ILD is the most common pulmonary manifestation in RA. The presenting form of ILD in RA is similar to that seen in idiopathic interstitial pneumonias (IIP), and the histological patterns of interstitial disease that we can find in RA are the same as those in IIP. These include usual interstitial pneumonia (UIN), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated ILD (RB-ILD), acute interstitial pneumonia (AIP) and lymphoid interstitial pneumonia (LIP) (Table 1).8,12 Most lung diseases associated with RA occur in the first 5 years after onset of the disease. At the time of RA onset, pulmonary complications can appear in 10%–20% of cases, and the presence of pulmonary fibrosis has been demonstrated in 14% of patients with a history of RA of less than 2 years. The prevalence of ILD varies depending on the criteria used to establish the diagnosis. The presence of clinically significant ILD has been described in approximately 7% of patients,7 while studies carried out in autopsies show an ILD prevalence of 35%.13 In studies in which chest high resolution computed tomography (HRCT) scanning was used to screen for ILD in RA patients, a prevalence of almost 20% was observed.14 In others where pulmonary function tests (PFT) were carried out, restrictive changes were observed in up to 40% of patients. In the Spanish RA registry, ILD has a prevalence of 3.7% when only chest X-ray is considered, and increases to 80% if the histological findings of lung biopsies are taken into account.15 In a study conducted in 2008 in RA patients without respiratory symptoms, in which HRCT scanning was performed, ILD was found in 21 of the 64 patients studied (33%).16

It has been observed that ILD, like other extra-articular manifestations, is more common in men than in women. The relationship of smoking with the development of ILD is not clear at present; some have viewed smoking as potential risk factor for the development of ILD, while others have associated it independently with the development of ILD.15,16 The presence of anti-citrulline antibodies (anti-CCP) or IgA and/or IgM rheumatoid factor (RF) increases the risk of developing extra-articular manifestations, and high RF titers have been associated with the presence of ILD and with a reduction in the carbon monoxide diffusing capacity (DLCO).17 The relationship between anti-CCP and lung disease is unknown. Other factors that have been associated with the onset of ILD in patients with RA are advanced age at diagnosis, disease activity and severity markers, appearance of rheumatoid nodules and more severe functional classification.18 The mean survival of patients with ILD and RA is less than 40% at 5 years. Bongartz et al.18 found a mean survival of 2.6 years after the diagnosis of ILD in their series.

The clinical manifestations are non-specific and the most common symptom is dyspnea on exertion, followed by non-productive cough. Chest pain is rare. Fever is a very uncommon symptom. The physical examination may be normal in the initial stages of lung involvement. Dry “Velcro” crackles subsequently appear on the pulmonary auscultation, and acropachy can be observed in advanced stages.

The diagnosis of ILD in RA is based on the combination of symptomatology suggestive of lung disease, consistent PFTs and typical radiological findings; in some cases a histological study may be necessary. Fibrobronchoscopy and bronchoalveolar lavage (BAL) may be useful for making the differential diagnosis with other interstitial diseases, and for discarding lung infections or drug-induced diseases.

PFTs are essential in the evaluation of pulmonary involvement in RA. They may be altered even in asymptomatic patients. The first parameter altered is the DLCO, as this is the most sensitive test; it may be reduced in 40% of patients, even with a normal plain chest X-ray, and in 82% of patients with abnormal HRCT scans, even if they are asymptomatic.13 DLCO correlates well with the degree of disease extension on the HRCT scan and also has prognostic value: a DLCO <54% of the expected value can predict disease progression.19 A restrictive pattern is later observed, with a reduction in the total lung capacity (TLC) and forced vital capacity (FVC), and an increase in the alveolar-arterial oxygen gradient. In some cases, a mixed pattern can be observed with obstructive changes, especially in smokers. In advanced stages of the disease, desaturation can be observed with physical exercise, and even hypoxemia at rest.

In many cases, the chest X-ray is normal. It is not a very sensitive technique for diagnosing early stage interstitial lung disease.14 Reticulonodular patterns, basal opacities, ground glass, a honeycomb pattern and, in advanced stages, signs of PH can be observed.

