Gabriella Castellino

Central nervous system involvement in Sjögren’s syndrome: unusual, but not unremarkable—clinical, serological characteristics and outcomes in a large cohort of Italian patients

OBJECTIVES To perform an observational retrospective cross-sectional case-control study to evaluate prevalence, clinical patterns and outcomes of CNS involvement in a large cohort of primary SS (pSS) patients. METHODS A total of 424 pSS patients, diagnosed according to the 2002 criteria proposed by the American-European Consensus Group, were checked for CNS involvement after exclusion of secondary causes. Demographic, clinical, seroimmunological data were compared between patients with and without CNS involvement. Neuroimaging data were also analysed. RESULTS CNS involvement was detected in 25 (5.8%) patients (24 females and 1 male) both at disease onset (52%) and later (48%) with a mean latency after diagnosis of 7 years. Diffuse (40%), focal/multifocal (36%), multiple sclerosis (MS)-like disease (20%) and isolated optic neuritis (4%) were the most common CNS clinical pictures. Disease duration, lung involvement and decreased C(4) were associated with CNS involvement, while articular manifestations were more frequently observed in patients without neurological complications. Most cases had an acute, often recurrent course with spontaneous remission or only mild neurological impairment. CONCLUSIONS CNS involvement represents a rare but not negligible complication of pSS, which may occur with a bimodal temporal pattern, both at onset and later, prompting attention in the differential diagnosis of apparently isolated neurological syndromes. Lung involvement emerged as the strongest risk factor for CNS involvement with a relative risk of 7.9, along with disease duration and decreased C(4).

Recent advances and future perspective in neuroimaging in neuropsychiatric systemic lupus erythematosus.

Involvement of the central nervous system (CNS) is one of the most important complications of systemic lupus erythematosus (SLE), occurring in 14-75% of SLE patients. Neurological and psychiatric involvement is mainly manifested as cerebrovascular disease, seizures, cognitive impairment, headaches and psychosis. However, diagnosis of brain involvement in SLE (i.e., neuropsychiatriclupus: NPSLE) as well as understandingof pathogeneticmechanisms still remains a difficult challenge.Althougha wide rangeof neurodiagnostictools have been used in the last decadeto assess CNS involvement, no single technique has proven to be definitive or reliable. Since neurometabolic impairment, neurochemistry and perfusion abnormalities in NPSLE may precede anatomic lesions, new functional techniques such as magnetic resonance spectroscopy, diffusion and perfusion weighted imaging, and magnetization transfer imaging may be useful in order to indentify pathologic changes unrevealed by conventionalimaging. So these new diagnostic tools could modify diagnostic and therapeutic approaches to this major unsolved problem, also shedding some light on the physiopathologyof CNS disease in SLE.

Single photon emission computed tomography and magnetic resonance imaging evaluation in SLE patients with and without neuropsychiatric involvement

OBJECTIVE To assess the relationship between clinical picture and neuroimaging in patients affected by SLE with and without neuropsychiatric (NP) involvement. METHODS One hundred and seven SLE patients including 66 with NP involvement (NPSLE) with focal or diffuse presentation and 41 without underwent single photon emission computed tomography (SPECT) and MRI. RESULTS After stratification for diffuse or focal NP involvement, in the 52 patients with diffuse presentation, abnormalities detected with MRI or SPECT did not differ from patients without NP; however, after combining the two techniques, a normal result was more frequently observed in patients without NP involvement (P = 0.010). In the 14 patients with focal presentation, MRI alone and concordant abnormal MRI plus SPECT were more frequently detected in the NPSLE group; again normal findings by both techniques simultaneously applied were more frequently found in SLE patients without NP involvement. White matter hyperintense T2-weighted lesions were the most frequent MRI abnormal findings in both groups, but the presence of multiple lesions (>5) involving both the hemispheres at subtentorial level was limited to NPSLE patients. Multifocal hypoperfused SPECT areas were more frequently observed in frontal and parietal lobes of NPSLE. CONCLUSIONS Combining SPECT and MRI appears more useful than the two techniques alone and may help the clinician in the assessment of patients with NP involvement since normal findings contemporarily detected by these two techniques have been rarely observed in patients with NP involvement especially in those with focal manifestations where MRI and SPECT were never simultaneously normal.

