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.

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.

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.

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.

HLA-B*2709 and lack of susceptibility to sacroiliitis: further support from the clinic.

Interferons (IFN) are well known triggers of immunomediated diseases in genetically predisposed subjects. We describe the unique case of a HLA-B*2709 positive subject who underwent IFN-alpha treatment for essential thrombocythemia and developed arthritis of the proximal interphalangeal joints of the hands but not sacroiliitis. The possible mechanisms of IFN-induced arthritis are discussed.

Genetics of psoriasis and psoriatic arthritis.

Psoriasis and psoriatic arthritis are linked diseases characterised by (distinct ?) immune-mediated pathogenetic mechanisms and by a genetic background interacting with environmental factors. Some candidate susceptibility genes have been studied extensively; they include HLA genes, genes within the HLA region and genes outside the HLA region; among them corneodesmosin and other genes of PSORS1 region, MICA and TNF-a polymorphisms. The main findings in the literature are discussed.

CD1 expression in psoriatic and rheumatoid arthritis.

OBJECTIVE: CD1 is a novel class of molecules which present non-protein antigens to T cells. The objective of this study was to evaluate the expression of CD1 in the skin and synovium of patients with psoriatic arthritis (PsA) in comparison with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Paired lesional skin (SK) and synovial membrane (SM) from four PsA patients, paired SK and SM from four RA patients, SM from eight RA and eight OA patients, and normal SK from four volunteers were studied using standard immunohistochemistry. RESULTS: In all PsA and RA skin samples CD1-positive cells were abundantly detected both in the dermis and in the epidermis. However, in the 24 SM examined CD1-positive cells were rarely found. In one patient only with RA, a few CD1a-positive cells were found in the SM. CD1b was scarcely expressed in the lining layer (LL) of five SM and in very few cells in the sublining layer (SL) of 11 SM. CD1c was rarely expressed in the LL of six SM and in very few cells in the SL of 13 SM. CONCLUSION: The paucity of CD1 in the PsA and RA synovium suggests that different subsets of antigen-presenting cells are involved in the pathogenesis of dermatitis and synovitis, respectively.

Increased pulmonary epithelial permeability in systemic sclerosis is associated with enhanced cutaneous nerve growth factor expression.

Background: Nerve growth factor (NGF), a neurotrophic factor that indirectly induces fibroblast proliferation and collagen production, has been found to be increased in the affected dermis of patients with systemic sclerosis (SSc). To investigate the possibility of a relationship between cutaneous NGF production and pulmonary damage in SSc, we studied seven non-smoking scleroderma patients. Methods: Abnormalities in lung structure were assessed by radiological lung examination, and pulmonary epithelial permeability (PEP) was determined by ventilation lung scintigraphy. All patients underwent skin punch biopsy with NGF immunohistological staining. Results: A statistically significant correlation was found between the PEP values and the cutaneous NGF staining scores, which were markedly increased in all of the patients examined, irrespective of the age, disease duration, or radiologically defined lung abnormalities. Conclusion: These results support the hypothesis that functional and anatomical changes in SSc target organs may be determined by a local tissue hyperproduction of NGF.

Bleomycin-induced scleroderma: report of a case with a chronic course rather than the typical acute/subacute self-limiting form.

We report a case of bleomycin-induced scleroderma in a 35-year-old woman treated with chemotherapy for Hodgkin's disease. Approximately 6 months after the first chemotherapy cycle, the patient developed skin sclerosis in both arms. The lesion showed no signs of spontaneous clinical amelioration and treatment with steroids was unsuccessful. A partial remission of the skin sclerosis was instead obtained by the administration of D-penicillamine. A family history revealed other cases of autoimmune diseases and HLA typing showed the presence of antigens associated with scleroderma. The association between bleomycin therapy and scleroderma is discussed.

Interleukin-1, interleukin-1 receptor antagonist and macrophage populations in rheumatoid arthritis synovial membrane.

To determine whether interleukin-1 (IL-1) and interleukin-1 receptor antagonist (IL-1ra) are produced by different macrophage subsets, we applied immunoperoxidase and double-labelling immunofluorescence techniques to 10 rheumatoid arthritis (RA) and 10 osteoarthritis (OA) synovial membranes. In RA, greater numbers of early 27E10+ macrophages were found in the sublining layer while mature 25F9+ macrophages were more abundant in the lining layers. The majority of IL-1alpha+ cells were also IL-1ra+ (79 +/- 12% sublining layer, 98 +/- 2% lining layer). In OA sublining layer, a higher percentage of cells double stained for 25F9 and IL-1ra was detected compared to those double stained for 25F9 and IL-1alpha (P < 0.004). In OA, 25F9+ macrophages demonstrated a lower percentage of IL-1alpha+ in the lining and sublining layers compared to RA (P < 0.02 and P < 0.004, respectively). It may be concluded that once monocytes have migrated into the RA joint, they undergo phenotypic and functional changes from an early profile (27E10+, CD14+, low percentage of IL-1+ and IL-1ra+ cells) to a mature profile (CD14+/-, 25F9+, RM3/1+, high percentage of IL-1+ and IL-1ra+ cells).

Cutaneous lymphocyte antigen-positive T lymphocytes preferentially migrate to the skin but not to the joint in psoriatic arthritis.

