Patients' Perspectives on Axial Pain in Relation to Inflammation and Structural Damage in a Large Cohort of Axial Spondyloarthritis Patients.

OBJECTIVE: The objective of this study was to explore to what extent patients with axial spondyloarthritis (axSpA) link experienced pain in the neck, back, and hips to inflammation and/or structural damage. METHODS: Patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort visiting the outpatient clinic between 2016 and 2019 filled out two additional questions in relation to the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) question 2: (1) "To what extent do you think the pain you experience in your neck, back, and hips is related to inflammation caused by axSpA?" and (2) "To what extent do you think the pain you experience in your neck, back, and hips is related to damage of the spine and joints caused by axSpA?" Answers had to be depicted on a numeric rating scale from 0 (none) to 10 (very much); a difference of ≥2 points between the scores of these questions was considered clinically relevant in favor of the highest scoring question. RESULTS: A total of 688 patients with axSpA (24% with nonradiographic axSpA [nr-axSpA]) were included (62% male, mean ± SD age 48 ± 14 years, and mean ± SD Ankylosing Spondylitis Disease Activity Score [ASDAS] 2.3 ± 1.0). Seventy-five percent of patients could not link the origin of their pain, 15% linked axial pain predominantly to inflammation, and 10% linked axial pain predominantly to damage. Patients in the inflammation group were younger, had shorter symptom duration, were more frequently diagnosed with nr-axSpA, had higher ASDASCRP , had more often elevated CRP levels, had fewer comorbidities, had better spinal mobility, and had less spinal radiographic damage. CONCLUSION: In our large observational cohort, the majority of patients with axSpA could not differentiate the origin of experienced axial pain. If patients were able to link axial pain to clinical inflammation or damage, it was in concordance with clinical assessments and radiographic outcome, which may be helpful in establishing the origin of pain and supporting better patient-centered treatment decisions.

Serum levels of bone turnover markers including calculation of Z-scores: Data from a Dutch healthy reference cohort.

Introduction: Bone turnover markers (BTM) are biochemical compounds reflecting different stages of bone metabolism. Their levels change with age and differ between males and females. This makes clinical interpretation and comparison more difficult. Therefore, our aim was to establish BTM reference values which can be used to calculate Z-scores for use in daily clinical practice. Methods: Serum markers of collagen resorption, bone formation/regulation, collagen formation and bone mineralization (sCTX, OC, PINP and BALP, respectively) were measured in non-fasting volunteers without bone-related abnormalities. Raw data was plotted and gender-specific age cohorts were established with their respective means and standard deviations (SD). Z-scores can be calculated using these reference values to correct for the influence of age and gender on BTM. Results: In total, 856 individuals were included of which 486 (57 %) were female. Individuals were aged between 7 and 70 years. Highest serum levels of BTM were found in childhood and puberty. Peak levels are higher in boys than girls and prevail at later ages. In adults, BTM levels decrease before reaching stable nadir levels. In adults, 10-year reference cohorts with means and SD were provided to calculate Z-scores. Conclusion: With our data, Z-scores of sCTX, OC, PINP and BALP can be calculated using reference categories (for age and gender) of Caucasian healthy volunteers. Clinicians can use BTM Z-scores to determine whether there are changes in bone turnover physiology beyond those expected during aging. BTM Z-scores facilitate harmonization of data interpretation in daily clinical practice and research.

The Effect of Two Years of Secukinumab Treatment on Bone Metabolism in Patients with Radiographic Axial Spondyloarthritis: Results from Daily Clinical Practice.

