[Intra-articular injection of cortisone]. / Intraartikuläre Injektion mit Kortison.

Intra-articular injections with glucocorticoids are standard procedures according to therapy guidelines in many rheumatic conditions. There is increasing evidence from clinical trials on the treatment of rheumatoid arthritis that more patients will attain the target of remission using a combination of systemic medication and intra-articular injections with glucocorticoids compared to systemic medication alone. Intra-articular injections with glucocorticoids play an important role in the therapeutic management of pediatric rheumatic diseases. In many countries competency in performing intra-articular injections is among the important skills necessary for certification as a specialist in rheumatology.

[Current news from the BIKER register]. / Aktuelles aus dem BIKER-Register.

Innovative developments in the pharmacotherapy of juvenile idiopathic arthritis and especially biologics allow the formulation of new therapeutic targets, such as the rapid induction of remission with shortening of the period of active disease and therefore preventing damage and disability. These new therapies also represent a challenge to the monitoring of drug safety, the pharmacovigilance. For this purpose the Society for Paediatric and Adolescent Rheumatology has set up an early register to record achievements in treatment improvement and in addition to independently assess information on drug safety, acute tolerance and long-term safety.

Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

Uveitis in juvenile idiopathic arthritis (JIA) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first-choice therapy, and immunosuppression is commonly used. However, treatment has not been standardized. Representatives from the German Ophthalmological Society, Society for Childhood and Adolescent Rheumatology, and the German Society for Rheumatology reached consensus on a standardized treatment strategy according to disease severity in the individual patient. The recommendations were based on a systematic literature analysis in MEDLINE and consensus expert meetings. Evidence and recommendations were graded, and an algorithm for anti-inflammatory treatment and final statements confirmed in a Delphi method. An interdisciplinary, evidence-based treatment guideline for JIA uveitis is presented.

[Evidence and consensus based treatment guidelines 2010 for juvenile idiopathic arthritis by the German Society of Paediatric Rheumatology]. / Interdisziplinäre S2-Therapieleitlinie der Juvenilen Idiopathischen Arthritis (2. Auflage).

BACKGROUND: Treatment of Juvenile Idiopathic Arthritis (JIA) has improved quality of life in children and adolescents with JIA. Standardisation of care offers the chance to improve the quality of care of those patients. New studies have been published after completion of our last treatment guideline (2007). An updated consensus process is mandatory. METHODS: A systematic literature analysis in PUBMED (key words: juvenile idiopathic (rheumatoid) arthritis, therapy; limits: humans, published in the last 3 years, all child 0-18 years, clinical trial) revealed 17 relevant studies. Studies relating to diagnosis of JIA, Uveitis, vaccination, transition were excluded. Representatives nominated by scientific societies and organisations were invited to consensus conferences which were hosted by a professional moderator. The following societies were invited: Berufsverband der Kinder- und Jugendärzte (BVKJ), Deutsche Gesellschaft für Kinder- und Jugendmedizin (DGKJ), Deutsche Gesellschaft für Rheumatologie (DGRh), Deutsche Ophthalmologische Gesellschaft (DOG), Deutsche Rheuma-Liga Bundesverband, Verein zur Förderung und Unterstützung rheumatologisch erkrankter Kinder und deren Eltern, Vereinigung für Kinderorthopädie, Zentraler Verband der Physiotherapeuten und Krankengymnasten (ZVK). Consensus conferences were each attended by more than 95% of the nominated representatives. Consensus statements were confirmed by nominal group technique and Delphi method. RESULTS AND CONCLUSION: Updated consensus statements regarding drug therapy, symptomatic and surgical management of JIA were compiled and judged strictly by the criteria of Evidence-Based Medicine (EBM).

IL10 promoter polymorphisms are associated with systemic onset juvenile idiopathic arthritis (SoJIA).

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a rare, but severe cause of childhood disability. Systemic onset JIA (SoJIA) accounts for approximately 5.8% of all JIA cases and is associated with cytokine dysregulation, including interleukin (IL-)1, IL-6 and tumour necrosis factor (TNF-)α. IL-10 is an immuno-regulatory cytokine, which in part regulates inflammation by controlling inflammatory cytokine expression. Dysregulation in IL-10 expression and certain single nucleotide polymorphisms (SNPs) in the IL-10 promoter were shown to be associated with autoimmune and infectious diseases. METHODS: Genomic DNA-samples from SoJIA patients from two German Paediatric Rheumatology centres, and healthy controls were analysed for three well defined IL-10 promoter SNPs (-1082G>A, -819C>T, and -592C>A). These SNPs are in tight linkage disequilibrium, and result in three predominant (or 'classical') haplotypes: ATA, ACC, and GCC. ATA and ACC are associated with low and medium, GCC is associated with high IL-10 expression. RESULTS: Here, we show a strong association of IL-10 promoter polymorphisms with SoJIA. We demonstrate a significantly increased frequency of low IL-10 expressing -1082A/A alleles, the medium IL-10 expressing ACC haplotype (p=0.01), and an enrichment of the rare GTC haplotype (p<0.001) in patients with SoJIA. Heterozygous -1082G/A alleles (p<0.001), and the GCC haplotype (p<0.001) on one allele protect from developing SoJIA. CONCLUSIONS: This suggests a central role of the immuno-regulatory cytokine IL-10 in the pathogenesis of SoJIA.

