1.Overview
Rheumatoid arthritis (RA) is a systemic autoimmune disease with erosive arthritis as the main manifestation. The disease is more prevalent in women. RA can occur at any age, with a peak incidence between the ages of 30 and 50. The prevalence of RA in mainland China is about 0.2%-0.4%. The disease is characterized by symmetric, persistent polyarthritis involving mainly the joints of the hands and wrists.
The pathology is characterized by chronic inflammation of the synovial membrane, formation of vascular opacities, and destruction of cartilage and bone in the joints, which can eventually lead to joint deformity and loss of function. In addition, patients may have systemic manifestations such as fever and fatigue. Various autoantibodies such as rheumatoid factor (RF) and anti-cyclic citrullinated polypeptide (CCP) antibodies can be found in the serum.
2.Clinical manifestations
2.1 Symptoms and signs
The main clinical manifestations of RA are symmetrical, persistent joint swelling and pain, often accompanied by morning stiffness. The most commonly affected joints are the proximal interphalangeal joints, metacarpophalangeal joints, wrist, elbow and toe joints; at the same time, the cervical spine, temporomandibular joints, sternoclavicular and acromioclavicular joints can also be involved. In the middle and late stages, patients may develop “swan neck” and “button flower” deformity of the fingers, joint ankylosis and metacarpophalangeal joint subluxation, which shows the metacarpophalangeal joint deviating to the ulnar side. In addition to joint symptoms, subcutaneous nodules, called rheumatoid nodules, may also appear; the heart, lungs and nervous system are involved.
2.2 Laboratory tests
Patients with RA may have mild to moderate anemia, increased erythrocyte sedimentation rate (ESR), elevated C-reactive protein (CRP) and serum IgG, IgM, IgA. Most patients may have a variety of autoantibodies such as RF, anti-CCP antibody, anti-RA33 antibody, anti-citrullinated fibrinogen (ACF) antibody, anti-keratin antibody (AKA) or antiperinuclear factor (APF) in the serum. These laboratory tests are important for the diagnosis and prognostic evaluation of RA.
2.3 Imaging examinations
2.3.1 X-ray examination.
X-rays of both hands, wrists and other involved joints are important for the diagnosis of the disease. In the early stage, x-ray shows swelling of soft tissues around the joints and osteoporosis near the joints; with the progress of the disease, joint surface destruction, joint space narrowing, joint fusion or dislocation may occur. The X-ray changes can be divided into 4 stages according to the degree of joint destruction (Table 1)
Table 1 X-ray stages of RA
Stage I (early stage)
l. No bone destructive changes on X-ray
2.Osteoporosis is visible
Stage II (middle stage)
l. X-ray shows osteoporosis, and there may be mild cartilage destruction, with or without mild subchondral bone destruction
2.Joint movement may be limited, but there is no joint deformity
3.Atrophy of the muscles adjacent to the joint
4.Extra-articular soft tissue lesions, such as nodules or tenosynovitis
Stage III (severe stage)
1.X-ray shows osteoporosis with cartilage or bone destruction
2.Joint deformity, such as subluxation. ulnar deviation or hyperextension. No fibrous or bony ankylosis
3.Extensive muscle atrophy
4, with extra-articular soft tissue lesions, such as nodules or tenosynovitis
Stage IV (end-stage)
l. Fibrous or bony ankylosis
2, each article within the criteria of stage III
Note: Required conditions for each stage criteria
2.3.2 Magnetic resonance imaging (MRI).
MRI is superior to X-ray in showing joint lesions and has been increasingly used in the diagnosis of RA in recent years.MRI can show synovial thickening, bone marrow edema and mild joint surface erosion that appear at the beginning of the inflammatory response of the joint, which is beneficial for the early diagnosis of RA.
2.3.3 Ultrasonography.
High-frequency ultrasound can clearly show the joint cavity, synovial membrane, bursa, joint cavity fluid, thickness and morphology of articular cartilage, etc. Color Doppler flow imaging (CDFI) and color Doppler energy map (CDE) can visually detect the distribution of blood flow in joint tissues and reflect the synovial membrane hyperplasia with high sensitivity. Ultrasonography can also dynamically determine the amount of joint effusion and the distance from the body surface, which can be used to guide joint puncture and treatment.
