Final Diagnosis -- A 10-year-old male with systemic lupus erythematosus

DIAGNOSIS: Systemic Lupus Erythematosus

Systemic Lupus Erythematosus (SLE) is a systemic disorder that was given the name of lupus "Latin for wolf" in the thirteenth century by Rogerius who used this term to describe erosive facial lesions that resemble wolf's bites. The history of lupus was divided into 3 eras

  1. The classical era that begins by describing the first cases of lupus, and it was characterized by the believe that the disease is solely a cutaneous illness
  2. The neoclassical era that starts by describing the systemic nature of the disease by Kaposi in 1872
  3. The modern era which was associated with the discovery of LE cell in 1948 by Hargraves [1]

Diagnostic Criteria for Lupus:

4 or more of the following 11 criteria are needed in order to establish the diagnosis of the disease:

  1. Malar rash
  2. Discoid rash
  3. Photosensitivity reaction to sunlight
  4. Oral ulcers: Usually painless
  5. Inflammatory arthritis: Nonerosive, involving two or more peripheral joints
  6. Serositis: Pleuritis or pericarditis
  7. Renal disorder: Excessive protein in the urine and/or cellular casts
  8. Neurologic disorder: Seizures and/or psychosis in the absence of drugs or metabolic disturbances which are known to cause such effects
  9. Hematologic disorder: Hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia. The leukopenia and lymphopenia must be detected on two or more occasions. The thrombocytopenia must be detected in the absence of drugs known to induce it
  10. Antinuclear antibody: Positive test for antinuclear antibodies (ANA) in the absence of drugs known to induce it
  11. Immunologic disorder: Positive anti-double stranded DNA test, positive anti-Sm test, positive antiphospholipid antibodies such as anticardiolipin, or false positive syphilis test (VDRL)

Why different types of antibodies are produced?

Nucleosomes are released from apoptotic cells in normal individuals without causing any problem. However, a spontaneous expansion of nucleosome-specific T cells that can react against self was observed in SLE patients. This expansion is the result of a defect in eliminating those cells via negative selection in the Thymus; it is believed that this is a lupus-specific event beginning early in life. A decrease in apoptosis rate was seen in SLE patients as a consequence of a defect in the Fas/Fas ligand system. Also, Fas Ligand autoantibodies were described in 1/3 of SLE patients which may play a further role in decreasing apoptosis rate [2]. In contrast to the decrease in apoptosis, the remnants of apoptotic material are increased by decreasing their clearance due to complement consumption caused by circulating immune complexes [3].

Essentially, a single expanded T cell clone specific for a peptide can stimulate B cells to produce different autoantibodies [4]. For example, a complex nuclear antigen composed of histone, DNA, and other elements can bind via its histone to the immunoglobulin receptors on one B cell. The complex antigen is then internalized, degraded, and presented as peptides in MHC II molecules on the cell surface. The T cells specific for the histone peptide epitope binds to this B cell, is activated, and in turn activates the previous B cell to secrete antibodies against histone that was recognized and bound by this B cell. Similarly, the same complex can bind via its DNA part to a second B cell which -again- presents the histone peptide to the histone-specific T cell that helps the second B cell to produce antibodies against DNA [5]. After antibodies are produced, an antibody-antigen interaction will take place to produce immune-complexes, which are responsible for tissue injury. [5] (Figure 4)

How Nephritis occurs?

The glomerular capillary's role in urine ultrafiltration creates a perfect environment for circulating immune-complexes to stick to the basement membrane via charge interaction mechanism. Circulating C1q complement binds to the glomerular immune complex deposits, and activates the classic complement pathway. An antibody called anti-C1q antibody that is found in some patients with autoimmune diseases (especially SLE), in addition to small percentage of healthy individuals, can bind to the solid C1q phase already attached to the tissue bound immune-complex. This antibody activates the complement cascade in a non-supressable way, and finally leads to tissue injury mediated by both complement membrane attack complex and the influx of inflammatory cells including neutrophils. [6] (Figure 5)

Will lupus nephritis develop or not? Why renal injury occurs in some and not all the individuals suffering from SLE?

Patients with SLE having anti-dsDNA but lacking anti-C1q autoantibodies are able to assemble immune-complexes. However, they exhibit mild renal disease as a consequence of complement activation that can be suppressed by complement suppressors.

