Rheumatoid Arthritis: Mikuls TR

Mikuls TR. · No affiliation provided · Ann Oncol. · Pubmed #17355949 links to  free full text

This publication has no abstract.

Erickson AR, Mikuls TR. · Section of Rheumatology and Immunology, University of Nebraska Medical Center, 988025 Nebraska Medical Center, Omaha, NE 98198-8025, USA. · Curr Rheumatol Rep. · Pubmed #17915098 No free full text.

Abstract: The availability of biologic agents targeting tumor necrosis factor (TNF)-alpha represents a significant advance in the management of rheumatoid arthritis. Anti-TNF-alpha therapy has been associated with dramatic improvements in the clinical signs and symptoms of rheumatoid arthritis and has been shown to greatly retard the destructive process that too often characterizes this condition. Although effective and well-tolerated in a substantial proportion of patients, primary and secondary failures of anti-TNF-alpha strategies have been well described, affecting up to one-third to one-half of subjects treated with these agents. Switching from one anti-TNF-alpha agent to a second (or even third) anti-TNF-alpha therapy has emerged as a means of addressing treatment failures with this drug class. This review examines data addressing the practice of switching anti-TNF-alpha agents in the context of initial treatment failure, with a focus on data from peer-reviewed reports.

Snow MH, Mikuls TR. · Department of Medicine, Section of Rheumatology and Immunology, University of Nebraska Medical Center, and Omaha Veterans Affairs Medical Center, Omaha, Nebraska, USA. · Curr Opin Rheumatol. · Pubmed #15838230 No free full text.

Abstract: PURPOSE OF REVIEW: The incidence and mortality of cardiovascular disease are increased in the context of rheumatoid arthritis. The purpose of this review is to examine our evolving understanding of the pathogenesis of cardiovascular disease in rheumatoid arthritis and to underscore the importance of tailored prevention of cardiovascular disease in this select population. RECENT FINDINGS: Recent reports have highlighted the shared pathobiology of cardiovascular disease and rheumatoid arthritis, both of which represent inflammatory disorders. Several reports have also provided much-needed insight into the deleterious impact that select therapies (including cyclo-oxygenase-2-specific inhibitors) may have in terms of the risk of cardiovascular disease in rheumatoid arthritis. Although further study is warranted, preliminary investigations also suggest that aggressive anti-inflammatory therapy, including the adjunctive use of statins, may play important cardioprotective roles in rheumatoid arthritis. SUMMARY: The pathogenesis of cardiovascular disease in rheumatoid arthritis is complex and involves several intermediate factors, including dyslipidemia, elevations in serum homocysteine, impaired insulin sensitivity, and endothelial dysfunction. Given the burden of cardiovascular disease in this population, it is important that health care providers caring for rheumatoid arthritis patients adopt a treatment course that is both comprehensive and individualized to address specific risk factors for cardiovascular disease.

Bridges SL, Hughes LB, Mikuls TR, Howard G, Tiwari HK, Alarcón GS, McNicholl JM, Moreland LW. · Departments of Medicine and Microbiology, Division of Clinical Immu-nology and Rheumatology, University of Alabama at Birmingham, 415 Lyons-Harrison Research Building, 701 19th Street South, Birmingham, Alabama 35294-0007, USA. · Clin Exp Rheumatol. · Pubmed #14969066 No free full text.

Abstract: African-Americans have been under-represented in genetic studies of rheumatoid arthritis (RA) susceptibility and severity. Genetic and non-genetic factors influencing the radiographic severity of RA and its response to treatment are poorly understood, particularly in African-Americans. The Consortium for the Longitudinal Evaluation of African-Americans with early RA (CLEAR) Registry, a collaborative effort among four institutions in the southeast USA, will hopefully provide a useful resource to study these issues.

Mikuls TR, Weaver AL. · Section of Rheumatology and Immunology, University of Nebraska Medical Center and the Omaha Veterans' Administration Medical Center, 983025 Nebraska Medical Center, Omaha, NE 68198, USA. · Curr Rheumatol Rep. · Pubmed #14531954 No free full text.

Abstract: Tumor necrosis factor-alpha (TNFa) plays a central role in rheumatoid arthritis (RA) pathogenesis. There are currently three available anti-TNFa agents for the treatment of RA--adalimumab, etanercept, and infliximab. These targeted therapies have select advantages over traditional disease-modifying antirheumatic drugs (DMARDs), agents that have long been the mainstay of RA treatment. Compared with conventional DMARDs, TNFa inhibitors display a rapid onset of action and have shown a significant effect in retarding the radiographic joint destruction that often characterizes RA disease progression. Although anti-TNFa drugs represent an important advance in RA treatment, postmarketing reports of serious infections, as well as other adverse events, highlight the need for continued postmarketing vigilance with the use of these agents. This review evaluates the unique attributes of the available TNFa inhibitors, focusing specifically on recent reports providing important insight into the understanding of drug-related efficacy and toxicity.

