Axial Inflammation Research Articles

The role of pulmonary rehabilitation in improving lung functions in patients with ankylosing spondylitis

Background Ankylosing spondylitis (AS) is a chronic inflammatory disease characterized by axial and peripheral entheseal inflammation and new bone production(1). The development of syndesmophytes, enthesophytes, and spinal fusion along the course of the disease is linked to chronic pain, functional impairment, and disability(2). Fibrosis of the upper lobes of the lungs (interstitial lung disease) and chest wall abnormalities are two of the emerging forms of pulmonary involvement in AS. (3). Pulmonary rehabilitation is a multifaceted program of education, counselling, breathing exercises, and other modalities that can increase the patient’s independence and ease of functioning(4). Aim To estimate the role of pulmonary rehabilitation in enhancing lung function in AS individuals in relation to disease activity, clinical, and functional parameters. Patients and methods This study was an interventional study: single-arm group (prospective randomized clinical study). Thirty people (30) participated in that study from those presented to Physical Medicine, Rheumatology and Rehabilitation inpatient and outpatient clinic at Ain Shams University hospitals, diagnosed as radiographic axial spondyloarthropathy (SPA) from 02/2022 to 12/2022. All patients underwent pulmonary rehabilitation program and were exposed to a detailed history, clinical, and pulmonary function testing. Disease activity was evaluated by Ankylosing Spondylitis Disease Activity Score C-reactive protein (ASDAS-CRP), Valuation of function by using Bath Ankylosing Spondylitis Functional index (BASFI), 6-Minute walk test (6MWT), the Modified Borg Dyspnoea Scale (MBS), and Timed Up and Go (TUG) test. All function and clinical scores were done at baseline and repeated after completing pulmonary rehabilitation program. Result The mean age of patients was 36.57 ± 7.83 years (23–45 years), with a median disease duration of (5 (3–9) years). In total, there were 19 out of the studied patients with restrictive pattern. With comparison between pre- and postintervention of pulmonary rehabilitation, there was a significant statistical difference in all, disease activity (ASDAS and BASFI) and functional (MBS, TUG, and 6MWT) parameters (P <0.001), except for occiput to the wall. Regarding pulmonary function tests, including forced vital capacity (FVC), expiratory volume in one second (FEV1), and peaked expiratory flow (PEF), there was a statistically significant change at baseline and at the end of exercise (P <0.001). Conclusion Improved respiratory function and disease activity and overall functional activity are possible outcomes of pulmonary rehabilitation programs in combination with other rehabilitation interventions.

Spine and Sacroiliac Joint Involvement in Newly Diagnosed Patients With Inflammatory Bowel Disease: Clinical and MRI Findings From a Population-Based Cohort.

In patients with inflammatory bowel disease (IBD), co-occurring spondyloarthritis (SpA) leads to poorer outcomes and impaired quality of life, highlighting the importance of early detection and effective treatment. This is the first study to assess the prevalence and distribution of axial symptoms and magnetic resonance imaging (MRI)-detected involvement of the spine and sacroiliac joints (SIJs) in early IBD. Newly diagnosed patients with IBD from a prospective, population-based cohort were consecutively recruited. Rheumatological interview, clinical, ultrasound, and MRI assessment for SIJ and spine inflammatory and structural lesions were made using validated scoring methods and consensus definitions of axial SpA (axSpA). Of 110 patients (ulcerative colitis: 70, Crohn's disease: 40, mean age of 42 years, and 40% male), 48 (44.9%) reported back and/or buttock pain, and 10 (9.1%) had inflammatory back pain. Seventeen (16.7%) patients had MRI findings indicative of axSpA; only 10 of these patients had axial symptoms. Inflammatory MRI lesions were present in SIJs and the spine of 27 (26.5%) and 30 (30.3%) patients, respectively. The Assessment of SpondyloArthritis International Society classification criteria for axSpA were met in 11 (10%) cases. MRI findings typical of axSpA were associated with peripheral joint and entheseal inflammation detected by ultrasound ( P = 0.04). No differences in clinical or imaging findings were found between patients with ulcerative colitis and Crohn's disease. One-in-6 newly diagnosed patients with IBD had MRI findings indicative of axSpA. As 40% of these patients were asymptomatic, this suggests that axSpA is underdiagnosed in early IBD. Multidisciplinary collaboration is essential to ensure early detection of axial inflammation and to enable optimal therapy preventing future structural damage and disability.

