Outcome of refractory to conventional and/or biologic treatment adult Still's disease following canakinumab treatment: Countrywide data in 50 patients.

OBJECTIVE: To assess the efficacy and safety of the IL-1b inhibitor canakinumab in all adults with refractory Still's disease identified from the National Organization For Medicines for off-label drug use. METHODS: In a retrospective longitudinal multicenter cohort of 50 patients (median age 39 years) with active Still's disease despite treatment with corticosteroids (n = 11), conventional and synthetic (n = 34) and/or biologic disease modifying anti-rheumatic drugs (n = 30), we assessed the efficacy of canakinumab 150-300 mg administered every 4 (n = 47) or 8 weeks (n = 3) as combination therapy or monotherapy (n = 7) during a median follow-up of 27 (3-84) months. RESULTS: Α complete response was initially observed in 78% of patients within 3 months (median), irrespective of age at disease onset. A partial response was evident in 20%. One patient had resistant disease. Treatment de-escalation was attempted in 15 of 39 complete responders and a complete drug discontinuation in 21 patients for 8 months (median). Eleven patients (22%) relapsed during treatment, one during de-escalation process, and 11 after treatment discontinuation. Overall, 9 of 11 relapses were successfully treated with canakinumab treatment intensification or re-introduction. At last visit, 18% of patients were off treatment due to remission and 26% due to disease activity. Canakinumab had a significant corticosteroid sparing effect allowing weaning in 21 of 41 cases. Infections (20%, severe 4%) and leucopenia (6%) led to treatment cessation in one patient. CONCLUSION: High rates of sustained remission were observed in this, largest so far, real-life cohort of adult patients with refractory Still's disease treated with canakinumab.

Cryoglobulinemic vasculitis in primary Sjögren's Syndrome: Clinical presentation, association with lymphoma and comparison with Hepatitis C-related disease.

OBJECTIVE: To describe the clinical spectrum of cryoglobulinemic vasculitis (CV) in primary Sjögren's syndrome (pSS), investigate its relation to lymphoma and identify the differences with hepatitis C virus (HCV) related CV. METHODS: From a multicentre study population of consecutive pSS patients, those who had been evaluated for cryoglobulins and fulfilled the 2011 classification criteria for CV were identified retrospectively. pSS-CV patients were matched with pSS patients without cryoglobulins (1:2) and HCV-CV patients (1:1). Clinical, laboratory and outcome features were analyzed. A data driven logistic regression model was applied for pSS-CV patients and their pSS cryoglobulin negative controls to identify independent features associated with lymphoma. RESULTS: 1083 pSS patients were tested for cryoglobulins. 115 (10.6%) had cryoglobulinemia and 71 (6.5%) fulfilled the classification criteria for CV. pSS-CV patients had higher frequency of extraglandular manifestations and lymphoma (OR=9.87, 95% CI: 4.7-20.9) compared to pSS patients without cryoglobulins. Purpura was the commonest vasculitic manifestation (90%), presenting at disease onset in 39% of patients. One third of pSS-CV patients developed B-cell lymphoma within the first 5 years of CV course, with cryoglobulinemia being the strongest independent lymphoma associated feature. Compared to HCV-CV patients, pSS-CV individuals displayed more frequently lymphadenopathy, type II IgMk cryoglobulins and lymphoma (OR = 6.12, 95% CI: 2.7-14.4) and less frequently C4 hypocomplementemia and peripheral neuropathy. CONCLUSION: pSS-CV has a severe clinical course, overshadowing the typical clinical manifestations of pSS and higher risk for early lymphoma development compared to HCV related CV. Though infrequent, pSS-CV constitutes a distinct severe clinical phenotype of pSS.

Autoantibody Specificities and Type I Interferon Pathway Activation in Idiopathic Inflammatory Myopathies.

