Sarcoid - Muscle, Bone, and Vascular Disease Manifestations PDF

Sarcoid: Muscle, bone, and vascular disease manifestations
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Official reprint from UpToDate

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Authors
Winston Sequeira, MD
Rohit Aggarwal, MD, MSc
Section Editor
Peter H Schur, MD
Deputy Editor
Paul L Romain, MD
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Dec 2015. | This topic last updated: Sep 22, 2015.
INTRODUCTION Sarcoidosis, a multisystem disorder of unknown etiology, is characterized pathologically by the
presence of noncaseating granulomas in affected organs (see "Pathogenesis of sarcoidosis"). It typically affects young
adults, and, although any organ may be affected, the disorder commonly presents with one or more of the following
three abnormalities:
Bilateral hilar adenopathy
Pulmonary infiltrates
Skin and/or eye lesions
Musculoskeletal disease is a less common problem. However, joint manifestations may be clinically significant in
patients with acute disease [1]. Overall, 4 to 38 percent of patients with sarcoidosis have one or more musculoskeletal
manifestations [2].
The bone, muscle, and vascular manifestations of sarcoidosis other than arthritis will be reviewed here. General issues
related to sarcoidosis and its pathogenesis are discussed separately. (See "Clinical manifestations and diagnosis of
pulmonary sarcoidosis" and "Pathogenesis of sarcoidosis".)
The American Thoracic Society (ATS) statement on sarcoidosis, as well as other ATS guidelines, can be accessed
through the ATS web site at www.thoracic.org/statements.
SARCOID ARTHROPATHY The articular manifestations of sarcoidosis and the diagnosis and treatment of sarcoid
arthropathy are presented separately. (See "Sarcoid arthropathy".)
MYOPATHY It is estimated that skeletal muscle is involved in 50 to 80 percent of individuals with sarcoidosis but is
rarely (0.5 to 2.5 percent) symptomatic [3-5]. Symptoms may result from muscle disease involving the diaphragm,
extraocular muscles, and other muscle groups [3,6-10]. Sarcoidosis should, therefore, be considered in patients
presenting with unexplained muscle weakness, pain, or nodular swelling. (See "Approach to the patient with muscle
weakness".)
Three clinical patterns of myopathy have been described [11]:
The most common form is the insidious onset of proximal muscle weakness with normal or elevated serum levels
of muscle enzymes. This myopathy responds poorly to corticosteroids. It should be appreciated, however, that
steroid therapy can induce a similar proximal myopathy. (See "Glucocorticoid-induced myopathy".)
An acute myopathy, observed most commonly in women, is associated with elevated muscle enzymes.
The least frequent pattern is a nodular myopathy, which can present as single or multiple painful nodules. In one
case, the large lesion resembled a tumor [4].
In one series of 11 patients with sarcoidosis with chronically progressive, generalized myopathy (confirmed with muscle
biopsy) and diffuse involvement of all four extremities and trunk, only two patients had muscular pain and only six had
elevated serum creatine kinase levels [12]. Muscle atrophy was a prominent finding, observed in 9 of the 11 patients,
mostly in the lower extremities. The hip abductors, knee flexors, and ankle plantar flexors were most commonly
involved on computed tomography (CT). The various imaging modalities (gallium, magnetic resonance imaging [MRI],
positron emission tomography [PET]) showed evidence of inflammatory muscle disease in only half of the patients. In
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this series, the therapeutic response was poor in patients with more chronic disease and the best outcomes were seen
with early diagnosis and treatment.
Early respiratory failure may be an early sign of sarcoid myopathy. Respiratory failure may be caused by weakness of
the intercostal muscles, diaphragm, and pharyngeal muscles [13].
Findings of granulomatous myositis on muscle biopsy are quite rare. Only 12 biopsies demonstrated granulomatous
inflammation in a retrospective review of the microscopic sections from 2985 skeletal muscle biopsy specimens
obtained over a 12-year period at one institution [14]. Idiopathic granulomatous inflammation was more common in
males; in females, it was more likely to be due to sarcoidosis.
