The CC homozygosis of the -174G>C IL-6 polymorphism predicts a lower efficacy of rituximab therapy in rheumatoid arthritis.

Identification of genetic biomarkers of response to biologics in rheumatoid arthritis (RA) is a relevant issue. Being IL-6 a key cytokine for B cell survival, the interleukin-6 (IL-6) -174G>C and the IL-6 receptor (IL-6R) D358A gene polymorphisms were investigated in 158 RA patients treated with rituximab (RTX). One hundred and twenty-eight (81.0%) were RF positive and 126 (79.7%) were anti-CCP positive. Response to therapy was evaluated at the end of the sixth month after the first RTX infusion, by using both the EULAR and the ACR criteria. The possible relationship with IL-6 serum levels was also studied. By univariate analysis, lack of response by the EULAR criteria was more prevalent in RA patients with the IL-6 -174 CC genotypes (39.1%), than in the GC/GG patients (18.5%) (OR 2.83; 95%CI=1.10-7.27; p=0.031). A good response was noticed in only one patient (4.3%) with the IL-6 -174 CC genotype, while it was present in 24.4% of GG/GC cases (p=0.06). By stepwise multivariate analysis (including RA duration, baseline DAS28, baseline HAQ, RF status, anti-CCP status and IL-6 genotype as covariates), the IL-6 -174CC genotype was selected as an independent predictor of no response to RTX by both EULAR and ACR≥50 criteria, while the IL-6R polymorphism resulted as not associated. No definite association between gene polymorphisms and IL-6 serum levels was noticed. Present results suggest a possible role for IL-6 genotyping to better plan treatment with RTX in RA, and larger studies are worthwhile.

Proteome analysis of biological fluids from autoimmune-rheumatological disorders.

Autoimmune-rheumatological diseases are worldwide distributed disorders and represent a complex array of illnesses characterized by autoreactivity (reactivity against self-antigens) of T-B lymphocytes and by the synthesis of autoantibodies crucial for diagnosis (biomarkers). Yet, the effects of the autoimmune chronic inflammation on the infiltrated tissues and organs generally lead to profound tissue and organ damage with loss of function (i.e., lung, kidney, joints, exocrine glands). Although progresses have been made on the knowledge of these disorders, much still remains to be investigated on their pathogenesis and identification of new biomarkers useful in clinical practice. The rationale of using proteomics in autoimmune-rheumatological diseases has been the unmet need to collect, from biological fluids that are easily obtainable, a summary of the final biochemical events that represent the effects of the interplay between immune cells, mesenchymal cells and endothelial cells. Proteomic analysis of these fluids shows encouraging results and in this review, we addressed four major autoimmune-rheumatological diseases investigated through proteomic techniques and provide evidence-based data on the highlights obtained in systemic sclerosis, primary and secondary Sjogren's syndrome, systemic lupus erythematosus and rheumatoid arthritis.

Ultrasound evaluation of ulnar neuropathy at the elbow: correlation with electrophysiological studies.

OBJECTIVES: To evaluate, in patients with ulnar neuropathy at the elbow (UNE), if ultrasonographic differences in ulnar nerve size correlate with severity score determined by electrodiagnostic studies. METHODS: We examined prospectively 38 patients (50 elbows) with UNE. Patients were classified into mild, moderate and severe groups according to electrodiagnostic studies. Cross-sectional areas (CSAs) of the ulnar nerve were measured 4 cm proximal to the medial epicondyle (CSA-prox), 4 cm distal to the epicondyle (CSA-dist) and at the maximum CSA (CSA-max) of the ulnar nerve found between these points. We used a control group of 50 normal elbows. RESULTS: The CSA-max in the patient group was highly correlated with the severity score obtained by electrodiagnostic studies: mild: 11.1 +/- 3.4 mm(2), moderate: 15.8 +/- 3.8 mm(2), severe: 18.3 +/- 5.1 mm(2) (P < 0.001). Patients with UNE had larger ulnar nerve CSAs than controls at all three levels (P = 0.012 for CSA-prox, P < 0.001 for CSA-max, P = 0.003 for CSA-dist). A cut-off point of > or =10 mm(2) for CSA-max yields both sensitivity and specificity of 88%. CONCLUSIONS: Ultrasonography can have a role not only in the diagnosis, but also in the severity stratification of patients with UNE.

