Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXIV. Cytotoxic treatment is an additional risk factor for the development of symptomatic osteonecrosis in lupus patients: results of a nested matched case-control study

BACKGROUND: Osteonecrosis is common in systemic lupus erythematosus (SLE) and often disabling. The role of glucocorticoids in its development is well known. OBJECTIVE: To explore other possible risk factors for osteonecrosis in SLE. METHODS: A nested matched case-control study undertaken in the context of a large, longitudinal, multiethnic lupus cohort (LUMINA), currently formed of 571 SLE patients meeting American College of Rheumatology criteria. All those developing symptomatic osteonecrosis after the diagnosis of SLE were considered cases. Two controls matched for age, disease duration, ethnicity, and centre were selected for each case. Cases and controls were compared by univariable analyses using selected variables. Variables with p<0.10 and those thought clinically relevant were entered into conditional logistic regression models including either the average dose or the highest dose of glucocorticoids, with osteonecrosis as the dependent variable. RESULTS: 32 cases were identified and 59 matched controls selected (in five cases only one control could be found). By univariable analyses, both groups were largely comparable for socioeconomic-demographic, clinical, and laboratory variables. Cases were less exposed to hydroxychloroquine (as assessed by the percentage of exposure time) (p = 0.026), used higher doses of glucocorticoids (average and highest doses) (p = 0.011 and 0.001, respectively), and received cytotoxic drugs more often (p = 0.015). In the multivariable analyses only cytotoxic drug use (both models) and the highest dose of glucocorticoids remained associated with the occurrence of osteonecrosis. CONCLUSIONS: Cytotoxic drug use is a risk factor for the development of symptomatic osteonecrosis in SLE patients, along with glucocorticoids. No definite protective factors were identified.     

Systemic lupus erythematosus in a multiethnic US cohort, XXXVII: association of lymphopenia with clinical manifestations, serologic abnormalities, disease activity, and damage accrual

OBJECTIVE: To determine if lymphopenia is associated with clinical/immunologic manifestations, disease activity, and disease damage in systemic lupus erythematosus (SLE). METHODS: The study group comprised 591 patients with SLE participating in a multiethnic, longitudinal outcome study. Cumulative clinical/immunologic (per American College of Rheumatology criteria) and pharmacologic treatment variables were obtained at enrollment (T0) and last visit (TL). Lymphopenia (<1,500/mm3) was scored only when clinically attributable to SLE and not to medications or other causes. Lymphocyte counts were expressed in 4 categories per the Systemic Lupus Activity Measure (SLAM): normal (> or =1,500/mm3), mild (1,000-1,499/mm3), moderate (500-999/mm3), and marked (<500/mm3). Disease activity was assessed with the SLAM and the Physician's Global Assessment (PGA). Disease damage was determined with the Systemic Lupus International Collaborating Clinics Damage Index (SLICC-DI). The relationship of lymphopenia with cumulative clinical/immunologic and pharmacologic treatment variables was first examined, then the association between the SLAM, PGA, and SLICC-DI scores with different categories of lymphopenia was examined by generalized estimating equation (GEE) regression analyses. Ethnicity, age, and sex were entered into all regression models. RESULTS: At T0 and TL, lymphopenia was found to be positively associated with renal involvement, leukopenia, anti-double-stranded DNA antibodies, anti-Ro antibodies, and the use of glucocorticoids, azathioprine, and methotrexate, but was negatively associated with photosensitivity. On GEE analyses, marked lymphopenia at T0 and moderate and marked lymphopenia for all visits were independently associated with higher SLAM, PGA, and SLICC-DI scores. CONCLUSION: Lymphopenia is associated with several clinical/immunologic manifestations in SLE. Moderate and marked lymphopenia are associated with higher disease activity and damage accrual.     

Immunodeficiency in childhood

Primary immunodeficiency disorders (PIDs) continue to illuminate mechanisms of human immunity and hypersensitivity. New discoveries in common variable immunodeficiency, the most enigmatic of PID syndromes, reveal molecular pathways of importance in human antibody production. FOXP3 mutations demonstrate the essential role that T-regulatory cells play in controlling autoantibody formation and disease. Interleukin-1 receptor-associated kinase 4 deficiency emphasizes the key role that innate immunity plays in the defense of bacterial disease occurring early in life. With respect to therapy, subcutaneous immunoglobulin treatment may indeed be a better treatment than intravenous immunoglobulin for many patients with antibody deficiency. Finally, PIDs remain in the vanguard for the treatment of inherited disorders by gene therapy. Gene therapy has cured patients with chronic granulomatous disease and severe combined immunode ficiency, but not without morbidity and mortality. Into the 21st century, PIDs continue to instruct us in human health and disease.     

Systemic lupus erythematosus in a multiethnic US cohort LUMINA LI: anaemia as a predictor of disease activity and damage accrual

OBJECTIVE: To examine if anaemia (and its severity) is associated with disease activity and damage accrual in systemic lupus erythematosus (SLE). METHODS: Four thousand four-hundred study visits in 613 SLE patients enrolled in LUMINA were studied. Anaemia was expressed in four categories of haematocrit (Hct) as defined by the Systemic Lupus Activity Measure-Revised (SLAM-R): no anaemia (Hct >35%), mild (Hct = 30-35%), moderate (Hct = 25-29%) and severe (Hct <25%). Anti-dsDNA antibodies were measured at baseline. Disease activity was assessed with the SLAM-R and damage with the Systemic Lupus International Collaborating Clinics Damage Index (SDI). The relationship between anaemia and anti-dsDNA antibodies with the SLAM and SDI scores was examined by univariate (one-way ANOVA) and multivariate (generalized linear models and generalized estimating equation regression) analyses. RESULTS: All categories of anaemia and anti-ds DNA were significantly associated with the SLAM-R at baseline and over time. However, only moderate and severe anaemia were associated with the SDI at baseline and over time, while the presence of anti-ds DNA was only associated with the SDI over time but not at baseline. Several clinical domains of the SLAM-R and SDI were associated with anaemia at baseline and over time. CONCLUSIONS: Mild, moderate and marked anaemia are strongly associated with disease activity in SLE. Moderate and marked anaemia are associated with damage accrual. These associations are observed both early and during the course of SLE. Different levels of anaemia could be used to monitor disease activity and predict organ/system damage in SLE.