The role of genetic variants in CRP in radiographic severity in African Americans with early and established rheumatoid arthritis.

This study investigates the association of CRP (C-reactive protein) single-nucleotide polymorphisms (SNPs) with plasma CRP levels and radiographic severity in African Americans with early and established rheumatoid arthritis (RA). Using a cross-sectional case-only design, CRP SNPs were genotyped in two independent sets of African Americans with RA: Consortium for the Longitudinal Evaluation of African Americans with RA (CLEAR 1) and CLEAR 2. Radiographic data and CRP measurements were available for 294 individuals from CLEAR 1 (median (interquartile range (IQR) 25-75) disease duration of 1 (0.6-1.6) year) and in 407 persons from CLEAR 2 (median (IQR 25-75) disease duration of 8.9 (3.5-17.7) years). In CLEAR 1, in adjusted models, the minor allele of rs2808630 was associated with total radiographic score (incident rate ratio 0.37 (95% confidence interval (CI) 0.19-0.74), P-value=0.0051). In CLEAR 2, the minor allele of rs3093062 was associated with increased plasma CRP levels (P-value=0.002). For each rs3093062 minor allele, the plasma CRP increased by 1.51 (95% CI 1.15-1.95) mg dl(-1) when all the other covariates remained constant. These findings have important implications for assessment of the risk of joint damage in African Americans with RA.

Genetic variants associated with methotrexate efficacy and toxicity in early rheumatoid arthritis: results from the treatment of early aggressive rheumatoid arthritis trial.

Methotrexate (MTX) has emerged as first-line therapy for early moderate-to-severe rheumatoid arthritis (RA), but individual variation in treatment response remains unexplained. We tested the associations between 863 known pharmacogenetic variants and MTX response in 471 Treatment of Early Aggressive Rheumatoid Arthritis Trial participants with early RA. Efficacy and toxicity were modeled using multiple regression, adjusted for demographic and clinical covariates. Penalized regression models were used to test joint associations of markers and/or covariates with the outcomes. The strongest genetic associations with efficacy were in CHST11 (five markers with P<0.003), encoding carbohydrate (chondroitin 4) sulfotransferase 11. Top markers associated with MTX toxicity were in the cytochrome p450 genes CYP20A1 and CYP39A1, solute carrier genes SLC22A2 and SLC7A7, and the mitochondrial aldehyde dehydrogenase gene ALDH2. The selected markers explained a consistently higher proportion of variation in toxicity than efficacy. These findings could inform future development of personalized therapeutic approaches.

Cigarette smoking, disease severity and autoantibody expression in African Americans with recent-onset rheumatoid arthritis.

OBJECTIVE: To examine the association of smoking with clinical and serological features in African Americans with recent-onset rheumatoid arthritis (RA) and to explore whether this association is dependent on the presence of the HLA-DRB1 shared epitope (SE). METHODS: In African Americans with recent-onset RA (n = 300), we examined the association of cigarette smoking (current versus past versus never and pack-years of exposure) with anti-cyclic citrullinated peptide antibody, rheumatoid factor (RF) (IgM and IgA), rheumatoid nodules and baseline radiographic erosions using logistic and cumulative logistic regression (adjusting for SE status). We also examined for evidence of interaction between smoking status and SE for all outcomes. RESULTS: Although there was no association with RF-IgA seropositivity, current smokers were approximately twice as likely as never smokers to have higher IgA-RF concentrations (based on tertiles; OR = 1.74; 95% CI 1.05 to 2.88) and nodules (OR = 2.43; 95% CI 1.13 to 5.22). These associations were most pronounced in those with more than 20 pack-years of exposure. There was no association of smoking status or cumulative tobacco exposure with anti-cyclic citrullinated peptide antibody, IgM-RF or radiographic erosions. There was also no evidence of a biological or statistical SE-smoking interaction for any of the outcomes examined. CONCLUSIONS: This is the first study to systematically examine the association of cigarette smoking with RA-related features in African Americans. Cigarette smoking is associated with both subcutaneous nodules and higher serum concentrations of IgA-RF in African Americans with RA, associations that may have important implications for long-term outcomes in this population.

