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Cure Arthritis Naturally

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Neutrophil

Endothelial

Fibroblast

IL, interleukin; M- or GM-CSF, macrophage or granulocyte-macrophage colony-stimulating factor; ICAM or VCAM, intercellular or vascular cell adhesion molecule; TIMP, tissue inhibitor of metal-loproteinases.

ROLE OF TNF-a IN DISEASE

Considering the variety of stimuli that can induce TNF-a and the pleiotropic activities of TNF-a, it is not surprising that numerous types of disease have been associated with elevated concentrations of this cytokine. Many bacterial, viral, and parasitic infections are believed to trigger TNF-a production. In addition to conditions induced by exogenous agents, TNF-a may have an important role in autoimmune diseases.

Some of the symptoms of autoimmune diseases, tissue transplantations, asthma, and other types of stress-related conditions have been attributed to TNF-a (3). TNF-a has been implicated in several autoimmune diseases including insulin-dependent diabetes mellitus, multiple sclerosis, and rheumatoid arthritis (10-12). The inflammatory bowel diseases of Crohn's disease and ulcerative colitis are also caused by immune disregulation, and a role for TNF-a in both the acute and chronic phases of these inflammatory processes has been documented. In addition to the direct cytotoxic effects of TNF-a on cells, a significant portion of the proinflammatory effects of TNF-a may be due to its induction of chemokines and cell surface adhesion molecules that can lead to inflammatory cell recruitment.

Crohn's Disease

A strong association between TNF-a and local inflammation is suggested by the elevated concentrations of both TNF-a mRNA and TNF-a protein in the intestinal mucosa and stools of Crohn's disease patients (13,14). Moreover, anti-TNF-a antibodies reduce the severity of disease in mouse colitis models (15) and in naturally occurring colitis found in cotton-top tamarins (16). Increasing evidence indicates that Crohn's disease is characterized by an immune response controlled by CD4+ T helper type 1 (Th1) cells (17,18). The Th1 cells produce IFN-y, TNF-a, and IL-2 that contribute to inflammation and a T-cell cytotoxic response. In contrast, Th2 cells produce IL-4, IL-5, and IL-10 which induce the production of particular subclasses of immunoglobulin and are associated with allergic responses. Interestingly, Th1 and Th2 cells are antagonistic to each other, and thus an immune response to a particular antigen can usually be categorized as predominantly Th1 or Th2 in nature. Crohn's disease seems to be predominantly Th1 in nature. The predominance of Th1 was suggested by a reconstituted SCID mouse model in which colitis was ameliorated by treatment with antibodies to IFN-y and TNF-a or by IL-10; all of which dampen the Th1 response and increase the Th2 response (15). The cellular mechanism of Crohn's disease may be caused by an exaggerated Th1 response to mucosal stimuli or persistent T cell activation due either to excessive proliferation or to a reduced level of T cell apoptosis. Regardless of the reason for a predominant and persistent Th1 response, TNF-a apparently plays an important role by perpetuating the chronic inflammatory state that is characteristic of Crohn's disease.

Rheumatoid Arthritis

Increased levels of TNF-a mRNA and protein have been detected in synovial fluid from joints of rheumatoid arthritis (RA) patients and synovial cell cultures (12,19,20). Feldmann et al. (20) proposed that in RA, TNF-a is near the beginning stages of a sequential induction cascade that involves upregulation of other proinflammatory cytokines such as IL-1 (21), IL-6, IL-8, and granulo-cyte-macrophage colony-stimulating factor (GM-CSF) (22,23). Additionally, other effector mechanisms such as activation of inflammatory cells, induction of chemokine production, and induction of adhesion molecules likely contribute to the inflammatory activities attributed to TNF-a. Successful amelioration of disease following specific inhibition of TNF-a activity in animal models of induced arthritis confirmed that TNF-a was an appropriate target for therapeutic intervention (24).

ANTI-TNF-a MONOCLONAL ANTIBODY (INFLIXIMAB, REMICADE)

TNF-a is a potential target for specific anticytokine therapy. Several strategies have been developed to neutralize the deleterious effects of TNF-a in disease states. One of these, based on monoclonal antibody (mAb) technology, led to the development of agents that bind to antigen with high specificity and affinity, thus neutralizing its biological activity. The advent of hybridoma technology (25) has permitted production of mAbs in commercial quantities. Initially, mAbs were purely murine in construct, but these had the potential of developing human antimouse antibodies when administered to the patients. Advances in biotechnology have made it possible to develop ''man-made'' and humanized mAbs which are much less immunogenic but still retain the high neutralizing activity for their targets.

