CARD15 mutations in Blau syndrome.

We have identified three missense mutations in the nucleotide-binding domain (NBD) of CARD15/NOD2 in four French and German families with Blau syndrome. Our findings indicate that, in addition to Crohn disease, CARD15 is involved in the susceptibility to a second granulomatous disorder.

Beneficial effects of one-year growth hormone administration to children with juvenile chronic arthritis on chronic steroid therapy. I. Effects on growth velocity and body composition.

Severe growth retardation and profoundly altered body composition are observed in children with systemic forms of juvenile chronic arthritis receiving glucocorticoids. The purpose of this study was to assess the effects of recombinant human GH (rhGH) on growth velocity (GV) and body composition studied by dual-energy X-ray absorptiometry, during a 1-yr treatment course, together with potential adverse effects on glucose tolerance. Fourteen patients were treated with rhGH (1.4 U/kg per week) for 1 yr and were then studied for a 2nd yr off GH. Baseline GH secretion, GH binding protein (BP), insulin-like growth factor-I (IGF-I), and IGFBP3 levels were at the lower limit of normal. The rhGH treatment increased IGF-I and IGFBP3 plasma levels to above-normal values. All patients showed an increase in GV, and mean GV increased from 1.9-5.4 cm/yr (P < 0.001). Compared with the value on day 0, lean body mass increased by 12.2% (P < 0.01), and the fat mass excess fell by 19.5% (P < 0.01). Decreased glucose tolerance (as determined by oral glucose tolerance test) and increased glycosylated hemoglobin levels were observed during treatment. This effect may be attributed to insulin resistance, as reflected by induced hyperinsulinemia. Eleven children were monitored for 1 yr after the cessation of GH therapy. GV fell to pretreatment values, whereas height in SD score at the end of the 2nd yr was lower (P < 0.01) than before treatment. Weight and fat mass again increased markedly. Although long-term controlled studies are needed to assess the risks and benefits of GH therapy in this setting, our results suggest that rhGH may partially counteract the adverse effects of glucocorticoids on growth and metabolism in patients with chronic inflammatory disease.

The effect of agents which modulate levels of the cyclic nucleotides on human lymphotoxin secretion and activity in vitro.

The ability of concanavalin-A (Con-A) to activate lymphocytes to secrete human lymphotoxin (LT) was tested in the presence of agents known to modify the intracellular levels of cyclic nucleotides (cAMP and cGMP). Lymphocytes were treated with these agents at different stages of activation: (1) during the first encounter with mitogens, and (2) after they had been fully activated and were restimulated. Two agents, Dibutyryl cAMP and theophylline, dramatically inhibit the amount of LT secreted during both "primary" and "secondary" activation by Con-A. In contrast; DL-isoproterenol had a weak effect during primary activation, but greatly reduced the level of LT secreted during secondary activation. Agents which affect the intracellular level of cGMP were also tested. Imidazole had no effect on LT secretion by either primary or secondary Con-A activated cells. In contrast, carbamyl choline greatly reduced LT secretion to a level comparable to Dibutyryl cAMP and theophylline. All agents tested protected, to some degree, the sensitive alpha-L cell against LT-induced destruction in vitro. Agents which affect the levels of cyclic nucleotides affect both the effectiveness of the aggressor cell and the sensitivity of the target cells in vitro.

Clinical variability and genetic homogeneity of the camptodactyly-arthropathy-coxa vara-pericarditis syndrome.

The camptodactyly-arthropathy-coxa vara-pericarditis syndrome (CACP) is an autosomal recessive condition characterized by the association of congenital or early onset camptodactyly and noninflammatory arthropathy with synovial hyperplasia. Progressive coxa vara deformity and/or noninflammatory pericardial or pleural effusions have been observed in some patients. Recently, the disease gene has been assigned to human chromosome region 1q25-q31, and truncating mutations have been identified in the megakaryocyte stimulating factor gene. Studying 12 patients from 8 unrelated families, we emphasized hip and spine involvement, particularly in the course of the disease as shown in a 58-year-old patient. Despite clinical variability, linkage studies support genetic homogeneity of the disease.

