Clinical Health Updates

Poor evidence for antioxidants for arthritis

Clinical Question:
Are antioxidants effective in treating arthritis?

Bottom Line:
Clinical trials testing the efficacy of vitamin E in the treatment of OA and inflammatory arthritis have been methodologically weak and have produced contradictory findings. There is presently no convincing evidence that selenium, vitamin A, vitamin C or the combination product selenium ACE is effective in the treatment of any type of arthritis.

Reference:
Canter PH, Wider B, Ernst E. The antioxidant vitamins A, C, E and selenium in the treatment of arthritis: a systematic review of randomized clinical trials. Rheumatology 2007;46:1223-1233.

Study Design:
Systematic review

Synopsis:
These authors searched multiple databases for randomized trials of vitamins A, C, E and of selenium in managing arthritis. Although the team searched the reference lists of retrieved articles, they did not search for unpublished data. This latter step is important since publication bias favors active treatment more than placebo. Two authors independently evaluated articles for inclusion, and disagreements were resolved through discussion with a third member of the team. Although the quality of the included studies was assessed using a standard scale (Jadad), the authors don’t say if this, too, was done independently. The authors found 22 papers reporting data on 20 randomized trials, 11 of which studied inflammatory arthritis and 9 studied osteoarthritis. Six of the studies used a nonsteroidal anti-inflammatory drug (NSAID) as a comparator, 1 compared other antioxidants, and 1 compared fish oil. The overall quality of the studies was marginal (average = 2.9 on a 5-point scale) and only 5 studies scored at least 4 points. The authors point out that even among these higher scoring studies, other methodologic flaws existed that were not captured by the Jadad scale. Unlike many other researchers, this group properly decided against pooling the results given the poor quality of the studies and just summarized the key findings. One trial suggested that vitamin E was better than placebo but equivalent to NSAIDs in patients with inflammatory arthritis. In osteoarthritis, 2 short-term trials suggest that vitamin E was better than placebo but 2 long-term trials found it to be equivalent to placebo. Two additional trials found vitamin E and NSAIDs comparable. The remaining studies failed to show any benefit.

Vitamin C prevents RSD in patients with wrist fracture

Clinical Question:
Does vitamin C prevent complex regional pain syndromes (reflex sympathetic dystrophy) in patients with wrist fractures?

Bottom Line:
In patients with wrist fractures, we only need to treat 13 patients with vitamin C to prevent one case of reflex sympathetic dystrophy. Vitamin C reduces the prevalence of complex regional pain syndrome after wrist fractures. A daily dose of 500 mg for fifty days is recommended.

Reference:
Zollinger PE, Tuinebreijer WE, Breederveld RS, Kreis RW. Can vitamin C prevent complex regional pain syndrome in patients with wrist fractures? A randomized, controlled, multicenter dose-response study. J Bone Joint Surg Am 2007;89:1424-1431.

Study Design:
Randomized controlled trial (double-blinded)

Funding:

Synopsis:
Four hundred sixteen adult patients (18 years or older) with a unilateral or bilateral wrist fracture (total 427 fractures) seen in the emergency department were randomly assigned to receive 50 days of placebo or vitamin C (daily doses of 200 mg, 500 mg or 1500 mg), regardless of whether the fractures were treated surgically or with immobilization. The main outcome of interest was whether the patient, by 12 months after the fracture, developed type 1 complex regional pain syndromes (reflex sympathetic dystrophy [RSD]). The diagnosis was made by the treating physician, who was masked to treatment and who used specific criteria, not by anyone involved in the study. The criteria for RSD was met when 4 of the following 5 symptoms were present or increased after activity: (1) unexplained diffuse pain not expected at the stage of fracture treatment; (2) a difference in skin color compared with the other hand and wrist; (3) diffuse edema; (4) a difference in skin temperature compared with the other hand and wrist; and (5) limited active range of motion of the wrist and fingers. The researchers had a remarkable 100% follow-up. At the end of the study, 10.1% of patients taking placebo developed RSD compared with 2.4% of those taking vitamin C (number needed to treat [NNT] = 13; 95% CI, 7 – 39). The rates of RSD by vitamin C dose was 4.2%, 1.8%, and 1.7%, respectively. So, it looks like 500 mg is the optimum daily dose. In a different study (Lancet 1999;354:2025-8), these same researchers also demonstrated vitamin C to be effective in preventing RSD after wrist fracture (NNT = 7).

