A revised estimate of twin concordance in systemic lupus erythematosus.

OBJECTIVE. Based on a small clinical series and previously published case reports, concordance for systemic lupus erythematosus (SLE) among monozygous (MZ) twins has been reported to be as high as 69%. Using a larger and less biased sample, we provide another estimate of this percentage. METHODS. We established a registry of twins with SLE, based upon self-reports and information provided by the patients' physicians. We used DNA fingerprinting to validate the reported zygosity in a sample of these twins. RESULTS. Of 107 twin pairs meeting the American College of Rheumatology 1982 revised criteria for the diagnosis of SLE, 24% of 45 MZ pairs and 2% of 62 dizygous (DZ) pairs were concordant. The frequency distributions of diagnostic criteria and disease symptoms in the SLE patients were similar to those in other published reports of SLE patients. Zygosity was confirmed by DNA fingerprinting in a subsample of 15 self-described MZ twins and 7 self-described DZ twins. All individuals had correctly predicted their zygosity. CONCLUSION. MZ concordance for SLE is similar to that for other autoimmune diseases and is much lower than previously believed.     

Systemic lupus erythematosus in identical twins: a case report

In this report we describe the case of identical twin sisters that developed systemic lupus erythematosus (SLE). These patients have in common major histocompatibility complex class I and class II alleles and identical red blood cell antigens, which is a clear indication of monozygotic twins. Both twins showed high titers of anti-dsDNA antibody. However, only one of them manifested signs of lupus psychosis and was positive for the LE test, rheumatoid factor, anti-Scl 70, anti-SSA, and antiribosomal P antibodies. Both sisters lived together; therefore, the environmental factors were considered to be the same. Interestingly, these patients expressed different types of autoantibodies and the manifestation of disease was also quite different. When one of the twins was diagnosed with SLE, we began to closely follow up signs of the disease in the other twin periodically. This enabled us to promptly diagnose the second twin with SLE and she was successfully treated without progression of the disease. It is important to mention that following up the subsequent history of an identical twin diagnosed with SLE allowed early detection of the disease in the other twin.     

A revised estimate of twin concordance in systemic lupus erythematosus

Objective. Based on a small clinical series and previously published case reports, concordance for systemic lupus erythematosus (SLE) among monozygous (MZ) twins has been reported to be as high as 69%. Using a larger and less biased sample, we provide another estimate of this percentage. Methods. We established a registry of twins with SLE, based upon self-reports and information provided by the patients' physicians. We used DNA fingerprinting to validate the reported zygosity in a sample of these twins. Results. Of 107 twin pairs meeting the American College of Rheumatology 1982 revised criteria for the diagnosis of SLE, 24% of 45 MZ pairs and 2% of 62 dizygous (DZ) pairs were concordant. The frequency distributions of diagnostic criteria and disease symptoms in the SLE patients were similar to those in other published reports of SLE patients. Zygosity was confirmed by DNA fingerprinting in a subsample of 15 self-described MZ twins and 7 self-described DZ twins. AH individuals had correctly predicted their zygosity. Conclusion. MZ concordance for SLE is similar to that for other autoimmune diseases and is much lower than previously believed.     

Serologic studies of monozygotic twins with systemic lupus erythematosus.

OBJECTIVE. The goal of these studies was to assess the role of genetic factors and disease expression in the pattern and titer of autoantibodies to several RNA protein antigens in patients with systemic lupus erythematosus (SLE) by studying identical twins concordant and discordant for disease expression. METHODS. Autoantibodies to Ro/SS-A, La/SS-B, U1 RNP, and Sm were measured by quantitative enzyme-linked immunosorbent assay using affinity-purified antigens. RESULTS. Detailed serologic studies were performed in 7 pairs of identical twins, 3 of whom were concordant and 4 of whom were discordant for disease expression. Autoantibody titers were higher in affected than in unaffected twins from discordant pairs, but in 3 of 4 pairs, the profile of anti-RNA proteins (e.g., Ro/SS-A, La/SS-B, U1 RNP, and Sm) was virtually identical. In the SLE pairs concordant for disease expression, the autoantibody titers were very similar, as were the anti-RNA protein profiles. When the identical twins were matched by sex, race, and age to pairs of nontwin SLE patients, the 6 white twins shared an average of 2.5 (+/- 1.05 SD) anti-RNA proteins, while the control SLE pairs shared only 0.33 (+/- 0.82), P less than 0.01 (t = 4.0, P less than 0.01). In addition, in the white SLE twins, all had elevated levels of anti-U1 RNP while in white nontwin SLE patients, the frequency of anti-U1 RNP was 30%. CONCLUSION. These data point to a dominant role for genetic factors in the determination of specific autoantibody profiles.     

