Can serum negative still diagnose RA? These new indicators are so useful!

*Only for medical professionals to read for reference.
There are so many dry goods, collect them soon! Rheumatoid arthritis (RA) is a relatively common autoimmune disease.
It is a systemic disease characterized by persistent symmetrical joint synovial inflammation and the appearance of multiple autoantibodies.

1/3 of RA patients are seronegative? At present, anti-cyclic citrulline (CCP) antibodies and rheumatoid factor (RF) are the detection indicators recommended in the 2010 American Academy of Rheumatology/European Alliance Against Rheumatism (ACR/EULAR) RA classification standards, but clinically about 1 /3 of RA patients are anti-CCP antibodies and RF seronegative.
Therefore, there is an urgent need for new serological markers to further improve the diagnosis of RA.
At present, many international studies have studied biomarkers, such as anti-aminomethyl Acylated protein (CarP) antibody, anti-glucose-6-phosphate isomerase (GPI) antibody, anti-RA33/36 antibody, etc.
There are too many antibodies to study.
If you look up the relevant literature one by one, it is really personal.
Live, so the editor organized it for everyone.

Multiple new indicators are also very helpful in diagnosing RA.
Anti-CarP antibody Anti-CarP antibody as a new type of autoantibody has attracted people's attention.

In 2011, Shi et al.
[1] reported for the first time that anti-CarP antibodies exist in RA serum, which is helpful for the early diagnosis of RA.

In the meta-analysis of Li[2], 7 included studies found that the sensitivity of anti-CarP antibody was 42% and the specificity was 96%.

A Meta-analysis study [3] included 6 articles in English to explore the diagnostic value of anti-CarP antibody for RA.
It was found that the sensitivity of CarP antibody in the diagnosis of RA was 43%, the specificity was 92%, and the receiver operating characteristic curve (ROC) curve The area under (AUC) value is 9.
43, and the analysis results show that the serum CarP antibody has relatively high specificity and sensitivity.

In addition, the serum CarP antibody AUC is relatively large, and the accuracy of RA diagnosis is relatively high.

The antibody can also be detected in RA serum with negative anti-CCP antibody.
Many studies have suggested that anti-CarP antibody may be involved in the occurrence and development of RA and is related to the progress of RA.

2 Anti-GPI antibody GPI is a multifunctional protein with a relative molecular mass of 40,000.
It can also be called phosphohexose isomerase or phosphoglucose isomerase.

GPI is secreted by T cells.
In addition to enzyme activity, it also has cytokine and growth factor-like activities.
It exists in the extracellular fluid and cytoplasm of various cells, especially in the joint cavity, especially on the surface of cartilage.

In recent years, people have gradually realized that GPI can be used as an autoantigen and is closely related to autoimmune diseases, especially RA [4, 5].

In 2001, Schaller et al.
[6] found that 64% of RA patients had elevated IgG-type anti-GPI antibodies and GPI antigen titers in the serum and synovial fluid.

Cha et al.
[7] also found that there are a large number of GPI antibodies in the synovial fluid of RA patients, indicating that GPI antigens and their antibodies may be involved in the pathogenesis of RA.

A study [8] to clarify the significance of GPI in the supplementary diagnosis of RA, tested 229 cases of RA patients with serum RF, CCP, and GPI, and found that 61 patients were RF-negative, and the GPI-positive rate of RF-negative patients was 36.
1%; 38 cases Patients with anti-CCP antibodies were negative, and the GPI positive rate in anti-CCP negative patients was 34.
2%; 29 patients were RF and anti-CCP negative, and the GPI positive rate in double-negative patients was 24.
1%, suggesting that the combined detection of GPI and other autoantibodies is helpful for RA diagnosis.

ROC curve analysis showed that the sensitivity of GPI independent diagnosis of RA was 54.
2%, and the specificity was 87.
3%.
The specificity results were similar to those reported in China [9-11], but the sensitivity was slightly lower, which may be different from the criteria and sample size of the enrolled patients.
Related.

Moreover, GPI also has a higher positive rate in RF-negative, anti-CCP-negative, and double-negative RA patients, which further shows that GPI has a certain diagnostic and supplementary diagnostic value for RA, and can be used as a combined diagnostic index in clinical applications.

3 Anti-RA33/36 antibody In 1989, Austrian scholar Hassfeld W et al.
used Western blotting (IBT) to detect RA33 antibody in the serum of RA patients, and found that the antibody is a highly specific antibody for the diagnosis of RA, and can be compared with the molecular weight of the antibody.
The 33KD nucleic acid protein reacted, so it was named anti-RA33 antibody.

At the same time, antibodies with molecular masses of 36000, 31000 and other antigens were found.
Among them, antibodies with a molecular mass of 36000 antigens also have specificity for the diagnosis of RA, so it was named RA36 antibody.

Anti-RA33 antibody and anti-RA36 antibody often appear simultaneously in the patient's serum, which is specific for the diagnosis of RA.

