bluuebunny/crossref_metadata_2025 huggingface dataset:
Role of HLA in congenital heart block: susceptibility alleles in mothers
Authors: Sire M-K , Julkunen H , Kaaja R , Kurki P , Koskimies S
Published: November 2003

In congenital heart block (CHB), abnormal maternal immunisation leads to autoantibody production against SS-A/Ro and SS-B/La antigens. These maternal antibodies are transferred across the placenta to the unborn child and are believed to transmit irreversible immunological injury in developing foetal heart tissue, thus causing 3rd-degree atrioventricular block. The mothers may suffer from systemic lupus erythematosus (SLE) or primary Sjögren's syndrome (SS), but they may be asymptomatic. Women with primary SS show a typical autoimmune HLA antigen pattern, namely higher frequency of HLA B8 and DR3 than in the normal population. The HLA pattern may affect individual ability to resist infecting bacteria and viruses and to response in various ways to autoantigens. It is probable that other factors such as genetic regulation of immune response are involved in CHB. We compared the HLA class I and class II alleles of mothers having CHB children with those of women suffering from primary SS and having healthy children, and with those of healthy Finns. Antibodies against 52-kD and 60-kD SS-A/Ro and 48-kD SS-B/La antigens were compared between the two groups of mothers. Our results show that anti-SS-A/Ro antibodypositive mothers all show a strong association with known autoimmune-predisposing HLA alleles, however, the mothers of CHB children differ in some HLA class I alleles, and especially in HLA haplotypes, from mothers of healthy children. Mothers with HLA A1, Cw7, B8 and without B15 are at particularly high risk of having CHB children.
Role of HLA in congenital heart block: susceptibility alleles in children
Authors: Sire M-K , Julkunen H , Kaaja R , Ekblad H
Published: November 2003

Congenital heart block (CHB) is a syndrome of uncertain pathogenesis leading to cardiac conduction disturbances in the foetus and newborns. It has been proposed that maternal antibodies transmit immunological injury in the developing foetal heart, thus causing irreversible damage of the atrioventricular node, leading to third-degree atrioventricular block. However, some genetic or environmental factors may also be involved. We have searched for genetic markers that play a role in immune response and that would be pathognomonic for the disease, either in mothers by regulating their immune response or in children by affecting antigen presentation and target for the maternal immune response. We have compared HLA class I and II alleles of the children with their mother and with healthy individuals and searched for HLA markers that would be emphasized in children. We have shown that particular DQ alleles in the child predispose to CHB, perhaps serving as antigen-presenting molecules on site. In addition, the HLA-Cw3 allele is involved, although its function remains to be clarified. In our results, children with CHB were often identical to their mothers in alleles of DRB, DQA and DQB loci, thus affecting foetomaternal recognition and suggesting that cell-mediated mechanisms could be involved in the pathogenesis.
Chronic or recurrent headache in patients with systemic lupus erythematosus: a case control study
Authors: Fernández-Nebro A , Palacios-Muñoz R , Gordillo J , Abarca-Costalago M , De Haro-Liger M , Rodríguez-Andreu J , González-Santos P
Published: November 2003

Controversy exists concerning the prevalence of headache in systemic lupus erythematosus (SLE) and its importance as a neuropsychiatric manifestation, especially when it occurs independently of disease activity and with the typical characteristics of primary chronic headache. Most reports to date have either studied both types of headache, whether or not related to systemic lupus erythematosus, or have not used adequate controls.

This study determines the prevalence and types of chronic primary headache in patients with systemic lupus erythematosus in a case-control study which we performed in a tertiary care hospital.

We studied 71 consecutive patients with systemic lupus erythematosus and 71 healthy unrelated subjects matched for age and sex from the same geographical area.

Clinical evaluation using a specific standard protocol for the presence and characteristics of headache according to the operative classification criteria of the International Headache Society.

The overall prevalence of headache, tension-type headache, and migraine was similar among patients and controls [33 (46.5%), 17 (23.9%) and 16 (22.5%) vs 31 (43.7%), 17 (23.9%) and 13 (18.3%), respectively]. The mean age of onset of headache was higher in the patients (28.7–14.3 vs 18.5–5.6 y; P = 0.001) and the subjective response to analgesics was lower than in the controls [19 (63%) vs 28 (93.3%); P = 0.004]. There were no differences in the presence of precipitating factors or family history of headache. There were no relevant clinical or immunological differences among the patients regarding the presence or absence of tension-type headache or migraine.

Patients with systemic lupus erythematosus do not differ from healthy controls for the presence and type of chronic or recurrent headache.
Anti-phospholipid antibodies in patients with multiple sclerosis and MS-like illnesses: MS or APS?
Authors: IJdo J W , Conti-Kelly A M , Greco P , Abedi M , Amos M , Provenzale J M , Greco T P
Published: November 2003

Objective: To describe the frequency, clinical, and laboratory features of patients diagnosed with multiple sclerosis (MS) or MS-like illnesses (MSL) among a large, prospectively followed cohort of anti-phospholipid antibody (aPL)-positive patients.

Methods: Between 1990 and 1995 patients referred to a university-affiliated rheumatology clinic were prospectively evaluated for aPL based on questionnaires designed to detect aPL-related symptoms and/or a family history of aPL-related illnesses. Magnetic resonance imaging (MRI) was performed when significant neurological features were present. A subgroup of all patients diagnosed with MS or MSL was identified and their clinical, laboratory, and imaging findings were reviewed.

