HC, a previously healthy 42 year old 40 kg woman presents to her primary care physician with a 3 month old history of pain and inflammation in her fingers, wrist, knees and feet. On questioning, she indicates that she has been experiencing stiffness for at least an hour every morning, along with fatigue and a lack of appetite when she wakes up. Her symptoms have become progressively worse the past month, and she can no longer wear her wedding ring. Physical exam indicates a bilateral symmetrical swelling and tenderness in the joints of her hand, wrist and feet. A subcutaneous nodule is evident on the extensor surface of her right forearm. She has been a pack-a-day smoker for the past 20 years. X-ray films of the hands & feet show swelling of soft tissues and narrowing of joint spaces with bilateral erosion of the joints in the hands & feet, with no evidence of calcification.
Her laboratory findings include the following:
ESR: 58 mm/hour (normal: <20 mm/hour for women <50 years old)
positive anti-cyclic citrullinated peptide (anti-CCP): 94 U (normal: <20 U)
positive RF at dilution of 1:300
negative anti-nuclear antibodies (ANA)
positive C-reactive protein (CRP): 40 mg/dL (normal: <0.7 mg/dL)
serum creatinine, BUN and liver enzymes were within the normal range
A diagnosis of rheumatoid arthritis is made, and after discussing the various therapeutic options, the physician recommends the initiation of therapy with oral methotrexate plus a concomitant folic acid supplement.
After a follow-up visit 6 months later her RF and CRP levels remained above normal, and she continued to have severe joint pain and radiographic evidence of progressive joint damage despite an increase in her dosage of methotrexate 3 months earlier. After obtaining a negative TB test, combination therapy of oral methotrexate and a TNF inhibitor (adalimumab s.c. every other week), was initiated. Evaluation of her status 6 months later indicated a reduction in radiographic progression, as well as reduced symptoms of joint pain and swelling.
Questions (Learning Objectives)
What role do different cytokines have on mediating the pathogenesis of rheumatoid arthritis including joint inflammation, destruction of bone & cartilage, and systemic effects?
What are the general principles of management of rheumatoid arthritis?
What role do NSAIDs and corticosteroids have in the treatment of rheumatoid arthritis?
What is methotrexate's mechanism of action as a DMARD?
What are the most commonly used subclasses of biologic DMARDs?
What are the major side effects associated with the use of any DMARD?
Antiinflammatory Drugs: NSAIDs, corticosteroids
Nonbiologic DMARDs: methotrexate, hydroxychloroquine, leflunomide, sulfasalazine
TNF-α inhibitors: adalimumab, certolizumab, etanercept, golimumab, infliximab
IL-6 receptor antagonists: tocilizumab
IL-1 receptor antagonists: anakinra
Biologic response modifiers: abatacept, rituximab
Janus Kinase Inhibitor: tofacitinib
Rheumatoid arthritis (RA) is an autoimmune disease that affects approximately 1% of the population, with women being affected two to three times as often as men (Schur et al, 2013).
RA differs from osteoarthritis (a progressive degenerative joint disease associated with age, joint injury and/or being overweight) that is commonly treated with physical therapy, analgesics, NSAIDs and/or surgery (Kalunian, 2013).
RA is caused by a complex interaction between inherited genes and environmental stimuli. Approximately 50% of the risk for RA is attributable to genetic factors (MacGregor et al, 2000).
Smoking is the major environmental trigger for RA, although infections may also unmask an autoimmune response that triggers the development of RA (McInnes & Schett, 2011).
Environment-gene interactions promote a loss of tolerance to “self-proteins” that contain citrulline residues, with such proteins being identified as foreign antigens by the immune system. This results in activated T cells & B cells that produce an anti-citrulline inflammatory response that affects the joints, resulting in swelling and degradation of both cartilage and bone (Figure 1) (Schur & Firestein, 2012).
Citrulline is an alpha amino acid that is enzymatically added to several types of proteins during post-translational modification.
The majority of patients with RA have a measurable titer of anti-citrullinated protein antibodies.
Why the loss of tolerance to citrillated proteins results in a localized onset of inflammation in the joint is still unclear (McInnes & Schet, 2011).
Inflammatory cytokines including TNF-α and interleukin (IL)-1 & IL-6 drive the destructive process in RA (Figure 1)(Scott et al, 2010).
Other tissues and organs are also commonly affected. Patients with RA have an increased risk of cardiovascular disease, osteoporosis, metabolic syndrome and increased mortality compared to the general population (standardized mortality rate ~1.5) (Figure 2) (Gabriel & Michaud, 2009; McInnes & Schett, 2011)).
