Timothy E. McAlindon

OARSI guidelines for the non-surgical management of knee osteoarthritis

OBJECTIVE To develop concise, up-to-date, patient-focused, evidence-based, expert consensus guidelines for the management of knee osteoarthritis (OA), intended to inform patients, physicians, and allied healthcare professionals worldwide. METHOD Thirteen experts from relevant medical disciplines (primary care, rheumatology, orthopedics, physical therapy, physical medicine and rehabilitation, and evidence-based medicine), three continents and ten countries (USA, UK, France, Netherlands, Belgium, Sweden, Denmark, Australia, Japan, and Canada) and a patient representative comprised the Osteoarthritis Guidelines Development Group (OAGDG). Based on previous OA guidelines and a systematic review of the OA literature, 29 treatment modalities were considered for recommendation. Evidence published subsequent to the 2010 OARSI guidelines was based on a systematic review conducted by the OA Research Society International (OARSI) evidence team at Tufts Medical Center, Boston, USA. Medline, EMBASE, Google Scholar, Web of Science, and the Cochrane Central Register of Controlled Trials were initially searched in first quarter 2012 and last searched in March 2013. Included evidence was assessed for quality using Assessment of Multiple Systematic Reviews (AMSTAR) criteria, and published criticism of included evidence was also considered. To provide recommendations for individuals with a range of health profiles and OA burden, treatment recommendations were stratified into four clinical sub-phenotypes. Consensus recommendations were produced using the RAND/UCLA Appropriateness Method and Delphi voting process. Treatments were recommended as Appropriate, Uncertain, or Not Appropriate, for each of four clinical sub-phenotypes and accompanied by 1-10 risk and benefit scores. RESULTS Appropriate treatment modalities for all individuals with knee OA included biomechanical interventions, intra-articular corticosteroids, exercise (land-based and water-based), self-management and education, strength training, and weight management. Treatments appropriate for specific clinical sub-phenotypes included acetaminophen (paracetamol), balneotherapy, capsaicin, cane (walking stick), duloxetine, oral non-steroidal anti-inflammatory drugs (NSAIDs; COX-2 selective and non-selective), and topical NSAIDs. Treatments of uncertain appropriateness for specific clinical sub-phenotypes included acupuncture, avocado soybean unsaponfiables, chondroitin, crutches, diacerein, glucosamine, intra-articular hyaluronic acid, opioids (oral and transdermal), rosehip, transcutaneous electrical nerve stimulation, and ultrasound. Treatments voted not appropriate included risedronate and electrotherapy (neuromuscular electrical stimulation). CONCLUSION These evidence-based consensus recommendations provide guidance to patients and practitioners on treatments applicable to all individuals with knee OA, as well as therapies that can be considered according to individualized patient needs and preferences.

2015 American College of Rheumatology Guideline for the Treatment of Rheumatoid Arthritis.

To develop a new evidence‐based, pharmacologic treatment guideline for rheumatoid arthritis (RA).

Risk factors for the incidence and progression of radiographic knee osteoarthritis.

OBJECTIVE Preventive strategies against knee osteoarthritis (OA) require a knowledge of risk factors that influence the initiation of the disorder and its subsequent progression. This population-based longitudinal study was performed to address this issue. METHODS Ninety-nine men and 255 women aged > or =55 years had baseline interviews and weight-bearing knee radiographs in 1990-1991. Repeat radiographs were obtained in 1995-1996 (mean followup duration 5.1 years, median age at followup 75.8 years). Risk factors assessed at baseline were tested for their association with incident and progressive radiographic knee OA by logistic regression. RESULTS Rates of incidence and progression were 2.5% and 3.6% per year, respectively. After adjusting for age and sex, the risk of incident radiographic knee OA was significantly increased among subjects with higher baseline body mass index (odds ratio [OR] 18.3, 95% confidence interval [95% CI] 5.1-65.1, highest versus lowest third), previous knee injury (OR 4.8, 95% CI 1.0-24.1), and a history of regular sports participation (OR 3.2, 95% CI 1.1-9.1). Knee pain at baseline (OR 2.4, 95% CI 0.7-8.0) and Heberdens nodes (OR 2.0, 95% CI 0.7-5.7) were weakly associated with progression. Analyses based on individual radiographic features (osteophyte formation and joint space narrowing) supported differences in risk factors for either feature. CONCLUSION Most currently recognized risk factors for prevalent knee OA (obesity, knee injury, and physical activity) influence incidence more than radiographic progression. Furthermore, these factors might selectively influence osteophyte formation more than joint space narrowing. These findings are consistent with knee OA being initiated by joint injury, but with progression being a consequence of impaired intrinsic repair capacity.

