To develop and evaluate a Localized Scleroderma (LS) Skin Severity Index (LoSSI) and global assessments' clinimetric property and effect on quality of life (QOL).
A 3-phase study was conducted. The ...first phase involved 15 patients with LS and 14 examiners who assessed LoSSI surface area (SA), erythema (ER), skin thickness (ST), and new lesion/extension (N/E) twice for inter/intrarater reliability. Patient global assessment of disease severity (PtGA-S) and Children's Dermatology Life Quality Index (CDLQI) were collected for intrarater reliability evaluation. The second phase was aimed to develop clinical determinants for physician global assessment of disease activity (PhysGA-A) and to assess its content validity. The third phase involved 2 examiners assessing LoSSI and PhysGA-A on 27 patients. Effect of training on improving reliability/validity and sensitivity to change of the LoSSI and PhysGA-A was determined.
Interrater reliability was excellent for ER intraclass correlation coefficient (ICC) 0.71, ST (ICC 0.70), LoSSI (ICC 0.80), and PhysGA-A (ICC 0.90) but poor for SA (ICC 0.35); thus, LoSSI was modified to mLoSSI. Examiners' experience did not affect the scores, but training/practice improved reliability. Intrarater reliability was excellent for ER, ST, and LoSSI (Spearman's rho = 0.71-0.89) and moderate for SA. PtGA-S and CDLQI showed good intrarater agreement (ICC 0.63 and 0.80). mLoSSI correlated moderately with PhysGA-A and PtGA-S. Both mLoSSI and PhysGA-A were sensitive to change following therapy.
mLoSSI and PhysGA-A are reliable and valid tools for assessing LS disease severity and show high sensitivity to detect change over time. These tools are feasible for use in routine clinical practice. They should be considered for inclusion in a core set of LS outcome measures for clinical trials.
T cells are considered autoimmune effectors in juvenile idiopathic arthritis (JIA), but the antigenic cause of arthritis remains elusive. Since T cells comprise a significant proportion of ...joint-infiltrating cells, we examined whether the environment in the joint could be shaped through the inflammatory activation by T cells that is independent of conventional TCR signaling. We focused on the analysis of synovial fluid (SF) collected from children with oligoarticular and rheumatoid factor-negative polyarticular JIA. Cytokine profiling of SF showed dominance of five molecules including IL-17A. Cytometric analysis of the same SF samples showed enrichment of αβT cells that lacked both CD4 and CD8 co-receptors herein called double negative (DN) T cells and also lacked the CD28 costimulatory receptor. However, these synovial αβT cells expressed high levels of CD31, an adhesion molecule that is normally employed by granulocytes when they transit to sites of injury. In receptor crosslinking assays, ligation of CD31 alone on synovial CD28
CD31
DN αβT cells effectively and sufficiently induced phosphorylation of signaling substrates and increased intracytoplasmic stores of cytokines including IL-17A. CD31 ligation was also sufficient to induce RORγT expression and
-activation of the
promoter. In addition to T cells, SF contained fibrocyte-like cells (FLC) expressing IL-17 receptor A (IL-17RA) and CD38, a known ligand for CD31. Stimulation of FLC with IL-17A led to CD38 upregulation, and to production of cytokines and tissue-destructive molecules. Addition of an oxidoreductase analog to the bioassays suppressed the CD31-driven IL-17A production by T cells. It also suppressed the downstream IL-17A-mediated production of effectors by FLC. The levels of suppression of FLC effector activities by the oxidoreductase analog were comparable to those seen with corticosteroid and/or biologic inhibitors to IL-6 and TNFα. Collectively, our data suggest that activation of a CD31-driven, αβTCR-independent, IL-17A-mediated T cell-FLC inflammatory circuit drives and/or perpetuates synovitis. With the notable finding that the oxidoreductase mimic suppresses the effector activities of synovial CD31
CD28
αβT cells and IL-17RA
CD38
FLC, this small molecule could be used to probe further the intricacies of this inflammatory circuit. Such bioactivities of this small molecule also provide rationale for new translational avenue(s) to potentially modulate JIA synovitis.
Bilateral agenesis of the cruciate ligaments is a rare congenital anomaly. We report a unique case of a young girl who had congenital short femur and diagnosed with polyarticular juvenile idiopathic ...arthritis (JIA) and later discovered to have congenital absence of both anterior and posterior cruciate ligaments and meniscal dysplasia in both the knees when MRI was performed at 11 years of age. The MRI was performed to evaluate knee laxity and persistent symptoms despite medical management and multiple steroid injections for arthritis treatment. This patient is one of the youngest with congenital absence of both the cruciate ligaments to be treated with ACL reconstruction. We highlight the unique radiographic imaging manifestations of congenital cruciate ligament agenesis and emphasize the role of MRI to confirm and depict additional intraarticular abnormalities.