Role of cytokines
Excessive production of IL-6 has been found in the synovial fluid and blood of patients with rheumatoid arthritis, and its levels correlate with disease activity and joint destruction (Yusof & Emery, 2013).
IL-6 plays a role in adaptive immunity through multiple mechanisms including:
stimulating B cells to differentiate into plasma cells, which in RA produce auto-antibodies.(Video) Rheumatoid Arthritis Quick Review
stimulates the proliferation and differentiation of T lymphocytes into T-helper cells, which produce the pro-inflammatory cytokine IL-17, which contributes to the recruitment of monocytes & neutrophils to the site of inflammation, which produce destructive tissue damage.
mediates many of the systemic effects of RA, including the development of C-reactive protein (CRP) (Yusof & Emery, 2013).
TNF-α is a key mediator in RA contributing to both systemic effects & bone destruction. Its multiple effects include:
mediates chronic systemic inflammation that may contribute to increased atherosclerosis & premature CV mortality that associated with RA (Deeks, 2013).
enhances the proliferation of T cells, increases the proliferation and differentiation of B cells, increases the expression of adhesion molecules on the endothelium, which promotes movement of T cells into the synovium (Schur & Firestein, 2014).
promotes the destruction of bone by increasing the number of osteoclasts and decreasing the number of osteoblasts at the site of inflammation (Schur & Firestein, 2014).
IL-1 (which consists of two agonists IL-1α & IL-1β) bind to IL-1 receptors that are expressed on a wide variety of cell types.
IL-1 contributes to both the local and systemic effects in RA. Its multiple effects include (Gabay et al, 2010):
promotes the recruitment of inflammatory cells at the site of inflammation by inducing the expression of adhesion molecules on endothelial cells
induces the production of multiple enzymes (e.g. phospholipase A2) resulting in the release of inflammatory mediators (e.g. PGE2)
stimulates the production of multiple metalloproteases, resulting in breakdown of connective tissue
inhibits the production of proteoglycans & type II collagen, exerting a global negative effect on joint cartilage
stimulates the maturation of osteoclasts, which contributes to joint bone erosion
Despite what is known about the contribution of IL-1 to the pathogenesis of RA, anakinra, a selective IL-1 antagonist has been found to be less effective than other biologics in the treatment of RA, which has limited its clinical use for this indication (Singh et al, 2009; Desai RJ et al, 2012; Schur & Cohen, 2014).
Figure 1. In rheumatoid arthritis autoimmune reactions stimulate macrophages and T cells to produce multiple inflammatory cytokines in the joints. This results in swelling and pain, progressive damage to cartilage and bone, and over time systemic effects that contribute to increased cardiovascular morbidity and mortality. The interactions between cytokines and multiple cell types underlying the pathogenesis of RA is more complex than illustrated.
Figure 2. Long-term systemic complications of rheumatoid arthritis. Inflammatory mediators produce effects in multiple organ systems that result in increased rates of metabolic syndrome, osteoporosis, cardiovascular disease & increased mortality that are not explained by traditional risk factors. Implicated cytokines include TNF-α, IL-1, IL-6 & complement immune complexes. (Adapted from McInnes & Schett, 2011).
Diagnosing Rheumatoid Arthritis
The diagnosis of RA is based upon multiple factors (Agarwal, 2011):
a patient's history of joint pain and stiffness
a physical exam documenting symmetrical (on both sides equally) joint swelling (synovitis)
The wrists, and joints in the hands & feet are most commonly involved
Morning stiffness lasting more than an hour suggests an inflammatory etiology (Wasserman, 2011).
laboratory tests including:
radiographs (X-rays) indicating joint damage
elevated inflammatory markers
erythrocyte sedimentation rate (ESR)♦
C-reactive protein (CRP) •
autoantibodies (rheumatoid factor or RF)†
anti-cyclic citrullinated peptide antibodies (anti-CCP)
♦ Inflammatory responses increase the proportion of fibrinogen in the blood, causing red blood cells to stick to each other, and this increases the rate at which red blood cells sediment in solution. This rate can be measured by calculating the erythrocyte sedimentation rate (ESR) in which anticoagulated blood is placed in an upright tube and the rate at which RBCs fall is measured in mm/hour (usually performed by an automated analyzer in a hematology lab). C-reactive protein levels & ESR can be used to follow disease activity and response to medication (Wasserman, 2011).
• Inflammation also produces an increase in C-reactive protein levels in the blood. The physiological role of C-reactive protein is to bind to phosphocholine expressed on the surface of dying cells (and some bacteria) to activate the complement system. Its presence is not specific for RA (Thompson et al, 1999).
