Is there any literature directly comparing voclosporin with other calcineurin inhibitors, such as tacrolimus or cyclosporine, for the treatment of active lupus nephritis? Additionally, are there any head-to-head studies comparing voclosporin with belimumab in the treatment of lupus nephritis? If not, what about case series, case reports, and meta analysis?

Comment by InpharmD Researcher

Direct head-to-head trials comparing voclosporin with tacrolimus, cyclosporine, or belimumab for active lupus nephritis are lacking, with comparative evidence primarily derived from indirect comparisons in network meta-analyses. Available analyses generally support renal efficacy with voclosporin-, tacrolimus-, and belimumab-containing regimens, although findings regarding the relative efficacy of voclosporin and tacrolimus have varied, and indirect comparisons have not demonstrated a significant difference between voclosporin and belimumab. Comparative evidence involving cyclosporine is particularly limited. Additional evidence is limited to case reports describing favorable renal responses following the replacement of voclosporin with cyclosporine and belimumab with voclosporin, respectively; however, conclusions regarding comparative efficacy cannot be established from these individual cases. An additional comprehensive literature search identified a network meta-analysis and 2 case series but did not materially change the overall conclusions. No direct head-to-head comparisons were identified; the additional evidence was limited to indirect comparisons, a 16-patient case series of concomitant voclosporin and belimumab, and a 3-patient case series of voclosporin following inadequate response to belimumab.

PubMed and Google Scholar were searched using combinations of “voclosporin,” “tacrolimus,” “cyclosporine,” “belimumab,” and “lupus nephritis.” Relevant head-to-head studies, meta-analyses, case series, and case reports were reviewed.

Background

A 2026 network meta-analysis evaluated calcineurin inhibitor (CNI)–based regimens in lupus nephritis, including 16 randomized controlled trials (RCTs) with 1,994 patients through March 1, 2025 (voclosporin [VOC] in 2 trials, tacrolimus [TAC] in 9, cyclosporine A [CsA] in 5). Every included trial compared a CNI-based regimen against a non-CNI comparator (steroid alone or with cyclophosphamide, mycophenolate mofetil [MMF], or azathioprine); no trial randomized patients between two different CNIs, and both VOC trials compared VOC + MMF + prednisone against MMF + prednisone. All VOC-versus-TAC and VOC-versus-CsA estimates were therefore indirect. VOC + MMF + steroid ranked highest for complete and total remission, followed by TAC + MMF + steroid, but the differences between these two regimens were not statistically significant for either outcome. Infection was the only safety outcome showing significant between-regimen differences, with VOC-based therapy ranking least favorably. The authors identified reliance on indirect evidence, treatment of "CNI" as a single class node, and predominance of Asian populations as key limitations, and recommended that future analyses model VOC, TAC, and CsA separately once head-to-head data become available. Belimumab was not among the interventions evaluated. [1]

A 2025 network meta-analysis evaluated 40 RCTs involving 5,450 patients and 17 initial treatment regimens for active lupus nephritis, using mycophenolic acid analogues (MPAA) as the common comparator. Compared with MPAA alone, complete renal response was increased with voclosporin + MPAA (risk ratio [RR] 1.90; 95% confidence interval [CI] 1.47–2.47; high-certainty evidence), belimumab + MPAA (RR 1.47; 95% CI 1.23–1.74; high-certainty evidence), and tacrolimus + MPAA (RR 1.54; 95% CI 1.14–2.07; low-certainty evidence), while evidence for cyclosporine was very low certainty, with an uncertain effect on complete renal response. Overall renal response was also increased with voclosporin + MPAA (RR 1.35), belimumab + MPAA (RR 1.29), and tacrolimus + MPAA (RR 1.24). Tacrolimus + MPAA was associated with increased infections versus MPAA (RR 1.71; low-certainty evidence), while voclosporin + MPAA was associated with a smaller increase in infections (RR 1.14; moderate-certainty evidence) and a trivial effect on severe infections; belimumab + MPAA had a trivial to no effect on severe or serious adverse events. Most comparisons among voclosporin, tacrolimus, cyclosporine, belimumab, and other active treatments relied on indirect evidence rather than head-to-head trials. [2]

