AS of Baths, SpAs and movies @B27

AS of Baths, Spas and movies @ B27

There is just something special about rheumatology.  It has acronyms and associations due to the multisystem nature of the conditions we see.

The spondyloarthropathies (SpAs) are a group of conditions with multiple associations of which Ankylosing Spondylitis (AS) is the hallmark condition. Patients with AS benefit from physio and hydrotherapy. The latter may sometimes take place in a local health spa. We use the Bath AS Scores to assess disease activity. AS has strong genetic association with the gene HLA-B27.

AS of Baths and SpAs – what do we know about B27?

The genetic association between Human Leukocyte Antigen (HLA)-B27 and Ankylosing Spondylitis was first discovered in the Westminster Hospital by Brewerton and Sturrock in 1973 with their publication in the Lancet. It remains one of the strongest associations between gene and disease.

What is known about HLA-B27

·        Present in 95% of patients with AS ·        Present in 8% of normal population ·        1 in 15 people who are HLA-B27 positive go on to develop AS ·        The child who is HLA-B27 positive with a parent with AS has a 15% chance of developing the condition ·        HLA-B27 accounts for up to 50% of overall genetic susceptibility to AS ·        Different subtypes of HLA-B27 have different strengths of association with AS

(HLA)-B27 or B27 is a protein that is expressed on the cells and has function in both health and disease. It can be a double-edged sword. It presents fragments of bacteria or viruses called peptide and present this to active immune cells (T cells) to overcome infection. Aberrations in the structure or processing of B27 are proposed as the mechanism for the development of AS.

Mechanism of action of HLA-B27 in AS

·   Arthritogenic peptide hypothesis – small proteins (peptides) from our own body presented by HLA-B27 become the target of immune cells (CD8+ T cells) because they look like peptides from bacteria or viruses. This results in joint inflammation. ·       HLA-B27 homodimers hypothesis – cell surface HLA-B27 can form homodimers (a pair of two chains of B27 joined together by a bond).  B27 homodimers bind to specific receptors expressed on Natural Killer and T lymphocytes which could play a role in the development of AS. ·  HLA-B27 misfolding hypothesis - accumulation of misfolded HLA-B27 in the endoplasmic reticulum (ER) during protein processing, produces an inflammatory response. ER stress resulting from the accumulation of misfolded HLA-B27 then activates the unfolded protein response (UPR) or the ER-overload response (EOR) that can result in joint inflammation. ·    Enhanced intracellular microbial survival hypothesis - the inability of HLA-B27-positive individuals to eliminate certain bacteria or viruses. Ineffective loading of these pathogens by HLA-B27 leads to reduced clearance and prolonged abnormal immune system activation.

Novel roles – B27 at the movies

These mechanisms have provided the basis for several explanations as to how HLA-B27 might predispose individuals to AS. I am particularly interested in the HLA-B27 homodimer hypothesis having worked on this in my doctoral thesis. The ability of HLA-B27 to form homodimers which are a pair of two chains of B27 joined together by a bond is interesting. Bond and Dimers, proponents of this hypothesis would say 'Dimers are Forever'. But like the secret agent 007, could B27 dimers unlock some secrets to why AS develops?

B27 dimers can interact with Natural Killer (NK) receptors called KIRs which are expressed both on NK and T cells. B27 dimers bind to a specific KIR called KIR3DL2. As of Bond and Dimers, this KIR is the KIR Royale. The new kid on the block in the proinflammatory response is the T helper 17 cells (Th17) which produce IL-17. IL-17 can further induce the secretion of cytokines such as TNF-α which are involved in the pathogenesis of AS. Th17 cells which express KIR3DL2 have been shown to produce increased amounts of IL-17 in response to another cytokine IL-23¹.  B27 dimers also cause an expansion of inflammatory T cells in AS².

Two recent papers also add to our understanding of the HLA-B27 story. Cauli et al² showed that the HLA-B27 subtype 05 forms more B27 dimers than the non-disease related of HLA-B27 subtype 09. B27 dimers promote the survival of KIR3DL2 expressing cells which may result in inflammation seen in AS. Another interesting model is the on the role of mechanical stress in AS. Jacques et al⁴ showed that by reducing mechanical stress and loading on the Achilles tendon in mice, there is reduced inflammation, scarring and new bone formation. HLA-B27 and IL-23 may alter the inflammatory response of joints or tendons to mechanical stress. One can postulate on galactic battles between inflammatory cells taking place at sites of mechanical stress. McGonagle D summarises this in the editorial ‘SpA :May the Force be with you’ ⁵.

Great strides have been made to understand this mechanism of action. The links HLA-B27, inflammatory cells (IL-17/IL-23) and response to mechanical stress could all be targets for future research and treatment.

References:

1. Bowness P et al. J Immunol. 2011 February 15; 186(4): 2672–2680.

2. Wong-Baeza I et al. J Immunol. 2013 Apr 1;190(7):3216-24.

3. Cauli A et al. Rheumatology (Oxford). 2013 Nov;52(11):1952-62

4. Jacques  P et al. Ann Rheum Dis. 2013 Aug 6. 

5. McGonagle et al Ann Rheum Dis. 2013 Nov 12.

@synovialjoints

Views are my own. These are opinions and cannot replace the need to see your physician for review of your individual medical condition.

