Safety of ixekizumab in patients with psoriatic arthritis: data from four clinical trials with over 2000 patient-years of exposure.

OBJECTIVES: Ixekizumab, a high-affinity monoclonal antibody that selectively targets interleukin 17A (IL-17A), has shown significant efficacy in the treatment of psoriatic arthritis (PsA) and sustained long-term clinical response without unexpected new safety outcome for an IL-17A inhibitor. Here, we report the updated safety profile of ixekizumab up to 3 years in patients with PsA. METHODS: This is an integrated safety analysis from four clinical trials in patients with PsA who received at least one dose of ixekizumab. Treatment-emergent adverse events (TEAEs) and selected adverse events (AEs) exposure-adjusted incidence rates (EAIRs) per 100 patient-years up to 3 years of exposure are reported. RESULTS: A total of 1401 patients with a cumulative ixekizumab exposure of 2247.7 patient-years were included in this analysis. The EAIR of patients with ≥1 TEAE was 50.3 per 100 patient-years and most TEAEs were mild to moderate in severity. Serious AEs were reported by 134 patients (EAIR=6.0). The most reported TEAEs were nasopharyngitis (EAIR=9.0) and upper respiratory tract infection (EAIR=8.3). Infections in general and injection site reactions were the most common TEAEs; the incidence rates of serious cases were low (EAIR ≤1.2). The EAIRs of malignancies (EAIR=0.7), inflammatory bowel disease (EAIR=0.1) including ulcerative colitis and Crohn's disease, depression (EAIR=1.6), and major adverse cerebro-cardiovascular events (EAIR=0.5) were low. As assessed, based on year of exposure, incidence rates were decreasing or constant over time. CONCLUSIONS: In this analysis, the overall safety profile and tolerability of ixekizumab are consistent with the known safety profile in patients with PsA. No new or unexpected safety events were detected. TRIAL REGISTRATION NUMBER: NCT01695239, NCT02349295, NCT02584855, NCT03151551.

Perceptions of Rheumatologists on Diagnosis of Psoriatic Arthritis in China.

Objective: High prevalence of undiagnosed psoriatic arthritis (PsA) and prolonged diagnostic delay are key troubles in the appropriate management of PsA. To analyze the possible causes for this phenomenon, a web-based nationwide survey was conducted to investigate rheumatologists' perceptions on PsA diagnosis in China. Methods: The electronic questionnaire consisting of 38 questions were designed by an expert panel and distributed with the online survey tool Sojump, which is a professional online survey platform. The completed questionnaires by real-name rheumatologists were collected. Results: A total of 1594 valid questionnaires were included. More than half of Chinese rheumatologists reported it was challenging to make a diagnosis of PsA. The four major challenges were "Difficulties in identification of atypical or hidden psoriasis", "Absence of diagnostic biomarkers", "No active self-report of history or family history of psoriasis" and "Various musculoskeletal manifestations". In diagnosing PsA, minor participants had incorrect knowledge of inflammatory arthropathy (13.7%), acute phase reactant (23.8%), and rheumatoid factor (28.7%). There were no significant differences in the knowledge of PsA and practice habits in diagnosing PsA between modern western medicine (WM)- and traditional Chinese medicine (TCM)-rheumatologists. The part-time rheumatologists were not as good as full-time rheumatologists in diagnosing PsA. Conclusions: About three quarters of Chinese rheumatologists are familiar with the elements in PsA diagnosis and have good practice habits in diagnosing PsA. Four main challenges in making PsA diagnosis are revealed. There was no significant difference in the knowledge of PsA between WM- and TCM-rheumatologists.

Treatment of Medicare Patients with Moderate-to-Severe Psoriasis who Cannot Afford Biologics or Apremilast.