Zoledronic acid reduces fracture risk in osteoporosis, osteopenia with previous fracture

Clinical Question:
Is zoledronic a safe and effective drug for preventing fractures in women with osteoporosis?

Bottom Line:
Zoledronic acid (Zometa) given once a year via intravenous infusion reduces the risk of clinical fracture in women with osteoporosis or osteopenia and previous fracture. Approximately 1 in 100 women will develop atrial fibrillation, though, as a result of treatment.

Reference:
Black DM, Delmas PD, Eastell R, et al, for the HORIZON Pivotal Fracture Trial. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809-1822.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Zoledronic acid is a bisphosphonate that has primarily been used in patients with multiple myeloma and in cancer patients with hypercalcemia. In this study, 7765 women between the ages of 65 years and 89 years with either osteoporosis (T score at femoral neck < -2.5) or osteopenia (T score < -1.5) and evidence of previous vertebral fracture were randomly assigned to receive either zoledronic acid 5 mg given intravenously at baseline, 12 months, and 24 months or matching placebo. All patients received 1000 mg to 1500 mg of calcium and 400 IU to 1200 IU of vitamin D daily. Patients were allowed to take nonbisphosphonate drugs for the treatment of osteoporosis. Approximately 600 women in each group did not return for the final evaluation. Groups were similar at baseline and analysis was by intention to treat. Approximately 80% of the women were not taking any other osteoporosis drugs; of those who were, raloxifene was the most commonly used (42%).

Patients receiving zoledronic acid had fewer hip fractures (1.4% vs 2.5%; P = .002; number needed to treat [NNT] = 111 for 3 years) and fewer clinical vertebral fractures (0.5% vs 2.6%; P < .001; NNT = 48) and fewer clinical fractures of any type (8.4% vs 12.8%; P < .001; NNT = 23). Although patients taking the drug had transient increases in serum creatinine, at the end of the study there was no difference in renal function between groups. Atrial fibrillation was also more common in women taking zoledronic acid (1.3% vs 0.5%; P < .001; NNH = 125). This has also been previously reported in a study of alendronate, although more data are needed. There was no difference between groups regarding other cardiovascular events or all-cause mortality and no instances of osteonecrosis of the jaw.

Omega-3 fatty acids have small analgesic effect

Clinical Question:
Can long-term dosing of omega-3 fatty acids decrease inflammatory joint pain?

Bottom Line:
In patients with joint pain due to rheumatoid arthritis, inflammatory bowel disease, or dysmenorrhea, continuous therapy with fish oil or other sources of omega-3 fatty acids produced statistically significant decreases in pain. The onset of action is approximately 3 months. Even though the benefit may be small, the lack of significant side effects and the beneficial effect on cardiovascular disease (Circulation 2002;106:2747-2757) make fish oil and other sources a useful option in patients with pain due to inflammation.

Reference:
Goldberg RJ, Katz J. A meta-analysis of the analgesic effects of omega-3 polyunsaturated fatty acid supplementation for inflammatory joint pain. Pain 2007;129;210-223.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Between 40% and 60% of Americans use complementary and alternative medicine to manage medical conditions, prevent disease, and promote health and well-being. Omega-3 polyunsaturated fatty acids (omega-3 PUFAs) have been used to treat joint pain associated with several inflammatory conditions. The investigators conducted a meta-analysis of 17 randomized, controlled trials assessing the pain relieving effects of omega-3 PUFAs in patients with rheumatoid arthritis or joint pain secondary to inflammatory bowel disease and dysmenorrhea. Meta-analysis was conducted with Cochrane Review Manager 4.2.8. for six separate outcomes using standardized mean differences (SMDs) as a measure of effect size:
(1) patient assessed pain
(2) physician assessed pain
(3) duration of morning stiffness
(4) number of painful and/or tender joints
(5) Ritchie articular index
(6) nonselective nonsteroidal anti-inflammatory drug consumption.
Supplementation with omega-3 PUFAs for 3-4 months reduces patient reported joint pain intensity (SMD: -0.26; 95% CI: -0.49 to -0.03, p=0.03), minutes of morning stiffness (SMD: -0.43; 95% CI: -0.72 to -0.15, p=0.003), number of painful and/or tender joints (SMD: -0.29; 95% CI: -0.48 to -0.10, p=0.003), and NSAID consumption (SMD: -0.40; 95% CI: -0.72 to -0.08, p=0.01). Significant effects were not detected for physician assessed pain (SMD: -0.14; 95% CI: -0.49 to 0.22, p=0.45) or Ritchie articular index (SMD: 0.15; 95% CI: -0.19 to 0.49, p=0.40) at 3-4 months.

