may infuence susceptibility, clinical phenotype and disease progression [29]. ATA positivity is strongly linked to the ­carriage of the HLA-DRB1*11 and HLA-DPB*1301 alleles [23]. ATA positivity, diffuse cutaneous disease and SSc-ILD have been associated with the rs763361 single-nucleotide polymorphism in the CD226 gene [30].

Other genetic linkages to SSc-ILD have included the HLA-C, HLA-DQB1, HLA-DRB1, CD247, IL-1α and IL-1β genes [31]. By contrast, single-nucleotide polymorphisms in the surfactant protein B gene are associated with a lower prevalence of SSc-ILD in Japanese SSc patients [32].

Clinical Presentation of SSc-ILD

In SSc-ILD, respiratory symptoms are notorious for their non-speci city and variability, with the severity of exercise limitation correlating poorly with disease severity, as judged by pulmonary function tests (PFT) and the extent of disease on HRCT. The dif culty in evaluating symptoms lies in the fact that in SSc, dyspnoea may arise from a multiplicity of causes including interstitial lung disease, pulmonary vascular limitation (even when overt PH is not present), cardiac involvement, musculoskeletal disease, loss of tness due to general debility and anaemia, with more than one factor often coexisting. In some patients, severe systemic disease results in a major reduction in daily activity, and loss of pulmonary reserve is not exposed. By contrast, knowledge of the likelihood of lung involvement leads to concerns about exercise intolerance in other cases, even when interstitial lung disease is absent or relatively limited. Accurate assessment of dyspnoea requires observation of the exercising patient. The absence of oxygen desaturation during a 6-min walk test (or a more strenuous form of exercise) suggests that dyspnoea largely results from extra-pulmonic factors.

A detailed history should include occupational exposures known to result in SSc and the impact of lung symptoms on quality of life. The duration of systemic disease (as judged by SSc symptoms and not by Raynaud phenomenon) may infuence treatment decisions, as discussed later. It is also important to explore the evolution of dyspnoea: a long-term lack of change in exertional dyspnoea is reassuring in patients with severe SSc-ILD. Aspiration due to gastro-esophageal regurgitation (GER) has been suggested as a potential cause of SSc-ILD although this hypothesis has yet to be validated. GER may cause troublesome cough (due to a vagally mediated cough refux) and in occasional patients, episodes of wakening with a choking sensation may be indicative of signi cant nocturnal aspiration of gastric contents.

Physical examination does not contribute greatly to the assessment of SSc-ILD. The classical nding of ne bi-basal crackles is often absent in limited SSc-ILD. Changes in the

intensity of crackles have not been validated as a reliable indicator of disease progression. Finger clubbing is very rare in SSc-ILD. In end-stage SSc-PH, positive clinical ndings include a loud pulmonary component of the second heart sound, a right ventricular heave, elevated jugular venous pressure, signs of peripheral oedema—but these signs are not reliably present in less advanced PH. Impairment in chest wall movement due to severe thoracic skin involvement is a rare extra-pulmonic cause of exertional dyspnoea.

Pulmonary Function Tests (PFTs)

PFTs have been used historically for both the staging of disease severity and the serial monitoring of SSc-ILD. It is generally accepted that in these regards, PFTs are more reliable than symptoms or chest radiography. However, the limitations of PFT need to be appreciated by the clinician. In staging severity, the normal PFT range, varying from 80% to 120% of expected values based on age, height and gender [33], is a major confounder. For example, an FVC value of 75% of predicted may equally represent a relatively minor fall of 5% or a very major reduction of 45% from premorbid values of 80% and 120%, respectively. Thus, it is essential that the evaluation of disease severity should be a multidisciplinary exercise, with the integration of PFT, HRCT ndings and symptoms. However, it can at least be concluded that severe reductions in lung volumes and measures of gas transfer are reliably indicative of severe pulmonary disease.

