Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis.

Table of Contents

Data Synthesis and Analysis (page 1-5) Supplement Table 1: Literature search strategy (Medline) (page 6-7) Supplement Table 2: Study and population characteristics (page 8-20) Supplement Table 3: Risk of bias assessment (page 21-28) References of included studies (page 29-38) Supplement Figure 1: Forest plot of absolute treatment effects (WOMAC 0-100) (page 39) Supplement Table 4: Relative and absolute treatment effects for pain (page 40) Supplement Figure 2: Rank Probability Curves for pain (page 41) Supplement Figure 3: Cumulative Ranking Curves with Surface Under the Cumulative Ranking Curve (SUCRA) for pain (page 42) Supplement Figure 4: Plot of inconsistency estimates for pain (page 43) Supplement Figure 5: Network of Treatment Comparisons for function (page 44) Supplement Table 5: Standardized mean differences (adjusted for small samples) for function at 3 months (page 45) Supplement Figure 6: Plot of inconsistency estimates for function (page 46) Supplement Figure 7: Network of Treatment Comparisons for stiffness (page 47) Supplement Table 6: Standardized mean differences (adjusted for small samples) for stiffness at 3 months (page 48) Supplement Figure 8: Plot of inconsistency estimates for stiffness (page 49) Supplement Table 7: Sensitivity analyses on the primary outcome pain (page 50) Supplement Table 8: Sensitivity analyses exploring for reporting bias (51) Supplement Table 9: Occurrence of Adverse Events in RCTs of Treatments for Osteoarthritis (page 52-53) Supplement Table 10: Study and participant characteristics of the subsets of studies exploring for reporting bias (page 54)

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Data Synthesis and Analysis Because the included studies used different outcome measures, the change from baseline WOMAC, VAS and Likert scale scores in each study were translated into Hedges’ g effect sizes (ES) (1). Hedges’ g is defined as the difference in change scores between two interventions divided by the pooled standard deviation of the differences with corrections for small sample sizes. To assess potential heterogeneity among the studies, we calculated the between-study variance, and also examined baseline characteristics of participants, interventions, outcomes, and study quality.

Network meta-analysis: A network meta-analysis synthesizes all available evidence within a consistent framework, fully preserving the randomization within each trial (2). It accounts for multiple comparisons within a trial when there are more than two treatment arms (3). This method analyzes all trials in one model and enables integration of direct evidence from head-tohead trials (when they exist) with indirect evidence (obtained from comparisons of treatments via their common reference). We used multivariable Bayesian hierarchical random effects models for mixed multiple-treatment comparisons with non-informative prior distributions (4, 5). The model contains parameters that describe the relative treatment effect of each intervention compared to a common comparator, oral placebo. Other treatment comparisons can be derived as differences between model parameters. We assumed a normal likelihood for the effect size. A random effects model was selected as some clinical and methodological heterogeneity was expected.

Multi-arm trials: When the results from multi-arm trials are presented as treatment differences (ES) relative to a control arm, a correlation between the treatment differences is induced for which the likelihood must account. In a three-arm trial comparing treatments A, B, and C, the treatment effects dAB and dCB are correlated. This was accounted for in the model by specifying 1


a multivariate normal likelihood for multi arm trials and by building the corresponding variancecovariance matrix (6, 7). The model assumes a common random effects variance across comparisons, which implies that the correlation of each pair of treatment effects is 0.5 (5, 8, 9).

A fundamental assumption in all random effects meta-analyses is that overall, or in defined subgroups, the trial-specific treatment differences are drawn from a common distribution. The main assumption behind the validity of network meta-analysis is transitivity (3). It means that the synthesis of studies making a direct comparison of two treatments makes sense only when the studies are sufficiently similar in important clinical and methodological characteristics (effect modifiers) (10). We assumed that the populations within these studies were similar and could be eligible for any of the treatments considered here based on the distributions of effect modifiers (mean age, percent female, baseline disease severity, baseline pain scores, duration of disease and study quality).

Another key assumption in a network meta-analysis is consistency, that direct and indirect effects are the same (11). This can be evaluated only when a loop in the evidence network exists, that is when there is direct and indirect evidence for a particular comparison (12). Consider a simplified network composed of three treatments A, B, and C. A direct estimate of 𝐷𝑖𝑟 𝐼𝑛𝑑 the C vs. B effect (head to head comparison), 𝑑𝐵𝐶 , is compared with an indirect estimate, 𝑑𝐵𝐶 , 𝐼𝑛𝑑 𝐷𝑖𝑟 𝐷𝑖𝑟 formed from the AB and AC direct evidence 𝑑𝐵𝐶 = 𝑑𝐴𝐶 - 𝑑𝐴𝐵 . We assume that there can be no

inconsistency within a multi-arm trial, and this means that there can be no inconsistency within a loop formed exclusively by multi-arm trials.

Consistency Analysis: For each of the loops we identified the comparison with the most statistical information, i.e., the comparison with lowest standard error overall. We then

2


performed two separate analyses within the same run in OpenBUGS using the same model employed for the main analysis: one including only the two interventions forming the identified comparison and another including all other comparisons. The first analysis basically reduces to a standard Bayesian meta-analysis, whereas the other analysis provides an indirect estimate of the same comparison as in the standard Bayesian meta-analysis but derived from all the other comparisons within the network. We defined inconsistency as the difference between these two 𝐷𝑖𝑟 𝐼𝑛𝑑 estimates calculated at each iteration and the inconsistency factors (IF =|𝑑𝐵𝐶 - 𝑑𝐵𝐶 |) were

calculated for each closed loop (13). The results are presented graphically to visually assess the level of agreement between direct and indirect estimates. A value near 0 indicates that the comparisons in the network are consistent. The more the value deviates from 0, the more inconsistent a particular loop.

Model implementation: In a Bayesian analysis, prior probabilities are specified for certain parameters and likelihoods are specified for the data. In order to avoid the prior beliefs influencing the results of the model, non-informative prior distributions were selected. Prior distributions of the relative treatment effects were assumed to be normal, with a mean of 0 and a variance of 10,000. The prior for the between study standard deviation was set to be a uniform distribution with range of 0-5. The upper limit of 5 represents a huge range of treatment effects within a particular comparison on a standardized mean difference scale. We also used uniform priors U(0-2) and U(0-10) as sensitivity analyses but no material changes were observed in the results (6).

Analyses were performed using Markov Chain Monte Carlo (MCMC) simulation implemented through OpenBUGS software version 3.2.2. We adapted the previously published OpenBUGS code to our application (6). We ran four parallel chains, and convergence was deemed to be achieved if the trace plots indicated that widths of pooled runs and individual run stabilized 3


around the same value and the Gelman-Rubin statistic (ratio of within-chain and between-chain variation) was around one (14). The parameters monitored were the treatment effects, betweenstudy variance, linear predictor (theta), deviance, total residual deviance, and the deviance information criteria (DIC). We found that convergence for all parameters was achieved within the first 25,000 iterations. The 125,000 iterations from each chain after the initial burn-in were used as posterior distribution in all analyses. Based on the autocorrelation plots a thinning of 5 was applied in all analyses.

The fit of the model to the data can be measured by calculating the posterior mean residual ̅ . The model fits the data adequately when 𝐷 ̅ approximates the number of deviance 𝐷 ̅ and the unconstrained data points. The deviance information criterion (DIC) is the sum of 𝐷 effective number of parameters, pD, and provides a measure of model fit penalized for model complexity. Lower values of the DIC suggest a better compromise between model fit and complexity. A difference in DIC of three units or more is usually considered important. DIC was used to compare different models; consistency to inconsistency models and adjusted to unadjusted models.

Results were presented as median ES for pain, function, and stiffness along with 95% central credibility intervals. Each Markov chain Monte Carlo (MCMC) cycle provided a ranking of the treatments according to the estimated effect size, so when repeated for a 500,000 iterations, the full set of simulations yielded a distribution of these ranks which was presented as cumulative rank probability plots. We also estimated the surface under the cumulative ranking (SUCRA) probabilities (15). SUCRAs expressed as percentages compare each intervention to an imaginary intervention that is always the best without uncertainty. A SUCRA of x% means that the drug achieves x% of the effectiveness of this imaginary drug, thus larger SUCRAs denote more effective interventions (16). 4


References: 1. 2. 3.

4. 5. 6.

7. 8. 9. 10.

11. 12. 13. 14. 15.

16.

Cooper H, Hedges LV. The Hand Book of Research Synthesis. New York: Russell Sage Foundation Publications; 1994. Dias S, Welton NJ, Sutton AJ, Ades AE. Evidence Synthesis for Decision Making 1: Introduction. Medical Decision Making. 2013;33(5):597-606. Salanti G. Indirect and mixed-treatment comparison, network, or multiple-treatments meta-analysis: many names, many benefits, many concerns for the next generation evidence synthesis tool. Research Synthesis Methods. 2012;3(2):80-97. Smith TC, Spiegelhalter DJ, Thomas A. Bayesian approaches to random-effects metaanalysis: a comparative study. Statistics in medicine. 1995;14(24):2685-99. Lu G, Ades AE. Combination of direct and indirect evidence in mixed treatment comparisons. Statistics in medicine. 2004;23(20):3105-24. Dias S, Sutton AJ, Ades AE, Welton NJ. Evidence Synthesis for Decision Making 2: A Generalized Linear Modeling Framework for Pairwise and Network Meta-analysis of Randomized Controlled Trials. Medical Decision Making. 2013;33(5):607-17. Franchini A, Dias S, Ades A, Jansen J, Welton N. Accounting for correlation in network meta‐analysis with multi‐arm trials. Research Synthesis Methods. 2012;3(2):142-60. Higgins JP, Whitehead A. Borrowing strength from external trials in a meta-analysis. Statistics in medicine. 1996;15(24):2733-49. Lu G, Ades A. Modeling between-trial variance structure in mixed treatment comparisons. Biostatistics. 2009;10(4):792-805. Baker SG, Kramer BS. The transitive fallacy for randomized trials: if A bests B and B bests C in separate trials, is A better than C? BMC medical research methodology. 2002;2:13. Cipriani A, Higgins JP, Geddes JR, Salanti G. Conceptual and technical challenges in network meta-analysis. Annals of internal medicine. 2013;159(2):130-7. Lu G, Ades AE. Assessing Evidence Inconsistency in Mixed Treatment Comparisons. Journal of the American Statistical Association. 2006;101(474):447-59. Dias S, Welton NJ, Caldwell DM, Ades AE. Checking consistency in mixed treatment comparison meta-analysis. Statistics in medicine. 2010;29(7-8):932-44. Brooks SP, Gelman A. Alternative methods for monitoring convergence of iterative simulations. Journal of Computational and Graphical Statistics. 1998;7(4):434-55. Salanti G, Ades AE, Ioannidis JP. Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. Journal of clinical epidemiology. 2011;64(2):163-71. Leucht S, Cipriani A, Spineli L, Mavridis D, Orey D, Richter F, et al. Comparative efficacy and tolerability of 15 antipsychotic drugs in schizophrenia: a multiple-treatments metaanalysis. Lancet. 2013;382(9896):951-62.

