Biomedical subjects
Publications and source records attributed to N T Ilowite.
Recent developments in the identification of prognostic features, measures of disease activity, and responses to therapy in the childhood rheumatic diseases are summarized. Progress in understanding the immunopathogenesis of neonatal lupus erythematosus phenomenon and Kawasaki disease is reviewed.
In juvenile rheumatoid arthritis (JRA), it is likely that the release of proteolytic enzymes from activated synovial fluid neutrophils overwhelms the major protease inhibitor, alpha 2-macroglobulin (alpha 2-MG), and leads to cartilage destruction. Due to the unique nature of the alpha 2-MG-protease complex, proteolytic function is maintained until the complex is cleared. In this study, we sought to determine the concentration of alpha 2-MG-protease complexes in synovial fluid of patients with JRA, the proteolytic activity found in their synovial fluid, and whether the alpha 2-MG complexes are associated with increased proteolytic activity. The JRA patients' synovial fluids had complex levels of 217.0 +/- 192.2 nmol/L--significantly elevated compared with plasma values (p < 0.001) and with control synovial fluid (p < 0.05). Elastase activity (almost entirely neutrophil elastase) was detected in all JRA synovial fluid samples (mean 2.9 +/- 2.6 mg/L) and significantly correlated with alpha 2-MG-complex values (r = 0.67, p < 0.01). Synovial fluid tryptic activity was detectable in all JRA patients but did not significantly correlate with alpha 2-MG complexes (r = 0.53, p > 0.05). Seventy-four percent of total elastase activity and 41% of total tryptic activity were contained in the alpha 2-MG-complex fractions. We suggest that the increased concentration of synovial fluid alpha 2-MG complexes with retained elastase activity contributes to continued proteolysis and joint destruction and may affect the subsequent disease course through its role as a modulator of IL-6.
OBJECTIVE: Multiple rheumatologic signs and symptoms have been described in adult human immunodeficiency virus (HIV) infection. Our goals were to determine the incidence and characteristics of rheumatologic manifestations in HIV infected children, and to examine their relationship to laboratory evidence of autoimmunity. METHODS: Forty HIV infected children were studied by means of a questionnaire, history, examination, and serologic testing including determination of concentrations of immunoglobulin, C3, C4, and of presence of antinuclear antibodies (ANA), rheumatoid factor (RF), and circulating immune complexes (CIC). RESULTS: Rheumatologic manifestations included arthralgia (15%), myalgia (8%), erythema multiforme (3%), and parotitis (20%). Hypergammaglobulinemia (98%), hypocomplementemia (25%), RF (10%), ANA (3%), and CIC (82% of patients studied) were also found. Patients with or without rheumatologic manifestations did not differ significantly in any laboratory variable measured. CONCLUSIONS: In contrast to HIV infected adults, HIV infected children, do not display serious rheumatologic manifestations. Mild rheumatologic symptoms are common, but there is little evidence that these are immune mediated. Parotid enlargement occurs and must be differentiated from Sjögren's syndrome. Differences between rheumatologic manifestations of HIV infection in children and adults may reflect host factors such as the immaturity of the pediatric immune system, or environmental factors such as modes of acquisition of HIV, duration of HIV infection, or exposure to other sexually transmitted organisms.
Juvenile rheumatoid arthritis (JRA) and the arthritis of Lyme borreliosis in children can mimic each other. As false positive reactions are frequent in ELISA for Lyme borreliosis, they cannot be used reliably to make the distinction. Ninety-nine children diagnosed as having JRA at a children's hospital in an endemic area were evaluated by ELISA and immunoblot for antibodies to Borrelia burgdorferi. Sera from 9% were positive by ELISA, 5 of which showed bands on immunoblot. None met criteria for positive immunoblot. The antigenic basis of false positive ELISA was most frequently a reactivity to both 21 and 41 kDa. Analysis by immunoblot can help to definitively exclude Lyme borreliosis in children presenting with JRA in an endemic area.
