doi: 10.1111/joim.12198 Approaches to the treatment of some of the troublesome manifestations of sarcoidosis A. Eklund 1 & R. M. du Bois 2 From the 1 Department of Medicine, Karolinska University Hospital, Karolinska Institutet and Centre for Molecular Medicine, Stockholm, Sweden; and 2 Respiratory Medicine, Imperial College, London, UK Abstract. Eklund A, du Bois RM (Karolinska University Hospital, Karolinska Institutet and Centre for Molecular Medicine, Stockholm, Sweden and Imperial College, London, UK). Approaches to the treatment of some of the troublesome manifestations of sarcoidosis. (Review). J Intern Med 2014; 275: 335–349. Sarcoidosis can be a major therapeutic challenge given its multiplicity of clinical presentations, variable combination of organ involvement and severity, and unpredictable longitudinal behaviour. Six manifesta- tions of sarcoidosis are especially difficult to manage because of (i) an incomplete knowledge of causation – fatigue and small fibre neuropathy, (ii) the rare occurrence in sarcoidosis – intra-abdominal compli- cations or (iii) the potentially life-threatening conse- quences in some patients – neurological disease, pulmonary hypertension and hypercalcaemia. In none of these situations have a prospective, double- blind, placebo-controlled trial of any therapy been conducted. Despite this absence of any firm evidence base to support therapeutic recommendations, these six entities can be extremely problematic for the practising clinician. It is for this reason that we have focused in this review on these six disease manifes- tations and provided a synopsis of each problem together with suggested treatment approaches, based on an analysis of the current literature. Keywords: sarcoidosis, less common manifestations, management, treatment. Introduction Sarcoidosis is a chronic inflammatory disease, characterized by the presence of predominantly noncaseating granulomata in multiple organs of the body; virtually, all organs may be affected but the burden of disease varies from one individual to another. Because of the inflammatory nature of the defining pathology, the mainstay of treatment for all forms of sarcoidosis has been corticosteroids. Many reviews discuss this therapeutic modality in detail (for example see [1–4]). It is notable that there have been few randomised controlled trials of the use of corticosteroids in most forms of sarcoid- osis, and this is partly to blame for the tendency for their overuse with the result that many patients experience the well-known profile of corticosteroid- induced adverse events. In this regard, in recent years, there has been a trend towards limiting the use of these agents in patients with symptomatic disease (excluding those with demonstrable but asymptomatic disease in vital organs such as the eye, heart or central nervous system) and also to- wards applying topical treatment for localized disease (e.g. eye drops, subcutaneous injections, inhaled corticosteroids). In addition, the use of cor- ticosteroid-sparing agents such as methotrexate, azathioprine and leflunomide is encouraged if too high a dose or too long a course of corticosteroids is required [5–8]. The efficacy of tumour necrosis factor (TNF) antagonism – especially with the chimeric anti-TNF monoclonal antibody infliximab – has been shown relatively recently, thus provi- ding additional therapeutic options particularly for more refractory disease [9–11]. These changes to therapeutic practice have been well documented. Therefore, the goal of this review was to highlight some of the less well-defined, troublesome and particularly difficult to treat sar- coidosis presentations. We will describe and suggest treatment approaches for fatigue, intra-abdominal disease, hypercalcaemia, small fibre neuropathy, other neurological disease and sarcoidosis-associ- ated pulmonary hypertension. We will address the individual characteristics of and provide sugges- tions for a therapeutic strategy for each of these six manifestations of sarcoidosis (Table 1). Fatigue in sarcoidosis Defining fatigue and its relationships Patients with sarcoidosis have commonly reported excessive fatigue as part of their disease process ª 2014 The Association for the Publication of the Journal of Internal Medicine 335 Review
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Approaches to the treatment of some of the troublesome manifestations of sarcoidosisdoi: 10.1111/joim.12198
Approaches to the treatment of some of the troublesome manifestations of sarcoidosis A. Eklund1 & R. M. du Bois2
From the 1Department of Medicine, Karolinska University Hospital, Karolinska Institutet and Centre for Molecular Medicine, Stockholm, Sweden; and 2Respiratory Medicine, Imperial College, London, UK
Abstract. EklundA,duBoisRM(KarolinskaUniversity Hospital, Karolinska Institutet and Centre for Molecular Medicine, Stockholm, Sweden and Imperial College, London, UK). Approaches to the treatmentofsomeof thetroublesomemanifestations of sarcoidosis. (Review). J Intern Med 2014; 275: 335–349. Sarcoidosis can be a major therapeutic challenge given itsmultiplicity of clinical presentations, variable combination of organ involvement and severity, and unpredictable longitudinal behaviour. Six manifesta- tions of sarcoidosis are especially difficult to manage because of (i) an incomplete knowledge of causation – fatigue and small fibre neuropathy, (ii) the rare occurrence in sarcoidosis – intra-abdominal compli- cations or (iii) the potentially life-threatening conse-
quences in some patients – neurological disease, pulmonary hypertension and hypercalcaemia. In none of these situations have a prospective, double- blind, placebo-controlled trial of any therapy been conducted. Despite this absence of any firm evidence base to support therapeutic recommendations, these six entities can be extremely problematic for the practising clinician. It is for this reason that we have focused in this review on these six disease manifes- tations and provided a synopsis of each problem togetherwith suggested treatment approaches, based on an analysis of the current literature.