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Supplement Table 1: Literature search strategy (Medline) 1. exp Osteoarthritis, Knee/ 2. (osteoarthritis adj3 knee$).tw. 3. (osteoarthritides or osteoarthrosis or osteoarthroses or degenerative arthritides or degenerative arthritis or gonoarthrosis).mp. 4. exp Randomized Controlled Trials/ 5. exp random allocation/ 6. exp Double-Blind Method/ 7. exp Single-Blind Method/ 8. exp clinical trials/ 9. exp Cross-Over Studies/ 10. randomized controlled trial.pt. 11. controlled clinical trial.pt. 12. (random$ or rct).tw. 13. (clin$ adj25 trial$).tw. 14. clinical trial.pt. 15. multicenter study.pt. 16. ((singl$ or doubl$ or trebl$ or tripl$) adj (blind$ or mask$)).tw. 17. exp Comparative Study/ 18. (acetaminophen or hydroxyacetanilide or apap or n-acetyl-p-aminophenol or pacetamidophenol or p-hydroxyacetanilide or paracetamol or acetamidophenol or n-4hydroxyphenyl acetanilide or acephen or acetaco or Tylenol or anacin-3 or anacin 3 or anacin3 or datril or panadol or acamol or algotropyl).mp. 19. (Diclophenac or Dicrofenac or Dichlofenal Diclofenac Sodium or Sodium Diclofenac or Diclofenac, Sodium or Diclonate P or Feloran or Voltarol or Novapirina or Orthofen or Ortofen or Orthophen or SR-38 or SR 38 or SR38 or Voltaren or Diclofenac Potassium or GP-45,840 or GP 45,840 or GP45,840 or DIEP or DHEP or Flector or D-1-O-G cpd or D-SG cpd).mp. 20. (naproxen or napro$ or 22204-53-1 or Naprosyn or Naprosin or aleve or Synflex or proxen or anaprox or MNPA or Methoxypropiocin).mp. 21. (alpha-Methyl-4-2-methylpropyl benzeneacetic Acid or 15687-27-1 or Spedifen or Ibuprofen or N01ORX9D6S or Brufen or Ibumetin or Ibuprofen-Zinc or IP-82 or IP 82 or IP82 or Motrin or Nuprin or Rufen or Salprofen or Trauma-Dolgit Gel or Trauma Dolgit Gel or TraumaDolgit Gel or Saren or Arflamin or Flubenil or AF 2259 or MDC 917 or NCX 4060 or pimeprofen).mp. 22. (celecoxib or Celebrex or SC 58635 or SC-58635 or 169590-42-5 or 2,5-dimethyl-celecoxib or celebra or cobix or celcoxx or celexib or selecap).mp. 6


23. (corticosteroids or steroids or prednisolone or Cortivazol or triamcinolone or betamethasone or dexamethasone or hydrocortisone or corticosteroid$).mp. 24. exp Glucocorticoids/ or exp Dexamethasone Isonicotinate/ or exp Dexamethasone/ or exp Prednisolone/ or exp Triamcinolone Acetonide/ or exp Triamcinolone/ or exp Betamethasone 17-Valerate/ or exp Betamethasone/ or exp Methylprednisolone Hemisuccinate/ or exp Methylprednisolone/ or exp Hydrocortisone/ or exp Adrenal Cortex Hormones/ 25. (glucocorticoid$ or corticoid$ or ketosteroid$ or androstenedione).tw. 26. or/23-25 27. injections, intra-articular/ 28. (intraarticular inject$ or intra-articular inject$).tw. 29. or/27-28 30. 26 and 29 31. (hyaluron* or hylan* or viscosup* or viskosup* or synvisc* or orthovisc* or ostenil* or suplasyn* or arthrum* or synov-hyal* or artz* or biotty* or go-on* or healon* or hya-ject* or hyalgan* or hyalart* or hyalectin* or nuflexxa* or polireumin* or hy-gag* or nrd101* or replasyn* or supartz* or durolane*).mp. 32. (visco* adj suppl*).mp. 33. or/31-32 34. 29 and 33 35. or/18-22 36. 30 or 34 or 35 37. or/1-3 38. or/4-17 39. and/36-38 40. limit 39 to humans

7


Supplement Table 2: Study and population characteristics

Study

Comparison Dose (mg/day) &N

Treatment 1 - Dose (mg/day) &N

Treatment 2 - Dose (mg/day) &N

Mean age (yr)

Pain measurement instrument, scale and/or score range

Femal e (%)

Body Mass Index

OA Grade

OA Duration (yr)

62

55

26.8

I - IV

nd

WOMAC (VAS 0 500)

70

75

29.0

II - IV

4

Global pain (VAS 0-100)

63

62

nd

II - IV

9

MDHAQ pain (VAS 0-100)

Oral Placebo vs. Acetaminophen

Case et al., 2003(1)

Placebo (oral) 28

Acetaminophen - 4000 29

Miceli-Richard et al., 2004(2)

Placebo (oral) 374


Pincus et al., 2004a(3)

Placebo (oral) 172


Pincus et al., 2004b(3)

Placebo (oral) 182


Altman et al., 2007(4)

Placebo (oral) 165

Herrero-Beaumont et al., 2007(5)

Placebo (oral) 104

Diclofenac 150 25

Celecoxib 200 181 Celecoxib 200 189

63

66

nd

II - IV

10



62

71

33.6

II - III

nd

WOMAC (VAS 0 100)


65

86

27.8

II - III

7

WOMAC (Likert 020)

Oral Placebo vs. Oral NSAIDs Sandelin et al., 1997(6) Yocum et al., 2000(7)

Placebo (oral + topical) 79

Diclofenac 100 + topical placebo 78

61

67

27.5

nd

nd

Placebo (oral) 155

Diclofenac - 100 152

63

67

nd

nd

9

VAS (0-100)

WOMAC (Likert 08


20) Ghosh et al., 2007(8)

Placebo (oral) 123

Diclofenac - 75 142

55

63

nd

nd

4

Simon et al., 2009(9)


Diclofenac - 100 + topical placebo 151

62

62

> 30 (62%)

nd

nd

WOMAC (Likert 020)

Davies et al., 1999(10)

Placebo (oral) 46

Ibuprofen - 2400 49

62

64

nd

nd

8

WOMAC (VAS 0 100)

Day et al., 2000(11)

Placebo (oral) 74

Ibuprofen - 2400 249

64

80

nd

nd

9

WOMAC (VAS 0 100)

Saag et al., 2000(12)

Placebo (oral) 69


61

80

nd

nd

6

WOMAC A1 (VAS 0 - 100)

Wiesenhutter et al., 2005(13)

Placebo (oral) 101


62

71

32.1

nd

8

WOMAC (VAS 0 100)

Puopolo et al., 2007(14)

Placebo (oral) 109


63

76

30.5

nd

7

WOMAC (VAS 0 100)

Dore et al., 1995(15)

Placebo (oral) 86

Naproxen - 1000 82

Fleischmann et al., 1997(16)

Placebo (oral) 94

Naproxen - 1000 92

Bensen et al., 1999(17)/ Zhao et al., 1999(18)

Placebo (oral) 203

Naproxen - 1000 198

64

Celecoxib 200 202

63

nd

nd

nd

63

69

32.5

nd

nd

63

72

32.0

I - III

10

VAS (0-10)

Walking pain (0 (none) - 4 (very severe)) Walking pain (0 (none) - 4 (very severe)) WOMAC (Likert 020)

9


Kivitz et al., 2002(19)

Placebo (oral) 205

Naproxen - 1000 204

60

65

nd

nd

9

WOMAC (Likert 020)

Lohmander et al., 2005(20)/ Svensson et al., 2006(21)

Placebo (oral) 108

Naproxen - 1000 403

60

74

29.9

nd

nd

WOMAC (VAS 0 100)

Schnitzer et al., 2005a(22)

Placebo (oral) 107

Naproxen - 1000 121

60

65

34.0

nd

nd

WOMAC (VAS 0 100)

Reginster et al., 2007(23)/ Leung et al., 2002(24)

Placebo (oral) 112

Naproxen - 1000 439

63

72

nd

nd

nd

WOMAC (VAS 0 100)

Schnitzer et al., 2010(25)

Placebo (oral) 221

Naproxen - 1000 227

61

70

33.2

nd

nd

WOMAC (VAS 0 100)


Placebo (oral) 254

Naproxen - 1000 256

60

71

33.7

I - III

nd

WOMAC (VAS 0 100)

Hochberg et al., 2011a(27)

Placebo (oral) 124

Naproxen - 1000 + Esomeprazole 40 246

Celecoxib 200 242

62

64

33.1

nd

nd

WOMAC (VAS 0 100)

Hochberg et al., 2011b(27)

Placebo (oral) 122

Naproxen - 1000 + Esomeprazole 40 241

Celecoxib 200 244

62

64

32.6

nd

nd

WOMAC (VAS 0 100)

McKenna et al., 2001(2)(28)

Placebo (oral) 200

Diclofenac - 150 199

Celecoxib 200 199

62

65

nd

nd

9

WOMAC (Likert 020)

Essex et al., 2012a(29)

No Placebo Group

Naproxen - 1000 292

60

66

nd

nd

8

WOMAC (Likert 020)

Essex et al., 2012b(30)

Placebo (oral) 67

Naproxen - 1000 128

58

80

nd

nd

5

Essex et al., 2013 (unpublished)(31)

Placebo (oral) 78

Naproxen - 1000 144

65

67

nd

nd

5

Celecoxib 200 294 Celecoxib 200 127 Celecoxib 200

VAS (0-100) VAS (0-100)

10


145

Essex et al., 2014(32)

Placebo (oral) 62

Naproxen - 1000 129

Celecoxib 200 127

60

66

nd

nd

6

VAS (0-100)

