Risk of disease flare in spondyloarthritis patients after tapering tumor necrosis factor inhibitors: A meta-analysis and literature review.

BACKGROUND: Tumor necrosis factor inhibitors (TNFis) have shown dramatic benefit in patients with spondyloarthritis (SpA). Tapering of TNFi medication may be considered in patients with sustained low disease activity because continued use of TNFis at standard doses may increase the risk of side effects including infections and impose an economic burden. However, the optimal TNFi tapering strategy for SpA patients with inactive disease has not been established. In the present study, we investigated whether tapering TNFi doses is associated with similar risk of disease flare to maintaining SpA patients on TNFis at the standard dosage. METHODS: The MEDLINE, Embase, and Cochrane databases were systemically searched to retrieve randomized control trials (RCTs) and observational studies published prior to August 2023, that compared disease flare in SpA (including axial SpA [axSpA], psoriatic arthritis [PsA], and SpA with IBD) patients who received standard TNFi doses and those who received a tapered dose of TNFi. Odds ratios (ORs) and 95% confidence intervals (CIs) were directly retrieved or calculated, and meta-analyses were performed. Bias was assessed using funnel plots with Begg and Mazumdar rank correlation / Egger's regression method. RESULTS: Among 2,237 SpA patients in the 12 studies (9 RCTs and 3 observational studies) retrieved, 1,301 received the standard TNFi dose, while 936 SpA patients underwent TNFi tapering. Of these, 216 (16.6%) standard-dose TNFi and 217 (23.2%) TNF-tapering patients experienced disease flares. The pooled OR for disease flare in TNFi-tapering patients was 1.601 (95% CI 1.276 - 2.008) compared with the standard-dose patients. The funnel plot showed no publication bias. CONCLUSIONS: The strategy of TNFi tapering was associated with a significantly increased risk of disease flare compared to maintaining SpA patients at the standard TNF dose. Further studies are needed to determine which patients can safely undergo tapering of TNFi and to develop safe tapering strategies.

Impact of anti-tumor necrosis factor treatment on lipid profiles in Korean patients with ankylosing spondylitis.

Objective: To investigate the effects of anti-tumor necrosis factor (TNF) treatment on lipid profiles and identify risk factors for an increase in total cholesterol (TC) after the anti-TNF treatment in ankylosing spondylitis (AS) patients. Methods: This retrospective cohort study analyzed AS patients who received the first-line anti-TNF treatment. Patients with at least nine months of follow-up were included; those who were under 18 years or on any lipid-lowering agent were excluded. A linear mixed model was used to assess the impact of anti-TNF inhibitors on disease activity and lipid profile (TC, low-density lipoprotein [LDL], high-density lipoprotein [HDL], and triglycerides [TG]). Univariable and multivariable linear regression were used to identify risk factors for an increase in TC after 3 months of anti-TNF treatment. Results: A total of 315 AS patients were enrolled (78.1% male, median age 32.0 [26.0~41.0]). TC, HDL, and TG levels significantly increased particularly within the first 3 months of anti-TNF treatment, while LDL level did not show significant changes. Changes in inflammatory markers and lipid particles (TC, LDL, TG) were correlated over time, but HDL showed no significant correlation. Older age, higher baseline erythrocyte sedimentation rate, and lower baseline LDL level were related to an increase in TC after 3 months of the anti-TNF treatment. Conclusion: In AS patients, anti-TNF treatment has been found to increase lipid particles, potentially due to its anti-inflammatory effects. Future research should explore the underlying mechanism and the clinical implications of dyslipidemia, particularly the occurrence of cardiovascular events, following anti-TNF treatment in AS patients.

The relationship between long-term use of nonsteroidal anti-inflammatory drugs and kidney function in patients with ankylosing spondylitis.