Studies have found that 27%-45% of serum-RF-negative RA patients can detect RA33 antibodies, indicating that anti-RA33 antibodies have complementary diagnostic value for RF-negative RA patients [12-14].

According to the ACR standard in 1987, when RA cannot be diagnosed, anti-RA33 can be detected, indicating that the anti-RA33/36 antibody has a better value for early diagnosis of RA [14-16].

4 Anti-mutant citrullinated vimentin antibody (anti-MCV antibody) Anti-MCV antibody is an autoantibody found in the blood of RA patients in recent years.
It belongs to anti-citrullinated protein antibody together with anti-CCP antibody.
CCP antigen determines The clusters are artificially synthesized.
MCV epitopes are derived from natural substances, and CCP epitopes are also less than MCV.
Therefore, in theory, the specificity and sensitivity of anti-MCV antibodies are higher [17], due to the table in anti-CCP and anti-MCV antibodies.
All positions have citrulline, so they can be called citrulline-related autoantibodies, and their production and deposition are important factors that cause the development of RA disease.

5 Anti-citrullinated α-enolase polypeptide 1 antibody (anti-CEP-1 antibody) CEP-1 is currently known α-enolase (α-ENO) epitope polypeptide.

Endogenous CEP can be detected in the synovial fluid of RA patients, and the level of anti-CEP-1 antibody in the synovial fluid is higher than that in the serum, suggesting that CEP can produce antibodies in the joints.

Lundberg et al.
[18] found that the sensitivity of anti-CEP-1 antibody in RA in the British cohort was 37%-62%, and the specificity was 98%.

An epidemiological survey in Sweden found that [19] the sensitivity of anti-CEP-1 antibody in RA was 43% and the specificity was 97%.

The research results of Chinese expert Li Ru [20] The sensitivity of anti-CEP-1 antibody in RA is 64.
3%, and the specificity is 94.
5%.

The positive rates of anti-CEP-1 antibodies in ACPA-negative, RF-negative, ACPA and RF-negative patients were 30.
3%, 41.
9%, and 22.
7%, respectively.

At present, although the reliability of anti-CEP-1 antibodies for the diagnosis of RA needs to be confirmed by clinical studies with a larger sample size, the current research results show that anti-CEP-1 antibodies are an aid to the combined diagnosis of RA or serologically negative RA Diagnosis has good clinical value.

6 Anti-peptidyl arginine deiminase 4 (PAD) antibody PAD is a post-translational modification enzyme that can catalyze the deimination of arginine residues in protein peptide chains into citrulline residues.

PAD4 is highly expressed in granulocytes in peripheral blood and only PAD is located in the nucleus in the PAD family.

Yamamoto et al.
found that PAD4 is a gene related to the pathogenesis of RA.

In 2003, Suzuki et al.
confirmed that PAD4 expression is very obvious in RA synovial fluid.
By analyzing 17 single nucleotide polymorphisms (SNPs) in the PAD4 gene, they found that 8 SNPs are strongly correlated with RA.
Sex.

The anti-PAD4 antibody in the serum of RA patients is also related to the disease activity and severity of the disease.

Cha et al.
[21] reported that PAD4 may play a role in the early stage of RA (≤34 months) and affect the production of anti-CCP antibodies. A study [22] used ELISA to detect serum PAD4 levels in 100 patients with RA, 23 patients with other rheumatism, and 24 healthy subjects.
The study found that PAD4 levels in the RA group were significantly higher than those in other rheumatic disease groups and healthy controls.
, PAD4 level is obviously correlated with DAS28 and ESR.
It can be seen that PAD4 may be one of RA disease activity indicators.

Therefore, PAD4 may also be one of the pathogenic antigens of RA and participate in the pathogenesis of RA.
However, how PAD4 breaks the immune tolerance of RA patients is still unclear, and further research is needed.

7 Scavenger Receptor A (SRA) Peking University People’s Hospital, Dr.
Hu Fanlei, published a study on Nature Communs found that SRA is highly expressed in RA serum, especially the early RA positive rate within six months of the disease course is 53%.
The positive rate of RA patients was 42%, and even before the onset of RA, there was a positive rate of 15%.
Before the onset of RA, the positive rate of SRA was higher than that of anti-CCP antibody and RF.
Although there was no statistical significance among the three, it was suggested Our SRA is very valuable as an early diagnosis of RA.

8 Matrix metalloproteinase 3 (MMP-3) MMP is a collective term for a group of endopeptidases that have great structural homology and can degrade extracellular matrix proteins.

Among them, MMP-3 is secreted by synovial cells, fibroblasts and chondrocytes, and is considered to be the most important protease to degrade articular cartilage.
The value of MMP-3 in the peripheral blood of RA patients is closely related to the destruction of articular cartilage.

Studies have found that early synovitis of RA has the expression of MMP-3, which is a promising biomarker of bone damage.
Studies have shown [23-25] that the level of MMP-3 in RA joint synovial fluid and serum is significantly higher than that of normal people.
Elevated levels of MMP-3 are closely related to joint disease.

