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Where is it "difficult" to treat refractory RA? These 11 tips to pay attention to!

 Last Update: 2023-01-01
 Source: Internet
 Author: User

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Refractory RA is a difficult problem in clinical treatment and also brings a huge burden
to patients.

The 2022 American College of Rheumatology (ACR) Annual Meeting was held
November 10-14, 2022 in Philadelphia, Pennsylvania, USA.
ACR Annual Meeting is the world's largest and most prestigious rheumatology academic conference, attended by more than 16,000 delegates from more than 100 countries around the world every year, and is an important platform
for relevant scholars to obtain the latest and most cutting-edge rheumatology research and clinical application information.

The "Medical Community" media and experts from the Youth Committee of the Rheumatology Branch of the Chinese Medical Association jointly created the live broadcast of "The Youth Committee of the Rheumatology Society Take You to See ACR", so that the majority of colleagues can grasp the essence of
the conference more conveniently.

In 2021, the European Union Against Rheumatism (EULAR) Task Force discussed and published a definition of "refractory RA" and provided recommendations
for the management of refractory RA.
However, in clinical treatment, there is still a large unmet need in patients with refractory RA
.

In the 2022 ACR Conference, the disease status and management of refractory RA is still a topic of concern and discussion among many scholars, and Professor Chen Zhu of the First Affiliated Hospital of China University of Science and Technology will explain the content
of this ACR conference on refractory RA in detail.

Refractory RA – unmet need

for treatmentRefractory RA for clinicians, Rheumatologists, in particular, are a big problem
.
There are many reasons for the occurrence of refractory RA, and the combination of multiple factors adds to the complexity
of disease management.
Patients often experience multiple treatment failures and are therefore incapacitated
prematurely.

Early drug options were limited, dominated by nonsteroidal anti-inflammatory drugs (NSAIDs), and by the 60s there were condition-modifying antirheumatic drugs (DMARDs
).
In the past 20 years, targeted synthetic biological agents have appeared [^1].
Although there are more and more treatment options, in fact, there are still many treatment difficulties in RA, such as
a very short treatment response time and difficulty in obtaining sustained remission.

Figure 1.
History of RA drug therapy

In a regisitative study from Sweden ^[²^], less than half of patients were able to respond for more than six months
, even in the case of DAS28, according to different criteria for disease remission.
So even in developed countries, there are still many unmet needs
for the treatment of RA patients.

Figure 2 The Swedish study

is difficult to define Therapeutic RA?

Failure to treat
RA is diagnosed if the following three are met.

1.
The first is treatment failure, that is, treatment should be carried out according to EULAR recommended guidelines, and the treatment of ≥ 2 b/tsDMARDs after the treatment of csDMARDs fails
.

2.
Patients and doctors agree that there is a problem
with the symptom management of RA.

3.
Meet at least 1 of the following 5 items, that is, there are signs of active or progressive disease:

a) At least moderate disease activity (DAS28-ESR>3.
2 or CDAI >10)

b) Signs and/or symptoms suggestive of active disease

c) Corticosteroids cannot be reduced to less than 7.
5 mg/day of prednisone or equivalent

d) Rapid radiographic progress

e) Reduced quality of life due to RA, although RA is well controlled

Key points in the management of refractory RA

Following the publication of the definition of refractory RA, EULAR subsequently published the Management Essentials
for Refractory RA.
The Management Points consist of two overarching principles: first, the following considerations are refractory RAs that meet the EULAR definition and are based on EULAR's recommended guidelines for RA; Second, pharmacological and non-pharmacological interventions should be guided
by the presence or absence of inflammation.

EULAR's key points for the management of refractory RA contain 11 considerations:

1.
If refractory RA is suspected, the first step should consider the possibility of misdiagnosis or other diseases (e.
g.
, fibromyalgia, polymyalgia rheumatica, etc.
);

2.
Ultrasonography may be considered when it is judged that inflammatory activity may exist according to clinical evaluation or comprehensive indicators;

3.
The results of clinical assessment and composite indicators should be interpreted with caution when comorbidities are present, particularly obesity and fibromyalgia, as these comorbidities can directly exacerbate inflammatory activity and overestimate disease activity;

4.
Treatment adherence should be discussed and optimized in the process of shared decision-making;

5.
After the treatment failure of the second b/tsDMARDs, especially the two TNF inhibitors, b/tsDMARDs with different mechanisms of action should be considered;

6.
If a third type of b/tsDMARDs is considered, the maximum dose found to be effective and safe in clinical trials should be used;

7.
Comorbidities that can directly or limit treatment options for RA and affect quality of life should be carefully considered and managed;

8.
B/tsDMARDs may be used in patients with hepatitis B/C virus infection, but close cooperation with a hepatologist and the addition of prophylactic or therapeutic antivirals should be considered;

9.
In addition to pharmacological measures, nonpharmacological measures (e.
g.
, exercise, psychotherapy, education, and self-management) should be considered to optimize the management of pain, fatigue and dysfunction;

10.
Patients should be provided with appropriate education and support, directly informing them of treatment goals and management options;

11.
Consider providing patients with self-management procedures, relevant educational knowledge, and psychological interventions to optimize patients' ability to
manage their own diseases.

