Interstitial Lung Disease in the Connective Tissue Diseases Danielle Antin-Ozerkis, MD a, *, Ami Rubinowitz, MD b , Janine Evans, MD c , Robert J. Homer, MD, PhD d , Richard A. Matthay, MD e The connective tissue diseases (CTDs) are a group of inflammatory, immune-mediated disorders in which a failure of self-tolerance leads to autoim- munity and subsequent tissue injury. Involvement of the respiratory system, particularly interstitial lung disease (ILD), is common and is an important contributor to morbidity and mortality. The CTDs in which ILD is most commonly observed include rheumatoid arthritis (RA), systemic sclerosis/ scleroderma (SSc), polymyositis (PM)/dermato- myositis (DM), Sjo ¨ gren syndrome, and systemic lupus erythematosus (SLE). When clinically apparent, CTD-associated inter- stitial lung disease (CTD-ILD) most often presents with the gradual onset of cough and dyspnea, although rarely it may present with fulminant respira- tory failure. ILD may be the first manifestation of systemic rheumatic disease in a previously healthy patient. Before making a diagnosis of ILD, other causes of parenchymal abnormalities, such as drug toxicity or opportunistic infection, must be ruled out. Among patients with known CTD, subclinical disease is common and raises difficult questions regarding screening, diagnosis, treatment, and the ability to tolerate planned therapies to address other systemic manifestations of disease. The radiographic findings and histopathologic appearance of ILD among the CTDs closely resembles those of the idiopathic interstitial pneu- monias. However, close examination of radio- graphs and pathologic tissue may offer clues to a diagnosis of underlying CTD. The diagnosis of idiopathic ILD should never be made without a careful clinical search for evidence of CTD, and long-term follow-up of patients with idiopathic disease should include repeated rheumatologic evaluation as new symptoms evolve. Few controlled trials address primary therapy for the lung disease, although corticosteroids and immunosuppressive agents are often used. Res- ponse to therapy and prognosis varies with the underlying CTD as well as with the histopathologic pattern, although further study on these issues is needed because data are limited. a Yale Interstitial Lung Disease Program, Pulmonary & Critical Care Medicine Section, Department of Internal Medicine, Yale University School of Medicine, 15 York Street, LLCI 101B, New Haven, CT 06510, USA b Department of Diagnostic Radiology, Yale University School of Medicine, PO Box 208042, Tompkin’s East 2, New Haven, CT 06520-8042, USA c Rheumatology Section, Department of Internal Medicine, Yale University School of Medicine, PO Box 208031, 300 Cedar Street, TAC S-425D, New Haven, CT 06520-8031, USA d Yale University School of Medicine, PO Box 208023, 310 Cedar Street, LH 108, New Haven, CT 06520-8023, USA e Pulmonary & Critical Care Medicine Section, Department of Internal Medicine, Yale University School of Medicine, PO Box 208057, 300 Cedar Street, New Haven, CT 06520-8057, USA * Corresponding author. E-mail address: [email protected]KEYWORDS Connective tissue Interstitial lung disease Inflammation Immunity Clin Chest Med 33 (2012) 123–149 doi:10.1016/j.ccm.2012.01.004 0272-5231/12/$ – see front matter Ó 2012 Elsevier Inc. All rights reserved. chestmed.theclinics.com
Transcript
Interstit ial LungDisease in theConnective TissueDiseases
Danielle Antin-Ozerkis, MDa,*, Ami Rubinowitz, MDb,Janine Evans, MDc, Robert J. Homer, MD, PhDd,Richard A. Matthay, MDe
The connective tissue diseases (CTDs) are a groupof inflammatory, immune-mediated disorders inwhich a failure of self-tolerance leads to autoim-munity and subsequent tissue injury. Involvementof the respiratory system, particularly interstitiallung disease (ILD), is common and is an importantcontributor to morbidity and mortality. The CTDsin which ILD is most commonly observed includerheumatoid arthritis (RA), systemic sclerosis/scleroderma (SSc), polymyositis (PM)/dermato-myositis (DM), Sjogren syndrome, and systemiclupus erythematosus (SLE).
When clinically apparent, CTD-associated inter-stitial lung disease (CTD-ILD) most often presentswith the gradual onset of cough and dyspnea,although rarely itmay presentwith fulminant respira-tory failure. ILD may be the first manifestation ofsystemic rheumatic disease in a previously healthypatient. Before making a diagnosis of ILD, othercauses of parenchymal abnormalities, such asdrug toxicity oropportunistic infection,mustbe ruledout. Among patients with known CTD, subclinical
a Yale Interstitial Lung Disease Program, Pulmonary & CrMedicine, Yale University School of Medicine, 15 York Stb Department of Diagnostic Radiology, Yale University SNew Haven, CT 06520-8042, USAc Rheumatology Section, Department of Internal MBox 208031, 300 Cedar Street, TAC S-425D, New Haven,d Yale University School of Medicine, PO Box 208023, 31USAe Pulmonary & Critical Care Medicine Section, DepartmMedicine, PO Box 208057, 300 Cedar Street, New Haven* Corresponding author.E-mail address: [email protected]
Clin Chest Med 33 (2012) 123–149doi:10.1016/j.ccm.2012.01.0040272-5231/12/$ – see front matter � 2012 Elsevier Inc. All
disease is common and raises difficult questionsregarding screening, diagnosis, treatment, and theability to tolerate planned therapies to address othersystemic manifestations of disease.
The radiographic findings and histopathologicappearance of ILD among the CTDs closelyresembles those of the idiopathic interstitial pneu-monias. However, close examination of radio-graphs and pathologic tissue may offer clues toa diagnosis of underlying CTD. The diagnosis ofidiopathic ILD should never be made withouta careful clinical search for evidence of CTD, andlong-term follow-up of patients with idiopathicdisease should include repeated rheumatologicevaluation as new symptoms evolve.
Few controlled trials address primary therapy forthe lung disease, although corticosteroids andimmunosuppressive agents are often used. Res-ponse to therapy and prognosis varies with theunderlying CTD as well as with the histopathologicpattern, although further study on these issues isneeded because data are limited.
itical Care Medicine Section, Department of Internalreet, LLCI 101B, New Haven, CT 06510, USAchool of Medicine, PO Box 208042, Tompkin’s East 2,
edicine, Yale University School of Medicine, POCT 06520-8031, USA0 Cedar Street, LH 108, New Haven, CT 06520-8023,
ent of Internal Medicine, Yale University School of, CT 06520-8057, USA
Patients with CTD-ILD are often asymptomaticearly in the disease course and symptoms areusually nonspecific. Many patients present withdyspnea on exertion, fatigue, or cough. However,CTD-ILD in an asymptomatic patient may bediscovered incidentally through radiographic ab-normalities. Once lung function is significantlyimpaired, progressive dyspnea often develops. Intime, diffusion defects lead to exertional hypox-emia. Increased dead space ventilation may alsocontribute to breathlessness. Ultimately, progres-sive fibrosis leads to increased work of breathingcaused by high static recoil of the lung.1
The diagnosis of CTD-ILD may be delayed ifpatients attribute mild dyspnea to deconditioningand age. Limited functional status in patients withsevere joint disease or significant muscle weaknessmay also contribute to delays in diagnosis. Con-versely, the early onset of cough may lead to anearlier pulmonary evaluation. Other symptoms refer-able to the respiratory system include pleuritic chestpain secondary to serositis and other pleural in-volvement, or, rarely, the development of pneumo-thorax.2,3 With advanced pulmonary fibrosis,pulmonary hypertension may develop, leading tosymptomsof cor pulmonale, suchas lower extremityedema and exertional chest discomfort or syncope.
