Therapy - Rheumatoid Arthritis

THERAPY

It is not surprising that our very incomplete knowledge of the pathogenesis of rheumatoid arthritis is reflected at the therapeutic level. Most of our current therapeutic approaches are palliative, aiming to reduce joint inflammation and tissue damage. Under these conditions, RA therapy is often a frustrating experience for patients and physicians.

A. Nonsteroidal Anti-inflammatory Drugs

This group of anti-inflammatory drugs includes, among others, aspirin, ibuprofen, naproxen, indomethacin, and the recently introduced COX-2 inhibitors. These compounds have as common mechanism of action the inhibition of the cyclooxygenase pathway of arachidonic acid metabolism, which results in a reduction of the local release of prostaglandins. Their administration is beneficial in many patients with rheumatoid arthri-tis.

B. Glucocorticoids

In more severe cases, in which the nonsteroidal anti-inflammatory drugs (NSAIDs) are not effective, glucocorticoids are indicated. However, the use of glucocorticoids in RA raises considerable problems, because in most instances their administration masks the inflam-matory component only as long as it is given. Thus, glucocorticoid therapy needs to be maintained for long periods of time at doses exceeding 20 mg/day, exposing the patient to very serious side effects, including muscle and bone loss, which may become more devas-tating than the original arthritis

C. Disease-Modifying Drugs

A variety of potent drugs have been used in attempts to reduce the intensity of the autoim-mune reaction and/or the consequent inflammatory reaction and attenuate the clinical man-ifestations of the disease. This group includes a series of drugs that seems mainly to have anti-inflammatory effects, such as auranofin and gold salts, hydroxychloroquine, minocy-cline, sulfasalazine, D-penicillamine, and a group of cytotoxic/immunosuppressive drugs that include methrotrexate, azathioprine, chlorambucil, cyclophosphamide, leflunomide, and cyclosporin A. All these agents have side effects, some more severe than others. Usu-ally less toxic compounds are used first and more toxic agents are introduced if the patient continues to deteriorate. Some authors have claimed that methrotrexate, administered in low weekly doses, is not associated with long-term side effects while controlling the in-flammatory component of the disease and delaying the appearance of the chronic phase. The use of agents specifically directed at reducing T-cell activation levels, such as cy-closporin A and leflunomide, by themselves or in association (e.g., leflunomide plus methrotexate), has also been successful.

D.  Biological Response Modifiers

Considerable interest has been devoted in recent years to the use of biological response modifiers (BRM). Two basic types of BRMs have been used: those that try to suppress activated T-cell populations and those that have the neu-tralization of pro-inflammatory cytokines as their major mechanism of action. To this date, there has been very limited success with BRMs targeting activated T cells, while the op-posite has been true with BRMs that downregulate the effects of proinflammatory cy-tokines. Among the latter, recombinant humanized anti-TNF (infliximab) and a recombi-nant form of a soluble TNF receptor (etarnecept) have been most successful in clinical trials and have received FDA approval. Other BRMs, such as monoclonal antibodies directed to IL-6 and IL-6 receptors, CD4, and ICAM-1 are still being evaluated.

It seems possible that maximal clinical benefit for RA patients may be obtained from the combination of more than one type of therapeutic agent. For example, the combination of infliximab and methrotexate seems particularly effective.

E. Reinduction of Tolerance

Attempts to reinduce tolerance to cartilage antigens postulated to be involved in the au-toimmune response by feeding animal cartilage extracts to RA patients have yielded promis-ing results. However, the clinical benefits reported so far have been observed in short-term studies, and research is necessary to determine if the benefits persist in the long run. Also, additional studies are needed to better define the mechanism(s) involved in oral tolerization.

Case 19.1 Revisited

Antibodies against single-stranded DNA can be detected in about one third of the patients. The epitopes recognized by anti-ssDNA antibodies correspond to DNA-associated pro-teins, corresponding to the homogeneous pattern seen by immunofluorescence. The detection of anti-ssDNA antibodies does not have diagnostic or prognostic sig-nificance because these antibodies are neither disease-specific nor involved in immune complex formation.

The low neutrophil count and splenomegaly seen in this patient are suggestive of Felty’s syndrome, the association of rheumatoid arthritis with autoimmune neutropenia.

The pathogenesis of rheumatoid arthritis is surrounded by questions. It is believed that activation of self-reactive T lymphocytes as a consequence of the presentation of a cross-re-active peptide (possibly of infectious origin) by an activated antigen-presenting cell is the ini-tial step. Such a peptide would be mostly expressed in the synovial tissues, and the activation of helper T cells (predominantly TH1) would be followed by the release of interferon-γand GM-CSF that activate macrophages and antigen presenting cells. Activated macrophages overexpress MHC-II molecules, creating conditions for continuing and stronger stimulation of helper T lymphocytes. As this cross-stimulation of TH1 lymphocytes and macrophages con-tinues, chemotactic factors are released and additional lymphocytes, dendritic cells, mono-cytes, and granulocytes are recruited into the area. As inflammatory cells become activated, they release metalloproteinases and pro-inflammatory mediators, such as TNF and PGE2. The release of metalloproteinases will cause damage to the synovium and cartilage. When the process evolves to this level of joint damage, the prognosis is poor.

     The subcutaneous nodule seen below the left elbow is a rheumatoid nodule, the clin-ical expression of vasculitis associated with RA.

It is common to observe some signs and symptoms more indicative of a systemic dis-ease, particularly vasculitis, secondary to immune complex deposition in the vessels of the dermis. Rheumatoid nodules are virtually pathognomonic of RA and indicate a poor prog-nosis.

RA predominantly affects women from 30 to 60 years of age for reasons that remain unclear but that may be related to hormonal influences in the TH1/TH 2 balance. Pregnancy is often associated with remission, probably reflecting the fact that estrogens favor TH 2 cell activity, which in the case of RA seems not to be as pathogenic as TH1 activity.

     In a case of severe RA such as the one described, administration of nonsteroidal anti-inflammatory agents is not likely to be effective. Disease-modifying agents, such as methotrexate, administered in low weekly doses, possibly in combination with leflunomide or infliximab, are likely to control the inflammatory component of the disease and delay the onset of the chronic phase without serious side effects.