Respiratory Symptoms

Patients with CTD-ILD are often asymptomatic early in the disease course, and symptoms are usually nonspecific. Many patients present with dyspnea on exertion, fatigue, or cough. However, CTD-ILD in an asymptomatic patient may be discovered incidentally through radiographic abnormalities. Once lung function is significantly impaired, progressive dyspnea often develops. Over time, diffusion defects lead to exertional hypoxemia. Increased dead space ventilation also may contribute to breathlessness. Ultimately, progressive fibrosis leads to increased work of breathing due to high static recoil of the lung.

The diagnosis of CTD-ILD may be delayed if patients attribute mild dyspnea to deconditioning and age. Limited functional status in patients with severe joint disease or significant muscle weakness may also contribute to delays in diagnosis. Conversely, the early onset of cough may lead to an earlier pulmonary evaluation. Other symptoms referable to the respiratory system include pleuritic chest pain secondary to serositis and other pleural involvement, or rarely the development of pneumothorax. With advanced pulmonary fibrosis, pulmonary hypertension may develop, leading to symptoms of cor pulmonale, such as lower extremity edema and exertional chest discomfort or syncope.

Other Review of Systems

In patients with recent-onset ILD without a known CTD diagnosis, a detailed clinical history can uncover symptoms suggestive of underlying CTD. For example, careful questioning regarding rashes may lead to the discovery of a heliotrope rash, Gottron papules, or “mechanic’s hands” in DM. A history of skin thickening, telangiectasias, or digital nail pitting may suggest SSc. Symptoms of acid reflux or regurgitation of food or a history of dysphagia may reflect underlying esophageal dysmotility and dysfunction, as seen in SSc and PM. Musculoskeletal system complaints such as joint pain, swelling, and inflammation, as well as morning stiffness, may lead to a diagnosis of RA, while muscle pain and proximal muscle weakness could indicate PM. Swollen, tight skin on the fingers may be observed in SSc and PM, and a history of Raynaud phenomenon is suggestive of underlying SSc, mixed connective tissue disease (MCTD), SLE, or PM. Any new symptoms can be suggestive, and open-ended questions may lead to a definitive diagnosis.

Physical Examination

Physical examination findings are often nonspecific but may include bibasilar fine, dry, “Velcro” crackles in patients with underlying lung fibrosis. Late signs of CTD-ILD may include digital clubbing and evidence of right-sided heart failure. Notably, dermatologic and musculoskeletal signs of CTD, including rashes, sclerodactyly, skin thickening, “mechanic’s hands,” synovitis, joint deformities, Raynaud phenomenon, and telangiectasias, may assist in uncovering primary or mixed diagnoses. Involvement of rheumatologists accustomed to nailfold capillaroscopy and detailed joint assessments may lead to the discovery of early signs of CTD.

Serologic Testing

Serologic testing in patients with idiopathic ILD has historically been limited to antinuclear antibodies (ANA) and rheumatoid factor (RF). The most recent ATS guidelines on idiopathic pulmonary fibrosis (IPF) cite only weak evidence in support of recommendations to test ANA, RF, and anticyclic citrullinated peptide (anti-CCP) antibodies, but nonetheless recommend serologic testing in the majority of patients. Distinguishing idiopathic from CTD-associated fibrotic lung disease is clinically important, particularly as new information has emerged on the treatment of IPF. In particular, immunosuppressive therapy such as with corticosteroids and azathioprine is often used in CTD-ILD but is now thought to be contraindicated in IPF patients because of increased mortality. New antifibrotic medications are indicated in the treatment of IPF but are not approved for CTD-ILD.

When careful evaluation for subtle historical and physical examination features is undertaken, it is estimated that at least 15% of patients will have evidence of underlying CTD. Nearly a quarter of patients in one series who presented with presumed idiopathic interstitial pneumonia and negative ANA, but who had clinical findings of antisynthetase syndrome, were found to have antisynthetase antibodies. Adjunct testing is often utilized in a search for systemic manifestations of CTD. Examples include the use of muscle enzymes (creatine kinase and aldolase), electromyography, magnetic resonance imaging (MRI) of the proximal skeletal muscles, and muscle biopsy in the evaluation of possible PM as well as barium esophagram and other motility testing in the search for evidence of dysmotility in SSc and MCTD. Although based on small case series, many centers that specialize in the evaluation of ILD patients routinely test for autoantibodies to Ro (anti-SSA) and La (anti-SSB), topoisomerase antibodies (anti-Scl-70), antisynthetase antibodies, antiribonucleoprotein antibodies, and anti-CCP antibodies, in addition to ANA and RF ( Table 13.1 ). Extended myositis antibody panels at some centers may include anti-MDA5 (also known as CADM-140 and associated with amyopathic dermatomyositis [ADM]), PMScl (associated with PM/SSc overlap), and Ro-52 (associated with more aggressive lung disease).

