Knee Pain
Acupuncture Seems Effective in Treating Chronic Knee Pain
By Gail C. Davis, RN, EdD
White A, Foster NE, Cummings M, Barlas P. Acupuncture treatment for chronic knee pain: a systematic review. Rheum. 2007;46:384-390.
Abstract
Objectives: To evaluate the effects of acupuncture on pain and function in patients with chronic knee pain.
Methods: Systematic review and meta-analysis of randomized controlled trials (RCTs) of adequate acupuncture. Computerized databases and reference lists of articles were searched in June 2006. Studies were selected in which adults with chronic knee pain or osteoarthritis of the knee were randomized to receive either acupuncture treatment or a control consisting of sham (placebo) acupuncture, other sham treatments, no additional intervention (usual care), or an active intervention. The main outcome measures were short-term pain and function, and study validity was assessed using a modification of a previously published instrument.
Results: Thirteen RCTs were included, of which eight used adequate acupuncture and provided Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) outcomes, so were combined in meta-analyses. Six of these had validity scores of more than 50%. Combining five studies in 1,334 patients, acupuncture was superior to sham acupuncture for both pain (weighted mean difference in WOMAC pain subscale score=2.0, 95% confidence interval [CI] of 0.57–3.40) and for WOMAC function subscale (4.32, 0.60–8.05). The differences were still significant at long-term follow up. Acupuncture was also significantly superior to no additional intervention. There were insufficient studies to compare acupuncture with other sham or active interventions.
Conclusions: Acupuncture that meets criteria for adequate treatment is significantly superior to sham acupuncture and to no additional intervention in improving pain and function in patients with chronic knee pain. Due to the heterogeneity in the results, however, further research is required to confirm these findings and provide more information on long-term effects.
Commentary
Knee pain (accompanied by interference with function) is a common problem in the general population, and its prevalence increases with age. Acupuncture as a form of sensory stimulation has become increasingly popular as a form of treatment, especially for individuals who experience drug-related problems. In this study, White et al. conducted a systematic review and meta-analysis to evaluate the effects of acupuncture on pain and function in patients with chronic knee pain. Acupuncture was defined as “adequate” for this study if it “consisted of at least six treatments, at least one per week, with at least four points needled for each painful knee for at least 20 min, and either needle sensation (de qi) achieved in manual acupuncture, or electrical stimulation of sufficient intensity to produce more than minimal sensation.”
A computerized search of databases (excluding Asian databases) of RCTs identified 157 that were potentially eligible for review. This number was reduced to 13, representing 2,362 patients. Studies were not limited to specific settings, and were conducted in North America (3), the Far East (2), and Europe (8).
The data were extracted from the selected studies independently by two of the authors. Quality, or internal validity, of each RCT was assessed. The review compared studies according to their short-term (25 weeks from randomization with the selected measurement being that nearest 12 weeks) and long-term (last measurement between 26 and 52 weeks) effects. Acupuncture was significantly superior to the comparison groups for short-term pain reduction and improvement of function. Assessment identified that one study contributed to high heterogeneity; when it was removed, results remained the same. Significant long-term effects of acupuncture were also found for both pain and function based on the analysis of three high-quality studies. The size of the effect on pain was 0.4 (small to moderate), and the 95% CIs were wide (0.1, 0.6).
While further evidence is needed before any clear claims regarding acupuncture’s use in treating chronic knee pain can be made, the findings suggest that it can be helpful. Its effect is noted as being comparable with taking NSAIDs. Because taking medicine is often associated with side effects, acupuncture may provide a good alternative treatment. Large, high-quality RCTs are needed to provide further evidence.
Until such studies are available to further guide the treatment of knee pain, I believe that the current evidence supports serious consideration for the use of acupuncture. The decision to use it should be made jointly by the patient and healthcare provider with consideration given to such factors as the patient’s desire to try an alternative treatment method, whether the patient is taking an anticoagulant or certain herbs, the availability of a well-qualified acupuncture practitioner, time commitment, and cost.
