Overview

Persistent digital ulceration is defined as the loss of epithelialization of any degree of the dermis and/or the subcutaneous tissue, distal to or at the proximal interphalangeal joint of the hands or feet not due to trauma or underlying calcinosis. DUs are a common complication of SSc and represent ischemic lesions occurring as a result of end-organ damage from SSc microvascular disease . DUs typically occur on the fingertips or over the extensor aspect of the hands.

The prevalence of DUs in SSc ranges from 10% to 58%, which are seen in about 30% of SSc patients each year . This wide-ranging prevalence is likely due to the lack of a standard classification or definition of DUs across studies, making it difficult to differentiate between DU activity (acute, recurrent, or persistent) and severity (requiring hospitalization, parenteral pharmaceutical treatment, and/or digital amputation). Critical digital ischemia must be distinguished from DUs, as is a medical emergency requiring urgent treatment. Moreover, differentiating SSc-related ischemic ulcers from traumatic ulcers and calcinosis-related ulceration poses a challenging clinical problem, the latter being more resistant to standard DU treatment.

DUs constitute a significant burden for SSc patients not only causing local pain and functional impairment but also negatively affecting patients’ quality of life and occupation . Chronic ulcers can become infected resulting in pain, gangrene, and/or osteomyelitis requiring hospitalization, parenteral medications, and autoamputation or surgical amputation .

Early identification of DUs and any contributing factors has been shown to improve outcomes , which have led to multiple studies exploring these associations. Risk factors for the development of SSc-DUs were highlighted in a recent systematic review, which included diffuse disease subtype, early age at onset of Raynaud’s phenomenon (RP), presence of anti-topoisomerase 1 antibodies, and presence of PAH .

Despite the high prevalence and significant morbidity associated with DUs, no standardized treatment algorithm has been published that can guide clinicians in their management of this challenging clinical manifestation. This may be in part due to the multifactorial pathogenesis involving abnormal vaso-reactivity, structural vascular disease with occlusive intimal hyperplasia and fibrosis, microthrombi formation, and platelet activation . Thus, the overall management of DU must address all of these factors and involve a multidisciplinary approach. Limited non-pharmacological and pharmacological treatment options are available for DUs. These options and their associated level of evidence are outlined in the following sections. We believe that a structured treatment algorithm would be beneficial in the treatment of DUs, as DUs (i) have a multifactorial etiology and (ii) may develop several complications including necrosis, digital tip loss, and infection.

Therapeutic options

Local management of DUs requires a multidisciplinary approach with a combination of non-pharmacological and pharmacological care . While evidence-based treatment guidelines for SSc exist, application to DUs in the clinic is challenging.

The end goals of treatment are prompt ulcer healing, minimization of local infection, and prevention of new DUs , but therapeutic targets or aims are difficult to monitor.

The monitoring of DU healing by expert-rated interval photographs has been an area of contention due to poor interobserver reliability . Therefore, to evaluate DU progress, the only direct parameter used at present is ulcer healing and the indirect parameter is the measurement of hand function . However, it must be noted that DUs do not always affect hand functionality; therefore, this indirect parameter has its limitations. Two questionnaires are used in clinical trials to capture this indirect measure including the Change in Hand Functionality Health Assessment Questionnaire – Disability Index (HAQ-DI) Hand Component, which assesses fine movements of the upper extremities, locomotor activities in the lower extremities, and movements of the upper and lower limbs. It is extracted from the Scleroderma Health Assessment Questionnaire and Change in Hand Functionality – Hand Disability in Systemic Sclerosis – Digital Ulcers (HDISS-DU) Score .

Non-pharmacological management involves early identification of DU and any associated infection, as well as patient education about lifestyle factors such as avoiding cold and stressful environments due to their impact on vasoconstriction, avoiding activities that cause recurrent digital trauma, quitting smoking, and ensuring regular wound care . In addition, medications or triggers that can cause or contribute to vasoconstriction including beta-blockers and high levels of caffeine intake should be avoided. Level 2 evidence from systematic reviews suggests that non-pharmacological management can reduce the frequency of RP attacks.

A broad overview of the pharmacological management of DUs includes adequate debridement, analgesia to prevent pain-induced vasoconstriction, antibiotics in the case of infection, and vasodilators to increase blood supply to the ischemic tissues. In addition, the supplementary therapies with varying levels of evidence can be considered, including an antiplatelet agent such as aspirin (level 4 evidence), botulinum toxin (level 3 evidence for reduced pain and accelerated DU healing), and statin therapy (level 2 for reducing the frequency of new DU occurrence) with its antioxidant, anti-inflammatory, and antifibrotic effects .