Determinants of disability in osteoarthritis of the knee.

OBJECTIVES: To evaluate the influences of radiographic severity, quadriceps strength, knee pain, age, and gender on functional ability in patients with osteoarthritis of the knee. METHODS: Equal numbers of knee pain positive and negative respondents to a survey of registrants aged more than 55 years at a general practice were invited to attend for knee radiographs and quadriceps femoris isometric strength estimations. Disability was measured using the Stanford Health Assessment Questionnaire. RESULTS: Complete data were available on 70 men (mean age 72.7 years) and 89 women (mean age 68.1 years); 44% reported knee pain, 48% had radiographic features of osteoarthritis, and 32% reported some degree of disability. Significant correlations were observed between disability and radiographic score, quadriceps strength, and knee pain. Logistic regression analysis, however, showed significant independent contributions from quadriceps strength (odds ratio 0.84 kgF), knee pain (odds ratio 1.67), and age (odds ratio 1.06 per year) only; the radiographic score had no influence on the model. These results were not influenced by confining the analysis to the group with radiographic features of osteoarthritis. CONCLUSIONS: Quadriceps strength, knee pain, and age are more important determinants of functional impairment in elderly subjects than the severity of knee osteoarthritis as assessed radiographically. Strategies designed to optimise muscle strength may have the potential to reduce a vast burden of disability, dependency, and cost.

Radiographic patterns of osteoarthritis of the knee joint in the community: the importance of the patellofemoral joint.

The intimate relation which the patella has with the knee joint and quadriceps muscle suggests that patellofemoral joint osteoarthritis is likely to be an important cause of knee pain and disability. Two hundred and seventy three subjects who reported knee pain in a postal questionnaire survey and 240 control subjects consented to have anteroposterior weightbearing and lateral knee radiographs. Each subject completed a Stanford Health Assessment Questionnaire (HAQ). Radiographic knee osteoarthritis was found in 53% of symptomatic and 17% of asymptomatic subjects. Three patterns predominated patellofemoral, medial, and medial/patellofemoral joint disease in 11, 21, and 7% of the men and in 24, 12, 6% of the women respectively. The occurrence of isolated symptomatic patellofemoral joint osteoarthritis in this sample aged more than 55 years was estimated as 8% in women and 2% in men. All patterns of symptomatic knee joint osteoarthritis increased with age in women but peaked at 70 years in men. Medial joint and patellofemoral joint osteoarthritis were significantly associated with disability (46 v 17% in controls and 64 v 25% in controls respectively) but higher HAQ scores were more common in subjects with patellofemoral joint osteoarthritis. Patellofemoral joint osteoarthritis is common, associated with disability, occurs in the absence of tibiofemoral disease, and can no longer be omitted from future studies of osteoarthritis of the knee joint.

