EULAR
Recommendations.
Treatment of Systemic Sclerosis.
Treatment of Systemic Sclerosis.
Scleroderma, Raynaud's,
Autoimmune Rare Disease.
#SclerodermaFreeWorld #RaynaudsFreeWorld
ABSTRACT
The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows.
All centres from the EULAR Scleroderma Trials and Research (EUSTAR) group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach.
The procedure
resulted in 16 recommendations being developed (instead of 14 in 2009) that
address treatment of several SSc-related organ complications:
Raynaud’s
phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH),
skin and lung disease, scleroderma renal crisis, and gastrointestinal involvement.
Compared
with the 2009 recommendations, the 2015 recommendations include phosphodiesterase
type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs,
riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues
and PDE-5 inhibitors for SSc-related PAH.
New
recommendations regarding the use of fluoxetine for SSc-related RP and
haematopoietic stem cell transplantation for selected patients with rapidly progressing
SSc were also added.
These
updated data-derived and consensus-derived recommendations will help rheumatologists
to manage patients with SSc in an evidence-based way.
These recommendations also give directions for future clinical research in SSc.
These recommendations also give directions for future clinical research in SSc.
INTRODUCTION
Based on the published evidence and expert opinion, 16 updated recommendations regarding pharmacological treatment of SSc-specific organ involvement were formulated.
It should
be recognised that the field of management of patients with SSc is larger than
pharmacological management alone.
Management of SSc also includes (early) diagnosis of the disease, early diagnosis of internal organ involvement, identification of patients at risk of development of new organ complications and deterioration of the disease, as well as non-pharmacological treatments, of which most of are beyond the scope of this project.
Management of SSc also includes (early) diagnosis of the disease, early diagnosis of internal organ involvement, identification of patients at risk of development of new organ complications and deterioration of the disease, as well as non-pharmacological treatments, of which most of are beyond the scope of this project.
There are
also several (potential) drugs, including new promising therapies that might be
helpful in management of patients with SSc that could not be included in these evidence-based
recommendations due to insufficient data at present.
RP in patients with SSc (SSc-RP) Recommendation:
Dihydropiridine-type
calcium antagonists, usually oral nifedipine, should be considered for first-line
therapy for SSc-RP. Phosphodiesterase type 5 (PDE-5) inhibitors should also be
considered in treatment of SSc-RP.
In view
of costs and feasibility, the experts recommended that intravenous prostanoids
are considered when oral therapies (including calcium channel blockers and
PDE-5 inhibitors) have failed. As most drugs used for treating RP may induce
vascular side
effects, the experts recommend particular attention if prostanoids are combined
with other vasodilators.
Recommendation:
Fluoxetine might be considered in treatment of SSc-RP attacks.
DUs in patients with SSc
Recommendation:
Intravenous iloprost should be considered in the treatment of DUs in patients
with SSc.
Recommendation:
PDE-5 inhibitors should be considered in the
treatment of DUs in patients with SSc.
Considering
the fact that oral prostanoids showed lower efficacy for treatment of
SSc-related RP, as compared with intravenous iloprost (see section on RP), the experts
decided, based on the results of the aforementioned two RCTs, to recommend intravenous
iloprost as a treatment for DUs in patients with SSc.
Further
studies are required to confirm beneficial effect of intravenous iloprost in
prevention of development of DUs in patients with SSc.
In view of risk of side effects and route of administration usually requiring hospitalisation, intravenous iloprost should be considered in particular in patients with SSc with DUs not responding to oral therapy.
In severe cases, combination therapy with oral vasodilator and intravenous iloprost can be used. However, the increased risk of side effects should be taken into account.
In view of risk of side effects and route of administration usually requiring hospitalisation, intravenous iloprost should be considered in particular in patients with SSc with DUs not responding to oral therapy.
In severe cases, combination therapy with oral vasodilator and intravenous iloprost can be used. However, the increased risk of side effects should be taken into account.
Recommendation:
PDE-5 inhibitors should be considered in the treatment of DUs in patients with
SSc.
