“50 years of the Centre for Rheumatic Diseases in Glasgow” (in conjunction with the Scottish Society for Rheumatology),22 May 2015: Oral Presentations

50 years of fun with the 13th element

Graham Russell^1,2

¹The Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, UK

²The Mellanby Centre for Bone Research, University of Sheffield Medical School, UK

Abstract There have been many impressive advances in recent years in understanding the cellular and genetic basis of bone disorders. These advances have not only led to a better understanding of the pathophysiological basis of bone diseases but also to new approaches to therapy.¹ The study of rare skeletal diseases has led to identification of multiple potential drug targets, several of which have been successfully exploited for treating skeletal diseases.^2,3 Recent examples include the development of the RANK-ligand antibody, denosumab, the cathepsin K inhibitor, odanacatib and antibodies to the wnt inhibitor, sclerostin.

My personal research has centred on the theme of phosphorus, hence the title of this talk, which refers to an entertaining book by John Emsley entitled ‘The 13th element’.⁴ This book describes the history and discovery of phosphorus as an element, through to the way it features in modern life for good and evil. Phosphorus was the 13th element to be discovered even though it is actually the 15th in the periodic table.

Phosphate compounds are widespread in nature and are key to an enormous number of biochemical processes. Inorganic pyrophosphate is the body’s natural water softener, which is destroyed by the well-known ecto-enzyme, alkaline phosphatase. In my PhD studies, I showed that circulating pyrophosphate levels were increased in the rare disease, hypophosphatasia, in which alkaline phosphatase is defective.⁵ Events have come full cycle, and hypophosphatasia is now being successfully treated by enzyme replacement with alkaline phosphatase.⁶ Our early studies on pyrophosphate as an inhibitor of mineralisation led on to the study of stable analogues, in particular the bisphosphonates.

The biological effects of the bisphosphonates (BPs), then called diphosphonates, were first reported in 1969.⁷ They were originally studied as inhibitors of calcification as well as of bone resorption, and the history of their development and clinical uses has been recently reviewed.⁸

Bisphosphonates have been used in clinical medicine for more than 40 years. A search in PubMed using the term ‘bisphosphonates’ reveals over 20,000 references. Their early use for bone scintigraphy has continued to the present day, and they also remain the standard of care for the treatment of Paget’s disease, for the prevention of skeletal-related events in patients with myeloma or bone metastases, and of fractures in osteoporosis. The very long-lasting effects of some bisphosphonates are quite remarkable, and the effects of zoledronate can persist for up to five years after just a single iv dose.⁹

In recent years, we have elucidated how bisphosphonates act within cells, so that the molecular actions of BPs are now rather well understood. The antiresorptive effects on osteoclasts of the nitrogen-containing bisphosphonates (including alendronate, risedronate, ibandronate and zoledronate) appear to result principally from their inhibition of farnesyl pyrophosphate synthase, a key enzyme in the mevalonate pathway, which generates isoprenoid lipids utilised for the post-translational modification of small GTP-binding proteins that are essential for osteoclast function. The detailed knowledge about the molecular actions of bisphosphonates has helped to explain their structure–activity relationships, and this has resulted in a better appreciation of important but subtle differences among the members of the bisphosphonate class of drugs.¹⁰

The actions of bisphosphonates as inhibitors of the mevalonate pathway of cholesterol biosynthesis mean that they may act not only on bone but also on non-skeletal tissues. These properties have opened up a wide range of new potential medical uses of these compounds, which include immunomodulation, life span extension, tissue regeneration and DNA repair.

In conclusion, bisphosphonates have stood the test of time and still currently dominate the market as highly effective agents for the treatment of bone diseases characterised by increased bone resorption. These drugs have a long history and their serendipitous discovery was followed by a fascinating odyssey of ‘ups and downs’ in clinical development. One hopes that new discoveries and ongoing innovation will result in even better management of bone diseases in the future, despite the hurdles set by the huge costs of development and regulatory requirements.

Comparison of outcomes between studies of intensive treatment strategies in early rheumatoid arthritis from a single centre over 20 years

James Dale^1,2, Duncan Porter³, Sarah Saunders², Catriona Grigor⁴, Hilary Capell² and Anne Stirling⁴

¹Institute of Infection, Immunity and Inflammation, University of Glasgow, UK

²Centre for Rheumatic Diseases, Glasgow Royal Infirmary, UK

³Department of Rheumatology, Gartnavel General Hospital, UK

⁴Department of Rheumatology, Inverclyde Royal Hospital, UK

Abstract Background: Randomised trials have demonstrated that treat to target strategies in early rheumatoid arthritis, that aim for at least low disease activity, produce significantly better short-term disease activity, radiographic and functional outcomes than less intensive strategies based on physician’s judgement.

