Interstitial lung disease

Diagnosis

Pulmonary function tests

Pulmonary function tests (PFTs) are sensitive, but relatively non-specific. The majority of patients demonstrate a restrictive defect with low total lung capacity (TLC) and low forced vital capacity (FVC), low transfer factor of the lung for carbon monoxide (TLCO) and oxygen desaturation at rest or on exertion . Decreased TLCO is the most sensitive test for predicting the presence of ILD, the extent of disease and the prognosis . PFTs are very valuable for monitoring disease change over time. Recommendations for monitoring are 3–6 monthly, then every 6–12 months if stable. Suggested parameters for significant decline are a 15% decrease in DLCO and 10% decrease in FVC from baseline values .

Imaging

High-resolution computed tomography (HRCT) has become the standard non-invasive method of diagnosis. Studies suggest a high level of correlation between HRCT features and underlying histopathological pattern of usual interstitial pneumonia (UIP) . However, HRCT findings of the non-specific interstitial pneumonia (NSIP) pattern can be diverse; therefore, surgical lung biopsy (SLB) may be helpful when findings are not typical of UIP . HRCT patterns of RA-ILD subtypes are outlined in Table 1 and illustrated in Fig. 1 .

a. Usual interstitial pneumonia (UIP) is typified by honeycombing affecting the basal segments of both lungs extending from the periphery inwards and associated with scarring and volume loss as fibrosis progresses. b. Non-specific interstitial pneumonia (NSIP) is characterised by increased alveolar density with a dense inflammatory process predominantly affecting the basal lung segments and progressing proximally.

Plain chest radiography can reveal reticular and fine nodular opacities in the lower zones, but it has a low sensitivity and can be normal until the process is relatively advanced .

Bronchoalveolar lavage

Bronchoalveolar lavage (BAL) is not routinely used due to non-specificity of its findings. BAL can be a useful adjunct to clinical and radiographic evaluation in excluding infection, certain cancers and rarer causes of ILD, for example, sarcoidosis. BAL in RA-ILD patients predominantly shows an inflammatory pattern with increased lymphocytes, macrophages and neutrophils .

Lung biopsy

The gold standard for establishing a histopathological diagnosis is the SLB, although due to its potential risks, it is rarely undertaken unless HRCT findings are indeterminate. If biopsy is performed, the preferred option is now video-assisted thoracoscopic surgery rather than open-lung or transbronchial biopsy .

Differential diagnosis

RA patients presenting with acute respiratory symptoms may have an exacerbation of pre-existing ILD (known or previously unknown), infection (particularly as many RA drugs are immunosuppressive), pulmonary embolism, a drug reaction or acute pulmonary oedema.

Although ILD more often arises in patients with established RA, it can be the presenting feature of RA in up to 10% of cases. Hence, in patients presenting with idiopathic interstitial pneumonia (IIP), an underlying connective tissue disorder (CTD) or RA should be excluded clinically and serologically . It is important to distinguish between primary RA-ILD and secondary diffuse lung disease as a result of indirect complications, including iatrogenic, for example, adverse effects of DMARDs, infection and lymphoproliferative disease. This differentiation can be challenging and is principally based on clinical judgment and context, a temporal link of disease development with a particular therapy and response to withdrawal of the suspected agent .

Treatment

To date, there is no specific treatment for RA-ILD, and with the lack of robust trial data, there is no current consensus for its management. Approaches include conservative, medical and surgical.

Conservative therapy

For patients with mild disease or contraindications to pharmacological treatments, such as multiple comorbidities, advanced age or frailty, conservative treatment encompassing education, psychosocial support and exercise rehabilitation may be advisable.

Pulmonary rehabilitation has beneficial short-term effects on dyspnoea, functional exercise capacity and quality of life in IPF . However, its utility in RA is as yet undefined, and likely to be limited due to the functional limits articular disease can impose on patients . The development of RA-specific protocols needs to be considered.

With cigarette smoke implicated in inducing and worsening both the severity of articular disease and lung damage, smoking cessation support is key. Supplemental oxygen therapy has an important role in palliating severe disease, though its effect on the disease course remains limited . Appropriate treatment for acute and coexisting infections should be given, while vaccinations against both influenza and pneumococcal infection are recommended for RA-ILD patients, particularly as many RA drugs are immunosuppressive.

Immunosuppressive agents

Traditionally, the treatment for RA-ILD has been empirical, with corticosteroids typically used as first-line agents based on limited evidence from the IIPs, and often with highly variable results, although certain ILD subtypes such as cryptogenic organising pneumonia can be steroid responsive and may be managed with aggressive corticosteroid therapy and frequent follow-up . Corticosteroids may be combined with other immunosuppressive agents such as cyclosporine and cyclophosphamide, though again with little evidence behind this approach. The roles of warfarin , N-acetylcysteine and azathioprine, all of which showed initial promise in IPF, have been discredited after disappointing trial results. There is an estimated fourfold increase in the risk of serious infections with corticosteroid use, which is a significant concern .

