1.Overview
Rheumatoid arthritis (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 small 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, showing ulnar deviation of the metacarpophalangeal joint. 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 19G, IgM, Iga. Most patients may have RF, anti-CCP antibody, anti-modified guanylated vimentin (MCV) antibody, anti-P68 antibody, anti-citrullinated fibrinogen (ACF) antibody, anti-keratin antibody (AKA) in the serum or antiperinuclear factor (APF) and many other autoantibodies. These laboratory tests are important for the diagnosis and prognostic evaluation of RA.
2.3 Imaging examinations
X-ray examination: X-ray films of the hands, wrists and other affected 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; as the disease progresses, 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 Io
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.
Ultrasonography: High-frequency ultrasound can clearly show the joint cavity, synovial membrane, bursa, joint cavity fluid, articular cartilage thickness and morphology, etc. Color Doppler flow imaging (CDFI) and color Doppler energy map (CDE) can visually detect the distribution of blood flow in the joint tissue 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. Typical cases are not difficult to diagnose according to the classification criteria of the American College of Rheumatology (ACR) in 1987 (Table 2), but for atypical and early RA is easy to misdiagnose or miss. 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.
In 2009, the ACR and the European League Against Rheumatism (EULAR) proposed a new classification criteria and scoring system for RA, namely: swelling and pain in at least 1 joint with evidence of synovitis (clinical or ultrasound or MRI); arthritis caused by other diseases is also ruled out, and there are typical changes of conventional radiological RA bone destruction, which can be diagnosed as RA. In addition, this criterion is important for the joint involvement, the In addition, the criteria scored four components of joint involvement, serological indicators, duration of synovitis and acute temporal reactants, and a total score of 6 or more could also diagnose RA (Table 3o
3.2 Determination 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. Table 4 lists the criteria for clinical remission of RA proposed by ACR, but the presence of active vasculitis, pericarditis, pleurisy, myositis and recent loss of body mass or fever due to RA cannot be considered as clinical remission.
3.4 Differential diagnosis
In the diagnosis of RA. Attention should be paid 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 (Ss) and scleroderma.
Osteoarthritis: This disease is more common in middle-aged and elderly people and mainly involves weight-bearing joints such as knees and hips. The joint pain worsens with activity, and there may be joint swelling and fluid accumulation. 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-rays show joint edge hyperplasia or osteophyte formation, with joint space narrowing in advanced town due to cartilage destruction.
Gouty arthritis: This disease is most common in middle-aged men and often presents with recurrent acute attacks of arthritis. The preferred site is the first metatarsophalangeal joint or tarsal joint, but it can also affect 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.
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 symmetrical interphalangeal arthritis is less common and RF negative.
Ankylosing spondylitis (AS): The disease is more frequent in young men and mainly affects 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.
Arthritis due to other diseases: Ss and other rheumatic diseases such as SLE can have joint involvement. However, most of these diseases have corresponding clinical manifestations and characteristic autoantibodies, usually without 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 surgery and other treatments.
4.1 General treatment
Patient education and the concept of holistic and standardized treatment are emphasized. Appropriate rest, physical therapy, body therapy, topical medication, proper joint activities and muscle exercises play an important role in relieving symptoms and improving joint function.
4.2 Drug treatment
Non-steroidal anti-inflammatory drugs (NSAIDs)
These drugs mainly inhibit the activity of cyclooxygenase (COX) and reduce the synthesis of prostaglandins to have anti-inflammatory, analgesic, antipyretic and reduce joint swelling, and are the most commonly used drugs in clinical treatment of RA (Table 5oNSAIDs have an important role in relieving joint swelling and pain and improving umbrella body symptoms. Their major adverse effects include gastrointestinal symptoms, liver and renal impairment, and possible increased cardiovascular adverse events. According to the existing evidence-based medical evidence and expert consensus, the following points should be noted in the use of NSAIDs: ① focus on the type, dose and dosage form of NSAIDs individualized; ② use the lowest possible effective dose, short course of treatment; ③ generally first choose a NSAID. application for several days to I week without significant effect should be increased to the full dose. If it is still ineffective, switch to another agent and avoid taking two or more NSAIDs at the same time; ④ For people with a history of peptic ulcer, it is advisable to use selective COX-2 inhibitors or other NSAIDs plus proton pump inhibitors; ⑤ The elderly can use NSAIDs with a short half-life or smaller doses; ⑥ People at high cardiovascular risk should use NSAIDs with caution, if necessary, it is recommended to use acetaminophen or naproxen; (7) NSAIDs should be used with caution in patients with renal insufficiency; (8) Pay attention to the use of NSAIDs.
