Drug therapy in juvenile spondyloarthritis.

PURPOSE OF REVIEW: This review summarizes latest developments in treatment of juvenile spondyloarthritis (JSpA), specifically enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA). RECENT FINDINGS: There has been addition of biologic disease modifying antirheumatic drugs (bDMARDs) beyond tumor necrosis factor inhibitors (TNFi) for JSpA such as IL-17 blockers, IL-23 blockers, and janus activating kinase inhibitors with favorable safety profile. Conducting robust clinical trials for this subpopulation of JIA remains a challenge; extrapolation studies are being used to obtain approval from regulatory agencies. SUMMARY: Newer drug therapies have expanded the scope of treatment for patients with JSpA. bDMARDs such as adalimumab, etanercept, infliximab, and secukinumab have demonstrated clinically significant treatment efficacy in ERA and JPsA. Based on extrapolation studies, intravenous golimumab, etanercept, abatacept, and ustekinumab have gained Food and Drug Administration (FDA) approval for JPsA. Long-term follow-up studies continue to demonstrate acceptable safety profiles. There is need for more real-world data on drug efficacy from Registry studies and research on effective de-escalation strategies.

Juvenile Idiopathic Arthritis With Associated Inflammatory Bowel Disease and CARD8 Mutation.

Juvenile idiopathic arthritis is a common chronic childhood disease, with a prevalence of ∼1 per 1000 children. Arthritis can also be a manifestation of other inflammatory conditions, such as inflammatory bowel disease (IBD). Studies suggest a genetic influence in IBD, including mutations in CARD8. CARD8 is a negative regulator of the NLRP3 inflammasome, and mutations in this gene are hypothesized to induce gastrointestinal inflammation. However, few studies have evaluated this association and most have included a limited number of patients. We present a case of a pediatric patient with IBD-associated arthritis and a CARD8 mutation. Our patient is a 7-year-old female who was initially evaluated by rheumatology for right leg pain and an intermittent rash. She had clinically active arthritis on exam and was started on methotrexate with only slight improvement. Additional workup revealed sacroiliitis by imaging, elevated inflammatory markers, no anemia, and a variant of unknown significance in CARD8. Adalimumab was recommended but before medication initiation, our patient's symptoms progressed to worsening joint pain, fatigue, fevers, nausea, vomiting, diarrhea, and hematochezia. Infectious testing was negative. Fecal calprotectin was >8000 µg/g. A colonoscopy revealed IBD most consistent with Crohn's disease. Adalimumab was ultimately added, and she has responded well to combination therapy. This case report highlights the association between CARD8 mutations and IBD, especially in the setting of IBD-associated arthritis.

Pain-Related Stigma and Its Associations With Clinical and Experimental Pain Severity in Youth With Chronic Musculoskeletal Pain Conditions.

OBJECTIVE: Many children with chronic musculoskeletal pain conditions experience stigma which can have negative downstream consequences. This study compares ratings of clinical pain (current pain intensity and pain interference), experimental pain (temporal summation, cold water tolerance, and cold pain intensity), and pain-related stigma among three groups of youth with rheumatic conditions. The relations among ratings of pain-related stigma and pain variables were explored. METHODS: Eighty-eight youth aged 8-17 years with a diagnosis of juvenile idiopathic arthritis (JIA = 32), juvenile fibromyalgia (JFM = 31), or non-specific chronic pain (NSCP = 25) completed measures of clinical pain ratings (average 7-day pain intensity, day of assessment pain (DoA), and pain interference), experimental pain (cold pain tolerance, cold pain intensity, and temporal summation of mechanical pain), and pain-related stigma. Data analysis compared pain-related stigma and pain ratings across the three groups and examined the relations among pain-related stigma and pain ratings. RESULTS: Youth with JFM reported higher ratings of clinical pain and pain-related stigma than their counterparts with NSCP or JIA. However, there were no differences in experimental pain. Pain-related stigma was associated with greater ratings of pain interference, particularly for those with JIA and NSCP. Pain-related stigma was also associated with greater average daily pain intensity but not DoA. CONCLUSION: Youth with medically unexplained pain report greater stigma and worse pain than their peers; thus, robust assessment of pain in this population is necessary. Future work should longitudinally explore the impact of pain-related stigma on pain outcomes and treatment responses.