Results: Of 322 patients evaluated for aPL-related symptoms or events, 189 (59%) were positive for at least one class of aPL. Twenty-six of 322 patients (8%) carried a diagnosis of MS or MSL, either at the initial evaluation or during the study period. Twenty-three of the 26 individuals (88%) tested positive for aPL, while the remaining 3 (11%) tested repeatedly negative. Eighteen of the 23 patients (78%) had either more than one class of aPL or had multiple positive titers. IgM aCL was noted in 18 of the 23 patients (78%). Oligoclonal bands were noted in five patients. Antinuclear antibodies (ANA) and low complement levels were frequently observed. Blinded MRI readings showed lesions consistent with MS in the majority of cases. Clinically, 7 patients had transverse myelitis (TM), while optic neuritis (ON) was present in 8 patients. Most patients had either occult symptoms of rheumatic disease or contributory family histories. None had a defined underlying connective-tissue disease.

Conclusion: A substantial number of aPL-positive patients have a concurrent diagnosis of MS or MSL, frequently presenting with elevated IgM aCL, optic neuritis, and transverse myelitis. The anti-phospholipid syndrome (APS) should be strongly considered as an alternative diagnosis to MS in these patients.
β2 glycoprotein I containing immune-complexes in lupus patients: association with thrombocytopenia and lipoprotein (a) levels
Authors: George J , Gilburd B , Langevitz P , Levy Y , Nezlin R , Harats D , Shoenfeld Y
Published: November 2003

In this study we determined the prevalence and clinical associations of immune-complexescontaining beta-2-glycoprotein I (b2GPI) in randomly selected SLE patients.

We studied 38 consecutive SLE patients attending the Rheumatology Unit. Previous arterial or venous-thrombosis were documented by the appropriate diagnostic test. Lipid profile including total cholesterol, LDL, VLDL, HDL and Lp(a) levels were determined from the sera of the fasting patients. Antibodies to cardiolipin, oxidized LDL and b2GPI were detected employing ELISA. b2GPI containing IgG immune-complexes were assayed by using a dot-blot assay.

Fourteen SLE patients (36.8%) were found to be positive for the presence of IgG anti-b2GPI antibodies. Ten of the SLE patients (26.3%) were found to have high levels of b2GPI containing immune-complexes. There was a positive correlation between b2GPI-IC levels and the occurrence of thrombocytopenia in the patients (P < 0.05). Furthermore, patients with SLE and venous thrombosis had higher levels of b2GPI-IC when compared with thrombosis-free patients or with healthy controls (P < 0.05). Patients with higher Lp(a) levels (> 50 mg/dl) possessed higher levels of b2GPI-IC as compared with patients with lower Lp(a) concentration (< 20 mg/dl) (P < 0.05).

These results suggest that IC-containing b2GPI can help in defining a subpopulation of SLE patients with increased risk of thrombocytopenia and further aid in resolving mechanisms of immune-mediated tissue damage.
The relationship between defects in lymphocyte production of transforming growth factor-β1 in systemic lupus erythematosus and disease activity or severity
Authors: Ohtsuka K , Gray J D , Stimmler M M , Horwitz D A
Published: November 2003

Transforming growth factor β (TGF-β) comprises of a family of proteins with pleiotropic signaling properties and potent immunoregulatory effects. In SLE we recently reported that lymphocyte production of the total and active forms of TGFβ1 was decreased. Here we asked whether these defects correlate with disease activity and/or severity. TGF-β1 production by blood lymphocytes from 17 prospectively studied SLE patients was compared with 10 rheumatoid arthritis (RA) patients and 23 matched healthy controls. The RA levels of active TGF-β1 were lower than controls, but were not deceased to the extent found in SLE. Levels of constitutive and anti-CD2 stimulated active TGF-β1 detected in picomolar amounts were markedly reduced in six untreated patients hospitalized with recent onset, very active and severe SLE and similarly reduced in 11 patients with treated, less active disease. By contrast, decreased production of total TGF-β1inversely correlated with disease activity. These studies suggest, therefore, that although impaired lymphocyte secretion of the latent precursor of TGF-β1 may result as a consequence of disease activity, a decreased capacity to convert the precursor molecule to its active form may pre-date disease onset. Insufficient exposure of T cells to picomolar concentrations of TGF-β1 at the time they are activated can result in impaired down-regulation of 1g synthesis. Therefore, decreased lymphocyte production of active TGF-β1 in SLE could be an immunologic defect which contributes to the B cell hyperactivity characteristic of this disease.
Cytokine-mediated down-regulation of B cell activity in SLE: effects of interleukin-2 and transforming growth factor-beta
Authors: Ohtsuka K , Gray J D , Quismorio F P , Lee W , Horwitz D A
Published: November 2003

