Biomarkers in the Pathogenesis, Diagnosis, and Treatment of Systemic Sclerosis.

Systemic sclerosis (SSc) is a complex autoimmune disease characterized by vascular damage, vasoinstability, and decreased perfusion with ischemia, inflammation, and exuberant fibrosis of the skin and internal organs. Biomarkers are analytic indicators of the biological and disease processes within an individual that can be accurately and reproducibly measured. The field of biomarkers in SSc is complex as recent studies have implicated at least 240 pathways and dysregulated proteins in SSc pathogenesis. Anti-nuclear antibodies (ANA) are classical biomarkers with well-described clinical classifications and are present in more than 90% of SSc patients and include anti-centromere, anti-Th/To, anti-RNA polymerase III, and anti-topoisomerase I antibodies. Transforming growth factor-ß (TGF-ß) is central to the fibrotic process of SSc and is intimately intertwined with other biomarkers. Tyrosine kinases, interferon-1 signaling, IL-6 signaling, endogenous thrombin, peroxisome proliferator-activated receptors (PPARs), lysophosphatidic acid receptors, and amino acid metabolites are new biomarkers with the potential for developing new therapeutic agents. Other biomarkers implicated in SSc-ILD include signal transducer and activator of transcription 4 (STAT4), CD226 (DNAX accessory molecule 1), interferon regulatory factor 5 (IRF5), interleukin-1 receptor-associated kinase-1 (IRAK1), connective tissue growth factor (CTGF), pyrin domain containing 1 (NLRP1), T-cell surface glycoprotein zeta chain (CD3ζ) or CD247, the NLR family, SP-D (surfactant protein), KL-6, leucine-rich α2-glycoprotein-1 (LRG1), CCL19, genetic factors including DRB1 alleles, the interleukins (IL-1, IL-4, IL-6, IL-8, IL-10 IL-13, IL-16, IL-17, IL-18, IL-22, IL-32, and IL-35), the chemokines CCL (2,3,5,13,20,21,23), CXC (8,9,10,11,16), CX3CL1 (fractalkine), and GDF15. Adiponectin (an indicator of PPAR activation) and maresin 1 are reduced in SSc patients. A new trend has been the use of biomarker panels with combined complex multifactor analysis, machine learning, and artificial intelligence to determine disease activity and response to therapy. The present review is an update of the various biomarker molecules, pathways, and receptors involved in the pathology of SSc.

Machine learning and magnetic resonance imaging: Differentiating benign from malignant osseous tumors.

Radiomics and machine learning applied to the isolated cartilaginous bone lesion on magnetic resonance imaging (MRI) is increasingly useful to distinguish malignant versus benign bone lesions, to determine whether repetitive imaging over time, to determine dynamic expansion, or immediate excisional biopsy are indicated.

Ultrasound-based measures in carpal tunnel syndrome: What to measure?

Carpal tunnel syndrome (CTS) is the most common peripheral entrapment neuropathy and is caused by compression of the median nerve (MN) at the level of transverse carpal ligament of the volar wrist. Radiomics is an advanced semi-automated image analysis method that is utilized to identify characteristics in the MN that can detect CTS with considerable reproducibility.

Sonoelastography: A powerful technique in musculoskeletal imaging.

Sonoelastography is a powerful method available to observe the musculoskeletal system, and appears particularly valuable in detecting early tendinopathies, pursuing complaints of localized musculoskeletal pain, analyzing soft tissue masses, and research applications in musculoskeletal medicine.

Outcomes and Complications of Corticosteroid Injection of Rheumatoid Nodules.

