Consensus on the management of patients with psoriatic arthritis in a dermatology setting.

BACKGROUND: Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis (PsO). Early diagnosis and prompt therapeutic intervention are crucial for limiting PsA progression and prevention of disability. Dermatologists are in a privileged position to detect early PsA. The management of patients with PsA in the dermatology setting is widely variable. OBJECTIVE: To provide practical recommendations for the management of patients with PsA in the dermatology setting including early diagnosis and treatment. METHODS: A consensus document was written by an expert panel composed by dermatologists (n = 12) and rheumatologists (n = 6). Eleven highly relevant questions were selected and elaborated with answers/statements based on a narrative literature review. The resulting document was discussed in a face-to-face meeting adopting a nominal group technique to reach consensus (i.e. 100% agreement) using the Delphi method. RESULTS: A consensus was achieved in defining the following: the clinical characteristics differentiating inflammatory and non-inflammatory signs and symptoms of joint disease; the most important differential diagnoses of PsA in clinical practice; the most useful screening questionnaires, serum laboratory tests and imaging techniques for the detection of early PsA; the criteria for dermatologist to refer patients with PsO to rheumatologist; the criteria for the diagnosis of PsA; the selection of the indices that the dermatologist could use for measuring the activity and severity of PsA in clinical practice; when systemic steroids and/or intra-articular steroid injections are indicated in the treatment of PsA. Finally, systemic treatments including synthetic and biologic disease-modifying antirheumatic drugs to be considered for the treatment of PsA have been reported. CONCLUSIONS: The implementations of these practical recommendations could be very helpful for the management of patients with PsA in the dermatology setting including early diagnosis and treatment.

European League Against Rheumatism (EULAR) recommendations for the management of psoriatic arthritis with pharmacological therapies: 2015 update.

BACKGROUND: Since the publication of the European League Against Rheumatism recommendations for the pharmacological treatment of psoriatic arthritis (PsA) in 2012, new evidence and new therapeutic agents have emerged. The objective was to update these recommendations. METHODS: A systematic literature review was performed regarding pharmacological treatment in PsA. Subsequently, recommendations were formulated based on the evidence and the expert opinion of the 34 Task Force members. Levels of evidence and strengths of recommendations were allocated. RESULTS: The updated recommendations comprise 5 overarching principles and 10 recommendations, covering pharmacological therapies for PsA from non-steroidal anti-inflammatory drugs (NSAIDs), to conventional synthetic (csDMARD) and biological (bDMARD) disease-modifying antirheumatic drugs, whatever their mode of action, taking articular and extra-articular manifestations of PsA into account, but focusing on musculoskeletal involvement. The overarching principles address the need for shared decision-making and treatment objectives. The recommendations address csDMARDs as an initial therapy after failure of NSAIDs and local therapy for active disease, followed, if necessary, by a bDMARD or a targeted synthetic DMARD (tsDMARD). The first bDMARD would usually be a tumour necrosis factor (TNF) inhibitor. bDMARDs targeting interleukin (IL)12/23 (ustekinumab) or IL-17 pathways (secukinumab) may be used in patients for whom TNF inhibitors are inappropriate and a tsDMARD such as a phosphodiesterase 4-inhibitor (apremilast) if bDMARDs are inappropriate. If the first bDMARD strategy fails, any other bDMARD or tsDMARD may be used. CONCLUSIONS: These recommendations provide stakeholders with an updated consensus on the pharmacological treatment of PsA and strategies to reach optimal outcomes in PsA, based on a combination of evidence and expert opinion.

The -308 TNFα and the -174 IL-6 promoter polymorphisms associate with effective anti-TNFα treatment in seronegative spondyloarthritis.

The genetic predisposition to a long-term efficacy of anti-tumor necrosis factor (TNF)α treatment in seronegative spondyloarthritis (SpA) was investigated by analysing the possible correlation between several single nucleotide gene polymorphisms and the retention rate of anti-TNFα therapies. We compared patients needing to switch the first anti-TNFα (Sw, No. 64) within at least 12 months of follow-up with patients not needing to switch (NSw, No. 123), observing at least 6 months of treatment to establish anti-TNFα failure, leading to treatment change. Response to treatment was evaluated by standardised criteria (BASDAI for axial involvement, DAS28-EULAR for peripheral involvement). The TNFα -308 A allele and the interleukin (IL)-6 -174GG homozygosis resulted as independent biomarkers predicting survival of the first anti-TNFα therapy in SpA patients (P=0.007, odds ratio (OR): 4.4, 95% confidence interval (CI)=1.5-13.1 and P=0.035, OR: 2.1, 95% CI=1.1-4.4). Also, the male gender (P=0.001, OR: 3.4, 95% CI=1.6-7.1) associated with the NSw phenotype, whereas no association was found either with the specific diagnosis or the predominant joint involvement.

