Temporomandibular involvement in children and adolescents with juvenile idiopathic arthritis: a 2-year prospective cohort study.

This study aimed to clinically evaluate temporomandibular joint (TMJ) involvement in juvenile idiopathic arthritis (JIA) and the ability to identify and/or predict development of TMJ-deformities over time using cone beam computed tomography (CBCT). The predictive value of self-reported TMJ pain was also assessed. A prospective longitudinal cohort study comprising 54 children with JIA, 39 girls and 15 boys, was performed. All children had active disease at baseline, 50% with the subtype oligoarthritis. Repeated clinical orofacial and CBCT examinations were performed over a two-year period. At baseline, 39% had radiographic TMJ deformities (24% unilateral, 15% bilateral), at 2-year follow-up, 42% (p > 0.05). Both progressing and improving TMJ deformities were observed. An association was found between TMJ-deformities and self-reported TMJ pain at baseline (p = 0.01). Maximum unassisted mouth opening (MUO) was smaller for children with TMJ-deformities (p < 0.05). The prevalence of palpatory muscle pain was high (48-59%) but not predictive of development of TMJ-deformities. TMJ noises increased over time and crepitations were associated with TMJ-deformities (p < 0.05). In conclusion, in children with JIA, self-reported TMJ pain and dysfunction were common and predictive of TMJ deformities. TMJ deformities were associated with smaller MUO and palpatory TMJ pain as well as crepitations. Trial registration. ClinicalTrials.gov Protocol id: 2010/2089-31/2.

Temporomandibular joint involvement in children with juvenile idiopathic arthritis-Symptoms, clinical signs and radiographic findings.

BACKGROUND: Although many children with juvenile idiopathic arthritis (JIA) develop arthritis and deformity of the temporomandibular joint (TMJ), many go undetected. OBJECTIVE: This study investigates whether findings from patient history and clinical examination using the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) can be used to diagnose TMJ involvement. METHODS: As a part of the screening program, 59 consecutive JIA patients age 7-14 years underwent a clinical examination according to RDC/TMD including self-reported orofacial pain and pain related to jaw function, and cone beam computer tomography (CBCT). Data were obtained from the patient's medical charts. Patients were divided into two groups based on the presence or absence of TMJ deformities on CBCT. RESULTS: Self-reported TMJ symptoms before inclusion were reported by 52% of children with and 18% of children without TMJ deformities on CBCT (p = .020). On a group level, the maximum unassisted (mouth) opening (MUO) with and without pain was within the normal range, but children with TMJ deformities showed a significantly smaller MUO with pain (p = .035). A diagnosis of osteoarthritis and osteoarthrosis was more prevalent in children with TMJ deformities. CONCLUSION: Although there were few differences between children with and without radiographic TMJ deformities, self-reported previous TMJ symptoms and reduced MUO with pain could indicate the presence of TMJ involvement. However, radiographic examinations are needed to confirm TMJ involvement. Thus, this study indicates that the RDC/TMD protocol is a blunt tool when targeting TMJ involvement in JIA.

Efficacy of Moderately Dosed Etoposide in Macrophage Activation Syndrome-Hemophagocytic Lymphohistiocytosis.

