Abstract
Diffuse cutaneous systemic sclerosis (dcSSc) is associated with high mortality resulting from early internal-organ involvement. Clinicians therefore tend to focus on early diagnosis and treatment of potentially life-threatening cardiorespiratory and renal disease. However, the rapidly progressive painful, itchy skin tightening that characterizes dcSSc is the symptom that has the greatest effect on patients’ quality of life, and there is currently no effective disease-modifying treatment for it. Considerable advances have been made in predicting the extent and rate of skin-disease progression (which vary between patients), including the development of techniques such as molecular analysis of skin biopsy samples. Risk stratification for progressive skin disease is especially relevant now that haematopoietic stem-cell transplantation is a treatment option, because stratification will inform the balance of risk versus benefit for each patient. Measurement of skin disease is a major challenge. Results from clinical trials have highlighted limitations of the modified Rodnan skin score (the current gold standard). Alternative patient-reported and other potential outcome measures have been and are being developed. Patients with early dcSSc should be referred to specialist centres to ensure best-practice management, including the management of their skin disease, and to maximize opportunities for inclusion in clinical trials.
Key points
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Much of the pain and disability of early diffuse cutaneous systemic sclerosis (dcSSc) results from skin thickening (scleroderma), which can be rapidly progressive, commencing distally then extending proximally.
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‘Progressors’ in terms of skin disease can now be identified by considering disease duration, extent of skin disease, autoantibody status and (potentially) gene-expression profiling of skin biopsy specimens.
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Improvement in the ability to predict progressive skin disease will inform the selection of patients for haematopoietic stem-cell transplantation, as well as more targeted inclusion of patients in clinical trials.
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Limitations of the modified Rodnan skin score are stimulating development of other outcome measures of skin disease, including patient-reported outcome measures, non-invasive imaging methods and composite scores.
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Best-practice management of early dcSSc includes early referral to a specialist centre, pain management, multidisciplinary input, immunosuppressive therapy and, when at all possible, inclusion in a clinical trial.
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Introduction
Systemic sclerosis (SSc) is a multisystem connective-tissue disease characterized by fibrosis, and by vascular and immunological abnormalities. The two main subtypes of SSc, defined according to the extent of skin involvement (scleroderma, meaning ‘hard skin’), are diffuse cutaneous SSc (dcSSc) and limited cutaneous SSc1. dcSSc is the subtype of greater concern, because it is characterized by rapid progression and a high prevalence of early internal-organ involvement (including lung, heart and kidney), which can be life-threatening. dcSSc is therefore associated with high mortality2,3,4, with a 5-year survival rate of around 70%, and clinicians understandably tend to focus their attention on early identification and treatment of internal-organ disease. However, on a day-to-day basis, in patients with early dcSSc (those within the first 3–5 years of the onset of symptoms), it is skin thickening that has the greatest impact on quality of life, causing pain, intractable itching and functional limitation.
Skin involvement in early dcSSc is an important topic, not only because of the effects of skin disease on the patient, but also because the skin is a very visible and accessible ‘window’ into the dcSSc disease process. Therefore, examining the skin enables the prediction and monitoring of disease progression and of treatment response. A Review of this topic is timely because of developments over the past 5 years in benchmarking of the burden of skin disease in patients with dcSSc and in understanding of how to identify ‘progressors’ (patients with progressive disease), not only on the basis of clinical features, but also through advances in molecular technologies applied to skin biopsy samples. In addition, controversies exist with regard to how best to measure the extent and consequences of skin disease, as highlighted by results from clinical trials, and there is an ongoing need to promote best-practice management of skin disease, as well as of internal-organ disease.
The aim of this Review is to provide a comprehensive description of the clinical and scientific implications of skin involvement in dcSSc. First, we describe skin involvement, patterns of progression and the associated clinical burden, including contractures and ulceration. Second, we outline how skin-disease progression can be predicted by consideration of clinical features (including disease duration, extent of skin disease and autoantibody status) and potentially by gene-expression profiling of biopsied skin. Identifying progressors is especially relevant now that autologous haematopoietic stem-cell transplantation (HSCT) is an option for patients at high risk of progression, so that only those patients most in need are exposed to the potential toxicity (and even lethality) of HSCT. Third, we discuss outcome measures of skin disease, specifically the modified Rodnan skin score (mRSS), but also patient-reported outcome measures and non-invasive imaging techniques. Fourth, we describe best-practice management, including general measures, immunosuppressant treatment and HSCT, and discuss the controversial topic of whether or not glucocorticoids should be prescribed. We do not discuss recent, ongoing or proposed studies of new targeted therapies (including biologic agents such as tocilizumab and rituximab), as these have been reviewed elsewhere5. However, the information we present reinforces that patients with early dcSSc should, whenever possible, be recruited into clinical trials, to maximize the chances of identifying an effective disease-modifying therapy for this currently incurable disease.
Clinical features and disease burden
Clinical features
In patients with early dcSSc, skin involvement commences distally, usually first affecting the fingers, which often become swollen and painful. This early oedematous phase is sometimes misdiagnosed as inflammatory arthritis and can be associated with carpal tunnel syndrome, but over a few weeks the skin hardens and the diagnosis of SSc usually becomes obvious. A defining feature of the dcSSc subtype is the (often rapid) progression of skin involvement to proximal to the elbow or knee and/or involving the trunk. Conversely, in limited cutaneous SSc, skin involvement is confined to the extremities (distal to the elbows and knees) and to the face and neck6.
During the early (inflammatory) phase of dcSSc, when the skin disease is progressing, the skin is often itchy and painful. Pigmentary change can occur7,8 and can be distressing to patients, especially those with darker skins. Skin tightening commonly leads to contractures, particularly fixed flexion deformities of the fingers9 (Fig. 1a), but also of the elbows and sometimes knees. Range of movement is often substantially reduced, for example, at the shoulder or at the ankle, subtalar and mid-tarsal joints. The flexion contractures predispose to overlying ulcers, which can be refractory to treatment and which can lead to underlying osteomyelitis. Rarely, the skin is so tightened that small superficial ulcers appear, unrelated to pressure points (Fig. 1b).
Itch, which is often described as the most troublesome skin symptom of early dcSSc, resolves when the early inflammatory phase subsides. In those patients who survive, the severity of the skin disease (as assessed by the mRSS) will generally plateau (usually within 3–5 years of onset)10, followed by gradual softening and atrophying of the skin, to the extent that years later, there might no longer be any skin thickening. The contractures, however, persist and are usually irreversible9 (Fig. 1c).