Its overexpression in the body can predict the destruction of rheumatoid arthritis joints, and can be used as one of the early diagnosis and treatment observation indicators of RA.

In summary, the eight markers summarized above have a certain effect on the diagnosis of RA.
It is hoped that these markers can enter the clinic as soon as possible in the future, so that RA patients can be diagnosed and treated early. References: [1] J shi J, Knevle R, suwannalai P, et al.
Autoantibodies recognizing carbamylated proteins are present in sera of patients with rheumatoid arthritis and predict joint damage.
[J].
Proc Natl Acad Sci USA, 2011, 108(42): 17372-17377.
[2] Li L, Deng C, Chen S, et al.
Meta-analysis: diagnostic accuracy of anti-carbamylated protein antibody for rheumatoid arthritis[J].
PLoS One.
2016,11(7):e0159000.
[3], Liu Chunyong, Zhang Ping, et al.
Meta-analysis of the diagnostic value of anti-carbamylated protein antibodies for rheumatoid arthritis[J].
Laboratory Medicine and Clinics,2020,17(1).
[4]Matsumoto I,MaccioniM, Lee DM,et al.
How antibodies to a ubiquitous cytoplasmic enzymemay provoke joint specific autoim mune disease[J].
Nat Immunol, 2002,3(4):360-365.
[5] Wang Youlian, Shang Ke, Liu Yanming, et al.
GPI antigen and anti-CCP antibody in the diagnosis of rheumatoid arthritis [J].
Jiangxi Medicine, 2010, 45(10): 1007-1009.
[6]Schaller M, Burton DR, Ditzel HJ.
Autoantibodies to GPI in rheumatoid arthritis: linkage between an animal model and human disease[J].
Nat Immunol, 2001, 2(8):746-753.
[7]Cha HS,Kim TJ,Kim JY,et a1.
Autoantibodies to glucose-6- phosphate isomerase are elevated in the synovial fluid of rheuma— toid arthritis patients[J].
Scand J Rheumatol, 2004, 33(3): 179-184.
[8] Xu Jing, Liu Jing, Zhu Lei, etc.
Determination of glucose 6-phosphate isomerase level and early diagnosis of rheumatoid arthritis[J].
Peking University Journal (Medical Edition), 2016, 48(6).
[9 ] Zhang Jiong, Zou Hejian, Chen Yuming, et al.
Comparison of diagnostic value of anti-cyclic citrullinated peptide antibody and glucose 6-phosphate isomerase antigen for rheumatoid arthritis[J].
Chinese Journal of Rheumatology, 2008, 12(1): 33-35.
[10] Dong Jianling, Yang Nanping, Zhang Jie, etc.
The significance of glucose phosphate isomerase antigen in the diagnosis of rheumatoid arthritis[J].
Chinese Journal of Rheumatology, 2009, 13(4): 263-266.
[11] Zhao Guanfei, Qi Fuhua, Wang Qingtao, et al.
The significance of glucose phosphate isomerase in the diagnosis of rheumatoid arthritis [J].
Chinese Journal of Laboratory Medicine, 2009, 32(5):562-566.
[12]Hassfeld W, Steiner G, Hartmunth K, et al.
Demonstration of a new antinudear antibody (anti -RA33) that is highly specific for rheumatoid arthristis[J].
Arthristis Rheum, 1989, 32: 1515-1520.
[13] Steiner G, Har tmuth K, Skiner K, et al.
2008, 58: 3009-3019.
DOI: 10.
1002/art.
2393[19]Kinloch A, Lundberg K, Wait R, et al.
Synovial fluid is a site of citrullination of autoantigens in inflammatory arthritis[J].
Arthritis Rheum, 2010, 58(8): 2287-2295.
DOI: 10.
1002 /art.
23618.
[20] Yang Mengxi, Li Ru, Guo Jianping, et al.
Significance of anti-citrullinated alpha enolase polypeptide 1 antibody in the diagnosis of rheumatoid arthritis[ J].
Chinese Journal of Rheumatology.
2017, 21(9): 580-584.
DOI: 10.
3760/cma.
j.
issn.
1007-7480.
2017.
09.
002 [21] Cha S, Choi CB, Han TU, et a1.
Association of anti-cyclic eitrollinated peptide antibody levels with PADl4 haplotypos in early rheumatoid arthritis and with shared epitope alleles in very late rheumatoid arthritis.
Arthritis Rheum, 2007,56: 1454-1463 [22] Qian Long, Shi Hingxing, Li Xiangpei, et al.
Serum peptidylarginine deiminase 4 levels in patients with rheumatoid arthritis and its significance[J].
Chinese Journal of Internal Medicine ,2011,50(2):107-110.
[23]Lerner A, Neidhöfer S, Reuter S, et al.
MMP3 is a reliablemarker for disease activity, radiological monitoring, diseaseoutcome predictability,