Predictive factors for partial remission according to the Ankylosing Spondylitis Assessment Study working group in patients with ankylosing spondylitis treated with anti-TNFα drugs.

The objective of this study was to evaluate the predictive factors for achieving partial remission (PR) in patients with ankylosing spondylitis (AS) treated with anti-TNFα. We longitudinally enrolled in a multi-center study 214 AS patients, classified according to New York criteria, treated with anti-TNFα drugs adalimumab (ADA), etanercept (ETA) and infliximab (INF) with at least 12 months of follow up. PR was reached when the score was <20 mm (on a visual analogue scale of 0-100 mm) in each of the following 4 domains: 1) patient global assessment (in the last week); 2) pain (spinal pain); 3) function [measured by the bath ankylosing spondylitis functional index (BASFI)]; 4) inflammation [mean of intensity and duration of morning stiffness, from the bath ankylosing spondylitis disease activity index (BASDAI)]. Two hundred fourteen AS patients (M/F=160/54; median age/range=43.2/19-78 years; median disease duration/ range=96/36-189 months) were treated with ADA (15.8%), ETA (28.9%) and INF (55.1%). At 12 and 24 months, high serum level of C reactive protein (CRP) (≥2 vs ≤0.8 mg/dL) were associated with higher rate of PR in AS patients treated with anti-TNFα drugs. At 24 months, PR was associated with shorter disease duration (≤36 vs ≥189 months) and higher erythrosedimentation rate (ESR) values (≥45 vs ≤17 mm/h). In male patients lower bath ankylosing spondylitis metrology index (BASMI) (≤2 vs ≥6) and absence of psoriasis were associated with higher PR rate only at 12 months. Other parameters assessed before treatment, such as BASDAI, BASFI, peripheral arthritis, inflammatory bowel disease and uveitis were not associated with PR. Our long-term longitudinal study in a setting of clinical practice showed that inflammatory parameters (i.e. CRP, ESR) and disease duration represent the most important predictive variables to achieve PR with an anti-TNFα treatment.

Inhibition of the de-myelinating properties of Aicardi-Goutières syndrome lymphocytes by cathepsin D silencing.

Molecular mechanisms relating interferon-alpha (IFN-alpha) to brain damage have recently been identified in a microarray analysis of cerebrospinal fluid lymphocytes from patients with Aicardi-Goutières Syndrome (AGS). These findings demonstrate that the inhibition of angiogenesis and the activation of neurotoxic lymphocytes are the major pathogenic mechanisms involved in the brain damage consequent to elevated interferon-alpha levels. Our previous study demonstrated that cathepsin D, a lysosomal aspartyl endopeptidase, is the primary mediator of the neurotoxicity exerted by AGS lymphocytes. Cathepsin D is a potent pro-apoptotic, neurotoxic, and demyelinating protease if it is not properly inhibited by the activities of leukocystatins. In central nervous system white matter, demyelination results from cathepsin over-expression when not balanced by the expression of its inhibitors. In the present study, we used RNA interference to inhibit cathepsin D expression in AGS lymphocytes with the aim of decreasing the neurotoxicity of these cells. Peripheral blood lymphocytes collected from an AGS patient were immortalized and co-cultured with astrocytes in the presence of interferon alpha with or without cathepsin D RNA interference probes. Cathepsin D expression was measured by qPCR, and neurotoxicity was evaluated by microscopy. RNA interference inhibited cathepsin D over-production by 2.6-fold (P<0.01) in AGS lymphocytes cultured in the presence of interferon alpha. AGS lymphocytes treated using RNA interference exhibited a decreased ability to induce neurotoxicity in astrocytes. Such neurotoxicity results in the inhibition of astrocyte growth and the inhibition of the ability of astrocytes to construct web-like aggregates. These results suggest a new strategy for repairing AGS lymphocytes in vitro by inhibiting their ability to induce astrocyte damage and leukodystrophy.

Psoriatic arthritis: treatment strategies using biologic agents.