Anti-TNFalpha blockers, autoantibodies and autoimmune diseases.

Anti-TNFalpha blockers are extensively used in the management of chronic inflammatory disorders. Their administration may be associated with the generation of autoantibodies; this review focuses on the autoimmune phenomena linked to anti-TNFalpha inhibition, on the hypothesized pathogenetic mechanisms and on the clinical implications. While the development of antinuclear and, less frequently, of anti-DNA antibodies is a common finding, the onset of autoimmune diseases during anti-TNFalpha blocker treatment is a rare event, which needs to be promptly recognized in order to plan the appropriate management. Moreover the specific autoantibodies associated with rheumatoid arthritis are considered before and after biotherapy. Similarities and differences among infliximab, etanercept and adalimumab concerning induced autoimmune phenomena are underlined.

A score of risk factors associated with ischemic digital ulcers in patients affected by systemic sclerosis treated with iloprost.

A single series of patients affected by systemic sclerosis (SSc) and cyclically treated with iloprost was reviewed in order to evaluate the incidence of digital ulcers (DUs) and to compare the characteristics between the patients with and without this painful and disabling vascular complication. The record charts of 85 SSc patients were revised. Ischemic DUs and scleroderma contracture ulcers were separately considered. Twenty-nine subjects developed ischemic DUs during the course of the disease; whereas, scleroderma contracture ulcers occurred in six subjects. Ischemic DUs were associated with younger age at scleroderma onset, a longer disease duration, a longer time delay from scleroderma diagnosis to iloprost therapy, a bigger skin involvement, the presence of joint contractures, a videocapillaroscopic late pattern, a history of smoking, and of corticosteroids therapy. After the exclusion of four subjects with concomitant peripheral arterial disease, a forward-stepwise logistic regression analysis showed that only four variables, i.e., age at scleroderma onset, delay in beginning iloprost therapy, history of smoking, and presence of joint contractures remained significantly associated with ischemic DUs. In a score reflecting the sum of these four risk factors, the prevalence of ischemic DUs increased progressively from the lowest to the highest value of the score. The predictivity of this model was evaluated by the receiver-operating characteristics curve, with an estimated area under the curve of 0.836 with 95% confidence interval from 0.736 to 0.937. All the patients with scleroderma contracture ulcers were characterized by both diffuse pattern of disease and positivity for anti-Scl70 antibody. In this retrospective study, scleroderma patients with ischemic DUs are characterized by early disease onset, delay in beginning iloprost therapy, smoking habit, and presence of joint contraction. A score reflecting the sum of these factors may be useful to predict the risk of developing ischemic DUs.

Clinical associations of anti-CENP-B and anti-Scl70 antibody levels measured by multiplexed fluorescent microsphere immunoassay in systemic sclerosis.

The aim of this study was to assess the association between anti-CENP-B and anti-Scl70 antibody levels, measured by multiplexed fluorescent microsphere immunoassay, and the clinical features in patients affected by systemic sclerosis. Clinical evaluation of 80 scleroderma patients was performed in order to evaluate disease activity and organ involvement. Scleroderma-specific autoantibodies were detected using multiplexed fluorescent microsphere immunoassay. Unexpectedly, 11 patients resulted positive for both anti-Scl70 and anti-CENP-B antibodies; six cases showed a weak positivity for one of the two autoantibodies and a stronger positivity for the other one; five cases showed an intense positivity for both autoantibodies. This latter subgroup was excluded from the analysis of the associations between autoantibody levels and the clinical features. In the anti-CENP-B positive patients higher antibody levels were associated with a less extensive skin involvement in comparison with the cases affected by a more extensive skin involvement (521 +/- 208 vs 395 +/- 166 U/ml, respectively, P 0.038). In the anti-Scl70 positive patients autoantibody levels were directly correlated with skin involvement (P 0.018), showing higher levels in patients with a more extensive skin involvement in comparison with cases characterized by less extensive skin involvement (734 +/- 135 vs 490 +/- 183 U/ml, respectively, P 0.001). The findings of our study supports the association between autoantibody profile and disease severity in systemic sclerosis. In particular high levels of anti-Scl70 antibodies are associated with a worse cutaneous involvement, while high levels of anti-CENP-B antibodies seem to have a protective effect on skin manifestations.

Cyclophosphamide treatment improves microvessel damage in systemic sclerosis.

