CASE 30
A 40-year-old female with no known past medical history other than suspected rheumatoid arthritis (RA) presents for evaluation of her pain. Patient reports morning stiffness, swelling and tenderness of her joints in her hands, shoulders, knees for over 6 months. She also reports fatigue and a maternal family history of rheumatoid arthritis. She brought in her old records which show laboratory and clinical criteria sufficient for the diagnosis of rheumatoid arthritis. She has not been following up with her primary care physician or her rheumatologist and has been trying to self manage with over the counter ibuprofen and acetaminophen. On examination she has synovitis of both hands, wrists, shoulders, and knees. She has some early changes of RA, such as ulnar deviation of the digits of her hands, and a few rheumatoid nodules on her arms. Based on the history and examination you diagnose her with an acute exacerbation of her RA. You also explain to her that her overall disease is not being adequately managed. Hence, you start her on oral prednisone and methotrexate.
What is the mechanism of immune suppression mediated by glucocorticoids?
What is the mechanism of action of methotrexate?
ANSWERS TO CASE 30:
Agents Used to Treat Rheumatoid Arthritis
Summary: A 40-year-old woman with worsening rheumatoid arthritis (RA) is prescribed corticosteroids and methotrexate.
Mechanism of immune suppression by glucocorticoids: Interference with cell cycle of activated lymphoid cells and activation of apoptosis in some lymphoid lines.
Mechanism of action of methotrexate: Inhibition of deoxyribonucleic acid (DNA) synthesis by inhibition of dihydrofolate reductase. Inhibits replication and function of T cells and possibly B cells.
CLINICAL CORRELATION
RA is an autoimmune disorder in which the body’s immune system attacks its own synovium. This causes joint stiffness, swelling and, if unchecked, joint destruction and disfigurement. Several immunosuppressive agents have been used with success in the treatment of RA. Glucocorticoids are used both for their anti-inflammatory and immunosuppressive effects. They are thought to interfere with the cell cycle of activated lymphoid cells and may activate apoptosis in some lymphoid lines. Its long-term use is limited by multiple side effects and toxicities, including induction of a Cushingoid syndrome, glucose intolerance, and reduction in bone density. Methotrexate is a cancer chemotherapeutic agent that also has immunosuppressive effects. It is a folate analog that interferes with DNA synthesis by inhibition of the dihydrofolate reductase enzyme. Its immunosuppressive effect is mediated through its inhibition of the replication and function of T, and possibly B, lymphocytes. Methotrexate can cause hepatotoxicity, bone marrow suppression, and severe GI side effects.
APPROACH TO:
Pharmacology of Agents Used in RA
OBJECTIVES
1. Know the agents used for RA and their mechanisms of action.
2. Know the toxicities and adverse effects of agents used for RA.
DEFINITIONS
Rheumatoid arthritis: Chronic disease that is characterized especially by pain, stiffness, inflammation, swelling, and sometimes destruction of joints.
Osteoarthritis: Arthritis characterized by degenerative and sometimes hypertrophic changes in the bone and cartilage of one or more joints and a progressive wearing down of apposing joint surfaces with consequent distortion of joint position usually without bone stiffening.
DISCUSSION
Class
Rheumatoid arthritis is caused by an inappropriate immune response that results in chronic inflammation in and around joints. The chronic inflammatory process includes the production of a number of cytokines and inflammatory mediators that cause destruction of cartilage within the joint. Pharmacologic treatment of RA includes treatment of the acute pain, treatment of the inflammation, and inhibition of the immune system.
Glucocorticoids such as prednisolone or cortisone are potent anti-inflammatory agents and are also immunosuppressive. Glucocorticoids may be administered orally or injected into an affected area. Drugs with an 11-keto group on the steroid nucleus (cortisone or prednisone) are converted to 11-hydroxyl group in the liver (to give cortisol and prednisolone). Other synthetic corticosteroids include dexamethasone, betamethasone, and triamcinolone. Various chemical substitutions within these drugs decrease first-pass inactivation by the liver, decrease binding to plasma proteins such as corticosteroid-binding globulin (CBG), and increase the affinity of the drug for its receptor. The actions of glucocorticoids are mediated by a specific nuclear receptor, the glucocorticoid receptor (GR). Receptor activation occurs on drug binding, which ultimately leads to increased or decreased transcription of specific genes. The anti-inflammatory action of the glucocorticoids is a result, in part, of induction of annexin-1 (also known as macrocortin), which is a specific inhibitor of phospholipase A2, and inhibits the transmigration of leukocytes. This decreases the production of prostaglandins and the inflammatory process. In addition, the production of a number of cytokines including IL-1, IL-2, IL-6, and TNF-α is decreased by glucocorticoids. This is caused in part by the induction of apoptosis in lymphocytes and leukocytes. Thus the anti-inflammatory and immunosuppressive actions of the glucocorticoids are closely linked. Glucocorticoids are potent inhibitors of cell-mediated immunity but have little effect on humoral immunity.
