The Italian Society for Rheumatology recommendations for the management of axial spondyloarthritis.

Over the last few years, the landscape of treatments for axial spondyloarthritis (SpA) has been rapidly evolving, urging international scientific societies to draft or update existing clinical practice guidelines (CPGs) on the management of axial SpA. The Italian Society for Rheumatology (SIR) committed to provide revised and adapted evidence- and expert-based recommendations for the management of patients with axial SpA in Italy. A systematic approach to the adaptation of existing CPGs - the ADAPTE methodology - was adopted to obtain updated recommendations suitable for the Italian context. A systematic literature search was performed in Medline and Embase databases to find international CPGs and consensus statements with recommendations for the management of axial SpA published in the previous five years. A working group composed of rheumatologists with proven experience in the management of axial SpA and methodologists identified the key research questions which guided study selection and data extraction. Guideline quality was assessed using the Appraisal of Guidelines Research and Evaluation (AGREE) II tool. The Italian recommendations were developed by endorsing or adapting and rewording some existing recommendations. The draft of the recommendations was sent to a multidisciplinary group of external reviewers for comment and rating. Six original CPGs were selected and used to create this SIR CPG, which includes a final set of 14 recommendations covering the management of patients with axial SpA across the following domains: assessment, pharmacological and non-pharmacological treatment, and follow-up. The dissemination and implementation of these SIR recommendations are expected to support an evidencebased clinical approach to the management of patients with axial SpA in Italy.

In memory of Dr. Luis Espinoza.

Not available.

Spa therapy induces clinical improvement and protein changes in patients with chronic back pain.

This study is primarily aimed at assessing serum changes on a large panel of proteins in patients with chronic back pain following spa therapy, as well as evaluating different spa therapy regimens as a preliminary exploratory clinical study. Sixty-six patients with chronic back pain secondary to osteoarthritis were randomly enrolled and treated with daily mud packs and bicarbonate-alkaline mineral water baths, or a thermal hydrotherapy rehabilitation scheme, the combination of the two regimens or usual medication only (control group), for two weeks. Clinical variables were evaluated at baseline, after 2 and 12 weeks. One thousand serum proteins were tested before and after a two-week mud bath therapy. All spa treatment groups showed clinical benefit as determined by improvements in VAS pain, Roland Morris disability questionnaire and neck disability index at both time points. The following serum proteins were found greatly increased (≥2.5 fold) after spa treatment: inhibin beta A subunit (INHBA), activin A receptor type 2B (ACVR2B), angiopoietin-1 (ANGPT1), beta-2-microglobulin (B2M), growth differentiation factor 10 (GDF10), C-X-C motif chemokine ligand 5 (CXCL5), fibroblast growth factor 2 (FGF2), fibroblast growth factor 12 (FGF12), oxidized low density lipoprotein receptor 1 (OLR1), matrix metallopeptidase 13 (MMP13). Three proteins were found greatly decreased (≤0.65 fold): apolipoprotein C-III (Apoc3), interleukin 23 alpha subunit p19 (IL23A) and syndecan-1 (SDC1). Spa therapy was confirmed as beneficial for chronic back pain and proved to induce changes in proteins involved in functions such as gene expression modulation, differentiation, angiogenesis, tissue repair, acute and chronic inflammatory response.

Musculoskeletal manifestations as determinants of quality of life impairment in patients with systemic lupus erythematosus.

