Adaptive treatment strategies for chronic conditions: shared-parameter G-estimation with an application to rheumatoid arthritis.

Most estimation algorithms for adaptive treatment strategies assume that treatment rules at each decision point are independent from one another in the sense that they do not possess any common parameters. This is often unrealistic, as the same decisions may be made repeatedly over time. Sharing treatment-decision parameters across decision points offers several advantages, including estimation of fewer parameters and the clinical ease of a single, time-invariant decision to implement. We propose a new computational approach to estimation of shared-parameter G-estimation, which is efficient and shares the double robustness of the "unshared" sequential G-estimation. We use this approach to analyze data from the Scottish Early Rheumatoid Arthritis (SERA) Inception Cohort.

Finite sample variance estimation for optimal dynamic treatment regimes of survival outcomes.

Deriving valid confidence intervals for complex estimators is a challenging task in practice. Estimators of dynamic weighted survival modeling (DWSurv), a method to estimate an optimal dynamic treatment regime of censored outcomes, are asymptotically normal and consistent for their target parameters when at least a subset of the nuisance models is correctly specified. However, their behavior in finite samples and the impact of model misspecification on inferences remain unclear. In addition, the estimators' nonregularity may negatively affect the inferences under some specific data generating mechanisms. Our objective was to compare five methods, two asymptotic variance formulas (adjusting or not for the estimation of nuisance parameters) to three bootstrap approaches, to construct confidence intervals for the DWSurv parameters in finite samples. Via simulations, we considered practical scenarios, for example, when some nuisance models are misspecified or when nonregularity is problematic. We also compared the five methods in an application about the treatment of rheumatoid arthritis. We found that the bootstrap approaches performed consistently well at the cost of longer computational times. The asymptotic variance with adjustments generally yielded conservative confidence intervals. The asymptotic variance without adjustments yielded nominal coverages for large sample sizes. We recommend using the asymptotic variance with adjustments in small samples and the bootstrap if computationally feasible. Caution should be taken when nonregularity may be an issue.

Randomized, placebo-controlled study on the effects of intravenous GSK3858279 (anti-CCL17) on a battery of evoked pain tests in healthy participants.

C-C Motif Chemokine Ligand 17 (CCL17) is a chemokine that binds and signals through the G-protein coupled CC-chemokine receptor 4 and has been implicated in the development of inflammatory and arthritic pain. GSK3858279 is a high-affinity, first-in-class, monoclonal antibody, binding specifically to CCL17 and inhibiting downstream signaling. In this phase I, randomized, single-center, double-blind, placebo-controlled, three-period, incomplete-block crossover study (NCT04114656), the analgesic effects and safety of intravenous GSK3858279 were assessed in a battery of evoked acute pain assessments on healthy, adult (aged ≥18 years), male participants. Participants were randomized 1:1 to receive either one placebo (0.9% w/v NaCl) dose followed by two GSK3858279 doses (PAA treatment sequence), or one GSK3858279 dose followed by two placebo doses (APP treatment sequence). The co-primary end points were ultraviolet B heat pain detection threshold (°C), cold pressor time to pain tolerance threshold (PTT, sec), and electrical PTT (mA, single stimulus). Twenty-one participants were enrolled (PAA = 11; APP = 10). Mean age (standard deviation) was 29.3 (7.9) years for PAA, 31.1 (7.7) years for APP. No significant differences were observed in the analgesic effect between GSK3858279 and placebo for any end point. Exposure to GSK3858279 was similar between Period 1 (APP sequence), and Periods 2 and 3 (PAA sequence), with some GSK3858279 carry-over. Changes in serum CCL17 levels were consistent with the expected GSK3858279 activity. All drug-related adverse events were mild in intensity and caused no discontinuations. The absence of an efficacy signal in this acute pain model does not preclude efficacy in chronic pain states.

The liver X receptor pathway is highly upregulated in rheumatoid arthritis synovial macrophages and potentiates TLR-driven cytokine release.

OBJECTIVES: Macrophages are central to the inflammatory processes driving rheumatoid arthritis (RA) synovitis. The molecular pathways that are induced in synovial macrophages and thereby promote RA disease pathology remain poorly understood. METHODS: We used microarray to characterise the transcriptome of synovial fluid (SF) macrophages compared with matched peripheral blood monocytes from patients with RA (n=8). RESULTS: Using in silico pathway mapping, we found that pathways downstream of the cholesterol activated liver X receptors (LXRs) and those associated with Toll-like receptor (TLR) signalling were upregulated in SF macrophages. Macrophage differentiation and tumour necrosis factor α promoted the expression of LXRα. Furthermore, in functional studies we demonstrated that activation of LXRs significantly augmented TLR-driven cytokine and chemokine secretion. CONCLUSIONS: The LXR pathway is the most upregulated pathway in RA synovial macrophages and activation of LXRs by ligands present within SF augments TLR-driven cytokine secretion. Since the natural agonists of LXRs arise from cholesterol metabolism, this provides a novel mechanism that can promote RA synovitis.