Management of Orofacial Manifestations of Juvenile Idiopathic Arthritis: Interdisciplinary Consensus-Based Recommendations.

Involvement of the temporomandibular joint (TMJ) is common in juvenile idiopathic arthritis (JIA). TMJ arthritis can lead to orofacial symptoms, orofacial dysfunction, and dentofacial deformity with negative impact on quality of life. Management involves interdisciplinary collaboration. No current recommendations exist to guide clinical management. We undertook this study to develop consensus-based interdisciplinary recommendations for management of orofacial manifestations of JIA, and to create a future research agenda related to management of TMJ arthritis in children with JIA. Recommendations were developed using online surveying of relevant stakeholders, systematic literature review, evidence-informed generation of recommendations during 2 consensus meetings, and Delphi study iterations involving external experts. The process included disciplines involved in the care of orofacial manifestations of JIA: pediatric rheumatology, radiology, orthodontics, oral and maxillofacial surgery, orofacial pain specialists, and pediatric dentistry. Recommendations were accepted if agreement was >80% during a final Delphi study. Three overarching management principles and 12 recommendations for interdisciplinary management of orofacial manifestations of JIA were outlined. The 12 recommendations pertained to diagnosis (n = 4), treatment of TMJ arthritis (active TMJ inflammation) (n = 2), treatment of TMJ dysfunction and symptoms (n = 3), treatment of arthritis-related dentofacial deformity (n = 2), and other aspects related to JIA (n = 1). Additionally, a future interdisciplinary research agenda was developed. These are the first interdisciplinary recommendations to guide clinical management of TMJ JIA. The 3 overarching principles and 12 recommendations fill an important gap in current clinical practice. They emphasize the importance of an interdisciplinary approach to diagnosis and management of orofacial manifestations of JIA.

Survey of current practices in the management of anti-TNF failure in juvenile spondyloarthritis.

OBJECTIVES: To evaluate the current practices in management of patients with juvenile spondyloarthritis (JSpA) who failed anti-tumour necrosis factor agents (anti-TNF). METHODS: An online survey was distributed to Childhood Arthritis and Rheumatology Research Alliance (CARRA) members of the JIA workgroup. Data collection included estimated number of JSpA patients who have failed anti-TNF therapy over two-year period, reasons for discontinuing anti-TNF therapy and other medications used afterward. The JSpA population was de ned as the following subtypes: enthesitis-related arthritis, psoriatic arthritis, undifferentiated spondyloarthritis, juvenile ankylosing spondylitis (AS) i.e. meeting modi ed NY criteria for AS before age 16, and reactive arthritis. Findings were summarised using descriptive statistics. RESULTS: The survey response rate was 36% (n= 60/169). The majority of participants were paediatric rheumatologists (93%). Many physicians have JSpA patients who failed anti-TNF therapy (63%). The most common reason for changing anti-TNF therapy was secondary non-response (72%). Sacroiliitis was the most important factor considered when assessing response to an anti-TNF agent and the most common reason for primary non-response (45%). When assessing anti-TNF failure for sacroiliitis, many (65%) felt imaging of the sacroiliac joints was the most important aspect in their decision making. The majority try a second anti-TNF agent after initial anti-TNF failure (87%) and switch to another medication class after 2 anti-TNF agents have failed (62%). CONCLUSIONS: More than half of paediatric rheumatologists surveyed have at least one JSpA patient who failed anti-TNF therapy. The majority failed because of secondary non-response. Sacroiliitis is an important but challenging aspect to manage for patients with JSpA.

A Rare STXBP2 Mutation in Severe COVID-19 and Secondary Cytokine Storm Syndrome.

