[Safety and efficacy of off-label use of biologic therapies in patients with inflammatory rheumatic diseases refractory to standard of care therapy : Data from a nationwide German registry (GRAID2)]. / Sicherheit und Wirksamkeitshinweise zum Off-label-Einsatz von Biologikatherapien nach Versagen konventioneller Therapien bei Patienten mit entzündlich rheumatischen Erkrankungen : Ergebnisse eines nationalen Registers (GRAID2).

BACKGROUND: The German Registry of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry study collecting data from patients with inflammatory, mainly rheumatic diseases refractory to standard of care therapy and treated with an off-label biologic therapy. The retrospective documentation comprised case history, diagnosis, course of disease (including safety and global efficacy). The objective was to evaluate the global clinical outcome and safety of off-label biologic therapy in clinical practice. RESULTS: Data from 311 patients with an overall observation period of 338.5 patient-years were collected. The mean patients age was 47.8 years with 56.9% females. The most frequently documented diagnoses comprised rejection prophylaxis/therapy after renal transplantation (NTX, 18.3%), ANCA-vasculitides (17.4%), systemic lupus erythematosus (SLE, 10.3%), autoinflammatory fever syndromes (8.4%), autoimmune myositis (7.4%) and pemphigus (5.8%). Documented biologic therapies included rituximab (RTX, 70.1%), tocilizumab (TCZ, 9.3%), infliximab (IFX, 7.1%), anakinra (ANK, 5.5%), adalimumab (ADA, 3.5%), etanercept (ETA, 2.3%) and certolizumab (CTZ, 0.6%). After initiation of off-label biologic treatment, tolerability was assessed by the physicians as "very good"/"good" in 95.5%. Altogether, 275 adverse events were documented and of these, 104 were classified as serious adverse events and occurred in 62 patients. In 19 of these patients severe infections (30.6%) were documented, resulting in a rate of 5.6 severe infections per 100 patient years. A total of six deaths were documented, while five of these cases were rated as not related to the biologics treatment. Notably, the use of RTX in patients with small vessel vasculitides and of TCZ in patients with large vessel vasculitides prior to their approval support their relevance in clinical management of patients with severe diseases. CONCLUSION: The results of this registry together with data of GRAID1 provide evidence that use of off-label biologic therapies in patients with inflammatory rheumatic diseases refractory to conventional treatment did not result in any new safety signal already known for these compounds or subsequently shown by clinical trials in certain entities.

[Off-label biological therapies in patients with large vessel vasculitis and/or polymyalgia rheumatica : Safety and efficacy analysis of a nationwide German registry (GRAID2)]. / Off-label-Biologikatherapie bei Patienten mit Großgefäßvaskulitiden und/oder Polymyalgia rheumatica : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the safety and clinical outcome of biological therapies in patients with large vessel vasculitis (LVV) or polymyalgia rheumatica (PMR) refractory to standard of care therapy in a real-life setting in Germany. METHODS: GRAID 2 (German Registry in Autoimmune Diseases 2) is a retrospective, noninterventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy treated with an initial off-label biological between August 2006 and December 2013. The retrospective documentation comprised case history, diagnosis, course of disease including safety and overall efficacy. RESULTS: Data from 14 patients were collected, 11 with LVV (78.6%) and 3 with isolated PMR (21.4%). Ten patients were treated with tocilizumab (71.4%), while 3 patients received infliximab infusions (21.4%) and 1 patient was treated with rituximab (7.1%). All clinical as well as laboratory efficacy parameters improved substantially. After the first application, tolerability of biologicals was assessed as "very good"/"good" by the physicians in 92.3% of the patients. Altogether, 8 adverse events (AEs) occurred in 4 patients including 3 infections (1 urogenital infection, 2 diverticulitis) representing a rate of 23.6 infections per 100 patient-years. One of these infections (diverticulitis under infliximab treatment) was rated as serious AE, requiring ICU treatment representing a rate of serious AEs of 7.9 per 100 patient-years. No deaths occurred during the observation period. CONCLUSION: With known limitations of a retrospective database, the results of this survey confirm data of smaller case series and proof-of-concept studies and suggest a substantial response to biological therapies in patients with otherwise refractory LVV or PMR with no new safety signals.

[Off-label biologic therapy of ANCA-associated and non-ANCA-associated small-vessel vasculitis : Efficacy and safety analysis of a national registry (GRAID2)]. / Off-label-Biologikatherapie von ANCA-assoziierten und nicht-ANCA-assoziierten Kleingefäßvaskulitiden : Wirksamkeits- und Sicherheitsanalyse eines nationalen Registers (GRAID2).