Hypocomplementemic urticarial vasculitis syndrome in identical twins

Hypocomplementemic urticarial vasculitis syndrome (HUVS) is a syndrome of recurrent urticarial vasculitis, arthralgia/arthritis, and hypocomplementemia. Angioedema, ocular inflammation, glomerulonephritis, and obstructive lung disease are other clinical findings. Although the etiology of HUVS is unknown, its resemblance to systemic lupus erythematosus (SLE) suggests a similar pathogenesis. SLE is known to occur in identical twins. This is the first report of a pair of identical twins with HUVS. Concordance for HUVS in identical twins suggests that the pathogenesis of the disease involves abnormal genetic immunoregulation.     

Familial systemic lupus erythematosus in Finland

OBJECTIVE: To perform a cross sectional nation-wide clinical study of familial systemic lupus erythematosus (SLE) in Finland. METHODS: We sought to identify all Finnish families in which at least 2 members satisfied the classification criteria for SLE. About 1,200 patients with SLE (80-85% of all patients attending Finnish hospitals) were contacted. Personal and/or phone interviews and examination of medical records were used to verify the diagnoses. A comparison of clinical characteristics was made between familial cases of SLE and matched sporadic controls. RESULTS: We identified 53 multiplex families with 113 SLE patients. Forty-six families had 2 affected members and 7 families had 3 affected members. There were 3 pairs of monozygotic female twins and one pair of dizygotic twins of the opposite sex concordant for SLE. Eleven (9.7%) of the 113 familial cases of SLE were male. No differences were found in the clinical presentation of SLE between familial and sporadic cases (sex, age at onset, major clinical manifestations, and common laboratory tests). The incidence of familial SLE was approximately 4-5%. CONCLUSION: Our study shows that familial and sporadic SLE are not different disease entities; this means that we can extrapolate the results of future genetic analyses in multiplex SLE families to all patients with SLE.     

Serologic studies of monozygotic twins with systemic lupus erythematosus

Objective. The goal of these studies was to assess the role of genetic factors and disease expression in the pattern and titer of autoantibodies to several RNA protein antigens in patients with systemic lupus erythematosus (SLE) by studying identical twins concordant and discordant for disease expression. Methods. Autoantibodies to Ro/SS-A, La/SS-B, U1 RNP, and Sm were measured by quantitative enzyme-linked immunosorbent assay using affinity-purified antigens. Results. Detailed serologic studies were performed in 7 pairs of identical twins, 3 of whom were concordant and 4 of whom were discordant for disease expression. Autoantibody titers were higher in affected than in unaffected twins from discordant pairs, but in 3 of 4 pairs, the profile of anti—RNA proteins (e.g., Ro/SS-A, La/SS-B, U1 RNP, and Sm) was virtually identical. In the SLE pairs concordant for disease expression, the autoantibody titers were very similar, as were the anti—RNA protein profiles. When the identical twins were matched by sex, race, and age to pairs of nontwin SLE patients, the 6 white twins shared an average of 2.5 (± 1.05 SD) anti—RNA proteins, while the control SLE pairs shared only 0.33 (± 0.82), P < 0.01 (t = 4.0, P < 0.01). In addition, in the white SLE twins, all had elevated levels of anti—U1 RNP while in white nontwin SLE patients, the frequency of anti—U1 RNP was 30%. Conclusion. These data point to a dominant role for genetic factors in the determination of specific autoantibody profiles.     

Evidence against HLA and immunological dependence of disease outbreak in SLE. Immunological characterisation of identical twins clinically discordant for SLE.

Identical female twins clinically discordant for 20 years for SLE were studied. Their HLA-haplotype was A1,28; B8w6,w35; Cw3,w7; Dr3,4. Both twins had a raised erythrocyte sedimentation rate, autoantibodies, and circulating immune complexes. The diseases sibling had a reversed OKT4/OKT8 ratio (0.43), decreased helper T cell number, defective pokeweed mitogen (PWM) induced plasma cell differentiation, and overactive hydrocortisone sensitive suppressor cells. Immunological abnormalities may be only partly HLA related (B8; Dr3), but are most probably secondary to the disease process in the sibling with SLE. Exogenous and/or endogenous factor(s) other than genetic or immunological are suggested as being operative in the predisposition to and expression of SLE.     

Monozygotic twins discordant for systemic lupus erythematosus.

A pair of monozygotic twins discordant for systemic lupus erythematosus(SLE) were studied and no differences noted in their immune respose to tetanus toxoid, keyhole lympet hemocyanin, DNCB, delayed sensitivity, or antibody titers to viruses. Both were noted to have biologically false positive serology at an early age, but only one twon developed SLE. The clinically unaffected twin underwent castration at an early age, suggesting that ovarian hormones may play an important role in the development of SLE.     

