Systemic sclerosis: The need for structured care

Best Practice & Research Clinical Rheumatology xxx (2016) 1e19

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Systemic sclerosis: The need for structured care Kathleen Morrisroe a, b, Tracy Frech c, d, Janine Schniering e, Britta Maurer e, Mandana Nikpour a, b, * a

Department of Medicine, The University of Melbourne at St. Vincent's Hospital, Melbourne, VIC, Australia Department of Rheumatology, The University of Melbourne at St. Vincent's Hospital, Melbourne, VIC, Australia c Division of Rheumatology, Department of Internal Medicine, University of Utah, Salt Lake City, UT, USA d Salt Lake Regional Veterans Affair Medical Center, Salt Lake City, UT, USA e Division of Rheumatology, University Hospital Zurich, Zurich, Switzerland b

a b s t r a c t Keywords: Systemic sclerosis Treatment algorithm Model of care Digital ulcers Scleroderma

Autoimmune connective tissue diseases (CTDs) have a propensity to affect multiple organ systems as well as physical function, quality of life, and survival. Their clinical heterogeneity, multisystem involvement, and low worldwide prevalence present challenges for researchers to establish a study design to help better understand the course and outcomes of CTDs. Systemic sclerosis (SSc) is a notable example of a CTD, wherein longitudinal cohort studies (LCS) have enabled us to elucidate disease manifestations, disease course, and risk and prognostic factors for clinically important outcomes, by embedding research in clinical practice. Nevertheless, further efforts are needed to better understand SSc especially with regard to recognizing organ involvement early, developing new therapies, optimizing the use of existing therapies, and defining treatment targets. The heterogeneous multi-organ nature of SSc would lend itself well to a structured model of care, wherein step-up treatment algorithms are used with the goal of attaining a prespecified treatment target. In this chapter, we discuss the rationale for a structured treatment approach in SSc and propose possible treatment algorithms for three of the more common disease manifestations, namely skin involvement, digital ulcers and gastrointestinal tract involvement. We discuss possible strategies for evaluating and implementing these algorithms in the setting of

* Corresponding author. Department of Rheumatology, The University of Melbourne, St Vincent's Hospital, 41 Victoria Parade, Fitzroy, VIC 3065, Australia. Tel.: þ61 3 9288 2211; fax: þ61 3 9417 0822. E-mail address: [email protected] (M. Nikpour). http://dx.doi.org/10.1016/j.berh.2016.04.004 1521-6942/© 2016 Elsevier Ltd. All rights reserved.

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LCS. We conclude by presenting a research agenda for the development of structured models of care in SSc. © 2016 Elsevier Ltd. All rights reserved.

Practice points  Longitudinal cohort studies (LCS) have contributed significant insight into disease manifestations, disease course, risk factors, and prognostic factors for clinically important outcomes in low-prevalence multisystem heterogeneous conditions such as connective tissue diseases (CTDs).  Systemic sclerosis (SSc) is an excellent example of how LCS have furthered our understanding of the natural history of SSc, with research being embedded in clinical practice.  Structured models of care are successful in changing clinical practice, thereby improving quality and efficiency of care and patient outcomes. In addition, they reduce diseaseassociated economic burden by reducing health-care utilization and increasing patients' ability to maintain paid employment.  A structured approach to the care of three of the key clinical manifestations of SSc, namely skin involvement, digital ulcers and gastrointestinal tract (GIT) involvement, is outlined in this chapter.