Methotrexate dosage reduction in patients with rheumatoid arthritis beginning therapy with infliximab: the Infliximab Rheumatoid Arthritis Methotrexate Tapering (iRAMT) trial.

OBJECTIVE: Infliximab plus methotrexate (MTX) is approved for the treatment of rheumatoid arthritis (RA). Based on the benefit/risk profile of this combination therapy, lower doses of MTX would be preferable when infliximab efficacy can be maintained. We evaluated the ability of patients receiving infliximab plus MTX to achieve and maintain a clinical response while the dose of MTX was tapered. METHODS: Infliximab infusions were administered at a minimum dosage of 3 mg/kg at 8-week intervals (following three loading doses at weeks 0, 2, and 6) to patients who had an inadequate response to MTX. MTX tapering was initiated at week 22 or later when at least a 40% improvement in the combined tender and swollen joint count was achieved; dosages were reduced by 5 mg every 8 weeks to a protocol-specified minimum dosage of 5 mg per week. If the required dosage of MTX after a flare was greater than the baseline dosage, the patient was considered a treatment failure. RESULTS: Of the 210 patients enrolled, 159 (76%) achieved a 40% or better improvement in the combined tender and swollen joint count and had their MTX doses tapered. In these 159 responders, the median (mean) dose of MTX was reduced from 15 (16.5) mg per week at baseline to 5 (7.1) mg per week at week 54. From the time of initial response, 79% of these patients had a zero- or a one-vial increase in infliximab, corresponding to an approximate dose increase of 1 mg/kg, through week 54. CONCLUSION: Approximately 75% of the patients participating in this trial achieved at least a 40% reduction in the combined swollen and tender joint count (correlating with an American College of Rheumatology 20% [ACR20] response in 83% of patients) while reducing the mean MTX dose by 57%.

Ludwig's angina. Report of a case and review of the literature.

In the preantibiotic era, Ludwig's angina frequently caused asphyxiation and death. Recognized less often today, this rapidly progressive submaxillary cellulitis may still be fatal. A case associated with Haemophilus influenzae bacteremia in an adult is presented. Twelve additional cases of cellulitis of the neck in adults with H influenzae bacteremia are summarized. One hundred forty-one cases of Ludwig's angina reported since 1945 are reviewed and compared with 315 earlier cases. In the cases reported in the antibiotic era, the mean age of the patients was 29 years. Most patients were previously healthy but had evidence of dental disease. Submandibular swelling, elevation of the tongue, fever, dysphagia, and trismus were each present in more than one half of patients. Streptococci and anaerobes were most frequently isolated from soft-tissue cultures. Untreated, this illness is fatal in one half of patients. Early recognition is therefore essential. Appropriate therapy includes maintenance of the airway, antibiotics, and surgical drainage when indicated.

Herpes zoster in patients with rheumatoid arthritis treated with weekly, low-dose methotrexate.

PURPOSE: Herpes zoster occurred in nine patients with methotrexate-treated rheumatoid arthritis. We compared these patients to a large group of methotrexate-treated rheumatoid arthritis patients in order to uncover potential factors explaining the occurrence of herpes zoster. PATIENTS AND METHODS: Data from 187 patients taking methotrexate were reviewed and compared with data from another nine patients who developed herpes zoster while taking the drug for rheumatoid arthritis, all from the same university-based arthritis clinic. Literature pertinent to infection in rheumatoid arthritis patients treated with methotrexate is reviewed. RESULTS: Herpes zoster occurred in 14.5 cases per 1,000 patient-years in our methotrexate-treated rheumatoid arthritis patients, as compared with the general population incidence of 1.3 to 4.8 cases per 1,000 patient-years. The infection was unrelated to duration of methotrexate usage, prednisone treatment, or the co-existence of diabetes mellitus, but appeared to occur in patients with high titers of rheumatoid factor and an overall longer duration of rheumatoid arthritis. There were no cases of systemic dissemination or recurrence of herpes zoster despite 27.4 years cumulative follow-up on continued methotrexate therapy. CONCLUSIONS: Herpes zoster may occur more frequently in patients with rheumatoid arthritis treated with low-dose methotrexate than in the general population. Herpes zoster in rheumatoid arthritis patients treated with methotrexate appears to be self-limited, benign, and statistically related to methotrexate use in the presence of longer-term rheumatoid disease.

