Ali S. Jawad

Incomplete response of inflammatory arthritis to TNFα blockade is associated with the Th17 pathway

Objectives To establish if changes in Th1/Th17 cell populations previously reported in experimental arthritis occur in patients with rheumatoid arthritis (RA) treated with anti-tumour necrosis factor α (TNFα) agents, and whether the therapeutic response to anti-TNFα is compromised in patients and mice because of elevated Th17/IL-17 levels. Finally, to assess the efficacy of combined blockade of anti-TNFα and anti-IL-17 in experimental arthritis. Methods A longitudinal study of two independent cohorts (cohort 1, n=24; cohort 2, n=19) of patients with RA treated with anti-TNFα biological agents was carried out to assess their Th17/IL-17 levels before and after the start of anti-TNFα therapy. IL-12/23p40 production was assessed in plasma Peripheral blood lymphocytes (PBLs) and monocytes. Mice with collagen-induced arthritis (CIA) were treated with anti-TNFα alone, anti-IL17 alone or a combination of the two. Efficacy of treatment and response was assessed from changes in Disease Activity Score 28–erythrocyte sedimentation rate scores in patients, and in clinical scores and histological analysis in CIA. Results Significant increases in circulating Th17 cells were observed in patients after anti-TNFα therapy and this was accompanied by increased production of IL-12/23p40. There was an inverse relationship between baseline Th17 levels and the subsequent response of patients with RA to anti-TNFα therapy. In addition, PBLs from non-responder patients showed evidence of increased IL-17 production. Similarly, in anti-TNFα-treated mice, there was a strong correlation between IL-17 production and clinical score. Finally combined blockade of TNFα and IL-17 in CIA was more effective than monotherapy, particularly with respect to the duration of the therapeutic effect. Conclusions These findings, which need to be confirmed in a larger cohort, suggest that a Th17-targeted therapeutic approach may be useful for anti-TNFα non-responder patients or as an adjunct to anti-TNFα therapy, provided that safety concerns can be addressed.

Th17 Lymphocytes in Respiratory Syncytial Virus Infection

Infection by respiratory syncytial virus (RSV) affects approximately 33 million infants annually worldwide and is a major cause of hospitalizations. Helper T lymphocytes (Th) play a central role in the immune response during such infections. However, Th lymphocytes that produce interleukin 17 (IL-17), known as Th17 lymphocytes, in addition to been protective can also cause pathology that accompany this type of infection. The protective effects of Th17 is associated with better prognosis in most infected individuals but heightened Th17 responses causes inflammation and pathology in others. Studies employing animal models haves shown that activated Th17 lymphocytes recruit neutrophils and facilitate tertiary lymphoid structure development in infected lungs. However, IL-17 also inhibits the ability of CD8+ lymphocytes to clear viral particles and acts synergistically with the innate immune system to exacerbate inflammation. Furthermore, IL-17 enhances IL-13 production which, in turn, promotes the activation of Th2 lymphocytes and excessive mucus production. Studies of these animal models have also shown that a lack of, or inadequate, responses by the Th1 subset of T lymphocytes enhances Th17-mediated responses and that this is detrimental during RSV co-infection in experimental asthma. The available evidence, therefore, indicates that Th17 can play contradictory roles during RSV infections. The factors that determine the shift in the balance between beneficial and adverse Th17 mediated effects during RSV infection remains to be determined.

Rheumatoid peripheral blood phagocytes are primed for activation but have impaired Fc-mediated generation of reactive oxygen species

Significant levels of circulating immune complexes (ICs) containing rheumatoid factors and immunoglobulin G in peripheral blood are a characteristic feature of rheumatoid arthritis (RA). ICs interact through Fcγ receptors (FcγR) to activate phagocytes in numerous inflammatory processes. The high concentration of neutrophils in synovial fluid during active phases of the disease, together with their destructive capacity, pose important questions as to their role in the pathogenesis of RA. Functional defects in RA or control peripheral blood neutrophil FcγRs were examined with a specific FcγR-mediated reactive oxygen species (ROS) assay. Heterologous cross-linking of FcγRIIa and FcγRIIIb on neutrophils resulted in a significantly decreased production of ROS by RA cells compared with controls matched for age and sex. However, expression and homologous ligation of receptors did not differ between these groups. These data suggest that neutrophil priming does occur before emigration into the joint and that blood neutrophils from patients with RA have a functional impairment in cooperative FcγR-mediated ROS generation. This may account for the increased susceptibility to bacterial infection that arises in patients with severe disease.

Harnessing the Therapeutic Potential of Th17 Cells.

