Effect of penicillamine therapy on circulating immune complexes in rheumatoid arthritis

Mohammed, I., Barraclough, D., Holborow, E. J., and Ansell, B. M. (1976).Annals of the Rheumatic Diseases, 35, 458-462. Effect of penicillamine therapy on circulating immune complexes in rheumatoid arthritis. The sera of 40 patients with severe progressive rheumatoid arthritis were examined for the presence of soluble immune complexes before penicillamine therapy was started, and again after treatment for a mean period of 14·4 months. The methods used were radiobioassay (macrophage uptake), Clq-binding capacity, and precipitation by 4% polyethylene glycol.

Before treatment the sera of 37 patients showed significantly enhanced uptake of ¹²⁵I-labelled aggregated human IgG by guinea pig macrophages. Treatment produced significant falls in mean erythrocyte sedimentation rate, differential agglutination titre, and serum IgG and IgM levels, and enhancing complexes (EC) decreased or disappeared in 20 patients. In 9 patients EC changed to inhibiting complexes, and in 8 EC levels were unchanged. In 6 of 8 patients with cutaneous vasculitis initially, both lesions and EC disappeared. The total protein and the IgG and IgM precipitated from patients' sera by 4% polyethylene glycol fell significantly on treatment. Antinuclear antibody titres were unchanged by penicillamine, and 3 patients acquired these antibodies during treatment.

These findings suggest that penicillamine treatment in rheumatoid arthritis reduces the level of circulating soluble immune complexes in which IgM rheumatoid factor is a component.

     

Effect of antimalarial treatment on circulating immune complexes in rheumatoid arthritis

The relationship between the effect of chloroquine treatment on circulating immune complexes in patients with rheumatoid arthritis (RA) was determined by the 125I Clq binding assay. Three groups were studied: (a) 20 patients treated daily for 6 months with chloroquine sulphate 250 mg plus prednisone 7.5 mg and nonsteroidal antiinflammatory drugs (NSAID); (b) 20 patients not taking antimalarials but treated with prednisone and NSAID; (c) 41 controls. Results suggest that chloroquine sulphate therapy induced a marked decrease of immune complexes in patients with RA, an effect not observed with treatment by prednisone and NSAID only.     

Circulating immune complexes and antinuclear antibodies in juvenile rheumatoid arthritis

Materials with the Clq binding properties of soluble immune complexes (IC) were found in sera from 11 of 51 consecutive (22%) children with juvenile rheumatoid arthritis (JRA) and in 17 of 20 adults with active sero-positive rheumatoid arthritis (RA). IC appeared more frequently in children with systemic onset disease whereas antinuclear antibody (ANA) was found more frequently in sera from those with pauciarticular disease. Only 3 JRA sera contained anti-immunoglobulin (rheumatoid factor); those 3 also had high Clq binding activities. Seven of 50 patients (14%) carried HLA-B27 but B27 was not associated with high Clq binding activity or presence of ANA. The presence of free ANA more frequently in children with mild disease and IC more frequently in children with relatively severe disease suggests that children with systemic JRA may have a relative defect in antibody-forming capacity or reticuloendothelial function which results in decreased clearance of circulating IC. Alternatively, systemic, polyarticular, and pauciarticular JRA may represent a spectrum of clinically similar diseases resulting from different etiologic agents.     

Separation and characterization of complement-fixing immune complexes in juvenile rheumatoid arthritis patients

Summary Immune complexes (IC) in sera from patients with juvenile rheumatoid arthritis (JRA) were isolated by the use of immunoabsorbent columns. Sera from 14 JRA patients (four seropositive for 19S IgM RF and 10 seronegative, but nine having hidden 19S IgM RF) were analyzed by the anti-human Clq (HClq) and anti-human C3 (HC3) columns. The columns were sequentially eluted with veronal buffer, 0.02 M EDTA, 0.5 M NaCl, and 1 M propionic acid. By the HClq column, IgM RF were detected in at least one of the separated IC fractions of 13 of 14 patients and IgG RF in three patients. By the HC3 column, only five patients demonstrated IgM RF and only one IgG RF in the eluted fractions. On sucrose density gradient analysis (SDGA), all IC were demonstrated in the peaks 19S. 19S IgM RF were demonstrated by ELISA in all 14 patients, but IgG RF in only three. These studies demonstrate that complement-fixing 19S IgM RF, IgG, and IgG RF containing IC can be detected in the serum of JRA patients.     

