LUPUS: A GP Guide to Diagnosis
The overall survival of patients with lupus nephritis has improved considerably over the last few decades; from less than 50% survival at 5 years in the 1960s to over 80% survival at 20 years in the 1990s. This improved survival is due to a combination of factors including the wider use of corticosteroids and immunosuppressants and the availability of more effective anti-hypertensive drugs, antibiotics, renal dialysis and transplantation. Early deaths from extra-renal lupus and infection are now uncommon but, instead, renal failure and cardiovascular disease have emerged as important determinants of morbidity and mortality.
Genetic factors seem to play a role in the pathogenesis of lupus. HLA-DR2, HLA-DR3, C4A null alleles and Fcy RIIa alleles have all been associated with the development of lupus. A number of clinical observations further support the genetic basis of lupus, including the increased incidence of lupus in families of individuals with the disease, racial differences in the incidence and severity of lupus and data showing a high concordance among identical twins for the disease.
The pathogenesis of lupus in general, and lupus nephritis in particular, is complex and multifactorial. Immunological dysregulation leads to the production of autoantibodies to nuclear and other cellular antigens. Tissue injury results from an immune-complex-mediated inflammatory process (as in glomerulonephritis) or from cellular dysfunction caused by autoantibodies (as in autoimmune cytopenias).
The American College of Rheumatology has published criteria for the classification of the disease rather than for use as a diagnostic tool, although in practice there is much blurring of this distinction. If 4 of the listed criteria are present at any time during the course of disease (Table 1), a diagnosis of lupus can be made with 98% specificity and 97% sensitivity.
Constitutional symptoms are common and include malaise, anorexia, fever and weight loss. Other non-specific manifestations include rashes, photosensitivity, arthritis and serositis. In many patients the disease is characterised by intermittent flares of constitutional symptoms, without evidence of major organ involvement. Involvement of major organ systems may occur in the heart, lungs, kidneys, or central nervous system (Table 2). These are responsible for most of the mortality and morbidity in this disorder. These manifestations may develop asynchronously over time and months to years may pass before it is evident that a patient has lupus.
Clinically apparent nephritis develops in about 40-75% of patients with lupus and the kidney is the organ most commonly affected. The heterogeneity of renal histology, clinical manifestations and the fluctuating and relapsing course of the disease can make diagnosis of lupus nephritis difficult. Nephritis typically develops early in the course of lupus and in most patients lupus nephritis will have appeared during the first 5 years after diagnosis.
During 1970 three major patterns of lupus nephritis based on renal histology were defined: focal proliferative, diffuse proliferative and membranous glomerulonephritis. This classification was subsequently expanded by a World Health Organisation (WHO) committee (Table 3). Patients with minimal changes or mesangial glomerulonephritis (WHO class I and II lesions) usually have an inherently low rate of progressive renal failure. Patients with membranous nephropathy (WHO class V) have an intermediate prognosis for renal function. By contrast, patients with focal or diffuse proliferative glomerulonephritis (WHO class III and IV) have a high risk of progressive renal failure.
In almost all cases, lupus nephritis develops in patients with evident lupus and extra-renal symptoms such as a rash, arthralgia, Raynaud's phenomenon and pleuro-pericarditis. Rarely, renal disease may be the presenting feature of lupus with a small number of patients subsequently, after a period of months to years, developing extra-renal signs of lupus. Proteinuria is a common finding and is often accompanied by a nephrotic syndrome. This is usually accompanied by various degrees of impairment of renal function. Microscopic haematuria is common but an acute nephrotic syndrome is not. A few patients present with a rapidly progressive glomerulonephritis which may be severe enough to lead to acute renal failure. In such patients, a diffuse crescentic nephritis often with intracapillary glomerular thrombi is often seen.
Laboratory tests are discussed in 'Testing for Lupus', however, the following should also be noted:
An elevated serum creatinine concentration indicates underlying renal involvement and has been reported as the best marker of an unfavourable outcome in renal disease. The presence of haematuria and/or proteinuria, particularly if accompanied by an active urinary sediment with red cells and casts, are suggestive of active renal disease.
