Psoriasis: Gladman D

Kimball AB, Gladman D, Gelfand JM, Gordon K, Horn EJ, Korman NJ, Korver G, Krueger GG, Strober BE, Lebwohl MG, Anonymous00020. · Department of Dermatology, Harvard Medical School and Massachusetts General Hospital, Boston, Massachusetts 02114, USA. · J Am Acad Dermatol. · Pubmed #18313171 No free full text.

Abstract: There have been several articles and reports in recent months about comorbidities and risks that affect psoriasis patients in addition to their underlying disease. This piece reviews the current literature and begins to address what should be done with this new information by updating the clinician about what health screening tests, preventative exams, and referrals should be considered in this population.

Prasad R, Gladman D. · Centre for Prognostics Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, Ontario, Canada. · Expert Opin Investig Drugs. · Pubmed #14996648 No free full text.

Abstract: Psoriatic arthritis (PsA) is now recognised as a progressively destructive inflammatory arthritis that can lead to joint deformity and functional disability. Early diagnosis and treatment with disease-modifying antirheumatic drugs (DMARDs) are necessary to control disease, particularly in patients with clinical factors and human leukocyte antigen markers predictive of progressive disease. However, there are few randomised controlled trials of the traditional DMARDs in PsA and none have demonstrated efficacy on axial manifestations or delay in radiological progression. The demonstration of raised levels of TNF-alpha in psoriatic skin and synovial tissue has provided a rationale for the application of biological agents in PsA. Furthermore, the recognition of the role of T-cell activation in both psoriasis and PsA has led to the therapeutic targeting of T lymphocytes, the results of which at this early stage are encouraging. This article reviews the studies of the most widely used traditional DMARDs in PsA followed by studies with leflunomide and the biological response modifiers, including TNF-alpha antagonists and T-cell-targeted therapies.

Brockbank J, Gladman D. · Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, Toronto, Ontario, Canada. · Drugs. · Pubmed #12421102 No free full text.

Abstract: Psoriatic arthritis (PsA) is considered to be one of the spondyloarthritides, and as such has both spinal and peripheral joint involvement. In 80% of patients, psoriasis usually precedes the development of arthritis. Although there are no widely accepted diagnostic criteria, a number of distinct clinical features allow it to be distinguished from other forms of inflammatory arthritis. It affects both sexes equally, and the pattern of joint involvement is characteristic with distal interphalangeal joint involvement, asymmetry, dactylitis, flail or ankylotic deformities of digits, and the frequent presence of enthesitis and spinal involvement. It may have a pattern of joint involvement similar to rheumatoid arthritis (RA) but in these patients rheumatoid factor and the other systemic features of RA are usually absent. Radiographs frequently reveal evidence of asymmetric sacroiliitis and spinal disease, and peripheral joints, as well as showing erosions, may also demonstrate profuse new bone formation and ankylosis. Profound osteolysis producing the pencil-in-cup deformity can also occur in the same individual. It is now recognised that PsA can be a destructive arthritis with an increased morbidity and mortality. Studies of standard disease-modifying therapies have been small and frequently inconclusive because of a high placebo response rate. This may be as a result of heterogeneity in patient selection, poor assessment tools, or the difference in underlying pathogenesis and subsequent response to therapy. In meta-analyses, sulfasalazine and methotrexate have been shown to be effective. Treating the skin alone seems to have little impact on joint disease, and the relationship between skin and joints is still unclear. However, recent studies with anti-tumour necrosis factor agents, such as etanercept and infliximab, have shown considerable significant clinical benefit and provided the hope that we will at last have effective therapies for this disease.

Kavanaugh A, McInnes I, Mease P, Krueger GG, Gladman D, Gomez-Reino J, Papp K, Zrubek J, Mudivarthy S, Mack M, Visvanathan S, Beutler A. · University of California, San Diego, La Jolla, CA 92093-0943, USA. · Arthritis Rheum. · Pubmed #19333944 No free full text.

