Abstracts
Sarcoidosis is a multisystem inflammatory disorder of unknown cause. It most commonly affects the pulmonary system but can also affect the musculoskeletal system, albeit less frequently. In patients with sarcoidosis, rheumatic involvement is polymorphic. It can be the presenting symptom of the disease or can appear during its progression. Articular involvement is dominated by nonspecific arthralgia, polyarthritis, and Löfgren's syndrome, which is defined as the presence of lung adenopathy, arthralgia (or arthritis), and erythema nodosum. Skeletal manifestations, especially dactylitis, appear mainly as complications of chronic, multiorgan sarcoidosis. Muscle involvement in sarcoidosis is rare and usually asymptomatic. The diagnosis of rheumatic sarcoidosis is based on X-ray findings and magnetic resonance imaging findings, although the definitive diagnosis is made by anatomopathological study of biopsy samples. Musculoskeletal involvement in sarcoidosis is generally relieved with nonsteroidal anti-inflammatory drugs or corticosteroids. In corticosteroid-resistant or -dependent forms of the disease, immunosuppressive therapy, such as treatment with methotrexate or anti-TNF-α, is employed. The aim of this review was to present an overview of the various types of osteoarticular and muscle involvement in sarcoidosis, focusing on their diagnosis and management.
Sarcoidosis; Joints; Muscles; Bone and Bones
A sarcoidose é um distúrbio inflamatório multissistêmico de causa desconhecida, frequentemente afetando o sistema pulmonar e também o sistema músculo-esquelético, mas de forma menos frequente. Em pacientes com sarcoidose, o acometimento reumático é polimórfico, podendo ser o sintoma de apresentação da doença ou aparecer durante sua progressão. O acometimento articular é dominado por artralgia inespecífica, poliartrite e síndrome de Löfgren, que é definida como a presença de adenopatia pulmonar, artralgia (ou artrite) e eritema nodoso. Manifestações esqueléticas, especialmente dactilite, aparecem principalmente como complicações de sarcoidose crônica e em vários órgãos. O acometimento muscular na sarcoidose é raro e geralmente assintomático. O diagnóstico de sarcoidose reumática baseia-se em achados radiográficos e de ressonância magnética, embora o diagnóstico definitivo seja feito pelo estudo anatomopatológico de amostras de biópsia. O acometimento músculo-esquelético na sarcoidose é geralmente aliviado com o uso de anti-inflamatórios não esteroidais ou corticosteroides. Em formas da doença resistentes ao corticosteroide ou corticosteroide dependentes, a terapia de imunossupressão, como o tratamento com metotrexato ou anti-TNF-α, é utilizada. O objetivo desta revisão foi apresentar uma visão geral dos vários tipos de acometimento osteoarticular e muscular na sarcoidose, com foco no diagnóstico e manejo.
Sarcoidose; Articulações; Músculos; Osso e Ossos
Introduction
Sarcoidosis is a granulomatous disease of unknown etiology that involves multiple
systems. It most commonly affects the lungs, lymph nodes, skin, and eyes but can also
affect other organs and systems, including the musculoskeletal system.(
11. Fayad F, Liote F, Berenbaum F, Orcel P, Bardin T. Muscle involvement
in sarcoidosis: a retrospective and followup studies. J Rheumatol. 2006;33(1):98-103.
PMid:16395757
) Rheumatic manifestations of sarcoidosis, although rare, include
inflammatory arthritis, periarticular soft tissue swelling, tenosynovitis, dactylitis,
bone involvement, sarcoid myopathy, and bone loss. The primary types of articular
involvement are Löfgren's syndrome and acute polyarthritis, whereas bone involvement is
dominated by sarcoid dactylitis and osteolysis. Muscle involvement often goes
unrecognized and can appear as chronic myopathy, acute myositis, or pseudotumor.
Sarcoidosis can also manifest as calcium balance disturbances, principally
hypercalcemia, which is often asymptomatic but can occasionally be the presenting
clinical symptom of the sarcoidosis.(
22. Statement on sarcoidosis. Joint Statement of the American Thoracic
Society (ATS), the European Respiratory Society (ERS) and the World Association of
Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of
Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care
Med. 1999;160(2):736-55.
https://doi.org/10.1164/ajrccm.160.2.ats...
)
The diagnosis of sarcoidosis is based on clinical and radiological findings, together
with evidence of noncaseating granulomas in biopsy specimens, after other granulomatous
disorders, such as tuberculosis, have been excluded.(
22. Statement on sarcoidosis. Joint Statement of the American Thoracic
Society (ATS), the European Respiratory Society (ERS) and the World Association of
Sarcoidosis and Other Granulomatous Disorders (WASOG) adopted by the ATS Board of
Directors and by the ERS Executive Committee, February 1999. Am J Respir Crit Care
Med. 1999;160(2):736-55.
https://doi.org/10.1164/ajrccm.160.2.ats...