Axial spondyloarthritis—current aspects

Axial spondyloarthritis (axSpA) is a frequent inflammatory rheumatic disease mainly affecting the axial skeleton causing inflammatory back pain. If chronic inflammation persists new bone formation may occur possibly leading to irreversible spinal stiffness. The disease has a strong genetic background with HLA-B27 as the major factor. For diagnostic purposes, imaging is of critical importance—especially conventional radiography and magnetic resonance imaging (MRI). While the former has advantages in the detection of bony changes such as the syndesmophytes, MRI is used to detect axial inflammation but also erosions in the sacroiliac joint. Treatment follows the treat-to-target strategy starting with non-steroidal anti-inflammatory drugs (NSAIDs) in the first line, and later, if high disease activity persists, therapy with biologic disease modifying anti-rheumatic drugs (bDMARDs) is according to international recommendations indicated. For the treatment of axSpA, important targets such as tumor necrosis factor alpha (TNFα) and interleukin (IL)-17 have been identified, and several of their inhibitors (i) including some biosimilars for the former have been approved. Recently, also inhibition of Janus kinases was shown to be efficacious. There is evidence that long term inhibition of inflammation with TNFi can reduce bone formation.

50 years of spondyloarthritis: a look back and a look ahead.

It is now 50 years since the concept of spondyloarthritis was introduced by Moll, Wright and co-authors from Leeds, UK. This review will review the original concept and mark significant milestones over the last 50 years while looking ahead to developments in the future. While the diseases included under this rubric in the original description may have changed the core conditions remain and are still characterized by axial inflammation as a common feature. Imaging, animal models, genetics and immunology have contributed to our knowledge of the pathogenesis and classification of these diseases and have led to the development of more effective treatments. Future developments, facilitated by large research consortia, will help build on our current knowledge and will help clarify disease heterogeneity and provide insights into new therapeutic pathways.

Body Mass Index Profile of Adult Patients with Inflammatory Bowel Disease in a Multicenter Study in Northeastern Brazil.

Inflammatory bowel disease (IBD) is a disease of increasing prevalence in developing countries. Obesity has emerged as a potential risk for IBD; however, the data in the literature are conflicting, and relevant studies in Brazil are limited. Here, we report body mass index profile (BMI) of patients with IBD treated at reference centers in three states of northeastern Brazil. Observational descriptive study conducted from January 2021 through December 2021 in patient with IBD. Of 470 patients with IBD, 194 (41%) were classified as normal weight, 42 (9%) as underweight, 155 (33%) as overweight, and 79 (17%) as obese; CD patients were significantly more likely to be underweight than UC patients (p=0.031)Overweight patients were older (median age: 47 years) than normal-weight and underweight patients at diagnosis (38.5 and 35.5 years, respectively [p<0.0001]). IBD onset and diagnosis among overweight and obese individuals were associated with older age. More extensive disease behavior patterns predominated in UC, while forms associated with complications were prevalent in CD, irrespective of nutritional status. There was a higher frequency of compatible symptoms with axial joint inflammation among obese patients (p=0.005) and a lower frequency of compatible symptoms with peripheral joint inflammation in underweight patients (p=0.044) than in patients of normal weight. No significant difference in the frequency of different drug or surgical treatments was observed among the groups. Despite the predominance of overweight and obesity in patients with IBD, no differences in the patterns of disease were seen between the overweight and normal-weight groups; however, obesity was associated with IBD onset in older adults and a higher frequency compatible symptom with axial joint inflammation. These data reinforce the importance of monitoring the nutritional status of IBD patients and the need for a multidisciplinary approach, as recommended in the current guidelines.

Dynamic thiol-disulfide homeostasis as an oxidative stress marker in ankylosing spondylitis and undifferentiated spondyloarthropathy.