Long-term follow-up of autologous stem cell transplantation for refractory juvenile idiopathic arthritis.

Since 1997, autologous stem cell transplantation (ASCT) had been applied to more than 40 children with polyarticular or systemic juvenile idiopathic arthritis (JIA). For this review, results of the follow-up are available from 25 children with systemic JIA and six with polyarticular JIA that were reported in detail from eight different pediatric European transplant centers. Before ASCT all children had progressive disease despite the use of corticosteroids, methotrexate (MTX) up to 1 mg/kg/week, cyclosporin (2.5 mg/kg/day) and/or anti-TNFalpha therapy. The clinical follow-up of these children ranges from 8 to 60 months (median 33 months).

Chronic infantile neurological cutaneous and articular/neonatal onset multisystem inflammatory disease syndrome: ocular manifestations in a recently recognized chronic inflammatory disease of childhood.

OBJECTIVE: To report on the ocular manifestations of the Chronic Infantile Neurological Cutaneous and Articular/Neonatal Onset Multisystem Inflammatory Disease (CINCA/NOMID) syndrome, a rare, recently identified, pediatric multisystem inflammatory disease with chronic cutaneous, neurological, and articular manifestations. DESIGN: Descriptive case-report study. SETTING: International collaborative study based on a questionnaire. RESULTS: We included 31 patients. The mean age at onset of eye manifestations was 4.5 years. Optic disc changes were the most common feature, occurring in 26 patients (83%), including optic disc edema, pseudopapilledema, and optic atrophy. Anterior segment manifestations varying from mild to severe were seen in 13 patients (42%); chronic anterior uveitis, in 17 patients (55%). Moderate to severe visual acuity loss in at least 1 eye was seen in 8 patients (26%) as a consequence of the disease. Posterior synechia, glaucoma, and white iritis were not observed in any patient. CONCLUSION: Ocular manifestations with potentially sight-threatening complications occur commonly in the CINCA/NOMID syndrome. The distinctive nature of these complications may assist the ophthalmologist in recognizing this rare disorder and distinguishing it from juvenile rheumatoid arthritis.

Comparative tolerability of treatments for juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) includes several forms of chronic arthritis in children. Treatments are chosen according to the type and severity of the disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids remain the mainstays of therapy. Traditional slower acting anti-rheumatic drugs, such as gold therapy, penicillamine, sulfasalazine, tiopronin and hydroxychloroquine, are usually poorly active in children. In addition, adverse effects are common, including severe macrophage activation syndrome with gold therapy or sulfasalazine. Low dose, once weekly methotrexate has emerged as the therapeutic agent of choice for children who fail to respond adequately to the administration of an NSAID, especially in those with the extended oligoarticular subtype of the disease. Other immunosuppressive agents, such as cyclosporin, are sometimes combined with methotrexate. In recent years, novel treatments have been developed. Autologous hematopoietic stem cell transplantation is effective in a number of children with severe JIA, whose disease has been refractory to conventional therapy. However, only short term follow-up data are currently available for this novel therapy. In addition, severe infections complicated by macrophage activation syndrome and death have been reported. Finally, anti-tumour necrosis factor-alpha therapy has shown efficacy in more than two-thirds of children with JIA and polyarthritis, and other cytokine inhibitors may be soon available.

Inflammation: "a natural experiment" for the systemic pathogenicity of cytokines.

