JBR–BTR, 2015, 98: 3-19.

PICTORIAL REVIEW

Thoracic involvement in connective tissue diseases: radio- logical patterns and follow-up

G. Serra1, A.-L. Brun1, P. Ialongo2, M.-L. Chabi1, P.A. Grenier1

Connective tissue diseases (CTDs) are a heterogeneous group of idiopathic inflammatory diseases involving various organs. A thoracic involvement is frequent, and chest-CT represents the imaging technique of reference in its assess- ment. Pulmonary abnormalities related to CTDs are various; although several disease-specific aspects have been described, the two most clinically relevant complications are represented by interstitial lung disease and pulmonary arterial hypertension. The early identification of a thoracic involvement, with the adoption of specific therapies, can significantly change patient’s prognosis. The aim of this article is to review the most common typical and atypical CT features of thoracic involvement occurring in CT, especially focusing on interstitial lung disease.

Key-word: Connective tissue, diseases – Lung, interstitial disease – Hypertension, pulmonary.

Connective tissue diseases (CTDs) at the time of diagnosis of CTD, or chronic inflammation in the alveolar are a heterogeneous group of in- more commonly manifest later in the walls. The patients usually response flammatory diseases derived from course of the disease (5, 6). well to corticosteroid therapy and an immunologic deregulation affect- The most common histopatholog- have a good prognosis. However pa- ing various organs. A thoracic in- ic patterns of ILD seen in the setting tients with OP associated with CTD volvement (pulmonary, pleural or of CTDs are non specific interstitial seem to have a greater tendency to mediastinal) can be frequently (NSIP), usual interstitial develop fibrosis and a higher mortal- found; its frequency and expression pneumonia (UIP), organizing pneu- ity than patients with cryptogenic depends on the type of disease, and monia (OP), OP (5, 6). The CTD, typically associ- may induce an extremely wide range (DAD), and lymphocytic interstitial ated with LIP, is SJOS; however LIP of abnormalities (1-3). pneumonia (LIP). may also occasionally be seen in SLE All CTDs can present a pulmonary NSIP is the most common histo- and RA (Table I). involvement: rheumatoid arthritis pathologic and high resolution CT Patients with CTD and chronic ILD (RA), progressive systemic sclerosis pattern of ILD seen in patients with similar to those with idiopathic ILD, (PSS), systemic lupus erythemato- CTDs, particularly PSS, PM/DM and may develop acute exacerbation. sus (SLE), polymyositis and derma- MCTD. It is characterized histologi- Such acute exacerbation is most tomyositis (PM/DM), mixed connec- cally by relatively homogeneous ex- common in chronic ILD associated tive tissue disease (MCTD), Sjögren pansion of the alveolar walls by in- with RA but may be seen in PSS, PM/ syndrome (SJOS), and relapsing flammation, fibrosis or both. UIP is DM and SJOS. Despite intensive an- polychondritis (RP). The identifica- the second most commonly pattern ti-inflammatory immunosuppressive tion of a pulmonary involvement at of chronic ILD and seen most fre- therapy, the prognosis of acute exac- its initial stage is crucial, as an early quently in patients with PSS and RA. erbation of CTD associated with ILD treatment can often improve pa- The pathologic findings of UIP con- is poor, with high mortality rate (5). tients’ prognosis. Interstitial lung sist of patchy heterogeneous pattern Occasionally, patients with CTD disease and pulmonary arterial hy- with foci of normal lung, interstitial without evidence of prior ILD may pertension, both significantly affect- inflammation, fibrosis and honey- present with acute respiratory dis- ing morbidity and mortality in these combing. Fibroblastic foci are pres- tress syndrome due to DAD (8). This patients, represent the two most ent but less extensive in CTD than in pattern may be the initial manifesta- clinically relevant thoracic manifes- idiopathic , and tion of lung involvement in these pa- tations (1, 4). this feature probably accounts for tients with rapid progression to re- the better prognosis in these pa- spiratory failure. This presentation Interstitial lung disease (ILD) tients (5, 7). has been described most commonly The most common CTD associat- in patients with SLE and PM/DM. The most common CTDs associ- ed with OP is PM/DM. OP also occurs CT is commonly used in the initial ated with ILD are RA, PSS, SLE, PM/ in increased frequency in RA and has evaluation and follow-up of patients DM, MCTD and SJOS. ILD may been described in SLE and SJOS. with CTD and clinically suspected precede ­the clinical and laboratory The histologic pattern of OP is made or proven ILD. The CT findings of manifestations of CTDs for several of intraluminal plugs of granulation chronic ILD seen in patients with months or years, and be present to- tissue within alveolar ducts and sur- CTD are similar to those seen in idio- gether with systemic manifestations rounding alveoli associated with pathic interstitial pneumonia (9). In the context of ILD occurring in a pa- tient having a CTD, CT is particularly helpful at it often shows more than From: 1. Service de Radiologie Polyvalente et Oncologique – Groupe Hospitalier ­Pitié-Salpêtrière, Charles Foix, APHP Université Pierre et Marie Curie, Paris, France et one pulmonary disease. Diagnostic 2. Service de Radiologie, Hôpital San Camillo-Forlanini, Rome, Italy. precision in CTD-ILD is challenging Address for correspondence: Pr Ph. A. Grenier, Service de Radiologie Polyvalente et because of a wide range of potential Oncologique - Groupe Hospitalier Pitié-Salpêtrière, Charles Foix, APHP, 83, Bld de simultaneous pathologies and the l’Hôpital, 75651 Paris, France. E-mail: [email protected] possibility of concurrent CTD (i.e.