Abstract: OBJECTIVE: To assess the efficacy and safety of golimumab in patients with active psoriatic arthritis (PsA). METHODS: Adult patients with PsA who had at least 3 swollen and 3 tender joints and active psoriasis were randomly assigned to receive subcutaneous injections of placebo (n = 113), golimumab 50 mg (n = 146), or golimumab 100 mg (n = 146) every 4 weeks through week 20. Efficacy assessments through week 24 included the American College of Rheumatology 20% improvement criteria (ACR20), the Psoriasis Area and Severity Index (PASI) in patients in whom at least 3% of the body surface area was affected by psoriasis at baseline, the Short Form 36 Health Survey (SF-36), the disability index of the Health Assessment Questionnaire (HAQ), the Nail Psoriasis Severity Index (NAPSI), the physician's global assessment of psoriatic nail disease, and enthesitis (using the PsA-modified Maastricht Ankylosing Spondylitis Enthesitis Score [MASES] index). RESULTS: At week 14, 48% of all patients receiving golimumab, 51% of patients receiving golimumab 50 mg, and 45% of patients receiving golimumab 100 mg achieved an ACR20 response (the primary end point), compared with 9% of patients receiving placebo (P < 0.001 for all comparisons). Among the 74% of patients in whom at least 3% of the body surface area was affected by psoriasis at baseline, 40% of those in the golimumab 50 mg group and 58% of those in the golimumab 100 mg group had at least 75% improvement in the PASI at week 14 (major secondary end point), compared with 3% of placebo-treated patients (P < 0.001 for both doses). Significant improvement was observed for other major secondary end points (the HAQ and the SF-36), the NAPSI, the physician's global assessment of psoriatric nail disease, and the PsA-modified MASES index in each golimumab group compared with placebo. This efficacy was maintained through week 24. Golimumab was generally well tolerated. CONCLUSION: Treatment with golimumab at doses of 50 mg and 100 mg significantly improved active PsA and associated skin and nail psoriasis through week 24.

Kavanaugh A, Antoni C, Krueger GG, Yan S, Bala M, Dooley LT, Beutler A, Guzzo C, Gladman D. · Center for Innovative Therapy, Division of Rheumatology, Allergy, and Immunology, University of California at San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0943, USA. · Ann Rheum Dis. · Pubmed #16096330 links to  free full text

Abstract: OBJECTIVES: To evaluate the effect of infliximab on health related quality of life (HRQoL) and physical function in patients with active psoriatic arthritis (PsA) in the IMPACT 2 trial. METHODS: 200 patients with PsA unresponsive to conventional treatment were randomised to intravenous infusions of infliximab 5 mg/kg or placebo at weeks 0, 2, 6, 14, and 22; patients with inadequate response entered early escape at week 16. HRQoL was assessed using the Short Form-36 (SF-36) at weeks 0, 14, and 24. Functional disability was assessed using the Health Assessment Questionnaire (HAQ) at every visit through week 24. Associations between changes in quality of life (SF-36) and articular (American College of Rheumatology (ACR)) and dermatological (Psoriasis Area and Severity Index (PASI)) responses were examined. RESULTS: Mean percentage improvement from baseline in HAQ was 48.6% in the infliximab group compared with worsening of 18.4% in the placebo group at week 14 (p < 0.001). Furthermore, 58.6% and 19.4% of infliximab and placebo treated patients, respectively, achieved a clinically meaningful improvement in HAQ (that is, > or = 0.3 unit decrease) at week 14 (p < 0.001). Increases in physical and mental component summary (PCS and MCS) scores and all eight scales of the SF-36 in the infliximab group were greater than those in the placebo group at week 14 (p < or = 0.001). These benefits were sustained through week 24. Patients achieving ACR20 and PASI75 responses had the greatest improvements in PCS and MCS scores. CONCLUSIONS: In patients with PsA, infliximab 5 mg/kg significantly improved HRQoL and physical function compared with placebo through 24 weeks.

Antoni CE, Kavanaugh A, Kirkham B, Tutuncu Z, Burmester GR, Schneider U, Furst DE, Molitor J, Keystone E, Gladman D, Manger B, Wassenberg S, Weier R, Wallace DJ, Weisman MH, Kalden JR, Smolen J. · Friedrich-Alexander University, Erlangen-Nuremberg, Germany. · Arthritis Rheum. · Pubmed #15818699 links to  free full text

