Introduction
Main text
Materials and methods
Literature search
Eligibility criteria
Risk of bias in individual studies (internal validity)
Data extraction strategy
Statistical analysis
Patient perspective
Results
Study selection
Study characteristics
Author | Year | No. of patients randomized | No. of patients receiving intervention | No. of patients receiving comparison | Trial duration (weeks) | Intervention | Comparator | Risk of bias* selection/performance/attrition/reporting |
---|---|---|---|---|---|---|---|---|
Dougados | 1986 | 30 | 15 | 15 | 26 | SSZ (P) | PL | A/A/A/A |
Feltelius | 1986 | 37 | 18 | 19 | 12 | SSZ (P) | PL | U/U/A/A |
Nissila | 1988 | 85 | 43 | 42 | 26 | SSZ (P) | PL | U/U/A/A |
Davis | 1989 | 30 | 15 | 15 | 12 | SSZ (P) | PL | U/U/A/A |
Kraag | 1989 | 53 | 26 | 27 | 16 | Supervised training (NP) | SC | U/U/I/A |
Winkler | 1989 | 63 | 31 | 32 | 24 | SSZ (P) | PL | U/U/U/A |
Corkill | 1990 | 62 | 32 | 30 | 48 | SSZ (P) | PL | A/A/I/A |
Krajnc | 1990 | 95 | 71 | 24 | 24 | SSZ (P) | PL | U/U/A/A |
Taylor | 1991 | 40 | 20 | 20 | 52 | SSZ (P) | PL | A/A/A/I |
Hidding | 1993 | 144 | 68 | 76 | 36 | Group physiotherapy (NP) | AC | A/A/I/A |
Kirwan | 1993 | 89 | 44 | 45 | 156 | SSZ (P) | PL | A/A/A/I |
Dougados | 1994 | 70 | 46 | 24 | 12 | Ximoprofen 5 mg (P) | PL | A/A/U/A |
1994 | 73 | 49 | 24 | 34 | Ximoprofen 10 mg (P) | PL | A/A/U/A | |
1994 | 69 | 45 | 24 | 8 | Ximoprofen 20 mg (P) | PL | A/A/U/A | |
1994 | 74 | 50 | 24 | 6 | Ximoprofen 30 mg (P) | PL | A/A/U/A | |
Clegg | 1996 | 264 | 131 | 133 | 36 | SSZ (P) | PL | U/U/A/A |
Helliwell | 1996 | 22 | 15 | 7 | 44 | In-patient physiotherapy (NP) | SC | I/I/I/A |
1996 | 22 | 15 | 7 | 44 | Out-patient hydrotherapy (NP) | SC | I/I/I/A | |
Dougados | 1999 | 148 | 108 | 40 | 6 | Piroxicam (P) | PL | U/U/A/A |
1999 | 160 | 120 | 40 | 6 | Meloxicam 15 mg (P) | PL | U/U/A/A | |
1999 | 164 | 124 | 40 | 6 | Meloxicam 22.5 mg (P) | PL | U/U/A/A | |
Altan | 2001 | 51 | 26 | 25 | 52 | MTX (P) | AC | U/U/I/I |
Dougados | 2001 | 118 | 80 | 38 | 6 | Celecoxib (P) | PL | U/U/U/A |
2001 | 128 | 90 | 38 | 6 | Ketoprofen (P) | PL | U/U/U/A | |
Van Tubergen | 2001 | 120 | 80 | 40 | 3 | Spa-exercise therapy (NP) | AC | A/A/I/A |
Braun | 2002 | 70 | 35 | 35 | 12 | Infliximab (B) | PL | A/A/A/I |
Gorman | 2002 | 40 | 20 | 20 | 16 | Etanercept (B) | PL | A/A/A/A |
Roychowdhury | 2002 | 30 | 14 | 16 | 24 | MTX (P) | PL | U/U/A/A |
Schmidt | 2002 | 70 | 34 | 36 | 26 | SSZ (P) | PL | U/U/U/A |
Sweeney | 2002 | 200 | 100 | 100 | 26 | Supervised training (NP) | SC | U/U/I/A |
Analay | 2003 | 51 | 27 | 24 | 12 | Supervised training (NP) | SC | A/A/I/A |
Brandt | 2003 | 33 | 16 | 17 | 6 | Etanercept (B) | PL | A/A/A/I |
