As in previous years, the consensus group to consider the use of biological agents in the treatment of rheumatic diseases met during the 13th Annual Workshop on Advances in Targeted Therapies in April, 2011. The group consisted of rheumatologists from a number of universities among the continents of Europe, North America, South America, Australia and Asia.

Pharmaceutical industry support was obtained from a number of companies for the annual workshop itself, but these companies had no part in the decisions about the specific programme or about the academic participants at this conference. Representatives of the supporting sponsors participated in the initial working groups to supply factual information. The sponsors did not participate in the drafting of the consensus statement.

This consensus was prepared from the perspective of the treating physician.

In view of the new data for abatacept, B cell-specific agents, interleukin 1 (IL-1) antagonists, tocilizumab (TCZ) and tumour necrosis factor α blocking agents (TNF inhibitors), an update of the previous consensus statement is appropriate. To allow ease of updating, the 2010 (data from March 2009 to January 2010) updates are incorporated into the body of the article, while 2011 updates (February 2010–January 2011) are separated and highlighted. The consensus statement is annotated to document the credibility of the data supporting it as much as possible. This annotation is that of Shekelle et al and is described in appendix 1.1 We have modified the Shekelle annotation by designating all abstracts as ‘category D evidence’, whether they describe well-controlled trials or not, as details of the study were often not available in the abstracts. Further, the number of possible references has become so large that reviews are sometimes included; if they contain category A references, they will be referred to as category A evidence.

The rheumatologists and bioscientists who attended …

https://ard.bmj.com/content/annrheumdis/72/suppl_2/ii2.full.pdf

Updated consensus statement on biological agents for the treatment of rheumatic diseases, 2010

Objective To develop a disease activity index for patients with primary Sjogren9s syndrome (SS): the European League Against Rheumatism (EULAR) Sjogren9s syndrome disease activity index (ESSDAI). Methods Thirty-nine SS experts participated in an international collaboration, promoted by EULAR, to develop the ESSDAI. Experts identified 12 organ-specific ‘domains’ contributing to disease activity. For each domain, features of disease activity were classified in three or four levels according to their severity. Data abstracted from 96 patients with systemic complications of primary SS were used to generate 702 realistic vignettes for which all possible systemic complications were represented. Using the 0–10 physician global assessment (PhGA) scale, each expert scored the disease activity of five patient profiles and 20 realistic vignettes. Multiple regression modelling, with PhGA used as the dependent variable, was used to estimate the weight of each domain. Results All 12 domains were significantly associated with disease activity in the multivariate model, domain weights ranged from 1 to 6. The ESSDAI scores varied from 2 to 47 and were significantly correlated with PhGA for both real patient profiles and realistic vignettes (r=0.61 and r=0.58, respectively, p Conclusions The ESSDAI is a clinical index designed to measure disease activity in patients with primary SS. Once validated, such a standardised evaluation of primary SS should facilitate clinical research and be helpful as an outcome measure in clinical trials.

https://ard.bmj.com/content/annrheumdis/69/6/1103.full.pdf

EULAR Sjögren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjögren's syndrome

Objectives To develop evidence-based European League Against Rheumatism (EULAR) recommendations for vaccination in patients with autoimmune infl ammatory rheumatic diseases (AIIRD). Methods A EULAR task force was composed of experts representing 11 European countries, consisting of eight rheumatologists, four clinical immunologists, one rheumatologist/clinical immunologist, one infectious disease physician, one nephrologist, one paediatrician/ rheumatologist and one clinical epidemiologist. Key questions were formulated and the eligible spectrum of AIIRD, immunosuppressive drugs and vaccines were defi ned in order to perform a systematic literature review. A search was made of Medline from 1966 to October 2009 as well as abstracts from the EULAR meetings of 2008 and 2009 and the American College of Rheumatology (ACR) meetings of 2007 and 2008. Evidence was graded in categories I–IV, the strength of recommendations was graded in categories A–D and Delphi voting was applied to determine the level of agreement between the experts of the task force. Results Eight key questions and 13 recommendations addressing vaccination in patients with AIIRD were formulated. The strength of each recommendation was determined. Delphi voting revealed a very high level of agreement with the recommendations among the experts of the task force. Finally, a research agenda was proposed. Conclusion Recommendations for vaccination in patients with AIIRD based on the currently available evidence and expert opinion were formulated. More research is needed, particularly regarding the incidence of vaccine-preventable infectious diseases and the safety of vaccination in patients with AIIRD.