Optimizing clinical monitoring of central nervous system involvement in SLE

Central Nervous System (CNS) involvement is a frequent SLE manifestation occurring in 15-75% of patients. However, diagnosis of CNS involvement is a difficult task and requires a careful clinical and laboratory assessment along with instrumental evaluation. In recent years major advances in neuroimaging techniques allowed a great improvement in our understanding of SLE pathogenesis. Anyway, since no single imaging technique covers all brain pathology and both inflammation and neurodegeneration contribute to SLE pathogenesis, it is very important to use a multimodality approach coupling a morphological with a functional imaging modality. In this setting, to date, conventional magnetic resonance imaging and single photon emission computed tomography are the most largely available and accessible techniques. Modern techniques such as perfusion weighted imaging, diffusion weighted imaging, magnetization transfer imaging and magnetic resonance spectroscopy provide useful information to assess brain tissue damage however, their clinical relevance in individual patients needs further evidence. In this review we would like to summarize what have we learned in the last few years about neuroimaging in NPSLE, what have been major advances in neuroimaging techniques and, finally, we would like to give some suggestions about what should be done in daily clinical practice to approach SLE patients with NP symptoms.

Incidence and prevalence of systemic lupus erythematosus in a district of North Italy

The objective of this study was to investigate the incidence and the prevalence of systemic lupus erythematosus (SLE) in an area of northeast Italy. We retrospectively examined all patients of 16 years and older of native Italian origin and resident in Ferrara district either admitted to hospital or referred to our outpatient clinic with a diagnosis of SLE determined between 1 January 1996 and 31 December 2002. SLE subjects were identified both by a search of hospital discharge code 710.0 according to the international classification of diseases-9 codes, and using a computerized search for this pathology code in the national health care system. Incidence and prevalence rates were calculated as number of cases per 100 000 inhabitants. Population data were based on the 2002 National Census. A total of 299 cases of SLE were identified. After a review of all cases by one experienced investigator, 98 were excluded because did not satisfied the 1982 revised criteria of the American College Rheumatology. Therefore, 201 patients had a definite diagnosis of SLE. The prevalence of SLE in the district was 57.9/100 000. The mean age at diagnosis was 41 years, the average duration of the disease from symptoms onset to diagnosis was 4.8 years and the female/male ratio 9: 1. Annual incidence in 2000 was 2.01/100 000, in 2001 1.15/100 000 and in 2002 2.6/100 000. This is the first study dealing with prevalence and incidence of SLE in an Italian district. Data obtained concerning prevalence, incidence, age at diagnoses and female predominance are in agreement with those published in literature.

The soluble terminal complement complex (SC5b-9) up-regulates osteoprotegerin expression and release by endothelial cells: implications in rheumatoid arthritis

OBJECTIVE Complement activation products contribute to a large number of inflammatory diseases, including RA. We have investigated whether osteoprotegerin (OPG) may concur with the soluble terminal complement complex (SC5b-9) to the inflammatory cascade characterizing RA. METHODS Levels of SC5b-9 and OPG in the plasma and SF of patients with active RA were determined by ELISA. The presence of SC5b-9 and OPG in RA synovial lesions was analysed by immunohistochemistry. Cultured endothelial cells were used for in vitro leucocyte/endothelial cell adhesion assays. In addition, endothelial cells were exposed to SC5b-9 in order to evaluate the effects on the production of OPG protein, as well as the activation of the OPG promoter. RESULTS Patients affected by active RA are characterized by elevated levels of both SC5b-9 and OPG in plasma and/or SF. Of note, we have observed a co-localization of SC5b-9 and OPG in endothelial cells of post-capillary venules of RA synovial lesions. Data on endothelial cell cultures showed that exposure to SC5b-9 induced the up-regulation of OPG expression/release, stimulating the transcriptional activity of the OPG promoter, and synergized with TNF-alpha in up-regulating OPG production. CONCLUSIONS Our findings demonstrate that SC5b-9 induces OPG production by endothelial cells and we propose that the SC5b-9-mediated up-regulation of OPG may be an important mechanism whereby complement contributes in promoting and/or enhancing the inflammation in RA.

Wegener‘s granulomatosis associated with antiphospholipid syndrome

We report a case of Wegener‘s granulomatosis (WG) with pulmonary hemorrhage also satisfying the criteria for antiphospholipid antibody syndrome (APS). This association has, to the best of our knowledge, never been described before. Pulmonary hemorrhage may be an early manifestation of several immune and idiopathic disorders such as ANCA-associated vasculitis. Several case-reports of APS patients with capillaritis have been described. A possible explanation is that microvascular thrombosis with subsequent increase in vascular permeability facilitates perivascular IgG and complement deposition leading to development of capillaritis. Whether the vascular disease is secondary to thrombosis or vasculitis or both is important in choosing the proper management strategy. We suggest that anticardiolipin antibodies (aCL) should be detected in ANCA-associated vascularitis because they may contribute to life-threatening events superimposed on vascular damage.