Objective: Although nonsteroidal anti-inflammatory drugs (NSAIDs) are the first-line treatment for ankylosing spondylitis (AS), their effect on kidney function remains unclear. This longitudinal study investigated the correlation between long-term NSAID use and kidney function in patients with AS using electronic medical records. Methods: The electronic medical records of 1,280 patients with AS collected from a single center between January 2001 and December 2018 were reviewed. The Assessment of Spondyloarthritis International Society (ASAS) NSAID Intake Score was used to determine the cumulative dose of all NSAIDs prescribed for a different time intervals. Each ASAS NSAID Intake Score was obtained for intervals of 6 months, 1 year, 2 years, 3 years, 5 years, and 10 years. The correlation between the ASAS NSAID Intake Score and final estimated glomerular filtration rate (eGFR) for each interval was investigated. Results: The mean ASAS Intake Scores for 6-month, 1-year, 2-year, 3-year, 5-year, and 10-year intervals were 55.30, 49.28, 44.84, 44.14, 44.61, and 41.17, respectively. At each interval, the pearson correlation coefficients were -0.018 (95% CI -0.031 to -0.006, p=0.004), -0.021 (95% CI -0.039 to -0.004, p=0.018), -0.045 (95% CI -0.071 to -0.019, p=0.001), -0.069 (95% CI -0.102 to -0.037, p<0.001), -0.070 (95% CI -0.114 to -0.026, p=0.002), -0.019 (95% CI -0.099 to 0.062, p=0.645), respectively. There was a very weak negative relationship between ASAS Intake Score and eGFR at each interval. Conclusion: Long-term NSAID use did not correlate with kidney function based on real-world data in patients with AS.

Association between changes in serum alkaline phosphatase levels and radiographic progression in ankylosing spondylitis.

This retrospective study evaluated the electronic medical records of patients with ankylosing spondylitis (AS) (January 2001-December 2018) to determine the relationship between serum alkaline phosphatase (ALP) levels and radiographic changes over time. Longitudinal data, including serum ALP levels, were imputed by linear interpolation at 3-month intervals. Among the serum ALP levels calculated for 8 years prior to modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) measurement, those having the highest beta coefficient with the mSASSS were selected in the correlation between ALP and longitudinal mSASSS. Linear mixed models with the selected serum ALP levels, mSASSS, and clinical variables were investigated. We included 1122 patients (mean follow-up, 8.20 [standard deviation: 2.85] years). The serum ALP level from 5 years and 3 months prior showed the highest beta coefficient with the mSASSS. In the linear mixed model, the serum ALP level at 5 years and 3 months before radiographic changes was significantly associated with the mSASSS (ß = 0.021, 95% confidence interval: 0.017-0.025, p < 0.001). Serum ALP levels measured approximately 5 years before may be a surrogate marker for predicting spinal radiographic changes. Long-term prospective clinical and experimental studies of > 5 years are required for biomarker discovery or therapeutic research on AS radiographic progression.

Clinical and genetic factors associated with radiographic damage in patients with ankylosing spondylitis.

OBJECTIVES: To identify clinical and genetic factors associated with severe radiographic damage in patients with ankylosing spondylitis (AS). METHODS: We newly generated genome-wide single nucleotide polymorphism data (833K) for 444 patients with AS. The severity of radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). To identify clinical and genetic factors associated with severe radiographic damage, multiple linear regression analyses were performed. Human AS-osteoprogenitor and control-osteoprogenitor cells were used for functional validation. RESULTS: The significant clinical factors of final mSASSS were baseline mSASSS (ß=0.796, p=3.22×10-75), peripheral joint arthritis (ß=-0.246, p=6.85×10-6), uveitis (ß=0.157, p=1.95×10-3), and smoking (ß=0.130, p=2.72×10-2) after adjusting for sex, age and disease duration. After adjusting significant clinical factors, the Ryanodine receptor 3 (RYR3) gene was associated with severe radiographic damage (p=1.00×10-6). For pathway analysis, the PI3K-Akt signalling pathway was associated with severe radiographic damage in AS (p=2.21×10-4, false discovery rate=0.040). Treatment with rhodamine B, a ligand of RYR3, dose-dependently induced matrix mineralisation of AS osteoprogenitors. However, the rhodamine B-induced accelerated matrix mineralisation was not definitive in control osteoprogenitors. Knockdown of RYR3 inhibited matrix mineralisation in SaOS2 cell lines. CONCLUSIONS: This study identified clinical and genetic factors that contributed to better understanding of the pathogenesis and biology associated with radiographic damage in AS.

The impact of smoking status on radiographic progression in patients with ankylosing spondylitis on anti-tumor necrosis factor treatment.

