Medication Summary
Corticosteroids are used in all patients with clinically significant renal disease. Immunosuppressive agents, particularly cyclophosphamide, azathioprine, and mycophenolate mofetil, are used in patients with aggressive renal lesions because they improve the renal outcome. They may also be used in patients with inadequate response or excessive toxicity to corticosteroids. Cyclosporine and tacrolimus have been used in some cases.
Corticosteroids
Class Summary
Corticosteroids are very useful in controlling acute inflammatory manifestations of systemic lupus erythematosus (SLE). Alone, they may be adequate in treating milder forms of lupus nephritis with a lower risk of progressive renal dysfunction, such as minimal mesangial lupus nephritis, mesangial proliferative lupus nephritis, early focal lupus nephritis, or membranous lupus nephritis. Oral corticosteroids can be used in most patients. If adequate absorption is a concern (eg, bowel edema in a patient with nephrosis), intravenous (IV) methylprednisolone can be used.
Prednisone
Prednisone is commonly used to treat inflammatory manifestations of SLE. Treatment of clinically significant lupus nephritis should include moderate-to-high doses initially.
Methylprednisolone (Medrol, Solu-Medrol, A-Methapred)
Methylprednisolone is used in much the same manner as prednisone. It is more potent: 4 mg of methylprednisolone is equivalent to 5 mg of prednisone. Intravenous dosing is used in the inpatient setting.
Immunosuppressives
Class Summary
In particular, cyclophosphamide, mycophenolate, and azathioprine are used in patients with aggressive renal lesions (eg, focal or diffuse lupus nephritis) because they improve renal outcome. These agents can also be used in patients with inadequate response or excessive toxicity to corticosteroids. Mycophenolate mofetil has been shown to be effective for treatment of lupus nephritis. Mycophenolate mofetil was found to be superior to azathioprine in maintaining control and preventing relapses of lupus nephritis in patients who have responded to induction therapy. [62]
Cyclophosphamide
Cyclophosphamide is indicated for treatment of most patients with focal lupus nephritis or diffuse lupus nephritis. Although it has significant toxicity, it has been shown to prevent the progression of nephritis and improve renal outcome.
Azathioprine (Imuran, Azasan)
Azathioprine is useful in moderate-to-severe lupus nephritis. It improves renal outcome, but it does not appear to be as effective as cyclophosphamide, although it is less toxic.
Mycophenolate mofetil (CellCept) or mycophenolic acid (Myfortic)
Mycophenolate mofetil is an option for induction therapy with class III/IV lupus nephritis. It has generally been well tolerated and, in several studies, has been as effective as (and possibly more effective than) more traditional therapies, including cyclophosphamide and azathioprine, with less toxicity. The American College of Rheumatology guidelines recommend mycophenolate mofetil as the preferred agent for African Americans and Hispanics.
Hydroxychloroquine (Plaquenil)
The exact anti-inflammatory mechanism of action of hydroxychloroquine is not well understood. Its effect is thought be related to increasing the pH within intracellular vacuoles, which alters protein degradation by acidic hydrolases in the lysosomes and assembly of macromolecules in the endosomes and the Golgi apparatus. Acidic pH is required for protein antigen processing for presentation on antigen-presenting cells with MCH class II receptors. The ultimate effect of hydroxychloroquine is to reduce antigen presentation by antigen-presenting cells to CD4- positive T lymphocytes, resulting in downregulation of the immune response. The American College of Rheumatology guidelines recommend that all patients with SLE and nephritis be treated with a background of hydroxychloroquine, unless contraindicated.
Monoclonal Antibodies
Belimumab (Benlysta)
Monoclonal antibody blocks the binding of BLyS (a B-cell survival factor) to B-cells. It inhibits the survival of B-cells and reduces B-cell differentiation into immunoglobulin-producing plasma cells. It is indicated for the treatment of active lupus nephritis in adults who are receiving standard therapy.
Rituximab (Rituxan, Riabni, Rituximab-abbs)
Monoclonal chimeric antibody directed against CD20 and induces a long-lasting B-cell depletion. Rituximab has been used as off-label treatment for lupus nephritis. It is recommended by EULAR/ERA-EDTA as an alternative option for nonresponsive class III to V lupus nephritis.
Calcineurin Inhibitors
Class Summary
Through the inhibition of calcineurin, these therapies reduce cytokine activation, block interleukin IL-2 expression and T-cell mediated immune responses.
Cyclosporine (Gengraf, Neoral, Sandimmune)
Cyclosporine inhibits production and release of interleukin II and interleukin II-induced activation of resting T-lymphocytes. Use is not approved by the FDA but recommended by EULAR/ERA-EDTA as an alternative option for pure class V lupus nephritis.
Tacrolimus (Astagraf XL, Envarsus XR, Hecoria)
Tacrolimus is an immunosuppressive agent that inhibits of calcineurin-induced dephosphorylation of synaptopodin, a critical protein that regulates actin filaments of the podocyte cytoskeleton. Use is not approved by the FDA but recommended by EULAR/ERA-EDTA as an alternative option for pure class V lupus nephritis.
Voclosporin (Lupkynis)
Novel high potency calcineurin-inhibitor reduces T-cell activation and stabilizes podocytes, which protect against proteinuria. First oral therapy approved in combination with immunosuppressive therapy for lupus nephritis
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Mesangial proliferative lupus nephritis with moderate mesangial hypercellularity. International Society of Nephrology/Renal Pathology Society 2003 class II (×200, hematoxylin-eosin).
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Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×100, hematoxylin-eosin).
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Focal lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class III (×200, immunofluorescence).