† Rheumatoid Factor (RF) is an autoantibody against the Fc portion of IgG that forms immune complexes that contribute to the disease process in RA. Its presence is not specific for RA, and can be present in older healthy patients, and patients with hepatitis C. Approximately 50-80% of patients with RA test positive for RF (Wasserman, 2011).
General Principles of Management of RA
The goal of treatment of RA is to control the inflammatory response in synovial fluid, and to prevent joint injury. The choice of therapy depends on the severity of disease, and the response of the patient to prior therapeutic interventions.
Current clinical guidelines recommend (Schur & Moreland, 2013):
Disease-Modifying AntiRheumatic Drugs (DMARDs) should be used in the early stages of treatment to preserve joint integrity and function (DMARDs can be subdivided into “non-biologic” & “biologic” DMARDs).
Antiinflammatory drugs such as NSAIDs & glucocorticoids should be used as adjuncts to therapy.
DMARDs are the most commonly used drugs for treating RA. They can halt, and potentially reverse damage to bone and cartilage.
DMARDs are typically used in a “treat to target” strategy, where they are aggressively used, with regular monitoring of disease activity to reach a specific target (e.g. little or no inflammation, little swelling in the joints, or X-ray evidence of halting the progression of damage to joint and bone tissue).(Video) Wrist and MCPJ deformity in rheumatoid arthritis
DMARDs have a slow onset of action, requiring weeks to months to achieve a full effect. NSAIDs and corticosteroids are commonly used as adjunct forms of therapy during the early onset of RA treatment, before the full therapeutic effect of a DMARD is achieved.
There are 2 major subtypes of DMARDs - Non-biologic & Biologic. Non-biologic DMARDs exert their effects by relatively nonspecific immunosuppressive, antiinflammatory and cytotoxic mechanisms, while Biologic DMARDs target specific cytokines involved in the pathogenesis of RA. The most commonly DMARDs are:
METHOTREXATE. It can be taken orally, has antiinflammatory effects and reduces the number of activated T cells and TNF-α levels. Clinical trials have confirmed its efficacy. It is commonly the drug of first choice when treating RA.
ANTI-TNF-α AGENTS: Etanercept & Adalimumab are the most commonly used. These two drugs consist of a TNF-α receptor fused with an antibody which binds free TNF-α, preventing it from binding to cellular TNF-α receptors. They appear to be equally effective as methotrexate. They have to be given either twice weekly (etanercept) or biweekly (adalimumab) by s.c. injection. They have some potentially serious side effects.
2nd Tier agents:
IL-6 RECEPTOR ANTAGONIST (tocilizumab) has been shown to have efficacy slightly higher than methotrexate, but with slightly higher incidence of side effects.
The Janus Kinase inhibitor Tofacitinib is as effective as methotrexate, but its “biologic” side effects of increased infections and cancer remain a cause for concern when it is used.
DRUG COMBINATIONS are commonly used when methotrexate alone is not sufficiently effective.
RISK OF SERIOUS INFECTIONS is a major concern for patients considering treatment for rheumatoid arthritis. Evidence indicates the risk for infection is highest when using Biologics compared to traditional DMARDs, but there is some risk associated with use of non-biologics such as methotrexate as well (Komano et al, 2011; Chiu & Chen, 2020).
Medications used to Treat Rheumatoid Arthritis
Corticosteroids & NSAIDs are used to provide temporary relief from the symptoms of arthritis, but are considered “adjunct” drugs for management of arthritis, secondary to the use of DMARDs because only DMARDs have been shown to potentially alter the course of disease by slowing or halting its progression.
DMARDs act on the immune system to slow or reverse the progression of arthritis.
“Nonbiologic” DMARDs exert their effects by relatively nonspecific immunosuppressive, antiinflammatory and cytotoxic mechanisms.
They are orally effective.
Note: frequently the term “DMARD” is used to refer to the non-biologic subclass of these drugs, and “biologics” is used to refer to biologic DMARDs.
They have a slow onset of action for producing clinical effects (weeks to months).
Because of the slow onset of action of DMARDs, corticosteroids & NSAIDs are often more heavily used as adjunct drugs during the early phase of RA treatment before the full effect of a DMARD is achieved.
Methotrexate is the most commonly used (first-line) DMARD. It is used in 50-70% of all patients with RA, and is the anchor drug for most combination therapies (Furst et al, 2012; Shah & St Clair, 2012; Schur & Cohen, 2013).
METHOTEXATE (low dose)
methotrexate has MORE THAN ONE MECHANISM OF ACTION, and the mechanism by which it is effective in treating cancer vs autoimmune diseases are different.
CANCER: methotrexate is a structural analog of folic acid and at the high concentrations used in cancer chemotherapy competitively inhibits the binding of dihydrofolic acid to dihydrofolate reductase (Furst et al., 2012).
