JAK-STAT Signaling and Beyond in the Pathogenesis of Spondyloarthritis and Their Clinical Significance.

PURPOSE OF REVIEW: Janus kinase-signal transducers and activators of transcription cell signaling proteins (JAK-STATs) play a key regulatory role in functioning of several inflammatory cytokines. JAK-STAT signaling proteins are the key regulators of the cytokine/cytokine receptor system involved in the pathogenesis of various autoimmune disease including spondyloarthritis (SpA). This article mainly highlights the JAK-STAT signaling system, its association with the relevant cytokine/cytokine-receptor system, and its regulatory role in pathogenesis of SpA. Also, we have briefly addressed the principle for the use JAKi in SpA and the current status of use of JAK inhibitors (JAKi) in SpA. RECENT FINDINGS: Recent developments with newer JAK molecules as well as other molecules beyond JAK inhibitors are now an exciting field for the development of novel therapies for autoimmune diseases and various malignant conditions. In this article, we have provided a special emphasis on how various cell signaling systems beyond JAK/STAT pathway are relevant to SpA and have provided a comprehensive review on this upcoming field in respect to the novel TYK2 inhibitors, RORγT inhibitors, mTOR inhibitors, NGF inhibitors, and various STAT kinase inhibitors. SpA are a group of autoimmune diseases with multifactorial etiologies. SpA is linked with genetic predisposition, environmental risk factors, and the immune system-mediated systemic inflammation. Here, we have provided the regulatory role of JAK/STAT pathway and other intracellular signaling system in the pathogenesis of SpA and its therapeutic relevance.

Janus kinase inhibitors for the treatment of psoriatic arthritis.

Psoriatic arthritis (PsA), a systemic disease, has multi-domain musculoskeletal pathologies along with dermatological manifestations. The current recommendations and the standard of care for the treatment of PsA is to address the domain-based pathologies and the disease severity of the six clinical domains unique to PsA, namely, arthritis of the large and small joints, skin involvement, nail involvement enthesitis, dactylitis and axial disease. With currently available therapies, there are good numbers of primary/secondary non-responders and there are added concerns because of intolerance and adverse effects. In that respect, JAK/STAT inhibitors bring new options for many such patients with psoriasis and PsA. Here, we will discuss currently approved JAK inhibitors for PsA and the others which are in different phases of development, including the TYK2 inhibitors.

JAK inhibitor: Introduction.

The Janus kinase (JAK)-signal transducer and activator of transcription (STAT) pathway is a key regulatory signaling system for cellular proliferation, differentiation, and apoptosis. In addition, JAK signaling pathway plays critical roles in orchestrating immune response through its interactions with the cytokine receptors and the transcriptions factors. Several key cytokines use JAK-STAT signaling proteins to transduce intra-cellular signals which are involved in the pathogenesis of autoimmune and inflammatory diseases such as in psoriatic disease (psoriasis, psoriatic arthritis), atopic dermatitis, alopecia areata, vitiligo, rheumatoid arthritis, ankylosing spondylitis, lupus erythematosus, Sjogren's syndrome, and other autoimmune diseases. In recent years, understandings of the molecular mechanisms of JAK-STAT pathway in the inflammatory proliferative cascades of autoimmune diseases has led to the development of JAK inhibitors and has opened a new dimension for the treatment of systemic and cutaneous inflammatory diseases. In this symposium we have provided a broad perspective on the use of Janus kinase inhibitors in cutaneous autoimmune diseases.

Recent Update on Immunopathogenesis of Psoriasis.