Keywords: sarcoidosis, less common manifestations, management, treatment.
Introduction
Sarcoidosis is a chronic inflammatory disease, characterized by the presence of predominantly noncaseating granulomata in multiple organs of the body; virtually, all organs may be affected but the burden of disease varies from one individual to another. Because of the inflammatory nature of the defining pathology, the mainstay of treatment for all forms of sarcoidosis has been corticosteroids. Many reviews discuss this therapeutic modality in detail (for example see [1–4]). It is notable that there have been few randomised controlled trials of the use of corticosteroids in most forms of sarcoid- osis, and this is partly to blame for the tendency for their overuse with the result that many patients experience the well-known profile of corticosteroid- induced adverse events. In this regard, in recent years, there has been a trend towards limiting the use of these agents in patients with symptomatic disease (excluding those with demonstrable but asymptomatic disease in vital organs such as the eye, heart or central nervous system) and also to- wards applying topical treatment for localized disease (e.g. eye drops, subcutaneous injections, inhaled corticosteroids). In addition, the use of cor- ticosteroid-sparing agents such as methotrexate,
azathioprine and leflunomide is encouraged if too high a dose or too long a course of corticosteroids is required [5–8]. The efficacy of tumour necrosis factor (TNF) antagonism – especially with the chimeric anti-TNF monoclonal antibody infliximab – has been shown relatively recently, thus provi- ding additional therapeutic options particularly for more refractory disease [9–11].
These changes to therapeutic practice have been well documented. Therefore, the goal of this review was to highlight some of the less well-defined, troublesome and particularly difficult to treat sar- coidosis presentations.Wewill describe andsuggest treatment approaches for fatigue, intra-abdominal disease, hypercalcaemia, small fibre neuropathy, other neurological disease and sarcoidosis-associ- ated pulmonary hypertension. We will address the individual characteristics of and provide sugges- tions for a therapeutic strategy for each of these six manifestations of sarcoidosis (Table 1).
Fatigue in sarcoidosis
Defining fatigue and its relationships
Patients with sarcoidosis have commonly reported excessive fatigue as part of their disease process
ª 2014 The Association for the Publication of the Journal of Internal Medicine 335
Review
even in the absence of evidence of a large burden of organic disease [12, 13]. In a study of 1197 patients, it was shown that excessive fatigue is more common in women than men, but this is also true in the general, nonsarcoidosis population [14]. In the last 10–15 years, the impact of sarcoidosis on health status and quality of life, especially fatigue, has been addressed in some detail by several groups including by Drent and colleagues (examples included in references 15–18). Validated instruments that measure various aspects of health status and quality of life (reviewed in detail by Drent et al. [13]) showed that chronic fatigue was a troublesome symptom for the majority of patients with sarcoidosis. Health status, which reflects the effect of disease on functioning, should be distinguished from quality of life, which is a measure of how a patient evaluates their level of function. Nonetheless, both are impaired in patients with sarcoidosis compared with healthy control subjects, and fatigue has been shown to relate to these measures [13]. It is important to stress that quality-of-life measures, including the fatigue component, do not necessarily relate to the impact of organ-based disease and that significant
life-changing symptomatology can occur, appar- ently in isolation. In this context, therapeutic decisions need to take into account all aspects of the individual’s disease including health status and quality of life.
Fatigue is not only difficult to define – it seems to exist in at least three forms: mild, intermittent and all day – but it is also related to other aspects of the patient’s symptomatology, which makes it compli- cated to distinguish cause and effect from associ- ations [19]. For example, patients with sarcoidosis also display more depressive symptoms (compared with healthy controls) so Is it the depression that causes the fatigue or are the two independent but inter-related syndromes? [20, 21]. Socio-economic status is negatively associated with disease sever- ity and also has an inter-relationship with fatigue.
There is, therefore, a complex inter-relationship between fatigue, health-related measures and psy- chosocial factors. Obstructive sleep apnoea in sarcoidosis with its attendant fatigue symptom- atology has been described [22] but excess daytime sleepiness, assessed by the Epworth Sleepiness
Table 1 Suggested therapeutic approaches. In all cases, the burden of organic disease should be treated with the standard therapies
Fatigue Consider neurostimulants – dexmethylphenidate, methylphenidate, armodafinil
anti-TNF agents if organic disease also troublesome
Intra-abdominal disease Try proton-pump inhibitors and antacids if upper G-I symptoms
Consider ursodeoxycholic acid if pruritus and fatigue discomforts
Hypercalcaemia/
hypercalciuria
corticosteroids, calcitonin and loop diuretics options
Moderate hypercalcemia – corticosteroids, consider ketoconazole or hydroxychloroquine
Hypercalciuria – more observational approach: options include corticosteroids diuretics
Small fibre neuropathy antidepressants
Neurological disease Severe symptoms – methylprednisolone intravenously in pulses
Long-term/high-dose corticosteroid regimen
Consider pulmonary hypertension therapies
Transplantation
A. Eklund & R. M. du Bois Review: Difficult management issues in sarcoidosis
336 ª 2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 275; 335–349
13652796, 2014, 4, D ow
nloaded from https://onlinelibrary.w
nline L ibrary on [02/04/2023]. See the T
erm s and C
articles are governed by the applicable C reative C
om m
ons L icense
Scale, has also been reported in the absence of sleep apnoea [23]. Given that the treatment options for obstructive sleep apnoea are likely to have a positive effect on fatigue, it is important to distin- guish between these two states. Other inter-rela- tionships have been suggested between fatigue and both small fibre neuropathy and muscle weakness. The impact of disease-modifying therapy in both worsening and possibly alleviating fatigue also needs to be considered.