Objective The objective of this study was to identify determinants of health-related quality of life (HRQoL) impairment in patients with systemic lupus erythematosus (SLE). Methods Overall, 101 SLE patients were recruited; 37 healthy subjects and 35 rheumatoid arthritis (RA) patients served as controls. HRQoL was evaluated using three patient reported outcomes (PROs): the Short Form-36 version 2 (SF-36v2) health survey, the fatigue scale version 4 (FACITv4) and the Heath Assessment Questionnaire (HAQ). A large set of demographic and clinical variables, including SLE arthritis subtypes, was evaluated searching for factors independently associated with worse QoL. Multivariate models were applied to identify factors independently associated with outcomes. Bonferroni's corrected p values < 0.05 were considered significant. Results SLE patients showed worse results than healthy controls ( p < 0.01) in all SF-36v2 domains and, with reference to the mental QoL, also than RA patients ( p < 0.01). Jaccoud's deformities, active arthritis, and fibromyalgia were the only factors independently associated with worse results in both physical and mental components summary of the SF-36v2 ( p < 0.01) and FACITv4 fatigue scale ( p < 0.01). Fragility fractures, deformities, and active arthritis negatively affected disability perception measured by the HAQ ( p < 0.01). No statistically significant differences in perceived HRQoL were highlighted between patients with deforming and erosive arthritis. However, they had significantly worse results than patients with non-deforming non-erosive arthritis across all investigated PROs ( p < 0.01). Conclusion In order to limit musculoskeletal manifestations as a source of impaired QoL in SLE patients, therapeutic strategies targeted to successfully manage active arthritis and fibromyalgia and to prevent deforming damage are needed.

Demyelinating syndrome in SLE: review of different disease subtypes and report of a case series.

Demyelinating syndrome (DS) is a rare manifestation of systemic lupus erythematosus (SLE) (1%) with high clinical heterogeneity and potentially severe prognosis. It can represent a diagnostic and therapeutic challenge for clinicians. A recent study described 5 different patterns of demyelinating disease presentation, characterised by specific clinical, laboratory and brain and spine magnetic resonance imaging abnormalities: 1) neuromyelitis optica; 2) neuromyelitis optica spectrum disorders; 3) DS prevalently involving the brain; 4) DS prevalently involving the brainstem; 5) clinically isolated syndrome. In this review we briefly discuss typical characteristics of each DS presentation in SLE and we describe 5 illustrative clinical cases, one for each subset of DS, considering both diagnostic and therapeutic options.

Population-based analysis of hospitalizations in a West-European region revealed major changes in hospital utilization for patients with systemic lupus erythematosus over the period 2001-2012.

OBJECTIVE: The objective of this paper is to evaluate hospital admissions in systemic lupus erythematosus (SLE) patients through a retrospective population-based study analyzing hospitalization data during 2001-2012 in Sardinia, an Italian region with universal health system coverage. METHODS: Data on the hospital discharge records with the ICD-9-CM code for SLE (710.0) were obtained from the Department of Health and Hygiene and analyzed, mostly focusing on primary and non-primary diagnosis and Diagnosis-Related Group (DRG) code. In order to establish the significance of the annual trend for number and type of primary and non-primary discharge diagnosis, the two-tailed Cochran-Armitage test for trend was applied. In order to estimate SLE prevalence, data from administrative database and medical records were assembled. RESULTS: This study included 6222 hospitalizations in 1675 patients (87% women). Hospitalizations with SLE as primary diagnosis were 3782 (58.0%) and significantly decreased during the study period. The annual number of renal, hematologic and neuropsychiatric disorders as non-primary diagnosis associated with SLE remained constant; however, their percentage increased (p < 0.0001) because of a declining number of admissions for SLE without associated diagnosis and without complications. Hospitalizations with SLE as non-primary diagnosis showed a significant upward trend in number and percentage of cerebrovascular accident (p = 0.0004), acute coronary syndrome (p = 0.0004) and chronic renal failure (p = 0.0003) as underlying primary diagnosis, while complications of pregnancy, labor and childbirth (p = 0.3375), malignancies (p = 0.6608) and adverse drug reactions (p = 0.2456) did not show statistically significant changes. Infections showed an increasing trend between 2001 and 2012 but did not reach statistical significance (p = 0.0304). After correction for hospitalization (93.8%) and survival (91.1%) rates calculated over the study period, the 2012 SLE prevalence in Sardinia was estimated to be 99.3 per 100,000 inhabitants. CONCLUSIONS: While overall hospitalizations for SLE patients declined, those for cerebrovascular accident, acute coronary syndrome and chronic renal failure as underlying primary diagnosis increased during the study period.

Bone mineral density in women on long-term mud-bath therapy in a Salus per Aquam (SPA) environment.

