Pros and Cons of Historic Therapies for OA and RA

1. Pros and Cons of Historic Therapies for OA and RA

2. Comprehensive Management of OA As part of the comprehensive management of osteoarthritis (OA), therapy is tailored to the severity of disease and takes into account any comorbid conditions (hypertension, other cardiovascular diseases, peptic ulcer disease, renal or hepatic impairment) that may affect the choice of specific pharmacologic agents. Since no disease-modifying therapies are yet available for patients with OA, pharmacotherapy is aimed at the relief of pain. The 1995 American College of Rheumatology (ACR) guidelines on OA specify nonpharmacologic modalities as first-line therapy, combined with simple, nonopioid analgesics, such as acetaminophen. Nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated in patients whose disease fails to respond to this initial regimen. A topical cream containing an NSAID or capsaicin may be helpful as monotherapy or as an adjunct to oral analgesic therapy. Intra-articular injections of corticosteroids and hyaluronic acid may be appropriate in certain patients when used judiciously. Severe cases of OA of the hip or knee may be candidates for surgical treatment, and an orthopedic consultation and evaluation for arthroscopic lavage and debridement, osteotomy, or total joint arthroplasty may be indicated.As part of the comprehensive management of osteoarthritis (OA), therapy is tailored to the severity of disease and takes into account any comorbid conditions (hypertension, other cardiovascular diseases, peptic ulcer disease, renal or hepatic impairment) that may affect the choice of specific pharmacologic agents. Since no disease-modifying therapies are yet available for patients with OA, pharmacotherapy is aimed at the relief of pain. The 1995 American College of Rheumatology (ACR) guidelines on OA specify nonpharmacologic modalities as first-line therapy, combined with simple, nonopioid analgesics, such as acetaminophen. Nonsteroidal anti-inflammatory drugs (NSAIDs) are indicated in patients whose disease fails to respond to this initial regimen. A topical cream containing an NSAID or capsaicin may be helpful as monotherapy or as an adjunct to oral analgesic therapy. Intra-articular injections of corticosteroids and hyaluronic acid may be appropriate in certain patients when used judiciously. Severe cases of OA of the hip or knee may be candidates for surgical treatment, and an orthopedic consultation and evaluation for arthroscopic lavage and debridement, osteotomy, or total joint arthroplasty may be indicated.

3. Pharmacotherapy for Arthritis OA Analgesics NSAIDs Intra-articular glucocorticoids Intra-articular hyaluronic acid RA NSAIDs DMARDs Intra-articular/oral glucocorticoids Symptomatic relief of pain and prevention of irreversible joint damage and disability are the goals of pharmacotherapy for both OA and rheumatoid arthritis (RA). The ACR’s 1995 guidelines on OA (currently being revised) recommend the use of acetaminophen as the initial drug for OA of the hip or knee, displacing NSAIDs from this first-line role because of concerns about GI toxicity and other adverse events associated with NSAIDs. On the other hand, the ACR’s 1996 guidelines on RA (currently being revised) recommend NSAIDs as first-line agents for the treatment of RA because of their analgesic and anti-inflammatory properties. Disease-modifying antirheumatic drugs (DMARDs) are indicated in patients whose RA fails to respond to NSAIDs. Low-dose oral glucocorticoids may be indicated in severe cases of RA. Intra-articular injections of glucocorticoids may be appropriate in severe cases of OA and RA, as well. Intra-articular hyaluronic acid may also be an option for OA.Symptomatic relief of pain and prevention of irreversible joint damage and disability are the goals of pharmacotherapy for both OA and rheumatoid arthritis (RA). The ACR’s 1995 guidelines on OA (currently being revised) recommend the use of acetaminophen as the initial drug for OA of the hip or knee, displacing NSAIDs from this first-line role because of concerns about GI toxicity and other adverse events associated with NSAIDs. On the other hand, the ACR’s 1996 guidelines on RA (currently being revised) recommend NSAIDs as first-line agents for the treatment of RA because of their analgesic and anti-inflammatory properties. Disease-modifying antirheumatic drugs (DMARDs) are indicated in patients whose RA fails to respond to NSAIDs. Low-dose oral glucocorticoids may be indicated in severe cases of RA. Intra-articular injections of glucocorticoids may be appropriate in severe cases of OA and RA, as well. Intra-articular hyaluronic acid may also be an option for OA.

