1. Coexistence of BEonchiectasis and Rheumatoid Arthritis 2013.4.15 장 나 은 Maria M Wilczynska MRCP, Alison M Condliffe PhD FRCP, and Damian J McKeon PhD FRCP Respir Care 2013; 58(4): 694 –701.

2. Rheumatoid arthritis (RA) - Chronic, progressive inflammatory disease - Prevalence of 1% across the general population - Strong association with a variety of pulmonary conditions : pulmonary fibrosis, lung nodules, bronchiolitis, tuberculosis, pleural effusions, and bronchiectasis (BE) Introduction

3. An association between RA and BE - The first studies published in the early 1960s - The prevalence of BE in the RA population is estimated at 2–3.1% - RA usually precedes the development of BE ( by 11.5–24.7 y) - The mean age at the onset of RA in the group with BE (46.1±14.0 y) was significantly lower than in the group without BE (51.2±11.4 y) - The development of BE does not influence or reflect RA severity - Disease activity and disability parameters are similar in the 2 groups Epidemiology

4. British Thoracic Society guideline for non-CF bronchiectasis Thorax 2010;65(7):577

5. Epidemiology

6. A link between autoimmunity in RA and airway damage - Demoruelle et al. : To evaluate the presence of pulmonary abnormalities in RA-related autoantibody– positive subjects without inflammatory arthritis Etiology None have inflammatory arthritis but were positive anti-CCP Ab seropositive early RA (<1-year duration) The lung may be an early site of autoimmune-related injury, and potentially a site of generation of RA-related autoimmunity

7. A link between autoimmunity in RA and airway damage - McMahon et al. : studied immunoglobulin (Ig) levels, autoantibodies, and complement levels in patients with RA-BE versus those with RA or BE alone : detected no significant differences Etiology RA-associated autoimmunity is not an important causative factor for BE

8. Genetic predisposition conferring susceptibility to both conditions - The presence of CFTR mutations in patients with RA may be a marker of developing RA-associated BE : The frequency of CFTR mutations was higher in family members with RA-BE or BE alone than in healthy controls * Increased frequency of cystic fibrosis F508 mutation in Bronchiectasis associated with rheumatoid arthritis Eur Respir J 1999;13(6):1281-1287 * Mutations of the cystic fibrosis gene in patients with Bronchiectasis associated with rheumatoid arthritis Ann Rheum Dis 2011;70(4):653-659 Etiology

9. Smoking - Smoking increases the risk of RA : Increased risk of anti-CCP antibody-positive RA was shown to be associated with smoking in a dose response manner : These findings were confirmed in a meta-analysis of 16 observational studies - The association of RA-BE with smoking are lacking : Patients with RA-BE are more likely to be non-smokers, compared to those with RA alone Risk Factors

10. Infections - Severe and recurrent lower-respiratory-tract infections (particularly in childhood) have long been recognized to predispose to BE : Au et al. - increased risk of infections is related to RA disease activity with more active disease - The role of DMARDs in predisposing to recurrent pulmonary infection Risk Factors

11. More pronounced obstructive airways disease with less reversibility in the RA-BE population than in the other types of BE Rheumatol Int 2005; 25(6):429-435 Goeminne et al. - a rise in RA disease activity score is associated with a decline of FEV Clin Rheumatol 2012;31(2):367-373 There are 2 small studies in which researchers reported that RA-BE lung was not associated with obstructive spirometry - no significant differences in spirometry between the patients with RA alone and RA-BE group Ann Rheum Dis 1995;54(4):308-310 Pulmonary Function Testing

12. Radiological investigations play a crucial role in the evaluation of RA-related lung disease - HRCT should be used in the diagnostic algorithm : especially since RA patients can have pulmonary involvement without clinical symptoms or signs of lung disease Now widespread availability of HRCT - Earlier identification of patients with BE Imaging

13. In RA populations the identification of BE on HRCT varied between 17-30.5% with a prevalence of symptomatic BE of 2.9% Patients with RA and normal chest radiographs - a prevalence of BE on HRCT reported as 13–30% Patients with RA and chronic respiratory symptoms or abnormal chest findings - a higher rate of BE (with traction BE: 51–75% and non-traction BE: 22–33%) Prospective study of the prevalence of BE in rheumatoid arthritis using HRCT - 46 unselected patients with RA undergoing HRCT : BE was the most common abnormality and was detected in 50% of the subjects : the majority of whom (18/23) had no antecedent respiratory symptoms Rev Rhum Ed 1998;65(7-9):453-461 Imaging

14. RA-BE subjects have mortality 7.3 times higher than the general population - 5 times higher risk than the RA group alone - 2.4 times higher risk than the BE group Chron Respir Dis 2011;8(1):21-30 In patients with RA-associated lung disease the 5-year survival rate was reported as 87.1% in the BE group - compared with RA and ILD had a lower 5-year survival rate (36.6%) Br J Rheumatol 1997;36(6):689-691 Prognosis