Seronegative spondyloarthropathies (SpA) are a group of chronic diseases characterized by axial inflammation, oligoarthritis, and enthesitis. Oxidative stress may contribute to a wide range of rheumatologic diseases, including SpA. This prospective case-control study was designed to compare thiol-disulfide levels as a marker of oxidative stress between SpA patients and healthy controls. A total of 144 patients diagnosed with undifferentiated spondyloarthropathy (USpA, n = 97) or ankylosing spondylitis (AS, n = 47) were included along with 80 healthy controls. Serum native thiol (NT), total thiol (TT), and disulfide (D) levels were measured using the fully automated Erel method. The ratios NT/TT, D/TT, and D/NT were calculated. Thiol-disulfide levels were compared between the SpA groups and the healthy controls. The NT and NT/TT ratios were found to be significantly lower in the SpA group (p < 0.001). The disulfide, D/NT, and D/TT ratios were found to be significantly higher in the SpA group (p < 0.001). In pairwise comparisons between the SpA subgroups, the NT and TT levels were lower in the USpA group than in the AS group (p = 0.021), but serum disulfide levels were higher in the USpA group than in the AS group (p = 0.004). Among the patients with SpA, the group taking antitumor necrosis factor (anti-TNF) had lower TT measurements compared to the group taking conventional disease modifying antirheumatic drugs (DMARD) (p = 0.039). The thiol-disulfide balance is disturbed in favor of disulfide in SpA patients compared to healthy volunteers. Native and total thiol measurements correlate with acute phase reactants and might be used to monitor disease activity. Anti-TNF therapy might control the oxidative degenerative process better than the conventional DMARD in SpA patients.

P424 Do antiTNF through levels correlate with joint extraintestinal manifestations (EIM) activity in Inflammatory bowel disease (IBD) patients?

Abstract Background Inflammatory arthropathies are the most common EIM associated to IBD with a prevalence of 20-50% for axial inflammation and 5-20% for peripheral arthritis. AntiTNF is the preferred treatment in patients with axial spondiloarthritis (AxSp) intolerant or refractory to NSAIDs and has shown efficacy in peripheral arthritis (pSp) as well. Nevertheless, an optimal antiTNF through level has not been yet stablished in this clinical setting. Thus, our aims were to evaluate the correlation between antiTNF through levels and joint EIM activity in IBD patients. Methods We conducted a prospective, multicenter cohort study. IBD patients diagnosed with articular EIM (AxSp, pSp or both) under antiTNF treatment at least 6 months were included. Anti-TNF concentrations were measured using ELISA. Blood samples were obtained just before the administration of the drug (trough levels), and an simultaneous evaluation by a reumatologist was performed. Definitions: inactive AxSp = ASDAS-CRP &amp;lt;1,3 and BASDAI&amp;lt;2 , low active AxSp: ASDAS-CRP &amp;lt;2,1 and BASDAI&amp;lt;4; inactive pSp=arthritis, enthesitis and dactylitis=0, low active pSp: arthritis, enthesitis and dactylitis ≤1. IBD activity was based on partial Mayo score for ulcerative colitis (UC) patients and on Harvey-Bradshaw score for Crohn′s disease (CD) patients. Results A total of 78 patients were included: Median age 52 ±15, 45% women, 82% CD (56% ileal; 18% colic; 24% ileocolic; 2% upper gastrointestinal involvement; 22% stricturing behaviour; 16% penetrating; 14% perianal disease), 18% UC (61% extensive, 15% left-sided, 23% proctitis), 11% had another EIM. HLA B-27 was present in 26% patients. Distribution of spondiloartrhopaties was: AxSp 42%, pSp 37%, or both 20%. Among CD patients, 18,9% presented clinical activity (n=14). Mean IBD disease duration was 11± 9,7 years. Fourteen patients (18%) were also under immunosupressive treatment .Through levels distributed by joint activity are shown in table 1.Figure 1 shows distribution of adalimumab through levels by AxSp activity. Conclusion No correlation between antiTNF through levels and joint EIM activity was found in these preliminary results. However, patients with active axial Sp treated with adalimumab had lower through levels than those with inactive axial Sp.

