Systemic sclerosis (SSc) is a rare, complex, multiorgan autoimmune disease characterized by fibrosis of the skin and internal organs. It is heterogeneous, usually affecting young to middle-aged women with a chronic, progressive course. Compared with patients with other rheumatic and pulmonary diseases, patients with SSc often require significantly more health care resources, including physician and staff time, to monitor and manage multiple organ system disorders.1 The costs of providing care across a wide range of provider services for an uncurable, chronic, progressive disease are burdensome and largely unsustainable from a reimbursement perspective, according to a new set of guidelines for SSc patient care by Saketoo et al, published in Best Practice & Research Clinical Rheumatology.1 Prepared by a global multidisciplinary committee of SSc specialists, this framework examines the practices that help to optimize treatment.

Disease Course

Systemic sclerosis is categorized as either having a limited cutaneous or diffuse cutaneous presentation, defined in this SSc framework for therapy as “descriptors of skin thickness distribution only and provide crude sub-typing of an extremely complex disease. Both forms are associated with significantly increased risks [for] death.” While skin fibrosis and gastrointestinal dysfunction are primary symptoms in the majority of patients, interstitial lung disease (ILD) is both common and the most serious complication, normally developing early in the disease course.1

Mortality among patients with SSc is increased by approximately 3 to 5 times.2 Estimates show that more than half of patients with SSc die as a direct result of their disease, most frequently caused by pulmonary fibrosis due to ILD, followed by pulmonary hypertension, and scleroderma renal crisis (SRC).1,3 Although multiorgan involvement frequently develops early, it may be difficult to detect. Inflammation is an underlying mechanism in organ damage, producing irreversible fibrosis in the end stages. The report claimed that these signs of significant vascular injury and dysfunction and full-blown Raynaud phenomenon (RP), without overt evidence of inflammatory infiltration, are present for several years before other symptoms develop.


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Raynaud Phenomenon

The high degree of microvascular reactivity in patients with SSc frequently manifests as Raynaud phenomenon years earlier.2,3 As many as 95% of patients later diagnosed with SSc have a history of Raynaud phenomenon.4 About half of patients with SSc with Raynaud phenomenon may develop serious complications such as digital ulcers, pits, or gangrene, which require aggressive treatment to maintain tissue integrity.5

Capillary Signs

Nailfold irregularities reflecting the vasculature struggling against the pathologic progression of the disease appear early in the course of SSc and are considered predictive of the disease. Patients with RP are known to develop connective tissue disease, which is preceded by the presence of abnormal capillaroscopy. Nailfold patterns contribute more than 20% toward SSc classification criteria.1 The framework authors recommend that a handheld or other capillaroscopic device is an important rheumatologic tool for earliest detection.1

During early active stages of SSc, the capillaries dilate, forming giant loops and microhemorrhages that expand outside of the damaged blood vessels. The capillary pattern evolves in later stages to show “drop-out” rarefaction of the capillary network, which may be obscured by edema of the fingers. In late SSc, marked rarefaction of the nailfold is evidence of the ineffective struggle of the vasculature to self-repair.1 The result is a network of weak and damaged blood vessels that fail to support the tissues of the skin and gastrointestinal tract. Further capillary damage can produce serious, potentially lethal cardiac complications and pulmonary hypertension, and may be indicated by other signs such as digital ulcers, telangiectasias, and osseous vascular complications.

Delays in Treatment are Crucial

Data show that delayed treatment is common in SSc.1 Identification of these underlying signs offers an opportunity for improved therapeutic outcomes with earlier diagnosis, whereby many SSc-related vascular, cardiac, gastrointestinal, nutritional, and musculoskeletal complications can be treated and even prevented. The symptom burden and the extent of impairment directly correlate to the degree of inflammation and/or fibrosis.

Therapeutic Goals

No current therapy exists to halt disease progression or existing disability. Therefore, treatment must focus on monitoring early signs and early intervention to delay progression. “Preventing death and permanent disability in SSc is accomplished with early and appropriate treatment,” the authors wrote, noting that a major obstacle is posed by the challenges to positively differentiating between earlier states of active progressive disease and the later transformation to fibrotic damage. At this point, they suggest, the spread of inflammation is still potentially reversible, but treatment must be of sufficient intensity to “quell” inflammation and other immune mechanisms involved.

A second challenge the authors described is that “[i]n any SSc phenotype, opportunities for early treatment are prone to be under-utilized, especially in slowly progressive phenotypes that, in contrast to severe progressive ILD, indolently accrue irreversible organ damage resulting in later-stage life-limiting complications such as pulmonary hypertension, cardiac involvement, and malnutrition.”1

The heterogeneity of the presentations of SSc makes it difficult to diagnose early in the disease course, as needed. Recent research has focused a great deal of attention on the development of biomarkers, with quite a few candidates identified. The therapeutic framework proposed by Saketoo et al points to specific antibodies that can be used to predict outcomes, including anti-centromere for predicting PAH, Scl-70 for predicting ILD, and RNA polymerase III for predicting renal crisis.1 Other factors such as male sex, early diffuse cutaneous disease, or the presence of tendon friction rubs predict higher mortality rates. Black patients with SSc are at higher risk for more rapid progression, greater mortality, a younger age of onset, and higher risk for early associated ILD and pulmonary hypertension, which may be due to differences in genetic profiles compared with White patients. Patients of Hispanic and Asian descent experience a greater severity of disease compared with White patients. Physical function and levels of activity are also key predictors of HRQoL and survival, they note.

The new framework recommends a comprehensive and interactional approach between providers of multiple disciplines in order to optimally manage the disease over time.1 The authors concluded, “Sharing care between recognised SSc centers and local cardiology/pulmonary/rheumatology/gastroenterology colleagues may prevent complications and poor outcomes, while providing support to local specialists.“

References

1. Saketkoo LA, Frech T, Varjú C, et al. A comprehensive framework for navigating patient care in systemic sclerosis: A global response to the need for improving the practice of diagnostic and preventive strategies in SSc. Best Pract Res Clin Rheumatol. Published online September 15, 2021. doi:10.1016/j.berh.2021.101707

2. Yanaba K. Strategy for treatment of fibrosis in systemic sclerosis: Present and future. J Dermatol. 2016;43:46-55. doi:10.1111/1346-8138.13026.

3. Denton CP. Advances in pathogenesis and treatment of systemic sclerosis. Clin Med (Lond). 2016;16:55-60. doi:10.7861/clinmedicine.16-1-55.

4. Cossu M, Beretta L, Mosterman P, de Hair MJH, Radstake TRDJ. Unmet Needs in Systemic Sclerosis Understanding and Treatment: the Knowledge Gaps from a Scientist’s, Clinician’s, and Patient’s Perspective. Clin Rev Allergy Immunol. 2018;55:312-331. doi:10.1007/s12016-017-8636-1.

5. McMahan ZH, Volkmann ER. An update on the pharmacotherapeutic options and treatment strategies for systemic sclerosis. Expert Opin Pharmacother. 2020;21:2041-2056. doi:10.1080/14656566.2020.1793960.