Marcello Govoni

Clinical and radiologic evolution of synovitis, acne, pustulosis, hyperostosis, and osteitis syndrome: A single center study of a cohort of 71 subjects

OBJECTIVE To assess the basic features and outcomes of synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. METHODS We identified all patients seen in our unit between 1990 and 2008 diagnosed according to the proposed inclusion criteria with SAPHO syndrome, who had a followup of at least 2 years. RESULTS Seventy-one patients (48 women, 23 men) with SAPHO syndrome were identified. The median disease duration at the end of followup was 10 years (interquartile range [IQR] 7-15 years), and the median followup duration was 11 years (IQR 6-11.5 years). Six patients were diagnosed with Crohns disease. Fourteen patients had never had cutaneous involvement, but 8 patients presented >1 skin manifestation. Nine patients (13%) presented a limited (<6 months) monophasic disease course, 25 cases (35%) had a relapsing-remitting course, and 37 patients (52%) had an acute painful phase with a prolonged course lasting >6 months. A total of 4% of the patients were HLA-B27 positive. Female sex (odds ratio [OR] 7.2, 95% confidence interval [95% CI] 2.2-22.9) and the presence at onset of anterior chest wall (ACW) involvement (OR 5.7, 95% CI 1.8-18.1), peripheral synovitis (P = 0.0036), skin involvement (OR 10.3, 95% CI 3.4-31.1), and high values of acute-phase reactants (OR 7.7, 95% CI 2.7-22) were correlated with a chronic disease course and involvement of new osteoarticular sites. CONCLUSION A chronic course is the more common evolution of SAPHO syndrome. Female sex, elevated erythrocyte sedimentation rate and C-reactive protein values, ACW involvement, peripheral synovitis, and skin involvement at the onset seem to be associated with a chronic course.

Long-term anti-TNF therapy and the risk of serious infections in a cohort of patients with rheumatoid arthritis: Comparison of adalimumab, etanercept and infliximab in the GISEA registry

OBJECTIVE To evaluate the risk of serious infections (SIs) in RA patients receiving anti-TNF therapy on the basis of the data included in the GISEA register. METHODS The study involved 2769 adult patients with long-standing RA (mean age 53.2±13.4 years; mean disease duration 9.0±8.3 years) enrolled in the GISEA register, who had been treated for at least 6 months with TNF inhibitors or had discontinued therapy due to SI: 837 (30%) treated with infliximab (IFN), 802 (29%) with adalimumab (ADA), and 1130 (41%) with etanercept (ETN). RESULTS 176 patients had experienced at least one of the 226 Sis during the 9 years of treatment with an anti-TNF agent, an overall incidence of 31.8/1000 patient-years (95% CI 25.2-38.3): 23.7/1000 patient-years (95% CI 13.1-34.2) on ADA; 12.8/1000 patient-years (95% CI 6.3-19.4) on ETN and 65.1/1000 patient-years (95% CI 48.4-81.8) on IFN. The risk was higher in the first than in the second year of treatment, but this difference was not statistically significant (p=0.08) (38.9% of the SIs were recorded in the first 12 months of treatment). The risk of SI was significantly different among the three treatment groups (p<0.0001). Multivariate models confirmed that the use of steroids (p<0.046), concomitant DMARD treatment during anti-TNF therapy (p=0.004), advanced age at the start of anti-TNF treatment (p<0.0001), and the use of IFN or ADA rather than ETN (respectively p<0.0001 and p=0.023) were strong and statistically significant predictors of infection. CONCLUSIONS Anti-TNF therapy is associated with a small but significant risk of SI that is associated with the concomitant use of steroids, advanced age at the start of anti-TNF treatment, and the type of anti-TNF agent.

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).

Factors and comorbidities associated with first neuropsychiatric event in systemic lupus erythematosus: does a risk profile exist? A large multicentre retrospective cross-sectional study on 959 Italian patients

OBJECTIVE To analyse risk factors and comorbidities potentially associated with CNS involvement in a large cohort of Italian patients affected by SLE. METHODS A number of generic (not strictly SLE related) and specific (disease related) risk factors to which all patients have been exposed in the span of 5 years before the first neuropsychiatric (NP) event or before the last available observation were checked for and their distribution was analysed in 959 SLE patients with and without NP involvement; all the first NP events that occurred in a time frame of 10 years were recorded and categorized as SLE related or SLE unrelated. RESULTS Three hundred and twenty-six SLE patients with and 633 SLE patients without NP manifestations were included in the study. A total of 469 NP events were recorded. Headache (26.1%), cerebrovascular events (22.7%), mood disorders (8.9%), seizures (14.4%) and cognitive dysfunctions (9.5%) were the most frequent SLE-related NP events. More risk factors [mean 4.52 (2.44) vs 3.73 (2.01); P < 0.0001] were observed in patients with than without NP involvement. Overall, aPLs, LA and APS were factors more strongly associated with NP involvement. CONCLUSIONS In SLE, NP involvement and aPLs were confirmed as closely related. Furthermore, other modifiable generic risk factors, such as hypertension, carotid vasculopathy and dyslipidaemia, appeared to be related to the occurrence of cerebral vascular accident (CVA) and cognitive dysfunctions, suggesting the need for a more intensive preventive strategy to optimize the management of NP lupus.

