What Is the Pathophysiology of Rheumatoid Arthritis?

Undifferentiated arthritis (UA) was once called "undefined arthritis", "sero-negative oligoarthritis", "undifferentiated sero-negative polyarthritis", "HLA-B27-related arthritis" "and many more. "Early arthritis", "early rheumatoid arthritis (RA)", or "UA" is used to refer to patients who may develop RA, and it is also used to refer to the early stage of diagnosis of RA. To date there is no accepted definition, diagnosis and treatment model.

Undifferentiated arthritis

Undifferentiated arthritis (UA) was once called "undefined arthritis", "sero-negative oligoarthritis", "undifferentiated sero-negative polyarthritis", "HLA-B27-related arthritis" "and many more. People with "early arthritis", "early

So far, there is no unified understanding of UA. Most people think that the occurrence of peripheral arthritis does not meet any other arthritis classification criteria can be considered undifferentiated arthritis, but should be ruled out as an early manifestation of some connective tissue disease. Verpoort et al. [1] believe that UA is caused by a hidden and persistent pathogenic factor and does not meet the ACR's RA classification criteria. According to statistics, the number of patients who changed from UA to RA in 1 year ranged from 6% to 55%. This difference in proportion is largely related to the different classification standards used by researchers and the different definitions of UA and RA used. Some studies assume that some UA patients are in the early stages of acute-onset RA patients. Helm-van et al. [2] classified 1,000 arthritis patients with an onset of disease within 2 weeks, and only 10% met the RA classification criteria, and about 1/3 were diagnosed with UA, and these UA parts can be naturally relieved, 1 / 3 developed into RA, and the rest remained undifferentiated or developed into other rheumatic diseases. Visser et al. [3] found that 15% of persistent arthritis or erosive arthritis could not be classified according to the RA classification standard of 1987 ACR, so it was called UA. They believe that the ACR's RA classification criteria lack a clear etiology, pathophysiology, or epidemiology and are not suitable for UA.

2.1 Infection Zeidler et al. [4] established an early arthritis clinic with a course of less than one year in 1984. It was found that most patients with early arthritis and cannot be clearly classified may be the early manifestations of a disease or Manifestation of unknown disease. He investigated the recent infection history of 226 patients (less than 4 weeks) and found that about half of the patients had a history of infection. He advocated strengthening microbiological examination. Proudman et al. [5] observed that almost 50% of polyarthritis cases can be relieved naturally within 12 weeks, and they believe that some self-limiting arthritis may be caused by viral infections, such as parvovirus B19, rubella virus and its vaccine, hepatitis virus B and C, Ross River virus, Barmab forest virus, etc. Bokarewa et al. [6] suggested that erosive arthritis caused by viral infection may be related to abnormal expression of Survivin protein, and Survivin can be used as an independent risk factor for predicting joint breakage and poor prognosis. Viral infection causes the host to be exposed to viral ds-RNA, which in turn triggers the activation of RNA-dependent protein kinases and hypoxanthine phosphate 3-kinase, promotes the proliferation of synovial cells and inhibits their apoptosis, thereby exacerbating arthritis.

2.2 Genetics Johansson et al. [7] compared the PTPN22 1858T allele carrying status in 92 early RA patients and 368 healthy controls, and found that the frequency of carrying the gene was significantly different between the two. In addition, other genes related to early RA have been found, such as peptidyl arginine deiminase 4 encoding a citrulline protease subtype. It is associated with early RA susceptibility in Asian populations such as Japan and Korea [8]. It shows that genetic factors affect RA and UA susceptibility through gene-gene interaction and gene-environment interaction [9]. The cause of UA is currently considered to be multi-source, and the specific cause needs further study.

