Card9/neutrophil signalling axis promotes IL-17A-mediated ankylosing spondylitis.

OBJECTIVE: Polymorphisms in the antifungal signalling molecule CARD9 are associated with ankylosing spondylitis (AS). Here, we investigated the cellular mechanism by which CARD9 controls pathogenic Th17 responses and the onset of disease in both experimental murine AS and patients. METHODS: Experiments in SKG, Card9-/-SKG, neutrophil-deplete SKG mice along with in vitro murine, neutrophil and CD4+ T cell cocultures examined Card9 function in neutrophil activation, Th17 induction and arthritis in experimental AS. In AS patients the neutrophil: Bath Ankylosing Spondylitis Functional Index relationship was analysed. In vitro studies with autologous neutrophil: T cell cocultures examined endogenous CARD9 versus the AS-associated variant (rs4075515) of CARD9 in T cellular production of IL-17A. RESULTS: Card9 functioned downstream of Dectin-1 and was essential for induction of Th17 cells, arthritis and spondylitis in SKG mice. Card9 expression within T cells was dispensable for arthritis onset in SKG mice. Rather, Card9 expression controlled neutrophil function; and neutrophils in turn, were responsible for triggering Th17 expansion and disease in SKG mice. Mechanistically, cocultures of zymosan prestimulated neutrophils and SKG T cells revealed a direct cellular function for Card9 within neutrophils in the potentiation of IL-17 production by CD4+ T cells on TCR-ligation. The clinical relevance of the neutrophil-Card9-coupled mechanism in Th17-mediated disease is supported by a similar observation in AS patients. Neutrophils from HLA-B27+ AS patients expanded autologous Th17 cells in vitro, and the AS-associated CARD9S12N variant increased IL-17A. CONCLUSIONS: These data reveal a novel neutrophil-intrinsic role for Card9 in arthritogenic Th17 responses and AS pathogenesis. These data provide valuable utility in our future understanding of CARD9-specific mechanisms in spondyloarthritis .

Cardiovascular disease in spondyloarthritis: a narrative review of risk factors and the effect of treatments.

PURPOSE OF REVIEW: This review summarizes the recent evidence available regarding the epidemiology of cardiovascular disease in spondyloarthritis (SpA), including the effect of disease modifying drugs on cardiovascular risk. RECENT FINDINGS: People with SpA suffer from an increased risk of cardiovascular disease compared to the general population. This elevated risk is explained by the high prevalence of traditional cardiovascular risk factors and inflammation from disease activity leading to endothelial dysfunction and accelerated atherosclerosis. Consequently, the American College of Cardiology/American Heart Association and the European League Against Rheumatism recommend enhanced cardiovascular risk screening in SpA patients. There is evidence from observational studies that methotrexate and tumor necrosis factor inhibitors reduce the risk of cardiovascular events in SpA. Unlike what is observed in the general population, the use of nonsteroidal anti-inflammatory drugs does not appear to increase cardiovascular disease risk in SpA. SUMMARY: Cardiovascular diseases are increasingly recognized in patients suffering from SpA, especially axial SpA and psoriatic arthritis. Cardiovascular diseases can cause significant morbidity, mortality, and add to the overall disease burden. Disease modifying drugs may mitigate some of the cardiovascular risk; however, a multidisciplinary team is needed to monitor patients and improve cardiovascular health status.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

