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.

[Whipple's disease, a non-rheumatoid cause of seronegative arthritis]. / De ziekte van Whipple, een niet-reumatische oorzaak van seronegatieve artritis.

BACKGROUND: In 15-25% of patients with rheumatoid arthritis, the presence of pathognomonic autoantibodies (anti-citrullinated protein (aCCP) or rheumafactor (RF) is lacking. In these cases of seronegative rheumatoid arthritis, diagnosis is based on clinical presentation. However, some of the patients with seronegative rheumatoid arthritis are misdiagnosed. CASE DESCRIPTION: Here we discuss a case of a 64 year old female, with a diagnoses of seronegative rheumatoid arthritis for 18 years. Although extensively treated with immunosuppressive medication, she did not reach remission. After second opinion in our hospital we diagnosed Whipple's disease. CONCLUSION: This case report illustrates the importance of a broad differential diagnosis of seronegative arthritis as well as the importance of re-assessment of patients diagnosed with seronegative rheumatoid arthritis, who do not reach remission upon immunosuppressive treatment.

[Whipple's disease, a non-rheumatoid cause of seronegative arthritis]. / De ziekte van Whipple, een niet-reumatische oorzaak van seronegatieve artritis.

BACKGROUND: In 15-25% of patients with rheumatoid arthritis, the presence of pathognomonic autoantibodies (anti-citrullinated protein (aCCP) or rheumafactor (RF) is lacking. In these cases of seronegative rheumatoid arthritis, diagnosis is based on clinical presentation. However, some of the patients with seronegative rheumatoid arthritis are misdiagnosed. CASE DESCRIPTION: Here we discuss a case of a 64 year old female, with a diagnoses of seronegative rheumatoid arthritis for 18 years. Although extensively treated with immunosuppressive medication, she did not reach remission. After second opinion in our hospital we diagnosed Whipple's disease. CONCLUSION: This case report illustrates the importance of a broad differential diagnosis of seronegative arthritis as well as the importance of re-assessment of patients diagnosed with seronegative rheumatoid arthritis, who do not reach remission upon immunosuppressive treatment.

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.

[An atypical presentation of tuberculosis]. / Een atypische presentatie van tuberculose.

BACKGROUND: In 2020 there were 623 known TB infections in the Netherlands according to the Dutch ministry of health (RIVM). About 4% were located in bones and joints. The incidence of Multi Drug Resistant (MDR) TB in The Netherlands is about 1%. CASE: We describe the case of a 46-year-old female with a painful and swelling of the mid phalangeal bone of the fourth left digit. Quantiferon was positive and PCR of the biopsy for Mycobacterium tuberculosis complex (MTC) in Ziehl-Neelsen staining confirmed tuberculous osteomyelitis. The strain was resistant for rifampicin, isoniazid, ethambutol and pyrazinamid classifying it as MDR. Treatment in a specialized center with second line drugs was indicated due to rare resistance. CONCLUSION: Tuberculosis may manifest anywhere throughout the body, also as an (atypical) swelling of the hand. The golden diagnostic standard for bone and joint TB is biopsy with Ziehl-Neelsen staining.

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.

High prevalence of hidradenitis suppurativa symptoms in axial spondyloarthritis patients: A possible new extra-articular manifestation.

