The Lung in a Cohort of Rheumatoid Arthritis Patients

An Overview of Different Types of Involvement and Treatment

Ana C. Duarte; Joanna C. Porter; Maria J. Leandro

Disclosures

Rheumatology. 2019;58(11):2031-2038. 

In This Article

Discussion

Lung disease is one of the extra-articular manifestations of RA that most concerns clinicians, not only due to the wide range of different types of involvement described and the potential increased risk and severity of respiratory infections, but also because of the lack of efficient therapies. Previous studies have already characterized lung involvement in other RA cohorts,[4,19,20] but in most of them drug-induced lung disease was not described.

Of the different subtypes of lung involvement, RA-ILD was the most prevalent in this cohort, occurring in 51.7% of the patients, which is in line with published data.[6,21,22] Despite the reported male predominance in RA-ILD,[6,7,19,21] in our cohort 66.7% of the RA-ILD patients were female. This female predominance was even higher in patients with isolated bronchiectasis (87.1%; P = 0.043).

Patients with RA-ILD also had a higher frequency of smoking habits and positive RF and ACPA, which is in accordance with the literature.[4,6,7,19,21] However, three (6.7%) patients with ILD had negative RF and ACPA. Two of these, both ex-smokers, had negative ANA and ENA and presented with NSIP. A third patient was a non-smoker and presented with UIP. This means that despite the postulated role of these autoantibodies in the aetiopathogenesis of RA-associated lung disease,[23] patients with negative RF and ACPA are also at risk for lung disease.

Although UIP has been reported as the most prevalent RA-ILD pattern in published data,[19,24,25] in our cohort UIP and NSIP were equally frequent (40% of the patients with ILD). However, two patients with NSIP had positive anti-PL12 antibodies, associated with an overlap with antisynthetase syndrome, and another patient with NSIP had positive anti-Scl70 antibody but without other symptoms compatible with SSc. In these three patients, ILD may be a manifestation of overlap disease. Five patients had unclassifiable ILD pattern in HRCT, but none underwent a lung biopsy. Three of them had disease for <2 years and two were clinically stable on treatment.

Airways involvement was the second most common feature, occurring in 41.4% of the patients, which is in line with previous data.[2,26] Isolated bronchiectasis was described in 35.6% RA patients on HRCT. When compared with ILD patients, those with isolated bronchiectasis had longer disease duration (OR = 1.05, 95% CI 1.007–1.095; P = 0.023) and longer interval between articular and respiratory disease diagnosis (OR = 1.05, 95% CI 1.006–1.096; P = 0.024). This might be explained by the pathogenesis of bronchiectasis, which is due to chronic suppurative infections with recurrent bronchial injury and architectural distortion.[27] These alterations promote a vicious cycle of further infection and damage, which may be further increased in RA patients treated with DMARDs.[26] In our cohort most of the patients with bronchiectasis had symptoms compatible with respiratory infection at the time of diagnosis, which might have contributed to their high levels of ESR and CRP (Table 2). On the other hand, patients with bronchiectasis tend to have a lower frequency of positive ACPA when compared with those with ILD (P = 0.074), which probably means that RA-associated auto-immunity plays a smaller role in bronchiectasis pathogenesis, as suggested in other studies.[26]

During follow-up, 29.2% (14/48) of the patients with bronchiectasis, either isolated or in association with ILD, were admitted to hospital due to respiratory infections. Despite a low number of patients having sputum sent for culture, in our cohort P. aeruginosa was the most common isolated bacteria in sputum, in accordance with previous data.[28] Prophylactic antibiotics should be considered in patients with frequent (three or more exacerbations per year) or severe infections requiring hospitalization/i.v. antibiotics.[28,29] Antibiotic treatment was instituted in six patients of our cohort, with good results. In patients with RA and concomitant bronchiectasis who need to start a biologic DMARD, etanercept and RTX might be preferred as these may be associated with lower incidence of respiratory infections in this group of patients.[30]

Despite the lack of specific guidelines for management of patients with concurrent RA and bronchiectasis, patients with sputum production might benefit from an evaluation by a respiratory physiotherapist for instruction in airway clearance, and use of mucolytics.[26] On the other hand, when reversible airways obstruction is present, a trial of inhaled long-acting beta2-agonists combined with inhaled CS should be considered.[31]