HTCT scanning is much more sensitive for detecting the abnormalities that occur in the lung, even in asymptomatic patients. The findings are very varied, but the most common are: reticular images, ground glass pattern, bronchial wall thickening, bronchial dilatation, consolidation, micronodules and a honeycomb pattern.2

Depending on the type of lung involvement, the radiological findings differ, adopting different patterns. Some of these are characteristic of certain histological patterns, and enable diagnostic and therapeutic decisions to be taken without having to perform a lung biopsy.3

In the UIP HRCT pattern, the most common findings are reticulation and a honeycomb pattern, predominantly in bases and peripheral zones, accompanied by traction bronchiectasis and small areas of ground glass opacities. In the NSIP HRCT pattern, ground glass opacities predominate and reticulation predominates in peripheral and basal areas; traction bronchectasis and a little honeycombing can also appear. The bronchiolitis pattern is characterized by centrilobular or peribronchial nodules and bronchial dilatation may coexist with bronchiectasis. In the COP pattern, airspace consolidation can be observed with ground glass opacities, and there may be centrilobular nodules.20

BAL does not have a specific value in diagnosis. Its main interest lies in excluding other diseases such as opportunistic infections, drug reactions and neoplasms.3 In RA, the cellularity of BAL is increased, and in general an increase can be observed in neutrophils and occasionally eosinophils. In early stages, in sub-clinical phases, there may be a predominance of lymphocytes, which is associated with a better prognosis and response to treatment.21,22

Any of the defined IIP histological patterns can be found in RA8,12 (Table 1). The histological pattern most often seen in RA-associated ILD is UIP,23,24 unlike in other collagen diseases, in which the NSIP pattern is more common; this is the second most frequently observed pattern in RA; in third place is COP. Other patterns can also be found, but with much lower prevalence: respiratory bronchiolitis (RB-ILD), DIP, LIP and diffuse alveolar damage (DAD).

The drugs used in the treatment of RA can have diverse side effects. They can also affect the lung and cause interstitial disease. Methotrexate (MTX) is the drug that is most commonly associated with lung disease in RA. MTX-pneumonitis is an idiosyncratic rather than dose-dependent reaction. Its onset has no relation with the cumulative dose, and it can even occur weeks after treatment ends. The presence of previous interstitial disease, advanced age, and abnormal PFTs are risk factors for the development of MTX-pneumonitis. However, in some studies, low-dose MTX treatments have not been observed to cause deterioration of ILD.25 Its diagnosis is difficult, as the symptoms are non-specific and can be confused with infection. Several criteria have been proposed for its diagnosis.26,27 Moreover, since a previous lung disease can be a risk factor for its development, algorithms have also been designed to minimize the risk of its use.27 In a patient with ILD who develops increasing dyspnea during MTX treatment, and in whom a reduction in DLCO is detected with respect to the previous measurement, or ground glass opacities appear, MTX should be discontinued.4,28

The anti-TNF-alphas (infliximab, etanercept and adalimumab) have demonstrated their effectiveness in the treatment of RA. In most cases, their side effects are related with their immunosuppressive effect, which manifests with infections, among which tuberculosis merits a special mention. TNF-alpha is a cytokine involved in the early immune response of a wide variety of inflammatory mediators, and is a critical mediator in the pathogenesis of pulmonary fibrosis.29 Isolated cases of improvement in symptoms, stabilization of lung function and radiological images have been reported with these drugs.29,30 However, cases of ILD onset31,32 and major clinical exacerbation have also been reported after commencing each of these drugs.33–35 ILDs related with anti-TNF treatment are more aggressive and have higher mortality compared with ILD in patients who receive MTX alone, and most cases occur shortly after receiving treatment. In prescription guidelines for anti-TNF treatment, caution is advised when exposing RA patients with pulmonary fibrosis and close monitoring of lung function is recommended.36