3.Diagnostic points
3.1 Diagnostic criteria
The diagnosis of RA mainly relies on clinical manifestations, laboratory tests and imaging examinations. The diagnosis of typical cases is not difficult according to the classification criteria of the American College of Rheumatology (ACR) in 1987 (Table 2), but for atypical and early RA, it is easy to misdiagnose or miss the diagnosis. In these patients, MRI and ultrasonography can be considered for early diagnosis in addition to tests such as RF and anti-CCP antibodies. Patients with suspected RA should be reviewed and followed up regularly.
Table 2 1987 American College of Rheumatology RA classification criteria
Condition
Definition
1. Morning stiffness
Stiffness in and around joints lasting at least 1h
2. Arthritis in >3 or more joint areas
At least 3 of the following 14 joint areas (two proximal interphalangeal joints, metacarpophalangeal joints, wrists, elbows, knees, ankles and metatarsophalangeal joints) were observed by the physician to have soft tissue swelling or fluid accumulation (not just bone augmentation)
3.Hand arthritis
Swelling in at least one of the wrist, metacarpophalangeal or proximal interphalangeal joint areas
4.Symmetric arthritis
The left and right joints are involved (when the proximal interphalangeal joints, metacarpophalangeal joints and metatarsophalangeal joints are involved on both sides, they are not necessarily absolutely symmetrical)
5.Rheumatoid nodules
The doctor observed subcutaneous nodules on the bony prominence, extensor surface or around the joint
6.RF positive
Elevated RF levels in the serum as evidenced by any test (the positive rate of this method in a healthy population is <5%< p="">)
7, imaging changes
Typical RA imaging changes in the posterior-anterior phase of the hand and wrist: must include bone erosion or definite bone decalcification in the affected joint and adjacent areas
Note: RA can be diagnosed by satisfying 4 or more of the above 7 conditions and excluding other arthritis, conditions 1-4 must last at least 6 weeks (as cited in Arthritis Rheumatism, 1988, 31: 315-324)
The new classification criteria and scoring system for RA proposed by the ACR and the European League Against Rheumatism (EULAR) in 2009, namely: swelling and pain in at least 1 joint with evidence of synovitis (clinical or ultrasound or MRI); and exclusion of other diseases causing arthritis In addition, this criterion scores 4 components of joint involvement, serological indicators, duration of synovitis and acute temporal reactants, and a total score of 6 or more is also diagnostic of RA(Table 3) .
3.2 Judgment of disease
The indicators for determining the activity of RA include the degree of fatigue, the duration of morning stiffness, the number and degree of joint pain and swelling, and inflammatory indicators (e.g., ESR, CRP). Clinical criteria such as DAS28 can be used to determine the degree of disease activity. In addition, factors that affect the prognosis of RA patients should be analyzed at the time of consultation. These factors include disease duration, somatic dysfunction (e.g. HAQ score), extra-articular manifestations, whether the serum is positive for autoantibodies and HLA-DRl / DR4, and the early appearance of bone destruction suggested by X-ray.
3.3 Criteria for remission
There are various criteria for determining remission of RA. The criteria for clinical remission of RA proposed by the ACR are listed in the treatment, but the presence of active vasculitis, pericarditis, pleurisy, myositis and recent weight loss or fever due to RA cannot be considered as clinical remission.
3.4 Differential diagnosis
In the diagnosis of RA. Care should be taken to differentiate it from arthritis due to other connective tissue diseases such as osteoarthritis, gouty arthritis, seronegative spondyloarthropathy (uSpA), systemic lupus erythematosus (SLE), dry syndrome (pSS) and scleroderma.
3.4.1 Osteoarthritis.
The disease is prevalent in middle-aged and elderly people and mainly involves weight-bearing joints such as the knee and hip. The joint pain worsens with activity, and there may be joint swelling and effusion. Some patients have characteristic Heberden nodes in the distal interphalangeal joints and Bouchard nodes in the proximal phalanges. Patients with osteoarthritis rarely present with symmetrical proximal interphalangeal and carpal involvement, no rheumatoid nodules, and short or no morning stiffness. In addition, patients with osteoarthritis tend to have mildly increased ESR and negative RF. x-ray shows hyperplasia or osteophyte formation at the joint edges and joint space narrowing in advanced town due to cartilage destruction.
