Research

Patrons:

• Professor Bhaskar Dasgupta of Southend Hospital
• Dr V Saravanan of Queen Elizabeth Hospital, Gateshead
• Mr D Anderson MP. Blaydon

The information on this research page has been updated again by Professor B Dasgupta in November 2011. Updates are shown in red text

The information on this research page was updated by Professor B Dasgupta in December 2010. Updates are shown in blue text

To those visiting or reading this Research, we are looking for some support funding towards Bio statistician time as well as Research Nurse Support. Donations will be most welcome. We formed this organisation to try and fund research into cause and cure and also to run support and self help groups. We cannot do it without your help. Currently this organisation has no funds and is run purely by volunteers.

RESEARCH ON POLYMYALGIA RHEUMATICA AND GIANT CELL ARTERITIS: ONGOING AND PROPOSED.

There are several important studies in the field of PMR and GCA Research. These studies will be added to and updated and are as follows below:

INTERNATIONAL ACR (AMERICAN COLLEGE OF RHEUMATOLOGY) -EULAR (EUROPEAN LEAGUE AGAINST RHEUMATISM) SPONSORED CLASSIFICATION STUDY FOR THE POLYMYALGIC SYNDROME – POLYMYALGIA CAN BE THE HERALD OF MANY MIMICKING CONDITIONS AND THIS STUDY WILL DETERMINE WHAT ARE THE KEY FEATURES THAT DISTINGUISH PMR FROM OTHER DISEASES.

This is an International study sponsored by ACR and EULAR -

December 2010

Study has now closed and a report on the study has been submitted to the EULAR and ACR committees. The initial comments on the PMR EULAR/ ACR Classification Criteria Report 11/2010 from ACR Subcommittee on Classification and Response Criteria are very positive and approving:

'"Thanks very much for providing us with this detailed report of your ongoing study and its progress. This is a tour de force with a well thought out, careful approach to defining classification criteria, and a well done large scale prospective study of persons with PMR and selected non PMRs likely to be confused with PMR cases. We are very impressed by the incredible amount of work that has gone into this--really a monumental effort! A few of us have read through your report and put some thoughts together for you which I hope will be helpful in drafting the manuscript…. Your manuscript will go first to ARD."

This paper is now being written and should be completed in the next two months.

November 2011

The manuscript describing the classification criteria for PMR has now been accepted by the annals of rheumatic diseases and is due for joint online publication with arthritis and rheumatism in the very near future. The manuscript which details the validated outcome measures from the prospective study in PMR has also been accepted by the journal of Rheumatology and is due for publication soon.

Development of Classification Criteria for the Polymyalgic syndrome

There is a need for a rational approach to management of PMR. We do not have standardized diagnostic criteria and reliable, valid and sensitive outcome measures. We therefore cannot accurately distinguish PMR from other conditions presenting with the polymyalgic syndrome, and have difficulty with evaluation and comparison of the efficacy of different therapeutic approaches, including novel drug therapies.

In order to tackle these challenges, an international PMR Consortium has convened and initiated a multinational effort. The long-term goal of the Consortium is to standardize classification criteria and outcome measures in patients with PMR and facilitate the conduct of well-designed clinical studies that incorporate these standardized and clinically relevant outcomes.

Specific Aim 1: To develop a reliable and valid composite disease activity score and remission criteria in PMR.

We presented a poster on this too at ACR and the have asked us to write a separate manuscript on this which is currently being written.

Aim 1a. We will evaluate measures such as patient-reported symptoms (pain, stiffness, function, global assessment, fatigue, Quality of Life), physician-reported (global assessment, tenderness, pain on motion and limitation, therapy), laboratory (ESR, CRP) and ultrasound -based measures to assess disease activity.

Aim 1b. We can then derive a preliminary composite disease activity score and remission criteria incorporating these core domains

Aim 1c. We will assess the discriminating ability of core domains and composite score in differentiating PMR from conditions mimicking PMR

Specific Aim 2: We will develop a preliminary definition of improvement for the evaluation of response to therapy in PMR

Aim 2a. To evaluate the within group sensitivity to change (responsiveness) and discriminate validity of core disease activity domains as measured by patient-based, physician-based, laboratory and ultrasound-based measures

Aim 2b. To derive a preliminary composite definition of improvement based on disease activity (Aim 1b) and change in core disease activity domains

Specific Aim 3: We will create an infrastructure for storage of blood samples in order to facilitate future research on novel disease-specific biomarkers and their therapeutic potential

This is the first comprehensive effort to develop classification and outcome criteria in PMR. The findings of this project will be used to develop preliminary evidence-based, consensus guidelines for evaluating outcomes in PMR and form the basis for international guidelines.
We have already proposed criteria for diagnosis that we are testing in a prospective study. Research results should be published by the end of 2010.

