Frequency of Th1, Th2 and Th17 producing T lymphocytes in bronchoalveolar lavage of patients with systemic sclerosis.

OBJECTIVE: The pathophysiology of the lung fibrotic process in systemic sclerosis (SSc) is not fully elucidated. Since this pattern represents the leading cause of death in SSc, the knowledge of its actual pathophysiology is basic to prevent and stage pulmonary damage. In this study, we aimed to further investigate the relationship between the functional profiles of bronchoalveolar lavage (BAL) T cells and the pulmonary manifestation of the disease. METHODS: With this aim, we assessed the frequency of Th1, Th2 and Th17 producing T-lymphocytes and their effector cytokines in BAL of SSc patients without signs or symptoms of lung interstitial involvement (SScFib-) and with interstitial lung fibrosis (SScFib+). We also study as control groups: patients with usual interstitial pneumonia (UIP), patients with sarcoidosis and 9 healthy controls (NHCs). RESULTS: SScFib- showed an increase in BAL Th1/Th2 balance compared to NHCs, which was even higher than that observed in sarcoidosis. SScFib+ showed a shift towards a lower Th1/Th2 ratio as compared to SScFib-. The frequency of Th17 BAL T cells did not change among study groups. CONCLUSION: Our data confirm the Th1/Th2 imbalance hypothesis on the pathogenesis of interstitial fibrosis in SSc patients, and suggest a possible utility in the assessment of BAL Th1/Th2 ratio.

[Socio-demographic aspects and therapeutic pathways in patients with rheumatoid arthritis in Italy]. / Aspetti socio-demografici e modalità di accesso alle terapie farmacologiche in pazienti con artrite reumatoide in Italia.

The research carried out by Censis Foundation, in collaboration with SIR (Italian Society of Rheumatology) and ANMAR (National Association of Rheumatic patients), with the sponsorship of Roche S.p.A., involved more than 600 patients, diagnosed with arthritis by a rheumatologist according to ACR criteria. The patients were recruited through a representative sample of 300 general practitioners. A number of different research and survey tools were used to collect data, helping to identify several of the problems that affect Italian patients: a survey form to be filled by the GPs, in order to verify the diagnosis and the comorbidity level; a questionnaire for the self-assessment of the disease activity, Rheumatoid Arthritis Disease Activity Index (RADAI), and a sociological questionnaire set up for the analysis of the main aspects of the patients' path. Among the most serious criticalities found, the difficulties and the time needed for the patients to get a clear AR diagnosis, the problems in interacting with health structures, and the differences in accessing pharmaceutical therapies (only a slight majority of patients use DMARDs drugs, a small amount takes biological drugs, while a large number of patients is treated exclusively with symptomatic drugs) stand out. The differences in patients' condition appear then to be exaggerated, regarding the chances to get an early diagnosis, the access path to specialised centres, and in receiving the most appropriate treatments. Moreover, these differences appear to be strongly dependent on both the social characteristics of the patients and the supply arrangement in their area.

MonitorNet: the Italian multi-centre observational study aimed at estimating the risk/benefit profile of biologic agents in real-world rheumatology practice.

MonitorNet is a database established by the Italian Society of Rheumatology (SIR) in January 2007 and funded by the Italian Medicines Agency (AIFA), for the active long-term follow-up of patients with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis treated with biologic agents. All hospital Rheumatology Units in Italy were invited to participate in a non-interventional, observational, epidemiological study. The study is conducted in a routine clinical setting (real-world practice) where biologics are prescribed on the basis of current recommendations. In this report we describe the design, methodology, and present preliminary data of the study. At the time of the analysis (April 2009) the database included 3510 patients: 2469 (70.3%) with established RA, 675 (19.2%) with PsA and 366 (10.4%) with AS. The cumulative follow up period was 8,787 patient-years (RA: 8,388, PsA: 157; AS: 242). There were 1,538 adverse events in 938 (26.7%) patients. Infections were recorded in 630 patients, skin-related adverse events in 142 and post-infusion reactions in 90. A total of 30 malignancies were reported. An interim analysis of efficacy was conducted on 2,148 RA patients. Seven hundred and thirty-one patients (35.8%) achieved EULAR remission (defined as DAS28<2.4). When assessed with the more restrictive CDAI and SDAI criteria, the frequency of remission was lower (17.9% and 14.7% respectively). Availability of funding for this study provided an opportunity to organize a collaborative national network of rheumatology clinics to develop a large multicentre observational study.