The relation between pain and joint inflammation in patients with juvenile rheumatoid arthritis has not previously been systematically evaluated. Eighteen patients with juvenile rheumatoid arthritis completed paediatric pain questionnaires and the joints affected were examined by thermography. Although significant correlations were shown between parent and doctor pain intensity ratings and joint temperature, correlations of patient pain intensity ratings and joint temperature were only significant in younger children. The degree of joint inflammation is only one factor of several contributing to the amount of subjective pain experienced by children with juvenile rheumatoid arthritis, indicating the need for a comprehensive assessment of the relatively independent variables of inflammation and pain in children with juvenile rheumatoid arthritis.
We previously reported that approximately one-third of patients with juvenile rheumatoid arthritis (JRA) express high concentrations of antibodies marked by the rheumatoid factor cross reactive idiotype (RCRI) in their sera (6). In order to determine if an expression of RCRI is associated with certain clinical features of the disease, we prospectively studied 49 patients with JRA over a six month period, and determined serum RCRI concentrations by inhibition ELISA. RCRI concentrations correlated significantly with the duration of morning stiffness (r = .3866, p less than .01), and the functional class (p less than .001), but not with the number of active joints. Expression of RCRI was higher in patients with systemic onset disease (p less than .03), compared to patients with pauciarticular or polyarticular disease. In patients studied on more than one occasion, the RCRI expression was relatively constant despite changes in disease activity. A subset of JRA patients with systemic onset disease, higher serum concentrations of the RCRI.
Seven girls between 8.6 and 17.7 years of age were treated for symptoms of juvenile primary fibromyalgia syndrome (JPFS) using cognitive-behavioral techniques (progressive muscle relaxation, guided imagery) aimed at reducing pain and facilitating sleep, as well as strategies aimed at increasing mastery over the pain and improving mood. Patients satisfying diagnostic criteria for JPFS based on the presence of chronic diffuse musculoskeletal pain lasting at least 3 months (mean = 9.4, SD = 8.28) and a minimum of 5 characteristic soft tissue trigger and/or tender points with absence of synovitis, were referred for intervention. Results indicated that in the majority of patients, such techniques were effective in reducing pain and facilitating improved functioning.
Decreasing chronic joint pain is a major goal in the management of juvenile rheumatoid arthritis. Cognitive-behavioral self-regulatory techniques were taught to children with juvenile rheumatoid arthritis to reduce musculoskeletal pain intensity and to facilitate better adaptive functioning. Subjects were 13 children between the ages of 4.5 and 16.9 years who had pauciarticular or systemic onset juvenile rheumatoid arthritis. Baseline data included an initial comprehensive assessment of pain, disease activity, and level of functional disability, as well as pain intensity ratings gathered over a 4-week period. Subjects were seen for eight individual sessions in which self-regulatory techniques (progressive muscle relaxation, guided imagery, meditative breathing) were taught, and parents were seen for two sessions in which key aspects of behavioral pain management techniques were reviewed. Results indicated that these techniques led to substantial reduction of pain intensity, which generalized to outside the clinic setting. Six- and 12-month follow-up data showed consistent decreases in pain as well as improved adaptive functioning. The data suggest that cognitive-behavioral interventions for pain are an effective adjunct to standard pharmacologic interventions for pain in patients with juvenile rheumatoid arthritis.
Rheumatoid factor cross-reactive idiotype (RF-CRI) is expressed in high concentrations in the sera of some patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). To determine if RF-CRI is specifically expressed in rheumatic disease or if it is secondary to polyclonal B-cell activation, we examined sera of 23 children with SLE, 16 adolescents with infectious mononucleosis (IM), and age-matched pediatric controls for RF-CRI expression. Concentrations of RF-CRI in serum, determined by an inhibition ELISA, were 24 +/- 17 micrograms/ml (mean +/- SD) in 25 normal children, 31 +/- 17 in 16 young adults with IM, and were significantly increased, 70 +/- 80 micrograms/ml, in the 23 children with SLE (p less than 0.036). Eleven of 23 SLE patients had serum RF-CRI greater than the mean +/- 2 SD for normal children. Ten of 23 SLE sera contained IgM rheumatoid factor (RF) activity. One patient with IM had a borderline elevated RF-CRI level, and 5 IM patients had RF in their sera. The serum IgM concentrations in sera were: SLE (192 +/- 93 mg/dl) and IM (234 +/- 77 mg/dl) sera. These levels were significantly elevated compared to controls (132 +/- 44 mg/dl), p less than 0.031 for SLE and p less than 0.001 for IM, suggesting that polyclonal activation of B cells was present in SLE and IM patient groups. Increased expression of RF-CRI in the SLE patients correlated directly with high titer anti-DNA antibody values (r = 0.3965, p less than 0.05) and RF activity when human IgG (r = 0.5026, p less than 0.05) was used as the RF binding substrate and inversely with serum C3 levels (r = 0.3925, p less than 0.05). RF-CRI expression did not correlate with RF that bound rabbit (r = 0.3123, p greater than 0.05). Increased serum RF-CRI expression is not a result of polyclonal B-cell activation. RF-CRI may be selectively up-regulated in patients with SLE.
