Reactive arthritis (RA) was conceived by Ahvonen in 1969, and in 1981, the American College of Rheumatology defined reactive arthritis as arthritis lasting for more than 1 month following urethritis or cervicitis. Later, it was found that reactive arthritis could also occur after intestinal infections. In the last 20 years or so, it has been found that reactive arthritis can be caused by most microbial infections, and reactive arthritis in a broad sense is one of the common arthritis. Given that there is some overlap between this disease and Ritter syndrome and ankylosing spondylitis, some scholars have also included reactive arthritis in the category of seronegative spondyloarthropathies. Wang Dehui, Department of Integrative Chinese Medicine, The First Affiliated Hospital of Xinjiang Medical University, Changji Branch
New understanding of reactive arthritis
1.Concept
According to Ahvonen’s suggestion, reactive arthritis is defined as a kind of aseptic arthritis that causes distant joints following microbial infections in other parts of the body.
2.Epidemiology
Most reports of early reactive arthritis come from Europe, and this disease has been found in China in recent years, but there is a lack of exact epidemiological investigation data in China.
The overall incidence of reactive arthritis in patients with intestinal or genitourinary tract infections is 1 to 3 percent. The incidence of reactive arthritis after Shigella enterica infection is about 3.6%, but the incidence of arthritis can be as high as 20% in those who are HLA-B27 positive. The incidence of reactive arthritis following Salmonella, Helicobacter, and Yersinia enterocolitica infections is 15-19%. The prevalence of reactive arthritis of intestinal origin, which is equally likely to affect men and women, depends on the frequency of intestinal infections and increases with poor hygiene and war conditions. Reactive arthritis following genitourinary tract infections occurs predominantly in men, with a male to female ratio of 9:1, and is thought to be mostly due to sexually acquired infections.
3. Etiology
The vast majority of microbial infections can cause reactive arthritis, but there are two main categories that have been studied more frequently.
(1) Non-gonococcal urethritis post-onset type: mainly Chlamydia trachomatis and Mycoplasma hyopneumoniae, about 10% to 20% can be caused by other microorganisms.
(2) Post-bacterial diarrhea pathogenic type: mainly Salmonella, Shigella, Yersinia, Campylobacter and Vibrio.
4.Pathogenesis
Reactive arthritis is induced by infection of non-joint sites (e.g., intestinal or genitourinary tract) caused by certain microorganisms. The mechanism of how microbial infection of these sites stimulates arthritis is not fully understood and may be related to the following factors.
(1) Presence of microorganisms or their components in the joint: pathogenic microorganisms, such as Chlamydia, and other bacteriologic components such as DNA or other antigenic components can be found in the synovial tissue, synovial fluid, and their sediments in this disease.
(2) Sources and routes of microorganisms or their components in the joints: Microorganisms and their components may reach the joints through the following routes: (1) Blood-borne: Infection factors or other particles may settle in the joints through the blood circulation. (2) Cellular carriage: Carried to the joint by cells, for example, Chlamydia can be carried to the joint by white blood cells after phagocytosis.
(3) The role of HLA-B27 in reactive arthritis: HLA-B27 positivity is common in patients with this disease, for example, HLA-B27 positivity can be 72% to 84% in cases of reactive arthritis after enteric infection, and up to 54% in cases of reactive arthritis after non-gonococcal urethritis. HLA-B27 is mainly associated with sacroiliac arthritis and not closely related to other arthritis.
In conclusion, reactive arthritis may be caused by the interaction of external and genetic factors, i.e., after pathogen infection, pathogens with low activity (i.e., culture-negative) or their bacteriophage components are transported to the joints through the blood and cellular pathways, and the pathogens and HLA cross-react to form immune complexes, or the genes encoded by the HLA-B27 antigen are chained together with the true disease susceptibility genes, creating chain imbalance, leading to an abnormal immune response, which causes joint inflammation. However, after the primary infection, most patients do not have a subsequent onset after the infection disappears, and only a minority of patients (1-20%) subsequently develop reactive arthritis. The reason for this discrepancy is unknown and may be related to factors such as body composition and the specificity of the bacterial strain. In addition, reactive arthritis induced by an infectious agent that is in complete remission can be reignited later by other microbial antigens, causing flare-ups and even chronic arthritis. Therefore, the occurrence of reactive arthritis seems to depend mainly on the genetic structure and immune abnormalities of the host, rather than on the type of pathogenic bacteria.