The classical PFT pro le in SSc-ILD is a restrictive ventilatory defect, with reduced total lung capacity, reduced forced vital capacity (FVC), an FEV1/FVC ratio of >0.8, reduced carbon monoxide diffusing capacity (DLco) and reduced lung compliance. Moderate restriction (FVC 50–75% of predicted) is found in up to 25–30% of SSc patients, with 10–15% having severe restriction [4]. DLco estimation can be viewed as a “gestalt” evaluation of resting pulmonary function, as it captures both ventilatory defects and reductions in blood volume within ventilated lung. Disproportionate reductions in DLco (when compared to lung volumes) can arise in two distinct scenarios. In smokers, the coexistence of interstitial lung disease and emphysema (widely known as the “combined pulmonary brosis and emphysema syndrome”) results in preservation of lung volumes (even when both processes are extensive) but a devastating reduction in DLco, a combination best documented in idiopathic interstitial pneumonia [34] but also seen in SSc-­ ILD [35]. A more frequent scenario in SSc-ILD (and in SSc in general) is disproportionate reduction in DLco due to signi cant pulmonary vascular limitation (with or without overt SSc-PH). In recent series, elevation of the FVC/DLco ratio has been used as a marker of pulmonary vascular limitation

[36, 37]. However, there are theoretical advantages in an alternative variable and the gas transfer coef cient (Kco), which quanti es carbon monoxide uptake per unit volume of ventilated lung. It is often overlooked that DLco is calculated as the product of measured Kco and measured VA [38] (accounting for the higher measurement variability of DLco than other pulmonary function variables). Thus, the use of the FVC/DLco ratio depends upon the accurate measurement of three variables (Kco, VA and FVC) whereas Kco carries the measurement variation of only one manoeuvre.

Spirometric volumes are highly reproducible in laboratories with an acceptable level of quality assurance. Body plethysmography is a more complex measurement performed inside a sealed, air-tight chamber and is used to estimate total lung capacity (TLC) and residual volume (RV). In interstitial lung disease, reductions in TLC and RV tend to mirror reductions in FVC and in most cases add little to FVC measurement. However, plethysmography should be performed at presentation in order to allow an alternative monitoring variable to be used in occasional patients, in whom forced spirometric manoeuvres are contraindicated by glaucoma, signi cant chest wall discomfort or severe microstomia.

In SSc-ILD, resting arterial gases tend to be normal in mild to moderate disease except when there is concurrent pulmonary hypertension. In advanced disease, hypoxia is usually associated with hypocapnia (refecting alveolar hyperventilation). The performance of arterial gases can generally be avoided in routine evaluation as simple oximetry is an adequate substitute, despite sometimes confounded by Raynaud phenomenon. Ear lobe capillary gases, which can be measured in many lung function laboratories, are also an acceptable substitute for arterial gases.

Maximal exercise testing adds little to the routine evaluation of SSc-ILD. However, in occasional patients with exertional dyspnoea that is disproportionate to the severity of SSc-ILD, maximal exercise testing is a useful means of excluding clinically signi cant interstitial lung disease. The absence of oxygen desaturation or widening of the alveolar-­ arterial oxygen gradient at end exercise may allow the clinician to conclude that exercise tolerance is limited by extra-pulmonary factors such as musculoskeletal disease or lack of tness. The 6-min walk test is more useful as it more closely approximates daily activity. Major desaturation should prompt the clinician to exclude SSC-PH and to consider the potential bene ts of ambulatory oxygen.

In routine monitoring, serial pulmonary function tests have a central role. The normal range is no longer a major confounder as signi cant change is indicative of disease progression, irrespective of premorbid pulmonary function levels. However, as in interstitial lung disease in general, measurement variation creates dif culties. Serial PFT trends are reliably indicative of disease progression only when FVC

change exceeds 10% of baseline values (e.g. a change from 2.0 to 1.8 L). DLco trends may also be helpful but are less speci c when there is concurrent pulmonary vascular limitation. Even when pulmonary function trends are signi cant, it is important that alternative explanations for functional decline are considered, including infection, pulmonary embolism and cardiac disease. It is important to remember that measurement variation can result equally in the under-­ statement of change. Lesser changes (e.g. a 5–10% change in FVC) may be indicative of disease progression. Thus, functional trends should be reconciled with symptomatic change and, in selected cases, serial imaging data.