It has previously been demonstrated that the overproduction of interleukin-6 (IL-6) is a key element in the clinical and biological abnormalities encountered in Castleman's disease (CD). The particular case of a male child with a localized form of CD is reported. In this patient, evidence was found of a correlation between systemic manifestations and circulating IL-6, and IL-6 gene overexpression in the germinal centers of hyperplastic lymph nodes. Circulating IL-6 levels were 10- to 100-fold higher than in all CD cases previously documented. This unique biological feature was closely associated with high levels of circulating IL-1 and tumor necrosis factor-alpha (TNF-alpha), which are known for their ability to induce and/or amplify IL-6 production. One month after surgical removal of the pathological lymph node, the clinical and biological abnormalities diminished, while circulating IL-6 levels dropped dramatically eight months later. It is worth noting that after resection, the time-course of the IL-6 decrease closely correlated with that of IL-1 and TNF-alpha. Considering that in various inflammatory diseases IL-1, TNF-alpha and IL-6 may act in a synergistic manner in inducing systemic manifestations, this case report raises new questions as to the nature of the systemic pathogenicity of cytokines in CD.

Joint diseases in the first year of life.

A great variety of diseases may express themselves in the form of joint involvement in patients under the age of one year. Articular infections are the most important disease to be recognized due to the urgent need for treatment. Inflammatory diseases and heritable disorders of various origins may also start early in life.

A recently recognised chronic inflammatory disease of early onset characterised by the triad of rash, central nervous system involvement and arthropathy.

Chronic Infantile Neurological Cutaneous and Articular (CINCA) syndrome, also called Neonatal Onset Multisystemic Inflammatory Disease (NOMID) is characterised by the triad of cutaneous rash, chronic meningitis and arthropathy. It is a chronic inflammatory illness that starts most often at birth and persists for the whole lifespan of the patient. Attempts at therapy have been disappointing. The long-term prognosis is poor, with progressive deafness and visual impairment, and worsening of the central nervous system manifestations. Some cases of death have been reported secondary to infection, vasculitis and amyloidosis. Usually observed as sporadic cases, some familial association is recognised.

Evaluation of methotrexate in the treatment of juvenile chronic arthritis according to the subtype.

Methotrexate therapy was evaluated in 30 children with juvenile chronic arthritis according to the type of onset. The systemic form seemed less responsive than the ANA positive form with a polyarticular course or polyarticular onset. The clinical improvement, particularly in the ANA positive polyarticular course was confirmed by a significant decrease in the values of the ESR. Side effects occurred in 12 patients and consisted of gastrointestinal upset, mouth ulcers, slight leucopenia and elevated transaminases. They led to discontinuation of the treatment in only one child. Concomitant therapy could be stopped in 50% of the patients with an ANA positive polyarticular course, but remained necessary in the two other groups. These results indicate a differential effect of MTX therapy according to the type of JCA.

Levels of cytokine inhibitors: a possible marker of disease activity in childhood dermatomyositis and polymyositis.

The levels of cytokines and of their inhibitors were assessed by ELISA in serum samples from 3 children with dermatomyositis (DM) and polymyositis (PM) who were followed for several years. We observed normal levels of IL-6 and TNF alpha, but increased concentrations of IL-1Ra and TNF-sR75 at disease onset, which was followed by a decrease in the levels of IL-1Ra and TNF-sR75 in the patients with a favorable disease outcome. In contrast, in the one patient who relapsed no correlation with the levels of cytokines or of their inhibitors could be established. These results suggest that cytokine inhibitors such as IL-1Ra and TNF-sR may be useful additional parameters for monitoring the evolution of DM and PM.

High dose immunoglobulin therapy in severe juvenile chronic arthritis: long-term follow-up in 16 patients.

Sixteen children with severe juvenile chronic arthritis received high dose intravenous immunoglobulin (IVGG). Extra-articular symptoms improved to some degree in 6 of ten patients. A decrease in the number of active joints occurred in 7 patients of the 11 who received more than ten months of IVGG. Hemoglobin levels increased, the ESR and platelet counts decreased and the IgG levels diminished in most of the patients who received long term treatment. The treatment was totally ineffective in three children who had very severe disease. Two children had respectively a vasculitic rash and urticaria thought to be side effects of the treatment. One had proteinuria. This last might have been due to other therapeutic agents given. Although clinical and biological benefits occurred in some, the state of the patients who had short term (m = 2-3 months) or long term (m = 2-7 years) therapy was not different at the last visit.