Side effects of PDE-5 inhibitors are discussed in the previous paragraph regarding PDE-5 inhibitors in the treatment of RP.
Based on these data, the experts concluded that PDE-5 inhibitors can be efficacious in treating SSc-related DUs.
Side effects of PDE-5 inhibitors are discussed in the previous paragraph regarding PDE-5 inhibitors in the treatment of RP.
Based on these data, the experts concluded that PDE-5 inhibitors can be efficacious in treating SSc-related DUs.
Whether other
than tadalafil PDE-5 inhibitors can prevent development of new DUs in patients
with SSc needs to be clarified in further studies.
Recommendation:
Bosentan should be considered for reduction of the number of new DUs in SSc,
especially in patients with multiple DUs despite use of calcium channel
blockers, PDE-5 inhibitors or iloprost therapy.
At
present, there is insufficient evidence that endothelin receptor antagonists
(ERA) have beneficial effects on SSc-RP attacks either.
There are two major concerns related to the use of bosentan and other ERA: potential liver injury and teratogenicity.
There are two major concerns related to the use of bosentan and other ERA: potential liver injury and teratogenicity.
Hormonal
contraceptives may not be reliable if co-administered with bosentan, because
bosentan may reduce their efficacy by interference with the cytochrome P450
system.
In view
of the results of both RAPIDS trials and considering potential toxicities
associated with bosentan, experts recommend usage of bosentan especially in
patients who have multiple DUs despite treatment with other vasodilators such
as calcium channel blockers, PDE-5 inhibitors and iloprost to prevent the development
of new DUs.
SSc-related PAH
Recommendation:
ERA, PDE-5 inhibitors or riociguat should be considered to treat SSc-PAH. Experts
recommend that ERA, selective PDE-5 inhibitors and riociguat should be
considered in the treatment of SSc-PAH in agreement with international
guidelines regarding treatment of PAH.
This has been underlined by the publication of the recently published new guidelines of the pulmonology and cardiology societies.
This has been underlined by the publication of the recently published new guidelines of the pulmonology and cardiology societies.
In severe
or progressing PAH cases combination therapy with different PAH-specific drugs
should be taken into account.
Although
at the time of developing these recommendations RCTs comparing combination
therapy with PAH-specific drugs versus monotherapy in patients with SSc-PAH
were lacking, this approach is in line with recent guidelines of the European
cardiology and pulmonology societies regarding management of PAH in general,
and seems particularly important in patients with SSc-PAH known to have more
progressive disease than patients with other forms of PAH.
Recommendation:
Intravenous epoprostenol should be considered for the treatment of patients
with severe SSc-PAH (class III and IV). Prostacyclin analogues should be
considered for the treatment of patients with SSc-PAH.
Despite
the lack of specific RCTs evaluating these drugs exclusively in patients with
SSc, experts recommend that these prostacyclin analogues should be considered
for treatment of SSc-PAH, in agreement with international guidelines for PAH treatment.
The
experts concluded that combining different classes of PAH-specific therapies may
be considered in the treatment of selected patients with SSc-PAH, especially in
those with severe or progressing disease.
This approach is in line with recently published guidelines regarding management of PAH in general, and seems particularly important in patients with SSc-PAH known to have more progressive disease than patients with other forms of PAH.
This approach is in line with recently published guidelines regarding management of PAH in general, and seems particularly important in patients with SSc-PAH known to have more progressive disease than patients with other forms of PAH.
Skin and lung disease
Recommendation:
Methotrexate may be considered for treatment of skin manifestations of early
diffuse SSc.
Thus, the
experts confirmed the earlier recommendation for methotrexate in early diffuse
SSc. It should be recognised that cyclophosphamide (CYC) has also been shown,
in RCTs, to improve skin changes in patients with SSc, and other agents such as
mycophenolate mofetil or azathioprine are used to treat skin involvement,
although their efficacy has not been studied extensively.
Recommendation:
In view of the results from two high-quality RCTs and despite its known
toxicity, CYC should be considered for treatment of SSc-related interstitial
lung disease (SSc-ILD), in particular for patients with SSc with progressive
ILD.