Prophylaxis and treatment of NSAID-induced gastroduodenal disorders

A significant percentage of patients taking nonsteroidal anti-inflammatory drugs (NSAIDs) experience some type of adverse gastrointestinal symptoms, lesions of the gastroduodenal tract being clinically the most relevant.NSAIDs cause gastrointestinal damage by 2 independent mechanisms: a topical effect, which is pH and pKa related, and a systemic effect mediated by cyclo-oxygenase (COX) inhibition with a reduction in prostaglandin synthesis. Using endoscopy, gastroduodenal lesions identified include subepithelial haemorrhages, erosions and ulcers. The prevalence of ulceration in NSAID users has been reported as being between 14 and 31% with a 2-fold higher frequency of gastric ulcers compared with duodenal ulcers.Among the strategies used to decrease the risk of ulcer development are: (i) the use of analgesics other than NS AIDs; (ii) use of the lowest possible dosage of NS AID; (iii) the use of a COX-2 selective NS AID; (iv) the use of low doses of corticosteroids instead of NSAIDs; (v) avoidance of concomitant use of NSAIDs and corticosteroids; and (vi) use of preventive therapy.In an attempt to reduce the incidence of NSAID-induced gastrointestinal lesions, the following approaches have been proposed: (i) use of the prostaglandin analogue misoprostol, which is an antiulcer drug which has been proven to be as effective in the prevention of NSAID-induced gastric and duodenal ulcers as in the reduction of serious upper gastrointestinal complications; (ii) histamine H2 receptor antagonists (H2 antagonists), e.g. ranitidine, cimetidine and famotidine, which are useful in the prevention of NSAID-induced duodenal ulcers during long term treatment, but not in the prevention of NSAID-induced gastric ulcers; (iii) proton pump inhibitors, e.g omeprazole, and pantoprazole, whose efficacy in preventing NSAID-associated ulcers has been recently demonstrated; and (iv) barrier agents, e.g. sucralfate, which cannot be recommended as prophylactic agents to prevent NSAID-induced gastropathy.The first step in the treatment of NSAID-associated ulcers lies in a reduction in the dosage of the NSAID or discontinuation of the drug. If NSAID treatment cannot be withdrawn, a proton pump inhibitor appears to be the most effective treatment in healing ulcers, accelerating the slow healing observed with H2 antagonists.

Factors and comorbidities associated with central nervous system involvement in systemic lupus erythematosus: a retrospective cross-sectional case-control study from a single center.

To evaluate, by a retrospective cross-sectional case–control study from a single center, the distribution of a number of factors and comorbidities potentially related to central nervous system involvement in SLE Italian patients, a number of “generic” (i.e. not strictly SLE related) and “specific” (i.e. SLE related) risk factors were checked and their distribution analyzed in SLE patients with (NPSLE) and without (SLE) neuropsychiatric (NP) involvement. One hundred and fifty-three SLE patients with NP involvement observed from 1999 to 2008 and 247 SLE patients without NP manifestations, matched for sex, age and disease duration were included in the study. A neuropsychiatric (NP) event represented the heralding symptom of the disease in 40.5% of NPSLE. Headache, cerebrovascular events, mood disorders and seizures were the most frequent NP manifestations. NPSLE patients had a major cumulative number of the investigated factors than controls without NP involvement. Antiphospholipid antibodies (aPL), lupus anticoagulant (LA), Antiphospholipid antibodies syndrome (APS), Raynaud’s phenomenon, smoke, assumption of contraceptives and higher cumulative dose of glucocorticosteroids (GC) were significantly more commonly observed among NPSLE. APS and systemic arterial hypertension were more frequently detected among patients with focal NP manifestations, especially cerebrovascular events. aPL, LA, APS, Raynaud’s phenomenon, smoke, contraceptives intake and higher cumulative dose of GC did prove more frequently detected in NPSLE patients than in controls. In particular, overall, arterial hypertension should be regarded as a potential independent “risk factor” for focal involvement, especially for cerebrovascular events.

The treatment of the rheumatological manifestations of the inflammatory bowel diseases

The strong link between the bowel and the osteo-articular system is suggested by many clinical and experimental observations. However, the therapeutic approach is still empirical. For symptomatic therapy it is better to favour the use of steroids and avoid non-steroidal anti-inflammatory drugs because they may induce intestinal ulcerations and can activate inflammatory bowel disease. Second line drugs (sulfasalazine, methotrexate, azathioprine, cyclosporine and leflunomide) should be used for selected indications. In some cases (severe spondylitis, severe and persistent enthesopathy) anti-TNF-α agents (infliximab) should be considered as first line therapy. In all cases it is mandatory to select the best therapeutic option for each individual patient, considering that the optimal treatment of bowel inflammation may induce “per se” a remission of the musculo-skeletal manifestations.