New Device for Knee OA

This is a recent article form eRheumatology News. The evidence of improvement not only in symptoms but also in Xray changes and delay to joint replacement is welcome news. The device appears to be safe, something I cannot say for most non-steroidal anti-inflammatory drugs (NSAIDs)

Volume 6, Issue 8, Page 22 (August 2007)

Douglas Garland, MD

DR. GARLAND is the director of the division of neurotrauma at Rancho Los Amigos Medical Center in Downey, Calif.

For patients with knee osteoarthritis in whom treatment with analgesics and nonsteroidal anti-inflammatory drugs are insufficient or intolerable, pulsed electrostimulation is a safe, effective, noninvasive option for reducing pain and improving function, and it may even reduce the need for total knee arthroplasty, according to Dr. Douglas Garland, the director of the division of neurotrauma at the Rancho Los Amigos Medical Center in Downey, Calif.
In a randomized, double-blind placebo-controlled trial, Dr. Garland and colleagues evaluated the safety and efficacy of a capacitively coupled, pulsed electrical stimulation (PES) device in 58 outpatients with moderate to severe osteoarthritis of the knee. Study participants were directed to use the active treatment device—a wrap-around knee garment with flexible, embedded electrodes that deliver small electrical currents of 0- to 12-volt output to the affected area—or the placebo device at home for 6–14 hours per day. After 3 months, the active treatment group had greater improvement than controls in a patient global evaluation, patient report of knee pain, and the Western Ontario and McMaster Universities questionnaire. The treatment group had 51% greater improvement in patient global scores, 31% in patient pain, 25% in WOMAC stiffness, 30% in WOMAC function, 20% in WOMAC pain, and 27% in total WOMAC scores. Additionally, substantially more patients in the treatment group had improvement by more than 50% on all measures (Osteoarthritis Cartilage 2007;15:630–7). Dr. Garland was the lead investigator for this study, which was funded by BioniCare Medical Technologies Inc., maker of the device.
Although the precise mechanism by which pulse electrostimulation acts on the human knee is unknown, “three decades of in vitro and animal research provide compelling evidence for a positive local effect on chondrocyte function through gene regulation,” the authors wrote. In this month's column, Dr. Garland discusses the clinical application and promise of pulsed electrostimulation.
Rheumatology News: What are some hypotheses for the improvements associated with PES treatment?
Dr. Garland: There are at least three mechanisms that can be observed clinically when one uses PES. First, in some patients, there is a dramatic reduction in their pain within 1 month after treatment is initiated. This could be the result of a reduction of cartilage degradative enzymes such as interleukin-1 and matrix metalloproteinases and consequent decrease in the inflammatory response, a blockage of the inflammatory response itself, or both. Second, in some patients, radiographs demonstrate an increase in joint space at 3 months. This is most likely secondary to the PES influencing or mimicking the negatively charged aggrecan molecule and attracting positive counter ions, such as sodium. The net effect will be swelling of the articular space and an increase in joint space radiographically. Finally, some patients have late, long-term radiographic increases in their joint space.
We have demonstrated new cartilage by biopsy in one of these patients. This is most likely the result of stimulation of the chondrocytes leading to the upregulation of cell proliferation and matrix synthesis.
RN: Which patients are most likely to benefit from PES therapy?
Dr. Garland: All patients potentially may respond to this treatment modality. One of my most gratifying results occurred in a retired female physician in her 80s who had leukemia and was not a surgical candidate. She was bedridden with constant pain. With bilateral treatment her pain was controlled and she became ambulatory with assistive devices.
RN: Are there any patients for whom the treatment is not appropriate?
Dr. Garland: Treatment is appropriate for all patients. As a surgeon, I recommend surgery [vs. PES] for patients who are more likely to experience future deterioration [at a faster rate] because of medical conditions. A patient's support system may determine whether surgery is an option: PES requires weeks to months of treatment for optimal pain relief, and the device can be bothersome to use daily or nightly for so long. Medicare is now pays for [PES] and most carriers may eventually follow its lead.
RN: Are there objective measures of improvement associated with PES?
Dr. Garland: I have assessed improvement with x-ray and gait analysis.
RN: How does PES compare with other types of electrical stimulation therapy?
Dr. Garland: Percutaneous neuromodulation pain devices control pain; they do not alter the disease. Another option, pulsed electromagnetic stimulation, has not yet been shown to have a stimulatory effect on damaged articular cartilage.
By Diana Mahoney, New England Bureau

OA knee of a woman in her 50s is shown pretreatment (left) and after 9 months of PES (right). Photos courtesy Dr. Douglas Garland

Dispelling Myths About Steroid Joint Injections

This is an article published in the Bulletin on the Rheumatic Diseases. It provides a good, consice reivew of the evidence supporting use of steroid injections into the joints. While somewhat technical, it dispells many of the myths that are propagated in the community. Sadly, many physicians are at fault of perpetuating these myths. Evidence Based Medicine supports the use and safety of this form of treatment in various rheumatic syndromes. Enjoy!

Note: unfortunately, the BRD is no longer an active publication. However, you can access some of the previous publications at http://www.arthritis.org/research/bulletin/archives.asp


The Rational Use of Steroid Injections in Arthritis and Nonarticular Musculoskeletal Pain Syndromes

Volume 52, Number 1

Christopher Wise, MD
Division of Rheumatology
Medical College of Virginia
Virginia Commonwealth University Health System
Richmond, VA

Summary Points
Local steroid injections may have lasting benefit when used in one or two involved joints in
rheumatoid arthritis, inflammatory oligoarthritis, peripheral joints in ankylosing spondylitis, juvenile rheumatoid arthritis, and crystal-induced arthritis.

Local steroid injections have short-term benefit in the involved knee of osteoarthritis, painful
shoulder, lateral epicondylitis, and carpal tunnel syndrome.

There is no documented benefit from trigger point injections.

