PEDIATRIC IMAGING 229 Connective Tissue Disorders in Childhood: Are They All the Same? Systemic connective tissue disorders are characterized by the pres- ence of autoantibodies and multiorgan system involvement. Juvenile systemic lupus erythematosus with or without associated antiphos- pholipid syndrome; juvenile dermatomyositis; sclerodermiform syndromes, including systemic and localized sclerodermas and eosinophilic fasciitis; mixed connective tissue disease; and Sjögren syndrome are the disorders that affect children most frequently. Diagnosis is difficult, because the clinical presentation of patients is diverse, from mild to severe disease. In addition, all organs may be affected. However, a variety of imaging techniques are now avail- able to investigate rheumatic disease in children. These imaging modalities offer the potential for earlier diagnosis and improved assessment of therapeutic response. This article reviews the main connective tissue disorders that affect children, highlighting their key imaging features on images acquired with different diagnostic imaging modalities and correlating these features with clinical and pathologic findings, when available. © RSNA, 2019 • radiographics.rsna.org María Navallas, MD Emilio J. Inarejos Clemente, MD Estíbaliz Iglesias, MD Mónica Rebollo-Polo, MD Jordi Antón, MD, PhD Oscar M. Navarro, MD Abbreviations: FLAIR = fluid-attenuated in- version recovery, JDM = juvenile dermatomyo- sitis, MCTD = mixed connective tissue disease, SLE = systemic lupus erythematosus, STIR = short tau inversion recovery RadioGraphics 2019; 39:229–250 https://doi.org/10.1148/rg.2019180078 Content Codes: From the Departments of Radiology (M.N., E.J.I.C., M.R.P.) and Rheumatology (E.I., J.A.), Hospital Sant Joan de Déu, Passeig Sant Joan de Déu 2, 08950 Esplugues de Llobregat, Barcelona, Spain; Department of Medical Imaging, Univer- sity of Toronto, Toronto, ON, Canada (M.N., O.M.N.); and Department of Diagnostic Imag- ing, The Hospital for Sick Children, Toronto, ON, Canada (M.N., O.M.N.). Presented as an education exhibit at the 2017 RSNA Annual Meeting. Received March 11, 2018; revision re- quested April 27 and received June 21; accepted June 25. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. Address correspon- dence to M.N. (e-mail: [email protected]). © RSNA, 2019 After completing this journal-based SA-CME activity, participants will be able to: ■ Identify the most common connective tissue disorders in children. ■ Discuss the current understanding of the most common connective tissue dis- orders in children, with a review of the pathogenesis, clinical features, and crite- ria for diagnosis. ■ Describe the imaging findings related to the most common pediatric connec- tive tissue disorders. See rsna.org/learning-center-rg. SA-CME LEARNING OBJECTIVES Introduction Connective tissue disorders are a heterogeneous group of systemic inflammatory diseases characterized by the presence of circulat- ing autoantibodies and autoimmune-mediated multiorgan system involvement (1). Juvenile systemic lupus erythematosus (SLE) with or without antiphospholipid syndrome, juvenile dermatomyositis (JDM), sclerodermiform syndromes, mixed connective tissue disease (MCTD), and Sjögren syndrome are the disorders that affect chil- dren most frequently. Their clinical manifestation is diverse, and potentially all organs can be affected. In addition, many of the early symptoms such as fatigue, fever, rash, and joint pain may mimic the presentation of infectious diseases and malignancies. Furthermore, over the course of time, new symptoms may arise related to the underlying disorder or to complications of therapy. Therefore, distinction among various possible diagnostic entities may be difficult, and making appropriate therapeutic choices depends on the skillful interpretation of labora- tory and imaging data in addition to the clinician’s experience and judgment. Imaging findings are crucial to the diagnosis and monitoring of connective tissue disorders, especially those of the brain, lung, and musculoskeletal system. MRI is the investigation of choice to detect and monitor brain disease. Thin-section CT of the chest is an important component of the evaluation of patients with derma- tomyositis, polymyositis, and systemic sclerosis. Radiography is an important starting point for detection of abnormalities in the joints. However, US and MRI are increasingly important in the evaluation of joint, tendon, and soft-tissue inflammation. This copy is for personal use only. To order printed copies, contact [email protected]
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Connective Tissue Disorders in Childhood: Are They All the Same?
Systemic connective tissue disorders are characterized by the pres- ence of autoantibodies and multiorgan system involvement. Juvenile systemic lupus erythematosus with or without associated antiphos- pholipid syndrome; juvenile dermatomyositis; sclerodermiform syndromes, including systemic and localized sclerodermas and eosinophilic fasciitis; mixed connective tissue disease; and Sjögren syndrome are the disorders that affect children most frequently. Diagnosis is difficult, because the clinical presentation of patients is diverse, from mild to severe disease. In addition, all organs may be affected. However, a variety of imaging techniques are now avail- able to investigate rheumatic disease in children. These imaging modalities offer the potential for earlier diagnosis and improved assessment of therapeutic response. This article reviews the main connective tissue disorders that affect children, highlighting their key imaging features on images acquired with different diagnostic imaging modalities and correlating these features with clinical and pathologic findings, when available.
