Three non-Caucasian women with systemic lupus erythematosus (SLE) patients developed lupus nephritis more than 15 years post-diagnosis. The cases pointed to possible serological harbingers of delayed lupus nephritis (DLN) that may warrant renal biopsy, researchers wrote in Lupus Science & Medicine.
According to David A, Isenberg MD, of University College London, and colleagues, these women — part of a British cohort of nearly 700 SLE patients — showed serological signs of increasing disease activity such as rising levels of anti-double strand DNA (anti-dsDNA) antibodies and falling levels of C3 complement, which predated any clinical or laboratory signs of LN by as long as 3 years.
Affecting as many as half of all SLE patients, lupus nephritis usually appears within 5 years of a diagnosis of SLE. DLN is a rare development that may become more common as the life expectancy of SLE patients rises. The authors noted that DLN can strike at any age and should be differentiated from late-onset LN, which occurs in patients diagnosed with SLE after age 50 with slightly better renal outcomes compared with early-onset LN.
By ethnicity, the three women in question were African, Indian, and Asian and received their SLE diagnoses at ages 28, 15, and 32 respectively. They were diagnosed with DLN 19 years, 17 years, and 15 years (ages 47, 32, and 47) after their initial SLE diagnoses. In the virtually non-existent literature on this condition, the researchers found only one other case, which showed an SLE-to-DLN gap 34 years.
At SLE diagnosis, all three patients had arthritis and two had serositis and rash, high antinuclear antibody titer with diffuse pattern and anti-Ro antibodies. But despite the increased risk of developing DLN associated with Sjoren syndrome, only one patient had this condition and only one had low C3 at SLE onset. None had antiphospholipid syndrome, another risk factor for DLN.
All three women had multiple SLE flares before DLN onset. Hydroxychloroquine was prescribed for most of the disease duration in all three, all received mycophenolate mofetil, and two were treated successfully with rituximab for SLE flares occurring long before LN onset.
Serum creatinine, estimated gromerular filtration rate, and urine protein-to-creatinine ratio were within the normal range in all cases, and proteinuria or hematuria was not detected until the patients presented with DLN. Two patients developed peripheral edema and hypertension. Estimated glomerular filtration rate fell below 70 mL/min/1.73 m2 in all cases.
But renal biopsies showed no chronic indicators of DLN-associated damage, suggesting de novo kidney disease.
Significantly, serological evidence of increasing disease activity set in long before LN was clinically obvious, with rising anti-dsDNA antibody levels accompanied by falling C3 values. Hypocomplementemia levels persisting for more than 6 months has been reported as an independent risk factor for LN, and a level below 0.65 mg/dL has been suggested as a marker of silent LN. All three patients had fallen below this threshold by 1 to 3 years before overt DLN.
“We acknowledge that silent LN could have been present during this period, becoming clinically evident as the systemic disease went out of control,” Isenberg and co-authors wrote. “However, the lack of chronic damage seen in the biopsies after extensive active SLE without LN argues against this form of long-standing subclinical kidney inflammation.”
This serological pattern antedated any changes in urine analysis or kidney function results and may be used in similar patients to raise awareness about the possibility of LN, according to the investigators.
In their view, persistent serological deterioration in apparently non-renal patients with very long established disease suggests the possible onset of kidney involvement and a need for biopsy. “Renal biopsy to search for silent LN or SLE therapy optimisation to prevent renal damage might be reasonable management options,” they wrote.
Rosalind Ramsey-Goldman, MD, of Northwestern University in Chicago, who was not involved in the study, said the cases support close the need for regular follow-up and early intervention to minimize kidney damage in the face of worsening serology. But in her view blood work alone without evidence of kidney problems is not sufficient to warrant the invasive procedure of renal biopsy.
Ramsey-Goldman, who has treated two Caucasian women for DLN, noted that there is often discordance between patients’ blood work and their clinical status. “Patients can be clinically quiescent but serologically active, and that presents a dilemma for physicians,” she told MedPage Today. “The serologically active patients have a higher risk of becoming sick but may never do so because biomarkers are far from perfect and we might treat people who would never have a problem. We would love to be able to treat preemptively to prevent flares or kidney disease but the drugs have a lot of side effects.”
Current research is focusing on finding better predictive biomarkers. “That would be a major win in terms of advising physicians on which patients to treat,” Ramsey-Goldman said.
Since most SLE patients do not have prolonged remission, she noted an outcome shift away from the too-high bar of total drug-free remission and all-normal serology to the less stringent concept of low disease activity. “If you can keep patients in this low range where the blood work is not terribly abnormal and the clinical symptoms are not severe, they are less likely to get into trouble,” she said. “But if the serology is very abnormal, you have to closely follow patients even if they’re not feeling too bad. The cases of these three women would fit that.”
The scenario of pronounced serological abnormalities and a history of flares could herald new flares that need to be picked early on to prevent kidney damage and avoid eventual dialysis or transplant, Ramsey-Goldman said.
The authors declared no conflicts of interest.
F. Perry Wilson, MD, MSCE Assistant Professor, Section of Nephrology, Yale School of Medicine and Dorothy Caputo, MA, BSN, RN, Nurse Planner