Thrombotic thrombocytopenic purpura that developed 3 years after systemic lupus erythematosus had remitted with rituximab therapy.

Patients with systemic lupus erythematosus (SLE) occasionally develop thrombotic thrombocytopenic purpura (TTP), which can be fatal. Here, we report a case of TTP developing 3 years after SLE remitted with rituximab (RTX) therapy. A 50-year-old woman was treated with RTX for marked immune thrombocytopenic purpura and autoimmune haemolytic anaemia due to SLE relapse. After induction of remission, she was treated with prednisolone alone without maintenance therapy with RTX. Approximately 3 years later, she was readmitted with marked thrombocytopenia and severe renal dysfunction. On admission, she was diagnosed with TTP for the first time based on severe reduction in a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity and detection of ADAMTS13 inhibitors. CD19+ B cells in the patient's serum increased to 34%, suggesting that B cells had reactivated once the effect of RTX had subsided. The patient was successfully treated with plasmapheresis, glucocorticoid pulse therapy, and RTX. There are no previous reports of newly diagnosed TTP with ADAMTS13 inhibitor production after having achieved remission of SLE with RTX. Therefore, our report also discusses the potential mechanisms of production of new autoantibodies after B-cell depletion therapy.

A Comparison of Line Blots, Enzyme-linked Immunosorbent, and RNA-immunoprecipitation Assays of Antisynthetase Antibodies in Serum Samples from 44 Patients.

Objective To determine the differences between anti-aminoacyl tRNA synthetase (ARS) antibodies among line blots, enzyme-linked immunosorbent assay (ELISA) anti-ARS tests, and RNA-immunoprecipitation (IP) assays. Methods Sera from patients with confirmed or suspected antisynthetase syndrome (ASS) that were positive for either the anti-ARS test or the line-blot assay were used to perform an RNA-IP assay and ELISA to detect individual anti-ARS antibodies. Results Among the 44 patients, 10 were positive only in line-blot assays, 6 were positive only in the anti-ARS test, and 28 were positive in both assays. We compared the accuracy of these assays against the gold standard RNA-IP assay. The κ coefficient was 0.23 in the line-blot assay, but this increased to 0.75 when the cut-off was increased from 1+ to 2+. The κ coefficient was 0.73 in the anti-ARS test. The κ coefficient was 0.85 for positivity in both assays. Patients with ASS that was positive in an RNA-IP assay more frequently had mechanic's hand (62.1% vs. 20%: p=0.031), myositis (51.7 vs. 10%: p=0.028) and more ASS symptoms than those who were positive only in line-blot assays (3.48 vs. 2.2: p=0.019). Conclusions Clinicians need to understand the features of each assay and determine diagnoses by also considering clinical presentations. Diagnoses should not be judged based only on the results of line-blot assays due to the risk of a misdiagnosis from false positives.

A Case of Granulomatosis with Polyangiitis with Various Breast Lesions as the Initial Symptoms: A Case-Based Review.

A 44-year-old woman presenting with pus-like discharge from the nipples visited our hospital for scleritis. Subcutaneous induration and ulceration were found on her breast. She was diagnosed with granulomatosis with polyangiitis (GPA) considering scleritis, sinusitis, cutaneous granuloma formation, and antiproteinase 3-antineutrophil cytoplasmic antibodies and was successfully treated with glucocorticoids. Fifteen months later, she developed pulmonary consolidation and a right breast nodule. Biopsies of the breast nodule showed granulomatous vasculitis, and she was treated with rituximab. While breast involvement in GPA is rare, unilateral breast mass is a typical clinical feature; thus, GPA should be considered in such cases.

A case of wild-type transthyretin cardiac amyloidosis with rheumatoid arthritis.

