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Is it still targeted for a blind man to touch an elephant?
Subclinical rheumatoid arthritis (subclinical RA) refers to a state in which patients are autoantibody positive and subclinical synovitis precedes the occurrence of clinical arthritis, and is increasingly common
in rheumatological practice.
However, in practice, there is no conclusive view on how to manage it, and whether initiation of condition-modifying antirheumatic drugs (DMARDs) in this state can prevent the development of
RA.
The "Medical Community" media and experts from the Youth Committee of the Rheumatology Branch of the Chinese Medical Association jointly created the live broadcast activity of "The Youth Committee of the Rheumatology Society Takes You to See ACR", so that the majority of colleagues can more conveniently grasp the essence of
the conference.
In this issue, Professor Zhao Yi of West China Hospital of Sichuan University was invited to share his wonderful sharing
based on the topics of this year's American College of Rheumatology (ACR) Annual Meeting.
What is subclinical RA?
For different RA patients, there are similar or different predicitated factors (genetic and environmental risk factors,
etc.
).
However, in the exposure of pathogenic factors, some people initially have local mucosa/systemic autoimmune manifestations, and at the same time have positive serum autoimmune antibodies (such as anti-citrullinated protein antibody (ACPA), rheumatoid factor (RF), etc.
], but there is no arthritis manifestation, and subclinical arthritis and undifferentiated arthritis will appear sequentially as the course of the disease progresses, and eventually evolve into a state
that meets the diagnostic criteria for RA.
In the above complete course of RA, the symptoms are divided into joint symptoms (joint pain) and non-articular symptoms (fatigue, discomfort, mucosal symptoms), and the concept of non-arthritic RA, arthritic RA, and subclinical arthritis (that is, there is imaging evidence of arthritis, but there is no synovitis on examination, tenosynovitis can be the first manifestation), and the so-called subclinical RA/ The first RA contains some or all of the three terms mentioned above, as shown in Figure 1 [1-2].
Figure 1.
Overview of the course of RA and its associated concepts
Does every subclinical RA become an RA?
Studies have shown that in seropositive individuals without arthritis (i.
e.
, ACPA-positive high-risk individuals), local ACPA is associated
with the development of mucosal inflammation.
Small samples were observed and detected in sputum samples About 67% of patients with ACPA or RF eventually progress to RA, and it seems that the probability of local inflammation + local ACPA-positive people eventually progressing to clinical RA is not low
.
Although the definition of subclinical RA is not uniform, the proportion of patients who progress to clinical RA with DMARDs or hormonal interventions ranges from 19% to 46% (Figure 2).
Figure 2.
Results of different trials of intervention in subclinical RA
Should DMARDs be initiated for subclinical RA?
Proponents
of the idea that individualized symptoms and tissue damage may occur during the autoimmune process of subclinical RA, so specific approaches can be used at different stages to try to prevent or improve clinical RA
。
For most people, RA is a lifelong disease, and clinical RA has limited treatment effect, usually with the goal of minimizing disease activity, so many people do not want to have RA, and it is in the patient's interest to intervene in subclinical RA
。
In addition, the autoimmune process of subclinical RA also has a negative impact on population health and mortality, so the subclinical stage of treatment of non-inflammatory arthritis may benefit patients, such as reducing pain, fatigue, and preventing inflammatory arthritis
.
However, there are also many challenges in the intervention subclinical stage, such as: ■
the definition of subclinical RA is not uniform;
■ Inaccurate prediction of subclinical progression to clinical RA;
■ More subjects at risk of RA are needed to participate in relevant clinical trials;
■ Effective interventions to prevent RA are not yet approved (e.
g.
abatacept, vitamin D and omega-3);
■ Insufficient understanding of the biological stages of RA development
.
At the same time, studies have found that the course of subclinical RA may be related to the early driving patterns of mucosa at different sites, and different clinical "subtypes" may also be related to the discovery of mucosa at different sites of autoantibodies (Figure 3) [3].
。
Figure 3.
Different mucosa
, namely mucosal inflammation and biological disorders, may first lead to local production of autoantibodies, followed by systemic transmission of autoimmunity, such as elevated serum autoantibodies, and eventually progression to clinical RA.
This finding makes it possible to prevent RA through mucosal specificity and checkpoint failure in the future (Figure 4).
Figure 4.
Schematic diagram of checkpoint failure for RA prevention
Therefore, proponents believe that improving the understanding of pathophysiology can ensure that preventive measures can be targeted at different stages of subclinical RA; In addition, criteria for risk stratification should be established and a definition of subclinical RA should be clarified to guide clinical trials so that preventive measures can be supported by sufficient evidence; Biomarkers such as imaging, genetic, environmental, mucosal conditions, etc.
need to be sought for in asymptomatic patients, and preventive interventions should include lifestyle interventions and new DMARD application concepts
.
