Introduction:
Systemic sclerosis (SSc) or scleroderma is a rare connective tissue disorder with unknown pathogenesis. Complex interactions between genetic and environmental factors, however, are believed to trigger its development.
Pathophysiology:
Although the exact cause remains unknown, SSc is characterized by the following pathogenic triad:
- vasculopathy,
- inflammation, and
- fibrosis.
Thus, SSc is an autoimmune, progressive, generalized disorder that damages small blood vessels, leads to abnormal immune reactions, and results in fibrosis of the skin and organs (eg, lungs, heart, and the digestive tract).
Fibrosis is the excessive deposition of fibrous tissues and extracellular matrix in an organ in response to an injury, and it is being increasingly recognized as a key cause of organ-specific morbidity (subsequently leading to organ failure) and mortality. Although the precise molecular mechanisms governing fibrosis are unclear, our understanding of the process has greatly evolved in recent years.
This blog sheds some light on the different aspects of SSc with a focus on current and emerging therapeutic options.
Types of SSc:
The following are the various types of SSc based on skin involvement:
- Diffuse cutaneous SSc (dcSSc): is associated with skin thickening that may involve skin proximal to the elbows and knees, face, and/or trunk and rapidly becomes generalized.
- Limited cutaneous SSc (lcSSc): Formerly known as the CREST syndrome this condition is associated with limited skin involvement like skin thickening distal to the elbows and knees and/or face. No trunk involvement is observed in this type of SSc.
- Limited SSc or SSc sine scleroderma (ssSSc): In this condition, patients do not demonstrate any skin involvement but experience Raynaud’s phenomenon and are at risk of organ involvement.
Both lcSSc and dcSSc are associated with several systemic manifestations and the presence of autoantibodies.
Epidemiology:
The global prevalence of SSc is approximately 1 in 5,500 persons. Women are predominantly affected by it, with the male-female ratio being around 1:4–1:5.
Clinical features:
SSc may affect multiple systems and cause different conditions.
Raynaud’s phenomenon:
It is often the first sign of SSc. In Raynaud’s phenomenon, smaller arteries supplying blood to especially the fingers and toes constrict excessively in response to cold, stress, or illness, thereby limiting blood supply to the affected area and resulting in gangrene in severe cases. Repeat occurrences of Raynaud’s phenomenon may contribute to vascular disease in systemic sclerosis through a mechanism of reperfusion injury of the endothelium, and may contribute to tissue fibrosis. The other signs of SSc usually appear a few months later in dcSSc and some years later in lcSSc.
Skin:
• Bilateral and symmetrical skin lesions
• Calcinosis cutis (calcium deposits in skin and subcutaneous tissue)
• Lack of facial expressions
• Thinning of nose and lips
• Limited ability to open the mouth
• Sclerodactyly (skin damage on fingers)
• Small, curled, or disappeared nails
• Telangiectasias (Small, widened blood vessels on the skin or spider veins)
• Pigmentation disorders
Gastrointestinal system:
- Esophageal dysfunction/dysmotility: Difficult esophageal movement is common and provokes gastroesophageal reflux and sometimes difficulty in swallowing (dysphagia)
- Bacterial overgrowth in the small intestine
- Nutritional deficiencies
- Fecal incontinence
- Rectal prolapse
Lungs:
Life-threatening complications can occur such as pulmonary fibrosis and, less frequently, pulmonary arterial hypertension Heart, kidneys, eyes, and the musculoskeletal system can also be affected by SSc and lead to specific clinical features.
It is suggested that around 45% of deaths in the Western world are attributed to a fibrosis component, which means that fibrosis is currently a significant unmet need. In particular, SSc has no therapies targeting the fibrosis; however, recent discoveries are shedding light on the mechanisms that underlie the disease process.
Diagnosis:
Diagnosis is based on typical clinical manifestations and on the evidence of specific microangiopathy.
Blood tests show typical antinuclear autoantibodies.
Antinuclear antibodies (ANA) may be present in more than 90% of SSc cases, and at least one of the more specific autoantibodies (anti-centromere, anti-SCL70, and anti-RNA polymerase III) is present in up to 70% of the cases.