Efficacy and safety of guselkumab in biologic-naïve patients with active axial psoriatic arthritis: study protocol for STAR, a phase 4, randomized, double-blinded, placebo-controlled trial

BackgroundAxial involvement constitutes a specific domain of psoriatic arthritis (PsA). Interleukin (IL)-23 inhibitors have demonstrated improvement in axial PsA (axPsA) symptoms, but have not shown efficacy in treating ankylosing spondylitis (AS), suggesting differences in axPsA processes and treatments. In a post hoc, pooled analysis of patients with investigator- and imaging-confirmed sacroiliitis in two phase 3, randomized, placebo-controlled studies (DISCOVER-1 and DISCOVER-2), patients treated with guselkumab, an IL-23p19 inhibitor, had greater axial symptom improvements compared with placebo. Confirmatory imaging at baseline was restricted to the sacroiliac (SI) joints, occurred prior to/at screening, and was locally read.MethodsThe STAR study will prospectively assess efficacy outcomes in PsA patients with magnetic resonance imaging (MRI)-confirmed axial inflammation. Eligible, biologic-naïve patients with PsA (N = 405) for ≥ 6 months and active disease (≥ 3 swollen and ≥ 3 tender joints, C-reactive protein [CRP] ≥ 0.3 mg/dL) despite prior non-biologic disease-modifying antirheumatic drugs, apremilast, and/or nonsteroidal anti-inflammatory drugs will be randomized (1:1:1) to guselkumab every 4 weeks (Q4W); guselkumab at week (W) 0, W4, then every 8 weeks (Q8W); or placebo with crossover to guselkumab at W24, W28, then Q8W. Patients will have Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥ 4, spinal pain component score (0–10 visual analog scale) ≥ 4, and screening MRI-confirmed axial involvement (positive spine and/or SI joints according to centrally read Spondyloarthritis Research Consortium of Canada [SPARCC] score ≥ 3 in ≥ 1 region). The primary endpoint is mean change from baseline in BASDAI at W24; multiplicity controlled secondary endpoints at W24 include AS Disease Activity Score employing CRP (ASDAS), Disease Activity Index for PsA (DAPSA), Health Assessment Questionnaire – Disability Index (HAQ-DI), Investigator’s Global Assessment of skin disease (IGA), and mean changes from baseline in MRI SI joint SPARCC scores. Centrally read MRIs of spine and SI joints (scored using SPARCC) will be obtained at W0, W24, and W52, with readers blinded to treatment group and timepoint. Treatment group comparisons will be performed using a Cochran-Mantel-Haenszel or chi-square test for binary endpoints and analysis of covariance, mixed model for repeated measures, or constrained longitudinal data analysis for continuous endpoints.DiscussionThis study will evaluate the ability of guselkumab to reduce both axial symptoms and inflammation in patients with active PsA.Trial registrationThis trial was registered at ClinicalTrials.gov, NCT04929210, on 18 June 2021.Protocol version: Version 1.0 dated 14 April 2021.

Improving the design of RCTs in non-radiographic axial spondyloarthritis.

Concerns have been raised that randomized placebo-controlled trials (RCTs) in non-radiographic axial spondyloarthritis (nr-axSpA) might be failing to identify patients that best show differences in clinical response rates between those receiving active drug and those receiving placebo therapies; in addition, some studies might even be showing spurious differences in responses to TNF and IL-17 inhibitor therapies. In particular, the most recent phase III RCTs in nr-axSpA have reported variable and generally lower response rates than observed in phase III trials of patients with ankylosing spondylitis and in trials conducted a decade ago in patients with early axSpA who were selected on the basis of axial inflammation evident on MRI scans. We argue that these observations at least partly reflect an RCT design that does not take full advantage of MRI to select patients who are responsive to therapy because the current MRI-based inclusion criteria cannot identify patients with axSpA with sufficient specificity. We propose that future studies should be designed using revised patient inclusion criteria based on expanded MRI evaluation and the application of data-driven definitions of a positive MRI for inflammatory and structural lesions typical of axSpA reported in an international multicentre analysis of MRI scans from the Assessment of SpondyloArthritis International Society (ASAS) classification cohort.