Sulphasalazine versus penicillamine in the treatment of rheumatoid arthritis

Summary Fifty-four patients with rheumatoid arthritis were randomized to either sulphasalazine or d-penicillamine in order to compare the short- and long-term efficacy of these two agents in the treatment of rheumatoid arthritis. Decisive improvement was observed in both treatment groups over a 1 year period. Side effects were common in both groups and accounted for termination of therapy in 11 patients during the first year. Radiological deterioration was evident in both treatment groups. A trend toward greater radiological deterioration was observed in patients receiving sulphasalazine, but this was not statistically significant. Only 11 of the 38 patients who completed 1 year of therapy were continuing to take the same drug 5 years later. Eight patients were continuing d-penicillamine and three were still taking sulphasalazine. Among the patients who completed 1 year of therapy, treatment was subsequently terminated because of loss of effective disease control in a significantly higher proportion of patients receiving sulphasalazine (P<0.01). The radiological data and the latter observations suggest that d-penicillamine may be a more effective agent for long-term treatment.     

Effect of pregnancy on immune complexes and rheumatoid factors in patients with rheumatoid arthritis

Rheumatoid arthritis is associated with circulating and intra-articular immune complexes and rheumatoid factors. The clinical activity of rheumatoid arthritis improves during pregnancy in the majority of women, with exacerbation following delivery. Concentrations of immune complexes, as detected by the Clq-binding assay, the Clq-solid phase assay, and the monoclonal rheumatoid factor-solid phase assay, decreased during gestation, with elevations following delivery. Concentrations of IgM-rheumatoid factor and IgG-rheumatoid factor, analyzed by radioimmunoassay, changed variably during pregnancy, increasing in some patients and decreasing in others. When examined serially before, during, and following pregnancy, changes in the concentration of circulating immune complexes and/or rheumatoid factors corresponded with the clinical changes in three patients. These observations document the significant effect of gestation on the concentration of circulating immune complexes in patients with rheumatoid arthritis. They also support the role of these laboratory tests in monitoring the clinical course of rheumatoid arthritis.     

Circulating immune complexes and rheumatoid arthritis

Circulating immune complexes (CIC), as detected by the Clq binding assay (ClqBA) in sera from patients with rheumatoid arthritis (RA) were not demonstrable on analysis by ultracentrifugation on sucrose gradients. This discrepancy could be explained by the finding that polyethylene glycol 6000(PEG), used in the ClqBA to separate free radiolabelled Clq from complex bound Clq, increased the avidity of rheumatoid factor (RF), resulting in the formation of Clq binding RF IgM IgG complexes. Addition of purified RF IgM to normal human serum generated a positive ClqBA in a dose dependent way. The increased complex formation between RF IgM and IgG by PEG was also demonstrated in an enzyme linked immunoabsorbent assay and with sucrose gradients, where complexes became detectable when PEG was present. On the other hand RF IgM IgG Clq complexes obtained from the ClqBA dissociated upon removal of PEG. We conclude that high amounts of immune complexes, detected in RA sera by the ClqBA, are at least partly the result of in vitro complex formation between RF IgM and IgG. Therefore the results of this assay do not reflect the situation in the circulation in vivo.     

Radiological findings in seropositive juvenile chronic arthritis (juvenile rheumatoid arthritis) with particular reference to progression.

The radiological effects of peripheral joint disease in 81 patients with seropositive juvenile chronic arthritis were studied retrospectively with an average length of follow up of 11 years. The patients comprised 63 girls and 18 boys with average ages of onset being 10.7 years and 12.1 years respectively. All had developed positive serology within the first year of the disease. X-rays available in 70 of these patients at five years from onset of the disease showed erosive change to be present in all but three. The sites most commonly affected included the carpus, the metacarpal, the metatarsal, and interphalangeal joints, though a third of the patients also showed erosive change in large joints such as hips, knees, or shoulders. Between five and 10 years after disease onset progression of x-ray changes was evident in most patients, with additional joints becoming involved in about one third, though the distribution of joints was similar. After 15 years or more of disease the radiological changes tended to be more stable, but various mechanical difficulties often secondary to poor growth and degenerative change and to primary destructive inflammatory arthritis were evident. No specific drug regimen was found to have been universally effective in suppressing disease, and the frequency of side effects was a significant factor in preventing treatment schedules being maintained for long enough to be effective.     

