Collagen Vascular Disease Associated With Interstitial Lung

Etiology

Collagen vascular diseases are immunologically mediated diseases that may be idiopathic or influenced by genetic and environmental factors, such as medications, smoking, and sex hormones. The causes of connective diseases are mostly unknown, though the role of autoimmunity is well-established.[3] 

Rheumatoid arthritis is theorized to be instigated by an infectious agent with tissue damage mediated by tumor necrosis factor. Various cytokines have been identified as contributing to the inflammatory response. Systemic lupus erythematosus is thought to be caused by an interaction between gene susceptibility and environmental agents and inflammation mediated by the deposition of auto-antibodies in specific tissues. Various viruses, such as Ebstein-Barr, Mycoplasma, and Borrelia bacterial species, have also been implicated as causes of systemic lupus erythematosus. Vascular injury is believed to be the initial pathologic event in scleroderma, while similar mechanisms of inflammation are involved in Sjogren's syndrome, polymyositis, and dermatomyositis. 

For the undifferentiated form of connective tissue disease-related ILD, a new classification was proposed by the European Respiratory Society/American Thoracic Society Task Force called "Interstitial pneumonia with autoimmune features (IPAF)."[4] The criteria for IPAF consist of the following:

1. Presence of interstitial pneumonia by lung biopsy or HRCT and exclusion of alternative etiologies and2. Lack the presence of a defined connective vascular disease and3. At least one feature from at least two of the following:

1. Clinical: Digital manifestation (ulcer, edema, etc.), Raynaud phenomenon, or polyarticular morning joint stiffness
2. Serologic: ANA ≥ 1:320 titer, Rheumatoid factor ≥2 × upper limit, Anti-CCP, Anti-dsDNA, Anti-Ro (SS-A), Anti-La (SS-B), Anti-ribonucleoprotein, Scl-70, Anti–PM-Scl, or Anti–MDA-5.
3. Morphologic: Radiologic (nonspecific interstitial pneumonia (NSIP) with or without organizing pneumonia or lymphoid interstitial pneumonia), histologic (NSIP with or without organizing pneumonia or lymphoid interstitial pneumonia), or unexplained pleural or pericardial effusion, or pulmonary vasculopathy suggested by PFT (i.e., unexplained decrease in Dl).[5]

Epidemiology

Approximately 30 % of patients with newly diagnosed ILD have underlying collagen vascular disease,[1] although the exact frequency of collagen vascular disease-associated ILD is unknown.[6] Up to 90% of patients with collagen vascular disease will have pulmonary involvement. ILD prevalence on high-resolution computed tomography (HRCT) is 70%-90% in systemic sclerosis, 4%-68% in rheumatoid arthritis, 20%-85% in mixed connective tissue disease, 10%-30% in Sjogren's syndrome, and up to 30% in systemic lupus erythematosus.[7] Due to this high prevalence of CTD-ILD, most guidelines recommend excluding connective tissue disease in newly diagnosed ILD.[8]

Rheumatoid arthritis affects up to two percent of the population, more commonly women, although rheumatoid arthritis-related interstitial lung disease is more common in middle-aged men. The highest incidence occurs between the ages of 25 and 50 years. Extra-articular involvement is seen in up to half of patients with rheumatoid arthritis, with pulmonary disease as the second most common cause of death.[9] Clinically significant ILD in the form of usual interstitial pneumonia (UIP) (most common), NSIP, or cryptogenic organizing pneumonia is seen in approximately five percent of patients.[10] Acute interstitial pneumonia is a rare entity with a rapidly fatal course.[11]

Progressive systemic sclerosis (SSc), or scleroderma, is a multisystem disease occurring predominantly in women. The highest incidence occurs between the ages of 45 and 64 years.[12] Patterns of ILD include NSIP and less commonly usual interstitial pneumonia. Of patients with collagen vascular disease, those with systemic sclerosis suffer the highest mortality, mainly secondary to pulmonary arterial hypertension (10% to 16% prevalence).[13] 

Systemic lupus erythematosus (SLE) is a complex multisystem autoimmune disease that predominantly affects women (>90% of cases) and non-Whites. Interstitial lung disease is a rare yet insidious complication, affecting 1 in 1000 individuals, with the most common manifestation being nonspecific interstitial pneumonia.[14]

Polymyositis (PM) and dermatomyositis (DM) are inflammatory myopathies that occur most commonly in women between the ages of 40 and 50 years. The frequency of ILD is purported to be between 5% and 30%, presenting most widely as nonspecific interstitial pneumonia or cryptogenic organizing pneumonia, which may precede the development of clinical myositis.[14] 

