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

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

Adherence to recommendations for cervical and breast cancer screening in systemic sclerosis.

The aim of the study was to evaluate the adherence of systemic sclerosis (SSc) female patients to cervix and breast cancer screening procedures, as suggested by local guidelines. A cohort of 84 SSc women was asked if they had undergone mammography and Pap test during the previous 2- and 3-year intervals, as indicated according to the Italian recommendations. The results were compared with those collected in patients affected by other chronic rheumatic disorders and in the general population. More than 85% of SSc women declared to comply with an age-related cervix and breast cancer screening schedule. The data were similar to those collected in patients affected by other chronic rheumatic disorders, whereas the subjects belonging to the general population reported to undergo breast cancer screening more frequently. Among SSc women, neither the educational level, nor the lung and skin involvement influenced their cancer screening program compliance. Only a positive history of ischemic digital ulcers seemed to interfere with mammography. Our study reported a very high percentage of SSc female patients who adhered to programs for the early detection of cervical and breast cancer. The significant adherence to guidelines may be due to the schedule adopted by the local health public service, which regularly invites eligible subjects by mail to undergo cancer screening at no charge.

Safety of rituximab in the routine treatment of rheumatoid arthritis in Italy in patients refractory to anti-TNFa drugs: results from the observational retrospective-prospective RUBINO study.

The paper reports the results from the observational retrospective-prospective RUBINO study conducted in Italy to assess the safety of rituximab in the treatment of rheumatoid arthritis (RA) in routine clinical practice. The percentage of patients who manifested at least one grade 3 or 4 adverse event (AE) assessed by the Common Terminology Criteria for Adverse Events version 3.0 (CTCAE v.3) during the observation period (primary objective) was evaluated. The percentage of patients manifesting a severe AE (SAE), clinical response to rituximab treatment, clinical remission according to disease activity score for 28 joints (DAS28) criteria, markers of disease and quality of life were also assessed. Fifty-three Italian rheumatology centers took part in the study. Patients with a diagnosis of RA and inadequate response to anti-tumor necrosis factor b (anti-TNFa) drugs were enrolled. Participating patients had previously received at least one cycle of rituximab, and treatment was still ongoing at the time of recruitment. Out of 205 patients enrolled, 60% manifested no form of AE, 14.2% had at least one grade 3 or 4 AE, and 11.2% patients reported an SAE. The overall percentage of patients manifesting AEs (40%) was lower compared to the DANCER (81% and 85%), REFLEX (85%) and RESET (85% and 69%) studies, but higher than that observed in the CERERRA registry (from 10.2% to 13.9%). This difference may be due to the shorter observation period applied in the CERERRA registry (only 12 months) compared to the RUBINO study (up to 3 years). All parameters of RA activity (erythrocyte sedimentation rate, C-reactive protein, health assessment questionnaire score, DAS28) improved significantly during the study.

Systemic lupus erythematosus and strongyloidiasis: a multifaceted connection.

We describe a case of systemic lupus erythematosus complicated by strongyloidiasis. The parasitic infection appeared with diarrhoea, weight loss and peripheral eosinophilia in association with recurrence of polyarthritis, probably due to a flare of systemic lupus erythematosus. The literature about the coexistence of systemic lupus erythematosus and strongyloidiasis has been reviewed.

Clinical, serologic and instrumental data of ten patients affected by sclerodermatous chronic graft versus host disease: similarities and differences in respect to systemic sclerosis.

Chronic graft versus host disease (cGVHD), the most common late complication of allogeneic haematopoietic stem cell transplantation (HSCT), may present with sclerodermatous lesions resembling in some cases the cutaneous involvement of systemic sclerosis (SSc). Certain pathogenetic findings connect the two diseases. In this report we describe ten subjects affected by cGVHD who underwent the examinations routinely carried out to stage SSc patients. Demographic, clinical, serologic and instrumental data were recorded. These patients showed differences in appearance, extent and progression of the sclerodermatous lesions with greater involvement of the trunk and proximal part of the limbs than the extremities. In seven subjects ANA test was positive; scleroderma-associated autoantibodies were not detected in any of the cases. Moreover, typical organ involvement of SSc was not found. Only one patient developed Raynauds phenomenon after HSCT and only one patient demonstrated a nailfold videocapillaroscopic scleroderma pattern. Except for cutaneous involvement of cGVHD, that may resemble SSc, the clinical features of the two diseases are quite different, suggesting that the fibrotic process characterizing cGVHD and SSc has different etiologies and different initial pathobiologic events.

Risk factors for a first thrombotic event in antiphospholipid antibody carriers. A multicentre, retrospective follow-up study.

