Background
Methods
Methods for systematic review: study eligibility criteria, outcomes and data abstraction
P: Adults 18 years or older, meeting the 1987 American College of Rheumatology Classification criteria for systemic lupus erythematosus (SLE) [16], who have lupus nephritis.I: Immunosuppressant drug alone or in combination with other immunosuppressant drugs or biologics (such as rituximab) or corticosteroids. Medication doses were categorized as low, standard or high dose/duration (LD, SD and HD).C: Placebo or another immunosuppressive with/without biologic.O: Benefit and harm outcomes (renal remission/response, renal relapse/flare, fertility, bone marrow suppression), defined as follows.
Bayesian network meta-analysis (NMA)
Results
Study characteristics
Author | Year | Randomization | Allocation concealment | Blinding of assessor and/or physician (for assessment of objective outcomes) | Blinding of participants (for assessment of subjective outcomes) | Intention to treat | Free of selective reporting | Source of funding |
---|---|---|---|---|---|---|---|---|
Austin | 2009 | Low risk | Low risk | High risk | High risk | Unclear risk | Unclear risk | Unclear risk |
Carette | 1983 | Unclear risk | Unclear risk | High risk | High risk | Low risk | High risk | Low risk |
Steinberg | 1991 | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk | Unclear risk |
Donadio | 1976 | Unclear risk | Unclear risk | High risk | High risk | Low risk | Unclear risk | Low risk |
Pohl | 1991 | Unclear risk | Unclear risk | High risk | High risk | Unclear risk | Unclear risk | Unclear risk |
Wang | 2007 | Unclear risk | Unclear risk | High risk | High risk | High risk | Unclear risk | Unclear risk |
Isenberg; An analysis of ALMS study | 2010 | Low risk | Low risk | Low risk | Unclear risk | Low risk | Low risk | Unclear risk |
Appel (ALMS study) | 2009 | Low risk | Low risk | Low risk | Unclear risk | Low risk | Low risk | Unclear risk |
Austin | 1986 | Low risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Balletta | 1992 | Unclear risk | Unclear risk | Low risk | Low risk | Low risk | Unclear risk | Low risk |
Bao | 2008 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Barron | 1982 | High risk | High risk | Low risk | Low risk | High risk | High risk | Low risk |
Boumpas | 1992 | Unclear risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Cade | 1973 | High risk | Unclear risk | Low risk | Low risk | Unclear risk | Unclear risk | Unclear risk |
Chan | 2000 | Low risk | Unclear risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Chen | 2011 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Clark | 1981 | Unclear risk | Unclear risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Clark | 1984 | Unclear risk | Unclear risk | Low risk | Low risk | Unclear risk | Unclear risk | Unclear risk |
Contreras | 2002 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
CYCLOFA-LUNE Study | 2010 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Derksen | 1988 | Low risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Donadio | 1974 | Low risk | Unclear risk | Low risk | Low risk | Unclear risk | High risk | Low risk |