Cyclophosphamide is commonly used to treat patients with aggressive ILD, although literature has shown limited benefit . Cyclophosphamide may be useful in extensive or rapidly progressive RA-ILD with high inflammatory activity and in steroid unresponsive suspected drug-induced pneumonitis . If patients enter remission, the use of agents such as mycophenolate may be useful in maintaining this state.

Mycophenolate mofetil (MMF) can stabilise or improve pulmonary function in CTD-ILD . In patients with early or limited RA-ILD, it appears effective at doses of 1–2 g per day ; however, it does not entirely ameliorate the articular manifestations of the disease, necessitating concomitant use of DMARDs . Data from a large retrospective cohort of 290 patients in UK showed an association between treatment with MMF and prolonged survival in comparison with those treated with azathioprine . It is hoped that these findings will be confirmed in a prospective study of patients with non-fibrotic RA-ILD.

Disease-modifying anti-rheumatic drugs (DMARDs)

The treatment of RA-ILD is complicated because DMARDs of proven articular benefit, particularly methotrexate (MTX) and leflunomide, have been implicated in the development of drug-related pneumonitis or accelerated respiratory failure with pre-existing ILD. This is detailed later in this chapter.

Biologic drugs

Rituximab

Rituximab is a monoclonal antibody against the B cell marker CD20, licensed for the treatment of RA in anti-TNF non-responders. Patients with RA-ILD were noted to have follicular B cell hyperplasia and interstitial plasma cell infiltrates, suggesting potential B cell involvement in its pathogenesis . Most published studies to date of the safety and efficacy of rituximab for patients with RA-ILD have been small, but the BRILL group have produced data from 290 patients followed over 25 years, showing an impressive improvement in mortality over this time. They ascribe much of this to the use of newer agents, including rituximab, which was associated with an improvement in survival when compared to TNFi therapy .

Other agents

There is a paucity of data regarding the efficacy and safety of newer biological therapies in RA-ILD, including T cell co-stimulation blocker abatacept, IL-6 receptor monoclonal antibody tocilizumab and IL-1 receptor antagonist anakinra.

Tyrosine kinase inhibitors (TKI) have demonstrated some encouraging results in IPF and systemic sclerosis (SSc–ILD), whereas other studies have shown poor or equivocal results. There is currently no literature to support their use in RA-ILD, whilst experiences in oncology implicate TKIs in severe or fatal ILD, particularly in patients with pre-existing pulmonary fibrosis. Pirfenidone, an antifibrotic agent, has been approved by NICE after demonstrating efficacy in IPF . A study of its efficacy is proposed in RA-UIP, and this should provide information regarding its potential future role. Bosentan, an endothelin receptor antagonist used for pulmonary arterial hypertension, raised interest for its potential role in the management of fibrosis, but the early promise shown in studies undertaken in IPF and CTD-ILD was not sustained . Studies specifically evaluating its use in RA-ILD are required to draw firm conclusions.

Lung transplant

For patients with advanced refractory disease, single lung transplantation should be considered. However, there are few studies evaluating post-transplant outcomes in RA-ILD patients. A retrospective study of survival in 10 RA-ILD patients who underwent transplantation compared with 53 patients with IPF and 17 with SSc-ILD reported similar survival rates in RA-ILD compared to IPF (67% vs. 69%, respectively), but better survival in SSc-ILD (82%) .

Lung transplantation may be most effective in patients under the age of 60 who do not have any significant comorbidity and have good functional ability and exercise tolerance. Referral to transplant should occur prior to oxygen dependence and decided with joint respiratory and rheumatology input. Where lung transplantation is contraindicated because of age, immobility and comorbidities, active palliation may be introduced. Measures include supplementary oxygen therapy and treatment of cough, gastro-oesophageal reflux and breathlessness.

Mortality and prognosis

In addition to the increased mortality associated with RA itself, RA-ILD is a significant cause of mortality. Median survival with untreated RA-ILD was only 3 years at the turn of the century , and ILD is the second commonest cause of premature death after cardiovascular disease, mainly due to progressive respiratory failure and infective complications. The major determinants of prognosis are ILD subtype and disease extent. UIP appears to carry a worse outlook compared to NSIP, cryptogenic organising pneumonia (COP) and overlap syndromes . More extensive fibrosis or worsening of the extent of disease on HRCT also predicts survival; extensive disease (>20% of lung affected on HRCT) doubles the relative risk of dying compared to limited involvement. However, there has been a significant improvement reported in the prognosis associated with RA-ILD over the last 15 years ( Table 2 ).

Background

The association between RA and BR is well recognised. The prevalence of BR in the RA population is estimated at 2%–3.1% , while the prevalence of RA in patients with BR is reported to be 3%–5.2% . Walker observed a 10-fold increased prevalence of BR in RA compared to the general population . A literature review revealed 289 reports of BR, with respiratory symptoms preceding articular involvement in 90% . BR often precedes RA by many years (16–28 years) , while RA develops at an earlier age in those with BR than in those without BR (46 vs. 51 years) . However, other studies have demonstrated that RA may precede the development of BR, and it appears possible that there exist two different mechanisms of development of BR in patients with RA.