) Treatment of rheumatic involvement often requires the use of nonsteroidal
anti-inflammatory drugs (NSAIDs), corticosteroids, or methotrexate. Biological therapies
such as the use of anti-TNF-α agents and anti-CD20 monoclonal antibodies have been shown
to be effective in some cases of severe or refractory sarcoidosis.(
33. Sweiss NJ, Curran J, Baughman RP. Sarcoidosis, role of tumor necrosis
factor inhibitors and other biologic agents, past, present, and future concepts. Clin
Dermatol. 2007;25(3):341-6.
https://doi.org/10.1016/j.clindermatol.2...
) The aim of this review was to present an overview of the various types of
musculoskeletal involvement in sarcoidosis, focusing on their diagnosis and
management.
Physiopathology
The exact cause of sarcoidosis remains unknown. The Th1-type of inflammation is present
in the sarcoid granuloma which expresses and produces a variety of inflammatory
cytokines, such as IL-2, IL-12, IL-6, and IFN-γ, as well as TNF-α, which is the central
mediator of this inflammatory process.(
44. Tozman EC. Sarcoidosis: clinical manifestations, epidemiology,
therapy, and pathophysiology. Curr Opin Rheumatol. 1991;3(1):155-9.
https://doi.org/10.1097/00002281-1991020...
) Because of clinical and histological similarities with mycobacterial and
fungal diseases, infectious causes have been investigated. However, such studies are
controversial.(
55. Tazi A. Update on sarcoidosis [Article in French]. Rev Pneumol Clin.
2005;61(3):203-10.
https://doi.org/10.1016/S0761-8417(05)84...
) Recent evidence suggests that a genetic component is implicated in
susceptibility to sarcoidosis. There is a strong link between sarcoidosis and variants
in the class I and II HLA locus. A recent study identified annexin A11 as a novel
non-HLA susceptibility locus for sarcoidosis.(
66. Hofmann S, Franke A, Fischer A, Jacobs G, Nothnagel M, Gaede KI, et
al. Genome-wide association study identifies ANXA11 as a new susceptibility locus for
sarcoidosis. Nat Genet. 2008;40(9):1103-6.
https://doi.org/10.1038/ng.198...
) Many other loci encoding TNF-α and co-stimulatory molecules on
antigen-presenting cells such as CD80 and CD86, as well as the chemokine receptors CCR2
and CCR5, have been found to increase susceptibility to sarcoidosis.(
77. Smith G, Brownell I, Sanchez M, Prystowsky S. Advances in the
genetics of sarcoidosis. Clin Genet. 2008;73(5):401-412.
https://doi.org/10.1111/j.1399-0004.2008...
)
Articular involvement
The reported prevalence of arthritis in sarcoidosis ranges from 10% to 38%.( 88. Eschard JP, Etienne JC. Osteoarticular manifestations of sarcoidosis [Article in French]. Rev Med Interne. 1994;15 Suppl 3:305S-307S. ) Nonspecific arthralgia affects the majority of sarcoidosis patients, especially females. With the exception of Löfgren's syndrome, joint manifestations are rarely seen at symptom onset in sarcoidosis. Two types of arthritis, differing in their clinical course and prognosis, have been identified. The first is acute polyarthritis, which is typically accompanied by erythema nodosum and occasionally by acute uveitis. Acute polyarthritis resolves without permanent sequelae. The second type is chronic sarcoid arthritis, which, although less common, can progress to joint deformity. Other forms of articular manifestations, such as periarticular soft tissue swelling and tenosynovitis, can also be seen.( 99. Torralba KD, Quismorio FP Jr. Sarcoid arthritis: a review of clinical features, pathology and therapy. Sarcoidosis Vasc Diffuse Lung Dis. 2003;20(2):95-103. )
Acute arthropathy
Acute polyarthritis occurs in 40% of patients with sarcoidosis, particularly in the
earlier stages of the disease, and can be the presenting feature. It is
self-limiting, is usually symmetric, and resolves without permanent
sequelae.(
1010. Zisman DA, Shorr AF, Lynch JP 3rd. Sarcoidosis involving the
musculoskeletal system. Semin Respir Crit Care Med.
2002;23(6):555-70.
https://doi.org/10.1055/s-2002-36520...
