A Longitudinal Analysis of Change in Lupus Nephritis in an International Inception Cohort Using a Multistate Markov Model Approach

John G. Hanly¹, Li Su², Murray Urowitz^3,4, Juanita Romero-Diaz⁵, C. Gordon⁶, Sang-Cheol Bae⁷, Sasha R Bernatsky⁸, Ann Clarke⁹, Daniel J Wallace¹⁰, Joan T. Merrill¹¹, David A. Isenberg¹², Anisur Rahman¹³, Ellen M. Ginzler¹⁴, Paul Fortin¹⁵, Dafna D. Gladman¹⁶, Jorge Sanchez-Guerrero¹⁷, Michelle Petri¹⁸, Ian N. Bruce¹⁹, Mary Anne Dooley²⁰, Rosalind Ramsey-Goldman²¹, Cynthia Aranow²², Graciela S. Alarcon²³, Barri J. Fessler²⁴, Kristján Steinsson²⁵, Ola Nived²⁶, Gunnar K. Sturfelt²⁷, Susan Manzi²⁸, Munther Khamashta²⁹, Ronald F. van Vollenhoven³⁰, Asad Zoma³¹, Guillermo Ruiz-Irastorza³², Manuel Ramos-Casals³³, S. Sam Lim³⁴, Thomas Stoll³⁵, Murat Inanc³⁶, Kenneth C. Kalunian³⁷, Diane L. Kamen³⁸, Peter Maddison³⁹, Christine A. Peschken⁴⁰, Søren Jacobsen⁴¹, Anca Askanase⁴², Chris Theriault⁴³, Kara Thompson⁴³ and Vernon Farewell⁴⁴, ¹Rheumatology, Division of Rheumatology, Capital Health and Dalhousie University, Halifax, NS, Canada, ²Nova Scotia Rehab Site, Division of Rheumatology, Capital Health and Dalhousie University, Halifax, NS, Canada, ³Rheumatology, TWH, Toronto, ON, Canada, ⁴Rheumatology, U of Toronto, Toronto Western Hospital, Toronto, ON, Canada, ⁵Immunology and Rheumatology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, Mexico city, Mexico, ⁶School of Immunity and Infection, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom, ⁷Rheumatology, Hanyang University Hospital for Rheumatic Diseases, Seoul, South Korea, ⁸Division of Rheumatolog, McGill Unversity Health Cener, Montreal, QC, Canada, ⁹Division of Rheumatology, Department of Medicine, University of Calgary, Calgary, AB, Canada, ¹⁰Cedars-Sinai Medical Center, West Hollywood, CA, ¹¹Clinical Pharmacology, Oklahoma Medical Research Foundation, Oklahoma City, OK, ¹²Rayne Institute, Centre for Rheumatology Research, UCL Division of Medicine, London, United Kingdom, ¹³Centre for Rheumatology Research, U College of London, London, United Kingdom, ¹⁴Medicine/Box 42, SUNY-Downstate, Brooklyn, NY, ¹⁵Medicine, Division of Rheumatology, Centre Hospitalier Universitaire de Quebec et Universite Laval, Quebec, QC, Canada, ¹⁶Department of Medicine, Division of Rheumatology, University of Toronto, Toronto, ON, Canada, ¹⁷Rheumatology, Toronto Western Hospital, Toronto, ON, Canada, ¹⁸Rheumatology, Johns Hopkins University Hospital, Baltimore, MD, ¹⁹Stopford Building, Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, Manchester Academic Health Science Centre, The University of Manchester, Manchester, United Kingdom, ²⁰UNC Kidney Centre, Chapel Hill, NC, ²¹Northwestern University Feinberg School of Medicine, Chicago, IL, ²²Feinstein Institute for Medical Research, Manhasset, NY, ²³Medicine, University of Alabama at Birmingham, Birmingham, AL, ²⁴UAB, Birmingham, AL, ²⁵Rheumatology, Univ. Hospital, Reykjavik, Iceland, ²⁶Rheumatology, Inst of Clinical sciences, Lund, Sweden, ²⁷Department of Rheumatology, Univ Hospital Lund, Lund, Sweden, ²⁸Rheumatology, Allegheny Health Network, Pittsburgh, PA, ²⁹Graham Hughes Lupus Research Laboratory, The Rayne Institute, St Thomas' Hospital, London, United Kingdom, ³⁰Department of Medicine, Unit for Clinical Therapy Research, Inflammatory Diseases (ClinTRID), The Karolinska Institute, Stockholm, Sweden, ³¹Rheumatology, Hairmyres Hospital, East Kilbride, United Kingdom, ³²Universidad del Pais Vasco, Servicio de Medicina Interna, Hospital de Cruces, Bizkaia, Spain, ³³Autoimmune Diseases, IDIBAPS, Hospital Clinic, Barcelona, Spain, ³⁴Emory University School of Medicine, Atlanta, GA, ³⁵Abteilung Rheumatologie/Rehab, Kantonsspital Schaffhausen, Schaffhausen, Switzerland, ³⁶Department of Internal Medicine, Division of Rheumatology, Istanbul University, Istanbul Faculty of Medicine, Istanbul, Turkey, ³⁷Center for Innovative Therapy, UCSD School of Medicine, La Jolla, CA, ³⁸Medicine, Medical University of South Carolina, Charleston, SC, ³⁹School of Sport, Health and Exercise Sciences, Bangor University, George Building, Bangor, Gwynedd, LL57 2PZ, UK., Bangor, United Kingdom, ⁴⁰Rheumatology, Univ of Manitoba, Winnipeg, MB, Canada, ⁴¹Rheumatology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark, ⁴²NYU School of Medicine, New York, NY, ⁴³Dept of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Halifax, NS, Canada, ⁴⁴Medicine, Division of Rheumatology, Capital Health and Dalhousie University, Halifax, NS, Canada