2022 American College of Rheumatology Guideline for the Prevention and Treatment of Glucocorticoid-Induced Osteoporosis.

OBJECTIVE: The objective is to update recommendations for prevention and treatment of glucocorticoid-induced osteoporosis (GIOP) for patients with rheumatic or nonrheumatic conditions receiving >3 months treatment with glucocorticoids (GCs) ≥2.5 mg daily. METHODS: An updated systematic literature review was performed for clinical questions on nonpharmacologic, pharmacologic treatments, discontinuation of medications, and sequential therapy. Grading of Recommendations Assessment, Development and Evaluation approach was used to rate the certainty of evidence. A Voting Panel achieved ≥70% consensus on the direction (for or against) and strength (strong or conditional) of recommendations. RESULTS: For adults beginning or continuing >3 months of GC treatment, we strongly recommend as soon as possible after initiation of GCs, initial assessment of fracture risks with clinical fracture assessment, bone mineral density with vertebral fracture assessment or spinal x-ray, and Fracture Risk Assessment Tool if ≥40 years old. For adults at medium, high, or very high fracture risk, we strongly recommend pharmacologic treatment. Choice of oral or intravenous bisphosphonates, denosumab, or parathyroid hormone analogs should be made by shared decision-making. Anabolic agents are conditionally recommended as initial therapy for those with high and very high fracture risk. Recommendations are made for special populations, including children, people with organ transplants, people who may become pregnant, and people receiving very high-dose GC treatment. New recommendations for both discontinuation of osteoporosis therapy and sequential therapies are included. CONCLUSION: This guideline provides direction for clinicians and patients making treatment decisions for management of GIOP. These recommendations should not be used to limit or deny access to therapies.

Neutrophil-to-Lymphocyte Ratio and Platelet-to-Lymphocyte Ratio as Biomarkers in Axial Spondyloarthritis: Observational Studies From the Program to Understand the Longterm Outcomes in Spondyloarthritis Registry.

OBJECTIVES: This study was conducted to assess the utility of neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) in predicting radiographic sacroiliitis and active disease in axial spondyloarthritis (SpA) and to explore the association between use of a tumor necrosis factor inhibitor (TNFi) and these laboratory values compared with traditional inflammatory markers. METHODS: Observational data from the Program to Understand the Longterm Outcomes in Spondyloarthritis (PULSAR) registry were analyzed. We generated receiver operating characteristic curves to calculate laboratory cutoff values; we used these values in multivariable logistic regression models to identify associations with radiographically confirmed sacroiliitis and active disease. We also used logistic regression to determine the likelihood of elevated laboratory values after initiation of TNFi. RESULTS: Most study participants (n = 354) were White, male, and HLA-B27 positive. NLR (odds ratio [OR] 1.459, P = 0.034), PLR (OR 4.842, P < 0.001), erythrocyte sedimentation rate (OR 4.397, P < 0.001), and C-reactive protein (CRP) level (OR 2.911, P = 0.001) were independent predictors of radiographic sacroiliitis. Models that included PLR with traditional biomarkers performed better than those with traditional biomarkers alone. NLR (OR 6.931, P = 0.002) and CRP (OR 2.678, P = 0.004) were predictors of active disease, but the model that included both NLR and CRP performed better than CRP alone. TNFi use reduced the odds of elevated NLR (OR 0.172, P < 0.001), PLR (OR 0.073, P < 0.001), erythrocyte sedimentation rate (OR 0.319, P < 0.001), and CRP (OR 0.407, P < 0.001), but models that included NLR or PLR and traditional biomarkers performed best. CONCLUSIONS: These findings demonstrate an association between NLR and PLR and sacroiliitis and disease activity, with NLR and PLR showing response after TNFi treatment and adding useful clinical information to established biomarkers, thus perhaps assisting in management of axial SpA.

Current treatment and molecular targets for axial spondyloarthritis: Evidence from randomized controlled trials.

Axial spondyloarthritis (axSpA) is a chronic inflammatory disease that predominantly affects the axial skeleton and is characterized by inflammatory back pain. While much has been published regarding non-steroidal anti-inflammatory drugs and tumor necrosis factor inhibitors, other classes of medications which leverage alternate molecular mechanisms receive less attention. In this review, we summarize a few of the novel targets in axSpA, review the putative mechanism of action of therapies that focus on these targets, and reference the germane recently completed, ongoing, or proposed randomized controlled clinical trials. The agents addressed include inhibitors of interleukin-23, interleukin-17, janus kinases, granulocyte-macrophage colony-stimulating factor, macrophage migration inhibitory factor, antibodies recognizing T cell receptor beta variable 9 gene positive clones, as well as inhibitors of mitogen-activated protein kinase-activated protein kinase-2.

