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 manifestations 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 complications or (iii) the potentially life-threatening consequences 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 manifestations and provided a synopsis of each problem together with suggested treatment approaches, based on an analysis of the current literature.
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 sarcoidosis, 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 towards applying topical treatment for localized disease (e.g. eye drops, subcutaneous injections, inhaled corticosteroids). In addition, the use of corticosteroid-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 providing 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 sarcoidosis presentations. We will describe and suggest treatment approaches for fatigue, intra-abdominal disease, hypercalcaemia, small fibre neuropathy, other neurological disease and sarcoidosis-associated pulmonary hypertension. We will address the individual characteristics of and provide suggestions for a therapeutic strategy for each of these six manifestations of sarcoidosis (Table 1).
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
Severe hypercalcemia – act immediately: rehydrate, consider zoledronic acid, give corticosteroids, calcitonin and loop diuretics options
Moderate hypercalcemia – corticosteroids, consider ketoconazole or hydroxychloroquine
Hypercalciuria – more observational approach: options include corticosteroids diuretics
|Small fibre neuropathy|| |
Consider intravenous immunoglobulin, anti-TNF agents
|Neurological disease|| |
Severe symptoms – methylprednisolone intravenously in pulses
Long-term/high-dose corticosteroid regimen
anti-TNF agents if refractory
|Pulmonary hypertension|| |
Treat co-existent sleep apnoea and cardiac abnormalities
Consider pulmonary hypertension therapies
Fatigue in sarcoidosis
Defining fatigue and its relationships
Patients with sarcoidosis have commonly reported excessive fatigue as part of their disease process 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 . 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. ) 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 . 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, apparently 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 complicated to distinguish cause and effect from associations . 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 severity and also has an inter-relationship with fatigue.
There is, therefore, a complex inter-relationship between fatigue, health-related measures and psychosocial factors. Obstructive sleep apnoea in sarcoidosis with its attendant fatigue symptomatology has been described  but excess daytime sleepiness, assessed by the Epworth Sleepiness Scale, has also been reported in the absence of sleep apnoea . Given that the treatment options for obstructive sleep apnoea are likely to have a positive effect on fatigue, it is important to distinguish between these two states. Other inter-relationships 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 quantify 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 inconclusive; 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 TNFα, imply an inflammatory basis, and 18F-fluorodeoxyglucose positron emission tomography (18FDG PET) studies also show that inflammation is associated with fatigue, but cause and effect have not been established [26-28]. Indeed, no such relationship has been shown in some studies . The role of TNFα in neurotransmission provides a putative link between cytokines and the brain, and thus fatigue, but again this is unproven . 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 multifactorial causation and inter-relationships, a holistic approach needs to be taken. It is important to identify and treat independently sleep abnormalities and small fibre neuropathy. Anxiety/depression also needs to be evaluated, and psychosocial counselling should be a part of the treatment process.
The key question is whether or not other pharmacological 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-existent problem. It would be difficult to justify using these agents for fatigue without any demonstrable co-existing organic problem. Given that inflammatory 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 day−1), possibly with the addition of hydroxychloroquine, for patients with troublesome fatigue without any clinical manifestations of organ involvement .
There have been some reports of benefit obtained by the use of neurostimulants in managing the fatigue associated with cancer . More recently, small numbers of patients with sarcoidosis have been treated with the neurostimulants dexmethylphenidate 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 day−1 . In another study, the same authors again employed a crossover study to assess the effects of an escalating dose of armodafinil (a drug that has been used to treat the fatigue of chronic diseases including multiple sclerosis [36, 37]) up to 250 mg day−1 in 15 patients . 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 conclusions that can be drawn on the efficacy of the neurostimulants.
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 rehabilitation 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.