Donadio | 1978 | Low risk | Unclear risk | Low risk | Low risk | Unclear risk | Unclear risk | Unclear risk |
Doria | 1994 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Dyadyk | 2001 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
El-Shafey | 2010 | Low risk | Unclear risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Fu | 1998 | Low risk | Low risk | Low risk | Low risk | Low risk | High risk | Low risk |
Ginzler | 2005 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Gourley | 1996 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Grootscholten (Dutch Lupus study) | 2006 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Hahn | 1975 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Hong | 2007 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Houssiau | 2002 | Low risk | Unclear risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Lewis | 1992 | Low risk | Unclear risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Li | 2009a | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Li | 2009b | Unclear risk | Unclear risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Lui | 1997 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
LUNAR Study | 2012 | Low risk | Unclear risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
MAINTAIN Nephritis Study | 2010 | Low risk | Unclear risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Mitwalli | 2011 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Mok | 2009 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Moroni | 2004 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Mulic-Basic | 2008 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
My-Lupus Study | 2010 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Ong | 2005 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Sabry | 2009 | High risk | High risk | Low risk | Low risk | Low risk | Low risk | Low risk |
Sesso | 1994 | Unclear risk | Unclear risk | High risk | Low risk | Low risk | Unclear risk | Low risk |
Steinberg | 1971 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Sundel/Sandel | 2008 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Wallace | 1998 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk | Unclear risk |
Yee | 2004 | Low risk | Unclear risk | Low risk | Low risk | Low risk | High risk | Low risk |
Li | 2012 | Unclear risk | Unclear risk | High risk | High risk | High risk | Unclear risk | Low risk |
Yap | 2012 | Unclear risk | Unclear risk | High risk | High risk | High risk | Unclear risk | Unclear risk |
Stoenoiu | 2012 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | High risk | Unclear risk | Unclear risk |
Chen | 2012 | Low risk | Low risk | High risk | High risk | High risk | Unclear risk | Unclear risk |
Arends (long term FU of Dutch Lupus study) | 2012 | Low risk | Low risk | Low risk | Low risk | Low risk | Low risk | Unclear risk |
Sundel (report of induction and maintenance phases of ALMS study) | 2012 | Low risk | Low risk | Low risk | Unclear risk | Low risk | Low risk | Unclear risk |
Walsh (post-hoc subgroup analysis of ALMS) | 2013 | Low risk | Low risk | Low risk | Unclear risk | Low risk | Low risk | Unclear risk |
