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ID PMID Title PublicationDate abstract
19148218 B-cell-directed therapy for inflammatory skin diseases. 2009 Feb The basic understanding of inflammatory dermatoses and autoimmune-mediated skin disorders has greatly advanced and broadened our understanding of underlying immune mechanisms that shape the complex network of chronic inflammation and autoimmunity. The new treatment options for psoriasis exemplify how new insights into (auto)immune responses, especially the role and function of various immune cells and proinflammatory cytokines, may lead to new therapeutic strategies. The concept of targeting B cells in autoimmune-mediated disorders is closely related to the discovery of autoantibodies and their cellular origin. However, the appreciation of B cells in autoimmunity has significantly changed and is not limited to their role as progenitors of autoantibody secreting plasma cells. Recent investigations of various inflammatory skin diseases, that is, autoimmune blistering disorders, collagen vascular diseases, and atopic dermatitis, actually support the concept that B cells might be as important as T cells in the etiopathogenesis of these disorders. The striking clinical improvement seen in patients with rheumatoid arthritis following B-cell depletion with the anti-CD20 mAb rituximab has tremendously catalyzed the interest in B-cell-targeted therapies in different autoimmune diseases. Future translational and clinical investigations are mandatory to precisely define the role and the contribution of impaired B-cell function in (auto)immune-mediated skin diseases.
19089533 Clinical and histopathological features of myopathies in Japanese patients with anti-SRP a 2009 To elucidate the clinical and histopathological features associated with autoantibodies to the signal recognition particle (SRP), we have studied 23 Japanese patients with this specificity among 3,500 patients with polymyositis/dermatomyositis and other connective tissue diseases. Anti-SRP antibodies were determined based on analysis of RNA and protein components by immunoprecipitation assays. The pathological analysis was performed by using special stainings including alkaline phosphatase, myosin ATPase, and modified Gomori trichrome stainings. Twenty-one (92%) of these 23 patients had myositis, 8 of whom (38%) required cytotoxic agents or intravenous immunoglobulin therapy in addition to corticosteroid therapy. Four patients (16%) had rheumatoid arthritis, two of whom had no features of myositis. Muscle biopsy specimens of 11 patients were examined histologically in detail. All 11 had muscle fiber necrosis and/or regeneration, but only one had infiltration of inflammatory cells. Six of the 11 (55%) patients showed type I fiber predominance by ATPase staining, while eight control myositis patients without anti-SRP antibodies did not. There was no correlation of other neurogenic features in histology with the presence of anti-SRP antibodies. These studies suggest that anti-SRP autoantibodies are most likely to be related to myopathies that are resistant to corticosteroid therapy and without inflammation histopathologically.
18762934 Limits of add-on trials: antirheumatic drugs. 2009 Jan PURPOSE: This paper assesses the design of clinical studies used in the process of regulatory approval, focusing on how add-on studies affect regulatory decisions. METHODS: The sample case taken is that of the new agents for rheumatoid arthritis (RA) authorised by the European Medicine Agency (EMEA). The European Public Assessment Reports (EPARs) accompanying the marketing authorisations were the source of information on the studies presented in the registration dossiers. RESULTS: The recently approved anti-RA agents are all indicated in combination with methotrexate (MTX) for treating adults with active RA who have responded inadequately to disease-modifier drugs (DMARDs). The add-on design was frequently used in registration studies. For infliximab, etanercept, adalimumab and rituximab, add-on trials contributed, together with parallel-group trials, to gaining the approval as combination therapy. Anakinra and abatacept were authorised on the basis of add-on trial results only. CONCLUSIONS: Add-on trials do not allow assessment of the intrinsic efficacy and safety of new agents and their value as alternatives to available treatments. The indications granted for the new anti-RA agents do not specify whether newer drugs can replace standard treatments in nonresponders, can do better in the overall patient population or can be used as first-line treatment.
