Table 3.
Predictors of placebo response: participant and disease characteristics at short‐, mid‐, and long‐term*
| Short‐term | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Potential predictors | Placebo‐only population, n = 621 in ten studies | Placebo only (glucocorticoid trials group), n = 181 in six studies | Placebo only (hyaluronic acid trials group), n = 458 in five studies | |||||||||||||||
| n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | |
| Age | 609 | 0.991 (0.97–1.01) | 0.346 | 6.19 (0.721) | 0.0 | 0.000 | 174 | 0.992 (0.95–1.03) | 0.694 | 5.62 (0.345) | 11.0 | 0.000 | 453 | 0.989 (0.97–1.01) | 0.280 | 1.96 (0.743) | 0.0 | 0.000 |
| Sex | 609 | 1.075 (0.61–1.91) | 0.806 | 15.46 (0.051) | 48.2 | 0.316 | 174 | 0.855 (0.25–2.91) | 0.801 | 8.98 (0.062) | 55.5 | 1.060 | 453 | 1.024 (0.53–1.98) | 0.945 | 8.72 (0.068) | 54.2 | 0.274 |
| BMI | 554 | 1.004 (0.96–1.05) | 0.884 | 8.49 (0.291) | 17.6 | 0.001 | 120 | 1.056 (0.96–1.56) | 0.257 | 3.32 (0.345) | 9.6 | 0.001 | 452 | 0.992 (0.95–1.04) | 0.747 | 4.28 (0.369) | 6.6 | 0.000 |
| Disease duration | 427 | 0.999 (0.99–1.00) | 0.721 | 4.97 (0.548) | 0.0 | 0.000 | 98 | 1.000 (0.99–1.01) | 0.912 | 3.47 (0.325) | 13.5 | 0.000 | 347 | 1.001 (1.00–1.01) | 0.825 | 5.32 (0.150) | 43.6 | 0.000 |
| OA other joints | 439 | 0.824 (0.41–1.64) | 0.582 | 7.47 (0.058) | 59.8 | 0.280 | – | N/A | – | – | – | – | 411 | 0.752 (0.35–1.62) | 0.466 | 6.68 (0.035) | 70.1 | 0.323 |
| Pain at baseline | 609 | 1.007 (0.99–1.02) | 0.329 | 11.44 (0.247) | 21.3 | 0.000 | 174 | 1.010 (0.99–1.03) | 0.299 | 3.49 (0.625) | 0.0 | 0.000 | 453 | 1.006 (0.98–1.03) | 0.618 | 7.72 (0.103) | 48.2 | 0.000 |
| Severe pain (≥70) | 609 | 0.987 (0.66–1.47) | 0.947 | 6.37 (0.606) | 0.0 | 0.000 | 168 | 1.072 (0.40–2.87) | 0.891 | 4.93 (0.295) | 18.9 | 0.241 | 453 | 0.913 (0.59–1.41) | 0.685 | 2.15 (0.707) | 0.0 | 0.000 |
| KL grade | 551 | 1.054 (0.79–1.40) | 0.718 | 6.24 (0.512) | 0.0 | 0.000 | 140 | 1.117 (0.64–1.94) | 0.693 | 4.55 (0.337) | 12.0 | 0.049 | 428 | 0.954 (0.66–1.38) | 0.804 | 3.46 (0.326) | 13.4 | 0.020 |
| Patient global | 437 | 1.003 (0.99–1.01) | 0.549 | 2.89 (0.409) | 0.0 | 0.000 | – | – | – | – | – | – | 409 | 1.002 (0.99–1.02) | 0.740 | 2.84 (0.242) | 29.6 | 0.000 |
| Effusion | 511 | 0.712 (0.45–1.13) | 0.151 | 3.86 (0.696) | 0.0 | 0.000 | 133 | 0.512 (0.19–1.36) | 0.178 | 1.58 (0.664) | 0.0 | 0.000 | 411 | 0.785 (0.46–1.33) | 0.367 | 1.71 (0.425) | 0.0 | 0.000 |
