclosed no significant relationships with the companies/organizations whose products or services may be discussed within Volume 25.

Lilly Rodriguez
ACCP Staff Liaison

By Antonio D. Gomez, MD; and Laura L. Koth, MD

Dr. Gomez is Assistant Clinical Professor, Department of Medicine, Division of Pulmonary and Critical Care Medicine, University of California, San Francisco; and Dr. Koth is Assistant Professor of Medicine, University of California, San Francisco, San Francisco, California.

Drs. Gomez and Koth have disclosed no significant relationships with the companies/organizations whose products or services may be discussed within this chapter.

Objectives

  1. Have an understanding of the evidence linking mycobacterial pathogens to sarcoidosis.
  2. Be familiar with new T-cell subsets that may play a role in the pathogenesis of sarcoidosis.
  3. Describe the principles of treatment for patients with pulmonary sarcoidosis.
  4. Describe the pros and cons of initiating treatment in pulmonary sarcoidosis.
  5. Understand the state of current data in support of infliximab for the treatment of sarcoidosis.

Key words: corticosteroids; infliximab; invariant natural killer T cells; mycobacteria; neurosarcoidosis; sarcoidosis; serum amyloid A; T regulatory cells; tumor necrosis factor-α

Abbreviations: HDL = high-density lipoprotein; iNKT = invariant natural killer T; LVD = left ventricular dysfunction; mKatG = Mycobacterium tuberculosis cabalase-peroxidase protein; PH = pulmonary hypertension; PPD = purified protein derivative; TNF = tumor necrosis factor; Treg = T regulatory cell

Sarcoidosis is a systemic granulomatous disease of unknown etiology. Numerous genetic and large epidemiologic studies have provided insights into the etiology of sarcoidosis, suggesting that the development of sarcoidosis requires two factors: a genetic predisposition plus one or more types of environmental exposure(s).1 The exposures are thought to provide the “antigenic stimulus” responsible for initiating an exaggerated immune response and development of granulomatous inflammation. This lesson addresses knowledge gaps related to the content of recent studies of the underlying biology of sarcoidosis and reports on newer adjunct treatments beyond corticosteroids.

Recent Studies to Identify a Causal Antigen

In basic, translational, and clinical studies in the last several years, researchers have made important progress in our thinking about the pathogenesis of sarcoidosis by trying to identify specific antigens associated with sarcoidosis but not other conditions. Although the concept that Mycobacterium tuberculosis may be involved in the development of sarcoidosis is not a new one, recent translational research has examined this possibility using newer technologies and has shed light on the fact that a reproducible percentage of subjects with sarcoidosis have evidence of mycobacterial nucleic acids or proteins being present or demonstrate specific immune responses to mycobacterial antigens.

The mKatG Protein
Work from several independent groups has discovered important biological links between sarcoidosis and the Mycobacterium tuberculosis catalase-peroxidase protein (mKatG). The group who identified this potential antigen of sarcoidosis capitalized on the long-standing observation that homogenates of sarcoid granulomatous tissue injected intradermally in patients with sarcoidosis elicit a nidus of granulomatous inflammation that is indistinguishable from spontaneously arising granulomas, a response known as the Kveim-Siltzbach reaction.2 Because Kveim extracts undergo extensive chemical processing prior to injection, this suggested that the “antigen” capable of inducing a sarcoidosis granulomatous response could be found in this homogenate and is likely poorly soluble. In newer research using serum and granulomatous tissues from sarcoidosis subjects and sophisticated protein methods (protein immunoblot followed by mass spectrometry), investigators have identified the poorly soluble protein mKatG in tissue homogenates. Validation studies using anti-mKatG monoclonal antibodies confirmed the presence of mKatG in 5 of 9 (55%) sarcoidosis tissues, but in none of 14 control tissues (P<.001).3 In addition, IgG antibodies to recombinant mKatG were detected in the sera of 12 of 25 sarcoidosis subjects (48%) compared with 0 of 11 purified protein derivative (PPD)-negative subjects (0%) and 4 of 10 (40%) PPD-positive subjects.3 These researchers concluded that mKatG is one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis.