The traditional management of psoriatic arthritis (PsA) includes NSAIDs, corticosteroids and DMARDs. Advancement in the knowledge of the immunopathogenesis of PsA has been associated with the development of biologic agents which have revolutionized the management of the disease. Among biologics drugs, there are the 4 currently available anti-TNFα blocking agents (etanercept, infliximab, adalimumab and golimumab) which are more effective than traditional DMARDs on symptoms/signs of inflammation, quality of life, function, and in inhibiting the progression of the structural joint damage. Despite of the high cost, TNF inhibitors are cost-effective on both the musculoskeletal and skin manifestations of psoriatic disease.

2010 update of the ASAS/EULAR recommendations for the management of ankylosing spondylitis.

This first update of the ASAS/EULAR recommendations on the management of ankylosing spondylitis (AS) is based on the original paper, a systematic review of existing recommendations and the literature since 2005 and the discussion and agreement among 21 international experts, 2 patients and 2 physiotherapists in a meeting in February 2010. Each original bullet point was discussed in detail and reworded if necessary. Decisions on new recommendations were made - if necessary after voting. The strength of the recommendations (SOR) was scored on an 11-point numerical rating scale after the meeting by email. These recommendations apply to patients of all ages that fulfill the modified NY criteria for AS, independent of extra-articular manifestations, and they take into account all drug and non-drug interventions related to AS. Four overarching principles were introduced, implying that one bullet has been moved to this section. There are now 11 bullet points including 2 new ones, one related to extra-articular manifestations and one to changes in the disease course. With a mean score of 9.1 (range 8-10) the SOR was generally very good.

The Aicardi-Goutières syndrome. Molecular and clinical features of RNAse deficiency and microRNA overload.

Intracellular RNAses are involved in various functions, including microRNA maturation and turnover. Mutations occurring in genes encoding RNAses cause Aicardi-Goutiéres syndrome (AGS). AGS mutations silence RNAse activity, thus inducing accumulation of endogenous RNAs, mainly consisting of short RNAs and microRNAs. Overload of intracellular RNA triggers Toll like receptor-dependent interferon-alpha production in the brain, which in turn activates neurotoxic lymphocytes and inhibits angiogenesis thus inducing the typical clinical phenotype of AGS. However, these pathogenic mechanisms are attenuated after three years of age by the endogenous production of DNAJP58IPK and Cystatin F, which arrest AGS progression. Because RNAses are involved in microRNA turnover, we evaluated the expression of 957 microRNAs in lymphocytes from AGS patients and control patients. Our results indicate that microRNA overload occurs in AGS patients. This upregulation inhibits microRNA turnover impeding the synthesis of the novel microRNAs required for the differentiation and myelination of the brain during the initial period of postnatal life. These pathogenic mechanisms result in AGS, a neurological syndrome characterized by irritability, mild hyperpyrexia, pyramidal and extrapyramidal signs, and spastic-dystonic tetraplegia. Typical cerebrospinal fluid alterations include lymphocytosis and elevated interferon-alpha levels. Brain imaging demonstrates cerebral calcifications, white matter abnormalities, and progressive cerebral atrophy.Thus, evidence exists that mutations silencing intracellular RNases affect microRNA turnover resulting in the severe clinical consequences in the brain characterizing the clinical feature of AGS.

An Italian shared dermatological and rheumatological proposal for the use of biological agents in psoriatic disease.

BACKGROUND: As psoriatic disease (PD) is a condition characterized by the combination of inflammatory skin (psoriasis) and osteo-articular manifestations (psoriatic arthritis), its treatment should cover both its clinical components. OBJECTIVE: The objective of this study was to propose a flexible framework for the use of biological agents in PD. METHODS: The proposal was drawn up by a group of dermatologists and rheumatologist expert in PD and was based on existing evidence and personal opinion. RESULTS: The three TNF-alpha inhibitors (adalimumab, etanercept, infliximab) are effective in all of the psoriatic manifestations and should be used in the case of moderate/severe disease refractory to systemic treatment with non-biological drugs. We propose the following definitions of moderate/severe disease: PASI > 10 or BSA > 10 or DLQI > 10 for plaque-psoriasis; BSA > or = 10 or DLQI > or = 10 for the other psoriatic skin lesions; DLQI > or = 10 or meaningful values of the NAPSI or mNAPSI for psoriatic nail involvement; > or = 1 inflamed joint + patient global VAS(3)4 + physician's judgement or arthritic joint deformities or radiographic joint damage plus > or = 5 inflamed small joints or > or = 1 large joints for peripheral joint involvement; > or = 1 digit with dactylitis and > or = 1 enthesitic sites + patient global VAS(3)4 + physician's judgement for dactylitis and enthesitis. BASDAI > or = 4 + physician's judgement for spondylitis; recurrent flares or risk of developing irreversible damage for uveitis. Other assessment instruments can be used if the physician is more familiar with them and if they have been validated. CONCLUSION We provide a shared dermatological and rheumatological proposal for the use of biological agents in PD.

