Prevalence of temporomandibular disorder in children and adolescents with juvenile idiopathic arthritis - a Norwegian cross- sectional multicentre study.

BACKGROUND: Children and adolescents with juvenile idiopathic arthritis (JIA) may suffer pain from temporomandibular disorder (TMD). Still, routines for the assessment of temporomandibular joint (TMJ) pain in health and dental care are lacking. The aims of this study were to examine the prevalence of TMD in children and adolescents with JIA compared to their healthy peers and to investigate potential associations between JIA and TMD. METHODS: This comparative cross-sectional study is part of a longitudinal multicentre study performed during 2015-2020, including 228 children and adolescents aged 4-16 years with a diagnosis of JIA according to the ILAR criteria. This particular substudy draws on a subset of data from the first study visit, including assessments of TMD as part of a broader oral health examination. Children and adolescents with JIA were matched with healthy controls according to gender, age, and centre site. Five calibrated examiners performed the clinical oral examinations according to a standardised protocol, including shortened versions of the diagnostic criteria for TMD (DC/TMD) and the TMJaw Recommendations for Clinical TMJ Assessment in Patients Diagnosed with JIA. Symptoms were recorded and followed by a clinical examination assessing the masticatory muscles and TMJs. RESULTS: In our cohort of 221 participants with JIA and 221 healthy controls, 88 (39.8%) participants with JIA and 25 (11.3%) healthy controls presented with TMD based on symptoms and clinical signs. Painful TMD during the last 30 days was reported in 59 (26.7%) participants with JIA vs. 10 (5.0%) of the healthy controls (p <  0.001). Vertical unassisted jaw movement was lower in participants with JIA than in controls, with means of 46.2 mm vs. 49.0 mm, respectively (p <  0.001). Among participants with JIA, a higher proportion of those using synthetic disease-modifying antirheumatic-drugs and biologic disease-modifying antirheumatic-drugs presented with painful masticatory muscles and TMJs at palpation. CONCLUSION: Symptoms and clinical signs of TMD were seen in approximately half of the JIA patients compared to about one fourth of their healthy peers. Painful palpation to masticatory muscles and decreased vertical unassisted jaw movement were more frequent in participants with JIA than among healthy controls and should be part of both medical and dental routine examinations in patients with JIA.

Fine-mapping the MHC locus in juvenile idiopathic arthritis (JIA) reveals genetic heterogeneity corresponding to distinct adult inflammatory arthritic diseases.

OBJECTIVES: Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases, comprising seven categories. Genetic data could potentially be used to help redefine JIA categories and improve the current classification system. The human leucocyte antigen (HLA) region is strongly associated with JIA. Fine-mapping of the region was performed to look for similarities and differences in HLA associations between the JIA categories and define correspondences with adult inflammatory arthritides. METHODS: Dense genotype data from the HLA region, from the Immunochip array for 5043 JIA cases and 14 390 controls, were used to impute single-nucleotide polymorphisms, HLA classical alleles and amino acids. Bivariate analysis was performed to investigate genetic correlation between the JIA categories. Conditional analysis was used to identify additional effects within the region. Comparison of the findings with those in adult inflammatory arthritic diseases was performed. RESULTS: We identified category-specific associations and have demonstrated for the first time that rheumatoid factor (RF)-negative polyarticular JIA and oligoarticular JIA are genetically similar in their HLA associations. We also observe that each JIA category potentially has an adult counterpart. The RF-positive polyarthritis association at HLA-DRB1 amino acid at position 13 mirrors the association in adult seropositive rheumatoid arthritis (RA). Interestingly, the combined oligoarthritis and RF-negative polyarthritis dataset shares the same association with adult seronegative RA. CONCLUSIONS: The findings suggest the value of using genetic data in helping to classify the categories of this heterogeneous disease. Mapping JIA categories to adult counterparts could enable shared knowledge of disease pathogenesis and aetiology and facilitate transition from paediatric to adult services.

Non-HLA gene polymorphisms in juvenile idiopathic arthritis: associations with disease outcome.