Other Systems
In the patient with longstanding CTD, the under-lying diagnosis is usually certain. However, in thepatient with recent-onset ILD without a knownCTD diagnosis, a detailed clinical history canuncover symptoms that suggest underlying CTD.For example, careful questioning regarding skinrashes may lead to the discovery of a heliotroperash, Gottron papules, or so-called mechanic’shands in DM.4 A history of skin thickening, telangi-ectasias, or digital nail pitting may suggest SSc.5
Symptoms of acid reflux or regurgitation of food,or a history of dysphagia, may reflect underlyingesophageal dysmotility and dysfunction, as seenin SSc and PM.4,5 Musculoskeletal systemcomplaints such as joint pain, swelling, and inflam-mation, as well as morning stiffness, may lead toa diagnosis of RA.6 Swollen, tight skin on thefingers may be observed in SSc and PM, andahistory ofRaynaudphenomenon suggests under-lying SSc, mixed CTD (MCTD), SLE, or PM.5,7,8
Physical Examination
Physical examination findings are often nonspe-cific but may include bibasilar fine, dry, velcro
crackles in the patient with underlying lungfibrosis.9 Late signs of CTD-ILDmay include digitalclubbing and evidence of right heart failure.Dermatologic and musculoskeletal signs ofCTD, including skin rashes, sclerodactyly, skinthickening, mechanic’s hands, synovitis, jointdeformities, Raynaud phenomenon, and telangi-ectasias, may assist in uncovering primary ormixed diagnoses.
Serologic Testing
Serologic testing in patients with idiopathic ILDhas historically been limited to antinuclear anti-bodies (ANA) and rheumatoid factor (RF). Themost recent American Thoracic Society (ATS)guidelines on idiopathic pulmonary fibrosis citeonly weak evidence in supporting recommenda-tions to test ANA, RF, and anti–cyclic citrullinatedpeptide (anti-CCP) antibodies, but nonethelessrecommend serologic testing in most patients.10
This is recommended because it is clinicallyimportant to distinguish idiopathic from CTD-associated fibrotic lung disease. When carefulevaluation for subtle historical and physical exam-ination features is undertaken, it is estimated thatat least 15% of patients have evidence of under-lying CTD.11 Nearly one-quarter of patients inone series who presented with presumed idio-pathic interstitial pneumonia and negative ANA,but who had clinical findings of antisynthetasesyndrome, were found to have antisynthetase anti-bodies.12 Although not evidence based, somecenters that specialize in the evaluation of patientswith ILD routinely test for autoantibodies to Ro(anti-SSA) and La (anti-SSB), topoisomerase anti-bodies (anti–Scl-70), antisynthetase antibodies,antiribonucleoprotein (anti-RNP) antibodies, andanti-CCP antibodies, in addition to ANA and RF(Table 1).13
Pulmonary Function Tests
Typical pulmonary function test (PFT) abnormali-ties include restrictive physiology and diffusionimpairment, the latter often predating otherdefects.14,15 Exercise testing is an important, ifunderused, modality of testing patients with ILD,frequently unmasking exertional desaturation inthe patient with a normal resting arterial saturation.Desaturation with exercise may be predicted byabnormalities in lung function,16,17 and can be ex-plained by a combination of inadequate pulmonarycapillary recruitment with reduced time availablefor gas exchange, as well as reduced mixedvenous oxygen content caused by areas of V/Qmismatch and intrapulmonary shunt.18,19 In moreadvanced fibrosis, pulmonary vascular obliteration
Table 1Autoantibody testing in the evaluation of ILD
Autoantibody Type Association with CTD
ANA ANA May be seen in various CTDs (SLE, SSc, SS, PM/DM)Nucleolar staining suggests SSc
dsDNA Anti–dsDNA antibody Highly specific for SLE
SSA Anti-Ro antibody SLE, SS, myositis associated
SSB Anti-La antibody Common in SS, 15% in SLE
Scl-70 Anti-DNA topoisomerase 1 Common in SSc (70% prevalence); highassociation with ILD
RF RF Sensitivity 60%–80% and specificity 60%–85%for RA
CCP Anti-CCP antibody Sensitivity 68% and specificity 96% for RA
RNP Anti-U1 small nuclear RNP High titers seen in MCTD
Jo-1, EJ, PL7, PL12, OJ Anti-tRNA synthetases Seen in DM/PM/antisynthetase syndrome
leads to resting arterial hypoxemia and profoundexertional desaturation. It is crucial to identifyexertional desaturation, because the use ofsupplemental oxygen and correction of exertionalhypoxemia improves exercise endurance.20
Chest Imaging
The first suggestion of underlying ILD may arisefrom an abnormal chest radiograph, typicallyshowing basilar, peripheral reticular, or reticulo-nodular opacities.21 However, particularly in earlydisease, the chest radiograph may be normal.22
High-resolution computed tomography (HRCT) ofthe chest is more sensitive than the chest radio-graph, particularly in the evaluation of CTD-ILD.In some cases of CTD-ILD, the pattern and distri-bution of radiographic abnormalities observed onHRCT accurately predict the pathologic findings.23
Common features that may be present on HRCTinclude ground-glass opacities (hazy areas ofincreased parenchymal density that do notobscure the underlying lung markings), reticulation(a series of crisscrossing lines resulting in aweblikepattern), bronchiectasis, and micronodules.21,24,25
The abnormalities in CTD-ILD occur predomi-nantly at the periphery of the lung and are oftenassociated with architectural distortion, tractionbronchiectasis, and honeycombing. HRCT find-ings in CTD-ILD are indistinguishable from thoseof the idiopathic interstitial pneumonias.26 Theradiographic differential diagnosis most oftenincludes usual interstitial pneumonia (UIP), non-specific interstitial pneumonia (NSIP), desquama-tive interstitial pneumonia (DIP), and organizing
pneumonia (OP) (Table 2). Mixed or unclassifiablepatterns may also occur. Mosaic, heterogeneouslung attenuation caused by small airway obstruc-tion with air trapping, as seen with bronchiolitis ob-literans, can also be seen.
Among patients with idiopathic ILD, certainHRCT features predict the histopathologic findingsof UIP, which is the pathologic equivalent ofidiopathic pulmonary fibrosis (IPF).24,27 In partic-ular, the characteristic radiographic UIP patternconsists of peripheral, subpleural, basilar-predominant, reticular opacities in combinationwith basilar honeycombing, but without features,such as ground-glass opacities, thatmight suggestanother form of ILD (Fig. 1). When present, thesefeatures have been shown to confidently predictthe presence of pathologic UIP when surgicalbiopsy is obtained in idiopathic ILD.28–30 Thesame correlation between radiographic and patho-logic UIP likely occurs in patients with CTD-ILD.31
A radiographic NSIP pattern has also beendescribed, in which the ILD is lower lobe predom-inant, often sparing the immediate subpleural area,and consisting of bilateral, patchy areas of ground-glass opacity with reticulation, architecturaldistortion, and traction bronchiectasis but withoutsignificant honeycombing (Fig. 2).32–35 Correlationbetween this radiographic pattern and the histo-pathologic pattern of NSIP is not reliable.33 Somecharacteristics in the inflammatory forms of CTD-ILD may suggest underlying abnormality, such asthe peripheral, patchy alveolar opacities in OP,but the radiographic appearance in such cases isnot specific and tissue may be required for diag-nosis.36 In CTD, it is common to see multiple
Table 2Features of the common radiographic and pathologic patterns observed in CTD-ILD
Distribution on HRCT Typical Radiographic Features Typical Pathologic Features
LIP Diffuse Ground-glass opacitiesCentrilobular nodulesSeptal and bronchovascularthickening
Thin-walled cysts
Diffuse interstitial infiltrationby T lymphocytes, plasmacells, macrophages
Alveolar septal distributionLymphoid hyperplasia
Abbreviations: DAD, diffuse alveolar damage; LIP, lymphoid interstitial pneumonia.Data from American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classifica-
tion of the Idiopathic Interstitial Pneumonias. Am J Respir Crit Care Med 2002;165(2):277–304.
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radiographic patterns simultaneously. When ob-served over time, HRCT manifestations in CTD-ILD typically show progressive reticular andhoneycomb change, with occasional acute exac-erbations of disease, in which diffuse ground-glass opacities are superimposed on underlyingfibrotic lung disease.37 Progressive fibrosis onHRCT is associated with worse prognosis.38
Despite the inability to clearly predict histologythrough the use of HRCT in all cases, manypatients with CTD do not undergo surgical lungbiopsy, because histopathologic diagnosis isthought unlikely to change management. It isonly when clinical or radiographic features areatypical that biopsy is pursued.
