Kalliopi Fragiadaki

Anti-TNF agents for Behçet's disease: analysis of published data on 369 patients.

OBJECTIVE Off-label use of anti-tumor necrosis factor (TNF) agents for Behçets disease (BD) is increasing. We evaluated published data on their efficacy and safety for patients with unmet medical needs due to severe disease manifestations, including ocular, gastrointestinal, and central nervous system involvement. METHODS Peer-reviewed articles on anti-TNF agents for BD appearing in Medline/PubMed through March 2010 were identified using the appropriate indexing terms. RESULTS We found 88, 12, and 13 primary articles from 20 countries on infliximab, etanercept, and adalimumab, reporting on 325, 37, and 28 patients, respectively. All patients were inadequately controlled with, or intolerant to, other immunosuppressive regimens, including interferon; 20 patients received more than 1 anti-TNF agent. In the only randomized placebo-controlled trial, 4-week administration of etanercept was effective in suppressing most of the mucocutaneous manifestations. In 16 open prospective studies evaluating the effect of repetitive infliximab injections (174 patients in total, men:women = 3:1, median follow-up = 16.2 months), sustained organ-specific, clinical responses were evident in 90%, 89%, 100%, and 91% of patients with resistant mucocutaneous, ocular, gastrointestinal, and central nervous system involvement, respectively. Combination of infliximab with azathioprine and/or cyclosporine-A appeared superior to monotherapy for sustained ocular remission. However, due to the fact that necessary data were lacking, formal estimation of anti-TNF treatment effect on the disease activity indexes for different organ involvement was not possible. CONCLUSIONS Although more controlled data are needed, there is enough published experience to suggest that TNF blockade represents an important therapeutic advancement for patients with severe and resistant, or intolerant, to standard immunosuppressive regimens BD.

A pilot study of endothelial dysfunction and aortic stiffness after interleukin-6 receptor inhibition in rheumatoid arthritis

Interleukin (IL)-6 is a pleiotropic proinflammatory cytokine involved in the pathogenesis of both atherosclerosis and rheumatoid arthritis. The role of the IL-6/IL-6 receptor pathway in the documented acceleration of atherosclerosis in rheumatoid arthritis has not been examined. In a non-randomized prospective pilot study we asked whether endothelial dysfunction, defined as impaired flow mediated dilatation (FMD), and aortic stiffness, assessed by pulse wave velocity (PWV) improve after 3 and 6 monthly therapeutic infusions of the anti-IL-6 receptor antibody tocilizumab for active rheumatoid arthritis. We found that FMD increased from 3.3 ± 0.8 to 4.4 ± 1.2 to 5.2 ± 1.9% (p = 0.003), whereas PWV decreased from 8.2 ± 1.2 to 7.7 ± 1.3 to 7.0 ± 1.0m/s (p < 0.001). Whether these beneficial arterial changes are direct effects of the IL-6/IL-6 receptor pathway inhibition, maintained over time and translate into better clinical outcome warrants further studies.

A single infliximab infusion vs corticosteroids for acute panuveitis attacks in Behçet’s disease: a comparative 4-week study

OBJECTIVE To compare a single infusion of the anti-TNF antibody infliximab vs CSs for acute panuveitis attacks in Behçets disease (BD). METHODS A prospective, observational study of patients with panuveitis, who received either an infliximab infusion (5 mg/kg, 19 eyes) or high-dose methylprednisolone intravenously (1 g/day for 3 days, 8 eyes), or intra-vitreal triamcinolone acetonide (4 mg, 8 eyes) at attacks onset. Baseline maintenance therapy remained unchanged during the following 30 days. Visual acuity, anterior chamber cells, vitreous cells and inflammation of the posterior eye segment were assessed at baseline and at Days 1, 7, 14 and 29 (±1) post-treatment. RESULTS While no significant differences were noted between i.v. and intra-vitreal CSs, infliximab was faster than CSs in decreasing total ocular inflammation scores and fundus inflammation scores (P = 0.01 and P < 0.0001 for treatment × time(2) interaction, respectively, using generalized estimating equation analysis). Independently of time, infliximab was superior to CSs in clearing retinal vasculitis (P < 0.003), as well as in resolution of retinitis (P = 0.008) and cystoid macular oedema (P < 0.007). Moreover, a faster regression of cystoid macular oedema was observed with infliximab compared with CSs (P < 0.03). The beneficial effects of the three treatment modalities on visual acuity were comparable from baseline to the end of follow-up. No side effects were noted with infliximab or methylprednisolone, whereas intra-vitreal triamcinolone acetonide caused ocular hypertension in four of the eight eyes, requiring surgical intervention in two. CONCLUSION A single infusion of infliximab should always be considered, even as an adjunct therapy, for the control of acute panuveitis attacks in BD.

