| Key Comparisons | Efficacy Strength of Evidence (in Bold) | Harms Strength of Evidence (in Bold) |
|---|---|---|
| Corticosteroids: Corticosteroid + csDMARD vs. csDMARDs | Remission significantly higher in corticosteroid plus MTX combination therapy than MTX alone Low: downgraded because open label design; high attrition; and not enough events to meet optimal information size Disease activity and radiographic progression Insufficient: both outcomes downgraded because open label design; high attrition; direction of effect varies; and large CIs cross appreciable benefits or harms Functional capacity Insufficient: downgraded because open label design; high attrition; direction of effect varies; and large CIs cross appreciable benefits or harms | No significant differences in serious adverse events Moderate: downgraded because open label design; high attrition; and large CIs cross appreciable benefits or harms No significant differences in discontinuation attributable to adverse effects Low: downgraded because open label design; high attrition; and large CIs cross appreciable benefits or harms |
| Corticosteroids: High-dose corticosteroid (≥250 mg) + MTX vs. IFX | ACR response, radiographic progression, or remission Insufficient: all outcomes downgraded because open label design; high attrition; and large CIs cross appreciable benefits or harms Functional capacity Insufficient: downgraded because open label design, and not enough events to meet optimal information size | Discontinuation attributable to adverse effects Insufficient: downgraded because open label design; high attrition; and large CIs cross appreciable benefits or harms Serious adverse events in methyl-PNL + MTX vs. IFX + MTX Insufficient: downgraded because open label design; high attrition; and large CIs cross appreciable benefits or harms |
| Corticosteroids: High-dose corticosteroid (≥250 mg) + MTX vs. MTX | ACR response, remission, or functional capacity Insufficient: downgraded because not enough events to meet optimal information size, and large CIs cross appreciable benefits or harms | Discontinuation attributable to adverse effects Insufficient: downgraded because not enough events to meet optimal information size, and large CIs cross appreciable benefits or harms Serious adverse events in methyl-PNL + MTX vs. MTX Insufficient: downgraded because not enough events to meet optimal information size, and large CIs cross appreciable benefits or harms |
| csDMARDs: csDMARDs vs. csDMARDs | Disease activity in PNL + SSZ vs. PNL + MTX Insufficient (based on RCTs): downgraded because high attrition; large baseline differences between groups; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size Disease activity in SSZ vs. MTX Insufficient (based on observational evidence): downgraded because high attrition; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size Radiographic progression in PNL + SSZ vs. PNL + MTX Insufficient: downgraded because high attrition; large baseline differences between groups; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size Remission in PNL + SSZ vs. PNL + MTX Insufficient: downgraded because high attrition; direction of effect varies; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size Functional capacity in PNL + SSZ vs. PNL + MTX Insufficient: downgraded because high attrition; large baseline differences between groups; and not enough events to meet optimal information size Functional capacity in SSZ vs. MTX Insufficient (based on observational evidence): downgraded because high risk of confounding by indication | Discontinuation attributable to adverse effects in PNL + SSZ vs. PNL + MTX Insufficient: downgraded because high attrition; direction of effect varies; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size Discontinuation attributable to adverse effects in SSZ vs. MTX Insufficient (based on observational evidence): downgraded because high risk of confounding by indication; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size |
| csDMARDs: csDMARD Combination Therapy vs. csDMARD Monotherapy | No significant differences in response or remission in MTX + SSZ vs. MTX Low (based on RCTs): downgraded because open label design; high attrition; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size Insufficient (based on observational evidence): Downgraded because high attrition; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size No significant differences in functional capacity for MTX + SSZ vs. MTX at 1 year or 5 years, or for comparisons of PNL + MTX + SSZ + HCQ vs. MTX or SSZ Low: downgraded because open label design; high attrition; and large CIs cross appreciable benefits or harms Radiographic progression for csDMARD combination therapy vs. csDMARD monotherapy Insufficient: downgraded because open label design; high attrition; and large CIs cross appreciable benefits or harms | No significant differences in discontinuation attributable to adverse effects in MTX + SSZ vs. MTX Low (based on RCTs): Downgraded because open label design; high attrition; and imprecision Insufficient (based on observational evidence): Downgraded because high risk of selection bias for treatment discontinuation and confounding by indication; and not enough events to meet optimal information size No significant differences in serious adverse events in MTX + SSZ vs. MTX Low: Downgraded because open label design, and high attrition |