OBJECTIVE: Macrophage activation syndrome (MAS) constitutes 1 subtype of the hyperinflammatory syndrome hemophagocytic lymphohistiocytosis (HLH), and the term MAS-HLH was recently proposed for HLH with underlying autoimmune/autoinflammatory conditions. The mortality of MAS-HLH has been estimated at 5-10%. Here we report our experiences with moderately dosed etoposide in severe MAS-HLH; the objective was to effectively reduce severe hyperinflammatory activity with limited side effects. METHODS: In addition to conventional antiinflammatory treatment, moderately dosed etoposide was administered to 7 children affected by rapidly progressing MAS-HLH with central nervous system (n = 5) and/or pulmonary (n = 5) involvement. Three had underlying systemic juvenile idiopathic arthritis (sJIA), 2 had atypical sJIA (no arthritis at diagnosis), and 2 had systemic lupus erythematosus. We performed lymphocyte cytotoxicity analyses in all 7 and genetic analyses in 6. RESULTS: All children promptly responded to moderately dosed etoposide (50-100 mg/m2 once weekly), added to conventional MAS-HLH treatment that was considered insufficient. The mean accumulated etoposide dose was 671 mg/m2 (range 300-1050 mg/m2) as compared to 1500 mg/m2 recommended in the first 8 weeks of the HLH-94/HLH-2004 protocols. One child developed neutropenic fever and another neutropenic sepsis (neutrophils 0.3 × 109/L at therapy onset). Five of 7 children had low percentages (< 5%) of circulating natural killer (NK) cells prior to or in association with diagnosis; NK cell activity was pathologically low in 2 of 5 children studied. Disease-causing variants in HLH-associated genes were not found. All children were alive at latest follow-up (2-9 yrs after onset); neurological symptoms had normalized in 4 of 5 affected children. CONCLUSION: Moderately dosed etoposide may be beneficial in severe and/or refractory MAS-HLH.

Self-rated walking disability and dynamic ankle joint stiffness in children and adolescents with Juvenile Idiopathic Arthritis receiving intraarticular corticosteroid joint injections of the foot.

BACKGROUND: Children and adolescents with Juvenile Idiopathic Arthritis (JIA) exhibit deviations in ankle dynamic joint stiffness (DJS, or moment-angle relationship) compared to healthy peers, but the relationship between ankle DJS and self-reported walking impairments has not been studied. This secondary analysis aimed to investigate the relationship between ankle DJS and self-reported walking disability in juveniles with JIA, and to determine whether intraarticular corticosteroid foot injections (IACI) were associated with long term changes in ankle DJS. RESEARCH QUESTIONS: Is ankle DJS altered in children with JIA reporting walking difficulties compared to children with JIA reporting no walking difficulties? Are IACIs associated with persistent alterations in ankle DJS? METHODS: Gait dynamics (DJS), foot pain, and foot-related disability were assessed in 33 children with JIA before intraarticular corticoid foot injection (IACI), and three months after IACI. Using self-reported walking capacity scores, children were classified as either having no walking difficulties (ND) or having walking difficulties (WD). Inferential statistics were used to compare demographics, pain, impairment scores, and ankle DJS between the groups. RESULTS: Before treatment, in the WD group, ankle DJS was significantly decreased both in the early rising phase (ERP = 0.03+0.02 vs. 0.05+0.02 Nm(kg*deg)- 1) and late rising phase (LRP = 0.11+0.06 vs. 0.24+0.22 Nm(kg*deg)-1) compared to the ND group. At three months, the ERP was still significantly decreased in the WD group (ERP = 0.03+0.01 vs. 0.05+0.03 Nm(kg*deg)-1). SIGNIFICANCE: Among children and adolescents with JIA who reported walking difficulties prior to IACIs, alterations in DJS in early stance phase (decreased ERP) remained three months after IACI suggesting persistent gait adaptations, possibly related to pain. Pre-treatment gait analysis may aid in identifying children who will not have long term benefit from IACIs in terms of improved gait, and therefore, may be informed and have the choice to be spared the risk of side effects associated with this treatment.

Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Human C1q Deficiency: The Karolinska Experience.

BACKGROUND: Human C1q deficiency is associated with systemic lupus erythematosus (SLE) and increased susceptibility to severe bacterial infections. These patients require extensive medical therapy and some develop treatment-resistant disease. Because C1q is produced by monocytes, it has been speculated that allogeneic hematopoietic stem cell transplantation (allo-HSCT) may cure this disorder. METHODS: We have so far treated 5 patients with C1q deficiency. In 3 cases, SLE symptoms remained relatively mild after the start of medical therapy, but 2 patients developed treatment-resistant SLE, and we decided to pursue treatment with allo-HSCT. For this purpose, we chose a conditioning regimen composed of treosulfan (14 g/m) and fludarabine (30 mg/m) started on day -6 and given for 3 and 5 consecutive days, respectively. Thymoglobulin was given at a cumulative dose of 8 mg/kg, and graft-versus-host disease prophylaxis was composed of cyclosporine and methotrexate. RESULTS: A 9-year-old boy and a 12-year-old girl with refractory SLE restored C1q production after allo-HSCT. This resulted in normal functional properties of the classical complement pathway followed by reduced severity of SLE symptoms. The boy developed posttransplant lymphoproliferative disease, which resolved after treatment with rituximab and donor lymphocyte infusion. Unfortunately, donor lymphocyte infusion induced severe cortisone-resistant gastrointestinal graft-versus-host disease, and the patient died from multiple organ failure 4 months after transplantation. The girl is doing well 33 months after transplantation, and clinically, all signs of SLE have resolved. CONCLUSIONS: Allo-HSCT can cure SLE in human C1q deficiency and should be considered early in subjects resistant to medical therapy.

