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.

Clinical expression and course in patients with late onset systemic lupus erythematosus.

BACKGROUND: To analyze the pattern of clinical expression and the 5-year disease course in Caucasian patients with late onset of systemic lupus erythematosus (SLE) and to compare the findings with an early onset SLE group. METHODS: Medical records of 551 patients who presented with SLE at hospitals of the region of Thessaloniki between 1989 and 2007 were studied. Patients who developed SLE at or after the age of 50 years were classified as the late onset group, while younger patients served as the early onset group. Data on clinical manifestations and damage accrual at disease onset and at 5 years was obtained and compared between the two groups. RESULTS: In 121 patients, the disease started after the age of 50 years. Elderly patients showed less pronounced female predominance and less often presented with malar rash, nephropathy, fever and lymphadenopathy, while lung involvement, pericarditis and sicca syndrome were more frequent. Damage accrual was similar in both groups. The main causes of damage at 5 years differed, with the elderly exhibiting more cardiovascular damage. They also had a higher incidence of hypertension and osteoporosis at 5 years. CONCLUSIONS: Caucasian SLE patients with late onset of the disease present with different clinical manifestations, suggesting that age affects the expression of SLE. Damage accrual at 5 years is similar in the elderly and the younger patients. However, the causes of this damage and the occurrence of other comorbidities follow a different pattern, possibly reflecting the disease process and the effects of aging.

Association of anti-CCP positivity and carriage of TNFRII susceptibility variant with anti-TNF-α response in rheumatoid arthritis.

OBJECTIVES: To investigate the possible influence of tumour necrosis factor-alpha (TNF), TNF receptor I (TNFRI) and TNF receptor II (TNFRII) gene polymorphisms on anti-TNF treatment responsiveness, stratified by autoantibody status. METHODS: A Greek multi-centre collaboration was established to recruit a cohort of patients (n=100) with active RA treated with anti-TNF drugs. TNF g.-238G>A (rs361525), g.-308G>A (rs1800629), g.-857C>T (rs1799724), TNFRI c.36A>G (rs4149584) and TNFRII c.676T>G (rs1061622) polymorphisms were genotyped by PCRRFLP assays. Serum RF and anti-CCP antibody status were determined using commercially available kits. Single-SNP, haplotype and stratification by autoantibody status analyses were performed in predicting response to treatment by 6 months, defined as the absolute change in DAS28. RESULTS: 31 patients (31%) were defined as non-responders due to failure to fulfill the DAS28 criteria. 79% and 66% were RF and anti-CCP positive, respectively. None of the genotyped SNPs was alone associated with responsiveness to drug treatment. However, after stratification by autoantibody status, carriage of TNFRII c.676G allele was associated with poorer response to drug treatment in anti-CCP positive patients (p=0.03), after 6 months of anti-TNF therapy. CONCLUSIONS: In concordance with previous studies, genetic polymorphisms alone cannot be used to safely predict clinical response to anti-TNF therapy however the combination of genetic factors and autoantibody status warrants further investigation in larger independent cohorts.

Clinical expression and morbidity of systemic lupus erythematosus during a post-diagnostic 5-year follow-up: a male:female comparison.

The aim of this study was to analyse the prevalence of the most relevant clinical features of the diagnosis of systemic lupus erythematosus (SLE) in a sample of male patients with lupus as well as the incidence of the main causes of morbidity in a 5-year period after the diagnosis. A further aim of this study was to investigate the impact of gender on expression and morbidity of SLE. Data were collected from the medical records of 59 male and 535 female patients with SLE who were diagnosed at the hospitals in the region of Thessaloniki. Several differences in the expression and morbidity of the disease were found in relation to the gender of the patient. Male patients had a higher prevalence of thromboses, nephropathy, strokes, gastrointestinal tract symptoms and antiphospholipid syndrome when compared with female patients, but tended to present less often with arthralgia, hair loss, Raynaud's phenomenon and photosensitivity as the initial clinical manifestations. During the 5-year follow-up, positive associations have been found between male gender and the incidence of tendonitis, myositis, nephropathy and infections, particularly of the respiratory tract. In conclusion, this study has provided information regarding the features of clinical expression and morbidity in male patients, and has shown that gender is a possible factor that can influence the clinical expression of SLE.

