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Longitudinal Immune Profiling of T Cell Exhaustion During IL-17A Blockade in a Patient With HLA-B27-negative Spondyloarthritis and Sjögren’s Syndrome: A Case Report

YU-SIANG SU, JENG-WEI LU, YI-JUNG HO, SHAN-WEN LUI, TING-YU HSIEH, WUN-LONG JHENG and FENG-CHENG LIU
In Vivo January 2026, 40 (1) 571-582; DOI: https://doi.org/10.21873/invivo.14222

Abstract

Background/Aim: Coexisting Sjögren’s syndrome (SS) and human leukocyte antigen-B27 (HLA-B27)-negative ankylosing spondylitis (AS) is rare and therapeutically challenging. In patients with prior Stevens-Johnson syndrome (SJS), non-steroidal anti-inflammatory drugs (NSAIDs) are contraindicated and tumor necrosis factor (TNF) inhibitors may be insufficient. Interleukin-17A (IL-17A) blockade with secukinumab offers an alternative, though its long-term effects on T cell exhaustion and regulation remain unclear. This report examines immune exhaustion and regulatory dynamics during IL-17A inhibition in a complex autoimmune case.

Case Report: A 52-year-old man with SJS, SS, and HLA-B27-negative AS switched to secukinumab after inadequate TNF inhibition. Flow cytometry over five years (2020, 2023, 2025) tracked early therapy, steroid tapering, and long-term stability. Initial immune profiling revealed expanded effector T cells [Fas cell surface death receptor (Fas)+, programmed death protein 1 (PD-1)+, T-cell immunoglobulin and mucin-domain containing-3 (Tim-3)+] and reduced regulatory subsets. Over time, as disease activity improved, exhaustion markers declined and regulatory T cell (Treg) populations partially recovered. By 2025, the patient maintained low disease activity with minimal steroid exposure. Laboratory data confirmed remission [C-reactive protein (CRP) 0.10 mg/dl, erythrocyte sedimentation rate (ESR) 2 mm/h], while patient-reported indices [Bath ankylosing spondylitis disease activity index (BASDAI) 4.1, ankylosing spondylitis disease activity score using C-reactive protein (ASDAS-CRP) 2.0] reflected stable low-to-moderate disease activity. Naïve T cells continued to show intermittent PD-1 and killer cell lectin-like receptor G1 (KLRG1) expression, suggesting persistent low-level immune adaptation.

Conclusion: This case shows phased immune rebalancing under long-term IL-17A blockade. Serial monitoring revealed dynamic exhaustion marker changes and partial regulatory recovery linked to clinical improvement, underscoring the value of longitudinal immune profiling for personalized management of complex autoimmune syndromes.

Keywords:

Introduction

Ankylosing spondylitis (AS) is a chronic inflammatory disease that primarily affects the axial skeleton, especially the sacroiliac joints and spine. It is classically associated with the human leukocyte antigen-B27 (HLA-B27) allele, which is present in up to 90% of patients with AS in Western populations. However, a subset of patients –particularly those of Asian descent– are HLA-B27-negative and often display atypical clinical features and distinct immunologic profiles (1, 2).

Sjögren’s syndrome (SS) is a systemic autoimmune disease marked by B cell hyperactivity, lymphocytic infiltration of exocrine glands, and progressive glandular dysfunction (3-5). The coexistence of AS and SS is exceedingly rare, with most reports limited to individual case studies or small retrospective cohorts (6). This overlap presents a unique immunopathologic paradox, as SS is largely B cell-driven while AS is primarily mediated by T cells and interleukin-17 (IL-17)-driven enthesitis (7).

The therapeutic management of such overlap syndromes is complicated by their divergent pathophysiological mechanisms and by the absence of standardized treatment guidelines. Nonsteroidal anti-inflammatory drugs (NSAIDs) and tumor necrosis factor inhibitors (TNFi) remain first-line therapies for AS (8), while SS is typically treated with immunosuppressants, hydroxychloroquine, and corticosteroids (9). However, in patients with contraindications to NSAIDs –such as those with a history of Stevens-Johnson syndrome– or with refractory disease, alternative therapies must be considered.