As in the previous 2009 recommendations there was
unanimous consensus of the experts with respect to the CYC dose and duration of
treatment to be tailored individually dependent on the clinical condition and
response.
Potential risks of bone marrow suppression, teratogenicity, gonadal failure and haemorrhagic cystitis must be always considered.
Potential risks of bone marrow suppression, teratogenicity, gonadal failure and haemorrhagic cystitis must be always considered.
Recommendation:
Haematopoietic stem cell transplantation (HSCT), should be considered for the
treatment of selected patients with rapidly progressive SSc at risk of organ
failure.
In view of the high risk of treatment-related side effects and of early treatment-related mortality, careful selection of patients with SSc for this kind of treatment and the experience of the medical team are of key importance.
In view of the high risk of treatment-related side effects and of early treatment-related mortality, careful selection of patients with SSc for this kind of treatment and the experience of the medical team are of key importance.
In view
of the results of the two RCTs and considering the risk of potential
treatment-related mortality and morbidity experts recommend that HSCT should be
considered for the treatment of selected patients with rapidly progressive SSc
at risk of organ failure.
To reduce
the risk of treatment-related side effects, HSCT should be performed in
selected centres with experience in this kind of treatment.
Careful evaluation of the benefit to risk ratio in individual patients with SSc selected for HSCT should be done by experts.
Further studies should help to identify subgroups of patients with SSc in whom HSCT would be most beneficial.
Careful evaluation of the benefit to risk ratio in individual patients with SSc selected for HSCT should be done by experts.
Further studies should help to identify subgroups of patients with SSc in whom HSCT would be most beneficial.
Scleroderma renal crisis
Recommendation: Experts recommend immediate use of ACE inhibitors in the treatment of SRC
The experts
recognise that glucocorticoids, which are used in SSc, are part of the
therapeutic strategy in the management of ILD, diffuse cutaneous disease or
musculoskeletal involvement, although the evidence regarding their efficacy in
SSc is
limited.
Considering
the potential risk of SRC associated with steroid use experts recommend that
patients with SSc treated with steroids should be carefully monitored with
respect to the development of SRC.
SSc-related GI disease
Recommendation:
PPIs should be used for the treatment of SSc-related gastro-oesophageal reflux
and prevention of oesophageal ulcers and strictures
Large,
specific RCT for the efficacy of PPI in patients with SSc are lacking. A small
RCT indicated that PPI may improve upper GI symptoms in patients with SSc.
The efficacy
of PPI in the treatment of GERD in the general population is well
documented
in meta-analyses of RCTs.
In
asymptomatic patients with SSc, PPI should be used with caution since long-term
therapy with PPIs might lead to nutritional deficiencies, possibly due to
reduced intestinal absorption, or increased risk of infections.
Recommendation:
Prokinetic drugs should be used for the management of SSc-related symptomatic
motility disturbances (dysphagia, GERD, early satiety, bloating,
pseudo-obstruction, etc)
The
experts conclude that all available prokinetic drugs can be applied to patients
with SSc with GI involvement on an individual basis, in consideration of
potential benefit to risk ratio.
Recommendation:
Intermittent or rotating antibiotics should be used to treat symptomatic small
intestine bacterial overgrowth (SIBO) in patients with SSc.
Research
agenda
In
addition to the recommendations, experts formulated a research agenda which
addresses usage of pharmacological treatments in SSc or SSc-related organ
complications which were considered of particular interest.
This
research agenda can be helpful in developing further clinical research in SSc.
DISCUSSION
As
compared with the previous (2009) EULAR recommendations for treatment of SSc,
the updated recommendations include several new treatments for specific
SSc-related organ involvement.
The greatest changes have been made in treatments of vascular complications of SSc and mirror the progress which had been made in this field during the last several years.
These include the introduction of PDE-5 inhibitors for SSc-related RP and DUs, riociguat and new aspects for ERAs, prostacyclin analogues and PDE-5 inhibitors for SSc-PAH.
The new recommendation regarding the use of fluoxetine for SSc-related RP was also added.