Anti-TNF-alpha treatment in rheumatoid arthritis with anti-Ro/SSA antibodies. Analysis of 17 cases among a cohort of 322 treated patients.

OBJECTIVE: To compare the efficacy and safety of anti-TNF-alpha treatment in RA patients with and without anti-Ro antibodies, in order to detect any change in their immunological or clinical profile. METHODS: Autoantibodies in 322 patients being treated with anti-TNF-alpha drugs were studied; 17 were found to be anti-Ro positive, while 305 were anti-Ro negative. RESULTS: Two groups, comparable in terms of sex distribution, RA duration and anti-TNF-alpha drug employed, showed symmetrical, erosive polyarticular RA with high disease activity. Anti-TNF-alpha led to significant improvement in both groups. At baseline rheumatoid factor and ANA, globally positive in 68.6% and 40%, were more frequent in anti-Ro positive sera. ANA showed a rising trend beginning in the 6th month of treatment in both groups, which was always statistically significant compared to baseline. Anti-dsDNA antibodies, measured using either CLIFT and ELISA or the Farr assay, remained stable in the first 6 months, then increased at 12th and 18th month, and subsequently declined. No difference was detected between the two groups regarding the number or cause of dropouts, but lupus-like disease was more frequent in anti-Ro positive subjects (p = 0.012). In addition, two cases of NHL were detected. CONCLUSION: Anti-TNF-alpha treatment was shown to be effective in patients with anti-Ro antibodies. Although anti-dsDNA and lupus-like disease were more frequent in anti-Ro positive patients, severe manifestations of systemic involvement were not observed. A longer follow-up is warranted to evaluate the risk of NHL in these patients.

Serum cytokines and steroidal hormones in polymyalgia rheumatica and elderly-onset rheumatoid arthritis.

BACKGROUND: Polymyalgia rheumatica (PMR) may create some difficulties in the differential diagnosis of elderly-onset rheumatoid arthritis (EORA) and of EORA with PMR-like onset (EORA/PMR). AIM: To investigate possible differences between three groups of patients, with regard to serum levels of inflammatory cytokines and steroidal hormones at baseline and after 1 month of treatment with glucocorticoids (prednisone 7.5-12.5 mg/day). PATIENTS AND METHODS: 14 patients with PMR, 15 with EORA and 14 with EORA/PMR, as well as 15 healthy, matched controls were analysed. Tumour necrosis factor alpha (TNFalpha), interleukin (IL)6, IL1 receptor antagonist (IL1Ra), cortisol, dehydroepiandrosterone sulphate (DHEAS) and 17-hydroxy-progesterone (PRG) were evaluated. RESULTS: Serum levels of both TNFalpha and IL6 were significantly higher in all three groups of patients than in controls (p<0.01). Serum IL6 levels were significantly higher in patients with both PMR and EORA/PMR than in patients with EORA (p<0.05). IL1Ra serum levels were significantly higher in patients with EORA than in controls (p<0.001) and in patients with PMR and EORA/PMR (p<0.05). DHEAS was significantly lower in patients with EORA/PMR than in those with EORA (p<0.05). PRG was significantly higher in all patient groups (p<0.05). After glucocorticoid treatment, serum TNFalpha and IL6 levels significantly decreased in all patient groups; IL1Ra significantly increased in patients with PMR and in those with EORA/PMR; cortisol, DHEAS, and PRG significantly decreased in patients with PMR and in those with EORA/PMR (p<0.05). CONCLUSIONS: Different cytokine and steroidal hormone patterns suggest that patients with PMR and those with EORA/PMR seem to be have a more intensive inflammatory reaction and are more efficient responders to glucocorticoid treatment than patients with EORA.

A comparison of the sensitivity of diagnostic criteria for polymyalgia rheumatica.

OBJECTIVE: To compare the performance of the several different diagnostic criteria sets currently in use for polymyalgia rheumatica (PMR). METHODS: 213 patients attending eight rheumatological centres in eight different European countries were studied. All had recently been referred and were considered by the senior investigator at each centre, selected because of their experience in treatment of PMR, to have this condition. By use of a standard international proforma, the requisite diagnostic points in each criteria set were sought. Sensitivity for each criterion from each set was then calculated, as well as the sensitivity of each criteria set as a whole. RESULTS: Of four criteria sets compared, the Bird (1979) criteria performed best with a sensitivity of 99.5%, and the Hunder (1982) criteria second best, with sensitivity of 93.3%. These both performed significantly better than the two other criteria sets, though each of these was admittedly developed for rather specialised reasons. CONCLUSIONS: Although this study compares homogeneity, we suggest the Bird 1979 or Hunder 1982 criteria should be used whenever possible. Studies that have used alternative criteria may have less sensitivity in diagnosis.