Radionuclide imaging with human polyclonal immunoglobulin (Tc-HIG) and bone scan in patients with rheumatoid arthritis and serum-negative polyarthritis.

BACKGROUND AND AIM: Rheumatoid arthritis (RA) is a chronic polyarthritic syndrome in which actively inflamed joints coexist with others being in remission. Compatible bone scan (BS) reveals joints with increased activity due to degenerative alterations, whilst scanning with human polyclonal immunoglobulin (HIG) is capable to show which of the joints present active inflammation of the synovial membrane. The aim of the study is to investigate the utility of molecular imaging with HIG in patients suffering from RA. PATIENTS AND METHODS: Forty patients (9 males plus 31 females), suffering from painful polyarthritic syndrome, with a mean age 45.3±7 years and a duration of disease 18.3±4.2 months were enrolled in the study. Twenty-six of the patients were serum positive to RA factor, considered as suffering from RA, whilst fourteen of them were RA factor negatives and they were considered as patients with serum-negative polyarthritis. All patients were submitted to x-rays and ultrasound examination (US) in joints of interest, plus whole body BS with (99m)Tc-MDP and finally scan with (99m)Tc-HIG. RESULTS: A total of 1680 joints have been evaluated. In 6 of the patients-two with serum negative RA (252 joints), radionuclide imaging with HIG was within normal limits, despite the fact that in compatible bone scan degenerative alterations have been mentioned in 30 joints. In all these patients disease was evaluated as inactive ("arthrotic changes"). In the remaining 34 patients-12 with serum negative RA (1428 joints), increased accumulation of HIG, concerning serum positive patients, has been mentioned to 163 joints ("arthritic changes"), whilst in the same group, BS revealed degenerative changes to 265 joints. Concerning serum negative patients, the respective results were 64 versus 190 joints. Increased uptake of HIG has been found in 189/226 swollen and painful joints (overall sensitivity according to clinical criteria 83.3%) and in 38 joints without any clinical evidence of inflammation, with clinical active inflammation presented after follow-up to 35 of them, yielding thus specificity at the level of 92%. Matched findings between these two methods have been mentioned to 185 out of 227 joints with an abnormal scan with HIG. Abnormal x-rays and US findings have been mentioned in 67 of the joints. CONCLUSIONS: According to the above mentioned, BS in RA reveals joints being actively inflamed or not, whilst radionuclide study with HIG is capable to distinguish actively inflamed joints, even in patients with serum negative RA, in a greater extent than anatomical imaging modalities.

Paget's disease of the vulva in a patient with scleroderma and underlying adenocarcinoma: case report.

Systemic sclerosis (SSc) is a multisystem connective tissue disease characterized by fibrosis of the skin and internal organs. Several studies have demonstrated an increased frequency of cancer in patients with SSc. We report a case of a 71-year-old woman with SSc, who presented with an eczematous lesion of the vulva. The diagnosis of Paget's disease of the vulva (PVD) was established. The patient underwent radical vulvectomy, but 18 months later died due to adenocarcinoma of unknown primary origin. SSc and PVD are associated with various types of malignancies and patients suffering from these diseases should be under surveillance in order for any suspicious symptoms of malignancy to be early detected and investigated.

Asymmetrical dimethylarginine in systemic sclerosis-related pulmonary arterial hypertension.