The greatest changes have been made in treatments of vascular complications of SSc and mirror the progress which had been made in this field during the last several years.
These include the introduction of PDE-5 inhibitors for SSc-related RP and DUs, riociguat and new aspects for ERAs, prostacyclin analogues and PDE-5 inhibitors for SSc-PAH.
The new recommendation regarding the use of fluoxetine for SSc-related RP was also added.
With
regard to treatment of other than vascular complications of SSc, the
recommendation for HSCT for selected patients with rapidly progressive SSc at
risk of organ failure has been added.
Similar to the 2009 recommendations, the present recommendations address only pharmacological treatments which were considered most relevant and received consensus from the expert panel.
As SSc is an uncommon and clinically heterogeneous disease, appropriate testing of therapies is difficult.
Similar to the 2009 recommendations, the present recommendations address only pharmacological treatments which were considered most relevant and received consensus from the expert panel.
As SSc is an uncommon and clinically heterogeneous disease, appropriate testing of therapies is difficult.
Indeed,
evidence supporting the present recommendations is often limited and some of
the recommendations are supported by the evidence extrapolated from studies
involving patients with diseases other than SSc or are based solely on expert opinion.
Similar
to the 2009 recommendations, there is still not sufficient data, to make specific
recommendation for paediatric patients. It would be important to have studies
at least for the effective paediatric dose of each medication, to be safely applied.
It should
be recognised that there are several other promising therapies, including
immunosuppressive drugs or new biological agents which could not be included in
the present recommendations because the evidence for their efficacy was
considered insufficient
at the time of developing these recommendations.
The
results of RCT evaluating new therapies in patients with SSc which were
published after closure of the systematic literature research are presented in
online supplementary table S4.
The first
of these trials evaluated the efficacy of sildenafil in DUs healing in patients
with SSc and is addressed in the comment following recommendation concerning
treatment of DUs.
Another
double-blind, phase 2 RCT involved 87 patients with early diffuse SSc and
elevated acute phase reactants.
Treatment with tocilizumab (subcutaneous 162 mg/week) was associated with a favourable trends in skin score improvement as compared with placebo after 24 weeks (p=0.09) and 48 weeks (p=0.06).
In addition, encouraging changes in FVC were noted.
In view of promising effects of tocilizumab on skin and lung involvement, it is concluded that further studies are warranted before definitive conclusions can be made about its risks and benefits in SSc.
Treatment with tocilizumab (subcutaneous 162 mg/week) was associated with a favourable trends in skin score improvement as compared with placebo after 24 weeks (p=0.09) and 48 weeks (p=0.06).
In addition, encouraging changes in FVC were noted.
In view of promising effects of tocilizumab on skin and lung involvement, it is concluded that further studies are warranted before definitive conclusions can be made about its risks and benefits in SSc.
The
results of another RCT, the SLS 2 comparing mycophenolate mofetil with CYC in
patients with SSc-ILD are expected to be published soon.
The preliminary results of this study, recently published as an abstract of the 2015 ACR annual congress, indicate that mycophenolate mofetil (up to 3 g/day orally for 2 years) was comparable with oral CYC (2 mg/kg/day for 1 year followed by matching placebo for the second year) with regard to FVC course at 24th month.
The preliminary results of this study, recently published as an abstract of the 2015 ACR annual congress, indicate that mycophenolate mofetil (up to 3 g/day orally for 2 years) was comparable with oral CYC (2 mg/kg/day for 1 year followed by matching placebo for the second year) with regard to FVC course at 24th month.
However, final
conclusions regarding the place of mycophenolate mofetil in the treatment of
SSc-ILD cannot yet be made.
Other therapies, considered promising by the experts, were addressed in the research agenda.
Other therapies, considered promising by the experts, were addressed in the research agenda.
Since ‘lack
of evidence of efficacy’ does not imply that ‘efficacy is absent’ the absence
of positive recommendation regarding specific drug should not be interpreted as
a contraindication for its use.
It should
also be emphasised that there are other treatment options, such as education,
physiotherapy or local management of ischaemic lesions which were beyond the
scope of the project or could not be included in the present recommendations
due to lack of consensus among the experts.