Oral Placebo vs. Celecoxib WOMAC (Likert 020)

Williams et al., 2000(33)

Placebo (oral) 232

Celecoxib - 200 223

63

67

32.1

nd

9

McKenna et al., 2001(34)

Placebo (oral) 60

Celecoxib - 200 63

62

71

nd

nd

11


Placebo (oral) 244

Celecoxib - 200 231

61

71

32.3

nd

10

WOMAC (Likert 020)

Gibofsky et al., 2003(36)

Placebo (oral) 96

Celecoxib - 200 189

63

67

nd

nd

9

WOMAC (Likert 020)

Tannenbaum et al., 2004(37)

Placebo (oral) 243

Celecoxib - 200 481

64

69

29.9

nd

5

WOMAC (Likert 020)


Placebo (oral) 231

Celecoxib - 200 444

61

66

31.8

nd

6

WOMAC (Likert 020)

Lehmann et al., 2005(39)

Placebo (oral) 424

Celecoxib - 200 420

62

70

29.7

nd

4

WOMAC (Likert 020)

Sheldon et al., 2005(40)

Placebo (oral) 382

Celecoxib - 200 393

61

62

32.5

nd

7

WOMAC (Likert 020)

Birbara et al., 2006(1)(41)

Placebo (oral) 78

Celecoxib - 200 157

60

72

nd

nd

nd

WOMAC (VAS 0 100)


Placebo (oral) 85

Celecoxib - 200 169

nd

WOMAC (VAS 0 100)

61

65

nd

nd

VAS (0-100)

11


Clegg et al., 2006(42)

Placebo (oral) 313

Celecoxib - 200 318

59

64

31.7

II - III

6

WOMAC (VAS 0 500)

Bingham et al., 2007(1)(43)

Placebo (oral) 126

Celecoxib - 200 236

62

67

nd

nd

nd

WOMAC (VAS 0 100)


Placebo (oral) 112

Celecoxib - 200 246

62

66

nd

nd

nd

WOMAC (VAS 0 100)

Rother et al., 2007(44)


Celecoxib – 20 + Topical placebo 132

63

60

nd

II - III

nd

WOMAC (VAS 0 100)

Boswell et al., 2008(1)(45)

Placebo (oral) 101

Celecoxib - 200 107

63

66

nd

II - III

7

WOMAC (VAS 0 100)


Placebo (oral) 167

Celecoxib - 200 163

8

WOMAC (VAS 0 100)

Conaghan et al., 2013(46)

Placebo (oral) 227

Celecoxib - 200 233

62

77

nd

nd

nd

Placebo (oral) 190

Celecoxib - 200 190

60

61

nd

nd

9

WOMAC (Likert 020)

Placebo (oral) 193

Celecoxib - 200 195

7

WOMAC (Likert 020)

Asmus et al., 2013(1)(47) (unpublished) Asmus et al., 2013(2)(47) (unpublished)

60

59

69

68

nd

nd

II - III

nd

WOMAC (Numerical rating scale (0-10))

Acetaminophen vs. Oral NSAIDs

Bradley et al., 1991(48)


Ibuprofen - 2400 61

57

73

nd

II - III

9



Naproxen - 750 75

60

75

nd

< IV

7

VAS walking pain (converted scale (0-3)) VAS pain on motion (0-10)

12


Pincus et al., 2001(50)


Diclofenac - 150 + misoprostol 400 μm 112

62

71

nd

II - IV

nd


Doherty et al., 2011(51)


Ibuprofen - 400 217

61

49

nd

nd

nd

WOMAC (VAS 0 100)

Acetaminophen vs. Celecoxib Geba et al., 2002(52)


Celecoxib - 200 94

63

68

nd

nd

nd

WOMAC (VAS 0 100)

Schnitzer et al., 2005b(53)


Celecoxib - 200 514

62

67

nd

nd

nd

WOMAC (VAS 0 100)

Oral NSAIDs vs. Intra-articular Hyaluronic Acid

Adams et al., 1995(54)

Usual NSAID therapy (usual dose + 3 weekly arthrocenteses) 32

IAHA (3 weekly inj) 25


Naproxen (1000 mg + 5 weekly IA saline inj) 125

IAHA (5 weekly IAHA inj + oral Placebo) 115

Dickson et al., 2001(56)

Dicloflenac (100 mg + 3 weekly arthrocenteses) 55

IAHA (3 weekly IA inj + oral Placebo) 53

Petrella et al., 2002(57)

Diclofenac (150mg + 100 μg misoprostol + 3 weekly IA saline) 26

IAHA (3 weekly IA inj + oral Placebo) 25

Ishijima et al., 2014(58)

Loxoprofen 100

IAHA (5 weekly IAHA inj) 100

IA Placebo + oral Placebo 129 Arthrocente sis + oral Placebo 57 IA Placebo + oral Placebo 28

Pain with motion (weight-bearing) (VAS (0-100))

62

68

25.3

I - III

6

63

59

31.5

II - III

nd

65

56

29.0

nd

nd

WOMAC (VAS 0 100)

66

39

30.6

I - III

nd

WOMAC (VAS 0 10)

nd

nd

nd

I - III

nd

VAS (0-100)

VAS (0-100)

13


Novartis_CACZ885 C2201 2012(59) (unpublished)

Naproxen 1000 49

IA Placebo 44

61

65

≤ 45

II - III

nd

WOMAC (Likert 020)

Intra-articular Corticosteroids vs. Intra-articular Hyaluronic Acid

Leardini et al., 1987(60)

Methylprednisolone (40mg 3 weekly inj) 20

IAHA (20 mg 3 weekly inj) 20

64

81

nd

II - III

nd

VAS spontaneous pain (0-100)


Methylprednisolone (40mg, 3 weekly inj) 20

IAHA (20mg 3 weekly inj) 20

65

88

28.5

II - IV

8


Methylprednisolone (40mg, 3 weekly inj) 45 Triamcinolone hexacetonide (20 mg, single inj followed by 4 Placebo inj) 27

IAHA (20mg, 5 weekly inj) 45

63

73

nd

II - IV

6



71

62

nd

nd

nd

VAS pain on activity

Tekeoglu et al., 1998(64)

Betamethasone (3mg; 3 weekly inj) 20

IAHA (20mg NAHA, 3 weekly inj) 20

58

100

29.7

II -III

1

Frizziero et al., 2002(65)


IAHA (20 mg, weekly inj) 52

50

53

26.4

I - III

nd

Tascioglu et al., 2003(66)



59

100

33.0

II - III

6

Triamcinolone hexacetonide (40 mg, single inj) 102


63

57

31.0

nd

nd

Pietrogrande et al., 1991(62)

Jones et al., 1995(63)

Caborn et al., 2004(67)

nd

VAS (0-100) VAS weightbearing pain (0100)

WOMAC A1 (0-4)

14


Skwara et al., 2009a(68)

Triamcinolone acetonide (10 mg) 26

IAHA (60 mg, 1 inj) 24

61

55

28.4

II - III

nd

Skwara et al., 2009b(69)

Triamcinolone (10 mg; 5 weekly inj) 15

IAHA (20 mg; 5 weekly inj) 20

61

52

29.1

II - III

nd

Shimizu et al., 2010(70)

Dexamethasone (4 mg; 1 inj) 25

IAHA (25mg; 5 weekly inj) 26

76

76

24.4

II - III

nd

Housman et al., 2014(71)

Methylprednisolone acetate (40 mg; 1 inj) 132

IAHA (1 or 2 inj) 259

61

67

31.2

I - III

3

Leighton et al., 2014 (72)

Methylprednisolone acetate (40 mg; 1 inj) 215

IAHA (60mg NASHA (Durolane), 1 inj) 218

62

49

28.3

II - III

5

VAS (0-100)

VAS (0-100) VAS walking pain (0-100) WOMAC A1 (0-4) WOMAC (Likert 020)

Intra-articular Placebo vs. Intra-articular Hyaluronic Acid Shichikawa et al., 1983a(73)

IA Placebo 52

Shichikawa et al., 1983b(74)

IA Placebo 102

Bragantini et al., 1987(75)

IA Placebo 18

Grecomoro et al., 1987(76)

IA Placebo 18

Dixon et al., 1988(77)

IA Placebo 33

Russell et al., 1992(78) (unpublished)

IA Placebo 71

IAHA (25mg Artzal; 5 weekly inj) 51 IAHA (25mg Artzal; 5 weekly inj) 96 IAHA (40 mg Hyalgan; 3 weekly inj) 20 IAHA (20 mg Hyalgan; 3 weekly inj) 20 IAHA (20 mg Hyalgan; up to 11 inj) 30 IAHA (20 mg; 3 weekly inj) 71

Pain Score (0-4)

62

83

nd

nd

nd

nd

70

nd

nd

nd

57

75

nd

II - IV

nd

65

56

nd

nd

nd

69

54

nd

nd

nd

VAS pain on movement (0-100)

62

56

nd

nd

nd

Pain Score (VAS 0-100)

Pain Score (0-10)

VAS (0-100)

VAS (0-100)

15


Dougados et al., 1993(79)

IA Placebo 46

Moreland et al., 1993(80) (unpublished)

IA Placebo 52

Puhl et al., 1993(81)

IA Placebo 100

Cohen et al., 1994(82) (unpublished)

IA Placebo 20

Creamer et al., 1994(83)

IA Placebo 12

Dahlberg et al., 1994(84)

IAHA (20 mg Hyalgan; 4 weekly inj) 49

68

71

nd

nd

nd

nd

67

nd

nd

3

62

64

26.6

nd

nd

nd

nd

nd

nd

nd


nd

nd

nd

nd

nd

IA Placebo 23

IAHA (25mg LMW NAHA; 5 weekly inj) 27

45

nd

27.1

nd

nd

Henderson et al., 1994(85)

IA Placebo 44


67

69

nd

II - IV

nd

Scale et al., 1994(86)

IA Placebo 15

IAHA (2 mL Hylan G-F 20, 3 weekly inj) 15

59

44

nd

II - IV (Larsen)

4

Carrabba et al., 1995(87)

IA Placebo 20

IAHA (20mg Hyalgan, 5 weekly inj) 20

60

63

24.9

nd

nd

Corrado et al., 1995(88)

IA Placebo 16


61

78

nd

nd

3

France 1995(89) (unpublished)

IA Placebo 80

IAHA 87

65

65

27.9

nd

nd

Formiguera Sala et al., 1995(90)