| Inflammation | 530 | 0.893 (0.60–1.33) | 0.575 | 5.59 (0.470) | 0.0 | 0.000 | 153 | 0.420 (0.16–1.14) | 0.088 | 2.24 (0.524) | 0.0 | 0.000 | 429 | 1.160 (0.75–1.79) | 0.502 | 1.83 (0.401) | 0.0 | 0.000 |
| Inflammation detected by imaging | 153 | 0.388 (0.10–1.53) | 0.177 | 2.22 (0.329) | 10.0 | 0.150 | 153 | 0.388 (0.10–1.53) | 0.177 | 2.22 (0.329) | 10.0 | 0.150 | – | – | – | – | – | – |
| Stiffness | 476 | 0.992 (0.98–1.00) | 0.186 | 4.37 (0.498) | 0.0 | 0.000 | 65 | 0.985 (0.96–1.01) | 0.287 | 0.65 (0.723) | 0.0 | 0.000 | 429 | 0.993 (0.98–1.01) | 0.331 | 4.07 (0.254) | 26.2 | 0.000 |
| Function | 476 | 0.990 (0.98–1.00) | 0.150 | 3.65 (0.601) | 0.0 | 0.000 | 65 | 1.008 (0.97–1.04) | 0.660 | 2.07 (0.355) | 3.4 | 0.000 | 429 | 0.987 (0.97–1.00) | 0.087 | 0.47 (0.925) | 0.0 | 0.000 |
| Midterm | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Placebo‐only population, n = 545 | Placebo only (Glucocorticoid trials group), n = 129 | Placebo only (Hyaluronic acid trials group), n = 434 | ||||||||||||||||
| n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | |
| Age | 545 | 0.997 (0.98–1.02) | 0.773 | 7.63 (0.470) | 0.0 | 0.000 | 129 | 1.013 (0.96–1.07) | 0.625 | 5.99 (0.200) | 33.2 | 0.001 | 434 | 0.994 (0.97–1.02) | 0.582 | 1.22 (0.747) | 0.0 | 0.000 |
| Sex | 545 | 1.163 (0.70–1.93) | 0.558 | 10.14 (0.181) | 31.0 | 0.149 | 129 | 2.446 (0.98–6.08) | 0.054 | 1.97 (0.579) | 0.0 | 0.000 | 434 | 0.903 (0.54–1.51) | 0.697 | 4.25 (0.236) | 29.3 | 0.080 |
| BMI | 498 | 0.997 (0.95–1.04) | 0.882 | 2.53 (0.865) | 0.0 | 0.000 | 83 | 0.992 (0.95–1.03) | 0.694 | 5.62 (0.345) | 11.0 | 0.000 | 433 | 0.997 (0.95–1.04) | 0.906 | 1.96 (0.744) | 0.0 | 0.000 |
| Disease duration | 394 | 1.001 (1.00–1.01) | 0.762 | 6.37 (0.383) | 5.8 | 0.000 | 82 | 0.998 (0.99–1.01) | 0.570 | 3.09 (0.379) | 2.8 | 0.000 | 330 | 1.001 (1.00–1.01) | 0.564 | 2.70 (0.440) | 0.0 | 0.000 |
| OA other joints | 412 | 0.809 (0.46–1.42) | 0.461 | 4.74 (0.192) | 36.7 | 0.118 | – | – | – | – | – | – | 393 | 0.848 (0.46–1.58) | 0.603 | 4.21 (0.122) | 52.5 | 0.159 |
| Pain at baseline | 545 | 1.006 (0.98–1.03) | 0.595 | 16.35 (0.038) | 51.1 | 0.001 | 129 | 1.019 (0.98–1.06) | 0.382 | 7.86 (0.097) | 49.1 | 0.001 | 434 | 0.998 (0.97–1.03) | 0.895 | 7.17 (0.067) | 58.2 | 0.000 |