The objective of this study was to assess bone mineral density (BMD) in women on long-term mud-bath therapy (MBT) for osteoarthritis in a Salus per Aquam (SPA) environment. Two hundred and fifty female patients were randomly enrolled in this study in the SPA center of Sardara (Cagliari, Italy) where they were treated with a combination of daily full body mudpacks and bicarbonate-alkaline mineral water baths at cycles of 2 weeks/year. BMD was evaluated by means of calcaneus ultrasonometry (Sahara Hologic Inc., Bedford, MA, USA) and results analyzed according to duration of treatment and clinical variables. In the group of patients undergoing MBT for more than 10 years (group A) and for 3 to 10 years (group B) a reduced frequency of osteopenia and osteoporosis was detected (35.8% and 7.6% group A; 38.4% and 8.5% group B, respectively) compared to controls (group C) (48.9% and 23.4%, P<0.01 and P<0.001). Furthermore, higher T-score values were detected in group A and B (-1.05±1.28 and -1.24±0.94, respectively) compared to group C (-1.93±0.78) (P<0.0002 and P<0.0001). Similar results were observed in the analysis of data restricted to women in menopause only. Long-term mud-bath therapy in SPA environment appeared to be beneficial for BMD.

Rituximab treatment for 'rhupus syndrome': clinical and power-Doppler ultrasonographic monitoring of response. A longitudinal pilot study.

OBJECTIVE: To evaluate the safety and efficacy of rituximab in patients suffering from rhupus unresponsive to therapy with non-biological disease-modifying anti-rheumatic drugs (DMARDs). METHODS: Six patients fulfilling criteria for both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) and with a DAS28 score >5.1 were enrolled to receive two fortnightly 1000 mg rituximab doses at baseline and after 28 weeks. All patients underwent clinical, laboratory, and power- Doppler (PD) ultrasonographic (US) assessment at baseline and after 14, 28 and 56 weeks. RESULTS: A sustained improvement in DAS28, SLEDAI, HAQ, laboratory markers and ultrasound indices together with a significant reduction in the daily dose of prednisone were observed throughout follow-up. CONCLUSION: Rituximab may be a safe and effective therapeutic option in refractory rhupus patients.

Psoriatic arthritis: genetics and pathogenesis.

Psoriatic arthritis is a complex disease affecting primarily peripheral and axial joints and entheses together with the skin. The pathogenesis is characterized by a genetic background and by inflammatory mechanisms which may be triggered by environmental factors. Several susceptibility genes have been investigated; they include HLA genes, genes within the HLA region and genes outside the HLA region. T cells, including the recently described subset Th17, are thought to play an important role in the acute and chronic phases of the disease. Some of these findings allowed novel therapeutic interventions or opened new promising approaches in treatment. The most relevant data of the literature are summarized and discussed.

Susceptibility to ankylosing spondylitis but not disease outcome is influenced by the level of HLA-B27 expression, which shows moderate variability over time.

OBJECTIVE: Previous reports have highlighted the relevance of HLA-B27 expression in the pathogenesis of ankylosing spondylitis (AS). The aim of the current study was to estimate the level of HLA-B27 expression on the cell surface of ex vivo monocytes and lymphocytes by a quantitative method and to correlate this with AS disease susceptibility, disease clinical indexes, and the occurrence of acute anterior uveitis (AAU). METHOD: We recruited 32 B27-positive patients with AS and 32 B27-positive healthy normal controls (NCs) for evaluation at different time points. The expression of HLA-B27 molecules was quantified by flow cytometry on ex vivo peripheral blood mononuclear cells (PBMCs). Patients were also evaluated by scores on the Bath AS disease activity (BASDAI), functional (BASFI), and metrology (BASMI) indexes. RESULTS: The expression of HLA-B27 molecules was significantly higher in patients with AS than in B27-matched controls in the case of both monocytes [219K (IQR 174K-308K) vs. 137K (IQR 96K-170K), p < 0.0001] and lymphocytes [82K (IQR 58K-118K) vs. 54K (IQR 44K-61K), p < 0.0001]; AS only vs. AS with AAU: p = 0.744 in monocytes and p = 0.701 in lymphocytes. Comparisons with metrology and functional indexes were also not significant (BASMI: r = 0.05, p = 0.77; BASFI: r = -0.09, p = 0.67). The overexpression of HLA-B27 molecules was stable after 1 week of follow-up. At 3 years follow-up, the variability was moderate and did not correlate with variations in disease activity (BASDAI: r = -0.01, p = 0.92 ns). CONCLUSIONS: The level of HLA-B27 expression in PBMCs correlates with the susceptibility to AS but not with the disease outcome, nor with the occurrence of extra-articular manifestations such as AAU.