Background: Ankylosing spondylitis (AS) is characterized by back pain which can lead to spinal ankylosis. Anti-tumor necrosis factor (TNF) dramatically alleviates symptoms, but spinal damage can still be progressive even during anti-TNF treatment. Smoking is a one of well-known risk factors for structural damage in AS. However, it has not been confirmed that smoking can affect radiographic progression even during anti-TNF treatment. Objective: To investigate factors associated with radiographic progression during anti-TNF treatment with a focus on smoking status which is known as one of poor prognostic factors for AS. Materials and methods: We conducted a retrospective cohort study of AS patients who began the first-line anti-TNF treatment between 2001 and 2018 according to availability of smoking data. All enrolled patients were observed until the last visit, the first-line anti-TNF discontinuation, or December 2019. Radiographic damage was assessed using the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). The mSASSS progression rate (units/year) was calculated using the baseline mSASSS, the final mSASSS during observation period, and the duration between them. Univariable and multivariable logistic regression analyses were performed to identify associated factors of mSASSS progression rate > 1 unit/year. Results: Among 459 AS patients, 185 (40.3%) patients were never smokers, 62 (13.5%) were ex-smokers and 212 (46.2%) were current smokers at baseline. Ex- and current smokers had higher mSASSS progression rates than never smokers [never smoker 0.1 (0.0-0.7), ex-smoker 0.6 (0.0-1.5), and current smoker 0.6 (0.0-1.5) units/year, P < 0.001]. In the multivariable logistic analysis, current smoking [adjusted odds ratio (OR) 1.69, 95% CI 1.01-2.82, P = 0.047] and higher baseline mSASSS [adjusted OR 1.03, 95% CI 1.01-1.04, P < 0.001] were associated with a mSASSS progression rate > 1 unit/year. Conclusion: Current smoking is a modifiable risk factor for radiographic progression in patients with AS on anti-TNF treatment. Quitting smoking should be strongly recommended.

Relationship Between Inflammation and Radiographic Progression in Patients With Ankylosing Spondylitis Attaining a BASDAI of Less Than 4 During Tumor Necrosis Factor Inhibitor Treatment.

OBJECTIVE: To determine the relationship between inflammation and radiographic progression over time in patients with ankylosing spondylitis (AS) attaining a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of < 4 during tumor necrosis factor inhibitor (TNFi) treatment. METHODS: Medical records data of patients with AS with BASDAI scores of < 4 during TNFi treatment were analyzed at 6-month intervals from January 2001 to December 2018. To determine the relationship between the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) and C-reactive protein (CRP) over time, we fitted linear mixed models with mSASSS as the response variable, baseline mSASSS and the cumulative sum of CRP with different lag times (6, 12, 18, 24, 30, and 36 months) as fixed effects, and patients as random effects. Associations between mSASSS and the cumulative sum of CRP, or the lag times with the highest beta coefficients, were further investigated with linear mixed models that included additional clinical variables. RESULTS: A total of 2956 intervals were obtained from 333 patients. Among different lag times, the cumulative sum of log CRP in the previous 18 to 36 months associated with mSASSS showed significant beta coefficients. In the final linear mixed model, the cumulative sum of log CRP in the previous 24 months was significantly associated with mSASSS at 24 months (ß 0.04, 95% CI 0.01-0.07, P = 0.004). CONCLUSION: Remnant inflammation correlates with radiographic progression, even in patients attaining a BASDAI of < 4 during TNFi treatment. CRP is a surrogate marker for radiographic progression despite clinical improvement with TNFi treatment.

Early control of C-reactive protein levels with non-biologics is associated with slow radiographic progression in radiographic axial spondyloarthritis.