) The most common form of acute arthropathy in sarcoidosis is Löfgren's
syndrome, which occurs in acute onset sarcoidosis and typically manifests as
bilateral hilar lymphadenopathy, arthritis, and erythema nodosum. Löfgren's syndrome
is associated with a good prognosis and spontaneous remission.(
1111. Löfgren S. Primary pulmonary sarcoidosis. I. Early signs and
symptoms. Acta Med Scand. 1953;145(6):424-31.
https://doi.org/10.1111/j.0954-6820.1953...
,
1212. Ma-á J, Gómez-Vaquero C, Montero A, Salazar A, Marcoval J,
Valverde J, et al. Löfgren's syndrome revisited: a study of 186 patients. Am J Med.
1999;107(3):240-5.
https://doi.org/10.1016/S0002-9343(99)00...
) In patients with sarcoidosis, acute polyarthritis most commonly involves
the ankles (in > 90% of cases), often bilaterally, followed by other large joints
of the lower limbs, only occasionally involving the small joints of hands and feet.
This type of polyarthritis is only mildly painful, migratory and transient.
Oligoarthritis or monoarthritis are relatively rare forms of acute sarcoid
arthropathy.
Chronic arthropathy
Chronic arthropathy is rare in sarcoidosis, occurring in only 0.2% of cases. It most
often affects black males and is usually accompanied by other systemic disorders,
mainly those of the lungs and eyes.(
44. Tozman EC. Sarcoidosis: clinical manifestations, epidemiology,
therapy, and pathophysiology. Curr Opin Rheumatol. 1991;3(1):155-9.
https://doi.org/10.1097/00002281-1991020...
) Various forms of chronic arthritis can occur in patients with
sarcoidosis: nondeforming arthritis with granulomatous synovitis; Jaccoud's
arthropathy; and joint swelling adjacent to a sarcoid bone lesion. Among such
patients, the arthritis is rheumatoid factor-positive in 10-47% of cases. That
nonspecific reactivity is due to increased circulating polyclonal IgG. Therefore,
sarcoidosis-related arthritis can mimic rheumatoid arthritis, especially when
accompanied by joint deformities. The differential diagnosis is usually made on the
basis of clinical criteria, including negative serology for anti-cyclic citrullinated
peptide antibodies and antinuclear antibodies, as well as the absence of the specific
erosive joint deformity seen in rheumatoid arthritis. (
1313. Govindarajan V, Agarwal V, Aggarwal A, Misra R. Arthritis in
sarcoidosis. J Assoc Physicians India. 2001;49:1145-7.
) A finding of granuloma on synovial biopsy helps in establishing the
diagnosis of sarcoidosis. Although all joints can be affected, affected ankles
strongly indicate the diagnosis of sarcoidosis. In some cases, X-rays show soft
tissue swelling. Magnetic resonance imaging (MRI) can depict lesions that cannot be
visualized on X-rays.
Involvement of periarticular structures
Among patients with sarcoidosis, tenosynovitis is common in the tendons of the ankles
and wrist, occasionally accompanied by carpal tunnel syndrome in the latter
case.(
1414. Fodor L, Bota IO, Fodor M, Ciuce C. Sarcoid flexor tenosynovitis as
a single early manifestation of the disease. J Plast Reconstr Aesthet Surg.
2012;65(8):e217-9.
https://doi.org/10.1016/j.bjps.2012.03.0...
) Although tenosynovitis, tendinitis, bursitis, and synovitis can be
demonstrated on MRI scans, they are nonspecific findings and biopsy is therefore
required in order to confirm the diagnosis of sarcoidosis.(
1515. Moore SL, Teirstein AE. Musculoskeletal sarcoidosis: spectrum of
appearances at MR imaging. Radiographics. 2003;23(6):1389-99.
https://doi.org/10.1148/rg.236025172...
)
Sacroiliitis in sarcoidosis
Sacroiliac involvement in sarcoidosis is rare and generally unilateral. Sarcoidosis
cannot be established without a biopsy to rule out tuberculosis or other infectious
process of that joint.(
1616. Awada H, Abi-Karam G, Fayad F. Musculoskeletal and other
extrapulmonary disorders in sarcoidosis. Best Pract Res Clin Rheumatol.
2003;17(6):971-87.
https://doi.org/10.1016/j.berh.2003.09.0...
) Sacroiliitis can reveal ankylosing spondylitis that can be associated
with sarcoidosis, especially in patients testing positive for HLA-B27.