BACKGROUND: Spondyloarthritis (SpA), a chronic inflammatory, rheumatic disease, and hidradenitis suppurativa (HS), a chronic, debilitating, inflammatory skin disease, share several clinical and pathophysiological features, such as the association with inflammatory bowel disease and elevated cytokine levels IL-17 and TNF-α. Recently, SpA was reported to be more prevalent (2.3-28.2%) in patients with HS than in the general population. Conversely, the prevalence of HS in SpA is not exactly known. OBJECTIVE: To determine the prevalence of HS in patients with axial SpA, a subtype of SpA primarily of the axial skeleton. Secondly, to identify patient characteristics associated with the presence of HS in axial SpA. METHODS: In this cross-sectional study, a self-screening questionnaire based on validated diagnostic HS questions was sent to all participating axial SpA patients from the Groningen Leeuwarden Axial Spondyloarthritis (GLAS) cohort fulfilling the ASAS axial SpA criteria. Self-reported HS symptoms were confirmed by previous medical diagnosis or verification by phone using highly specific validated questions. RESULTS: In total, 75.6% (449/592) questionnaires were eligible for analyses. Included patients had a mean age of 50 ± 13 years, 64% was male, mean symptom duration was 23 ± 13 years, and 79% was HLA-B27 positive. HS diagnosis could be confirmed in 41 patients, resulting in an estimated prevalence of 9.1%. In comparison to patients without a positive history of HS, these patients were more often female (54% vs. 35%, P = 0.02), showed higher axial SpA disease activity (mean BASDAI 4.5 vs. 3.6, p = 0.01 and ASDASCRP 2.6 vs. 2.2, P = 0.003) and worse quality of life (QoL) (median ASQoL 9.0 vs. 4.0, P < 0.001). Also, a history of heel enthesitis and dactylitis was more prevalent (34% vs. 19%, P = 0.03 and 15% vs. 6%, P = 0.05, respectively). Multivariable analysis showed that a higher score on ASDAS was independently associated with HS (OR: 1.639, 95% CI: 1.176-2.284). CONCLUSION: In our cohort of axial SpA patients, HS is more prevalent than in the general population (9.1% versus 0.053-4.1%). HS is associated with female gender, lower QoL, and especially higher axial SpA disease activity.

Uncovering the heterogeneity of disease impact in axial spondyloarthritis: bivariate trajectories of disease activity and quality of life.

OBJECTIVE: The goal of managing axial spondyloarthritis (axSpA) is to improve and maintain patients' health-related quality of life (HRQoL), mainly through targeting towards low disease activity. Here, we aim to gain insight into the joint evolution of HRQoL and disease activity by identifying and characterising latent subgroups of patients with longstanding disease displaying similar trajectories throughout 8 years of follow-up. METHODS: Data from Outcome in Ankylosing Spondylitis (AS) International Study (n=161) and Groningen Leeuwarden AS cohort (n=264) were used. Biennially, HRQoL was assessed by AS Quality of Life (ASQoL) and disease activity by AS Disease Activity Score-C reactive protein (ASDAS-CRP). Bivariate trajectories of these outcomes were estimated by group-based trajectory modelling. Next, trajectories were profiled by comparing the latent groups with respect to baseline factors using analysis of variance and χ² test. RESULTS: Five bivariate trajectories were distinguished, in which ASQoL and ASDAS-CRP were tightly linked: (t1) low impact of disease; (t2) moderate impact; (t3) high impact with major improvement; (t4) high impact with some improvement; (t5) very high impact. Profiling revealed, for example, that (t1) was characterised by male gender and Human Leucocyte Antigen B27 positivity; (t3) by younger age, shorter symptom duration and biological intake and (t5) by the highest proportion of females. CONCLUSIONS: We identified five bivariate trajectories of HRQoL and disease activity demonstrating a clear mutual relationship. The profiles revealed that both individual-related and disease-related features define the type of disease course in respect to HRQoL and disease activity in axSpA. This may provide clinicians insight into the differences among patients and help in the management of the disease.

Ankylosing spondylitis patients at risk of poor radiographic outcome show diminishing spinal radiographic progression during long-term treatment with TNF-α inhibitors.

