Rheumatic immune diseases are a group of systemic diseases that mainly involve bones, joints and their surrounding soft tissues and organs, and disease-modifying antirheumatic drugs (DMARDs), also known as slow-acting drugs, can be used for the treatment of rheumatic immune diseases, including traditional synthetic DMARDs (csDMARDs), biological DMARDs (bDMARDs), targeted synthetic DMARDs (tsDMARDs), which can effectively control/delay the progression of the disease. So, how are DMARDs used in rheumatic immune diseases?
传统合成DMARDs（csDMARDs）
For example, calcineurin inhibitors (CNI) drugs (cyclosporine A, tacrolimus), methotrexate (MTX), hydroxychloroquine, etc., can be used for the treatment of rheumatic immune diseases.
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CNIs
CNI drugs are powerful immunosuppressants, mainly including oral cyclosporine A and tacrolimus, which can reduce the release of interleukin-2, selectively inhibit the activation and proliferation of T lymphocytes, and inhibit cytokine transcription by inhibiting calcineurin activity, and can be used for the treatment of rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) [especially lupus nephritis (LN), SLE hematologic involvement], Polymyositis (PM) (especially with interstitial lung disease (ILD)), dermatomyositis (DM), Henoch-Schonlein purpura nephritis (HSPN), juvenile idiopathic arthritis (JIA), Primary Sjögren's syndrome (pSS), systemic sclerosis (SSc), macrophage activation syndrome (MAS), autoimmune hepatitis (AIH), adult Still disease, psoriatic arthritis (PsA), Behcet's disease, juvenile dermatomyositis (JDM), etc.
Table: Recommended doses of CNIs
Precautions: CNI drugs can show gastrointestinal reactions, nephrotoxicity, electrolyte disorders, infections, neurological complications, thrombotic microangiopathy, dyslipidemia, etc., cyclosporine A can see gingival hyperplasia, hirsutism, hypertension, and tacrolimus can also see hyperglycemia. It should be used with caution in patients with severe renal insufficiency and severe active infection. Cyclosporine A is contraindicated in patients with severe renal dysfunction, uncontrolled hypertension, severe infectious diseases, malignant tumors (excluding basal cell carcinoma), history of malignancy, and those receiving photochemotherapy therapy.
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MTX
MTX is a metabolic antagonist, which can inhibit dihydrofolate reductase, cell proliferation, induce apoptosis, inhibit the proliferation of inflammatory cells, immunosuppression, anti-inflammatory, and maintain the immune environment, and can be used for the treatment of RA (oral dose is usually 7.5-20mg/week, adjust the dose according to the condition and treatment response), SLE, polymyalgia rheumatica, vasculitis, DM/polymyositis, PsA, etc.
Precautions: MTX can be seen gastrointestinal discomfort, mild elevation of aminotransferases, gastritis, liver fibrosis/cirrhosis, bone marrow suppression, infection, severe kidney disease, interstitial pneumonia, pancreatitis, hemorrhagic enteritis, osteoporosis, encephalopathy, etc., and it is recommended to supplement 5mg of folic acid per week to reduce gastrointestinal reactions during medication. If ALT or AST levels persist > more than 3 times the upper limit of normal, the drug should be discontinued. Avoid use in patients with pre-existing bone marrow suppression, severe hepatic and renal impairment, active hepatitis B or hepatitis C virus infection, alcohol or drug abuse. It is contraindicated during pregnancy and lactation, and the drug needs to be discontinued for at least 3 months before conception.
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Hydroxychloroquine
Hydroxychloroquine can regulate immunity, anti-rheumatism, and can be used for the treatment of RA (hydroxychloroquine + MTX, hydroxychloroquine + MTX + sulfasalpyridine), SLE, SS, etc.
The recommended starting dose is 400 mg daily for 3 to 6 months ≥.
Precautions: Hydroxychloroquine can see blurred vision, retinopathy, macular degeneration, itching, nausea, anorexia, abdominal pain, headache, dizziness, nervous tension, sensorimotor disorders, etc. It is contraindicated in patients with fundus macular degeneration and known allergy to 4-aminoquinolines.