Abstract: OBJECTIVE: To investigate the efficacy and tolerability of infliximab therapy for the articular and dermatologic manifestations of active psoriatic arthritis (PsA). METHODS: One hundred four patients with PsA in whom prior therapy with at least 1 disease-modifying antirheumatic drug (DMARD) had failed were recruited into this investigator-initiated, multicenter, randomized, double-blind, placebo-controlled clinical trial. During the initial blinded portion of the study, patients received infusions of infliximab (5 mg/kg) or placebo at weeks 0, 2, 6, and 14. After week 16, patients initially assigned to receive placebo crossed over to receive infliximab 5 mg/kg every 8 weeks through week 50, while patients initially randomized to infliximab continued to receive active treatment at the same dose through week 50. The primary efficacy outcome was achievement of the American College of Rheumatology 20% criteria for improvement in rheumatoid arthritis (ACR20) at week 16. Additional predefined clinical efficacy assessments included the Psoriasis Area and Severity Index (PASI) score, the ACR50 and ACR70 criteria, the Disease Activity Score in 28 joints, the Health Assessment Questionnaire, ratings of enthesitis and dactylitis, and the Psoriatic Arthritis Response Criteria score. RESULTS: The proportion of infliximab-treated patients who achieved an ACR20 response at week 16 (65%) was significantly higher than the proportion of placebo-treated patients who achieved this response (10%). In addition, 46% of infliximab-treated patients achieved an ACR50 response, and 29% achieved an ACR70 response; no placebo-treated patient achieved these end points. Among patients who had PASI scores of >/=2.5 at baseline, 68% of infliximab-treated patients achieved improvement of >/=75% in the PASI score at week 16 compared with none of the placebo-treated patients. Continued therapy with infliximab resulted in sustained improvement in articular and dermatologic manifestations of PsA through week 50. The incidence of adverse events was similar between the treatment groups. CONCLUSION: Therapy with infliximab at a dose of 5 mg/kg significantly improved the signs and symptoms of arthritis, psoriasis, dactylitis, and enthesitis in patients with active PsA that had been resistant to DMARD therapy. With continued infliximab treatment, benefits were sustained through 50 weeks. The benefit-to-risk ratio appeared favorable in this study population.

Kaltwasser JP, Nash P, Gladman D, Rosen CF, Behrens F, Jones P, Wollenhaupt J, Falk FG, Mease P, Anonymous00102. · Abteilung Rheumatologie, Medizinische Klinik III, Zentrum der Innere Medizin, J. W. Goethe-Universität, Frankfurt am Main, Germany. · Arthritis Rheum. · Pubmed #15188371 links to  free full text

Abstract: OBJECTIVE: Current treatment options for psoriatic arthritis (PsA) are limited. Leflunomide, an oral pyrimidine synthesis inhibitor, is highly effective in the treatment of rheumatoid arthritis, and small studies have suggested similar efficacy in PsA. We undertook this double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of leflunomide in patients with PsA and psoriasis. METHODS: One hundred ninety patients with active PsA and psoriasis (at least 3% skin involvement) were randomized to receive leflunomide (100 mg/day loading dose for 3 days followed by 20 mg/day orally) or placebo for 24 weeks. The primary efficacy end point was the proportion of patients classified as responders by the Psoriatic Arthritis Response Criteria (PsARC). Additional efficacy (joint and skin involvement), safety, and quality-of-life assessments were performed. RESULTS: At 24 weeks, 56 of 95 leflunomide-treated patients (58.9%; 95% confidence interval [95% CI] 48.4-68.9) and 27 of 91 placebo-treated patients (29.7% [95% CI 20.6-40.2]) were classified as responders by the PsARC (P < 0.0001). Significant differences in favor of leflunomide were also observed in the proportions of patients achieving modified American College of Rheumatology 20% improvement criteria, improvement in the designated psoriasis target lesion, and mean changes from baseline in Psoriasis Area and Severity Index scores and quality-of-life assessments. Diarrhea and alanine aminotransferase increases occurred at higher rates in the leflunomide group. No cases of serious liver toxicity were observed. CONCLUSION: Leflunomide is an effective treatment for PsA and psoriasis, providing a safe and convenient alternative to current therapies.

Nair RP, Duffin KC, Helms C, Ding J, Stuart PE, Goldgar D, Gudjonsson JE, Li Y, Tejasvi T, Feng BJ, Ruether A, Schreiber S, Weichenthal M, Gladman D, Rahman P, Schrodi SJ, Prahalad S, Guthery SL, Fischer J, Liao W, Kwok PY, Menter A, Lathrop GM, Wise CA, Begovich AB, Voorhees JJ, Elder JT, Krueger GG, Bowcock AM, Abecasis GR, Anonymous00129. · Department of Dermatology, University of Michigan, Ann Arbor, Michigan 48109, USA. · Nat Genet. · Pubmed #19169254 No free full text.

