This is the first study evaluating the effect of IL-17A blockade on progressive r-IgAN previously treated with PRC. The combined therapy seems highly effective in controlling proteinuria and hematuria and stabilizing renal function, which is associated with changes in circulating Th17.1 and Th2 cells. The presence of only one nonresponder emphasizes that this combined therapy might target a critical pathophysiological pathway, the IL-17A, and the gut-kidney axis. In line with this proposed mechanism, orally administered enteral budesonide, designed to address inflammation within the gut-associated lymphoid system in IgAN patients, has demonstrated significant advantages in managing proteinuria and maintaining eGFR stability31,32. To the best of our knowledge, no therapy has proven such an effect in patients with r-IgAN, even without driving 24-h proteinuria below the 1 g threshold33.
Our novel approach designed with the intention of downregulating the Th1 inflammatory response, followed by IL-17A blockade and was based on several experimental studies evaluating anti-IL-17 therapy, in which worsening of colitis in patients21 or glomerulonephritis in animal models34 was observed in the presence of an active Th1 pro-inflammatory response. More recently, a study described that autonomous activation of IL-17 receptor is responsible for continuous inflammation35. This could explain the lack of efficacy in some IL-17-associated pathologies when IL-17A inhibition is administered alone.
Proteinuria decreased by 71% with respect to baseline. All but one patient (patient #3) achieved partial remission of proteinuria (< 1 g/24 h) at any time throughout the follow-up, which may improve renal prognosis36. Notably, the maximum decrease obtained in proteinuria [median (p25–p75)] was 0.5 g/24 h (0.4–0.7), which suggests the high antiproteinuric effect of the combined therapy in our patients.
The mean eGFR at baseline in our patients was lower than 60 mL/min/1.73 m2, which is considered an independent high-risk factor for developing end-stage renal disease37. Except for patient #3, the annual decline improved significantly to 4.9 mL/min/1.73 m2 (mean), which is clinically meaningful. Furthermore, a 1-year eGFR slope could be considered a surrogate renal endpoint in IgAN patients38; therefore, the combined therapy showed benefits in both proteinuria and eGFR. Patient #3 experienced a rapid progressive eGFR decline and was needed to start dialysis 36 months after the inclusion in the study. Patient #7 continued decreasing eGFR; however, the patient started combined therapy with a low eGFR (32 mL/min/1.73 m2) and nephrotic proteinuria (5.1 g/24 h). At the end of the follow-up, his proteinuria was well controlled (0.8 g/24 h); therefore, whether this benefit will slow the decline in kidney function will be evaluated in the coming months.
The benefits of the combined therapy were independent of antihypertensive treatment and body weight since no significant changes in these markers were observed. However, hypotensive drugs had to be reduced in two patients. At the same time, systolic blood pressure tended to decrease at the end of the follow-up period, which suggests a potential benefit of the combined therapy on blood pressure in our patients. The role of adaptive immunity (Th1 and Th17 cells) and IL-17 in the pathogenesis of hypertension has been confirmed by its actions on the proximal and distal tubules, in the thick ascending limb, and the epithelial sodium channel in the collecting duct39. Notably, the sole use of SCK did not show benefits in blood pressure in patients with psoriasis, psoriatic arthritis, and axial spondyloarthritis40. Further investigation is needed to determine whether the decrease in hypotensive drugs in our patients results from the effect of IL-17A blockade on the arteries, renal environment, or both.
Following the study hypothesis, combined therapy slightly decreased circulating Th1 cells and stabilized Treg cells during the follow-up. In contrast with our findings, Treg cells decreased in skin lesions from patients with psoriasis treated with SCK41 and decreased peripheral Treg cells in ankylosing spondylitis patients42. During IL-17A blockade, peripheral Treg cells remained stable, potentially enhancing the safety of IL-17 inhibition. We observed that peripheral Th17 cells initially tended to fall but returned to baseline values at the end of the follow-up. We do not have a clue about this finding, but we do humbly speculate that the peripheral number of Th17 cells may not reflect the effect on the kidney of the combined therapy (given the profound changes observed in proteinuria and eGFR) or maybe reflect changes in the Th17 cells phenotype could have produced it.
Unexpectedly, peripheral Th17.1 cells increased during the study. These cells are considered pathogenic in lupus, multiple sclerosis, and sarcoidosis43; specifically, Th17.1 cells display high expression of multidrug resistance protein 1 (MDR1) and low expression of glucocorticoid receptors44 that confer a limited response to steroids. In IgAN, Th17.1 cells express the chemokines C-C motif chemokine receptor 6 (CCR6) and C-X-C motif chemokine receptor 3 (CXCR3), which increase the recruitment of proinflammatory cells and produce tubulointerstitial fibrosis34,45, respectively. Therefore, the accumulation of these cells in the blood highlights their potential critical role in r-IgAN pathogenesis. If the elevation of circulating Th17.1 cells results from cellular trafficking from inflamed tissues, as proposed in multiple sclerosis patients after natalizumab treatment46, or stems from enhanced differentiation of precursor cells with a concurrent reduction in their pathogenic potential, it necessitates comprehensive investigation.
