Alexios Iliopoulos

Comparative effectiveness and survival of infliximab, adalimumab, and etanercept for rheumatoid arthritis patients in the Hellenic Registry of Biologics: Low rates of remission and 5-year drug survival

OBJECTIVE To compare effectiveness, drug survival, and safety between infliximab, adalimumab, and etanercept, in a nationwide cohort of rheumatoid arthritis (RA) patients. METHODS This study is a prospective cohort study of 1208 active RA patients. Effectiveness, drug survival, and serious adverse events during entire follow-up (median 2.9 years) were monitored. RESULTS EULAR and CDAI responses were comparable between the three agents (EULAR good/moderate responses at 12 months ranged 76-79%). At 12 months, 15-23% achieved remission. For adalimumab and etanercept, adjusted hazard rate (HR) for EULAR/ACR remission (reference: infliximab) was 2.7 and 2.1 (95% confidence interval was 1.7-4.1 and 1.3-3.4, respectively); males (HR 1.6; 1.1-2.4), use of glucocorticoids (HR 2.0; 1.3-3.0), and swollen joint count >7 (HR 0.36; 0.24-0.55) were independent predictors. Five-year drug survival was 31%, 43%, and 49% for infliximab, adalimumab, and etanercept, respectively (p = 0.010). Infliximab was associated with significantly more withdrawals due to adverse events. Disease activity, CRP, and use of glucocorticoids predicted efficacy-related drug survival; age, use of methotrexate, and prior DMARDs failures predicted safety-related survival. Risk for serious infections was lower with adalimumab (odds ratio [OR] 0.62; 0.38-1.00) or etanercept (OR 0.39; 0.21-0.72) than infliximab, independent of the effects of age (OR 1.65; 1.37-2.00 per 10 years), tender joint count >10 (OR 1.86; 1.21-2.86), and glucocorticoids >35mg/week (OR 1.83; 1.12-2.99). CONCLUSIONS Response rates were comparable among anti-TNF agents. Overall, 5-year drug survival was below 50%, with infliximab demonstrating increased safety-related discontinuations. Remission rates are low in clinical practice. Strategies to increase effectiveness and long-term survival of anti-TNF agents in RA are needed.

Psoriasiform lesions appearing in three patients with rheumatoid arthritis during therapeutic administration of abatacept, a selective inhibitor of T-cell costimulation.

Editor Cytotoxic T-lymphocyte-associated antigen4–IgG1 (Abatacept; Bristol-Myers Squibb, New York, NY, USA), the first of a new class of drugs known as costimulation blockers, is currently approved for the treatment of rheumatoid arthritis (RA). Abatacept is a soluble chimeric protein which binds to CD80 and CD86 on antigen-presenting cells and inhibits the engagement of CD28 on T cells, thus preventing effective T-cell activation. Moreover, in a recently published 6-month, double-blind, placebo-controlled phase 2 study of abatacept for psoriatic arthritis, this drug was effective for joint disease and showed marked activity against skin disease. Indeed, preliminary evidence had suggested that abatacept was efficacious in decreasing the clinical activity of skin lesions in patients with psoriasis vulgaris by blocking T-cell costimulation, as well as that it reversed the cellular pathology of psoriatic plaques, including the activation of keratinocytes, dendritic cells and endothelial cells. We report on three patients who, paradoxically, developed psoriasiform lesions after initiation of abatacept treatment for active RA. The first patient was a 63-year-old woman who developed severe symmetric psoriatic nail disease in four toes during the 9th month of treatment. She presented with severe subungual hyperkeratosis, yellow discoloration, onycholysis and psoriatic plaques in the perionychium of her toes (Fig. 1a). Fungal culture was negative, suggesting absence of onychomycosis. The second patient was a 60-year-old man who developed numerous 2to 4-mm symmetrical pustules accompanied with desquamation and erythema localized on the soles during the 10th month of treatment (Fig. 1b). The third patient was a 62-year-old man, who developed well-defined, slightly pruritic, erythematosquamous plaque of the left calf (Fig. 2a) during the 14th month of abatacept treatment. Histology revealed acanthosis of the epidermis with regularly elongated and club-shaped rete ridges, inflammatory infiltration in the dermis and confluent parakeratosis with pycnotic nuclei of neutrophils (Munro microabscess) (Fig. 2b). None of these patients had a personal of family history of psoriasis. Notably, the first patient had developed a plantar pustular psoriasis during previous treatment with the anti-TNF agent adalimumab, which is a known paradoxical adverse event of anti-TNF treatment. Psoriasis area severity index was less than 10 in all patients and lesions subsided with topical steroid treatment alone; discontinuation of abatacept was not necessary. The coexistence of RA and psoriasis of the skin in the same patient is rare. In the German national data bank for rheumatological diseases, only 0.5% of patients with definite RA had simultaneously psoriasis of the skin. Nevertheless, the patients who develop psoriasiform lesions while under treatment with abatacept may have a genetic predisposition to psoriasis, which is not uncommon (prevalence 2.5%), in addition to their arthritis. In contrast to anti-TNF agents, abatacept does not induce