Independent studies using peripheral blood mononuclear cells from patients with sarcoidosis and from control individuals detected sarcoid-associated “classic” immune responses (T helper 1-type) in response to stimulation by mKatG peptides in 15 of 26 sarcoidosis patients, 1 of 24 PPD-negative subjects, and 7 of 8 PPD-positive subjects.4 Similar studies by another group found in a US and Swedish cohort that approximately 50% of sarcoidosis subjects had T helper 1-type (interferon-γ) immune responses to mKatG.5 Interestingly, the proportion of “positive” mKatG responders remained constant, regardless of years of sarcoidosis disease activity, including those with active disease for >10 years. The investigators also found that patients who experienced spontaneous remission of their disease lost their immune responses to mKatG. Additional analysis indicated that T cells that made interferon-γ in response to mKatG protein were enriched in the lung.5

Other Potential Sarcoid Antigens
In addition to mKatG protein, many other mycobacterial proteins and/or peptides have been shown to induce T helper 1-type immune responses in peripheral blood mononuclear cells, and/or lung T cells. These include early secreted antigenic target protein 6 (ESAT-6), mycolyl transferase (Ag85A), superoxide dismutase A (sodA), and heat shock protein 70 (HSP).6-8

Collectively, these data support the concept that mycobacterial peptides/proteins can serve as antigenic stimuli that induce immune responses characteristically observed in sarcoidosis. However, these data do not prove that mycobacterial proteins cause the disease; the proteins are merely, at this point, associated with sarcoidosis. Moreover, only one third to one half of all patients studied demonstrated characteristic T helper 1-type immune responses to mycobacterial proteins. Other observations important to point out are the fact that positive immune responses were measured in the blood and were further enriched in diseased organs. This argues that analysis of immune cells in the blood can reveal important data relevant to the biology of sarcoidosis, an observation that should not be minimized. Another important finding in one of the studies was the fact that mKatG immune responses were independent of the length of time of known disease. This argues that the systemic inflammatory profile in sarcoidosis may be more stable over time than suspected, and further, that it may also be independent of clinical disease variants (eg, thoracic vs extrathoracic disease), such as those manifested in different populations (eg, US vs Swedish patients, as noted above).5 In short, much more work must be done to better understand the link between mycobacterial proteins and the sarcoid disease process.

Role of Serum Amyloid A in Sarcoidosis

Serum amyloid A refers to a family of apolipoproteins. The common forms are induced by inflammatory signals (eg, interleukin-1) and are produced largely by hepatocytes. These apolipoproteins are considered a type of “acute-phase protein.” Serum amyloid A has been found to play an immunomodulatory role, including inducing chemotaxis and promoting the expression of adhesion molecules and metalloproteinases. It also enhances the binding of high-density lipoprotein (HDL) to macrophages and helps in delivery of lipids to sites of injury for use in tissue repair. The first association between serum amyloid A and sarcoidosis was demonstrated by measuring significant decreases in HDL cholesterol serum concentrations in patients with sarcoidosis vs control individuals (indicating that serum amyloid A was displacing cholesterol from HDL). A subsequent study found significant increases in serum amyloid A that correlated to disease activity.9

These findings were followed up in 2010 by a study showing that high levels of serum amyloid A were found in granulomas from subjects with sarcoidosis, but very little serum amyloid A was found in granulomas in other diseases.10 This research group further found that serum amyloid A correlated with the presence of CD3+ T cells within sarcoid granulomas. Additional experiments revealed that serum amyloid A could activate inflammatory transcription factors and cytokines via a receptor important in innate immune responses (specifically, Toll-like receptor 2). These investigators proposed a model in which serum amyloid A is induced in response to mycobacterial organisms. As the mycobacteria are destroyed by the host immune response, remnant proteins, such as mKatG, are left behind. These proteins serve as antigens that are “trapped” by the amyloid aggregation that occurs in granulomas. This trapped as well as free serum amyloid can activate Toll-like receptor 2 on immune cells and induce production of cytokines that promote T helper 1-type inflammation. Chronic sarcoidosis, in this model, is the result of ineffective clearance of the deposited amyloid proteins, which allows for continued inflammatory responses.10

