George E. Fragoulis

Therapeutic Targeting of IL-17 and IL-23 Cytokines in Immune-Mediated Diseases

The discovery of the biological functions of the interleukin-23/-17 axis led to the identification of IL-23 and IL-17 as important participants in the pathogenesis of several immune-mediated diseases. Therapeutic agents targeting these cytokines and/or their receptors have now been developed as potential treatment strategies for common immune-mediated diseases. Anti-IL-17 and anti-IL-12/-23 regimens appear particularly effective in psoriasis, with promising results in spondyloarthropathies also emerging. Overall, these agents appear well tolerated, with adverse-event rates that are commensurate with those in other biologic treatment programs. The strategic utility of these new agents, however, remains uncertain, and further studies will be required to determine their place in the context of existing conventional and biologic immune-modifying agents.

IgG4 syndrome: old disease, new perspective.

In the last few decades, the evolution of biomedical sciences has contributed to a better understanding of the pathogenesis of human disease, the description of new clinical entities, sorting out of disease subgroups, and development of targeted therapeutic interventions1.nnA new syndrome was identified recently, called IgG4 syndrome. Many terms such as “IgG4-related systemic sclerosing disease,” “IgG4-related autoimmune disease,” “IgG4-related systemic disease,” “IgG4-positive multiorgan lymphoproliferative syndrome,” and others have been used to identify the disease.nnIgG4 syndrome has various clinical manifestations, such as sclerosing pancreatitis, sclerosing cholangitis, prostatitis, tubulointerstitial nephritis, interstitial pneumonia, and enlargement of salivary glands. In previous years, these clinical entities appeared to be unrelated. Recent studies, however, revealed that they share some common denominators, such as elevated serum IgG4 levels and tissue infiltration by IgG4-positive plasma cells, accompanied by tissue fibrosis and sclerosis2. These serological and histopathological features are considered hallmarks for diagnosis of IgG4 syndrome. Thus, the enlargement of salivary glands, accompanied by high serum IgG4 concentrations and IgG4-positive plasma cells in the infiltrates of the salivary glands, previously called … nnAddress correspondence to Dr. Moutsopoulos. E-mail: hmoutsop{at}med.uoa.gr

IgG4-related sialadenitis and Sjögren's syndrome

IgG4-related disease (IgG4-RD) has emerged as a new entity in the last decade. It comprises numerous conditions previously thought to be unrelated. Macroscopically, these diseases cause diffuse organ swelling and formation of pseudotumorous masses. Histopathologically, they are characterized by a lymphoplasmacytic infiltrate with increased IgG4+ plasma cells and storiform fibrosis. Despite rapid progress within the last years, our knowledge on these conditions is still fragmented. To date, more than forty organs have been reported to be included in IgG4-RD, and salivary gland involvement is amongst the most common organs affected [IgG4-related sialadenitis (IgG4-RS)]. Interestingly, IgG4-RS shares commonalities with Sjögrens syndrome (SS), like glandular enlargement, sicca symptoms, arthralgias, hypergammaglobulinemia, hypocomplementemia, and circulating antinuclear antibodies. Nonetheless, they differ in that the incidence of anti-Ro and anti-La reactivity is not frequently found in patients with IgG4-RS, their salivary glands are infiltrated by a large number of IgG4+ plasma cells and IgG4-RS symptoms respond promptly to steroids. The aim of this review was to describe the clinical, serological, histopathological and pathophysiological aspects of IgG4-RS in the context of IgG4-RD and highlight the differences between IgG4-RS and SS.

Clinical and Laboratory Predictors of Distinct Histopathogical Features of Lupus Nephritis

AbstractThe authors aimed to explore whether distinct clinical, serological, and urinalysis findings are associated with specific histological classes of lupus nephritis. Clinical and laboratory features were recorded at the time of clinical diagnosis from 297 consecutive patients with biopsy-confirmed lupus nephritis. Univariate and logistic regression analyses were performed and a risk score was developed to estimate the risk for developing different classes of lupus nephritis. Variables independently associated with class II included absence of malar rash, negative anti-dsDNA, and ⩽5 urine leucocytes/high power field (hpf); with III/IV: age at nephritis diagnosis ⩽32 years old, presence of musculoskeletal features, new-onset hypertension, positive anti-dsDNA, >5 urine leucocytes/hpf, creatinine >1.2u200amg/dL, cellular casts >1/hpf, and absence of nephrotic range proteinuria; with V: age at nephritis diagnosis >32 years, malar rash, absence of musculoskeletal complaints or serum C3 hypocomplementemia, nephrotic range proteinuria, and ⩽9 urine erythrocytes/hpf. A risk predictive score of specific histological classes was calculated for each patient. Associations between 2, 3 or more risk factors with specific histological classes were also revealed [Odds ratios (95% confidence interval) (≥2 risk factors) was 6.7 (2.8–17.4) for class II nephritis, 15.6 (5.1–47.8), and 8.2 (3.6–19.0) for classes III/IV and for class V, respectively (≥3 risk factors)]. The identification of independent factors associated with specific classes of lupus nephritis can provide guidance in selecting specific therapeutic modalities, particularly in cases in which renal biopsy is contraindicated.

