The role of trauma and isomorphic reaction in the pathogenesis of psoriatic arthritis

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Introduction. Psoriatic arthritis (PA) is a chronic inflammatory disease of the joints, spine, and entheses, which is observed, according to various sources, in approximately 6-42% of patients with psoriasis [1]. Approximately 70-80% of patients develop psoriasis before PA, 10-15% develop psoriasis and PA simultaneously, and 10-15% of patients develop psoriasis after PA [2]. PA is characterized by clinical heterogeneity in the form of enthesitis, dactylitis, peripheral or axial arthritis, incl. sacroiliitis. At the same time, the defeat of entheses is often observed before the developed clinic of arthritis, making it difficult to diagnose the disease in a timely manner. PA often remains undiagnosed [3]. According to various data, up to 27% of patients with psoriasis who are regularly observed by a dermatologist have undiagnosed PA [4, 5]. The reasons for the late diagnosis of PA in patients with psoriasis, in addition to the clinical heterogeneity of the disease, include the lack of comprehensive data on all links in the pathogenesis of PA, the ability of PA to proceed latently for a long time, as well as similarity with other arthritis [6]. One of the proposed trigger factors for the development of PA is trauma [7]. At the same time, microtraumatization of entheses with the greatest functional load (for example, in the hands and feet) is of great interest. By the time of the development of clinical arthritis, the patient usually has a pronounced lesion of the ligamentous apparatus, which may remain asymptomatic for a long time.
Purpose: to study the role of biomechanical stress, microtraumatization in the development of PA in patients with psoriasis.
Materials and methods: an analysis was made of Russian and foreign literature for the period of 2010-2021, devoted to the role of isomorphic reaction in the development of enthesitis, dactylitis and, subsequently, arthritis in patients with PA. Literature released before 2010 was not included in the study.
Results.
Relevance. Trauma is of great importance in the development of psoriasis and PA. A hyperergic reaction in the skin in patients with psoriasis in response to physical, mechanical or chemical damage is observed in approximately 25% (according to other sources - 50-70%) and often repeats the outlines of this damage, for example, scratches, cuts, scars, etc. [8, 9]. The role of the isomorphic reaction in the development of PA has not been sufficiently studied. It is still unclear whether trauma is a trigger, risk factor, or predictor of this disease. Traumatization and PA are associated through the activation of the innate immune system by biomechanical factors [10, 11]. The role of increased activation of T-cells in the foci of traumatic provocation, leading to a consistent transition of chronic inflammation of entheses to synovial membranes due to their anatomical proximity, is assumed [12, 13]. Specific manifestations of an isomorphic reaction in PA have not been established. Presumably, it includes a reaction from the musculoskeletal system in response to injury due to increased persistence of T cells, which is reflected in the form of enthesitis, synovitis, and extra-articular bone proliferation [14]. It is emphasized that this phenomenon is specific for PA [7]. Thus, the isomorphic reaction in response to trauma, as a dermatological phenomenon, is of interest not only for the diagnosis of psoriasis, but also for the diagnosis of PA in patients with psoriasis.
Mechanism of isomorphic reaction formation. It is known that in patients with psoriasis and PA, the content of CD8-lymphocytes is higher than in healthy individuals. Presumably, their role, which consists in immune aggression against target organs, is significant in both psoriasis and PA [7, 15]. High expression of CD8-lymphocytes is accompanied by the production of cytokines in the skin (interleukins (IL) 1 and 6, tumor necrosis factor alpha (TNF-α), nerve growth factor (Nerve Growth Factor - NGF)), their persistence in the blood with "settlement" in areas of periarticular tissues damaged due to physical activity or trauma [7, 9], which leads to the development of enthesitis, which, however, is often asymptomatic [16]. This assumption is consistent with the data of Steel K. J. (2020), who described an increased expression of CD8 lymphocytes not only in the skin of patients with psoriasis, but also in the synovial fluid of patients with PA [17]. Thus, both in patients with psoriasis and in patients with PA, common mechanisms are involved in the implementation of the Koebner phenomenon [18].
Relationship of injury, isomorphic reaction and clinical manifestations of psoriasis and PA. The Koebner phenomenon in patients with psoriasis occurs within 10–15 days at the site of exposure to healthy skin, as well as in areas subject to the greatest stress and pressure [19]. According to some reports, for this reason, the favorite localization of lesions in psoriasis (sacral region, skin of the knee and elbow regions, scalp) can also be explained by an isomorphic reaction [8, 19]. Back in the 1970s, Moll and Wright first suggested that in patients with psoriasis, the Koebner phenomenon also explains the development of dactylitis and spondyloarthritis as a result of a high mechanical load on the joints of the hands and spine [20].