Treatment of sarcoid arthropathy
In 90% of cases, acute polyarthritis resolves spontaneously. In others, it requires
treatment with NSAIDs, corticosteroid injections into the joint, or a short course of
corticosteroids at 10-15 mg/day. Hydroxychloroquine and colchicine can be used in
some cases, especially in those of Löfgren's syndrome.(
1717. Thelier N., Allanore Y. Localisations ostéoarticulaires de la
sarcoïdose. EMC - Appareil locomoteur. 2009:1-11 [Article 14-027-C-10].
10.1016/S0246-0521(09)48227-5
https://doi.org/10.1016/S0246-0521(09)48...
) The use of other immunosuppressive agents should be reserved for
patients with progressive chronic sarcoid arthropathy that is refractory to treatment
with systemic corticosteroids or in whom steroids have generated side effects.
According to the Brazilian Thoracic Association Guidelines for Interstitial Lung
Diseases,(
1818. Baldi BG, Pereira CA, Rubin AS, Santana AN, Costa AN, Carvalho CR,
et al. Highlights of the Brazilian Thoracic Association guidelines for interstitial
lung diseases. J Bras Pneumol. 2012;38(3):282-91.
https://doi.org/10.1590/S1806-3713201200...
) there are alternative treatments, such as methotrexate, azathioprine,
leflunomide and hydroxychloroquine. Methotrexate is an efficient and
corticosteroid-sparing therapeutic agent for the treatment of musculoskeletal
manifestations of sarcoidosis.(
1919. Kaye O, Palazzo E, Grossin M, Bourgeois P, Kahn MF, Malaise MG.
Low-dose methotrexate: an effective corticosteroid-sparing agent in the
musculoskeletal manifestations of sarcoidosis. Br J Rheumatol.
1995;34(7):642-4.
https://doi.org/10.1093/rheumatology/34....
) Many studies have shown the importance of TNF-α in sarcoid granuloma
development, which makes TNF-α a potential target in the treatment of sarcoidosis.
Many interesting reports suggest some efficacy of TNF-α antagonists (infliximab,
etanercept, and adalimumab) in refractory sarcoidosis with musculoskeletal
involvement.(
2020. Yee AM, Pochapin MB. Treatment of complicated sarcoidosis with
infliximab anti-tumor necrosis factor-alpha therapy. Ann Intern Med.
2001;135(1):27-31.
https://doi.org/10.7326/0003-4819-135-1-...
21. Ulbricht KU, Stoll M, Bierwirth J, Witte T, Schmidt RE. Successful
tumor necrosis factor alpha blockade treatment in therapy-resistant sarcoidosis.
Arthritis Rheum. 2003;48(12):3542-3.
https://doi.org/10.1002/art.11357...
22. Khanna D, Liebling MR, Louie JS. Etanercept ameliorates sarcoidosis
arthritis and skin disease. J Rheumatol. 2003;30(8):1864-7.
-
2323. Callejas-Rubio JL, Ortego-Centeno N, Lopez-Perez L, Benticuaga MN.
Treatment of therapy-resistant sarcoidosis with adalimumab. Clin Rheumatol.
2006;25(4):596-7.
https://doi.org/10.1007/s10067-005-0037-...
) Paradoxical cases of proven sarcoidosis have been reported in patients
receiving anti-TNF-α agents for other chronic inflammatory rheumatic diseases. This
paradoxical effect of anti-TNF-α agents must be known by the clinician.(
2424. Toussirot E, Pertuiset E. TNF? blocking agents and sarcoidosis: an
update [Article in French]. Rev Med Interne. 2010;31(12):828-37.
https://doi.org/10.1016/j.revmed.2010.02...
,
2525. Vigne C, Tebib JG, Pacheco Y, Coury F. Sarcoïdose : un effet
secondaire sous-estimé et éventuellement grave du traitement par anti-TNF
alpha. Rev Rhum. 2013;80(1):90-3.
https://doi.org/10.1016/j.rhum.2012.06.0...
) The use of B-cell-depleting agents might also be of benefit in sarcoid
arthritis. A recent case report of a patient with sarcoidosis of the lungs and joints
showed that rituximab is effective in treating sarcoidosis without major side
effects.(
2626. Belkhou A, Younsi R, El Bouchti I, El Hassani S. Rituximab as a
treatment alternative in sarcoidosis. Joint Bone Spine.
2008;75(4):511-2.
https://doi.org/10.1016/j.jbspin.2008.01...
) Based on the success of rituximab in this disease, other B-cell
therapies, such as ocrelizumab, need to be evaluated in systemic
sarcoidosis.(
2727. Kausar F, Mustafa K, Sweis G, Sawaqed R, Alawneh K, Salloum R.
Ocrelizumab: a step forward in the evolution of B-cell therapy. Expert Opin Biol
Ther. 2009;9(7):889-95.
https://doi.org/10.1517/1471259090301883...