OBJECTIVE: To test the hypothesis that non-HLA single-nucleotide polymorphisms (SNPs) associated with the risk of juvenile idiopathic arthritis (JIA) are risk factors for an unfavourable disease outcome at long-term follow-up. METHODS: The Nordic JIA cohort is a prospective multicentre study cohort of patients from the Nordic countries. In all, 193 patients met the inclusion criteria of having an 8 year follow-up assessment and available DNA sample. Seventeen SNPs met the inclusion criteria of having significant associations with JIA in at least two previous independent study cohorts. Clinical endpoints were disease remission, actively inflamed joints and joints with limitation of motion (LOM), articular or extra-articular damage, and history of uveitis. RESULTS: Evidence of associations between genotypes and endpoints were found for STAT4, ADAD1-IL2-IL21, PTPN2, and VTCN1 (p = 0.003-0.05). STAT4_rs7574865 TT was associated with the presence of actively inflamed joints [odds ratio (OR) 20.6, 95% confidence interval (CI) 2.2-> 100, p = 0.003] and extra-articular damage (OR 7.9, 95% CI 1-56.6, p = 0.057). ADAD1_rs17388568 AA was associated with a lower risk of having joints with LOM (OR 0.1, 95% CI 0-0.55, p = 0.016). PTPN2_rs1893217 CC was associated with a lower risk of having joints with LOM (OR 0.2, 95% CI 0-0.99, p = 0.026), while VTCN1_rs2358820 GA was associated with uveitis (OR 3.5, 95% CI 1-12.1, p = 0.029). CONCLUSION: This exploratory study, using a prospectively followed JIA cohort, found significant associations between long-term outcome and SNPs, all previously associated with development of JIA and involved in immune regulation and signal transduction in immune cells.

Validity and predictive ability of the juvenile arthritis disease activity score based on CRP versus ESR in a Nordic population-based setting.

OBJECTIVE: To compare the juvenile arthritis disease activity score (JADAS) based on C reactive protein (CRP) (JADAS-CRP) with JADAS based on erythrocyte sedimentation rate (ESR) (JADAS-ESR) and to validate JADAS in a population-based setting. METHODS: The CRP and ESR values and the corresponding JADAS scores (JADAS10/27/71) were compared in a longitudinal cohort study of 389 children newly diagnosed with juvenile idiopathic arthritis (JIA) in the Nordic JIA study. The construct validity and the discriminative and predictive ability of JADAS were assessed during a median disease course of 8 years by comparing JADAS with other measures of disease activity and outcome. RESULTS: At the first study visit the correlation between JADAS27-CRP and JADAS27-ESR was r=0.99 whereas the correlation between CRP and ESR was r=0.57. Children with higher JADAS scores had an increased risk of concomitant pain, physical disability and use of disease-modifying antirheumatic drugs (DMARDs). A higher JADAS score at the first study visit also significantly predicted physical disability, damage and no remission off medication at the final study visit, and also use of DMARDs during the disease course. Sensitivity to change, demonstrated as change in JADAS score compared with the American College of Rheumatology paediatric measures of improvement criteria, mostly showed excellent classification ability. CONCLUSION: The JADAS-CRP and JADAS-ESR correlate closely, show similar test characteristics and are feasible and valid tools for assessing disease activity in JIA.

Does removal of aids/devices and help make a difference in the Childhood Health Assessment Questionnaire disability index?

OBJECTIVE: To assess whether the removal of aids/devices and/or help from another person in the Childhood Health Assessment Questionnaire (C-HAQ) leads to a significant change in the disability index (DI) score and responsiveness in juvenile idiopathic arthritis (JIA). METHODS: Changes in the C-HAQ DI score in a cross-sectional sample of 2663 children with JIA and in 530 active patients with JIA in a trial of methotrexate (MTX) were compared. RESULTS: Patients in the MTX trial had higher disease activity and disability than the cross-sectional sample. The frequency of aids/devices (range 1.2-10.2%) was similar between the two samples, while help (range 5.3-38.1%) was more frequently used in the MTX group. Correlation between disease severity variables and the two different C-HAQ DI scoring methods did not change substantially. There was a decrease in the C-HAQ DI score for both the cross-sectional (mean score from 0.64 with the original method to 0.54 without aids/devices and help, p<0.0001) and the MTX sample (mean score from 1.23 to 1.07, p<0.0001). A linear regression analysis of the original C-HAQ DI score versus the score without aids/devices and help demonstrated the substantial overlap of the different scoring methods. Responsiveness in the responders to MTX treatment did not change with the different C-HAQ DI scoring methods (range 0.86-0.82). CONCLUSION: The removal of aids/devices and help from the C-HAQ does not alter the interpretation of disability at a group level. The simplified C-HAQ is a more feasible and valid alternative for the evaluation of disability in patients with JIA.

