Nicola J. Gullick

In vivo activated monocytes from the site of inflammation in humans specifically promote Th17 responses

Th17 cells are a recently defined subset of proinflammatory T cells that contribute to pathogen clearance and tissue inflammation by means of the production of their signature cytokine IL-17A (henceforth termed IL-17). Although the in vitro requirements for human Th17 development are reasonably well established, it is less clear what their in vivo requirements are. Here, we show that the production of IL-17 by human Th17 cells critically depends on both the activation status and the anatomical location of accessory cells. In vivo activated CD14+ monocytes were derived from the inflamed joints of patients with active rheumatoid arthritis (RA). These cells were found to spontaneously and specifically promote Th17, but not Th1 or Th2 responses, compared with resting CD14+ monocytes from the blood. Surprisingly, unlike Th17 stimulation by monocytes that were in vitro activated with lipopolysaccharide, intracellular IL-17 expression was induced by in vivo activated monocytes in a TNF-α- and IL-1β-independent fashion. No role for IL-6 or IL-23 production by either in vitro or in vivo activated monocytes was found. Instead, in vivo activated monocytes promoted Th17 responses in a cell-contact dependent manner. We propose that, in humans, newly recruited memory CD4+ T cells can be induced to produce IL-17 in nonlymphoid inflamed tissue after cell–cell interactions with activated monocytes. Our data also suggest that different pathways may be utilized for the generation of Th17 responses in situ depending on the site or route of accessory cell activation.

Interleukin-17+CD8+ T Cells Are Enriched in the Joints of Patients With Psoriatic Arthritis and Correlate With Disease Activity and Joint Damage Progression

Psoriatic arthritis (PsA) is associated with HLA class I genes, in contrast to the association with HLA class II in rheumatoid arthritis (RA). Since IL‐17+ cells are considered important mediators of synovial inflammation, we sought to determine whether IL‐17–producing CD8+ T cells may be found in the joints of patients with PsA and whether these cells might contribute to the disease process.

Co-morbidities in established rheumatoid arthritis

Co-morbid conditions are common in patients with rheumatoid arthritis (RA). Although the presence of co-morbid conditions can be assessed using standardised indexes such as the Charlson index, most clinicians prefer to simply record their presence. Some co-morbidities are causally associated with RA and many others are related to its treatment. Irrespective of their underlying pathogenesis, co-morbidities increase disability and shorten life expectancy, thereby increasing both the impact and mortality of RA. Cardiac co-morbidities are the most crucial, because of their frequency and their negative impacts on health. Treatment of cardiac risk factors and reducing RA inflammation are both critical in reducing cardiac co-morbidities. Gastrointestinal and chest co-morbidities are both also common. They are often associated with drug treatment, including non-steroidal anti-inflammatory drug and disease-modifying drugs. Osteoporosis and its associated fracture risk are equally important and are often linked to long-term glucocorticoid treatment. The range of co-morbidities associated with RA is increasing with the recognition of new problems such as periodontal disease. Optimal medical care for RA should include an assessment of associated co-morbidities and their appropriate management. This includes risk factor modification where possible. This approach is essential to improve quality of life and reduce RA mortality. An area of genuine concern is the impact of treatment on co-morbidities. A substantial proportion is iatrogenic. As immunosuppression with conventional disease-modifying drugs and biologics has many associated risks, ranging from liver disease to chest and other infections, it is essential to balance the risks of co-morbidities against the anticipated benefits of treatment.

Linking Power Doppler Ultrasound to the Presence of Th17 Cells in the Rheumatoid Arthritis Joint

