Interferon Alpha-2a Treatment for Post-Uveitic Refractory Macular Edema.

Purpose: To assess the efficacy of interferon (IFN) alpha-2a in the treatment of post-uveitic refractory macular edema (ME).Methods: Retrospective cohort of patients with post-uveitic refractory ME, who received subcutaneous IFN alpha-2a injections for at least 3 months. Baseline central macular thickness (CMT) and best-corrected visual acuity (BCVA) were compared with those at follow-up visits up to 12 months.Results: Thirty-seven patients were included. Treatment duration (median [interquartile range]) was 14[8-24] months with a follow-up of 17[10-38] months. CMT (mean [standard deviation]) decreased from 438[140] to 335[119] µm after 1 month (p < 0.0001) and remained significantly lower up to 12 months (286[98] µm, p = 0.001). BCVA (0.48[0.33] logMAR at baseline) improved by 0.26[0.33] logMAR (p = 0.001) at 12 months. There were 14 recurrences. Seven patients had treatment side effects, without serious adverse events.Conclusions: IFN alpha-2a was effective, safe, and well tolerated in treating post-uveitic refractory ME.

Tocilizumab in glucocorticoid-naïve large-vessel vasculitis.

Glucocorticoids (GC) are the mainstay of treatment of large-vessel vasculitis (LVV), but a sizeable number of patients relapse upon tapering the GC dose or after discontinuation of GC therapy. In addition, GC cause numerous adverse events. Therefore, in patients with longstanding disease and in those at risk for GC-related adverse events, the use of alternative therapeutic agents should be considered. Interleukin-6 (IL-6) is a key player in the pathogenesis of LVV. Preliminary data suggest the efficacy of the IL-6 receptor inhibitor tocilizumab (TCZ) in patients with LVV. We report 2 treatment-naïve patients with a recent diagnosis of LVV who received monthly TCZ infusions (8 mg/kg body weight) for 6 consecutive months as monotherapy because of relative contraindications and patients' reluctance to take GC. In both cases we observed a complete clinical response and normalisation of inflammatory markers as well as a decrease in vascular FDG uptake and SUV ratio on fluorodeoxyglucose positron emission/computerised tomography. Serum IL-6 and soluble IL-6 receptor (sIL-6R) levels rose in both patients after TCZ therapy. TCZ may be an effective alternative to GC treatment for LVV patients at risk for GC-related adverse events. Larger studies are required to confirm our findings.

[Disease activity assessment in large vessel vasculitis]. / Valutazione dell'attività di malattia nelle vasculiti dei grandi vasi.

Disease activity assessment in large vessel vasculitis (LVV) is often challenging for physicians. In this study, we compared the assessment of disease activity based on inflammatory markers, clinical indices (Indian Takayasu Activity Score [ITAS] and the Kerr/National Institute of Health indices [Kerr/NIH]), and 18F-Fluorodesossiglucose (FGD) vascular uptake at positron emission tomography (Pet). We found that Pet results did not statistically correlate with the clinical indices ITAS and Kerr/NIH, because FDG uptake was increased (grade>2 on a 0-3 scale in at least one evaluated vascular segment) in many patients with inactive disease according to clinical and laboratory parameters (i.e., negative ITAS and Kerr/NIH indices as well as normal erythrocyte sedimentation rate (ESR) and C-reactive protein (PCR)). Similarly, interleukin- 6 and its soluble receptor did not statistically correlate with disease activity. In contrast, clinical indices showed a significant correlation between each other and with inflammatory markers (VES and PCR). These data suggest that while clinical indices and inflammatory markers may be useful to assess disease activity, Pet may be more sensitive.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis involving the central nervous system: case report and review of the literature.