Effects of patient and disease characteristics on global functioning in patients with axial spondyloarthritis in routine care

BackgroundThe ASAS Health Index (ASAS HI) was developed to assess global functioning in patients with axial spondyloarthritis (axSpA). Influencing factors have not been studied to date, especially the influence of inflammation and structural changes in the spine has remained unclear to date. ObjectiveTo find out whether and to what degree do axial inflammation, radiographic damage and other clinical features influence global functioning of patients with axSpA. MethodsPatient reported outcomes (ASAS HI, pain, BASDAI, BASFI, EQ-5D and SF-36) were assessed, spinal mobility by BASMI and depression by SF-36 scores. Axial inflammation was quantified using the MRI Berlin score and structural damage as detected by conventional radiographs by the modified Stokes AS Spinal Score (mSASSS). Correlation and regression analyses were performed to analyze the association between global functioning and other variables. ResultsA total of 191 axSpA patients with different degrees of global functioning and disease activity was included, 60.2% had r-axSpA. Syndesmophytes were found in 38.5% of patients - with a median mSASSS score of 3.8 (IQR 1.0-18.7) in r-axSpA and 0.0 (IQR 0.0-1.2) in nr-axSpA patients. The mean MRI score was 2.3 (IQR 0.5-7.6). ASAS HI values correlated significantly with BASMI, BASDAI, BASFI, BMI and MRI scores. However, no significant correlation was found for mSASSS and CRP. Regression analyses revealed that global functioning was significantly influenced by disease activity, physical function, obesity and depression but not by structural damage or spinal inflammation as detected MRI. ConclusionsOur study shows that global functioning is strongly associated with physical function, body weight and depression in patients with axSpA but not with spinal inflammation and structural damage. This may be explained by the relatively low mSASSS of these well treated patients.

What Constitutes a Positive MRI for Clinical Trial Recruitment of Psoriatic Arthritis Patients With Axial Involvement?

There has been a resurgence of interest in defining the axial inflammation component of psoriatic arthritis (PsA) since recent randomized controlled trials (RCTs) raised the possibility that this entity may respond differentially to therapeutics compared to patients with axial spondyloarthritis. A workshop was conducted during the 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis annual meeting to review the literature on diagnosing PsA and to determine which criteria might be most appropriate. There was quite strong agreement that magnetic resonance imaging (MRI) had an important role to play in helping to define axial inflammation in PsA and that a data-driven methodology for generating optimal MRI quantitative cut-offs for lesions in the sacroiliac joints and/or spine that reflect imaging typical of axial inflammation in PsA would be most desirable.

A role for neutrophils in early enthesitis in spondyloarthritis

BackgroundNeutrophils are present in the early phases of spondyloarthritis-related uveitis, skin and intestinal disease, but their role in enthesitis, a cardinal musculoskeletal lesion in spondyloarthritis, remains unknown. We considered the role of neutrophils in the experimental SKG mouse model of SpA and in human axial entheses.MethodsEarly inflammatory infiltrates in the axial and peripheral entheseal sites in SKG mice were evaluated using immunohistochemistry and laser capture microdissection of entheseal tissue. Whole transcriptome analysis was carried out using Affymetrix gene array MTA 1.0, and data was analyzed via IPA. We further isolated neutrophils from human peri-entheseal bone and fibroblasts from entheseal soft tissue obtained from the axial skeleton of healthy patients and determined the response of these cells to fungal adjuvant.ResultsFollowing fungal adjuvant administration, early axial and peripheral inflammation in SKG mice was characterized by prominent neutrophilic entheseal inflammation. Expression of transcripts arising from neutrophils include abundant mRNA for the alarmins S100A8 and S100A9. In normal human axial entheses, neutrophils were present in the peri-entheseal bone. Upon fungal stimulation in vitro, human neutrophils produced IL-23 protein, while isolated human entheseal fibroblasts produced chemokines, including IL-8, important in the recruitment of neutrophils.ConclusionNeutrophils with inducible IL-23 production are present in uninflamed human entheseal sites, and neutrophils are prominent in early murine spondyloarthritis-related enthesitis. We propose a role for neutrophils in the early development of enthesitis.