Is mizoribine a new therapeutic agent for Sjögren's syndrome?

In a multicenter, open-label study conducted in Japan between July 2004 and May 2005, Nakayamada et al. tested the safety and efficacy of mizoribine for the treatment of primary Sjögrens syndrome (pSS). Mizoribine 50 mg was administered three times a day for 16 weeks to 59 patients with pSS, 7 of whom withdrew because of adverse drug reactions; however, no serious adverse events were noted. In the 48 patients who completed the study, an increase from baseline in median salivary secretion volume, evaluated using the Saxon test, was apparent at week 8 and was significant at week 16 (P <0.05). At 16 weeks, significant improvements from baseline were also seen in patients assessments of dry mouth and dry eyes, physicians assessment of oral sicca symptoms, labioangular sicca symptoms and physicians overall assessment, all measured using a 10 cm visual analog scale. The findings suggest that mizoribine could be an effective treatment for pSS.

Analysis of the cell populations composing the mononuclear cell infiltrates in the labial minor salivary glands from patients with rheumatoid arthritis and sicca syndrome.

OBJECTIVESnSicca symptoms occur in around 30% of rheumatoid arthritis (RA) patients. Herein, we examined the characteristics of RA patients bearing sicca symptomatology (RA-sicca) with a special focus on the immunohistopathological features of their labial minor salivary gland (LMSG) biopsies.nnnMETHODSnOur cohort included 100 consecutive RA patients which were interrogated using a sicca symptoms questionnaire. Positive responders were evaluated for ocular and oral dryness and underwent an LMSG biopsy. All samples were immunohistochemically evaluated for the presence and distribution of specific leukocyte subsets using appropriate markers and for the expression of certain immunoregulatory molecules by salivary gland epithelial cells. Positively stained and total mononuclear cells (MNC) were counted in the entire section. Counts were expressed as cell frequency (percentage of cell type number/total infiltrating MNC number).nnnRESULTSnIn the majority (86.1%) of the 44 RA-sicca cases, periductal infiltrates were observed in LMSG biopsies. The frequencies of infiltrating cell subtypes and their correlation with lesion severity were different from that previously described in primary Sjögrens syndrome (pSS). Moreover, DCs and ΜΦs frequencies were increased in RA-sicca patients who had a biopsy focus score <1 and absence of anti-Ro/anti-La autoantibodies, in contrast to what was observed for B cells. In about half of the biopsies, salivary gland epithelial cells expressed CD80/B7.1 molecules, most commonly in patients with a positive biopsy or anti-Ro/anti-La autoantibodies.nnnCONCLUSIONnLMSG infiltrates composition in RA-sicca patients is distinct from that described in pSS. These differences, further attest to diverse pathophysiologic processes operating in these two entities.

Neutropaenia in early rheumatoid arthritis: frequency, predicting factors, natural history and outcome

Objectives To determine the frequency, severity and natural history of neutropaenia in early rheumatoid arthritis (RA), explore its associations with clinical features and assess its impact on clinical management. Methods The Scottish Early Rheumatoid Arthritis inception cohort prospectively recruited patients with newly diagnosed RA and followed them up every 6 months. Patients with RA who developed at least one episode of neutropaenia (grade 1: <2.0×10^9/L; grade 2: <1.5×10^9/L; grade 3: <1.0×10^9/L; grade 4: <0.5×10^9/L) were compared with those who did not. Comparisons were also made between patients who experienced one or more episodes of neutropaenia and between patients with different neutropaenia grades. Results 77 neutropaenia episodes were recorded in 58 of 771 (7.5%) patients with RA, who were followed up for a median (range) of 18 (6–48) months. Neutropaenia occurred at a median (range) of 12 (0–120) months after RA diagnosis. The majority had mild neutropaenia (grade 1: n=42; grade 2: n=14; grade 3: n=1; grade 4: n=1). Neutropaenia was transient (single episode) in the majority (44; 75.8%) of cases but led to treatment discontinuation in 14 (24.1%) patients. Patients who developed neutropaenia were more likely to be female (p=0.01) and non-smokers (p=0.007) and had lower baseline neutrophil levels (p<0.0001). Binomial regression analysis confirmed the latter (p<0.0001, B: −0.491) as neutropaenia predictor. The rate of infections did not differ between patients who developed neutropaenia and those who did not (p=0.878). Conclusion Neutropaenia was a common finding in this cohort. It was usually mild, transient and not associated with increased infection rates. Neutropaenia occurrence was associated with non-smoking, female gender and lower baseline neutrophil levels.