Pulmonary Function Tests

Typical pulmonary function test (PFT) abnormalities include restrictive physiology and diffusion impairment, the latter often predating other defects. Exercise testing is an important if underutilized modality of testing patients with ILD, frequently unmasking exertional desaturation in the patient with a normal resting arterial saturation. Desaturation with exercise may be predicted by abnormalities in lung function. It can be explained by a combination of inadequate pulmonary capillary recruitment with reduced time available for gas exchange, as well as reduced mixed venous oxygen content due to areas of V/Q mismatch and intrapulmonary shunt. In more advanced fibrosis, pulmonary vascular obliteration leads to resting arterial hypoxemia and profound exertional desaturation. Oxygen desaturation with activity is common among patients with ILD.

Chest Imaging

The first suggestion of underlying ILD may arise from an abnormal chest radiograph, typically demonstrating basilar, peripheral reticular, or reticulonodular opacities. However, particularly in early disease, the chest radiograph may be normal. High-resolution computed tomography (HRCT) of the chest is more sensitive than the chest radiograph, particularly in the evaluation of CTD-ILD. Other thoracic features of CTD may also suggest the underlying diagnosis, if not previously known, including pleural and pericardial effusions or thickening and esophageal dilation.

In some cases of CTD-ILD, the pattern and distribution of radiographic abnormalities observed on HRCT accurately predict the pathologic findings. Common features that may be present on HRCT include ground-glass opacities (hazy areas of increased parenchymal density that do not obscure the underlying lung markings), reticulation (a series of crisscrossing lines resulting in a weblike pattern), bronchiectasis, and centrilobular nodules. The abnormalities in chronic, fibrotic CTD-ILD occur predominantly at the periphery and the bases of the lung and are often associated with architectural distortion, traction bronchiectasis, and honeycombing. HRCT findings in CTD-ILD are indistinguishable from those of the idiopathic interstitial pneumonias. The radiographic differential diagnosis most often includes usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), desquamative interstitial pneumonia, and organizing pneumonia (OP), as well as mosaic, heterogeneous lung attenuation due to air trapping from obstructive small airways disease, as seen with bronchiolitis obliterans. Mixed or unclassifiable patterns are common and should suggest a diagnosis of CTD-ILD if not previously suspected ( Table 13.2 ).

Among patients with idiopathic ILD, certain HRCT features predict the histopathologic findings of UIP, which is the pathologic equivalent of IPF. In particular, the characteristic “radiographic UIP pattern” consists of peripheral, subpleural, basilar-predominant, reticular opacities in combination with basilar honeycombing, but without features, such as ground-glass opacities, that might suggest another form of ILD ( Fig. 13.1 ). When present, these features have been demonstrated to confidently predict the presence of pathologic UIP when surgical biopsy is obtained in idiopathic ILD. The same correlation between radiographic and pathologic UIP is assumed to occur in patients with CTD-ILD.

A 73-year-old woman with rheumatoid arthritis and usual interstitial pneumonia radiographic pattern. Frontal chest radiograph (A) demonstrates reduced lung volumes with lower lobe–predominant coarse interstitial markings compatible with pulmonary fibrosis. High-resolution (1.25- mm-thick sections) CT images at the level of the midthorax (B) and lower thorax (C) show peripheral reticular markings with architectural distortion and small subpleural cysts/honeycombing ( arrows ). The patient also has a large hiatal hernia ( asterisk ).

