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.

Interleukin-13 in autoimmune rheumatic diseases: relationship with the autoantibody profile.

OBJECTIVE: Several cytokines play a role in the production of autoantibodies such as RF and ANA by B-lymphocytes; the role of IL-13 in this process has not been previously studied. We investigated the relationship between the serum concentration of this cytokine and circulating autoantibodies. METHODS: IL-13 serum levels, as well as RF and ANA, were evaluated in 282 patients with autoimmune rheumatic diseases including RA (n=84), SLE (n= 114), SS (n=52) and Scl (n=32). RESULTS: Serum levels of IL-13 (pg/ml) were significantly higher in patients with RA (p < 0.00003), SLE (p < 0.03), SS (p < 0.0007), or Scl (p < 0.025) compared to controls. IL-13 serum levels correlated with those of RF in RA (p < 0.00001), SLE (p < 0.003) and Scl (p < 0.03). IL-13 levels were higher in RA (p<0.0003), SLE (p<0.005) and Scl (p<0.05) patients with RF than in patients without RF. SS patients with antiSSA/Ro antibodies had significantly higher IL-13 levels than SS patients without this autoantibody (p < 0.04). No statistically significant correlation was found between IL-13 levels and any other antinuclear autoantibody, total immunoglobulin levels or the main clinicalfeatures of each disease. CONCLUSION: The evidence of higher IL-13 levels in our RA, SLE, SS and Scl patients confirms that this cytokine is involved in the pathogenesis of autoimmune rheumatic diseases. The relationship of this cytokine with RF in RA, SLE and Scl, as well as with antiSSA/ Ro antibody in SS, strengthens the hypothesis that it plays a role in autoantibody production. However, the different autoantibody synthesis by B-cells recognises different pathways depending on the underlying autoimmune disease.

Sacroiliac joint involvement in primary hyperparathyroidism: pathogenetic considerations.

The present report describes the first case of primary hyperparathyroidism with monolateral sacroiliac ankylosis assessed by coronal CT scans. The coexistence of ankylosis with erosive changes, without features of spondyloarthritis or degenerative changes, could be related to hyperparathyroidism.

Natural killer cells and gamma/delta T cells in synovial fluid and in peripheral blood of patients with psoriatic arthritis.

OBJECTIVE: NK surface markers and gamma/delta TCR antigen are involved in non-MHC-restricted cytotoxicity, which represents a major effector mechanism of the cell-mediated immune response. We evaluated in PsA patients SF and PB lymphocytes expressing these cellular subsets in order to obtain information on the possible role played by them in the disease. METHODS: We studied 29 PsA and 27 RA patients, as well as 27 healthy controls. In 17 PsA and 16 RA patients with knee joint effusion, analysis of SF was performed. SF and PB lymphocyte analysis was performed by direct dual immunofluorescence flow cytomettry using anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-TCR-gamma/delta-1 and anti-CD16 and anti-CD56 monoclonal antibodies. RESULTS: PsA and RA patients had, with respect to controls, lower values (both as percentages and in absolute numbers) of PB T cells expressing gamma/delta TCR. SF Iymphocytes of PsA and RA patients were characterised, as compared to PB lymphocytes, by lower numbers (both in absolute numbers and in relative terms) of NK and NK-T cells. Considering the absolute numbers of the various lymphocyte subsets, a strong correlation was found in PsA SF between gamma/delta T cells and NK (p < 0.0007) or NK-T cells (p < 0.0003), as well as between NK and NK-T cells (p < 0.0019). There was instead no statistically significant correlation among the different SF or PB lymphocytes and the most relevant clinical or serological parameters. CONCLUSION: This study, analyzing the impairment of different subsets involved in non-MHC-restricted cytotoxicity, suggests that this component of the cell-mediated immune response seems to play a pivotal role in the development of PsA.

Comparison of cyclosporin A and methotrexate in the treatment of psoriatic arthritis: a one-year prospective study.