The economic burden of juvenile idiopathic arthritis-results from the German paediatric rheumatologic database.

OBJECTIVE: To estimate the cost of juvenile idiopathic arthritis (JIA) and to evaluate the influence of specific disease characteristics on the various costs domains. METHODS: Data on JIA outpatients (n=369) who were enrolled in the national paediatric rheumatologic database and completed a cost questionnaire were analysed. Direct JIA-related costs, families' out-of-pocket expenses and parents' income loss were calculated per patient and year, using physicians' reports, parents' 3-month recall, and average prices as the basis. RESULTS: The mean total cost of JIA was estimated to be 4,663 euro per patient per year. The highest costs were calculated for patients with seropositive polyarthritis and systemic arthritis (7,876 euro), and the lowest costs were seen for patients with persistent oligoarthritis (2,904 euro). Health-care costs accounted for 89% of total costs, and medication contributed to almost half of this value. A considerable amount of the cost was borne by the families, with a mean out-of-pocket cost of 223euro and a mean indirect cost due to time loss from work of 270 euros per year per family. Cost increased with disease activity and pain, disease duration, and time period from symptom onset to first paediatric rheumatologist visit; it also increased with the presence of uveitis. However, function, as measured by the Childhood Health Assessment Questionnaire, was the only factor significantly contributing to the variation in patient total costs. CONCLUSION: JIA imposes a significant economic burden. Medication (i.e. biologic drugs) contributes substantially to the total costs. However, these must be considered in the light of the patients' long-term outcomes.

Update of the evidence based, interdisciplinary guideline for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis.

BACKGROUND: Uveitis in juvenile idiopathic arthritis (JIAU) is frequently associated with the development of complications and visual loss. Topical corticosteroids are the first line therapy, and disease modifying anti-rheumatic drugs (DMARDs) are commonly used. However, treatment has not been standardized. METHODS: Interdisciplinary guideline were developed with representatives from the German Ophthalmological Society, Society for Paediatric Rheumatology, Professional Association of Ophthalmologists, German Society for Rheumatology, parents' group, moderated by the Association of the Scientific Medical Societies in Germany. A systematic literature analysis in MEDLINE was performed, evidence and recommendations were graded, an algorithm for anti-inflammatory treatment and final statements were discussed in a consensus meeting (Nominal Group Technique), a preliminary draft was fine-tuned and discussed thereafter by all participants (Delphi procedure). RESULTS: Consensus was reached on recommendations, including a standardized treatment strategy according to uveitis severity in the individual patient. Thus, methotrexate shall be introduced for uveitis not responding to low-dose (≤ 2 applications/day) topical corticosteroids, and a TNFalpha antibody (preferably adalimumab) used, if uveitis inactivity is not achieved. In very severe active uveitis with uveitis-related deterioration of vision, systemic corticosteroids should be considered for bridging until DMARDs take effect. If TNFalpha antibodies fail to take effect or lose effect, another biological should be selected (tocilizumab, abatacept or rituximab). De-escalation of DMARDs should be preceded by a period of  ≥ 2 years of uveitis inactivity. CONCLUSIONS: An interdisciplinary, evidence-based treatment guideline for JIAU is presented.

Methotrexate for uveitis associated with juvenile idiopathic arthritis: value and requirement for additional anti-inflammatory medication.