Davis | 2003 | 277 | 138 | 139 | 24 | Etanercept (B) | PL | A/A/A/A |
Calin | 2004 | 84 | 45 | 39 | 12 | Etanercept (B) | PL | U/U/A/A |
Gonzalez-Lopez | 2004 | 35 | 17 | 18 | 24 | MTX (P) | PL | A/A/A/I |
Codish | 2005 | 28 | 14 | 14 | 12 | Balneo therapy (NP) | AC | U/U/I/A |
D’Las Penas | 2005 | 40 | 20 | 20 | 16 | Supervised training (NP) | SC | A/A/I/A |
Lim | 2005 | 50 | 25 | 25 | 8 | Supervised training (NP) | SC | U/U/I/A |
Marzo-Ortega | 2005 | 42 | 28 | 14 | 30 | Infliximab (B) | PL | A/A/U/A |
Van der Heijde | 2005 | 279 | 201 | 78 | 24 | Infliximab (B) | PL | U/U/A/A |
Van der Heijde | 2005 | 134 | 103 | 31 | 6 | Etoricoxib (P) | PL | A/A/A/A |
2005 | 123 | 92 | 31 | 6 | Etoricoxib (P) | PL | A/A/A/A | |
2005 | 130 | 99 | 31 | 6 | Naproxen (P) | PL | A/A/A/A | |
Altan | 2006 | 60 | 30 | 30 | 24 | Balneo therapy (NP) | AC | U/U/I/A |
Barkhuizen | 2006 | 189 | 137 | 52 | 12 | Celecoxib 200 mg (P) | PL | U/U/U/A |
2006 | 213 | 161 | 52 | 12 | Celecoxib 400 mg (P) | PL | U/U/U/A | |
2006 | 209 | 157 | 52 | 12 | Naproxen (P) | PL | U/U/U/A | |
Ince | 2006 | 30 | 15 | 15 | 12 | Supervised training (NP) | SC | U/U/I/A |
Van der Heijde | 2006 | 315 | 208 | 107 | 24 | Adalimumab (B) | PL | A/A/A/A |
Van der Heijde | 2006 | 180 | 155 | 25 | 24 | Etanercept (B) | PL | U/U/U/A |
2006 | 175 | 150 | 25 | 24 | Etanercept (B) | PL | U/U/U/A | |
Lambert | 2007 | 82 | 38 | 44 | 24 | Adalimumab (B) | PL | U/U/A/A |
Huang | 2008 | 126 | 83 | 43 | 8 | Etanercept (B) | PL | U/U/U/U |
Inman | 2008 | 177 | 138 | 39 | 14 | Golimumab (B) | PL | A/A/A/A |
2008 | 179 | 149 | 39 | 14 | Golimumab (B) | PL | A/A/A/A | |
Barkham | 2010 | 40 | 20 | 20 | 12 | Etanercept (B) | PL | U/U/A/A |
Inman | 2010 | 76 | 39 | 37 | 12 | Infliximab (B) | PL | U/U/U/A |
Braun | 2011 | 566 | 379 | 187 | 16 | Etanercept (B) | AC | A/A/A/A |
Dougados | 2011 | 82 | 39 | 43 | 12 | Etanercept (B) | PL | U/U/A/I |
Navarro-Sarabia | 2011 | 108 | 54 | 54 | 12 | Etanercept (B) | AC | A/A/A/A |
Hu | 2012 | 46 | 26 | 20 | 12 | Adalimumab (B) | PL | U/U/U/I |
Bao | 2014 | 213 | 108 | 105 | 24 | Golimumab (B) | PL | U/U/U/A |
Huang | 2014 | 344 | 229 | 114 | 12 | Adalimumab (B) | PL | A/A/A/A |
Characteristics of the core outcome measurement set
Author | Physical function | Pain | Spinal mobility | Spinal stiffness | Patient’s global assessment | Peripheral joints/entheses | Acute phase reactants | Spine/hip radiograph | Fatigue |
---|---|---|---|---|---|---|---|---|---|
SM-ARD trials | |||||||||
Dougados (1994) [41] | +,+ (DFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | − | − | − | −/− | − |
