Sunday 30 April 2017

Emerging Strategies for the Treatment of Systemic Sclerosis. Journal of Scleroderma and Related Disorders Volume 1 Number 2 May - August 2016.

Emerging Strategies for the Treatment of Systemic Sclerosis.

Journal of Scleroderma and Related Disorders.

Volume 1 Number 2 May - August 2016.

Emerging Strategies for the Treatment of Systemic Sclerosis.

Journal of Scleroderma and Related Disorders.

Volume 1 Number 2 May - August 2016.

Living with a chronic, progressive, degenerative disease, to which there is currently no cure, makes you discover inner strength which you did not know you had. 

As Bob Marley sang ‘You do not know how strong you are, until you have to be’.

Not only does a scleroderma diagnosis bring along a multitude of debilitating life hijacking symptoms, this is combined with the current reality that there is no cure available or known.

Pharmaceutical agents used for treating scleroderma target symptom suppression as opposed to treating or acting on the underlying cause.

Which, also, currently remains a mystery on the scleroderma, systemic sclerosis pathway.


I wrote about the importance of research and its role for the scleroderma patient and the rare disease patient, Click here

In essence, in my view, an investment in global medical research is essential for the scleroderma patient.

The time it takes for newer biologic innovative medicines to reach the market place needs to be reduced.

As does, the time taken to access innovative medicines shown to have an improvement in disease progression and severity.

Time is a luxury for the scleroderma patient and for all rare disease patients. Medical research is making improvements, but patients are quite literally “dying for a cure.”

I am grateful that I am still around to be a scleroderma patient in the hope that investment and commitment to accelerate medical research, will instigate a light bulb moment needed for a ‘scleroderma free world’.


During Scleroderma Awareness month June 2016, the UK published national guidelines for the treatment and management of scleroderma. Click  here

The paper ‘Emerging strategies for treatment of Systemic Sclerosis’ was published within Volume 1 Number 2 May – August 2016, of the Journal of Scleroderma and Related Disorders  (JSRD)

The authors, Dr Dinesh Khanna, Dr Jorg Distler, Dr Peter Sandner and Dr Oliver Distler discuss the current medical understanding of the scleroderma disease process along with possible biologic pathways responsive to newer drug compounds and their mode of action.

Here is my brief synopsis, citing excerpts from the paper, ‘Emerging strategies for treatment of Systemic Sclerosis’:


Pathological features of SSc include microvascular damage, dysregulation of adaptive and innate immunity, and fibrosis that can involve the skin, heart, lungs, kidneys, gastrointestinal tract and other organs.

The rate of progression and extent of organ fibrosis are the primary determinants of clinical outcome…..

Currently, there are no treatments that modify the underlying cause(s) of SSc, in part because those causes are incompletely understood.

Thus, current therapies generally target disease complications, including organ involvement.

Early diagnosis of SSc, and assessment and treatment of organ involvement, are critical aspects of patient management because organ involvement is responsible for most of the complications and mortality in SSc…..

Furthermore, efforts to identify and validate circulating biomarkers to assess rate of progression and organ involvement are evolving rapidly.’

The Paper estimates a prevalence of 300-500 cases per million adults in the US, with another population-based sample in Canada consistent with his estimate, 443 cases per million.

This is thought to vary in the EU, 31-88cases per million in England, to 158, 154, and 277 cases per million in France, Greece and Spain respectively.

Higher incidence in women than men (ratios of 4.6 to 5.7:1).

There is also evidence for difference in prevalence across racial and ethnic groups, with rates slightly higher among blacks than whites, lower among people of Asian ancestry, and higher in some Native American groups.

Severity of disease and its course can also vary according to gender and ethnic background.

For example, black patients are more likely than white patients to have diffuse cutaneous disease, and black patients have a higher risk of mortality.

Even though the prevalence of SSc is lower in men than women, on average male patients with SSc have a worse prognosis and higher disease-specific mortality than female patients.

Emerging Treatment Strategies

'Identification of several key pathways in the SSc process have opened potential targets for therapies.

These pathways include vascular damage and immune activation, and, the fibrotic pathway.

The vascular damage can be seen by reductions in the number of capillaries and narrowing of the vessel lumen leading to impaired blood flow and starving the tissues of oxygen.

This produces inflammation and overactivation of immune cells, with less inflammation in later disease but persistent activation of the immune system.

RITUXIMAB acts on reducing the excessive circulating immune B cells.

A recent study reported that it had significantly reduced the modified mRSS compared with matched controls, these patients also showed a less decline in lung function.

Ongoing trials are exploring the efficacy and safety of rituximab in SSc associated polyarthritis (NCT01748084) and SSc-associated PAH (NCT01086540).

