Latest Research Studies into PMR and GCA

After many years in the shadows, polymyalgia rheumatica  (PMR) and giant cell arteritis (GCA) are at last coming into the spotlight of research interest among rheumatologists and other scientists.  It is part of the mission of PMRGCAuk to encourage more research into both PMR and GCA because there is still more gap than there is research-based knowledge about these conditions.  There is so much we still need to learn about what causes these illnesses, what is happening in the body and what treatments are appropriate.  That is before we even start thinking about prevention or cure.

We will update these pages with recent research and will continue to archive older papers, which you will be able to access very soon.

Improving the quality of care for people with giant cell arteritis

FEATURED PAPER FOR SEPTEMBER 2021

Authors: Chetan Mukhtyar, Georgina Ducker, Sarah Fordham, Sonja Mansfield-Smith and Colin Jones

Journal: Clinical Medicine
Date of publication: July 2021
Digital Object Identifier: https://doi.org/10.7861/clinmed.2021-0126

Description of the research
The question
This was a quality improvement project rather than a true research project. The authors identified the following issues that they needed solutions for
1. They were seeing less referrals than they should have. This meant the individuals with GCA were either not being referred to hospital or being seen in non-specialist areas of the hospital.
2. There was no protocol for the use of glucocorticoids (steroids) and other drugs and therefore there was a wide variation in the regimens used.
3. There was no central mechanism for arranging temporal artery biopsy. In the absence of dedicated surgeons, the yield of material for testing was variable. There was no availability of ultrasonography.
4. Patient empowerment was non-existent. Access to appointments and medication plans was restricted.
5. Follow-up in specialist clinics was non-existent.

How did they approach the problem?
They performed a scoping exercise to begin with to understand the problems. Through multi-disciplinary negotiations, they developed a new treatment regimen, diagnostic pathway including introduction of ultrasonography, a new specialist clinic; and appointed a specialist nurse.

What did they find?
1. The number of referrals rose from 19 in 2012 to 137 in 2019.
2. The number of individuals who were formally diagnosed with GCA rose from 19 in 2012 to 51 in 2019.
3. The modality of diagnosis has changed from 17/19 diagnoses made by a biopsy to just 4/51 needing a biopsy.
4. In 10 years, the total cost of diagnostics in the service dropped from £208k to £110K despite seeing more than 2.5 times the number of referrals.
5. The cost of diagnosis per GCA patient fell from £1284 to £262.08, saving more than £140K per year in just diagnostics.
6. All individuals with newly diagnosed GCA receive formal education about their condition and their medicines and on-going follow-up in a specialist clinic.

Limitations of the study
This is report from a single centre. While the problems that the authors found are ubiquitous, their solutions may not be applicable generally. Rather than a blueprint to follow, they should be regarded as a template to modify according to the needs of the centre.

Take-away messages
• Multi-speciality and multi-disciplinary input are essential to the development of GCA services.
• Improvements in services may result in cost-savings making their application more attractive.

Myocardial infarction during giant cell arteritis: A cohort study

FEATURED PAPER FOR AUGUST 2021

Authors: Hélène Greigert, Marianne Zeller, Alain Putot, Eric Steinmetz, Béatrice Terriat, Maud Maza, Nicolas Falvo, Géraldine Muller, Louis Arnould, Catherine Creuzot-Garcher, André Ramon, Laurent Martin, Georges Tarris, Tibor Ponnelle, Sylvain Audia, Bernard Bonnotte, Yves Cottin, Maxime Samson

Journal: European Journal of Internal Medicine
Date of publication: July 2021
Digital Object Identifier: doi.org/10.1016/j.ejim.2021.02.001

Description of the research
The question
To define the nature of heart attacks in individuals with GCA and compare them to those without GCA

How did they approach the problem?
The authors identified individuals with GCA from a database that captures data for all individuals that have a temporal artery biopsy. All cases of GCA had a positive biopsy result and fulfilled internationally accepted criteria. All individuals who suffered a heart attack were captured on a different database. From the two databases, the authors found cases of GCA who had suffered a heart attack and selected 5 other controls per case of GCA. Controls were individuals who had suffered a heart attack but did not have GCA. The controls were evenly matched with the cases for other factors known to predispose to heart attacks (high blood pressure, diabetes, cholesterol levels, smoking, family history, and previous cardiovascular events).