Imaging

High-resolution computed tomography (HRCT) can now be viewed as the reference standard for the detection of SSc-­ ILD. The chest radiograph is insensitive in the detection of SSc-ILD [39]. HRCT ndings closely resemble those seen in idiopathic NSIP [15] typically consisting of a variable mixture of ground-glass attenuation and reticulation (Fig. 12.2). In a minority of patients with overt honeycomb change, a histological pattern of usual interstitial pneumonia can be suspected. The historical belief that ground-glass attenuation is indicative of reversible infammatory disease has not stood the test of time. In occasional patients with prominent ground glass, without associated reticulation or traction bronchiectasis, disease is, indeed, likely to be reversible (Fig. 12.3a). However, in the great majority of cases, ground glass is admixed with reticulation, and there is traction bronchiectasis (Fig. 12.3b), a combination of HRCT signs that is reliably indicative of ne brosis [13, 40, 41].

Apart from the detection of disease, HRCT provides an alternative means of evaluating disease severity. Precise quanti cation of disease extent is arduous and insuf ciently “user friendly” to be a part of routine evaluation. However, rapid semi-quantitative assessment of disease extent on HRCT helps the clinician to address the confounding effect of the normal range in the interpretation of pulmonary function tests. As discussed later, HRCT can also be used to stage disease as mild or extensive.

Serial HRCT evaluation tends to be over-used by clinicians, based on the supposition that a sensitive test must add to the accuracy of monitoring. In reality, HRCT is often too sensitive in the detection of change. No de nition of “signi - cant” HRCT change has been validated, and therefore, subtle regional HRCT change in patients with stable pulmonary function tests is dif cult to interpret. In other patients with major pulmonary function trends, there may be little or no change on HRCT. Furthermore, the long-term risk of malignancy with excessive exposure to radiation should not be overlooked. Thus, the inclusion of HRCT in a routine-­

Fig. 12.3  (a) HRCT appearances in a patient with biopsy-proven cellular NSIP. There is a diffuse increase in lung attenuation without admixed reticulation or traction bronchiectasis. (b) HRCT appearances in a patient with biopsy-proven brotic NSIP. The diffuse increase in

attenuation on HRCT represents ne brosis, with the presence of obvious traction bronchiectasis an important clue that interstitial disease was likely to be irreversible

monitoring protocol is dif cult to justify. Serial HRCT should only be performed on a case-by-case basis to answer speci c clinical questions, with the most frequent scenarios being discordance between symptomatic change and pulmonary­ function trends and disproportionate decline in measures of gas transfer, ascribable equally to progression of interstitial lung disease and worsening of pulmonary vascular disease.

Prognostic Evaluation of SSc-ILD: When

Should Treatment Be Instituted?

The routine use of HRCT in the initial evaluation of SSc often discloses limited interstitial abnormalities of uncertain signi cance. This creates a major dilemma for the clinician. It is axiomatic that early treatment is needed when disease is intrinsically progressive. However, when abnormalities are

mild or “sub-clinical”, overly aggressive intervention can result in major side effects without therapeutic gain. Intrinsically progressive disease cannot be identi ed reliably. However, based on accumulated clinical experience, the decision to institute therapy should be infuenced by the severity of lung disease, the duration of systemic disease and evidence of ongoing disease progression.

It is widely accepted that the threshold for treatment is critically dependent on disease severity. Severe disease is a marker of repeated past disease progression and is, therefore, indicative of an increased likelihood of future disease progression. Furthermore, in severe disease, further progression is associated with major changes in exercise tolerance and quality of life. In a staging system centred on disease severity, Goh and co-workers evaluated the prognostic value of candidate FVC and HRCT disease extent thresholds [19]. Key prognostic thresholds consisted of a percent predicted FVC value of 70% and an HRCT extent threshold of 20%

(i.e. 20% of the total lung volume). In the staging system for SSc-ILD shown in Box 12.1, lung disease was classi ed as “mild” or “extensive”, based on rapid semi-quantitative HRCT evaluation and in cases with an “indeterminate” disease­ extent, an FVC threshold of 70%. The Goh system has subsequently been validated in USA and Australian cohorts [42, 43]. These studies establish that the staging of severity using HRCT and FVC data is likely to be useful in informing treatment decisions in clinical practice.