OBJECTIVES: To report a case of biopsy-proven, ANCA-associated vasculitis (AAV) involving the central nervous system (CNS) and to review the relevant literature. METHODS: Descriptive case report of one patient with AAV-related CNS vasculitis and review of the relevant literature (PubMed search from 1966 to February 2010). RESULTS: A 61-year-old female patient with AAV developed cognitive impairment. Cerebrospinal fluid analysis was unremarkable, while magnetic resonance (MR) imaging showed multiple left hemisphere infarctions and MR angiography revealed multiple stenoses of the distal branches of the left median cerebral artery. Treatment with glucocorticoids, cyclophosphamide, and intravenous immunoglobulins led to improvement. CNS vasculitis often arises when vasculitis is active elsewhere. There is no clear preponderance of gender or of age of onset. Both ANCA-positive and -negative cases of CNS vasculitis are documented. The diagnosis is usually based on clinical CNS manifestations and multiple ischaemic (sometimes haemorrhagic) MR lesions mainly affecting the white matter. Angiography is often negative. Treatment with glucocorticoids and cyclophosphamide, sometimes with adjunctive intravenous immunoglobulins, usually improves clinical features and MR lesions. CONCLUSIONS: AAV rarely involves the CNS. CNS vasculitis should be suspected if patients have neurological manifestations consistent with CNS involvement, particularly if they have evidence of disease activity elsewhere, and if MR shows multiple ischaemic (sometimes haemorrhagic) lesions mainly affecting the white matter. Sepsis, coagulation disorders, and severe hypertension must be ruled out. Awareness of this rare but severe complication can allow early recognition and prompt treatment.

[Chronic periaortitis]. / Chronische Periaortitis.

Chronic periaortitis is a rare fibroinflammatory disorder which affects the abdominal aorta and may spread into the retroperitoneum, often encasing the ureters. An aneurysma of the abdominal aorta and vasculitis of the thoracic aorta and of supra-aortic vessels may also coexist. Chronic periaortitis can be idiopathic or secondary to different triggers such as drugs, tumors and infections. Abdominal and/or low back pain is the hallmark symptom. Laboratory markers of inflammation are usually increased. The diagnosis rests on computerized tomography or magnetic resonance imaging, which typically show a retroperitoneal mass displacing the aorta anteriorly and the ureters medially. Positron-emission tomography may assist in defining disease activity and extension. Chronic periaortitis should be differentiated from other fibrosing disorders of various origins. Histology is required in atypical cases to secure the diagnosis. Treatment is based on high-dose steroids with a tapering scheme combined with immunosuppressive agents in refractory or relapsing disease. In case of ureter obstruction early DJ-catheter placement is required. Operative interventions to relieve ureter obstruction are rarely necessary provided immunosuppressive treatment is timely instituted.

Toll-like receptor 4 (TLR4) gene polymorphisms in giant cell arteritis.

OBJECTIVE: To investigate potential associations between toll-like receptor 4 (TLR4) gene polymorphisms and susceptibility to, and clinical features of giant cell arteritis (GCA). METHODS: A total of 155 patients with biopsy-proven GCA who were residents of Reggio Emilia, Italy, and 210 population-based controls from the same geographical area were genotyped for two coding single nucleotide polymorphisms of TLR4 (Asp299Gly and Thr399Ile) by molecular methods. The patients were subgrouped according to the presence or absence of polymyalgia rheumatica and severe ischemic complications (visual loss and/or cerebrovascular accidents). RESULTS: The distribution of allele and genotype frequencies did not differ significantly between GCA patients and healthy controls. Carriers of the -299 G allele (G/A+ G/G) [odds ratio (OR) 1.78, 95% confidence intervals (CI) 0.90-3.50)] were more frequent among GCA patients than among the controls, but the difference was not statistically significant. No significant associations were found when GCA patients with and without PMR or with and without severe ischemic complications were compared. CONCLUSION: Our data suggest that the TLR4 gene polymorphisms are not associated with susceptibility to, and clinical expression of, GCA in Italian patients.

Risk factors for severe cranial ischaemic events in an Italian population-based cohort of patients with giant cell arteritis.

OBJECTIVE: To evaluate the impact of traditional cardiovascular risk factors, carotid atherosclerosis and the effect of anti-platelet/anti-coagulant therapy on the occurrence of severe cranial ischaemic events (CIEs) in GCA. METHODS: We identified 180 Reggio Emilia (Italy) residents with biopsy-proven GCA diagnosed between 1986 and 2005. We evaluated data on demographics, clinical features, laboratory investigations, cardiovascular risk factors, anti-platelet/anti-coagulant use and carotid atherosclerosis. RESULTS: Systemic signs/symptoms were significantly less frequent (P = 0.004) and ESR and C-reactive protein (CRP) values at diagnosis were significantly lower (P = 0.03 and P = 0.04, respectively) in patients with CIEs. The prevalence of hypertension and ischaemic heart disease was significantly higher in patients with CIEs than in those without (P = 0.01 and P = 0.006, respectively). Patients treated with anti-platelet/anti-coagulant therapy were significantly more likely to suffer CIEs than those without (P = 0.03), while CIEs were significantly associated with ischaemic heart disease in this subset of patients (P = 0.02). By multivariate logistic regression, we found that the best predictors for the development of severe CIEs included the absence of high (>5.38 mg/dl) CRP levels at diagnosis (OR = 0.31, 95% CI 0.08, 1.20), the absence of systemic manifestations (OR = 0.30, 95% CI 0.08, 1.08), the presence of hypertension (OR = 7.77, 95% CI 0.83, 72.76), and a past history of ischaemic heart disease (OR = 8.65, 95% CI 0.92, 80.95). CONCLUSIONS: In GCA, hypertension, a past history of ischaemic heart disease and a low inflammatory response are associated with a higher risk of developing severe CIEs.