A very recent study has confirmed significant increases of serum amyloid A in the serum of patients with sarcoidosis vs control individuals.11 This study also found that serum amyloid A was inversely correlated with FEV1, and these serum levels were significantly higher in persons with chronic sarcoidosis who required prolonged and multiple steroid treatments compared with patients who did not. Thus, these studies provide very recent and provocative data further implicating serum amyloid A in the pathogenesis of sarcoidosis and also suggest the potential use of serum amyloid A levels as a biomarker.

Novel Subsets of T Cells in Sarcoidosis

Emerging data suggest that specific subsets of T cells may contribute to the pathogenesis of sarcoidosis. Although it is too early to know whether these T cells are pathogenic or protective, there is reproducible evidence demonstrating abnormalities of these cells in sarcoidosis in terms of their numbers, their function, or both.

Invariant Natural Killer T Cells
Invariant natural killer T (iNKT) cells are innate immune cells that express surface markers for both T cells and natural killer cells. They are thought to play a role in innate immune responses owing to their ability to secrete T helper 1-type and T helper 2-type cytokines within minutes of T-cell receptor activation. To date, there have been at least two independent studies in two different racial/geographic cohorts demonstrating that this subset of T cells is markedly diminished in patients with sarcoidosis compared with control individuals.12,13 In one study of 60 patients with sarcoidosis from the United Kingdom, iNKT cells were significantly decreased in both the circulation and the lung (in BAL fluid) compared with 60 matched control subjects.12 An independent study in Japan found similar decreases in iNKT cells in the blood of patients with sarcoidosis.13 The reason for the decrease in iNKT cells remains debatable, as there are conflicting data regarding whether these cells home in on the diseased organs and thus appear “decreased” in the circulation. An alternative hypothesis is that they are activated and apoptose as part of the inflammatory processes that occur in sarcoidosis. Further studies are necessary to understand the effector function of iNKT cells in sarcoidosis.

T Regulatory Cells
T regulatory cells (Tregs) are a novel subset of T cells that are able to suppress cytokine production and the proliferation of activated T cells. Currently, there are several studies evaluating the levels and function of Tregs in sarcoidosis that have provided conflicting results. In the first study, Tregs were found to be increased in blood and BAL fluid in patients with sarcoidosis compared with control individuals.14 Functionally, this study found that sarcoid Tregs were able to suppress proliferation, which might explain the anergy phenomenon observed in sarcoidosis14; however, the investigators reported that sarcoid Tregs were unable to completely down-regulate the production of inflammatory cytokines. In the second study, the investigators found marked decreases of Treg cells in BAL fluid from indivduals with sarcoidosis compared with control subjects.15 A likely explanation for the conflicting results relates to the fact that different cell markers were used to identify the Treg populations. Despite these issues, Tregs are increasingly recognized as regulators of immune responses, and therefore, additional studies in sarcoidosis should be pursued.

Treatment Overview

Despite advances in our understanding of the biology and potential etiologies, treatment strategies for sarcoidosis are largely unchanged. Therapy with corticosteroids is still the first line of treatment and has been so since cortisone was first used in 1951.16,17 The initial response to corticosteroids will have an effect on the decision to use additional immunosupression, and the organ(s) affected can influence the choice of the agent used. Current treatment practices are based on small randomized controlled trials, case reports, or analyses of case series. Because of these limited data, treatment regimens are usually based on the individual characteristics of each patient, taking into account disease severity and organ involvement.