Most importantly, regardless of whether measures to prevent clinical RA intervene in the subclinical "autoimmune" phase, the health status and quality of life of these patients should also be intervened and improved
.
Opponents should argue that although there is evidence that DMARD interventions do have a preventive effect on RA, such as:
● rituximab can delay the onset of RA by 1 year;
● Although methotrexate did not prevent the development of clinical arthritis, the participants who received the intervention had less symptoms and damage than the placebo group;
● The effect of hydroxychloroquine is not better than that of placebo;
Abatacept can delay RA performance for 18 months
.
However, there is currently a lack of biomarkers for subclinical disease monitoring and medication guidance, and studies have confirmed that ACPA is weakly positive and easy to turn negative, although the incidence of inflammatory arthritis in the high-risk relative cohort of RA patients is high, but most autoantibody-positive subjects do not develop inflammatory arthritis and spontaneously return to autoantibody-negative status, which makes the intervention of subclinical RA lack an observation window [4] and in practice intervention was carried out too late because of the above shortcomings (Figure 5).
Figure 5 Stages of development of subclinical RA
In addition, which of ACPA-positive and/or RF positive, positive ACPA and arthralgia, inflammatory arthritis not meeting RA criteria for ACR, arthralgia and more than 1 joint ultrasound abnormality, all/none of the above is subclinical RA?
Unfortunately, to date, subclinical RA has not been accurately defined
.
At the same time, it is not known which type of patients will progress from subclinical RA to RA, what are its triggers, which of the triggers can be intervened, how to screen for subclinical RA, and why RA recurs, drug resistance and many other problems are unknown, so intervention in subclinical RA is tantamount to blind people touching elephants
.
In a 2017 study in the Netherlands, for example, 1.
4% of people over 50 years of age were positive for ACPA, and only half of them were eventually diagnosed with RA [5].
Not only is there a risk of overtreatment with DMARD interventions in these people, but lifestyle interventions have also been shown to reduce seronegative and positive RA [6].
The speakers also pointed out that at most 1 in every 5-6 patients with strong ACPA will progress to clinical RA in the second year, and preventive treatment means overtreatment of 4-5 people, so DMARD intervention
for such patients is not supported.
Summary
are put forward based on medical practice in the United States.
This is also of practical guiding significance
for the clinical practice of RA in China.
Expert profiles
Professor Zhao Yi
● Leader of learning and technology in Sichuan Province
● Academic and technical leader of Sichuan Provincial Health Commission
● Vice Chairman of the Youth Committee of the Rheumatology Branch of the Chinese Medical Association
● Vice Chairman of the Youth Committee of the Rheumatology and Immunologist Branch of the Chinese Medical Doctor Association
● Chairman-elect of the Rheumatology Professional Committee of Sichuan Medical Association
● Member of Immunosorbent Branch of Chinese Medical Doctor Association
● Vice President of Rheumatology and Immunology Branch of Sichuan Medical Practitioners Association
● Undertake 1 national key research and development program and 3 national natural science foundations
References:
[1]Raza K, Gerlag D M.Preclinical inflammatory rheumatic diseases: an overview and relevant nomenclature[J].
Rheumatic Disease Clinics, 2014, 40(4): 569-580.
[2]van Steenbergen H W, Aletaha D, Beaart-van de Voorde L J J, et al.
EULAR definition of arthralgia suspicious for progression to rheumatoid arthritis[J].
Annals of the rheumatic diseases, 2017, 76(3): 491-496.
[3]Holers V M, Kuhn K A, Demoruelle M K, et al.
Mechanism-driven strategies for prevention of rheumatoid arthritis[J].
Rheumatology & Autoimmunity, 2022, 2(03): 109-119.
[4]Tanner S, Dufault B, Smolik I, et al.
A prospective study of the development of inflammatory arthritis in the family members of Indigenous North American people with rheumatoid arthritis [J].
Arthritis & Rheumatology, 2019, 71(9): 1494-1503.
[5]Van Zanten A, Arends S, Roozendaal C, et al.
Presence of anticitrullinated protein antibodies in a large population-based cohort from the Netherlands[J].
Annals of the rheumatic diseases, 2017, 76(7): 1184-1190.
[6]Hahn J, Malspeis S, Choi M Y, et al.
Association of Healthy Lifestyle Behaviors and the Risk of Developing Rheumatoid Arthritis among Women[J].
Arthritis Care & Research, 2022.
Where to see more rheumatology clinical knowledge? Come to the "doctor's station" and take a look 👇