Inhibition of spleen tyrosine kinase in the treatment of rheumatoid arthritis.

The pathogenesis of RA is a complex and ever-changing landscape but amid the chaos of the disease process we have found effective treatment regimes. However, our current therapeutics, although targeting various components of both the innate and adaptive immune response, do not result in disease remission. Protein kinase inhibitors are attractive targets due to their ability to influence downstream signalling and their oral bioavailability. Fostamatinib (R788) inhibits spleen tyrosine kinase (Syk) and has been in clinical trials involving both MTX inadequate responders (MTX-IRs) and biologic inadequate responders. Studies on the MTX-IR population revealed ACR20 responses of 67-72% at higher doses (150 mg bd and 100 mg bd), ACR50 responses of 43-57% and ACR70 responses of 28-40%. The trial in the biologic non-responder population showed no efficacy, however, post hoc analyses of the data suggested that a further trial in this population is warranted. The most common adverse events included gastrointestinal effects, hypertension, neutropenia and transaminitis. Many adverse effects were dose responsive and hypertension was amenable to treatment. Upper respiratory tract infections were more likely at higher doses, but no serious infections with tuberculosis, fungi or opportunistic infections were reported. The oral availability of these agents makes them attractive treatment options for our patients, although the literature from the oncology field suggests that patients will only choose the oral route if efficacy is equivalent. Long-term follow-up studies are ongoing and will be critical for rare side effects. The role of these agents in our current arsenal is unclear and economic analyses are awaited.

JAK inhibitors disrupt T cell-induced proinflammatory macrophage activation.

OBJECTIVES: Macrophage subsets, activated by T cells, are increasingly recognised to play a central role in rheumatoid arthritis (RA) pathogenesis. Janus kinase (JAK) inhibitors have proven beneficial clinical effects in RA. In this study, we investigated the effect of JAK inhibitors on the generation of cytokine-activated T (Tck) cells and the production of cytokines and chemokines induced by Tck cell/macrophage interactions. METHODS: CD14+ monocytes and CD4+ T cells were purified from peripheral blood mononuclear cells from buffy coats of healthy donors. As representative JAK inhibitors, tofacitinib or ruxolitinib were added during Tck cell differentiation. Previously validated protocols were used to generate macrophages and Tck cells from monocytes and CD4+ T cells, respectively. Cytokine and chemokine including TNF, IL-6, IL-15, IL-RA, IL-10, MIP1α, MIP1ß and IP10 were measured by ELISA. RESULTS: JAK inhibitors prevented cytokine-induced maturation of Tck cells and decreased the production of proinflammatory cytokines TNF, IL-6, IL-15, IL-1RA and the chemokines IL-10, MIP1α, MIP1ß, IP10 by Tck cell-activated macrophages in vitro (p<0.05). CONCLUSIONS: Our findings show that JAK inhibition disrupts T cell-induced macrophage activation and reduces downstream proinflammatory cytokine and chemokine responses, suggesting that suppressing the T cell-macrophage interaction contributes to the therapeutic effect of JAK inhibitors.

The impact of autoantibodies against citrullinated, carbamylated, and acetylated peptides on radiographic progression in patients with new-onset rheumatoid arthritis: an observational cohort study.