Marked variability in clinical presentation and outcome of patients with C1q immunodeficiency.

OBJECTIVE: Globally approximately 60 cases of C1q deficiency have been described with a high prevalence of Systemic Lupus Erythematosus (SLE). So far treatment has been guided by the clinical presentation rather than the underlying C1q deficiency. Recently, it was shown that C1q production can be restored by allogeneic hematopoietic stem cell transplantation. Current literature lacks information on disease progression and quality of life of C1q deficient persons which is of major importance to guide clinicians taking care of patients with this rare disease. METHODS: We performed an international survey, of clinicians treating C1q deficient patients. A high response rate of >70% of the contacted clinicians yielded information on 45 patients with C1q deficiency of which 25 are published. RESULTS: Follow-up data of 45 patients from 31 families was obtained for a median of 11 years after diagnosis. Of these patients 36 (80%) suffer from SLE, of which 16 suffer from SLE and infections, 5 (11%) suffer from infections only and 4 (9%) have no symptoms. In total 9 (20%) of the C1q deficient individuals had died. All except for one died before the age of 20 years. Estimated survival times suggest 20% case-fatality before the age of 20, and at least 50% of patients are expected to reach their middle ages. CONCLUSION: Here we report the largest phenotypic data set on C1q deficiency to date, revealing high variance; with high mortality but also a subset of patients with an excellent prognosis. Management of C1q deficiency requires a personalized approach.

Effect of Intraarticular Corticosteroid Foot Injections on Walking Function in Children With Juvenile Idiopathic Arthritis.

OBJECTIVE: To evaluate gait dynamics and self-reported foot-related disability before and after treatment with intraarticular corticosteroid injections (IACI) in children with juvenile idiopathic arthritis (JIA) and foot involvement, and determined whether children with polyarticular and oligoarticular disease responded similarly to IACI treatment. METHODS: Forty-three children (35 girls and 8 boys) with JIA were consecutively recruited (mean ± SD age 11.1 ± 4.2 years, mean disease duration 4.5 ± 3.6 years). Sixty-five percent were diagnosed with polyarthritis. All children received IACI treatment for ankle and/or foot joint synovitis. Fifty-eight percent received additional injections in the knee and/or hip joint. Forty healthy children, matched by age and sex, comprised the control group. Gait dynamics and foot-related disability were assessed before IACI treatment and at 3 weeks and 3 months following the injections. RESULTS: Foot-related disability and inflammatory joint symptoms improved following treatment. Gait dynamics were compromised before treatment and did not improve following treatment (mean ± SD nondimensional walking speed 0.49 ± 0.05 in the control group; 0.44 ± 0.07 in the JIA group pretreatment; 0.43 ± 0.10 in the JIA group 3 weeks following treatment; and 0.43 ± 0.07 in the JIA group 3 months following treatment) (P = 0.001 in controls versus pretreatment JIA group, P = 0.45 JIA over time). Mean ± SD ankle power was 3.81 ± 0.67 in the control group; 3.01 ± 1.19 in the JIA group pretreatment; 3.19 ± 1.30 in the JIA group 3 weeks after treatment; and 3.22 ± 1.03 in the JIA group 3 months after treatment (P < 0.001 in controls versus pretreatment JIA group, P = 0.51 JIA over time). The ankle power to hip power ratio was reduced (P = 0.01 in controls versus pretreatment JIA group), indicating a power shift from the ankles to the hips, which was more prominent in children with polyarthritis. CONCLUSION: As a result of IACI treatment, improvements were found in self-reported foot-related disability and inflammatory joint symptoms, but gait dynamics were unchanged. Children with polyarticular disease and those with greater self-reported walking difficulties prior to IACI treatment demonstrated worse outcomes, and children in these groups should be monitored carefully after treatment.