Objective: Rheumatoid nodules (RN), a classic cutaneous extra-articular manifestation of rheumatoid arthritis, can often cause discomfort or cosmetic embarrassment. This research determined the effectiveness and complications of corticosteroid injection of the RN. Methods: Using a repeated measure design, 66 consecutive symptomatic RN were measured, underwent corticosteroid injection with 1 to 2mL of a 50:50 mixture of 1% lidocaine and triamcinolone acetonide (20-40mg), and then reassessed at four months for softening, reduction in size, and complications, including infection. Results: The mean age of our patient group was 53.3±10.6 years; 45 percent were Hispanic, 55 percent were non-Hispanic White, 100 percent were seropositive (rheumatoid factor and/or anti-CCP antibody), and 87.5 percent were female. Baseline mean RN diameter was 0.50±0.51cm and four months after injection was reduced to 0.29±0.33cm (decreased 42% or 0.21±0.57cm reduction, 95% CI: 0.46 <0.21< 0.37, p=0.013), 100 percent (66/66) were less painful, and 77 percent (51/66) were palpably softened. However, 70 percent (46/66) demonstrated cutaneous atrophy and/or hypopigmentation at four months, 53 percent (35/66) nodules recurred within 12 months, and 47 percent (31/66) nodules were eventually surgically removed. Limitations: Two (3%) of the larger RN (2.5cm on the olecranon and 2cm on the 2nd toe) became infected and failed antibiotic therapy, necessitating surgical excision for complete resolution. Conclusion: For short-term symptomatic relief, smaller RN can be safely injected with triamcinolone. Large symptomatic RN (≥2cm) are at greater risk of infection; thus, in these cases, lower corticosteroid doses or surgical excision may be preferred. In the long-term, effective systemic antirheumatic therapy with treat-to-target is the best approach.

Systemic sclerosis in Native Americans of the American Southwest.

OBJECTIVE: Many indigenous non-Caucasian populations, including Native Americans, have been reported to have higher rates, distinct clinical phenotypes, increased complications, and greater severity of systemic sclerosis (SSc). However, little is known of SSc specifically in Native Americans of the American Southwest. This study compared the clinical and serologic manifestations and outcomes of SSc in Native Americans and non-Native Americans (non-Natives) of this region. METHODS: This cross-sectional retrospective study included 137 SSc patients (109 [80%] were non-Native and 28 [20%] were Native Americans) followed over a mean of 11.5 ± 7.6 years. Participants were repetitively evaluated with medical history, physical examination, echocardiography, chest imaging, and serologic testing. Disease characteristics and outcomes were statistically compared between Native Americans and non-Native patients. RESULTS: The estimated prevalence of SSc in Native Americans was 40.0 cases/100 000 vs 17.1 cases/100 000 for non-Natives (odds ratio 2.34, 95% confidence interval [CI] 1.55-3.55, P < .001). The cohorts were similar in terms age, age of onset, limited vs diffuse cutaneous SSc, telangiectasias, gastroesophageal reflux disease, Raynaud phenomenon, serologies, interstitial lung disease, pulmonary arterial hypertension, scleroderma renal crisis, cancer prevalence, and overall mortality (all P > .05). However, for Native Americans, mortality specifically from fatal infections was 3.94-fold that of non-Natives (hazard ratio 6.88, 95% CI 1.37-34.64; P < .001). CONCLUSION: In Native Americans of the American Southwest, SSc is increased in prevalence but is phenotypically similar to SSc in non-Natives. However, mortality due specifically to infection is increased in Native Americans with SSc.

Systemic sclerosis manifestations and clinical outcomes in Hispanics/Latinos of the American Southwest.

Objective: Certain Hispanic/Latino (Hispanic) populations have been reported to have higher rates and severity of systemic sclerosis; however, little is known of systemic sclerosis in the American Southwest. This study compared manifestations of systemic sclerosis in Hispanics with non-Hispanics of New Mexico. Methods: This cross-sectional longitudinal study included 109 systemic sclerosis patients followed over a mean of 12.6 ± 8.9 years. Subjects were repetitively evaluated including physical examination, echocardiography, chest imaging, and serologic testing and observed for complications. Disease characteristics and long-term outcomes were statistically compared between self-identified Hispanic and non-Hispanic subjects. Results: A total of 73 (67%) systemic sclerosis subjects were Hispanic and 36 (33%) were non-Hispanic. The cohorts were similar in mean age, age of systemic sclerosis onset, limited versus diffuse cutaneous systemic sclerosis, telangiectases, gastroesophageal reflux disease, Raynaud's phenomenon, autoantibody profile, interstitial lung disease, pulmonary hypertension, scleroderma renal crisis, mortality, and comorbid malignancy (all p > 0.05). However, the standardized mortality ratio was increased in both cohorts relative to age-adjusted mortality: Hispanic: 2.08, confidence interval (1.94-2.24); non-Hispanic: 1.56, confidence interval (1.46-1.68). Furthermore, the standardized incidence ratio for malignancy was increased in both cohorts: Hispanic: 1.45, confidence interval (1.35-1.56); non-Hispanic: 1.24, confidence interval (1.16-1.34). The mean age of cancer diagnosis occurred at a significantly younger age in Hispanics (Hispanics: 53.1 ± 9.7 years; non-Hispanics 63.7 ± 7.9 years; 95% confidence interval: -19 ⩽ 10.6 ⩽ 2.2; p = 0.016). Conclusion: Systemic sclerosis phenotype, autoantibodies, complications, outcomes, malignancy rates, and mortality are generally similar between Hispanics and non-Hispanics with systemic sclerosis in the American Southwest. However, age-adjusted comorbid malignancy and mortality rates are significantly increased in both groups.