AUTOIMMUNE DISORDERS: methotrexate's mechanism of action in autoimmune diseases is different. Methotrexate inhibits multiple enzymes involved in the synthesis of nucleotides, including aminoimidazole carboxamide ribonucleotide transformylase (AICART). Inhibition of AICART results in the accumulation of its substrate (AICAR ribonucleotide), which is a potent inhibitor of adenosine deaminase, resulting in an increase in adenosine levels (Inoue & Yuasa, 2013).
ADENOSINE release into the extracellular space produces a potent anti-inflammatory effect, including a reduction in the number of activated T cells, and a reduction of TNF-α levels (Montesinos et al, 2003; Hasko et al, 2008).
Rodents that lack adenosine receptors do not have the same anti-inflammatory effect of methotrexate compared to animals expressing adenosine receptors (Montesinos et al., 2003).
Other mechanisms (perhaps mediated by inhibition of other folate-dependent enzymes) resulting in a clonal deletion of T cells by apoptosis, and decreased production of IL-1 and other inflammatory mediators may also contribute to its anti-inflammatory effects (Kremer, 2013).
Renal excretion is the primary route of elimination (a combination of glomerular filtration and active tubular secretion). Elimination is non-linear and dose dependent due to saturation of renal tubular reabsorption, with a half life of 3-10 hrs at low doses & up to 15 hrs at higher doses.
leukopenia, anemia, GI ulcerations, alopecia (due to inhibition of cell proliferation) & is reduced with use of leucovorin or folic acid
patients with hepatic damage (e.g. hepatitis C)
significant renal impairment (which impairs clearance)
Pregnancy Risk Category X. Absolutely contraindicated in pregnancy.
Other currently available DMARDs include:
mechanism: unclear mechanism, but suppresses T-lymphocyte responses to mitogens, decreases leukocyte chemotaxis, inhibits lysosomal enzymes, inhibits DNA & RNA synthesis, & trap free radicals (Furst et al, 2012)
mechanism: inhibits dihydroorotate dehydrogenase, resulting in an inhibition of T-cell proliferation and reduced production of autoantibodies by B cells (Furst et al, 2012)
mechanism: inhibits the release of inflammatory cytokines (Furst et al, 2012)
“Biologics” are the newest class of drugs for treating RA, and act by targeting and neutralizing specific mediators of the immune system that result in joint damage, such as TNF-α & IL-6.(Video) Arizona Arthritis and Rheumatology Associates
Biologics are generally considered second-line agents, and can be used in combination with methotrexate.
Patients taking biologic DMARDs should be tested for hepatitis B & C and tuberculosis before initiating treatment.
Most need to be administered by subcutaneous injection. The exception to the rule is the Janus kinase inhibitor tofacitinib, which is taken orally.
TNF-α inhibitors are currently the most commonly used biologics, and TNF-α blockade has become the central strategy of targeted antiinflammatory therapy in the disease (McInnes & Schett, 2011; Furst et al., 2012).
The IL-6 antagonist tocilizumab is considered the 2nd major advance in cytokine blockade in RA. It has profound effects on both synovitis & systemic features of the disease (McInnes & Schett, 2011). It is approved for RA patients who have failed treatment with at least one TNF-α inhibitor (Agarwal, 2011).
An explanation of drug stem nomenclature is shown in Table 1.
Currently available Biologics include:
A dimer of human IgG1 & the human TNF receptor
has shown similar efficacy as methotrexate in clinical trials. It may have a slightly lower rate of serious infections compared to other biologic DMARDs (Schur & Cohen, 2014)
twice weekly sc maintenance dosing due to its short half-life
a recombinant 100% human IgG1 monoclonal antibody specific for TNF-α
similar efficacy as methotrexate (Schur & Cohen, 2014)
can be given s.c. every 2 weeks (which some patients prefer)
InfliximabSee AlsoAbstracts zum 40. Kongress der Deutschen Gesellschaft für Rheumatologie (DGRh) - PDF Free DownloadL5-S1 Disc Bulge, Slip Disc, Stenosis & SpondylolisthesisBest Golf Grips For Arthritic Hands in 2022
the first anti-TNF-α drug that became available
a chimeric monoclonal antibody containing 25% mouse, 75% human IgG1 that binds to soluble & membrane bound TNF-α
generally it is not given as monotherapy because patients can develop a tolerance or decline in efficacy due to the development of inactivating anti-chimeric antibodies (HACA) when infliximab is given without other immunosuppressant drugs. Hence when used it is usually combined with methotrexate or another immunosuppressant.
a newer agent with less long-term clinical experience (therefore not used as much to date)
a human monoclonal antibody that binds to both the soluble and transmembrane bioactive forms of human TNFα.
