Winfried Graninger

Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force

Background Reaching the therapeutic target of remission or low-disease activity has improved outcomes in patients with rheumatoid arthritis (RA) significantly. The treat-to-target recommendations, formulated in 2010, have provided a basis for implementation of a strategic approach towards this therapeutic goal in routine clinical practice, but these recommendations need to be re-evaluated for appropriateness and practicability in the light of new insights. Objective To update the 2010 treat-to-target recommendations based on systematic literature reviews (SLR) and expert opinion. Methods A task force of rheumatologists, patients and a nurse specialist assessed the SLR results and evaluated the individual items of the 2010 recommendations accordingly, reformulating many of the items. These were subsequently discussed, amended and voted upon by >40 experts, including 5 patients, from various regions of the world. Levels of evidence, strengths of recommendations and levels of agreement were derived. Results The update resulted in 4 overarching principles and 10 recommendations. The previous recommendations were partly adapted and their order changed as deemed appropriate in terms of importance in the view of the experts. The SLR had now provided also data for the effectiveness of targeting low-disease activity or remission in established rather than only early disease. The role of comorbidities, including their potential to preclude treatment intensification, was highlighted more strongly than before. The treatment aim was again defined as remission with low-disease activity being an alternative goal especially in patients with long-standing disease. Regular follow-up (every 1–3 months during active disease) with according therapeutic adaptations to reach the desired state was recommended. Follow-up examinations ought to employ composite measures of disease activity that include joint counts. Additional items provide further details for particular aspects of the disease, especially comorbidity and shared decision-making with the patient. Levels of evidence had increased for many items compared with the 2010 recommendations, and levels of agreement were very high for most of the individual recommendations (≥9/10). Conclusions The 4 overarching principles and 10 recommendations are based on stronger evidence than before and are supposed to inform patients, rheumatologists and other stakeholders about strategies to reach optimal outcomes of RA.

Treat-to-target in systemic lupus erythematosus: recommendations from an international task force

The principle of treating-to-target has been successfully applied to many diseases outside rheumatology and more recently to rheumatoid arthritis. Identifying appropriate therapeutic targets and pursuing these systematically has led to improved care for patients with these diseases and useful guidance for healthcare providers and administrators. Thus, an initiative to evaluate possible therapeutic targets and develop treat-to-target guidance was believed to be highly appropriate in the management of systemic lupus erythematosus (SLE) patients as well. Specialists in rheumatology, nephrology, dermatology, internal medicine and clinical immunology, and a patient representative, contributed to this initiative. The majority convened on three occasions in 2012–2013. Twelve topics of critical importance were identified and a systematic literature review was performed. The results were condensed and reformulated as recommendations, discussed, modified and voted upon. The finalised bullet points were analysed for degree of agreement among the task force. The Oxford Centre level of evidence (LoE, corresponding to the research questions) and grade of recommendation (GoR) were determined for each recommendation. The 12 systematic literature searches and their summaries led to 11 recommendations. Prominent features of these recommendations are targeting remission, preventing damage and improving quality of life. LoE and GoR of the recommendations were variable but agreement was >0.9 in each case. An extensive research agenda was identified, and four overarching principles were also agreed upon. Treat-to-target-in-SLE (T2T/SLE) recommendations were developed by a large task force of multispecialty experts and a patient representative. It is anticipated that ‘treating-to-target’ can and will be applicable to the care of patients with SLE.

Improvement of insulin sensitivity in insulin resistant subjects during prolonged treatment with the anti‐TNF‐α antibody infliximab

