| Outcome Type | Specific Outcome | Results | Strength of Evidence | Summary of Rationale for Strength of Evidence |
|---|---|---|---|---|
| Disease activity | Response | No significant difference between non-TNF biologic (ABA) + MTX and ABA alone7 | Low | Downgraded because high attrition |
| Disease activity | Responsea | Significantly improved response for TNF biologic (ADA) + MTX than ADA alone and for ADA than MTX15 | Moderate | Downgraded because high attrition |
| Disease activity | Responsea | Significantly improved response for TNF biologic (ETN) + MTX than MTX alone12, 14 | Moderate | Downgraded because medium level of study limitations |
| Disease activity | Responsea | Significantly improved response for non-TNF biologics (ABA or RIT) + MTX than MTX alone7, 30, 31 | Moderate | ABA + MTX: Downgraded because high attrition; RIT + MTX: Not enough events to meet optimal information size |
| Disease activity | Remission | Significantly higher remission for TNF biologic (ADA) + MTX than ADA alone and for ADA than MTX15 | Moderate | Downgraded because high attrition |
| Disease activity | Radiographic Changes | Significantly less radiographic progression for TNF biologic (ADA) + MTX than ADA alone and for ADA than MTX15 | Moderate | Downgraded because high attrition |
| Disease activity | Radiographic Changes | Significantly less radiographic progression for non-TNF biologic (TCZ) + MTX than TCZ alone and for TCZ than MTX32, 33 | Moderate | Downgraded because medium level of study limitations |
| Disease activity | Radiographic Changes | Significantly less radiographic progression for TNF biologic (ETN) alone and combined with MTX than MTX alone12, 14 | Moderate | Downgraded because medium level of study limitations |
| Disease activity | Radiographic Changes | Significantly less radiographic progression for non-TNF biologic (TCZ) + MTX than MTX alone32, 33 | Moderate | Downgraded because medium level of study limitations |
| Disease activity | Radiographic Changes | Significantly less radiographic progression for non-TNF biologic (RIT) + MTX than MTX alone30 | Moderate | Downgraded because not enough events to meet optimal information size |
| Disease activity | Responsea | Significantly improved response with TNF biologic (ADA) + MTX compared with MTX alone15, 16, 34–37 | Low | Downgraded because high attrition |
| Disease activity | Responsea | Significantly improved response with TNF biologic (CZP) + MTX compared with MTX alone38, 39 | Low | Downgraded because high attrition; large confidence intervals; and not enough events to meet optimal information size |
| Disease activity | Responsea | Significantly improved response with TNF biologic (IFX) + MTX than csDMARD combination therapy10 | Low | Downgraded because medium level of study limitations |
| Disease activity | Responsea | No significant difference between TNF biologic (IFX) + csDMARD combination and csDMARD combination therapies40 | Low | Downgraded because large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size |
| Disease activity | Remission | No significant difference between non-TNF biologic (ABA) + MTX and ABA alone7 | Low | Downgraded because high attrition |
| Disease activity | Remission | Significantly higher remission for non-TNF biologic (TCZ) + MTX than TCZ alone and for TCZ than MTX32, 33 | Low | Downgraded because large CIs cross appreciable benefits or harms |
| Disease activity | Remission | Significantly increased remission for TNF biologics (ADA, CZP, ETN, IFX) plus MTX, or TNF biologic alone (ETN), compared with MTX alone12–17, 34–37, 41 | Lowb | ADA + MTX: Downgraded because high attrition; CZP + MTX: Downgraded because high attrition; large CIs; and not enough events to meet optimal information size; ETN + MTX and ETN alone: Downgraded because medium level of study limitations, and not enough events to meet optimal information size; IFX + MTX: Downgraded because medium level of study limitations |
| Disease activity | Remission | No significant difference between TNF biologic (IFX) + csDMARD combination and csDMARD combination therapies10 | Low | Downgraded because large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size |