In
conclusion, it is believed that these updated recommendations will help to
improve care of patients with SSc in an evidence-based way and indicate
direction for further clinical research.
Considering
the significant complexity and heterogeneity of SSc and the limited evidence
for treatments, it is recommended that patients with SSc should be referred to
specialised centres with appropriate expertise in SSc management.
May 2017.
Scleroderma Family Day
2020
25th
Anniversary Meeting
The Atrium, Royal Free
Hospital, London, NW3 2QG
Chair: Professor Chris
Denton
PROVISIONAL PROGRAMME
09.30 – 10.00 Registration
and Coffee
10.00 – 10.20 Welcome Dame
Carol Black
Prof Chris Denton &
David Abraham
10.20 – 10.40 What
is a Biopsy? Dr Kristina Clark
10.40 – 11.05 Dental
aspects of Scleroderma Prof Stephen Porter
11.05 – 11.25 Gastrointestinal
problems – Dr Fiza
Ahmed
shedding
new light on old problems
11.25 – 11.50 Pulmonary
hypertension and the heart Dr Gerry
Coghlan
11.50 – 12.15 Scleroderma
cohort studies – Dr
Francesco
‘Learning
from our patients’ del Galdo
12.15 – 14.15 LUNCH
BREAK – see below
14.15 – 14.45 25
years of progress – Prof
Chris Denton
from
‘black box’ to ‘positive trials’
14.45 – 15.15 International
speaker – Dr
Madelon Vonk
Scleroderma
Management in Netherlands
15.30 Raffle
Lunchtime Discussions Groups /
Demonstrations include:
Clinical Trials Rachel
Ochiel and team
National Institute of Health Research Christine Menzies
Drug Information / monitoring Pharmacy
Massage Keith Hunt MBE
Pulmonary Hypertension Education / nursing Sally
Reddecliffe/Adele Dawson
Rheumatology Laboratory Research
Laboratory Staff
Scleroderma Education / Nursing Louise
Parker/ Joseph Cainap
Thermography Dr Kevin Howell
SRUK Ollie Scott
Sjogren’s syndrome British
Sjogren’s Society
To Read My Articles:
Gift in My Will, Click here
Planning for the Future, Click here
Rare Disease Day:
Rare Disease Day 2020:
Listen to my interview with John Smeeton, (Silver Fox), from the Royal Free Radio, here
Raise awareness and donate to medical research, order your #SclerodermaFreeWorld #RaynaudsFreeWorld tshirt here
Rare Disease Day 2020:
Listen to my interview with John Smeeton, (Silver Fox), from the Royal Free Radio, here
Raise awareness and donate to medical research, order your #SclerodermaFreeWorld #RaynaudsFreeWorld tshirt here
Rare Disease Day 2019: 11am 97.4RockFM headlines, NO CURE, Click here
Rare Disease Day 2018 – Research, Taking
Part in Clinical Trials. Scleroderma, Raynaud's, Autoimmune Rare Disease, Click here
2018 Scleroderma Awareness Raising and Medical Research, Click here
This year, 2020, I am celebrating 22 years of being a patient at the Scleroderma Unit, The Royal Free Hospital - a world leading expert specialist, research centre.
Read more, here.
I had the pleasure of being a presenter and part of the European co-hort who gave a presentation at the European Parliament, Brussels, in honour of World Scleroderma Day 2015.
I am immensely grateful to James Carver, former MEP, for organizing this event in memory of his late wife Carmen, who sadly passed from Scleroderma.
#SclerodermaFreeWorld #RaynaudsFreeWorld #Research
Please DONATE to help
fund medical research at The Scleroderma Unit,The Royal Free Hospital, London.
Alternatively, to make a direct donation to fund medical research via the Royal Free Charity, Scleroderma Unit, Click here
100% of your monies will be used for medical research purposes only. NO wages or admin costs. Thank You.
