Consequences of Sarcoidosis

Marjolein Drent, MD, PhDa,b,c,*, Bert Strookappe, MScc,d, Elske Hoitsma, MD, PhDc,e, Jolanda De Vries, MSc, PhDc,f,g

KEYWORDS Cognitive impairment Depressive symptoms Exercise limitation Fatigue Pain Rehabilitation Sarcoidosis Small fiber neuropathy Quality of life

KEY POINTS Consequences of sarcoidosis are wide ranging, and have a great impact on patients’ lives. Sarcoidosis patients suffer not only from organ-related symptoms, but also from a wide spectrum of rather nonspecific disabling symptoms. Absence of evidence does not mean evidence of absence. Management of sarcoidosis requires a multidisciplinary personalized approach that focuses on somatic as well as psychosocial aspects of the disease.

INTRODUCTION of sarcoidosis patients include symptoms that cannot be explained by granulomatous involve- The clinical expression, natural history, and prog- ment of a particular organ.4 Apart from lung- nosis of sarcoidosis are highly variable and its related symptoms (eg, coughing, breathlessness, course is often unpredictable.1 Clinical manifesta- 1,2 and dyspnea on exertion), patients may suffer tions vary with the organs involved. The lungs from a wide range of rather nonspecific disabling are affected in approximately 90% of patients symptoms.2,5 These symptoms, such as fatigue, with sarcoidosis, and the disease frequently also fever, anorexia, arthralgia, muscle pain, general involves the lymph nodes, skin, and eyes. Remis- weakness, muscle weakness, exercise limitation, sion occurs in more than one-half of patients within and cognitive failure, often do not correspond 3 years of diagnosis, and within 10 years in two- 2,5–9 2 with objective physical evidence of disease. thirds, with few or no remaining consequences. These issues are often troubling to pulmonologists Unfortunately, up to one-third of patients have and other sarcoidologists because they do not persistent disease, leading to significant impair- 3 relate directly to a physiologic abnormality, are ment of their quality of life (QoL). Interpretation difficult to quantify and hence to monitor, and are of the severity of the sarcoidosis can be compli- challenging to treat.4 cated by its heterogeneity. Several major concerns

The authors have nothing to disclose. a Department of Pharmacology and Toxicology, Faculty of Health, Medicine and Life Science, Maastricht Uni- versity, PO Box 616, Maastricht 6200 MD, The Netherlands; b ILD Center of Excellence, St. Antonius Hospital, Koekoekslaan 1, Nieuwegein 3435 CM, The Netherlands; c ILD Care Foundation Research Team, PO Box 18, Bennekom 6720 AA, The Netherlands; d Department of Physical Therapy, Gelderse Vallei Hospital (ZGV), PO Box 9025, Ede 6710HN, The Netherlands; e Department of Neurology, Alrijne Hospital, PO Box 9650, Leiden 2300 RD, The Netherlands; f Department of Medical Psychology, St. Elisabeth Hospital Tilburg, Tilburg, The Netherlands; g Department of Medical and Clinical Psychology, Tilburg University, PO Box 90153, Tilburg 5000 LE, The Netherlands * Corresponding author. ILD Care Foundation Research Team, PO Box 18, Bennekom 6720 AA, The Netherlands. E-mail address: [email protected]

Clin Chest Med - (2015) -–- http://dx.doi.org/10.1016/j.ccm.2015.08.013

Symptoms such as fatigue can be nonspecific globally recognized as a disabling symptom. The and difficult to objectify. Moreover, absence of evi- reported prevalence varies from 60% to 90% of dence does not mean evidence of absence.5,7 sarcoidosis patients,5 and up to 25% of fatigued Sarcoidosis-related complaints, including fatigue, sarcoidosis patients report extreme fatigue. Physi- may become chronic and affect patients’ QoL cians generally assess disease severity and pro- even after all other signs of disease activity gression in sarcoidosis on the basis of clinical have disappeared.7,10,11 Hence, patients consult tests, such as pulmonary function tests, chest ra- their physician not only with organ-specific diographs, and serologic tests. However, these symptoms—directly related to the organ(s) objective clinical parameters correlate poorly involved—but also with nonspecific health com- with the patients’ subjective sense of well-be- plaints, such as fatigue, cognitive failure, exercise ing.8,20 Sarcoidosis patients may suffer from sub- intolerance, and muscle weakness.12 These impair- stantial fatigue even in the absence of other ments in sarcoidosis are disabling, especially when symptoms or disease-related abnormalities. For they become chronic.13,14 Sarcoidosis consists of example, fatigue and general weakness may several overlapping clinical syndromes (“the persist even after routine clinical test results have sarcoidosis”), each with its own specific pathogen- returned to normal.5 There is a positive association esis. A complete evaluation of sarcoidosis could between symptoms