A 2024 network meta-analysis evaluated 10 RCTs involving 1,989 adults with lupus nephritis and compared biologic therapies, multitarget therapy consisting of tacrolimus + MMF + glucocorticoids, and standard therapy for induction treatment. Compared with standard therapy, complete renal remission was higher with multitarget therapy (odds ratio [OR] 2.78; 95% CI 1.81–4.26), voclosporin 23.7 mg (OR 2.61; 95% CI 1.79–3.79), voclosporin 39.5 mg (OR 1.90; 95% CI 1.07–3.37), and belimumab (OR 1.75; 95% CI 1.13–2.70); multitarget therapy ranked highest for complete renal remission, followed by voclosporin 23.7 mg, while belimumab ranked lower. Total renal remission was also higher than standard therapy with multitarget therapy (OR 3.20; 95% CI 1.98–5.19), voclosporin (OR 2.16; 95% CI 1.40–3.34), and belimumab (OR 1.56; 95% CI 1.07–2.27). No statistically significant differences among treatment regimens were observed for serious adverse events or serious infections. Comparisons between voclosporin, tacrolimus-based multitarget therapy, and belimumab were primarily indirect, and the authors stated that direct head-to-head trials were lacking. [3]

A 2025 network meta-analysis compared belimumab (BEL), rituximab (RTX), and voclosporin (VOC) in lupus nephritis, searching PubMed, Embase, Web of Science, the Cochrane Register, and ClinicalTrials.gov through October 2024. Five registered RCTs enrolling 1,212 subjects were included (Rovin 2012, Rovin 2019, Furie 2020, Rovin 2021/AURORA 1, Saxena 2024/AURORA 2), yielding six network nodes: VOC 23.7 mg at 1 year, VOC 39.5 mg at 1 year, VOC 23.7 mg at 2 years, BEL at 2 years, RTX at 1 year, and placebo. Per the inclusion criteria and Table 1, each trial compared its active agent against placebo added to background therapy; the only direct active-versus-active edge in the network was between the two VOC doses within the three-arm dose-ranging trial. For complete renal remission, SUCRA rankings were VOC-1Y (93.3%) > high-dose VOC-1Y (64.7%) > VOC-2Y (60.8%) > BEL-2Y (58.5%) > placebo (14.9%) > RTX-1Y (7.8%); all interventions except RTX were significantly superior to placebo, and VOC-1Y was significantly superior to RTX-1Y (OR 3.20; 95% CI 1.41–7.24). The VOC-versus-BEL comparison was not statistically significant (OR 1.49, 95% CI 0.84–2.65). For safety, placebo was superior to high-dose VOC for adverse events (OR 0.23, 95% CI 0.07–0.82); no significant differences were found for serious adverse events. The authors noted that with only five trials the effect estimates were imprecise, the SUCRA rankings unstable, and the conclusions preliminary. No calcineurin inhibitor other than VOC was evaluated. [4]

A 2021 network meta-analysis assessed four RCTs involving 936 patients and compared voclosporin + MMF, tacrolimus + MMF, and MMF or cyclophosphamide monotherapy as induction treatment for lupus nephritis. Tacrolimus + MMF was associated with a higher complete remission rate than monotherapy (OR 2.85; 95% credible interval [CrI] 1.87–4.39), while voclosporin + MMF was also associated with higher complete remission than monotherapy (OR 1.99; 95% CrI 1.35–2.97). Tacrolimus + MMF appeared to be more efficacious than voclosporin + MMF (OR 1.43; 95% CrI 0.80–2.57) and ranked highest for efficacy (surface under the cumulative ranking curve [SUCRA] 0.942), followed by voclosporin + MMF (SUCRA 0.558). For safety, monotherapy ranked highest, followed by voclosporin + MMF and tacrolimus + MMF, with no statistically significant differences in serious adverse events between monotherapy and either combination. The authors concluded that both CNI-based combination regimens were more effective than monotherapy, although additional head-to-head studies are needed to better establish their relative efficacy and safety. [5]