Glucocorticoids are useful in the management of inflammation in RA, bursitis, lupus erythematosus, nephrotic syndrome, and ulcerative colitis. Glucocorticoids are also used to treat hypersensitivity reactions and allergic reactions and to reduce organ or graft rejection.
The use of glucocorticoids is limited by a number of adverse effects. Most of these adverse effects are predictable as exaggerated physiologic effects. Suppression of the pituitary-adrenal axis, hyperglycemia, increased protein metabolism, altered fat metabolism, and increased salt retention (a mineralocorticoid effect) are frequently seen. Osteoporosis and peptic ulcers can be induced by glucocorticoids, and increased susceptibility to infections and poor wound healing also occur.
Methotrexate is a folate analog that inhibits dihydrofolate reductase. This enzyme is responsible for the production of tetrahydrofolate cofactors necessary for purine and thymidylate biosynthesis. Inhibition of the enzyme leads to impaired DNA synthesis, which has the greatest impact on rapidly dividing cells. Methotrexate is immunosuppressive, and this activity has led to its use in RA, psoriasis, and other autoimmune disorders. Its use as an anticancer agent includes childhood acute lymphoblastic leukemia, lymphoma, and osteogenic sarcoma. Serious adverse effects associated with methotrexate include myelosuppression, producing severe leukopenia, bone marrow aplasia, and thrombocytopenia. GI effects are common with nausea and vomiting, as well as mouth sores or ulcers. Hepatotoxicity, including acute elevations in transaminase levels, fibrosis, and cirrhosis, has been reported. Pulmonary effects include a nonproductive cough and pneumonitis. Methotrexate is a teratogen contraindicated in pregnancy.
More disease-specific approaches in treating RA have led to the development of disease-modifying antirheumatic drugs (DMARDs).
Recent evidence supports a central role of tumor necrosis factor alpha (TNF-α) in the pathogenesis of RA. TNF-α appears responsible for much of the tissue injury in the disease. Based on these observations, two new classes of drugs have been developed that specifically target the TNF pathway. One class of drugs is antibodies specific for human TNF-α. These antibodies interact with TNF-α and block its ability to interact with TNF-α receptors. Infliximab is a chimeric antibody containing a human constant region and murine variable regions. It is administered by infusion approximately once every 8 weeks. Infliximab is also indicated in refractory luminal and fistulizing Crohn’s disease. Adalimumab is a similar, fully human anti-TNF-α antibody that is self-injected twice weekly. Etanercept is a fusion protein created by combining the ligand-binding portion of the human TNF-α receptor with the Fc portion of IgG. The protein acts to bind TNF-α and blocks the association of TNF with its receptor. It is self-injected four times a week. These drugs have proven very effective in patients with RA, and disease progression has been markedly diminished and even reversed in some instances. TNF-α also plays an important role in the body’s immune responses, especially to infectious agents.
One of the most serious adverse effects seen with the anti-TNF antibody preparations are severe infections such as tuberculosis. These drugs should not be administered to patients who have any sign of infection. An increased risk of malignancy has also been reported in patients treated with the anti-TNF antibodies. Neurologic problems including dizziness, visual disturbances, and peripheral weakness have also been reported. The adverse effect profile of etanercept is similar with serious infections, neurologic disturbances, and a high frequency, 20–30 percent, of injection site reactions.
Anakinra, another DMARD, is a recombinant protein that mimics the action of IL-1Ra, a natural antagonist of the IL-1 receptor. Anakinra reduces the cartilage degradation and bone resorption caused by IL-1 in RA. Rituximab is a monoclonal antibody against CD-20, which is expressed mainly on B cells. It is approved for use in lymphomas and leukemias and RA. Tocilizumab is an anti-IL-6 receptor (IL-6R) antibody. IL-6 is an important proinflammatory cytokine and its inhibition is efficacious in RA.
