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.

Modulation of Interleukin-23 Signaling With Guselkumab in Biologic-Naive Patients Versus Tumor Necrosis Factor Inhibitor-Inadequate Responders With Active Psoriatic Arthritis.

OBJECTIVE: We assessed and compared immunologic differences and associations with clinical response to guselkumab, a fully human interleukin (IL)-23p19 subunit inhibitor, in participants with active psoriatic arthritis (PsA) who were biologic-naive or had inadequate response to tumor necrosis factor inhibitors (TNFi-IR). METHODS: Serum biomarker levels at baseline and after treatment with guselkumab 100 mg every 8 weeks were compared between biologic-naive (n = 251) and TNFi-IR (n = 93) subgroups identified in the pooled DISCOVER-1/DISCOVER-2/COSMOS data set. Baseline biomarker levels determined by achievement of week 24 clinical responses (≥75%/90% improvement in Psoriasis Area and Severity Index [PASI 75/90], Investigator's Global Assessment [IGA] of psoriasis score 0/1 and ≥2-point improvement], ≥20% improvement in American College of Rheumatology criteria [ACR20]) were compared between prior treatment subgroups. RESULTS: Baseline IL-22, TNFα, and beta defensin-2 (BD-2) levels were significantly lower in biologic-naive than in TNFi-IR participants. With guselkumab, week 24 IL-17A, IL-17F, IL-22, serum amyloid A, C-reactive protein, IL-6, and BD-2 levels were significantly reduced from baseline in biologic-naive and TNFi-IR participants (≥1.4-fold difference, nominal P < 0.05). Clinical responders to guselkumab exhibited significantly higher baseline levels of several biomarkers than nonresponders (IL-17A, IL-17F, BD-2 in biologic-naive PASI 90 responders; IL-17A, BD-2 in TNFi-IR IGA 0/1 responders; IL-22, BD-2 in TNFi-IR PASI 90 responders [nominal P < 0.05]) and trended higher in TNFi-IR ACR20 responders. CONCLUSION: Guselkumab modulates IL-23 signaling and provides consistent pharmacodynamic effects in both biologic-naive and TNFi-IR PsA patients. Significantly elevated baseline IL-22, TNFα, and BD-2 levels and associations between baseline IL-22, IL-17A, and BD-2 levels and skin responses to guselkumab suggest greater dysregulation of IL-23/Th17 signaling in patients with TNFi-IR.

EXPLORing Arthritis with Total-body Positron Emission Tomography.

Arthritis has significant adverse consequences on musculoskeletal tissues and often other organs of the body. Current methods for clinical evaluation of arthritis are suboptimal, and biomarkers that are objective and measurable indicators for monitoring of arthritis disease activity are in critical demand. Recently, total-body positron emission tomography (PET) has been developed that can collect imaging signals synchronously from the entire body at ultra-low doses and reduced scan times. These scanners have increased signal collection efficiency that overcomes several limitations of standard PET scanners in the evaluation of arthritis, and they may potentially provide biomarkers to assess local and systemic impact of the arthritis disease process. This article reviews current results from using total-body PET in the assessment of common arthritic conditions, and it outlines future opportunities and challenges.

Novel Insights From Basic Science in Psoriatic Disease at the GRAPPA 2022 Annual Meeting.

Recent basic science advances in psoriatic disease (PsD) were presented and discussed at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2022 annual meeting. Topics included clinical applications of biomarkers, what the future of biomarkers for PsD may hold, the challenges of developing biomarker research to the point of clinical utility, advances in total-body positron emission tomography/computed tomography imaging, and emerging concepts from single-cell studies in PsD.

JAK-STAT inhibitors in Immune mediated diseases: An Overview.

For any biological response, transmission of extracellular signals to the nucleus is required for DNA transcription and gene expression. In that respect, cytokines/chemokines are well-known inflammatory agents which play a critical role in signalling pathways by activating the Janus kinase-signal transducers and activators of transcription (JAK-STAT) signalling proteins (Janus kinase-signal transducers and activators of transcription) which are a group of intracellular kinase molecules. Cytokines are a category of small proteins (∼5-25 kDa) that play a major role in cell signalling and are major drivers of an autoimmune response. Here we will discuss the role of Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative cascades of autoimmune disease and about the recent progress in the development of oral synthetic Janus kinase inhibitors (JAKi) and their therapeutic efficacies in dermatologic and systemic autoimmune diseases. Therapeutic efficacy of Janus kinase inhibitors is now well established in the treatment of array of autoimmune and inflammatory disease: spondylarthritis with a special focus on psoriatic arthritis (PsA) and its dermatologic manifestations (psoriasis) and ankylosing spondylitis (AS), atopic dermatitis (AD), alopecia areata (AA), rheumatoid arthritis (RA) and inflammatory bowel disease (IBD). In addition to the first-generation Janus kinase inhibitors several new-generation Janus kinase inhibitors are currently being evaluated. It is expected that these Janus kinase inhibitors likely have higher potency and less adverse effects as compared to their predecessors. Here we have discussed: (1) the functional significance of the Janus kinase-signal transducers and activators of transcription kinase cascades in the inflammatory-proliferative processes of autoimmune diseases and its cellular/molecular mechanisms and (2) progress in the development of oral synthetic Janus kinase inhibitors and their therapeutic efficacies in several systemic and cutaneous autoimmune diseases.