Several patients with distal muscle involvement and granulomatous myositis suggestive of sarcoid have been reported
with disease that clinically mimics inclusion body myositis [15].
Electromyography Electromyographic studies in patients with sarcoidosis and muscle weakness may reveal a
myopathic pattern. In some cases, widespread myotonia can mimic the pattern observed in acid maltase disease [6].
(See "Lysosomal acid alpha-glucosidase deficiency (Pompe disease, glycogen storage disease II, acid maltase
deficiency)".)
Imaging studies Imaging studies may help distinguish and diagnose the different types of myopathy. One study, for
example, evaluated the relative utility of magnetic resonance imaging (MRI), CT scanning, and gallium scanning in four
patients with biopsy-proven lower-extremity myositis [16]. Only MRI was positive in all four individuals and could
distinguish between atrophic and nodular myopathy. By comparison, gallium scanning (with increased uptake) only
identified nodular lesions, and computed tomography failed to provide any additional information. Nodular myopathy
produces a characteristic pattern on MRI: a star-shaped area of low-signal intensity centered within the nodule
surrounded by areas of high intensity [17]. This finding may help direct the location of a muscle biopsy, thereby
increasing the yield. It is important to be aware that the central hypointense area persists after steroid therapy [18].
18F-fluorodeoxyglucose positron emission tomography (PET) scans can identify active sarcoid lymph nodes in the hilum
and myocardium; findings include a patchy pick-up in the skeletal muscle [19], which is referred to as the tiger man
sign, similar to the leopard man sign described on gallium-67 scintigraphy [20]. PET scans can be helpful in identifying
asymptomatic sarcoid muscle disease [21].
Muscle biopsy Biopsy of affected muscle in patients with sarcoid myopathy reveals a diffuse cellular distribution
with macrophages and CD4 positive T cells [22]. In addition, CD8 positive T cells are irregularly distributed within the
granulomatous cellular infiltrate in early lesions and surrounding the granulomas in more mature lesions [22,23].
Fibronectin and hyaluronidase can be demonstrated in the increased connective tissue with desmin differentiating the
myogenic giant cells from Langhans giant cells. Endomysial and perivascular inflammation is present, along with areas
of muscle fiber degeneration and regeneration [14]. Fiber destruction in this disease is caused mainly by fiber infiltration
rather than by mechanical compression or ischemia [24]. On occasion, there may be evidence of a neuromyopathy with
granuloma around intramuscular nerve fibers [25].
Myopathy: Diagnosis and differential diagnosis The approach to the patient suspected of having sarcoid
myopathy depends upon the presence or absence of a diagnosis of sarcoidosis. In the patient with undiagnosed
weakness, the evaluation is similar to that of any patient presenting with symptoms suggestive of muscle disease (see
"Approach to the patient with muscle weakness"). In this setting, a sarcoid myopathy is suspected if a myopathy exists
in association with additional manifestations of sarcoidosis.
A biopsy showing granulomatous myositis is highly suggestive of, but is not diagnostic of, sarcoidosis. This finding can
also occur in a number of other disorders, including granulomatosis with polyangiitis (Wegeners), polymyositis,
dermatomyositis, and Crohn's disease [9]. Associated signs and symptoms of sarcoidosis should, therefore, be present
before a definite diagnosis can be established. (See "Clinical manifestations and diagnosis of pulmonary sarcoidosis".)
Open surgical muscle biopsy has typically been used to assess muscle disease in patients with suspected sarcoid
myopathy. Needle biopsy techniques have been used in a few patients with nodular disease; cytologic examination of
specimens obtained by fine-needle aspiration may provide diagnostically useful material [26,27].
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Although fine-needle aspiration has the advantage of being minimally invasive, the sensitivity and specificity of this
approach for patients with nodular myopathy are uncertain. However, in the setting of previously diagnosed sarcoidosis
and suggestive MRI features (see 'Imaging studies' above), cytologic evidence for granulomatous inflammation and an
absence of both neoplasia and pathogenic infectious agents may allow a diagnosis of sarcoid myopathy to be made
without open or cutting needle muscle biopsy. However, false negatives may result, in part because of patchy muscle
involvement in sarcoid myopathy.