One of the more important points to consider is that if a patient is considering refractory RA, the first thing to consider is not a treatment strategy, but to confirm that the diagnosis is reliable
.
Some patients may have fibromyalgia or polymyalgia rheumatica
.
Therefore, it is important to
consider the possibility of misdiagnosis or other comorbidities.
In addition, when considering the third type of b/tsDMARDs, the maximum dose
found to be effective and safe in clinical trials should be used.

Disease burden of refractory RA

The disease burden of refractory RA is first and foremost an increase
in the cost of treatment.
The main sources of cost for patients with refractory RA in Europe included 28% from informal help from family and friends, 26% from medications, and 16% from loss
of work capacity.
Refractory RA is usually disabling in the United States, costing $13,098 per person for patients under 65 years of age, even with disability benefits, and $13,098 per person over 65 years of age $
9,972.

A study from Keio University in Japan collected 1709 patients with RA ^[³^], with 10% (173)
of refractory RA meeting the EULAR definition.
There were three types of refractory causes, including multidrug resistance (34.
1%), presence of comorbidities (9.
8%), and socioeconomic factors (56.
1%)
.
Patients with refractory RA in Japan have higher
RF and CCP positivity rates.
Multivariate regression analysis found antibody positivity and a longer course of disease are independent risk factors
for the development of treatment-resistant RA.

In terms of treatment, conversion of biologics is very common, with nearly 50% of patients achieving remission or low disease activity when switching to a third biologic, but the increased number of conversions also indicates that patients are more difficult to treat and positively correlated
with disease activity.

The psychological impact of refractory RA on patients is also an area
of concern.
Patients with RA with comorbid depression have an increased risk of death, with the highest risk of death < 55 years of age, men having a higher risk of death than women, and seropositive patients having a higher
risk of death.

Emotions and pain are anatologically similar in brain regions, and there are the same brain regions that manage both mood and pain
at the same time.
A statistical analysis found that 85% of patients with chronic pain had moderate to severe depression
.
Therefore, for patients with RA, especially refractory RA with a long course of disease, clinical attention should be paid to changes in mental and psychological status, such as whether depression or anxiety
is comorbid.
It is necessary to detect potential manifestations of depression in time and intervene and treat them in time, otherwise the prognosis of patients is poor
.

The other aspect is low socioeconomic status, that is, the economic status
of the patient.
A large number of studies have found that low socioeconomic status is associated
with high disease activity.
The same phenomenon is true in many countries, where disease activity is generally higher
in patients with less economic means.

summary

EULAR's definition of refractory RA is disease-centric, and a unified definition standard is conducive to providing a reference
for clinical trials, retrospective clinical studies, and clinicians' decisions on immunosuppressive therapy.

Refractory RA has a greater disease burden, including increased healthcare costs, disability, loss of independence, and a higher risk of cardiovascular disease and psychiatric illness
.

Subsequent lines of investigation into refractory RA focused on socioeconomic determinants, static load, and mental health and social isolation
.
Expert profiles

Professor Chen Zhu

● Chief Physician, Department of Rheumatology and Immunology, First Affiliated Hospital of University of Science and Technology of China● Distinguished Researcher, Doctoral Supervisor, University of Science and Technology of China● Doctor of Medicine, University of Erlangen-Nuremberg, Germany● Postdoctoral Fellow of Cornell University Special Surgery Hospital● Reserve Candidate for Academic and Technical Leader of Anhui Province● Youth Committee Member of Rheumatology Branch of Chinese Medical Association ● Youth Committee Member of Rheumatology and Immunologist Branch of Chinese Medical Doctor Association● Standing Committee Member
of Rheumatology Branch of Anhui Medical Association Reference:[1]Kerrigan SA, McInnes IB.
Nat Rev Rheumatol.
2020 Mar; 16(3):179-183.

[2] Einarsson, Jon T et al.
Rheumatology (Oxford).
2019 Feb 1; 58(2):227-236.

[3] Takanashi, Satoshi et al.
Rheumatology (Oxford).
2021 Nov 3; 60(11):5247-5256.

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