Study of thymic size and function in children and adolescents with treatment refractory systemic sclerosis eligible for immunoablative therapy.

Following hematopoietic stem cell transplantation (HSCT), thymic reconstitution of peripheral T lymphocytes is essential to avoid a chronically immunodeficient state and disease recurrence. The purpose of this study was to determine if children and adolescents with treatment refractory SSc, awaiting HSCT, have sufficient thymic function to reconstitute T lymphocyte function after transplantation. Thirteen children with systemic scleroderma were enrolled and assessed by physical exam, chest MRI, measurement of autoantibodies, B and T cell immuno-phenotyping, and quantization of T cell receptor rearrangement excision circles (TREC) as a marker of thymopoiesis. MRI detected thymic tissue in 9/13 children. TREC levels were detectable in all but one child but were significantly reduced (p<0.001) when compared to a control population. SSc patients also had a reduced percentage of naïve (CD45RA+CD31+) CD4+ T lymphocytes, further indicating diminished thymopoiesis. Our data suggest that thymic function in children with SSc might be insufficient for an adequate immunoreconstitution following transplantation in some patients. A thorough evaluation of immune and thymic functions to identify those patients prior to HSCT is recommended.

Experience with multiple stent implantations in primary antiphospholipid syndrome in childhood: a case report.

The antiphospholipid syndrome (APS) is an autoimmune condition characterized by the persisting presence of antiphospholipid antibodies in association with thrombosis and/or pregnancy morbidity. Primary APS is quite rare in childhood and exact prevalence is not known. However, substantial proportion of thrombotic events in children is being attributed to APS. We herein present a 9-year-old boy presented with impending pericardial tamponade and large pleural effusions likely secondary to transudation of fluid from his gradually developed collateral circulation which was resulted from almost completely occluded vena caval system due to primary APS. He was treated with multiple angioplasty-stenting which offered symptomatic relief and better quality of life. To our knowledge, this is the first reported paediatric case of primary APS presented with extensive occlusive lesions in both caval systems and treated with repeated endovascular stent placements.

Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis.

OBJECTIVE: This study was undertaken to evaluate the long-term safety and effectiveness of etanercept alone or in combination with methotrexate (MTX) in children with selected categories of juvenile idiopathic arthritis (JIA). METHODS: Patients ages 2-18 years with rheumatoid factor (RF)-positive or RF-negative polyarthritis, systemic JIA, or extended oligoarthritis were eligible for the study. Patients received MTX alone (> or =10 mg/m(2)/week [ approximately 0.3 mg/kg/week], maximum dosage 1 mg/kg/week), etanercept alone (0.8 mg/kg/week, maximum dose 50 mg), or etanercept plus MTX for 3 years in an open-label, nonrandomized study. Safety was assessed by measuring rates of adverse events, and effectiveness was assessed using the physician's global assessment of disease activity and the pediatric total joint assessment. RESULTS: A total of 197, 103, and 294 patients were enrolled in the MTX, etanercept, and etanercept plus MTX groups, respectively. Exposure-adjusted rates of adverse events were similar among the 3 treatment groups (18.3, 18.7, and 21.6 per 100 patient-years in the MTX, etanercept, and etanercept plus MTX groups, respectively). Respective rates per 100 patient-years of serious adverse events (4.6, 7.1, and 6.0) and medically important infections (1.3, 1.8, and 2.1) were also similar among the 3 treatment groups. Scores for physician's global assessment and total active joints improved from baseline, and improvement was maintained for the duration of the study. CONCLUSION: These data confirm the findings of other long-term studies and suggest that etanercept or etanercept plus MTX has an acceptable safety and effectiveness profile in children with selected categories of JIA. Improvement was maintained for 3 years in those continuing to receive medication.

Identification of new SLE-associated genes with a two-step Bayesian study design.