Fatigue is difficult to measure, but there are a number of instruments that can be used to quan- tify the problem. The best validated for sarcoidosis is the Fatigue Assessment Scale, for which the minimal clinically important difference has been defined (four units) and which allows change over time and thus the impact of any intervention to be determined more precisely than other instruments [19, 24, 25].
Cause of fatigue
If the definition of and inter-relationships for fatigue are somewhat unclear, the cause is no less elusive. As in most areas of sarcoidosis research, studies to support unequivocally the views gained from clinical experience are lacking. Similarly, studies to elucidate the cause of fatigue are incon- clusive; nevertheless, it is clearly multifactorial, and there is evidence to suggest a biochemical basis. Studies investigating the roles of C-reactive protein and cytokines, including interleukin-1 (IL- 1) and TNFa, imply an inflammatory basis, and 18F-fluorodeoxyglucose positron emission tomog- raphy (18FDG PET) studies also show that inflam- mation is associated with fatigue, but cause and effect have not been established [26–28]. Indeed, no such relationship has been shown in some studies [29]. The role of TNFa in neurotransmission provides a putative link between cytokines and the brain, and thus fatigue, but again this is unproven [30]. At best, it can be concluded that inflammation may be involved but the precise role remains unknown. The inter-relationships between factors that can contribute to fatigue are shown in Fig. 1.
Treatment of fatigue
With this background of uncertain and multifacto- rial causation and inter-relationships, a holistic approach needs to be taken. It is important to identify and treat independently sleepabnormalities and small fibre neuropathy. Anxiety/depression
also needs to be evaluated, and psychosocial coun- selling should be a part of the treatment process.
The key question is whether or not other pharma- cological approaches may be helpful. The beneficial effects of TNF inhibition on fatigue using either infliximab or adalimumab have been reported [31, 32]. The drugs had been primarily indicated for refractory organ disease with fatigue as a co-exis- tent problem. It would be difficult to justify using these agents for fatigue without any demonstrable co-existing organic problem. Given that inflamma- tory factors may play a causative role, it would be reasonable to assess the effects of a small dose of corticosteroids (no greater than 10 mg day1), pos- sibly with the addition of hydroxychloroquine, for patients with troublesome fatigue without any clinical manifestations of organ involvement [33].
There have been some reports of benefit obtained by the use of neurostimulants in managing the fatigue associated with cancer [34]. More recently, small numbers of patients with sarcoidosis have been treated with the neurostimulants dexmethyl- phenidate and methylphenidate and also with armodafinil. In a crossover study of 10 patients, Lower et al. observed improvement in Fatigue Assessment Scores in response to an escalating dose of dexmethylphenidate up to a maximum of 20 mg day1 [35]. In another study, the same authors again employed a crossover study to
socio-economic factorssleep
Fig. 1 Suggested factors that can interact to produce fatigue.
A. Eklund & R. M. du Bois Review: Difficult management issues in sarcoidosis
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assess the effects of an escalating dose of armod- afinil (a drug that has been used to treat the fatigue of chronic diseases including multiple sclerosis [36, 37]) up to 250 mg day1 in 15 patients [38]. Improvements in Fatigue Assessment Scores were seen. In both studies, patients were allowed to remain on their existing sarcoidosis therapy, which impacts on the robustness of the conclu- sions that can be drawn on the efficacy of the neurostimulants.
Suggested approach
Fatigue is still a complex mystery. We believe that careful counselling, together with perhaps small doses of anti-inflammatory agents, should be the mainstay of therapy once confounders such as sleep apnoea have been excluded. Patients may also benefit from a carefully constructed rehabili- tation programme designed to improve well-being without adding to exhaustion and with agreed programmes and treatment reduction plans agreed in advance.
Anti-TNF therapy may be justified if there is co- existent troublesome organic disease. In selected cases, particularly those with severe debilitating disease, neurostimulants may be discussed although the evidence base for this approach remains weak.