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 postprandial epigastric pain, nausea and vomiting, and sometimes causing protein-losing enteropathy, weight loss and signs of G-I bleeding and obstruction [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 formation 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 recommended 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 involvement without signs of sarcoidosis in the lungs . Fatigue is a common symptom, and right upper quadrant abdominal pain may occur, but seldom pruritus and jaundice. Elevation of alkaline phosphatase levels is considered to be a more reliable sign of involvement than increased levels of transaminases, which are often only slightly elevated [53, 54]. Ultrasound, abdominal computed tomography (CT) scans and biopsies are useful diagnostic tools. Sometimes, portal hypertension with accompanying oesophageal varices and hepatomegaly may be a consequence of hepatic sarcoidosis . Cholestatic signs may mimic primary biliary sclerosis (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 secondary to hypersplenism (Fig. 2).
The pancreas is an intra-abdominal organ that is much less often affected. The diagnosis of pancreatic 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, nausea and abdominal pain may be followed by weight loss. Ascites caused by sarcoidosis is very uncommon, but can occur as a consequence of involvement 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, methotrexate, azathioprine or leflunomide may be used as corticosteroid-sparing agents, and infliximab could be considered in corticosteroid-refractory cases . In general, methotrexate has been the 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  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-TNFα agents is still too limited for general recommendation, but they are worth considering in difficult cases . Methotrexate is also an option as a corticosteroid-sparing agent but requires careful monitoring because of potential liver toxicity . 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 ultrasound investigation of the liver followed in some cases by biopsy. Azathioprine and hydroxychloroquine provide alternatives although experience of their use is limited . Azathioprine is generally less hepatotoxic than methotrexate, but can on the other hand seriously affect blood counts, particularly in patients with low or deficient serum thiopurine 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 . Liver transplantation is a final option.
Spleen involvement without symptoms does not necessitate treatment but enlargement causing cytopenia may require treatment with corticosteroids, eventually in combination with corticosteroid-sparing 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 following 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 manifestations 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 corticosteroids alone or in combination with corticosteroid-sparing agents.
In our opinion, hepatic involvement characterized by modest increases in liver-related enzymes rarely needs intervention. However, if enzyme abnormalities worsen progressively or discomforting fatigue and pruritus develop, ursodeoxycholic acid with its favourable adverse effect profile could be given. In addition and similar to the approach to G-I involvement outlined above, corticosteroids with corticosteroid-sparing agents could be considered although there is as yet no solid evidence to confirm that they will protect against progressive liver disease.
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. Vitamin D is a group of cholesterol-derived sterols, the most important of which in man are vitamin D3 (cholecalciferol) and vitamin D2 (ergocalciferol). Both can be obtained from the diet, but previtamin D3 can also be synthesized from 7-dehydrocholesterol in the skin under the influence of ultraviolet light. After spontaneous isomerization at body temperature, the previtamin D3 is converted to cholecalciferol (vitamin D3). The metabolically active form of vitamin D3, calcitriol (i.e. 1,25-(OH)2-D3), is produced in a two-step hydroxylation process that takes place first in the liver and then in the kidneys. The second hydroxylation can also occur extrarenally in sarcoidosis, for example, in alveolar macrophages [75-78]. Calcitriol increases G-I absorption of calcium and phosphate, stimulates osteoclast activity in bones and may play a role in immunoregulation by downregulating the activation of lymphocytes . High levels of calcitriol will suppress parathyroid hormone (PTH) levels in sarcoidosis . However, parathyroidism and sarcoidosis may coexist. In 1987, a PTH-related peptide (PTHrP) was discovered that may be secreted in association with malignancy . It is also involved in calcium metabolism in sarcoidosis as elevated plasma levels have been shown, and its presence has been demonstrated by immunohistochemistry in lymph node biopsies from patients with sarcoidosis . PTHrP can simulate most of the properties of PTH including increase in bone resorption and distal tubular calcium reabsorption . Impaired renal function as a result of nephrocalcinosis and/or granulomatous nephritis, nephrolithiasis and decreased bone density are some of the consequences of a disturbed calcium metabolism .