In our earlier study, we utilized a Bayesian design to probe the association of approximately 1000 genes (approximately 10,000 single-nucleotide polymorphisms (SNPs)) with systemic lupus erythematosus (SLE) on a moderate number of trios of parents and children with SLE. Two genes associated with SLE, with a multitest-corrected false discovery rate (FDR) of <0.05, were identified, and a number of noteworthy genes with FDR of <0.8 were also found, pointing out a future direction for the study. In this report, using a large population of controls and adult- or childhood-onset SLE cases, we have extended the earlier investigation to explore the SLE association of 10 of these noteworthy genes (109 SNPs). We have found that seven of these genes exhibit a significant (FDR<0.05) association with SLE, both confirming some genes that have earlier been found to be associated with SLE (PTPN22 and IRF5) and presenting novel findings of genes (KLRG1, interleukin-16, protein tyrosine phosphatase receptor type T, toll-like receptor (TLR)8 and CASP10), which have not been reported earlier. The results signify that the two-step candidate pathway design is an efficient way to study the genetic foundations of complex diseases. Furthermore, the novel genes identified in this study point to new directions in both the diagnosis and the eventual treatment of this debilitating disease.

Relationship between health-related quality of life and SLE activity and damage in children over time.

We previously described the development and validation of the 'Simple Measure of the Impact of Lupus Erythematosus in Youngsters' (SMILEY) for the reliable assessment of health-related quality of life (HRQOL) in children with systemic lupus erythematosus (SLE). The objectives of this new study were to determine the relationship of SMILEY scores to patient's/parent's assessment of HRQOL and SLE status, and physician's assessment of disease activity and damage over time. In this multicentre study, 68 children with SLE and parents completed SMILEY including the global HRQOL and SLE status assessments, physicians completed disease activity and damage tools at two time-points. Spearman rho was calculated between SMILEY scores and other scales, and between interval changes in SMILEY scores and other scales. SMILEY scores correlated with patient/parent assessments of global HRQOL and SLE status, disease activity and damage, confirming previous findings. The change in disease activity and damage measures correlated most strongly with the changes in SMILEY domains, Limitation and Burden of SLE. Results provide preliminary evidence that Limitation and Burden of SLE domains of SMILEY reflect the impact of disease activity and damage on HRQOL.

Mycophenolate mofetil treatment of severe renal disease in pediatric onset systemic lupus erythematosus.

OBJECTIVE: To report the first clinical experience with mycophenolate mofetil (MMF, CellCept) in: children with lupus nephritis. METHODS: Eleven children with various forms of lupus nephritis were treated with oral MMF at a mean dose of 22 mg/kg/day (range 17-42) for a mean of 9.8 months (range 3-17). All children received concomitant prednisone and 7/11 were taking concomitant hydroxychloroquine. Indications for MMF included treatment refractory nephritis despite high dose oral or IV prednisone, azathioprine, and/or cyclophosphamide. Treatment outcome was monitored through assessment of Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) score, renal function, and serologic markers such as complement and anti dsDNA antibodies. RESULTS: While renal function normalized in 4/4 patients with membranous glomerulonephritis, little effect was observed in children with proliferative glomerulonephritis. Ten children experienced a marked reduction in SLEDAI score. Anti-dsDNA antibody and serum complement levels improved or remained stable in 80% of the children. Concomitant prednisone was decreased in 6/11 patients (55%) without deterioration of renal function. Adverse events, observed in 8 patients (73%), were not dose dependent, and included infections, leukopenia, nausea, pruritus, headache, and fatigue. CONCLUSION: MMF may represent a valuable alternative to traditional cytotoxic agents for children with class V lupus nephritis, but was less effective in attenuating disease progression in class IV glomerulonephritis. MMF had a steroid sparing effect and appeared to be effective in controlling serologic disease activity in pediatric onset SLE. Adverse events such as infections may limit its use and remain a concern.

Safety and efficacy of high dose etanercept in treatment of juvenile rheumatoid arthritis.