Introduction Autoimmune connective tissue diseases (CTDs) are rheumatic conditions with a propensity to affect multiple organ systems. They include conditions such as systemic sclerosis (SSc), systemic lupus er€ gren's syndrome, and mixed connective tissue disythematosus (SLE), inflammatory myopathies, Sjo ease (MCTD). The clinical heterogeneity of these conditions results in significant knowledge gaps and unmet needs. Accordingly, our understanding of their natural history, pathogenesis, triggers, and response to treatment must be expanded [1]. Longitudinal cohort studies (LCS) have significantly elucidated disease manifestations, disease course, risk factors, and prognostic factors for clinically important outcomes in low-prevalence multisystem heterogeneous conditions such as the CTDs, which are otherwise very difficult to study. SSc is an excellent example of how LCS have furthered our understanding of the natural history of SSc, with research being embedded in clinical practice. SSc is a chronic CTD with variable involvement of the skin and internal organs and a worldwide prevalence ranging from 7 per million to 489 per million [2]. Among the rheumatic diseases, SSc has the highest case-based mortality with an average loss of life expectancy of >20 years relative to the general population [3]. It is also one of the most costly rheumatic diseases, with SSc patients utilizing more health-care dollars per annum than their age- and sex-matched counterparts with rheumatoid arthritis (RA) or psoriatic arthritis [4]. Morbidity in SSc is substantial, comparable with that of heart disease, depression, and some cancers [5]. Morbidity and irreversible organ damage can occur within the first 2 years of disease onset, leading to impaired physical function and reduced health-related quality of life (HRQoL) [5]. Therefore, the early stages of SSc present a narrow, but important window of opportunity for preventing irreversible organ damage. Due to the relatively low disease frequency of SSc, multicenter collaborations are needed to recruit a sufficient number of patients to power research studies. Collaboration between centers currently occurs in SSc via several LCS such as the Pittsburgh Scleroderma Centre, Australian Scleroderma Interest Group (ASIG), Canadian Scleroderma Research Group (CSRG), European Scleroderma Trials and Research Group (EUSTAR), and Genetics versus Environment in Scleroderma Outcomes Study (GENISOS) cohorts, among others. These collaborations have been key to furthering our understanding of certain disease manifestations in SSc such as interstitial lung Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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disease (ILD) and treatment outcomes such as lung transplantation (Pittsburgh Scleroderma center), clinical biomarkers, and the role of autoantibodies (ASIG, CSRG). Trials have been conducted, and European management recommendations (EUSTAR) and the natural disease history have been established by following up an inception cohort over time (GENISOS). Together, these cohorts highlight how LCS have contributed significant insight into the disease process, defining treatment goals, identifying best practices, testing research hypotheses, and guiding government bodies for policy change or implementation [1]. Despite European League of Associations for Rheumatology (EULAR) recently publishing SSc specific evidence-based and consensus-driven guidelines to aid clinicians in their clinical decision making [6], prospectively acquired data from Australian and Canadian cohorts reveal that physicians do not follow best evidence in the treatment of SSc, with only 25e40% of SSc patients receiving the recommended treatment [7]. This occurs for several possible reasons, including lack of specific treatment algorithms as opposed to general management guidelines. The failure to follow best evidence in management is of particular concern in SSc where damage occurs early, with 40% of patients showing organ damage within the first 2 years of disease onset, which worsens rapidly over the subsequent 5 years of follow-up [8]. When left untreated, patients present with progressive, irreversible organ damage, physical disability, and high mortality [8]. This is crucial for organ manifestations such as digital ulcers (DUs), gastrointestinal (GIT) involvement, pulmonary arterial hypertension (PAH), and ILD, for which treatments have been proposed. If implemented early, these treatments can reduce morbidity and mortality and in turn improve HRQoL. Given the significant burden of morbidity and mortality associated with SSc, identifying and implementing strategies to optimize outcomes should be a research priority. Possible approaches include (i) better recognition of early organ involvement, (ii) development of new therapies, (iii) optimization of the use of existing therapies, and (iv) definition of treatment targets. RA is an example of a rheumatic disease where application of all four of these strategies has led to significantly improved outcomes. In particular, a treat-to-target approach including optimizing the use of existing therapies through “step-up treatment algorithms” and defining low disease activity and remission treatment targets has revolutionized the care of RA. As a disease entity with multi-organ manifestations, SSc would lend itself well to such a structured model of care, although treatment algorithms would need to be tailored to each of the specific disease manifestations. These structured treatment algorithms would outline a suggested course of treatment for a specific clinical manifestation and provide a logical flow of evidence-based treatment recommendations. The literature suggests that structured models of care such as these are successful in changing clinical practice, improving quality and efficiency of care, and improving patient outcomes [9]. Furthermore, these algorithms reduce the economic burden of these diseases by reducing health-care utilization and increasing patients' ability to maintain paid employment [10,11]. A standardized treatment algorithm for various SSc clinical manifestations is beneficial for both the treating physician and the patient. It ensures that the physician is aware of the most up-to-date treatment recommendations, and it provides alternative options in difficult clinical cases. The treatment choice is ultimately at the physician's discretion based on intimate knowledge of the clinical situation and the characteristics of the patient being treated. For the patient, a standardized treatment algorithm ensures that he or she receives the best available care and is treated according to best practice and evidence-based guidelines. In the rest of this chapter, we discuss the possibility of a structured approach to the care of three of the key clinical manifestations of SSc, namely skin involvement, DUs, and gastrointestinal tract (GIT) involvement. PAH and ILD are discussed in Chapters 2 and 3, respectively. We outline the rationale for such an approach and the considerations specific to each manifestation, and we propose a possible treatment algorithm, or alternatively a research agenda, to develop a structured treatment algorithm. We also discuss potential treatment targets of these algorithms. Following this, we discuss the possible evaluation and implementation of such structured models of care in the setting of LCS.