IA Placebo 20


62

73

nd

nd

1

IAHA (2 mL Hylan G-F 20, 3 weekly inj) 52 IAHA (25mg Artz, 5 weekly inj) 95 IAHA (20mg Hyalgan; 3 weekly inj) 19

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

16


Lohmander et al., 1996(91)

IA Placebo 93

IAHA (25mg Artzal; 5 weekly inj) 96

58

56

27.4

I - II (Ahlback)

2

UK 1996(89) (unpublished)

IA Placebo 115

IAHA 116

61

57

28.5

nd

nd

Wu et al., 1997(92)

IA Placebo 41

69

28

nd

nd

2

Wobig et al., 1998(93)

IA Placebo 59

62

65

27.3

I -IV (Larsen)

nd

Hizmetli et al., 1999(94) (unpublished)

IA Placebo 25

IAHA (2ml, 3 weekly inj) 25

56

68

nd

I -II

nd

Huskisson et al., 1999(95)

IA Placebo 50


65

67

nd

II - III

nd

Brandt et al., 2001(96)

IA Placebo 69

IAHA (30 mg HMW HA (Orthovisc), 3 weekly inj) 66

66

63

30.7

II - III

nd

Bunyaratavej et al., 2001(97)

IA Placebo 25


60

78

28.0

I - IV

3

Tamir et al., 2001(98)

IA Placebo 17

IAHA (20 mg BioHy, 5 weekly inj) 20

71

74

nd

II - IV

nd

Karlsson et al., 2002(99)

IA Placebo 57

IAHA (Artzal or hylan GF 20, 3 weekly inj) 153

71

65

28.0

I - II (Ahlback)

nd

Saravanan et al., 2002(100) (unpublished)

IA Placebo 33

IAHA (2ml hylan G-F 20, 3 weekly inj) 33

nd

nd

nd

II - III

nd

Jubb et al., 2003(101)

IA Placebo 200


64

68

29.8

II - III

8

IAHA (2.5ml Artz, 5 weekly inj) 56 IAHA (2ml hylan G-F 20) 57

VAS (0-100) VAS (0-100) Pain Score (1-7)

VAS (0-100)

no pain outcome

VAS (0-100)

WOMAC (Likert 525)

VAS (0-100)

MODEMS (1-5) WOMAC (Likert 020)

nd

VAS (0-100)

17


Tsai et al., 2003(102) (unpublished)

IA Placebo 100


65

76

nd

nd

nd

VAS (0-100)


IA Placebo 174

IAHA (60mg NASHA (Durolane), 1 inj) 172

63

55

29.9

II - IV

6

WOMAC (Likert 020)

Day et al., 2004(104)

IA Placebo 115

62

56

29.4

nd

nd

WOMAC (Likert 020)

65

68

29.0

0 - IV

nd

55

60

28.2

nd

2

WOMAC (Likert 525)

58

48

29.2

I - III

nd

WOMAC (VAS 0500)

8

Pham et al., 2004(105)

IA Placebo + Oral Placebo 80

IAHA (25 mg Artz, 5 weekly inj) 108 IAHA (NRD 101; 3 weekly inj + Oral Placebo) 122 IAHA (20mg hylan G-F 20, 3 weekly inj) 30

Cubukcu et al., 2005(106)

IA Placebo 10

Neustadt et al., 2005(107)

Arthrocentesis (4 weekly inj) 114

IAHA (30mg Orthovisc, 4 weekly inj) 115

Rolf et al., 2005(108)

IA Placebo 91

IAHA ( Hylan G-F 20 or Artzal; 3 weekly inj) 181

Sezgin et al., 2005(109)

IA Placebo 19

Kotevoglu et al., 2006(110)

IA Placebo 18


IA Placebo (6 weekly inj) 53

Blanco et al., 2008(112)

IA Placebo 20

IAHA (30mg Orthovisc, 3 weekly inj) 22 IAHA (Orthovisc or hylan G-F 20, 3 weekly inj) 41 IAHA (6 weekly inj: 3 of IA placebo then 3 of 40mg HA) 53 IAHA (900 kDa HA, 5 weekly inj) 22

VAS (0-100)

no pain outcome

54

37

27.2

I - III (Outerbri dge)

59

76

29.8

II - III

3

WOMAC (Likert 020)

59

88

nd

II - IV

4

WOMAC (Likert 525)

63

56

30.5

I - III

nd

WOMAC (VAS 0 50)

68

81

33.4

IV

nd

WOMAC (VAS 0 100)

18


Lundsgaard et al., 2008(113)

IA Placebo 80

IAHA (20 mg Hyalgan, 4 weekly inj) 82


IA Placebo 50

IAHA (LMW or HMW or Dual MW HA; 3 weekly inj) 150

70

57

27.0

I - III

8

Sanofi 2008(115) (unpublished)

IA Placebo 80

IAHA (20 mg Hyalgan, 3 weekly inj) 79

nd

nd

nd

nd

nd


IA Placebo 295

IAHA (20 mg/2ml, 3 weekly inj) 291

62

63

32.7

II - III

nd

WOMAC (VAS 0 100)

Baltzer et al., 2009(117)

IA Placebo 107

IAHA (2mL Hyaject, 3 weekly inj) 135

57

55

nd

II - III

nd

WOMAC (VAS 0 10)

Diracoglu et al., 2009(118)

IA Placebo 20

IAHA (hylan G-F 20, 3 weekly inj) 40

58

88

31.2

II - III

nd

WOMAC (VAS 0 10)

Chevalier et al., 2010(119)

IA Placebo 129

IAHA (hylan G-F 20) 124

63

71

29.4

II - IV

nd

WOMAC (Likert 04)

Jorgensen et al., 2010(120)

IA Placebo 169


62

62

28.9

nd

6

Kul-Panza et al., 2010(121)

IA Placebo 22

IAHA (30mg MMW NAHA, 3 weekly inj) 23

61

85

30.2

I - IV

7

WOMAC (Likert 020)

Huang et al., 2011(122)

IA Placebo 98


65

76

25.6

I - II

1

WOMAC (VAS 0 100)

Navarro-Sarabia et al., 2011(123)

IA Placebo 153

IAHA (2.5ml, 5 weekly inj/cycle; 4 cycles over 2 years) 153

63

84

28.6

II - III

7

69

55

29.5

I - IV

nd

VAS (0-100)

VAS walking pain (0-100)

VAS (0-100)

VAS (0-10)

VAS (0-100)

19


DeCaria et al., 2012(124)

IA Placebo 15

IAHA (40mg HA, 3 weekly inj) 15

72

47

29.9

II - III

nd

WOMAC (Likert 020)

Kosuwon et al., 2012(125)

IA Placebo 30

IAHA (25mg GoOn, 5 weekly inj) 30

61

100

26.5

II - III

nd

WOMAC (Likert 020)

Strand et al., 2012(126)

IA Placebo 128

IAHA (30 mg crosslinked HA, 1 inj) 247

60

60

28.4

I - III

3

WOMAC (VAS 0 100)

Intra-articular Placebo vs. Intra-articular Corticosteroids

Friedman et al., 1980(127)

IA Placebo 17

Triamcinolone hexacetonide - 20mg 17

60

nd

nd

nd

3

Gaffney et al., 1995(128)

IA Placebo 40

Triamcinolone hexacetonide - 20mg 42

67

71

29.7

nd

7

Jones et al., 1996(129)

IA Placebo 30

Methylprednisolone acetate - 40mg 29

71

62

nd

nd

nd

Ravaud et al., 1999(130)

IA Placebo 28

Cortivazol - 3.75mg 25

65

68

28.5

II - IV

nd

Raynauld et al., 2003(131)

IA Placebo 33

Triamcinolone acetonide- 40mg 33

63

68

nd

II - III

9

WOMAC (VAS 0 100)

Chao et al., 2010(132)

IA Placebo 29

Triamcinolone acetonide - 40mg 30

64

3

nd

nd

14

WOMAC (Likert 020)

IA Placebo 30

Triamcinolone OR Betametazone OR Methyprednisolone 90

60

63

nd

≥ II

nd

Yavuz et al., 2012(133)

Pain Score (0-10)

VAS (0-100)

VAS (0-100)

VAS (0-100)

VAS (0-100)

NAHA= sodium hyaluronate; NASHA= non-animal sodium hyaluronic acid; LMW= low molecular weight; HMW= high molecular weight; WOMAC= Western Ontario and McMaster Universities Arthritis Index; VAS=Visual analog scale; IA= Intra-articular; HA= Hyaluronic acid; nd= No data

20


Supplement Table 3: Risk of bias assessment Groups Comparable at Baseline?

Random Sequence Generation

Adequate Allocation Concealment

Participant Blinding

Assessor Blinding

Intentionto-treat Analysis

Industry Funding

Case et al., 2003(1)

No

Unclear

No

Yes

Yes

Yes

No

Miceli-Richard et al., 2004(2)

Yes

Unclear

No

Yes

Yes

Yes

Yes

Pincus et al., 2004a(3)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Pincus et al., 2004b(3)

Yes

Yes

Yes

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes

Yes

Yes

Herrero-Beaumont et al., 2007(5)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Sandelin et al., 1997(6)

Yes

Yes

Unclear

Yes

Yes

Yes

Yes

Yocum et al., 2000(7)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Ghosh et al., 2007(8)

Unclear

Unclear

Unclear

Yes

No

No

Unclear

Simon et al., 2009(9)

Unclear

Yes

Yes

Yes

Yes

Yes

Yes

Davies et al., 1999(10)

Yes

Unclear

Unclear

Yes

Yes

No

Yes

Day et al., 2000(11)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Saag et al., 2000(12)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Wiesenhutter et al., 2005(13)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Puopolo et al., 2007(14)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Study

21


Dore et al., 1995(15)

Yes

Unclear

Unclear

Yes

Yes

No

Yes


Yes

Yes

Yes

Yes

Yes

Yes

Yes

Bensen et al., 1999(17)/Zhao et al., 1999(18)

Yes

Yes

Yes

Yes

Yes

Unclear

Yes

Kivitz et al., 2002(19)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Lohmander et al., 2005(20)/ Svensson et al., 2006(21)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Schnitzer et al., 2005a(22)

Yes

Yes

Yes

Yes

Yes

Unclear

Yes

Reginster et al., 2007(23)/ Leung et al., 2002(24)

Yes

Yes

Yes

Yes

Yes

Unclear

Yes


Yes

Yes

Yes

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes

Yes

Yes

Hochberg et al., 2011a(27)