3.4.2 Gouty arthritis.
The disease is mostly seen in middle-aged men and often manifests as recurrent acute attacks of arthritis. The preferred site is the first metatarsophalangeal joint or tarsal joint, but may also invade the knee, ankle, elbow, wrist and hand joints. Patients with this disease have negative serum autoantibodies, while blood uric acid levels are mostly elevated. In chronic severe cases, gout stones may appear around the joints and in the auricles.
3.4.3 Psoriatic arthritis.
The disease is more commonly associated with involvement of the distal joints of the fingers or toes, with psoriatic skin or nail lesions before or during the course of the disease, and may have joint deformities, but symmetric interphalangeal arthritis is less common and RF negative.
3.4.4 Ankylosing spondylitis (AS).
The disease is prevalent in young men and mainly invades the sacroiliac joints and the spine. Some patients may present with asymmetric large joint swelling and pain in the lower extremities, mainly in the knee, ankle and hip joints. The disease is often associated with tendon telangiectasia and is HLA-B27 positive and RF negative. The x-ray changes of sacroiliac arthritis and spine are of muscular significance for the diagnosis.
3.4.5 Arthritis due to other diseases.
Other rheumatic diseases such as SSc and SLE can have joint involvement. However, most of these diseases have corresponding clinical manifestations and characteristic autoantibodies, and there is usually no bone erosion. Atypical RA also needs to be differentiated from infectious arthritis, reactive arthritis and rheumatic fever.
4.Treatment
The aim of RA treatment is to control the disease and improve joint function and prognosis. The principles of early treatment, combination of drugs and individualized treatment should be emphasized. Treatment methods include general treatment, drug therapy and surgical and other treatments.
4.1 General treatment
Patient education and the concept of holistic and standardized treatment are emphasized. Appropriate rest, physiotherapy, physical therapy, topical medication, proper joint activities and muscle exercises play an important role in relieving symptoms and improving joint function.
RA clinical remission is considered to be in clinical remission if 5 or more of the following 6 criteria are met and for at least 2 consecutive months.
1.Morning stiffness time less than 15min
2.No fatigue
3.No joint pain
4.No joint pressure or joint pain when moving
5.No joint or tendon sheath swelling
6, ESR (Weil’s method) <30 mm/1 h for women and <20 mm/1 h for men
4.2 Drug treatment
4.2.1 Non-steroidal anti-inflammatory drugs (NSAIDs)
These drugs have anti-inflammatory, analgesic, antipyretic and joint swelling reducing effects mainly by inhibiting cyclooxygenase (COX) activity and reducing prostaglandin synthesis, and are the most commonly used drugs for RA treatment (Table 4). Their major adverse effects include gastrointestinal symptoms, liver and renal impairment, and a possible increase in cardiovascular adverse events.
According to the available evidence-based medical evidence and expert consensus, the following points should be noted in the use of NSAIDs.
①Focus on individualization of the type, dose and dosage form of NSAIDs;
(2) Use the lowest possible effective dose and short duration of treatment;
The NSAIDs should be increased to the full dose when there is no significant effect for several days to I week. If it is still ineffective, switch to another agent and avoid taking 2 or more NSAIDs at the same time;
④For those with a history of peptic ulcer, selective COX-2 inhibitors or other NSAIDs plus proton pump inhibitors are appropriate;
⑤ The elderly can use NSAIDs with short half-life or smaller doses;
(6) NSAIDs should be used with caution in people with high cardiovascular risk, and if needed, acetaminophen or naproxen is recommended;
(7) NSAIDs should be used with caution in patients with renal insufficiency;
The topical preparations of NSAIDs (such as diclofenac diethylamine emulsion, capsaicin cream, ketoprofen gel, piroxicam patch, etc.) and phytomedicinal creams have certain effects on relieving joint swelling and pain, with fewer adverse effects, and should be advocated for clinical use.