New criteria for inflammatory back pain in patients with chronic back pain: a real patient exercise by experts from the Assessment of SpondyloArthritis international Society (ASAS).

OBJECTIVE: Inflammatory back pain (IBP) is an important clinical symptom in patients with axial spondyloarthritis (SpA), and relevant for classification and diagnosis. In the present report, a new approach for the development of IBP classification criteria is discussed. METHODS: Rheumatologists (n = 13) who are experts in SpA took part in a 2-day international workshop to investigate 20 patients with back pain and possible SpA. Each expert documented the presence/absence of clinical parameters typical for IBP, and judged whether IBP was considered present or absent based on the received information. This expert judgement was used as the dependent variable in a logistic regression analysis in order to identify those individual IBP parameters that contributed best to a diagnosis of IBP. The new set of IBP criteria was validated in a separate cohort of patients (n = 648). RESULTS: Five parameters best explained IBP according to the experts. These were: (1) improvement with exercise (odds ratio (OR) 23.1); (2) pain at night (OR 20.4); (3) insidious onset (OR 12.7); (4) age at onset <40 years (OR 9.9); and (5) no improvement with rest (OR 7.7). If at least four out of these five parameters were fulfilled, the criteria had a sensitivity of 77.0% and specificity of 91.7% in the patients participating in the workshop, and 79.6% and 72.4%, respectively, in the validation cohort. CONCLUSION: This new approach with real patients defines a set of IBP definition criteria using overall expert judgement on IBP as the gold standard. The IBP experts' criteria are robust, easy to apply and have good face validity.

The radiological assessment of axial involvement in psoriatic arthritis: a validation study of the BASRI total and the modified SASSS scoring methods.

OBJECTIVES: To assess the validity of the BASRI and m-SASSS scores for the radiological axial involvement in psoriatic arthritis (PsA). Secondary end-points were to report on clinical, functional and radiographic characteristics of axial involvement. METHODS: Inclusion criteria were satisfaction of the CASPAR criteria and the presence of clinical, functional and/or radiological axial involvement. Three observers scored the radiographs by BASRI and m-SASSS. The construct validity was assessed by examining the correlation of instruments with patient reported outcomes and anthropometric measures. The reliability and the feasibility of the scores were also considered. RESULTS: Seventy-seven patients were enrolled (58 M, 19 F, mean age 49.4 + or - 10.8 yrs, disease duration 13.9 + or - 7.9 yrs). Both instruments showed some modest but significant correlation with clinical measures. When compared, the BASRI showed a correlation with BASMI (rho=0.47, p<0.001), cervical rotation (rho=-0.49, p<0.001), tragus to wall (rho=0.34, p<0.01) and occiput to wall (rho=0.49, p<0.001), modified Schober test (rho=-0.24, p<0.05) and RLDQ (rho=-0.24, p<0.05). When compared, m-SASSS showed a correlation with BASMI (rho=0.39, p<0.001), cervical rotation (rho=-0.41, p<0.001), tragus to wall (rho=0.31, p<0.01) and occiput to wall (rho=0.42, p<0.001), modified Schober and Schober test (rho=-0.34, p<0.001; rho= -0.32, p<0.01), finger to floor (rho=0.37, p<0.01). No correlation was found with BASFI, BASDAI and HAQ. Test-retest showed a good reliability of the scores. Both were feasible but BASRI was the quickest. CONCLUSION: Our results showed that BASRI and m-SASSS were valid instruments for use in spondylitis associated with psoriatic arthritis. Longitudinal data is required to provide sensitivity to change of the two scores.

Management of Behçet disease: a systematic literature review for the European League Against Rheumatism evidence-based recommendations for the management of Behçet disease.

OBJECTIVES: To present and analyse the literature sources regarding the management of Behçet disease (BD) identified during the systematic literature research, which formed the basis for the European League Against Rheumatism (EULAR) evidence-based recommendations for the management of BD. METHODS: Problem areas and related keywords regarding the management of BD were determined by the multidisciplinary expert committee commissioned by EULAR for developing the recommendations. A systematic literature research was performed using MedLine and Cochrane Library resources through to December 2006. Meta-analyses, systematic reviews, randomised controlled trials (RCTs), open studies, observational studies, case control studies and case series' involving > or = 5 patients were included. For each intervention the effect size and number needed to treat were calculated for efficacy. Odds ratios and numbers needed to harm were calculated for safety issues of different treatment modalities where possible. RESULTS: The literature research yielded 137 articles that met the inclusion criteria; 20 of these were RCTs. There was good evidence supporting the use of azathioprine and cyclosporin A in eye involvement and interferon (IFN)alpha in mucocutaneous involvement. There were no RCTs with IFNalpha or tumour necrosis factor (TNF)alpha antagonists in eye involvement. Similarly controlled data for the management of vascular, gastrointestinal and neurological involvement is lacking. CONCLUSION: Properly designed, controlled studies (new and confirmatory) are still needed to guide us in managing BD.

