Background/Purpose:

TNF-like weak inducer of apoptosis (TWEAK) is a member of the TNF superfamily that signals through its distinct, highly inducible receptor, FGF-inducible molecule 14 (Fn14) on renal epithelial and mesenchymal cell types. The TWEAK/Fn14 pathway mediates key pathologic processes involved in renal disease in SLE. Previous studies have demonstrated that lupus patients with active renal disease have higher levels of urinary TWEAK (uTWEAK) compared to those without active renal disease. Furthermore, uTWEAK levels correlated significantly with renal disease activity on the same day as assessed by the renal SLE Disease Activity Index (SLEDAI) scores. However, the value of uTWEAK to predict SLE disease activity during follow up is unknown. The aim of this study was to explore the ability of uTWEAK levels to predict SLE renal and non-renal disease activity in the subsequent year after measurement.

Methods: The SPARE study is a prospective, longitudinal, observational study conducted at single center. Consecutive adult patients attending the SLE clinic were eligible if they met the ACR Criteria for SLE. At baseline, uTWEAK levels were measured by ELISA and normalised with urinary creatinine. Patients within uTWEAK quartiles were compared with respect to the frequency of disease activity measured at clinic visits in the following year. Estimates of differences and p-values were based on generalized estimating equations (GEE) models to account for repeated visits from the same patient. Cox proportional hazards models were fit to time to first renal flare within the first year, adjusting for either log2-transformed or quartile of uTWEAK along with sex, race, complement (C3, C4), and dsDNA; p-values for uTWEAK were based upon the effect estimates. Renal flares were defined as increase in SLEDAI renal descriptors or doubling of urine protein/cr.

Results: 293 patients were included in the analysis: 91% were female; 59% Caucasian and 33% African American. The mean age was 46.2 (±12) years. Patients with higher uTWEAK at baseline were more likely to have renal SLEDAI, uPCR >0.5, PGA >1 and SLEDAI >3 during the follow-up year (Table 1). There were no differences in the non-renal SLEDAI score components or levels of anti-dsDNA and complement. The variables associated with time to first renal flare within one year of follow up included male gender, asian race, complement, dsDNA and uTWEAK. The median time (days) to renal flare declined with increasing quartile of uTWEAK (q1=323 / q2=195 / q3=183 / q4=141; p=0.05 for comparing hazard q4 to q1). In the model where log2-transformed uTWEAK was treated as a continuous variable, each 2-fold increase in uTWEAK corresponded to 1.34 times the instantaneous risk of having a flare in the first year (p=0.04).

Variable	Low uTWEAK Patient n=73 Visit n=310	Medium low uTWEAK Patient n=73 Visit n=294	Medium high uTWEAK Patient n=73 Visit n=300	High uTWEAK  Patient n=74 Visit n=313	P-value	Adjusted P-value for race	Adjusted P-value for trend
PGA >1	13%	15%	16%	27%	0.099	0.135	0.0098
SLEDAI ≥3	22%	21%	27%	30%	0.42	0.24	0.044
urine protein/cr ≥0.5	5%	5%	12%	15%	0.12	0.20	0.012
Anti-dsDNA ≥ 10	24%	19%	21%	21%	0.90	0.91	0.62
C3 <79	7%	10%	16%	15%	0.15	0.20	0.12
C4 <12	8%	10%	14%	11%	0.62	0.70	0.62
ESR >20	58%	46%	50%	45%	0.30	0.58	0.66
Any SLEDAI Renal	3%	5%	9%	12%	0.013	.0.016	0.0088
Any SLEDAI Musculoskeletal	2%	3%	2%	5%	0.40	0.38	0.14
Any SLEDAI Immunologic	32%	26%	31%	28%	0.85	0.82	0.85
Any SLEDAI Skin	31%	31%	28%	23%	0.53	0.92	0.84
Any SLEDAI Hematology	3%	5%	5%	4%	0.87	0.85	0.14

Conclusion: Shorter time to renal flare and increased renal disease activity over a 1 year period is associated with higher urinary TWEAK levels in patients with SLE

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/time-to-renal-flare-and-renal-disease-activity-over-a-1-year-period-is-associated-with-urinary-tweak-levels-in-patients-with-systemic-lupus-erythematosus/