As the name suggests, mixed connective tissue disease (MCTD) manifests as a combination of the above etiologies. Ninety percent of patients are female, with the incidence highest in the second and third decades. Interstitial lung disease is the most common pulmonary manifestation, occurring in up to 66% of patients.[15][16] The most common pattern of interstitial lung disease is nonspecific interstitial pneumonia, followed by usual interstitial pneumonia and lymphocytic interstitial pneumonia, with ground glass opacities as the most frequent parenchymal abnormality.[10][17]

Sjogren's syndrome (SS) is an autoimmune disease characterized by T-cell infiltration of various organs, most often the lacrimal and salivary glands. It affects up to 3% of adults, mostly women aged 30 to 40. Interstitial lung disease is more common in primary Sjogren's syndrome, manifesting as lymphocytic interstitial pneumonia, nonspecific interstitial pneumonia, usual interstitial pneumonia, or cryptogenic organizing pneumonia.[18][19]

Pathophysiology

Interstitial lung disease is characterized by a combination of chronic inflammation and a pro-inflammatory cascade with varying degrees of fibrosis.[20]

Histopathology

On histopathologic examination, interstitial lung disease associated with collagen vascular disease includes usual interstitial pneumonia (UIP), nonspecific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), diffuse alveolar damage (DAD), lymphocytic interstitial pneumonia (LIP), and apical fibrosis.[21] Although nonspecific, suggestive findings include lymphoid hyperplasia and prominent plasma cell inflammation with interstitial inflammation.[22] There are varying degrees of inflammation and fibrosis, which often correspond to reticular or ground glass opacification on CT.[23]

Usual interstitial pneumonia appears as architectural distortion, fibrosis with honeycombing, and fibroblastic foci. There are heterogeneous areas of fibrosis interspersed with normal lung parenchyma.[24]

Nonspecific interstitial pneumonia can be classified as the cellular or fibrotic type, depending on the degree of interstitial inflammation and fibrosis. There is diffuse cellular inflammation in a homogenous pattern with patchy intervening lung tissue and preservation of lung architecture.[24] Fibrosing NSIP is one o the most commonly found histopathologies in ILD related to connective vascular disease.[14] 

Cryptogenic organizing pneumonia appears as intraluminal organizing fibrosis in the distal airspaces with patchy preservation of lung architecture and mild chronic interstitial inflammation.

Diffuse alveolar damage appears as alveolar edema, hyaline membranes, and fibroblastic proliferation with little mature collagen.

Lymphocytic interstitial pneumonia appears as infiltration of T-lymphocytes, plasma cells, and macrophages with lymphoid hyperplasia.

Acute lupus pneumonitis may appear as alveolar damage and necrosis, leading to inflammatory cell infiltration, edema, and hyaline membrane formation. Histopathologic findings are commonly those of usual interstitial pneumonia or nonspecific interstitial pneumonia.[25]

In rheumatoid arthritis, interstitial pneumonitis and fibrosis are the most common manifestations.[26] Most patients with interstitial fibrosis have usual interstitial pneumonia or nonspecific interstitial pneumonia. Follicular bronchiolitis may be present with or without fibrosing NSIP. The spectrum of histologic patterns includes pulmonary rheumatoid nodules, usual interstitial pneumonia, cryptogenic organizing pneumonia, lymphoid hyperplasia, and cellular interstitial infiltrates in an NSIP-type pattern.[27] 

Systemic sclerosis frequently involves pulmonary fibrosis in both limited and diffuse forms of the disease, secondary to nonspecific interstitial pneumonia or usual interstitial pneumonia, and follicular bronchiolitis or cryptogenic organizing pneumonia is occasionally seen.[28]

Although diffuse interstitial pneumonitis is uncommon in systemic lupus erythematosus, histopathologic findings are those of nonspecific interstitial pneumonia or usual interstitial pneumonia.[21]

Interstitial lung disease associated with polymyositis or dermatomyositis may manifest as cryptogenic organizing pneumonia, usual interstitial pneumonia, nonspecific interstitial pneumonia, or diffuse alveolar damage, each of which determines a different prognosis. Diffuse alveolar damage and usual interstitial pneumonia portend a worse prognosis (30% survival at five years), contrary to those with cryptogenic organizing pneumonia or nonspecific interstitial pneumonia.[29]