The extent of the disease may be evaluated using:
- computed tomography (CT),
- electrocardiogram (ECG),
- echocardiography,
- radiography (X-ray) of the hands, or
- esophageal and gastric fibroscopy.
Management:
Currently, the approved treatment options are limited and targeted at disease manifestations affecting specific organs (eg, to slow the rate of decline in pulmonary function). A single drug capable of protecting multiple organs/systems is unavailable. Drugs that can slow the overall SSc progression across multiple target organs/systems and can be used to treat a patient, not an organ, are needed.
Thus, SSc management remains challenging.
Different guidelines describing the overall treatment strategies for patients with SSc or specific strategies for the management of organ manifestations are available. These treatment algorithms are often used in the management of patients with SSc.
- Raynaud’s phenomenon is treated with a combination of lifestyle modification and calcium channel blockers.
- Proton pump inhibitors are used for the treatment of gastric reflux.
- Low doses of corticosteroids with immunosuppressive agents are indicated in cases with recent and severe cutaneous involvement or in progressive lung fibrosis.
- Pulmonary vasodilators are given in the case of pulmonary arterial hypertension. Patients require regular clinical follow-ups with early pulmonary function tests and echocardiography.
- Typically, the first-line therapy for patients with early progressive cutaneous disease is methotrexate.
- Patients with concomitant myositis are treated with methotrexate or intravenous immunoglobulin (IVIg). For patients with both cutaneous findings and interstitial lung disease, studies have suggested the efficacy of mycophenolate mofetil or rituximab.
- In patients with disease refractory to first-line treatments, second-line therapies include:
- UVA-1 phototherapy,
- IVIg, or
- Rituximab.
- Telangiectasia may be managed with camouflage techniques, pulse dye laser, and intense pulse light.
- Calcinosis cutis therapy is guided by the size of the calcium deposits, with limited treatment options.
- Mouth augmentation and oral stretching exercises are recommended for patients with reduced oral aperture.
- Most patients with SSc benefit from a gentle skincare regimen to alleviate pruritis, which is a commonly reported symptom.
Prognosis:
The prognosis depends on the type of SSc affecting patients:
- lcSSc has relatively good prognosis with a10-year survival rate of 80-90%. However, pulmonary arterial hypertension, which occurs in about 10% of the cases, and severe lung fibrosis may lead to a more severe prognosis.
- dcSSc is more severe with a 10-year survival rate of 60-80% because of the higher risk of life-threatening complications like renal crisis, severe digestive involvement, severe lung fibrosis, and, sometimes, severe heart involvement and pulmonary arterial hypertension.
Newer promising therapies:
- Clinical trials investigating the utility of emerging therapies such as abatacept and tocilizumab in the treatment of SSc are underway and preliminary results are promising.
- Nintedanib was found to significantly reduce the rate of fall in forced vital capacity (FVC) associated with SSc, but no benefits to skin fibrosis were noted.
- The new cannabinoid receptor2 agonist lenabasum has shown efficacy and safety in a phase II trial. However, the results of phase III trial did not demonstrate efficacy for lenabasum in subjects with dcSSc who were receiving standard treatments including substantial immunosuppressive therapies.
- The efficacy and safety of brodalumab were evaluated in patients with SSc having moderate to severe skin thickening. It demonstrated significant improvement in the modified Rodnan total skin thickness score at week 24 and improvement in skin sclerosis was sustained till 52 weeks.
- Other drugs are currently being tested in clinical trials even though targeted therapies have not been approved for fibrosis in SSc.
Conclusion:
Overall, SSc is a clinically heterogenous autoimmune disease affecting multiple organ systems. Therefore, healthcare professionals should regularly assess for extracutaneous involvement and use evidence-based recommendations to select the most appropriate therapy for patients with SSc. Moreover, there is a need to move from organ-centric treatment to patient-centric treatment.
Our services:
The expert medical team at Bioviser provided complete support on the publication analysis and publication planning for a large global pharmaceutical company. We conducted an in-depth literature review, screened more than 5,000 relevant published articles, and synthesized the results to complete the publication analysis focused on SSc. We also provided tactical recommendations for future publications.