4. Pros and Cons of Simple Analgesics Pros Pain relief Less risk of adverse GI/renal effects vs. NSAIDs Cons Weak anti-inflammatory effects Addiction, constipation, dizziness (opioids) Variable response Simple analgesics, such as acetaminophen, may achieve symptomatic relief of pain in OA and RA and are associated with fewer serious adverse events than NSAIDs. It has been suggested that rheumatologists may underestimate the desire for, and use of, simple analgesics by patients with RA. The disadvantages of analgesics (which are more relevant to the treatment of RA than OA) include their weak anti-inflammatory effects. Opioid analgesics are useful in treating acute exacerbations of pain, but can cause addiction, constipation, dizziness, and other unwanted effects. Simple analgesics, such as acetaminophen, may achieve symptomatic relief of pain in OA and RA and are associated with fewer serious adverse events than NSAIDs. It has been suggested that rheumatologists may underestimate the desire for, and use of, simple analgesics by patients with RA. The disadvantages of analgesics (which are more relevant to the treatment of RA than OA) include their weak anti-inflammatory effects. Opioid analgesics are useful in treating acute exacerbations of pain, but can cause addiction, constipation, dizziness, and other unwanted effects.

5. Use of NSAIDs in Arthritis Involved in half of all office visits for musculoskeletal disorders Account for half of all Rxs in elderly Most often prescribed for OA High rate of early discontinuation because of side effects Because of their analgesic and anti-inflammatory properties, NSAIDs are the most frequently used analgesics for arthritis, prescribed in over half of all physician visits for musculoskeletal disorders. Fifty percent of all NSAID prescriptions are for the treatment of OA. The greatest use of NSAIDs occurs among the elderly, and, given the frequency of comorbid conditions and concomitant drug regimens among older patients, there is significant potential for serious NSAID-related adverse events in this population. Another concern is the high rate of NSAID discontinuation among OA patients after relatively short periods of time because of side effects. This prevents them from achieving the full benefits of NSAID treatment. Because of their analgesic and anti-inflammatory properties, NSAIDs are the most frequently used analgesics for arthritis, prescribed in over half of all physician visits for musculoskeletal disorders. Fifty percent of all NSAID prescriptions are for the treatment of OA. The greatest use of NSAIDs occurs among the elderly, and, given the frequency of comorbid conditions and concomitant drug regimens among older patients, there is significant potential for serious NSAID-related adverse events in this population. Another concern is the high rate of NSAID discontinuation among OA patients after relatively short periods of time because of side effects. This prevents them from achieving the full benefits of NSAID treatment.

6. Advantages of NSAIDs Analgesic and anti-inflammatory effects Rapid pain relief/improved function Lack CNS effects of opioids Variety of agents/regimens NSAIDs offer several advantages in treating the pain and inflammation of OA and RA, as they provide rapid analgesia and avoid the unwanted central nervous system (CNS) effects of opioids. Because NSAIDs comprise several different chemical classes, various agents and dosing regimens are available. This is particularly helpful when arthritis fails to respond to the first NSAID prescribed. NSAIDs offer several advantages in treating the pain and inflammation of OA and RA, as they provide rapid analgesia and avoid the unwanted central nervous system (CNS) effects of opioids. Because NSAIDs comprise several different chemical classes, various agents and dosing regimens are available. This is particularly helpful when arthritis fails to respond to the first NSAID prescribed.

7. Disadvantages of NSAIDs GI toxicity Disturbed platelet function Renal toxicity Hepatic toxicity Variable response In addition to sharing therapeutic benefits, NSAIDs also share several significant adverse effects, including disturbances in platelet function, renal toxicity, hepatic toxicity, and especially, GI toxicity. It has been suggested that the variable response to NSAIDs may be attributed to varying selectivity for cyclooxygenase (COX-1) (affecting the propensity for GI or renal toxicity) vs. COX-2 (affecting their anti-inflammatory and analgesic efficacy). In addition to sharing therapeutic benefits, NSAIDs also share several significant adverse effects, including disturbances in platelet function, renal toxicity, hepatic toxicity, and especially, GI toxicity. It has been suggested that the variable response to NSAIDs may be attributed to varying selectivity for cyclooxygenase (COX-1) (affecting the propensity for GI or renal toxicity) vs. COX-2 (affecting their anti-inflammatory and analgesic efficacy).