Mixed connective tissue disease may demonstrate interstitial fibrosis secondary to usual interstitial pneumonia or nonspecific interstitial pneumonia.[21]

Sjogren’s syndrome most commonly presents with lymphocytic interstitial pneumonia, characterized by diffuse interstitial infiltration of lymphoplasma cells, often with mild fibrosis.[30] Overinflation of the secondary pulmonary lobule may represent cyst formation and/or air-trapping.[31]

History and Physical

Patients with interstitial lung disease typically present with exertional dyspnea and nonproductive cough. Extrapulmonary symptoms such as arthralgia, myalgia, fatigue, or malaise may also be present and suggest an underlying collagen vascular disease. Past medical history of asthma may suggest eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss). Family history may suggest a particular diagnosis, as some collagen vascular diseases have a genetic basis. A detailed medication history is needed to exclude the possibility of drug-induced lung disease. Smoking, drug use, employment history, and occupational exposure are important to ascertain, as smoking cigarettes has been strongly linked to developing pulmonary fibrosis.[32] 

In addition, certain demographics are important distinguishers as most patients with connective vascular disease-associated ILD are in the young age category (between 20 to 40 years of age). On the contrary, most patients with idiopathic pulmonary fibrosis present later (more than 60 years of age). 

Pulmonary auscultation may reveal rales or crackles. Skin findings may include skin thickening and telangiectasias (systemic sclerosis), Raynaud phenomenon (systemic sclerosis and systemic lupus erythematosus), discoid, or butterfly rash (systemic lupus erythematosus), heliotrope rash (polymyositis and dermatomyositis), and Gottron papules (polymyositis and dermatomyositis). Xerostomia, xerophthalmia, and parotid swelling may be seen in patients with Sjogren's syndrome.[33]

Evaluation

The diagnosis of interstitial lung disease can be made with pulmonary function testing (PFT) demonstrating restrictive lung disease with diminished total lung capacity (TLC), decreased forced vital capacity (FVC), and impaired diffusion of oxygen and carbon dioxide. Reduction in forced vital capacity determines the severity of restrictive physiology. PFT is predominantly a guide of disease severity and response to treatment and should not be used alone to diagnose interstitial lung disease as it is nonspecific.[24] 

Autoimmune serologic testing may detect antibodies and other markers specific to certain subtypes of collagen vascular disease. Surgical lung biopsy remains the gold standard for determining the subtype of interstitial lung disease.[7]

A chest radiograph is often the first radiologic modality used in the investigation of interstitial lung disease, though it is insufficient in making a diagnosis. The X-ray may detect basilar reticulonodular infiltrates or cystic changes in various subtypes of interstitial lung disease, though many patients with interstitial lung disease may have an unremarkable study.

High-resolution computed tomography (HRCT) of the chest shows various patterns in different interstitial lung diseases.

In nonspecific interstitial pneumonia, there are bilateral and generally symmetric ground-glass opacities and subpleural reticulation, occasionally with microcystic honeycombing, with subpleural sparing. Traction bronchiectasis or bronchiectasis is a nearly universal feature in fibrotic nonspecific interstitial pneumonia, as is lower-lobe architectural distortion. Cellular and fibrotic nonspecific interstitial pneumonia are ultimately distinguished only by histology.[21]

Usual interstitial pneumonia may be indistinguishable from nonspecific interstitial pneumonia, with ground glass opacities and subpleural reticulation in an apicobasal gradient. Consolidation and honeycombing, however, are more common in usual interstitial pneumonia.[10] Findings in usual interstitial pneumonia include intralobular septal thickening, honeycombing, traction bronchiectasis, and subpleural reticular opacities in a peripheral, subpleural, or basal distribution. The presence of macrocytic honeycombing is typical for UIP.

Lymphocytic interstitial pneumonia is characterized by diffuse ground-glass opacities with thin-walled central or perivascular cysts. There may be centrilobular nodules, bronchovascular bundle thickening, and interlobular septal thickening.

Organizing pneumonia appears as patchy bilateral and peripheral consolidations and ground-glass opacities. Alveolar opacities may appear triangular, polygonal, or wedge-shaped in appearance, range in size from small nodules to mass-like consolidations, and expand or migrate over time. The atoll or reverse halo sign may be appreciated.[34] 

Diffuse alveolar damage demonstrates diffuse consolidation and ground-glass opacification, often with lobular sparing as well as traction bronchiectasis in later stages.[21] Crazy paving (a linear pattern superimposed on a background of ground-glass opacity) may be appreciated.

