Oral VS subcutaneous injection, application of "methotrexate" should pay attention to these problems!

*For medical professionals to read for reference The exact cause of the disease is unknown[1], and it is often accompanied by extra-articular organ involvement and positive serum rheumatoid factor, which can lead to joint deformity and loss of function
.

 In the course of clinical treatment, methotrexate (MTX) is the "gold standard" drug for the treatment of RA (inhibiting the proliferation of inflammatory cells to achieve anti-inflammatory effects)
.

Compared with various biological preparations for the treatment of RA in recent years, MTX has the advantages of low price, convenient administration and good safety [1]
.

 MTX use matters that RA patients must know ) patients with moderate to high disease activity (disease activity score: DAS>3.
2), MTX monotherapy is strongly recommended [2]
.

 For initially treated patients, oral MTX is conditionally recommended rather than subcutaneously
.

(Level of Evidence: Moderate) A starting/titrated dose of MTX ≥15 mg/week over 4-6 weeks is conditionally recommended
.

(Level of evidence: moderate/very low) 2.
Alternative use of MTX: subcutaneous injection Although oral MTX is clearly indicated in the guidelines as a better choice, the gastrointestinal discomfort caused by oral MTX still discourages many patients, and this The occurrence of these adverse reactions is related to the dose of MTX
.

 Although folic acid can be supplemented during MTX treatment to reduce gastrointestinal side effects (5 mg of folic acid is supplemented 24 hours after MTX application, when the dose of MTX is larger, the dose of folic acid can be considered to increase appropriately), this still limits the use of high-dose oral MTX in the treatment of RA.
aspect of use
.

 Therefore, when RA patients do not respond well to oral MTX therapy, parenteral administration can be considered; among parenteral routes of administration (subcutaneous injection, intramuscular injection, and intravenous injection), subcutaneous injection is simpler, easier, and more painful.
It is smaller, well tolerated and has a comparable safety profile [3]
.

 3.
Things to pay attention to before using MTX Contraindications for MTX use include severe kidney disease, liver disease, leukopenia <3.
0×109/L, thrombocytopenia <100×109/L, age greater than 70 years old, malignant tumor, pregnancy or Inadequate contraception, history of alcohol/drug abuse, acute or chronic infections, and lung disease
.

 Therefore, before the application of MTX, it is recommended to evaluate the relevant risk factors, improve blood routine, liver and kidney function, chest X-ray (within 1 year before the drug), viral hepatitis screening, pregnancy test, etc.
Judging the patient's comprehension ability and compliance and other conditions, for patients with the above medical history, insufficient understanding ability, and poor compliance, the medication should be adjusted according to the condition
.

 How to reduce medication in RA patients using MTX? In the 2021 guidelines, it is recommended that patients reach their goal (low disease activity or remission, that is, DAS ≤ 3.
2) for at least 6 months before considering drug reduction
.

 In the 2015 guidelines, patients with low disease activity are recommended to continue DMARDs treatment, and the DMARDs for patients in remission are gradually reduced [4]
.

In the 2021 guidelines, dose reduction recommendations were made in the absence of data on when and how best to reduce doses in patients with low disease activity or in remission
.

The recommendation of the 2021 guideline is: continue to use the current dose > dose reduction > gradual discontinuation > sudden discontinuation (reduction refers to reducing the dose of DMARDs or extending the dosing interval; gradual discontinuation of DMARDs refers to gradually reducing the dose of DMARDs, and then discontinued) Therefore, whether DMARDs should be tapered or continued at the current dose is still a widely debated issue
.

What is the better option during MTX taper? If considering tapering of subcutaneous methotrexate (MTXsc), its own advantages (eg better efficacy, better tolerability) may turn into disadvantages, is oral reduction more effective? Recently, an article published in Rheumatology investigated this issue, which specifically tested the cumulative recurrence rate after 1 year in RA patients treated with oral MTX and MTXsc [5]
.

Studies have shown that patients with reduced MTXsc have a higher risk of developing the disease compared to patients who received oral MTX
.

  Let's take a look at the content of this study with Jiemei~ Study introduction 1.
Test population: The RA patients participating in the trial had good disease control, that is, DAS≤2.
4 and swollen joint count (SJC44)≤1
.

Are using at least one csDMARD and a TNF inhibitor (TNFi)
.

 2.
Methods: A total of 88 patients were included in the study, 17 and 71 patients received MTXsc and oral MTX, respectively
.

The median disease duration was 5.
9 years
.

The average dose of MTX for both routes of administration was 20 mg per week
.

 Participants were randomized into two groups, one with a tapered csDMARD first, then TNFi, and the other with a tapered TNFi first, and then a csDMARD tapered
.

The dose of csDMARD was halved at baseline, quartered at 3 months, and stopped at 6 months
.

Patients enrolled in the trial who developed relapse (DAS>2.
4 or SJC44>1) were restarted treatment and intensified every 3 months until DAS≤2.
4 and SJC44≤1
.

 3.
Conclusions: After 12 months, 53% of patients with reduced MTXsc relapsed, compared with only 27% of patients with reduced oral MTX (p=0.
037, Figure 1A)
.

Among patients who were re-treated for 3 months after relapse, 67% and 68%, respectively, had good disease control (p=0.
93, Figure 1A)
.

 Panel A: The first part on the X-axis is the cumulative percentage of patients who relapsed during follow-up.
The second part is the cumulative percentage of patients with active disease (DAS>2.
4+/SJC44>1) from relapse and retreatment, although we already know The conclusion is reached, but some issues still need to be concerned, such as: the same dose of MTXsc is more effective than oral MTX, or because MTXsc is better tolerated by patients than oral MTX
.

Thus a more comprehensive view of this conclusion~ Summary In conclusion, RA patients should consider the differences caused by different routes of administration when deciding to reduce MTX
.

Due to the increased risk of disease after gradually reducing MTXsc, clinicians should pay more close attention to patients whose MTXsc is gradually reduced, control the incidence of patients in time, and minimize disease recurrence
.

References: [1] Huang Jing, Shu Xiaoming, Wang Gui, et al.
The mechanism of action of methotrexate in the treatment of rheumatoid arthritis [J].
Chinese Journal of Clinicians: Electronic Edition, 2016.
[2] Fraenkel L, Bathon JM , England BR,et al.
2021 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis[J].
Arthritis Care Res (Hoboken).
2021 Jun 8.
doi: 10.
1002/acr.
24596.
Epub ahead of print.
[3] Wen Yuanyuan, Liu Shengyun, Zhang Lei.
Comparison of the efficacy and safety of subcutaneous injection of high-dose methotrexate needles and oral low-dose methotrexate tablets in the treatment of rheumatoid arthritis [J].
Medicine and Philosophy: B, 2012, 33(3 ): 2.
[4] Singh JA, Saag KG, Bridges SL Jr, et al.
American College of Rheumatology.
2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.
Arthritis Care Res(Hoboken).
2016 Jan;68( 1):1-25.
[5] Agnes EM Looijen, Elise van Mulligen, et al.
Tapering subcutaneous methotrexate causes more disease flares compared to tapering oral administration in established rheumatoid arthritis patients[J].
Rheumatology,2022,page1-5.