The number of older adults with rheumatoid arthritis (RA) is rising, partially due to longer life expectancy and partially due to better care of RA and its comorbidities, thereby enabling patients with the disease to live longer than they would have done in earlier years.1 Moreover, more patients are being diagnosed with RA in older age; and as individuals age, they experience an increase in comorbid conditions, including pulmonary diseases.1
A recent review article1 shines a spotlight on coexisting RA and lung disorders, particularly interstitial lung disease (ILD), noting that there is a “paucity of data” focusing on the intersection of these two specific conditions.
RA is often categorized by age at onset, with young-onset RA (YORA) diagnosed at <60 years of age and late-onset RA (LORA) diagnosed at ≥60 years. Complications and joint erosions typically increase with the progression of age.2 The review by Messina et al aims to explore “to what extent ILS occurs in RA individuals, and what are the clinical consequences in older patients.” This is important not only because the incidence of older adults with RA and ILD is increasing but also because the comorbidity is associated with poorer outcomes.
The estimated prevalence of RA-related ILD (RA-ILD) ranges from 1% to as much as 58%, depending on the particular study methodology and population.1 The lifetime risk of developing ILD in patients with RA ranges between 6% and 15%, and ILD may precede the development of articular manifestations.3 Moreover, ILD is the third most common cause of mortality in people with RA.4,5 However, despite its high incidence, it is often under recognized and, in >30% of patients, the condition remains subclinical.1 Although RA is more common in women, RA-ILD is twice as common in men, for reasons that remain “unclear.”1
What is the Relationship Between RA and Pulmonary Disease?
Normal aging involves changes in lung structure and function.1
Normal Age-Related Lung Changes
Age-Related Change Result Homogeneous alveolar enlargement1 Reduced lung elastic recoils Reduced chest wall compliance1 Reduced TLC Reduced muscle strength1 Reduced TLC Airway obstruction6 Reduced FEV1 and FVC Immunosenescence (immune system dysfunctions)7 Lung fibrosis Inflammaging (chronic, sterile low-grade inflammation)7 Lung fibrosis
Although all components of the lungs are involved with RA, the most frequent pulmonary involvement is ILD. Risk factors for the development of RA-ILS are male sex, older age, LORA, and longer disease duration.1
There is no specific diagnostic screening tool or program for ILD-RA.3 However, screening for respiratory symptoms should be part of RA follow-up and, conversely, patients with ILD should be evaluated for potential systemic involvement.3
ILD-RA can be challenging to diagnose, and infection as well as drug-induced pneumonitis should be considered in the differential diagnosis.3 The SARS-CoV-2 virus (COVID-19) has severe respiratory symptoms, and patients with rheumatic disease are particularly susceptible,9 so COVID-19 should be included as part of the differential diagnosis.
Differential diagnoses include:
- Drug-induced lung toxicities
- Chronic obstructive pulmonary disease (COPD)
- Congestive heart failure (CHF)
- Pleural effusions
- Malignancy (eg, lung cancer, lymphoma)
- Acute exacerbations of RA-ILD
- Smoking-related parenchymal lung diseases
- Rheumatoid nodules, and
Messina et al delineate the typical presentations of RA-ILD, noting that the most common symptoms are exertional dyspnea and non-productive cough. Common findings on physical examination are listed below.
- Tachypnea and bibasilar inspiratory crackles
- Clubbing (when associated with usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HCRT)
- Cyanosis, edema, signs of pulmonary hypertension (PH) in advanced stages of the disease
- Restrictive ventilatory defect with reduction in TLC and FVC on pulmonary function texts (with or without decreased diffusing capacity of the lung for carbon monoxide [DLCO])
- DLCO is “highly predictive” of the presence of ILD, and
Abnormal lung function may include oxygen desaturation during 6-min walk test (6MWT), with a desaturation of <88% associated with worse prognosis and potential need for oxygen therapy.
Messina et al note that a decrease in FVC of ≥10% or a decrease in the DLCO of ≥15% over 6–12 months is considered “clinically relevant” and associated with increased mortality.
Radiological and Pathological Findings Suggestive of ILD-RA
Chest x-ray is “an insensitive method” to detect patients with ILD-RA, so HRCT is a “mandatory part of the diagnostic workup” if ILD is suspected.3 The UIP pattern is the most common radiological and pathological finding in RA-ILD (in contrast to other forms of connective tissue disease-related ILD).10 The authors review some of the noteworthy features of patients who present with a UIP pattern.