In this context, IL-17A inhibitors such as secukinumab have emerged as viable options for axial spondyloarthritis. While their clinical efficacy in AS is well established, their long-term effects on immune modulation-especially on T cell exhaustion, regulatory dynamics, and effector subsets remain incompletely understood (10, 11).

This case report aims to contribute to this gap by presenting longitudinal immune profiling data over a five-year course of IL-17A inhibition in a patient with coexisting SS and HLA-B27-negative AS. This study received approval from the Institutional Review Board (IRB) of Tri-Service General Hospital, National Defense Medical Center, Taiwan (IRB No. A202515185; approved on October 17, 2025). All procedures complied with institutional guidelines and the ethical standards of the Declaration of Helsinki and its amendments.

Case Report

The coexistence of SS and AS is rare, yet it presents a unique therapeutic dilemma due to their divergent immunopathological mechanisms (12). SS is typically associated with B cell hyperactivity and glandular inflammation (13), while AS –especially in HLA-B27-negative individuals– is primarily driven by aberrant T cell responses and IL-17-mediated enthesitis (14). This diagnostic and therapeutic challenge becomes even more complex in HLA-B27-negative cases, where atypical immunologic features may influence both disease expression and treatment response (15-17). Beyond clinical management, such overlapping autoimmune processes raise mechanistic questions regarding long-term immune regulation, particularly under selective cytokine blockade (16-18).

In patients with a prior history of Stevens-Johnson syndrome (SJS), the use of conventional non-steroidal anti-inflammatory drugs (NSAIDs) –a mainstay of AS treatment– is often precluded due to the risk of severe hypersensitivity (19). Tumor necrosis factor (TNF) inhibitors, although widely used, may be insufficient or poorly tolerated in certain patients. In these contexts, IL-17A inhibition with secukinumab has emerged as a viable alternative (20, 21). However, the long-term immunological effects of IL-17 blockade –especially on T cell exhaustion, regulatory homeostasis, and effector dynamics– remain incompletely characterized (22-24).

T cell exhaustion, marked by sustained expression of inhibitory receptors [e.g., programmed death protein 1 (PD-1), T-cell immunoglobulin and mucin-domain containing-3 (Tim-3), killer cell lectin-like receptor G1 (KLRG1)] and diminished effector potential, represents a pivotal yet understudied phenomenon in chronic autoimmune disease (25, 26). This case thus provides a rare opportunity to longitudinally examine T cell exhaustion dynamics during five years of IL-17A inhibition in a patient with coexisting SS and HLA-B27-negative AS, with immune phenotyping guided by serial monitoring of exhaustion and activation markers (24, 27).

This is the case of a 52-year-old man with a complex history of immune-related conditions. His medical course began at age 32 with a severe episode of SJS, triggered by an intramuscular injection of ketorolac. The reaction was extensive –marked by widespread skin detachment, mucosal involvement, ocular damage, and upper gastrointestinal (GI) bleeding– eventually requiring intensive care support.

He later developed severe ocular sequelae of SJS, requiring amniotic membrane transplantation, and was subsequently diagnosed with Sjögren’s syndrome based on reduced salivary function and biopsy findings. At age 42, further evaluation confirmed a diagnosis of SS based on markedly reduced salivary function and a positive minor salivary gland biopsy (focus score = 1). Two years later, he developed progressive inflammatory back pain and morning stiffness. Although HLA-B27 testing was negative, imaging revealed bilateral grade II sacroiliitis, leading to a diagnosis of AS. Representative pelvic computed tomography scan (CT) imaging from 2017 (Figure 1) demonstrates sacroiliac joint changes consistent with chronic sacroiliitis, supporting the radiologic criteria for AS diagnosis in this patient.

Figure 1.
Figure 1.

Axial pelvic computed tomography (CT) from 2017 showing bilateral sacroiliac joint changes, including subchondral sclerosis and subtle joint space irregularities, consistent with grade II sacroiliitis. These findings supported the diagnosis of ankylosing spondylitis in a human leukocyte antigen-B27 (HLA-B27)-negative patient with inflammatory back pain.

