Lisa G. Criscione-Schreiber

Microparticles as antigenic targets of antibodies to DNA and nucleosomes in systemic lupus erythematosus

Systemic lupus erythematosus is a prototypic autoimmune disease characterized by antibodies to DNA and other nuclear molecules. While these antibodies can form immune complexes, the mechanisms generating the bound nuclear antigens are not known. These studies investigated whether microparticles can form complexes with anti-DNA and other anti-nucleosomal antibodies. Microparticles are small membrane-bound vesicles released from dead and dying cells; these particles contain a variety of cellular components, including DNA. To assess antigenicity, microparticles generated in vitro from apoptotic cell lines were tested using murine monoclonal anti-DNA and anti-nucleosomal antibodies as well as plasma from lupus patients. Antibody binding was assessed by flow cytometry. As these studies showed, some but not all of the monoclonal antibodies bound to microparticles prepared from apoptotic HL-60, THP-1 and Jurkat cells. For HL-60 cells, both staurosporine and UV radiation led to the production of antigenically active particles. For the anti-DNA antibody with high particle binding, prior treatment of DNase reduced activity. With plasma from patients with SLE, antibody binding to microparticles was present although a clear relationship with anti-DNA antibody levels was not observed. To determine whether lupus plasma contains immune complexes with particle properties, particle preparations were tested for bound IgG by flow cytometry. These studies indicated that lupus plasma contains particles with IgG binding, with numbers correlated with anti-DNA levels. Together, these findings indicate that microparticles display DNA and nucleosomal molecules in an antigenic form and could represent a source of immune complexes in SLE.

An autoreactive antibody from an SLE/HIV-1 individual broadly neutralizes HIV-1.

Broadly HIV-1-neutralizing antibodies (BnAbs) display one or more unusual traits, including a long heavy chain complementarity-determining region 3 (HCDR3), polyreactivity, and high levels of somatic mutations. These shared characteristics suggest that BnAb development might be limited by immune tolerance controls. It has been postulated that HIV-1-infected individuals with autoimmune disease and defective immune tolerance mechanisms may produce BnAbs more readily than those without autoimmune diseases. In this study, we identified an HIV-1-infected individual with SLE who exhibited controlled viral load (<5,000 copies/ml) in the absence of controlling HLA phenotypes and developed plasma HIV-1 neutralization breadth. We collected memory B cells from this individual and isolated a BnAb, CH98, that targets the CD4 binding site (CD4bs) of HIV-1 envelope glycoprotein 120 (gp120). CH98 bound to human antigens including dsDNA, which is specifically associated with SLE. Anti-dsDNA reactivity was also present in the patients plasma. CH98 had a mutation frequency of 25% and 15% nt somatic mutations in the heavy and light chain variable domains, respectively, a long HCDR3, and a deletion in the light chain CDR1. The occurrence of anti-dsDNA reactivity by a HIV-1 CD4bs BnAb in an individual with SLE raises the possibility that some BnAbs and SLE-associated autoantibodies arise from similar pools of B cells.

The impact of cyclophosphamide on menstruation and pregnancy in women with rheumatologic disease.

Background While cyclophosphamide (CYC) can save the life of a young woman with severe rheumatologic disease, it may lead to the long-term side-effects of infertility and premature menopause. We compared the reproductive health histories of young women with rheumatologic disease with and without prior CYC exposure to identify the impact of this medication on this important component of health. Methods This research includes a case-series study of women diagnosed with SLE, vasculitis, and scleroderma prior to age 35. Each patient completed a questionnaire about desired childbearing, menstrual regularity, infertility, and pregnancy history. Women with prior CYC therapy were queried about the use of gonadotropin-releasing hormone agonists (GnRH-a) for fertility preservation. The responses to this questionnaire were compared for women with and without CYC exposure. Results Of the 43 participants, 23 had prior CYC exposure and 20 were CYC naïve. The current age of these groups was similar (average age 32), but women with prior CYC were four years younger at diagnosis than women without CYC. More women with prior CYC had cessation of menses in the year prior to the study (30.4% vs 0%, p < 0.05). Of the women with prior CYC exposure, those with loss of menses were older at study enrollment, older at CYC treatment, and had a higher cumulative CYC dose than those with preserved menstruation. While more women with GnRH-a co-therapy during CYC had maintained menses, this difference did not reach statistical significance. Women with prior CYC without GnRH-a co-therapy had a higher frequency of nulliparity and had greater trouble conceiving than women with GnRH-a co-therapy. Few pregnancies were conceived following CYC exposure and all resulted in elective termination, miscarriage, or preterm birth. Conclusion In this cohort of young women with rheumatologic disease, more women with prior CYC than without had amenorrhea, nulliparity, and infertility. GnRH-a co-therapy may prevent these adverse effects of CYC.

