Is treat-to-target really working in rheumatoid arthritis? a longitudinal analysis of a cohort of patients treated in daily practice (RA BIODAM).

OBJECTIVES: To investigate whether following a treat-to-target (T2T)-strategy in daily clinical practice leads to more patients with rheumatoid arthritis (RA) meeting the remission target. METHODS: RA patients from 10 countries starting/changing conventional synthetic or biological disease-modifying anti-rheumatic drugs were assessed for disease activity every 3 months for 2 years (RA BIODAM (BIOmarkers of joint DAMage) cohort). Per visit was decided whether a patient was treated according to a T2T-strategy with 44-joint disease activity score (DAS44) remission (DAS44 <1.6) as the target. Sustained T2T was defined as T2T followed in ≥2 consecutive visits. The main outcome was the achievement of DAS44 remission at the subsequent 3-month visit. Other outcomes were remission according to 28-joint disease activity score-erythrocyte sedimentation rate (DAS28-ESR), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI) and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) Boolean definitions. The association between T2T and remission was tested in generalised estimating equations models. RESULTS: In total 4356 visits of 571 patients (mean (SD) age: 56 (13) years, 78% female) were included. Appropriate application of T2T was found in 59% of the visits. T2T (vs no T2T) did not yield a higher likelihood of DAS44 remission 3 months later (OR (95% CI): 1.03 (0.92 to 1.16)), but sustained T2T resulted in an increased likelihood of achieving DAS44 remission (OR: 1.19 (1.03 to 1.39)). Similar results were seen with DAS28-ESR remission. For more stringent definitions (CDAI, SDAI and ACR/EULAR Boolean remission), T2T was consistently positively associated with remission (OR range: 1.16 to 1.29), and sustained T2T had a more pronounced effect on remission (OR range: 1.49 to 1.52). CONCLUSION: In daily clinical practice, the correct application of a T2T-strategy (especially sustained T2T) in patients with RA leads to higher rates of remission.

Chronic TNF in the aging microenvironment exacerbates Tet2-loss-of-function myeloid expansion.

Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cell (HSC) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing TNF favours TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2-mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF-/- genotypes reconstituted with WT CD45.1+ and Tet2-/-CD45.2+ HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2-/-cells in old WT recipient mice, with strong skewing towards the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF-/- recipient mice, suggesting that TNF signalling is essential for the expansion Tet2-mutant myeloid clones. Examination of human rheumatoid arthritis patients with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-mutant CHIP.

Effect of pregnancy on scleroderma progression.

Objective: To explore the trajectory of scleroderma disease activity in women who experienced a pregnancy after systemic sclerosis diagnosis compared to nulliparous women. Methods: We analyzed data from the Canadian Scleroderma Research Group registry by identifying nulliparous women and women with ⩾1 pregnancy after systemic sclerosis diagnosis. Patient characteristics were compared between groups at registry entry. Controlling for age, smoking, and time since systemic sclerosis diagnosis, generalized estimating equations tested the effect of pregnancy on force vital capacity, diffusing capacity of the lungs for carbon monoxide, right ventricular systolic pressure, glomerular filtration rate, antibody status, active digital ulcers, physician global assessment of activity, and severity over 9 years. Results: At registry entry, numbers of women in the nulliparous and pregnancy after systemic sclerosis diagnosis groups were 153 and 45, respectively. Corresponding numbers at 6 and 9 years were 48 and 21, and 18 and 9, respectively. The prevalence of anti-topoisomerase positivity was 18.3% in nulliparous and 12.5% in pregnancy after systemic sclerosis diagnosis. Baseline differences included mean (Standard deviation) age of diagnosis (nulliparous: 38.8 (14.0), pregnancy after systemic sclerosis diagnosis: 22.6 (6.8) years, p < 0.001), disease duration (nulliparous: 9.6 (8.9), pregnancy after systemic sclerosis diagnosis: 21.9 (9.6) years; p < 0.001), and inflammatory arthritis (nulliparous: 41 (28%), pregnancy after systemic sclerosis diagnosis: 22 (49%), p = 0.009). There were no significant differences between groups in the change of any outcomes over time. Conclusion: Results demonstrated that having ⩾1 pregnancy after systemic sclerosis diagnosis did not appear to significantly impact long-term renal, respiratory, or global function outcomes. While this offers a hopeful message to systemic sclerosis patients planning a pregnancy, physicians and patients should remain vigilant for potential post-partum complications.

Combined Stimulation with Interleukin-18 and Interleukin-12 Potently Induces Interleukin-8 Production by Natural Killer Cells.

The combination of interleukin (IL)-18 and IL-12 (IL-18+IL-12) potently stimulates natural killer (NK) cells, triggering an innate immune response to infections and cancers. Strategies exploiting the effects of IL-18+IL-12 have shown promise for cancer immunotherapy. However, studies have primarily characterized the NK cell response to IL-18+IL-12 in terms of interferon (IFN)-γ production, with little focus on other cytokines produced. IL-8 plays a critical role in activating and recruiting immune cells, but it also has tumor-promoting functions. IL-8 is classically produced by regulatory NK cells; however, cytotoxic NK cells do not typically produce IL-8. In this study, we uncover that stimulation with IL-18+IL-12 induces high levels of IL-8 production by ex vivo expanded and freshly isolated NK cells and NK cells in peripheral blood mononuclear cells. We further report that tumor necrosis factor (TNF)-α, produced by NK cells following IL-18+IL-12 stimulation, regulates IL-8 production. The IL-8 produced is in turn required for maximal IFN-γ and TNF-α production. These findings may have important implications for the immune response to infections and cancer immunotherapies. This study broadens our understanding of NK cell function and IL-18+IL-12 synergy by uncovering an unprecedented ability of IL-18+IL-12-activated peripheral blood NK cells to produce elevated levels of IL-8 and identifying the requirement for intermediates induced by IL-18+IL-12 for maximal cytokine production following stimulation.