General Principles
Sarcoidosis poses unique challenges when considering whether to treat, the duration of treatment, and what agents to use. There are several reasons for this uncertainty. First, spontaneous remission is common. With the exception of a few clinical characteristics/syndromes (eg, Löfgren syndrome), long-term prognosis is difficult to predict at the time of presentation. Various serologic biomarkers have been investigated, but have not been shown to consistently predict the course of sarcoidosis. For example, the significance of angiotensin-converting enzyme levels has long been the focus of investigation, but initial angiotensin-converting enzyme levels are not associated with disease progression or the rate of remission. A small analysis predominantly comprising African American patients showed that elevated serum levels of 1,25-dihydroxyvitamin D were associated with chronic relapsing sarcoidosis.18 While promising, this finding will need to be confirmed in larger and heterogenous populations before 1,25-dihydroxyvitamin D can be used clinically to predict which patients will require treatment. Second, sarcoidosis is a relatively uncommon disease with a variable presentation, making it difficult to perform large randomized, double-blind, placebo-controlled trials. Third, sarcoidosis can affect any organ and can present with a variety of symptoms.

For these reasons, the decision to treat a patient with sarcoidosis is not always straightforward. When therapy is initiated, the goal should be to prevent prolonged end-organ dysfunction while minimizing adverse effects of the medications. In essence, the risk-benefit ratio of a given treatment must be compared with the risk-benefit ratio of not treating and may depend on the organ primarily involved.

Decision To Treat
In general, pulmonary sarcoidosis does not always require immediate treatment. Sarcoidosis limited to bilateral hilar adenopathy (stage 1) is not treated because of the high rate of remission, but patients should be closely followed for signs of progression or involvement of other organs. Patients with parenchymal involvement, who have mild symptoms or minimal functional limitations, should be followed closely and treated only if the disease worsens. The ideal follow-up interval has been debated, but is generally limited to 6 months. If the disease is unchanged at 6 months, the patient can be observed without treatment for an additional 6 months. This strategy offers the most palatable balance between the benefits and risks of treatment. If the patient presents with severe pulmonary dysfunction and functional limitations, a follow-up period is not needed and patients should begin treatment with corticosteroids.

Extrapulmonary sarcoidosis is common and even though it can be life threatening in certain scenarios, it does not invariably require treatment. However, even asymptomatic extrapulmonary sarcoidosis involving the eyes or heart or that causes severe hypercalcemia requires immediate therapy with corticosteroids. The current American Thoracic Society/European Respiratory Society guidelines recommend screening all patients for these conditions with ophthalmologic examination, EKG, and peripheral blood sampling (chemistry panel, Ca2+, complete blood counts, and liver function), respectively.19 Asymptomatic involvement of the eye needs to be treated promptly to prevent permanent visual impairment. Cardiac sarcoidosis carries a significant risk of morbidity and sudden death. Conduction-system abnormalities should be followed up with transthoracic echocardiogram and contrast-enhanced MRI or PET imaging. Severe hypercalcemia (>11 mg/dL) typically requires therapy with corticosteroids, especially if it is accompanied by an elevated serum creatinine level or nephrolithiasis. Patients with evidence of sarcoidosis in any other organs do not need to be treated unless they have significant symptoms or evidence of impairment.

Recent Treatment Developments

The reader is directed to the December 1, 2008, Pulmonary, Critical Care, Sleep Update review of the treatment of sarcoidosis20 for details on the basic corticosteroid regimen, alternative pharmacologic agents for sarcoidosis, and treatment regimens for specific types of extrapulmonary involvement. What follows is a review of selected articles published since the last PCCSU on the treatment of sarcoidosis covering new developments related to specific organs with particular emphasis on the anti-tumor necrosis factor (TNF)-α agent infliximab.