8. Frequency of NSAID-RelatedAdverse Events Frequency Adverse Event >10% Dyspepsia; reversible platelet inhibition 1%-10% Gastric or small bowel bleeding, ulceration, or perforation <1% CNS effects Hepatic toxicityRashRenal insufficiency Bronchospasm The most common (occurring in >10% of patients) adverse event associated with NSAID use is dyspepsia. Reversible inhibition of platelet aggregation occurs with all NSAIDs, except for aspirin, which causes platelet inhibition for the life of the platelet. Gastric or small bowel bleeding or ulceration occurs in 1% to 10% of patients receiving NSAIDs. The least frequent adverse events associated with NSAIDs (those occurring in <1% of patients) include CNS effects such as confusion, depression, and headache; hepatic toxicity; rash; renal insufficiency; and, in patients with aspirin sensitivity, bronchial spasm. Because of the variability in toxicity among NSAIDs, the lowest effective dose for first-line treatment is recommended. The availability of newer NSAIDs, such as COX-2 specific inhibitors, may lead to a reconsideration of the optimal NSAID regimen and monitoring strategy. The most common (occurring in >10% of patients) adverse event associated with NSAID use is dyspepsia. Reversible inhibition of platelet aggregation occurs with all NSAIDs, except for aspirin, which causes platelet inhibition for the life of the platelet. Gastric or small bowel bleeding or ulceration occurs in 1% to 10% of patients receiving NSAIDs. The least frequent adverse events associated with NSAIDs (those occurring in <1% of patients) include CNS effects such as confusion, depression, and headache; hepatic toxicity; rash; renal insufficiency; and, in patients with aspirin sensitivity, bronchial spasm. Because of the variability in toxicity among NSAIDs, the lowest effective dose for first-line treatment is recommended. The availability of newer NSAIDs, such as COX-2 specific inhibitors, may lead to a reconsideration of the optimal NSAID regimen and monitoring strategy.

9. Do Changes to NSAID Regimens Reduce Risk of GI Toxicity? Nonacetylated salicylates or low-dose ibuprofen Yes Coadministration of misoprostol, PPIs, or high-dose H2 blockers Yes Enteric-coated/buffered aspirin No Parenteral therapy No Prodrugs No Nonacetylated salicylates and ibuprofen have been shown to be associated with a lower rate of GI adverse effects than other NSAIDs. It has been suggested that the relatively low doses used with these agents may be responsible for their more favorable GI tolerability. The risk of NSAID ulcers may also be reduced by replacing the protective PGs depleted by NSAIDs (via coadministration of misoprostol) or inhibiting gastric acid secretion (via coadministration of proton-pump inhibitors [PPIs] or high-dose H2 blockers). Other strategies to avoid the local toxicity of NSAIDs—such as the use of enteric coating, parenteral administration, and prodrugs—have not prevented eventual gastric and duodenal ulceration. Thus it appears that the systemic, not local, effects of COX-1 inhibition (depletion of protective PGs in the GI mucosa rather than topical gastric injury) are responsible for NSAID-related toxicity.Nonacetylated salicylates and ibuprofen have been shown to be associated with a lower rate of GI adverse effects than other NSAIDs. It has been suggested that the relatively low doses used with these agents may be responsible for their more favorable GI tolerability. The risk of NSAID ulcers may also be reduced by replacing the protective PGs depleted by NSAIDs (via coadministration of misoprostol) or inhibiting gastric acid secretion (via coadministration of proton-pump inhibitors [PPIs] or high-dose H2 blockers). Other strategies to avoid the local toxicity of NSAIDs—such as the use of enteric coating, parenteral administration, and prodrugs—have not prevented eventual gastric and duodenal ulceration. Thus it appears that the systemic, not local, effects of COX-1 inhibition (depletion of protective PGs in the GI mucosa rather than topical gastric injury) are responsible for NSAID-related toxicity.