4.2.2.1 Methotrexate (MTX).
It is effective when given orally, intramuscularly, intra-articularly or intravenously, and is administered once a week. It can be used in combination with other DMARDs if necessary. The commonly used dose is 7.5 to 20 mg/week. Common adverse reactions include nausea, stomatitis, diarrhea, alopecia, rash, and hepatic damage, with a few cases of bone marrow suppression. Interstitial lung lesions are occasionally seen. There is no conclusive evidence on whether it causes miscarriage, malformation and affects fertility. Folic acid should be supplemented appropriately during the dosing period, and routine blood and liver function should be checked regularly.
4.2.2.2 Salicylazosulfapyriding (SASP).
Can be used alone for shorter duration and mild RA, or in combination with other DMARDs for longer duration and moderate and severe disease. Generally takes effect after 3-6 months. Gradual dose increases from small doses help to reduce adverse effects. It can be started at 250-500mg orally 3 times daily and gradually increased to 750mg 3 times daily. The main adverse effects include nausea, vomiting, abdominal pain, diarrhea, skin rash, increased transaminases, and occasionally decreased white blood cells and platelets. Regular blood tests, liver function and kidney function should be performed during the drug administration.
4.2.2.3 Leflunomide (1eftunomide, LEF).
The dose is 10-20 mg/d, taken orally. It is mainly used for patients with longer duration of disease, severe disease and poor prognostic factors. Major adverse effects include diarrhea, pruritus, hypertension, increased liver enzymes, rash, alopecia, and decreased white blood cells. It is prohibited for pregnant women because of its teratogenic effect. Routine blood and liver function should be checked regularly during the drug administration.
4.2.2.4 Antimalarial drugs (antimalarials).
Including two kinds of hydroxychloroquine and chloroquine. They can be used alone for patients with short duration and mild disease. It should be combined with other DMARDs for those with severe disease or poor prognostic factors. The drugs are slow-acting and take 2-3 months to work. The dose is hydroxychloroquine 200mg twice daily. Chloroquine 250mg once a day. The former has fewer adverse effects, but the fundus should be checked once a year before and during treatment to monitor for possible retinal damage caused by the drug. Chloroquine is less expensive, but ocular damage and cardiac-related adverse reactions (e.g., conduction block) are more common than hydroxychloroquine and should be noted.
4.2.2.5 Penicillamine (D-penicillamine, D-Pen).
250-500mg/d, orally. Generally used in patients with mild disease or combined with other DMARDs in severe RA. adverse effects include nausea, anorexia, rash, mouth ulcers, loss of smell and liver and kidney damage. Blood and urine routine and liver and kidney function should be checked regularly during treatment.
4.2.2.6 Kinoprofen (auranofin).
It is an oral gold preparation with an initial dose of 3 mg, which is increased to 6 mg after 2 weeks for maintenance treatment. It can be used for different degrees of RA, and should be used in combination with other DMARDs for patients with severe disease. Common adverse reactions include diarrhea, pruritus, stomatitis, liver and kidney damage, leukopenia, and occasionally peripheral neuritis and encephalopathy. Blood and urine routine and liver and kidney function should be checked regularly.
4.2.2.7 Azathioprine (AZA).
The commonly used dose is l-2mg/kg/d, generally 100-150mg/d. It is mainly used for patients with RA who have severe disease. Adverse effects include nausea, vomiting, hair loss, rash, liver damage, bone marrow suppression, possible damage to the reproductive system, and occasionally teratogenic. Routine blood and liver function should be checked regularly during drug administration.
4.2.2.8 Cyclosporin A (CsA).
The main advantage of Cs A over other immunosuppressants is that there is little myelosuppression, and it can be used in patients with RA who have more severe or prolonged disease and poor prognostic factors. The main adverse reactions include hypertension, hepatic and renal toxicity, gastrointestinal reactions, gingival hyperplasia and hypertrichosis. The severity and duration of adverse reactions are related to the dose and blood concentration. Routine blood tests, blood creatinine and blood pressure should be checked during the drug administration.