Elderly patients are a group with a high frequency of psoriasis. Their disease burden has negative impacts on their quality of life. While there is a clear need to treat these patients, there are challenges in doing so. This work seeks to define the challenges that exist in treating elderly Medicare patients, as well as to provide treatment suggestions for providers to follow if they encounter one or more of these challenges. Providers face the following challenges when creating treatment plants for elderly patients with psoriasis: difficulty in obtaining drug coverage through Medicare, increased medical comorbidities, and polypharmacy. Providers aim for regimens that are affordable, safe, and efficacious, but it is not always clear how to achieve this combination, especially in elderly Medicare patients. This work is relevant in that it aims to explain the logistical roadblocks posed by Medicare coverage and provide solutions for commonly encountered issues in the treatment of a disabling and common disease in a high-risk population. Specifically, alternative treatment options to biologics and small-molecule inhibitors are discussed and include topical therapies, phototherapy, methotrexate, acitretin, and cyclosporine and for psoriatic arthritis include corticosteroids and leflunomide. The specific risks and benefits of these therapies in the elderly population are provided, allowing providers to make patient-specific decisions about optimal regimens.

Dietary Recommendations for Adults With Psoriasis or Psoriatic Arthritis From the Medical Board of the National Psoriasis Foundation: A Systematic Review.

Importance: Psoriasis is a chronic, inflammatory skin disease and has significant associated morbidity and effect on quality of life. It is important to determine whether dietary interventions help reduce disease severity in patients with psoriatic diseases. Objective: To make evidence-based dietary recommendations for adults with psoriasis and/or psoriatic arthritis from the Medical Board of the National Psoriasis Foundation. Evidence Review: We used literature from prior systematic reviews as well as additional primary literature from the MEDLINE database from January 1, 2014, to August 31, 2017, that evaluated the impact of diet on psoriasis. We included observational and interventional studies of patients with psoriasis or psoriatic arthritis. The quality of included studies was assessed using the Newcastle-Ottawa scale for observational studies and the Cochrane Risk of Bias Tool for interventional studies. We made evidence-based dietary recommendations, which were voted on by the National Psoriasis Foundation Medical Board. Findings: We identified 55 studies meeting the inclusion criteria for this review. These studies represent 77 557 unique participants of which 4534 have psoriasis. Based on the literature, we strongly recommend dietary weight reduction with a hypocaloric diet in overweight and obese patients with psoriasis. We weakly recommend a gluten-free diet only in patients who test positive for serologic markers of gluten sensitivity. Based on low-quality data, select foods, nutrients, and dietary patterns may affect psoriasis. For patients with psoriatic arthritis, we weakly recommend vitamin D supplementation and dietary weight reduction with a hypocaloric diet in overweight and obese patients. Dietary interventions should always be used in conjunction with standard medical therapies for psoriasis and psoriatic arthritis. Conclusions and Relevance: Adults with psoriasis and/or psoriatic arthritis can supplement their standard medical therapies with dietary interventions to reduce disease severity. These dietary recommendations from the National Psoriasis Foundation Medical Board will help guide clinicians regarding the utility of dietary interventions in adults with psoriatic diseases.

Psoriasis treatment in HIV-positive patients: a systematic review of systemic immunosuppressive therapies.

The management of psoriatic disease in the human immunodeficiency virus (HIV)-positive population is challenging. The clinical course often is progressive and refractory; therefore, first- and second-line therapies including topical agents, phototherapy, and oral retinoids often are inadequate. Most other currently available systemic therapies for psoriatic disease are immunosuppressive, which poses a distinct clinical challenge. A comprehensive systematic review of the literature via a PubMed search of articles indexed for MEDLINE using the terms psoriasis and HIV and psoriatic arthritis and HIV combined with several systemic immunosuppressive agents yielded a total of 25 reported cases of systemic immunosuppressive therapies used to treat psoriatic disease in HIV-positive patients including methotrexate, cyclosporine, etanercept, adalimumab, infliximab, and ustekinumab. The limited data suggest that biologic therapies may be effective for cases of psoriasis recalcitrant to other systemic agents and may have a positive effect on CD4 and viral counts when used in combination with highly active antiretroviral therapy (HAART); however, further studies are needed.