10. Variability in Response to NSAIDs Drug Factors Dose-response Plasma half-life Protein binding Enantiomeric conversion Urinary excretion Pharmacodynamic variation Patient Factors “Responders” vs. “nonresponders” Varying disease pathology Differences in incidence of adverse reactions Patient preferences The choice of NSAID in OA or RA is complicated by the wide variability in clinical response to these agents among individual patients, even those receiving fixed doses of chemically similar compounds. Although the exact cause of this variability is not certain, several pharmacologic factors related to NSAIDs as well as interpatient differences may be involved. Drug-related factors affecting the variation in response to NSAIDs include dose-response, protein binding, the metabolic profile of the drug (half-life, urinary excretion, activation of enantiomers [isomers], etc.), and pharmacodynamic variation. Individual patients also differ in their response to particular NSAIDs, with some patients termed “responders” and others termed “nonresponders.” Factors affecting the individual response of a patient to a particular NSAID include: variations in disease pathology, differences in the incidence of adverse effects, and interpatient variation in preferences for particular NSAIDs.The choice of NSAID in OA or RA is complicated by the wide variability in clinical response to these agents among individual patients, even those receiving fixed doses of chemically similar compounds. Although the exact cause of this variability is not certain, several pharmacologic factors related to NSAIDs as well as interpatient differences may be involved. Drug-related factors affecting the variation in response to NSAIDs include dose-response, protein binding, the metabolic profile of the drug (half-life, urinary excretion, activation of enantiomers [isomers], etc.), and pharmacodynamic variation. Individual patients also differ in their response to particular NSAIDs, with some patients termed “responders” and others termed “nonresponders.” Factors affecting the individual response of a patient to a particular NSAID include: variations in disease pathology, differences in the incidence of adverse effects, and interpatient variation in preferences for particular NSAIDs.

11. Pros and Cons of Intra-articular Glucocorticoids Pros Potent local anti-inflammatory effect Symptomatic relief Cons Short-term benefit Requires a procedure Risk of postinjection flare or infection Potential for cartilage breakdown Intra-articular injection of glucocorticoids may be a useful adjunct treatment for local flares. While the improvement associated with intra-articular corticosteroids may be rapid and dramatic, the benefits of these agents are short-lived. Many physicians are experienced in injecting glucocorticoids into the knee. However, for joints other than the knee, it may be preferable for a rheumatologist, orthopedist, or radiologist to perform the injection while using fluoroscopic guidance. There is a small risk (5%) of postinjection flare due to crystal-induced synovitis. Infection also may occur, but it is extremely rare. Intra-articular injections of corticosteroids given more than 3-4 times per year in any given joint may be associated with cartilage breakdown.Intra-articular injection of glucocorticoids may be a useful adjunct treatment for local flares. While the improvement associated with intra-articular corticosteroids may be rapid and dramatic, the benefits of these agents are short-lived. Many physicians are experienced in injecting glucocorticoids into the knee. However, for joints other than the knee, it may be preferable for a rheumatologist, orthopedist, or radiologist to perform the injection while using fluoroscopic guidance. There is a small risk (5%) of postinjection flare due to crystal-induced synovitis. Infection also may occur, but it is extremely rare. Intra-articular injections of corticosteroids given more than 3-4 times per year in any given joint may be associated with cartilage breakdown.

12. Pros and Cons of Intra-articular Hyaluronic Acid Therapy Pros Reduces knee pain in OA More effective than Placebo injection Single steroid injection Cons Requires weekly injections for 3 to 5 weeks Further research needed Long-term efficacy/safety Best candidates A therapy that shows promise in relieving pain associated with OA of the knee is the intra-articular injection of hyaluronic acid, a compound that binds proteoglycan molecules to form macromolecular aggregates. Findings from double-blind, randomized, placebo-controlled trials have suggested greater efficacy for intra-articular hyaluronic acid injections than placebo in reducing knee pain. Efficacy superior to that of single injections of intra-articular steroids has also been demonstrated. It is uncertain which OA patients are most likely to benefit from intra-articular hyaluronic acid injections. Patients must receive weekly injections for 3 to 5 weeks, so there may be less compliance with this treatment regimen.A therapy that shows promise in relieving pain associated with OA of the knee is the intra-articular injection of hyaluronic acid, a compound that binds proteoglycan molecules to form macromolecular aggregates. Findings from double-blind, randomized, placebo-controlled trials have suggested greater efficacy for intra-articular hyaluronic acid injections than placebo in reducing knee pain. Efficacy superior to that of single injections of intra-articular steroids has also been demonstrated. It is uncertain which OA patients are most likely to benefit from intra-articular hyaluronic acid injections. Patients must receive weekly injections for 3 to 5 weeks, so there may be less compliance with this treatment regimen.