Leflunomide has been used as an alternative to MTX in patients with underlying lung disease. However, in 2001, at the British Society of Rheumatology meeting, the first adverse effects of leflunomide on the lung in patients with RA were reported.37 In Japan, an incidence of 0.5% of ILD in patients treated with leflunomide has been described.38 Until now, a few cases of ILD associated with tocilizumab have been identified: one case in the series of Smolen et al.39 and one isolated case described by Kawasshiri et al.40 Several cases of ILD associated with ritiximab treatment have also been noted in patients with lymphoma39 and some cases of organizing pneumonia have been reported in patients diagnosed with RA after commencing rituximab treatment.41,42

Pulmonary complications could be responsible for 10%–20% of the mortality in patients with RA. The survival of patients with ILD is lower than that expected in patients with RA without ILD. In general, the evolution and prognosis of patients with ILD associated with collagen disease are better than those of patients with idiopathic pulmonary fibrosis (IPF).43,44 The prognosis for ILD associated with RA is better than for IPF.45 However, the survival of patients with RA who have an ILD with a UIP pattern is the same as that of IPF.43 In general, the mean 5-year survival of patients with ILD and RA is less than 40%. Various clinical factors have been described that may predict lower survival: progressive dyspnea measured on standardized scales; reduction in lung size on the chest X-ray; degree of extension of the disease on the HRCT scan; decrease in FVC and decrease in the gas transfer capacity.46

ILD has traditionally been treated with corticoids, combined or not with other immunosuppressants, without taking the underlying histopathology into consideration. ILD with a UIP pattern has a poor response to corticoids, while OP usually has a very favorable evolution,20 so it seems logical to base treatment on the underlying interstitial pneumonia pattern.

In general, aggressive treatment is justified in patients in whom there is evidence of inflammation on the HRCT scan, lymphocytosis in the BAL and who do not have a UIP pattern, especially if they are young patients with progressive deterioration in lung function. Other treatments that should be considered are pulmonary rehabilitation and oxygen therapy if there is respiratory failure. When the disease is very advanced, lung transplantation must be considered.

These appear in fewer than 1% of chest X-rays in patients with RA. Up to 22% of cases can be detected on the chest HRCT scan; this prevalence increases in autopsies of patients with RA.47

They are more common in chronic patients, but in some cases may be the first manifestation of RA. They are generally asymptomatic and rarely cause coughing or hemoptysis. They are more common in patients with subcutaneous nodules, smokers and high RF.48 They are round, well-defined opacities and can be single or multiple, unilateral or bilateral. Their size is also variable, from millimeters to several centimeters, and they are most often found in the upper lobes in a subpleural position. Histologically they have the same characteristics as subcutaneous rheumatoid nodules, with a central area of fibrinoid necrosis enveloped by a layer of histiocytes with a typical palisade arrangement, surrounded peripherally by granulation tissue and chronic inflammation. In 50% of cases, they cavitate. Differential diagnosis must be made with primary pulmonary neoplasia if it is a single nodule, or with metastases if there are multiple nodules, and with granulomas, mycosis, pulmonary vasculitis and histiocytosis X. The clinical evolution is variable, and they can increase in number or size, cavitate, decrease or remain stable. The prognosis is good, and very rarely becomes complicated resulting in pneumothorax, pyopneumothorax or bronchopleural fistula. The only definitive diagnosis is the histological study.

This was first described in 1953 by Caplan in coal miners with pneumoconiosis and RA.49 It is characterized by the onset, in patients with RA, of rounded nodular images in both lung fields, with predominantly peripheral location and which may cavitate, together with typical pneumoconiosis abnormalities. The pathogenesis of the nodules in Caplan's syndrome is not well known, and it is believed that the inorganic material could be the trigger for immunological phenomena that favor (in the context of RA) the formation of nodules.50

A quite significant prevalence of bronchiectasis has been observed in patients with RA, but is very variable depending on the series consulted (0%–30%).53 CT scanning is the most sensitive test for its diagnosis. The colonization of these bronchiectases by different microorganisms is the cause of repeated respiratory infections, which is very important to take into account in these patients who receive immunosuppressive treatment for their underlying disease.