[Osteopecilia associated with psoriatic arthritis]. / Ostéopoécilie associée à un rhumatisme psoriasique.

Osteopecilia is a benign and rare condensing osteopathy. Its association with inflammatory rheumatism is very rare. We here report the case of a 25-year old patient with skin psoriasis, presenting with groin pain of inflammatory origin. Physical examination showed limitation of hip motions, lower limb-length inequality and pain on right sacroiliac mobilization. Laboratory tests showed inflammatory syndrome and negative immunological assessment. The radiograph of the pelvis revealed osteopecilia associated with destructive coxitis. CT scan of the pelvis showed coxitis and osteopecilia associated with bilateral sacroiliitis. The diagnosis of psoriatic arthritis associated with osteopecilia was retained. The patient was treated with methotrexate and NSAIDS. Osteopecilia usually is unexpectedly detected. Diagnostic radiology is essential to avoid unnecessary explorations and treatments.

Modificación de la dosis de terapias biológicas en psoriasis moderada-grave: análisis descriptivo en condiciones de práctica clínica / Dose Modification in Biologic Therapy for Moderate to Severe Psoriasis: A Descriptive Analysis in a Clinical Practice Setting

INTRODUCCIÓN: La modificación de dosis de biológicos en pacientes con psoriasis en remisión adecuadamente seleccionados podría reducir el riesgo de exposición al fármaco y su carga económica. MATERIAL Y MÉTODOS: Estudio observacional, descriptivo y transversal en 112 pacientes con psoriasis moderada-grave tratados con biológicos durante ≥6 meses en enero de 2014. El objetivo consistió en alcanzar y mantener una respuesta PASI 75. Los pacientes iniciaron el tratamiento con la pauta estándar; en aquellos que cumplieron el objetivo se redujo la dosis, y cuando no alcanzaron la respuesta con la pauta estándar esta se intensificó. RESULTADOS: Un 42,9% siguió la pauta estándar, un 50% la reducida y un 7,1% la intensificada. El fármaco con el que más se redujo la dosis fue adalimumab (57,7%) y los que más se intensificaron fueron ustekinumab e infliximab (17,9% y 12,5%). Los pacientes que recibieron dosis reducidas presentaron una psoriasis de más evolución (p = 0,049) y llevaban más tiempo en tratamiento con el mismo biológico (p = 0,009) (diferencias significativas). Hubo una proporción significativamente superior de pacientes con artritis psoriásica entre los no aptos a reducir dosis (p = 0,023). El ahorro del gasto fue del 21,5% con adalimumab, 13,8% con etanercept, 0,9% con ustekinumab y 0,55% con infliximab. CONCLUSIONES: Presentaron una probabilidad de reducción de dosis significativamente mayor aquellos pacientes con más tiempo de evolución y más tiempo bajo el mismo tratamiento biológico. Entre los pacientes sin reducción de dosis hubo mayor proporción con artritis psoriásica. El ahorro global con este algoritmo de modificación de dosis fue del 13%. Se requieren estudios controlados que ayuden a definir el perfil de paciente más adecuado para reducir la dosis sin pérdida de eficacia del tratamiento