Lung RN are a rare pulmonary RA complication and are more common in males, active smokers and patients with seropositive RA and cutaneous RN.[6,32] They are mostly asymptomatic[32,33] and uncomplicated nodules may spontaneously regress or improve with standard RA treatment.[32] Despite some reports of lung and cutaneous RN enlargement in patients treated with MTX and leflunomide,[6,32] regression has been reported with anti-TNF agents,[33] RTX[34] and tocilizumab.[35] Current clinical practice advocates early RA diagnosis and treatment, often using drugs that have demonstrated efficacy in the resolution of RN, and this might explain the current reduced prevalence of lung RN. This strategy can also lead to a reduction in pleural effusions, the pathogenesis of which appears to share the same inflammatory pathways as synovial effusions.[36] Therefore, apart from small and asymptomatic pleural effusions that do not require specific therapy, in most patients treatment of underlying RA improves pleural disease.[36] Thoracentesis might be needed for symptomatic relief[36] and decortication is ultimately required in patients with persistent pleural effusions, as shown in our cohort. MTX-induced lung disease, which has been reported in 0.3–8% of the patients,[6,9] occurred in two patients in our cohort. At last follow-up, 25.3% of the patients were on MTX despite the evidence of lung disease, recognizing the essential role of this drug in controlling disease activity, including in the lung.[8]

Recent studies have demonstrated a good efficacy and safety profile for RTX in RA-ILD patients when disease has progressed despite other treatments.[14,37,38] In our cohort, at 12-months revaluation, 2/2 patients with organizing pneumonia and 5/5 with NSIP demonstrated improvement or stabilization in follow-up PFTs, confirmed on HRCT. Regarding patients with a UIP pattern of RA-ILD, at the 12-month revaluation, 2/3 patients had a decline in forced vital capacity and 1/2 had HRCT worsening (this last patient did not have lung function tests performed). However, after 36 months of RTX, 2/2 patients demonstrated stability in gas transfer and 1/2 in forced vital capacity. In addition, two patients with UIP that stopped RTX due to articular inefficacy showed worsening in revaluation PFTs. This might indicate that despite the worse outcomes of UIP pattern when compared with organizing pneumonia and NSIP, treatment with RTX in these patients might halt disease progression.

Lung disease-related mortality in our cohort was estimated at 8%, and all the deaths were in patients with ILD. Progressive worsening of lung function was more associated with a UIP pattern (OR = 9.0, 95% CI 1.39–58.44; P = 0.021), and this was the most common pattern among patients who died due to lung disease (57.1%), in line with previous findings.[39–42]

Clinical scores may be useful for identifying patients with RA-ILD who are at increased risk of death. The GAP index, used for idiopathic pulmonary fibrosis, also has proved prognostic value in patients with RA-ILD.[16–18] Of the seven patients in our cohort that died due to ILD, four were GAP stage I and three were GAP stage II at the time of lung disease diagnosis. Of the patients that were GAP stage II at diagnosis, 75% died within 3 years, in keeping with GAP prognostication.[15]

There is increasing interest in the use of radiology-based prediction models to refine clinical-based scoring systems in ILD. Although there is no specific model for RA-ILD, the Fleischner updated guidelines to increase diagnostic confidence of UIP when HRCT shows a probable pattern[43] or the Goh system for SSc-ILD[44] have been validated in this group. Both of them, either alone[45,46] or combined,[47] have demonstrated that definite UIP pattern and extensive disease (>20% fibrosis on HRCT) are associated with progressive fibrosis and worse survival. Future models will almost certainly incorporate radiological and clinical scores to refine mortality prediction in this patient group.

There are limitations to this study. Most of the patients enrolled in this study were investigated for lung disease after becoming symptomatic. Therefore, we believe that pulmonary involvement was underestimated. In all patients the diagnosis was based on HRCTs, which were assessed by expert thoracic radiologists and in most cases reviewed in a multidisciplinary meeting, including radiologists, pulmonologists and rheumatologists. The fact that this was a retrospective study has other limitations, such as missing information. However, the data presented constitute a very complete characterization of a considerable number of RA patients with lung involvement and raise important issues for clinical practice, such as the use of RTX in RA-ILD and prophylactic antibiotics in patients with recurrent chest infections. In the future, larger prospective studies would be desirable to reinforce the potential role of RTX in RA-ILD treatment.

Comments

3090D553-9492-4563-8681-AD288FA52ACE

processing....