BACKGROUND: Primary (familial) hemophagocytic lymphohistiocytosis (pHLH) is a potentially lethal syndrome of infancy, caused by genetic defects in natural killer (NK) cell and CD8 T cell cytotoxicity, leading to hyperinflammation, elevated cytokine levels, and a disorganized immune response resulting in multi-organ system failure and frequently death. Secondary HLH (sHLH) can be triggered in the setting of malignances, diseases of chronic immune system activation, or by infectious etiologies. While pHLH is usually a result of homozygous gene mutations, monoallelic hypomorphic and dominant-negative mutations in pHLH genes have been implicated in sHLH. Coronavirus disease 2019 (COVID-19) has been an omnipresent viral infection since its arrival, and severe cases can present with cytokine storm and have clinical features and laboratory findings consistent with sHLH. Herein, we report an adolescent with severe COVID-19, decreased NK cell function, and features of sHLH. Her genetic evaluation identified a monoallelic missense mutation in the pHLH gene STXBP2, and NK cell assays of her blood showed decreased cytolysis and degranulation ex vivo. METHODS: Patient data was extracted through an electronic medical record review. Using a lentiviral approach, the patient's STXBP2 mutation and wild-type (WT) STXBP2 were separately transduced into the NK-92 human NK cell line. The WT and mutant STXBP2 transduced NK-92 cells were stimulated with NK-sensitive K562 erythroleukemia target cells in vitro, and NK cell degranulation and cytolysis were measured via CD107a expression and Live/Dead near-IR dye, respectively. RESULTS: Compared to WT STXBP2, the patient's STXBP2 mutation caused significantly decreased NK cell cytolysis and associated degranulation in vitro. CONCLUSION: These findings add weight to the hypothesis that some severe cases of COVID-19 may be accompanied by sHLH and hyperinflammation, especially in the setting of heterozygous pHLH genetic mutations. This has implications both diagnostically and therapeutically for severe COVID-19.

Changes over time in inflammatory and structural lesions at the sacroiliac joint in children with spondyloarthritis exposed and unexposed to tumor necrosis factor inhibitor.

BACKGROUND: The objective of this work was to describe magnetic resonance imaging (MRI) changes over time in inflammatory and structural lesions at the sacroiliac joint (SIJ) in children with spondyloarthritis (SpA) exposed and unexposed to tumor necrosis factor inhibitor (TNFi). METHODS: This was a retrospective, multicenter study of SpA patients with suspected or confirmed sacroiliitis who underwent at ≥2 pelvic MRI scans. Images were reviewed independently by 3 radiologists and scored for inflammatory and structural changes using the Spondyloarthritis Research Consortium of Canada (SPARCC) SIJ inflammation score (SIS) and structural score (SSS). Longitudinal, quantitative changes in patient MRI scans were measured using descriptive statistics and stratified by TNFi exposure. We used an average treatment effects (ATE) regression model to explore the average effect of TNFi exposure over time on inflammatory and structural lesions, adjusting for baseline lesion scores. RESULTS: Forty-six subjects were evaluated using the SIS (n = 45) and SSS (n = 18). Median age at baseline imaging was 13.6 years, 63% were male and 71% were white. Twenty-three subjects (50%) were TNFi exposed between MRI studies. The median change in SIS in TNFi exposed and unexposed subjects with a baseline SIS ≥0 was - 20.7 and - 14.3, respectively (p = 0.09). Eleven (85%) TNFi exposed and 8 (89%) unexposed subjects with a baseline SIS ≥0 met the SIS minimal clinically important difference (MCID; ≥2.5). Using the ATE model adjusted for baseline SIS, the average effect of TNFi on SIS in patients with a baseline SIS ≥2 was - 14.5 (p < 0.01). Unadjusted erosion change score was significantly worse in TNFi unexposed versus exposed subjects (p = 0.03) but in the ATE model the effect of TNFi was not significant. CONCLUSION: This study quantitatively describes how lesions in the SIJs on MRI change over time in patients exposed to TNFi versus unexposed. Follow-up imaging in TNFi exposed patients showed greater improvement than the unexposed group by most metrics, some of which reached statistical significance. Surprisingly, a majority of TNFi unexposed children with a baseline SIS≥2 met the SIS MCID. Additional studies assessing the short and long-term effects of TNFi on inflammatory and structural changes in juvenile SpA are needed.

Juvenile Spondyloarthritis in the Childhood Arthritis and Rheumatology Research Alliance Registry: High Biologic Use, Low Prevalence of HLA-B27, and Equal Sex Representation in Sacroiliitis.