PURPOSE: To study the value of methotrexate (MTX) and the requirement for additional anti-inflammatory drugs for the treatment of severe chronic iridocyclitis associated with juvenile idiopathic arthritis (JIA). METHODS: Institutional study of 35 consecutive patients with JIA started on MTX as the single systemic immunosuppressive drug for the treatment of associated iridocyclitis. The clinical epidemiologic data, course of visual acuity (VA), development of complications, and the need for additional anti-inflammatory drugs were analyzed. RESULTS: Mean follow-up with MTX treatment was 27.6 months. Uveitic complications were present in 31 patients before MTX treatment. With MTX, quiescence of uveitis was obtained with (n=21) or without (n=4) additional topical steroids. Additional systemic immunosuppressive drugs were required in another 7 patients: cyclosporine A (n=4), azathioprine (n=1), infliximab (n=1), or etanercept (n=1). Three patients had active uveitis at the end of the follow-up period. During MTX therapy, uveitis first developed in the unaffected fellow eyes in 2 patients, and secondary glaucoma or ocular hypertension occurred in 7 patients. The VA deteriorated in 6, improved in 13, and was stable in the remaining eyes. CONCLUSIONS: The data suggest that MTX is very effective in controlling inflammation of uveitis in patients with JIA. However, additional topical steroids or systemic immunosuppressive drugs are often required.

EGF and TGF alpha influence in vitro lung development by the induction of matrix-degrading metalloproteinases.

Remodeling of the extracellular matrix by matrix-degrading metalloproteinases (MMPs) has been implicated in the early morphogenesis of branched organs. Growth factors such as EGF and TGF alpha are known to regulate the expression of MMPs in a variety of systems. We therefore examined the effects of EGF, TGF alpha, and collagenase upon in vitro branching of the embryonic lung. Lung rudiments from 11.5 day post coitum mice underwent extensive growth and repetitive branching during a 3-day period in organ culture. Lungs treated with EGF or TGF alpha were larger than controls, yet displayed fewer branches along with markedly dilated end buds which lacked clefts, indicating that these growth factors inhibit normal lung branching. Addition of purified mammalian collagenase to lung cultures similarly inhibited epithelial branching and produced end bud enlargement. In addition, gelatin-substrate enzymography of the conditioned medium from EGF- and TGF alpha-treated lungs revealed a marked induction of a metalloproteinase activity which most likely corresponds to the 72kDa type IV collagenase/gelatinase which degrades basement membrane collagens. Lungs maintained in the presence of both TGF alpha and TIMP, a specific inhibitor of MMPs, branched repeatedly and displayed normal, narrow end buds as seen with controls, suggesting that TIMP is capable of preventing or reversing the observed growth factor mediated effects upon lung branching. Taken together, these results provide evidence that the growth factors EGF and TGF alpha guide lung development, at least in part, by inducing the expression of matrix-degrading metalloproteinases.

Decreased prorenin processing develops before autonomic dysfunction in type 1 diabetes.

It is well documented that diabetic patients with chronic complications have decreased renin secretion and elevations in the renin precursor prorenin. It is uncertain, however, whether the abnormal processing of prorenin is reflective of microvascular disease, hypertension, or autonomic neuropathy. Dechaux et al. (Transplant Proc. 18:1598-1599, 1986) observed abnormalities in prorenin processing in uncomplicated diabetes and suggested that it was the result of subclinical autonomic neuropathy. To test this hypothesis, we measured renin, prorenin, and autonomic function in early type 1 diabetes at a time when there is little or no microvascular disease or hypervolemia. Thirty-seven patients (10 males, 27 females) enrolled 2-22 months after diagnosis in a longitudinal study in which renin, prorenin, and autonomic function were measured annually for 3 years. Forty-one age-matched control subjects were also studied. PRA in the diabetic patients at the time of the second and third evaluations was 1.71 +/- 0.24 ng angiotensin I/mL x h and 1.67 +/- 0.24 ng angiotensin I/mL x h, respectively, significantly lower (P < 0.05) than that of the control subjects in whom PRA was 2.96 +/- 0.38 ng angiotensin I/mL x h. Prorenin was not different in the diabetic patients in comparison with controls. The renin to prorenin ratio in the diabetic patients at the time of the first, second, and third evaluations was 0.260 +/- 0.03, 0.235 +/- 0.05, and 0.227 0.05, respectively, significantly lower (P < 0.01) than in control subjects in whom the renin to prorenin ratio was 0.475 +/- 0.08. Despite this, at the time of the first and second evaluations, there was no evidence of autonomic dysfunction and no correlation between any test of autonomic function and the renin to prorenin ratio. At the time of the third evaluation, however, the intermediate frequency (0.04-0.15 Hz) power spectra while patients were supine (an index of sympathetic modulation of heart rate variability) showed a highly significant (P < .001) correlation with the renin to prorenin ratio. High frequency (0.15-0.40 Hz) spectra from supine patients at the third evaluation also correlated with the renin to prorenin ratio (P < 0.01). We conclude abnormal processing of prorenin develops in diabetic patients prior to microvascular disease, even before the first evidence of autonomic dysfunction. Although the latter may play a contributory role, additional as yet unidentified mechanisms seem to interrupt the processing of prorenin in early diabetes.

