V. Bojinca

Monitoring Drug and Antidrug Levels: A Rational Approach in Rheumatoid Arthritis Patients Treated with Biologic Agents Who Experience Inadequate Response While Being on a Stable Biologic Treatment

Clinical response in patients with rheumatoid arthritis (RA) treated with biologic agents can be influenced by their pharmacokinetics and immunogenicity. The present study evaluated the concordance between serum drug and antidrug levels as well as the clinical response in RA patients treated with biological agents who experience their first disease exacerbation while being on a stable biologic treatment. 154 RA patients treated with rituximab (RTX), infliximab (IFX), adalimumab (ADL), or etanercept (ETN) were included. DAS28, SDAI, and EULAR response were assessed at baseline and reevaluated at precise time intervals. At the time of their first sign of inadequate response, patients were tested for both serum drug level and antidrug antibodies level. At the next reevaluation, patients retreated with RTX that had detectable drug level had a better EULAR response (P = 0.038) with lower DAS28 and SDAI scores (P = 0.01 and P = 0.03). The same tendency was observed in patients treated with IFX and ETN regarding EULAR response (P = 0.002 and P = 0.023), DAS28 score (P = 0.002 and P = 0.003), and SDAI score (P = 0.001 and P = 0.026). Detectable biologic drug levels correlated with a better clinical response in patients experiencing their first RA inadequate response while being on a stable biologic treatment with RTX, IFX, and ETN.

Co-stimulatory and adhesion molecules of dendritic cells in rheumatoid arthritis

Dendritic cells (DCs) in the rheumatoid arthritis (RA) joint mediate the immunopathological process and act as a potent antigen presenting cell. We compared the expression of co‐stimulatory and adhesion molecules on DCs in RA patients versus controls with traumatic joint lesions and evalulated the correlation between the immunophenotypical presentation of DCs and the clinical status of the disease. Samples of peripheral venous blood, synovial fluid (SF) and synovial tissue (ST) were obtained from 10 patients with RA at the time of hip or knee replacement and from 9 control patients with knee arthroscopy for traumatic lesions. Clinical status was appreciated using the DAS28 score. Blood, SF and dissociated ST cell populations were separated by centrifugation and analyzed by flow cytometry. Cells phenotypes were identified using three‐color flow cytometry analysis for the following receptors HLA‐DR, CD80, CD83, CD86, CD11c, CD18, CD54, CD58, CD3, CD4, CD8, CD19, CD20, CD14, CD16, CD56. HLA‐DR molecules, co‐stimulatory receptors CD80, CD86, CD83 and adhesion molecules CD18, CD11c, CD54, CD58, were analyzed by two‐color immunofluorescence microscopy on ST serial sections. In patients with active RA (DAS28>5.1) we found a highly differentiated subpopulation of DCs in the ST and SF that expressed an activated phenotype (HLA‐DR, CD86+, CD80+, CD83+, CD11c+, CD54+, CD58+). No differences were found between circulating DCs from RA patients and control patients. Our data suggest an interrelationship between clinical outcome and the immunophenotypical presentation of DCs. Clinical active RA (DAS28>5.1) is associated with high incidence of activated DCs population in the ST and SF as demonstrated by expression of adhesion and co‐stimulatory molecules.

Management of rheumatoid arthritis: Impact and risks of various therapeutic approaches

Rheumatic diseases are highly prevalent chronic disorders and the leading cause of physical disability worldwide, with a marked socio-economic impact. Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology with an autoimmune pathogenesis, characterised by arthropathy with chronic, deforming, destructive evolution and multiple systemic manifestations. The management of RA has undergone significant changes as far as objectives and approaches are concerned, ending in the current strategy known as ‘treat to target’. The therapeutic array of RA includes several categories of medicinal products, of varying potential. There are several criteria for the classification of medicinal products used against this disease, one of the most important and modern of which divides such substances according to their effects on the progress of the disease: symptom-modifying antirheumatic drugs (including non-steroidal anti-inflammatory drugs and corticoids), disease-modifying antirheumatic drugs (including various substances, such as gold salts, antimalarials, sulfasalazine, D-penicillamine; non-specific immunosuppressive medication, such as methotrexate, cyclophosphamide, azathioprine and leflunomide) and biological therapy is a recent addition, providing new insight into the treatment of this disease. The selection of the optimal therapy for RA should be based on guidelines and recommendations, but also on clinical particular aspects and patient preferences.

A Pilot Study of the Association of Tumor Necrosis Factor Alpha Polymorphisms with Psoriatic Arthritis in the Romanian Population

Tumor necrosis factor alpha (TNF-alpha) is an important pro-inflammatory cytokine implicated in the pathogenesis of psoriatic arthritis. We have performed a case-control association study of three TNF-alpha gene polymorphisms in a group of Romanian psoriatic arthritis patients versus ethnically matched controls. A second group of patients with undifferentiated spondyloarthritis was used in order to look for similarities in the genetic background of the two rheumatic disorders. The −857C/T polymorphism was associated with susceptibility to psoriatic arthritis in our population at the individual level (p = 0.03, OR 1.65, 95% CI 1.05–2.57) and in combined haplotypes with the −238G/A and −308G/A SNPs. Regarding the investigated polymorphisms and derived haplotypes, no potential association was found with the susceptibility to undifferentiated spondyloarthritis in Romanian patients.