Centocor Inc. (Malvern, PA) has developed a genetically engineered form of the mouse monoclonal antibody, A2, which is specific for human TNF-a. Human constant domains of both the heavy and light chains were substituted for the murine structural equivalents (26). This genetic replacement strategy yields a molecule, chimeric A2 (or cA2), that retains the full antigen (TNF-a) binding properties of the original A2 antibody. The human constant domain structures confer decreased immunogenicity and optimum antibody effector functioning within the human immune system. The final infliximab antibody possesses a normally glycosylated IgG1 structure with an approximate molecular weight of 150,000 D and the pharmacokinetic characteristics of a human immunoglobulin. The generic name for cA2 is infliximab and its trademark is REMICADE.

As described previously, TNF-a initiates intracellular signaling by cross linking TNF receptors present in the cell membrane. The therapeutic benefit of infliximab is likely due, in part, to a blockade of TNF-a-mediated cellular events by preventing the association of TNF-a with its receptors (26-28). Infliximab blocks the biological activity of both soluble and transmembrane TNF-a. Infliximab does not neutralize TNF-P (lymphotoxin-a), related cytok-ine that utilizes the same receptors as TNF-a (26). Cells expressing transmembrane TNF-a bound by infliximab can be lysed in vitro by complement or effector cells (27). Infliximab inhibits the functional activity of TNF-a in a wide variety of in vitro bioassays utilizing human fibroblasts, endothelial cells, neutrophils (28), B and T lymphocytes (29,30), and epithelial cells (31). Since infliximab does not cross react with TNF-a in species other than human and chimpanzees, animal reproduction studies have not been conducted with infliximab. In a developmental toxicity study conducted in mice using an analogous antibody that selectively inhibits the functional activity of mouse TNF-a, no evidence of maternal toxicity, embryotoxicity, or teratogenicity was observed (31-34).

Clinical Pharmacology Results

To detect and measure infliximab in patients' sera without interference from the large amounts of normal immunoglobulin, specific enzyme immunoassays were employed. The infliximab detection assays use immunological reagents that specifically detect the murine portions of infliximab and do not interact with the human immunoglobulin structural domains. The lower limit of detection of infliximab in these assays was 0.5 |g/mL or less (31).

The single-administration pharmacokinetics of infliximab were investigated in several clinical trials. The infliximab pharmacokinetic profile is similar to that of an intact IgG1 immunoglobulin and is likely metabolized by the same pathways as for human immunoglobulins. Weight-adjusted intravenous injections of 1, 5, 10, or 20 mg infliximab per kilogram yielded linear, dose-dependent increases in the pharmacokinetic parameters of maximum serum concentration (Cmax) and area under the curve (AUC). In contrast, the volume of distribution (Vdss) and clearance were relatively independent of the administered dose and indicated that infliximab is predominantly distributed within the vascular compartment. Infliximab also exhibits a prolonged terminal halflife of 9.5 days that is comparable with that of a human immunoglobulin (35). No evidence of accumulation was observed after repeated dosing in patients with fistulizing disease given 5 mg/kg infliximab at weeks 0, 2, and 6 or in patients with moderate or severe Crohn's disease retreated with four infusions of 10 mg/kg infliximab at 8-week intervals (36).

Pharmacodynamic investigations indicate that infliximab binds to its intended target, TNF-a, in vivo and inhibits the deleterious functions of this inflammatory cytokine. Treatment with infliximab reduced infiltration of inflammatory cells and TNF-a production in inflamed areas of the intestine (37) and reduced the proportion of mononuclear cells from the lamina propria able to express TNF-a and INF-y (38). After treatment with infliximab, patients with Crohn's disease had decreased levels of serum IL-6 and C-reactive protein compared to baseline (31). Peripheral blood lymphocytes from infliximab-treated patients, however, showed no decrease in proliferative responses to in vitro mitogenic stimulation when compared to cells from untreated patients (30).