Osteoarthritis: New Insights. Part 2: Treatment Approaches

There is no known cure for osteoarthritis, and the goal of contemporary management of the patient with osteoarthritis remains control of pain and improvement in function and health-related quality of life with avoidance, if possible, of therapeutic toxicity. Recent studies have demonstrated the potential of treatments ranging from newly approved oral medications to nutriceuticals, patient education interventions, and surgery. Increasingly, appropriate treatment of osteoarthritis combines one or more oral agents with exercise and other biomechanical techniques. This article is part 2 of a two-part summary of a National Institutes of Health (NIH) conference, Stepping Away from OA: Prevention of Onset, Progression, and Disability of Osteoarthritis. The conference brought together experts from diverse backgrounds and provided a multidisciplinary and comprehensive summary of recent advances in the prevention of osteoarthritis onset, progression, and disability. For research questions and opportunities identified at the conference, see www.nih.gov/niams/reports/oa/oareport.htm(accessed on 25 May 2000). Systemic and Topical Treatments Dr. Marc C. Hochberg (University of Maryland School of Medicine, Baltimore, Maryland), Dr. Timothy McAlindon (Boston University School of Medicine, Boston, Massachusetts), and Dr. David T. Felson (Boston University School of Medicine): Drug therapy for pain management is most effective when combined with nonpharmacologic strategies (1, 2). In 1995, the American College of Rheumatology issued guidelines for the medical management of osteoarthritis of the hip and knee (2, 3). Since then, several systematic reviews of drug therapy for osteoarthritis have been published (4-6). The following recommendations for systemic and topical treatments (except for glucosamine and chondroitin, which were not evaluated) are derived from updated recommendations of the American College of Rheumatology for the treatment of osteoarthritis. Systemic Treatments Nonopioid Analgesics For many patients with osteoarthritis, the relief of mild to moderate joint pain afforded by the simple analgesic acetaminophen is comparable to that achieved with a nonsteroidal anti-inflammatory drug (NSAID) (7, 8). Accordingly, although acetaminophen fails to adequately relieve pain in many patients, it merits a trial as initial therapy on the basis of its overall cost, efficacy, and toxicity profile (9, 10). The daily dose of acetaminophen should not exceed 4 g. Although it is one of the safest analgesics, acetaminophen can be associated with clinically important adverse events, such as prolongation of the half-life of warfarin (11). At therapeutic doses acetaminophen rarely causes hepatic toxicity, but it should be used cautiously in patients with existing liver disease and avoided in patients with chronic alcohol abuse because of known increased risk in these patients (12-14). Even though acetaminophen was reported to be weakly associated with end-stage renal disease, the Scientific Advisory Committee of the National Kidney Foundation recommended it as the drug of choice for analgesia in patients with impaired renal function (15). Tramadol, a centrally acting oral analgesic, is a synthetic opioid agonist that inhibits reuptake of norepinephrine and serotonin. It has been approved by the U.S. Food and Drug Administration for treatment of moderate to severe pain and can be considered for use in patients in whom acetaminophen therapy has failed and who have contraindications to NSAIDs, including the cyclooxygenase-2 (COX-2)specific inhibitors. Although numerous studies have examined use of tramadol to treat general pain, few controlled studies have examined its use in osteoarthritis. The efficacy of tramadol has been found to be comparable to that of ibuprofen in patients with hip and knee osteoarthritis (16), and it is useful as adjunctive therapy in patients with osteoarthritis whose symptoms were inadequately controlled with NSAIDs (17). Daily doses of tramadol have generally been in the range of 200 to 300 mg given in four divided doses. Side effects are common and include nausea, constipation, and drowsiness. Despite the opioid pharmacology of tramadol, a comprehensive surveillance program has failed to demonstrate significant abuse, and tramadol remains an unscheduled agent. Seizures have been reported as a rare side effect, either at doses above the recommended range or at doses within the recommended range in patients with a history of epilepsy and those taking concomitant medications that lower the seizure threshold. NSAIDs For patients who do not obtain adequate symptom relief with nonopioid analgesics, use of NSAIDs should be considered. The choice between a nonselective NSAID and a COX-2specific inhibitor should be made after evaluation of risk factors, particularly for upper gastrointestinal and renal toxicity. Data from epidemiologic studies show that among persons 65 years of age or older, 20% to 30% of all hospitalizations and deaths due to peptic ulcer disease were attributable to therapy with NSAIDs (18-20). Furthermore, the risk for a catastrophic gastrointestinal event in elderly patients taking NSAIDs is dose dependent (18). Risk factors for upper gastrointestinal bleeding in patients treated with NSAIDs include age 65 years or older, history of peptic ulcer disease or previous upper gastrointestinal bleeding, concomitant use of oral corticosteroids or anticoagulants, and possibly smoking and alcohol consumption (21-23). Risk factors for reversible renal failure in patients with intrinsic renal disease who are treated with NSAIDs include age 65 years or older, hypertension or congestive heart failure, and concomitant use of diuretics and angiotensin-converting enzyme inhibitors (24). Additional considerations involved in a practitioners decision to treat an individual patient with osteoarthritis include existing comorbid conditions and concomitant therapy, as well as the side effects and costs of specific treatments. The options for medical management of the patient with osteoarthritis who is at increased risk for a serious adverse upper gastrointestinal event, such as bleeding, perforation, or obstruction, are use of a COX-2specific inhibitor or a nonselective NSAID with gastroprotective therapy. Two COX-2specific inhibitors, celecoxib and rofecoxib, have been approved by the U.S. Food and Drug Administration for use in patients with osteoarthritis (25, 26). Celecoxib has been found to be more effective than placebo and as effective as naproxen for symptoms in patients with hip or knee osteoarthritis (27-29). Rofecoxib has also been found to be more effective than placebo and is comparable in efficacy to both ibuprofen and diclofenac in patients with hip or knee osteoarthritis (30, 31). Endoscopic studies have shown that celecoxib and rofecoxib are associated with an incidence of gastroduodenal ulcers lower than that of comparator NSAIDs and similar to that of placebo (25). These data suggest an advantageous safety profile compared with nonselective NSAIDs, especially for treatment of high-risk patients (21-23). However, no large long-term studies have been published that were designed to demonstrate differences between COX-2specific inhibitors and nonselective NSAIDs with respect to major gastrointestinal clinical outcomes; such studies are in progress. A further advantage of COX-2specific inhibitors with respect to upper gastrointestinal bleeding is that celecoxib and rofecoxib do not have a clinically significant effect on platelet aggregation or bleeding time. In addition, at doses recommended for treatment of osteoarthritis, these drugs appear to be better tolerated than comparator nonselective NSAIDs, with a lower incidence of dyspepsia and other gastrointestinal side effects. As with nonselective NSAIDs, however, COX-2specific inhibitors can cause renal toxicity. Caution must be exercised, therefore, if these drugs are used in patients with mild to moderate renal insufficiency, and they should not be used in patients with severe renal insufficiency. In addition, celecoxib is contraindicated in patients with a history of allergic reaction to a sulfonamide. The alternative to use of a COX-2specific inhibitor is use of a nonselective NSAID with a gastroprotective agent, an approach endorsed by the American College of Gastroenterology (23). As noted earlier, serious adverse upper gastrointestinal events attributed to NSAIDs in the elderly are dose dependent. Therefore, if nonselective NSAIDs are used, therapy should be begun at low, analgesic doses and increased to full anti-inflammatory doses only if lower doses do not provide adequate relief of symptoms. In a study of 8843 patients with rheumatoid arthritis, misoprostol at a dosage of 200 g four times daily reduced the incidence of serious ulcer complications, including perforation, bleeding, and obstruction, by 51% (32). In a 12-week randomized, double-blind, placebo-controlled endoscopy study, misoprostol at a dosage of 200 g three times per day had comparable efficacy in prevention of both gastric and duodenal ulcers; however, 200 g twice daily conferred significantly less protection against gastric ulcers (33). Side effects, particularly diarrhea and flatulence, may occur with this agent in a dose-dependent manner (33). Alternative approaches to prophylaxis with misoprostol include use of omeprazole or high-dose famotidine, both of which have been shown in carefully conducted endoscopy studies to be effective in treating and preventing NSAID-induced gastropathy (34-37). Histamine-2 blockers in usual doses, however, have not been found to be as effective as misoprostol (36), whereas omeprazole (20 mg/d or 40 mg/d) was as effective as misoprostol (200 g twice daily) in treatment of existing ulcers and was better tolerated and associated with a lower rate of relapse (37). Of note, proton-pump inhibitors have not been approved by the U.S. Food and Dr