We have recently reported that transforming growth factor-beta (TGF-b) co-stimulates interleukin-2 (IL-2) activated CD8/ T cells to down-regulate antibody production. In SLE, lymphocyte production of both IL-2 and TGF-b is decreased. Here we report that a brief treatment of PBMC from SLE patients with IL-2 and TGF-b can result in marked inhibition of spontaneous polyclonal IgG and autoantibody production. Peripheral blood mononuclear cells (PBMC) from 12 patients with active SLE were exposed to IL-2 with or without TGF-b for three days, washed and cultured for seven more days. The mean decrease in IgG secretion was 79%. The strongest inhibitory effect was observed in cases with the most marked B cell hyperactivity. Spontaneous production of anti-nucleoprotein (NP) antibodies was observed in four cases and cytokine treatment of PBMC decreased autoantibody production by 50–96%. IL-2 inhibited Ig production by either TGF-b-dependent or independent mechanisms in individual patients. In a study of anti-CD2 stimulated IgG production in a patient with active SLE, we documented that IL-2 and TGF-b reversed the enhancing effects of CD8/ T cells on IgG production and induced suppressive activity instead. These results raise the possibility that cytokine-mediated down-regulation of B cell hyperactivity in SLE may have therapeutic potential.
[Anti-β2 Glycoprotein I—β2 Glycoprotein I] immune complexes in patients with antiphospholipid syndrome and other autoimmune diseases
Authors: Biasiolo A , Rampazzo P , Brocco T , Barbero F , Rosato A , Pengo V
Published: November 2003

Antiphospholipid syndrome (APS) is defined by the presence of aPL antibodies in patients with thromboembolic phenomena. Some antiphospholipid (aPL) antibodies, such as those directed against β2-glycoprotein I (β2GPI), are associated with thromboembolism, possess Lupus Anticoagulant (LA) activity and recognize their target antigen only when bound to specific surfaces or to phospholipids (PL). To ascertain whether both free and antibody-bound β2GPI circulate in APS, we set up an ELISA to detect [IgG anti-β2GPI–β2GPI] immune complexes. In this system, rabbit anti-human β2GPI antibodies were adsorbed onto plastic plates, incubated with patient plasma, and bound complexes were detected by means of alkaline phosphatase-labeled goat anti-human IgG; each assay was stopped when positive controls consisting of in vitro generated immune complexes reached an Optical Density (OD) of 0.5 at 405 nm. Plasma from 16 patients with APS showed a mean OD405 of 0.291 (range 0.115–0.558), not statistically different from the mean obtained for 15 age-and sex-matched healthy volunteers (mean OD405 = 0.169, range 0.066–0.264). Surprisingly, levels of immune complexes in 14 patients with other autoimmune diseases and no circulating anti-β2GPI antibodies were statistically higher (mean OD405 = 0.552, range 0.204–0.991) than those of healthy subjects and patients with APS. These data indicate that while autoantibodies to β2GPI are mainly unbound in plasma of patients with APS, they are complexed with their antigen in patients with other autoimmune diseases, possibly reflecting a higher binding affinity.
Nodular regenerative hyperplasia of the liver and antiphospholipid antibodies: report of two cases and review of the literature
Authors: Morlá R M , Ramos-Casals M , García-Carrasco M , Cervera R , Font J , Bruguera M , Rojas-Rodríguez J , Ingelmo M
Published: November 2003

Nodular regenerative hyperplasia of the liver (NRHL) is a rare disorder characterized by diffuse micronodular transformation of the hepatic parenchyma without fibrous septa between the nodules. This condition appears to be associated in many ocasions with systemic autoimmune diseases. We describe two new patients with NRHL in whom antiphospholipid antibodies (aPL) were detected in their sera and review the few similar cases reported previously. We also discuss the possible relationship between aPL and NRHL and suggest that these antibodies may play a role in the pathogenesis of some cases of NRHL, specially those with an associated antiphospholipid syndrome.
Synergetic effect between interleukin-1 receptor antagonist allele (IL1RN*2) and MHC class II (DR17,DQ2) in determining susceptibility to systemic lupus erythematosus
Authors: Tjernström F , Hellmer G , Nived O , Truedsson L , Sturfelt G
Published: November 2003

We investigated whether IL1RN alleles separately or in combination with MHC class II variants, contribute to susceptibility to SLE and to analysed if IL1RN alleles are markers of disease severity.

We investigated 81 patients from a defined area in southern Sweden diagnosed between 1981–1992 and 10 consecutive Caucasian families with multiple cases of SLE. As control group 189 healthy blood donors was used. PCR amplification of defined gene sequences was used in determining the IL1RN polymorphism as well as the MHC class II variants. The IL-1RA levels were measured by an immunoassay.

We found an increased frequency of IL1RN*2 in both the epidemiological cohort and in the multicase families (P < 0.01). Alone IL1RN*2 and MHC class II (DR17,DQ2) separately increased the SLE risk moderately. The occurrence of IL1RN*2 and MHC class II variants DR17 and DQ2 together increased the risk to develop SLE by a sevenfold. The IL-1RA gene polymorphism did not correlate with disease severity or with renal involvement. We found an association between IL1RN*1 and arthritis (P < 0.001). Serum level of IL-1RA did not correspond to any specific IL1RN allele.