Objectives: To determine whether successive studies of intensive early rheumatoid arthritis treatment strategies from a single centre have shown similar improvements in disease activity and functional ability over the last 20 years.

Methods: Common demographic, disease activity and functional ability data were gathered from the Tight Control of RA (TICORA 1999–2001, n = 111, routine versus intensive therapy), Triple Therapy in Early Active RA (TEAR 2003–2005, n = 96, step-up versus parallel DMARD escalation) and Targeting Synovitis in Early RA (TaSER 2009–2012, n = 111, DAS28 versus musculoskeletal ultrasound-driven step-up escalation) study files. For the TEAR study, DAS28ESR scores were converted to DAS44ESR value using the formula DAS44ESR = (DAS28ESR–0.938)/1.072.

Results: Baseline demographic features and sero-positivity rates were similar between the studies. Patients in the older studies presented with significantly shorter symptom duration than the TaSER study (mean [SD] TICORA = 20[16] versus TEAR 11[11] versus TaSER 5[3] months, respectively, p < 0.0001) and had higher baseline disease activity and physical disability.

Treatment response: All intensive treatment groups exhibited a significantly greater improvement in DAS44 than the TICORA control group. After 12–18 months DAS44 scores were similar between the intensive treatment groups and significantly better than the TICORA control group (Graph 1). DAS44 remission rates were similar between the intensive treatment groups and consistently higher than the TICORA Control group at all time points.

Functional ability: The HAQ scores for both TaSER groups were significantly better than both TEAR groups after 12 months and both TICORA groups after 18 months (Graph 2). Further, all intensive treatment groups exhibited a similar improvement in HAQ over the follow-up period.

Conclusions: Intensive step-up and parallel DMARD escalation strategies produce similar short-term disease activity outcomes and improvements in functional ability that are significantly better than non-targeted therapy. RA groups that present with longer symptom durations and higher levels of disease activity and functional impairment, may exhibit greater improvements in disease activity, but may not regain functional ability to the same degree as groups who present earlier, with lower levels of disease activity.

Disclosure of Interest: J. Dale Grant/research support from: Pfizer UK, Paid instructor for: Abbvie, D. Porter: None declared, S. Saunders: None declared, C. Grigor: None declared, H. Capell: None declared, A. Stirling: None declared

The state-of-the-art in treating rheumatoid arthritis

Jim O’Dell

University of Nebraska, USA

In this session Professor O'Dell from the University of Nebraska provided a wide ranging overview of current treatment regimens useful for treating rheumatoid arthritis.

While the work of many investigators was covered during his presentation, the study from his own group, published in 2013 in The New England Journal of Medicine (369: 307–318), was particularly relevant to treatment strategies in the UK. For the past 25 years Professor O'Dell has led RAIN (Rheumatoid Arthritis Investigational Network) and this double blind, non-inferiority study was conducted in 12 RAIN, 8 Canadian medical and 16 Veterans affairs centres respectively.

A total of 353 participants with RA were included. All had experienced a sub-optimal response to methotrexate in adequate doses (between 15 and 25 mg weekly) and were randomly assigned to either triple therapy with methotrexate, sulphasalazine and hydroxychloroquine, or to methotrexate plus etanercept. At week 24 those patients who had not achieved a predefined response were switched in blinded fashion to the other therapy, and disease activity score for 28 joints (DAS28) at week 48 was used as the primary outcome measure.

Both groups had a significant improvement at 24 weeks compared with their baseline on methotrexate alone. Participants in triple therapy group adhered to treatment 78% of the time and those in the etanercept methotrexate group 79% of the time. At 24 weeks 27% in both groups required a switch to the alternative option and the response after switching did not differ significantly between the two groups. There were no significant differences between the two groups in secondary outcome measures (including pain, health related quality of life, radiographic progression, or adverse events).

This study is of considerable importance: double blind, investigator-led project including a biologic agent is challenging to undertake. Not only is it difficult to obtain a matching placebo for oral therapy as well as etanercept, it is also not easy to recruit these numbers of patients in competition with studies funded and organised by the pharmaceutical industry.

The results have far reaching implications for clinicians providing information for both patients and professionals in the clinic, as well as for health managers balancing budgets since triple therapy is inexpensive compared with biologic therapies. While 27% of patients did require a switch to a biological therapy, 73% did not - an important finding and one which is useful for planning.

Abstract Our expectations for our patients with rheumatoid arthritis have changed dramatically over the last quarter century. Many without a great deal of thought quickly give the biologicals the credit for this metamorphosis. As important as the biologicals have been, that easy but superficially explanation does not begin to do justice to the other more important changes that have occurred in the same time frame. This talk will focus on those other important changes, including but not limited to the marked increased use of methotrexate at ever increasing doses, the remarkable benefits seen with effective use of combinations of conventional DMARDs and methotrexate plus biologicals and perhaps most importantly the concept of treating to a target of low disease activity. OPEN IN VIEWER

OPEN IN VIEWER

Graph 2.