Th17 cells provide protective immunity to infections by fungi and extracellular bacteria as well as cancer but are also involved in chronic inflammation. The cells were first identified by their ability to produce interleukin 17A (IL-17A) and, subsequently, associated with chronic inflammation and autoimmunity. Th17 cells have some gene profile similarity with stem cells and can remain dormant in mucosal tissues for long periods. Indeed, recent studies suggest that functionally distinct subsets of pro- and anti-inflammatory Th17 cells can interchange phenotype and functions. For development, Th17 cells require activation of the transcription factors STAT3 and RORγt while RUNX1, c-Maf, and Aiolos are involved in changes of phenotype/functions. Attempts to harness Th17 cells against pathogens and cancer using vaccination strategies are being explored. The cells gain protective abilities when induced to produce interferon γ (IFNγ). In addition, treatment with antibodies to IL-17 is effective in treating patients with psoriasis, psoriatic arthritis, and refectory rheumatoid arthritis. Moreover, since RORγt is a nuclear receptor, it is likely to be a potential future drug target for modulating Th17 functions. This review explores pathways through which Th17 subsets are induced, the molecular basis of their plasticity, and potential therapeutic strategies for their modulation in diseases.

Heterogeneous yet stable Vδ2(+) T-cell profiles define distinct cytotoxic effector potentials in healthy human individuals

Significance A type of human white blood cell, known as the Vδ2(+) T cell, has shown promise in immunotherapies against a range of tumors. However, in recent clinical trials patient responses and clinical outcomes have been variable and unpredictable. To address this, we here reveal a significant variability in Vδ2(+) T-cell functional potential between individuals in the general population, which develops shortly after birth, is stable over time, and is manifested by differential mechanistic capacities to kill tumor targets. These results support personalized clinical approaches to identify patients with “Vδ2 profiles” that are compatible with killing of their particular tumor and suggest that tailored Vδ2-profile–specific activation protocols may maximize the chances of future treatment success. Human γδ T cells display potent responses to pathogens and malignancies. Of particular interest are those expressing a γδ T-cell receptor (TCR) incorporating TCRδ-chain variable-region-2 [Vδ2(+)], which are activated by pathogen-derived phosphoantigens (pAgs), or host-derived pAgs that accumulate in transformed cells or in cells exposed to aminobisphosphonates. Once activated, Vδ2(+) T cells exhibit multiple effector functions that have made them attractive candidates for immunotherapy. Despite this, clinical trials have reported mixed patient responses, highlighting a need for better understanding of Vδ2(+) T-cell biology. Here, we reveal previously unappreciated functional heterogeneity between the Vδ2(+) T-cell compartments of 63 healthy individuals. In this cohort, we identify distinct “Vδ2 profiles” that are stable over time; that do not correlate with age, gender, or history of phosphoantigen activation; and that develop after leaving the thymus. Multiple analyses suggest these Vδ2 profiles consist of variable proportions of two dominant but contrasting Vδ2(+) T-cell subsets that have divergent transcriptional programs and that display mechanistically distinct cytotoxic potentials. Importantly, an individual’s Vδ2 profile predicts defined effector capacities, demonstrated by contrasting mechanisms and efficiencies of killing of a range of tumor cell lines. In short, these data support patient stratification to identify individuals with Vδ2 profiles that have effector mechanisms compatible with tumor killing and suggest that tailored Vδ2-profile–specific activation protocols may maximize the chances of future treatment success.

PET/CT imaging in inflammatory myopathies

Inflammatory muscle diseases are a group of muscle disorders characterized by muscle weakness, fatigue, and an association with malignancy and paraneoplastic syndrome. A diagnosis of idiopathic inflammatory myopathy is suggested by abnormal myometry and rising creatine kinase, but tissue diagnosis is also needed. Magnetic resonance imaging (MRI) helps localize the appropriate site of biopsy, demonstrate the extent of muscle involvement, and monitor the response to therapy. However, the sensitivity of magnetic resonance (MR) is limited, and whole‐body imaging is still far from routine. [18F]Fluoro‐desoxy‐glucose (FDG) positron emission tomography (PET)/computed tomography (CT) is currently the ultimate metabolic imaging technique for the management of cancer. It has also been shown to detect inflammatory conditions and to monitor their response to treatment. The use of FDG PET in screening for underlying malignancies is widely reported and recommended in patients with paraneoplastic syndrome. Unfortunately, only a few reports have been published to show the value of FDG PET in inflammatory muscle diseases, which as we show herein, deserve further pursuit.

TNFα in the regulation of Treg and Th17 cells in rheumatoid arthritis and other autoimmune inflammatory diseases.