Acute or chronic aspiration, such as from esophageal dysmotility in systemic sclerosis or respiratory muscle weakness in polymyositis/dermatomyositis, may appear as centrilobular nodules, tree-in-bud opacities, and/or bronchial wall thickening.[35]

In rheumatoid arthritis, irregular hyperattenuating areas represent intralobular lines and interlobular septal thickening. Honeycombing may be seen at the lung bases. CT patterns include subpleural reticulation or ground-glass opacities with or without honeycombing (nonspecific interstitial pneumonia, usual interstitial pneumonia, cryptogenic organizing pneumonia), centrilobular branching structures with or without bronchial dilatation or traction bronchiectasis (usual interstitial pneumonia, cryptogenic organizing pneumonia), and consolidation (cryptogenic organizing pneumonia). The reticular pattern predominates in early disease, whereas honeycombing and consolidation typically appear in progressive disease.[10][36]

There may be evidence of interstitial pneumonitis and fibrosis involving the lower lobes in a peripheral and posterior distribution in systemic sclerosis.[37] Findings on CT have been shown to correlate with pulmonary function tests, and the extent of honeycombing significantly correlates with a decrease in diffusing capacity for carbon monoxide.[17]

In systemic lupus erythematosus, ground-glass opacities and consolidations may reflect interstitial pneumonitis and fibrosis. Interstitial abnormalities, including interlobular septal thickening, irregular linear hyperattenuating areas, and architectural distortion, may be seen in up to one-third of patients and are commonly mild and focal.[38]

In polymyositis and dermatomyositis, there may be prominent interlobular septa, ground-glass opacities, patchy consolidation, parenchymal bands, bronchial thickening, and subpleural lines. Consolidation with or without ground-glass opacification corresponds to cryptogenic organizing pneumonia or diffuse alveolar damage. Patchy consolidations, parenchymal bands, and bronchial thickening are reversible, while ground-glass opacities with subpleural lines representing usual interstitial pneumonia may progress to honeycombing.[39]

In mixed connective tissue disease, abnormalities may include irregular linear hyperattenuating areas with reticulation at the lung bases. In the later stages of the disease, there may be honeycombing with fibrosis extending apically, as well as areas of consolidation that may be related to cryptogenic organizing pneumonia.[21]

In Sjogren's syndrome (SS), the most common findings on CT are bronchiectasis and centrilobular nodular or branching linear hyperattenuating areas and ground-glass opacities. The usual interstitial pneumonia (UIP) pattern is uncommon in patients with SS; the characteristic pattern of lymphocytic interstitial pneumonia with extensive ground-glass opacification and thin-walled cysts may be seen. Poorly defined centrilobular nodules and bronchovascular thickening represent lymphoplasma cell infiltration of interstitial tissue.[31]

Treatment / Management

Treatment of collagen vascular disease-associated interstitial lung disease is geared towards the underlying connective tissue disease using pharmacological and non-pharmacological therapies.[40] Non-pharmacological strategies include oxygen supplementation for eligible patients, pulmonary rehabilitation, exercise, and physical therapy. Given that the clinical response to treatment varies based on the underlying ILD etiology, therapeutic strategy varies too, particularly since the response of connective vascular disease related-ILD tends to be more favorable than other types of ILD such as IPF, choice of therapy should be considered with caution.[5]

Immunosuppression

Immunosuppression is the primary treatment of connective vascular disease-related-ILD. Although clinical trials are lacking traditionally, immunosuppression includes corticosteroids alone. Prior to initiating immunosuppressive therapy, screening for infection and organ dysfunction is recommended due to the increased risk of new or reactivated infections (such as tuberculosis (TB) and hepatitis B).[41][42]

In symptomatic cases of lung diseases associated with Sjögren syndrome (SS) who have worsening symptoms, the most common treatment is Prednisone (starting dose is 0.5 to 1 mg/kg ideal body weight with a maximum daily dose of 60 mg). When corticosteroid is not tolerated or lacks clinical response, immunomodulatory treatment is indicated, such as with mycophenolate or azathioprine. This type of therapy is more appropriate for cellular forms of ILD ( such as cellular NSIP, organizing pneumonia, or lymphoid interstitial pneumonia). There are recommendations to initiate therapy with a less toxic agent, such as azathioprine (AZA) or mycophenolate mofetil (MMF), in combination with slow tapering of corticosteroid dose.[40]

In symptomatic patients with rheumatoid arthritis-ILD and no evidence of lung infection, it is recommended t initiate treatment with Prednisone with starting dose is 0.5 to 1 mg/kg based on ideal body weight. (but the maximum dose should not exceed 60 mg/day).[43] A response usually takes up to one to three months. The dose should slowly be tapered to 10 mg/day after the clinical response is achieved (based on symptoms and PFTs). When there is a UIP or fibrotic NSIP pattern on HRCT or biopsy, the response to glucocorticoids is rare.