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.

Janus kinase inhibitors for alopecia areata: A narrative review.

The Janus kinase (JAK) and Signal Transducer and Activator of Transcription (STAT) pathway has been identified as a key player in the pathophysiology of alopecia areata and a potential target for therapy. Here, we give a narrative review of what is known about Janus kinase inhibitors in alopecia areata. Several clinical trials as well as smaller studies have demonstrated hair regrowth and remission with oral Janus kinase inhibitors therapy, even in patients who failed conventional treatment. Baricitinib is the only US FDA-approved treatment for alopecia areata but data for other oral Janus kinase inhibitors such as tofacitinib, ruxolitinib and ritlecitinib are also promising. Fewer clinical trials have investigated topical Janus kinase inhibitors for alopecia areata, with many of them terminated early due to unfavourable results. Overall, Janus kinase inhibitors are an efficacious addition to the therapeutic arsenal for treatment-refractory alopecia areata. Further work is needed to examine the effects of long-term usage of Janus kinase inhibitors, the efficacy of topical Janus kinase inhibitors, as well as to identify biomarkers that could predict differential therapeutic responses to the various Janus kinase inhibitors.

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.

Total-Body 18F-FDG PET/CT in Autoimmune Inflammatory Arthritis at Ultra-Low Dose: Initial Observations.

Autoimmune inflammatory arthritides (AIA), such as psoriatic arthritis and rheumatoid arthritis, are chronic systemic conditions that affect multiple joints of the body. Recently, total-body (TB) PET/CT scanners exhibiting superior technical characteristics (total-body coverage, geometric sensitivity) that could benefit AIA evaluation, compared with conventional PET/CT systems, have become available. The objectives of this work were to assess the performance of an ultra-low-dose, 18F-FDG TB PET/CT acquisition protocol for evaluating systemic joint involvement in AIA and to report the association of TB PET/CT measures with joint-by-joint rheumatologic examination and standardized rheumatologic outcome measures. Methods: Thirty participants (24 with AIA and 6 with osteoarthritis) were prospectively enrolled in this single-center, observational study. All participants underwent a TB PET/CT scan for 20 min starting at 40 min after intravenous injection of 78.1 ± 4.7 MBq of 18F-FDG. Qualitative and quantitative evaluation of 18F-FDG uptake and joint involvement were performed from the resulting images and compared with the rheumatologic assessments. Results: TB PET/CT enabled the visualization of 18F-FDG uptake at joints of the entire body, including those of the hands and feet, in a single bed position, and in the same phase of radiotracer uptake. A range of pathologies consistent with AIA (and non-AIA in the osteoarthritis group) were visualized, and the feasibility of extracting PET measures from joints examined by rheumatologic assessments was demonstrated. Of 1,997 evaluable joints, there was concordance between TB PET qualitative assessments and joint-by-joint rheumatologic evaluation in the AIA and non-AIA cohorts for 69.9% and 91.1% joints, respectively, and an additional 20.1% and 8.8% joints, respectively, deemed negative on rheumatologic examination showed PET positivity. On the other hand, 10.0% and 0% joints in the AIA and non-AIA cohorts, respectively, were positive on rheumatologic evaluation but negative on TB PET. Quantitative measures from TB PET in the AIA cohort demonstrated a moderate-to-strong correlation (Spearman ρ = 0.53-0.70, P < 0.05) with the rheumatologic outcome measures. Conclusion: Systemic joint evaluation in AIA (and non-AIA) is feasible with a TB PET/CT system and an ultra-low-dose protocol. Our results provide the foundation for future larger studies to evaluate the possible improvements in AIA joint assessment via the TB PET/CT technology.

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.

GRAPPA 2019 Research Recipient Awards Report.

A summary of the research conducted by the recipients of the 2019 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Research Awards is presented. Dr. Alla Ishchenko's project was "Role of Metabolomics in Diagnosis, Disease Severity, and Progression in Psoriasis and Psoriatic Arthritis: A 2-year Prospective Pilot Study" and Dr. Zhenrui Shi's project was "Preclinical Analysis of CCR6 and CCL20 in Mouse and Human Joints, Respectively, as Targets of Therapeutic Intervention in Psoriatic Arthritis."

