Ina Koetter

Mixed response to tocilizumab for ankylosing spondylitis

Since the introduction of tumour necrosis factor (TNF) antagonists for the treatment of ankylosing spondylitis (AS) the majority of patients can be successfully treated. However, individual patients have persistent disease activity. We report on a 36-year-old male patient with HLA-B27-positive AS. No peripheral arthritis or extra-articular manifestation was documented. After insufficient response to standard treatment with non-steroidal anti-inflammatory drugs (NSAIDs), sulfasalazine, methotrexate and all three available TNF antagonists (infliximab, etanercept and adalimumab), the last of these even in an intensified dose of 40 mg weekly, a rescue treatment with the interleukin 6 (IL-6) antagonist tocilizumab (TCZ; Roche Pharma, Roche Pharma, Grenzach-Wyhlen, Germany) was initiated. TCZ was administered intravenously with 8 mg/kg bodyweight every 4 weeks. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) served as clinical response measure. For functional assessment the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Bath Ankylosing Spondylitis Metrology Index (BASMI) were applied. For global …

Optimization of Autologous Stem Cell Transplantation for Systemic Sclerosis — A Single-center Longterm Experience in 26 Patients with Severe Organ Manifestations

Objective. Autologous stem cell transplantation (aSCT) for systemic sclerosis (SSc) has been shown to be effective in recent reports. This aggressive approach and the disease itself are associated with a high mortality. We report our experiences in 26 consecutive patients. Methods. Between 1997 and 2009, 26 patients were scheduled for aSCT. Our standard transplant regimen consists of cyclophosphamide (CYC) and granulocyte colony-stimulating factor (GCSF) for mobilization and CYC plus antithymocyte globulin for conditioning before the retransfusion of CD34 selected stem cells. The major outcome variable was the response to treatment [reduction of modified Rodnan skin score (mRSS) by 25%] at Month 6. Secondary endpoints were the transplant-related mortality and the progression-free survival. Results. Significant skin and lung function improvement of the mRSS was achieved in 78.3% of patients at Month 6. The overall response rate was 91%, as some patients improved even after Month 6. Three patients died between mobilization and conditioning treatment, 2 due to severe disease progression and 1 whose death was considered treatment-related (i.e., GCSF or CYC toxicity). Depending on definitions, transplant-related mortality was 4% and treatment-related mortality 11%. Seven patients experienced a relapse during the 4.4 years of followup. The progression-free survival was 74%. Four patients died during followup and the most frequent causes of death were pulmonary and cardiac complications of SSc. Conclusion. aSCT led to significant improvement in most patients with SSc. The procedure requires further optimization; hence we are modifying our screening and treatment strategy. To minimize infectious complications, CYC for mobilization and GCSF were reduced. We intensified our screening for cardiac involvement and modified our conditioning regimen in case of cardiac involvement.

Disease progression in systemic sclerosis-overlap syndrome is significantly different from limited and diffuse cutaneous systemic sclerosis

Background Systemic sclerosis (SSc)-overlap syndromes are a very heterogeneous and remarkable subgroup of SSc-patients, who present at least two connective tissue diseases (CTD) at the same time, usually with a specific autoantibody status. Objectives To determine whether patients, classified as overlap syndromes, show a disease course different from patients with limited SSc (lcSSc) or diffuse cutaneous SSc (dcSSc). Methods The data of 3240 prospectively included patients, registered in the database of the German Network for Systemic Scleroderma and followed between 2003 and 2013, were analysed. Results Among 3240 registered patients, 10% were diagnosed as SSc-overlap syndrome. Of these, 82.5% were female. SSc-overlap patients had a mean age of 48±1.2 years and carried significantly more often ‘other antibodies’ (68.0%; p<0.0001), including anti-U1RNP, -PmScl, -Ro, -La, as well as anti-Jo-1 and -Ku antibodies. These patients developed musculoskeletal involvement earlier and more frequently (62.5%) than patients diagnosed as lcSSc (32.2%) or dcSSc (43.3%) (p<0.0001). The onset of lung fibrosis and heart involvement in SSc-overlap patients was significantly earlier than in patients with lcSSc and occurred later than in patients with dcSSc. Oesophagus, kidney and PH progression was similar to lcSSc patients, whereas dcSSc patients had a significantly earlier onset. Conclusions These data support the concept that SSc-overlap syndromes should be regarded as a separate SSc subset, distinct from lcSSc and dcSSc, due to a different progression of the disease, different proportional distribution of specific autoantibodies, and of different organ involvement.

