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Latest Advances in Connective Tissue Disorders: Scleroderma

Latest Advances in Connective Tissue Disorders

Simon Bowman, PhD, FRCP, Vijay Rao, MRCP

Ther Adv Musculoskel Dis. 2013;5(4):234-249.


The principle abnormality in scleroderma is of skin and internal organ thickening (fibrosis). The spectrum of the disorder ranges from more localized disease such as the CREST syndrome (Calcinosis, Raynaud's, oEsophageal dysfunction, Sclerodactyly, Telangiectasia) to widespread skin and internal organ fibrosis. The more serious and potentially life-shortening complications of the disease are pulmonary arterial hypertension (PAH), interstitial lung disease (ILD) and kidney involvement. There are no specific therapies for the disease in general but over the past few years there have been significant improvements in the overall management of each of these more serious components.

Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a major cause of death in scleroderma. Prior to specific therapies the 5-year survival rate of patients with scleroderma and PAH was 10% compared with 80% for patients without PAH [Fischer et al. 2012]. It is now over 10 years since the key studies of bosentan, an endothelin receptor antagonist, demonstrated improvement in haemodynamic parameters and symptoms in PAH [Rubin et al. 2002]. Among the FDA-approved therapies it is recommended that calcium channel blockade, bosentan, ambrisentan, sildanefil and tadalafil are used for less severely ill patients while intravenous iloprost, teprostinil and epoprostenol are used for more severely affected patients [Walker and Pope, 2011, 2012].

One key advance in the management of this condition has been the introduction of regular annual or alternate year [in low-risk patients with stable disease >10 years with no dyspnoea, a carbon monoxide diffusing capacity (DLCO) > 70% and a forced vital capacity % (FVC%):DLCO% ratio <1.6] screening with echocardiography and lung function tests to identify early asymptomatic PAH [Pope et al. 2012]. A disproportionate fall in the DLCO, particularly to less than 50% or a FVC%:DLCO% ratio of over 1.6 is suggestive of PAH rather than ILD. Echocardiographic estimation of pulmonary systolic arterial pressure of over 35–45 mmHg is another indicator of potential PAH requiring confirmation by right heart catheterization.

The DETECT study (,%20D3%2013%2010%2008%20(5-column).pdf) is currently ongoing to further evaluate screening for PAH in scleroderma. Brain natriuretic peptide (BNP) or N-terminal BNP are being studied for their potential as screening tools for PAH but are not sensitive enough for routine clinical use yet [Cavagna et al. 2010; Chung et al. 2010]. Riociguat, a soluble guanylate cyclase stimulator is a potential therapy of interest in PAH [Schermuly et al. 2011].

Interstitial Lung Disease

ILD is another major cause of mortality. There have been two randomized controlled trials of cyclophosphamide in the treatment of scleroderma-associated ILD [Hoyles et al. 2006; Tashkin et al. 2006]. Tashkin and colleagues evaluated 145 patients with scleroderma and ILD in the USA, randomized to either oral cyclophosphamide up to 2 mg/kg/day or placebo. There was a statistically significant but small beneficial effect at 12 and 24 months in favour of cyclophosphamide on FVC of 2.53% (CI 0.28–4.79%) and some modest effect on symptoms and quality of life. A further study, Scleroderma Lung Study-2 (SLS-2), will compare cyclophosphamide with MMF over 2 years. The second trial [Hoyles et al. 2006] involved 45 patients in the UK who were randomized to receive either prednisolone and six infusions of cyclophosphamide at monthly intervals followed by maintenance therapy with azathioprine, or to receive placebo formulations of each of these. At 12 months there was no significant difference between the groups, although a trend towards improvement in FVC (p = 0.08) and six withdrawals in the placebo group compared with three in the active group. Nevertheless, these trials do not suggest major benefit for a potentially toxic therapy. A meta-analysis of 69 patients in the literature who received MMF demonstrated similar results [Tzouvelekis et al. 2012].

In the absence of highly effective therapy one recent approach has been to try and stratify patients with more extensive disease for whom intensive therapy might be more likely to be worthwhile [Goh et al. 2008]. Goh and colleagues reviewed a cohort of 215 patients with scleroderma ILD for whom high-resolution computed tomography (HRCT) and pulmonary function tests (PFT) data were available. A total of 75 (35%) died. An HRCT with over 20% lung involvement by ILD (ground glass or reticulation) was identified as a threshold for increased mortality. Patients with lung disease of less than 20% were classified as having limited ILD with a better prognosis and those with over 20% as having extensive ILD with a worse prognosis. In those patients whose HRCT could not be clearly classified in this way, the FVC was utilized such that those with an FVC of at least 70% were classified into the limited ILD group and those with an FVC less than 70% were classified as having more extensive disease. The logic of this approach is that systemic sclerosis (SSc)-associated ILD often corresponds to nonspecific interstitial pneumonia (inflammation > fibrosis) rather than the usual interstitial pneumonia (fibrosis > inflammation) in the majority of cases [Mouthon et al. 2007] and therefore individuals with more extensive ILD would receive cyclophosphamide therapy whereas MMF therapy may be more appropriate for patients with limited scleroderma-related ILD. Although they are only present in a small number of patients (around 3%) the presence of antibodies against the U11/U12 RNP complex may indicate ILD in patients with scleroderma [Fertig et al. 2009].

It is also important to remember simple treatable contributors to lung pathology, such as reflux disease as well as optimizing other general health issues such as good nutrition [Baron et al. 2009] and treating causes of iron deficiency anaemia, for example due to gastric antral vascular ectasia [Ingraham et al. 2010]. Development of a cough can be due to dryness (secondary Sjögren's syndrome), fibrosis, laryngeal or gastro-oesophageal reflux or more serious general pathology (e.g. lung cancer) [Colaci et al. 2013].

Renal Crisis

Scleroderma renal crisis describes the development of new and severe hypertension in association with renal failure in patients with scleroderma. It is usually but not exclusively associated with diffuse disease and patients with anti-RNA polymerase antibodies [Denton et al. 2009; Khanna and Denton, 2010]. Prior to the introduction of ACE inhibition the outcome was poor. Even so, the renal outcome is variable with the best outlook occurring if it is treated early and aggressively [Batal et al. 2009, 2010]. Management involves strict monitoring, tight control of blood pressure, inpatient management with intravenous prostacyclin in the event of microangiopathic haemolytic anaemia or hypertensive retinopathy.

Digital Ulceration and Raynaud's

Severe Raynaud's phenomenon, particularly with digital ulceration, is a major clinical problem in SSc. Calcium channel blockers are typically used as effective first-line medical therapy. ACE inhibition was commonly used second line until clinical trials demonstrated that although this may be effective therapy in scleroderma renal crisis it has little or no benefit in preventing digital ulceration [Gliddon et al. 2007]. α Blockers, angiotensin receptor inhibitors (e.g. losartan), serotonin uptake inhibitors (fluoxetine), moxisylyte and other oral therapies may be worth trying in particular patients [Henness and Wigley, 2007; Stewart and Morling, 2012]. Patients who fail to respond to oral therapy have traditionally been treated with 3–5-day or longer courses of iloprost [Henness and Wigley, 2007; Walker and Pope, 2011]. Sildenafil has also shown to have potential benefit in small studies [Brueckner et al. 2010]. Two randomized controlled trials have demonstrated that bosentan reduces the development of new ulcers, although it does not speed healing of existing ulcers [Korn et al. 2004; Matucci-Cerinic et al. 2011].