A subset of systemic lupus erythematosus with progressive cystic bone lesions.

Clinical and serological findings of 16 patients with systemic lupus erythematosus (SLE) who had progressive cystic bone lesions were compared with a control group of 19 patients with SLE without radiological evidence of bone cysts. Central nervous system manifestations, synovitis, and other radiologically observed skeletal abnormalities were more prevalent in the patients with cysts than in the control group. Higher concentrations of C reactive protein, and a greater incidence of rheumatoid factor positivity were seen in the patients with cysts than in the control patients, but no other serological differences were found. It is suggested that patients with SLE with progressive cystic lesions form a subgroup of the syndrome characterised by an increased acute phase reaction.

Membranous glomerulonephritis in rheumatoid arthritis not related to gold or D-penicillamine therapy: a report of four cases and review of the literature.

In a series of 96 patients with membranous glomerulonephritis (MGN) there were 14 who had concomitant rheumatoid arthritis. Ten of these had been treated with gold or D-penicillamine; in four patients neither of these drugs could have been responsible for the MGN. One of them received intrasynovial osmium tetroxide two months before the clinical onset of MGN. Three of the patients had positive rheumatoid factor. HLA-type was examined in three patients and all showed B27 antigen but not DR3. No patient developed signs of systemic lupus erythematosus during the follow-up (mean 5.9 years). In two patients MGN persisted as judged from urinary abnormalities, one patient recovered after a relapse period and one developed secondary amyloidosis.

Cell-mediated immune response in the diseased joints in patients with reactive arthritis.

To evaluate the level of lymphocyte activation in reactive and rheumatoid arthritis, density gradient-isolated, synovial fluid mononuclear cells were stained with a panel of antisera directed at lymphocyte activation markers using an avidin-biotin-peroxidase complex (ABC) method. More specifically, we studied the expression of immune response-associated class II HLA antigen (Ia), of receptors for interleukin 2 (Tac) and transferrin (T9), as well as of gp 40/80 glycoprotein (4F2). Although Ia+ cells formed about 60% of all the synovial fluid mononuclear cells in both disease conditions, the proportion of Tac+ (33 +/- 4% vs 3 +/- 1%, P less than 0.001), T9+ (34 +/- 4% vs 5 +/- 2%, P less than 0.001), and 4F2+ (48 +/- 6% vs 3 +/- 2%, P less than 0.001) cells was high only in reactive arthritis. All the patients who had reactive arthritis followed a favourable clinical course during the 4-month-long prospective follow-up, whereas disease activity was stable in patients with rheumatoid arthritis. These findings suggest that the diseased joints in reactive arthritis are a site for an active, but normally down-regulated, cell-mediated immune response.

Reversible non-oliguric impairment of renal function during azapropazone treatment.

An impairment of the renal function was observed in three patients who received azapropazone for various rheumatic disorders with simultaneous hyperuricaemia. A distinct increase in serum creatinine occurred in all patients. In one case the renal biopsy suggested a hypersensitivity reaction with a consequent acute tubulo-interstitial nephritis as the mechanism of the impaired renal function. The renal insufficiency was reversible in all cases after the withdrawal of azapropazone.

Cellular immunohistopathology of acute, subacute, and chronic synovitis in rheumatoid arthritis.

Cellular inflammation in rheumatoid arthritis (RA) synovial membrane was studied in biopsy specimens taken at different stages of synovitis and disease. Patients were classified into three subgroups: acute RA, subacute RA, and chronic RA. Inflammatory cells were characterised by a histochemical esterase method and immunohistochemical peroxidase-antiperoxidase (PAP) and avidin-biotin-peroxidase (ABC) staining. The amounts and distribution of inflammatory cells were different in various stages of the synovitis. In acute onset RA monocytes and granulocytes predominated, suggesting that the beginning of rheumatoid inflammation is similar to inflammatory reaction in general. The presence of T cells and also of plasma cells in subacute RA suggests underlying subclinical changes also in apparently healthy joints in RA. The most typical feature of prolonged synovitis in chronic RA was its intensity, characterised by the presence of large T cell and plasma cell infiltrates. Our findings suggest that the immunological mechanisms are secondary to the tissue damage caused by the initial inflammatory events of unknown cause. However, the immunological mechanisms may still play a central role in the aetiopathogenesis, because findings in chronic RA suggest a defective down-regulation of the immune response.

Bone lesions in systemic lupus erythematosus.

Routine joint radiographs of 125 patients with systemic lupus erythematosus were studied. A total of 121 patients had a clinical history of articular symptoms. Cystic bone lesions were found in 51 patients (41%). The lesions, which were typically located subchondrally in the small joints of hands and feet, appeared as well-defined radiolucent areas surrounded by either normal bone or a narrow sclerotic zone. Nutritional disturbance in the bones, caused by the vasculitis associated with systemic lupus erythematosus, is proposed as a possible pathogenetic mechanism of the cystic lesions.

Evaluation of six tests for circulating IgG complexes with special reference to IgM rheumatoid factors: analysis of systemic lupus erythematosus and rheumatoid arthritis series.