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Table I. — Thoracic manifestations of connective tissue diseases. RA PSS SLE PM/DM MCTD SJOS RP UIP +++ + ++ + ++ + NSIP ++ +++ ++ ++ +++ ++ OP + + + +++ + DAD + + ++ ++ + Follicular /LIP + + + +++ Alveolar hemorrhage + + +++ + ++ ++ + Tracheobronchial WT/Stenosis +++ ++ + ++ + Obliterative bronchiolitis ++ + ++ Nodules ++ PAH + +++ + + ++ ++ + ++ Diaphragm dysfunction + ++ + UIP Usual Interstitial Pneumonia RA Rhumatoid Arthritis NSIP Non Specific Interstitial Pneumonia PSS Progressive Systemic Sclerosis OP Organizing pneumonia SLE Systemic Lupus Erythomatosus DAD Diffuse Alveolar Damage PM/DM Polymyositis/Dermatomyositis LIP Lymphocytic Interstitial Pneumonia MCTD Mixed Connective Tissue Disease WT Wall thickening SJOS Sjögren’s syndrome PAH Pulmonary Arterial Hypertension RP Relapsing Polychondritis

rheumatoid arthritis and Sjögren Pulmonary arterial hypertension sia of -associated lymphoid syndrome). In addition further pos- (PAH) tissue (BALT) with the follicles dis- sible confounders include the pres- tributed along the bronchioles. Fol- ence of smoking or drug-related ab- PAH is defined as mean resting licular bronchiolitis is part of the normalities and immunosuppression pulmonary artery pressure higher or spectrum of lymphoproliferative dis- related infection (1). Actually ILD, equal to 25 mmHg and a pulmonary ease and may be sometimes overlap particularly NSIP, OP and DAD may capillary wedge pressure lower than with LIP. Most cases of follicular also be a reaction pattern to many 15 mmHg. Patients with CTD present bronchiolitis or lymphocytic bronchi- drugs. Because most patients with a higher risk to develop PAH, with or olitis are associated with CTD, espe- CTD are treated with anti-inflam­ without the association with pulmo- cially RA, SJOS and PSS. matory or immunosuppressive med- nary interstitial involvement (1, 4). Bronchial inflammation (follicular ication, drug-induced lung disease Clinical presentation, symptoms and ) may result in bronchiec- should always be considered in the therapeutic approach are the same tasis unrelated to interstitial lung fi- differential diagnosis, or a potential of those of a primary pulmonary hy- brosis. Bronchiectasis and/or associ- cause of the lung abnormalities (10). pertension. PSS and MCTD are the ated obliterative bronchiolitis occur Patients with drug-induced pulmo- two entities more frequently associ- relatively frequently in patients with nary toxicity usually present sub- ated with PAH (12); it is less frequent RA, SJOS and SLE. acute clinical symptoms (fever, dys- in case of SLE and unusual in pa- Airway wall thickening and lumi- pnea, cough) progressing over many tients with RA and PM/DM (Table I). nal narrowing due to inflammatory weeks. The identification of a drug- The physiopathologic process ex- and fibrotic changes in cartilage are induced pulmonary involvement is plaining the development of pulmo- characteristic of RP. based on an exclusion diagnosis: nary hypertension in patients with Alveolar hemorrhage due to capil- pulmonary infection or acute exacer- CTDs has not been completely clari- laritis is a well-known complication bation of interstitial pneumonia fied yet (13). The histopathologic of SLE, and may also occur in pa- should always be taken into first con- features resemble those of a primary tients with RA, PSS, PM/DM or sideration (5). . A throm- MCTD. Because patients with CTD are boembolic origin could be suggest- Other extrapulmonary thoracic treated with steroids or other immu- ed in patients with SLE with an- abnormalities, such as esophageal nosuppressive drugs, they are at risk tiphospholipid syndrome. Screening dilatation, pleuro-pericardial effu- of and opportu- echocardiography is indicated in all sion/thickening or an osteoarticular nistic infections. The prevalence of patients affected by PSS or MCTD. involvement can suggest an underly- pneumocystis Jiroveci pneumonia In selected cases, right catheterism ing CTD. Mediastinal lymphadenop- seems to be particularly increased (gold standard) is necessary for a de- athies are another frequent finding in patients with CTD and ILD who finitive diagnosis. in this group of patients, with or are being treated with corticoste- without the association with ILD. roids (11). As a result, pneumocystis Other thoracic manifestations (3, 4) Jiroveci pneumonia should be the Rheumatoid Arthritis (RA) differential diagnosis of new exten- Follicular bronchiolitis is charac- sive ground glass opacity on CT in terized histologically by a peribron- RA is a relatively frequent disease these patients. chial lymphocytic follicular hyperpla- (1-2% of the adult population world-

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wide). Its incidence is higher in wom- en (age: 25-50 years). It is character- ized by bilateral and symmetric arthritis, morning stiffness, and the presence of rheumatoid factor. Extra-articular manifestations are observed in half of the patients and occur more frequently in men. Pul­ monary­ involvement is the second cause of death after infections. By contrast, in individuals with no symptoms of , up to half have lung parenchymal ab- normalities on CT. Cigarette smok- ing has a synergistic effect on the pulmonary manifestations of RA, and smoking is the most consistent independent predictor of ILD in RA.

