Fibromyalgia and psychiatric disorders.

Fibromyalgia (FM) is a common and polymorphic syndrome, characterized by long-lasting, widespread musculoskeletal pain, in the presence of 11 or more tender points located at specific anatomical sites. A heterogeneous series of disturbances, mainly involving autonomic, neuroendocrine and neuropsychic systems, is usually present. Even if subjective, the chronic psychophysical suffering state of FM adversely affects the patient's quality of life, performance and mood. Cognitive behavioural therapy and antidepressant drugs are useful in FM treatment, suggesting a close link between the syndrome and psychiatric, psychological and behavioural factors. Our aim was to evaluate the personality profiles of FM patients, as well as the aggregation and relationships between FM and psychiatric disorders (PD), reviewing the available evidences in current literature on this comorbidity. Personality variables associated with psychological vulnerability are frequent in FM patients. Personality disorders are rarely reported. Compared with controls, FM patients show a significantly higher prevalence of depressive and anxiety disorders, reported in 20-80% and 13-63.8% of cases, respectively. This high variability may depend on the psychosocial characteristics of patients, since most of the studies were performed on tertiary care consulting patients, however, even referring to the lower percentages, the occurrence of PD is significantly higher in FM subjects compared to the general population (7%). Moreover, elevated frequencies of PD have been detected in relatives of FM patients. The FM/PD aggregation suggests a common physiopathology, and alterations of neurotransmitter systems may constitute the shared underlying factor.

HLA-DRB4 as a genetic risk factor for Churg-Strauss syndrome.

OBJECTIVE: To explore the association between HLA alleles and Churg-Strauss syndrome (CSS), and to investigate the potential influence of HLA alleles on the clinical spectrum of the disease. METHODS: Low-resolution genotyping of HLA-A, HLA-B, and HLA-DR loci and genotyping of TNFA -238A/G and TNFA -308A/G single-nucleotide polymorphisms were performed in 48 consecutive CSS patients and 350 healthy controls. RESULTS: The frequency of the HLA-DRB1*07 allele was higher in the CSS patients than in controls (27.1% versus 13.3%; chi(2) = 12.64, P = 0.0003, corrected P [P(corr)] = 0.0042, odds ratio [OR] 2.42, 95% confidence interval [95% CI] 1.47-3.99). The HLA-DRB4 gene, present in subjects carrying either HLA-DRB1*04, HLA-DRB1*07, or HLA-DRB1*09 alleles, was also far more frequent in patients than in controls (38.5% versus 20.1%; chi(2) = 16.46, P = 0.000058, P(corr) = 0.000232, OR 2.49, 95% CI 1.58-3.09). Conversely, the frequency of the HLA-DRB3 gene was lower in patients than in controls (35.4% versus 50.4%; chi(2) = 7.62, P = 0.0057, P(corr) = 0.0228, OR 0.54, 95% CI 0.35-0.84). CSS has 2 major clinical subsets, antineutrophil cytoplasmic antibody (ANCA)-positive, with features of small-vessel vasculitis, and ANCA-negative, in which organ damage is mainly mediated by tissue eosinophilic infiltration; analysis of HLA-DRB4 in patients categorized by different numbers of vasculitic manifestations (purpura, alveolar hemorrhage, mononeuritis multiplex, rapidly progressive glomerulonephritis, and constitutional symptoms) showed that its frequency strongly correlated with the number of vasculitis symptoms (P for trend = 0.001). CONCLUSION: These findings indicate that HLA-DRB4 is a genetic risk factor for the development of CSS and increases the likelihood of development of vasculitic manifestations of the disease.

Infliximab plus prednisone or placebo plus prednisone for the initial treatment of polymyalgia rheumatica: a randomized trial.