| csDMARDs: csDMARDs vs. TNF Biologics ADA + MTX vs. ADA or ADA vs. MTX | ACR response and remission significantly higher, radiographic progression less, and functional capacity significantly improved with ADA + MTX vs. ADA or with ADA vs. MTX Moderate: downgraded because high attrition | No significant differences in discontinuation because adverse events or serious adverse events for ADA + MTX vs. ADA or for ADA vs. MTX Moderate: downgraded because high attrition |
| csDMARDs: csDMARDs vs. Non-TNF Biologics ABA + MTX vs. ABA or ABA vs. MTX | No significant differences in ACR response or remission for ABA + MTX vs. ABA or for ABA vs. MTX Low: both outcomes downgraded because high attrition No significant differences in functional capacity for ABA + MTX vs. ABA or for ABA vs. MTX Low: downgraded because high attrition | No significant differences in discontinuation attributable to adverse effects or serious adverse events for ABA + MTX vs. ABA or for ABA vs. MTX Low: both outcomes downgraded because high attrition |
| csDMARDs: csDMARDs vs. Non-TNF Biologics TCZ + MTX vs. TCZ or TCZ vs. MTX | Remission significantly higher for TCZ + MTX vs. TCZ and TCZ vs. MTX Low: downgraded because large CIs cross appreciable benefits or harms Functional capacity for TCZ + MTX vs. TCZ and TCZ vs. MTX Insufficient: downgraded because direction of effect varies, and large CIs cross appreciable benefits or harms Disease activity for TCZ + MTX vs. TCZ and TCZ vs. MTX Insufficient: downgraded because direction of effect varies, and large CIs cross appreciable benefits or harms | No significant differences in discontinuation attributable to adverse effects or serious adverse events for TCZ + MTX vs. TCZ or for TCZ vs. MTX Moderate: both outcomes downgraded because medium level of study limitations |
| csDMARDs: csDMARD vs. tsDMARD | ACR response, disease activity, remission, and radiographic progression for TOF + MTX vs. MTX or TOF Insufficient: all outcomes downgraded because high attrition; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size Functional capacity for TOF + MTX vs. MTX or TOF Insufficient: downgraded because large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size | Discontinuation attributable to adverse effects or serious adverse events for TOF + MTX vs. MTX or TOF Insufficient: both outcomes downgraded because high attrition; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size |
| Biologics TNF Biologics: TNF Biologic vs. csDMARD Monotherapy ADA + MTX vs. MTX | Functional capacity significantly improved for ADA + MTX vs. MTX Moderate: downgraded because high attrition ACR response significantly higher with ADA + MTX vs. MTX Low: downgraded because high attrition, and large CIs cross appreciable benefits or harms Remission significantly higher with ADA + MTX vs. MTX Low: both outcomes downgraded because high attrition, and large CIs cross appreciable benefits or harms Radiographic progression less with ADA + MTX vs. MTX Low: downgraded because high attrition, and large CIs cross appreciable benefits or harms | No significant differences in discontinuation because adverse events for ADA + MTX vs. MTX Low: downgraded because high attrition; direction of effect varies; and large CIs cross appreciable benefits or harms No significant differences in serious adverse events for ADA + MTX vs. MTX Low: both outcomes downgraded because high attrition; direction of effect varies; and large CIs cross appreciable benefits or harms |
| Biologics TNF Biologics: TNF Biologic vs. csDMARD Monotherapy CZP + MTX vs. MTX | ACR response significantly higher and radiographic progression less for CZP + MTX vs. MTX Low: both outcomes downgraded because high attrition; large CIs; and not enough events to meet optimal information size Remission significantly higher and functional capacity improved for CZP + MTX vs. MTX Low: both outcomes downgraded because high attrition; large CIs; and not enough events to meet optimal information size | No significant differences in discontinuation because adverse effects or serious adverse events Low: downgraded because high attrition; large CIs; and not enough events to meet optimal information size |