Anti-TNF Agents
Infliximab in Giant Cell Arteritis and Polymyalgia Rheumatica
By Eric S. Schned, MD
Hoffman GS, Cid MC, Rendt-Zagar KE, et al. Infliximab for maintenance of glucocorticosteroid-induced remission of giant cell arteritis. Ann Intern Med. 2007;146:621-630.
Abstract 1
Background: Tumor necrosis factor-a (TNF-a) is present in arteries in giant cell arteritis (GCA).
Objective: To evaluate the efficacy of infliximab, an anti-TNF-a agent, in GCA.
Design: Randomized, controlled trial.
Setting: Twenty-two sites in the United States, United Kingdom, Belgium, Italy, and Spain.
Patients: Forty-four patients with newly diagnosed GCA that was in glucocorticosteroid (GCC)-induced remission.
Intervention: Participants were randomly assigned in a two-to-one ratio to receive infliximab (5 mg/kg of body weight) or placebo. Sixteen patients were assigned to GCC plus placebo, and 28 patients to GCC plus infliximab.
Measurements: End points were measured through Week 22, when an interim analysis resulted in early stopping of the planned 54-week trial. Primary end points were the number of patients who remained free of relapse through Week 22 and adverse events. Secondary end points were time to first relapse, biomarkers, cumulative GCC dose, and the number of patients who remained relapse free while the GCC dosage was tapered to 10 mg/d.
Results: Infliximab therapy did not increase the proportion of patients without relapse at Week 22 compared with placebo (43% versus 50%, respectively; difference, -7 percentage points [95% CI, -38 to 23 percentage points]; p=0.65), nor did it increase the proportion of patients whose GCC dosages were tapered to 10 mg/d without relapse (61% versus 75%, respectively; difference, -14 percentage points [CI, -42 to 14 percentage points]; p=0.31). The incidence of infection was 71% with infliximab and 56% with placebo (difference, 15 percentage points [CI, -14 to 45 percentage points]).
Limitations: The sample was too small to rule out modest effects of infliximab and included only patients with a new diagnosis. Only one dose of infliximab was evaluated, and the study was terminated early.
Conclusions: This trial is too small to draw definitive conclusions, but it provides evidence that using infliximab as maintenance therapy in patients in GCC-induced remission of newly diagnosed GCA is of no benefit and may be harmful. If infliximab has benefit, it is unlikely to be great.
Salvarani C, Macchioni P, Manzini C, et al. Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica. Ann Intern Med. 2007; 146: 631-639.
Abstract 2
Background: A reliable alternative to steroids for treating polymyalgia rheumatica (PMR) has not yet been identified. Although infliximab has been used occasionally in steroid-resistant cases, its efficacy has not been demonstrated in a controlled study.
Objective: To compare the efficacy of prednisone plus infliximab with that of prednisone plus placebo in patients with newly diagnosed PMR.
Design: Randomized, placebo-controlled trial.
Setting: Seven rheumatology clinics in Italy.
Patients: Fifty-one patients with newly diagnosed PMR. Patients with associated GCA and those who had been previously treated with steroids or biological or immunosuppressive agents were excluded.
Intervention: Initial therapy with oral prednisone tapered from 15 mg/d to 0 mg/d over 16 weeks according to a standard protocol, plus infusions of placebo or infliximab, 3 mg/kg of body weight, at Weeks 0, 2, 6, 14, and 22.
Measurements: The primary efficacy end point was the proportion of patients without relapse or recurrence through Week 52. Secondary outcomes were the proportion of patients no longer taking prednisone, the number of relapses and recurrences, the duration of prednisone therapy, and the cumulative prednisone dose.
