[Background/Purpose ]

Infliximab was introduced in 2002 as the first biological DMARD (bDMARD) in Japan.  Currently, 5 TNF inhibitors, tocilizumab, and abatacept are available. Tacrolimus and leflunomide were included as immunosuppressant and synthetic DMARD (sDMARD), and methotrexate (MTX) was approved up to 16 mg/week since 2011. We investigated the type and prognosis of infections in RA patients through the course of the evolution of DMARDs during the last 15 years in Japan.

[Methods ]

We collected, retrospectively, the hospitalized cases of RA under the diagnosis of infections from 1999 to 2013. The diagnosis of infection was based clinically, when it was not confirmed microbiologically. The years between 1999 and 2013 were divided into 5, each consisting of 3 years. The clinical characteristics of the patients, type of infections, hospitalized durations, and mortality were summed up in each period, and their changes in these 5 periods were investigated.

[Results ]

The numbers of hospitalized cases in the 5 periods from 1999 to 2013 were 40, 60, 87, 88, and 84, respectively. When compared between the 1st period of 1999 to 2001 and 5th period of 2011 to 2013, there was no difference in age (median 66.5 vs. 67 years), sex (female to male ratio, 2.6 vs. 2.8), and RA disease duration (median 11.5 vs. 11 years). Glucocorticoid was administered in over 80% of the patients in each period. When compared between the 1st and 5th periods, MTX-use increased from 37.5% to 50.0%, and 15.5% of the patients on MTX were administered over 8 mg/week in the last period. The frequency of bDMARDs-use was 5.0% and 38.1%, in the 1st  and 5th period, respectively. Immunosuppressants were used in 10.0% and 16.7%, and sDMARDs other than MTX were used in 37.5% and 14.3% of the patients, in the 1st and 5th period, respectively. The respiratory system was most frequently infected in each period. The mortality in each period was 7.5%, 6.7%, 4.6%, 9.1%, and 7.0%, from 1st to 5th, respectively (p=0.48), and there was no difference in the hospitalized duration (p=0.33). Although there was no significant difference in the prognosis, the frequency of Pneumocystis jirovecii pneumonia (PCP), and the mortality thereof increased from 7.5% to 16.7%, and 33.3% to 80.0% between 1st and 5th period. By univariate analysis of all patients, the mortality was significantly associated with PCP (crude Odds ratio 12.04, p<0.01, 95% CI 4.84 to 29.97), concurrent interstitial pneumonia (crude Odds ratio 2.56, p=0.031, 95% CI 1.09 to 6.01), and glucocorticoid-use (crude Odds ratio 1.06, p=0.001, 95% CI 1.02 to 1.10). PCP was associated with MTX- (crude Odds ratio 3.78, p<0.01, 95% CI 1.74 to 8.20) and glucocorticoid-use (crude Odds ratio 1.05, p<0.01, 95% CI, 1.02 to 1.08). There was no association between bDMARDs-use and PCP (crude Odds ratio 1.74, p=0.17), or mortality (crude Odds ratio 0.78, p=0.67).

[Conclusion ]

With the evolution of treatment in RA during the last 15 years, infections complicated in RA have changed. Although there was no difference in hospitalized durations or mortality, the frequency of PCP and death thereof have been increasing. Compared to Western countries, PCP is more prevalent in Japan, and early diagnosis and treatment are mandatory.