Associated morbidity
Although it has long been recognized that the skin involvement in early dcSSc is painful, disabling and disfiguring, these elements of the disease burden have only been quantified in the past few years. The European Scleroderma Observational Study (ESOS)11 involved 326 patients with early dcSSc from 19 countries (with a median disease duration from onset of skin thickening of 11.9 months), and although the main aim was to assess treatment outcomes, ESOS also provided the opportunity to examine associations between severity of skin involvement and both functional ability and quality of life. Severity of skin involvement was measured with the mRSS. At the baseline visit, high mRSS was associated with high levels of disability (with ‘grip’ and ‘activity’ being most affected) as assessed by the Health Assessment Questionnaire disability index (HAQ-DI) (Spearman’s ρ = 0.34, P < 0.0001), and specifically with high levels of hand disability, as assessed by the Cochin Hand Function Scale (ρ = 0.35, P < 0.0001)12. Fine finger movements were particularly affected. mRSS was also associated with severity of pain, as assessed on a 0–100 visual analogue scale (ρ = 0.17, P = 0.002), and severity of fatigue, as assessed by the Functional Assessment of Chronic Illness Therapy fatigue score (ρ = −0.20, P = 0.0005). Examining changes over 12 months, increases in the mRSS were associated with worsening disability as measured by HAQ-DI (ρ = 0.40, P < 0.0001). In summary, ESOS demonstrated that the greater the degree of skin thickening, the greater the disability (with an emphasis on hand disability), pain and fatigue, and that if skin thickening progresses then so too does disability. This association in early dcSSc has since been confirmed in other studies: in a single-centre retrospective study13, an increase in mRSS was associated with worsening disability as measured by HAQ-DI in the subgroup of patients with early dcSSc (ρ = 0.36, P = 0.004), and in a study of 154 patients from Canada with early dcSSc14, changes in mRSS correlated with changes in HAQ-DI (Pearson’s r = 0.43 for 1-year data, r = 0.41 for 2-year data).
Predicting progression of skin disease
Associations with skin-disease severity
Among patients with early dcSSc, various trajectories of skin involvement are observed: skin score can progress (sometimes rapidly), stabilize or improve. An important aim is to identify those patients with progressive skin involvement, not only because it is painful and disabling, but also because extensive and/or progressive skin disease portends a poor outcome. Survival is reduced in patients with high skin scores15,16,17. A high ‘skin-thickness progression rate’ (the mRSS at first visit divided by patient-reported duration of skin thickening) is a predictor of early mortality and of scleroderma renal crisis18. Researchers who conducted an analysis of the European Scleroderma Trials and Research (EUSTAR) database identified reduced survival of progressors among patients with dcSSc: a group of 78 ‘skin progressors’ had lower survival (and more decline in lung function) than 943 ‘non-progressors’19. Conversely, a reduction in skin thickening is reassuring, because it is associated with improvement in survival20 and reduction of internal-organ involvement21.
Predictors of progression
Accurate prediction of progressive skin involvement would enable clinicians to make informed decisions regarding whether or not to initiate potentially toxic treatments, usually an immunosuppressant but potentially (in highly selected patients) HSCT. Although treatment-related mortality with HSCT has fallen considerably since the introduction of the technique, it remains a concern, so the procedure should only be carried out in those at highest risk. Prediction of progressive skin disease is also important for researchers designing clinical trials of potential disease-modifying therapies; inclusion and exclusion criteria should be selected to include progressors rather than non-progressors, who are less likely to benefit from treatment. Progressors are often defined as those experiencing a 5-unit and 25% increase in mRSS over 12 months22,23,24.
Tendon friction rubs are an indicator of disease that is very likely to progress25,26. In a study of an inception cohort from the University of Pittsburgh (reported in 2011)18, anti-RNA polymerase III antibody positivity was associated with rapid skin-disease progression. More recently, several groups have investigated other predictors of progressive skin disease. Low mRSS, short disease duration and joint synovitis were predictors of disease progression in an analysis from the EUSTAR database22, whereas a high baseline mRSS (and absence of friction rubs) predicted improvement27. These results led to the suggestion that only patients with an mRSS of ≤22 should be included in clinical trials of early dcSSc, because patients with higher scores are unlikely to have progressive skin disease22. This fairly stringent cut-off excludes many patients. An analysis of the ESOS cohort23, in whom mRSS was assessed at 3-month intervals (enabling detailed assessment of disease trajectory), demonstrated that patients with higher skin scores could reasonably be included in clinical trials if their disease duration was short. Among the 293 patients with sufficient data to assess their status, the 66 progressors had shorter disease duration than the 227 non-progressors (median 8.1 months versus 12.6 months, P = 0.001), as well as lower mRSS (median 19 units versus 21 units, P = 0.030), with those patients who were anti-RNA polymerase III antibody positive going on to have the highest skin scores and peaking earliest. Two predictive models were derived for progressive skin thickening23: the first included mRSS, duration of skin thickening and their interaction, and the second added anti-RNA polymerase III antibody positivity. Both models were more accurate than a model with an mRSS cut-off of 22, and for a given skin score were more flexible, enabling a higher baseline skin score to be compensated for by a shorter disease duration23. Application of these models should maximize numbers of the most informative patients (progressors) to be included in clinical trials. Subsequently, results from other studies have confirmed the role of skin score and disease duration as predictors of progression. A 2021 analysis from the Pittsburgh cohort28 led to the conclusion that ideally only patients with a disease duration of <18 months should be included in clinical trials, although the findings from ESOS23 suggest that some flexibility in disease duration could be permitted in the presence of low skin scores. Findings from the Genetics versus Environment in Scleroderma Outcomes Study (GENISOS)24 cohort suggested that an mRSS of ≤27 was predictive of progression, despite a mean disease duration of 2.4 ± 1.5 years (which is longer than the disease duration of the ESOS cohort23). In a Japanese multicentre prospective cohort study29, disease duration of ≤12 months and an mRSS of ≤19 predicted progression (sensitivity 73.9%, specificity 81.1%), which is consistent with the findings from ESOS23.