Introduction

The injection of joints and periarticular structures with corticosteroids is commonly used by rheumatologists, orthopedists, and other practitioners to treat musculoskeletal pain. Few procedures in medical practice have the potential to be as effective in achieving symptomatic relief. Surveys have estimated that a majority of internists finishing their residency training feel a need for more training in these procedures.

In 1950, Hollander first reported transient improvement in patients with rheumatoid arthritis injected with cortisone. By the early 1960s, he had reported a series of more than 100,000 injections of joints, bursae, and tendon sheaths in patients (1). Aspiration and therapeutic injection of joints and periarticular tissues has become a common and essential part of rheumatology practice.

The evidence to support the efficacy of injections is mostly anecdotal or based on uncontrolled or retrospective observations.

In general, localized conditions are more amenable to injection than are generalized conditions, and inflammatory types of arthritis are more likely to benefit than noninflammatory or degenerative conditions.

The Clinical Evidence for Efficacy of Steroid Injections
Inflammatory arthritis: Therapeutic injection of corticosteroids is probably most effective in one or two joints affected by inflammatory arthritis. Most of the experience in this area has been reported in rheumatoid arthritis and juvenile rheumatoid arthritis. Anecdotal experience has been reported in crystal-induced arthritis, the spondyloarthropathies, and less common conditions such as systemic lupus and sarcoidosis.

In rheumatoid arthritis, injections are used in individual joints and are adjunctive to disease-modifying drug therapy. Most of Hollander’s early reports suggested long-lasting relief in a vast majority of joints injected, with improvement lasting several months in most patients. In 1972, McCarty reported that injections in the small joints of the hands and wrists resulted in remission in 88% of patients for an average of 22 months, much better than comparable joints not injected in the opposite hands of the same patients (2). In a subsequent report on 956 injections in 140 patients followed for an average of 7 years, 75% of injected joints remained in remission (3). In this series, patients received about 2 injections during the first year of treatment and averaged 0.6 injections per patient-year for the next 15 years.

Corticosteroid injection is considered to be a safe and effective option for prompt relief of acute crystal-induced arthritis, both in gout and pseudogout. In most published series of patients with gout, intraarticular steroids have been successful in relieving pain and swelling completely in over 95% of patients within 48 hours.

Patients with inflammatory oligoarthritis, without definitive diagnosis, can be treated with local steroid injections, and the response to these injections can be used as a prognostic marker. In a series of 51 patients with recent onset inflammatory arthritis involving 5 or fewer joints, injecting all joints with clinical synovitis resulted in improvement in all patients and a complete resolution of synovitis at 2 weeks in 57% of patients. The response at 2 weeks was the best predictor of a continued improvement that persisted for 6 to12 months (4).

Patients with refractory sacroiliac joint pain related to ankylosing spondylitis or other spondyloarthropathies may benefit from injection of the sacroiliac joints. These injections require radiographic confirmation of needle placement in the joint space. In uncontrolled studies, a good response has been reported in roughly 80% of injections, with an average time of improvement of 6 to 9 months, and one study has shown slight benefit of steroid compared to placebo injection.

Joint injection has been utilized with increasing frequency in recent years in juvenile rheumatoid arthritis, particularly in the pauciarticular variant. Complete remission lasting over 6 months has been reported in roughly 65% to 80% of joints injected, most commonly in the knees (5).

Benefit also has been demonstrated in smaller numbers of ankles, wrists, shoulders, elbows, and hips, with a majority of children being able to stop oral medications, and correction of joint contracture noted. One study demonstrated a significant decrease in leg length discrepancy in a population of children treated with repeated injections (average of 3.25 injections per child over 42 months), compared to a population in another center not injected (6).

Osteoarthritis: Clinical studies that support efficacy of steroid injections in osteoarthritis suggest a less predictable and smaller degree of response than in inflammatory arthritis (7). In controlled studies, most benefit compared to placebo seems to last 1 to 6 weeks, with return to the same pain levels seen in placebo groups by around 12 weeks after injection. Factors associated with a better response to steroid injections have included less severe radiographic changes, the presence of effusion at the time of injection, and successful aspiration of fluid at the time of injection.

Injections are not usually performed in patients with osteoarthritis of the hip due to the technical difficulty of accurate needle placement. Reports of response to hip injections, under fluososcopic guidance, suggest a response that lasts for up to 8 to 12 weeks in a majority of patients with milder disease.

Nonarticular conditions: Few controlled studies to support the efficacy of “trigger point injections” have been published. A recent review of 23 papers dealing with trigger-point injections concluded that none of the trials were of sufficient quality to demonstrate or refute the efficacy of any needling technique beyond placebo in the treatment of myofascial pain (8).

Steroid injections are of benefit in the initial management of rotator cuff tendinitis, frozen shoulder, and other causes of shoulder pain. Most controlled studies have demonstrated significant improvement from steroid injection compared to placebo injection, usually lasting up to 4 to 6 months (9).

Local steroid injections also are usually of benefit in the treatment of lateral epicondylitis (tennis elbow). Controlled studies typically document improvement of 90% compared to 50% in placebo treatment in the first month or two after injection, but outcomes at 6 to 12 months are usually not affected (10).

In femoral trochanteric pain syndromes (ie, bursitis), the response rate to locally injected steroids has been reported to be in the 60% to 100% range, with improvement lasting up to 26 weeks in a majority, but no placebo-controlled studies have been done.

Around the knee, anecdotal and retrospective studies have shown that a majority of patients with anserine bursitis, synovial plicas, and other types of periarticular knee pain respond to local steroid injection, but no controlled studies have been done in these conditions.

In carpal tunnel syndrome, most studies report up to 90% short-term relief of symptoms from a single injection, but longer-term relief ranges from 20% to 90%. Surgery is eventually required in about half of patients treated with injection. A good response to local injection is sometimes useful as a diagnostic test and is a predictor of good surgical response.