Mechanism

The mechanism underlying the association of RA and BR has been the subject of much research lately. Antibodies to citrullinated peptides are quite specific for RA and may play a role in the disease process. Furthermore, citrullinated peptides are found within the lungs of patients with RA, especially in smokers where citrullination is triggered in the context of smoking-induced inflammation . This mechanism is important in patients with either ILD or BR, as evidenced by very high rates of anti–cyclic citrullinated peptide (CCP) antibodies in both RA-ILD and BR. Some authors have hypothesised that infection as a result of BR provides a prolonged source of antigenic stimulation, which in genetically predisposed individuals, can lead to the development of RA . In these patients, the infection appears to trigger B cells, which potentiate chronic inflammatory damage .

It has also been proposed that RA and BR may share a similar genetic predisposition . It is also plausible that DMARDs suppress the immune system and predispose to pulmonary infection, contributing to the development of BR. A French study found that patients with RA and symptomatic BR were more likely to be heterozygous for the ΔF508 mutation, compared to those with RA without BR and those with BR of unknown aetiology . ΔF508 mutation is associated with cystic fibrosis, which is also associated with citrullination in the lung, offering further support for the concept that infection can trigger this process. There is a dearth of specific studies on the association of RA-BR with smoking, but the limited data available suggest that patients with RA-BR are more likely to be non-smokers than those with RA alone

Clinical features

It is important to recognize that BR coexistent with RA differs from other types of BR. Patients with concomitant RA and BR have worse obstructive airways disease, increased susceptibility to recurrent pulmonary infections, faster lung function decline with reduced life expectancy and higher mortality, compared to subjects with either RA or BR alone. Although BR has been demonstrated on HRCT in ∼30% of cases of RA, not all patients have symptoms . Those who do complain of a cough, which is often episodically productive of coloured sputum, also have associated decreased exercise tolerance. Signs may include finger clubbing and asymmetric lung crackles with partial clearance on coughing. The diagnosis is most often confirmed by computed tomography.

Management

BR and RA are both chronic conditions requiring long-term medical management. Specific guidelines for the management of patients with concurrent RA-BR are lacking, and the evidence base to formulate such recommendations is limited. At present, it is advisable that the management of such patients should be broadly based on the guidelines in place for the separate conditions, but influenced by the clinical experience and tailored according to individual basis. RA-BR patients require regular follow-up, with the involvement of a multidisciplinary team, including a chest physician, prompt treatment of infections and recognition of adverse effects secondary to immunosuppressive treatment.

It is recommended all patients with RA-BR should undergo review by a specialist chest physician with an interest in BR, who should liaise closely with the responsible rheumatologist. Screening for other causes of BR, in particular for immune deficiency (which may occur secondary to treatment for RA), should be carried out. For patients with asymptomatic chest disease and quiescent RA, annual review would seem sufficient. Patients with sputum production should be reviewed by a respiratory physiotherapist for instruction in airway clearance and the use of mucolytics. Patients with active IJD or symptomatic pulmonary disease are at risk of more advanced/progressive respiratory problems and should be offered regular clinical monitoring every 6 months, with lung function testing, screening for bacterial colonisation by sputum culture and radiological assessment. The physiology of the bronchiectatic lung in RA differs from non-rheumatoid–related BR. Spirometry shows more pronounced obstructive airways disease with less reversibility in the RA-BR population than in the other types of BR . A trial of inhaled corticosteroids may be appropriate for those with reversible airways obstruction. Prior to commencement of immunosuppression, all patients should be offered vaccination against pneumococcal and influenza infection. Strict follow-up should be offered to patients with RA on biological and non-biological DMARDs, so treatment can be stopped or changed when serious adverse events occur. Long-term oral corticosteroids increase the risk of infections and should be avoided. Most DMARDs should be suspended during antibiotic therapy if infection develops. Hydroxychloroquine is the exception to this rule.

For patients commencing TNFi therapy, careful screening for mycobacteria is appropriate. Extreme caution with these agents in patients with active RA-BR is warranted. By contrast, the use of the anti–B cell drug rituximab, advocated by NICE for patients who fail anti-TNF drugs, may stabilise both BR and articular disease . Prompt assessment and treatment with appropriate oral or intravenous antibiotics should always be readily available. Antibiotic prophylaxis should be considered in patients with frequent (three or more exacerbations per year) or severe infections requiring hospitalisation/intravenous antibiotics. The choice of agent should be guided by sputum microbiology, but Azithromycin in the dose of 250 mg 3 days a week is often prescribed. For patients with severe or progressive disease, or those who do not respond to first-line treatment options, the ‘multidisciplinary team for patients with RA-BR’, which includes a radiologist, a chest physician, a rheumatologist, a specialist nurse and a physiotherapist, should be available for review and advice.

Smoking cessation advice is appropriate, despite the lack of evidence that smoking contributes to the development of BR in this setting. There is evidence that enrolment in a pulmonary rehabilitation program improves outcomes in patients with RA-BR having reduced exercise tolerance or a low health-related quality of life. Given the observation that RA-BR subjects have a mortality rate 5 times higher than in patients with RA alone, and 2.4 times greater than patients with isolated BR , it is clear that further evidence on the optimal therapeutic approach to these patients is required.