An initial literature search identified 630 potential articles for review, of which 32 were found to address the use of IVIg in lupus nephritis (). Several treatment regimens using different dosages have been reported, most commonly 400
mg/kg/day for 4-5 daily doses (high dose, standard dosing for ITP), although 400
mg/kg/dose 1 × monthly, or 85
mg/kg/day for 4-5 days (low dose), has also been described. In SLE patients, there is no published data on how long exogenous Ig remains present after administration, and there is a lack of consensus on dosing intervals and the duration of therapy. Most publications fail to specify the source of IVIg administered, which precludes analysis of individual preparation methods. As has been pointed out before, comparison of outcomes between studies is hampered by counting day 1 as first day of treatment, or the day of kidney biopsy, rather than first day of symptoms [24
Studies identified in review of literature on IVIG therapy for lupus nephritis.
The short-term effects of IVIg were reported initially in 1989 in three patients with mild SLE who had been treated with 300–500
mg/kg/dose, 1 dose every 4 weeks [26
]. Although this low dose had been effective in some autoimmune neurological diseases, the immediate effects on auto-Ab titers in these SLE patients were modest. When the high-dose regimen (400
mg/kg/day for 5 days) was used, greater reductions in auto-Ab titers were noted [26
]. In a cohort study from Germany, 12 patients with mild-to-moderate disease given 2 courses of high-dose IVIG had a decline in anti-dsDNA Abs within 1 week. Antinuclear antibodies and complement protein levels were not affected. Within 6 weeks, improvements were noted in clinical disease activity scores which lasted 5 to 12 months [27
]. In an Israeli cohort study, clinical disease scores were also improved in 62 patients receiving low-dose IVIg (~500
mg/kg/dose once every 5 ± 2 weeks for a mean of 6 doses) [28
]. Unsatisfactory responses were noted for thrombocytopenia, alopecia, vasculitis, and proteinuria. Based on these reports, dosage appears to be important.
Several case reports were identified describing the use of IVIg for various nonrenal manifestations of SLE. The results described were encouraging () but have infrequently led to larger prospective trials [29
]. Benefits in treating cutaneous lupus have not been reproducible [40
]. Cohorts (n
= 26) with autoimmune hemolytic anemia [41
] and with thrombocytopenia (n
= 59) [42
] have been published and showed short-term benefits without sustained responses. Positive effects on achievement of live births have been reported in pregnant women with SLE and antiphospholipid antibodies after treatment with IVIg [38
], but randomized controlled trials demonstrated equivalency or even inferiority of IVIg compared to heparin and aspirin [43
]. However, investigators continue to search for subsets of SLE patients who will benefit from IVIg, and clinicians continue to prescribe it for SLE patients who fail initial therapy regimens. In a cohort study from Israel, 20 patients with SLE and organ specific disease involvement were treated with 1–8 courses of high-dose IVIg [46
]. Improvements in clinical disease scores, hypocomplementemia, and autoantibody titers were seen in 80% of patients. However, when looking at organ specific response rates, the improvements were seen more in CNS disease, arthritis, fever, and thrombocytopenia than in proteinuria.
Initial case reports of IVIg therapy of SLE manifestations.
Few studies have followed their patients for long term. A 2012 study from Israel followed patients for a mean of 30 months after initiating therapy [47
]. Eleven patients with SLE were treated with high-dose IVIG monthly for 6 months, followed by additional courses given every 2-3 months. At latest followup, 6 patients had complete remission, 3 had partial remissions, and 2 patients were nonresponders, defined by improvements in clinical disease scoring. In responders, IVIG had a significant steroid-sparing effect. Adverse effects were reported in 18% of patients during their first course of IVIg, and 50% of all patients treated. Common adverse effects included headache, fatigue, nausea, visual disturbances, and limb pain. Adverse effects resulted in truncation of 8 courses, and two patients suffered severe effects (seizure, pulmonary embolus).