•Cruciate ligament agenesis is a rare entity, and can be associated with other congenital skeletal anomalies.•The condition can be overlooked prior to definitive characterization on MRI, dut its diverse clinical presentation.•Specific radiographic features may suggest the diagnosis of cruciate ligament agenesis.
Anti-cyclic citrullinated peptide (anti-CCP) antibodies have been found in sera of 76% of patients with rheumatoid arthritis (RA), mainly in rheumatoid factor (RF) positive patients, with a ...specificity of 96%. We evaluated the presence of anti-CCP antibodies in patients with juvenile idiopathic arthritis (JIA) and assessed the possibility of synthetic citrullinated peptides as antigenic determinants in JIA.
The presence of anti-CCP antibodies was determined using 3 synthetic citrullinated peptide variants and 2 commercial kits (Inova Diagnostics and Axis-Shield Diagnostics) optimized for detecting JIA-specific antibodies in serum by an ELISA based assay. We evaluated 66 patients with JIA (16 RF positive polyarthritis, 18 RF negative polyarthritis, 19 oligoarthritis, and 13 systemic arthritis). We also tested 9 adult RA patients, 34 patients with systemic lupus erythematosus (SLE), and 25 healthy persons as controls.
Significant concentrations of anti-CCP antibodies were detected in the majority of RF positive JIA patients with polyarthritis. Using the 2 synthetic linear peptides, 12/16 (75%) were positive; 9/12 (75%) were positive with the Inova kit and 9/10 (90%) were positive with the Axis-Shield kit. However, utilizing the synthetic linear peptides, significant concentrations of anti-CCP antibodies were detected in 51/66 (77%) JIA patients, including 15/18 (83%) RF negative polyarthritis, 16/19 (84%) oligoarthritis, and 8/13 (62%) systemic arthritis patients. No healthy control showed elevated antibody levels. In contrast, 4/9 (44%) patients with adult RA and 2/6 (33%) with SLE had elevated anti-CCP levels. The synthetic cyclic variant cfc-1-cyc yielded significant anti-CCP levels for 13/14 (93%) patients with RF negative polyarthritis, 6/10 (60%) with oligoarthritis, and 3/7 (43%) with systemic arthritis, and 8/9 (88%) RF positive patients. No healthy control had increased anti-CCP levels. However, 4/9 (44%) adult RA and 9/34 (26%) SLE patients were found to have elevated anti-CCP levels. Using the Inova and Axis-Shield kits, much smaller percentages were found in the RF negative patients, with only 4/16 (25%) in the oligoarthritis and RF negative polyarthritis patients with the Inova kits and 0/25 (0%) by the Axis-Shield kits. The Inova kit revealed elevated anti-CCP antibodies in 5/9 (56%) adult RA patients and in 8/34 (24%) SLE patients. No healthy control had elevated anti-CCP antibodies. However, the Axis-Shield kits did not detect anti-CCP antibodies in adult RA (0/9) or SLE (0/34) patients. Moreover, 0/25 (0%) healthy individuals exhibited anti-CCP levels. The presence of anti-CCP antibodies correlated more frequently with the presence of RF.
This study confirms the presence of anti-CCP antibodies in patients with JIA, especially those with RF positive polyarthritis, by all ELISA based methods. Use of synthetic peptides also revealed anti-CCP antibodies in a percentage of RF negative patients with polyarthritis, oligoarthritis, and systemic arthritis; there was a loss in specificity, but an increase in sensitivity. These results suggest that antibodies to these antigenic peptides may be markers for JIA, and indicate a possible role of citrulline-containing epitopes in the pathogenesis of JIA.
A 14-year-old African American girl presented with diminished vision in both eyes 1 week after undergoing an oophorectomy for a right ovarian mass. Systemic metastatic work-up was negative. Visual ...acuity was 20/40 in the right eye and 20/50 in the left eye. Slit-lamp biomicroscopy was unremarkable in both eyes. Fundus examination showed diffuse patchy areas of retinal pigment epithelial atrophy in the macula and peripheral retina bilaterally. Color vision had decreased in each eye. Electroretinography revealed nondetectable rod and cone responses. Both pattern and flash visual evoked potential (VEP) testing showed delayed latency in both eyes. She was treated with pulse intravenous methylprednisolone for 3 days along with intravenous immunoglobulins and rituximab, followed by systemic prednisolone and biweekly intravenous immunoglobulins and rituximab for 3 months. Antiretinal autoantibodies against 48-kDa (arrestin) and 64-kDa and 94-kDa proteins were positive, suggestive of carcinoma-associated retinopathy. After 3 months, visual acuity was 20/40 in each eye with improvement in color vision and VEP findings.