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Applying a structured model of care to DUs in SSc 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 [12]. 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 [12]. 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 [13] and occupation [14]. Chronic ulcers can become infected resulting in pain, gangrene, and/or osteomyelitis requiring hospitalization, parenteral medications, and autoamputation or surgical amputation [13,14]. Early identification of DUs and any contributing factors has been shown to improve outcomes [14], 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 [15]. 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 [12,16]. 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 nonpharmacological and pharmacological care [12,17]. 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 [12,17], 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 [18]. 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 [19]. 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 e 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 e Hand Disability in Systemic Sclerosis e Digital Ulcers (HDISS-DU) Score [20]. Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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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 [12,17]. 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, antiinflammatory, and antifibrotic effects [21]. 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 [22]. Alternatively or additionally, refractory DUs can be treated with a prostacyclin analog such as intravenous iloprost with level 2 evidence from RCTs [12]. 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. 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. Structured approach to the management of skin disease in SSc Overview Skin fibrosis, which clinically manifests as tightened and thickened skin, is the hallmark of SSc [23,24]. Cutaneous manifestations are critical for SSc diagnosis, prognosis, and classification [25]. Based on the extent of skin involvement, two principal disease subsets are distinguished: limited cutaneous (lcSSc) and diffuse cutaneous SSc (dcSSc) [26]. 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 [23,25]. Skin involvement significantly contributes to the high morbidity associated with SSc and affects the HRQoL in both physical and mental domains [27]. Patients present with pain, impaired hand function, and disfigurement due to pigment changes, hand contractures, facial telangiectasias, and tightened skin [28]. 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 [29,30]. Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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OR if pulmonary arterial hypertension present

Fig. 1. Flowchart for management of digital ulcers in systemic sclerosis.

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Conversely, improvement of skin thickening was shown to correlate with a better prognosis and survival [31]. 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 [32,33]. 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 [34,35]. 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 [36e38]. Challenges Substantial disease heterogeneity, including time to peak skin score and spontaneous regression of skin fibrosis, is characteristic of the natural history of dcSSc [39,40]. 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 [41]. 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 [40,42]. 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 [31,40,42,43] until two recent EUSTAR cohort analyses [42]. Based on 637 dcSSc patients, 6.4e9.7% 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 [42] 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. [44], this study identified a baseline mRSS of 18e25 as a criterion in favor of progressors over regressors [44]. 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 27e40% of patients with a worsening mRSS [45]. 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 [23]. 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 [38,42]. Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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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 [42,44]. Therefore, the identification of such factors is crucial. Therapeutic options To date, the options for antifibrotic treatment of SSc skin fibrosis are limited [56]. Nonpharmacological 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 [57]. 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 [57e59]. 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 [35,36]. 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 [6,56,60,61]. Cyclophosphamide, a potent suppressor of humoral and T-cell-mediated immune responses that has so far been used for the treatment of SSc-ILD [41,49], showed some improvement of skin fibrosis after a 6-month course [62]. 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) [49,63]. Very recently, hematopoietic stem cell transplantation (HSCT) was added to the EULAR/EUSTAR recommendations as an antifibrotic, immunomodulatory approach to treating rapidly progressing patients [64]. In two RCTs, HSCT showed promising efficacy in terms of a significant reduction in mRSS and long-term event-free survival [65,66]. 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 [56]. 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 [23]. 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 [67,68]. Further, preclinical studies antagonizing IL-6 with antibodies or active immunization

Table 1 Selection of current clinical trials for novel treatment agents for SSc skin disease. Therapeutic agent

Mechanism of Action

Trial status

Clinical trial identifier

Belimumab IVA337 JBT-101 Abatacept Riociguat Tocilizumab Micro reinjection of autologous adipose tissue

BAFF inhibitor PPAR activator CB2 agonist CTLA-4 analog sGC stimulator IL-6R inhibitor Microfat grafting

Phase II (ongoing) Phase II (recruiting) Phase II (recruiting) Phase II (recruiting) Phase II (recruiting) Phase III (recruiting) Interventional (recruiting)