Psoriasis is a chronic disabling complex inflammatory disorder prevalent worldwide with environmental and genetic components that involve predominantly skin in addition to nails and joints associated with various systemic comorbidities having periods of exacerbations and remissions. Psoriasis is characterized by hyper-proliferation as well as abnormal differentiation of epidermal keratinocytes and lymphocyte infiltration (mainly T cells) with resultant inflammatory cytokines and chemokines. Immunological and genetic studies over the last decade have identified genetic susceptibility risk alleles, molecular, cellular and immunological mechanisms involved in immunopathogenesis of psoriasis. The current disease model emphasizes the role of aberrant Th1 and Th17 responses regulated by a complex network of different cytokines, including TNF-α, IL-17 and IL-23; signal transduction pathways downstream to the cytokine receptors; and various activated transcription factors, including NF-κB, interferon regulatory factors and signal transducer and activator of transcriptions. Cytokines targeting biologics (IL-17, IL-23 and TNFα) therapies have revolutionized the management of severe skin disease having beneficial effects on joints and systemic inflammation of psoriasis as well. Further better understanding of immunopathogenesis of psoriasis will pave way for precision medicine based on specific immunopathogenic targets in a given phenotype of disease. Complex interplay of psoriasis with associated comorbidities is also a future area of research for overall better patient management and to improve their quality of life.

Phenotype and pathological significance of MCAM+ (CD146+) T cell subset in psoriatic arthritis.

BACKGROUND: CD146 (MCAM-melanoma cell adhesion molecule) is a cell surface adhesion molecule for Laminin 411. T cells expressing MCAM are mainly responsible for IL-17 production. IL-17 secreting T helper cells (Th17 cells) are critical for the pathogenesis of psoriatic arthritis (PsA). Here we hypothesized enrichment of CD146+IL-17+ memory T cells in PsA synovium and studied the association of CD146 expression and CD4+IL-17+ activated memory (CD11a+CD45RO+) T cells in synovial fluid and blood of PSA, rheumatoid arthritis (RA, a positive control) and osteoarthritis (OA) patients. METHODS: Hi-D FACS studies were done to identify IL-17 in CD4+CD146+CD45RO+ and CD8+CD146+CD45RO+ T cells. RESULTS: We observed that effector CD146+(MCAM+) T cells are enriched at the synovial inflammation site in PsA. CONCLUSION: As CD146+ T cells are a key resource for IL-17 it is likely that the enrichment of these MCAM+ pathologic cells are critical for the disease process of PsA.

Targeting the CCR6/CCL20 Axis in Entheseal and Cutaneous Inflammation.

OBJECTIVE: To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target. METHODS: First, we quantified CCL20 levels in peripheral blood and synovial fluid from PsA patients and examined the presence of CCR6+ cells in synovial and tendon tissue. Utilizing an interleukin-23 minicircle DNA (IL-23 MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression as well as the preventive and therapeutic effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1ß to assess the production of CCL20 by quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated using a Transwell system. RESULTS: We observed an up-regulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsy specimens. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and, accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD. CONCLUSION: Our study highlights the pathogenic role of the CCR6/CCL20 axis in enthesitis and introduces the prospect of a novel therapeutic approach for treating patients with PsO and PsA.

Janus kinase-signal transducers and activators of transcription cell signaling in Spondyloarthritis: rationale and evidence for JAK inhibition.

PURPOSE OF REVIEW: The Janus kinase-signal transducers and activators of transcription (JAK-STAT) signaling proteins represent a group of intracellular kinase molecules that play a central role in the signaling pathways induced by cytokines, chemokines, and certain growth factors associated with systemic and local inflammation of autoimmune diseases including in Spondyloarthritis (SpA). Here, we will discuss (i) the functional significance of the JAK-STAT kinase cascades in the inflammatory-proliferative processes of SpA and its cellular/molecular mechanisms (ii) progress in the development of oral synthetic JAK inhibitors (JAKi) and their therapeutic efficacies in SpA. RECENT FINDINGS: Development JAKi is a fast-moving field in the medical science. Several new-generation JAKi are being identified for psoriatic arthritis and ankylosing spondylitis. It is expected these JAKi likely to have higher potency and less adverse effects. SUMMARY: Here, we are providing an updated review on the significance of JAK-STAT signaling proteins in SpA with an emphasis on new-generation of JAK-STAT inhibitors for the treatment of SpA.

