Nature sub-journal: How to manage skin involvement in patients with systemic sclerosis?

*For medical professionals to read for reference only.
Tormenting but neglected skin involvement.
Diffuse systemic sclerosis (dcSSc) has a high mortality rate due to visceral involvement, so clinics are often keen to focus on identifying early visceral involvement and complications.
In terms of treatment, another major problem of dcSSc-skin involvement has been ignored in disease management
.

Most importantly, the progressive pain, thickening, and pruritus of skin involvement have a significant impact on the patient's quality of life, and to date, there is no fixed disease-modifying therapy
.

This situation happens to be the Achilles' heel of dcSSc management
.

How to deal with this weakness? Take a lesson from a study published in Nature Reviews
.

Figure 1.
Screenshot of the study [1] Characteristics of skin involvement in dcSSc Hardening of the fingers Often misdiagnosed as arthritis or carpal tunnel syndrome when patients experience swelling and pain in their hands, but the skin of the fingers of patients with dcSSc can change over several weeks hard, so that a differential diagnosis can be made with the above two diseases
.

■ Rapid progression In addition, dcSSc is characterized by rapid skin involvement that can progress to the vicinity of the elbows or knees, and even to the trunk
.

In contrast, in patients with localized SSc (lcSSc), skin involvement is limited to the extremities, that is, the distal ends of the elbows and knees, and the face and neck
.

■ Itching and pain During the inflammatory phase of early dcSSc, when skin involvement begins to progress, it usually presents with itching and pain, and changes in pigmentation may occur
.

Of all the symptoms, pruritus is usually the most troubling skin symptom in patients with early dcSSc, which disappears when the early inflammation subsides
.

■ At the same time of contracture, the skin may be tense and lead to contracture of nearby parts, especially the flexion deformity of the fingers (Fig.
2a).
The elbow and knee joints are also affected by this contracture, which reduces the range of motion of the patient's joints, such as shoulders, ankles, and talars.
Lower and middle tarsal joints,
etc.

■ Ulcers In addition, contractures can lead to refractory ulcers and can lead to osteomyelitis
.

In rare cases, small superficial ulcers develop due to skin tightness (Fig.
2b)
.

The severity of a patient's skin disease (assessed by the modified Rodnan skin score, or mRSS) typically plateaus within 3 to 5 years of onset, followed by gradual softening and shrinking of the skin, which may stop thickening for several years thereafter
.

However, contractures persisted and were usually irreversible (Fig.
2c)
.

 Figure 2.
Skin involvement in dcSScization: a.
Early finger flexion contracture; b.
Early superficial skin ulceration; c.
Late persistent contracture (Image copyright Northern Care Alliance NHS Foundation Trust) How should disease progression be quantified? Although it has long been recognized that cutaneous involvement in early dcSSc can be painful, disfiguring, and disabling, it is only in recent years that quantitative tools have begun to describe the involvement of these diseases
.

The European Scleroderma Observational Study (ESOS) [2] concluded from 326 patients with early dcSSc in 19 countries (mean disease duration from skin thickening, 11.
9 months) that the more skin thickening, the greater the disability ( especially hand disabilities), pain and fatigue, and thickened skin means increased disease
.

 ■ Definition of disease progression Skin involvement can be painful and somewhat disabling, and extensive skin involvement progression may point to a worse prognosis
.

Studies have shown that patients with high skin involvement scores have a reduced survival rate [3]
.

An analysis of data from the European Scleroderma Trials and Research Database (EUSTAR) showed that in patients with dcSSc, those who progressed with skin involvement had a lower survival rate than those who progressed without skin involvement, while those with less skin thickening had relatively improved survival [ 4]
.

Some investigators have found that a high "skin thickness progression rate" (mRSS at first visit divided by patient-reported duration of skin thickening) is a precursor to early mortality and scleroderma renal crisis [5]
.

Therefore, the accurate definition of disease progression and the development of tools to predict the trend of disease progression are of great significance for improving patient outcomes
.

 Accurate prediction of progressive cutaneous involvement could allow clinicians to more clearly intervene with immunosuppressive agents or hematopoietic stem cell transplantation (HSCT), especially since HSCT treatment has yielded a phased result with a significant reduction in associated mortality
.

 At the same time, the development of tools to define and predict disease progression will also benefit the design of relevant clinical trials
.

In the traditional definition, disease progression was "a 25% increase in mRSS score at 5 measurement sites within 22-24 days over a 12-month period"
.

 ■ Predictive factors In addition to this, there are also literatures that tendon friction and positive anti-RNA polymerase III antibody [5] are associated with the progression of skin involvement
.

Of note, some studies suggest that low mRSS, short disease duration, and joint synovitis are predictors of disease progression, while high baseline mRSS without tendon friction may also have some significance in predicting disease progression, as patients with mRSS > 22 Progressive skin involvement is unlikely [6]
.

 Instead of focusing on mRSS scores, some studies have begun to look at overall gene expression in patient skin and found that SSc patient skin does have a unique transcriptional profile
.

For example, some samples exhibited transcriptional profiles similar to healthy individuals, but also samples with distinct fibrotic and inflammatory features
.

In addition, these studies also found that the skin gene expression profile of patients with SSc changes over time and parallels the clinical progression of skin involvement [7-9]
.

Therefore, SSc skin gene expression signature is also expected to help predict the prognosis of dcSSc [10]
.

Existing studies have explored some genes as biomarkers, and it is believed that it will bring surprises over time [11]
.

However, apart from clinical predictors such as disease duration, baseline skin involvement score, and anti-RNA polymerase III antibody positivity status, the utility of skin gene expression profiling in predicting treatment response is currently unclear
.