A “radiographic NSIP pattern” has also been described, in which the ILD is lower lobe predominant, often sparing the immediate subpleural lung and consisting of bilateral, patchy areas of ground-glass opacity with reticulation, architectural distortion, and traction bronchiectasis but without significant honeycombing ( Fig. 13.2 ). Correlation between this radiographic pattern and the histopathologic pattern of NSIP is not reliable, as biopsies will commonly show histologic patterns other than NSIP, including UIP. Some characteristics in the inflammatory forms of CTD-ILD may be suggestive of underlying pathology, such as the peripheral, patchy alveolar opacities in OP, which are sometimes peribronchovascular and migratory, but the radiographic appearance in such cases is not specific and tissue may be required for diagnosis. In CTD, it is common to see multiple radiographic patterns simultaneously. When observed over time, HRCT manifestations in CTD-ILD typically demonstrate progressive reticular and honeycomb change, with occasional acute exacerbations of disease, in which diffuse ground-glass opacities are superimposed on underlying fibrotic lung disease. Progressive fibrosis on HRCT is associated with worse prognosis. Despite the inability to clearly predict histology through the use of HRCT in all cases, many patients with CTD do not undergo surgical lung biopsy, as histopathologic diagnosis is believed unlikely to change management. Biopsy may be considered in the setting of atypical CT findings or to help with prognostication, but the decision should be individualized with an assessment of risk and benefit in each individual case.

High-resolution (1.25- mm-thick sections) CT images obtained through the midthorax (A) and lower thorax (B) in a 57-year-old woman with scleroderma who presented with cough and shortness of breath. There are bilateral areas of ground-glass opacity with a peripheral distribution (A) and lower lobe predominance (B), as well as reticular markings and traction bronchiectasis ( arrows ), all compatible with a nonspecific interstitial pneumonia pattern.

Bronchoalveolar Lavage

Bronchoalveolar lavage (BAL) has long been advocated in the evaluation of CTD-ILD because it offers a relatively noninvasive way to sample the cellular and protein composition of the lower respiratory tract in the absence of lung biopsy. Saline is instilled into the distal airways with the bronchoscope wedged in a subsegmental bronchus. Aliquots of fluid are then aspirated, forming the BAL fluid sample. The cellular differential in healthy adults consists predominantly of alveolar macrophages. Other leukocytes are present in smaller numbers, usually <15% lymphocytes, <3% neutrophils, and <2% eosinophils. Research has focused on correlations between fluid characteristics and clinical features, including the presence or absence of ILD, the severity of ILD, progression of disease, and overall prognosis, as well as response to therapy.

Although BAL fluid analysis has been performed in all of the CTDs, it has received particular attention in SSc. In particular, the presence or absence of “alveolitis” has been described to reflect local inflammation, in which neutrophils and eosinophils are predominant. Despite the correlation between BAL alveolitis and severity of lung disease in SSc, BAL cytology has not been consistently demonstrated to correlate well with prognosis or response to therapy. Similarly, in many of the other CTD-ILDs, BAL neutrophilia seems to correlate with poorer lung function but has not consistently proven useful for diagnosis or assessing prognosis and response to therapy. Multiple biomarkers in BAL fluid have been proposed to give prognostic information, but no individual finding has been adequately replicated in larger studies.

The promise of BAL sampling to give clinical information is likely limited by several issues. The largest constraint is a lack of standardization in the performance of the procedure. Some of the many variables between operators include the amount of fluid instilled, the pressure with which the fluid is aspirated, the location sampled and whether this is guided by HRCT abnormalities, which aliquots are examined and whether the first is discarded, and the skill of the technician examining the fluid. Despite published guidelines, wide variability continues to exist and likely explains much of the inconsistent data that have resulted. Another major factor in the inconsistent interpretation of BAL fluid results is that there are other explanations relevant to the CTD-ILD population for alterations in BAL cellularity, including infection, smoking, and recurrent aspiration.

Despite these issues, BAL is an important adjunct in the evaluation of radiographic abnormalities, primarily in ruling out alternative diagnoses to CTD-ILD, including eosinophilia observed in some drug reactions, diffuse alveolar hemorrhage (DAH), and opportunistic infection. Bronchoscopy with BAL should be considered in the evaluation of new airspace opacities in any patient receiving immunosuppressive therapy to exclude infection.

