Rheumatoid arthritis, how to take medicine outside the instructions?

*Only for medical professionals to read and refer to the expert consensus on the use of rheumatoid arthritis (RA) off-label.
The academic forum of the committee was held online from 4.
9 to 4.
10.
Well-known experts from home and abroad gathered here, and it was brilliant.
Authoritative experts in rheumatology presented their opinions, brought cutting-edge medical progress in rheumatology, and conducted academic studies on hot topics and women's humanities.
communicate and discuss
.

Professor Dai Lie from the Department of Rheumatology and Immunology, Sun Yat-sen Memorial Hospital of Sun Yat-sen University gave a detailed explanation of the Chinese expert consensus on RA off-label use (2022 version), which pointed out the direction for rheumatology immunologists to use drugs
.

What is "off-label drug use"? Drug use off-label, also known as "off-label use" and "unregistered drug use", refers to the use of the drug that is not within the scope of the drug label approved by the drug regulatory authority, such as the indication, dosage, course of treatment, route or population.

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As of 2022, the update of domestic drug insert sheets for RA is relatively lagging behind
.

New RA treatment drugs are constantly on the market, new evidence-based medical evidence and constantly updated domestic and foreign guidelines suggest that more drugs can be used for RA patients during pregnancy, pregnancy, lactation and other special periods
.

Professor Dai Lie pointed out that, in view of this situation, a consensus on RA off-label drug use urgently needs to be launched
.

The consensus writing group formulated 12 recommendations after repeated discussions and revisions through literature review, expert consultation, the US IBM MICROMEDEX database, domestic and foreign drug instructions, and domestic and foreign RA-related treatment guidelines
.

1.
Off-indication medication▎Recommendation 1.
Methotrexate (MTX) is the first-choice disease-modifying anti-rheumatic drug (DMARD) for the treatment of RA
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According to the domestic drug instructions of MTX, MTX treatment of RA is a drug that is beyond the drug instructions
.

However, the basis for recommending oral MTX for the treatment of RA is as follows: ① Foreign drug inserts: The US Food and Drug Administration (FDA) has approved oral MTX for the treatment of adult RA
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② Treatment guidelines: MTX is the preferred DMARD for RA treatment guidelines recognized by China, the American College of Rheumatology (ACR) [1, 2] and the European League Against Rheumatism (EULAR) [3]
.

③ The US IBM MICROMEDEX database: the effectiveness of MTX in the treatment of RA is grade I, the recommendation grade is IIa, and the evidence strength is
B.

▎Recommendation 2.
Folic acid can be used to prevent folic acid deficiency that may be caused by MTX, and it is recommended to take folic acid after 24 hours of MTX treatment
.

Professor Dai Lie pointed out that MTX can interfere with folic acid metabolism, which may lead to folic acid deficiency, so folic acid should be supplemented the next day after taking MTX
.

However, the drug inserts of folic acid in various countries do not mention the toxic and side effects used to prevent MTX
.

At present, the guidelines of various countries, including the British Society of Rheumatology, the Chinese expert consensus, and the Japanese Society of Rheumatology, have all proposed the supplementation of folic acid after taking MTX
.

The US IBM MICROMEDEX database shows that the effectiveness of folic acid for the prevention of MTX side effects is grade IIa, recommendation grade IIb, and evidence strength class
A.

▎Recommendation 3.
Oral cyclophosphamide (CTX) is only used for RA patients with severe extra-articular involvement such as interstitial pneumonia and vasculitis
.

Domestic injection CTX and oral CTX tablets have no indications for RA treatment, but Germany approved injection CTX for the treatment of RA.
In 2010, EULAR/ACR pointed out that for refractory severe RA or those with contraindications to existing biological agents and DMARDs, CTX is one of the drugs that can be considered
.

It is worth noting that the ACR, EULAR, and Chinese RA treatment guidelines updated after 2013 did not mention CTX
.

The benefit/risk ratio of CTX in the treatment of RA is not satisfactory, so it is not recommended as a first-line treatment drug, only for RA patients with severe extra-articular involvement such as interstitial pneumonia and vasculitis
.

▎Recommendation 4.
Rituximab (RTX) can be used for the treatment of patients with moderate to severe active RA with a history of lymphoproliferative disease or poor response to TNF-α inhibitors
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The domestic indication of RTX is lymphoma, and the treatment of RA is an off-indication drug
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The 2021 ACR guidelines conditionally recommend RTX over other DMARDs in patients with moderately to severely active RA with a prior history of lymphoproliferative disease because RTX does not increase the risk of recurrence or exacerbation of lymphoproliferative disease
.