BACKGROUND: A reliable alternative to steroids for treating polymyalgia rheumatica has not yet been identified. Although infliximab has been used occasionally in steroid-resistant cases, its efficacy has not been demonstrated in a controlled study. OBJECTIVE: To compare the efficacy of prednisone plus infliximab with that of prednisone plus placebo in patients with newly diagnosed polymyalgia rheumatica. DESIGN: Randomized, placebo-controlled trial. SETTING: 7 rheumatology clinics in Italy. PATIENTS: 51 patients with newly diagnosed polymyalgia rheumatica. Patients with associated giant cell arteritis and those who had been previously treated with steroids or biological or immunosuppressive agents were excluded. INTERVENTION: Initial therapy with oral prednisone tapered from 15 mg/d to 0 mg/d over 16 weeks according to a standard protocol, plus infusions of placebo or infliximab, 3 mg/kg of body weight, at weeks 0, 2, 6, 14, and 22. MEASUREMENTS: The primary efficacy end point was the proportion of patients without relapse or recurrence through week 52. Secondary outcomes were the proportion of patients no longer taking prednisone, the number of relapses and recurrences, the duration of prednisone therapy, and the cumulative prednisone dose. RESULTS: Four patients (3 in the infliximab group and 1 in the placebo group) did not complete the trial. The proportion of patients who were free of relapse and recurrence at 52 weeks did not differ between groups (6 of 20 patients [30%] in the infliximab group vs. 10 of 27 patients [37%] in the placebo group; adjusted risk difference, -3 percentage points [95% CI, -31 to 24 percentage points]; P = 0.80). In a sensitivity analysis that included dropouts, the best-case scenario yielded a difference of 5 percentage points (CI, -21 to 31 percentage points) between the groups. The secondary outcomes at weeks 22 and 52 did not differ between the groups. LIMITATIONS: The study had a small sample and a short follow-up. A low dosage of infliximab was used, and the prednisone dosage was rapidly tapered. CONCLUSIONS: Although too small to be definitive, the trial provides evidence that adding infliximab to prednisone for treating newly diagnosed polymyalgia rheumatica is of no benefit and may be harmful. If there is benefit, it is unlikely to be large. Australian Clinical Trials Registry number: ACTRN012606000205538.

Peripheral neuropathy in Wegener's granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis.

OBJECTIVE: To compare the clinical aspects of peripheral neuropathy associated with Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS) and microscopic polyangiitis (MP). METHODS: Cohort study conducted in a single university hospital. Patients were included when a definite diagnosis of WG, CSS or MP was made according to the current classification criteria in our hospital, between 1999 and 2006. All patients underwent periodically clinical and electrophysiological screening for peripheral neuropathy, assessment of disability, and clinical and laboratory evaluation during a mean follow-up of 38 months. RESULTS: Sixty-four consecutive patients diagnosed with WG (26 patients), CSS (26 patients) and MP (12 patients) were recruited. Peripheral neuropathy occurred in 27/64 patients: six with WG, 15 with CSS and six with MP. Neuropathy occurred earlier in the disease history in CSS and MP compared with WG. Among patients with WG, those who developed peripheral neuropathy during follow-up were older than those without neuropathy both at the time of onset and of diagnosis of vasculitis. Distal symmetric polyneuropathy was present in 11 patients, and single or multiple mononeuropathy in 16. Patients with WG had a less severe form of mononeuritis multiplex than CSS or MPA patients. Disability and pain were greater in patients with mononeuropathy, although one-third of them were painless. Relapses of neuropathy were extremely infrequent. CONCLUSIONS: Peripheral neuropathy in WG occurs less frequently, later in the disease course and in a milder form than in CSS and MP. Single or multiple mononeuropathy associated with these subsets of vasculitis can often be painless.

Respiratory system involvement in antineutrophil cytoplasmic-associated systemic vasculitides: clinical, pathological, radiological and therapeutic considerations.

Wegener's granulomatosis (WG), microscopic polyangiitis (MPA) and Churg- Strauss syndrome (CSS) are small-vessel vasculitides that, because of their frequent association with antineutrophil cytoplasmic antibodies (ANCA), are usually referred to as ANCA-associated systemic vasculitides (AASV). The diagnosis of AASV is made on the basis of clinical findings, biopsy of an involved organ and the presence of ANCA in the serum. Lung disease is a very common and important clinical feature of AASV. In WG, almost all patients have either upper airway or lower respiratory tract disease. Solitary or multiple nodules, frequently cavitated, and masses are the most common findings on chest radiography. Asthma is a cardinal symptom of CSS, often preceded by allergic rhinitis. Pulmonary transient and patchy alveolar infiltrates are the most common radiographic findings. In MPA, diffuse alveolar haemorrhage as a result of alveolar capillaritis is the most frequent manifestation of respiratory involvement, and is clinically expressed as haemoptysis, respiratory distress and anaemia. However, diffuse alveolar haemorrhage may also be subclinical and should be suspected when a chest radiograph demonstrates new unexplained bilateral alveolar infiltrates in the context of falling haemoglobin levels. Normal and high-resolution CT have a higher sensitivity than chest radiography for demonstrating airway, parenchymal and pleural lesions. However, many of these radiological findings are nonspecific and, therefore, their interpretation must take into account all clinical, laboratory and pathological data. Therapy of AASV is commonly divided into two phases: an initial 'remission induction' phase, in which more intensive immunosuppressant therapy is used to control disease activity, and a 'maintenance' phase, which uses less intensive therapy, for maintaining disease remission while lowering the risk of adverse effects of immunosuppressant drugs. In patients with AASV refractory to standard therapy with corticosteroids and oral cyclophosphamide, new therapeutic options are now available. Recurrence of pulmonary symptoms suggesting a flare indicates the need for a careful search for an opportunistic lung infection or iatrogenic pulmonary complications. In conclusion, involvement of the respiratory system is a very common and important organ manifestation of AASV. Respiratory system involvement comprises a wide spectrum of clinical features and radiological findings, and because of its frequency and prognostic significance, a complete assessment of the respiratory system should be included in the work-up of all patients with AASV.