Intra-abdominal manifestations
Gastrointestinal tract
It is a challenge for physicians caring for patients with sarcoidosis to judge whether or not symptoms from the gastrointestinal (G-I) tract are caused by the disease, and even more challenging to diagnose G-I involvement when no clinical signs are present. In autopsy studies, asymptomatic G-I sarcoidosis has been reported in 5–10% of patients [39, 40], but symptomatic disease is much less common. Sarcoidosis is most frequently observed in the antrum of the stomach. Ulcers, nodules, polyp formation and sometimes a linitis plastica-type picture may be found, often giving rise to post- prandial epigastric pain, nausea and vomiting, and sometimes causing protein-losing enteropathy, weight loss and signs of G-I bleeding and obstruc- tion [41–49]. Any part of the G-I tract may be involved, but the small intestine is often spared making it relatively easy to differentiate from Crohn’s disease. Other causes of granuloma for- mation such as tuberculosis, fungal infection and
lymphoma should also be excluded. Upper and lower G-I endoscopy with multiple random biopsies in the absence of macroscopic findings is recom- mended as part of the diagnostic procedure.
Liver, spleen and pancreas
Compared with G-I involvement, the prevalence of hepatic granulomas is much more common in autopsy studies, often being found in more than 70% of patients; the prevalence is somewhat lower in biopsy studies [41, 50, 51]. Abnormal liver function tests are more commonly reported than hepatomegaly, and there may be hepatic involve- ment without signs of sarcoidosis in the lungs [52]. Fatigue is a common symptom, and right upper quadrant abdominal pain may occur, but seldom pruritus and jaundice. Elevation of alkaline phos- phatase levels is considered to be a more reliable sign of involvement than increased levels of trans- aminases, which are often only slightly elevated [53, 54]. Ultrasound, abdominal computed tomog- raphy (CT) scans and biopsies are useful diagnostic tools. Sometimes, portal hypertension with accom- panying oesophageal varices and hepatomegaly may be a consequence of hepatic sarcoidosis [55]. Cholestatic signs may mimic primary biliary scle- rosis (PBC) and primary sclerosing cholangitis (PSC). Splenic involvement has been reported to be common in large Finnish biopsy series [56, 57], sometimes causing left upper abdominal quadrant discomfort and peripheral blood cytopenia second- ary to hypersplenism (Fig. 2).
The pancreas is an intra-abdominal organ that is much less often affected. The diagnosis of pancre- atic involvement may be made as a consequence of surgical intervention following detection on CT or ultrasound of a mass in the head of the pancreas suspicious for carcinoma [58–60]. Jaundice, nau- sea and abdominal pain may be followed by weight loss. Ascites caused by sarcoidosis is very uncom- mon, but can occur as a consequence of involve- ment in the peritoneal serosa, sometimes as a result of portal hypertension or heart failure.
Evidenced-based guidelines for specific treatment of G-I tract sarcoidosis are lacking, but most studies support the use of corticosteroids at least to reduce symptoms [61, 62]. Alternatively, meth- otrexate, azathioprine or leflunomide may be used as corticosteroid-sparing agents, and infliximab could be considered in corticosteroid-refractory cases [40]. In general, methotrexate has been the
A. Eklund & R. M. du Bois Review: Difficult management issues in sarcoidosis
338 ª 2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 275; 335–349
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nloaded from https://onlinelibrary.w
nline L ibrary on [02/04/2023]. See the T
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articles are governed by the applicable C reative C
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ons L icense
most frequently used corticosteroid-sparing agent in the treatment of sarcoidosis. Leflunomide, given alone or in combination with methotrexate, is sometimes advocated as an alternative second-line drug, but the experience of using it in sarcoidosis is still limited. Proton-pump inhibitors and antacids could have additional benefit [63] for peptic ulcer- like or reflux symptoms. Surgery should be restricted to patients with life-threatening bleeding or luminal obstruction.
Most patients with hepatic sarcoidosis, at least those who are asymptomatic, may remain untreated as use of corticosteroids does not seem to have a major influence on the disease course and does not prevent portal hypertension [41, 64–66]. The experience with anti-TNFa agents is still too limited for general recommendation, but they are worth considering in difficult cases [67]. Methotrexate is also an option as a corticosteroid- sparing agent but requires careful monitoring because of potential liver toxicity [68]. Primarily monitoring is achieved by regular assessment for
any new symptoms that could reflect toxicity, regular measurement of liver enzyme activity and in particular assessment for signs of cholestasis. Adverse effects could also be monitored by ultra- sound investigation of the liver followed in some cases by biopsy. Azathioprine and hydroxychloroq- uine provide alternatives although experience of their use is limited [69]. Azathioprine is generally less hepatotoxic than methotrexate, but can on the other hand seriously affect blood counts, particu- larly in patients with low or deficient serum thiop- urine S-methyltransferase levels. Ursodeoxycholic acid stimulates impaired hepatobiliary secretion, has a mild side-effect profile and has been reported to have a positive effect on liver enzymes, fatigue and pruritus [54, 70]. Biliary sarcoidosis can mimic PSC, but the response to corticosteroids is much better in patients with the former condition [71]. Liver transplantation is a final option.
Spleen involvement without symptoms does not necessitate treatment but enlargement causing cy- topenia may require treatment with corticosteroids, eventually in combination with corticosteroid-spar- ing agents. Occasionally, the sheer size of the spleen causes so much discomfort that splenectomy is recommended and will exclude the risk of sudden life-threatening haemorrhage following rupture, either spontaneously or after blunt trauma.