Results from skin global gene-expression studies indicate that SSc skin has a distinct transcript profile (although considerable heterogeneity exists). Although these results demonstrate the presence of prominent fibrotic and inflammatory signatures (which can co-occur in individual patients), a subgroup of SSc skin samples has a gene-expression pattern that resembles the transcript profile of healthy individuals (a ‘normal-like’ pattern)30,31,32. In addition, evidence increasingly indicates that the skin gene-expression profile of a patient with SSc changes over time, in parallel with the clinical course of skin involvement31,33. SSc skin gene-expression signatures might help to predict outcomes of dcSSc. Higher ‘fibroinflammatory’ scores are associated with higher skin scores (both mRSS and locally at the biopsy site)30. Results from a study of the Prospective Registry of Early Systemic Sclerosis (PRESS) cohort, published in 2020, suggest that gene-expression profiles in samples from forearm skin biopsies of patients with early dcSSc are associated with prior skin-disease progression, but are not predictive of future progression31. These findings contrast with those from a phase 2 trial of tocilizumab, in which expression of five fibrotic and inflammatory genes in forearm skin biopsy samples from patients treated with a placebo was associated with mRSS progression34. Inflammatory, fibroproliferative and normal-like skin gene-expression subsets were identified using a machine-learning approach32, and might help to explain the variable response to immunomodulatory therapies. In a randomized controlled study of treatment with abatacept in dcSSc, the results of which were published in 2020, patients with the inflammatory or normal-like expression profiles responded to treatment, whereas no statistically significant treatment effect occurred in the overall study population35. Results from other studies (published from 2018 to 2021) have indicated that patients with an inflammatory skin gene-expression profile have shorter disease duration and higher skin score than individuals with other expression profiles31,36,37. Consistent with these findings, results published in 2021 from a longitudinal study indicated that immune cell and fibroblast signatures decline over time, and overall skin gene expression trends towards normalization in patients with early diffuse SSc33. Currently, it is not known to what extent skin gene-expression profiling can help to predict response to treatment beyond the information provided by easily obtained clinical predictors such as disease duration, baseline skin score and anti-RNA polymerase III antibody positivity status. Anti-RNA polymerase III antibody is one of the SSc-specific autoantibodies that are associated with the diffuse cutaneous subtype of SSc, another is anti-topoisomerase I antibody11. As mentioned above, patients with dcSSc with anti-RNA polymerase III positivity experience more rapidly progressive skin involvement than the overall population of patients with dcSSc11. Notably, differences in gene expression and pathway enrichment between major autoantibody subgroups in early dcSSc38 might reflect both distinct and overlapping biological mechanisms determining progression and regression of skin disease at the patient level. Integration of high-dimensional gene and protein expression data by weighted gene co-expression network analysis (WGCNA) elucidates likely pathogenic mechanisms39 and points towards the potential to better define longitudinal differences to link gene33 and protein expression to clinical changes (Fig. 2). This analysis should provide additional insights into local pathogenesis of skin fibrosis39, and might help to identify candidate biomarkers that can be used for inpatient stratification or assessment of outcome, building upon results from studies of biomarkers validated in conditions such as liver cirrhosis, including the enhanced liver fibrosis score, which correlates with skin severity and progression40,41.
In summary, we now have a much better insight than 5 years ago into the factors that predict disease progression, and progress is being made towards a stratified approach to therapy. As we continue to advance our knowledge, it will be possible to build upon the conceptual framework for the association between skin-score trajectory and the biology of progression and regression, as outlined in Fig. 2.
Outcome measures
Reliable outcome measures that are sensitive to change are a prerequisite to monitoring both disease progression and the response to treatment. However, identification and/or development of reliable outcome measures for SSc skin disease has proved to be a major challenge, leading to much discussion between clinicians and industry partners, and demonstrating the need for further research. Here, we describe the main outcome measures used for the assessment of skin involvement42. The current outcome measures are not ideal, but efforts are ongoing to improve them through modification of existing tools and development of new measures, including (at least for early-phase studies) non-invasive imaging techniques.
The mRSS
Measurement of the extent of skin involvement is complex, and needs to take into account the surface area affected and the degree of involvement at various body sites. The mRSS43, which involves skin palpation at 17 sites, has been fully validated as per OMERACT principles44, but presents challenges. The mRSS is described in detail elsewhere43, and key points relating to its use and limitations are presented in Box 1.
Self-assessment of skin involvement
The ‘hands on’ nature of the mRSS has implications for both clinical practice and clinical trials in the era of COVID-19, when patient visits to hospital are being minimized. Therefore, patient self-assessment of skin involvement, which was previously proposed45,46, but not widely applied, is now an attractive option. An exciting development is the Patient Self-Assessment of Skin Thickness in Upper Limb (PASTUL) questionnaire47. In an initial study of 104 patients with SSc, 78 (75%) of whom also had an mRSS assessment, there was moderate correlation between PASTUL scores and both total mRSS (r = 0.56) and upper-limb mRSS (r = 0.58). PASTUL scores also strongly correlated with results from the Scleroderma Skin Patient-Reported Outcome (SSPRO)48. Once fully validated, PASTUL could be an important addition to clinical trials, bringing the possibility of more-frequent skin scoring during trial treatment than has previously been possible (and in the patient’s own home).
Other outcome measures
The limitations of the mRSS have resulted in exploration of the use of other outcome measures of skin involvement, including composite measures. These measures are attracting increasing interest for application in trials of early dcSSc.
Patient-reported outcomes
The SSPRO48 is an 18-item questionnaire for the assessment of skin-related quality of life in patients with SSc. Researchers have already applied the SSPRO in clinical trials49, and its further use is likely. The HAQ-DI, although not specific to the skin involvement of early dcSSc, captures much of the associated disability and has the advantage that most clinicians are familiar with it. In the past 5 years, several trials have included the HAQ-DI as an outcome measure35,49,50,51,52,53,54,55. Because itch can be a very prominent feature in early dcSSc, itch assessment should also be considered, for example, with the 5-D itch scale56, which researchers included in a 2020 phase 2 study of the safety and efficacy of the cannabinoid receptor 2 agonist lenabasum for the treatment of patients with SSc49.
Non-invasive imaging methods
The two main methods in this category are high-frequency ultrasonography and optical-coherence tomography (OCT). Ultrasonography reliably measures skin thickness, according to results from several cross-sectional studies57,58,59,60, and a 2021 study advocated ultrasonography as an outcome measure61. Ultrasonographic measurement of skin thickness with a 4–15 MHz linear probe correlated well with histological assessment (r = 0.6926, P = 0.009) and with local (forearm) mRSS (r = 0.7961, P = 0.001) in 13 patients with SSc (nine of whom had dcSSc) who underwent forearm skin biopsy62. As the imaging resolution with ultrasonographic devices improves and ultrasonography-based elastography becomes available in a clinical setting, additional studies will be needed to assess the reliability and validity of improved ultrasonographic skin-thickness measurement modalities in SSc63. Moreover, accurate measurement by ultrasonography requires training and is time-consuming if performed at multiple body sites in individual patients, which probably explains why ultrasonography has not been adopted as an outcome measure in later-phase multicentre studies.
The technical challenges associated with ultrasonography will most likely also apply to OCT, which is another promising tool for the assessment of skin thickness that is currently in early-phase proof-of-concept studies. OCT essentially takes in vivo ‘optical biopsy’ images of the skin64 to visualize skin structure. In this way, epidermal thickness can be measured at high resolution (<10 µm). Very few studies have so far examined the use of OCT in patients with SSc65,66. Although OCT can provide higher imaging resolution than ultrasonography-based techniques, currently it has limited imaging depth, which complicates assessment of lower layers of dermis in certain body areas, underscoring the need for further development in this area. Polarization-sensitive OCT (PS-OCT)67 is an extension to OCT that involves the measurement of birefringence (an optical property of collagen) in addition to skin thickness. Birefringence can be considered a measure of skin ‘heterogeneity’ and, therefore, potentially a measure of fibrosis. Epidermal thickness measured by PS-OCT correlated with histological thickness in a study that involved ten patients with SSc and ten healthy individuals68. Larger prospective studies that examine change over time are required to validate both ultrasonography and OCT as possible outcome measures.
Durometry
As a measure of skin hardness, durometry has long been advocated as a possible outcome measure in clinical trials of early dcSSc69, but not widely adopted. However, in 2020 durometry was revisited70, and it deserves further investigation, including in longitudinal studies with examination of sensitivity to change. A durometer is hand-held, portable and relatively easy to use, making durometry a potentially useful additional outcome measure in multicentre studies.