AIM: Predicting radiographic progression is vital for assessing the prognosis of patients with radiographic axial spondyloarthritis, and C-reactive protein (CRP) may be a valuable biomarker for this purpose. This study aimed to investigate the relationship between changes in the CRP level and spinal radiographic progression in patients with radiographic axial spondyloarthritis who were initially treated with non-biologics. METHODS: Patients with radiographic axial spondyloarthritis who were followed up for 18 years at a single center and initially treated with nonsteroidal anti-inflammatory drugs and/or conventional disease-modifying antirheumatic drugs for 3 months were included. Patients with a CRP level of <0.8 mg/dL or 50% of the baseline CRP at 3 months were assigned to the controlled CRP group (n = 351), and the remaining patients were assigned to the uncontrolled CRP group (n = 452). A generalized estimating equation was used to analyze the differences in the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) between the 2 groups. RESULTS: The increase in the mSASSS was slower in the controlled CRP group than in the uncontrolled CRP group (interaction term ß = -.499, 95% confidence interval -0.699 to -0.300). CONCLUSION: Controlled CRP achieved in response to initial treatment with non-biologic agents for 3 months was significantly associated with a slower rate of spinal radiographic change in patients with radiographic axial spondyloarthritis. The CRP level at 3 months after initial non-biologic treatment is a good predictor of radiographic progression.

Gender differences in factors associated with low quality of life and depression in Korean patients with ankylosing spondylitis.

PURPOSE: To identify predictors of low health-related quality of life (HRQoL) and depression in ankylosing spondylitis (AS) patients with a focus on gender differences. METHODS: We conducted a cross-sectional cohort study. Both AS-related clinical data and contextual factors were obtained. HRQoL and depressive mood were assessed by EuroQol-5 dimension (EQ-5D) and the Center for Epidemiological Studies Depression Scale (CES-D), respectively. Gender-stratified multivariable logistic regression analyses were performed. RESULTS: Among 211 patients, 161 were males. Males had similar disease activity and higher radiographic damage compared with females. There was no significant difference in EQ-5D index score between genders. CES-D score was higher in females. Higher ASDAS-C-reactive protein (CRP) was associated with low HRQoL in both males (Odds ratio [OR] 4.25, 95% confidence interval [CI] 2.42-7.46) and females (OR 2.94, 95% CI 1.02-8.48). Being employed was associated with decreased possibility of having low HRQoL in males (OR 0.39, 95% CI 0.16-0.95). Regarding depression, higher ASDAS-CRP (OR 1.87, 95% CI 1.03-3.40), current smoking (OR 2.98, 95% CI 1.09-8.15), and being employed (OR 0.17, 95% CI 0.06-0.46) were associated with depression in males. For females, living with a partner was related to depression (OR 0.08, 95% CI 0.01-0.93). CONCLUSION: AS patients with high disease activity are likely to be suffering from low HRQoL. Both disease-related factors and contextual factors were associated with depression, and predictors showed some differences between genders. Awareness of gender differences in comprehensive assessment can lead us to better personalized management in AS patients.

Low BASDAI score alone is not a good predictor of anti-tumor necrosis factor treatment efficacy in ankylosing spondylitis: a retrospective cohort study.

BACKGROUND: The purpose of this study was to determine the prevalence of high disease activity as measured using the Ankylosing Spondylitis Disease Activity Score (ASDAS) in ankylosing spondylitis (AS) patients who nonetheless have low Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores after anti-tumor necrosis factor (TNF) treatment. Its clinical impact on anti-TNF survival was also investigated. METHODS: We conducted a single-centre retrospective cohort study of AS patients having low BASDAI scores (< 4) and available ASDAS-C-reactive protein (CRP) data after 3 months of first-line anti-TNF treatment. Patients were grouped into high-ASDAS (≥ 2.1) and low-ASDAS (< 2.1) groups according to the ASDAS-CRP after 3 months of anti-TNF treatment. Their characteristics were compared. And survival analyses were carried out using Kaplan-Meier curves and log-rank test with the event being discontinuation of anti-TNF treatment due to lack/loss of efficacy. RESULTS: Among 116 AS patients with low BASDAI scores after 3 months of anti-TNF treatment, 38.8% were grouped into the high-ASDAS group. The high-ASDAS group tended to have greater disease activity after 9 months of treatment (BASDAI 2.9 ± 1.1 vs. 2.3 ± 1.4, p=0.007; ASDAS-CRP 1.8 ± 0.6 vs. 1.5 ± 0.7, p=0.079; proportion of high ASDAS-CRP 27.8% vs. 13.8%, p=0.094) and greater risk of discontinuing anti-TNF treatment due to lack/loss of efficacy than the low-ASDAS group (p=0.011). CONCLUSIONS: A relatively high proportion of AS patients with low BASDAI scores had high ASDAS-CRP. These low-BASDAI/high-ASDAS-CRP patients also had a greater risk for discontinuation of anti-TNF treatment due to low/lack of efficacy than the low-ASDAS group. The use of the ASDAS-CRP alone or in addition to the BASDAI may improve the assessment of AS patients treated with anti-TNF agents.