Among patients already diagnosed with sarcoidosis, the development of a myopathy is most commonly suspected
among those with the insidious development of progressive proximal weakness. Acute presentations may also occur.
Abnormal laboratory findings, such as elevated muscle enzymes, specific findings on MRI, and biopsy evidence of
granulomatous infiltration further support the diagnosis. Reduced walking capacity and dyspnea may be caused by
impaired inspiratory muscle strength, which can only be reliably detected by non-volitional tests of inspiratory muscle
strength [28].
Sarcoid myopathy: Treatment Glucocorticoids may be used to treat symptomatic patients, assuming that the
myopathy is not thought to be glucocorticoid-induced. This suggested approach is based upon clinical experience, as
there have been no placebo-controlled studies of glucocorticoids for sarcoid myopathy. Standard doses of prednisone
used for other forms of inflammatory myopathies are administered. (See "Initial treatment of dermatomyositis and
polymyositis in adults".)
For a patient with one or a few painful nodular sarcoid muscle lesions, combined therapy consisting of the intralesional
injection of triamcinolone, rest, and a nonsteroidal antiinflammatory agent may also be helpful [8].
BONE INVOLVEMENT Sarcoidosis of bone occurs in approximately 5 percent of patients (range of 1 to 13 percent)
[29]. Although bony involvement may be the earliest manifestation of sarcoidosis [30], it is usually accompanied by
infiltrative skin lesions. When present, the presence of bone lesions generally implies a more chronic and severe
disorder [29,31]. Almost one-half of affected patients are asymptomatic. Osteoporosis and osteopenia are also noted
in patients with sarcoidosis.
Focal bone lesions The proximal and middle phalanges are most frequently involved; however, the skull, vertebrae,
ribs, maxilla, and nasal bones also may be affected [32-35]. Dactylitis, a sausage-like swelling of a digit, as seen in
seronegative spondyloarthropathy and gout, may occur with or without phalangeal bone involvement in patients with
sarcoidosis [36].
Cystic bone lesions The bony lesions are usually cystic; sclerotic lesions are rarely noted (see 'Sclerotic
lesions' below). Multiple small cystic lesions sometimes result in a lacy pattern, which is a typical lesion seen in
sarcoid bone disease. These changes, most often seen in the head of the proximal or middle phalanx of the hands, are
typically detected by plain film radiography, but, in some cases, lesions may only be seen on magnetic resonance
images [37,38]. The presence of these findings should prompt further evaluation for underlying sarcoidosis if the
diagnosis has not been previously established.
Hand radiographs demonstrate lytic lesions of the heads of the proximal or middle phalanges (image 1) and, less
frequently, of the metacarpal bones.
Punched-out cysts, a fine lattice, or both, in combination with a background of diffuse osteoporosis, may be the
only radiographic abnormalities [39].
Permeative defects may involve tunneling with remodeling of the cortex; this process converts the concave shaft
into a tubular structure. Destruction of the cortex may then lead to multiple fractures and sequestrum formation
[31].
Involvement of the skull may be associated with painless nodules of the scalp.
Lupus pernio, nodular skin lesions of the nose and malar areas, may be observed with lesions of the nasal bones
and hard palate.
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Sclerotic lesions As noted above, sclerotic bone lesions are rare in patients with sarcoidosis; when present,
they commonly affect the axial skeleton, with the bones of the pelvis, spine, and ribs being most often involved [40].
These lesions appear to occur exclusively in middle-aged black patients [41].
The onset of sclerotic sarcoid bone lesions is insidious and may precede other manifestations of the disease. A bone
scan, which is positive, is nonspecific.
Sarcoidosis of the long bones may resemble Paget disease since both disorders are associated with increased uptake
on bone scans and with lytic and sclerotic lesions on radiography. Unlike Paget disease, however, the serum alkaline
phosphatase concentration is usually normal or only mildly elevated in patients with sarcoidosis.