Radiological manifestations of dis- ease (1, 4, 14) (probably secondary to previous effusions) represents the most frequent thoracic abnormality. Effusions are less frequent, usually unilateral, containing small amounts of liquid and often self-resolving over a period of weeks to months; in some patients they can persist over years. Rheumatoid pulmonary nodules (necrobiotic nodules) are more fre- quently observed in smokers (men > women), in association with sub- cutaneous nodules and significant blood elevation of the rheumatoid Fig. 1. — Rheumatoid nodules in a 50 y.o. female smoker factor. Rheumatoid nodules can also ­patient who have suffered from RA for many years. appear before the clinical manifesta- Axial CT images show the presence of bilateral pulmonary tions of disease and their histologi- nodules with irregular and spiculated contours predominantly cal characteristics (fibrinoid necro- distributed in the upper lung zones. Some of these nodules are sis) resemble those of the sub- cavitated. cutaneous nodules. Their diameter

Fig. 2. — Typical CT pattern of UIP in a patient with RA. Axial and coronal reformat show bilateral subpleural honeycombing in the lower lobes. Associated findings include ground-glass opacities with superimposed intralobular reticulations and traction bronchiectasis.

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Fig. 3. — CT pattern of fibrotic NSIP in a 48 y.o. female patient RA. Axial CT images and coronal reformatted slab on which minimal intensity projection was applied, show bilateral patchy areas of ground-glass opacities with superimposed intralobular reticulations and traction bronchiectasis. The abnormal areas have a pre- dominant peribronchovascular distribution.

ranges between 0.5 and 5 cm and they usually present a peripheral dis- tribution, with middle and upper pre- dominance (Fig. 1). These nodules, usually asymptomatic, can cavitate (50-100% of cases), grow in dimen- sions or spontaneously disappear over time. Rarely, a communication with the pleural surface and cavitat- ed nodules can occur, causing pneu- mothorax, pleural effusions or ­em­pyemas. Because of drug-related immunosuppression, cavitated nod- ules may become infected. Inner cal- cifications are uncommon; the pres- ence of calcifications has been associated with the Caplan-Colinet syndrome (association between rheumatoid polyarthritis and pneu- moconiosis). Fig. 4. — Follicular bronchiolitis in a patient with RA. The most common fibrotic ILD in Axial CT image showing multiple small ill-defined centrilobu- lar nodular opacities with diffuse and homogeneous distribu- RA are UIP and NSIP. Unlike other tion. CTDs, UIP is more frequent than NSIP in patients with RA.

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Fig. 5. — 47 y.o. male patient with RA who has presented with cough and chronic sputum for several years. Axial CT image showing bilateral cylindrical bronchiectasis in the lower lobes. Some foci of small centrilobular nodular and Fig. 7. — Typical appearance of fibrotic NSIP in a patient with linear branching opacities (tree-in-bud sign) are also seen in the PSS. lower lobes, reflecting chronic infectious bronchiolitis. Bilateral traction bronchiectasis superimposed to ground- glass opacities predominant in the lower lung zones. Note the sparing of the subpleural areas of lung parenchyma, and the dilatation of the esophagus due to esophageal dysmotility.

ground-glass opacities, poorly de- fined centrilobular nodules, inter­ lobular septal thickening and lung cysts. However most of the cases of LIP are associated with SJOS rather than RA. There is a strong association ­between the duration of RA and air- way disease, with obliterative bron- chiolitis and bronchiectasis frequent- ly coexisting (15) (Fig. 5). Bronchiectasis may be related to autoimmune bronchial destruction, smoking or infection (16). Oblitera- tive bronchiolitis is subclinical in many patients with RA. The charac- Fig. 6. — NSIP pattern in a 33 y.o. female patient with PSS. teristics HRCT findings consist of ar- Axial CT image showing diffuse bilateral ground-glass opaci- eas of decreased lung attenuation ties. Note the minimal bilateral peripheral reticulation and dila- and vascularity with redistribution of tion of the esophagus. blood flow to more normal lung ­resulting in a mosaic perfusion ­attenuation pattern with expiratory The characteristic CT features of distortion may be present in case of air trapping. UIP are intralobular reticulations advanced fibrosis (Fig. 3). About 20% of patients with RA ­associated with honeycombing in a Other lung diseases that may have mild PAH because of pulmo- peripheral and basal distribution ­occur in patients with RA include OP nary vasculopathy affecting the (Fig. 2). The disease tends to creep and follicular bronchiolitis. OP is smaller vessels. In patients with RA, anteriorly and subpleuraly in the usually seen in the middle or lower PAH may also occur secondary to ­upper lobes. Traction bronchiectasis zones, frequently in a peribroncho- ILD or cardiac disease. and bronchiolectasis are frequently vascular or peripheral distribution. associated. Ground-glass opacities The CT pattern of OP is made of Radiological manifestations of may be observed, but with less ex- ­bilateral areas of airspace consolida- ­complications tent than NSIP. In advanced disease, tion more or less associated with air architectural distortion and volume bronchogram and some areas of Amyloidosis can be difficult to loss are present. ground-glass opacities. identify on CT because the appear- The CT pattern of NSIP is made of CT signs of follicular bronchiolitis ances are not specific. Irregular or ground-glass opacities with underly- include centrilobular and peribron- amorphous calcifications are occa- ing distortion and fine reticulation chial nodules measuring 1 to 12 mm sionally identifiable within large which may or may not be subpleural in diameter more or less associated ­mediastinal or pulmonary amyloid and basal. Traction bronchiectasis with patchy areas of ground-glass deposits. and traction bronchiolectasis may opacities that are generally bilateral Several drugs employed in the appear in case of fibrotic NSIP, and, and diffuse in distribution (Fig. 4). medical treatment of RA can cause a loss of volume and architectural The CT characteristics of LIP include pulmonary toxicity: gold salts and