another new agent with less long-term clinical experience (therefore not used as much to date)
a recombinant humanized IgG1 antibody Fab fragment specific for TNF-α
IL-6 receptor antagonists
a recombinant anti-human IL-6 receptor monoclonal antibody that binds to both soluble and membrane-bound IL-6 receptors, inhibiting IL-6 mediated signaling
the AMBITION clinical trial found that it was slightly superior to methotrexate as monotherapy for RA, but had a slightly higher incidence of side effects (Jones et al, 2010)
IL-1 receptor antagonists (limited efficacy against RA)
Biologic response modifiers
Abatacept (a T-cell costimulation blocker)
Rituximab (an anti-CD20 B-cell depleting monoclonal Ab)
Janus Kinase Inhibitor (orally effective)
inhibits cytokine & growth factor signalling by inhibiting Janus kinases, a family of intracellular tyrosine kinases.
tofacitinib mono-therapy has been found to be superior to methotrexate in reducing the symptoms and progression of RA. However, its use was associated with an increased risk of infections and cancer, similar to other “biologics” (Lee et al, 2014).
TNF-α inhibitor side effects:
INCREASED RISK OF OPPORTUNISTIC INFECTIONS (bacterial, fungal, viral) & LYMPHOMAS
Activation of latent tuberculosis
BIOLOGICS INCREASE INFECTION RISK
The use of both traditional DMARDS (e.g. methotrexate) and Biologic DMARDS (e.g. TNF–α inhibitors) is associated with an increased risk for serious infections, however the risk when using Biologics (e.g. TNF-α inhibitors) is significantly higher (Chiu & Chen, 2020)..(Video) My Rheumatoid Arthritis (RA) Story
TNF-α inhibitors double infection risk compared to traditional DMARDS (Komano et al, 2011).
Meta-analysis (Singh et al, 2015) indicates that relative to traditional DMARDs alone, the number of infections seen with Biologic DMARDs increases by:
6 per 1000 patients per year with standard Biologic therapy
17 per 1000 patients for high-dose Biologic DMARDs
55 per 1000 patients for combination Biologic therapy
The risk for infection when using biologics (e.g.TNF-α inhibitors) needs to be balanced against their potential for therapeutic benefits when making clinical decisions about their use.
Combination Therapy with DMARDS
Approximately half of patients with RA end up on combination therapy (Furst et al, 2012). Effective combinations include (Breedveld et al, 2006; Shah & St Clair, 2011):
methotrexate, sulfasalazine, and hydroxychloroquine (triple therapy)
methotrexate and leflunomide
methotrexate plus a TNF-α inhibitor
methotrexate plus another biological DMARD
|TABLE 1: Drug Nomenclature♠|
|-cept||fusion of a receptor to the Fc part of human IgG1|
|-ab||a monoclonal antibody (mAb)|
|-mab||a humanized mAb|
|-ximab||a chimeric foreign (mouse)/human mAb|
|-kinra||interleukin receptor antagonist|
|-tinib||tyrosine kinase inhibitor|
Rarely Used Drugs in the Treatment of Severe Rheumatoid Arthritis
When there is a risk of major organ damage in cases of severe rheumatoid arthritis, other strong chemotherapeutic drugs may also be used. These include azathioprine (Imuran ®), cyclophosphamide (Cytoxan ®) & cyclosporine (Neoral ®).
Self Assessment Quiz
Treatment of Arthritis (4 Qs)
Agarwal SK (2011): Core management principles in rheumatoid arthritis to help guide managed care professionals. J Managed Care Pharmacy 17: S03-S08.
Breedveld FC, Weisman MH et al (2006): The PREMIER study. A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis & Rheumatism. 54(1):26-37.
Chiu YM, Chen DY (2020): Infection risk in patients undergoing treatment for inflammatory arthritis: non-biologics versus biologics. Expert Rev Clin Immunol 16(2):207-228. doi: 10.1080/1744666X.2019.1705785.
Deeks ED (2013): Certolizumab Pegol. A review of its use in the management of rheumatoid arthritis. Drugs 73:75-97.
Desai RJ, Hansen RA et al (2012): Mixed treatment comparison of the treatment discontinuations of biologic disease-modifying antirheumatic drugs in adults with rheumatoid arthritis. Ann Pharmacother 46(11):1491-1505.
Furst DE, Ulrich RW, Prakash S (2012): Nonsteroidal Anti-Inflammatory Drugs, Disease-Modifying Antirheumatic Drugs, Nonopioid Analgesics, & Drugs Used in Gout (Chapter 36). In: Basic and Clinical Pharmacology. 12th Edition. Katzung BG, Masters SB, Trevor AJ (Editors). McGraw-Hill / Lange. (Access-Medicine).