Abstract: Psoriasis is a common immune-mediated disorder that affects the skin, nails and joints. To identify psoriasis susceptibility loci, we genotyped 438,670 SNPs in 1,409 psoriasis cases and 1,436 controls of European ancestry. We followed up 21 promising SNPs in 5,048 psoriasis cases and 5,041 controls. Our results provide strong support for the association of at least seven genetic loci and psoriasis (each with combined P < 5 x 10(-8)). Loci with confirmed association include HLA-C, three genes involved in IL-23 signaling (IL23A, IL23R, IL12B), two genes that act downstream of TNF-alpha and regulate NF-kappaB signaling (TNIP1, TNFAIP3) and two genes involved in the modulation of Th2 immune responses (IL4, IL13). Although the proteins encoded in these loci are known to interact biologically, we found no evidence for epistasis between associated SNPs. Our results expand the catalog of genetic loci implicated in psoriasis susceptibility and suggest priority targets for study in other auto-immune disorders.

Rahman P, Snelgrove T, Peddle L, Siannis F, Farewell V, Schentag C, Gladman D. · Memorial University of Newfoundland, St. John's, Newfoundland. · Arthritis Rheum. · Pubmed #18576348 links to  free full text

This publication has no abstract.

Lebwohl M, Bagel J, Gelfand JM, Gladman D, Gordon KB, Hsu S, Kalb RE, Kimball AB, Korman NJ, Krueger GG, Mease P, Morison WL, Paller A, Pariser DM, Ritchlin C, Strober B, Van Voorhees A, Weinstein GD, Young M, Horn L. · Department of Dermatology, Mount Sinai School of Medicine, New York, New York, USA. · J Am Acad Dermatol. · Pubmed #17980456 No free full text.

Abstract: BACKGROUND: Biologics are widely used in the treatment of psoriasis and psoriatic arthritis. OBJECTIVE: Our aim was to arrive at a consensus on the kind of monitoring and the vaccinations that should be performed before and during biologic therapy. METHODS: Medical literature and data presented at meetings were reviewed and a consensus conference was held by members of the Medical Board of the National Psoriasis Foundation. RESULTS: Consensus was established on monitoring and vaccination practices that included discussion and recognition of variations in those practices. History, physical examination, chemistry screen with liver function tests, complete blood cell count, and platelet count and tuberculosis testing are widely obtained at baseline and with variable frequencies thereafter. Patients treated with efalizumab have platelet counts checked more often; liver function tests are repeated more frequently in patients treated with infliximab; patients taking tumor necrosis factor blockers undergo tuberculosis testing more often; and patients treated with alefacept have CD4 counts checked approximately every 2 weeks. Avoidance of live vaccines during biologic therapy and administration of essential vaccines before biologic therapy were discussed, although vaccination is performed only to a variable degree. There was no consistency in the measurement of antinuclear antibodies among the experts. LIMITATIONS: There are few evidence-based studies on monitoring practices for patients with psoriasis taking biologic therapies. CONCLUSIONS: In patients taking biologic therapies for psoriasis, monitoring of blood chemistries, blood counts, CD4 counts, antinuclear antibodies, tuberculin skin tests, history, and physical examination may be warranted depending on the particular therapy and the particular patient. Vaccination practices are also addressed.

Kavanaugh A, Antoni C, Mease P, Gladman D, Yan S, Bala M, Zhou B, Dooley LT, Beutler A, Guzzo C, Krueger GG. · Division of Rheumatology, Allergy and Immunology, University of California at San Diego, 9500 Gilman Drive, San Diego, CA 92093, USA. · J Rheumatol. · Pubmed #16960923 No free full text.