OBJECTIVE: To describe characteristics of children with enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (PsA) who were enrolled in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) registry. METHODS: All children with ERA and those with juvenile PsA were identified. Demographic characteristics, clinical characteristics, and treatments were described. The children with sacroiliitis and those without sacroiliitis were compared. In the children with sacroiliitis, the first visit with clinically active sacroiliitis (which came first in 72% of cases) was compared to the first visit without clinically active sacroiliitis. RESULTS: A total of 902 children with ERA or juvenile PsA were identified. Children with ERA were older at diagnosis (ages 10.8 years versus 8.2 years; P < 0.01) and were more likely to be male (56% versus 38%; P < 0.01). Polyarticular involvement was reported in 57% of children with ERA and in 72% of those with juvenile PsA. Of the children tested, HLA-B27 was positive in 38% of those in the ERA group and in 12% of those in the juvenile PsA group. At least 1 biologic was taken by 72% of those with ERA and 64% of those with juvenile PsA. Sacroiliitis (diagnosed clinically and/or by imaging) was reported in 28% of the children (40% of those with ERA and 12% of those with juvenile PsA). Of these, 54% of the children were female, 36% were HLA-B27 positive, and 81% took at least 1 biologic. In children with sacroiliitis, scores according to the physician global assessment of disease activity, parent/patient global assessment of well-being, and clinical Juvenile Arthritis Disease Activity Score 10 were all significantly worse at the first visit with clinically active sacroiliitis versus the first visit without active sacroiliitis. CONCLUSION: In this registry, there are more than 900 children with ERA or juvenile PsA. There was high biologic use in this population, especially in those with sacroiliitis. Further, there was equal sex representation in those children with sacroiliitis.

Precision medicine in juvenile idiopathic arthritis-has the time arrived?

The introduction of disease-modifying anti-rheumatic drug therapies for treating children and adolescents with chronic arthritis (ie, juvenile idiopathic arthritis [JIA]) has revolutionised care and outcomes. The biologic revolution continues to expand, with ever-changing immunological targets coming to market after basic research and clinical trials. The first class of biologics that was beneficial for children with JIA was tumour necrosis factor (TNF) inhibitors. If used early and aggressively, TNF inhibitors are capable of inducing disease remission for most of the seven subtypes of JIA, with the exception of systemic JIA (which more frequently responds to interleukin [IL]-1 or IL-6 inhibition). Nevertheless, there are still subsets of patients with JIA with disease that is difficult to treat or who develop extra-articular features that require a different therapeutic approach. Although finding an effective biological therapy for individual children with JIA can be trial and error, ongoing research and clinical trials are providing insight into a more personalised approach to care. In addition, redefining the JIA classification, in part based on shared similarities with various adult arthritides, could allow for extrapolation of knowledge from studies in adults with chronic arthritis.

Nutritional combinatorial impact on the gut microbiota and plasma short-chain fatty acids levels in the prevention of mammary cancer in Her2/neu estrogen receptor-negative transgenic mice.

Breast cancer is the second leading cause of cancer-related mortality in women. Various nutritional compounds possess anti-carcinogenic properties which may be mediated through their effects on the gut microbiota and its production of short-chain fatty acids (SCFAs) for the prevention of breast cancer. We evaluated the impact of broccoli sprouts (BSp), green tea polyphenols (GTPs) and their combination on the gut microbiota and SCFAs metabolism from the microbiota in Her2/neu transgenic mice that spontaneously develop estrogen receptor-negative [ER(-)] mammary tumors. The mice were grouped based on the dietary treatment: control, BSp, GTPs or their combination from beginning in early life (BE) or life-long from conception (LC). We found that the combination group showed the strongest inhibiting effect on tumor growth volume and a significant increase in tumor latency. BSp treatment was integrally more efficacious than the GTPs group when compared to the control group. There was similar clustering of microbiota of BSp-fed mice with combination-fed mice, and GTPs-fed mice with control-fed mice at pre-tumor in the BE group and at pre-tumor and post-tumor in the LC group. The mice on all dietary treatment groups incurred a significant increase of Adlercreutzia, Lactobacillus genus and Lachnospiraceae, S24-7 family in the both BE and LC groups. We found no change in SCFAs levels in the plasma of BSp-fed, GTPs-fed and combination-fed mice of the BE group. Marked changes were observed in the mice of the LC group consisting of significant increases in propionate and isobutyrate in GTPs-fed and combination-fed mice. These studies indicate that nutrients such as BSp and GTPs differentially affect the gut microbial composition in both the BE and LC groups and the key metabolites (SCFAs) levels in the LC group. The findings also suggest that temporal factors related to different time windows of consumption during the life-span can have a promising influence on the gut microbial composition, SCFAs profiles and ER(-) breast cancer prevention.

