Hans-Peter Tony

IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial

Objectives: The phase III RADIATE study examined the efficacy and safety of tocilizumab, an anti-IL-6 receptor monoclonal antibody in patients with rheumatoid arthritis (RA) refractory to tumour necrosis factor (TNF) antagonist therapy. Methods: 499 patients with inadequate response to one or more TNF antagonists were randomly assigned to receive 8 mg/kg or 4 mg/kg tocilizumab or placebo (control) intravenously every 4 weeks with stable methotrexate for 24 weeks. ACR20 responses, secondary efficacy and safety endpoints were assessed. Results: ACR20 was achieved at 24 weeks by 50.0%, 30.4% and 10.1% of patients in the 8 mg/kg, 4 mg/kg and control groups, respectively (less than p<0.001 both tocilizumab groups versus control). At week 4 more patients achieved ACR20 in 8 mg/kg tocilizumab versus controls (less than p = 0.001). Patients responded regardless of most recently failed anti-TNF or the number of failed treatments. DAS28 remission (DAS28 <2.6) rates at week 24 were clearly dose related, being achieved by 30.1%, 7.6% and 1.6% of 8 mg/kg, 4 mg/kg and control groups (less than p = 0.001 for 8 mg/kg and p = 0.053 for 4 mg/kg versus control). Most adverse events were mild or moderate with overall incidences of 84.0%, 87.1% and 80.6%, respectively. The most common adverse events with higher incidence in tocilizumab groups were infections, gastrointestinal symptoms, rash and headache. The incidence of serious adverse events was higher in controls (11.3%) than in the 8 mg/kg (6.3%) and 4 mg/kg (7.4%) groups. Conclusion: Tocilizumab plus methotrexate is effective in achieving rapid and sustained improvements in signs and symptoms of RA in patients with inadequate response to TNF antagonists and has a manageable safety profile. Trial registration number: NCT00106522.

Autologous Hematopoietic Stem Cell Transplantation vs Intravenous Pulse Cyclophosphamide in Diffuse Cutaneous Systemic Sclerosis: A Randomized Clinical Trial

IMPORTANCE High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION isrctn.org Identifier: ISRCTN54371254.

Evaluation of pannus and vascularization of the metacarpophalangeal and proximal interphalangeal joints in rheumatoid arthritis by high-resolution ultrasound (multidimensional linear array).

OBJECTIVE To evaluate the extent of intraarticular vascularization and pannus formation in metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of patients with rheumatoid arthritis (RA) by high-resolution ultrasound (US). METHODS A newly developed, high-resolution multidimensional linear array US was utilized to obtain longitudinal and transverse scans of joints with active RA (n = 21), moderately active RA (n = 39), or inactive RA (n = 93), and of joints from healthy controls (n = 120). RESULTS Healthy joints had no detectable pannus, whereas pannus could be detected in 52% of the joints with active RA, 82% of the joints with moderately active RA, and 67% of the joints with inactive RA. There was a significant difference in vascularization in the joints of all subgroups of RA patients and those of healthy subjects (P < 0.001). Moreover, vascularization differed significantly among the RA subgroups: inactive versus moderately active RA (P < 0.02) and inactive versus active RA (P < 0.05). Both pannus and vascularization appeared to be localized preferentially on the radial side of the joints. CONCLUSION Evaluation of pannus and the extent of vascularization within the joints of patients with RA by high-resolution US might be helpful in the assessment of disease activity, and thus influence therapeutic strategies.

High resolution ultrasound detects a decrease in pannus vascularisation of small finger joints in patients with rheumatoid arthritis receiving treatment with soluble tumour necrosis factor α receptor (etanercept)

Objective: High resolution ultrasound (HRUS) was used to investigate the effects of tumour necrosis factor α (TNFα) blockade on pannus formation and vascularisation of small finger joints in patients with active rheumatoid arthritis (RA). Methods: Five patients with active RA were treated with etanercept, a soluble TNFα receptor protein, for one month. Before, during, and after treatment the patients were followed up by clinical rheumatological examination, determination of their subjective pain score, blood chemistry, and by HRUS of the second metacarpophalangeal (MCP) joint of the right hand. Results: One month after treatment with etanercept, rheumatological examination showed a significant decrease in a modified single joint rheumatic disease activity index (from 2.9 (SD 0.2) to 1.2 (0.7); p<0.05) in all patients. Moreover, a significant decrease in the general pain score (from 4.7 (0.4) to 1.8 (0.6); p<0.05) and in C reactive protein (CRP) levels was seen (from 3.02 (0.9) to 0.24 (0.1); p<0.05). Concordantly, HRUS showed a significant reduction in pannus vascularisation of the MCPII joints (from 23 602 (5339) to 2907 (1609) colour signals/region of interest, CS/ROI; p<0.001). Pearsons correlation coefficient between the results obtained by HRUS and the clinical response was 0.85. Conclusion: HRUS is promising as an additional useful method in the assessment of RA activity, and probably also in monitoring therapeutic responses.