OBJECTIVE: To compare the effectiveness and toxicity of cyclosporin A (CsA) vs low-dose methotrexate (MTX) over a period of one year in the treatment of psoriatic arthritis (PsA) with peripheral involvement. METHODS: Thirty-five patients with PsA were enrolled in a prospective, controlled, randomized trial. CsA was initially given in doses of 3 mg/kg/day to a maximum permitted dose of 5 mg/kg/day; MTX was given in oral doses of 2.5 mg every 12 hours for 3 consecutive doses each week up to a maximum dose of 15 mg/weekly. Clinical and laboratory evaluations were performed at entry and monthly thereafter. RESULTS: After 6 and 12 months the number of painful joints, the number of swollen joints, the Ritchie index, the duration of morning stiffness, grip strength, CRP, the patient's and the physician's assessment of PsA activity, as well as the PASI, were significantly improved in both treatment groups. ESR values were significantly reduced only in the MTX group (p < 0.01), which also showed a significantly increase of liver enzymes. The changes in the main clinical and laboratory parameters during the course of CsA or MTX treatment were not significantly different except for the AST and ALT levels (p < 0.05). After one year of therapy CsA and MTX were withdrawn in 41.2% and 27.8% of the patients respectively, but these differences were not statistically significant. CONCLUSION: Our one-year prospective trial shows that low-dose CsA and MTX are both effective in the treatment of PsA, but the differences in the tolerability of these drugs must be considered at the start of therapy.

Interleukin-6 and soluble interleukin-2-receptor in psoriatic arthritis: correlations with clinical and laboratory parameters.

OBJECTIVE: In this study we evaluated the relationships of IL-6 and sIL-2R levels with the main clinical and laboratory parameters in PsA patients with peripheral polyarthritis. METHODS: Serum levels of IL-6 and sIL-2R were measured by an enzyme immunoassay kit in patients with peripheral (< 4 joints) PsA (n = 47), with RA (n = 41), or with psoriasis (N = 15) and in healthy volunteers (n = 15) RESULTS: The patients with PsA had higher serum levels of IL-6 and sIL-2R than healthy volunteers and psoriatic patients, while they showed lower levels of IL-6 and sIL-2R than RA patients. We found abnormal values for IL-6 and sIL-2R in 63.8% and 57.4% of PsA patients, respectively. IL-6 levels correlated with the number of painful and swollen joints, RAI, physician's assessment, CRP and ESR, while sIL-2R levels correlated only with the number of swollen joints, the physician's assessment and ESR. IL-6 and sIL-2R correlated with each other. CONCLUSION: Our study shows that IL-6 and sIL-2R may play a role in the pathogenetic mechanism of psoriatic arthritis.

Immunohistologic markers of immune activation and changes of glycosylation of serum proteins in primary Sjögren's syndrome.

OBJECTIVE: [corrected] To assess the possible correlations between the immune activation of certain surface antigens at the lip salivary gland (LSG) level, and changes in glycosylation of serum proteins in primary Sjögren's syndrome (SS). METHODS: LSG biopsy samples were obtained from 22 SS patients (mean age 56.3 years; mean disease duration 70.8 months) and prepared for immunohistochemical analysis using murine monoclonal antibodies for interleukin-2 receptor (IL-2R) (CD25) and for the class II major histocompatibility antigen HLA-DR. The glycosylation of serum proteins was evaluated in all patients by an enzyme-linked lectin assay (ELLA) using concanavalin A (Con A). RESULTS: In LSG specimens the presence of IL-2R was observed at the infiltrating level, mainly periductally, in 13 (59%) cases and on the epithelial cells of 14 (64%) patients. In 13 out of 22 SS patients (59%) a marked positivity both of the infiltrates and of the epithelium was found for anti-HLA-DR monoclonal antibody. The degree of expression of different antigens on LSG samples was correlated with their histologic class according to Tarpley evaluation. The positivity for IL-2R and HLA-DR molecules on glandular tissues was correlated. A significant increase in the total Con A reactivity of serum proteins was found in those patients expressing IL-2R and HLA-DR antigens on LSG specimens. CONCLUSIONS: The co-expression of IL-2R and HLA-DR antigens on both the epithelium and infiltrates of LSG is consistent with a participation of these cells in the immune process of SS. Moreover, changes in the glycosylation of serum proteins seem to be related to the presence of these immunoactivation markers of the disease at the LSG level, suggesting that the control of protein glycosylation could be mediated by the same mechanisms involved in the tissue damage of SS.