OBJECTIVES: SSc is a CTD characterized by vascular involvement, with generalized disturbance of the microcirculation, which may lead to pulmonary artery hypertension (PAH). Asymmetrical dimethylarginine (ADMA) is an endogenous nitric oxide (NO) inhibitor. Increased concentrations of plasma ADMA may also contribute to endothelial dysfunction in patients with pulmonary vascular disease. The aim of our study was to elucidate the possible relationship between serum ADMA and PAH in patients with SSc. Moreover, we sought to investigate the effect of ADMA levels on the functional capacity of these patients. METHODS: Plasma ADMA levels were measured in 66 patients with SSc (63 females, mean age 57.8 +/- 12.8 yrs, median duration of disease 9.9 yrs, 47 with lcSSc and 19 with dcSSc disease) and 30 healthy controls (29 females, mean age 58.2 +/- 8.4 yrs). Systolic pulmonary artery pressure (sPAP) assessed by echocardiography, lung function tests, 6-min walk test (6MWT) and serum ADMA levels were recorded from patients. RESULTS: In 24 patients, the diagnosis of PAH was established. Mean value of ADMA for SScPAH patients was 0.44 +/- 0.22 micromol/l compared with 0.26 +/- 0.18 micromol/l for patients without PAH and 0.25 +/- 0.20 micromol/l for controls (P = 0.001). ADMA levels were inversely correlated with the 6MWT (r = -0.55, P = 0.005). CONCLUSIONS: In patients with SScPAH, increased ADMA serum levels and their negative association with exercise capacity suggests that the NO pathway is involved in the development of pulmonary vascular disease.

Demyelination in rheumatic diseases.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterised by multifocal areas of demyelination in the white matter of the brain and spinal cord. Autoantibodies, for example antinuclear antibodies, can also be present. MS and other demyelinating processes, such as transverse myelitis and optic neuritis (which may be clinically isolated cases or be part of the clinical spectrum of MS), are sometimes difficult to differentiate from CNS involvement in systemic autoimmune diseases like systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Sjoegren's syndrome (SS), and Adamantiades-Behcet disease (BD). An acute isolated neurological syndrome presents the biggest diagnostic problem, since it is common in MS, but can also be the only feature or first manifestation in SLE, APS, SS, and BD. Indeed, the clinical presentation and lesions evidenced by magnetic resonance imaging may be similar.

Tuberculosis in patients receiving anti-TNF agents despite chemoprophylaxis.

SETTING: A major concern surrounding the use of tumor necrosis factor-alpha (TNF-alpha) inhibitors is their potential to increase the risk of opportunistic infections, particularly tuberculosis (TB). OBJECTIVE: To estimate the incidence of active TB in patients with rheumatic diseases receiving anti-TNF drug therapy and to evaluate the effectiveness of an antituberculosis chemoprophylaxis regimen. DESIGN: Retrospective study of the files of 613 patients with rheumatic diseases who had received anti-TNF agent (etanercept, infliximab and adalimumab) therapy from July 2000 to June 2004 at the Aristotle University of Thessaloniki, Greece. All patients had a tuberculin skin test (TST) and a postero-anterior chest radiograph (CXR) prior to anti-TNF therapy. When indicated (TST > or =10 mm and/or fibrotic lesions on CXR), treatment for latent TB was established (6 months isoniazid [INH] or 3 months INH and rifampicin [RMP]). Anti-TNF agent therapy was started again 2 months later. RESULTS: Of 45 patients who fulfilled the criteria for chemoprophylaxis, only 36 were treated correctly. Eleven patients developed active TB 2-35 months after the beginning of anti-TNF therapy. Six patients developed pulmonary and five extra-pulmonary TB. Eight of these had received infliximab and three adalimumab. CONCLUSION: The incidence of active TB in this study population was estimated at 449 cases per 100,00 population annually. Anti-tuberculosis chemoprophylaxis was only of partial preventive success in these patients.

Etanercept 50 mg once weekly is as effective as 25 mg twice weekly in patients with ankylosing spondylitis.