Bronchoalveolar Lavage
Bronchoalveolar lavage (BAL) has long been advo-cated in the evaluation of CTD-ILD because it
offers a noninvasive way to sample the cellularand protein composition of the lower respiratorytract in the absence of lung biopsy. Saline isinstilled into the distal airways with the broncho-scope wedged in a subsegmental bronchus.Aliquots of fluid are then aspirated, forming theBAL fluid sample. The cellular differential in healthyadults consists predominantly of alveolar macro-phages. Other leukocytes are present in smallernumbers, usually less than 15% lymphocytes,less than 3% neutrophils, and less than 2% eosin-ophils.39 Research has focused on correlationsbetween fluid characteristics and clinical features,including the presence or absence of ILD, theseverity of ILD, progression of disease, and overallprognosis, as well as response to therapy.Although BAL fluid analysis has been performed
in all of the CTDs, it has received particular atten-tion in SSc. In particular, the presence or absenceof alveolitis has been described to reflect local
Fig. 1. A 73-year-old woman with a radiographic pattern of RA and UIP. Frontal chest radiograph (A) showsreduced lung volumes with lower lobe–predominant coarse interstitial markings compatible with pulmonaryfibrosis. High-resolution (1.25-mm thick sections) computed tomography (CT) images at the level of the midthor-ax (B) and lower thorax (C) show peripheral reticular markings with architectural distortion and small subpleuralcysts/honeycombing (arrows). The patient also has a large hiatal hernia (asterisk).
Interstitial Lung Disease 127
inflammation, in which neutrophils and eosino-phils are predominant. Despite the correlationbetween BAL alveolitis and severity of lungdisease in SSc, BAL cytology has not beenconsistently shown to correlate well with prog-nosis or response to therapy.40 Similarly, inmany of the other CTD-ILDs, BAL neutrophilia
Fig. 2. High-resolution (1.25-mm thick sections) CT images(B) in a 57-year-old woman with scleroderma who presenteeral areas of ground-glass opacity with a peripheral distribas reticular markings and traction bronchiectasis (arrowsmonia (NSIP) pattern.
seems to correlate with poorer lung function buthas not consistently proved useful for diagnosisor assessing prognosis and response totherapy.41–44 Multiple biomarkers in BAL fluidhave been proposed to give prognostic informa-tion, but no individual finding has been adequatelyreplicated in larger studies.
obtained through the midthorax (A) and lower thoraxd with cough and shortness of breath. There are bilat-ution in (A) and lower lobe predominance (B), as well), all compatible with a nonspecific interstitial pneu-
Fig. 3. NSIP. There is diffuse septal fibrosis with a mildmononuclear infiltrate, as well as mild diffuse type IIcell hypertrophy. No organizing pneumonitis or fibro-blast foci are seen. No granulomas or eosinophilicinfiltrate are present. Honeycombing is absent. Thereis a mild accumulation of alveolar macrophages in thealveoli. 20� objective.
Antin-Ozerkis et al128
The promise of BAL sampling to give clinicalinformation is likely limited by several issues. Thelargest constraint is a lack of standardization inthe performance of the procedure. Some of themany variables between operators include theamount of fluid instilled, the pressure with whichthe fluid is aspirated, the location sampled andwhether this is guided by HRCT abnormalities,which aliquots are examined and whether the firstis discarded, and the skill of the technician exam-ining the fluid.45,46 Despite published guidelines,wide variability continues to exist and likelyexplains much of the inconsistent data that haveresulted.47,48 Another major factor in the inconsis-tent interpretation of BAL fluid results is thatthere are other explanations relevant to theCTD-ILD population for alterations in BAL cellu-larity, including infection, smoking, and recurrentaspiration.46
Despite these issues, BAL is an importantadjunct in the evaluation of radiographic ab-normalities, primarily in ruling out alternativediagnoses to CTD-ILD, including eosinophiliaobserved in some drug reactions, diffuse alveolarhemorrhage, and opportunistic infection.49–51
Bronchoscopy with BAL should be considered inthe evaluation of new air space opacities in anypatient receiving immunosuppressive therapy.
Fig. 4. OP. There is florid fibromyxoid granulationtissue within alveolar ducts and a moderate lympho-plasmacytic infiltrate. No hyaline membranes,necrosis, neutrophilic or eosinophilic infiltrate, orgranulomas are seen. Established collagen fibrosis isnot present, including lack of honeycombing. 10�objective.
Pathology
The major pathologic patterns recognized in CTD-ILD are the same as those recognized by the 2002European Respiratory Society (ERS)/ATS reclassi-fication of the idiopathic interstitial pneumonias(see Table 2).52 UIP may be more common thanNSIP in RA.53 In other CTDs, particularly SSc andPM/DM, the NSIP pattern is the most commonform (Fig. 3).54,55 OP is more commonly observedin RA and PM/DM but may be present in SLE,Sjogren syndrome, and SSc (Fig. 4).23 Diffusealveolar damage (DAD), lymphoid interstitial pneu-monia (LIP), and follicular bronchiolitis are lesscommonly observed patterns, but can complicateCTD.2 Other findings, such as lymphoid hyper-plasia and plasma cell infiltration, are morecommon in CTD-ILD and, when present patholog-ically, should suggest the diagnosis if CTD has notpreviously been suspected.56 Another notablefeature of CTD-ILD is that several pathologicpatterns may be present in the same biopsyspecimen.2,57
Prognosis in the idiopathic interstitial pneumo-nias is tightly linked with histopathologic pattern.UIP (IPF) carries a poor prognosis, whereas NSIPin general carries a significantly better prog-nosis.16,30,58 Despite similar radiographic and
pathologic characteristics to the idiopathic inter-stitial pneumonias, most forms of CTD-ILD havebeen shown to carry a better prognosis than idio-pathic ILD.26,59,60 Among the CTD-ILDs, however,
Interstitial Lung Disease 129
RA may be the exception to this finding. Recentdata suggest that the course of UIP in RA-ILDmay be similar to that of IPF.61
Treatment of CTD-ILD
Immunosuppressive therapyMany forms of CTD-ILD show responsivenessto immunosuppression. The decision to initiateimmunosuppressive therapy should include anassessment of the likelihood of response as wellas the risks and side effects of the medications.Corticosteroids have many potential toxicities,including glucose intolerance, bone loss, cataractdevelopment, delirium, and mood instability.62
Underlying clinical characteristics, such as thepatient’s age and comorbidities (diabetes mellitus,osteoporosis, psychiatric disease) should bestrongly considered. Frequently in CTD-ILD,a more prolonged course of therapy is warrantedand the early addition of steroid-sparing medica-tions can allow for lower doses of corticosteroids.Severity of disease, or particular CTD (such asSSc), may dictate the use of cytotoxic agentssuch as cyclophosphamide. These medicationsshould only be prescribed by physicians familiarwith their use and potential toxicities. Measuresof objective improvement, including PFTs, exer-cise oximetry, and radiographic studies shouldbe used; this is particularly true with the useof corticosteroids, which lead to an increasein energy level and mood, making subjectivemeasures of patient assessment problematic.When patients either show progression despiteongoing therapy or show no improvement in therate of decline in lung function after 6 months oftherapy, discontinuation should be considered toavoid toxicity without the likelihood of benefit.
Supportive therapyMeasures intended to improve quality of life anddecrease respiratory symptoms should be consid-ered in all patients with CTD-ILD. Pulse oximetrytesting can uncover resting and exertional hypox-emia. Even simple ambulation in the hallway canunmask exertional desaturation and the need forsupplemental oxygen. The use of oxygen in theILD population has not been studied in controlledtrials in ILD, but is recommended to maintain satu-rations greater than 90% at rest or with exercise.63
Similarly, nocturnal oxygen is used, based on datashowing the negative impact nocturnal hypoxemiahas on quality of life.64 A wide variety of options areavailable to provide convenient, portable systems.