NCT01670565 NCT02503644 NCT02465437 NCT02161406 NCT02283762 NCT02453256 NCT02206672

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showed convincing antifibrotic effects in animal models of dermal fibrosis [69e71]. Recently, the first promising clinical results were obtained in a phase II clinical trial with beneficial effects on skin fibrosis and lung function (NCT01532869) [72]. Another promising monoclonal antibody for the treatment of skin fibrosis is rituximab, a B-cell-depleting antibody targeting the B-cell marker CD20. Observational caseecontrol studies have reported beneficial effects of rituximab on skin thickening [49,73,74]. Proof of efficacy in large-scale RCTs is still lacking. Currently, the efficacy of another Bcell-targeting agent, belimumab, is being tested in an RCT study (Table 1). Belimumab is a B-cellactivating 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 [75e77]. 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 [78] (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-b) signaling [79,80]. 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-b pathway in SSc animal models of dermal fibrosis [81]. Given these promising preclinical data, a proof-of-concept study has been launched in dcSSc (NCT02503644). In addition,

Fig. 2. Structured management of skin disease in SSc.

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fresolimumab, a recombinant, fully human monoclonal antibody directed against human TGF-b 1, 2, and 3, has shown promising results in early dcSSc with rapid inhibition of TGF-b-regulated gene expression in response to fresolimumab and parallel improvement in mRSS [82]. 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 [7]. 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. Applying a structured model of care to GIT involvement in SSc Overview The GIT is the most commonly involved internal organ in SSc. The pathophysiology is considered similar to other organ involvement in SSc with progressive microangiopathy, immune dysregulation, and fibrosis and myenteric plexus dysfunction. Disease duration may play a role in the severity of GIT manifestation due to progressive vascular hypoperfusion and ischemia and/or collagen accumulation [83]. The role of autoantibodies in the pathogenesis of GIT dysfunction is unclear [84,85]. The GIT is the presenting disease feature in 10%, occurs at some stage during the disease in up to 95%, and is responsible for 6e12% of mortality in SSc patients [86]. As such, early identification and accurate diagnosis of SSc-GIT, assessment of severity, appropriate treatment, and minimization of the impact on quality of life are of paramount importance. GIT symptom management, the need for simultaneously investigating multiple treatments in the SSc patient population, and appropriate application of investigations present challenges. A structured approach to the care of GIT involvement in SSc is challenged by the lack of evidence-based treatment algorithms and of disease-modifying therapies. However, algorithms must be appropriately developed to better inform the selection of therapeutic targets in international research. The GIT in SSc research agenda It is well recognized that the Outcomes in Rheumatology Clinical Trials (OMERACT) filter should inform the development of therapeutic recommendations by identifying the essential characteristics of outcome measures [87,88] and ensuring content validity across patient-important and interventionspecific information [88]. In SSc, there is much interest in reproducible and feasible biomarkers, which are highly sensitive and specific, reflect disease status, and relate to disease activity and/or severity throughout the clinical evolution [89]. For SSc-GIT research, both the invasiveness and availability of testing for biomarker acquisition are serious limitations. Thirteen international SSc experts have recently published evidence-based points to consider for future clinical trials in SSc using EULAR standards [91]. Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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GIT investigation The history is perhaps the most essential aspect of appropriate SSc-GIT care, but SSc-GIT symptoms are frequently overlooked and undertreated [92]. Often, GIT information can be obtained using questionnaires, which can also assess the impact on HRQoL. Perhaps the most commonly used and widely translated questionnaire specific to GIT assessment in SSc is the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract Questionnaire 2.0 (GIT 2.0), which is a validated, patient-reported outcome measure to assess HRQoL and GIT severity in SSc [93e95]. This 34-item instrument has seven subscales: reflux, distention/bloating, diarrhea, fecal soilage, constipation, emotional well-being, social function, and a total GI score. The total GI score is the average of six of seven scales (excludes constipation), which is scored from 0.0 (better HRQoL) to 3.0 (worse HRQoL). Of note, this questionnaire does not adequately assess malnutrition, pelvic floor-related symptoms, or mild small bowel bacterial overgrowth, which are significant issues in SSc [92,95e97]. Nonetheless, it does help inform a treating physician of the symptom severity and can guide the appropriateness of further investigations, particularly for upper GIT symptoms [98]. The National Institute of Health Patient-Reported Outcome Measurement Information System (PROMIS(®)) has developed a GIT domain with comprehensive items assessing eight domains of GI symptoms: gastroesophageal reflux (GERD) (13 items), disrupted swallowing (seven items), diarrhea (five items), bowel incontinence/soilage (four items), nausea and vomiting (four items), constipation (nine items), belly pain (six items), and gas/bloat/flatulence (12 items); this has been tested in patients with SSc [99,100]. The GIT