- More frequently older males and current or former smokers;
- Tend to have more respiratory system-related hospitalizations; and
- Worse prognosis.
The most common cause of mortality in RA is cardiovascular disease (CVD), with ILD as the second most common.1 Additional risk factors for mortality are listed below.
- ILD-associated PH
- Advanced age
- Longer disease duration
- Male sex
- Extent of fibrosis
- UIP pattern evaluated by HRCT
- Severity of lung function impairment (based on DLCO and FVC, AE, and RA activity), and
- Combined pulmonary fibrosis and emphysema (CPFE) may be identified on HRCT scans and is associated with an increased risk of PH.
The Importance of Multidisciplinary Collaboration
Because of the complexity of RA-ILD, a multidisciplinary approach is critical, and should include a pulmonologist, a rheumatologist and perhaps a cardiologist, as well as relevant allied health professionals.1 All members of the team should weigh in and evaluate clinical, functional, and radiological assessments before crafting a treatment plan.1
Although new treatment strategies for RA, including “early and effective” disease-modifying antirheumatic drugs (DMARDs), have “resulted in reduced disease activity,” the optimally treatment of lung involvement is “still a dilemma,” with no randomized controlled trials in RA-ILD to inform the decision.3
Treatments for RA-ILD generally differ, based on the age of the patient, since younger patients do not tend to have age-related diseases and comorbidities.1 YORA patients typically receiving early treatment with DMARDs and biologic agents, compared to LORA patients, who are more frequently treated with corticosteroids.11 One reason for this may be that corticosteroids tend to bring rapid relief of symptoms and are therefore used more frequently, even though adverse effects are more common in older patients.12 While DMARDs also have the risk of adverse effects, several studies have demonstrated that they are well tolerated in older patients.13,14
Treatment with anti-inflammatory and/or immunosuppressive agents is “commonly indicated” for RA-ILD, although the combination of corticosteroids and immunosuppressive therapy is “strongly contraindicated” in other conditions, such as IPF.1 A study of combination therapy with mycophenolate mofetil (MMF) and low-dose prednisone found in patients with connective tissue disorders (CTDs) found improvement in lung functional parameters in patients with RA-associated non-UIP pattern as well as stabilization of these parameters in patients with the UIP pattern.15 The combination was well tolerated, with an adverse event-related discontinuation rate of <10%.
Methotrexate is commonly used as a first-line DMARD in RA and has been shown to improve overall survival in these patients; however, it can also induce lung toxicity (acute pneumonitis) in RA patients—although the toxicity is usually reversible.16 However, methotrexate-related development of interstitial lung disease is a “controversial and still unsolved issue,” according to the review authors. The issue is clinically relevant because “differentiating methotrexate-induced lung toxicity from the RA-related lung diseases is crucial to avoid discontinuation of such important treatment.”1
The authors cite one study with “reassuring findings” suggesting a low risk (1% of the study population [n=223]) of methotrexate-induced pneumonitis in patients with rheumatic and other connective diseases being treated with low-dose methotrexate.17 A study of risk factors for methotrexate-induced lung injury found older age to be among the strongest predictors.18
Rituximab, a chimeric monoclonal antibody, is an effective treatment of the articular manifestations of RA. There have also been reports of improvement in CTD-associated ILD following treatment with rituximab.19 Nevertheless, rituximab may also exert a potentially toxic effect on the lungs, with one study suggesting that older individuals (median age 70 years) are at higher risk.20,21
Anti-Tumor Necrosis Factor Alpha (anti-TNFα drugs)
Anti-TNFα drugs include infliximab, etanercept, adalimumab, certolizumab, and golimumab, and are considered to be the “most effective therapeutic option” in treating RA, especially when initiated in patients with early onset disease or high disease activity.1 On the other hand, their use has also been associated with new-onset or exacerbation of ILD, with a higher risk in patients >65 years old.22
“Given the risk of worsening pre-existing RA-associated ILD and the lack of definite indications due to the difficulty in conducting randomized prospective studies on the topic, a ruling on DMARD use for RA-ILD patients has not been determined, and a prudent use of DMARDs is recommended in clinical practice,” Messina et al state.
