Rheumatoid Arthritis: Khanna D

Khanna D, Arnold EL, Pencharz JN, Grossman JM, Traina SB, Lal A, MacLean CH. · Division of Immunology, University of Cincinnati and VAMC, OH, USA. · Semin Arthritis Rheum. · Pubmed #16461068 No free full text.

Abstract: OBJECTIVE: To describe the scientific evidence that supports each of the explicit process measures in the Arthritis Foundation's Quality Indicator Set for Rheumatoid Arthritis. METHODS: For each of the 27 measures in the Arthritis Foundation's Quality Indicator set, a comprehensive literature review was performed for evidence that linked the process of care defined in the indicator with relevant clinical outcomes and to summarize practice guidelines relevant to the indicators. RESULTS: Over 7500 titles were identified and reviewed. For each of the indicators the scientific evidence to support or refute the quality indicator was summarized. We found direct evidence that supported a process-outcome link for 15 of the indicators, an indirect link for 7 of the indicators, and no evidence to support or refute a link for 5. The processes of care described in the indicators for which no supporting/refuting data were found have been assumed to be so essential to care that clinical trails assessing their importance have not, and probably never will be, performed. The process of care described in all but 2 of the indicators is recommended in 1 or more practice guidelines. CONCLUSION: There are sufficient scientific evidence and expert consensus to support the Arthritis Foundation's Quality Indicator Set for Rheumatoid Arthritis, which defines a minimal standard of care that can be used to assess health care quality for patients with rheumatoid arthritis.

Khanna D, Tsevat J. · Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, 1000 Veterans Ave, Rm 32-59 Rehabilitation Bldg, Los Angeles, CA 90095, USA. · Am J Manag Care. · Pubmed #18095785 links to  free full text

Abstract: Chronic diseases often have a relapsing and remitting course with substantial impact on function and quality of life. Rheumatoid arthritis (RA) is considered a chronic, inflammatory autoimmune disorder that causes disabling and painful inflammation in the joints that can lead to detrimental effects on health-related quality of life (HRQOL). This article provides an overview of HRQOL and a comprehensive description of the attributes of different instruments to measure it. A wide variety of instruments have been created to measure HRQOL using 2 approaches: health status and health utility. Commonly used generic health status instruments in RA are the Medical Outcomes Study 36-Item Short Form (SF-36) and the Health Assessment Questionnaire Disability Index. Health utility measures are divided into 2 categories, direct and indirect. The most common direct health utility measures are the standard gamble, time to trade-off, and rating scale, while the most commonly used indirect measures are EuroQOL, SF-6D, and the Health Utility Index. Different applications of the instruments are analyzed in this article, including their utility to estimate burden of disease, as end points in clinical trials, and to monitor outcomes in clinical practice, as well as their uses in public policy and in individual decision making.

Ranganath VK, Khanna D, Paulus HE. · Division of Rheumatology, Department of Medicine, University of California, Los Angeles, California 90095-1670, USA. · Clin Exp Rheumatol. · Pubmed #17083757 No free full text.

Abstract: As additional DMARDs have been added to the armamentarium of rheumatologists over the last 60 years, the approach to the treatment of rheumatoid arthritis has changed. Many clinical studies now are geared toward evaluating the concept of eradicating inflammation as a method to seek the elusive goal of sustained remission in RA. One of the first descriptions of remission in 'RA' was by Short et al in 1948, when he documented the natural progression of the disease. Since that time, various criteria have been developed to define RA remission utilizing clinical, radiographic, and laboratory measures. The most stringent of criteria is the American College of Rheumatology Remission Criteria, developed in 1980, which consists of clinical symptoms and signs of inflammation including fatigue, joint pain, morning stiffness, joint tenderness, joint swelling, and erythrocyte sedimentation rate (ESR). Several reports have compared ACR remission criteria to Disease Activity Score (DAS) values to identify equivalent DAS remission values, and these have been extrapolated to modified versions of the DAS, the Simple Disease Activity Index (SDAI), and Clinical Disease Activity Index (CDAI). The ACR remission criteria and the response measures were not designed for use as the target or goal for the clinical management of individual RA patients in routine clinical practice. Nevertheless, rheumatologists yearn for the eradication of inflammation in all RA patients, and attaining remission may be achievable in the future.

Ahmed M, Khanna D, Furst DE. · David Geffen School of Medicine, Los Angeles, CA, USA. · Expert Opin Drug Metab Toxicol. · Pubmed #16863437 No free full text.

Abstract: Rheumatoid arthritis (RA), a chronic inflammatory multisystem disorder marked by joint pain, stiffness, swelling and multiple systemic involvements, requires a multifaceted approach for its management. It includes symptomatic treatment with analgesics as well as disease-modifying medications to alter the course of RA over time. NSAIDS have been widely used for their symptomatic effects, but their use is not free from adverse effects, which may include life-threatening adverse events such as gastrointestinal (GI) bleeding and perforation. Meloxicam, an oxicam derivative that is a member of the enolic acid group of NSAIDs, has recently been approved by the US FDA for use in RA and osteoarthritis. At the FDA-recommended doses meloxicam is COX-2 preferential. By virtue of this COX-2 preferential activity it is expected to have lower GI toxicity as compared with COX-2 nonselective NSAIDs. Clinical trials have shown that meloxicam at 7.5 - 15 mg/day is as effective as diclofenac, piroxicam and naproxen as an anti-inflammatory and analgesic, and was associated with fewer GI adverse effects.

de Buys P, Khanna D, Furst DE. · Division of Immunology, Department of Medicine, University of Cincinnati, Cincinnati, OH, United States. · Autoimmun Rev. · Pubmed #16137610 No free full text.