INTRODUCTION: In biologic therapy, dose modification in carefully selected patients when psoriasis is in remission could reduce treatment costs and the risks associated with drug exposure. MATERIAL AND METHODS: Observational, descriptive, crosssectional study, performed in January 2014, of 112 patients with moderate to severe psoriasis who had been on biologic therapy for at least 6 months. The therapeutic objective in all cases was to achieve and maintain a 75% reduction in Psoriasis Area and Severity Index (PASI 75). All the patients had started treatment with the standard regimen. During treatment, the dose had been reduced in patients who achieved the therapeutic objective and escalated in those who failed to respond adequately to standard doses. RESULTS: At the time of the study, 42.9% of the patients were receiving the standard dose, 50% were on a reduced dose, and 7.1% were on an escalated regimen. The agent with which the dose was most often reduced was adalimumab (57.7%), and the agents with which therapy was most often escalated were ustekinumab (17.9%) and infliximab (12.5%). Patients who received reduced doses had significantly longer-standing disease (P=.049) and longer treatment duration with the same biologic agent (P=.009). In the group that did not fulfill the criteria for dose reduction, the proportion of patients with psoriatic arthritis was significantly higher (P=.023). Cost savings were as follows: 21.5% with adalimumab, 13.8% with etanercept, .9% with ustekinumab, and .55% with infliximab. CONCLUSIONS: Patients with longer-standing disease and longer treatment duration with the same biologic agent were significantly more likely to be candidates for dose reduction. The proportion of patients with psoriatic arthritis was greater in the group of patients who did not fulfill the conditions for dose reduction. The overall cost saving achieved using the dose modification algorithm described in this study was 13%. Controlled studies are needed to define the profile of the patients best suited for dose reduction strategies without loss of treatment efficacy

CBP30, a selective CBP/p300 bromodomain inhibitor, suppresses human Th17 responses.

Th17 responses are critical to a variety of human autoimmune diseases, and therapeutic targeting with monoclonal antibodies against IL-17 and IL-23 has shown considerable promise. Here, we report data to support selective bromodomain blockade of the transcriptional coactivators CBP (CREB binding protein) and p300 as an alternative approach to inhibit human Th17 responses. We show that CBP30 has marked molecular specificity for the bromodomains of CBP and p300, compared with 43 other bromodomains. In unbiased cellular testing on a diverse panel of cultured primary human cells, CBP30 reduced immune cell production of IL-17A and other proinflammatory cytokines. CBP30 also inhibited IL-17A secretion by Th17 cells from healthy donors and patients with ankylosing spondylitis and psoriatic arthritis. Transcriptional profiling of human T cells after CBP30 treatment showed a much more restricted effect on gene expression than that observed with the pan-BET (bromo and extraterminal domain protein family) bromodomain inhibitor JQ1. This selective targeting of the CBP/p300 bromodomain by CBP30 will potentially lead to fewer side effects than with the broadly acting epigenetic inhibitors currently in clinical trials.

Ustekinumab associated with flares of psoriatic arthritis.

IMPORTANCE: Ustekinumab is a human monoclonal antibody that binds to the shared p40 subunit of interleukin (IL) 12 and IL-23. It is approved in the United States for adults (>18 years) with moderate to severe plaque psoriasis who are candidates for phototherapy or systemic therapy. In 1 phase 2 trial of ustekinumab for treatment of psoriatic arthritis, joint disease improved. OBSERVATION: We report 4 cases of ustekinumab monotherapy for plaque psoriasis that resulted in disabling flares of known psoriatic arthritis or unmasked previously occult joint disease. In all of our cases, psoriasis improved dramatically with ustekinumab therapy while psoriatic arthritis flared. CONCLUSIONS AND RELEVANCE: Despite early results of a phase 2 ustekinumab trial suggesting efficacy for both plaque psoriasis and psoriatic arthritis, our case series raises concern that ustekinumab may unmask or aggravate joint disease in selected patients. These data underscore the need for further investigation of ustekinumab's effects on psoriatic arthritis.

Undertreatment, treatment trends, and treatment dissatisfaction among patients with psoriasis and psoriatic arthritis in the United States: findings from the National Psoriasis Foundation surveys, 2003-2011.