The GRADE Method.

The Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach has emerged as an extremely common method for rating quality of a body of evidence in systematic reviews and for converting this evidence into guidelines. The American College of Rheumatology has effectively adopted this method, with minor modifications, for recent guidelines. This article reviews some of the basic principles of the GRADE approach and provides additional resources for use of GRADE.

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.

Heterogeneous treatment effects of intensive glycemic control on major adverse cardiovascular events in the ACCORD and VADT trials: a machine-learning analysis.

BACKGROUND: Evidence to guide type 2 diabetes treatment individualization is limited. We evaluated heterogeneous treatment effects (HTE) of intensive glycemic control in type 2 diabetes patients on major adverse cardiovascular events (MACE) in the Action to Control Cardiovascular Risk in Diabetes Study (ACCORD) and the Veterans Affairs Diabetes Trial (VADT). METHODS: Causal forests machine learning analysis was performed using pooled individual data from two randomized trials (n = 12,042) to identify HTE of intensive versus standard glycemic control on MACE in patients with type 2 diabetes. We used variable prioritization from causal forests to build a summary decision tree and examined the risk difference of MACE between treatment arms in the resulting subgroups. RESULTS: A summary decision tree used five variables (hemoglobin glycation index, estimated glomerular filtration rate, fasting glucose, age, and body mass index) to define eight subgroups in which risk differences of MACE ranged from - 5.1% (95% CI - 8.7, - 1.5) to 3.1% (95% CI 0.2, 6.0) (negative values represent lower MACE associated with intensive glycemic control). Intensive glycemic control was associated with lower MACE in pooled study data in subgroups with low (- 4.2% [95% CI - 8.1, - 1.0]), intermediate (- 5.1% [95% CI - 8.7, - 1.5]), and high (- 4.3% [95% CI - 7.7, - 1.0]) MACE rates with consistent directions of effect in ACCORD and VADT alone. CONCLUSIONS: This data-driven analysis provides evidence supporting the diabetes treatment guideline recommendation of intensive glucose lowering in diabetes patients with low cardiovascular risk and additionally suggests potential benefits of intensive glycemic control in some individuals at higher cardiovascular risk.

Trends in Timing of and Glycemia at Initiation of Second-line Type 2 Diabetes Treatment in U.S. Adults.

OBJECTIVE: Therapeutic inertia threatens the potential long-term benefits of achieving early glycemic control after type 2 diabetes diagnosis. We evaluated temporal trends in second-line diabetes medication initiation among individuals initially treated with metformin. RESEARCH DESIGN AND METHODS: We included data from 199,042 adults with type 2 diabetes in the U.S. Department of Veterans Affairs health care system initially treated with metformin monotherapy from 2005 to 2013. We used multivariable Cox proportional hazards and linear regression to estimate associations of year of metformin monotherapy initiation with time to second-line diabetes treatment over 5 years of follow-up (primary outcome) and with hemoglobin A1c (HbA1c) at the time of second-line diabetes treatment initiation (secondary outcome). RESULTS: The cumulative 5-year incidence of second-line medication initiation declined from 47% among metformin initiators in 2005 to 36% in 2013 counterparts (P < 0.0001) despite a gradual increase in mean HbA1c at the end of follow-up (from 6.94 ± 1.28% to 7.09 ± 1.42%, Ptrend < 0.0001). In comparisons with metformin monotherapy initiators in 2005, adjusted hazard ratios for 5-year initiation of second-line diabetes treatment ranged from 0.90 (95% CI 0.87, 0.92) for 2006 metformin initiators to 0.68 (0.66, 0.70) for 2013 counterparts. Among those receiving second-line treatment within 5 years of metformin initiation, HbA1c at second-line medication initiation increased from 7.74 ± 1.66% in 2005 metformin initiators to 8.55 ± 1.92% in 2013 counterparts (Ptrend < 0.0001). CONCLUSIONS: We observed progressive delays in diabetes treatment intensification consistent with therapeutic inertia. Process-of-care interventions early in the diabetes disease course may be needed to reverse adverse temporal trends in diabetes care.