生物制剂DMARDs（bDMARDs）
Such as tumor necrosis factor (TNF)-α inhibitors, IL-6 antagonists, IL-17 antagonists, T cell regulators, B cell regulators, etc., can be used for the treatment of RA, AS, etc.
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TNF-α inhibitors
It can be anti-inflammatory, such as infliximab, etanercept, adalimumab, golimumab, certolizumab, and can be used to treat RA, AS, polyarticular juvenile idiopathic arthritis (pJIA), etc.
Precautions: Injection site reactions, infection, infusion reactions, tumor risk, bone marrow suppression, demyelinating disease, congestive heart failure, etc. It is contraindicated in patients with active infection, tuberculosis, moderate to severe heart failure, etc.
Suggested Dosage:
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Infliximab
Infliximab may be used in combination with MTX for moderately to severely active RA. It is recommended to inject 3mg/kg intravenously for the first time, and then take the drug again in the 2nd and 6th weeks, and then once every 8 weeks. For patients with inadequate response to RA, the dose can be increased to 10 mg/kg, and/or the dosing interval can be adjusted to once every 4 weeks. Infliximab is recommended to be 5 mg/kg for AS, followed by a second dose at the second and sixth weeks, and then every 6 weeks.
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Etanercept
The recommended dose of etanercept for RA and AS is 25 mg subcutaneously twice a week (72-96 hours apart) or 50 mg once a week.
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Adalimumab
The recommended dose of adalimumab for RA and AS is 40 mg subcutaneously once every 2 weeks. If the efficacy of RA monotherapy decreases, it can be done once a week.
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Golimumab
The recommended dose of golimumab for RA and AS is 50 mg/time subcutaneous injection, once a month. For RA, it must be used in conjunction with MTX.
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Sertolizumab
Sertolizumab in combination with MTX in adults with moderately to severely active RA. 400 mg subcutaneously is recommended for the first dose, week 2, and week 4, followed by 200 mg every 2 weeks.
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IL-6 antagonists
For example, tocilizumab can be anti-inflammatory, and can be used for RA, systemic juvenile idiopathic arthritis (SoJIA), etc.
Suggested dose: The recommended starting dose for RA is 8mg/kg intravenous infusion, once every 4 weeks, which can be combined with MTX. If there is a low neutrophil count, abnormal liver enzymes, or a low platelet count, it can be reduced to 4 mg/kg.
Precautions: Infection, elevated liver enzymes, severe infection, gastrointestinal perforation, neutropenia, dyslipidemia, decreased platelet count, demyelinating changes, malignant tumors, infusion reactions, etc. It is contraindicated in the active period of infection.
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IL-17 antagonists
For example, secukinumab can be anti-inflammatory, and it can be used in adults with AS who do not respond well to conventional treatment.
The recommended dose for AS is 150 mg/time subcutaneously, which can be administered in weeks 0, 1, 2, 3, and 4, and then every 4 weeks.
Precautions: Infection, oral herpes, neutropenia, conjunctivitis, diarrhea, urticaria, etc. It is contraindicated in patients with active infection.
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Monoclonal antibodies that inhibit the B-cell pathway
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Belimumab
Belimumab can be used in children ≥aged 5 years of age and adults with SLE who still have high disease activity (eg, anti-double-stranded DNA antibody positivity, low complement, SLE disease activity index ≥8) and autoantibody-positive despite conventional therapy.
The recommended dose is 10 mg/kg intravenous infusion, once every 2 weeks for the first 3 doses and every 4 weeks thereafter.
Precautions: upper respiratory tract infection, bronchitis, diarrhea, infusion reactions, etc. Not recommended for hepatitis B virus or hepatitis C virus infection, severely active central nervous system lupus, hypogammaglobulinemia or IgA deficiency, severely active lupus nephritis, human immunodeficiency virus, transplant patients.
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Tataercept
Adults with high disease activity, autoantibody-positive SLE in combination with tetaercept in combination with conventional therapy.