Most UA patients develop disease in an insidious manner, and the joints of the extremities such as the metacarpophalangeal joint, wrist joint, swelling, pain, stiffness, and some patients may have predisposing factors such as infection. Symptoms of joint swelling and pain can be accompanied by extra-joint manifestations such as general discomfort and fatigue. It can be onset in a single joint or on multiple joints at the same time. Most of the joints can be small joints of the extremities or large joints such as knees and elbows. The course of the disease ranges from several weeks to several years, and can progress to RA, systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), osteoarthritis, reactive arthritis, etc. Some patients are still not eligible for ACR during follow-up for decades. In the classification criteria of RA, some patients have natural remission or no change in symptoms for many years [1].

To date there is no uniform diagnostic standard. Schumacher [10] defined UA as swollen or painful joints in at least one joint with abnormal inflammatory indicators, including increased erythrocyte sedimentation (ESR) or elevated C-reactive protein (CRP), and increased peripheral white blood cell counts in his study. , Or rheumatoid factor (RF) positive, at the same time the possibility of joint symptoms of crystal arthritis and other diseases must be ruled out.

Raza et al. [11] analyzed the immune and interstitial cells of patients with preliminary diagnosis of RA by analyzing the T cell phenotype, macrophages, cytokines and chemokines associated with interstitial cells in the synovial fluid of patients with early synovitis. Study the process of change. The synovial fluid of patients with inflammatory arthritis with a course of 3 months was collected, and the synovial fluid of patients with acute crystalline arthritis, diagnosed RA, and osteoarthritis was used as a control. Compared with the control group, the development was 3 months later. In patients with early arthritis of RA, T cells, macrophages and cytokines (IL-2, IL-4, IL-13, IL-17, IL-15, fibroblast growth factor, epidermal growth factor) -related Plasma cells increased significantly. Moreover, this cytokine characteristic does not exist in the serum of patients with confirmed RA.

At present, there is no sensitive and specific diagnostic criteria for UA. To this end, further comprehensive examinations such as imaging, synovial fluid examination, and synovial biopsy are necessary. Austrian Hassfeld et al. [12] and Cordonnier et al. [13] tested anti-RA33 antibodies in patients with unclassifiable early arthritis, and found that 27% and 28.6% of RA were positive for anti-RA33 before diagnosis, suggesting a better prediction. value. Nie Hong et al. [14] research showed that some patients with positive anti-RA33 antibodies and clinically difficult to diagnose RA had a positive RA after 1 to 3 years of follow-up.

Studies have shown that anti-RA33 / 36 antibody, Sa antigen antibody system, anti-keratin antibody, anti-perinuclear factor antibody have certain value in the diagnosis of RA, but the diagnostic value of UA has yet to be confirmed by further research.

Liu Qingzhong [15] used ELISA and rate-scattering turbidimetry to detect anti-CCP antibodies in the serum of 112 UA patients and followed up to explore the value of anti-CCP antibodies in predicting the development of UA to RA. The results showed that the sensitivity of anti-CCP antibodies to RA prediction was 73.3%, the specificity was 92.6%, and the positive and negative predictive values were 91.7% and 75.7%, respectively, suggesting that anti-CCP antibodies have good application value in the diagnosis of early RA. At the same time, the predictive value of RF was evaluated, and the results showed that its specificity, positive and negative predictive values were significantly inferior to anti-CCP antibodies, and there was no correlation with anti-CCP antibodies. Studies have shown a weak correlation between C-reactive protein and anti-CCP antibodies.

Wu Maochun et al. [16] tested anti-CCP antibodies in 130 UA patients. Studies have shown that 56 patients with positive anti-CCP antibodies were eventually diagnosed with RA, and 74 other negative patients were being followed up.