| Severe pain (>70) | 545 | 0.987 (0.61–1.60) | 0.957 | 8.15 (0.320) | 14.1 | 0.069 | 129 | 2.980 (1.01–8.82) | 0.049 | 0.12 (0.989) | 0.0 | 0.000 | 434 | 0.752 (0.48–1.18) | 0.214 | 2.74 (0.433) | 0.0 | 0.000 |
| KL grade | 492 | 0.863 (0.63–1.18) | 0.357 | 2.76 (0.737) | 0.0 | 0.000 | 99 | 0.709 (0.34–1.46) | 0.352 | 2.25 (0.325) | 11.1 | 0.046 | 410 | 0.911 (0.64–1.30) | 0.606 | 0.08 (0.962) | 0.0 | 0.000 |
| Patient global | 411 | 0.998 (0.98–1.02) | 0.855 | 7.06 (0.070) | 57.5 | 0.000 | – | – | – | – | – | – | 392 | 0.993 (0.98–1.01) | 0.234 | 2.24 (0.326) | 10.7 | 0.000 |
| Effusion | 486 | 0.904 (0.55–1.49) | 0.693 | 2.06 (0.841) | 0.0 | 0.000 | 93 | 0.573 (0.16–2.00) | 0.383 | 0.83 (0.661) | 0.0 | 0.000 | 393 | 1.010 (0.99–1.03) | 0.420 | 0.37 (0.830) | 0.0 | 0.000 |
| Inflammation | 505 | 0.930 (0.52–1.66) | 0.804 | 7.57 (0.181) | 34.0 | 0.163 | 112 | 0.573 (0.16–2.00) | 0.383 | 0.83 (0.661) | 0.0 | 0.000 | 411 | 1.033 (0.48–2.24) | 0.934 | 5.92 (0.052) | 66.2 | 0.309 |
| Inflammation detected by imaging | 112 | 0.462 (0.09–2.48) | 0.367 | 0.68 (0.408) | 0.0 | 0.000 | 112 | 0.462 (0.09–2.48) | 0.367 | 0.68 (0.408) | 0.0 | 0.000 | – | – | – | – | – | – |
| Stiffness | 429 | 0.991 (0.98–1.00) | 0.161 | 4.18 (0.382) | 4.4 | 0.000 | 36 | 0.967 (0.92–1.02) | 0.210 | 0.12 (0.726) | 0.0 | 0.000 | 411 | 0.992 (0.98–1.01) | 0.320 | 3.94 (0.268) | 23.9 | 0.000 |
| Function | 429 | 0.979 (0.96–1.00) | 0.010 | 3.86 (0.425) | 0.0 | 0.000 | 36 | 0.974 (0.85–1.12) | 0.706 | 1.98 (0.159) | 49.5 | 0.006 | 411 | 0.978 (0.96–0.99) | 0.006 | 1.15 (0.564) | 0.0 | 0.000 |
| Long‐term | ||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Placebo‐only population, n = 349 | Placebo only (glucocorticoid trials group), n = 72 | Placebo only (hyaluronic acid trials group), n = 277 | ||||||||||||||||
| n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | n | OR (95% CI) | P‐value | Cochran's Q (P‐value) | I 2, % | τ2 | |
| Age | 349 | 1.021 (0.98–1.06) | 0.271 | 8.32 (0.140) | 39.9 | 0.001 | 72 | 1.037 (0.95–1.13) | 0.408 | 3.91 (0.141) | 48.9 | 0.003 | 277 | 0.997 (0.97–1.02) | 0.807 | 1.54 (0.462) | 0.0 | 0.000 |
| Sex | 349 | 1.408 (0.82–2.42) | 0.214 | 0.42 (0.981) | 0.0 | 0.000 | 72 | 1.484 (0.54–4.09) | 0.446 | 0.19 (0.908) | 0.0 | 0.000 | 277 | 1.140 (0.70–1.87) | 0.604 | 1.09 (0.581) | 0.0 | 0.000 |