Phagocyte-specific S100 proteins and high-sensitivity C reactive protein as biomarkers for a risk-adapted treatment to maintain remission in juvenile idiopathic arthritis: a comparative study.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a chronic inflammatory joint disease affecting children. Even if remission is successfully induced, about half of the patients experience a relapse after stopping anti-inflammatory therapy. The present study investigated whether patients with JIA at risk of relapse can be identified by biomarkers even if clinical signs of disease activity are absent. METHODS: Patients fulfilling the criteria of inactive disease on medication were included at the time when all medication was withdrawn. The phagocyte activation markers S100A12 and myeloid-related proteins 8/14 (MRP8/14) were compared as well as the acute phase reactant high-sensitivity C reactive protein (hsCRP) as predictive biomarkers for the risk of a flare within a time frame of 6 months. RESULTS: 35 of 188 enrolled patients experienced a flare within 6 months. Clinical or standard laboratory parameters could not differentiate between patients at risk of relapse and those not at risk. S100A12 and MRP8/14 levels were significantly higher in patients who subsequently developed flares than in patients with stable remission. The best single biomarker for the prediction of flare was S100A12 (HR 2.81). The predictive performance may be improved if a combination with hsCRP is used. CONCLUSIONS: Subclinical disease activity may result in unstable remission (ie, a status of clinical but not immunological remission). Biomarkers such as S100A12 and MRP8/14 inform about the activation status of innate immunity at the molecular level and thereby identify patients with unstable remission and an increased risk of relapse.

Etanercept treatment improves longitudinal growth in prepubertal children with juvenile idiopathic arthritis.

OBJECTIVE: Anti-tumor necrosis factor (TNF) therapy is known to decrease disease activity of juvenile idiopathic arthritis (JIA), but its effect on longitudinal growth in relation to puberty is not clear. We studied longitudinal growth in response to etanercept treatment in prepubertal and pubertal patients with JIA. METHODS: Out of 52 children treated with etanercept, we studied 20 prepubertal and 11 early/midpubertal patients adherent to treatment for at least 1 year. We collected data on growth and glucocorticoid medication and calculated each patient's height standard deviation score (SDS) in relation to the mid-parental height, the change of this value (DeltahSDS) from 1 to 0 and 0 to 1 year of treatment, and the change between the DeltahSDS values to assess growth improvement. RESULTS: In the prepubertal group, the relative height SDS (mean +/- standard error of the mean) was 1.8 +/- 0.2, 2.1 +/- 0.3, and 1.9 +/- 0.3, and in the pubertal group 1.1 +/- 0.4, 1.3 +/- 0.3, and 1.1 +/- 0.3 at 1, 0, and +1 year of treatment, respectively. The DeltahSDS before etanercept was 0.3 +/- 0.1 in prepubertal and 0.2 +/- 0.2 in pubertal patients. Over the first year with etanercept, DeltahSDS was +0.2 +/- 0.1 in prepubertal (p = 0.001 vs before etanercept; paired Student t-test) and +0.2 +/- 0.1 in pubertal patients (p = 0.071). Nevertheless, most prepubertal (17/20) and pubertal (8/11) patients had improved growth (DeltahSDS) in response to etanercept treatment when analyzed individually. The need for intraarticular glucocorticoid injections was negatively correlated to the improved growth (p = 0.001). CONCLUSION: TNF inhibition with etanercept improved growth in a majority of patients with JIA. Our data demonstrate that growth improvement with etanercept was independent of the pubertal growth spurt.

Trunk and center of mass movements during gait in children with juvenile idiopathic arthritis.