of suspected small fiber neu- make use of a panel with 4 disease domains or di- ropathy (SFN) and fatigue, as well as between dys- mensions: extent of disease, severity, activity, and pnea and fatigue.13,21,22 So far, no organic impact.15–17 Severity of sarcoidosis in each organ substrate has been found for the symptoms of is defined as the degree of organ damage sustained sarcoidosis-associated fatigue. from sarcoidosis. The interpretation of the severity To date, no appropriate definition of fatigue of sarcoidosis can be complicated by its heteroge- exists. Fatigue can be seen and measured as a neity. The organ damage can be estimated subjec- unidimensional or multidimensional concept. The tively by the intensity of symptoms, objectively as a multidimensional concept of fatigue can be percentage decline from normal capacity (eg, per- divided into at least 2 categories: physical and centage of the predicted normal value on pulmo- mental or passive and active fatigue.5,10 nary function testing), or by critical location of Some sarcoidosis patients are debilitated by lesions (eg, cardiac block). However, pulmonary the symptoms of their disease and are unable to function test results do not always represent work; others are underemployed and incapable changes in the severity of pulmonary sarcoidosis,18 of achieving their full potential owing to their which illustrates that the demonstration of sarcoid health issues.23 Individuals affected by the dis- activity remains an enigma. Assessment of inflam- ease frequently seem to be completely healthy, matory activity in sarcoidosis patients without dete- so their symptoms are often not taken seriously riorating lung function or radiologic deterioration but by family, friends, employers, and health care with unexplained persistent disabling symptoms is professionals. Consequently, some patients lose an important and often problematic issue. Histori- their desire and ability to socialize with others cally, evaluation of the various available tools for effectively, causing relationships and family dy- the assessment of inflammatory activity has been namics to ultimately suffer. These combined fac- hampered by the lack of a gold standard. This article tors impact on an individual’s economic status, focuses on the impact of the broad range of interpersonal relationships, and family dynamics, sarcoidosis-related problems on patients’ lives. increase their stress levels, and induce depression in patients. SYMPTOMS The etiology of this troublesome problem remains elusive and is usually multifactorial. Fatigue In addition to symptoms related to the organs can be a consequence of the treatment itself, for involved, patients may suffer from all kinds of instance, as a complication of corticosteroid ther- less specific symptoms. These sarcoidosis- apy. The diagnosis of sarcoidosis-associated related disabling symptoms can significantly fatigue requires extensive evaluation to identify decrease a person’s QoL, especially in chronic and treat potentially reversible causes.5,6 Its etiol- 19 sarcoidosis. All these symptoms may have major ogy may involve granuloma formation and consequences and impact on the patients’ lives cytokine release. However, despite effective and those of their relatives. treatment of the sarcoidosis, many patients continue to experience fatigue.5,24 Comorbidities Fatigue associated with sarcoidosis, including depres- Fatigue is the most frequently described and sion, anxiety, hypothyroidism, and altered sleep devastating symptom in sarcoidosis, and is patterns, may all contribute to fatigue.23,25 Consequences of Sarcoidosis 3

Despite an exhaustive search for treatable clinical Box 1 causes of fatigue, most patients’ complaints of fa- Symptoms suggestive of small fiber tigue are not correlated with clinical parameters of neuropathy disease activity.5,24 Sensory symptoms Dyspnea Paina Dyspnea is, by definition, subjective, but a greater Paresthesias value should be given to its quantification by Sheet intolerance validated scales in the initial evaluation and Restless legs syndromeb follow-up of patients with sarcoidosis. The mecha- nism for dyspnea in sarcoidosis is multifacto- Symptoms of autonomic dysfunction 12,22,26 rial. Research has found that the degree of Hyperhidrosis or hyperhidrosis dyspnea in sarcoidosis does not correlate with Diarrhea or constipation lung function tests.27 Pulmonary function test results do not always reflect changes in the severity Urinary incontinence or urine retention of pulmonary sarcoidosis. Moreover, several Gastroparesis studies have reported that neither lung function Sicca syndrome test results nor chest radiographs correlate with nonspecific health complaints or with QoL.19,28 In Blurry vision the follow-up, the level of dyspnea often, but not Facial flushing always, changes in the same direction as