18541233 Search for a functional glucocorticoid receptor in the mammalian lens. 2009 Feb Prolonged glucocorticoid treatment of medical conditions such as rheumatoid arthritis or asthma can lead to the formation of a posterior subcapsular cataract as a negative side effect. Currently, the only treatment for this cataract is surgery because very little is known about the mechanism of glucocorticoid action in the mammalian lens. Understanding of a lens glucocorticoid response is essential for the treatment and prevention of a steroid induced cataract. It has been suggested that glucocorticoids exert their effects on the lens indirectly, non-specifically, or through non-classical mechanisms. While these modes of action may contribute to the formation of glucocorticoid induced posterior subcapsular cataract, the finding of a classical, specific, functional lens glucocorticoid receptor suggests that glucocorticoids target lens epithelial cells directly, specifically, and similar to what has been observed in other cells types. This review explores the discovery of the glucocorticoid receptor in humans lens epithelial cells and the lens specific glucocorticoid response. The distinct changes in lens epithelial cell signaling pathways (MAPK and PI3K-AKT) suggest that glucocorticoids modulate several cellular functions and may explain why a lens glucocorticoid response has been difficult to elucidate.
20662067 Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes o 2010 Nov OBJECTIVE: To explore biologic correlates to age at onset in patients with juvenile idiopathic arthritis (JIA) using peripheral blood mononuclear cell (PBMC) gene expression analysis. METHODS: PBMCs were isolated from 56 healthy controls and 104 patients with recent-onset JIA (39 with persistent oligoarticular JIA, 45 with rheumatoid factor-negative polyarticular JIA, and 20 with systemic JIA). RNA was amplified and labeled using NuGEN Ovation, and gene expression was assessed with Affymetrix HG-U133 Plus 2.0 GeneChips. RESULTS: A total of 832 probe sets revealed gene expression differences (false discovery rate 5%) in PBMCs from children with oligoarticular JIA whose disease began before age 6 years (early-onset disease) compared with those whose disease began at or after age 6 years (late-onset disease). In patients with early-onset disease, there was greater expression of genes related to B cells and less expression of genes related to cells of the myeloid lineage. Support vector machine analyses identified samples from patients with early- or late-onset oligoarticular JIA (with 97% accuracy) or from patients with early- or late-onset polyarticular JIA (with 89% accuracy), but not from patients with systemic JIA or healthy controls. Principal components analysis showed that age at onset was the major classifier of samples from patients with oligoarticular JIA and patients with polyarticular JIA. CONCLUSION: PBMC gene expression analysis reveals biologic differences between patients with early-and late-onset JIA, independent of classification based on the number of joints involved. These data suggest that age at onset may be an important parameter to consider in JIA classification. Furthermore, pathologic mechanisms may vary with age at onset, and understanding these processes may lead to improved treatment of JIA.
21145125 The soluble Interleukin 6 receptor: generation and role in inflammation and cancer. 2011 Jun Soluble cytokine receptors are frequently found in human serum, most of them possessing antagonistic properties. The Interleukin 6 receptor (IL-6R) is found as a transmembrane protein on hepatocytes and subsets of leukocytes, but soluble isoforms of the IL-6R (sIL-6R) are generated by alternative splicing or by limited proteolysis of the ADisintegrin And Metalloproteinases (ADAM) gene family members ADAM10 and ADAM17. Importantly, the sIL-6R in complex with its ligand Interleukin 6 (IL-6) has agonistic functions and requires cells expressing the signal transducing ß-receptor gp130 but not the membrane-bound IL-6R. We have called this process IL-6 trans-signaling. Naturally occurring isoforms of soluble gp130 (sgp130), which are generated by alternative splicing, are natural inhibitors of IL-6 trans-signaling, leaving IL-6 classic signaling via the membrane-bound IL-6R unaffected. We used recombinant sgp130Fc protein and recently generated transgenic mice expressing high levels of sgp130Fc to discriminate between classic and trans-signaling in vivo, and demonstrated that IL-6 trans-signaling is critically involved in generation and maintenance of several inflammatory and autoimmune diseases including chronic inflammatory bowel disease, rheumatoid arthritis, peritonitis and asthma, as well as inflammation-induced colon cancer.
21122476 Endotherapia: a new frontier in the treatment of multiple sclerosis and other chronic dise 2010 Nov Currently, several drugs are accessible for the treatment of many chronic diseases (multiple sclerosis, amyotrophic lateral sclerosis, rheumatoid arthritis, etc.), but most of them have a large list of side effects. Here, we propose a new therapeutic approach called Endotherapia for the treatment of chronic diseases. This approach combines a biomedical evaluation of circulating immunoglobulins directed against specific self-antigens and self-antigens modified by free radicals. The therapy proposed here is a "tailor-made" combination of small molecules (e.g., fatty acids and vitamins) linked to a non-immunogenic chain of poly-L.Lysine (PLL). Each individual linkage or PLL derivative offers great advantages, such as an increase in the half-life of the active small molecules. Endotherapia also involves clinical aspects, allowing an exact diagnosis of the disease and the identification of specific circulating antibodies in the serum of patients in several clinical trials (e.g., multiple sclerosis). Endotherapia has been shown to be very safe. In summary, Endotherapia is the result of an immunopathological strategy addressing chronic incurable diseases with a multifactorial etiology. In light of the results obtained, it seems that Endotherapia is a promising therapy for chronic diseases, with no side effects, which is evidently mandatory in the management of long-term pathologies.