In patients diagnosed with sarcoidosis, serum creatinine (and/or cystatin C), calcium and albumin levels should be measured and the ionized calcium calculated, and in addition, 24-h urinary calcium excretion should be determined. Measurement of clearance (EDTA or iohexol) will provide additional information on renal function when needed.
Treatment of hypercalcaemia
Hypercalcaemia may occur at any time during the disease course but severely increased levels accompanied by excessive thirst, nausea, confusion and fatigue are rare. Such patients with severe hypercalcaemia must first of all discontinue any ongoing calcium or vitamin D supplementation therapy and then receive rehydration therapy and corticosteroids. Bisphosphonates administered intravenously in a single dose could be added to the regimen at this time. If the hypercalcaemia is due to sarcoidosis, a rapid reduction (within a few days) is expected in the serum calcium; after a time lag, the urinary excretion rate should decrease. In some cases, sarcoidosis-induced hypercalcaemia may be resistant to this approach. In these more difficult situations, a loop diuretic may need to be administered and calcitonin is an option. Lack of response can indicate increased PTH release, and hyperparathyroidism should be suspected and investigated. Furthermore, coexisting disorders such as malignancies and other granulomatous diseases should be excluded.
Modestly increased serum calcium levels are more common than severe hypercalcaemia and can be corrected by corticosteroids alone in moderate doses (15–25 mg daily), or by starting treatment with, or adding, the antifungal drug ketoconazole . Another option is to inhibit the activity of 25(OH)D3-1α-hydroxylase, the enzyme that catalyses the hydroxylation of calcidiol to calcitriol, by administering hydroxychloroquine; this decreases the 25-hydroxylation and thereby lowers serum calcium levels. Finally, corticosteroids in combination with immunosuppressive drugs such as methotrexate, and the recently introduced infliximab, will have a general effect on calcium levels by controlling the overall granulomatous process . The daily intake of fluid should be more than 2 L. Some authors have recommended that exposure to sunlight should be minimized to avoid formation of active vitamin D3 metabolites, whereas others have argued that this will only have a marginal effect on calcium metabolism [73, 75]. It seems reasonable to recommend limited exposure to sunshine and avoidance of excessive intake of calcium-rich food, although this will not protect against the formation of renal stones.
Isolated hypercalciuria is usually not harmful. Hypercalciuria in combination with nephrolithiasis may be treated with bisphosphonates and corticosteroids. We have had some positive experiences of administering thiazide diuretics in patients with hypercalciuria. However, thiazides have also been reported to induce severe hypercalcaemia; therefore, close monitoring is recommended . Renal stones, often identified by ultrasound and reported to occur in 10% of patients, can be eliminated by shockwave lithotripsy.
Avoidance of corticosteroid-induced osteoporosis in patients with sarcoidosis, especially in those with disturbed calcium metabolism, sometimes poses a complex problem for the physician. It is reasonable to perform bone density measurement before long-term corticosteroid treatment is started and to repeat this at regular intervals. If there are no signs of dysregulated calcium metabolism and the bone density is normal, no immediate preventive action has to be taken in a young patient with sarcoidosis. However, if there is reduced bone density and in postmenopausal women, bisphosphonates should be considered in combination with recommendations for physical activity, and in some cases, hormone-replacement therapy . Both a repeat serum calcium test and measurement of 24-h calcium excretion are recommended after starting treatment. Some physicians advocate cholecalciferol for primary prevention if hypercalcaemia has been excluded .
Recently, the effects of vitamin D supplementation on surrogate markers of skeletal health in patients with sarcoidosis and mild vitamin 25(OH)-D insufficiency were reported. There were no beneficial effects observed but a slight risk of hypercalcaemia. At present, there seems to be little evidence for vitamin D supplementation in this group of patients .