Abstract: Hematopoietic stem cell transplant (HSCT) for autoimmune diseases has been recognized as a potential treatment for patients who have failed conventional therapy. Autologous (self) donor cells have been preferred over allogeneic (HLA-matched) cells for rescue after high dose immunotherapy, given the previous higher rates of mortality, graft versus host disease (GVHD), and the need for more intense myeloablation associated with the latter. The European Group for bone Marrow Transplantation in Basel Switzerland (EBMT) and various groups within the US funded by the NIH (including the Autologous Blood and Marrow Transplant Registry (ABMTR)) have been pivotal in maintaining registries on patients transplanted as well as promoting homogeneity for future studies including Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and Systemic Sclerosis (SSc). Although, patients transplanted for RA show initial success, relapse of the disease is common. In many, however, a second positive result can be obtained with the addition of DMARD therapy to which they were previously unresponsive, suggesting a "debulking" of disease by HSCT. SLE patients also have a high rate of success after HSCT, although current mortality rates appear high. Transplant in SSc patients has offered durable responses with improving transplant-related mortality related to careful patient selection.

Khanna D, McMahon M, Furst DE. · University of California, Los Angeles 90095, USA. · Arthritis Rheum. · Pubmed #15077286 links to  free full text

This publication has no abstract.

Khanna D, McMahon M, Furst DE. · Division of Rheumatology, David Geffen School of Medicine at UCLA, Los Angeles, California, USA. · Drug Saf. · Pubmed #15061685 No free full text.

Abstract: Tumour necrosis factor-alpha (TNFalpha) is a proinflammatory cytokine that is synthesised by a variety of cell types in response to infectious or inflammatory stimuli. Although TNFalpha plays an adaptive role in immune protection and wound healing at 'physiological' levels, excess TNFalpha production can lead to adverse consequences. TNFalpha is a pivotal cytokine involved in the pathogenesis and progression of rheumatoid arthritis (RA). TNFalpha antagonists have been shown to be effective in the treatment of signs and symptoms of RA and the US FDA has approved three TNFalpha antagonists, etanercept, infliximab, and most recently, adalimumab, for the treatment of RA. However, differences have emerged, with respect to their demonstrated efficacy in other diseases (e.g. Crohn's disease). Worldwide, over half a million patients have been treated with TNFalpha antagonists and concerns regarding their safety have been raised. There is a risk of reactivation of granulomatous diseases, especially tuberculosis, with all three agents and appropriate measures should be taken for detection and treatment of latent infections. An association between non-Hodgkin's lymphoma and treatment with TNFalpha antagonists has been reported, although patients with active, long-standing RA are already known to have an increased incidence of non-Hodgkin's lymphoma. No associations with solid tumours have been found to date. The biological plausibility of lymphomas associated with immunomodulatory agents raises concern and vigilance is appropriate until the relationship is fully characterised. Large phase II and III trials have shown a detrimental effect of TNFalpha antagonists in advanced heart failure and these agents should be avoided in this population. Rare case reports of drug-induced lupus, seizure disorder, pancytopenia and demyelinating diseases have been noted after TNFalpha antagonists and continued vigilance is warranted in patients on TNFalpha antagonists for the development of these diseases. At present there is no evidence implicating TNFalpha antagonists with embryotoxicity, teratogenicity or increased pregnancy loss.

Figueroa F, Braun-Moscovici Y, Khanna D, Voon E, Gallardo L, Luinstra D, Pina X, Henstorf G, Laurence S, Neiman R, Furst D. · Department of Medicine, Universidad de los Andes, Santiago de Chile, Chile. · J Rheumatol. · Pubmed #17216678 No free full text.

Abstract: OBJECTIVE: To examine whether self-assessment of tender and swollen joints by patients with rheumatoid arthritis (RA) can be used to evaluate changes in disease activity instead of joint counts by physicians. METHODS: Eighty-two patients with RA taking part in controlled studies were recruited for investigation. The patient's self-assessment of joint tenderness and swelling was completed both before and 30 minutes after examination by a physician. Examinations of tender and swollen joints by a rheumatologist were performed at baseline and 3 months later. The correlations and verification of agreement of these clinical assessments were analyzed. RESULTS: Within-patient and patient-physician correlations for joint tenderness counts were high (r = 0.96 and 0.78, respectively). Patient-physician correlation for joint swelling counts was still significant, although much lower (r = 0.34). Patients' and physicians' estimations of the change in disease activity over 3 months did not differ (p > 0.76 for all comparisons). CONCLUSION: Joint tenderness counts were consistent when comparing intra-patient and patient-physician assessments, while joint swelling counts were poorly correlated. Patient and physician assessments of change over 3 months were parallel and similar for joint tenderness count. Self-administered tender joint counts might be a useful tool to evaluate the response to therapy in RA.