HighlightsTNF&agr; mediates cell responses and inflammation by binding to TNF receptors 1 and 2.In T cells, TNF&agr; can promote cell death or proliferation depending on context.TNF&agr; enhances T cell responses but sustained exposure renders them hypo‐responsive.TNF&agr; signalling molecule polymorphisms are autoimmune disease susceptibility factors.Tregs and Th17 cells are modulated by TNF&agr; and its blockade alters their numbers. ABSTRACT TNF&agr; is a principal pro‐inflammatory cytokine vital for immunity to infections. However, its excessive production is involved in chronic inflammation and disease pathology in autoimmune diseases. Evidence for its pathogenic role is validated by the fact that its neutralisation by therapeutic agents in vivo is beneficial in ameliorating disease and controlling symptoms. Paradoxically, however, treatment with TNF&agr; inhibitors can either have no clinical effects, or even exacerbate disease in some patients. The explanation for such contradictory outcomes may lay in how and which downstream signalling pathways are activated and drive disease. TNF&agr; causes its effects by binding to either or both of two membrane‐bound receptors, TNFR1 and TNFR2. Engagement of the receptors can induce cell death or cell proliferation. T cells both produce and respond to TNF&agr; and depending on whether the cytokine is membrane‐bound or soluble and the level of expression of its two receptors, the biological outcome can be distinct. In addition, polymorphisms in genes encoding TNF&agr; and T cell signalling proteins can significantly impact the outcome of TNF&agr; receptor engagement. Early studies revealed that effector T cells in patients with rheumatoid arthritis (RA) are hyporesponsive due to chronic exposure to TNF&agr;. However, recent evidence indicates that the relationship between TNF&agr; and T cell responses is complex and, at times, can be paradoxical. In addition, there is controversy as to the specific effects of TNF&agr; on different T cell subsets. This review will summarise knowledge on how TNF&agr; modulates T cell responses and the effect of engaging either of its two receptors. Furthermore, we discuss how such interactions can dictate the outcome of treatment with TNF&agr; inhibitors.

Musculoskeletal manifestations of diabetes mellitus

The prevalence of Type 1 and Type 2 diabetes are increasing significantly worldwide. Whilst vascular complications of diabetes are well recognized, and account for principle mortality and morbidity from the condition, musculoskeletal manifestations of diabetes are common and whilst not life threatening, are an important cause of morbidity, pain and disability. Joints affected by diabetes include peripheral joints and the axial skeleton. Charcot neuroarthropathy is an important cause of deformity and amputation associated with peripheral neuropathy. A number of fibrosing conditions of the hands and shoulder are recognized, including carpal tunnel syndrome, adhesive capsulitis, tenosynovitis and limited joint mobility. People with diabetes are more prone to gout and osteoporosis. Management of these conditions requires early recognition and close liaison between diabetes and rheumatology specialists.

The effect of ethnicity and genetic ancestry on the epidemiology, clinical features and outcome of systemic lupus erythematosus.

In this in-depth review, we examine the worldwide epidemiology of SLE and summarize current knowledge on the influence of race/ethnicity on clinical manifestations, disease activity, damage accumulation and outcome in SLE. Susceptibility to SLE has a strong genetic component, and trans-ancestral genetic studies have revealed a substantial commonality of shared genetic risk variants across different genetic ancestries that predispose to the development of SLE. The highest increased risk of developing SLE is observed in black individuals (incidence 5- to 9-fold increased, prevalence 2- to 3-fold increased), with an increased risk also observed in South Asians, East Asians and other non-white groups, compared with white individuals. Black, East Asian, South Asian and Hispanic individuals with SLE tend to develop more severe disease with a greater number of manifestations and accumulate damage from lupus more rapidly. Increased genetic risk burden in these populations, associated with increased autoantibody reactivity in non-white individuals with SLE, may explain the more severe lupus phenotype. Even after taking into account socio-economic factors, race/ethnicity remains a key determinant of poor outcome, such as end-stage renal failure and mortality, in SLE. Community measures to expedite diagnosis through increased awareness in at-risk racial/ethnic populations and ethnically personalized treatment algorithms may help in future to improve long-term outcomes in SLE.

Clinical Review: Familial Mediterranean Fever-An Overview of Pathogenesis, Symptoms, Ocular Manifestations, and Treatment.

Abstract Familial Mediterranean fever is an autoinflammatory multisystem disease, which most commonly affects patients from the Mediterranean basin. This review discusses the common polymorphisms in the MEFV gene as well as the role of pyrin in disease pathogenesis. Patients with familial Mediterranean fever typically develop peritonitis, pleuritis, arthritis, and fever. In addition, a number of authors have reported ophthalmic features. These case reports and series are further explored in this review. Colchicine has transformed the prognosis for patients with familial Mediterranean fever. The rationale for the use of colchicine, as well as the evidence for newer biologic agents is also covered.