PetrI | 2010 | Low risk | Unclear | High risk | High risk | Low risk | Unclear risk | Low risk |
Zeher | 2011 | Low risk | Low risk | High risk | High risk | High risk | Unclear risk | High risk |
Dooley | 2011 | Unclear risk | Unclear risk | Unclear risk | Unclear risk | High risk | Unclear risk | High risk |
Treatment efficacy: complete/partial renal remission/response
Treatment | Reference | Odds ratio (95 % CrI) | Relative risk (95 % CrI) | Risk difference % (95 % Crl) |
---|---|---|---|---|
CYC | PRED |
2.35 (1.28, 4.23)
|
1.60 (1.60, 2.24)
|
0.21 (0.06, 0.34)
|
MMF |
3.26 (1.57, 6.72)
|
1.82 (1.82, 2.60)
|
0.28 (0.11, 0.44)
| |
TAC |
2.51 (1.11, 5.76)
|
1.64 (1.64, 2.44)
|
0.22 (0.03, 0.41)
| |
CSA |
5.69 (2.02, 17.61)
|
2.15 (2.15, 3.18)
|
0.40 (0.17, 0.58)
| |
CYC LD | CYC |
0.32 (0.10, 0.89)
|
0.51 (0.51, 0.95)
|
−0.26 (−0.45, −0.03)
|
CYC LD | MMF |
0.23 (0.08, 0.61)
|
0.45 (0.45, 0.81)
|
−0.34 (−0.53, −0.12)
|
CYC HD |
0.40 (0.20, 0.74)
|
0.65 (0.65, 0.89)
|
−0.22 (−0.38, −0.07)
| |
CSA | AZA |
3.20 (1.04, 10.19)
|
1.53 (1.53, 2.39)
|
0.26 (0.01, 0.47)
|
CYC LD | TAC |
0.30 (0.09, 0.91)
|
0.50 (0.50, 0.95)
|
−0.28 (−0.50, −0.02)
|
PLASMA | CSA |
0.19 (0.04, 0.92)
|
0.49 (0.49, 0.97)
|
−0.38 (−0.66, −0.02)
|
CYC LD |
0.13 (0.03, 0.52)
|
0.38 (0.38, 0.76)
|
−0.45 (−0.69, −0.15)
| |
CYC HD |
0.23 (0.06, 0.72)
|
0.55 (0.55, 0.87)
|
−0.33 (−0.57, −0.08)
| |
CYC HD |
0.23 (0.06, 0.72)
|
0.55 (0.55, 0.87)
|
−0.33 (−0.57, −0.08)
| |
Random-effects model | Residual deviance | 82.2 vs. 77 data points | ||
Deviance information criteria | 389.332 | |||
Fixed-effects model | Residual Deviance | 88.8 vs. 77 data points | ||
Deviance information criteria | 390.488 |
Treatment failure: renal relapse/renal flare
Treatment | Reference | Odds ratio (95 % CrI) | Relative risk (95 % CrI) | Risk difference % (95 % Crl) |
---|---|---|---|---|
AZA | PRED | 0.33 (0.08, 1.23) | 0.50 (0.17, 1.12) | −0.24 (−0.47, 0.05) |
MMF |
0.17 (0.04, 0.67)
|
0.29 (0.09, 0.78)
| −0.34 (−0.53, −0.09) | |
CYC |
0.18 (0.05, 0.58)
|
0.31 (0.11, 0.71)
| −0.33 (−0.51, −0.12) | |
CSA | 0.24 (0.03, 1.60) | 0.39 (0.07, 1.26) | −0.29 (−0.52, 0.11) | |
CYC + AZA | 0.32 (0.05, 1.67) | 0.48 (0.10, 1.29) | −0.25 (−0.50, 0.12) | |
MMF-AZA | 0.41 (0.03, 5.46) | 0.58 (0.07, 1.83) | −0.20 (−0.51, 0.36) | |
MMF | AZA |
0.51 (0.32, 0.87)
|
0.59 (0.38, 0.90)
| −0.10 (−0.20, −0.02) |
CYC | 0.55 (0.24, 1.26) | 0.62 (0.32, 1.21) | −0.09 (−0.26 0.03) | |
CSA | 0.74 (0.18, 2.95) | 0.80 (0.23, 2.01) | −0.04 (−0.23, 0.23) | |
CYC + AZA | 0.95 (0.27, 3.09) | 0.96 (0.34, 2.11) | −0.01 (−0.19, 0.24) | |
MMF-AZA | 1.23 (0.14, 12.15) | 1.16 (0.19, 3.76) | 0.04 (−0.25, 0.53) | |
CYC | MMF | 1.06 (0.44, 2.58) | 1.05 (0.51, 2.29) | 0.01 (−0.13, 0.12) |
CSA | 1.43 (0.32, 6.17) | 1.33 (0.36, 3.81) | 0.04 (−0.12, 0.35) | |
CYC + AZA | 1.84 (0.51, 6.00) | 1.62 (0.56, 3.85) | 0.08 (−0.07, 0.35) | |
MMF-AZA | 2.39 (0.27, 23.30) | 1.94 (0.31, 6.94) | 0.13 (−0.12, 0.63) | |
CSA | CYC | 1.35 (0.27, 6.52) | 1.27 (0.31, 3.86) | 0.04 (−0.14, 0.37) |
CYC + AZA | 1.72 (0.44, 6.37) | 1.53 (0.49, 3.83) | 0.08 (−0.09, 0.3) | |