Abstract: OBJECTIVE: To examine the effect of infliximab on employment status, time lost from work, and productivity in a double-blind, placebo-controlled study of patients with active psoriatic arthritis (PsA). METHODS: Two hundred adult patients with PsA were randomized to intravenous infusions of either infliximab 5 mg/kg or placebo at Weeks 0, 2, 6, 14, and 22, with early escape at Week 16. Employment status, workdays missed, and productivity were assessed at baseline and at Week 14. The effect of PsA on daily productivity was assessed using a visual analog scale. RESULTS: At baseline, similar percentages of patients in both treatment groups were employed and similar percentages missed workdays; the mean productivity score at baseline was similar between groups (roughly 3 on a scale of 0 to 10). At Week 14, median productivity increased significantly in the infliximab group compared with the placebo group (67.5% vs 9.2%; p < 0.0001). Compared with the placebo group, higher proportions of patients in the infliximab group improved employment status from unemployed at baseline to employed at Week 14 (11.5% vs 0%; p = 0.084) and from part-time to full-time employment (30.0% vs 10.0%; p = 0.582). Among patients employed at baseline and Week 14, a lower proportion of patients in the infliximab group than in the placebo group had missed workdays in the 4 weeks prior to Week 14 (p = 0.138). CONCLUSION: After 14 weeks of treatment, infliximab improved productivity in patients with active PsA. There was also a trend toward increased employment and reduced time lost from work for patients treated with infliximab.

Rahman P, Sun S, Peddle L, Snelgrove T, Melay W, Greenwood C, Gladman D. · Memorial University of Newfoundland, St. Clare's Mercy Hospital, St. John's, Newfoundland, Canada. · Arthritis Rheum. · Pubmed #16918024 No free full text.

Abstract: OBJECTIVE: The interleukin-1 (IL-1) cytokine elicits a wide variety of biologic activities that initiate and promote an inflammatory response. The loci in the IL1 gene cluster have recently been associated with ankylosing spondylitis (AS). Since there is clinical and immunologic overlap between psoriatic arthritis (PsA) and AS, we wanted to examine the association between a panel of single-nucleotide polymorphisms (SNPs) in the IL1 gene family cluster and chromosome 2q12-13 in a PsA cohort. METHODS: Two hundred twelve PsA patients and 150 ethnically matched controls were genotyped with 11 SNPs in IL1A, 9 SNPs in IL1B, and 9 SNPs in IL1F5-10. Univariate analyses of the 29 single markers and short intragenic haplotypes identified several associated regions. Seventeen markers of interest were noted and further investigated to determine which markers or short haplotypes independently predict case-control status, using a stepwise logistic model. RESULTS; Two regions contributing independently to risk of disease in PsA were noted: a region spanned by markers rs3783547, rs3783543, and rs17561 in IL1A, and a region near the end of IL1B, through IL1F7, IL1F8, and into IL1F10. The best model contained markers rs3811047, rs1562304, and rs3811058, and 1 haplotype constructed from the 3 markers in region 1, with a likelihood ratio of 25.34 (4 degrees of freedom). CONCLUSION: The IL1 locus appears to be a high-priority susceptibility locus in PsA, with at least 2 independent regions that confer increased risk.

Taylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H, Anonymous00006. · University of Otago, Wellington, New Zealand. · Arthritis Rheum. · Pubmed #16871531 links to  free full text

Abstract: OBJECTIVE: To compare the accuracy of existing classification criteria for the diagnosis of psoriatic arthritis (PsA) and to construct new criteria from observed data. METHODS: Data were collected prospectively from consecutive clinic attendees with PsA and other inflammatory arthropathies. Subjects were classified by each of 7 criteria. Sensitivity and specificity were compared using conditional logistic regression analysis. Latent class analysis was used to calculate criteria accuracy in order to confirm the validity of clinical diagnosis as the gold standard definition of "case"-ness. Classification and Regression Trees methodology and logistic regression were used to identify items for new criteria, which were then constructed using a receiver operating characteristic curve. RESULTS: Data were collected on 588 cases and 536 controls with rheumatoid arthritis (n = 384), ankylosing spondylitis (n = 72), undifferentiated arthritis (n = 38), connective tissue disorders (n = 14), and other diseases (n = 28). The specificity of each set of criteria was high. The sensitivity of the Vasey and Espinoza method (0.97) was similar to that of the method of McGonagle et al (0.98) and greater than that of the methods of Bennett (0.44), Moll and Wright (0.91), the European Spondylarthropathy Study Group (0.74), and Gladman et al (0.91). The CASPAR (ClASsification criteria for Psoriatic ARthritis) criteria consisted of established inflammatory articular disease with at least 3 points from the following features: current psoriasis (assigned a score of 2; all other features were assigned a score of 1), a history of psoriasis (unless current psoriasis was present), a family history of psoriasis (unless current psoriasis was present or there was a history of psoriasis), dactylitis, juxtaarticular new bone formation, rheumatoid factor negativity, and nail dystrophy. These criteria were more specific (0.987 versus 0.960) but less sensitive (0.914 versus 0.972) than those of Vasey and Espinoza. CONCLUSION: The CASPAR criteria are simple and highly specific but less sensitive than the Vasey and Espinoza criteria.