These trials will also provide information about anti-vasculopathic, anti-fibrotic, and immune modulatory effects of rituximab.

ABATACEPT acts on immune T cells deactivation.

A small study in patients with SSc-related refractory polyarthritis or myopathy found that abatacept significantly improved joint parameters, although there was no change in skin or lung fibrosis.

However in another study, abatacept was shown to have significant improvement on Mrss score.

These results suggest that it may be possible to identify a subset of dcSSc patients most likely to respond to abatacept.

A phase II multicenter international trial is underway to study abatacept in patients with dcSSc; the trial uses skin fibrosis as the primary endpoint (NCT02161406).


Evolving understanding of the SSc disease process indicates that vascular and immune activation initiate a fibrotic process that then becomes self-sustaining through several mechanisms.

Fibrosis may continue long after evidence of immune activity subsides in affected tissues.

Thus, many of the current efforts for developing therapies are focused on interfering with mechanism responsible for unregulated self-sustaining fibrosis.

Early studies have shown that skin fibroblasts isolated from patients with SSc continued to produce higher amounts of collagen and other extracellular matrix components compared to those fibroblasts from normal subjects.


(TGFβ) has been recognised as a central mediator of fibrotic signalling in SSc.

This makes it a natural target for potential antifibrotic therapies in SSc.

The human antibody metelimumab showed no evidence of a treatment effect, however, fresolimumab has shown a statistically significant decline in mRSs scores within a few weeks after administration of one or two doses.

A decline in the expression of the (TGFβ)-regulated genes thrombospondin-1 and cartilage oligomeric protein, as well as significant declines in the infiltration of myofibroblasts into the dermis.

This study was too small to effectively evaluate adverse effects, although several patients had bleeding episodes, and anaemia was common.

Soluble guanylate cyclase inhibitors such as Riociguat and BAY41-2272 are showing promising results with inhibiting skin fibrosis.

Riociguat is currently licensed for Pulmonary Arterial Hypertension with an ongoing phase II multicenter international trial of patients with dcSSc (NCT02283762) underway.

Interleukin-6 (IL-6) is produced by B cells, T cells, and fibroblasts, and it promotes inflammation and fibrosis.

Serum IL-6 levels are elevated in certain patients with SSc, particularly early dcSSc, and these levels have been suggested to correlate with progression of skin involvement, worsening lung fibrosis, and reduced long term survival.

However, where fibrosis is less inflammation dependent, an anti-IL-6 antibody was ineffective.

This finding may indicate that strategies targeting IL-6 may be most effective in patients with inflammatory SSc.

Tocilizumab is an antibody to the IL-6 receptor approved for the treatment of rheumatoid arthritis.

Treatment with tocilizumab showed significant improvement in joint parameters as well as improved outcomes with lung resolution.

No statistically significant change was seen in skin score. A phase III trial of tocilizumab in SSc is currently recruiting participants (NCT02453256).

Tyrosine kinase signalling pathways

In addition to (TGFβ), various other growth factors and cytokines are thought to be involved in promoting fibrosis on SSc, such as connective tissue growth factor (CTGF) and the platelet-derived growth factors (PDGFs).

Imatinib is a tyrosine kinase inhibitor (TKI) targeting PDGF, c-abl, c-kit, and has been shown to prevent fibrogenesis in the laboratory.

So far, the study results show Imatinib to trend toward increased lung capacity and improved skin score, making it a possible benefit in the SSc-ILD population at low doses due to its adverse event profile increasing with dose concentration.

Nilotinib is a TKI active against the PDGF receptor as well as c-Abl and other tyrosine kinases.

In a small study, skin scores were improved, as well as predictive markers of response were evidenced.

Higher baseline levels of expression of genes related to (TGFβ) or PDGF signalling were associated with response and expression of these genes declined during treatment.

Nilotinib was associated with abnormalities in liver function tests and QTc prolongation, the latter of which required discontinuation of treatment in two patients.

Dasatinib is another multi target TKI approved to treat chronic myelogenous leukemia, however, it showed a high serious adverse event profile in a small scleroderma patient study.

Nintedanib is a TKI-targeting fibroblast growth factor (FGF) receptor, PDGF receptor, and vascular endothelial growth factor (VEGF) receptor, as well as Src-family tyrosine kinases.

So far, studies are showing promising results with skin and lung fibrosis reduction.

A phase III trial of nintedanib with patients with SSc and ILD is ongoing (NCT02597933).

Pirfenidone is an anti-fibrotic agent with anti-inflammatory properties including inhibition of pro-inflammatory cytokines and inhibition of inflammatory cell proliferation. a controlled clinical trial in patients with SSc-ILD is planned, further to a safety and tolerability trial results showing dosing tolerability.

