Systemic Sclerosis and Other Connective Tissue Diseases

CLASSIFICATION

Mechanisms of PH have specific associations in different CTDs that reflect the multisystem nature of the associated disorders, but are in line with current approaches to classification of PH.8 Treatment approaches are shared for other forms of PH, but in CTD there may be mixed mechanisms that complicate treatment approaches, and this may affect long-term outcome and response to therapy. The complexity of the different mechanisms for PH in CTD make it important to systematically investigate all suspected cases so that appropriate mechanisms can be addressed. Histologically, cases of SSc-PAH resemble those with other forms of Group 1 PAH (Figure 2).

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SCREENING AND DIAGNOSIS

It is well established that screening is important due to the high risk of developing PH as described. There have been a variety of approaches suggested for screening, and it includes ad hoc approaches that were developed based on echocardiogram (ECHO) and pulmonary function test (PFT). There have been several risk scores proposed, but these would need careful external validation.910 The European Society of Cardiology (ESC) and European Respiratory Society (ERS) recommendations reflect expert guidance, and for SSc and scleroderma spectrum diseases including mixed connective tissue disease (MCTD), annual screening is recommended.1112 For other CTDs such as systemic lupus erythematosus (SLE) and myositis, the risk is less clear and annual screening is not recommended at present.

The DETECT score was developed as part of an exercise to develop better noninvasive assessment of risk by comparing many variables with the gold standard test of right heart catheterization (RHC).13 From 115 variables that included laboratory, clinical, ECHO, and lung function, measures were demonstrated to be independently associated with risk of having PAH at RHC. These were combined into a weighted score that has been refined into an online application and a smartphone app. This allows identification of cases that are at high risk of having PAH and so suggests that they undergo RHC. It does not diagnose PAH and can only be applied to those cases that fulfill the protocol cohort characteristics of at least 3 years SSc spectrum disorder duration and a diffusion lung capacity for carbon monoxide (DLCO) of less than 60%. Thus, applicability in practice is somewhat limited, although it was incorporated into the most recent expert recommendations for screening. In addition, it was developed as a cross-sectional study and so the timing or utility of repeated measures over time is unclear and unproven.

Other approaches that have been suggested for screening include the Australian Scleroderma Interest Group (ASIG) algorithm that integrates N-terminal pro b-type natriuretic peptide (NT-proBNP), ECHO, and PFT, and although this has been reported to perform well it requires additional validation, but may offer cost-saving advantages.1415 A suggested algorithm for screening for PAH in SSc is summarized in Figure 3. This is based on expert consensus and evidence review.1112

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Other forms of PH can confound screening, and the risk of progression in these cases is unclear. Comorbidity is likely to affect screening, for example, after scleroderma renal crisis, the DLCO appears to be less predictive,2 and also the effect of concurrent emphysema has been shown in a recent study.16 Scores are being developed now that focus not on identifying PAH, but any cause of PH, as these may be of greater applicability in clinical practice. These have been developed and validated in non-contemporaneous cohorts of patients.2

In practice, it is important to assess risk of development of PH during regular follow-up and, although not yet fully validated, dynamic prediction models are using landmark analysis fit with regular PFT assessments that are available from most annual screening programs. Trajectory of change for DLCO is a good predictor of the development of PH in SSc, especially in the absence of lung fibrosis.17