Rare
Disease Day is a fantastic opportunity for the entire rare disease
community to shine a spotlight on their reality, combining as one unified
voice. Where, at least one commonality presides –
Medical
Research
provides the brightest light,
for the illumination of
the rare disease patients’ plight.
provides the brightest light,
for the illumination of
the rare disease patients’ plight.
Although
rare disease patients are few in number, eg. 2.5 million scleroderma patients
worldwide, (the World Scleroderma Foundation), the commonalities and golden
hallmark for each rare disease patient are the same overall.
For optimum
patient care, 3 hallmarks preside: 
INVESTMENT in MEDICAL RESEARCH is CRUCIAL.
To read my articles:
Celebrating 20 years of being a patient at the Scleroderma Unit, Click here
2019 New Challenges, Click here
NIHR Video: 'My
Experience of Clinical Trials', Click here
If we only had more RESEARCH investment for Scleroderma, Raynaud's, Autoimmune Rare Disease, Click here
The Importance of Medical Research and Awareness to the Scleroderma, Raynaud's, Autoimmune Rare Disease patient, Click here
If we only had more RESEARCH investment for Scleroderma, Raynaud's, Autoimmune Rare Disease, Click here
The Importance of Medical Research and Awareness to the Scleroderma, Raynaud's, Autoimmune Rare Disease patient, Click here
2018 Scleroderma Awareness Raising and Medical Research, Click here
SCLERODERMA:
Global Patient Profiles 2018 Video, Click here
Unmet Medical Needs, Click here
Calcinosis Video, Click here
The scleroderma tooth fairy, Click here
Skin Cancer and scleroderma, Click here
Unmet Medical Needs, Click here
Calcinosis Video, Click here
The scleroderma tooth fairy, Click here
Skin Cancer and scleroderma, Click here
 |
| Sept 2017 |
 |
| Prof Chris Denton and I, Sept 2017 |
 |
| June 2019 |
 |
This year, 2020, I am celebrating 22 years of being a patient at the Scleroderma Unit, The Royal Free Hospital - a world leading expert specialist, research centre.
I am eternally grateful to the global scleroderma trail blazers Dame
Prof Black and Prof Chris Denton, whose commitment and dedication to unlocking
the scleroderma enigma, is nothing other than, superhuman. Along with the
Raynaud's world trail blazer, Dr Kevin Howell.
I am truly humbled and inspired by their work ethic and commitment to
their patients.
I am wholly appreciative for Prof Denton’s continued medical expertise
and support, especially during my barrister qualifying years, 1997 -
2004.
1st March 2004, I qualified as a self employed practising
barrister. Further to having been told in 1997, by my original diagnosing doctor, that I
was looking at a 15month prognosis.
 |
| Chat Magazine May 2019 |
I very much hope to utilise my professional skills
and qualifications along with my patient experience, to help achieve the
#SclerodermaFreeWorld dream, hoping to improve understanding and best practice,
in the meantime. Read more, here
World Scleroderma Day
2015, 29th June.
 |
| James Carver, myself, Prof Chris Denton |
I had the pleasure of being a presenter and part of the European co-hort who gave a presentation at the European Parliament, Brussels, in honour of World Scleroderma Day 2015.
I am immensely grateful to James Carver, former MEP, for organizing this event in memory of his late wife Carmen, who sadly passed from Scleroderma.
To view the presentation, Click here
Raynaud's:
October:
Raynaud's, Click here
 |
| The global Raynaud's trailblazer - Dr Howell and I, Sept 2017 |
For latest updates follow / subscribe:
@SclerodermaRF
@RaynaudsRf
@SclerodermaRF
@RaynaudsRf
Twitter, Instagram, Blogger, YouTube, Facebook Page:
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Alternatively, to make a direct donation to fund medical research via the Royal Free Charity, Scleroderma Unit, Click here
100% of your monies will be used for medical research purposes only. NO wages or admin costs. Thank You.
Last Update: Feb 2020.
EULAR
Recommendations.
Treatment of Systemic Sclerosis.
Treatment of Systemic Sclerosis.
Scleroderma, Raynaud's,
Autoimmune Rare Disease.
#SclerodermaFreeWorld #RaynaudsFreeWorld
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