Six tests for circulating immune complexes (CIC) developed in four laboratories and representing four main principles [affinity of human platelets, Clq, of RF for aggregated IgG, and of conglutinin (Kg) for complex-bound C3] were evaluated on series of SLE and definite RA. All tests detected human model complexes in the presence of NHS and discriminated the patient series from the blood donor series, most powerful being the PIPA (platelet test). The high correlation between the RF-binding inhibition tests (RFbI) and the RF-latex test suggested interference due to intrinsic RFs. This received further support from experimental analyses in which RA sera mixed with varying doses of heat-aggregated IgG were assayed by the pRFbI test.

Immunological effects of Biarison in the treatment of rheumatoid arthritis and systemic lupus erythematosus. A preliminary report.

In two different double-blind studies (Study 1: 27 patients with active rheumatoid arthritis in an early phase, and Study 2: 20 selected patients with rheumatoid arthritis and acute knee effusion) the efficacy of Biarison, a new non-steroidal antiinflammatory agent was compared with that of indomethacin. The daily dose of Biarison was 600-900 mg and that of indomethacin 50-100 mg. Overall clinical improvement was observed in both treatment groups, but the two treatments differ in their effects on the erythrocyte sedimentation rate (ESR) and the immunoglobulin levels in both serum and synovial fluid. In the Biarison group there was a significant decrease in ESR and serum IgG, IgM and IgA. Biarison has also been used in the treatment of active SLE (Study 3), and a good clinical improvement was noticed in 5 out of 8 patients. These preliminary results suggest that Biarison may influence the immunological processes in both rheumatoid arthritis and systemic lupus erythematosus.

Granulomatous glomerulonephritis in a patient with rheumatoid arthritis treated with gold salts.

The clinical course of rheumatoid arthritis in the patient described was characterized by two episodes of microhaematuria, both occurring shortly after the administration of gold salt. The second of these episodes developed into progressive renal failure. Renal biopsy disclosed a rarely described granulomatous glomerulonephritis. Various known pathogenic mechanisms of renal injury are evaluated concerning their applicability in this patient. However, although it is believed that the gold salt therapy was the main agent in the pathogenesis of this fatal renal complication, the mechanism whereby such a pathogenesis proceeded remains unclear.

Immunofluorescence study of renal biopsies in chronic rheumatoid arthritis.

Renal biopsy specimens from 20 patients, 14 women and 6 men, with rheumatoid arthritis (RA) of at least 6 months' duration were studied by direct immunofluorescence microscopy for the presence of immune deposits. Pathological changes were most prominent in patients with longstanding or malignant disease and in patients previously on gold salt therapy. Staining for IgG and C3 was negative in 4 patients with an arthritis of 2 year's duration or less. Fifteen patients had glomerular deposits containing IgG or C3, or both. In 6 of these patients staining was also positive for IgM and in 3 for IgA. In 8 patients C3 was distributed in irregular deposits along the tubular basement membrane. These results suggest that in patients with RA, immunological processes have an untoward effect on the kidneys. The long-term effects of these processes might contribute, moreover, to the development of late renal complications. There is no evidence, however, that the renal immune deposits documented so frequently in this study derive from the rheumatoid disease itself.

Resolution of renal amyloidosis secondary to rheumatoid arthritis.

A patient with seronegative rheumatoid arthritis developed a nephrotic syndrome. Histological examination of renal biopsy disclosed moderate amyloidosis. Ultrastructurally the glomerular amyloid deposits were seen to be located both within the mesangium and subepithelially in the peripheral capillaries. The patient was treated with prednisone and cyclophosphamide for two years. The nephrotic syndrome remitted and a follow-up biopsy showed almost total disappearance of Congo red positive amyloid substance. Electron microscopy showed abundant finely granular material but only small amounts of fibrillar amyloid in the mesangial regions and intramembranous lucent areas containing few amyloid fibrils but no subepithelial deposits in the peripheral capillaries. We conclude that the mesangial amyloid substance was degraded to granular material and that the subepithelial amyloid deposits were resolved by mechanisms similar to those involved in the resolution of subepithelial immune complex deposits, i.e. through slow washing out and incorporation into the basement membrane.

Hypothesis for the pathogenesis of sodium aurothiomalate (Myocrisin) induced immune complex nephritis.

Renal complications associated with gold salt treatment in rheumatoid arthritis occur in fewer than 5% of treated patients. Recent investigations have shown that the renal lesion manifested clinically as membranous glomerulonephritis is caused by immune complexes. This paper presents a hypothesis for the mechanism by which gold causes this lesion: autoimmunization due to released tubular antigen(s). This hypothetical mechanism is strikingly similar to that responsible for autologous autoimmune nephrosis in the rat (Heymann's nephritis).

A long-term double-blind comparative study on proquazone (Biarison) and ibuprofen in rheumatoid arthritis.