Sarcoidosis in the pancreas, often diagnosed fol- lowing surgery on suspicion of carcinoma, can be treated with corticosteroids to alleviate pain and reduce elevated levels of serum amylase and lipase.
Suggested therapeutic approach
Symptoms caused by intra-abdominal manifesta- tions of sarcoidosis are uncommon but may be difficult to distinguish from other causes of similar symptoms. Once sarcoidosis has been established, a decision on treatment or observation should be made. Our belief is that proton-pump inhibitors and antacids should be the first-line approach for upper G-I symptoms. More bothersome symptoms originating from the G-I tract and not calling for surgical intervention should be treated with corti- costeroids alone or in combination with corticoste- roid-sparing agents.
In our opinion, hepatic involvement characterized by modest increases in liver-related enzymes rarely needs intervention. However, if enzyme abnormal- ities worsen progressively or discomforting fatigue
Fig. 2 Fluorodeoxyglucose positron emission tomogra- phy/computed tomography scan illustrating inflammatory hepatic and splenic lesions in a patient with sarcoidosis. Courtesy of Dr. Milan Lomsky, Department of Clinical Physiology, Nuclear Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
A. Eklund & R. M. du Bois Review: Difficult management issues in sarcoidosis
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and pruritus develop, ursodeoxycholic acid with its favourable adverse effect profile could be given. In addition and similar to the approach to G-I involve- ment outlined above, corticosteroids with cortico- steroid-sparing agents could be considered although there is as yet no solid evidence to confirm that they will protect against progressive liver disease.
Hypercalcaemia
Abnormal calcium metabolism is a well-known feature of sarcoidosis. It is a consequence of a disturbed balance between G-I absorption, protein binding, bone turnover and renal excretion. The most common manifestation is hypercalciuria which is observed in approximately 30% of patients, whereas hypercalcaemia is found in 5–11% [72–75]. There is a strong relationship between vitamin D and calcium metabolism. Vita- min D is a group of cholesterol-derived sterols, the most important of which in man are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Both…
Approaches to the treatment of some of the troublesome manifestations of sarcoidosis A. Eklund1 & R. M. du Bois2
From the 1Department of Medicine, Karolinska University Hospital, Karolinska Institutet and Centre for Molecular Medicine, Stockholm, Sweden; and 2Respiratory Medicine, Imperial College, London, UK
Abstract. EklundA,duBoisRM(KarolinskaUniversity Hospital, Karolinska Institutet and Centre for Molecular Medicine, Stockholm, Sweden and Imperial College, London, UK). Approaches to the treatmentofsomeof thetroublesomemanifestations of sarcoidosis. (Review). J Intern Med 2014; 275: 335–349. Sarcoidosis can be a major therapeutic challenge given itsmultiplicity of clinical presentations, variable combination of organ involvement and severity, and unpredictable longitudinal behaviour. Six manifesta- tions of sarcoidosis are especially difficult to manage because of (i) an incomplete knowledge of causation – fatigue and small fibre neuropathy, (ii) the rare occurrence in sarcoidosis – intra-abdominal compli- cations or (iii) the potentially life-threatening conse-
quences in some patients – neurological disease, pulmonary hypertension and hypercalcaemia. In none of these situations have a prospective, double- blind, placebo-controlled trial of any therapy been conducted. Despite this absence of any firm evidence base to support therapeutic recommendations, these six entities can be extremely problematic for the practising clinician. It is for this reason that we have focused in this review on these six disease manifes- tations and provided a synopsis of each problem togetherwith suggested treatment approaches, based on an analysis of the current literature.
Keywords: sarcoidosis, less common manifestations, management, treatment.
Introduction
Sarcoidosis is a chronic inflammatory disease, characterized by the presence of predominantly noncaseating granulomata in multiple organs of the body; virtually, all organs may be affected but the burden of disease varies from one individual to another. Because of the inflammatory nature of the defining pathology, the mainstay of treatment for all forms of sarcoidosis has been corticosteroids. Many reviews discuss this therapeutic modality in detail (for example see [1–4]). It is notable that there have been few randomised controlled trials of the use of corticosteroids in most forms of sarcoid- osis, and this is partly to blame for the tendency for their overuse with the result that many patients experience the well-known profile of corticosteroid- induced adverse events. In this regard, in recent years, there has been a trend towards limiting the use of these agents in patients with symptomatic disease (excluding those with demonstrable but asymptomatic disease in vital organs such as the eye, heart or central nervous system) and also to- wards applying topical treatment for localized disease (e.g. eye drops, subcutaneous injections, inhaled corticosteroids). In addition, the use of cor- ticosteroid-sparing agents such as methotrexate,
azathioprine and leflunomide is encouraged if too high a dose or too long a course of corticosteroids is required [5–8]. The efficacy of tumour necrosis factor (TNF) antagonism – especially with the chimeric anti-TNF monoclonal antibody infliximab – has been shown relatively recently, thus provi- ding additional therapeutic options particularly for more refractory disease [9–11].