©RSNA, 2019 • radiographics.rsna.org
María Navallas, MD Emilio J. Inarejos Clemente, MD Estíbaliz Iglesias, MD Mónica Rebollo-Polo, MD Jordi Antón, MD, PhD Oscar M. Navarro, MD
Abbreviations: FLAIR = fluid-attenuated in- version recovery, JDM = juvenile dermatomyo- sitis, MCTD = mixed connective tissue disease, SLE = systemic lupus erythematosus, STIR = short tau inversion recovery
RadioGraphics 2019; 39:229–250
Content Codes:
From the Departments of Radiology (M.N., E.J.I.C., M.R.P.) and Rheumatology (E.I., J.A.), Hospital Sant Joan de Déu, Passeig Sant Joan de Déu 2, 08950 Esplugues de Llobregat, Barcelona, Spain; Department of Medical Imaging, Univer- sity of Toronto, Toronto, ON, Canada (M.N., O.M.N.); and Department of Diagnostic Imag- ing, The Hospital for Sick Children, Toronto, ON, Canada (M.N., O.M.N.). Presented as an education exhibit at the 2017 RSNA Annual Meeting. Received March 11, 2018; revision re- quested April 27 and received June 21; accepted June 25. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. Address correspon- dence to M.N. (e-mail: [email protected]).
©RSNA, 2019
After completing this journal-based SA-CME activity, participants will be able to:
Identify the most common connective tissue disorders in children.
Discuss the current understanding of the most common connective tissue dis- orders in children, with a review of the pathogenesis, clinical features, and crite- ria for diagnosis.
Describe the imaging findings related to the most common pediatric connec- tive tissue disorders.
See rsna.org/learning-center-rg.
introduction Connective tissue disorders are a heterogeneous group of systemic inflammatory diseases characterized by the presence of circulat- ing autoantibodies and autoimmune-mediated multiorgan system involvement (1). Juvenile systemic lupus erythematosus (SLE) with or without antiphospholipid syndrome, juvenile dermatomyositis (JDM), sclerodermiform syndromes, mixed connective tissue disease (MCTD), and Sjögren syndrome are the disorders that affect chil- dren most frequently.
Their clinical manifestation is diverse, and potentially all organs can be affected. In addition, many of the early symptoms such as fatigue, fever, rash, and joint pain may mimic the presentation of infectious diseases and malignancies. Furthermore, over the course of time, new symptoms may arise related to the underlying disorder or to complications of therapy. Therefore, distinction among various possible diagnostic entities may be difficult, and making appropriate therapeutic choices depends on the skillful interpretation of labora- tory and imaging data in addition to the clinician’s experience and judgment.
Imaging findings are crucial to the diagnosis and monitoring of connective tissue disorders, especially those of the brain, lung, and musculoskeletal system. MRI is the investigation of choice to detect and monitor brain disease. Thin-section CT of the chest is an important component of the evaluation of patients with derma- tomyositis, polymyositis, and systemic sclerosis. Radiography is an important starting point for detection of abnormalities in the joints. However, US and MRI are increasingly important in the evaluation of joint, tendon, and soft-tissue inflammation.
This copy is for personal use only. To order printed copies, contact [email protected]
230 january-February 2019 radiographics.rsna.org
African, and Hispanic persons are affected more frequently than are white persons. The average age of onset is 12 years, with rare cases occur- ring in patients 5 years old or younger (5). The female-to-male distribution is 4.6:1 (6).
Common laboratory findings in children with SLE include the presence of autoantibod- ies such as antinuclear antibodies with different antigen specificities, elevation of acute phase reactants, and hypocomplementemia. C-reactive protein levels are often in the normal range, except in patients with accompanying infection, serositis, or arthritis. Hematuria and proteinuria are frequent findings at urinalysis, given the high prevalence of nephritis.
Treatment is challenging owing to multisystem involvement and substantial complications that may arise from therapy. Nonsteroidal anti-inflam- matory drugs, hydroxychloroquine or chloro- quine, glucocorticoid medications, immunosup- pressive drugs, intravenous immunoglobulin, and plasmapheresis may be useful. Biologic therapies for juvenile SLE are under study.
The presenting manifestations of SLE in chil- dren are diverse, and any organ system may be involved (Table 1). The most common initial symp- toms are gradual onset of fever, weight loss, and malaise. Generalized signs of immune activation are also seen, such as lymphadenopathy and hepa- tosplenomegaly. Children also may have arthritis and renal disease. The classic malar rash may be absent at the time of diagnosis. Other findings in- clude Raynaud phenomenon and neuropsychiatric, pulmonary, and hematologic manifestations. Most pediatric patients have more severe disease than their adult counterparts have, with greater renal, neurologic, and hematologic involvement.
Lupus nephritis affects up to 80% of children with juvenile SLE (3). Its early diagnosis is critical in minimizing the risk of end-stage kidney disease. The imaging findings are generally nonspecific and similar to those in patients with renal diseases from other causes. At US, the kidneys are gener- ally hyperechoic, with loss of corticomedullary dif- ferentiation. Their size depends on the duration of renal involvement, although they may be enlarged because of nephritis or secondary to thrombosis of the renal veins or inferior vena cava (Fig 1) (7,8). The reference technique for diagnosis remains histopathologic analysis of a kidney biopsy sample.
Juvenile SLE arthritis involves small and large joints and is almost always nonerosive and non- deforming. Conventional radiographs may show soft-tissue swelling, joint effusion, and periarticu- lar osteopenia in addition to Jaccoud arthropathy, which is characterized by digital hyperextension at the proximal interphalangeal joints (swan-neck de- formity) and proximal interphalangeal flexion as-
juvenile Systemic Lupus Erythematosus
Juvenile SLE is a chronic autoimmune disease of unknown cause. This multisystem illness is characterized by immune dysregulation, with alterations in both innate and adaptive immunity. Genetic, hormonal, immunologic, and environ- mental factors are suspected to contribute.
The Systemic Lupus International Collaborat- ing Clinics (SLICC) criteria have been recognized as adequate for diagnosis and management of juvenile SLE in the absence of specific pediatric classification criteria (2,3). Antinuclear antibodies, arthritis, acute cutaneous lupus, low serum com- plement, and antidouble-stranded DNA (anti-ds DNA) are the most sensitive criteria for diagnosis.