In keeping with FDA instructions, the 2021 ACR guidelines specifically state that RTX should only be used in patients with RA who have not responded well to TNF-α inhibitors
.

2.
Use beyond the route of administration▎Recommendation 5.
Oral administration of MTX is the first choice for the treatment of RA, but subcutaneous injection of RA patients with oral intolerance or the maximum tolerated dose of oral therapy can be considered.
According to the domestic drug instructions, subcutaneous injection of MTX belongs to Use beyond the route of administration
.

The US FDA has approved subcutaneous MTX for the treatment of adults with severe RA who are refractory to or intolerant of first-line therapy, including full-dose non-steroidal anti-inflammatory drugs (NSAIDs)
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The Chinese, ACR and EULAR guidelines for the treatment of RA all recommend that subcutaneous injection of MTX is an option for RA patients who are intolerant of oral MTX or who fail to meet the standard of treatment
.

3.
Superpopulation drug use▎Recommendation 6.
Female RA patients can use traditional NSAIDs to control symptoms in the early and middle trimesters of pregnancy
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Traditional NSAIDs can be used while breastfeeding
.

Table 1 Domestic instructions for using traditional NSAIDs and the basis for recommended medication GC, and the equivalent dose of prednisone should be less than 20 mg/d; prednisolone acetate injection can be used for intra-articular injection
.

Lactating RA patients can use GC to control the disease
.

Table 2 The domestic instructions for using GC & the basis of recommended medication ▎Recommendation 8.
Female RA patients during pregnancy and lactation can be treated with sulfasalazine (SSZ), but the recommended dose does not exceed 2g/d, and folic acid is supplemented at the same time
.

Table 3 The domestic instructions for using SSZ & the basis of recommended medication▎Recommendation 9.
Female RA patients during pregnancy and lactation can be treated with hydroxychloroquine (HCQ)
.

Table 4 The domestic instructions for using HCQ and the basis of recommended medication▎Recommendation 10.
Female RA patients during pregnancy and lactation can be treated with cyclosporine (CsA), and blood pressure and renal function should be closely monitored during medication
.

Table 5.
Domestic instructions for the use of CsA and the basis for recommended medication There are differences in gestational age for safe use
.

The drug inserts of some TNF-α inhibitors do not recommend their use in pregnant and lactating women
.

Professor Dai Lie pointed out that there are more evidence-based medical evidences for the use of TNF-α inhibitors during pregnancy
.

The molecular weight of TNF-α inhibitors is relatively large, and they can only pass through the placental barrier in the form of active transport, and bind to FcRn on the placenta through the Fc segment of the drug, thereby entering the fetal circulation through the syncytiotrophoblast
.

On the other hand, FcRn on syncytiotrophoblasts was almost undetectable until 14 weeks of gestation and began to increase in the second and third trimesters
.

Therefore, the use of TNF-α inhibitors in the first and second trimesters of pregnancy is relatively safe
.

The basis for recommending medication during pregnancy are as follows: Table 6 Basis for medication during pregnancy▎Recommendation 12.
Male RA patients who are preparing for pregnancy can continue to use MTX.
The domestic instructions point out that MTX can affect reproductive function, so males need to use contraception during medication
.

However, a prospective observational cohort study showed that the use of low-dose MTX in men did not increase the incidence of adverse pregnancy outcomes
.

The 2020 ACR Reproductive Health Guidelines pointed out that the current data does not suggest teratogenic adverse reactions in male RA patients using MTX, so it is recommended that men who are trying to conceive can continue to use MTX
.

Summary Professor Dai Lie gave a detailed explanation of the Chinese expert consensus on off-label use of RA (version 2022), and analyzed three types of off-indication medication, medication beyond the route of administration, medication beyond the population, and 12 recommended opinions one by one.
It provides guidelines for rheumatology clinicians to treat RA off-label
.

But at the same time, Professor Dai Lie also emphasized that although these drugs have some evidence-based medical evidence, they still need to be used with caution in clinical applications.

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In addition, for female RA patients during pregnancy and lactation, the drugs recommended in this consensus should be used under the joint guidance of rheumatologists and obstetricians
.

Reference [1] Fraenkel, L.
, et al.
, 2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.
Arthritis Care Res (Hoboken), 2021.
73(7): p.
924-939.
[2] Sammaritano, LR, et al.
, 2020 American College of Rheumatology Guideline for the Management of Reproductive Health in Rheumatic and Musculoskeletal Diseases.
Arthritis Rheumatol, 2020.
72(4): p.
529-556.
[3]Smolen, JS, et al.
al.
, EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update.
Ann Rheum Dis, 2017.
76(6): p.
960-977.