Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease mainly causing synovitis and deforming arthritis. Extra-articular complications (EAC) are defined as the pathologies not directly related to joint disease. RA has extra-articular complications (EAC), especially cardiovascular and respiratory, which increase morbidity, and mortality1. EAC of RA occurs in approximately 40-50% of cases and needs aggressive treatment2. These are often complications due to vasculitis, chronic inflammatory process, and nodules, often more in severe RA and are most directly related to RA factor titer3.

EAC can involve many organs, especially skin, cardiovascular, lungs, peripheral nervous system, ocular, and haematological. However, CNS, kidneys and GIT involvement due to RA per se are less common but these organs are often involved due to RA related medications or amyloidosis or systemic vasculitis4. The prevalence of most EAC in RA patients has decreased due to more effective therapies such as Disease Modifying Anti Rheumatoid Drugs (DMARDs). However, the incidence of RA related lung disease has not declined, and this could be due to increased diagnostic skills and increased survival of the RA patients2.

This review will mainly focus on RA related lung diseases and their clinical significance [Table 1]. In some patients, lung involvement can start before articular manifestations in 10-20% of cases5. Hence, it's essential to keep in mind RA as one possible cause of lung involvement of unclear cause. Lung involvement in RA can be any of the following alone or in variable combinations; interstitial lung diseases, pleural disease, pulmonary capillary disease, pulmonary hypertension, nodules, and airway disease. Drug-related lung toxicities and increase risk of infections are also common6. Most of these complications occur in the severe disease7.

Pathophysiology of RA-ILD:

Possible mechanisms of initiation of RA-ILD includes many hypotheses. Citrullination of lung proteins promotes increased binding to HLA-DRB1 and increases immunogenicity8. Smoking can cause Citrullination and hence increase the risk of RA-ILD9. Lung infections can lead to the Citrullination of lung proteins. Those with abnormal HL-DRB1 also have a high risk of RA. Bronchus-associated lymphoid tissue (BALT) found in RA patients' lung tissues can produce cytokines and anti-CCP. These mechanisms may explain why some patients have positive anti-CCP and lung disease only or why 10-20% of cases have lung involvement before articular manifestations10. These patients with de novo lung disease without any symptoms or signs of rheumatoid arthritis should have rheumatoid arthritis excluded. These patients often present with chronic dyspnoea and dry cough and may have fine end inspiratory crackles at lung bases. RA-ILD patients often have high titre of RA factor and / or anti-CCP in the blood10,11.

Epidemiological factors for RA-ILD:

RA-ILD is more common in men in the 50- 60s, smokers, high titer of RA factor, longstanding RA and elevated anti-CCP antibodies' titer. Male to female ratio for RA-ILD is 2:1, although the prevalence of RA is more common in females. Age is an important and consistent risk factor for RA-ILD12. RA-ILD is the most common lung manifestation of RA, and approximately 30% of RA patients have ILD on HRCT13. However, the prevalence rate varies from 4% to 68% depending on the population studied (country, symptomatic, asymptomatic or autopsy) and the methodology used for diagnosis (HRCT, Chest X-ray or lung function tests).

HRCT Chest & Lung Function Tests:

Infections can mimic many of the radiological changes of RA related lung disease, so it's prudent to exclude infections and other aetiologies as clinically appropriate. Lung function tests will show a restrictive pattern with reduced lung volumes, FVC, and KCO13. Usual interstitial pneumonitis is the most common (40-62%) pattern of RA-ILD seen in RA, unlike other autoimmune diseases affecting lungs where non-specific interstitial pneumonitis (NSIP) is more common ILD [Fig 1]. UIP is sub pleural, predominantly basal, reticular shadowing with honeycombing and no ground-glass opacities. The second common (1132%) ILD pattern in RA is NSIP, basal ground glass opacities without honeycombing14. Third common patterns of RA-ILD includes cryptogenic organizing pneumonia (COP) which shows areas of non-infective consolidations. Other less common patterns include lymphocytic interstitial pneumonitis (LIP), desquamative interstitial pneumonitis (DIP), damaging alveolar disease (DAD), or combined pulmonary fibrosis with centrilobular emphysema (CPFE)15.

There is an excellent correlation b/w radiological and histopathological finding in cases with IPF and similar correlation exist for RA-ILD16. This is why radiological findings are sufficient for diagnosis in majority of the cases suspected to have RA-ILD and surgical biopsy is needed only when radiological findings are non-diagnostic. UIP has poor response to immunosuppressive drugs and hence poor prognosis. NSIP and COP has good response to steroids and better prognosis. Hence radiological or tissue certainty is very important.