Guo Dawen et al. [17] followed up patients with undiagnosed undifferentiated arthritis for 3 years and found that 39% of patients developed RA, of which 93.8% of anti-CCP antibody positive patients and 23.7% of negative patients developed RA in 3 years. Positive CCP antibodies are a high risk factor for RA. During the development from UA to RA, anti-CCP antibodies gradually appeared, which may be involved in the pathological process of RA, which is related to severe bone destruction. They also found that as the number of ACR-compliant items increased, patients with anti-CCP antibody-negative UA also had an increased risk of developing RA. When only 1 item of anti-CCP-positive UA patients meets the ACR standard, the compliance rate of RA is 75%; when more than 2 items, all patients with anti-CCP antibody-positive UA develop RA, and it is confirmed that anti-CCP antibodies are at least 3 before the onset of RA. It can be measured in 2015, suggesting that only 1 item should meet the ACR standard, and anti-CCP antibodies should be detected. Positive patients should be considered as high-risk groups with RA. Therefore, anti-CCP antibodies have important predictive value for the onset of RA and are good indicators for early diagnosis of RA.

Some European countries have established early arthritis clinics, suggesting that patients with a disease duration greater than 12 weeks, RF positive, accelerated ESR, and DW4 / DW14 genotypes are at high risk of developing RA. Another statistic shows that disease duration greater than 12 weeks is an important indicator for judging the development of RA. Some people also proposed the general screening criteria for early RA, that is, when the patient saw any of the following conditions, such as swelling of 3 joints, swelling of the metatarsophalangeal joint / metacarpophalangeal joint, morning stiffness 30 min, further relevant examination should be done To determine if you have early RA. At the 2003 ACR conference, Olivier et al reported that they followed up 314 patients with UA for up to 1 year. These patients had at least 2 joint swellings that lasted more than 4 weeks, and the course of disease was less than 6 months. Disease-modifying antirheumatic drugs (DMARDs) and hormone therapy. One year later, 176 patients were diagnosed with RA, and 138 patients with non-RA and other rheumatic diseases. The results showed that the independent parameters for predicting RA were anti-CCP antibodies, joint swelling numbers, grip strength, and AKA positive. The best predictors were anti-CCP antibodies.

General treatment

Promote disease prevention knowledge and protect joints: First, let patients have an understanding of the disease, physical exercise must be carried out step by step, prevent joints from excessive movement and weight bearing, and avoid mechanical damage to joints. In severe cases, it should be braked or fixed with plaster to prevent deformity. Reduce weight and use handles and canes to reduce the load on affected joints. Those related to the profession should change jobs. Exercise about muscle groups can maintain and improve joint activity to enhance joint stability.

Physical therapy: Hyperthermia, hydrotherapy, infrared, ultrashort wave, electrical stimulation, etc. can enhance local blood circulation, relieve muscle tension, and reduce pain and other symptoms. Traction therapy has a better effect on patients with cervical spondylotic nerve root type. It can relax muscles, relieve pain, and prevent adhesion of adjacent tissues to nerve roots, but it must be performed under the guidance of a specialist.

(3) Tuina and traditional Chinese medicine: Tuina and acupuncture treatment in Chinese medicine have obvious effects in reducing arthritis symptoms. Traditional Chinese medicine patch can activate blood and relieve pain, and sometimes has good effects

Symmons et al. [18] observed 3,500 UA patients treated with DMARDs and believed that patients with a tendency to persistent arthritis should start treatment of DMARDs as soon as possible (preferably within the first 12 weeks). If patients respond poorly to DMARDs, they should switch to biological therapy as soon as possible. Observed results are significant, many patients have completely resolved, or have not developed significant disability or radiological abnormalities. If patients have poor curative effects on DMARDs, their prognosis is also poor, and individualized treatment plans need to be designed. The following factors all affect the remission of these patients: age, gender, social status, personal habits (smoking, drinking, dieting, exercise), psychological factors (coping strategies), genetic factors (severe arthritis patients), special factors (Drug use, detoxification methods, effects, discussion of efficacy among patients), etc. They established their own "pre-treatment remission criteria", that is, no joint soft tissue swelling in the past 3 months without patients receiving DMARDs or steroids; and "post-treatment remission criteria": 3 months after patients received DMARDs Swelling of joint soft tissue. During 3 years of observation, 32% of arthritis patients had remission, 18% of patients developed RA, and 11% of patients had no joint soft tissue swelling after 1 to 3 years of follow-up. In the etiology correlation analysis, we learned that there are 3 basic changes that are very important independent predictors of remission: RF negative, less than 6 joint swellings and no ankle swelling.