Patients with lupus almost invariably express antibodies to components of the cell nucleus (ANA). A fluorescent antinuclear test is positive in greater than 95% of patients. In this test, various staining patterns (homogeneous, speckled, rim, nucleolar) can be demonstrated depending on the content of different autoantibodies in the serum. A positive fluorescent ANA test is useful because of its sensitivity, although it lacks specificity as it is also found in other connective tissue diseases. More specific but less sensitive tests include anti-double-stranded DNA (anti-dsDNA) and anti-Sm autoantibodies. Anti-DNA antibodies bind the helical backbone of native DNA, whereas anti-Sm antibodies bind to proteins on an RNA-protein complex termed a snRNP. Antibodies to double stranded DNA have the highest specificity for lupus but are only present in approx. 50% of patients. The interpretation of anti-DNA antibodies is also complicated by the lack of standardisation and currently various assays for anti-DNA antibodies are available: the most commonly used are the ELISA, Crithidia immunofluorescence assay, and the Farr radiobinding assay. These assays differ in the source of DNA and the physical chemical properties of the anti-dsDNA antibodies detected. In general, anti-dsDNA antibody levels reflect disease activity, particularly if accompanied by falling complement levels. Antinuclear and anti-dsDNA antibody levels have been less consistently related to features of active glomerulonephritis.
Patients with lupus will often have a false positive response to serological tests for syphilis such as the Venereal Disease Research Laboratory (VDRL) and rapid plasma reagin (RPR) tests because of antibodies to cardiolopin or other phospholipids. Often, antibodies to phospholipids will also interfere with clotting tests resulting in prolongation of the partial thromboplastin time. Anti-cardiolipin antibodies and/or the lupus anticoagulant are found in patients with the antiphospholipid syndrome.
Reduced serum complement concentrations are useful in diagnosis and in assessing disease activity. Many patients with lupus have activation of the classic component cascade with consumption of C1q, C4 and C3. Persistent C3 or CH50 complement depression has been associated with progression of renal disease in some, but not all, groups of patients.
Serologic abnormalities may develop many months before evidence of clinical renal involvement and should prompt close observation to detect changes in urinary sediment and protein excretion rate. Although changes in laboratory tests are extremely useful indicators of disease activity, most doctors do not base therapeutic decisions solely upon them because their sensitivity is less than absolute. Disease activity assessment in lupus must use the additional information provided by the clinical features.
A renal biopsy is justified when there is evidence of glomerular disease, particularly if this is accompanied by extra-renal features of disease. The indications for glomerular disease are a urinary sediment indicative of active nephritis (>10 dysmorphic red blood cells per high power field and/or casts of red and white blood cells), proteinuria (>200mg/24 hour) and/or renal insufficiency. Histology allows an assessment of disease activity and provides a basis for therapeutic options, as well as providing prognostic information.
Disease monitoring should always include an assessment of clinical symptoms. Objective laboratory measurements of anaemia, thrombocytopenia, leucopenia, lymphopenia, serum creatinine and creatinine clearance are useful for monitoring lupus activity. The levels of complement and autoantibodies including antinuclear antibodies, anti-dsDNA antibodies are useful markers of disease activity. Urinalysis should be performed at each visit. The persistence/emergence of haematuria and/or proteinuria should rouse the possibility of active renal disease.
The majority of patients with lupus are successfully managed with non-steroidal anti-inflammatory agents, hydroxychloroquine and low dose corticosteroids. Steroid dose is increased in response to flares and gradually tapered during periods of remission. High dose corticosteroids and immunosuppressive drugs are reserved for patients with life threatening manifestations including severe lupus nephritis, central nervous system, cardiopulmonary disease or haematological abnormalities such as thrombocytopenia.
There are several considerations in the approach to the treatment of patients with lupus nephritis. The first is based on the histological severity of the renal lesion. The second is based on the severity of the clinical presentation. The third consideration is the choice of therapy for inducing remission of acute disease and for maintaining remission and treating relapses. The heterogeneity of the clinical course of lupus nephritis and the relatively few randomised controlled trials make choice of treatment difficult and there are still substantial disagreements on the optimum treatment of lupus nephritis.
Most such patients present with proteinuria and microscopic haematuria, often with little in the way of renal impairment. There are no controlled trials to guide treatment. Patients are treated with corticosteroids in the hope that this will prevent progression to a more severe glomerulonephritis although this cannot be assured.
In patients with lupus nephritis, the frequency of membranous nephropathy is approximately 12% when the definition of the renal histology is confined to pure membranous nephropathy or with mild mesangial hypercellularity, expansion and scattered deposits (WHO classes Va and Vb). The frequency increases to approximately 26% when there is in addition a focal segmental proliferative (WHO class Vc) or diffuse proliferative glomerulonephritis (WHO class Vd). The clinical presentation is with proteinuria and, in about 50% of cases, a nephrotic syndrome. Patients with WHO class Va and Vb lesions have a low rate of progressive renal failure whilst patients with WHO class Vc or Vd lesions have higher risk of progressive renal failure that is comparable to that of patients with a proliferative glomerulonephritis. Here again, there are no controlled trials of treatment and thus there is no consensus on treatment. In some studies patients with WHO class Va and Vb have been treated with prednisolone and a smaller proportion also received methylprednisolone pulses or oral cyclophosphamide and azathioprine. By contrast, most patients with WHO class Vc and Vd have been treated with cyclophosphamide or azathioprine in addition to prednisolone. With these approaches to treatment, the 10 year survival free of death and renal failure in WHO class Va and Vb was 72-92% and in WHO class Vc and Vd was 35-81%.