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Fig. 8. — Typical CT pattern of UIP occurring in a patient with PSS. Bibasal and subpleural honeycombing (left). Note the dilatation of pulmonary arteries reflecting pulmonary arterial hypertension (PAH) (pulmonary artery/ascending aorta diameters ratio is > to 1) (right). Dilatation of the esophagus due to esophageal dysmotility is also present.

main pulmonary manifestations are interstitial fibrosis and PAH (1). Interstitial pulmonary fibrosis re­ presents the most frequent thoracic manifestation (50% of patients) and it is associated to the presence of anti-topoisomerase antibodies (anti- Scl-70) (18). The majority of patients with pulmonary lung fibrosis and PSS have a histological pattern of NSIP rather than UIP (19). PAH represents the most frequent cause of death. It may occur in pa- tients with very restrictive lung dis- ease at pulmonary function tests and is probably secondary to the pres- ence of ILD or heart disease. Isolated PAH may occur in patients with PSS, Fig. 9. — Pulmonary infection in a patient with SLE presenting particularly those with limited form with fever, dyspnea and chest pain. (PAH occurs in 50% of patients with Post-contrast CT scan showing bilateral pleural effusion and CREST) (1). airspace consolidation with air bronchogram in the right middle, lingula, and lower lobes. Note a round area of hypoattenuation Radiological manifestations of dis- seen within the right lower lobe (arrow) corresponding to a lung ease abscess. The main CT features are those of fibrotic or non fibrotic NSIP includ- penicillamine can possibly cause ogy, characterized by three patho- ing intralobular reticulations super- DAD or obliterative bronchiolitis; also logical features: inflammation,imposed on ground-glass opacities methotrexate can frequently deter­ vascular damage and fibrosis. It is a (Fig. 6); this is potentially associated mine pulmonary damage with pneu- rare disease more frequent in wom- with traction bronchiectasis and monia (17). The most frequent CT en with a peak incidence between 45 bronchiolectasis (Fig. 7). In case of features of a drug-induced pulmo- and 64 years. Only 1% of the patients advanced fibrosis a volume loss and nary toxicity are multiple ground- with PSS present respiratory symp- architectural distortion can also be glass opacities, centrilobular nodules toms at time of diagnosis, but about observed. A subpleural sparing of and mediastinal lymphad­ e­no­pathies 60% of them will develop a pulmo- the parenchyma is often present (5, (10, 17). A complete resolution can nary involvement. 20, 21) (Fig. 7). Less frequently, foci often be achieved by the ­interruption CREST syndrome, a limited form of airspace consolidation, pulmo- of treatment and administration of of systemic sclerosis, is character- nary cysts or rare honeycombing high doses of corticosteroids. ized by five main clinical features: foci can be found (Fig. 8). calcinosis, Raynaud’s phenomenon, CT signs of PAH are primarily Progressive Systemic Sclerosis esophageal dysmotility, sclerodacty- ­given by an enlarged caliber of the (PSS) ly and telangiectasia. Lung involve- pulmonary trunk (> 29 mm), a dilata- ment occurs more frequently in the tion of the right and left pulmonary PSS is a multisystemic chronic au- diffuse forms of PSS than in limited arteries and their segmental branch- toimmune disease of unknown etiol- forms (CREST syndrome). The two es. A diameter of the pulmonary

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Fig. 10. — A 38 y.o. male patient with SLE. Axial CT images showing bilateral patchy areas of ground-glass opacity with superimposed reticulation and traction bronchiecta- sis suggesting fibrotic NSIP.

Fig. 11. — A 27 y.o female patient with SLE presenting with dyspnea. Absence of infection. A,B. Axial CT images (left) showing patchy areas of airspace consolidations associated with some areas of ground-glass opacity suggestive of OP pattern. C,D. CT scan performed 2 years later (right). In spite of corticosteroid and immuno-suppressive treatment there is persistence of ILD. Airspace consolidation was replaced by ground-glass opacities, linear opacities and small cysts suggestive of lung fibrosis.

