Faculty Bibliography

OBJECTIVE:To examine effects of the COX-2 inhibitor market withdrawals on NSAID utilization among patients at increased risk of gastrointestinal (GI) and cardiovascular (CV) toxicities. METHODS:A prospective cohort study was conducted using patients enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) Registry. The study population included rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients prescribed NSAIDs by rheumatologists from 1/1/2003 to 12/31/2005. Three cohorts were defined based on calendar year. The primary outcome assessed whether or not an NSAID gastroprotective strategy was prescribed. Secondary outcomes included rates of COX-2 inhibitor utilization and gastroprotective co-therapy utilization, stratified by the presence of cardiac and GI risk factors. RESULTS:NSAID gastroprotection utilization decreased from 65.1% in 2003 to 47.7% (p<0.001) in 2005. COX-2 inhibitor use decreased from 55.1% to 29.2% (p<0.001), whereas nonselective NSAIDs (nsNSAIDs) use increased from 50.2% to 73.9% (p=<0.01). Among patients with two or more risk factors for NSAID related GI bleeding, gastroprotection decreased from 74.4% in 2003 to 60.9% (p<0.01). For patients with two or more CV risk factors from 2003 to 2005, COX-2 inhibitor utilization decreased significantly, whereas nsNSAID utilization increased significantly.CONCLUSIONS:The COX-2 inhibitor withdrawals resulted in a rapid decline in NSAID gastroprotection prescribed by participating U.S. rheumatologists despite the availability of other gastroprotective options. Channeling toward nsNSAID use was widespread, including among patients at increased CV risk. Longer term follow-up is required to determine the clinical significance of these changes in NSAID prescribing, particularly for NSAID-related GI and CV-related toxicities

OBJECTIVE: Scleroderma-related interstitial lung disease (SSc-ILD) has limited therapeutic options due to unclear pathogenesis. Recently, PDGF receptor (PDGFR) amplification has been postulated to cause fibrosis. We hypothesized that a combination of immunosuppressive agents, e.g. cyclophosphamide (CYC) and imatinib (PDGFR inhibitor), might be useful for treating SSc-related ILD. Our objective was to evaluate the safety and efficacy of this combination therapy in scleroderma-related pulmonary disease. METHODS: Five patients with advanced SSc-ILD underwent comprehensive cardiopulmonary evaluation, followed by administration of oral imatinib (200 mg/day) and intravenous CYC (500 mg every 3 weeks). Safety was assessed by close monitoring of complete blood count, liver and cardiac functions. Efficacy was evaluated by measuring pulmonary functions at 6 and 12 months. RESULTS: Of the five patients in the study, four had severe and one had mild restrictive lung disease. All patients tolerated the combination treatment without myelosuppression, deterioration of liver functions or cardiac status. Only one patient had mild fluid overload requiring diuretics. Two patients completed 1 yr of treatment. Only the patient with mild restrictive lung disease showed improvement in pulmonary function. CONCLUSION: The combination of intravenous CYC and oral imatinib was well-tolerated without major side effects. Clinical improvement was seen in only the patient with mild restrictive disease. To our knowledge, this is the first study examining the safety, tolerability and efficacy of imatinib in combination with CYC in scleroderma-related pulmonary disease. Large prospective trials are needed to further determine optimal timing, dose and duration of this regimen.

Rheumatoid arthritis (RA) and adult periodontitis share common pathogenetic mechanisms and immunologic and pathological findings. One oral pathogen strongly implicated in the pathogenesis of periodontal disease, Porphyromonas gingivalis, possesses a unique microbial enzyme, peptidylarginine deiminase (PAD), the human equivalent of which has been identified as a susceptibility factor for RA. We suggest that individuals predisposed to periodontal infection are exposed to antigens generated by PAD, with deiminated fibrin as a likely candidate, which become systemic immunogens and lead to intraarticular inflammation. PAD engendered antigens lead to production of rheumatoid factor-containing immune complexes and provoke local inflammation, both in gingiva and synovium via Fc and C5a receptors

To examine the relative influence of speed of information processing versus working memory ability, CFS participants with psychiatric comorbidity (CFS-Psych) and CFS without a psychiatric history (CFS-noPsych) were examined on tests of visual and auditory processing speed and visual and auditory working memory. Compared to healthy controls (HC) and a group of participants with rheumatoid arthritis (RA), the CFS-noPsych group displayed significantly reduced performance on tests of information processing speed, but not on tests of working memory. No significant differences were observed between the CFS-Psych group and any other group in the study. The implications of group heterogeneity on the understanding of cognitive impairment in CFS are discussed