Mean HAQ.

Unravelling leukocyte activation in inflammatory arthritis

Marina Frleta

University of Glasgow, UK

Abstract Whereas molecular mechanisms mediating treatment responses to biologic DMARDS in rheumatoid arthritis are emerging, those pathways that subserve treatment resistance are poorly explored. We previously assembled a cross-sectional cohort of rheumatoid arthritis patients with distinct therapy response characteristics including rapid sustained response to conventional (c)DMARD, cDMARD failure and recurrent DMARD (conventional and biologic) resistance. We herein identified epigenetic signature of CD14+ monocytes from resistant-to-treatment patients, and, particularly miR-23∼24∼27 cluster to be dysregulated. Our in vitro investigation further elucidated IFNβ and IFNγ to be a main cause for a downregulation of pri-miR-23∼24∼27 cluster expression in monocytes, while we confirmed IL-6 R to be the primary functional target of miR-23 and miR-27 members of the cluster. Together these data identify previously unknown connection between type I and II IFN responses and proinflammatory activation of peripheral blood monocytes in RA patients.

MicroRNA in rheumatology

Mariola Kurowska-Stolarska

University of Glasgow, UK

Abstract The development of new treatments for rheumatoid arthritis is limited by our incomplete understanding of disease pathogenesis. Particularly poorly understood are those pathways mediating disease onset, failed repair and the development of treatment-refractory states. Myeloid cells (including dendritic cells, monocytes and macrophages) are crucial in these processes. We recently discovered a novel epigenetic control mechanism of myeloid cells mediated via microRNA. For example, microRNA-155 co-ordinates pro-inflammatory cytokine production by synovial macrophages through the inhibition of the negative regulator of TLR pathways SHIP-1; while microRNA-223 regulates the production of IL-1 family members through the regulation of inflammasome. Neutralisation of microRNA-155 in RA-synovial macrophages and in animal model of arthritis led to decreased activation of macrophages and amelioration of arthritis. In addition, we found that the function of dendritic cells such as activation of auto-reactive T cells in early RA and in animal models could be regulated by microRNA-34a. We believe that targeting the microRNAs or the associated pathways will provide an evidence base for new therapeutic strategies.

A new look at tendinopathy

Neal Millar

University of Glasgow, UK

Abstract Dysregulated tissue repair and inflammation characterise many common musculoskeletal pathologies, including tendon disorders. Tendinopathies represent a common precipitant for musculoskeletal consultation in primary care and comprise 30–50% of all sports injuries. This work highlights interleukin 33 as an alarmin in tendon by triggering inflammation and switching collagen production towards biomechanically inferior collagen III synthesis. Additionally we found that microRNA 29a acts as a critical regulator of tenocyte biology by integrating IL-33 effector function and collagen matrix changes. This provides a novel insight into the coordinated regulation of disparate biochemical pathways by a microRNA to thereby modulate emerging tissue pathology.

Periodontitis and rheumatoid arthritis

Shauna Culshaw

University of Glasgow Dental School, UK

Abstract Periodontitis is a chronic inflammatory disease. Microbial plaque biofilm is necessary but not sufficient for the initiation and progression of periodontitis. In the gingival tissues in patients with periodontitis, there is an inflammatory milieu – a myriad of cells and cytokines, which ultimately causes bone destruction and eventually tooth loss. There is evidence of slight but significant increase in serum auto-antibodies specific for citrullinated and native self-proteins in patients with periodontitis. There are some parallels in the pathogenesis of periodontitis and RA, and there has been substantial interest in the relationship between these diseases. Patients with RA are more likely to have periodontitis. Whether periodontitis patients are more likely to develop RA remains to be established. There is preliminary evidence that careful treatment of periodontal disease in patients with RA may slightly reduce inflammation and might improve some markers of RA. However, further studies are warranted. Nonetheless, all patients with periodontal disease will benefit from periodontal treatment. We would be happy to assess and if appropriate treat any patients with rheumatoid arthritis who wish periodontal assessment at Glasgow Dental School. Please contact for further details.

Update on Sjogren’s syndrome

Simon Bowman

British Society for Rheumatology, UK

Abstract Learning objectives: 1. To better understand simple clinical approaches to managing common oral, ocular and systemic features of primary Sjogren’s syndrome (pSS). 2. To understand the clinical use and techniques of salivary gland ultrasound, sialography and labial minor salivary gland biopsy in pSS. 3. To understand the context of recent and proposed clinical trials in pSS.

