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Preliminary test of the LFA rapid evaluation of activity in lupus (LFA-REAL): an efficient outcome measure correlates with validated instruments

Askanase, Anca; Li, Xiaoqing; Pong, Avery; Shum, Katrina; Kamp, Stan; Carthen, Fredonna; Aberle, Teresa; Hanrahan, Leslie; Daly, Paola; Giles, Jon; Merrill, Joan T
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.
PMCID:4378376
PMID: 25861457
ISSN: 2053-8790
CID: 4874542

Development of Lupus Nephritis: Preclinical Evaluation of Patients Who Subsequently Develop Systemic Lupus Erythematosus Demonstrate Elevation of Select Soluble Mediators Prior to and at Disease Classification in Patients with Nephritis [Meeting Abstract]

Munroe, Melissa E; Anderson, Jourdan R; Robertson, Julie M; Niewold, Timothy B; Tsokos, George C; Keith, Michael P; Merrill, Joan T; Buyon, Jill P; Harley, John B; James, Judith A
ISI:000370860203482
ISSN: 2326-5205
CID: 2029592

A Paper Patient-Based Flare Study in SLE [Meeting Abstract]

Sturgess, Joanna; Allan, Elizabeth; Isenberg, David A; Aranow, Cynthia; Aringer, Martin; Askanase, Anca; Bae, Sang-Cheol; Bernatsky, Sasha R; Bruce, Ian N; Buyon, Jill P; Cervera, Ricard; Clarke, Ann; Dooley, Mary Anne; Fortin, Paul R; Giles, Ian; Ginzler, Ellen M; Gladman, Dafna; Gordon, Caroline; Griffiths, Bridget; Hanly, John G; Inanc, Murat; Jacobsen, Soren; Kamen, Diane L; Khamashta, Munther; Lanyon, Peter; Lim, SSam; Manzi, Susan; Mosca, Marta; Nived, Ola; Peschken, Christine A; Petri, Michelle; Kalunian, Kenneth C; Rahman, Anisur; Ramsey-Goldman, Rosalind; Ruiz-Irastorza, Guillermo; Sanchez-Guerrero, Jorge; Schneider, Matteus; Steinsson, Kristjan; Sturfelt, Gunnar K; Urowitz, Murray; van Vollenhoven, Ronald F; Vasconcelos, Carlos; Wallace, Daniel J; Zoma, Asad; Merrill, Joan T; Morand, Eric; Chambers, Sharon; Costedoat-Chalumeau, Nathalie; Croca, Sara
ISI:000370860202004
ISSN: 2326-5205
CID: 2029802

Ribosomal and immune transcripts associate with relapse in acquired ADAMTS13-deficient thrombotic thrombocytopenic purpura

Edgar, Contessa E; Terrell, Deirdra R; Vesely, Sara K; Wren, Jonathan D; Dozmorov, Igor M; Niewold, Timothy B; Brown, Michael; Zhou, Fang; Frank, Mark Barton; Merrill, Joan T; Kremer Hovinga, Johanna A; Lammle, Bernhard; James, Judith A; George, James N; Farris, A Darise
Approximately 40% of patients who survive acute episodes of thrombotic thrombocytopenic purpura (TTP) associated with severe acquired ADAMTS13 deficiency experience one or more relapses. Risk factors for relapse other than severe ADAMTS13 deficiency and ADAMTS13 autoantibodies are unknown. ADAMTS13 autoantibodies, TTP episodes following infection or type I interferon treatment and reported ensuing systemic lupus erythematosus in some patients suggest immune dysregulation. This cross-sectional study asked whether autoantibodies against RNA-binding proteins or peripheral blood gene expression profiles measured during remission are associated with history of prior relapse in acquired ADAMTS13-deficient TTP. Peripheral blood from 38 well-characterized patients with autoimmune ADAMTS13-deficient TTP in remission was examined for autoantibodies and global gene expression. A subset of TTP patients (9 patients, 24%) exhibited a peripheral blood gene signature composed of elevated ribosomal transcripts that associated with prior relapse. A non-overlapping subset of TTP patients (9 patients, 24%) displayed a peripheral blood type I interferon gene signature that associated with autoantibodies to RNA-binding proteins but not with history of relapse. Patients who had relapsed bimodally expressed higher HLA transcript levels independently of ribosomal transcripts. Presence of any one potential risk factor (ribosomal gene signature, elevated HLA-DRB1, elevated HLA-DRB5) associated with relapse (OR = 38.4; p = 0.0002) more closely than any factor alone or all factors together. Levels of immune transcripts typical of natural killer (NK) and T lymphocytes positively correlated with ribosomal gene expression and number of prior episodes but not with time since the most recent episode. Flow cytometry confirmed elevated expression of cell surface markers encoded by these transcripts on T and/or NK cell subsets of patients who had relapsed. These data associate elevated ribosomal and immune transcripts with relapse history in acquired, ADAMTS13-deficient TTP.
PMCID:4324966
PMID: 25671313
ISSN: 1932-6203
CID: 2627952