https://ard.bmj.com/content/annrheumdis/70/3/414.full.pdf

EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases

BACKGROUND Pemphigus vulgaris is a potentially fatal autoimmune mucocutaneous blistering disease. Conventional therapy consists of high-dose corticosteroids, immunosuppressive agents, and intravenous immune globulin. METHODS We studied patients with refractory pemphigus vulgaris involving 30% or more of their body-surface area, three or more mucosal sites, or both who had inadequate responses to conventional therapy and intravenous immune globulin. We treated the patients with two cycles of rituximab (375 mg per square meter of body-surface area) once weekly for 3 weeks and intravenous immune globulin (2 g per kilogram of body weight) in the fourth week. This induction therapy was followed by a monthly infusion of rituximab and intravenous immune globulin for 4 consecutive months. Titers of serum antibodies against keratinocytes and numbers of peripheral-blood B cells were monitored. RESULTS Of 11 patients, 9 had rapid resolution of lesions and a clinical remission lasting 22 to 37 months (mean, 31.1). All immunosuppressive therapy, including prednisone, could be discontinued before ending rituximab treatment in all patients. Two patients were treated with rituximab only during recurrences and had sustained remissions. Titers of IgG4 antikeratinocyte antibodies correlated with disease activity. Peripheral-blood B cells became undetectable shortly after initiating rituximab therapy but subsequently returned to normal values. Side effects that have been associated with rituximab were not observed, nor were infections. CONCLUSIONS The combination of rituximab and intravenous immune globulin is effective in patients with refractory pemphigus vulgaris.

Treatment of pemphigus vulgaris with rituximab and intravenous immune globulin.

B-cell-targeted therapy for autoimmune disease emerged from theoretical proposition to practical reality between 1997 and 1998, with the availability of the B-cell-depleting monoclonal antibody rituximab. Since then, a score of autoantibody-associated disorders have been treated, with most convincing evidence of efficacy seen in subjects with rheumatoid arthritis. Several classes of B-cell-targeted agent are now under investigation. From the outset, a major goal of B-cell targeting has been the re-establishment of some form of immunological tolerance. In some subjects, the observed improvement of disease for years following therapy fuels hope that this goal might ultimately be achievable.

B-cell targeting in rheumatoid arthritis and other autoimmune diseases.

Objective To investigate the safety and efficacy of B cell depletion treatment of patients with active primary Sjogren's syndrome of short duration (early primary SS) and patients with primary SS and mucosa-associated lymphoid tissue (MALT)-type lymphoma (MALT/primary SS). Methods Fifteen patients with primary SS were included in this phase II trial. Inclusion criteria for the early primary SS group were B cell hyperactivity (IgG >15 gm/liter), presence of autoantibodies (IgM rheumatoid factor, anti-SSA/SSB), and short disease duration ( Results Significant improvement of subjective symptoms and an increase in salivary gland function was observed in patients with residual salivary gland function. Immunologic analysis showed a rapid decrease of peripheral B cells and stable levels of IgG. Human anti-chimeric antibodies (HACAs) developed in 4 of 15 patients (27%), all with early primary SS. Three of these patients developed a serum sickness-like disorder. Of the 7 patients with MALT/primary SS, complete remission was achieved in 3, and disease was stable in 3 and progressive in 1. Conclusion Findings of this phase II study suggest that rituximab is effective in the treatment of primary SS. The high incidence of HACAs and associated side effects observed in this study needs further evaluation.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/art.21260

Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study.

Nonalcoholic fatty liver disease (NAFLD) is a spectrum of hepatic diseases linked to metabolic and cardiovascular disorders that impair quality of life and increase morbidity and mortality. There has been significant interest in replacing conventional diagnostic tools such as liver biopsy with non-invasive biomarkers for the diagnosis of NAFLD. Thymosin Beta 4 (Tβ4) is a G-actin sequestering peptide involved in many critical biological processes. This study aimed to evaluate the role of Tβ4 in the diagnosis of NAFLD, and its relation to metabolic syndrome. Eighty patients were enrolled in this study, divided into two equal groups of NAFLD cases (n=40) and a control group (n=40). The two groups were subjected to history taking, physical examination, measurement of waist circumference and body mass index (BMI). Laboratory workup included serum Tβ4, insulin resistance (HOMA-IR), fibrosis-4 score (FIB-4), fatty liver index (FLI) and NAFLD fibrosis score (NFL) were calculated for both groups. Serum Tβ4 was significantly lower in NAFLD patients (P < 0.001) and there was a significant positive correlation between serum Tβ4 and HDL (P = 0.034). On the other hand, there was a significant negative correlation between serum Tβ4 and waist circumference (P < 0.001), total cholesterol level (P < 0.001), insulin level (P < 0.001), HOMA-IR (P < 0.001), serum triglycerides (P= 0.025) and FLI (P = 0.004). Serum Tβ4 at a cut-off value of ≤900 ng/ml had 100 % sensitivity, 100 % specificity, 100% positive predictive value and 100% negative predictive value for the prediction of NAFLD. In conclusion, serum Tβ4 could be used as a biomarker for the diagnosis of NAFLD.

K Mansour

Papers

Rituximab treatment in patients with primary Sjögren's syndrome: an open-label phase II study.

Role of Thymosin Beta 4 in the diagnosis of Nonalcoholic Fatty Liver and its relation to Metabolic Syndrome in Egyptian patients.