Novel classification of axial spondyloarthritis to predict radiographic progression using machine learning.

OBJECTIVES: Prediction and determination of drug efficacy for radiographic progression is limited by the heterogeneity inherent in axial spondyloarthritis (axSpA). We investigated whether unbiased clustering analysis of phenotypic data can lead to coherent subgroups of axSpA patients with a distinct risk of radiographic progression. METHODS: A group of 412 patients with axSpA was clustered in an unbiased way using a agglomerative hierarchical clustering method, based on their phenotype mapping. We used a generalised linear model, naïve Bayes, Decision Trees, K-Nearest-Neighbors, and Support Vector Machines to construct a consensus classification method. Radiographic progression over 2 years was assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). RESULTS: axSpA patients were classified into three distinct subgroups with distinct clinical characteristics. Sex, smoking, HLA-B27, baseline mSASSS, uveitis, and peripheral arthritis were the key features that were found to stratifying the phenogroups. The three phenogroups showed distinct differences in radiographic progression rate (p<0.05) and the proportion of progressors (p<0.001). Phenogroup 2, consisting of male smokers, had the worst radiographic progression, while phenogroup 3, exclusively suffering from uveitis, showed the least radiographic progression. The axSpA phenogroup classification, including its ability to stratify risk, was successfully replicated in an independent validation group. CONCLUSIONS: Phenotype mapping results in a clinically relevant classification of axSpA that is applicable for risk stratification. Novel coupling between phenotypic features and radiographic progression can provide a glimpse into the mechanisms underlying divergent and shared features of axSpA.

Elevated levels of soluble CD40 ligand are associated with antiphospholipid antibodies in patients with systemic lupus erythematosus.

OBJECTIVES: The CD40L/CD40 pathway is involved in the pathophysiology of atherothrombotic disease, and elevated levels of soluble CD40L (sCD40L) were reported in SLE patients. However, the clinical implication of sCD40L in SLE remains elusive. METHODS: We measured levels of plasma sCD40L in 241 SLE patients and 37 healthy controls and investigated its association with clinical manifestation and laboratory parameters. RESULTS: Levels of plasma sCD40L in SLE patients were significantly elevated compared with healthy controls (p=0.013) and positively correlated with levels of soluble P-selectin (γ=0.336, p<0.001). SLE patients who experienced arterial thrombosis had a higher level of sCD40L than those who did not (p=0.029). Plasma sCD40L levels were positively correlated with the titers of anti-cardiolipin and anti-ß2 glycoprotein I antibodies (γ=0.338, p<0.001 and γ=0.364, p<0.001, respectively). Its levels were also significantly higher in patients with clinical antiphospholipid syndrome (APS) than in non-APS patients, irrespective of antiphospholipid antibody (aPL) positivity. Of those with arterial thrombosis, sCD40L levels were significantly elevated in patients with positive aPL, compared to those with negative aPL (p=0.011). Multiple regression analysis revealed that the presence of hypertension and positive aPL were independently associated with the occurrence of arterial thrombosis in SLE patients. A parallel analysis showed that sCD40L was also an independent variable for arterial thrombosis; however, this association disappeared when aPL, a strong variable, was included in the model because of collinearity between aPL and sCD40L. CONCLUSIONS: Plasma sCD40L levels were elevated in SLE patients who had positive aPL and experienced arterial thrombosis, suggesting that enhanced release of sCD40L through platelet activation presumably by aPL could contribute to the development of atherothrombotic disease.

A case of multicentric reticulohistiocytosis.

Multicentric reticulohistiocytosis (MRH) is a rare non-Langerhans histiocytosis of unknown etiology with a predilection for joint and skin. The characteristic clinical features are papulonodular skin eruptions and inflammatory polyarthritis, sometimes progressive to arthritis mutilans, a severe destructive arthropathy. Although these manifestations can present at the same time, it is more common that one feature precedes the others. Notably, these features are similar to those found in some rheumatic diseases, such as rheumatoid arthritis or dermatomyositis, and this can lead to a misdiagnosis, especially during periods where only one feature is present. Herein, we report a female patient with polyarthralgia and subsequent skin eruptions, who was eventually diagnosed with MRH. Her symptoms seemed to resemble those of some rheumatic diseases, but several features such as affected joints and the characteristic shape of the skin lesions did not correspond to that. The histological result of infiltration of histiocytes and multinucleated giant cells in the skin ultimately facilitated the correct diagnosis. In this paper, we review MRH briefly and highlight several differential points which enable us to increase the likelihood of correctly diagnosing MRH.