Noted, that oligoarthritis often develops in the same areas of constant trauma, and weight lifting increases the likelihood of developing psoriatic spondylitis [21, 22]. It is assumed that a similar skin isomorphic reaction on the part of entheses and joints in areas subjected to local biomechanical trauma develops in patients genetically predisposed to PA, which, as a rule, includes patients with psoriasis phenotype 1 [9, 23]. Thus, a tendency to an increased reaction in response to mechanical stress is observed both in patients with psoriasis and in patients with PA, and, presumably, can be explained by an isomorphic reaction.
Association of localization of inflammation in PA with mechanical damage. It has been noted that most often dactylitis in PA affects the 2nd and 3rd fingers of the dominant hand, as well as the fourth toes [23, 24]. McGonagle (2019) reports that this indicates a certain role of permanent microtraumatization in the development of PA, in addition, in his opinion, the importance of trauma in the development of PA is indicated by more often damage to the toes compared to the fingers [24]. In an earlier study by Tinazzi I. et al. (2018) found that an excessive reaction to injury in the form of thickening was observed on the side of the annular ligaments of the hands, where dactylitis subsequently developed [21]. The study involved 96 patients with PA, 23 patients with psoriasis, 27 with rheumatoid arthritis (RA), and 19 healthy individuals. According to the results of the study, it was patients with PA, in contrast to other groups of subjects, who had thicker annular ligaments according to ultrasound (ultrasound) (68% of patients, p<0.001), and among them, patients with damage to the annular ligament and dactylitis of the second finger (p=0.020). The authors conclude that the isomorphic reaction plays an important role in the inflammation of the periarticular tissues, which develops even before arthritis [21]. It was noted that the ligamentous apparatus becomes inflamed in PA even in the absence of joint inflammation and before it [25]. In a later study by Tinazzi I. et al. (2020) also showed that the manifestation of biomechanical loads in PA is detected even in the preclinical stage of arthritis [26]. The relationship between previous trauma, hand enthesis lesions and subsequent dactylitis was also indicated in the study by Yong-Zhi Ji (2019) [27]. In 2020, Sapundzhieva T. (2020) revealed a high incidence of inflammation of the tendons of the hand due to physical activity in patients with psoriasis, who subsequently developed synovitis [28]. Thus, it was found that damage to the ligamentous apparatus in PA is detected earlier than inflammation of the articular surfaces, is associated with constant microtraumatization due to localization features and high functional loads, and, presumably, is caused by the same mechanisms as the hyperergic reaction from epitheliocytes in psoriasis. [29, 30].
Difficulties in interpreting the Koebner phenomenon for diagnosing extra-articular manifestations of PA and differential diagnosis of PA. Currently, the Koebner phenomenon refers to clinical dermatological, and not rheumatological or radiological phenomena. The skin isomorphic reaction in patients with psoriasis can be explained by traumatic exposure, however, there is no evidence that damage to the periarticular tissues associated with traumatization is associated exclusively with the Koebner phenomenon, while in other arthritis, the effect of trauma as an inflammation trigger is also observed [7] . The well-known assumption that extra-articular changes (dactylitis, enthesitis, tendinitis) are much more frequent in patients with PA, but not in patients with other arthritis [31], points in favor of the association of trauma as an initiating factor for the development of the Koebner phenomenon in PA. The most difficult differential diagnosis of PA and RA. The results of some comparative imaging studies show that extra-articular manifestations of arthritis in the form of periarticular edema and enthesitis are observed almost exclusively in PA, but not in RA [32]. For example, this is consistent with the data of Gazel U. (2020), where enthesitis and soft tissue edema were found much more often in patients with PA than in patients with RA [33]. In a study by Sayam R.D. (2020) noted that soft tissue edema around the flexor tendons in the dominant hand indicated the role of physical activity and microtrauma and was registered in a third of patients with PA, but not in patients with RA [34]. The authors of a foreign study (2018) of 228 patients also revealed a relationship between the incidence of periarticular tissue damage and psoriasis (family history of psoriasis, skin lesions and/or the presence of onychodystrophy) in patients with various connective tissue diseases [35]. According to another study (2019), an isomorphic reaction is also reflected in the form of a bone neoplasm (according to radiography) and is observed in PA, but not in other arthritis [36].

In a study of extra-articular signs of PA, Tang Y. also reported (2020) that some patients with psoriasis had similar extra-articular manifestations as in PA [37]. Thus, it can be assumed that the extra-articular manifestations of PA, which are often detected before the onset of arthritis, are to some extent due to an isomorphic reaction caused, in turn, by exercise and/or trauma.
Conclusion. Biomechanical stress plays an important role in the pathogenesis of psoriatic arthritis, and its role is subject to further study. There is a certain parallel between the clinical manifestations of an isomorphic reaction in the skin of patients with psoriasis and manifestations of a deep isomorphic reaction in the tendon-ligamentous apparatus in patients with PA. In both cases, this reaction is initiated by a traumatic impact, and in patients with PA, repetitive low-intensity injuries acquire a certain significance. This reaction in patients with PA is reflected in the form of extra-articular manifestations, which often develop before the clinical manifestation of arthritis, and can be successfully visualized using instrumental diagnostics, which in the future can probably be used for early detection of PA in patients with psoriasis.

About the authors

Ksenia M. Koreshkova

Bashkir State Medical University

Author for correspondence.
Email: saitik16@yandex.ru
ORCID iD: 0000-0001-6039-8311
SPIN-code: 4427-1594

assistant lecturer

Russian Federation, 3, Lenina str., Ufa, Republic of Bashkortostan, 450008

Zarema R. Khismatullina

Bashkir State Medical University

Email: hzr07@mail.ru
ORCID iD: 0000-0001-8674-2803
SPIN-code: 6602-4060

MD, Dr. Sci. (Med.), Professor

Russian Federation, 3, Lenina str., Ufa, Republic of Bashkortostan, 450008

References

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