We were fortunate to have 4 members attend this meeting, Patricia Ryan, Seamus Beausang, Ann O’ Brien and myself. The meeting on Wednesday was very detailed and intense and the following is a synopsis of the content.
Evolving spectrum of Scleroderma morbidity and mortality – Dr Bernie Lynch, Galway University Hospital talk of Royal Free Scleroderma group for information and latest research showing that posterior tibial nerve stimulation may help in the symptoms of faecal incontinence.
Case Presentation – Dr Allyson Egan, consultant in Vasculitis in Manchester, looked at gastro intestinal complications and gut motility symptoms – treat with antibiotic treatment to overcome bacteria overload, which exacerbates these symptoms.
Connective Tissue disease of the lung – Dr Mike Henry, Cork University Hospital
Use of cryobiopsy to obtain lung samples is less risky to the patient and provides a better quality sample.
Imaging of large vessel Vasculitis – Prof Raashid Luqmani, Oxford University. Giant cell Arteritis is more prevalent in females.
In large vessel Vasculitis there is a 25% risk of aneurysm 10-20 years post diagnosis, which will require surgery (4 times more likely in male smokers).
DCVAS project involving 6000 patients and using imaging (Angiography, MRI, PET, Ultrasound) for classification and diagnosis.
The difference between large vessel Giant cell arteritis (LV GCA) and cranial Giant cell arteritis is that when using ultrasound the LV GCA vessel is not compressible.
TABUL study looks at use of Ultrasound versus biopsy for diagnosis. Scans are more economic and less invasive, and used as screening tool. Biopsy used in unconfirmed cases. In an ultrasound scan, ‘Halo’ is the hardened/thickened arteries, which appear dark in Vasculitis, and this differentiates it from polymyalgia.
GSK have a Siracmab trial on going which uses scanning 4-5 times throughout the trial to monitor progress.
Therapy of Large Vessel Vasculitis – Dr Eamonn Molloy, St Vincent’s University Hospital. Steroids – side effects, relapse rates high.
Methotrexate, 3 studies on going (meta analysis), underwhelming response, relapse common after 6 months, at moment low dose is used but not clear if increasing dose will be of benefit.
Inflixmab – randomised control trial, use higher starting dose than Rheumatoid arthritis, small benefit, poor response, so trial stopped.
Abatacept – Targets T cells in blood, using co- stimulation blockade.
AGATA study led by Carol Langford, 49 patients, 41 concluded study. There was a greater % of relapse. This was a 3 band randomised control trial.
Toncilizumab – Phase 2 results published in the Lancet last year, this shows an improvement compared to treatment with steroids only.
GiACTA study – largest trial to date, blinded and uses a steroid reduction regime, serial imaging is advisable to monitor.
ACR 2016 approximately 50% relapse rate when Tonsilimab is stopped. Ustekinumab has been approved for psoriasis, but could potentially block both IL6 and IL23 pathways, which would keep disease under control. This is a small, unblinded study (25 people), which combined a low dose of steroids. After 18 months 5 were able to stop steroid use and 15/17 stopped other immunosuppressants, 10 suffered adverse effects.
Takyasus Vasculitis – affects younger population, cranial symptoms.
Generally treated with steroids only – no other drugs used. Trials ongoing with Infliximab, Eteracept, Abatacept (no sign of improvement) and Toncilizumab (double blind, relapsing patients).
Behcet’s Disease in the land of Behcet – Prof Omer Karadag, Hacettepe University, Ankara, Turkey. Prevalence along historic trading Silk Road, although affects both sexes equally, men tend to develop more severe symptoms. Most have HLA – B51 gene positivity and 50% have a positive family history. Symptoms include oral and genital ulcers, DVTs, lung involvement, ophthalmology symptoms, venous/arterial involvement, joint problems, gastro intestinal involvement and rashes with pistules. Cognitive problems are similar to those associated with Lupus. In 1990 there was an international study to group diagnostic criteria. Treatment is with biological agents.