Yes

Yes

Yes

Yes

Yes

Hochberg et al., 2011b(27)

Yes

Yes

Yes

Yes

Yes

McKenna et al., 2001(2)(28)

Yes

Unclear

Unclear

Yes

Yes

Essex et al., 2012a(29)

Yes

Yes

Yes

Yes

Yes

Essex et al., 2012b(30)

Yes

Yes

Yes

Yes

Yes

Essex et al., 2013 (31) (unpublished)

Yes

Unclear

Unclear

Yes

Yes

Essex et al., 2014 (32)

Yes

Unclear

Unclear

Yes

Yes

Yes (modified ITT) Yes (modified ITT) Yes Yes (modified ITT) Yes (modified ITT) Yes (modified ITT) Yes (modified ITT)

Yes

Yes Yes Yes

Yes

Yes

Yes

22



Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

McKenna et al., 2001(34)

Yes

Yes

Yes

Yes

Yes

Yes

Yes


Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Gibofsky et al., 2003(36)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Tannenbaum et al., 2004(37)

Yes

Yes

Yes

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes

Yes

Yes

Lehmann et al., 2005(39)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Sheldon et al., 2005(40)

Yes

Yes

Yes

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes

Clegg et al., 2006(42)

Yes

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes

Rother et al., 2007(44)

Yes

Yes

Unclear

Yes

Yes


Yes

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes

Yes (modified ITT) Yes (modified ITT) Yes Yes (modified ITT) Yes (modified ITT) Yes Yes (modified ITT) Yes (modified ITT)

Yes

Yes No Yes

Yes Yes Yes

Yes

23


Conaghan et al., 2013(46)

Yes

Yes

Yes

Yes

Yes

Yes

Asmus et al., 2013(1)(47) (unpublished)

Yes

Unclear

Unclear

Yes

Yes

Asmus et al., 2013(2)(47) (unpublished)

Yes

Unclear

Unclear

Yes

Yes

Bradley et al., 1991(48)

Yes

Unclear

Unclear

Yes

Yes

Unclear

No


Yes

Yes

Yes

Yes

Yes

No

No

Pincus et al., 2001(50)

Yes

Yes

Unclear

Yes

Yes

No

Yes

Doherty et al., 2011(51)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Geba et al., 2002(52)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Schnitzer et al., 2005b(53)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Adams et al., 1995(54)

Yes

Unclear

Unclear

Unclear

Unclear

No

Yes


Yes

Unclear

Unclear

Yes

Yes

Unclear

Yes

Dickson et al., 2001(56)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes

Yes

Yes

Ishijima et al., 2014(58)

Unclear

Unclear

No

No

No

Yes

Yes

Novartis_CACZ885C2201 2012(59) (unpublished)

Unclear

Unclear

Unclear

Yes

Yes

No

Yes


Yes

Unclear

Unclear

No

Yes

Yes

Yes


Yes

Unclear

Unclear

No

No

Yes

Yes

Yes (modified ITT) Yes (modified ITT)

Yes Yes

Yes

24


Pietrogrande et al., 1991(62)

Yes

Unclear

Unclear

No

No

Yes

Yes

Jones et al., 1995(63)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Tekeoglu et al., 1998(64)

Unclear

Unclear

Unclear

No

No

Yes

Unclear

Frizziero et al., 2002(65)

Yes

Yes

Yes

No

Yes

Yes

Unclear

Tascioglu et al., 2003(66)

Yes

Unclear

Unclear

No

No

No

Unclear

Caborn et al., 2004(67)

Yes

Unclear

Unclear

No

Yes

Yes

Yes

Skwara et al., 2009a(68)

Yes

Yes

Yes

Yes

Yes

No

Unclear

Skwara et al., 2009b(69)

Yes

Yes

Yes

Yes

Yes

No

Unclear

Shimizu et al., 2010(70)

Yes

Yes

N/A

No

No

No

No

Housman et al., 2014(71)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Leighton et al., 2014(72)

Yes

Yes

Yes

Yes

Yes

Yes (modified ITT)

Yes

Shichikawa et al., 1983a(73)

Yes

Yes

Yes

Yes

Yes

No

Yes

Shichikawa et al., 1983b(74)

Yes

Yes

Yes

Yes

Yes

No

Yes

Bragantini et al., 1987(75)

Yes

Unclear

Unclear

Unclear

Unclear

No

Yes

Grecomoro et al., 1987(76)

Unclear

Unclear

No

Yes

Yes

No

Unclear

Yes

Unclear

Unclear

Yes

Yes

No

Yes

Unclear

Unclear

No

No

No

No

Yes

Yes

Unclear

Unclear

No

No

No

Yes

Dixon et al., 1988(77) Russell et al., 1992(78) (unpublished) Dougados et al., 1993(79)

25


Moreland et al., 1993(80) (unpublished)

Unclear

Yes

Yes

Yes

Yes

Yes

Yes

Puhl et al., 1993(81)

No

Yes

Yes

Yes

Yes

No

Yes

Cohen et al., 1994(82) (unpublished)

Yes

Unclear

Unclear

Yes

Yes

No

Yes

Creamer et al., 1994(83)

Unclear

Unclear

No

No

Yes

Yes

Yes

Dahlberg et al., 1994(84)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Henderson et al., 1994(85)

Yes

Yes

Yes

Yes

Yes

No

Unclear

Scale et al., 1994(86)

Yes

Unclear

Unclear

Yes

Yes

No

Yes

Carrabba et al., 1995(87)

Yes

Unclear

No

Unclear

Unclear

Yes

Yes

Corrado et al., 1995(88)

Yes

Unclear

No

Unclear

Unclear

No

Unclear

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Unclear

Yes

Yes

Unclear

Unclear

Yes

Unclear

Yes

Yes

Yes

Yes

Yes

No

Yes

Unclear

Yes

Yes

Yes

Yes

Yes

Yes

Wu et al., 1997(92)

Yes

Unclear

No

Unclear

Unclear

No

Unclear

Wobig et al., 1998(93)

No

Unclear

Unclear

Yes

Yes

Yes

Yes

Unclear

Unclear

Unclear

Yes

Yes

No

Unclear

Huskisson et al., 1999(95)

Yes

Unclear

Unclear

Yes

Yes

Yes

Unclear

Brandt et al., 2001(96)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Bunyaratavej et al., 2001(97)

Yes

Unclear

Unclear

Yes

Yes

Yes

Unclear

France 1995(89) (unpublished) Formiguera Sala et al., 1995(90) Lohmander et al., 1996(91) UK 1996(89) (unpublished)

Hizmetli et al., 1999(94) (unpublished)

26


Tamir et al., 2001(98)

Yes

Unclear

No

No

Unclear

No

Yes

Karlsson et al., 2002(99)

Yes

Yes

Yes

Yes

Yes

No

Yes

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

Yes

Jubb et al., 2003(101)

Yes

Unclear

Unclear

Yes

Yes

No

Yes

Tsai et al., 2003(102) (unpublished)

Unclear

Unclear

Unclear

Yes

Yes

Yes

Yes


Yes

Yes

Yes

Yes

Yes

Yes

Yes

Day et al., 2004(104)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Pham et al., 2004(105)

Yes

Yes

Yes

Yes

Yes

Yes

Unclear

Cubukcu et al., 2005(106)

Yes

Unclear

Unclear

No

Unclear

Yes

Unclear

Neustadt et al., 2005(107)

Yes

Yes

Yes

Yes

Yes

No

Yes

Rolf et al., 2005(108)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Sezgin et al., 2005(109)

Yes

Unclear

Unclear

No

Unclear

Yes

Unclear

Kotevoglu et al., 2006(110)

Yes

Unclear

Unclear

Unclear

Unclear

No

Unclear


Yes

Yes

Yes

Yes

Yes

Yes

Yes

Blanco et al., 2008(112)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Lundsgaard et al., 2008(113)

Yes

Yes

Yes

Yes

Yes

Yes

No


Yes

Yes

Yes

Yes

Yes

Yes

No

Unclear

Unclear

Unclear

Unclear

Yes

Unclear

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Saravanan et al., 2002(100) (unpublished)

Sanofi 2008(115) (unpublished) Altman et al., 2009(116)

27


Baltzer et al., 2009(117)

Yes

Yes

Unclear

Unclear

Unclear

Yes

Yes

Diracoglu et al., 2009(118)

Yes

Yes

Unclear

Yes

Yes

No

Unclear

Chevalier et al., 2010(119)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

Jorgensen et al., 2010(120)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Kul-Panza et al., 2010(121)

Yes

Yes

Unclear

Yes

Yes

No

Unclear

Huang et al., 2011(122)

Yes

Unclear

Unclear

Yes

Yes

Yes

Yes

Navarro-Sarabia et al., 2011(123)

Yes

Yes

Yes

Yes

Yes

Yes

Yes

DeCaria et al., 2012(124)

Yes

Yes

Yes

Yes

Yes

Yes

No

Kosuwon et al., 2012(125)

Yes

Unclear

Unclear

Yes

Yes

No

No

Strand et al., 2012(126)

Yes

Yes

Unclear

Yes

Yes

Yes

Yes

Unclear

Yes

Yes

Yes

Yes

Unclear

No

Yes

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

Unclear

Yes

Yes

Yes

Unclear

Ravaud et al., 1999(130)

Yes

Yes

Yes

Yes

Yes

Yes

No

Raynauld et al., 2003(131)

Yes

Unclear

Yes

Yes

Yes

Yes

No

Chao et al., 2010(132)

Unclear

Unclear

Unclear

Yes

Yes

No

No

Yavuz et al., 2012(133)

Yes

Unclear

Unclear

Yes

Yes

Unclear

Unclear

Friedman et al., 1980(127) Gaffney et al., 1995(128) Jones et al., 1996(129)

