Tumor necrosis factor  by drdoc on-line

Tumor necrosis factor alpha is a cytokine produced primarily by monocytes and macrophages. It is found in synovial cells and macrophages in the tissues.
It shares many properties with another cytokine - interleukin 1.
It is not unique to RA, but occurs in many inflammatory diseases, and also as a response to endotoxins from bacteria for example.

The TNF causes:

Stimulation of IL1 and GM-CSF.
Increased tissue damage by IL1.
Induction of collagenases by fibroblasts and chondrocytes.
Has a role in modulating HLA class 2 expression, as well as the adhesion molecules.

The receptors for the Tumor necrosis factor are on several mononuclear cells, in the synovial membrane, as well as the peripheral blood and synovial fluid. There are also soluble receptors - receptors that are free in solution. These are shed from mononuclear cells. Increased soluble receptors are seen in RA, SLE, Systemic sclerosis, MCTD, RA, and to a certain degree OA, although the latter is less than the levels in RA. The soluble TNF receptors block the TNF by mopping up and blocking the levels of TNF, so that less is available to activate the mononuclear cells. They thus act as natural inhibitors. The incidence and extent of the levels of the soluble receptor correlates with disease activity.

The therapeutic use of the soluble receptor is restricted because the half life of the molecule is short, and thus combinations of the soluble receptor with immunoglobulin or other molecules has been attempted to try and increase the half life to enable therapeutic applications.
It is the combination of recombinant soluble form of human p75 TNFR to the Fc fragment of IGG, that is known as etanercept or ENBREL, that is made by Immunex Corporation.

The alternative method to block TNF - is the use on anti TNF antibody. This is done by using monoclonal antibody. Blocking the TNF results in reduced IL1 GM-CSF and IL8.
Provisional animal studies show good benefit in mouse arthritis models. Some human studies have been done in RA in limited studies. The most well known is cA2 antibody:
Maini et al, Lancet, 344:1105-1110, 1994. The cA2 studies were the first to show a cytokine blockade to be helpful in RA.

The abstract to that article is enclosed

Randomised double-blind comparison of chimeric monoclonal antibody to Tumor necrosis factor alpha (cA2) versus placebo in rheumatoid arthritis. Author Elliott MJ; Maini RN; Feldmann M; Kalden JR; Antoni C; Smolen JS; Leeb B; Breedveld FC; Macfarlane JD; Bijl H; et al Source Lancet, 1994 Oct 22, 344:8930, 1105-10

Abstract : Tumor necrosis factor alpha (TNF alpha) is a critical inflammatory mediator in rheumatoid arthritis, and may therefore be a useful target for specific immunotherapy. In support of this hypothesis, we previously observed beneficial responses in patients with active rheumatoid arthritis after open-label administration of a chimeric monoclonal antibody to TNF alpha (cA2). We now report the results of a four-centre, randomised double-blind trial of a single infusion of 1 or 10 mg/kg cA2 compared with placebo in 73 patients with active rheumatoid arthritis. The primary endpoint of the study was the achievement at week 4 of a Paulus 20% response, an amalgam of six clinical, observational, and laboratory variables. Intention-to-treat analysis of data from individual patients showed only 2 of 24 placebo recipients responding at this time, compared with 11 of 25 patients treated with low-dose cA2 (p = 0.0083) and 19 of 24 patients treated with high-dose cA2 (p < 0.0001). Over half of the high-dose cA2 patients responded by the more stringent 50% Paulus criteria at this time (p = 0.0005). The magnitude of these responses was impressive, with maximum mean improvements in individual disease-activity assessments, such as tender or swollen-joint counts and in serum C-reactive protein, exceeding 60% for patients on high-dose treatment. There were two severe adverse events. 1 patient on 1 mg/kg cA2 developed pneumonia ("possibly" treatment-related) and 1 on 10 mg/kg had a fracture ("probably not" treatment-related). The results provide the first good evidence that specific cytokine blockade can be effective in human inflammatory disease and define a new direction for the treatment of rheumatoid arthritis.


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Article by drdoc on-line
Cape Town
Sept 1998

updated 2001