Biomedical subjects
Publications and source records attributed to R M Laxer.
The CT appearance of asymptomatic splenic necrosis in a 11-year-old girl with Wegener's granulomatosis is presented. Sonography showed splenic inhomogeneity with patency of the splenic artery and vein. Follow-up CT showed lobulation and shrinkage of the spleen with return to a normal attenuation.
PURPOSE: The mainstay of pharmacologic therapy in patients with dermatomyositis is corticosteroids. However, because patients sometimes become refractory to these drugs and because these drugs have potential short- and long-term toxicities, alternate therapy is highly desirable. Therefore, a pilot study was initiated using high-dose intravenous gammaglobulin (IVGG) in the treatment of dermatomyositis. PATIENTS AND METHODS: IVGG was administered to five patients with juvenile dermatomyositis. Prior to IVGG treatment, all patients had persistent muscle weakness despite daily corticosteroids and three patients had developed unacceptable steroid toxicity. Two of the patients had previously developed toxicity while receiving immunosuppressive therapy. RESULTS: IVGG therapy resulted in improved muscle strength and ameliorated skin rash in all patients. The percentage increase in muscle strength as measured by sphygmomanometry following the 9-month course of IVGG ranged from 56% to 606% in the proximal lower extremities and from 30% to 186% in the proximal upper extremities. Following IVGG therapy, prednisone could be discontinued or the dose reduced in all patients. CONCLUSION: This study suggests that IVGG may allow steroid sparing in dermatomyositis and may provide a safe alternative to cytotoxic therapy.
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Juvenile rheumatoid arthritis (JRA) is a chronic, relapsing, inflammatory childhood disease characterized by arthritis and systemic inflammation. At present there is no rapid, efficient laboratory method of assessing disease activity and degree of immune activation. We measured serum soluble interleukin 2 receptor (sIL-2R) levels in 85 samples from 72 patients (22 samples from patients with systemic JRA, 34 from polyarticular patients, 29 from pauciarticular patients, of which 10 were HLA-B27 positive). The mean sIL-2R level from patients was 1565 U/ml, which is significantly elevated compared to control values of 594 U/ml (p less than or equal to 0.005). The highest levels were seen in patients with systemic JRA (mean value 2121 U/ml) while the lowest values were seen in HLA-B27 positive (+) patients (mean value 899 U/ml). Patients with clinically active disease had significantly elevated levels (mean value 1745 U/ml) compared to patients with inactive disease (mean value 846 U/ml, p less than or equal to 0.01). Highest levels were seen in patients with active systemic JRA (mean value 2419 U/ml) while patients with pauciarticular JRA and B27 + JRA had the lowest sIL-2R levels (1167 and 1045 U/ml, respectively). sIL-2R levels were elevated in all subgroups of clinically active patients compared to controls (p less than or equal to 0.0005). Three of the 4 patients with serial sIL-2R measurements showed falling values during the period of clinical remission. Using regression analysis and likelihood ratio tests, we found a significant correlation between sIL-2R levels and both disease activity and joint count (p less than or equal to 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)
We report a case of Behçet's syndrome with myositis in a pediatric patient, emphasizing the importance of muscle involvement in the differential diagnosis of calf pain and swelling in Behçet's syndrome. A review of the English-language literature from 1965 to the present suggests that the clinical picture of Behçet's syndrome in children differs from that in adults, in that there is a lower frequency of ocular disease, and unusual manifestations appear to be more common.
Intravenous (IV) gamma globulin has been successfully used as replacement therapy for antibody-deficient patients and, more recently, in the treatment of autoimmune diseases such as idiopathic thrombocytopenic purpura, myasthenia gravis, and Kawasaki disease. In view of the successful treatment of these diseases, we initiated a pilot study of the effect of IV gamma globulin in systemic juvenile rheumatoid arthritis (JRA). Eight patients with active systemic JRA that was unresponsive to first-line agents, second-line agents, and/or corticosteroids received this therapy monthly for 6 months. Outcome measures included changes in articular and extraarticular features, steroid dosage, and laboratory parameters. Following IV gamma globulin therapy, there was significant improvement in arthritis and/or morning stiffness in 5 of 8 patients, while extraarticular features significantly improved in 7 of 8 patients. At study entry, 6 of 8 patients were receiving prednisone; at study end, prednisone was discontinued in 3 patients and decreased by more than 50% in the other 3. Overall, there was an 80% reduction in the prednisone dosage. Initially, all patients had anemia, low levels of serum albumin, and an elevated erythrocyte sedimentation rate, while a thrombocytosis was seen in 7 of 8 patients. Serum IgG was initially elevated in 6 patients. IV gamma globulin therapy resulted in a significant increase in hemoglobin and albumin levels and a significant decrease in the mean serum IgG level, platelet count, and erythrocyte sedimentation rate. In only 1 patient did IV gamma globulin fail to significantly improve the clinical or laboratory features of the disease. We suggest that this therapy may be beneficial in the treatment of systemic JRA.