physical examination is often of limited value for diagnostic purposes, which makes registry data less informative for international collaborative efforts. The oral cavity is perhaps the most accessible part of the GIT for assessment. Sublingual frenulum abnormalities have been observed and can be quantified, but the clinical significance of such features is not known [101]. Microstomia may limit the ability to adequately assess the oral cavity. Nonetheless, due to the presence of mucosal atrophy and periodontal disease, comanagement with dental or periodontal specialists is an important consideration and potential area for collaborative research efforts [102]. The most commonly requested GIT diagnostic tests are used to assess reflux and dysphagia, as the esophagus is the most commonly involved part of the GIT in SSc [103]. Involvement of the lower twothirds of the esophagus can result in GERD, erosive, and/or Candida esophagitis, and, if more chronic, stenosis, strictures, and Barrett's metaplasia [104]. Esophagogastroduodenoscopy (EGD) allows direct visualization of the lining of the esophagus, stomach, and duodenum. It is diagnostic for erosive lesions and gastric antral vascular ectasia (GAVE; “watermelon stomach”) and it can monitor the clinical course of Barrett's. However, it does not provide functional information. Functional assessments of the esophagus include esophagram, manometry, pH testing, and impedance. Each provides slightly different information and has important limitations. A barium esophagram visualizes the esophagus and stomach under fluoroscopy, but it only provides a rough estimate of the degree of esophageal muscle contractions. Esophageal manometry helps identify dysmotility of the esophagus and/or the dysfunction of the lower esophageal sphincter (LES), although it does not correlate well with GERD. An ambulatory 24-h pH probe allows measurements of acid exposure in the esophagus. These results are compared to the normal acid exposure in the esophagus and are considered the “gold standard” for the diagnosis of GERD. Impedance testing is required to measure liquid movement from the stomach into the esophagus to diagnose bile reflux. A newer diagnostic tool for esophageal functional assessment is the functional luminal imaging probe (FLIP; Crospon, Inc., Galway, Ireland), a balloon-tipped catheter that measures esophageal cross-sectional area and pressures. It is not yet widely available in clinical practice [105]. Of note, all of these tests, which provide different information, are intended for investigation of the same subjective symptoms of heartburn, dysphagia, nausea, and volume regurgitation and/ or emesis. Gastric motility disorders in SSc may include delayed gastric emptying (gastroparesis) and rapid gastric emptying (dumping syndrome) as well as functional dyspepsia, which may be due to dysfunction of the autonomic nervous system, smooth muscle cells, and enteric neurons [106]. Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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Diagnosis of gastroparesis is most commonly made by a nuclear medicine gastric emptying study, which detects the rate at which food leaves the stomach. Gastric or duodenal manometry can also be performed to measure the strength and pattern of muscle contractions. Breath tests can be conducted to identify dietary intolerance or malabsorption, for example, to lactose or fructose (glucose hydrogen breath test; HBT), Helicobacter pylori (urea breath test; UBT), or small intestinal bacterial overgrowth (SIBO) (HBT and methane; H2/CH4 breath testing). Although the gold standard for the diagnosis of SIBO is a jejunal aspirate culture with a microbial concentration >105 CFU/ml, this is both difficult and invasive. The glucose H2/CH4 breath test is the most commonly used test for diagnosing SIBO and is the only fully validated SIBO test in SSc [107]. This emphasizes the need for standardizing routine testing in SSc-GIT. The structure of the large intestine and anorectal area can be assessed by colonoscopy, barium enema, or ultrasonography. Functional characterization can be achieved by nuclear scintigraphy, or defecating proctography, fecogram, and defecography. Defecography is particularly useful when evaluating complaints of constipation and difficult evacuation, but it is only available at certain centers. Similarly limited in availability, manometry tests of the anal sphincter muscles as well as anorectal balloon capacity and compliance testing can provide further information on function. Transrectal electromyography (EMG) is perhaps the most informative test, although invasive and limited in availability, which tests electrical activity in the anal sphincter and pelvic floor muscles. Laboratory tests are of limited value in the assessment of SSc-GIT complaints with a few notable exceptions. The anti-mitochondrial antibody (AMA) is helpful for the diagnosis of primary biliary cirrhosis overlap, which is found in 2e2.5% of SSc patients [108,109]. Celiac serology (anti-tissue transglutaminase and immunoglobulins) is recommended if gluten hypersensitivity is suspected. Stool studies for Clostridium difficile in patients exposed to antibiotics, fecal elastase if exocrine pancreas insufficiency is suspected, and fecal calprotectin for assessment of SIBO eradication may be useful in the right clinical context [110,111]. As these tests are not routinely used for SSc-GIT assessment, understanding their application in structured care is a challenge [37]. In summary, GIT investigations are invasive, availability may vary, and their role is uncertain. As such, treating physicians often implement empirical approaches for SSc-GIT symptoms. Evaluating investigations in a heterogeneous SSc patient population in a standardized manner is necessary to best understand complex pathogenesis (Fig. 3).