How Useful is Anti-TNF Serum Level and Anti-drug Antibodies Detectionin Evaluating Patients with Spondyloarthritis?

Objective: The aim of this study was to assess whether infliximab and adalimumab drug serum levels and the detection of anti-drug antibodies can be of use in better observing disease activity in patients with spondyloarthritis, besides classical tools such as BASDAI, ASDAS and inflammatory markers. We proposed to evaluate the influence of ADA in non-responders and in drug-related adverse events. Methods: Over one year, we enrolled 115 patients with SpA, treated with infliximab or adalimumab. Patients who delayed prescribed drug administration were excluded from the study cohort. The population comprised 69 patients - 33 on IFX and 35 on ADA. NSAIDs administration was recommended “on demand”. Demographic, clinical (BASDAI, ASDAS) and laboratory (ESR, CRP) data was collected together with drug serum level and anti-drug antibodies using ELISA. The statistical analysis was performed using the SPSS software, version 20.0 with the aid of Student t-test, Spearman and Pearson tests. Results: Detectable IFX serum levels were identified in 60% of patients while 40% had undetectable drug titers. The IFX-negative had significantly higher disease activity scores: BASDAI (P=0.023), ASDAS-ESR (P<0.001) and ASDAS-CRP (P<0.001). Significant differences were found in the same subgroups regarding inflammatory markers, with higher ESR (P<0.001) and CRP (P=0.032) in patients with undetectable IFX levels. When measuring ADL serum levels, 82% had detectable drug concentrations, with lower BASDAI (P<0.001), ASDAS-ESR and ASDASCRP (P<0.001) and higher ESR and CRP at collection time when compared to ADL-negative patients. NSAID consumption correlated to undetectable levels of IFX and ADL as well as with anti-drug antibodies for both IFX and ADL positivity. All patients who experienced drug related adverse events on both IFX and ADL had positive anti-drug antibodies. Conclusion: Serum drug level measurement and anti-drug antibody detection can be used as a completion of a clinician’s tools in assessing disease activity, leading to an optimal patient management.

Stevens‑Johnsons syndrome or drug‑induced lupus ‑ a clinical dilemma: A case report and review of the literature

Tumor necrosis factor inhibitors are the first biological agents used in the treatment of rheumatoid arthritis (RA) to have yielded satisfactory results in terms of clinical improvement and radiologic progression, but they are also associated with the possibility of occurrence of a number of autoimmune systemic events [drug-induced lupus (DIL), vasculitis, sarcoidosis] and localized adverse events [uveitis, psoriasis, interstitial lung disease, erythema multiforme including the major form Stevens-Johnson syndrome (SJS)]. During treatment with TNF inhibitors, many patients develop positivity for antinuclear, antihistone and anti-double stranded DNA antibodies, though only a minority of patients will develop clinical manifestations and approximately less than 1% will fulfill the classification criteria for systemic lupus erythematosus. Mucocutaneous manifestations are the most frequent manifestations of DIL following treatment with TNF inhibitors, and can be severe and occasionally difficult to differentiate from erythema multiforme/SJS. Stopping the causative drug (the TNF inhibitor) and general supportive measures are usually sufficient in mild forms, but in moderate to severe forms, systemic glucocorticoids and sometimes immunosuppressive drugs are required. The present report presents the case of a patient with rheumatoid arthritis who developed severe recurrent cutaneous reactions and positive autoantibodies during TNF inhibitor treatment, with difficulties in differential diagnosis and treatment. A review of the literature is also presented.

Difficulties in Diagnosis and Treatment of a Case of Cerebrotendinous Xanthomatosis (CBX)

The tendon pathology is very complex including traumatic, inflammatory and storage disorders. Cerebrotendinous Xanthomatosis (CBX) is a rare lipid storage disorder, characterized by the accumulation of fats in various areas of the body (mainly central nervous system and tendons). A mutation in the CYP27A1 gene leads to a deficient break down of cholesterol, who is responsible to the formation of a molecule called cholestanol which accumulates in different tissues. We present the case of a young woman presenting with bilateral Achilles tendon painful swelling and mild mental retardation.

Swollen Ankle Due to the Presence of Accessory Soleus Muscle - Case Report.

Swollen ankle might be a problem of differential diagnosis in young patients performing physical exercises. A mass on the posteromedial region of the ankle might be attributed to the presence of Accessory Soleus Muscle (ASM), the most common supernumerary muscle in the lower leg. We present the case of a young male with swelling and moderate pain on the posteromedial part of the right ankle after prolonged physical exercise. Musculoskeletal examination identified ASM. A conservative approach (symptomatic medication, physical therapy) was recommended with good results.

