**1. Introduction**

244 Rheumatoid Arthritis – Etiology, Consequences and Co-Morbidities

Stavropoulos-Kalinoglou A, Metsios GS, Koutedakis Y, Nevill AM, Douglas KM, Jamurtas

World Health Organization. Definition, Diagnosis and Classification of Diabetes Mellitus

rheumatoid arthritis patients. *Ann Rheum Dis*. 2007 Oct;66(10):1316-21 Steven M. Comparison of Quality of Care for Patients in the Veterans Health Administration and Patients in a National Sample. *Ann Intern Med.* 2004 Dec;141:938-945. Stevens RJ, Douglas KM, Saratzis AN, et al. Inflammation and atherosclerosis in rheumatoid

arthritis. *Expert Rev Mol Med*. 2005 May 6;7(7):1-24.

Organization. 1999.

A, van Zanten JJ, Labib M, Kitas GD. Redefining overweight and obesity in

and Its Complications: Report of a WHO Consultation*.* Geneva: World Health

Nontuberculous mycobacteria (NTM) are a large, diverse group of ubiquitous environmental organisms found in tap water, soil, dust, plants, animals, and food. NTM infection can cause various diseases, such as pulmonary disease (PD), which are most frequently observed in immunocompromised individuals. Diseases associated with NTM are particularly severe in those receiving tumor necrosis factor (TNF)-alpha (α) blockers, which predispose individuals to NTM infection. Experts generally agree that patients with active NTM disease should receive TNF-α blockers only if they are also receiving adequate therapy for NTM disease. On the other hand, the Japanese College of Rheumatology recommends that TNF-α blockers not be used in patients with active NTM infection, because NTM is resistant to most antimycobacterial drugs.

Bronchiectasis is one of the most frequent manifestations of NTM infection, not only in NTM-PD patients, but also in rheumatoid arthritis (RA) patients. It is difficult to distinguish the bronchiectasis associated with NTM-PD from that with RA on chest radiography or high-resolution computed tomography (HRCT). Due to the ease of NTM contamination from the environment, the diagnosis of NTM-PD is extremely difficult. The most recent American Thoracic Society (ATS) and Infectious Disease Society of America (IDSA) guidelines recommend diagnosing NTM-PD via a combination of clinical, radiographic, bacteriologic (two positive sputum cultures, or one positive bronchoalveolar lavage (BAL) culture or transbronchial biopsy), and histological criteria. In NTM-PD patients receiving TNF-α blockers, *Mycobacterium avium* was the most common etiologic organism, accounting for half of all NTM isolates (Winthrop et al., 2009). Recently, Kitada et al. (2008) established an enzyme immunoassay (EIA) for the serological diagnosis of *M. avium*-complex (MAC)- PD by examining the level of serum IgA antibody to the glycopeptidolipid (GPL) core, which is a MAC-specific antigen. Unlike bronchoscopy and sputum culture examinations, EIA kits are less invasive and provide more rapid diagnosis of MAC-PD.

In this chapter, we discuss the characteristics of NTM, relationship between NTM infections and RA patients, particularly those receiving TNF-α blockers, and diagnosis of MAC-PD with RA patients using the recently developed EIA kit.

Nontuberculous Mycobacterium Infections in Rheumatoid Arthritis Patients 247

This type of lung disease, which represents "a TB-like pattern" of disease, is quite similar to that associated with post-primary TB. Cavitary disease is often seen in older men with substantial smoking histories and chronic PD (*e.g.*, COPD, pneumoconiosis, prior TB, and sarcoidosis) (Bandoh et al., 2004; Christensen et al., 1981; Dhillon & Watanakunakorn, 2000; Fowler et al., 2006; Glassroth, 2008; Morita et al., 2005; Sonnenberg et al., 2000; Teosk & Lo, 1992; Wickremasinghe et al., 2005; Witly et al., 1994). Cavitary disease associated with NTM mostly occurs in the apical and posterior segments of the upper lobe, although multiple lung segments may be involved. Cavitations typically include thick walls and no air-fluid level, and are often associated with pleural thickening, which is more extensive than that seen in TB. However, pleural effusion and substantial lymph node enlargement are less common than in TB (Albelda et al., 1985; Christensen et al., 1981; Reich & Johnson, 1991; Woodring et al., 1987) (Fig. 1). The symptoms of NTM-induced cavitary disease include cough, fever, weight loss, weakness, haemoptysis, and respiratory insufficiency (Griffith et

(a) (b)

In fibronodular bronchiectasis, CT findings are characterized by small centrilobular nodules or tree-in-bud opacities, with cylindrical bronchiectasis typically detected in the same lobe (Han et al., 2003; Hartman et al., 2003; Moore, 1993; Obayashi et al., 1999; Primack et al., 1995; Swensen et al., 1994) (Fig. 2). Bronchiectasis is more commonly associated with NTM than in TB (Primack et al., 1995), with bilateral bronchiectasis and bronchiolitis occurring in one third of NTM patients, as detected by HRCT. However, the coexistence of bronchiectasis and bronchiolitis (*i.e.*, centrilobular nodules and mosaic pattern) is also highly suggestive of NTM infection (Koh et al., 2005). Typical HRCT findings are often observed in the right middle lobe or lingual, which are anatomically predisposed to impaired clearance of secretions, a condition referred to as "Lady Windermere syndrome" (Reich & Johnson, 1992). Fibronodular bronchiectasis is most common in elderly women without preexisting pulmonary conditions or histories of tobacco abuse, but who often have anatomic abnormalities of the chest (Chan et al., 2007; Daley & Griffith, 2002; Dhillon & Watanakunakorn, 2000; Field & Cowie, 2006; Iseman et al., 1991; Jarzembowski & Young, 2008; Okumura et al., 2008; Prince et al., 1989; Taiwo & Glassroth, 2010). The major symptom

Fig. 1. HRCT images of the lungs of a 63-year-old woman with MAC-PD. *M*. *avium* was detected in several sputum cultures. (a) Cavities with thick walls and no air-fluid level were seen in the right upper lobe (arrowheads) (b) Bronchiectasis with infiltration in the right middle lobe (arrows) and a cavity in the right lower lobe (arrowhead) were detected.

1. Cavitary disease

al., 2007; Piersimoni & Scarparo, 2008).

2. Fibronodular bronchiectasis
