AB0180 A MULTICENTER SELF-CONTROLLED CASE SERIES STUDY INVESTIGATING THE PREVENTIVE EFFECT OF SULFASALAZINE AGAINST PNEUMOCYSTIS PNEUMONIA
Authors: T. Nunokawa, T. Kakutani, N. Chinen, K. Shimada, M. Kimura, M. Tateishi, F. Chen, K. Setoguchi, M. Sugihara
Journal: Annals of the Rheumatic Diseases (2021)

Background: An animal study revealed that sulfasalazine (SSZ) enhances Pneumocystis clearance from the lung by accelerating macrophage activity.[1] Although the preventive effect of SSZ on Pneumocystis pneumonia (PCP) in patients with rheumatoid arthritis (RA) is reported in case-control studies, some important confounders might remain unmeasured and distort the results. [2-3]. The self-controlled case series (SCCS) method involves only cases and controls fixed confounders automatically.[4] Objectives: To evaluate the prophylactic effect of SSZ against PCP in patients with RA, controlling unmeasurable confounders by the SCCS method. Methods: A retrospective study was conducted at five hospitals. Patients with RA who developed PCP between 2003 and 2019 were included. PCP was defined by the following criteria: (1) detection of Pneumocystis jirovecii in respiratory specimens by polymerase chain reaction; (2) clinical manifestations (pyrexia, dry cough, dyspnea, or hypoxia); (3) diffuse interstitial infiltrate on chest imaging; (4) absence of prophylaxis for PCP. Incidence rate ratio (IRR) for Pneumocystis pneumonia associated with sulfasalazine use was calculated by conditional Poisson regression. Results: We identified 48 episodes of PCP in 47 cases. Of these, 15 (31.9%) died. Thirty received SSZ in certain periods of their observations (Table 1). While 46 episodes of PCP developed in the period of 168.9 person-years without SSZ use, only one episode of PCP developed in the period of 103.7 person-years with SSZ use. SSZ use had a decreased risk of PJP (adjusted IRR 0.007, 95% CI &lt;0.001-0.067) after adjusted for age group, the use of glucocorticoid, methotrexate, and tacrolimus, and the use of biologic agent or janus kinase inhibitor (Table 2). Table 1. Characteristic of the 47 patients enrolled in the study. Male/female, n (%) 14 (29.8)/33 (70.2) Observational period (years), median (IQR) 72.0 (66.3-79.1) Lung disease, n (%) 4.7 (1.4-9.5) Use of sulfasalazine, n (%) 23 (48.9) Outcome of PCP, death, n (%) 30 (63.8) Age at the onset of PCP (years), median (IQR) 15 (31.9) PCP, Pneumocystis pneumonia; IQR, interquartile range. Table 2. Unadjusted and adjusted incidence rate ratio for Pneumocystis pneumonia associated with sulfasalazine use. Observation length (years) Episodes of PCP, n (%) Unadjusted IRR 95% CI) Adjusted IRR a (% CI) Use of SSZ 103.7 1 (2.1) 0.010 (0.001-0.092) 0.007 (&lt;0.001-0.067) No use of SSZ 168.9 47 (97.9) reference reference IRR, incidence rate ratio; PCP, Pneumocystis pneumonia; SSZ, sulfasalazine. Conclusion: Our study demonstrated the preventive effect of SSZ against PCP with confounders controlled by the SCCS. References: [1]Wang, J., et al. Immune modulation with sulfasalazine attenuates immunopathogenesis but enhances macrophage- mediated fungal clearance during pneumocystis pneumonia. PLoS Pathog. 2010;19;6(8):e1001058. [2]Nunokawa, T. et al. Prophylactic effect of sulfasalazine against Pneumocystis pneumonia in patients with rheumatoid arthritis: A nested case-control study. Semin. Arthritis Rheum. 2019;48(4):573-578. [3]Nunokawa, T., et al. Effect of Sulfasalazine Use on the Presence of Pneumocystis Organisms in the Lung among Patients with Rheumatoid Arthritis: A Test-Negative Design Case-Control Study with PCR Tests. Mod. Rheumatol. 2019;29(3):436-440. [4]Petersen, I., et al. Self controlled case series methods: an alternative to standard epidemiological study designs. BMJ. 2016;12;354:i4515. Disclosure of Interests: None declared