21036646 Diagnostic strategy for patients with hypogammaglobulinemia in rheumatology. 2011 May The discovery of hypogammaglobulinemia, which is defined as a plasmatic level of immunoglobulin (Ig) under 5 g/L is rare in clinical practice. However, the management of immunodepressed patients in rheumatology, sometimes due to the use of immunosuppressive treatments such as anti-CD20 in chronic inflammatory rheumatisms, increases the risk of being confronted to this situation. The discovery of hypogammaglobulinemia in clinical practice, sometimes by chance, must never be neglected and requires a rigorous diagnosis approach. First of all, in adults, secondary causes, in particular lymphoid hemopathies or drug-related causes (immunosuppressors, antiepileptics) must be eliminated. A renal (nephrotic syndrome) or digestive (protein-losing enteropathy) leakage of Ig is also possible. More rarely, it is due to an authentic primary immunodeficiency (PID) discovered in adulthood: common variable immunodeficiency (CVID) which is the most frequent form of PID, affects young adults between 20 and 30 years and can sometimes trigger joint symptoms similar to those in rheumatoid arthritis; or Good syndrome, which associates hypogammaglobulinemia, thymoma and recurrent infections around the age of 40 years. In most cases, after confirming hypogammaglobulinemia on a second test, biological examinations and thoracic-abdominal-pelvic CT scan will guide the diagnosis, after which the opinion of a specialist can be sought depending on the findings of the above examinations. At the end of this review, we provide a decision tree to guide the clinician confronted to an adult-onset hypogammaglobulinemia.
20962632 Skeletal manifestations of systemic autoimmune diseases. 2010 Dec PURPOSE OF REVIEW: There is an increased risk of osteoporotic fractures and osteonecrosis often at a young age among patients with certain systemic autoimmune diseases. The loss of bone mineral density and bone integrity seen with these diseases often cannot be explained by traditional risk factors alone. In this review, we focus on rheumatoid arthritis and systemic lupus erythematosus, two systemic autoimmune diseases in which skeletal manifestations have been well described. RECENT FINDINGS: There is recent evidence that autoimmunity and its associated inflammation and vitamin D deficiency play key roles in the pathogenesis of adverse skeletal effects. SUMMARY: Understanding these processes carries implications for the prevention and treatment of osteoporosis and osteonecrosis among patients with autoimmune diseases.
20926873 What is the patient's perspective: How important are patient-reported outcomes, quality of 2010 Inflammatory bowel disease (IBD) is known to influence physical, psychological, familial and social dimensions of life. Over the past two decades, attention has been focused on the ability of IBD to alter patients' quality of life. A number of general and disease-specific scales have been used to assess quality of life in patients with IBD. The Inflammatory Bowel Disease Questionnaire (IBDQ) is the most widely disease-specific tool used in clinical trials. Forty to fifty million individuals in the USA now live with potentially disabling conditions. Disability usually refers to an individual's inability to perform a task successfully. Disability refers to the problems that are experienced in different areas or health domains, whereas quality of life refers to how the individual feels about these limitations and restrictions. Data about disability are objective descriptions that differ from subjective appraisals such as quality of life, well-being, and personal satisfaction with life. For instance, difficulties in walking (disability) may be in stark contrast to how the individual feels about this difficulty (quality of life). It should be emphasized that the concepts of health-related quality of life and disability are different but not mutually exclusive. When compared to quality of life, disability remains poorly investigated in IBD. Work is the only dimension of disability that has been widely assessed in IBD. Similar to multiple sclerosis and rheumatoid arthritis, developing a specific instrument capable of evaluating disability in IBD is a prerequisite to undertaking clinical trials aimed at identifying therapies capable of changing their clinical course.