A Randomized Trial of Tai Chi for Fibromyalgia

BACKGROUND Previous research has suggested that tai chi offers a therapeutic benefit in patients with fibromyalgia. METHODS We conducted a single-blind, randomized trial of classic Yang-style tai chi as compared with a control intervention consisting of wellness education and stretching for the treatment of fibromyalgia (defined by American College of Rheumatology 1990 criteria). Sessions lasted 60 minutes each and took place twice a week for 12 weeks for each of the study groups. The primary end point was a change in the Fibromyalgia Impact Questionnaire (FIQ) score (ranging from 0 to 100, with higher scores indicating more severe symptoms) at the end of 12 weeks. Secondary end points included summary scores on the physical and mental components of the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36). All assessments were repeated at 24 weeks to test the durability of the response. RESULTS Of the 66 randomly assigned patients, the 33 in the tai chi group had clinically important improvements in the FIQ total score and quality of life. Mean (+/-SD) baseline and 12-week FIQ scores for the tai chi group were 62.9+/-15.5 and 35.1+/-18.8, respectively, versus 68.0+/-11 and 58.6+/-17.6, respectively, for the control group (change from baseline in the tai chi group vs. change from baseline in the control group, -18.4 points; P<0.001). The corresponding SF-36 physical-component scores were 28.5+/-8.4 and 37.0+/-10.5 for the tai chi group versus 28.0+/-7.8 and 29.4+/-7.4 for the control group (between-group difference, 7.1 points; P=0.001), and the mental-component scores were 42.6+/-12.2 and 50.3+/-10.2 for the tai chi group versus 37.8+/-10.5 and 39.4+/-11.9 for the control group (between-group difference, 6.1 points; P=0.03). Improvements were maintained at 24 weeks (between-group difference in the FIQ score, -18.3 points; P<0.001). No adverse events were observed. CONCLUSIONS Tai chi may be a useful treatment for fibromyalgia and merits long-term study in larger study populations. (Funded by the National Center for Complementary and Alternative Medicine and others; ClinicalTrials.gov number, NCT00515008.)

Occupational activity and osteoarthritis of the knee.