Composite scores
Composite scores incorporate multiple elements and might therefore be more representative of disease status than individual measures. At present there are no composite scoring systems specifically for skin disease in patients with SSc. However, the ACR provisional composite response index in dcSSc (CRISS)71,72, which is heavily weighted by the mRSS, was used in patients with dcSSc in several studies that had results published in 2020 (refs35,49,51,52,53). The ACR-CRISS includes five measures: the mRSS, percentage predicted forced vital capacity, the HAQ-DI, and patient and clinician global assessments.
Dynamic biomarkers
Longitudinal measurements of expression in skin of two genes, THBS1 and MS4A4A, correlate with mRSS measurements73. However, no studies have yet produced evidence of changes in skin gene expression that correlate with how patients with dcSSc ‘feel, function and survive’, to establish them as surrogate outcome measures.
Serum is another possible source of composite biomarkers, such as those used for the enhanced liver fibrosis score38,41, as well as novel proteomic markers that are currently being explored as candidates for the assessment of treatment response74. However, evidence suggests that substantial heterogeneity could exist in the longitudinal relationships between serum markers and mRSS38.
Best-practice management
Although there is currently no cure for SSc (so it is important that whenever possible patients are recruited into clinical trials), there is no room for nihilism, as much can be done to support patients through the worrying phase of early dcSSc. Management options include symptomatic treatment for progressive skin disease and (in most patients) immunosuppression. Notably, the evidence base in favour of immunosuppression is weak11. In addition, a small minority of patients are candidates for HSCT6. Despite recent interest in the tyrosine kinase inhibitor nintedanib as a treatment for SSc-related interstitial lung disease, the SENSCIS trial provided no evidence of an improvement in skin score75, although it was primarily a trial investigating lung disease rather than a study of patients with early dcSSc.
Here, we describe aspects of best-practice management of skin thickening in early dcSSc, as shown in Fig. 3. Decisions on treatment (particularly on the choice of immunosuppressant) are influenced by the presence or absence of other SSc ‘complications’, such as concomitant myositis or interstitial lung disease76.
Early recognition
Diagnosis of early dcSSc is often delayed77, which prevents timely identification and early treatment of (for example) internal-organ involvement and delays patient education. These delays can be addressed by raising physicians’ awareness of the signs and symptoms of dcSSc. Any patient with new onset of skin thickening that could indicate early dcSSc should be referred to a specialist centre, especially if the skin thickening has rapidly progressed. Although Raynaud phenomenon is a symptom in most patients with early dcSSc, in some individuals it develops only after skin thickening, so the use of Raynaud phenomenon as a ‘red flag’78 does not always apply to dcSSc, in contrast to the situation in limited cutaneous SSc, in which the onset of Raynaud phenomenon usually precedes the diagnosis of SSc by many years6.
General measures
The four main general measures for the management of skin involvement in early dcSSc are analgesia, treatment of itch, physiotherapy and occupational therapy. Clinical psychology input is an additional consideration.
Analgesia
The pain of skin disease in early dcSSc is often insufficiently recognized, even though it has a considerable effect on quality of life. Among the 326 patients recruited into ESOS12, the mean and median scores for the sHAQ pain scale (which has a range of 0–100, with 100 indicating the greatest disability) were 32.9 (standard deviation 26.9) and 29.0 (interquartile range 8.7–52.7), and skin thickening correlated with pain (ρ = 0.17, P = 0.002). Development of contractures and ulcers further contributes to pain. Analgesia is therefore a key aspect of management. The pain might have a neurogenic component79, so treatment with gabapentin or pregabalin can be considered. Some patients will benefit from referral to a pain-management clinic.
Management of itch
Management of this symptom is very challenging. Antihistamines can be tried, but seldom seem to be helpful. Some patients find benefits with 1% menthol in aqueous cream. Anecdotally (A.H., unpublished observations), low-dose prednisolone can relieve itch. Prednisolone is, however, a risk factor for scleroderma renal crisis, as discussed below.
Physiotherapy and occupational therapy
Researchers have given little attention to the roles of physiotherapy and occupational therapy in early dcSSc, even though it seems logical that these approaches could be helpful to maintain range of movement and maximize function. Anecdotally, patients benefit from stretching exercises to maintain range of movement, and many enjoy hydrotherapy (A.H., unpublished observations). In a 2021 study that included 34 patients with dcSSc, but with unspecified disease duration, results suggested a benefit from hand exercises80. Ideally, all patients with early dcSSc should be assessed by an occupational therapist, as almost all patients have considerable functional disability, including impairment of hand function12. ‘Remote’ occupational therapy via a mobile app81 could be a way forward, at least in some patients.
Clinical psychology input
Patients with early dcSSc report feeling overwhelmed by their disease, with loss of control. This feeling relates in large part to the disability, pain and fatigue that are directly or indirectly related to skin disease. Clinical psychology referral should be considered.
Immunosuppressant therapy
Both the British Society for Rheumatology (BSR)–British Health Professionals in Rheumatology (BHPR)82 and EULAR83 recommend immunosuppressant therapy for the skin disease of SSc. The BSR–BHPR guidelines suggest the use of mycophenolate mofetil (MMF), methotrexate or cyclophosphamide, whereas the EULAR recommendation is for methotrexate. Among the few clinical trials of immunosuppressants that have specifically examined skin disease primarily in early dcSSc, two used methotrexate84,85, none used MMF (despite results from several early retrospective and prospective observational studies that suggest benefit86,87,88) and none used cyclophosphamide. In ESOS11, the researchers examined the relative effectiveness of commonly used immunosuppressants in patients with early dcSSc. The treatment options in this observational study were methotrexate (oral or subcutaneous at a target dose of 20–25 mg weekly), MMF (target dose 1 g twice daily), cyclophosphamide (intravenous or oral) or no immunosuppressant. A trend in favour of immunosuppression was seen, as after 12 months, mRSS fell in all groups, but more so in the immunosuppressant groups: for methotrexate (n = 65) −4.0 units (95% CI −5.2 units to −2.7 units), for MMF (n = 118) −4.1 units (95% CI −5.3 units to −2.9 units), for cyclophosphamide (n = 87) −3.3 units (95% CI −4.9 units to −1.7 units) and for no immunosuppressant (n = 56) −2.2 units (95% CI −4.0 units to −0.3 units) (P-value for between-group differences = 0.346). The conclusion from ESOS was that immunosuppression conferred benefit, but that this benefit was modest. Improvements in mRSS in patients with dcSSc (although not specifically early dcSSc) also occurred in the Scleroderma Lung Study I (cyclophosphamide compared with placebo) and the Scleroderma Lung Study II (cyclophosphamide and MMF compared with patients treated with placebo in Scleroderma Lung Study I) at 12, 18 and 24 months (P < 0.05)89. Further support for the use of MMF comes from the results of an Australian observational study90 and from a report of five patients with recurrence of progressive skin involvement after either discontinuation or dose reduction of MMF91.