Khanna D, Park GS, Paulus HE, Simpson KM, Elashoff D, Cohen SB, Emery P, Dorrier C, Furst DE. · Division of Immunology, Department of Medicine, University of Cincinnati and Veterans Affairs Medical Center, Cincinnati, Ohio 45267-0563, USA. · Arthritis Rheum. · Pubmed #16200612 links to  free full text

Abstract: OBJECTIVE: To examine the effect of folic acid on the efficacy of methotrexate (MTX) treatment in rheumatoid arthritis (RA) at 12 months in 2 phase III randomized controlled trials (RCTs) of leflunomide in which MTX was used as a comparator. METHODS: Analyses were restricted to patients randomized to receive MTX who had rheumatoid factor data. The US study recruited 482 patients with active RA; 179 received at least 1 dose of MTX, and all were mandated to receive 1 mg of oral folic acid once or twice daily. The multinational European study recruited 999 patients with active RA; 489 received at least 1 dose of MTX, and oral folic acid was not required, although 50 received folate after developing an adverse event. Because of similar entry criteria for both studies, the data for patients with available primary outcome data at week 52 were pooled (n = 668), and the patients were grouped by folic acid use (n = 225) and nonuse (n = 443). To account for the significant between-study differences in the MTX groups, baseline covariates were adjusted using propensity scores so that folic acid users could be matched with nonusers. This allowed for a comparison of differences in American College of Rheumatology (ACR) 20% improvement criteria at week 52. RESULTS: At study entry, non-folic acid users had a significantly lower mean body weight, shorter mean RA duration, and higher mean disease activity (measured by joint counts, patient's and physician's global assessments, and acute-phase reactant levels). The mean MTX dosage at week 52 was similar in the 2 RCTs. Using propensity score matching techniques, the proportion of patients achieving an ACR 20% response at week 52 averaged 17% higher in the non-folic acid group than in the folic acid group (range 15-21%). Similarly, the proportion of patients achieving ACR 50% and ACR 70% responses averaged 14% (range 12-16%) and 12% (range 9-14%) higher, respectively, in the non-folic acid group. Adverse events were reported in 93% of US study patients and 94% of the multinational study patients. Elevated liver transaminase levels (above the upper limit of normal) were reported in 29% of the US study patients (majority receiving folic acid) and 62% of the multinational study patients (majority not receiving folic acid). CONCLUSION: After using propensity scores to adjust for differences in the baseline characteristics of folic acid users and non-folic acid users, 9-21% fewer MTX-treated RA patients taking folic acid had ACR 20%, 50%, or 70% improvement at 52 weeks compared with those who did not receive folic acid in the 2 phase III RA clinical trials. As a post hoc analysis, the results of this data analysis should be considered "hypothesis generating" and an impetus for future studies regarding the effects of folic acid on the efficacy of MTX in RA.

Mundwiler ML, Maranian P, Brown DH, Silverman JM, Wallace D, Khanna D, Louie J, Furst DE, Weisman MH. · North Suburban Rheumatologists, Des Plaines, IL 60016, USA. · Arthritis Res Ther. · Pubmed #19545417 links to  free full text

Abstract: INTRODUCTION: Magnetic resonance imaging (MRI) may reveal rheumatoid arthritis (RA) changes in the feet when hands are normal. The purpose of this study was to determine the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of a metatarsophalangeal (MTP) erosion on MRI to predict a subsequent radiographic erosion in the same joint. Similar analyses were performed for bone marrow edema, predicting a subsequent MRI erosion. Descriptive results of other lesions are reported. METHODS: Fifty patients with RA of less than 5 years' duration who were rheumatoid factor-positive and/or anti-cyclic citrullinated peptide-positive were recruited. Patients on anti-tumor necrosis factor (TNF) therapy were excluded. Anti-TNF therapy could begin after enrollment. MRI and radiographs of the 3rd, 4th, and 5th MTP joints bilaterally were taken at baseline and at 6, 12, and 24 months. Clinical data were collected. RESULTS: Fifty patients were recruited; 46 patients had suitable data. Results for MRI erosions predicting subsequent radiographic erosions for 6, 12, and 24 months, respectively, were as follows: sensitivity 0.75, 0.60, 0.75; specificity 0.93, 0.94, 0.94; PPV 0.086, 0.10, 0.17; NPV 0.998, 0.995, 0.995. Results for MRI bone marrow edema predicting MRI erosions at 6 and 12 months, respectively, revealed sensitivity 0.50, 0.67; specificity 0.97, 0.97; PPV 0.25, 0.50; NPV 0.99, 0.99. Synovitis was the most common finding and, when present in isolation, resolved on 67.3% of subsequent studies. MRI erosions persisted on subsequent studies with one exception. Forty-six percent of the cohort was on anti-TNF therapy after study inception. CONCLUSIONS: The PPV of MRI erosions to predict subsequent radiographic erosions was low. Similarly, the PPV of bone marrow edema to predict a later MRI erosion was low. Alternatively, the NPV of the absence of an MRI erosion or bone marrow edema predicts that a later radiographic erosion or MRI erosion will likely not develop. Anti-TNF therapies may have resulted in the lower-than-anticipated PPVs. MRI descriptions of bone edema may represent a more critical time to treat in order to avoid damage, whereas an MRI erosion represents more permanent damage. This study suggests that imaging modalities more sensitive than radiographs are necessary to monitor disease in the biologic era.

Amjadi SS, Maranian PM, Paulus HE, Kaplan RM, Ranganath VK, Furst DE, Khanna PP, Khanna D, Anonymous00069. · Division of Rheumatology, University of California Los Angeles School of Medicine, Department of Health Services, 1000 Veteran Avenue, Room 32-59, Rehabilitation Center, Los Angeles, CA 90095, USA. · J Rheumatol. · Pubmed #19369459 No free full text.

