Chester W. Fink

Methotrexate in resistant juvenile rheumatoid arthritis : results of the U.S.A.-U.S.S.R. double-blind, placebo-controlled trial

BACKGROUND The antimetabolite methotrexate has been shown in placebo-controlled trials to be effective in adults with rheumatoid arthritis. Methotrexate may also be effective in children with resistant juvenile rheumatoid arthritis, but the supporting data are from uncontrolled trials. METHODS Centers in the United States and the Soviet Union participated in this randomized, controlled, double-blind trial designed to evaluate the effectiveness and safety of orally administered methotrexate. Patients received one of the following treatments each week for six months: 10 mg of methotrexate per square meter of body-surface area (low dose), 5 mg of methotrexate per square meter (very low dose), or placebo. The use of prednisone (less than or equal to 10 mg per day) and two nonsteroidal antiinflammatory drugs was also allowed. RESULTS The 127 children (mean age, 10.1 years) had a mean duration of disease of 5.1 years; 114 qualified for the analysis of efficacy. According to a composite index of several response variables, 63 percent of the children who received low-dose methotrexate improved, as compared with 32 percent of those in the very-low-dose group and 36 percent of those in the placebo group (P = 0.013). As compared with the placebo group, the low-dose group also had significantly larger mean reductions from base line in the number of joints with pain on motion (-11.0 vs. -7.1), the pain-severity score (-19 vs. -11.5), the number of joints with limited motion (-5.4 vs. -0.7), and the erythrocyte sedimentation rate (-19.0 vs. -6 mm per hour). In the methotrexate groups only three children had the drug discontinued because of mild-to-moderate side effects; none had severe toxicity. CONCLUSIONS Methotrexate given weekly in low doses is an effective treatment for children with resistant juvenile rheumatoid arthritis, and at least in the short term this regimen is safe.

Methotrexate in Resistant Juvenile Rheumatoid Arthritis

BACKGROUND The antimetabolite methotrexate has been shown in placebo-controlled trials to be effective in adults with rheumatoid arthritis. Methotrexate may also be effective in children with resistant juvenile rheumatoid arthritis, but the supporting data are from uncontrolled trials. METHODS Centers in the United States and the Soviet Union participated in this randomized, controlled, double-blind trial designed to evaluate the effectiveness and safety of orally administered methotrexate. Patients received one of the following treatments each week for six months: 10 mg of methotrexate per square meter of body-surface area (low dose), 5 mg of methotrexate per square meter (very low dose), or placebo. The use of prednisone (less than or equal to 10 mg per day) and two nonsteroidal antiinflammatory drugs was also allowed. RESULTS The 127 children (mean age, 10.1 years) had a mean duration of disease of 5.1 years; 114 qualified for the analysis of efficacy. According to a composite index of several response variables, 63 percent of the children who received low-dose methotrexate improved, as compared with 32 percent of those in the very-low-dose group and 36 percent of those in the placebo group (P = 0.013). As compared with the placebo group, the low-dose group also had significantly larger mean reductions from base line in the number of joints with pain on motion (-11.0 vs. -7.1), the pain-severity score (-19 vs. -11.5), the number of joints with limited motion (-5.4 vs. -0.7), and the erythrocyte sedimentation rate (-19.0 vs. -6 mm per hour). In the methotrexate groups only three children had the drug discontinued because of mild-to-moderate side effects; none had severe toxicity. CONCLUSIONS Methotrexate given weekly in low doses is an effective treatment for children with resistant juvenile rheumatoid arthritis, and at least in the short term this regimen is safe.

Different HLA-D associations in adult and juvenile rheumatoid arthritis.

HLA-D typing was performed in 126 patients with juvenile rheumatoid arthritis. HLA-DW4, the antigen found in previous studies to characterize adult rheumatoid arthritis, had a significantly lower frequency in children with arthritis than in normal controls (P less than 0.04). By contrast, in children the antigens HLA-DW7 (P less than 0.03) and HLA-DW8 (P less than 0.01) were increased compared to controls. The antigen TMo, detected with homozygous typing cells from a child with juvenile rheumatoid arthritis, was found to be related to the cross-reactive specificities HLA-DW7 and DW11. 46% of the patients with persistent pauciarticular arthritis of childhood typed for the antigen TMo, compared to only 1% of normal controls. Thus the relative risk for persistent pauciarticular arthritis in relation to the presence of TMo was 67.7 (P less than 0.0001). These results provide evidence of fundamental differences between adult rheumatoid arthritis and arthritis of childhood. The latter group appears to include a population distinguishable clinically and characterized in these studies by the HLA-D determinant TMo.

