How do you approach Systemic Sclerosis (SSc) patients and screen for CTD-ILD (SSc-ILD)?

Various studies, particularly from the EUSTAR (European Scleroderma Trials and Research Group) cohort, have noted that 38% of SSc patients had evidence of lung fibrosis on HRCT. This prevalence underscores the urgency of our screening process. Some patients are asymptomatic, especially in the early stages, and may not present with symptoms such as cough and/or shortness of breath on exertion.

The salient risk factors identified for the development of interstitial lung disease include male sex, a higher modified Rodnan skin score (MRSS), early disease as lungs tend to be involved in the early stages, presence of heart involvement, and the presence of anti-topoisomerase antibodies (aka Scl-70 antibody). Anti-centromere antibodies are also associated with, but less commonly, and generally milder interstitial lung disease; nevertheless, they are not exempt from having ILD, which may also require treatment or close follow-up in some cases.

We have a dedicated Systemic Sclerosis clinic, where we regularly conduct comprehensive screening assessments at our Waikato Hospital, a tertiary teaching hospital. Patients suspected of having autoimmune diseases are referred electronically through the general practitioner’s referral system, which can be corresponded with if needed for further details or additional tests by this triage system. These patients have a detailed history and a complete clinical examination in the clinic. They are also asked relevant questions about various organ systems and searched for salient features, such as fine basal crepitations, indicating lung involvement at each visit (initially, visits may be at 4-6 monthly intervals).

They also undergo a baseline chest X-ray, pulmonary function test, gas transfer (DLCO and KCO), a baseline high-resolution computed tomography (HRCT), and an echocardiogram (ECHO). These HRCT scans are also discussed in our biweekly Radiology-Rheumatology meetings. HRCT is also used to estimate the degree of ILD (i.e., less than or more than 20% involvement). Laboratory tests (if not previously conducted by general practitioners) will confirm the type of SSc-related autoantibody present, along with baseline blood tests that include Quantiferon Gold TB Screen, HIV, Hepatitis B and C, basic biochemistry, and haematology tests. They are also tested for other coexisting antibodies, as we have noted that a greater-than-normal cohort has had other associated autoantibodies, the most common being thyroid antibodies.

What integrated services are involved in SSc-ILD (&CTD-ILD)?

Once the diagnosis is established through clinical assessment, radiological evaluation, and respiratory function tests, indicating that the patient has significant interstitial lung disease, the patient is referred to the respiratory physician (who conducts the dedicated ILD Clinics) for respiratory follow-up as well. They may or may not discuss this in their respiratory multidisciplinary meeting (MDM) as well.

The respiratory physician reviews these patients in their ILD clinic, where discussions about the risks and benefits of immunosuppressive agents (ISA) take place, patient education is further enhanced, and treatment is initiated (if not already started in our Rheumatology clinic). As part of the therapy, proton pump inhibitors are prescribed to prevent or reduce reflux (both symptomatic and silent) that could exacerbate interstitial lung disease. If dysphagia is also a concern, the speech and language therapist and a gastroenterologist may be involved in assessments, which include swallowing evaluations and an upper GI endoscopy. Other services, such as neurology, cardiology, and gastroenterology departments, are consulted on a case-by-case basis for the relevant co-existent symptoms.

How do you determine which treatment regimen will be offered and to which patients? What barriers are present that need to be addressed in some progressive cases?

Mycophenolate mofetil (MMF) and cyclophosphamide (CYP) are the available drug options in New Zealand. We have to follow the guidelines set by PHARMAC, the government body that regulates and funds the use of various pharmaceutical agents. If we wish to use other biological agents, such as tocilizumab or rituximab, we must apply electronically to the NPPA committee for a special Named Patient Pharmaceutical Assessment (NPPA).

MMF is one of the most commonly used immunosuppressive agents (ISA) for CTD-ILD. However, if there is poor tolerance of MMF either because of diarrhoea [which can be an essential side effect as well as a limiting factor] or other side effects or there remains unremitting disease progression, then we would consider applying for rituximab as an NPPA or cyclophosphamide be offered to these patients, particularly in elderly patients. The former is preferred as an alternative agent for younger women of childbearing age. Failing this, they are considered for the current ongoing clinical trials in SSc-ILD. If there is significant and progressive fibrosis, we also consider applying to NPPA for Nintedanib therapy. At present, we do not have autologous haematopoietic stem cell therapy (aHSCT) for severe progressive dcSSc in New Zealand (although it is available for haematological conditions). Therefore, we tend to liaise with our Australian Haematology colleagues who perform this mode of therapy, with approval from the Governmental Body set up for this purpose.

How do you monitor SSc-ILD (mild and untreated) and SSc-ILD that is treated? When do you consider repeat HRCT?

According to the EUSTAR registry, 60% of patients with topoisomerase antibodies developed interstitial lung disease (ILD), compared to 21.3% of those with centromere antibodies. All patients should undergo a baseline ILD screening, regardless of their SSc-autoantibody profile, which includes lung function tests, high-resolution computed tomography (HRCT), a plain chest X-ray, and echocardiography. Due to the variability in disease progression, close monitoring is essential especially in the first 5 years, regardless of treatment status. Patients with increased risk factors and HRCT scores (as determined by radiological scoring) showing either <20% or >20% lung involvement, and FVC values of either <70% or >70%, are stratified into limited or extensive disease categories, which guide treatment decisions.

Low-risk patients who are asymptomatic and have HRCT scores <20% and FVC >70% require regular monitoring with pulmonary function tests, DLCO, and clinical symptom assessment. Initially, they may need to be reviewed at least every 4-6 months. Any progressive changes in symptoms or lung function may warrant the possibility of a repeat HRCT (especially if not on any ISA). The ILD-RISC score can also aid physicians in determining when to order HRCT during follow-up. Annual screenings with ECHO and pulmonary function tests are necessary to monitor disease progress and ensure that no further complications arise as the disease progresses, which may require intensification of therapy or treatment modification (e.g., if fibrosis is ensuing, then a combination of Nintedanib and MMF may need to be considered).

Any emerging treatments in SSc / or future trials?

Currently, research on systemic sclerosis includes trials of soluble guanylate cyclase activators (sGC) for interstitial lung disease (ILD) and cutaneous manifestations in SSc (esp. dcSSc). Connective tissue growth factor (CTGF) is overrepresented in Systemic Sclerosis. Hence, Pamrevlumab, a fully recombinant human monoclonal antibody targeting CTGF, has shown promising results in a phase two randomised double-blind study [PRAISE trial]. Furthermore, Treprostinil, as demonstrated in the INCREASE trial, has been associated with a 1.8% improvement in predicted forced vital capacity (FVC) after 16 weeks. These findings highlight the potential of these treatments in managing systemic sclerosis. Lastly, chimeric antigen receptor T-cell therapy (CAR-T cell therapy) is also being trialled in SSc in centres of excellence overseas. We await the outcomes of this and a few other trials currently in progress.