Suggested therapeutic approach
We propose the following approach to treat severe hypercalcaemia (serum calcium level >3.5 mmol L−1). Therapeutic intervention should begin immediately, and we recommend rehydration with up to 5 L saline (9 mg mL−1 NaCl) during the first 24 h, with due care given to fluid balance. A bisphosphonate (zoledronic acid 4 mg) should be given as a single dose added to one of the saline units. Concomitant intake of prednisolone, initially 30 mg daily, should cause a rapid decrease in serum calcium if the hypercalcaemia is caused by sarcoidosis; if not, other causes must be excluded. The corticosteroid dose can be tapered rapidly with careful monitoring of calcium levels. In addition, a renal complication in combination with a lesser degree of hypercalcaemia is an indication for therapy. We do not believe that modest exposure to ultraviolet light or strict dietary restrictions will substantially affect a disturbed calcium metabolism in sarcoidosis.
We advocate close surveillance of bone density (and radiography if clinical signs of spine compression are present) when corticosteroids are given long term or in high doses. Bone protection with oral bisphosphonates or infusion of zoledronic acid (5 mg given intravenously once per year) is recommended. Patients at increased risk (decreased bone density, >50 years of age and/or postmenopausal women) may be treated prophylactically with oral calcium supplementation if serum and urinary calcium levels are regularly monitored . Postmenopausal women should consult a gynaecologist to decide whether oestrogen-replacement therapy is appropriate.
The treatment approach to hypercalciuria without concomitant stone formation can, in our opinion, be observational and often requires no treatment. Bisphosphonates or corticosteroids should be considered if there is a history of stone formation.
Small fibre neuropathy
Amongst the most recently described and especially debilitating problems encountered in sarcoidosis is small fibre neuropathy. The condition presents as peripheral pain and disturbances of sensation together with abnormal temperature sensation. Fibres in the autonomic system may also be affected. Hoitsma et al. performed quantitative sensory testing in 31 patients with sarcoidosis with pain or autonomic dysfunction and revealed that 81% had reduced temperature sensitivity . Punch skin biopsy in seven of these patients with sarcoidosis showed a reduction in the density of intra-epidermal nerve fibres compared with control subjects (Fig. 3). The authors warned that the diagnosis may be associated with autonomic dysfunction, which might be responsible for life-threatening events and sudden death of unknown cause which are not uncommon in sarcoidosis. It is particularly important to be able to provide a definitive diagnosis for the cause of an individual's pain that might easily otherwise be attributed to psychological problems. It has been shown that the prevalence of small fibre neuropathy may be as a high as 60% amongst patients with sarcoidosis [89, 90]. If the condition is suspected, quantitative sensory testing is required to make the diagnosis. The more standard nerve conduction studies are usually negative, so a high index of suspicion is needed.
Treatment of small fibre neuropathy
There are no well-validated therapies available at present for small fibre neuropathy, and the usual therapies that are given for more generalized sarcoidosis and tested in this context seem to be ineffective. As for all neuropathic pain, antidepressants, anticonvulsants and opiates have been used with some success. There are also anecdotal reports of success with intravenous immunoglobulin and infliximab. The novel peptide ARA 290 was investigated in small fibre neuropathy in a recent study from the Netherlands . This peptide is modelled on erythropoietin and has anti-inflammatory and tissue repair-activating properties. It has been shown to be effective in the small fibre neuropathy that is seen in diabetes mellitus . In a double-blind placebo-controlled study of 22 patients with small fibre neuropathy and sarcoidosis, using a series of quality of life and other health-related scoring vehicles, those on active therapy showed significant improvements compared with placebo including the small fibre neuropathy screening list score that has been developed for use specifically in sarcoidosis-related small fibre neuropathy .