OBJECTIVE: To investigate the influence of patient characteristics on the course of spinal radiographic progression in a large prospective longitudinal cohort study of ankylosing spondylitis (AS) patients treated long-term with TNF-α inhibitors. METHODS: Consecutive patients from the Groningen Leeuwarden AS (GLAS) cohort starting TNF-α inhibitors with spinal radiographs at least available at baseline and 6 years of follow-up were included. Radiographs were scored using mSASSS by two independent readers. Generalized estimating equations (GEE) were used to explore the associations between baseline characteristics and spinal radiographic progression. The course of radiographic progression in patients with and without risk factors for poor radiographic outcome was investigated using different time models (linear and non-linear). Single linear imputation was used in case of missing radiographic data at the intermediate (2 or 4 years) follow-up visits. RESULTS: 80 AS patients were included with mean baseline mSASSS 8.7±13.3. Baseline syndesmophytes, male gender, older age, longer symptom duration, smoking, and higher BMI were significantly associated with more radiographic damage over time. GEE analysis in patients with these risk factors revealed that radiographic progression followed a non-linear course with mean mSASSS progression rates reducing from max. 2.8 units over 0-2 years to min. 0.9 units over 4-6 years. The GEE model revealed a linear course with overall very low progression (≤1 mSASSS units/2yrs) in patients without risk factors. Complete case analysis in 53 patients showed similar results. CONCLUSION: AS patients at risk of poor radiographic outcome showed the highest but diminishing spinal radiographic progression during long-term treatment with TNF-α inhibitors.

Incorporating assessment of the cervical facet joints in the modified Stoke ankylosing spondylitis spine score is of additional value in the evaluation of spinal radiographic outcome in ankylosing spondylitis.

BACKGROUND: To aim was to investigate the additional value of incorporating the de Vlam cervical facet joint score in the modified ankylosing spondylitis (AS) spine score (mSASSS) for the evaluation of spinal radiographic outcome in AS. METHOD: Baseline and 4-year radiographs from 98 consecutive patients from the Groningen Leeuwarden AS (GLAS) cohort, who had AS treated with TNF-α inhibitors, were scored by two readers; the vertebral bodies were assessed according to the mSASSS (0-72) and cervical facet joints (C2-C7) were assessed according to the method of de Vlam (0-15). The combined AS spine score (CASSS) was calculated as the sum of both total scores (range 0-87) and compared with the original mSASSS according to three aspects of the Outcome Measures in Rheumatology Clinical Trials (OMERACT) filter: feasibility, discrimination, and truth. RESULTS: Feasibility: the CASSS was calculated in 91% of the patients. No additional radiographs were necessary and the assessment took only a few extra minutes. Discrimination: both scoring methods had excellent inter-observer reliability (intra-class correlation coefficient (ICC) status scores >0.99, progression scores 0.92). Incorporating the cervical facet joints did not result in an increase in measurement error. The CASSS detected more patients with definite damage (61% vs. 57%) and definite progression (55% vs. 48%). Truth: higher CASSS scores at baseline and higher progression scores were seen in 41 (46%) and 22 (25%) patients, respectively. Cervical rotation correlated better with cervical CASSS than with cervical mSASSS (Spearman's rho = 0.68 vs. 0.59). CONCLUSIONS: The CASSS is a relevant and easy modification of the mSASSS. It captures more patients with AS who have spinal radiographic damage and progression, which is of great additional value in the evaluation of radiographic outcome in this heterogeneous and overall slowly progressing disease.

Radiographic damage and progression of the cervical spine in ankylosing spondylitis patients treated with TNF-α inhibitors: Facet joints vs. vertebral bodies.

OBJECTIVES: To investigate radiographic damage and 4-year progression of the cervical facet joints in a prospective observational cohort of AS patients treated with TNF-α inhibitors, to compare this with damage and progression of the cervical vertebral bodies, and to study the relation with patient characteristics and clinical outcome. METHODS: Patients from the Groningen Leeuwarden AS (GLAS) cohort starting TNF-α inhibitors with baseline and 4-year radiographs were included. Cervical facet joints and vertebral bodies were scored by two independent readers according to the method of de Vlam and mSASSS, respectively. RESULTS: At baseline, 25 of 99 (25%) AS patients had partial or complete ankylosis of the cervical facet joints, whereas 51 (52%) patients had non-bridging or bridging syndesmophytes of cervical vertebral bodies. During 4 years, 13 (13%) patients developed new (partial) ankylosis of the facet joints, whereas 26 (26%) developed new (bridging) syndesmophytes. Facet joint damage and progression without involvement of the vertebral bodies were seen in 5 (5%) and 8 (8%) patients, respectively. Damage of facet joints was associated with longer disease duration, history of IBD/uveitis/psoriasis, higher disease activity, larger occiput-to-wall distance, higher mSASSS, and presence of syndesmophytes. Progression of the facet joints was associated with larger occiput-to-wall distance and more facet joint damage at baseline. CONCLUSIONS: Cervical facet joints were frequently involved in AS. During 4 years of TNF-α blocking therapy, 13% of the patients showed radiographic progression of cervical facet joints of which the majority did not show progression of vertebral bodies.