Statin-associated immune-mediated necrotizing myositis in Native Americans.

OBJECTIVES: Statin-associated immune-mediated necrotizing myopathy (IMNM) and idiopathic inflammatory myositis (IIM) are myopathies with overlapping features. This study compared the manifestations of IMNM to IIM in Native Americans. METHOD: Twenty-one Native American patients with inflammatory myopathy (IM) were characterized as to diabetes mellitus, hyperlipidaemia, statin exposure, myopathy diagnosis, muscle histology, autoimmune and myositis-specific autoantibodies, therapy and outcome. RESULTS: IM consisted of 52.4% IMNM, 42.9% IIM and 4.8% metabolic myopathy. IMNM vs IIM patients were older [61.6 years (s.d. 9.8) vs 39.8 (14.3)], diabetes mellitus (100% vs 55.6%), hyperlipidaemia (100% vs 33.3%), statin-exposure (100% vs 22.2%), creatine kinase [CK; 11 780 IU (s.d. 7064) vs 1707 (1658)], anti-3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGCR) antibodies (85.7% vs 11.1%) and necrotizing IM (81.8% vs 11.1%), but shorter disease duration [26.2 months (s.d. 395) vs 78.4 (47.9)], RP (9.1% vs 55.6%), cutaneous manifestations (0% vs 55.6%), ANA (18.2% vs 66.7%) or any autoantibody (18.2% vs 88.9%) (all P < 0.05). MRI abnormalities, histologic IM, myositis-specific autoantibodies, pulmonary hypertension, oesophageal dysfunction, interstitial lung disease, disability and persistently elevated CK were similar. IMNM vs IIM was treated more with IVIG (72.7% vs 11.1%; P = 0.009) and less with antimetabolites (45.5% vs 88.9%; P = 0.05) and rituximab (18.2% vs 55.6%; P = 0.09). CONCLUSIONS: IMNM may occur in Native Americans and is associated with diabetes mellitus, hyperlipidaemia, statin use and older age and is characterized by marked CK elevation, necrotizing myopathy and anti-HMGCR antibodies with few cutaneous or vascular manifestations.

Intraarticular injection of the interphalangeal joint for therapy of digital mucoid cysts.

Mucoid cysts are associated with osteoarthritis (OA) of the digital joints and frequently recur after needle drainage, injection, or surgical ablation. This study determined whether intraarticular injection of the adjacent interphalangeal joint rather than the cyst itself might be effective in resolving digital mucoid cysts. Using paired case series design and sterile technique, 25 consecutive OA digital joints with an adjacent mucoid cyst underwent dorsal non-transtendinous intraarticular injection with a 25-gauge needle and 20-mg triamcinolone acetonide, followed by puncture and manual expression of cyst fluid. Patient pain was measured with the 10-cm Visual Analogue Pain Scale prior to the procedure and at 6 months. Cyst resolution was determined at 6 months and 3 years. The subjects were 61.0 ± 7.7 years old and 60% (15/25) female. Mucoid cysts were adjacent to 19 distal interphalangeal, 3 metacarpophalangeal, and 3 interphalangeal joints. Pre-procedural pain was 4.7 ± 1.0; procedural pain was 6.2 ± 0.6 cm, and post-procedural pain at 6 months was 1.2 ± 0.8 cm (74.5% reduction, 95% CI of difference: 3.0 < 3.5 < 4.0 (p < 0.0001)). 84% (21/25) of the cysts resolved at 6 months; however, 60% (15/25) of the mucoid cysts recurred within 3 years and required retreatment (14 adjacent joints re-injected and 1 ablative cyst surgery). No complications were noted. Intraarticular corticosteroid injection using a dorsal non-transtendinous approach of the joint adjacent to a mucoid cyst is effective resolving cysts and reducing pain at 6 months; however, 60% of mucoid cysts reoccur within 3 years and may require reinjection or surgery.Trial registration: This was not a clinical trial.