Initial treatment with Golimumab, a tumor necrosis factor-alpha (TNF-α) inhibitor, resulted in only partial symptomatic improvement. Between 2014 and 2019, he required over 20 courses of intravenous corticosteroids –frequently in mini-pulse format– to manage disease flares. However, these were insufficient for long-term disease control and posed cumulative risks. To provide a chronological overview of his clinical trajectory and immunological monitoring, we constructed a longitudinal timeline summarizing key diagnoses, treatment milestones, and immune profiling events (Figure 2).

Figure 2.
Figure 2.

Longitudinal clinical timeline of a patient with human leukocyte antigen-B27 (HLA-B27)-negative ankylosing spondylitis and coexistent Sjögren’s syndrome. Key clinical diagnoses (white boxes), treatment interventions (colored bars), and serial immune profiling (red dots) are shown from 2004 to 2025. Secukinumab was initiated in early 2019 and maintained through 2025. Corticosteroids were tapered after 2023 but continued at low dose. Three time points of flow cytometric analysis are indicated.

In 2019, Secukinumab was initiated. Serial immune profiling was performed at three time points-early treatment (2020), corticosteroid tapering and disease remission (2023), and sustained low disease activity (2025). These timepoints corresponded with major shifts in his clinical course and immune status. During the early treatment phase, flow cytometry revealed elevated Fas and PD-1 expression across effector and central memory T cell subsets, particularly cluster of differentiation 8 (CD8)+ T cells, consistent with immune activation and early exhaustion (24, 25). Concurrently, regulatory T cell subsets –including cluster of differentiation 39 (CD39)+Helios+ regulatory T cells (Tregs) and cluster of differentiation 127 (CD127)−forkhead box P3 (FoxP3)+ populations– remained low, reflecting an unbalanced immune state.

As corticosteroids were tapered and disease control improved (2023), exhaustion markers gradually declined, and regulatory subsets partially recovered. By 2025, the patient maintained low disease activity [Ankylosing spondylitis disease activity score using C-reactive protein (ASDAS-CRP) 1.7, bath ankylosing spondylitis disease activity index (BASDAI) 3.9; C-reactive protein (CRP) 0.10 mg/dl, erythrocyte sedimentation rate (ESR) 2 mm/h] without further steroid use. Immune profiling at that time revealed persistent but attenuated PD-1 and Tim-3 expression in naïve and effector T cell compartments-suggestive of ongoing subclinical immune modulation.

These findings suggest that long-term IL-17A inhibition contributed not only to clinical remission but also to dynamic rebalancing of immune cell populations, including exhaustion and regulatory axes. By 2025, he had achieved low disease activity (ASDAS-CRP 1.7, BASDAI 3.9), and inflammatory markers (CRP 0.10 mg/dl, ESR 2 mm/h) stayed near baseline. More importantly, his energy improved, and he reported being able to go about his daily life with far fewer limitations.

To better understand how his immune system responded to long-term IL-17A blockade, we performed flow cytometric analysis at three time points −2020, 2023, and 2025– corresponding to early treatment, post-steroid discontinuation, and long-term remission. Trends in cluster of differentiation 4 (CD4)+ T helper cells across these stages, including notable changes in activation and exhaustion markers, are summarized in Figure 3. To capture the evolving immunological impact of prolonged IL-17A inhibition in this complex case, serial flow cytometry analyses were conducted at three key time points-2020, 2023, and 2025. These time points were strategically selected to reflect distinct phases of disease control: the first during early secukinumab therapy, the second during clinical remission, and the third at sustained low disease activity.

Figure 3.
Figure 3.

Longitudinal changes in activation and exhaustion markers in cluster of differentiation 4 (CD4)+ T helper cells. The figure displays expression trends of Fas cell surface death receptor (Fas), programmed death protein 1 (PD-1), and T-cell immunoglobulin and mucin-domain containing-3 (Tim-3) across naïve, central memory (CM), and effector (Eff) subsets, measured at three timepoints between 2020 and 2025. Fas expression was notably elevated during early treatment, particularly in central memory Th cells, but declined alongside clinical improvement. PD-1 and Tim-3 expression, markers of T cell exhaustion, followed a similar trend. These immune shifts paralleled clinical remission and corticosteroid tapering during long-term interleukin 17A (IL-17A) inhibition. HC: Healthy controls; data obtained from healthy volunteers.