Motion of the body center of mass (CoM) can often indicate the overall effect of the strategy of forward progression used. In the present study, focus is placed on trunk movements in the sagittal, coronal, and transverse/rotation plane, as well as placement of the CoM, during gait in children with juvenile idiopathic arthritis (JIA). Seventeen children with JIA, all with polyarticular lower extremity involvement were examined before and approximately two weeks after treatment with intra-articular cortico-steroid injections. Movement was recorded with a 6-camera 3D motion analysis system in both the children with JIA and in 21 healthy controls. Trunk and center of mass movements were compared between JIA and controls, and effects of intra-articular cortico-steroid treatment were evaluated. Children with JIA were more posteriorly tilted in the trunk, contrary to the common clinical impression, and had their CoM placed more posterior and off-centred, which may have been a result of pain. With such knowledge, it might be possible to better understand the effects of their pain and involvement, and ultimately to plan a treatment strategy for improving their gait patterns.

Sensory and affective components of pain as recorded with the Pain-O-Meter (POM) among children with acute and chronic pain.

AIM: To explore the usefulness of the Pain-O-Meter sensory and affective words scale (POM-WDS) with regard to whether children aged 6-16 who suffer from chronic and acute pain know the words and what words they chose to describe their pain. METHODS: Sixty-one children participated, mean age 11 y, suffering from acute pain (n=25) and pain associated with juvenile idiopathic arthritis (JIA, n=36). Children rated their pain intensity on the POM-VAS (visual analogue scale, 0-10 cm). Thereafter, children were asked whether each sensory and affective word on the POM-WDS was known to them, and whether each word described their pain experience. RESULTS: Seventeen out of 23 words were known to at least 70% of the sample. The least recognized word was grinding. Children age 6-16 knew fewer words than the adolescents. Age was a significant determinant for whether the children knew the words grinding (odds ratio (OR) 20.08, p<0.01), gnawing (OR 5.92, p < 0.05), unbearable (OR 8.02, p<0.05), and excruciating (OR 20.17, p<0.001). Terrible (OR 33.3, p<0.05), aching (OR 44.5, p<0.05) and sore (OR 5.4, p<0.05) were selected more often by children with acute pain than with JIA. CONCLUSION: Further studies will be required to determine the suitability of using the POM-WDS with children.

The Pediatric Rheumatology International Trials Organization/American College of Rheumatology provisional criteria for the evaluation of response to therapy in juvenile systemic lupus erythematosus: prospective validation of the definition of improvement.

OBJECTIVE: To use the Pediatric Rheumatology International Trials Organization (PRINTO) core set of outcome measures to develop a validated definition of improvement for the evaluation of response to therapy in juvenile systemic lupus erythematosus (SLE). METHODS: Thirty-seven experienced pediatric rheumatologists from 27 countries, each of whom had specific experience in the assessment of juvenile SLE patients, achieved consensus on 128 patient profiles as being clinically improved or not improved. Using the physicians' consensus ratings as the gold standard measure, the chi-square, sensitivity, specificity, false-positive and false-negative rates, area under the receiver operating characteristic curve, and kappa level of agreement for 597 candidate definitions of improvement were calculated. Only definitions with a kappa value greater than 0.7 were retained. The top definitions were selected based on the product of the content validity score multiplied by its kappa statistic. RESULTS: The definition of improvement with the highest final score was at least 50% improvement from baseline in any 2 of the 5 core set measures, with no more than 1 of the remaining worsening by more than 30%. CONCLUSION: PRINTO proposes a valid and reproducible definition of improvement that reflects well the consensus rating of experienced clinicians and that incorporates clinically meaningful change in core set measures in a composite end point for the evaluation of global response to therapy in patients with juvenile SLE. The definition is now proposed for use in juvenile SLE clinical trials and may help physicians to decide whether a child with SLE responded adequately to therapy.

[Tricuspid valve stenosis--an serious complication to Port-a-cath]. / Trikuspidalisstenos--en allvarlig komplikation till Port-a-cath.