Sleep Disturbances and Interleukin 6 Receptor Inhibition in Rheumatoid Arthritis

Objective. Interleukin 6 (IL-6)-mediated interactions have been associated with sleep disturbances in healthy subjects. In this pilot study we examined whether administration of the IL-6 receptor antagonist tocilizumab in patients with rheumatoid arthritis (RA) affects sleep disturbances. Methods. Fifteen patients (13 women) with sleep disturbances at baseline received 6 monthly infusions of tocilizumab 8 mg/kg for moderately or severely active RA. Sleep quality was assessed by Pittsburgh Sleep Quality Index (PSQI), daytime sleepiness by Epworth Sleepiness Scale, disease activity by the 28-joint Disease Activity Score-erythrocyte sedimentation rate, functional disability by Health Assessment Questionnaire Disability Index (HAQ-DI), and fatigue by the Functional Assessment of Chronic Illness Therapy (FACIT-Fatigue Scale; FFS) at baseline and first, second, third, and sixth month of treatment. Medications used before enrollment remained unchanged during followup. Results. Sleep quality improved and daytime sleepiness decreased significantly at first-month assessment (p < 0.00001 and p < 0.004, respectively, by repeated measurement analysis) compared to baseline, and these changes became more evident through 6 months. Disease activity decreased, fatigue decreased, and functional status improved significantly. Changes in PSQI score over time were not associated with the corresponding changes in DAS28-ESR (r = 0.37, p = 0.17), but correlated significantly with HAQ-DI changes (r = 0.60, p = 0.02) and marginally with changes in FFS scores (r = −0.46, p = 0.08). Conclusion. Improvement of sleep quality after tocilizumab treatment in patients with RA does not appear to directly result from decreased disease activity, further suggesting that aberrant IL-6 regulation is associated with sleep disturbances.

Adalimumab or Cyclosporine as Monotherapy and in Combination in Severe Psoriatic Arthritis: Results from a Prospective 12-month Nonrandomized Unblinded Clinical Trial

Objective. To assess the efficacy and safety of adalimumab or cyclosporine (CYC) as monotherapy or combination therapy for patients with active psoriatic arthritis (PsA), despite methotrexate (MTX) therapy. Methods. A prospective 12-month, nonrandomized, unblinded clinical trial of 57, 58, and 55 patients who received CYC (2.5–3.75 mg/kg/day), adalimumab (40 mg every other week), or combination, respectively. Lowering of concomitant nonsteroidal antiinflammatory drugs (NSAID) and corticosteroids and reductions of adalimumab and/or CYC doses in responding patients were not restricted. Results. Mean numbers of tender/swollen joints at baseline were 9.7/6.7 in CYC-treated, 13.0/7.8 in adalimumab-treated, and 14.5/9.4 in combination-treated patients, indicating lesser disease severity of patients assigned to the first group. The Psoriatic Arthritis Response Criteria at 12 months were met by 65% of CYC-treated (p = 0.0003 in favor of combination treatment), 85% of adalimumab-treated (p = 0.15 vs combination treatment), and 95% of combination-treated patients, while the American College of Rheumatology-50 response rates were 36%, 69%, and 87%, respectively (p < 0.0001 and p = 0.03 in favor of combination treatment). A significantly greater mean improvement in Health Assessment Questionnaire Disability Index was achieved by combination treatment (−1.11) vs CYC (−0.41) or adalimumab alone (−0.85). Combination therapy significantly improved Psoriasis Area and Severity Index-50 response rates beyond adalimumab, but not beyond the effect of CYC monotherapy. Doses of NSAID and corticosteroids were reduced in combination-treated patients; CYC doses and frequency of adalimumab injections were also reduced in 51% and 10% of them, respectively. No new safety signals were observed. Conclusion. The combination of adalimumab and CYC is safe and seemed to produce major improvement in both clinical and serological variables in patients with severely active PsA and inadequate response to MTX.