Results: Four patients (three in the infliximab group and one in the placebo group) did not complete the trial. The proportion of patients who were free of relapse and recurrence at 52 weeks did not differ between groups (six of 20 patients [30%] in the infliximab group versus 10 of 27 patients [37%] in the placebo group; adjusted risk difference, -3 percentage points [95% CI, -31 to 24 percentage points]; p=0.80). In a sensitivity analysis that included dropouts, the best-case scenario yielded a difference of 5 percentage points (CI, -21 to 31 percentage points) between the groups. The secondary outcomes at Weeks 22 and 52 did not differ between the groups.
Limitations: The study had a small sample and a short follow-up. A low dosage of infliximab was used, and the prednisone dosage was rapidly tapered.
Conclusions: Although too small to be definitive, the trial provides evidence that adding infliximab to prednisone for treating newly diagnosed PMR is of no benefit and may be harmful. If there is benefit, it is unlikely to be large.
Commentary
The need for meaningful alternatives to GCCs in treating GCA and PMR is painfully obvious to rheumatologists. Eighty percent of patients with GCA will experience at least one adverse event due to GCCs and overall morbidity of this therapy is high, especially in an older population. Unfortunately, studies to find safer treatments, such as methotrexate, to reduce the dose or duration of GCC therapy and lead to prolonged remissions have been disappointing to date.1,2
Growing knowledge of the role cytokine mediators in the vessels affected by GCA, including TNF, raises the possibility that the TNF-a inhibitors might be effective steroid-sparing agents. Several case reports suggested that infliximab could produce remissions in patients with GCA and PMR.3,4 Case studies are often encouraging—although sometimes misleading because of the bias in publishing positive results. Randomized trials are always important in determining the true value of a therapy, often dashing the hopes provided by the preliminary reports.
Two randomized, placebo-controlled trials with similar designs have recently been published, exploring the role of infliximab in treating patients with early GCA and PMR respectively. Disappointingly, both studies came to the same conclusion: Infliximab is of no benefit in either disease.
In the first of these studies, Hoffman and a group of international collaborators investigated the effects of infliximab in patients with GCA. These investigators randomized 44 patients with newly diagnosed GCA (less than four weeks’ duration) in a 2:1 ratio to receive infliximab, 5 mg/kg, or placebo at Weeks 0, 2, and 6, and every eight weeks thereafter. Patients had already achieved remission with GCCs. GCCs were then tapered in a carefully prescribed fashion so that, in the absence of a relapse, GCC dosage of 10 mg/day would be achieved at four months and would be discontinued by six months.
Importantly, as the data in this study indicate, the proportion of patients who were relapse-free through Week 22 (a primary study end point) was similar between infliximab and placebo patients (43% versus 50%; p=0.65).
Further, secondary study end points were also not different between infliximab and placebo groups: cumulative dose of GCCs at Week 22 (3,154 mg versus 3,049 mg; p=0.95); the proportion of patients who remained relapse-free during taper of GCCs to 10 mg/day (61% versus 75%; p=0.31); mean GCC dose at relapse (13.4 mg/day versus 11.8 mg/day; p=0.59); and biochemical markers of inflammation (C-reactive protein, erythrocyte sedimentation rate, and interleukin-6 levels).
There was no difference in the proportion of patients who achieved complete remissions, defined as no sign of active GCA for at least 12 weeks after cessation of GCCs: 39% versus 44% (p=1.00). Of the patients who achieved complete remission, 73% of the infliximab group and 86% of the placebo group later had a relapse. Of note, there was no difference in the frequency of adverse events or serious adverse events between the two groups. Thus, while the addition of infliximab was safe, it did not add benefit.
In view of the putative role of cytokines in the pathogenesis of GCA, these results may appear surprising. There are several explanations for the failure of infliximab to show activity. The authors acknowledge that a higher dose of infliximab might have been efficacious. Also, methotrexate was not administered concomitantly with infliximab and this might have altered efficacy. However, only about one-quarter of patients developed anti-infliximab antibodies 20 weeks after the last dose was administered, so that lack of efficacy could not be attributed to anti-drug antibodies.