Objective: Examine whether memory impairment in chronic fatigue syndrome (CFS) is due to deficits in acquisition, storage, or retrieval. Study Design: Prospective, between-groups design. Participants: Twenty-nine CFS participants without psychiatric comorbidity (CFS-noPsych) and 22 participants with an Axis I psychiatric diagnosis since CFS onset. Two control groups: 30 healthy persons and 19 participants with rheumatoid arthritis. Main Outcome Measures: After being equated for initial learning, recall and recognition were assessed after 30- and 90-min delays. Results: Both CFS groups required more trials to learn the word list than did healthy controls. The CFS-noPsych group performed significantly below healthy controls on recall but not on recognition. Learning/acquisition correlated with measures of complex information processing and not with depressive symptomatology or fatigue. Conclusions: Impaired verbal learning and memory in CFS is primarily a result of deficient acquisition.

The anti-inflammatory effects of both n-3 and n-6 polyunsaturated fatty acids (PUFA) have been demonstrated in vitro and in many disease states, in particular in the treatment of rheumatoid arthritis. The benefit of n-3 PUFA supplementation has been documented in animal models of periodontal inflammation and a trend towards reduced inflammation has been seen in human experimental gingivitis. The purpose of this study was to examine the potential anti-inflammatory effects of PUFA supplementation, by administration of fish oil as a source of the n-3 PUFA, eicosapentaenoic acid, and borage oil as a source of the n-6 PUFA, gamma-linolenic acid (GLA), to adults with periodontitis. Thirty adult human subjects with periodontitis were administered either fish oil 3000 mg daily; borage oil 3000 mg daily; fish oil 1500 and borage oil 1500 mg daily, or placebo. The modified gingival index, the plaque index (PI), periodontal probing depths and beta-glucuronidase levels in gingival crevicular fluid were measured at baseline and after 12 weeks of treatment. Improvement in gingival inflammation was observed in subjects treated with borage oil (P<0.016), with a trend apparent in subjects treated with fish oil or a combination of PUFA. There was no statistically significant improvement in PI, although a trend was apparent in those receiving borage oil. Improvement in probing depth was seen in those subjects treated with either fish oil alone or borage oil alone, but statistical significance was only seen for the comparison of borage oil and placebo (P<0.044). No change was seen in gingival crevicular fluid (GCF) beta-glucuronidase levels. The use of borage oil supplementation, a source of the n-6 PUFA, GLA, can have beneficial effects on periodontal inflammation. n-6 PUFA supplementation seemed to offer more impressive results than either n-3 PUFA supplementation or the combination of lower doses of the two supplements. Additional studies will be necessary to more fully assess the potential of these agents to favorably affect periodontal inflammation

Autoantibodies to the insulin receptor have been demonstrated to antagonize the physiologic actions of insulin, most often resulting in hyperglycemia unresponsive to massive doses of insulin (type B insulin resistance). Patients with these anti-insulin receptor antibodies typically have a coexistent autoimmune disorder, most commonly systemic lupus erythematosus (SLE) or undifferentiated autoimmune syndromes. Attempting to determine the prevalence and significance of anti-insulin receptor antibodies, sera from consecutive patients with SLE and early undifferentiated connective tissue disease (UCTD) were tested for the presence of anti-insulin receptor antibodies by radio-immuno assay. Thirty-eight patients participated in the study. Twenty-six had SLE and 12 had UCTD. One patient with SLE (2.6%) was positive for anti-insulin receptor antibodies. None of the patients demonstrated evidence of insulin resistance, hypoglycemia, ovarian hyperandrogenism, or acanthosis nigricans, findings commonly linked with the presence of anti-insulin receptor antibodies. The results presented here indicate that the incidence of anti-insulin receptor antibodies in patients with SLE or UCTD, without associated history of altered glucose metabolism, is quite low. Because in most cases the disturbance of glucose metabolism dominates the clinical picture at presentation and the associated systemic autoimmune syndrome presents either simultaneously with or subsequent to the diagnosis of diabetes, the measurement of anti-insulin receptor antibodies should be reserved for patients with indications of disordered glucose homeostasis.