Translating tissue expression of STAT 1, 3 and 6 in prurigo nodularis to clinical efficacy of oral tofacitinib – A prospective single-arm investigational study

Introduction

Prurigo nodularis (PN) is characterised by an immunological interplay among T helper (Th) 2, Th17, Th22, and Th1 cells, along with dysregulation of fibroblastic biology and neural dysfunction.¹ T helper subtypes are assessed by the tissue expression of signal transducer and activator of transcription (STAT) proteins, a part of the Janus kinase (JAK)/STAT signalling pathway. STAT proteins mediate the actions of immune cells, including STAT1 and STAT4 (Th1), STAT5 and STAT6 (Th2), and STAT3 and STAT5 (Th17).² Notably, cytokines such as IL-4, IL-13, IL-17, IL-22, and IL-31, which are up-regulated in PN, act via the JAK/STAT pathway.^3,4

STAT1, STAT3, and STAT6 are all implicated in the pathophysiology of PN, with a dominance of STAT3 and STAT6,^5,6 suggesting that the Th2/Th17 pathway and its related cytokines play a significant role in PN. The marked neural proliferation observed in PN is a consequence of certain cytokines, specifically IL-4, IL-13, and IL-31.^4,6 The role of STAT receptors in PN, particularly in the context of concurrent use of JAK inhibitors, has not been previously investigated. In this study, we assessed the expression of STAT1, STAT3, and STAT6 in biopsies of PN lesions and evaluated the efficacy of oral tofacitinib.

Methods

Results

STAT expression

Immunohistochemistry analysis revealed significant expression of STAT6 and STAT3 in 13 and 10 patients, respectively, and STAT1 expression in 4 patients. [Figure 1, Table 2].

Close

Figure 1a:

IHC of the involved skin showing moderate nuclear positivity in the keratinocytes (STAT3, 100x).

Export to PPT

Close

Figure 1b:

IHC of the uninvolved skin showing weak nuclear positivity in the keratinocytes (STAT3, 400x).

Export to PPT

Close

Figure 1c:

IHC of involved skin showing strong nuclear positivity in the keratinocytes (STAT6, 400x).

Export to PPT

Close

Figure 1d:

IHC of the uninvolved skin showing absence of STAT6 staining in the nuclei of keratinocytes (STAT6, 400x).

Export to PPT

Table 2: STAT1, 3 and 6 expression in prurigo nodularis

STAT	Positive	Negative	Chi-square test	P value*
STAT6	13 (8.5) [2.38]	4 (8.5) [2.38]	4.3714	0.036546
STAT1	4 (8.5) [2.38]	13 (8.5) [2.38]
STAT3	10 (7) [1.29]	7 (10) [0.9]	9.5294	0 .002022
STAT1	4 (7) [1.29]	13 (10) [0.9]

* Significant at p < 0.05.

Treatment with Systemic Tofacitinib

The mean treatment duration was 5.6 ± 2.2 months, with a 50% reduction in pruritus observed after 11.2 ± 6.44 days [Figure 2]. No significant correlation was found between disease duration and treatment response (p=0.16). The final mean PGSS was 4.1 ± 1.1, reflecting a statistically significant reduction of 66.1% [Table 3, Figure 3]. At the time of data analysis, 14 of the 16 patients were in remission on low-dose therapy, while 2 had completed treatment. One patient who relapsed after discontinuing treatment had therapy restarted [Figure 4].

Close

Figure 2:

A depiction of the duration of disease (months) and onset of response (days). The X axis represents individual patients.

Export to PPT

Table 3: Efficacy of tofacitinib for the treatment of moderate to severe prurigo nodularis

Mean duration of treatment	5.6±2.2 months
Mean onset of action	11.2±6.44 days
Mean final PGSS	4.1±1.1 (P value 0.0004)
Number of PN cases as per PGSS (post-treatment)
Mild	14
Moderate	3
Severe	0
Remission on low-dose therapy	15
Remission off therapy	2
Relapse	1

Close

Figure 3:

A depiction of the duration of tofacitinib (months) and the baseline PGSS score (PGSSb) and current PGSS score (PGSSc).The X axis represents individual patients.

Export to PPT

Close

Figure 4:

(a) Multiple hyperpigmented to flesh-coloured nodules and plaques present over the back. (b) Resolution of lesions on the back with post-inflammatory hyperpigmentation post tofacitinib therapy. Tofacitinib (extended release tablet) 11 mg for mean duration of 3 months. (c) Multiple flesh-coloured nodules present over both upper limbs. (d) Resolution of lesions on upper limbs with post-inflammatory hyperpigmentation post-tofacitinib therapy. Tofacitinib (extended release tablet) 11 mg for mean duration of 3 months

Export to PPT

Side effects observed included mild elevations in transaminases (SGOT or SGPT) in two patients and increased triglycerides in one patient and a reduction in lymphocyte/neutrophil counts in another patient. Acneiform eruptions were seen in two patients, and varicella occurred in a single patient. Except for the patient with varicella in whom treatment was temporarily paused for two weeks, no other patient had their treatment discontinued due to side effects.