| Disease activity | Remission | Significantly higher remission for non-TNF biologic (TCZ) + MTX than MTX alone32, 33 | Low | Downgraded because medium level of study limitations, and large CIs cross appreciable benefits or harms |
| Disease activity | Radiographic Changes | Significantly less radiographic progression for some biologics (TNF: ADA, CZP; non-TNF: ABA) plus MTX compared with MTX alone13, 15, 31 | Lowb | ADA + MTX: Downgraded because high attrition, and large CIs cross appreciable benefits or harms CZP + MTX: Downgraded because high attrition; large CIs; and not enough events to meet optimal information size ABA + MTX: Downgraded because high attrition |
| Disease activity | Radiographic Changes | No significant difference between TNF biologic (IFX) + csDMARD combination therapy compared with csDMARD combination therapy alone40 | Low | Downgraded because large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size |
| Disease activity | Responsea | Non-TNF biologic (TCZ) + MTX compared with TCZ alone and TCZ compared with MTX32, 33 | Insufficient | Downgraded because direction of effect varies, and large CIs cross appreciable benefits or harms |
| Disease activity | Responsea | IFX + MTX compared with MTX alone17, 18, 41 | Insufficient | Downgraded because not enough events to meet optimal information size; direction of effect varies; and large CIs cross appreciable benefits or harms |
| Disease activity | Responsea | TNF biologic (ADA or ETN) compared with non-TNF biologic (RIT)8 | Insufficient | Downgraded because no ITT analysis; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size |
| Disease activity | Responsea | TCZ + MTX compared with MTX alone32, 33 | Insufficient | Downgraded because direction of effect varies, and large CIs cross appreciable benefits or harms |
| Disease activity | Responsea | ADA + MTX compared with csDMARD combination with PRED9 | Insufficient | Downgraded because high attrition; not enough events to meet optimal information size; and large CIs cross appreciable benefits or harms |
| Disease activity | Remission | ADA + MTX compared with csDMARD combination with PRED9 | Insufficient | Downgraded because high attrition; not enough events to meet optimal information size; and large CIs cross appreciable benefits or harms |
| Disease activity | Remission | TNF biologic (ADA or ETN) compared with non-TNF biologic (RIT)8 | Insufficient | Downgraded because no ITT analysis; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size |
| Disease activity | Radiographic Changes | IFX + MTX compared with MTX alone17, 41 | Insufficient | Downgraded because not enough events to meet optimal information size; direction of effect varies; and large CIs cross appreciable benefits or harms |
| Disease activity | Radiographic Changes | ADA + MTX compared with csDMARD combination with PRED9 | Insufficient | Downgraded because high attrition; not enough events to meet optimal information size; and large CIs cross appreciable benefits or harms |
| Functional Capacity | N/A | Significantly greater improvement in TNF biologic (ADA) plus MTX than ADA alone and for ADA than MTX15 | Moderate | Downgraded because high attrition |
| Functional Capacity | N/A | Significantly greater improvement for TNF biologic (ADA) + MTX than MTX alone15, 16, 34–37 | Moderate | Downgraded because high attrition |
| Functional Capacity | N/A | Significantly greater improvement for non-TNF biologic (RIT) combined with MTX than MTX alone30 | Moderate | Downgraded because not enough events to meet optimal information size |
| Functional Capacity | N/A | No significant differences in functional capacity for ABA + MTX vs. ABA or for ABA vs. MTX7 | Low | Downgraded because high attrition |
| Functional Capacity | N/A | Significantly greater improvement in TNF biologic (CZP, IFX) plus MTX than MTX alone13, 17, 41 | Lowb | CZP + MTX: Downgraded because high attrition; large confidence intervals; and not enough events to meet optimal information size IFX + MTX: Downgraded because medium level of study limitations |
| Functional Capacity | N/A | Significantly greater improvement in non-TNF biologic (RIT) than TNF biologics (ADA, ETN)8 | Low | Downgraded because no ITT analysis |