Glomerulonephritis does not develop in the presence of anti-C1q antibodies alone since no immune complexes are formed. The patients with SLE having both anti-ds DNA and anti-C1q autoantibodies have more severe lupus nephritis due to complement activation via the classical pathway and the influx of inflammatory cells; unless the amount of C1q present locally is low and not yet enough to pass beyond the complement activation threshold. (Figure 6) [6]

Laboratory assays:

From a laboratory diagnostic view, most labs begin with ANA screening as a first step, if positive, additional tests such as ENAs antibodies are requested. [7, 8] (Figure 7). However, up to 5% of SLE patients are ANA negative but have at least 1 positive ENA [usually SS-A]. As a result of this; a current screening approach consists of screening for both ANA and ENAs is suggested to detect the ANA negative cases, and to save time, rather than waiting for the ANA result before ordering ENA testing. (Figure 8)

Clinico-pathologic importance of some immunologic lab tests in SLE's diagnosis and differential diagnosis: [7-8]

In addition to antibody evaluation, total complement activity (CH50 or CH100) may be ordered to evaluate the entire classical complement pathway integrity. Other complement components such as C3 and C4 are ordered as needed. Higher levels of C4d and lower level of CR1 were seen in SLE patients when compared with healthy patients, and platelet CD4 was detected in 18% of SLE patients, and was found to be nearly 100% disease specific marker [9].

SLE biomarkers for diseases activity:

Traditionally, dsDNA was linked with SLE renal disease activity, yet conflicting results were seen in some recent studies. Another biological marker "anti-nucleosome antibody" was observed in most of the patients who are suffering from renal disease but are dsDNA negative. Also, and as mentioned previously, anti-C1q antibodies were more prevalent in patients with documented lupus renal disease. Increased Interferon ? as well as interferon inducible gene upregulation predict more severe disease, and propose multiorgan involvement [9].


Renal involvement is one of the SLE's principal prognostic factors. Recently, an improvement in survival rates of patients suffering from SLE was appreciated, especially for pediatric patients [10, 11]. Nowadays, infections and renal failures are the main causes of morbidity and mortality in SLE pediatric patients [11].


In the past, Corticosteroids were the only available treatment option. Theses days, NSAIDs are used as a first line of treatment especially for arthritis, yet Corticosteroids are used to reduce inflammation when the symptoms are not controlled by NSAID alone, and Cytotoxic drugs are reserved for the most severe cases.


  1. Hochberg MC The history of lupus erythematosus. Md Med J. 1991 Oct;40(10):871-3
  2. Suzuki N, Ichino M, Mihara S, Kaneko S, Sakane T. Inhibition of Fas/Fas ligand-mediated apoptotic cell death of lymphocytes in vitro by circulating anti-Fas ligand autoantibodies in patients with systemic lupus erythematosus. Arthritis Rheum. 1998 Feb;41(2):344-53. Review.
  3. Mevorach D. Systemic lupus erythematosus and apoptosis: a question of balance. Clin Rev Allergy Immunol. 2003 Aug;25(1):49-60. Review.
  4. Datta SK. Production of pathogenic antibodies: cognate interactions between autoimmune T and B cells. Lupus. 1998;7(9):591-6. Review.
  5. Fred Rosen, Raif Geha. "Case studies in immunology 3". Third edition. Pages 187-189. Garland Publishing New York, NY.
  6. Flierman R, Daha MR. Pathogenic role of anti-C1q autoantibodies in the development of lupus nephritis-a hypothesis. Mol Immunol. 2006 Jul 24
  7. Kumar, Abbas, Fausto "Robbins and Cotran Pathologic Basis of Disease" Seventh edition. Pages 227-235.Elsevier Saunders Philadelphia, PA.
  8. Kam Shojania Rheumatology: 2. What laboratory tests are needed? CMAJ o April 18, 2000; 162 (8)
  9. Navratil JS, Manzi S, Kao AH, Krishnaswami S, Liu CC, Ruffing MJ, Shaw PS, Nilson AC, Dryden ER, Johnson JJ, Ahearn JM. Platelet C4d is highly specific for systemic lupus erythematosus. Arthritis Rheum. 2006 Feb;54(2):670-4. Erratum in: Arthritis Rheum. 2006 Jun;54(6):2009.
  10. Liu CC, Manzi S, Ahearn JM. Biomarkers for systemic lupus erythematosus: a review and perspective. Curr Opin Rheumatol. 2005 Sep;17(5):543-9. Review.
  11. Klippel JH. Systemic lupus erythematosus: demographics, prognosis, and outcome. J Rheumatol Suppl. 1997 May;48:67-71. Review.
  12. Gonzalez B, Hernandez P, Olguin H, Miranda M, Lira L, Toso M, Quezada A, Norambuena X, Talesnik E, Mendez C, Navarrete C. Changes in the survival of patients with systemic lupus erythematosus in childhood: 30 years experience in Chile. Lupus. 2005;14(11):918-23.

Contributed by Ibrahim Batal, MD and Bruce Rabin, MD, PhD

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