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Fig. 12. — Airway disease occurring in a 37 y.o. female patient Fig. 13. — Diffuse pulmonary hemorrhage occurring in a with SLE. 42 y.o. male patient with SLE and antiphospholipid syndrome. Axial CT image showing bilateral cylindrical bronchiectasis in Axial CT image showing bilateral patchy areas of ground- the lower lobes, associated with obliterative bronchiolitis (de- glass opacities and airspace consolidation. creased lung attenuation and vascularity).

trunk being greater than that of the with PSS have been reported. On CT nary embolism is a consideration, adjacent ascending aorta has proven scans only non specific appearances particularly in patients who have an- to be a useful CT sign of PAH (Fig. 8). are present (widespread consolida- tiphospholipid syndrome (1). In advanced cases, a dilatation of the tion and ground-glass opacities). Lower infections right cardiac cavities and the azygos Patients with PSS show a higher are caused by both common and and hemiazygos venous systems risk of developing lung (usu- ­opportunistic pathogens because can be associated. Presence of con- ally adenocarcinoma) including non patients are frequently immuno­ trast media reflux in the inferior vena smokers. suppressed and have altered cellular cava and the hepatic veins repre- immunity. sents another relevant radiological Systemic Lupus Erythematosus The shrinking lung syndrome is sign of right heart dysfunction. Peri- (SLE) characterized by pulmonary volume cardial effusion, an indirect sign of loss causing dyspnea and pleural insufficient lymphatic and venous SLE is a systemic autoimmune pain, associated with a restrictive drainage (secondary to right heart disease more common in women in syndrome at pulmonary function high blood pressures), can be ob- reproductive age principally affect- tests (24). Respiratory muscle weak- served in severe cases, as indicator ing skin, articulations, kidneys, blood nesses, diaphragmatic neuropathy of poor prognosis. However a non cells and the nervous system. SLE and pleural inflammation might play dilated pulmonary artery does not tissular lesions derive from an im- a role in the genesis of this syndrome necessary exclude PAH. Echocar- mune-complex deposition with com- which usually shows a good re- diography is useful to screen for pul- plement activation. The presence of sponse to medical treatment with monary hypertension (12). anti-DNA and anti-smooth muscle good prognosis. An esophageal involvement is antibodies is highly specific for SLE. Acute Lupus is a rare very common in patients with PSS A thoracic involvement is observed and severe complication (mortality (97% of cases), presenting with a in a high percentage of patients (50- 50%) caused by a DAD with necrosis, ­lumen dilatation (Figs. 7, 8) and/or 100%), most frequently represented cellular infiltrations, hyaline mem- motility disorders, which can be the by and infectious branes deposition, capillary inflam- cause of inhalation pneumonia or pneumonia (22, 23). Most of the mation and hemorrhage (not always bronchiolitis. CT scan will show ­patients with SLE usually present present). It is clinically characterized ­mucus plugs, “tree-in-bud” patterns, ­minor respiratory symptoms or no by fever, dyspnea, cough, hypox- centrilobular nodules, lobular or symptoms at all. emia and pleural pain (22). perilobular airspace consolidations Pulmonary involvement is not Interstitial pneumonia is an un- and bronchiectasis (4). necessary associated with signifi- usual complication, most frequently A pleural involvement is rare, cant morbidity and may be asymp- presenting as NSIP (22); SLE-associ- seen as pleural pseudoplaques or tomatic. Pleural effusions are usually ated NSIP shows no response to diffuse pleural thickening. small, bilateral, protein-rich exu- medical treatment. Few isolated cases of DAD and dif- dates. Although pleuritic symptoms More frequent in patients with fuse alveolar hemorrhage in patients may express active lupus, pulmo- ­antiphospholipid antibodies, pulmo-

→ Fig. 14. — Severe PAH in a 28 y.o. female patient with SLE. A. Post-contrast CT scan (axial and sagittal MIP reformatted images) showing dilatation of the trunk and main branches of the pulmonary artery without any arterial thrombosis. B. Coronal reformatted CT images, targeted on the right lung, showing the presence of small ill-defined centrilobular nodular opacities (arrows).

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A

B

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A B Fig. 15. — Association of OP and NSIP in a 40 y.o. female patient with dermatomyositis. A. Bilateral subpleural and perilobar areas of airspace consolidation and ground-glass opacities. B. Follow-up CT scan performed 18 months later showing the disappearance of airspace consolidation, replaced by subtle ground- glass opacities in the periphery of the lungs.