OBJECTIVE: To evaluate safety and efficacy of high dose etanercept (> 0.8 mg/kg, maximum 25 mg subcutaneously twice weekly) (Enbrel) in children with juvenile rheumatoid arthritis (JRA) and inadequate prior response to standard dose etanercept. METHODS: Retrospective chart review of 8 children (6 girls, 2 boys, mean age 8.4 yrs, range 5-16 yrs). Five children had systemic onset, polyarticular course JRA; 2 had polyarticular onset; and one had pauciarticular onset, polyarticular course JRA. All children had failed at least 3 mo (mean 9 mo) treatment with standard dose etanercept (0.4 mg/kg SC twice a week). All 8 children had increase in the etanercept dose to at least 0.8 mg/kg (mean 1.1 mg/kg, maximum 25 mg SC twice weekly) for a mean of 7 mo (range 3-10 mo). Efficacy of high dose etanercept was evaluated by changes in joint count, laboratory data, and ability to decrease concomitant medication. RESULTS: Improvements in the joint count and laboratory findings (erythrocyte sedimentation rate, hemoglobin and platelet count) were observed in 2 of 8 (25%) children. In these 2, concomitant prednisone was reduced or discontinued. In contrast, no changes in disease activity or laboratory findings were observed in the other 6 children. Overall, high dose etanercept was well tolerated. No laboratory abnormalities were detected and no child withdrew because of adverse events. CONCLUSION: High dose etanercept is safe and well tolerated in children, but efficacy seems limited. In children with unsatisfactory response to standard dose etanercept, an increased dose or treatment prolongation may not offer any additional benefit.

Etanercept therapy in children with treatment-resistant uveitis.

OBJECTIVE: To evaluate the safety and efficacy of the tumor necrosis factor fusion protein etanercept in children with treatment-resistant uveitis. METHODS: Ten children with chronic active uveitis (7 girls and 3 boys, mean age 7.5 years [range 3-12 years]) were enrolled in this prospective study. In 7 children, uveitis was associated with pauciarticular juvenile rheumatoid arthritis. Five children were antinuclear antibody positive. All patients had failed previous therapy with topical steroids and methotrexate and/or cyclosporine. All were treated with etanercept at a dosage of 0.4 mg/kg twice weekly for the first 3 months, and then, if eyes did not improve, with 25 mg twice weekly (mean 1.1 mg/kg) for at least 3 additional months. RESULTS: At the beginning of the trial, uveitis affected 18 eyes in the 10 children. Within 3 months, 10 of 16 affected eyes (63%; P = 0.017) showed a rapid decrease in anterior chamber cell density, including remission of uveitis in 4 eyes. In children with visual acuity of less than 20/25, 4 of 10 eyes (40%) improved. An exacerbation of uveitis during etanercept therapy occurred in only 1 child (1 of 14 eyes [7%]). Other ocular outcome parameters, such as intraocular pressure, synechia formation, and lens clarity, remained unchanged. Following a dosage increase to an average of 1.1 mg/kg after 3 months in 7 children, no further improvement was noted. CONCLUSION: Our data suggest that etanercept injected subcutaneously twice a week has a beneficial effect on treatment-resistant chronic uveitis in children. Further controlled studies with etanercept in systemic or topical form are necessary to confirm its efficacy and optimal mode of administration.

Case series: neuropsychiatric symptoms with pediatric systemic lupus erythematosus.

OBJECTIVE: To describe the psychiatric presentation, serologic findings, and neuroimaging patterns in children and adolescents with central nervous system involvement with systemic lupus erythematosus (CNS-SLE). METHOD: Pediatric patients with psychiatric symptoms who fulfilled the 1997 revised diagnostic American College of Rheumatology criteria for SLE were studied. Complement levels, and anti-double-stranded DNA, anti-Smith, anti-phospholipid, and anti-neuronal antibodies were evaluated. Computed tomography, magnetic resonance imaging, and single photon emission computed tomography (SPECT) neuroimaging studies were reviewed. RESULTS: The 10 patients with CNS-SLE presented with psychosis, mood disturbance, or confusion, and 8 patients had concomitant neurologic symptoms. The 8 girls and 2 boys ranged in age from 7.5 to 17 years. Serum anti-neuronal antibodies were positive with onset of symptoms and declined with improvement. Initial SPECT was abnormal in all 10 patients and remained abnormal. CONCLUSION: SPECT and anti-neuronal antibodies help confirm CNS involvement in patients with SLE and neuropsychiatric symptoms.

Primary angiitis of the central nervous system in children: 5 cases.

We describe 5 children who meet criteria for primary angiitis of the central nervous system (PACNS). All patients presented with headache and/or focal neurologic deficits and exhibited clinical and/or radiographic evidence of disease progression. Two patients had disease progression prior to combined treatment with cyclophosphamide and corticosteroids; one progressed while receiving intravenous cyclophosphamide and stabilized after a change to daily oral dosing; one progressed after discontinuing therapy after less than 12 months and improved after retreatment; and one progressed on steroid therapy alone but was lost to followup. Children who have frequent or severe headaches or focal neurologic deficits should be carefully evaluated and those meeting criteria for PACNS should be treated aggressively.