Sir, Insulin resistance (IR) is an important component in the pathophysiology of type-II diabetes, hypertension, hyperlipidaemia and finally cardiovascular disease with both genetic and environmental factors contributing to its development. Tumour necrosis factor alpha (TNFα ), a proinflammatory cytokine, may play a prominent role in obesity associated IR as well as β -cell dysfunction [1]. Elevated expression of TNFα in obese insulin resistant rodents and humans was observed along with the indication of elevated plasma TNFα in some studies. TNFα has tissue specific effects on glucose homeostasis and is known to impair insulin receptor signalling experimentally. Furthermore, cytokines that activate (NF)-kB (a nuclear transcription factor closely involved into regulation of cellular inflammatory response), such as TNFα , are thought to be a common denominator for β cell apoptosis in type 1 and type 2 diabetes [2]. In addition, it has been suggested that TNFα is a powerful regulator of adipose tissue [3]. Neutralizing TNFα in obese fa/fa-rats has shown increased insulin sensitivity [4]. So far, in humans two studies failed to demonstrate an effect of acute administration of either a chimeric anti-TNFα antibody [5] or a recombinant soluble human TNFα receptor [6] on insulin sensitivity in obese or type-II diabetic subjects. Prolonged administration of anti–TNFα antibody is used in the treatment of chronic inflammatory diseases such as rheumatic diseases [7] or Crohn’s disease [8]. Here we report observational findings of chronic treatment with infliximab (a chimeric anti-TNFα antibody) on insulin sensitivity as assessed by the homeostasis model assessment (HOMA: fasting plasma glucose (mmol L − 1 ) × fasting serum insulin (mU L − 1 ) divided by 225 [9]), in such patients. Our index case, a 31 years old male with a body-mass-index (BMI) of 31·2 kg m − 2 was diagnosed with type-II diabetes in November 1999 with an HbA 1c of 9·2%. The patient lost weight within 8 months to a BMI of 22·4 kg m − 2 and was treated with insulin (approx. 28 IU per day). As a result stable, good glycaemic control (fasting blood glucose: 6·05 mmol L − 1 ) in the absence of hypoglycaemia could be reached and maintained till 2001. In January 2001 treatment with infliximab (5 mg kg − 1 ) every 8 weeks, was started due to refractory psoriatic arthritis. At this time point he exhibited an unexpectedly severe insulin resistance with a HOMA of 36·98 despite maintenance of normal body weight (In healthy subjects the median HOMA is about 1·4 whereas only 10% of them exhibit a HOMA between 4·5 and 20). After 4–5 months, the patient noticed a decline in insulin requirements and the occurrence of hypoglycaemia. In October 2001, after a severe hypoglycaemic episode, the patient stopped insulin treatment. In July 2002, still on infliximab treatment glucose status was reevaluated. Fasting plasma glucose was 5·17 mmol L − 1 and 2-h after challenge with 75 g glucose 10·56 mmol L − 1 were observed indicating the presence of impaired glucose tolerance instead of insulin requiring diabetes. The respective serum insulin was 32·8 mU L − 1 and 96·4 mU L − 1 , HbA1c was 5·4%. Today the patient is still without insulin therapy. This observation prompted us to evaluate insulin sensitivity retrospectively, using the HOMA, in samples stored from patients treated with infliximab after obtaining informed consent (Fig. 1). Interestingly, with exception of our lean index patient, only the most obese patients (patients 3 and 5), available for analysis (Table 1), showed a pronounced insulin resistance at baseline and improved substantially. In contrast, the other patients (patients 2 and 4) with a lower BMI were insulin sensitive at baseline and did not change during infliximab Division of Rheumatology (B. Yazdani-Biuki, H. P. Brezinschek, J. Hermann, T. Mueller, W. Graninger), Diabetes and Metabolism Clinic (H. Stelzl, T. C. Wascher), and Division of Oncology ( P. Krippl), Department of Internal Medicine, Medical University Graz, Austria.

Borderline pulmonary arterial pressure is associated with decreased exercise capacity in scleroderma.

RATIONALE Pulmonary arterial hypertension is associated with impaired exercise capacity and decreased survival in patients with scleroderma. Randomized controlled studies showed significant benefit of targeted therapies in patients with a resting mean pulmonary arterial pressure (MPAP) greater than 25 mm Hg. The clinical relevance of pulmonary arterial pressure values in the upper normal range is unknown. OBJECTIVES To examine the clinical relevance of pulmonary arterial pressure in scleroderma patients. METHODS After a noninvasive screening program, 29 patients with systemic sclerosis without significant lung fibrosis and without known pulmonary arterial hypertension underwent right heart catheterization and simultaneous cardiopulmonary exercise test. A six-minute walk distance (6MWD) was determined within 48 hours. MEASUREMENTS AND MAIN RESULTS A resting MPAP above the median (17 mm Hg) was associated with decreased 6MWD (396 +/- 71 vs. 488 +/- 76 m; P < 0.005) and peak Vo(2) (76 +/- 11% vs. 90 +/- 24%; P = 0.05). Resting pulmonary vascular resistance was inversely correlated with 6MWD (r = 0.45; P < 0.05). At 25 and 50W, MPAP above the median (23 and 28 mm Hg) was associated with decreased 6MWD (P < 0.005; P < 0.0005). At peak exercise, MPAP showed no association with 6MWD or peak Vo(2); however, cardiac index was positively (r = 0.45; P < 0.05) and pulmonary vascular resistance was negatively correlated with 6MWD (r = -0.38; P < 0.05). CONCLUSIONS MPAP and resistance in the upper normal range at rest and moderate exercise are associated with decreased exercise capacity and may indicate early pulmonary vasculopathy in patients with systemic sclerosis. Investigations on the prognostic and therapeutic implications of such borderline findings are warranted. Clinical trial registered with http://www.clinicaltrials.gov (NCT00609349).