The incidence of juvenile SLE is 0.36–2.5 per 100 000 persons per year, and the prevalence is 1.89–25.7 per 100 000 persons (4). Asian,
TEAChing POinTS Thromboses are the hallmarks of antiphospholipid syndrome.
The deep veins of the lower extremities are the most common sites of venous thrombosis, and the cerebral vasculature is the most common site for arterial thrombosis.
In patients with juvenile dermatomyositis, MRI is useful in se- lecting a site for muscle biopsy to reduce the false-negative rate of a blind biopsy. In addition, by establishing the distribu- tion and magnitude of the inflammatory process throughout the entire body, whole-body MRI allows a more accurate as- sessment of the total inflammatory burden than that at clinical examination and can be used to assess treatment response. Another advantage of whole-body MRI is its ability to allow identification of signal intensity abnormalities in the fascia and in the subcutaneous tissue, which are often undetected at clinical assessment and are potential markers of disease sever- ity, because they are associated with a higher load of muscle inflammation. Moreover, subcutaneous changes have been indicated as potential precursors to the development of dys- trophic calcification. Another advantage of whole-body MRI is the ability to detect different patterns of muscle inflamma- tion (patchy vs diffuse). A diffuse pattern could be related to a worse prognosis.
The typical MRI findings of eosinophilic fasciitis include fascial thickening with high T2 signal intensity and enhancement. Extension into the adjacent muscle and subcutaneous tissue occurs less frequently.
The lungs are frequently affected in patients with MCTD, mainly by interstitial lung disease. CT findings of pulmonary involvement tend to be a combination of those seen in other connective tissue diseases, and a diagnosis can be achieved only by ruling out those other entities. Ground-glass opacities with septal thickening and subpleural honeycombing are the most salient CT features.
At US, normal salivary gland tissue shows homogeneous echotexture with echogenicity similar to that of the thyroid gland. In patients with Sjögren syndrome, US shows abnor- mal salivary gland architecture, with parenchymal hetero- geneity, multiple scattered hypoechoic foci, and/or multiple cystlike changes in the gland parenchyma (known as benign lymphoepithelial cysts).
RG • Volume 39 Number 1 Navallas et al 231
vial sheath of the tendon and thickening of the synovium. Synovial proliferation in SLE is less prominent than that in juvenile idiopathic arthritis (Fig 2) (8). Enthesitis also has been described, most commonly at the distal inser- tion of the patellar tendon (11). US findings include a hypoechoic thickened tendon at its bony attachment with a loss of normal fibrillar architecture, which may exhibit Doppler signal
sociated with distal interphalangeal hyperextension (boutonnière deformity) (9). Jaccoud arthropathy is caused by laxity of ligaments, tenosynovitis, and inflammation of the joint capsule with subsequent fibrotic retraction (10). The joint space is gener- ally preserved. Tenosynovitis may accompany the arthropathy of the small joints of the hands.
If any imaging is required, US can allow detection of increased fluid within the syno-
Table 1: Main imaging Findings in juvenile SLE
Body System Findings
thrombosis Musculoskeletal Nonerosive nondeforming arthritis of small and large joints
Synovitis Tenosynovitis and enthesitis Joint effusion Soft-tissue swelling Periarticular osteopenia Jaccoud arthropathy Secondary to treatment and/or chronic illness Osteonecrosis Insufficiency fractures Septic arthritis and osteomyelitis Steroid myopathy
Neurologic Most common: white matter T2 hyperintensities Others: gray matter T2 hyperintensities, cerebral atrophy, infarcts, dural venous
thrombosis, acute hypertensive encephalopathy, and transverse myelitis Cardiovascular Most frequent: pericardial effusion
Others: myocarditis, valvular disease, and coronary artery disease Pleuropulmonary Most common: pleural effusion
Others: pneumonia, pulmonary hemorrhage, lupus pneumonitis, cryptogenic orga- nizing pneumonia, shrinking lung syndrome, and pulmonary embolism
Multisystem: antiphospho- lipid syndrome
Abdominal Most serious complication: bowel ischemia Others: hepatosplenomegaly, acute cholecystitis, and pancreatitis
Figure 1. Lupus nephritis in a 15-year-old girl. Longitudinal (a) and transverse (b) US images show renal enlargement with increased echogenicity of the parenchyma and decreased corticomedullary differentiation.
232 january-February 2019 radiographics.rsna.org
and bony changes including enthesophytes, erosions, or irregularity. MRI findings include thickening and abnormal signal intensity in tendons and ligaments, edema of perienthesal soft tissues, bone marrow edema, erosions and enthesophytes in adjacent osseous structures, and adjacent joint or bursal fluid (12) (Fig 3).
Children with SLE are at risk for developing osteonecrosis in weight-bearing bones, mainly in the femoral heads and tibial plateaus, especially if they have a previous history of long-standing corticotherapy. Other musculoskeletal findings include steroid myopathy, septic arthritis and osteomyelitis, and insufficiency fractures.
Juvenile SLE often is associated with a variety of neuropsychiatric manifestations, headache being the most common concern. MRI is the technique of choice for the workup of neuropsy- chiatric disease, although the results might be normal in 54%–59% of cases (13,14). White mat- ter hyperintensities on T2-weighted images are the most commonly observed abnormality. Other findings include gray matter T2 hyperintensities, cerebral atrophy, transverse myelitis, dural venous sinus thrombosis, and infarcts (Fig 4) (13).
In practice, in a young patient who has expe- rienced a stroke, the diagnosis of SLE should be considered (7). In addition, in children, intra- cranial hemorrhage in the absence of trauma or coagulopathy should also suggest the possibility of SLE (7). Posterior reversible encephalopathy syndrome also has been described, likely as a result of endothelial damage, hypertension, and cytotoxic medications (15).
Heart disease in children with SLE has a prevalence of approximately 32%–42% (16) and is often silent. Pericardial effusion is the most common finding (17). Echocardiography is the
initial imaging modality for diagnosis. If further imaging is required, cardiac MRI or angiocardi- ography may be helpful.
