Higher levels of physical activity are associated with less evasive coping, better physical function and quality of life in patients with axial spondyloarthritis.

OBJECTIVE: To evaluate daily physical activity (PA) in relation to psychosocial factors, such as anxiety, depression and different types of coping strategies, as well as patient- and disease-related factors in patients with axial spondyloarthritis (axSpA). METHODS: Consecutive outpatients from the Groningen Leeuwarden AxSpA (GLAS) cohort completed the modified Short Questionnaire to assess health-enhancing PA (mSQUASH), Hospital Anxiety and Depression Scale (HADS) and Coping with Rheumatic Stressors (CORS) questionnaires, as well as standardized patient- and disease-related assessments. Univariable and multivariable linear regression analyses and comparison of lowest and highest PA tertiles were performed to explore associations between the HADS, CORS, patient- and disease-related factors and PA. RESULTS: In total, 84 axSpA patients were included; 60% male, mean age 49 (SD ±14) years, median symptom duration 20 (25th-75th percentiles: 12-31) years, mean ASDAS 2.1 (±1.0). Higher PA levels were significantly associated with better scores on patient-reported disease activity (BASDAI), physical function (BASFI) and quality of life (ASQoL). Furthermore, higher levels of PA were associated with less impact of axSpA on wellbeing and lower HADS depression scores. In the multivariable linear regression model, less use of the coping strategy 'decreasing activities' (ß: -376.4; p 0.003) and lower BMI (ß:-235.5; p: 0.030) were independently associated with higher level of PA. Comparison of patients from the lowest and highest PA tertiles showed results similar to those found in the regression analyses. CONCLUSION: In this cohort of axSpA patients, higher levels of daily PA were associated with better patient-reported outcomes and lower depression scores. Additionally, the passive coping strategy "decreasing activities" and lifestyle factor BMI were independently associated with PA. Besides anti-inflammatory treatment, coping strategies and lifestyle should be taken into account in the management of individual axSpA patients. Incorporating these aspects into patient education could increase patient awareness and self-efficacy. In the future, longitudinal studies are needed to better understand the complex relationship between patient-, disease- and psychosocial factors associated with daily PA.

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.

High BMI is associated with lower TNF-α inhibitor serum trough levels and higher disease activity in patients with axial spondyloarthritis.

BACKGROUND: TNF-α inhibitor (TNFi) serum trough levels have previously been found to be related to disease activity in axial spondyloarthritis (axSpA). However, most research regarding serum trough levels has been conducted in patients who only recently started TNFi therapy. Therefore, our objective was to explore TNFi serum trough level measurements in relation to disease activity and BMI in the total axSpA population in daily clinical practice, also including patients on long-term TNFi therapy. METHODS: Consecutive patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort were approached for a TNFi serum trough level measurement during their regular outpatient visit at the UMCG. Spearman's correlation coefficient was used to analyse the relation of serum trough levels with disease activity and BMI. Logistic regression was performed to analyse the relation between therapeutic drug levels and disease activity, corrected for potential confounders, including BMI. RESULTS: Thirty-four patients on adalimumab and 21 patients on etanercept were included. Mean age was 45 ± 12 years, 47% were male, median BMI was 26.4 (IQR 23.9-32.5) and median treatment duration was 41 months (range 2-126). According to definitions of Sanquin, 47% of patients had therapeutic serum trough levels. No significant correlations were found between TNFi levels and disease activity (ASDAS-CRP: adalimumab: ρ = -0.16, p = 0.39; etanercept: ρ = -0.29, p = 0.20). TNFi levels were moderately correlated with BMI (adalimumab: ρ = -0.48, p = 0.004; etanercept: ρ = -0.50, p = 0.021). Patients with active disease (ASDAS ≥ 2.1) showed higher BMI than patients with inactive disease (median 29.7 vs. 24.6, p = 0.015). In multivariable regression analyses, BMI was identified as the only confounder for the relationship between therapeutic drug levels and ASDAS. CONCLUSION: In this cross-sectional, observational study of axSpA patients mainly on long-term treatment with TNFi, higher BMI was significantly associated with lower adalimumab and etanercept serum trough levels and higher disease activity.

Translation and cross-cultural adaptation of the mSQUASH into Spanish.