Myositis is a heterogeneous group of autoimmune diseases, with different pathogenic mechanisms contributing to the different subsets of disease. The aim of this study was to test whether the autoantibody profile in patients with myositis is associated with a type I interferon (IFN) signature, as in patients with systemic lupus erythematous (SLE). Patients with myositis were prospectively enrolled in the study and compared to healthy controls and to patients with SLE. Autoantibody status was analysed using an immunoassay system and immunoprecipitation. Type I IFN activity in whole blood was determined using direct gene expression analysis. Serum IFN-inducing activity was tested using peripheral blood cells from healthy donors. Blocking experiments were performed by neutralizing anti-IFNAR or anti-IFN-α antibodies. Patients were categorized into IFN high and IFN low based on an IFN score. Patients with autoantibodies against RNA-binding proteins had a higher IFN score compared to patients without these antibodies, and the IFN score was related to autoantibody multispecificity. Patients with dermatomyositis (DM) and inclusion body myositis (IBM) had a higher IFN score compared to the other subgroups. Serum type I IFN bioactivity was blocked by neutralizing anti-IFNAR or anti-IFN-α antibodies. To conclude, a high IFN score was not only associated with DM, as previously reported, and IBM, but also with autoantibody monospecificity against several RNA-binding proteins and with autoantibody multispecificity. These studies identify IFN-α in sera as a trigger for activation of the type I IFN pathway in peripheral blood and support IFN-α as a possible target for therapy in these patients.

Absence of somatic MYD88 L265P mutations in patients with primary Sjogren's syndrome.

Sjogren's syndrome (SS) is a chronic autoimmune disorder with the highest risk for lymphoma development among all autoimmune diseases. In order to evaluate whether the presence of the recently described MYD88 L265P mutation in patients with Waldenström's macroglobulinemia (WM) is contributory to SS-associated lymphomagenesis, a quantitative allele-specific PCR method was performed in peripheral blood derived from 90 SS patients as well as in minor salivary gland tissues derived from 12 primary SS patients with or without lymphoma. MYD88 L265P was not detected in either of the samples tested. Although the absence of the MyD88 L265P somatic mutation in our SS cohort does not exclude a common germline susceptibility gene in SS, it might suggest a distinct operating pathogenetic mechanism in SS-related lymphoma compared with WM and other hematological malignancies.

Increased prevalence of anti-thyroid antibodies in patients with limited scleroderma.

OBJECTIVES: Thyroid dysfunction in the setting of systemic sclerosis (SSc) has been described previously. We aimed to determine the prevalence of anti-thyroid antibodies (ATA) in a large SSc cohort and to ascertain whether they are associated with distinct clinical phenotypes. METHODS: A total of 138 patients with SSc [46 with diffuse (dSSc) and 92 with limited scleroderma (lSSc)] and 100 healthy controls (HC) were tested for the presence of ATA [anti-thyroglobulin (anti-Tg) and anti-thyroid peroxidase (anti-TPO) antibodies] using a commercial enzyme-linked immunosorbent assay (ELISA). Clinical and serological data were recorded. RESULTS: An increased prevalence of anti-TPO but not anti-Tg antibodies was detected in patients with SSc compared to HC (27.5% vs. 14%, p = 0.016). Of note, a statistically significant increase of anti-TPO was detected only in patients with lSSc compared to HC (32.6% vs. 14%, p = 0.003). No correlations with other clinical features were detected. CONCLUSIONS: An increased prevalence of anti-TPO antibodies was identified in patients with lSSc. We propose that ATA testing should be offered to this subgroup of patients.

Antithyroid antibodies in antiphospholipid syndrome: prevalence and clinical associations.

Autoimmune thyroid disease has been associated with several systemic autoimmune disorders. However, limited data are available regarding the prevalence and clinical associations of thyroid autoimmunity in antiphospholipid syndrome (APS). Seventy-five patients with APS, 75 patients with systemic lupus erythematosus (SLE) and 75 healthy controls were tested for the presence of antithyroid antibodies (ATAs) (anti-thyroglobulin and anti-thyroid peroxidase [anti-TPO]) using commercial ELISA. Clinical data were also recorded. Although no significant differences in the prevalence of ATAs were detected among APS, SLE patient groups and healthy controls, a significant increase of anti-TPO antibodies in patients with APS-SLE was found. An increased prevalence of ATAs in APS population with ischemic central nervous system (CNS) clinical manifestations was also detected. We present novel associations between thyroid autoimmunity and ischemic CNS clinical manifestations in the setting of APS.

Takayasu arteritis: epidemiological, clinical, and immunogenetic features in Greece.