MMF-AZA | 2.24 (0.24, 23.15) | 1.85 (0.28, 6.46) | 0.13 (−0.13, 0.63) | |
CYC + AZA | CSA | 1.27 (0.20, 8.09) | 1.20 (0.30, 5.35) | 0.03 (−0.29, 0.35) |
MMF-AZA | 1.67 (0.13, 25.89) | 1.43 (0.19, 8.68) | 0.08 (−0.31, 0.62) | |
MMF-AZA | CYC + AZA | 1.30 (0.22, 9.13) | 1.20 (0.28, 3.68) | 0.04 (−0.01, 0.46) |
Random-effects model | Residual deviance | 32.06 vs. 28 data points | ||
Deviance information criteria | 146.869 | |||
Fixed-effects model | Residual deviance | 34.31 vs. 28 data points | ||
Deviance information criteria | 147.018 |
Amenorrhea/ovarian failure
Treatment | Reference | OR (95 % CrI) | RR (95 % CrI) | RD % (95 % Crl) |
---|---|---|---|---|
CYC | PRED |
3.81 (1.26, 14.31)
|
2.64 (1.18, 7.51)
|
0.25 (0.04, 0.47)
|
MMF | 0.48 (0.09, 3.04) | 0.52 (0.11, 2.58) | −0.07 (−0.23, 0.13) | |
AZA | 2.74 (0.26, 28.27) | 2.12 (0.30, 8.18) | 0.17 (−0.15, 0.65) | |
CYC LD | 9.06 (0.63, 121.50) | 3.79 (0.68, 11.71) | 0.45 (−0.06, 0.81) | |
MMF | CYC |
0.13 (0.03, 0.41)
|
0.20 (0.05, 0.56)
| −0.31 (−0.47, −0.16) |
AZA | 0.69 (0.09, 5.08) | 0.79 (0.14, 1.95) | −0.08 (−0.37, 0.36) | |
CYC LD | 2.23 (0.23, 23.20) | 1.46 (0.34, 2.71) | 0.19 (−0.27, 0.55) | |
AZA | MMF | 5.25 (0.78, 54.39) | 3.68 (0.81, 19.08) | 0.22 (−0.02, 0.68) |
CYC LD |
16.35 (1.97, 247.70)
|
6.49 (1.72, 30.95)
|
0.50 (0.06, 0.87)
| |
CYC LD | AZA | 3.20 (0.55, 21.24) | 1.69 (0.68, 6.12) | 0.22 (−0.11, 0.60) |
Random-effects model | Residual deviance | 15.93 vs. 17 data points | ||
Deviance information criteria | 72.233 | |||
Fixed-effects model | Residual deviance | 16.16 vs. 17 data points | ||
Deviance information criteria | 72.069 |
Bone marrow toxicity: cytopenia (including leucopenia)
Treatment | Reference | OR (95 % CrI) | RR (95 % CrI) | RD % (95 % Crl) |
---|---|---|---|---|
CYC SD | MMF |
2.16 (1.14, 4.03)
|
1.99 (1.13, 3.37)
|
0.07 (0.01, 0.16)
|
AZA SD |
2.42 (1.01, 7.07)
|
2.19 (1.01, 5.06)
|
0.09 (0.00, 0.27)
| |
CYC LD |
5.31 (1.26, 24.65)
|
4.03 (1.23, 10.11)
|
0.22 (0.02, 0.56)
| |
CYC HD |
5.36 (1.95, 18.08)
|
4.06 (1.81, 8.96)
|
0.22 (0.07, 0.48)
| |
RTX + MMF SD | 3.50 (0.61, 23.14) | 2.95 (0.63, 9.43) | 0.14 (−0.03, 0.56) | |
AZA SD | CYC SD | 1.11 (0.39, 4.03) | 1.09 (0.44, 3.07) | 0.01 (−0.11, 0.22) |
CYC LD | 2.45 (0.51, 13.07) | 2.01 (0.56, 5.91) | 0.15 (−0.08, 0.50) | |
CYC HD | 2.47 (0.77, 9.99) | 2.03 (0.80, 5.38) | 0.15 (−0.04, 0.43) | |
RTX + MMF SD | 1.63 (0.26, 11.77) | 1.49 (0.30, 5.31) | 0.07 (−0.13, 0.49) | |
CYC LD | AZA SD | 2.16 (0.42, 10.83) | 1.80 (0.49, 5.39) | 0.13 (−0.12, 0.47) |
CYC HD | 2.20 (0.56, 8.96) | 1.83 (0.65, 5.16) | 0.13 (−0.10, 0.40) | |
RTX + MMF SD | 1.43 (0.18, 11.42) | 1.33 (0.23, 5.33) | 0.05 (−0.21, 0.48) | |
CYC HD | CYC LD | 1.01 (0.29, 3.75) | 1.01 (0.46, 2.74) | 0.00 (−0.28, 0.24) |
RTX + MMF SD | 0.66 (0.06, 7.15) | 0.74 (0.12, 3.78) | −0.07 (−0.48, 0.40) | |
RTX + MMF SD | CYC HD | 0.65 (0.08, 5.36) | 0.73 (0.13, 2.81) | −0.08 (−0.41, 0.37) |
Random-effects model | Residual deviance | 31.43 vs. 33 data points | ||
Deviance information criteria | 165.076 | |||
Fixed-effects model | Residual deviance | 38.78 vs. 33 data points | ||
Deviance information criteria | 167.984 |