Anti-CD20 therapy in patients with rheumatoid arthritis: Predictors of response and B cell subset regeneration after repeated treatment

OBJECTIVE B cell depletion with the anti-CD20 antibody rituximab has proven efficacy in patients with rheumatoid arthritis (RA). The effects on B cell homeostasis after repeated treatments and the relationship of certain B cell subsets to clinical response or relapse are currently not known. METHODS In this open-label study, 17 patients with RA refractory to standard therapy were treated with 1 cycle of rituximab. Of these 17 patients, 11 received a second cycle of rituximab therapy. Immunophenotyping was performed before therapy and during B cell recovery. RESULTS Twelve of 17 patients showed a good European League Against Rheumatism response after receiving 1 cycle of rituximab therapy. At the time of B cell recovery, the IgD+,CD27+ memory B cell subset was significantly larger (P = 0.019) in the nonresponder group. Within the group of 12 responders, 6 patients, whose disease was characterized by a significantly higher proportion of overall CD27+ memory B cells before therapy, experienced an early relapse (weeks 24-40 posttreatment). Eleven patients were re-treated, again resulting in a good clinical response. B cell reconstitution followed a similar pattern after each cycle. The early reconstitution phase was characterized by immature CD38++,IgD+,CD10+ B cells, whereas the number of naive B cells increased continuously thereafter. The number of memory B cells was still reduced at the time of the second depletion but recovered to levels similar to those following the first cycle of therapy. CONCLUSION Data derived from repeated B lymphocyte depletion with rituximab in patients with RA suggest that analysis of certain memory B cell subsets provides information on efficacy, response, and late as well as early relapse, consistent with the conclusion that targeting memory B cells is a key to its mechanism of action.

Safety and clinical outcomes of rituximab therapy in patients with different autoimmune diseases: experience from a national registry (GRAID)

IntroductionEvidence from a number of open-label, uncontrolled studies has suggested that rituximab may benefit patients with autoimmune diseases who are refractory to standard-of-care. The objective of this study was to evaluate the safety and clinical outcomes of rituximab in several standard-of-care-refractory autoimmune diseases (within rheumatology, nephrology, dermatology and neurology) other than rheumatoid arthritis or non-Hodgkins lymphoma in a real-life clinical setting.MethodsPatients who received rituximab having shown an inadequate response to standard-of-care had their safety and clinical outcomes data retrospectively analysed as part of the German Registry of Autoimmune Diseases. The main outcome measures were safety and clinical response, as judged at the discretion of the investigators.ResultsA total of 370 patients (299 patient-years) with various autoimmune diseases (23.0% with systemic lupus erythematosus, 15.7% antineutrophil cytoplasmic antibody-associated granulomatous vasculitides, 15.1% multiple sclerosis and 10.0% pemphigus) from 42 centres received a mean dose of 2,440 mg of rituximab over a median (range) of 194 (180 to 1,407) days. The overall rate of serious infections was 5.3 per 100 patient-years during rituximab therapy. Opportunistic infections were infrequent across the whole study population, and mostly occurred in patients with systemic lupus erythematosus. There were 11 deaths (3.0% of patients) after rituximab treatment (mean 11.6 months after first infusion, range 0.8 to 31.3 months), with most of the deaths caused by infections. Overall (n = 293), 13.3% of patients showed no response, 45.1% showed a partial response and 41.6% showed a complete response. Responses were also reflected by reduced use of glucocorticoids and various immunosuppressives during rituximab therapy and follow-up compared with before rituximab. Rituximab generally had a positive effect on patient well-being (physicians visual analogue scale; mean improvement from baseline of 12.1 mm).ConclusionsData from this registry indicate that rituximab is a commonly employed, well-tolerated therapy with potential beneficial effects in standard of care-refractory autoimmune diseases, and support the results from other open-label, uncontrolled studies.

Comparative effectiveness of tumour necrosis factor α inhibitors in combination with either methotrexate or leflunomide

Objective: The objective of this study was to compare the effectiveness of a combination of tumour necrosis factor α (TNFα) inhibitors with either methotrexate or leflunomide in the treatment of patients with rheumatoid arthritis in a real-world setting. Methods: Data from 1769 outpatients enrolled in the German biologics register RABBIT who were treated with one of the TNFα inhibitors adalimumab, etanercept, or infliximab in combination with either methotrexate (n  =  1375) or leflunomide (n  =  394) were included in the analysis. Clinical status including disease activity as well as treatment data were documented by the treating rheumatologist at baseline and at 3, 6, 12, 18, 24, 30 and 36 months of follow-up. Results: Patients treated with a combination of biologics with leflunomide had significantly higher baseline disease activity than those treated with methotrexate. The highest disease activity was found for patients treated with the combination infliximab/leflunomide. After 36 months, the discontinuation rates were 46.3%, 51.3% and 61.5% for combinations of etanercept, adalimumab and infliximab with methotrexate and 53.4%, 63.1% and 67.1% for combinations with leflunomide, respectively. European League Against Rheumatism response rates after 24 months ranged from 74% to 81% for combinations with methotrexate and 72% to 81% for combinations with leflunomide. Conclusion: The current clinical practice is to use methotrexate as a first choice for the combination with TNFα antagonists. In a number of patients methotrexate has to be replaced by another disease-modifying antirheumatic drug. Our data support the view that leflunomide is a useful alternative if methotrexate is contraindicated.