4.2.2.9 Cyclophosphamide (CYC).
Less commonly used in RA. may be tried in severe disease when remission is difficult with multiple drug therapy. The main adverse effects include gastrointestinal reactions, alopecia, bone marrow suppression, liver damage, hemorrhagic cystitis, gonadal suppression, etc. Clinically, the early application of DMARDs should be emphasized in patients with RA, and the combination of 2 or more DMARDs should be considered in patients with severe disease, multiple joint involvement, extra-articular manifestations or early joint destruction and other poor prognostic factors. The main combination methods include MTX, LEF, HCQ and any two or three of SASP, and the combination of cyclosporine A and penicillamine with the above drugs can also be considered. However, different combination methods should be selected according to the patient’s condition and individual situation.
4.2.3 Biological agents
Biological agents that can be used to treat RA include tumor necrosis factor (TNF)-α antagonists, interleukin (IL)-l and IL-6 antagonists, anti-CD20 monoclonal antibodies and T-cell co-stimulatory signaling inhibitors.
4.2.3.1 TNF-α antagonists.
The main agents in this class include etanercept, infliximab, and adalimumab. Compared with conventional DMARDs, the main features of TNF-a antagonists are rapid onset of action, significant inhibition of bone destruction, and good overall patient tolerability. The recommended dose and administration of etanercept is 25 mg/dose by subcutaneous injection twice weekly or 50 mg once weekly. The recommended dose of infliximab for RA is 3 mg/kg/dose once at weeks 0, 2, and 6, and once every 4 to 8 weeks thereafter. The dose of adalimumab for RA is 40 mg/dose, subcutaneously, once every 2 weeks. These agents can have injection site reactions or infusion reactions and may have increased infection and etc. TB screening should be performed prior to drug administration to exclude active infection and tumors.
4.2.3.2 IL-6 antagonist (tocilizumab).
Primarily used for moderate-to-severe RA and may be effective in patients who respond poorly to TNF-α antagonists. The recommended use is 4 to 10 mg by intravenous infusion, given every 4 weeks. Common adverse reactions are infection, gastrointestinal symptoms, rash and headache.
4.2.3.3 IL-l antagonists.
Anakinra (anakinra) is the only IL-1 antagonist currently approved for the treatment of RA. The recommended dose is 100 mg,/d by subcutaneous injection. The main adverse effects are dose-related injection site reactions and a possible increase in the probability of infection.
4.2.3.4 Anti-CD20 monoclonal antibodies.
The recommended dose and administration of rituximab (rituxanab) is: the first course may be given as an intravenous infusion of 500-1000 mg, repeated once after 2 weeks. A second course of treatment may be received after 6-12 months depending on the condition. Each injection of rituximab is preceded by an appropriate dose of intravenous methylprednisolone given within half an hour. Rituximab is mainly used in active RA where TNF-a antagonists are not effective. a common adverse reaction is infusion reactions, and intravenous administration of glucocorticoids reduces the incidence and severity of infusion reactions. Other adverse reactions include hypertension, rash, pruritus, fever, nausea, and arthralgia, and may increase the probability of infection.
4.2.3.5 CTLA4-Ig.
Abatacept is used to treat patients with more severe disease or poor response to TNF-α antagonists. The recommended doses, depending on the patient’s body mass, are 500 mg (<60 kg), 750 mg (60-100 kg), and 1000 mg (>100 kg), administered intravenously at weeks 0, 2, and 4, respectively, and injected every 4 weeks. The main adverse effects are headache, nausea, and possibly increased incidence of infection and tumor.
4.2.4 Glucocorticoids
Glucocorticoids (referred to as hormones) can rapidly improve joint swelling and pain and systemic symptoms. In patients with severe RA with cardiac, pulmonary or neurological involvement, etc., short-acting hormones may be given in doses that depend on the severity of the disease. For joint lesions, if needed, a small dose of hormone (prednisone ≤ 7.5 mg) is usually indicated for only a small number of patients with RA.
Hormones may be used in the following conditions.
(i) Severe RA with extra-articular manifestations such as vasculitis.
②Patients with RA who cannot tolerate NSAIDs as a “bridge” treatment.
③Patients with RA in whom other treatments are not effective.