28


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Brandt KD, Block JA, Michalski JP, Moreland LW, Caldwell JR, Lavin PT. Efficacy and safety of intraarticular sodium hyaluronate in knee osteoarthritis. ORTHOVISC Study Group. Clinical orthopaedics and related research. 2001(385):130-43. Bunyaratavej N, Chan KM, Subramanian N. Treatment of painful osteoarthritis of the knee with hyaluronic acid. Results of a multicenter Asian study. Journal of the Medical Association of Thailand = Chotmaihet thangphaet. 2001;84 Suppl 2:S576-81. Tamir E, Robinson D, Koren R, Agar G, Halperin N. Intra-articular hyaluronan injections for the treatment of osteoarthritis of the knee: a randomized, double blind, placebo controlled study. Clinical and experimental rheumatology. 2001;19(3):265-70. Karlsson J, Sjogren LS, Lohmander LS. Comparison of two hyaluronan drugs and placebo in patients with knee osteoarthritis. A controlled, randomized, double-blind, parallel-design multicentre study. Rheumatology. 2002;41(11):1240-8. Saravanan V MT, Stobbs D, Daymond TJ. Inflammatory effusion after viscosupplementation with Hylan G-F 20 [Abstract 336]. Rheumatology. 2002;41((Suppl 1)):121. Jubb RW, Piva S, Beinat L, Dacre J, Gishen P. A one-year, randomised, placebo (saline) controlled clinical trial of 500-730 kDa sodium hyaluronate (Hyalgan) on the radiological change in osteoarthritis of the knee. International journal of clinical practice. 2003;57(6):467-74. Tsai CL, Chang CC, Chen SC, Beinat L, Piva S. Treatment of knee osteoarthritis in Asian population with an intra-articular hyaluronan of MW 500-730 KDa [Abstract P333]. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2003;11(Suppl A):119. Altman RD, Akermark C, Beaulieu AD, Schnitzer T. Efficacy and safety of a single intra-articular injection of non-animal stabilized hyaluronic acid (NASHA) in patients with osteoarthritis of the knee. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2004;12(8):642-9. Day R, Brooks P, Conaghan PG, Petersen M. A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee. The Journal of rheumatology. 2004;31(4):775-82. Pham T, Le Henanff A, Ravaud P, Dieppe P, Paolozzi L, Dougados M. Evaluation of the symptomatic and structural efficacy of a new hyaluronic acid compound, NRD101, in comparison with diacerein and placebo in a 1 year randomised controlled study in symptomatic knee osteoarthritis. Annals of the rheumatic diseases. 2004;63(12):1611-7. Cubukcu D, Ardic F, Karabulut N, Topuz O. Hylan G-F 20 efficacy on articular cartilage quality in patients with knee osteoarthritis: clinical and MRI assessment. Clinical rheumatology. 2005;24(4):336-41. Neustadt D, Caldwell J, Bell M, Wade J, Gimbel J. Clinical effects of intraarticular injection of high molecular weight hyaluronan (Orthovisc) in osteoarthritis of the knee: a randomized, controlled, multicenter trial. The Journal of rheumatology. 2005;32(10):1928-36. Rolf CG, Engstrom B, Ohrvik J, Valentin A, Lilja B, Levine DW. A comparative study of the efficacy and safety of hyaluronan viscosupplements and placebo in patients with symptomatic and arthroscopy-verified cartilage pathology. Journal of drug assessment. 2005;8:183-200. Sezgin M, Demirel A, Karaca C, Ortancıl Ö, Ülkar G, Kanık A, et al. Does hyaluronan affect inflammatory cytokines in knee osteoarthritis? Rheumatology international. 2005;25(4):264-9.

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110.

111. 112. 113.

114. 115. 116.

117. 118. 119.

120. 121. 122.

123.

Kotevoglu N, Iyibozkurt PC, Hiz O, Toktas H, Kuran B. A prospective randomised controlled clinical trial comparing the efficacy of different molecular weight hyaluronan solutions in the treatment of knee osteoarthritis. Rheumatology international. 2006;26(4):325-30. Petrella RJ, Petrella M. A prospective, randomized, double-blind, placebo controlled study to evaluate the efficacy of intraarticular hyaluronic acid for osteoarthritis of the knee. The Journal of rheumatology. 2006;33(5):951-6. Blanco FJ, Fernández-Sueiro JL, Pinto-Tasende JA, J.C. Fernández-López JC, Ramallal M, Freire A, et al. Intra-articular hyaluronan treatment of patients with knee osteoarthritis waiting for replacement surgery. The Open Arthritis Journal. 2008;1:1-7. Lundsgaard C, Dufour N, Fallentin E, Winkel P, Gluud C. Intra-articular sodium hyaluronate 2 mL versus physiological saline 20 mL versus physiological saline 2 mL for painful knee osteoarthritis: a randomized clinical trial. Scandinavian journal of rheumatology. 2008;37(2):142-50. Petrella RJ, Cogliano A, Decaria J. Combining two hyaluronic acids in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Clinical rheumatology. 2008;27(8):975-81. Sanofi-Aventis. A Double Blind, Randomized Trial of Intra-articular Injections of 20 mg of HYALGAN® for the Treatment of Knee Pain due to Osteoarthritis [NCT00130468]. 2008. Altman RD, Rosen JE, Bloch DA, Hatoum HT, Korner P. A double-blind, randomized, saline-controlled study of the efficacy and safety of EUFLEXXA for treatment of painful osteoarthritis of the knee, with an open-label safety extension (the FLEXX trial). Seminars in arthritis and rheumatism. 2009;39(1):1-9. Baltzer AW, Moser C, Jansen SA, Krauspe R. Autologous conditioned serum (Orthokine) is an effective treatment for knee osteoarthritis. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2009;17(2):152-60. Diracoglu D, Vural M, Baskent A, Dikici F, Aksoy C. The effect of viscosupplementation on neuromuscular control of the knee in patients with osteoarthritis. Journal of back and musculoskeletal rehabilitation. 2009;22(1):1-9. Chevalier X, Jerosch J, Goupille P, van Dijk N, Luyten FP, Scott DL, et al. Single, intra-articular treatment with 6 ml hylan G-F 20 in patients with symptomatic primary osteoarthritis of the knee: a randomised, multicentre, double-blind, placebo controlled trial. Annals of the rheumatic diseases. 2010;69(1):113-9. Jorgensen A, Stengaard-Pedersen K, Simonsen O, Pfeiffer-Jensen M, Eriksen C, Bliddal H, et al. Intra-articular hyaluronan is without clinical effect in knee osteoarthritis: a multicentre, randomised, placebo-controlled, double-blind study of 337 patients followed for 1 year. Annals of the rheumatic diseases. 2010;69(6):1097-102. Kul-Panza E, Berker N. Is hyaluronate sodium effective in the management of knee osteoarthritis? A placebo-controlled double-blind study. Minerva medica. 2010;101(2):63-72. Huang TL, Chang CC, Lee CH, Chen SC, Lai CH, Tsai CL. Intra-articular injections of sodium hyaluronate (Hyalgan(R)) in osteoarthritis of the knee. a randomized, controlled, double-blind, multicenter trial in the Asian population. BMC musculoskeletal disorders. 2011;12:221. Navarro-Sarabia F, Coronel P, Collantes E, Navarro FJ, de la Serna AR, Naranjo A, et al. A 40-month multicentre, randomised placebo-controlled study to assess the efficacy and carry-over effect of repeated intra-articular injections of hyaluronic acid in knee osteoarthritis: the AMELIA project. Ann Rheum Dis. 2011;70(11):1957-62. 37


124.

125.

126.

127. 128. 129. 130.

131.

132. 133.

DeCaria JE, Montero-Odasso M, Wolfe D, Chesworth BM, Petrella RJ. The effect of intra-articular hyaluronic acid treatment on gait velocity in older knee osteoarthritis patients: a randomized, controlled study. Archives of gerontology and geriatrics. 2012;55(2):310-5. Kosuwon W, Sirichatiwapee W, Visanuyotin T, Jeeravipoolvarn P, Laupattarakasem W. Determination of cartilage volume using MRI in patients with knee osteoarthritis: efficacy study of 25 milligrams of sodium hyaluronate (2.5 Ml) versus placebo. Clinical and Experimental Pharmacology. 2012;2(2). Strand V, Baraf HS, Lavin PT, Lim S, Hosokawa H. A multicenter, randomized controlled trial comparing a single intraarticular injection of Gel-200, a new cross-linked formulation of hyaluronic acid, to phosphate buffered saline for treatment of osteoarthritis of the knee. Osteoarthritis and cartilage / OARS, Osteoarthritis Research Society. 2012;20(5):350-6. Friedman DM, Moore ME. The efficacy of intraarticular steroids in osteoarthritis: a double-blind study. The Journal of rheumatology. 1980;7(6):850-6. Gaffney K, Ledingham J, Perry JD. Intra-articular triamcinolone hexacetonide in knee osteoarthritis: factors influencing the clinical response. Annals of the rheumatic diseases. 1995;54(5):379-81. Jones A, Doherty M. Intra-articular corticosteroids are effective in osteoarthritis but there are no clinical predictors of response. Annals of the rheumatic diseases. 1996;55(11):829-32. Ravaud P, Moulinier L, Giraudeau B, Ayral X, Guerin C, Noel E, et al. Effects of joint lavage and steroid injection in patients with osteoarthritis of the knee: results of a multicenter, randomized, controlled trial. Arthritis and rheumatism. 1999;42(3):47582. Raynauld JP, Buckland-Wright C, Ward R, Choquette D, Haraoui B, Martel-Pelletier J, et al. Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial. Arthritis and rheumatism. 2003;48(2):370-7. Chao J, Wu C, Sun B, Hose MK, Quan A, Hughes TH, et al. Inflammatory characteristics on ultrasound predict poorer longterm response to intraarticular corticosteroid injections in knee osteoarthritis. The Journal of rheumatology. 2010;37(3):650-5. Yavuz U, Sokucu S, Albayrak A, Ozturk K. Efficacy comparisons of the intraarticular steroidal agents in the patients with knee osteoarthritis. Rheumatology international. 2012;32(11):3391-6.