Life-table analysis of cyclosporin A treatment in psoriatic arthritis: comparison with other disease-modifying antirheumatic drugs.

OBJECTIVES: The aim of this study was to determine the cumulative probability of taking CsA in comparison to other DMARDs, as well as the reason for discontinuation of each DMARD, in a large cohort of PsA patients. METHODS: We prospectively studied 172 consecutive patients with a diagnosis of PsA who had been admitted to our rheumatological unit since 1984. We collected information about treatment with DMARDs including: number, dose, duration and causes of withdrawal, including side effects or inefficacy. Cumulative survival analysis was performed by the Kaplan-Meier test and the differences between these survival curves were determined by the Mantel-Hanszel test. RESULTS: The probability curve of continuing to take CsA was significantly lower than that of MTX (p < 0.046). The rate of adverse effects responsible for stopping DMARD therapy was higher in the CsA group, especially with respect to the antimalarial group (p < 0.014). The most common cause of CsA withdrawal was hypertension. The rate of withdrawal due to inefficacy in the CsA group was not significantly different from those observed in the other groups. Nevertheless, the total frequency of discontinuation due to toxicity and inefficacy in the MTX group was significantly lower compared to the gold salts (p < 0.05) and CsA groups (p < 0.01). CONCLUSION: Life-table analysis suggests that PsA patients taking CsA are less likely than patients on MTX to continue long term treatment. Therefore CsA, which seems to be less safe than the antimalarials, could be considered a useful drug in the treatment of PsA, but does seem to represent the drug of first choice, particularly when compared to MTX.

Magnetic resonance imaging (MRI) of the brain in SLE: ECLAM and SLEDAI correlations.

Twenty-one unselected SLE patients were examined with Magnetic Resonance Imaging (MRI) for cerebral areas of high signal intensity (HSI). Nine patients (42.9%) had HSI and 6 (28.6%) had large (> or = 6 mm) lesions suggestive of cerebral involvement. Despite the lack of correlation among these lesions and clinical or immunological features, the SLEDAI and ECLAM indices were correlated to the number of large lesions (p < 0.002). Our findings suggest that brain MRI may be useful in the evaluation of SLE patients, not only those with evident neurologic symptoms, but also asymptomatic subjects with high disease activity indices.

Lupus erythematosus panniculitis: an immunohistochemical study.

An immunohistochemical study on a case of lupus erythematosus panniculitis (LEP), without discoid lupus erythematosus (DLE) or systemic lupus erythematosus (SLE) signs, showed that the cells in skin infiltrates were immunologically committed lymphocytes (OKT4, OKT8, OKT11 and HLA-DR positive cells) and elements of the monocyte-macrophage lineage (Leu M3 and Leu M5 positive). No immunophenotypically identifiable B-lymphocytes were seen. Immunofluorescent IgG, IgM, C3 and C4 deposits were found in blood vessel walls of the deep dermis. These findings, similar to that described in the skin changes of SLE and DLE, suggest that immunological mechanisms are operative in localized LEP, where the dermal lesions are the only expression of the disease.

One year treatment with low dose methotrexate in rheumatoid arthritis: effect on class specific rheumatoid factors.

We evaluated the effect of a one-year treatment of low dose methotrexate (MTX) on class specific rheumatoid factors in 27 patients with rheumatoid arthritis (RA). Enzyme-linked immunosorbent assay (ELISA) showed after 6 and 12 months a significant reduction of IgM-RF, IgA-RF and IgG-RF levels from the baseline values. During MTX treatment, changes of each RF isotype were not correlated with any other isotype and its corresponding immunoglobulin changes. Moreover, immunological changes were not related to the improvement of clinical parameters. Our results showed that low dose MTX can specifically affect levels of RF isotypes, which are involved in the immune pathogenesis of RA.