OBJECTIVES--To test the hypothesis that specific occupational physical activities are risk factors for knee osteoarthritis (OA). METHODS--A population-based case-control study of knee osteoarthritis was carried out in which 109 men and women with painful, radiographically confirmed knee OA were compared with 218 age and sex matched controls who had not suffered knee pain and had normal radiographs. Information collected included a lifetime occupational history and details of specific workplace physical activities. RESULTS--After adjustment for obesity and Heberdens nodes, the risk of knee OA was significantly elevated in subjects whose main job entailed more than 30 minutes per day squatting (OR 6.9, 95% CI 1.8-26.4) or kneeling (OR 3.4, 95% CI 1.3-9.1), or climbing more than ten flights of stairs per day (OR 2.7, 95% CI 1.2-6.1). The increase in risk associated with kneeling or squatting appeared to be more marked in subjects whose jobs entailed heavy lifting, but the size of the study did not permit precise delineation of any such interaction. CONCLUSIONS--These data suggest that prolonged or repeated knee bending is a risk factor for knee OA, and that risk may be higher in jobs which entail both knee bending and mechanical loading.

Contribution of meniscal extrusion and cartilage loss to joint space narrowing in osteoarthritis.

OBJECTIVE This study was undertaken to determine the contribution of meniscal extrusion and cartilage loss to joint space narrowing on conventional radiographs by correlation with magnetic resonance imaging (MRI). SUBJECTS AND METHODS Sixty-two consecutive patients, 32 patients with osteoarthritis and 30 without osteoarthritis, over the age of 60 years that were referred for both radiographic and MRI of the knee were included in the study. In each case, relative joint space narrowing on conventional AP radiographs was assessed utilizing the Kellgren-Lawrence scoring system. Subsequently, the degree of meniscal extrusion and the integrity of articular cartilage were evaluated from MR in the same patients. RESULTS Each of 30 patients with normal joint space (Kellgren Grade 0) were noted to have normal articular cartilage, grade 1 meniscal extrusion was identified in only three of these patients. In comparison, meniscal extrusion was identified in all 32 patients with joint space narrowing (Kellgren Grades 1-4). Definite thinning or loss of articular cartilage was identified in only 15 of the 32 cases. In 17 patients with radiographic joint space narrowing (Kellgren Grades 1-3) and meniscal extrusion, no loss of articular cartilage was observed. A statistically significant correlation (P<0.001) was observed between Kellgren Grade and degree of meniscal extrusion and cartilage thinning on MRI. CONCLUSION Conventional radiographs are an unreliable method of evaluating for articular cartilage loss in patients with early osteoarthritis. Initial joint space narrowing on conventional radiographs is secondary to meniscal extrusion rather than thinning of articular cartilage in most cases.

Therapeutic trajectory of hyaluronic acid versus corticosteroids in the treatment of knee osteoarthritis: a systematic review and meta-analysis.

OBJECTIVE To compare the efficacy of intraarticular hyaluronic acid with corticosteroids for knee osteoarthritis (OA). METHODS Our data sources were Medline, EMBASE, CINAHL, BIOSIS, and the Cochrane database, as well as hand- searched reviews, manuscripts, and supplements. For unpublished data we used author contacts. Randomized trials that reported effects of intraarticular hyaluronic acid versus corticosteroids on knee OA were selected based on inclusion criteria. Two reviewers extracted data independently. Using a random-effects model, we computed effect sizes for pain change from baseline at 2, 4, 8, 12, and 26 weeks. We also performed multivariate analyses accounting for within and between-study covariance. We performed sensitivity analyses for trials that reported intent-to-treat (ITT) analysis and blinding, and directly compared Hyalgan with methylprednisolone. RESULTS The 7 eligible trials included 606 participants. Five reported ITT analyses. At week 2 the effect size was -0.39 (95% confidence interval [95% CI], -0.65, -0.12) favoring corticosteroids; at week 4 it was -0.01 (95% CI -0.23, 0.21) suggesting equal efficacy. At week 8 the effect size was 0.22 (95% CI -0.05, 0.49) favoring hyaluronic acid, and at week 12 it was 0.35 (95% CI 0.03, 0.66) favoring hyaluronic acid. At week 26 the effect size was 0.39 (95% CI 0.18, 0.59), favoring hyaluronic acid. The multivariate analyses and sensitivity analyses generated consistent results. CONCLUSION From baseline to week 4, intraarticular corticosteroids appear to be relatively more effective for pain than intraarticular hyaluronic acid. By week 4, the 2 approaches have equal efficacy, but beyond week 8, hyaluronic acid has greater efficacy. Understanding this trend is useful to clinicians when treating knee OA.