Discussion

We observed increased tissue expression of STAT3 and STAT6 [Figure 1, Table 2]. STAT3 is activated by cytokines from the IL-6 and IL-10 families, as well as IL-21, IL-27, G-CSF, leptin, and IFN.^8,9 STAT3 regulates the Th17 immune response, while STAT6 is primarily involved in the transduction of IL-4 and IL-13 signals.^9,10 IL-4 is a key cytokine that mediates the differentiation of Th2 cells and immunoglobulin isotype switching.^11,12 Additionally, STAT6 promotes the proliferation and maturation of B cells, enhances MHC-II and IgE expression, and plays a crucial role in mast cell activation. Our results explain the increased expression of mast cells and neural markers, suggesting STAT6 activation and are consistent with a previous study.^1,6

Cytokines mediate their action through T helper cell subtypes, including Th1, Th2, Th17, and Th22, primarily via the JAK-STAT signaling pathway.⁹ These cytokines interact with cutaneous nerve fibers, keratinocytes, macrophages, mast cells, eosinophils and the JAK-STAT signalling pathway to shape the inflammatory response in PN. Interleukin (IL)-4 and IL-13 directly activate sensory neurons in the skin, driving itch sensation and enhancing the production of pro-inflammatory cytokines, IgE and fibroblasts through STAT6 signaling.^11-13 IL-31, a Th2 cytokine, signals via the IL-31 receptor and oncostatin M receptor (OSMR) β to activate itch-sensing neurons, stimulate neuronal growth, and promote inflammatory cell activation.^14,15 Additionally, IL-31 encourages fibroblast activity, drives T helper (Th) 2 polarisation and encourages further IL-31 production.¹⁶ While Th1, Th17, and Th22 cells play minor roles in inducing inflammation, IL-17 notably induces endothelin-1 (a histamine-independent pruritogen)¹⁷ while IL-22 facilitates epidermal differentiation, cutaneous inflammation, and keratinocyte proliferation.¹⁸

While a marked Th2 response is characteristic of PN, studies have shown that, unlike atopic dermatitis (AD), PN exhibits a strong fibrotic response in the stromal compartment, accompanied by abnormal activation of keratinocytes. This occurs alongside a relatively dampened type 2 inflammatory response compared to AD.^19,20 Thus, the Th2 response in PN is less pronounced than in AD. Blocking IL-31Rα reduces both Th2/IL-13 and Th17/IL-17 responses, thereby stabilizing extracellular matrix remodeling.²¹

Our data suggest that JAK inhibitors can suppress the inflammatory activity of Th2/Th17 cells (STAT6/STAT3).²² Current treatment options for patients with PN are limited and many patients are dissatisfied with their therapy.²¹ The use of systemic tofacitinib has been largely speculative, with only a few reports addressing STAT expression.²³ The cytokines involved, along with the STAT expression profile in PN, suggest that a treatment targeting multiple cytokines and immune cell pathways, such as JAK inhibitors, could offer a beneficial and potentially cost-effective approach to managing PN.²⁴

Although most of our patients responded favorably to tofacitinib, the majority remained on low doses, suggesting that a maintenance dose may be necessary for patients with PN. A meta-analysis of 45 patients treated with dupilumab found that the mean time to first improvement was 10.15 ± 10.56 weeks, with final improvement achieved at 19.28 ± 13.71 weeks. Complete clearance of pruritus, when observed, occurred approximately four months after initiating dupilumab.²³ However, our results suggest that tofacitinib is both more effective and acts more rapidly than dupilumab, with a 50% reduction in pruritus occurring in 11.2 ± 6.44 days and complete remission achieved on a low dose in 5.6 ± 2.2 months.

Published case reports have documented promising results with the use of tofacitinib (a JAK1/3 inhibitor), baricitinib (a JAK1/2 inhibitor), and upadacitinib (a JAK1 inhibitor) in the treatment of PN. Phase 2 clinical trials are currently investigating the efficacy of two other JAK1 inhibitors, abrocitinib (NCT05038982) and povorcitinib (NCT05061693), while a phase 3 trial is underway for ruxolitinib cream (a JAK1/JAK2 inhibitor) (NCT05755438, NCT05764161).²⁵ Based on our findings, a pan-JAK inhibitor, such as tofacitinib, appears to be the most cost effective treatment option for PN.

Limitation and conclusions

Our study confirms the enhanced tissue expression of STAT3 and STAT6, which corresponds to the major cytokines involved in prurigo nodularis and in turn the therapeutic efficacy of a JAK inhibitor. The limitations of our work is that ideally tissue cytokine as well as JAK-STAT expression both prior to and following treatment with JAK inhibitors would be ideal, to validate the impact of tofacitinib on clinical outcomes and immune pathways. Nevertheless, the consistent reduction in itching, marked clinical improvement, and favorable safety profile suggest that tofacitinib holds significant potential for treating PN.