nary embolism is a complication adenopathies, d) pleuropericardial frequent in women (40-50 y.o.). Typi- possibly leading to chronic pulmo- abnormalities and pleural irregulari- cal features are subacute onset, nary thromboembolic disease. Pul- ties. In case of diffuse alveolar hem- proximal symmetric muscle weak- monary arterial hypertension (PAH) orrhage, the CT appearances are not ness, elevated serum creatine kinase can be secondary to thrombosis, ILD, specific, made of widespread activity, and mononuclear cell infil- valvular disease, or may occasional- ground-glass opacities and airspace trates in the muscle biopsy. In addi- ly be primary and results from unex- consolidation (Fig. 13). The CT fea- tion patients with DM have charac- plained plexiform lesions in the pre- tures of diffuse alveolar hemorrhage teristics skin abnormalities. PM/DM capillary vasculature (22). may be indistinguishable from those occur isolated or in connection with Diffuse alveolar hemorrhage is a of infectious pneumonia or DAD (5). another CTD. rare and severe complication (2-5% In acute lupus pneumonitis, exten- Since the results of auto-antibod- of cases), not always presenting with sive ground-glass opacities and con- ies were available, patients with idio- hemoptysis, associated with a high fluent airspace consolidations are pathic inflammatory myopathies rate of mortality. associated with air bronchogram have been classified according to the and pleural effusion. These radiolog- clinico-serologic classification. This ical features may be indistinguish- includes pure polymyositis, pure Radiological manifestations of dis- able from other causes of bilateral dermatomyositis, overlap myositis, ease airspace consolidation that may and cancer associated myositis (26). The most common CT abnormali- complicate SLE (infection, alveolar Overlap myositis is defined as myo- ties are bilateral pleural effusion, hemorrhage, or OP). sitis with at least one clinical overlap pleural thickening, pericardial effu- In case of shrinking lung syn- feature and/or an overlap auto-anti- sion and infectious pneumonia (Fig. drome CT scans or chest radiographs body. Cancer associated myositis is 9). Infectious pneumonia can be can show unilateral or bilateral dia- defined by the presence of clinical community-acquired or phragmatic elevation with or without paraneoplastic features and without be caused by atypical germs, such as parenchymal involvement, made of an overlap auto-antibody or anti- mycobacteria, pneumocystis j., CMV, passive in the subpleural MI-2. aspergillus or nocardia. Pulmonary area along the diaphragm and asso- ILD is frequent in overlap myositis tuberculosis should always be ciated with some parenchymal and seems to be associated with the screened during high-dose cortico- bands in the lung bases (24). presence of autoantibodies tRNA steroids and immunosuppressive When PAH is present CT scan may synthetase. The antisynthetase syn- drugs administration. show small ill-defined centrilobular drome features include arthritis, ILD, Several CT abnormalities may be nodules varied in numbers and con- fever, Raynaud’s phenomenon, and observed in patients with SLE who spicuity and having no lung zone mechanic hands. ILD is particularly did not have respiratory symp- predominance (Fig. 14). These small common in the antisynthetase syn- toms (22, 23). They include a) CT nodular opacities may reflect the drome occurring up to 80%. Anti- findings of ILD, more often taking the presence of cholesterol granulomas JO-1 is the most common overlap appearance of fibrotic or non-fibrotic resulting from pulmonary hemor- autoantibody. Antibodies to other NSIP, and less frequently those of rhage (25). synthetases also exist (anti-PL-7, UIP or OP (Fig. 10, 11); b) bronchiec- anti-PL-12, anti-OJ, anti-KU) which tasis made mainly of mild dilatation, Polymyositis and dermatomyositis seem to preferentially identified indi- more or less associated with obliter- (PM/DM) viduals with amyopathic lung dis- ative bronchiolitis (decreased lung ease. Antisynthetase predicts more attenuation, decreased vascularity PM and DM are idiopathic inflam- severe ILD, and ILD progression and expiratory air trapping) (Fig. 12); matory myopathies with an autoim- is associated with acute onset (27). c) axillary and mediastinal lymph- mune pathogenesis. They are more In addition, pulmonary involvement

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in patients with antisynthetase syn- drome (anti JO1) predicts disease- modifying antirheumatic drug use (28). The main clinical manifestations of pulmonary involvement in PM/DM are represented by hypoventilation with secondary respiratory insuffi- ciency, which can be determined by respiratory muscles functional de- fects, ILD or aspiration pneumonia or diffuse bronchiolitis (caused by pha- ryngeal muscles dysfunction) (29). The presence of an interstitial in- A volvement significantly affects the morbidity and mortality of patients with PM/DM. Its onset can precede the appearance of cutaneous and muscular abnormalities in 20-50% of cases; otherwise, it can be identified at time of diagnosis or during follow- up (30). The most common patho- logic findings include NSIP and OP often occurring in combination (31). A rapidly progressive form of lung disease may occur, reflecting DAD.

Radiological manifestations of the disease The characteristic CT appearance B consists of patchy bilateral airspace consolidation which has a subpleu- Fig. 16. — Association of OP and fibrotic NSIP in a 53-yo-­ female patient with polymyositis and antisynthetase syndrome ral and/or peribronchial distribution (anti-JO1). in the majority of cases (Fig. 15). It A. Initial CT scan showing airspace consolidation with air most commonly involves the lower bronchogram made of traction bronchiectasis. lung zones to a greater degree than B. The CT scan performed after 3 years of treatment shows the the upper lung zones. This pattern disappearance of airspace consolidation replaced by ground- reflects the presence of OP (5). Poor- glass opacities with superimposed traction bronchiectasis and ly defined band-like opacities that some small lung cysts. have an arcade-like or polygonal ap- pearance (perilobular pattern) are also common. Other findings include

Fig. 17. — UIP pattern in a 57 y.o. female patient with anti-synthetase syndrome (anti-JO1). Axial and coronal CT images showing bi-basal and peripheral honeycombing associated with reticulations superimposed to ground-glass opacities, and some traction bronchiectasis.