Carnitine: a therapeutic option for childhood psoriatic onycho-pachydermo-periostitis (POPP).

Psoriatic onycho-pachydermo-periostitis (POPP)is a rare subset of psoriatic arthritis, characterized by onychopathy, painful thickening of the periungual soft tissues, and radiological features consisting of an exuberant periosteal reaction of the terminal phalanx. The POPP treatment is debated, and side effect risk of therapies may not be offset by their benefits. We report on a successful treatment with carnitine in a 15-year old boy suffering from POPP.

Outcome and prognostic factors during the course of primary small-vessel vasculitides.

OBJECTIVE: To identify the prognostic factors of relapse and/or death during the course of primary small-vessel vasculitides (PSVV), and to differentiate their prognostic relevance by the type of vasculitis. METHODS: Seventy-five patients were retrospectively followed up after diagnosis: 36 with Wegener's granulomatosis (WG), 23 with Churg-Strauss syndrome (CSS), and 16 with microscopic polyangiitis. Cox regression analysis was used to identify the significant predictors of relapse and death. RESULTS: Gastrointestinal (GI) involvement was associated with an increased risk of relapse, mainly in the patients with CSS, whereas renal disease and perinuclear antineutrophil cytoplasmic antibody positivity were correlated with a lower risk of relapse. Presence of nasal Staphylococcus aureus tended to increase the risk of relapse in CSS [hazard ratio (HR) 4.45, p = 0.087], but to decrease it in WG (HR 0.12, p = 0.066). Older age, renal and hepatic involvement, erythrocyte sedimentation rate >or= 100 mm/h, and serum creatinine level >or= 1.5 mg/dl were all related to higher risk of death in univariate analysis; however, only cerebral (HR 8.52, p = 0.021) and hepatic involvement (HR 4.40, p = 0.028) and serum creatinine level >or= 1.5 mg/dl (HR 5.72, p = 0.044) were independently correlated with an unfavorable prognosis for survival. The risk of death associated with each of these indicators did not depend on the form of PSVV. CONCLUSION: GI involvement increases the risk of relapse in CSS, whereas the prognostic significance of nasal S. aureus in terms of relapse seems to be opposite in patients with CSS and those with WG. Patients with cerebral, hepatic, and renal involvement have the poorest prognosis for survival. Our data do not show that the prognostic relevance of these factors depends on the form of PSVV.

Steroid-reversible parkinsonism as presentation of polymyalgia rheumatica.

Polymyalgia rheumatica (PMR) is an inflammatory disorder typically affecting elderly people, characterized by pain and stiffness in the neck and in the shoulder and pelvic girdless with prompt clinical response to low doses of corticosteroids. PMR is closely related to giant cell arteritis (GCA), likely sustained by a "subclinical vasculitis". Whereas in GCA both the central and peripheral nervous systems may be involved, only a PMR case of global, steroid-reversible dementia has been hitherto described. We report two elderly patients who abruptly developed, as PMR presenting symptom, an akinetic-rigid parkinsonian syndrome that promptly and completely resolved after corticosteroid treatment.

Respiratory system involvement in ANCA-associated systemic vasculitides.