An increased frequency of IL1RN*2 suggests the presence of a gene, implemented in SLE-susceptibility, in the IL1RN region of chromosome 2. IL1RN*2 and specific variants of MHC class II act in synergy to increase disease susceptibility. IL1RN*1 may be a marker of risk for development of arthritis.
Chilblain lupus erythematosus is associated with antibodies to SSA/Ro
Authors: Franceschini F , Calzavara-Pinton P , Quinzanini M , Cavazzana I , Bettoni L , Zane C , Facchetti F , Airò P , McCauliffe D P , Cattaneo R
Published: November 2003

Chilblain lupus erythematosus (CL) of Hutchinson is a subtype of lupus erythematosus (LE) characterized by erythematous lesions induced by cold, damp climates. A number of patients affected by CL eventually develop features of systemic lupus erythematosus (SLE).We report here 9 patients with chilblain cutaneous lesions, 6 of them were affected by SLE and 2 by SCLE. The onset of CL preceded the diagnosis of LE, from 1 to 10 years in 3 cases, it was concurrent in one case and was subsequent in the remaining 4 cases. Raynaud's phenomenon and photosensitivity were other prominent clinical features in patients with CL. Nailfold capillaroscopy revealed pathological changes in every patient examined. ANA and anti-SSA/Ro antibodies were detected in all nine patients. Anti-SSB/La were detected in 2 cases, anti-Sm in one case, and anti Sm and anti-RNP in a one case. Antibodies to dsDNA and complement consumption were found in the six patients with SLE. The fine specificity of anti-SSA/Ro was determined by immunoblotting: anti-60kD and anti-52 kD were detected in three sera, anti-60kD alone in 5 sera, while one serum did not blot.

In conclusion, the present study suggests that chilblain LE is associated with SSA/Ro autoantibodies, as is SCLE, hypergammaglobulinemic purpura and neonatal lupus erythematosus.
Apheresis for lupus erythematosus
Authors: Wallace D J
Published: November 2003

Indications for the use of apheresis technologies in managing lupus erythematosus have undergone numerous conceptual changes since the procedure was automated in the 1960s and first attempted for systemic lupus erythematosus (SLE) in 1974. Once thought to be a promising treatment for a variety of aspects of SLE, apheresis has been relegated to occupying a few important niches as an adjunct in managing the disorder. This article will review the history, physiology and rationale of apheresis pertaining to SLE. A focused critical review of pertinent literature is presented, along with specific recommendations relating to the place of apheresis in the lupus therapeutic spectrum.
Systemic lupus erythematosus in three ethnic groups: III A comparison of characteristics early in the natural history of the LUMINA cohort
Authors: Alarcón G S , Friedman A W , Straaton K V , Moulds J M , Lisse J , Bastian H M , McGwin G , Bartolucci A A , Roseman J M , Reveille J D
Published: November 2003

Aim: To determine and contrast the socioeconomic-demographic and clinical features of patients with recent onset (5 y) systemic lupus erythematosus (SLE) from three ethnic groups, Hispanic, African-American and Caucasian (H, AA, C).

Subjects and methods: SLE cases (American College of Rheumatology criteria) (incident (n ‘ 56), prevalent (n ‘ 173)), were enrolled in a longitudinal study at The University of Alabama at Birmingham, The University of Texas-Houston Health Science Center and The University of Texas Medical Branch at Galveston. Socioeconomic-demographic, clinical, immunological, behavioral and psychological data were obtained using validated instruments and standard laboratory techniques, and compared.

Results: 70 H, 88 AA and 71 C SLE patients constitutethis cohort. H and AA patients were younger and of lower socioeconomic-demographic status. They also had evidence of more frequent organ system involvement (renal, cardiovascular), more auto-antibodies, more active disease (after adjusting for discrepant socioeconomic-demographic features), lower levels of social support and more abnormal illness-related behaviors (more in H than in AA). H also were more likely to have an abrupt disease onset; C were more likely to be on antimalarials but less likely to be on corticosteroids. H, AA, and C used health care resources comparably. They had similar levels of pain and physical and mental functioning after adjusting for age, disease duration, income, education, social support, illness-related behaviors, and Systemic Lupus Activity Measure or SLAM scores.

Conclusions: H and AA patients have more active SLE, at an earlier age of onset, and a less favorable socioeconomic-demographic structure (worse among the H than AA) which predispose them to a less favorable natural history.
A case of SLE with acute, subacute and chronic cutaneous lesions successfully treated with Dapsone
Authors: Neri R , Mosca M , Bernacchi E , Bombardieri S
Published: November 2003

We describe a patient with systemic lupus erythematosus (SLE) who exhibited severe cutaneous involvement characterized by the simultaneous presence of acute, subacute and discoid lesions in association with anti-Sl antibodies. After she failed to respond to chloroquine, medium to low dose steroids, steroid pulses, retinoids and cyclophosphamide, the patient was treated with Dapsone and a dramatic improvement in the cutaneous lesions was seen after only one month.
Impaired cytotoxic T lymphocyte activity in systemic lupus erythematosus following in vitro polyclonal T cell stimulation: a contributory role for non-T cells
Authors: Stohl W , Hamilton A S , Deapen D M , Mack T M , Horwitz D A
Published: November 2003

