A RHEUMATOLOGIST’S PRACTICAL GUIDE TO SCREENING STRATEGIES FOR PAH IN CONNECTIVE TISSUE DISEASE


Dr John Pauling is Consultant Rheumatologist at the Royal National Hospital for Rheumatic Diseases in Bath. He has a clinical interest in connective tissues diseases (CTDs) with a particular focus on Raynaud’s phenomenon and systemic sclerosis (SSc). He contributes to a number of UK Scleroderma Study Group and Scleroderma Clinical Trials Consortium initiatives. Dr John Pauling is Senior Lecturer in the Department of Pharmacy and Pharmacology in the University of Bath.

Vasculopathy is one of the pathological hallmarks of CTD and a major clinical feature in SSc,1 in which virtually all patients experience symptoms of Raynaud’s phenomenon.2 PAH is a potentially life-threatening vascular manifestation of SSc that affects approximately 15% of patients at some stage in the disease course.3,4 PAH associated with SSc (PAH-SSc) is one of the most important causes of PAH.5 Click here to learn more about the different types of pulmonary hypertension (PH).

Despite the availability of PAH-specific therapies, outcomes for patients with PAH-SSc remain poor,5 and PAH remains a major cause of mortality in SSc.3 Unlike, idiopathic PAH, clinicians have the opportunity to actively screen for PAH-SSc; potentially allowing earlier intervention and improved patient outcomes.6 It is therefore vital this is performed annually, regardless of symptoms (Figure 1).3,7

Figure 1. Impact of screening on survival in patients with SSc. Adapted from Humbert et al, 2011.6 CI, confidence interval; HR, hazard ratio; SSc, systemic sclerosis

 

Screening can guide clinicians on who should be referred for right heart catheterisation (RHC), leading to earlier diagnosis and improvements in long-term outcomes compared with diagnosis during routine care.6

I recommend that screening should involve:

1. A thorough history
Ask patients about symptoms that could indicate the presence of PAH-SSc. This includes increasing breathlessness, reduced exercise tolerance, chest pain, ankle swelling and presyncopal symptoms.8 Clinicians should be aware that patients with existing mobility issues may not notice a reduction in their exercise tolerance. Symptoms that should prompt immediate consideration of PAH-SSc include syncope, light-headedness and chest pain.3
Clinicians must also be aware that PAH can co-exist with parenchymal lung disease, particularly in association with anti-nucleolar antibodies.3,9 Therefore, don’t assume worsening breathlessness is due to interstitial lung disease, particularly if the forced vital capacity (FVC) and extent of fibrosis on cross-sectional imaging has remained stable.3

2. Clinical examination
Undertake a thorough clinical examination for features of right ventricular (RV) strain but be aware that major clinical features may be absent in early disease until RV function declines.3 Look for widespread telangiectases that are an independent risk factor PAH.10 Examine for a RV heave and raised jugular venous pressure (JVP).3,11 Examine the ankles for pedal oedema but be aware that this is sometimes caused by calcium channel blockers if the JVP is not elevated.12
Increasing capillary dropout on nailfold capillaroscopy may represent a future prognostic factor for PAH-SSc, although this is not yet undertaken on a serial basis in clinic.13


3. Non-invasive screening tests
PAH-SSc can only be diagnosed using RHC.8 However, several non-invasive tests such as transthoracic echocardiography (TTE), pulmonary function tests (PFTs) and circulating N-terminal pro-B-type natriuretic peptide (NT-proBNP) can detect features that may indicate its presence.7 These tests should be performed annually to guide clinicians in their decision to refer patients for further investigation.7

 