BACKGROUND AND AIM OF THE WORK: The respiratory system may be involved in all systemic vasculitides (SV), although with a variable frequency. Lung disease is a very common and important feature of the antineutrophil cytoplasmic antibodies (ANCA)-associated SV (AASV), such as Wegener's granulomatosis (WG), Churg-Strauss syndrome (CSS), and microscopic polyangiitis (MPA). The aim of the work is to review the clinical findings, as well as the radiological and pathological features of respiratory system involvement in AASV. METHODS: A detailed search via the PubMed index from the National Library of Medicine, covering the period from 1980 to December 2004, was accomplished. RESULTS: In WG, almost all patients have either upper airway or lower respiratory tract disease. Solitary or multiple nodules and masses are the most common findings on chest radiograph. Asthma is a main symptom of CSS, often preceded by allergic rhinitis, frequently complicated by nasal polyposis and sinusitis. Pulmonary transient and patchy alveolar infiltrates are the most common radiographic findings. In MPA, diffuse alveolar haemorrhage (DAH) due to alveolar capillaritis is the most frequent manifestation of the respiratory involvement, clinically expressing with haemoptysis, respiratory distress and anaemia. CONCLUSIONS: The involvement of the respiratory system is a very common and important feature of AASV. There is substantial overlap in many of the clinical pulmonary features of AASV. In some cases, distinguishing between these diseases on the basis of the clinical features alone is difficult and pathological assessment is needed.

OPG/RANKL system imbalance in a case of hepatitis C-associated osteosclerosis: the pathogenetic key?

Hepatitis C-associated osteosclerosis (HCAO) is an impressive example of acquired diffuse osteosclerosis in adults, recently described in ten patients infected with hepatitis C virus (HCV). Its hallmark is a painful and generalized increase of bone mass. Bone biopsies show enhanced accretion rate, usually without histological abnormalities. The HCAO pathogenesis is hitherto unknown. HCV might induce a slow bone cell infection and the production of bone growth factors, such as insulin-like growth factors. Recently, receptor activator of nuclear factor-kappaB (RANK), its ligand (RANKL), and soluble decoy receptor osteoprotegerin (OPG) have been identified as a pivotal cytokine system in the bone remodeling control. We describe the 11th case of HCAO. Notably, the patient's bone biopsy showed the presence of a high number of OPG-positive osteoblasts, a slight increase of RANKL-positive stromal cells, and a dramatic reduction of the osteoclasts. Moreover, OPG serum levels were increased. These findings reported here for the first time are consistent with a pathogenetic role of the OPG/RANKL system imbalance in HCAO.

Clinical and histological coexistence of inflammatory pseudotumour of the lymph nodes and rheumatoid arthritis.

Inflammatory pseudotumour (IPT) of the lymph nodes is an uncommon, self-limiting, non-neoplastic proliferation of spindle cells, associated with a polymorphous inflammatory cell infiltrate embedded in a collagen-rich stroma and a variable degree of fibrosis, arising in the nodal parenchyma. Its clinical picture is characterised by site-specific signs and the presence, in most cases, of constitutional symptoms. The pathogenesis of IPT is unknown, but it has been interpreted as an aberrant reactive condition of the nodal connective framework, possibly related to viral infections or chronic inflammatory conditions. Its prognosis is usually favourable. We here report the simultaneous onset of seronegative rheumatoid arthritis (RA) and nodal IPT in a 31-year-old woman. Notably, in the nodal biopsy the coexistence of rheumatoid nodules, as well as histological and immunohistochemical features of IPT, was observed. To our knowledge, such an association has not been previously reported and the hypothesis that IPT could represent an unusual epiphenomenon of an RA-related chronic inflammatory response is suggested.

Apoptosis and Sjögren syndrome.