They note that abatacept, an antagonist of T-lymphocyte co-stimulation, “seems to be promising” because—in contrast to other DMARDs—it is associated with better prognosis and lower risk or ILD exacerbation or worsening.23
Ongoing studies of antifibrotic agents in autoimmune CTDs are underway, pointing to the possibility of “new and promising perspectives” in the treatment of RA-ILD. One agent under investigation for treating ILD is nintedanib, an intracellular inhibitor of tyrosine kinases that is approved for treatment of IPF. A study24 of 663 patients with ILD (other than IPF), with a mean age of 67.5 (±8.1 years), and including patients with RA-ILD, found that subjects who received nintedanib experienced a slower rate of ILD progression. Another study underway is investigating the safety, tolerability, and efficacy of pirfenidone, which suppresses TGF-β, in patients with RA-ILD.25
Nonpharmacologic interventions should “always be considered” in chronic lung disease.3 For example, pulmonary rehabilitation has been shown to improve walking distance, quality of life, and dyspnea, and pulmonary physiotherapy (including breathing exercises) and can be helpful in managing dyspnea and productive cough.3
Preventing infections is essential, so providers should encourage patients to received influenza and pneumococcal vaccines and to engage in optimal hand hygiene.3 Vigilance regarding these interventions is particularly important during the coronavirus pandemic, since individuals with autoimmune and pulmonary diseases are especially vulnerable to contracting COVID-19.26 Smoking cessation counseling should be offered to all smokers with RA-ILD, as well as smokers with either of these conditions.3 Supplementary oxygen “can be beneficial as part of palliative care for patients with hypoxemia.”3 In the event of very severe and progressive cases, lung transplantation can be considered.3
The association between ILD and RA may be seen as a “two-way street.”27 On the one hand, ILD may be present before or around RA onset in as many as 1 in 3 patients; on the other hand, antibodies often implicated in RA have been found in >20% of patients with IPF, of whom one-third may subsequently develop RA.27 Thus, “a broader view (eg, multidisciplinary ILD committees) on the issues implied in the relationship between ILD and RA should be considered in the design of future prospective collaborative studies.”27
- Messina R, Guggino G, Benfante A, Scichilone N. Interstitial Lung Disease in Elderly Rheumatoid Arthritis Patients. Drugs Aging. 2020;37(1):11-18.
- Mueller RB, Kaegi T, Finckh A, Haile SR, Schulze-Koops H, von Kempis J. Is radiographic progression of late-onset rheumatoid arthritis different from young-onset rheumatoid arthritis? Results from the Swiss prospective observational cohort. Rheumatology (Oxford). 2013;53(4):671–7.
- Bendstrup E, Møller J, Kronborg-White S, Prior TS, Hyldgaard C. Interstitial Lung Disease in Rheumatoid Arthritis Remains a Challenge for Clinicians. J Clin Med. 2019;8(12):2038.
- Marigliano B, Soriano A, Margiotta D, Vadacca M, Afeltra A. Lung involvement in connective tissue diseases: a comprehensive review and a focus on rheumatoid arthritis. Autoimmun Rev. 2013;12(11):1076-84.
- Sihvonen S, Korpela M, Laippala P, Mustonen J, Pasternack. Mortality and causes of death in patients with rheumatoid arthritis. Scand J Reumatol. 2004;33:221–7.
- Sorino C, Battaglia S, Scichilone N, et al. Diagnosis of airway obstruction in the elderly: contribution of the SARA study. Int J Chron Obstruct Pulmon Dis. 2012;7:389-95.
- Aw D, Silva AB, Palmer DB. Immunosenescence: emerging challenges for an ageing population. Immunology. 2007;120:435–46.
- Murtha LA, Morten M, Schuliga MJ, et al. The role of pathological aging in cardiac and pulmonary fibrosis. Aging Dis. 2019;10(2):419–28.
- Ye C, Cai S, Shen G, et al. Clinical features of rheumatic patients infected with COVID-19 in Wuhan, China. Ann Rheum Dis. 2020;79(8):1007-1013.
- Kim EJ, Collard HR, King TE Jr. Rheumatoid arthritis-associated interstitial lung disease: the relevance of histopathologic and radiographic pattern. Chest. 2009;136(5):1397-1405.