These changes to therapeutic practice have been well documented. Therefore, the goal of this review was to highlight some of the less well-defined, troublesome and particularly difficult to treat sar- coidosis presentations.Wewill describe andsuggest treatment approaches for fatigue, intra-abdominal disease, hypercalcaemia, small fibre neuropathy, other neurological disease and sarcoidosis-associ- ated pulmonary hypertension. We will address the individual characteristics of and provide sugges- tions for a therapeutic strategy for each of these six manifestations of sarcoidosis (Table 1).
Fatigue in sarcoidosis
Defining fatigue and its relationships
Patients with sarcoidosis have commonly reported excessive fatigue as part of their disease process
ª 2014 The Association for the Publication of the Journal of Internal Medicine 335
Review
even in the absence of evidence of a large burden of organic disease [12, 13]. In a study of 1197 patients, it was shown that excessive fatigue is more common in women than men, but this is also true in the general, nonsarcoidosis population [14]. In the last 10–15 years, the impact of sarcoidosis on health status and quality of life, especially fatigue, has been addressed in some detail by several groups including by Drent and colleagues (examples included in references 15–18). Validated instruments that measure various aspects of health status and quality of life (reviewed in detail by Drent et al. [13]) showed that chronic fatigue was a troublesome symptom for the majority of patients with sarcoidosis. Health status, which reflects the effect of disease on functioning, should be distinguished from quality of life, which is a measure of how a patient evaluates their level of function. Nonetheless, both are impaired in patients with sarcoidosis compared with healthy control subjects, and fatigue has been shown to relate to these measures [13]. It is important to stress that quality-of-life measures, including the fatigue component, do not necessarily relate to the impact of organ-based disease and that significant
life-changing symptomatology can occur, appar- ently in isolation. In this context, therapeutic decisions need to take into account all aspects of the individual’s disease including health status and quality of life.
Fatigue is not only difficult to define – it seems to exist in at least three forms: mild, intermittent and all day – but it is also related to other aspects of the patient’s symptomatology, which makes it compli- cated to distinguish cause and effect from associ- ations [19]. For example, patients with sarcoidosis also display more depressive symptoms (compared with healthy controls) so Is it the depression that causes the fatigue or are the two independent but inter-related syndromes? [20, 21]. Socio-economic status is negatively associated with disease sever- ity and also has an inter-relationship with fatigue.
There is, therefore, a complex inter-relationship between fatigue, health-related measures and psy- chosocial factors. Obstructive sleep apnoea in sarcoidosis with its attendant fatigue symptom- atology has been described [22] but excess daytime sleepiness, assessed by the Epworth Sleepiness
Table 1 Suggested therapeutic approaches. In all cases, the burden of organic disease should be treated with the standard therapies
Fatigue Consider neurostimulants – dexmethylphenidate, methylphenidate, armodafinil
anti-TNF agents if organic disease also troublesome
Intra-abdominal disease Try proton-pump inhibitors and antacids if upper G-I symptoms
Consider ursodeoxycholic acid if pruritus and fatigue discomforts
Hypercalcaemia/
hypercalciuria
corticosteroids, calcitonin and loop diuretics options
Moderate hypercalcemia – corticosteroids, consider ketoconazole or hydroxychloroquine
Hypercalciuria – more observational approach: options include corticosteroids diuretics
Small fibre neuropathy antidepressants
Neurological disease Severe symptoms – methylprednisolone intravenously in pulses
Long-term/high-dose corticosteroid regimen
Consider pulmonary hypertension therapies
Transplantation
A. Eklund & R. M. du Bois Review: Difficult management issues in sarcoidosis
336 ª 2014 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2014, 275; 335–349
13652796, 2014, 4, D ow
nloaded from https://onlinelibrary.w
nline L ibrary on [02/04/2023]. See the T
erm s and C
articles are governed by the applicable C reative C
om m
ons L icense
Scale, has also been reported in the absence of sleep apnoea [23]. Given that the treatment options for obstructive sleep apnoea are likely to have a positive effect on fatigue, it is important to distin- guish between these two states. Other inter-rela- tionships have been suggested between fatigue and both small fibre neuropathy and muscle weakness. The impact of disease-modifying therapy in both worsening and possibly alleviating fatigue also needs to be considered.
Fatigue is difficult to measure, but there are a number of instruments that can be used to quan- tify the problem. The best validated for sarcoidosis is the Fatigue Assessment Scale, for which the minimal clinically important difference has been defined (four units) and which allows change over time and thus the impact of any intervention to be determined more precisely than other instruments [19, 24, 25].
Cause of fatigue
If the definition of and inter-relationships for fatigue are somewhat unclear, the cause is no less elusive. As in most areas of sarcoidosis research, studies to support unequivocally the views gained from clinical experience are lacking. Similarly, studies to elucidate the cause of fatigue are incon- clusive; nevertheless, it is clearly multifactorial, and there is evidence to suggest a biochemical basis. Studies investigating the roles of C-reactive protein and cytokines, including interleukin-1 (IL- 1) and TNFa, imply an inflammatory basis, and 18F-fluorodeoxyglucose positron emission tomog- raphy (18FDG PET) studies also show that inflam- mation is associated with fatigue, but cause and effect have not been established [26–28]. Indeed, no such relationship has been shown in some studies [29]. The role of TNFa in neurotransmission provides a putative link between cytokines and the brain, and thus fatigue, but again this is unproven [30]. At best, it can be concluded that inflammation may be involved but the precise role remains unknown. The inter-relationships between factors that can contribute to fatigue are shown in Fig. 1.
