Faculty Bibliography

OBJECTIVE: To compare the efficacy and safety of intravenous (IV) abatacept, a selective T cell costimulation modulator, versus placebo for the treatment of active class III or IV lupus nephritis, when used on a background of mycophenolate mofetil and glucocorticoids. METHODS: This was a 12-month, randomized, phase II/III, multicenter, international, double-blind study. A total of 298 patients were treated in 1 of 3 IV treatment arms: placebo, abatacept at the standard weight-tiered dose (approximating 10 mg/kg), or abatacept at 30 mg/kg for 3 months, followed by the standard weight-tiered dose (abatacept 30/10). The primary end point, time to confirmed complete response, was a composite measure that required maintenance of glomerular filtration rate, minimal proteinuria, and inactive urinary sediment over the 52-week treatment period. RESULTS: There were no differences among treatment arms in the time to confirmed complete response or in the proportion of subjects with confirmed complete response following 52 weeks of treatment. Treatment with abatacept was associated with greater improvements from baseline in anti-double-stranded DNA antibody, C3, and C4 levels. Among 122 patients with nephrotic-range proteinuria, treatment with abatacept resulted in an approximately 20-30% greater reduction in mean urinary protein-to-creatinine ratio compared with placebo. Abatacept was well tolerated; rates of deaths, serious adverse events, and serious infections were similar across treatment arms. Gastroenteritis and herpes zoster occurred more frequently with abatacept treatment. CONCLUSION: Although the primary end point was not met, abatacept showed evidence of biologic activity and was well tolerated in patients with active class III or IV lupus nephritis.

Despite rapid accumulation of knowledge about complex immune dysregulation in systemic lupus erythematosus (SLE) and major primary lupus syndromes, and a plethora of promising new treatments reaching preclinical and early clinical studies, advanced-phase trials of new biologic agents have repeatedly failed to achieve their clinical end points. It is possible that none of these agents work, but the accuracy of this suggestion is as unclear as the case for efficacy, owing to issues in the design of studies and the opacity of the data that have resulted. Disease heterogeneity and complexity might be a hurdle that is simply too high to overcome by existing methodological approaches, and the way forward to interpretable trial results remains unclear. Nonetheless, well-characterized patterns of immune pathology are shared by substantial subsets of patients, and selective targeting of one or more relevant immune system molecules seems to offer the promise of safer and more effective treatments. Evolution dictates a more personalized approach to therapy and trial design, but this option seems challenging in the current economic, regulatory and scientific environment. This Review addresses these concerns by considering the progress of some of the investigational treatments targeting key physiological abnormalities in lupus.

OBJECTIVES/OBJECTIVE:TO COMPARE TWO MEASURES OF SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) RESPONSE: the British Isles Lupus Assessment Group (BILAG)-based Composite Lupus Assessment (BICLA) and the Systemic Lupus Responder Index (SRI) against a clinician's assessment of improvement. METHODS:Ninety-one lupus patients were identified with two visits at which Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and BILAG had been scored and with active disease (SLEDAI≥6) at the first visit. A physician rated the disease activity at the second visit as clinically significant improvement, no change or worsening. SRI and BICLA were scored both with and without the medication criteria often used in trials to restrict response definitions. RESULTS:68 patients were considered improved, 17 same and 6 worse at follow-up. SRI versus BICLA, performed without considering medication changes, captured physician-rated improvement with 85% vs 76% sensitivity and 74% vs 78% specificity. With medication limits both instruments had 37% sensitivity and 96% specificity for physician-assessed improvement. Seven patients considered improved by the clinician met the BICLA but not the SRI definition of improvement by failing to achieve a four-point improvement in SLEDAI. 13 clinician-rated responders met SRI but not BICLA by improving in less than all organs. CONCLUSIONS:Shortfalls of SRI and BICLA may be due to BICLA only requiring partial improvement but in all organs versus SRI requiring full improvement in some manifestation(s) and not all organs. SRI and BICLA with medication restrictions are less likely to denote response when the physician disagrees and could provide stringent proof of efficacy in appropriately powered clinical trials.