In prospective studies of patients with de Quervain’s tenosynovitis, 60% to 76% of patients have been adequately controlled with a single injection, and another 10% to 33% required a second injection. About 30% had exacerbations an average of one year later, but only 10% to 17% of patients required surgical release. A small controlled study demonstrated that injection was much better than splinting (11). Similar success rates have been reported in patients with flexor tenosynovitis (trigger fingers) and ganglion cysts.

In general, the response in tarsal tunnel syndrome is usually temporary, while that in Morton’s neuroma is more often prolonged. Reported response rates for plantar fasciitis are variable, but one controlled trial has shown a significant improvement at 1 month compared to placebo but no different from placebo at 3 months (12).

Local injections for neck pain and low back pain have been used for a number of years, but controlled or prospective studies have shown variable results, depending on patient selection and methodology. Most studies of radiographically assisted facet joint injection of steroids in the lumbar or cervical areas show no difference compared to placebo, facet block, or local paraspinous injections. Injections of the sacroiliac joint in patients with non-inflammatory pain have shown a slight benefit from steroids compared to lidocaine alone.

Contraindications to Corticosteroid Injection
Contraindications to diagnostic arthrocentesis and injection are few. Established infection, such as a cellulitis, in the area of the joint is considered to be an absolute contraindication to inserting a needle into a joint. However, if inflammation in an underlying joint or bursa is felt to be the cause of the appearance of infection, then aspiration of the joint or bursa should be attempted.

The risk of introducing blood-borne bacteria into a joint is possible, but such complications are not well-documented. Arthrocentesis through an area of irregular or disrupted skin, as seen in psoriasis, should be avoided due to the increased numbers of colonizing bacteria in these areas.

Caution should be exercised in patients with bleeding disorders or those taking anticoagulants. However, the risk of significant hemarthrosis after arthrocentesis is low, even in patients on regular warfarin therapy with INR levels up to as high as 4.5 (13).

Complications
Iatrogenic infection is the most serious but least common complication of arthrocentesis and joint injection. In Hollander’s earlier large series, an incidence of infection of 0.005% was reported in a series of 400,000 injections (14). Subsequent series have noted a frequency of infection from 1:2,000 to 1:10,000, with higher rates noted in patients with rheumatoid arthritis, occurring almost exclusively in debilitated patients on immunosuppressive therapy.

A recent study suggested that inserting a needle into the joint carries a small fragment of skin into the joint space in most cases, with identifications of bacterial nucleic acide by polymerase chain reaction in about a third of these (15). Considering the rarity of joint infection after arthrocentesis, these findings suggest that bacteria introduced at the time of arthrocentesis are either not viable or quickly cleared in almost all cases.

The most common complications of local steroid injections are related to local irritation of synovial and subcutaneous tissues and atrophy of soft tissues related to the effects of locally injected steroids. Postinjection “flare” may develop in 1% to 6% of patients a few hours after injection and may last up to 48 hours.

Weakening of tendons and tendon rupture also have been reported as a result of locally injected steroids, emphasizing the importance of avoiding direct injection of steroids into the body of tendons. Most reports of tendon rupture have been anecdotal. The risk of tendon rupture is low in the hands and wrists, where tendon rupture has been seen in less than 0.2% in most series. The highest risk for rupture seems to occur in area of the Achilles tendon and plantar fascia, where the risk of rupture after steroid injection has been estimated to be as high as 10% (16).

Systemic absorption invariably occurs with locally injected depot corticosteroids. Studies have documented a decrease in plasma cortisol and suppression of the hypothalamic-pituitary axis lasting from 2 to 7 days after a single injection. In addition, a single injection of triamcinolone in knees of rheumatoid arthritis patients causes a marked reduction in serum markers of bone formation within a day of injection, which returns to normal levels in 14 days, but no change in bone resorption markers, suggesting a potential transient, adverse effect on bone density (17).

Some patients experience prominent erythema, warmth, and diaphoresis of the face and torso within minutes to hours after steroid injections. This is most likely related to systemic absorption, but idiosyncratic reaction to preservatives in steroid preparations also has been implicated. Similarly, some patients may experience other typical metabolic effects of systemic steroids, such as transient rises in blood glucose or decreases in peripheral blood eosinophil or lymphocyte counts.

Avascular necrosis of bone (ischemic necrosis) has long been considered a potential complication of intraarticular steroids, with a reported prevalence of this complication in injected joints ranging from less than 0.1% up to 3%. However, most studies have suggested that the occurrence of this complication is more related to the severity of the associated disease or systemic steroid therapy, rather than to local steroid injection.

The potential for negative effects of locally injected corticosteroids on cartilage metabolism has been controversial. Anecdotal reports of Charcot-like arthropathy attributed to intraarticular steroids first appeared in the late 1950s and 1960s in patients receiving large numbers of injections. Studies in the 1960s and 1970s demonstrated that locally injected steroids caused negative effects in normal animal cartilage, including decreased protein and matrix synthesis, degenerative changes in chondrocytes, and fissures in cartilage matrix. However, similar studies done in primate joints failed to show any negative effects from intraarticular corticosteroids. In addition, studies done in subsequent years have demonstrated protective effects on cartilage lesions and reduction in osteophyte development in animal models of experimentally induced osteoarthritis and some decrease in macrophage infiltration has been demonstrated in humans.

More recent observations in patients with oligoarticular juvenile rheumatoid arthritis suggest that frequent steroid injections have the potential to help protect cartilage from the destructive process of the underlying disease process, and are not associated with negative effects on articular cartilage. In addition, a study of patients with rheumatoid arthritis has shown no increase in the need for subsequent joint replacement surgery in the joints receiving four or more injections in a one-year period of time (18).

General Arthrocentesis Technique and Other Measures
Approaching the joint for aspiration and injection. Sterile technique designed to avoid the introduction of skin bacteria into the joint should be observed in all procedures. Aspiration of fluid prior to steroid injection will increase the degree and duration of efficacy of most of injections. A study of 191 knee injections in patients with rheumatoid arthritis showed that aspiration of fluid reduced the rate of relapse to 23% within a 6-month period compared to 47% in joints not aspirated (19).