Mikuls TR. · Department of Internal Medicine, Section of Rheumatology and Immunology, University of Nebraska Medical Center and Omaha VA Medical Center, Omaha, NE 68198-3025, USA. · Best Pract Res Clin Rheumatol. · Pubmed #12915155 No free full text.

Abstract: Rheumatoid arthritis (RA) affects approximately 0.5-1% of the population and imposes substantial societal costs including an increased risk of work-related disability and accelerated mortality. It is increasingly clear that RA-related co-morbidities, including cardiovascular disease (CVD), infection, osteoporosis, lymphoproliferative malignancy, and peptic ulcer disease, serve as major determinants of disease-associated outcome. In this review, the impact of these select co-morbidities on RA outcome is discussed. In addition, this review explores potential mechanisms underlying their association with RA, the possible iatrogenic role of agents used to treat the disease, and measures aimed at both prevention and treatment of disease-specific co-morbidity.

Mikuls TR, Moreland LW. · Department of Medicine, Section of Rheumatology and Immunology, University of Nebraska Medical Center, Omaha, Nebraska, USA. · Drug Saf. · Pubmed #12495361 No free full text.

Abstract: In the last decade, there have been substantial advances in the treatment of rheumatoid arthritis with the addition of several new disease-modifying agents to the therapeutic armamentarium. Biological agents targeting tumour necrosis factor (TNF) represent one such important addition. Infliximab, a chimeric anti-TNF monoclonal antibody, has shown remarkable promise in alleviating the signs and symptoms of rheumatoid arthritis in addition to retarding radiographic disease progression when used in combination with methotrexate. In its pivotal phase III trial, the addition of infliximab to patients with methotrexate-refractory disease was associated with substantial clinical benefit. Using American College of Rheumatology criteria for improvement, one-half of patients receiving infliximab (3 mg/kg every 8 weeks) plus methotrexate showed at least 20% improvement compared with only 20% of those receiving placebo plus methotrexate (p < 0.001) with over one-half of eventual responders obtaining criteria for improvement by the second week of observation. Although its use has been met with much deserved enthusiasm, recent reports have highlighted several potential serious adverse effects associated with infliximab (and other TNF antagonists), including infusion reactions, congestive heart failure, drug-induced lupus, and CNS demyelination. In addition, recent reports have cited the potential for reactivation of mycobacterial and fungal infection in patients receiving infliximab, mandating appropriate tuberculosis screening prior to drug initiation. Although the frequency of serious drug-related toxicity (requiring discontinuation of the agent) appears to be quite low, these reports underscore the need for caution and close surveillance with the administration of TNF inhibitors, particularly given that strategies aimed at preventing toxicity remain unproven. Despite its potential for toxicity, infliximab remains a valuable alternative for patients with rheumatoid arthritis.

Mikuls TR, Saag KG. · Department of Medicine, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, Alabama, USA. · Rheum Dis Clin North Am. · Pubmed #11396093 No free full text.

Abstract: It is increasingly clear that coexistent disease plays a pivotal role in RA outcome and that efforts aimed at specifically addressing these comorbidities need to be aggressively sought, investigated, and implemented once proven effective. RA-associated costs are currently increasing at twice the rate of the medical care index. Comorbidity in the setting of RA independently predicts disease-associated disability (a major cost component) and mortality, underscoring the need for a more comprehensive approach to RA, one that adequately addresses disease-specific comorbidities. At present, many primary and secondary preventative measures (Table 1) for RA-specific comorbidities remain largely unproved and require rigorous investigation in a randomized prospective fashion. Despite this ongoing need, advances are being made in our understanding of the underlying pathogenesis of these comorbid conditions and their relation with RA. This improved understanding should translate into further effective interventions. Bisphosphonates, for instance, have been shown to be effective in the prevention of GIOP and associated fractures. The past several years have seen other exciting therapeutic advances in RA. DMARD combinations have been shown to be more effective and no more toxic than MTX monotherapy. In addition to the recent release of COX-2 NSAIDs, three new disease-modifying agents (leflunomide, etanercept, and infliximab) have been added to the therapeutic armamentarium; these are options that have markedly changed the treatment landscape in RA. Although these important advances have generated much deserved optimism, the precise effect that these agents may have on RA-specific comorbidity remains to be seen. The next decade should prove to be an exciting time in RA management. Better identification, understanding, and management of RA comorbidities have great potential to improve quality of life and survival among our patients with RA.