What did they find?
They found 13 cases (GCA plus heart attack) and 65 controls (heart attacks without history of GCA). Those with GCA had lower haemoglobin levels, greater levels of inflammation and were more likely to have involvement of the left main coronary artery (the larger of the two arteries supplying the heart muscle).

Limitations of the study
This was a small study because they didn’t find too many people with GCA who had also suffered a heart attack. This make the data slightly unreliable but is still a good message for individuals with GCA. The database that they used to identify those who had suffered a heart attack only captured events if the cases needed cardiac intensive care. This therefore may have missed out on people who had minor heart attacks.

Take-away messages
• Individuals with GCA are more likely to have involvement of the left main coronary artery as a cause of their heart attack.

A meta-analysis of the epidemiology of giant cell arteritis across time and space

FEATURED PAPER FOR JULY 2021

Authors: Katherine J. Li, Daniel Semenov, Matthew Turk and Janet Pope

Journal: Arthritis Research & Therapy
Date of publication: March 2021
Digital Object Identifier: 10.1186/s13075-021-02450-w

Description of the Research
The question

Has there been a change in the frequency of GCA worldwide?
What is the frequency of GCA worldwide?
How many people have GCA worldwide?
What is the effect of GCA on mortality?
Is there a connection with geographical latitude?

How did they approach the problem?
The authors searched the publicly available databases of scientific literature up to current time. All studies ever done meeting pre-set criteria were included in the analysis.

What did they find?
Out of 5426 scientific papers, only 107 met the pre-set criteria.
In descending order, the highest yearly incidence (frequency of new occurrences per year per 100,000 people over the age of 50) was in Scandinavia (21.6), the Americas (8.8), Oceania (7.9), Europe (7.3), Middle East (5.7), Africa (4.6), East Asia (0.3). The global incidence was 10/100,000 people over the age of 50. Between 1981 and 2017, the global incidence was reducing by 0.4 / 100,000 / year.
The prevalence (number of people over the age of 50 with GCA in any year) was
51.7 /100,000.
The studies did not provide enough data to produce reliable information on the effect of GCA on mortality compared to the general population.
The incidence of GCA rises with latitudes. The prevalence and mortality do not change with geography.

Limitations of the study
It is the nature of science that doctors will study the disease that they are treating. In a continent as big as North America, GCA has been studied the most in Minnesota which has a large Scandinavian population. This will skew the rates of the entire continent. But an even bigger problem that the authors faced was the definition of what was called GCA in the individual studies. Up to a few years ago, GCA could only be diagnosed by biopsy and that wasn’t very reliable as a diagnostic marker. That will have led to obvious problems in the interpretation of the data.

Take-away messages
• There is a gradual decline in the rates of GCA even though people are living longer.
• Scandinavia has the highest incidence of GCA in the world
GCA becomes commoner from the equator to the poles.

A French cohort of patients with giant cell arteritis: glucocorticoid treatment and its associated side effects

FEATURED PAPER FOR JUNE 2021

Authors: Ségolène Perrineau, Thibault Ghesquière, Pierre Charles, Romain Paule, Maxime Samson, Martine Gayraud, Anthony Chauvin, Benjamin Terrier, Loic Guillevin, Bernard Bonnotte, Luc Mouthon, Alexis Régent, French Vasculitis Study Group (FVSG)

Journal: Clinical and Experimental Rheumatology
Date of publication: March – April 2021
Digital Object Identifier: (This journal does not use DOI)

Description of the research
The questions
What is the frequency of side effects associated with glucocorticoid (steroids like prednisolone) therapy?
Are there any risk factors that might predict the side effects?

How did they approach the problem?
The authors included the records of consecutive individuals diagnosed with GCA in 3 hospitals between 2009 and 2018. They compared the profiles of those individuals who had 1-2 side effects with those who had more than 2 side effects.

What did they find?
They had diagnosed 206 individuals with GCA. The initial starting dose of prednisolone was a median (a statistically more appropriate form of ‘average’) of 45 mg daily. The median follow-up time was 34 months. Side effects occurred in 64% of individuals – the commonest being fractures (13%), severe infection (13%), weight gain (10%). 154 individuals suffered 1-2 side effects, 49 suffered >2 side effects. Age (odds rose by 4.8x for every 5-year rise), previous diabetes before GCA (odds 5x) and suffering a relapse (odds 2.4x) were all independently predictive of risk of side effects.