Histological assessment of RA-ILD:

BAL (Broncho-alveolar lavage) helps diagnosis of ILD and also helps in therapeutic in cases such as LIP and DIP17. BAL fluid has higher concentration of cytokines and inflammatory mediators such as platelet derived growth factors, interferon and transforming growth factors in cases with NSIP pattern when compared to those with UIP pattern. Also, majority of the smokers have UIP pattern18. Studies have shown a smaller number of fibroblasts and increased CD4 lymphocytes in histopathological specimen from patients with RA-UIP when compared with IPF. This may be the reason why RA-UIP or CTD-UIP may have better prognosis than IPF. However, study conducted by Park et al. didn’t find any statistically significant difference in survival among UIP pattern of any cause (related to RA or IPF)19.

Treatment and prognosis of RA-ILD:

RA-ILD is treated with the use of immunosuppressants regardless of the underlying ILD pattern, smoking cessation, treatment for GORD, Oxygen supplementation, rehabilitation for lung diseases, and preventative vaccines. The mainstay for immunosuppressive therapy is corticosteroids. Other immunosuppressants such as Cyclophosphamide (Cyc), Azathioprine (AZA), Cyclosporine (CS), or Mycophenolate (MMF) are used, and response is better in cases with NSIP or COP20. Methotrexate (MTX) is not proven to worsen preexisting RA-ILD. Similarly, it's not clear whether TNF inhibitors or Rituximab worsen or improve RA-ILD. A lung transplant may be considered in young patients, especially those with UIP whose lung disease doesn't respond to drug therapy21. UIP has a poor prognosis like IPF. Risk factors for poor prognosis are male, old age, the extent of fibrosis, and reduction in KCO13. Many studies have demonstrated poor survival in patients with UIP and spontaneous or treatment related resolution in patients with NSIP19.

Fig. 1: Comparison of various patterns of ILD in different connective tissue disorders:

0 10 20 30 40 50 60 70 80 90 100 RA SS UCTD Scl UIP NSIP GGO/Other 0 10 20 30 40 50 60 70 80 90 100 RA SS UCTD Scl UIP NSIP GGO/Other

Abbreviations: GGO (Ground glass opacities), NSIP (Non-specific interstitial pneumonitis), RA (Rheumatoid arthritis), SS (Sjogren’s syndrome), UCTD (Undifferentiated connective tissue diseases), UIP (Usual interstitial pneumonitis). Prevalence quoted from the article by Eunice JK et al.22.

Suggested screening for RA-ILD:

Although there are no clear guidelines for ILD screening in asymptomatic RA patients, however, some studies do suggest screening by symptoms (dry cough dyspnoea), examination (fine end inspiratory basal crackles, clubbing) and chest x-ray at the initial diagnosis and then every year. Any patient with suspected ILD should get HRCT chest and lung function tests. This may help detect these patients at early stage and prevent the progression. If HRCT shows RA-ILD but is unequivocal about the pattern, such patients may need surgical biopsy if not contra-indicated. Those with UIP pattern should be counselled about poor prognosis and may be referred for assessment related to possible lung transplant when clinically practical22. These suggestions may need further exploration with regard to cost effectiveness.

Clinical & radiological presentations:

Prevalence of RA nodules vary from 0.4% in radiological studies up to 32% in autopsies studies of RA patients. Mostly there are no symptoms and no specific treatment is needed.

Nodules, like subcutaneous nodule have fibrinoid necrosis, vasculitis and macrophages. These are rounded nodules mostly located in sub pleural part of the middle or upper lobe. Size can vary from single to multiple and a few mm to several centimetres (up to 7cm). These can cavitate due to necrosis and cause pleural effusion, pneumothorax, hydro pneumothorax, bronchopleural fistula, or superadded infection23.

Predisposing factors and treatment:

These are more common in those with subcutaneous RA nodules. Similarly, patients may have nodules in myocardium and /or cardiac valves as well. Other risk factors are RA factor's high titer, male patients and smokers. Methotrexate and TNF inhibitors can increase the nodule size. These nodules have no relation with the disease activity in the joints6.

