A 52-year-old patient with rheumatoid arthritis (RA) developed scleredema-like skin induration after treatment with the tumor necrosis factor alpha (TNFalpha) blocking agent, infliximab. Skin induration occurred within a few weeks of initiation of infliximab, resolved with discontinuation of the drug, and recurred with rechallenge with the drug, implicating infliximab as the offending agent. Laboratory evaluation revealed a high titer of human antichimeric antibodies (HACA). The skin induration improved within a few weeks of discontinuation of infliximab and did not recur with the use of etanercept. Scleredema has been reported in association with bacterial and viral infections, diabetes mellitus, and monoclonal gammopathies. Infliximab use should be added to the list of potential associations with scleredema. This effect appears possibly specific to infliximab and may be related to the development of HACA because it did not occur with the use of etanercept in this patient. In addition, there appears to be a complex relationship between TNFalpha and tumor growth factor beta (TGF-beta), a cytokine which promotes collagen synthesis and deposition. TNFalpha blockade with infliximab may affect TNFalpha-TGF-beta interactions and may be implicated in the development of scleredema in this case.

Antibodies, Monoclonal↗

PubMed2005

Pharmacogenetics of therapies in rheumatoid arthritis.

Rheumatoid arthritis (RA) is an inflammatory, aggressive arthritis causing irreversible joint destruction and damage when left untreated. Disease-modifying antirheumatic drugs (DMARDs) are the mainstay of treatment for RA and ameliorate not only the clinical signs and symptoms but also joint damage associated with the disease. In recent years, biological therapies have been introduced for the treatment of RA, and the effectiveness of these agents in slowing the clinical and radiographic progression in RA has been established beyond question. However, there is significant variability in the response of patients with RA to these therapies. Moreover, the biological therapies are expensive, totaling several thousand dollars in yearly patient costs. Pharmacogenomics, the study of genetic variations in drug-metabolizing enzymes and their translation to differential responses to drugs, is a nascent but rapidly evolving field. The application of pharmacogenomics to therapies used in RA, particularly the new expensive biological agents, holds great promise for tailoring therapy with these agents based on a patient's genetics. Published literature on the pharmacogenetics of commonly used DMARDs and the emerging body of literature on the pharmacogenetics of the new biological therapies in RA are the focus of this review. As evident from the contents of this review, pharmacogenomics is an exciting field which is progressing productively and rapidly. Pharmacogenomic approaches offer powerful tools to optimize drug therapy in individual patients.

Antirheumatic Agents↗

PubMed2005

Pharmacogenomics of tumor necrosis factor antagonists in rheumatoid arthritis.

Tumor necrosis factor (TNF)-alpha plays a central role in the pathogenesis of rheumatoid arthritis (RA) and is instrumental in causing joint destruction, the clinical hallmark of the disease. Recognizing this, in recent years biological therapies have been developed that work by blocking the damaging effects of TNF-alpha on synovium and cartilage. Three such agents are currently approved for treatment in RA - etanercept, infliximab and adalimumab. Although these agents are very effective in slowing the clinical and structural progression in RA, they are expensive, totaling several thousand dollars in yearly costs. Furthermore, only about 60% of patients respond effectively to these agents. As RA is a chronic disease, with most patients expected to remain on these therapies for life, ways to prospectively identify patients most likely to benefit from these agents are being explored. Pharmacogenomic approaches form the basis of most such screening methods. Polymorphisms in genes encoding TNF-alpha, TNF-alpha receptors, other cytokines, and the major histocompatibility complex region, and their ability to predict response to anti-TNF therapies, have been the focus of many recent studies. The results from such studies are mixed, with some suggesting that single nucleotide polymorphisms (SNPs) in these genes are significant, while others conclude that such SNPs are irrelevant in predicting response. Such conflicting results are likely to be due to a variety of factors, as discussed in this article. Whether pharmacogenomics will allow prediction of anti-TNF therapy efficacy in RA remains a question with no clear answers to date. Large, prospective, multicenter studies with the examination of not just individual SNPs, but also multi-SNP haplotypes, are needed to address this question in the future.

Antirheumatic Agents↗

PubMed2004

Single nucleotide polymorphism profiling across the methotrexate pathway in normal subjects and patients with rheumatoid arthritis.

Methotrexate (MTX) is a commonly used disease-modifying antirheumatic drug in rheumatoid arthritis (RA). Polymorphisms occur in several genes encoding key enzymes in the folic acid pathway, which is influenced by MTX, but have not been evaluated in patients with RA. The effect of race on allele frequency has also not been evaluated. In this study, the allele frequencies of polymorphisms in six key enzymes in the MTX-folate pathway in patients with RA and healthy controls, including several common racial groups were studied. European- and African-American patients with RA and European and African healthy controls were genotyped for 22 genetic loci in six genes in the MTX cellular pathway. Differences in genotype distributions between the different racial groups were evaluated using chi(2) tests. Allele frequencies were significantly different (p < 0.001) for eight single nucleotide polymorphisms between the European and African controls. The allele frequencies of two polymorphisms showed significant differences (p < 0.001) between the African- and European-American patients with RA. Thus, racial differences exist between the allele frequencies of several polymorphisms in enzymes in the MTX-folate pathway in patients with RA and healthy controls. Whether such differences contribute to a differential response to MTX in patients with RA deserves to be investigated.

Black or African American↗

PubMed2003

14. Immunologic rheumatic disorders.

We provide the basics for the clinician who might be called on to consider the diagnosis of diseases such as systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA) in their practice. We will emphasize clinical recognition and first-line laboratory testing. Only characteristics of the classic rheumatic inflammatory diseases, RA, SLE, Sjögren syndrome, scleroderma, and dermatomyositis/polymyositis, will be covered. In the past decade, RA is the only disease for which treatment has substantially improved. The treatment of RA has been revolutionized by the use of methotrexate and, more recently, tumor necrosis factor inhibitors. The goal of RA treatment today is to induce a complete remission as early as possible in the disease process, with the mantra being "elimination of synovitis equals elimination of joint destruction." The hope is that if the major mediators of Sjögren syndrome or SLE or scleroderma can be identified and then blocked, as in the example of tumor necrosis factor inhibitors in RA, more specific treatments will become available. Thus, RA has become an excellent model of this evolving paradigm. Through the identification of major mediators in its pathogenesis, novel and highly efficacious therapeutic agents have been developed.

Humans↗