Treatment of Juvenile Spondyloarthritis: Where We Stand.

Juvenile spondyloarthritis is a subset of juvenile idiopathic arthritis (JIA) with onset in late childhood and adolescence and a strong association with human leukocyte antigen (HLA) B-27 positivity and familial aggregation that has the potential for axial involvement, potentially leading to ankylosing spondylitis. Current therapy for severe disease relies heavily on tumor necrosis factor inhibitors (TNFi). Treatment paradigms in children largely consist of extrapolation from studies on adults with spondyloarthritis. Additional therapies studied in adults include non-steroidal anti-inflammatory drugs (NSAIDs), blockade of the interleukin-17 (IL-17) and IL-23 axes, blockade of T-cell stimulation, phosphodiesterase (PDE)-4 inhibition, and Janus-activated kinase (JAK) pathway alteration. IL-17 blockade and IL-23 blockade are guideline approved after TNFi failure (and even as an alternative to TNFi) in adults, depending on concomitant inflammatory bowel and skin disease, with JAK and PDE-4 inhibition options following biologic failure. Neither pediatric nor adult guidelines address IL-6 blockade, T-cell co-stimulation blockade, or combination biologic therapy.

Identification of Prevotella Oralis as a possible target antigen in children with Enthesitis related arthritis.

OBJECTIVES: Patients with Crohn's disease often produce antibodies against flagellated intestinal bacteria. There are mixed data as to whether such antibodies are present in patients with spondyloarthritis. Our objectives were to evaluate for the presence of antibodies against intestinal organisms in children with enthesitis related arthritis (ERA). METHODS: Children with ERA and healthy controls were recruited at three sites. Sera were plated on a nitrocellulose array and incubated with labelled antibodies to human IgA and IgG. RESULTS: At UAB, patients and controls had similar antibody levels against the majority of the bacteria selected, with the exception of increased IgA antibodies among ERA patients against Prevotella oralis (1231 [IQR 750, 2566] versus 706 [IQR 428, 1106], p = .007.) These findings were partially validated at a second but not at a third site. CONCLUSIONS: ERA patients may produce increased IgA antibodies against P. oralis. The possible significance of this finding bears further exploration.

Benefit of Anakinra in Treating Pediatric Secondary Hemophagocytic Lymphohistiocytosis.

OBJECTIVE: To assess the benefit of the recombinant human interleukin-1 receptor antagonist anakinra in treating pediatric patients with secondary hemophagocytic lymphohistiocytosis (HLH)/macrophage activation syndrome (MAS) associated with rheumatic and nonrheumatic conditions. METHODS: A retrospective chart review of all anakinra-treated patients with secondary HLH/MAS was performed at Children's of Alabama from January 2008 through December 2016. Demographic, clinical, laboratory, and genetic characteristics, outcomes data, and information on concurrent treatments were collected from the records and analyzed using appropriate univariate statistical approaches to assess changes following treatment and associations between patient variables and outcomes. RESULTS: Forty-four patients with secondary HLH/MAS being treated with anakinra were identified in the electronic medical records. The median duration of hospitalization was 15 days. The mean pretreatment serum ferritin level was 33,316 ng/ml and dropped to 14,435 ng/ml (57% decrease) within 15 days of the start of anakinra treatment. The overall mortality rate in the cohort was 27%. Earlier initiation of anakinra (within 5 days of hospitalization) was associated with reduced mortality (P = 0.046), whereas thrombocytopenia (platelet count <100,000/µl) and STXBP2 mutations were both associated with increased mortality (P = 0.008 and P = 0.012, respectively). In considering patients according to their underlying diagnosis, those with systemic juvenile idiopathic arthritis (JIA) had the lowest mortality rate, with no deaths among the 13 systemic JIA patients included in the study (P = 0.006). In contrast, those with an underlying hematologic malignancy had the highest mortality rate, at 100% (n = 3). CONCLUSION: These findings suggest that anakinra appears to be effective in treating pediatric patients with non-malignancy-associated secondary HLH/MAS, especially when it is given early in the disease course and when administered to patients who have an underlying rheumatic disease.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