Postprocedure instructions and care. Most practitioners advise restricted activities after steroid injections, particularly in weight-bearing joints, but opinions vary and no specific regimen of rest would be considered standard practice. In a large series reported in 1995, McCarty et al used a regimen that emphasized 3 weeks of splinting for upper extremity joints and 6 weeks of crutch walking for lower extremity joints, suggesting that rest after the injection was important in prolonging the effect of injections (3).

One small controlled study showed that rest provided no advantage over regular activities in regard to short- or long-term outcomes. However, in a larger prospective controlled trial of knees in patients with rheumatoid arthritis, a 24-hour period of strict bed rest after injection resulted in a more prolonged improvement that persisted for 6 months compared to patients that were not restricted (20).

Summary
The injection of joints and periarticular structures with corticosteroids continues to be one of the most effective means of short-term treatment of pain. The most benefit has been documented in rheumatoid arthritis and other forms of inflammatory arthritis, but a response is often seen in osteoarthritis for shorter periods of time. Steroid injections are also very effective in the management of painful shoulders, elbows, wrists, and hip girdle areas. Steroid injections for articular syndromes are safe with a relatively low risk of adverse reactions, most of which are self-limited.

References
1. Hollander JL. Intrasynovial corticosteroid therapy: a decade of use. Bull Rheum Dis 1961;11:239-240.

2. McCarty DJ. Treatment of rheumatoid joint inflammation with triamcinolone hexacetonide. Arthritis Rheum 1972;15:157-73.

3. McCarty DJ, Harman JG, Grassanovich JL, Qian C. Treatment of rheumatoid joint inflammation with intrasynovial triamcinolone hexacetonide. J Rheumatol 1995;22:1631-5.

4. Green M, Marzo-Ortega H, Wakefield RJ, et al. Predictors of outcome in patients with oligoarthritis: results of a protocol of intraarticular cortico-steroids to all clinically active joints. Arthritis Rheum 2001;44:1177-83.

5. Padeh S, Passwell JH. Intraarticular corticosteroid injection in the management of children with chronic arthritis. Arthritis Rheum 1998;41:1210-4.

6. Sherry DD, Stein LD, Reed AM, Schanberg LE, Kredich DW. Prevention of leg length discrepancy in young children with pauciarticular juvenile rheumatoid arthritis by treatment with intraarticular steroids. Arthritis Rheum 1999;42:2330-4.

7. Creamer P. Intra-articular corticosteroid treatment in osteoarthritis. Curr Opin Rheumatol 1999;11:417-21.

8. Cummings TM, White AR. Needling therapies in the management of myofascial trigger point pain: a systematic review. Arch Phys Med Rehabil 2001;82:986-92.

9. Green S, Buchbinder R, Glazier R, Forbes A. Systematic review of randomised controlled trials of interventions for painful shoulder: selection criteria, outcome assessment, and efficacy. Bmj 1998;316:354-60.

10. Smidt N, van der Windt DA, Assendelft WJ, Deville WL, Korthals-de Bos IB, Bouter LM. Corticosteroid injections, physiotherapy, or a wait-and-see policy for lateral epicondylitis: a randomised controlled trial. Lancet 2002;359:657-62.

11. Avci S, Yilmaz C, Sayli U. Comparison of nonsurgical treatment measures for de Quervain’s disease of pregnancy and lactation. J Hand Surg [Am] 2002;27:322-4.

12. Crawford F, Atkins D, Young P, Edwards J. Steroid injection for heel pain: evidence of short-term effectiveness. A randomized controlled trial. Rheumatology (Oxford) 1999;38:974-7.

13. Thumboo J, O’Duffy JD. A prospective study of the safety of joint and soft tissue aspirations and injections in patients taking warfarin sodium. Arthritis Rheum 1998;41:736-9.

14. Hollander JL. Intrasynovial corticosteroid therapy in arthritis. Md State Med J 1970;19:62-6.

15. Glaser DL, Schildhorn JC, Bartolozzi AR, et al. Do you really know what is on the tip of your needle? The inadvertant introduction of skin into the joint (abstract). Arthritis Rheum 2000; 43:S149.

16. Acevedo JI, Beskin JL. Complications of plantar fascia rupture associated with corticosteroid injection. Foot Ankle Int 1998;19:91-7.

17. Emkey RD, Lindsay R, Lyssy J, Weisberg JS, Dempster DW, Shen V. The systemic effect of intraarticular administration of corticosteroid on markers of bone formation and bone resorption in patients with rheumatoid arthritis. Arthritis Rheum 1996;39:277-82.

18. Roberts WN, Babcock EA, Breitbach SA, Owen DS, Irby WR. Corticosteroid injection in rheumatoid arthritis does not increase rate of total joint arthroplasty. J Rheumatol 1996;23:1001-4.

19. Weitoft T, Uddenfeldt P. Importance of synovial fluid aspiration when injecting intra-articular corticosteroids. Ann Rheum Dis 2000;59:233-5.

20. Chakravarty K, Pharoah PD, Scott DG. A randomized controlled study of post-injection rest following intra-articular steroid therapy for knee synovitis. Br J Rheumatol 1994;33:464-8.

AHA Updates NSAID Advice for Heart Disease Patients

From Medscape Medical News
February 28, 2007 — The American Heart Association (AHA) has issued new guidance discouraging the use of both cyclooxygenase 2 (COX-2) inhibitors and regular nonsteroidal anti-inflammatory drugs (NSAIDs) in patients with known heart disease or those thought to be at high risk of getting heart disease.

The statement, published online in the February 26 Rapid Access issue of Circulation, recommends a new stepwise approach to the treatment of musculoskeletal pain in such patients, starting with nonpharmacologic treatments, such as physical therapy and exercise, weight loss to reduce stress on joints, and heat or cold therapy. If this does not provide enough pain relief, acetaminophen, aspirin, and even short-term use of narcotic analgesics are recommended as first-line drugs. Then, NSAIDs with the lowest COX-2 selectivity should be used next, and the more selective COX-2 inhibitors should be placed at the bottom of the list and used only as a last resort.