Peripheral blood mononuclear cells (PBMCs) were isolated from fresh blood samples and stained using a 12-color flow cytometry panel targeting key surface markers of activation (Fas), exhaustion (PD-1, Tim-3), and differentiation. The panel included both T and B cell lineage markers, allowing for simultaneous tracking of multiple immune subsets across naive, memory, effector, and regulatory compartments. Our immunophenotyping approach was guided by established flow cytometry standardization guidelines (28, 29). Figure 4 summarizes the longitudinal trends of exhaustion and activation markers in CD8+ cytotoxic T cells. These shifts reflect dynamic modulation in immune activation over time and offer insight into the broader immunological response to secukinumab.

Figure 4.
Figure 4.

Longitudinal dynamics of activation and exhaustion markers in cluster of differentiation 8 (CD8)+ cytotoxic T cells. This figure illustrates changes in Fas and PD-1 expression across naïve, central memory (CM), and effector (Eff) CD8+ T cell subsets, measured in 2020, 2023, and 2025. During early treatment, elevated levels of Fas cell surface death receptor (Fas) and programmed death protein 1 (PD-1) were observed, especially in effector CD8+ T cells, suggesting initial immune activation. These markers declined over time, coinciding with clinical remission. HC: Healthy controls; data obtained from healthy volunteers.

As treatment progressed, changes in other immune cell populations began to emerge as well. Some of these shifts were expected; others more subtle. Regulatory T cells, for example, showed an early peak in activated subsets (CD39+Helios+), which later declined, likely reflecting reduced inflammatory drive. Interestingly, memory Tregs remained elevated across all timepoints, suggesting a stable immunosuppressive baseline that may have supported long-term remission. Cytotoxic T cells also demonstrated dynamic behavior. While human leukocyte antigen-DR isotype (HLA-DR) expression –a marker of activation– fluctuated over time, it rebounded in 2025, possibly indicating restored immune surveillance. CD127 expression, which relates to T cell survival, showed a variable pattern that could reflect changes in T cell renewal or homeostasis.

On the B cell side, class-switched memory cells gradually expanded, while double-negative B cells showed more erratic changes. These findings may reflect underlying shifts in the memory B cell compartment, possibly influenced by ongoing immunomodulation. Similar B cell subset dynamics have been reported in autoimmune contexts, including spondyloarthritis (30, 31). Collectively, these broader changes are summarized in Figure 5, and they offer a glimpse into how multiple arms of the immune system responded –and adapted–over time during IL-17A inhibition. Figure 5 summarizes longitudinal changes in six key immune populations: CD39+Helios+ Tregs, memory Tregs, CD127+ and HLA-DR+ cytotoxic T cells, class-switched memory B cells, and double-negative B cells. Regulatory subsets showed an early increase during steroid tapering, followed by partial normalization. CD8+ T cells exhibited fluctuating activation and survival marker expression. Meanwhile, B cell compartments remained relatively stable, with minor variations in class-switched and double-negative subsets. These trends suggest a shift toward immune rebalancing during prolonged IL-17A blockade.

Figure 5.
Figure 5.

Immune modulation across regulatory, cytotoxic, and B cell subsets during long-term interleukin 17A (IL-17A) inhibition. HC: Healthy controls; data obtained from healthy volunteers.

Discussion

Serial immune monitoring over five years showed that exhaustion and regulatory markers changed in parallel with the patient’s clinical course, particularly during early treatment, steroid tapering, and long-term remission. In the following discussion, we explore how these immune dynamics may reflect regulated adaptation, therapeutic effects, and potential biomarkers in chronic autoimmune overlap. The coexistence of SS and AS is uncommon and presents a unique immunopathological paradox. While SS is characterized by B cell hyperactivity and glandular inflammation, AS is primarily driven by T cell-mediated enthesitis and IL-17 signaling (18). This paradox is further complicated in HLA-B27-negative patients, who often display atypical disease patterns and distinct immune signatures (32). In such settings, treatment decisions are constrained not only by clinical factors but also by underlying immunological mechanisms.