Multiple cervical cord compressions in psoriatic arthritis.

Coexistent atlantoaxial subluxation (AAS) and subaxial spondylitic changes led to multiple cervical cord compressions in a psoriatic arthritis (PA) patient. Magnetic resonance imaging and myelography were unable to define exactly which cervical lesion was responsible for neurological symptoms. After surgical intervention for the worsening of bulbar symptoms, clinical course of neurological complaints suggested that neurological involvement was due only to anterior/vertical AAS.

Avascular necrosis of the femoral head in long-term follow-up of systemic sclerosis: report of two cases.

A long-term follow-up of two patients with scleroderma (SS) who developed a polyarthritis with bilateral femoral head osteonecrosis is reported. The severe parallel evolution of the small and large joint lesions and the late appearance of osteonecrotic changes in our patients suggest that avascular osteonecrosis is related to the osteoarticular progression of the longstanding SS.

Soluble interleukin-2 receptor in Sjögren's syndrome: relation to main serum immunological and immunohistochemical parameters.

Our aim was to study sIL-2R relationship with main serum immunological and LSG immunohistochemical parameters, including surface antigen expression of immune activation, in 27 patients with primary SS. Serum sIL-2R levels were significantly higher in SS (p<0.00005), as well as in SLE (p<0.05) and RA (p< 0.000001) patients than in controls. In SS patients with abnormal slL-2R values (n = 7) we found higher levels of anti-SSB/La antibodies (p<0.05), IgM-RF (p<0.014) and CRP (p<0.003) with respect to those with normal sIL-2R values (n = 20). Moreover, sIL-2R levels correlated positively with those of anti-SSB/La antibodies (p<0.0037) and with CRP (p<0.008). The comparison of groups with (A) and without (B) abnormal slL-2R levels reveals a statistically different percentage of patients with foci number > 1 (86% vs 40%; p <0.047), and CD25 expression on lymphocytes (100% vs 40%; p < 0.008). The frequency (p < 0.025) of CD25 expression on lymphocytes was higher in group A than in group B. The frequency of CD25 expression on the infiltrates correlated not only with sIL-2R levels (p<0.047), but also with anti-SSB/La antibody values (p < 0.044), with Tarpley histological classes (p < 0.009) and with frequency of HLA-DR expression on lymphocytes (p<0.004) and on epithelial cells (p<0.002). The frequency of epithelial CD25 expression also correlated with that of epithelial HLA-DR (p<0.004). Our report suggests that slL-2R is linked to glandular involvement in primary SS.

Long-term follow-up of low-dose methotrexate therapy in one case of idiopathic retroperitoneal fibrosis.

Idiopathic retroperitoneal fibrosis (RPF) is characterized by the development of a fibrotic mass surrounding the abdominal aorta and its branches, of unknown aetiology. Several immunological mechanisms can be operative in the pathogenesis of RPF. Based on this assumption we treated a patient affected by idiopathic RPF with low-dose methotrexate (MTX) therapy. To our knowledge this is the first example of the effectiveness and safety of a long-term low-dose MTX treatment in the post-surgical management of RPF.

Relationship of interleukin-12 and interleukin-13 imbalance with class-specific rheumatoid factors and anticardiolipin antibodies in systemic lupus erythematosus.

The aim of the study was to evaluate whether the imbalance between IL-12 and IL-13 serum levels, reflecting Th1/Th2 activity, is related to class-specific circulating rheumatoid factors (RF) and anticardiolipin (aCL) antibodies in SLE. Using ELISA we measured serum IL-12, IL-13, RF and aCL antibodies in 73 SLE patients and 20 healthy controls. The determination of IL-12/IL-13 ratio showed that IL-12 levels were above (group A), equal to (group B) or below (group C) IL-13 levels in 71.2%, 15.1% and 13.7% of SLE patients, respectively. IgM-RF levels were significantly higher in group C than in groups A ( P < 0.002) and B ( P < 0.019). Group C had also higher IgM-aCL levels than group A ( P < 0.04). No relationship between IL-12/IL-13 ratio and clinical or other laboratory parameters was found. It was concluded that the increased levels of both IgM-RF and IgM-aCL in patients with prevalent Th2 activity suggest that the predominance of Th2 over Th1 could drive autoantibody production in SLE patients.

