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.

Use of Quantitative Vertebral Bone Marrow Fat Fraction to Assess Disease Activity and Chronicity in Patients with Ankylosing Spondylitis.

OBJECTIVE: We quantitatively measured the fat fraction (FF) in the vertebrae of patients with ankylosing spondylitis (AS) using magnetic resonance imaging (MRI) and investigated the role of FF as an indicator of both active inflammation and chronicity. MATERIALS AND METHODS: A total of 52 patients with AS who underwent spinal MRI were retrospectively evaluated. The FF values of the anterosuperior and anteroinferior corners of the bone marrow in the L1-S1 spine were assessed using the modified Dixon technique. AS activity was measured using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), AS Disease Activity Score (ASDAS), and serum inflammatory marker levels. AS disease chronicity was assessed by AS disease duration and the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). Univariable and multivariable regression analyses were conducted to investigate the correlation between FF and other clinical characteristics. RESULTS: The mean FF ± standard deviation of the total lumbar spine was 43.0% ± 11.3%. At univariable analysis, spinal FF showed significant negative correlation with BASDAI (ß = -0.474, p = 0.002) and ASDAS with C-reactive protein (ASDAS-CRP; ß = -0.478, p = 0.002) and a significant positive correlation with AS disease duration (ß = 0.440, p = 0.001). After adjusting for patient age, sex, and total mSASSS score, spinal FF remained significantly negatively correlated with BASDAI (ß = -0.543, p < 0.001), ASDAS-CRP (ß = -0.568, p < 0.001), and ASDAS with erythrocyte sedimentation rate (ß = -0.533, p = 0.001). Spinal FF was significantly lower in patients with very high disease activity (ASDAS-CRP > 3.5) than in those with only high disease activity (2.1 ≤ ASDAS-CRP ≤ 3.5) (p = 0.010). CONCLUSION: Spinal FF may help assess both AS disease activity and chronicity.

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.

Bone morphogenetic protein 6 polymorphisms are associated with radiographic progression in ankylosing spondylitis.

BACKGROUND AND OBJECT: Nearly 25 genetic loci associated with susceptibility to ankylosing spondylitis (AS) have been identified by several large studies. However, there have been limited studies to identify the genes associated with radiographic severity of the disease. Thus we investigated which genes involved in bone formation pathways might be associated with radiographic severity in AS. METHODS: A total of 417 Korean AS patients were classified into two groups based on the radiographic severity as defined by the modified Stoke' Ankylosing Spondylitis Spinal Score (mSASSS) system. Severe AS was defined by the presence of syndesmophytes and/or fusion in the lumbar or cervical spine (n = 195). Mild AS was defined by the absence of any syndesmophyte or fusion (n = 170). A total of 251 single nucleotide polymorphisms (SNPs) within 52 genes related to bone formation were selected and genotyped. Odds ratios (OR) and 95% confidence interval (95% CI) were analysed by multivariate logistic regression controlling for age at onset of symptoms, sex, disease duration, and smoking status as covariates. RESULTS: We identified new loci of bone morphogenetic protein 6 (BMP6) associated with radiographic severity in patients with AS that passed false discovery rate threshold. Two SNPs in BMP6 were significantly associated with radiologic severity [rs270378 (OR 1.97, p = 6.74 × 10(-4)) and rs1235192 [OR 1.92, p = 1.17 × 10(-3)]) adjusted by covariates. CONCLUSION: This is the first study to demonstrate that BMP6 is associated with radiographic severity in AS, supporting the role wingless-type like/BMP pathway on radiographic progression in AS.

Growing heterotopic calcification in the prevertebral space of a cervical spine as a late complication of irradiation: case report.

Heterotopic calcification following head and neck irradiation has rarely been reported. It usually develops as a late complication of radiotherapy in patients with malignancies, including breast cancer, lymphoma, and genitourinary malignancies. The occurrence of heterotopic calcification in the prevertebral space of the cervical spine has not been described as a late complication of irradiation. Here, we report a case of prevertebral heterotopic calcification in a patient with history of chemotherapy and radiotherapy for tonsil cancer 21 years ago.

Intraarticular osteochondroma of shoulder: a case report.

Osteochondroma is a cartilage-capped osseous protrusion that arises from the surface of a bone. Osteochondroma occurs mostly in the metaphysis of long tubular bones such as the femur, tibia, and humerus. Osteochondroma is rare in the diaphysis and in the epiphysis. There was only one case in which a patient had a limited range of motion in the shoulder joint due to an intraarticular osteochondroma of the proximal humerus. We present a rare case of intraarticular osteochondroma involving the proximal humerus with pathologic findings and imaging features on computed tomography and magnetic resonance imaging.

Arachnoid ossificans of thoracolumbosacral spine in the advanced ankylosing spondylitis: a case report.

Arachnoid ossificans is a rare type of chronic arachnoiditis characterised by the presence of calcification or ossification of the dura and arachnoid. There are a few reports of these findings in relation to various disease entities, but only one case has been reported in relation to ankylosing spondylitis. We describe a 76-year-old man of ankylosing spondylitis with arachnoiditis ossificans, who has suffered from low back pain and neuropathic leg pain.

A case of atypical fibroxanthoma of subungual type: ultrasound and magnetic resonance imaging findings.

Subungual atypical fibroxanthoma is a rare mesenchymal skin tumor of intermediate malignancy. It classically presents as a relatively nondescript, erythematous nodule; it may ulcerate and bleed, but pain and pruritus are uncommon. In the differential diagnoses of subungual tumors, glomus tumor, soft tissue chondroma, keratoacanthoma, hemangioma, lobular capillary hemangioma, epidermal and mucoid cysts, squamous cell carcinoma, and malignant melanoma have been suggested. But atypical fibroxanthoma has not been included in the differential diagnoses. We report a case that occurred in a 56-year-old man with subungual atypical fibroxanthoma mimicking malignant soft tissue tumor in the right fifth toe.