BACKGROUND: There is a lack of outcome measures for the assessment of physical activity in patients with axial spondyloarthritis (axSpA). For this matter, the modified Short QUestionnaire to Assess Health (mSQUASH) was developed and validated, originally in Dutch. OBJECTIVE: To translate and cross-culturally adapt the mSQUASH into Spanish and to evaluate the equivalence of the translated version in patients with axSpA. METHODS: The mSQUASH was translated following forward-backward procedure according to the protocol of Beaton. Two bi-lingual translators produced independent forward translations of the mSQUASH into Spanish, and the versions were harmonized in a consensual version. Another translator back translated the synthesized version into Dutch. A scientific committee reached consensus on discrepancies and developed a pre-final version of the questionnaire. The field test with cognitive debriefing involved 10 patients with axSpA with different gender, age, disease duration, educational level and working status. RESULTS: The translation process of the mSQUASH was completed without major issues. The first translation needed several iterations due to small discrepancies in the wording. Back-translation was performed without difficulties, and the scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing showed the Spanish questionnaire to be clear, relevant, understandable and comprehensive. The preliminary version was accepted with minor modifications. CONCLUSIONS: The resulting Spanish version of the mSQUASH showed good linguistic and face validity according to the field test, revealing potential for use in clinical practice and research. In order to conclude the cross-cultural adaptation of the mSQUASH into Spanish, the next step is the assessment of psychometric properties of the Spanish version.

Translation and cross-cultural adaptation of the mSQUASH into Spanish / Traducción y adaptación transcultural del mSQUASH al español

Background: There is a lack of outcome measures for the assessment of physical activity in patients with axial spondyloarthritis (axSpA). For this matter, the modified Short QUestionnaire to Assess Health (mSQUASH) was developed and validated, originally in Dutch. Objective: To translate and cross-culturally adapt the mSQUASH into Spanish and to evaluate the equivalence of the translated version in patients with axSpA. Methods: The mSQUASH was translated following forward-backward procedure according to the protocol of Beaton. Two bi-lingual translators produced independent forward translations of the mSQUASH into Spanish, and the versions were harmonized in a consensual version. Another translator back translated the synthesized version into Dutch. A scientific committee reached consensus on discrepancies and developed a pre-final version of the questionnaire. The field test with cognitive debriefing involved 10 patients with axSpA with different gender, age, disease duration, educational level and working status. Results: The translation process of the mSQUASH was completed without major issues. The first translation needed several iterations due to small discrepancies in the wording. Back-translation was performed without difficulties, and the scientific committee agreed upon a final version of the questionnaire. Cognitive debriefing showed the Spanish questionnaire to be clear, relevant, understandable and comprehensive. The preliminary version was accepted with minor modifications. Conclusions: The resulting Spanish version of the mSQUASH showed good linguistic and face validity according to the field test, revealing potential for use in clinical practice and research. In order to conclude the cross-cultural adaptation of the mSQUASH into Spanish, the next step is the assessment of psychometric properties of the Spanish version. (AU)

Antecedentes: Las medidas de resultado para la evaluación de la actividad física en pacientes con espondiloartritis axial (EspAax) son escasas. Por ello, se desarrolló y validó el modified Short QUestionnaire to Assess Health (mSQUASH), originalmente en holandés. Objetivo: Desarrollar el proceso de traducción y adaptación transcultural del mSQUASH al español, y evaluar la equivalencia de la versión traducida en pacientes con EspAax. Métodos: El mSQUASH se tradujo siguiendo el procedimiento adelante-atrás según el protocolo de Beaton. Dos traductores bilingües realizaron traducciones directas independientes del mSQUASH al español, y las versiones se armonizaron en una versión consensuada. Otro traductor volvió a traducir la versión sintetizada al holandés. Un comité científico llegó a un consenso sobre las discrepancias y elaboró una versión pre-final del cuestionario. En las entrevistas cognitivas participaron 10 pacientes con EspAax de diferente sexo, edad, duración de la enfermedad, nivel educativo y situación laboral. Resultados: El proceso de traducción del mSQUASH se completó sin problemas mayores. La primera traducción necesitó varias iteraciones debido a pequeñas discrepancias en la redacción. La traducción inversa se realizó sin dificultades y el comité científico acordó la versión final del cuestionario. La evaluación cognitiva demostró que el cuestionario en español era claro, pertinente, comprensible y completo. La versión preliminar fue aceptada con pequeñas modificaciones. Conclusiones: La versión española resultante del mSQUASH mostró una buena validez lingüística y aparente, revelando potencial para su uso en práctica clínica e investigación. Para concluir la adaptación transcultural del mSQUASH al español, el siguiente paso es la evaluación de las propiedades psicométricas de la versión española. (AU)

Psoriasis seems often underdiagnosed in patient with axial spondyloarthritis.