Tumour necrosis factor inhibitors slow radiographic progression in patients with ankylosing spondylitis: 18-year real-world evidence.

OBJECTIVES: Tumour necrosis factor inhibitors (TNFis) have been suggested to slow radiographic progression in patients with ankylosing spondylitis. However, limitations such as variations in disease activity, complex drug administration and short follow-up duration make it difficult to determine the effect of TNFis on radiographic progression. The aim of the study was to investigate whether long-term treatment with TNFis can reduce radiographic progression in patients with ankylosing spondylitis using 18-year longitudinal real-world data. METHODS: This retrospective study was conducted between January 2001 and December 2018 at a single centre. Among the 1280 patients whose electronic medical records were reviewed, data of 595 patients exposed to TNFis at least once were included. Among them, time intervals of TNFi exposure or non-exposure were determined in 338 patients ('on the TNFis' or 'off the TNFis' intervals, respectively). The difference in the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS) change rate between 'on the TNFis' and 'off the TNFis' intervals was investigated. RESULTS: We obtained 2364 intervals of 338 patients (1281 'on the TNFis' and 1083 'off the TNFis' intervals). In the marginal structural model for inverse probability of treatment weighting, the change rate of mSASSS significantly decreased with the use of TNFis (ß=-0.112, p=0.004), and the adjusted mSASSS changes were 0.848 and 0.960 per year during 'on the TNFis' and 'off the TNFis' intervals, respectively. CONCLUSION: Compared with treatment without TNFis, treatment with TNFis slowed radiologic progression significantly.

Effect of biologics in the level of cytokines in the synovial fluid of patients with ankylosing spondylitis.

BACKGROUND/AIMS: Biologics are very effective drugs for patients with ankylosing spondylitis (AS). However, there are patients who are not responding to biologics. This study aimed to evaluate the level of tumor necrosis factor α (TNF-α), interleukin (IL)-23, and IL-17 from synovial fluid in patients with AS and rheumatoid arthritis (RA) and differences of the level of those cytokines according to drugs. METHODS: Synovial fluid was obtained from 34 patients (42 samples) with AS and 45 patients (47 samples) with RA with active arthritis of the knee, and the cytokine levels were measured. The differences in the levels between patients treated with and without biologics (biologics and non-biologics groups, respectively) were analyzed in AS and RA. The correlations between cytokines were examined in the non-biologics and biologics groups. RESULTS: The TNF-α level in AS was significantly lower than that in RA (p = 0.016). The IL-17 and IL-23 levels were not different between AS and RA (p = 0.409 and p = 0.562, respectively). In AS and RA, TNF-α, IL-17, and IL-23 showed good correlation among each other in the non-biologics group. However, there was no significant correlation in biologics group. In some patients in the AS group, the IL-17 or IL-23 level was markedly elevated in the biologics group. CONCLUSION: Treatment with biologics affects the cytokine profile in inflammatory synovial fluid in patients with both AS and RA. Furthermore, IL-23 and IL-17 cytokine might be an important factor in some patients who are unresponsive to biologics in AS.

Evaluation of disease chronicity by bone marrow fat fraction using sacroiliac joint magnetic resonance imaging in patients with spondyloarthritis: A retrospective study.