Background Power Doppler ultrasound (PDUS) is increasingly used to assess synovitis in Rheumatoid Arthritis (RA). Prior studies have shown correlations between PDUS scores and vessel counts, but relationships with T cell immunopathology have not been described. Methodology/Principal Findings PBMC were isolated from healthy controls (HC) or RA patients and stimulated ex vivo with PMA and ionomycin for 3 hours in the presence of Golgistop. Paired synovial fluid (SF) or synovial tissue (ST) were analysed where available. Intracellular expression of IL-17, IFNγ, and TNFα by CD4+ T cells was determined by flow cytometry. Synovial blood flow was evaluated by PDUS signal at the knees, wrists and metacarpophalangeal joints of RA patients. Serum, SF and fibroblast culture supernatant levels of vascular endothelial growth factor-A (VEGF-A) were measured by ELISA. The frequency of IL17+IFNγ-CD4+ T cells (Th17 cells) was significantly elevated in peripheral blood (PB) from RA patients vs. HC (median (IQR) 0.5 (0.28–1.59)% vs. 0.32 (0.21–0.54)%, p = 0.005). Th17 cells were further enriched (mean 6.6-fold increase) in RA SF relative to RA PB. Patients with active disease had a higher percentage of IL-17+ T cells in ST than patients in remission, suggesting a possible role for Th17 cells in active synovitis in RA. Indeed, the percentage of Th17 cells, but not Th1, in SF positively correlated with CRP (r = 0.51, p = 0.04) and local PDUS-defined synovitis (r = 0.61, p = 0.002). Furthermore, patients with high levels of IL-17+CD4+ T cells in SF had increased levels of the angiogenic factor VEGF-A in SF. Finally, IL-17, but not IFNγ, increased VEGF-A production by RA synovial fibroblasts in vitro. Conclusions/Significance Our data demonstrate a link between the presence of pro-inflammatory Th17 cells in SF and local PDUS scores, and offer a novel immunological explanation for the observation that rapid joint damage progression occurs in patients with persistent positive PDUS signal.

TNF-α blockade induces IL-10 expression in human CD4+ T cells

IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF-inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg/Foxp3 independent, requires IL-10 and is overcome by IL-1β. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterised by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-α blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells.

An Examination of Work Instability, Functional Impairment, and Disease Activity in Employed Patients with Rheumatoid Arthritis

Objective. To evaluate the relationship between the Disease Activity Score 28-joint count (DAS28), Health Assessment Questionnaire (HAQ), and Rheumatoid Arthritis-Work Instability Scale (RAWIS); and to define thresholds for clinical assessments associated with moderate to high RA-WIS. Methods. Employed patients with RA were evaluated using DAS28, HAQ, and RA-WIS during routine clinics. Relationships between these assessments were evaluated by simple correlation. Multiple linear regression modeling was performed using RA-WIS as an outcome variable and HAQ, DAS28, age, sex, occupation, and disease duration as input variables. Receiver-operating characteristic curves were then formulated to determine optimal DAS28, and HAQ cutoff points for RA-WIS ≥ 10, along with the odds ratio (OR). Results. Ninety patients with RA completed the RA-WIS, which was moderately correlated with DAS28 (r =0.53) and HAQ (r = 0.66). Fifty-four percent of RA-WIS was explained by DAS28 (p = 0.002), HAQ (p = 0.001), and sex (p = 0.04). A DAS28 of 3.81 and HAQ of 0.55 were clinically important thresholds. High DAS28 and HAQ were associated with high RA-WIS (ORDAS 14.17, ORHAQ 25.13, ORDAS+HAQ 29.9). Conclusion Functional impairment and disease activity significantly and independently contributed to patient-perceived work instability risk.

Current perspectives on tocilizumab for the treatment of rheumatoid arthritis: a review

Rheumatoid arthritis (RA) remains a major clinical problem with many patients having continuing systemic inflammatory disease resulting in progressive erosive damage and high levels of disability. A range of pro-inflammatory cytokines including tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6 are involved in RA pathogenesis; these cytokines can be specifically inhibited by biological agents. Tocilizumab (TCZ) is a recombinant humanized anti-IL-6 receptor monoclonal antibody, administered monthly by intravenous infusion that prevents IL-6 signal transduction. There is strong evidence that it is both clinically efficacious and cost-effective. There have been several key clinical trials evaluating the safety and efficacy of TCZ in RA patients. We review five Phase II trials and seven Phase III trials enrolling a total of 626 and 5268 RA patients respectively. The American College of Rheumatology (ACR) response criteria were used as the primary or secondary outcome measure in all trials. Overall these trials demonstrated that TCZ was effective in the treatment of RA in a number of patient groups, including those with an inadequate response to methotrexate (MTX) or TNF inhibition. TCZ use, both as monotherapy and in combination with MTX, improved the signs and symptoms of RA within several weeks of commencing treatment. Additionally, TCZ was shown to reduce radiological disease progression and improve physical function, both as monotherapy and in combination with MTX. A 5-year extension study demonstrated that TCZ sustained good long-term efficacy and safety profiles. TCZ was generally well tolerated. Although its use increased the risk of an adverse event, these were usually mild to moderate in severity and treatment did not increase the risk of a serious adverse event in comparison to controls. Due to moderate increases in serum levels of total cholesterol, triglycerides, high-density lipoproteins and serum transaminases seen in those patients treated with TCZ, as well as severe neutropenia in some, regular blood monitoring of full blood count, liver function and lipids is recommended. Given its clinical efficacy in the treatment of RA, TCZ may be beneficial in the treatment of other autoimmune diseases where IL-6 plays a role in the inflammatory cascade.