Treatment of Crohn's Disease with Infliximab

The results of the nonclinical studies discussed above indicated that infliximab can efficiently neutralize human TNF-a. The data suggested that infliximab is a well-tolerated therapeutic agent for chronic inflammatory diseases such as Crohn's disease and RA.

Open-label Studies

The first patient to be treated with infliximab was a young girl with severe steroid refractory Crohn's colitis. Infliximab was administered twice at a dose of 10 mg/kg. Treatment was followed by a rapid decrease in the signs and symptoms of Crohn's disease (diarrhea, abdominal pain, fever, anorexia). In addition, dramatic healing of mucosal ulcers occurred and no apparent side effects were observed (39).

Encouraged by these results, an open-label 8-week study evaluating the effects of a single infusion of infliximab in 10 patients was conducted (40): Eight patients received 10 mg/kg and two patients received 20 mg/kg infliximab. These 10 patients with active, steroid-dependent Crohn's disease were assessed based on clinical evaluation using the Crohn's disease activity index (CDAI), Crohn's disease endoscopic index of severity (CDEIS), and evaluation of acute-phase reactants, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR). The CDAI is the most commonly used measurement tool for evaluating clinical disease activity in clinical trials in Crohn's disease patients. The CDAI (41) consists of variables measuring clinical signs and symptoms of Crohn's disease and has been repeatedly validated (42). The index incorporates eight items: the number of liquid or very soft stools, the patient's assessment of abdominal pain/cramping, the patient's assessment of general well-being, extraintestinal manifestations of Crohn's disease, the presence of an abdominal mass, use of antidiarrheal drugs, hematocrit, and body weight. These items yield a composite score ranging from 0 to approximately 600. Higher scores indicate more disease activity. Patients with a score <150 are considered to have inactive disease, whose patients with a score >450 are critically ill.

Nine patients were evaluable for assessment of efficacy; all nine patients showed a rapid reduction in the CDAI that was maintained through the last evaluation at week 8. The one patient who could not be evaluated had a perforated bowel (which may have been present before treatment) identified at 10 days postinfusion. Results for the CDAI in individual patients are shown in Figure 2. Eight of the nine patients (88.9%) were in clinical remission (CDAI <150) at the 2-week evaluation visit and at all follow-up visits through 8 weeks (40).

Using the CDEIS scoring system (43,44), endoscopic evaluations at baseline and 4 and 8 weeks showed mucosal healing in all infliximab-treated patients. The median CDEIS of 15.8 at baseline was improved to 5.6 at the 4-week evaluation and remained at 5.6 at the 8-week evaluation. An example of the endoscopic benefit provided by a single infusion of infliximab is shown in Figure 3. Reductions in CRP and ESR were seen as early as 24 and 72 h, respectively, following infliximab infusion. For both parameters, further reductions occurred and were sustained through 8 weeks (40). A decrease in circulating IL-6 concentration, in secreted phospholipase A2 activities, and in mucosal expression of chemokines monocyte chemoattractant protein-1 (MCP-1), Macrophage inflammatory protein-1-alpha (MIP-1a), and regulated upon activation, normal T-cell expressed, and presumably excreted (RANTES) was also demonstrated, indicating potent anti-inflammatory effects of infliximab therapy (45).

A multicenter, open-label study was conducted at six centers in the United States and Europe to evaluate the dose-escalating (1, 5, 10, and 20 mg/kg) effects of infliximab therapy (46). Response parameters included the

Figure 2 Plots of CDAI scores over time for each patient in the 10-mg/kg (left panel) and 20-mg/kg (right panel) treatment groups. In the left panel, open symbols represent the individual patient's scores and the closed symbols represent the median scores of all patients who received the 10-mg/kg dose. A CDAI score below 150 is associated with remission.

Figure 2 Plots of CDAI scores over time for each patient in the 10-mg/kg (left panel) and 20-mg/kg (right panel) treatment groups. In the left panel, open symbols represent the individual patient's scores and the closed symbols represent the median scores of all patients who received the 10-mg/kg dose. A CDAI score below 150 is associated with remission.

Baseline 4 Weeks l'ost Treatment

Figure 3 Healing of colonic ulcerations in a patient after treatment with infliximab at enrollment (A) and 4 weeks after infusion of infliximab (B). Photographs were obtained from videotapes, allowing comparison of the exact same location. (From ref. 40.)