Mikuls TR, Moreland LW. · Division of Clinical Immunology and Rheumatology, University of Birmingham, 1813 6th Ave South, MEB 625, Birmingham, AL 35294, USA. · Expert Opin Pharmacother. · Pubmed #11336570 No free full text.

Abstract: There is accumulating evidence that tumour necrosis factor (TNF) plays a major role in the pathogenesis of rheumatoid arthritis (RA). Recent biotechnological advances have allowed for the development of agents that directly target TNF, a pro-inflammatory cytokine. In the last 2 years, the US FDA and the EU's Commission of the European Communities have approved two biological agents for the treatment of refractory RA, etanercept and infliximab. Etanercept is a fusion protein, composed of the Fc portion of IgG1 and the extracellular domain of the TNF receptor (p75). Infliximab is a chimeric monoclonal antibody (mAb) composed of murine variable and human constant regions. In placebo-controlled trials, both agents have proven to be effective and well-tolerated in RA patients. This review evaluates the available TNF inhibitors, summarises pertinent clinical trials and underscores differences between the two agents in terms of molecular structure, efficacy, safety data, antigenicity and pharmacokinetics.

Mikuls TR, Kahn D, Utrie PC, Miller SJ, Koehnke R, Goeckeler W, Saag KG. · Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, USA. · Scand J Rheumatol. · Pubmed #11846055 No free full text.

Abstract: We examined the preliminary safety and efficacy of intravenous samarium-153-EDTMP (Sm-153) in the treatment of refractory rheumatoid arthritis (RA). In an open-label sequential group comparison of 0.5, 1.0, and 2.0 mCi/kg, Sm-153 was administered as a single intravenous infusion to 24 patients with refractory disease. Across treatment doses, the frequency of American College of Rheumatology (ACR) 20% responses was 25%, 29%, 25%, and 33% at 2, 4, 8, and 12 weeks, respectively. Expected significant declines in absolute neutrophil count, hemoglobin, and platelet counts were observed with nadirs seen between 2-4 weeks. Sm-153, at doses of 0.5 and 1.0 mCi/kg, is well tolerated but minimally effective in the treatment of refractory RA as measured using ACR response criteria.

Gregersen PK, Amos CI, Lee AT, Lu Y, Remmers EF, Kastner DL, Seldin MF, Criswell LA, Plenge RM, Holers VM, Mikuls TR, Sokka T, Moreland LW, Bridges SL, Xie G, Begovich AB, Siminovitch KA. · The Feinstein Institute for Medical Research, North Shore-Long Island Jewish Health System, Manhasset, NY, USA. · Nat Genet. · Pubmed #19503088 No free full text.

Abstract: We conducted a genome-wide association study of rheumatoid arthritis in 2,418 cases and 4,504 controls from North America and identified an association at the REL locus, encoding c-Rel, on chromosome 2p13 (rs13031237, P = 6.01 x 10(-10)). Replication in independent case-control datasets comprising 2,604 cases and 2,882 controls confirmed this association, yielding an allelic OR = 1.25 (P = 3.08 x 10(-14)) for marker rs13031237 and an allelic OR = 1.21 (P = 2.60 x 10(-11)) for marker rs13017599 in the combined dataset. The combined dataset also provides definitive support for associations at both CTLA4 (rs231735; OR = 0.85; P = 6.25 x 10(-9)) and BLK (rs2736340; OR = 1.19; P = 5.69 x 10(-9)). c-Rel is an NF-kappaB family member with distinct functional properties in hematopoietic cells, and its association with rheumatoid arthritis suggests disease pathways that involve other recently identified rheumatoid arthritis susceptibility genes including CD40, TRAF1, TNFAIP3 and PRKCQ.

Mikuls TR, Payne JB, Reinhardt RA, Thiele GM, Maziarz E, Cannella AC, Holers VM, Kuhn KA, O'Dell JR. · Department of Medicine, Nebraska Arthritis Outcomes Research Center (NAORC), University of Nebraska Medical Center and Omaha Veterans Affairs Medical Center, Omaha, NE, USA. · Int Immunopharmacol. · Pubmed #18848647 No free full text.