Liver involvement in systemic lupus erythematosus: incidence, clinical course and outcome of lupus hepatitis.

OBJECTIVES: The aims of this study were to assess the spectrum of liver disease occurring in systemic lupus erythematosus (SLE), primarily the incidence, clinical course and outcome of lupus hepatitis (LH). METHODS: The records of 283 SLE out-patients referred to our Unit between 1994 and 2008 were reviewed to identify clinical or laboratory evidence of liver involvement. Liver enzyme values were considered abnormal when a sustained increase in serum transaminase levels above the normal value was observed for a period of at least three months or when the increase was confirmed in two consecutive assessments. Study inclusion criteria were a follow-up of at least 12 months and three liver function tests per year over the course of disease. RESULTS: A total of 242 patients with a mean follow-up of 72.2+/-59.1 months were identified. Liver enzyme abnormalities were observed in 45 (18.6%) patients. Of these, only 14 cases (5.8%) could be attributed to LH. Clinical course and response to therapy enabled the identification of three different patterns: remitting, unremitting and relapsing forms. Acute hepatitis and liver failure were not observed. Low serum alanine transaminase levels at diagnosis and high doses of prednisone were associated to resolution of LH. Clinical course or response to therapy did not appear to be affected by liver histology or serological findings. CONCLUSIONS: LH is generally sub-clinical with a fluctuating course and responds well to moderate to high doses of prednisone without progression to end-stage liver disease.

Defective cerebral gamma-aminobutyric acid-A receptor density in patients with systemic lupus erythematosus and central nervous system involvement. An observational study.

Gamma-aminobutyric acid-A (GABA-A) receptors play a crucial role in regulating neuronal excitability and cognitive functions. Single-photon emission computerized tomography (SPECT) analysis of GABA-A receptors binding by (123)I-labelled Iomazenil ((123)I-IMZ) has been applied in some neuropsychiatric disorders to investigate conditions where GABA-A receptor density can be detected in several pathophysiological conditions. In this study we investigate cerebral GABA-A receptor density in a small series of patients with systemic lupus erythematosus (SLE) and cognitive impairment characterized by recurrent, episodic memory loss. Nine female patients with SLE and cognitive alterations underwent to a clinical neuropsychiatric evaluation including digital video-EEG, brain MRI, (99m)Tc-ECD brain SPECT and (123)I-IMZ brain SPECT. All patients tested showed diffuse or focal GABA-A receptor density reduction. This is, to our knowledge, the first report on GABA-A receptor density abnormalities associated with cognitive defects in SLE patients. We hypothesize that in our series a decrease in GABA-A receptor density might be related to the neurological manifestations. Further studies are needed to clarify this aspect and the possible mechanisms. GABA-A receptor density impairment might be due to the SLE-related cerebral vasculopathy, or to neuronal-reacting auto-antibodies or drugs which could interfere with GABA-A receptors expression/binding. This study may support the concept that cognitive impairment in systemic lupus erythematosus could be the outcome of fine-tuned neurotransmission alterations.

The 10-year follow-up data of the Euro-Lupus Nephritis Trial comparing low-dose and high-dose intravenous cyclophosphamide.

OBJECTIVE: To update the follow-up of the Euro-Lupus Nephritis Trial (ELNT), a randomised prospective trial comparing low-dose (LD) and high-dose (HD) intravenous (IV) cyclophosphamide (CY) followed by azathioprine (AZA) as treatment for proliferative lupus nephritis. PATIENTS AND METHODS: Data for survival and kidney function were prospectively collected during a 10-year period for the 90 patients randomised in the ELNT, except in 6 lost to follow-up. RESULTS: Death, sustained doubling of serum creatinine and end-stage renal disease rates did not differ between the LD and HD group (5/44 (11%) vs 2/46 (4%), 6/44 (14%) vs 5/46 (11%) and 2/44 (5%) vs 4/46 (9%), respectively) nor did mean serum creatinine, 24 h proteinuria and damage score at last follow-up. Most patients in both groups were still treated with glucocorticoids, other immunosuppressant agents and blood pressure lowering drugs. After 10 years of follow-up, the positive predictive value for a good outcome of an early drop in proteinuria in response to initial immunosuppressive therapy was confirmed. CONCLUSION: The data confirm that a LD IVCY regimen followed by AZA-the "Euro-Lupus regimen"-achieves good clinical results in the very long term.