Pleuropulmonary involvement in SLE has been reported to occur in 5%–67% of pediat- ric patients (18). The most frequent radiologic manifestation is pleural effusion. Pneumonia, pulmonary hemorrhage, lupus pneumonitis, and cryptogenic organizing pneumonia are acute conditions that may produce regions of airspace consolidation at radiography or CT (Fig 5). Pulmonary hemorrhage often appears as areas of ground-glass opacity, which, when superim-
Figure 2. Arthritis of the elbow in a 14-year-old girl with juvenile SLE who presented with pain and decreased extension of the right elbow. Sagittal (a) and axial (b) contrast material–enhanced fat-sup- pressed T1-weighted MR images of the right elbow show mild active synovitis (arrow) and bone marrow enhancement (arrowhead in b).
Figure 3. Juvenile SLE in a 16-year-old boy with left hip pain. Coronal short tau inversion-recovery (STIR) MR image of the hips shows increased signal intensity adjacent to the left greater trochanter (arrow) and to the left ischial tuberosity (ar- rowhead), in keeping with left gluteal and left hamstring en- thesopathy, respectively.
RG • Volume 39 Number 1 Navallas et al 233
ized by a progressive decrease in lung volume that usually is identified on chest radiographs as a progressive elevation of the diaphragm. It is secondary to recurrent inflammation or fibrosis and weakened diaphragm and chest wall muscles. Pulmonary embolism also has been reported in patients with juvenile SLE (19,20).
Antiphospholipid syndrome is an autoimmune multisystem disorder characterized by arterial, venous, or small-vessel thromboembolic events and/or pregnancy morbidity with persistent an- tiphospholipid antibodies (21). It can manifest as a primary disease or with an underlying systemic autoimmune disease, particularly SLE. Thromboses
Figure 4. Juvenile SLE in an 11-year-old girl with visual and auditory hallucinations and changes in behavior. (a, b) Axial fluid-attenuated inversion-recovery (FLAIR) MR images show hyperintense foci in the periventricular and deep white matter and in the basal ganglia (arrows), which is in keeping with multiple ischemic insults. (c, d) Axial diffusion-weighted MR image (b = 1000) (c) and apparent diffusion coefficient map (d) show diffusion restriction of the FLAIR hyperintense focus at the right putamen (arrowhead), which is consistent with a recent infarction.
Figure 5. Juvenile SLE and antiphospholipid syndrome in a 14-year-old boy with swelling of the right lower extremity, ane- mia, and fever for 15 days. Frontal radiograph of the chest shows retrocardiac airspace opacities (arrow), left pleural effusion (arrow- head), and an enlarged cardiomediastinal silhouette due to peri- cardial effusion, as proven on the basis of a subsequent echocar- diogram (not shown).
posed on interlobular septal thickening, form the so-called “crazy-paving” pattern. Shrinking lung syndrome is a complication of SLE character-
234 january-February 2019 radiographics.rsna.org
juvenile Dermatomyositis JDM is the most frequent inflammatory myopa- thy in children. It usually affects skeletal muscle and skin but also can affect the respiratory, cardiac, and gastrointestinal systems. Mucocu- taneous abnormalities are often pathognomonic of the disease when the patient presents, the most typical being heliotrope discoloration of the upper eyelids and Gottron papules. Cutaneous vasculopathy, generalized lipodystrophy, meta- bolic abnormalities, hematologic manifestations including macrophage activation syndrome (Fig 7), and osteoporosis also may be encountered.
Although the diagnosis is made according to criteria described by Bohan and Peter (25,26), the presence of the characteristic heliotrope rash and Gottron papules is usually enough to suggest it. Tests such as electromyography,
Figure 6. Antiphospholipid syndrome in a 16-year-old boy with juvenile SLE. (a) Axial contrast-enhanced CT image of the chest (soft-tissue window) shows bilateral pulmonary embolisms (arrows). (b) Axial contrast-enhanced CT image of the chest (lung window) shows secondary lung infarctions (arrowheads). (c) Coronal contrast-enhanced CT image of the abdomen shows nonoc- clusive thrombosis of the inferior vena cava (arrow).
are the hallmarks of antiphospholipid syndrome. The deep veins of the lower extremities are the most common sites of venous thrombosis, and the cerebral vasculature is the most common site for arterial thrombosis. Infarcts and hyperintense T2 white matter foci are the most common brain CT and MRI abnormalities found, respectively (22). Dural sinus thrombosis also has been noted in these patients (23). Abdominal thrombotic and ischemic manifestations include visceral infarc- tion, which is diagnosed according to the pres- ence of wedge-shaped nonenhancing capsular- based and sharply defined lesions in the liver, kidneys, or spleen, and intestinal ischemia, which is diagnosed according to the presence of abnor- mal bowel wall thickening and enhancement, as- sociated hemorrhage, or pneumatosis. Pulmonary embolism is the main pulmonary finding (Fig 6).
Gastrointestinal manifestations occur in approx- imately 20% of children with SLE and may involve any segment of the gastrointestinal tract. Com- pared with adults, children more often have lupus- related causes of abdominal disease. The most seri- ous gastrointestinal complication is bowel ischemia caused by mesenteric vasculitis. Abdominal CT may show bowel wall thickening, abnormal wall enhancement, mesenteric edema, vascular engorge- ment, intestinal pseudo-obstruction, irregularities in the mesenteric arteries, and ascites (24). Acute cholecystitis, when due to primary SLE involve- ment, usually is not related to gallstones but rather to periarterial fibrosis and acute vasculitis. Pancre- atitis may be due to vasculitis, ischemia of small pancreatic vessels, immune complex deposition, or a combination of these entities. The US and CT features of acute pancreatitis include peripancre- atic edema, phlegmon formation, peripancreatic fatty infiltration, indistinctness of the pancreatic margins, and glandular enlargement (7).