3.1. Salvage Therapy of Refractory Lupus Nephritis
Most studies identified that reported efficacy of IVIg in lupus nephritis restricted entry to patients who had failed their initial induction therapy of IV corticosteroids and cytotoxic agents. Twelve case reports were identified (). The first cases were published in 1982 in Japan, with subsequent cases from Europe and North America [37
]. Patients received 1 or 2 courses of high-dose IVIg in combination with corticosteroids, with or without plasma exchange or cytotoxic agents. By biopsy, the responders had class II, III, IV, or V nephritis. Patients recovered renal function with reductions in proteinuria and reduced immune deposits on repeat biopsy.
Studies included in IVIg therapy for lupus nephritis.
Two cohort studies of high-dose IVIg were identified. In an Israeli cohort, 7 patients with biopsy proven class IV or V nephritis were treated with 1 to 6 courses of high-dose IVIg after failing therapy with IV cyclophosphamide and prednisone [56
]. All patients had nephrotic syndrome. All 7 experienced decreases in proteinuria and improvement or resolution of nephrotic syndrome. One patient had a complete remission which persisted at least three years. Only one patient had a relapse, which occurred 4 months after discontinuation of the IVIg [56
]. In an Italian cohort study, 12 treatment refractory patients with SLE were treated with 6–24 monthly courses of high-dose IVIg [57
]. A progressive clinical improvement was observed in 11 patients, associated with increases complement protein levels and decreases in auto-Abs, and marked improvements in renal function and proteinuria.
One cohort study was identified that used a longer course of lower-dose IVIg. In a Bulgarian cohort study of patients with all forms of treatment refractory chronic glomerulonephritis, better outcomes were reported in the 58 patients who had SLE [58
]. All patients were treated with a low-dose IVIg regimen, 85
mg/kg/day on alternate days, for a total of three days, repeated quarterly for up to 7 years. At the conclusion of the study, 30% of the patients with lupus nephritis achieved full remission (unchanged or improved renal function, resolution of nephrotic syndrome, and proteinuria <0.5
gram/day) and 40% patients achieved partial remission (unchanged or improved renal function, improvement in nephrotic syndrome, and proteinuria <1.5
gram/day). Of nonresponders, nearly all died or survived with end-stage renal disease (ESRD), indicating the severity of disease in this cohort. Reported adverse effects were fever, chills, nausea, vomiting, headache, and rash, and none occurred in more than 10% of individuals.
Additional cohort studies were identified which involved important subsets of patients with SLE. One study demonstrated efficacy of a single course of IVIg in three patients with acute kidney injury from combined inflammatory nephritis and thrombotic microangiopathy [59
]. The only study of IVIg treatment in patients with ESRD involved 2 patients with symptomatic SLE on dialysis treated with high-dose IVIg [60
]. Both patients demonstrated clinical and serologic improvement and tolerated the IVIg administration well. There were only transient declines in serum albumin concentrations noted, which might reflect saturation of neonatal FcRs that protect albumin from lysosomal degradation [75
]. In the only report of IVIg use in children with lupus nephritis, 9 children with biopsy-proven class IV or V nephritis were treated with high-dose IVIg [61
]. These children had not responded to pulse methylprednisolone or intravenous cyclophosphamide. Five of 8 with class IV nephritis saw marked improvement in renal function and decreases in IgG deposits on repeat biopsy, while the remaining three experienced a reduction in their class of nephritis. The sole patient with class V disease had a partial renal response. Occasional fever, chills, hypotension, and rash were reported in these cohorts, but overall prevalence of adverse effects is unclear from the literature.
Overall, the response rates to the various IVIg regimens are promising. However, all of the studies were uncontrolled trials that leave open the possibility that these patients would have done just as well without the IVIg, as there is known to be delayed benefits of IV solumedrol, IV cyclophosphamide, azathioprine, and other immunosuppressants.