OBJECTIVE: To investigate whether T cell migration into different sites of inflammation (skin and synovium) within the same individual is principally regulated by tissue-specific homing or by more general mechanisms related to inflammation. METHODS: Expression of cutaneous lymphocyte antigen (CLA) and its ligand, E-selectin, was analyzed by immunohistochemistry and immunofluorescence using paired skin and synovial membrane (SM) samples from patients with psoriatic arthritis (PsA). To investigate disease specificity, delayed-type hypersensitivity (DTH) skin lesions, induced by tuberculin purified protein derivative, and SM from patients with rheumatoid arthritis (RA), were studied as controls. To directly examine cell migration in in vivo, the proportion of CLA+ T lymphocytes migrating into suction-induced skin blisters was assessed by flow cytometry. Using the same technique, levels of paired peripheral blood and synovial fluid (SF) T cells were also analyzed. RESULTS: CLA+ T cells preferentially accumulated in the skin, but not in the joint, of patients with PsA. Similarly, CLA+ T lymphocytes predominated in the DTH skin lesions of RA patients, but were very rare in the SM of RA patients, and were scarcely represented in the SF of patients with several chronic inflammatory arthropathies. In addition, CLA+ T lymphocytes preferentially migrated into epidermal skin blisters. This preferential pattern of CLA+ T cell accumulation was not related to the selective expression of E-selectin, since this was similar in the skin and SM of both PsA and RA patients. CONCLUSION: The distinct pattern of T cell infiltration into sites of inflammation within the skin and synovium is regulated by both organ-specific homing and general inflammation-related mechanisms.

Reduction of synovial inflammation after anti-CD4 monoclonal antibody treatment in early rheumatoid arthritis.

OBJECTIVE: To study the effect of chimeric anti-CD4 monoclonal antibody (MAb) therapy on synovial inflammation, in order to interpret the clinical experience with anti-CD4 treatment. METHODS: The immunohistologic features of synovial biopsy specimens before and 4 weeks after anti-CD4 MAb (cM-T412) therapy were studied in patients with rheumatoid arthritis. The patients received intravenous doses of either placebo (n = 1) or 10 mg (n = 4), 25 mg (n = 2), or 50 mg (n = 1) of cM-T412 daily for 5 consecutive days. RESULTS: Although the patients did not experience clinical improvement, significant decreases in the number of circulating CD4+ cells, the degree of synovial inflammatory infiltration, and the mean scores for expression of adhesion molecules were found in the 7 patients 4 weeks after receiving cM-T412. The scores for infiltration with CD4+ and other inflammatory cells were particularly reduced following treatment with either 25 mg or 50 mg cM-T412. Cytokines, such as interleukin-1 beta and tumor necrosis factor alpha, could still be detected in the synovial tissue after treatment. CONCLUSION: The decline in the numbers of inflammatory cells and adhesion molecules in synovial tissue after CD4+ cell depletion supports the view that CD4+ T cells orchestrate local cellular infiltration. The lack of clinical effect of anti-CD4 therapy might be explained by an insufficient decrease in the number of synovial CD4+ cells and by the persistence of cytokines. Determination of whether more adequate dosing would lead to a clinical improvement must await further study.

Cytokine and adhesion molecule expression in the minor salivary glands of patients with Sjögren's syndrome and chronic sialoadenitis.

OBJECTIVE: To investigate the role of cytokines and cell adhesion molecules in the pathogenesis of Sjögren's syndrome (SS). METHODS: Using an indirect immunoperoxidase technique we assessed the expression of the cytokines interleukin-1 alpha (IL-1 alpha), interleukin-1 beta (IL-1 beta), interleukin-8 (IL-8), transforming growth factor beta (TGF beta) and granulocyte macrophage colony stimulating factor (GM-CSF), of the adhesion molecules intercellular adhesion molecule-1 (ICAM-1), lymphocyte function associated antigen-1 (LFA-1), the activated molecular form of LFA-1 (NKI-L16), CD2, and LFA-3, and of a panel of cellular markers in the minor salivary glands. RESULTS: In SS and chronic sialoadenitis (CS), the ductal epithelial cells and acini expressed all the cytokines examined. The percentage of glandular mononuclear cells which stained positive for cytokines did not differ significantly between SS and CS. NKI-L16 was detected on 33.6 (SD 10.1)% and 15.3 (4.3)% of LFA-1 cells in SS and CS, respectively (p < 0.002). CONCLUSION: SS and CS did not differ in the pattern of cytokines examined. The characteristic cell clustering seen in the salivary glands in SS may be caused by the upregulation of NKI-L16.

Tracheo-bronchial mucociliary clearance in patients with primary and secondary Sjögren's syndrome.

We determined the tracheo-bronchial mucociliary clearance (MCC) in order to evaluate a possible impairment of this function in patients affected by Sjögren's syndrome (SS) with or without overt clinical symptoms of xerotrachea. The MCC was expressed as flow rate (mm/min) and studied in 22 non-smoking SS patients (10 pSS and 12 sSS) and in 8 control subjects by specifically adapted ventilation lung scintigraphy (VLS). The MCC in the control group was 5.9 +/- 1.1 mm/min. No values were produced for MCC in 16 SS patients (8 pSS and 8 sSS) in the time interval considered and were reduced in the remaining 6 SS patients (3.3 +/- 1.2 mm/min). In all nine cases with clinical evidence of xerotrachea no values for MCC were obtained. A significant correlation was found between the MCC values and the rate of stimulated salivary excretion determined by dynamic scialoscintigraphy in the same patients (p < 0.001). These preliminary data show that the majority of SS patients studied presented with MCC impairment, always found when clinical symptoms of xerotrachea were present.