Effective Management of PASS Syndrome With Intravenous Immunoglobulin and Anti-Interleukin-1 Therapy: An Insightful Case Study

Abstract

PASS syndrome (PASS) is a rare and complex autoimmune disease that manifests as pyoderma gangrenosum (PG), acne vulgaris, hidradenitis suppurativa (HS), and ankylosing spondylitis (AS). Unlike other autoinflammatory syndromes such as PAPA and PASH, PASS does not have documented gene mutations, making diagnosis and treatment particularly challenging [1]. Table 1 provides a comprehensive overview of various autoinflammatory diseases that share clinical features with PASS, including involvement of the skin, joints, and lymph nodes. This suggests a potential overlap in their underlying mechanisms. PAPA syndrome is characterized by sterile pyogenic arthritis, acne, and PG and is associated with a defect in the PSTPIP1 gene [2]. PASH syndrome includes acne, PG, and HS, but unlike PASS, it does not involve the joints. A defect in the NCSTN gene is linked to PASH. PAPASH syndrome, which combines features of both PAPA and PASH, presents with pyogenic arthritis, acne, PG, and HS. In contrast to these syndromes associated with specific gene defects, PASS is characterized by the presence of seronegative spondyloarthritis alongside acne, PG, and HS [3]. In addition to PASS, PAPASH, and the syndromes listed above, several other autoinflammatory disorders exist. These diseases exhibit a spectrum of clinical presentations, with unique combinations of skin and musculoskeletal manifestations. Examples include synovitis, acne, pustulosis, hyperostosis, osteitis syndrome, and chronic recurrent multifocal osteomyelitis [4]. Additionally, PsAPASH syndrome, also known as PAPASH-PsA, presents as a combination of psoriatic arthritis with PG, acne, and HS [5].

Research suggests that cytokines like interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-18 play a key role in the development of PASS [6, 7]. Elevated IL-1 levels are central to the inflammatory response, while TNF-α worsens tissue inflammation, particularly in HS and AS. IL-18 further amplifies this inflammatory cascade, contributing to the chronic and debilitating nature of the disease. The involvement of these cytokines highlights the importance of potential targeted therapies, making cytokine inhibitors a crucial part of treatment strategies [7].

Traditional PASS treatment involves systemic corticosteroids and immunosuppressive drugs like methotrexate and cyclosporine to control inflammation and prevent flare-ups. Additionally, biological agents like TNF-α inhibitors may be used, though their effectiveness can vary among patients. A case study by Kırmızıer et al. [8] presented a compelling example. A 25-year-old man with severe PASS, including ulcerated skin lesions, inflammatory nodules, joint swelling, and persistent back pain, showed no improvement despite treatment with corticosteroids and adalimumab. However, the introduction of intravenous immunoglobulin (IVIG) and methylprednisolone resulted in a significant decrease in acute-phase reactants and a partial improvement of skin lesions. Subsequently, adding anakinra, an IL-1 receptor antagonist, led to the complete remission of joint symptoms and substantial healing of skin lesions (Table 2). This case highlights the effectiveness of targeting IL-1 signaling in managing autoinflammatory diseases like PASS.

This case report contributes to the limited knowledge on PASS by demonstrating a successful treatment alternative for patients unresponsive to conventional therapies. The innovative combination of IVIG and anakinra offers a new therapeutic pathway, emphasizing the importance of personalized treatment approaches for rare and complex diseases. By documenting the patients' response to this regimen, the authors provide valuable insights that could inform future clinical practice and guidelines development. A key strength of this report lies in the detailed documentation of the patient's clinical course and treatment response, which provides a comprehensive understanding of the potential therapeutic benefits of IVIG and anakinra in PASS. However, the inherent limitation of a single case study is the restricted generalizability of the findings. Additionally, long-term follow-up data would be beneficial to assess the sustained efficacy and safety of these treatments for patients with PASS.

Given the positive outcomes observed in this case, further research is warranted to explore the long-term efficacy and safety of IVIG and anti-IL-1 treatments in a larger cohort of patients with PASS. Clinical trials and multicenter studies could provide more robust data, ultimately aiding in the establishment of standardized treatment protocols. Moreover, investigating the mechanisms by which these treatments exert their effects may lead to the development of targeted therapies for similar autoinflammatory conditions.

While IL-1 is a well-established central mediator in autoinflammatory conditions, the intricate nature of the inflammatory cytokine cascade necessitates exploring various therapeutic strategies [9]. Several successful treatment approaches have been reported for PASS. The initial case report by Bruzzese et al. describing the first documented case of PASS, highlighted successful treatment with a TNF-α inhibitor [10]. Subsequent case series have further supported the efficacy of TNF-α inhibitors like infliximab and adalimumab in managing PASS [11]. However, some cases demonstrated a lack of response to etanercept, suggesting potential variability in the effectiveness of TNF-α inhibitors. This variability might be due to the form of TNF-α targeted; soluble and membrane-bound TNF-α may play distinct roles in PASS pathogenesis [10]. Similar to the findings of Kırmızıer et al. successful treatment of PASS with anti-IL-1 therapies has also been reported. A patient with PASS who exhibited elevated IL-1 levels during a flare achieved complete resolution of skin and joint symptoms with anti-IL-1 therapy [12]. However, cases of primary failure to the IL-1 receptor antagonist anakinra have also been observed [11]. Another study reported that the initial response to anakinra diminished over time, necessitating a switch to infliximab to achieve remission [13]. A recent study explored the use of the IL-17A inhibitor secukinumab, demonstrating near-complete improvement in a patient over a two-year follow-up after failing conventional immunosuppressive therapies [14]. These findings collectively highlight the critical role that the balance of individual cytokines plays in determining therapeutic efficacy. This underscores the need for personalized treatment approaches tailored to each patient's unique cytokine profile to optimize clinical outcomes.

The successful treatment of PASS with IVIG and anakinra, as reported in this case study, represents a significant advancement in managing this challenging condition. These findings suggest that IL-1 inhibition may be a promising strategy to achieve clinical remission and improve patient outcomes in PASS. Continued research and collaboration within the medical community are essential for a deeper understanding of the disease, allowing for refinement of treatment strategies, and ultimately leading to better care for patients with PASS and related autoinflammatory disorders. By documenting this case, Kırmızıer et al. have opened new avenues for PASS treatment, offering hope for patients and clinicians alike. This case highlights the importance of innovative and individualized treatment approaches for rare and complex diseases. It also underscores the need for ongoing research and clinical trials to validate and expand on these promising findings.

Ji-Won Kim and Hyoun-Ah Kim jointly contributed to the conception, writing, and revision of this editorial. Both authors read and approved the final manuscript.

The authors declare no conflicts of interest.