This is a very rare but very serious complication. It is characterized by acute or sub-acute obstruction of the small airways, causing dry cough and rapidly progressive dyspnea. It produces an obstructive pattern that is refractory to bronchodilator treatment, secondary to obstruction of the bronchioles due to inflammation and fibrosis of the bronchial walls. The chest X-ray may be normal or show signs of air trapping. Bronchial wall thickening, areas of centrilobular emphysema and bronchiectases can be observed on the HRCT scan. There is constrictive bronchiolitis with lymphocytic infiltrate in the lung biopsy. It is a very severe clinical condition with a very poor response to treatment and a high mortality rate.

ILD appears more often in patients with diffuse systemic sclerosis than in those who have limited systemic sclerosis. The prevalence of ILD depends on the population selected for the studies and the definition of ILD applied, but can be observed in up to 74% of patients. It is associated mainly with the presence of severe Raynaud's phenomenon, digital ulcers and tendon involvement. ILD can be the first clinical manifestation of systemic sclerosis.55 African-American ethnicity, degree of skin involvement, hypothyroidism, cardiac involvement, creatine phosphokinase (CPK) and creatinine levels have been associated with the development of early pulmonary involvement.56

The presence of certain antibodies is related with an increased likelihood of developing ILD. However, their sensitivity and predictive values are low. A large proportion of patients with systemic sclerosis have positive anti-nuclear antibodies (ANA), and anti-topoisomerase I antibodies are found in up to 40% of patients with lung involvement. On the other hand, it has been observed that the presence of anti-centromere antibodies could be a protective factor against the development of ILD. The presence of anti-toposiomerase type I antibodies is associated with lower baseline FVC levels (P<.001) and accelerated decline in FVC.57 In another study, a prevalence of ILD of 79% was observed in patients with antibodies against U11/U12 ribonucleoprotein (RNP).58 In recent years, major studies have been conducted in order to find biomarkers that are capable of predicting the development of pulmonary fibrosis, and which correlate with its clinical course and clinical response to different therapeutic agents.59,60 Krebs von den Lungen 6 antigen (KL-6) and pulmonary surfactants A and D (PS-A and -D) have been related with the onset of ILD.61,62 In a cohort of Japanese patients, elevated PS-A and -D levels were found in patients with ILD, and it was observed that the PS-D isoform was more sensitive for the diagnosis and identification of pulmonary fibrosis than the A isoform.63 A correlation was also observed between the PS-D, FVC and DLCO levels.60 Another study found that patients with systemic sclerosis had higher levels of both proteins than healthy individuals, and that patients with alveolitis had higher levels than those who did not.64 These results were later confirmed, and it was observed that the KL-6 and SP-D levels correlated positively with the degree of fibrosis in the CT scan, with KL-6 more strongly correlated.65 Another marker, CC chemokine ligand (CCL) 18 has also been observed to be higher in systemic sclerosis than in systemic lupus erythematosus (SLE) and healthy individuals, and its increase in systemic sclerosis is associated with pulmonary fibrosis and decreased DLCO and FVC. It was observed that the levels were lower in patients with inactive ILD than in those with active fibrosis.66 A glycoprotein, YKL-40, may be a marker for evaluating pulmonary involvement in patients with systemic sclerosis,67 although it is not specific, since it is also elevated in other conditions, such as hepatic fibrosis and numerous malignant tumors.

Clinical onset is insidious and the manifestations appear at a late stage, perhaps due to the relative physical inactivity of patients with systemic sclerosis, so screening with non-invasive tests is recommended when there is clinical suspicion of systemic sclerosis. At disease onset, chest X-rays, PFTs, DLCO and even the 6-min walk test and HRCT scans should be performed. The most typical symptoms are dry cough, limited exercise tolerance and progressive dyspnea, although there is not usually a good clinical correlation between the dyspnea and radiological findings. There is a good correlation between the symptoms, DLCO and histological findings. Cough is rare, and occasionally there may be hemoptysis secondary to the presence of bronchial telangiectases. Bibasilar “Velcro”-like crackles at the end of inspiration, and in some cases cyanosis, acropachy and signs of right heart failure, can be observed on the physical examination.