The statement says that all drugs should be used at the lowest dose necessary to control symptoms and prescribed for the shortest time possible.

The stepwise approach to pharmacologic therapy for musculoskeletal symptoms in patients with or at risk for cardiovascular disease includes the following drugs to be administered in this order:

Acetaminophen, tramadol, narcotic analgesics (short-term)

Nonacetylated salicylates

Non-COX-2 selective NSAIDs

NSAIDs with some COX-2 activity

COX-2 selective NSAIDs
Lead author of the AHA statement, Elliott Antman, MD, of the Brigham and Women's Hospital in Boston, Massachusetts, told heartwire that when using a NSAID, clinicians should start with naproxen as this is one of the least COX-2 selective agents. He said the available data suggest that naproxen has a neutral effect on the heart. "There haven't been that many trials with naproxen, so we don't know for sure, but the previous view that naproxen may be cardioprotective as it was associated with a lower rate of cardiac events than COX-2 inhibitors is now known to be wrong. We now know that COX-2 inhibitors definitely increase risk, and it appears that naproxen is neutral in this regard."

Once the decision is made to prescribe a NSAID, the statement says that several additional points should be considered. These include:

In patients at increased risk for thrombotic events, low-dose aspirin plus a proton-pump inhibitor could be added.

COX inhibitors can lead to impaired renal perfusion, sodium retention, and increases in blood pressure, which may contribute to their adverse cardiovascular effects. Therefore, renal function and blood pressure should be monitored in subjects taking COX-2 inhibitors, and extra caution should be exerted when these drugs are given to subjects with preexisting hypertension, renal disease, and heart failure.
The statement says that more data are also needed on the cardiovascular safety of conventional NSAIDs. But until such data are available, the use of any COX inhibitor, including over-the-counter NSAIDs, for long periods should only be considered in consultation with a clinician.

Now Enough Data to Make Firm Recommendations

Dr. Antman told heartwire that the AHA statement has been issued at the current time because there is now enough evidence to make some firm recommendations on the use of COX-2 inhibitors and NSAIDs in patients with or at risk for heart disease. "There have been several "advisories" and notes of caution issued on this subject during the past few years, but there have been numerous different reports on this issue, and there is confusion in the minds of both clinicians and patients about how to treat musculoskeletal pain in heart disease patients. The AHA feels it is important to have very clear guidance for clinicians on this and now is a good time to issue this guidance as we now have incontrovertible evidence that COX-2 inhibitors increase the risk of MI [myocardial infarction], and there is also now strong evidence to suggest that this is also a problem with regular NSAIDs," he commented.

Reasonable Approach for All Patients

Dr. Antman said that while the advice in this AHA statement is aimed particularly at the treatment of musculoskeletal pain in patients with or at high risk for heart disease and that patients at a low risk for heart disease can probably be treated more liberally, he would still recommend that this stepped-care strategy is a reasonable approach for all patients, as the patient's exact risk for heart disease is often unclear.

Hypertension — A Problem With All Painkillers?

Another study published in the February 26 issue of the Archives of Internal Medicine suggests that acetaminophen and aspirin, as well as NSAIDs, may increase the risk for hypertension. Referring to this article, Dr. Antman told heartwire that this is a separate concern that may be related to the inhibition of prostaglandins. "We know that NSAIDs can increase blood pressure. This is in addition to their pro-thrombotic effects. They have a double negative. While aspirin and acetaminophen may also have an effect on blood pressure, aspirin is known to be cardioprotective and acetaminophen appears to have neutral thrombotic effect."

Some Question Narcotics as First-Line Treatment

Heartwire asked a few cardiologists with an interest in this field and some rheumatologists for their thoughts on the AHA statement. While all appear to support the recommendation that COX-2 inhibitors should be last on the list, some experts have questioned the advice to give a narcotic before a non-COX-2 selective NSAID, particularly naproxen.

One to voice this opinion was cardiologist Scott Solomon, MD, of the Brigham and Women's Hospital in Boston, Massachusetts. "I think the recommendation of using narcotics in the short term prior to using non COX-2 selective NSAIDS will be quite controversial, and I will be surprised if the rheumatology community will concur with this. Overall, there are very little data on cardiovascular risk with non-selective NSAIDS, although that is not the same as saying there is no risk. Physicians need to weigh any potential cardiovascular risks of non-selective NSAIDs together with the clear increased risk of GI bleeding against risk of abuse with narcotics," he commented to heartwire.

Rheumatologist, Michael Weinblatt, MD, also of Brigham and Women's Hospital, concurred. "I totally agree with Dr Solomon's concerns about initial use of narcotics. It should also be noted that multiple different diseases are grouped in the musculoskeletal family including rheumatoid arthritis which is a systemic inflammatory disease with increased morbidity and mortality. I would not agree with the recommendations that initial therapy of that disease focus on non-pharmacologic approaches. In fact the initial approach of RA [rheumatoid arthritis] is institution of therapeutic doses of anti-inflammatory drugs and disease modifying therapies. The use of narcotics as an initial therapy for rheumatoid arthritis is not supported by the extensive rheumatology literature," he said.

Dr. Antman responds that it is important that clinicians read the entire scientific statement to appreciate the context in which the recommendations are being made. He notes that the statement makes it clear that both safety and efficacy should be considered and the least risky medication should be tried first. "Clearly, if a physician felt that even a short course of narcotic analgesics posed an unacceptable risk of abuse in a given patient, that would not be an appropriate option to consider in the first line of the stepped care approach. On the other hand it can be argued that a short course of narcotic analgesics in the appropriately chosen patient with known heart disease or who is at risk for heart disease may well be a more desirable early option to try rather than jumping quickly to riskier drugs such as those with more COX 2 selectivity," he said.

