RA actually caused "breathing pain"? Hear what the experts have to say

*For medical professionals only

Rheumatoid arthritis (RA) is no stranger to everyone, it is one of the most common diseases in rheumatology and immunology, and RA patients often complain of joint swelling and pain, morning stiffness and mobility disorders
.
However, RA is not a disease that simply affects the joints, but can also affect various organs and systems, and is a veritable systemic autoimmune disease
.
These extra-articular manifestations often predict a poor prognosis and should be given special clinical attention
.

Interstitial lung disease (ILD) is one of the major organ lesions in multisystem involvement of RA and one of
its most serious comorbidities.
The clinical manifestations, etiology and clinical diagnosis and treatment of RA combined with ILD have become common concerns of doctors in rheumatology, respiratory, and intensive care medicine
.
In this issue, "Medical Community" is honored to invite Professor Linhe Linhe of Fujian Provincial Hospital Rheumatology and Immunology to share his wonderful views
with us.

"Ahem cough" -

Don't miss red flags of RA involving the lungs

Epidemiological data suggest that the lifetime prevalence of ILD in patients with RA with clinically significant manifestations is 5% to 10%.

According to the different screening methods of ILD, the incidence varies from 2.
7~3.
8/100,000 patients ^[1].

Professor Lin He told us that patients with RA with ILD in clinical practice may have clinical manifestations such as active dyspnea, restrictive ventilation disorders, decreased diffusion function (DLCO) of the lungs, and hypoxemia, among which exertional dyspnea and dry cough are the most common
.
ILD causes severe respiratory damage to people with RA and can affect almost every activity in their daily lives, reducing their quality of life
.
If not effectively controlled, it may cause severe breathing difficulties and even respiratory failure, which is life-threatening
.
In addition, RA patients with ILD are also prone to various infections of the respiratory system, further aggravating ILD lesions
.
Infections on this basis are more difficult to treat than those without ILD, and are one of the causes of life-threatening ^[2-3].

Patients with RA and ILD have a threefold greater risk of death than those with RA alone, and ILD has become the second leading cause of death in patients with RA, after cardiovascular disease ^{[1, 4].}

Professor Lin He pointed out, "It is precisely because of the clinical harm of ILD that everyone is paying more and more attention to RA-related ILD, and a lot of research work
has been done on its etiology and clinical diagnosis and treatment.
”

Which people with RA may be at high risk for ILD? In this regard, Professor Lin He said that the probability of ILD in RA patients is related to many factors, including the patient's gender, age, lifestyle, disease activity and duration
of RA.
"Clinically, we have observed a higher
proportion of ILD in men and older RA patients.
" According to clinical observations and related research findings, Professor Lin He told us: "Those who smoke for a long time or have a history of lung infection in the past have poor lung basic conditions and are more likely to cause lung damage
.
"In addition, patients with RA with a longer course of disease and high disease activity are also at high risk of ILD, especially those with high levels of autoantibodies, such as anti-cyclic citrullinated peptide antibodies (anti-CCP antibodies) ^[4-5].

Prof.
Lin He recommends that patients
with RA with these high-risk factors should be closely monitored.

lung lesions and joint involvement,

Who is "matchmaking" them?

Patients with RA are nearly nine times more likely to develop ILD than the general population ^[6].

How are lung lesions and joint involvement, two seemingly unrelated manifestations of the disease, linked? Professor Lin He sorted out the relevant clues
for us from some existing research data.

"At present, the exact etiology and pathogenesis of RA-related ILD are unknown, and many studies
have been conducted in the academic community.
" Professor Lin He pointed out that the occurrence of RA-related ILD is closely related to environmental factors (such as lung tissue and cell damage caused by cigarette smoke, pathogens or other irritants in the environment), genetic factors (such as the presence of susceptibility genes), and immune factors (such as immune tolerance failure, autoantibodies and autoimmune production) (Figure 1) ^[7].

Figure 1: Development mechanism of RA-ILD ^[7].

RA is an autoimmune disease in which multiple autoantibodies
are usually present in the patient.
Among them, rheumatoid factor (RF) and anti-citrullinated protein antibody (ACPA) occupy a very important position
in the occurrence and development of RA.
Compared with traditional RF, ACPA is a newly discovered important antibody associated with the pathogenesis of RA, which is not only a highly sensitive and specific diagnostic marker, but also a predictor of disease severity and progression ^[8].

ACPA can cause damage to the local mucosa, airways, and lung interstitium in a variety of ways, such as promoting the formation and release of inflammatory cytokines and the formation and deposition of immune complexes
.
Studies have shown a strong correlation between elevated ACPA titers and RA-related airway disease ^[7]; Signs of aggregation and activation of immune cells have been found in bronchial tissue and bronchoalveolar lavage fluid in patients with ACPA-positive RA ^[7]; Elevated ACPA titers are also associated with an increased prevalence of ILD in patients with RA ^[9].
.
.
These findings suggest that ACPA may mediate the development of lung disease in patients with RA and is inextricably linked
to the progression of RA-ILD disease.