EULAR response criteria for polymyalgia rheumatica: results of an initiative of the European Collaborating Polymyalgia Rheumatica Group (subcommittee of ESCISIT).

OBJECTIVE: To develop response criteria for polymyalgia rheumatica (PMR) for monitoring treatment and comparing alternative treatments regimens. METHODS: 76 patients, mean (SD) age 68.7 (7.7) years, were enrolled. Corticosteroids, and non-steroidal anti-inflammatory drugs (NSAIDs) were the only drugs allowed during the observation period. Erythrocyte sedimentation rate (ESR), C reactive protein (CRP), alpha(2) globulin, serum iron, pain, physician's global assessment (PGA), morning stiffness (MST), muscle tenderness (MT), myalgia, and the elevation of upper limbs (EUL) were determined regularly. The daily corticosteroid and NSAID doses as the corticosteroid response time were recorded. To ensure evaluation of an adequate number of patients (n = 57) week 24 was chosen for final analysis. RESULTS: ESR, CRP, alpha(2) globulin, pain, PGA, MST, myalgia, MT, and EUL showed significant improvement (p<0.0001) at week 24 compared with week 0. Multiple regression analysis showed that changes of ESR (p = 0.08), CRP (p = 0.41), alpha(2) globulin (p = 0.13), MST (p = 0.1), and MT (p = 0.07) were independent of pain, but myalgia (p<0.001) and EUL (p = 0.003) were pain dependent. Consequently, a core set of PMR response criteria, comprising ESR or CRP, pain, PGA, MST, and EUL was established. Assessment of treatment responses with this core set resulted in 90%, 70%, 50%, and 20% improvement in 31/57 (54%), 46/57 (81%), 51/57 (89%), and 54/57 (95%) of the patients, respectively. CONCLUSION: These PMR response criteria are a promising tool for better monitoring of disease activity and treatment in PMR. It is proposed that these criteria should be used in clinical trials in the near future to explore alternative treatment options for PMR.

Cutaneous vasculitis and reactive arthritis following respiratory infection due to Chlamydia pneumoniae: report of a case.

Unlike Chlamydia trachomatis and C. psittaci, the association of C. pneumoniae infection with immunological complications, such as reactive arthritis (ReA) or erythema nodosum (EN) has been rarely reported. Here we present the case history of a patient with C. pneumoniae community acquired pneumonia (CAP) who subsequently developed a ReA and a cutaneous vasculitis. A 45-year-old HLA B27 negative male developed an asymmetric and additive arthritis and a cutaneous leukocytoclastic vasculitis with IgM and complement papillary deposition along hypodermic vessel walls about three weeks after the onset of respiratory symptoms. The diagnosis of chronic Chlamydia pneumoniae infection was based on serology and PCR. Cultural and serological investigations for other infectious agents commonly involved in ReA were negative. This is the first report on the occurrence of two immune-based complications, associated to Chlamydia pneumoniae infection. Therefore, since this infection is very common in our population, although often asymptomatic, should be systematically considered as a common causative agent of ReA and of vasculitis.

Severe hypercalcemia and systemic lupus erythematosus.

A rare case of severe hypercalcemia strongly associated with Systemic Lupus Erythematosus (SLE) is reported. On admission, a young woman showed severe hypercalcemia and photosensitivity. Criteria for diagnosis of SLE were not sufficient. All causes, common and uncommon, of hypercalcemia were excluded. Radiographs of the skeleton were normal. One year later diagnosis of SLE was evident. In addition, diffuse and severe osteopenia and chest deformities had occurred. The treatment of SLE normalized persistently calcemia. Mild elevation of calcium levels occurred during flares of SLE. It has been hypothesized that hypercalcemia in patients with SLE could be caused by the presence of stimulatory anti-PTH receptor antibodies. This case report suggests that in patients with severe hypercalcemia associated with SLE early diagnosis and treatment of SLE may prevent bone loss. In these patients the prevention of severe bone damage is very important. Indeed, severe osteopenia may favour skeletal deformities and fractures; in addition it may represent a serious obstacle in using adequate doses of glucocorticoids for treatment of SLE.

Interleukin 8 and monocyte chemoattractant protein-1 in patients with juvenile rheumatoid arthritis. Relation to onset types, disease activity, and synovial fluid leukocytes.