A large body of evidence shows that a struc-tured form of exercise such as pulmonary re-habilitation improves muscle strength andendurance in chronic obstructive pulmonary
disease (COPD).65,66 Compelling data supportingthe use of pulmonary rehabilitation in ILD arenow increasing.67–71 In addition to the benefits ofimproved exercise tolerance, patients with ILDmay also benefit from education regarding oxygenuse, breathing and pacing techniques, and socialsupport.65 Pulmonary rehabilitation can assistin the identification of anxiety and depression,a common problem for patients with chroniclung disease.72
Treatment of comorbiditiesPatients with CTD-ILD frequently have comorbidconditions that need to be addressed concomitantwith the ILD. Particularly in dyspneic patients,investigations for the presence of ischemic heartdisease shouldbeundertaken in patientswith othercardiovascular risk factors. The risk for ischemicheart disease is increased among patients withILD, and patients with SLE and RA are at risk forpremature atherosclerosis.73–75 Patients shouldalso be counseled regarding smoking cessation.In particular, patients with some forms of pulmo-nary fibrosis have an increased risk of developinglung cancer, and CTD itself may carry some riskfor malignancy.63,76,77 The prevalence of obstruc-tive sleep apnea may be high among patients withILD, even in the absence of excessive sleepinessor obesity, and polysomnography should beconsidered.78–80 Patients with ILD may be atincreased risk for development of thromboembolicdisease, and particularly patients with CTD such asSLE should have new complaints of leg swelling orshortness of breath evaluatedwith this inmind.81,82
There is a high prevalence of gastroesophagealreflux disease (GERD), often asymptomatic,among patients with IPF.83,84 Some data suggestthat GERD may be linked to the development ofIPF and is correlated with worsening of disease.85
Close ties between SSc lung disease and GERDare also suspected and many forms of CTD maybe strongly associated with GERD.86,87 The ques-tion of when to seek evidence of and to treatasymptomatic GERD is less clear.63
Pulmonary hypertension develops in a signifi-cant proportion of patients with ILD, often causedby the effects of chronic hypoxia and the destruc-tion of capillaries by the fibrotic process.88 In addi-tion, pulmonary arterial hypertension (PAH) maycomplicate several of the CTDs, particularlyscleroderma, MCTD, SLE, PM/DM, and morerarely RA.89 Pulmonary hypertension contributesto diffusion impairment and symptoms. Right heartcatheterization may be needed to further charac-terize the nature of the pulmonary hypertension,as well as to assess for any role of left heartdysfunction.88,90 Therapy for the combination of
Box 12010 ACR/EULAR criteria for the diagnosisof RA
1. Presence of synovitis in at least 1 joint
2. Absence of an alternative diagnosis toexplain the synovitis
3. Score of at least 6 out of 10 from table givenlater
4. Evidence of longstanding or inactive diseasewith previous fulfillment of criteria
1. Joints2–10 large joints (shoulder,elbow, hip, knee, ankle)
1 point
1–3 small joints 2 points4–10 small joints 3 pointsMore than 10 joints (at least1 small joint)
5 points
2. SerologyLow positive RF or anti-CCP 2 pointsHigh positive RF or anti-CCP 3 points
3. Acute phase reactantsIncreased CRP or ESR 1 point
4. Duration of symptoms
Antin-Ozerkis et al130
ILD and pulmonary hypertension is controversialbut may be considered.91,92
Lung transplantationLung transplantation should be considered forpatients with advanced, progressive CTD-ILD.Data suggest that carefully selected patients withCTD may have equivalent survival to other patientsundergoing lung transplantation, particularly ifesophageal dysfunction is addressed.93–95 TheLung Allocation Score (LAS) tends to prioritizepatients with advanced ILD.96 Decisions regardingwhether and when to list are difficult in CTD-ILD,because the rate of progression is difficult topredict, and a sudden, unanticipated exacerbationof disease may occur.97 In the idiopathic interstitiallung diseases, fibrotic lung disease with a severelyimpaired diffusion capacity (DLCO) (<39% pre-dicted) predicts poor survival because of the under-lying disease and this measure is often used toprompt evaluation for listing.98 Lung transplantationrequires the emotional and physical ability totolerate a complexmedical regimenof immunosup-pressive therapy.99
Adapted from Aletaha D, Neogi T, Silman AJ, et al.2010 Rheumatoid arthritis classification criteria: anAmerican College of Rheumatology/European LeagueAgainst Rheumatism collaborative initiative. ArthritisRheum 2010;62(9):2574.
RA
RA is a chronic inflammatory disease affecting thesynovial lined joints and symmetrically involves thesmall joints of the hands and feet.6 The diagnosisof RA has typically been made with the use ofcriteria proposed by the American RheumatismAssociation in 1987.6 However, the use of newermolecular markers such as anti-CCP antibodieshas led to earlier diagnosis, reflected in the criteriaproposed in 2010 by the American College ofRheumatology (ACR) and European LeagueAgainst Rheumatism (EULAR) (Box 1).100,101 RAoccurs most commonly in women between theages of 35 and 50 years, although men are alsoaffected.102,103
Pulmonary disease is amajor source of morbidityand mortality in RA, manifesting most commonlyas ILD, obstructive airways disease, rheumatoidnodules, and pleural involvement.102 RA-associ-ated ILD (RA-ILD) is often diagnosed in the settingof longstanding RA, but may present before or atthe same time as arthritis and other rheumatologiccomplaints.104 In general, RA-ILD tends to beslowly progressive; however, some patients mayexperience periods of sudden deterioration andapproximately 10% of patients die of progressiverespiratory failure.37,105,106 Hospitalization fora respiratory cause predicts high mortality overthe subsequent 5 years.107 Risk factors for thedevelopment of RA-ILD include older age, malesex, and a history of cigarette smoking.108
Early reports prompted increased awareness ofILD in RA.109–112 Estimates of its prevalence vary,largely because of variations in the sensitivity ofthe modalities used. For example, ILD identifiedby chest radiograph alone in patients with RAwas present in fewer than 5% of patients.22
Studies using PFTs identified ILD in 33% to 41%of patients with RA and HRCT identified abnormal-ities in 20% to 63%, which has been confirmed byautopsy studies.14,15,105,106,113–115 Retrospectivepopulation-based studies have estimated a lowerrate of clinically significant ILD among patientswith RA (6.3%–9.4%).116,117 Although it is possiblethat HRCT and PFT identify abnormalities withoutclinical significance, it is also likely that significantILD is underrecognized in this population.
Clinical Features
Generally, ILD occurs in patients with well-established RA.118 However, up to 20% of patientshave onset of ILD before the diagnosis of RA.108
Patients with idiopathic ILD are often found tohave RA-related autoantibodies such as RF and
Interstitial Lung Disease 131
anti-CCP but no articular findings of RA; somemayeventually develop clinical RA.119 The delaybetween presentation of lung disease and subse-quent joint symptoms can be as long as 6years.108,120
RA-ILD typically presents with progressivedyspnea, although cough and pleuritic chest painmay occur.3 Physical examination findings areoften nonspecific and may include bibasilar fine,dry, velcro crackles. Digital clubbing and evidenceof right heart failure are late signs of RA-ILD.
Like other forms of CTD-ILD, PFTs in RA-ILDtypically show restrictive physiology and diffusionimpairment. A defect in DLCO is often the earliestPFT finding in RA-ILD.14,15 Exertional arterialoxygen desaturation may be present despitenormal resting saturations and is predicted byabnormalities in lung function.16,17
Radiographic Features
The most common features on HRCT in RA-ILDare glass opacities, reticulation, bronchiectasis(Fig. 5), and micronodules.21,24,25 In particular,the findings in RA-ILD have been grouped into 4main patterns: a UIP pattern consisting of bibasilarsubpleural reticulations and honeycombing; anNSIP pattern consisting of predominantly lowerlobe reticulation and ground-glass opacities;a bronchiolitis pattern showing centrilobular mi-cronodules and bronchiectasis or bronchiolecta-sis; and an OP pattern consisting of largelyperipheral airspace consolidation and ground-glass opacities.24 Based on several small studies,it is likely that the radiographic UIP pattern inRA-ILD predicts a pathologic finding of UIP.31,53
It is not clear that the radiographic NSIP patternsimilarly predicts its pathologic correlate.33,121
Patients with a ground-glass–predominant patternmay have a better prognosis than those with
Fig. 5. A 56-year-old woman with RA and bronchiec-tasis. High-resolution (1.25-mm thick sections) CTimage through the lower thorax shows mild, cylin-drical bronchiectasis (arrows) in both lower lobes.
well-established fibrosis.37 On serial HRCT, RA-ILD may manifest radiographically with acuteexacerbations of disease characterized by theonset of diffuse ground-glass opacities, or withprogressive reticulation, traction bronchiectasis,and honeycombing.37 Care should be taken withthe interpretation of ground-glass opacities whenpresent in a mosaic pattern. High-resolution inspi-ratory and expiratory images are needed to distin-guish ground-glass opacities from small airwaysobstruction, in which the denser areas reflectnormal lung adjacent to radiolucent areas of airtrapping. This finding is observed in RA-associated bronchiolitis obliterans (Fig. 6).