)
Osseous sarcoidosis
Bone involvement is reported in 1-15% of sarcoidosis patients. It is more common in
black patients and is usually accompanied by infiltrative skin lesions, especially lupus
pernio.(
2828. Barnard J, Newman LS. Sarcoidosis: immunology, rheumatic
involvement, and therapeutics. Curr Opin Rheumatol.
2001;13(1):84-91.
https://doi.org/10.1097/00002281-2001010...
)
Involvement of small bones
Although bone lesions are frequently asymptomatic, some sarcoidosis patients present
with symptomatic dactylitis. Bone, skin and soft tissue are involved, especially in
the second and third phalanges, resulting in sausage-like fingers resembling those
seen in the spondyloarthropathies. (
2929. Flipo RM, Cotton A. Sarcoidosic dactylitis [Article in French]. Rev
Med Interne. 1995;16(9):724-5.
https://doi.org/10.1016/0248-8663(96)807...
)
The bony lesions are usually cystic, sclerotic lesions rarely being reported. Multiple cystic lesions sometimes result in a "lacy" pattern, which is typical of sarcoid bone disease. The classic lesions in the small bones of the hands and feet are known as Perthes disease and Jüngling's disease. They are well characterized on standard X-rays.
There are three radiological types of sarcoid bone disease: type I, characterized by
big cystic lesions (Figure 1), which is quite
rare and can be associated with a stress fracture from a pathological fracture; type
II, characterized by multiple, small circumscribed cysts, occasionally conflicting,
and polycyclic (Figure 2); and type III,
characterized by tunneling of the cortex of the phalanx, which leads to remodeling of
the cortical and trabecular architecture. All three forms can coexist in the same
bone. Acro-osteolysis, presenting as nodular densities in the terminal phalanges, can
also occur.(
1717. Thelier N., Allanore Y. Localisations ostéoarticulaires de la
sarcoïdose. EMC - Appareil locomoteur. 2009:1-11 [Article 14-027-C-10].
10.1016/S0246-0521(09)48227-5
https://doi.org/10.1016/S0246-0521(09)48...
)
Pattern of bone involvement found on X-rays in a patient with sarcoidosis: multiple, large cysts (type I). From the collection of Professor Yannick Allanore, of the Department of Rheumatology A, Descartes University, Medical School, Cochin Hospital, Paris, France. Used with the permission of Professor Allanore.
X-ray of hands showing cysts and acro-osteolysis (type II). From the collection of Professor Yannick Allanore, of the Department of Rheumatology A, Descartes University, Medical School, Cochin Hospital, Paris, France. Used with the permission of Professor Allanore.
Involvement of long bones
Involvement of the axial skeleton and long bones is uncommon in sarcoidosis.
Vertebral sarcoidosis can present as purely lytic lesions, as purely sclerotic
lesions (in rare cases) mimicking blastic metastases, or as a mixture of the two. The
lower dorsal and upper lumbar vertebrae are mostly involved. Because it can guide the
selection of biopsy sites, MRI has gained attention as a modality that facilitates
the histopathological confirmation of the diagnosis and can be used in evaluating the
efficacy of the treatment of bone lesions. The MRI findings are nonspecific; showing
multifocal lesions that are hypointense on T1-weighted images and hyperintense on
T2-weighted images.(
3030. Rúa-Figueroa I, Gantes MA, Erausquin C, Mhaidli H, Montesdeoca
A. Vertebral sarcoidosis: clinical and imaging findings. Semin Arthritis Rheum.
2002;31(5):346-52.
https://doi.org/10.1053/sarh.2002.31553...
)
Any bone, including the skull, ribs, nasal bone, and long bones, can be affected in
sarcoidosis. In the skull, sarcoidosis manifests as asymmetrical, asymptomatic lytic
lesions of variable size. Positron emission tomography/computed tomography (PET/CT)
imaging can be useful in the assessment of bone involvement in sarcoidosis
patients.(
3131. Mostard RL, Prompers L, Weijers RE, van Kroonenburgh MJ, Wijnen PA,
Geusens PP, et al. F-18 FDG PET/CT for detecting bone and bone marrow involvement in
sarcoidosis patients. Clin Nucl Med. 2012;37(1):21-5.
https://doi.org/10.1097/RLU.0b013e318233...
)
Treatment of osseous sarcoidosis
Asymptomatic osseous sarcoidosis generally does not require therapy, although the
indications for therapeutic intervention are not well defined. However, treatment is
usually indicated when the symptoms include uncontrolled pain, stiffness, or bony
destruction. Therapy generally consists of oral corticosteroids at 15-20 mg/day. The
dosage is adjusted according to the clinical response.(
3232. Smith K, Fort JG. Phalangeal osseous sarcoidosis. Arthritis Rheum.
1998;41(1):176-9.
https://doi.org/10.1002/1529-0131(199801...