The present case describes a patient with coexisting SS and HLA-B27-negative AS who underwent five years of IL-17A inhibition. Uniquely, this treatment course was accompanied by serial immune phenotyping focused on exhaustion and regulatory markers. To our knowledge, this is among the first longitudinal characterizations of T cell exhaustion dynamics in this particular context (32-35). This case thus offers an opportunity to explore how chronic IL-17 blockade may modulate immune exhaustion, regulatory homeostasis, and disease control over time. In chronic autoimmune settings, sustained expression of inhibitory receptors –such as PD-1, Tim-3, and KLRG1− is widely recognized as a hallmark of T cell exhaustion. These markers reflect the T cell’s attempt to limit immunopathology under conditions of persistent antigen exposure and pro-inflammatory cytokine signaling (36). In this case, we observed an early elevation of these exhaustion markers across multiple subsets, followed by partial resolution over time. This temporal pattern may represent an adaptive immunoregulatory mechanism in response to prolonged IL-17A inhibition.

Notably, CD4+ effector T cells initially exhibited high expression of PD-1 and Tim-3, suggesting ongoing antigenic stimulation and functional dampening. Over time, the expression declined moderately, which may indicate partial recovery of immune balance under disease control. Similarly, CD8+ central and effector memory cells showed dynamic shifts in KLRG1+ and PD-1+ expression, potentially reflecting changes in differentiation states and tissue homing potential (34). Interestingly, naïve T cells –both CD4+ and CD8+–also displayed elevated inhibitory markers at baseline, which is atypical in healthy individuals. This may reflect prior systemic activation or bystander effects of chronic inflammation in HLA-B27-negative autoimmunity (34). The longitudinal modulation of these exhaustion markers thus highlights their dual role-not merely as indicators of dysfunction, but also as markers of adaptation and regulatory containment in chronic immune perturbation.

Beyond symptomatic control, IL-17A inhibition in this case appears to have promoted a broader rebalancing of immune regulation. Notably, regulatory T cell subsets –including CD39+Helios+ Tregs and memory Tregs–showed early recovery following corticosteroid tapering. This suggests that IL-17A blockade may facilitate the restoration of regulatory homeostasis, possibly by alleviating inflammatory pressure that inhibits Treg function (30, 37-39). This naturally leads to a key question: can IL-17 inhibition promote not just quiescence, but active immunological tolerance? While further studies are needed, the partial reconstitution of regulatory subsets –concurrent with sustained clinical remission– supports the notion that IL-17A blockade may modulate immune architecture beyond its pro-inflammatory targets (34, 35).

The immune monitoring trajectory in this case demonstrates a phased correlation with clinical milestones. During the early phase of treatment in 2020, both CD4+ and CD8+ T cells exhibited high expression of exhaustion markers –including PD-1, Tim-3, and KLRG1− suggesting intense immune activation likely driven by chronic antigenic stimulation and inflammation (36). Concurrently, regulatory T cell subsets remained suppressed, reflecting an immune landscape skewed toward effector dominance and systemic immune dysregulation. After steroid tapering had significantly progressed in 2023, a partial normalization of exhaustion markers emerged. PD-1 and Tim-3 expression declined modestly in effector T cells, while CD39+Helios+ Tregs and memory Tregs showed early recovery (39). These shifts aligned with improved clinical stability and marked the transition into a lower-inflammatory state, likely facilitated by IL-17A blockade.

In 2025, sustained disease remission was accompanied by persistent –but lower magnitude– expression of PD-1 and Tim-3 in T cells. This pattern may not reflect ongoing dysfunction, but rather a “regulated suppression” phenotype: a controlled, restrained immune activation that supports disease control without provoking relapse. These findings highlight how serial immunophenotyping can do more than reflecting disease activity-it may also track how the immune system recalibrates itself over time (28). We recognize that this report reflects the experience of just one patient, which places limits on how broadly the findings can be applied. The immune changes we describe –especially the fluctuations in exhaustion markers and the gradual return of regulatory balance– should be seen as observations rather than firm conclusions. Without functional experiments or comparison to other patients, there is no way to know if these changes are unique to this case or reflect a broader pattern. Larger cohorts, more frequent time points, and mechanistic studies would be needed to answer that.