A 72-year-old woman was diagnosed with rheumatoid arthritis (RA) 6 years ago and was referred to our hospital for the management of RA. She achieved remission with methotrexate, and her arthritis was well-controlled. Two years ago, a routine, preoperative check-up revealed left ventricular hypertrophy. One month before the current admission, she experienced worsening heart failure, and echocardiography and other findings suggested cardiac amyloidosis as the underlying cause. She was then admitted to our hospital. Biopsies of both the myocardium and duodenum showed amyloid deposits, and the initial immunohistochemical examination suggested amyloid A (AA) amyloidosis, as the deposits were slightly positive to anti-AA antibody and were sensitive to potassium permanganate pre-treatment. Thus, cardiac and duodenal AA amyloidosis secondary to RA was considered. However, the patient had no renal lesions and her RA was strictly controlled, findings atypical of AA amyloidosis. On repeat immunohistochemical testing, the cardiac and duodenal samples were negative for AA but stained positive for transthyretin (TTR). The diagnosis of a wild-type TTR amyloidosis (ATTRwt) was confirmed on the basis of an absence of the TTR gene mutation. The patient was successfully treated with diuretics and enalapril, and tafamidis (potent and selective TTR stabiliser). A pacemaker was implanted for concomitant complete atrioventricular block. This case is the first reported case of systemic ATTRwt complicated by RA. The treatment strategy for amyloidosis differs greatly depending on the type of amyloid deposition. Therefore, it is important to properly identify the amyloid protein, even if the diagnosis is complicated by RA.

Physiologic Target, Molecular Evolution, and Pathogenic Functions of a Monoclonal Anti-Citrullinated Protein Antibody Obtained From a Patient With Rheumatoid Arthritis.

OBJECTIVE: In plasma from a patient with rheumatoid arthritis (RA), we previously isolated a human monoclonal anti-citrullinated protein antibody (ACPA), CCP-Ab1, that recognizes various citrullinated antigens. In this study, we aimed to explore the physiologic target of CCP-Ab1 and the role of molecular evolution, through affinity maturation, of this ACPA in the onset and the exacerbation of RA. METHODS: The target protein of CCP-Ab1 was identified in the plasma of a patient with RA and purified under native conditions. Germline-reverted (GL-rev) CCP-Ab1 was generated, and its reactivity was compared to that of mature CCP-Ab1. The functions of CCP-Ab1 and GL-rev CCP-Ab1 in the onset or exacerbation of autoimmune arthritis were analyzed using autoimmune arthritis-prone SKG mice. RESULTS: CCP-Ab1 bound citrullinated fibrinogen under native conditions. In cultures with GL-rev CCP-Ab1, the binding affinity to citrullinated fibrinogen was drastically reduced (P < 0.05). The elements implicated in GL-rev CCP-Ab1 binding to a citrullinated peptide, cfc1-cyc, were almost identical to those implicated in CCP-Ab1 binding. In arthritis-prone SKG mice, CCP-Ab1, but not GL-rev CCP-Ab1, induced significant exacerbation of experimental arthritis (P < 0.05). Increased production of interleukin-6, both in the joint tissue and in the serum, was observed in SKG mice treated with CCP-Ab1 compared to those treated with GL-rev CCP-Ab1 (P < 0.05). Furthermore, the immune complex formed by CCP-Ab1 and fibrinogen was detected at higher concentrations in the synovial tissue of SKG mice administered CCP-Ab1 (P < 0.05 versus control treatment groups). CONCLUSION: These data show that germline-encoded CCP-Ab1, which binds weakly to citrullinated fibrinogen, undergoes hypermutation through the activation of naive B cells by citrullinated peptides/proteins, thereby stimulating high reactivity to citrullinated fibrinogen. These findings deepen our understanding of the role of molecular evolution of ACPAs in the onset and exacerbation of RA.

Autoantibodies reactive to PEP08 are clinically related with morbidity and severity of interstitial lung disease in connective tissue diseases.