Feasibility of dual-phase 99mTc-MDP SPECT/CT imaging in rheumatoid arthritis evaluation.

BACKGROUND: To prospectively demonstrate the feasibility of performing dual-phase SPECT/CT for the assessment of the small joints of the hands of rheumatoid arthritis (RA) patients, and to evaluate the reliability of the quantitative and qualitative measures derived from the resulting images. METHODS: A SPECT/CT imaging protocol was developed in this pilot study to scan both hands simultaneously in participants with RA, in two phases of 99mTc-MDP radiotracer uptake, namely the soft-tissue blood pool phase (within 15 minutes after radiotracer injection) and osseous phase (after 3 hours). Joints were evaluated qualitatively (normal vs. abnormal uptake) and quantitatively [by measuring a newly developed metric, maximum corrected count ratio (MCCR)]. Qualitative and quantitative evaluations were repeated to assess reliability. RESULTS: Four participants completed seven studies (all four were imaged at baseline, and three of them at follow-up after 1-month of arthritis therapy). A total of 280 joints (20 per hand) were evaluated. The MCCR from soft-tissue phase scans was significantly higher for clinically abnormal joints compared to clinically normal ones; P<0.001, however the MCCR from the osseous phase scans were not different between the two joint groups. Intraclass Correlation Coefficient (ICC) for MCCR was excellent [0.9789, 95% confidence interval (CI): 0.9734-0.9833]. Intra-observer agreement for qualitative SPECT findings was substantial for both the soft-tissue phase (kappa =0.78, 95% CI: 0.72-0.83) and osseous-phase (kappa =0.70, 95% CI: 0.64-0.76) scans. CONCLUSIONS: Extracting reliable quantitative and qualitative measures from dual-phase 99mTc-MDP SPECT/CT hand scans is feasible in RA patients. SPECT/CT may provide a unique means for assessing both synovitis and osseous involvement in RA joints using the same radiotracer injection.

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.

Efficacy and safety of tildrakizumab in patients with active psoriatic arthritis: results of a randomised, double-blind, placebo-controlled, multiple-dose, 52-week phase IIb study.

OBJECTIVES: To evaluate efficacy and safety of the anti-interleukin-23p19 monoclonal antibody tildrakizumab in patients with psoriatic arthritis (PsA). METHODS: In this randomised, double-blind, placebo-controlled, phase IIb study, patients with active PsA were randomised 1:1:1:1:1 to tildrakizumab 200 mg every 4 weeks (Q4W); tildrakizumab 200, 100 or 20 mg Q12W; or placebo Q4W. Patients receiving tildrakizumab 20 mg or placebo switched to tildrakizumab 200 mg Q12W at W24; treatment continued to W52. The primary efficacy endpoint was proportion of patients with ACR20 response (≥20% improvement by American College of Rheumatology criteria) at W24. Secondary efficacy endpoints were assessed without adjustment for multiplicity. Safety was evaluated from treatment-emergent adverse events (TEAEs). RESULTS: 391/500 patients screened were randomised and treated. At W24, 71.4%-79.5% of tildrakizumab-treated versus 50.6% of placebo-treated patients achieved ACR20 (all p<0.01). Patients receiving tildrakizumab versus placebo generally achieved higher rates of ACR50, Disease Activity Score in 28 joints with C reactive protein <3.2, minimal disease activity and 75%/90%/100% improvement from baseline Psoriasis Area and Severity Index responses at W24 and through W52. Improvement in dactylitis and enthesitis was not observed; results were mixed for other outcomes. Responses in patients switched to tildrakizumab 200 mg at W24 were consistent with treatment from baseline. TEAEs and serious TEAEs occurred in 64.5% and 3.3%, respectively, of all patients through W52 and were comparable among treatment arms. CONCLUSIONS: Tildrakizumab treatment significantly improved joint and skin manifestations of PsA other than dactylitis and enthesitis. Treatment was generally well tolerated through W52. Clinicaltrials.gov NCT02980692.

GRAPPA 2019 Research Recipient Awards Report.

A summary of the research conducted by the recipients of the 2019 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) Research Awards is presented. Dr. Alla Ishchenko's project was "Role of Metabolomics in Diagnosis, Disease Severity, and Progression in Psoriasis and Psoriatic Arthritis: A 2-year Prospective Pilot Study" and Dr. Zhenrui Shi's project was "Preclinical Analysis of CCR6 and CCL20 in Mouse and Human Joints, Respectively, as Targets of Therapeutic Intervention in Psoriatic Arthritis."