Background/Purpose

To compare renal remission rates with immunosuppressives by performing a systematic review and network meta-analyses (NMA) of RCTs of lupus nephritis.

Methods

We performed a systematic review and NMA of randomized trials of patients with lupus nephritis, who were treated with immunosuppressant alone or in combination with other immunosuppressant or biologics  (such as rituximab or belimumab) compared with another immunosuppressant with/without biologic or placebo.  We compared the rates of complete renal remission or partial renal remission. Complete renal remission was usually defined as return to normal serum creatinine, urine protein ≤0.5 g/d, and inactive urinary sediment  (≤5 white blood cells per high-power field and ≤5 red blood cells per high-power field, and a reading of lower than 2+ on dipstick and absence of red cell casts).  Partial remission was variably defined in the studies, with the most common definition of improvements in urinary parameters between 25-50%.  Bayesian NMA were conducted. A binomial likelihood model, which allows for the use of multi-arm trials was used. Informed priors were assigned for basic parameters and odds ratios, as well as risk ratios and risk differences, and 95% credible intervals were modeled using Markov chain Monte Carlo methods. Brooks-Gelman-Rubin plots were used to assess model convergence. Model fit was examined using the deviance information criterion (DIC) and the residual deviance. The degree of inconsistency was assessed by comparing statistics for the deviance and deviance information criterion in fitted consistency and inconsistency models. In further sensitivity analyses, fixed effects models and models using vague priors were also conducted.

Results

39 RCTs with 2,730 patients provided data; 35 were 2-arm RCTs and 4 were 3-arm RCTs. Comparisons showed that cyclophosphamide  (CYC), mycophenolate mofetil  (MMF), tacrolimus  (TAC), cyclosporine  (CSA) and MMF+TAC were superior to prednisone alone in achieving renal remission  (Table 1).  Compared to MMF, CYC HD and PRED were less likely to lead to renal remission.  Compared to AZA, TAC and MMF+TAC were superior. MMF+TAC was superior to MMF-AZA, CYC-AZA, CYC HD, CYC LD MMF+RTX and LEF in leading to renal remission.

Conclusion

Our NMA compared the ability of immunosuppressive medications and combinations to lead to remission (complete and/or partial) in RCTs of patients with lupus nephritis. Comparative effectiveness of medications is now available to assist treatment decision-making, with the caveats of trial heterogeneity and indirect comparisons.  

 

Table 1. Comparison of various drugs for the renal remission  (complete or partial) in patients with lupus nephritis showing statistically significant results
Treatment	Reference	Odds Ratio     (95% Credible Interval [CrI])	Relative Risk     (95% CrI)	Risk Difference %   (95% Crl)
CYC	PRED	2.31  (1.30, 4.22)	1.58  (1.16, 2.23)	20.17  (6.34, 34.07)
MMF		3.12  (1.57, 6.53)	1.79  (1.28, 2.57)	27.31  (10.94, 43.19)
TAC		2.42  (1.10, 5.70)	1.61  (1.06, 2.42)	21.30  (2.18, 40.50)
CSA		5.74  (2.02, 17.24)	2.14  (1.44, 3.15)	40.06  (17.03, 57.38)
MMF+TAC		27.98  (4.96, 199.00)	2.65  (1.91, 3.88)	57.83  (36.83, 70.77)
CYC LD	CYC	0.29  (0.10, 0.78)	0.48  (0.20, 0.89)	-27.97  (-45.30, -6.08)
PRED HD		0.10  (0.02, 0.37)	0.20  (0.05, 0.57)	-43.03  (-57.32, -23.28)
CYC HD		0.51  (0.26, 0.93)	0.70  (0.43, 0.97)	-16.13  (-31.07, -1.68)
MMF+TAC		12.05  (2.41, 77.92)	1.66  (1.32, 2.22)	37.05  (18.88, 51.83)
CYC LD	MMF	0.22  (0.07, 0.56)	0.43  (0.18, 0.78)	-34.64  (-52.98, -13.94)
PRED HD		0.07  (0.02, 0.28)	0.17  (0.04, 0.51)	-49.95  (-66.00, -29.11)
MMF+TAC		9.01  (1.66, 59.84)	1.48  (1.14, 2.00)	30.01  (9.85, 47.21)
TAC	AZA	1.41(0.69,3.00)	1.17(0.83,1.70)	8.25(-8.84,25.97)
PRED HD		0.13  (0.03, 0.53)	0.23  (0.06, 0.68)	-35.66  (-53.97, -13.53)
MMF+TAC		16.26  (2.87, 115.10)	1.92  (1.37, 3.00)	44.39  (21.99, 62.90)
MMF+TAC	TAC	11.48  (2.04, 79.76)	1.63  (1.20, 2.45)	35.83  (13.57, 55.76)
PLASMA	CSA	0.19  (0.04, 0.88)	0.50  (0.19, 0.96)	-37.43  (-66.07, -2.86)
CYC LD		0.12  (0.03, 0.45)	0.36  (0.14, 0.71)	-47.26  (-70.23, -18.60)
PRED HD		0.04  (0.01, 0.20)	0.15  (0.04, 0.45)	-62.69  (-81.20, -35.30)
CYC HD		0.21  (0.06, 0.63)	0.52  (0.29, 0.82)	-35.63  (-57.84, -11.18)
MMF+TAC	PLASMA	26.12  (3.20, 251.20)	2.51  (1.36, 6.41)	55.26  (22.09, 79.93)
MMF+TAC	CYC LD	41.94  (6.24, 350.20)	3.46  (1.76, 9.19)	65.20  (37.15, 84.18)
CYC HD	PRED HD	5.26  (1.38, 19.97)	3.55  (1.24, 12.49)	26.44  (6.39, 44.36)
LEF HD		6.86  (1.17, 43.02)	4.04  (1.12, 16.45)	32.60  (2.50, 65.59)
MMF+TAC		126.80  (14.94, 1266.00)	8.54  (2.76, 35.22)	81.06  (54.12, 93.36)
MMF+RTX		11.14  (2.15, 64.45)	5.16  (1.61, 21.04)	44.52  (14.61, 71.13)
MMF+TAC	CYC HD	23.82  (4.25, 172.00)	2.37  (1.57, 4.35)	53.32  (30.63, 72.30)
MMF+TAC	LEF HD	18.21  (2.20, 180.10)	2.03  (1.17, 5.75)	46.59  (12.63, 77.20)
MMF+TAC	CYC-AZA	26.24  (2.75, 286.40)	2.50  (1.22, 8.94)	54.99  (15.47, 83.42)
MMF+TAC	MMF-AZA	29.26  (2.21, 449.80)	2.69  (1.13, 15.55)	57.31  (10.56, 88.09)
MMF+RTX	MMF+TAC	0.09  (0.01, 0.64)	0.62  (0.32, 0.92)	-34.81  (-63.87, -7.03)

CYC HD = 500-1000 mg/m² qmon x 6 mons; CYC LD = 500-1000 mg/m² qmon x 3 mons; PRED HD = 1000mg/m²qd x 3mons then qmon for 1 year; PRED = 20-60 mg qd x 1-3 mons then 10-20 mg qd

MMF+TAC= MMF plus TAC; MMF+RTX = MMF plus RTX; CYC-AZA = CYC followed by AZA; MMF-AZA = MMF followed by AZA

---

« Back to 2014 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/rates-of-renal-remission-with-immunosuppressives-in-lupus-nephritis-a-systematic-review-and-network-meta-analysis/