Assessment of Synovitis in Erosive Osteoarthritis of the Hand using DCE-MRI and Comparison with that in its Major Mimic, the Psoriatic Arthritis

RATIONALE AND OBJECTIVES To investigate the diagnostic value of high-resolution dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for assessment of synovitis in erosive osteoarthritis (EOA) of the hand and compare the results with those acquired in its potential mimic, the psoriatic arthritis (PsA). MATERIALS AND METHODS Twenty-six patients (17 PsA, 9 EOA) were examined at 3 T. The time course of synovial contrast uptake was measured by ROI analysis using a three-dimensional encoded spoiled gradient-echo sequence. Characteristic parameters of synovial uptake curves (time to peak [TTP], peak value, mean transit time [MTT], area under the curve [AUC], and maximum upslope) of PsA and EOA patients were compared using gamma variate analysis and calculation of the late relative enhancement 15 minutes after contrast administration. RESULTS Enhancement curves of PsA and EOA patients paralleled each other at comparable levels in the early phase after contrast injection without statistical difference in the following calculated characteristic curve parameters: TTP, peak value, MTT, AUC, and maximum upslope. However, significant difference was found in the late relative enhancement 15 minutes after contrast injection (P = .0275) with higher values in EOA patients. CONCLUSION DCE-MRI provides assessment of synovitis in both patients with EOA and PsA. Interestingly, synovial enhancement characteristics were comparable for the most part in these two disorders. However, late enhancement might help in differentiation which is essential for guiding therapy.

Vasoactive Therapy in Systemic Sclerosis: Real-life Therapeutic Practice in More Than 3000 Patients.

Objective. Vasculopathy is a key factor in the pathophysiology of systemic sclerosis (SSc) and the main cause for Raynaud phenomenon (RP), digital ulcers (DU), and/or pulmonary arterial hypertension (PAH). It is so far unknown how patients with SSc are treated with vasoactive agents in daily practice. To determine to which extent patients with SSc were treated with different vasoactive agents, we used data from the German Network for Systemic Scleroderma registry. Methods. The data of 3248 patients with SSc were analyzed. Results. Patients were treated with vasoactive drugs in 61.1% of cases (1984/3248). Of these, 47.6% received calcium channel inhibitors, followed by 34.2% treated with angiotensin-converting enzyme (ACE) inhibitors, 21.1% treated with intravenous (IV) prostanoids, 10.1% with pentoxifylline, 8.8% with angiotensin 1 receptor antagonists (AT1RA), 8.7% with endothelin 1 receptor antagonists (ET1RA), 4.1% with phosphodiesterase type 5 (PDE5) inhibitors, and 5.3% with others. Patients with RP received vasoactive therapy in 63.3% of cases, with DU in 70.1%, and with PAH in 78.2% of cases. Logistic regression analysis revealed that patients with PAH were significantly more often treated with PDE5 inhibitors and ET1RA, and those with DU with ET1RA and IV prostanoids. In addition, 41.8% of patients were treated with ACE inhibitors and/or AT1RA. Patients registered after 2009 received significantly more often ET1RA, AT1RA, and IV prostanoids compared with patients registered prior to 2005. Conclusion. These data clearly indicate that many patients with SSc do not yet receive sufficient vasoactive therapy. Further, in recent years, a marked change of treatment regimens can be observed.

Autologous stem cell transplantation with thiotepa-based conditioning in patients with systemic sclerosis and cardiac manifestations

OBJECTIVE The aim of this study was to find a new and less cardiotoxic conditioning regimen for high-dose chemotherapy and autologous stem cell transplantation (aSCT) in patients with severe SSc and pre-existing cardiac involvement. METHODS Six patients with cardiac involvement were treated for SSc with a conditioning regimen including reduced-dose CYC plus the non-cardiotoxic alkylant thiotepa. All patients received an implantable cardioverter defibrillator (ICD) before aSCT. The response at months 6 and 12 was measured according to reduction of the modified Rodnan skin score (mRSS). CT histography was used to monitor pulmonary manifestations, as were echocardiography, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin for the cardiac involvement. Cardiac events were defined as death or hospitalisation due to heart failure or appropriate discharge of the ICD. RESULTS Between December 2008 and May 2012, four male and two female patients with a median age of 41 years received aSCT. The median mRSS significantly decreased from 26.5 to 18 and 17.5 at month 6 and 12, respectively. The total lung volume also significantly improved. Within the median follow-up of 1.6 years (range 1-3.8) two patients experienced a relapse of SSc, which results in a progression-free survival rate of 66.6%. Three patients experienced ICD discharge. CONCLUSION For patients with SSc and cardiac involvement, the use of thiotepa and reduced-dose CYC is feasible and effective. The rate of ICD discharge underlines the need for protection in these endangered patients. This preliminary experience allowed us to use this regimen for our currently recruiting prospective trial (NCT01895244).

