User login
How do clinical prediction rules compare with joint fluid analysis in diagnosing gout?
EVIDENCE-BASED ANSWER:
Clinical prediction rules effectively diagnose gout without joint fluid analysis. The American College of Rheumatology clinical prediction rules, the most accurate rules developed for research purposes, have a sensitivity of 92%, specificity of 89%, positive likelihood ratio of 8.36, and negative likelihood ratio of 0.09 (strength of recommendation [SOR]: A, prospective cohort studies).
The Netherlands criteria, developed for use in primary care, have a positive predictive value of more than 80%, a positive likelihood ratio of 3.48, and a negative likelihood ratio of 0.17 (SOR: A, prospective cohort study).
EVIDENCE SUMMARY
In 2015, the American College of Rheumatology (ACR) redefined the clinical criteria for diagnosis of gout based on a 3-step system1 that can be found at: http://goutclassificationcalculator.auckland.ac.nz. The ACR rule was derived from a cross-sectional study of 983 patients in 25 rheumatology centers in 16 countries who presented with a swollen joint.2 Of the 983 patients, 509 had gout; the prevalence was 52%. Data from 653 of these patients were used to develop the rule and then validated in the remaining 330 patients.
Compared with the gold standard of monosodium urate crystals in synovial fluid, the ACR rule has a sensitivity of 92% and a specificity of 89%. The rule, designed for the research setting, involves using synovial fluid analysis, ultrasound imaging, and radiography, which makes it less useful in a primary care setting.
The Netherlands rule for primary care
A prospective diagnostic study in 328 family medicine patients (74% male; mean age 57) with monoarthritis tested the ability of multiple clinical variables to diagnose gout using monosodium urate crystals in synovial fluid as the gold standard.3 The prevalence of gout in this population was 57%.
The best diagnostic rule (Netherlands rule) comprised the following predefined variables: male sex, previous patient-reported arthritis attack, onset within one day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or cardiovascular disease (angina pectoris, myocardial infarction, heart failure, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease), and serum uric acid level above 5.88 mg/dL. The rule gives one point for each item. A score >8 had a positive likelihood ratio for diagnosing gout of 3.48 (TABLE1) and a higher positive predictive value (PPV) than family physicians’ clinical impressions (83% vs 64%).
The prevalence of gout in patients with scores of <4, 4 to 8, and >8 were 2.8%, 27%, and 80%, respectively. For scores of 4 to 8, the probability of gout is indeterminate, and synovial fluid analysis is recommended.
The Netherlands rule, validated in a secondary care practice of 390 patients with monoarthritis, found that a score >8 had a PPV of 87% and a score <4 had a negative predictive value of 95%.4 The probability of gout based on this rule can be calculated at http://www.umcn.nl/goutcalc.
In the study used to develop the Netherlands rule, no patients with a high probability of gout had septic arthritis. The ability of the rule to differentiate between gout and septic arthritis was tested retrospectively in 33 patients with acute gout (podagra excluded) diagnosed by the presence of monosodium urate joint crystals and 27 patients with septic arthritis diagnosed by positive bacterial culture.5 Patients with gout had significantly higher scores than patients with septic arthritis (7.8 ± 1.59 vs 3.4 ± 2.3; P<.001).
American Rheumatology Association, New York, and Rome prediction rules
A study of 82 Veterans Administration patients compared the American Rheumatology Association (ARA), New York, and Rome prediction rules with regard to their ability to diagnose gout with synovial urate crystals.6 The ARA criteria for gout diagnosis require either tophi or monosodium urate crystals in synovial fluid, or 6 out of a list of 12 other criteria.7
The New York prediction rule requires that patients meet 2 or more of the following criteria: at least 2 attacks of painful joint swelling with complete resolution within 2 weeks, podagra, tophi, and rapid response to colchicine treatment, defined as a major reduction in the objective signs of inflammation within 48 hours.
The Rome prediction rule requires meeting 2 of 3 criteria: serum uric acid >7 mg/dL in men and >6 mg/dL in women, presence of tophi, and history of attacks of painful joint swelling with abrupt onset and resolution within 2 weeks.
The New York prediction rule had the highest positive likelihood ratio of 4.4 compared with the ARA (1.8) and Rome (4.3) rules.6 The utility of the New York and Rome rules, although they have fewer criteria than ARA, is limited by the fact that they include a previous episode of joint swelling and tophi. These criteria increase their specificity but make them less useful in diagnosing a first episode of gout, when tophi are unlikely to have developed.
Prediction rules are more sensitive in established gout
The new ACR prediction rule was compared with the ARA, Rome, and New York clinical prediction rules using urate crystals as the gold standard in early (less than 2 years) and established disease (longer than 2 years).8 All clinical prediction rules were more sensitive in established disease than early disease (95.3% vs 84.1%; P<.001) and more specific in early disease than established disease (79.9% vs 52.5%; P<.001).
1. Neogi T, Jansen TL, Dalbeth N, et al. 2015 Gout Classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2015;74:1789-1798.
2. Taylor WJ, Fransen J, Jansen TL, et al. Study for Updated Gout Classification Criteria (SUGAR): identification of features to classify gout. Arthritis Care Res (Hoboken). 2015;67:1304-1315.
3. Janssens HJ, Fransen J, van de Lisdonk EH, et al. A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis. Arch Intern Med. 2010;170:1120-1126.
4. Kienhorst LB, Janssens HJ, Fransen J, et al. The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study. Rheumatology (Oxford). 2015;54:609-614.
5. Lee K, Choi ST, Kang EJ, et al. SAT0377 The performance of a novel scoring system in the differential diagnosis between acute gout and septic arthritis. Ann Rheum Dis. 2013;72:A711.
6. Malik A, Schumacher HR, Dinnella JE, et al. Clinical diagnostic criteria for gout: comparison with the gold standard of synovial fluid crystal analysis. J Clin Rheumatol. 2009;15:22.
7. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20:895-900.
8. Taylor WJ, Fransen J, Dalbeth N, et al. Performance of classification criteria for gout in early and established disease. Ann Rheum Dis. 2016;75:178-182.
EVIDENCE-BASED ANSWER:
Clinical prediction rules effectively diagnose gout without joint fluid analysis. The American College of Rheumatology clinical prediction rules, the most accurate rules developed for research purposes, have a sensitivity of 92%, specificity of 89%, positive likelihood ratio of 8.36, and negative likelihood ratio of 0.09 (strength of recommendation [SOR]: A, prospective cohort studies).
The Netherlands criteria, developed for use in primary care, have a positive predictive value of more than 80%, a positive likelihood ratio of 3.48, and a negative likelihood ratio of 0.17 (SOR: A, prospective cohort study).
EVIDENCE SUMMARY
In 2015, the American College of Rheumatology (ACR) redefined the clinical criteria for diagnosis of gout based on a 3-step system1 that can be found at: http://goutclassificationcalculator.auckland.ac.nz. The ACR rule was derived from a cross-sectional study of 983 patients in 25 rheumatology centers in 16 countries who presented with a swollen joint.2 Of the 983 patients, 509 had gout; the prevalence was 52%. Data from 653 of these patients were used to develop the rule and then validated in the remaining 330 patients.
Compared with the gold standard of monosodium urate crystals in synovial fluid, the ACR rule has a sensitivity of 92% and a specificity of 89%. The rule, designed for the research setting, involves using synovial fluid analysis, ultrasound imaging, and radiography, which makes it less useful in a primary care setting.
The Netherlands rule for primary care
A prospective diagnostic study in 328 family medicine patients (74% male; mean age 57) with monoarthritis tested the ability of multiple clinical variables to diagnose gout using monosodium urate crystals in synovial fluid as the gold standard.3 The prevalence of gout in this population was 57%.
The best diagnostic rule (Netherlands rule) comprised the following predefined variables: male sex, previous patient-reported arthritis attack, onset within one day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or cardiovascular disease (angina pectoris, myocardial infarction, heart failure, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease), and serum uric acid level above 5.88 mg/dL. The rule gives one point for each item. A score >8 had a positive likelihood ratio for diagnosing gout of 3.48 (TABLE1) and a higher positive predictive value (PPV) than family physicians’ clinical impressions (83% vs 64%).