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: SLE and nephritis

Session Information

Date: Tuesday, November 10, 2015

Title: Systemic Lupus Erythematosus - Clinical Aspects and Treatment V: Neuropsychiatric Lupus

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose: Patients with lupus nephritis (LN) may
have improvement or deterioration in renal status over time. To capture bidirectional
change we used a reversible multistate Markov model to study transitions in glomerular filtration rate (GFR) and
proteinuria (PrU) in a prospective, international, inception cohort of SLE
patients receiving
standard of care.

Methods: Patients were evaluated at enrollment
and annually. LN was identified from the ACR classification criteria and/or
renal biopsy. Data included medications, estimated GFR (eGFR) and PrU (ePrU), disease
activity (SLEDAI-2K), organ damage [(SLICC)/ACR damage index (SDI)] and lupus
autoantibodies including IgG anticardiolipin (aCL) and lupus anticoagulant
(LAC). GFR states were defined: state 1 (eGFR: >60 ml/min); state 2 (eGFR:
30–60 mL/min); and state 3 (eGFR: <30 ml/min). Similarly, PrU states were
defined: state 1 (ePrU: <0.25 gr/day); state 2 (ePrU: 0.25–3.0 gr/day); and
state 3 (ePrU: >3.0 gr/day). Multistate models were used to provide
estimates of relative transition rates and state occupancy probabilities for
various time periods.

Results: Of 1,826 SLE patients, 89% were
female, 49.2% Caucasian with mean±SD age 35.1±13.3
years. The mean disease duration at enrollment was 0.5±0.3
years and follow-up was 4.6±3.4 years. LN occurred in 700/1,826 (38.3%)
patients. There was no observed change in eGRF state for 2303/2430 (94.8%), 136/255
(53.3%) and 26/55 (47.3%) visits when the previous eGFR state was 1, 2 and 3
respectively. The corresponding values for ePrU states were 1167/1460 (79.9%), 547/983
(55.6%) and 59/205 (28.8%). For both outcomes the likelihood of improvement
(states 2 to 1 and 3 to 2) was greater than deterioration (states 1 to 2 and 2
to 3). The transition from state 3 to ESRD was more likely with eGFR (54%) than
ePrU (9%). Probability estimates of transitioning between eGFR and ePrU states,
ESRD and death at 1, 2 and 5 years were determined. At year one the highest
probability was for patients to remain in the initial eGFR (95%, 55%, 42%) or
ePrU (81%, 56%, 31%) state. Following 2 and 5 years, the estimated probability
for improvement in either eGFR or ePrU was higher than deterioration. Multivariate
analysis identified older age (p<0.001), race/ethnicity (Hispanic, Asian and
African ancestry) (p<0.001), higher ePrU state (p<0.001), higher renal
biopsy chronicity score (p=0.013) and baseline aCL antibodies (p=0.039) as predictors
for deterioration in eGFR states and male sex (p=0.04) for improvement. For
ePrU, multivariate analysis identified race/ethnicity (Hispanic, Asian and
African ancestry) (p=0.009), corticosteroid use (p=0.031), higher eGFR state
(p=0.011) and higher renal biopsy chronicity score (p=0.015) as predictors for
deterioration. Positive LAC (p=0.006) and ISN/RPN class V nephritis (p=0.013)
were associated with lower improvement rate.