Limitations of the study
The authors included individuals with a clinical diagnosis of GCA which was not supported by a ‘diagnostic test’ (a biopsy or a scan). Those individuals might have either received less than or even more than average doses of prednisolone, which might skew the results.

The authors have not included those individuals who did not have any side effects in their risk analysis. In some ways, understanding what is unique about them might give us the best clues to avoiding prednisolone related side effects.

The analysis did not include total amount of prednisolone exposure.

Take-away messages
• Older age at diagnosis predisposes to more side effects.
• People with pre-existing diabetes are at greater risk of suffering side effects of prednisolone treatment.

 

Association between Specimen Length and Number of Sections and Diagnostic Yield of Temporal Artery Biopsy for Giant Cell Arteritis

FEATURED PAPER FOR MAY 2021

Authors: Francesco Muratore, Luigi Boiardi, Alberto Cavazza, Giacomo Tiengo, Elena Galli, Raffaella Aldigeri, Nicolo Pipitone, Luca Cimino, Martina, Bonacini, Stefania Croci, and Carlo Salvarani

Journal: Arthritis Care Res (Hoboken)
Date of publication: March 2021
Digital Object Identifier: https://doi.org/10.1002/acr.24393

Description of the research
The question
Is there a connection between the size of the biopsy, the detail of examination and making a diagnosis of GCA?

How did they approach the problem?
The authors performed a search of their hospital database to identify all temporal artery biopsies between 1991 and 2012. The biopsies that had been reported as not showing inflammation were retrieved from their archives and additional levels were examined for hitherto unrecognised inflammation.

What did they find?
694 temporal artery biopsies had been performed. 427 had been reported as not showing inflammation. There was no difference in the size of the biopsies that showed GCA versus those that did not show GCA. The optimum length of the artery that showed GCA (beyond which the diagnostic rate was not increased) was 5 mm. But since a blood vessel shrinks after it has been taken out of the body by about 20%, the size that a surgeon should aim to remove should be about 6mm. When additional levels of the samples that were negative were examined, they found 3 samples that were positive. So, a more detailed examination may improve the diagnostic rates marginally.

Limitations of the study
An artery has three layers. GCA starts in the outermost layer and the inflammation travels inwards. The authors have classified only those specimens as showing inflammation if it affected at least two layers – the outer and middle. That means that for those showing inflammation of the outermost layer only, they may have been misinterpreted as not showing GCA.

This is a controversial issue in the world of GCA. Pathologists reporting the biopsy may look for ‘classical’ changes and report the biopsy as being negative. Clinicians who have examined the patient may be happy to diagnose GCA with the presence of inflammation in just one layer because there may not be another cause of inflammation affecting the artery in that patient.

Take-away messages
• A temporal artery biopsy should be about 6 mm in size.
• Detailed examination of biopsies results in marginal gains in terms of diagnostic rates; conversely a negative biopsy does not rule out GCA.
• The presence of an international consensus in what constitutes a positive result is needed.

Incidence Trends and Mortality of Giant Cell Arteritis in Southern Norway

FEATURED PAPER APRIL 2021

Authors: Jintana B Andersen, Geirmund Myklebust, Glenn Haugeberg, Are H Pripp, Andreas P Diamantopoulos

Journal: Arthritis Care Res (Hoboken)
Date of publication: March 2021
Digital Object Identifier: https://doi.org/10.1002/acr.24133

Description of the research
The question
Is the frequency of GCA rising in Southern Norway)?
Does GCA cause a greater risk of death?

How did they approach the problem?
The authors looked into the records of a hospital serving two counties to find the number of people who were diagnosed as having GCA over a period of 14 years.  They compared their numbers with publicly available information about the population of those counties.

What did they find?
206 people had been diagnosed over 14 years with having GCA. The female to male ratio was 2.5:1.  The mean age was 73.  The annual incidence (frequency of occurrence) was calculated to be 16:8 per 100,000 people over the age of 50.  The peak decade of incidence was 70-79 years of age.  No one below the age of 50 had been diagnosed as having GCA.

The risk of death was no different to the population but was higher in men with GCA than women with GCA.  The incidence of GCA does not appear to be rising when compared to previous decades going back to the 1970’s.