OBJECTIVES: To asses risk factors for a first thrombotic event in antiphospholipid antibody (aPL) positive carriers and evaluate the efficacy of prophylactic treatments. METHODS: Recruitment criteria were age 18-65 years, no history of thrombosis, positivity for lupus anticoagulant and/or IgG/IgM anticardiolipin antibody (aCL) on > or =2 occasions at least 6 weeks apart. Demographic, laboratory and clinical parameters were collected at enrolment and at the time of the thrombotic event. RESULTS: 370 patients/subjects (mean (SD) age 34 (9.9) years) were analysed retrospectively for a mean (SD) follow-up of 59.3 (45.5) months. Thirty patients (8.1%) developed a first thrombotic event during follow-up. Hypertension and medium/high levels of IgG aCL were identified by multivariate logistic regression analysis as independent risk factors for thrombosis. Thromboprophylaxis during high-risk and long-term periods was significantly protective. CONCLUSIONS: Hypertension or medium/high titres of IgG aCL are risk factors for a first thrombotic event in asymptomatic aPL carriers and primary prophylaxis is protective.

Lower limb enthesopathy in patients with psoriasis without clinical signs of arthropathy: a hospital-based case-control study.

BACKGROUND: Psoriasis is associated with a form of spondyloarthropathy in 10-30% of cases. A major feature of psoriatic arthritis is enthesitis. In some patients with psoriasis the presence of enthesitis could be underdiagnosed. OBJECTIVE: To investigate the presence of lower limbs entheseal abnormalities in patients with chronic plaque psoriasis without signs and symptoms of psoriatic arthritis. METHODS: Thirty patients with psoriasis and 30 controls underwent ultrasonographic evaluation of Achilles, quadriceps, patellar entheses and plantar aponeurosis. Ultrasonographic findings were scored according to the Glasgow Ultrasound Enthesitis Scoring System (GUESS). RESULTS: Mean GUESS score was significantly higher in patients with psoriasis as compared with controls: 7.9 (0.6) vs 2.9 (0.3); p<0.0001. In particular, the thickness of all tendons examined was significant higher in cases than in controls (p<0.0001), as well as the number of enthesophytes in all sites examined. In both cases and controls, the GUESS score was directly correlated with age (r = 0.22; p = 0.008), body mass index (r = 0.23, p = 0.0067) and waist circumference (r = 0.17; p = 0.02). In contrast, the GUESS score was not correlated with the duration and severity of psoriasis according to the Psoriasis Area and Severity Index (r = 0.03; p = 0.8) and body surface area involvement (r = 0.07; p = 0.6). CONCLUSIONS: Entheseal abnormalities can be documented by ultrasonography in clinically asymptomatic patients with psoriasis. These findings could be related to a subclinical entheseal psoriatic inflammation. We suggest close follow-up of patients with psoriasis with entheseal abnormalities for early diagnosis of psoriatic arthritis.

[Sustained response to infliximab treatment in two cases of early rheumatoid arthritis that has been maintained after drug withdrawal]. / Due casi di artrite reumatoide trattati in fase precoce con infliximab con mantenimento dell'effetto dopo la sospensione del farmaco.

The authors report two cases of active seropositive rheumatoid arthritis who were treated in an early phase of the disease with infliximab plus methotrexate obtaining a clinical remission. The benefit was maintained after the discontinuation of the anti-TNF alpha inhibitor for adverse events, indicating that the early administration of the drug may be followed by a sustained remission.

[Chikungunya arthritis: report of 6 cases]. / Artropatia da Chikungunya: descrizione di 6 casi.

Chikungunya is an arboviral disease transmitted by Aedes mosquitoes. The disease typically consists of an acute illness characterised by fever, rash, and incapacitating arthralgia, that can persist for months. Chikungunya virus, a member of the genus Alphavirus, has recently caused a large outbreak on islands in the Indian Ocean and on the Indian subcontinent. The ongoing outbreak has involved more than 1.5 million patients, including travellers who have visited these areas. We describe our casistic of six travellers with Chikungunya arthropathy. All patients experienced fever and rash of short term during a travel in areas of epidemicity. All patients had peripheral poliarthralgias, which duration was >2 months in 4 cases (66%) and >6 months in 1 case (16%).

Sulfasalazine-induced immune thrombocytopenia.

Sulfasalazine is a well established disease-modifying anti-rheumatic drug commonly used in the treatment of rheumatic disorders and inflammatory bowel disease. Sulfasalazine was generally well tolerated in clinical trials, the most frequently reported adverse effects being adverse gastrointestinal effects, headache, dizziness and rash; myelosuppression can also occur. We are now reporting the first case of autoimmune thrombocytosis following sulfasalazine treatment.