Amyloidosis of the small intestine secondary to rheumatoid arthritis or juvenile rheumatoid arthritis: report of two cases

We report two cases of gastrointestinal amyloidosis, complicated with juvenile rheumatoid arthritis (JRA) in one and rheumatoid arthritis (RA) in the other. A 21-year-old woman, who had been suffering from JRA for the past 12 years, was transferred to our hospital due to intense pain in the epigastrium and back, diarrhea, high fever, and paralytic ileus. Treatment by corticosteroid, antibiotics protease inhibitor and total parenteral nutrition was not effective. Laparoscopic surgery was performed because of repeated melena followed by an episode of hypovolemic shock. The resected specimen of the ileum showed histologically marked amyloid deposition in the arteriolar walls. A 83-year-old man with RA for 14 years was admitted to our hospital with complaints of abdominal pain, nausea and diarrhea. He underwent an emergency operation for perforation of the ileum. The resected specimen revealed amyloid deposition and non-caseating granulomas. The fragility and impaired blood supply caused by amyloid deposition in the vascular walls may have terminated in the severe intestinal lesion. Further clinicopathological studies along this line are keenly desired in order to establish therapeutic modalities for gastrointestinal amyloidosis.     

Separation and characterization of immune complexes containing 19S IgM rheumatoid factor-IgG in juvenile arthritis

Sera from 10 patients with juvenile arthritis (JA), 2 seropositive and 8 with hidden rheumatoid factor (RF), were subjected to affinity chromatography on a rabbit anti-human IgM column. Material retained by the column was eluted sequentially by 1M NH₃ and 0.1M glycine-HCl buffer, pH 3.0. The affinity fractions contained both 19S IgM RF and IgG, while corresponding fractions from healthy controls contained neither. Sera from 15 patients with JA, 1 seropositive and 11 with hidden RF, were subjected to 4% polyethylene glycol precipitation followed by acid dissociation of the precipitate. Ten of 15 resultant fractions contained both IgM RF and IgG, while corresponding fractions from healthy controls contained only traces of IgG. Sera from 7 of these JA patients were subjected to sucrose density gradient centrifugation and the resultant fractions analyzed for the presence of immune complexes by the Clq solid-phase assay. Immune complexes were detected at and ahead of the IgM marker, as expected for IgM RF-IgG complexes. These combined data show that the majority of JA patients with classic or hidden 19S IgM RF have immune complexes containing IgM RF and IgG in their sera.     

Pharmacokinetic interactions of penicillamine in rheumatoid arthritis

The pharmacokinetic effect of the combined treatment of penicillamine with indomethacin and chloroquine was investigated in patients with rheumatoid arthritis. The mean plasma penicillamine concentration increased by 26% during indomethacin and 34% during chloroquine treatment. This new pharmacokinetic interaction may have important clinical implications.     

Comparison of penicillamine and gold treatment in early rheumatoid arthritis.

In a series of 100 adult patients with definite rheumatoid arthritis of at most 3 years' duration and with no previous penicillamine, gold or systemic corticosteroid treatment, 50 patients were treated with D-penicillamine and 50 with gold for one yar. The dose of penicillamine was 600 mg daily. Sodium aurothiomalate was given 50 mg weekly up to a total of 13 mg/kg and thereafter 50 mg once a month. In both treatment groups a statistically significant decrease in the number of painful and/or swollen joints, an increase in haemoglobin and a decrease in ESR, serum ceruloplasmin-, alpha1-acid glycoprotein-, IgG-, IgM- and IgA levels was observed. All the changes in these clinical and laboratory tests were of the same degree in both treatment groups. In the penicillamine group 12 out of 20 seropositive patients became seronegative and in another 5 the Waaler-Rose titre dropped clearly. In the gold group, 7 out of 16 seropositive patients became seronegative, and the Waaler-Rose titre dropped in another 5. An equal increase in the number of eroded joints in hands and toes was seen in the penicillamine and the gold group. Penicillamine was discontinued because of side effects in 13 patients (26%), and gold treatment in 15 (30%). Proteinuria and/or haematuria were the most common causes of discontinuation in the penicillamine group.     