Abstract: SUMMARY: Antibody titers to P. gingivalis are increased in patients with rheumatoid arthritis and are associated with disease-specific autoimmunity. BACKGROUND: Periodontitis (PD) has been implicated as a risk factor for rheumatoid arthritis (RA). We sought to characterize antibody titers to P. gingivalis (a pathogen in PD) in subjects with RA, PD, and in healthy controls and to examine their relationship with disease autoantibodies. METHODS: P. gingivalis antibody was measured in subjects with RA (n=78), PD (n=39), and in controls (n=40). Group frequencies of bacterial titer elevations were compared using the Chi-square test and antibody titers were compared using non-parametric tests. Correlations of P. gingivalis titer with C-reactive protein (CRP), antibody to cyclic citrullinated peptide (anti-CCP), and rheumatoid factor (RF) were examined in those with RA while CRP and autoantibody concentrations were compared based on seropositivity to P. gingivalis. RESULTS: Antibody titers to P. gingivalis were highest in PD, lowest in controls, and intermediate in RA (p=0.0003). Elevations in P. gingivalis (titer> or =800) were more common in RA and PD (67% and 77%, respectively) than in controls (40%) (p=0.002). In RA, there were significant correlations with P. gingivalis titer with CRP, anti-CCP-IgM, and -IgG-2. CRP (p=0.006), anti-CCP-IgM (p=0.01) and -IgG2 (p=0.04) concentrations were higher in RA cases with P. gingivalis titers > or =800 compared to cases with titers <800. CONCLUSION: Antibodies to P. gingivalis are more common in RA subjects than controls, although lower than that in PD. Associations of P. gingivalis titers with RA-related autoantibody and CRP concentrations suggests that infection with this organism plays a role in disease risk and progression in RA.

Lundberg K, Kinloch A, Fisher BA, Wegner N, Wait R, Charles P, Mikuls TR, Venables PJ. · Kennedy Institute of Rheumatology, Imperial College London, London, UK. · Arthritis Rheum. · Pubmed #18821669 No free full text.

Abstract: OBJECTIVE: To map the antibody response to human citrullinated alpha-enolase, a candidate autoantigen in rheumatoid arthritis (RA), and to examine cross-reactivity with bacterial enolase. METHODS: Serum samples obtained from patients with RA, disease control subjects, and healthy control subjects were tested by enzyme-linked immunosorbent assay (ELISA) for reactivity with citrullinated alpha-enolase peptides. Antibodies specific for the immunodominant epitope were raised in rabbits or were purified from RA sera. Cross-reactivity with other citrullinated epitopes was investigated by inhibition ELISAs, and cross-reactivity with bacterial enolase was investigated by immunoblotting. RESULTS: An immunodominant peptide, citrullinated alpha-enolase peptide 1, was identified. Antibodies to this epitope were observed in 37-62% of sera obtained from patients with RA, 3% of sera obtained from disease control subjects, and 2% of sera obtained from healthy control subjects. Binding was inhibited with homologous peptide but not with the arginine-containing control peptide or with 4 citrullinated peptides from elsewhere on the molecule, indicating that antibody binding was dependent on both citrulline and flanking amino acids. The immunodominant peptide showed 82% homology with enolase from Porphyromonas gingivalis, and the levels of antibodies to citrullinated alpha-enolase peptide 1 correlated with the levels of antibodies to the bacterial peptide (r2=0.803, P<0.0001). Affinity-purified antibodies to the human peptide cross-reacted with citrullinated recombinant P gingivalis enolase. CONCLUSION: We have identified an immunodominant epitope in citrullinated alpha-enolase, to which antibodies are specific for RA. Our data on sequence similarity and cross-reactivity with bacterial enolase may indicate a role for bacterial infection, particularly with P gingivalis, in priming autoimmunity in a subset of patients with RA.

Fay BT, Whiddon AP, Puumala S, Black NA, O'Dell JR, Mikuls TR. · Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198-2055, USA. · J Clin Rheumatol. · Pubmed #18431092 No free full text.

Abstract: BACKGROUND: Minocycline is recognized as an effective, well-tolerated therapy in rheumatoid arthritis (RA), although its use has been associated with the development of cutaneous hyperpigmentation. OBJECTIVES: To assess the clinical determinants and frequency of minocycline-induced hyperpigmentation in patients with RA. METHODS: A retrospective medical record review of all patients with RA seen in 2 academic rheumatology practices was performed to identify subjects who had received at least 1 month of continuous minocycline therapy. Patient demographics, disease characteristics, medication use, and medication side effects were abstracted from the medical record. Using Cox proportional hazards regression and restricting the analysis to the initial minocycline course, we examined the association of patient factors and concomitant medications with the development of hyperpigmentation. RESULTS: Of 121 patients with at least 1 minocycline course of 30 days or more, 44 (36%) developed documented hyperpigmentation, including 33 during the initial course over a median duration of 9.1 month (range 2.2-77.8 months). Hyperpigmentation was most commonly seen on the upper and lower extremities and the head/neck region. Minocycline-induced hyperpigmentation led to the discontinuation of treatment in 3 patients, with 12 additional patients receiving a dose reduction. Increasing age was the only clinical determinant significantly associated with hyperpigmentation (HR = 1.04; 95% CI 1.00-1.07, P = 0.04). There were no significant associations of sex, weight, concomitant prednisone, or aspirin use with the development of hyperpigmentation. CONCLUSIONS: Minocycline-induced hyperpigmentation is a common complication seen with minocycline use in the treatment of RA, and seems to increase with age.