Baseline 4 Weeks l'ost Treatment

Figure 3 Healing of colonic ulcerations in a patient after treatment with infliximab at enrollment (A) and 4 weeks after infusion of infliximab (B). Photographs were obtained from videotapes, allowing comparison of the exact same location. (From ref. 40.)

CDAI, the inflammatory bowel disease questionnaire (IBDQ, a quality of life instrument), and the endoscopist's lesion severity assessment based on a 10-cm visual analog scale scoring system. A total of 20 patients (5 patients per group) were evaluable for the efficacy analysis. Among the 20 evaluable patients, 18 (90.0%) achieved a clinical response (decrease of >70 points in the baseline CDAI during the 4 weeks following infusion.) The response rate did not differ among the four dose groups, although the loss of response over time was greater in the 1-mg/kg infliximab dose group. In addition, endoscopic improvement was observed at 4 weeks in the 5-, 10-, and 20-mg/kg inflixi-mab dose groups and was sustained through the last evaluation at 8 weeks. In contrast, improvement in the endoscopy score was not observed in the 1 mg/kg infliximab-treated patients. The lesser treatment benefit observed with the 1 mg/kg infusion led to the study of doses of >5 mg/kg in the subsequent placebo-controlled trials (46).

Controlled Trials

Infliximab in Active Crohn's Disease. This study was a multicenter, randomized, double-blind, placebo-controlled trial conducted in 18 centers in North America and Europe. Patients were randomly assigned to receive one of four single-infusion treatment regimens: placebo, 5, 10, or 20 mg/kg infliximab (47). One hundred and eight patients were enrolled into the study. To be eligible, patients were required to be receiving concurrent therapy with corticosteroids, aminosalicylates, or the immunomodulatory agents 6-mercap-topurine (6-MP) or azathioprine (AZA) or had failed therapy with aminosalicylates, 6-MP/AZA, methotrexate (MTX), or cyclosporine. The data collected at baseline to characterize the patient population confirmed that enrolled patients had moderate to severe Crohn's disease (median CDAI of 306 with a range of 215-437) not responding adequately to conventional therapies.

The primary endpoint was at 4 weeks and was defined as a reduction in the CDAI of 70 points or more. The key secondary endpoint was the number of patients achieving clinical remission; defined as a reduction in CDAI below 150. Patients not achieving the primary endpoint were offered an open-label infusion of 10 mg/kg after the 4-week evaluation visit. Each of the three in-fliximab treatment groups demonstrated a statistically significant larger proportion of patients achieving a clinical response (81.5, 50.0, and 64.3% for the 5-, 10-, and 20-mg/kg dose groups, respectively) than the placebo group (16.7%) (47). No evidence of a dose-relationship of the clinical response was observed; in fact, the highest clinical response rate was observed in the 5-mg/kg infliximab group (81.5%). When the three infliximab treatment groups were combined into a single group (n = 83), 65.1% of these patients had a clinical response compared to 16.7% of the 24 placebo-treated patients evaluated (P <.001). Approximately one-third (32.5%) of the infliximab-treated patients achieved a clinical remission compared to 4.2% of placebo-treated patients (P = .005), with the highest remission rate being observed in the 5-mg/kg infliximab group (48.1%). The clinical response and remission rates for each treatment group and the three infliximab treatment groups combined are shown in Figure 4 for the evaluation visits at week 2 and week 4. There data indicate that the onset of the clinical benefit is rapid; occurring by the first evaluation visit at 2 weeks.

In terms of signs and symptoms of Crohn's disease, infliximab was effective in reducing diarrhea, abdominal pain, and cramping and also improved the patient's general well-being. The highest level of benefit was observed in the group of patients receiving 5 mg/kg infliximab. To further assess the effectiveness of infliximab in Crohn's disease, the IBDQ quality of life instrument and CRP were measured throughout the study. For each of the CDAI, IBDQ, and CRP outcome measurements, a consistent benefit compared to placebo was present by the first posttreatment evaluation visit, as shown in Figure 5. With the 5-mg/kg dose, median values for the CDAI, IBDQ, and CRP were at levels associated with disease remission (47).

Weeks

Weeks

—O— Placebo

» 10 rngfkg

—All infliximab

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