The main classification criteria will be a simple scoring algorithm. The following is extracted from a presentation I gave to ACR Atlanta which was mentioned as one of the highlights of ACR 2010 by the President of the ACR.

CLASSIFICATION CRITERIA FOR THE POLYMYALGIC SYNDROME

Eligibility: The target population for testing the new PMR criteria will be patients greater than 50 years of age presenting with the polymyalgic syndrome i.e. with new onset (less than 12 weeks) bilateral shoulder pain and abnormal acute phase response. The criteria may only be applied to those patients where the symptoms are not better explained by an alternate diagnosis. Mimicking conditions that should be considered and excluded include the inflammatory and non-inflammatory conditions studied as comparators in this report. The recommended approach and necessary investigations are the subject of recent guidelines on PMR ( BSR guidelines on PMR).

The classification criteria: The following criteria items can be applied to eligible patients to identify patients with PMR suitable for low dose corticosteroid therapy. These consist of four clinical and laboratory criteria along with optional ultrasound criteria.

The scoring is 0-6 (without ultrasound) and 0-8 (with ultrasound). In the absence of identified, competing diagnoses, a score of 4 or greater (with or without ultrasound) is indicative of PMR. A score of less than 4 (based on clinical plus laboratory criteria) cannot be considered to have PMR. We recommend that such patients be referred to specialist care for additional assessments and investigations such as ultrasound, rather than empirically treated with corticosteroids. We have added ultrasound as an optional item to the main criteria since it is not yet widely available to rheumatology departments (and less so in primary care) across the world. Ultrasound does significantly improve specificity of PMR diagnosis, and shows particularly good performance in differentiating PMR from non-inflammatory conditions and hence is a recommended investigation for PMR.

*Optional ultrasound criteria

PROSPECTIVE STUDY OF CLINICAL OUTCOMES AND QUALITY OF LIFE (QOL) IN PMR

This ongoing study has reported major impacts on QOL and many relapses in PMR. It shows the importance of correctly assessing and treating this condition. This paper and others has led to the BSR Guidelines on PMR (Issued June 2009 and posted on this website).

December 2010

Study completed - second paper being written.

November 2011

Prospective study of clinical outcomes & Quality of Life in PMR. The second paper with the long term outcomes is still being analysed and written.

IMMUNOGENETICS OF GCA – TRYING TO DETERMINE THE GENETIC INFLUENCES ON THIS CONDITION.

This project relates to identifying genes that cause GCA. Sarah Mackie based in Leeds is carrying out this project and is collecting samples to study genes.

December 2010

Ongoing. The target is to recruit 1000 patients - half way there.

November 2011

Ongoing. The target is to recruit a thousand patients. Considerable progress has been made

PROSPECTIVE STUDY OF THE COMPARATIVE STUDY OF ACCURACY OF TEMPORAL ARTERY ULTRASOUND VERSUS BIOPSY IN THE DIAGNOSIS OF GCA.

A study of the accuracy of temporal artery ultrasound versus temporal artery biopsy in the diagnosis of giant cell arteritis (GCA).

This study has been funded by the HTA (Health Technology Assessment) - due to start March 2010

Temporal artery biopsy is the standard diagnostic technique in GCA since it shows the type and degree of inflammation in the temporal arteries. Recently, temporal artery ultrasound has been shown to be of benefit in assessing this condition. Scientific papers have shown that the ‘Halo’ sign of inflammation in the temporal artery on ultrasound may be a good diagnostic test for GCA. Ultrasound has the benefit of being non-invasive and less painful for the patient. However it does depend on expensive equipment and skilled and trained ultra-sonographers.

We will study approximately 400 new patients with newly diagnosed giant cell arteritis across the UK in around 20 participating centres.

All patients will be evaluated with temporal artery ultrasound followed by biopsy. Patients will be followed for 6 months. At the end of 6 months the outcome for every patient will be evaluated to decide which of the two procedures performed better in the diagnosis of giant cell arteritis.

December 2010

Study ongoing - the two main centres recruiting patients to the study are Oxford and Southend

November 2011

this study has been on going for nearly 18 months. The recruitment has been based primarily at two centres, ie, in Southend as well as in Oxford. Over 100 patients have been recruited to the study. Other centres are in training in terms of ultrasonography and are gradually coming on board with the study.

PROSPECTIVE STUDY OF LEVELS OF ANNEXIN V (A SUBSTANCE THAT MEDIATES THE ANTI-INFLAMMATORY EFFECTS OF STEROIDS) IN PMR AND GCA. THIS PROPOSAL HAS BEEN SUBMITTED FOR FUNDING.