1T magnetic resonance imaging in the diagnosis of giant cell arteritis: comparison with ultrasonography and physical examination of temporal arteries.

OBJECTIVE: To assess the usefulness of 1T magnetic resonance imaging (MRI) of temporal arteries and to compare 1T MRI with duplex ultrasonography (US) and physical examination of temporal arteries for the diagnosis of giant cell arteritis (GCA) in patients with suspected GCA. METHOD: The superficial temporal arteries of 20 consecutive patients with a suspected diagnosis of GCA were examined using a 1T MRI scanner. Fat-saturated multislice T1-weighted spin-echo images were acquired perpendicularly to the orientation of the vessel. In all cases, MRI results were compared to US and temporal artery examination findings. Temporal artery biopsies were performed in all patients. RESULTS: Mural contrast enhancement of the temporal arteries on MRI had a sensitivity of only 33.3% and a specificity of 87.5% for the diagnosis of biopsy-proven GCA. Compared with the diagnosis of GCA by the American College of Rheumatology criteria, MRI had a sensitivity and specificity of 27.2% and 88.9%, respectively. Temporal artery abnormalities on physical examination and the presence of a hypoechoic halo on US had a higher sensitivity (66.7% and 77.7%, respectively) and a higher specificity (100% for both) compared to MRI findings. CONCLUSION: 1T MRI is not useful for the diagnosis of GCA because of its low sensitivity. US and physical examination of temporal arteries had a better diagnostic accuracy. However, our data does not exclude a diagnostic role for higher-resolution MRI.

Cervical interspinous bursitis in active polymyalgia rheumatica.

OBJECTIVE: To evaluate the inflammatory involvement of cervical interspinous bursae in patients with polymyalgia rheumatica (PMR) using MRI. METHODS: In all, 12 consecutive, untreated new patients with PMR were investigated. Five patients with fibromyalgia, two patients with cervical osteoarthritis and six patients with spondyloarthritis with neck pain served as controls. MRI of the cervical spine was performed in all 12 PMR case patients and in 13 control patients. Two of the four patients with PMR with pelvic girdle pain also had MRI of the lumbar spine. RESULTS: MRI evidence of interspinous cervical bursitis was found in all patients with PMR, and in three patients with fibromyalgia, in two with psoriatic spondylitis and one with cervical osteoarthritis. A moderate to marked (grade >or=2 on a semiquantitative 0-3 scale) cervical bursitis occurred significantly more frequently in patients with PMR than in control patients (83.3% compared with 30.7%, p = 0.015). In all patients and controls with cervical bursitis the involvement was found at the C5-C7 cervical interspaces. MRI of the lumbar spine showed lumbar interspinous bursitis at the L3-L5 lumbar interspaces in the two patients with PMR and pelvic girdle pain examined. CONCLUSIONS: Cervical interspinous bursitis is a likely basis for discomfort in the neck of patients with PMR. The prominent inflammatory involvement of cervical bursae supports the hypothesis that PMR is a disorder of prominent involvement of extra-articular synovial structures.

-463 G/A myeloperoxidase promoter polymorphism in giant cell arteritis.

OBJECTIVE: To investigate potential associations between-463 G/A myeloperoxidase (MPO) promoter polymorphism and susceptibility to, and clinical features of giant cell arteritis (GCA). METHODS: A total of 156 patients with biopsy-proven GCA who were residents of Reggio Emilia, Italy, and 235 population-based controls from the same geographic area were genotyped for-463 G/A promoter polymorphism of the MPO gene by molecular methods. The patients were subgrouped according to the presence or absence of polymyalgia rheumatica and severe ischaemic complications (visual loss and/or cerebrovascular accidents). RESULTS: The distribution of the MPO-G/A genotype differed significantly between patients with GCA and the controls (p(corr) = 0.003). Allele G was significantly more frequent in patients with GCA than in the controls (p(corr) = 0.0002, OR 2.0, 95% CI 1.4 to 2.9). Homozygosity for the G allele was significantly more frequent in patients with GCA than in controls (p(corr) = 0.0002, OR 2.2, 95% CI 1.4 to 3.4). No significant associations were found when patients with GCA with and without polymyalgia rheumatica or with and without severe ischaemic complications were compared. CONCLUSIONS: Our findings show that the-463 G/A promoter polymorphism of the MPO gene is associated with GCA susceptibility and support a role for MPO in the pathophysiology of GCA.

