Ilias Lazarou

Classification, Diagnosis, and Management of Idiopathic Inflammatory Myopathies

The detection and characterization of a large array of autoantibodies, including at least 8 different antisynthetase, anti-SRP, -200/100 (HMGCR), -Mi-2, -CADM-140 (MDA5), -SAE, -p155, -MJ (NXP-2), and -PMS1, frequently associated with distinct and well-defined clinicopathological features, allowed for significant improvement in the definition and diagnosis of idiopathic inflammatory myopathies (IIM). Classification remains difficult, with lingering divergence between the different specialties involved in IIM care, but several categories clearly stand out, including dermatomyositis (DM), overlap myositis (OM), polymyositis, necrotizing myositis, and sporadic inclusion body myositis (s-IBM). Biopsy and histological analysis remain crucial, particularly in the absence of autoantibodies, to accurately specify the diagnosis and rule out mimics such as muscular dystrophies and metabolic myopathies. Numerous infectious agents (in particular human immunodeficiency virus and human T cell lymphotrophic virus-1) and drugs (statins, tumor necrosis factor inhibitors, and proton pump inhibitors) can cause mimic IIM that must also be excluded. Pharmacological treatment, in addition to glucocorticoids and immunoglobulins, now includes mycophenolate mofetil and rituximab, which proved helpful in resistant cases, particularly rituximab in DM and OM. Exercise, initially seen as potentially deleterious, recently was shown to be efficacious and safe. IIM can thus be reasonably well controlled in most cases, although aggressive disease remains refractory to treatment, including some cases of necrotizing myopathy. Sporadic IBM still seems resistant to all medications tested to date.

Ultrasound-guided synovial biopsy: a systematic review according to the OMERACT filter and recommendations for minimal reporting standards in clinical studies

OBJECTIVES To describe existing techniques of US-guided synovial biopsy (USG-SB) and critically appraise the literature on this technology through the OMERACT filter. METHODS USG-SB techniques are described and compared. A systematic literature search of PubMed and Embase was performed for original research reports including US and SB. The subjects, procedure protocols and reported results were analysed. A future research agenda is proposed. RESULTS USG-SB can be performed using a portal-and-forceps or a dedicated semi-automatic guillotine-type biopsy needle approach. Of 50 reports identified, 7 were included in the review. Large, intermediate and small joints were all amenable to USG-SB. We found great heterogeneity with regard to indications for and definition of a successful procedure and of synovitis. Adverse events were assessed in most papers with an overall major complication rate of 0.4%. However, there was a lack of construct validity using a histological comparator. Relatively few papers reported details on the technique used, tissue processing, synovitis scoring and blinding for tissue analysis. CONCLUSION USG-SB can be regarded as a valuable tool for large-scale synovial tissue sampling. Standardization of the techniques of USG-SB and tissue processing is needed. Future research should focus on the reliability, responsiveness and feasibility of this procedure in prospective studies.

Low pre-treatment B-cell counts are not a risk factor of infection in patients treated with rituximab for autoimmune diseases: An observational study.

OBJECTIVES Rituximab (RTX) is increasingly used in patients with refractory rheumatoid arthritis (RA) and other severe autoimmune diseases (AID). In practice, many clinicians are reluctant to prescribe RTX in patients with low B-cell counts because of the presumed risk of infection. The aim of this study was therefore to investigate whether B-cell counts before treatment or retreatment with RTX predict the occurrence of infections. METHODS Observational, single-centre study of 161 patients treated with RTX for RA and other AID at a tertiary hospital. CD19+ B-cell counts were assessed by flow cytometry and multivariate statistical analysis adjusted for various potential predictors was performed. RESULTS The rate of severe infection was 5.9/100 patient-years in RA patients and 24.9 in non-RA AID (P<0.001). Low B-cell counts at the time of RTX infusion were not associated with subsequent severe (HR=0.55, P=0.60) or overall infection (HR=0.85, P=0.58). Significant pre-treatment predictors of severe infection were a diagnosis other than RA (HR=4.68, P<0.001), immunoglobulin (Ig) G levels <7g/L (HR=2.36, P=0.01), age (HR=1.03, P=0.01), and diabetes (HR=3.61, P=0.01). CONCLUSIONS Low B-cell counts before RTX infusion did not predict subsequent infections in this population treated with RTX for RA and other AID, therefore not supporting the practice of pre-treatment assessment of B-cells. Nevertheless, a higher risk of severe infection was confirmed for low pre-treatment IgG levels, older age, diabetes, and AID other than RA.