To determine whether non-T cells contribute to impaired generation of nonrestricted cytotoxic T lymphocyte (CTL) activity in human SLE, peripheral blood mononuclear cells (PBMC) and sorturified T cells from normal subjects and SLE patients were stimulated with anti-CD3 mAb, maintained in IL2, and assayed for cytolytic activity against 51Cr-labeled Daudi target cells. In addition, T cell and non-T cell fractions were isolated from nine pairs of monozygotic (MZ) twins discordant for SLE, reconstituted in a criss-cross pattern, and stimulated and assayed for cytolytic activity. Cytolytic responses were significantly lower in SLE PBMC cultures than in normal PBMC cultures. Addition of SLE serum to normal PBMC cultures did not inhibit generation of normal cytolytic responses, and neither `resting' SLE PBMC prior to stimulation nor addition of neutralizing anti-IL10 mAb or costimulating anti-CD28 mAb restored generation of SLE cytolytic responses to normal. Nevertheless, despite the significantly greater cytolytic responses in normal PBMC cultures than in SLE PBMC cultures, cytolytic responses in normal purified T cell cultures were only modestly and insignificantly greater than those in SLE purified T cell cultures. Moreover, substitution of `healthy' non-T cells for SLE non-T cells in four of the nine MZ twin-pairs appreciably enhanced cytolytic responses, and substitution of SLE non-T cells for `healthy' non-T cells in five of the seven twin-pairs tested appreciably diminished cytolytic responses. Taken together, these results indicate that, in addition to any inherent SLE T cell abnormalities, impaired function of SLE non-T cells contributes to impaired generation of nonrestricted CTL activity.
Immunological abnormalities in primary APS evolving into SLE: 6 years follow-up in women with repeated pregnancy loss
Authors: Carbone J , Orera M , Rodríguez-Mahou M , Rodríguez-Pérez C , Sánchez-Ramón S , Seoane E , Rodríguez J J , Zabay J M , Fernández-Cruz E
Published: November 2003

We have performed a prospective study to determine the prevalence of immunological abnormalities and the evolution from primary antiphospholipid syndrome (APS) into systemic lupus erythematosus (SLE) in women who had had unexplained repeated pregnancy loss (PL) and APS. Of 105 women with abortions or fetal deaths, 33(31%) fulfilled criteria for APS. Among these patients with primary APS, 24% had antinuclear antibodies (ANA), 91% had elevated circulating immune complexes (CIC), 70% had low total haemolytic complement (CH100), 52% had low levels of complement 4 (C4) and 30% had low levels of complement 3 (C3), in a significantly higher prevalence than women whose pregnancies were successful (control group). Through out a 6 y follow-up, 3 (9%) of the patients with APS who had autoimmune related abnormalities when entered into the study developed features of lupus like disease (LLD) or fullblown SLE. Our findings suggest that women with unexplained repeated PL with APS who presented with positive ANA, high levels of CIC, low levels of CH100, C3 and C4, may define a subset of patients exhibiting immunological alterations similar to those of SLE. These parameters may help in the assessment of prognosis in APS patients with PL. Those patients should be carefully surveyed with regard to the development of connective tissue diseases.
Pulmonary hypertension secondary to systemic lupus erythematosus: prolonged survival following treatment with intermittent low dose iloprost
Authors: Mok M Y , Tse H F , Lau C S
Published: November 2003

Pulmonary hypertension (PHT) associated with systemic lupus erythematosus (SLE) has a dismal prognosis. Vasodilators and immunosuppressive therapy have been tried over the years with discouraging results. Prostacyclin (PGI2) which has potent vasodilatatory and anti-platelet effects has been demonstrated to significantly decrease pulmonary arterial pressure and pulmonary vascular resistance during acute infusion. Satisfactory response has been reported in SLE patients with PHT treated with short-term intravenous continuous PGI2 infusion. We report here a 48-month experience of the use of monthly low dose infusion of a PGI2 analogue, iloprost, in a SLE patient with pulmonary hypertension in New York Heart Association functional Class III. There was an initial haemodynamic response to an acute infusion of iloprost. Repeated infusions were followed by marked improvement in her functional status and her mean pulmonary arterial pressure dropped from 80 mmHg in the first few months and remained static at around 55 mmHg for the subsequent years.
Clinical and immunological manifestations in 134 Puerto Rican patients with systemic lupus erythematosus
Authors: Vilá L M , Mayor A M , Valentín A H , García-Soberal M , Vilá S
Published: November 2003

To gain a better understanding of systemic lupus erythematosus (SLE) in Puerto Ricans we studied the clinical and serologic manifestations in a cohort of 134 patients. The female to male ratio was 18: 1. Mean age at diagnosis was 32 12 y. The mean duration of disease and follow-up were 7.4 6.0 and 5.8 6.0 years respectively. Mortality was 3%. Photosensitivity (76.9%) and malar rash (71.9%) were the most common clinical manifestations. Arthritis was observed in 67.5% of patients. Anemia was seen in 67.2% of patients, but only 12.7% had autoimmune hemolytic anemia. Leukopenia (41.8%) and lymphopenia (64.9%) were also common. Serositis was observed in only 28%. Severe kidney damage such as nephrotic syndrome (14.2%) or renal failure (4%) was infrequent. Cardiovascular (12.7%) and neurologic (9.0%) manifestations were also uncommon. Antinuclear antibodies (ANA) were detected in 93.3%, anti-dsDNA antibodies in 54.5%, anti-Ro antibodies in 30.1% and anti-La antibodies in 14.2%. Low C3 and low C4 were observed in 38.3% and 35.7% respectively. This study suggests that Puerto Ricans with SLE present a mild form of disease predominantly manifested by cutaneous, musculoskeletal and hematologic involvement, but low prevalence of major organ damage and low mortality.
C1q inhibits autoantibody binding to calreticulin
Authors: Racila D M , Sontheimer R D
Published: November 2003