How should lupus flares be measured? Deconstruction of the Safety of Estrogen in Lupus Erythematosus National Assessment-Systemic Lupus Erythematosus Disease Activity Index flare index

Thanou, Aikaterini; Chakravarty, Eliza; James, Judith A; Merrill, Joan T
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.
PMCID:4542656
PMID: 24729400
ISSN: 1462-0324
CID: 986632

Disease activity in lupus correlates with expression of the transcription factor ARID3a

Ward, Julie M; Rose, Kira; Montgomery, Courtney; Adrianto, Indra; James, Judith A; Merrill, Joan T; Webb, Carol F
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.
PMCID:4245462
PMID: 25185498
ISSN: 2326-5205
CID: 1180852

Subcutaneous Tocilizumab vs Placebo in Combination With Disease Modifying Antirheumatic Drugs in Patients With Rheumatoid Arthritis

Kivitz, Alan; Olech, Ewa; Borofsky, Michael; Zazueta, Beatriz M; Navarro-Sarabia, Federico; Radominski, Sebastiao C; Merrill, Joan T; Rowell, Lucy; Nasmyth-Miller, Clare; Bao, Min; Wright, Stephen; Pope, Janet E
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.
PMCID:4276289
PMID: 24942540
ISSN: 2151-464x
CID: 1065452

A 2014 update on the management of patients with systemic lupus erythematosus

Merrill, Joan T; Buyon, Jill P; Utset, Tammy
Systemic lupus erythematosus (SLE) is a chronic, relapsing autoimmune connective tissue disease, primarily affecting the skin, joints, kidneys, heart, lungs, nervous system, blood elements, and serosal membranes. SLE is characterized by cytokine dysregulation, polyclonal B-cell activation, autoantibody production, and increased immune complex formation due to aberrations involving hyperactive B cells, T cells, and cells of the monocytic lineage. The symptoms of SLE are often diverse and nonspecific, and timely identification of SLE and associated comorbidities in patients is critical as aggressive monitoring and therapy may be warranted, especially in patients with poor prognoses. Based on the up-to-date understanding of the pathophysiology of SLE, the first targeted biological agent belimumab has been approved by the US Food and Drug Administration (FDA) in more than 50 years, and many targeted agents are being evaluated in late-stage clinical trials. There is a clear need to discuss how and when to incorporate new and emerging biological agents in managing patients with SLE. Additionally, the potential for increased risk of infections is a factor that heavily influences the rheumatologists decision to use biological agents in managing patients with SLE. Hence, in this roundtable educational activity, expert faculty will review and discuss the strategies for timely diagnosis of SLE and associated comorbidities. They will also discuss the current understanding of the pathophysiology of SLE and how new and emerging biological agents help address the underlying pathophysiological aberrations in patients with SLE. The faculty will also review strategies to minimize the risk of infections and other toxicities in patients with SLE.
PMID: 25437901
ISSN: 0049-0172
CID: 1369172

Elevated Regulatory Mediators and Interferon Gamma Associated Responses, but Not Interferon Alpha, BLyS or IP-10, Accompany High-Titer Anti-Ro Autoantibodies in Asymptomatic Mothers of Children with Neonatal Lupus. [Meeting Abstract]

Izmirly, Peter M; Clancy, Robert M; Munroe, Melissa; Rasmussen, Sara; Saxena, Amit; Scher, Jose U; Thanou, Aikaterini; Kamp, Stan; Merrill, Joan T; Buyon, Jill P; James, Judith
ISI:000344384903229
ISSN: 2326-5205
CID: 1444042

Outcome of Lupus Nephritis and Impact on Health Related Quality of Life: Results from an International, Prospective, Inception Cohort Study. [Meeting Abstract]

Hanly, John G; O'Keeffe, Aidan; Su, Li; Urowitz, Murray B; Romero-Diaz, Juanita; Gordon, Caroline; Bae, Sang-Cheol; Bernatsky, Sasha R; Clarke, Ann E; Wallace, Daniel J; Merrill, Joan T; Isenberg, David A; Rahman, Anisur; Ginzler, Ellen M; Fortin, Paul; Gladman, Dafna D; Sanchez-Guerrero, Jorge; Petri, Michelle A; Bruce, Ian; Dooley, Mary Anne; Ramsey-Goldman, Rosalind; Aranow, Cynthia; Alarcon, Graciela S; Fessler, Barri; Steinsson, Kristjan; Nived, Ola; Sturfelt, Gunnar; Manzi, Susan; Khamashta, Munther A; van Vollenhoven, Ronald F; Zoma, Asad; Ramos-Casals, Manuel; Ruiz-Irastorza, Guillermo; Lim, SSam; Stoll, Thomas; Inanc, Murat; Kalunian, Kenneth C; Kamen, Diane L; Maddison, Peter; Peschken, Christine A; Jacobsen, Soren; Askanase, Anca; Buyon, Jill P; Theriault, Chris; Thompson, Kara; Farewell, Vernon; Systemic Lupus Int Collaborating
ISI:000344384902068
ISSN: 2326-5205
CID: 1443372