Dougados (1999) [42] | +,+ (DFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | +,+ (VAS) | − | +,+ (CRP) | −/− | − |
Dougados (2001) [43] | +,+ (BASFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | +,+ (VAS) | − | +,+ (CRP) | −/− | − |
Van der Heijde (2005_2) [44] | +,+ (BASFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | +,+ (VAS) | +,+ (BASDAI question 4) | +,+ (CRP) | −/− | − |
Barkhuizen (2006) [27] | +,+ (BASFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | +,+ (VAS) | − | +,+ (CRP) | −/− | − |
Physical therapy trials | |||||||||
Kraag (1990) [45] | +,+ (TADLQ) | +,+ (VAS) | +,+ (Schober) | +,+ (TADLQ) | − | − | − | −/− | − |
Hidding (1993) [46] | +,+ (DFI 0) | +,+ (VAS) | +,+ (Schober) | +,+ (VAS) | +,+ (VAS) | +,+ (enthesitis index) | − | −/− | − |
Helliwell [31] | − | +,+/− (VAS) | +,+ (Schober) | +,+/− (VAS) | − | − | − | −/− | − |
Van Tubergen (2001) [47] | +,+ (BASFI) | +,+ (VAS) | − | +,+ (minutes) | +,+ (VAS) | − | − | −/− | − |
Sweeney (2002) [48] | +,+ (BASFI) | +,+ (SES) | − | − | +,+ (BAS-G) | − | − | −/− | − |
Analay (2003) [49] | +,+ (BASFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | − | − | − | −/− | − |
Codish (2005) [50] | +,+ (BASFI) | +,+ (VAS) | +,+/− (Schober) | − | − | − | − | −/− | − |
Fernandez-de-Las-Penas (2005) [51] | +,+ (BASFI) | − | +,+ (Schober) | − | − | − | − | −/− | − |
Lim [30] | +,+ (BASFI) | +,+/− (VAS) | +,+ (FFD) | − | − | − | − | −/− | − |
Ince (2006) [52] | − | − | +,+ (Schober) | − | − | − | − | −/− | − |
Altan (2006) [53] | +,+ (BASFI) | +,+ (VAS) | +,+ (Schober) | +,+ (NRS) | +,+ (NRS) | − | − | −/− | − |
DC-ART trials | |||||||||
Dougados (1986) [54] | +,+ (DFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | − | +,+ (enthesitis index) | +,+ (ESR) | −/− | − |
Feltelius [28] | − | +,+/− (VAS) | +,+/− (Schober) | +,+ (VAS) | +,+ (VAS) | +,+ (enthesitis index) | +,+ (ESR) | −/− | − |
Nissila (1988) [55] | − | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | +,+ (VAS) | +,+ (22-joint count) | +,+ (CRP) | −/− | − |
Davis (1989) [56] | − | +,+ (VAS) | +,+ (occiput-to-wall distance) | +,+ (VAS) | − | − | +,+ (CRP) | −/− | − |
Winkler (1989) [57] | − | +,+ (VAS) | +,+ (Schober) | +,+ (hours) | +,+ (VAS) | +,+ (66-joint count) | +,+ (ESR) | −/− | − |
Corkill [58] | − | +,+ (VAS) | +,+ (occiput-to-wall distance) | +,+ (VAS) | − | − | +,+ (CRP) | −/− | − |
Krajnc (1990) [59] | − | − | +,+ (Schober) | − | − | − | −/− | − | |
Taylor [34] | − | +,+ (VAS) | +,+ (Schober) | +,+ (VAS) | +,+/− (NRS) | +,+/− (joint count) | +,+ (CRP) | +,+/− SIJ score | − |
Kirwan [29] | +,− (HAQ) | +,− (VAS) | +,+ (Schober) | +,+/− (VAS) | +,– (VAS) | +,+/− (44-joint count) | − | −/− | − |