BACKGROUND: Axial spondyloarthritis (axSpA) is known to be associated with several extra-skeletal manifestations (ESM), including the inflammatory skin disease psoriasis. It is important to recognize and diagnose psoriasis timely in axSpA in order to provide optimal treatment and outcome for both axSpA and psoriasis. METHODS: In this observational study, all patients from the Dutch Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort included before June 2016 were sent a questionnaire with self-screening psoriasis questions including prototypical color pictures. RESULTS: Of the 592 questionnaires sent, 448 (75.7%) were eligible for analysis. Of these 448 respondents, 58 (13%) had a positive self-screening for psoriasis symptoms, currently or in the past. In 28 (48%) of 58 patients, psoriasis diagnosis could be verified by medical records, resulting in a psoriasis prevalence rate of 6.3%. In comparison with patients with a confirmed psoriasis diagnosis, patients reporting psoriasis symptoms without a verified diagnosis mentioned more mild than moderate-severe psoriasis symptoms (25% vs. 3%, p = 0.02), and their psoriasis lesions were less often located on the torso area (3% vs. 18%, p = 0.04), the intergluteal cleft (0% vs. 25%, p = 0.02), and legs (7% vs. 43%, p < 0.01). Of the 31 axSpA patients who reported currently active psoriasis, 74% had only mild psoriasis symptoms. CONCLUSIONS: Especially mild psoriasis seems often underdiagnosed in patients with axSpA using a patient questionnaire with prototypical pictures of psoriasis lesions. This questionnaire could be beneficial in tracing patients with undiagnosed psoriasis in daily clinical practice. As a next step, further validation of this questionnaire is needed.

Patients' Needs Concerning Patient Education in Axial Spondyloarthritis: A Qualitative Study.

INTRODUCTION: Within the EULAR recommendations, patient education (PE) is stated as the basis of the management of axial spondyloarthritis (axSpA). However, educational needs are scarcely qualitatively studied in axSpA. Therefore, we aimed to explore experiences and needs of PE in patients with axSpA. METHODS: A phenomenological approach was used, with semi-structured in-depth interviews with patients with axSpA including broad variation in characteristics. Thematic analysis was applied. To enhance credibility, data saturation, research triangulation, peer debriefing, member checking, theoretical notes, and bracketing were performed. RESULTS: Three interrelated themes regarding PE were identified from 20 interviews: illness perception, content, and 'availability'. Illness perception affects how patients experience and process PE, which consequently influences coping strategies. Prognosis, treatment, and coaching to self-management were identified as the most important content of PE. Regarding 'availability', face-to-face PE is preferred for exploring needs, supplemented by self-education, which can be freely applied. Additionally, sufficient time and a comprehensible amount of information were important and participants emphasized the need for axSpA-tailored information for relatives and friends. Participants reported a trusting patient-healthcare provider (HCP) relationship, and multidisciplinary and interdisciplinary attunement between HCPs as prerequisites for effective PE. CONCLUSIONS: This first qualitative study exploring patients' experiences and needs of PE in axSpA revealed that prognosis, treatment, and coaching to self-management are important regarding content, and the combination of face-to-face contact and self-education the preferred modalities. It seems essential that patients' illness perceptions are taken into account for effective PE. These results add relevant insights for future PE guidelines in axSpA.

Mucosal-associated invariant T cells in patients with axial spondyloarthritis.