Study of Annexin as a disease activity marker in PMR and GCA
This study is funded by the British Heart Foundation - started November 2009

There is a lack of good blood tests that can be used to monitor how well a person is doing on treatment for PMR and GCA. Recent work by Professor Mauro Perretti at St Barts Hospital has shown that a molecule called Annexin is triggered by steroids and mediates the anti-inflammatory effects. We will study the levels of annexin in newly diagnosed cases of PMR and GCA to see whether these mirror disease activity as assessed by the doctor and patient. Studying the regulation of annexin in these conditions will also give us an understanding of what causes the inflammatory response in PMR and GCA.

December 2010

Nearly finished recruitment - investigator meeting to discuss results scheduled in February 2011.

November 2011

The study has finished recruitment and the results suggest that Annexin V could perform as a good dye marker to assess disease activity in both PMR & GCA.

PROSPECTIVE STUDY OF EFFICACY OF LEFLUNOMIDE USE AS AN ADJUNCTIVE AGENT IN THE TREATMENT OF PMR AND GCA. THIS STUDY WILL GO FOR FUNDING APPLICATION LATER THIS YEAR.

Study of Leflunomide as an alternative drug to methotrexate for treating uncontrolled PMR or GCA

Proposals are currently being prepared for the ARC clinical trials group

Both PMR and GCA often do not respond to steroids alone. They need additional immunosuppressive agents such as methotrexate. Methotrexate does not always work in PMR and GCA and in this setting alternative drugs are needed. We have found leflunomide useful in individual cases. A randomized controlled trial is needed to study its efficacy and safety in PMR and GCA and this proposal will be submitted to the ARC shortly.

December 2010

The intial application has been submitted to study 300 new patients with GCA and GCA patients with flares not being controlled with steroids. In addition at testing the effect and safety of leflunomide we are also testing two different doses of steroid treatment.

We will know more by end December 2010.

November 2011

The study was submitted to the ARUK for funding. The ARUK has asked for further clarification and the proposal is being revised and re-submitted. The deadline in June 2012.

PROSPECTIVE STUDY OF TOCILIZUMAN (WHICH INHIBITS AN INFLAMMATORY MEDIATOR INTERLUKIN 6) IN PMR.

This proposal has been submitted for funding.

December 2010

Still on hold - not heard further from Roche - makers of tocilizumab
However anecdotal case reports show very good efficacy in cases of resistant PMR or GCA who have aortic and large vessel inflammation on PET scan.

November 2011

A study of Tocilizumab in PMR is due to start at the Hospital of Special Surgery in New York, USA. A study of Tocilizumab in GCA is in planning and is due to start in late 2012. An international advisory board to plan this trial has been convened and met for the first time in October 2011 with Prof Dasgupta as one of the key participants. This exciting trial could be a potential gain change in the treatment of GCA as well as PMR. The Advisory Board had several presentations including case studies from Southend showing the excellent response to Tocilizumab in GCA and large vessel vasculitis.

STUDY OF NEW FORMULATIONS OF STEROID TREATMENT IN PMR

December 2010

A new exciting study of delayed release prednisolone in PMR is in the design phase and an investigators meeting in being held in December 2010 – more news shortly.

November 2011

A trial of delayed release Prednisolone in PMR is in the late design phase and should be ready to start in mid-2012.

STUDY OF NEW FORMULATIONS OF STEROID TREATMENT IN GCA

Initial Discussion Meeting November 2009.

Steroids are very effective for the treatment of PMR and GCA. Unfortunately they have many side effects such as weight gain, osteoporosis, fractures, diabetes, eye complications such as cataract, glaucoma and raised blood pressure.

Several new compounds are being developed which allow the same effectiveness of steroids but are associated with less potential toxicity for the patient. We are developing trails of such drugs – initially in PMR but if found to be useful and free of side effects, they will also be tested in GCA.

December 2010

A new exciting study of delayed release prednisolone in GCA is in the design phase and a draft proposal has been submitted – more news shortly

November 2011

The pilot study of delayed release Prednisolone in GCA has been developed and will be funded by NAPP Pharmaceuticals. This has been submitted to the Research Ethics Committee for further regulatory approvals and hopefully should start in early 2012. This will study thirty patients with new onset GCA, half of whom will be treated with standard of care immediate release Prednisolone and the other half will be treated with delayed release Prednisolone. The study duration will be six months.

PMR-GCA UK FUNDED RESEARCH

You will be very pleased to note that with funding from PMR GCA UK (£10,000) and other Research grants we have appointed Dr Nada Hassan as Research Fellow with special interest in PMR and GCA from September 2009.

Dr Hassan finished her one year term on August 2010 and has completed the cardiovascular risk study and the studies below.