Shaver TS, Anderson JD, Weidensaul DN, Shahouri SS, Busch RE, Mikuls TR, Michaud K, Wolfe F. · Arthritis and Rheumatology Clinics of Kansas, USA. · J Rheumatol. · Pubmed #18412311 No free full text.

Abstract: OBJECTIVE: To investigate the results and feasibility of available scales to measure minimal disease activity (MDA) and remission in rheumatoid arthritis (RA) in the clinic. METHODS: We studied 849 consecutive patients with RA seen in a community rheumatology practice for routine RA care by 4 rheumatologists, beginning in March 2007 and ending in August 2007. Patients and physicians completed a simple form at each visit. We calculated the Disease Activity Score 28 (DAS28), Clinical Disease Activity Index (CDAI), physician assessment of global activity, and the Patient Activity Scale (PAS-II). From these we calculated remission and MDA prevalence in this community practice. RESULTS: The DAS28 could not be determined in more than 50% of patients because of referring physician and insurance company restrictions. Remission prevalences differed by assessment method: DAS28 28.5%, CDAI 6.5%-8.1%, physician global 12.5%, PAS 13.7%. MDA was 26.9% using the American College of Rheumatology core set variables, 34.7% using the DAS28, and 26.8% using the PAS-II. The kappa statistic was only fair (0.2 to 0.4) for most comparisons between assessment methods. No significant differences were noted for remission and MDA according to biologic therapy. CONCLUSION: The CDAI and/or physician global and PAS-II are simple acceptable ways to measure RA activity in the clinic, but results differ strikingly according to method. Further standardization appears to be required for full implementation of the CDAI. Caution is urged before using these methods for regulatory purposes.

Hughes LB, Morrison D, Kelley JM, Padilla MA, Vaughan LK, Westfall AO, Dwivedi H, Mikuls TR, Holers VM, Parrish LA, Alarcón GS, Conn DL, Jonas BL, Callahan LF, Smith EA, Gilkeson GS, Howard G, Moreland LW, Patterson N, Reich D, Bridges SL. · University of Alabama at Birmingham 35294-2182, USA. · Arthritis Rheum. · Pubmed #18240241 links to  free full text

Abstract: OBJECTIVE: To determine whether shared epitope (SE)-containing HLA-DRB1 alleles are associated with rheumatoid arthritis (RA) in African Americans and whether their presence is associated with higher degrees of global (genome-wide) genetic admixture from the European population. METHODS: In this multicenter cohort study, African Americans with early RA and matched control subjects were analyzed. In addition to measurement of serum anti-cyclic citrullinated peptide (anti-CCP) antibodies and HLA-DRB1 genotyping, a panel of >1,200 ancestry-informative markers was analyzed in patients with RA and control subjects, to estimate the proportion of European ancestry. RESULTS: The frequency of SE-containing HLA-DRB1 alleles was 25.2% in African American patients with RA versus 13.6% in control subjects (P = 0.00005). Of 321 patients with RA, 42.1% had at least 1 SE-containing allele, compared with 25.3% of 166 control subjects (P = 0.0004). The mean estimated percent European ancestry was associated with SE-containing HLA-DRB1 alleles in African Americans, regardless of disease status (RA or control). As reported in RA patients of European ancestry, there was a significant association of the SE with the presence of the anti-CCP antibody: 86 (48.9%) of 176 patients with anti-CCP antibody-positive RA had at least 1 SE allele, compared with 36 (32.7%) of 110 patients with anti-CCP antibody-negative RA (P = 0.01, by chi-square test). CONCLUSION: HLA-DRB1 alleles containing the SE are strongly associated with susceptibility to RA in African Americans. The absolute contribution is less than that reported in RA among populations of European ancestry, in which approximately 50-70% of patients have at least 1 SE allele. As in Europeans with RA, the SE association was strongest in the subset of African American patients with anti-CCP antibodies. The finding of a higher degree of European ancestry among African Americans with SE alleles suggests that a genetic risk factor for RA was introduced into the African American population through admixture, thus making these individuals more susceptible to subsequent environmental or unknown factors that trigger the disease.

