1. BSR Guidelines and Annual Tests
Christopher P. Denton
#SRUKAC18

2. Overview
Evidence base for management of systemic sclerosis is progressing
British Society for Rheumatology (BSR) develops guidelines to help professionals give high quality care and define best practice.
Annual testing for heart, lung or other complications is recommended.
The presentation will give summarise the BSR Systemic Sclerosis Guideline and best approaches for regular testing.
#SRUKAC18

3. Level of evidence and grade of recommendationIA
Evidence from meta-analysis of randomized controlled trials IB
Evidence from at least one randomized controlled trial
IIA
Evidence from at least one controlled study without randomization
IIB
Evidence from at least one other type of quasi-experimental study
III
Evidence from non-experimental descriptive studies, such as comparative studies, correlation studies, and case-control studies IV
Evidence from expert committee reports or opinions or clinical experience of respected authorities, or both
Grade of Recommendation: A
Directly based on Level I evidence B
Directly based on Level II evidence or extrapolated recommendations from Level I evidence C
Directly based on Level III evidence or extrapolated recommendations from Level I or II evidence D
Directly based on Level IV evidence or extrapolated recommendations from Level I, II, or III evidence
Shekelle PG, Woolf SH, Eccles M, Grimshaw J. 
Developing clinical guidelines. West J Med. 1999, 170:348-51

4. EULAR/EUSTAR recommendations for the treatment of systemic sclerosis
I SSc-related digital vasculopathy (RP, digital ulcers)
1. Calcium channel blockers and iloprost for Raynaud’s
2. Intravenous prostanoids (in particular iloprost) should be considered for treatment of digital ulcers in SSc
3. Bosentan should be considered in SSc with multiple digital ulcers
II SSc-PAH
4. Bosentan should be strongly considered to treat SSc-PAH
5. Sildenafil may be considered to treat SSc-PAH
6. Sitaxentan is withdrawn and should not be used for SSc-PAH
7. Intravenous epoprostenol should be considered for the treatment of severe SSc-PAH
III SSc-related skin involvement
8. Methotrexate may be considered for treatment of skin manifestations of early diffuse SSc
IV SSc-ILD
9. Cyclophosphamide should be considered for treatment of SSc-ILD
V SRC
10. ACE inhibitors should be used in the treatment of SRC
11. Patients on steroids should be carefully monitored for SRC
VI SSc-related gastrointestinal disease
12. PPI should be used for the treatment of SSc-related gastro-oesophageal reflux,
13. Prokinetic drugs should be used for the management of SSc-related symptomatic motility disturbances
14. When malabsorption is caused by bacterial overgrowth, antibiotics may be useful in SSc
Kowal-Bielecka et al, Ann Rheum Dis 2009;68:

5. EULAR/EUSTAR Recommendations for management of systemic sclerosis – updated 2016 (from 2009)
Updated EULAR recommendations for the treatment of systemic sclerosis (SSc), using EULAR standard operating procedures.
16 recommendations were developed (instead of 14 in 2009) addressing:
Raynaud's phenomenon (RP),
digital ulcers (DUs)
pulmonary arterial hypertension (PAH)
skin and lung disease
scleroderma renal crisis
gastrointestinal involvement.
2016 changes include:
phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, updates 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 progressive SSc were also added.
Kowal-Bielecka O et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann Rheumatic Dis 2017; 76:

6. BSR and BHPR Standards, Guidelines and Audit Working Group.
The Scleroderma (Systemic Sclerosis) guideline …. 36 months in development
Denton CP, Hughes M, Gak N, Vila J, Buch MH, Chakravarty K, Fligelstone K, Gompels LL, Griffiths B, Herrick AL, Pang J, Parker L, Redmond A, van Laar J, Warburton L, Ong VH
BSR and BHPR Standards, Guidelines and Audit Working Group.
Submitted January 11th 2016
Accepted April 12th 2016
Published May 2016