Topical preparations of NSAIDs (such as diclofenac diethylamine emulsion, capsaicin cream, ketoprofen gel, piroxicam patch, etc.) and botanical creams have a certain effect on relieving joint swelling and pain, with fewer adverse effects, and should be advocated for clinical use.
Disease modifying antirheumatic drugs (DMARDs)
These drugs are slower to work than NSAIDs, taking about 1_6 months, so they are also called slow-acting anti-rheumatic drugs (SAARDso these drugs do not have obvious pain relief and anti-inflammatory effects, but can delay or control the progress of the disease. The DMARDs commonly used to treat RA are shown in Table 6.
Methotrexate (MTX): effective when given orally, intramuscularly, intra-articularly or intravenously, and administered once a week. It can be used in combination with other DMARDs if necessary. The common dose is 7.5-20mg/week. Common adverse reactions include nausea, stomatitis, diarrhea, alopecia, rash, and liver 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 and blood and liver functions should be checked regularly during the dosing period.
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. It usually takes effect after 4 to 8 weeks of administration. Gradually increasing the dose from small doses can help reduce adverse effects. It can be started at 250.500 mg orally 3 times daily and gradually increased to 750 mg 3 times every Et. 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.
Leflunomide (1eftunomide. LEF): The dose is 10-20mg/d, orally. It is mainly used for patients with long duration of disease, severe disease and poor prognostic factors. The main adverse effects include diarrhea, pruritus, hypertension, increased liver enzymes, rash, hair loss and decreased white blood cells. It is prohibited for pregnant women because of its teratogenic effect. Blood test and liver function should be checked regularly during the drug administration.
Antimalarials: These include hydroxychloroquine and chloroquine. They can be used alone for patients with short duration and mild disease. They should be combined with other DMARDs in severe cases or with poor prognostic factors. These drugs are slow-acting and take 2_3 months to take effect. The dose is hydroxychloroquine 200mg twice a day. 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 with hydroxychloroquine and should be noted.
Penicillamine (D-pen, D-pen): 250-500m state, orally. Generally used in patients with mild disease or in combination 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.
Jinuofen (auranofin): oral gold preparation, the initial dose is 3mtCd, after 2 weeks to 6m state maintenance treatment. It can be used for RA of different manuscript sui degree, and should be used in combination with other DMARDs for patients with severe disease. Common adverse effects include diarrhea, pruritus, stomatitis, liver and kidney damage, leukopenia, and occasionally peripheral neuritis and encephalopathy. Blood and urine routines and liver should be checked regularly. Renal function.
Azathioprine (AZA): commonly used dose is l-2mg?kg-hd, generally 100.150mgCd. mainly used in patients with severe RA. Adverse reactions include nausea, vomiting, alopecia, rash, liver damage, bone marrow suppression, possible damage to the reproductive system, and occasionally teratogenic. Blood tests and liver function should be checked regularly during the drug administration.
Cyclosporin A (CysA): Compared with other immunosuppressants, the main advantage of CysA is that there is little bone marrow suppression, and it can be used in patients with RA who have severe or long disease duration and poor prognosis. The commonly used dose is 1-3 mg?kg–?d a. The main adverse reactions are 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. Blood count, creatinine and blood pressure should be checked during the drug administration.
Cyclophosphamide (CYC): Less commonly used in RA, and may be tried in severe cases when remission is difficult with multiple medications. The main adverse effects include gastrointestinal reactions, alopecia, bone marrow suppression, liver damage, hemorrhagic cystitis, and gonadal suppression. 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 chosen according to the patient’s condition and individual situation.