Expression of the C5a receptor (CD88) on synovial mast cells in patients with rheumatoid arthritis

OBJECTIVE To analyze the immunophenotype and functional properties of synovial mast cells (SyMC) in patients with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS Synovial tissue was obtained from 25 patients with RA and 17 patients with OA. Tissue was dispersed by enzymatic digestion using collagenase. Surface receptor expression on SyMC was analyzed by monoclonal antibodies (MAb) and indirect immunofluorescence staining. Histamine release experiments were performed using the MC agonist recombinant human (rHu) stem cell factor (SCF), the anaphylatoxin rHuC5a, and an anti-IgE antibody. RESULTS In both groups of patients (RA and OA), SyMC were found to react with MAb to IgE, SCF receptor (c-kit, CD117), as well as CD antigens likewise expressed in lung MC (CD9, CD29, CD33, CD43, CD44, CD45). However, a significantly increased proportion of SyMC from RA patients reacted with MAb against C5a receptor (C5aR; CD88), compared with SyMC from OA (mean +/- SD percentage of SyMC reacting with CD88 MAb S5/1 in RA 27.5 +/- 8.6% versus 0.0% in OA, and with CD88 MAb W17/1 in RA 58.3 +/- 15.2% versus 12.5 +/- 15.0% in OA; P < 0.05). Furthermore, in RA, significant histamine release from SyMC above control was induced by rHuC5a, anti-IgE, and rHuSCF, whereas SyMC in OA released histamine after stimulation with anti-IgE and rHuSCF, but not rHuC5a. CONCLUSION SyMC exhibit phenotypic and functional properties similar to MC in other tissues. In patients with RA, but not OA, SyMC express significant amounts of C5aR (CD88) and release histamine in response to rHuC5a. These results indicate a role for SyMC and C5a/C5aR in the pathogenesis of RA.

HLA-DR antigens in systemic lupus erythematosus: association with specificity of autoantibody responses to nuclear antigens.

HLA-DR antigens and autoantibodies to the nuclear or cytoplasmic antigens Ro/SSA, La/SSB, Sm, and RNP were determined in North American and Austrian patients with systemic lupus erythematosus (SLE). Analysis of the association of antibodies to these ribonucleic acid (RNA)-protein antigens with HLA-DR antigens showed that HLA-DR3 was related to the presence of anti-Ro/SSA or anti-La/SSB, or both. In contrast, anti-Sm or anti-RNP, or both were associated with HLA-DR4. HLA-DR5 was associated with absence of these autoantibodies. The data extend evidence for the complexity and heterogeneity of SLE. Moreover, they indicate that, in SLE, genes linked to those coding for HLA-DR antigens, are related to the specificity of autoantibody responses rather than to the primary immunological abnormalities of this disorder.

Consensus statement on blocking the effects of interleukin-6 and in particular by interleukin-6 receptor inhibition in rheumatoid arthritis and other inflammatory conditions

Background Since approval of tocilizumab (TCZ) for treatment of rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA), interleukin 6 (IL-6) pathway inhibition was evaluated in trials of TCZ and other agents targeting the IL-6 receptor and ligand in various RA populations and other inflammatory diseases. This consensus document informs on interference with the IL-6 pathway based on evidence and expert opinion. Methods Preparation of this document involved international experts in RA treatment and RA patients. A systematic literature search was performed that focused on TCZ and other IL6-pathway inhibitors in RA and other diseases. Subsequently, incorporating available published evidence and expert opinion, the steering committee and a broader expert committee (both including RA patients) formulated the current consensus statement. Results The consensus statement covers use of TCZ as combination- or monotherapy in various RA populations and includes clinical, functional and structural aspects. The statement also addresses the second approved indication in Europe JIA and non-approved indications. Also early phase trials involving additional agents that target the IL-6 receptor or IL-6 were evaluated. Safety concerns, including haematological, hepatic and metabolic issues as well as infections, are addressed likewise. Conclusions The consensus statement identifies points to consider when using TCZ, regarding indications, contraindications, screening, dose, comedication, response evaluation and safety. The document is aimed at supporting clinicians and informing patients, administrators and payers on opportunities and limitations of IL-6 pathway inhibition.