Chest X-ray is of little use for early diagnosis; HRCT scanning is the most sensitive imaging test at this stage. In established ILD, a bilateral reticular pattern which is generally more pronounced in the bases can be observed, thin-walled cysts in bases known as honeycomb lung. HRCT scanning enables the type of lung lesions and their degree of extension to be determined, and detects involvement in up to 44% of patients with a normal chest X-ray. It has been seen that 85% of patients who present a normal HRCT scan at diagnosis do not develop ILD after 5 years of follow-up.68 For this reason, it is proposed that a CT scan be performed at diagnosis, and if there is no involvement, repeat after 2 and 5 years.69 In systemic sclerosis, we can find images with NSIP, UIP, DAD and COP patterns. Seventy-six percent (76%) of cases are NSIP, while UIP is only found in 11% of cases.70 At present, it is accepted that lung biopsy is not necessary in patients with scleroderma-associated ILD, except in cases in which there is a discrepancy between the clinical manifestations and the findings on the HRCT scan.19 It is considered that there is limited disease if there is involvement <20% on the HRCT scan and extensive disease if it is >20%.71

In all patients with systemic sclerosis, even in the absence of symptoms, PFTs should be carried out as screening. Most often there is evidence of a restrictive disorder with a reduction in the FVC below 80% and/or a decline in the DLCO below 75. The decrease in DLCO is the most sensitive static parameter and the first to be affected. It has been observed that up to 50% of patients with ILD may have abnormal PFTs at disease onset, even when asymptomatic, although only 16% have a reduction in FVC below 55%.72 An isolated reduction in the diffusion capacity confers an unfavorable prognosis for some authors.73 A DLCO <40% is correlated with a 5-year survival of 5%, while with a DLCO >40%, the 5-year survival is greater than 75%. The 6-min walk test may be altered in patients with systemic sclerosis, even in some cases with other normal PFTS and HRCT scans. However, this test has several limitations in these patients: measuring the saturation presents difficulties due to the presence of severe Raynaud's phenomenon, and musculoskeletal abnormalities in these patients mean that the results are not always a reflection of the pulmonary involvment.74

There are different opinions on the usefulness and clinical significance of BAL in patients diagnosed with scleroderma. BAL is not specific, but may reveal the presence of inflammatory alveolitis with neutrophils above 3% and the presence of more than 2% of eosinophils. The presence of alveolitis in the BAL is correlated with the severity, and has been related with a progressive deterioration in lung function.75

ILD associated with connective tissue disease has a better prognosis than idiopathic ILD.76 Black and Asian ethnicity, males, cardiac involvement and early onset of the disease are associated with more severe interstitial involvement.77 The prognosis worsens with FVC and DLCO less than 70%, extensive involvement on the HRCT scan and rapid deterioration, defined as a 10% reduction in the FVC and 15% reduction in DLCO in 1 year. Monitoring every 6 months with PFTs is recommended, or earlier if there is clinical deterioration in the absence of a valid cause.

On one hand, basic support treatment is required which includes oxygen therapy in cases where there is respiratory failure, rehabilitating treatment and treatment of gastro-esophageal reflux, since it is one of the factors that has been related with ILD, both idiopathic and associated with connective tissue disease. On the other hand, pharmacological treatment aimed directly at ILD includes treatment with corticosteroids and immunosuppressants. The use of corticoids is recommended in cases with NSIP-type radiological pulmonary involvement, although the increased risk that these patients have for presenting renal crises in connection with the administration of high glucocorticoid doses should be remembered, so the use of doses of under 15mg/day is recommended. In the recommendations established by the European League Against Rheumatism (EULAR), cyclophosphamide is recommended for the treatment of lung involvement.78 Cyclophosphamide treatment has been shown to improve PFTs, CT findings and quality of life measured using the Health Assessment (HAQ) and Short Form 36 Health Survey (SF36) questionnaires.79–82 The improvement may be more pronounced in patients with greater pulmonary involvement, with FVC <70%.82 It has been observed that some of the side effects of oral cyclophosphamide treatment may be reduced with the use of intravenous cyclophosphamide.82 Some results have been published on the use of mycophenolate in patients with scleroderma, in whom an improvement in FVC was shown after 12 months of treatment.82,83 Rituximab has demonstrated an improvement in interstitial disease in some isolated cases. Recently the 1-year results of a randomized study conducted with 14 patients with scleroderma were published, and it was observed that the group who received treatment showed an improvement in FVC and DLCO.84 Lung transplant is an option in patients with scleroderma and ILD whose involvement progresses despite having received cyclophosphamide treatment.