38


Supplement Figure 1: Forest plot of absolute treatment effects (WOMAC 0-100)

Acetaminophen

19.55 (16.48, 22.85)

IA Placebo

21.97 (16.48, 27.46)

Celecoxib

22.85 (21.09, 24.83)

Naproxen

23.95 (21.53, 26.36)

Ibuprofen

25.27 (21.09, 29.44)

Diclofenac

27.02 (23.07, 30.76)

IA Corticosteroids 29.00 (22.63, 35.15) IA Hyaluronic acid 29.44 (24.17, 34.93) 0.00

10.00

20.00

30.00

40.00

Blue line at 20.00 represents the line of clinical significance

39


Supplement Table 4: Relative and absolute treatment effects for pain Relative Efficacy* (SMD)

Absolute Efficacy† (SMD)

Absolute Efficacy (WOMAC: 0-100)

Acetaminophen

0.18 (0.04, 0.33)

0.89 (0.75, 1.04)

19.55 (16.48, 22.85)

IA Placebo

0.29 (0.04, 0.54)

1.00 (0.75, 1.25)

21.97 (16.48, 27.46)

Celecoxib

0.33 (0.25, 0.42)

1.04 (0.96, 1.13)

22.85 (21.09, 24.83)

Naproxen

0.38 (0.27, 0.49)

1.09 (0.98, 1.20)

23.95 (21.53, 26.36)

Ibuprofen

0.44 (0.25, 0.63)

1.15 (0.96, 1.34)

25.27 (21.09, 29.44)

Diclofenac

0.52 (0.34, 0.69)

1.23 (1.05, 1.40)

27.02 (23.07, 30.76)

IA Corticosteroids

0.61 (0.32, 0.89)

1.32 (1.03, 1.60)

29.00 (22.63, 35.15)

IA Hyaluronic acid

0.63 (0.39, 0.88)

1.34 (1.10, 1.59)

29.44 (24.17, 34.93)

* Relative efficacy in comparison to oral placebo; † absolute treatment effect as change from baseline

40


1

1

0.8

0.8

0.8

0.6 0.4 0.2

0.6 0.4 0.2

1

2

3

4

5

6

7

8

0.4 0.2 0

1

9

2

3

4

5

6

7

8

9

1

0.8

0.8

0.8

0.2 0

Rank Probability

1

Rank Probability

1

0.4

0.6 0.4

0.2

2

3

4

5

6

7

8

9

2

3

4

5

6

7

8

1

9

0.8

0.8

Rank Probability

0.8

Rank Probability

1

0.6 0.4 0.2 0

1

2

3

4

5

6

7

8

9

Rank of Intra-articular Placebo

8

9

2

3

4

5

6

7

8

9

8

9

Rank of Celecoxib

1

0

7

0.2

1

0.2

6

0.4

Rank of Naproxen

0.4

5

0 1

Rank of Ibuprofen

0.6

4

0.6

0 1

3

Rank of Diclofenac

1

0.6

2

Rank of Intra-articular Corticosteroids

Rank of Intra-articular Hyaluronic Acid

Rank Probability

0.6

0

0

Rank Probability

Rank Probability

1

Rank Probaility

Rank Probability

Supplement Figure 2: Rank Probability Curves for pain

0.6

0.4 0.2 0

1

2

3

4

5

6

7

Rank of Acetaminophen

8

9

1

2

3

4

5

6

7

Rank of Oral Placebo

41


Supplement Figure 3: Cumulative Ranking Curves with Surface Under the Cumulative Ranking Curve (SUCRA) for pain

0.8

0.6

SUCRA=91.4%

0.4 0.2 0

0.8

SUCRA=85.6%

0.6 0.4 0.2

2

3

4

5

6

7

8

9

0.6

0.2

2

3

4

5

6

7

8

9

1

0.4 0.2 0

0.8

2

3

4

5

6

7

8

0.6

SUCRA=50.1%

0.4

0.2

9

2

Rank of Ibuprofen

3

4

5

6

7

8

0.2

SUCRA=31.9%

1

2

3

4

5

6

7

2

3

8

9

Rank of Intra-articular Placebo

4

5

6

7

8

9

8

9

Rank of Celecoxib 1

0.8

0.6 0.4 0.2

SUCRA=15.8% 0

0

9

0.2

1

Cumulative Probability


0.4

8

SUCRA=38.2%

0.4

9

1

0.6

7

0.6

Rank of Naproxen

0.8

6

0 1

1

5

0.8

0

1

4

1



SUCRA=61.6%

3

Rank of Diclofenac

1

0.6

2

Rank of Intra-articular Corticosteroids

1 0.8

SUCRA=75.3%

0.4

0 1

Rank of Intra-articular Hyaluronic Acid


0.8

0 1


1


1

Cumulative Probaility


1

0.8 0.6

SUCRA=0.2% 0.4 0.2 0

1

2

3

4

5

6

7

Rank of Acetaminophen

8

9

1

2

3

4

5

6

7

Rank of Oral Placebo

42


Supplement Figure 4: Plot of inconsistency estimates for pain Loop

Absolute Inconsistency Factor [95% Confidence Interval]

OBA ONA ODA OCA OCN OCD ACN ACD NIH HIS DIH

Supplement Figure 4: Plot of inconsistency estimates (difference between direct and indirect estimates) with their 95% confidence intervals for pain. The overhead line denotes the comparison for which the inconsistency factor is estimated. O=Oral placebo; A=Acetaminophen; D=Diclofenac; B=Ibuprofen; N=Naproxen; C=Celecoxib; H=Intra-articular hyaluronic acid; S=Intra-articular Corticosteroids; I=Intra-articular placebo Zero inconsistent loops out of 11.

43


Supplement Figure 5: Network of Treatment Comparisons for function

Oral Placebo

IA Placebo

Acetaminophen

IA Corticosteroids Diclofenac

Ibuprofen

IA Hyaluronic acid

Celecoxib

Naproxen

Circle size reflects n of participants and the line width reflects N of direct comparisons. No connecting line between two circles indicates that there was no direct comparison between the two treatments. IA = Intra-articular

44


Supplement Table 5: Standardized mean differences (adjusted for small samples) for function at 3 months

Oral Placebo IA Placebo

IA Placebo

Acetaminophen

IA CS

Celecoxib

Ibuprofen

Naproxen

Diclofenac

IA HA

0.15 (-0.22, 0..53)

0.15 (0.02, 0.29) 0.0 (-0.39, 0.40)

0.21 (-0.20, 0.63) 0.06 (-0.13, 0.26) 0.06 (-0.37, 0.50)

0.33 (0.27, 0.40) 0.18 (-0.20, 0.55) 0.18 (0.04, 0.32) 0.12 (-0.30, 0.53)

0.35 (0.20, 0.50) 0.20 (-0.21, 0.60) 0.20 (0.03, 0.37) 0.14 (-0.31, 0.57) 0.02 (-0.14, 0.18)

0.39 (0.29, 0.48) 0.24 (-0.15, 0.62) 0.24 (0.07, 0.40) 0.18 (-0.25, 0.60) 0.06 (-0.05, 0.16) 0.04 (-0.14, 0.21)

0.43 (0.26, 0.61) 0.28 (-0.06, 0.61) 0.28 (0.07, 0.49) 0.22 (-0.16, 0.59) 0.10 (-0.08, 0.28) 0.08 (-0.14, 0.31) 0.05 (-0.15, 0.24)

0.45 (0.08, 0.84) 0.30 (0.20, 0.40) 0.30 (-0.09, 0.70) 0.24 (0.06, 0.43) 0.12 (-0.25, 0.51) 0.10 (-0.29, 0.51) 0.06 (-0.32, 0.46) 0.02 (-0.31, 0.36)

Acetaminophen IA CS Celecoxib Ibuprofen Naproxen Diclofenac

Effect sizes favor the above (column-heading) intervention in each comparison. Statistically significant effect sizes are bolded. IA=intra-articular; CS=Corticosteroid; HA=Hyaluronic acid

45


Supplement Figure 6: Plot of inconsistency estimates for function Loop


ABC ODA

0.30 [ -1.01 , 1.62 ]

ABD OBA

0.20 [ -0.48 , 0.88 ]

ABF OCA

0.06 [ -0.51 , 0.63 ]

AEF OCN

0.06 [ -0.32 , 0.44 ]

ACF OCD

0.06 [ -0.78 , 0.89 ]

BCF ACD

0.18 [ -1.30 , 1.67 ]

GHI HIS

0.16 [ -0.68 , 0.99 ]

CGI DIH

0.06 [ -1.09 , 1.21 ]

-1.9

-0.86

0.19

1.23

2.27

Inconsistency for triangular loops

Supplement Figure 6: Plot of inconsistency estimates (difference between direct and indirect estimates) with their 95% confidence intervals for function. The overhead line denotes the comparison for which the inconsistency factor is estimated. O=Oral placebo; A=Acetaminophen; D=Diclofenac; B=Ibuprofen; N=Naproxen; C=Celecoxib; H=Intra-articular hyaluronic acid; S=Intra-articular Corticosteroids; I=Intra-articular placebo

Zero inconsistent loops out of 8.

46


Supplement Figure 7: Network of Treatment Comparisons for stiffness Oral Placebo

IA Placebo

Acetaminophen

IA Corticosteroids Diclofenac

IA Hyaluronic acid

Ibuprofen

Celecoxib

Naproxen

Circle size reflects n of participants and the line width reflects N of direct comparisons. No connecting line between two circles indicates that there was no direct comparison between the two treatments. IA = Intra-articular

47


Supplement Table 6: Standardized mean differences (adjusted for small samples) for stiffness at 3 months

Oral Placebo IA Placebo

IA Placebo

Acetaminophen

IA CS

Celecoxib

IA HA

Naproxen

Diclofenac

Ibuprofen

0.10 (-0.26, 0.46)

0.10 (-0.05, 0.26) 0.0 (-0.38, 0.40)

0.13 (-0.28, 0.55) 0.03 (-0.19, 0.25) 0.03 (-0.41, 0.46)

0.28 (0.21, 0.35) 0.18 (-0.19, 0.54) 0.17 (0.02, 0.33) 0.15 (-0.27, 0.56)

0.33 (-0.03, 0.69) 0.23 (0.13, 0.34) 0.22 (-0.17, 0.61) 0.20 (0.0, 0.41) 0.05 (-0.31, 0.42)

0.36 (0.25, 0.47) 0.26 (-0.12, 0.64) 0.26 (0.07, 0.44) 0.23 (-0.20, 0.65) 0.08 (-0.03, 0.20) 0.03 (-0.35, 0.41)

0.41 (0.25, 0.57) 0.31 (-0.02, 0.64) 0.30 (0.09, 0.52) 0.28 (-0.11, 0.66) 0.13 (-0.03, 0.30) 0.08 (-0.25, 0.41) 0.05 (-0.14, 0.24)

0.42 (0.28, 0.56) 0.32 (-0.07, 0.71) 0.31 (0.13, 0.50) 0.29 (-0.15, 0.72) 0.14 (-0.01, 0.30) 0.09 (-0.30, 0.48) 0.06 (-0.12, 0.24) 0.01 (-0.20, 0.22)

Acetaminophen IA CS Celecoxib IA HA Naproxen Diclofenac

Effect sizes favor the above (column-heading) intervention in each comparison. Statistically significant effect sizes are bolded. IA=intra-articular; CS=Corticosteroid; HA=Hyaluronic acid

48


Supplement Figure 8: Plot of inconsistency estimates for stiffness Loop


ABC ODA

0.37 [ -1.03 , 1.76 ]

ABD OBA

0.19 [ -0.70 , 1.09 ]

ABF OCA

0.05 [ -0.69 , 0.78 ]

AEF OCN

0.06 [ -0.42 , 0.54 ]

ACF OCD

0.05 [ -0.79 , 0.89 ]

BCF ACD

0.27 [ -1.22 , 1.76 ]

GHI HIS

0.24 [ -0.85 , 1.33 ]

CGI DIH

0.04 [ -1.07 , 1.16 ]

-1.81

-0.77

0.27

1.32

2.36

Inconsistency for triangular loops

Supplement Figure 8: Plot of inconsistency estimates (difference between direct and indirect estimates) with their 95% confidence intervals for stiffness. The overhead line denotes the comparison for which the inconsistency factor is estimated. O=Oral placebo; A=Acetaminophen; D=Diclofenac; B=Ibuprofen; N=Naproxen; C=Celecoxib; H=Intra-articular hyaluronic acid; S=Intra-articular Corticosteroids; I=Intra-articular placebo

Zero inconsistent loops out of 8.