Pulmonary Disease
In recent years, anti-TNF-α agents have been the focus of investigation for pulmonary sarcoidosis. Baughman and colleagues21 found a small (2.5% increase from baseline FVC at 24 weeks) but significant improvement in the FVC of patients with chronic pulmonary sarcoidosis receiving infliximab compared with patients treated with placebo. In this trial, treatment was administered for 24 weeks and patients were followed for an additional 28 weeks from the last dose. Some patients did deteriorate when treatment was discontinued, but no means of identifying which patients were at risk of continued decline was evident. In a small case series of 14 patients with sarcoidosis, clinical deterioration occurred in 86% after infliximab was discontinued.22 Fifty percent of the patients deteriorated within 3 months of treatment discontinuation. This seems to suggest that if pulmonary relapse occurs after infliximab therapy, it will happen within a few months of discontinuation. The ideal duration of infliximab therapy is still unknown, but it may be limited by the development of adverse events, specifically anaphylaxis.

Sarcoidosis affecting the large, medium, and small airways is common. The decision to treat and the choice of agent are largely based on the presence and severity of symptoms. Airway hyperreactivity associated with sarcoidosis is also common, seen in approximately 20% of all sarcoidosis patients.23 In mild cases of airway hyperreactivity and cough, a trial of inhaled corticosteroids can be prescribed to avoid the toxicity associated with systemic therapy. Treatment with inhaled therapy should last for at least 2 weeks and it usually does not require more than a few months to see any effect. A low-dose systemic corticosteroid can be used to treat mild airway hyperreactivity if inhaled therapy fails or if symptoms worsen. As in most forms of sarcoidosis, alternative agents have been used but the evidence for their use is based on small reports. It should be noted that inhaled therapy is not regarded as a viable initial treatment strategy for parenchymal sarcoidosis.24

Cardiac Sarcoidosis
Cardiac sarcoidosis is potentially life threatening and can lead to sudden death by ventricular arrhythmias. Granulomas infiltrate the myocardium, causing conduction-system abnormalities or congestive heart failure. Early identification of cardiac involvement and close monitoring is the key to prevent catastrophic events. The diagnosis can be made by endomyocardial biopsy showing nonnecrotizing granulomata. The patchy nature of the granulomatous infiltration makes the sensitivity of this method poor. Because of the poor sensitivity of cardiac biopsy, gadolinium-enhanced cardiac MRI and PET scans emerged as the studies of choice for evaluating the myocardium in patients in whom cardiac sarcoidosis is suspected. Corticosteroids are considered first-line therapy, but several alternatives have demonstrated favorable outcomes. The data on alternative drugs are limited to small case reports. An automatic implantable cardioverter defibrillator can be considered for a patient with a high risk of sudden death or ventricular arrhythmias.

Several recent reports have shown the potential benefit of combination treatment with corticosteroid plus infliximab or infliximab monotherapy for cardiac sarcoidosis.25,26 The current state of the evidence in favor of TNF-α antagonists for cardiac sarcoidosis is limited to case reports and case series. Moreover, infliximab has been associated with heart failure and should therefore be used with caution in sarcoidosis patients with left ventricular dysfunction (LVD). Nonetheless, these encouraging case reports provide another option for the treatment of cardiac sarcoidosis.

Skin Involvement
Skin disease in sarcoidosis is most commonly manifested as erythema nodosum, but subcutaneous nodules, hypopigmented patches, lupus pernio, and alopecia can also be seen. Lesions usually do not need systemic therapy unless there is cosmetic disfigurement. Topical corticosteroids are usually effective and systemic corticorsteroids are rarely required. If corticosteroids fail, then alternative agents, such as methotrexate and hydroxychloroquine, are most commonly used. Evidence to support the use of alternative agents is limited to case series or anecdotal reports.

Infliximab has also been used. A retrospective analysis of patients with lupus pernio compared infliximab-containing regimens with systemic corticosteroid-only, noncorticosteroid, and combination therapy with systemic corticosteroid and noncorticosteroid.27 Infliximab treatment was associated with resolution or near resolution of lupus pernio and was significantly more effective than the other treatment regimens. Regimens not containing systemic corticosteroids or infliximab (ie, noncorticosteroid only) did not result in significant improvement. Infliximab is a viable alternative for skin manifestations of sarcoidosis that are refractory to more conventional therapies and cause cosmetically disfiguring lesions. Skin lesions have also been treated with laser therapy, but the data in support of this therapy are limited to case reports.28,29