Summary: The diagnosis of pSS is a clinical one but criteria such as the American European Consensus Criteria or American College of Rheumatology Criteria that require either positive anti-Ro/La antibodies or a positive minor labial salivary gland biopsy can be helpful in clinical practice. A combined ACR-EULAR criteria is in preparation. Salivary gland ultrasound demonstrating hypoechoic areas can also be very useful. Sialography can identify strictures in patients with recurrent swelling/infection. Only biopsies that demonstrate focal lymphocytic sialadenitis are ‘positive’ and the presence of germinal centres indicates a greater risk of lymphoma in the future. Careful attention to oral and ocular hygiene is an important component of patient care and may not always receive the attention this deserves in management strategies. Hydroxychloroquine is widely used to treat fatigue and arthralgia but clinical trials make it clear that whilst potentially effective the benefit is modest. In some patients low dose corticosteroids or conventional disease-modifying drugs may have a role to play. There is a large unmet need for new therapies and clinical trial data for infliximab, rituximab, belimumab and abatacept as well as consideration of other strategies will be discussed.

Understanding arthritic pain: Novel mediators and mechanisms

Stephen B McMahon

King’s College London, UK

Abstract Pain is a common and disabling feature of many arthritic conditions. It is frequently not well controlled by existing therapies. In this lecture, I will review the scope of the problem and some recent developments aimed at improving our understanding of the underlying mechanisms and treatment. In particular, I will review our understanding of what molecular entities drive pain in damaged joint and how these resulting signals are processed – and in many cases amplified – in the central nervous system. An important question is why people with apparently similar levels or disease or inflammation can experience very different amounts of pain. I will review how genetic and epigenetic processes might contribute to relative pain vulnerability or resilience.

Improving outcome in rheumatic disease by genetic profiling: Fact or fantasy?

Stuart H Ralston^1,2

¹Centre for Genomic and Experimental Medicine, University of Edinburgh, UK

²Western General Hospital, UK

Abstract Genetic factors play a significant role in the pathogenesis of many rheumatic diseases. Technological advances in genotyping coupled with advances in study have resulted in the identification of several genetic variants with robust evidence of association with common diseases like rheumatoid arthritis, SLE, osteoarthritis, osteoporosis and Paget’s disease of bone. Huge advances have been made in understanding the molecular basis of rare diseases. Together, these studies have provided new insights into the pathophysiology of rheumatic diseases and have identified new molecular targets that can for drug design. Research is now in progress to explore the role of genetic or epigenetic profiling as a means of identifying patients at risk of developing progressive disease or of complications as well as predicting response to drug treatments. The lecture will provide a review of advances in these areas and reflect upon when and where genetic and epigenetic profiling will become part of routine clinical practice.

Update in scleroderma: What’s new?

Timothy RDJ Radstake

Utrecht Infection and Immunity, FOCIS Center of Excellence, Department of Rheumatology & Clinical Immunolog, Laboratory of Translational Immunology, University Medical Center Utrecht, The Netherlands

Abstract Inflammatory diseases encompass a wide palette of chronic and acute conditions, including asthma, rheumatoid arthritis, psoriasis, uveitis, sepsis, HIV and Crohn’s disease, which cover about 60% of health care. Inflammatory conditions often lead to fibrosis which account for ∼50% of deaths in developed world. The underlying cause of acute or chronic inflammation is a deranged immune system bringing harm rather than protection to cells, tissues and body. Despite emerging advances in clinical management (e.g. the use of biologics), we are still at the dawn of completely understanding the overwhelming complexity of all facets and factors that together lead to a derailed immune system. Therefore, current medical regimens are non-targeted resulting in high rates of complications and low clinical efficacy. As a result ∼90% of current therapies fail in ∼60% of the patients which is absolutely staggering given the amount of money invested in the development of novel drugs. We believe that all of this can be explained by the enormous complexity and plasticity of the immune system that is not fully explored by the reductionist’s research approaches applied hitherto. Hence, a more holistic approach is needed focusing on isolated immune cell subsets, levering multiple omics layers and exploiting computational analysis to integrate all data elements with the sole purpose to identify patient-specific causative molecular pathways for therapeutic targeting (personalised medicine). I will explain how we harnessed the systems medicine approach to better understand what factor led to derailed immune systems in systems sclerosis (SSc). I will demonstrate that plasmacytoid dendritic cells (pDCs) are the driving force in SSc. Furthermore, pDCs are altered on the molecular level far before the clinical onset of SSc and that these alterations are on multiple regulatory layers including the transcriptome as well as the epigenome of these cells. Lastly, I will demonstrate that integration and computational analysis of the different OMICS layers lead to the identification of molecular targets within inflammatory disease that cross so-called diagnostic pillars.