3.2. Use of IVIg as Part of Induction Therapy for Lupus Nephritis
Only a few studies were identified that treated lupus nephritis with IVIg as part of the initial therapy. The numbers of patients treated are small, and the doses administered tended to be lower. One case report reported efficacy and safety in a patient with a complement deficiency [62
]. As part of the 1999 cohort study from Israel mentioned above, 5 of the 20 patients treated with 1–8 courses of high-dose IVIg had renal involvement, ranging from mild proteinuria or nephrotic syndrome [46
]. Improvements in renal disease were noted, but were inferior to those reported in the CNS disease, arthritis, and thrombocytopenia. Patients with nephritis in the 2008 cohort study also showed some response: resolution of urinary casts in 88% of patients, but of proteinuria in only 20% [28
]. Conversely, An Italian cohort of three patients with renal flare failed to respond to 2 courses of high-dose IVIg and steroids [63
In a randomized study of 14 patients with class IV lupus nephritis, IVIg was compared to intravenous cyclophosphamide [64
]. Five patients received low-dose IVIg (400
mg/kg) monthly for eighteen months. Nine patients received cyclophosphamide 1
IV every two months for six months, then every three months for twelve months. The method of randomization was not described, and it is unclear if there was any dropout after randomization. Patients could also be treated with prednisone at the physicians' discretion. After the 18-month treatment period, a marked improvement in renal function (both serum creatinine and creatinine clearance) was noted in both groups. IVIg was not shown to be inferior to this dose of IV cyclophosphamide. However, IVIg had a modest steroid sparing effect over cyclophosphamide.
The utility of IVIg as first line therapy for lupus nephritis, therefore, remains unclear. No study has compared IVIg to the most commonly used IV cyclophosphamide regimens (NIH, Eurolupus protocols) or to mycophenolate. In addition, no study of IVIg as add on therapy with any of these induction regimens has been published.
3.3. The Use of IVIg as Maintenance Therapy for Lupus Nephritis
No studies were identified using IVIg as a maintenance therapy for lupus nephritis.
3.4. Adverse Effects of IVIg in SLE
Most patients with SLE and nephritis tolerated their IVIg therapies. However, deterioration of renal function following IVIG treatment has been recognized [65
]. A CDC report cited 120 cases of nephrotoxicity worldwide, with only 26% of cases occurring in patients with preexisting renal disease [72
]. Incidence has been reported in 10–33% of some cohorts [65
]. Determining the etiology of acute kidney injury in patients with SLE can be challenging. The majority of nephrotoxicity cases prior to 2000 (90%) have been attributed to IVIg preparations utilizing the stabilizers maltose and sucrose. Intracellular accumulation of these sugars leads to cellular swelling and vacuole formation in tubular epithelial cells of the kidney [74
]. Additional risk factors for renal toxicity following IVIG therapy include age >70 years, renal impairment pre-treatment, and diabetes mellitus [73
]. In addition to the risk of AKI, IVIg was associated with renal flares [74
]. The risk appears to be greater in children, as 3 of 6 patients treated with IVIg in one pediatric cohort from Toronto developed renal flare [71
]. Patients with anti-phospholipids or other thrombophilias should receive aspirin therapy to minimize risks for thrombosis associated with infusions of IVIg [67
]. Mild adverse reactions of IVIg are common and include infusion reactions, headache, dermatitis, hepatitis, pseudo-hyponatremia, neutropenia, and aseptic meningitis [47
]. Infusion reactions typically respond to slowing down the infusion rate, and the other reactions respond to withdrawal of IVIg infusions. Headaches are less frequent when high dose IVIg is given 400
mg/kg/day over 5 days than when given 1
gm/kg/day over 2 days [46
Finally, the choice of IVIg preparation can be influenced by the SLE patient's comorbidities. In SLE patients with impaired glucose tolerance or diabetes mellitus, preparations with sucrose or maltose should be avoided to minimize risk of hyperglycemia. Patients with nephrotic syndrome or edema should receive more concentrated Ig preparations, whereas patients with renal insufficiency should receive preparations with lower osmolalities. In SLE patients with effective IgA deficiency, the use of IVIg preparations with higher levels is contraindicated as it can result in severe hypersensitivity and anaphylaxis.