5.Clinical manifestations
(1) Joint manifestations: Taking reactive arthritis after gastrointestinal and genitourinary tract infection as an example, typical clinical manifestations occur mostly 2-4 weeks after infection as asymmetric peripheral arthritis, preferably in the lower extremities, often oligoarthritis, involving an average of 4 joints. The knee, ankle and metatarsophalangeal joints are the most common. Upper extremity joints may also be involved, with hip lesions being uncommon and sternoclavicular, shoulder, and temporomandibular joints being even less commonly involved. More than 1/3 of patients have arthritis in the lower extremities only, and some patients have involvement of the upper extremity joints alone. Involved joints present with periarticular swelling, skin redness, increased temperature, joint tenderness, and pain with active and passive motion. Involvement of the sacroiliac or other spinal joints is also a feature of the disease, with an overall incidence of approximately 50%, producing lower back pain, pain at the sacroiliac joints and local pressure pain. In those severe, chronic and recurrent cases, spondylitis is somewhat more likely to occur, with X-ray confirmation of sacroiliac arthritis in about 20% of cases, but only about 10% eventually meeting the clinical diagnostic criteria for ankylosing spondylitis. Whether the latter is the result of reactive arthritis or an independent occurrence of ankylosing spondylitis associated with HLA-B27 is uncertain, and the author prefers the latter.
In addition to arthritis, there can also be tendon terminal inflammation, most commonly Achilles tendonitis and plantar fasciitis, which can cause heel pain and other manifestations. Involvement of the toes and fingers may present as a bologna-like toe (finger), showing diffuse swelling.
(2) Extra-articular manifestations: Extra-articular manifestations can provide important diagnostic clues for the disease, such as male urethritis, female cervicitis, conjunctivitis, iritis, whirling glans, tendon terminal inflammation, damage to the skin mucosa (such as overflowing cutaneous keratosis, erythema nodosum and oral ulcers) and aortitis.
(3) Based on the three common routes of infection, reactive arthritis may present as the following morbidity types.
a. Post-non gonococcal urethritis type: This type is significantly more common in men than in women, and is usually caused by sexual infection; symptoms of urethritis can be mild or severe, and in some cases there may even be no symptoms of urethritis; reactive arthritis often occurs 1 to 3 weeks after urethritis, and this type often recurs due to reinfection. The incidence of sacroiliac arthritis is 33%. Systemic symptoms are often mild, and fever, if present, is low.
b. Post-bacterial diarrheal onset type: This type has an equal proportion of men and women. Reactive arthritis often occurs 1 to 3 weeks after enteritis, and at least 80% can recover completely initially; however, arthritis can also become chronic or recurrent after some Salmonella infections, and sacroiliac arthritis can occur in about 20% of patients 5 to 10 years after Yersinia and Shigella infections.
6.Laboratory examination
(1) Routine examination: In the acute stage, the total number of white blood cells is increased, and the urine protein is below 1g/d in most cases. Blood sedimentation (ESR) may be increased and C-reactive protein (CRP) may be elevated. Serum rheumatoid factor and antinuclear antibodies are negative. In some cases, streptococcal growth is often seen in the throat swab culture and ASO is positive.
(2) Joint fluid culture: negative, but its sediment or synovial membrane can detect extremely low activity of chlamydia or its bacterial component DNA or its antigen; chlamydial antibody titer is elevated, and chlamydia culture of stool or other excreta of patients in acute stage is positive.
(3) HLA-B27 test: HLA-B27 is often positive.
(4) X-ray examination: early stage may be abnormal, several months after the appearance of symptoms can be seen in the choroidal periosteal reaction, bone cortical erosion, periostitis and new bone formation; with symptoms of heel pain can be seen in the metatarsal tendon membrane and/or Achilles tendon attachment point bone erosion, calcification of the Achilles tendon, plantar tendon membrane, these changes are the manifestation of tendon telangiectasia; asymmetric sacroiliac arthritis, severe cases may have significant joint destruction, joint cavity narrowing, etc.; spine can be seen Asymmetrical ossified ligaments (ligamentous osteophytes).