Spinal involvement Only a small number of patients with lytic or sclerotic lesions of the spine in association with
sarcoidosis have been reported [42]. The disease most commonly affects the lower dorsal and upper lumbar
vertebrae, but the cervical spine including the atlantoaxial (C1-C2) joint may be involved [43,44]. Sternal involvement
associated with diffuse spinal sarcoid has been reported [45]. Widespread lytic lesions may mimic metastatic disease
on radiographs and on bone scintigraphy [46,47].
Magnetic resonance imaging (MRI) may be particularly informative with vertebral sarcoidosis. Granulomatous
inflammation prolongs T1 and T2 relaxation times [42]. As a result, MRI may demonstrate single or multiple focal
lesions that are hypointense on T1 and hyperintense on T2; lesions typically enhance with contrast administration [48].
A biopsy may be necessary to exclude infection if the disc and spine are concurrently involved [49]. An association
between vertebral sarcoidosis and paravertebral ossification simulating ankylosing spondylitis and reactive arthritis has
also been described [50]. At least 17 patients have had radiographic sacroiliac involvement [51,52]. This coexistence is
uncommon (6.6 percent in one study of 61 patients with sarcoidosis [52]).
Focal bone lesions: Diagnosis and differential diagnosis In a patient with an established diagnosis of
sarcoidosis and radiographic features that are typical for this disease (eg, cystic bone lesions with well defined
margins), it may not be necessary to perform any additional studies before making a diagnosis of sarcoid involvement
of bone.
However, if there are sclerotic lesions or if there is extension of an infiltrative lesion that encroaches on nearby
structures (eg, spinal vertebral disease with extradural compression of the spinal cord or spinal nerves) a biopsy is
often required to exclude other conditions such as metastatic disease of the breast or prostate, lymphoma, Paget,
osteopetrosis, and mastocytosis [41].
Osteopenia and osteoporosis Few studies exist evaluating bone mineral density in patients with sarcoidosis.
Although bone density may be normal or high in early disease, osteoporosis and/or osteopenia may eventually develop
over time. One study, for example, evaluated bone mineral density using quantitative computed tomography in 36
untreated patients and 190 healthy individuals [53]. Five patients, all with untreated disease of greater than two years,
had bone mineral content more than two standard deviations below normal values.
Osteopenia in sarcoid may be caused by one or more of the following factors:
Diffuse skeletal granulomatosis [54]
Calcitriol and osteoclastic activating factor produced by activated T cells [55]
Treatment with glucocorticoids, particularly in the postmenopausal patient [56] (see "Pathogenesis, clinical
features, and evaluation of glucocorticoid-induced osteoporosis")
Bone loss: Prevention and treatment The prevention and treatment of bone loss in patients with sarcoidosis is
difficult. Calcium and vitamin D, both commonly administered to patients at risk for osteoporosis, are relatively
contraindicated in sarcoidosis because of the propensity toward hypercalcemia [57] (see "Hypercalcemia in
granulomatous diseases"). Thus, calcitonin and/or a bisphosphonate may be preferred in patients with steroidassociated osteopenia [58,59]. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)
VASCULITIS Rarely, vasculitis involving small, medium, or large arteries occurs in sarcoidosis [60]. The vessels may
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be infiltrated by granulomas, or there may be granulomatous inflammation of the vessel wall [61]. Necrotizing vasculitis
may contribute to neurologic injury and peripheral neuropathy in sarcoidosis. (See "Neurologic sarcoidosis".)
Rarely, patients present with early-onset sarcoidosis (EOS), a sporadic form of early childhood presentation of Blau
syndrome, in association with large vessel vasculitis [60,62]. Both EOS and Blau syndrome are specifically caused by
NOD2 (nucleotide-binding oligomerization domain containing gene) mutations, presenting during the first months or first
years of life (usually appearing before age four), with disease characterized clinically by rash, iritis, and arthritis
[62,63].