The efficacy and tolerance of proquazone, 900 mg, and ibuprofen, 1200 mg, were compared in a randomized, double-blind clinical trial of 6 months' duration, with 44 patients, 21 on proquazone and 23 on ibuprofen. Comparison of proquazone-treated patients with patients treated with iburofen showed a significantly better improvement , as is demonstrated by the significant differences in the Lansbury Index, in nocturnal pain, final assessment of therapeutic effect, and number of interruptions due to lack of efficacy. All differences were in favour of proquazone, proving its therapeutic superiority over ibuprofen. The side effects in the proquazone group were mainly gastrointestinal, and 2 patients broke off treatment prematurely due to diarrhoea (in one patient, lack of efficacy was a contributory cause). A third patient discontinued because of moderate nausea and dizziness. In the ibuprofen group, 4 patients discontinued because of side effects (skin eruptions, dizziness, epigastric discomfort, and one thrombocytopenia) in addition to lack of efficacy. Proquazone seems to be an effective and well tolerated anti-inflammatory analgesic.

Influence of proquazone (Biarison) on the levels of complement components (C3 and C4) in synovial fluid and on IgM in serum in patients with active rheumatoid arthritis. A preliminary report.

Four patients with erosive rheumatoid arthritis and one with psoriasis arthropathy were treated with 600-900 mg/day proquazone for 4-7 weeks. All patients had acute knee effusions. The complement components C3 and C4, as well as IgG, IgA, IgM and total protein, were measured in both the synovial fluid and serum before and after treatment. In the 4 patients with rheumatoid arthritis, a marked increase in C3 and/or C4 levels in the synovial fluid was found, correlating in 3 cases with a good clinical response. However, no corresponding changes in complement levels were recorded in the serum. The patient with psoriasis arthropathy did not show any reaction. These preliminary results suggest that proquazone may influence the immunological processes in rheumatoid arthritis.

Gold-induced immune complex nephritis in seronegative rheumatoid arthritis.

Proteinuria, with or without the nephrotic syndrome, developed in 8 patients with seronegative rheumatoid arthritis after the institution of gold therapy. Light microscope examination of renal biopsies showed normal findings in 7, and a focal increase in the mesangial matrix of one glomerulus in the eighth. In all patients immunofluorescence showed deposits of IgG and C3 along the glomerular basement membrane, indicative of immune complex nephritis. The renal biopsies of 5 patients were studied with the electron microscope and subepithelial deposits were detected in all. The Rose-Waaler test for the detection of IgM-rheumatoid factor (IgM-RF) was repeatedly negative in all patients. These results suggest that the development of gold nephropathy may be related to an absence of IgM-RF in serum.

Acid glycosaminoglycans in plasma. II. Findings in rheumatoid arthritis.

The glycosaminoglycans (GAG) directly adsorbable from undiluted plasma on DE-52 anion-exchange cellulose (free GAG) and the GAG adsorbable on AG 1 X 2 anion exchange resin after papain proteolysis (bound GAG) were determined in 35 patients suffering from active erosive rheumatoid arthritis (RA) and in 50 control subjects. Free GAG levels were significantly elevated in both female (p less than 0.001) and male (p less than 0.05) RA patients. Bound GAG levels were significantly depressed in female (p less than 0.02) but not in male RA patients. Total GAG concentrations in RA patients and in controls were fairly similar. No consistent differences in the electrophoretic patterns of the plasma GAG from RA patients and controls were discernible. The free GAG concentrations in RA plasma samples did not correlate with seropositivity or ESR.

The development and resolution of glomerular basement membrane changes associated with subepithelial immune deposits.

The morphogenesis of glomerular basement membrane changes associated with subepithelial immune deposits was studied in kidney biopsies from patients with gold-induced membranous glomerulonephoritis. Serial biopsies showed focal accumulations of additional basement membrane material around the deposits, suggesting that the deposited material stimulated the epithelium to increased synthesis. Moreover, the deposits were gradually displaced towards the inner (endothelia) side of the basement membrane during the course of the disease, suggesting that this layer undergoes a slow continuous turnover, with removal at its endothelial aspect. The two processes--increased epithelial synthesis and turnover--are suggested to constitute the basis of a natural healing process resulting in elimination of the deposits and structural restoration of the basement membrane. The epithelial slit membranes were dislocated externally by the deposits or the excessive basement membrane material, indicating that their barrier function is preserved even in this pathologic condition.

Gold nephropathy prototype of membranous glomerulonephritis.

In 7 of 10 kidney biopsies from patients with seronegative rheumatoid arthritis who had developed proteinuria during treatment with gold, electron microscopy showed changes typical of membranous glomerulonephritis. When the disease was of short duration, the only lesions seen were subepithelial deposits. The deposits were often located between intact epithelial foot processes and were demarcated externally by the slit membranes. In disease of longer duration, basement membrane changes occurred; these included projections and a layer of basement membrane over the deposits. The findings indicate that subepithelial deposits are primarily formed between intact foot processes, which would explain their unique discrete character (the basis of the typical granular immunofluorescent staining pattern of immune complex glomerulonephritis). The secondary basement membrane changes seem to evolve according to a constant pattern. The evolutionary process, probably signifying a healing process, is believed to be governed primarily by a synthesis of basement membrane performed by the epithelial cells.