In terms of vasodilators, dihydropiridine calcium channel blockers (CCBs) such as nifedipine serve as first-line therapy with level 1 evidence from randomized controlled trials (RCTs) and meta-analysis, confirming their beneficial effect of reducing ischemic attacks associated with RP and DUs. If refractory or intolerant to CCB, then addition of a phosphodiesterase 5 inhibitor is the next treatment with level 1 evidence from a meta-analysis, which proved reduction in the frequency and duration of ischemic attacks associated with RP. In those with established DUs, this was found to inhibit the development of further DUs . Alternatively or additionally, refractory DUs can be treated with a prostacyclin analog such as intravenous iloprost with level 2 evidence from RCTs . Hospitalization and treatment with an intravenous prostacyclin are also recommended for those with features of acute ischemia. Unfortunately, access to prostacyclins for treatment of DU may be limited at some institutions.

Surgical options such as a digital sympathectomy are often a last resort when these treatment options have failed.

Time for structured care

Given the evidence summarized previously, we designed a therapeutic algorithm for DUs in SSc as summarized in the flowchart ( Fig. 1 ). We propose this treatment algorithm to show that DU is one manifestation in SSc that might lend itself to a structured model of care with a therapeutic target such as ulcer healing or prevention of occurrence of new ulcers.

Flowchart for management of digital ulcers in systemic sclerosis.

Despite the potential benefits of a structured treatment algorithm for DUs, the limitations include the variable nature of DUs themselves occurring in isolation or in multiple sites on multiple digits, healing or non-healing, presence of infection, the variability of each individual and their comorbidities, and also the availability and cost of the selected pharmacological agent.

Overview

Skin fibrosis, which clinically manifests as tightened and thickened skin, is the hallmark of SSc . Cutaneous manifestations are critical for SSc diagnosis, prognosis, and classification . Based on the extent of skin involvement, two principal disease subsets are distinguished: limited cutaneous (lcSSc) and diffuse cutaneous SSc (dcSSc) . While skin fibrosis is limited to the fingers, face, and distal extremities with a rather insidious onset in lcSSc, patients with dcSSc experience a more rapid disease progression with fibrosis additionally affecting the proximal extremities and/or the trunk .

Skin involvement significantly contributes to the high morbidity associated with SSc and affects the HRQoL in both physical and mental domains . Patients present with pain, impaired hand function, and disfigurement due to pigment changes, hand contractures, facial telangiectasias, and tightened skin . More importantly, the extent of skin involvement and its progression rate are predictors for the severity of internal organ involvement and therefore mortality in dcSSc patients . Conversely, improvement of skin thickening was shown to correlate with a better prognosis and survival .

Measurement of skin involvement

The modified Rodnan skin score (mRSS) is the most well-established measure of skin fibrosis in clinical practice as well as a recognized outcome measure in clinical trials with skin fibrosis as the primary end point. The mRSS assesses skin thickness at 17 body surfaces with a semiquantitative scale from 0 (normal) to 3 (severe) and a maximum score of 51. Although widely accepted as reliable, valid, and responsive to change, inter- and intra-observer variability is an important intrinsic limitation . To reduce these variabilities, standardization of skin scoring methods between different centers is critical. In multicenter clinical trials, it is recommended that the same investigator assess the mRSS of the same patient at each visit. Regular training on the performance of the mRSS has been shown to reduce inter- and intra-observer variability . Despite the limitations, the mRSS remains the primary outcome measure in clinical trials, especially because other measures of skin fibrosis such as ultrasonography and durometer measurements, despite showing promising preliminary data, lack standardization and have not yet been fully validated .