TREATMENT OF PAH-CTD

Once diagnosed, it is important to treat PAH in the context of CTD. The potential for benefit was first suggested by the trial of epoprostenol in SSc-PAH that demonstrated improved exercise capacity after treatment.1819 Failure to demonstrate survival benefit was a sign that SSc-PAH may respond differently than idiopathic pulmonary arterial hypertension (IPAH). When oral therapies became available it was fortunate that CTD-associated PAH was included in the study cohort as it meant that all forms of Group 1 PAH became eligible for therapy. Subgroup analysis of the first studies of oral agents pointed toward a blunted impact on the primary endpoint, and this was consistent and raised concerns.2021 However, real-life experience2223 and longer-term studies were more encouraging and demonstrated much improved survival compared with historic datasets. This has been seen in other studies including recent trials of riociguat, the newest class of PAH therapy licensed again through trials with short-term gain in exercise capacity as the primary endpoint.24 Recent studies using combination therapy and event-driven morbidity-mortality endpoints have been much more positive for CTD-PAH and SSc-PAH, and these trials have led to formal analyses of CTD subgroups with very comparable reduction in hazard ratio to that seen in the IPAH patients.2526 This supports current treatment recommendations that do not differentiate in treatment strategy between CTD and other forms of PAH. Further evidence of disease modification comes from the ATPAHSS study, which demonstrated significant improvement in right ventricular mass and pulmonary vascular resistance in PAH-SSc with initial combination therapy of ambrisentan and tadalafil.28 This remains one of the very few studies that show unequivocal hemodynamic and structural benefits in the PAH-SSc subgroup that may underpin the long-term clinical benefit observed in event-driven clinical trials. Thus, cases are stratified by risk at diagnosis and usually started on single or double PAH-specific therapy with careful monitoring of response so that intensification of therapy can occur as soon as appropriate. The differences for CTD-PAH relate to screening recommendations, and to the absence of a formal vasodilator test at RHC and the avoidance of oral anticoagulation for PAH in CTD where recent registry data suggest detrimental impact on survival.2829 Although CTDs are autoimmune in nature, SSc-PAH does not generally respond to immunosuppression. In contrast, SLE and MCTD-associated PAH may show good clinical response; therefore, it is generally recommended to give immunosuppression concurrently with targeted PAH therapy in these CTDs,30 with good long-term outcome.31 It is notable that this is especially good in MCTD-associated PAH, raising the possibility that pulmonary vasculitis may be a relevant pathology in some cases of MCTD or SLE-associated PAH, or that the underlying disease activity impacts outcome in PAH. Notably, advanced therapy use in PAH-CTD with intravenous prostanoids appears to be less used in PAH-CTD than for IPAH, which may reflect practical difficulties of CTD comorbidity, but might negatively impact outcome.32 Another challenge is that lung transplantation is less likely to be undertaken in the PAH-CTD population as comorbidities such as severe gastroesophageal reflux or steroid-associated osteoporosis often excludes patients from moving to transplantation, although recent outcome analyses suggest comparable outcome to other transplant recipients.33

IMPACT OF ASSOCIATED CTD

Cases of SSc-associated PAH have worse long-term outcome than IPAH and other types of CTD-associated PAH. This was demonstrated in a recent study that examined those cases that have anti-U1RNP-specific antinuclear antibody (ANA) positivity, and so include overlap and MCTD diagnoses. It important to note again that cases of SLE and MCTD-associated PAH appear to benefit from immunosuppression given in combination with targeted PAH therapy. In general, registry data have shown that long-term outcome is worse for SSc-associated PAH than cases with SLE or MCTD, and specific predictors of poor outcome in PAH-SSc have been identified.34 Historical studies have shown unequivocally that SSc-PAH has worse outcome than IPAH, although more recent data are showing comparable outcomes. Excellent long-term outcome in MCTD-associated PAH is in line with previous reports from a French cohort.31 Concomitant immunosuppression is important in managing these cases, but has not been shown to be consistently beneficial in SSc-PAH. Hemodynamically, SLE-PAH is more severe than SSc-PAH despite the better long-term outcome.35 This may in part reflect different mechanisms of the underlying vasculopathy and possibly greater comorbidity in SSc including pulmonary and cardiac fibrosis.

