Stefan Hagelberg

Juvenile idiopathic arthritis and risk of cancer: a nationwide cohort study.

OBJECTIVE Reports of therapy-related adverse events suggest an elevated rate of malignancy in patients with juvenile idiopathic arthritis (JIA) treated with biologic therapies. However, the scarcity of data on the underlying risk of malignancy in JIA hampers interpretation of these signals. Therefore, the aim of this study was to determine the risk of cancer in patients with JIA as compared with that in the general population. METHODS Through linkage with a national database, the Swedish Patient Register (comprising inpatient discharges in 1969-2007 and specialist outpatient visits in 2001-2007 in Sweden), a national JIA cohort (n = 9,027) was identified, and each JIA case was matched with 5 general population comparators. Using data from the Swedish Cancer, Census, Death, and Biologics Registers, the occurrence of cancer, vital status, and start of a biologic therapy were identified. The relative risk (RR) of first occurrence of a primary cancer in patients who had not been treated with biologics (biologics-naive patients with JIA) was estimated using Poisson regression, stratified a priori by year of earliest identification of JIA (before 1987 versus 1987 and thereafter). In sensitivity analyses, the data were followed up to 1999, when biologics first became available. RESULTS In this biologics-naive JIA cohort, 60 malignancies were observed during 131,144 person-years of followup, compared with 266 cancers observed during 661,758 person-years in the general population comparator (0.46 cases/1,000 person-years versus 0.40 cases/1,000 person-years; RR 1.1, 95% confidence interval [95% CI] 0.9-1.5). Patients with JIA identified before 1987 were not at increased risk of cancer, whereas JIA identified in 1987 and thereafter was significantly associated with incident lymphoproliferative malignancies (RR 4.2, 95% CI 1.7-10.7) and cancers overall (RR 2.3, 95% CI 1.2-4.4). Sensitivity analyses did not reveal any ready explanation for this heterogeneity. CONCLUSION Although absolute risks were low, an elevated risk of malignancy was observed among biologics-naive patients in whom the diagnosis of JIA was made in the past 20 years, which may have implications for the interpretation of cancer signals in patients with JIA treated with newer therapies.

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.

Molecular basis of hereditary C1q deficiency—revisited: identification of several novel disease-causing mutations

C1q is the central pattern-recognition molecule in the classical pathway of the complement system and is known to have a key role in the crossroads between adaptive and innate immunity. Hereditary C1q deficiency is a rare genetic condition strongly associated with systemic lupus erythematosus and increased susceptibility to bacterial infections. However, the clinical symptoms may vary. For long, the molecular basis of C1q deficiency was ascribed to only six different mutations. In the present report, we describe five new patients with C1q deficiency, present the 12 causative mutations described till now and review the clinical spectrum of symptoms found in patients with C1q deficiency. With the results presented here, confirmed C1q deficiency is reported in 64 patients from at least 38 families.

Lower extremity isometric joint torque in children with juvenile chronic arthritis.

OBJECTIVE To determine the intratester reliability of joint torque testing with a hand-held dynamometer (HHD) during contractions of four major lower extremity muscles in children with juvenile chronic arthritis (JCA) and to compare results for children with JCA to results for children without disability. METHODS Eleven children with JCA and 14 children with normal musculoskeletal function were tested with a HHD using isometric muscle contractions of the right quadriceps, hamstrings, tibialis anterior and triceps surae. RESULTS Intratester reliability values exceeded the 0.92 level, regardless of the number of trials, for all motions tested. Statistically lower joint torque values were found in a subgroup of children with JCA for contractions of the tibialis anterior (p=0.003) and triceps surae (p=0.05) muscles. CONCLUSIONS HHD offers a reliable means of testing the joint torque generated with contraction of these lower extremity muscles in children with JCA. Findings in children with JCA compared to children without disability agree with previous reports concerning quadriceps muscle function, but also point to concerns for muscles associated with generating ankle joint torque.Objective: To determine the intratester reliability of joint torque testing with a hand-held dynamometer (HHD) during contractions of four major lower extremity muscles in children with juvenile chronic arthritis (JCA) and to compare results for children with JCA to results for children without disability. Methods: Eleven children with JCA and 14 children with normal musculoskeletal function were tested with a HHD using isometric muscle contractions of the right quadriceps, hamstrings, tibialis anterior and triceps surae. Results: Intratester reliability values exceeded the 0.92 level, regardless of the number of trials, for all motions tested. Statistically lower joint torque values were found in a subgroup of children with JCA for contractions of the tibialis anterior (p = 0.003) and triceps surae (p = 0.05) muscles. Conclusions: HHD offers a reliable means of testing the joint torque generated with contraction of these lower extremity muscles in children with JCA. Findings in children with JCA compared to children without disability agree with previous reports concerning quadriceps muscle function, but also point to concerns for muscles associated with generating ankle joint torque.