However, the specific mechanism of action of ACPA is not yet known, and there are many conjectures and assumptions
in the academic community.
From the perspective of joint manifestations and the chronological sequence of lung lesions, a considerable proportion of RA patients have ILD before the onset of joint symptoms, and ACPA can also exist in the body several years before the onset of RA, indicating that the lungs are likely to be the early organ site of ACPA-induced damage, and the immune response of citrulline polypeptides in the lungs may cause secondary joint inflammation and joint injuries; As for the phenomenon that joint symptoms precede ILD, scholars speculate that this is likely to be the result of the migration of immune responses to citrullinated peptides at joints to the lungs, and the high ACPA concentration in the local and systemic systems causes a significant inflammatory response in the lungs, leading to the occurrence of ILD ^{[7, 9].}

。 Regardless of the order in which joint symptoms and lung damage occur, ACPA plays an extremely important "bridge" role, linking
lung damage and joint symptoms in RA-ILD.

Multidisciplinary joint diagnosis and treatment,

Innovative drugs help control RA-ILD

The diagnosis and treatment of RA-ILD has always been a difficult point
in clinical work.
Early screening and diagnosis is essential
for patient populations with high-risk factors for RA-ILD.
Professor Lin He said that the clinical diagnosis and treatment of RA-ILD requires multidisciplinary cooperation ^[10].

"Connective tissue diseases like RA are our area of rheumatology and immunology, and connective tissue is the main tissue component of the lungs, and many rheumatic immune diseases can affect the lungs; At the same time, lung diseases belong to the scope
of respiratory diagnosis and treatment.
Therefore, patients with lung diseases are often first diagnosed in the respiratory department, and patients also need pulmonary function tests, lung CT examinations, and if necessary, etiological examinations and pathological examinations
.
Professor Lin He also pointed out, "In addition to the observation and judgment of clinical symptoms, the detection of serum biomarkers, imaging and histopathological evaluation are also important means of
clinical diagnosis.
" Therefore, respiratory, radiology, pathology and laboratory are also key departments in multidisciplinary cooperation
.
”

Speaking about the treatment of RA-ILD, Professor Lin He said that there is currently no specific drug, and the ideal treatment goal in clinical practice is to stabilize and improve the condition of ILD while alleviating RA, and prevent the progression or deterioration
of the disease.
Among the various commonly used therapeutic drugs, traditional synthetic disease-modifying antirheumatic drugs (csDMARDs) are the first-line drugs for the clinical treatment of RA, and methotrexate (MTX), as one of the classic csDMARDs, is the anchor drug
recommended by many domestic and foreign guidelines.
However, there are cases where MTX may induce ILD or exacerbate the condition of patients with RA, and although there is no high-quality evidence-based medical evidence to confirm that MTX treatment worsens patient outcomes, caution should be exercised in clinical practice in the face of possible risks ^{[9, 11].}

"The emergence of various biologics is a breakthrough in
the field of RA treatment in recent years.
As a second-line treatment for RA, biologics can effectively improve the clinical symptoms and joint function
of patients.
"Although the current research results on the risk of ILD development and progression of biologic therapy in RA patients vary greatly, overall, the efficacy of the use of non-TNF inhibitor biologics on the stabilization and improvement of ILD in RA patients is more precise and the risk is relatively low ^[11].
]
。 ”

In the relevant drug introduction, Professor Lin He highlighted a new type of biological agent, abatacept
.
By blocking co-stimulatory signals, abatacept inhibits the activation of T lymphocytes and reduces the inflammatory response
in RA patients.
Previous studies have shown that abatacept has significant efficacy advantages in patients with ACPA-positive RA ^[12-15], combined with the possible important role of ACPA in RA-ILD mentioned above, does abatacept also have a unique effect on the stabilization of patients with RA-ILD?

Professor Lin He pointed out that according to post-marketing surveillance data and safety data in clinical trials, patients with RA have a low incidence of ILD after receiving abatacept ^[16-17], and no lung damage caused by treatment has been found in clinical practice
.
Moreover, studies have confirmed that abatacept is beneficial for the stabilization of patients with RA-ILD:

• In a single-center retrospective study in Japan, abatacept or abasept was a significant independent protective factor against new or exacerbations of lung disease, including ILD and obstructive pulmonary disease, in patients with RA (hazard ratio OR: 0.
  07, 95% CI: 0.
  01-0.
  99) ^[18] ；

Figure 2: Independent factors associated with airway disease or ILD progression

• Meta-analysis results showed that abatacept significantly reduced the rate of ILD exacerbations in RA patients; Compared with TNF inhibitors and csDMARDs, patients treated with abatacept had a 90 percent lower relative risk of ILD deterioration compared with TNF inhibitors and csDMARDs ^[19].