The prevalence of gout in patients with scores of <4, 4 to 8, and >8 were 2.8%, 27%, and 80%, respectively. For scores of 4 to 8, the probability of gout is indeterminate, and synovial fluid analysis is recommended.
The Netherlands rule, validated in a secondary care practice of 390 patients with monoarthritis, found that a score >8 had a PPV of 87% and a score <4 had a negative predictive value of 95%.4 The probability of gout based on this rule can be calculated at http://www.umcn.nl/goutcalc.
In the study used to develop the Netherlands rule, no patients with a high probability of gout had septic arthritis. The ability of the rule to differentiate between gout and septic arthritis was tested retrospectively in 33 patients with acute gout (podagra excluded) diagnosed by the presence of monosodium urate joint crystals and 27 patients with septic arthritis diagnosed by positive bacterial culture.5 Patients with gout had significantly higher scores than patients with septic arthritis (7.8 ± 1.59 vs 3.4 ± 2.3; P<.001).
American Rheumatology Association, New York, and Rome prediction rules
A study of 82 Veterans Administration patients compared the American Rheumatology Association (ARA), New York, and Rome prediction rules with regard to their ability to diagnose gout with synovial urate crystals.6 The ARA criteria for gout diagnosis require either tophi or monosodium urate crystals in synovial fluid, or 6 out of a list of 12 other criteria.7
The New York prediction rule requires that patients meet 2 or more of the following criteria: at least 2 attacks of painful joint swelling with complete resolution within 2 weeks, podagra, tophi, and rapid response to colchicine treatment, defined as a major reduction in the objective signs of inflammation within 48 hours.
The Rome prediction rule requires meeting 2 of 3 criteria: serum uric acid >7 mg/dL in men and >6 mg/dL in women, presence of tophi, and history of attacks of painful joint swelling with abrupt onset and resolution within 2 weeks.
The New York prediction rule had the highest positive likelihood ratio of 4.4 compared with the ARA (1.8) and Rome (4.3) rules.6 The utility of the New York and Rome rules, although they have fewer criteria than ARA, is limited by the fact that they include a previous episode of joint swelling and tophi. These criteria increase their specificity but make them less useful in diagnosing a first episode of gout, when tophi are unlikely to have developed.
Prediction rules are more sensitive in established gout
The new ACR prediction rule was compared with the ARA, Rome, and New York clinical prediction rules using urate crystals as the gold standard in early (less than 2 years) and established disease (longer than 2 years).8 All clinical prediction rules were more sensitive in established disease than early disease (95.3% vs 84.1%; P<.001) and more specific in early disease than established disease (79.9% vs 52.5%; P<.001).
EVIDENCE-BASED ANSWER:
Clinical prediction rules effectively diagnose gout without joint fluid analysis. The American College of Rheumatology clinical prediction rules, the most accurate rules developed for research purposes, have a sensitivity of 92%, specificity of 89%, positive likelihood ratio of 8.36, and negative likelihood ratio of 0.09 (strength of recommendation [SOR]: A, prospective cohort studies).
The Netherlands criteria, developed for use in primary care, have a positive predictive value of more than 80%, a positive likelihood ratio of 3.48, and a negative likelihood ratio of 0.17 (SOR: A, prospective cohort study).
EVIDENCE SUMMARY
In 2015, the American College of Rheumatology (ACR) redefined the clinical criteria for diagnosis of gout based on a 3-step system1 that can be found at: http://goutclassificationcalculator.auckland.ac.nz. The ACR rule was derived from a cross-sectional study of 983 patients in 25 rheumatology centers in 16 countries who presented with a swollen joint.2 Of the 983 patients, 509 had gout; the prevalence was 52%. Data from 653 of these patients were used to develop the rule and then validated in the remaining 330 patients.
Compared with the gold standard of monosodium urate crystals in synovial fluid, the ACR rule has a sensitivity of 92% and a specificity of 89%. The rule, designed for the research setting, involves using synovial fluid analysis, ultrasound imaging, and radiography, which makes it less useful in a primary care setting.
The Netherlands rule for primary care
A prospective diagnostic study in 328 family medicine patients (74% male; mean age 57) with monoarthritis tested the ability of multiple clinical variables to diagnose gout using monosodium urate crystals in synovial fluid as the gold standard.3 The prevalence of gout in this population was 57%.
The best diagnostic rule (Netherlands rule) comprised the following predefined variables: male sex, previous patient-reported arthritis attack, onset within one day, joint redness, first metatarsophalangeal joint (MTP1) involvement, hypertension or cardiovascular disease (angina pectoris, myocardial infarction, heart failure, cerebrovascular accident, transient ischemic attack, or peripheral vascular disease), and serum uric acid level above 5.88 mg/dL. The rule gives one point for each item. A score >8 had a positive likelihood ratio for diagnosing gout of 3.48 (TABLE1) and a higher positive predictive value (PPV) than family physicians’ clinical impressions (83% vs 64%).
The prevalence of gout in patients with scores of <4, 4 to 8, and >8 were 2.8%, 27%, and 80%, respectively. For scores of 4 to 8, the probability of gout is indeterminate, and synovial fluid analysis is recommended.
The Netherlands rule, validated in a secondary care practice of 390 patients with monoarthritis, found that a score >8 had a PPV of 87% and a score <4 had a negative predictive value of 95%.4 The probability of gout based on this rule can be calculated at http://www.umcn.nl/goutcalc.
In the study used to develop the Netherlands rule, no patients with a high probability of gout had septic arthritis. The ability of the rule to differentiate between gout and septic arthritis was tested retrospectively in 33 patients with acute gout (podagra excluded) diagnosed by the presence of monosodium urate joint crystals and 27 patients with septic arthritis diagnosed by positive bacterial culture.5 Patients with gout had significantly higher scores than patients with septic arthritis (7.8 ± 1.59 vs 3.4 ± 2.3; P<.001).
American Rheumatology Association, New York, and Rome prediction rules
A study of 82 Veterans Administration patients compared the American Rheumatology Association (ARA), New York, and Rome prediction rules with regard to their ability to diagnose gout with synovial urate crystals.6 The ARA criteria for gout diagnosis require either tophi or monosodium urate crystals in synovial fluid, or 6 out of a list of 12 other criteria.7
The New York prediction rule requires that patients meet 2 or more of the following criteria: at least 2 attacks of painful joint swelling with complete resolution within 2 weeks, podagra, tophi, and rapid response to colchicine treatment, defined as a major reduction in the objective signs of inflammation within 48 hours.
The Rome prediction rule requires meeting 2 of 3 criteria: serum uric acid >7 mg/dL in men and >6 mg/dL in women, presence of tophi, and history of attacks of painful joint swelling with abrupt onset and resolution within 2 weeks.
The New York prediction rule had the highest positive likelihood ratio of 4.4 compared with the ARA (1.8) and Rome (4.3) rules.6 The utility of the New York and Rome rules, although they have fewer criteria than ARA, is limited by the fact that they include a previous episode of joint swelling and tophi. These criteria increase their specificity but make them less useful in diagnosing a first episode of gout, when tophi are unlikely to have developed.
Prediction rules are more sensitive in established gout
The new ACR prediction rule was compared with the ARA, Rome, and New York clinical prediction rules using urate crystals as the gold standard in early (less than 2 years) and established disease (longer than 2 years).8 All clinical prediction rules were more sensitive in established disease than early disease (95.3% vs 84.1%; P<.001) and more specific in early disease than established disease (79.9% vs 52.5%; P<.001).
1. Neogi T, Jansen TL, Dalbeth N, et al. 2015 Gout Classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2015;74:1789-1798.
2. Taylor WJ, Fransen J, Jansen TL, et al. Study for Updated Gout Classification Criteria (SUGAR): identification of features to classify gout. Arthritis Care Res (Hoboken). 2015;67:1304-1315.
3. Janssens HJ, Fransen J, van de Lisdonk EH, et al. A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis. Arch Intern Med. 2010;170:1120-1126.
4. Kienhorst LB, Janssens HJ, Fransen J, et al. The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study. Rheumatology (Oxford). 2015;54:609-614.