OBJECTIVE: To compare the efficacy, pharmacokinetics and safety of etanercept 50 mg once weekly with 25 mg twice weekly and placebo in patients with ankylosing spondylitis. METHODS: A 12-week, double-blind, placebo-controlled study compared the effects of etanercept 50 mg once weekly, etanercept 25 mg twice weekly and placebo in 356 patients with active ankylosing spondylitis (3:3:1 randomisation, respectively). The primary end point was the proportion of patients achieving a response at week 12 based on the Assessment in Ankylosing Spondylitis Working Group criteria (ASAS 20). The pharmacokinetics of etanercept 50 mg once weekly and 25 mg twice weekly were analysed. RESULTS: Baseline characteristics and disease activity were similar among the three groups: etanercept 50 mg once weekly, etanercept 25 mg twice weekly and placebo. The percentage of patients discontinuing therapy was 9.0%, 9.3% and 13.7% for the three respective groups. ASAS 20 response at 12 weeks was achieved by 74.2% of patients with etanercept 50 mg once weekly and 71.3% of those with etanercept 25 mg twice weekly, both significantly higher than the percentage of patients taking placebo (37.3%, p<0.001). Percentages of patients with ASAS 5/6 response (70.3%, 72.0% and 27.5%, respectively; p<0.001) and those with ASAS 40 response (58.1%, 53.3% and 21.6%, respectively; p<0.001) followed a similar pattern. Significant improvement (p<0.05) was seen in measures of disease activity, back pain, morning stiffness and C reactive protein levels as early as 2 weeks. Serum etanercept exposure was similar between the etanercept groups. Incidence of treatment-emergent adverse events, including infections, was similar among all three groups, and no unexpected safety issues were identified. CONCLUSIONS: Patients with ankylosing spondylitis can expect a comparable significant improvement in clinical outcomes with similar safety when treated with etanercept 50 mg once weekly or with 25 mg twice weekly.

Fibromyalgia--new concepts of pathogenesis and treatment.

Fibromyalgia (FMS) is a debilitating disorder characterized by chronic diffuse muscle pain, fatigue, sleep disturbance, depression and skin sensitivity. There are no genetic or biochemical markers and patients often present with other comorbid diseases, such as migraines, interstitial cystitis and irritable bowel syndrome. Diagnosis includes the presence of 11/18 trigger points, but many patients with early symptoms might not fit this definition. Pathogenesis is still unknown, but there has been evidence of increased corticotropin-releasing hormone (CRH) and substance P (SP) in the CSF of FMS patients, as well as increased SP, IL-6 and IL-8 in their serum. Increased numbers of activated mast cells were also noted in skin biopsies. The hypothesis is put forward that FMS is a neuro-immunoendocrine disorder where increased release of CRH and SP from neurons in specific muscle sites triggers local mast cells to release proinflammatory and neurosensitizing molecules. There is no curative treatment although low doses of tricyclic antidepressants and the serotonin-3 receptor antagonist tropisetron, are helpful. Recent nutraceutical formulations containing the natural anti-inflammatory and mast cell inhibitory flavonoid quercetin hold promise since they can be used together with other treatment modalities.

Demyelination in rheumatic diseases.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) characterised by multifocal areas of demyelination in the white matter of the brain and spinal cord. Autoantibodies, for example antinuclear antibodies, can also be present. MS and other demyelinating processes, such as transverse myelitis and optic neuritis (which may be clinically isolated cases or be part of the clinical spectrum of MS), are sometimes difficult to differentiate from CNS involvement in systemic autoimmune diseases like systemic lupus erythematosus (SLE), antiphospholipid syndrome (APS), Sjoegren's syndrome (SS), and Adamantiades-Behcet disease (BD). An acute isolated neurological syndrome presents the biggest diagnostic problem, since it is common in MS, but can also be the only feature or first manifestation in SLE, APS, SS, and BD. Indeed, the clinical presentation and lesions evidenced by magnetic resonance imaging may be similar.

Early T cell activation in the skin from patients with systemic sclerosis.

OBJECTIVES: To determine if T cells in skin lesions in systemic sclerosis (SSc) express the early activation antigen CD69 that participates in cell-cell interactions. METHODS: Skin biopsy specimens from 17 patients with SSc were analysed by immunohistochemistry using the indirect peroxidase method and monoclonal antibodies for CD3 (T cell marker), CD69 (early T cell activation marker), and CD68 (macrophage marker). RESULTS: Mononuclear cells, containing mostly T cells and macrophages, were increased in SSc skin lesions and were present in perivascular areas. CD69 was expressed in these mononuclear cells. There was no correlation between the number of CD3+, CD69+, or CD68+ cells and the Rodnan skin score or disease duration. CONCLUSIONS: The expression of early T cell activation antigen CD69 in skin lesions suggests that T cells may actively participate in cell-cell contact with fibroblasts to promote fibrosis.

Efficacy and safety of adalimumab as monotherapy in patients with rheumatoid arthritis for whom previous disease modifying antirheumatic drug treatment has failed.