Pathology

The major pathologic patterns recognized in CTD-ILD are the same as those recognized by the 2002 ERS/ATS reclassification of the idiopathic interstitial pneumonias ( Table 13.2 ). UIP may be more common than NSIP in RA. In other CTDs, particularly SSc and PM/DM, the NSIP pattern is the most common form ( Fig. 13.3 ). OP is more commonly observed in RA and PM/DM but may be present in SLE, Sjögren syndrome, and SSc ( Fig. 13.4 ). Diffuse alveolar damage (DAD), lymphoid interstitial pneumonia (LIP), and follicular bronchiolitis are less commonly observed patterns, but can complicate CTD. Other findings, such as lymphoid hyperplasia and plasma cell infiltration, are more common in CTD-ILD, and when present pathologically should suggest the diagnosis if CTD has not previously been suspected. Another notable feature of CTD-ILD is that several pathologic patterns may be present in the same biopsy specimen.

Nonspecific interstitial pneumonia. There is diffuse septal fibrosis with a mild mononuclear infiltrate, as well as mild diffuse type II cell hypertrophy. No organizing pneumonitis or fibroblast foci are seen. No granulomas or eosinophilic infiltrate is present. Honeycombing is absent. There is a very mild accumulation of alveolar macrophages in the alveoli. 20× objective.

Organizing pneumonia. There is florid fibromyxoid granulation tissue within alveolar ducts and a moderate lymphoplasmacytic infiltrate. No hyaline membranes; necrosis, neutrophilic, or eosinophilic infiltrate; or granulomas are seen. Established “collagen” fibrosis is not present, including lack of honeycombing. 10× objective.

Prognosis in the idiopathic interstitial pneumonias is linked with histopathologic pattern. UIP (IPF) carries a poor prognosis, while NSIP in general carries a significantly better prognosis. Despite radiographic and pathologic characteristics similar to the idiopathic interstitial pneumonias, most forms of CTD-ILD have been demonstrated to carry a better prognosis than idiopathic ILD. Among the CTD-ILDs, however, RA may be the exception to this finding. Recent data suggest that the course of UIP in RA-ILD may be similar to that of IPF.

Treatment of Connective Tissue Disease–Associated Interstitial Lung Disease

Clinical Features

Generally, ILD occurs in patients with well-established RA. However, up to 20% of patients have onset of ILD before the diagnosis of RA. Among patients with idiopathic ILD who are found to have RA-related autoantibodies such as RF and anti-CCP but no articular findings of RA, some eventually develop clinical RA. The delay between presentation of lung disease and subsequent joint symptoms can be as long as 6 years. Similar to other forms of CTD, it is important to distinguish interstitial abnormalities related to drug toxicity or opportunistic infection before attributing the findings to RA-ILD. Often making this distinction is challenging and relies on the relationship between the time of medication exposure, response to withdrawal of the agent, and other adjunct testing, such as bronchoscopy with BAL.

RA-ILD typically presents with progressive dyspnea, although cough and pleuritic chest pain may occur. Physical examination findings are often nonspecific and may include bibasilar fine, dry, “Velcro” crackles. Digital clubbing and evidence of right-sided heart failure are late signs of RA-ILD.

PFTs in RA-ILD typically demonstrate restrictive physiology and diffusion impairment. A defect in D lco is often the earliest PFT finding in RA-ILD. Exertional arterial oxygen desaturation may be present despite normal resting saturations and is predicted by abnormalities in lung function.

Radiographic Features

The most common features on HRCT in RA-ILD are ground-glass opacities, reticulation, bronchiectasis ( Fig. 13.5 ), and micronodules. In particular, the findings in RA-ILD have been grouped into four main patterns: a UIP pattern consisting of lower lobe–predominant subpleural reticulations and honeycombing; an NSIP pattern consisting of predominantly lower lobe reticulation and ground-glass opacities; a bronchiolitis pattern demonstrating centrilobular micronodules and bronchiectasis or bronchiolectasis; and an OP pattern consisting of largely peripheral airspace consolidation and ground-glass opacities. Based on several small studies, it is likely that the radiographic UIP pattern in RA-ILD predicts a pathologic finding of UIP The presence of a radiographic UIP pattern seems to predict increased mortality. It is not clear that the radiographic NSIP pattern is similarly predictive of its pathologic correlate. Patients with a ground-glass–predominant pattern may have a better prognosis than those with well-established fibrosis. On serial HRCT, RA-ILD may manifest radiographically with acute exacerbations of disease characterized by the onset of diffuse ground-glass opacities, or with progressive reticulation, traction bronchiectasis, and honeycombing. Care should be taken with the interpretation of ground-glass opacities when a mosaic pattern is present. Inspiratory and expiratory high-resolution images are useful to help distinguish ground-glass opacities from mosaic lung attenuation due to small airways obstruction, in which the denser areas reflect normal lung adjacent to radiolucent areas of air trapping. This finding is observed in RA-associated bronchiolitis obliterans ( Fig. 13.6 ).