Calreticulin (CR) is a new rheumatic disease-associated autoantigen that is intimately associated with the Ro/SS-A ribonucleoprotein. CR autoantibodies are frequently observed in patients with photosensitive forms of lupus erythematosus (LE). CR has been shown to be highly homologous to cC1q-R, the cell surface receptor that binds the collagenous domain of the first component of complement, C1q. C1q has also been shown to directly bind to CR. We therefore asked whether the binding of C1q to CR might interfere with the binding of CR autoantibody to CR. Full-length recombinant human CR, an E.coli fusion proteins was used as antigen in a direct enzyme-linked immunosorbent assay (ELISA). CR autoantibody-containing sera were assayed before and after C1q removal by two different methods: by heating sera at 56C for 30 min or adding monoclonal anti-C1q antibodies. ELISA optical density (OD) values were found to be consistently higher in sera depleted of C1q by both methods compared to unmodified sera. The addition of purified C1q to C1q-depleted sera resulted in ELISA OD values similar to those of unmodified sera. These results suggest that C1q levels present in human serum can inhibit the binding of CR autoantibody to CR. One can speculate that the failure of C1q to mask CR autoepitopes in individuals with genetic deficiency of C1q could contribute to the high rate of photosensitive LE that occurs in such individuals.
Seasonal variations in activity of systemic lupus erythematosus in a subarctic region
Authors: Haga H-J , Brun J G , Rekvig O P , Wetterberg L
Published: November 2003

Photosensitivity is one of the major clinical features of Systemic Lupus Erythematosus (SLE), and is considered to be implicated in the disease pathogenesis. We studied seasonal variations of SLE disease activity at latitude 70 North where there is no sunlight in the winter time, in contrast to 24 h daily sunlight in the summer (midnight sun). The associations between the level of plasma melatonin in June and December with disease manifestations were also studied.

Twenty-one SLE patients were examined each month for 1 y, and disease activity was assessed by laboratory parameters as well as clinical disease activity parameters SLEDAI and doctor's global assessment. Melatonin levels were quantified by a RIA-assay.

There was no significant change of clinical measures or laboratory parameters of disease activity from one month to the next during the one year, except photosensitive rashes. January was the only month without SLE-flares or arthritis, in contrast to rest of the year. The levels of plasma melatonin were highest in December for seven patients and highest in June for one patient (P < 0.005). Plasma melatonin levels did not correlate with measures of clinical disease activity.

At a latitude of 70 North there were no major seasonal variations in SLE disease activity during the one year. There was an accumulation of photosensitivity in the summer months, but no indications of worsening of the disease in the winter months. In contrast to the rest of the year, there was no flare in January which had only 5.6 h of sunshine. The level of p-melatonin did not correlate with measures of disease activity.
CD4 TCRBV CDR3 Analysis in prevalent SLE Cases from two ethnic Groups
Authors: Fraser P A , Lu L-Y , DeCeulaer K , Schur P H , Fici D , Awdeh Z , Ding W-Z , Levitan E , Lew R , Uko G , Gonzalez C
Published: November 2003

We examined CD4+ T cell TCRBV-CDR3 transcripts from 19 lupus patients and 16 controls to test the hypothesis that CD4+ TCRBV-CDR3 expression in SLE differs from normals. Within the disease group we also performed exploratory analyses to determine the association between risk of oligoclonality and HLA-DRB specificities and the duration of the CDR3 patterns. Oligoclonal patterns consistent with CDR3 restriction were three times more likely in SLE than in controls (OR=3.7). TCRBV1, BV4, BV5.1, BV7, BV9, BV18 and BV22 gene segment CDR3 patterns of oligoclonality were seenexclusively amonglupus patients. HLA-DRB3increasedtherisk ofoligoclonalexpressionin SLE. In four patients studied over time, the pattern of TCRBV-CDR3 expression was stable in a second sample obtained 6–14 months later. The increased frequency of CD4+ T cell TCRBV-CDR3 oligoclonal expression in SLE when compared to controls and the persistence of these patterns are consistent with an expanded pool of autoreactive CD4 T cells in SLE which recognize peptides derived from autoantigens. The association of HLA-DRB3 genes with increased risk of CDR3 oligoclonality among the SLE subjects is compatible with the hypothesis that molecules encoded by HLA-DRB3 may facilitate autoantigen recognition by CD4 T cells.
The SLICC/ACR damage index: progress report and experience in the field
Authors: Gladman D D , Urowitz Murray B
Published: November 2003

The SLICC/ACR damage index for SLE was developed to assess accumulated damage since the onset of the disease. The damage includes non-reversible changes in organs and systems affected by the disease process itself, its therapy, or inter-current illness. This paper describes the development of the damage index, its validation and its use. It is recommended as an outcome measure for longitudinal studies of prognosis and response to new therapies, and as a stratification measure for clinical trials.
Quality of life and economic evaluation in SLE clinical trials
Authors: Gordon Caroline , Clarke Ann E
Published: November 2003