Glucocorticoids
The use of glucocorticoids in early dcSSc is highly controversial92, and although some clinicians prescribe them, others do not, as demonstrated by the observation that 44% of patients who were recruited into ESOS had been prescribed them11. Glucocorticoids are likely to reduce the itch and pain (from the skin) that occur in patients with early dcSSc because these symptoms are thought to result from skin inflammation. However, glucocorticoids are a risk factor for renal crisis, especially when used in high doses93,94,95. Many clinicians are, therefore, understandably reluctant to prescribe glucocorticoids for patients with early progressive dcSSc, who are already at high risk of renal crisis, a risk that is further increased with anti-RNA polymerase III antibody positivity96,97. Notably, patients who are anti-RNA polymerase III antibody positive often have rapidly progressive disease23 and are therefore particularly likely to have itchy, painful skin that might benefit from glucocorticoid treatment. This controversial issue is currently being investigated in a randomized placebo-controlled trial of the use of prednisolone in patients with early dcSSc (ClinicalTrials.gov identifier: NCT03708718)55.
Intravenous iloprost
Intravenous iloprost is widely used in the treatment of SSc-related digital vasculopathy, but might have other beneficial effects, such as the downregulation of expression of connective-tissue growth factor98. In our experience (C.D. and A.H., unpublished observations), intravenous iloprost can help to heal the superficial ulcers that can occur in patients with very tightened skin (Fig. 1b), suggesting that there is an ischaemic element to these ulcers.
Autologous HSCT
HSCT should be considered in highly selected patients with rapidly progressive dcSSc. In all three trials that provided the evidence base for this recommendation (ASSIST99, ASTIS100 and SCOT101), patients who underwent HSCT demonstrated benefit in terms of mRSS compared with patients treated with cyclophosphamide, although mRSS was not the primary end point (mRSS was, however, part of the composite primary end point in the ASSIST study99). Improvement in mRSS was also reported in a prospective ‘real-world’ study of 80 patients who underwent HSCT102. The treatment-related mortality of HSCT in the SCOT study was 3% at 54 months and 6% at 72 months101, and therefore lower than previously reported (a 2001 phase 1/2 trial reported a procedure-related mortality of 17%)103, most likely reflecting careful patient selection and adjustments to the transplantation regime. A key question that is currently being addressed104 is whether HSCT should be recommended as a first-line therapy as opposed to being reserved for patients who do not respond to immunosuppressant therapies. This difficult decision will be informed by the stratified medicine approach referred to earlier (taking into account advances in our ability to predict those patients most likely to have progressive disease), and by ensuring that individualized care is tailored to patients’ needs and expectations105.
Conclusions
The past 5 years have provided new insights into the most visible and characteristic manifestation of early dcSSc — skin thickening (scleroderma) — which is often rapidly progressive. Importantly, we now recognize the burden of skin disease, which has a very considerable effect on quality of life; previously, it was often overlooked. We are now in a good position to predict which patients will develop rapid progression of skin thickening, thereby enabling early intervention with immunosuppressive therapies or with HSCT, and/or inclusion into clinical trials. The lack of reliable outcome measures of skin disease represents a major unmet need. However, the challenges of monitoring skin disease, both in the clinic and in the setting of clinical trials, are now better understood, and research is ongoing. Better outcome measures (and improved identification of progressors) will maximize the efficiency of future clinical trials of the many promising new targeted therapies. Pending identification of a safe and effective treatment, clinicians should not forget current best-practice guidelines, which can provide at the very least some symptomatic relief from painful, disabling skin disease.
References
LeRoy, E. C. et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J. Rheumatol. 15, 202–205 (1988).
Domsic, R. T. et al. Derivation and external validation of a prediction rule for five-year mortality in patients with early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 68, 993–1003 (2016).
Pokeerbux, M. R. et al. Survival and prognosis factors in systemic sclerosis: data of a French multicenter cohort, systematic review, and meta-analysis of the literature. Arthritis Res. Ther. 21, 86 (2019).
Jaafar, S. et al. Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort. Arthritis Res. Ther. 23, 170 (2021).
Campochiaro, C. & Allanore, Y. An update on targeted therapies in systemic sclerosis based on a systematic review from the last 3 years. Arthritis Res. Ther. 23, 155 (2021).
Denton, C. P. & Khanna, D. Systemic sclerosis. Lancet 390, 1685–1699 (2017).
Solanki, K. K., Hor, C., Chang, W. S. J., Frampton, C. & White, D. H. N. Clinical utility of hypo- and hyperpigmentation of skin in diffuse cutaneous systemic sclerosis. Int. J. Rheum. Dis. 20, 767–773 (2017).
Leroy, V. et al. Association of skin hyperpigmentation disorders with digital ulcers in systemic sclerosis: analysis of a cohort of 239 patients. J. Am. Acad. Dermatol. 80, 478–484 (2019).
Buni, M. et al. Predictors of hand contracture in early systemic sclerosis and the effect on function: a prospective study of the GENISOS cohort. J. Rheumatol. 46, 1597–1604 (2019).
Amjadi, S. et al. Course of the modified Rodnan skin thickness score in systemic sclerosis clinical trials: analysis of three large multicenter, double-blind, randomized clinical trials. Arthritis Rheum. 60, 2490–2498 (2009).
Herrick, A. L. et al. Treatment outcome in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study (ESOS). Ann. Rheum. Dis. 76, 1207–1218 (2017).
Peytrignet, S. et al. Disability, fatigue, pain and their associates in early diffuse cutaneous systemic sclerosis: the European Scleroderma Observational Study. Rheumatology 57, 370–381 (2018).
Peytrignet, S. et al. Changes in disability and their relationship with skin thickening, in diffuse and limited cutaneous systemic sclerosis: a retrospective cohort study. Scand. J. Rheumatol. 48, 230–234 (2019).
Zheng, B. et al. Changes in skin score in early diffuse cutaneous systemic sclerosis are associated with changes in global disease severity. Rheumatology 59, 398–406 (2020).
Clements, P. J. et al. Skin thickness score as a predictor and correlate of outcome in systemic sclerosis. Arthritis Rheum. 43, 2445–2454 (2000).
Shand, L. et al. Relationship between change in skin score and disease outcome in diffuse cutaneous systemic sclerosis. Arthritis Rheum. 56, 2422–2431 (2007).
Ledoult, E. et al. Early trajectories of skin thickening are associated with severity and mortality in systemic sclerosis. Arthritis Res. Ther. 22, 30 (2020).
Domsic, R. T., Rodriguez-Reyna, T., Lucas, M., Fertig, N. & Medsger, T. A. Skin thickness progression rate: a predictor of mortality and early internal organ involvement in diffuse scleroderma. Ann. Rheum. Dis. 70, 104–109 (2011).
Wu, W. et al. Progressive skin fibrosis is associated with a decline in lung function and worse survival in patients with diffuse cutaneous systemic sclerosis in the European Scleroderma Trials and Research (EUSTAR) cohort. Ann. Rheum. Dis. 78, 648–656 (2019).
Steen, V. D. & Medsger, T. A. Improvement in skin thickening in systemic sclerosis associated with improved survival. Arthritis Rheum. 44, 2828–2835 (2001).