56-year-old woman with rheumatoid arthritis and bronchiectasis. High-resolution (1.25- mm-thick sections) CT image through the lower thorax demonstrates mild, cylindrical bronchiectasis ( arrows ) in both lower lobes.

65-year-old woman with rheumatoid arthritis and progressive shortness of breath secondary to bronchiolitis obliterans. High-resolution (1.25- mm sections) CT images performed during expiration at the level of the upper thorax (A) and midthorax (B) demonstrate multifocal lucent areas of moderate to severe air trapping. The grayer areas are normal lung at expiration.

Pathologic Features

In contrast to the other CTD-ILDs, the pathology of RA-ILD demonstrates a preponderance of UIP. Certain features, such as lymphoid hyperplasia and plasma cell infiltration, as well as the presence of more than one pathologic process in the same biopsy specimen, are quite common in RA-ILD and should suggest the diagnosis ( Fig. 13.7 ). Some less common histopathologic patterns observed in RA include OP, follicular bronchiolitis, LIP, and DAD. RA-ILD may not share the favorable prognosis some other forms of CTD-ILD seem to carry. In fact, data suggest that the course of UIP in RA-ILD may be inexorable and fatal as seen in IPF (idiopathic UIP).

Lymphoid hyperplasia. In the center of the image, there is a lymphoid follicle with a germinal center. Fibroblast foci and organizing pneumonitis are not present. There is established fibrosis. While lymphoid hyperplasia in end-stage lung is nonspecific, in areas away from end-stage lung, this finding suggests collagen vascular disease. 4× objective.

Diagnostically, the differentiation between infection, drug reaction, and underlying RA-ILD can be difficult, as many of the drugs used to treat RA can cause pulmonary toxicity (e.g., methotrexate, leflunomide, and the tumor necrosis factor alpha [TNF-α] inhibitors [etanercept, infliximab, and adalimumab]) and can also predispose to opportunistic infection. The diagnosis of RA-ILD should take into consideration the clinical features, the radiographic appearance, the pathology, and the temporal correlation with drug initiation or withdrawal. Several different pathologic patterns may be consistent with drug toxicity, including cellular interstitial infiltrates, granulomas, tissue eosinophilia, and a DAD pattern with perivascular inflammation.

Treatment

There are many unanswered questions pertaining to RA-ILD, in particular, whether to treat subclinical disease and which therapies should be utilized. However, progressive lung disease is typically treated aggressively because response has been reported with corticosteroids, azathioprine, cyclosporine, and cyclophosphamide. If there is no response, therapy can be discontinued to avoid toxicity without hope of benefit. MMF has been reported to have a beneficial effect on CTD-ILD and may be considered in RA-ILD, although it does not generally treat the articular manifestations, necessitating that an additional agent be added. Data for the use of rituximab in RA-ILD are mixed. Some reports have indicated safety and stabilization of disease, while others have been inconclusive. Some reports suggest that TNF-α inhibitors may be effective in RA-ILD, but others report cases of pulmonary toxicity in patients with underlying ILD. Limited data exist regarding the use of other biologics such as abatacept, tocilizumab, and anakinra. Lung transplant referral should be considered in patients with severe fibrotic lung disease. Patients receiving lung transplants for RA-ILD seem to have survival rates similar to IPF patients and experience a significant improvement in quality of life with regard to respiratory symptoms.