Treatment of collagen induced arthritis in DBA/1 mice with L-asparaginase.

OBJECTIVE: To evaluate the safety and efficacy of L-asparaginase as an immunosuppressive agent in a mouse model of rheumatoid arthritis. METHODS: Male DBA/1 mice with collagen-induced arthritis (CIA) were treated at different intervals with various doses of native and pegylated L-asparaginase from E. coli. The mice were observed for 4 weeks during which time arthritis was scored. Outcome parameters included effect on severity and progression of established arthritis as well as prevention of disease. In addition, X-rays from the affected joints were obtained for comparison. RESULTS: Both native L-asparaginase at a dose of 50 IU/injection intraperitoneally three days a week and pegylated asparaginase (PEG-L-asparaginase) at a dose of 25 IU/injection twice a week, significantly reduced the mean arthritic score (MAS) in mice with established arthritis (p < 0.001 for PEG-L-asparaginase). When native L-asparaginase was administered before the onset of arthritis (days 14-post immunization) the number of mice developing arthritis as well as the number of arthritic paws and the severity of arthritis in the treatment group were significantly decreased (p < 0.0001). Significant differences were found in the X-ray evaluation between treated and control mice. None of the animals died due to drug related events or showed signs of asparaginase induced toxicity. CONCLUSION: Our data provide the first direct evidence that L-asparaginase is a potent antiarthritic agent and may represent an effective second line agent for future treatment studies in juvenile and adult rheumatoid arthritis.

Superantigens and cystic fibrosis: resistance of presenting cells to dexamethasone.

Staphylococcus aureus, a common pulmonary pathogen in cystic fibrosis (CF), produces exotoxins that are extremely potent superantigens. A number of animal studies have shown that superantigens cause pulmonary inflammation, but the possible role of superantigens in CF has not been investigated. The present study assessed possible differences between control and CF B cells in presenting superantigens to T cells. Immortalized B-cell lines were used as superantigen-presenting cells to avoid environmental influences (e.g., infection or antibiotics) common to freshly isolated cells. The results show that CF B-cell lines presented a staphylococcal superantigen to the immortalized T-cell line (Jurkat) as effectively as did control B-cell lines as measured by interleukin-2 production. However, in contrast to the case for control B-cell lines, dexamethasone did not inhibit CF B-cell lines from presenting superantigen. The resistance of superantigen-presenting CF B cells to corticosteroids suggests that the pulmonary response to superantigens may be poorly regulated in CF, leading to an exaggerated inflammatory response to S. aureus.

Etanercept in children with polyarticular juvenile rheumatoid arthritis. Pediatric Rheumatology Collaborative Study Group.

BACKGROUND: We evaluated the safety and efficacy of etanercept, a soluble tumor necrosis factor receptor (p75):Fc fusion protein, in children with polyarticular juvenile rheumatoid arthritis who did not tolerate or had an inadequate response to methotrexate. METHODS: Patients 4 to 17 years old received 0.4 mg of etanercept per kilogram of body weight subcutaneously twice weekly for up to three months in the initial, open-label part of a multicenter trial. Those who responded to treatment then entered a double-blind study and were randomly assigned to receive either placebo or etanercept for four months or until a flare of the disease occurred. A response was defined as an improvement of 30 percent or more in at least three of six indicators of disease activity, with no more than one indicator worsening by more than 30 percent. RESULTS: At the end of the open-label study, 51 of the 69 patients (74 percent) had had responses to etanercept treatment. In the double-blind study, 21 of the 26 patients who received placebo (81 percent) withdrew because of disease flare, as compared with 7 of the 25 patients who received etanercept (28 percent) (P=0.003). The median time to disease flare with placebo was 28 days, as compared with more than 116 days with etanercept (P<0.001). In the double-blind study, there were no significant differences between the two treatment groups in the frequency of adverse events. CONCLUSIONS: Treatment with etanercept leads to significant improvement in patients with active polyarticular juvenile rheumatoid arthritis. Etanercept is well tolerated by pediatric patients.

Omental flap obtained by laparoscopic surgery for reconstruction of the chest wall.