Ibuprofen (Alaxan) better analgesic after a single dose

Clinical Question:
Which analgesic is more effective for children with acute musculoskeletal pain?

Bottom Line:
After a single dose, more children will achieve adequate analgesia after 1 hour with ibuprofen than with codeine or acetaminophen, although after 2 hours the difference may no longer exist.

Reference:
Clark E, Plint AC, Correll R, Gaboury I, Passi B. A randomized, controlled trial of acetaminophen, ibuprofen, and codeine for acute pain relief in children with musculoskeletal trauma. Pediatrics 2007;119:460-467.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
The authors determined which of 3 analgesics, acetaminophen, ibuprofen, or codeine, given as a single dose, provides the most efficacious analgesia for children presenting to the emergency department with pain from acute musculoskeletal injuries. Children 6 to 17 years old with pain from a musculoskeletal injury (to extremities, neck, and back) that occurred in the preceding 48 hours before presentation in the emergency department were randomly assigned to receive orally 15 mg/kg acetaminophen, 10 mg/kg ibuprofen, or 1 mg/kg codeine. Children, parents, and the research assistants were blinded to group assignment. The primary outcome was change in pain from baseline to 60 minutes after treatment with study medication as measured by using a visual analog scale. A total of 336 patients were randomly assigned, and 300 were included in the analysis of the primary outcome (100 in the acetaminophen group, 100 in the ibuprofen group, and 100 in the codeine group). Study groups were similar in age, gender, final diagnosis, previous analgesic given, and baseline pain score. Patients in the ibuprofen group had a significantly greater improvement in pain score (mean decrease: 24 mm) than those in the codeine (mean decrease: 11 mm) and acetaminophen (mean decrease: 12 mm) groups at 60 minutes. In addition, at 60 minutes more patients in the ibuprofen group achieved adequate analgesia (as defined by a visual analog scale <30 mm) than the other 2 groups. There was no significant difference between patients in the codeine and acetaminophen groups in the change in pain score at any time period or in the number of patients achieving adequate analgesia.

ESWT improves chronic patella tendonitis

Clinical Question:
Does extracorporeal shockwave therapy improve symptoms in patients with chronic patella tendonitis?

Bottom Line:
In this flawed study, extracorporeal shockwave therapy appeared to be more effective and safer than traditional conservative treatments in the management of patients with chronic patellar tendinopathy.

Reference:
Wang CJ, Ko JY, Chan YS, Weng LH, Hsu SL. Extracorporeal shockwave for chronic patellar tendinopathy. Am J Sports Med 2007;35:972-978.

Study Design:
Non-randomized controlled trial

Synopsis:
Chronic patellar tendinopathy is an overuse syndrome with pathologic changes similar to tendinopathies of the shoulder, elbow, and heel. Extracorporeal shockwave was shown effective in many tendinopathies. The authors investigated whether extracorporeal shockwave therapy may be more effective than conservative treatment for chronic patellar tendinopathy. They did a randomized controlled clinical trial; Level of evidence, 2. This study consisted of 27 patients (30 knees) in the study group and 23 patients (24 knees) in the control group. In the study group, patients were treated with 1500 impulses of extracorporeal shockwave at 14 KV (equivalent to 0.18 mJ/mm(2) energy flux density) to the affected knee at a single session. Patients in the control group were treated with conservative treatments including nonsteroidal anti-inflammatory drugs, physiotherapy, exercise program, and the use of a knee strap. The evaluation parameters included pain score, Victorian Institute of Sports Assessment score, and ultrasonographic examination at 1, 3, 6, and 12 months and then once a year. At the 2- to 3-year follow-up, the overall results for the study group were 43% excellent, 47% good, 10% fair, and none poor. For the control group, the results were none excellent, 50% good, 25% fair, and 25% poor. The mean Victorian Institute of Sports Assessment scores were 42.57 +/- 10.22 and 39.25 +/- 10.85, respectively, before treatment (P = .129) and 92.0 +/- 10.17 and 41.04 +/- 10.96, respectively, after treatment (P < .001). Satisfactory results were observed in 90% of the study group versus 50% of the control group (P < .001). Recurrence of symptoms occurred in 13% of the study group and 50% of the control group (P = .014). Ultrasonographic examination showed a significant increase in the vascularity of the patellar tendon and a trend of reduction in the patellar tendon thickness after shockwave treatment compared with conservative treatments. However, no significant difference in the appearance, arrangement, and homogeneity of tendon fibers was noted between the 2 groups. There were no systemic or local complications or device-related problems.

