Lupus Clinical Overview
H. Michael Belmont, M.D.
Medical Director, Hospital for Joint Diseases
New York University Medical Center
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MANAGEMENT
The management of lupus renal disease ultimately should be based on risk stratification and the prognostic information available clinically or by renal biopsy. WHO Class I lupus nephritis which is defined by normal histologic findings requires no specific therapy.
CLASS II-MESANGIAL
Class II-A mesangial lupus nephritis with mesangial deposition of immunoglobulin if unaccompanied by proteinuria and active urinary sediment does not require treatment. Class II-B mesangial lupus nephritis when accompanied by significant proteinuria (e.g.: greater than 1 gram per day) usually requires treatment with steroids, especially if accompanied by hematuria, leukocyturia, other evidence of active urinary sediment, elevated anti-double stranded DNA, or low C3. These patients may be treated with between .5 and 1 mg/kg of prednisone or equivalent per day for from four to twelve weeks. Subsequently, steroids are tapered by 5-10 mg. increments every 1-3 weeks.
CLASS III and IV-PROLIFERATIVE
The initial treatment of Class III and IV, focal and diffuse proliferative nephritis, is controversial. Many clinicians, including the author, recommend therapy of the first episode with prednisone, 1 mg/kg per day or equivalent, for from four to twelve weeks. For those patients who have a significant response with reduction in proteinuria, leukocyturia, hematuria, anti-DNA levels and resolution of hypocomplementemia, steroids are tapered at one to two week intervals by initially 10 and then 5 mg increments. In the absence of ongoing active renal disease, these patients are monitored for recurrence of active lupus renal disease. For late and infrequent relapses attempts at remission with additional courses of prednisone is considered. For an incomplete response as well as early or frequent relapses cyclophosphamide is initiated Figure 1.
Some clinicians, however, recommend cyclophosphamide contemporaneously with prednisone for Class III or Class IV disease, especially in the presence of moderate to high activity and elevated chronicity biopsy scores. Cyclophosphamide is administered at a dose of between .5 and 1 gram per m2 of body surface monthly for six months. Each subsequent dose is titrated upward or downward by 10-25% to achieve a nadir white blood cell count at 10-14 days of approximately 3,500 per cubic millimeter. Cyclophosphamide is typically administered with between four to 24 hours of intravenous hydration to avoid hemorrhagic cystitis. Those centers who use abbreviated intravenous hydration often use two mercaptoethylamine sulfonate sodium (MESNA) to further minimize the risk of bladder toxicity. Odansetron or granesetron can be used as an anti-emetic to reduce nausea and vomiting.
Justifying the use of prednisone as first line therapy of even Class III and IV disease is the observation that remissions of proliferative nephritis have been observed with oral steroids, some with no recurrence of nephritis during follow-up periods of 30-40 years (4). Additionally, treating with prednisone alone allows for preservation of reproductive function such that pregnancies can be completed in intervals before relapsed disease requires cyclophosphamide (19). It is also notable that the efficacy of cyclophosphamide is best established in patients previously treated for their renal disease with steroids. For example, in the study by Austin et al., comparing prednisone with cyclophosphamide therapy, patient enrollment occurred only after a mean of 22 months of treatment with steroids for nephritis and 3 years for SLE. The benefits of intravenous cyclophosphamide were achieved in groups of patients failing prednisone, establishing cyclophosphamide as salvage or rescue therapy for patients unresponsive to steroids (15,16,19). The major argument against using steroids alone for proliferative nephritis, especially Class IV, is concern that any delay in initiating treatment with cyclophosphamide will permit renal scarring, which may be underestimated by serum creatinine and creatinine clearance. Therefore, treatment should be individualized accounting for the prognostic information available from the clinical or biopsy data and the relative risks of treatment in the specific circumstance.
Once initiated the duration of cyclophosphamide therapy is also individualized. For patients with a less prognostically severe biopsy and an early clinical response, cyclophosphamide can be limited to the six month induction course of treatment. Recognizing, however, Boumpas et. al. established that patients with a longer course of cyclophosphamide (i.e. 14 treatments over 30 months) had a lower incidence of relapse of nephritis, maintenance therapy consisting of the same dose of cyclophosphamide administered every three months for an additional one to two years is indicated for patients with prognostically severe biopsies (17).
Prednisone and cyclophosphamide therapy of proliferative lupus nephritis is usually effective in between 60 and 90% of patients. However, there will be patients who will prove refractory, defined as either failing to respond, or relapsing with reappearance of a nephrotic syndrome or nephritic component (i.e. hypertension and active urinary sediment) sometimes even with loss of renal function that require intensification of therapy. These patients may be treated with the resumption of monthly dosing of cyclophosphamide, the addition of higher doses of glucocorticoids which can consist of either 1 mg/kg per day of prednisone or equivalent, or pulses of methylprednisolone such as 1 gram per day for from one to three days. The combination of methylprednisolone and cyclophosphamide on a monthly basis in these patients may prove effective, although is certainly associated with the range of toxicities attributable to each of these aggressive treatments. The addition of plasmapheresis synchronized or otherwise is of uncertain benefit in this setting.
Alternative approaches to patients with proliferative nephritis would include initial therapy with prednisone plus azathioprine, prednisone followed by azathioprine, or prednisone plus cyclophosphamide during the six month induction followed by maintenance with azathioprine.
