Photo Credit: Dr. Microbe
This study pushes the field of rheumatology closer to precision medicine and away from a one-size-fits-all approach to treatment.
For patients with proliferative lupus nephritis (LN), immunohistochemical analysis of renal tissue shows promise as a precision medicine approach to their treatment, researchers in Japan suggest.
“Predominant expression of interferon-α in LN renal tissue was related to renal activity and poor prognosis,” senior study author Yoshiya Tanaka, MD, PhD, and colleagues write in Lupus Science & Medicine. “The results indicated the possibility of stratifying cases according to the IHC [immunohistochemistry] of target molecules, which might lead to precision medicine.”
Lupus Nephritis Is a Serious Complication of SLE
In LN, a serious complication of the autoimmune disease systemic lupus erythematosus (SLE), the immune system attacks and damages the kidneys, potentially leading to kidney failure, dialysis, or kidney transplant, according to the Lupus Foundation of America.
Most patients with LN are prescribed glucocorticoids and immunosuppressants, including cyclophosphamide and mycophenolate mofetil, and new lupus therapies such as the biologics belimumab and anifrolumab are becoming increasingly available.
Researchers Investigated Three Molecular Targets
Dr. Tanaka and colleagues investigated whether the expression of molecular targets of biologics in LN kidney tissue was linked with disease activity, prognosis, and pathological findings. To do this, they studied three molecular targets of cytokines: B-cell activating factor (BAFF), interferon (IFN)-α, and interleukin (IL)-12 (Figure).
They identified individuals in the LOOPS registry of patients with SLE who were treated in an academic hospital system. Between 2011 and 2019, the study enrolled 50 patients with class III/IV proliferative LN as the case group, while 5 patients with class II LN and IgA glomerulonephritis with active glomerular lesions, and 10 with idiopathic hematuria were designated as controls. All patients with LN underwent needle renal biopsy at LN onset. Patients treated with biologics such as rituximab or belimumab before biopsy were excluded from the study.
The biopsy samples were fixed in formalin, embedded in paraffin, stained, and examined by light, immunofluorescent, and electron microscopy. The researchers performed immunohistochemical analyses by counting the number of cells that were positive for CD3, CD20, interferon (IFN)-α, interleukin (IL)-12, and B-cell activating factor (BAFF) and assigning an IHC score to each cytokine based on the number of positive cells per mm2 of renal cortex.
Proliferative LN cases were sorted into three subgroups determined by the immunohistochemical score based on the dominance of IFN-α (n=17), IL-12 (n=16), and BAFF group (n=17) proteins.
Hypocomplementemia and glomerular endocapillary hypercellularity were significantly higher in the IFN-α group, while chronic lesions were significantly higher in the IL-12 group (P<0.05). After 52 weeks, patients in the IFN-α group had poorer renal prognosis in treatment response.
Key Question: Which Cells Respond to the Cytokines?
According to Jeremy Tilstra, MD, PhD, since the study “focuses on identifying three different molecular targets in LN, all of which we have treatments that target them,” the findings can be immediately applied to patients.
“Specifically, one could more aggressively treat patients who have an IFN-α signature with IFN-α-targeted therapy plus other medications, as patients in this study with that phenotype had worse outcomes,” adds Dr. Tilstra, who was not involved in the study.
“However, while the study points out which cells are producing the three different cytokines, it does not look at which cells respond to the cytokines, and that will be important for future work,” he notes. “Also, we know that many signaling factors have disease-promoting and disease-protective effects. Therefore, just because these cytokines are produced does not mean they are, in fact, the mediators of disease.”
“This study continues to push the field of rheumatology closer to precision medicine and away from a one-size-fits-all approach to treatment,” Dr. Tilstra concludes. “It sets the stage for lupus treatment to move to the next phase whereby treatments are selected based on molecular markers targeted to individual patients, which is similar to what is done for cancer treatment.”