In some patients, large vessel involvement may resemble Takayasu arteritis. The total number of cases reported of
sarcoidosis and Takayasu-like aortitis is very small and limited to case reports, but the rarity of these two syndromes
suggest that the number of cases is too high for it to be mere coincidence [64]. Moreover, in most cases sarcoidosis
preceded the aortitis by several years, suggesting a common basis. A review of 60 cases of Takayasu arteritis found
two cases of sarcoidosis associated with aortitis [65]. The ages of reported cases of sarcoidosis with features of
Takayasu-like aortitis ranged from 10 to 50 years of age, and most patients had good outcomes when they were
treated with glucocorticoids. (See "Periodic fever syndromes and other autoinflammatory diseases: An overview",
section on 'Blau syndrome' and "Clinical features and diagnosis of Takayasu arteritis".)
There are many similarities between granulomatosis with polyangiitis (Wegeners) and sarcoidosis [66]. Both are
granulomatous diseases, and they have several common manifestations, such as inflammatory orbital disease, scleritis,
rhinosinusitis, midline necrotizing nasal lesions, and upper and lower respiratory tract involvement. However, the most
common presentation, which can be cause confusion between the two syndromes clinically, is the occurrence of
pulmonary parenchymal lesions, including pulmonary nodularities [67-71].
Some case reports of sequential development of sarcoidosis and granulomatosis with polyangiitis suggest the
possibility of a similar etiopathogenesis of these two syndromes [72-75].
It is important to differentiate between the two entities due to treatment and prognostic implications. Antineutrophil
cytoplasmic antibodies (ANCA) are typically present in the former and absent in the latter (see "Clinical manifestations
and diagnosis of granulomatosis with polyangiitis and microscopic polyangiitis"). Other clinical features like involvement
of pauci-immune glomerulonephritis, etc, and/or classic histopathological findings may help distinguish the syndromes.
Vasculitis: Treatment Sarcoid-associated vasculitis is more benign than that observed in granulomatosis with
polyangiitis (Wegeners) and usually does not require the use of cytotoxic agents. Oral glucocorticoids (eg, prednisone
administered at doses of 40 to 60 mg/day) are quite adequate in most cases.
CLUBBING True clubbing is rare in sarcoidosis, although nail bed thickening is common (figure 1) [76]. In one study,
for example, clubbing was observed in only 2 of 136 patients at disease presentation and in only two more at follow-up
[77]. Unilateral clubbing and localized periostitis without clubbing have also been described [78,79]. Dystrophic nails
frequently accompany bony abnormalities; however, there are two reports in which the diagnosis was made with
nailfold biopsy in patients without bone disease [80].
OTHER ASSOCIATED DISEASES A post-sarcoidosis chronic fatigue-like syndrome has been described [29]. In this
setting, there is no evidence of active disease, and all laboratory tests, including serum ACE, are normal. (See "Clinical
features and diagnosis of chronic fatigue syndrome (systemic exertion intolerance disease)".)
Sarcoidosis has also been described in patients with other autoimmune diseases; these include rheumatoid arthritis,
systemic sclerosis, systemic lupus erythematosus, Sjgren's syndrome, primary biliary cholangitis (previously referred
to as primary biliary cirrhosis), and myasthenia gravis [81-83]. Since autoantibodies, circulating immune complexes, and
altered lymphocyte function are common to all these diseases, they may all be part of a predisposition to autoimmune
disease [84].
SUMMARY AND RECOMMENDATIONS
Muscle disease
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Symptomatic muscle disease is a rare manifestation of sarcoidosis (see 'Myopathy' above). Three types of
clinical muscle disease are recognized: insidious proximal muscle weakness, acute myopathy with weakness and
elevated muscle enzymes, and nodular myopathy.
In a patient with sarcoidosis, the presence of muscle weakness, muscle pain, or muscle nodules is suggestive of
sarcoid myopathy. The differential diagnosis includes glucocorticoid-induced and other drug-induced myopathies,
and, in patients with a muscle biopsy that reveals multiple noncaseating granulomas, other granulomatous
diseases must also be considered. (See 'Myopathy: Diagnosis and differential diagnosis' above.)
We suggest glucocorticoid treatment for patients with symptomatic acute or chronic myopathy (Grade 2C).
Considerations regarding agent, dose, and frequency are similar to those for dermatomyositis and polymyositis.
(See "Initial treatment of dermatomyositis and polymyositis in adults".)