Subclinical peripheral arterial disease in rheumatoid arthritis

OBJECTIVE Rheumatoid arthritis (RA) is associated with accelerated atherosclerosis in the carotid arteries, but little is known about the magnitude of this process in peripheral arteries. Assessing preclinical atherosclerosis in both arterial beds in RA might provide additional prognostic value during risk stratification for primary prevention. Therefore in the present structural study we examined femoral versus carotid subclinical atherosclerosis in RA and controls. METHODS Intima-media thickness (IMT) and atheromatous plaque presence and vulnerability in femoral versus carotid arteries were examined in 80 RA patients without overt cardiovascular disease or diabetes and 80 controls matched 1:1 for age, gender and traditional cardiovascular disease risk factors. RESULTS Femoral IMT and plaque prevalence were increased in RA than controls (p=0.001 and 0.008, respectively). These increases remained significant after adjustment for potentially confounding factors that differed between groups, such as C-reactive protein and HDL-cholesterol serum levels, and statin use. Femoral plaque vulnerability did not differ between RA and controls. The presence of RA was found to be an independent predictor of increased femoral IMT (p=0.004), after adjustment for traditional cardiovascular risk factors, C-reactive protein and treatment with angiotensin converting enzyme inhibitors and statins. Femoral plaques were less frequent than carotid plaques in RA patients (22.5% vs 45.0% respectively, p=0.003) and in contrast to carotid plaques were independent of age and glucose levels. CONCLUSIONS Subclinical peripheral atherosclerosis in RA is more advanced than in controls. Prospective studies are required to confirm that RA is an independent risk factor for peripheral arterial disease.

Orbital Lobular Panniculitis in Weber-Christian Disease: Sustained Response to Anti-TNF Treatment and Review of the Literature

Weber-Christian disease is a febrile, relapsing, non-suppurative panniculitis of unknown etiology. Lobular panniculitis is the essential feature in biopsy specimens and evolves through three recognizable stages. We report a case of Weber-Christian disease with bilateral orbital involvement, at different stages, affecting the orbital fat along with enophthalmos in one orbit, and the upper preaponeurotic fat pad in the other. Weber-Christian disease was refractory to treatment with conventional immunosuppressive regimens; however, early inflammatory-but not chronic fibrotic-orbital lesions responded dramatically to anti-tumor necrosis factor (TNF) therapy. A literature review revealed five additional cases of orbital Weber-Christian disease, none treated with anti-TNF antibodies. Of these, four presented initially with proptosis, representing early stages of inflammation, and two subsequently developed enophthalmos, representing late, inactive stage of the disease. Although orbital Weber-Christian disease is rare, ophthalmologists need to be aware of this entity. Depending on the stage of inflammation, Weber-Christian disease should be included in the differential diagnosis of both proptosis and enophthalmos. Anti-TNF antibodies can successfully treat patients at the early inflammatory stage.

Predictors of morbidity and mortality in early systemic sclerosis: Long-term follow-up data from a single-centre inception cohort

OBJECTIVES To determine predictors of morbidity and mortality in systemic sclerosis (SSc) in a long-term follow-up of an inception cohort of early SSc patients. METHODS We evaluated clinical manifestations, laboratory and lung function tests at disease onset as predictors of morbidity and mortality in 3rd, 6th and 9th year in SSc patients recruited within 12 months of disease onset. RESULTS A total of 115 SSc patients (97 women, mean age 48.1 ± 13.5 years, 54 diffuse subtype) were included. In multivariate regression analysis, predictors at disease onset for the presence of pulmonary fibrosis in 6th year of follow-up were diffuse subtype (OR: 4.4, p = 0.033), digital ulcers (OR: 7.9, p = 0.014) and esophageal involvement (OR: 4.79, p = 0.038). Arrythmias at disease onset predicted pulmonary hypertension (OR: 6.05, p = 0.022), while age (OR: 1.12, p = 0.002) and anti-Scl70 (OR: 4.3, p = 0.038) predicted arrhythmias in 6th year. During a follow-up of 101.8 ± 48.5 months, 23/115 patients died. Cox proportional hazard models analysis revealed 6 independent predictors of mortality present at disease onset: age at disease onset (45-59 years (HR: 3.0, p = 0.098), ≥60 years (HR: 4.3, p = 0.073), male gender (HR: 3.63, p = 0.025), diffuse subtype (HR: 2.83, p = 0.095), pulmonary fibrosis (HR: 3.7, p = 0.032), echocardiography-diagnosed pulmonary hypertension (HR = 7.49, p = 0.008) and DLCO < 60% (HR: 3.17, p = 0.035). Mortality rates at 3 and 6 years were 14% and 24% for patients with 3 independent predictors and 46% and 53% for patients with 4-6 predictors, respectively. CONCLUSION Clinical phenotypes at disease onset may predict morbidity and mortality in SSc and guide treatment decisions.