Pulmonary artery hypertension therapy, now and tomorrow – Dr Gerry Coughlan, Royal Free Hospital, London. Using Selexipag aggressively in both Scleroderma and Lupus patients proves effective. Rituximab decreases the B cells; Uberimex attacks the IL 64 pathways, while Toncilimab attacks the IL6 pathways. Looking at stem cell transplantation. Use ESC/ERS guidelines to address the multimodality of these conditions. Echo assessment is not effective but MRI scans prove useful.
Scleroderma therapy now and tomorrow – Prof Chris Denton, Royal Free Hospital. Use BSR and BHPR and NICE guidelines as the roadmap for management of Scleroderma. There are improved survival prospects with regular screening, lung fibrosis detected by high density CT scan. MMF treatment is better tolerated than cyclophosamide. There is 10% mortality when using Stem cell transplant but those who survive report a better quality of life afterwards. Gastro intestinal best practice in Scleroderma – tibial nerve stimulation improves the GI symptoms. Benzentyle is used to treat the Raynauds symptoms – targeted therapy blocks particular pathways/ extracellular matrix component of the diseases. Toncilumab is in Phase 3 of its Clinical trial and looks promising.`
Microbiome Science – Professor Fergus Shanahan, University College Cork
Microbiomes are microorganisms that naturally share our body space throughout our lives. They are natural and necessary and are influenced by our diet and lifestyle.
Pregnancy and infancy up to 3 years – microbiomes are being developed
Infancy to puberty – no shift in microbiomes unless exposed to disease or metabolic shifts in the body
Puberty – Elderly : potential disruption due to physiological changes and lifestyle effects.
Elderly – effectiveness of microbiomes start to deteriorate.
Research project showed that ambulatory (mobile) elderly in non rehabilitation, long stay, residential homes became more prone to frailty, infection and inflammatory conditions due to loss of microbial diversity in the restricted diet (less variation than would be available in own home). Tests on mice showed the same results. Research like this can lead to identifying the risk factor responsible for developing illnesses and complications, i.e. looking at the bug can help us develop the drug.
Role of the microbiome in polyarteritis Nodosa – Prof Omer Karadag, Hacettepe University, Ankara, Turkey
Looking at the DCVAS study, which involves 164 patients.
Poly arteritis nervosa is very rare and can occur in clusters. There are several types, primary, genetic, drug induced and associated with Hepatitis B. Relapse rates vary between the subgroups, research being carried out in Turkey, Japan and France.
BIOVAS study – looking at use of biologics in non-ANCA associated Vasculitis and their effectiveness – Pani Gopalune, Addenbrookes Hospital
The drugs being trialled under open label are Toncilumab, Rituximab and Adalimumab It is a Randomised control trial using a double blind format. As numbers are restricted, a modified crossover trial is used (switching to the other test drug to test effectiveness) but if trial drug is deemed unsuccessful after several months, Rituximab is used as the rescue drug.
Urinary Soluble CD163 in Active Renal Vasculitis – Sarah Moran, HRB Research Fellow, Trinity University.
Talked about the development of research into the cd163protein test. This test is stable at room temperature and can sit for up to 7 days, which means that even if it is taken at a rural hospital, it can be transported to the Biobank Vasculitis lab facilities.
Stephen McAdoo, Addenbrookes
Using combined Rituximab and Cyclophosamide in Vasculitis.
EULAR have guidelines for management of ANCA associated Vasculitis, and rationale for research was to look at combining rituximab with reducing Cyclophosamide and steroids in new or relapsing patients. Each was given 2x1g Rituximab, 6x500mg Cyclophosamide with a rapidly decreasing dose of steroids.
62 achieved remission, after 2 years these were B cell deplete.
90% became ANCA negative, but 60% showed reversal after 6 months.
Microscopic Polyangiitis Arteritis patients mostly had relapses, signified by a return of the B cells.
There were infectious complications in 35% of patients. After 4 years, most participants are on maintenance therapy.
Fiona Pierce, Nottingham
Completed a PhD in ANCA Associated Vasculitis funded by Vasculitis UK looking at effects of diagnostic delay and possibility of developing a risk prediction model. She accessed the Clinical Practice Research Datalink (recording all primary care interventions), the Office for National Statistics mortality data and National Hospital Statistics and routinely collected data on clinical trials and registries, to look at the incidence and prevalence of Vasculitis, diagnostic delay and its effects on premature mortality. With input from Arthritis UK, Fiona determined that looking at pre diagnostic features would be a way of predicting early death. Using this information, a risk prediction model could be established and also we could glean insights into the aetiology, helping us to reduce effects and avoid progression.