| BMI | 337 | 0.980 (0.93–1.03) | 0.429 | 2.16 (0.706) | 0.0 | 0.000 | 60 | 0.996 (0.82–1.21) | 0.969 | 1.53 (0.217) | 34.5 | 0.007 | 277 | 0.977 (0.93–1.03) | 0.395 | 0.54 (0.764) | 0.0 | 0.000 |
| Disease duration | 283 | 0.999 (1.00–1.01) | 0.672 | 0.12 (0.989) | 0.0 | 0.000 | 29 | 1.001 (0.99–1.02) | 0.866 | 0.05 (0.828) | 0.0 | 0.000 | 254 | 0.999 (0.99–1.00) | 0.636 | 0.00 (0.997) | 0.0 | 0.000 |
| OA other joints | 272 | 0.896 (0.54–1.50) | 0.678 | 1.12 (0.570) | 0.0 | 0.000 | – | – | – | – | – | – | 255 | 0.896 (0.54–1.50) | 0.678 | 1.12 (0.570) | 0.0 | 0.000 |
| Pain at baseline | 349 | 1.007 (0.99–1.03) | 0.441 | 5.19 (0.393) | 3.6 | 0.000 | 72 | 1.018 (0.98–1.06) | 0.375 | 2.56 (0.277) | 22.0 | 0.000 | 277 | 1.004 (0.98–1.03) | 0.759 | 2.29 (0.318) | 12.6 | 0.000 |
| Severe pain (>70) | 349 | 0.889 (0.44–1.79) | 0.741 | 6.55 (0.257) | 23.6 | 0.179 | 72 | 1.275 (0.24–6.69) | 0.774 | 3.51 (0.173) | 43.0 | 0.926 | 277 | 0.755 (0.36–1.58) | 0.456 | 2.50 (0.287) | 19.9 | 0.095 |
| KL grade | 327 | 0.873 (0.52–1.46) | 0.603 | 5.20 (0.268) | 23.0 | 0.079 | 72 | 0.793 (0.24–2.61) | 0.702 | 4.08 (0.130) | 50.9 | 0.567 | 255 | 0.947 (0.58–1.56) | 0.830 | 0.79 (0.373) | 0.0 | 0.000 |
| Patient global | 272 | 1.00 (0.98–1.02) | 0.879 | 3.76 (0.153) | 46.8 | 0.000 | – | – | – | – | – | – | 255 | 0.992 (0.98–1.01) | 0.331 | 0.91 (0.340) | 0.0 | 0.000 |
| Effusion | 315 | 0.593 (0.21–1.66) | 0.321 | 3.81 (0.149) | 47.5 | 0.390 | – | – | – | – | – | – | 255 | 0.881 (0.44–1.76) | 0.720 | 0.54 (0.461) | 0.0 | 0.000 |
| Inflammation | 315 | 0.854 (0.30–2.42) | 0.766 | 5.60 (0.061) | 64.3 | 0.504 | – | – | – | – | – | – | 255 | 1.295 (0.74–2.26) | 0.364 | 0.94 (0.333) | 0.0 | 0.000 |
| Inflammation detected by imaging | – | N/A | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – | – |
| Stiffness | 267 | 0.990 (0.97–1.01) | 0.310 | 2.51 (0.286) | 20.2 | 0.000 | – | – | – | – | – | – | 255 | 0.993 (0.98–1.01) | 0.380 | 0.58 (0.447) | 0.0 | 0.000 |
| Function | 267 | 0.978 (0.95–1.01) | 0.194 | 3.59 (0.166) | 44.2 | 0.000 | – | – | – | – | – | – | 255 | 0.981 (0.94–1.03) | 0.402 | 3.44 (0.064) | 70.9 | 0.001 |
*
Participant and disease characteristics were adjusted for age, sex, and BMI. BMI, body mass index; CI, confidence interval; KL, Kellgren‐Lawrence; N/A, not available; OA, osteoarthritis; OR, odds ratio.