Butt C, Gladman D, Rahman P. · St. Clare's Mercy Hospital, Memorial University of Newfoundland, St. John's, Newfoundland, Canada. · J Rheumatol. · Pubmed #16783862 No free full text.

Abstract: OBJECTIVE: Peroxisome proliferator-activated receptor-gamma (PPAR-gamma) activation has been shown to play a role in suppressing angiogenesis and inflammation, both important pathological features of psoriatic arthritis (PsA). Given the potential physiological role for PPAR-gamma in PsA, we examined known coding polymorphisms in the PPAR-gamma gene in a Caucasian population. METHODS: PsA was diagnosed as an inflammatory arthritis in patients with psoriasis, in the absence of other etiologies for inflammatory arthritis. Control subjects were ascertained from the same population and were all Caucasian. DNA samples were genotyped for 4 PPAR-gamma variants by time-of-flight mass spectrometry using the Sequenom platform. All 4 single-nucleotide polymorphisms (SNP) were previously-reported coding variations, 3 of which caused an amino acid change: Pro12Ala (rs1801282), Pro40Ala (rs1805192), and Pro115Gln (rs1800571); the fourth SNP, C161T (rs3856806), was synonymous. All primers were designed using Sequenom SpectroDesigner software, and scanned using a mass spectrometry workstation. RESULTS: Of the 4 SNP examined, Pro40Ala and Pro115Gln were found to be nonpolymorphic in our population. Minor allele frequency for patients with PsA and controls for Pro12Ala (G) were 9.0% vs 13.8% (p = 0.017) and for C161T (T) 10.7% vs 12.0% (p = 0.56), respectively. All genotypes satisfied Hardy-Weinberg equilibrium. CONCLUSION: An association between PsA and a known coding SNP of the PPAR-gamma gene was observed in our Caucasian population. Further studies are now warranted for validation of our findings in an independent cohort.

Butt C, Peddle L, Greenwood C, Hamilton S, Gladman D, Rahman P. · Memorial University of Newfoundland, Hospital for Sick Children, Department of Public Health Sciences, University of Toronto, Toronto, Canada. · Arthritis Res Ther. · Pubmed #16507123 links to  free full text

Abstract: Recent studies have implicated PTPN22 and tp53 in susceptibility to several autoimmune diseases, including rheumatoid arthritis, suggesting that these genes are important in maintaining immune homeostasis. Because autoimmune diseases may share similar susceptibility loci, investigation of these genes in psoriatic arthritis (PsA) is of potential relevance. As a result we investigated known coding polymorphisms in PTPN22 and tp53 in a homogenous Caucasian PsA cohort from Newfoundland, Canada and an admixed Caucasian PsA cohort from Toronto, Canada. We observed a moderate association of the R620W variant of PTPN22 with PsA in the Toronto population only. Because of the conflicting findings reported regarding the association of PTPN22 with PsA, further studies in other PsA populations are warranted.

Kavanaugh A, Antoni CE, Gladman D, Wassenberg S, Zhou B, Beutler A, Keenan G, Burmester G, Furst DE, Weisman MH, Kalden JR, Smolen J, van der Heijde D. · Center for Innovative Therapy, University of California-San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0943, USA. · Ann Rheum Dis. · Pubmed #16439444 links to  free full text