Monozygotic twins discordant for systemic lupus erythematosus

A pair of monozygotic twins discordant for systemic lupus erythematosus (SLE) were studied and no differences noted in their immune response to tetanus toxoid, keyhole lympet hemocyanin, DNCB, delayed sensitivity, or antibody titers to viruses. Both were noted to have biologically false positive serology at an early age, but only one twin developed SLE. The clinically unaffected twin underwent castration at an early age, suggesting that ovarian hormones May-June play an important role in the development of SLE.     

Clues from genetic and epidemiologic studies

There are clear indications that genetic variables influence the pathogenesis of SLE. The frequency of the disease in first-degree relatives of SLE subjects appears to be in the range of 1–2%, but this is in great excess relative to the frequency of SLE in the general population. The frequency of concordance of the disease in monozygotic twin pairs is in excess of 50%. The frequency of concordance of dizygotic twins may be no higher than that in other first-degree relatives. Data in twins support the conclusion that familial aggregation is due to genetic rather than to other familial factors. The high female-to-male ratio of patients with SLE may reflect sex hormonal influence on immunoreactivity rather than the genetic aspects of sex per se. The approximately threefold higher incidence of SLE in black subjects relative to white, in some studies, may reflect a heightened activity of the humoral immune system in blacks.     

Studies of twins with systemic lupus erythematosus: A review of the literature and presentation of 12 additional sets

To assess the role of genetic factors in systemic lupus erythematosus (SLE), 12 twin pairs (seven definitely monozygotic, three definitely dizygotic) of which one or both twins had SLE, were studied and compared to 17 twin pairs (12 definitely monozygotic) previously described. In the present series, four of seven (57 per cent) definitely monozygotic pairs were clinically concordant for SLE, satisfying the preliminary criteria of the American Rheumatism Association (ARA). Concordance for the presence of antinuclear factor (ANF) and hypergammaglobulinemia was 71 and 87 per cent, respectively. These data closely agree with those on the 12 definitely monozygotic sets previously described. All three of the dizygotic sets in the present series were discordant for clinical SLE, although one clinically well twin had marked serologie abnormalities.Comparison of these data with those from other first degree relatives of our twins clearly suggests a strong genetic component in the pathogenesis of SLE. The relative contribution of nongenetic and environmental factors to the expression of the disease is discussed.     

Impaired recovery and cytolytic function of CD56+T and non—T cells in systemic lupus erythematosus following in vitro polyclonal T cell stimulation. Studies in unselected patients and monozygotic disease-discordant twins

Objective. To determine whether there is impaired generation and cytolytic function of CD56+ T cells and non-T cells in human systemic lupus erythematosus (SLE). Methods. Peripheral blood mononuclear cells (PBMC) were obtained from 73 patients with SLE, 39 normal controls, and 9 pairs of monozygotic (MZ) twins discordant for SLE. PBMC were stimulated with anti-CD3 monoclonal antibody, maintained in interleukin-2, and assayed for percentages of total CD56+ cells and CD56+ T cells by flow cytometry, and for cytolytic activity against ⁵¹Cr-labeled Daudi target cells. Results. Despite normal total cell expansion, the percentages of recovered CD56+ T cells and total CD56+ cells were 1.6-fold and 1.8-fold lower, respectively, in patients with SLE compared with normal controls (P = 0.011 and P < 0.001, respectively). Cytolytic activities of isolated total CD56+ cells and CD56+ T cells and were also reduced in patients with SLE compared with normal controls (P = 0.033). These defects associated with SLE were independent of disease activity and immunosuppressive medications, and they reflected impaired maturation of cytolytic effector cells rather than a deficiency in precursor cell number. In MZ twins discordant for SLE, recovered percentages of CD56+ cells and cytolytic responses were very low in 4 of 8 and 6 of 9 co-twins with SLE, respectively. Cell-mixing experiments with the PBMC of the MZ twins demonstrated that the E+ cell fractions (containing all T cells and CD56+ non-T cells) from the co-twins with SLE had decreased ability to generate cytolytic activity compared with the corresponding E+ cell fractions from the healthy co-twins. However, recovered percentages of CD56+ cells and non-T cells and cytolytic responses were also depressed in 4 of 8 and 4 of 9 healthy co-twins, respectively. Conclusion. Impaired CD56+ T cell and non-T cell responses are a feature of SLE and may antedate the onset of clinical disease.     

Clinical and immunologic studies in identical twins discordant for systemic lupus erythematosus

Middle-aged female identical twins, one of whom had systemic lupus erythematosus (SLE), were evaluated for immunologic reactivity to previous antigenic challenges, including primary immunization with a foreign antigen, keyhole limpet hemocyanin (KLH). These two women had lived together for all of their 58 years and neither was receiving anti-inflammatory or immunosuppressive drugs at the time of these studies. Both twins demonstrated comparable 7S and 198 humoral antibody response to KLH, as well as similar viral antibody titers. However, the twin with SLE was anergic to common antigens, streptokinase-streptodornase, Trichophyton and Candida; furthermore delayed hypersensitivity to KLH did not develop after immunization. This observed discrepancy between humoral and cellular immunity in genetically similar subjects may be significant in the pathogenesis of SLE.     