In a related study, Salvarani and Italian colleagues investigated the effects of TNF blockade on patients with PMR. These investigators randomized 51 patients with newly diagnosed PMR (mean duration of symptoms before therapy of 10 to 11 weeks) in a 1:1 ratio to receive infliximab, 3 mg/kg, or placebo infusions at Weeks 0, 2, 6, 14, and 22. All patients received prednisone 15 mg for the first four weeks, which was then tapered at four-week intervals to 15 mg, 10 mg, 5 mg, and 2.5 mg daily dosages. Patients with clinical or histological evidence of GCA were excluded.
I do not routinely add second-line agents in my new patients with giant cell arteritis and polymyalgia rheumatica, but I am aggressive in trying to minimize adverse effects of glucocorticosteroids.
The proportion of patients free of relapse at 52 weeks—the primary end point—was not different between infliximab and placebo groups, and the groups also did not differ in all secondary end points, including the proportion of patients without relapse at Week 22 (55% versus 54%; p=1.00); the proportion of patients no longer taking GCCs at Week 22 (55% versus 64%; p=0.56) or Week 52 (50% versus 54%; p=1.00); median relapses in all patients (one versus one; p=0.69); median cumulative dose of prednisone at 52 weeks (17.1 gm versus 12.2 gm; p=0.31). There was no difference in adverse drug events (eight in each group).
The authors acknowledge several limitations of the study. Patients all had newly diagnosed PMR. Pathophysiological studies show an association between high TNF-a production and steroid-resistant disease. Could infliximab have a beneficial role in more chronic PMR? Also, the dose of infliximab was low—3 mg/kg—and prednisone was tapered quickly over 16 weeks, which could have contributed to the high frequency of flare-ups.
These two studies will probably put an end to investigations on the use of infliximab as a steroid-sparing agent for GCA and PMR. The studies are small and the confidence intervals were wide for most outcomes in both studies. While it is possible that a small beneficial effect could exist for infliximab in these diseases, the expense of this agent probably would preclude its cost-effectiveness for relatively small potential benefits.
The search for good alternatives to GCCs will undoubtedly continue—and it should because the side effects of this therapy are high in older patients. Because of evidence that other cytokines—notably interleukin-1, interleukin-6, and interferon-gamma—contribute to vascular inflammation in GCA, it is likely that these cytokines will be targeted in future trials.
So what does one do while waiting for more definitive solutions? I do not routinely add second-line agents in my new patients with GCA and PMR, but I am aggressive in trying to minimize adverse effects of GCCs. I add prophylactic bisphosphonates, follow bone-density scans, vaccinate, and treat hyperlipidemia, hypertension, and hyperglycemia.
Despite conflicting evidence on efficacy, I have occasionally added methotrexate in some of my patients on long-term steroids who have intolerable adverse effects from GCCs. I’ve sometimes been successful in subsequently tapering GCCs.
Lastly, I vigorously pursue other possible—and common—causes of confounding musculoskeletal pain that patients may find responsive to GCCs, but can be treated safely in other ways, such as rotator cuff inflammation or tears, cervical disc disease, and myofascial pain—what I call pseudo-polymyalgia. Treating these might allow steroid tapering in otherwise resistant disease.
References:
- Jover JA, Hernandez-Garcia C, Morado IC, et al. Combined treatment of giant cell arteritis with methotrexate and prednisone; a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2001;134:106-114.
- International Network for the Study of Systemic Vasculitides. A multi-center, randomized, double-blind, placebo-controlled trial of adjuvant methotrexate treatment for giant cell arteritis. Arthritis Rheum. 2002;46:1309-1318.
- Cantini F, Niccoli L, Salvarani C, et al. Treatment of long-standing active giant-cell arteritis with infliximab: report of 4 cases. Arthritis Rheum. 2001;44:2933-2935.
- Salvarani C, Cantini F, Niccoli L, et al. Treatment of refractory polymyalgia rheumatica with infliximab: a pilot study. J Rheumatol. 2003 10(4):760-763.