OBJECTIVE: Takayasu arteritis (TA) is an uncommon disease with clinical heterogeneity across different ethnic groups. We aimed to evaluate the epidemiological, clinical, and immuno-genetic features of TA in Greece. METHODS: Demographic, clinical, laboratory, angiographic, and therapeutic data of 42 patients from 4 large referral centers were retrieved. Serology and Human Lymphocyte Antigen (HLA) typing was performed in 22 patients. RESULTS: We studied 37 women and 5 men with a median age of 31 years at disease onset. Median delay in diagnosis was 24 months and median follow-up was 47 months (range 0-178). Constitutional or musculoskeletal symptoms were present in 86%, especially early in the disease course. Vascular findings were universal with reduced or absent pulse being the most common manifestation (98%). Hypertension was frequent (78%). Extensive disease prevailed and stenotic lesions were more common than aneurysms (95% vs. 40%). Erythrocyte sedimentation rate and C-reactive protein showed modest correlation with disease activity. HLA-B52 was expressed by 37% of the patients vs. 2.4% of the controls (p<0.001). Glucocorticoids and cytotoxic agents were used in most patients with remission rates of 83%. A total of 42 surgical procedures were performed with success rates of 87%. CONCLUSION: TA in Greece clinically and epidemiologically resembles the pattern of disease in Japan and the Western hemisphere. There is considerable delay in diagnosis, which may partially reflect failure to recognize a rare disease. New surrogate markers are needed to assess disease activity. Glucocorticoids are the cornerstone of treatment and cytotoxic drugs are frequently used as steroid sparing agents.

Exposure to nuclear antigens contributes to the induction of humoral autoimmunity during tumour necrosis factor alpha blockade.

OBJECTIVE: Type I interferons and apoptotic particles contribute to antinuclear autoimmunity in experimental models. This study assessed whether similar mechanisms contribute to break peripheral B-cell tolerance in humans by studying the induction of antinuclear antibodies by tumour necrosis factor blockade in spondyloarthritis. METHODS: 40 spondyloarthritis patients treated with infliximab or etanercept and 20 renal cell carcinoma patients treated with sorafenib were studied. Serum antinucleosome IgM and nucleosomes were measured by ELISA. Type I interferon serum activity was measured using a functional reporter cell assay. Synovial apoptosis was assessed by terminal transferase nick end-labelling (TUNEL) assay and anti-active caspase-3 immunostaining. Complement was measured by nephelometry. RESULTS: Despite a similar clinical improvement and reduction of synovial inflammation, antinucleosome IgM were induced by infliximab but not etanercept. This induction did not correlate with type I interferon activity, which was transiently downmodulated by infliximab but persistently upregulated by etanercept. In contrast, antinucleosome IgM levels did correlate with serum nucleosome levels, which were significantly upregulated by infliximab but not by etanercept treatment. This increase in serum nucleosome levels was not directly related to massive cell death, but rather to a decrease of complement 3 and 4 serum levels during infliximab treatment. CONCLUSION: Infliximab and etanercept have a differential effect on both type I interferon activity and nucleosome levels. Only elevated serum nucleosomes relate to the induction of antinucleosome antibodies after infliximab treatment.

Stress, coping strategies and social support in patients with primary Sjögren's syndrome prior to disease onset: a retrospective case-control study.

OBJECTIVES: Previous evidence suggests the role of psychological stress in triggering the onset of autoimmunity. We aimed to investigate whether stress following major and minor life events could precede the onset of primary Sjögren's syndrome (pSS). The role of coping strategies and social support, as compensating buffering mechanisms, was also explored. METHODS: 47 patients with pSS were compared with two control groups: 35 patients with lymphoma (disease controls, DC) and 120 healthy controls (HC) with disease onset within the previous year. All subjects completed questionnaires assessing the occurrence of major and minor stressful events, coping strategies and social support prior to disease onset. Data analysis was performed by univariate and multivariate logistic regression models. RESULTS: A higher number of patients with pSS reported the occurrence of negative stressful life events prior to disease onset compared with patients with lymphoma and HC, while the number and impact of daily hassles did not differ between the three groups. Coping strategies were defective and the overall social support was lower in patients with pSS compared with DC and HC groups. In the multivariate model, pSS status was associated with maladaptive coping and lower overall social support relative to DC and HC, as well as with an increased number of negative stressful life events compared with HC but not DC. CONCLUSIONS: Prior to disease onset, patients with pSS experience high psychological stress following major negative life events, without developing satisfactory adaptive coping strategies to confront their stressful life changes. Lack of social support may contribute to the relative risk of disease development.