Adressing Dr. Weinblatt's comments, Dr. Antman says, "The focus of our statement was on the selection of oral drugs from a cardiovascular risk perspective rather than to provide guidelines for disease management to rheumatologists. Our statement is not at all inconsistent with the rheumatology guidelines that recommend topical agents and oral therapy for tendonitis/bursitis; topical and intra-articular agents and oral agents for noninflammartory conditions; and disease modifying therapies followed by oral agents in inflammatory conditions."

Naproxen an Exception?

Eric Topol, MD, who was one of the first to identify the cardiac problems with COX-2 inhibitors, also feels strongly that narcotics should not be given before naproxen. "I use naproxen as the first line agent since it has never been invoked as having cardiovascular toxicity. The data (in the AHA statement) indicting all NSAIDs is over the top in my opinion."

Dr. Antman responds that "The AHA statement provides a compilation of the latest available data on the more traditional NSAIDs and clearly shows an increased risk of CV [cardiovascular] events whether one is looking at randomized trials, observational studies, or registries. Most of the data as summarized in the table in the statement indicate a risk with ibuprofen or diclofenac. The available data on naproxen, a non-COX-2 selective NSAID, suggest it is probably neutral with respect to cardiovascular risk and therefore as per our recommendations indeed it should be tried prior to NSAIDs with some COX-2 activity and certainly before the COX-2 selective NSAIDs."

Others Support of AHA Stance

Other cardiologists contacted by heartwire were supportive of the AHA statement, even the recommendation for early use of narcotics. Harlan Krumholz, MD, described the statement as "an important distillation of the published literature," and Debabrata Mukherjee, MD, of the University of Kentucky, in Lexington, said he thought the stepwise approach advocated was "a very reasonable approach." Dr. Mukherjee added, "We still have concerns about coxibs and they should only be used as a last resort in patients with or at risk of heart disease. I think short term use of tramadol or narcotics prior to even naproxen is reasonable as we now understand the risks of even non-selective NSAIDs and the concern of an aspirin-NSAID interaction. Although one has to be judicious in using narcotics in individuals with prior history of drug or substance abuse and they should not be used for more than few weeks."

Circulation. Published online February 26, 2007.

The complete contents of Heartwire, a professional news service of WebMD, can be found at www.theheart.org, a Web site for cardiovascular healthcare professionals.

Learning Objectives for This Educational Activity

Upon completion of this activity, participants will be able to:
Describe the physiologic effects of COX inhibitors.
Identify current recommendations for the use of analgesics in musculoskeletal pain.
Clinical Context

The use of analgesics has become controversial, in part due to the possibility of cardiovascular events associated with COX. The 2 major COX isoenzymes are COX-1 and COX-2. COX-1 is expressed at a relatively constant rate in most tissues, whereas COX-2 production is increased with inflammation. Activation of both COX-1 and COX-2 increase the production of prostaglandin H2, which in turn serves as a precursor to prostacyclin, thromoboxane A2, and several other prostaglandins.

COX-2 expression is reduced in the gastrointestinal tract, which explains why analgesics that selectively inhibit COX-2 can reduce the relative risk for gastrointestinal tract bleeding compared with other COX inhibitors. The current advisory statement from the American Heart Association balances this benefit vs the possibility of increased cardiovascular risk associated with these medications.

Study Highlights

COX-2 inhibition can result in an increased risk for thrombosis due to increased activity of thromboxane A2 and reduced activity of prostacyclin. In addition, all NSAIDs can increase sodium and water retention, increasing the risk for exacerbations of hypertension and heart failure. Finally, COX-2 up-regulation may reduce myocardial ischemia and infarction during acute cardiac events, and inhibition of this isoenzyme can increase infarct size and lead to myocardial rupture.
"Nonselective" NSAIDs also differ with regard to COX selectivity. Diclofenac has greater COX-2 selectivity than ibuprofen, which in turn has greater COX-2 selectivity compared with naproxen.
Initial treatment of musculoskeletal pain should include nonpharmacologic therapy, including physical therapy, heat/cold, and orthotics. Acetaminophen and aspirin are probably the best initial choices for analgesia, although these agents should be used at the lowest possible dose for the shortest possible period.
For patients who fail conservative therapy for musculoskeletal pain, NSAIDs may be chosen as a next step. Clinicians and patients should realize that the use of NSAIDs may slightly increase the risk for cardiovascular and cerebrovascular events. With this in mind, clinicians should try to use NSAIDs with lower selectivity for COX-2.
Naproxen is probably the NSAID associated with the lowest risk for thrombosis. The Alzheimer's Disease Anti-inflammatory Prevention Trial (ADAPT) questioned the safety of naproxen, but this trial had significant limitations.
Patients with a history of gastrointestinal tract bleeding or who are at high risk for bleeding who require analgesia should be prescribed acetaminophen first. For these patients who require NSAID therapy, proton-pump inhibitors have been demonstrated to reduce the risk for recurrent gastrointestinal tract bleeding among patients receiving low-dose aspirin.
Patients with active atherosclerotic processes are at increased risk for the thromboembolic complications of COX-2 inhibitors. Renal function and blood pressure should be monitored during treatment with COX-2 inhibitors.
Ibuprofen, but not rofecoxib, acetaminophen, or diclofenac, appears to reduce the physiologic efficacy of aspirin in preventing thrombosis. Current recommendations call for delaying ibuprofen dosing until at least 30 minutes after taking aspirin or at least 8 hours prior to aspirin dosing.