Even so, the course of this patient gives a rare look at how the immune system may adapt under prolonged IL-17A blockade in the setting of overlapping autoimmune disease. What stood out to us was how the shifts in immune markers seemed to track with the clinical course. That parallel suggests immune monitoring might eventually be used not just to describe disease activity, but to help anticipate therapeutic response. One additional idea emerges from this case: the possibility that long-term cytokine inhibition can bring about a state of “controlled exhaustion”. In this state, the immune response is dampened, yet not completely silenced-enough to keep disease activity under control. Whether that balance represents a lasting adaptation or only a reversible suppression is something future longitudinal work will need to explore (34, 35).

Conclusion

Over the course of five years of IL-17A inhibition, in a patient with both Sjögren’s syndrome and HLA-B27-negative ankylosing spondylitis, we observed the immune system shifting in phases. Serial immunophenotyping showed that exhaustion markers and regulatory subsets did not change randomly, but seemed to rise and fall alongside clinical events such as steroid tapering and the maintenance of remission.

Taken together, these observations suggest that chronic cytokine blockade might not simply dampen immunity, but could create a state of controlled suppression-less dysfunction than restraint, allowing tolerance and disease stability to exist side by side. The fact that even naïve T cells showed shifts in exhaustion markers suggests that immune exhaustion in chronic autoimmunity may be more of a regulated, adaptive process than a simple sign of irreversible impairment.

Of course, the limitation here is that this is a single-patient observation. Still, the trajectory we documented points to the potential value of immune profiling as a complementary tool to clinical assessment, helping capture how disease and treatment interact over time (28). Larger studies, with more patients and functional validation, will be needed to examine whether tracking exhaustion dynamics can eventually help predict treatment response or longer-term immune reprogramming.

Acknowledgements

We thank UCB Pharma for providing funding support for English language editing.

Footnotes

  • Authors’ Contributions

    YSS: Conceptualization, methodology, writing-original draft, writing review and editing. JWL: Conceptualization, methodology, writing-original draft, writing review and editing. YJH: Conceptualization, methodology, project administration, writing-review and editing. SWL: Conceptualization, methodology, writing-review and editing. TYH: Conceptualization, methodology, writing-review and editing. WLJ: Conceptualization, methodology, writing-review and editing. FCL: Conceptualization, investigation, supervision, writing-review and editing.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest or competing interests related to this study.

  • Funding

    This study was supported by the National Science and Technology Council, Taiwan (grants NSTC 112-2314-B-016-033, NSTC 113-2314-B-016-052, NSTC 114-2314-B-016-052-MY3 and NSTC 114-2314-B-016 -052 -MY3) and Tri-Service General Hospital, Taiwan (grants TSGH-E-112218 and TSGH-E-113238).

  • Artificial Intelligence (AI) Disclosure

    During the preparation of this manuscript, a large language model (ChatGPT, by OpenAI) was used solely for language editing and stylistic improvements in select paragraphs. No sections involving the generation, analysis, or interpretation of research data were produced by generative AI. All scientific content was created and verified by the authors. Furthermore, no figures or visual data were generated or modified using generative AI or machine learning-based image enhancement tools.

  • Received October 22, 2025.
  • Revision received November 10, 2025.
  • Accepted November 13, 2025.

This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0).

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Longitudinal Immune Profiling of T Cell Exhaustion During IL-17A Blockade in a Patient With HLA-B27-negative Spondyloarthritis and Sjögren’s Syndrome: A Case Report
YU-SIANG SU, JENG-WEI LU, YI-JUNG HO, SHAN-WEN LUI, TING-YU HSIEH, WUN-LONG JHENG, FENG-CHENG LIU
In Vivo Jan 2026, 40 (1) 571-582; DOI: 10.21873/invivo.14222
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