A high incidence of disease flares in an open pilot study of infliximab in patients with refractory inflammatory myopathies.

OBJECTIVE: To investigate the effect of the tumour necrosis factor (TNF) blocking agent infliximab in patients with treatment-resistant inflammatory myopathies. METHODS: A total of 13 patients with refractory polymyositis (PM), dermatomyositis (DM), or inclusion body myositis (IBM) were treated with 4 infliximab infusions (5 mg/kg body weight) over 14 weeks. Outcome measures included myositis disease activity score with improvement defined according to The International Myositis Assessment and Clinical Studies Group (IMACS), and MRI. Repeated muscles biopsies were investigated for cellular infiltrates, major histocompatibility complex (MHC) class I and II, TNF, interleukin (IL)1alpha, IL6, high mobility group box chromosomal protein 1 (HMGB-1), interferon gamma (IFNgamma), myxovirus resistance protein A (MxA) and membrane attack complex (MAC) expression. Type I IFN activity was analysed in sera. RESULTS: Nine patients completed the study. Three patients discontinued due to adverse events and one due to a discovered malignancy. Three of the completers improved by >or=20% in three or more variables of the disease activity core set, four were unchanged and two worsened >or=30%. No patient improved in muscle strength by manual muscle test. At baseline, two completers had signs of muscle inflammation by MRI, and five at follow-up. T lymphocytes, macrophages, cytokine expression and MAC deposition in muscle biopsies were still evident after treatment. Type I IFN activity was increased after treatment. CONCLUSIONS: Infliximab treatment was not effective in refractory inflammatory myopathies. In view of radiological and clinical worsening, and activation of the type I IFN system in several cases, infliximab is not an alternative treatment in patients with treatment-resistant myositis.

Antibody response to the human stress protein BiP in rheumatoid arthritis.

OBJECTIVES: The human stress protein BiP (immunoglobulin binding protein) has been implicated in the pathogenesis of rheumatoid arthritis (RA) since BiP was found to stimulate synovial T-cell proliferation and anti-BiP antibodies are present in the serum of RA patients. The aim of this study was the development of a rapid and reproducible enzyme-linked immunosorbent assay (ELISA) to determine the specificity and sensitivity of anti-BiP antibodies in RA. METHODS: An ELISA was developed that detected antibodies to BiP. The prevalence of anti-BiP antibodies was determined in sera from patients with early and established RA, sera antedating the onset of RA and sera from patients with other inflammatory and autoimmune diseases and healthy controls. RESULTS: We have confirmed the increased prevalence of antibodies to BiP in the sera of a large cohort of patients with established RA (specificity 71% and sensitivity 73%) and early RA (specificity 65% and sensitivity 66%). In pre-disease sera, median 2.5 yr (interquartile range 1.1-4.7) before symptoms of joint disease, the sensitivity for anti-BiP antibodies was 45% and the specificity was 65% for the development of RA. CONCLUSION: Antibodies to BiP are found in the sera of patients with RA and in sera antedating the onset of RA.

Lupus nephritis: current issues.

Despite the development of new modalities, cyclophosphamide (CYC) remains the preferred initial treatment for severe proliferative lupus nephritis. Controversies continue about the best route, dosage, and duration of CYC treatment. For recalcitrant disease, new immunosuppressive and immunomodulating agents, immunoablative high dose CYC, nucleoside analogues, apheresis, and the biological response modifiers can be considered.

Sjögren's syndrome: autoantibodies to cellular antigens. Clinical and molecular aspects.

Autoantibodies to cellular autoantigens are usually found in sera of patients with systemic autoimmune rheumatic diseases. Patients with Sjögren's syndrome (SS) frequently present autoantibodies to both organ and non-organ-specific autoantigens. The most commonly detected autoantibodies are those directed against the ribonucleoproteins Ro/SSA and La/SSB. The presence of the antibodies in SS is associated with early disease onset, longer disease duration, parotid gland enlargement, higher frequency of extraglandular manifestations and more intense lymphocytic infiltration of the minor salivary glands. Over the past several years, the structure and function of these autoantigens have been extensively studied. Several centers, using different techniques, have investigated the B cell epitopes on the protein components Ro 60 kD, Ro 52kD, and La 48 kD. Finally, increased evidence of direct involvement of anti-Ro/SSA and anti-La/SSB autoantibodies in the pathogenesis of tissue injury has been contributed by several studies.