Prevalence and risk factors of anterior atlantoaxial subluxation in ankylosing spondylitis.

OBJECTIVE: In ankylosing spondylitis (AS), the cervical spine, like other sections of the spine and sacroiliac joints, is vulnerable during the disease process. Atlantoaxial subluxation (AAS) has been studied in connection with AS, but its risk factors and progression have not been clarified. Therefore, this study assessed the prevalence and risk factors of AAS in patients with AS. METHODS: A total of 819 patients with AS who fulfilled the modified New York criteria and were examined with a full-flexion lateral view of the cervical spine by radiograph were enrolled from an outpatient clinic. The medical records of the patients were retrospectively reviewed and the anterior atlantodental interval (AADI) in the lateral flexion view of the cervical spine radiograph was investigated by 2 experienced musculoskeletal radiologists. We defined the AAS as an AADI of > 3 mm, and progression of AADI as a progression rate > 0.5 mm/year. RESULTS: AAS was found in 14.1% (116/819) of patients. Progression of AADI occurred in 32.1% (26/81) patients with AAS and 5.0% (16/320) patients without AAS (p < 0.001). The development of AAS was significantly associated with elevated C-reactive protein [CRP; OR 2.19 (1.36-3.53)], peripheral arthritis [OR 2.05 (1.36-3.07)], use of anti-tumor necrosis factor antagonists because of failure of nonsteroidal antiinflammatory drugs/disease-modifying antirheumatic drugs [NSAID/DMARD; OR 2.28 (1.52-3.42)], and uveitis [OR 1.71 (1.13-2.59)]. These factors were adjusted for age, sex, and disease duration by logistic regression analysis. No clear association was found for HLA-B27, seropositivity, or smoking status with AAS. CONCLUSION: AAS is a frequent complication, and the progression of AADI was more rapid in cases with AAS. The presence of peripheral arthritis, or high disease activity with elevated CRP level or refractory to conventional NSAID/DMARD, independently increased the risk of AAS, suggesting that clinicians should focus on the detection and monitoring of AAS, especially in cases with associated risk factors.

Early-onset childhood sarcoidosis with incidental multiple enchondromatosis.

The triad of rash, arthritis, and uveitis seems to be characteristic for early-onset childhood sarcoidosis. We describe an interesting case of early-onset childhood sarcoidosis coexisting enchondromatosis, which clinically masquerade as Langerhans cell histiocytosis. A 33 months old girl presented with skin rash, subcutaneous nodules with polyarthritis, and revealed the involvement of lymph nodes as well as spleen during work-up. She also presented with multiple osteolytic lesions which pathologically proven enchondromatosis. Oral prednisone was prescribed at 2 mg/kg/day for 2 months until when subcutaneous nodules and joint swellings almost disappeared, and then slowly tapered over a period of 5 months. We report an unusual case of early-onset childhood sarcoidosis presented with osteolytic bone lesions which were irrelevant to sarcoidosis.

Acute retropharyngeal calcific tendinitis in an unusual location: a case report in a patient with rheumatoid arthritis and atlantoaxial subluxation.

Retropharyngeal calcific tendinitis is defined as inflammation of the longus colli muscle and is caused by the deposition of calcium hydroxyapatite crystals, which usually involves the superior oblique fibers of the longus colli muscle from C1-3. Diagnosis is usually made by detecting amorphous calcification and prevertebral soft tissue swelling on radiograph, CT or MRI. In this report, we introduce a case of this disease which was misdiagnosed as a retropharyngeal tuberculous abscess, or a muscle strain of the ongus colli muscle. No calcifications were visible along the vertical fibers of the longus colli muscle. The lesion was located anterior to the C4-5 disc, in a rheumatoid arthritis patient with atlantoaxial subluxation. Calcific tendinitis of the longus colli muscle at this location in a rheumatoid arthritis patient has not been reported in the English literature.

Tuberculous pleural effusion: new pulmonary lesions during treatment.

PURPOSE: To evaluate patients who have a paradoxical response (development of new opacities) to treatment for tuberculous pleural effusion not related to acquired immunodeficiency syndrome. MATERIALS AND METHODS: In 16 patients, follow-up chest radiographs (n = 16) and initial (n = 2) and follow-up (n = 9) computed tomographic (CT) scans of the chest were retrospectively reviewed by two radiologists. Patient records (n = 16) and results of percutaneous needle aspiration and/or biopsy (n = 6) were reviewed by one radiologist. RESULTS: Eighteen episodes of new lesion development were identified on radiographs in 16 patients. Each episode showed single (nine of 18 episodes, 50%) or multiple (nine of 18 episodes, 50%) nodules, most of which were in the peripheral lung (16 of 18 episodes, 89%) ipsilateral to the side of previous effusion (17 of 18 episodes, 94%). On CT scans, all lesions were peripheral pulmonary nodules, not round atelectasis. Needle aspiration and/or biopsy of the lesions showed findings consistent with tuberculosis in all six patients. Lesions usually evolved within 3 months after the start of medication (13 of 18 episodes) and finally disappeared (15 episodes) or left residual opacities (three episodes) 3-18 months later, with continuation of medication. CONCLUSION: New lung lesions that develop during medication for tuberculous pleural effusion should be considered a transient worsening that ultimately improves with continuation of medication.