RG • Volume 39 Number 1 Navallas et al 235
MRI, or muscle biopsy may be useful to con- firm the diagnosis.
In patients with juvenile dermatomyositis, MRI is useful in selecting a site for muscle biopsy to re- duce the false-negative rate of a blind biopsy (27). In addition, by establishing the distribution and magnitude of the inflammatory process through- out the entire body, whole-body MRI allows a more accurate assessment of the total inflamma- tory burden than that at clinical examination and can be used to assess treatment response (Fig 8). Another advantage of whole-body MRI is its ability to allow identification of signal intensity abnormalities in the fascia and in the subcutane- ous tissue, which are often undetected at clinical
assessment and are potential markers of disease severity, because they are associated with a higher load of muscle inflammation. Moreover, subcu- taneous changes have been indicated as potential precursors to the development of dystrophic cal- cification (28). Another advantage of whole-body MRI is the ability to detect different patterns of muscle inflammation (patchy vs diffuse). A diffuse pattern could be related to a worse prognosis (29).
JDM is widely distributed throughout the world and shows no predilection for race in children. It has an incidence of 1.9 cases per 1 000 000 children younger than 16 years (30), a median age at onset of 7 years, and a female-to- male ratio of 2.2:1 (31).
Figure 7. JDM, macrophage activation syndrome, and pharmacologic immunosuppression in a 15-year-old girl. (a) Axial T2- weighted MR image shows cortical and subcortical high-signal-intensity abnormalities with a posterior predominance (arrows). There also are increases in the extra-axial space and prominence of the convexity sulci and lateral ventricles that are compatible with atro- phy. These findings are nonspecific and could be related to posterior reversible encephalopathy syndrome or small-vessel vasculitis. (b) Follow-up axial T2-weighted MR image shows interval improvement in the cortical and subcortical lesions, with persistent diffuse atrophy. (c, d) Axial contrast-enhanced abdominal CT images show a diffuse increase in pancreatic size (arrow in c) associated with a large pseudocyst (arrowhead in d), with signs of active bleeding (arrow in d) and free…
Systemic connective tissue disorders are characterized by the pres- ence of autoantibodies and multiorgan system involvement. Juvenile systemic lupus erythematosus with or without associated antiphos- pholipid syndrome; juvenile dermatomyositis; sclerodermiform syndromes, including systemic and localized sclerodermas and eosinophilic fasciitis; mixed connective tissue disease; and Sjögren syndrome are the disorders that affect children most frequently. Diagnosis is difficult, because the clinical presentation of patients is diverse, from mild to severe disease. In addition, all organs may be affected. However, a variety of imaging techniques are now avail- able to investigate rheumatic disease in children. These imaging modalities offer the potential for earlier diagnosis and improved assessment of therapeutic response. This article reviews the main connective tissue disorders that affect children, highlighting their key imaging features on images acquired with different diagnostic imaging modalities and correlating these features with clinical and pathologic findings, when available.
©RSNA, 2019 • radiographics.rsna.org
María Navallas, MD Emilio J. Inarejos Clemente, MD Estíbaliz Iglesias, MD Mónica Rebollo-Polo, MD Jordi Antón, MD, PhD Oscar M. Navarro, MD
Abbreviations: FLAIR = fluid-attenuated in- version recovery, JDM = juvenile dermatomyo- sitis, MCTD = mixed connective tissue disease, SLE = systemic lupus erythematosus, STIR = short tau inversion recovery
RadioGraphics 2019; 39:229–250
Content Codes:
From the Departments of Radiology (M.N., E.J.I.C., M.R.P.) and Rheumatology (E.I., J.A.), Hospital Sant Joan de Déu, Passeig Sant Joan de Déu 2, 08950 Esplugues de Llobregat, Barcelona, Spain; Department of Medical Imaging, Univer- sity of Toronto, Toronto, ON, Canada (M.N., O.M.N.); and Department of Diagnostic Imag- ing, The Hospital for Sick Children, Toronto, ON, Canada (M.N., O.M.N.). Presented as an education exhibit at the 2017 RSNA Annual Meeting. Received March 11, 2018; revision re- quested April 27 and received June 21; accepted June 25. For this journal-based SA-CME activity, the authors, editor, and reviewers have disclosed no relevant relationships. Address correspon- dence to M.N. (e-mail: [email protected]).
©RSNA, 2019
After completing this journal-based SA-CME activity, participants will be able to:
Identify the most common connective tissue disorders in children.
Discuss the current understanding of the most common connective tissue dis- orders in children, with a review of the pathogenesis, clinical features, and crite- ria for diagnosis.
Describe the imaging findings related to the most common pediatric connec- tive tissue disorders.
See rsna.org/learning-center-rg.
introduction Connective tissue disorders are a heterogeneous group of systemic inflammatory diseases characterized by the presence of circulat- ing autoantibodies and autoimmune-mediated multiorgan system involvement (1). Juvenile systemic lupus erythematosus (SLE) with or without antiphospholipid syndrome, juvenile dermatomyositis (JDM), sclerodermiform syndromes, mixed connective tissue disease (MCTD), and Sjögren syndrome are the disorders that affect chil- dren most frequently.
Their clinical manifestation is diverse, and potentially all organs can be affected. In addition, many of the early symptoms such as fatigue, fever, rash, and joint pain may mimic the presentation of infectious diseases and malignancies. Furthermore, over the course of time, new symptoms may arise related to the underlying disorder or to complications of therapy. Therefore, distinction among various possible diagnostic entities may be difficult, and making appropriate therapeutic choices depends on the skillful interpretation of labora- tory and imaging data in addition to the clinician’s experience and judgment.