Fig. 3. Proposed structured care model for SSc-GIT algorithms.

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Therapeutic options Traditionally, therapies are targeted to the suspected SSc-GIT complication suggested by the symptoms. GERD is first treated empirically with proton pump inhibitors (PPI) and lifestyle modifications, such as sleeping on an incline and avoiding aggravating foods [110,112]. Early treatment with PPI has been shown to reduce the GERD-related complication of ILD [113,114]. While H2 blockers, antacids, and sucralfate have also been suggested as early management options for GERD with the goal of healing esophagitis, these recommendations are not supported by data [115]. The long-term consequences of acid suppression have not been assessed, and the risks of enteric infection and effects on absorption of vitamins and minerals have not been clarified in SSc patients. Of note, unlike Barrett's esophagus, stricture, and GAVE management, all of which are diagnosed and/or treated by endoscopy, reflux treatment for SSc is almost universally started before diagnostic studies, thus complicating our understanding of the effects of this therapy and highlighting the importance of structured data collection [110]. Prokinetics are often used as adjuncts for patients with reflux due to delayed gastric emptying and gastroparesis, which produces symptoms of early satiety, nausea, bloating, and abdominal pain [116]. Erythromycin and ghrelin are the only prokinetic medications that have been shown to affect gastric emptying in SSc [117]. Octreotide, a somatostatin analog, has been proven to treat chronic intestinal pseudo-obstruction in SSc [118,119], but it can decrease gastric emptying, highlighting the challenge of empirical therapy in this patient population. The adverse effects of prokinetics can include diarrhea, one of the symptoms of SSc-GIT disease, which is well recognized as being multifactorial in origin [110]. Of note, experts recommend that antidiarrheal medications, such as loperamide, should not be used empirically prior to identifying the cause. Cholestyramine or other bile acid sequestrants are suggested as treatment options for diarrhea [110]; however, it should be noted that these drugs can cause constipation, nausea, flatulence, bloating, and abdominal pain, which limits empirical use and further complicates the standardization of therapy. Antibiotic therapy is often empirically initiated when SIBO is suspected in SSc. In a systematic review and meta-analysis of ten studies comparing the clinical efficacy of antibiotics (rifaximin, metronidazole, neomycin, ciprofloxacin, and chlortetracycline) for symptomatic patients with documented SIBO, antibiotics were more effective than placebo [120]. Rifaximin was the most studied antibiotic (eight studies), which was found to be most effective when combined with partially hydrolyzed guar gum. However, formulary restrictions may limit the availability of rifaximin as first-line therapy in many hospitals. Treatment with antibiotics alone does not completely address the microbial dysbiosis associated with SIBO and the addition of pre- or probiotics, which may enhance gut barrier function, decrease the inflammatory response, stabilize gut flora, and potentially modulate visceral hypersensitivity. Thus, further study is warranted in this respect. Dietary modification is said to be a mainstay for symptoms of malnutrition, SIBO, and gastroparesis [110]. However, international dietary patterns vary, making standardized algorithms challenging. Nonetheless, some SSc experts recommend a fermentable oligosaccharide, disaccharide, monosaccharide, and polyol (FODMAP)-restricted diet [112]. Of note, studies of FODMAP diets in SSc are needed to establish long-term efficacy and safety, particularly their effects on colonic health and microbiome [121]. Therapeutic teams of dieticians familiar with dietary interventions, mental health providers, gastroenterologists, and surgeons who can set appropriate goals to improve and increase overall nutritional intake are an important aspect of management. Nevertheless, access to medical care remains a challenge [110]. Potential therapeutic targets As highlighted earlier, the lack of standard application of investigations and initial empirical treatment of GIT symptoms in SSc patients may have led to the lack of substantial evidence for treating physicians [110]. Nonetheless, the literature can guide us on potential therapeutic targets. While histological studies of the esophagus and small and large intestine have important limitations such as variable disease duration and heterogeneous disease severity, inflammation, ischemia, fibrosis, and neural function are likely to be involved in the spectrum of SSc-GIT dysfunction [110]. Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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Immunosuppression is commonly used to treat the inflammatory manifestations of SSc, particularly the skin, lungs, and joints. Common side effects of immunosuppressive drugs include GIT symptoms, such as nausea and change in bowel habits. As such, selecting an immunosuppressive drug for a disease with GIT symptoms, such as SSc, can be particularly challenging [122]. The role of immunosuppressive drugs to prevent or treat GIT disease in SSc remains largely unknown. It has not been adequately characterized and reported by clinical trial data published to date. Vascular dysfunction is among the earliest and key SSc manifestations, which can guide potential therapeutic targets [123]. Nitric oxide (NO) produced by the enteric nervous system represents an important regulatory checkpoint, and aberrant NO signaling contributes significantly to enteric disease by altering vascular tone, gut motility, blood supply, mucosal barrier function, secretions, and immunity. Large amounts of bioactive NO are also generated from dietary sources via a nitric oxide synthase (NOS)-independent chemical reaction of dietary nitrite with hydrochloric acid in the stomach and via microbial reduction following aerobic conversion in the oral cavity, or via an anaerobic reaction with nitrate in the colon mediated by Escherichia coli. [124] Patients receiving therapeutics targeting NO production and its bioactive intermediates for treatment of PAH in SSc should be monitored adequately for their GIT symptoms and their gut microbiota characterized. The GIT microbiota secretes factors with specific health benefits, such as immunomodulation and pathogen inhibition. It is possible to target the gut biofilm by providing the metabolic fuel needed for the growth and expansion of beneficial microorganisms (prebiotics) or by administering such microorganisms to the host (probiotics) [125]. As antibiotics can modify the gut microbiome, empirical SIBO treatment regimens in SSc should be structured and studied. In summary, the relationship between elements of the immune system and the nervous system in maintaining gut homeostasis is of interest in SSc. Vascular-derived signals from enteric neurons and glia may confer wide-ranging protective functions and represent important therapeutic targets for SScGIT disease. However, structured GIT care must take into account all therapeutics and other organ involvement to best inform recommended practice.