It seems reasonable to treat patients with membranous nephropathy and proliferative glomerulonephritis with cyclophosphamide as well as prednisolone because of the proven efficacy of this regime in patients with proliferative lupus glomerulonephritis. Patients with pure lupus membranous nephropathy with or without minor mesangial proliferation may be treated with prednisolone and the adding of azathioprine as a corticosteroid sparing agent should be considered.
As the prognosis of patients with these types of lupus nephritis was much poorer than those of patients with mesangial proliferative glomerulonephritis and membranous nephropathy, these patients have been the focus of most of the clinical trials of treatment. In patients with severe focal proliferative or diffuse proliferative glomerulonephritis, corticosteroids alone will reduce the extra-renal manifestations but are less efficient at preserving renal function. There is now overwhelming evidence that the addition of cyclophosphamide to prednisolone confers benefit when compared with patients treated with prednisolone alone. The evidence that azathioprine confers such benefit is less good although it is considered that this agent has a role in maintaining remission. A series of clinical trials from the National Institutes of Health (NIH) provided evidence of the effectiveness of intermittent intravenous cyclophosphamide together with oral prednisolone in preserving renal function in patients with severe lupus nephritis. This regime is preferable to continuous oral cyclophosphamide as it has less bladder toxicity, although the frequency of gonadal toxicity is unaffected. It is not yet known whether pulse cyclophosphamide is less carcinogenic than continuous oral therapy. From the NIH data, monthly pulse cyclophosphamide (0.5-0.75g/m2) adjusted for the glomerular filtration rate and leucocyte count at 10-14 days is given monthly for the first 6 months, then quarterly for 18-24 months. The longer course of cyclophosphamide has been associated with fewer relapses than a shorter 6 month course. Preliminary data with pulse oral cyclophosphamide has shown encouraging results and, if validated, will minimise the inconvenience associated with intravenous therapy. To reduce the bladder toxicity of intravenous cyclophosphamide, patients should be hydrated either with oral or intravenous fluid, and 2-mercaptoethane sulfonate sodium (mesna) given concomitantly. Prednisolone is given in conjunction with the cyclophosphamide at an initial dose of (0.5-1mg/Kg/day) for 6-8 weeks with gradual tapering, preferably to an alternate day regime to minimise toxicity. This regime has been reported in detail and references must be checked prior to the use of such immunosuppressive regime.
The various drugs used in the treatment of lupus are discussed in 'Drug Therapy of Lupus', however, these additional notes are applicable to lupus nephritis.
Several studies have examined the role of plasmapheresis in the treatment of lupus patients with lupus nephritis. Although plasmapheresis was well tolerated with few adverse effects, the impact on renal function was disappointing. The controlled trials have either shown slight but insignificant benefit or no benefit of plasmapheresis.
Since removal of autoantibodies leads to a compensatory enhanced production of autoantibodies by pathogenic B-cell clones, the concept of synchronising plasmapheresis with subsequent pulse cyclophosphamide to target proliferating B-cell clones was introduced. Initial studies have shown good remission rates in patients with lupus nephritis, but patient numbers were small and the dose of cyclophosphamide used was high (1.2-1.4g/m2). Clearly, controlled trials are needed to clarify the usefulness of this synchronised approach and balance the potential therapeutic gain with the treatment-associated adverse effects. The use of such high doses of cyclophosphamide, with its adverse profile, cannot be justified without further validation. This synchronisation approach is currently being investigated in a randomised controlled study by the International Lupus Plasmapheresis Study Group.
Currently, there is limited data on the use of intravenous immunoglobulin in the treatment of lupus nephritis and as such this treatment cannot be recommended.
The nephrotoxicity of cyclosporin is a major problem and pending randomised controlled studies comparing this drug with other immunosuppressive agents, it cannot be recommended for use in lupus nephritis.
Although methotrexate may have potential benefits in mild nephritis it is renally excreted and cannot be used in patients with renal impairment.
Fish oils that are rich in eicosapentaenoic acids suppressed manifestations of lupus in murine models of lupus. Eicosapentaenoic acids and their metabolites can suppress T-cell proliferation and block the production of certain inflammatory cytokines (TNF, IL-1 and IL-2). A clear benefit of eicosapentaenoic acids has not been shown in controlled studies involving patients with lupus nephritis and cannot be recommended at present.