Serum levels of Dkk-1, sclerostin and VEGF in patients with ankylosing spondylitis and their association with smoking, and clinical, inflammatory and radiographic parameters

OBJECTIVE To evaluate serum Dickkopf-1 (Dkk-1), sclerostin and vascular endothelial growth factor (VEGF) levels in patients with ankylosing spondylitis (AS) compared to healthy controls as well as their association with smoking, and clinical, inflammatory and radiographic parameters. METHODS Serum samples for total Dkk-1, sclerostin and VEGF were obtained from 57 tumour necrosis factor (TNF) inhibitor naïve patients with AS and 34 sex-, age- and body mass index (BMI)-matched controls. The erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Bath AS Disease Activity Index (BASDAI), Bath AS Functional Index (BASFI), modified Stroke AS Spine Score (mSASSS) and smoking status were assessed for each patient. RESULTS There was no significant difference in serum bone metabolism markers between AS patients and controls. Dkk-1 levels were significantly (P<0.05) higher in AS patients with elevated ESR and CRP and no syndesmophytes, and were significantly (P<0.001) correlated with sclerostin levels (r=0.592). VEGF levels were significantly (P<0.05) higher in AS patients with current and ever smoking, elevated ESR and CRP, and high BASDAI and BASFI, and were significantly (P<0.05) correlated with ESR (r=0.284), CRP (r=0.285), BASDAI (r=0.349) and BASFI (r=0.275). In multivariate regression analyses, high Dkk-1 levels were significantly (P≤0.001) associated with elevated ESR and CRP, no syndesmophytes and high sclerostin levels, and high VEGF levels significantly (P<0.05) with ever smoking, and elevated ESR and CRP. CONCLUSION In AS, serum Dkk-1 concentrations appear to be related not only to syndesmophyte formation but also to systemic inflammation. Furthermore, high VEGF levels may be associated with smoking exposure.

Intertoe Squamous Cell Carcinoma Developed in a Patient with Rheumatoid Arthritis under Etanercept Therapy

The use of tumor necrosis factor-α (TNF-α) inhibitors in the treatment of various inflammatory conditions has altered the field of medical therapeutics. Squamous cell carcinoma is the second most common cancer of the skin, usually affecting sun-exposed areas of the body. We present here the case of a 75-year-old woman with rheumatoid arthritis, who developed an intertoe squamous cell carcinoma (SCC) of the right foot. According to her history, she received etanercept and methotrexate for 5 years for rheumatoid arthritis. The rare localization of this cancer could suggest a possible linkage of the malignancy to the chronic intake of anti-TNF-α treatment. This is the first reported case of an interdigital SCC developed under the use of an anti-TNF-α agent.

Atrial fibrillation following intravenous zolendronic acid for osteoporosis.

S ince the publication of the HORIZONPivotal Fracture Trial in 2007, there has been a great concern regarding the possible association of intravenous (IV) zolendronic acid treatment of postmenopausal osteoporosis with atrial fibrillation (AF). The frequency of serious AF was found to be increased 2.5-fold in patients treated with zolendronic acid compared with placebo. A retrospective review of the safety data from the Fracture Intervention Trial, a randomized study of alendronate involving 6459 postmenopausal women revealed a trend toward a significant increase of serious AF events in alendronatetreated patients (hazard ratio, 1.51; 95% confidence interval, 0.97Y2.40; P = 0.07). This finding raised further concern for a possible class effect of bisphosphonates. However, a later meta-analysis did not associate the use of alendronate with an increased risk of AF. In addition, other randomized controlled trials of zolendronic acid in patients with hip fracture (HORIZON-Recurrent Fracture Trial), in osteoporotic men, or in the 6-year extension of the HORIZON-Pivotal Fracture Trial, did not confirm the initial results. Nevertheless, the latter study did report a significant increase of strokes in the zolendronic acid group. A report issued in 2008 by the US Food and Drug Administration found no association between overall bisphosphonate exposure and the rate of serious or nonserious AF. However, in cancer patients, where much higher doses of bisphosphonates are used for hypercalcemia and bone metastasis, an increased frequency of AF was found in case-control and cohort studies. Likewise, a recent metaanalysis pooling data from both osteoporotic and cancer patients derived from 6 randomized controlled trials and 6 observational studies suggested an association between bisphosphonate use and the onset of AF. It should be mentioned that data from large registries regarding the use of IV bisphosphonates in osteoporosis are lacking. In addition, there is no published information on AF in osteoporotic patients treated with IV zolendronic acid from single centers, reflecting everyday clinical practice where comorbidities and concomitant medications have to be taken into consideration. Several potential mechanisms have been proposed by which bisphosphonates could predispose to the development of AF. One possibility is that these drugs exert their arrhythmogenic effect by reducing serum levels of calcium and phosphate. Another possibility could be the release of proinflammatory cytokines following parenteral administration of bisphosphonates. Finally, a third hypothesis is that bisphosphonates could affect atrial