TTE

There are a number of echocardiographic features that can indicate the presence of PAH in SSc. This type of TTE is best done by a skilled sonographer with experience in assessing right-sided structures. The tricuspid regurgitation velocity (TRV) is typically used to estimate the RV systolic pressure (estimated RVSP), and TRV values >2.8 m/s can suggest a possible raised pressure.7 The TRV, however, can overestimate the true RVSP in people with incompetent tricuspid valves and underestimate the RVSP in patients with modest tricuspid regurgitation despite high pulmonary arterial pressures (e.g. where the dilated right ventricle is failing).14 A reduction in the tricuspid annular plane systolic excursion (TAPSE) of <2.0 cm and a sharp pulmonary acceleration time (PAT), also called RV outflow tract acceleration time (RVOT-AT), of <110 ms can also be used to suggest the presence of PAH.14 The right-sided chamber volumes and function are another valuable marker of the extent and severity of PAH.14 TTE also allows an evaluation of left-sided structure and function, which can help indicate the presence of group 2 PH secondary to left heart disease.14 TTE should be undertaken annually in patients with scleroderma-spectrum disorders (SSc and mixed CTD with a strong scleroderma phenotype).7

Click here to read more about the echocardiographic assessment of PH and guidance on the interpretation of results.

PFTs

PFTs should also be undertaken annually in patients with scleroderma-spectrum disorders. The typical PFT findings are a reduced carbon monoxide transfer factor (TLco – also known as DLco, diffusing capacity of the lung for carbon monoxide) in the presence of a preserved or elevated FVC.7,15
Steen and colleagues have demonstrated the value of a rising FVC:TLco ratio in predicting the presence of PAH-SSc, when >1.4.16
Clinicians should be aware that an isolated fall in the TLco can also occur as a result of anaemia – another cause of exertional dyspnoea in SSc.17

NT-proBNP

NT-proBNP has proved to be a valuable circulating biomarker in PAH-SSc. It is a non-specific marker of ventricular strain and can be raised in left ventricular disease. It is also cleared by the kidneys and is elevated in renal impairment.18 Nonetheless, it is useful to establish a baseline NT-proBNP for patients and re-test this during follow-up assessments.7

SCREENING MODELS

Various screening models exist that aim to guide clinicians on who is at risk and should be referred for RHC.

Each model has its advantages and disadvantages. Most are highly sensitive, but the specificity may vary.18 In this article we will discuss three screening models for PAH in SSc:

>  The joint European Society of Cardiology and European Respiratory Society (ESC/ERS) clinical guidelines screening strategy
>  The DETECT algorithm
>  The Australian Scleroderma Interest Group (ASIG) algorithm

 

2015 ESC/ERS GUIDELINES SCREENING STRATEGY

The European clinical guidelines recommend that a resting TTE is performed on all asymptomatic patients, followed by annual screening with echo, TLco and biomarkers.7

Depending on the echocardiographic probability of PH, RHC may be recommended. The risk level (see below) is based on the TRV and the presence of other echocardiographic signs.7 Read about how to calculate the echocardiographic probability here.

Management guidance following echo for asymptomatic patients with risk factors or associated conditions for PAH. Adapted from Galiè et al, 2016 (Web addenda, Table IX).19 PH, pulmonary hypertension; RHC, right heart catheterisation

As discussed above, the TRV in isolation can overestimate the true RVSP in people with incompetent tricuspid valves and underestimate the RVSP in patients with modest tricuspid regurgitation despite high pulmonary arterial pressures (e.g. where the dilated right ventricle is failing).14 Therefore, it should always be used in conjunction with other echocardiographic, clinical and lung physiological markers.7 These guidelines cannot be applied to patients without a tricuspid regurgitant jet, some of whom may still have PAH-SSc.20

However, TTE does have the advantage of allowing an evaluation of left-sided structure and function, which can indicate the presence of group 2 PH secondary to left heart disease.14

The following two screening approaches consider TTE findings as part of a broader assessment of non-invasive investigations.

 

THE DETECT ALGORITHM

The DETECT algorithm is a two-part model based on a data-driven study of 466 patients with SSc. It combines six variables from different investigations, in addition to an echo.21 Read about the protocol in detail here and access the online calculator here.

  • Step 1: six non-invasive assessments are used to determine the need for an echo
  • Step 2: variables from the echo are combined with the score from step 1 to determine whether referral for RHC is indicated

Figure 2. The DETECT 2-step screening approach for PAH in SSc.21 Adapted from Coghlan, Ann Rheum Dis 2014

Click to expand

 

DETECT is an evidence-based protocol with a false negative rate of only 4%.21 The DETECT algorithm highlights the many clinical and investigational features that can indicate the presence of PAH-SSc; but in my opinion, the uptake of this tool in routine clinical practice has been limited outside of specialist centres, as serum urate and ECG are not routinely assessed by many rheumatologists.