OBJECTIVE: To evaluate the clinical efficacy and safety of off-label biological therapies in patients with ANCA-associated vasculitis (AAV) and non-ANCA-associated small-vessel vasculitis (nAAV) in clinical practice. METHODS: The German Registry in Autoimmune Diseases 2 (GRAID2) is a national, retrospective, non-interventional, multicentre observational study (August 2006 until December 2013) on patients with autoimmune diseases refractory to standard immunosuppressive therapy treated with off-label biologicals. RESULTS: Data from 64 patients (20.6% of all GRAID2 patients) were collected: 54 patients (84.4%) had ANCA-associated vasculitis (AAV) and 10 patients (15.6%) had non-ANCA-associated small-vessel vasculitis (nAAV). Of the AAV patients, 96.3% were treated off-label with rituximab (RTX) and 3.7% with tumor necrosis factor alpha (TNFα)-inhibitors. Of patients with nAAV, 30% were treated with RTX, 60% with TNFα-inhibitors, and 10% with tocilizumab. The main reasons for off-label biological treatment in AAV patients were pulmonary, renal, or ear, nose, and throat involvement. These manifestations clearly improved in most patients after off-label biological therapy was initiated. Daily glucocorticoid dosage could be reduced. The off-label biological therapy was generally well tolerated. In AAV patients, 4.18 severe infections per 100 patient years were observed. There was one death in the nAAV group caused by fungal infection and ileus. A correlation between this fatality and RTX treatment was regarded as possible. CONCLUSION: Safety and efficacy of off-label RTX-treatment in AAV-patients could be assessed in the GRAID2 data. Results point to good efficacy and safety of RTX in this special patient cohort and support the approval of RTX for AAV induction therapy.

[Efficacy and safety analysis of off-label treatment with biologics in autoinflammatory diseases : Experiences from a German registry (GRAID2)]. / Wirksamkeits- und Sicherheitsanalyse von Off-label-Biologikatherapien bei Patienten mit autoinflammatorischen Erkrankungen : Erfahrungen aus einem Deutschen Register (GRAID2).

OBJECTIVE: To evaluate the safety and efficacy of therapy with biologics in patients with autoinflammatory diseases (AIF) or macrophage activating syndrome (MAS) in a real-life setting in Germany. METHODS: The German Register of Autoimmune Diseases 2 (GRAID2) is a retrospective, non-interventional, multicenter registry collecting data from all patients with inflammatory rheumatic diseases refractory to conventional therapy and treated with initial off-label biologics between August 2006 and December 2013. Patients with MAS could be included without prior treatment with a biologic agent. RESULTS: Data from 26 patients with AIF and 5 with MAS were collected. Of the AIF patients 13 (50%) were diagnosed with adult onset Still's disease (AOSD), 6 (23%) with familial Mediterranean fever (FMF), 4 (15.4%) with tumor necrosis factor-associated periodic syndrome (TRAPS), 1 (3.8%) patient with cryopyrin-associated periodic syndrome (CAPS) and 2 (8%) with undifferentiated fever syndromes. The 5 MAS patients suffered from rheumatoid arthritis (RA) with chronic myeloid leukemia, systemic lupus erythematosus and in 2 cases AOSD. In 1 patient a chronic neurological disease was documented without further differentiaton. All patients with TRAPS were primarily treated with etanercept and all CAPS patients with canakinumab. The AOSD and FMF patients were treated with anakinra as the first line off-label biologic in 6 out of 13 and 5 out of 6 cases, respectively. The MAS patients responded very well or well to therapy in 40% and 60% had a moderate response. There were no non-responders. Within the group of AIF patients the physicians documented a very effective or effective treatment in 38.5%, a moderate response in 30.8% and no response in 30.7%. The tolerance was very good in 5 out of 5 of the MAS and in 92% of the AIF patients. CONCLUSION: The data of this retrospective register provide indications for an effective and safe treatment with off-label biologic medication in patients with AIF and MAS in daily practice.

[Interleukin-6 inhibition as a potential therapeutic target in rheumatic diseases]. / Interleukin-6-Blockade als potenzielles therapeutisches Target bei entzündlich-rheumatischen Erkrankungen.

As a pro-inflammatory cytokine, the 21-kDa glycoprotein interleukin-6 (IL-6) plays a crucial role in the initiation of acute inflammation, as well in the perpetuation of a chronic inflammatory immune response. Thus, IL-6 might be involved in the pathogenesis of various autoimmune diseases. So far, the IL-6-rezeptor-antibody tocilizumab (TCZ, RoActemtra®) is the only approved drug for the treatment of IL-6-mediated disease, including rheumatoid arthritis (RA), systemic juvenile idiopathic (sJIA) and polyarticular juvenile arthritis (pJiA), as well as Castleman's disease (in Japan only). In recent years, an emerging number of case reports and small uncontrolled case series have reported on the successful treatment of various other chronic inflammatory diseases, which has resulted in the idea of a broad therapeutic potential for IL-6 blockade. Numerous IL-6 targets are currently in phase II/III study programs for RA as well as for other indications. This review focuses on the development of tocilizumab and other IL-6 targets as a therapeutic option for various diseases in rheumatology.