Differential effects of dietary supplementation with fish oil or soy lecithin on human platelet adhesion.

To investigate the possible regulating role of omega-6 and of omega-3 fatty acids on platelet adhesiveness, we randomised 60 volunteers into three groups to take 20 ml (equivalent to 0.3 g omega-6, 3.6 g omega-3; omega-6/omega-3 ratio 0.1) per day of a fish oil supplement, or to take 25 g (equivalent to 1.5 g omega-6, 0.5 g omega-3; omega-6/omega-3 ratio 3) per day of a soy lecithin supplement, or to continue on their usual diet without any supplement (control group) for a period of 15 days. Platelet adhesion on fibrinogen-coated 96-well microtitre plates was evaluated in the resting condition and after stimulation with 2 microM ADP or 0.02 U/ml thrombin. Compared to the values before the experimental period, the fish oil group showed a significant reduction in stimulated adhesion (with ADP: from 18.8% to 15.6%, p<0.01; with thrombin: from 24.4% to 20.8%, p<0.005), whereas no difference was noted in the resting condition (from 3.6% to 3.5%, NS). In the soy lecithin group, platelet adhesion was increased in all test conditions (with ADP: from 18.7% to 23.2%, p<0.001; with thrombin: from 24.0% to 29.9% p<0.001; resting: from 3.5% to 6.6%, p<0.001). No significant changes were observed in the control group. A good correlation was found between platelet adhesion data and the changes in the platelet fatty acid omega-6/omega-3 ratio caused by the different supplementations. Our results indicate an inhibitory effect of fish oil rich in omega-3 fatty acids on stimulated human platelet adhesiveness and a stimulatory effect of soy lecithin rich in omega-6 fatty acids on resting and stimulated adhesion. They suggest moreover that the omega-6/omega-3 ratio is a determinant of platelet adhesion.

C3 nephritic factor and SLE: report of four cases and review of the literature.

We present four patients with C3 nephritic factor associated with partial lipodystrophy and/or mesangiocapillary glomerulonephritis type II. Each of these patients subsequently developed features of SLE, with an onset between 2 and 24 years after the development of the lipodystrophy or glomerulonephritis. All four patients had antinuclear antibodies and three of the four had anti-Ro antibodies. These patients bring to six the number of reported cases of this association. Possible explanations for the link between these two conditions are discussed.

Elimination diet in the treatment of selected patients with hypersensitivity vasculitis.

We have evaluated the effects of an elimination diet in 5 patients with hypersensitivity vasculitis and a personal or family history of allergy. The presence of autoimmune disorders, infections and neoplastic diseases was excluded on the basis of physical examination, clinical history and laboratory data. Three patients had elevated serum immune complexes and evidence of complement consumption before the oligoantigenic diet. In one patient food allergy was diagnosed on the basis of a positive and concordant challenge test, skin prick test and RAST. The study consisted of a 3 week elimination diet, followed by open and double blind challenge tests with specific foods and additives. Four patients achieved a complete remission and one patient experienced great improvement on the elimination diet. In three cases the vasculitis relapsed following the introduction of food additives; in one case with the addition of potatoes and green vegetables (i.e., beans and green peas) and in the last case with the addition of eggs to the diet. The offending foods and additives were subsequently eliminated from the usual diet and no relapses were observed in 2 years of follow-up. These results show that in selected patients with a history of allergy, hypersensitivity vasculitis can be triggered and sustained by food antigens or additives.

Middle ear function in rheumatoid arthritis: a multiple frequency tympanometric study.

OBJECTIVE: To evaluate the modifications in the mechanical properties of the middle ear in rheumatoid arthritis by assessing its resonance frequency. METHODS: Thirty patients with rheumatoid arthritis (RA) aged 20 to 68 years (mean age 45.8 +/- 12.4 yrs) were investigated by multiple frequency tympanometry and their data were compared with those obtained in a control group of 48 subjects aged from 19 to 65 years. RESULTS: Normal values, calculated at the 95th percentile from the control group, ranged from 800 to 1250 Hz. Eleven RA patients (36.6%) displayed abnormal resonance values. These findings were monolateral in 9 patients and bilateral in 2 (in all a total of 13 ears). Nine out of 13 ears with abnormal multiple frequency tympanometry data were characterized by an increase in resonance and 4 by a decrease. CONCLUSION: These findings were attributed to abnormal acoustic impedence of the middle ear and indicate a possible involvement of the ossicular diarthroses in RA. Our study suggests that RA may involve the incudo-malleolar and incudo-stapedial joints, altering the ossicular mechanisms in response to static air pressure modifications.