Abstract: OBJECTIVE: New methodologies allow the scores for the Health Assessment Questionnaire-Disability Index (HAQ-DI) to be translated into preferences/utility scores. We evaluated the construct validity of the HAQ-DI-derived Short Form-6D (SF-6D) score and assessed its responsiveness to change over 6- and 12-month followup periods in patients with early aggressive rheumatoid arthritis (RA). METHODS: Patients (n=277) participating in an RA observational study completed self-reported measures of symptoms and the HAQ-DI at baseline and at 6 and 12 months. Total Sharp scores, C-reactive protein, and erythrocyte sedimentation rate were assessed along with clinical data. Construct validity was assessed by examining the association between SF-6D score and patient-reported and clinical measures using Spearman correlation coefficients. The responsiveness of SF-6D to change was assessed using patient and physician assessments of the disease as clinical anchors. The magnitude of responsiveness was calculated using SF-6D effect size (ES). RESULT: Mean SF-6D scores were 0.690, 0.720, and 0.723 at baseline and 6 and 12-month followup, respectively. Baseline patient-reported measures had moderate to high correlations with baseline SF-6D (r=0.43 to 0.52); whereas clinical measures had negligible to low correlations with SF-6D (r=0.001 to 0.32). ES was moderate for the groups that were deemed to have improved (ES 0.63-0.75) but negligible to small for those that did not (ES 0.13-0.46). CONCLUSION: Our data support the validity and responsiveness of the HAQ-DI derived SF-6D score in an early RA cohort. These results support the use of the HAQ-DI derived SF-6D in RA cohorts and clinical trials lacking preference-based measures.

Pope JE, Khanna D, Norrie D, Ouimet JM. · Division of Rheumatology, Department of Medicine, University of Western Ontario, London, Canada. · J Rheumatol. · Pubmed #19132791 No free full text.

Abstract: OBJECTIVE: Patient-reported outcomes are used in clinical practice and trials. We studied a large clinical practice to determine the minimally important difference (MID) estimates for (1) the Health Assessment Questionnaire-Damage Index (HAQ-DI): improvement and worsening using patient global assessment anchor; and (2) pain using a patient-reported pain anchor. METHODS: Patients with rheumatoid arthritis (RA; N = 225) had clinic visits at 2 timepoints within 1 year, completed the HAQ-DI and pain visual analog scale (VAS; 0-100 mm), and answered the question, "How would you describe your overall status/overall pain since the last visit?", as much worsened, somewhat worsened, the same, somewhat improved, or much improved. If rated as somewhat improved or worsened, they were defined as the minimally changed subgroups. RESULTS: Eighty-three percent were women, mean age 60 years, with disease duration 11.7 +/- 10.7 years. The baseline HAQ-DI was 0.97 +/- SD 0.76, and at followup 1.0 +/- 0.77 (mean change +0.03 +/- 0.40). The baseline pain VAS was 42.3 +/- 28.8, and at followup 38.5 +/- 27.9 (mean change -2.8 +/- 25.9). The mean (SD) HAQ-DI change score was -0.09 (0.42) for somewhat improved and 0.15 (0.33) for somewhat worsened. The HAQ-DI change for somewhat/much better was -0.20 +/- 0.52, and for somewhat/much worse +0.21 +/- 0.33. For pain, somewhat improved changed by -11.9 mm on the VAS, and somewhat worsened by 6.8 mm. Estimates for HAQ-DI and pain were larger than the for no-change group, 0.03 (0.32) and -3.2 (20.9). CONCLUSION: The MID for HAQ-DI in clinical practice is smaller than it is in trials. This may have implications for observational studies and clinical care.

Khanna D, Pope JE, Khanna PP, Maloney M, Samedi N, Norrie D, Ouimet G, Hays RD. · Division of Rheumatology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California, USA. · J Rheumatol. · Pubmed #19004044 No free full text.

Abstract: OBJECTIVE: To estimate the minimally important difference (MID) for a fatigue visual analog scale (VAS) using patient-reported anchors (fatigue, pain, and overall health). METHODS: Patients with rheumatoid arthritis (RA; n = 307) had 2 clinic visits at a median of 5.9 months apart. They completed a fatigue VAS (0-10 scale) and the retrospective anchor items, "How would you describe your overall fatigue/pain/overall health since the last visit?" with response options: Much worsened, Somewhat worsened, Same, Somewhat better, or Much better. The fatigue anchor was used for primary analysis and the pain/overall health anchors for sensitivity analyses. The minimally changed group was defined by those reporting they were somewhat better or somewhat worsened. RESULTS: The mean [standard deviation (SD)] age was 59.4 (13.2) years, disease duration was 14.1 (11.5) years, and 83% of patients were women. The baseline mean (SD) Health Assessment Questionnaire-Disability Index score was 0.84 (0.75). The baseline fatigue VAS score was 4.2 (2.9) and at followup was 4.3 (2.8) [mean change of -0.07 (2.5); p = not significant]. The fatigue change score (0-10 scale) for Somewhat better and Somewhat worsened for the fatigue anchor averaged -1.12 and 1.26, respectively. Using the pain anchor, the fatigue change score for Somewhat better and Somewhat worsened averaged -0.87 and 1.13; and using the global anchor, the fatigue change score for Somewhat better and Somewhat worsened averaged -0.82 and 1.17, respectively. Effect size estimates using 3 anchors were small for the Somewhat better (range 0.27-0.39) and Somewhat worsened (0.40-0.44) groups, but larger than for the no-change group (0.03-0.08). CONCLUSION: The MID for fatigue VAS is between -0.82 for -1.12 for improvement and is 1.13 to 1.26 for worsening on a 0-10 scale in a large RA clinical practice, and is similar to that seen in RA clinical trials. This information can aid in interpreting fatigue VAS in day-to-day care in clinical practice.

Ranganath VK, Paulus HE, Onofrei A, Khanna D, Reed G, Elashoff DA, Kremer JM, Furst DE. · Department of Medicine, Division of Rheumatology, UCLA Rehabilitation Center, University of California, Los Angeles, California 90095-1670, USA. · J Rheumatol. · Pubmed #18785317 No free full text.