SAT0664 Is there an early ultrasonographic pattern in salivary glands in both primary and secondary sjogren syndrome

Background Sjogren Syndrome (SS) affects mainly exocrine glands. Ultrasonography (US) demonstrates specificity and sensibility in major salivary glands (SG) evaluation. Recent data confirm US might be used as primary evaluation technique for its ability to show structural alterations of parenchyma [1]. Objectives To assess the gray scale (GS) parenchymal inhomogeneity of major SG in patients with established primary and secondary SS and correlate with clinical and biological data. Methods Consecutive patients with SS were recruited and SG US was performed. Inhomogeneity of glandular parenchyma was quantified binary on each gland. ESSDAI and ESSPRI scores were calculated. Statistics was performed with SPSS. Results Twenty one (42.85% primary SS, 90.47% female) consecutive patients were included. Mean age was 53.66+/-12.99 years and disease duration 5.33+/-3.74 years. Antibody SSA/SSB presence was found in 85.7% (18/21). ESSDAI mean was 8.67+/-8.9 (0–29), ESSPRI 10.13+/-5.59 (0–20). There were no differences regarding ESSDAI and ESSPRI in the two groups (primary and secondary SS). Right parotid gland showed alterations in 71.4% patients (77% with primary SS, 66% with secondary SS). Frequently inhomogeneity was found in all major SG (33%, 22% left and right submandibular, 77%, 44.4% left and right parotid glands) in primary SS. Both submandibular glands were symmetrically involved (p<0.02). Duration of disease was negatively correlated to inhomogeneity of right parotid gland (p<0.02). Conclusions Inhomogeneity in major SG in GS US was found in the majority of patients with primary and secondary SS. The symmetrical involvement of submandibular glands was significant. The inhomogeneity appears in the early period of diagnosis. No major differences were found between two groups. References Damjanov N, Milic V, Nieto-González JC, Janta I, Naredo E. Multiobserver Reliability of Ultrasound Assessment of Salivary Glands in Patients with Established Primary Sjögren Syndrome. J Rheumatol. 2016 Oct;43(10):1858–1863. Disclosure of Interest None declared

AB1068 Ultrasound of salivary glands in sjogren's syndrome- which semi-quantitative scoring system is the best?

Background Sjogren Syndrome (SS) affects mainly exocrine glands. The latest diagnostic criteria designed for clinical studies are also used as guidance in clinical practice [1]. Ultrasonography (US) demonstrates specificity and sensibility in parotid and submandibular gland evaluation (SG). Parameters considered are echogenicity, homogeneity and margins regularity [1,2,3]. To standardize the assessment of B mode US of SG, different semi-quantitative scores were proposed. Objectives To apply and compare 9 US semi-quatitative scoring systems in B mode scanning of salivary glands in Sjogren Syndrome. Methods A research using keywords “salivary glands”, “ultrasonograpy”, “Sjogren Syndrome”, “semi-quantitative score” in Medline/Pubmed was performed. There was a selection of most relevant articles. There were not considered relevant publications with impact factor <1. We performed the examination on SG in B mode US and applied these scores (De Vita, Niemela, Hocevar, Salaffi, Yukinori, Cornec,Theander) to our patients (primary and secondary SS). Results Eighty four SG in patients diagnosed with primary and secondary (57.15%) SS were assessed. In the group of patients with SSA/SSB presence (85.7%), mean score was De Vita 1.78+/-1.21, Niemela 2.56+/-2.17, Hocevar and Wernicke 2.39+/-2.14, Salaffi 2.83+/-2.52, Yukinori 2.39+/-2.14, Milic 3.39+/-2.14, Cornec 1.78+/-1.215, Theander 1.28+/-0.752. Schirmer test and the need for using the artificial tears was correlated to SG alterations in scoring systems proposed by Niemela (r 0.465, p<0.05) and Salaffi ( r 0.496, p<0.02). All scoring systems were strongly correlated between them (r>0.8, p<0.01). Conclusions Inhomogeneity of parenchyma was considered in all scoring systems. Others considered relevant glandular dimension and margins regularity [2,3.4]. There was no difference between the scoring systems. Xeroftalmia valided through Schirmer test is correlated to SG parenchymal alterations. Our data is an update about semi-quantitative scoring systems in US of SG in SS. References Vitali C, Bombardieri S, Jonsson R et al. Classification criteria for Sjögrens Syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. AnnRheum Dis 2002;61:554–8. Makula E, Pokorny G, Palkό A.The place of magnetic resonance and ultrasonographic examinations of the parotid gland in the diagnosis and follow-up of primary Sjögrens syndrome. Rheumatology (Oxford). 2000;39(1):97–104. Niemelä RK, Takalo R, Hakala M. Ultrasonography of salivary glands in primary Sjogrens syndrome. A comparison with magnetic resonance imaging and magnetic resonance sialography of parotid glands. Rheumatology (Oxford). 2004 Jul;43(7):875–9. El Miedany YM, Ahmed I, El Gafaary M. Quantitative ultrasonography and magnetic resonance imaging of the parotid gland: can they replace the histopathologic studies in patients with Sjogrens syndrome? Joint Bone Spine.2004;71(1):29–38. Disclosure of Interest None declared