IMPORTANCE: Psoriasis and psoriatic arthritis inflict significant morbidity. Data on undertreatment, treatment use, and treatment satisfaction are paramount to identify priority areas for advocacy, education, and research to improve patient outcomes. OBJECTIVES: To determine the extent of nontreatment and undertreatment of psoriatic diseases, trends in treatment use, treatment satisfaction, and reasons for medication discontinuation among patients with psoriasis and psoriatic arthritis. DESIGN, SETTING, AND PARTICIPANTS: We used the national survey data collected by the National Psoriasis Foundation via biannual surveys conducted from January 1, 2003, through December 31, 2011, in the United States. Survey data were collected from randomly sampled patients with psoriasis and psoriatic arthritis in the US population from a database of more than 76,000 patients with psoriatic diseases. MAIN OUTCOMES AND MEASURES: Nontreatment, undertreatment, and treatment trends determined by the use of prescription medication (topical, phototherapeutic, oral systemic, and biologic), as well as treatment satisfaction and reasons for medication discontinuation. RESULTS: A total of 5604 patients with psoriasis or psoriatic arthritis completed the survey. From 2003 through 2011, patients who were untreated ranged from 36.6% to 49.2% of patients with mild psoriasis, 23.6% to 35.5% of patients with moderate psoriasis, and 9.4% to 29.7% of patients with severe psoriasis. Among those receiving treatment, 29.5% of patients with moderate psoriasis and 21.5% of patients with severe psoriasis were treated with topical agents alone. The most frequently used phototherapy modality is UV-B, whereas methotrexate is the most commonly used oral agent. Although adverse effects and a lack of effectiveness were primary reasons for discontinuing biological agents, the inability to obtain adequate insurance coverage was among the top reasons for discontinuation. Overall, 52.3% of patients with psoriasis and 45.5% of patients with psoriatic arthritis were dissatisfied with their treatment. CONCLUSIONS AND RELEVANCE: Nontreatment and undertreatment of patients with psoriasis and psoriatic arthritis remain a significant problem in the United States. While various treatment modalities are available for psoriasis and psoriatic arthritis, widespread treatment dissatisfaction exists. Efforts in advocacy and education are necessary to ensure that effective treatments are accessible to this patient population.

Semi-quantitative assessment of the distribution of skin lesions in patients with psoriasis and psoriasis arthritis.

BACKGROUND: We propose that the distribution of skin lesions in psoriasis may be assessed using parametric maps on a pixel-by-pixel basis. MATERIAL AND METHODS: We processed 428 patient-drawn self-descriptions of the psoriasis lesions on a supplied body template. We compared 195 patients with a confirmed diagnosis of psoriatic arthritis (PsA) with 89 who had this diagnosis rejected (Psor). Additionally, 28 Psor cases supplied drawings performed after 3 weeks of climate therapy (PsorCT) to test the treatment efficacy. The drawings were scanned, lesion areas were segmented, followed by construction of parametric maps of lesion distributions and calculation of statistical differences between groups. RESULTS AND DISCUSSION: In PsorCT, the lesions occupied 11.2% (0-42%) [median (min.-max.)] of the body area. The area decreased to 2.4% (6-11%) after heliotherapy. The differences were statistically significant for all the areas studied and spread evenly over the body surface. PsA had a relatively low psoriasis lesion occupancy of 2.5% (0-42%) compared with Psor 9.8% (0-34%), which is attributed to the difference in recruitment. Correcting for this, we demonstrate a clear tendency for the head, palms, feet, groin and nails to be preferred lesion sites in PsA in contrast to psoriasis. CONCLUSION: Pixel-based analysis of self-reported skin lesion distributions is a powerful tool to assess systematic differences due to treatment or disease variants.

In vitro spontaneous osteoclastogenesis of human peripheral blood mononuclear cells is not crucially dependent on T lymphocytes.

