Anti-TNF Therapy Is Associated with an Increase in Serious Infections in Patients with Spondyloarthritis (SpA), Especially during the First 12 Monts of Treatment: Results from the GISEA Registry

Background/Purpose: Infection is by far the most common and most important adverse effect of TNF inhibitors (TNFI) in the treatment of rheumatoid arthritis (RA) and spondyloarthritis (SpA). The aim of this study was to evaluate the risk of SIs in the TNFI-treated SpA patients in the Gruppo Italiano Studio Early Arthritis (GISEA) Registry, and assess the predictors of their occurrence. Methods: The Registry, which is designed to collect real-world clinical data concerning RA and SpA patients receiving biological drugs as part of routine care, was approved by local Ethics Committees, and enrols patients aged ≥18 years who have given their written informed consent. The baseline information includes demographics, disease duration, HAQ, DAS-28, BASDAI, BASFI and BASMI scores, steroid use (defined as actively receiving oral steroids at the time of recruitment), smoking history and comorbidities. Results: The analysis involved 3321 SpA patients (1731 males, 52.2%; mean age 47±13 years; median disease duration three years, interquartile range [IQR] 0, 8 years): 1065 (32%) treated with infliximab (IFN), 1052 (32%) with adalimumab (ADA), and 1204 (36%) with etanercept (ETN). Two thousand, one hundred and five (63.4%) had a median of one comorbity (IQR 0, 2], the most frequent being hypertension (701), thyroid diseases (281), diabetes mellitus (207), cardiopathy (189), and osteoporosis (145). In combination with the biological drug, 919 patients (27.7%) received steroids and 2451 (79.9%) at least one DMARD. The median follow-up was three months (IQR 12 years). During 12 years of TNFI treatment, 259 patients experienced at least one of 391 microbiologically diagnosed SIs, 32% of which were recorded in the first 12 months. Overall incidence was 43.9/1000 patient-years of follow-up (95% CI 39.6–48.4): 29.9/1000 (95% CI 23.1–38.1) among those treated with ADA; 36.1/1000 (95% CI 30.0–43.1) among those treated with ETN; and 61.4/1000 (95% CI 53.3–70.5) among those treated with IFN. The most frequent were lower respiratory tract infections (pneumonia and bronchitis), followed by cutaneous infections. Bacteria were the most frequent micro-organisms (228, 58.3%), followed by fungal infections (40, 10.2%) and viral infections including herpes zoster (22, 5.6%). Univariate analysis showed that female gender (p=0.019) and comorbidities (p<0.001) were associated with a high risk of SI, and that the use of ETN or ADA rather than IFN (p<0.001 and p0.001) was associated with a lower risk of SI. Multivariate models showed that the number of comorbidities (hazard ratio [HR] 1.29, 95%CI 1.2–1.4; p<0.001), age at the start of anti-TNF treatment (HR 0.99, 95%CI 0.97-0.99; p=0.030), steroid use (HR 1.40, 95%CI 1.1–1.8; p=0.012), male gender (HR 0.72, 95%CI 0.5-0.9; p=0.012) were statistically significant predictors of infection. The factors independently associated with a decreased risk of SIs were the use of ETN (HR 0.52, 95%CI 0.4-0.7; p<0.001) or ADA (HR 0.59, 95%CI 0.4-0.8; p=0.002) rather than INF. Conclusion: These data add to currently available evidence suggesting that TNFI therapy is associated with a small but significant overall risk of SI in SpA patients.