Clegg (1996) [60] | +,+ (DFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | +,+/− (NRS) | +,+ (44-joint count) | +,+ (CRP) | −/− | − |
Altan [35] | +,+ (DFI) | +,+ (VAS) | +,− (Schober) | +,+ (minutes) | +,+ (NRS) | +,+ (enthesitis index) | +,+ (CRP) | −/− | − |
Braun [36] | +,+ (BASFI) | +,+/− (NRS) | +,+ (BASMI) | +,+/− (minutes) | +,+ (NRS) | +,+ (44-joint count) | +,+ (CRP) | −/− | +,+/− (NRS) |
Gorman (2002) [61] | +,+ (BASFI) | +,+/− (VAS) | +,+ (Schober) | +,+ (minutes) | +,+ (VAS) | +,+ (66-joint count) | +,+ (CRP) | −/− | − |
Roychowdhury (2002) [62] | − | − | +,+ (BASMI) | +,+ (minutes) | − | − | +,+ (CRP) | −/− | − |
Schmidt (2002) [63] | +,+ (DFI) | +,+ (VAS) | +,+ (Schober) | +,+ (minutes) | − | +,+ (enthesitis index) | +,+ (CRP) | −/− | − |
Brandt [37] | +,+ (BASFI) | +,+/− (NRS) | +,+ (BASMI) | +,+/− (NRS) | − | +,+/− (66-joint count) | +,+/− (CRP) | −/− | +,+/− (NRS) |
Davis (2003) [64] | +,+ (BASFI) | +,+/− (VAS) | +,+ (Schober) | +,+ (minutes) | +,+ (VAS) | +,– (68-joint count) | +,+ (CRP) | −/− | − |
Calin (2004) [65] | +,+ (BASFI 0) | +,+ (VAS) | +,+ (BASMI) | +,+ (minutes) | +,+ (VAS) | +,– (68-joint count) | +,+ (CRP) | −/− | +,+ (VAS) |
Gonzalez-Lopez [38] | +,+ (BASFI) | +,+ (VAS) | − | +,+ (VAS) | +,+ (VAS) | +,+ (44-joint count) | +,− (ESR) | −/− | − |
Marzo-Ortega (2005) [66] | +,+ (BASFI) | +,+ (VAS) | − | +,+ (minutes) | − | +,+ (enthesitis index) | +,− (ESR) | −/− | − |
Van der Heijde (2005_1) [44] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | − | +,+ (VAS) | +,+ (enthesitis Index) | +,+ (CRP) | −/− | − |
Van der Heijde [32] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | +,+ (VAS) | +,+ (VAS) | +,+ (44-joint count) | +,+ (CRP) | −/− | − |
Van der Heijde (2006_2) [67] | +,+ (BASFI) | +,+ (VAS) | +,+ (Schober) | +,+ (VAS) | +,+ (VAS) | +,+ (70-joint count) | +,+ (CRP) | −/− | − |
Lambert (2007) [68] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | +,+ (VAS) | +,+ (VAS) | +,+ (44-joint count) | +,+ (CRP) | −/− | − |
Inman (2008) [69] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | +,+ (VAS) | +,+ (VAS) | − | +,+ (CRP) | −/− | +,+ (JESQ) |
Barkham (2010) [70] | +,+ (BASFI) | − | − | +,+ (VAS) | − | − | – | −/− | − |
Inman (2010) [71] | +,+ (BASFI) | − | +,+ (BASMI) | − | +,+ (BAS-G) | − | +,+ (CRP) | −/− | − |
Braun (2011) [72] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | +,+/− (VAS) | +,+ (VAS) | +,+ (66-joint count) | +,+ (CRP) | −/− | − |
Dougados [39] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | − | +,− (VAS) | − | +,+ (CRP) | −/− | − |
Navarro-Sarabia (2011) [73] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | − | +,+ (VAS) | +,+ (66-joint count) | +,+ (CRP) | −/− | +,+/− (VAS) |