5. Lee K, Choi ST, Kang EJ, et al. SAT0377 The performance of a novel scoring system in the differential diagnosis between acute gout and septic arthritis. Ann Rheum Dis. 2013;72:A711.
6. Malik A, Schumacher HR, Dinnella JE, et al. Clinical diagnostic criteria for gout: comparison with the gold standard of synovial fluid crystal analysis. J Clin Rheumatol. 2009;15:22.
7. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20:895-900.
8. Taylor WJ, Fransen J, Dalbeth N, et al. Performance of classification criteria for gout in early and established disease. Ann Rheum Dis. 2016;75:178-182.
1. Neogi T, Jansen TL, Dalbeth N, et al. 2015 Gout Classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2015;74:1789-1798.
2. Taylor WJ, Fransen J, Jansen TL, et al. Study for Updated Gout Classification Criteria (SUGAR): identification of features to classify gout. Arthritis Care Res (Hoboken). 2015;67:1304-1315.
3. Janssens HJ, Fransen J, van de Lisdonk EH, et al. A diagnostic rule for acute gouty arthritis in primary care without joint fluid analysis. Arch Intern Med. 2010;170:1120-1126.
4. Kienhorst LB, Janssens HJ, Fransen J, et al. The validation of a diagnostic rule for gout without joint fluid analysis: a prospective study. Rheumatology (Oxford). 2015;54:609-614.
5. Lee K, Choi ST, Kang EJ, et al. SAT0377 The performance of a novel scoring system in the differential diagnosis between acute gout and septic arthritis. Ann Rheum Dis. 2013;72:A711.
6. Malik A, Schumacher HR, Dinnella JE, et al. Clinical diagnostic criteria for gout: comparison with the gold standard of synovial fluid crystal analysis. J Clin Rheumatol. 2009;15:22.
7. Wallace SL, Robinson H, Masi AT, et al. Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum. 1977;20:895-900.
8. Taylor WJ, Fransen J, Dalbeth N, et al. Performance of classification criteria for gout in early and established disease. Ann Rheum Dis. 2016;75:178-182.
Evidence-based answers from the Family Physicians Inquiries Network
Which patients with metabolic syndrome benefit from metformin?
EVIDENCE-BASED ANSWER:
Patients at highest risk for progression to diabetes benefit from metformin.
In patients with metabolic syndrome who are in the highest-risk quartile for progression to diabetes (predicted mean 3-year risk, 60%), metformin, 850 mg twice daily, reduces the absolute risk by about 20% over a 3-year period. Metformin doesn’t reduce the incidence in patients at lower risk of progression (strength of recommendation [SOR]: C, post-hoc analysis of a randomized controlled trial [RCT]).
Intensive lifestyle modification reduces absolute risk in all patients proportionate to risk quartile (from 5% reduction for the lowest quartile to 28% for the highest). Over a 10-year period, intensive lifestyle modification reduces the absolute risk of diabetes by 34% and metformin reduces the risk by 18% for all patients at increased risk (considered as a group)—that is, not separated by risk quartile (SOR: A, large prospective RCTs).
Lower doses or shorter courses of metformin reduce fasting plasma glucose (SOR: C, RCTs with laboratory outcomes) and may reduce the risk of developing diabetes by a smaller amount (SOR: C, flawed RCT).
EVIDENCE SUMMARY
A post-hoc analysis of a prospective RCT (the Diabetes Prevention Program) comprising 3081 patients with impaired glucose metabolism who received metformin, a lifestyle modification program, or no intervention (placebo) found that metformin reduced the risk of developing diabetes only for patients in the highest risk quartile over 2.8 years. Lifestyle modification reduced diabetes risk in all patients.1
Investigators stratified patients who met National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome into risk quartiles for progression to diabetes using a model they developed based on 7 parameters: fasting plasma glucose, hemoglobin A1c, history of high blood glucose, waist:hip ratio, waist circumference, triglycerides, and height (TABLE1). The model reasonably fit outcomes—the percentage of patients in each quartile who developed diabetes—with an area under the receiver operator characteristic curve of 0.73 (a measure of diagnostic accuracy where 1 is a perfect predictor and 0.5 is random).
Lifestyle modification reduced risk in all quartiles with progressively greater effect as risk increased (lowest risk quartile: ARR=4.9%, 3-year NNT=20.4; highest risk quartile: ARR=28.3%; 3-year NNT=3.5).
There were 2 key weaknesses of the risk model: It wasn’t validated in a separate population and the true incidence of diabetes among patients taking placebo was higher than predicted. The investigators compared their risk prediction model results with the Framingham Risk Score (FRS) for diabetes and found that they correlated well, although the FRS results were consistently about 6% (absolute) higher when corrected for duration. (The FRS calculator is available online at www.framinghamheartstudy.org/risk-functions/diabetes/.)
Lifestyle change reduces diabetes risk more than metformin
The original Diabetes Prevention Program found that intensive lifestyle intervention and metformin reduced the number of diabetes cases over 2.8 years among 3234 patients at risk for developing diabetes.2
Compared with no intervention, fewer patients developed diabetes with either metformin or lifestyle improvement, although lifestyle change had the larger effect (no intervention: 11 cases per 100 person-years; metformin: 7.8 cases; 95% confidence interval [CI], 6.8-8.8; ARR=3.2% per year vs no intervention; lifestyle improvements: 4.8 cases; 95% CI, 4.1-5.7; ARR=6.2% per year vs no intervention).
The effect of metformin and lifestyle change persists at 10 years
A 10-year follow-up study to the Diabetes Prevention Program found that, compared with no intervention, both metformin and lifestyle interventions continued to be associated with a lower incidence of diabetes (no intervention: 7.8 cases per 100 person-years; 95% CI, 4.8-6.5; metformin: 6.4 cases; 95% CI, 4.2-5.7; ARR=1.4% per year; lifestyle interventions: 5.3 cases; 95% CI, 5.1-6.8; ARR=2.5% per year).3
Researchers originally randomized 3234 patients with body mass index ≥24 kg/m2, fasting blood sugar 95 to 125 mg/dL, and 2-hour post 75-gm glucose value of 149 to 199 mg/dL to 3 groups: intensive lifestyle modification (weight loss goal of 7%, 150 minutes a week of exercise), metformin (850 mg twice daily), and no intervention. After the 2.8-year follow-up period, 2766 patients continued for another 5.7 years of follow-up. Investigators offered group lifestyle counseling to all patients and continued metformin at the same dose in the second group.
Earlier study shows an effect for metformin, but with a caveat
An earlier RCT found that metformin reduced the risk of developing diabetes in patients with metabolic syndrome.4 Investigators randomized 70 patients to metformin (250 mg 3 times daily) or placebo for a year. Fewer patients developed diabetes with metformin (3% vs 16.2%, P=.011; NNT=7.6) and more had a normal glucose tolerance test result (84.9% vs 51.4%, P=.011; NNT=3). However, by current American Diabetes Association criteria, half of the subjects had early diabetes at baseline.
Metformin lowers fasting blood sugar, but may not reverse metabolic syndrome
A post-hoc analysis of another RCT found that metformin reduced fasting plasma glucose (FPG) levels in patients with upper-body obesity and metabolic syndrome (by 1999 World Health Organization criteria but not NCEP ATP III criteria).5
Investigators randomized 457 patients to metformin 850 mg once daily or placebo and followed them for a year. FPG levels decreased with metformin but increased with placebo (reduction FPG 5.9 mg/dL vs increase FPG 12.3 mg/dL; P<.04). The investigators didn’t report whether any patients developed diabetes.
However, another RCT (155 patients) that compared metformin 850 mg twice daily with placebo in subjects with metabolic syndrome but without diabetes found greater normalization of FPG (5% vs 0%; P=.005), but no reversal of metabolic syndrome or change in Framingham 10-year risk score after 12 weeks.6
1. Sussman JB, Kent DM, Nelson JP, et al. Improving diabetes prevention with benefit based tailored treatment: risk based reanalysis of Diabetes Prevention Program. BMJ. 2015;350:h454.
2. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
3. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Outcomes Study. Lancet. 2009:374:1677-1686.
4. Li CL, Pan CY, Lu JM, et al. Effect of metformin on patients with impaired glucose tolerance. Diabetes Med. 1999;16:477-481.