Transforming growth factor beta within fibrotic scleroderma lungs.

PURPOSE, PATIENTS, AND METHODS: Since transforming growth factor beta (TGF beta) has been implicated as an important mediator of pulmonary fibrosis, we measured TGF beta protein and gene expression in alveolar epithelial lining fluid (ELF) of fibrotic scleroderma lungs sampled by bronchoalveolar lavage (BAL). TGF beta protein was qualitatively examined by Western blot analysis, and quantitatively by radioreceptor assays. Gene expression was evaluated in BAL mononuclear cells by Northern blot analysis with quantification of relative gene expression by densitometric analysis of the autoradiograms. RESULTS: Normal and scleroderma subjects had a 24-kd protein that comigrated with defined human TGF beta 1 and immunoreacted with anti-TGF beta antibody. The normal population had a significantly higher average TGF beta concentration (705 pM) compared with the scleroderma subjects (177 pM). The TGF beta 1 gene was expressed in amounts that did not significantly differ between the scleroderma and normal groups. On an individual subject basis, the TGF beta concentration variability did not correlate with variations in BAL cellularity or TGF beta 1 gene expression within the recovered mononuclear cells. CONCLUSIONS: It is concluded that both normal and fibrotic lungs have TGF beta 1 present at the alveolar epithelial surface. However, in the fibrotic scleroderma lungs, TGF beta protein content and gene expression were not increased at the alveolar epithelial surface. The simultaneous analysis of TGF beta protein content, gene expression, and cellular constituents within individual ELF specimens showed that the cellular components of the ELF do not appear to be major determinants of TGF beta protein concentration at the alveolar epithelial surface.

Inflammatory central nervous system involvement in rheumatoid arthritis.

We describe a patient with seropositive rheumatoid arthritis who developed pachymeningitis resulting in optic atrophy. Clinical, histopathologic, and radiologic findings in 18 additional cases of inflammatory CNS disease associated with rheumatoid arthritis are reviewed. The three characteristic neuropathologic findings were rheumatoid nodules, pachymeningitis or leptomeningitis, and vasculitis. In most cases, more than one of these histopathologic processes were found. The typical host was middle-aged with long-standing severe nodular disease. However, contrary to previous reports, CNS disease occurred in a significant number of patients without active synovitis and extracranial vasculitis and nodules. Although no correlation between specific neurologic symptoms and neuropathology was noted, patients with CNS nodules tended to be asymptomatic more often than patients with vasculitis or meningitis. CSF analysis and computed axial tomography were helpful diagnostic tools, but diagnosis was ultimately made only by directed biopsy or at autopsy. Treatment with surgical decompression and/or corticosteroids has proved beneficial in several cases. Inflammatory CNS involvement in rheumatoid arthritis should be considered in any patient with neurologic symptoms in whom infectious and malignant processes are ruled out. An aggressive, invasive approach for diagnostic biopsies seems warranted.

Prospective analysis of liver biopsies before and after methotrexate therapy in rheumatoid patients.