Chondroitin of little benefit in pain of advanced OA

Clinical Question:
Is treatment with chondroitin more effective than placebo for controlling the pain of osteoarthritis?

Bottom Line:
Most of the available research on this topic is of low quality, and the high-quality research that exists does not point to a benefit of chondroitin. Studies of glucosamine are mixed in their demonstration of benefit. Given its low cost and lack of side effects, glucosamine alone or in combination with chondroitin is a reasonable option for patients who should give it a trial of several months to determine benefit.

Reference:
Reichenbach S, Sterchi R, Scherer M, et al. Meta-analysis: Chondroitin for osteoarthritis of the knee or hip. Ann Intern Med 2007;146:580-590.

Study Design:
Meta-analysis (randomized controlled trials)

Synopsis:
Previous meta-analyses described moderate to large benefits of chondroitin in patients with osteoarthritis. However, recent large-scale trials did not find evidence of an effect. The authors determined the effects of chondroitin on pain in patients with osteoarthritis. They searched the Cochrane Central Register of Controlled Trials (1970 to 2006), MEDLINE (1966 to 2006), EMBASE (1980 to 2006), CINAHL (1970 to 2006), and conference proceedings; checked reference lists; and contacted authors. The last update of searches was performed on 30 November 2006. Studies were included if they were randomized or quasi-randomized, controlled trials that compared chondroitin with placebo or with no treatment in patients with osteoarthritis of the knee or hip. There were no language restrictions. The authors extracted data in duplicate. Effect sizes were calculated from the differences in means of pain-related outcomes between treatment and control groups at the end of the trial, divided by the pooled SD. Trials were combined by using random-effects meta-analysis. 20 trials (3846 patients) contributed to the meta-analysis, which revealed a high degree of heterogeneity among the trials (I2 = 92%). Small trials, trials with unclear concealment of allocation, and trials that were not analyzed according to the intention-to-treat principle showed larger effects in favor of chondroitin than did the remaining trials. When the authors restricted the analysis to the 3 trials with large sample sizes and an intention-to-treat analysis, 40% of patients were included. This resulted in an effect size of -0.03 (95% CI, -0.13 to 0.07; I2 = 0%) and corresponded to a difference of 0.6 mm on a 10-cm visual analogue scale. A meta-analysis of 12 trials showed a pooled relative risk of 0.99 (CI, 0.76 to 1.31) for any adverse event.

Synovial WBC and percent PMNs best for septic arthritis diagnosis

Clinical Question:
What are the most useful symptoms, signs, and laboratory tests for diagnosing septic arthritis in adults presenting with an acutely painful and swollen joint?

Bottom Line:
Clinical findings identify patients with peripheral, monoarticular arthritis who might have septic arthritis. However, the synovial WBC and percentage of polymorphonuclear cells from arthrocentesis are required to assess the likelihood of septic arthritis before the Gram stain and culture test results are known.

Reference:
Margaretten ME, Kohlwes J, Moore D, Bent S. Does this patient have septic arthritis? JAMA 2007;297:1478-1488.

Study Design:
Systematic review

Synopsis:
In patients who present with an acutely painful and swollen joint, prompt identification and treatment of septic arthritis can substantially reduce morbidity and mortality. The investigators reviewed the accuracy and precision of the clinical evaluation for the diagnosis of nongonococcal bacterial arthritis. Data has been gathered from PubMed and EMBASE searches (1966 through January 2007), limited to human, English-language articles and using the following Medical Subject Headings terms: arthritis, infectious, physical examination, medical history taking, diagnostic tests, and sensitivity and specificity. Studies were included if they contained original data on the accuracy or precision of historical items, physical examination, serum, or synovial fluid laboratory data for diagnosing septic arthritis. Three authors independently abstracted data from the included studies. Fourteen studies involving 6242 patients, of whom 653 met the gold standard for the diagnosis of septic arthritis, satisfied all inclusion criteria. Two studies examined risk factors and found that age, diabetes mellitus, rheumatoid arthritis, joint surgery, hip or knee prosthesis, skin infection, and human immunodeficiency virus type 1 infection significantly increase the probability of septic arthritis. Joint pain (sensitivity, 85%; 95% confidence interval [CI], 78%-90%), a history of joint swelling (sensitivity, 78%; 95% CI, 71%-85%), and fever (sensitivity, 57%; 95% CI, 52%-62%) are the only findings that occur in more than 50% of patients. Sweats (sensitivity, 27%; 95% CI, 20%-34%) and rigors (sensitivity, 19%; 95% CI, 15%-24%) are less common findings in septic arthritis. Of all laboratory findings readily available to the clinician, the 2 most powerful were the synovial fluid white blood cell (WBC) count and percentage of polymorphonuclear cells from arthrocentesis. The summary likelihood ratio (LR) increased as the synovial fluid WBC count increased (for counts <25,000/microl:> or =25,000/microL: LR, 2.9; 95% CI, 2.5-3.4; for counts >50,000/microL: LR, 7.7; 95% CI, 5.7-11.0; and for counts >100,000/microL: LR, 28.0; 95% CI, 12.0-66.0). On the same synovial fluid sample, a polymorphonuclear cell count of at least 90% suggests septic arthritis with an LR of 3.4 (95% CI, 2.8-4.2), while a polymorphonuclear cell count of less than 90% lowers the likelihood (LR, 0.34; 95% CI, 0.25-0.47).