49


Supplement Table 7: Sensitivity analyses on the primary outcome pain – Standardized mean differences (adjusted for small samples) with 95% credible intervals for each treatment versus oral placebo

Primary analysis (studies reporting pain on any scale)

Studies reporting pain on WOMAC scale

Studies reporting pain on VAS or other scale

Studies with >50 participants/ group

Studies with >100 participants/ group

Intra-articular hyaluronic acid

0.63 [0.39, 0.88]

0.80 [0.47, 1.14]

0.54 [-0.01, 1.09]

0.57 [0.33, 0.81]

0.43 [0.15, 0.70]

Intra-articular corticosteroids

0.61 [0.32, 0.89]

0.73 [0.34, 1.11]

0.53 [-0.06, 1.12]

0.47 [0.15, 0.80]

0.33 [0.02, 0.68]

Diclofenac

0.52 [0.34, 0.69]

0.62 [0.44, 0.80]

0.24 [-0.29, 0.76]

0.51 [0.36, 0.66]

0.60 [0.44, 0.77]

Ibuprofen

0.44 [0.25, 0.63]

0.42 [0.24, 0.61]

0.44 [-0.18, 1.07]

0.43 [0.27, 0.59]

0.34 [0.13, 0.54]

Naproxen

0.38 [0.27, 0.49]

0.38 [0.27, 0.49]

0.39 [0.05, 0.73]

0.39 [0.30, 0.48]

0.39 [0.29, 0.50]

Celecoxib

0.33 [0.25, 0.42]

0.33 [0.25, 0.41]

0.37 [0.07, 0.66]

0.34 [0.27, 0.40]

0.34 [0.27, 0.41]

Intra-articular placebo

0.29 [0.04, 0.54]

0.49 [0.17, 0.82]

0.16 [-0.39, 0.71]

0.36 [0.11, 0.60]

0.29 [0.01, 0.58]

Acetaminophen

0.18 [0.04, 0.33]

0.21 [0.02, 0.39]

0.14 [-0.15, 0.44]

0.18 [0.06, 0.30]

0.19 [0.06, 0.31]

Oral Placebo

Reference

Reference

Reference

Reference

Reference

Heterogeneity

0.22 [0.18, 0.27]

0.18 [0.13, 0.23]

0.33 [0.24, 0.43]

0.16 [0.12, 0.20]

0.15 [0.10, 0.20]

129

72

57

86

56

Treatment

Number of studies

50


Supplement Table 8: Sensitivity analyses exploring for reporting bias – Standardized mean differences (adjusted for small samples) with 95% credible intervals for pain for each treatment versus oral placebo

Primary analysis (all studies reporting pain)

Studies reporting pain only

Studies reporting pain and function

Studies reporting pain, function, and stiffness

Intra-articular hyaluronic acid

0.63 [0.39, 0.88]

0.63 [0.04, 1.22]

0.60 [0.22, 0.98]

0.59 [0.21, 0.97]

Intra-articular corticosteroids

0.61 [0.32, 0.89]

0.65 [0.02, 1.28]

0.47 [0.04, 0.89]

0.44 [0.00, 0.88]

Diclofenac

0.52 [0.34, 0.69]

0.76 [0.31, 1.21]

0.41 [0.23, 0.58]

0.41 [0.24, 0.58]

Ibuprofen

0.44 [0.25, 0.63]

0.47 [-0.47, 1.43]

0.42 [0.27, 0.57]

0.42 [0.27, 0.58]

Naproxen

0.38 [0.27, 0.49]

0.41 [0.05, 0.78]

0.37 [0.28, 0.47]

0.38 [0.27, 0.50]

Celecoxib

0.33 [0.25, 0.42]

0.41 [0.09, 0.73]

0.32 [0.25, 0.39]

0.32 [0.24, 0.39]

Intra-articular placebo

0.29 [0.04, 0.54]

0.28 [-0.31, 0.86]

0.28 [-0.10, 0.66]

0.31 [-0.08, 0.68]

Acetaminophen

0.18 [0.04, 0.33]

0.29 [-0.06, 0.63]

0.15 [0.01, 0.29]

0.20 [0.03, 0.37]

Oral Placebo

Reference

Reference

Reference

Reference

Heterogeneity

0.22 [0.18, 0.27]

0.35 [0.26, 0.46]

0.14 (0.09, 0.19)

0.13 [0.07, 0.20]

129

55

74

54

Treatment

Number of studies

51


Supplement Table 9: Occurrence of Adverse Events in RCTs of Treatments for Osteoarthritis Outcome Oral Placebo vs. Acetaminophen Any adverse events Serious adverse events Withdrawals due to adverse events Any gastrointestinal adverse events Any cardiovascular adverse events Oral Placebo vs. Non-selective NSAIDs Any adverse events Serious adverse events Withdrawals due to adverse events Any gastrointestinal adverse events Any cardiovascular adverse events Oral Placebo vs. Celecoxib Any adverse events Serious adverse events Withdrawals due to adverse events Any gastrointestinal adverse events Any cardiovascular adverse events Acetaminophen vs. Non-selective NSAIDs Any adverse events Serious adverse events Withdrawals due to adverse events Any gastrointestinal adverse events Any cardiovascular adverse events Acetaminophen vs. Celecoxib Any adverse events Serious adverse events Withdrawals due to adverse events Any gastrointestinal adverse events Any cardiovascular adverse events Intra-articular Corticosteroids vs. Intra-articular Hyaluronic Acid Any adverse events Serious adverse events Withdrawals due to adverse events Local Reactions Septic Joint Intra-articular Placebo vs. Intraarticular Hyaluronic Acid Any adverse events Serious adverse events Withdrawals due to adverse events

RCTs, n

Patients, n

Median Event Rates (Inter-Quartile Range), % Comparison Treatment

5 5 4 4 nd

2030 2030 1377 1705 nd

26.3 (16.9) 1.2 (0.4) 6.4 (4.5) 10.0 (3.7) nd

28.3 (18.1) 1.0 (0.9) 7.0 (5.8) 9.3 (0.6) nd

20 15 23 23 10

6710 5244 7318 7487 3817

50.5 (13.1) 0.9 (0.9) 5.6 (3.7) 12.6 (11.3) 2.0 (1.3)

58.2 (12.1) 1.2 (1.3) 8.4 (4.2) 21.6 (10.6) 3.0 (0.8)

26 25 23 25 14

9741 9512 9061 9196 5296

45.8 (19.3) 0.6 (1.2) 5.5 (3.4) 9.7 (7.7) 0.9 (1.7)

45.5 (11.3) 0.9 (1.1) 5.0 (3.7) 12.1 (7.9) 1.5 (2.6)

nd nd 5 3 3

nd nd 1035 754 754

nd nd 7.6 (12.8) 15.2 (5.4) 1.5 (1.5)

nd nd 12.0 (4.9) 19.2 (1.5) 1.1 (2.1)

4 3 2 4 2

1709 1518 983 1709 983

35.4 (17.6) 0.3 (0.5) 7.1 (0.7) 12.9 (8.1) 5.6 (0.8)

32.9 (12.4) 0.4 (0.1) 3.3 (0.8) 12.0 (3.1) 3.0 (0.9)

10 7 11 11 9

1480 1279 1514 1516 1089

5.5 (57.2) 0.0 (4.3) 2.7 (6.0) 3.0 (9.1) 0 (0)

0.0 (64.6) 0.0 (2.0) 1.9 (3.7) 2.2 (21.8) 0 (0)

35 36 36

5993 6278 6404

21.7 (56.0) 0 (0) 1.0 (2.6)

16 (54.6) 0 (0.9) 0.9 (3.9) 52


Local Reactions 39 Septic Joint 18 Intra-articular Placebo vs. Intraarticular Corticosteroids Any adverse events nd Serious adverse events nd Withdrawals due to adverse events 3 Local Reactions 5 Septic Joint 2 RCTs = Randomized Controlled Trials; nd = no data

6193 1875

4.7 (16.1) 0 (0)

8.4 (14.4) 0 (0)

nd nd 232 334 188

nd nd 0.0 (1.7) 3.3 (17.9) 0 (0)

nd nd 0.0 (3.5) 6.9 (8.0) 0 (0)

53


Supplement Table 10: Study and participant characteristics of the subsets of studies exploring for reporting bias

Treatment

All studies reporting pain

Studies reporting pain only

Studies reporting pain and function

Studies reporting pain, function, and stiffness

Number of studies

129

55

74

54

Mean age (Range)

55 - 76

55 - 76

55 - 72

55 - 72

Percent Female (Range)

3 - 100

3 - 100

39 - 100

37 - 100

Similarity of groups at baseline, n (%)

111 (86)

42 (76)

69 (93)

52 (96)

Adequate randomization, n (%)

71 (55)

24 (44)

47 (63)

34 (62)

Adequate allocation concealment, n (%)

62 (48)

19 (35)

43 (58)

30 (55)

Adequate patient blinding, n (%)

106 (82)

39 (71)

67 (91)

50 (93)

Adequate outcome assessor blinding, n (%)

106 (82)

38 (69)

68 (92)

51 (95)

ITT analysis, n (%)

67 (52)

17 (31)

50 (67)

39 (73)

54


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Effectiveness of Nonpharmacologic Interventions in Systemic Sclerosis: A Systematic Review.

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