Mikuls TR, Hughes LB, Westfall AO, Holers VM, Parrish L, van der Heijde D, van Everdingen M, Alarcón GS, Conn DL, Jonas B, Callahan LF, Smith EA, Gilkeson G, Howard G, Moreland LW, Bridges SL. · Department of Medicine, University of Nebraska Medical Center and Omaha VA Medical Center, Omaha, NE 68198-6270, USA. · Ann Rheum Dis. · Pubmed #18198196 No free full text.

Abstract: 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.

Mikuls TR, Kazi S, Cipher D, Hooker R, Kerr GS, Richards JS, Cannon GW. · Omaha Veterans Affairs Medical Center, University of Nebraska, Omaha, Nebraska, USA. · J Rheumatol. · Pubmed #17552044 No free full text.

Abstract: OBJECTIVE: To examine the association of race/ethnicity with measures of disease activity and severity among male US veterans with rheumatoid arthritis (RA). METHODS: Measures of disease activity and severity were examined in a group of US veterans (n = 573) with RA, comparing measures in African American men (n = 79) with Caucasian men (n = 494). Dichotomous variables were compared using logistic regression while continuous variables were examined using linear regression, adjusting for the effects of age, disease duration, and smoking status. RESULTS: Compared to Caucasians, African Americans were slightly younger (65.0 vs 67.1 yrs; p = 0.09) at enrollment and had a similar age at disease onset (50.5 vs 50.6 years; p = 0.98). After adjusting for age, disease duration, and smoking status, there were no differences based on race/ethnicity in rheumatoid factor positivity, the presence of radiographic changes, physical functioning, swollen joint counts, Disease Activity Score (DAS28), or global well-being scores. In contrast, African Americans were about 50% less likely than Caucasians with RA to have subcutaneous nodules (adjusted OR 0.51, 95% CI 0.30-0.86) and had lower tender joint counts (p = 0.007), associations that were attenuated and not significant with further adjustment for collection site. CONCLUSION: With the possible exception of lower rates of rheumatoid nodules and lower tender joint counts in African Americans, there is little evidence to support the existence of important racial/ethnic differences in RA disease expression between African American and Caucasian men.

Mikuls TR, Holers VM, Parrish L, Kuhn KA, Conn DL, Gilkeson G, Smith EA, Kamen DL, Jonas BL, Callahan LF, Alarcón GS, Howard G, Moreland LW, Bridges SL. · University of Nebraska Medical Center, Omaha Veterans Administration Medical Center, Omaha, NE, USA. · Arthritis Rheum. · Pubmed #16948136 links to  free full text

This publication has no abstract.

Criswell LA, Saag KG, Mikuls TR, Cerhan JR, Merlino LA, Lum RF, Pfeiffer KA, Woehl B, Seldin MF. · Rosalind Russell Medical Research Center for Arthritis, Department of Medicine, University of California, San Francisco, CA, USA. · Ann Rheum Dis. · Pubmed #16887863 No free full text.

Abstract: OBJECTIVE: To determine whether the impact of tobacco exposure on rheumatoid arthritis (RA) risk is influenced by polymorphisms at the HLA-DRB1 and glutathione S-transferase M1 (GSTM1) loci. METHODS: Subjects were participants from a case-control study nested within the Iowa Women's Health Study, a population based, prospective cohort study of postmenopausal women. Incident RA cases (n = 115) were identified and medical records reviewed to confirm RA diagnosis. Controls without RA (n = 466) were matched with RA cases by age and ethnic background. HLA-DRB1 typing classified subjects according to the presence of alleles encoding the RA "shared epitope" (SE) sequence. GSTM1 was genotyped using a multiplex polymerase chain reaction assay. Conditional logistic regression was used to estimate the odds ratios (ORs) and 95% confidence intervals. RESULTS: Strong positive associations of smoking (OR = 6.0, p = 0.004), SE positivity (OR = 4.6, p = 0.0006), and GSTM1 null genotype (OR = 3.4, p = 0.007) with risk of RA, and significant gene-environment interactions (smoking by SE interaction p = 0.034; smoking by GSTM1 interaction p = 0.047) were observed. Stratified analyses indicated that exposure to tobacco smoke primarily increased the risk of RA among subjects who lacked genetic risk factors for the disease (that is, SE negative or GSTM1 present). CONCLUSIONS: Although these findings require confirmation in other groups, the results support the importance of considering both genetic and environmental factors, and also their interaction, in studies of complex diseases like RA.