Pathologic Features
In contrast with the other CTD-ILDs, the pathologyof RA-ILD shows a preponderance of UIP.53
Certain features, such as lymphoid hyperplasiaand plasma cell infiltration, as well as the presenceof more than 1 pathologic process in the samebiopsy specimen, are common in RA-ILD andshould suggest the diagnosis (Fig. 7).2,56,57
Some less common histopathologic patternsobserved in RA include OP, follicular bronchiolitis,LIP, and DAD.2 RA-ILD may not share the favor-able prognosis that some other forms of CTD-ILD seem to carry.122 Recent data suggest thatthe course of UIP in RA-ILD may be inexorableand fatal, as seen in IPF (idiopathic UIP).61
Diagnostically, the differentiation between in-fection, drug reaction, and underlying RA-ILDcan be difficult, because many of the drugsused to treat RA can cause pulmonary toxicity
Fig. 6. A 65-year-old woman with RA and progressiveshortness of breath secondary to bronchiolitis obliter-ans. High-resolution (1.25-mm sections) CT imagesperformed during expiration at the level of the mid-thorax show multifocal lucent areas of moderate tosevere air trapping. The greyer areas are normallung at expiration.
Fig. 7. Lymphoid hyperplasia. In the center of theimage, there is a lymphoid follicle with a germinalcenter. Fibroblast foci and organizing pneumonitisare not present. There is established fibrosis.Although lymphoid hyperplasia in end-stage lung isnonspecific, in areas away from end-stage lung,this finding suggests collagen vascular disease. 4�objective.
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(eg, methotrexate, leflunomide, and the TNF-ainhibitors etanercept, infliximab, and adalimumab)and can also predispose to opportunistic infec-tion.123–129 The diagnosis of RA-ILD should takeinto consideration the clinical features, the radio-graphic appearance, the pathology, and thetemporal correlation with drug initiation.130,131
Several different pathologic patterns may beconsistent with drug toxicity, including cellularinterstitial infiltrates, granulomas, tissue eosino-philia, and a DAD pattern with perivascularinflammation.123,132
Treatment
There are many unanswered questions pertainingto RA-ILD, in particular whether to treat subclinicaldisease and which therapies should be used.However, progressive lung disease is typicallytreated aggressively because response has beenreported with corticosteroids, azathioprine, cyclo-sporine, and cyclophosphamide.9,133,134 If there isno response, therapy can be discontinued to avoidtoxicity without hope of benefit. Mycophenolatemofetil (MMF)has been reported to have a benefi-cial effect on CTD-ILD and may be considered inRA-ILD.135,136 Data for the use of rituximab inRA-ILD are lacking. Some reports suggest thattumor necrosis factor a (TNF-a) inhibitors may beeffective in RA-ILD, but others report cases of
pulmonary toxicity in patients with underlyingILD.127,128,137 Lung transplant referral should beconsidered in patients with severe fibrotic lungdisease.
SYSTEMIC SCLEROSIS (SCLERODERMA)
SSc is a multisystem disorder characterized byendothelial and epithelial cell injury, fibroblast dys-regulation, and immune system abnormalities thatultimately lead to systemic inflammation, fibrosis,and vascular injury.138,139 Clinically, the diseaseis heterogeneous and may involve multiple organsystems, most commonly the respiratory system,the skin, and the digestive system. Pulmonaryinvolvement is the leading cause of morbidityand mortality among patients with SSc.140 ILD isexceptionally common among patients with SSc,historically found in 28% of patients, and with theuse of HRCT in more than 65% of all patientswith SSc and up to 93% of patients with abnormalPFT results.141,142 Clinically significant ILD is foundin at least 40% of patients, and is a major con-tributor to morbidity and mortality.143 At autopsy,most patients have microscopic evidence oflung fibrosis.144 Clinically significant ILD is morecommonly observed in diffuse SSc than in thelimited form, but all types of SSc, including SScsine scleroderma (SSc without skin involvement)may be complicated by ILD.145,146
PFTs
Early ILD in SSc is often asymptomatic and is de-tected only by PFT and HRCT abnormalities. Inparticular, the earliest sign of SSc-associated ILD(SSc-ILD) on PFT is a decrement in DLCO, whichcorrelates better than other lung function parame-ters with extent of radiographically evident ILD byHRCT.147 In particular with SSc, decrements inDLCO can reflect concomitant pulmonary vasculardisease and evaluation should be undertaken todistinguish between ILD and pulmonary arterialhypertension.148 Declines in both forced vitalcapacity (FVC) and DLCO at diagnosis correlatewell with severity of disease and with overall prog-nosis.149 In particular, an FVC less than 80% pre-dicted at diagnosis strongly predicts both theseverity of decline in FVC percent predicted overthe subsequent 5 years, as well as time to declinein DLCO less than 70% predicted.150 In addition,among patients with early SSc, FVC less than50% strongly predicts mortality.151 Most of thedeterioration in FVC seems to occur in the first 2years after diagnosis, making initial screeningand follow-up PFTs particularly important duringthat period.152 Patients with antitopoisomeraseantibodies (anti–Scl-70) may be at higher risk for
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this more rapid decline.153 Low 6-minute walkdistance correlates with functional impairment inSSc-ILD, but may not be a reliable outcomemeasure for use in clinical trials, because it canbe affected by musculoskeletal issues, includingpain, weakness, and vascular insufficiency, aswell as by concomitant PAH.154
Radiographic Features
As with all CTD-ILD, HRCT is more sensitive thanthe chest radiograph at identifying ILD in SSc aswell as in characterizing the extent of fibrosis.155
Radiographic features in SSc-ILD typically res-emble those described in NSIP, characterized bysubpleural ground-glass opacities and fine retic-ular markings with traction bronchiectasis, butlittle or no honeycombing (Fig. 8).156 The presenceof ground-glass opacities on initial computedtomography (CT) is a predictor for progression tomore advanced fibrosis, whereas an initial CTwithout ground-glass opacities predicts a lack ofprogression for most patients.157 Despite long-held presumptions that ground-glass opacitiesrepresent active alveolitis and inflammation, theirpresence may often reflect fine fibrosis and be irre-versible despite therapy in SSc-ILD.158 Intraob-server and interobserver variability has hamperedthe use of HRCT data for research and clinicalassessment; however, computer-aided modelsmay offer some improvement in reliability.159,160
Combined staging systems, incorporating simplemeasurements of radiographic lung involvementwith PFT data, may improve predictions of diseaseprogression and mortality but also require furtherstudy.161
Fig. 8. A 58-year-old woman with scleroderma andfibrotic NSIP. Axial CT image through the lower thoraxshows reticular markings, architectural distortion, andextensive traction bronchiectasis compatible withpulmonary fibrosis. A dilated distal esophagus (arrow)is also present.
Other clues to the presence of scleroderma thatcan be detected on chest CT include a dilatedesophagus and the presence of soft tissue cal-cification.162 Because esophageal dysmotility iscommon in these patients, they are also atincreased risk of aspiration pneumonia, whichcan be seen at imaging as dependent areas ofconsolidation and ground-glass opacity, as wellas small, clustered centrilobular nodules.86
Pathologic Features
The most common histopathologic pattern in SSc-ILD is NSIP, with a minority of biopsies showingUIP or end-stage fibrosis.149 Unlike the markedcontrast in survival seen between idiopathic UIP(IPF) and idiopathic NSIP, there seems to be littledifference in mortality based on histopathologicsubsets in SSc.54,149 For this reason, surgicalbiopsy is generally not obtained in SSc-ILD unlessatypical features are present. More recently,a central distribution of radiographic abnormalitieson CT has been associated with the pathologicfinding of centrilobular fibrosis and clinicalevidence of esophageal reflux in SSc.87 Thisfinding suggests that there may be a causal linkbetween subclinical aspiration and some formsof SSc-ILD. Abnormal esophageal motility,decreased lower esophageal sphincter pressure,and gastroparesis can all contribute to reflux inSSc and chronic aspiration may occur.163 Amongpatients with more severe esophageal dysfunc-tion, PFT parameters are more severely impaired,and there is an increased frequency of radiograph-ically apparent ILD.164–167 Over time, thesepatients seem to have more rapid progression oflung impairment.167 It is not clear whether thisassociation is causal for most patients or whethersimultaneous worsening of lung and gastrointes-tinal (GI) disease reflects progression of fibrosisin multiple organ systems.