(5) MRI examination: it can show the early damage, and inflammatory changes can be seen in subcortical bone, which is easy to occur in small joints and sacroiliac joints.
7.Diagnosis and differential diagnosis
(1) Diagnosis: The joint symptoms of reactive arthritis are the same as in all cases of spondyloarthritis, with tendon terminal inflammation being one of, if not the only, prominent manifestation. Inflammatory lesions typically occur at the site of tendon attachment to bone and not in the synovium, manifesting as symptoms of waxy fingers (toes), in contrast to rheumatoid arthritis in which inflammation is primarily confined to synovial tissue. Among them, Achilles tendinitis and metatarsal tendinitis are common symptoms in patients with reactive arthritis, and other extra-articular manifestations are also valuable diagnostic bases.
The diagnosis of reactive arthritis is not difficult and can be made with a history of infection within the last three weeks, typical symptoms of asymmetric mono- or oligo-arthritis, and sometimes a combination of extra-articular manifestations. However, reactive arthritis lacks a specific diagnostic test, and a prodromal infection is a basis for determining the diagnosis, usually at intervals of 1 to 7 days, with a maximum of 4 weeks. Reactive arthritis usually has an incubation period of 1 to 3 weeks, with rapid recovery of symptoms from the prodromal infection, but pain in the joint and other extra-articular symptoms can occur soon after. Typical cases occur in HLA-B27-positive young adults and present as asymmetric oligoarthritis of the major weight-bearing joints of the lower extremities, while rare in young children. Monoarticular manifestations account for 5% to 20% of cases. The clinical features of arthritis developing secondary to genital and intestinal infections are similar and indistinguishable, typically starting characteristically 1 to 3 weeks after an episode of urethritis or diarrhea. It is important to note that symptoms of UTI can also be present in reactive arthritis triggered by an intestinal infection.
Therefore, in young men, acute lower extremity arthralgia (e.g., knee pain) with chronic plantar and Achilles tendon pain and visible pressure pain in the hip joint may be suspected. At this point, it is important to ask for a past history of urethritis and diarrhea, but urethritis can sometimes be asymptomatic. The presence of sacroiliac arthritis may also suggest reactive arthritis if there is no obvious evidence of infection and no gastrointestinal symptoms. Because it is an HLA-B27-related disease, the family history is equally important.
In recent years, reactive arthritis and Wright syndrome appear to be equivalent or generic, but the latter has more of a classic triad of arthritis, conjunctivitis, and uveitis. In contrast, the diagnosis of reactive arthritis does not require the extra-articular features of Wright syndrome (conjunctivitis, iritis, rash, non-infectious uveitis, cardiac and neuropathy), HLA-B27 positivity, or the typical features of spondyloarthropathies (inflammatory low back pain, hip pain, and Achilles tendinitis, iritis), but these, if present, should be documented.
The diagnostic criteria proposed at the 3rd International Symposium on Reactive Arthritis have the following conditions.
Typical peripheral arthritis: multiple, asymmetric oligoarthritis of the lower extremities is the prominent manifestation. And additionally.
① Evidence of antecedent infection, specifically requiring that
a. Clear clinical manifestations of diarrhea or uveitis within 4 weeks prior to the onset of arthritis, with laboratory evidence, but not required.
b. If there is no clear clinical infection, laboratory evidence of prior infection must be demonstrated.
(2) Exclude other known causes of mono- or oligoarticular arthritis, such as other spondyloarthropathies, infectious arthritis, crystallization-induced arthritis, Lyme disease, and streptococcal reactive arthritis.
(2) Differential diagnosis: reactive arthritis is mainly distinguished from other arthritis, if needed, from bacterial arthritis, psoriatic arthritis, early rheumatoid arthritis, ankylosing spondylitis and gout. Reactive arthritis can occur after streptococcal infection, and rheumatoid arthritis can also occur, but rheumatic fever patients with anti-streptococcal hemolysin “O”, anti-streptococcal kinase, anti-hyaluronidase and anti-nucleosidase combined test positive rate of up to 95%, while reactive arthritis negative; rheumatic fever patients with HLA-B27 negative, while reactive The majority of patients with arthritis are HLA-B27 positive; heart inflammation occurs frequently in patients with rheumatic fever, but is rare in reactive arthritis.