Updated therapies for the management of Psoriatic Arthritis.

Psoriatic arthritis (PsA) is a large volume of our clinical practice and its management can be challenging. Traditional DMARDs have been used over last six decades and observational studies have substantiated an effective use of many of these drugs. However, in last two decades use of anti-TNF agents has brought a new dimension in treatment of PsA and in many other autoimmune diseases. Regulatory role of the Th17 cells and its cytokines in the pathogenesis of PsA has successfully paved the foundations of anti-IL antibody based therapies in PsA. Newer therapies targeting the IL-23/IL-17 cytokines and its signaling proteins are now in development and bringing new promises for management of PsA. Herein, we provide an overview of the landscape of drug therapies, including IL-17, IL-12/23, IL-23 inhibitors, and janus kinase (JAK) inhibitors, as well as those in development, such as RORγt inhibitors, anti-NGF agents, mTOR inhibitors and T cell ion-channel blockers.

Functional significance of MAIT cells in psoriatic arthritis.

BACKGROUND: Mucosal-associated invariant T (MAIT) cells are gaining more relevance for autoimmune diseases because of its (i) innate and adaptive immune response (ii) tissue homing properties (iii) production of IL-17A. These cells are predominantly CD8+ cells, because of its strong association with MHC-I. Tc17 CD8+/MAIT cells likely to have a critical role in psoriatic arthritis (PsA). Herein, we have explored pathological significance of MAIT cell in PsA. METHODS: Peripheral blood mononuclear cells (PBMC) and synovial fluid mononuclear cells (SFMC) were collected from age/sex matched (n = 10 for each) PsA, rheumatoid arthritis (RA) and osteoarthritis patients (OA). Hi-D FACS studies were performed: (i) activated memory cells (CD3+CD45RO+) T cells were identified (ii) gating strategies were made to identity the MAIT (CD3+Vα7.2TCR+CD161hi) cells, its phenotype pattern; and functional significance in respect to IL-17A production and responsiveness to human rIL-23. Anti CD3/CD28 ab cocktail was used to activate cells along with rIL-23 to culture and enrich the MAIT cells. The percentages of each cell population and the mean fluorescence intensity (MFI) were analyzed using Flow Jo software. RESULTS: MAIT cells were enriched in synovial fluid of PsA (4.29 ±â€¯0.82%) compared to PBMC (1.04 ±â€¯0.71). With stimulation, SFMC MAIT cells produced significantly more IL-17A (32.66 ±â€¯4.01%) compared to that of RA (23.93 ±â€¯2.81%, p < 0.05) and OA (5.02 ±â€¯0.16%, p < 0.05). MAIT cells were predominantly CD8+ (>80%). Significant upregulation of IL-23R was noted in synovial fluid MAIT cells of PsA (24.97 ±â€¯2.33%, p < 0.001) and RA (21.93 ±â€¯2.29%, p < 0.001) compared to that of OA (2.13 ±â€¯2.29). This IL-23R was functionally active as evidenced by profound mitotic effect in presence of rIL-23. CONCLUSION: MAIT cells are poly functional; produce multiple cytokines (IL-17A, IFN-γ, TNF-α). Here, we demonstrated synovial fluid MAIT cells as a major source of IL-17A and majority of MAIT cells were CD8+. Functionally active IL-23R on these migrated MAIT cells brings a new dimension. They may not need MR1 associated activation rather lesional IL-23 in the synovium can independently regulate these critical Tc17 CD8+ MAIT cells. Thus, these cells likely to be a part of the IL-23/IL-17A cytokine network and play a critical role in the pathogenesis of PsA.

Risk of tuberculosis with anti-tumor necrosis factor-alpha therapy in patients with psoriasis and psoriatic arthritis in Indian population.