Cholestatic Liver Disease after Rituximab and Adalimumab and the Possible Role of Cross-Reacting Antibodies to Fab 2 Fragments

Background Millions of patients are treated with therapeutic monoclonal antibodies (Tmabs) for miscellaneous diseases. We investigated sera from six patients who received immune globulin, from one patient with refractory anti-neutrophil-cytoplasmic antibody (ANCA)-associated granulomatosis with polyangiitis (GPA) who developed two episodes of acute cholestatic liver disease, one after treatment with rituximab and a second after adalimumab and a healthy control group. Methods Three sera from the patient and six sera from patients who received immune globulin were analyzed for antibodies to rituximab and adalimumab by ELISA. Additionally, sera from the patients and from nine healthy blood donors were coated with the Fab fragment of an unrelated humanized monoclonal antibody, with human Fc proteins as well as a mouse IgG globulin. Results Viral serology for hepatitis A, B, C and autoantibodies specific for autoimmune liver disorders were negative. In all three sera from the patient antibodies to rituximab could be detected, but also antibodies to adalimumab were present even at time points when the patient had not yet received adalimumab, indicating cross reactivity between both substances. Testing against an unrelated human Fab fragment revealed positive results, indicating that the patient had antibodies against human Fab fragments in general. The Fc proteins were negative, and patients’ sera did also not react with mouse IgG globulins. Remarkably, 2 out of 5 patients which were treated with immune globulin had antibodies against human Fab fragments in general whereas in none of the samples from healthy controls antibodies to Fab fragment could be detected. Conclusion This is the first study demonstrating cholestatic liver disease induced by two different Tmabs. Cross - reacting antibodies to Fab2 fragments in general are probably involved. Further studies must show if these Fab2 antibodies in general are related with drug-induced side effects and accelerated drug clearance in patients on Tmab therapy.

Gastrointestinal involvement in granulomatosis with polyangiitis and microscopic polyangiitis: histological features and outcome

Gastrointestinal (GI) involvement in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) is rare.

Rituximab and leflunomide for Wegener’s granulomatosis: a long-term follow-up

Corresponding Author: Joerg Henes MD University Hospital Department of Internal Medicine II Otfried -Mueller -Str. 10 D -72076 Tuebingen Germany Tel.: +49 -7071 -2985138 Fax: +49 -7071 -295138 e -mail: joerg. henes @med.uni -tuebingen.de DISCLOSURES: NON E peer-00580343, version 1 - 28 Mar 2011

SAT0440 New Data on Renal Crisis and Predictive Markers from More Than 3000 Patients

Background To improve detection and follow-up of patients with systemic sclerosis, the German Network for Systemic Scleroderma (DNSS) was founded 2003 and comprise rheumatologists, dermatologists, pulmonologists and nephrologists from more than 40 medical centers. Renal crisis is rare but still a medical emergency in patients with SSc. Objectives Up to date, more than 3000 patients have been grouped into four descriptive disease subsets, i.e. limited cutaneous disease (lcSSc), diffuse cutaneous disease (dcSSc), overlap-syndrome and undifferentiated connective tissue disease (UCTD) with scleroderma features. Methods In this analysis, we have focused on renal crisis within the three main subsets, e.g. lcSSc, dcSSc and overlap-syndromes to identify baseline aspects, which are predictive for future SSc associated renal crisis. Results Recent analyses of up to now 3180 patients revealed that 56% of patients suffer from limited SSc (lcSSc), 34% from diffuse SSc (dcSSc) and 11% of patients were diagnosed with an overlap-syndrome. Eighteen patients developed a renal crisis (1.4%, 18/3180), while 10% (315/3180) were classified with kidney involvement and 8% (257/3180) with proteinuria. Of these, 66.7% (12/18) were diagnosed with the diffuse form of SSc, while just 27.8% (5/18) were diagnosed with lcSSc and 5.6% (1/18) with SSc-overlap syndromes. Predictive factors for renal crisis in our patient cohort included the diffuse form of SSc (odds ratio (OR) 4.6, p=0.005, 95%>confidence interval (CI) 1.6-13.5), a modified Rodnan skin score (mRSS) of more than 15 (OR 4.7; p=0.002, 95%>CI 1.7-13), positive anti-RNA polymerase (RNAP) autoantibodies (OR 24.6, p<0.0001, 95%>CI 6.1-99.5), tendon friction rubs (OR 5.4, p=0.004, 95%>CI 1.7-16.9), hypertension (OR 6.1, p<0.0001, 95%>CI 2.3-16.5), proteinuria (OR 11.8, p<0.0001, 95%>CI 4.3-32.1) and elevated CK-levels (OR 5.1, p=0.01, 95%>CI 1.4-18.9). Interestingly, positive anti-topoisomerase autoantibodies did not predict a higher risk for renal crisis. Patients diagnosed with renal crisis were significantly more frequent on ACE-inhibitors (61.1%, 11/18, p=0.001). Of these, 5 patients also suffered from proteinuria and 7 patients from hypertension. Patients on systemic glucocorticoids had also an increased risk to develop a renal crisis (OR 5.1, p=0.002, 95%>CI 1.8-14.3), independent of the dosage (> or <7.5mg/day). Conclusions Renal crisis has become a rare complication in SSc. The highest risk was associated with the detection of RNAP antibodies, followed by proteinuria, hypertension, tendon friction rubs, elevated CK-levels and a modified Rodnan skin Score above 15. Close monitoring of patients at high risk for SSc associated renal crisis is mandatory. Disclosure of Interest None declared