OBJECTIVE: In vitro spontaneous osteoclastogenesis from peripheral blood mononuclear cells (PBMCs) is increased in diseases with excessive bone loss. The purpose of this study was to reassess the role of T lymphocytes in this process. METHODS: Fresh or cryopreserved PBMCs obtained from healthy subjects and from patients with rheumatoid arthritis, psoriatic arthritis, and non-psoriatic spondylarthritis were cultured at high density and stained for tartrate-resistant acid phosphatase (TRAP). Resorption of mineralized matrix was assessed by a dentin disc assay. CD14+ monocytes and CD3+ T cells were selected using magnetically labeled antibodies. RESULTS: Numerous multinucleated, TRAP+, dentin-resorbing osteoclasts developed spontaneously from fresh PBMCs from healthy individuals. This process was abrogated by T cell depletion and was restored by exogenous macrophage colony-stimulating factor (M-CSF) and RANKL, indicating the important role of T cells in spontaneous osteoclastogenesis in vitro. Using physiologic freezing and thawing as a model for the activation of PBMCs, spontaneous osteoclastogenesis was significantly increased in cryopreserved versus fresh cells. Under these conditions, spontaneous osteoclastogenesis was not dependent on T lymphocytes, since it was not influenced by T cell depletion and persisted in purified CD14+ cell cultures supplemented with M-CSF and RANKL. In contrast to studies with fresh PBMCs, spontaneous osteoclastogenesis under these conditions did not appear to be clearly different between healthy subjects and patients with arthritis. CONCLUSION: Spontaneous osteoclastogenesis in vitro is dependent on T lymphocytes or on the direct activation of monocytic cells, depending on the test conditions. This variability warrants better validation of the relevance of this functional test for in vivo osteoclastogenesis.

The clinical spectrum of psoriasis.

The clinical picture of psoriasis is not uniform. Being one of the most common chronic inflammatory skin disorders, psoriasis may present in many different forms and may include extracutaneous manifestations. Classifications have been proposed based on disease onset or the clinical course of psoriasis. Chronic plaque psoriasis occurs in a variety of clinical forms primarily distinguished by size, distribution, and dynamics of psoriatic plaques. In addition, psoriasis inversa, localized and generalized pustular forms, erythrodermic psoriasis, as well as a number of more uncommon forms have been recognized, a distinction on clinical grounds that is relevant for the overall prognosis and impact on the patients' quality of life as well as for the choice of therapy. The broad and rather colorful clinical spectrum of psoriasis as well as implications for clinical practice will be comprehensively reviewed in this article.

Psoriasis and psoriatic arthritis: clinical features and disease mechanisms.

Psoriasis is a chronic skin disorder affecting approximately 1% to 3% of the world's population. A considerable proportion of patients with psoriasis will develop a form of inflammatory arthritis known as psoriatic arthritis whose prevalence is poorly defined. Significant advances have been made in determining the pathophysiology of both of these diseases, with recent findings strongly implicating T cells and inflammatory cytokines such as tumor necrosis factor alpha in their pathogenesis. There exists an increasing array of therapies to benefit both skin and musculoskeletal manifestations. Newer therapies, such as the biologics, are providing more targeted approaches with potentially fewer systemic toxicities, providing control of disease symptoms and inhibiting progressive joint damage in those with arthritis, as well as improving long-term function and quality of life.

Elevated angiogenin levels in synovial fluid from patients with inflammatory arthritis and secretion of angiogenin by cultured synovial fibroblasts.

Angiogenesis is a key process in the pathogenesis of inflammatory arthritis. Angiogenin is one of the most potent inducers of neovascularization in experimental models in vivo. To look for evidence that angiogenin is involved in inflammatory joint disease, we examined plasma and synovial fluid (SF) samples from rheumatology patients and synovial fibroblast cell culture supernatants. Angiogenin levels were determined by radioimmunoassay and ELISA. Plasma angiogenin concentrations ranged from 96 to 478 ng/ml, with no significant difference between patients and normal controls. In SF, angiogenin concentrations were significantly higher in patients with acute or chronic synovitis (rheumatoid arthritis (RA): median, 104 ng/ml; range 13-748, n = 14; crystal-induced arthritis (CIA): median, 149 ng/ml; range, 37-616, n = 14, and other chronic inflammatory arthritis: median, 42 ng/ml; range, 15-205; n = 9) than in the 18 patients with osteoarthritis (OA) (median, 20 ng/ml; range 8-116) (P < 0.0001, anova). Angiogenin levels in SF from RA patients in remission with secondary OA were similar to those achieved in primary OA, and decreased in parallel with the resolution of acute gout. Angiogenin protein was released by cultured synovial fibroblasts from OA and RA patients, and reached 1.18 ng/106 cells/day. These data suggest that angiogenin may mediate local inflammation in arthritis via effects on angiogenesis and leucocyte regulation.