Nevskaya, T. et al. Skin improvement is a surrogate for favourable changes in other organ systems in early diffuse cutaneous systemic sclerosis. Rheumatology 59, 1715–1724 (2020).
Maurer, B. et al. Prediction of worsening of skin fibrosis in patients with diffuse cutaneous systemic sclerosis using the EUSTAR database. Ann. Rheum. Dis. 74, 1124–1131 (2015).
Herrick, A. L. et al. Patterns and predictors of skin score change in early diffuse systemic sclerosis from the European Scleroderma Observational Study. Ann. Rheum. Dis. 77, 563–570 (2018).
Mihai, C., Dobrota, R., Assassi, S., Mayes, M. D. & Distler, O. Enrichment strategy for systemic sclerosis clinical trials targeting skin fibrosis: a prospective, multiethnic cohort study. ACR Open Rheumatol. 2, 496–502 (2020).
Khanna, P. P. et al. Tendon friction rubs in early diffuse systemic sclerosis: prevalence, characteristics and longitudinal changes in a randomized controlled trial. Rheumatology 49, 955–959 (2010).
Avouac, J. et al. Joint and tendon involvement predict disease progression in systemic sclerosis: a EUSTAR prospective study. Ann. Rheum. Dis. 75, 103–109 (2016).
Dobrota, R. et al. Prediction of improvement in skin fibrosis in diffuse cutaneous systemic sclerosis: a EUSTAR analysis. Ann. Rheum. Dis. 75, 1743–1748 (2016).
Domsic, R. T. et al. Defining the optimal disease duration of early diffuse systemic sclerosis for clinical trial design. Rheumatology 60, 4662–4670 (2021).
Kuwana, M. et al. Initial predictors of skin thickness progression in patients with diffuse cutaneous systemic sclerosis: results from a multicentre prospective cohort in Japan. Mod. Rheumatol. 31, 386–393 (2021).
Assassi, S. et al. Dissecting the heterogeneity of skin gene expression patterns in systemic sclerosis. Arthritis Rheumatol. 67, 3016–3026 (2015).
Skaug, B. et al. Global skin gene expression analysis of early diffuse cutaneous systemic sclerosis shows a prominent innate and adaptive inflammatory profile. Ann. Rheum. Dis. 79, 379–386 (2020).
Franks, J. M. et al. A machine learning classifier for assigning individual patients with systemic sclerosis to intrinsic molecular subsets. Arthritis Rheumatol. 71, 1701–1710 (2019).
Skaug, B. et al. Large-scale analysis of longitudinal skin gene expression in systemic sclerosis reveals relationships of immune cell and fibroblast activity with skin thickness and a trend towards normalisation over time. Ann. Rheum. Dis. https://doi.org/10.1136/annrheumdis-2021-221352 (2021).
Stifano, G. et al. Skin gene expression is prognostic for the trajectory of skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 70, 912–919 (2018).
Khanna, D. et al. Abatacept in early diffuse cutaneous systemic sclerosis: results of a phase II investigator-initiated, multicenter, double-blind, randomized, placebo-controlled trial. Arthritis Rheumatol. 72, 125–136 (2020).
Hinchcliff, M. et al. Mycophenolate mofetil treatment of systemic sclerosis reduces myeloid cell numbers and attenuates the inflammatory gene signature in skin. J. Invest. Dermatol. 138, 1301–1310 (2018).
Showalter, K. et al. Machine learning integration of scleroderma histology and gene expression identifies fibroblast polarisation as a hallmark of clinical severity and improvement. Ann. Rheum. Dis. 80, 228–237 (2021).
Clark, K. E. N. et al. Molecular basis for clinical diversity between autoantibody subsets in diffuse cutaneous systemic sclerosis. Ann. Rheum. Dis. 80, 1584–1593 (2021).
Clark, K. et al. High-density proteomic analysis of skin blister fluid and plasma in systemic sclerosis identifies local and systemic differences for key proteins [abstract]. Arthritis Rheumatol. 72, https://acrabstracts.org/abstract/high-density-proteomic-analysis-of-skin-blister-fluid-and-plasma-in-systemic-sclerosis-identifies-local-and-systemic-differences-for-key-proteins/ (2020).
Abignano, G. et al. The enhanced liver fibrosis test: a clinical grade, validated serum test, biomarker of overall fibrosis in systemic sclerosis. Ann. Rheum. Dis. 73, 420–427 (2014).
Abignano, G. et al. European multicentre study validates enhanced liver fibrosis test as biomarker of fibrosis in systemic sclerosis. Rheumatology 58, 254–259 (2019).
Sumpton, D. et al. Scope and consistency of outcomes reported in trials of patients with systemic sclerosis. Arthritis Care Res. 72, 1449–1458 (2020).
Khanna, D. et al. Standardization of the modified Rodnan skin score for use in clinical trials of systemic sclerosis. J. Scleroderma Relat. Disord. 2, 11–18 (2017).
Merkel, P. A. et al. Current status of outcome measure development for clinical trials in systemic sclerosis. Report from OMERACT 6. J. Rheumatol. 30, 1630–1647 (2003).
Nagy, Z. et al. Establishment and partial validation of a patient skin self-assessment questionnaire in systemic sclerosis. Rheumatology 48, 309–314 (2009).
Daungkum, K. et al. Self-assessment of skin tightness severity by scleroderma patients. Int. J. Rheum. Dis. 19, 989–995 (2016).
Spierings, J., Ong, V. & Denton, C. P. PASTUL questionnaire: a tool for self-assessment of scleroderma skin during the COVID-19 pandemic. Ann. Rheum. Dis. 80, 819–820 (2021).
Man, A. et al. Development and validation of a patient-reported outcome instrument for skin involvement in patients with systemic sclerosis. Ann. Rheum. Dis. 76, 1374–1380 (2017).
Spiera, R. et al. Safety and efficacy of lenabasum in a phase II, randomized, placebo-controlled trial in adults with systemic sclerosis. Arthritis Rheumatol. 72, 1350–1360 (2020).
Khanna, D. et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 387, 2630–2640 (2016).
Khanna, D. et al. Tocilizumab in systemic sclerosis: a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Resp. Med. 8, 963–974 (2020).
Khanna, D. et al. Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial. Ann. Rheum. Dis. 79, 618–625 (2020).
Allanore, Y. et al. A randomised, double-blind, placebo-controlled, 24-week, phase II, proof-of-concept study of romilkimab (SAR156597) in early diffuse cutaneous systemic sclerosis. Ann. Rheum. Dis. 79, 1600–1607 (2020).
Allanore, Y. et al. Lysophosphatidic acid receptor 1 antagonist SAR100842 for patients with diffuse cutaneous systemic sclerosis: a double-blind, randomized, eight-week placebo-controlled study followed by a sixteen-week open-label extension study. Arthritis Rheumatol. 70, 1634–1643 (2018).
Herrick, A. L., Griffiths-Jones, D. J., Ryder, W. D., Mason, J. C. & Denton, C. P. Clinical trial protocol: PRednisolone in early diffuse cutaneous Systemic Sclerosis (PRedSS). J. Scleroderma Relat. Disord. 6, 146–153 (2021).