Box 12.1

The mild/extensive severity staging system for prognostic evaluation in SSc-ILD. Extensive disease is associated with an increase in mortality of over threefold and a much higher likelihood of disease progression in the next year.

The UKRSA staging system

HRCT extent

The duration of systemic disease is also an important consideration as the risk of progression of SSc-ILD is greater early in the course of systemic disease. Steen and colleagues observed that the risk of progression is highest in the rst 4 years of systemic disease and especially in the rst 2 years. The risk is even greater when the onset of lung disease precedes the cutaneous manifestations of SSc [4]. With regard to treatment decisions, interstitial lung disease that is detected early in the course of systemic disease can be viewed as intrinsically progressive, with a reduced threshold for introducing therapy. By contrast, in patients with minor pulmonary function impairment after more than 5 years of systemic disease, mild SSc-ILD is less likely to evolve to severebrotic lung disease.

Recent progression of disease, as judged by a variable combination of serial PFT tends, serial imaging data and symptomatic change, is, in itself, an indication for therapy. In SSc-ILD, decline in pulmonary function indices over 1 year or 2 years, including FVC, DLco and Kco levels, has been linked to mortality in two series, independently of base-

line disease severity [44, 45]. Intervening to stabilize disease that is overtly progressive is warranted on simple commonsensical grounds.

Pleuroparenchymal broelastosis (PPFE), a clinical– pathological entity affecting the visceral pleura and the sub-­ pleural parenchyma with an upper-lobe predilection, was recently observed in 18% of patients in two large SSc cohorts [46]. The presence of PPFE was associated with increased mortality, independently of pulmonary disease severity and short-term pulmonary function trends. However, PPFE was only marginally associated with subsequent serial FVC decline and is not currently an accepted indication for earlier treatment of SSc-ILD, pending further research.

Thus, the severity of disease, the duration of systemic disease and evidence of recent progression should all be taken into account when treatment decisions are made. Currently, no validated algorithm exists to incorporate all these factors into management. Treatment decisions must be made on a case-by-case basis, acknowledging the wishes of the patient (which often become the key determinant when the grounds for introducing therapy are marginal). When immediate treatment is not warranted, rigorous monitoring is essential, primarily based on the performance of serial PFT, with an intention to treat if disease progression becomes evident. Based on accumulated clinical experience, both in SSc-ILD and idiopathic interstitial lung disease, three to six monthly repetition of PFT is recommended with the time interval between PFT prolonged after disease has been stable for at least 2 years.

As in interstitial lung disease in general, a biomarker in SSc-ILD that accurately predicted disease progression would greatly increase the accuracy of treatment decisions. Biomarkers evaluated in IPF and subsequently investigated in SSc-ILD include MMP-7, surfactant protein-D [SP-D], Krebs von den Lungen-6 [KL-6] and C-C motif chemokine ligand 18 [CCL18] [47]. Antibodies against CXCR3 and CXCR4 chemokine receptors have also been explored. Currently, serum KL-6 and CCL18 levels hold the most promise based on their association with pulmonary disease progression in a large cohort [48], in keeping with observations in smaller cohort studies. In another large cohort, serum interleukin 6 was predictive of lung function decline and mortality in SSc-ILD patients with limited disease but not in those with severe disease [49]. However, the prognostic utility of these biomarkers in individual patients remains uncertain: further validation is required to allow their use in routine practice.

Bronchoalveolar lavage (BAL) cellularity has been viewed historically as an invaluable aide to treatment decisions in patients with SSc-ILD. In a number of small cohorts, a BAL neutrophilia was linked to a worse outcome. However, these observations took no account of the now well-­ recognized association between the presence of a BAL neu-