Inventory of the new progress of CTD-PAH and interstitial lung disease!

*For medical professionals to read for reference, connective tissue disease-related pulmonary hypertension, interstitial pulmonary disease, and venous thromboembolism all require more clinical attention
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In line with the original intention of "delivering the latest academic progress and assisting clinical diagnosis and treatment of rheumatism", at the time of farewell to the old and ushering in the new year, the "Medical Community" media has joined hands with 14 well-known experts from the top domestic rheumatology and immunology departments, covering 12 hot diseases in the field of rheumatism and immunity, opening "Riding the 'Wind' and Breaking the Waves - 2021 Annual Inventory of Rheumatism"
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 In this issue, Professor Li Mengtao of Peking Union Medical College Hospital shared the latest progress in the field of CTD
.

Let's learn together! // CTD-PAH Let's take a look at CTD-PAH first
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A study published in EurRespir J in 2019 showed that the 5-year survival rate of patients with systemic lupus erythematosus (SLE) combined with PAH (SLE-PAH) was only 72.
9%, compared with the 5-year survival rate of SLE patients without PAH (about 97%).
) was significantly reduced
.

 At baseline, when PAH was diagnosed, 48.
3% of patients had significant active symptoms of shortness of breath (Figure 1)
.

This reminds us that early diagnosis and early treatment are necessary to improve the prognosis of patients with SLE-PAH or CTD-PAH
.

Figure 1 Research results In June 2021, Professor Li Mengtao's team published an article in the journal Arthritis Rheumatology
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The study included 3634 SLE patients with a mean follow-up of 4 years, during which 92 PAH events occurred
.

The study has derived a risk model that comprehensively evaluates risk factors such as rash, arthritis, and kidney disease to obtain a relative risk value
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For high-risk patients, further strict follow-up and ultrasonography can be performed to achieve the goals of early screening and early diagnosis
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 With the increasing number of therapeutic drugs, the intensity of treatment for SLE-PAH patients has become a matter of great clinical concern
.

It is now recognized that there is a need to stratify patients according to disease prognosis
.

The REVEAL cohort in the United States has calculated a risk stratification model for PAH, namely REVEAL 2.
0, but it was verified in the SLE-PAH cohort of CSTAR, but there was a certain overlap between the low-risk, intermediate-risk and high-risk curves, indicating that the REVEAL 2.
0 model There are still shortcomings for prediction of SLE-PAH
.

 A risk stratification model in the expert consensus of the European Society of Cardiology and the European Society of Respiratory Diseases was validated in the SLE-PAH cohort, and it was found that this stratification method can help to judge the prognosis clinically.
Patients should be treated more aggressively (Figure 2)
.

Figure 2 Results of the study The previous treatments for CTD-PAH mainly focused on two directions, including the treatment of the underlying disease, i.
e.
, autoimmune inflammation, and the use of targeted drugs to improve vascular tone imbalance and anti-proliferative treatment
.

 Systemic sclerosis (SSc)-associated PAH (SSc-PAH) is a type of CTD-PAH with the worst prognosis
.

A 2021 study showed that rituximab improved 6-minute walk distance in SSc-PAH (Figure 3)
.

The study believes that the treatment of underlying diseases should also be paid attention to for these patients
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Figure 3 Results of the study There are three main pathways for the targeted therapy of PAH, namely the endothelin pathway, the nitric oxide pathway and the prostacyclin pathway
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At present, a variety of targeted drugs for different pathogenic pathways are available in clinical practice
.

So how can the combined treatment effect be better? Studies have shown that for patients with different risk stratifications, initial dual-drug combination therapy can effectively reduce pulmonary vascular resistance and improve PAH status (Figure 4)
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Another real-world study (RWS) also found the advantage of triple-drug combination therapy, which improved patient outcomes more significantly than dual-drug combination and monotherapy
.

 Figure 4.
A randomized controlled trial (RCT) published in the journal J Am Coll Cardiol used a combination of macitentan, tadalafil, and cilocipa in the treatment of PAH, compared with macitentan + Tadalafil control, found no significant difference between the two groups
.

However, for some malignant clinical events, the three-drug combination can reduce the incidence to a certain extent, suggesting that the three-drug combination is still a very promising clinical treatment strategy
.

// CTD-ILD‍‍‍‍‍‍‍‍‍‍The number of patients with CTD-ILD is even higher than CTD-PAH
.

How to identify and diagnose CTD-ILD early and prevent its transition from inflammation to fibrosis is the focus of clinical attention
.

The prevalence of CTD-ILD is shown in Table 1
.

 Table 1 Prevalence of CTD-ILD Regarding the early diagnosis of CTD-ILD, a study published in Ann Rheum Dis in 2021 showed that MUC5B gene mutation may be an important predictor of ILD in patients with rheumatoid arthritis
.

However, the gene has not been well verified in China, so whether the conclusion of this study is applicable to the Chinese population needs further research
.

 In the clinical treatment of CTD-ILD, anti-inflammatory treatment for the underlying disease is still emphasized
.

A study published in the journal Lancet Respir Med in 2020 found that for SSc-ILD patients, tocilizumab was able to improve lung function and delay disease progression (Figure 5)
.

Studies suggest that tocilizumab is an important treatment option for patients with SSc-ILD, especially those in the inflammatory phase
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So which patients can benefit from tocilizumab? Figure 5 Results of the study Another further subgroup analysis showed that, irrespective of the extent and severity of ILD involvement, tocilizumab was helpful in stabilizing the progression of impaired lung function
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 The SENSCIS study published in the journal Lancet Respir Med in 2021 found that mycophenolate mofetil alone can stabilize the progression of SSc-ILD, but mycophenolate mofetil combined with nintedanib can play a better therapeutic effect
.

 Methotrexate, an anchor drug for rheumatoid arthritis, used to raise questions: Does it contribute to the development and exacerbation of ILD? A recent meta-analysis published in Eur Respir J answers this question—the use of methotrexate, instead of aggravating ILD, stabilizes and improves ILD, and may even prevent the onset of ILD
.

 In addition, a study in Arthritis Rheumatol pointed out that for ILD, combination therapy can also be considered when monotherapy is not effective
.

 There has been little progress in the field of anti-fibrotic therapy for ILD in recent years
.

2020 Lancet Respir Med journal article stated that pirfenidone can play a role in the anti-fibrotic treatment of ILD
.

// Early studies of CTD with increased risk of VTE showed an increased risk of VTE for all patients with CTD (Figure 6)
.

Fig.
6 Research results The model for early diagnosis and prediction of SLE-VTE is still under preliminary construction and validation, and will provide guidance for primary prevention and identification of high-risk patients in the future
.

 Primary prevention drugs for SLE-VTE mainly include aspirin and hydroxychloroquine, and secondary prevention drugs include heparin and warfarin
.

So can new oral anticoagulants be used in CTD-VTE patients? Preliminary assessments of the antiphospholipid syndrome phenotype in previous studies suggest that newer oral anticoagulants may be associated with greater bleeding risk and their efficacy is less certain
.

In this regard, Professor Li Mengtao believes that this type of drug can bring great benefits to patients, but whether it can be applied to CTD-VTE patients still lacks relevant research evidence, so more efforts are needed from colleagues
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