OBJECTIVE: To measure serum and synovial fluid (SF) levels of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in patients with juvenile rheumatoid arthritis (JRA) and to compare them with adult rheumatoid factor-positive rheumatoid arthritis (RA). METHODS: IL-8 and MCP-1 were measured by immunoassay (1) in sera obtained from 55 children with JRA and from 16 adults with RA, and (2) in SF obtained from 30 children with JRA and 11 adults with RA. RESULTS: Patients with active systemic JRA had serum levels of IL-8 and MCP-1 higher than in controls (p<0.01) and in patients with active polyarticular or pauciarticular JRA (p<0.05). In patients with RA serum MCP-1 levels were higher than in patients with the 3 JRA onset types, while no difference was found for IL-8 levels. Patients with systemic JRA and with current systemic features had serum levels of IL-8 and MCP-1 higher (p = 0.03 and p = 0.04, respectively) than patients in which systemic features had subsided. No significant differences in SF IL-8 or MCP-1 levels were found among the 3 JRA onset types or adults with RA. In patients with JRA SF leukocyte counts were correlated with SF IL-8 levels (p = 0.002), but not with MCP-1 levels. Moreover, SF levels of both IL-8 and MCP-1 were correlated with those of IL-1beta (p<0.001) and IL-6 (p<0.01), but not with those of TNF-alpha. CONCLUSION: Elevated serum levels of IL-8 and MCP-1 in patients with systemic JRA with current systemic features at sampling suggest systemic production of the 2 chemokines during systemic phases of the disease. Similar SF levels of IL-8 and MCP-1 among the 3 JRA onset-types and RA suggest comparable local production of the 2 chemokines.

Differences in synovial fluid cytokine levels between juvenile and adult rheumatoid arthritis.

OBJECTIVE: To evaluate quantitative or qualitative differences in synovial fluid (SF) cytokine levels among patients with systemic juvenile rheumatoid arthritis (JRA), antinuclear antibody positive pauciarticular JRA, or adult RA. METHODS: SF levels of interleukin 1alpha (IL-1alpha), IL-1beta, IL-1 receptor antagonist (IL-1Ra) IL-11, tumor necrosis factor-alpha (TNF-alpha), soluble TNF receptor 1 (sTNFR1), leukemia inhibitory factor (LIF), all measured by immunoassays, and of IL-6, measured with a bioassay using B9 cells, were evaluated in 11 patients with systemic JRA, 24 with pauciarticular JRA, and 22 adult patients with RA. RESULTS: SF IL-6 levels were significantly higher in patients with systemic JRA than patients with pauciarticular JRA (p = 0.003) or RA (p = 0.002). IL-1alpha was detectable in 12/24 SF samples from pauciarticular JRA, in 2/22 SF from RA, and in no sample from systemic JRA (p = 0.004 vs RA; p = 0.005 vs systemic JRA). SF IL-11 levels were significantly higher in patients with RA than patients with systemic JRA (p = 0.012) or pauciarticular JRA (p = 0.005). We found no significant differences in SF levels of IL-1beta, IL-1Ra, TNF-alpha, sTNFR1, or LIF. CONCLUSION: In systemic JRA, SF levels of IL-6 are significantly higher than in pauciarticular JRA or in RA; IL-1alpha is present in a significant proportion of patients with pauciarticular JRA, but not in those with RA or systemic JRA.

Purpura fulminans as clinical manifestation of atypical SLE with antiphospholipid antibodies: a case report.

Purpura Fulminans and DIC were the main clinical manifestations of the antiphospholipid syndrome observed in a 62-year-old man. The patient was well until 44 years of age when he began to suffer from recurrent thrombophlebitis, without other symptoms suggestive of immune disease. At the time of hospital admission the pt. appeared acutely ill, showing high fever, severe anemia, massive urinary blood loss, multiple purpuric patches evolving to hemorrhagic bullae and gangrene rapidly spreading over about 30% of the total body area. No signs of neurological involvement or of visceral thrombotic occlusions were present. Clotting tests were consistent with a diagnosis of DIC, further confirmed by skin biopsy showing the presence of thrombi in dermal arterioles. The autoantibody research was positive as follows: Waaler-Rose 1:40, Anti-DNA 1:80; ANF 1:640, aCA IgG 100 GPL. LA was diagnosed according to standard criteria: prolonged KCT and RVVT not corrected by a mixture of normal plasma and abnormal TTI. Plasma exchange in association with heparin and prednisone was effective in arresting the progression of the skin lesion; nevertheless the patient died ten days after hospital admission for sepsi and acute renal failure.

A seasonal pattern in the onset of polymyalgia rheumatica.