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Diffuse lupus nephritis with hypertensive vascular changes. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
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Diffuse lupus nephritis with early crescent formation. International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
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Diffuse lupus nephritis with extensive crescent formation (rapidly progressive glomerulonephritis). International Society of Nephrology/Renal Pathology Society 2003 class IV (×200, hematoxylin-eosin).
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Membranous lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, hematoxylin-eosin).
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Membranous lupus nephritis showing thickened glomerular basement membrane. International Society of Nephrology/Renal Pathology Society 2003 class V (×200, silver stain).
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Advanced sclerosis lupus nephritis. International Society of Nephrology/Renal Pathology Society 2003 class VI (×100, hematoxylin-eosin).
Tables
Gene Locus |
Gene Name |
Gene Product |
1p13.2 |
PTPN22 |
Lymphoid-specific protein tyrosine phosphatase |
1q21-q23 |
CRP |
CRP |
1q23 |
FCGR2A, FCGR2B |
FcγRIIA (R131), FcγRIIB |
1q23 |
FCGR3A, FCGR3B |
FcγRIIIA (V176), FcγRIIIB |
1q31-q32 |
IL10 |
IL-10 |
1q36.12 |
C1QB |
C1q deficiency |
2q32.2-q32.3 |
STAT4 |
Signal transducer and activator of transcription 4 |
2q33 |
CTLA4 |
Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) |
6p21.3 |
HLA-DRB1 |
HLA-DRB1: DR2/*1501, DR3/*0301C1q deficiency |
6p21.3 |
C2, C4A, C4B |
C2, C4 deficiencies |
6p21.3 |
TNF |
TNF-a (promoter, -308) |
10q11.2-q21 |
MBL2 |
Mannose-binding lectin |
CRP = C-reactive protein; HLA = human leukocyte antigen; IL = interleukin; TNF = tumor necrosis factor. |
||
Class I Minimal mesangial lupus nephritis |
Light microscopy findings |
Normal |
Immunofluorescence electron microscopy findings |
Mesangial immune deposits |
|
Clinical manifestations |
Mild proteinuria |
|
Class II Mesangial proliferative lupus nephritis |
Light microscopy findings |
Purely mesangial hypercellularity or mesangial matrix expansion with mesangial immune deposits |
Immunofluorescence electron microscopy findings |
Mesangial immune deposits; few immune deposits in subepithelial or subendothelial deposits possible |
|
Clinical manifestations |
Mild renal disease such as asymptomatic hematuria or proteinuria that usually does not warrant specific therapy |
|
Class III Focal lupus nephritis Class III (A) Active lesions - Focal proliferative lupus nephritis Class III (A/C) Active and chronic lesions - Focal proliferative and sclerosing lupus nephritis Class III (C) Chronic inactive lesions - Focal sclerosing lupus nephritis |
Light microscopy findings |
Active or inactive focal, segmental, or global glomerulonephritis involving < 50% of all glomeruli |
Immunofluorescence electron microscopy findings |
Subendothelial and mesangial immune deposits |
|
Clinical manifestations |
Active generalized SLE and mild-to-moderate renal disease with hematuria and moderate proteinuria in many patients; worsening renal function in significant minority, potentially progressing to class IV lupus nephritis |
|
Class IV Diffuse lupus nephritis Class IV-S (A) Active lesions - Diffuse segmental proliferative lupus nephritis Class IV-G (A) Active lesions - Diffuse global proliferative lupus nephritis Class IV-S (A/C) Active and chronic lesions - Diffuse segmental proliferative and sclerosing lupus nephritis Class IV-G (A/C) Active and chronic lesions - Diffuse global proliferative and sclerosing lupus nephritis Class IV-S (C) Chronic inactive lesions with scars - Diffuse segmental sclerosing lupus nephritis Class IV-G (C) Chronic inactive lesions with scars - Diffuse global sclerosing lupus nephritis |
Light microscopy findings |
Active or inactive diffuse, segmental or global glomerulonephritis involving = 50% of all glomeruli; subdivided into diffuse segmental (class IV-S) when = 50% of involved glomeruli have segmental lesions (involving less than half of glomerular tuft) and diffuse global (class IV-G) when = 50% of involved glomeruli have global lesions |
Immunofluorescence electron microscopy findings |
Subendothelial immune deposits |
|
Clinical manifestations |
Clinical evidence of renal disease including hypertension, edema, active urinary sediment, worsening renal function, and nephrotic range proteinuria in most cases; active extrarenal SLE in many patients |
|
Class V Membranous lupus nephritis |
Light microscopy findings |
Diffuse thickening of glomerular basement membrane without inflammatory infiltrate; possibly, subepithelial deposits and surrounding basement membrane spikes on special stains, including silver and trichrome; may occur in combination with class II or IV; may show advanced sclerosis |
Immunofluorescence electron microscopy findings |
Subepithelial and intramembranous immune deposits; subendothelial deposits present only when associated proliferative component is present |
|
Clinical manifestations |
Clinical and laboratory features of nephrotic syndrome, usually without manifestations of active SLE |
|
Class VI Advanced sclerosis lupus nephritis |
Light microscopy findings |
Advanced glomerular sclerosis involving = 90% of glomeruli, interstitial fibrosis, and tubular atrophy, all morphological manifestations of irreversible renal injury |
Clinical manifestations |
Significant renal insufficiency or end-stage renal disease in most cases; unlikely to respond to medical therapy |
|
SLE = systemic lupus erythematosus. |
||
Activity Index |
Chronicity Index |
• Endocapillary hypercellularity with or without leukocyte infiltration; luminal reduction • Karyorrhexis • Fibrinoid necrosis • Rupture of glomerular basement membrane • Cellular or fibrocellular crescents • Subendothelial deposits on light microscopy • Intraluminal immune aggregates |
• Glomerular sclerosis; segmental, global • Fibrous adhesion • Fibrous crescents |