Clinical Risk Factors for the Presence and Development of Vertebral Fractures in Patients With Ankylosing Spondylitis.

INTRODUCTION: To investigate the prevalence and incidence of radiographic vertebral fractures and the association with patient characteristics, clinical assessments, and medication use in a large prospective cohort of patients with ankylosing spondylitis (AS) in daily clinical practice. METHODS: Consecutive AS patients from the Groningen Leeuwarden AS (GLAS) cohort with baseline and 2-year lateral radiographs of the thoracic and lumbar spine were included. Radiographs were scored for vertebral fractures by 2 readers according to the method of Genant et al. Differences in baseline characteristics between patients with and without radiographic vertebral fractures were explored. RESULTS: Of 292 included AS patients, 59 (20%) had radiographic vertebral fractures at baseline, 15 (6%) developed new fractures, and 7 (2%) showed an increase in the severity of existing fractures during 2 years of follow-up. Most fractures were mild and located in the midthoracic and thoracolumbar region of the spine. The presence of vertebral fractures was significantly associated with older age, higher body mass index, longer smoking duration, larger occiput-to-wall distance, more spinal radiographic damage, and lower hip bone mineral density (BMD). The development of new or progressive vertebral fractures was also associated with older age and low BMD. Patients using nonsteroidal antiinflammatory drugs (NSAIDs) at baseline showed less prevalent and incident vertebral fractures. CONCLUSION: In this large AS cohort in daily clinical practice, radiographic vertebral fractures were frequently present in AS, especially in older patients with more advanced disease, low hip BMD, and a less healthy lifestyle. Interestingly, NSAID use was associated with a reduced vertebral fractures risk.

Reduction in Spinal Radiographic Progression in Ankylosing Spondylitis Patients Receiving Prolonged Treatment With Tumor Necrosis Factor Inhibitors.

OBJECTIVE: To evaluate the course of spinal radiographic progression for up to 8 years of followup in a large cohort of ankylosing spondylitis (AS) patients treated with tumor necrosis factor (TNF) inhibitors. METHODS: Consecutive patients from the Groningen Leeuwarden AS cohort starting TNF inhibitors between 2004 and 2012 were included. Baseline and biannual radiographs were randomized with radiographs of TNF-naive AS patients and scored in chronologic order according to modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). The course of radiographic progression (linear or nonlinear) was investigated using generalized estimating equations. Primary analysis was performed in patients with complete data over 4, 6, and 8 years of followup. Sensitivity analysis was performed after single linear imputation of missing radiographic data and after adjusting for patient characteristics with possible influence on radiographic progression. RESULTS: At baseline, median mSASSS of 210 included AS patients was 2.8 (interquartile range 0.0-12.0), mean ± SD mSASSS 10.0 ± 15.5. During the first 4 years, radiographic progression followed a linear course (estimated mean progression rate was 1.7 for 0-2 and 2-4 years). A deflection from a linear course was found in patients with complete and imputed data over 6 and 8 years. The estimated mean 2-year progression rate reduced from 2.3 to 0.8 in patients with complete 8-year data. The same pattern was found after adjustment for baseline mSASSS scores, presence of syndesmophytes, sex, HLA-B27 status, age, symptom duration, smoking duration, body mass index, disease activity, and nonsteroidal antiinflammatory drug use. CONCLUSION: This observational cohort study in AS patients receiving long-term TNF inhibitors showed a reduction in spinal radiographic progression after more than 4 years of followup.