The recommended dose is 160 mg/subcutaneous injection once a week. If necessary, the dose can be reduced to 80mg/time.
Precautions: Infection, bronchitis, injection site reactions, diarrhea, globulin decrease, herpes, cough, etc. Not recommended for patients with severe hepatic and renal impairment, severely active lupus nephritis, severely active central nervous system lupus, hepatitis B virus or hepatitis C virus infection, human immunodeficiency virus, hypogammaglobulinemia or IgA deficiency, transplant patients.
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Rituximab
Rituximab can be used in the treatment of SLE.
The recommended dose of refractory severe SLE is 375 mg/m2 once a week for 4 weeks; or 1 g/m2, repeat 1 time after 2 weeks.
Precautions: Nausea, infection, neutropenia, angioedema, leukopenia, itchy skin, decreased IgG levels, rash, etc.
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Monoclonal antibodies that inhibit the T cell pathway
For example, Brazil recept can be used in adults with moderately to severely active RA who do not respond well to DMARDs, and can be used in combination with MTX.
The recommended dose is 125 mg subcutaneously once a week.
Precautions: Upper respiratory tract infection, headache, nausea, nasopharyngitis, etc. It is contraindicated in patients with severe and uncontrollable infections such as sepsis and opportunistic infections.
靶向改善病情抗风湿药物（tsDMARDs）
JAK inhibitors such as tofacitinib, upadatinib, and baricitinib can block the cytokine transduction pathway, inhibit the production of inflammatory cytokines, and inhibit the activation of immune cells. JAK inhibitors can be used in adults with RA who are intolerant or have poor response to csDMARDs and bDMARDs (one or more). JAK inhibitors are recommended in combination with csDMARDs when used for RA and PsA.
Upadacitinib and tofacitinib can be used for adults with AS who do not respond well to 2-4 weeks of nonsteroidal anti-inflammatory drugs (NSAIDs) or TNF-α inhibitors. Upadacitinib and tofacitinib can be used for patients with PsA who do not respond well to traditional treatment, including skin lesions, peripheral arthritis, axial involvement, dactylitis, enthesitis, and ulcerative colitis. For patients with AS or SpA who are inconvenient to use bDMARDs for treatment, tofacitinib and upadatinib can be used. Upadacitinib can be used in adults with active radiographically negative axial spondyloarthritis (nr-axSpA) who have a poor response to NSAIDs and have inflammation. Tofacitinib and upadacitinib can be used in combination with NSAIDs when used in AS.
Suggested dose: Tofacitinib for RA is recommended to be 5 mg twice a day; For AS, it is recommended to use 5 mg once a day; For PsA, it is recommended to use 5 mg 2 times a day. Tofacitinib extended-release tablets for RA recommend 11 mg once a day; For AS, 11 mg 1 time a day is recommended; For PsA, 11 mg 1 time a day is recommended. Baricitinib is recommended for severe cases of RA of 2 mg once a day and patients with poor response of 4 mg once a day. Upadacitinib for RA is recommended to be 15 mg once a day; For AS and nxSpA, 15 mg once a day is recommended; For PsA, it is recommended to use 15 mg once a day.
Precautions: Upper respiratory tract infection, nasopharyngitis, headache, diarrhea, malignant tumor, severe infection, thromboembolic events, major adverse cardiovascular events, etc. Tofacitinib, upadatinib, and baricitinib should be avoided in patients with Child-Pugh grade C, baricitinib should be avoided in patients with eGFR <30ml/(min·1.73m2), and upadacitinib should be avoided in patients with eGFR <15ml/(min·1.73m2). Tofacitinib is not recommended in combination with immunosuppressants such as cyclosporine A, tacrolimus, or azathioprine, and should avoid concomitant use of strong CYP3A4 inducers (eg, rifampicin, carbamazepine). Upadacitinib should be avoided in combination with a strong CYP3A4 inducer. Tofacitinib is used in combination with strong CYP3A4 inhibitors such as clarithromycin, itraconazole, voriconazole, posaconazole, ketoconazole, etc., and 5 mg once a day is recommended.
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