PATHOBIOLOGY OF PAH-CTD AND MIXED-ETIOLOGY PH

One of the major challenges of PAH in CTD is that mixed forms of the disease occur. This is partly due to the systemic underlying mechanisms of CTD and also the complications of the associated diseases that include cardiac involvement, lung fibrosis, and vasculitis as well as thrombotic susceptibility in conditions such as antiphospholipid antibody syndrome. In addition, the age and demographics of typical CTD patients increase risk of other relevant cardiopulmonary disease. The complex mixed mechanisms can impact treatment response. For example, cardiac disease (Group 2), lung fibrosis with ventilation: perfusion mismatch (Group 3), and cases with pulmonary veno-occlusive disease (PVOD) may all be worsened by pulmonary vasodilator therapy. This can affect diagnosis and screening as well as clinical impact on PAH. For example, a recent study has highlighted the challenge of concurrent emphysema in defining screening thresholds for PAH in SSc.16

CTD WITH BORDERLINE ELEVATION OF MPAP

One of the consequences of active screening for PH in SSc is that cases with borderline elevation of mPAP are identified. These are defined by mPAP at rest of between 21 and 24 mm Hg. Some of these may be cases that will develop more significant PH on exercise, but this does not form part of the current hemodynamic definition of PH. These borderline cases are likely to be a mixed group, including some cases where elevated pressure relates to associated lung fibrosis, so more relevant to Group 3 PH associated with hypoxia. It is not uncommon for patients with significant lung fibrosis to be present in this category. Another group of those with borderline elevation of mPAP are those with postcapillary PH. These are cases that may progress to Group 2 PH and include many patients with diastolic dysfunction. The significance of this group is unclear in terms of the impact of these elevated pressures, but they undoubtedly include a substantial number that develop PH on exercise. However, the main relevance of detecting borderline elevation of mPAP is that it has now been clearly shown that these cases have a much higher risk of developing PAH (Group 1) than those with normal pulmonary artery (PA) pressure. This was demonstrated in a retrospective series that indicated that around one-third of borderline cases developed PAH during follow-up and this was associated with reduced survival.36 Interestingly, in this study, the transpulmonary gradient (TPG) was suggested to be a better predictor of progression to PAH than mPAP in this cohort. Although this observation requires confirmation, it may be especially relevant in CTD such as SSc because cases of borderline elevated mPAP can be associated with increased pulmonary artery wedge pressure (PAWP), reflecting cardiac abnormalities that are prevalent in SSc. Since the TPG takes PAWP into account, it might better reflect pulmonary vascular resistance than mPAP and so give a better prediction of evolving precapillary pulmonary vasculopathy.

Additional information about the borderline mPAP cases of SSc came from the DETECT cohort that showed that those in this group were distinct form the rest of the cohort in this group of patients that all underwent RHC.37 Additional light has been shed by a recent report of more than 100 cases of borderline mPAP that were identified as part of the DETECT cohort or using the same selection criteria. In this study, it was observed that approximately 29% of cases with mPAP 21 to 24 mm Hg developed PH during follow-up, the majority with Group 1 PAH.38 Interestingly, this was not associated with worse survival than the normal PAP group, and this may reflect the prompt treatment that these cases received when they progressed. Thus, for SSc borderline elevation of mPAP is accepted as a high-risk factor for the future development of PAH.

CONCLUSION

Recent studies including cohort and registry data have been improving understanding and outcomes.3439 CTD-PAH is now clearly treatable, but in need of better treatments and advances. It is important because as hematopoietic stem cell transplantation (HSCT) emerges as a potential treatment for severe SSc, the presence of PH4041 can make this impossible due to the fluid load and hazards of sepsis associated with the HSCT procedure.42 Historically, the focus of PH in CTD has been to identify PAH cases and the opportunities that arise from screening due to the high frequency of PAH in certain CTDs. In addition, there has been the appreciation that cases of PAH-CTD and especially SSc-PAH have worse outcomes than IPAH, but this is changing due to the clinical trial data outlined above and due to the differing demographics of IPAH that are emerging in recent registry series.43