A 2026 Bayesian network meta-analysis of 12 RCTs indirectly compared triple immunosuppressive regimens for active and severe lupus nephritis, including 2,797 patients in the efficacy analysis and 2,963 patients in the safety analysis; no head-to-head trials directly comparing these regimens were identified. Standard of care (SOC) plus voclosporin did not significantly differ from SOC plus tacrolimus (benefit ratio [BR] 1.13; 95% credible interval [CrI] 0.77–1.66) or SOC plus belimumab (BR 1.28; 95% CrI 0.90–1.85) for primary renal remission, although voclosporin ranked second behind tacrolimus according to SUCRA probabilities (82.27% vs 95.12%). Serious adverse events and serious infectious events did not significantly differ among the evaluated immunosuppressive therapies. These findings represent indirect comparisons based on aggregate trial-level data rather than direct head-to-head evidence; observational studies, including case series and case reports, were excluded. [6]

Literature Review

A search of the published medical literature revealed 4 studies investigating the researchable question:

Level of evidence

C - Multiple studies with limitations or conflicting results Read more→

Please see Tables 1-4 for your response.

Two-Hour Post-dose (C2)-Monitored Cyclosporine Microemulsion as a Practical Alternative to Voclosporin in Mixed Class IV/V Lupus Nephritis: A Case Report
Design	Case report
Case presentation	A 43-year-old man with hypertension, prediabetes, stage 2 chronic kidney disease, and nephrotic-range proteinuria presented with progressive generalized edema and was diagnosed with mixed class IV/V lupus nephritis on kidney biopsy. Initial treatment included mycophenolate mofetil (MMF) 1.5 g twice daily, hydroxychloroquine, losartan, empagliflozin, and glucocorticoids; voclosporin 23.7 mg twice daily was subsequently added for persistent nephrotic-range proteinuria (UPCR 4.6 g/g), but after approximately 2 months, UPCR remained 4.9 g/g with stable kidney function and voclosporin was discontinued due to insurance coverage denial. Cyclosporine microemulsion was then initiated at 250 mg twice daily and subsequently adjusted using 2-hour post-dose concentrations to a target of 600–800 ng/mL, with early supratherapeutic concentrations prompting dose reductions. After 5 months of cyclosporine microemulsion therapy with continued background treatment, UPCR decreased from 4.9 to 0.47 g/g and complement levels normalized, while serum creatinine remained stable at approximately 1.3 mg/dL; blood pressure, serum magnesium, and blood glucose also remained stable during follow-up.
Study Author Conclusions	In this patient with mixed class IV and V lupus nephritis, C2-guided cyclosporine microemulsion therapy, in combination with mycophenolate, tapering glucocorticoids, angiotensin receptor blockade, and SGLT2 inhibition, was associated with complete proteinuric remission, normalization of complement levels, and preservation of kidney function. This fully oral, non-depletive regimen avoided exposure to cytotoxic and B-cell-depleting therapies. While the observed response is biologically plausible based on established calcineurin-mediated immunologic and podocyte-stabilizing mechanisms, conclusions regarding equivalence or generalizability cannot be drawn from a single case. C2-guided cyclosporine may represent a pragmatic, individualized alternative in selected patients when access to voclosporin is limited, warranting further systematic evaluation.

Table 1 References:
[7] Akella D, Ramoutar V. Two-Hour Post-dose (C2)-Monitored Cyclosporine Microemulsion as a Practical Alternative to Voclosporin in Mixed Class IV/V Lupus Nephritis: A Case Report. Cureus. 2026;18(1):e102585. Published 2026 Jan 29. doi:10.7759/cureus.102585