Diagnostic considerations:

Chronic infections such as TB and fungus are common in immunocompromised rheumatoid arthritis patients and can mimic these nodules with cavitation. Wegner’s granulomatosis or Churg Strauss Vasculitis can also have similar pictures. Infections often have constitutional symptoms, air-bronchogram, tree in bud opacities and mediastinal lymphadenopathy. Irregular margins with sharp projections, spiculated appearance, and rapid growth in size may also point toward malignancies24. Malignancy is an important differential, especially if the patient is a smoker. A follow-up interval CT scan may help monitor any change in the size or shape. PET scan can also help characterize and differentiate from malignant cause. RA nodules classically have low uptake due to necrosis and fibrosis unless there is active inflammation. When the diagnosis is equivocal, biopsy may be needed25,26. RA nodules with occupational (asbestosis, coal, or silica exposure) pneumoconiosis are called Kaplan syndrome. Prognosis is generally god in these patients27.

Primary or secondary pulmonary hypertension:

High risk of venous thromboembolism (VTE) & pulmonary emboli (PE), vasculitic changes in pulmonary capillaries, RA-ILD and airway diseases & rheumatoid related heart disease causes pulmonary hypertension (PHTN) in RA patients [28]. However, a significant number (21%) of RA patients have isolated pulmonary hypertension without having lung or heart or VTE related factors29.

These patients may be less symptomatic due to limited mobility unless the disease is advanced. An echocardiogram is the first tool used, and patients may need the right heart catheterization in some cases. Pulmonary artery systolic pressure of more than 30 mmHg by Doppler Echocardiography is defined as pulmonary hypertension. RA related PHTN cases can be treated similar to other such cases due to connective tissue diseases6.

Pleural effusions and pleuritis:

Pleural inflammation, impaired fluid resorption by pleura, and rupture of nodules are the primary mechanism for exudative pleural effusion. Pleurisy and pleural thickening are common in RA. Pneumothorax is rare, but pleural effusion can coexist with pericardial effusion. Pleural effusion is often unilateral and more in old age.

Diagnostic imaging:

CT or Chest X-ray or ultrasound can be used to detect pleural effusions. CT helps better as it can elaborate pleural nodules, bronchopleural fistula, or underlying parenchymal disease as well6. Pleural fluid aspiration and analysis is essential. Sometimes video-assisted thoracoscopy and pleural biopsy are also needed, especially to exclude other causes such as TB or malignancies30.

Pleural fluid analysis:

Exudate effusion in rheumatoid arthritis usually has a high RA factor titer Low glucose later is due to reduced crossing ability caused by the pleural thickening and increased glucose consumption by inflammatory cells31. Chronic effusion has more drop in glucose, which can be low or normal in acute effusion. Chronic effusion also causes cholesterol crystals (pseudo-chylous effusion) without high Triglycerides or chylomicrons. Acute can have neutrophils, whereas chronic is mainly lymphocytic. Eosinophils can also be present in the fluid. Multinucleated giant cell with intracellular inclusions of IgG &/or RA factors) are classic but not always present32.

Treatment:

Pleural effusion treatment is treated with therapeutic aspiration if they are large. Otherwise, treatment is that of the underlying cause, and effusions often resolve slowly over periods of months. The risk of pleural fibrosis and trapped lung is an important factor to consider when deciding to wait and watch policy. Surgical decorticating is needed for trapped lungs6.

The upper airway Disease:

Laryngeal involvement can be involved due to arthritic changes of the cricoarytenoid joint, dislocation of the joint, nodule formation on the vocal cord, or vasculitis affecting recurrent laryngeal nerve or vagus nerve. Vocal cord examination with laryngoscopes will help diagnose; however, HRCT will help detect the cricoarytenoid joint synovitis or deformities.

Treatment is airway support for acute obstruction or otherwise that of the underlying RA33.

Lower airways disease:

Bronchioles can have follicular bronchiolitis (FB), obliterative bronchiolitis (OB), bronchial hyperresponsiveness or bronchiectasis. FB is BALT hyperplasia causing thickened bronchial walls and restrictive or obstructive lung function test. HRCT shows branching peri bronchial small (<3mm) nodules34. OB is fibrosing/constricting bronchiolitis with the rapidly progressive obstructive disease more common in females with long standing seropositive RA. Penicillamine, gold salts, and sulfasalazine can also cause OB. HRCT is non-specific emphysema, bronchiectasis, and wall thickening6.

Treatment:

Follicular bronchiolitis needs standard treatment for RA PLUS may need corticosteroids and Macrolides. Treatment for OB is difficult and needs strong immunosuppressive drugs, which may or may not work. A lung transplant may be required35.