Download the free Detect PAH app (Actelion Pharmaceutical Ltd) Available on iOS here. Or use the online calculator http://www.detect-pah.com.

Figure 3. Screenshots of DETECT PAH app

 

THE AUSTRALIAN SCLERODERMA INTEREST GROUP ALGORITHM

The ASIG algorithm was created by a panel of Australian rheumatologists, cardiologists and respiratory physicians. It includes initial echo and PFTs. Depending on the estimated systolic pulmonary arterial pressure and PFT values, such as TLco and FVC, patients are assigned a level of risk: high, moderate, mild or no probability of PAH.5 Read about the protocol in more detail here.

Figure 4. Australian Scleroderma Cohort Study algorithm for screening for pulmonary hypertension.5 Adapted from Morrisroe, Arthritis Res Ther 2017

Click to expand

 

The ASIG and DETECT algorithms have similarly excellent sensitivity and negative predictive value.20 I find the ASIG algorithm simpler to interpret and think that the clinical and investigative variables required are available to most practising rheumatologists.

A longitudinal multicentre ASIG study of 1,636 patients with SSc between 2007 and 2016 noted that the majority of patients were screened annually; however, only 29.7% of patients the algorithm indicated should have a RHC actually underwent the investigative procedure.5 This highlights the importance of referral to a specialist PH centre for unexplained symptoms or where abnormal investigation results indicate the possible presence of PAH-SSc.

 

CONCLUSION

When evaluating a patient with SSc, it is vital to look at the patient as a whole. Clinicians should look at the complete picture of signs, symptoms and investigation results. All patients with unexplained dyspnoea should be fully investigated to establish a cause; clinicians should not be falsely reassured by a relatively normal echocardiogram report.

As a general rule, TTE and PFTs should be undertaken annually in patients with scleroderma-spectrum disorders.7 Serial NT-proBNP results might also be useful in identifying a patient at risk of PAH-SSc.18

Irrespective of your preferred screening algorithm, it is essential that this high-risk group is investigated and appropriately referred to a specialist PH centre whenever PAH-SSc is suspected. Screening patients with SSc for PAH can lead to early diagnosis and improvements in long-term outcomes, compared with patients diagnosed during routine care.6

 

“The specialist PH centres will make the final nuanced judgement as to whether RHC is warranted so don’t feel despondent if a referral to a PH centre doesn’t result in a RHC. Similarly, RHC often excludes PAH-SSc despite features suggestive of this on non-invasive imaging. The presence of a normal RHC should reassure the referring clinician. Indeed, if every referral to a specialist centre confirms the presence of PAH, there is a danger that the threshold for referral is being set too high and there may be patients failing to have their PAH-SSc diagnosed in a timely fashion. Early diagnosis is critical to allow earlier intervention and support improved patient outcomes.”

Dr John Pauling

 

Detect PAH is a medical device developed by Actelion Pharmaceuticals Ltd.

References

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  12. Zipes D, et al. Braunwald’s Heart Disease, A Textbook of Cardiovascular Medicine, 11th ed. Philadelphia: Elsevier; 2018
  13. Paxton D and Pauling JD. Semin Arthritis Rheum 2018;482–94
  14. Imperial College Healthcare NHS Trust (2018). Echocardiographic Assessment of Pulmonary Hypertension: Standard Operating Procedure. Available from: http://www.echoprotocol.co.uk. Accessed February 2019
  15. Sundaram S and Chung L. Curr Rheumatol Rep 2018;20:10
  16. Steen VD, et al. Arthritis Rheum 1992;35(7):765–70
  17. Hudson M, et al. Clin Rheumatol 2013;32:1467–74
  18. Blyth KG, et al. Eur Resp J 2007;29:737–44
  19. Hao Arthritis Res Ther 2015;17:7
  20. Coghlan JG, et al. Ann Rheum Dis 2014;73:1340–49

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