The objective of this study is to evaluate nailfold videocapillaroscopy changes in scleroderma patients treated regularly on cyclic basis with iloprost and to find associations with clinical, serologic, and pharmacological variables. Forty-nine patients affected by systemic sclerosis (44 women and five men, mean age 52.4 years, mean disease duration 8.0 years, 31 patients with limited cutaneous subset and 18 with diffuse cutaneous form of the disease) underwent two nailfold videocapillaroscopies at a distance of 3 years from each other; the examinations were performed by an operator blinded to clinical features and to drug treatment. Six patients showed an amelioration of nailfold videocapillaroscopic abnormalities who changed from active to early pattern; five of these cases (83.3%) had been given cyclophosphamide therapy and the remaining case methotrexate plus azathioprine. Cyclophosphamide administration was significantly associated with amelioration of nailfold videocapillaroscopic pattern (p<0.001). None of the patients who received cyclophosphamide demonstrated worsening of the microvascular lesions; the progression of nailfold videocapillaroscopic pattern was inversely correlated to cyclophosphamide treatment (p=0.02). In our study, cyclophosphamide treatment demonstrated to be effective for scleroderma microvascular damage as directly observed by nailfold videocapillaroscopy.

Comparative effect of tacrolimus 0.1% ointment and clobetasol 0.05% ointment in patients with oral lichen planus.

BACKGROUND: Oral lichen planus (OLP) is considered to be an autoimmune disease of unknown aetiology that affects the mucosae, especially the oral cavity. OBJECTIVE: We compared tacrolimus 0.1% ointment and clobetasol 0.05% ointment for the treatment of OLP. PATIENTS AND METHODS: A total of 32 patients (20 females and 12 males; all white, Italian origin, mean age of 43.6+/-18.4 years; 16 patients per treatment group) were treated with tacrolimus or clobetasol ointment for 4 weeks in a randomized, double-blind, clinical trial. Pain severity, burning sensation, and mucosal lesion extension were assessed using a four-point scale. RESULTS: At the end of the treatment period, symptom scores were significantly lower in the tacrolimus group than in the clobetasol group. CONCLUSION: The results of this study suggest that tacrolimus 0.1% ointment is more effective than clobetasol propionate 0.05% ointment in the treatment of OLP. However, other studies are needed to confirm the effectiveness of this treatment before it can be recommended for use in clinical practice.

Dramatic progression of skin involvement in systemic sclerosis after the appearance of anti-Scl70 antibody: a case report.

The authors describe a young man suffering from systemic sclerosis who showed a dramatic progression of skin involvement after the appearance of anti-Scl70 antibody.

Iloprost infusion does not reduce oxidative stress in systemic sclerosis.

Systemic sclerosis is a connective tissue disease in which oxidative stress represents an important player among the complex pathogenetic mechanisms of the disease. Iloprost, an analogue of natural prostacyclin, is used in systemic sclerosis for the treatment of severe Raynaud's phenomenon and ischemic ulcers. There is a clear evidence that iloprost attenuates oxidative damage induced by ischemia-reperfusion phenomena. The aim of this study is to evaluate the effect of iloprost on oxidative status in ten patients with systemic sclerosis by measuring urinary levels of 8-isoprostaglandin-F(2alpha), a member of F(2)-isoprostanes. We found that systemic sclerosis patients cyclically treated with iloprost showed increased urinary level of 8-isoprostaglandin-F(2alpha )in comparison with healthy subjects; urinary 8-isoprostaglandin-F(2alpha) did not diminish soon after the iloprost infusion as well as 3, 15 and 30 days after the drug administration. Unlike experimental studies, in vivo the strong vasodilator effect of iloprost infusion did not reduce oxidative status.

Celiac disease in a rheumatology unit: a case study.

