J.T. Whicher

Synovial fluid concentration of five different cytokines in rheumatic diseases.

Interleukin-1 beta, interleukin-2, tumour necrosis factor alpha, and the interferons, alfa and gamma, were measured concurrently in synovial fluid samples from 68 patients with rheumatic diseases. Mean interleukin-1 beta concentrations (130.3 (SD 22) pg/ml) were higher in synovial fluids from patients with rheumatoid arthritis (RA) than in those from patients with osteoarthritis (27.8(4.5)pg/ml), while measurements in synovial fluids from patients with seronegative spondarthritis were intermediate (72.7 (32) pg/ml). Interleukin-2 and tumour necrosis factor alpha concentrations were lower in the inflammatory arthropathies (RA: 4.5 (0.6) U/ml, 0.39 (0.04) ng/ml; seronegative spondarthritis: 3.1 (0.3) U/ml, 0.33 (0.03) ng/ml respectively) than those in patients with osteoarthritis (5.2 (0.6) U/ml; 0.05 (0.04) ng/ml). Interleukin-2 and tumour necrosis factor alpha concentrations correlated in all groups (r = 0.7), as did the interferons alfa and gamma (r = 0.7). There was no relation between interleukin-1 beta and either interleukin-2 or tumour necrosis factor alpha, or between the interferons and any other cytokine. Several distinct cytokine patterns were noted. Synovial fluids from two non-arthritic subjects were also examined: interleukin-1 beta concentrations were low, but concentrations of the other cytokines were higher than those seen in most arthritic fluids.

Serum amyloid-A protein concentration in rheumatoid arthritis and its role in monitoring disease activity.

The serum concentrations of serum amyloid-A protein (SAA), C-reactive protein (CRP), and alpha 1-acid glycoprotein (alpha 1-AGP) have been measured in 185 patients with rheumatoid arthritis. SAA and CRP concentrations correlated well (r = 0.86) both within and above the normal ranges, though SAA showed a greater incremental increase than CRP. All patients with normal SAA levels also had normal CRP and alpha 1-AGP concentrations. In contrast, in 40% of patients with normal CRP and alpha 1-AGP concentrations the SAA was raised, sometimes markedly so. The clinical and serological assessments of disease activity in these patients were not significantly different from those with concomitantly raised levels of CRP. These findings suggest that SAA is a more sensitive marker of inflammation than is CRP. The role of the measurement of SAA as a monitor for inflammatory disease activity is discussed.

Activation of the alternative pathway of complement by monosodium urate monohydrate crystals and other inflammatory particles.

Activation of serum C3 by monosodium urate monohydrate (MSU) crystals and other particles was determined by immunofixation following electrophoretic separation of C3 and its activation products. Densitometry allowed quantitation of results. MSU, hydroxyapatite, brushite, and calcium pyrophosphate dihydrate crystals split C3 under conditions which demonstrate activation via the alternative pathway (AP). Quantitatively similar results were obtained in immunoglobulin deficient serum. Activation was crystal specific and was reduced by heating, grinding, sonication, and aging of crystals. Other inflammatory particles (e.g., blackthorn) activated C3 via the AP: noninflammatory particles (e.g., diamond) caused insignificant activation. It is suggested that particle-induced activation of the alternative pathway of complement may be important in the initiation of crystal-induced synovitis.

Comparative study of C reactive protein and serum amyloid A protein in experimental inflammation.

The responses of C reactive protein, measured by radial immunodiffusion and radioimmunoassay, and serum amyloid A protein, measured by radial immunodiffusion, were compared in eight subjects with inflammation induced experimentally by intradermal injection of monosodium urate crystals. A significant increase in serum amyloid A was noted after a lag phase of eight hours, the increase in median concentration at 48 hours being about eightfold. A parallel but less marked increase was found in C reactive protein when measured by radioimmunoassay (fourfold increase in median concentration at 48 hours) after a small but significant decrease during the lag phase. The changes in C reactive protein remained within the reference range and were not detectable by radial immunodiffusion.

Systemic response to local urate crystal induced inflammation in man: a possible model to study the acute phase response.

The production of a systemic inflammatory response to intradermal monosodium urate crystal injection is described. A transient, self-limiting local response is associated with a systemic response detectable by a rise in the white cell count and serum amyloid A protein. The white cell change parallels the evolution of the local response, whereas the serum amyloid A response lags behind the local lesion, peaking after the local lesion is resolving. Intradermal monosodium urate injection is proposed as a possible inflammatory stimulus to explore the acute phase protein response in different disease states.

THE PROSTAGLANDIN‐INDUCED ACUTE PHASE RESPONSE IS DEFECTIVE IN ENDOTOXIN TOLERANT MICE AND IN HUMANS WITH SCLERODERMA*

A number of prostaglandins such as PGE,, E,, Fk and A, have been shown to cause an acute phase increase in the serum levels of haptoglobin and caeruloplasmin in rabbits.’ The mechanism of this response is unknown though other substances which provoke similar responses such as bacterial endotoxins are thought to act via the production of “leucocyte endogenous mediators” (LEM); peptides derived from peripheral phagocytic cells which act on the liver to increase acute phase protein synthesis. We have investigated the prostaglandin induced acute phase response in man and in endotoxin tolerant mice by infusing PGE,.’

Serum concanavalin-A binding in rheumatoid arthritis.

A nephelometric assay of concanavalin-A binding of serum acute phase proteins (con-A binding) has been used in cross-sectional and sequential studies of disease activity in rheumatoid arthritis (RA). Con-A binding correlated well with blood viscosity, C-reactive protein, and other individual acute phase reactants in patients with active RA. Twenty-four patients were treated for 6 months with D-penicillamine and assessed clinically and seriologically. Clinical improvement was accompanied by significant falls in both C-reactive protein and con-A binding, although the serological changes did not always occur in parallel in individual patients. The advantages of this simple, cheap assay of acute phase proteins are discussed.