Systemic sclerosis is the connective tissue disease that is most often associated with PH, and is one of the most common causes of morbidity and mortality. It is the most common manifestation of pulmonary vascular disease in systemic sclerosis, and its prevalence varies depending on the series consulted, from 7% to 50%. It can appear alone or associated with ILD. It is more common in women, and the older the patient is at the time of diagnosis. Approximately one third of patients are asymptomatic; the most common symptom is dyspnea on exertion, which is usually late onset and progressive. Another symptom, although less common, is syncope during exercise. The clinical presentation, diagnostic procedure and treatments used do not differ from those used in idiopathic PH.85 Its onset causes a decrease in the survival rate from 88% to 40% 2 years after diagnosis. An annual echocardiogram is therefore recommended in all patients diagnosed with scleroderma. It has been observed that N-terminal pro-brain natriuretic peptide (NT-proBNP) and active BNP levels in these patients have high sensitivity and specificity for its diagnosis, and that decrease in the DLCO of below 60% is a predictive factor for developing PH.86

This is an uncommon manifestation in SLE, and occurs in 1%–5% of these patients.91 In some cases it may be the presenting form of SLE.92 It is characterized clinically by fever, dyspnea, cough and occasionally hemoptysis. Bilateral infiltrates can be found on the chest X-ray, predominantly in the bases. Ground-glass infiltrates and areas of reticular thickening with a honeycomb pattern can be seen on the HRCT scan. Histopathological examination of the lesion is not specific, and shows alveolar wall damage with necrosis, edema and alveolar hemorrhage and formation of hyaline membranes; capillaritis can also appear. Granular deposits of immunoglobulin G and complement can be found in the alveolar septa.89

The frequency of this complication is higher in patients with anti-SSA antibodies.93 The prognosis is poor, with mortality close to 50%. It has a worse prognosis if there are predominantly neutrophils or eosinophils in the BAL, and if it appears in the post-partum period. In survivors, it may progress to chronic interstitial pneumonitis with severe restrictive ventilatory impairment.

It is essential to make the differential diagnosis with infections, so it is usually necessary to perform a BAL to look for potential pathogens. Empirical antibiotic treatment should be administered until infection has been discarded. The treatment of acute pneumonitis is based on corticoids at high doses of 1–2mg/kg/day and, in very critically ill patients, pulses of 1mg/day for 3 days. If there is a lack of response, other immunosuppressants such as cyclophosphamide, intravenous immunoglobulins and plasmapheresis can be added.89

This is a rare complication in SLE, with a prevalence of around 3%–9%.94 It may exist in sub-clinical form in one third of patients, in whom abnormalities can be observed on the HRCT scan, despite being asymptomatic.95

The symptomatology is similar to idiopathic pneumonitis, with progressive dyspnea on exertion, dry cough and onset of dry “Velcro” crackles in the auscultation, predominantly in the bases. The radiological findings do not differ from those produced by idiopathic pneumonitis either. Ground glass infiltrates, a reticular pattern and honeycombing may also appear. The radiological findings are related and are predictive of the histopathological pattern. The ground glass infiltrates are related with the NSIP pattern, and the honeycombing with UIP. The histological patterns found in lung disease secondary to SLE are similar to those in idiopathic pneumonitis; the most common is the NSIP pattern, followed by the UIP pattern; LIP and COP patterns have also been observed.96

Treatment should be individualized, as in general this pneumonitis is less aggressive than idiopathic pneumonitis. Infection should be ruled out by BAL or lung biopsy. Treatment is based on high-dose corticoids, and it is sometimes necessary to add another immunosuppressant, such as cyclophosphamide, azathioprine or mycophenolate.97

COP is characterized histologically by the formation of fibrous tissue in the bronchioles and alveolar ducts. It causes dry cough, dyspnea, chest pain, fever and respiratory failure. Peripheral patchy alveolar infiltrates (which may be bilateral) can be found on the radiological studies, with thickening of the bronchi. It can be diagnosed with transbronchial biopsy or, occasionally, with a lung biopsy. It usually progresses favorably when treated with corticoids, although it is sometimes necessary to add another immunosuppressant.