For patients with focal nodular myopathy, we suggest intralesional injection of triamcinolone, bed rest, and a
nonsteroidal antiinflammatory drug (NSAID) rather than oral glucocorticoids (Grade 2C).
Bone disease
Bone lesions are uncommonly noted in patients with sarcoidosis. They may be detected by imaging studies in
approximately 5 percent of patients but are symptomatic in only about one-half of the affected patients. (See
'Bone involvement' above.)
Cystic lesions of the phalanges are the most typical bone lesion but may also be found in the skull, vertebral
bodies, and flat bones. (See 'Cystic bone lesions' above and 'Spinal involvement' above.)
Diagnosis of osseous sarcoidosis may be made in a patient with an established diagnosis of sarcoidosis and with
typical cystic bone lesions. We recommend bone biopsy to evaluate sclerotic bone lesions since these are rarely
seen in sarcoidosis, and other causes of sclerotic/blastic bone lesions, such as metastatic cancer, should be
excluded. (See 'Sclerotic lesions' above.)
Osteopenia and osteoporosis in patients with sarcoidosis may be due to the disease itself or to glucocorticoid
treatment (see 'Osteopenia and osteoporosis' above). We recommend the use of bisphosphonates for prevention
and treatment of glucocorticoid-induced bone mineral loss (Grade 1A). (See "Prevention and treatment of
glucocorticoid-induced osteoporosis".)
Because of a propensity to hypercalcemia in sarcoidosis, we suggest avoiding use of calcium supplements and
vitamin D (Grade 2C).
Vasculitis
Vascular involvement of vessels of any size may occur. Extension of granulomatous inflammation into a blood
vessel or granuloma formation within a vessel wall may lead to ischemia or infarction. Distinguishing
granulomatous vasculitis due to sarcoidosis from other systemic granulomatous diseases such as granulomatosis
with polyangiitis (Wegeners) may be aided by measuring antineutrophil cytoplasmic antibodies (ANCA). (See
'Vasculitis' above.)
We suggest treating granulomatous vasculitis due to sarcoidosis with oral glucocorticoids (eg, prednisone 40 to
60 mg/day, or equivalent) (Grade 2C).
Other rheumatic and autoimmune disorders
Clubbing, chronic fatigue, and various diseases of presumed autoimmune pathogenesis (eg, Sjgren's syndrome,
primary biliary cholangitis [previously referred to as primary biliary cirrhosis], etc) have been described in
association with sarcoidosis. (See 'Clubbing' above and 'Other associated diseases' above.)
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Topic 5586 Version 9.0
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GRAPHICS
Sarcoid arthropathy
Hand radiograph shows multiple phalangeal cysts with erosion of the

cortex in a patient with sarcoid arthropathy.
Graphic 70918 Version 2.0
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Clubbing of the fingers
In a normal finger, the length of the perpendicular dropped from point A

to point B should be greater than a similar line from C to D. In clubbing,
the relationships are reversed - that is, the distance C-D is greater than
the distance A-B. The other important change is the angle described by
A-C-E. In the normal finger this is usually <180 degrees whereas in
clubbing it is >180 degrees.
Panels A and C redrawn from: DeRemee RA. Facets of the algorithmic
synthesis. In: DeRemee RA, (Ed), Clinical profiles of diffuse interstitial
pulmonary disease, Mount Kisco, NY, Futura Publishing Company, Inc, 1990,
pp. 9-44.
Panel B redrawn from: Bates B. A Guide to Physical Examination and History
Taking, 5th Ed. Philadelphia: J.B. Lippincott Company, 1991.
Graphic 52839 Version 3.0
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Disclosures
Disclosures: Winston Sequeira, MD Nothing to disclose. Rohit Aggarwal, MD, MSc Nothing to disclose. Peter H Schur, MD Nothing to
disclose. Paul L Romain, MD Nothing to disclose.
Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are addressed by vetting through a
multi-level review process, and through requirements for references to be provided to support the content. Appropriately referenced content is
required of all authors and must conform to UpToDate standards of evidence.
Conflict of interest policy
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