Invasive group B streptococcus (GBS) disease in Norway 1996-2006.

The aim of this study was to survey the occurrence of invasive group B streptococcus (GBS) disease in Norway and detect possible trends in characteristics of invasive GBS strains from 1996 to 2006. Data from national monitoring systems for infectious diseases in Norway were analysed. Of 638,452 live births in the period, 434 cases of invasive GBS disease in infants were reported. In adults and children older than 1 year of age, 969 cases were reported. The incidence of invasive GBS disease increased significantly in the elderly, while the incidence of neonatal early-onset disease was stable with 0.46 cases per 1,000 live births. The incidence of late-onset disease increased in 2005 and 2006. The lethality of GBS in infants increased from an average of 6.5% in 1996-2005 to 20% in 2006. Serotypes III and V were predominant in 839 invasive GBS strains characterized-type III in infants and type V in the elderly. The distribution of serotypes did not change throughout the period. The distribution of detected surface proteins was stable from 1996 to 2005, but the detection rates in types III and V were low. Molecular methods for GBS typing introduced in 2006 made characterization of nearly all strains possible and appear more applicable to epidemiological studies of GBS than conventional methods. Resistance to erythromycin and clindamycin increased significantly in 2006. The increased incidence in the elderly, the increased lethality in infants in 2006, and the increased resistance to erythromycin and clindamycin the same year might indicate changing characteristics of invasive GBS strains.

Developmental regulation of expression of rabbit C-reactive protein and serum amyloid A genes.

Serum amyloid A (SAA) and C-reactive protein (CRP) are acute phase plasma proteins which increases 100- to 1000-fold after inflammatory stimuli. In this study pregnant rabbits were given lipopolysaccharide (LPS) or subjected to laparotomy with fetal injections of LPS at different stages of gestation. Newborn rabbits were given LPS or saline. SAA and CRP mRNA were studied using Northern blot analyses and scanning densitometry. In vitro transcribed RNAs were used as standards for quantitative mRNA analyses. A gradual increase in LPS-induced SAA and CRP mRNA levels was observed during development, but only SAA mRNA induction was seen at gestational day 19. Fetal SAA and CRP mRNA induction was not seen after maternal LPS stimulation. The constitutive level of SAA and CRP mRNA was significantly lower in fetal rabbits than in adults. The control level of SAA mRNA in one-day-old rabbits was higher than the normal adult level, while the neonatal CRP mRNA level was lower. SAA2 seemed to be the major acute phase reactant in both fetal, neonatal and adult rabbits, while relatively more SAA3 was found during early developmental stages. The study demonstrated that CRP and three SAA genes are differentially regulated during development.

Expression of serum amyloid A genes in mink during induction of inflammation and amyloidosis.

Serum amyloid A (SAA) is an acute phase protein and the precursor of amyloid protein A (AA) in deposits of secondary amyloidosis. Several isotypes exist in mink, but previous studies suggest that mink AA is derived from only one. To assess the effect of repeated episodes of inflammation and induction of amyloidosis, qualitative and quantitative changes in hepatic and extrahepatic SAA mRNA were studied. Young female mink received subcutaneous lipopolysaccharide injections for amyloid induction. Studies were performed using RNA probes and oligonucleotide probes specific for each of two SAA mRNA species. Northern blot hybridization showed that hepatic SAA1 and SAA2 mRNA levels increased dramatically after inflammatory stimulation, and were subsequently maintained at elevated levels, showing considerable interindividual variation, but only a slight decrease during repeated inflammatory stimuli and the early stages of amyloid deposition. No preferential accumulation of mRNA specifying a particular isotype was found during the experiment. Differential expression of mink SAA mRNA during repeated inflammatory stimulation does not seem to explain why only SAA2-derived AA is found in amyloid deposits. Extrahepatic SAA mRNA seemed to be independently regulated and may thus represent another, yet not characterized, SAA isotype.