Hu [40] | +,+ (BASFI) | +,+ (VAS) | − | − | − | − | +,+ (CRP) | −/− | +,+/− (VAS 0–10) |
Bao (2014) [74] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | − | − | − | +,+ (CRP) | −/− | +,+ (JESQ) |
Huang (2014) [75] | +,+ (BASFI) | +,+ (VAS) | +,+ (BASMI) | +,+ (VAS) | +,+ (VAS) | +,+ (44-joint count) | +,+ (CRP) | −/− | – |
Physical function
Variable | No. of trials/comparisons | SMD | 95% CI | I2 | Tau2 | P for interaction |
---|---|---|---|---|---|---|
All trials, physical function | 33/43 | − 0.50 | − 0.61, − 0.40 | 64% | 0.07 | – |
Fixed-effect model | − 0.53 | − 0.57, − 0.45 | ||||
Intervention | 0.08 | 0.42 | ||||
Pharmacological | − 0.53 | − 0.64, − 0.42 | ||||
Non-pharmacological | − 0.40 | − 0.74, − 0.05 | ||||
Intervention | 0.08 | 0.44 | ||||
Biological treatment | − 0.57 | − 0.68, − 0.46 | ||||
Other treatment | − 0.46 | − 0.63, − 0.28 | ||||
All trials, pain | 30/41 | − 0.48 | − 0.66, − 0.30 | 87% | 0.28 | – |
Fixed-effect model | − 0.50 | − 0.56, − 0.44 | ||||
Intervention | 0.19 | < 0.001 | ||||
Pharmacological | − 0.64 | − 0.78, − 0.49 | ||||
Non-pharmacological | 0.26 | − 0.20, 0.72 | ||||
Intervention | 0.29 | 0.28 | ||||
Biological treatment | − 0.64 | − 0.80, − 0-49 | ||||
Other treatment | − 0.41 | − 0.68, − 0.14 | ||||
All trials, spinal mobility | 30/45 | − 0.32 | − 0.48, − 0.17 | 83% | 0.21 | – |
Fixed-effect model | − 0.32 | − 0.38, − 0.26 | ||||
Intervention | 0.19 | 0.28 | ||||
Pharmacological | − 0.35 | − 0.51, − 0.19 | ||||
Non-pharmacological | − 0.02 | − 0.61, 0.56 | ||||
Intervention | 0.33 | 0.65 | ||||
Biological treatment | − 0.31 | − 0.47, − 0.15 | ||||
Other treatment | − 0.28 | − 0.52, − 0.03 | ||||
All trials, spinal stiffness | 25/34 | − 0.59 | − 0.74, − 0.44 | 75% | 0.14 | – |
Fixed-effect model | − 0.61 | − 0.68, − 0.54 | ||||
Intervention | 0.18 | 0.95 | ||||
Pharmacological | − 0.60 | − 0.76, − 0.44 | ||||
Non-pharmacological | − 0.61 | − 0.93, − 0.29 | ||||
Intervention | 0.16 | 0.34 | ||||
Biological treatment | − 0.77 | − 0.88, − 0.65 | ||||
Other treatment | − 0.55 | − 0.75, − 0.35 | ||||
All trials, PGA | 21/28 | − 0.71 | − 0.89, − 0.54 | 83% | 0.18 | – |
Fixed-effect model | − 0.74 | − 0.81, − 0.67 | ||||
Intervention | 0.19 | 0.15 | ||||
Pharmacological | − 0.77 | − 0.96, − 0.59 | ||||
Non-pharmacological | − 0.37 | − 0.81, 0.07 | ||||
Intervention | ||||||
Biological treatment | − 0.84 | − 1.09, − 0.60 | 0.20 | 0.23 | ||
Other treatment | − 0.60 | − 0.87, − 0.34 | ||||
All trials, PJ/E | 15/15 | 0.05 | − 0.11, 0.22 | 68% | 0.06 | – |
Fixed-effect model | 0.00 | − 0.08, 0.09 | ||||
Intervention | 0.00 | < 0.001 | ||||
Pharmacological | − 0.06 | − 0.15, 0.03 | ||||