5. Fontbonne A, Diouf I, Baccara-Dinet M, et al. Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper-body obese subjects with mild glucose anomalies: a post-hoc analysis of the BIGPRO1 trial. Diabetes Metab. 2009;35:385-391.
6. Nieuwdorp M, Stroes ESG, Kastelein JJP. Normalization of metabolic syndrome using fenofibrate, metformin or their combination. Diabetes Obesity Metab. 2007;9:869-878.
EVIDENCE-BASED ANSWER:
Patients at highest risk for progression to diabetes benefit from metformin.
In patients with metabolic syndrome who are in the highest-risk quartile for progression to diabetes (predicted mean 3-year risk, 60%), metformin, 850 mg twice daily, reduces the absolute risk by about 20% over a 3-year period. Metformin doesn’t reduce the incidence in patients at lower risk of progression (strength of recommendation [SOR]: C, post-hoc analysis of a randomized controlled trial [RCT]).
Intensive lifestyle modification reduces absolute risk in all patients proportionate to risk quartile (from 5% reduction for the lowest quartile to 28% for the highest). Over a 10-year period, intensive lifestyle modification reduces the absolute risk of diabetes by 34% and metformin reduces the risk by 18% for all patients at increased risk (considered as a group)—that is, not separated by risk quartile (SOR: A, large prospective RCTs).
Lower doses or shorter courses of metformin reduce fasting plasma glucose (SOR: C, RCTs with laboratory outcomes) and may reduce the risk of developing diabetes by a smaller amount (SOR: C, flawed RCT).
EVIDENCE SUMMARY
A post-hoc analysis of a prospective RCT (the Diabetes Prevention Program) comprising 3081 patients with impaired glucose metabolism who received metformin, a lifestyle modification program, or no intervention (placebo) found that metformin reduced the risk of developing diabetes only for patients in the highest risk quartile over 2.8 years. Lifestyle modification reduced diabetes risk in all patients.1
Investigators stratified patients who met National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome into risk quartiles for progression to diabetes using a model they developed based on 7 parameters: fasting plasma glucose, hemoglobin A1c, history of high blood glucose, waist:hip ratio, waist circumference, triglycerides, and height (TABLE1). The model reasonably fit outcomes—the percentage of patients in each quartile who developed diabetes—with an area under the receiver operator characteristic curve of 0.73 (a measure of diagnostic accuracy where 1 is a perfect predictor and 0.5 is random).
Lifestyle modification reduced risk in all quartiles with progressively greater effect as risk increased (lowest risk quartile: ARR=4.9%, 3-year NNT=20.4; highest risk quartile: ARR=28.3%; 3-year NNT=3.5).
There were 2 key weaknesses of the risk model: It wasn’t validated in a separate population and the true incidence of diabetes among patients taking placebo was higher than predicted. The investigators compared their risk prediction model results with the Framingham Risk Score (FRS) for diabetes and found that they correlated well, although the FRS results were consistently about 6% (absolute) higher when corrected for duration. (The FRS calculator is available online at www.framinghamheartstudy.org/risk-functions/diabetes/.)
Lifestyle change reduces diabetes risk more than metformin
The original Diabetes Prevention Program found that intensive lifestyle intervention and metformin reduced the number of diabetes cases over 2.8 years among 3234 patients at risk for developing diabetes.2
Compared with no intervention, fewer patients developed diabetes with either metformin or lifestyle improvement, although lifestyle change had the larger effect (no intervention: 11 cases per 100 person-years; metformin: 7.8 cases; 95% confidence interval [CI], 6.8-8.8; ARR=3.2% per year vs no intervention; lifestyle improvements: 4.8 cases; 95% CI, 4.1-5.7; ARR=6.2% per year vs no intervention).
The effect of metformin and lifestyle change persists at 10 years
A 10-year follow-up study to the Diabetes Prevention Program found that, compared with no intervention, both metformin and lifestyle interventions continued to be associated with a lower incidence of diabetes (no intervention: 7.8 cases per 100 person-years; 95% CI, 4.8-6.5; metformin: 6.4 cases; 95% CI, 4.2-5.7; ARR=1.4% per year; lifestyle interventions: 5.3 cases; 95% CI, 5.1-6.8; ARR=2.5% per year).3
Researchers originally randomized 3234 patients with body mass index ≥24 kg/m2, fasting blood sugar 95 to 125 mg/dL, and 2-hour post 75-gm glucose value of 149 to 199 mg/dL to 3 groups: intensive lifestyle modification (weight loss goal of 7%, 150 minutes a week of exercise), metformin (850 mg twice daily), and no intervention. After the 2.8-year follow-up period, 2766 patients continued for another 5.7 years of follow-up. Investigators offered group lifestyle counseling to all patients and continued metformin at the same dose in the second group.
Earlier study shows an effect for metformin, but with a caveat
An earlier RCT found that metformin reduced the risk of developing diabetes in patients with metabolic syndrome.4 Investigators randomized 70 patients to metformin (250 mg 3 times daily) or placebo for a year. Fewer patients developed diabetes with metformin (3% vs 16.2%, P=.011; NNT=7.6) and more had a normal glucose tolerance test result (84.9% vs 51.4%, P=.011; NNT=3). However, by current American Diabetes Association criteria, half of the subjects had early diabetes at baseline.
Metformin lowers fasting blood sugar, but may not reverse metabolic syndrome
A post-hoc analysis of another RCT found that metformin reduced fasting plasma glucose (FPG) levels in patients with upper-body obesity and metabolic syndrome (by 1999 World Health Organization criteria but not NCEP ATP III criteria).5
Investigators randomized 457 patients to metformin 850 mg once daily or placebo and followed them for a year. FPG levels decreased with metformin but increased with placebo (reduction FPG 5.9 mg/dL vs increase FPG 12.3 mg/dL; P<.04). The investigators didn’t report whether any patients developed diabetes.
However, another RCT (155 patients) that compared metformin 850 mg twice daily with placebo in subjects with metabolic syndrome but without diabetes found greater normalization of FPG (5% vs 0%; P=.005), but no reversal of metabolic syndrome or change in Framingham 10-year risk score after 12 weeks.6
EVIDENCE-BASED ANSWER:
Patients at highest risk for progression to diabetes benefit from metformin.
In patients with metabolic syndrome who are in the highest-risk quartile for progression to diabetes (predicted mean 3-year risk, 60%), metformin, 850 mg twice daily, reduces the absolute risk by about 20% over a 3-year period. Metformin doesn’t reduce the incidence in patients at lower risk of progression (strength of recommendation [SOR]: C, post-hoc analysis of a randomized controlled trial [RCT]).
Intensive lifestyle modification reduces absolute risk in all patients proportionate to risk quartile (from 5% reduction for the lowest quartile to 28% for the highest). Over a 10-year period, intensive lifestyle modification reduces the absolute risk of diabetes by 34% and metformin reduces the risk by 18% for all patients at increased risk (considered as a group)—that is, not separated by risk quartile (SOR: A, large prospective RCTs).
Lower doses or shorter courses of metformin reduce fasting plasma glucose (SOR: C, RCTs with laboratory outcomes) and may reduce the risk of developing diabetes by a smaller amount (SOR: C, flawed RCT).
EVIDENCE SUMMARY
A post-hoc analysis of a prospective RCT (the Diabetes Prevention Program) comprising 3081 patients with impaired glucose metabolism who received metformin, a lifestyle modification program, or no intervention (placebo) found that metformin reduced the risk of developing diabetes only for patients in the highest risk quartile over 2.8 years. Lifestyle modification reduced diabetes risk in all patients.1
Investigators stratified patients who met National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) criteria for metabolic syndrome into risk quartiles for progression to diabetes using a model they developed based on 7 parameters: fasting plasma glucose, hemoglobin A1c, history of high blood glucose, waist:hip ratio, waist circumference, triglycerides, and height (TABLE1). The model reasonably fit outcomes—the percentage of patients in each quartile who developed diabetes—with an area under the receiver operator characteristic curve of 0.73 (a measure of diagnostic accuracy where 1 is a perfect predictor and 0.5 is random).