Tattoo Granulomas With Uveitis.

Bilateral intraocular inflammation and simultaneous development of tattoo granulomas has been described in several case reports. The pathophysiology of this process is poorly understood, and it has been hypothesized that it could be a similar mechanism to systemic sarcoidosis versus a delayed hypersensitivity response. Granulomatous tattoo reaction with associated uveitis can manifest with or without evidence of systemic sarcoidosis, and it is usually responsive to immunosuppression and/or tattoo removal. We present a patient with no prior diagnosis of sarcoidosis who developed bilateral panuveitis and tattoo changes suggestive of tattoo granulomas with uveitis (TAGU). The patient was initially managed with intraocular steroids and systemic steroids with minimal improvement of symptoms. The patient later required steroid sparing therapy with a tumor factor inhibitor to achieve remission. There is a growing prevalence of tattooing among the general population and a low reported rate of tattooing complications. Granulomatous tattoo reaction with associated uveitis should be a consideration in patients with tattoos presenting with "idiopathic" uveitis.

Ethnic Disparities in Atherosclerotic Cardiovascular Disease Incidence and Prevalence Among Rheumatoid Arthritis Patients in the United States: a Systematic Review.

OBJECTIVE: Rheumatoid arthritis (RA) is associated with increased atherosclerotic cardiovascular disease (ASCVD). General population cohorts have shown African American individuals to have greater and Hispanic Americans to have lower cardiovascular disease prevalence when compared with non-Hispanic white individuals; however, the reasons for these findings are not clear. This systematic review seeks to describe the incidence and prevalence of ASCVD stratified by race/ethnicity within the US RA population. METHODS: MEDLINE, Embase, and Cochrane databases were searched for studies that reported incidence or prevalence of ASCVD (including, but not limited to, fatal and nonfatal stroke, myocardial infarction, and cardiovascular death) in those with RA. Abstracts and full texts were screened separately for inclusion by two reviewers, with a third reviewer to resolve discrepancies. RESULTS: We screened 2625 abstracts and fully reviewed 138 manuscripts. Twenty-one were included that cited at a minimum the percentage of non-Hispanic whites in their population. No publication meeting entry criteria initially stratified ASCVD by race/ethnicity. The average prevalent ASCVD in RA is 46.9% (95% CI: 46.8-47) (range of prevalent ASCVD: 30%-47%). The average incident ASCVD is 8.2% (95% CI: 8.14-8.25) (range of incident ASCVD 1%-46%). CONCLUSION: In this systematic review, we found a paucity of data on racially/ethnically diverse RA patients and ASCVD outcomes. Future studies should report the prevalence of ASCVD in various races/ethnicities with RA in the United States. These data would help inform clinicians on how best to manage cardiovascular disease risk in RA.

Association of Glycemic Control Trajectory with Short-Term Mortality in Diabetes Patients with High Cardiovascular Risk: a Joint Latent Class Modeling Study.