Human regulatory T cells are selectively activated by low‐dose application of the CD28 superagonist TGN1412/TAB08

CD28 superagonists (CD28SAs) are potent T‐cell‐activating monoclonal antibodies (mAbs). In contrast to their benign behavior and marked therapeutic efficacy as activators of regulatory T (Treg) cells in preclinical rodent models, a phase I trial of the human CD28SA TGN1412 (now called TAB08) in 2006 resulted in a life‐threatening cytokine release syndrome (CRS). We studied TAB08‐mediated Treg‐cell activation in a recently developed in vitro system of human PBMCs, which also reproduces the CRS experienced by the healthy volunteers. We show that just as in rodents, CD28SAs are potent activators and expanders of Treg cells from healthy donors and rheumatoid arthritis patients, even under effective blockade of pro‐inflammatory cytokine release by a corticosteroid. Moreover, CD28SA titration identifies a dose range where pro‐inflammatory cytokine secretion from conventional T cells is absent while appreciable Treg‐cell activation is maintained. Finally, we report that low‐dose application of TAB08 to healthy volunteers results in dose‐dependent systemic release of the Treg‐cell signature cytokine IL‐10 in the absence of the pro‐inflammatory factors associated with the CRS of the 2006 TGN1412 study. These results demonstrate the potential of appropriately dosed CD28SA and corticosteroid comedication to mobilize human Treg cells for the treatment of autoimmune and inflammatory conditions.

In Vivo Effects of the Anti―Interleukin-6 Receptor Inhibitor Tocilizumab on the B Cell Compartment

OBJECTIVE Interleukin-6 (IL-6) receptor inhibition by tocilizumab was recently licensed for the treatment of rheumatoid arthritis (RA). IL-6 induces in vitro differentiation of B cells into antibody-forming cells; however, the in vivo effects of IL-6 inhibition on the B cell compartment are currently not known. The purpose of this study was to examine this feature. METHODS Sixteen patients with active RA were treated in an open-label study with tocilizumab (8 mg/kg every 4 weeks). Immunophenotyping was performed at baseline, week 12, and week 24. RESULTS Memory B cell subsets declined significantly during tocilizumab therapy. Preswitch memory B cells decreased from a median of 19.6% to 12.3% at week 24 and postswitch memory B cells declined from a median of 18.6% to 15.0% at week 24 (P = 0.04). In parallel, CD19+IgA+ and CD19+IgG+ B cells decreased significantly. The proportion of IgA-expressing B cells fell from a median of 9.2% at baseline to 4.3% at week 12 and to 3.6% at week 24 (P = 0.01). IgG+ B cells declined from a median of 6.7% at baseline to 4.9% at week 12 (P = 0.007) and 2.8% at week 24 (P = 0.01). In parallel, serum levels of IgA and IgG were significantly diminished at week 24 (P < 0.05). There was a good correlation between relative and absolute numbers of IgA+ B cells with serum IgA at week 24. CONCLUSION Tocilizumab induced a significant reduction in the frequency of peripheral preswitch and postswitch memory B cells. In addition, the number of IgG+ and IgA+ B cells declined and correlated well with reduced serum immunoglobulin levels. The data indicate that IL-6 blockade affects the B cell hyperreactivity in RA patients.

Detection of elevated levels of IL-4, IL-6, and IL-10 in blister fluid of bullous pemphigoid

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease with autoantibodies directed against antigens associated with hemidesmosomes of basal keratinocytes. In addition to autoantibodies and activated complement, cellular mechanisms are crucial for blister formation in this disease. Mononuclear cells, which are the first cells infiltrating BP lesions, mainly belong to CD3, CD4+ T-helper (Th) cells. Elevated concentrations of IL-2, IFNγ, TNFβ, and IL-5 have been recently demonstrated in BP blister fluid. In this study, we were interested in levels of other Thtype cytokines, including IL-3, IL-4, IL-6, IL-10, and GM-CSF in blister fluid of BP. Cytokines were determined by ELISA or bioassay. Levels in the blister fluid from ten BP patients were compared with those in serum samples taken at the time of blister puncture and with those in suction blister fluid of ten healthy volunteers. In blister fluid of BP, we found significantly elevated concentrations of IL-4, IL-6, and IL-10 relative to both concurrent serum samples and suction blister fluid from controls. No differences were detected for either IL-3 or GM-CSF. Our results suggest that IL-4, IL-6, and IL-10 are released at the site of blister formation in BP.