Lifestyle modification reduced risk in all quartiles with progressively greater effect as risk increased (lowest risk quartile: ARR=4.9%, 3-year NNT=20.4; highest risk quartile: ARR=28.3%; 3-year NNT=3.5).
There were 2 key weaknesses of the risk model: It wasn’t validated in a separate population and the true incidence of diabetes among patients taking placebo was higher than predicted. The investigators compared their risk prediction model results with the Framingham Risk Score (FRS) for diabetes and found that they correlated well, although the FRS results were consistently about 6% (absolute) higher when corrected for duration. (The FRS calculator is available online at www.framinghamheartstudy.org/risk-functions/diabetes/.)
Lifestyle change reduces diabetes risk more than metformin
The original Diabetes Prevention Program found that intensive lifestyle intervention and metformin reduced the number of diabetes cases over 2.8 years among 3234 patients at risk for developing diabetes.2
Compared with no intervention, fewer patients developed diabetes with either metformin or lifestyle improvement, although lifestyle change had the larger effect (no intervention: 11 cases per 100 person-years; metformin: 7.8 cases; 95% confidence interval [CI], 6.8-8.8; ARR=3.2% per year vs no intervention; lifestyle improvements: 4.8 cases; 95% CI, 4.1-5.7; ARR=6.2% per year vs no intervention).
The effect of metformin and lifestyle change persists at 10 years
A 10-year follow-up study to the Diabetes Prevention Program found that, compared with no intervention, both metformin and lifestyle interventions continued to be associated with a lower incidence of diabetes (no intervention: 7.8 cases per 100 person-years; 95% CI, 4.8-6.5; metformin: 6.4 cases; 95% CI, 4.2-5.7; ARR=1.4% per year; lifestyle interventions: 5.3 cases; 95% CI, 5.1-6.8; ARR=2.5% per year).3
Researchers originally randomized 3234 patients with body mass index ≥24 kg/m2, fasting blood sugar 95 to 125 mg/dL, and 2-hour post 75-gm glucose value of 149 to 199 mg/dL to 3 groups: intensive lifestyle modification (weight loss goal of 7%, 150 minutes a week of exercise), metformin (850 mg twice daily), and no intervention. After the 2.8-year follow-up period, 2766 patients continued for another 5.7 years of follow-up. Investigators offered group lifestyle counseling to all patients and continued metformin at the same dose in the second group.
Earlier study shows an effect for metformin, but with a caveat
An earlier RCT found that metformin reduced the risk of developing diabetes in patients with metabolic syndrome.4 Investigators randomized 70 patients to metformin (250 mg 3 times daily) or placebo for a year. Fewer patients developed diabetes with metformin (3% vs 16.2%, P=.011; NNT=7.6) and more had a normal glucose tolerance test result (84.9% vs 51.4%, P=.011; NNT=3). However, by current American Diabetes Association criteria, half of the subjects had early diabetes at baseline.
Metformin lowers fasting blood sugar, but may not reverse metabolic syndrome
A post-hoc analysis of another RCT found that metformin reduced fasting plasma glucose (FPG) levels in patients with upper-body obesity and metabolic syndrome (by 1999 World Health Organization criteria but not NCEP ATP III criteria).5
Investigators randomized 457 patients to metformin 850 mg once daily or placebo and followed them for a year. FPG levels decreased with metformin but increased with placebo (reduction FPG 5.9 mg/dL vs increase FPG 12.3 mg/dL; P<.04). The investigators didn’t report whether any patients developed diabetes.
However, another RCT (155 patients) that compared metformin 850 mg twice daily with placebo in subjects with metabolic syndrome but without diabetes found greater normalization of FPG (5% vs 0%; P=.005), but no reversal of metabolic syndrome or change in Framingham 10-year risk score after 12 weeks.6
1. Sussman JB, Kent DM, Nelson JP, et al. Improving diabetes prevention with benefit based tailored treatment: risk based reanalysis of Diabetes Prevention Program. BMJ. 2015;350:h454.
2. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
3. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Outcomes Study. Lancet. 2009:374:1677-1686.
4. Li CL, Pan CY, Lu JM, et al. Effect of metformin on patients with impaired glucose tolerance. Diabetes Med. 1999;16:477-481.
5. Fontbonne A, Diouf I, Baccara-Dinet M, et al. Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper-body obese subjects with mild glucose anomalies: a post-hoc analysis of the BIGPRO1 trial. Diabetes Metab. 2009;35:385-391.
6. Nieuwdorp M, Stroes ESG, Kastelein JJP. Normalization of metabolic syndrome using fenofibrate, metformin or their combination. Diabetes Obesity Metab. 2007;9:869-878.
1. Sussman JB, Kent DM, Nelson JP, et al. Improving diabetes prevention with benefit based tailored treatment: risk based reanalysis of Diabetes Prevention Program. BMJ. 2015;350:h454.
2. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403.
3. Diabetes Prevention Program Research Group. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Outcomes Study. Lancet. 2009:374:1677-1686.
4. Li CL, Pan CY, Lu JM, et al. Effect of metformin on patients with impaired glucose tolerance. Diabetes Med. 1999;16:477-481.
5. Fontbonne A, Diouf I, Baccara-Dinet M, et al. Effects of 1-year treatment with metformin on metabolic and cardiovascular risk factors in non-diabetic upper-body obese subjects with mild glucose anomalies: a post-hoc analysis of the BIGPRO1 trial. Diabetes Metab. 2009;35:385-391.
6. Nieuwdorp M, Stroes ESG, Kastelein JJP. Normalization of metabolic syndrome using fenofibrate, metformin or their combination. Diabetes Obesity Metab. 2007;9:869-878.
Evidence-based answers from the Family Physicians Inquiries Network
Does knuckle popping lead to arthritis?
EVIDENCE-BASED ANSWER:
No, habitual knuckle popping, or cracking (over the course of several decades) isn’t associated with clinical or radiographic evidence of osteoarthritis (strength of recommendation [SOR]: B, retrospective cohort and case control studies). However, attempting to pop the knuckles can produce acute soft tissue injury (SOR: C, case reports).
Evidence summary
A cross-sectional study found no correlation between knuckle popping and osteoarthritis (OA) of the hand.1 Investigators recruited 300 consecutive patients (ages 45 years and older, mean age 63 years) and evaluated them for a history of habitual knuckle popping (74 of 300 patients, mean duration 35 years) and hand arthritis or dysfunction. Investigators excluded patients with neuromuscular, inflammatory, or malignant diseases.
Investigators found OA equally in both patients who did and didn’t pop their knuckles (12 of 74 vs 36 of 226, respectively; P nonsignificant); joint swelling was more common in participants with a history of knuckle popping (84% vs 6%; P<.01). Investigators didn’t describe how OA was diagnosed or specify which joints were affected.
Another cross-sectional study also found no correlation between habitual knuckle popping of the metacarpal phalangeal joint and the prevalence of OA in that joint.2 Investigators recruited 28 patients (mean age 78.5 years; 23 women and 5 men) from a Jewish home for the aged and asked them whether they had habitually cracked their knuckles during their lifetime. They then performed clinical and radiographic hand examinations (excluding patients with a history of traumatic injury, rheumatoid arthritis, gout, chondrocalcinosis, and hemochromatosis).
Knuckle popping didn’t correlate with OA of the metacarpal phalanges (1 of 15 knuckle popping patients vs 5 of 13 patients who didn’t pop their knuckles; P=.06). All 6 patients with radiographic evidence of OA showed involvement at the metacarpal phalangeal and distal interphalangeal joints, whether or not they popped their knuckles.
Years spent cracking knuckles doesn’t predict OA
A case control study found no correlation between OA in the hands and habitual knuckle popping.3 Investigators recruited 215 patients 50 to 89 years old who had received a radiograph of their right hand during the previous 5 years and divided them into cases with OA (135 patients), and controls without OA (80 patients). Patients completed questionnaires assessing the prevalence (20%), frequency (1 to 20 times per day), and duration (26 to 36 years) of knuckle popping.