The significance of hepatic changes in methotrexate-treated RA patients is unclear at this time. In our group of RA patients, there was a slight increase in the incidence of triaditis and fat during methotrexate therapy. Disease duration greater than or equal to 10 years was associated with increased hepatic triaditis before treatment. Age greater than 50 years was associated with increased hepatic fat before and after treatment. It appears that patients' ages and duration of underlying RA account for some changes, independent of methotrexate therapy. Several of our patients changed from higher to lower histologic grade or had an apparent decrease in fibrosis, fat, or triaditis on the pathologists' reports and the blind readings of the repeat biopsies. This may be explained by sampling error. More importantly, some of these changes may not be of clinical significance. One report of methotrexate-induced cirrhosis in patients with psoriasis demonstrated that in all but one of 14 patients who continued receiving methotrexate the cirrhosis decrease or did not progress. This may also be true of the hepatic fibrosis seen in RA after methotrexate treatment. In this study, there did not appear to be changes seen on pretreatment liver biopsy that were predictive of subsequent fibrosis or cirrhosis. Our data indicate that pretreatment biopsy is unwarranted in a population similar to ours. However, our practice has been to try to avoid methotrexate in patients with diabetes, prior liver disease, alcoholism, or obesity because of previous reports suggesting that these patients are at increased risk for the development of cirrhosis. Only the above-mentioned patient, eventually diagnosed as having cirrhosis, might have been handled differently. Including the study, none of the approximately 700 RA patients in the literature having liver biopsies after methotrexate therapy have developed cirrhosis consequent to its use. Most of these had received a total dose of approximately 1,500 mg in small weekly doses, and alcohol was prohibited. Below this cumulative dose the risk of clinically significant liver damage in carefully selected patients is very low. In view of this experience, the recommendation that RA patients have liver biopsies after 1,500 mg of methotrexate (a holdover from the psoriasis literature) may be too conservative in low-risk RA patients, provided methotrexate is administered weekly and alcohol is prohibited. Recognizing that the absolute need for biopsy is unproven, a more realistic milestone for those choosing biopsy might be after each 2,000 to 2,500 mg.(ABSTRACT TRUNCATED AT 400 WORDS)

Soluble tumor necrosis factor receptor (p75) fusion protein (ENBREL) as a therapy for rheumatoid arthritis.

Soluble tumor necrosis factor (TNF) receptor fusion protein (p75) (Enbrel) is a reversible inhibitor of the biologic effects of TNF. Enbrel has been shown in placebo-controlled trials to significantly improve the signs and symptoms of rheumatoid arthritis. Clinical trials are now in progress to assess the safety and efficacy of Enbrel in combination with methotrexate in refractory rheumatoid arthritis along with trials to compare Enbrel to methotrexate in patients with early rheumatoid arthritis.

Potential biologic agents for treating rheumatoid arthritis.

The encouraging clinical results observed in trials using anti-TNF therapy clearly warrant further studies to determine whether TNF inhibitors are capable of modifying the destructive component of this disease in long-term follow-up studies as well as to assess the safety of long-term use (see the article by Keystone in this issue). It is also reasonable to propose that interfering with the cytokine cascade earlier in the course of disease may be of even greater therapeutic benefit. As the pathogenetic mechanisms in RA are more clearly defined, especially in early disease and in those individuals destined to develop severe disease, the potential of other biologic agents to specifically inhibit these critical pathways may provide better treatments for our patients. Many potential targets in the immune-mediated process of RA are currently being rigorously evaluated in clinical trials. Use of combinations of biologic therapies, perhaps in human patients with RA, should be of considerable interest in future trials.

Perioperative use of methotrexate in patients with rheumatoid arthritis undergoing orthopedic surgery.

Methotrexate (MTX) is commonly prescribed for the treatment of rheumatoid arthritis. Its use seems to be an independent risk factor for infection with common pathogens and opportunistic organisms. Some rheumatologists and orthopedic surgeons hold the opinion that MTX should be temporarily withheld to lessen the likelihood of postoperative infection or poor wound healing. Alternatively, some clinicians believe that MTX should be continued throughout the perioperative period to avoid flares in rheumatoid arthritis disease activity. There are no definitive studies on which to rely in this decision-making process, but the authors believe that withholding MTX for 2 weeks of the perioperative period is a reasonable and prudent approach.

T-cell receptor peptide vaccination in the treatment of rheumatoid arthritis.