Voclosporin Treatment of Proliferative Lupus Nephritis in Childhood: A Case Report
Design	Case series
Case presentation 1	A 15-year-old female with newly diagnosed systemic lupus erythematosus presented with hair loss, malar and photosensitive rashes, arthritis, peripheral swelling, fatigue, hypoalbuminemia, hematuria, and a urine protein-to-creatinine ratio (UPCR) of 8 mg/mg. Kidney biopsy demonstrated class IV lupus nephritis with 43% cellular crescents, an NIH activity index of 15/24, and a chronicity index of 3/12. Following 3 intravenous methylprednisolone doses, she received prednisone 60 mg daily, mycophenolate mofetil 600 mg/m² twice daily, lisinopril 5 mg daily, hydroxychloroquine 4 mg/kg/day, and voclosporin 23.7 mg twice daily; her UPCR decreased from 2.45 mg/mg at voclosporin initiation to 0.55 mg/mg after 2 months, and prednisone was discontinued approximately 5 months after voclosporin initiation. Repeat biopsy approximately 10 months after diagnosis showed resolution of active disease, no progression of chronicity, improvement to class III lupus nephritis, and no evidence of calcineurin inhibitor toxicity; voclosporin was discontinued at 1 year, and she remained in remission on mycophenolate mofetil, lisinopril, and hydroxychloroquine approximately 2 years after diagnosis.
Case presnetation 2	A 12-year-old female presented with systemic lupus erythematosus, macrophage activation syndrome, hepatitis, pancreatitis, Streptococcus pneumoniae and Staphylococcus aureus sepsis, and Pseudomonas aeruginosa cellulitis. Kidney biopsy performed approximately 6 weeks later demonstrated class IV lupus nephritis with an NIH activity index of 12/25 and a chronicity index of 1/12, after which mycophenolate mofetil and belimumab were added to corticosteroid therapy. Because of persistent proteinuria, belimumab was discontinued and replaced with voclosporin 1.5 months later; at the time of this change, the UPCR was 3.5 mg/mg and the patient was receiving prednisone 50 mg daily. Within 1 month of starting voclosporin, proteinuria resolved and complement concentrations normalized, and prednisone was gradually tapered and discontinued 7.5 months after voclosporin initiation; blood pressure remained normal, with no hyperkalemia, new abdominal symptoms, or acute kidney injury reported.
Study Author Conclusions	In conclusion, we present 2 pediatric patients with LN treated with voclosporin with minimal side effects. UPCs decreased, renal function and blood pressures remained stable, and both patients were able to discontinue steroids. Because these patients were treated with a combination of medications, the specific effect of the voclosporin relative to the other medications remains uncertain; however, we speculate that the voclosporin contributed to the clinical and laboratory improvement observed in both patients. Further research is required to evaluate the efficacy, optimal dosing, and adverse effect profile of voclosporin in pediatric LN.

Table 2 References:
[8] Cody EM, McCord S, Fair D, Simon N, Gallan AJ, Nocton JJ. Voclosporin treatment of proliferative lupus nephritis in childhood: a case report. Kidney Int Case Rep. Published online May 28, 2026. doi:10.1016/j.kintcr.2026.100037

