The association of HI and arthritis has been reported in literature, although to date few cases have been described. It is unclear whether the concomitant arthritis can be regarded as JIA or whether it represents a different entity with unique features to considered as part of HI itself. The longer survival of HI patients may increase the number of patients who may develop arthritis throughout the disease course, and will increase the probability to better understand in the future the best management of joint involvement
In the published cases, arthritis often showed sometimes a rather aggressive course, leading to joint erosions and even to early joint replacement. Most patients showed early arthritis onset. Acute phase reactants were usually only slightly increased, while ANA, FR and ENA were found to be negative. Response to IACI was generally good, although temporary, and response to conventional and biologic DMARS was variable.
In JIA immune cells, including T and B lymphocytes, infiltrate the synovial membrane of inflamed joints, suggesting that the adaptive immune system is involved in the pathogenesis of the disease. [24] Recently, a particular T lymphocyte population, Th17 cells, has been found to be crucial in JIA pathogenesis: tumor necrosis factor (TNF)-α inhibitors are the main biological drugs used in JIA and interfere with these cells, giving an explanation of efficacy of etanercept treatment in JIA. [25]
Harlequin Ichthyosis is characterized by a profound dysregulation of lipid secretion into the stratum corneum and skin barrier function. Currently, therapy is aimed to treatment of scaling, using keratolytics such as urea,[26] or long-term retinoids, [27] which may negatively affect bone density, [28] and can generate skin erosion and thinning leading to further epidermal barrier function impairment. [29] Retinoids have also been shown to cause arthropathy, but this typically presents in the axial skeleton as ossification along the anterior longitudinal ligament and as pelvic hyperostosis.
As already found in other dermatoses such as atopic dermatitis and psoriasis, cytokine dysregulation and barrier impairment are both factors that underpin the disease. According to that, psoriasis-like immune dysregulation and lipid alterations seems to characterize the ichthyoses. [30] In different ichthyoses, high levels of IL-17 and TNF-α cytokine was documented. [31,32] This is accompanied by increased systemic and skin-homing T-cell activation and multicytokine polarization, with IL-17/IL-22 polarization predominance. [33] Ustekinumab, a monoclonal antibody directed against IL-23, was able to reduce skin erythema, scaling, and Trans Epidermal Water Loss (TEWL), a skin barrier functional index, in two patients with an ichthyotic syndrome. [31] To investigate the therapeutic potential of IL-17 targeting drugs, a clinical trial of secukinumab (anti-IL17-antibody) in patients with ichthyoses (NCT03041038), is currently ongoing.
Cutaneous and systemic immune inflammation has been well studied and successfully treated in other skin diseases such as psoriasis and atopic dermatitis. [33] However, inflammation in ichthyosis is little considered. In psoriasis, biologic treatment with IL-17 antagonist is reported as highly effective in reversing the inflammation and the cutaneous disease. [31] Of interest, the role of anti- TNF-α treatment in psoriasis and psoriatic arthritis is already well documented. [34]
Conventional DMARDs in patients with HI and chronic inflammatory arthritis have already been used without significant side effects. In a single case report worsening of erythroderma and increased cutaneous infections were reported, with poor disease control even using MTX and a biologic agent in combination.[22] In our patient, the severity of arthritis required the association of conventional and biological DMARDs with improvement of arthritis and decrease of erythema, without any infectious events reported at 18 months follow-up, nor any other adverse events.
The role of other proinflammatory cytokines and other biology treatments in ichthyosis have been proposed. Interleukine (IL)1 alpha is constitutively expressed in the upper epidermis [35,36], as is its receptor [37], and the soluble decoy receptor (IL1RA) [38,39], and a fine balance in expression of IL1 alpha and IL1RA has to be granted in healthy skin. [40] Some studies suggest that up-regulation of IL-1 is common to all Autosomal Recessive Congenital Ichthyosis, and the entity of this upregulation is related to clinical severity. An in vitro study on disease-mimic organotypic cultures treated with IL-1 receptor antagonist was beneficial on hyperkeratosis in a dose-dependent fashion. [41]
JIA is now thought to be a multifactorial pathology, in which genetic susceptibility meets an environmental trigger, leading to an uncontrolled response toward putative self- antigens. [42]
Some of the environmental triggers that have been studied as risk factors for the development of arthritis are frequently reported in HI patients.[43] Infections during the first year of life were associated with increased risks for seronegative JIA.[44] Extensive antibiotic use is also common in the early life of these patients. Antibiotics were associated with JIA development in a large pediatric population, and could play a role in JIA pathogenesis by acting through microbiome disruption. [45] Prematurity and caesarian-section delivery are frequent in patients with HI. Some studies have proposed that unlabored C-sections may slightly increase the risk of JIA due to changes in newborn microbiota and immune response. [44,46]