York Kiat Tan

Ex Vivo–Expanded but Not In Vitro–Induced Human Regulatory T Cells Are Candidates for Cell Therapy in Autoimmune Diseases Thanks to Stable Demethylation of the FOXP3 Regulatory T Cell–Specific Demethylated Region

Regulatory T cell (Treg) therapy is a promising approach for transplant rejection and severe autoimmunity. Unfortunately, clinically meaningful Treg numbers can be obtained only upon in vitro culture. Functional stability of human expanded (e)Tregs and induced (i)Tregs has not been thoroughly addressed for all proposed protocols, hindering clinical translation. We undertook a systematic comparison of eTregs and iTregs to recommend the most suitable for clinical implementation, and then tested their effectiveness and feasibility in rheumatoid arthritis (RA). Regardless of the treatment, iTregs acquired suppressive function and FOXP3 expression, but lost them upon secondary restimulation in the absence of differentiation factors, which mimics in vivo reactivation. In contrast, eTregs expanded in the presence of rapamycin (rapa) retained their regulatory properties and FOXP3 demethylation upon restimulation with no stabilizing agent. FOXP3 demethylation predicted Treg functional stability upon secondary TCR engagement. Rapa eTregs suppressed conventional T cell proliferation via both surface (CTLA-4) and secreted (IL-10, TGF-β, and IL-35) mediators, similarly to ex vivo Tregs. Importantly, Treg expansion with rapa from RA patients produced functionally stable Tregs with yields comparable to healthy donors. Moreover, rapa eTregs from RA patients were resistant to suppression reversal by the proinflammatory cytokine TNF-α, and were more efficient in suppressing synovial conventional T cell proliferation compared with their ex vivo counterparts, suggesting that rapa improves both Treg function and stability. In conclusion, our data indicate Treg expansion with rapa as the protocol of choice for clinical application in rheumatological settings, with assessment of FOXP3 demethylation as a necessary quality control step.

Imaging in rheumatoid arthritis

The optimal management of rheumatoid arthritis (RA) requires tools that allow early and accurate disease diagnosis, prediction of poor prognosis and responsive monitoring of therapeutic outcomes. Conventional radiography has been widely used in both clinical and research settings to assess RA joint damage due to its feasibility, but it has limitations in early disease detection and difficulty distinguishing between active treatments in modern trials. Imaging modalities such as magnetic resonance imaging (MRI) and ultrasound (US) have the advantage of detecting both joint inflammation and damage and hence they can provide additional and unique information. This can be especially useful in the context of early and/or undifferentiated joint disease when detection of soft tissue and bone marrow abnormalities is desirable. This review focusses on the recent literature concerning modern imaging, and provides clinicians with an insight into the role of imaging in modern RA diagnosis, prognosis and monitoring.

Imaging tools in rheumatoid arthritis: ultrasound vs magnetic resonance imaging

As modern imaging tools such as US and MRI become increasingly available, rheumatologists now have access to highly sensitive measures to assist in the evaluation of both the inflammatory and structural damage components underlying various arthritides over the disease duration. Both US and MRI have associated strengths and weaknesses, and at times they can provide complementary information. This review compares the performance of US vs MRI as diagnostic, prognostic and monitoring tools for RA, and to provide insights into which modality can provide the optimal information for a desired outcome in a given clinical trial or practice situation.

The eye: a window of opportunity in rheumatoid arthritis?

Rheumatoid arthritis (RA), the most common autoimmune disorder associated with dry eye syndrome, is also associated with sight-threatening ocular diseases such as peripheral ulcerative keratitis, scleritis and corneal melts. Tissue damage on the ocular surface of patients with RA is autoimmune-mediated. Findings from patients with dry eye have implicated defects in innate immunity (Toll-like receptors, S100A and resident antigen-presenting cells), cytokines, chemokines and T helper (TH)-cell subsets (including TH1 and TH17) in disease pathogenesis. Some of these features are probably important in dry eye related to RA, which can occur at a different time from articular disease and is more clinically severe than idiopathic dry eye. Ocular surface immune factors can be influenced by the systemic immune landscape. Depending on the severity of ocular inflammation in RA, treatment can include ciclosporin, topical corticosteroids, tacrolimus, autologous serum and systemic immunosuppression. Tissue damage is treated by inhibiting matrix metalloproteinases. Potential therapeutic strategies benefit from an improved understanding of ocular surface immunology, and include targeting of T-cell subsets, B-cell signalling or cytokines.

Pneumocystis jirovecii pneumonia in patients with autoimmune disease on high-dose glucocorticoid.

ObjectiveIndications for Pneumocystis jirovecii pneumonia (PCP) prophylaxis in patients with autoimmune disease remain unclear. We aimed to determine (1) the incidence of PCP in patients with autoimmune disease in general, in a clinical setting where prophylaxis is not routine, and (2) whether high-dose glucocorticoid (≥30 mg oral prednisolone or equivalent per day) is a risk factor for PCP infection. MethodsA retrospective review of the medical records of patients with autoimmune diseases hospitalized to a tertiary center over a 5-year study period was carried out. Patient demographics, mean glucocorticoid dose (in the last 1 month), and the outcomes of patients who developed PCP were analyzed. ResultsThe incidence rate of PCP infection was 75 per 100,000 patients per year. The in-hospital mortality was 50%, and all those who died were on high-dose glucocorticoid at the time of PCP diagnosis. There was a significant difference between the occurrence of PCP in patients who were on high-dose vs non–high-dose glucocorticoid (df = 1, P = 0.009), with a relative risk of 19 (P = 0.010; 95% confidence interval, 2.0–182.8). The mean oral prednisolone dose of patients who developed PCP and those who did not were 55.5 versus 10.7 mg, respectively, P = 0.002. ConclusionHigh-dose glucocorticoid may be associated with an increased risk of PCP infection in patients with autoimmune diseases.

