Table 1

Overview of placebo-controlled trials comparing early versus delayed DMARD initiation in early RA looking at radiographic joint damage and disability

First author, year of publication	Type of trial	Quality score* (%)	Patients	N	Follow-up time	Intervention	Control	Outcome of interest	Relevant result	Association between early DMARD intervention and outcome
Radiographic damage
Borg, 198865	Randomised, double-blind, placebo-controlled trial.	80	Definite or classical RA (1958 criteria), symptoms <2 years, active disease.*	132 (67/65)	2 years	Auranofin 6 mg daily.	Placebo 6 mg daily. Median delay to DMARD start 12 months.	Larsen.	Auronafin arm: median increase Larsen score 6.0 → 13.0. Placebo arm: median increase 9.5 → 21.5. Difference between groups p<0.05.	S
The Australian Multicentre Clinical Trial Group, 199266	Randomised, double-blind, placebo-controlled trial.	60	Probable, definite or classical RA (1958 criteria), disease duration <12 months, no erosions.*	105 (52/53)	6 months	SSZ 2000 mg daily.	Placebo 2000 mg daily. Delay to DMARD start unknown.	Positive or negative for erosions on X-rays of the hand and feet.	After 6 months, 12% of patients had erosions in the hands, 10% in the feet. 'A tendency towards a statistically significant difference between groups with SSZ group.	NS
Hannonen, 199367	Randomised, double-blind, placebo-controlled trial.	73	Definite RA (1958 criteria), disease duration <12 months, active disease.*	78 (38/40)	48 weeks	SSZ 2000 mg daily.	Placebo 2000 mg daily. Delay to DMARD start unknown.	Modified Sharp score.	Mean increase in radiological score (erosions + joint space narrowing): 3.5 in SSZ arm vs 7.1 in placebo arm (p=0.13).	NS
Buckland-Wright, 199368	Randomised controlled trial.	27	Diagnosis of RA, disease duration <2 years.*	29 (13/16)	18 months	Gold 50 mg/week + NSAIDs.	Delayed Gold 50 mg/week (after 6 months) + NSAIDs.	Erosion area.	First 6 months, significant increase in both groups, second 6 months a lower proportion in Gold group had erosion area progression (p<0.005). Third 6 months decrease in erosion area in both groups.	S
Egsmose, 199517†	Randomised, double-blind, placebo-controlled trial.	80	Definite or classical RA (1958 criteria), symptoms <2 years, active disease.*	75 (40/35)	5 years	Auronafin 6 mg daily.	Placebo 6 mg daily. Median delay to DMARD start 12 months.	Larsen.	At 5 years, the Larsen score in the placebo arm had reached values roughly twice those in the auronafin arm (p=0.004).	S
van der Heide, 199669	Randomised controlled trial.	80	1987 RA, disease duration <1 year.*	238 (181/57)	12 months	HCQ 400 mg/day or intramuscular Gold 50 mg/week or MTX (up to 15 mg/week).	NSAIDs. Possibility to start DMARDs after 12 months.	Modified Sharp score.	Mean increase in radiological damage score: +7 in DMARD arm vs +8 in control group (not statistically significant).	NS
Choy, 200271	Randomised, double-blind, placebo-controlled trial.	73	1987 RA, disease duration <1 year, active disease.*	117 (62/55)	12 months	SSZ 2000 mg daily + placebo diclofenac.	Diclofenac 100 mg daily + placebo SSZ. Delay to DMARD start unknown.	Erosions, assessed by Sharp method.	Mean number of new erosions in SSZ arm 2.0 vs 7.5 in diclofenac arm (p=0.002).	S
van Everdingen, 200270	Randomised, double-blind, placebo-controlled trial.	87	1987 RA, disease duration <1 year, active disease.*	81 (40/41)	2 years	Prednisone 10 mg/day.	Placebo 10 mg/day. Possibility to start DMARD after 6 months.	Modified Sharp score.	Mean change in modified Sharp score: 16 prednisone vs 29 in placebo arm (p=0.007).	S
Verstappen, 200372*‡	Randomised controlled trial.	80	1987 RA, disease duration <1 year.*	189 (145/44)	5 years	HCQ 400 mg/day or intramuscular Gold 50 mg/week or MTX (up to 15 mg/week).	NSAIDs. Possibility to start DMARDs after 12 months.	Sharp/van der Heijde.	Mean increase Sharp/van der Heijde score per year 7.3 for intervention arm vs 6.8 for control arm (not statistically significant).	NS