Persistent normalization of serum levels of uric acid in a gouty patient after administration of cyproterone acetate.

In this article we describe a gouty caucasian male patient who had high levels of serum uric acid since 1970s. Serious adverse reactions to allopurinol discouraged its administration. We prescribed cyproterone acetate (CA) because of severe prostatic hypertrophy, associated with a suspect small cancer. The administration of this drug obtained persistent normalization of serum uric acid levels. Our observation, that needs to be confirmed in other cases, could suggest a possible new treatment for gout in male patients with prostatic disorders.

The psoriatic arthritis cost evaluation study: a cost-of-illness study on tumour necrosis factor inhibitors in psoriatic arthritis patients with inadequate response to conventional therapy.

OBJECTIVE: To evaluate costs, benefits and cost-effectiveness of anti-TNF agents in PsA patients with inadequate response to conventional treatment. METHODS: A total of 107 patients, from nine Italian rheumatology centres, with different forms of PsA were given anti-TNF treatment, mainly etanercept (87%). Information on resource use, health-related quality of life, disease activity, function and laboratory values were collected at baseline and through out the 12 months of therapy. Cost (expressed in euro 2007) and utility (measured by EuroQol) before and after anti-TNF therapy initiation were compared in order to estimate the incremental cost per quality-adjusted life year (QALY) gained, and cost-effectiveness acceptability curve was calculated. RESULTS: At the end of 12 months, there was a significant increase in direct cost due to an increase of drug cost caused by TNF inhibitors that was only partially offset by the decrease in indirect cost. In the last 6 months of therapy, the direct cost increased by euro5052, the cost for the National Health System (NHS) by euro5044 and the social cost by euro4638. However, a gain of 0.12 QALY resulted in a cost per QALY gained of euro40 876 for the NHS and of euro37 591 for the society. The acceptability curve showed that there would be a 97% likelihood that anti-TNF therapy would be considered cost-effective at willingness-to-pay threshold of euro60 000 per QALY gained. CONCLUSION: Cost-effectiveness ratios are within the commonly accepted willingness-to-pay threshold. These results need to be confirmed in larger samples of patients.

HCV infection: pathogenesis, clinical manifestations and therapy.

Chronic hepatitis C virus (HCV) infection is a worldwide public health problem with a global prevalence of 2-3%. It is believed that about 170 million people are currently infected (about 3% of the world's population), and a further 3-4 million are infected each year. HCV is the main reason for liver transplantation in the developed world, and the main cause of liver-related morbidity and mortality in a number of countries, including Italy. It is not only a frequent cause of chronic liver diseases such as hepatitis, cirrhosis and hepatocellular carcinoma, but is also involved in the pathogenesis of various autoimmune and rheumatic disorders (arthritis, vasculitis, sicca syndrome, porphyria cutanea tarda, lichen planus, nephropathies, thyroid diseases, and lung fibrosis), as well as in the development of B-cell lymphoproliferative diseases. Furthermore, patients suffering from C hepatitis tend to produce rheumatoid factor, cryoglobulins and a large series of autoantibodies (ANA, anti-SSA/SSB, SAM, ATG, aCL). The use of glucocorticoids or immuno-suppressant agents in HCV infected individuals, which are needed to treat autoimmune and rheumatic disorders, leads to a risk of worsening the clinical outcome of HCV. Under these conditions, the viral infection often needs to be treated with antiviral agents, mainly pegylated interferon combined with ribavirin. However, cyclosporine A seems to be safe and effective in patients with autoimmune disease (AD) and concomitant chronic HCV infection as is documented by the reduction in viremia and transaminases, particularly in patients with high baseline levels. Finally, HCV is the main trigger of mixed cryoglobulinemia. An attempt at viral eradication is therefore indicated in most patients, and is particularly effective in the case of mild or moderate manifestations. In severe cases, rituximab is an apparently safe and effective alternative to conventional immunosuppression and, specifically, it controls B-cell proliferation.