Background: Our objective was to explore bone-related outcome and bone turnover markers (BTM) during 2 years of secukinumab treatment in patients with radiographic axial spondyloarthritis (r-axSpA) in daily clinical practice. Methods: Included were consecutive r-axSpA outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort treated with secukinumab for 2 years. At baseline and 2 years, spinal radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS; 0-72), cervical facet joint involvement according the "de Vlam" scoring method (0-15) and radiographic vertebral fractures (VF) using the "Genant" method (grade 0-3). At all visits, BTM reflecting collagen resorption (serum type I collagen C-telopeptide; sCTX), collagen formation (procollagen type 1 N-terminal peptide; PINP) and bone mineralization (bone-specific alkaline phosphatase; BALP) were measured and expressed in Z-scores to correct for the normal influence of age and gender. Results: 17 r-axSpA patients were included; 53% male, mean age was 47±15 years, mean Ankylosing Spondylitis Disease Activity Score (ASDAS) 3.9±1.2, and 53% was biological naïve. The median 2-year progression rates were 1.1 for mSASSS and 0.5 for facet joints, which was less than the smallest detectable change. One traumatic VF (grade 3) occurred. Serum levels of sCTX and PINP remained stable during secukinumab treatment and BALP decreased significantly after 2 years, with median 0-2 year change in Z-scores of +0.1, -0.4, and -1.2, respectively. Conclusion: This explorative study of r-axSpA patients treated with secukinumab in daily clinical practice showed low radiographic spinal progression during 2 years of follow-up. Collagen resorption and formation markers remained stable, whereas mineralization marker BALP decreased significantly after 2 years. Our results are in line with the results of in vitro studies demonstrating that inhibition of IL17-A resulted in suppression of osteogenic differentiation with significant decrease in mineralization.

After an initial balance favoring collagen formation and mineralization, bone turnover markers return to pre-treatment levels during long-term TNF-α inhibition in patients with ankylosing spondylitis.

BACKGROUND: Bone turnover balance favors bone formation, especially mineralization, during the first 3 years of treatment with TNF-α inhibitors (TNFi). Our aim was to evaluate the course of serum bone turnover markers (BTM) and to investigate if facilitation of mineralization reflected by BTM BALP continues to increase during 6 years of TNFi treatment in patients with ankylosing spondylitis (AS) in daily clinical practice. METHODS: Included were outpatients from the University Medical Center Groningen (UMCG) participating in the Groningen Leeuwarden Axial SpA (GLAS) cohort who were treated with TNFi for at least 6 years. Serum markers of collagen resorption, bone regulation, collagen formation and facilitator of bone mineralization (sCTX, OC, PINP and BALP, respectively) were measured at baseline, 3 and 6 months, 1, 2, 4 and 6 years. Z-scores were calculated to correct for age and gender. RESULTS: 53 AS patients were eligible for analyses (66% male, mean age 39±11 years). Disease activity showed rapid and sustained improvement after start of TNFi. Evaluating BTM, sCTX did not significantly change during 6 years of treatment. OC was only significantly increased at 3 months compared to baseline, with median change in Z-score of +0.5. PINP significantly increased at 3 and 6 months and 2 years of treatment, with maximum median change in Z-score of +0.3. Interestingly, BALP was significantly increased at all time points up to and including 2 years of TNFi treatment, with maximum change in median Z-score of +1.2, and decreased thereafter. CONCLUSION: In AS patients receiving long-term TNFi, bone turnover balance favored collagen formation and facilitation of mineralization during the first 2 years of treatment. Thereafter, at 4 and 6 years of follow-up, BTM Z-scores returned to pre-treatment levels.

Baseline serum biomarkers of inflammation, bone turnover and adipokines predict spinal radiographic progression in ankylosing spondylitis patients on TNF inhibitor therapy.

OBJECTIVE: To analyze whether biomarker levels at baseline or their change after 3 months or 2 years predict radiographic spinal progression in ankylosing spondylitis (AS) patients treated with TNF-α inhibitors (TNFi). METHODS: 137 AS patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were included before starting TNFi. Serum biomarkers were measured at baseline, 3 months and 2 years: Markers of inflammation (calprotectin, matrix metalloproteinase-3, vascular endothelial growth factor), bone turnover markers (bone-specific alkaline phosphatase, serum C-terminal telopeptide fragments of type I collagen (sCTX), osteocalcin, osteoprotegerin, procollagen type I and II N-terminal propeptide, sclerostin) and adipokines (high-molecular-weight adiponectin, leptin, visfatin). Spinal radiographs were scored at baseline, 2 and 4 years. Logistic regression was performed to examine the association between biomarker values and radiographic spinal progression, adjusting for known risk factors for radiographic progression. RESULTS: Baseline calprotectin and visfatin levels were associated with mSASSS progression ≥2 points (OR 1.195 [95%CI 1.055-1.355] and 1.465 [1.137-1.889], respectively), while calprotectin was also associated with new syndesmophyte formation after 2 years (OR 1.107 [1.001-1.225]). Baseline leptin level was associated with mSASSS progression ≥4 points after 4 years (OR 0.614 [0.453-0.832]), and baseline sCTX level with syndesmophyte formation after 4 years (OR 1.004 [1.001-1.008]). Furthermore, change of visfatin and leptin levels over the first 2 years showed significant association with radiographic progression after 4 years. CONCLUSION: Independent of known risk factors, serum levels of biomarkers at baseline are able to predict radiographic spinal progression over 2 and 4 years in AS patients on TNFi therapy.