Other Agents Used to Treat RA Azathioprine is a cytotoxic agent that suppresses T-cell activity to a greater extent than B-cell activity. It is an orally active agent that is metabolized to mercaptopurine, which is also immunosuppressive. It is used alone or in combination with corticosteroids in the treatment of RA and other autoimmune disorders such as lupus erythematosus. Adverse effects include bone marrow suppression, leukopenia, and, less frequently, anemia. Hydroxychloroquine is an antimalarial agent that reduces inflammation and progression of RA. Several mechanisms have been proposed to account for this activity, including inhibition of toll-like receptors such as TLR9, increasing annexin A5 expression, and decreasing lysosomal function. Nausea and vomiting are common adverse effects and a rarely a destructive retinopathy is encountered. Cyclophosphamide is an alkylating agent developed as an anticancer drug. It suppresses B-cell function more than T-cell function. It has been used to treat a number of autoimmune disorders including Wegener granulomatosis, RA, and nephrotic syndrome in children. Its anticancer uses include non-Hodgkin lymphoma and Burkitt lymphoma. Myelosuppression, nausea and vomiting, and alopecia are common adverse reactions.
Gold salts have been used to treat patients with progressive RA who have not obtained relief from NSAIDs. Use of gold salts has diminished with the introduction of the DMARDs discussed above. Gold has a high affinity for sulfur, and most preparations contain gold attached to a sulfur atom.
Aurothioglucose, gold sodium thiomalate, and auranofin all contain a gold atom attached to a sulfur moiety. Gold preparations are injected IM and reach peak concentrations in 2–6 hours. Gold accumulates in organs that are rich in phagocytes and in the lysosomes of synovial cells. Gold salts decrease the migration and the activity of macrophages, but its precise mechanism of action is unclear. Gold salts do not have anti-inflammatory activity. The most common adverse effects of gold salts are skin lesions and ulceration in mucus membranes. Impaired renal function and blood dyscrasias are also seen in about 10 percent of patients treated with gold salts.
COMPREHENSION QUESTIONS
30.1 Infliximab is effective in RA because it does which of the following?
A. Binds to TNF-α and sequesters it from receptors
B. Is a TNF-α receptor agonist
C. Is a TNF-α receptor antagonist
D. Is a synovium-specific anti-inflammatory agent
30.2 The immunosuppressive effect of methotrexate is a result of its inhibition of which of these?
A. Dihydrofolate reductase
B. Leukocyte migration
C. Microtubule function
D. Phospholipase A2
30.3 A 55-year-old woman is being treated for RA. Her disease has become much worse, and a new medication is added. After 6 months, she notes night sweats, weight loss, chronic cough, and a chest radiograph that indicates a cavitary lesion. Which of the following medications was most likely prescribed for the RA?
A. Gold salts
B. Infliximab
C. Methotrexate
D. Naprosyn
ANSWERS
30.1 A. The anti-TNF-α antibodies bind to TNF-α and prevent its association with receptors. They are not direct receptor antagonists.
30.2 A. Methotrexate inhibits dihydrofolate reductase, which impairs rapidly dividing cells such as lymphocytes and leukocytes.
30.3 B. The anti-TNF-α immunoglobulin agents are usually well tolerated and modify the disease process of RA; however, they tend to predispose patients to infections, particularly tuberculosis. The patient in the question has a typical clinical presentation of tuberculosis. Diagnosis would be confirmed by sputum culture and acid fast smear, and therapy started with multiple antituberculosis agents.
PHARMACOLOGY PEARLS
DMARDs, with the best evidence for the anti-TNF-α agents, stop the progression of RA and may induce remission.
Methotrexate is a folate analog that inhibits dihydrofolate reductase and acts as an immunosuppressive agent.
Glucocorticoid agents act as immunosuppressive agents and anti-inflammatory agents but have numerous adverse effects.
REFERENCES
Singh JA, Christensen R, Wells GA, et al. A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 2009;181:787–96.
Graudal N, Jürgens G. Similar effects of disease-modifying antirheumatic drugs, glucocorticoids, and biologic agents on radiographic progression in rheumatoid arthritis: meta-analysis of 70 randomized placebo-controlled or drug-controlled studies, including 112 comparisons. Arthritis Rheum 2010;62:2852–63.