The reconstruction of complex defects of the chest wall after infection of the sternotomy wound presents a great challenge. Various options have been described for these reconstructions using muscle and omental flaps to fill the space and cover the defect. A case of reconstruction of a large defect of the chest cage and abdominal wall in a 62-year-old patient is presented. After surgery for revascularization of the myocardium, the patient developed mediastinitis, osteomyelitis, and necrosis of the sternum. The pectoralis major muscle was utilized for the reconstruction, but total loss of the flap occurred. After débridement, an omental flap obtained by laparoscopy was employed based on the left gastroepiploic artery. The omentum was transposed without complications through the abdominal wall defect. An overlay skin graft with the omentum as receptor bed completed the closure. There are advantages in using minimally invasive videolaparoscopy compared with laparotomy in obtaining the omentum, with the same result regarding reconstruction of the defect.

[Reconstruction of a thoracic wall defect using a flap of omentum obtained by laparoscopy]. / Obtenção de retalho de epíplon por via laparoscópica para reconstrução de defeito da parede torácica.

Reconstructive of complex chest wall defects following infected sternotomy represents a surgical challenge. Several options were described for these defects reconstructions, using muscles flaps and omentum which provided obliteration of dead space and coverage. We present a reconstruction of a major chest and abdominal wall defect in a 62-year old patient, who had mediastinitis, osteomyelitis and necrosis of sternum after myocardial revascularization. The pectoralis major was used unsuccessfully, with total loose of the flap. After wound failure, a flap of omentum based on the left gastroepiploic vessels was obtained by a laparoscopic surgery, with no complication. The omentum was translocated through the defect that reached the abdominal wall covering the defect and allowing the use of split-thickness grafts. The laparoscopic procedure showed advantages over the laparotomy in the management of omentum, with the same results in the reconstruction of the defect added the advantages of a minimal invasive procedure, mainly in patient with bad clinical conditions.

Preliminary evidence for cyclosporin A as an alternative in the treatment of recalcitrant juvenile rheumatoid arthritis and juvenile dermatomyositis.

OBJECTIVE: To evaluate the safety and efficacy of cyclosporin A (CyA) with and without methotrexate (MTX) in refractory juvenile rheumatoid arthritis (JRA) and juvenile dermatomyositis (JDMS). METHODS: Twenty-two patients (17 with JRA, 5 with JDMS) with refractory disease were studied retrospectively. All received CyA at a mean dose of 3.2 mg/kg/day over a mean period of 16 mo (range 6-42). All other medications except nonsteroidal antiinflammatory drugs, prednisone, and hydroxychloroquine were discontinued. In addition, 16/22 patients received concomitant MTX. RESULTS: Improvements in laboratory variables, joint counts, joint swelling, and morning stiffness were observed in most of the children with JRA. Muscle strength increased and muscle enzyme levels decreased in the patients with JDMS. CyA treatment permitted prednisone to be discontinued in 5/20 and reduced by greater than 50% in 10/20 patients. There was no evidence of hepatic or bone marrow toxicity or lymphoproliferative disease. Serum creatinine increased in 13/22 patients, but the actual values all remained within normal limits. CONCLUSION: CyA may be an effective agent in the treatment of refractory JRA and JDMS and concomitant MTX seems to be well tolerated. These preliminary data also suggest that combined CyA/MTX therapy may be associated with further improvement in clinical outcome.

Childhood central nervous system lupus; longitudinal assessment using single photon emission computed tomography.