| Biologics TNF Biologics: TNF Biologic vs. csDMARD Monotherapy ETN + MTX or ETN vs. MTX | ACR response significantly higher and radiographic progression less for ETN + MTX and ETN vs. MTX Moderate: both outcomes downgraded because medium level of study limitations Remission rates significantly higher for ETN + MTX and ETN vs. MTX Low: downgraded because medium level of study limitations, and not enough events to meet optimal information size Functional capacity mixed for ETN + MTX and ETN vs. MTX Low: downgraded because direction of effect varies, and large CIs | No significant differences in discontinuation because adverse effects or serious adverse events Low: both outcomes downgraded because medium level of study limitations, and not enough events to meet optimal information size |
| Biologics TNF Biologics: TNF Biologic vs. csDMARD Monotherapy IFX + MTX vs. MTX | Remission rates significantly higher and functional capacity greater for IFX + MTX vs. MTX Low: both outcomes downgraded because medium level of study limitations Disease activity and radiographic progression for IFX + MTX vs. MTX Insufficient: both outcomes downgraded because not enough events to meet optimal information size; direction of effect varies; and large CIs cross appreciable benefits or harms | No significant differences in discontinuation attributable to adverse effects or serious adverse events Low: both outcomes downgraded because medium level of study limitations |
| Biologics TNF Biologics: TNF Biologic vs. csDMARD Combination Therapy (e.g., triple therapy) ADA + MTX vs. MTX + PRED + HCQ + SSZ | Disease activity, radiographic progression, or remission for ADA + MTX vs. MTX + PRED + HCQ + SSZ Insufficient: all outcomes downgraded because high attrition; not enough events to meet optimal information size; and large CIs cross appreciable benefits or harms Functional capacity for ADA + MTX vs. MTX + PRED + HCQ + SSZ Insufficient: downgraded because high attrition, and not enough events to meet optimal information size | Serious adverse events Insufficient: downgraded because high attrition; not enough events to meet optimal information size; and large CIs cross appreciable benefits or harms |
| Biologics TNF Biologics: TNF Biologic vs. csDMARD Combination Therapy (e.g., triple therapy) IFX + MTX vs. MTX + SSZ + HCQ | ACR response significantly higher for IFX + MTX vs. MTX + SSZ + HCQ Low: downgraded because medium level of study limitations | No significant differences in discontinuation attributable to either adverse effects or serious adverse events Low: both outcomes downgraded because medium level of study limitations |
| Biologics TNF Biologics: TNF Biologic vs. csDMARD Combination Therapy (triple therapy) IFX + MTX + SSZ + HCQ + PRED vs. MTX + SSZ + HCQ + PRED | No significant differences in ACR response, radiographic progression, or remission for IFX + MTX + SSZ + HCQ + PRED vs. MTX + SSZ + HCQ + PRED Low: all outcomes downgraded because large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size No significant differences in functional capacity for IFX + MTX + SSZ + HCQ + PRED vs. MTX + SSZ + HCQ + PRED Low: downgraded because not enough events to meet optimal information size | No significant differences in discontinuation attributable to adverse effects or serious adverse events Low: both outcomes downgraded because large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size |
| Biologics Non-TNF Biologics: Non-TNF Biologic vs. csDMARD Monotherapy ABA + MTX vs. MTX | Disease activity significantly improved and remission rates higher for ABA + MTX vs. MTX Moderate: both outcomes downgraded because high attrition, and large baseline differences between groups Radiographic progression significantly less for ABA + MTX vs. MTX Low: downgraded because high attrition Functional capacity mixed for ABA + MTX vs. MTX Low: downgraded because high attrition; direction of effect varies; large CIs cross appreciable benefits or harms, and not enough events to meet optimal information size | No significant differences in discontinuation attributable to adverse effects or serious adverse events Low: both outcomes downgraded because high attrition |
| Biologics Non-TNF Biologics: Non-TNF Biologic vs. csDMARD Monotherapy RIT + MTX vs. MTX | Disease activity significantly improved and radiographic progression less for RIT + MTX vs. MTX Moderate: both outcomes downgraded because not enough events to meet optimal information size Remission rates significantly higher for RIT + MTX vs. MTX Moderate: downgraded because not enough events to meet optimal information size Functional capacity significantly improved for RIT + MTX vs. MTX Moderate: downgraded because single-study body of evidence | No significant differences in discontinuation attributable to adverse effects or serious adverse events Moderate: both outcomes downgraded because not enough events to meet optimal information size |