Her results show
- a higher incidence of mortality in hospitals due to the severity of symptoms at presentation.
- People of mixed ethnicity have an increased incidence of developing AAV at a younger age.
In view of this last point, we need to look at developing information in other languages.
Vasculitis UK Update, Mr John Mills
Vasculitis UK is now part of RAIRDA, which is an umbrella group of Vasculitis UK, Lupus UK, Scleroderma UK and the British Society of Rheumatologists. They are looking at educating the professionals and have an officer of parliamentary affairs in Westminister. They are offering travel bursaries for medical staff/students to attend the upcoming Vasculitis Symposium in Tokyo and £50,000 in Research bursaries.
State of the Art; Remission induction and maintainence in ANCA Associated Vasculitis; Update on UKIVAS and EUVAS activities: Dr David Jayne, Cambridge University.
There is a Vasculitis course starting in Cambridge next year. Roche are looking at the long-term side safety effects of Rituximab in the patient group.
Treatment studies update
PEXIVAS study, Plasma exchange, 700 participants, recruitment closed 2016. These will be followed for 5 years, which will accumulate a lot of data.
Meplzumab is being trialled for EGPA/ Churg Strauss, in the MIRRA trial. GSK released results that this drug met all secondary endpoints in patients with EGPA.
AVACOPAN, a new clinical trial looking at using an oral C5a blocking receptor in inducing and maintaining remission in ANCA Associated Vasculitis. 2 Phase II trials have been reported in 2016 and phase III will start this year. The ultimate aim of the trial is to assess ability to remove the use of steroids completely. (CLEAR trail).
Mycophenolate Mofetil versus Cyclophosamide: in patients with IgA Nephropathy. Reducing use of Cyclophosamide would reduce the long term, toxic side effects, results not released yet.
ABATACEPT – non severe GPA, currently recruiting.
Maintenance studies update
REMAIN – can Azathiaprine and steroids be stopped after 2 years? ANCA can be regulated after 2 years but is likely to relapse, therefore trial will continue on these treatments for 4 years.
MAINRITSAN – is Rituximab better than Azathiaprine? Biomarkers are not sufficiently sensitive at present to assess properly.
RITZAREM – looking at use of Rituximab for 4 years
BELIMUMAB – treatment of GPA and MPA, downgraded to phase II clinical trial, results will be due next year.
The French are doing research into statin use in Vasculitis.
The likelihood of DVT development in Vasculitis is 10%
The incidence of malignancy in Rituximab use is 1%, it also 1% in rituximab and cyclophosamide use.
Need to look at T cell exhaustion in Vasculitis and its effects.
Outcomes and Management of the patient with small vessel Vasculitis post kidney transplantation: Dr Mike Clarkeson, Consultant Nephrologist CUH.
Venous access complications in dialysis can be avoided by preserving veins in the non-dominant arm to significantly improve transplant outcomes. Transfusions for anaemia can make finding a donor more difficult especially for a woman who has had a child.
Dialysis can extend life for 10 years.
End Stage Kidney Disease (ESKD) is higher in Microscopic Polyangiitis than Granulomatosis with Polyangiitis.
Factors considered in deciding when to transplant
- Chronic Kidney Disease stage 4
- Lack of improvement over time
- Birmingham Vasculitis Assessment Scale
- ANCA status (do not need to be ANCA negative)
- Time since remission
- Infection risk considerations
DUTRAVAS study (Dutch) looking at 1-5 year survival post transplant.
Relapse rate is shown to be 13/110 with most on heavy immunosuppression, resulting in low levels of immunoglobulins.
Disease recurrence shown in severe vasculopathy associated with graft loss.
Following transplant there is a 50% risk of developing bronchiectasis and an increased risk of having a stroke.
In the future we need non invasive, inexpensive, freely available tools to help identify flares to prevent complications following transplant.
Apologies for the length of this summary, but I felt it is important to let you know of all the good work currently being done by these interested clinicians in UK and Ireland.
All details re research being currently undertaken can be viewed at the website