Adolescent chronic pain and association to perinatal factors: linkage of Birth Registry data with the Young-HUNT Study.

BACKGROUND: The aim of this study was to examine the associations of birthweight, gestation and 5-min Apgar score with self-reported chronic nonspecific pain in a large, unselected adolescent population. METHODS: The third population-based Nord-Trøndelag Health Study (HUNT) included 8200 adolescents aged 13-19 years, constituting 78.2% of adolescents in Nord-Trøndelag County. In the target age group, 13-18 years, data on pain frequency from 10 localizations were available from 7373 adolescents. Chronic nonspecific pain was defined as pain at least once a week during the last 3 months, not related to any known disease or injury. Chronic multisite pain was defined as chronic pain in at least three localizations, and chronic daily pain was defined as chronic pain almost every day. Perinatal data were retrieved from the Medical Birth Registry of Norway, and data were available for 7120 of the 7373 adolescents. Covariates included adolescent and maternal general health measures from the HUNT study. RESULTS: We found no consistent association between preterm birth and chronic pain and no clear association between birthweight and chronic pain complaints in adolescence. Post-term birth in boys and a low 5-min Apgar score in both sexes tended to increase the reporting of chronic pain in adolescence. CONCLUSIONS: Perinatal factors, and especially preterm birth and low birthweight, did not seem to have a major impact on pain complaints in adolescence.

Epidemiology of juvenile chronic arthritis in northern Norway: a ten-year retrospective study.

OBJECTIVE: To study the incidence and prevalence of juvenile chronic arthritis (JCA) in northern Norway. METHODS: Cases from the period 1985-1994 were retrospectively identified from the hospital files of the only pediatric department treating JCA in the study area. The European League Against Rheumatism (EULAR) criteria for JCA were used. RESULTS: The annual incidence of JCA was 22.6/100,000 children under 16 years of age. The incidence of oligoarticular JCA was 11.8, and the incidence of systemic JCA was 0.8/100,000. In the incidence group 25% were ANA positive, 14% developed uveitis and 42% of the tested patients were HLA-B27 positive. The point prevalence was 148.1/100,000. CONCLUSION: These incidence and prevalence data are higher than those reported in most other studies. The impact of genetic differences, cyclic variations and other factors in relation to the onset and course of JCA merit further investigation.

The Norwegian version 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 Norwegian language 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 Norwegian CHAQ and CHQ have already been published and therefore they were fully revalidated in this study. A total of 148 subjects were enrolled: 88 patients with JIA (6% systemic onset, 45% polyarticular onset, 10% extended oligoarticular subtype, and 39% persistent oligoarticular subtype) and 60 healthy children. The CHAQ clinically discriminated between patients with various JIA subtypes, with the systemic, polyarticular and extended oligoarticular subtypes having a higher degree of disability, pain, and a lower overall well-being when compared to those with persistent oligoarticular arthritis. 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 Norwegian version of the CHAQ-CHQ is a reliable, and valid tool for the functional, physical and psychosocial assessment of children with JIA.

Molecular and phenotypic characterization of invasive group B streptococcus strains from infants in Norway 2006-2007.

Multilocus sequence typing of an almost complete collection of invasive group B streptococcus (GBS) strains from infants in Norway, conducted in 2006-2007, revealed 27 sequence types (ST), of which 23 clustered into five clonal complexes. The case fatality rate of invasive GBS disease in infants was 16/98 (16.3%). Type V strains were predominant among strains resistant to erythromycin and clindamycin (11/18; 61.1%). All type V strains from fatal cases (5/16) were ST1, resistant to erythromycin and clindamycin, and belonged to three pulsed-field gel electrophoresis-clusters. Further analysis of virulence characteristics of these apparently highly virulent subtypes of type V, ST1 GBS strains is warranted.

Cytokine-induced differential expression of serum amyloid A genes in fetal and neonatal rabbits.