Imaging findings are crucial to the diagnosis and monitoring of connective tissue disorders, especially those of the brain, lung, and musculoskeletal system. MRI is the investigation of choice to detect and monitor brain disease. Thin-section CT of the chest is an important component of the evaluation of patients with derma- tomyositis, polymyositis, and systemic sclerosis. Radiography is an important starting point for detection of abnormalities in the joints. However, US and MRI are increasingly important in the evaluation of joint, tendon, and soft-tissue inflammation.
This copy is for personal use only. To order printed copies, contact [email protected]
230 january-February 2019 radiographics.rsna.org
African, and Hispanic persons are affected more frequently than are white persons. The average age of onset is 12 years, with rare cases occur- ring in patients 5 years old or younger (5). The female-to-male distribution is 4.6:1 (6).
Common laboratory findings in children with SLE include the presence of autoantibod- ies such as antinuclear antibodies with different antigen specificities, elevation of acute phase reactants, and hypocomplementemia. C-reactive protein levels are often in the normal range, except in patients with accompanying infection, serositis, or arthritis. Hematuria and proteinuria are frequent findings at urinalysis, given the high prevalence of nephritis.
Treatment is challenging owing to multisystem involvement and substantial complications that may arise from therapy. Nonsteroidal anti-inflam- matory drugs, hydroxychloroquine or chloro- quine, glucocorticoid medications, immunosup- pressive drugs, intravenous immunoglobulin, and plasmapheresis may be useful. Biologic therapies for juvenile SLE are under study.
The presenting manifestations of SLE in chil- dren are diverse, and any organ system may be involved (Table 1). The most common initial symp- toms are gradual onset of fever, weight loss, and malaise. Generalized signs of immune activation are also seen, such as lymphadenopathy and hepa- tosplenomegaly. Children also may have arthritis and renal disease. The classic malar rash may be absent at the time of diagnosis. Other findings in- clude Raynaud phenomenon and neuropsychiatric, pulmonary, and hematologic manifestations. Most pediatric patients have more severe disease than their adult counterparts have, with greater renal, neurologic, and hematologic involvement.
Lupus nephritis affects up to 80% of children with juvenile SLE (3). Its early diagnosis is critical in minimizing the risk of end-stage kidney disease. The imaging findings are generally nonspecific and similar to those in patients with renal diseases from other causes. At US, the kidneys are gener- ally hyperechoic, with loss of corticomedullary dif- ferentiation. Their size depends on the duration of renal involvement, although they may be enlarged because of nephritis or secondary to thrombosis of the renal veins or inferior vena cava (Fig 1) (7,8). The reference technique for diagnosis remains histopathologic analysis of a kidney biopsy sample.
Juvenile SLE arthritis involves small and large joints and is almost always nonerosive and non- deforming. Conventional radiographs may show soft-tissue swelling, joint effusion, and periarticu- lar osteopenia in addition to Jaccoud arthropathy, which is characterized by digital hyperextension at the proximal interphalangeal joints (swan-neck de- formity) and proximal interphalangeal flexion as-
juvenile Systemic Lupus Erythematosus
Juvenile SLE is a chronic autoimmune disease of unknown cause. This multisystem illness is characterized by immune dysregulation, with alterations in both innate and adaptive immunity. Genetic, hormonal, immunologic, and environ- mental factors are suspected to contribute.
The Systemic Lupus International Collaborat- ing Clinics (SLICC) criteria have been recognized as adequate for diagnosis and management of juvenile SLE in the absence of specific pediatric classification criteria (2,3). Antinuclear antibodies, arthritis, acute cutaneous lupus, low serum com- plement, and antidouble-stranded DNA (anti-ds DNA) are the most sensitive criteria for diagnosis.
The incidence of juvenile SLE is 0.36–2.5 per 100 000 persons per year, and the prevalence is 1.89–25.7 per 100 000 persons (4). Asian,
TEAChing POinTS Thromboses are the hallmarks of antiphospholipid syndrome.
The deep veins of the lower extremities are the most common sites of venous thrombosis, and the cerebral vasculature is the most common site for arterial thrombosis.
In patients with juvenile dermatomyositis, MRI is useful in se- lecting a site for muscle biopsy to reduce the false-negative rate of a blind biopsy. In addition, by establishing the distribu- tion and magnitude of the inflammatory process throughout the entire body, whole-body MRI allows a more accurate as- sessment of the total inflammatory burden than that at clinical examination and can be used to assess treatment response. Another advantage of whole-body MRI is its ability to allow identification of signal intensity abnormalities in the fascia and in the subcutaneous tissue, which are often undetected at clinical assessment and are potential markers of disease sever- ity, because they are associated with a higher load of muscle inflammation. Moreover, subcutaneous changes have been indicated as potential precursors to the development of dys- trophic calcification. Another advantage of whole-body MRI is the ability to detect different patterns of muscle inflamma- tion (patchy vs diffuse). A diffuse pattern could be related to a worse prognosis.
The typical MRI findings of eosinophilic fasciitis include fascial thickening with high T2 signal intensity and enhancement. Extension into the adjacent muscle and subcutaneous tissue occurs less frequently.
The lungs are frequently affected in patients with MCTD, mainly by interstitial lung disease. CT findings of pulmonary involvement tend to be a combination of those seen in other connective tissue diseases, and a diagnosis can be achieved only by ruling out those other entities. Ground-glass opacities with septal thickening and subpleural honeycombing are the most salient CT features.
At US, normal salivary gland tissue shows homogeneous echotexture with echogenicity similar to that of the thyroid gland. In patients with Sjögren syndrome, US shows abnor- mal salivary gland architecture, with parenchymal hetero- geneity, multiple scattered hypoechoic foci, and/or multiple cystlike changes in the gland parenchyma (known as benign lymphoepithelial cysts).