Copper and zinc status in rheumatoid arthritis: studies of plasma, erythrocytes, and urine, and their relationship to disease activity markers and pharmacological treatment.

We studied the status of copper and zinc in rheumatoid arthritis (RA). The aims of the work were to ascertain whether or not RA is associated with copper and/or zinc deficiency, to establish the relationship between these trace metals and the main biohumoral and clinical indices of the disease, and to examine the effect on copper and zinc of the drugs normally used by RA patients. Metal levels were measured by atomic absorption spectroscopy in the plasma, whole blood cells and 24 hr urine of 120 RA patients; 70 patients suffering from primary osteoarthritis were used as the control group. In the plasma of RA patients copper and ceruloplasmin levels were found to be significantly increased whereas zinc levels were significantly decreased. No major variations were observed in the blood cell and 24 hr urine copper and zinc levels. Plasma copper was significantly correlated with some of the biohumoral markers of RA, but did not correlate with any of the clinical indices of the disease. Plasma zinc was significantly correlated with numerous of the biohumoral as well as clinical markers of RA. With the exception of an increased urinary excretion of copper in D-penicillamine treated RA patients, drug therapy did not influence the copper status in RA. Conversely, plasma zinc was found to be lower in RA patients taking NSAIDs and/or steroids. These results suggest the following conclusions: i) RA patients do not seem to be deficient in either copper or zinc; ii) plasma copper appears to be a poor index of RA severity; iii) plasma zinc could have some practical value in defining the overall severity of the disease.

Analysis of the T cell receptor repertoire in rheumatoid arthritis.

OBJECTIVE: To evaluate whether there is a restricted T cell receptor repertoire in rheumatoid synovium and to analyse the CDR3 region of the V beta families found to be more expressed in the synovial membrane than in the peripheral blood, in order to ascertain the presence of clonotypic expansion of T lymphocytes. METHODS: The level of expression of individual V beta and V alpha families of the TCR was evaluated in paired synovial membrane and peripheral blood T cells from 8 female patients affected by rheumatoid arthritis, using the RT-PCR method. Nucleotide sequences of the CDR3 region of some V beta families were analysed in order to identify the presence of conserved sequences. Sequencing was carried out with the dideoxy chain termination method using modified T7 DNA polymerase. RESULTS: All of the V alpha and V beta families were amplified in both compartments of the 8 patients. Four patients did not show any preferential expression of the TCR alpha or beta chains in synovium compared with peripheral blood. The other 4 patients showed increased expression of one or more V alpha and/or V beta families in the synovium. We did not find any correlation between the duration of disease, rheumatoid factor status, HLA-DR type and the V gene families which were elevated in the synovium. Analysis of the CDR3 region showed the presence of conserved amino acid sequences in the synovium, but not in the peripheral blood. CONCLUSION: The V families found to be increased in 4 of the 8 patients studied were different, except for V beta 1 which was more highly expressed in 2 patients. The presence of conserved amino acid sequences in the CDR3 region is consistent with an antigen-driven T cell expansion at the site of autoimmune inflammation. These findings do not support our original hypothesis of the possible usefulness of therapy based on the inactivation or elimination of presumed pathogenic T cells using TCR-derived peptides or monoclonal antibodies against particular TCRs.

Neutrophil functions, spondylarthropathies and HLA-B27: a study of 43 patients.

OBJECTIVES: Several hypotheses have been proposed regarding the role of HLA-B27 antigen in the pathogenesis of the spondylarthropathies. METHODS: We studied some neutrophil functions in vivo in patients affected by ankylosing spondylitis or by reactive arthritis, with or without HLA-B27, and in healthy control subjects. In vivo neutrophil migration was investigated by Senn's skin window technique. An adhesion assay was also conducted and superoxide production was measured in circulating and migrating neutrophils after different stimuli. RESULTS: Neutrophil migration in vivo was higher in the HLA-B27 positive patients than in the controls, while no difference was found between the HLA-B27 negative patients and controls. Our data showed an increased response to formyl-methionyl-leucyl-phenylalanine by circulating neutrophils in the patients with ankylosing spondylitis, both HLA-B27 positive and negative, in comparison with all the other subjects. CONCLUSIONS: Our results revive the question of the role of HLA-B27 in the regulation of neutrophil migration; the reported in vivo priming of circulating neutrophils seems to be related to ankylosing spondylitis rather than to HLA-B27.