7. BSR and BHPR guideline for the management of systemic sclerosis
Work started September 2012
February submitted to BSR and first stage of external peer review – presented draft April 2015
Target for completion September 2015
Scope and structure of draft guideline
General approach to SSc management
Key therapies and treatment of organ based disease
Service organization and delivery within NHS England
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8. Overview of management of systemic sclerosis
dcSSc
Therapy:
Vascular
Identification and treatment of severe organ-based complications
Immunosuppressive
SYSTEMIC SCLEROSIS
Overlap SSc
Manage according to severity and activity of overlap features – arthritis, myositis, lupus
Management of common morbidity
Raynaud’s, upper GI, anorectal disease, erectile dysfunction, calcinosis, telangiectasia
Therapy of major
Organ-based complications
lcSSc
Denton et al, Rheumatology 2016;55:

9. Overview of major SSc complications
Digital vasculopathy
Gastrointestinal
Lung fibrosis
Pulmonary hypertension
UIP
NSIP
Figure 4. Overview of major SSc complications
Clinical and pathological or radiological features of the key organ based complications of systemic sclerosis are shown on this figure including GI involvement, lung fibrosis, pulmonary arterial hypertension, cardiac fibrosis, myositis, calcinosis and severe digital ischaemia. Lung fibrosis may have a UIP pattern or more often NSIP. Pulmonary hypertension may be identified by enlargement of the pulmonary arterial trunk relative to the aorta and if lung fibrosis is absent is more likely to reflect PAH. Digital vasculopathy may lead to ulceration, gangrene and amputation in severe cases. Specific complications shown include digital ulceration (a), dry gangrene (b), auto amputation (c) intestinal pseudo-obstruction (d), gastric antral vascular ectasia (e), lung fibrosis with a UIP (f) or NSIP (g) appearance on HRCT, pulmonary arterial hypertension shown histologically (h) or on CT (i), cardiac fibrosis (j), scleroderma renal crisis (k), digital contractures (l), calcinosis (m) and acro-osteolysis (n). These individual complications are described in the text.
Cardiac
Renal
Musculoskeletal
Calcinosis
Acro-osteolysis
Denton and Khanna, Lancet 2017, 390:

10. Improving survival in systemic sclerosis: a historical perspective
lcSSc 12 24 36 48 60 50 70 80 90
100
93%
91%
P=0.534
Disease duration (months)
Survival (%)
Disease onset
n=234
n=286
84%
69%
P=0.018
dcSSc
Nihtyanova et al, QJM 2010; 103:109-15

11. Pro-active screening for cardiorespiratory complications uncovers increased burden of systemic sclerosis and permits earlier intervention
Nihtyanova et al, QJM 2010; 103:109-15

12. Screening for internal organ involvement in Systemic sclerosis
Baseline and regular follow-up assessment to be considered yearly for systemic sclerosis patients
Pulmonary hypertension
Echo with Doppler every year
PFT/DLCO yearly
DETECT algorithm if eligible
RHC to confirm PAH if suspected
Lung fibrosis
Gastro-intestinal and nutrition
PFT with DLCO at baseline and every 4-6 months during first 3 years
Consider HRCT of lungs
Screening for internal organ involvement in Systemic sclerosis
Symptom based investigations such as barium swallow, gastric emptying study and breath test
Figure 3. Investigation strategy for systemic sclerosis
Systematic investigation of newly diagnosed cases of SSc and during regular follow up is important to identify significant complications that may require management. This systematic approach allows proactive management and has been associated with improved overall survival in recently described cohorts of SSc.
Renal
Cardiac
For anti-RNA pol III or early diffuse SSc
BP monitoring 3 times a week
Prednisone > 15 mg/day with caution
Estimated creatinine clearance and urinalysis at regular interval
Echo with Doppler every year
ECG
Troponin/BNP
CMR if high risk
Denton and Khanna, Lancet 2017, 390:

13. Part A: General approach to SSc management
Early recognition and diagnosis of dcSSc is a priority with referral to a specialist SSc centre (III, C)
Patients with early dcSSc should be offered immunosuppression: MTX, MMF or intravenous cyclophosphamide (CYC) (III/C). D-penicillamine is not recommended (IIa/C)
Autologous haemopoietic stem cell transplant (HSCT) may be considered in some cases particularly where there is risk of severe organ involvement, balancing concerns about treatment toxicity (IIa/C)
Skin involvement may be treated with either MTX (II,B) or MMF (III,C). Other options include CYC (III,C), oral steroid therapy (in as low a dose and with close monitoring of renal function; III,C) and possibly rituximab (III,C)
Azathioprine or MMF should be considered after CYC to maintain improvement in skin sclerosis and/or lung function (III,C).

14. Part B. Key therapies and treatment of organ based disease
Raynaud’s phenomenon (RP) and digital ulcers (DU)
Lung fibrosis
Pulmonary hypertension
Gut disease
Renal complications
Cardiac disease
Skin manifestations
Calcinosis in SSc
Musculoskeletal manifestations
Autologous haematopoietic stem cell transplantation (HSCT)

15. Recommendations for Raynaud’s phenomenon in systemic sclerosis
Although there is no evidence base to support ‘general measures’, most clinicians believe that patient education, specifically general/lifestyle measures including keeping warm, the avoidance of cold ambient environments and smoking cessation, are key aspects of management. Final consensus: 100%.
First line treatments are calcium channel blockers (Ia,A) and angiotensin II receptor antagonists (Ib,C) Final consensus 100%.
Other treatments that may be considered if these are either ineffective or not tolerated are: selective serotonin reuptake inhibitors, alpha-blockers and statin therapy (III,C) Final consensus 100%.
Phosphodiesterase-type 5 (PDE-5) inhibitors are being used increasingly for SSc-related RP (IIa,C). Intravenous prostanoid (e.g. iloprost) (Ia,B) and digital (palmar) sympathectomy (+/- botulinum toxin injection) should be considered in severe and/or refractory cases (III,D) Final consensus 100%.

16. Treatment and prevention of digital vascular disease in SSc
Parenteral prostacyclin
Bosentan
PDE5 inhibitors
Angiotensin axis
(ACEi) ARB
Statin
Antithrombotic therapy
Clopidogrel, aspirin
LMW heparin
Surgical approaches
Radical microarteriolysis
Botulinum toxin injection
Raynaud’s therapy
Oral vasodilators, SSRI
Topical GTN microemulsion,
Lessons from pulmonary hypertension

17. NHS England policy for DU in SSc*
Sildenafil
Prostenoids (iloprost)
Bosentan access for severe cases
Severe refractory disease: persistent or progressive ulceration of one or more digits causing or threatening tissue loss despite optimal treatment with vasodilators including IV prostanoids and oral sildenafil, or
Multiple DUs: 3 or more DUs either currently or occurring in the last 12 months despite IV prostanoids and sildenafil.
Challenging process (18 months) with reduced access during development compared with previous arrangements (IFR)
*First published: January 2015
Prepared by NHS England Specialised Services Clinical Reference Group for Specialised Rheumatology
Published by NHS England, in electronic format only.

18. Pulmonary hypertension in systemic sclerosis
10-year incidence of pulmonary hypertension in RFH cohort
PAH-SSc
(mPAP > 25 mm Hg; PAWP ≤ 15 mm Hg, no major PF)
All pulmonary hypertension (PH-SSc) (mPAP > 25 mm Hg)
Figure 1. Cumulative frequency of pulmonary hypertension (PH-SSc) and pulmonary arterial hypertension (PAH-SSc) in an actively screened systemic sclerosis cohort
In this cohort of systemic sclerosis (SSc) patients undergoing routine annual screening cases were referred for diagnostic right heart catherization (RHC) based on standard screening thresholds or clinical suspicion of PH. Approximately 1-2% of cases per year of long term follow up develop PH (A). The majority of these cases are PAH-SSc, with this classification being more frequent in cases of lcSSc (B).
Nihtyanova, Denton et al Arthritis Rheumatol 2014 ;66:

19. Licensed targeted therapies for PAH in systemic sclerosis
Endothelin receptor antagonists
Nitric oxide pathway stimulants
Prostacyclin analogues
i.v., s.c., inh.
p.o.
p.o.
Bosentan* (approved 2001)
Ambrisentan
Sitaxentan (withdrawn)
Macitentan (approved 2013)
Sildenafil (approved 2005)
Tadalafil
Riociguat – guanylate cyclase agonist (approved 2013)
Epoprostenol
Treprostinil
Iloprost
Selexipag (approved 2015)
Beraprost NO
cGMP
Mechanism
ET1
PGI2

20. Improved survival for scleroderma associated pulmonary arterial hypertension
Retrospective cohort analysis of the RFH PAH-SSc registry
Long term morbidity-mortality benefit from combination PAH therapy
N Engl J Med 2013
Eur Respir J 2014
ARD 2015
n = 1156
29% CTD-PAH
33% baseline ERA plus PDE5i
Selexipag
Placebo
Sitbon et al, N Engl J Med. 2015
P<0.001
Hazard ratio
Macitentan
Ambrisentan + Tadalafil
100 80 60 40 20 12 24 36 48
Time (months)
Survival (%)
Conventional therapy
bosentan
PAH-SSc
n=45
n=47
81%
68%
74%
47%
p = 0.016
Bosentan – non-selective endothelin receptor antagonist
Approved in 2001
Supportive therapy and intravenous prostacyclin for severe disease
Williams MH, et al. Heart 2006; 92:

21. Recommendation for autologous haematopoietic stem cell transplantation in systemic sclerosis:
Current evidence support the use of HSCT in poor prognosis diffuse SSc that does not have severe internal organ manifestations that render the treatment highly toxic (Ib, B) Final consensus 80%.
Definitive statements regarding relative safety and efficacy compared with other immunosuppressive strategies and definition of appropriate cases for HSCT will require further data (III,C) Final consensus 90%.

22. Part C. Service organization and delivery within NHS
SSc must be managed within an integrated system of primary, secondary and tertiary level care.
In secondary care it is important to have a specialised multi-disciplinary team
Care should be delivered as close to a patient’s home as possible but include the essential level of SSc expertise.
Education, clinical nurse specialist-led clinic for rapid access and availability of telephone helplines form part of a recommended template for high quality SSc care.
Additional support should also be offered through liaison with patient-based organisations such as Scleroderma and Raynaud’s UK.

23. Organisation of 21st Century Scleroderma Care – an integrated multi-specialist network
Stakeholders
Patient organisations
SRUK
FESCA
NHS England
Specialist Rheumatology CRG
UKSSG
EUSTAR
SCTC
WSF
BSR
AR UK
Industry partners
National Pulmonary Hypertension Centre
Patient flows
Primary care
Rheumatologist
Dermatologist
Physicain
Medical specialist
Cardiology
Pulmonology
UK Specialist Scleroderma Centre
shared care model
Gastro-enterology
Nephrology
Haemato-oncology
Dermatology
Surgery
Plastic
Orthopaedics GI
Multi disciplinary clinical service
Research
Biobank
Training
Basic science
Trials
Clinical projects, outcomes and processes

24. Many thanks to …. Our patients The “Scleroderma team” at Royal Free
Research Funders
Colleagues in many institutions and organisations
UKSSG colleagues
International collaborators – EUSTAR, WSF, SCTC and FESCA
Arthritis Research Campaign (UK), Raynaud’s and Scleroderma Association (UK), Wellcome Trust (UK), Nuffield Foundation (UK), Scleroderma Society (UK), Rosetrees Trust, Scleroderma Research Foundation (USA), MRC, EULAR, Royal Free Charity