Long-Term Safety and Efficacy of Epratuzumab in the Treatment of Moderate-to- Severe Systemic Lupus Erythematosus: Results From an Open-Label Extension Study.

OBJECTIVE: The primary objective was to assess the long-term safety of repeated courses of epratuzumab therapy in patients with moderate-to-severe systemic lupus erythematosus. Secondary objectives were to assess long-term efficacy and health-related quality of life (HRQOL). METHODS: Eligible patients from the 12-week, phase IIb, randomized, placebo-controlled EMBLEM study enrolled into the open-label extension (OLE) study, SL0008. In the SL0008 study, patients received 1,200 mg epratuzumab infusions at weeks 0 and 2 of repeating 12-week cycles, plus standard of care. Safety measures included treatment-emergent adverse events (TEAEs) and serious TEAEs. Efficacy measures included combined treatment response, the British Isles Lupus Assessment Group score, the Systemic Lupus Erythematosus Disease Activity Index score, and the physician's and patient's global assessment of disease activity. Total daily corticosteroid dose and HRQOL (by the Short Form 36 health survey) were also assessed. RESULTS: A total of 113 of the 203 patients (55.7%) who entered the SL0008 study continued epratuzumab therapy until study closure (total cumulative exposure: 381.3 patient-years, median exposure: 845 days, and maximum exposure: 1,185 days/approximately 3.2 years). TEAEs were reported in 192 patients (94.6%); most common were infections and infestations (68.0%, 138 patients). Serious TEAEs were reported in 51 patients (25.1%), and 14 patients (6.9%) had serious infections. In patients treated for 108 weeks (n = 116), the median corticosteroid dose was reduced from 10.0 mg/day at OLE screening to 5.0 mg/day at week 108. Improvements in efficacy and HRQOL measures in EMBLEM were maintained in the OLE, while placebo patients exhibited similar improvements in disease activity upon a switch to epratuzumab. CONCLUSION: Open-label epratuzumab treatment was well tolerated for up to 3.2 years, and associated with sustained improvements in disease activity and HRQOL, while steroids were reduced.

Time perspective predicts the progression of permanent organ damage in patients with systemic lupus erythematosus.

Patients whose perspective is oriented to the future more than to the present may have better long-term health outcomes. We examined if time perspective predicted future organ damage in patients with systemic lupus erythematosus (SLE). We assessed the time perspectives of 87 patients with SLE using a questionnaire at a baseline visit. Permanent organ damage was assessed by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index during the same visit, and reassessed after a median of 4.6 years. Patients who were oriented more to the future were less likely to have an increase in the Damage Index than those oriented more to the present. In a multivariate analysis, each 1-point increase in the degree of orientation to the future (on a scale of 1-6) was associated with a 22% decrease in the likelihood that the Damage Index would increase over time (odds ratio 0.78; 95% confidence interval 0.64-0.94; P = 0.009). Other measures that predicted an increase in the Damage Index were lower education levels, greater health locus of control attributed to chance and greater health locus of control attributed to powerful others. In conclusion, time perspective is a significant predictor of future organ damage in SLE. Patients who have a greater orientation to the future are less likely to develop permanent organ damage.

Psychosocial correlates of morbidity in women with systemic lupus erythematosus.

OBJECTIVE: Modifiable psychosocial factors that are associated with health outcomes may provide new opportunities for treatment. We investigated the associations of various psychosocial factors with 3 measures of morbidity in women with systemic lupus erythematosus (SLE). METHODS: We collected information on 16 social, psychological, behavioral, and medical care factors in a cross sectional survey of 100 women with SLE, and related these to measures of physical disability (assessed by the Health Assessment Questionnaire Disability Index), SLE activity (assessed by the Systemic Lupus Activity Measure), and cumulative organ damage (assessed by the SLICC/ACR Damage Index). RESULTS: In multivariate analyses, greater physical disability was significantly associated with higher depression scale scores and higher body mass indexes. Greater SLE activity was associated with less adequate social support. Greater cumulative organ damage was associated with lower self-esteem and a time orientation that favored the present over the future. Financial barriers to medical care, knowledge about SLE, health locus of control, marital status, and health behaviors including compliance with medications, smoking, alcohol use, and exercise, were not significantly associated with any measure of morbidity. CONCLUSION: Selected psychosocial factors are associated with morbidity in SLE, but differ with the measure of morbidity examined.