While Th2 cells were not originally the focus of the combined therapy, our research indicates a significant decrease in Th2 cells, with an observed inverse correlation between these changes and Th17 cells, suggesting a bidirectional influence. We speculate that the blockade of IL-17A following SCK administration could induce this effect. According to data from a murine model of atopic dermatitis, IL-17 is instrumental in transforming naive T cells into Th2 cells while concurrently diminishing Th2 chemokine expression and populations of IL-4-producing cells in the absence of IL-17A47. Additionally, emerging evidence supports the interplay between Th17 and Th2 cells through the transcription factor retinoic acid-related orphan receptor γt (RORγt). For instance, RORγt has a dual role: it not only regulates Th17 cells but also inhibits their conversion into Th2 cells48. Vitamin D metabolites are known agonists of RORγt49, and paricalcitol (19-nor-1alpha-25-dihydroxyvitamin D2) may influence RORγt. Thus, we consider it feasible that combination therapy could decrease Th2 cells. Therefore, whether a beneficial synergistic effect of combined therapy on Th2 cells exists, or if SCK alone can impact Th2 cells in IgAN, warrants further investigation.
The decrease in Th2 cells could be beneficial and it is supported by the fact that higher circulating levels of Th2 cells have been observed in IgAN patients compared to healthy controls50. Additionally, the reversal of the Th1/Th2 cell imbalance, as observed in our patients, might reduce the severity of IgAN51. In our patients, the Th2/Treg ratio decreased due to the impact on Th2 cells. While the number of circulating Treg cells remained stable in our study, the potential influence of Treg cells on Th2 cells could theoretically be attributed to improved Treg cell functionality resulting from the combined therapy. The negative correlation between the number and function of Treg and Th2 cells has been well-documented52.
The pathogenic role of Th1 and Th2 cells in IgAN is a subject of debate, without a proven predominance one over other. Importantly, Th1 is widely acknowledged as a pathogenic factor in IgA nephropathy, contributing to glomerular sclerosis, exacerbating proteinuria severity, and serving as an indicator for renal function decline. INF-γ is crucial for synergistic interactions with other pathogenic cytokines53, and for crescentic formations, highlighting its role in the initial stages of the disease. Nonetheless, the heightened expression of Th2 cytokines is associated with tubular interstitial injury and mesangial cell proliferation, and fibrosis54 indicating their involvement in chronic renal damage, which may explain the progressive degradation of renal function. In our specific set of severe patients suffering from chronic disease, the impact of Th2 cells seems to exceed that from Th1 cells, but both populations might be relevant when managing IgA nephropathy. Moreover, the dominance between Th1 and Th2 cells may shift as the disease evolves, influencing disease progression and management strategies.
Despite the observed benefits in r-IGAN patients, the question arises as to whether the isolated use of the treatment could have produced the same effect. Contrary to our findings, the solitary use of SCK did not show benefit in proteinuria, as per the study and some clinical cases22,23,24,27. While Treg cell counts were stabilized in our study, a decrease in Treg cell numbers has been observed in cutaneous tissue and at peripheral levels in ankylosing spondylitis42. In light of our hypothesis, this could be potentially detrimental if IL-17 is blocked. Furthermore, in patients with ankylosing spondylitis, the use of SCK did not decrease Th2 cells55, paralleling recent findings in psoriatic patients56. In contrast, in our study we observed a significant decrease in Th2 cells.
Finally, the combined therapy may play a role in the autonomous activation of IL-17 receptor, IL-17 activates the protein tyrosine phosphatase SHP2 (SHP2) and employs it for the autonomous activation of the IL-17R signal in the absence of IL-17. Additionally, SHP2 is activated by TGF-beta57. Significantly, TGF-beta is downregulated by paricalcitol58, which could facilitate the inhibition of IL-17R, thereby enhancing the blockade of IL-17.
The combined therapy, in general, was well tolerated. Two patients needed hospital admission, one for trigeminal herpes zoster infection and the other one by SARS-CoV-2 infection, who was not previously vaccinated. In the first patient, although the infection appeared after the onset of SCK, the patient’s age, high proteinuria, and basal immunosuppression therapy were risk factors for developing herpes zoster infection. Candidiasis was observed in two patients, as expected according to the datasheet, and satisfactorily resolved with oral fluconazole. Two patients had oligosyntomatic SARS-CoV-2 infection. Considering the pandemic situation, having contracted SARS-CoV-2 infection in these patients may not be related solely to the combined therapy.
The main strengths of this study include the inclusion of rapid progressive and difficult-to-treat refractory IgAN patients, the evaluation of the IL-17A blockage and the relative long-term sustained response in clinical practice. This subset of patients is commonly excluded from clinical trials and lacks effective alternative therapies. The drawbacks of our study include being a single-center study, having a small sample size, lacking a control group, not being able to phenotype Th cells, nor to assess their renal actions induced by the combined therapy. Due to a small sample size, a low statistical power to detect significant differences before and after treatments should be recognized, so the reported data should be interpreted with caution and not generalized until larger studies validate our results.
In conclusion, the novel sequential combined therapy—first with anti-inflammatory PRC followed by IL-17A blockade—appears effective in managing r-IgAN patients. These initial observations undeniably pave the way for potential therapeutic advancements in tackling challenging progressive refractory cases of this disease. The current data underscores the need for more extensive studies to validate its efficacy and safety.
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- Source: https://www.nature.com/articles/s41598-024-55425-7