A2A and A3 adenosine receptor expression in rheumatoid arthritis: upregulation, inverse correlation with disease activity score and suppression of inflammatory cytokine and metalloproteinase release

IntroductionThe reduction of the inflammatory status represents one of the most important targets in rheumatoid arthritis (RA). A central role of A2A and A3 adenosine receptors (ARs) in mechanisms of inflammation has been reported in different pathologies. The primary aim of this study was to investigate the A2A and A3ARs and their involvement in RA progression measured by Disease Activity Score in 28 or 44 joints (DAS28 or DAS).MethodsARs were analyzed by saturation binding assays, mRNA and Western blotting analysis in lymphocytes from early and established RA patients. The effect of A2A and A3AR agonists in nuclear factor kB (NF-kB) pathway was evaluated. Tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleukin-6 (IL-6) release was carried out by A2A and A3AR activation. AR pharmacological regulation in matrix metalloproteinase-1 (MMP-1) and metalloproteinase-3 (MMP-3) release was also studied.ResultsIn lymphocytes obtained from RA patients, A2A and A3ARs were up-regulated if compared with healthy controls. A2A and A3AR activation inhibited the NF-kB pathway and diminished inflammatory cytokines such as TNF-α, IL-1β and IL-6. A2A and A3AR agonists mediated a reduction of MMP-1 and MMP-3 release. A2A and A3AR density inversely correlated with DAS28 and DAS suggesting a direct role of the endogenous activation of these receptors in the control of RA joint inflammation.ConclusionsTaken together these data demonstrate that the inflammatory and clinical responses in RA are regulated by A2A and A3ARs and support the use of A2A and/or A3AR agonists as novel and effective pharmacological treatment in RA patients.

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.

SAPHO syndrome and infections

The syndrome of synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) encompasses a broad spectrum of cutaneous manifestations associated with osteitic and hyperostotic lesions, which typically may involve the anterior chest wall (ACW). The aetiopathogenetic mechanisms as well as the nosographic framing of the disease are still not fully defined although an important role has been suggested for Propionibacterium acnes (P. acnes). This germ might be able to stimulate both the innate and the T-cell-mediated immune system. The elicited immunological response could be an attempt to eliminate the germ thus inducing the perpetuation of the inflammation. Whether the osteo-articular changes seen in SAPHO could be attributable directly to the infection or to an inflammatory reaction induced by pathogenic material remains a debated issue. The current concept of SAPHO syndrome as a reactive infectious osteitis in genetic predisposed subjects seems appealing, but it has not been yet demonstrated.

Neurological Involvement in Primary Sjo¨gren’s Syndrome: Clinical and Instrumental Evaluation in a Cohort of Italian Patients

Abstract: To evaluate nervous system involvement in a cohort of Italian patients with primary Sjögren’s syndrome (pSS), 87 unselected patients (83 female, and four male) observed consecutively at our institution over a period of 5 years were screened by clinical and instrumental (MRI, SPECT, electrophysiological testing, CSF analysis) investigations for peripheral and central neurological abnormalities. Seroimmunological parameters and extraglandular features other than neurological manifestations were also evaluated. Seven patients had central nervous system (CNS) disease (8%), mostly non-focal dysfunction, and 12 had peripheral nervous system (PNS) disease (13.8%), mostly mild or severe sensory or sensory-motor polyneuropathies. One patient had concomitant CNS and PNS involvement. Compared with CNS disease, PNS involvement occurred in older patients (450 years), independent of the disease duration. Patients with and without neurological abnormalities did not differ for seroimmunological parameters (including antiphospholipid antibodies) or extraglandular manifestations. From a statistical point of view, the only relevant finding was the detection of a slight increase in serum IgA and IgM levels (p50.05) in patients with an intact nervous system. Neurological involvement in pSS, be it central or peripheral, is not a rare finding. A careful clinical neurological evaluation, combined with a multiplicity of instrumental investigations, is recommended in the global assessment of pSS patients.

CNS involvement in primary Sjögren's syndrome: prevalence, clinical aspects, diagnostic assessment and therapeutic approach.

Among the systemic manifestations of primary Sjögren’s syndrome, neurological involvement is still an intriguing and debated issue. Although peripheral nervous system abnormalities are a well documented occurrence with a reported prevalence ranging from 10 to 20%, opinions differ as to the prevalence of CNS disease, with suggestions from ‘nonexistent’ to ‘very common’. The lack of agreement probably reflects the different populations selected, different inclusion criteria and lack of rigorous epidemiological studies. In our experience, CNS involvement was detected in 7 of 87 (8%) unselected consecutive patients observed over a period of 5 years.The spectrum of CNS involvement is wide, including focal, diffuse, neuropsychiatric and spinal cord symptoms, frequently characterised by insidious onset, remitting course and, sometimes, progressive evolution. The diagnostic approach enabling early recognition of this complication relies on careful clinical assessment using history and physical examination combined with neuropsychological testing and instrumental, laboratory and imaging investigations such as magnetic resonance imaging, single photon emission computed tomography, electrophysiological testing and CSF analysis.The clinical picture often shows spontaneous remission, but when overt neurological symptoms occur or become progressive, therapeutic interventions with high dose corticosteroids and cytotoxic agents, such as intravenous cyclophosphamide pulse therapy, may be indicated.

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.