20865107 Incidence and risk of chondrolysis in Denmark: A nationwide population-based study. 2010 Aug 9 BACKGROUND: Chondrolysis is a rare disease with destruction of cartilage of joints. Incidence and risk factors have not been studied in a formal epidemiologic population-based setting. METHODS: We used the Danish National Registry of Patients (NRP) covering all Danish hospitals to identify all cases of chondrolysis from 1994 to 2008. Incidence rates were estimated using the general population as the denominator. For each chondrolysis patient, 10 age-matched population controls were sampled for a case-control analysis. For cases and controls, we ascertained in the NRP history of diabetes, rheumatoid arthritis, orthopedic surgery, including surgery of shoulder and upper arm, injury to shoulder girdle or upper arm, and treatment with pain pump. We determined the prevalence of these risk factors in cases and controls, and computed odds ratios (OR). RESULTS: We identified 43 patients with chondrolysis in the 15-year study period. The incidence rate was 5.5 per 10,000,000 person-years. Diabetes was more prevalent in chondrolysis cases, compared with the 430 controls (OR = 6.7; 95% confidence intervals [CI]: 1.1-39.9). Orthopedic surgery was also associated with an increased risk of chondrolysis (OR = 28.8, 95% CI: 11.0-75.6), while previous injury was not (OR = 0.8; 95% CI: 0.1-5.9). CONCLUSION: Chondrolysis was rarely diagnosed in Denmark. Diabetes and orthopedic surgery may be risk factors.
20803050 Reimbursement of pharmaceuticals: reference pricing versus health technology assessment. 2011 Jun Reference pricing and health technology assessment are policies commonly applied in order to obtain more value for money from pharmaceuticals. This study focussed on decisions about the initial price and reimbursement status of innovative drugs and discussed the consequences for market access and cost. Four countries were studied: Germany, The Netherlands, Sweden and the United Kingdom. These countries have operated one, or both, of the two policies at certain points in time, sometimes in parallel. Drugs in four groups were considered: cholesterol-lowering agents, insulin analogues, biologic drugs for rheumatoid arthritis and "atypical" drugs for schizophrenia. Compared with HTA, reference pricing is a relatively blunt instrument for obtaining value for money from pharmaceuticals. Thus, its role in making reimbursement decisions should be limited to drugs which are therapeutically equivalent. HTA is a superior strategy for obtaining value for money because it addresses not only price but also the appropriate indications for the use of the drug and the relation between additional value and additional costs. However, given the relatively higher costs of conducting HTAs, the most efficient approach might be a combination of both policies.
20703490 [Tocilizumab. What comes after TNF-blockers in clinical routine?]. 2010 Sep Tocilizumab, a monoclonal humanized antibody against IL-6, was licensed in January 2009 in combination with Methotrexate for the treatment of adult patients with moderately to severely active rheumatoid arthritis and inadequate response to one or more DMARDs or TNF antagonists. Tocilizumab is given once every 4 weeks as a 60-min single intravenous infusion at a dosage of 8 mg/kg body weight and may be used as a monotherapy in the case of MTX or DMARD incompatibility. Clinical response is rapid and lasting according to clinical measurements such as ACR response rates or DAS28, irrespective of previous therapy. Within 2 weeks of the first infusion, inflammatory parameters such as CRP and ESR decline and the haemoglobin concentration increases. Adverse events often include mild respiratory infections, transient elevation in liver enzymes, decrease in neutrophile counts and increase in serum lipids. In 8% of patients a lipid lowering therapy needs to be initiated. Diverticulitis with perforation has been observed. Serious infections occur in the range known with other biological therapies. The radiological data show a reduced rate of joint destruction after 1 year of therapy. Long-term follow-up shows good clinical efficacy with an increasing percentage of patients with good clinical response and good safety profile.