Pulmonary Function Tests

Early ILD in SSc is often asymptomatic and is detected only by PFT and HRCT abnormalities. In particular, the earliest sign of SSc-associated ILD (SSc-ILD) on PFT is a decrement in D lco , which correlates better than other lung function parameters with the extent of radiographically evident ILD by HRCT. In particular with SSc, decrements in D lco can be reflective of concomitant pulmonary vascular disease, and evaluation should be undertaken to distinguish between ILD and PAH. Declines in both forced vital capacity (FVC) and diffusion capacity (D lco ) at diagnosis correlate well with severity of disease and with overall prognosis. In particular, an FVC less than 80% predicted at diagnosis is highly predictive of both the severity of decline in FVC percent predicted over the subsequent 5 years, as well as time to decline in D lco < 70% predicted. Additionally, among patients with early SSc, FVC <50% is highly predictive of mortality. Most of the deterioration in FVC seems to occur in the first 2 years after diagnosis, making initial screening and follow-up PFTs particularly important during that period. Patients with antitopoisomerase antibodies (anti-Scl-70) may be at higher risk for this more rapid decline. Low 6-min walk distance correlates with functional impairment in SSc-ILD, but may not be an adequately reliable outcome measure for use in clinical trials, as it can be affected by musculoskeletal issues, including pain, weakness, and vascular insufficiency, as well as by concomitant PAH.

Radiographic Features

As with all CTD-ILD, HRCT is more sensitive than the chest radiograph at identifying ILD in SSc as well as in characterizing the extent of fibrosis. Radiographic features in SSc-ILD typically resemble those described in NSIP, characterized by subpleural ground-glass opacities and fine reticular markings with traction bronchiectasis, but little or no honeycombing ( Fig. 13.8 ). The presence of ground-glass opacities on initial CT is a predictor for progression to more advanced fibrosis, whereas an initial CT without ground-glass opacities predicts a lack of progression for most patients. Despite long-held presumptions that ground-glass opacities represent active alveolitis and inflammation, their presence may often reflect fine fibrosis and be irreversible despite therapy in SSc-ILD. Intra- and interobserver variability has hampered the use of HRCT data for research and clinical assessment; however, computer-aided models may offer some improvement in reliability. Combined staging systems, incorporating simple measurements of radiographic lung involvement with PFT data, may improve predictions of disease progression and mortality, but also require further study.

A 58-year-old woman with scleroderma and fibrotic nonspecific interstitial pneumonia. Axial CT image through the lower thorax (A) shows reticular markings, architectural distortion, and extensive traction bronchiectasis compatible with pulmonary fibrosis. A dilated distal esophagus ( arrow ) is also present. Axial CT images through the upper thorax with bone windows show amorphous areas of calcification in the soft tissues surrounding the right shoulder ( arrows in B) and anterior to the right scapula ( arrows in C) due to calcinosis. The right scapula is denoted by the asterisk in (C).

Other clues to the presence of scleroderma that can be detected on chest CT include a dilated esophagus and the presence of tumoral calcinosis (soft tissue calcification) ( Fig. 13.8 ). Because esophageal dysmotility is common in these patients, they are also at increased risk of aspiration pneumonia, which can be seen at imaging as dependent areas of consolidation and ground-glass opacity, as well as small, clustered centrilobular nodules.

Pathologic Features

The most common histopathologic pattern in SSc-ILD is NSIP, with a minority of biopsies demonstrating UIP or end-stage fibrosis. Unlike the marked contrast in survival seen between idiopathic UIP (IPF) and idiopathic NSIP, there seems to be little difference in mortality based on histopathologic subsets in SSc. For this reason, surgical biopsy is generally not obtained in SSc-ILD unless atypical features are present. A central distribution of radiographic abnormalities on CT has been associated with the pathologic finding of centrilobular fibrosis and clinical evidence of esophageal reflux in SSc. This finding suggests that there may be a causal link between subclinical aspiration and some forms of SSc-ILD. Abnormal esophageal motility, decreased lower esophageal sphincter pressure, and gastroparesis can all contribute to reflux in SSc, and chronic aspiration may occur. Among patients with more severe esophageal dysfunction, PFT parameters are more severely impaired, and there is an increased frequency of radiographically apparent ILD. Over time, these patients seem to have more rapid progression of lung impairment. It is not clear whether this association is causal for most patients or whether simultaneous worsening of lung and GI disease reflects progression of fibrosis in multiple organ systems.

Treatment

Treatment in SSc-ILD has typically been targeted at the inflammatory component of the disease, although with only modest improvement in outcomes. Prednisone and other corticosteroids were used in the past, but with the discovery of a link between high-dose steroid use and scleroderma renal crisis, this has fallen out of favor. Most studies of other immunosuppressive agents have included low dose of prednisone, and for this reason, it is often included in treatment regimens.