Cryptogenic organizing pneumonia mimicking malignancy in a patient with rheumatoid arthritis.

A 53-year-old woman with an 8-year history of rheumatoid arthritis (RA) presented with fatigue and malaise. She had no evidence of tender or swollen joints. Laboratory investigations revealed anemia (hemoglobin 10.2 g/dl) of recent onset and an unexpectedly elevated erythrocyte sedimentation rate (114 mm/h). A chest radiograph showed a …

Comparative Analysis and Predictors of 10-year Tumor Necrosis Factor Inhibitors Drug Survival in Patients with Spondyloarthritis: First-year Response Predicts Longterm Drug Persistence

Objective. To evaluate the 10-year drug survival of the first tumor necrosis factor inhibitor (TNFi) administered to patients with spondyloarthritis (SpA) overall and comparatively between SpA subsets, and to identify predictors of drug retention. Methods. Patients with SpA in the Hellenic Registry of Biologic Therapies, a prospective multicenter observational cohort, starting their first TNFi between 2004–2014 were analyzed. Kaplan-Meier curves and Cox regression models were used. Results. Overall, 404 out of 1077 patients (37.5%) discontinued treatment (followup: 4288 patient-yrs). Ten-year drug survival was 49%. In the unadjusted analyses, higher TNFi survival was observed in patients with ankylosing spondylitis (AS) compared to undifferentiated SpA and psoriatic arthritis [PsA; significant beyond the first 2.5 (p = 0.003) years and 7 years (p < 0.001), respectively], and in patients treated for isolated axial versus peripheral arthritis (p = 0.001). In all multivariable analyses, male sex was a predictor for longer TNFi survival. Use of methotrexate (MTX) was a predictor in PsA and in patients with peripheral arthritis. Absence of peripheral arthritis and use of a monoclonal antibody (as opposed to non-antibody TNFi) independently predicted longer TNFi survival in axial disease because of lower rates of inefficacy. Achievement of major responses during the first year in either axial or peripheral arthritis was the strongest predictor of longer therapy retention (HR 0.33, 95% CI 0.26–0.41 for Ankylosing Spondylitis Disease Activity Score inactive disease, and HR 0.35, 95% CI 0.24–0.50 for 28-joint Disease Activity Score remission). Conclusion. The longterm retention of the first TNFi administered to patients with SpA is high, especially for males with axial disease. The strongest predictor of longterm TNFi survival is a major response within the first year of treatment.

Multicenter Cross-sectional Study of Patients with Rheumatoid Arthritis in Greece: Results from a cohort of 2.491 patients

Aim of the study: To evaluate the current disease characteristics, treatment and comorbidities of rheumatoid arthritis (RA) in Greece. Methods: Multicenter, cross-sectional study with a 9-month recruitment period between 2015 and 2016. Demographics, disease characteristics, treatment and comorbidities were collected via a web-based platform. Results: 2.491 RA patients were recruited: 96% from tertiary referral centers, 79% were females with a mean age of 63.1 years and disease duration of 9.9 years. Fifty-two percent were rheumatoid factor and/or anti-CCP positive, while 41% had erosive disease. Regarding treatment, 82% were on conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs), 42% on biologic DMARDs (TNFi: 22%, non-TNFi: 20%) and 40% on corticosteroids (mean daily dose: 5.2 mg). Despite therapy, 36% of patients had moderate and 12% high disease activity. The most frequent comorbidities were hypertension (42%), hyperlipidemia (33%), osteoporosis (29%), diabetes mellitus (15%) and depression (12%). Latent tuberculosis infection (positive tuberculin skin test or interferon gamma release assay) was diagnosed in 13 and 15.3% of patients, respectively. Regarding chronic viral infections, 6.2% had history of herpes zoster while 2% and 0.7% had chronic hepatitis B and C virus infection, respectively. A history of serious infection was documented in 9.6%. Only 36% and 52% of the participants had ever been vaccinated against pneumococcus and influenza virus, respectively. Conclusion: This is one of the largest epidemiologic studies providing valuable data regarding the current RA characteristics in Greece. Half of patients were seropositive but despite therapy, half displayed residual disease activity, while preventive vaccination was limited.