New Advances in the Treatment of Reactive Arthritis
At present, the treatment of reactive arthritis is still mainly empirical, and there is not much information on prospective studies with large samples.
1. Symptomatic treatment
The symptomatic treatment of arthritis is based on non-steroidal anti-inflammatory drugs (NSAIDs), which are particularly effective in the post-bacterial diarrheal onset type. It also includes physical therapy, corticosteroid intra-articular injections, etc. Tendon terminal inflammation can be supplemented with topical dosage forms of NSAIDs for treatment.
2.Antibiotic treatment
At present, it is believed that a variety of antibiotics have both immunomodulatory and anti-collagenolytic potential. In addition to the treatment of prodromal infections, antibiotics can also be used for the acute treatment of reactive arthritis and the treatment of chronic migration extension. However, further information on the clinical effects of antibiotic therapy, such as the preventive effect of treating primary infections with antibiotics on reactive arthritis, and whether treatment with antibiotics at the onset of reactive arthritis can improve the condition and prognosis, has yet to be accumulated.
Some scholars believe that short-term application of antibiotics is ineffective in the acute phase of reactive arthritis, and long-term use of antibiotics may be effective in significantly shortening the course of the disease and reducing joint swelling and pain. For example, 3 months of tetracycline family antibiotics are effective in Chlamydia trachomatis-induced reactive arthritis. Drugs of the tetracycline family may have both antibacterial and anti-inflammatory effects. It is also believed that antibiotics should be started at the early stage of disease onset to improve both prognosis and symptoms, while the effect of application during the progressive period of the disease is unclear.
It is inconclusive whether antibiotic therapy can improve the chronic symptoms of reactive arthritis, sacroiliitis and ankylosing spondylitis. In chlamydial-derived arthritis, extended use of antibiotics may be more effective than nonsteroidal anti-inflammatory drugs, regardless of the duration of the disease. In contrast, the application of ciprofloxacin for 3 months in patients with enterogenic arthritis resulted in a significant reduction in arthralgia, morning stiffness, and painful movement in patients in the treatment group.
In addition, it is well established that in sexually transmitted reactive arthritis, treatment of the initial uveitis with appropriate antibiotics reduces the risk of subsequent arthritis, and the patient’s sexual partner should be treated at the same time. Non-gonococcal urethritis type if reactive arthritis after chlamydial infection, treatment with antibiotics for 1 to 3 months is beneficial, but the effect is not constant. The ineffectiveness of antibiotic treatment for reactive arthritis inspired by intestinal infection may be related to the different pathogenesis or different response to different antibiotics. Patients with HLA-B27 positive reactive arthritis with diarrhea or positive pathogenic bacteria in the stool are indications for treatment with antibiotics and often require treatment for up to two weeks.
3.Corticosteroid treatment
Corticosteroids are effective for synovitis in reactive arthritis, but the systemic application of corticosteroids is generally not advocated, and long-acting corticosteroid joint cavity injection can be chosen for monoarthritis.
4.Anti-rheumatic therapy
For some chronic reactive arthritis of long duration, as well as recurrent disease, anti-rheumatic therapy can be used.
Among the anti-rheumatic drugs, the most commonly used is lutetrabenazine, which has a good effect on patients with peripheral and mid-axis arthritis, especially those originating from intestinal infections, and generally improves significantly after 3 to 6 months of medication, with an average treatment time of about 12 months. Azathioprine is more effective in patients with active and destructive peripheral arthritis. Methotrexate can be used in patients with chronic reactive arthritis with skin and mucous membrane invasion.
5.Chinese medicine treatment
Reactive arthritis should fall under the category of “paralysis”. In the Nei Jing, it is said that “wind, cold and dampness are combined to form paralysis”, and it is believed that wind, cold and dampness are the external causes of the disease, but it is emphasized that “where the evil comes together, its qi must be deficient” and “deficiency of positive qi” is highlighted as the internal cause. The internal cause of the disease. The etiology of reactive arthritis is due to the deficiency of liver and kidney, weakness of qi and blood, and the induction of wind, cold and dampness. The basic pathology is characterized by the deficiency of positive energy with evil, and a mixture of cold and heat. However, the treatment of TCM is based on identification and symptomatic treatment, and there is not much clinical experience accumulated.