Anti-tumor necrosis factor-alpha (TNF-α) immunotherapy has revolutionized the treatment of inflammatory diseases, such as psoriasis and psoriatic arthritis. However, a major concern is that patients receiving this therapy have an increased risk of infection, particularly of reactivation of latent tuberculosis (TB). There were an estimated 10.4 million new cases of tuberculosis in 2016, worldwide, and India has one of the largest TB case burden with an estimated incidence of 2.79 million cases of TB in the same year. Anti-TNF agents like etanercept and infliximab are available in India approved for psoriasis and psoriatic arthritis. But long-term use of these agents possesses a risk of reactivation of latent TB. In this review article, we assessed the risk of TB with anti-TNF therapy especially in patients with psoriasis and psoriatic arthritis in India. At the end of the article, we have also suggested a recommendation for screening of latent tuberculosis and its management, before starting anti-TNF-α therapy.

IL-9 receptor: Regulatory role on FLS and pannus formation.

OBJECTIVE: Functions of the Th9 cells and its signature cytokine IL-9 in human autoimmune diseases is currently under extensive research. Here we are reporting new functions of IL-9-receptor (IL-9R); its regulatory role on (i) FLS (fibroblast like synoviocyte) biology and (ii) pannus formation in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). METHODS: RA, PsA, and OA synovial tissue biopsies were obtained; FLS were derived and cultured from these tissues. T quantify protein and messenger RNA levels of IL9-receptor (IL-9R) Western blot and real-time PCR techniques were used. For Pro-growth/survival effect of IL-9 (rIL-9) Annexin-V (apoptosis assay) and MTT assays were used. RESULTS: Immunoblot and RT-PCR studies demonstrated IL9-R in FLS of RA, PsA, and OA. IL9-R was functionally active. rIL-9 induced significant proliferation of FLS (p < 0.001) and had an inhibitory effect on TNF-α induced apoptosis. Proliferation of FLS induced by rIL-9 could be significantly inhibited (p < 0.001) with an IL-9R antibody. Further we observed, rIL-9 induced increased secretion of IL-6, IL-8 and also unregulated MMP-3 expression in FLS. CONCLUSIONS: Proliferation of FLS, induction of pro-nflammatory cytokines and upregulation of metaloprotinase (MMP 3) the key pathologic events for pannus formation are regulated by IL-9 and its recptor. Thus the IL-9/IL-9R system is a new contributing factor in the cytokine network of PsA and RA.

Correction to: Inflammation, Atherosclerosis, and Psoriasis.

Following publication of this article [1] it came to our attention that we neglected to reference an article by Ishwarlal Jialal published in Critical Pathways in Cardiology [2].

Janus kinase/signal transducer and activator of transcription pathways in spondyloarthritis.

PURPOSE OF REVIEW: Cytokines are major drivers of autoimmunity, and biologic agents targeting cytokines have revolutionized the treatment of immune-mediated diseases. Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway represents a group of several intracellular molecules with a key role in signal pathways activated by growth factors and cytokines. These kinase proteins are associated with the signaling process of multiple key cytokines, which regulates various T-cell subpopulations and their effector cytokines. Development of novel drugs to inhibit this kinase cascade is an emerging field in clinical immunology. Thus, it is essential to have insights about the regulatory role of the JAK-STAT cytokine signaling in relation to autoimmune diseases and its applications in spondyloarthritis. RECENT FINDINGS: JAK-STAT kinase signaling proteins have been extensively studied in rheumatoid arthritis. Initial observations suggest that JAK-STAT kinase signaling cascade regulates activation and proliferation of the IL17 effector memory T cells and thus has a potential role in the pathogenesis of psoriasis, psoriatic arthritis and ankylosing spondylitis. SUMMARY: Here, we provide an overview of the clinical rheumatologists about the significance of JAK-STAT signaling system in rheumatic diseases and introduce the potential application of JAK and STAT inhibitors in spondyloarthritis.

Mechanistic rationales for targeting interleukin-17A in spondyloarthritis.