Immunologic observations on 9 sets of twins either concordant or discordant for SLE

The influence of genetic and nongenetic factors on abnormalities of the immune response in systemic lupus erythematosus (SLE) was studied in 9 sets of twins in which one or both twins had SLE. Particular emphasis was placed on contrasting the results between the sibs of 3 monozygotic pairs discordant for clinical SLE. Depression of cell-mediated immunity, determined by lymphocyte blastogenic response to mitogens, was associated with the clinical expression of illness. In contrast, auto-reactive antilymphocyte antibodies and lymphocyte tubuloreticular structures were found in both clinically affected and unaffected subjects and were more prominently associated with the presence of other serologic abnormalities. No evidence of antigens or cell surface determinants unique to affected sibs was encountered.     

Studies of immune functions of patients with systemic lupus erythematosus.

In normal individuals T cells are stimulated to proliferate by autologous non-T cells; this is called the autologous mixed lymphocyte reaction (MLR). Previous studies demonstrated that such an autologous MLR was markedly impaired in patients with active systemic lupus erythematosus (SLE). To determine whether the defect resided in the responding cell or the stimulating cell, mixing experiments were performed using cells from identical twins. We identified two sets of identical twins discordant for SLE activity and correspondingly discordant in their degree of responsiveness in the autologous MLR. Reciprocal mixing experiments were performed in which T cells from one twin of each pair were mixed with non-T cells from the other twin of that pair. These studies indicated that patients with active SLE have a defect in the ability of non-T cells to stimulate as well as a defect in the ability of both Tgamma and Tnongamma cells to respond in the autologous MLR. Patients with inactive SLE have a defect only in responsiveness of Tgamma cells.     

Studies of immune functions of patients with systemic lupus erythematosus

In normal individuals T cells are stimulated to proliferate by autologous non-T cells; this is called the autologous mixed lymphocyte reaction (MLR). Previous studies demonstrated that such an autologous MLR was markedly impaired in patients with active systemic lupus erythematosus (SLE). To determine whether the defect resided in the responding cell or the stimulating cell, mixing experiments were performed using cells from identical twins. We identified two sets of identical twins discordant for SLE activity and correspondingly discordant in their degree of responsiveness in the autologous MLR. Reciprocal mixing experiments were performed in which T cells from one twin of each pair were mixed with non-T cells from the other twin of that pair. These studies indicated that patients with active SLE have a defect in the ability of non-T cells to stimulate as well as a defect in the ability of both Tγ and Tnonγ cells to respond in the autologous MLR. Patients with inactive SLE have a defect only in responsiveness of Tγ cells.     

The coexistence of systemic lupus erythematosus and multiple sclerosis in a mother and daughter

The occurrence of both multiple sclerosis (MS) and systemic lupus erythematosus (SLE) has previously been described in several members within the same family and in twins of successive generations, but the finding of both diseases in one patient is a great rarity. We here report on a rare coexistence of MS and SLE both in mother and daughter. Both patients fulfill the diagnostic criteria of primary-progressive subtype of MS as well as SLE. The finding constitutes supporting evidence of a common genetic background for these two autoimmune disorders.     

The significance of the concordance rate for Type 1 (insulin-dependent) diabetes in identical twins

Summary We studied prospectively 49 non-diabetic identical twins of recently-diagnosed Type 1 (insulin-dependent) diabetic patients for up to 24 years (median 9 years). During this time 15 developed Type 1 diabetes. Actuarial analysis indicates that by 12 years 34% of the twins will have developed Type 1 diabetes and that thereafter only another 2% will do so. Inevitable bias in ascertainment of the twins makes it likely that the true figure is less. We conclude that factors which are not genetically determined must be important in the pathogenesis of the disease. The rates of developing Type 1 diabetes in the co-twins declines sharply in the years after diagnosis of the index twin, which suggests that the initiation of the process leading to Type 1 diabetes occurs within a finite, and not a prolonged, period.     

Systemic lupus erythematosus and dermatomyositis with symptomatic bilateral sacroiliitis: an unusual and interesting association

Systemic lupus erythematosus (SLE) is a multisystem autoimmune connective-tissue disease with a complex phenotype and varying disease course. Although SLE often causes a polyarticular synovitis, there are only a few case reports of abnormalities of the synovial lined sacroiliac joints. We report a case with an overlap syndrome of SLE and dermatomyositis who subsequently developed bilateral symptomatic sacroiliitis. We conclude that sacroiliitis, although rare, can occur in patients with active SLE as a manifestation of the disease per se.