Anti-Ro52 autoantibodies (Ro52-autoAbs) appear in the sera of connective tissue disease (CTD) patients with interstitial lung disease (ILD). Studies using patient sera have shown a correlation between the generation of Ro52-autoAbs and the clinical morbidity and severity of CTD with ILD. In this study, we used a single B-cell manipulating technology and obtained 12 different monoclonal Ro52-autoAbs (mRo52-autoAbs) from the selected four patients suffering from severe ILD with a high titer of Ro52-autoAbs in their sera. Western blot analysis revealed that 11 of 12 mRo52-autoAbs bound to the coiled-coil domain of Ro52. Competitive ELISA demonstrated that mRo52-autoAbs competed with each other to bind to Ro52. Epitope mapping showed that two of them specifically bound to a peptide (PEP08) in the coiled-coil domain. We then examined the titer of Ro52-autoAbs in the sera of 192 CTD patients and assessed the relationship between the serum levels of Ro52-autoAbs that were reactive to PEP08 peptide and the clinical morbidity and severity of ILD. Statistical analysis revealed that the production of PEP08-reactive Ro52-autoAbs correlated with the morbidity and severity of ILD in CTD. Assessment of the production of PEP08-reactive Ro52-autoAbs in autoimmune diseases is useful for predicting the clinical morbidity of ILD.

Monoclonal antibody against citrullinated peptides obtained from rheumatoid arthritis patients reacts with numerous citrullinated microbial and food proteins.

OBJECTIVE: To investigate the reactivity of monoclonal anti-citrullinated protein antibody (ACPA) obtained from peripheral blood B cells of rheumatoid arthritis (RA) patients with human autoantigens as well as environmental proteins by determining the essential epitope for the ACPA. METHODS: A human monoclonal ACPA (cyclic citrullinated peptide antibody 1 [CCP-Ab1]) was obtained by screening peripheral blood lymphocytes from 31 patients with RA using a novel monoclonal antibody-secreting cell (ASC) screening system, the immunospot-array assay on a chip. The essential epitope for CCP-Ab1 was determined using epitope mapping. Then, human, microbial, and plant proteins that share the essential epitope identified were searched using BLAST. Finally, representative proteins identified by the search were produced in vitro, and their reactivity with CCP-Ab1 was examined. RESULTS: CCP-Ab1 bound CCP in a citrulline-indispensable manner. In CCP, the 6 amino acid residues required for CCP-Ab1 binding were identified. In the BLAST search, 38 human, 56 viral, 1,383 fungal, 547 bacterial, and 1,072 plant proteins were found to share the essential epitope, and CCP-Ab1 reacted with all of the recombinant citrullinated proteins tested, which included the various environmental factors, such as various plant proteins that are part of the daily diet. CONCLUSION: Our findings demonstrate, for the first time, that a monoclonal ACPA (CCP-Ab1) derived from RA patients cross-reacts not only with various autoantigens but also with numerous plant and microbial proteins. We propose that countless environmental factors, including microbes and diet, may trigger the generation of ACPAs that then cross-react with various citrullinated human autoantigens through molecular mimicry to induce RA.

Accidental cannulation of a femoral central venous catheter into the iliolumbar vein: incidental detection by bone scintigraphy.

Central venous catheterization at the femoral site is associated with higher complication rates of infections and thrombosis than at the jugular or subclavian sites. However, the procedure of insertion at the femoral site is considered safer. We present a unique but dangerous positioning of a left femoral central venous catheter into the iliolumbar vein. We were aware of this accidental cannulation by chance when our patient underwent bone scintigraphy. Although a few cases were reported about accidental cannulation into the ascending lumbar vein, this is the first case where a femoral central venous catheter was misplaced into the iliolumbar vein.

Cytophagic histiocytic panniculitis in a 74-year-old man.

Cytophagic histiocytic panniculitis is a chronic histiocytic disease of the subcutaneous adipose tissue characterised by lobular panniculitis with histiocytes containing blood cell fragments. It is also associated with marked systemic features such as fever, pancytopenia, hepatosplenomegaly, liver abnormalities and coagulopathy. We report a case of cytophagic histiocytic panniculitis in a 74-year-old man successfully treated using combination therapy with prednisolone and cyclosporine A.