Autoinflammation in psoriatic arthritis: time to better define the multifaceted enemy

Psoriatic arthritis (PsA) is a very heterogeneous disease involving the skin, joints, eyes, gastrointestinal and cardiometabolic systems.¹ In the perspective of ‘psoriatic syndrome’ or ‘psoriatic disease’, PsA is a distinct, important and complex entity.¹ PsA is a mysterious disease and still bears many aspects to explore. For instance, although we know many things about the relationship between psoriasis (PsO) and PsA—even though we have a long road to go—it took about 18 centuries for the literature to report this relationship after the papers published about PsO.² On the other hand, the mystery is being explored day by day, especially about pathogenesis. Till now, current literature has been focused on the autoimmune aspects of PsA pathogenesis, for example, human leucocyte antigens and clonal expansions of CD8⁺ T cells.³ Although a few genome-wide association studies and small studies found PsA and PsO susceptibility genes related to innate immunity,⁴ no study has focused on the individual patient-level role of autoinflammatory disorder genes in PsA patients.

In this issue of RMD Open, Atschekzei et al have turned the spots on genes related to autoinflammatory disorders’ clinical characteristics of a PsA cohort with their article entitled ‘Identification of variants in genes associated with autoinflammatory disorders in a cohort of patients with PsA’. In their study, 120 consecutive, non-relative PsA patients were enrolled according to the CASPAR criteria. Targeted next-generation sequencing via a validated panel was performed to find rare genes associated with immune dysregulation or autoinflammatory disorders. Overall disease characteristics and treatment regimens of this cohort were similar to current literature. Of 37 (30.8%) patients among 120 patients had 45 rare, monoallelic germline variations. Among these variations, 25 autosomal dominant disorder (AID)-related variations were found in 20 (16.7%) patients. Five patients had AP1S3 variant, which is associated with pustular ⁵PsO; four patients with late-onset seronegative arthritis had PLCG2 variant, which encodes a signalling mediator and is associated with antibody deficiency and immune dysregulation syndrome⁶ and two of the three patients with Crohn’s disease had NOD2 variant, which is responsible from the production of an intracellular innate immune system receptor.⁷ Other AID-related genes were TNFAIP3, COPA, TNFRSF1A, NFKB1, NLRP12, CARD14, IL1RN and DDX58. Pustular PsO and Crohn’s disease were significantly more common in patients with any AID-related variant. Not surprisingly, but as confirmatory, patients with any AID-related variant had higher C reactive protein (CRP) levels at the last visit. Although not statistically significant, these patients had a higher rate of treatment escalation. This study is the next step in genetic studies to explore the heritability of PsA, as it used focused next-generation sequencing.

According to our current understanding of the immune system and disorders, PsA has autoimmunity and autoinflammatory features. Absence of female predominance (PsA frequency is similar in both sexes)⁸; activation of the innate immune system as a consequence of trauma and propagation of disease manifestations (deep Koebner phenomenon)^{9 10}; episodic course in some patients¹¹; extra-articular manifestations (gastrointestinal tract involvement and uveitis), which are mainly innate immune activation driven by IL-23 or Th-17¹²; overlapping features of several IL-1 driven autoinflammatory diseases such as hidradenitis suppurativa (HS), SAPHO (synovitis, acne, pustulosis, hyperostosis, osteitis), PsAPASH (PsA, pyoderma gangrenosum, acne and HS) are all demonstrating the role of autoinflammation in the pathogenesis of PsA¹³ clinically. From the cellular and molecular perspective, Toll-like receptor activation¹³ via interferons and IL-1 and 6, IL-23 and Th-17-driven innate immune activation.^{14 15} TNF-induced negative immune regulation of the innate immune system,¹⁶ and NETosis¹⁷ driven by polymorphonuclear cells can be counted as the components of autoinflammation in PsA pathogenesis.

As a clinician, I am very excited to see and read these kinds of studies. Although the authors clearly stated that they could not demonstrate the pathogenicity of the genetic variants, the results of this study will, hopefully, lead to more sophisticated studies, including functional and genetic studies. Eventually, this growing body of evidence will lead to drug development and clinical trials of already in-use drugs in PsA patients. Although anakinra had limited activity in PsA,¹⁸ some candidate molecules (eg, IL-18 and IL-36) hypothesised by the authors need further evaluation for therapeutic evaluation. In daily practice, a subgroup of PsA patients is unresponsive to currently available biologics and/or has elevated inflammatory response (CRP level, etc) despite optimal therapy. Autoinflammatory aspects of PsA should be one of the future targets of PsA studies in this subgroup of patients.

Today, we know that PsA has several clinical subsets. It is still a highly relevant question whether these different clinical subtypes have clear-cut differences regarding clinical and genetic reflections of autoinflammation, specifically innate immunity. Future studies will hopefully focus on this aspect, besides the therapeutic interventions.

Metabolic comorbidities in patients with PsA are well described in current literature. Besides, a high CRP level, as a marker of inflammation, is a well-known risk factor for cardiovascular diseases (CVD).¹⁹ It is an interesting question whether these genetic alterations of innate immunity have a role in the presence of metabolic disturbances in PsA patients and if they can be used as a predictor of metabolic comorbidities and CVD.

Autoinflammation seems a vital part of the PsA pathogenesis, especially in the presence of pustular PsO and Crohn’s disease. Therapeutic application of this growing body of evidence is expected by clinicians dealing with PsA.

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