Case Series of the Combination of Voclosporin and Belimumab Treatment of Lupus Nephritis
Design	Retrospective case series N= 16
Objective	To assess the safety and clinical effectiveness of dual therapy using voclosporin and belimumab in individuals with lupus nephritis confirmed via kidney biopsy
Study Groups	All patients (n= 16)
Inclusion Criteria	Age ≥18 years; diagnosis of systemic lupus erythematosus by ACR or SLICC criteria; active renal disease (proteinuria UPCR >0.5 g/g and/or active urinary sediment, and/or histologic activity); initiation of combination therapy; at least 6 months of follow-up data
Exclusion Criteria	Pregnancy or lactation; baseline eGFR <30 mL/min/1.73 m2; concurrent participation in interventional clinical trials; uncontrolled infection; inadequate clinical data
Methods	Medical records were reviewed for 16 consecutive eligible patients treated at the Johns Hopkins University rheumatology and nephrology clinics between 2012 and 2025. Belimumab was administered according to its labeling at 10 mg/kg IV or 200 mg SC weekly; voclosporin was initiated at 23.7 mg orally twice daily, with dose adjustments. Background therapy included MMF or mycophenolic acid, oral glucocorticoids, hydroxychloroquine, and renin-angiotensin-aldosterone system blockade. Baseline was defined as the laboratory value closest to the first kidney biopsy; peak UPCR was the highest value before initiation of combined therapy, and nadir UPCR was the lowest value after both agents were started. Demographics, lupus nephritis class, previous and concomitant treatments, UPCR, serum creatinine, eGFR, complement levels, anti-dsDNA antibodies, and urine microscopy were collected. Follow-up assessments occurred at months 1, 3, and 6 and quarterly thereafter. Longitudinal laboratory values were synchronized with medication start and end dates and summarized as medians with IQRs; paired comparisons were performed using the Wilcoxon signed-rank test, with p<0.05 considered statistically significant.
Duration	2012 to 2025
Outcome Measures	Primary: Reduction in proteinuria (UPCR) Secondary: Improvement in serologic markers (C3, C4, anti-dsDNA), steroid sparing effect
Baseline Characteristics	The case series included 16 female patients with biopsy-proven lupus nephritis, with a median age of 36 years (range, 17–50); 56.2% were African American, 25.0% were White, and 18.8% were Asian. The median time since systemic lupus erythematosus diagnosis was 5.0 years (interquartile range [IQR] 3.0–9.0), and kidney biopsy classes included IV/V in 31.2%, V in 25.0%, III in 25.0%, II in 12.5%, and II/V in 6.2%. Median baseline UPCR was 1.06 g/g (IQR, 0.41–2.67), serum creatinine was 0.77 mg/dL (IQR 0.68–0.93), anti-dsDNA was 203.5 IU/mL (IQR 20.5–305.0), C3 was 65.0 mg/dL (IQR 47.3–88.6), and C4 was 6.50 mg/dL (IQR 4.82–21.0). At the first kidney biopsy, all patients were receiving mycophenolate, hydroxychloroquine, and glucocorticoids; 31.2%, 25.0%, and 18.8% were also receiving azathioprine, tacrolimus, and cyclophosphamide, respectively.
Results	Following initiation of voclosporin plus belimumab, median UPCR decreased from a pre-combination peak of 2.175 g/g (IQR 1.073–5.639) to a post-combination nadir of 0.082 g/g (IQR 0.058–0.198; p< 0.0001) and remained reduced at final follow-up at 0.131 g/g (p= 0.00058). Median C3 increased from 65.0 to 109.5 mg/dL (p= 0.00085), median C4 increased from 6.5 to 20.5 mg/dL (p= 0.00191), and median anti-dsDNA decreased from 51.5 to 12.0 IU/mL among 12 patients with paired measurements (p= 0.00195). Median serum creatinine increased from 0.77 to 0.89 mg/dL (p= 0.0437), while 10 of 16 patients (62.5%) tapered corticosteroids to ≤5 mg/day or discontinued them. No patients were hospitalized for lupus flares or infections during responsive combination therapy.
Adverse Events	No patients were hospitalized for lupus flares or infections during the responsive combination therapy.
Study Author Conclusions	This retrospective case series suggests that combined voclosporin and belimumab therapy may be associated with sustained renal remission and corticosteroid reduction in patients with proliferative and membranous LN. The regimen was associated with a rapid decline in proteinuria, a median nadir UPCR of 0.082 g/g, modest overall decline in kidney function, and normalization of complement levels in many patients. Notably, 62% of patients were able to taper to minimal corticosteroid doses or discontinue steroids altogether. These preliminary findings support the potential benefit of this multi-targeted approach, but confirmation in larger, controlled prospective studies is needed.
Critique	This case series provides directly relevant clinical experience with concomitant voclosporin and belimumab, including longitudinal renal and serologic measurements and corticosteroid use. However, it does not provide a head-to-head comparison of voclosporin versus belimumab or versus another calcineurin inhibitor; its small, uncontrolled, single-center design, concurrent background therapies, treatment interruptions, and transitions to other agents prevent the observed outcomes from being attributed specifically to the voclosporin-belimumab combination.

Table 3 References:
[9] Timlin H, Koirala A, Geetha D. Case series of the combination of voclosporin and belimumab treatment of lupus nephritis. Glomerular Dis. 2026;6:208-215. doi:10.1159/000552239.

