Rheumatoid Arthritis: Massarotti EM

Massarotti EM. · Division of Rheumatology, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts 02115, USA. · Clin Ther. · Pubmed #18405783 No free full text.

Abstract: BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic joint inflammation, which if left untreated leads to progressive disability and joint destruction. A combination of antiinflammatory agents, steroids, disease-modifying antirheumatic drugs, and biological agents are used to treat RA. Beyond the use of conventional measures of disease activity, such as American College of Rheumatology (ACR) response rates, the importance of patient-reported outcomes (PROs) in assessing therapeutic benefits is gaining increasing emphasis in clinical trials of RA and other chronic illnesses. Clinical trials testing new RA therapeutics generally include health-related quality of life (HRQoL) measures and assessments of function and disability. Abatacept, a costimulation modulator that selectively targets the activation of T cells and downregulates the immune response, has been approved by the US Food and Drug Administration for the treatment of RA, with or without methotrexate. OBJECTIVE: The aim of this review was to summarize the clinical outcomes and PROs in published trials of abatacept. METHODS: A literature search was performed using the MEDLINE, EMBASE, and BIOSIS databases (restricted to articles posted between January 2000 and September 2007) with the search terms CTLA-4Ig, abatacept, and Orencia to identify published trials of abatacept. Primary clinical trial publications in patients with RA were selected. The ACR response and PROs data presented in the identified publications are summarized in this review. RESULTS: Our search identified 6 studies that met our selection criteria, which included 1 Phase IIa study, 2 Phase IIb studies, and 3 Phase III studies. The Phase IIa study found that abatacept was more effective than placebo and that physical function improved in treated patients compared with placebo. The 2 Phase IIb studies in 339 patients with RA previously treated with methotrexate found statistically significant improvements in HRQoL with abatacept at 6 months and 1 year. Similar findings were noted in the published Phase III trials. Across clinical trials, abatacept has been associated with clinically meaningful and statistically significant improvements in conventional measures of disease activity, HRQoL, and physical function. CONCLUSIONS: These 6 published trials found that abatacept was associated with significant improvements in both conventional measures of disease activity and PROs. Continued assessment of these outcomes will be required to further support the findings of the Phase II and III abatacept clinical trial literature reviewed here.

Massarotti EM. · Tufts University School of Medicine, Itzhak Perlman Family Arthritis Treatment Center, Division of Rheumatology, New England Medical Center, Boston, Massachusetts, USA. · Med Clin North Am. · Pubmed #11982303 No free full text.

Abstract: Infection with B. burgdorferi can cause a large joint inflammatory arthritis in patients who have not been treated for early Lyme disease; the knee is the most common joint affected. The diagnosis depends on a history of known exposure to the spirochete, characteristic clinical features, and serologic studies (ELISA and Western blot) confirming exposure to the spirochete. In most patients, antibiotic therapy is curative, but in a smaller percentage of patients, the presence of the HLA-DR beta 1*0401 haplotype can trigger treatment-resistant arthritis, in which antibiotic therapy is ineffective; in these instances, remittive agents, such as hydroxychloroquine and methotrexate, are indicated. Arthroscopic synovectomy may be considered when antibiotic therapy is not curative. Fibromyalgia can follow infection with B. burgdorferi but is unresponsive to antibiotic therapy; it is treated with tricyclic antidepressants and an exercise program. Lyme arthritis is the only chronic inflammatory arthritis in which the specific cause is known and can be cured. As such, it serves as an excellent model with which to study the pathogenesis of more common inflammatory arthritides, such as rheumatoid arthritis.

Lee AT, Li W, Liew A, Bombardier C, Weisman M, Massarotti EM, Kent J, Wolfe F, Begovich AB, Gregersen PK. · North Shore-LIJ Research Institute, Manhasset, NY 11030, USA. · Genes Immun. · Pubmed #15674368 No free full text.

Abstract: We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR=1.75, 95% CI 1.46-2.10, P=1.3 x 10(-9)). The PTPN22 risk allele was not significantly associated with RF negative disease (OR=1.19, 95% CI 0.92-1.53, P=0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR=4.57, 95% CI 2.35-8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.