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In the following case series, we present four patients with different connective tissue diseases (CTD) showing a remarkably positive response on treatment with Obinutuzumab despite former rituximab-non-response in three cases. Demographic data including, age, gender, disease duration, type of involvement, previous as well as concomitant treatments are shown in table 1. Efficacy of treatment was assessed by clinical, laboratory and radiologic findings or global patient assessment for rheumatological symptoms, respectively. Clinical response was defined by an improvement of involved organ functions as well as a reduction of the severity of symptoms. Global tolerance was evaluated.
Two patients with SLE and active glomerulonephritis were treated with Obinutuzumab after rituximab failure. One patient each additionally suffered from antiphospholipid syndrome and neuropsychiatric lupus, respectively. After one cycle with obinutuzumab (1 g, day 0, 14), both patients came off dialysis and showed a stable kidney function over a time period of at least 6 months. One patient had cardiac involvement and highly elevated NT-pro-BNP which markedly decreased after treatment with obinutuzumab. Serological markers such as anti-ds-DNA antibodies and C3-complement consumption strongly improved after therapy.
We further included a patient with anti-Jo1-syndrome who did not respond to her previous treatments including Rituximab, IVIG, Cyclophosphamide and repeated prednisolone pulse therapies. Her disease was manifested by myositis (creatine-kinase (CK) max. 8946 U/L) and CT-confirmed interstitial lung disease with a decreased CO-diffusion capacity of 57.3% expected. After one cycle of obinutuzumab, muscle weakness improved and CK and lactate dehydrogenase levels markedly decreased.
In this patient, CREST syndrome was diagnosed with sclerodactyly, Raynaud’s phenomenon, oesophageal hypomotility, teleangiectasia, calcinosis cutis and pulmonary arterial hypertension and an ANA-titre of 1:10 000 in 2006. In 2013, she developed chronic lymphocytic leukaemia requiring a B-cell depleting treatment for which obinutuzumab was chosen in accordance with current national and European guidelines.
After two cycles of obinutuzumab, the patient had a complete remission of the haematological disease and showed diminishing calcinosis cutis which gradually disappeared completely until the end of the treatment.
Conclusion and pharmacological considerations
Obinutuzumab has recently been proven as an effective option in proliferative lupus nephritis leading to significantly better renal response compared with placebo.1 The data presented here suggest an efficacy of obinutuzumab in different CTD even after failure of rituximab. We hypothesise that the low dependency of complement factors, the altered mechanisms of action including enhanced antibody-dependent cellular cytotoxicity (ADCC) of obinutuzumab and its presumably enhanced efficacy in inflamed tissues are factors supporting our hypothesis that obinutuzumab should be studied in various CTD after rituximab failure, but especially as first-line biologic after failure of conventional disease-modifying antirheumatic drugs (DMARDs).2–5
Patient consent for publication
Handling editor Josef S Smolen
Contributors We ensure that the given number and order of authors was accepted by all participants and that all authors listed were actively taking part on collecting and processing data as well as on writing and reviewing the given manuscript.
Funding The study was supported by: Medical Faculty of University of Heidelberg, Eva Luise and Horst Köhler Foundation (to WM).
Competing interests WM, NB and H-ML have received consulting fees, speaking fees and/or honoraria from Roche (less than US$10 000 each), and unallocated funds for research from Roche (€15 000)
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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