Voclosporin for the Treatment of Lupus Nephritis Flares in Patients with Inadequate Response to Mycophenolate Mofetil and Belimumab: A Case Series
Design	Case series
Case presentation 1	A woman in her late thirties with a 10-year history of Sjögren syndrome was evaluated for new-onset lower-extremity edema and found to have serum creatinine of 5.3 mg/dL, proteinuria that increased from 6 to 13.3 g/day, active urinary sediment, hypertension, low C3, and class IV-G (A) lupus nephritis (LN) on kidney biopsy. Following methylprednisolone and cyclophosphamide induction, serum creatinine improved to 1.24 mg/dL; maintenance mycophenolate mofetil (MMF) 2 g/day plus belimumab subsequently reduced proteinuria to 1.09 g/day after approximately 9 months. Two months later, proteinuria increased to 4.6 g/day despite stable kidney function, prompting glucocorticoid treatment and replacement of belimumab with voclosporin while MMF was continued. Proteinuria decreased to 0.7 g/day after 2 months, 0.5 g/day after 7 months, and 0.36 g/day after 12 months, with serum creatinine stabilizing at 1.33 mg/dL and inactive urinary sediment.
Case presentation 2	A man in his mid-forties with myasthenia gravis and systemic lupus erythematosus was found to have proteinuria of 2.4 g/day, active urinary sediment, positive anti-dsDNA antibodies, preserved kidney function, and biopsy-confirmed class III (A) lupus nephritis (LN). Methylprednisolone, MMF, and an angiotensin-converting enzyme inhibitor reduced proteinuria to 0.8 g/day at 6 months; however, a subsequent flare occurred after belimumab was added to MMF, and a Chlamydia pneumoniae infection was followed by LN reactivation characterized by proteinuria of 4.5 g/day, elevated anti-dsDNA antibodies, hypocomplementemia, and slightly reduced kidney function. After the infection resolved, the patient received methylprednisolone, resumed MMF 2 g/day, and initiated voclosporin in place of belimumab. Proteinuria decreased to 3.87 g/day at 1 month, 1.67 g/day at 3 months, and 1.10 g/day at 6 months; at 1 year, kidney function remained stable, and no treatment-limiting adverse events were observed.
Case presentation 3	A woman in her early forties with a 2-year history of systemic lupus erythematosus developed proteinuria of 2.5 g/day after 6 months of belimumab, with preserved kidney function and biopsy-confirmed class III (A) LN. Despite discontinuation of belimumab and treatment with methylprednisolone and MMF 3 g/day, proteinuria remained 2.7 g/day at 6 months; belimumab was subsequently resumed for persistent arthritis and episcleritis, after which proteinuria worsened to 5.9 g/day. Belimumab was again discontinued, and voclosporin was initiated with MMF 2 g/day when proteinuria was 5 g/day and serum creatinine was 0.97 mg/dL. Proteinuria progressively decreased to 1.7, 1.4, 0.7, and 0.1 g/day at 3, 6, 9, and 12 months, respectively, with normalization of urinary sediment; a mild increase in serum creatinine improved from a peak of 1.41 to 0.98 mg/dL after voclosporin dose adjustment.
Study Author Conclusions	LN flares significantly increase the risk of progression to kidney failure, underscoring the need for timely, targeted interventions. Voclosporin, a next-generation calcineurin inhibitor, exerts both immunomodulatory and podocyte-stabilizing effects and has demonstrated rapid and sustained reductions in proteinuria when combined with MMF. Our experience suggests that voclosporin is an effective option for inducing renal response in patients with LN nephrotic flare and prior belimumab failure. Most recently, the advent of obinutuzumab, a B-cell depleting agent, is expected to become a reasonable alternative with possible advantages in non-responders.

Table 4 References:
[10] Bertola R, Silvagni E, Scichilone L, Pollicelli E, Govoni M, Bortoluzzi A. Voclosporin for the treatment of lupus nephritis flares in patients with inadequate response to mycophenolate mofetil and belimumab: a case series. J Nephrol. Published online August 12, 2026. doi:10.1093/joneph/aajag126.