The seasonal distribution in the onset of polymyalgia rheumatica (PMR) was determined in 58 patients with the disease and compared with that in 44 patients affected by rheumatoid arthritis of elderly onset (EORA). Thirty six (62%) cases of PMR developed during May to August; by contrast, only 14 (31%) cases of EORA developed in the same months, this latter disease failing to show any seasonal clustering. The monthly distribution of PMR correlated with outside temperature and hours of sunshine. These data suggest that PMR might be triggered by such factors as actinic damage of superficial vessels or infective agents with a seasonal cycle. Finally, the summer clustering of PMR may be helpful in the differential diagnosis from EORA.

Autoantibodies to poly(ADP-ribose)polymerase in autoimmune diseases.

Antibodies to various nuclear proteins are frequently found in sera of patients affected by connective tissue diseases and other autoimmune diseases. We investigated the specificity of circulating autoantibodies to poly(ADP-ribose)polymerase (pADPRP) in different autoimmune and connective tissue diseases: Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis (RA), Progressive Systemic Sclerosis (PSS), Sjogren's Syndrome (SS), Undifferentiated Connective Tissue Disease (UCTD), Cryptogenic Fibrosing Alveolitis (CFA) and Sarcoidosis. pADPRP was purified from calf thymus. Antibody specificity was detected by ELISA, western blot and enzyme activity precipitation. Positive values (mean O.D. values + 3 S.D. of 36 normal controls) were obtained in 7/15 SLE patients, 1/18 RA patients, 1/30 PSS, 3/14 SS, 0/5 UCTD, 5/21 CFA and 4/25 Sarcoidosis. The positive sera also recognized the pADPRP protein when tested by western blot. Furthermore the enzyme activity was inhibited after immunoprecipitation by some highly positive sera.

Selective bone marrow involvement of lymphoplasmacytic cells secreting monoclonal IgA rheumatoid factor in a patient with Sjögren's syndrome and serum hyperviscosity.

The clinical features and results of serological studies of a patient with Sjögren's syndrome, IgA kappa monoclonal gammopathy, and hyperviscosity syndrome are reported. The novel aspect of this case is the selective localisation to the bone marrow of lymphoplasmacytoid cells secreting IgA kappa morphologically identical to the cells infiltrating the salivary glands. The serum of the patient contained large amounts of immunoglobulin-anti-immunoglobulin immune complexes. By gel filtration chromatography it was shown that the immune complexes formed a peak of molecular weight 680 kilodaltons. The immune complexes were dissociable under acidic conditions. The immunoglobulin with rheumatoid activity was characterised as monoclonal IgA kappa protein. Treatment with plasmapheresis combined with immunosuppressive treatment with cyclophosphamide reduced the serum viscosity with concomitant clinical improvement.

Proliferation kinetics of plasma cells and of normal haemopoietic cells in multiple myeloma.

DNA synthesis time (Ts) and 3H thymidine (TdR) labelling index (LI) of bone marrow (BM) myelomatous plasma cells (PC) and of the residual haemopoietic cell population (RHCP) were measured by in vitro quantitative 14C-TdR autoradiography in five patients with multiple myeloma (MM) in different phases of disease (three at presentation and two at relapse) and in one patient with solitary extra-osseous myeloma. One other patient with plasma cell leukaemia (PCL) was studied during an initial relapse phase and later during the leukaemic terminal phase. PC Ts was 18.8 +/- 3.7 (from 13.3 to 25.0) hr and PC LI was 2.5 +/- 1.8% (from 1.0 to 6.3%). In the case of PCL, circulating PC had a Ts of 14.4 hr and a LI of 3.1. From these experimental measurements, the fractional turnover rate (FTR-percentage of cells produced per unit time) and the potential doubling time (Td) of BMPC were calculated assuming that all BMPC were in a steady-state at the time of the study. BMPC FTR was 3.53 +/- 2.3% cells per day (from 1.2 to 6.72) and BMPC Td was 46.8 +/- 27.5 days (from 15.0 to 75.4). Comparison with results obtained in BM blasts of children with acute lymphoblastic leukaemia (ALL) indicated that BMPC had a lower proliferative activity (P less than 0.001), although BMPC Ts was not significantly different. In two patients a tumour doubling time of 6 and 13 months was determined by clinical follow up. Comparison of this parameter with Td showed a cell loss factor of more than 90% in both patients. Kinetic data relative to RHCP showed slight variations with respect to those found in normal subjects, with a general tendency towards a prolongation of Ts and a reduction of LI.