Abstract: OBJECTIVE: We examined the relationships of rheumatoid arthritis (RA), disease duration (DD), number of previous disease modifying antirheumatic drugs (DMARD), and frequency of DMARD changes, with regard to changes in function in patients with RA evaluated by modified Health Assessment Questionnaire (mHAQ) after the start of a new DMARD. METHODS: In total, 889 patients with active RA from the CORRONA database [patients had mHAQ>or=0.5 and/or Disease Activity Score 28-joint count (DAS28)>or=1.6] started a new DMARD (baseline) and had at least one followup visit 6-12 mo later. Change in mHAQ from baseline to followup visit was modeled using univariate/multivariate linear regression analysis. Due to colinearity, separate multivariate regression models were performed including/excluding the predictors disease duration, number of prior DMARD, and frequency of DMARD changes. RESULTS: Baseline age, mHAQ, erythrocyte sedimentation rate (ESR), DAS28, and number of prior DMARD differed across DD groups. The univariate linear regression model showed that higher baseline values of mHAQ, DAS28, swollen joint count (SJC), tender joint count (TJC), Clinical Disease Activity Index (CDAI), ESR, physician global assessment, prednisone use, and subsequent addition/discontinuation of DMARD were associated with improvement of the mHAQ at followup (p=0.05). Multivariate linear regression models showed that mHAQ improvement was associated with shorter DD, higher baseline mHAQ, addition of subsequent DMARD, and the DMARD frequency index (no. previous DMARD/yrs of DD) (p<0.05). Number of DMARD patients used previously was not associated with change of mHAQ in either model. CONCLUSION: Our study demonstrates that in clinical rheumatologic practices, more frequent changes in DMARD are associated with greater improvement in function (by mHAQ). It does not support the idea that number of previous DMARD used predicts response. Indirectly, these data support the concept that DMARD should be changed if optimal responses are not achieved within a specified time.

Motivala SJ, Khanna D, FitzGerald J, Irwin MR. · UCLA Semel Institute for Neuroscience and Human Behavior, Cousins Center for Psychoneuroimmunology, University of California, Los Angeles 90095-7076, USA. · Arthritis Rheum. · Pubmed #18240230 links to  free full text

Abstract: OBJECTIVE: Psychological stress is thought to aggravate disease activity in rheumatoid arthritis (RA), although the physiologic mechanisms are unclear. Tumor necrosis factor alpha (TNFalpha) is an inflammatory cytokine involved in the exacerbation of RA, and TNFalpha antagonists have emerged as efficacious treatments. The purpose of this study was to determine whether RA patients show increased monocyte production of TNFalpha following acute psychological stress and whether such responses are abrogated in RA patients taking TNFalpha antagonists. METHODS: A standardized stress task was administered to 3 groups of subjects: RA patients taking TNFalpha antagonists, RA patients not taking such medications, and healthy controls. Lipopolysaccharide-stimulated monocyte production of inflammatory cytokines was repeatedly measured using intracellular staining and flow cytometry. Subjective stress, cardiovascular responses, adrenocorticotropic hormone (ACTH) levels, and cortisol levels were also measured. RESULTS: The stress task induced increases in subjective stress, cardiovascular activity, and levels of ACTH and cortisol, with similar responses in the 3 groups. In addition, the stress task induced a significant increase (P < 0.001) in monocyte production of TNFalpha among RA patients who were not taking TNFalpha antagonists. However, monocyte production of TNFalpha did not change following psychological stress in RA patients taking TNFalpha antagonists or in healthy controls. CONCLUSION: Brief psychological stress can trigger increased stimulated monocyte production of TNFalpha in RA patients. The use of TNFalpha antagonists protects against stress activation of cellular markers of inflammation in RA patients.

Charles-Schoeman C, Khanna D, Furst DE, McMahon M, Reddy ST, Fogelman AM, Paulus HE, Park GS, Gong T, Ansell BJ. · Division of Rheumatology, University of California, Los Angeles David Geffen School of Medicine, Los Angeles, California 90095-1670, USA. · J Rheumatol. · Pubmed #17552046 No free full text.

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) have a 2-3-fold increased risk of myocardial infarction. Recent work suggests that plasma high density lipoproteins (HDL) from patients with RA are more proinflammatory than HDL from controls. We examined the effects of atorvastatin 80 mg daily on the inflammatory properties of HDL and clinical disease activity in RA. METHODS: Twenty subjects with active RA (mean Disease Activity Score 5.13 +/- 0.92) without dyslipidemia and no history of coronary artery disease were randomized in a double-blind placebo-controlled trial to receive 80 mg of atorvastatin (A) or placebo (P) daily in addition to stable antirheumatic drug therapy. Disease activity variables were followed over 12 weeks and the anti-/proinflammatory properties of HDL were determined by a cell-free assay (CFA) that measures lipid oxidation products. RESULTS: After 12 weeks, subjects completing the A protocol had a mean reduction in CFA values of 14.8 +/- 21.7%, while subjects completing P protocol had a mean increase in CFA values of 7.1 +/- 13.2% (p = 0.026). There was a trend for a decrease in highly sensitive C-reactive protein (hs-CRP) over 12 weeks in the A group compared to an increase in hs-CRP in the P group (p > 0.05), but changes in measures of clinical disease activity and plasma cytokine/intercellular adhesion molecule-1 levels were not significantly different in the A and P groups. CONCLUSION: In patients with active RA, HDL was rendered more antiinflammatory by high-dose atorvastatin compared to placebo. Functional characterization of HDL may warrant further investigation as a method of cardiovascular risk assessment in RA patients without traditional coronary risk factors. (ClinicalTrials.gov number NCT00356473).