Treatment of fatigue
With this background of uncertain and multifacto- rial causation and inter-relationships, a holistic approach needs to be taken. It is important to identify and treat independently sleepabnormalities and small fibre neuropathy. Anxiety/depression
also needs to be evaluated, and psychosocial coun- selling should be a part of the treatment process.
The key question is whether or not other pharma- cological approaches may be helpful. The beneficial effects of TNF inhibition on fatigue using either infliximab or adalimumab have been reported [31, 32]. The drugs had been primarily indicated for refractory organ disease with fatigue as a co-exis- tent problem. It would be difficult to justify using these agents for fatigue without any demonstrable co-existing organic problem. Given that inflamma- tory factors may play a causative role, it would be reasonable to assess the effects of a small dose of corticosteroids (no greater than 10 mg day1), pos- sibly with the addition of hydroxychloroquine, for patients with troublesome fatigue without any clinical manifestations of organ involvement [33].
There have been some reports of benefit obtained by the use of neurostimulants in managing the fatigue associated with cancer [34]. More recently, small numbers of patients with sarcoidosis have been treated with the neurostimulants dexmethyl- phenidate and methylphenidate and also with armodafinil. In a crossover study of 10 patients, Lower et al. observed improvement in Fatigue Assessment Scores in response to an escalating dose of dexmethylphenidate up to a maximum of 20 mg day1 [35]. In another study, the same authors again employed a crossover study to
socio-economic factorssleep
Fig. 1 Suggested factors that can interact to produce fatigue.
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assess the effects of an escalating dose of armod- afinil (a drug that has been used to treat the fatigue of chronic diseases including multiple sclerosis [36, 37]) up to 250 mg day1 in 15 patients [38]. Improvements in Fatigue Assessment Scores were seen. In both studies, patients were allowed to remain on their existing sarcoidosis therapy, which impacts on the robustness of the conclu- sions that can be drawn on the efficacy of the neurostimulants.
Suggested approach
Fatigue is still a complex mystery. We believe that careful counselling, together with perhaps small doses of anti-inflammatory agents, should be the mainstay of therapy once confounders such as sleep apnoea have been excluded. Patients may also benefit from a carefully constructed rehabili- tation programme designed to improve well-being without adding to exhaustion and with agreed programmes and treatment reduction plans agreed in advance.
Anti-TNF therapy may be justified if there is co- existent troublesome organic disease. In selected cases, particularly those with severe debilitating disease, neurostimulants may be discussed although the evidence base for this approach remains weak.
Intra-abdominal manifestations
Gastrointestinal tract
It is a challenge for physicians caring for patients with sarcoidosis to judge whether or not symptoms from the gastrointestinal (G-I) tract are caused by the disease, and even more challenging to diagnose G-I involvement when no clinical signs are present. In autopsy studies, asymptomatic G-I sarcoidosis has been reported in 5–10% of patients [39, 40], but symptomatic disease is much less common. Sarcoidosis is most frequently observed in the antrum of the stomach. Ulcers, nodules, polyp formation and sometimes a linitis plastica-type picture may be found, often giving rise to post- prandial epigastric pain, nausea and vomiting, and sometimes causing protein-losing enteropathy, weight loss and signs of G-I bleeding and obstruc- tion [41–49]. Any part of the G-I tract may be involved, but the small intestine is often spared making it relatively easy to differentiate from Crohn’s disease. Other causes of granuloma for- mation such as tuberculosis, fungal infection and
lymphoma should also be excluded. Upper and lower G-I endoscopy with multiple random biopsies in the absence of macroscopic findings is recom- mended as part of the diagnostic procedure.
Liver, spleen and pancreas
Compared with G-I involvement, the prevalence of hepatic granulomas is much more common in autopsy studies, often being found in more than 70% of patients; the prevalence is somewhat lower in biopsy studies [41, 50, 51]. Abnormal liver function tests are more commonly reported than hepatomegaly, and there may be hepatic involve- ment without signs of sarcoidosis in the lungs [52]. Fatigue is a common symptom, and right upper quadrant abdominal pain may occur, but seldom pruritus and jaundice. Elevation of alkaline phos- phatase levels is considered to be a more reliable sign of involvement than increased levels of trans- aminases, which are often only slightly elevated [53, 54]. Ultrasound, abdominal computed tomog- raphy (CT) scans and biopsies are useful diagnostic tools. Sometimes, portal hypertension with accom- panying oesophageal varices and hepatomegaly may be a consequence of hepatic sarcoidosis [55]. Cholestatic signs may mimic primary biliary scle- rosis (PBC) and primary sclerosing cholangitis (PSC). Splenic involvement has been reported to be common in large Finnish biopsy series [56, 57], sometimes causing left upper abdominal quadrant discomfort and peripheral blood cytopenia second- ary to hypersplenism (Fig. 2).