The objective of the study is to present a series of 20 patients who have been attending a rheumatology unit and were diagnosed with celiac disease in adult life. The record-charts of 20 Italian not consanguineous patients affected by celiac disease (1 man and 19 women, mean age of 46.7), diagnosed at >16 years of age, followed by a rheumatology unit were reviewed (group 1). Any other autoimmune disease diagnosed in the patients were given was recorded; moreover, the reason for rheumatologist evaluation was registered as well as the presence of symptoms suggestive of celiac disease and the obstetric history. The clinical features were compared with those of a group of 40 celiac patients (8 men and 32 women, mean age of 43.1) followed by a medicine department (group 2); even in these cases the diagnosis of celiac disease was performed in adult life. Sixteen out of 20 patients in Group 1 were diagnosed as suffering from celiac disease by the rheumatologist. Seventeen concomitant autoimmune disorders among which nine were connective tissue diseases were found in 15 patients. The main reason for rheumatologist evaluation was arthromyalgias. Ten patients showed one or more clinical features suggestive of celiac disease; moreover, eight patients had a history of sideropenic anemia. After the adoption of a gluten-free diet there were three pregnancies that all ended with alive newborns, differently from the obstetric history before celiac disease diagnosis, characterized by a relevant number of miscarriages and foetus deaths. In Group 2, a total of ten autoimmune diseases concomitant with celiac disease were found in eight patients; autoimmune thyroid disorders represented the most frequent cases. No connective tissue diseases were recognized. Celiac disease may coexist with connective tissue diseases; the recognition of this association is difficult because celiac disease may present with atypical or even symptomless forms or in some cases may resemble a multisystem disorder or may mimic a rheumatologic condition; on the other hand, the variety of symptoms of rheumatic disorders may make difficult the diagnosis of celiac disease in association with a systemic autoimmune disease. These confounding factors often lead to a delay in performing the right diagnostic formulation.

Hydroxychloroquine-induced DRESS syndrome.

The authors describe the first case of drug rash with eosinophilia and systemic symptoms syndrome caused by hydroxychloroquine treatment in a male patient affected by seronegative arthritis.

Relationship between matrix metalloproteinases/tissue inhibitors of matrix metalloproteinases systems and autoantibody patterns in systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is a connective tissue disease characterized by tissue fibrosis that reflects an imbalance between collagen production and degradation. Matrix metalloproteinases (MMPs) are a family of endopeptidases involved in the remodelling of extracellular matrix (ECM). This activity is controlled by tissue inhibitors of MMP (TIMPs). Aim of this study was the evaluation of MMP-9/TIMP-1 and MMP-2/TIMP-2 systems in patients with SSc. DESIGN AND METHODS: SearchLight Human MMP Array 1 was used to measure MMPs and TIMPs in 32 SSc patients and 32 matched healthy controls. RESULTS: SSc patients showed higher values of both MMP-9 and TIMP-1 in comparison with controls. The patients with anticentromere antibodies (ACA) positivity showed higher values of MMPs and TIMPs in comparison with either controls or the patients with anti-Scl70-positive antibodies. CONCLUSION: Results of this investigation suggest that SSc patients with ACA positivity, after a primary fibrogenetic noxa, react with a more abundant release of MMP/TIMP, whereas patients with anti-Scl70 antibody show a normal response.

Association of polymorphisms in the IL1B and IL2 genes with susceptibility and severity of systemic sclerosis.

OBJECTIVE: To investigate possible associations of 9 single-nucleotide polymorphisms in the IL10, IL1B, IL1A, IL1RN, IL2, LTA, and IL6 genes with susceptibility to systemic sclerosis (SSc), and with clinical subtype of SSc patients. METHODS: A total of 78 patients with SSc [diffuse SSc (dcSSc), n = 31; limited SSc, (lcSSc), n = 47] and 692 healthy blood donors were genotyped for the following polymorphisms: IL10 T-3575A, IL10 A-1082G, IL1B C-31T, IL1B C-511T, IL1A C-889T, IL1RN A9589T, IL2 T-384G, LTA T-91G, and IL6 G-174C. RESULTS: Alleles in IL1B-31 and IL1B-511 showed a significantly different distribution between cases and controls. Carriers of at least one copy of the IL1B-31-C allele had an increased risk of SSc [odds ratio (OR) 2.8, 95% confidence interval (CI) 1.6-5.2, p < 0.001], while a similar strong association was also evident for IL1B-511-T carriers (OR 3.1, 95% CI 1.7-5.7, p < 0.001). Interestingly, carriers of the IL2-384-G allele were significantly more frequent among patients with lcSSc (80.8%), compared to patients with the diffuse subtype (45.1%) (OR 5.1, 95% CI 1.8-14.3, p = 0.001) and in subjects positive to anticentromere antibodies (OR 4.2, 95% CI 1.5-11.9, p = 0.007). Lastly, the distribution of the IL2-384 genotype showed statistically significant differences between controls and patients with lcSSc (OR 3.5, 95% CI 1.7-7.4, p < 0.001). There were no differences between patients with dcSSc and controls. CONCLUSION: IL1B and IL2 gene polymorphisms may be involved in susceptibility to SSc. Moreover, the IL2-384-G allele may be a marker for the limited phenotype of SSc.