CLASS V-MEMBRANOUS
Class V membranous lupus nephritis is often treated at the outset with 1 mg/kg per day of prednisone or equivalent for six to twelve weeks. Regardless of a response, steroids are usually then discontinued. Cyclophosphamide is generally reserved for those patients who have a concurrent proliferative component with their lupus membranous nephritis and continue to have clinical features of activity which typically requires not only proteinuria but either an active urinary sediment, persistent high anti-DNA, or hypocomplementemia. Therefore, patients with lupus membranous nephropathy and persistent nephrotic syndrome who have a component of proliferative nephritis are considered for cytotoxic therapy. Patients with pure membranous nephritis and incessant nephrotic syndrome are candidates for therapy with cyclosporin (27). The dose typically is 3.5 mg to 5 mg/kg per day with close monitoring of the blood pressure and for a paradoxical effect on the serum creatinine reflective of the nephrotoxic effects of this agent.
An additional mechanism of injury in patients with lupus nephritis relates to the hypercoagulability that accompanies the anti-phospholipid antibody syndrome. These patients may develop hypertension, proteinuria, urinary sediment and abnormal renal function. These patients are candidates for therapy with anticoagulation or anti-platelet agents.
GENERAL MEASURES
Additional elements in management of lupus renal disease include the aggressive treatment of hypertension. Hypertension often accompanies proliferative lupus nephritis and can persist even after periods of active immunologic injury. Studies clearly establish that hypertension is a poor prognostic sign. Therefore, aggressive management of hypertension is required. The spectrum of antihypertensive agents have been used but there is ongoing interest in the benefit of angiotensin converting enzyme (ACE) inhibitors, especially in patients with persistent proteinuria. ACE inhibitors may have renal protective properties, as was demonstrated in the diabetic nephropathy model, over and above their antihypertensive effects.
Hypercholesterolemia may accompany the nephrotic syndrome seen both in membranous and proliferative lupus nephritis. Additionally, hypercholesterolemia may be a complication of chronic steroid management. Regardless, persistent hypercholesterolemia, especially if accompanied by elevated LDL cholesterol and diminished HDL cholesterol will promote atherosclerosis. Therefore, efforts to lower serum cholesterol are prudent, although there are no prospective controlled studies demonstrating improved outcome. It is recommended these patients follow a low cholesterol, low fat diet and when hyperlipidemia is persistent and profound receive lipid lowering agents such as the HMG Co-A reductase inhibitors.
Dietary restriction of salt is recommended in all patients with the hypertension that can accompany active lupus renal disease. Additionally, patients who have developed renal insufficiency are placed on a low protein diet to reduce the adverse effects of protein on renal hemodynamics and hyperfiltration.
Despite the best of efforts some patients will develop ESRD. Seasoned clinicians, familiar with the generally good experience with hemo and peritoneal dialysis as well as renal transplantation in lupus patients (32), recognize the need to abandon immunosuppressive therapy once advanced glomerulosclerosis has developed.
NOVEL THERAPIES
There are several experimental drugs which may improve our approach to lupus renal disease. Specific agents that are undergoing clinical investigation include LJP397, which is known as a B cell tolerogen. This is a novel therapy consisting of four oligonucleotides attached to a triethylene glycol platform, which when infused, is bound by the Fab portion of anti-DNA antibodies in the membrane of auto-reactive B cells. Cross linking of anti-DNA antibody in the cell membrane of B cells results in a down regulation of anti-DNA immunoglobulin synthesis and apoptosis of these B cells. In animal models of lupus renal disease, this approach has not only reduced the production of anti-DNA, but mitigated renal disease. Human studies have suggested that this is a non-toxic therapy and beginning in 1997 a multicenter randomized double blind study investigating its efficacy was initiated.
Additional agents that may have a role in the treatment of lupus nephritis include a monoclonal antibody to the fifth component of complement. The monoclonal anti-C5 reduces the production of C5a and C5b-9 and the inflammatory reaction which appears consequent to the generation of immune complexes in the kidney. An additional agent, anti-CD40ligand monoclonal antibody, has the ability to reduce the production of auto-antibodies. Anti-CD40ligand not only inhibits production of pathogenic antibodies but can inhibit inflammatory cytokine production and T cell dependent activation of endothelial cells.
Although lupus renal disease is clinically and histologically heterogeneous and there is no ideal study performed to date with sufficient sample size to establish the superiority of any specific mode of therapy in the treatment of lupus nephritis, an understanding of the incidence, immunopathogenesis, disease severity stratification by WHO class and NIH indices, and familiarity with the available therapeutic modalities is associated with preservation of renal function in the vast majority of patients. However, there is little doubt that novel treatment that is more effective and less toxic would be welcomed by the community of physicians responsible for the care of patients with lupus.
TABLE 2: NIH RENAL PATHOLOGY SYSTEM
| ACTIVITY INDEX | CHRONICTY INDEX |
| Glomerular abnormalities | |
| 1. Cellular proliferation | 1. Glomerular sclerosis |
| 2. Fibrinoid necrosis, karyorrhexis | 2. Fibrous crescents |
| 3. Cellular crescents | |
| 4. Hyaline thrombi, wire loops | |
| 5. Leukocyte infiltration | |
| Tubulointerstitial abnormalities | |
| 1. Mononuclear cell infiltrates | 1. Interstitial fibrosis |
| 2. Tubular atrophy |
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