Ranganath VK, Yoon J, Khanna D, Park GS, Furst DE, Elashoff DA, Jawaheer D, Sharp JT, Gold RH, Keystone EC, Paulus HE, Anonymous00172. · UCLA, Department of Medicine, Division of Rheumatology, Rehabilitation Center, Room 32-59, 1000 Veteran Avenue, Los Angeles, CA 90095-1670, USA. · Ann Rheum Dis. · Pubmed #17472996 No free full text.

Abstract: OBJECTIVE: To evaluate concordance and agreement of the original DAS44/ESR-4 item composite disease activity status measure with nine simpler derivatives when classifying patient responses by European League of Associations for Rheumatology (EULAR) criteria, using an early rheumatoid factor positive (RF+) rheumatoid arthritis (RA) patient cohort. METHODS: Disease-modifying anti-rheumatic drug-naïve RF+ patients (n = 223; mean duration of symptoms, 6 months) were categorised as ACR none/20/50/70 responders. One-way analysis of variance and two-sample t tests were used to investigate the relationship between the ACR response groups and each composite measure. EULAR reached/change cut-point scores were calculated for each composite measure. EULAR (good/moderate/none) responses for each composite measure and the degree of agreement with the DAS44/ESR-4 item were calculated for 203 patients. RESULTS: Patients were mostly female (78%) with moderate to high disease activity. A centile-based nomogram compared equivalent composite measure scores. Changes from baseline in the composite measures in patients with ACRnone were significantly less than those of ACR20/50/70 responders, and those for ACR50 were significantly different from those for ACR70. EULAR reached/change cut-point scores for our cohort were similar to published cut-points. When compared with the DAS44/ESR-4 item, EULAR (good/moderate/none) percentage agreements were 92 with the DAS44/ESR-3 item, 74 with the Clinical Disease Activity Index, and 80 with the DAS28/ESR-4 item, the DAS28/CRP-4 item and the Simplified Disease Activity Index. CONCLUSION: The relationships of nine different RA composite measures against the DAS44/ESR-4 item when applied to a cohort of seropositive patients with early RA are described. Each of these simplified status and response measures could be useful in assessing patients with RA, but the specific measure selected should be pre-specified and described for each study.

Furst DE, Gaylis N, Bray V, Olech E, Yocum D, Ritter J, Weisman M, Wallace DJ, Crues J, Khanna D, Eckel G, Yeilding N, Callegari P, Visvanathan S, Rojas J, Hegedus R, George L, Mamun K, Gilmer K, Troum O. · Division of Rheumatology, Department of Medicine, University of California Los Angeles, CA 90095-1670, USA. · Ann Rheum Dis. · Pubmed #17412737 links to  free full text

Abstract: OBJECTIVE: To incorporate a new trial design to examine clinical response, cytokine expression and joint imaging in patients with rheumatoid arthritis (RA) switching from etanercept to infliximab treatment. METHODS: A randomised, open-label, clinical trial of 28 patients with an inadequate response to etanercept was conducted. Eligible patients received background methotrexate and were randomised 1:1 to discontinue etanercept and receive infliximab 3 mg/kg at weeks 0, 2, 6, 14 and 22, or to continue etanercept 25 mg twice weekly. Data were analysed for clinical response, serum biomarker levels, radiographic progression, MRI and adverse events. RESULTS: At week 16, 62% of infliximab-treated patients achieved American College of Rheumatology 20% criteria for improvement in RA (ACR20) responses compared with 29% of etanercept-treated patients. A 30.8% decrease from baseline in Disease Activity Score 28 was observed in patients receiving infliximab, compared with a 16.0% decrease in patients receiving etanercept. ACR20 and American College of Rheumatology 50% criteria for improvement in RA responses correlated at least minimally with intracellular adhesion molecule-1 and interleukin 8 in patients receiving infliximab. 38% of patients who were switched to infliximab showed reductions in Health Assessment Questionnaire scores (>0.4), compared with 0% of patients receiving etanercept. MRI analyses were inconclusive. Both drugs were well tolerated; 54% of infliximab-treated patients and 50% of etanercept-treated patients reported adverse events. CONCLUSIONS: In this exploratory, open-label trial (with single-blind evaluator), patients were randomised to continue with etanercept or switch to infliximab. The small sample size of this hypothesis-generating study was underpowered to show statistical differences between groups. There was a numerical trend favouring patients who switched to infliximab, therefore warranting further study with a more rigorous design.

Khanna D, Oh M, Furst DE, Ranganath V, Gold RH, Sharp JT, Park GS, Keystone EC, Paulus HE, Anonymous00313. · Division of Immunology, Department of Medicine, University of Cincinnati and the Veterans Affairs Medical Center, Cincinnati, Ohio 45267-0563, USA. · Arthritis Rheum. · Pubmed #17394230 links to  free full text