Analysis of inflammation-related microRNA expression in patients with ankylosing spondylitis.

Ankylosing spondylitis (AS) is a complex genetic disease characterized by axial skeletal inflammation. Available scientific evidence suggests that a relationship may exist between miRNA expression levels and the pathogenesis of AS. This study investigated the clinical diagnostic value of miR-146a, miR-15a, miR-20a, miR-125a-3p, miR-125a-5p, miR-125b-5p, miR-148a, miR-149a, miR-499, and miR-155a in AS. A total of 44 AS patients and 56 healthy controls (HCs) were included in the study. MiRNA expression levels were detected using fluorescence quantitative PCR (qPCR). Results showed that the expression levels of miR-146a, miR-125a-3p, miR-125a-5p, miR-125b-5p, and miR-155a decreased, whereas miR-499a expression increased significantly in AS patients compared to that in the controls. Logistic regression analysis with receiver operating characteristic (ROC) curves showed that combined miR-146a/miR-125a-5p/miR-125b-5p/miR-499a/miR-155a (area under curve [AUC] = 0.824, 95% confidence interval [CI] = 0.727-0.921) had high sensitivity and specificity for AS diagnosis. C-reactive protein (CRP) levels were positively correlated with the expression of miR-125a-5p (rs = 0.438, p = 0.005) and miR-155a (rs = 0.414, p = 0.006), which indicates that miR-125a-5p and miR-155a can perhaps aggravate AS-induced inflammation. Our findings suggest the association of miR-125a-5p and miR-155a with disease activity in AS patients. Furthermore, miR-146a, miR-125a-5p, miR-125b-5p, miR-499a, and miR-155a could have potential diagnostic value in AS.

No efficacy of anti-IL-23 therapy for axial spondyloarthritis in randomised controlled trials but in post-hoc analyses of psoriatic arthritis-related ‘physician-reported spondylitis’?

The three monoclonal antibodies ustekinumab, guselkumab and risankizumab targeting the p 40 or the 19 subunit of interleukin -23 have now been approved for the indication psoriasis and the former...

Paradoxical Augmentation of Experimental Spondyloarthritis by RORC Inhibition in HLA-B27 Transgenic Rats.

ObjectiveIL-17A plays a major role in the pathogenesis of spondyloarthritis (SpA). Here we assessed the impact of inhibition of RAR related orphan receptor-γ (RORC), the key transcription factor controlling IL-17 production, on experimental SpA in HLA-B27 transgenic (tg) rats.MethodsExperimental SpA was induced by immunization of HLA-B27 tg rats with heat-inactivated Mycobacterium tuberculosis. Splenocytes obtained at day 7, 14 and 21 after immunization were restimulated ex vivo to assess the induction of pro-inflammatory cytokines. Rats were then prophylactically treated with a RORC inhibitor versus vehicle control. The biologic effect of RORC inhibition was assessed by pro-inflammatory cytokine expression in draining lymph nodes. Arthritis and spondylitis were monitored clinically, and the degree of peripheral and axial inflammation, destruction and new bone formation was confirmed by histology.ResultsEx vivo mRNA and protein analyses revealed the rapid and selective induction of IL-17A and IL-22 production by a variety of lymphocyte subsets upon disease induction in HLA-B27 tg rats. Prophylactic RORC inhibition in vivo suppressed the expression of IL-17A, IL17F, and IL-22 without affecting the expression of other T helper cell subset related genes. This biological effect did not translate into clinical efficacy as RORC inhibition significantly accelerated the onset of arthritis and spondylitis, and aggravated the clinical severity of arthritis. This worsening of experimental SpA was confirmed by histopathological demonstration of increased inflammation, destruction, and new bone formation.ConclusionDespite a significant suppression of the IL-17 axis, RORC inhibitor treatment accelerates and aggravates experimental SpA in the HLA-B27 tg rat model.

Targeting the Interleukin-23/Interleukin-17 Inflammatory Pathway: Successes and Failures in the Treatment of Axial Spondyloarthritis.