Enhanced arthrocentesis of the effusive knee with pneumatic compression.

AIM: Complete arthrocentesis of the effusive knee ameliorates patient pain, reduces intra-articular and intraosseous pressure, removes inflammatory cytokines, and has been shown to substantially improve the therapeutic outcomes of intra-articular injections. However, conventional arthrocentesis incompletely decompresses the knee, leaving considerable residual synovial fluid in the intra-articular space. The present study determined whether external pneumatic circumferential compression of the effusive knee permitted more successful arthrocentesis and complete joint decompression. METHODS: Using a paired sample design, 50 consecutive effusive knees underwent conventional arthrocentesis and then arthrocentesis with pneumatic compression. Pneumatic compression was applied to the superior knee using a conventional thigh blood pressure cuff inflated to 100 mm Hg which compressed the suprapatellar bursa and patellofemoral joint, forcing fluid from the superior knee to the anterolateral portal where the fluid could be accessed. Arthrocentesis success and fluid yield in mL before and after pneumatic compression were determined. RESULTS: Successful diagnostic arthrocentesis (≥3 mL) of the effusive knee was 82% (41/50) with conventional arthrocentesis and increased to 100% (50/50) with pneumatic compression (P = .001). Synovial fluid yields increased by 144% (19.8 ± 17.1 mL) with pneumatic compression (conventional arthrocentesis; 13.7 ± 16.4 mL, pneumatic compression: 33.4 ± 26.5 mL; 95% CI: 10.9 < 19.7 < 28.9 mL, P < .0001). CONCLUSIONS: Conventional arthrocentesis routinely does not fully decompress the effusive knee. External circumferential pneumatic compression markedly improves arthrocentesis success and fluid yield, and permits complete decompression of the effusive knee. Pneumatic compression of the effusive knee with a thigh blood pressure cuff is an inexpensive and widely available technique to improve arthrocentesis outcomes.

Libman-Sacks endocarditis and associated cerebrovascular disease: The role of medical therapy.

BACKGROUND: Libman-Sacks endocarditis in patients with systemic lupus erythematosus (SLE) is commonly complicated with embolic cerebrovascular disease (CVD) or valve dysfunction for which high-risk valve surgery is frequently performed. However, the role of medical therapy alone for Libman-Sacks endocarditis and associated acute CVD remains undefined. OBJECTIVE: To determine in this cross-sectional and longitudinal study if conventional anti-inflammatory and anti-thrombotic therapy may be an effective therapy in SLE patients with Libman-Sacks endocarditis and associated acute CVD. METHODS AND MATERIALS: 17 SLE patients with Libman-Sacks endocarditis detected by two-and-three-dimensional transesophageal echocardiography (TEE) and complicated with acute CVD [stroke/TIA, focal brain injury on MRI, or cognitive dysfunction] were treated with conventional anti-inflammatory and anti-thrombotic therapy for a median of 6 months and then underwent repeat TEE, transcranial Doppler, brain MRI, and neurocognitive testing for re-assessment of Libman-Sacks endocarditis and CVD. RESULTS: Valve vegetations decreased in number, diameter, and area (all p ≤0.01); associated valve regurgitation significantly improved (p = 0.04), and valve thickening did not progress (p = 0.56). In 13 (76%) patients, valve vegetations or valve regurgitation resolved or improved in number and size or by ≥1 degree, respectively, as compared to 4 (24%) patients in whom vegetations or valve regurgitation persisted unchanged or increased in size or by ≥1 degree (p = 0.03). Also, cerebromicroembolism, lobar and global gray and white matter cerebral perfusion, ischemic brain lesion load, and neurocognitive dysfunction resolved or significantly improved (all p ≤0.04). CONCLUSION: These preliminary data suggest that combined conventional anti-inflammatory and antithrombotic therapy may be an effective treatment for Libman-Sacks endocarditis and its associated CVD and may obviate the need for high-risk valve surgery.

Aortic adventitial thickness as a marker of aortic atherosclerosis, vascular stiffness, and vessel remodeling in systemic lupus erythematosus.