Abstract: OBJECTIVE: Infliximab is effective in improving signs and symptoms of joint/skin involvement, functional status, and quality of life in patients with psoriatic arthritis (PsA). Using IMPACT trial data, we assessed the effect of infliximab (IFX) on structural damage in PsA. METHODS: Patients with active PsA were randomly assigned to receive placebo (PBO/IFX) or infliximab 5 mg/kg (IFX/IFX) at weeks 0, 2, 6, and 14, with the primary endpoint at week 16. The PBO group received infliximab loading doses at weeks 16, 18, and 22. Thereafter, all patients received infliximab 5 mg/kg every 8 weeks through week 50. Hand/feet radiographs were obtained at weeks 0 and 50. Total radiographic scores were determined using the PsA modified van der Heijde-Sharp (vdH-S) score. Projected annual rate of progression was calculated by dividing x ray score by disease duration (years). RESULTS: As reported previously, 65% of infliximab treated patients versus 10% of PBO treated patients achieved an ACR20 response at week 16 (p<0.001). At week 50, 69% of patients achieved an ACR20 response. Radiographs (baseline and week 50) were available for 72/104 patients. At baseline, estimated mean annual rate of progression was 5.8 modified vdH-S points/year. Mean (median) changes from baseline to week 50 in the total modified vdH-S score were -1.95 (-0.50) for PBO/IFX and -1.52 (-0.50) for IFX/IFX patients (p = NS). At week 50, 85% and 84% of patients in the PBO/IFX and IFX/IFX groups had no worsening in the total modified vdH-S score. CONCLUSION: Infliximab inhibits radiographic progression in patients with PsA through week 50.

Rahman P, Siannis F, Butt C, Farewell V, Peddle L, Pellett F, Gladman D. · St Clare's Mercy Hospital, Memorial University of Newfoundland, 1 South-154 LeMarchant Rd, St John's, Newfoundland, Canada A1C-5B8. · Ann Rheum Dis. · Pubmed #16284098 links to  free full text

Abstract: BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a cytokine of critical importance in psoriatic arthritis. OBJECTIVES: (1) To examine the association between TNFalpha promoter gene polymorphisms and psoriatic arthritis in two well characterised Canadian populations with the disease; (2) to carry out a meta-analysis of all TNFalpha association studies in white psoriatic arthritis populations. METHODS: DNA samples were genotyped for five TNF variants by time of flight mass spectrometry using the Sequenom platform. All five single nucleotide polymorphisms were in the 5' flanking region of TNFalpha gene at the following positions: -1031 (T-->C), -863 (C-->A), -857 (C-->T), -308 (G-->A), and -238 (G-->A). Primary analyses were based on logistic regression. Summary estimates of disease/genotype relations from several studies were derived from random effects meta-analyses. RESULTS: 237 psoriatic arthritis subjects and 103 controls from Newfoundland and 203 psoriatic arthritis subjects and 101 controls from Toronto were studied. A combined analysis of data from both populations, showed a significant association between disease status and the -238(A) variant (p=0.01). The meta-analysis estimate for the -238(A) TNFalpha variant in eight psoriatic arthritis populations was also significant (odds ratio=2.29 (95% confidence interval, 1.48 to 3.55)). CONCLUSIONS: Analysis of TNFalpha variants in psoriatic arthritis populations shows that the -238 (A) variant is a significant risk factor for this disease.

Butt C, Sun S, Peddle L, Greenwood C, Hamilton S, Gladman D, Rahman P. · Department of Statistics, University of Toronto, Ontario, Canada. · J Rheumatol. · Pubmed #16142871 No free full text.

Abstract: OBJECTIVE: To examine the association of single nucleotide polymorphisms (SNP) in the NFKB1 gene, as well as 2 genes in the nuclear factor (NF)-kappaB functional complex (RelA and NFKBIA), in patients with psoriatic arthritis (PsA) from Newfoundland. METHODS: Patients with PsA and controls were genotyped for one 4-base insertion/deletion and 5 SNP in NFKB1, 4 SNP in RelA, and 7 SNP in NFKBIA by time-of-flight mass spectrometry, using the Sequenom platform. Chi-square analysis was used to test the single locus associations between SNP in the NF-kappaB complex and PsA. Associations between multi-locus haplotypes and case or control status were tested using the software PHASE. RESULTS: Two hundred and twenty-four patients with PsA (52% male) and 88 ethnically matched controls (64% male) were genotyped. No association was noted with any of the SNP tested for the single locus associations in NFKB1, RelA, and NFKBIA or with multi-locus haplotypes. In particular, the allele frequency for the NFKB1 -94delATTG was 41.7% in cases and 41.6% in the controls (p = 0.97). CONCLUSION: No association between the NFKB1 -94 ins/delATTG promoter polymorphism or with other NF-kappaB complex SNP in patients with PsA from Newfoundland was observed.