OBJECTIVE: To evaluate the efficacy and safety of monotherapy with adalimumab in patients with RA for whom previous DMARD treatment has failed. METHODS: In a 26 week, double blind, placebo controlled, phase III trial, 544 patients with RA were randomised to monotherapy with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, 40 mg weekly, or placebo. The primary efficacy end point was > or =20% improvement in the ACR core criteria (ACR20 response). Secondary efficacy end points included ACR50, ACR70, EULAR responses, and the Disability Index of the Health Assessment Questionnaire (HAQ DI). RESULTS: After 26 weeks, patients treated with adalimumab 20 mg every other week, 20 mg weekly, 40 mg every other week, and 40 mg weekly had significantly better response rates than those treated with placebo: ACR20 (35.8%, 39.3%, 46.0%, 53.4%, respectively v 19.1%; p< or =0.01); ACR50 (18.9%, 20.5%, 22.1%, 35.0% v 8.2%; p< or =0.05); ACR70 (8.5%, 9.8%, 12.4%, 18.4% v 1.8%; p< or =0.05). Moderate EULAR response rates were significantly greater with adalimumab than with placebo (41.5%, 48.2%, 55.8%, 63.1% v 26.4%; p< or =0.05). Patients treated with adalimumab achieved better improvements in mean HAQ DI than those receiving placebo (-0.29, -0.39, -0.38, -0.49 v -0.07; p< or =0.01). No significant differences were found between adalimumab and placebo treated patients for serious adverse events, serious infections, or malignancies. Injection site reaction occurred in 10.6% and 0.9% of adalimumab and placebo treated patients, respectively (p< or =0.05). CONCLUSION: Among patients with RA for whom previous DMARD treatment had failed, adalimumab monotherapy achieved significant, rapid, and sustained improvements in disease activity and improved physical function and was safe and well tolerated.

Lupus anticoagulant--antiphospholipid antibodies and thrombophilia. Relation to protein C--protein S--thrombomodulin.

In order to define the behavior of the lupus anticoagulant and/or antiphospholipid antibodies, we investigated the possible association with protein C, protein S and thrombomodulin. In 19 patients with established diagnosis of an autoimmune disease and coexisting lupus anticoagulant protein C (antigen and activity), protein S (total and free), anticardiolipin and antiphosphatidylserine antibodies were estimated. In one case the IgG globulin fraction containing the inhibitor was separated. The activation rate of pure protein C to its activated form using thrombin/thrombomodulin as activator was then measured in the presence or absence of lupus anticoagulant. No overall decrease of protein C or protein S was detected in patients' plasma. Nevertheless, the lupus anticoagulant had a specific effect on the protein C system, inhibiting the catalytic activity of thrombomodulin without causing a functional protein C deficiency. This specific effect upon thrombomodulin can be a main cause, but not necessarily the only one, for the thrombophilic tendency of patients with the lupus anticoagulant.

Impaired fibrinolysis as an essential contribution to thrombosis in patients with lupus anticoagulant.

Lupus anticoagulants (LA) are IgG or IgM antibodies against phospholipids which in vivo represent an important thrombophilic factor despite their in vitro anticoagulant activity. We investigated the fibrinolytic system of 20 patients with connective tissue disease and positive LA, compared to a control group of 24 age- and disease-matched patients without LA. There was no statistically significant difference of alpha 2-antiplasmin, plasminogen, fibrinogen, t-PA activity, D-dimers and heparin cofactor II, between the two groups. Although t-PA was uniformly low in both groups, plasminogen activator inhibitor activity (PAI) was significantly higher in LA cases (p less than 0.001). Increased PAI levels represent an inhibitory factor of the fibrinolytic defense mechanism, which together with other functional deviations may contribute to the thrombophilic tendency of LA patients.

Acute psoriatric arthropathy precipitated by oxprenolol.

A previously normal 58-year-old woman developed a widespread psoriatic rash and asymmetrical peripheral polyarthritis a week after beginning treatment with oxprenolol for hypertension. Skin and joint disease resolved simultaneously after drug withdrawal and have not recurred.