) Methotrexate and hydroxychloroquine can also be used. Although there is
some evidence that anti-TNF-α agents are efficacious in sarcoid bone lesions, this
effect needs to be verified.(
3333. Doty JD, Mazur JE, Judson MA. Treatment of sarcoidosis with
infliximab. Chest. 2005;127(3):1064-71.
https://doi.org/10.1378/chest.127.3.1064...
)
Muscle sarcoidosis
Muscle sarcoidosis is a rare entity and is usually asymptomatic. It is symptomatic in
only 1% of cases. It typically appears as a complication of systemic
sarcoidosis.(
3434. Fayad F, Duet M, Orcel P, Lioté F. Systemic sarcoidosis: the
"leopard-man" sign. Joint Bone Spine. 2006;73(1):109-12.
https://doi.org/10.1016/j.jbspin.2005.04...
) The histological pattern of sarcoid myopathy is as a noncaseating granuloma
in the perimysial connective tissue. Large granulomas compress and destroy adjacent
muscle fibers, resulting in degeneration and focal lymphocyte infiltration, and foci of
necrosis or fibrosis can also be observed.(
3434. Fayad F, Duet M, Orcel P, Lioté F. Systemic sarcoidosis: the
"leopard-man" sign. Joint Bone Spine. 2006;73(1):109-12.
https://doi.org/10.1016/j.jbspin.2005.04...
) Fiber destruction in this disease is caused mainly by fiber infiltration
rather than by mechanical compression or ischemia.
In a patient with sarcoidosis, the presence of muscle weakness, muscle pain, or muscle
nodules is suggestive of sarcoid myopathy. Fatigue and general weakness are common,
which could explain why patients with sarcoidosis frequently experience exercise
intolerance.(
3535. Sharma OP. Fatigue and sarcoidosis. Eur Respir J.
1999;13(4):713-4.
https://doi.org/10.1034/j.1399-3003.1999...
,
3636. Drent M, Wirnsberger RM, de Vries J, van Dieijen-Visser MP, Wouters
EF, Schols AM. Association of fatigue with an acute phase response in sarcoidosis.
Eur Respir J. 1999;13(4):718-22.
https://doi.org/10.1034/j.1399-3003.1999...
) The cause is not only sarcoid myopathy but also the high circulating levels
of inflammatory cytokines such as TNF-α, IL-6, and IFN-γ.
In sarcoid myopathy, three clinical patterns are generally recognized(
3737. Tohme-Noun C, Le Breton C, Sobotka A, Boumenir ZE, Milleron B,
Carette MF, et al. Imaging findings in three cases of the nodular type of muscular
sarcoidosis. AJR Am J Roentgenol. 2004;183(4):995-9.
https://doi.org/10.2214/ajr.183.4.183099...
): chronic myopathy (seen in 86% of cases), which is the most common form,
characterized by an insidious onset of proximal muscle weakness with normal or elevated
serum levels of muscle enzymes; acute myositis (seen in 11% of cases); and nodular or
tumor-like myositis (seen in only 3% of cases). Nodular myopathy manifests as multiple,
tumor-like, palpable nodules in the muscles.(
3737. Tohme-Noun C, Le Breton C, Sobotka A, Boumenir ZE, Milleron B,
Carette MF, et al. Imaging findings in three cases of the nodular type of muscular
sarcoidosis. AJR Am J Roentgenol. 2004;183(4):995-9.
https://doi.org/10.2214/ajr.183.4.183099...
,
3838. Akasbi N, Tahiri L, Daoudi A, Bendahou M, Harzy T. Frohse's arcade
syndrome revealing sarcoidosic myopathy. Joint Bone Spine.
2011;78(5):522-3.
https://doi.org/10.1016/j.jbspin.2011.03...
) The use of MRI and PET/CT facilitates the diagnosis of muscle
sarcoidosis.
The mainstay of the treatment of patients with muscle sarcoidosis is 8-12 weeks of
systemic glucocorticoid therapy at an initial daily dose of 0.5-1 mg/kg with progressive
tapering. Methotrexate, chloroquine and azathioprine have been used in
corticosteroid-resistant and corticosteroid-dependent forms.(
3939. Zisman DA, Biermann JS, Martinez FJ, Devaney KO, Lynch JP 3rd.
Sarcoidosis presenting as a tumorlike muscular lesion. Case report and review of the
literature. Medicine (Baltimore). 1999;78(2):112-22.
https://doi.org/10.1097/00005792-1999030...