Dr Nada Hassan with help from Professor Bhaskhar Dasgupta, Kings College London, Stroke Physician Dr Paul Guyler are currently working on:

Other proposals in development

We are putting together proposals for two further studies:

1. To study cardiovascular risk factors including any aortic and large vessel complications in PMR and GCA: Many inflammatory diseases such as rheumatoid arthritis and lupus are associated with higher levels of cardiovascular disease such as strokes, heart attacks and blood clots. There are no studies to see whether PMR and GCA are also conditions associated with such higher health risks. There is also evidence that there is a higher incidence of aortic aneurysms and large vessel disease in these conditions. We are developing a study protocol to assess cardiovascular risk in PMR and GCA

2. Can early intensive treatment prevent vision loss and other similar strokes in GCA? GCA is still associated with a high incidence of vision loss (in up to a third). This may be prevented by urgent diagnosis and treatment – such as the use of infusion of intravenous steroids and perhaps clot-busting drugs within 3-4 hours of start of symptoms. Stroke units across the country are now able to prevent death and disability from strokes by using such an approach. We feel such an intensive approach merits a trial in GCA. If successful – national regulatory bodies will then be approach to advocate a mandatory urgent approach to diagnosis and treatment of these diseases.

These studies have now completed!

To give evidence to this intensive approach we are proposing the following:

A multi-centre prospective study of recognition and management times, and referral pathways for newly presenting giant cell arteritis By the GCA Study Group

November 2011

PMR/GCA UK funded – fast track pathway for GCA. This fast track pathway has been agreed between different departments in the acute Trust, ie, Rheumatology, Stroke Unit and the A&E, as well as PCT and various GP leads. The fast track pathway has been approved by the Joint Service Development Board and should be due to start early 2012.

An Account of an International Meeting of Rheumatologists in Bristol November 2009 to Discuss the Setting-Up of Clinical Trials to Test New Versions of Glucocorticoids by Mary Osborne Hart, a Member of the Patient Group

(Glucocorticoids are steroids produced naturally in the body by the adrenal glands. One of their roles is to inhibit the inflammation process. They are also artificially made and prescribed under various names, including Prednisone and Prednisolone, for various conditions including rheumatic diseases.)

The aim of the day was to agree on a formula for setting up clinical trials to study new variations of Prednisone/Prednisolone type drugs which would have fewer, less severe adverse effects than the current drugs.

As any patient with PMR will know, the benefits of glucocorticoids are considerable but there are inevitably side-effects associated with their use. The higher the dose and the longer the course of treatment, the more severe the adverse effects.

There is currently no hard evidence of high quality to help in deciding dosage, and no consensus of opinion between rheumatologists as to the best method to use. At the moment patients are treated with either a high initial dose followed by a rapid reduction in dosage (which generally leads to more relapses but a lower cumulative dose) or a moderate initial dose followed by a slow reduction in dosage (which generally leads to fewer relapses but a higher cumulative dose).

A relapse was considered to be a return of symptoms severe enough to require an increase of medication. Up to 5mgs of Prednisone/Prednisolone was considered to be a low dose and one at which the benefits of the drug definitely outweighed the risks. A moderate dose was considered to be between 7.5mgs and 30mgs and one at which the benefits and risks were approximately equal. Anything above 30mgs was considered a high dose, and at this level the adverse effects might begin to outweigh the benefits.

The aim of current pharmacological research is to produce a new product that will work as effectively as those used at present, while having a lower glucocorticoid(GC) content. This could be achieved by, for example, using selective GC antagonists that will “trick” the body into thinking it has received more steroids than in fact it has, or combining the GCs with another drug that will amplify their effect, or encapsulating the GCs in liposomes to reduce systemic exposure.

As Polymyalgia Rheumatica is a disease that responds well to high/moderate doses of GCs followed by a lengthy period of gradual dose reduction, it was felt that these patients were an ideal group on which to base the necessary clinical trials for these new drugs.

The various issues around the setting-up of a clinical trial were highlighted by a Clinical Research expert and a Chief Medical Officer from a pharmaceutical company, and eventually a consensus of opinion was reached on the likely way forward.

It was also felt desirable to research and compare the two treatment methods (i.e. high dosage, rapid reduction and moderate dosage, slow reduction) so consequently the research would preferably be done in two groups to discover whether one method was better than the other.

Other Information I Found to be of Interest:

1. Only a very small proportion of people with PMR also have/develop GCA, although around half of GCA patients also have PMR.
2. It was the general opinion that PMR should be treated in secondary care because it is a very complicated disease that is more difficult to diagnose than rheumatoid arthritis. In some areas of the country there are rapid access clinics for suspected PMR patients, the aim being to diagnose and begin treatment within 3 weeks.
3. Inflammation levels in the body fluctuate during a 24 hour period, the highest point occurring in the middle of the night. Ideally medication should be taken around 2am but this is totally impractical.

I found this a very interesting and informative day. I was particularly impressed by the openness of the discussions and the willingness of those present to listen to and to take on board the questions/contributions made by the patient group. Oh – and the food was very good too!

Written by Mary Osborn Hart - patient

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