Recurrent pregnancy loss and autoantibody profile in autoimmune diseases.

OBJECTIVE: To explore the association of non-organ-specific autoimmune responses against three distinct Ro antigen-related reactivities (Ro52, Ro60, p57) with a history of pregnancy loss in women with autoimmune disorders. Materials and methods. Seventy unselected anti-Ro/SSA-positive women were studied in a retrospective cohort study. Forty anti-Ro/SSA-positive women were age matched to an equal number of women with autoimmune disorders who were anti-Ro/SSA negative in a case-control study. The association of reactivities against three distinct antigen specificities (Ro52, Ro60, p57) with recurrent pregnancy loss was investigated. Independence and modification of these associations from the effect of antithyroglobulin, antithyroid peroxidase and anticardiolipin antibodies were also examined. RESULTS: In the cohort study, reactivity against each of the three antigen specificities (Ro52, Ro60, p57) was independently associated with a history of recurrent pregnancy loss. In the case-control study, the effects were still independent and were not modified when other autoantibodies were considered. In particular, the number of reactivities against Ro52, Ro60 and p57 peptides, and the presence of antithyroglobulin antibodies, were independent predictors of recurrent pregnancy loss (odds ratios 3.35 per each additional reactivity and 5.54 in the presence of antithyroglobulin; P=0.002 and 0.025, respectively). CONCLUSIONS: In women with autoimmune disorders, a history of recurrent pregnancy loss is independently associated with reactivity against each of the three antigen specificities (Ro52, Ro60, p57) and also with the presence of antithyroglobulin antibodies, suggesting that cumulative autoimmune responses against these non-organ-specific and organ-specific antigens correlate with the risk of stillbirth and spontaneous abortion.

Rheumatoid arthritis in the elderly.

Rheumatoid arthritis of late onset (LORA) referred as the subset of rheumatoid arthritis with age of onset over 60 years old, seems to differ from young onset disease (YORA) by a more equal sex distribution, a higher frequency of abrupt disease onset, more large joint complaints and less extraarticular features. Different immunogenetic associations are also reported between the two age groups. The percentages of rheumatoid factor (RF) and C-reactive protein (CRP) positivity differ in various surveys in both groups examined. Favorable prognostic factors could be considered the absence of rheumatoid factor activity and the presence of pitting edema of the hands. Greek patients with LORAS appear not to have differences in comparison to their younger counterparts. Disease modifying drugs and low doses of prednisone are the mainstream of therapy with need for further caution in the aged group.

Pregnancy outcome and anti-Ro/SSA in autoimmune diseases: a retrospective cohort study.

OBJECTIVE: In the present retrospective cohort study, the association of anti-Ro/SSA antibody with pregnancy loss and adverse pregnancy outcome in women with autoimmune diseases was investigated. MATERIALS AND METHODS: Obstetric histories of 154 anti-Ro/SSA-positive women with autoimmune diseases [78 systemic lupus erythematosus (SLE) and 76 non-SLE] were analysed and compared to a control group of 142 anti-Ro/SSA-negative women (71 SLE and 71 non-SLE) matched for disease diagnosis and age at the time of anti-Ro/SSA diagnosis. Obstetric history was also obtained and analysed from a group of healthy women, frequency matched to anti-Ro/SSA-positive women on age at study entry. RESULTS: The rate of pregnancy loss and adverse pregnancy outcome did not differ significantly between anti-Ro/SSA-positive women, anti-Ro/SSA-negative women and healthy controls. Anti-Ro/SSA-positive SLE women reported a significantly higher rate (18.0%) of therapeutic abortions compared to anti-Ro/SSA-negative women (5.6%, P=0.0244) and healthy controls (4.6%, P=0.0013). Anti-Ro/SSA non-SLE-positive women reported a significantly higher rate (23.7%) of recurrent pregnancy loss in comparison to anti-Ro/SSA-negative women (7.04%, P=0.0063) and healthy controls (6.4%, P=0.0004). CONCLUSIONS: Although anti-Ro/SSA antibody does not adversely affect pregnancy outcome in SLE patients, it appears to be associated with recurrent pregnancy loss in non-SLE patients.