The peroxisome proliferator-activated receptor-γ (PPAR-γ) is a key suppressor of fibrosis.

A genome-wide association study provided evidence for a role of PPAR-γ in susceptibility to SSc and PPAR-γ is downregulated in patients with SSc.

However, caution is exercised as the use of PPAR-γ agonists increases cardiovascular event risk.

So far, the drug molecule IVA337 has not been associated with this adverse event and is the subject of an ongoing proof-of-concept phase II trial in patients with dcSSc (NCT02503644).

Lysophosphatidic acid (LPA) related ligands

Mouse models have shown that by blocking this receptor, fibrosis is reduced. Studies have shown the chemical compound SAR 100842 to reduce expression of fibrosis related genes in SSc skin fibroblasts, with patients treated with SAR100842 showing a decline in skin score.


Management of SSc still rests on the treatment of organ specific complications, and no disease-modifying therapies are yet available.

However, recent years have seen major advances in our understanding of the pathophysiologic processes responsible for the immunologic fibrotic mechanisms of disease.

This is complemented by development of better outcome measures and data driven approaches to assess for cohort enrichment. 

Concurrently, studies in large patient cohorts have yielded valuable insights into clinical and laboratory markers of disease activity and prognostic markers of progression, which should serve to identify clinically relevant disease subtypes to refine enrolment criteria for clinical trials.

Considered together, these advances hold great promise for the development of disease modifying therapies that will improve the well-being of patients with SSc, reduce or prevent complications of the disease and ultimately prolong survival.’

In the meantime, I know that I am fortunate to now be 13 years immunosuppressant and chemotherapy free.

I will continue to “Live the dream, Scleroderma Style,” with hope, remaining as my best friend and companion – I even have the T-shirt.

To read JSRD Volume 1 Number 1 Jan – April 2016, Click here


April 2017. 

To read my articles: 

Rare Disease Day 2018, Research - Taking Part in Clinical Trials, Click here   

March Autoimmune Disease Awareness Month 2018, Click here   

Global patient video, Click here   

Becoming a Patient Research Ambassador for the NIHR, 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   

Scleroderma Awareness Month 2017 Patient Profiles Campaign, Click here     
Scleroderma Awareness Month 2017 Patient Profiles Campaign Patient Index, Click here        
The Pandora’s Box of the rare autoimmune disease Scleroderma, Raynaud's and Cancer, Click here

Key Event Dates 2018, Click here     

Importance of an Early Diagnosis, Click here     

Taking Part in Clinical Research Trials, Click here   

The Importance of a Multi Disciplinary Medical ‘Dream Team’, Click here 

Expert Specialist Centres, Click here      

My Skin is Cured from Scleroderma, Click here      

UK Guidelines for Managing and Treating Scleroderma, Click here      

Fatigue, Click here      

Mobility, Click here    

Diet and nutrition, Click here     

Raynaud's, Click here  

World Scleroderma Day 29th June 2016, Click here

World Scleroderma Day 29th June 2017, Click here   

Why Global Collaboration is important to the Rare Disease Patient, Click here      

The theme to this years Rare Disease Day is Research

Rare Disease Day 2018 – Research, Taking Part in Clinical Trials. Scleroderma, Raynaud's, Autoimmune Rare Disease, Click here     

2016 Rare Disease Day Patient Voice
2016 Rare Disease UK Parliamentary Reception   

2017 Rare Disease Day Flashback  

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. 

I highlighted other areas of medical research interest within Week 3 of my Patient Profiles Campaign for Scleroderma Awareness Month 2017. 


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: 

Early Diagnosis
Expert Specialist Centres
Access to Innovative Medicines

Where MEDICAL RESEARCH investment is VITAL.

Research is the key. Abstracts from 2016 World Congress, Click here

Scleroderma Awareness Month Campaign 2016, Click here


View video, here   

Preamble - here

The Family Day at the Scleroderma Unit, The Royal Free Hospital is taking place on the 19th May 2018. Browse the program, here

This year, I am celebrating 20 years of being a patient at this world leading expert specialist research centre. 

Sept 2017

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.
I am truly humbled and inspired by their work ethic. 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 diagnosing doctor, that I was looking at a 15month prognosis. 

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.
For latest updates follow: 

Facebook Page:

Twitter: @SclerodermaRF  @RaynaudsRf  

#SclerodermaFreeWorld           #RaynaudsFreeWorld
#ADAM #Scleroderma

Living the dream, scleroderma style.  

Please DONATE to help fund medical research at The Scleroderma Unit,The Royal Free Hospital, London.  

100% of your monies will be used for medical research purposes only. No wages or admin costs. Thank You.


Last Update: April 2018 

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