Aortic regurgitation in seropositive juvenile arthritis.

Seropositive juvenile chronic arthritis is a relatively uncommon form of childhood arthritis, but it often causes severe destruction of joints associated with considerable functional disability. During the last 7 years lone aortic regurgitation has been seen to develop in 4 such patients and pursue a particularly aggressive course. Sudden deterioration occurred in 2, 1 of whom required urgent aortic valve replacement and 1 died while awaiting assessment. Because of this it is important to include regular cardiac appraisal as part of the routine assessment in seropositive juvenile arthritis.     

In vitro induction of proinflammatory cytokine secretion by juvenile rheumatoid arthritis synovial fluid immune complexes

Objective. To characterize juvenile rheumatoid arthritis synovial fluid (SF) immune complexes and to examine their interaction with leukocytes. Methods. SF immunoglobulin-containing fractions were prepared by sequential chromatography on protein A and Sephacryl 300. Fractions were subdivided according to molecular weight, characterized for immunoglobulin and complement content, and incubated with either promonocytic U937 cells or normal human peripheral blood mononuclear cells (PBMC). Results. High molecular weight SF immunoglobulin-containing fractions stimulated the release of interleukin-lβ (IL-1β) from U937 cells. These same complexes stimulated tumor necrosis factor α (TNFα), IL-lβ, IL-6, IL-8, and granulocytemacrophage colony-stimulating factor (GM-CSF) from PBMC. Lower molecular weight material was less efficient in inducing any of the cytokines. TNFα and IL-1β were the earliest of the messenger RNAs examined to be induced by the high molecular weight complexes. However, the secretion of IL-6, IL-8, and GM-CSF stimulated by the complexes was not completely dependent upon the secretion of IL-1β. Addition of IL-1 receptor antagonist to the cell cultures reduced GM-CSF and IL-6 production by 40% and IL-8 production by 25% in PBMC. Conclusion. SF immunoglobulin fractions contain immune complexes that vary in size, composition, and phlogistic potential. High molecular weight complexes are capable of inducing a spectrum of proinflammatory cytokines, all of which have been implicated in the pathogenesis of rhematic disease.     

Flurbiprofen in the treatment of juvenile rheumatoid arthritis

Thirty-four patients with juvenile rheumatoid arthritis, who were treated with flurbiprofen at a maximum dose of 4 mg/kg/day, had statistically significant decreases from baseline in 6 arthritis indices after 12 weeks of treatment. Improvements were seen in the number of tender joints, the severity of swelling and tenderness, the time of walk 50 feet, the duration of morning stiffness and the circumference of the left knee. The most frequently observed side effect was fecal occult blood (25% of patients); however, there was no other evidence of gastrointestinal (GI) bleeding in these patients. One patient was prematurely discontinued from the study for severe headache and abdominal pain. Most side effects were mild and related to the GI tract.     

Auranofin in the treatment of juvenile rheumatoid arthritis

A 6-month double-blind, parallel, randomized, placebo-controlled multicenter trial of auranofin (0.15–0.20 mg/kg/day) was conducted in 231 children with juvenile rheumatoid arthritis (JRA) in the United States and in the Union of Soviet Socialist Republics. Approximately 80% of the children had polyarticular disease. The auranofin-treated patients showed greater mean decreases from baseline in 11 of the 12 articular disease indices measured than did the placebo-treated subjects after 3 months of therapy, and in 9 of the 12 indices after 6 months. However, the actual intergroup mean differences were relatively small and were not statistically significant. According to the physician's global assessment, 69% of the auranofin-treated patients and 61% of the placebo-treated patients demonstrated clinically significant improvement from baseline after 6 months (P = 0.24). Children whose disease onset occurred less than 2 years prior to entry improved more than did those who had arthritis for a longer period. In addition, those with polyarticular involvement at baseline improved more than did patients with mild disease. However, these relationships were observed in both the auranofin- and placebo-treated groups, and again, there were no significant intergroup differences. Diarrhea was the most common adverse effect of auranofin. We conclude that the clinical efficacy of auranofin is modestly higher than that of placebo in the treatment of JRA, as evidenced by the consistent trends observed in the data. However, the magnitude of the individual intergroup differences is not statistically significant. Auranofin appears to be very safe in children with JRA.