| Functional Capacity | N/A | Mixed results for TNF biologic (ETN) or non-TNF biologic (ABA) plus MTX compared with MTX alone7, 12, 14, 31 | Lowb | ABA + MTX: Downgraded because high attrition; ETN + MTX: Downgraded because direction of effect varies, and large CIs |
| Functional Capacity | N/A | No significant difference between TNF biologic (IFX) + csDMARD combination and csDMARD combination therapies40 | Low | Downgraded because large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size |
| Functional Capacity | N/A | TCZ + MTX vs. TCZ and TCZ vs. MTX32, 33 | Insufficient | Downgraded because direction of effect varies, and large CIs cross appreciable benefits or harms |
| Functional Capacity | N/A | ADA + MTX compared with csDMARD combination with PRED9 | Insufficient | Downgraded because high attrition, and not enough events to meet optimal information size |
| Functional Capacity | N/A | TCZ + MTX compared with MTX32, 33 | Insufficient | Downgraded because direction of effect varies, and large CIs cross appreciable benefits or harms |
| Harms | SAEs and D/C attributable to AEs | No significant differences between TNF biologic (ADA) + MTX and ADA alone or between ADA and MTX15 | Moderate | Downgraded because high attrition |
| Harms | SAEs and D/C attributable to AEs | No significant differences between non-TNF biologic (TCZ) + MTX and TCZ alone or between TCZ and MTX32, 33 | Moderate | Downgraded because medium level of study limitations |
| Harms | SAEs and D/C attributable to AEs | No significant differences between non-TNF biologic (TCZ) + MTX and MTX alone32, 33 | Moderate | Downgraded because medium level of study limitations |
| Harms | SAEs and D/C attributable to AEs | No significant differences among non-TNF biologic (RIT) + MTX and MTX alone30 | Moderate | Downgraded because single-study body of evidence |
| Harms | SAEs and D/C attributable to AEs | No significant differences between non-TNF biologic (ABA) + MTX and ABA alone or bet6ween ABA and MTX7 | Low | Downgraded because high attrition |
| Harms | SAEs and D/C attributable to AEs | No significant differences between TNF biologics (ADA, CZP, ETN, IFX) plus MTX and MTX alone12–17, 34–37 | Lowb | ADA + MTX: Downgraded because high attrition; direction of effect varies; and large CIs cross appreciable benefits or harms CZP + MTX: Downgraded because high attrition; large confidence intervals; and not enough events to meet optimal information size ETN + MTX: Downgraded because not enough events to meet optimal information size IFX + MTX: Downgraded because medium level of study limitations |
| Harms | SAEs and D/C attributable to AEs | No significant difference between non-TNF biologic (ABA) plus MTX and MTX alone31 | Low | Downgraded because high attrition |
| Harms | SAEs and D/C attributable to AEs | No significant difference between TNF biologic (IFX) + MTX or IFX + csDMARD combination and csDMARD combination therapies10, 40 | Lowb | IFX + MTX: Downgraded because medium level of study limitations IFX + csDMARD combination: Downgraded because large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size |
| Harms | SAEs | ADA + MTX compared with csDMARD combination with PRED9 | Insufficient | Downgraded because high attrition; not enough events to meet optimal information size; and large CIs cross appreciable benefits or harms |
| Harms | SAEs and D/C attributable to AEs | TNF biologic (ADA or ETN) compared with non-TNF biologic (RIT)8 | Insufficient | Downgraded because no ITT analysis; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size |
Response defined by ACR or DAS28.
Strength of evidence grade applies to each specific drug therapy named in the Results column.
ABA = abatacept; ACR = American College of Rheumatology; ADA = adalimumab; AE = adverse event; CI = confidence interval; csDMARDs = conventional synthetic disease modifying antirheumatic drug; CZP = certolizumab pegol; D/C = discontinuation; DAS28 = Disease Activity Score based on 28 joints; DMARD = disease-modifying antirheumatic drug; ETN = etanercept; IFX = infliximab; ITT = intent-to-treat; MTX = methotrexate; N/A = not applicable; PRED = prednisone; R1T = rituximab; SAE = serious adverse event; TCZ = tocilizumab; TNF = tumor necrosis factor.
From: Evidence Summary
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