Objective
To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti–tumor necrosis factor (anti‐TNF) therapy and the ...occurrence of disease flare following withdrawal of anti‐TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA).
Methods
In this prospective, multicenter study, 137 patients with polyarticular‐course JIA whose disease was clinically inactive while receiving anti‐TNF therapy were enrolled. Patients were observed for an initial 6‐month phase during which anti‐TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti‐TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti‐TNF withdrawal. Spearman's rank correlation test, Mann‐Whitney U test, Kruskal‐Wallis test, receiver operating characteristic (ROC) curve, and Kaplan‐Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti‐TNF withdrawal.
Results
Over the 6‐month initial phase with anti‐TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular‐course JIA; following anti‐TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti‐TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti‐TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti‐TNF withdrawal were inversely correlated with the time to disease flare (r = −0.36).
Conclusion
Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular‐course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.
Objective
To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti–tumor necrosis factor (anti‐TNF) therapy in children with polyarticular forms of juvenile ...idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease.
Methods
In 16 centers 137 patients with clinically inactive JIA who were receiving anti‐TNF therapy (42% of whom were also receiving methotrexate MTX) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti‐TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life‐table analysis, t‐tests, chi‐square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare.
Results
Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti‐TNF therapy for the initial 6 months and were included in the phase of the study in which anti‐TNF therapy was stopped. Stopping anti‐TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05).
Conclusion
Over one‐third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti‐TNF therapy. Several predictors of lower likelihood of flare were identified.
Biologics treatment with antitumour necrosis factor alpha (TNFα) is efficacious in patients with juvenile idiopathic arthritis (JIA). Despite displaying clinical inactivity during treatment, many ...patients will flare on cessation of therapy. The inability to definitively discriminate patients who will relapse or continue to remain in remission after therapy withdrawal is currently a major unmet medical need. CD4 T cells have been implicated in active disease, yet how they contribute to disease persistence despite treatment is unknown.
We interrogated the circulatory reservoir of CD4
immune subsets at the single-cell resolution with mass cytometry (cytometry by time of flight) of patients with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission. These patients were examined prior to therapy withdrawal for putative subsets that could discriminate relapse from remission. We verified on a separate JIA cohort (n=16) the dysregulation of these circulatory subsets 8 months into therapy withdrawal. The immunological transcriptomic signature of CD4 memory in relapse/remission patients was examined with NanoString.
An inflammatory memory subset of CD3
CD4
CD45RA
TNFα
T cells deficient in immune checkpoints (PD1
CD152
) was present in relapse patients prior to therapy withdrawal. Transcriptomic profiling reveals divergence between relapse and remission patients in disease-centric pathways involving (1) T-cell receptor activation, (2) apoptosis, (3) TNFα, (4) nuclear factor-kappa B and (5) mitogen-activated protein kinase signalling.
A unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs.
Abstract
We reported previously that children with JIA carry senescent CD31+CD8+ T cells disproportionate with age. Such cells are inflammatory effectors via CD31-driven TCR-independent activation ...pathway. Here, we hypothesized that these T cells interact with non-hematopoietic cells in the synovial space to perpetuate joint inflammation. JIA patients medically indicated to undergo arthrocentesis were recruited. Synovial aspirates were screened by flow cytometry, and short-term cultures were established. Results showed two subsets of plastic-adherent fibrocyte-like cells (FLC). About 75% were procollagen-CD45-CD14- cells that variably expressed CD34. The other ~25% were procollagen+CD45+CD14+IL17RA+ CD34- FLC; a finding unlike similar cells reported for adult-onset rheumatoid arthritis. FLC exposed to rIL-17 and/or rTNFα induced production of MMPs that were reversed with corticosteroid, TNFi, anti-IL6R, or experimental NFkB inhibitors. Co-culture of FLC with autologous CD8 T cells resulted in production of the same array of MMPs and inflammatory cytokines that were partially blocked by neutralizing anti-CD31 antibody. These results suggest a FLC-CD8 T cell communication circuit in the maintenance of joint inflammation in JIA. Further understanding of the regulation and/or the consequences of this local cell-cell interaction could shed light into the systemic complications of this childhood disease that impose lifelong health burden. Supported by Nancy E Taylor Foundation and NIH.
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