The IL-23/IL-17 pathway has been implicated in the etiopathogenesis of axial spondyloarthritis through studies of genetic polymorphisms associated with disease, an animal model with over-expression of IL-23 that resembles human disease, and observations that cytokines in this pathway can be found at the site of disease in both humans and animal models. However, the most direct evidence has emerged from clinical trials of agents targeting cytokines in this pathway. Monoclonal antibodies targeting IL-17A have been shown to ameliorate signs and symptoms, as well as MRI inflammation in the spine and sacroiliac joints, in patients with radiographic and non-radiographic axial spondyloarthritis. This was evident in patients refractory to non-steroidal anti-inflammatory agents as well as patients failing treatment with tumor necrosis factor inhibitor therapies. Treatment with a bispecific antibody targeting both IL-17A and IL-17F was also effective in a phase II study. Post-hoc analyses have even suggested a potential disease-modifying effect in reducing development of spinal ankylosis. However, benefits for extra-articular manifestations were limited to psoriasis and did not extend to colitis and uveitis. Conversely, trials of therapies targeting IL-23 did not demonstrate any significant impact on signs, symptoms, and MRI inflammation in axial spondyloarthritis. These developments coincide with recent observations that expression of these cytokines is evident in many different cell types with roles in innate as well as adaptive immunity. Moreover, evidence has emerged for the existence of both IL-23-dependent and IL-23-independent pathways regulating expression of IL-17, potentially associated with different roles in intestinal and axial skeletal inflammation.

Ankylosing Spondylitis.

The seronegative spondyloarthropathies are a group of autoimmune inflammatory diseases lacking rheumatoid factor or antinuclear antibody in their serum. They include ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis, spondylitis associated with Crohn's disease and ulcerative colitis, and undifferentiated spondyloarthropathies. Inflammation mostly affects the axial joints, entheses, and extra-articular structures such as uveal tract, gastrointestinal tract, mucocutaneous tissue, and heart. Uveitis is the most common extra-articular manifestation. Spondyloarthropathies, especially AS, have a strong association with the presence of Human Leukocyte Antigen (HLA)-B27 gene. AS happens earlier in HLA-B27 patients and men are more prone to the disease. Uveitis, typically unilateral non-granulomatous acute anterior uveitis, occurs in up to 50% of the patients with AS. HLA-B27 positivity correlates with more frequent flare-ups. Conjunctivitis and scleritis are rare ocular manifestations of AS. To establish the diagnosis of AS, at least one clinical and one radiologic parameter are required for definitive diagnosis. Magnetic resonance imaging (MRI) or bone scan can help early detection of the axial skeleton inflammation. The course of eye and joint involvement are not correlated. Short-term treatment with topical corticosteroids and cycloplegic agents control the uveitis attack. In resistant cases, local or systemic therapy with corticosteroids are recommended. NSAIDs, disease-modifying anti-rheumatic drugs (DMARDs), methotrexate, azathioprine, anti-IL-17A monoclonal antibodies, and TNF-α antagonists are effective treatments for ocular and systemic manifestations of AS. If not treated adequately, uveitis may become recalcitrant and extend posteriorly. Functional impairment due to joint destruction can also occur as a result of under-treatment.

Why Inhibition of IL-23 Lacked Efficacy in Ankylosing Spondylitis.

