Measuring lupus arthritis activity using contrasted high-field MRI. Associations with clinical measures of disease activity and novel patterns of disease.

OBJECTIVE: Arthritis in SLE is poorly described, and there is no objective measure for quantification of arthritis. In this pilot study, we aim to assess the utility of the Rheumatoid Arthritis MRI Scoring System (RAMRIS) for the quantification of lupus arthritis. METHODS: Patients were eligible for entry into the study if they were evaluated at the Medical University of South Carolina Lupus Center and determined by their treating rheumatologist to have active hand arthritis due to SLE. Standard of care lupus activity measures were collected, along with a detailed physical exam. MRIs were obtained using standard musculoskeletal sequences with gadolinium contrast. Semiquantitative scoring of the images used the Outcome Measures in Rheumatology Clinical Trials RAMRIS system. RESULTS: RAMRIS demonstrates large amounts of synovitis, tenosynovitis, bone marrow oedema and erosive disease in only a minority of patients. Some patients were not scored as having any synovitis or tenosynovitis. We describe potential features of lupus arthritis that are not captured in the RAMRIS scores and may be contributing to symptoms. CONCLUSION: Lupus arthritis is an entity separate from rheumatoid arthritis and requires the development of new quantitative methods to describe and quantitate it. MRI findings suggest the inadequacy of a typical lupus musculoskeletal measure including swollen/tender joint counts to assess the level of disease activity.

Clinical Application of a Modular Genomics Technique in Systemic Lupus Erythematosus: Progress towards Precision Medicine.

Monitoring disease activity in a complex, heterogeneous disease such as lupus is difficult. Both over- and undertreatment lead to damage. Current standard of care serologies are unreliable. Better measures of disease activity are necessary as we move into the era of precision medicine. We show here the use of a data-driven, modular approach to genomic biomarker development within lupus-specifically lupus nephritis.

Corticosteroids in Lupus Nephritis and Central Nervous System Lupus.

Corticosteroids are a mainstay of therapy for severe organ-threatening systemic lupus erythematosus. Lupus nephritis and central nervous system (CNS) lupus remain two of the most debilitating and potentially life-threatening manifestations of lupus. The dose and duration of corticosteroids required for control of lupus nephritis and CNS lupus have never been tested in a randomized trial design, so current recommendations are based on observation and expert opinion. As more targeted individualized therapeutic approaches are developed for lupus nephritis and CNS lupus, reliance on long-term corticosteroids will decrease, as will the long-term damage and early mortality associated with their use.

BAFF (B cell activating factor) transcript level in peripheral blood of patients with SLE is associated with same-day disease activity as well as global activity over the next year.

OBJECTIVES: Quantitating gene expression is a potential method of developing biomarkers in systemic lupus erythematosus (SLE). Because of the known pathological role of B cell activating factor (BAFF) in SLE, we explored the association between BAFF gene expression and clinical activity in SLE. METHODS: A total of 275 patients with SLE completed this phase of a prospective observational study. At entry into the study, the BAFF gene expression levels were determined in peripheral blood RNA. Serum concentration of BAFF protein was also measured. We then determined clinical associations with SLE disease history, SLE activity on the same day and SLE activity over the course of the next year. RESULTS: Elevated BAFF gene expression was associated with a history of more leucopenia and serologically with more autoantibodies (anti-dsDNA, anti-Sm, anti-Ro, anti-La and anti-RNP) and low complement. Patients with higher amounts of BAFF transcript had higher measured levels of clinical disease activity. Initial high levels of BAFF gene expression also predicted increased disease activity over the course of the next year. In contrast, serum concentration of BAFF protein was not strongly associated with same-day global disease activity or with future disease activity. CONCLUSIONS: BAFF gene expression level is associated with clinical and serological SLE activity on the same day and predictive of clinical activity over the next year. BAFF gene expression is a better measure and predictor of SLE disease activity than the serum BAFF protein level.

Simple electrostatic model improves designed protein sequences.

Electrostatic interactions are important for both protein stability and function, including binding and catalysis. As protein design moves into these areas, an accurate description of electrostatic energy becomes necessary. Here, we show that a simple distance-dependent Coulombic function parameterized by a comparison to Poisson-Boltzmann calculations is able to capture some of these electrostatic interactions. Specifically, all three helix N-capping interactions in the engrailed homeodomain fold are recovered using the newly parameterized model. The stability of this designed protein is similar to a protein forced by sequence restriction to have beneficial electrostatic interactions.

Repacking the Core of T4 lysozyme by automated design.

Automated protein redesign, as implemented in the program ORBIT, was used to redesign the core of phage T4 lysozyme. A total of 26 buried or partially buried sites in the C-terminal domain were allowed to vary both their sequence and side-chain conformation while the backbone and non-selected side-chains remained fixed. A variant with seven substitutions ("Core-7") was identified as having the most favorable energy. The redesign experiment was repeated with a penalty for the presence of methionine residues. In this case the redesigned protein ("Core-10") had ten amino acid changes. The two designed proteins, as well as the constituent single mutants, and several single-site revertants were over-expressed in Escherichia coli, purified, and subjected to crystallographic and thermal analyses. The thermodynamic and structural data show that some repacking was achieved although neither redesigned protein was more stable than the wild-type protein. The use of the methionine penalty was shown to be effective. Several of the side-chain rotamers in the predicted structure of Core-10 differ from those observed. Rather than changing to new rotamers predicted by the design process, side-chains tend to maintain conformations similar to those seen in the native molecule. In contrast, parts of the backbone change by up to 2.8A relative to both the designed structure and wild-type. Water molecules that are present within the lysozyme molecule were removed during the design process. In the redesigned protein the resultant cavities were, to some degree, re-occupied by side-chain atoms. In the observed structure, however, water molecules were still bound at or near their original sites. This suggests that it may be preferable to leave such water molecules in place during the design procedure. The results emphasize the specificity of the packing that occurs within the core of a typical protein. While point substitutions within the core are tolerated they almost always result in a loss of stability. Likewise, combinations of substitutions may also be tolerated but usually destabilize the protein. Experience with T4 lysozyme suggests that a general core repacking methodology with retention or enhancement of stability may be difficult to achieve without provision for shifts in the backbone.