Lymphotoxin formation by lymphocytes and muscle in polymyositis

Muscle pieces from 11 patients with dermatomyositis or polymyositis were incubated with autologous peripheral blood lymphocytes and the supernates examined for the production of lymphotoxin, a mediator of delayed hypersensitivity, using human fetal muscle monolayers as the target cell. In the case of all 10 active patients, production of lymphotoxin was demonstrated. This mediator was also demonstrated when muscle alone was incubated from two patients with extensive cellular infiltration. Lymphotoxic activity was not found in supernates obtained by incubation of muscle from nine control subjects with their autologous peripheral blood lymphocytes. Addition of methyl prednisolone to active cultures inhibited the action of lymphotoxin on the muscle monolayers. Lymphotoxin was not demonstrated when breast tumor tissue from a patient with dermatomyositis was incubated with autologous lymphocytes. The lymphotoxic agent in the active supernates had similar chromatographic properties to those of a sample of purified lymphotoxin. These findings suggest that muscle injury in polymyositis is a result of a cellular immune response to an antigen present in involved muscle tissue.

Comparison of tolmetin sodium and aspirin in the treatment of juvenile rheumatoid arthritis

The Pediatric Rheumatology Collaborative Study Group was established in 1973 to undertake systematic trials of new drugs in the treatment of juvenile rheumatoid arthritis. The first drug evaluated was tolmetin (1-methyl-5-p-toluoylpyrrole-2 acetic acid), a new nonsteroid anti-inflammatory agent. A four-week open trial with 30 patients and a subsequent 12-week double-blind trial against aspirin with 107 patients were conducted. Tolmetin and aspirin had equal anti-inflammatory and analgesic effects in the treatment of JRA. Elevations of transaminase values attributed to aspirin were not found with tolmetin. Adverse effects accompanying administration of tolmetin did not appear to be of major clinical significance.

Sarcoid arthritis in children.

Abstract The clinical features of the six cases of sarcoid arthritis here reported, and of the five previously recorded cases of sarcoid arthritis in childhood, appear to form a syndrome characterized by large, painless, boggy synovial and tendon sheath effusions with little limitation of motion, by typical eye and skin changes, and by an indolent clinical course with minimal or absent constitutional symptoms. These manifestations make it possible to distinguish sarcoid arthritis clinically from juvenile rheumatoid arthritis.

Ibuprofen suspension in the treatment of juvenile rheumatoid arthritis

Ninety-two children with juvenile rheumatoid arthritis were randomly assigned to treatment in a multicenter, double-blind, 12-week trial designed to compare the efficacy and safety of a liquid formulation of ibuprofen at a dosage of 30 to 40 mg/kg/day versus those of aspirin at a dosage of 60 to 80 mg/kg/day. No significant intergroup differences in response rates or in the amount of improvement in articular indexes of disease activity were observed. More children treated with aspirin discontinued treatment early because of adverse reactions. After this trial, 84 additional patients with juvenile rheumatoid arthritis entered a 24-week, multidose (30, 40, and 50 mg/kg/day), open trial of ibuprofen suspension. Favorable response rates for the three groups were similar, and continued improvement was observed throughout the 24-week period. A dose-response relationship was observed with respect to adverse reactions of the upper gastrointestinal tract. We conclude that ibuprofen suspension is an effective nonsteroidal antiinflammatory drug and that its tolerability in children is acceptable.

Effect of levodopa (L-dopa) on serum growth hormone in children with short stature.