- Villa-Blanco JI, Calvo-Alén J. Elderly onset rheumatoid arthritis: differential diagnosis and choice of first-line and subsequent therapy. Drugs Aging. 2009;26:739–50.
- Tutuncu Z, Kavanaugh A. Rheumatic disease in the elderly: rheumatoid arthritis. Rheum Dis Clin North Am. 2007;33(1):57-70.
- Fleischmann RM, Baumgartner SW, Tindall EA, Weaver AL, Moreland LW, Schiff MH, et al. Response to etanercept (Enbrel) in elderly patients with rheumatoid arthritis: a retrospective analysis of clinical trial results. J Rheumatol. 2003;30(4):691–6.
- Schneeweiss S, Setoguchi S, Weinblatt ME, et al. Anti-tumor necrosis factor alpha therapy and the risk of serious bacterial infections in elderly patients with rheumatoid arthritis. Arthritis Rheum. 2007;56(6):1754-64.
- Fischer A, Brown KK, Du Bois RM, et al. Mycophenolate mofetil improves lung function in connective tissue disease-associated interstitial lung disease. J Rheumatol. 2013;40(5):640-646.
- Barrera P, Laan RF, van Riel PL, Dekhuijzen PN, Boerbooms AM, van de Putte LB. Methotrexate-related pulmonary complications in rheumatoid arthritis. Ann Rheum Dis. 1994;53(7):434-439.
- Sathi N, Chikura B, Kaushik VV, Wiswell R, Dawson JK. How common is methotrexate pneumonitis? A large prospective study investigates. Clin Rheumatol. 2012;31(1):79-83.
- Alarcón GS, Kremer JM, Macaluso M, et al. Risk factors for methotrexate-induced lung injury in patients with rheumatoid arthritis. A multicenter, case-control study. Methotrexate-Lung Study Group. Ann Intern Med. 1997;127(5):356-64.
- Fischer A, Chartrand S. Assessment and management of connective tissue disease-associated interstitial lung disease. Sarcoidosis Vasc Diffuse Lung Dis. 2015;32(1):2-21.
- Lioté H, Lioté F, Séroussi B, Mayaud C, Cadranel J. Rituximab-induced lung disease: A systematic literature review. Eur Respir J. 2010;35(3):681-7.
- Md Yusof MY, Kabia A, Darby M, et al. Effect of rituximab on the progression of rheumatoid arthritis-related interstitial lung disease: 10 years’ experience at a single centre. Rheumatology (Oxford). 2017;56(8):1348-1357.
- Perez-Alvarez R, Perez-de-Lis M, Diaz-Lagares C, et al. Interstitial lung disease induced or exacerbated by TNF-targeted therapies: analysis of 122 cases. Semin Arthritis Rheum. 2011;41(2):256-64.
- Kurata I, Tsuboi H, Terasaki M, et al. Effect of Biological Disease-modifying Anti-rheumatic Drugs on Airway and Interstitial Lung Disease in Patients with Rheumatoid Arthritis. Intern Med. 2019;58(12):1703-1712.
- Flaherty KR, Wells AU, Cottin V, et al; INBUILD Trial Investigators. Nintedanib in Progressive Fibrosing Interstitial Lung Diseases. N Engl J Med. 2019;381(18):1718-1727.
- Solomon JJ, Danoff SK, Goldberg HJ, et al; Trail Network. The Design and Rationale of the Trail1 Trial: A Randomized Double-Blind Phase 2 Clinical Trial of Pirfenidone in Rheumatoid Arthritis-Associated Interstitial Lung Disease. Adv Ther. 2019;36(11):3279-3287.
- Fonseca M, Summer R, Roman J. Acute Exacerbation of Interstitial Lung Disease as a Sequela of COVID-19 Pneumonia. Am J Med Sci. 2021;361(1):126-129.
- Castellanos-Moreira R, Rodríguez-García SC, Haro I, Sanmarti R. Relationship between rheumatoid arthritis and interstitial lung disease is a ‘two-way street’. Response to: ‘Autoantibodies and interstitial lung disease in rheumatoid arthritis: towards a ‘mix-and-match’ approach’ by Alunno et al. Ann Rheum Dis. Published online May 28, 2020. doi:10.1136/annrheumdis-2020-217432