Serum amyloid A (SAA) is expressed locally in chronic inflammatory conditions such as chronic obstructive pulmonary disease (COPD), where macrophages that do not accord with the classic M1/M2 paradigm also accumulate. In this study, the role of SAA in regulating macrophage differentiation was investigated in vitro using human blood monocytes from healthy subjects and patients with COPD and in vivo using an airway SAA challenge model in BALB/c mice. Differentiation of human monocytes with SAA stimulated the proinflammatory monokines IL-6 and IL-1β concurrently with the M2 markers CD163 and IL-10. Furthermore, SAA-differentiated macrophages stimulated with lipopolysaccharide (LPS) expressed markedly higher levels of IL-6 and IL-1β. The ALX/FPR2 antagonist WRW4 reduced IL-6 and IL-1β expression but did not significantly inhibit phagocytic and efferocytic activity. In vivo, SAA administration induced the development of a CD11c(high)CD11b(high) macrophage population that generated higher levels of IL-6, IL-1β, and G-CSF following ex vivo LPS challenge. Blocking CSF-1R signaling effectively reduced the number of CD11c(high)CD11b(high) macrophages by 71% and also markedly inhibited neutrophilic inflammation by 80%. In conclusion, our findings suggest that SAA can promote a distinct CD11c(high)CD11b(high) macrophage phenotype, and targeting this population may provide a novel approach to treating chronic inflammatory conditions associated with persistent SAA expression.

Summary Background There are safety concerns regarding immunomodulators (thiopurines and methotrexate) for treatment of inflammatory bowel disease (IBD). Aim To compare the long‐term tolerability, and persistence of thiopurine and methotrexate therapy in IBD. Methods A retrospective cohort study was performed at two hospitals between 1 January 2004 and 31 December 2016 for patients commenced on thiopurines or methotrexate for IBD. Treatment discontinuation rates, intolerances and disease activity were obtained from medical records. Results There were 782 patients commenced on immunomodulator therapy; 244 (31%) on methotrexate with folate (67% subcutaneous therapy) and 538 (69%) on thiopurine (73% azathioprine). Median follow‐up was 42 vs 47 months (P = 0.09). In patients on thiopurines, median 6‐TGN was 298 pmol/8 x 108 RBCs, while the median dose of methotrexate was 25 mg weekly. Methotrexate recipients had a higher rate of prior immunomodulator intolerance, were typically older and had a longer disease duration (54% vs 3%, median 43 vs 36 years, 6 vs 5 years, respectively, each P < 0.05). Overall, 208 (27%) discontinued therapy due to adverse events, (40% on methotrexate vs 19% on thiopurines, P < 0.001), including nausea (18% vs 4%), fatigue (7% vs 2%) and hepatotoxicity (8% vs 2%, each P < 0.001). Hospitalisations from adverse events (0.8% vs 0.9%) and serious infections (9% vs 12%), and deaths (1% vs 0%) were comparable between groups (all P > 0.05). Discontinuation due to adverse events occurred later in patients on methotrexate than on thiopurines (median 7 vs 5 months, P = 0.08). Conclusion Discontinuation of methotrexate occurred at rates twice that of dose‐optimised thiopurine therapy.

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Background Early or first-line treatment with biologics as opposed to conventional immunomodulators is not always necessary to achieve remission in Crohn’s disease (CD) and may not be cost-effective. This study aimed to develop a simple model to predict the need for early biologic therapy in order to risk stratify CD patients and guide initial treatment selection. Methods A model-building study using supervised statistical learning methods was conducted utilising a retrospective cohort across two tertiary centres. All biologic-naïve CD patients who commenced an immunomodulator between 1/1/2004 and 31/12/2016 were included. A predictive score was derived using Cox regression modelling of immunomodulator failure and was internally validated using bootstrap resampling. Results Of 410 patients (median age 37 years, 47% male, median disease duration 4.7 years), 229 (56%) experienced immunomodulator failure (39 required surgery, 24 experienced a new stricture, 44 experienced a new fistula/abscess, 122 required biologic escalation) with a median time to failure of 16 months. Independent predictors of treatment failure included raised CRP, low albumin, complex disease behaviour, younger age and baseline steroids. Highest CRP and lowest albumin measured within 3 months prior to immunomodulator initiation outperformed baseline measurements. After model selection, only highest CRP and lowest albumin remained and the resultant Crohn's Immunomodulator CRP-Albumin (CICA) index demonstrated robust optimism-corrected discriminative performance at 12, 24 and 36 months (AUC 0.84, 0.83, 0.81 respectively). Conclusions The derived CICA index based on simple, widely available markers is feasible, internally valid and has a high utility in predicting immunomodulator failure. This requires external, prospective validation.

Background and Aims Vitamin D has a regulatory role in innate and adaptive immune processes. Previous studies have reported that low pre-treatment vitamin D concentrations are associated with primary non-response (PNR) and non-remission to anti-TNF therapy. This study aimed to assess whether pre-treatment 25-hydroxyvitamin D concentrations predicted PNR and non-remission to infliximab and adalimumab in patients with active luminal Crohn’s disease. Methods 25-hydroxyvitamin D concentrations were measured in stored baseline samples from 659 infliximab- and 448 adalimumab-treated patients in the Personalised Anti-TNF Therapy in Crohn’s disease (PANTS) study. Cut-offs for vitamin D were: deficiency &lt; 25nmol/L, insufficiency 25-50nmol/L and adequacy/sufficiency &gt; 50nmol/L. Results 17.1% (189/1107; 95% confidence interval [CI] 15.0 - 19.4%) and 47.7% (528/1107; 95% CI 44.8 - 50.6%) patients had vitamin D deficiency and insufficiency, respectively. 22.2% (246/1107) patients were receiving vitamin D supplementation. Multivariable analysis confirmed that sampling during non-summer months, South Asian ethnicity, lower serum albumin concentrations and nontreatment with vitamin D supplements were independently associated with lower vitamin D concentrations. Pre-treatment vitamin D status did not predict response or remission to anti-TNF therapy at week 14 (infliximab Ppnr = 0.89, adalimumab Ppnr = 0.18) or non-remission at week 54 (infliximab p = 0.13, adalimumab p = 0.58). Vitamin D deficiency was, however, associated with a longer time to immunogenicity in patients treated with infliximab, but not adalimumab. Conclusion Vitamin D deficiency is common in patients with active Crohn’s disease. Unlike previous studies, pre-treatment vitamin D concentration did not predict PNR to anti-TNF treatment at week 14 or non-remission at week 54.