the Orthostatic intolerance forced vital capacity.29 Spontaneous resolution Sexual dysfunction of radiographic lesions is more common in asymp- tomatic patients.17 The intensity of dyspnea at a Pain in small fiber neuropathy often has a burning, tingling, shooting, or prickling character. initial evaluation correlates with the need for b 30 Restless legs syndrome is a disorder characterized long-term treatment. by disagreeable leg sensations that usually occur before sleep onset and cause an almost irresistible Small Fiber Neuropathy and Autonomic urge to move. Dysfunction In 2002, SFN was recognized as a symptom of sarcoidosis.31 Unlike granulomatous large neuron dizziness, constipation, bladder incontinence, involvement, SFN seems to be a common compli- sexual dysfunction, trouble sweating, or red or cation occurring in up to 40%32 to 60% of patients white skin discolorations (see also Box 1).34 with sarcoidosis.33 Involvement of cardiac sympathetic nerves might SFN is a peripheral nerve disorder that selec- play a role in the prognosis, because indices of tively affects thinly myelinated Ad fibers and autonomic cardiac dysfunction have been identi- unmyelinated C fibers.34 These fibers are associ- fied as strong predictors of cardiovascular ated with thermal and nociceptive sensations, morbidity and mortality.34 and pathology of these nerves may lead to a Because routine nerve conduction tests eval- “painful neuropathy.” However, these nerves uate only large nerve fiber function, and quantita- also affect the autonomic nervous system, and tive techniques for the assessment of small nerve SFN may also lead to an “autonomic neuropathy” fibers are not routinely applied, the diagnosis of (Box 1).35,36 SFN can easily be missed.35,37 This lack may Symptoms of SFN are disabling for patients, lead to frustration for both physician and patient have a high impact on QoL, and are often difficult owing to the failure to diagnose a neuropathic to treat.35 Damage to or loss of small somatic pain syndrome. There is as yet no gold standard nerve fibers results in pain, burning, or tingling sen- for the diagnosis of SFN. Diagnosis is usually es- sations, or numbness, typically affecting the limbs tablished on the basis of clinical features, in com- in a distal to proximal gradient. Symptoms can be bination with abnormal findings of specialized very severe, are usually worse at night, and often tests such as the assessment of intraepidermal affect sleep. People sometimes sleep with their nerve fiber density in skin biopsy, temperature feet uncovered because they cannot bear the sensation tests for sensory fibers, and sudomotor touch of the sheets. Walking may be difficult owing and cardiovagal testing for autonomic fi- to severe pain caused by the pressure on the floor. bers.32,33,38 The Small Fiber Neuropathy When autonomic fibers are affected, patients may Screening List was developed in a sarcoidosis experience dry eyes, dry mouth, orthostatic population as a first screening tool.21 4 Drent et al

PSYCHOLOGICAL BURDEN Studies also showed that anxiety was more com- Depressive Symptoms mon in sarcoidosis patients than in the general population and among healthy persons.49,50 The Depressive symptoms in sarcoidosis are at least percentages for anxiety disorders are obviously partly an expression of exhaustion owing to the lower; for instance, 6.3% of sarcoidosis patients ongoing disease. Depressive symptoms have been have a panic disorder.51 In any case, anxiety is a found to be associated negatively with and affect major problem in sarcoidosis patients. Because patients’ fatigue scores.10 In addition, the relation- fatigue is 1 symptom that is known to cooccur ship between fatigue and depressive symptoms with anxiety, it is not surprising that anxiety in gen- parallels the findings for other chronic illnesses, eral and trait anxiety were found to be related to fa- such as diabetes, chronic obstructive pulmonary tigue.5,24,47 One study also found that trait anxiety disease, cardiac disease, and rheumatoid arthritis.39 predicted fatigue at follow-up.47 Trait anxiety re- Moreover, the severity and nature of fatigue moder- fers to the tendency of persons to react with anx- ate anxiety and depressive symptoms in sarcoid- iety in new situations. In contrast, state anxiety is osis. Fatigue and autonomic dysfunction are both defined as anxiety that is elicited in a particular dominant symptoms and risk factors for depres- situation and does not last long. In addition to fa- sion.40 The symptoms may share several neurobio- tigue, 1 study found that the severity of sarcoidosis logical abnormalities, for example, an increase in symptoms was also related to anxiety.52 Studies of tumor necrosis factor-a.40 The relationship between the relation between anxiety and dyspnea re- depressive symptoms and fatigue may also be ported