Antibodies to glutamic acid decarboxylase and peripheral nerve function in type 1 diabetes.

Autoimmune mechanisms have been implicated in the pathophysiology of diabetic neuropathy. We studied the association between glutamic acid decarboxylase (GAD65) and islet cell (IA-2) autoantibodies as well as autoantibodies to the autonomic nervous system and peripheral nerve function in recent onset type 1 diabetes. Thirty-seven patients (27 females and 10 males) enrolled 2-22 months after diagnosis. Humoral factors, glycemic control, and peripheral nerve function were measured annually for 3 yr. Patients with high GAD65Ab had worse glycemic control and higher insulin requirements. Patients with high GAD65Ab had slower motor nerve conduction velocities in the median, ulnar, and peroneal nerves (P < 0.025 for each nerve). The mean motor nerve conduction velocity Z scores at the time of the third evaluation was 0.341 +/- 0.25 for the low GAD65Ab patients and -0.600 +/- 0.25 for the high GAD65Ab patients (P < 0.01). Similar differences between the low and high GAD65Ab groups were observed for F wave latencies, thermal threshold detection, and cardiovascular autonomic function. The composite peripheral nerve function Z scores in the low GAD65Ab patients were 0.62 +/- 11, 0.71 +/- 0.19, and 0.21 +/- 0.14 at the first, second, and third evaluations, significantly different from those in the high GAD65Ab patients in whom they were -0.35 +/- 0.15, -0.46 +/- 0.18, and -0.42 +/- 0.16 (P < 0.001). In summary, GAD65Ab in patients with recent onset type 1 diabetes are associated with worse glycemic control and slightly worse peripheral nerve function. Although the latter remained within normal limits and none of the patients had clinical neuropathy, the GAD65Ab-related differences in composite peripheral nerve function were highly significant (P < 0.001) and could not be attributed to GAD65Ab-related differences in glycemic control.

Gastrointestinal symptoms and permeability in patients with juvenile idiopathic arthritis.

OBJECTIVE: Examining for gastrointestinal involvement in juvenile idiopathic arthritis is an important part of diagnostic and therapeutic procedures. Only few scientific data are available. METHODS: In a prospective study, 41 patients with juvenile idiopathic arthritis were examined for clinical and laboratory data of gastrointestinal involvement. Sugar absorption tests with lactulose, mannitol, and sucrose were applied to assess gastric and intestinal mucosal lesions. Faecal albumin and alpha 1-antitrypsin levels were measured to examine gastrointestinal protein loss, a test for occult blood in stool was administered and Helicobacter pylori serology was performed. RESULTS: 39% of our study population complained of chronic abdominal pain. The patient group showed increased sucrose excretion (p = 0.002), but a normal lactulose/mannitol ratio compared with healthy controls (p = 0.472). 21% of the patients had an elevated faecal alpha 1-antitrypsin level, but only one patient showed occult blood loss. There was no correlation between risk factors and clinical or laboratory signs of gastrointestinal involvement. CONCLUSION: We conclude that a high percentage of children and adolescents with juvenile idiopathic arthritis treated with non-steroidal antiinflammatory drugs show clinical or laboratory signs of gastrointestinal involvement.

Sulindac for polyposis of the colon.

The effect of sulindac, a nonsteroid antiinflammatory drug, on colon polyposis has been evaluated in seven patients after subtotal colectomy and ileoproctostomy and in four patients with intact colons. The patients all had Gardner's syndrome or familial polyposis coli. All polyps were eliminated, except for a few that arose in the rectal mucosa and the anal canal. No cancers developed in these patients on follow-up.

Efficacy and safety of oral and parenteral methotrexate therapy in children with juvenile idiopathic arthritis: an observational study with patients from the German Methotrexate Registry.