Multiple small, uncontrolled trials suggested a beneficial effect of cyclophosphamide on symptoms, lung function, radiographic abnormalities, and survival. The Scleroderma Lung Study I was the first randomized, placebo-controlled trial to evaluate the effect of oral cyclophosphamide on lung function in SSc-ILD. Cyclophosphamide had a statistically significant, although modest (2.53%), positive effect on the primary outcome of difference in FVC percent predicted at 1 year. Some important secondary outcomes such as dyspnea, skin thickening, and health-related quality of life were also improved. Cyclophosphamide was associated with increased short-term toxicity in the study and is known to have long-term risks, including elevated risk for bladder cancer and other malignancies. Subset analysis has suggested that the group most likely to benefit from treatment includes those patients with more severe restriction and fibrosis at baseline. Long-term follow-up demonstrated that the beneficial effects of cyclophosphamide on lung function were lost by 24 months. Despite the small absolute change in FVC percent predicted, it has been suggested that the stability of lung function attained in treated patients may represent the true success in SSc-ILD and that immunosuppressive therapy to prevent progression of disease may be required long term.

Methods to diminish the toxicity of treatment include alteration in the administration of cyclophosphamide from daily oral administration to monthly infusions, which minimize the cumulative dose; switching from cyclophosphamide after 6 to 12 months to another, less toxic agent such as azathioprine or MMF; or replacing cyclophosphamide entirely by initiating therapy with such agents. MMF demonstrated some early promising results. The Scleroderma Lung Study II, the results of which were released in abstract form only as of this writing, examines the role of MMF as primary therapy for SSc-ILD compared with cyclophosphamide. Patients were randomized to 2 years of MMF as compared with 1 year of oral cyclophosphamide followed by 1 year of placebo. Both treatment arms experienced the same 5% increase in FVC, but adverse events and withdrawal from study were more common in the cyclophosphamide arm. Azathioprine has similarly been used when less severe disease is present, or when the side effects of cyclophosphamide are prohibitive. This agent may offer some efficacy but is not well studied and is limited by side effects in a substantial minority of patients. It can be used for maintenance after cyclophosphamide and seems to offer some utility in this regard.

Other agents have been evaluated as potential alternatives to cyclophosphamide; however, none has fulfilled its promise. The endothelin-1 inhibitor bosentan was proposed for its antifibrotic effects in SSc skin and lungs, but failed to show treatment efficacy in SSc-ILD. Imatinib mesylate, a tyrosine kinase inhibitor, interferes in several profibrotic pathways and has been proposed for use in SSc. Uncontrolled trials suggest improvement in skin scores with modest improvement in FVC as well. Further study is needed to assess the role of imatinib in SSc-ILD; however, no effect was seen in a recent study in IPF. Rituximab, an inhibitor of B-cell proliferation, has been demonstrated in a small study of SSc-ILD patients to improve FVC and D lco , and reports of safety with increased use have made a case for further study. However, concerns regarding its potential for lung toxicity do exist. Other biologic agents and newer therapies require further study, including pirfenidone and anticonnective tissue growth factor antibodies. Early data have supported the role of stem cell transplantation in SSc, with improvement in ground-glass opacities on HRCT as well as FVC. Trials in the United States and Europe have enrolled patients to examine this high-risk strategy more fully, and further data are awaited.

Lung transplantation may be considered for advanced fibrotic lung disease but has been controversial in the past. SSc is considered a systemic disease, which may increase overall morbidity and mortality after transplantation. In particular, concern has been raised about the role of gastroesophageal reflux because of motility issues in SSc that may predispose to chronic graft dysfunction. However, among carefully selected patients, early (1-year) and late (5-year) mortality seems to be similar to that of other groups, even with severe esophageal dysfunction; patients with severe fibrotic lung disease should be referred for evaluation.

Clinical Features

The clinical presentation of PM/DM typically involves the subacute onset of proximal muscle symptoms, which may include myalgias, muscle fatigue, or frank weakness, in which patients complain of difficulty rising from a chair or lifting objects. In cases of DM, skin manifestations are present and may include the heliotrope rash, a violaceous discoloration of the eyelids; periorbital edema; Gottron papules, maculopapular erythematous lesions present on the extensor surface of the metacarpophalangeal and proximal interphalangeal 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 the lateral and palmar surfaces of hands and fingers, which has specific histopathologic features.