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.

Hemarthrosis as acute presentation of acquired hemophilia in a patient with systemic lupus erythematosus: successful treatment and long-lasting remission.

Hemorrhagic events due to production of antibodies directed against coagulation factors are rarely observed in systemic lupus erythematosus (SLE). We report the case of a patient with clinically quiescent SLE who developed factor VIII inhibitor in acquired hemophilia presenting as hemarthrosis. Initial treatment with FVII, FVIII and FIX plasma concentrate, metilprednisolone and immunoglobulins i.v. were started but new hemorrhagic manifestation occurred. Plasma exchange was also administered, but it was discontinued early due to partial efficacy. In addition, pulse cyclophosphamide 0.5 g/m(2) was started. Eight weeks later, FVIII and FIX activity returned within normal ranges, FVIII and FIX inhibitors decreased significantly and hemorrhagic manifestations disappeared. The rare occurrence of acquired hemophilia due to the presence of anti-factor VIII antibodies associated to SLE, which was reviewed, might explain the lack of therapeutic guide-lines; indeed therapeutic options are available but the outcome in each single patient is not predictable.

Association of MICA alleles with psoriatic arthritis and its clinical forms. A multicenter Italian study.

OBJECTIVE: Analysis of the association between psoriatic arthritis (PsA) clinical forms and MICA gene transmembrane polymorphisms. METHODS: Patients were classified as having peripheral asymmetric oligoarthritis (AO), peripheral symmetric poly-arthritis (PA) and spondylitis (SP), or disease combinations (PA/SP, OA/SP). Two hundred and twenty-six patients with PsA were typed for MICA exon 5 microsatellite (TM) by heteroduplex analysis and compared with 225 normal controls. RESULTS: MICA-TM microsatellite typing revealed that, among the different clinical forms of PsA, only the combined PA/SP subset shows a significant positive association with MICA-A9 and a lower frequency of MICA-A4, A5 genotype in PsA patients with a decrease, only in the PA/SP cohort, of all MICA-A5 combinations except MICA-A5, -A9. CONCLUSION: These results suggest a role for genes within the HLA region in the pathogenesis of PsA, and reinforce the idea that the different forms of PsA may have heterogeneous genetic basis.

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.

A functional polymorphism of the vasoactive intestinal peptide receptor 1 gene correlates with the presence of HLA-B*2705 in Sardinia.

The association of HLA-B27 with ankylosing spondylitis (AS) is the strongest among all inflammatory diseases. However, the exact role of these molecules in disease pathogenesis is still unknown. The existence of HLA-B27 variants rarely found in patients introduces a further level of complexity. It is now accepted that other genes of minor impact contribute to modify disease susceptibility and these genes might be diverse in different populations depending on the genetic background. We report here a study performed in Sardinia, an outlier population in which two major HLA-B27 subtypes are present, B (*)2705 strongly associated with AS and B (*)2709 which is not, and show the co-occurrence of the B (*)2705 allele with a single nucleotide polymorphism (SNP) mapping at 3'-UTR of the receptor 1 (VIPR1) for the vasoactive intestinal peptide (VIP), a neuropeptide with anti-inflammatory properties. This same SNP is associated with a different kinetics of down-modulation of the VIPR1 mRNA in monocytes after exposure to lipopolysaccharide (P=0.004). This particular setting, HLA-B (*)2705 and a functional polymorphism in VIPR1 gene, might be due to a founder effect or might be the result of a selective pressure. Irrespectively, the consequent downregulation of this receptor in the presence of a 'danger' signal might influence susceptibility to AS.