) Thalidomide and infliximab have been found to be beneficial in some cases
of sarcoid myopathy. The effectiveness of these medications seems related to TNF-α
inhibition. Corticosteroid-induced myopathy can also occur as a complication of the
treatment of sarcoidosis. Affected patients typically develop proximal muscle weakness
that has a gradual onset (over several weeks) and is accompanied by muscle wasting. A
common manifestation is difficulty getting up from a chair or climbing stairs. Myalgia
and muscle tenderness are not observed.(
4040. Khaleeli AA, Edwards RH, Gohil K, McPhail G, Rennie MJ, Round J, et
al. Corticosteroid myopathy: a clinical and pathological study. Clin Endocrinol
(Oxf). 1983;18(2):155-66.
https://doi.org/10.1111/j.1365-2265.1983...
)
Combination of sarcoidosis and rheumatic disease
Sarcoidosis can be associated with other chronic inflammatory disease like systemic
lupus erythematosus (SLE), Sjögren's syndrome or psoriatic arthritis. In sarcoidosis,
suspicion of SLE is raised when the patient develops a butterfly rash or discoid
lesions. The treatment of sarcoidosis patients with SLE is challenging and should be
individualized.(
4141. Maples CJ, Counselman FL. Lupus pernio. J Emerg Med.
2007;33(2):187-9.
https://doi.org/10.1016/j.jemermed.2006....
) The use of anti-TNF-α agents should be avoided in patients who have active
SLE. In rare cases, sarcoidosis and Sjögren's syndrome can both affect the salivary
glands. Dryness and diffuse swelling of oral mucosal tissues can be the presenting
symptom of sarcoidosis.(
4242. Mansour MJ, Al-Hashimi I, Wright JM. Coexistence of Sjögren's
syndrome and sarcoidosis: a report of five cases. J Oral Pathol Med.
2007;36(6):337-41.
https://doi.org/10.1111/j.1600-0714.2007...
)
Approximately 6% of all patients with sarcoidosis develop a psoriatic form of arthritis.
(
4343. Visser H, Vos K, Zanelli E, Verduyn W, Schreuder GM, Speyer I, et
al. Sarcoid arthritis: clinical characteristics, diagnostic aspects, and risk
factors. Ann Rheum Dis. 2002;61(6):499-504.
https://doi.org/10.1136/ard.61.6.499...
) Although anti-TNF-α therapy is helpful in psoriasis, it can also
paradoxically induce progressive psoriasis, and patients treated with anti-TNF-α agents
should be closely monitored.
Changes in calcium metabolism
In sarcoidosis, hypercalciuria is more common than is hypercalcemia. Either can be
caused by nephrocalcinosis, kidney stones, or renal failure. Granulomatous macrophages
increase conversion of 25-hydroxyvitamin D to active 1,25-dihydroxyvitamin D
(calcitriol), leading to increased calcium absorption by the intestine. (
4444. Baughman RP, Janovcik J, Ray Et Al M. Calcium and vitamin D
metabolism in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis.
2013;30(2):113-20.
) The high levels of calcitriol induce osteoclast activation and bone
resorption. In addition, corticosteroid-treated patients are at a higher risk of
osteoporosis. Bone loss could be also increased by high levels of parathyroid
hormone-related peptide identified in sarcoid tissue.(
4545. Conron M, Young C, Beynon HL. Calcium metabolism in sarcoidosis and
its clinical implications. Rheumatology (Oxford). 2000;39(7):707-13.
https://doi.org/10.1093/rheumatology/39....
) Corticosteroids have been successfully used to improve disorders of calcium
metabolism. (
4646. Rajakariar R, Sharples EJ, Raftery MJ, Sheaff M, Yaqoob MM. Sarcoid
tubulo-interstitial nephritis: long-term outcome and response to corticosteroid
therapy. Kidney Int. 2006;70(1):165-9.
https://doi.org/10.1038/sj.ki.5001512...
) Mycophenolate mofetil and infliximab have been used in select
cases.(
4747. Moudgil A, Przygodzki RM, Kher KK. Successful steroid-sparing
treatment of renal limited sarcoidosis with mycophenolate mofetil. Pediatr Nephrol.
2006;21(2):281-5.
https://doi.org/10.1007/s00467-005-2086-...
,
4848. Ahmed MM, Mubashir E, Dossabhoy NR. Isolated renal sarcoidosis: a
rare presentation of a rare disease treated with infliximab. Clin Rheumatol.
