Double-blind trial of levamisole, penicillamine and azathioprine in rheumatoid arthritis. Clinical, biochemical, radiological and scintigraphic studies.
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Biomedical subjects
Publications and source records attributed to P Halberg.
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Circulating immune complexes (CIC) and complement C4, C3 and CH50 levels in serum were monitored during 6-30 months in 10 patients with rheumatoid arthritis and extra-articular manifestations (EM). A total of 58 observations were made, 17 at times when new EM emerged, 41 at times when the patients were in a steady state. CIC were demonstrated by two methods, viz. a complement consumption test (CCT) and a polyethyleneglycol (PEG) precipitation assay. The precipitates were analysed for their content of IgG, IgM and IgA. The CCT titre decreased significantly at the time of a new EM, whereas PEG precipitates were found most often at this time. Two types of precipitate could be demonstrated. One consisted of IgG only, which was found most often when the patients were in a steady state. The other one was composed of IgG and other immunoglobulins, most often IgA. The latter type was found most often at the time when the patients developed new EM. Subnormal serum complement levels were demonstrated frequently. The level of C4 was significantly lower at the time of a new EM, compared with the level of patients with RA but without EM. The decrease in anticomplementary effect and the signs of complement activation suggest that the qualitative and quantitative changes in CIC observed at the time of new EM were the cause rather than the consequence of the clinical manifestations.
The joints of hands and feet of 25 patients (1150 joints) with rheumatoid arthritis were compared, joint by joint, clinically and radiologically, over 2 years of treatment with remission-inducing drugs. Joints with clinical signs of synovitis decreased from 47% to 17% (p less than 0.001), while the number of joints with radiological lesions increased from 23% to 27% (p less than 0.01). Definite radiological progression of bone lesions was seen in 7% of the joints. Joints with clinical synovitis had a higher risk of progressive bone damage than joints without clinical synovitis (p less than 0.001) and joints in which the clinical signs of synovitis persisted during the study had a higher risk of progressing bone lesions than joints in which the clinical synovitis subsided (p less than 0.001). Progressive bone damage was seen more often in swollen joints than in tender joints without swelling or joints without clinical signs of synovitis (p less than 0.001), the difference in radiological progression between the latter two groups being non-significant. Twenty-one per cent of the joints with progressive bone lesions had no clinical signs of synovitis during the period.
A systematic search for immune complexes (IC) in blood and skin revealed no correlation to IC-related disorders in 35 patients who had undergone jejunoileal bypass for obesity. Tests for cryoprecipitates and endotoxins proved negative.
Biopsy specimens from granulomatous skin lesions of 14 patients with active sarcoidosis were examined by immunofluorescence microscopy. In seven lesions, deposits of IgM, IgA or complement C3 were demonstrated in the dermal vessel walls and/or at the dermal-epidermal junction. Similar deposits were found in three of twelve biopsy specimens from clinically normal skin from a buttock of the same patients. The results support the hypothesis that deposition of circulating immune complexes in the vessel walls may be of importance for the development of granulomatous lesions in sarcoidosis.
Four previously healthy Danish homosexual men developed Kaposi's sarcoma or opportunistic infections with fever of unknown origin and lymphadenopathy. One patient died of a Pneumocystis carinii pneumonia. Three patients had defective cell-mediated immunity with absent leucocyte interferon production and decreased proliferative response to mitogens and antigens. T lymphocyte helper subsets and natural killer cell activity were reduced. Unstimulated mononuclear cells produced leucocyte migration inhibitor factor. Two patients were sexual partners and three had never been to the USA, where cases of severe acquired immunodeficiency have been reported. Thus, the syndrome must also be suspected in European homosexual men who present with fever of unknown origin, opportunistic infections, or Kaposi's sarcoma.
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Previous immunofluorescence studies on pyoderma gangrenosum (PG) proved negative. Biopsies from the ulcer edge of 8 patients with PG were examined by immunofluorescence microscopy. Deposits of complement C3 were seen in the vessel walls of all samples, IgM in three and IgA in one. Granular deposits of C3 were seen at the dermal--epidermal junction in 2 patients. Biopsies from clinically normal skin of 6 of the patients were negative. It is suggested that deposition of immune complexes in the dermal vessel walls may play a role in the pathogenesis of PG.
The prevalence of circulating immune complexes (CIC) and C4 and C3 activation products (C4 and C3 A.P.) was investigated in sera from 106 blood donors, 100 hospital staff-members, 63 patients with rheumatoid arthritis and active synovitis, and in 25 hospital staff-members who had monthly tests performed during one year. CIC were detected by means of a complement consumption test and a polyethylene glycol precipitation test. C4 and C3 A.P. were demonstrated by means of crossed immunoelectrophoresis. No significant differences in the prevalence of CIC were found between blood donors and hospital staff-members (3 and 9%, respectively) and no age and sex differences were observed. In the longitudinal study of hospital staff-members, a significantly increased incidence of CIC was found during the winter months. CIC were found in 86% of the patients with rheumatoid arthritis. C4 and C3 A.P. were found significantly more often in sera with than without CIC. The significance of CIC detection may be increased by the simultaneous demonstration of C4 and C3 A.P. and by making allowance for seasonal variations.
One hundred twenty-seven biopsy specimens from clinically normal light-protected skin of 88 patients with active and inactive lupus erythematosus (LE) were examined for deposits of IgG, IgM, IgA, and C3 at the dermal-epidermal junction (DEJ). Deposits were found in 91% of those with active disease and in 33% of those with inactive disease. The finding of such deposits reflected active disease just as did a decrease in serum C3 and C4 levels, elevated anti-double-stranded DNA, the presence of LE cells, lymphopenia, and an elevation of the ESR. The presence or absence of deposits in repeated biopsy specimens indicated changing disease activity, as estimated clinically, just as did changes in the other variables mentioned. Neither immunoreactants in skin nor any other laboratory abnormality reflected renal disease or other type of organ involvement. Deposits of IgG were not more commonly found in patients with renal disease.
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