Juvenile dermato/polymyositis: a retrospective analysis of 33 cases with special focus on initial CPK levels.

Retrospective analysis of 33 patients with juvenile dermato/polymyositis showed 45% complete recovery, 26% remission (steroid dependent), 6% wheelchair-dependency, 3% deaths and 10% development of other connective tissue diseases after a mean follow up of 4 years. Patients who received 2 mg/kg of prednisone had the worst prognosis but since they apparently represent a subgroup it is questionable whether high dose prednisone was the cause of the poor prognosis. This subgroup is characterized by high CPK serum levels (a 10-fold increase or more) and an acute type of onset. An initial high ANA titer was found to predict the later development of other connective tissue disorders.

Epidemiologic survey of juvenile chronic arthritis in France. Comparison of data obtained from two different regions.

An epidemiologic survey of JCA was carried out in two regions of France, the western part of Paris and Brittany, differing in terms of geological background and demography. The prevalence was 0.77 and 0.100% and the incidence 0.019 and 0.013%, respectively. The type of onset, the course of the disease, the immunological data and the degree of final disability were similar in both regions. These data were compared to other studies and the factors of possible discrepancy analysed.

Macrophage activation syndrome and rheumatic disease in childhood: a report of four new cases.

A macrophage activation syndrome (MAS) developed in four children with chronic rheumatic diseases. The presentation included fever, hepatic and splenic enlargement, profound depression of blood counts, lowering of ESR, elevation of SGOT/PT and hypofibrinogenemia. The most characteristic sign of MAS was the presence in the bone marrow aspirate of well differentiated macrophages showing active haemophagocytosis with haematopoietic elements in their cytoplasm. Activation of the macrophage was also illustrated by high levels of monokines in the serum of 2 patients. This immuno-hematological process of unknown etiology can be triggered by ubiquitous events such as infections and treatment with anti-inflammatory drugs. It is a potentially lethal complication which should be diagnosed rapidly, since administration of high-dose steroids with discontinuation of potentially toxic drugs can induce remission. Cyclosporin A was effective in two patients and may be of value in the management of the macrophage-activation syndrome. Its efficacy supports the central involvement of a T-cell dysfunction. It must be borne in mind that children with rheumatic diseases, especially the systemic form of juvenile chronic arthritis, are highly vulnerable to life-threatening macrophage activation, which appears to be more frequent than previously recognized. Very careful monitoring of apparently "innocent" drugs and intercurrent viral infections is thus required.

Is onset type evaluated during the first 3 months of disease satisfactory for defining the sub-groups of juvenile chronic arthritis? A EULAR Cooperative Study (1983-1986).

This study represents an attempt to collect observations from co-operating countries to evaluate the previously suggested criteria for juvenile chronic arthritis during the onset periods 0-3 and 3-6 months, preferably studied prospectively. Only 267 of 378 forms returned were satisfactory for inclusion because of failure to observe exclusion criteria or insufficient information. Despite this it was possible to conclude that systemic disease represented 25% of the group and that these features tended to decline during the 6 month period. Gut inflammation was seen in 4.5% and the frequency of chronic iridocyclitis increased during the observation period to 4.5%. Variation in joint state during this period suggests that course classification may be important, as 23 of 118 who were pauciarticular at 3 months became polyarticular by six months, but only 46 of 76 who were polyarticular at 3 months remained in this state at six months.