Gabay C, Lamacchia C, Palmer G (2010): IL-1 pathways in inflammation and human diseases. Nat Rev Rheumatol 6:232-241.
Gabriel SE, Michaud K (2009): Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatoid diseases. Arthritis Res Ther 11(3):229.
Hasko G, Linden J et al (2008): Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov 7:759-770.
Inoue K, Yuasa H (2013): Molecular basis for pharmacokinetics and pharmacodynamics of methotrexate in rheumatoid arthritis therapy. Drug Metab Pharmacokinetics, Published online Nov 26, 2013.
Jones G, Sebba A et al (2010): Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 69(1):88-96.
Kalunian KC (2013): Initial pharmacologic therapy of osteoarthritis. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA. Cited 1/8/14.
Komano Y et al (2011): Incidence and risk factors for serious infection in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitors: A report from the Registry of Japanese Rheumatoid Arthritis Patients for Longterm Safety. J Rheumatol 38:1258.
Kremer JM (2013): Use of methotrexate in the treatment of rheumatoid arthritis. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA. Cited 1/9/14.
Lee EB et al (2014): Tofacitinib versus Methotrexate in Rheumatoid Arthritis. NEJM 370:2377-2386.
MacGregor AJ, Snieder H et al (2000): Characterizing the quantitative genetic contribution to rheumatoid arthritis using data from twins. Arthritis Rheum 43(1):30-37.
McInnes IB, Schett G (2011): The pathogenesis of rheumatoid arthritis. N Engl J Med 365:2205-19.
Montesinos MC, Desai D et al (2003): Adenosine A2A or A3 receptors are required for inhibition of inflammation by methotrexate and its analog MX-68. Arthritis Rheum 48(1):240.
Schur PH, Cohen S (2014): Treatment of rheumatoid arthritis resistant to initial DMARD therapy in adults. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA. Cited 3/24/14.
Schur PH, Firestein GS (2014): Pathogenesis of rheumatoid arthritis. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA. Cited 3/24/14.
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Schur PH et al (2013): Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis. In: UpToDate, Basow, DS (Ed), UpToDate, Waltham, MA. Cited 4/15/14.
Scott DL, Wolfe F, Huizinga TW (2010): Rheumatoid arthritis. Lancet 376(9746): 1094-1108.
Shah A, St Clair, W (2012): Rheumatoid Arthritis (Chapter 321). In: Harrison's Internal Medicine. 18e. McGraw-Hill.
Singh JA, Christensen R, et al (2009): A network meta-analysis of randomized controlled trials of biologics for rheumatoid arthritis: a Cochrane overview. CMAJ 181(11):787 (abstact).
Singh JA et al (2012): 2012 Update of the 2008 American College of Rheumatology Recommendations for the Use of Disease-Modifying Antirheumatic Drugs and Biologic Agents in the Treatment of Rheumatoid Arthritis. Arthritis Care & Research 64(5):625-639.
Singh JA et al (2015): Risk of serious infection in biological treatment of patients with rheumatoid arthritis: a systematic review and meta-analysis. The Lancet. May 12, 2015.
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- Pain or aching in more than one joint.
- Stiffness in more than one joint.
- Tenderness and swelling in more than one joint.
- The same symptoms on both sides of the body (such as in both hands or both knees)
- Weight loss.
- Fatigue or tiredness.
Rheumatoid arthritis is an autoimmune disease. Normally, your immune system helps protect your body from infection and disease. In rheumatoid arthritis, your immune system attacks healthy tissue in your joints. It can also cause medical problems with your heart, lungs, nerves, eyes and skin.
Methotrexate is usually the first medicine given for rheumatoid arthritis, often with another DMARD and a short course of steroids (corticosteroids) to relieve any pain. These may be combined with biological treatments.
No, rheumatoid arthritis doesn't go away. It's a condition you'll have for the rest of your life. But you may have periods where you don't notice symptoms. These times of feeling better (remission) may come and go.
Rheumatoid arthritis is an autoimmune condition, which means it's caused by the immune system attacking healthy body tissue. However, it's not yet known what triggers this. Your immune system normally makes antibodies that attack bacteria and viruses, helping to fight infection.
The most commonly affected areas during the onset of RA are the small joints in your hands and feet. This is where you may first feel stiffness and an ache. It's also possible for RA inflammation to affect your knees and hips.
Stress tends to make RA symptoms worse. People with post-traumatic stress disorder (PTSD) have a higher risk of developing RA and other autoimmune diseases. People who have experienced childhood trauma were more likely to have rheumatic diseases.