Long-Term Adalimumab (Humira) Safe for Rheumatoid Arthritis Patients

NEW YORK (Reuters Health) Jul 10 - Long-term treatment of rheumatoid arthritis (RA) with adalimumab is generally safe and well tolerated, according to a report in the July issue of the Annals of the Rheumatic Diseases.
More than one million patients have been treated with tumor necrosis factor antagonists, including adalimumab, the authors explain, but safety concerns persist.
Dr. Michael H. Schiff from Denver Arthritis Clinic and colleagues analyzed safety data collected from adalimumab's early clinical trials in 1997 through 2005.
The rate of serious infections in the clinical trial safety database was 5.1 per 100 patient-years, the authors report, which "is similar to rates reported for the general RA population."
Since the initiation of tuberculosis screening, there have been 23 cases in Europe (0.33 cases/100 patient-years) and 4 cases in North America (0.08 cases/100 patient-years).
The rates of lymphoma after adalimumab exposure (0.21 cases/100 patient-years) were consistent with those reported for RA populations nave to anti-TNF therapy, the researchers note.
Rates of demyelinating disorders, systemic lupus erythematosus, and congestive heart failure have also been low in patients taking adalimumab, the report indicates.
"Analyses of safety data from adalimumab global clinical trials and US postmarketing reports show that adalimumab therapy is generally safe and well tolerated in patients with RA," the authors write.
The relatively low rates of these serious adverse adalimumab-associated events "do not appear to outweigh the substantial clinical benefits adalimumab offers the RA population," they conclude.
Ann Rheum Dis 2006;65:889-894.

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by rlp

This report is welcomed news regarding the long term safety of Adalimumab. As with any new therapy, once the medication is prescribed to the public at large new side effects may be identified that were not during the clinical studies. Such was the case when Etanercept (Enbrel) and Infliximab (Remicade) were approved. After the therapies were prescribed on a large scale, cases of severe Tuberculosis associated with these drugs were reported. In the case of Adalimumab, no surprises so far identified. There is now increase in comfort level for Adalimumbab.

NOF Scientific Statement on Osteonecrosis of the Jaw and Bisphosphonates

Osteonecrosis of the Jaw (ONJ)
June 14, 2006


What is it?

Recently reports have described a dental condition, ONJ, in which bone in the lower jaw or less commonly the upper jaw becomes exposed, typically after a dental extraction or some other trauma to the jaw, and the wound that occurs fails to heal in the usual time frame. Infection in the area can occur and the area may be painful. This can become a chronic problem in many of those who develop it. With careful dental management, use of antibiotics and daily rinsing of the mouth with antibiotic solutions some patients with the condition do experience healing over time.

Current information suggests that this condition appears to occur infrequently in patients with cancer and rarely in patients with benign conditions such as osteoporosis or Paget’s disease of bone who are being treated with bisphosphonate medications.

Of the cases reported to date, nearly 95% were cancer patients receiving an intravenous bisphosphonate, pamidronate (Aredia®) or zoledronate (Zometa®), typically given every three to four weeks. A very small number of patients being treated with the bisphosphonate pills alendronate (Fosamax®) or risedronate (Actonel®) for osteoporosis prevention or treatment have also been reported to have developed ONJ. Fosamax® and Actonel® have been available in the U.S. since 1995 and 1998, respectively, and have been used safely by many millions of patients.

Last year the U.S. Food and Drug Administration (FDA) decided that a statement about ONJ would be required in the safety information provided in the package inserts of all bisphosphonate products so that doctors and patients would have this information.


What are points to consider?

Whenever a medication is prescribed, it is important for the patient to understand both the benefits and the potential risks or side effects associated with that medication.

Fosamax® and Actonel® were approved by the FDA for use in the prevention and treatment of osteoporosis after extensive clinical studies found them to be generally well tolerated and effective in reducing bone loss to prevent osteoporosis and in reducing the likelihood of fractures in patients with osteoporosis.

Based on information available to date, the incidence of ONJ appears to be rare in people taking oral bisphosphonates. It is important however, that patients taking bisphosphonates continue to get regular dental check-ups and to let their dentist know about all the medications they take.

There are reports that some dentists are advising patients to stop the use of bisphosphonates for a period of time (e.g. a month or two) before and after a tooth extraction or implant surgery, but there is no clear evidence, at this time, as to whether this is necessary.


Summary

Based on the currently available information, NOF believes that the benefits of oral bisphosphonate medications outweigh the potential risk of ONJ in the vast majority of patients who are receiving them. Without these medications, patients for whom they are appropriate treatment would be at higher risk of fractures, and fractures are the source of significant pain and disability that impact on function and quality of life.



NOF encourages all osteoporosis patients taking oral bisphosphonates to discuss their individual situation with their doctor or other health care professional. As clinical information is still incomplete and the causes not fully understood, research into ONJ continues. As new information becomes available, NOF will be providing updates.



Reference:

Woo SB, Hellstein JW, Kalmar JR. Systematic review: bisphosphonates and osteonecrosis of the jaws. Annals of Internal Medicine. 2006 May 16;144(10):753-61.

http://www.nof.org/patientinfo/osteonecrosis.htm

Glucosamine: where are we now?

The GAIT trial (Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis) was recently published in the New England Journal of Medicine. The study was designed to answer the question of wether or not Glucosamine has any benefit in treating patients with osteoarthritis. It compared three treatment groups: Glucosamine, Chondroitin, Glucosamine and Chondroitin, Celebrex only, or placebo. The authors concluded that neither Glucosamine nor Chondroitin helped reduce pain in patients with osteoarthritis of the knee. However, a subgroup of patients with moderate to severe osteoarthritis may experience some benefit fromt he combination of Glucosamine in combination with condroitin.

I heard an interview with Dr. Mark Hochberg, one of the worlds leading authorities in osteoarthritis and editor of a major textbook of Rheumalogy. He discussed his recomendations to patients and views on the subject in light of the GAIT trial results. He stated that since this trial did not conclude there is any benefit from the medication, he is instructing his patients to discontinue the supplement. He then admitted that some of his patients felt worse after discontinuation of the drug and restarted the medication against his advice. I found this response very interesting. If I did the same thing in my practice I feel I would lose a tremendous amount of credibility. I'll elaborate my own views later.

There have been other studies prior to the GAIT trial that yielded mixed results. A study out of Prescott, Az VA Medical Center found that Glucosamine was no better than placebo. In contrast, a study out of Belgium published in the Lancet found that Glucosamine not only helped relieve symptoms of osteoarthritis but also helped delay progression of osteoarthritis by Xray of the knee. A study out of Prague, Czech Republic also found significant symptom relief and delay of progression by Xray while yet another study out of the UK found no benefit when compared to Placebo. The long-awaited study from the NIH (the GAIT tria) was supposed to answer all these questions. In my humble opinion, it raised more questions than answered.