Genome-wide screen for systemic lupus erythematosus susceptibility genes in multiplex families.

Systemic lupus erythematosus (SLE) is the prototype of human autoimmune diseases. Its genetic component has been suggested by familial aggregation (lambdas = 20) and twin studies. We have screened the human genome to localize genetic intervals that may contain lupus susceptibility loci in a sample of 188 lupus patients belonging to 80 lupus families with two or more affected relatives per family using the ABI Prism linkage mapping set which includes 350 polymorphic markers with an average spacing of 12 cM. Non-parametric multipoint linkage analysis suggests evidence for predisposing loci on chromosomes 1 and 18. However, no single locus with overwhelming evidence for linkage was found, suggesting that there are no 'major' susceptibility genes segregating in families with SLE, and that the genetic etiology is more likely to result from the action of several genes of moderate effect. Furthermore, the support for a gene in the 1q44 region as well as in the 1p36 region is clearly found only in the Mexican American families with SLE but not in families of Caucasian ethnicity, suggesting that consideration of each ethnic group separately is crucial.

Socioeconomic status and health in women with systemic lupus erythematosus.

OBJECTIVE: Health outcomes of patients with chronic illnesses are commonly worse in people of lower socioeconomic status (SES). We investigated psychosocial factors that may mediate the relationship between SES and measures of morbidity in women with systemic lupus erythematosus (SLE). METHODS: We collected information on SES, psychosocial factors, and health status in a cross sectional survey of 100 women with SLE. SES was rated using the Hollingshead Two-Factor Index, a weighted average of years of formal education and occupational prestige (higher Hollingshead Index=lower SES). Health status measures included the Health Assessment Questionnaire Disability Index (HAQ), the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SLICC/ACR), the Systemic Lupus Activity Measure (SLAM), and the SLE Disease Activity Index (SLEDAI). Potential mediators consisted of 18 environmental, medical care, social, psychological, and behavioral factors. RESULTS: Patients with higher Hollingshead Indexes (lower SES) had more functional disability as measured by the HAQ (r=0.22: p=0.03) and more cumulative organ damage as measured by the SLICC/ACR Damage Index (r = 0.19; p=0.06). SES was not related to either the SLAM or SLEDAI. Significant univariate associations were present between the Hollingshead Index and 10 potential mediating variables: household crowding, insurance status, organizational barriers to medical care, depression, health locus of control by powerful others, SLE knowledge, social support, marital status, body mass index, and regular alcohol use. However, in multiple linear regression analyses, only 3 of these variables modified the relationship between Hollingshead Index and the HAQ: more severe depression scores, higher body mass index, and more restricted access to medical care. More severe depression and greater locus of control by powerful others tended to mediate the relationship between low SES and greater organ damage. CONCLUSION: SES is related to morbidity in women with SLE. There are identifiable and potentially modifiable mediators of this relationship.

Catastrophic antiphospholipid syndrome: response to repeated plasmapheresis over three years.

The catastrophic antiphospholipid syndrome (CAPS) is rare and usually fatal. In this report, we describe an unusual patient who, 31 years after experiencing an atypical preeclampsia-eclampsia presentation known today as the HELLP syndrome (hemolysis, elevated liver enzymes, and low platelets), developed CAPS, which seemed to complicate a diagnosis of primary antiphospholipid syndrome. She responded to repeated plasmapheresis over 3 years. Anticoagulants, corticosteroids, intravenous gamma globulin, and intravenous cyclophosphamide had all failed to halt the progression of CAPS, but repeated plasmapheresis not only halted the condition, but it led to the reversal of a leukoencephalopathy. The relationship between HELLP syndrome and CAPS is discussed, and possible pathogenetic mechanisms that explain the efficacy of repeated plasmapheresis in this setting are suggested. It is postulated that perhaps plasmapheresis, through removal of cytokines or other mediators, disrupts the interaction between phospholipid-protein complexes and endothelial cells. Repeated plasmapheresis should be considered in the most refractory cases of CAPS when more conventional treatment regimens have failed.

Successful treatment of optic neuropathy in association with systemic lupus erythematosus using intravenous cyclophosphamide.