Treatment
Treatment in SSc-ILD has typically been targetedat the inflammatory component of the disease,although with only modest improvement inoutcomes. Prednisone and other corticosteroidswere used in the past but, with the discovery ofa link between high-dose steroid use and sclero-derma renal crisis, this has fallen out of favor.168
Most studies of other immunosuppressive agentshave included low dose of prednisone and, forthis reason, it is often included in treatmentregimens.
Multiple small, uncontrolled trials have sug-gested a beneficial effect of cyclophosphamideon symptoms, lung function, radiographic
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abnormalities, and survival.169–171 The Sclero-derma Lung Study I was the first randomized,placebo-controlled trial to evaluate the effect oforal cyclophosphamide on lung function in SSc-ILD.172 Cyclophosphamide had a statisticallysignificant, although modest (2.53%), positiveeffect on the primary outcome of difference inFVC percent predicted at 1 year.172 Some impor-tant secondary outcomes such as dyspnea, skinthickening, and health-related quality of life werealso improved. Cyclophosphamide was associ-ated with increased short-term toxicity in thestudy, and is known to have long-term risksincluding increased risk for bladder cancer andother malignancies.173 Subset analysis has sug-gested that the group most likely to benefit fromtreatment includes those patients with moresevere restriction and fibrosis at baseline,although this remains unproven.172,174 Long-termfollow-up showed that the beneficial effects ofcyclophosphamide on lung function were lost by24 months.174 Despite the small absolute changein FVC percent predicted, it has been suggestedthat the stability of lung function attained in treatedpatients may represent the true success in SSc-ILD and that immunosuppressive therapy toprevent progression of disease may be requiredlong-term.175
Methods to diminish the toxicity of treatmentinclude alteration in the administration of cyclo-phosphamide from daily oral administration tomonthly infusions, which minimize the cumulativedose; switching from cyclophosphamide after 6 to12 months to another, less toxic agent such asazathioprine or MMF; or replacing cyclophospha-mide by initiating therapy with such agents.175–177
MMF has shown some early promising results insmall studies and further data are awaited.178,179
The Scleroderma Lung Study II, which is ongoing,is examining the role of MMF as primary therapyfor SSc-ILD compared with cyclophosphamide.Azathioprine has similarly been used when lesssevere disease is present, or when the side effectsof cyclophosphamide are prohibitive. This agentmay offer some efficacy but is not well studiedand is limited by side effects in a substantialminority of patients.180 It is more frequently usedfor maintenance after cyclophosphamide andseems to offer some usefulness in this regard.181
Other agents have been evaluated as potentialalternatives to cyclophosphamide; however, nonehas fulfilled its promise. The endothelin-1 inhibitorbosentan was proposed for its antifibrotic effectsin SSc skin and lungs, but failed to show treatmentefficacy in SSc-ILD.182 Imatinib mesylate, a tyro-sine kinase inhibitor, interferes in several profi-brotic pathways and has been proposed for use
in SSc. Uncontrolled trials suggest improvementin skin scores with modest improvement in FVCas well.183 Further study is needed to assess therole of imatinib in SSc-ILD; however, no effectwas seen in a recent study in IPF.184 Rituximab,an inhibitor of B-cell proliferation, has been shownin a small study of patientswith SSc-ILD to improveFVC andDLCO.
185 Other biologic agents and newertherapies require further study, including pirfeni-done and anti–connective tissue growth factorantibodies. Early data have supported the role ofstem cell transplantation in SSc, with improvementin ground-glass opacities on HRCT as well asFVC.186 Trials in the United States and Europeare enrolling patients to examine this high-riskstrategy more fully.187
Lung transplantation may be considered foradvanced fibrotic lung disease but has beencontroversial. SSc is considered a systemicdisease that may increase overall morbidity andmortality after transplantation. In particular,concern has been raised about the role of gastro-esophageal reflux caused by motility issues in SScthat may predispose to chronic graft dysfunction.However, among carefully selected patients, early(1-year) and late (4-year) mortality seems to besimilar to that of other groups, and patients withsevere fibrotic lung disease without concomitantadvanced GI or renal disease should be referredfor evaluation.93,95,188
IDIOPATHIC INFLAMMATORY MYOPATHIES
The idiopathic inflammatory myopathies (IIMs) areautoimmune disorders typically affecting the skel-etal muscle, leading to inflammation and proximalmuscle weakness.189,190 Systemic involvement,including inflammation of the skin, lung, joints, andGI tract may be present.191 In particular, the pres-ence of ILD has long been recognized and contrib-utes significantly to morbidity and mortality.192–194
There are several subtypes of the IIMs, all of whichmay be complicated by ILD, including PM, DM,amyopathic DM (ADM), and the antisynthetasesyndrome.Criteria for classification of the IIMs are still in
evolution. Initial diagnostic criteria proposed byBohan and Peter189,190 included the presence ofsymmetric proximal muscle weakness in combina-tion with increased serum muscle enzymes,typical electromyography and muscle biopsy find-ings, and typical rash; these criteria continue to beclinically useful. However, evolving immunohisto-chemical and pathologic features, as well as thediscovery of myositis-related autoantibodiessuch as the anti-tRNA synthetase Jo-1, have led
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to the proposal of other classification schemes,although none is universally accepted.195,196
Clinical Features
The clinical presentation of PM/DM typicallyinvolves the subacute onset of proximal musclesymptoms, which may include myalgias, musclefatigue, or frank weakness, in which patientscomplain of difficulty rising from a chair or liftingobjects. In cases of DM, skin manifestations arepresent and may include the heliotrope rash,a violaceous discoloration of the eyelids; peri-orbital edema; Gottron papules, maculopapularerythematous lesions present on the extensorsurface of the metacarpophalangeal and proximalinterphalangeal joints of the hands; the shawl sign,poikilodermatous macules on the shoulders, arms,or upper back; and mechanic’s hands, a scaly,cracked, hyperkeratotic erythema found on thelateral and palmar surfaces of hands and fingers,which has specific histopathologic features.197,198
Several pulmonary manifestations may be seenin the IIMs and are a major contributor to morbidityand mortality.199,200 Primary muscle weaknessmay lead to hypoventilation and respiratory failure,and may be complicated by pneumonia caused byweak cough and poor airway clearance.201–203
Aspiration pneumonia may occur because ofrespiratory muscle weakness but most commonlyreflects the presence of skeletal muscle dysfunc-tion in the pharynx and upper esophagus.202
Interstitial lung disease is the most commonpulmonary complication of the IIMs, although,like other CTD-ILDs, the incidence of myositis-associated ILD (MA-ILD) is greatly affected bythe mode of ascertainment, with high ratesobserved with the combined use of PFTs andHRCT. In a recent prospective study of patientswith a new diagnosis of PM or DM, many ofwhom had no respiratory symptoms, 78% ofpatients were shown to have some lung involve-ment as defined by radiographic evidence (chestradiograph or HRCT abnormalities) or restrictivephysiology and diffusion impairment on PFTs (totallung capacity and DLCO <80% predicted).204
Among a population of patients with anti–Jo-1antibodies, 86% were shown to have ILD.205
These numbers may be overestimates based onthe lack of HRCT evidence of ILD for all patients,but they do suggest that parenchymal involvementis common and should be aggressively sought.