Anti-idiotypic (Id) antibodies (Abs) are generated in the humoral response to antigen (Ag). Some of these anti-Id Abs are capable of binding to the combining site or paratope of Abs that bind Ag. These Ab2 can competitively inhibit the binding of Ab1 to Ag may trigger an Ab1 response similar to the response induced by Ag. To determine if specific Ab2 that inhibit the binding of IgE Abs to ryegrass (RG)-pollen allergens are present in the sera of RG-allergic (RGA) individuals before the initiation of allergen-specific hyposensitization with RG-pollen extract, we studied sera from five RGA and four nonallergic (NA) subjects in an IgE anti-RG RAST-inhibition assay. Ab2-enriched serum fractions were prepared from these study subjects by exhaustive mixed grass-pollen affinity chromatography to remove IgE and IgG anti-RG Ab1 from whole serum aliquots containing Ab1. Unabsorbed, twice-concentrated sera were diluted to one-time concentrated sera with equal volumes of either Ab2-enriched sera without Ab1 or borate-buffered saline absorbed by mixed grass-pollen affinity chromatography. IgE anti-RG Ab1 was determined by a standard RG RAST assay. We have detected Ab2 in the sera of the RGA patients, which inhibit the binding of autologous and allogeneic IgE anti-RG to RG Ags in solid phase. Parallel RG RAST assays with sera from NA subjects demonstrated no significant inhibition. Ab2-enriched sera from some grass-allergic and some NA subjects inhibited IgE anti-RG binding found in some RGA patients' sera. We conclude that anti-Id Abs, Ab2, specific for IgE anti-RG, Ab1, are present in some RGA patients and NA individuals.
The major rheumatoid factor cross-reactive idiotype, which was defined by prototypic monoclonal IgM rheumatoid factors from Waldenstrom's macroglobulinaemia patient Wa, is present on 60% of all monoclonal IgM RF paraproteins. One-third of patients with juvenile rheumatoid arthritis (JRA), who are seronegative for classic IgM rheumatoid factor (RF), express the Wa idiotype in high titre in their sera. To determine if the Wa idiotype is present on hidden rheumatoid factors in JRA patient sera, we studied hidden RF expression by both ELISA and haemolytic assay techniques. The majority of JRA sera with increased concentrations of the Wa idiotype did not have increased RF activity nor hidden RF activity. In some JRA patients, the Wa idiotype may be expressed on a parallel set of immunoglobulin molecules, related to RFs, but lacking the ability to bind to IgG.
One third of patients with juvenile rheumatoid arthritis (JRA) are seronegative for classic or hidden IgM rheumatoid factor (RF) yet express the major RF crossreactive idiotype (RCRI). We studied 60 children with JRA and 57 pediatric controls for IgA RF and RCRI expression to determine whether RCRI is associated with IgA RF in JRA. Twenty-one patients had IgA RF using rabbit or human IgG as substrate. Twenty-seven patients with JRA expressed high concentrations of RCRI in their sera. Only 9 of these had IgA RF. Eleven of the RCRI+ sera contained neither IgA RF nor classic or hidden IgM RF, and IgA RF was found in patients with all JRA onset subtypes. In JRA, RCRI may be expressed on either IgG RF or on parallel set antibodies without RF activity.
Patients with systemic lupus erythematosus (SLE) appear to be at increased risk for development of neoplastic disease. We describe the case of a male teenager with SLE and Burkitt's lymphoma. His presentation was similar to that of an exacerbation of his underlying SLE. We believe this to be the first case of Burkitt's lymphoma in a patient with SLE. The association of SLE and malignancy, with emphasis on lymphoproliferative states, is discussed.
