Faculty Bibliography

OBJECTIVE:Current disease activity measures for systemic lupus erythematosus (SLE) are difficult to score or interpret and problematic for use in clinical practice. Lupus Foundation of America (LFA)-Rapid Evaluation of Activity in Lupus (REAL) is a pilot application composed of anchored visual analogue scores (0-100 mm each) for each organ affected by lupus. This study evaluated the use of LFA-REAL in capturing SLE disease activity. METHODS:In a preliminary test of LFA-REAL, this simplified, organ-based system was compared with the most widely used outcome measures in clinical trials, the British Isles Lupus Assessment Group 2004 Index (BILAG), the SLE Disease Activity Index (SLEDAI) and the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) SLEDAI Physician's Global Assessment (SS-PGA). The level of agreement was analysed using Spearman rank correlations. RESULTS:91 patients with SLE with mild to severe disease activity were evaluated, their median SLEDAI score was 4.0 (range 0-28) and BILAG score 8.0 (0-32). The median SS-PGA was 38 mm (4-92) versus the total REAL 50 mm (0-268), which expands in range by additive organ scores. Thirty-three patients had moderate to severe disease activity (≥1.5 on SS-PGA landmarks). The median SS-PGA score of this group was 66 mm (50-92) versus median REAL score of 100 mm (59-268), confirming ability to detect a wider distribution of scores at higher disease activity. Total REAL correlated with SLEDAI, BILAG and SS-PGA (correlation coefficient=0.816, 0.933 and 0.903, respectively; p<0.001 for all). Individual LFA-REAL organ scores for musculoskeletal and mucocutaneous also correlated with corresponding BILAG domain scores (correlation coefficient=0.925 and 0.934, p<0.001). CONCLUSIONS:In this preliminary exercise, there were strong correlations between LFA-REAL and validated lupus disease activity indices. Further development may be valuable for consistent scoring in clinical trials, grading optimal assessment of change in disease activity and reliable monitoring of patients in practice.

Objective. Accurate assessment of lupus flares is critical but problematic in clinical trials. This study examined the impact of modifications to the classic Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA)-SLEDAI flare index (cSFI).Methods. Ninety-one SLE patient records were evaluated at two visits at which the SLEDAI and BILAG had been scored prospectively. The cSFI was compared with an experimental version (eSFI) that eliminated medication criteria and separated the mild/moderate flare category into its components by clinical judgement based on records. The revised SFI (SFI-R) and some physician's global assessments (PGAs) were also scored using chart notes.Results. eSFI-rated moderate flares had higher PGA and BILAG scores than those rated as mild. When medication criteria were excluded, 42 of 55 cSFI severe flares and 15 of 49 mild/moderate flares were downgraded in severity. Comparing flares that remained severe with those that were downgraded, disease activity was higher by PGA (P < 0.001), SLEDAI (P < 0.001), BILAG (P < 0.001), number of active BILAG organs (P < 0.04) and flaring SFI-R organs (P < 0.01). PGA (P < 0.001) and the number of SFI-R domains flaring (P < 0.001) were higher in mild/moderate eSFI flares than in those that were downgraded. Twenty-one of 83 (25%) medication changes occurred with no flare. Forty-six of 52 (88%) medication changes defining severe flare by cSFI involved patients rated by physicians with no, mild or moderate flares.Conclusion. A deconstructed flare index improves the discrimination of mild from moderate flares and selects more ill patients with true clinical worsening for each category of flare.

Objective: Systemic lupus erythematosus (SLE) is a complex and multifactorial autoimmune disease with striking clinical, immunologic and genetic heterogeneity, despite nearly ubiquitous antinuclear antibody (ANA) production. Multiple gene polymorphisms have been associated with the disease, but individually account for only a very small percentage of overall SLE risk. In earlier studies, constitutive expression of the DNA-binding protein, A+T rich interacting domain 3a (ARID3a) in transgenic mouse B lymphocyte lineage cells led to spontaneous ANA production and preferential development of B cells associated with production of polyreactive antibodies. Therefore, we asked if ARID3a was over-expressed in B lymphocytes of SLE patients and if ARID3a expression was associated with disease severity. Methods: A cross section of SLE patients and age and gender-matched controls were analyzed longitudinally for lupus disease activity, numbers of ARID3a+ peripheral blood mononuclear B cells from multiple B cell subsets, immunoglobulin and cytokine levels. Results: Fifty of 115 patients (43%) had dramatically increased numbers of ARID3a+ B cells compared to healthy controls. ARID3a is not expressed in naive B cells of healthy controls, but was abundant in these precursors of antibody-secreting cells in SLE patients. Total numbers of ARID3a+ B cells correlated with increased disease activity as defined by SLE Disease Activity Index scores in individuals assessed at three time points. Conclusion: These findings identify B cell anomalies in SLE that allow stratification of patient samples based on ARID3a expression and implicate ARID3a as a potential marker of CD19+ B lymphocytes correlated with disease activity. (c) 2014 American College of Rheumatology.

Objective. The efficacy and safety of subcutaneous tocilizumab (TCZ-SC) vs placebo (PBO-SC) was evaluated in patients with RA with an inadequate response to DMARDs in the BREVACTA study. Methods. Patients (n=656) were randomized 2:1 to receive TCZ-SC 162 mg every other week (q2w) or PBO-SC q2w for 24 weeks; 20% previously received anti-TNF treatment. Escape therapy with TCZ-SC 162 mg weekly was offered from week 12 for inadequate response. The primary endpoint was ACR20 response at week 24. Key secondary outcomes were radiographic progression and safety. Results. TCZ-SC was superior to PBO-SC for ACR20 response at week 24 (60.9% vs 31.5%; P<0.0001). All secondary endpoints showed TCZ-SC to be superior to PBO-SC: ACR50 and ACR70 (40% vs 12% and 20% vs 5%; both P<0.0001) and DAS28 remission (DAS28<2.6 32% vs 4%; P<0001). The mean change in mTSS score was significantly lower with TCZ-SC vs PBO (0.62 vs 1.23; P=0.0149). AEs and SAEs were comparable between the TCZ-SC and PBO-SC groups: respectively, 4.6% and 3.7% had at least one SAE, and infection was the most common SAE in 2.1% and 1.8%. More injection-site reactions occurred with TCZ-SC vs PBO-SC (7.1% vs 4.1%). No anaphylaxis or serious hypersensitivity reactions occurred. There were 3 deaths in the TCZ-SC group and 0 in the PBO-SC group. Conclusion. TCZ-SC q2w had significantly greater efficacy, including ACR endpoints and inhibition of joint damage compared with PBO-SC. TCZ-SC was well tolerated, and its safety profile was comparable with that of previous TCZ-IV studies. (c) 2014 American College of Rheumatology.