OBJECTIVE: To develop recommendations for the screening, monitoring, and treatment of uveitis in children with juvenile idiopathic arthritis (JIA). METHODS: Pediatric rheumatologists, ophthalmologists with expertise in uveitis, patient representatives, and methodologists generated key clinical questions to be addressed by this guideline. This was followed by a systematic literature review and rating of the available evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A group consensus process was used to compose the final recommendations and grade their strength as conditional or strong. RESULTS: Due to a lack of literature with good quality of evidence, recommendations were formulated on the basis of available evidence and a consensus expert opinion. Regular ophthalmic screening of children with JIA is recommended because of the risk of uveitis, and the frequency of screening should be based on individual risk factors. Regular ophthalmic monitoring of children with uveitis is recommended, and intervals should be based on ocular examination findings and treatment regimen. Ophthalmic monitoring recommendations were strong primarily because of concerns of vision-threatening complications of uveitis with infrequent monitoring. Topical glucocorticoids should be used as initial treatment to achieve control of inflammation. Methotrexate and the monoclonal antibody tumor necrosis factor inhibitors adalimumab and infliximab are recommended when systemic treatment is needed for the management of uveitis. The timely addition of nonbiologic and biologic drugs is recommended to maintain uveitis control in children who are at continued risk of vision loss. CONCLUSION: This guideline provides direction for clinicians and patients/parents making decisions on the screening, monitoring, and management of children with JIA and uveitis, using GRADE methodology and informed by a consensus process with input from rheumatology and ophthalmology experts, current literature, and patient/parent preferences and values.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Treatment of Juvenile Idiopathic Arthritis: Therapeutic Approaches for Non-Systemic Polyarthritis, Sacroiliitis, and Enthesitis.

OBJECTIVE: To develop treatment recommendations for children with juvenile idiopathic arthritis manifesting as non-systemic polyarthritis, sacroiliitis, or enthesitis. METHODS: The Patient/Population, Intervention, Comparison, and Outcomes (PICO) questions were developed and refined by members of the guideline development teams. A systematic review was conducted to compile evidence for the benefits and harms associated with treatments for these conditions. GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the quality of evidence. A group consensus process was conducted among the Voting Panel to generate the final recommendations and grade their strength. A Parent and Patient Panel used a similar consensus approach to provide patient/caregiver preferences for key questions. RESULTS: Thirty-nine recommendations were developed (8 strong and 31 conditional). The quality of supporting evidence was very low or low for 90% of the recommendations. Recommendations are provided for the use of nonsteroidal antiinflammatory drugs, disease-modifying antirheumatic drugs, biologics, and intraarticular and oral glucocorticoids. Recommendations for the use of physical and occupational therapy are also provided. Specific recommendations for polyarthritis address general medication use, initial and subsequent treatment, and adjunctive therapies. Good disease control, with therapeutic escalation to achieve low disease activity, was recommended. The sacroiliitis and enthesitis recommendations primarily address initial therapy and adjunctive therapies. CONCLUSION: This guideline provides direction for clinicians, caregivers, and patients making treatment decisions. Clinicians, caregivers, and patients should use a shared decision-making process that accounts for patients' values, preferences, and comorbidities. These recommendations should not be used to limit or deny access to therapies.

2019 American College of Rheumatology/Arthritis Foundation Guideline for the Screening, Monitoring, and Treatment of Juvenile Idiopathic Arthritis-Associated Uveitis.