Machold et al. [19] believe that more and more evidence shows that early DMARD treatment is effective, but there is no consensus on how to determine the treatment plan. They also found that a small number of patients received DMARD treatment than those who did not receive it or received it 12 months after the disease. The radiological results of DMARD patients are poor, so the efficacy is affected by many factors, such as age, gender, morning stiffness, RF, health assessment questionnaire (HAQ), CRP, and the number of swollen joints. After analysis, it is considered early (less than course 6). (Months of months) treatment can achieve significant results, and for patients without mild radiological symptoms of joints, at least one year after diagnosis. Most of the arthritis symptoms will not be relieved naturally for more than 12 weeks. Many patients develop RA, and patients with obvious initial manifestations benefit from early DMARD treatment, and even later treatments play a role. Biologics, especially anti-TNF monoclonal antibodies, can increase efficacy.

Harrison et al. [20] defined natural remission as: symptoms disappeared for more than 3 months without medication. They studied 358 patients with UA who had a natural response rate of 13% to 55%. Factors affecting the natural remission of UA are: the appearance of HLA-DR4, lack of anti-CCP antibodies, and rheumatoid factor positive. Emery et al. [21] have observed 800 cases of early arthritis patients for more than 3 years, 95% of patients have received DMARD treatment, bone loss has been achieved when the course of disease is more than 6 months, and bone loss is also suppressed after treatment. Hand bone loss can be as high as 30% within the first 2 years of the disease course.

Undifferentiated arthritis can be self-limiting or develop into RA, SLE, AS, osteoarthritis, reactive arthritis, etc. Some patients can not be clearly classified after decades of follow-up, or their symptoms have not changed for many years [1].

"Undifferentiated" gives us thinking: Before the typical symptoms of a disease are shown, these patients suggest a known type of arthritis; It is an undifferentiated or frustrated disease that does not develop into A typical definite rheumatic disease; is an overlapping syndrome that cannot be classified as a single rheumatism; arthritis of unknown cause, the cause of which needs to be further explored in the future. Therefore, adherence to long-term systematic follow-up is extremely important.

[1] Nie Hong, Ma Baozhen, Tan Kuilin, et al. Extraction of RA33 nuclear antigen and its application in the detection of Fengguan autoantibodies. Journal of Shanghai Second Medical University, 1999, 19 (3): 268-269.

[2] Liu Qingzhong, Zhi Xiaoyang, Zhang Wenhui, et al. Predictive value of anti-CCP antibodies for the development of undifferentiated arthritis to rheumatoid arthritis. Anhui Medical Journal, 2006, 27 (4): 275-277.

[3] Wu Maochun, Zheng Lihua, Chen Yong, et al. Significance of anti-CCP antibody detection in the differential diagnosis of undifferentiated arthritis. Modern Diagnosis and Treatment, 2008, 19 (2): 78-79.

[4] Guo Dawen, Wang Yi, Gao Honghua, et al. Predictive value of anti-cyclic citrullinated peptide antibodies in the onset of rheumatoid arthritis. China Laboratory Diagnosis, 2005, 9 (1): 13-14.

[5] Symmons DP, Silman AJ. What determines the evolution of early undifferentiated arthritis and rheumatoid arthritis? An update from the Norfolk Arthritis Register. Arthritis Res Ther, 2006, 8: 214.

[6] Machold KP, Nell VP, Stamm TA. Traditional DMARD therapy: is it sufficient. Arthritis Res Ther, 2006, 8: 211.

[7] Harrison BJ, Symmons DP, Brennan P, et al. Natural remission in inflammatory polyarthritis: issues of definition and prediction. Br J Rheumatol, 1996, 35: 1 096-1 100.

[8] Zhang Naiquan. Clinical Rheumatology. Shanghai: Shanghai Science and Technology Press, 1999: 129-131