OBJECTIVE: Neuropsychiatric manifestations in children with systemic lupus erythematosus (SLE) occur in 30-60% of patients during the course of disease. Unlike other manifestations of childhood SLE, few laboratory studies and imaging modalities aid in the diagnosis of central nervous system (CNS) lupus. We and others have reported the usefulness of single photon emission computed tomography (SPECT) in the initial assessment of cerebral blood flow in children with active CNS involvement. We extend these observations to longterm followup using the SPECT scan to determine its usefulness in the subsequent course of CNS lupus in children. METHODS: Eleven children who developed CNS disease and fulfilled the classification criteria for SLE were included in an open pilot study. The patients were followed up to 3.5 years and presented with CNS manifestations: encephalopathy with or without grand mal seizures (N = 4), focal seizures with depression or hallucinations (N = 3), optic neuritis with transverse myelitis (N = 2), and psychosis with audiovisual hallucinations (N = 2). Initially, all children had lumbar puncture, SPECT, and serologic testing; 9 children had electroencephalogram (EEG), 7 had computerized tomography (CT), and 10 had magnetic resonance imaging (MRI). SPECT was repeated in 7 patients 1-4 months after the initial CNS event and thereafter in 10 patients annually. RESULTS: At the time of the initial CNS event, 9/11 children (82%) had normal results for lumbar puncture, 7/9 (78%) for EEG, 5/7 (71%) for CT, and 6/10 (60%) for MRI. All patients (100%) had diffusely abnormal SPECT: In addition, 5/11 (45%) tested positive for IgG antibodies to cardiolipin and dsDNA, and 4/11 (36%) had antibodies to Sm. In 5/7 children whose SPECT was repeated 1 to 4 months after the CNS event, additional perfusion defects were documented compared with initial SPECT: During the subsequent 1-3.5 years and concomitant with treatment, CNS manifestations resolved clinically, but none of the SPECT scans became normal. Perfusion defects improved over time in 4 patients and worsened in 6. CONCLUSION: SPECT scan remains a sensitive tool during initial CNS events in children with CNS lupus documenting the presence of damage during short term followup of 1-4 months. However, during longterm followup abnormalities documented by SPECT no longer correlate with the patient's clinical course, limiting the usefulness of SPECT as a clinical tool in children who recover from CNS disease.

Prevalence of anti-neutrophil cytoplasmic antibodies (ANCA) in juvenile chronic arthritis.

OBJECTIVE: Sera from 66 children with active JCA of oligoarticular, polyarticular or systemic onset, 13 sera from patients in disease remission, 15 sera from patients with reactive arthritis, and 11 from Lyme arthritis patients were tested for the presence of anti-neutrophil cytoplasmic antibodies (ANCA) in order to evaluate their diagnostic significance in JCA. RESULTS: ANCA were found in 21% (14/66) of the active JCA sera, all showing an atypical pANCA staining pattern using indirect immunofluorescence on ethanol fixed granulocytes. 71% of these sera also showed antinuclear antibodies (ANA) on HEp-2 cells. By additional staining on paraformaldehyde fixed granulocytes to exclude staining artefacts due to ethanol fixation, 2 of the pANCA positive sera showed cytoplasmic staining. In no case did we find nuclear fluorescence suggesting a true cytoplasmic localization of the involved antigens. All ANCA positive sera were negative for anti-MPO and anti-LF antibodies. ANCA prevalence in our study group did not correlate with the disease subgroup, disease duration or other clinical characteristics. However, we found ANCA only in active disease. CONCLUSION: Our data suggest that the diagnostic importance of ANCA in JCA is restricted to only a few JCA patients. In these cases, however, ANCA positivity supports the diagnosis of JCA. Further studies are needed to substantiate this finding, as well as possible subgroup specificities. Standardized techniques of granulocyte fixation and antigen specific tests are needed to produce comparable results in different study groups.

High dose methotrexate in the treatment of refractory juvenile rheumatoid arthritis.

OBJECTIVE: To assess the response to and safety of long term, high dose (> or = 1 mg/kg/week or > or = 15 mg/m2/week) methotrexate (MTX) administration, in a cohort of 21 children with longstanding, severe juvenile rheumatoid arthritis (JRA). METHODS: Children received MTX at an average weekly dose of 27 mg for a mean of 15.2 months. Outcome was assessed using a disease activity score based on changes in concomitant therapy, laboratory parameters, physician's global assessment, and radiologic evaluation. RESULTS: Seven patients (33%) improved, including one child who achieved complete remission, while 14/21 children (67%) did not benefit from high dose MTX. Subsequently, 6/14 (43%) of the non-responders discontinued high dose MTX and began cyclosporine. Radiologic progression, regardless of clinical outcome, was documented in 10/15 (67%) of the patients. The drug was well tolerated despite mild gastrointestinal symptoms and transient liver enzyme elevation. CONCLUSION: The results of this open retrospective pilot trial suggest that high dose MTX is well tolerated, but that its role in the treatment of children with refractory JRA may be limited. Radiologic progression, despite improvement in the clinical status or in the laboratory parameters, supports the hypothesis that MTX acts as a potent antiinflammatory agent.