The pancreas is an intra-abdominal organ that is much less often affected. The diagnosis of pancre- atic involvement may be made as a consequence of surgical intervention following detection on CT or ultrasound of a mass in the head of the pancreas suspicious for carcinoma [58–60]. Jaundice, nau- sea and abdominal pain may be followed by weight loss. Ascites caused by sarcoidosis is very uncom- mon, but can occur as a consequence of involve- ment in the peritoneal serosa, sometimes as a result of portal hypertension or heart failure.
Evidenced-based guidelines for specific treatment of G-I tract sarcoidosis are lacking, but most studies support the use of corticosteroids at least to reduce symptoms [61, 62]. Alternatively, meth- otrexate, azathioprine or leflunomide may be used as corticosteroid-sparing agents, and infliximab could be considered in corticosteroid-refractory cases [40]. In general, methotrexate has been the
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most frequently used corticosteroid-sparing agent in the treatment of sarcoidosis. Leflunomide, given alone or in combination with methotrexate, is sometimes advocated as an alternative second-line drug, but the experience of using it in sarcoidosis is still limited. Proton-pump inhibitors and antacids could have additional benefit [63] for peptic ulcer- like or reflux symptoms. Surgery should be restricted to patients with life-threatening bleeding or luminal obstruction.
Most patients with hepatic sarcoidosis, at least those who are asymptomatic, may remain untreated as use of corticosteroids does not seem to have a major influence on the disease course and does not prevent portal hypertension [41, 64–66]. The experience with anti-TNFa agents is still too limited for general recommendation, but they are worth considering in difficult cases [67]. Methotrexate is also an option as a corticosteroid- sparing agent but requires careful monitoring because of potential liver toxicity [68]. Primarily monitoring is achieved by regular assessment for
any new symptoms that could reflect toxicity, regular measurement of liver enzyme activity and in particular assessment for signs of cholestasis. Adverse effects could also be monitored by ultra- sound investigation of the liver followed in some cases by biopsy. Azathioprine and hydroxychloroq- uine provide alternatives although experience of their use is limited [69]. Azathioprine is generally less hepatotoxic than methotrexate, but can on the other hand seriously affect blood counts, particu- larly in patients with low or deficient serum thiop- urine S-methyltransferase levels. Ursodeoxycholic acid stimulates impaired hepatobiliary secretion, has a mild side-effect profile and has been reported to have a positive effect on liver enzymes, fatigue and pruritus [54, 70]. Biliary sarcoidosis can mimic PSC, but the response to corticosteroids is much better in patients with the former condition [71]. Liver transplantation is a final option.
Spleen involvement without symptoms does not necessitate treatment but enlargement causing cy- topenia may require treatment with corticosteroids, eventually in combination with corticosteroid-spar- ing agents. Occasionally, the sheer size of the spleen causes so much discomfort that splenectomy is recommended and will exclude the risk of sudden life-threatening haemorrhage following rupture, either spontaneously or after blunt trauma.
Sarcoidosis in the pancreas, often diagnosed fol- lowing surgery on suspicion of carcinoma, can be treated with corticosteroids to alleviate pain and reduce elevated levels of serum amylase and lipase.
Suggested therapeutic approach
Symptoms caused by intra-abdominal manifesta- tions of sarcoidosis are uncommon but may be difficult to distinguish from other causes of similar symptoms. Once sarcoidosis has been established, a decision on treatment or observation should be made. Our belief is that proton-pump inhibitors and antacids should be the first-line approach for upper G-I symptoms. More bothersome symptoms originating from the G-I tract and not calling for surgical intervention should be treated with corti- costeroids alone or in combination with corticoste- roid-sparing agents.
In our opinion, hepatic involvement characterized by modest increases in liver-related enzymes rarely needs intervention. However, if enzyme abnormal- ities worsen progressively or discomforting fatigue
Fig. 2 Fluorodeoxyglucose positron emission tomogra- phy/computed tomography scan illustrating inflammatory hepatic and splenic lesions in a patient with sarcoidosis. Courtesy of Dr. Milan Lomsky, Department of Clinical Physiology, Nuclear Medicine, Sahlgrenska University Hospital, Gothenburg, Sweden.
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and pruritus develop, ursodeoxycholic acid with its favourable adverse effect profile could be given. In addition and similar to the approach to G-I involve- ment outlined above, corticosteroids with cortico- steroid-sparing agents could be considered although there is as yet no solid evidence to confirm that they will protect against progressive liver disease.
Hypercalcaemia
Abnormal calcium metabolism is a well-known feature of sarcoidosis. It is a consequence of a disturbed balance between G-I absorption, protein binding, bone turnover and renal excretion. The most common manifestation is hypercalciuria which is observed in approximately 30% of patients, whereas hypercalcaemia is found in 5–11% [72–75]. There is a strong relationship between vitamin D and calcium metabolism. Vita- min D is a group of cholesterol-derived sterols, the most important of which in man are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Both…
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