inconsistent results.49,53 based on a cytokine imbalance, initiated by an in- Studies examining stress in sarcoidosis are still flammatory immune response in sarcoidosis.39,41 scarce. One study found that the magnitude of The cytokine balance of patients suffering from stressful life events was higher in sarcoidosis pa- depression also seems to be disturbed.42 tients than in healthy controls.54 Patients also Not only fatigue, but also psychological symp- seemed to use inadequate coping strategies with toms such as depressive symptoms and anxiety, regard to stress.54 Another study reported a rela- play an important role in sarcoidosis.15,43–46 They tion between increased life stress and impaired have been reported in 17% to 66% of patients lung function.55 Finally, 1 study focusing on with sarcoidosis. Understanding the nature of the perceived stress found it to be high and related relationships between fatigue, depressive symp- to sarcoidosis symptoms.23 Perceived/experi- toms, and anxiety remains difficult however. The na- enced stress is caused by interpreting a situation ture of fatigue moderates the relationships between as threatening. This indicates that the same situa- fatigue and anxiety and between fatigue and tion may be perceived as stressful by 1 person and depressive symptoms in sarcoidosis. In a study by as a challenge by another. Interpreting a situation De Kleijn and colleagues,47 fatigue was often re- as threatening may result in several reactions ported with concurrent depressive symptoms known as fight or flight, or freeze. In each of these, (34%–36%) and anxiety (43%–46%). About one- the person is scared, but this translates into third of the patients (31%) reported high-trait anxi- different behavior: anger and aggressive behavior ety as well as high levels of depressive symptoms (fight), anxiety and escaping from the situation at baseline. The study also suggested that the rela- (flight), or no reaction at all (freeze). Fight and flight tionship between depressive symptoms and fatigue reactions require a physical reaction. is bidirectional. Depressive symptoms may indi- Anxiety consists of physical or hyperarousal rectly lead to more symptoms, because they are symptoms, such as increased heart rate, perspira- associated with poor self-care (diet, exercise, giving tion, and dizziness, which are inherent to the reac- up smoking, and medication regimens) in patients tion of the sympathetic nervous system.56 In with chronic diseases in general.39 However, phys- addition to a physical component, anxiety also ical symptoms and the resulting functional impair- has a cognitive component, that is, a thought (or ments caused by complications of medical illness chain of thoughts) that determines the emotion are also likely to impose a burden on the patient’s experienced. If someone is confronted with a situ- life and to provoke depression.39 Hence, not only fa- ation and has thoughts such as, “I can do this” and tigue but also depressive symptoms and anxiety “I want to test whether I can overcome this,” the should be an integral part of the multidisciplinary situation is regarded as a challenge, and the noted management of sarcoidosis patients. physical symptoms will not occur. If the same situation induces thoughts such as “I cannot handle Anxiety and Stress this” and “I must do something, but I have no Several studies have shown that the prevalence of idea what,” the situation is perceived as threat- anxiety in sarcoidosis patients is 33% to 36%.47,48 ening and the physical symptoms related to Consequences of Sarcoidosis 5 anxiety occur. This relationship between stress chronic fatigue can be successfully treated with and anxiety—and the 2 components of anxiety cognitive–behavioral therapy. (cognitive and physical)—might explain the relationships found between symptoms and anxiety/ Cognitive Impairment and Memory Loss stress. In addition to organ-specific symptoms and Another aspect to take into consideration is the nonspecific health complaints such as fatigue duration of stress or anxiety. A brief feeling of and physical impairments, patients also have to stress and anxiety is very common and is consid- deal with side effects of medical treatment. Pa- ered healthy, because the person uses the fight or tients with sarcoidosis often report everyday flight reactions to cope with the situation. In this cognitive deficits.6 There is growing interest in sense, a parallel can be drawn with pain and fa- cognitive failure research in populations of pa- tigue, which are both healthy responses to a stim- tients with various chronic diseases.57,58 Func- ulus that may harm the body or demand too much tional cognitive impairment, if present, may lead of the body, respectively. It becomes unhealthy to increased fatigue and low compliance with when the stress and anxiety become persistent, medical