Mikuls TR, Endo JO, Puumala SE, Aoun PA, Black NA, O'Dell JR, Stoner JA, Boilesen EC, Bast MA, Bergman DA, Ristow KM, Ooi M, Armitage JO, Habermann TM. · Department of Medicine, University of Nebraska Medical Center,Omaha, NE 68198-3025, USA. · J Clin Oncol. · Pubmed #16520462 No free full text.

Abstract: PURPOSE: Although preliminary studies suggest that non-Hodgkin's lymphoma (NHL) complicating rheumatoid arthritis (RA) may be a clinically distinct entity compared with that occurring in the general population, studies examining the impact of antecedent RA on survival are limited. In this prospective study, we examined the association of RA with survival in patients with NHL. PATIENTS AND METHODS: Using two large lymphoma registries, we identified patients with evidence of RA preceding NHL. Survival in RA patients was compared with that of controls using proportional hazards regression, adjusting for the effects of age, sex, lymphoma diagnosis-to-treatment lag time, calendar year, International Prognostic Index score, and NHL grade. RESULTS: The frequency of NHL subtypes was similar in RA patients (n = 65) and controls (n = 1,530). Compared with controls, RA patients with NHL had similar overall survival (hazard ratio [HR] = 0.95; 95% CI, 0.70 to 1.30) but were at lower risk of lymphoma progression or relapse (HR = 0.41; 95% CI, 0.25 to 0.68) or death related to lymphoma or its treatment (HR = 0.60; 95% CI, 0.37 to 0.98), but were more than twice as likely to die from causes unrelated to lymphoma (HR = 2.16; 95% CI, 1.33 to 3.50). CONCLUSION: RA is associated with improved NHL-related outcomes, including a 40% reduced risk of death occurring as a result of lymphoma or its treatment and approximately a 60% lower risk of lymphoma relapse or progression compared with non-RA controls. However, the survival advantage gained in RA from the acquisition of lymphomas with favorable prognoses is negated through an increased mortality from other comorbid conditions.

O'Dell JR, Elliott JR, Mallek JA, Mikuls TR, Weaver CA, Glickstein S, Blakely KM, Hausch R, Leff RD. · University of Nebraska Medical Center, Omaha, USA. · Arthritis Rheum. · Pubmed #16447240 links to  free full text

Abstract: OBJECTIVE: To compare the efficacy of doxycycline plus methotrexate (MTX) versus MTX alone in the treatment of early seropositive rheumatoid arthritis (RA), and to attempt to differentiate the antibacterial and antimetalloproteinase effects of doxycycline. METHODS: Sixty-six patients with seropositive RA of <1 year's duration who had not been previously treated with disease-modifying antirheumatic drugs were randomized to receive 100 mg of doxycycline twice daily with MTX (high-dose doxycycline group), 20 mg of doxycycline twice daily with MTX (low-dose doxycycline group), or placebo with MTX (placebo group), in a 2-year double-blind study. Treatment was started with an MTX dosage of 7.5 mg/week, which was titrated every 3 months until remission was reached (maximum dosage of 17.5 mg/week). The primary end point was an American College of Rheumatology 50% improvement (ACR50) response at 2 years. RESULTS: ACR50 responses were observed in 41.6% of patients in the high-dose doxycycline group, 38.9% of those in the low-dose doxycycline group, and 12.5% of patients in the placebo group. Results of chi-square analysis of the ACR50 response in the high-dose doxycycline group versus that in the placebo group were significantly different (P = 0.02). Trend analysis revealed that the ACR20 response and the ACR50 response were significantly different between groups (P = 0.04 and P = 0.03, respectively). MTX doses at 2 years were not different among groups. Four patients in the high-dose doxycycline group, 2 patients in the low-dose doxycycline group, and 2 patients in the placebo group were withdrawn because of toxic reactions. CONCLUSION: In patients with early seropositive RA, initial therapy with MTX plus doxycycline was superior (based on an ACR50 response) to treatment with MTX alone. The therapeutic responses to low-dose and high-dose doxycycline were similar, suggesting that the antimetalloproteinase effects were more important than the antibacterial effects. Further studies to evaluate the mechanism of action of tetracyclines in RA are indicated.