Extract: The diagnostic usefulness of levodopa (l-dopa) as a provocative agent for stimulating growth hormone (GH) release was investigated in 22 children with short stature. Complete endocrine evaluation showed 17 to have normal pituitary function (group I) and 5 GH deficiency (group II). Serial serum GH measurements were made under basal conditions after arginine infusion, insulin hypoglycemia, and single dose oral administration of l-dopa (100–500 mg). Mean GH levels after l-dopa in group I were, in nanograms per milliliter: 0 min, 4.8; 30 min, 7.0; 60 min, 16.5; 90 min, 12.6; 120 min, 8.4; 150 min, 3.2; 180 min, 1.9. A significant GH rise was seen in 15 of 17 children, but a normal response as defined in the text was observed in 13 of 17. Peak GH response occurred between 30 and 120 min. Mean peak GH responses to l-dopa were 21.3, arginine 25.2, and insulin 21.3. The two nonresponders to l-dopa in group I showed normal GH response to insulin. The response to arginine was normal in one and partial in the other. Group II subjects showed no GH response to the three agents. Side effects to l-dopa were minimal and usually limited to temporary nausea. By virtue of its ready availability and simplicity of administration, the l-dopa test appears to be a good means of determining GH reserve.Speculation: l-dopa administered as a single oral dose seems to be a simple and valid agent for evaluation of pituitary GH reserve.

JUVENILE ARTHRITIS, HLA-A2 AND BINDING OF DEK ONCOGENE-PEPTIDES

Previous studies have shown that susceptibility to Pauciarticular Juvenile Arthritis is associated with HLA-A*0201. Recently, autoantibodies against the protein of the DEK oncogene have been found in sera of patients with this disease. If T cells are involved in the pathogenesis of joint lesions, it is possible that they target autoantigens presented by HLA-A*0201. Therefore, we investigated whether DEK-derived peptides can bind efficiently to HLA-A*0201. Nonameric peptides selected considering anchor positions 2 and 9, and preferred amino acids at other positions, were incubated either with the human TAP-deficient cell line 174CEM.T2 (T2) or with the homozygous B cell line JESTHOM (A*0201, B*2705, Cw1), previously depleted of endogenous peptides. Binding was measured as the increase of detection of fully assembled, HLA-A*0201 molecules by flow cytometry with the anti-HLA-A2 monoclonal antibody (mAb) BB7.2. Three out of ten selected DEK-derived peptides showed binding to HLA-A*0201, which was peptide concentration-dependent (1 microM to 100 microM). DEK155-163 (AMLKSICEV), which also has two preferred amino acid residues at positions 6 and 8, yielded the highest binding. DEK163-171 (VLDLERSGV) and DEK72-80 (SLQREPFTI), which also has one preferred amino acid residue at position 8, also were able to bind to HLA-A*0201. Furthermore, peptide-induced, fully assembled, HLA-A*0201 molecules were immunoprecipitated with the BB7.2 mAb from metabolically-labeled T2 cells incubated with DEK72-80, DEK155-163, and DEK163-171. A faint band was observed in the immunoprecipitates of cells incubated with DEK65-73 (it carries a preferred amino acid residue at position 6), suggesting that this peptide interacts weakly with HLA-A*0201. These results indicate that several nonameric peptides derived from the DEK protein can bind to HLA-A 0201 and suggest that the complexes formed may be able to stimulate CD8+ T cells in patients with Pauciarticular Juvenile Arthritis.

Pauciarticular juvenile rheumatoid arthritis: Clinical and immunogenetic aspects

One of the greatest problems in diagnosing pauciarticular disease early is that the peripheral arthritis often appears before other, more diagnostic, manifestations. The late development of a typical rash or nail changes in psoriatic arthritis or the later complaints of back stiffness or radiographic evidence of sacroiliitis that are seen in juvenile ankylosing spondylitis make early diagnosis of the peripheral arthritis difficult. Two recent cases illustrate this point. One was that of a 15-year-old girl who, 12 years after a brief episode of a swollen knee, had a sudden perforation of a short segment of small bowel affected with Crohns disease. Another was that of a boy seen 8 years after having had a swollen knee for a few months. His back pain of recent onset was found to be due to ankylosing spondylitis rather than an injury, as he had supposed. Notwithstanding these diagnostic nightmares, there is often some clue to show that a given arthritis is not simply pauciarticular juvenile-onset arthritis. These clues in adults have already been mentionedheel pain, plantar fasciitis, spurs, hip disease, and acute rather than the more usual chronic iridocyclitis seen in juvenile-onset polyarthritis. Reported cases of Reiters syndrome (RS) in childhood have usually followed gastrointestinal infections rather than sexual exposure, but children seem to have the same high incidence of B27 positivity as do adults. Jacobs has described 10 children, all but one being male, that he has called