Conclusion: Multistate modeling in patients with
LN generates probability estimates of transitions between disease states that reflect
improvement or deterioration in renal outcomes. This approach can identify predictors
of change in renal status and can inform clinical trial design by providing minimum
expectations for benefit from new therapeutic interventions for LN.

Disclosure: J. G. Hanly, None; L. Su, Bristol-Myers Squibb, 2; M. Urowitz, Bristol-Myers Squibb, 2; J. Romero-Diaz, None; C. Gordon, Bristol-Myers Squibb, 2; S. C. Bae, None; S. R Bernatsky, None; A. Clarke, None; D. J. Wallace, Bristol-Myers Squibb, 2; J. T. Merrill, Bristol-Myers Squibb, 2; D. A. Isenberg, Bristol-Myers Squibb, 2; A. Rahman, Bristol-Myers Squibb, 2; E. M. Ginzler, None; P. Fortin, None; D. D. Gladman, Abbvie, 2,Amgen, 5,BMS, 5,Celgene, 2,Eli Lilly and Company, 5,Janssen Pharmaceutica Product, L.P., 2,Novartis, 2,Pfizer Inc, 5,UCB, 2; J. Sanchez-Guerrero, Bristol-Myers Squibb, 2; M. Petri, None; I. N. Bruce, Bristol-Myers Squibb, 2; M. A. Dooley, Lilly, 9,Aurinia, 9,GSK, 5,Genentech and Biogen IDEC Inc., 5,EMD Serono, 5,Medimmune, 5,UCB, 5; R. Ramsey-Goldman, None; C. Aranow, None; G. S. Alarcon, None; B. J. Fessler, None; K. Steinsson, Bristol-Myers Squibb, 2; O. Nived, Bristol-Myers Squibb, 2; G. K. Sturfelt, Bristol-Myers Squibb, 2; S. Manzi, Bristol-Myers Squibb, 2,Bristol-Myers Squibb, 2; M. Khamashta, Bristol-Myers Squibb, 2; R. F. van Vollenhoven, AbbVie, BMS, GSK, Pfizer, Roche, UCB, 2,AbbVie, Biotest, BMS, Crescendo, GSK, Janssen, Lilly, Merck, Pfizer, Roche, UCB, Vertex, 5; A. Zoma, Bristol-Myers Squibb, 2; G. Ruiz-Irastorza, Bristol-Myers Squibb, 2; M. Ramos-Casals, None; S. S. Lim, None; T. Stoll, Bristol-Myers Squibb, 2; M. Inanc, None; K. C. Kalunian, Bristol-Myers Squibb, 2; D. L. Kamen, None; P. Maddison, Bristol-Myers Squibb, 2; C. A. Peschken, None; S. Jacobsen, Bristol-Myers Squibb, 2; A. Askanase, None; C. Theriault, None; K. Thompson, None; V. Farewell, Bristol-Myers Squibb, 2.

To cite this abstract in AMA style:

Hanly JG, Su L, Urowitz M, Romero-Diaz J, Gordon C, Bae SC, R Bernatsky S, Clarke A, Wallace DJ, Merrill JT, Isenberg DA, Rahman A, Ginzler EM, Fortin P, Gladman DD, Sanchez-Guerrero J, Petri M, Bruce IN, Dooley MA, Ramsey-Goldman R, Aranow C, Alarcon GS, Fessler BJ, Steinsson K, Nived O, Sturfelt GK, Manzi S, Khamashta M, van Vollenhoven RF, Zoma A, Ruiz-Irastorza G, Ramos-Casals M, Lim SS, Stoll T, Inanc M, Kalunian KC, Kamen DL, Maddison P, Peschken CA, Jacobsen S, Askanase A, Theriault C, Thompson K, Farewell V. A Longitudinal Analysis of Change in Lupus Nephritis in an International Inception Cohort Using a Multistate Markov Model Approach [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/a-longitudinal-analysis-of-change-in-lupus-nephritis-in-an-international-inception-cohort-using-a-multistate-markov-model-approach/. Accessed .

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