Clinical assessment in psoriatic arthritis.

Due to the heterogeneous clinical picture, with a possible combination in any individual patient of axial disease, peripheral arthritis, enthesitis and dactylitis, psoriatic arthritis (PsA) is difficult to assess. Validated assessment tools for PsA are lacking. Recently, international study groups have a special interest in developing and validating standardized tools to assess PsA. We will review the existing assessment modalities of PsA focusing on axial disease, peripheral arthritis, enthesitis and dactylitis. Measures of function and disability recommended for PsA will be also reviewed.

Giant-cell arteritis of the female genital tract associated with occult temporal arteritis and FDG-PET evidence of large-vessel vasculitis.

We describe a case of giant cell arteritis (GCA) of the female genital tract. Fluorine-18-fluorodeoxyglucose positron emission tomography (18F-FDG PET) and CT-scan showed evidence of large-vessel vasculitis involving the thoracic aorta and its branches, while temporal artery biopsy showed arteritis despite the absence of clinical manifestations suggestive of GCA. We review the literature and discuss the relationship between "cranial" GCA, large-vessel GCA and female genital GCA.

Long-term outcome of giant cell arteritis.

Giant cell arteritis is usually a self-limiting disease with a variable duration of months to years. However, in a subset of patients the disease may follow a protracted course, requiring long-term treatment with glucocorticoids. To date, glucocorticoids are the only agents whose efficacy has been unquestionably proven. More specifically, they can both improve the clinical symptoms of giant cell arteritis and also prevent its complications, including visual loss. Glucocorticoids therapy is notoriously fraught with numerous side effects, therefore it is sensible to taper glucocorticoids as quickly as possible. Flares are not uncommon and tend often to occur upon tapering of glucocorticoids dosage or on withdrawal of glucocorticoids therapy. However, in most cases flares are mild and appear to respond favorably to an increase in glucocorticoids dosage or reintroduction of glucocorticoids therapy, respectively. Mortality rates of giant cell arteritis patients are comparable to those of the general population, but there is evidence for an increased frequency of potentially life-threatening ischemic events, such as myocardial infarction and cerebro-vascular accidents, especially early on in the disease course. The risk conferred by the disease appears to decrease with time, presumably as a consequence of glucocorticoids treatment, whereas it can remain significantly elevated in patients whose disease activity is not sufficiently controlled by the treatment. By contrast, there is no evidence that giant cell arteritis is associated with an increased prevalence of malignancies or that it may represent a paraneoplastic syndrome.

Recommendations of the Italian Society for Rheumatology for the use of biologic (TNF-alpha blocking) agents in the treatment of psoriatic arthritis.

AIM: To propose recommendations for the use of biologic (TNF-alpha blocking) agents in the treatment of psoriatic arthritis (PsA). METHODS: We developed these recommendations by reviewing the evidence published in medical journals and in abstracts of the American College of Rheumatology (ACR) and of the European League against Rheumatism. A draft of the recommendations was circulated to a group of Italian Rheumatologists with a special interest in PsA and in therapy with biologic agents, and their suggestions were incorporated in the final version. RESULTS: A consensus was achieved regarding the initiation and the monitoring of anti-TNF-alpha agents in PsA. More specifically, we propose that anti-TNF-alphaagents be considered in active PsA resistant to non-steroidal anti-inflammatory drugs, to at least two local steroid injections and at least 2 conventional disease-modifying anti-rheumatic agents (in cases of oligo/monoarthritis and/or enthesitis), and to at least two conventional disease-modifying anti-rheumatic agents (in patients with peripheral joints synovitis). Disease activity monitoring should be based on a variety of outcome measures including the ACR response criteria modified for use in PsA, the Bath ankylosing spondylitis disease activity index (BASDAI), and the Maastricht ankylosing spondylitis enthesis score (MASES). A favorable Expert opinion, based on evaluation of clinical symptoms and signs, of laboratory investigations (particularly acute phase reactants), and of imaging studies (whenever appropriate) should also be obtained. CONCLUSION: These recommendations may be used for guidance in deciding which patients with PsA should receive biologic therapy. Regular updates of these recommendations will be implemented on the basis of the results of new clinical studies and of data from post-marketing surveillance.