Several pulmonary manifestations may be seen in the IIMs and are a major contributor to morbidity and mortality. Primary muscle weakness may lead to hypoventilation and respiratory failure and may be complicated by pneumonia because of weak cough and poor airway clearance. Aspiration pneumonia may occur due to respiratory muscle weakness but most commonly reflects the presence of skeletal muscle dysfunction in the pharynx and upper esophagus.

ILD is the most common pulmonary complication of the IIMs, although like other CTD-ILDs, the incidence of myositis-associated ILD (MA-ILD) is greatly affected by the mode of ascertainment, with high rates observed with the combined use of PFTs and HRCT. The presence of ILD in this population contributes significant to mortality from the disease. In a prospective study of patients with a new diagnosis of PM or DM, many of whom had no respiratory symptoms, 78% of patients were demonstrated to have some lung involvement as defined by radiographic evidence (chest radiograph or HRCT abnormalities) or restrictive physiology and diffusion impairment on PFTs (total lung capacity and D lco < 80% predicted). Among a population of patients with anti-Jo-1 antibodies, 86% were demonstrated to have ILD. These numbers may be overestimates based on the lack of HRCT evidence of ILD for all patients, but they do suggest that parenchymal involvement is common and should be aggressively sought.

MA-ILD may occur concomitantly with the onset of myositis or rash but may precede the diagnosis of IIM. Cases of DM with typical skin rash in association with ILD may occur without biochemical evidence for muscle involvement, known as ADM. The clinical course of MA-ILD is variable, ranging from a total lack of symptoms to fulminant hypoxemic respiratory failure, although many patients present subacutely and experience chronic, progressive disease. Dyspnea and cough are the most common symptoms reported in MA-ILD. Notably, almost one-third of patients with MA-ILD are asymptomatic, demonstrating the need for evaluation of these patients with PFTs and chest imaging. DM and particularly ADM may be more associated with an acute and fatal presentation, which is characterized by histopathologic findings of DAD, and resistance to treatment. The strongest predictor for the onset of ILD in IIM is the presence of antisynthetase antibodies, particularly anti-Jo-1.

The “antisynthetase syndrome” has been described to include ILD, myositis, arthritis, fever, Raynaud phenomenon, and “mechanic’s hands.” In many cases, only a few features are present, and in many the lung manifestations may predominate. In addition to anti-Jo-1, other antisynthetase antibodies (such as anti-PL7, anti-PL12, anti-EJ) have been associated with the development of ILD with IIM. Particular antibodies may be more or less strongly associated with the development of ILD or myositis, and subtypes based on antibody specificity may predict the clinical course. Among the myositis-associated antibodies, the presence of anti-SSA in conjunction with anti-Jo-1 has been associated with more severe and progressive ILD.

Pulmonary Function Testing

PFTs are important in the assessment of MA-ILD and help assess disease severity and response to therapy. They also help to distinguish between the role of MA-ILD and diaphragmatic weakness, although this may not be straightforward. Like other forms of ILD, PFTs in MA-ILD demonstrate restrictive physiology and reduced D lco . However, respiratory muscle insufficiency is also characterized by reductions in FVC and total lung capacity as well as reduction in other tests such as the maximum voluntary ventilation and maximal inspiratory and expiratory pressures. Reductions in the D lco may also be the result of pulmonary hypertension, which can coexist with ILD, or due to atelectasis from diaphragmatic weakness.

Radiographic Features

HRCT findings are similar to those in other forms of CTD-ILD. In MA-ILD, the most common abnormalities are ground-glass opacities, reticular markings, and airspace consolidation ( Fig. 13.9 ). Honeycombing is less common. The radiographic findings suggest the underlying pathology (i.e., dense consolidation reflecting DAD and OP; honeycombing reflecting UIP); however, these findings are not specific. Centrilobular nodules, linear opacities, and traction bronchiectasis may also be observed. Some studies have suggested that dense, peripheral consolidation in a pattern consistent with OP is associated with a better prognosis, while ground-glass opacities predict a worse outcome.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

1. Palliative and End-of-Life Care in Idiopathic Pulmonary Fibrosis
2. Nonpharmacologic Therapy for Idiopathic Pulmonary Fibrosis
3. Idiopathic Pulmonary Fibrosis: Phenotypes and Comorbidities
4. Histopathologic Approach to the Surgical Lung Biopsy in Interstitial Lung Disease

Stay updated, free articles. Join our Telegram channel

Join