Methotrexate is widely regarded as one of the safest of all arthritis drugs, though it carries some potential downsides. Gastrointestinal symptoms such as nausea and vomiting are its most frequent side effects.
Like other forms of arthritis, RA can't be reversed. Even if you show evidence of low inflammation and your joints aren't swollen and tender, your doctor may want you to continue taking some medication to avoid a flare of the disease.
Doctors usually first prescribe methotrexate (Rheumatrex, Trexall) to treat rheumatoid arthritis. If that alone doesn't calm the inflammation, they may try or add a different type of conventional DMARD such as hydroxychloroquine (Plaquenil), leflunomide (Arava), sulfasalazine (Azulfidine), or tofacitinib (Xeljanz).
Nonsteroidal Anti-Inflammatory Drugs
NSAIDs are the most effective oral medicines for OA. They include ibuprofen (Motrin, Advil) naproxen (Aleve) and diclofenac (Voltaren, others). All work by blocking enzymes that cause pain and swelling.
“80% of sufferers can lead a normal life with the aid of medication. In the past, rheumatoid arthritis meant being condemned to a wheelchair,” says arthritis expert Daniel Aletaha from the Department of Medicine III, (Division of Rheumatology).
- Fatigue. Before experiencing any other symptoms, a person with RA may feel extremely tired and lack energy. ...
- Slight fever. Inflammation associated with RA may cause people to feel unwell and feverish. ...
- Weight loss. ...
- Stiffness. ...
- Joint tenderness. ...
- Joint pain. ...
- Joint swelling. ...
- Joint redness.
Clinical History. The typical case of rheumatoid arthritis begins insidiously, with the slow development of signs and symptoms over weeks to months. Often the patient first notices stiffness in one or more joints, usually accompanied by pain on movement and by tenderness in the joint.
An anti-CCP antibody test — also called an ACCP test or CCP-test — looks for the presence of these antibodies to help confirm rheumatoid arthritis. An anti-CCP test can also help doctors determine the severity of a rheumatoid arthritis case.
Your doctor may offer blood tests looking for rheumatoid factor (RF) and/or anti-CCP (anti-cyclic citrullinated peptide) antibodies to diagnose rheumatoid arthritis, even though these tests aren't always definitive. Some people with early-stage RA or other autoimmune diseases may have false positives or negatives.
Read about high blood pressure or hypertension. Learn how changes in lifestyle—like getting more exercise and having less salt—may help control it.
The first number, called systolic blood pressure, is the pressure caused by your heart contracting and pushing out blood.. Low blood pressure , or hypotension, is systolic blood pressure lower than 90 or diastolic blood pressure lower than 60.. Anyone can have high blood pressure.. For those who drink, men should not have more than two drinks a day and women no more than one a day to lower their risk of high blood pressure.. Smoking increases your risk for high blood pressure, heart disease , stroke , and other health problems.. If your doctor prescribes medication to lower your blood pressure, remember:. If you take blood pressure medication and your blood pressure goes down, it means medication and lifestyle changes are working.
Metoprolol oral tablet is a prescription medication used to treat high blood pressure, chest pain, and heart stress after a heart attack. It's a drug called a beta-blocker. It's available as generic drugs and as the brand-name drugs Lopressor and Toprol XL. Learn about side effects, warnings, dosage, and more.
Metoprolol oral tablet is available as generic drugs and as brand-name drugs.. Using these drugs with metoprolol could increase the levels of metoprolol in your body.. the antiretroviral ritonavir antihistamines, including diphenhydramine antimalarial drugs, such as hydroxychoroquine and quinidine antifungal drugs, such as terbinafine the blood pressure drug hydralazine. Form: immediate-release oral tablet (metoprolol tartrate) Strength: 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg Form: extended-release oral tablet (metoprolol succinate) Strength: 25 mg, 50 mg, 100 mg, and 200 mg. Form: immediate-release oral tablet (metoprolol tartrate) Strength: 50 mg and 100 mg. Form: extended-release oral tablet (metoprolol succinate) Strength: 25 mg, 50 mg, 100 mg, and 200 mg. Form: immediate-release oral tablet (metoprolol tartrate) Strength: 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg Form: extended-release oral tablet (metoprolol succinate) Strength: 25 mg, 50 mg, 100 mg, and 200 mg. Form: immediate-release oral tablet (metoprolol tartrate) Strength: 50 mg and 100 mg. Form: extended-release oral tablet (metoprolol succinate) Strength: 25 mg, 50 mg, 100 mg, and 200 mg. Form: immediate-release oral tablet (metoprolol tartrate) Strength: 25 mg, 37.5 mg, 50 mg, 75 mg, and 100 mg. Form: extended-release oral tablet (metoprolol succinate) Strength: 25 mg, 50 mg, 100 mg, and 200 mg. Form: extended-release oral tablet (metoprolol succinate) Strength: 25 mg, 50 mg, 100 mg, and 200 mg. Typical maintenance dosage: Your doctor can double the dosage every 2 weeks to the highest dosage level your body will tolerate, or up to 200 mg per day.. Metoprolol oral tablet can be used either as a short-term drug or a long-term drug.. If you miss doses or don’t take the drug on schedule: Not taking metoprolol every day, skipping days, or taking doses at different times of day also come with risks.