Functional disability
Borg, 198865	Randomised, double-blind, placebo-controlled trial.	80	Definite or classical RA (1958 criteria), symptoms <2 years, active disease.*	132 (67/65)	2 years	Auronafin 6 mg daily.	Placebo 6 mg daily. Median delay to DMARD start 12 months.	HAQ. Keitel Functional Index.	Median change in HAQ score: −0.17 in intervention arm vs −0.02 in control arm (p<0.05). Median change in Keitel index −5 in intervention arm vs 1 in control arm (p<0.01).	S
Egsmose, 199517†	Randomised, double-blind, placebo-controlled trial.	80	Definite or classical RA (1958 criteria), symptoms <2 years, active disease.*	75 (40/35)	5 years	Auronafin 6 mg daily.	Placebo 6 mg daily. Median delay to DMARD start 12 months.	HAQ. Keitel Functional Index.	After 5 years, differences in HAQ score (p=0.08) and Keitel index (p<0.006) in favour of intervention arm.	S
The HERA Study Group, 199573	Randomised, double-blind, placebo-controlled trial.	93	1987 RA, disease duration <2 years, active disease.*	119 (59/60)	36 weeks	HCQ up to 400 mg/day.	Placebo up to 400 mg/day. Possibility to start DMARD therapy after 24 weeks.	Physical function index (combination AIMS, HAQ and MACTAR).	At 36 weeks, there was significant benefit for the HCQ arm in the physical function index (p=0.020).	S
van der Heide, 199669	Randomised controlled trial.	80	1987 RA, disease duration <1 year.*	238 (181/57)	12 months	HCQ 400 mg/day or intramuscular Gold 50 mg/week or MTX (up to 15 mg/week).	NSAIDs. Possibility to start DMARDs after 12 months.	HAQ.	Mean change in HAQ score −0.4 in intervention arm vs −0.1 in control arm. Mean difference 0.3 (95% CI 0.2 to 0.6).	S
Tsakonas, 200074*†§	Randomised, double-blind, placebo-controlled trial.	93	1987 RA, disease duration <2 years, active disease.*	115 (58/57)	45 months	HCQ up to 400 mg/day.	Placebo up to 400 mg/day. 9-month delay to DMARD start.	Physical function index (combination AIMS, HAQ and MACTAR).	After 45 months, mean change in physical function index −0.48 in intervention arm vs −0.40 in control group (no p value given).	NS
Choy, 200271	Randomised, double-blind, placebo-controlled trial.	73	1987 RA, disease duration <1 year, active disease.*	117 (62/55)	12 months	SSZ 2000 mg daily + placebo diclofenac.	Diclofenac 100 mg daily + placebo SSZ. Delay to DMARD start unknown.	HAQ.	No clinically relevant changes in HAQ score were observed within or between groups.	NS
van Everdingen, 200270	Randomised, double-blind, placebo-controlled trial.	87	1987 RA, disease duration <1 year, active disease.*	81 (40/41)	2 years	Prednisone 10 mg/day.	Placebo 10 mg/day. Possibility to start DMARD after 6 months.	HAQ.	Mean change in HAQ after 24 months: 0.1 in intervention arm vs 0.0 in control arm (p>0.2).	NS
Verstappen, 2003‡	Randomised controlled trial.	80	1987 RA, disease duration <1 year.*	189 (145/44)	5 years	HCQ 400 mg/day or intramuscular Gold 50 mg/week or MTX (up to 15 mg/week).	NSAIDs. Possibility to start DMARDs after 12 months.	HAQ.	Mean change in HAQ score after 5 years of follow-up: −0.20 in intervention arm vs −0.12 in control, not statistically significant.	NS

*Studies with a quality score ≥75% were considered to have high-quality scores.
†This study reports on the same population as the study by Borg etal.65
‡This study reports on the same population as the study by van der Heide etal.69
§This study reports on the same population as the study by the HERA Study Group.73
AIMS, Arthritis Impact Measurement Scales;DMARD, disease-modifying antirheumatic drug;HAQ, Health Assessment Questionnaire; HCQ, hydroxychloroquine;MACTAR, McMaster-Toronto Arthritis Patient Preference Disability QuestionnaireMTX, methotrexate; NS, not significant;NSAIDs, non-steroidal anti-inflammatory drug; RA, rheumatoid arthritis;S, significant;SSZ, sulfasalazine.