Patients most commonly popped proximal interphalangeal joints (15.9%) followed by metacarpal phalangeal joints (13.5%), distal interphalangeal joints (6.1%), and first carpal metacarpal joints (2.3%). OA most often affected the distal interphalangeal joint (68.4%), followed by the first carpal metacarpal (57.1%), proximal interphalangeal (54.1%), and metacarpal phalangeal joints (28.6%). Investigators found no difference in the prevalence of knuckle popping between cases and controls (18% in cases vs 23.2% in controls; P=.361).
When investigators evaluated total knuckle popping exposure in “crack years” (number of times per day multiplied by years) in the distal interphalangeal or metacarpal phalangeal joints, they found no significant association between crack years and OA (distal interphalangeal joint, mean 108 crack years; metacarpal phalangeal joint, mean 75 crack years).
50 years of knuckle popping without ill effects
An n-of-1 case control study found similar results.4 The researcher, a physician, popped only the knuckles of his left hand, twice a day, for 50 years. He compared his hands at the end of the trial and found no arthritis in either hand and no visible differences.
But knuckle popping does have a downside
A paper described 2 case reports of acute injuries sustained during attempted knuckle popping—a partial tear of the ulnar collateral ligament of the thumb and subluxation of the extensor tendon of the fifth digit.5 Both injuries were associated with forceful manipulation of the digits, and both resolved with conservative management within 4 weeks.
1. Castellanos J, Axelrod D. Effect of habitual knuckle cracking on hand function. Ann Rheum Dis. 1990;49:308-309.
2. Swezey RL, Swezey SE. The consequences of habitual knuckle cracking. West J Med. 1975;122:377-379.
3. Deweber K, Olszewski M, Ortolano R. Knuckle cracking and hand osteoarthritis. J Am Board Fam Med. 2011;24:169-174.
4. Unger DL. Does knuckle cracking lead to arthritis of the fingers? Arthritis Rheum. 1998;41:949-950.
5. Chan PS, Steinberg DR, Bozentka DJ. Consequences of knuckle cracking: a report of two acute injuries. Am J Orthop (Belle Mead NJ). 1999;28:113-114.
EVIDENCE-BASED ANSWER:
No, habitual knuckle popping, or cracking (over the course of several decades) isn’t associated with clinical or radiographic evidence of osteoarthritis (strength of recommendation [SOR]: B, retrospective cohort and case control studies). However, attempting to pop the knuckles can produce acute soft tissue injury (SOR: C, case reports).
Evidence summary
A cross-sectional study found no correlation between knuckle popping and osteoarthritis (OA) of the hand.1 Investigators recruited 300 consecutive patients (ages 45 years and older, mean age 63 years) and evaluated them for a history of habitual knuckle popping (74 of 300 patients, mean duration 35 years) and hand arthritis or dysfunction. Investigators excluded patients with neuromuscular, inflammatory, or malignant diseases.
Investigators found OA equally in both patients who did and didn’t pop their knuckles (12 of 74 vs 36 of 226, respectively; P nonsignificant); joint swelling was more common in participants with a history of knuckle popping (84% vs 6%; P<.01). Investigators didn’t describe how OA was diagnosed or specify which joints were affected.
Another cross-sectional study also found no correlation between habitual knuckle popping of the metacarpal phalangeal joint and the prevalence of OA in that joint.2 Investigators recruited 28 patients (mean age 78.5 years; 23 women and 5 men) from a Jewish home for the aged and asked them whether they had habitually cracked their knuckles during their lifetime. They then performed clinical and radiographic hand examinations (excluding patients with a history of traumatic injury, rheumatoid arthritis, gout, chondrocalcinosis, and hemochromatosis).
Knuckle popping didn’t correlate with OA of the metacarpal phalanges (1 of 15 knuckle popping patients vs 5 of 13 patients who didn’t pop their knuckles; P=.06). All 6 patients with radiographic evidence of OA showed involvement at the metacarpal phalangeal and distal interphalangeal joints, whether or not they popped their knuckles.
Years spent cracking knuckles doesn’t predict OA
A case control study found no correlation between OA in the hands and habitual knuckle popping.3 Investigators recruited 215 patients 50 to 89 years old who had received a radiograph of their right hand during the previous 5 years and divided them into cases with OA (135 patients), and controls without OA (80 patients). Patients completed questionnaires assessing the prevalence (20%), frequency (1 to 20 times per day), and duration (26 to 36 years) of knuckle popping.
Patients most commonly popped proximal interphalangeal joints (15.9%) followed by metacarpal phalangeal joints (13.5%), distal interphalangeal joints (6.1%), and first carpal metacarpal joints (2.3%). OA most often affected the distal interphalangeal joint (68.4%), followed by the first carpal metacarpal (57.1%), proximal interphalangeal (54.1%), and metacarpal phalangeal joints (28.6%). Investigators found no difference in the prevalence of knuckle popping between cases and controls (18% in cases vs 23.2% in controls; P=.361).
When investigators evaluated total knuckle popping exposure in “crack years” (number of times per day multiplied by years) in the distal interphalangeal or metacarpal phalangeal joints, they found no significant association between crack years and OA (distal interphalangeal joint, mean 108 crack years; metacarpal phalangeal joint, mean 75 crack years).
50 years of knuckle popping without ill effects
An n-of-1 case control study found similar results.4 The researcher, a physician, popped only the knuckles of his left hand, twice a day, for 50 years. He compared his hands at the end of the trial and found no arthritis in either hand and no visible differences.
But knuckle popping does have a downside
A paper described 2 case reports of acute injuries sustained during attempted knuckle popping—a partial tear of the ulnar collateral ligament of the thumb and subluxation of the extensor tendon of the fifth digit.5 Both injuries were associated with forceful manipulation of the digits, and both resolved with conservative management within 4 weeks.
EVIDENCE-BASED ANSWER:
No, habitual knuckle popping, or cracking (over the course of several decades) isn’t associated with clinical or radiographic evidence of osteoarthritis (strength of recommendation [SOR]: B, retrospective cohort and case control studies). However, attempting to pop the knuckles can produce acute soft tissue injury (SOR: C, case reports).
Evidence summary
A cross-sectional study found no correlation between knuckle popping and osteoarthritis (OA) of the hand.1 Investigators recruited 300 consecutive patients (ages 45 years and older, mean age 63 years) and evaluated them for a history of habitual knuckle popping (74 of 300 patients, mean duration 35 years) and hand arthritis or dysfunction. Investigators excluded patients with neuromuscular, inflammatory, or malignant diseases.
Investigators found OA equally in both patients who did and didn’t pop their knuckles (12 of 74 vs 36 of 226, respectively; P nonsignificant); joint swelling was more common in participants with a history of knuckle popping (84% vs 6%; P<.01). Investigators didn’t describe how OA was diagnosed or specify which joints were affected.
Another cross-sectional study also found no correlation between habitual knuckle popping of the metacarpal phalangeal joint and the prevalence of OA in that joint.2 Investigators recruited 28 patients (mean age 78.5 years; 23 women and 5 men) from a Jewish home for the aged and asked them whether they had habitually cracked their knuckles during their lifetime. They then performed clinical and radiographic hand examinations (excluding patients with a history of traumatic injury, rheumatoid arthritis, gout, chondrocalcinosis, and hemochromatosis).
Knuckle popping didn’t correlate with OA of the metacarpal phalanges (1 of 15 knuckle popping patients vs 5 of 13 patients who didn’t pop their knuckles; P=.06). All 6 patients with radiographic evidence of OA showed involvement at the metacarpal phalangeal and distal interphalangeal joints, whether or not they popped their knuckles.
Years spent cracking knuckles doesn’t predict OA
A case control study found no correlation between OA in the hands and habitual knuckle popping.3 Investigators recruited 215 patients 50 to 89 years old who had received a radiograph of their right hand during the previous 5 years and divided them into cases with OA (135 patients), and controls without OA (80 patients). Patients completed questionnaires assessing the prevalence (20%), frequency (1 to 20 times per day), and duration (26 to 36 years) of knuckle popping.
Patients most commonly popped proximal interphalangeal joints (15.9%) followed by metacarpal phalangeal joints (13.5%), distal interphalangeal joints (6.1%), and first carpal metacarpal joints (2.3%). OA most often affected the distal interphalangeal joint (68.4%), followed by the first carpal metacarpal (57.1%), proximal interphalangeal (54.1%), and metacarpal phalangeal joints (28.6%). Investigators found no difference in the prevalence of knuckle popping between cases and controls (18% in cases vs 23.2% in controls; P=.361).