Biological agents
Biological agents that can be used to treat RA mainly include tumor necrosis factor (TNF) ton antagonists, interleukin (IL) I and IL-6 antagonists, anti-CD20 monoclonal antibodies and T-cell co-stimulatory signaling inhibitors.
TNF-ot 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 25m daily, subcutaneous injections twice a week or 50m island shine once a week. The recommended dose of infliximab for the treatment of RA is 3 mg?kg-h times one, once each 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 an increased risk of infection and tumors, occasional drug-induced lupus-like syndrome, and demyelinating lesions. Tuberculosis screening should be performed prior to drug administration to exclude active infections and tumors.
1L I6 antagonist (tocilizumab): Primarily used for moderate-to-severe RA and may be effective in patients who respond poorly to TNF-a antagonists. The recommended use is 4 to 10 m to g by intravenous infusion, administered every 4 weeks. Common adverse reactions are infection, gastrointestinal symptoms, rash, and headache.
1L_l antagonist: 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.
Anti-CD20 monoclonal antibody: The recommended dose and usage of rituximab (rituxiaIIIb) is 500.000 mg intravenously for the first course of treatment, repeated once after 2 weeks. A second course may be received after 6-12 months depending on the condition. Each injection of rituximab is preceded by an intravenous dose of 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.
CTLA4 I Ig: Abatacept is used to treat patients with more severe disease or who have had a poor response to TNF-a antagonists. The recommended dose is 500 mg (<60100=""750=""1000="">100 kg) administered intravenously every 4 weeks at weeks O, 2 and 4, respectively, depending on the patient’s body mass. The main adverse effects are headache, nausea, and possibly increased incidence of infection and tumors.
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 m state) is usually used only in a small number of patients with RA. Hormones can be used in the following situations: ①Severe 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, and calcium and vitamin D should be supplemented during hormone therapy. hormone injections in the joint cavity are beneficial in reducing the symptoms of arthritis, but too frequent joint puncture may increase the risk of infection and steroid crystal arthritis may occur.
Botanical preparations
Leigandine: Effective in relieving joint swelling and pain, but there is a lack of research on whether it slows joint destruction. It is usually given as 30. 60 mg/d 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 softening, hair loss, headache, nausea, vomiting, abdominal pain, diarrhea, bone marrow suppression, elevated liver enzymes, and elevated blood creatinine.
Total Paeonia lactiflora: The commonly used dose is 600mg, 2-3 times daily. It is effective in reducing joint swelling and pain. Its adverse reactions are less frequent, mainly abdominal pain, diarrhea and poor appetite.
Cyanophylline: 20-60mg per dose, taken orally before meals, 3 times daily, can reduce joint swelling and pain. The main adverse reactions include skin itching, rash and leukopenia.
4.3 Surgical treatment
If the condition of RA patients cannot be controlled after active medical treatment, surgery can be considered to correct the deformity and improve the quality of life. However, surgery does not cure RA, so drug treatment is still needed after surgery. Commonly used surgeries include synovectomy, artificial joint replacement, joint fusion and soft tissue repair.
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.
Artificial joint replacement: For those whose joint deformity obviously affects the function, who are not treated by internal medicine, and whose x-ray shows that the joint space disappears or is obviously narrowed, artificial joint replacement can be considered. This procedure can improve the patient’s daily living ability, but there should be standardized drug treatment before and after surgery to avoid recurrence.
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, joint fusion can be used as a salvage procedure for failed arthroplasty.
? Soft tissue surgery: In addition to joint deformity, atrophy of the joint capsule and surrounding muscles and tendons is also the cause of joint deformity in RA patients. 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 used. Bursitis in the shoulder and hip joints requires surgical removal if conservative treatment is ineffective. Rouge fossa cysts occasionally require surgical treatment. Rheumatoid nodules are large, have painful symptoms, and can be considered for surgical removal when they affect life.
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 be considered immune purification, such as plasma exchange 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 interrogative stem cell therapy may be effective in the remission of RA, but only for a small number of patients, and further clinical studies are 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-DRI/DR4 positive serum, and early bone destruction should be treated aggressively. Most patients with RA can go into clinical remission with standard medical treatment.