Rheumatology comes to Town

Rheumatology community descends on Reading

What happens when you get 70 people from the Rheumatology community coming together? A fiesta! Yes, a fiesta or celebration of knowledge, exchange of information, collaboration and networking. A joining of great minds and people to forward our joint cause in rheumatology.

Reading is the host of the famous annual summer rock festival but this was a different party. Yesterday 8/11, I hosted the Winter Oxford Regional Rheumatology Conference in Reading.

Discussion time at the Oxford Regional Conference

There were 7 abstracts presented by trainees with the best presentation winning the inaugural Royal Berkshire Rheumatology Prize. The lion signifies the Royal County of  Berkshire, UK. There is a statue of the Maiwand Lion in Forbury Park to commemorate the valour and devotion to men from the 66th (Berkshire) Regiment of Foot during the campaign in Afghanistan between 1878 and 1880. The home team won the prize, public voting of course!

The Royal Berkshire Rheumatology Prize

Professor John Isaacs, University of Newcastle, UK was the keynote speaker and he gave us a superb overview on Biosimilars - friend or foe? Will Dixon from the Arthritis Research UK Manchester, gave us a review of the risk of infections with biologics and steroids, data from the BSR Biologics Register.

Keynote address by Prof. John Isaacs

In the afternoon, we shifted to the BSR Simple Tasks campaign. I have been very enthusiastic about this initiative to improve patient outcome. This will bring together a joint collaboration between the BSR, ACR and patient groups NRAS, NASS and Arthritis Care. Having seen the Simple Task initiative at the ACR 13 in San Diego, it was nice to have this now on home turf. What 3 things can we do for this campaign? Follow the conversation on Twitter #SimpleTasksUK

BSR Simple Tasks presentation by Dr. Peter Prouse 

The final presentation was from my senior colleague, Dr. Tony Bradlow a gave an account of Rheumatology then and now. In 25 years we have seen a real revolution in rheumatology. We are now in the 'new' rheumatology with better diagnostics and treatment.

So as I reflect on this day, I think of this quote:

Every generation needs a new revolution - Thomas Jefferson

Intensive DMARDs and biologics (and in the future probably biosimilars) has revolutionised treatment of arthritis. As a rheumatology community we have an obligation to renew, reinvent and redefine our specialty to improve patient outcomes. Two campaigns come to mind #SimpleTaskUK and #AS_it_is (see my previous blog), where we can all do our part to make this happen.

@synovialjoints

Views are my own. These are opinions and cannot replace the need to see your physician for review of your individual medical condition.

AS it is +2 days post Guy Fawkes night

AS it is 7/11 at the Palace of Westminster - NASS Campaign

Thesaurus: Adv.1.as it is - in the actual state of affairs and often contrary to expectations

The average time it takes to diagnose Ankylosing Spondylitis (AS) is 8.5 years. Yes, you heard it right. This is the actual state of affairs and certainly contrary to what we would expect.

We can do better. We need to make it happen. We can make it happen.

I was in Parliament today 7/11 at the launch of the National Ankylosing Spondylitis Society's (NASS) 'AS it is' campaign. The reception was hosted by Huw Irranca-Davies MP and Andrew George MP.

'AS it is' aims to set a higher standard of care for people with AS. This follows the whole journey from diagnosis to treatment to follow up. This calls for better access to treatment, physiotherapy and employment support. Debbie Cook, NASS Director, summed this up eloquently in her speech.

'AS it is' also calls for more. It calls for the introduction of a national clinical guidance and quality standard of care for AS patients. Peter Kay, National Clinical Director for MSK services spoke about the need for better detection of inflammatory back pain (IBP) and access to services for patients with AS.

As I go around 'preaching' the IBP message to GPs and allied health professionals in primary care, I hope it will make early detection a reality. Early detection improves outcomes.

So as we recall +2 days post the Gunpowder plot of 1605, today there was a real sense of explosion and bang at the launch of 'AS it is'. Let's do our part to make it happen. #AS_it_is

Houses of Parliament 7/11 NASS Campaign

With Debbie Cook, NASS Director at launch of 'AS it is'

At the NASS reception, Houses of Parliament

@synovialjoints

Views are my own. These are opinions and cannot replace the need to see your physician for review of your individual medical condition.

Welcome to the blog of Dr. Antoni Chan

Joint Venture

Welcome to my blog.  This is my journey from tweeting (follow me on Twitter @synovial joints ) to blogging. I started tweeting in September 2013 to find out who was attending the 2013 American Congress of the Rheumatology (ACR) in San Diego. Very quickly, I was able  to make  contact with rheumatologists across the world. What impressed me more was the rapid exchange and dissemination of information. The tweets were updates from meetings, seminars, conferences attended or articles read. These were sent out in real time. There is no system that can match the speed of these medical updates. This however relies on the goodwill of fellow rheumatologists and patients willing to share and discuss information, thoughts and ideas. I call this a Joint Venture.

This Joint Venture was best demonstrated at the #ACR 13 in San Diego where there was rapid fire of tweets across the many sessions at the conference. It added a new dimension to the ACR which I have been attending for a decade. I had a chance to meet the people who make this Joint Venture possible at the  ACR Tweetup evening. This has encouraged me to share my thoughts and ideas on my new blog. Hope you enjoy reading future posts from my blog!

New friends met at the ACR Tweetup 2013, San Diego.

@synovialjoints

Views are my own. These are opinions and cannot replace the need to see your physician for review of your individual medical condition.