Pulmonary Hypertension
Pulmonary hypertension (PH) in sarcoidosis has recently been the focus of several investigations. PH in sarcoidosis can be the result of pulmonary fibrosis, compression of pulmonary arteries or veins by enlarged lymph nodes, or precapillary vasoconstriction. Baughman and colleagues30 retrospectively studied 130 patients with sarcoidosis who had persistent dyspnea despite therapy. They found that 38.5% had PH without evidence of LVD and 15.4% had PH with LVD. Those with PH alone had significantly higher mortality rates than those with PH and LVD. The study did not examine the role of therapy, but a retrospective analysis of 22 sarcoidosis patients with PH described the response to PH-specific medication, such as sildenafil, bosentan, or a prostanoid analog.31 All patients had advanced restrictive lung disease from sarcoidosis and were awaiting lung transplant, but those with elevated pulmonary arterial wedge pressures were excluded from the analysis. They reported improvements in the patients’ New York Heart Association class, 6-min walk distance, pulmonary vascular resistance, and mean pulmonary arterial pressures following treatment with PH-specific therapy. Collectively, these studies suggest that PH in sarcoidosis is more common than previously appreciated and that, even in the setting of advanced parenchymal lung disease, therapy specifically targeting the pulmonary vasculature has functional benefits and can serve as a bridge to transplantation. It remains to be seen whether corticosteroids or other immune suppression can improve or reverse the PH associated with sarcoidosis.

Fatigue in Sarcoidosis
Fatigue has long been recognized as a prominent and common symptom in patients with sarcoidosis. Fatigue can sometimes be the only clinical symptom of sarcoidosis and can cause significant morbidity and loss of productivity. The mechanism by which sarcoidosis causes fatigue is unknown, but may be related to the overall inflammatory burden of disease. Fatigue usually does not respond to systemic corticosteroids or other noncorticosteroid therapies.

Lower and colleagues32 used a cross-over, double-blind, randomized trial using dexmethylphenidate hydrochloride to treat fatigue in 10 subjects with sarcoidosis complaining of chronic fatigue thought to be secondary to sarcoidosis. Compared with placebo, treatment with dexmethylphenidate hydrochloride improved fatigue scores on two different scales and did so with no increase in side effects, but the treatment period lasted only 8 weeks. Confirmation of these findings with a longer duration of treatment will be required before widespread use of this or other stimulants can be recommended for long-term use.

The effect of infliximab on fatigue has not been examined in clinical trials, but Elfferich and colleagues33 performed a retrospective cross-sectional analysis of a large cohort of individuals with sarcoidosis to assess the prevalence of cognitive decline and fatigue. Subjects taking an anti-TNF-α medication had significantly larger improvements in cognitive and fatigue scores at 6-month follow-up. Patients who took corticosteroids showed no improvement in fatigue or cognitive scores in the follow-up period. Despite these findings, using anti-TNF-α drugs specifically to treat fatigue in the absence of another compelling indication is not advised because the potential for serious adverse events related to these medications is not outweighed by the benefits.

Neurosarcoidosis
Sarcoidosis can affect any part of the central or peripheral nervous system. All forms of clinically symptomatic neurosarcoidosis should be treated. First-line therapy is systemic corticosteroids, but this is not always effective and usually dose elevation is required before a response is seen. Clinical relapses are common as the dose of corticosteroid is tapered and occur at doses as high as 20 mg/d.

Infliximab infusion has also been reported for the treatment of neurosarcoidosis.34,35 Moravan and colleagues34 reported improved clinical symptoms and neuroimaging findings in 7 patients treated with a combination of infliximab and mycophenolate mofetil. Serious adverse events were not seen during the follow-up period (6 to 18 months). These results suggest that infliximab taken alone or in combination with other immunosuppressive medications can be a safe and effective alternative to corticosteroids in the treatment of neurosarcoidosis. The coming years will undoubtedly see continued reports of infliximab use for neurosarcoidosis.


References

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