Background: Several studies implicate Th17-cells and its cytokine (IL-17) in disease pathogenesis of spondyloarthritis (SpA), with available evidence supporting a pathogenic role of CD8+ T-cells. However, data on the involvement of CD8+ mucosal-associated invariant T-cells (MAIT) and their phenotypic characterization and inflammatory function including IL-17 and Granzyme A production in a homogenous population of SpA-patients with primarily axial disease (axSpA) are lacking. Objectives: Quantify and characterize the phenotype and function of circulating CD8+MAIT-cells in axSpA-patients with primarily axial disease. Methods: Blood samples were obtained from 41 axSpA-patients and 30 age- and sex-matched healthy controls (HC). Numbers and percentages of MAIT-cells (defined as CD3+CD8+CD161highTCRVα7.2 +) were determined, and production of IL-17 and Granzyme A (GrzA) by MAIT-cells were examined by flow cytometry upon in vitro stimulation. Serum IgG specific for CMV was measured by ELISA. Results: No significant differences in numbers and percentages of circulating MAIT-cells were found between axSpA-patients and HCr zijn meer resultaten de centrale memory CD8 T cellen. cellen van patirculating MAIT cells.. Further phenotypic analysis revealed a significant decrease in numbers of central memory MAIT-cells of axSpA-patients compared to HC. The decrease in central memory MAIT-cells in axSpA patients was not attributed to an alteration in CD8 T-cell numbers, but correlated inversely with serum CMV-IgG titers. Production of IL-17 by MAIT-cells was comparable between axSpA-patients and HC, whereas a significant decrease in the production of GrzA by MAIT-cells from axSpA-patients was observed. Conclusions: The decrease in cytotoxic capability of circulating MAIT-cells in axSpA-patients might implicate that these cell types migrate to the inflamed tissue and therefore associate with the axial disease pathogenesis.

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.

Translation and cross-cultural adaptation of the modified Short QUestionnaire to Assess Health-enhancing physical activity (mSQUASH) into Turkish.

Aims The aim was to translate and cross-culturally adapt the modified Short Questionnaire to Assess Health-enhancing physical activity (mSQUASH) into Turkish Methods The mSQUASH was translated into Turkish and backward-translation into Dutch was performed afterwards using the Beaton method. After the Turkish version was reviewed and revised by an expert committee that included translators, two patients and the research team a pre-final version was produced. The-pre final version then entered a field-test with cognitive debriefing in 10 patients with axSpA. The final result was the Turkish mSQUASH version. Results The translation process went without difficulties. Small discrepancies were either resolved during the synthesis or expert consensus meetings. Mean (SD) time to complete the mSQUASH was 6.1 (2.4) minutes in field-test procedure. The cognitive debriefing showed that the items of the Turkish mSQUASH were clear, relevant, easy to understand and easy to complete. None of the patients reported that an important aspect of physical activity was missing from the questionnaire items. Patients raised the concern that not all sport examples were culturally suitable; tennis was replaced by volleyball and basketball after the cognitive debriefing, to make it more appropriate to the Turkish culture. Conclusion The final Turkish version of the mSQUASH showed acceptable linguistic and field validity for use in both clinical practice and research. However, further assessment of the psychometric properties (validity and reliability) of the Turkish version of the mSQUASH is needed before it can be implemented.

Differences in characteristics, health status and fulfillment of exercise recommendations between axial spondyloarthritis patients with and without supervised group exercise.

OBJECTIVE: Since decades, supervised group exercise (SGE) is recommended for people with axial spondyloarthritis (axSpA). This study examines if weekly SGE contributes to fulfillment of exercise recommendations in axSpA patients. METHODS: Cross-sectional data from three studies with axSpA patients in The Netherlands, including two with outpatient populations (n = 196 and n = 153) and one with SGE participants (n = 128), were analysed. Sociodemographic and disease characteristics, SGE participation, health status (ASAS Health Index), spinal mobility and fulfillment of the recommendations for leisure-time aerobic (≥150 min/week moderate-intensity or ≥75 min/week vigorous-intensity) and strength and mobility (≥2 sessions/week) exercise (measured with SQUASH-questionnaire) were assessed. Differences between patients with and without SGE were analysed. RESULTS: In the two outpatient populations (n = 349), 17 patients (5%) used SGE. The SGE participants (n = 145) were significantly older, had longer disease duration, were less frequently employed, used less medication and had worse spinal mobility than patients without SGE (n = 332). There were no significant differences in health status. Patients with SGE fulfilled the moderate-intensity aerobic (89 % vs. 69%) and strength and mobility (44 % vs. 29%) exercise recommendations more often than patients without SGE, but the aerobic exercise recommendation was less often fulfilled with vigorous-intensity exercise (5 % vs. 12%). CONCLUSION: SGE is used by just few, especially older, axSpA patients and contributes to fulfilling recommendations for moderate-intensity, mobility and strength exercise. Both in patients with and without SGE, only a minority fulfilled the recommendations for vigorous-intensity, strength and mobility exercises. Therefore, future promotion of exercise should focus on implementing these types of exercise.