INTRODUCTION: There is limited human imaging data on the association of adventitial thickness (AT) with arterial disease. Systemic lupus erythematosus (SLE) is a prototypical disease model for studying markers of premature arterial disease. OBJECTIVE: To determine if increased aortic AT is associated with aortic atherosclerosis [increased intima media thickness (IMT) or plaques], stiffness [increased pressure-strain elastic modulus (PSEM)], and vessel remodeling. METHODS: In total, 70 SLE patients and 26 age- and sex-matched controls underwent transesophageal echocardiography (TEE). Two-dimensional guided M-mode images were obtained to assess AT, IMT, and plaques, and PSEM at the proximal, mid, and distal thoracic aorta. Images were interpreted by 3 observers unaware of the subjects' clinical data and each other's measurements. Abnormal aortic AT, IMT, and PSEM were defined as > 2SD above the overall mean values in controls and corresponded to > 1 mm, > 1 mm, and > 10.6 Pascal units, respectively. Plaques were defined as focal-protruding IMT > 50% of the surrounding vessel wall. RESULTS: Abnormal aortic AT, atherosclerosis, and abnormal stiffness were more frequent in SLE patients than in controls (all p ≤ 0.02). In SLE patients, abnormal AT combined with atherosclerosis was associated with larger aortic end-diastolic diameters than in controls (p ≤ 0.05). In SLE patients, aortic AT was greater in patients with atherosclerosis and in those with abnormal stiffness than in patients without these abnormalities (all p ≤ 0.02). In patients with abnormal AT, the degree of aortic stiffness was similar to those with atherosclerosis (p = 0.22). CONCLUSION: In patients with SLE, increased aortic AT is associated with aortic atherosclerosis, abnormal stiffness, and eccentric vessel remodeling. Key Points • In patients with SLE, abnormal aortic adventitial thickness is associated with aortic atherosclerosis, abnormal stiffness, and eccentric vessel remodeling. • In patients with SLE, aortic adventitial thickening may contribute to the extent of aortic atherosclerosis, abnormal aortic stiffness, and vessel remodeling. • To our knowledge, this is the first human imaging study to characterize the aortic adventitial layer and delineate its association with aortic disease.

Atypical Chronic Inflammatory ANCA-Positive Deforming Arthritis After Cocaine-Levamisole Exposure.

BACKGROUND/OBJECTIVE: Immunostimulatory drugs including immune checkpoint inhibitors and levamisole can induce inflammatory disease including vasculitis, rashes, tissue necrosis, and arthritis. METHODS: This prospective cohort study determined the 5-year outcomes of cocaine-levamisole-induced inflammatory disease as to outcomes and survival. Thirty-one consecutive cocaine-levamisole autoimmune patients and 45 primary vasculitis patients were characterized as to clinical differentiating features, antineutrophil cytoplasmic antibody (ANCA) status, treatment, the presence of acute and chronic arthritis, and 5-year outcome. RESULTS: Seventy-one percent (22/31) of cocaine-levamisole vasculopathy cases were ANCA positive (86% p-ANCA and 14% c-ANCA), whereas 53% (23/45) of the primary vasculitis were ANCA positive (p = 0.04). The ANCA-positive cocaine-levamisole cohort at onset were characterized by younger age (45 ± 12 vs 53 ± 14 years, p = 0.04), superficial skin necrosis (82% vs 54%, p = 0.036), depressed complement C3 (27% vs 4%, p = 0.33), antiphospholipid antibodies (50% vs 4%, p < 0.001), neutropenia (18% vs 0%, p = 0.044), and elevated antimyeloperoxidase (MPO) antibody levels (100% vs 67%, p < 0.001). Chronic cocaine-levamisole disease was characterized by severe cicatrical deformities of the face and extremities (45.5% vs 8.3%, p = 0.005). Arthralgias (71% vs 82%, p = 0.19) and acute arthritis (33% vs 32%, p = 0.25) were similar between the 2 groups. However, a substantial proportion cocaine-levamisole-induced autoimmune patients (18% vs 0%, p = 0.045) developed a chronic deforming inflammatory arthritis that was rheumatoid factor, anti-cyclic-citrillinated antibody antibody, and HLA-B27 negative, but p-ANCA-and MPO antibody positive. CONCLUSIONS: Patients exposed to cocaine-levamisole may develop serious chronic sequelae including cicatrical cutaneous and facial deformities and an atypical seronegative, p-ANCA and MPO antibody-positive, HLA-B27-negative chronic deforming inflammatory arthritis.