AIM: This study investigated the use of fat fraction (FF) measurements in the sacroiliac (SI) joint to determine radiologic progression in patients with spondyloarthritis (SpA). METHOD: A total of 138 patients who underwent pelvic magnetic resonance imaging (MRI) between September 2014 and March 2015 were retrospectively evaluated. The FF based upon fat deposition (%) using fat signaling on T1 and T2 weighted images in the sacroiliac joint was quantified using a 6-echo variant of the modified Dixon technique. We defined the normal bone marrow as normal FF, bone marrow edema as active inflammatory FF, and fat metaplasia as post-inflammatory FF. RESULTS: The mean FF of normal marrow was 52.0% ± 10.4% and 50.5% ± 10.1% in the left and right SI joints, respectively. The mean FF of post-inflammatory fat deposition was 81.9% ± 9.7% and 82.3% ± 9.6% in the left and right SI joints, respectively. The mean FF of active inflammatory fat deposition was 15.8% ± 5.9% and 13.5% ± 6.7% in the left and right SI joints, respectively. In multiple linear regression, post-inflammatory FF was found to be significantly associated with radiologic progression, such as symptom duration, SI joint grade, and modified Stoke Ankylosing Spondylitis Spine Score. CONCLUSION: Post-inflammatory FF indicates the chronicity of SpA. Evaluating FF using MRI in the SI joint will help to determine radiologic progression.

Comparison on radiographic progression for 5 years between juvenile onset ankylosing spondylitis and adult onset ankylosing spondylitis: an observational study of the Korean SpondyloArthropathy Registry (OSKAR) data.

OBJECTIVES: To evaluate differences in radiographic progression between adult-onset ankylosing spondylitis (AoAS) and juvenile-onset ankylosing spondylitis (JoAS). METHODS: A total of 533 patients (418 patients with AoAS and 115 patients with JoAS) from the Observation Study of Korean spondyloArthropathy Registry (OSKAR) cohort were enrolled. All baseline OSKAR data were analysed in relation to disease onset and radiographic progression was analysed between the groups over 5 years. The modified Stoke AS Spinal Score (mSASSS) were used by two experienced radiologists. Clinical data were collected to investigate the associations between clinical factors and radiographic progression. Radiographic scores were compared using analysis of covariance model after adjusting for confounding factors. RESULTS: Inter-reader reliability for baseline mSASSS was very good. Inter-reader reliability for the changes in the mSASSS was also good. A significant difference in baseline mSASSS (mean ± SD) unit was detected between the AoAS and JoAS groups (18.1±17.4 vs. 14.3±13.8, p=0.015). We assessed the change in mSASSS to confirm whether age at onset affected radiographic progression. A simple comparison revealed a significant difference between changes on the mSASSS (mean ± SEM) between the JoAS and AoAS groups (1.75±0.71 vs. 3.77±0.56, p<0.001). After adjusting for multiple comparisons, change on the mSASSS remained lower in patients with JoAS than those with AoAS (0.28±1.33 vs. 4.08±0.62, p=0.016). CONCLUSIONS: Patients with JoAS had slower radiographic spinal damage progression over 5 years than those with AoAS.

Radiographic progression in patients with ankylosing spondylitis according to tumor necrosis factor blocker exposure: Observation Study of Korean Spondyloarthropathy Registry (OSKAR) data.

OBJECTIVE: To evaluate the influence of tumor necrosis factor (TNF) blocker on the radiographic progression in ankylosing spondylitis (AS) patients. METHODS: A total of 610 patients were recruited. We stratified two groups (TNF blocker naïve and exposure patients). After then, we analyzed the radiographic spinal progression. Univariable and multivariable analyses were performed to identify predictors associated with radiographic progression, which was assessed by the modified Stokes AS Spinal Score (mSASSS). As this was an observational study, the patients were not randomized to the treatment arm. Therefore, propensity score matching was also done with age, gender, and the baseline CRP. The generalized estimating equation model was performed in the post-matched samples. Potential confounders were included in the model. RESULTS: Agreements between the two readers were excellent. Of the 610 patients with AS, 341 patients did not have any exposure to TNF blocker. The radiographic progression (mean±SEM) was not significantly different between groups (4.73±1.01, and 6.14±2.00, P=0.54) in spite of adjusting for confounding factors (age, gender, disease duration, smoking, CRP level, NSAID intake, and baseline mSASSS). Propensity score matching was done to confirm the effect of TNF blockers on radiographic progression. Even after adjusting for the TNF blocker exposure, the result still remained not significant with an OR for progression while taking TNF blocker of 0.69 (P=0.41; 95% CI: 0.29-1.63). CONCLUSION: Our registry data showed that TNF blocker failed to affect the radiographic progression over 5 years in AS patients.