Interferon therapy in rheumatic diseases: state-of-the-art 2010

Purpose of revie

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.</jats:sec

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

Tocilizumab for the Treatment of Familial Mediterranean Fever&mdash;A Randomized, Double-Blind, Placebo-Controlled Phase II Study

Background: The purpose of this trial was to evaluate the effectiveness and safety of the IL-6 receptor antibody Tocilizumab (TCZ) in the treatment of Familial Mediterranean Fever (FMF). Methods: This was a randomized, double-blinded, placebo-controlled phase II trial in adult patients with active FMF and an inadequate response or intolerance to colchicine (crFMF). The physician&rsquo;s global assessment of disease activity (PGA), based on a five-point scale for six symptoms, was used as a clinical score, which had to be &gt;2 at screening, together with elevated c-reactive protein (CRP) or erythrocyte sedimentation rate (ESR) and serum amyloid A (SAA) levels, to be eligible for inclusion. Patients were randomized 1:1 to either receive monthly TCZ or a placebo over a period of 24 weeks. The primary endpoint was the number of patients achieving an adequate response to treatment at week 16, defined as a PGA of &le;2 and normalized ESR or CRP and normalized SAA. Results: We randomized 25 patients with a median age of 31 years. At week 16, an adequate treatment response was achieved by two patients in the TCZ and none of the patients in the placebo arm (p = 0.089). SAA levels normalized with TCZ, but not with the placebo (p = 0.015). Conclusion: In this first randomized, placebo-controlled study in patients with active crFMF, more patients in the TCZ arm experienced a response to treatment in comparison to those receiving the placebo. As the prevention of amyloidosis is a major treatment goal in FMF, the normalization of SAA in TCZ-treated patients is essential. These findings have to be confirmed in a larger trial