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Fig. 18. — Fibrotic NSIP in a 58 y.o. female patient with SJOS. Axial and sagittal reformatted CT images showing reticulations with traction bronchiectasis and bronchiolectasis, distortion of thickened interlobular septa and fissures.

ground glass opacities, ill-defined ways associated with ILD. PAH is the most serious complication of peribronchiolar or centrilobular nod- usually severe, associated with a MCTD, and infection secondary to ular opacities, large nodular or mass- lower survival rate, suggesting the immunosuppression in the other fre- like area of consolidation, ring-like or specific pulmonary vascular involve- quent cause of death. crescent shaped opacities and occa- ment (30-34). Most patients with MCTD present sionally irregular linear opacities. On with one of the following clinical fea- serial evaluation under treatment, Mixed Connective Tissue Disease tures: Raynaud’s phenomenon, ar- airspace consolidation may be partly (MCTD) thralgia, arthritis, swollen hands, or fully reversible (Fig. 15) or re- sclerodactyly or acrosclerosis and placed by ground glass opacities Patients having characteristic fea- myositis. Esophageal dysmotility more or less associated with super- tures of more than one CTD, are and reflex are frequently reported. imposed intralobular reticulations, said to have an overlap syndrome Generalized lymphadenopathy is linear pattern and traction bronchi- or undifferentiated­ CTD. MCTD is a also a frequent manifestation and ectasis corresponding to NSIP that distinct­ condition characterized by secondary Sjögren syndrome is rela- becomes apparent after clarification antiribonucleoprotein­ antibody, dis- tively common. of consolidation (32, 33) (Fig. 16). ease-specific HLA profiles, and mod- Thoracic involvement is quite Honeycombing is relatively uncom- erately specific clinical features. The common. Cardiac abnormalities in- mon and reflects UIP (Fig. 17). majority of patients with MCTD do clude pericarditis, myocarditis, and In patients with acute rapidly pro- not evolve into other CTD. The ma- complete heart block. Pleural effu- gressive lung disease due to DAD, jority of patients are women with an sion is one of the most common clin- extensive consolidation and ground average age of diagnosis of 37 years. ical manifestations usually small and glass opacities are present. The main characteristics are the resolving spontaneously. When the diaphragm becomes in- presence of features of SLE, PSS, Pulmonary hemorrhage, diffuse volved, there is a bilateral hemidia- PM/DM occurring together or evolv- alveolar damage, organizing pneu- phragm elevation, reduced lung vol- ing sequentially during observation. monia, NSIP, UIP, airway disease ume and linear basal atelectasis (1, The prognosis for patients with may be seen in these patients (35). 4). MCTD is highly variable, but a severe This is consistent with the other The occurrence of PAH in antisyn- progressive disease course in un- manifestations of MCTD which have thetase syndrome is significant, al- usual. Pulmonary hypertension is features of PSS, SLE or PM/DM. A

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A B Fig. 19. — Diffuse obliterative bronchiolitis in a patient with SJOS suffering from airflow limitation. A. Inspiratory CT scan (left) showing diffuse hypoattenuation of lung parenchyma due to reduced vascularity. Presence of bron- chial wall thickening. B. Expiratory CT scan (right): absence of increased in lung attenuation at expiration compared to inspiration as normally expected. This reflects the presence of diffuse expiratory air trapping.