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We report the cases of neonatal lupus erythematosus associated with significant hepatic involvement in three living infants and in one infant who died 3 hours after delivery. The three living infants had neonatal cholestasis as a major component of their clinical findings. Pathologic changes included giant cell transformation, ductal obstruction, and extramedullary hematopoiesis. Liver involvement has been noted incidentally in children with neonatal lupus erythematosus, but it has generally been attributed to hemodynamic compromise as a result of congenital heart block or systemic toxic reactions. We speculate that neonatal hepatitis proceeding to hepatic fibrosis may occur in neonatal lupus erythematosus, analogous to the occurrence of "idiopathic" congenital heart block. The neonatal hepatitis associated with neonatal lupus erythematosus is a form distinguishable from the "idiopathic" group. Liver involvement may be more common than was previously recognized, and prospective studies to look for maternal autoantibodies in idiopathic neonatal liver disease should be undertaken.
The clinical, laboratory, and radiological features, including histocompatibility typing, of 28 patients with juvenile psoriatic arthritis are reported. The most common presentation was that of psoriasis preceding or occurring simultaneously with arthritis. The most common course of juvenile psoriatic arthritis was to start as an oligoarthritis and progress, usually to polyarthritis. No patients with juvenile psoriatic arthritis had uveitis. Overall, most patients had a good outcome (93% in functional class I and II), though 8/28 (29%) did require disease modifying drugs over a mean period of 8.8 years of follow up. The clinical features of these patients were very similar to those of a group of 158 adult patients with psoriatic arthritis with the same disease duration followed up in the clinic. Although there was an increased prevalence of B17 in both juvenile and adult psoriatic arthritis, juvenile psoriatic arthritis showed increased prevalence of A2, whereas adult psoriatic arthritis showed increased prevalence of B27, Bw39, and Cw6. This HLA association differed from that reported in other forms of juvenile arthritis.
In order to assess the interaction between methotrexate (MTX) and nonsteroidal antiinflammatory drugs (NSAID), we studied the pharmacokinetics of oral MTX alone and in the presence of the usually prescribed NSAID in 7 children with chronic arthritis. The NSAID studied included tolmetin, indomethacin, naproxen, and aspirin. Six patients were treated with multiple NSAID. The mean MTX elimination half-life was prolonged when NSAID were coadministered (1.7 +/- 0.5 vs 1.2 +/- 0.1 h; p = 0.03). However, neither the apparent MTX clearance (CI) (10.6 +/- 5.5 vs 13.1 +/- 3.5 l/h; p = 0.19), the area under the serum MTX concentration-time curve (Auc) (2.1 +/- 1.0 vs 1.5 +/- 0.6 mumol/l/h; p = 0.08) or the apparent volume of distribution (Vd) (23.0 +/- 6.2 vs 21.9 +/- 6.4 l; p = 0.53) was significantly altered by the administration of NSAID. Although the differences between the mean Cl and Auc were not statistically significant, a wide variation in the impact of NSAID on MTX Cl was observed. In 6 of 7 patients, the Auc increased during NSAID administration from 19 to 140%. This degree of increase may be clinically significant in some individuals. It is consequently recommended to closely monitor patients who are receiving MTX and NSAID for MTX toxicity until these results can be verified in a larger population.
We have addressed the problem of anti-La autoimmune responses by defining the specific binding sites of human mAb to the La protein. Two human anti-La mAb were developed; one an IgM (kappa) (designated 8G3) and the second an IgG1 (kappa) (9A5) isotype. The mAb 8G3 immunoprecipitated the La RNA and La protein from crude human cell lysates; bound the 50-kDa La protein and a 28-kDa digestion fragment in immunoblots, and recognized a small defined internal segment from the cloned La protein. In contrast, the IgG isotype (9A5) failed to precipitate native La from cell lysates but bound the same segment of digested La protein and the same polypeptide of 131 amino acids in length from the cloned La protein. Immunoprecipitation experiments performed with these mAb demonstrated that the La protein is a component of a subset of Ro particles. The data suggest that the La protein is not present on the hY RNA in the absence of the Ro polypeptide. These observations may define functional subsets or maturation states of hY RNA based on their association with Ro or Ro and La polypeptides.
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Chronic recurrent multifocal osteomyelitis is a recently recognized disease characterized by remissions and exacerbations of multiple bone lesions which radiographically and pathologically have the appearance of hematogenous osteomyelitis. No consistent etiology can be identified, and antimicrobial agents seem to have no beneficial effect. A review of the appearances on imaging modalities and the clinical and pathologic manifestations is undertaken in seven cases of CRMO. No therapeutic regimen resulted in consistent clinical or radiographic improvement. We suggest the sequelae of this process are not as benign as previously reported.