OBJECTIVE: To develop recommendations for the screening, monitoring, and treatment of uveitis in children with juvenile idiopathic arthritis (JIA). METHODS: Pediatric rheumatologists, ophthalmologists with expertise in uveitis, patient representatives, and methodologists generated key clinical questions to be addressed by this guideline. This was followed by a systematic literature review and rating of the available evidence according to the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. A group consensus process was used to compose the final recommendations and grade their strength as conditional or strong. RESULTS: Due to a lack of literature with good quality of evidence, recommendations were formulated on the basis of available evidence and a consensus expert opinion. Regular ophthalmic screening of children with JIA is recommended because of the risk of uveitis, and the frequency of screening should be based on individual risk factors. Regular ophthalmic monitoring of children with uveitis is recommended, and intervals should be based on ocular examination findings and treatment regimen. Ophthalmic monitoring recommendations were strong primarily because of concerns of vision-threatening complications of uveitis with infrequent monitoring. Topical glucocorticoids should be used as initial treatment to achieve control of inflammation. Methotrexate and the monoclonal antibody tumor necrosis factor inhibitors adalimumab and infliximab are recommended when systemic treatment is needed for the management of uveitis. The timely addition of nonbiologic and biologic drugs is recommended to maintain uveitis control in children who are at continued risk of vision loss. CONCLUSION: This guideline provides direction for clinicians and patients/parents making decisions on the screening, monitoring, and management of children with JIA and uveitis, using GRADE methodology and informed by a consensus process with input from rheumatology and ophthalmology experts, current literature, and patient/parent preferences and values.

Juvenile Psoriatic Arthritis: A Report from the GRAPPA 2017 Annual Meeting.

Juvenile psoriatic arthritis (JPsA), a subtype of juvenile idiopathic arthritis (JIA), constitutes 5% of JIA. The literature is inconsistent regarding features of JPsA, and physicians debate whether it is a distinct entity within JIA. A biphasic age of onset distribution has been noted. Early-onset disease is characterized by female predominance, small joint involvement, dactylitis, and positive antinuclear antibodies. Late-onset JPsA resembles adult-onset psoriatic arthritis (PsA), with male predominance, psoriasis, enthesitis, and axial disease. Recent studies report improved outcomes, likely due to the widespread use of traditional and biologic disease-modifying antirheumatic drugs. Conflicting HLA associations have been reported in JPsA, but notably both HLA class I and II allele associations are suggested. Similar to PsA cohorts, subjects with JPsA have a lower frequency of a protective interleukin 23R allele than controls or other JIA subtypes. Data in the Childhood Arthritis and Rheumatology Research Alliance (CARRA) patient registry suggest the aggressive characteristics of JPsA: 24.6% of children have joint damage 4.6 years after symptom onset. Pediatric and adult PsA classification criteria define different JPsA cohorts within the registry and support a previous suggestion that the International League of Associations for Rheumatology criteria for JPsA may be overly stringent. Increased collaboration between pediatric and adult physicians and comparative research on these clinically related conditions are warranted.

Temporomandibular joint arthritis in juvenile idiopathic arthritis, now what?

BACKGROUND: Arthritis involving the temporomandibular joint (TMJ) complicates 40 - 96% of cases of juvenile idiopathic arthritis (JIA), potentially leading to devastating changes to form and function. Optimal evaluation and management of this joint remains a matter of ongoing discussion. METHODS: We performed a PubMed search for all articles with keywords "temporomandibular" and "arthritis", covering the dates 2002 through February 28, 2018. A separate PubMed search was performed for all articles with keywords "temporomandibular joint", "arthritis", and "treatment" covering the same dates. FINDINGS: The TMJ is a particularly challenging joint to assess, both clinically and with imaging studies. Clinical assessment of the TMJ is hampered by the low sensitivity of joint pain as well as the absence of physical exam findings early in the disease process. As with all joints, plain radiography and computed tomography only detect arthritic sequelae. Additionally, there is mixed data on the sensitivity of ultrasound, leaving magnetic resonance imaging (MRI) as the optimal diagnostic modality. However, several recent studies have shown that non-arthritic children can have subtle findings on MRI consistent with TMJ arthritis, such as joint effusion and contrast enhancement. Consequently, there has been an intense effort to identify features that can be used to differentiate mild TMJ arthritis from normal TMJs, such as the ratio of the enhancement within the TMJ itself compared to the enhancement in surrounding musculature. With respect to treatment of TMJ arthritis, there is minimal prospective data on medical therapy of this complicated joint. Retrospective studies have suggested that the response to medical therapy of the TMJ may lag behind that of other joints, prompting use of intraarticular (IA) therapy. Although most studies have shown short-term effectiveness of corticosteroids, the long-term safety of this therapy on local growth as well as on the development of IA heterotopic bone have prompted recommendations to limit use of IA corticosteroids. Severe TMJ disease from JIA can also be managed non-operatively with splints in a growing child, as well as with surgery. CONCLUSION: In this review, we summarize literature on the diagnosis and management of TMJ arthritis in JIA and suggest a diagnostic and therapeutic algorithm for children with refractory TMJ arthritis.