B-flow ultrasound in a case of giant cell arteritis.

We present the case of a 75-year-old woman with suspected giant cell arteritis. In the diagnostic procedure, we used B-flow ultrasound, a non-Doppler technology for blood flow imaging. The advantages of this technique and its possible role in the diagnosis of giant cell arteritis are discussed.

[Homocysteine and rheumatic disease]. / Omocisteina e malattie reumatiche.

In the last decade hyperhomocysteinemia has become an element of great interest as a recognized factor of independent risk for atherotrombosis. Moreover a role has been suggested in some different diseases, like rheumatic ones. Hyperhomocysteinemia could represent a mechanism of amplification of vascular damage in rheumatic disease, therefore it could interact with treatements. Moreover it could contribute to explain the high incidence of cardiovascular events, than they do not find support in traditional risk factors.

Coexistence of systemic sclerosis with other autoimmune diseases.

To evaluate the coexistence of additional autoimmune disease in a population of patients suffering from systemic sclerosis. The record-charts of 118 Italian patients affected by systemic sclerosis (12 men, 106 women, mean age of 57.2 years, mean duration of disease 8.7 years) followed by a single centre were reviewed; any other diagnose of autoimmune disease the patient was given was recorded. Thirty-eight scleroderma patients (32.2%) were affected by one or two concomitant autoimmune diseases, for a total of 42 diagnoses. The most represented associated autoimmune diseases were autoimmune thyroiditis (17 cases) and primary Sjögren's syndrome (10 cases). Both pulmonary fibrosis as diagnosed by chest X-ray and the extension of skin involvement evaluated by Rodnan total skin score were not correlated with an increased incidence of an additional autoimmune disorder. Our study shows that approximately one third of patients affected by systemic sclerosis developed one or more additional autoimmune diseases. Therefore patients with systemic sclerosis should be carefully evaluated both at onset and during the follow-up for the possible coexistence of other autoimmune disorders.

Determination of ANA specificity using multiplexed fluorescent microsphere immunoassay in patients with ANA positivity at high titres after infliximab treatment: preliminary results.

To evaluate ANA specificity using the fully automated multiplexed fluorescent microsphere immunoassay in patients affected either by rheumatoid arthritis or ankylosing spondylitis who developed strong positivity for ANA as assessed by indirect immunofluorescent method on HEp-2 cells during infliximab treatment. Three men affected by ankylosing spondylitis and 12 women affected by rheumatoid arthritis who developed ANA positivity at high titres during infliximab treatment underwent the identification of ANA specificity by multiplexed fluorescent microsphere immunoassay; moreover anti-DNA and anti-ENA antibodies were tested by indirect immunofluorescence and ELISA method, respectively. In 4 out of 15 cases, the determination of ANA reactivity by multiplexed fluorescent microsphere immunoassay was also performed on the serum collected before infliximab administration. One patient affected by rheumatoid arthritis showed multiple ANA reactivities against SS-A, SS-B, RNP, Sm, Jo-1 and histones; one patient affected by ankylosing spondylitis resulted positive for the same autoantibodies, except for anti-Sm antibody. Moreover, two patients, one with rheumatoid arthritis and one with ankylosing spondylitis, showed single antibody specificity to SS-B and RNP, respectively. The remaining 11 cases did not show any positivity. Instead, all the patients resulted negative for anti-ENA antibodies by the ELISA method. In the four cases tested for ANA specificity by multiplexed fluorescent microsphere immunoassay before and after infliximab administration no difference was found. The search for anti-DNA antibody always resulted negative by both the traditional immunofluorescent assay and the novel technique. The use of multiplexed fluorescent microsphere immunoassay in patients treated with infliximab with ANA positivity at high titres allowed to find some ANA specificities which were not revealed by ELISA method. Nevertheless, the majority of patients resulted negative in spite of ANA positivity at high titres; the molecular target of ANA which develop after infliximab administration still remains to be identified.