Twenty-seven patients with Raynaud syndrome (mean age at onset 11.7 years) were studied to determine the prevalence of primary Raynaud syndrome and to assess the predictive role of antinuclear antibody, nail-fold capillary microscopy, and photoelectric plethysmography in this population. Fourteen patients (52%) had a connective tissue disease, four (15%) had a probable connective tissue disease, and nine (33%) had primary Raynaud syndrome. In all patients with either a connective tissue disease or a probable connective tissue disease, there was a positive reaction to antinuclear antibody, in contrast to patients with primary Raynaud syndrome, in whom antinuclear antibody was not detected. Nail-fold capillary microscopy scores differed significantly between patients with either a connective tissue disease or a probable connective tissue disease and those with primary Raynaud syndrome for both enlarged loop score (p less than 0.025 and less than 0.05, respectively) and avascular score (p less than 0.005 and less than 0.01, respectively). Photoelectric plethysmography scores were reduced in all groups but did not differ significantly between groups. Our findings suggest that in children with Raynaud syndrome, the primary type is more common than was originally suspected, and that both antinuclear antibody and nail-fold capillary microscopy, but not photoelectric plethysmography, can distinguish patients with primary Raynaud syndrome from those with either a connective tissue disease or a probable connective tissue disease.
Tumor necrosis factor production by peripheral blood mononuclear cells was measured in 18 patients with Kawasaki disease. In patients studied during the acute febrile phase of their disease, there was increased spontaneous TNF production (mean 26.9 +/- 40.3 U/ml) compared with that of control subjects (1.0 +/- .86 U/ml) (p less than or equal to 0.025). Spontaneous TNF production by patients tested in the subacute or convalescent phase of the illness was significantly lower than that in patients tested during the acute illness (p less than or equal to 0.025). In all patients studied with serial acute and subacute-convalescent samples, TNF production was normal in the follow-up samples. Because TNF is a potent mediator of inflammation and causes damage to vascular endothelial cells, we suggest that TNF may be important in the pathogenesis of both the immune activation and endothelial cell damage characteristic of this illness.
Juvenile arthritis includes a variety of rheumatic disorders with varied articular and extraarticular manifestations. The heterogeneity of JA cannot be overemphasized in a rational approach to therapy. Fortunately, most children with JA improve significantly with first-line treatment, especially those with pauciarticular disease. Only a small number of these patients go on to require second-line treatment, usually because of the evolution of their condition into the polyarticular type. Patients with polyarticular, RF-positive disease and patients with early-onset polyarthritis in association with systemic-onset disease both have poor prognoses in terms of ultimate joint function, and should receive second-line treatment early in their therapy. Injectable gold is the drug of choice for the former patients, if an initial trial of NSAIDs has failed. Patients with polyarticular onset, RF-negative disease generally have a better prognosis than other patients with polyarticular involvement. One may wait considerably longer before introducing a second-line agent for these patients. An antimalarial agent may be a reasonable choice for these patients, especially those with limited polyarticular involvement (5 to 10 active joints). This latter principle may also be applied to patients who evolve from pauciarticular to polyarticular involvement. In all such cases, penicillamine is almost never used as first choice. If the patient is a young child, the difficulty with injecting gold and the hazards of antimalarial agents may limit the use of these treatments. In situations such as this, auranofin or sulfasalazine may be the drug of choice. Cytotoxic/antimetabolic therapy should be reserved for those children who have continued active disease despite full courses of two SAARDs, or for those who have been unable to take SAARDs because of their side effects. Corticosteroid therapy should be used only when specifically indicated, and every attempt should be made to wean the patient from it as soon as feasible. The aim of therapy is to ensure that patients enter their remission in the best condition possible. For this to be assured, a sensible approach to drug therapy is mandatory.
The specificity of juvenile rheumatoid arthritis (JRA) sera for histone subclasses was examined by immunoblotting. Antibodies to H1 alone were found in 4 of 21 pauciarticular-onset JRA sera, 4 of 19 polyarticular-onset JRA sera, and 2 of 11 systemic-onset JRA sera. Antibodies to H5 alone were found in 1 of 21 pauciarticular JRA sera, 1 of 19 polyarticular JRA sera, and 3 of 11 systemic JRA sera. Antibodies to both H1 and H5 were found in 4 of 21 pauciarticular JRA sera, 4 of 19 polyarticular JRA sera, and 1 of 11 systemic JRA sera. Antibodies to the core histones (H2A and H2B) were found in 1 of 21 pauciarticular JRA sera, 1 of 19 polyarticular JRA sera, and no systemic JRA sera. No reactivity to histones was observed in 30 sera from age-matched children with nonrheumatic diseases. The presence of H1 and H5 antibodies did not correlate with antinuclear antibody titers or with a homogeneous pattern of immunofluorescence. The predominance of H1 and H5 antibodies and relative absence of antibodies binding to core histones in JRA contrast with findings in adult systemic lupus erythematosus. Further, the presence of antibodies to H5 alone in some of the JRA patients indicates that the immune response in these patients is directed to determinants that are not shared by sequences of mammalian proteins.
In summary, we have described two patients with CRMO and psoriasis, and have reviewed the musculoskeletal manifestations associated with pustular eruptions of the palms and soles. In view of the frequent occurrence of PPP in patients with CRMO, we suggest that the occurrence of psoriasis in our two patients is more than coincidence, and that noninfectious, inflammatory lesions of bone may be another musculoskeletal manifestation of psoriasis. This rare association, as well as the association of PPP with disorders associated with new bone formation, may shed new insights on the relatively common finding of periosteal elevation associated with psoriatic arthritis and the occasional severe juxta-articular osteolytic destructive bone lesions seen in psoriatic arthritis.