OBJECTIVE: The German Methotrexate Registry has been collecting data concerning the efficacy and safety of methotrexate (MTX) treatment since 2005. The aim of this retrospective analysis is to compare oral and parenteral MTX treatment regarding efficacy and safety. METHODS: Inclusion criteria were diagnosis of juvenile idiopathic arthritis, MTX treatment for at least 6 months, a consistent route of administration of MTX, and no previous or concomitant treatment with biologic agents. Efficacy was measured by the American College of Rheumatology (ACR) pediatric (Pedi) criteria. Primary outcome was efficacy defined as the number of patients reaching ACR Pedi 30 improvement criteria after 6 months of treatment. Secondary outcome criteria were the ACR Pedi 50 and Pedi 70 criteria at 6 and 12 months, respectively. Analyses were performed with the intent-to-treat population. RESULTS: Of the 411 eligible patients, 259 (63%) received oral MTX and 152 (37%) received subcutaneous MTX. In both patient groups, a comparable weekly dose of MTX (0.4 mg/kg versus 0.42 mg/kg) was used, and a comparable number of patients received concomitant steroids. The primary outcome in both treatment groups was that a comparably high number of patients showed a clinical response according to the ACR Pedi 30 score after 6 months of treatment (73% versus 72%; P = 0.87). Twenty-two percent of patients with oral therapy and 27% with subcutaneous therapy had at least 1 documented adverse event. Discontinuation of treatment was observed in both groups with equal frequency, while significantly more patients with subcutaneous application discontinued MTX because of adverse events (11% versus 5%; P = 0.02). CONCLUSION: In this retrospective analysis, parenteral MTX was not superior to oral administration regarding efficacy and tolerability.

Azathioprine as a treatment option for uveitis in patients with juvenile idiopathic arthritis.

AIM: To investigate the therapeutic value of azathioprine as monotherapy or combined with other immunosuppressive drugs for uveitis in patients with juvenile idiopathic arthritis (JIA). METHODS: A retrospective multicentre study including 41 children with JIA (28 (68.2%) female) with unilateral or bilateral (n=28) chronic anterior uveitis. Azathioprine was used to treat uveitis that was active in patients receiving topical or systemic corticosteroids, methotrexate or other immunosuppressive drugs. The primary end point was assessment of uveitis inactivity. Secondary end points comprised dose sparing of topical steroids and systemic corticosteroids, and immunosuppression. RESULTS: At 1 year, uveitis inactivity was achieved in 13/17 (76.5%) patients by using azathioprine as systemic monotherapy and in 5/9 (56.6%) as combination therapy. During the entire azathioprine treatment period (mean 26 months), inactivity was obtained in 16/26 patients (61.5%) with monotherapy and in 10/15 (66.7%) when combined with other immunosuppressives (p=1.0). With azathioprine, dosages of systemic immunosuppression and steroids could be reduced by ≥ 50% (n=12) or topical steroids reduced to ≤ 2 drops/eye/day in six patients. In three patients (7.3%), azathioprine was discontinued because of nausea and stomach pain. Conclusions Azathioprine may be reconsidered in the stepladder approach for the treatment of JIA-associated uveitis. The addition of azathioprine may also be beneficial for patients not responding properly to methotrexate.

Limited value of cyclosporine A for the treatment of patients with uveitis associated with juvenile idiopathic arthritis.

AIMS: Juvenile idiopathic arthritis (JIA) is often associated with severe chronic anterior uveitis (CAU), and immunosuppressive therapy may be required. In this study, the value of cyclosporine A (CsA) as monotherapy or as combination therapy for treating uveitis was studied in a large cohort of JIA children. METHODS: Multicentre retrospective study including 82 JIA children (girls n=60) suffering from unilateral or bilateral (n=55) CAU. The indication for CsA was active uveitis, although patients were on topical or systemic corticosteroids, MTX, or other immunosuppressive drugs. RESULTS: Inactivity of uveitis during the entire treatment period (mean 3.9 years) was obtained with CsA monotherapy in 6 of 25 (24%) patients, but more often when CsA was combined with the immunosuppressives (35/72 patients; 48.6%, P=0.037), or MTX (18/37 patients, 48.6%, P=0.065), which had already been given. With CsA (mean dosage 2.9 mg/kg), systemic immunosuppressive drugs and steroids could be reduced by >or=50% (n=19) or topical steroids reduced to

[Juvenile idiopathic arthritis and uveitis: epidemiology including data from a national database]. / Juvenile idiopathische Arthritis und Uveitis: Epidemiologie einschliesslich der Daten aus der Kerndokumentation.

Uveitis is a potentially vision-threatening extra-articular manifestation of juvenile idiopathic arthritis (JIA) that manifests in approximately 13 % of all patients. According to the national ophthalmological and paediatric rheumatological database, one out of four children with JIA and uveitis develops ocular complications such as synechiae, band keratopathy, cataract, glaucoma and macula oedema. Independent risk factors of uveitis include the presence of a certain JIA subgroup, of antinuclear antibodies and age at onset. A late diagnosis, however, seems to be the relevant risk factor for uveitis complications in the course of the disease. The diagnosis of uveitis as early as possible is therefore the most important factor for a reduction of the morbidity of uveitis. Due to the usual lack of symptoms the diagnosis of uveitis requires, however, an examination by an ophthalmologist. This should be done immediately after the diagnosis of JIA and repeated in a risk-adapted manner during the follow-up.