Mikuls TR, Saag KG, Curtis J, Bridges SL, Alarcon GS, Westfall AO, Lim SS, Smith EA, Jonas BL, Moreland LW, Anonymous00291. · Department of Medicine, University of Nebraska Medica Center and Omaha VA Medical Center, Omaha, NE 68198-3025, USA. · J Natl Med Assoc. · Pubmed #16173331 links to  free full text

Abstract: PURPOSE: To examine the prevalence of osteopenia and/or osteoporosis among African Americans with early rheumatoid arthritis (RA) and to assess the effect of using race/ethnicity-specific normative data. METHODS: Bone mineral density (BMD) of the hip and spine was assessed in African Americans with early RA. To examine the impact of using different normative data on disease classification, we calculated two sets of T scores, the first using sex-matched reference data from Caucasians and the second using data from African Americans. Osteoporosis was defined as a BMD at either site > or =2.5 SD below the young adult mean. Osteopenia was defined as a BMD > or =1 SD and <2.5 SD below this mean. RESULTS: Using Caucasian referent data, 33% (n=48) of patients had osteopenia or worse (n=48, 32.9%) and 5% (n=8) were osteoporotic. With the use of African-American normative data, 55% (n=94) were osteopenic or worse, and 16% (n=27) were osteoporotic. CONCLUSION: African Americans with RA are at risk of osteopenia and/or osteoporosis. Different diagnostic classifications may occur in this population based solely on the normative data used for assessing fracture risk. These results underscore the need for a standardized approach in defining osteopenia and osteoporosis in African Americans.

Mikuls TR, O'Dell JR, Stoner JA, Parrish LA, Arend WP, Norris JM, Holers VM. · Department of Medicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA. · Arthritis Rheum. · Pubmed #15593224 links to  free full text

Abstract: OBJECTIVE: To examine the association of treatment response and disease duration with changes in rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibody levels among patients with rheumatoid arthritis (RA). METHODS: The study sample included 66 RA patients who completed double-blind, randomized clinical protocols and for whom baseline and followup serum samples were available. Anti-CCP and RF levels were measured using commercially available assay kits. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to describe the association of response and disease duration with declines in antibody levels. RESULTS: Patients had a mean +/- SD age of 49.9 +/- 12.0 years and were predominantly female (n = 51; 77%). The mean +/- SD duration between the times at which the baseline and followup serum samples were obtained was 13.7 +/- 8.6 months. Among the 64 subjects with positive antibody at baseline, 33 (52%) experienced a > or =25% reduction in the anti-CCP antibody level during the course of treatment, and 35 patients (55%) had a > or =25% reduction in RF. After adjustment for the baseline anti-CCP antibody level, only a shorter disease duration (< or =12 months) was significantly associated with a decline in the level of anti-CCP antibody (OR 3.0, 95% CI 1.0-8.8), and no association with treatment response was observed. Conversely, treatment response was the only significant determinant of a decrease in RF levels (OR 3.6, 95% CI 1.2-10.4). CONCLUSION: Shorter disease duration predicts greater declines in anti-CCP antibody levels with treatment in RA. Although treatment response is a robust determinant of a decrease in RF, it does not appear to be associated with declines in the anti-CCP antibody level.

Merlino LA, Curtis J, Mikuls TR, Cerhan JR, Criswell LA, Saag KG, Anonymous00131. · College of Public Health, University of Iowa, Iowa City. · Arthritis Rheum. · Pubmed #14730601 links to  free full text

Abstract: OBJECTIVE: Vitamin D is a potent regulator of calcium homeostasis and may have immunomodulatory effects. The influence of vitamin D on human autoimmune disease has not been well defined. The purpose of this study was to evaluate the association of dietary and supplemental vitamin D intake with rheumatoid arthritis (RA) incidence. METHODS: We analyzed data from a prospective cohort study of 29,368 women of ages 55-69 years without a history of RA at study baseline in 1986. Diet was ascertained using a self-administered, 127-item validated food frequency questionnaire that included supplemental vitamin D use. Risk ratios (RRs) and 95% confidence intervals (95% CIs) were estimated using Cox proportional hazards regression, adjusting for potential confounders. RESULTS: Through 11 years of followup, 152 cases of RA were validated against medical records. Greater intake (highest versus lowest tertile) of vitamin D was inversely associated with risk of RA (RR 0.67, 95% CI 0.44-1.00, P for trend = 0.05). Inverse associations were apparent for both dietary (RR 0.72, 95% CI 0.46-1.14, P for trend = 0.16) and supplemental (RR 0.66, 95% CI 0.43-1.00, P for trend = 0.03) vitamin D. No individual food item high in vitamin D content and/or calcium was strongly associated with RA risk, but a composite measure of milk products was suggestive of an inverse association with risk of RA (RR 0.66, 95% CI 0.42-1.01, P for trend = 0.06). CONCLUSION: Greater intake of vitamin D may be associated with a lower risk of RA in older women, although this finding is hypothesis generating.