Outcome in SLE patients should include assessment of disease activity and chronic damage and also measurement of health-related quality of life and the economic impact of the disease. This paper reviews the methods available for doing this and the results of existing studies in SLE patients.
Early stopping of clinical trials in lupus and other uncommon rheumatologic diseases
Authors: LaValley Michael P , Felson David T
Published: November 2003

Use of statistical methods for early stopping of clinical trials allows more efcient and ethical utilization of subjects. In uncommon diseases, where the pool of potential subjects is limited, these methods provide a way to maximize the information gathered from trials. For trials in lupus, methods for early stopping should be more widely utilized. We discuss the ethics, practical aspects, pros and cons, and statistical foundations of some established methods for early stopping, with an emphasis on those that have available implementation in computer software. An example of the design and analysis of a treatment trial in systemic lupus erythematosus with the triangular test method of early stopping is also given.
Methodological issues of corticosteroid use in SLE clinical trials
Authors: Corzillius M , Bae S-C
Published: November 2003

Objective: To describe and analyze how investigators handled concurrent steroid intake in SLE clinical trials; to identify remaining methodological problems and to discuss potential solutions.

Methods: A review of the literature was performed in Medline to identify randomized controlled trials (RCT) in lupus published during the past decade. A set of criteria was defined a priori to analyze these trials covering different aspects of steroid use in RCTs with regard to eligibility, randomization, post-randomization steroid use, analysis and reporting.

Results: Seventeen trials met the inclusion criteria and were analyzed. Median sample size was 30, ranging from 10–71. In three trials corticosteroid application was the study intervention. Three reports did not address steroid use among study subjects at all. In seven trials steroid use was part of the eligibility criteria in some way. Of the trials that allowed concurrent steroid use, seven checked for equal distribution of baseline steroids. In some cases clinically relevant differences did not reach statistical significance as sample sizes were very small. In only one study was randomization stratified for steroid use. Instructions for post-randomization steroid use were specified in only 3 of 14 trials where steroids were not part of the intervention. In 11 RCTs concurrent steroid use was free or no information was provided. Steroid dosing during the intervention was reported as a secondary outcome measure in four trials.

Conclusions: As sample sizes are often small, simple randomization is not reliable to avoid relevant between-group differences in baseline steroids. The power of statistical testing for group differences is limited for the same reason. Stratified randomization is rarely used. Free concurrent steroid use during the intervention is frequently allowed in lupus RCTs despite the risk of bias. Better data and accepted standards for a priori specified steroid regimens in RCTs are highly warranted.
Responsiveness and sensitivity to change of SLE disease activity measures
Authors: Corzillius M , Fortin P , Stucki G
Published: November 2003

The ability of outcome measures to detect change over time is critical for their usefulness in clinical trials. Two concepts are applied in the assessment of evaluative instruments: We endorse the recommendation that a distinction be made between sensitivity and responsiveness. Sensitivity to change refers to the capacity of instruments to measure change statistically. Sensitivity statistics relate the magnitude of observed change to some measure of variablity and are essentially signal-to-noise ratios. Responsiveness addresses the detection of clinically relevant change. The methodology is still evolving but a common approach has been to correlate the observed change in scores with external standards that are believed to indicate clinical relevance (e.g., physician-or patient-based transition scales).

Sensitivity to change and responsiveness of SLE activity indices have been addressed in a small number of studies. These indicate that the most widely used systems (SLEDAI. SLAM, BILAG) are sensitive to change although the available evidence does not allow preference for one instrument over the others. Little research has been done on the responsiveness of these measures.

This article reviews the methodological concepts in measuringclinical change and summarizes reports on sensitivity and responsiveness of lupus activity scores.
Development of an FDA guidance document for clinical trials in SLE
Authors: Siegel J N
Published: November 2003

To make the process of developing new therapeutic agents more efficient, it is critical that investigators and industry sponsors understand in advance what information they will need to provide to the US Food and Drug Administration (FDA) in order to license and market their product. To facilitate that process, the FDA publishes guidance documents describing current thinking about various issues that arise at all stages of product development. The FDA is currently in the process of formulating a guidance document about clinical development programs for systemic lupus erythematosus (SLE). The goal of this document is to describe some of the types of clinical trials that could be used to demonstrate safety and efficacy of therapeutic agents in SLE.
World Wide Web: Opportunities, challenges, and threats
Authors: Edworthy S M
Published: November 2003

The Internet provides new opportunities to gather information on the population and may provide alternatives to the traditional methods of conducting clinical trials in systemic lupus erythematosus. The ‘world wide web-www’ has grown extensively in the past decade and it is estimated that there will be over 1 billion individuals on the net by the year 2005.

Notifying, recruiting and assessing patients using Internet technology are already potential uses of this electronic medium. However, total reliance on the Internet could lead to biased sampling of patients with lupus. Women with low incomes or who are unemployed are less likely to have access to the Internet. Individuals with neurological deficits may have trouble using the Internet effectively. Data collected on the web may not have high reliability and much work needs to be completed to determine the psychometric properties of information derived from this source.