Psoriasis and psoriatic arthritis: immunological aspects and therapeutic guidelines.

Psoriasis is an inflammatory skin disease that affects 1-3% of the European population. Chronic plaque psoriasis, the commonest form of the condition - affecting the majority of patients - usually manifests as red, heavily scaled plaques on elbows, knees, scalp and lower back, but any skin surface may be affected. Psoriasis is associated with an inflammatory sero-negative arthritis, namely "psoriatic arthritis", in approximately 15%of patients with psoriasis and occurs more commonly in people with inflammatory bowel disease such as patients with Crohn's disease. Several studies have demonstrated the role of genetic predisposition, innate and adaptive immunity in the pathogenesis of psoriasis. There is considerable evidence that innate immunity and specifically a dysregulation of the innate immune response is central to the development of psoriasis. The role of TNFalpha is particularly intriguing. The evidence includes further observations that a variety of anti-TNF approaches such as monoclonal antibodies and fusion proteins of soluble TNF receptors are effective therapies both in psoriasis and psoriatic arthritis. In this review, in addition to pathogenetic aspects, some preliminary guidelines for the use of anti-TNFalpha therapy in patients with psoriasis and psoriatic arthritis will be discussed.

Current concepts and new developments in the treatment of psoriatic arthritis.

OBJECTIVES: Psoriatic arthritis (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. Many agents have been proposed for the treatment of PsA, but their use is based more on clinical experience than on sound scientific evidence. METHODS: We reviewed MedLine up to November 2002, searching for 'psoriatic arthritis', 'drug therapy, 'controlled trials' and 'outcomes' and all possible acronyms for these terms. All relevant papers were then examined in detail. RESULTS: PsA is a condition that runs a variable clinical course. Mild forms can usually be controlled by non-steroidal anti-inflammatory drugs (NSAIDs). Intra-articular glucocorticoid injections are indicated in patients with persistent mono- or oligoarthritis. Patients with severe and progressive articular disease not responsive to NSAIDs should be treated with disease-modifying anti-rheumatic drugs (DMARDs) to prevent joint damage and disability. Currently, methotrexate and sulphasalazine are considered the DMARDs of choice, but the evidence for the use of methotrexate in PsA is still largely empirical, while the clinical benefit induced by sulphasalazine appears to be modest. Other DMARDs proposed for the treatment of PsA include cyclosporin, gold salts and, more recently, leflunomide. However, none of the DMARDs available to date are effective in the treatment of psoriatic pelvispondylitis; in addition, a number of patients with severe peripheral arthritis fail to respond to standard DMARDs. Recently, tumour necrosis factor alpha inhibitors have proved effective in many PsA patients with pelvispondylitis or recalcitrant peripheral synovitis. CONCLUSIONS: None of the current treatments for PsA is curative, but significant clinical amelioration can be achieved in the vast majority of patients. Identification and prompt treatment of patients with severe articular disease is crucial for the achievement of a satisfactory clinical response and the improvement of the long-term outcome.

[Role of chemokines in the pathogenesis of chronic synovitis during rheumatoid arthritis]. / Ruolo delle chemochine nella patogenesi della sinovite cronica in corso di artrite reumatoide.

Chemokines play a central role in the pathogenesis of rheumatoid arthritis (RA) synovitis which is characterised by new blood vessel formation, thickening of the lining layer and infiltration of immune cells. The inflammatory infiltrate is generated by a series of events which include the recruitment of leukocytes from the blood stream into the tissue, their local retention and activation to effector cells. All these processes are finely regulated by the interplay of different cell adhesion molecules (CAMs) and chemoattractant factors called chemokines (CK). CK are a superfamily of small proteins that play a crucial role in immune and inflammatory reactions. These chemoattractant cytokines share structural similarities including four conserved cysteine residues which form disulphide bonds in the tertiary structure of the proteins. CK mediate their effects by binding specific receptors (CK-R) characterised by a domain structure which spans the cell membrane seven times and signal through heterotrimeric GPT-binding proteins. Activation of the CK network results in an amplification of the inflammatory cascade and consequently in the progressive destruction of RA joints. The recognition of the central role of CK in inflammation has paved the way to the development of new agents capable of interfering with CK and CK-R. This review will focus in particular on the role of CK in regulating leukocyte trafficking in RA joints.