BACKGROUND: The relationship between risk factor or biomarker trajectories and contemporaneous short-term clinical outcomes is poorly understood. In diabetes patients, it is unknown whether hemoglobin A1c (HbA1c) trajectories are associated with clinical outcomes and can inform care in scenarios in which a single HbA1c is uninformative, for example, after a diagnosis of coronary artery disease (CAD). OBJECTIVE: To compare associations of HbA1c trajectories and single HbA1c values with short-term mortality in diabetes patients evaluated for CAD DESIGN: Retrospective observational cohort study PARTICIPANTS: Diabetes patients (n = 7780) with and without angiographically defined CAD MAIN MEASURES: We used joint latent class mixed models to simultaneously fit HbA1c trajectories and estimate association with 2-year mortality after cardiac catheterization, adjusting for clinical and demographic covariates. KEY RESULTS: Three HBA1c trajectory classes were identified: individuals with stable glycemia (class A; n = 6934 [89%]; mean baseline HbA1c 6.9%), with declining HbA1c (class B; n = 364 [4.7%]; mean baseline HbA1c 11.6%), and with increasing HbA1c (class C; n = 482 [6.2%]; mean baseline HbA1c 8.5%). HbA1c trajectory class was associated with adjusted 2-year mortality (3.0% [95% CI 2.8, 3.2] for class A, 3.1% [2.1, 4.2] for class B, and 4.2% [3.4, 4.9] for class C; global P = 0.047, P = 0.03 comparing classes A and C, P > 0.05 for other pairwise comparisons). Baseline HbA1c was not associated with 2-year mortality (P = 0.85; hazard ratios 1.01 [0.96, 1.06] and 1.02 [0.95, 1.10] for HbA1c 7-9% and ≥ 9%, respectively, relative to HbA1c < 7%). The association between HbA1c trajectories and mortality did not differ between those with and without CAD (interaction P = 0.1). CONCLUSIONS: In clinical settings where single HbA1c measurements provide limited information, HbA1c trajectories may help stratify risk of complications in diabetes patients. Joint latent class modeling provides a generalizable approach to examining relationships between biomarker trajectories and clinical outcomes in the era of near-universal adoption of electronic health records.

Universal Health Literacy Precautions Are Associated With a Significant Increase in Medication Adherence in Vulnerable Rheumatology Patients.

OBJECTIVE: Our objective was to determine the impact of the Health Literacy Universal Precautions Toolkit, adapted for rheumatology, on medication adherence, patient satisfaction, and feasibility in all patients; its effect on the clinical disease activity index (CDAI) was studied in a rheumatoid arthritis (RA) subpopulation. METHODS: Data collected during a 6-month prospective quality assurance intervention was compared with data from a prior 6-month period. Interventions included 1) encouraging questions, 2) teach-back communication, and 3) brown-bag medication review. Analysis was performed using linear regression or generalized estimating equation (GEE) regression. RESULTS: During the intervention period, 46 physicians completed 1737 patient visits. Questions were encouraged, and teach-back communication was performed in more than 90% of visits. Brown-bag medication reviews were performed in 47% of visits overall and 69% of visits in a subgroup that received additional reminder calls. Visit duration and patient satisfaction were not significantly increased. Adherence for rheumatology-related medications that were prescribed both before and during the intervention increased by 22% (P ≤ 0.001; by GEE). Teach-back communication predicted a statistically significant improvement in medication adherence in this subpopulation (by linear regression). The mean CDAI did not improve; however, African American race and Hispanic ethnicity were associated with a decreased CDAI (by GEE). CONCLUSION: Implementation of the Health Literacy Universal Precautions Toolkit, adapted for rheumatology, improved medication adherence in our safety-net clinic, with particularly strong effects seen with teach-back communication. In certain populations, use of the toolkit may also improve RA disease activity. This is the first study to document improved medication adherence with this intervention in a real-world setting.

Mechanical Shock During Shipping of Medications: The Roles of Packaging and Transportation Vendors.

Protein-based medications are expensive and susceptible to damage from mechanical shock, which may occur during shipping to patients from pharmacies. Our objectives were to evaluate the performance of 2 packaging systems and to describe the mechanical shock that occurs during shipments. The packaging systems evaluated were boxes containing expanded polystyrene (EPS) or soft lint-like foam, prepared with and without polymer cooling packs. In laboratory-based studies, accelerometers measured g forces in boxes dropped from varying heights. Transportation studies evaluated the EPS cooler when sent to locations via 2 vendors. The relationship between drop height and maximum force vector was approximately linear for drop heights of 7.5″ through 30″, with lower magnitude forces at 45″ and 60″. Soft foam reduced force by 9.8 g on average compared to EPS (p < 0.009). The presence of polymer packs mitigated forces; frozen packs reduced forces by 28 g versus thawed packs (p < 0.001). Transportation experiments demonstrated most impacts were in the low (10-24 g) and low-medium (25-49 g) range (95% of all impacts). There was no difference between impacts during shipments with the vendors, and there was no correlation between distance traveled and number of impacts. Overall, mechanical shock during shipping is both prevalent and contingent upon the packing materials used.