Gait in children with juvenile chronic arthritis. Timing and force parameters.

Objectives : To examine gait in children with juvenile chronic arthritis (JCA) with reference to velocity, ground reaction forces and temporal parameters. Methods : Fifteen children with JCA were assigned into two groups (uni- and bilateral involvement and classified as pauci- or polyarticular arthritis). Fourteen healthy children participated in the control group. Light-beams were used to determine walking velocity and the children with JCA rated their pain on a visual analogue scale. Two force plates registered the ground reaction forces and foot-switches were used to obtain temporal parameters. Results : The mean velocity for the children with JCA was significantly less than for the healthy controls. Velocity normalized to height showed a tendency for the children with JCA to walk slower than controls. Differences between JCA children and healthy controls were observed for peak vertical forces during heel contact and push-off. No temporal differences were observed between the groups. Conclusions : Such kinetic and temporal information may provide the clinician with a sensitive tool for pre- and post assessment of intra-articular steroid injections and/or physical 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.

THE PROTEIN TOLERANCE OF VERY LOW BIRTH WEIGHT INFANTS FED HUMAN MILK PROTEIN ENRICHED MOTHER'S MILK

ABSTRACT. Pooled breast milk was ultra‐filtrated and freeze‐dried to give a product with a protein content of 60 g/100 g powder. More than half of the secretory IgA activity against E. coli O antigen was preserved. This concentrated protein was added to the mothers fresh milk providing a protein supply of 3.0‐3.5 g/kg/24 hours in four VLBW infants, at a calorie supply of 110 kca/kg/24 hours. Growth followed the intrauterine rate. Free amino acid levels, acid‐base balance and urea concentrations of peripheral whole blood indicated tolerance of the increased supply of human milk protein.

Amino Acid Levels in the Critically ill Preterm Infant Given Mother's Milk Fortified with Protein from Human or Cow's Milk

ABSTRACT. Twenty preterm infants undergoing neonatal intensive care were randomly allocated to one of two feeding regimens: human milk enriched with either human milk protein (HMP) or adapted cows milk protein (CMP). The birthweights (1076 ± 301 g; 1031 ± 309 g) and the gestational ages (28.4 ± 1.6 weeks; 27.7 ± 2.1 weeks) were comparable. The amount of protein added to the milk was set at 0.7 g/100 ml in order to provide a total supply of 3.0‐3.5 g/kg/24 h. All infants received additional amounts of carbohydrate, calcium, phosphorous, and sodium chloride. Capillary whole blood amino acids were measured with high pressure liquid chromatography (HPLC). The amino acid levels did not differ significantly when the feeding groups were compared week by week, but the glycine/valine ratio was higher (p<0.05) in the HMP group after three weeks of fortification. Longitudinal changes after protein enrichment could be demonstrated in both groups. Alanine and threonine increased after one week (p<0.01) in both groups. Glycine in the HMP group peaked after two weeks (p<0.02), and valine in the CMP group increased (p<0.02) after one week on the feeding regimen. However, the amino acids never reached levels above those seen after a meal in normal term newborns. Other variables related to protein intake, such as protein and urea in serum, did not vary between the groups. Growth, expressed as gains in weight, length, and head circumference was poor but comparable. The quality of the protein, whether a human milk protein isolate or a cows milk whey protein product, used for the fortification of human milk up to a protein load of 3.0‐3.5 g/kg/24 h, did not cause any alterations of significance in the amino acid profiles of peripheral blood.

BLOOD LEVELS OF CRITICAL AMINO ACIDS IN VERY LOW BIRTHWEIGHT INFANTS ON A HIGH HUMAN MILK PROTEIN INTAKE

Lindblad, B. S., Hagelberg, S. and Lundsjö, A. (Department of Paediatrics, Karolinska Institute, St. Görans Childrens Hospital, Stockholm, Sweden). Blood levels of critical amino acids in very low birthweight infants on a high human milk protein intake. Acta Paediatr Scand, Suppl. 296: 24, 1982. — A method for a semi–industrial production of human milk subfractions (human milk protein and human milk fat isolates) is described. Four very low birthweight (VLBW) newborn were given a human milk protein isolate added to the mothers own fresh expressed milk in addition to sodium chloride up to 20 mEkv/liter. Growth followed the intrauterine growth curve. Urea levels did not increase in spite of providing a double‐normal protein intake. There was no metabolite acidosis and the blood levels of free amino acids determined with a micro‐method did not exceed those seen after a normal meal. The concentrated human milk protein product showed a considerable specific sIgA activity against E. coli 0‐antigen. It seems possible to use similar “lacto‐engineering”‐techniques in order to satisfy the increased protein requirements of the VLBW infant, while providing the caloric requirements, without causing any visible disturbance of blood‐homeostasis of urea, amino acids or base excess. The method could provide knowledge about the “human milk protein requirements” and a controlled study has been started.

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/m2) and fludarabine (30 mg/m2) 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.