Non-pharmacological | 0.99 | 0.63, 1.35 | ||||
Intervention | 0.04 | 0.02 | ||||
Biological treatment | − 0.10 | − 0.20, − 0.01 | ||||
Other treatment | 0.27 | − 0.10, 0.64 | ||||
All trials, acute phase reactants | 27/31 | − 0.51 | − 0.70, − 0.32 | 84% | 0.22 | – |
Fixed-effect model | − 0.62 | − 0.69, − 0.55 | ||||
Intervention | – | – | ||||
Pharmacological | − 0.51 | − 0.70, − 0.32 | ||||
Non-pharmacological | – | – | ||||
Intervention | 0.12 | 0.001 | ||||
Biological treatment | − 0.77 | − 1.02, − 0.52 | ||||
Other treatment | − 0.22 | − 0.37, − 0.07 | −0.07 | |||
All trials, spine radiographs | 1/1 | 0.96 | 0.22, 1.69 | – | – | – |
Fixed-effect model | – | – | ||||
Intervention | – | – | ||||
Pharmacological | – | – | ||||
Non-pharmacological | – | – | ||||
Intervention | ||||||
Biological treatment | ||||||
Other treatment | 0.96 | 0.22, 1.69 | ||||
All trials, fatigue | 3/4 | − 0.65 | − 0.82, − 0.48 | 0% | 0.00 | – |
Fixed-effect model | − 0.65 | − 0.82, − 0.48 | ||||
Intervention | – | – | ||||
Pharmacological | − 0.65 | − 0.82, − 0.48 | ||||
Non-pharmacological | – | – | ||||
Intervention | – | – | ||||
Biological treatment | − 0.65 | − 0.82, −0.48 | ||||
Other treatment |
Pain
Spinal mobility
Spinal stiffness
Patient’s global assessment
Peripheral joints and enthesitis index
Acute phase reactants
Spine/hip radiographs
Fatigue
Association with primary endpoint
Univariate meta-regression analysis based on trials reporting primary endpoint | Univariate meta-regression analysis based on trials reporting all four domains significantly affecting primary endpoint** (k = 15) | Multivariable meta-regression analysis based on trials reporting all four domains significantly affecting primary endpoint** (k = 15) | |||||
---|---|---|---|---|---|---|---|
Domain | k | OR (95% CI) | P value | OR (95% CI) | P value | OR (95% CI) | P value |
Overall* | 39 | 3.26 (2.58, 4.13) | < 0.001 | 3.72 (2.92, 4.74) | < 0.001 | ||
PF | 31 | 2.79 (1.58, 4.90) | 0.001 | 3.9 (1.67, 9.15) | 0.005 | 0.56 (0.27, 1.16) | 0.105 |
Pain | 27 | 2.11 (1.45, 3.06) | < 0.001 | 5.6 (2.4, 13.15) | 0.001 | 5.19 (2.28, 11.77) | 0.001 |
SM | 31 | 1.20 (0.94, 1.5) | 0.142 | 2.25 (1.27, 3.99) | 0.009 | 1.03 (0.64, 1.68) | 0.883 |
SS | 22 | 1.29 (0.81, 2.06) | 0.268 | 1.88 (0.62, 1.56) | 0.227 | – | – |
PGA | 20 | 2.15 (1.41, 3.30) | 0.001 | 2.58 (1.53, 4.34) | 0.002 | 1.87 (1.14, 3.07) | 0.018 |
PJ/E | 10 | 8.14 (0.36, 186.27) | 0.161 | 16.99 (0.00, 3687 | 0.403 | – | – |
APR | 23 | 1.68 (1.05, 2.68) | 0.031 | 1.61 (0.99, 2.63) | 0.054 | 0.86 (0.58, 1.29) | 0.381 |
SR | – | – | – | – | – | – | – |
Fatigue | 4 | 2.59 (0.00, 1360) | 0.581 | – | – | – | – |