In symptomatic cases of ILD associated with polymyositis and dermatomyositis, the main therapy is corticosteroid alone or with a second agent to reduce inflammation and minimize progression. Usually, the estimated response rate to corticosteroid alone is 50%, special when there is an NSIP pattern on HRCT. The recommended dose of therapy is similar to other connective vascular diseases associated with ILD (Prednisone with starting dose is 0.5 to 1 mg/kg, ideal body weight not to exceed 50 mg /day, and to be tapered slowly after the first month of treatment).

For steroid-sparing treatment or in cases of mild to moderate ILD (FVC>70%), azathioprine or mycophenolate can be used as a second steroid-sparing agent; however, in severe ILD (FVC <70% and lung involvement on HRCT >20%) a stronger immunosuppressive agent (such as cyclophosphamide, rituximab, or tacrolimus) should be used then mycophenolate is added after the clinical response is achieved.[44]

In rapidly progressive ILD cases associated with systemic lupus erythematosus (SLE), immunosuppression with pulse intravenous (IV) methylprednisolone, IV cyclophosphamide, or rituximab is usually required to control inflammation and minimize permanent lung damage.[45]

Antifibrotics

Treatment with antifibrosis medications (such as nintedanib and pirfenidone) has been employed recently with variable efficacy in cases where there is evidence of progressive fibrotic NSIP or UIP features (affecting more than 10% of lung volume on HRCT and forced vital capacity (FVC) of at least 45% of the predicted).[46] 

In cases of SSc-ILD and progressive fibrosing-ILD, using nintedanib led to a lower annual rate of decline in FVC with similar adverse effects compared with a placebo.[47] Likewise, pirfenidone has shown some benefit in progressive and unclassified ILD cases, including those with IPAF and acceptable safety profiles.[48] (A1)

Oxygen therapy improves breathing, facilitates exercise, prevents complications of hypoxia and pulmonary arterial hypertension, and fosters well-being. Physical rehabilitation may help improve mobility and achieve activities of daily living. Lung transplantation may be an option for patients with advanced and irreversible diseases.[20]

Lung transplantation is considered in the end-stages of cases of ILD, with similar survival rates to IPF.[49] The survival rates in the first year following lung transplant for the rheumatoid arthritis-ILD, IPF, and Scleroderma-associated ILD groups were reported to be 67%, 69%, and 82%, respectively.(B2)

Differential Diagnosis

Other entities that cause interstitial lung diseases, such as sarcoidosis and occupational disorders, must be considered. Acute viral pneumonia, including COVID-19 pneumonia, may also appear clinically and radiologically similar to acute exacerbation of interstitial lung disease. Cardiogenic and non-cardiogenic pulmonary edema may cause diffuse alveolar and interstitial opacities with interlobular septal thickening that may simulate interstitial lung disease.[50]

Prognosis

Collagen vascular disease-associated interstitial lung disease is associated with significant morbidity and mortality. Collagen vascular disease-associated interstitial lung disease typically bears a better prognosis than idiopathic interstitial lung disease and a slower progression than idiopathic pulmonary fibrosis. The mortality rates are similar among various connective vascular disease-related-ILD (including rheumatoid arthritis, scleroderma, polymyositis, and dermatomyositis-related ILD) and remained steady over the last two decades.[51]

Mortality is highest in women, non-Hispanic white populations, and those who develop pulmonary hypertension, have higher oxygen requirements, and require mechanical ventilation.[32][52] Nearly 20% of patients with nonspecific interstitial pneumonia die within five years of diagnosis.[53] 

More extensive disease, as determined by a higher lung burden on high-resolution CT and diminished forced vital capacity on pulmonary function testing, correlates with future mortality in many patients.[7]

Complications

Interstitial lung disease and pulmonary arterial hypertension are the main causes of mortality and morbidity in patients with collagen vascular disease.[10] Drug toxicity and infection are also common complications affecting this patient population.

Drugs used to treat rheumatoid arthritis, such as gold salts and penicillamine, may cause diffuse alveolar damage or obliterative bronchiolitis.[9] Methotrexate therapy has been associated with pneumonitis.[54]