Questionable effectiveness of acupuncture for fibromyalgia

Clinical Question:
Is acupuncture effective in managing patients with fibromyalgia?

Bottom Line:
The body of literature evaluating acupuncture in managing patients with fibromyalgia is sparse and demonstrates small, short-lived benefits for this chronic problem. Since all the studies that found acupuncture effective also used electroacupuncture, traditional acupuncture may be of no use at all.

Reference:
Mayhew E, Ernst E. Acupuncture for fibromyalgia–a systematic review of randomized clinical trials. Rheumatology (Oxford) 2007;46:801-804.

Study Design:
Systematic review

Synopsis:
Acupuncture is often used and frequently advocated for the symptomatic treatment of fibromyalgia. A systematic review has previously demonstrated encouraging findings. As it is now outdated, we wanted to update it. This authors searched seven electronic databases for relevant randomized clinical trials (RCTs). The data were extracted and validated independently by both authors. As no meta-analysis seemed possible, the results were evaluated in narrative form. Five RCTs met our inclusion criteria, all of which used acupuncture as an adjunct to conventional treatments. Their methodological quality was mixed and frequently low. Three RCTs suggested positive but mostly short-lived effects and two yielded negative results. There was no significant difference between the quality of the negative and the positive RCTs. All positive RCTs used electro-acupunture.

Adding MTX to sulfasalazine better for RA (MASCOT)

Clinical Question:
In patients with rheumatoid arthritis who do not respond to sulfasalazine, does adding methotrexate provide better outcomes than either drug used alone?

Bottom Line:
In patients with rheumatoid arthritis (RA) treated with an an inexpensive combination of DMARDs proved more effective than monotherapy in patients with rheumatoid arthritis with a suboptimal response to SASP. There was no increase in toxicity. These results provide an evidence base for the use of this combination as a component of tight control strategies.

Reference:
Capell HA, Madhok R, Porter DR, et al. Combination therapy with sulfasalazine and methotrexate is more effective than either drug alone in patients with rheumatoid arthritis with a suboptimal response to sulfasalazine: results from the double-blind placebo-controlled MASCOT study. Ann Rheum Dis 2007;66:235-41.

Study Design:
Randomized controlled trial (double-blinded)

Synopsis:
Optimal use of disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis is vital if progression of disease is to be reduced. Methotrexate (MTX) and sulfasalazine (SASP) are widely used inexpensive DMARDs, recently often combined despite no firm evidence of benefit from previous studies. The author try to established whether a combination of SASP and MTX is superior to either drug alone in patients with rheumatoid arthritis with a suboptimal response to 6 months of SASP. A randomised controlled study of step-up DMARD treatment in early rheumatoid arthritis. In phase I, 687 patients received SASP for 6 months. Those with a disease activity score (DAS) > or =2.4 were offered additional treatment in phase II (SASP alone, MTX alone or a combination of the two). The primary outcome measure was change in DAS. At 6 months, 191 (28%) patients had a DAS <2.4, 123 (18%) were eligible but did not wish to enter phase II, 130 (19%) stopped SASP because of reversible adverse events and 165 (24%) entered phase II. DAS at 18 months was significantly lower in those who received combination treatment compared with those who received either SASP or MTX: monotherapy arms did not differ. Improvement in European League Against Rheumatism and American College of Rheumatology 20, 50 and 70 scores favoured combination therapy.