When investigators evaluated total knuckle popping exposure in “crack years” (number of times per day multiplied by years) in the distal interphalangeal or metacarpal phalangeal joints, they found no significant association between crack years and OA (distal interphalangeal joint, mean 108 crack years; metacarpal phalangeal joint, mean 75 crack years).
50 years of knuckle popping without ill effects
An n-of-1 case control study found similar results.4 The researcher, a physician, popped only the knuckles of his left hand, twice a day, for 50 years. He compared his hands at the end of the trial and found no arthritis in either hand and no visible differences.
But knuckle popping does have a downside
A paper described 2 case reports of acute injuries sustained during attempted knuckle popping—a partial tear of the ulnar collateral ligament of the thumb and subluxation of the extensor tendon of the fifth digit.5 Both injuries were associated with forceful manipulation of the digits, and both resolved with conservative management within 4 weeks.
1. Castellanos J, Axelrod D. Effect of habitual knuckle cracking on hand function. Ann Rheum Dis. 1990;49:308-309.
2. Swezey RL, Swezey SE. The consequences of habitual knuckle cracking. West J Med. 1975;122:377-379.
3. Deweber K, Olszewski M, Ortolano R. Knuckle cracking and hand osteoarthritis. J Am Board Fam Med. 2011;24:169-174.
4. Unger DL. Does knuckle cracking lead to arthritis of the fingers? Arthritis Rheum. 1998;41:949-950.
5. Chan PS, Steinberg DR, Bozentka DJ. Consequences of knuckle cracking: a report of two acute injuries. Am J Orthop (Belle Mead NJ). 1999;28:113-114.
1. Castellanos J, Axelrod D. Effect of habitual knuckle cracking on hand function. Ann Rheum Dis. 1990;49:308-309.
2. Swezey RL, Swezey SE. The consequences of habitual knuckle cracking. West J Med. 1975;122:377-379.
3. Deweber K, Olszewski M, Ortolano R. Knuckle cracking and hand osteoarthritis. J Am Board Fam Med. 2011;24:169-174.
4. Unger DL. Does knuckle cracking lead to arthritis of the fingers? Arthritis Rheum. 1998;41:949-950.
5. Chan PS, Steinberg DR, Bozentka DJ. Consequences of knuckle cracking: a report of two acute injuries. Am J Orthop (Belle Mead NJ). 1999;28:113-114.
Evidence-based answers from the Family Physicians Inquiries Network
Which SSRIs most effectively treat depression in adolescents?
EVIDENCE-BASED ANSWER:
We don’t know which selective serotonin reuptake inhibitors (SSRIs) are the most effective and safe because no studies have compared these antidepressants with each other.
Three SSRI antidepressant medications—fluoxetine, sertraline, and escitalopram—produce modest improvements (about 5% to 10%) in standardized depression scores without a significant increase in the risk of suicide-related outcomes (suicidal behavior or ideation) in adolescent patients with major depression of moderate severity. As a group, however, the newer-generation antidepressants, including SSRIs, increase suicide-related outcomes by 50%. Citalopram, paroxetine, venlafaxine, and mirtazapine don’t improve depression scores (strength of recommendation [SOR]: A, meta-analyses of randomized controlled trials [RCTs]).
An updated national guideline recommends specific psychological therapy for adolescents with mild depression and combined psychotherapy and fluoxetine for moderate or severe depression, with sertraline or citalopram as second-line agents (SOR: A, RCTs).
EVIDENCE SUMMARY
A Cochrane systematic review (19 RCTs; 3335 patients, total) of newer-generation antidepressants for treating depression in adolescents found that, overall, they produced both a small decrease in symptom severity scores and an increased risk of suicide-related outcomes.1
Three SSRIs slightly lower one symptom severity score
Investigators performed a meta-analysis of all trials (14 RCTs; 2490 patients, total) that used the same standardized symptom severity score (the Children’s Depression Rating Scale—Revised [CDRS-R], range 17 to 113 points) to evaluate the following medications: fluoxetine, sertraline, escitalopram, citalopram, paroxetine, venlafaxine, and mirtazapine.1
All participants were outpatients who met criteria for a primary diagnosis of major depression, excluding comorbid conditions. The CDRS-R scores were evaluated by clinicians; the mean baseline score was 57 (40 is considered a threshold score for diagnosis, and above 60 indicates severe symptoms). Only 5 trials reported patients’ self-rated depression symptom severity (in patients taking fluoxetine and paroxetine) and none reported improvement. Treatment courses ranged from 8 to 12 weeks.
As a group, the newer antidepressants slightly reduced CDRS-R scores in adolescents (by 4.21 points, 95% confidence interval [CI], 0.41-5.95) but increased suicide-related outcomes (relative risk [RR]=1.47; 95% CI, 0.99-2.19). The individual antidepressants fluoxetine, sertraline, and escitalopram each produced statistically significant but clinically small reductions in CDRS-R scores of 5% to 10% without significantly increasing suicide-related outcomes (TABLE1). The other medications evaluated individually didn’t improve CDRS-R scores, and only venlafaxine increased suicide-related outcomes.
Other symptom severity scores show no improvement with SSRIs
Five additional RCTs not included in the meta-analysis that used standardized symptom severity scores other than the CDRS-R (Schedule for Affective Disorders and Schizophrenia for School-Aged Children [K-SADS], Montgomery-Asberg Depression Rating Scale [MADR], and Hamilton Depression Rating Scale [HAM-D]) found no improvement with fluoxetine (2 RCTs; 63 patients, total), citalopram (one RCT, 233 patients), or paroxetine (2 RCTs; 466 patients, total).
Certain drugs cause significantly more adverse events than placebo
Ten RCTs evaluated adverse events in adolescents treated with fluoxetine, escitalopram, citalopram, and paroxetine and reported a small increase over placebo when all medications were combined as a group (RR=1.11; 95% CI, 1.05-1.17). Investigators reported that the individual antidepressants fluoxetine, escitalopram, venlafaxine, and mirtazapine produced significantly more adverse events than placebo (P values not given). No studies compared antidepressant medications against each other for either efficacy or potential harms.
RECOMMENDATIONS
A newly revised expert guideline recommends treating mildly depressed adolescents with a specific psychological therapy—individual cognitive behavioral therapy, interpersonal therapy, family therapy, or psychodynamic psychotherapy—for at least 3 months.2
For adolescents with moderate to severe depression, the guideline advocates psychotherapy with the option of adding fluoxetine, although using antidepressants in adolescents who haven’t at least tried psychotherapy is outside of the drug’s indications.
The guideline also recommends careful monitoring for adverse effects and close review of mental state—weekly for the first 4 weeks of treatment, for example. If fluoxetine doesn’t help, sertraline and citalopram are recommended as alternatives.
1. Hetrick SE, McKenzie JE, Cox GR, et al. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD004851.
2. Hopkins K, Crosland P, Elliott N, et al. Diagnosis and management of depression in children and young people: summary of updated NICE guidance. BMJ. 2015;350:h824.
EVIDENCE-BASED ANSWER:
We don’t know which selective serotonin reuptake inhibitors (SSRIs) are the most effective and safe because no studies have compared these antidepressants with each other.
Three SSRI antidepressant medications—fluoxetine, sertraline, and escitalopram—produce modest improvements (about 5% to 10%) in standardized depression scores without a significant increase in the risk of suicide-related outcomes (suicidal behavior or ideation) in adolescent patients with major depression of moderate severity. As a group, however, the newer-generation antidepressants, including SSRIs, increase suicide-related outcomes by 50%. Citalopram, paroxetine, venlafaxine, and mirtazapine don’t improve depression scores (strength of recommendation [SOR]: A, meta-analyses of randomized controlled trials [RCTs]).
An updated national guideline recommends specific psychological therapy for adolescents with mild depression and combined psychotherapy and fluoxetine for moderate or severe depression, with sertraline or citalopram as second-line agents (SOR: A, RCTs).