OBJECTIVE: To examine the frequency and characteristics of headaches and their association with global disease activity and health-related quality of life (HRQOL) in patients with systemic lupus erythematosus (SLE). METHODS: A disease inception cohort was assessed annually for headache (5 types) and 18 other neuropsychiatric (NP) events. Global disease activity scores (SLE Disease Activity Index 2000 [SLEDAI-2K]), damage scores (Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index [SDI]), and Short Form 36 (SF-36) mental and physical component summary scores were collected. Time to first headache and associations with SF-36 scores were analyzed using Cox proportional hazards and linear regression models with generalized estimating equations. RESULTS: Among the 1,732 SLE patients enrolled, 89.3% were female and 48.3% were white. The mean +/- SD age was 34.6 +/- 13.4 years, duration of disease was 5.6 +/- 5.2 months, and length of followup was 3.8 +/- 3.1 years. At enrollment, 17.8% of patients had headache (migraine [60.7%], tension [38.6%], intractable nonspecific [7.1%], cluster [2.6%], and intracranial hypertension [1.0%]). The prevalence of headache increased to 58% after 10 years. Only 1.5% of patients had lupus headache, as identified in the SLEDAI-2K. In addition, headache was associated with other NP events attributed to either SLE or non-SLE causes. There was no association of headache with SLEDAI-2K scores (without the lupus headache variable), SDI scores, use of corticosteroids, use of antimalarials, use of immunosuppressive medications, or specific autoantibodies. SF-36 mental component scores were lower in patients with headache compared with those without headache (mean +/- SD 42.5 +/- 12.2 versus 47.8 +/- 11.3; P < 0.001), and similar differences in physical component scores were seen (38.0 +/- 11.0 in those with headache versus 42.6 +/- 11.4 in those without headache; P < 0.001). In 56.1% of patients, the headaches resolved over followup. CONCLUSION: Headache is frequent in SLE, but overall, it is not associated with global disease activity or specific autoantibodies. Although headaches are associated with a lower HRQOL, the majority of headaches resolve over time, independent of lupus-specific therapies.

OBJECTIVE: Patients with systemic lupus erythematosus (SLE) are at increased risk of herpes zoster (HZ). Although a vaccine for HZ has been approved by the US Food and Drug Administration, its use in immunocompromised individuals remains controversial because it is a live-attenuated virus vaccine. We performed a pilot study of the immunogenicity of the HZ vaccine (Zostavax) in patients with SLE. METHODS: Ten patients with SLE and 10 control subjects >/= age 50 years participated in this open-label vaccination study. All were seropositive for varicella zoster virus (VZV). Patients with SLE were excluded for SLE Disease Activity Index (SLEDAI) > 4, or use of mycophenolate mofetil, cyclophosphamide, biologics, or > 10 mg prednisone daily. Followup visits occurred at 2, 6, and 12 weeks. Clinical outcomes included the development of adverse events, particularly HZ or vesicular lesions, and SLE flare. Immunogenicity was assessed with VZV-specific interferon-gamma-producing enzyme-linked immunospot (ELISPOT) assays and with antibody concentrations. RESULTS: All subjects were women. Patients with SLE were slightly older than controls (60.5 vs 55.3 yrs, p < 0.05). Median baseline SLEDAI was 0 (range 0-2) for patients with SLE. No episodes of HZ, vesicular rash, serious adverse events, or SLE flares occurred. Three injection site reactions occurred in each group: mild erythema or tenderness. The proportion of subjects with a > 50% increase in ELISPOT results following vaccination was comparable between both groups, although absolute SLE responses were lower than controls. Antibody titers increased only among controls following vaccination (p < 0.05). CONCLUSION: The HZ vaccination yielded a measurable immune response in this cohort of patients with mild SLE taking mild-moderate immunosuppressive medications. No herpetiform lesions or SLE flares were seen in this small cohort of patients. ClinicalTrials.gov ID:NCT01474720.

The genetic factors underlying the pathogenesis of lupus nephritis associated with systemic lupus erythematosus are largely unknown, although animal studies indicate that nuclear factor (NF)-kappaB is involved. We reported previously that a knockin mouse expressing an inactive form of ABIN1 (ABIN1[D485N]) develops lupus-like autoimmune disease and demonstrates enhanced activation of NF-kappaB and mitogen-activated protein kinases in immune cells after toll-like receptor stimulation. In the current study, we show that ABIN1[D485N] mice develop progressive GN similar to class III and IV lupus nephritis in humans. To investigate the clinical relevance of ABIN1 dysfunction, we genotyped five single-nucleotide polymorphisms in the gene encoding ABIN1, TNIP1, in samples from European-American, African American, Asian, Gullah, and Hispanic participants in the Large Lupus Association Study 2. Comparing cases of systemic lupus erythematosus with nephritis and cases of systemic lupus erythematosus without nephritis revealed strong associations with lupus nephritis at rs7708392 in European Americans and rs4958881 in African Americans. Comparing cases of systemic lupus erythematosus with nephritis and healthy controls revealed a stronger association at rs7708392 in European Americans but not at rs4958881 in African Americans. Our data suggest that variants in the TNIP1 gene are associated with the risk for lupus nephritis and could be mechanistically involved in disease development via aberrant regulation of NF-kappaB and mitogen-activated protein kinase activity.

Co-stimulatory molecules help to regulate interactions between T cells and antigen-presenting cells and may play an important role in the pathogenesis of lupus. Both work in murine models and some early studies in human lupus support further examination of these molecules as therapeutic targets. Complexities of lupus clinical trial variables may have hampered progress in this area but recent developments in the field may make interventional trials more feasible in the near future. To date biologics which provide direct blockade of interactions between CD40 and CD154, B7RP-1 and ICOS, and CD80 or CD86 with CD28 have been assessed in multicenter clinical trials. These data will be reviewed and critiqued.