Ten RCTs (n=535) were included in the review.
Three studies were considered to be of a good methodological quality, three were of a medium quality, and four were of a poor quality. Seven of the included studies used an intention-to-treat analysis.
Disease activity.
Tetracycline was associated with a statistically significant reduction in tender joint count compared with the control; the SMD was -0.39 (95% CI: -0.74, 0.05, P=0.03) based on 494 patients in 7 RCTs (random-effects). However, there was evidence of significant statistical heterogeneity (chi-squared 17.74, d.f.=6, P=0.0069). The subgroup analysis of tetracycline compared with placebo trials did not alter the results, although the removal of trials evaluating doxycycline found a greater reduction in tender joint count.
Tetracycline was associated with a statistically significant improvement in swollen joint count compared with the control; the SMD was -0.23 (95% CI: -0.41, 0.05, P=0.01) based on 494 patients in 7 RCTs (random-effects). There was no evidence of significant statistical heterogeneity (chi-squared 5.99, d.f.=6, P=0.42). Subgroup analyses of tetracycline compared with placebo, and the exclusion of trials evaluating doxycycline, did not affect the results obtained.
Tetracycline was associated with a statistically significant improvement in ESR compared with the control; the WMD was -8.96 (95% CI: -14.51, 3.42, P=0.002) based on 494 patients in 7 RCTs (random-effects). There was no evidence of statistical heterogeneity (chi-squared 8.96, d.f.=6, P=0.18). The subgroup analysis of tetracycline compared with placebo trials did not alter the results, although the removal of trials using doxycycline found a greater reduction in ESR.
The studies evaluating CRP were inconclusive. One RCT found no significant difference between tetracycline and the control, while one RCT found a significant difference.
There was no statistically significant improvement in the patient global assessment of disease activity in those given tetracycline compared with those given the control; the SMD was -0.15 (95% CI: -0.036, 0.5) based on 425 patients in 5 RCTs.
There was no statistically significant improvement in the physician global assessment of disease activity in patients given tetracycline compared with those given the control; the SMD was 0.00 (95% CI: -0.7, 0.7) based on 360 patients in 4 RCTs (random-effects). Subgroup analyses of tetracycline compared with placebo did not affect the results obtained.
Tetracycline was associated with a statistically significant reduction in self-reported pain levels compared with the control; the SMD was -0.68 (95% CI: -1.03, 0.33) based on 140 patients in 2 RCTs. However, a subgroup analysis of trials comparing tetracycline with placebo did not find a statistically significant reduction in self-reported pain.
Disease damage.
No statistically significant reduction in erosions was reported in patients given tetracycline compared with the control; the SMD was 0.17 (95% CI: -0.29, 0.64; P=0.5) based on 299 patients in 2 RCTs (random-effects). There was evidence of significant statistical heterogeneity (chi-squared 3.30, d.f.=1, P=0.069).
No statistically significant improvement in joint space narrowing was found in patients given tetracycline compared with those given the control; the SMD was 0.04 (95% CI: -0.19, 0.27).
Disability.
Tetracycline was associated with a significant improvement in the Health Assessment Questionnaire compared with the control; the SMD was -0.15 (95% CI: -0.28, 0.02) based on 394 patients in 4 RCTs. Subgroup analyses of tetracycline compared with placebo did not affect the results obtained.
Adverse events.
No statistically significant difference in the absolute risk of adverse events was found between patients given tetracycline compared with those given the control; the ARR was 0.10 (95% CI: -0.01, 0.21) based on 381 patients in 8 RCTs (random-effects). Subgroup analyses of tetracycline compared with placebo did not affect the results obtained.
Response to treatment.
The number of patients responding to treatment was significantly higher in the tetracycline group than in the control group; the RR was 1.78 (95% CI: 1.0, 3.16) based on 421 patients in 4 RCTs (random-effects). This remained significant after the exclusion of 2 RCTs of patients with early onset RA.