The term spondyloarthritis (SpA) is used to describe a group of inflammatory autoimmune diseases, including ankylosing spondylitis and psoriatic arthritis, with common genetic risk factors and clinical features. SpA is clinically distinct from rheumatoid arthritis and typically affects the spine, sacroiliac joints, entheses, and, less commonly, peripheral joints. Although the pathogenesis of SpA is not fully understood, recent findings have identified the interleukin (IL)-17 pathway as a key mediator of disease pathogenesis. Clinical evidence for the efficacy of IL-17A inhibition by biologic agents was initially shown in patients with chronic plaque psoriasis, another autoimmune disease mediated by the IL-17 pathway. Subsequently, similar positive efficacy for inhibition of IL-17A was seen in patients with ankylosing spondylitis and psoriatic arthritis. Inhibition of IL-17A may also improve cardiovascular and metabolic comorbidities often found in patients with SpA because studies have linked these disorders to the IL-17 pathway. In this review, we will examine key preclinical studies that demonstrated the mechanistic role of IL-17A in the development SpA and discuss how these observations were translated into clinical practice.

Management of psoriatic arthritis: Early diagnosis, monitoring of disease severity and cutting edge therapies.

Psoriatic arthritis (PsA) is a heterogeneous disease that can involve a variety of distinct anatomical sites including a patient's peripheral and axial joints, entheses, skin and nails. Appropriate management of PsA requires early diagnosis, monitoring of disease activity, and utilization of cutting edge therapies. To accomplish the former there are a variety of PsA-specific tools available to screen, diagnose, and assess patients. This review will outline the recently developed PsA screening tools, including the Toronto Psoriatic Arthritis Screening Questionnaire (TOPAS), the Psoriasis Epidemiology Screening Tool (PEST), the Psoriatic Arthritis Screening and Evaluation (PASE), and the Psoriasis and Arthritis Screening Questionnaire (PASQ). We will also review the Classification Criteria for Psoriatic Arthritis (CASPAR) and current PsA disease severity measures, such as the Disease Activity index for Psoriatic Arthritis (DAPSA), the Psoriatic Arthritis Joint Activity Index (PsAJAI) and the Composite Psoriatic Disease Activity Index (CPDAI). As is the case for PsA screening and assessment tools, there are also a variety of new therapies available for PsA. Historically, patients with PsA were treated with NSAIDS and traditional disease-modifying anti-rheumatic drugs (DMARDs). However, the ability of these medications to slow down the radiographic progression of joint disease has not been demonstrated. In contrast, anti-TNF agents, such as etanercept, infliximab, adalimumab, golimumab and certolizumab, are effective in this regard. Emerging PsA treatments include an oral phosphodiesterase 4 inhibitor, apremilast; a Janus kinase (JAK) inhibitor, tofacitinib; and several new biologics that target the IL-23/IL-17 pathway including secukinumab, brodalumab, ixekizumab, and ustekinumab. Herein we will review the mechanisms of action of these drugs, their results in clinical trials, and guidelines for administration. Lastly, treatment recommendations from the European League Against Rheumatism (EULAR) and The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) will be discussed.

IL-23/IL-17 axis in spondyloarthritis-bench to bedside.

Cytokines play a critical role in the pathogenesis of psoriatic arthritis, ankylosing spondylitis, and other types of spondyloarthritis (SpA). Besides IFN-γ and TNF-α; IL-23/IL-17 cytokines play a dominant role in the inflammatory and proliferative cascades of SpA. Recently, in a series of elegant experiments using mouse models and human tissues, it has been demonstrated that IL-23-induced Th17 cytokines (IL-17 and IL-22) can contribute to following pathologic events associated with SpA: development of psoriatic plaque, pannus formation in the joint, joint erosion, and new bone formation. In this review article, we have discussed the contributing role of the IL-23/IL-17 cytokine axis in the pathogenesis of PsA and AS. IL-23/IL-17-targeted therapies are very promising for SpA, and we have provided an outline about usefulness of these new groups of biologics in SpA.