THU0429 Nailfold video capillaroscopy and deterioration of skin involvement and lung function tests in systemic sclerosis: a 3-year prospective study

Background Nailfold video-capillaroscopy(NVC) is a non-invasive method to assess peripheral microangiopathy. Abnormal capillaroscopic patterns are almost universally found in patients with Systemic Sclerosis (SSc) and assist the diagnosis of SSc. However, little is known about the prognostic value of NVC in skin and lung involvement progression in these patients. Objectives To test the hypothesis that baseline capillaroscopic indices, as well as possible changes in capillaroscopic indices over time, correlate with deterioration in skin thickening and lung function tests in a prospective SSc cohort. Methods Fifty-five consecutive SSc patients from a tertiary care university centre (49 women, 29 limited cutaneous SSc, mean age: 50.84±14.88 years, mean disease duration 6.74±6.25 years) were evaluated by NVC at baseline and after a median of 3.1 years. Qualitative assessment of NVC findings permitted categorization of patients to a predominantly normal, early, active or late capillaroscopic pattern. Capillary loss, capillary dilatation, giant or ramified capillaries and microhemorrhages were further assessed using a semi-quantitative rating scale (score 0–3), derived as the mean of three fields in each of the 2nd, 3rd, 4th and 5th finger of both hands. Scoring was performed by two different assessors. Skin thickening was measured using the modified Rodnan Skin Score (mRSS). FVC and DLCO were performed within 6 months from the NVC. Deterioration in FVC and DLCO was considered clinically significant when>10%. Between baseline and follow-up evaluation 36% of patients had been receiving both major antiproliferative and vasodilator therapy, while15% and 29% had been receiving only antiproliferative or vasodilator therapy, respectively. Results Intraclass correlation coefficient (ICC) for interrater reliability analyses was very good for all semi-quantitative capillaroscopy scores [ICC: 0.97 (0.74–0.99) for capillary loss score, 0.94 (0.85–0.98) for dilatation score,0.98 (0.97–0.99) for giant score, 0.94 (0.84–0.97) for microhemorrhages score), except for the ramification score [ICC: 0.52 (-0.2,–0.81)] which was excluded from all analyses. Linear regression, adjusted for age and gender, showed no association between either baseline capillaroscopy scores or of their changes and changes in mRSS over time. FVC and DLCO deteriorated in 13 and 11 patients, respectively. Binary logistic regression analysis adjusted for age and gender showed no association either baseline capillaroscopy scores or of their changes with deterioration in FVC or DLCO, with the exception of the change in microhemorrhages score, which correlated inversely with deterioration in FVC [p=0.013, Odds Ratio=0.051 (CI: 0.005–0.534)]. Regarding qualitative analysis of capillaroscopic findings, the baseline capillaroscopy pattern remained unchanged in 35, deteriorated in 15 and improved in 5 patients. No difference was found between these 3 groups regarding change in mRSS (ANOVA, p=0.634), deterioration in FVC (x2test, p=0.502) or deterioration in DLCO (x2 test, p=1.00). Conclusions Although a possible confounding effect of treatment cannot be excluded, NVC seems to have poor prognostic value for the progression of skin thickening and interstitial lung disease in rigorously treated SSc patients. Disclosure of Interest None declared

Headache in patients with Paget’s Disease of Bones

Paget’s disease of bone (PDB) is a focal remodeling disorder of unknown origin. Head bones are frequently involved and patients may suffer from deformities and specific symptoms, mainly headache, or neurological deficits, such as deafness. Several pathophysiological entities can give rise to headache in PDB patients. Clinical, laboratory, radiological and scintigraphic findings contribute to distinguish headache related to PDB from other causes of headache. Up to the present, treatment with intravenous zolendronic acid has been reported to improve symptoms of PDB and induce long-standing biochemical and scintigraphic remission. In this review, the main strands of literature about epidemiology, pathophysiology, clinical characteristics and treatment of PDB-related headache are drawn together.