6. Prognosis
Most patients with reactive arthritis are self-limiting, and the arthritis usually subsides within 3-5 months, but individual cases can last for more than 1 year or even 10 years. If there are recurrent episodes of arthritis and long duration of the disease, joint ankylosis may occur. Occasionally, the disease may be complicated by aortic valve insufficiency, heart block, and IgA nephropathy. The long-term prognosis depends on two main factors: the presence of HLA-B27 and the recurrence of the antecedent infection. Initial attacks are less symptomatic in HLA-B27-negative individuals than in HLA-B27-positive individuals.
Other types of reactive arthritis
1. Reactive arthritis after streptococcal infection
In 1982, some scholars reported that transient arthritis can occur after upper respiratory tract streptococcal infection, which is now called reactive arthritis after streptococcal infection. It is also called post-streptococcal reactive arthritis (PSRA). This type has an age of onset of 20 to 50 years, with recurrent tonsillitis and arthritis, which can last from 2 weeks to 20 years. Pain at the tendon attachment site is seen, and most have bilateral sternoclavicular arthritis, often with multiple arthralgias, and at 1 week of onset, forced bed rest due to difficulty walking. Arthritis after streptococcal infection often does not occur joint destruction, repeated infection can cause recurrent arthritis, antibiotic treatment is effective, most cases can be cured by tonsillectomy.
2. Reactive arthritis after tuberculosis infection
Prevalent in young adults, the clinical manifestation is often asymmetric arthritis of the lower extremities, divided into two types: acute and chronic. Acute type has an acute onset, may have fever, headache and joint redness, swelling and pain, with knee, ankle and sacroiliac joints, most of the large joints involved, can be manifested as wandering arthritis, often accompanied by nodular erythema or herpetic conjunctivitis. The chronic form is characterized by chronic polyarticular pain and may be associated with joint erythema or subcutaneous nodules. As with other reactive arthritis, there is a high rate of B27 positivity.
Laboratory tests: Tuberculin test is usually strongly positive, sedimentation is increased, C-reactive protein is increased, rheumatoid factor is negative, IgG is increased and complement is decreased. X-ray examination of the diseased joints is often without joint bone destruction.
Joint fluid examination: joint fluid is exudate, cell count is 4200-12000×106/L, classification is mainly lymphocytes (51%-87%), joint fluid culture is negative, joint fluid anti-tuberculosis IgM antibody is often positive.
The disease is mostly associated with pulmonary tuberculosis, and a few with extrapulmonary tuberculosis. It can also be seen in those with a strong positive tuberculin test and no obvious foci of tuberculosis infection. Arthritis may occur in conjunction with or prior to tuberculosis infection, or occasionally after a period of tuberculosis infection.
Anti-rheumatic therapy is ineffective in this disease, while anti-tuberculosis therapy is effective, with rapid improvement of joint symptoms. For the more severe arthritis, NSAIDs can be added, and in particularly severe cases, prednisone tablets 7.5-15mg are given daily for a short period of time, once in the early morning, and the dosage is reduced and stopped after the symptoms improve. After treatment, joint symptoms such as redness, swelling and pain generally improve to varying degrees within 1 to 2 weeks, 4 to 8 weeks in acute cases, and 8 to 12 weeks in chronic cases, and the symptoms disappear or basically disappear. Since the disease mainly manifests pathologically as acute inflammatory manifestations such as congestion and edema of the synovial membrane and exudation, there is no significant synovial hyperplasia, destruction of bone and narrowing of the joint cavity, so it usually does not leave joint deformities.
The disease is easily misdiagnosed as other types of arthritis, and if prednisone is given blindly for long-term treatment, it may lead to the spread of tuberculosis and delay the patient’s condition. Therefore, in young and middle-aged patients who present with asymmetric arthritis of the large joints of the lower extremities without obvious signs of intestinal or urinary tract infections, it is important to consider the possibility of reactive arthritis caused by tuberculosis infection.