Serum amyloid A (SAA) is an acute-phase plasma protein which increases 100- to 1000-fold in response to inflammatory stimuli. In this study pregnant rabbits were subjected to laparotomy and their fetuses were injected with lipopolysaccharide (LPS) or various cytokines. Newborn rabbits were likewise stimulated. Hepatic SAA mRNA was studied using Northern blot analyses and scanning densitometry. In vitro derived RNA was used as standard for quantitative mRNA analyses. Cytokine concentrations in amniotic fluid and serum were analysed by biological assays. Fetal rabbits responded to cytokine stimulation by increased hepatic SAA mRNA expression, both during late gestation and in the early neonatal period. However, differences in dose-responses, kinetics and mRNA concentrations were seen dependent on gestational age. IL-1 and tumour necrosis factor (TNF) induced hepatic accumulation of both SAA1, SAA2 and SAA3, while only SAA1 and SAA2 mRNA accumulation was seen after IL-6 stimulation. High levels of IL-1 and TNF found in amniotic fluid from LPS-stimulated fetal rabbits corresponded with high levels in fetal, but not in maternal, serum. High levels of IL-1 and TNF, but no IL-6, were seen in newborn control sera and in adult serum 1 day after a normal delivery. The study details the complexity of the cytokine-induced in vivo response of SAA mRNA in fetal and neonatal rabbits.

Differential expression of rabbit serum amyloid A genes in response to various inflammatory agents.

Serum amyloid A (SAA) is an acute-phase plasma protein which increases up to 1000-fold after an acute-phase stimulus. Several SAA genes and corresponding protein isotypes exist in individual species. Liver is the main source of production, but extra-hepatic SAA expression has been described. In this study inflammation was induced in rabbits with lipopolysaccharide, turpentine, or casein. Transcription of SAA mRNA was studied using Northern blot analysis with probes specific for three different rabbit SAA isotypes and analysed by scanning densitometry. In the stimulated liver slight variation in SAA mRNA transcription level was seen after stimulation with different inflammatory agents. After lipopolysaccharide-stimulation SAA gene expression was also seen in most of the extra-hepatic organs. After turpentine stimulation SAA mRNA was seen in the liver, the ovary, and the small intestines, and after casein stimulation only in the liver and the ovary. SAA1 and SAA2 were induced exclusively in the liver, while SAA3 was induced mainly in the extra-hepatic organs. This indicates that the SAA genes probably are independently regulated both in relation to stimulus, gene- and tissue-specificity.

Rat bite fever (Streptobacillus moniliformis) with septicemia in a child.

A 5-year-old girl was admitted to hospital with fever, headache and nausea. Her C-reactive protein raised from less than 11 mg/l to 65 mg/l and she developed a maculopapular, petechial rash, especially pronounced on the soles and palms. After incubation for 3 days, Streptobacillus moniliformis was found in all blood cultures that had been taken. Some weeks before her admission, the girl had been playing with her grandmother's pet rats, which later had died from an unknown disease. There was no history of rat bite. Her condition improved rapidly after treatment with penicillin and chloramphenicol, and she was discharged from hospital after 10 days without sequelae.

Rabbit serum amyloid protein A: expression and primary structure deduced from cDNA sequences.

Serum amyloid A protein (SAA), the precursor of amyloid protein A (AA) in deposits of secondary amyloidosis, is an acute phase plasma apolipoprotein produced by hepatocytes. The primary structure of SAA demonstrates high interspecies homology. Several isoforms exist in individual species, probably with different amyloidogenic potential. The nucleotide sequences of two different rabbit serum amyloid A cDNA clones have been analysed, one (corresponding to SAA1) 569 base pairs (bp) long and the other (corresponding to SAA2) 513 bp long. Their deduced amino acid sequences differ at five amino acid positions, four of which are located in the NH2-terminal region of the protein. The deduced amino acid sequence of SAA2 corresponds to rabbit protein AA previously described except for one amino acid in position 22. Eighteen hours after turpentine stimulation, rabbit SAA mRNA is abundant in liver, while lower levels are present in spleen. None of the other extrahepatic organs studied showed any SAA mRNA expression. A third mRNA species (1.9 kb) hybridizing with a single-stranded RNA probe transcribed from the rabbit SAA cDNA, was identified. SAA1 and SAA2 mRNA were found in approximately equal amounts in turpentine-stimulated rabbit liver, but seem to be coordinately decreased after repeated inflammatory stimulation.

The primary structure of rabbit serum amyloid A protein isolated from acute phase serum.