The GAIT study however has been criticized for a number of reasons. First, the reduction of pain in the placebo group was unusually high - about 2/3 of patients in the placebo group found significant relief. Second, the investigators used Glucosamine HCL rather than Glucosamine Sulfate. The latter is more commonly prescribed and it is the prescription form available in Europe through Rottapharm. Third, there seemed to be some benefit in patients with moderate to severe osteoarthritis of the knee when glucosamine was combined with chondroitin. Finally, the results were surprising given that other studies found that patients derived significant pain relief.

So, what should doctors tell their patients? Since the therapy with glucosamine sulfate is very safe, I think a trial is worthwhile. Take glucosamine sulfate (not glucosamine hydrochloride) for 3 months. If you feel better, then continue the therapy. If you do not feel any improvement, then discontinue the product. This approach seems reasonable at least until the reusults of a disease modifying effect are available. That is, if the product prevents progression of arthritis so as to prevent the need for a joint replacement, then we may reconsider.


• N Engl J Med. 2006 Feb 23;354(8):858-60.

Glucosamine, chondroitin sulfate, and the two in combination for painful knee osteoarthritis.

• Arthritis Rheum. 2005 Aug 15;53(4):628-9; author reply 629-30.

Randomized, double-blind, placebo-controlled glucosamine discontinuation trial in knee osteoarthritis.
Arch Intern Med. 2002 Oct 14;162(18):2113-23.


Glucosamine sulfate use and delay of progression of knee osteoarthritis: a 3-year, randomized, placebo-controlled, double-blind study.

Rheumatology (Oxford). 2002 Mar;41(3):279-84.


A randomized, double-blind, placebo-controlled trial of glucosamine sulphate as an analgesic in osteoarthritis of the knee.

Lancet. 2001 Jan 27;357(9252):251-
Long-term effects of glucosamine sulphate on osteoarthritis progression: a randomised, placebo-controlled clinical trial.

• West J Med. 2000 Feb;172(2):95.

Randomized, controlled trial of glucosamine for treating osteoarthritis of the knee.

Joint Injections in Rheumatoid Arthritis

Over the last several months there has been a few articles that highlighted the benefits of intraarticular (IA) corticosteroid injections (cortisone shots to the joint). My bias in clinical practice has been for sometime to opt for IA injections in lieu of oral or intramuscular corticosteroid injections. I feel the clinical response is more robust and there appear to be less systemic side effects. So what are those benefits?

First and foremost is structural protection of the joint. Some studies have found that not only does the inflammation improve but there is less damage to the joint tissues. Second, the thickness of the synovium (the lining of the joint which is the source of inflammation and joint damage in Rheumatoid Arthritis) decreases resulting in less swelling and less erosion into the bone and cartilage. Third, there seems to be less "spill over" of inflammation from the injected joint to other joints. The result is that even the joints that were not injected improve to some extent. Fourth, there is less side effects. Since the medication is concentrated at the site of inflammation, there is less distribution to other tissues and thus less exposure to the potential harms of the medications. This includes the dreaded suppression of the adrenal glands. Fifth, there appears to be little consequence, if any, to the injected joint.

Finally, there is the surprising potential effect on lymphoma. We know that patients with Rheumatoid arthritis have a two-fold increase in risk of this cancer. Baecklund et al reported their findings from a large cohort study in Sweden. They followed more than seventy thousand patients with RA between 1964 and 1995. 378 patients developed lymphoma. When evaluating for risk factors, they found that the risk of lymphoma was primarily associated with the level of inflammation and not the medications prescribed (as it was previously believed). One surprise was that those patients who received corticosteroids at some point during their treatment had less inflammation and thus a lower risk of developing lymphoma. Actually, that may not seem particularly unexpected. But what was unexpected was that the lowest risk of lymphoma was found among patients who received a greater number of IA corticosteroid injections, more so than systemic corticosteroid therapy.

It seems that joint injections have an impact not only on the joint injected but on the disease process as whole. Following this line of thinking, researchers in Denmark prescribed methotrexate and injected up to four joints every two weeks. They had remarkable results that rivaled those of new biologics. The results are even more remarkable considering that they were using very low doses of methotrexate.

Given much of the recent evidence compounded with my favorable experience with IA corticosteroid therapy, my threshold for injection the joint has significantly decreased.


Furtado RN, Oliveira LM, Natour J.
Polyarticular corticosteroid injection versus systemic administration in treatment of rheumatoid arthritis patients: a randomized controlled study.
J Rheumatol. 2005 Sep;32(9):1691-8.

Leitch R, Walker SE, Hillard AE.
The rheumatoid knee before and after arthrocentesis and prednisolone injection: evaluation by Gd-enhanced MRI.
Clin Rheumatol. 1996 Jul;15(4):358-66.

Emkey RD, Lindsay R, Lyssy J, Weisberg JS, Dempster DW, Shen V.
The systemic effect of intraarticular administration of corticosteroid on markers of bone formation and bone resorption in patients with rheumatoid arthritis.
Arthritis Rheum. 1996 Feb;39(2):277-8


Balch HW, Gibson JM, El-Ghobarey AF, Bain LS, Lynch MP.
Repeated corticosteroid injections into knee joints.
Rheumatol Rehabil. 1977 Aug;16(3):137-40.

Hetland ML, et al
Combination treatment with methotrexate, cyclosporine, and intraarticular betamethasone compared with methotrexate and intraarticular betamethasone in early active rheumatoid arthritis: An investigator-initiated, multicenter, randomized, double-blind, parallel-group, placebo-controlled study.
Arthritis Rheum. 2006 Apr 27;54(5):1401-140

Baecklund E, et al
Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis.
Arthritis Rheum. 2006 Mar;54(3):692-701.