Matrix metalloproteinase 9, apoptosis, and vascular morphology in early arthritis.

OBJECTIVE: To examine matrix metalloproteinase 9 (MMP-9) in the synovial fluid (SF) and synovial membrane (SM) in relation to vascular endothelial cell (EC) apoptosis, vascular endothelial growth factor (VEGF), and SM vascular pattern. METHODS: Thirty-four patients underwent needle arthroscopy of the knee joint; 12 had early rheumatoid arthritis (RA), 12 had early psoriatic arthritis (PsA), and 10 had osteoarthritis (OA). The early RA and early PsA patients were matched for disease activity. SF levels of MMP-9 and VEGF were measured by an enzyme-linked immunosorbent assay, and EC apoptosis was measured by TUNEL assay. MMP-9 expression was examined in SM by immunohistochemistry. Synovial tissue explants were stimulated with VEGF, and MMP-9 levels were measured in the supernatants. The synovial vascular pattern was recorded. RESULTS: SF MMP-9 levels were significantly higher in early PsA patients than in early RA patients; OA patients had minimal levels. MMP-9 levels correlated with blood vessel morphology and SF VEGF levels. MMP-9 expression was greater in early PsA SM than in early RA SM, but the difference was not significant. In contrast however, EC apoptosis was greater in early RA SM than in early PsA SM. MMP-9 levels increased 2-fold and 9-fold, respectively, in SM explant culture supernatants on day 7 in response to stimulation with 25 ng/ml and 50 ng/ml of VEGF. CONCLUSION: SF MMP-9 levels correlate with the pattern of SM neovascularization and SF VEGF levels in early inflammatory arthritis, and VEGF increases MMP-9 production by SM. Endothelial cell apoptosis, however, appears to be more prevalent in early RA. This combination of factors may explain the pattern of differential angiogenesis in these arthritides.

Mig, GRO alpha and RANTES messenger RNA expression in lining layer, infiltrates and different leucocyte populations of synovial tissue from patients with rheumatoid arthritis, psoriatic arthritis and osteoarthritis.

To investigate lymphocyte and monocyte recruitment-specific chemokine expression in synovial tissues from patients with rheumatoid arthritis (RA), psoriatic arthritis (PA) and osteoarthritis (OA), synovial membranes and cytocentrifuge preparations of 7 RA, 8 PA and 10 OA patients were examined by in situ hybridisation with antisense probes of Mig, GRO alpha and RANTES and by immunohistochemistry. Patients' local disease activity (swelling and tenderness) in order to was graded and histological evaluation was performed compare these data with their chemokine expression profiles. Mig and RANTES hybridisation signals were detected in the synovial lining layer and in cellular infiltrates, whereas GRO alpha expression was localised exclusively in the lining layer of PA and RA. Cytological analysis revealed Mig and GRO alpha mRNA mainly in monocytic cells expressing KIM6, while RANTES mRNA was demonstrated predominantly in lymphocytic cells expressing CD3. In OA synovial membranes, significantly fewer hybridisation signals were present than in RA and PA synovial membranes. Patients with PA and RA had mild to severe local disease activity, whereas OA patients showed only mild disease activity. Histologically, PA and RA inflammatory scores ranged from 1 to 5, while OA synovium was consistently graded 1. Therefore, we conclude that the differential expression of Mig, GRO alpha and RANTES in resident and in inflammatory cells has an important role in regulating leucocyte traffic in inflammatory arthropathies. The diverse leucocyte specificity of Mig, GRO alpha and RANTES may thus regulate the recruitment of different leucocyte populations, as detected in PA and RA. Therefore, the pattern of cellular infiltration in human synovitis and the corresponding clinical signs of inflammation basically reflect the localisation and expression intensity of chemokines, which may be an important target for future disease modulation.