13. 1996 ACR Guidelines for the Management of RA Ultimate goal Remission (rarely achieved) Management goals Control disease activity Alleviate pain Maintain function Maximize QOL Slow joint damage According to the 1996 ACR guidelines for the management of RA (currently being revised), the ultimate goal is to achieve complete remission of the disease. This is rarely achieved, and the ACR has therefore compiled a list of management goals for RA. These management goals include controlling disease activity, alleviating pain, maintaining function so that the patient can continue activities of daily living and work, maximizing quality of life (QOL), and slowing the rate of joint damage as much as possible. According to the 1996 ACR guidelines for the management of RA (currently being revised), the ultimate goal is to achieve complete remission of the disease. This is rarely achieved, and the ACR has therefore compiled a list of management goals for RA. These management goals include controlling disease activity, alleviating pain, maintaining function so that the patient can continue activities of daily living and work, maximizing quality of life (QOL), and slowing the rate of joint damage as much as possible.

14. Modified Therapeutic Pyramid for RA The ACR’s 1996 guidelines for managing RA challenged the traditional treatment pyramid for RA. Previously, initial therapy consisted of analgesics, NSAIDs, and nonpharmacologic modalities to minimize dysfunction. Pharmacologic therapy was introduced in a sequential manner, with DMARDs added only after RA had progressed for several years. The modified therapeutic pyramid calls for earlier and more aggressive use of disease-modifying agents to delay joint damage and dysfunction. Once the diagnosis of RA has been established through history and physical examination and supported by laboratory and radiologic findings, disease severity dictates the progression from NSAIDs to low-dose corticosteroids, DMARDs, and experimental therapies. Treatment (combined pharmacologic and nonpharmacologic) is stepped up or down as necessary.The ACR’s 1996 guidelines for managing RA challenged the traditional treatment pyramid for RA. Previously, initial therapy consisted of analgesics, NSAIDs, and nonpharmacologic modalities to minimize dysfunction. Pharmacologic therapy was introduced in a sequential manner, with DMARDs added only after RA had progressed for several years. The modified therapeutic pyramid calls for earlier and more aggressive use of disease-modifying agents to delay joint damage and dysfunction. Once the diagnosis of RA has been established through history and physical examination and supported by laboratory and radiologic findings, disease severity dictates the progression from NSAIDs to low-dose corticosteroids, DMARDs, and experimental therapies. Treatment (combined pharmacologic and nonpharmacologic) is stepped up or down as necessary.

15. Pros and Cons of Oral Glucocorticoids in RA Pros Treat flares Minimize/control disease activity Cons Greater toxicity with higher doses, longer duration Discontinuation difficult Low-dose oral glucocorticoids control disease activity and help improve function, and are typically used in combination with an NSAID and at least one DMARD. Toxicities associated with systemic steroids (osteoporosis, cataracts, weight gain, hypertension, development of cushingoid facies, diabetes, atherosclerosis, increased susceptibility to infection, a vascular necrosis, myopathy, and psychosis) are more likely with higher doses and longer duration of treatment. In addition, there are potential difficulties associated with the discontinuation of prednisone in patients with active RA and abrupt cessation of prednisone after long-term use. Low-dose oral glucocorticoids control disease activity and help improve function, and are typically used in combination with an NSAID and at least one DMARD. Toxicities associated with systemic steroids (osteoporosis, cataracts, weight gain, hypertension, development of cushingoid facies, diabetes, atherosclerosis, increased susceptibility to infection, a vascular necrosis, myopathy, and psychosis) are more likely with higher doses and longer duration of treatment. In addition, there are potential difficulties associated with the discontinuation of prednisone in patients with active RA and abrupt cessation of prednisone after long-term use.