large proportion of patients with - SJOS is histologically character- Patients with SJOS have a higher ly MCTD appear to have steroid-re- ized by a polyclonal lymphocytic-B risk of developing a lymphomatous sponsive and reversible interstitial infiltration of several organs, most disease (most commonly B type, non lung disease. Approximately a third frequently the salivary and lacrimal Hodgkin), arising from the salivary of patients have fibrotic lung disease glands and the tracheobronchial glands with possible pulmonary or on CT (36). tree. Most of the patients present a gastric involvement. typical glandular involvement with Global prognosis for patients af- Radiological manifestations of dis- xerophthalmia and xerostomy; one fected by SJOS is relatively good; it ease (1, 4, 36) third of the patients can present ex- get worse in case of secondary forms tra-glandular manifestations. The in- or in patients developing a lympho- The abnormalities that could be volvement of the upper respiratory matous disease. described in MCTD include small tract can cause dryness and a crusty nodules (presumably reflecting lym- appearance of the nasal mucosa, phoid hyperplasia), ground-glass Radiological manifestations of dis- sometimes complicating with epi- opacities, intralobular reticulations ease (38-41) staxis, perforation or predominant in the lower lung zones. otitis media. An involvement of the CT provides substantial informa- Evidence of fibrosis is seen as intra- lower respiratory tract can cause tion regarding the panel of pulmo- lobular reticulations, architectural chronic dry cough, recurrent bron- nary involvement in SJOS. The pat- distortion and traction bronchiecta- chitis and exercise-induced dyspnea. terns include ILD (Fig. 18), airway sis. A small proportion of patients Interstitial pulmonary involve- abnormality, PAH and patterns sug- have airspace consolidation, honey- ment is common in patients with a gestive of LIP. combing, cysts and bronchiectasis. primitive form of disease, presenting Airway related abnormalities are PAH may be associated with ILD or as LIP, NSIP, UIP or OP (37). frequent and consist of bronchial be the only intrathoracic manifesta- Both types of SJOS may develop wall thickening, bronchiectasis, tree- tion, manifested as pulmonary arte- a lymphoproliferative disorder in-bud sign and mosaic attenuation rial enlargement. Small pericardial sometimes associated with amyloï- pattern with expiratory air trapping effusion and small ill-defined centri- dosis. The spectrum of lymphop­ reflecting obliterative bronchiolitis lobular nodules may be present. roliferative diseases in Sjögren (Fig. 19). syndrome­ includes follicular bron- The main CT abnormalities of LIP Sjögren’s Syndrome (SJOS) chiolitis, LIP, nodular lymphoid hy- consist of patchy or confluent bilat- perplasia, mucosa-associated lym- eral ground-glass opacity and poorly SJOS is an autoimmune disorder phoid tissue (MALT) lymphoma, and defined centrilobular nodules. Thin- characterized by dry eyes, (kerato- lymphoma (38). Follicular bronchiol- walled cysts, usually few in number conjunctivitis sicca) and dry mouth itis is the most common form of are seen in 60-80% of patients usu- (xerostomia) which particularly af- bronchiolitis occurring in patients ally associated with ground-glass fects middle age women. A primitive with SJOS; lymphocytic bronchiol- opacities, but occasionally as an iso- and a secondary form of disease itis (lymphocytic infiltration without lated finding (42) (Fig. 20). have been described: the first is an follicles) and infectious bronchiolitis The association of nodules and isolated form; the second is associ- represent the main differential diag- lung cysts should raise the diagnosis ated to other CTDs. nosis. of amyloidosis associated with LIP.

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Fig. 21. — SJOS in a 52 y.o. male patient. Axial CT images showing a focal area of airspace consolida- Fig. 20. — A 64 y.o. female patient with SJOS. tion within the left lower lobe surrounded by ground-glass CT images showing the presence of several thin-walled lung ­opacity revealing a low grade B-lymphoma. Presence of several cysts having a predominant subpleural and peribronchiolar thin-walled cysts with peribronchovascular and subpleural distribution.­ ­distribution very suggestive of LIP.

A B Fig. 22. — Airway disease in a 69 y.o. male patient who has suffered from RP from many years. A., B. Axial CT images targeted on the and main stem bronchi showing thickened and partly calcified anterior and lateral walls of the trachea and main stem bronchi (arrow heads). B. There is also a large thickening with calcifications of costal cartilages (arrows).

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A

C

Fig. 23. — Narrowing of the trachea and bronchi lumens in a 32 y.o. female patient with RP. A. Axial CT images targeted on the tracheal cross-section at the level of the aortic arch (left image). The thickening of the anterior and lateral walls of the trachea (arrow heads) increased significantly (from 23 to 41 mm) after 5 months of follow-up (right image). B. Axial CT images with lung window settings showing diffuse narrowing of the trachea and main stem bronchi lumens ­(arrows). C. Dynamic expiratory CT scan showing air trapping in the left lung due to complete collapse of the left main bronchus at ­expiration (arrow).

including the , nose, joints and tracheobronchial tree. Histologically, the acute inflammatory infiltrates B present in the cartilages and peri- chondrial tissue induces progressive dissolution and fragmentation of the cartilage followed by fibrosis. The mean age at diagnosis is the fifth decade with an almost equal sex In such cases, nodules represent Relapsing polychondritis (RP) ratio and more severe airway dis- amyloid­ deposits that may calcify. ease in female patients. About 50% Pulmonary lymphoma should be RP is a rare autoimmune disease of patients will develop laryngeal, suspected in presence of pulmonary of unknown aetiology characterized tracheal or bronchial involvement. consolidations (Fig. 21), large nod- by recurrent inflammatory episodes One third of patients have an associ- ules or pleural effusions. that affects cartilage at various sites, ated autoimmune disease, most

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commonly systemic vasculitis or RA. abnormalities, all thoracic structures vascular disease. Rheumatol Int, The prognosis of patients who have can be implied, and should always 2009, 29: 1327-1330. both systemic vasculitis and RP is be attentively assessed. Moreover, 12. Zompatori M., Leone M.B., Giannotta worse than of patients with only compared to idiopathic forms, ILD M., et al.: Pulmonary hypertension and systemic sclerosis: the role of RP (43). occurring in CTD patients may pres- high-resolution computed tomogra- The respiratory tract symptoms ent with some particular characteris- phy. Radiol Med, 2013, 118: 1360- are usually the results of laryngotra- tics of patterns, evolution over time 1372. cheal chrondritis and include hoarse- and prognosis. The role of the radi- 13. Hansell D.M. 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