BACKGROUND: A range of anti-modified protein antibodies (AMPAs) are associated with rheumatoid arthritis. We aimed to assess the relationship between AMPA profiles and radiographic progression in patients with new-onset rheumatoid arthritis. METHODS: In this cohort study, we obtained samples and data from the Scottish Early Rheumatoid Arthritis (SERA) inception cohort and biobank, which recruited patients with new-onset rheumatoid arthritis or undifferentiated arthritis who had at least one swollen joint from 20 hospitals across Scotland. AMPAs in plasma samples were measured by ELISAs at baseline. Paired radiographs of the hands and feet were taken at baseline and at 1 year and were scored with the Sharp-van der Heijde (SvH) method. We calculated differences in radiographic progression using estimated marginal mean changes between baseline and 1 year, with the baseline values of radiographic variables, rheumatoid factor, sex, age at recruitment, symptom duration, and Disease Activity Score 28 with C-reactive protein included as covariates. FINDINGS: Between March 1, 2011, and April, 30, 2015, 1073 patients were recruited to the SERA study. 362 patients with rheumatoid arthritis were included in our study and had their AMPA profiles determined. Patients were grouped into four main autoantibody profiles by reactivities to post-translational modifications: single positivity for anti-citrullinated peptide antibodies (ACPAs; 73 [20%]); double positivity for ACPAs and anti-acetylated peptide antibodies (AAPAs; 45 [12%]); triple positivity for ACPAs, AAPAs, and anti-carbamylated peptide antibodies (151 [42%]); and AMPA negativity (74 [20%]). 19 (5%) patients were in one of the minor autoantibody groups. Of the 233 patients with both antibody data and radiographs of sufficient quality, triple-positive patients had more radiographic progression between baseline and 12 months (estimated mean change in total SvH score 1·8, 95% CI 0·9-2·6, SE 0·4) than did single-positive patients (0·5, 0·1-1·0, 0·2; estimated mean difference in the total change in SvH score 1·2, 95% CI 0·1-2·4, SE 0·5). There was no difference in radiographic progression between single positive patients and AMPA negative patients (estimated mean change in total SvH score 0·7, 95% CI 0·1-1·4, SE 0·3; estimated mean difference in the total change in SvH score -0·2, 95% CI -1·1 to 0·7, SE 0·4). INTERPRETATION: This study suggests that the optimal prediction of future rates of radiographic progression in patients with rheumatoid arthritis will require an assessment of autoantibodies against multiple post-translationally modified proteins or peptides. FUNDING: The EU FP7 HEALTH programme, the Scottish Translational Medicine Research Collaboration, and the Chief Scientist Office Scotland.

The mannose receptor (CD206) identifies a population of colonic macrophages in health and inflammatory bowel disease.

To understand the contribution of mononuclear phagocytes (MNP), which include monocyte-derived intestinal macrophages, to the pathogenesis of inflammatory bowel disease (IBD), it is necessary to identify functionally-different MNP populations. We aimed to characterise intestinal macrophage populations in patients with IBD. We developed 12-parameter flow cytometry protocols to identify and human intestinal MNPs. We used these protocols to purify and characterize colonic macrophages from colonic tissue from patients with Crohn's disease (CD), ulcerative colitis (UC), or non-inflamed controls, in a cross-sectional study. We identify macrophage populations (CD45+CD64+ HLA-DR+) and describe two distinct subsets, differentiated by their expression of the mannose receptor, CD206. CD206+ macrophages expressed markers consistent with a mature phenotype: high levels of CD68 and CD163, higher transcription of IL-10 and lower expression of TREM1. CD206- macrophages appear to be less mature, with features more similar to their monocytic precursors. We identified and purified macrophage populations from human colon. These appear to be derived from a monocytic precursor with high CCR2 and low CD206 expression. As these cells mature, they acquire expression of IL-10, CD206, CD63, and CD168. Targeting the newly recruited monocyte-derived cells may represent a fruitful avenue to ameliorate chronic inflammation in IBD.

MiR-155 has a protective role in the development of non-alcoholic hepatosteatosis in mice.

Hepatic steatosis is a global epidemic that is thought to contribute to the pathogenesis of type 2 diabetes. MicroRNAs (miRs) are regulators that can functionally integrate a range of metabolic and inflammatory pathways in liver. We aimed to investigate the functional role of miR-155 in hepatic steatosis. Male C57BL/6 wild-type (WT) and miR-155(-/-) mice were fed either normal chow or high fat diet (HFD) for 6 months then lipid levels, metabolic and inflammatory parameters were assessed in livers and serum of the mice. Mice lacking endogenous miR-155 that were fed HFD for 6 months developed increased hepatic steatosis compared to WT controls. This was associated with increased liver weight and serum VLDL/LDL cholesterol and alanine transaminase (ALT) levels, as well as increased hepatic expression of genes involved in glucose regulation (Pck1, Cebpa), fatty acid uptake (Cd36) and lipid metabolism (Fasn, Fabp4, Lpl, Abcd2, Pla2g7). Using miRNA target prediction algorithms and the microarray transcriptomic profile of miR-155(-/-) livers, we identified and validated that Nr1h3 (LXRα) as a direct miR-155 target gene that is potentially responsible for the liver phenotype of miR-155(-/-) mice. Together these data indicate that miR-155 plays a pivotal role regulating lipid metabolism in liver and that its deregulation may lead to hepatic steatosis in patients with diabetes.