treatment. Currently, however, no data because this will have negative effects on the im- are available on the extent of cognitive underper- mune system. In our modern society, physical re- formance among sarcoidosis patients. Research actions are often elicited by thoughts that do not in multiple sclerosis patients found that memory require physical action. Think about (recurrent) complaints were not associated with memory per- negative thoughts, such as “I am a loser,” “My formance, but were associated with fatigue com- illness makes me a burden to other people,” plaints.58 It is tempting to speculate that this may “Symptoms will probably become worse,” and “I also be the case in sarcoidosis patients. There is will soon die from this disease.” a special interest in sarcoidosis owing to the high From this perspective, various researchers have prevalence of fatigue and everyday cognitive fail- justly suggested that sarcoidosis patients may ure, together with the relatively young age of the benefit from psychological interventions47,51 patients. focusing on coping and appraisal, such as stress reduction treatment.23,55 In each case, the Physical Impairment basis for the interventions should be a type of cognitive–behavioral therapy, including so-called Sarcoidosis obviously imposes a burden on pa- third-generation cognitive-behavioral therapy–like tients’ lives (Fig. 1).12,59 Symptoms of fatigue and mindfulness-based cognitive therapy, because dyspnea induce exercise limitation, and fatigue this type of therapy has proved to be effective in also leads to physical inactivity, and the specific patients with anxiety disorder. Finally, it is impor- sarcoidosis symptoms, or the thought of living tant to realize that anxiety (just like depressive with a progressive, incurable condition, create symptoms/depression) is known to be among anxiety and mood disturbance, and affect the factors prolonging chronic fatigue, and that emotional well-being. Although less recognized

Fig. 1. Negative vicious circle of physical deconditioning: disabling symptoms in sarcoidosis can reduce daily physical activities, resulting in general deconditioning and a reduced quality of life. (Adapted from Swigris JJ, Brown KK, Make BJ, et al. Pulmonary rehabilitation in idiopathic pulmonary fibrosis: a call for continued investigation. Re- spir Med 2008;102(12):167580, and Marcellis RG, Lenssen AF, de Vries J, et al. Reduced muscle strength, exercise intolerance and disabling symptoms in sarcoidosis. Curr Opin Pulm Med 2013;19(5):528.) 6 Drent et al

than exertional dyspnea, lack of energy or exhaus- diseases. It is a concept that concerns patients’ tion is a very common and frustrating physical evaluation of their functioning in a wide range of symptom in patients with sarcoidosis. Patients domains, but always including the physical, psy- with sarcoidosis (as well as other interstitial lung chological, and social domains.3 Assessment diseases) often have diminished exercise capacity covering only these three domains is known as and reduced muscle strength, as demonstrated assessment of health-related QoL.3,73 by reduced oxygen uptake (measured during QoL is often confused with health status, which a maximal cardiopulmonary exercise test) or a concerns patients’ physical, psychological, and shorter-than-predicted distance covered during a social functioning.3 Psychological factors such as 6-minute walking test. Monitoring that takes mus- burnout, emotional distress, and work-related so- cle strength and exercise capacity into account cial support influence levels of QoL.72 A study has been found to improve the routine monitoring among sarcoidosis patients found that the stron- of sarcoidosis.28,60,61 Like others, Marcellis and gest predictor of all dimensions of QoL was the colleagues28 found exercise intolerance and mus- corresponding QoL at baseline.13 This trend might cle weakness to be frequent problems in sarcoid- be explained by the fact that sarcoidosis-related osis, both in fatigued and nonfatigued patients. symptoms remain relatively stable over time.13,47 Exercise intolerance in sarcoidosis is most Social support has been described as a buffer often multifactorial, involving lung–mechanical, against pain and disability, and also as being asso- musculoskeletal, and gas exchange abnormal- ciated with greater activity levels among individ- ities.12,28,62–64 Several studies have reported that uals with pain.72,74 Support from friends and neither lung function test results nor chest radio- family can also be related to the psychological di- graphs correlate with these nonspecific health mensions of QoL.75 A study among people with complaints, nor with QoL.11,23,44–46 Moreover, pul- chronic pain found that a rich social network was monary function test results at rest seem to be related to higher perceived QoL.76 