Methotrexate (MTX):

MTX can cause acute pneumonitis, a hypersensitivity response, more within the first year, with histologically having eosinophils and non-necrotizing granuloma but non-specific HRCT findings. It improves by stopping the drug and adding corticosteroids if needed—chronic fibrosing interstitial lung disease with fibrosis. Also, MTX can cause worsening of rheumatoid nodules. Risk factors include old age, other extra-articular complications, diabetes, low albumin, genetic predisposition to drug sensitivity, and prior use of other DMARDs36.

Leflunomide & Other DMARDs:

It can cause epithelial-mesenchymal transition, hence promoting fibrotic ILD, ten times more in Asians (1%) as compared to the Western37. Gold salt, penicillamine, and sulfasalazine can cause bronchiolitis obliterated. Biological and immunosuppressive drugs do increase the risk of infections.

TNF inhibitors & Rituximab:

There is no clear cause-effect relationship documented. However, various small studies suggested these drugs may rarely exacerbate ILD, but the risk is very low and inconsistent. TNF inhibitors increase the risk of reactivation of TB38.

Pulmonary complications associated with rheumatoid arthritis play a vital role in decision making for RA patients' management. Firstly, many drugs used to treat RA, such as methotrexate, leflunomide, sulfasalazine, gold salt, penicillamine, and possibly biological drugs, can also affect the lungs directly as a side effect or indirectly by promoting infections. Secondly, infections and other medical illnesses such as malignancies can also mimic many of the RA-associated lung pathologies and are more common in RA patients than among the general population. This leads to a considerable delay in the early recognition of the RA related complications and hence increase morbidity and mortality. Thirdly, RA-related lung pathologies are common in severe and chronic RA, smokers, and the older population which affects the patient's ability to cope with the intensive nature of the treatment needed. Fourthly, RA related lung disease are the second common contributing factor for increased mortality (next only to cardiac complications)2,4,5-7.

Most lung complications are insidious onset, often subclinical, or present with non-specific symptoms that may not surface due to reduced mobility of RA patients. Hence, when they present clinically, it may already have progressed. This is especially true about ILD. Also, unlike other connective tissue disorders that present more with NSIP, RA mostly has UIP which is the most poorly responding variety of ILD and the prognosis is poorer. A significant proportion of RA patients (10- 20%) can present just with the pulmonary disease without articular disease at the onset7,9,12,13.

We should have an aggressive approach with a high index of suspicion about lung complications in rheumatoid patients to detect and adequately manage RA associated systemic diseases. Though not a part of guidelines, however, thorough history, lung auscultation, and routine chest X-ray at regular intervals may help raise suspicion. HRCT and lung function tests should be done when there is any clue regarding rheumatoid related lung issues. HRCT often gives a diagnosis. Rheumatoid arthritis patients may need further testing, such as bronchoalveolar lavage (BAL), surgical lung biopsy, pleural biopsy, transthoracic echocardiography, and right heart catheterization depending on the clinical indication22.

Once diagnosed, RA related lung disease (s) should be managed by multimodality approach including adequate control of rheumatoid arthritis by immunosuppression, smoking cessation, oxygen therapy, pulmonary rehabilitation, cardiac risk assessment, and management. Specific treatment related to the complications (as discussed earlier) should also be added to the regimen. Early evaluation for lung transplant should be done for suitable transplant patients whose pulmonary disease is poorly controlled despite adequate medical therapy such as obliterative bronchiolitis or advanced ILD due to UIP19,21,35.

Due to the multifactorial impact of rheumatoid related extra-articular complications on management, morbidity, and mortality the team treating such patients should be vigilant for early detection and treatment of complications. Further information is needed to establish the biological agents' safety regarding, or cause-effect relation (if any) with, the pulmonary complications.

Abbreviations: BAL (Broncho-alveolar lavage), CPFE (Combined pulmonary fibrosis & emphysema), CTPA (CT pulmonary angiogram), DIP (Desquamative interstitial pneumonitis), DAD (Diffuse alveolar damage), FB (Follicular bronchiolitis), FBC (Forced vital capacity), HRCT (High resolution CT), ILD (interstitial lung disease), KCO (Corrected carbon mono-oxide diffusion), LIP (Lymphocytic interstitial pneumonitis), NSIP (Nonspecific interstitial pneumonitis), OB (Obstructive bronchiolitis), PE (Pulmonary embolism), RA (Rheumatoid arthritis), RLN (Recurrent laryngeal nerve), UIP (Usual interstitial pneumonitis), , VAT (Video assisted thoracoscopy), V/Q (Ventilation perfusion scan).