Predictors of preterm birth in patients with mild systemic lupus erythematosus

Objective While increased disease activity is the best predictor of preterm birth in women with systemic lupus erythematosus (SLE), even women with low disease activity are at increased risk of this complication. Biomarkers that would identify at-risk pregnancies could allow interventions to prevent preterm birth. Method Measures of SLE activity, inflammation, placental health and renal function between 20 and 28 weeks gestation (mid-gestation) were correlated to preterm birth and gestational age at delivery in a prospective cohort of pregnant women with SLE. Result Of the 40 pregnancies in 39 women, all with mild–moderate SLE disease, 9 (23.7%) of the 38 live births were delivered preterm. Low C4 was the only marker of SLE activity associated with younger gestational age at delivery. Elevated ferritin and lower oestradiol correlated with younger gestational age at delivery. Renal function remained normal during all pregnancies at mid-gestation and did not correlate with preterm birth. Higher serum uric acid, however, correlated with younger gestational age at delivery. Conclusions In women with SLE with mild–moderate disease activity, ferritin, oestradiol and uric acid levels at mid-gestation may predict preterm birth. These markers may prove to be clinically useful in identifying pregnancies at particularly high risk for adverse outcomes.

Randomized, Double-Blind, Placebo-Controlled Trial of the Effect of Vitamin D3 on the Interferon Signature in Patients With Systemic Lupus Erythematosus.

Vitamin D modulates the immune response and blocks induction of an interferon (IFN) signature by systemic lupus erythematosus (SLE) sera. This study was undertaken to investigate the effects of vitamin D supplementation on the IFN signature in patients with SLE.

Self-efficacy and pain catastrophizing in systemic lupus erythematosus: Relationship to pain, stiffness, fatigue, and psychological distress

To determine how self‐efficacy for pain control and pain catastrophizing, both potentially modifiable pain coping cognitions, are related to pain, stiffness, fatigue, and psychological distress in patients with systemic lupus erythematosus (SLE).

Depressive symptoms and associated factors in systemic lupus erythematosus.

BACKGROUND Depressive symptoms affect anywhere from 11% to 71% of patients with systemic lupus erythematosus (SLE), which may be related to SLE disease activity, other clinical variables, or sociodemographic factors. OBJECTIVE We aimed to measure the rate of depressive symptoms in our cohort of patients with SLE and to identify modifiable factors associated with depressive symptoms. METHODS Patients in our university-based SLE registry completed the Beck Depression Inventory-II (BDI-II), pain scores, and demographic information. Disease activity was measured using the physicians global assessment (PGA) and Selena-SLE disease activity index (Selena-systemic lupus erythematosus disease activity index (SLEDAI)). Patients were identified as having moderate or severe depressive symptoms (BDI-II ≥ 18) or not (BDI-II < 18). Nonparametric tests and χ(2) tests were used as appropriate to compare variables between groups. RESULTS Fifty-three of 127 people (41.7%) were identified as having moderate or severe depressive symptoms, which were associated with higher pain levels and lower self-reported of current health status. Patients with moderate or severe depressive symptoms were more likely (49%) than those with no or mild depressive symptoms (18%) to have lupus arthritis (P < 0.01). Of the 53 patients with moderate or severe depressive symptoms, only 26 (49.0%) were prescribed antidepressants, and only 8/53 patients (15.0%) were prescribed the maximum dose of antidepressant. CONCLUSIONS This study identified moderate or severe depressive symptoms in 41.7% of our cohort of patients with SLE. The most significant variable associated with these symptoms was pain; improved treatment of pain, and in particular from lupus arthritis, may result in alleviation of depressive symptoms in patients with SLE.

Competency-based goals, objectives, and linked evaluations for rheumatology training programs: a standardized template of learning activities from the Carolinas Fellows Collaborative.

American Council on Graduate Medical Education program requirements mandate that rheumatology training programs have written goals, objectives, and performance evaluations for each learning activity. Since learning activities are similar across rheumatology programs, we aimed to create competency‐based goals and objectives (CBGO) and evaluations that would be generalizable nationally.

What Is a Rheumatologist and How Do We Make One

Graduate medical education is a critical time in the training of a rheumatologist, and purposeful evaluation of abilities during this time is essential for long‐term success as an independent practitioner. The internal medicine subspecialties collectively developed a uniform set of reporting milestones by which trainees can be assessed and receive formative feedback, providing clarity of accomplishment as well as areas for improvement in training. Furthermore, the reporting milestones provide a schema for assessment and evaluation of fellows by supervisors. The internal medicine subspecialties were also tasked with considering entrustable professional activities (EPAs), which define the abilities of a subspecialty physician who has attained sufficient mastery of the field to be accountable to stakeholders and participate in independent practice. Although EPAs have been established for a few specialties, they had not yet been described for rheumatology. EPAs have value as descriptors of the comprehensive abilities, knowledge, and skills of a practicing rheumatologist. The rheumatology EPAs have a role in defining a specialist in rheumatology upon completion of training, and also represent the ways our specialty defines our abilities that are enduring throughout practice.

Expert panel consensus on assessment checklists for a rheumatology objective structured clinical examination.

While several regional fellowship groups conduct rheumatology objective structured clinical examinations (ROSCEs), none have been validated for use across programs. We aimed to establish agreement among subspecialty experts regarding checklist items for several ROSCE stations.