This is a rare, although potentially fatal, complication of SLE. Its prevalence varies between less than 2% and 5.4% of patients with SLE, and it may be the first manifestation of this disease.98 The symptoms usually develop in hours or a few days, with fever, cough, dyspnea and hemoptysis. It usually occurs in patients with active SLE. Radiologically, bilateral alveolar infiltrates can be observed; magnetic resonance imaging may be useful for demonstrating the presence of blood.90 The DLCO is usually elevated, which differentiates it from acute pneumonitis. BAL is useful for discarding infection and enables the diagnosis to be confirmed, as macroscopically it shows a hemorrhagic fluid and microscopically, abundant hemosiderin-laden macrophages.

It is important to make a differential diagnosis with infection, pulmonary embolism and vasculitis, and to discard coagulopathies. The definitive diagnosis is lung biopsy, in which two patterns can be found: capillaritis with immune complex deposits or hemorrhage.90

Treatment is based on the use of high-dose corticoids together with cyclophosphamide. Plasmapheresis is also useful. Rituximab could also be useful, but further studies are required.99

This is not a common complication of SLE. Its prevalence varies between 3% and 4% in SLE patients, according to the series.100,101 It is not related with either the duration or severity of the lupus, and may be a presenting form of SLE. It has a worse prognosis and poorer survival than primary PH.102

The diagnostic test is Doppler ultrasound, which enables the pulmonary arterial pressure to be estimated and helps to discard other causes of PH. The diagnosis should be confirmed with right cardiac catheterization, which will show pulmonary artery pressure >25mmHg and capillary wedge pressure <15mmHg, with decreased cardiac output.

Treatment is similar to PH, although calcium channel antagonists have not proven as effective. They include anti-coagulants, calcium antagonists, endothelin receptor antagonists (bosentan, ambrisentan), sildenafil and prostacyclins.103,104 Treatment with immunosuppressants such as cyclophosphamide may bring some additional benefit.104

This refers to an episode of respiratory failure without clear evidence of pulmonary disease in patients hospitalized for SLE. Its pathogenesis is unclear, although it is postulated that it is due to leukoagglutination and activation of complement in the pulmonary capillaries. It usually responds favorably to treatment with corticoids alone or in combination with aspirin.105

This consists of the onset of dyspnea, weakness of the respiratory muscles and a decrease in the lung volumes on the chest X-ray, with elevation of the diaphragm and a restrictive pattern in the functional tests in the absence of parenchymal involvement that justifies it. The prevalence is around 0.9% of patients with SLE.99

Clinically, patients report dyspnea on exertion, which sometimes remains even at rest and worsens when supine. Cough is rare. In the auscultation, there may be diminished breath sounds at the bases, and sometimes crackles. Radiologically, it manifests with elevation of the diaphragm and laminar atelectasis at the bases. A restrictive pattern will be observed in the PFTs.

It has a good prognosis and an acceptable response to treatment, which consists of corticoids, to which bronchodilators and theophylline can be added.

This is a type of lymphoproliferative disease that usually coexists with LIP and lymphocytic bronchitis. Histologically, it is characterized by nodules of lymphocytic infiltrates with germinal center hyperplasia around the bronchioles. It responds well to corticoid treatment.107,108

This is a rare disease, in which there is angiodestructive, granulomatous and lymphoreticular proliferation. It can affect the lungs, skin and central nervous system.

The prevalence of primary pulmonary lymphoma in patients with SS is estimated to be between 1% and 2%.112 They are generally B-cell MALT lymphomas. Its radiological presentation is very varied, and it can appear as masses, single or multiple nodules that may be cavitated and diffuse infiltrates. It is sometimes indistinguishable radiologically from other types of benign diseases. Diagnosis should be made with lung biopsy.