EVIDENCE SUMMARY
A Cochrane systematic review (19 RCTs; 3335 patients, total) of newer-generation antidepressants for treating depression in adolescents found that, overall, they produced both a small decrease in symptom severity scores and an increased risk of suicide-related outcomes.1
Three SSRIs slightly lower one symptom severity score
Investigators performed a meta-analysis of all trials (14 RCTs; 2490 patients, total) that used the same standardized symptom severity score (the Children’s Depression Rating Scale—Revised [CDRS-R], range 17 to 113 points) to evaluate the following medications: fluoxetine, sertraline, escitalopram, citalopram, paroxetine, venlafaxine, and mirtazapine.1
All participants were outpatients who met criteria for a primary diagnosis of major depression, excluding comorbid conditions. The CDRS-R scores were evaluated by clinicians; the mean baseline score was 57 (40 is considered a threshold score for diagnosis, and above 60 indicates severe symptoms). Only 5 trials reported patients’ self-rated depression symptom severity (in patients taking fluoxetine and paroxetine) and none reported improvement. Treatment courses ranged from 8 to 12 weeks.
As a group, the newer antidepressants slightly reduced CDRS-R scores in adolescents (by 4.21 points, 95% confidence interval [CI], 0.41-5.95) but increased suicide-related outcomes (relative risk [RR]=1.47; 95% CI, 0.99-2.19). The individual antidepressants fluoxetine, sertraline, and escitalopram each produced statistically significant but clinically small reductions in CDRS-R scores of 5% to 10% without significantly increasing suicide-related outcomes (TABLE1). The other medications evaluated individually didn’t improve CDRS-R scores, and only venlafaxine increased suicide-related outcomes.
Other symptom severity scores show no improvement with SSRIs
Five additional RCTs not included in the meta-analysis that used standardized symptom severity scores other than the CDRS-R (Schedule for Affective Disorders and Schizophrenia for School-Aged Children [K-SADS], Montgomery-Asberg Depression Rating Scale [MADR], and Hamilton Depression Rating Scale [HAM-D]) found no improvement with fluoxetine (2 RCTs; 63 patients, total), citalopram (one RCT, 233 patients), or paroxetine (2 RCTs; 466 patients, total).
Certain drugs cause significantly more adverse events than placebo
Ten RCTs evaluated adverse events in adolescents treated with fluoxetine, escitalopram, citalopram, and paroxetine and reported a small increase over placebo when all medications were combined as a group (RR=1.11; 95% CI, 1.05-1.17). Investigators reported that the individual antidepressants fluoxetine, escitalopram, venlafaxine, and mirtazapine produced significantly more adverse events than placebo (P values not given). No studies compared antidepressant medications against each other for either efficacy or potential harms.
RECOMMENDATIONS
A newly revised expert guideline recommends treating mildly depressed adolescents with a specific psychological therapy—individual cognitive behavioral therapy, interpersonal therapy, family therapy, or psychodynamic psychotherapy—for at least 3 months.2
For adolescents with moderate to severe depression, the guideline advocates psychotherapy with the option of adding fluoxetine, although using antidepressants in adolescents who haven’t at least tried psychotherapy is outside of the drug’s indications.
The guideline also recommends careful monitoring for adverse effects and close review of mental state—weekly for the first 4 weeks of treatment, for example. If fluoxetine doesn’t help, sertraline and citalopram are recommended as alternatives.
EVIDENCE-BASED ANSWER:
We don’t know which selective serotonin reuptake inhibitors (SSRIs) are the most effective and safe because no studies have compared these antidepressants with each other.
Three SSRI antidepressant medications—fluoxetine, sertraline, and escitalopram—produce modest improvements (about 5% to 10%) in standardized depression scores without a significant increase in the risk of suicide-related outcomes (suicidal behavior or ideation) in adolescent patients with major depression of moderate severity. As a group, however, the newer-generation antidepressants, including SSRIs, increase suicide-related outcomes by 50%. Citalopram, paroxetine, venlafaxine, and mirtazapine don’t improve depression scores (strength of recommendation [SOR]: A, meta-analyses of randomized controlled trials [RCTs]).
An updated national guideline recommends specific psychological therapy for adolescents with mild depression and combined psychotherapy and fluoxetine for moderate or severe depression, with sertraline or citalopram as second-line agents (SOR: A, RCTs).
EVIDENCE SUMMARY
A Cochrane systematic review (19 RCTs; 3335 patients, total) of newer-generation antidepressants for treating depression in adolescents found that, overall, they produced both a small decrease in symptom severity scores and an increased risk of suicide-related outcomes.1
Three SSRIs slightly lower one symptom severity score
Investigators performed a meta-analysis of all trials (14 RCTs; 2490 patients, total) that used the same standardized symptom severity score (the Children’s Depression Rating Scale—Revised [CDRS-R], range 17 to 113 points) to evaluate the following medications: fluoxetine, sertraline, escitalopram, citalopram, paroxetine, venlafaxine, and mirtazapine.1
All participants were outpatients who met criteria for a primary diagnosis of major depression, excluding comorbid conditions. The CDRS-R scores were evaluated by clinicians; the mean baseline score was 57 (40 is considered a threshold score for diagnosis, and above 60 indicates severe symptoms). Only 5 trials reported patients’ self-rated depression symptom severity (in patients taking fluoxetine and paroxetine) and none reported improvement. Treatment courses ranged from 8 to 12 weeks.
As a group, the newer antidepressants slightly reduced CDRS-R scores in adolescents (by 4.21 points, 95% confidence interval [CI], 0.41-5.95) but increased suicide-related outcomes (relative risk [RR]=1.47; 95% CI, 0.99-2.19). The individual antidepressants fluoxetine, sertraline, and escitalopram each produced statistically significant but clinically small reductions in CDRS-R scores of 5% to 10% without significantly increasing suicide-related outcomes (TABLE1). The other medications evaluated individually didn’t improve CDRS-R scores, and only venlafaxine increased suicide-related outcomes.
Other symptom severity scores show no improvement with SSRIs
Five additional RCTs not included in the meta-analysis that used standardized symptom severity scores other than the CDRS-R (Schedule for Affective Disorders and Schizophrenia for School-Aged Children [K-SADS], Montgomery-Asberg Depression Rating Scale [MADR], and Hamilton Depression Rating Scale [HAM-D]) found no improvement with fluoxetine (2 RCTs; 63 patients, total), citalopram (one RCT, 233 patients), or paroxetine (2 RCTs; 466 patients, total).
Certain drugs cause significantly more adverse events than placebo
Ten RCTs evaluated adverse events in adolescents treated with fluoxetine, escitalopram, citalopram, and paroxetine and reported a small increase over placebo when all medications were combined as a group (RR=1.11; 95% CI, 1.05-1.17). Investigators reported that the individual antidepressants fluoxetine, escitalopram, venlafaxine, and mirtazapine produced significantly more adverse events than placebo (P values not given). No studies compared antidepressant medications against each other for either efficacy or potential harms.
RECOMMENDATIONS
A newly revised expert guideline recommends treating mildly depressed adolescents with a specific psychological therapy—individual cognitive behavioral therapy, interpersonal therapy, family therapy, or psychodynamic psychotherapy—for at least 3 months.2
For adolescents with moderate to severe depression, the guideline advocates psychotherapy with the option of adding fluoxetine, although using antidepressants in adolescents who haven’t at least tried psychotherapy is outside of the drug’s indications.
The guideline also recommends careful monitoring for adverse effects and close review of mental state—weekly for the first 4 weeks of treatment, for example. If fluoxetine doesn’t help, sertraline and citalopram are recommended as alternatives.
1. Hetrick SE, McKenzie JE, Cox GR, et al. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD004851.
2. Hopkins K, Crosland P, Elliott N, et al. Diagnosis and management of depression in children and young people: summary of updated NICE guidance. BMJ. 2015;350:h824.
1. Hetrick SE, McKenzie JE, Cox GR, et al. Newer generation antidepressants for depressive disorders in children and adolescents. Cochrane Database Syst Rev. 2012;11:CD004851.
2. Hopkins K, Crosland P, Elliott N, et al. Diagnosis and management of depression in children and young people: summary of updated NICE guidance. BMJ. 2015;350:h824.
Evidence-based answers from the Family Physicians Inquiries Network