Time for structured care The available RCT data in SSc are not adequate for informing the care of the SSc-GIT. Evidence-based guidelines are limited by the fact that GIT diagnostic studies are invasive, expensive, and not widely available. Empirical treatments are often used to relieve GIT symptoms early in their course with potential adverse effects, which can affect long-term GIT outcomes. Thus, it is difficult to conclude that the current expert-based guidelines are adequately informed. As such, there is a need for international collaborative efforts to design treatment algorithms for better insight into both the empirical treatment of GIT involvement [110] and clinical trial design [91] in SSc. The UK scleroderma study group has recognized this need and published GIT treatment algorithms, also highlighting the need for further research in this area [110]. Structured GIT care in SSc is expected in future. The routine use of questionnaires in clinical practice can help physicians understand SSc-GIT symptoms and natural history. Guidelines on the appropriate use of diagnostic studies upon exacerbation of symptoms can elucidate the role of therapeutics according to the levels of evidence. Furthermore, tracking the effect of immunosuppressive and vasodilatory drugs on gut homeostasis is essential for structured care in SSc. While a task force or working group can be set up to design expert-based treatment algorithms, the use of online screening surveys conducted through patient portals may help relate well-characterized GIT data to patients' perception of symptoms [126]. These patient-centered GIT algorithms could be applied to large cohorts to assess the feasibility of their application as well as their usefulness in a real-life setting. Ideally, a clinical trial design, which allows the evaluation of multiple treatments across international centers in an efficient manner, can be used to better understand the effects of vascular- and immune-based SSc therapy on GIT homeostasis [127]. An adaptive pragmatic design that measures treatment efficacy could be particularly informative for multiple SSc-GIT international cohorts, where different empirical therapies are used, rigorous blinding is not realistic, and there is a need to assess multiple GIT therapies over time [128]. Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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Evaluating and implementing structured models of care in a longitudinal cohort setting Overview The three clinical manifestations outlined earlier highlight the clinically heterogeneous multisystem disease SSc. The heterogeneity of disease and the varying strengths of evidence supporting treatments in SSc pose a significant challenge for the treating physician. Thus, despite the availability of evidence-based recommendations for SSc treatment [6], only 25e40% of SSc patients receive this recommended treatment [7]. While a structured “evidence-based protocol” approach to care has become standard practice in certain chronic medical conditions such as diabetes mellitus, hyperlipidemia, hypertension, and RA, it is yet to be applied in CTDs such as SSc [129,130]. This may be due to the heterogeneous nature of SSc and a lack of (i) published treatment algorithms for this multi-organ disease [131], (ii) relevant and valid outcome measures, and (iii) evidence that such an approach to treatment alters outcomes. We believe that a structured approach to care may be superior to standard care because it is (i) based on best evidence, (ii) incorporates pharmacological and non-pharmacological therapies, and (iii) allows a more systematic and considered approach to management. Moreover, a structured model of care has been proven to improve outcomes in other rheumatologic diseases such as RA [129,130]. Even among the CTDs, SSc is a unique entity. Unlike SLE and systemic vasculitis wherein almost all disease manifestations may be treated with immunosuppression, only a few disease manifestations in SSc are due predominantly to inflammation. Patients with SSc frequently display