Moreover, poor predictors of exercise capacity. Changes in work-related social support is known to positively gas exchange upon exercise can be fairly accu- predict return to work, whereas lack of social sup- rately predicted by percent diffusing capacity of port at work is a well-known risk factor for devel- the lung for carbon monoxide,65,66 but can be pre- opment of pain.77 In sarcoidosis, there is poor sent even with normal diffusing capacity of the agreement between physicians and patients with lung for carbon monoxide.67 Fatigue that, as regard to the perceived symptoms attributable to mentioned, is among the major problems in the disease, with a particular failure of clinicians sarcoidosis, can reduce patients’ day-to-day func- to recognize the impact of non–organ-specific fea- tioning.5 Consequently, decreased physical activ- tures.15,17 It has been proposed that assessment ity can induce general deconditioning, which in of the health status and QoL of sarcoidosis pa- turn contributes to increased perceived fatigue tients would help to bridge this gap, aiding and a sense of dyspnea, as well as insufficient communication and treatment, and complement- physical activity.60,68 Assessment of the presence ing existing clinical assessments. Various aspects of physical impairments is recommended, of sarcoidosis, such as the relatively young age at because it provides additional information about disease onset, the often unpredictable and chronic the patient’s functional status, disease severity, nature of the disease, the uncertainly about the and progression.28,60,62–64 Because the patients’ cause and the broad range of frequently persistent ability to handle physical activity is clearly symptoms may account for the aggravating influ- decreased, however, the activities should be ence on patients’ lives as well as those of their adjusted, and rehabilitation programs should be families and friends, especially because a truly designed carefully.61,69,70 appropriate treatment of sarcoidosis is still lacking. Fatigue, breathlessness, reduced exercise Overall Impact on Patients’ Lives: Quality of capacity, and arthralgia are the most frequently Life reported symptoms. It seems that these The impact of any disease depends on the way the sarcoidosis-related symptoms are associated patient perceives the disease and modifies his or with a lower QoL.8,13,44,47,53,78 Women have lower her activities of daily living. Living with a long- scores on the physical health, psychological term disease like sarcoidosis significantly affects health, social relationships, and environmental do- QoL, with negative consequences for general mains, and the general assessment of overall QoL. health and social and psychosocial well-be- Research found that the use of corticosteroids ing.3,71–73 QoL is an important outcome measure predicted a lower QoL in all domains except spiri- of treatment, especially with regard to chronic tuality. Having a partner was associated with the Consequences of Sarcoidosis 7

QoL domains of psychological health and level of of intravenous immunoglobulin and anti–tumor ne- independence, whereas a low educational level crosis factor-a therapy.6,79,80 The precise potency predicted better scores for the social relationships of these drugs needs further study however. domain, and arthralgia predicted poorer scores for this domain.8 Fatigue had a negative effect on pa- Additional Alternatives to Pharmacologic tients’ QoL scores for the physical health, psycho- Treatment logical health, and level of independence domains. Developing the most appropriate therapeutic approach for sarcoidosis, including rehabilitation TREATMENT OPTIONS programs, requires careful consideration of the Pharmacologic Treatment possible impact of pain, the SFN-related symptoms, the fatigue and coping strategies, as well There is a lack of standardized management stra- as all other relevant aspects of this multisystem tegies for sarcoidosis. Most sarcoidosis patients disease.3,4,6,49,81 Various treatments are available show spontaneous resolution of the disease and for fatigue with a partly psychological cause, and do not require systemic pharmacologic treat- 2 patients with a clinical depression can be pre- ment. Glucocorticoids are the cornerstone thera- scribed antidepressants. Some patients may peutic agent, and have a favorable short-term require help to improve their coping and self- effect on functional impairments, including respi- management skills, to improve their QoL. Cogni- ratory impairment and symptoms. However, the tive therapy may be indicated to treat coping long-term beneficial effect remains uncertain. In problems or stress perception. Sleeping problems view of the limitations we are aware of presently, should be treated appropriately.25 In general, care authorization would be doubtful if glucocorticoids providers