One of the greatest threats to contend with is protecting the confidentiality of patient information when using electronic communication. Safeguards against inadvertent or unintended release of information must receive high priority in any attempt to use the Internet for clinical trials. Particular attention should be paid to email messages, which have the potential to be intercepted or sent to individuals without clearance to see patient information. Nevertheless, the costs to systems performance caused by security measures must also be considered and balanced against the need for access by those with appropriate authority.

A number of websites already exist for the benefit of patients and providers. Clinicians and scientists interested in the field of lupus research will need to keep up to date on the rapidly proliferating information that is becoming available. This article lists sites which can be visited now.
Dealing with discreteness: making `exact’ confidence intervals for proportions, differences of proportions, and odds ratios more exact
Authors: Agresti A
Published: November 2003

‘Exact’ methods for categorical data are exact in terms of using probability distributions that do not depend on unknown parameters. However, they are conservative inferentially. The actual error probabilities for tests and confidence intervals are bounded above by the nominal level. This article examines the conservatism for interval estimation and describes ways of reducing it. We illustrate for confidence intervals for several basic parameters, including the binomial parameter, the difference between two binomial parameters for independent samples, and the odds ratio and relative risk. Less conservative behavior results from devices such as (1) inverting tests using statistics that are ‘less discrete’, (2) inverting a single two-sided test rather than two separate one-sided tests each having size at least half the nominal level, (3) using unconditional rather than conditional methods (where appropriate) and (4) inverting tests using alternative p-values. The article concludes with recommendations for selecting an interval in three situations—when one needs to guarantee a lower bound on a coverage probability, when it is sufficient to have actual coverage probability near the nominal level, and when teaching in a classroom or consulting environment.
Methods of reducing loss of efficiency due to discreteness of distributions
Authors: Cohen A , Sackrowitz H B
Published: November 2003

All models of this paper involve R × C contingency tables in which the total frequency is fixed (full multinomial model), or in which the row totals are fixed (product multinomial model). For the most part, we assume that the column categories are ordered. For the full multinomial model the null hypothesis of interest is independence, i.e., the ( ij)th cell probability is the product of the marginal probabilities of the ith row and jth column. In the product multinomial model the null hypothesis is that the R multinomial distributions have the same vector of cell probabilities.

Our review includes (1) a careful listing of two-sided and one-sided alternatives, and (2) methodology to reduce the loss of efficiency of tests because of the discreteness of the model (The methodologies discussed are efficient in several senses. Tests are exact. Tests have very favorable and robust power properties. Tests make use of back-up statistics, thereby providing a finer grid of p-values. In some special cases, e.g., a 2 × C table and a one-sided alternative, conditional p-values are found, within seconds, simply by entering row frequencies into a given website. Thus, computational efficiency is exceptional.), and (3) a critique of some exact linear permutation tests (that are conditional on row and column margins) for both two-sided and some one-sided alternatives. Furthermore, recommendations as to which tests to use for specific alternatives are made.
Saddlepoint distribution function approximations in biostatistical inference
Authors: Kolassa J E
Published: November 2003

Applications of saddlepoint approximations to distribution functions are reviewed. Calculations are provided for marginal distributions and conditional distributions. These approximations are applied to problems of testing and generating confidence intervals, particularly in canonical exponential families.
Analysis of a Bayesian repeated measures model for detecting differences in GP prescribing habits
Authors: Sithole Jabu S , Jones Peter W
Published: November 2003

A linear mixed model is used to detect a change, if any, in the prescribing habits in the UK at the general practice (family medicine) level due to an educational intervention given repeated measures data before and after the intervention and a control group. Inferences are corrected for general practice size and fundholding status. The estimates of the model parameters are obtained using Bayesian inference by applying Gibbs sampling. We develop three different priors for the parameters of the model. These three priors correspond to ‘sceptical,’ ‘reference’ and ‘enthusiastic’ priors in terms of the opinion about the treatment effects that they represent. We compare the results obtained by using these three priors for the parameters in the random effects model.
Wavelets and statistical analysis of functional magnetic resonance images of the human brain
Authors: Bullmore Ed , Fadili Jalal , Breakspear Michael , Salvador Raymond , Suckling John , Brammer Michael
Published: November 2003

Wavelets provide an orthonormal basis for multiresolution analysis and decorrelation or ‘whitening’ of nonstationary time series and spatial processes. Wavelets are particularly well suited to analysis of biological signals and images, such as human brain imaging data, which often have fractal or scale-invariant properties. We briefly define some key properties of the discrete wavelet transform (DWT) and review its applications to statistical analysis of functional magnetic resonance imaging (fMRI) data. We focus on time series resampling by ‘wavestrapping’ of wavelet coefficients, methods for efficient linear model estimation in the wavelet domain, and wavelet-based methods for multiple hypothesis testing, all of which are somewhat simplified by the decorrelating property of the DWT.
Bayesian techniques for sample size determination in clinical trials: a short review
Authors: Pezeshk Hamid
Published: November 2003

The aim of this paper is to review some key techniques of Bayesian methods of sample size determination. The approach is to cover a small number of simple problems, such as estimating the mean of a normal distribution. The methods considered are in two groups: inferential and decision theoretic. In the inferential Bayesian methods of sample size determination, we are solely concerned with the inference about the parameter(s) of interest. The fully Bayesian or decision theoretic approach treats the problem as a decision problem and employs a loss or utility function.