BACKGROUND: Optic neuropathy is a rare manifestation of systemic lupus erythematosus (SLE). In a previous series most patients with optic neuropathy in association with SLE had a final visual acuity of 20/200 or less despite corticosteroid therapy. METHODS: Three patients (five affected eyes) with severe retrobulbar optic neuropathy in association with SLE were treated promptly with intravenous cyclophosphamide and corticosteroids. RESULTS: All patients recovered excellent visual acuity. CONCLUSION: Although optic neuropathy in association with SLE might have several different aetiologies, intravenous cyclophosphamide should be strongly considered as a therapeutic alternative.

Neuropsychiatric lupus and hormones.

Neuropsychiatric lupus can present with a broad spectrum of severity, ranging from mild chronic symptomatology to acute life threatening illness. There are no accepted diagnostic or classification criteria, but most agree that the manifestations can be described as representing diffuse CNS insult or a more focal or localized process. The pathogenesis is unknown, but it is likely that there is more than one mechanism given the heterogeneous clinical presentations. It is probable that autoantibody formation, vascular injury, and cytokine production all play a role. There are no randomized controlled trials to help guide therapeutic decision making, but there is data to suggest that treatment of severe NPSLE with IV cyclophosphamide may be of benefit. Additionally, there may be a role for IVGG or synchronized plasmapheresis in cases that fail to respond to IV-CYC. An important role for sex steroids in the etiology of NPSLE is suggested by various observations. Investigational therapy with dehydroepiandrosterone (DHEA) appeared to have benefits with respect to milder symptoms of NPSLE.

Role of intravenous cyclophosphamide in the treatment of severe neuropsychiatric systemic lupus erythematosus.

PURPOSE: We assessed the outcome of 31 patients with severe neuropsychiatric (NP) systemic lupus erythematosus (NPSLE) treated with intravenous cyclophosphamide (IV-CYC), and identified clinical predictors of response to therapy. METHODS: The authors performed a retrospective chart review and classified patients by NP manifestation and response to therapy as measured by serial anatomic imaging and neurodiagnostic studies coupled with clinical assessment of improvement. RESULTS: Neuropsychiatric manifestations occurred with the following frequencies: organic brain syndromes (OBS) 55%, stroke syndromes 35%, peripheral or mononeuropathy 32%, seizures 29%, psychiatric symptoms 26%, transverse myelitis 16%, cranial neuropathies 13%, other 16%. Most patients had multiple NP manifestations, with a median of two. Ninety percent of patients had failed therapy with corticosteroids with or without cytotoxic drugs prior to treatment with IV-CYC. Eight patients received synchronous plasmapheresis along with IV-CYC. After treatment with IV-CYC, NP deficits substantially improved in 61% (group I), stabilized in 29% (group S), and progressively deteriorated in 10% (group P). Patients in group I had significantly fewer NP manifestations than combined group S+P, two versus four, and a lower frequency of OBS, 37% versus 83%. CONCLUSION: Intravenous cyclophosphamide appears to be an effective treatment for some patients with severe NPSLE refractory to other forms of therapy. Higher number of NP manifestations and presence of OBS may predict poor outcome and identify a group of patients for whom early aggressive therapy may be indicated.

Central nervous system systemic lupus erythematosus mimicking progressive multifocal leucoencephalopathy.

The case is reported of a patient with central nervous system systemic lupus erythematosus (SLE) with features of progressive multifocal leucoencephalopathy (PML) seen clinically and by magnetic resonance imaging. A brain biopsy sample showed microinfarcts. The use of magnetic resonance imaging and IgG synthesis rates in evaluating central nervous system lupus, the co-occurrence of SLE and PML, and the differentiation of these entities by magnetic resonance imaging and by histology are considered.

Reiter's syndrome: a male and female disease.

A diagnosis of Reiter's syndrome was made in 12 males and 13 females based on an asymmetrical oligoarthritis with lower extremity predominance and at least 1 characteristic extraarticular manifestation. The pattern of disease was similar in both sexes; females had more extensive upper extremity joint involvement and ocular inflammation; males had more nonbacterial urethritis. Eighty-two % of males and 62% of females were HLA-B27 positive. We suggest that Reiter's syndrome has not been diagnosed in more females in the past because of an historical bias, a reliance on the complete classical triad, and confusion with seronegative rheumatoid arthritis.