The Swiss German and Swiss French versions of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report herein the results of the cross-cultural adaptation and validation into the Swiss German and Swiss French languages of the parent's version of two health related quality of life instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific health instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. The Swiss German and Swiss French CHAQ-CHQ were adapted from the German and French versions of the CHAQ-CHQ, and revalidated in this study. A total of 147 subjects were enrolled: 85 patients with JIA (22% systemic onset, 31% polyarticular onset, 32% extended oligoarticular subtype, and 15% persistent oligoarticular subtype) and 62 healthy children. The CHAQ clinically discriminated between healthy subjects and JIA patients, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to their healthy peers. Also the CHQ clinically discriminated between healthy subjects and JIA patients, with the systemic onset, polyarticular onset and extended oligoarticular subtypes having a lower physical and psychosocial well-being when compared to their healthy peers. In conclusion the Swiss German and Swiss French versions of the CHAQ-CHQ are reliable, and valid tools for the functional, physical and psychosocial assessment of children with JIA.

Systemic onset juvenile chronic arthritis, polyarticular pattern and hip involvement as markers for a bad prognosis.

OBJECTIVE: To explore all the common clinical and biological variables that are characteristic of Systemic onset Juvenile Chronic Arthritis (SoJCA) in order to determine which of them are suitable as predictors of a bad articular outcome (persistence of inflammatory symptoms and/or established limitation of the range of motion (ROM). MATERIAL AND METHODS: Clinical charts for 124 SoJCA patients were retrospectively reviewed. From them, 91 were finally included in the study because they had all of the clinical and biological data at disease onset properly recorded. All have been followed for at least 3 years since the beginning of the disease. Data collected at onset, and after 3 and 6 months of the disease included: 1) systemic symptoms; 2) joint involvement, using both the usual articular count and the value of an articular index (Helsinki Index = HI) which intentionally excludes those joints that are not uniformly recorded in clinical charts; and 3) biological data. HI was used to separate the patients into two groups. When applied 3 years after the disease onset, HI > or = 10 represented a bad articular outcome while HI < 10 meant a good prognosis. SPSS for Windows 6.1 was used for both the univariate and multivariate analyses. RESULTS: From the multivariate logistic regression analysis, two different "clusters" of clinical data were found to be the best predictors of a bad articular outcome. A bad prognosis was linked at onset with the presence of generalized lymphadenopathies, age < 8 years and an HI > 6; at six months a bad outcome was linked with the presence of a polyarticular pattern plus hip involvement. CONCLUSION: Clinical parameters at the beginning of the disease were shown to be extremely useful in predicting the articular outcome of SoJCA. Therefore, they could constitute a good instrument to help clinicians tailor the best therapy for their patients.

The French version of the Childhood Health Assessment Questionnaire (CHAQ) and the Child Health Questionnaire (CHQ).

We report the results of the cross-cultural adaptation and validation into the French language of two health status instruments. The Childhood Health Assessment Questionnaire (CHAQ) is a disease specific instrument that measures functional ability in daily living activities in children with juvenile idiopathic arthritis (JIA). The Child Health Questionnaire (CHQ) is a generic health related quality of life instrument designed to capture the physical and psychosocial well-being of children independently from the underlying disease. Five hundred children were enrolled including 306 patients with JIA classified into systemic (23%), polyarticular (22%), extended oligoarticular (25%), and persistent oligoarticular (30%) subtypes, and 194 healthy children. Both instruments were reliable with intra-class correlation (ICC) coefficients for the test-retest procedure of 0.91 for the CHAQ, and 0.87 and 0.89 for the physical and psychosocial summary scores of CHQ, respectively. Agreement between parents and children evaluated for the CHAQ was high with an ICC of 0.89 for the disability index; weighted kappa coefficients for the 8 domains ranged from 0.61 to 0.72. Convergent validity was demonstrated by significant correlations with the JIA core set of variables (physician and parent global assessment, scores for active joints and joints with limited range of motion, erythrocyte sedimentation rate) for both instruments. Both CHAQ and CHQ discriminated between healthy and JIA children, but only the disease specific CHAQ questionnaire discriminated clearly between the 4 JIA subtypes. In conclusion, the French versions of the CHAQ and the CHQ are reliable, and valid health assessment questionnaires to be used in children suffering from JIA.