Limitations of the study
This was a study that asked a narrow question and often those studies are the best studies because they are focussed.  One could argue that this does not mean much for the UK, but since almost all those who get GCA have Scandinavian or Northern European genes, this does matter.

Take-away messages
GCA is not rising in its frequency.
It is rare affecting about 17 out of every 100,000 people over the age of 50.
It does not increase the risk of death, but men do worse than women (which is true for the general population as well).

Diagnostic value of axillary artery ultrasound in patients with suspected giant cell arteritis

FEATURED PAPER MARCH 2021

Authors: Hilde Hop, Douwe J Mulder, Maria Sandovici, Andor W J M Glaudemans, Arie M van Roon, Riemer H, J A Slart, and Elisabeth Brouwer

Journal: Rheumatology (Oxford)
Date of publication: December 2020
Digital Object Identifier: https://doi.org/10.1093/rheumatology/keaa102

Description of the research
The question
What is the role of ultrasonography scanning of the axillary artery (the main blood vessel supplying the arm) in addition to the superficial temporal artery in individuals suspected of having GCA?

How did they approach the problem?
They looked at individuals who underwent ultrasonography scanning in their hospital when they were suspected of having GCA.  Since 2013, routine protocol has dictated that they scan the superficial temporal artery and the axillary artery.  A simple analysis of how many they would have diagnosed with just scanning the superficial temporal artery and how many more were picked up using axillary artery ultrasonography was carried out.

What did they find?
Of 113 individuals referred, 41 were found to be suffering with GCA. 21 (51%) had an abnormal ultrasound scan of the superficial temporal artery.  A further 8 (20%) were diagnosed because of an abnormal axillary artery ultrasonography image.

Limitations of the study
It was a retrospective study, so the flow of the cases was not built to answer the specific question.  Having appreciated that, the real-life experience outside of a ‘study’ might mean that it is more generally applicable. 

In their hospital they use dedicated sonographers who simply look at the images and report them. Arguably, if the doctors had scanned the patients after their physical examination, they might have achieved better results (sonographers interpret the images based on strict cut-off values.  This is usually the correct thing to do.  But currently there are no agreed cut-off values on the size of the abnormality.  So that interpretation requires the addition of clinical judgement of the doctor.  For example, if it was decided that a freckle can only be called a freckle if it is above a certain size, then a number of technicians who diligently measure the freckle sized would decide that there were considerably fewer freckles.  However, the rest of us would have no trouble in seeing a freckle and calling it such.  In this case, there are agreed definitions for what the abnormality should look like but not how big it should be).

Take-away messages
• Giant cell arteritis affects blood vessels beyond the superficial temporal artery and often may not involve them at all.  Thus, the phrase ‘temporal arteritis’ is a misnomer.
• If the diagnosis of GCA is suspected, a normal ultrasound scan of the temporal arteries must lead to further scanning of other blood vessels starting with the axillary arteries.

Risk factors for severe cranial ischaemic complications in giant cell arteritis

FEATURED PAPER FEBRUARY 2021

Authors: Alojzija Hočevar, Rok Ješe, Matija Tomšič, Žiga Rotar

Journal: Rheumatology (Oxford)
Date of publication: October 2020
Digital Object Identifier: https://doi.org/10.1093/rheumatology/keaa058

Description of the research
The question: What are the risk factors for visual loss and stroke in individuals with GCA?

How did they approach the problem?
The authors studied individuals diagnosed with GCA who had been examined and investigated in a structured manner. They were divided into two groups – those with stroke and/or visual involvement AND those without. All of them were treated as per the European recommendations from 2009.

What did they find?
They identified 295 new instances of GCA. 61 of them had suffered stroke or visual involvement. 52 had visual involvement including 22 who had blindness (3 suffered blindness in both eyes), 5 had strokes and 4 suffered both visual involvement and a stroke.
Those above the age of 75 years at diagnosis, smokers and those presenting with jaw pain on chewing were most likely to suffer a severe complication.

Limitations of the study
This study is from a single centre and that can sometimes lead to biases in the way that diagnosis is made. For example, those suffering a stroke might be looked after at a different place in that city and that might artificially reduce the numbers of individuals thought to suffer with complications. Secondly, causality is not fully established. In this study if a complication happened within 1 month of the diagnosis, it was attributed to GCA. We know that high doses of steroids can be a burden on the heart and provoke complications of its own.