Challenges

Substantial disease heterogeneity, including time to peak skin score and spontaneous regression of skin fibrosis, is characteristic of the natural history of dcSSc . Patients with progressive skin disease are at the greatest risk for internal organ involvement and mortality and require early therapeutic intervention. They benefit more from therapeutic intervention than patients already displaying regression of skin fibrosis . Thus, identification of markers that predict skin fibrosis progression is a major unmet need. For clinical trial design, it is crucial to recruit patients at risk of mRSS progression to be able to reliably measure therapeutic effects. Similarly, the identification of regressors would be important in order to exclude them from clinical trials to prevent overestimation of treatment effects . This would also be needed in daily practice to avoid unnecessary immunosuppressive treatment with potentially toxic side effects. Attempts to identify patients likely to show worse or improved skin fibrosis have been largely unsuccessful until two recent EUSTAR cohort analyses . Based on 637 dcSSc patients, 6.4–9.7% were identified as progressors with clinically relevant worsening of skin fibrosis at the 12-month follow-up. Short disease duration (<15 months), a low baseline mRSS (<22), and synovitis were independent predictors of progressive skin fibrosis for dcSSc patients with a 4.5-fold increased prediction rate. Alternatively, based on available data from 919 dcSSc patients, including 218 (24%) regressors and 95 (10%) progressors, Dobrota et al. showed that a high baseline mRSS was predictive of skin improvement. In line with the results of Maurer et al. , this study identified a baseline mRSS of 18–25 as a criterion in favor of progressors over regressors . Notably, further supporting data were provided by Kuwana et al. Of note, Domsic et al. aimed to validate the findings of Maurer et al. in the US Pittsburgh cohort. Importantly, in the US, the autoantibody profile of dcSSc differs from European patients in that the former comprised a higher percentage of anti-RNA-polymerase III (anti-RNAP)-positive patients. They showed more rapid disease progression and often higher skin scores at baseline. While principally confirming the results of Maurer et al., Domsic et al. found that the restriction of the mRSS to a cutoff of ≤22 would exclude 27–40% of patients with a worsening mRSS . Therefore, care has to be taken when predictive models are transferred to other study cohorts, and local patient populations and differences in autoantibody subsets should be considered.

These studies have implications for both clinical practice and clinical trial design. By providing new inclusion criteria for the optimization of the ratio of progressors to regressors in clinical studies, the likelihood of identifying treatment effects over the placebo group might be increased. These criteria would also provide a basis for risk stratification, to define a therapeutic window for intervention in dcSSc . Among 629 dcSSc patients included in a meta-analysis of seven multicenter clinical trials that could not prove therapeutic efficacy, the mean baseline mRSS of 25.1 with a high percentage of regressors could have led to the failure of most studies in SSc to date .

However, these prediction models have important limitations. Using an optimized set of parameters, Maurer et al. could only enrich to a maximum of 44.4% progressors. Furthermore, Dobrota et al. noted that only 16% of the variations in skin fibrosis regression could be explained by the final prediction model, indicating that other contributing factors, for example, biomarkers, might be key to determining worsening/improvement of skin fibrosis . Therefore, the identification of such factors is crucial.

Therapeutic options

To date, the options for antifibrotic treatment of SSc skin fibrosis are limited . Non-pharmacological interventions are of great importance in routine care. These include massage, lymphatic drainage, and physical therapy with mobility exercises for the treatment of tissue edema and sclerodactyly. An innovative approach for the treatment of SSc-associated sclerodactyly is the use of human adipose-derived stromal cells (ADSCs). ADSCs have high plasticity including the potential for multi-lineage differentiation and self-renewal . Recent case series have shown that treatment of SSc patients with ADSCs leads to reduced skin tightening, as well as improvement in hand function, finger edema, and quality of life . An ongoing interventional clinical study is analyzing the effect of a perioral microinjection of adipose tissue in dcSSc patients in order to assess its efficacy on skin fibrosis, physical face changes, and quality of life ( Table 1 ).

Current pharmacological agents primarily focus on immunosuppression and immunomodulation. Corticosteroids are commonly used, although their efficacy was not proven in an RCT and higher doses exposed patients to the risk of SSc-associated renal crisis . To date, only one drug, methotrexate (MTX), which has shown borderline efficacy in skin fibrosis in two RCTs, has been listed in the EULAR/EUSTAR treatment recommendations . Cyclophosphamide, a potent suppressor of humoral and T-cell-mediated immune responses that has so far been used for the treatment of SSc-ILD , showed some improvement of skin fibrosis after a 6-month course . Mycophenolate mofetil (MMF), a potent inhibitor of lymphocyte proliferation, showed beneficial effects on skin and lung fibrosis in a case series. An as yet unpublished RCT suggests that MMF has similar efficacy to cyclophosphamide for the lungs and skin ( NCT00883129 ) .

Very recently, hematopoietic stem cell transplantation (HSCT) was added to the EULAR/EUSTAR recommendations as an antifibrotic, immunomodulatory approach to treating rapidly progressing patients . In two RCTs, HSCT showed promising efficacy in terms of a significant reduction in mRSS and long-term event-free survival . However, this survival benefit was accompanied by 10% treatment-related mortality. Therefore, HSCT is only recommended in carefully selected patients with rapidly progressing skin disease at a high risk of organ failure . Given the modest benefit of current therapeutic options, the associated risks, and decreased efficacy over time, there is an urgent need for targeted disease-specific therapeutic agents .