Chlorothiazide - Intravenous (IV) Dilution
Pharmacokinetics and Metabolism Chlorothiazide is not metabolized but is eliminated rapidly by the kidney; 96 percent of an intravenous dose is excreted unchanged in the urine within 23 hours.. Cumulative effects of the drug may develop in patients with impaired renal function.. Thiazides may add to or potentiate the action of other antihypertensive drugs.. PRECAUTIONSGeneral All patients receiving diuretic therapy should be observed for evidence of fluid or electrolyte imbalance: namely, hyponatremia, hypochloremic alkalosis, and hypokalemia.. Hyperglycemia may occur with thiazide diuretics.. Thiazides may decrease urinary calcium excretion.. Non-steroidal Anti-inflammatory Drugs - In some patients, the administration of a non-steroidal anti-inflammatory agent can reduce the diuretic, natriuretic, and antihypertensive effects of loop, potassium-sparing and thiazide diuretics.. Therapy should be individualized according to patient response.. Chlorothiazide sodium for injection may be given slowly by direct intravenous injection or by intravenous infusion.. Add 18 mL of Sterile Water for Injection to the vial to form an isotonic solution for intravenous injection.
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Medication ConversionImmediate-Release DoseEquivalent Extended-Release DoseAcetaminophen (Tylenol) four times daily to less frequent dosing or conversion to acetaminophen extended release (Tylenol ER)325 mg QID/q6h 500 mg QID/q6h 1000 mg QID/q6h→ Consider TID or BID dosing with IR or ER formulation, based on resident pain level Metoprolol tartrate (twice daily) to metoprolol succinate (once daily)25 mg BID 50 mg BID 100 mg BID→ 50 mg daily (Succinate) → 100 mg daily (Succinate) → 200 mg daily (Succinate) Carvedilol (twice daily) to carvedilol CR (once daily)3.125 mg BID 6.25 mg BID 12.5 mg BID 25 mg BID→ 10 mg daily (ER) → 20 mg daily (ER) → 40 mg daily (ER) → 80 mg daily (ER) Metformin IR (twice daily) to metformin IR or ER (once daily)500 mg BID 750 mg BID 1000 mg BID→ 1000 mg (IR or ER)* daily → 750 mg (ER), 2 tabs once daily → 1000 mg (ER), 2 tabs once daily Proton pump inhibitors twice daily to once dailyFull daily dose, e.g., omeprazole 20 mg BID→ Halve total daily dose, e.g., omeprazole 20 mg daily* For metformin, reasonable to give up to 1000 mg of immediate release (IR) formulation in a single dose.. This includes medications that require additional administration times as well as large, chalky pills which frequently cause residents to cough or require close physical contact from staff to help swallow.. We are thus making medication recommendations that we believe will promote our residents’ health and safety in light of both their chronic conditions and threats posed by COVID-19.. Our in-house team, with input from residents, direct care workers, and family members and care partners has identified the following residents with medication regimens that could be modified.. Recently, our clinical team including nurses, pharmacists, and your primary care clinician reviewed your medical conditions and medications.. As we consider possible medication changes, we value each resident’s input about their own care.. Your care team plans to discuss possible medication changes with you (and if you would like, with your family member or care partner).
Blood Pressure Changes (Hypertension & Hypotension) chemotherapy side effect, causes, symptom management and when to contact your healthcare provider during cancer treatment.
Blood pressure monitoring - Your healthcare provider may take your. blood pressure when you visit the office to check for changes in blood pressure.. The cuff will be slowly inflated and deflated, and your healthcare. provider will be able to determine your blood pressure readings in the form of a. top number your systolic blood pressure reading and a bottom number, your diastolic. blood pressure reading.. The normal blood pressure is 120/80, although most people do not have blood pressure. of exactly 120/80.Low blood pressure is much less common than high blood. pressure.. High blood pressure. is high blood pressure, no matter what causes it when the reading was. taken.. Medications - If you are taking certain medications to control. your high blood pressure or heart rate, for example, these may cause changes in blood. pressure to a lower level.. If you are prescribed a medication for your high blood pressure, and your blood. pressure changes too dramatically your dose may be decreased.