Co-occurrence of psoriatic arthritis with collagenous colitis: clinicopathologic findings of a case.

A 58-year-old man developed psoriatic arthritis and, after 6 months, persistent watery diarrhoea. Biopsies from the colorectal mucosa showed thickened subepithelial collagen consistent with collagenous colitis. There also was an inflammatory cell infiltration (mainly lymphocytes and monocytes) in the chorion. These findings and the parallel course of articular and bowel complaints suggest a clinicopathologic correlation between arthritis and colic involvement.

Interleukin-13 in systemic sclerosis: relationship to nailfold capillaroscopy abnormalities.

The aim of this study was to investigate whether interleukin-13 (IL-13) serum levels correlate to different nailfold capillaroscopy (NC) findings in patients with systemic sclerosis (SSc). IL-13 serum levels were measured using an ELISA method. The following NC abnormalities were considered: the presence of giant loops, haemorrhages, loss of capillaries, disorganisation of the vascular array, ramified/bushy capillaries and sludging of blood. A semiquantitative rating scale was adopted to score these changes, as well as a rating system for avascular areas and three morphological NC patterns ('early', 'active' and 'late'). Mean capillary density was determined by counting the total number of capillaries in a 1 mm length, and the arterial and venous diameters of the capillary as well as the total loop diameter were measured. In SSc patients IL-13 serum levels were significantly higher than in controls ( P < 00.1), whereas in patients with ( n=8) and without ( n=24) abnormal IL-13 serum levels (>17 pg/ml) the comparison of the NC features showed significantly relevant differences concerning a more frequent 'active' NC pattern ( P < 0.02), the presence of haemorrhages ( P < 0.0037) and sludging of blood ( P < 0.038), as well as larger total loop ( P < 0.036) and arterial ( P < 0.03) diameters, in those patients with elevated IL-13 serum levels. The study confirmed that IL-13 serum levels are higher in the sera of patients with SSc, and shows for the first time the significant correlations between this serological finding and some of the main relevant SSc capillaroscopic features, leading us to believe that this cytokine not only seems to sustain the immunological and fibrotic process of SSc, but might have a role in determining the more severe microvascular lesions in this disease.

Ultrasound transmission velocity of the proximal phalanxes of the non-dominant hand in the study of osteoporosis.

The aim of our study was to evaluate a quantitative ultrasound technique for measuring bone tissue at the proximal phalanxes of the non-dominant hand. We correlated the mean value of the amplitude-dependent speed of sound (AD-SoS) measured at the distal metaphysis of the last four proximal phalanxes with age, months since menopause and bone mineral density (BMD) of the lumbar spine in 264 women. We further assessed the ability of the AD-SoS to discriminate between normal and osteoporotic subjects with documented vertebral fractures. We found a positive correlation between the AD-SoS and the lumbar spine BMD, whereas the AD-SoS negatively correlated with age and months since menopause. The AD-SoS showed a higher correlation with age changes and months since menopause than BMD. The AD-SoS was significantly higher in healthy females than in osteoporotic ones (p < 0.001). Multiple logistic regression analysis showed for age-adjusted values that AD-SoS decrease is significantly associated to the presence of fracture. Our results suggest that AD-SoS is valuable in assessing age and menopause related bone loss and is useful for diagnosing osteoporosis.

Rheumatoid nodules and cyclosporin A treatment.

The authors describe the appearance of rheumatoid nodules during cyclosporin A (CsA) therapy for RA. Their course was evaluated by sonography that revealed an increase in number and size of rheumatoid nodules. The relationship between CsA treatment and the onset of nodulosis is not clear and further studies are needed to assess the role of CsA treatment in the extra-articular manifestations of rheumatoid arthritis such as rheumatoid nodules.