Take-away messages
GCA is yet another disease, where smokers will do badly
• Those individuals that suffer with progressive pain on chewing at the time of diagnosis may continue to be at higher risk of suffering a complication even after starting steroids for a short period of time.
• While you can do nothing about your age, should one get GCA after the age of 75, you would be at a higher risk of suffering a complication.

An exploratory cross-sectional study of subclinical vascular damage in patients with polymyalgia rheumatica.

FEATURED PAPER JANUARY 2021

Authors: Rossana Scrivo , Valeria Silvestri, Francesco Ciciarello, Paola Sessa, Iolanda Rutigliano, Cristina Sestili, Giuseppe La Torre, Cristiana Barbati, Alessio Altobelli, Cristiano Alessandri, Fulvia Ceccarelli, Manuela Di Franco, Roberta Priori, Valeria Riccieri, Antonio Sili Scavalli, Francesca Romana Spinelli, Luciano Agati, Francesco Fedele, Bruno Gossetti, Fabrizio Conti, Guido Valesini

Journal: Scientific Reports
Date of publication: July 2020
Digital Object Identifier: https://doi.org/10.1038/s41598-020-68215-8

Description of the research:
The question: Do people with PMR have damage to their blood vessels?

How did they approach the problem?
They measured parameters acquired by imaging techniques (thickness of the carotid artery in the neck -IMT, stiffness of the arteries – CAVI, size of the aorta in the tummy – APAD) and blood tests for chemicals (leptin, adiponectin and resistin – chemicals which may alter the body’s metabolism and inflammatory responses) secreted by body fat in people with PMR and compared them to people without PMR (but who had other major risk of cardiovascular disease – people with hypertension, diabetes, high cholesterol, obesity and cigarette smokers).

What did they find?
They recruited 48 individuals with PMR and 56 with controls with major cardiovascular risk factors. The only meaningful difference between the two groups was the exposure to prednisolone. The individuals with PMR had been treated with an average 7 mg of prednisolone for over 28 months. All three measurements acquired by imaging techniques were meaningfully worse in individuals with PMR and two of the three chemical levels (leptin and adiponectin) were also higher in individuals with PMR.

Limitations of the study
• They diagnosed PMR using a criteria formulated in 2012. Since then, there have been some publications that a number of people with PMR may also have had GCA to begin with. So it is possible that some of their PMR group may have had GCA. Nevertheless, the findings are significant.
• The difference in prednisolone exposure may mean that the findings are a result of prednisolone exposure rather than because of PMR. But since one goes with the other, the findings are still meaningful.

Take-away messages
• Individuals with PMR also have damage to their arteries (perhaps because some of them may also have GCA that is unrecognised).
• This sets the ball rolling for future studies to look at the need for greater vigilance for events like heart attacks and strokes in individuals suffering with PMR.

Prevalence of Giant Cell Arteritis Relapse in Patients Treated with Glucocorticoids: A Meta‐Analysis.

FEATURED PAPER DECEMBER 2020

Authors: Sabine Mainbourg, Alexandra Addario, Maxime Samson, Xavier Puéchal, Mathilde François, Stéphane Durupt, François Gueyffier, Michel Cucherat, Isabelle Durieu, Quitterie Reynaud, Jean‐Christophe Lega

Journal: Arthritis Care & Research
Date of publication: June 2020
Digital Object Identifier: https://doi.org/10.1002/acr.23901

Description of the research:
The question: What is the relapse rate in patients with GCA treated with steroids alone?

How did they approach the problem?
They searched a medical literature database (Medline) to identify all relevant research up to December 2017. All identified literature was studied and included in their analysis if it had information about patients with GCA who were treated just with steroids. After checking the quality of the studies, the researchers pooled the data from the various small studies to make one large study.

What did they find?
The researchers found 300 studies, of which 34 studies (which included 2505 participants) had looked at this problem. The relapse rate was 47.2%. The relapse rate was higher (65.8%) in studies that attempted steroid withdrawal before 12 months, when compared to those studies that planned to use the steroids for longer (relapse rate 34.5%).

Limitations of the study
• The way that GCA was diagnosed and relapse was confirmed differed in the various studies, which may have affected the result.
• The nature of the relapses (minor shoulder pains versus full blown GCA) was not differentiated.

Take-away messages
• About half of all sufferers with GCA are likely to have a relapse at some point
• Rapid taper of steroids increases the likelihood of relapse