(iv) Patients with indications for local hormone therapy (e.g., intra-articular injections). The principle of hormone therapy for RA is small doses and short courses. The use of hormones must be accompanied by the application of DMARDs. calcium and vitamin D should be supplemented during hormone therapy. joint cavity injections of hormones are beneficial in reducing arthritic symptoms, but too frequent joint cavity punctures may increase the risk of infection and steroid crystal arthritis may occur.
4.2.5 Botanical preparations
4.2.5.1 Radix Rehmanniae.
It is effective in relieving joint swelling and pain, and there is a lack of research on whether it slows joint destruction. Generally, tretinoin polysaccharide 30-60 mg/d is given in 3 divided doses after meals. The main adverse effect is gonadal suppression, leading to male infertility and female amenorrhea. It is generally not used in patients of childbearing age. Other adverse reactions include rash, hyperpigmentation, nail tenderness, alopecia, headache, dyspepsia, nausea, vomiting, abdominal pain, diarrhea, bone marrow suppression, elevated liver enzymes and elevated blood creatinine.
4.2.5.2 Total peony glycosides.
The commonly used dose is 600 mg, 2-3 times daily. It is effective in reducing joint swelling and pain. Its adverse effects are relatively few, mainly abdominal pain, diarrhea, poor appetite, etc.
4.2.5.3 Cyanophylline.
20-60 mg per dose, taken orally 3 times daily before meals, can reduce joint swelling and pain. The main adverse effects include skin pruritus, rash and leukopenia.
4.3 Surgical treatment
RA patients whose condition cannot be controlled after active medical formal treatment can be considered for surgery to correct the deformity and improve the quality of life. However, surgery does not cure RA, so postoperative medication is still needed. Commonly used surgeries include synovectomy, artificial joint replacement, joint fusion and soft tissue repair.
4.3.1 Synovectomy.
For those who still have obvious joint swelling and synovial thickening after active and regular medical treatment, and whose x-ray shows that the joint space has not disappeared or is not significantly narrowed, synovectomy can be considered to prevent further destruction of articular cartilage, but regular medical treatment is still required after surgery.
4.3.2 Artificial joint replacement.
For those whose joint deformity obviously affects the function, who are ineffective by medical treatment, and whose x-ray shows the disappearance or obvious narrowing of the joint space, artificial joint replacement can be considered. This operation can improve the patient’s ability to perform daily life, but preoperative and postoperative medication should be standardized to avoid recurrence.
4.3.3 Joint fusion.
With the successful application of artificial joint replacement, joint fusion has been rarely used in recent years, but it is feasible for patients with advanced arthritis, severe joint destruction, and joint instability. In addition, arthrofusion can be used as a salvage procedure for failed arthroplasty.
4.3.4 Soft tissue surgery.
In addition to joint deformity, atrophy of the joint capsule and surrounding muscles and tendons are also responsible for joint deformity in patients with RA. Therefore . Joint function can be improved by joint capsule dissection, joint capsule dissection, tendon release or lengthening, etc. For carpal tunnel syndrome, transverse carpal ligament dissection and decompression can be performed. Bursitis of the shoulder and hip joints require surgical removal if conservative treatment is ineffective. Rouge fossa cysts occasionally require surgical treatment. Rheumatoid nodules that are large, have painful symptoms and affect life can be considered for surgical excision.
4.4 Other treatments
In addition to the aforementioned treatment methods. For a small number of standardized drug treatment is not effective, there are high titers of autoantibodies in the serum, immunoglobulin significantly increased can consider immune purification, such as plasma replacement or immunosorbent treatment. However, clinical emphasis should be placed on strict control of the indications and treatment principles such as combination of DMARDs. In addition. Autologous stem cell transplantation, T-cell vaccine and mesenchymal stem cell therapy may be effective in the remission of RA, but only for a small number of patients, and further clinical studies are still needed.
5. Prognosis
The prognosis of RA patients is related to the duration of the disease, the extent of the disease and the treatment. Patients with multiple joint involvement, heavy extra-articular manifestations, high titers of autoantibodies and HLA-DR1/DR4 positivity in the serum, and early bone destruction should be treated aggressively. Most patients with RA can go into clinical remission with standard medical treatment.