Elman, S., Hynan, L. S., Gabriel, V. & Mayo, M. J. The 5-D itch scale: a new measure of pruritus. Br. J. Dermatol. 162, 587–593 (2010).
Moore, T. L., Lunt, M., McManus, B., Anderson, M. E. & Herrick, A. L. Seventeen-point dermal ultrasound scoring system - a reliable measure of skin thickness in patients with systemic sclerosis. Rheumatology 42, 1559–1563 (2003).
Hesselstrand, R., Scheja, A., Wildt, M. & Akesson, A. High-frequency ultrasound of skin involvement in systemic sclerosis reflects oedema, extension and severity in early disease. Rheumatology 47, 84–87 (2008).
Liu, H. et al. A preliminary study of skin ultrasound in diffuse cutaneous systemic sclerosis: does skin echogenicity matter? PLoS ONE 12, e0174481 (2017).
Naredo, E. et al. Performance of ultra-high-frequency ultrasound in the evaluation of skin involvement in systemic sclerosis: a preliminary report. Rheumatology 59, 1671–1678 (2020).
Murphy, S. L. et al. Development of a musculoskeletal ultrasound protocol to examine upper extremity rehabilitation outcomes in systemic sclerosis. J. Diagn. Med. Sonogr. 37, 13–23 (2021).
Chen, C. et al. Ultrasound assessment of skin thickness and stiffness: the correlation with histology and clinical score in systemic sclerosis. Arthritis Res. Ther. 22, 197 (2020).
Santiago, T. et al. Ultrasonography for the assessment of skin in systemic sclerosis: a systematic review. Arthritis Care Res. 71, 563–574 (2019).
Fercher, A. F., Drexler, W., Hitzenberger, C. & Lasser, L. Optical coherence tomography — principles and applications. Rep. Prog. Phys. 66, 239–303 (2003).
Abignano, G. et al. Virtual skin biopsy by optical coherence tomography: the first quantitative imaging biomarker for scleroderma. Ann. Rheum. Dis. 72, 1845–1851 (2013).
Liu, C.-H. et al. Translational optical coherence elastography for assessment of systemic sclerosis. J. Biophotonics 12, e201900236 (2019).
Adams, D. C. et al. Assessing the progression of systemic sclerosis by monitoring the tissue optic axis using PS-OCT. Sci. Rep. 10, 2561 (2020).
Marjanovic, E. J. et al. Polarisation-sensitive optical coherence tomography measurement of retardance in fibrosis, a non-invasive biomarker in patients with systemic sclerosis. Sci. Rep. 12, 2893 (2022).
Merkel, P. et al. Validity, reliability, and feasibility of durometer measurements of scleroderma skin disease in a multicenter treatment trial. Arthritis Rheum. 59, 699–705 (2008).
De Oliveira, M. F. C. et al. Durometry as an alternative tool to the modified Rodnan’s skin score in the assessment of diffuse systemic sclerosis patients: a cross-sectional study. Adv. Rheumatol. 60, 48 (2020).
Khanna, D. et al. The American College of Rheumatology provisional composite response index for clinical trials in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 68, 299–311 (2016).
Khanna, D., Huang, S., Lin, C. J. F. & Spino, C. New composite endpoint in early diffuse cutaneous systemic sclerosis: revisiting the provisional American College of Rheumatology Composite Response Index in Systemic Sclerosis. Ann. Rheum. Dis. 80, 641–650 (2021).
Rice, L. M. et al. A longitudinal biomarker for the extent of skin disease in patients with diffuse cutaneous systemic sclerosis. Arthritis Rheumatol. 67, 3004–3015 (2015).
Rice, L. M. et al. A proteome-derived longitudinal pharmacodynamic biomarker for diffuse systemic sclerosis skin. J. Invest. Dermatol. 137, 62–70 (2017).
Distler, O. et al. Nintedanib for systemic sclerosis–associated interstitial lung disease. N. Engl. J. Med. 380, 2518–2528 (2019).
Kafaja, S. & Clements, P. Management of widespread skin thickening in diffuse systemic sclerosis. Curr. Treat. Options Rheumatol. 2, 49–60 (2016).
Distler, O. et al. Factors influencing early referral, early diagnosis and management in patients with diffuse cutaneous systemic sclerosis. Rheumatology 57, 813–817 (2018).
Matucci-Cerinic, M. et al. The challenge of early systemic sclerosis for the EULAR Scleroderma Trial and Research group (EUSTAR) community. It is time to cut the Gordian knot and develop a prevention or rescue strategy. Ann. Rheum. Dis. 68, 1377–1380 (2009).
Sousa-Neves, J., Cerqueira, M., Santos-Faria, D., Afonso, C. & Teixeira, F. Neuropathic pain in systemic sclerosis patients: a cross-sectional study. Reumatol. Clin. 15, e99–e101 (2019).
Gokcen, N., Badak, S. O., Sarpel, T., Sertdemir, Y. & Erken, E. The efficacy of a home-based, self-administered hand exercise program for patients with systemic sclerosis: a randomized controlled, evaluator-blind, clinical trial. J. Clin. Rheumatol. https://doi.org/10.1097/RHU.0000000000001752 (2021).
Murphy, S. L. et al. Intensive and app-delivered occupational therapy to improve upper extremity function in early diffuse cutaneous systemic sclerosis: a pilot two-arm trial. Rheumatology 60, 5002–5011 (2021).
Denton, C. P. et al. BSR and BHPR guideline for the treatment of systemic sclerosis. Rheumatology 55, 1906–1910 (2016).
Kowal-Bielecka, O. et al. Update of EULAR recommendations for the treatment of systemic sclerosis. Ann. Rheum. Dis. 76, 1327–1339 (2017).
Van den Hoogen, F. H. et al. Comparison of methotrexate with placebo in the treatment of systemic sclerosis: a 24 week randomized double-blind trial, followed by a 24 week observational trial. Br. J. Rheumatol. 35, 364–372 (1996).
Pope, J. E. et al. A randomized, controlled trial of methotrexate versus placebo in early diffuse scleroderma. Arthritis Rheum. 44, 1351–1358 (2001).
Derk, C. T. et al. A prospective open-label study of mycophenolate mofetil for the treatment of diffuse systemic sclerosis. Rheumatology 48, 1595–1599 (2009).
Le, E. N., Wigley, F. M., Shah, A. A., Boin, F. & Hummers, L. K. Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis. Ann. Rheum. Dis. 70, 1104–1107 (2011).
Mendoza, F. A., Nagle, S. J., Lee, J. B. & Jimenez, S. A. A prospective observational study of mycophenolate mofetil treatment in progressive diffuse cutaneous systemic sclerosis of recent onset. J. Rheumatol. 39, 1241–1247 (2012).
Namas, R. et al. Efficacy of mycophenolate mofetil and oral cyclophosphamide on skin thickness: post hoc analyses from two randomized placebo-controlled trials. Arthritis Care Res. 70, 439–444 (2018).