20642910 Mucinous cystadenoma of the appendix. Case report. 2010 May BACKGROUND: Pathology of the appendix represents >50% of surgical activity. It is necessary to consider rare pathologies such as mucoceles. These have a high frequency in females with a F/M ratio of 4:1, as well as in patients >50 years of age. The objective of this study is to report on a case of mucinous cystadenoma of the appendix. CLINICAL CASE: We present the case of a 34-year-old male with a history of juvenile rheumatoid arthritis diagnosed at 9 years of age. At 22 years of age, the patient underwent bilateral hip arthroplasty. Since 1998, the patient has presented with renal amyloidosis and has been under steroid treatment to date. The current problem evolved 1 year ago during control studies for his disease. Computed tomography (CT) of the abdomen was done, demonstrating a tumor in the right iliac fossa. Colonoscopy confirmed a tumor with smooth edges located in the cecum. Surgery was recommended with a diagnosis of lipoma of the cecum. During surgery, a large tumor was found, indicating a poor prognosis. Right hemicolectomy was done. Surgical specimen was sent to pathology with a report of mucinous cystadenoma. CONCLUSIONS: The group of symptoms of cystadenoma is nonspecific. Diagnostic methods include X-rays, ultrasound, CT and colonoscopy. Mucinous cystadenoma is the most common form of mucocele of the appendix. Diagnostic protocols are the same for benign appendix pathology. Treatment is surgical and type of surgery depends on the size of the mucocele. Mucoceles of the appendix are pathologies with a favorable prognosis when appropriate treatment is done.
20453440 Association of IRF5, STAT4 and BLK with systemic lupus erythematosus and other rheumatic d 2010 Recent large-scale studies in the Caucasian populations identified many new susceptibility genes to systemic lupus erythematosus (SLE). In this review, we discuss our findings on some of such genes, interferon regulatory factor 5 (IRF5), signal transducer and activator of transcription 4 (STAT4) and B lymphoid tyrosine kinase (BLK), in the Japanese population. All of these genes were associated with SLE also in Japanese; however, there are notable differences. In IRF5, the risk haplotype in Caucasians was not present in Japanese. Instead, a SNP that does not exist in Caucasians defined a protective haplotype in Japanese. In STAT4 and especially in BLK, the risk allele frequency was substantially larger in the Japanese population than in Caucasians; as a result, the genetic contribution of these genes in the population is considered to be greater in the Japanese. Presence of susceptibility genes shared by the Caucasian and Asian populations as well as population-specific susceptibility genes was supported by the first genome-wide association study in the Asians published from China in 2009. We and other investigators also found that IRF5, STAT4 and BLK are associated not only with SLE, but also rheumatoid arthritis and systemic sclerosis. Thus, a substantial proportion of susceptibility genes are shared by multiple autoimmune rheumatic diseases.
20377387 Analysis of NF-kappaB signaling pathways by proteomic approaches. 2010 Apr NF-kappaB is a transcription factor that plays important roles in the regulation of apoptosis and inflammation as well as innate and adaptive immunity. Consequently, dysregulations in the NF-kappaB activation cascade have been associated with the pathogenesis of several diseases such as cancer, atherosclerosis and rheumatoid arthritis. Although NF-kappaB signaling pathways have been extensively investigated in this context, its varying components and targets are far from being completely elucidated. There is still an urgent need for the detection of novel NF-kappaB target proteins, novel interaction partners and novel regulators in the activation cascade, in particular with regard to its role in the aforementioned diseases. Therefore, several groups have performed different proteomic approaches to further investigate NF-kappaB signal transduction pathways. Most of these studies have been carried out in the area of cancer research; however, there are also several analyses in the field of inflammatory or autoimmune diseases. Furthermore, there have been a number of basic investigations that principally examined binding partners or so far unknown target proteins of NF-kappaB-related proteins. With these approaches, a number of novel and interesting proteins have been found that interfere with NF-kappaB signal transduction and might have an impact on NF-kappaB-related diseases. The results of these studies are summarized and discussed in this review.
20376213 Free Radical Scavenging Activity of Calotropis gigantea on Streptozotocin-Induced Diabetic 2009 Nov Swarnabhasma, an Ayurvedic preparation containing Calotropis gigantea R. Br. (Asclepiadaceae) is extensively used by Ayurvedic physicians for treatment of diabetes mellitus, bronchial asthma, rheumatoid arthritis and nervous disorders. In the present study, we report the effect of chloroform extracts of Calotropis gigantea leaf and flower on free radical scavenging activity, and lipid profile in streptozotozin-induced diabetic rats. The lipid peroxidation, superoxide dismutase, and catalase were measured in liver homogenate and serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, lipid profile were measured in blood serum. Administration of single dose of streptozotozin (55 mg/kg, i.p.) caused significant increases in lipid peroxidation, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, cholesterol and triglyceride levels, while superoxide dismutase and catalase levels were significantly decreased. Further, administration of chloroform extracts of Calotropis gigantea leaf and flower to streptozotocin-induced diabetes rats at a dose of 10, 20 and 50 mg/kg orally for 27 d lead to a significant decrease in lipid peroxidation, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, alkaline phosphatase, cholesterol and triglyceride levels. Consequently, superoxide dismutase and catalase levels were significantly increased. Glibenclamide was used as a positive control (10 mg/kg). It was observed that the effect of chloroform extracts of Calotropis gigantea on alkaline phosphatase, cholesterol, superoxide dismutase, serum glutamic pyruvic transaminase, serum glutamic oxaloacetic transaminase, levels are comparable to that of those produced by the positive control.