2007;26(8):1346-9.
https://doi.org/10.1007/s10067-006-0357-...
)
Bone loss in sarcoidosis
The bone loss in sarcoidosis can be caused by multiple factors, including diffuse skeletal granulomatosis, calcitriol, osteoclast activating factor, and glucocorticoid therapy, particularly in postmenopausal patients. In one study of corticosteroid therapy in patients with sarcoidosis, the authors found that the rate of bone loss in corticosteroid-treated postmenopausal patients with sarcoidosis was greater than that reported for corticosteroid-treated patients with rheumatoid arthritis or asthma.( 4949. Montemurro L, Fraioli P, Riboldi A, Delpiano S, Zanni D, Rizzato G. Bone loss in prednisone treated sarcoidosis: a two-year follow-up. Ann Ital Med Int. 1990;5(3 Pt 1):164-8 )
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,
should be considered with caution in patients with hypercalcemia, hypercalciuria, high
levels of parathormone, and kidney stones.(
5050. Sweiss NJ, Lower EE, Korsten P, Niewold TB, Favus MJ, Baughman RP.
Bone health issues in sarcoidosis. Curr Rheumatol Rep.
2011;13(3):265-72.
https://doi.org/10.1007/s11926-011-0170-...
) Guidelines published by the American College of Rheumatology recommend that
patients receiving corticosteroids should undergo bone mineral density
testing.(
5151. Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, et
al. American College of Rheumatology 2010 recommendations for the prevention and
treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken).
2010;62(11):1515-26.
https://doi.org/10.1002/acr.20295...
) The World Health Organization fracture assessment risk tool can be used in
order to calculate patient risk of fracture.
For patients with sarcoidosis at risk of developing osteoporosis because of prolonged
use of corticosteroids, bisphosphonates are effective in preventing
glucocorticoid-induced bone loss. The American College of Rheumatology recommends using
bisphosphonates in low-risk patients receiving corticosteroids at doses of = 7.5 mg/day,
as well as in all medium- or high-risk patients receiving corticosteroids. Of the
available bisphosphonates, alendronate, risedronate, zoledronic acid, and teriparatide
effectively reduce bone loss and can thus diminish fracture risk.(
5151. Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, et
al. American College of Rheumatology 2010 recommendations for the prevention and
treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken).
2010;62(11):1515-26.
https://doi.org/10.1002/acr.20295...
) Further studies on bisphosphonate use in osteoporosis during sarcoidosis
are needed.
Final considerations
Although sarcoidosis can affect any organ, sarcoidosis involving the musculoskeletal system is rare. The disease can affect the muscles, joints and the bones. Those conditions, which are polymorphic, can be the presenting symptoms the disease or can appear during the course of its progression. Corticosteroids are the cornerstone of sarcoidosis treatment but only have a postponing effect. Prospective, randomized, controlled trials assessing anti-TNF-α agents are needed in order to evaluate their efficacy in cases of sarcoidosis with rheumatic complications.
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44Baughman RP, Janovcik J, Ray Et Al M. Calcium and vitamin D metabolism in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis. 2013;30(2):113-20.
-
45Conron M, Young C, Beynon HL. Calcium metabolism in sarcoidosis and its clinical implications. Rheumatology (Oxford). 2000;39(7):707-13.
» https://doi.org/10.1093/rheumatology/39.7.707 -
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48Ahmed MM, Mubashir E, Dossabhoy NR. Isolated renal sarcoidosis: a rare presentation of a rare disease treated with infliximab. Clin Rheumatol. 2007;26(8):1346-9.
» https://doi.org/10.1007/s10067-006-0357-4 -
49Montemurro L, Fraioli P, Riboldi A, Delpiano S, Zanni D, Rizzato G. Bone loss in prednisone treated sarcoidosis: a two-year follow-up. Ann Ital Med Int. 1990;5(3 Pt 1):164-8
-
50Sweiss NJ, Lower EE, Korsten P, Niewold TB, Favus MJ, Baughman RP. Bone health issues in sarcoidosis. Curr Rheumatol Rep. 2011;13(3):265-72.
» https://doi.org/10.1007/s11926-011-0170-1 -
51Grossman JM, Gordon R, Ranganath VK, Deal C, Caplan L, Chen W, et al. American College of Rheumatology 2010 recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken). 2010;62(11):1515-26.
» https://doi.org/10.1002/acr.20295
-
*
Study carried out in the Rheumatology Department of Hassan II University Hospital, Fez, Morocco.
-
**
A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br
Publication Dates
-
Publication in this collection
Mar-Apr 2014
History
-
Received
21 Sept 2013 -
Accepted
21 Feb 2014