The mSQUASH; a valid, reliable and responsive questionnaire for daily physical activity in patients with axial spondyloarthritis.

AIM: Adaptation of the Short QUestionnaire to Assess Health-enhancing physical activity (SQUASH) in order to improve measurement properties in axSpA patients. METHODS: The original SQUASH was adapted using a qualitative stepwise approach with in-depth interviews including healthcare professionals and patients. Content validity was explored by comparing modified-SQUASH (mSQUASH) and original SQUASH. Next, mSQUASH was validated according to the OMERACT filter. International Physical Activity Questionnaire (IPAQ) was used as comparator and tri-axial accelerometer as gold standard for criterion validity and classification accuracy of intensity. Construct validity was assessed using Spearman correlations with clinical outcome assessments. For test-retest reliability, intra-class correlation coefficients (ICCs) were calculated. Responsiveness was assessed using standardized response mean (SRM), stratified by Anchor method. RESULTS: The mSQUASH measured a systematically higher activity count and had less missing values (8% vs. 16%) then SQUASH. mSQUASH correlated better with accelerometer compared to IPAQ (ρ = 0.60 vs. ρ = 0.34). Accelerometer measured most activity in light intensity, whereas mSQUASH and IPAQ predominately measured moderate intensity. Correlations with ASDAS, BASDAI, BASFI and ASQoL were better for mSQUASH then IPAQ. Test-retest reliability was good in both questionnaires. In contrast to IPAQ, responsiveness was in correspondence with self-reported changes in physical activity for mSQUASH (SRM -0.84 for improvement and 0.88 for decrease). The average completion time of the mSQUASH was 7 minutes. CONCLUSIONS: The development of the mSQUASH resulted in an easy applicable, valid, reliable and responsive questionnaire for the assessment of daily physical activity in axSpA patients, which can be used in research and daily clinical practice.

Immune response to varicella-zoster virus before and after renal transplantation.

BACKGROUND: Herpes zoster (HZ) risk is high in renal transplant recipients. Vaccination prior to transplantation may provide a useful strategy for the prevention of HZ in the posttranplantation period. However, it is not known whether immunity to varicella-zoster virus (VZV) is affected due to treatment surrounding transplantation. METHODS: Both humoral and cellular immunity to VZV were determined prior to and 2-3 years after renal transplantation in 60 adult patients, and 62 matched healthy controls. VZV-specific cellular immunity was measured by an interferon gamma (IFNγ) enzyme-linked immunospot (ELISpot) assay and by analyzing T-cell functionality using flowcytometry. VZV-IgG levels were measured using an in-house glycoprotein enzyme-linked immunosorbent assay (gpELISA). RESULTS: Using paired analysis, it was determined that numbers of IFNγ-producing cells did not change after transplantation, but were significantly lower in transplant recipients after transplantation than in controls (p = 0.028). Patients in whom the post-transplant period was complicated by rejection or any acute infection (excluding HZ) had a lower number of IFNγ-producing cells than patients who did not. VZV IgG levels did not differ from controls, but a significant decrease was observed after transplantation (p < 0.0001). CONCLUSIONS: VZV-specific cellular immunity, which is essential in the prevention of HZ, did not markedly change in patients following renal transplantation. This suggests that preventive vaccination before transplantation may be beneficial. Our results extend knowledge on VZV immunity after transplantation, vital when considering strategies for the prevention of HZ in these patients.