MA-ILD may occur concomitantly with the onsetof myositis or skin rash but may precede the diag-nosis of IIM.194,206 Cases of DM with typical skinrash in association with ILD may occur withoutbiochemical evidence for muscle involvement,
and is known as ADM.207 The clinical course ofMA-ILD is variable, ranging from a total lack ofsymptoms to fulminant hypoxemic respiratoryfailure, although many patients present subacutelyand experience chronic, progressive disease.199
Dyspnea and cough are the most common symp-toms reported in MA-ILD. Almost one-third ofpatients with MA-ILD are asymptomatic, showingthe need for evaluation of these patients withPFTs and chest imaging.208 DM, and particularlyADM, may be more associated with an acute andfatal presentation, which is characterized by histo-pathologic findings of DAD, and resistance totreatment.207,209,210 The strongest predictor forthe onset of ILD in IIM is the presence of antisyn-thetase antibodies, particularly anti–Jo-1.208,211
The antisynthetase syndrome has been des-cribed to include ILD, myositis, arthritis, fever, Ray-naud phenomenon, and mechanic’s hands.212 Inmany cases, only a few features are present, and,in many, the lung manifestations may predominate.In addition to anti–Jo-1, other antisynthetase anti-bodies (such as anti-PL7, anti-PL12, anti-EJ) havebeen associated with the development of ILD withIIM.213 Particular antibodies may be more or lessstrongly associated with the development of ILDor myositis and subtypes based on antibody speci-ficity may predict clinical course.214,215 Among themyositis-associated antibodies, the presence ofanti-SSA in conjunction with anti–Jo-1 has beenassociated with more severe and progressiveILD.216,217
Pulmonary Function Testing
PFTs are important in the assessment of MA-ILDand help assess disease severity and responseto therapy. They also help to distinguish betweenthe role of MA-ILD and diaphragmatic weakness,although this may not be straightforward.218 Likeother forms of ILD, PFTs in MA-ILD show restric-tive physiology and reduced DLCO. However,respiratory muscle insufficiency is also character-ized by reductions in FVC and total lung capacityas well as reduction in other tests such as themaximum voluntary ventilation (MVV) and maximalinspiratory pressure (MIP) and expiratory pressure(MEP).203 Reductions in the DLCO may also be theresult of pulmonary hypertension, which cancoexist with ILD, or be caused by atelectasisfrom diaphragmatic weakness.218
Radiographic Features
HRCT findings are similar to those in other formsof CTD-ILD. In MA-ILD, the most common ab-normalities are ground-glass opacities, reticu-lar markings, and alveolar airspace opacities
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(Fig. 9).219 Honeycombing is less common. Theradiographic findings suggest the underlyingdisorder (ie, dense consolidation reflecting DADand OP; honeycombing reflecting UIP); however,these findings are not specific.219 Micronodules,linear opacities, and traction bronchiectasis mayalso be observed.219 Some studies have sug-gested that dense, peripheral consolidation ina pattern consistent with OP is associated witha better prognosis, whereas ground-glass opaci-ties predict a worse outcome.220,221
Pathologic Features
Surgical lung biopsy is not typically obtainedin the diagnosis of MA-ILD, and the role of patho-logic diagnosis remains controversial. In studiesreporting pathologic findings in MA-ILD, mostpatients have NSIP, with UIP and OP as the nextmost frequent possibilities, and DAD in a minorityof patients.218 Although some studies have sug-gested that DAD carries a poorer prognosis thaneither OP or cellular NSIP, it is not clear that path-ologic pattern alters treatment choice, and otherstudies have not confirmed an impact of histo-pathologic pattern on overall survival.54,194,199,222
In the setting of rapid-onset ILD, surgical biopsymay not be clinically feasible andmay lead to post-operative complications in a patient who will likelyreceive high-dose corticosteroids and otherimmunosuppressive agents.
Treatment
All treatment is empiric in MA-ILD, because nocontrolled studies exist to guide treatment deci-sions. MA-ILD seems responsive to corticoste-roids, but high doses may be required.192,223
Corticosteroids continue to be the most common
Fig. 9. A 58-year-old woman with OP secondary toPM. Axial images at the level of the lower thoraxshow peripheral, subpleural areas of consolidation,as indicated by the arrows.
and widely accepted therapy for MA-ILD.224 Inacute, life-threatening disease, pulse dose regi-mens (1 g/d) of methylprednisolone may berequired. Additional therapy is often needed inMA-ILD and may be added either for eithersteroid-sparing effect or for additional efficacy. Inparticular, some forms of MA-ILD with low creatinekinase levels may respond poorly to corticoste-roids alone and require treatment with otheragents.225 Choice of agent often depends on clini-cian familiarity as well as on the severity of illness.Azathioprine, an inhibitor of purine synthesis, is
efficacious in treating myositis in the IIMs.224 It isa commonly used agent in many CTD-ILDs andis often used in MA-ILD, although with few reportsin the literature.54,226 Cyclophosphamide is typi-cally chosen for rapidly progressive or severeMA-ILD, either via monthly intravenous pulse infu-sions or oral therapy.227 Pulse dosage between300 and 800 mg/m2 has been described toimprove MA-ILD in treatment-resistant disease.228
Methotrexate has long been used in the treatmentof myositis in the IIMs and has been used in thetreatment of MA-ILD.224 However, the knownpulmonary toxicity that may occur with this drugcan be difficult to distinguish from progressiveMA-ILD, making this agent less ideal.229 Otheragents such as cyclosporine, tacrolimus, MMF,intravenous immune globulin, and rituximab haveall been used in small numbers of patients withrefractory disease, and may be used in selectsituations.225,230–235
SJOGREN SYNDROME
Sjogren syndrome is characterized by lymphocyticinfiltration of the exocrine glands and marked B-cell hyperreactivity.236 In particular, the salivaryand lacrimal glands are affected, leading to thesicca syndrome characterized by dry eye (kerato-conjunctivitis sicca) and dry mouth (xerostomia),often accompanied by arthritis.237 When Sjogrensyndrome is seen in isolation, it is called primarySjogren syndrome. Secondary Sjogren syndromemay accompany other CTDs such as RA, SSc,SLE, and PM/DM.238 In addition to the main siccasymptoms of Sjogren syndrome, involvement ofthe stomach, pancreas, kidney, and peripheralnervous system may occur.238,239 Middle-agedwomen are most commonly affected.240 The diag-nosis depends on a combination of ocular and oralsymptoms of dryness, objective testing forxerophthalmia and xerostomia, histopathologicfeatures on minor salivary gland biopsy, andautoantibodies to Ro (anti-SSA) and/or La (anti-SSB).241
Fig. 10. A 63-year-old woman with Sjogren syndromeand lymphocytic interstitial pneumonia.Axial CT imagesthrough the upper thorax show multiple thin-walledcysts of varying sizes scattered throughout the lungs.
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Clinical Features
Like other forms of CTD-ILD, the prevalence oflung involvement in Sjogren syndrome dependson the methodology used to determine activedisease and varies between 9% and 60%.242
Although radiographic abnormalities observedon HRCT may be common, the prevalence ofclinically significant pulmonary disease was 11%in a large cohort of patients with Sjogrensyndrome.243 Many patients are asymptomaticand lung involvement is mild and only slowlyprogressive.242,244,245 Most commonly, lunginvolvement is manifested by both upper andlower airways disease, ILD, and lymphoprolifera-tive disorders. Many patients complain of a drycough (sicca cough), which is a result of xerosisof the airways caused by involvement of thesubmucosal glands.246
Symptoms of ILD most often include dyspneaand cough, with a minority complaining of chestpain and wheezing.247 Sicca symptoms arepresent in most patients.247 Inspiratory cracklesare commonly found, although wheezing mayalso be present. Clubbing is rare.247 PFTs aremost often normal in patients with Sjogrensyndrome but, among those with ILD, restrictionand diffusion abnormalities predominate.236,247,248
Care must be taken with interpretation, becauseairways obstruction is common in Sjogren syn-drome and may lead to mixed obstructive andrestrictive physiology.249
Radiographic Features
HRCT is abnormal in more than one-third of unse-lected patients with Sjogren syndrome.250 Multipleabnormalities may be observed and include find-ings of large airways disease (bronchiectasis, bron-chial wall thickening), small airways disease (airtrapping, bronchiolectasis, centrilobular nodules,and tree-in-bud opacities), and interstitial disease(ground-glass opacities, air space consolidation,interlobular septal thickening, honeycombing,cysts and micronodules).237,250,251 The presenceof thin-walled cysts suggests the diagnosis of LIP,which is a lymphoproliferative disorder commonin Sjogren syndrome (Fig. 10).252,253 LIP is consid-ered to be a steroid-responsive lung disease butmay rarely evolve into lymphoma.252,253 Findingsthat may suggest lymphoma include nonresolvingair space consolidation, nodules greater than 1cm in size, and enlarging lymph nodes.254 If thesefeatures are present, biopsy should be considered.The presence of air trapping on expiratory filmsmay be helpful in distinguishing small airwaysdisease from ILD, and may be present in theabsence of PFT abnormalities.255 In general, in
Sjogren syndrome–associated ILD (SS-ILD), HRCTfeatures, and histopathology tend to correlatewell, particularly for NSIP.247,256
Pathologic Features
Older studies of histologic pattern in Sjogrensyndrome reported LIP as the most commonILD.257 More recent studies, using the newerERS/ATS classification of ILD, describe a higherfrequency of NSIP, although with UIP, OP, andLIP also observed.247,256 Rarely, primary pulmo-nary lymphoma and amyloidosis are found.247
When CT features are typical for NSIP, biopsyneed not be pursued but, when features thatsuggest lymphoma are present, tissue samplingis advisable.