OBJECTIVE: To examine the role of apoptosis in the pathogenesis of Sjögren syndrome (SS), a chronic autoimmune disease characterized by the infiltration of mononuclear cells in the salivary and lacrimal glands, leading to the destruction of the parenchymal tissue. METHODS: A detailed search via MEDLINE (PubMed) and Biosis, covering the period from January 1994 to July 2002, was accomplished, combining the key terms SS and apoptosis. A qualitative review of the articles was undertaken and the obtained information was summarized. RESULTS: Apoptosis of the acinar and ductal epithelial cells of the salivary and lacrimal glands has been proposed as a possible mechanism responsible for the impairment of secretory function. Apoptotic cell death may be induced by either cytotoxic T cells through the release of proteases, such as perforin and granzyme B, or the interaction of Fas ligand (FasL/CD95L), expressed by T lymphocytes, with Fas (Apo-1/CD95) on epithelial cells. The increased rate of apoptosis of epithelial cells in SS may result from either the imbalance between the down-regulated apoptosis-inhibitor Bcl-2 and the up-regulated apoptosis-inducer Bax, or the autocrine and/or paracrine Fas/FasL interaction. Lymphocytes infiltrating the salivary glands are blocked in their ability to commit to apoptosis, despite the expression of the apoptosis-inducer Fas. The expression of Bcl-2 in these cells may explain their resistance to apoptosis, resulting in a prolonged production of proinflammatory cytokines and autoantibodies, as well as in their longer survival that may result in the late development of lymphoma in some SS patients. Studies of the SS-like sialoadenitis of nonobese diabetic (NOD) mice with severe combined immunodeficiency (NOD.scid) suggest that the primary defect responsible for the initiation of SS resides in the epithelial cells that undergo apoptosis mediated by the autocrine Fas/FasL interaction. This first not-immune-mediated phase of target cell destruction is followed by a lymphocyte-dependent autoimmune aggression, which leads to extensive tissue damage and subsequent loss of secretory function. Apoptosis of the salivary epithelial cells has been shown in other animal models of SS and in cell lines in vitro. Apoptosis may also play a role in the pathogenesis of some extraglandular manifestations of SS, such as interstitial nephritis and peripheral CD4(+) lymphocytopenia. CONCLUSIONS: The possible role of apoptosis in SS is suggested from the literature review. A better understanding of the mechanisms responsible for the epithelial cell apoptosis may allow the discovery of new therapeutic strategies. By inhibiting programmed cell death, the glandular damage and the subsequent impairment of the secretory function should be reduced.

Familial vasculitides: Churg-Strauss syndrome and Wegener's granulomatosis in 2 first-degree relatives.

Churg-Strauss syndrome (CSS) and Wegener's granulomatosis (WG) are uncommon primary vasculitides, characterized by the involvement of the small to medium size vessels and by the frequent presence of serum antineutrophil cytoplasmic antibodies (ANCA). The pathogenesis of ANCA associated vasculitides is unclear, but roles for both genetic and environmental factors have been suggested. Familial cases of WG, but not CSS, have been reported. We describe the occurrence of CSS in a man and, 5 years later, WG in his son. These patients live together in an urban area of Northern Italy and share the HLA haplotype A*03; B*07; C*w07; DRB 1*0404, DQB 1*0302. To our knowledge, this is the first report of the familial clustering of CSS and WG in first-degree relatives.

Familial giant cell arteritis and polymyalgia rheumatica: aggregation in 2 families.

The ethnic and geographic prevalence, the familial aggregation, and the reported association with some HLA class II antigens of both giant cell arteritis (GCA) and polymyalgia rheumatica (PMR) strongly suggest the role of genetic factors in the pathogenesis of these diseases. We describe the familial aggregation of GCA and PMR in 2 unrelated families from Northern Italy. In the first family, 2 sisters developed GCA a few months apart. In the second, one sister had GCA, and 2 years later her siblings developed PMR nearly simultaneously. Patients with GCA in the first family shared the whole HLA genotype (A*24,*26, B*38,*55, DRB1*11,*14, DQB1*05,*07, DRB3*). In the second family, both PMR siblings carried the A*68, B*44, DRB1*11, DQB1*07, DRB3* alleles. Thus all patients of both families shared DRB1*11, DQB1*07, and DRB3*. Predisposing immunogenetic factors of both GCA and PMR are discussed.

[Hepatitis C virus and pulmonary fibrosis]. / Virus dell'epatite C e fibrosi polmonare.

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease characterized by an accumulation of alveolar macrophages and neutrophils in the lower respiratory tract, parenchymal injury, and interstitial fibrosis. Although the etiology of IPF is unknown, it has been suggested that viral agents, among which hepatitis C virus (HCV), may be involved in inducing the disease. In patients with chronic hepatitis HCV+ and in those with mixed cryoglobulinemia HCV-associated, HCV may trigger a subclinical lymphocyte alveolitis. Furthermore, pulmonary fibrosis associated with a variety of rheumatic disorders has been reported in 8/300 patients with active chronic hepatitis HCV+. Bronchoalveolar lavage, carried out in 4/8 patients, showed an increased percentage of neutrophils in all of them and a mild increase of lymphocytes in 2 patients. Thoracoscopic lung biopsy was carried out in 2 patients and showed a desquamative interstitial pneumonia; in one case HCV-RNA was found in the pulmonary parenchyma. Although the above observations seem indicate a role for HCV in IFP, further studies are required to define its true importance in the etiopathogenesis of the interstitial lung disease.