have to raise supportive care issues and were to be introduced at present. A subset of pa- provide information about alternative care pro- tients require more aggressive treatment. The grams beside medication, which aim to reduce published data on the different treatment options the symptoms and improve the well-being of in sarcoidosis are limited and treatment therefore 2 sarcoidosis patients. Patients should be informed remains mostly empirical. The decision on about the importance of exercise and they should whether to start systemic immunosuppressive be encouraged to stay active. treatment or not should be based on the patients’ symptomatology, including the impact on their REHABILITATION QoL, as well as the extent of compromised organ function. Patients should be instructed to lead an as active Recent studies have demonstrated the effec- and involved a life as possible because exercise tiveness of various neurostimulants, including intolerance and muscle weakness are frequent methylphenidate, for the treatment of fatigue asso- problems in sarcoidosis influencing QoL (see ciated with sarcoidosis. These and other agents Fig. 1).28 Rehabilitation has many benefits for pa- may be useful adjuncts for the treatment of this tients with sarcoidosis, including social participa- type of fatigue. There is obviously a need for tion, psychological well-being, maintaining levels studies evaluating the causes of, and new thera- of activity, learning to use breathing exercises peutic options for, sarcoidosis-associated fatigue. and ways to adapt exercises for the home environ- Psychological interventions should also be exam- ment.69,70,82,83 In the broader context of medical ined. Standard sarcoidosis treatments such as encounters, physical therapy or rehabilitation can those using corticosteroids and other immunosup- help to avoid a negative vicious circle of decondi- pressive agents are often ineffective for SFN- tioning.61,69 Research has found that fatigue in pa- related symptoms.4 Symptomatic neuropathic tients with sarcoidosis was reduced after a period pain treatment in sarcoidosis patients is not of physical training.69,70 Moreover, their psycho- different from the treatment of neuropathic pain logical health and physical functioning also from other causes, and consists of antidepres- improved.69 Sarcoidosis patients generally benefit sants, anticonvulsants and prolonged-release opi- from additional nonpharmacologic treatments, not oids. However, in common with their effects in only physical training but also nutritional supple- other neuropathic pain states, these agents pro- ments and counseling.69,70,84,85 Patients should vide limited pain relief in just 30% to 60% of pa- be counseled about their responsibilities in man- tients, at the cost of considerable side effects. aging their own condition, about ways to engage These data indicate that there is an urgent need different services when required, and about life- for analgesic agents with high efficacy for neuro- style, for example, the importance of regular exer- pathic pain patients, causing no debilitating side cise as well as pulmonary rehabilitation programs. effects. Case reports mention beneficial effects Patients’ self-perceived knowledge about the 8 Drent et al

importance of exercise for their health (in addition information recall may be enhanced by addressing to drug therapy) should be improved. Care pro- emotions by means of affective communication. viders should be able to refer patients to rehabilita- Extensive research has shown that physicians’ af- tion (including pulmonary rehabilitation) by fective communication (ie, being emotionally sup- physical therapists or other professionals with an portive and adopting a warm, empathic, and awareness and knowledge of sarcoidosis, if they reassuring manner) may improve patients’ out- expect these patients to benefit, or if the patients comes, including decreased levels of anxiety and ask for referral. Rehabilitation services or pro- distress.87,88 Physicians’ affective communication grams led by physical therapists should be avail- not only tempers emotional arousal, but also en- able to patients at reasonable cost. Prospective hances recall of medical information.88 Research studies should be designed to answer lingering in various disorders has shown that such affective questions about the value of exercise training for statements improved recall, especially with regard patients with sarcoidosis, including what benefits prognostic information and, to some extent, treat- can be expected of maintenance programs and ment information. Obviously, because sarcoidosis how long these benefits will last. Our own research requires a multidisciplinary approach in view of its found that patients reported fewer feelings of un- wide range of symptoms, communication among certainty and anxiety