The observations that lupus is a disease predominantly affecting young women with a tendency to flare during pregnancy or with oral contraceptive administration, suggests that hormonal factors may be determinants of pathogenesis or severity. Attempts to control lupus by manipulating oestrogen and testosterone levels have had only modest success. Despite in vitro data, there is little evidence to support the use of androgens or anti-oestrogen in lupus nephritis.
Several studies have examined the use of monoclonal antibody therapy in patients with lupus nephritis. CD5 is a molecule on the surface of T cells and a subpopulation of B cells, and the use of anti-CD5 ricin A chain immuno-conjugate (CD% PLUS) led to an improvement in urine and laboratory parameters in 5 of 8 patients with glomerulonephritis. This approach in clinical practice remains to be validated.
The T cell antigen CTLA-4 linked to murine IgGy 2a (CTLA4Ig) has been shown to block autoantibody production and prolong life span in NZB/NZW F1 mice. Similarly, antibodies to CD40 ligand have been shown to inhibit autoantibody production and prevent the spontaneous development of nephritis in NZB/NZW mice. The immunosuppressive properties of these classes of drugs have not been thoroughly tested and warrant further testing before any recommendations can be made of their efficacy in lupus nephritis.
Oral tolerance therapy may have a role in the treatment of lupus if the offending antigens can be identified. Since lupus is an autoimmune disease, characterised by the production of autoantibodies, candidates such as DNA or ribonucleic acid may be potential antigens for such therapy in the future.
Knowledge about prognosis assists physicians in their choice of treatment and provides patients with information on the possible outcomes. Patients with proliferative glomerulonephritis (WHO III and IV) tend to have a worse outcome for renal function when compared to patients with milder lesions. The combination of severe active and chronic histological changes on a renal biopsy is also reported to adversely affect outcome. Patients without chronic histologic changes, even in the face of active lupus nephritis, had a lower risk of developing renal failure, 90% or more remaining free of renal failure after 10 years. A number of clinical variables are associated with a greater probability of renal progression in lupus nephritis. These include: black race, low haematocrit, raised serum creatinine level, presence of hypertension, high urinary protein excretion, low C3 complement and poor socioeconomic status. Failure to respond to prednisolone and cyclophosphamide are also predictors of subsequent development of renal failure, as are nephrotic flares.
Between 17-30% of patients with lupus nephritis develop end stage renal failure by 10 years. Both haemodialysis and continuous ambulatory peritoneal dialysis are well tolerated and there is tendency for lupus disease activity to diminish after the start of dialysis. If there is no overt disease activity, patients on dialysis can discontinue immunosuppressants and continue with a small dose of prednisolone. Overall survival on dialysis is good with a 75% survival at 10 years. Graft survival and function in patients with lupus after transplantation are comparable to those obtained in patients with other diseases, and recurrence of lupus nephritis is uncommon after transplantation.
Any patient with symptoms of organic dysfuncion (Tables 1 & 2), supported by laboratory evidence of dysfunction, must be referred to a specialist so that the diagnosis can be established, disease severity assessed and a management plan formulated. Immunosuppressive therapy and corticosteroids have undoubtedly had an impact on renal preservation in patients with severe lupus nephritis. Despite numerous studies, the most efficacious treatment with the least toxicity remains to be established. No consensus has yet been reached on a number of therapeutic issues including: the optimal induction drug regimen, optimal regimen for treating relapse and maintenance therapy to prevent relapses. However, it is hoped that early diagnosis and treatment will prevent progression of renal damage which can develop rapidly in those with severe lupus nephritis.
Complications of drug treatment account for much of the morbidity that develops in lupus, in particular, complications of high dose or chronic corticosteroids (infection, osteonecrosis, osteoporosis, coronary artery disease) and cyclophosphamide (infection, sterility, bladder toxicity and malignancy). The risk of infections is substantial in patients taking corticosteroids and immunosuppressants. Infections should be treated with appropriate antibiotic and immunosuppressants will need to be temporarily withdrawn if there is overwhelming sepsis or neutropenia. Both the hospital physicians and general practitioners have a very important role to play in the management of these patients, especially in monitoring drug toxicity, blood pressure and renal function. Regular clinical review of the patient's condition, together with laboratory tests and urinalysis to detect marrow depression, disease activity or progressive disease is mandatory in the management of these patients.
Table 1 - The 1982 revised criteria for the classification of systemic lupus erythematosus Malar rash |
Table 2 - Major organ involvement in systemic lupus erythematosus Renal |
Table 3 - The World Health Organisation Classification of Lupus Nephritis
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*Alternatively cases in these subcategories may be classified under category IV
Table 4. Investigations in systemic lupus erythematosus Full blood examination |
Dr. Wai Y. Tse |
Dr. Dwomoa Adu |