The effect of vitamin D supplementation on peripheral regulatory T cells and β cell function in healthy humans: a randomized controlled trial

Increasing evidence supports the role of vitamin D (vitD) in modifying the risk to develop type 1 diabetes (T1D) and other autoimmune diseases. VitD3 might stimulate regulatory T cells (Tregs), a central player in the maintenance of self‐tolerance. In addition, direct effects of vitD on β‐cell function are postulated. The aim of our study was to evaluate the effect of a high dose vitD supplementation on Tregs frequency (%Tregs) and β‐cell function assessed by a mixed meal tolerance test (MMTT) in healthy humans.

Aerobic capacity in adult dermatomyositis/polymyositis patients and healthy controls

OBJECTIVE Assessment of myositis patients has relied on symptoms, strength testing, and serum muscle enzyme activity. Recently, functional assessments and evaluation of strength by dynamometry and of disease activity by magnetic resonance imaging have also been added. Aerobic testing in selected patients has been considered useful. DESIGN Case-control study. SETTING University Hospital, Vienna, Austria. PATIENTS Twenty-two subjects (8 outpatients with chronic dermatomyositis and 3 outpatients with chronic polymyositis, and 11 healthy controls) participated, allowing the identification of 11 case-control pairs matched by age (+/-3 years) and gender (mean age, 48+/-14 yrs; ratio of women to men, 18/4). MAIN OUTCOME MEASURES Target parameters were peak oxygen uptake (peak VO2) to estimate aerobic exercise capacity and peak isometric torque for muscle strength. Creatine phosphokinase (CPK) was measured to assess elevation of muscle enzymes. RESULTS The mean peak VO2 in patients with dermatomyositis/polymyositis was 15.3 mL/min/kg (SD = 5.8) and in the healthy controls 28.7 mL/min/kg (SD = 7.8). Cardiorespiratory capacity expressed as peak VO2 was thus significantly reduced at 53% (p = .0001) of the control value. Muscle strength expressed as peak isometric torque was significantly lower (p = .01) in patients (mean 148+/-73 Nm) when compared to the control group (mean 261+/-99 Nm). In myositis patients peak VO2 and peak isometric torque correlate well with each other (r = .7631; p = .0001), but not at all with serum CPK levels (r = .056; p = .869). CONCLUSION Peak VO2 is significantly diminished in patients with dermatomyositis/polymyositis, compared with age- and sex-matched controls. Serum CPK did not significantly correlate with VO2. Aerobic exercise testing may be a useful assessment parameter in selected patients with dermatomyositis/ polymyositis.

Parenteral administration of 8-methoxypsoralen in photopheresis

BACKGROUND Extracorporeal photochemotherapy (EP) is used for the treatment of cutaneous T-cell lymphoma (CTCL), progressive systemic sclerosis (PSS), pemphigus vulgaris, and rheumatoid arthritis. During this procedure, the oral administration of the photoactive drug 8-methoxypsoralen (8-MOP) results in an unpredictable range of serum levels and in side effects limiting its efficacy. OBJECTIVE To circumvent this limitation, extracorporeally administrable 8-MOP (EX-8-MOP) was developed. It is administered directly to the leukocyte/plasma concentrate in the treatment bag of the EP apparatus before irradiation with UVA light. METHODS Efficacy, tolerance, and side effects of EX-8-MOP were evaluated in 108 consecutive treatments of 16 patients who had previously been treated with oral 8-MOP (91 treatments). RESULTS With EX-8-MOP constant drug levels for UV light exposure were obtained; for equivalent levels only a small fraction of the oral dose (1/250 to 1/500) was required with none of the side effects associated with oral 8-MOP. Effective and reproducible inhibition of lymphocyte proliferation and cell viability was attained. No difference in clinical efficacy could be observed. CONCLUSION EX-8-MOP eliminates the need for premedication and drug level monitoring of 8-MOP and should improve the effectiveness of EP.