Primary malignant achromic melanoma of the lung

Currently, less than thirty cases of primary malignant melanoma of the lung have been reported in the literature. Thus, strict criteria for diagnosis have been published and include: malignant melanoma associated with bronchial epithelial changes; a solitary lung tumor; no prior history of skin, mucous membrane, intestinal or ocular melanoma; and absence of any other detectable tumor at the time of diagnosis. In this article we present a case of melanoma of the lung without evidence of extra‐pulmonary disease.

Felty's syndrome and hypofibrinogenemia: an unusual target for anti-cyclic citrullinated peptide antibodies?

Abstract Background. Rheumatoid arthritis (RA) is a risk factor for the development of Feltys syndrome and large granular lymphocyte (LGL) leukemia. Anti-cyclic citrullinated peptide (CCP) antibodies are considered highly specific for RA and are directed against various citrullinated antigens, including citrullinated fibrinogen. Anti-CCP antibodies may interfere with the detection of citrullinated proteins and their function. In this article, we describe the possible inhibition of fibrinogen by anti-CCP antibodies with clinical consequences which have never been reported in the literature to our best knowledge. Case report. We present the case of a 79-year-old Caucasian woman with a longstanding history of untreated seropositive RA and who had been investigated for severe neutropenia since several months. The association of splenomegaly led to suspicion of Feltys syndrome. Flux cytometry was compatible with T-cell LGL leukemia. In addition, severe hypofibrinogenemia was detected. The later finding has not been consistently associated with the former clinical entities. Further investigations demonstrated that the anti-CCP antibodies of the patient also recognized the P41 peptide of citrullinated fibrinogen. The patient deceased of intracranial hemorrhage. Conclusion. It is likely, yet not definite, that high anti-citrullinated fibrinogen titers may contribute to low fibrinogen levels and could have contributed to the fatal hemorrhagic event.

A7.6 Clinical and pathological differences of elderly- and younger-onset rheumatoid arthritis in an early arthritis cohort

Background and objectives Elderly-onset rheumatoid arthritis (EORA), starting after the age of 60, is a subset of disease with different characteristics from the classic younger-onset RA (YORA). We aimed to compare clinical and pathological features between these two disease subsets in the Barts Early Arthritis Cohort (BEAC). Material and methods We included BEAC patients fulfilling ACR 2010 criteria and assessed clinical and pathological variables at baseline and at 6 months of DMARD therapy. The primary outcome was the achievement of low disease activity (LDA) according to DAS28 at 6 months. We used multivariate logistic regression to determine predictors of LDA at 6 months. Results We included 140 patients, 99 YORA and 41 EORA. EORA patients were more frequently male (51.2 vs. 26.3, p = 0.004) and Caucasian (68.3 vs. 39.4, p = 0.02), had more proximal joint involvement at presentation (55.0 vs. 35.1, p = 0.031), more common abrupt (27.5 vs. 4.1, p < 0.001) and polymyalgia rheumatica (PMR)-like onset (23.7 vs. 0, p < 0.001), weight loss (15.0 vs. 4.1, p = 0.026), anaemia (48.6 vs. 28.4, p = 0.033), extra-articular manifestations (27.5 vs. 6.2, p = 0.004) and cardiovascular comorbidity (73.2 vs. 29.3, p < 0.001). At baseline, disease activity parameters, including ESR, CRP, joint counts, and composite scores (DAS28, CDAI and SDAI), were similar between both groups. Synovial pathotype classification (ectopic lymphoid-like structures positive (ELS+); diffuse myeloid infiltrate or non-inflammatory/pauci-immune) did not reveal differences between groups as a whole (p = 0.12). However, EORA patients presented pauci-immune pathotype less frequently (25.0 vs. 44.3, p = 0.045). Macrophage, B-cell, T-cell and plasmocyte semi-quantitative scores were also similar. At 6 months (n = 105), EORA (OR = 0.28, p = 0.047), female gender (OR = 0.23, p = 0.016), current smoking (OR = 0.11, p = 0.002) and high baseline DAS28 (OR = 0.41, p < 0.001) were negatively associated with reaching DAS28 LDA. Contrastingly, PMR-like onset was strongly predictive of DAS28 LDA (OR = 63.9, p = 0.004). Conclusions In an early arthritis cohort, EORA patients presented different clinical features at presentation, but similar synovial pathological characteristics. Adjusting for other significant factors such as gender, smoking, baseline DAS28 and PMR-like onset, EORA was negatively associated with the achievement of LDA at 6 months according to DAS28.