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

2019 Update of the American College of Rheumatology/Spondylitis Association of America/Spondyloarthritis Research and Treatment Network Recommendations for the Treatment of Ankylosing Spondylitis and Nonradiographic Axial Spondyloarthritis.

OBJECTIVE: To update evidence-based recommendations for the treatment of patients with ankylosing spondylitis (AS) and nonradiographic axial spondyloarthritis (SpA). METHODS: We conducted updated systematic literature reviews for 20 clinical questions on pharmacologic treatment addressed in the 2015 guidelines, and for 26 new questions on pharmacologic treatment, treat-to-target strategy, and use of imaging. New questions addressed the use of secukinumab, ixekizumab, tofacitinib, tumor necrosis factor inhibitor (TNFi) biosimilars, and biologic tapering/discontinuation, among others. We used the Grading of Recommendations, Assessment, Development and Evaluation methodology to assess the quality of evidence and formulate recommendations and required at least 70% agreement among the voting panel. RESULTS: Recommendations for AS and nonradiographic axial SpA are similar. TNFi are recommended over secukinumab or ixekizumab as the first biologic to be used. Secukinumab or ixekizumab is recommended over the use of a second TNFi in patients with primary nonresponse to the first TNFi. TNFi, secukinumab, and ixekizumab are favored over tofacitinib. Co-administration of low-dose methotrexate with TNFi is not recommended, nor is a strict treat-to-target strategy or discontinuation or tapering of biologics in patients with stable disease. Sulfasalazine is recommended only for persistent peripheral arthritis when TNFi are contraindicated. For patients with unclear disease activity, spine or pelvis magnetic resonance imaging could aid assessment. Routine monitoring of radiographic changes with serial spine radiographs is not recommended. CONCLUSION: These recommendations provide updated guidance regarding use of new medications and imaging of the axial skeleton in the management of AS and nonradiographic axial SpA.

Genome-wide DNA methylation analysis in ankylosing spondylitis identifies HLA-B*27 dependent and independent DNA methylation changes in whole blood.

BACKGROUND AND OBJECTIVE: Ankylosing spondylitis is a chronic inflammatory disease characterized by inflammation of the sacroiliac joints and the spine that can lead to significant pain, immobility, and disability. The etiology and pathogenesis of ankylosing spondylitis are incompletely understood, though most patients carry the HLA-B*27 allele. The objective of this study was to evaluate DNA methylation changes in ankylosing spondylitis with the goal of revealing novel mechanistic insights into this disease. METHODS: Genome-wide DNA methylation analysis was performed in whole blood DNA samples using the Infinium MethylationEPIC array in patients with ankylosing spondylitis compared to age, sex, and race matched patients with osteoarthritis as a non-inflammatory disease control. We studied 24 patients with ankylosing spondylitis, including 12 patients who carry HLA-B*27 and 12 patients who are HLA-B*27 negative. DNA methylation analysis was performed with adjustment for blood cell composition in each sample. RESULTS: We identified a total of 67 differentially methylated sites between ankylosing spondylitis patients and osteoarthritis controls. Hypermethylated genes found included GTPase-related genes, while hypomethylated genes included HCP5, which encodes a lncRNA within the MHC region, previously associated with genetic risk for psoriasis and toxic epidermal necrolysis. Carrying HLA-B*27 was associated with robust hypomethylation of HCP5, tubulin folding cofactor A (TBCA) and phospholipase D Family Member 6 (PLD6) in ankylosing spondylitis patients. Hypomethylation within HCP5 involves a CpG site that contains a single nucleotide polymorphism in linkage disequilibrium with HLA-B*27 and that controls DNA methylation at this locus in an allele-specific manner. CONCLUSIONS: A genome-wide DNA methylation analysis in ankylosing spondylitis identified DNA methylation patterns that could provide potential novel insights into this disease. Our findings suggest that HLA-B*27 might play a role in ankylosing spondylitis in part through inducing epigenetic dysregulation.