Serum amyloid A (SAA) protein, a sensitive acute phase protein and the precursor of protein AA in secondary amyloid, was purified from pooled acute phase rabbit serum using two different methods: isolation of protein SAA directly by octyl-Sepharose chromatography of total serum, and dissociation and isolation of apoSAA from acute phase high density lipoprotein (HDL). The protein SAA fraction obtained was further purified using gel filtration and ion exchange chromatography. Rabbit protein SAA has 104 amino acid residues, like human SAA, and has a partially blocked N terminus. The highly conserved region from position 33 to position 63 found in SAA from all species studied was confirmed also in rabbit SAA. No microheterogeneities were observed. The amino acid sequence showed extensive N-terminal homology with the rabbit amyloid A protein, except for the microheterogeneity in position 12 in protein AA. It also showed identical amino acid sequence with that deduced from the rabbit cDNA clone pSAA 55. Complete homologies were found with clone SAA 2, except for positions 22 and 78, clone SA8-1, except for positions 22 and 79 and clone SA7-3, except for position 22. This pSAA 55/SA7-3/SA8-1/SAA2-like protein was the only SAA isotype found both in total serum and in the HDL fraction. Isotypes corresponding to other SAA-like genes could not be found in this pool of acute phase rabbit sera.

Serum amyloid A protein in mink during endotoxin induced inflammation and amyloidogenesis.

Two-dimensional electrophoresis was used to study SAA and AA proteins in mink during lipopolysaccharide-induced inflammation and amyloidogenesis. Three isotypes, SAA pI 6.8 and SAA pI 6.5 (both SAA1-like), and SAA pI 6.0 (SAA1- and SAA2-like), were identified in serum after both single and multiple LPS injections. Total SAA serum levels were highest in the early phase of induction, followed by a decrease ranging from 1 to 50% of the peak value during the rest of the experiment. The variation in the total SAA levels correlated with the total SAA mRNA levels. Low total SAA levels were seen both in non-amyloidotic and amyloidotic animals, and a general decrease of all isotypes was demonstrated. In hepatic amyloid fibrils, several AA isotypes, with amino acid sequence homologous exclusively to that of SAA2, were found. In the corresponding splenic material, fragments of histones H2A and H2B constituted most of the low molecular mass proteins, and no protein AA was detected. In spite of low serum levels and a non-specific isotype removal, the results confirm that SAA2 is amyloidogenic in mink.

In vitro evaluation of an enhanced human serum amyloid A (SAA2) promoter-regulated soluble TNF receptor fusion protein for anti-inflammatory gene therapy.

Tumour necrosis factor (TNF)-alpha contributes to the pathogenesis of many inflammatory diseases. Recombinant soluble TNF receptor fusion proteins (sTNFR:Ig) are potent TNF antagonists, both in vitro and in vivo. The concentration of serum amyloid A (SAA) increases by up to 1000-fold during inflammation, largely owing to cytokine-driven transcriptional upregulation. A reporter plasmid, comprising the proximal 0.7 kb of the human SAA2 promoter fused to a luciferase gene, was used in transient transfection experiments in human HepG2 hepatoma cells to assess the quantitative and qualitative TNF antagonist properties of a construct in which sTNFR:Ig synthesis is under the control of a chimera of the SAA2 promoter and a tat/HIV element. The SAA2-tat/HIV-sTNFR:Ig construct retained the fine-tuned cytokine responsiveness of the SAA2 promoter, while exhibiting the quantitatively enhanced level of protein expression conferred by the tat/HIV element. It produced a biologically significant TNF inhibition that was at least as strong as that achieved using a CMV promoter-driven sTNFR:Ig construct. There was a dose- and time-dependent relationship between the pro-inflammatory cytokine used, and the generation of TNF antagonist activity by SAA2-tat/HIV-sTNFR:Ig. Although sTNFR:Ig protein can be induced by either TNF-alpha or interleukin (IL)-1beta, its antagonist activity is limited to the former cytokine. The SAA2-tat/HIV-sTNFR:Ig construct, and derivatives thereof, may therefore be ideally suited to gene therapy applications that require the local production of potent and specific immune modifiers only when there is active pathology. It may consequently be of particular use in the future treatment of diseases such as rheumatoid arthritis.