multiple disease features and are often prescribed multiple therapies. In light of these considerations, an integrated approach to the care of the multi-organ manifestations of SSc is required. We believe that a structured model of care approach to SSc management needs to be evaluated. These treatment algorithms can be integrated into a clinical care setting and evaluated against standard care by means of pragmatic trials nested in LCS. In this manner, each treatment approach and its outcomes can be compared. A pragmatic trial design is ideal for evaluating the therapeutic efficacy of a protocol-based approach to care in a complex chronic disease such as SSc, whereby broad inclusion criteria and flexible conditions maximize the applicability of the trial's results to everyday practice in the clinical care setting. Summary and research agenda SSc is a complex CTD that poses a management challenge for the treating physician. Its many and varied clinical manifestations with differing etiologies often require multiple therapeutic agents with different modes of action. Unfortunately, in the present treatment era, there is no cure for SSc and effective disease-modifying agents are lacking. The current treatment approach is at the physician's discretion and is at best symptomatic in nature. Prospectively acquired data from Australian and Canadian cohorts reveal that physicians do not follow best evidence in the treatment of SSc in a large proportion of cases [132]. Currently, no evidence-based standardized treatment algorithm is available for SSc. We believe that the implementation of structured treatment algorithms for common manifestations, with clearly defined treatment targets, can reduce organ damage, morbidity, and mortality. It also allows the comparison of the structured treatment with usual care within a pragmatic trial, in addition to rendering it cost-effective. If structured treatment proves to be superior to usual care, then this novel model of care can significantly alter the approach to SSc management. We propose the following research agenda in order to design useful treatment algorithms that can be easily applied to clinical practice. The first step would be to form organ-focused expert groups in order to review the existing literature and to determine the feasibility of developing treatment algorithms for the various disease manifestations associated with SSc. The second step might be to create treatment algorithms based on best evidence and expert consensus. The third step might be to define treatment targets and determine the optimal step-up frequency for treatment. The fourth step would be to evaluate the benefits of the treatment algorithm compared with usual care and to determine the cost-effectiveness of applying a structured model of care versus usual care in a longitudinal cohort Please cite this article in press as: Morrisroe K, et al., Systemic sclerosis: The need for structured care, Best Practice & Research Clinical Rheumatology (2016), http://dx.doi.org/10.1016/j.berh.2016.04.004

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setting. Here, the outcomes of interest might be preservation of organ function, HRQoL, physical function, and survival. Finally, the last step would be the implementation of these organ-based treatment algorithms into clinical practice with the ultimate aim of improving patient care. Acknowledgments Dr Morrisroe holds a National Health and Medical Research Council of Australia (NHMRC) Postgraduate Scholarship (APP1113954). Dr Nikpour holds an NHMRC Clinical Research Fellowship (APP1071735). References *[1] Gerss JW, Kopcke W. Clinical trials and rare diseases. Adv Exp Med Biol 2010;686:173e90. [2] Chifflot H, Fautrel B, Sordet C, et al. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum 2008;37(4):223e35. *[3] Hao YJ, Hudson M, Carreira P, et al. Early mortality in Australian, Canadian and Spanish scleroderma patients: rationale for establishing a multi-national inception cohort of patients with systemic sclerosis. 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