| Biologics Non-TNF Biologics: Non-TNF Biologic vs. csDMARD Monotherapy TCZ + MTX vs. MTX | Radiographic progression less for TCZ + MTX vs. MTX Moderate: downgraded because large baseline differences between groups Remission significantly higher for TCZ + MTX vs. MTX Low: downgraded because medium level of study limitations, and large confidence intervals cross appreciable benefits or harms Disease activity and functional capacity for TCZ + MTX vs. MTX Insufficient: both outcomes downgraded because direction of effect varies, and large CIs cross appreciable benefits or harms | No significant differences in discontinuation attributable to adverse effects or serious adverse events Moderate: both outcomes downgraded because medium level of study limitations |
| Biologics: TNF vs. Non-TNF Biologics | Functional capacity significantly improved for RIT vs. ADA or ETN Low: downgraded because no ITT analysis, and high risk of selection bias for treatment discontinuation and confounding by indication Disease activity or remission for RIT vs. ADA or ETN Insufficient: both outcomes downgraded because no ITT analysis; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size | Discontinuation attributable to adverse effects or serious adverse events Insufficient: both outcomes downgraded because no ITT analysis; large CIs cross appreciable benefits or harms; and not enough events to meet optimal information size |
| Combination Strategies: 1: Sequential monotherapy starting with MTX vs. 2: Step-up combination therapy vs. 3: Combination with high-dose tapered PRED vs. 4: Combination therapy with IFX | Disease activity significantly more improved for strategy 3 (combination therapy with high dose tapered PRED) and strategy 4 (combination therapy with IFX) than with either strategy 1 (sequential monotherapy) or 2 (step-up therapy) in short term (1 year), but no significant differences in long term (4 or 10 years) Moderate: downgraded because large CIs cross appreciable benefits or harms No significant differences in long term radiographic progression (10 years) Moderate: downgraded because large CIs cross appreciable benefits or harms No significant differences in long term remission (4 or 10 years) Moderate: downgraded because large CIs cross appreciable benefits or harms No significant differences in long term functional capacity (2, 5, or 10 years) Low: downgraded because not enough events to meet optimal information size, and large CIs cross appreciable benefits or harms | No significant differences in serious adverse events Low: downgraded because large CIs cross appreciable benefits or harms |
| Combination Strategies: 1: Immediate MTX + ETN vs. 2: Immediate MTX + SSZ + HCQ vs. 3: Step-up MTX to combo MTX + ETN vs. 4: Step-up MTX to combo MTX + SSZ + HCQ | Disease activity, remission, radiographic progression, or functional capacity for immediate combination therapy (MTX + ETN) vs. step-up triple therapy (MTX + SSZ + HCQ) Insufficient: all outcomes downgraded because high attrition; no ITT analysis; and large CIs cross appreciable benefits or harms | Discontinuation attributable to adverse effects or serious adverse events Insufficient: both outcomes downgraded because high attrition; no ITT analysis; and large CIs cross appreciable benefits or harms |
| Combination Strategies: ADA + MTX adjusted based on DAS vs. MTX | Disease activity, remission, or radiographic progression for ADA + MTX adjusted based on DAS vs. MTX Insufficient: all outcomes downgraded because high attrition, and large CIs cross appreciable benefits or harms Functional capacity for ADA + MTX adjusted based on DAS vs. MTX Insufficient: downgraded because high attrition, and large CIs cross appreciable benefits or harms | Discontinuation attributable to adverse effects or serious adverse events Insufficient: both outcomes downgraded because high attrition, and large CIs cross appreciable benefits or harms |
ABA = abatacept; ACR = American College of Rheumatology; ADA = adalimumab; CI = confidence interval; csDMARD = conventional synthetic DMARD; CZP = certolizumab pegol; DAS = Disease Activity Score; DMARD = disease-modifying antirheumatic drug; ETN = etanercept; HCQ = hydroxychloroquine; IFX = infliximab; ITT = intent-to-treat; MTX = methotrexate; obs = observational; PRED = prednisone; RIT = rituximab; SSZ = sulfasalazine; TCZ = tocilizumab; TNF = tumor necrosis factor; TOF = tofacitinib; tsDMARD = targeted synthetic DMARD; vs. = versus.
From: Discussion
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