after a training program.86 the various health care workers involved and This finding has promising implications for clinical between them and the patients is of great impor- practice. Because sarcoidosis patients may suffer tance.89 Although the effect of affective communi- from various impairments, such as arthralgia, mus- cation has not yet been studied in sarcoidosis, this cle pain, and fatigue, the intensity of the training may be expected to improve patient compliance. should be personalized to avoid training aggra- Patient participation is increasingly recognized as vating these impairments, resulting in high dropout a key component in the design of health care pro- rates. This need also argues for a multidisciplinary cesses and is also advocated as a means of approach to the routine management of improving patient compliance. The concept has sarcoidosis. been applied successfully to various areas of More research is needed to provide evidence for patient care, such as decision making and the the relationship between physical therapy and management of chronic diseases. Patient partici- recall. Such studies should assess whether aware- pation in shared treatment decision making is hy- ness of the importance of physical activities in pothesized to improve treatment adherence and daily life and their consequences for sarcoidosis clinical outcomes. Although this has not yet been patients might affect adherence to treatment or studied in sarcoidosis, other research findings medication regimens. The duration, frequency, reveal the significance of patient participation as and intensity of exercise programs are critical to a key factor in improving treatment adherence achieve physical benefits.82,86 In general “high-fre- and clinical outcome. Quality improvement strate- quency, low-impact” exercise can be recommen- gies for sarcoidosis management should, there- ded. Future prospective studies are warranted to fore, emphasize patient participation. Further fine-tune the training parameters, duration, and research is essential to establish key determinants frequency. of the success of patient participation in improving efficacy of care for sarcoidosis patients. COMMUNICATION AND PATIENT Patient participation has promising implications PARTICIPATION for the multidisciplinary management of sarcoidosis. However, the effect of affective communica- Providing information and communication can be tion on recall should be established further hampered by the complexity of sarcoidosis and because evidence is lacking, especially for exten- its heterogeneity. Moreover, management of pa- sive consultations. Other interesting topics for tients with sarcoidosis requires more than pre- future studies include whether self-perceived scribing drugs. It is important for physicians to medical knowledge about sarcoidosis and its listen to their patients; it is wise to take what the related consequences, including treatment op- patient says seriously. Obviously, understanding tions, is sufficient to achieve beneficial effects. and remembering medical information is crucial for every patient, because it is a prerequisite for SUMMARY coping with their disease and making informed treatment decisions. Most patients do remember Sarcoidosis is a multisystem disorder of unknown their diagnosis, but have difficulty remembering cause(s) that imposes a burden on patient’s lives. information about things like treatment plans, In addition to the specific organ-related symp- recommendations, and side effects. Patients’ toms, less specific disabling symptoms, including Consequences of Sarcoidosis 9 fatigue and physical impairments, may have a ma- 11. Sharma OP. Fatigue and sarcoidosis. Eur Respir J jor influence on the daily activities and the social 1999;13(4):713–4. and professional lives of the patients, resulting in 12. Marcellis RG, Lenssen AF, de Vries J, et al. Reduced a reduced QoL. A multidisciplinary approach is muscle strength, exercise intolerance and disabling recommended for these patients, one that focuses symptoms in sarcoidosis. Curr Opin Pulm Med on somatic as well as psychosocial aspects of this 2013;19(5):524–30. erratic disorder. Patients self-perceived knowl- 13. Drent M, Marcellis R, Lenssen A, et al. Association edge about the importance of exercise and life- between physical functions and quality of life in style for their health (in addition to drugs) should sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis be improved. Developing the most appropriate 2014;31(2):117–28. therapeutic approach for sarcoidosis, including 14. Morgenthau AS, Iannuzzi MC. Recent advances in rehabilitation programs, requires careful consider- sarcoidosis. Chest 2011;139(1):174–82. ation of the possible impact of fatigue, SFN symp- 15. Cox CE, Donohue JF, Brown CD, et al. 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