In several human T-cell-mediated autoimmune diseases and animal models of such illnesses, T-cell receptors (TCR) specific for antigens that initiate or perpetuate the disease share a limited number of variable region determinants. Vaccinations with peptides derived from over-represented TCRs are effective treatment for some of these disorders. RA is a chronic inflammatory disease in which there is prominent T-cell infiltration in the synovial lining layer. TCR V beta 3, V beta 14, and V beta 17 have been found to be over-represented among IL-2 receptor-positive T-cells from patients with RA. A phase II clinical trial in RA, using a combination of three peptides derived from V beta 3, V beta 14, and V beta 17, has yielded promising results. Larger clinical efficacy and safety studies must be performed to determine if TCR peptide vaccination will become a viable treatment alternative for patients with RA.

The use of analgesics in the management of pain in rheumatic diseases.

Pain is the most common complaint of patients who see rheumatologists. In this article, the current treatment options for pain are reviewed; these include acetaminophen, nonsteroidal anti-inflammatory drugs, new specific cyclooxygenase-2 inhibitors, opioid analgesics, centrally acting muscle relaxants, antidepressants, and topical analgesics and counterirritants. The doses of medication and known adverse effects of these medications are highlighted.

Effects of nonsteroidal antiinflammatory drugs on bone loss in chronic inflammatory disease.

Several controlled clinical trials have indicated that nonsteroidal antiinflammatory drugs may slow alveolar bone loss in periodontitis. Demonstration of this efficacy is dependent on the development of accurate, sensitive, and specific quantitative methods for the assessment of bony change, such as digital subtraction radiography. Further studies of such methodologies are required to more fully investigate the effect of nonsteroidal antiinflammatory drugs in rheumatoid arthritis.

Recent advances in anti-tumour necrosis factor (TNF) therapy in rheumatoid arthritis: focus on the soluble TNF receptor p75 fusion protein, etanercept.

Tumour necrosis factor (TNF) is the dominant mediator of the cytokine cascade that causes inflammation and joint detruction in rheumatoid arthritis. A new class of agents under investigation, the biological TNF inhibitors, inhibit the activity of TNF. Recombinant human TNF receptor p75 Fc fusion protein (TNFR:Fc; etanercept) blocks the activity of the cytokine TNF. The preclinical and pivotal trials evaluating etanercept in rheumatoid arthritis are reviewed in this article.

Vaccination against rheumatoid arthritis: concepts and progress.

Recently, interest has grown in the potential benefit of vaccination approaches in humans with rheumatoid arthritis. Approaches evaluated include the use of T cell receptor peptide vaccines, autologous T cells, major histocompatibility complex (MHC) peptides, allogeneic mononuclear cells and oral collagen. The use of T cell receptor peptide vaccination in rheumatoid arthritis has been limited to dose-finding and pharmacokinetic studies with Vbeta14 and Vbeta17 peptides. The results of an ongoing placebo-controlled clinical trial with a combination of Vbeta3, Vbeta14 and Vbeta17 peptides will be of interest. Since the pathogenic T cells in rheumatoid arthritis are not known, the use of mixed T cell populations for attenuated autologous T cell vaccination may be necessary. This approach has been evaluated in a small number of patients. Significant clinical or adverse effects were not observed. The appropriate dose, route of administration and method of attenuation of autologous T cells remains to be more clearly defined. In addition, any immunisation approach that targets T cells that are not pathogenic has the potential of immunising against beneficial T cell clones. Rheumatoid arthritis is associated with certain MHC class II alleles (e.g. HLA-DR1 and DR4). Rheumatoid arthritis frequently remits during pregnancy, although the mechanisms associated with this are not clear. Based on this observation, several therapeutic approaches have been evaluated in rheumatoid arthritis. These include placenta-eluted gamma globulins (which contain antibodies to HLA-DR antigens), DR4/DR1 peptide vaccines and allogeneic mononuclear cell vaccination. In uncontrolled trials, each of these approaches has been shown to have no adverse effects and encouraging clinical benefits have been observed, although double-blind placebo-controlled studies will be needed to assess these approaches. Encouraging clinical results have been reported to date with oral administration of type II collagen as a therapy for rheumatoid arthritis, and large multicentre controlled trials are currently under way.