Treatment
Treatment in SS-ILD is most often initiated withcorticosteroids, although little is known about theoptimal treatment. In some milder cases of LIP,observation without therapy may be reason-able.247 In more advanced fibrotic lung disease,it is less clear that immunosuppressive therapyreverses the underlying injury, and it may exposethe patient to excessive risk without significantbenefit. In general, SS-ILD seems to be treatmentresponsive. When SS-ILD is treated, symptomscan improve rapidly, although objective treatmentresponse may occur over months and may beincomplete.247 The addition of steroid-sparingagents, such as azathioprine, may improve lungfunction but has not been rigorously studied anduse of these agents is largely anecdotal.257 Earlydata suggest that B-cell depletion with rituximab
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may play some role in the treatment of SS-ILD anddeserves further study.258,259
SLE
SLE is an immune-mediated disease that mostcommonly occurs in younger women.260 It typi-cally presents with malar, discoid, and photosensi-tivity rashes, oral ulcers, nonerosive arthritis,glomerulonephritis, and hematologic abnormali-ties.261 Autoantibodies including ANA, anti–double-stranded DNA (dsDNA), and anti-Smithare commonly detected and are part of the diag-nostic criteria.261 The most common form ofpulmonary involvement in SLE is pleuritis, butparenchymal lung disease, pulmonary vasculardisease, airways disease, and respiratory muscledysfunction may all occur.260 Diffuse parenchymallung disease in SLE may have either acute orchronic presentation.
Acute Lupus Pneumonitis
One of the less common complications of SLE isacute lupus pneumonitis, which occurs in 1%to 12% of patients and may be the present-ing feature of SLE.262 Patients present withacute onset of fever, cough, dyspnea, and hy-poxemia.262 Acute respiratory failure requiringmechanical ventilatory support may occur. Phys-ical examination may show bibasilar rales, andradiographic findings are significant for diffuseground-glass and alveolar filling patterns on chestradiograph and HRCT.In all forms of acute parenchymal lung disease in
SLE, there is significant overlap in terms of presen-tation, with similar clinical history, radiographicfindings, and progression. The most importantpiece of the clinical evaluation is to rule out infec-tion. In particular, patients with SLE are at high riskfor both bacterial and opportunistic infection. Inaddition to the common use of immunosuppres-sive medications, SLE itself is associated withinnate immune dysfunction resulting from comple-ment deficiency, immunoglobulin deficiency,defects in chemotaxis and phagocytosis, as wellas functional asplenia.263 Empiric antibiotics aretypically begun in an acutely ill patient and bron-choalveolar lavage should be performed if clini-cally feasible, particularly in the patient alreadyreceiving immunosuppressive drugs.Surgical lung biopsy is not always feasible or
warranted in acute lupus pneumonitis, but, whenperformed, is nonspecific and commonly showsDAD characterized by hyaline membranes andtype II pneumocyte proliferation and inflammation.Capillary inflammation and fibrin thrombi may be
present, and immunofluorescence studies haveshown immune complement deposition.264
Prognosis for acute lupus pneumonitis is gener-ally thought to be poor, with older studies report-ing mortalities of 50% and residual lungimpairment among the survivors.262 Newer dataare not available to assess whether alterations insupportive care have changed these outcomes.Treatment is largely anecdotal, with emphasis onempiric antibiotics accompanied by a carefulsearch for opportunistic infection, followed bycorticosteroids. High doses are used for criticallyill patients and include a 3-day pulse of methyl-prednisolone (1 g per day) followed by 1 to 2 mg/kg/d depending on clinical response. Additionalcytotoxic therapies such as cyclophosphamideand azathioprine have been reported to improvelung function, but no well-controlled studies areavailable to guide practice.265,266
Diffuse Alveolar Hemorrhage
Diffuse alveolar hemorrhage (DAH) is also rare but,when it occurs, it contributes to high mortality andmay be recurrent among survivors.267,268 The clin-ical presentation is similar to that of acute lupuspneumonitis with the abrupt onset of dyspnea,cough, and hypoxemia. Fever may be presentand hemoptysis may occur; however, at leasthalf of patients may present without thisfeature.267,269 Lupus nephritis or other active SLEinvolvement may be concomitant.An acute drop in hematocrit may suggest the
diagnosis. Radiographic findings may be initiallyunimpressive but can progress to diffuse ground-glass opacities and alveolar consolidation andcan be indistinguishable from acute lupus pneu-monitis, infectious pneumonia, or the acute respi-ratory distress syndrome (ARDS).269 BAL isa crucial diagnostic step in the evaluation of thesepatients, both for the exclusion of infection, as wellas for the diagnosis of DAH, which can be madewith the observation of progressively bloodylavage fluid and hemosiderin-laden macrophagesin the fluid. Among more clinically stable patients,DLCO measurements obtained within the first 48hours after the hemorrhage have been reportedto show an increase of 30% more than baselinevalues while the erythrocytes are still within the al-veoli.269 Surgical lung biopsies are not typicallyperformed in acutely ill patients. Histopathologicfindings in DAH most commonly show blandhemorrhage, but some cases of capillaritis withimmune complex deposition as well as smallvessel vasculitis and microangiitis have beenreported.263,268,270
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DAH may be triggered by infection and initialtreatment consists of empiric antibiotics, whichmay significantly improve survival.269 High-dosecorticosteroids are generally combined with intra-venous cyclophosphamide.267 Plasmapheresismay also improve survival.271–273 MMF has beenreported to be efficacious in maintaining remissionfrom DAH episodes.274
Chronic ILD in SLE
Chronic ILDmay be observed in SLE and has beenreported as being less common than in otherCTDs, with a reported prevalence of 3% to13%.275 However, subclinical disease is likelycommon, based on HRCT studies that estimatethe prevalence of ILD at 38% among patientswith lupus without previously diagnosed lungdisease.276 In some cases, an association isseen between ILD and anti-SSA antibodies, but itis unclear whether this is pathogenic and whethersuch findings describe an overlap with Sjogrensyndrome.277,278
Likeother formsof ILD,SLE-associated ILD (SLE-ILD) commonly presents with the insidious onset ofdyspnea and occasional nonproductive cough. ILDmaypresent acutely, as in acute lupus pneumonitis,and chronic lung disease may result from priorepisodes of lupus pneumonitis.262 ILD onset isassociated with longer disease duration, malegender, older age, as well as later onset of SLE.279
HRCT findings in SLE-ILD are similar to those ofother chronic ILD and show bibasilar-predominantreticulations and ground-glass with progression totraction bronchiectasis with some honeycombing.The most typical histopathologic patterns areNSIP, UIP, and LIP; however, surgical biopsy israrely obtained.60,280
Treatment of SLE-ILD is not standardized andthe choice to treat is an individualized decisionbased on clinical progression and radiographicfindings. In particular, the presence of ground-glass opacities might suggest a more active alve-olar inflammatory process with the possibility oftreatment responsiveness. Corticosteroids areoften used and, when chronic therapy is antici-pated, steroid-sparing agents such as azathioprineand MMF are added. MMF has been shown tohave a good safety profile in patients with CTD-ILD.135,281 Cyclophosphamide has been usedfor refractory disease.266 Rituximab has been re-ported to have controlled progressive and refrac-tory ILD in 1 case.282
SUMMARY
Lung disease is a common manifestation of theCTDs and may be a presenting feature. Subclinical
disease is common. Clinically apparent disease isoften slowly progressive but may present in anacute fashion, contributing to high morbidity andmortality. Infection and drug reaction may shareclinical features with CTD-ILD and should beconsidered when evaluating the patient with dysp-nea and abnormal radiographic findings. Treat-ment of CTD-ILD is not well studied but typicallyincludes corticosteroid therapy and immunosup-pressive agents, as well as careful supportivecare. Further study is needed for the many unan-swered questions in this field.
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