Boulos, D. et al. Long-term efficacy and tolerability of mycophenolate mofetil therapy in diffuse scleroderma skin disease. Int. J. Rheum. Dis. 20, 481–488 (2017).
Mendoza, F. A., Lee-Ching, C. & Jimenez, S. A. Recurrence of progressive skin involvement following discontinuation or dose reduction of mycophenolate mofetil treatment in patients with diffuse systemic sclerosis. Semin. Arthritis Rheum. 50, 135–139 (2020).
Herrick, A. L. Controversies on the use of steroids in systemic sclerosis. J. Scleroderma Relat. Disord. 2, 84–91 (2017).
Steen, V. D. & Medsger, T. A. Case-control study of corticosteroids and other drugs that either precipitate or protect from the development of scleroderma renal crisis. Arthritis Rheum. 41, 1613–1619 (1998).
DeMarco, P. J. et al. Predictors and outcomes of scleroderma renal crisis: the high-dose versus low-dose D-penicillamine in early diffuse systemic sclerosis trial. Arthritis Rheum. 46, 2983–2989 (2002).
Guillevin, L. et al. Scleroderma renal crisis: a retrospective multicentre study on 91 patients and 427 controls. Rheumatology 51, 460–467 (2012).
Nguyen, B. et al. HLA-DRB1*0407 and *1304 are risk factors for scleroderma renal crisis. Arthritis Rheum. 63, 530–534 (2011).
Hamaguchi, Y. et al. Clinical and immunologic predictors of scleroderma renal crisis in Japanese systemic sclerosis patients with anti-RNA polymerase III antibodies. Arthritis Rheumatol. 67, 1045–1052 (2015).
Stratton, R. et al. Iloprost suppresses connective tissue growth factor production in fibroblasts and in the skin of scleroderma patients. J. Clin. Invest. 108, 241–250 (2001).
Burt, R. K. et al. Autologous non-myeloablative haemopoietic stem-cell transplantation compared with pulse cyclophosphamide once per month for systemic sclerosis (ASSIST): an open-label, randomised phase 2 trial. Lancet 378, 498–506 (2011).
Van Laar, J. M. et al. Autologous hematopoietic stem cell transplantation vs intravenous pulse cyclophosphamide in diffuse cutaneous systemic sclerosis: a randomized clinical trial. JAMA 311, 2490–2498 (2014).
Sullivan, K. M. et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N. Engl. J. Med. 378, 35–47 (2018).
Henes, J. et al. Autologous stem cell transplantation for progressive systemic sclerosis: a prospective non-interventional study from the European Society for Blood and Marrow Transplantation Autoimmune Disease Working Party. Haematologica 106, 375–383 (2021).
Binks, M. et al. Phase I/II trial of autologous stem cell transplantation in systemic sclerosis: procedure related mortality and impact on skin disease. Ann. Rheum. Dis. 60, 577–584 (2001).
Spierings, J. et al. A randomised, open-label trial to assess the optimal treatment strategy in early diffuse cutaneous systemic sclerosis: the UPSIDE study protocol. BMJ Open 11, e044483 (2021).
Spierings, J. et al. Treatment decision-making in diffuse cutaneous systemic sclerosis: a patient’s perspective. Rheumatology 59, 2052–2061 (2020).
Khanna, D. et al. Minimal clinically important differences for the modified Rodnan skin score: results from the Scleroderma Lung Studies (SLS-I and SLS-II). Arthritis Res. Ther. 21, 23 (2019).
Clements, P. et al. Inter- and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J. Rheumatol. 22, 1281–1285 (1995).
Gordon, J. K. et al. Reliability and validity of the tender and swollen joint counts and the modified Rodnan skin score in early diffuse cutaneous systemic sclerosis: analysis from the prospective registry of early systemic sclerosis cohort. J. Rheumatol. 44, 791–794 (2017).
Showalter, K., Merkel, P. A., Khanna, D. & Gordon, J. K. for the Scleroderma Clinical Trials Consortium. Assessment of skin disease in scleroderma: practices and opinions of investigators studying scleroderma. J. Scleroderma Relat. Disord. 5, 167–171 (2020).
Park, J. W. et al. Impact of EUSTAR standardized training on accuracy of modified Rodnan skin score in patients with systemic sclerosis. Int. J. Rheum. Dis. 22, 96–102 (2019).
Low, A. H. L. et al. Evaluation of Scleroderma Clinical Trials Consortium training recommendations on modified Rodnan skin score assessment in scleroderma. Int. J. Rheum. Dis. 22, 1036–1040 (2019).
Czirjak, L., Foeldvari, I. & Muller-Ladner, U. Skin involvement in systemic sclerosis. Rheumatology 47 (Suppl. 5), v44–v45 (2008).
Ross, L. et al. Can patient-reported symptoms be used to measure disease activity in systemic sclerosis? Arthritis Care Res. 72, 1459–1465 (2020).
Allanore, Y. et al. Health assessment questionnaire-disability index (HAQ-DI) use in modelling disease progression in diffuse cutaneous systemic sclerosis: an analysis from the EUSTAR database. Arthritis Res. Ther. 22, 257 (2020).
Acknowledgements
This work was supported by the NIHR Manchester Biomedical Research Centre and NIH/NIAMS (R61AR078078).
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A.H. has received consultancy fees from Boehringer-Ingelheim, Camurus, CSL Behring and Gesynta, research funding from Gesynta and speaker’s fees from Janssen. S.A. has received grant support from Boehringer-Ingelheim, Janssen and Momenta Pharmaceuticals, and has received personal fees for participation in advisory board meetings from AstraZeneca, Boehringer-Ingelheim, Corbus Pharmaceuticals, CSL Behring and Novartis. C.D. has received grants and personal fees from CSL Behring and GlaxoSmithKline, grants from Arxx Therapeutics, Inventiva and Servier, and personal fees from Acceleron, Bayer, Boehringer-Ingelheim, BristolMyersSquibb, Corbus, Horizon, Roche and Sanofi.
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Glossary
- Contractures
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Deformities resulting from tissue shortening or hardening; in patients with SSc contracture is caused by tightening of the skin.
- Ulcers
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Skin lesions with discernible depth and loss of the epithelium.
- Scleroderma renal crisis
-
A complication of SSc that involves sudden onset of hypertension accompanied by renal failure.
- Tendon friction rubs
-
Palpable rubs that are found, for example, over wrists, ankles and knees, and are thought to result from inflammatory change in the tenosynovium.
- Elastography
-
Assessment of the elasticity and stiffness of soft tissues, usually by ultrasonography.
- Raynaud phenomenon
-
Colour change of the fingers on exposure to cold or to emotional stress: the classic triphasic change is white to blue to red.
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Herrick, A.L., Assassi, S. & Denton, C.P. Skin involvement in early diffuse cutaneous systemic sclerosis: an unmet clinical need. Nat Rev Rheumatol 18, 276–285 (2022). https://doi.org/10.1038/s41584-022-00765-9
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DOI: https://doi.org/10.1038/s41584-022-00765-9
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