Nelson GW, Martin MP, Gladman D, Wade J, Trowsdale J, Carrington M. · Basic Research Program, Science Applications International Corporation-Frederick, National Cancer Institute, Frederick, MD 21702, USA. · J Immunol. · Pubmed #15383555 links to  free full text

Abstract: Functionally relevant combinations of HLA and killer Ig-like receptor (KIR) genotypes influence resistance to several diseases in humans. Analysis of genetic data from such studies is challenging because it involves multiple linked and unlinked loci that exert their influence in an epistatic manner. We previously reported that subjects with certain activating receptors were susceptible to developing psoriatic arthritis (PsA), an effect that was strongest when HLA ligands for corresponding homologous inhibitory receptors were missing. In this study, we present a novel model in which susceptibility to PsA is determined by the overall balance of activating and inhibitory composite KIR-HLA genotypes. This model fits our knowledge of clonal NK cell expression of KIR and regulation of NK cell activity better than does the previous model, as reflected in a robust trend for increasing susceptibility to PsA with more activating genotypes. These data emphasize the remarkable influence of KIR/HLA combinations on this disease.

Martin MP, Nelson G, Lee JH, Pellett F, Gao X, Wade J, Wilson MJ, Trowsdale J, Gladman D, Carrington M. · Basic Research Program, SAIC-Frederick, MD 21702, USA. · J Immunol. · Pubmed #12218090 links to  free full text

Abstract: NK cell activity is partially controlled through interactions between killer Ig-like receptors (KIR) on NK cells and their respective HLA class I ligands. Independent segregation of HLA and KIR genes, along with KIR specificity for particular HLA allotypes, raises the possibility that any given individual may express KIR molecules for which no ligand is present. Inhibitory receptor genes KIR2DL2/3 and KIR2DL1 were present in nearly all subjects sampled in this study, whereas their respective activating homologs, KIR2DS2 and KIR2DS1, are each present in about half of the subjects. In this work we report that subjects with activating KIR2DS1 and/or KIR2DS2 genes are susceptible to developing psoriatic arthritis, but only when HLA ligands for their homologous inhibitory receptors, KIR2DL1 and KIR2DL2/3, are missing. Absence of ligands for inhibitory KIRs could potentially lower the threshold for NK (and/or T) cell activation mediated through activating receptors, thereby contributing to pathogenesis of psoriatic arthritis.

Gu J, Märker-Hermann E, Baeten D, Tsai WC, Gladman D, Xiong M, Deister H, Kuipers JG, Huang F, Song YW, Maksymowych W, Kalsi J, Bannai M, Seta N, Rihl M, Crofford LJ, Veys E, De Keyser F, Yu DT. · University of California at Los Angeles, CA 90095, USA. · Rheumatology (Oxford). · Pubmed #12096225 links to  free full text

Abstract: OBJECTIVES: To identify genes which are more highly expressed in the peripheral blood mononuclear cells (PBMC) of patients with spondyloarthropathy (SpA), rheumatoid arthritis (RA) and psoriatic arthritis (PsA), in comparison to normal subjects. METHODS: A 588-gene microarray was used as a screening tool to select a panel of such genes from PBMC of these subjects and of normal subjects. Results were then validated by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The following genes were more highly expressed in arthritis patients than in normal subjects: macrophage differentiation marker MNDA (myeloid nuclear differentiation antigen), MRP8 and MRP14 (migratory inhibitory factor-related proteins); signalling molecules JAK3 (janus kinase 3) and MAP kinase p38 (mitogen-activated protein kinase); receptors TNFR2/p75, C-C-chemokine receptor type 1 (CCR1), C-X-C-chemokine receptor type 4 (CXCR4) and integrin beta1; and the cytokines/chemokines interleukin (IL) 1beta and IL-8. Expression of CXCR4 was unexpectedly high among all arthritis subjects. Using RT-PCR, ELISA and immunohistology, expression of stromal cell-derived factor 1 (SDF-1) was demonstrated in arthritis joints. CONCLUSIONS: The CXCR4/SDF-1 is a potential pro-inflammatory axis for RA, PsA and SpA.

Butt C, Sun S, Greenwood C, Gladman D, Rahman P. · No affiliation provided · Rheumatology (Oxford). · Pubmed #15769785 links to  free full text

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