20199147 Generation of anti-proteinase 3 monoclonal antibodies and development of immunological met 2010 Feb Proteinase 3 (PR3), a neutrophil granule serine protease, is the major autoantigen for autoantibodies in the systemic vasculitic disease, Wegener's granulomatosis. It is also found to be involved in various inflammatory diseases including Crohn's disease, rheumatoid arthritis, cystic fibrosis, and gingivitis. However, there is no high quality antibody available to detect endogenous PR3 in biological samples such as plasma and tissue. Several commercial anti-PR3 monoclonal antibodies (MAbs) were obtained by using HMC-1/PR3 cell granule extracts as the antigen, but the resulting antibodies could not be applied for immunoblotting or other immunological methods. Therefore, we produced human recombinant PR3 in Escherichia coli and developed several MAbs that are highly sensitive and can be used for immunoblotting, FACS analysis, and immunofluorescent staining. The PR3 MAbs recognized both rhPR3 and human plasma-derived neutrophil PR3 in reducing and non-reducing conditions at low nanogram levels. In addition, new MAbs detect endogenous PR3 from normal human plasma and urine with high specificity. The new anti-PR3 MAbs will be an essential tool for investigating the role of PR3 in inflammatory and autoimmune diseases.
20110516 The minimally important difference for patient-reported outcomes in spondyloarthropathies 2010 Apr OBJECTIVE: To study minimal important differences (MID) in spondyloarthropathies (SpA). MID are important in determining clinically relevant changes and for interpretation of trials and treating patients. MID have been widely studied in rheumatoid arthritis, but less so in SpA. METHODS: Patients with SpA had to be seen for 2 consecutive visits and have completed the Health Assessment Questionnaire (HAQ) and 100 mm visual analog scale on both visits for fatigue, pain, sleep, and global assessment. At the second visit they had to answer a question regarding any change in their overall health (from last visit), responding with much better, better, same, worse, or much worse. The MID were the mean changes for those who were either better or worse. RESULTS: Our study involved 140 eligible patients with a SpA: 69% were men, the mean age was 45 years, and the mean disease duration was 14.5 years. Almost half the patients rated themselves as unchanged from the previous visit but the remainder were either better or worse, with a minority rating themselves as much better or much worse. The MID for better and worse outcomes were HAQ (-0.136; 0.220), pain (-6.93; 18.97), fatigue (-1.43; 14.42), and sleep (-2.23; 10.76). No gender differences were observed. CONCLUSION: Our results demonstrate that the MID vary depending on better versus worse (bidirectionally different). MID may be smaller in clinical practice than what is observed in trials.
20100356 PCA-based bootstrap confidence interval tests for gene-disease association involving multi 2010 Jan 26 BACKGROUND: Genetic association study is currently the primary vehicle for identification and characterization of disease-predisposing variant(s) which usually involves multiple single-nucleotide polymorphisms (SNPs) available. However, SNP-wise association tests raise concerns over multiple testing. Haplotype-based methods have the advantage of being able to account for correlations between neighbouring SNPs, yet assuming Hardy-Weinberg equilibrium (HWE) and potentially large number degrees of freedom can harm its statistical power and robustness. Approaches based on principal component analysis (PCA) are preferable in this regard but their performance varies with methods of extracting principal components (PCs). RESULTS: PCA-based bootstrap confidence interval test (PCA-BCIT), which directly uses the PC scores to assess gene-disease association, was developed and evaluated for three ways of extracting PCs, i.e., cases only(CAES), controls only(COES) and cases and controls combined(CES). Extraction of PCs with COES is preferred to that with CAES and CES. Performance of the test was examined via simulations as well as analyses on data of rheumatoid arthritis and heroin addiction, which maintains nominal level under null hypothesis and showed comparable performance with permutation test. CONCLUSIONS: PCA-BCIT is a valid and powerful method for assessing gene-disease association involving multiple SNPs.