New therapeutic approaches to the management of rheumatoid arthritis.

Rheumatoid arthritis (RA) is a common disease that affects up to 1% of the population, and causes significant morbidity and early mortality. The aetiology of RA is unknown; however, in the last 10 to 15 years significant advances in molecular technology have provided a greater understanding of the pathogenesis of the disease. This has led to the development of new approaches to the treatment of RA. The disease modifying antirheumatic oral agent leflunomide inhibits the proliferation of activated T cells that are important in the inflammation and degradation of synovial tissues. The 2 biological agents approved for the treatment of RA, infliximab and etanercept, are inhibitors of the pro-inflammatory cytokine, tumour necrosis factor-alpha (TNFalpha). Infliximab is a chimeric human/mouse monoclonal antibody which is administered by intravenous infusion and binds with high affinity to TNFalpha, thereby neutralising its effects. Etanercept is a recombinant, soluble TNF receptor molecule which is administered subcutaneously and binds to TNFalpha in the serum rendering it biologically inactive. The protein A immunoadsorption column is a medical device that in conjunction with plasmapheresis can be used in patients with refractory RA. These agents have provided new and effective therapies for the treatment of patients with RA.

Health-related quality of life and functional status of patients with rheumatoid arthritis randomly assigned to receive etanercept or placebo.

OBJECTIVE: To compare the functional status and well-being of patients with rheumatoid arthritis (RA) who were randomly assigned to receive placebo, etanercept 10 mg, or etanercept 25 mg during a 26-week, phase III, double-blind clinical trial. BACKGROUND: No single indicator of disease activity, severity, or therapeutic efficacy has been established for RA. During the past decade, health-related quality of life, a multidimensional way to assess physical, emotional, and social aspects of a disease or its treatment, has become an important outcome in RA studies and in assessments of RA drug therapies. METHODS: A total of 234 patients completed the Health Assessment Questionnaire (HAQ), the Short-Form 36 (SF-36) (n = 48 patients), items assessing energy and mental health from the Medical Outcomes Study (MOS), and a single-item rating scale assessing current health (feeling thermometer) at baseline and several times during 6 months. RESULTS: Significant improvements from baseline to last assessment were reported with etanercept versus placebo and in the HAQ Disability Index score (ie, the total HAQ score) and all 8 HAQ categories (P < 0.05), with the exception of grip. Significant improvements with etanercept in the MOS energy and mental health subscales, current health (from the feeling thermometer), and mental and physical function components of the SF-36 were reported (P < 0.05). CONCLUSIONS: Patients receiving 10- or 25-mg doses of etanercept reported significantly better functional status and well-being than did patients receiving placebo.

Health status response of rheumatoid arthritis to treatment with DAB486IL-2.

OBJECTIVE: To examine and compare health status and disease activity changes in patients with rheumatoid arthritis (RA) in a clinical trial of the biologic agent DAB486IL-2. METHODS: Data on 45 patients with RA who were enrolled in a multicourse, double-blind trial, consisting of a first, placebo-controlled, course followed by open-label treatment with the active agent to a total of 3 active courses, were examined for evidence of improvement in health status (measured using the 5 components of the Arthritis Impact Measurement Scales 2 [AIMS2]) and disease activity (measured using standard clinical measures and erythrocyte sedimentation rate). RESULTS: Over a single course of treatment, DAB486IL-2-treated patients showed significant improvement relative to placebo-treated patients on the symptom and social components of AIMS2 and in patient's assessment of disease activity. With subsequent open-label courses of treatment with DAB486IL-2, all 5 AIMS2 health status components and the disease activity measures of tender and swollen joint counts, grip strength, and the observer and patient assessments showed steady and generally parallel improvement. CONCLUSION: Short-term health status effects of this biologic agent were detected using the AIMS2.