16. Overview of DMARDs DMARDs can potentially prevent or reduce joint damage, and early initiation of DMARD therapy is now recommended for RA patients unresponsive to NSAIDs. While these agents share many characteristics, including relatively slow onset of clinical response and relative efficacy, there are differences among DMARDs in convenience, toxicity, and cost. Specific guidelines for monitoring individual DMARDs were established by the ACR in 1996, with the goal of preventing potential adverse effects and fostering the safe use of these drugs. Potential adverse effects vary with individual agents, as indicated in this chart. For example, the major (albeit infrequent) toxicity associated with antimalarial agents such as hydroxychloroquine (HCQ) is retinopathy; GI and cutaneous toxicities are rare and less serious adverse effects. Common, but less serious, toxicities associated with methotrexate (MTX) include GI disturbances and mucositis.DMARDs can potentially prevent or reduce joint damage, and early initiation of DMARD therapy is now recommended for RA patients unresponsive to NSAIDs. While these agents share many characteristics, including relatively slow onset of clinical response and relative efficacy, there are differences among DMARDs in convenience, toxicity, and cost. Specific guidelines for monitoring individual DMARDs were established by the ACR in 1996, with the goal of preventing potential adverse effects and fostering the safe use of these drugs. Potential adverse effects vary with individual agents, as indicated in this chart. For example, the major (albeit infrequent) toxicity associated with antimalarial agents such as hydroxychloroquine (HCQ) is retinopathy; GI and cutaneous toxicities are rare and less serious adverse effects. Common, but less serious, toxicities associated with methotrexate (MTX) include GI disturbances and mucositis.

17. Overview of DMARDs (cont’d)

18. Overview of DMARDs (cont’d) The most common side effects of D-penicillamine are rash, stomatitis, and dysgeusia. Other signficant but rare toxicities include proteinuria, nephrotic syndrome, and autoimmune disease.The most common side effects of D-penicillamine are rash, stomatitis, and dysgeusia. Other signficant but rare toxicities include proteinuria, nephrotic syndrome, and autoimmune disease.

19. Overview of DMARDs (cont’d) Various toxicities requiring monitoring are associated with cyclosporine and azathioprine. Laboratory tests and system review/examination are recommended to avoid these toxicities. Leflunomide and etanercept also require monitoring. Leflunomide, a pyrimidine synthesis inhibitor, is associated with such adverse effects as weight loss and alopecia. Etanercept, an anticytokine drug, has been reported in postmarketing studies to cause serious infections and sepsis, sometimes within a few weeks of instituting therapy. The incidence of injection site reactions associated with etanercept is about 37%. Based on an analysis of the toxicities of various DMARDs, it has been suggested that HCQ and MTX possess the most favorable efficacy-to-toxicity ratios. Various toxicities requiring monitoring are associated with cyclosporine and azathioprine. Laboratory tests and system review/examination are recommended to avoid these toxicities. Leflunomide and etanercept also require monitoring. Leflunomide, a pyrimidine synthesis inhibitor, is associated with such adverse effects as weight loss and alopecia. Etanercept, an anticytokine drug, has been reported in postmarketing studies to cause serious infections and sepsis, sometimes within a few weeks of instituting therapy. The incidence of injection site reactions associated with etanercept is about 37%. Based on an analysis of the toxicities of various DMARDs, it has been suggested that HCQ and MTX possess the most favorable efficacy-to-toxicity ratios.

20. Major Limitations of Historic Therapies for RA NSAIDs Serious GI toxicity Glucocorticoids Dose/duration/adverse-effect limitations DMARDs Slow onset Immunosuppression While there is no known cure for RA or means of preventing it, there is evidence that early aggressive treatment may alter the course of this debilitating disease. The majority of patients with RA receive an NSAID and one or more DMARDs, with or without low-dose oral glucocorticoids. The major limitations of these existing regimens—the potential for serious GI toxicity of NSAIDs, the adverse effects of systemic use of glucocorticoids, and the immunosuppression associated with DMARDs—have prompted intensive efforts to develop safer anti-inflammatory and disease-modifying therapies for RA.While there is no known cure for RA or means of preventing it, there is evidence that early aggressive treatment may alter the course of this debilitating disease. The majority of patients with RA receive an NSAID and one or more DMARDs, with or without low-dose oral glucocorticoids. The major limitations of these existing regimens—the potential for serious GI toxicity of NSAIDs, the adverse effects of systemic use of glucocorticoids, and the immunosuppression associated with DMARDs—have prompted intensive efforts to develop safer anti-inflammatory and disease-modifying therapies for RA.