Monitoring in established RA: Role of imaging and soluble biomarkers

Rheumatoid arthritis (RA) disease activity often remains difficult to define and to quantify. As a result, numerous techniques to estimate clinical activity have been developed and are in clinical use. Therefore, more objective biomarkers for early detection and accurate measurement and quantification of the disease burden are desired for clinical use and investigative studies. Several imaging and soluble biomarkers have been studied in the disease including conventional radiography, ultrasound, magnetic resonance imaging (MRI), and serum biomarker assays. While these tools are available to physicians in many settings, their role in routine clinical care remains unclear. The goals of this review are to outline the current state of the literature regarding each of these objective tools, assess their strengths and weaknesses, and clarify the knowledge gaps to be filled before these techniques may be more widely used.

Orbital Aspergillosis or Giant Cell Arteritis — A Diagnostic Dilemma

Orbital aspergillosis is an uncommon but potentially fatal disease. Its initial clinical presentation can be nonspecific and may be easily confused with other systemic diseases (such as neoplasms, other orbital infections which could include bacterial, mycobacterium and fungal infections), systemic vasculitis and other inflammatory conditions. Use of systemic corticosteroid may result in transient symptom relief further delaying the diagnosis. We describe its occurrence in a 76-year-old Chinese female with underlying rheumatoid arthritis who presented with a four-week history of left fronto-temporal headache, and ipsilateral blurring of vision with an elevated erythrocyte sedimentation rate (ESR). Although temporal artery biopsy was negative for giant cell arteritis (GCA), high-dose corticosteroids were initially started for presumptive GCA. There was an initial transient improvement in headache and in her left eyes visual acuity. However, this was followed by a worsening headache and complete visual loss in her left eye. Magnetic resonance imaging (MRI) revealed a new orbital apical mass-like lesion extending from the sphenoid sinus which was diagnosed as aspergillus infection on biopsy. Her condition improved and remained stable after the institution of appropriate anti-fungal therapy.

Insights into osteoarthritis from MRI.

Magnetic resonance imaging (MRI) has added a new dimension to the study of osteoarthritis, a long‐known degenerative joint disease with limited therapeutic options. It has advanced our understanding of joint pathophysiology and identifying that osteoarthritis as a simple ‘wear and tear’ process of the articular cartilage has indeed become a thing of the past. Recent work has focused on the study and validation of MRI scoring/quantification systems, as well as the identification of MRI predictors of symptoms/disease progression. The latter may serve to identify patients at greater risk for osteoarthritis disease progression to be enrolled in clinical trials. Like all imaging tools, MRI use has its associated problems. Structural changes seen in patients with osteoarthritis are often seen in asymptomatic subjects and this makes an MRI definition of osteoarthritis less straightforward. The ability to pick up multiple structural abnormalities simultaneously and high sensitivity in delineating structural changes can makes interpretation of true pathology more complicated. Although there has been much progress in the field of MRI in osteoarthritis, there remain many clinical/technical issues that need to be addressed. Until more data are obtained from clinical trials, the question of whether MRI is useful in therapeutics intervention in osteoarthritis remains unanswered.

Novel joint selection methods can reduce sample size for rheumatoid arthritis clinical trials with ultrasound endpoints

To determine whether novel methods of selecting joints through (i) ultrasonography (individualized‐ultrasound [IUS] method), or (ii) ultrasonography and clinical examination (individualized‐composite‐ultrasound [ICUS] method) translate into smaller rheumatoid arthritis (RA) clinical trial sample sizes when compared to existing methods utilizing predetermined joint sites for ultrasonography.

Dichotomous versus semi-quantitative scoring of ultrasound joint inflammation in rheumatoid arthritis using novel individualized joint selection methods

The aim of the study is to compare the responsiveness of two joint inflammation scoring systems (dichotomous scoring (DS) versus semi-quantitative scoring (SQS)) using novel individualized ultrasound joint selection methods and existing ultrasound joint selection methods. Responsiveness measured by the standardized response means (SRMs) using the DS and the SQS system (for both the novel and existing ultrasound joint selection methods) was derived using the baseline and the 3-month total inflammatory scores from 20 rheumatoid arthritis patients. The relative SRM gain ratios (SRM-Gains) for both scoring system (DS and SQS) comparing the novel to the existing methods were computed. Both scoring systems (DS and SQS) demonstrated substantial SRM-Gains (ranged from 3.31 to 5.67 for the DS system and ranged from 1.82 to 3.26 for the SQS system). The SRMs using the novel methods ranged from 0.94 to 1.36 for the DS system and ranged from 0.89 to 1.11 for the SQS system. The SRMs using the existing methods ranged from 0.24 to 0.32 for the DS system and ranged from 0.34 to 0.49 for the SQS system. The DS system appears to achieve high responsiveness comparable to SQS for the novel individualized ultrasound joint selection methods.