15.  DMARDs (Disease-modifying anti-rheumatic drugs) Non-biological DMARDs - Hydroxychloroquine, gold and corticosteroids - Newer agents: methotrexate (MTX), sulfasalazine and leflunomide Biological DMARDs - Tumor necrosis factor inhibitors (adalimumab, etanercept and infliximab) - Anti-CD 20 therapy (rituximab) - T cell costimulator modulators (abatacept) DMARDs and Infection Risk

16. Use of corticosteroids in RA was associated with an increased infections risk - Doran et al. : hazard ratio 1.56, 95% CI 1.22–2.01 - Saag et al : odds ratio 8.0, 95% CI 1.0–64.0 The prevalence of infections : DMARDs with or without corticosteroids - Canadian cohort study (27,710 patients) DMARDs and Infection Risk 1. Corticosteroids Arthritis Rheum 2008;59(8):1074-1081 Arthritis Rheum 2002; 46(9):2294-2300 Am J Med 1994;96(2):115-123

17. The infection rate in patients with RA - treated with low-dose methotrexate (MTX) in a 6-year open prospective study comparing MTX with azathioprine (AZA) in a 3-year open prospective study : a trend for more infections to occur early in the treatment period (within 1.5 years) and with more severe RA : no difference in the infection rate of MTX and AZA Semin Arthritis Rheum 1995;24(6):411-421 High- or low-dose MTX was not associated with an increased risk of serious infection, when compared with the non-MTX group the Registry of Japanese Rheumatoid Arthritis Patients on Biologics for Long-term Safety (REAL) data Mod Rheumatol 2011; 21(4):444-448 DMARDs and Infection Risk 2. MTX

18. No evidence that sulfasalazine is associated with an increased risk of serious infections, as reported in several randomized controlled trials J Rheumatol 1992;19(11):1672-1677 J Rheumatol 1990;17(6):764-770 Drugs 1995;50(1):137-156 DMARDs and Infection Risk 3. Sulfasalazine

19. Rituximab was studied in population of 3,189 patients - The overall rate for serious infections was reported as 4.35 events/100 patient-years, similar to that observed in the placebo group J Rheumatol 2010;37(3):558-567 Safety profile studies of adalimumab (2,300 patients), etanercept (2,385 patients), and abatacept did not increase the risk of infection in RA patients DMARDs and Infection Risk 4. Biological DMARDs Placebo +methotrexate (n = 570) Rituximab + methotrexate (n = 877) Total patients (%) with ≥ 1 AE infection 223 (39.1)353 (40.3) Total patients (%) with a serious infection 9 (1.6)15 (1.7)

20. In contrast, infliximab was associated with an increased risk of infection when used in RA - In a group of 504 RA patients : infections accounted for the highest number of adverse events (1.6%) : the most common type was non-tuberculosis-type bacteria (n =38), with tuberculosis accounting for 4 cases Arthritis Res Ther 2010;12(3):R121 - There is an increased absolute 0.2% a year risk of reactivation of tuberculosis in the RA subjects treated with biological agents BMJ 2011; 343: d4027 DMARDs and Infection Risk 4. Biological DMARDs

21. BE and RA are both chronic conditions requiring long-term medical management - Specific guidelines for management of patients with concurrent RA-BE are lacking Screening for other causes of BR, in particular for immune deficiency (which may occur secondary to treatment for RA), should be carried out Asymptomatic chest disease and quiescent RA - Annual review would seem sufficient Patients with active inflammatory disease or symptomatic pulmonary disease - Should be offered regular monitoring, 3–6 monthly (PFT, screening for bacterial colonization by sputum culture, and radiological assessment) Management

22. A trial of inhaled corticosteroids may be appropriate for those with reversible airways obstruction Management

23. All patients, especially prior to immunosuppression therapy - should be offered vaccination against pneumococcal and influenza infection The choice of DMARD should be made with the pulmonary disease taken into consideration - Consultation between rheumatology and respiratory specialists - Corticosteroids and some DMARDs increase the risk of infections and may have other effects on the lungs (such as pneumonitis of fibrotic reactions) - Moderate to severe BE or frequent exacerbations : reasonable to select DMARDs with a lower propensity to worsen pulmonary infection - Therapy with anti-TNF agents, careful screening for NTM and Tb seems appropriate Management

24. Antibiotic prophylaxis - should be considered in patients with frequent exacerbation (≥3/yr) or severe infections requiring hospitalization/IV antibiotics Management

25. Out-patient pulmonary rehabilitation - patients with RA-BE with a reduced exercise tolerance and low health related QOL - achieve an improvement in exercise capacity and health related QOL Management