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.

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.

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.