In recent years, biological therapies targeting key molecular players in SSc have come into focus with promising results in clinical trials. One of these novel targeted agents is tocilizumab, a humanized monoclonal antibody targeting the interleukin (IL)-6 receptor (IL-6R). IL-6 has been implicated in the pathophysiology of SSc, in particular in the early inflammatory disease stage . Further, preclinical studies antagonizing IL-6 with antibodies or active immunization showed convincing antifibrotic effects in animal models of dermal fibrosis . Recently, the first promising clinical results were obtained in a phase II clinical trial with beneficial effects on skin fibrosis and lung function ( NCT01532869 ) . Another promising monoclonal antibody for the treatment of skin fibrosis is rituximab, a B-cell-depleting antibody targeting the B-cell marker CD20. Observational case–control studies have reported beneficial effects of rituximab on skin thickening . Proof of efficacy in large-scale RCTs is still lacking. Currently, the efficacy of another B-cell-targeting agent, belimumab, is being tested in an RCT study ( Table 1 ). Belimumab is a B-cell-activating factor (BAFF) belonging to the tumor necrosis factor family. BAFF inhibition exhibited antifibrotic effects in tight skin-1 mice, an inflammation-independent mouse model of skin fibrosis. In addition, enhanced BAFF signaling was detected in SSc patients, with BAFF directly affecting the pro-fibrotic gene expression in SSc dermal fibroblasts . As T cells are also key cellular players in SSc, inhibition of T-cell activation might be a promising therapeutic approach. Abatacept is a cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) analog that can inhibit T-cell activation by blocking T-cell co-stimulation. In the first RCT, abatacept was shown to efficiently improve skin involvement in dcSSc patients ( NCT00442611 ). Interestingly, soluble guanylate cyclase (sGC) stimulators were recently shown to reduce dermal fibrosis in preclinical SSc animal models by blocking non-canonical transforming growth factor beta (TGF-β) signaling . Given their vasoactive properties, these stimulators are likely to have an additional beneficial effect on the vascular manifestations of SSc disease. A large clinical study to address the efficacy of sGC stimulators on skin fibrosis in SSc has been launched ( Table 1 ). Other promising targets for treatment of skin fibrosis are peroxisome proliferator-activated receptors (PPAR) analogs. Recently, Wei et al. demonstrated the antifibrotic effects of the PPAR-y receptor agonist triterpenoid, by antagonizing the canonical TGF-β pathway in SSc animal models of dermal fibrosis . Given these promising preclinical data, a proof-of-concept study has been launched in dcSSc ( NCT02503644 ). In addition, fresolimumab, a recombinant, fully human monoclonal antibody directed against human TGF-β 1, 2, and 3, has shown promising results in early dcSSc with rapid inhibition of TGF-β-regulated gene expression in response to fresolimumab and parallel improvement in mRSS . A selection of novel therapeutic agents for the treatment of SSc, which are currently being assessed for efficacy in clinical studies, is listed in Table 1 .

Time for structured care

The highly heterogeneous disease phenotype and lack of adequate outcome measures of skin fibrosis present a major challenge for the management of SSc skin disease in routine care. High-quality evidence-based data on the treatment of skin fibrosis are scarce. The conventional immunosuppressive drugs currently in use have rather modest effects, which decrease over time and are associated with considerable potential adverse effects.

Based on the currently available data, there are no structured treatment approaches for managing skin fibrosis in SSc, but a structured approach to management is being considered ( Fig. 2 ). The (early) determination of the subtype of skin disease (lcSSc vs. dcSSc) and of the disease stage is crucial because a) the occurrence of organ complications (e.g., vascular vs. fibrotic) differs between the two principal skin phenotypes and b) organ complications in both subtypes are likely to progress more rapidly early in the disease course . With respect to skin involvement, patients with limited cutaneous disease usually do not require systemic therapy. In patients with the diffuse cutaneous subtype, ideally, risk stratification should be performed to identify patients who are likely to progress, as only these should be considered for treatment.

Only gold members can continue reading. Log In or Register to continue

Share this:

• Click to share on Twitter (Opens in new window)
• Click to share on Facebook (Opens in new window)

Related

Related posts:

Improving care of autoimmune connective tissue diseases: Lessons from longitudinal cohorts Pregnancy and autoimmune connective tissue diseases Cardiovascular risk and its modification in patients with connective tissue diseases Raynaud’s phenomenon Antiphospholipid syndrome Primary Sjögren’s syndrome

Stay updated, free articles. Join our Telegram channel

Join