Suggested therapeutic approach
Even in the absence of any proven therapy, we believe that achieving a specific diagnosis is a major boost to patients' well-being. To not know what is causing a problem, and perhaps to have it considered as a psychological rather than a physical condition, can be undermining; at least knowing that there is an organic problem can be the first important step in dealing with it. If knowing that there is in fact an organic, rather than psychological, problem does not provide some relief, a low-dose corticosteroid may be tried, and antidepressants, anticonvulsants and opiates should be considered if the problem remains unacceptable to the patient.
Neurological involvement in sarcoidosis may manifest a wide variety of symptoms, sometimes dramatic but sometimes very discrete. Neurosarcoidosis may affect any part of the central and peripheral nervous system and thus give rise to a range of symptoms such as headache, seizures, encephalopathy, neuroendocrinological dysfunction, paraesthesia, paraplegia and peripheral neuropathy. Isolated neurological disease occurs in only 1% of patients with sarcoidosis and may then provide a diagnostic dilemma, particularly if a biopsy is impractical because of the location of disease. However, neurological involvement as part of a multisystem disorder is more common and has been calculated to affect 5–15% of patients [11, 94]. Further, autopsy findings of neurosarcoidosis are more common than antemortem diagnosis [95, 96]. Cranial neuropathy is a typical manifestation as the basal meninges tend to become infiltrated by disseminated granulomas and plaque formation . The facial nerves, in some cases the optic nerves, are most frequently involved, but any combination of cranial nerve involvement is possible. Facial nerve palsy will usually resolve, but optic neuropathy has a poorer prognosis . The disease course is also unfavourable in patients with chronic meningitis, intracranial mass and spinal cord sarcoidosis. Sequelae can be devastating, and mortality rates are approximately 10% .
The most sensitive diagnostic tool is gadolinium-enhanced magnetic resonance imaging (MRI), but the value of cerebrospinal fluid analysis is limited (Fig. 4). 18FDG PET investigation is emerging as another sensitive index of disease location. If there is evidence of extra-neurological sarcoidosis, an MRI pattern consistent with sarcoidosis is generally sufficient to confirm the neurological diagnosis without the need for central nervous system biopsy. A central nervous system biopsy may be indicated when there is no extra-neurological disease. MRI or PET scans can reveal accessible locations for biopsy, preferably from leptomeninges.
Treatment of neurological disease
Treatment recommendations are based only on findings in uncontrolled small series of patients due to the rarity of the disorder and the variability in clinical manifestations. According to Nozaki and Judson, specific treatment for neurosarcoidosis needs to be given for at least 6 months . The mainstay therapy is corticosteroids . As a tendency for relapse of symptoms has been observed when prednisone is administered at less than 20 mg daily, the regimen may have to be continued long term or at a higher dose . In moderate cases, the initial dose of prednisone is often 1 mg kg−1 day−1 orally (up to 60 mg day−1), but in severe disease, methylprednisolone may be given intravenously in pulses ranging from 500 to 1000 mg day−1 for the first 3–5 days followed by a high-dose regimen of oral corticosteroids. To avoid severe side effects of the corticosteroids, a corticosteroid-sparing agent such as methotrexate (15–20 mg weekly) is often given to enable a reduction in the dose of corticosteroids. Other immunomodulating and/or immunosuppressive agents have also been used such as azathioprine and cyclophosphamide [6, 103]. The latter should not be given at a dose exceeding 150 mg day−1 and should be administered intravenously as oral medication tends to be less effective and cause more side effects such as haemorrhagic cystitis and bladder cancer. Hydroxychloroquine, cyclophosphamide and cyclosporine A are other potential treatment options [104, 105]. The immunosuppressant mycophenolate mofetil is sometimes used. It seems to have few adverse effects (e.g. dose-related diarrhoea), but experience with the drug in sarcoidosis is limited so far [93, 106-108].