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vial sheath of the tendon and thickening of the synovium. Synovial proliferation in SLE is less prominent than that in juvenile idiopathic arthritis (Fig 2) (8). Enthesitis also has been described, most commonly at the distal inser- tion of the patellar tendon (11). US findings include a hypoechoic thickened tendon at its bony attachment with a loss of normal fibrillar architecture, which may exhibit Doppler signal
sociated with distal interphalangeal hyperextension (boutonnière deformity) (9). Jaccoud arthropathy is caused by laxity of ligaments, tenosynovitis, and inflammation of the joint capsule with subsequent fibrotic retraction (10). The joint space is gener- ally preserved. Tenosynovitis may accompany the arthropathy of the small joints of the hands.
If any imaging is required, US can allow detection of increased fluid within the syno-
Table 1: Main imaging Findings in juvenile SLE
Body System Findings
thrombosis Musculoskeletal Nonerosive nondeforming arthritis of small and large joints
Synovitis Tenosynovitis and enthesitis Joint effusion Soft-tissue swelling Periarticular osteopenia Jaccoud arthropathy Secondary to treatment and/or chronic illness Osteonecrosis Insufficiency fractures Septic arthritis and osteomyelitis Steroid myopathy
Neurologic Most common: white matter T2 hyperintensities Others: gray matter T2 hyperintensities, cerebral atrophy, infarcts, dural venous
thrombosis, acute hypertensive encephalopathy, and transverse myelitis Cardiovascular Most frequent: pericardial effusion
Others: myocarditis, valvular disease, and coronary artery disease Pleuropulmonary Most common: pleural effusion
Others: pneumonia, pulmonary hemorrhage, lupus pneumonitis, cryptogenic orga- nizing pneumonia, shrinking lung syndrome, and pulmonary embolism
Multisystem: antiphospho- lipid syndrome
Abdominal Most serious complication: bowel ischemia Others: hepatosplenomegaly, acute cholecystitis, and pancreatitis
Figure 1. Lupus nephritis in a 15-year-old girl. Longitudinal (a) and transverse (b) US images show renal enlargement with increased echogenicity of the parenchyma and decreased corticomedullary differentiation.
232 january-February 2019 radiographics.rsna.org
and bony changes including enthesophytes, erosions, or irregularity. MRI findings include thickening and abnormal signal intensity in tendons and ligaments, edema of perienthesal soft tissues, bone marrow edema, erosions and enthesophytes in adjacent osseous structures, and adjacent joint or bursal fluid (12) (Fig 3).
Children with SLE are at risk for developing osteonecrosis in weight-bearing bones, mainly in the femoral heads and tibial plateaus, especially if they have a previous history of long-standing corticotherapy. Other musculoskeletal findings include steroid myopathy, septic arthritis and osteomyelitis, and insufficiency fractures.
Juvenile SLE often is associated with a variety of neuropsychiatric manifestations, headache being the most common concern. MRI is the technique of choice for the workup of neuropsy- chiatric disease, although the results might be normal in 54%–59% of cases (13,14). White mat- ter hyperintensities on T2-weighted images are the most commonly observed abnormality. Other findings include gray matter T2 hyperintensities, cerebral atrophy, transverse myelitis, dural venous sinus thrombosis, and infarcts (Fig 4) (13).
In practice, in a young patient who has expe- rienced a stroke, the diagnosis of SLE should be considered (7). In addition, in children, intra- cranial hemorrhage in the absence of trauma or coagulopathy should also suggest the possibility of SLE (7). Posterior reversible encephalopathy syndrome also has been described, likely as a result of endothelial damage, hypertension, and cytotoxic medications (15).
Heart disease in children with SLE has a prevalence of approximately 32%–42% (16) and is often silent. Pericardial effusion is the most common finding (17). Echocardiography is the
initial imaging modality for diagnosis. If further imaging is required, cardiac MRI or angiocardi- ography may be helpful.
Pleuropulmonary involvement in SLE has been reported to occur in 5%–67% of pediat- ric patients (18). The most frequent radiologic manifestation is pleural effusion. Pneumonia, pulmonary hemorrhage, lupus pneumonitis, and cryptogenic organizing pneumonia are acute conditions that may produce regions of airspace consolidation at radiography or CT (Fig 5). Pulmonary hemorrhage often appears as areas of ground-glass opacity, which, when superim-
Figure 2. Arthritis of the elbow in a 14-year-old girl with juvenile SLE who presented with pain and decreased extension of the right elbow. Sagittal (a) and axial (b) contrast material–enhanced fat-sup- pressed T1-weighted MR images of the right elbow show mild active synovitis (arrow) and bone marrow enhancement (arrowhead in b).
Figure 3. Juvenile SLE in a 16-year-old boy with left hip pain. Coronal short tau inversion-recovery (STIR) MR image of the hips shows increased signal intensity adjacent to the left greater trochanter (arrow) and to the left ischial tuberosity (ar- rowhead), in keeping with left gluteal and left hamstring en- thesopathy, respectively.
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ized by a progressive decrease in lung volume that usually is identified on chest radiographs as a progressive elevation of the diaphragm. It is secondary to recurrent inflammation or fibrosis and weakened diaphragm and chest wall muscles. Pulmonary embolism also has been reported in patients with juvenile SLE (19,20).
Antiphospholipid syndrome is an autoimmune multisystem disorder characterized by arterial, venous, or small-vessel thromboembolic events and/or pregnancy morbidity with persistent an- tiphospholipid antibodies (21). It can manifest as a primary disease or with an underlying systemic autoimmune disease, particularly SLE. Thromboses
Figure 4. Juvenile SLE in an 11-year-old girl with visual and auditory hallucinations and changes in behavior. (a, b) Axial fluid-attenuated inversion-recovery (FLAIR) MR images show hyperintense foci in the periventricular and deep white matter and in the basal ganglia (arrows), which is in keeping with multiple ischemic insults. (c, d) Axial diffusion-weighted MR image (b = 1000) (c) and apparent diffusion coefficient map (d) show diffusion restriction of the FLAIR hyperintense focus at the right putamen (arrowhead), which is consistent with a recent infarction.
