Implications/Analysis of Family History

Although we are not provided with any family history, RA does have a genetic component. A major genetic risk factor for RA is HLA-DR4, with about 70% of patients with RA expressing this HLA allele (control 28%). Studies with monozygotic twins also support a genetic component for RA (˜17% concordance). This indicates that environmental factors also play a role in the genesis of RA.

Implications/Analysis of Clinical History

The course of RA varies from patient to patient. In Jurgat’s case, disease progression has been very aggressive. The ineffectiveness of therapies to control the inflammatory processes reflects the fact that the underlying cause of RA remains unknown.

Implications/Analysis of Laboratory Tests

Although we are not provided with information regarding rheumatoid factor (autoantibodies), 66% of patients with RA have rheumatoid factor, an antibody that targets the Fc portion of IgG (control population 5%). Furthermore, patients with high titers of these autoantibodies have a more severe disease. Generally, tests for rheumatoid factor detect IgM isotype, but IgG and IgA isotypes may also be present. Rheumatoid factor is present in several infectious diseases (e.g., malaria, syphilis, leprosy) and other autoimmune disorders (e.g., systemic lupus erythematosus). Another test with prognostic significance is the C-reactive protein test, which is an indicator of inflammation. There are, however, no specific tests to confirm a diagnosis of RA.

Additional Laboratory Tests

In cases of severe erosive deforming arthritis, radiography to assess the bone erosion and cartilage destruction would be of value, particularly to monitor the efficacy of new therapies.

Antibodies to Block Cells from Entering Synovial Tissues

One of the key features of inflammation is the recruitment of circulating leukocytes to the site of inflammation. The migration of cells from the blood vessels is dependent on the expression of adhesive molecules that sequentially induce rolling and firm adhesion on the vascular endothelium, followed by diapedesis as cells squeeze between endothelial cells. The expression of adhesive molecules depends primarily on the presence of the inflammatory cytokines, TNFα and IL-1, which are secreted by activated tissue macrophages.

Adhesive molecules that are expressed on the activated endothelium and induce rolling are referred to as selectins (P-selectin, E-selectin), and their counter molecules (carbohydrates) are present on circulating leukocytes. In contrast, the integrins (heterodimer proteins) are expressed on circulating leukocytes and their counter molecules are expressed on the activated endothelium.

TNFα and IL-1 alter both the expression (upregulate) and affinity (increase) of the integrins on leukocytes and upregulate their counter molecules on the activated endothelium (see question #1 and Case 8). Transmigration of cells into tissues requires the homo-interaction of PECAM-1, which is constitutively expressed on both leukocytes and endothelium. Activated endothelium and leukocytes also secrete enzymes (metalloproteinases) that degrade the basement membrane and permit diapedesis into the tissue.

Thus, one novel approach to treating nonspecific inflammatory diseases such as RA would be to prevent integrin/counter molecule interaction. In early clinical trials murine antibodies to block these interactions were administered, but the effectiveness of these antibodies was dramatically reduced when patients developed human anti-mouse antibodies (HAMA) responses. More recently, a human antibody (Fab fragment MOR 101, MorphoSys) that targets ICAM-1 has been developed using recombinant technology. Because LFA-1:ICAM-1 interactions are probably more important for migration at sites of inflammation than for normal recirculation, antibodies to these have been among the first under consideration. Data to date suggest these may prove of value, although this patient failed to benefit.

TNFα Neutralizing Agents

Another novel approach to use would involve agents that block the action of cytokines believed to be important in the pathophysiology of disease. IL-1 and TNFα were two of the cytokines believed to be most suited for targeting, based on experimental studies and clinical observation. Reagents designed to block inflammation caused by TNFα were shown to be effective. One of these reagents is a human anti-TNF monoclonal antibody (adalimumab). The other is a fusion protein consisting of the extracellular TNF-binding portion of the TNF receptor that has been linked to the Fc portion of human IgG1 (Enbrel/Etanercept). Both of these reagents bind TNF so that it is not available for binding to its cognate receptor on endothelial (and other) cells.

There is a major proviso worthy of note for patients using TNF-neutralizing reagents. TNFα is important in signaling intracellular destruction of chronic pathogens (e.g., Mycobacterium species). Patients receiving this therapy have often had a recrudescence of tuberculosis. It would be wise to question this patient about any past history of tuberculosis and, if positive, to monitor her closely while she receives this therapy.

Anti-Interleukin Antibodies

Interestingly, a natural antagonist of IL-1 exists (IL-1ra) so in addition to anti–IL-1 antibodies this molecule has also been tried clinically. Neither of these reagents has proved to be of great benefit clinically.

Immune Complexes in RA

Note that some of Jurgat’s complaints may represent inflammation caused by immune complex deposition. Thus, often patients with RA have circulating rheumatoid factor in their serum, an antibody to serum immunoglobulin itself. This, in turn, can lead to immune complex deposition in various tissues (serosal lining of lungs and heart) and joints with subsequent inflammation (Fig. 23-1). Both T and B cells sensitized to autoantigens (likely collagen of the connective tissue) can also stimulate inflammatory responses.

FIGURE 23-1 Early stages of rheumatoid arthritis. Hand shows swelling of proximal interphalangeal joints and effusions in metacarpophalangeal joints.

(From Hochberg M, et al: Practical Rheumatology, 3rd ed. St. Louis, Mosby, 2004.)

Migration of Lymphocytes into Tissues

Normal lymphocyte recirculation through lymphoid/nonlymphoid tissues occurs in a nonrandom fashion, under the control of the expression of a number of receptors/counter receptors expressed on the lymphocyte/target tissue respectively. During the development of an inflammatory response the expression of a number of adhesion molecules also changes quite dramatically, as described earlier. Newer therapies are focused on inhibiting/blocking molecules that facilitate entry of circulating leukocytes to the site of inflammation.