 In addition to the conceptual definition, physicochemical and technical tools also play a role in assessing disease progression: non-invasive imaging methods such as high-frequency ultrasound and optical coherence tomography (OCT) have great potential for measuring skin thickness and skin collagen , and the durometer has also been revisited as a method of measuring skin hardness
.

■ Scoring With the iterative progress of the concept of diagnosis and treatment, scholars have found that the comprehensive scoring method also contains hope
.

A composite score incorporates multiple factors and may be more representative of disease status than a single indicator
.

There is currently no comprehensive scoring system specifically for skin involvement in patients with SSc
.

However, the American College of Rheumatology (ACR) Temporary Composite Response Index (CRIS) has been used in the evaluation of dcSSc patients in many studies [1].
ACR-CRIS includes five indicators: mRSS, predicted forced vital capacity ratio (FVC) , Health Assessment Questionnaire Disability Index (HAQ-DI), and Patient/Clinician Global Assessment Scale (PGA/PhGA)
.

What is the best current management model for dcSSc? Although there is no cure for SSc at present, the reality pushes clinicians to move forward.
The most important thing is to optimize disease management strategies, especially symptomatic treatment and immunosuppression for patients with progressive skin involvement.
therapy or HSCT therapy
.

In patients with skin thickening in early dcSSc, the optimal management model is shown in Figure 3
.

 Figure 3.
Optimal management model for patients with progressive skin involvement in early dcSSc [1] ■ Diagnosis of early dcSSc is often difficult to identify, leading to delayed diagnosis, which affects early treatment of visceral involvement and patient education and communication
.

This problem can be ameliorated by increasing physician awareness of dcSSc (especially increased sensitivity to skin thickening)
.

In addition, Raynaud's phenomenon often precedes a definitive diagnosis of SSc, so conventional wisdom holds that Raynaud's phenomenon is a characteristic symptom of dcSSc, but it is also important to keep in mind that Raynaud's phenomenon sometimes occurs after skin involvement has progressed, so Raynaud's phenomenon is used as a "signal" "Thoughts don't form mindsets
.

■ In terms of treatment measures, the management of early dcSSc skin involvement mainly focuses on four aspects: analgesia, antipruritic, physiotherapy and occupational therapy
.

In recent years, people have increasingly emphasized the significance of clinical psychology intervention
.

①Analgesia: Many early dcSSc patients with no pain sensation are prone to lack of adequate awareness of the pain symptoms caused by skin involvement, and patients must be made aware that disease contractures and ulcers can exacerbate pain, and this pain requires analgesic treatment
.

Such pain may have a neurogenic component, and treatment with pregabalin, gabapentin, or referral to a pain specialist may be considered
.

②Relieving itching: The symptomatic treatment of itching is full of challenges.
Conventional treatment can use antihistamines, but the effect is not good
.

Some patients have experienced that water emulsions containing menthol have a certain antipruritic effect, and there is also unproven experience that low-dose prednisolone can relieve itching
.

However, prednisolone is a risk factor for scleroderma renal crisis and should be used with caution
.

③Physiotherapy and occupational therapy: Although little research has focused on the value of physical therapy and occupational therapy in early dcSSc, these therapies may help maintain, preserve and maximize the patient's motor function, such as stretching, hydrotherapy, etc.
Unproven therapy
.

④Clinical psychological intervention: Some early dcSSc patients feel that they feel "overwhelmed" and "out of control" about their disease, and this feeling is related to pain and fatigue caused by skin involvement to some extent
.

Therefore, such patients may also consider seeking clinical psychotherapy
.

⑤ Immunosuppressive therapy: British Society of Rheumatology (BSR), British Association of Health Professionals in Rheumatology (BHPR) and EULAR all have relevant recommendations, that immunosuppressive therapy should be performed for SSc skin diseases [12-13]
.

The BSR/BHPR recommends mycophenolate mofetil (MMF), methotrexate, or cyclophosphamide, while the EULAR recommends methotrexate
.

⑥ Glucocorticoid therapy: Whether glucocorticoids should be used in patients with early dcSSc is still full of controversy [14]
.

Glucocorticoids may reduce skin-derived pruritus and pain in patients with early dcSSc, as some scholars believe that these symptoms are caused by skin inflammation
.

However, high-dose corticosteroids are a risk factor for renal crisis and should be used with caution
.

⑦ Autologous HSCT: HSCT is generally used in specific rapidly progressive dcSSc patients, and multiple studies have shown that patients treated with HSCT have an advantage in mRSS compared with patients treated with cyclophosphamide
.

In addition, HSCT treatment-related mortality was 3% at 54 months and 6% at 72 months, which was lower than the previous mortality rate of 17% [15], which also reflected the prevalence of screening indications.
importance
.

At present, HSCT is only suitable for patients with poor response to immunosuppressive therapy, and whether it can be used as first-line treatment remains to be discussed
.

⑧Other treatments: Intravenous iloprost is widely used in the treatment of SSc-related digital vascular lesions, and some studies have found other effects.
Some unproven experience shows that intravenous iloprost can help heal severe skin tightness.
The patient had a superficial ulcer (Fig.
1b), which also revealed an ischemia-related problem similar to ulcer disease
.

Summary At present, we can predict the risk of disease skin involvement progression based on the course of disease, the degree of skin involvement, autoantibody status, and the gene expression profile of skin biopsy specimens, and can further clarify the selection of patients for hematopoietic stem cell transplantation, which can be determined by mRSS score.
limited cognition to develop other outcome measures, including patient reports, non-invasive imaging methods and comprehensive scores, etc.
, to finally define the optimal practice plan of early dcSSc, combining pain management, multidisciplinary team, immunosuppressive therapy and clinical trials to maximize the patient degree of benefit
.

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