Tricuspid valve stenosis and occlusion of superior vena cava are severe complications to Port-a-cath. In a child with SLE, symptoms started to develop about five to seven years after Port-a-cath insertion and cyclophosphamid injections. The patient developed hepatomegaly with abdominal and venous distension. Open heart surgery was necessary to remove the catheter. At operation it was found that the catheter was placed adjacent and through the tricuspid valve. The valve was severely stenosed with thrombus formation. The catheter and thrombus were removed, commissurotomy and bicuspidization of the valve and chordeal replacement performed to achieve an acceptable functional result. The superior vena cava was repaired with a pericardial patch. Retrospective analyses of the echocardiograms and chest x-rays show that the catheter was nearly related to the tricuspid valve and with the tip in the right ventricle. In such circumstances it is recommended with early withdrawal of the catheter, and in patients with immunological disease the indwelling time should be considered and limited.

The juvenile arthritis foot disability index: development and evaluation of measurement properties.

OBJECTIVE: To develop a new juvenile arthritis foot disability index (JAFI) and to test it for validity and reliability. METHODS: Samples of 14 children/adolescents and 30 children/adolescents with juvenile idiopathic arthritis (JIA) and 29 healthy children/adolescents participated. We used a questionnaire derived from the International Classification of Functioning, Disability and Health that included 27 statements divided into the dimensions Impairment, Activity Limitation, and Participation Restriction. Comments on the contents were invited from parents and adolescents. Convergent and divergent construct validity was examined by comparing the 3 JAFI dimensions to joint impairment scores, the Childhood Health Assessment Questionnaire (CHAQ), and self-rated, foot-related participation restriction. Known groups construct validity was assessed by comparing answers from children with JIA to those from healthy children. Test-retest stability was investigated over one week. RESULTS: One item was added after suggestions from 2 participants. A consistent pattern of increasing JAFI scores was found with increasing joint impairment scores, CHAQ scores, and self-rated foot-related participation restriction. Foot-related disability as assessed by JAFI was more pronounced in children with JIA than in healthy controls. One statement showing a floor effect was excluded. No internal redundancy (rs > 0.90) between items was found, and internal consistency within each subscale was satisfactory (rs > 0.50) for all items but one. No systematic differences were found between test and retest, and weighted kappa coefficients for the 3 JAFI dimensions were 0.90, 0.85, and 0.88. CONCLUSION: The JAFI appears to be valid and reliable for assessing foot-related disability among children/adolescents with JIA. Its sensitivity to change remains to be investigated.

Longterm followup of childhood lupus nephritis.

OBJECTIVE: To determine the longterm outcome in children with onset of lupus nephritis before 18 years of age. METHODS: Sixty-seven patients with onset of lupus nephritis prior to age 18 were identified. The mean followup time was 11 years (range 5-19). The mean age at diagnosis was 13.2 years (range 4-17). The male:female ratio was 1:3.8. Renal biopsies were classified using the WHO classification. Fifteen patients had Class II, 8 patients Class III, 32 patients Class IV, and 11 patients Class V and one patient refused biopsy. The cohort consists of the 66 patients who had a renal biopsy. Five patients received cyclophosphamide (CYC) and 17 received azathioprine (AZA) as part of the initial treatment of Class IV nephritis. Eight additional patients received CYC because of a flare of disease while receiving AZA, and 8 other patients received AZA because of a flare of disease while taking prednisone therapy. RESULTS: Four patients died; 6 developed endstage renal disease (ESRD); all but one of the patients who died and/or had ESRD had WHO Class IV [diffuse proliferative glomerulonephritis (DPGN)]; only 2 Caucasians developed ESRD, although 16 out of 36 Caucasians had DPGN; serum creatinine at followup was normal in 84% of the survivors; presently 70% of the patients take less than 7.5 mg prednisone/day and 62% do not take cytotoxic drugs. No patient is currently treated with CYC. All 8 patients with Class III nephritis were taking medication at last followup. CONCLUSION: The longterm outcome in this group of children with lupus nephritis, in whom AZA was the most commonly used immunosuppressive agent, was excellent, with 94% patient survival at a mean followup of 11 years. Our results suggest that non-Caucasian patients with pediatric onset lupus nephritis may be at increased risk for renal failure compared to Caucasians.