The term spondyloarthritis pertains to both axial and peripheral arthritis including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), which is strongly linked to psoriasis and also the arthritis associated with inflammatory bowel disease. The argument supporting the role for IL-23 across the spectrum of SpA comes from 4 sources. First, genome wide associated studies (GWAS) have shown that all the aforementioned disorders exhibit IL-23R pathway SNPs, whereas HLA-B27 is not linked to all of these diseases-hence the IL-23 pathway represents the common genetic denominator. Secondly, experimental animal models have demonstrated a pivotal role for the IL-23/IL-17 axis in SpA related arthropathy that initially manifests as enthesitis, but also synovitis and axial inflammation and also associated aortic root and cutaneous inflammation. Thirdly, the emergent immunology of the human enthesis also supports the presence of IL-23 producing myeloid cells, not just at the enthesis but in other SpA associated sites including skin and gut. Finally, drugs that target the IL-23 pathway show excellent efficacy for skin disease, efficacy for IBD and also in peripheral arthropathy associated with SpA. The apparent failure of IL-23 blockade in the AS which is effectively a spinal polyenthesitis but evidence for efficacy of IL-23 inhibition for peripheral enthesitis in PsA and preliminary suggestions for benefit in axial PsA, raises many questions. Key amongst these is whether spinal inflammation may exhibit entheseal IL-17A production independent of IL-23 but peripheral enthesitis is largely dependent on IL-23 driven IL-17 production. Furthermore, IL-23 blocking strategies in animal models may prevent experimental SpA evolution but not prevent established disease, perhaps pointing towards a role for IL-23 in innate immune disease initiation whereas persistent disease is dependent on memory T-cell responses that drive IL-17A production independently of IL-23, but this needs further study. Furthermore, IL-12/23 posology in inflammatory bowel disease is substantially higher than that used in AS trials which merits consideration. Therefore, the IL-23 pathway is centrally involved in the SpA concept but the nuances and intricacies in axial inflammation that suggest non-response to IL-23 antagonism await formal definition. The absence of comparative immunology between the different skeletal sites renders explanations purely hypothetical at this juncture.

Brazilian recommendations for the use of nonsteroidal anti-inflammatory drugs in patients with axial spondyloarthritis

Spondyloarthritis (SpA) is a group of chronic inflammatory systemic diseases characterized by axial and/or peripheral joints inflammation, as well as extra-articular manifestations. Over some decades, nonsteroidal anti-inflammatory drugs (NSAIDs) have been the basis for the pharmacological treatment of patients with axial spondyloarthritis (axSpA). However, the emergence of the immunobiologic agents brought up the discussion about the role of NSAIDs in the management of these patients. The objective of this guideline is to provide recommendations for the use of NSAIDs for the treatment of axSpA. A panel of experts from the Brazilian Society of Rheumatology conducted a systematic review and meta-analysis of randomized clinical trials for 15 predefined questions. The Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations were used, and at least 70% agreement of the voting panel was needed. Fourteen recommendations for the use of NSAIDs in the treatment of patients with axSpA were elaborated. The purpose of these recommendations is to support clinicians’ decision making, without taking out his/her autonomy when prescribing for an individual patient.

Dynamic Thiol/Disulphide Homeostasis as Oxidative Stress Marker in Ankylosing Spondylitis and Undifferentiated Spondyloarthropathy.

Seronegative spondyloarthropathies (SpA) are a group of chronic diseases, characterized by axial inflammation, oligoarthritis, and enthesitis. Oxidative stress may contribute to a wide range of diseases such as rheumatologic diseases including SpA. This prospective case-control study was designed to compare the thiol-disulfide levels as a marker of oxidative stress in SpA patients with healthy controls. A total of 144 patients who were diagnosed as undifferentiated spondyloarthropathy (UspA, n=97), ankylosing spondylitis (AS, n=47), and 80 healthy controls were included. Serum native thiol (NT), total thiol (TT), disulfide (D) levels were measured with the fully automated Erel?s method. NT/TT, D/TT, and D/NT ratios were calculated. Thiol-disulfide levels were compared between SpA groups and healthy controls. NT and NT/TT ratios were found to be significantly lower in the SpA group. (p<0.001). Disulfide, D/NT, and D/TT ratios were found to be significantly higher in the SpA group (p <0.001 for each comparison). In pairwise comparisons between SpA subgroups, NT and TT levels were lower in USpA group compared to AS group (P=0.021). Serum disulfide levels were higher in USpA group compared to AS group (P=0,004). Anti-tumor necrosis factor (Anti-TNF) group had lower TT measurements compared to the classical disease-modifying anti-rheumatic drugs (cDMARD) group in patients with SpA (P=0.039). Thiol-disulfide balance is disturbed in favor of disulfide in SpAs patients compared to healthy volunteers. Native and total thiol measurements correlate with acute phase reactants and might be used to monitor disease activity. Anti-TNF therapy might control the oxidative degenerative process better than the classical DMARD in SpA patients.