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.

Central sensitization has major impact on quality of life in patients with axial spondyloarthritis.

INTRODUCTION: Persistent pain has large potential impact on quality of life (QoL). During the course of the disease, many patients with axial spondyloarthritis (axSpA) report persistent pain. Central sensitization (CS) may explain part of this chronic pain. However, the role of CS in relation to QoL has been sparsely studied in axSpA. Therefore, our aim was to explore the relationship between CS and QoL in patients with axSpA. METHODS: Consecutive outpatients from the Groningen Leeuwarden axSpA (GLAS) cohort completed the Central Sensitization Inventory (CSI; range 0-100) and the AS Quality of Life (ASQoL; range 0-18). Multivariable linear regression analysis was used to explore the relationship between CSI and ASQoL scores correcting for potential confounders. RESULTS: Of the 178 included axSpA patients, mean CSI score was 38.0 ± 14.1 and 45% scored ≥40, which indicates a high probability of CS. Mean ASQoL score was 6.0 ± 5.3 and mean ASDASCRP 2.1 ± 1.0. A CSI score ≥40 was significantly associated with higher ASQoL score (mean 9.7 vs. 3.3), higher ASDASCRP (mean 2.6 vs. 1.7), female gender (60% vs. 29%) and more often entheseal involvement (61% vs. 26%). In univariable analysis, CSI score explained a large proportion of the variation in ASQoL (B = 0.06, 95%CI: 0.05-0.07; R2=0.46). This association remained significant after correction for ASDASCRP, gender, entheseal involvement, comorbidities, symptom duration, smoking status, BMI class and educational level (B = 0.04, 95%CI: 0.03-0.05). CONCLUSION: CS is strongly related to patient-reported QoL in patients with axSpA independently from other patient- and disease-related aspects.

Extraskeletal Manifestations in Axial Spondyloarthritis Are Associated With Worse Clinical Outcomes Despite the Use of Tumor Necrosis Factor Inhibitor Therapy.

OBJECTIVE: To investigate the prevalence and 4-year incidence of acute anterior uveitis (AAU), inflammatory bowel disease (IBD) and psoriasis (PsO), and to explore associations of newly developed extraskeletal manifestations (ESMs) with clinical disease outcome in a large cohort of patients with axial spondyloarthritis (axSpA). METHODS: All consecutive patients included in the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort between 2004 and 2011 were analyzed. History of ESMs at baseline and newly developed ESMs during 4-year follow-up were only recorded when diagnosis by an ophthalmologist, gastroenterologist, or dermatologist was present. RESULTS: Of the 414 included patients with axSpA, 31.4% had a positive history of ≥ 1 ESMs: 24.9% AAU, 9.4% IBD, and 4.3% PsO. History of PsO was significantly associated with more radiographic damage, especially of the cervical spine. Of the 362 patients with 4-year follow-up data, 15.7% patients developed an ESM: 13.3% patients had AAU (of which 3.6% had a first episode and 9.7% had recurrent AAU), 1.9% developed IBD, and 0.8% developed PsO. Patients with newly developed ESMs (without history of ESMs) had worse Ankylosing Spondylitis Quality of Life scores (mean 10.0 vs. 5.8, P = 0.001), larger occiput-wall distance (median 6.3 vs. 2.0, P = 0.02) and more limited modified Schober test (mean 12.6 vs. 13.6, P = 0.01) after 4 years of follow-up. The majority of patients developing an ESM used anti-tumor necrosis factor therapy. CONCLUSION: History of ESMs was present at baseline in one-third of patients with axSpA. The 4-year incidence of ESMs was relatively low, but patients who developed a new ESM reported worse quality of life.

Change in disease activity is associated with TNF-α inhibitor serum levels in patients with axial spondyloarthritis in daily clinical practice.