The major rheumatoid factor cross-reactive idiotype (RF-CRI), defined by prototypic monoclonal IgM rheumatoid factors, is expressed in high frequency by pokeweed mitogen-derived plasma cells from patients with rheumatoid arthritis who express RF in their sera. Unlike adults with rheumatoid arthritis, most patients with juvenile rheumatoid arthritis are seronegative for RF, as detected by classic IgG binding assays. We report that approximately 50% of seronegative patients with juvenile rheumatoid arthritis express the RF-CRI in high frequency among their pokeweed mitogen-derived plasma cells, and that approximately 33% of patients express the RF-CRI in high titer in their sera. The possible mechanisms for expression of an idiotypic marker of RF without expression of IgG binding activity by classic assays are discussed.
Dyslipoproteinemia, a feature of systemic lupus erythematosus may contribute to premature atherosclerosis. In order to develop an experimental model for this dyslipoproteinemia we measured plasma concentrations of lipoproteins in juvenile NZB/W (lupus) and NZB/B (control) mice. Additionally to evaluate the effects of a diet rich in n - 3 fatty acids we measured lipoprotein concentrations in mice on normal or menhaden oil-enriched diets. The lupus mice had elevated triglycerides compared to the controls, similar to that seen in human SLE patients (161 +/- 31 vs 113 +/- 13 mg/dl, P less than 0.003). In contrast, the menhaden oil diet fed NZB/W mice had triglycerides similar to the NZB/B control fed group. In the NZB/W murine SLE model, dyslipoproteinemia is an early sign of disease as has been shown in man, therefore this model will be useful in elucidating the mechanism of dyslipoproteinemia in SLE.
A toddler with common variable hypoimmunoglobulinemia (CVH), inflammatory bowel disease, and recurrent Pneumocystis carinii pneumonia (PCP) on intravenous gammaglobulin (IVIG) replacement was evaluated for a combined cellular immunodeficiency. He had a normal number of circulating T-cells, natural killer (NK) cells, T-cell subset percentages, and his peripheral blood mononuclear (PBM)-derived B-cell number was low. PBM mitogen blastogenesis and mixed lymphocyte reaction (MLR) were normal. MLR activated T-cells expressed class I and II MHC antigens, interleukin 2 (IL-2), and B-cell growth factor (IL-5)-related receptors. The patient's T-cells induced control B-cell maturation with pokeweed mitogen (PWM-PC), and did not suppress PWM-PC production by allogeneic PBM. Bone marrow (BM) CD19+ B-cell number varied between 10 and 44% of all PBM, and the BM B-cell-enriched fraction failed to differentiate to PWM-PC with autologous or allogeneic T-cell help. The NK activity assayed using K562 target cells was deficient, 9.2 x 7.7% (6.9-9.2%) pt, control 35.9 x 35.8% (16.3-67.2% +/- 12.8). In the presence of interferon-alpha, 800 U/ml, the patient's NK activity increased to 17.2 x 14.9% (12.6-17.2%), control 35.9 x 51.0% (36.5-72.3% +/- 12.0). The patient's cell-mediated lympholysis of HLA nonidentical, allogeneic stimulators was normal. Maintaining trough serum IgG levels above 500 mg/dl was required to suppress recurrent PCP. This functional NK deficiency may be relevant to the development of recurrent PCP in IVIG-treated CVH patients.
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The major rheumatoid factor cross-reactive idiotype (RCRI), a tertiary structure formed by both light and heavy chains, is found on 60% of all monoclonal IgM kappa RFs. To determine if the RCRI is expressed in patients with rheumatic disease, we used polyclonal rabbit anti-idiotypic antibodies to detect RCRI in sera and in pokeweed mitogen cultures of blood mononuclear cells (PBM) from patients with rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). We detected increased expression of RCRI+, plasma cells in PWM cultures, and in sera from these patients. We have determined that some 7S IgM molecules from RF+RA patients are RCRI+, and can bind IgG in a sensitive RF ELISA. We have also observed that the CD5+ B cell subset, which is responsible for autoantibody production, generates RCRI+ antibodies. We review these data and discuss the relationship of the idiotypic network of interacting antibodies with rheumatic disease.