Abstract: OBJECTIVE: To evaluate published proposed definitions of minimal disease activity (MDA) and remission in patients with early rheumatoid arthritis (RA). METHODS: The cohort comprised disease-modifying antirheumatic drug (DMARD)-naive patients with early seropositive active RA (n = 200) treated with traditional DMARDs in the prebiologic era. MDA definitions included Disease Activity Score in 28 joints (DAS28) <or=2.85, or achieving 5 of 7 World Health Organization (WHO)/International League of Associations for Rheumatology (ILAR) core set measure thresholds as proposed by the Outcome Measures in Rheumatology Clinical Trials. Other MDA definitions included Simplified Disease Activity Index (SDAI) score <or=11 and Clinical Disease Activity Index (CDAI) score <or=10. Remission definitions included American College of Rheumatology (ACR) remission, DAS28 <2.6, DAS28 <2.4, achieving all 7 WHO/ILAR core set measure thresholds, SDAI <or=3.3, and CDAI <or=2.8. Physical function was assessed using the Health Assessment Questionnaire (HAQ) disability index (DI) and radiographic progression was assessed using the Sharp score. RESULTS: At baseline, no patients were in MDA or remission. Depending on the MDA definition, 20-32%, 27-32%, and 30-48% were in MDA at 6, 12, and 24 months, respectively. Depending on the remission definition, 0.7-15%, 0-24%, and 0-33% were in remission at 6, 12, and 24 months, respectively. For example, at 6 months, lowest (highest) responses for MDA were seen with DAS28 <or=2.85 (SDAI <or=11) and for remission with ACR remission criteria (DAS28 <2.6). Patients who achieved either MDA or remission had lower HAQ DI and radiographic scores compared with patients who achieved neither. CONCLUSION: Our study demonstrated that different proportions of patients were classified as MDA or remission depending on the definition used. This has implications in predefining MDA or remission for a clinical trial or to establish goals for optimum management of RA in clinical practice.

Park GS, Wong WK, Oh M, Khanna D, Gold RH, Sharp JT, Paulus HE. · Department of Biostatistics, School of Public Health, University of California, Los Angeles, CA 90095-1772, USA. · Stat Methods Med Res. · Pubmed #17338292 No free full text.

Abstract: Various methods are used to measure radiographic joint damage in patients with rheumatoid arthritis (RA), but determining proportions of responsive patients is difficult. A key problem in observational studies when assessing damage outcomes is incorporating time to treatment initialization and adjusting for observed baseline differences. We examined five different definitions to select an appropriate index to classify radiographic damage in RA patients as progressive or nonprogressive. In addition, we compared different times from symptom onset to treatment and their effects on patient radiographic categorization. Propensity scores to adjust for baseline differences, including time since symptom onset, were used to match those treated early with those treated later using the stratification, radius, nearest neighbor and kernel methods. The mean effect of treatment on the treated was computed for each matching method. Observational data were analyzed for 185 early RA patients from the Western Consortium study followed six to sixty months (mean thirty-one months). For the selected index, 75 patients were categorized as nonprogressors; they had significantly lower disease activity, more clinical improvement and were treated earlier than the progressors. Of those treated within three months of symptom onset, 57% were classified as radiographically progressive versus 35% of those treated later (P = 0.0058). However, after propensity score adjustment for baseline differences, we noticed nonsignificant (P > 0.05) nonprogression in patients given earlier treatment. We conclude that propensity score analysis reduced but did not remove all bias.

Ahmed M, Luggen M, Herman JH, Weiss KL, Decourten-Myers G, Quinlan JG, Khanna D. · Division of Immunology, Department of Medicine, University of Cincinnati Medical Center, 231 Albert Sabin Way, Cincinnati, OH 45267, USA. · J Rheumatol. · Pubmed #16981287 No free full text.

Abstract: Tumor necrosis factor-a (TNF-a) inhibition, used in the treatment of rheumatoid arthritis (RA), is associated with central nervous system (CNS) events including new onset and/or exacerbations of pre-existing demyelinating neurological diseases. We describe a patient with refractory RA where adalimumab, a fully humanized IgG1 monoclonal antibody against TNF-a, may have contributed to the development of meningoencephalitis, with brain biopsy suggestive of hypertrophic pachymeningitis, a rare complication of this disease. The patient had recurrence of neurological symptoms upon repeated administration of adalimumab, and resolution of symptoms after withdrawal.

Cole JC, Khanna D, Clements PJ, Seibold JR, Tashkin DP, Paulus HE, Irwin MR, Motivala SJ, Furst DE. · Consulting Measurement Group, Huntington Beach, CA 91403, USA. · Qual Life Res. · Pubmed #16826439 No free full text.

Abstract: OBJECTIVE: Structural validity for the Health Assessment Questionnaire-Disability Index (HAQ-DI) has recently been provided for patients with rheumatoid arthritis (RA). The goal of the current study was to examine the structural validity of the HAQ-DI in patients with systemic sclerosis (SSc, scleroderma) and to compare its performance with that in patients with RA. METHODS: The HAQ-DI structural validity was first assessed in a sample of 100 scleroderma patients using confirmatory factor analysis. Second, the similarity of factor structures between SSc patients (n = 291) and RA patients (n = 278) was tested using a multigroup structural validity model to assure that comparison of scores between these two diagnostic groups is appropriate. RESULTS: Results yielded a single-factor HAQ-DI score which favored the current scoring system of the HAQ-DI (model fit was CFI = 0.99 and RMSEA = 0.04). Moreover, even the most stringent model of multigroup structural validity affirmed the similarity between SSc and RA patients on the HAQ-DI (model fit was CFI = 0.99 and RMSEA = 0.04) nor was it different from a model without any demands on group similarity: CFI difference = 0.007; chi(2) = 4.29, df = 26, p=0.99. CONCLUSION: The current results indicate that a single-factor HAQ-DI is appropriate for future clinical trials in scleroderma and, in addition, HAQ-DI scores among patients with SSc and early RA can be compared legitimately with one another.