OP0032 Baseline Synovial B-Cell Status Predicts Response to Rituximab Therapy in RA

Background B-cells are key mediators in RA pathogenesis through the initiation of several pathways that lead to the perturbation of the immune system. Rituximab, an anti-CD20 monoclonal antibody is recommended for use after failure with traditional disease modifying agents and anti-TNF therapy. Despite using peripheral blood B-cells as a marker to ensure depletion, the clinical response to Rituximab remains variable, highlighting an unmet need for further biomarkers of response. Mechanisms that underpin the variation in clinical outcome are yet to be fully elucidated but may relate to distinct differences in cellular infiltrate and target expression within the synovium. Objectives The aim of this open-labelled pilot study was to test the hypothesis that patients with a B-cell rich versus B-cell poor synovial pathotype have an enhanced response to B-cell depletion following therapy with Rituximab. Methods Synovial biopsy (Ultrasound guided n=34, arthroscopic n=6) was performed at baseline in 40 patients with active RA (as defined by a DAS-28 score of >5.1) who had failed treatment with standard disease modifying therapy. 35 patients had received prior anti-TNF therapy, a subset of 5 patients were anti-TNF naïve. Rituximab was administered, with appropriate pre-medication, as two intravenous infusions at a dose of 1g 14 days apart. Synovial tissue was fixed in formalin, paraffin-embedded and cut to serial sections (3μm). Histological grading and lymphoid organization of the synovium was assessed by immunohistochemical analysis. After staining for CD20, the presence or absence of B-cells was determined by a semi-quantitative score (0-4)1. CD21 staining was carried out on samples with large aggregates to determine the presence of FDC in germinal centres (GC) within the synovium. Disease response to treatment (improvement in DAS-28>1.2) at 16 weeks was correlated with the presence or absence of B-cells and GC using Fishers exact test and Chi-squared testing, respectively. Results IHC for CD20 results were available from 39 patients. 29 [74%] patients were females, mean age 58.5 [29-80], 36 [92%] were anti-CCP positive and 32 [82%] were RF positive. 12 [30%] showed a response (DAS-28 >1.2) improvement at 3 months. 24 [62%] patients had little or no B-cell infiltrate within the synovium. In this subgroup, 20 [83%] did not exhibit a significant clinical response. (p=0.031). In B-cell rich non-responders, the presence of GC was noted in 5 out of 6 individuals [83%]; only 1 patient who was GC positive responded to Rituximab. (p=0.01, n=37) Conclusions This open-labeled pilot study strongly suggests that response to Rituximab therapy is determined by the presence or absence of B-cells within the synovium. In patients with B-cell rich synovium, the presence of GC appears to be an important marker of resistance to Rituximab therapy. This pilot study also highlights the potential to utilize synovial pathotype as a biomarker to predict disease outcomes and response. References Kraan, M.C., Haringman, J.J., Post W.J., Versendaal, J., Breedveld, F.C., Tak. P.P. Immunohistological analysis of synovial tissue for differential diagnosis in early arthritis. Rheumatology 1999; 38:1074–1080. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.5609