See also: Drug targetting under “Pharmacology”
Introduction:
Systemic lupus erythematosus (SLE) is a complex autoimmune disease with multisystem involvement. It is multifactorial and involves epigenetic, genetic, ecological, and environmental factors. Primarily it leads to activation of both innate and adaptive immunity, which consequently leads to autoreactive B cell activation by T cells and leads to immune complexes deposition in tissues leading to an autoimmune cascade that may be limited to the single organ or can cause a widespread systemic involvement. SLE is heterogeneous in presentation, with a broad spectrum of clinical manifestations ranging from clinically mild self-resolving symptoms to severe life-threatening organ involvement. See Hashim
Lupus Nepthritis also known as “membranous glomerulonephritis” refers to an inflammation of the kidney caused by the chronic autoimmune disease SLE. Those afflicted with lupus nephritis may or may not have renal symptoms, but the disease can manifest itself through weight gain, high blood pressure, darker foamy urine or swelling around the eyes, legs, ankles or fingers. In some cases, the only renal manifestation of the disease is painless hematuria or proteinuria, but in some cases patients develop lupus nephritis, leading to acute or end stage renal failure.
Symptoms/Clinical Features:
This condition has a broad spectrum of clinical features ranging from mild cutaneous involvement to severe organ damage, such as kidney failure, pulmonary hypertension, and cardiac failure. The diagnosis of SLE is based on clinical and laboratory findings. The improved classification criteria used by the European League Against Rheumatism (EULAR) and the American College of Rheumatology (ACR) serve as the most advanced and precise criteria to date.
SLE exhibits a broad spectrum of presentations ranging from mild symptoms to severe, life-threatening conditions. Adults diagnosed before 50 years of age usually present with cutaneous symptoms (malar rash) and renal abnormalities (lupus nephritis), displayed higher 10-year survival, and reported using more immunosuppressive therapy than patients getting diagnosed after 50 years of age.
Preclinical lupus (PL) is a phase in developing SLE when the patient is at higher risk of developing SLE but is found asymptomatic on presentation. However, autoantibodies are mostly detectable in these patients’ serum. Antinuclear antibody (ANA), hematological and immunological disorders, arthritis, and cutaneous manifestations were among the most presented symptoms of PL syndrome. Therefore, a significant proportion of preclinical lupus (approximately 10% to 20%) often transitions to SLE.
Pathology
Systemic lupus erythematosus (SLE) is a multisystem chronic autoimmune disease with a relapsing and remitting course. Its prevalence is higher in women of child bearing age, with a female predominance of 9:1. The exact etiology of this disease is not understood well. However, it has been demonstrated that environmental and genetic factors interact to trigger immune responses resulting in the excessive production of pathogenic autoantibodies by the B cells and cytokines dysregulation leading to tissue and organ damage. SLE is characterized by the presence of antibodies to nuclear and cytoplasmic antigens. Furthermore, other autoantibodies might be present in SLE patients, such as anti-Scl-70 antibodies (present in systemic sclerosis), anti-La, and anti-Ro antibodies (present in Sjogren disease), anticardiolipin antibodies, and anti-phospholipid antibodies thus indicating a wide association between SLE and other autoimmune diseases. See Hashim
Complement is known to be involved in eitology and progression of renal inflammation and lupus nephritis. Complement cascade proteins and their proteolytically generated fragments (i.e., fragments of C3 and C4) are deposited on the glomerulocapillary, mesangial and tubulointerstitial cells during may types of renal injury. Renal biopsies are routinely stained for deposits of C3 activation fragments (C3b/iC3b/C3d) and glomerualr C3 deposits are found in most forms of glomerulonephritis (Sargsyan, Kidney International (2012) 81, 152-159
Diagnosis
Biopsy: The most commonly used system for classifying the different histologic patters of lupus nephritis is based upon the appearance of glomeruli by light microscopy. Percutaneous renal biopsy is the gold standard for diagnosis of lupus nephritis and for monitoring the course of disease.
Noninvasive detection of C3 fragments in the kidneys:
Complement activation is central to the pathogenesis of many inflammatory and autoimmune diseases. It is also a robust marker of tissue inflammation since activation of the complement system leads to the rapid covalent linkage of multiple c3b, iC3b, and C3d molecules to cell surfaces. Immunostaining for tissue C3 fragments is routinely performed on kidney biopsy samples when patients are suspected of having an autoimmune disease and when the presence of flomerular C3 deposits indicates active glomerulonephritis. (Serkova, Radiology, 255(2), 2010).
targeted CR2-Fc-SPIO fusion proteins: Thurman (US 13/148028; see also Sargsyan, Kidney International (2012) 81, 152-159) disclose conjugating superparagmentic iron oxide (SPIO) particles and ultrasmall SPIO particles conjugated with complement receptor type 2 (CR2)-Fc which can be used as negative contrast agents for MRA for the detection of intra-renal C3b/iC3b/C3d deposits in the kidneys of mouse models for lupus nepthritis. Interestingly, CR2-targeted SPIO reduced T2 relaxation times occured in the inner medulla of the mice kidneys, in spit of the fact that this is little C3b/iC3b/C3d at this location. The authors explain this result that during intra-renal trafficking of CR2 targeted SPIO, the CR2 interaction may trap them within the diseased kidney.
Treatment
The management of SLE is challenging and requires a multidisciplinary approach. The treatment algorithm is based on the severity of the diseases and the organs involved. Though the disease affects multiple systems, the course may vary in individuals depending on the severity, the number of flare-ups, and remission. Life expectancy may be reduced depending on the significant organ involvement, such as kidneys, lungs, and heart. Otherwise, with close follow-up, around 80% to 90% of patients with SLE may have an average life expectancy.
Steroids: Patients with active proliferative nephritis are usually treated with steroids in combination with cytotoxic agents or mycophenolate mofetil.
B-cell Activator Factor/B-lymphocyte stimulator (BLyS) Inhibitors:
–Benlysta (belimumab -Glaxo Smith): is an anti-BLyS monocloanl antibody for systemic lupus erythematosus and lupus nephritis. Overactive B cell responses are seen in autoimmune diseases such as systemic lupus erythematosus. Belimumab binds to BAFF and prevents it from binding to B cells. Without BAFF, B cells commit suicide and no longer contribute to the autoimmune damage of systemic lupus erythematosus.
CD19 and CD20 Targeted T cell engager:
–CMG1A46: is a dual CD19 and CD20 targeted T cell engager for lupus and related auto-immune conditions. GSK plc (LSE/NYSE: GSK) and Chimagen Biosciences (Chimagen), a privately held biotechnology company, signed an agreement for GSK to acquire CMG1A46, a clinical-stage dual CD19 and CD20-targeted T cell-engager (TCE), from Chimagen for $300 million upfront. GSK plans to develop and commercialise CMG1A46 with a focus on B cell-driven autoimmune diseases, such as systemic lupus erythematosus (SLE) and lupus nephritis (LN), with potential to expand into related autoimmune diseases.