During the last decade or so, human anti-TNF-α monoclonal antibodies such as infliximab and adalimumab have been introduced as therapeutic options [9, 109, 110]. There is debate regarding whether these agents should be introduced early in the disease course, as the response can be rapid, or whether they should be used when there are signs of relapse during weaning of corticosteroids [96, 100, 101, 111, 112]. In a small study, it was shown that treatment with infliximab caused improvement in patients with MRI-documented neurosarcoidosis (n = 6), who had failed to respond to corticosteroids and mycophenolate mofetil .
Thalidomide has been advocated as a therapeutic option in selected cases of refractory sarcoidosis due to its anti-inflammatory, TNFα-inhibiting properties, despite the well-known severe teratogenic adverse effects . Completely reliable contraception is essential in women of child-bearing age if this approach is taken.
In rare cases that are refractory to all other treatments, radiotherapy (20–25 Gy) might be considered to prevent progression [114, 115]. In others, hydrocephalus or a cranial mass can require surgical intervention. Anti-epileptic therapy is needed when seizures are caused by the disease, and involvement in neuroendocrine organs often requires life-long hormonal replacement as there may be irreversible neuronal damage.
Suggested therapeutic approach
New imaging techniques with MRI have recently enabled physicians to obtain support for a suspected diagnosis of neurological involvement in sarcoidosis more readily than previously. A wide variety of symptoms can be observed ranging from vague signs to life-threatening, rapidly progressing and alarming manifestations. Thus, the need for treatment is also highly variable. We suggest that first-line treatment should be high-dose corticosteroids (prednisolone 60–80 mg) in combination with methotrexate (up to 20 mg weekly) as a corticosteroid-sparing agent. The corticosteroids should not be tapered too quickly. The tapering should be adjusted to the degree of regression of neurological symptoms, change in MRI disease burden and also to any corticosteroid-induced adverse effects. Cyclophosphamide is another option (500–1000 mg intravenously every 2–4 weeks). Infliximab is a promising alternative in refractory cases; however, it must be emphasized that experience is still limited in this context. Thalidomide could be an option, but due to its severe teratogenic and other adverse effects, we suggest that it might be considered only in those relatively few patients refractory to all other treatment.
Pulmonary hypertension in sarcoidosis
The prevalence of pulmonary hypertension in sarcoidosis varies greatly from 6 to 79% depending on the sensitivity of the tools used to screen for this complication and the clinical population studied . High-resolution CT scanning can show features that are suggestive of pulmonary hypertension (Fig. 5). What seems clear is that its presence often goes undetected and, given the worse prognosis that is associated with the development of pulmonary hypertension, it is gratifying that more attention is now being paid to this important problem, possibly as a consequence of the increasing data on the use of pulmonary hypertension therapies in other diseases. Right heart catheterization is needed to make a definitive diagnosis, but obviously, all patients with sarcoidosis should not be subjected to this procedure as a screening investigation. Patients with evidence of right heart dysfunction, with extensive lung fibrosis or with disproportionate breathlessness when taken in context with the amount of imaging or physiological abnormality, and those with a disproportionately reduced gas transfer for carbon monoxide (DLco) should be suspected of having pulmonary hypertension and investigated with right heart catheterization. ECHO cardiography can be a useful intermediate and non-invasive screening test but can both underestimate and overestimate the pulmonary arterial pressures.
Because there are multiple mechanisms that can result in pulmonary hypertension, screening of any single compartment will be relatively unproductive. In this regard, extensive parenchymal destruction and fibrosis, hypoxia, pulmonary vascular granulomata, pulmonary vasoreactivity, pulmonary venule granulomas with a presentation of pulmonary veno-occlusive disease, central obstruction of pulmonary vessels by lymphadenopathy or mediastinal fibrosis, porto-pulmonary hypertension in the presence of extensive liver disease, and left heart systolic or diastolic dysfunction have all been cited as potential causes of pulmonary hypertension in sarcoidosis [1, 116, 117].