Impact of genistein on the gut microbiome of humanized mice and its role in breast tumor inhibition.

Since dietary polyphenols can have beneficial effects in prevention and treatment of cancer, we tested the hypothesis that breast cancer patients' intestinal microbiota is modulated by genistein (GE), an isoflavone found in soy, and that microbial alterations may offset the side effects brought about by chemotherapy. We demonstrated successful humanization of germ-free mice by transplanting fecal samples from breast cancer patients before and after chemotherapy. Mice were then grouped based on chemotherapy status and GE or control diet. We did not find any significant differences between pre-chemotherapy and post-chemotherapy bacterial composition and abundances. Germ-free mice on a GE diet showed differences in microbial composition as compared to mice on control diet. Four weeks after introduction of the customized GE diet, there was distinct clustering of GE-fed mice as compared to the control-fed group. In the gut microbiome of GE-treated humanized mice, there was an increase in abundance of genera Lactococcus and Eubacterium. Phylum Verrucomicrobia showed statistically significant (p = 0.02) differences in abundances between the GE-fed and control-fed groups. There was an increase in bacteria belonging to family Lachnospiraceae and Ruminococcaceae in GE-fed mice. Marked changes were observed in GE catabolism in mice humanized with fecal material from two of three patients' post-chemotherapy with complete disappearance of 4-ethylphenol and 2-(4-hydroxyphenol) propionic acid conjugates. The post-tumor samples did not show any distinct clustering of the gut microbiota between the two diet groups. There was an increase in latency of about 25% for tumor growth of the humanized mice that were on a GE diet as compared to humanized mice on a control diet. The average tumor size for the GE group was significantly decreased compared to the non-GE group. Collectively, our results suggest that the intestinal microbiota becomes altered with a GE diet before induction of tumor. Our findings indicate that GE modulates the microbiome in humanized mice that may contribute to its effects on increasing the latency of breast tumor and reducing tumor growth.

Risk of tuberculosis among Alabama children and adolescents treated with tumor necrosis factor inhibitors: a retrospective study.

BACKGROUND: Tumor Necrosis Factor inhibitors (TNFi) have dramatically improved the outlook for patients with inflammatory arthritides and bowel disease (IBD), but are associated with increased infection risks, including tuberculosis (TB). Pediatric inflammatory diseases are uncommon, and the risk of TB in children taking TNFi remains unclear. The objective of this study was to report the incidence of TB disease among TNFi recipients at a single pediatric medical center serving most of Alabama compared to that of the general population of Alabama children. METHODS: Instances of TNFi usage among patients under age 20 years from July 1, 2007 through April 17, 2015 were captured from electronic health records at Children's of Alabama (CoA), which has the only pediatric rheumatology clinic in Alabama, and where a substantial number of children in Alabama with inflammatory bowel disease receive care., and reports of TB cases were obtained from the Alabama Department of Public Health (ADPH). Incidence was expressed as TB cases/10,000 person-years, using population estimates from the Alabama Center for Health Statistics. RESULTS: 1033 Alabama patients at CoA who were residents of Alabama were identified who received TNFi for a total of 1564 person-years. One adolescent on TNFi developed severe extrapulmonary TB (incidence density = 6.4 per 10,000; 95% CI 0.9-45.4 per 10,000). Sixty-three cases occurred in persons not on TNFi (incidence density = 0.064 per 10,000; 95% CI 0.050-0.082 per 10,000). CONCLUSIONS: One case of TB disease among TNFi-exposed children was identified for 1564 person-years in Alabama residents. Although rare, this is higher than expected relative to the general rate of TB in Alabama. Thus, continued diagnostic vigilance for TB in children taking TNFi is required. TRIAL REGISTRATION NUMBER: Not applicable.