Khanna D, Wu H, Park G, Gersuk V, Gold RH, Nepom GT, Wong WK, Sharp JT, Reed EF, Paulus HE, Tsao BP, Anonymous00374. · David Geffen School of Medicine at the University of California, Los Angeles, and the Veterans Affairs Medical Center, Cincinnati, Ohio 45267-0563, USA. · Arthritis Rheum. · Pubmed #16572445 links to  free full text

Abstract: OBJECTIVE: To determine whether the tumor necrosis factor alpha (TNFA) -308 guanine-to-adenosine polymorphism and/or the shared epitope (SE) is associated with radiographic damage in patients with early rheumatoid arthritis (RA). METHODS: The cohort consisted of 189 patients with early seropositive RA (median 5.6 months since symptom onset) who had active disease, no previous disease-modifying antirheumatic drug treatment, and >or=2 sets of scored radiographs of the hands/wrists and forefeet. TNFA -308 polymorphism was analyzed by polymerase chain reaction pyrosequencing. The SE was defined as presence of any 1 of the following HLA-DRB1 alleles: *0101, *0102, *0401, *0404, *0405, *0408, *0410, *1001, *1402, or *1406. Radiographic progression was assessed by the total Sharp score. RESULTS: Using a weighted least-squares regression analysis, patients with the -308 TNFA AA plus AG genotypes (n=49) had significantly higher rates of progression in erosion scores (median 0.84 versus 0.48 units/year), joint space narrowing (JSN) scores (0.42 versus 0.04), and total Sharp scores (1.70 versus 0.61) compared with patients with the TNFA GG genotype (n=140). Presence of the SE (n=137) was associated with significantly lower progression rates (per year) for total Sharp scores (median 0.9 versus 1.25 units/year) and JSN scores (0.04 versus 0.41), but not for erosion scores (0.50 versus 0.61) compared with patients without the SE (n=52). In a least-squares multiple linear regression model, the presence of the AA plus AG genotypes was associated with a significantly higher progression rate after adjusting for the presence of the SE, interaction between the SE and the AA plus AG genotypes, baseline log C-reactive protein level, Health Assessment Questionnaire Disability Index, total Sharp score, swollen joint count, and presence of osteophytes (osteoarthritis). There was a strong linkage disequilibrium between DRB1*0301 and TNFA polymorphism (D'=0.84, r2=0.45, P<0.001). CONCLUSION: This study showed an association between the TNFA -308 polymorphism and progression of radiographic damage in patients with early seropositive RA. This association appeared to be independent of the SE, but might be dependent on other genetic variants in linkage disequilibrium with the -308 TNFA A allele and DRB1*0301. Further studies should be conducted to validate these results in both longitudinal observational cohorts and randomized clinical trials.

Cole JC, Motivala SJ, Khanna D, Lee JY, Paulus HE, Irwin MR. · University of California, Los Angeles, CA, USA. · Arthritis Rheum. · Pubmed #16082630 links to  free full text

Abstract: OBJECTIVE: The extensively used Health Assessment Questionnaire Disability Index (HAQ-DI) has been well received by the research and clinical community, notably because of its measurement strengths including reliability and stability of scores over time, utility in observational studies and clinical trials, predictive relationship with morbidity and mortality in rheumatoid arthritis (RA), and its translation for use in different countries. However, HAQ-DI scoring has not been validated. The purpose of this study was to examine the structural validity of the HAQ-DI and evaluate the latent factors underlying HAQ-DI scoring. METHODS: This study used a cross-validation approach on a total of 278 patients with RA. Exploratory and confirmatory factor analyses were performed. RESULTS: Results yielded a single-factor HAQ-DI score, which favored the current scoring system of the HAQ-DI. Additionally, modification indices suggested improved model fit with the secondary inclusion of correlated residual scores from a motor skills subdomain. CONCLUSION: The current study provides the first validation of the HAQ-DI scoring system as determined by its latent factor structure. In addition, the findings suggest some benefit from a secondary interpretation of the scores based on domains that measure motor skills.

Khanna D, Ranganath VK, Fitzgerald J, Park GS, Altman RD, Elashoff D, Gold RH, Sharp JT, Furst DE, Paulus HE, Anonymous00023. · University of California at Los Angeles, USA. · Arthritis Rheum. · Pubmed #16052588 links to  free full text

Abstract: OBJECTIVE: To investigate the impact of patient age at symptom onset on radiographic joint damage at study entry, and on subsequent progression of damage in a cohort of patients with early seropositive rheumatoid arthritis (RA). METHODS: We studied 186 patients with RA of <15 months' duration. All patients had active disease and had not received disease-modifying antirheumatic drugs. At study entry and during followup, total Sharp scores (TSS), RA-associated joint space narrowing (RA-JSN), and erosions were determined on hand and foot radiographs. Baseline radiographs were also scored for osteoarthritis (OA)-related JSN (OA-JSN) and osteophytes. Older patients (>55 years) and younger patients (</=55 years) were compared by t-test, Mann-Whitney U test, chi-square, or Fisher's exact test. Multiple linear regression models were also constructed. RESULTS: The older group (n = 74) had a higher baseline total Sharp score (median 6.21) compared with the younger group (n = 112) (median 2.33) (P = 0.0002). This was mainly due to a higher baseline JSN score in the older group (median 3.96 versus 1.08) and not to differences in erosion score (median 0.91 versus 0.70). Disease activity and duration of RA symptoms were similar in the 2 groups, as were progression rates of the TSS, JSN score, and erosion score. At baseline, 26% of patients had osteophytes, with a prevalence of 13% in the younger age group and 50% in the older group. The presence of OA-JSN was highly correlated with the presence of osteophytes (r = 0.72). Also, increased age and RA-JSN were associated with increased severity of osteophytes and OA-JSN at baseline. Multiple linear regression analysis showed that both age and hand osteophytes contributed to the increase in baseline RA-JSN score and TSS, but not to erosion score. CONCLUSION: In a cohort of patients with early RA, an increase in the baseline RA-JSN score and TSS can be accounted for in part by the presence of hand OA.