Treatment for sarcoidosis-associated pulmonary hypertension
The ideal treatment for pulmonary hypertension in sarcoidosis is difficult to define because of the multiplicity of potential causes that require separate approaches. Treatment should first be directed at the underlying granulomatous pathology of the disease, with corticosteroids and corticosteroid-sparing therapy as indicated, if the evidence suggests that the burden of granulomas is the main pathological consideration. Other treatable factors, including hypoxia, should be managed, and comorbidities such as sleep apnoea and cardiac dysfunction need to be identified and treated appropriately.
A number of positive case studies in response to pulmonary hypertension therapy in patients with sarcoidosis have been reported, but very few clinical trials have explored the value of pulmonary vasoactive agents; all involved small numbers of patients and thus do not enable clear conclusions to be drawn [1, 116, 118]. These studies focused on agents that modulate the endothelin, prostacyclin and nitric oxide pathways.
In a retrospective analysis of 22 patients treated with a variety of agents for pulmonary hypertension, including bosentan and sildenafil, New York Heart Association classification improved after a median of 11 months' treatment in 50% . Other studies of endothelin pathway blockade have investigated bosentan (one case report of improvement on therapy ; one study of five patients, one of whom was treated with epoprostenol in addition to bosentan, in which mean pulmonary arterial pressures improved ; and a study of seven patients, four also on epoprostenol, showing haemodynamic improvement particularly in those with relatively well-preserved lung volumes ) and ambrisentan (one study of 21 patients showing no efficacy ).
With regard to trials of prostacyclin analogues, in a retrospective study of seven patients, six showed an acute response to intravenous epoprostenol; five of the six continued long-term epoprostenol therapy with improvement in symptomatology . In another study, inhaled prostacyclin administered to 22 patients resulted in an improvement in pulmonary vascular resistance in 20% of the cohort .
Studies of nitric oxide therapy, including phosphodiesterase type-5 inhibitors which increase local nitric oxide levels, have also been reported. In one small study of acute vasoresponsiveness, inhaled nitric oxide therapy reduced mean pulmonary arterial pressures and pulmonary vascular resistance (n = 8) . Following the acute response, sildenafil was administered with no response even though a previous study from the same group had shown improvements in haemodynamic indices following sildenafil treatment (n = 12) .
Suggested therapeutic approach
With these studies comprising very small numbers of patients often in retrospective cohorts, the evidence for the use of any pulmonary hypertension therapy for the pulmonary hypertension of sarcoidosis is clearly weak and cannot provide any basis for making definitive recommendations. Two trials of therapy for this indication have been registered (http://clinicaltrials.gov/): the first study investigating the endothelin receptor antagonist bosentan is now completed, but no data have yet been published, and the second is a trial of the phosphodiesterase type-5 inhibitor tadalafil which is still recruiting. The numbers of patients in each study are low (n = 43 and n = 20, respectively). In this regard, neither trial is likely to provide unequivocal evidence that would allow a clear recommendation to be made. Further investment in larger multicentre clinical trials is needed, and it is hoped that positive results in either of these trials might lead to a larger study being undertaken. The problem is of course the relative rarity of pulmonary hypertension in sarcoidosis, but, given the encouragement from the Orphan Drug and other legislature, it is hoped that the pharmaceutical industry may invest further in this most difficult of conditions.
At the present time, it would seem that the most practical approach is to treat the burden of granulomatous diseases with the standard therapies, correct hypoxia, manage comorbid conditions, including sleep apnoea and cardiac abnormalities, and consider pulmonary hypertension therapy in selected cases and after very careful discussions with the patient; therapy could increase the degree of ventilation–perfusion mismatch with worsening oxygenation. The pulmonary veno-occlusive variant of pulmonary hypertension must be rigorously excluded because of the potentially fatal pulmonary oedema response that might occur with proximal dilatation of vessels upstream from an occluded venous outflow. All patients with identified pulmonary hypertension must be evaluated for lung transplantation because of the poor outcome once this complication has developed.
Conflict of interest statement
The authors have no conflict of interest to declare.