Figure 5. Juvenile SLE and antiphospholipid syndrome in a 14-year-old boy with swelling of the right lower extremity, ane- mia, and fever for 15 days. Frontal radiograph of the chest shows retrocardiac airspace opacities (arrow), left pleural effusion (arrow- head), and an enlarged cardiomediastinal silhouette due to peri- cardial effusion, as proven on the basis of a subsequent echocar- diogram (not shown).
posed on interlobular septal thickening, form the so-called “crazy-paving” pattern. Shrinking lung syndrome is a complication of SLE character-
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juvenile Dermatomyositis JDM is the most frequent inflammatory myopa- thy in children. It usually affects skeletal muscle and skin but also can affect the respiratory, cardiac, and gastrointestinal systems. Mucocu- taneous abnormalities are often pathognomonic of the disease when the patient presents, the most typical being heliotrope discoloration of the upper eyelids and Gottron papules. Cutaneous vasculopathy, generalized lipodystrophy, meta- bolic abnormalities, hematologic manifestations including macrophage activation syndrome (Fig 7), and osteoporosis also may be encountered.
Although the diagnosis is made according to criteria described by Bohan and Peter (25,26), the presence of the characteristic heliotrope rash and Gottron papules is usually enough to suggest it. Tests such as electromyography,
Figure 6. Antiphospholipid syndrome in a 16-year-old boy with juvenile SLE. (a) Axial contrast-enhanced CT image of the chest (soft-tissue window) shows bilateral pulmonary embolisms (arrows). (b) Axial contrast-enhanced CT image of the chest (lung window) shows secondary lung infarctions (arrowheads). (c) Coronal contrast-enhanced CT image of the abdomen shows nonoc- clusive thrombosis of the inferior vena cava (arrow).
are the hallmarks of antiphospholipid syndrome. The deep veins of the lower extremities are the most common sites of venous thrombosis, and the cerebral vasculature is the most common site for arterial thrombosis. Infarcts and hyperintense T2 white matter foci are the most common brain CT and MRI abnormalities found, respectively (22). Dural sinus thrombosis also has been noted in these patients (23). Abdominal thrombotic and ischemic manifestations include visceral infarc- tion, which is diagnosed according to the pres- ence of wedge-shaped nonenhancing capsular- based and sharply defined lesions in the liver, kidneys, or spleen, and intestinal ischemia, which is diagnosed according to the presence of abnor- mal bowel wall thickening and enhancement, as- sociated hemorrhage, or pneumatosis. Pulmonary embolism is the main pulmonary finding (Fig 6).
Gastrointestinal manifestations occur in approx- imately 20% of children with SLE and may involve any segment of the gastrointestinal tract. Com- pared with adults, children more often have lupus- related causes of abdominal disease. The most seri- ous gastrointestinal complication is bowel ischemia caused by mesenteric vasculitis. Abdominal CT may show bowel wall thickening, abnormal wall enhancement, mesenteric edema, vascular engorge- ment, intestinal pseudo-obstruction, irregularities in the mesenteric arteries, and ascites (24). Acute cholecystitis, when due to primary SLE involve- ment, usually is not related to gallstones but rather to periarterial fibrosis and acute vasculitis. Pancre- atitis may be due to vasculitis, ischemia of small pancreatic vessels, immune complex deposition, or a combination of these entities. The US and CT features of acute pancreatitis include peripancre- atic edema, phlegmon formation, peripancreatic fatty infiltration, indistinctness of the pancreatic margins, and glandular enlargement (7).
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MRI, or muscle biopsy may be useful to con- firm the diagnosis.
In patients with juvenile dermatomyositis, MRI is useful in selecting a site for muscle biopsy to re- duce the false-negative rate of a blind biopsy (27). In addition, by establishing the distribution and magnitude of the inflammatory process through- out the entire body, whole-body MRI allows a more accurate assessment of the total inflamma- tory burden than that at clinical examination and can be used to assess treatment response (Fig 8). Another advantage of whole-body MRI is its ability to allow identification of signal intensity abnormalities in the fascia and in the subcutane- ous tissue, which are often undetected at clinical
assessment and are potential markers of disease severity, because they are associated with a higher load of muscle inflammation. Moreover, subcu- taneous changes have been indicated as potential precursors to the development of dystrophic cal- cification (28). Another advantage of whole-body MRI is the ability to detect different patterns of muscle inflammation (patchy vs diffuse). A diffuse pattern could be related to a worse prognosis (29).
JDM is widely distributed throughout the world and shows no predilection for race in children. It has an incidence of 1.9 cases per 1 000 000 children younger than 16 years (30), a median age at onset of 7 years, and a female-to- male ratio of 2.2:1 (31).
Figure 7. JDM, macrophage activation syndrome, and pharmacologic immunosuppression in a 15-year-old girl. (a) Axial T2- weighted MR image shows cortical and subcortical high-signal-intensity abnormalities with a posterior predominance (arrows). There also are increases in the extra-axial space and prominence of the convexity sulci and lateral ventricles that are compatible with atro- phy. These findings are nonspecific and could be related to posterior reversible encephalopathy syndrome or small-vessel vasculitis. (b) Follow-up axial T2-weighted MR image shows interval improvement in the cortical and subcortical lesions, with persistent diffuse atrophy. (c, d) Axial contrast-enhanced abdominal CT images show a diffuse increase in pancreatic size (arrow in c) associated with a large pseudocyst (arrowhead in d), with signs of active bleeding (arrow in d) and free…
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