Association of Anemic Hypoxia and Increased Pulmonary Artery Systolic Pressure in Patients With Systemic Lupus Erythematosus.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is a rare but serious complication of systemic lupus erythematosus (SLE). Chronic hypoxia is known to cause PAH resulting from pulmonary vascular remodeling. We investigated the association between anemic hypoxia and PAH in SLE patients. METHODS: Systolic pulmonary artery pressure (PAP) was measured in 132 SLE patients by echocardiography. Increased PAP was defined as resting PAP > 40 mm Hg. Oxygen delivery (DO2) was estimated as the product of cardiac output and arterial oxygen content. RESULTS: Of 132 patients, 17 (12.9%) had increased PAP, and these patients had significantly lower DO2 values than patients with normal PAP (P = 0.002). The DO2 values inversely correlated with PAP values (γ = -0.308, P < 0.001) and plasma N-terminal pro-brain natriuretic peptide levels (γ = -0.323, P = 0.001), but positively correlated with hemoglobin levels (γ = 0.402, P < 0.001). Compared to those with normal PAP, patients with increased PAP had significantly longer durations of anemia over the preceding 6-24 months. Patients with anemia of longer durations (≥3 months) in the preceding 6 months had a higher risk of increased PAP compared to those with shorter durations (P < 0.001). When SLE patients were divided into 3 groups according to hemoglobin and PAP, serum interleukin-6 (IL-6) levels increased across groups with higher PAP (P = 0.001 for trend), but decreased across tertiles of hemoglobin levels (P = 0.008 for trend). CONCLUSION: Our data indicate an association between chronic anemic hypoxia and increased PAP in SLE patients and suggest that increased IL-6 might participate in this process.

Elevated serum levels of syndecan-1 are associated with renal involvement in patients with systemic lupus erythematosus.

OBJECTIVE: Syndecan-1 (SDC-1) is a major constituent of the endothelial glycocalyx, which plays a role in maintaining vascular homeostasis and functions as a glomerular filtration barrier. SDC-1 is readily shed into the blood under various conditions, but the clinical implication of circulating SDC-1 in patients with systemic lupus erythematosus (SLE) remains unclear. We aimed to investigate the association of serum SDC-1 level with certain clinical manifestations of SLE. METHODS: We measured serum SDC-1 levels by ELISA in 111 patients with SLE, 18 with rheumatoid arthritis (RA), and 20 healthy subjects, and investigated its association with clinical manifestations and laboratory variables. RESULTS: Serum SDC-1 levels were higher in patients with SLE than in those with RA and healthy controls (both p < 0.001) and were positively correlated with SLE Disease Activity Index (SLEDAI; r = 0.367, p < 0.001) and anti-dsDNA antibody level (r = 0.259, p = 0.007), but inversely correlated with serum C3 and CH50 levels (r = -0.305, p = 0.001 and r = -0.244, p = 0.012). Patients with active nephritis had higher serum SDC-1 levels than patients with inactive nephritis and those without nephritis (both p < 0.001). In addition, serum SDC-1 levels were correlated with renal SLEDAI score (r = 0.540, p < 0.001) and excretion of proteinuria as measured by spot urine protein/creatinine ratio (r = 0.538, p < 0.001). In 14 patients with lupus nephritis (LN) whose serum samples were obtained at the time of renal biopsy, there was a positive correlation between serum SDC-1 levels and activity index (r = 0.632, p = 0.015). CONCLUSION: Serum SDC-1 levels are increased in SLE patients with nephritis, indicating that SDC-1 might be a useful serum biomarker for active LN.

High levels of uric acid in systemic lupus erythematosus is associated with pulmonary hypertension.

AIM: To estimate the point prevalence of pulmonary hypertension (PH) and determine the associated factors for PH in patients with systemic lupus erythematosus (SLE). METHODS: A prospective cross-sectional study of 114 patients with SLE was conducted in a single tertiary center. Transthoracic echocardiography was performed to estimate the pulmonary arterial pressures. PH was defined as resting systolic pulmonary artery pressure (sPAP) ≥ 40 mmHg, in the absence of left heart disease. RESULTS: PH was identified in nine patients (7.9%) who had few cardiopulmonary symptoms. SLE patients with PH had higher SLE disease activity index score. In particular, serum uric acid (UA) was significantly higher in patients with PH than in those without PH. In multivariate analysis, UA remained significant for the presence of PH. Moreover, serum UA level correlated significantly with plasma NT-pro-B-type natriuretic peptide level as well as sPAP. At the cutoff level of 6.5 mg/dL, serum UA had reasonable accuracy for predicting the presence of PH in SLE patients (sensitivity 66.7% and specificity 96.2%). CONCLUSION: A significant number of SLE patients in rheumatology practice have undiagnosed PH with few discernible symptoms. Serum UA level may be useful as a surrogate marker for screening of PH in patients with SLE.

Successful treatment of protein-losing enteropathy due to AA amyloidosis with octreotide in a patient with rheumatoid arthritis.

Protein-losing enteropathy (PLE) is a rare syndrome of gastrointestinal protein loss that may complicate a variety of diseases. This excessive protein loss across the gut epithelium can be explained by several mechanisms, such as augmentation of the intestinal mucosal capillary permeability, mucosal disruption, intestinal or mesenteric vasculitis, and lymphangiectasia. However, these pathophysiologic alterations of the gut are closely linked to the underlying cause, and primary treatment for PLE should be directed at the underlying condition. Here, we report a female patient with rheumatoid arthritis who developed severe PLE due to AA amyloidosis and was successfully treated with octreotide. She had been suffered from rheumatoid arthritis for 18 years, and her arthritic symptoms at the time of presentation were not definite but manifested as severe diarrhea and general edema with hypoalbuminemia. PLE due to gastrointestinal amyloidosis was confirmed by increased fecal α1-antitrypsin clearance and a colonoscopic biopsy that was positive for amyloid deposits. The diarrhea dissipated with conventional treatment, but the general edema resolved only after introducing a long-acting somatostatin analog (octreotide), along with a gradual recovery of the serum albumin level. This case teaches us that in the case of PLE due to AA amyloidosis that is refractory to conventional treatment, the administration of octreotide should be considered.