FAS/FAS-L dependent killing of activated human monocytes and macrophages by CD4+CD25-responder T cells, but not CD4+CD25+regulatory T cells

Conclusive resolution of an immune response is critical for the prevention of autoimmunity and chronic inflammation. We report that following co-culture with autologous CD4+CD25- responder T cells, human CD14+ monocytes and monocyte-derived macrophages become activated but also significantly more prone to apoptosis than monocytes/macrophages cultured alone. In contrast, in the presence of CD4+CD25+ regulatory T cells (Tregs), monocytes and macrophages survive whilst adopting an anti-inflammatory phenotype. The induction of monocyte death requires responder T cell activation and cell-contact between responder T cells and monocytes. We demonstrate a critical role for FAS/FAS-L ligation in responder T cell-induced monocyte killing since responder T cells, but not Tregs, upregulate FAS-ligand (FAS-L) mRNA, and induce FAS expression on monocytes. Furthermore, responder T cell-induced monocyte apoptosis is blocked by neutralising FAS/FAS-L interaction, and is not observed when monocytes from an autoimmune lymphoproliferative syndrome (ALPS) patient with complete FAS-deficiency are used as target cells. Finally, we show that responder T cell-induced killing of monocytes is impaired in patients with active rheumatoid arthritis (RA). Our data suggest that resolution of inflammation in the course of a healthy immune response is aided by the unperturbed killing of monocytes with inflammatory potential by responder T cells and the induction of longer-lived, Treg-induced, anti-inflammatory monocytes.

Rheumatoid arthritis: clinical utility of the RAID (RA impact of disease) score.

A new patient self-assessment tool shows promise as a simple measure of the overall impact of rheumatoid arthritis on a patient, but will it be able to gain the international acceptance required to become a clinical standard?

Abatacept in the treatment of adult dermatomyositis and polymyositis: a randomised, phase IIb treatment delayed-start trial

Objectives To study the effects of abatacept on disease activity and on muscle biopsy features of adult patients with dermatomyositis (DM) or polymyositis (PM). Methods Twenty patients with DM (n=9) or PM (n=11) with refractory disease were enrolled in a randomised treatment delayed-start trial to receive either immediate active treatment with intravenous abatacept or a 3 month delayed-start. The primary endpoint was number of responders, defined by the International Myositis Assessment and Clinical Studies Group definition of improvement (DOI), after 6 months of treatment. Secondary endpoints included number of responders in the early treatment arm compared with the delayed treatment arm at 3 months. Repeated muscle biopsies were investigated for cellular markers and cytokines. Results 8/19 patients included in the analyses achieved the DOI at 6 months. At 3 months of study, five (50%) patients were responders after active treatment but only one (11%) patient in the delayed treatment arm. Eight adverse events (AEs) were regarded as related to the drug, four mild and four moderate, and three serious AEs, none related to the drug. There was a significant increase in regulatory T cells (Tregs), whereas other markers were unchanged in repeated muscle biopsies. Conclusions In this pilot study, treatment of patients with DM and PM with abatacept resulted in lower disease activity in nearly half of the patients. In patients with repeat muscle biopsies, an increased frequency of Foxp3+ Tregs suggests a positive effect of treatment in muscle tissue.