Ocular manifestations of IgG4-related disease in children. More common than anticipated? Review of the literature and case report

IgG4-related disease (IgG4-RD) is an entity with various clinical manifestations. Histopathologically, it is characterized by lymphoplasmacytic infiltrates enriched in IgG4 (+) plasmacytes and usually fibrosis of the affected tissue. Most of the patients have also increased IgG4 serum levels and they respond to glucocorticosteroids. In children, due to its rare occurrence, IgG4-RD is ill defined. From the published studies, so far, it appears that ocular manifestations are very common in the paediatric population with IgG4-RD. Herein, we describe a new case of a child with IgG4-RD with ocular involvement manifested with orbit and eyelid swelling, successfully treated with steroids. In addition, we review the clinical, laboratory, histopathologic and radiologic characteristics of the published paediatric cases with IgG4-RD and ocular involvement, critically comparing them with the characteristics of the adult population. It seems that ocular manifestations are more frequently observed in children than in adults. Also, the pattern of involvement is different, with extraocular muscles and soft tissues being more commonly affected than the lacrimal glands.

FRI0142 Neutropenia in rheumatoid arthritis. incidence, prognostic factors, natural history and outcome

Background Neutropenia is an uncommon finding in the context of rheumatoid arthritis (RA). The incidence and association with RA features is not yet well-defined. Objectives To determine the incidence and severity of neutropenia in an early RA inception cohort, explore possible association with RA features and describe its impact on patients management. Methods The Scottish Early Rheumatoid Arthritis (SERA) inception cohort prospectively recruited newly diagnosed RA patients (ACR-EULAR 2010 criteria), who were followed-up every 6 months. Patients who developed at least one episode of neutropenia (grade 1: <2000/μL, grade 2: <1500/μL, grade 3: <1000/μL, grade 4: <500/μL) were compared with patients who never developed neutropenia. Binominal logistic regression was performed, exploiting the enter model and using the occurrence of neutropenia as dependent variable. Results 77 episodes of neutropenia were observed in 60 (8.6%) out of 698 RA patients, who were followed up for a median (range) time of 18 (6–48) months. Neutropenia occured in 12 (0–120) [median (range)] months after RA diagnosis. The majority had mild neutropenia (grade 1: n=49, grade 2: n=9, grade 3: n=0, grade 4: n=2) and the mean ± SD number of neutrophils/μL was 1.68±0.35. Of the 77 neutropenic episodes recorded, coexistent lymphopenia was found in 13.0%, leukopenia in 70.1%, thrombocytopenia in 1.3% and anaemia in 32.5%. At the time of the neutropenia, most of the patients were in remission (DAS28<2.6: 53%, DAS28<3.2: 15.5%, DAS28≤5.1: 22.4%, DAS28>5.1: 8.6%). Neutropenia was a single episode in the majority (76.7%) of the patients and led to treatment discontinuation in 11.7% of them. Patients who subsequently developed neutropenia, were more likely females (p=0.03) and non-smokers (p=0.0009) (Table 1). Treatment received for RA was comparable between the two groups. Binominal regression analysis confirmed female gender [p=0.017, Exp(B): 2.587] and not smoking [p=0.032, Exp(B): 2.880] as predictors of neutropenia development. During total follow-up time, patients who had at least one episode of neutropenia they also manifested more commonly anaemia (p=0.04) and lymphopenia (p=0.03). The rate of infections/1000 person-months did not differ between patients who developed neutropenia and those who did not [5.75 (2.47–11.33) vs 4.1 (3.13–5.47), p=0.399].Table 1. Baseline patients characteristics Neutropenia No Neutropenia p value Patients characteristics N=60 N=638 Age, mean (mean±SD) 58.7±14.5 58.7±13.2 0.978 Female gender, No (%) 50 (83.3%) 414 (64.9%) 0.03 Total follow-up (months), median (range) 18 (6–48) 18 (6–48) 0.173 Smoking, No (%) 5 (8.3) 172 (27.0) 0.0009 Smoking (present/past/never) 5/23/32 172/240/225 0.002 Anaemiaa, No (%) 8/57 (14.0) 133/631 (21.1) 0.235 Thrombocytopeniab, No (%) 0/57 (0.0) 0/631 (0.0) 1.000 Leukopeniac, No (%) 1/57 (1.7) 3/631 (0.4) 0.293 Lymphopeniad, No (%) 4 (7.0) 34/631 (5.4) 0.545 RF positive, No (%) 28/36 (77.8) 295/401 (73.5) 0.693 Anti-CCP positive, No (%) 34/48 (70.8) 410/527 (77.8) 0.282 Baseline DAS28 (mean±SD) 4.8±1.6 5.02±1.42 0.408 aHb<120 g/L, bplatelets <100000/μl, cwhite blood cells: <4x109/L, dlymphocytes: <1x109/L. Conclusions Neutropenia was observed in about 9% of patients in this early RA cohort. It was usually mild, transient and not associated with increased infection rates. Interestingly, not-smoking and female gender were associated with neutropenia. Disclosure of Interest None declared