OBJECTIVES: To investigate, in daily clinical practice, TNF-α inhibitor serum trough levels in patients experiencing an increase in axial spondyloarthritis (ax-SpA) related symptoms. Secondly, to explore if these serum trough levels are associated with disease activity (DA) and/or change in DA. METHODS: Patients from the GLAS cohort treated with TNF-α inhibitors who had a serum trough level measurement during follow-up because of an increase in ax-SpA related symptoms between June 2015 and June 2018 were included. Serum trough levels were stratified in a therapeutic and below therapeutic range, based on published reference values of Sanquin in 2019. DA was assessed by ASDAS and BASDAI and change in DA (i.e. ΔASDAS or BASDAI compared to the visit before increasing symptoms). RESULTS: 31 patients had a serum trough level measurement because of increasing symptoms. These patients had a median treatment duration of 4.8 years (IQR 0.9-8.6). 22 (71%) had active disease according to ASDAS (score ≥2.1) and 15 (47%) had therapeutic drug levels. The increase in DA was significantly larger in patients with below therapeutic drug levels compared to patients with therapeutic levels (ΔASDAS: 0.94±0.81 vs. -0.07±1.26, p<0.05; ΔBASDAI: 1.72±1.73 vs. -0.53±1.8, p<0.005). No significant differences were found in absolute DA scores between patients with or without therapeutic drug levels. CONCLUSIONS: In this observational study in daily clinical practice, approximately half of ax-SpA patients who experienced an increase in symptoms had below therapeutic TNF-α inhibitor serum trough levels. Change in DA and not absolute DA scores was significantly associated with drug levels.

B Cell Involvement in the Pathogenesis of Ankylosing Spondylitis.

Extensive research into ankylosing spondylitis (AS) has suggested the major role of genetics, immune reactions, and the joint-gut axis in its etiology, although an ultimate consensus does not yet exist. The available evidence indicates that both autoinflammation and T-cell-mediated autoimmune processes are actively involved in the disease process of AS. So far, B cells have received relatively little attention in AS pathogenesis; this is largely due to a lack of conventional disease-defining autoantibodies. However, against prevailing dogma, there is a growing body of evidence suggestive of B cell involvement. This is illustrated by disturbances in circulating B cell populations and the formation of auto-reactive and non-autoreactive antibodies, along with B cell infiltrates within the axial skeleton of AS patients. Furthermore, the depletion of B cells, using rituximab, displayed beneficial results in a subgroup of patients with AS. This review provides an overview of our current knowledge of B cells in AS, and discusses their potential role in its pathogenesis. An overarching picture portrays increased B cell activation in AS, although it is unclear whether B cells directly affect pathogenesis, or are merely bystanders in the disease process.

CD27-CD38lowCD21low B-Cells Are Increased in Axial Spondyloarthritis.

B-cells have received little attention in axial spondyloarthritis (axSpA) and for this reason their role in pathogenesis remains unclear. However, there are indications that B-cells may be involved in the disease process. Our objective was to obtain insights into the composition of the peripheral B-cell compartment of axSpA patients compared to healthy donors (HD) and patients with primary Sjögren's syndrome (pSS), a typical B-cell-associated autoimmune disease. Special emphasis was given to CD27-negative B-cells expressing low levels of CD21 (CD21low B-cells), since this subset is implicated in autoimmune diseases with strong involvement of B-cells. Transitional B-cells (CD38hi) were excluded from the analysis of the CD27-CD21low B-cell compartment. This study included 45 axSpA patients, 20 pSS patients and 30 HDs. Intriguingly, compared to HDs the frequency of CD27-CD38lowCD21low B-cells was significantly elevated in both axSpA and pSS patients (P<0.0001 for both comparisons). The frequency of CD27-CD38lowCD21low B-cells expressing the activation-induced immune markers T-bet and CD11c was decreased in axSpA patients compared to HDs. A higher proportion of CD27-CD38lowCD21low B-cells expressed the chemokine receptor CXCR3 in axSpA compared to HDs, suggestive for active involvement of these cells in an inflammatory process. The frequency of CD27-CD38lowCD21low B-cells in axSpA patients correlated positively with age and erythrocyte sedimentation rate. Furthermore, axSpA patients with extra-skeletal manifestations (ESM) showed increased frequencies of CD27-CD38lowCD21low B-cells compared to patients without ESM. In conclusion, our findings are suggestive of active B-cell involvement in the pathogenesis of axSpA, against prevailing dogma.