Kanae Kubo

Systemic lupus erythematosus and thrombotic thrombocytopenic purpura: a case report and literature review.

AbstractWe describe a patient with systemic lupus erythematosus (SLE) who developed severe and acute thrombotic thrombocytopenic purpura (TTP). Detection of the fragmentation of peripheral red blood cells (RBC) helped the early diagnosis of TTP and the patient was rescued by extensive plasma exchange started promptly after the diagnosis. Because manifestations of TTP are similar to those in SLE, it is sometimes difficult to make an accurate diagnosis of TTP in SLE patients. We emphasise here the significance of the early diagnosis of TTP by the observation of fragmented RBC and the intensive therapy, including plasma exchange, for this very severe condition.

Antiproteinuric effect of ARB in lupus nephritis patients with persistent proteinuria despite immunosuppressive therapy

Recent immunosuppressive treatments for lupus nephritis have improved renal survival rate, however, there still exists lupus nephritis refractory to these treatments. Angiotensin receptor blockers (ARBs) are known not only to decrease blood pressure but also to have an independent renoprotecting effect by interrupting renin-angiotensin system. The aim of this study was to evaluate whether ARBs have an additive effect on refractory lupus nephritis. Enrolled in this trial were twelve patients with lupus nephritis who were diagnosed by renal biopsy and remained proteinuria despite corticosteroids and/or immunosuppressive treatments. ARB, losartan or candesartan, was administered for six months. Various clinical parameters were compared before and after ARB administration. Proteinuria decreased after ARB treatment in 83% of the patients and the median amount of proteinuria significantly decreased from 2530 mg/gCr to 459 mg/gCr (P = 0.03). In addition, serum albumin and cholesterol levels were significantly improved. Systolic blood pressure significantly decreased, but none had symptoms of hypotension. The antiproteinuric effect of ARB did not correlate with the reduction of blood pressure. Interestingly, higher total complement activity levels before ARB treatment were associated with a greater reduction of proteinuria. The addition of ARB would be a safe and effective treatment for lupus nephritis with persistent proteinuria despite corticosteroids and/or immunosuppressive treatments.

Protein-losing enteropathy associated with hypocomplementemia and anti-nuclear antibodies.

Abstract: We report a case of protein-losing enteropathy associated with an autoimmune disorder, presumably systemic lupus erythematosus. Although typical manifestations of systemic lupus erythematosus were lacking, a high serum cholesterol level, a low serum complement level, positivity for anti-nuclear antibody, and positivity for anti-single-strand DNA antibody suggested an autoimmune mechanism as the cause of the condition. Although immunohistological examination of duodenal and ileal biopsy specimens failed to reveal deposits of immune complex or complement in the vessels, capillary hyperpermeability was suspected as the mechanism of the condition.

Neuromyelitis optica spectrum disorder complicated with Sjogren syndrome successfully treated with tocilizumab: A case report.

A 38-year-old woman with relapsing longitudinal extensive transverse myelitis and Sjogrens syndrome (SS) was admitted with lower extremity muscle weakness. Studies showed high serum titer of anti-aquaporin4 antibody and gadolinium-enhanced-MRI T1-weighted lesions within thoracic cord. Clinical findings suggested neuromyelitis optica-spectrum disorder (NMO-SD). High-dose corticosteroids, plasma exchange and cyclophosphamide were not effective. After starting tocilizumab, her neurological findings gradually improved. This report describes the first evidence to show tocilizumab could be effective for NMO-SD with SS.

Tocilizumab-induced leucocytoclastic vasculitis in a patient with rheumatoid arthritis

SIR, Biologic agents are widely used for the treatment of RA in today’s treat-to-target era [1]. Although their safety and efficacy are acceptable, autoimmune adverse events associated with biologics have increasingly been reported. According to the BIOGEAS Study Group [2], vasculitis and SLE are the most frequent autoimmune diseases induced by biologics, and most reports were associated with anti-TNF agents. Among 139 cases of vasculitis, 137 cases were related to anti-TNF agents, except for 1 case related to rituximab and 1 to abatacept. Cutaneous involvement is most frequent, and leucocytoclastic vasculitis has been reported only with anti-TNF agents [3]. We report the first case of tocilizumab-induced leucocytoclastic vasculitis in a patient with RA. Written informed consent for publication of this case was obtained from the patient. A 62-year-old Japanese woman had been suffering from seropositive RA for 23 years. She had a history of treatment with infliximab for 5 years, but this was switched to etanercept because of secondary failure, and etanercept was switched to tocilizumab because of primary failure. Subsequently she was treated with tocilizumab 8 mg/kg/ month, MTX 4 mg/week and prednisolone 3 mg/day for 2.5 years, and low disease activity was achieved. In April 2013 she presented with abdominal pain and arthralgia with a low-grade fever. Three weeks later she noticed the emergence of multiple palpable purpura on her forearms, buttocks, thighs and lower extremities (Fig. 1A). Most of her proximal interphalangeal joints were swollen and the 28-joint DAS (DAS28) increased to 5.98. ESR increased to 38 mm in the first hour (normal value <16 mm in women) and CRP was 5.35 mg/dl (normal value <0.3 mg/dl). Platelet count, renal function and urinalysis were normal. Serum IgG, IgA and IgM levels and complement factors (CH50, C3 and C4) were within normal limits. Serum anti-streptolysin O was negative. ANA and ANCA were negative. Circulating immunocomplex and cryoglobulin were absent. Upper gastrointestinal endoscopy showed normal gastric mucosa, and faecal occult blood testing was negative. Skin biopsy of the purpura of the lower legs revealed leucocytoclastic vasculitis with granulocyte invasion to small vessel walls in the dermis, nucleus disruption and extravasation of erythrocytes (Fig. 1B). Immunofluorescent staining did not show IgA deposition. According to the 1990 ACR criteria, Henoch Schönlein purpura can be diagnosed from clinical and pathological findings even when lacking IgA deposition. However, this case did not fulfil the definition of IgA vasculitis of the 2012 Revised International Chapel Hill Consensus Conference classification. We diagnosed this case as leucocytoclastic vasculitis. The cause of the leucocytoclastic vasculitis was difficult to ascertain because no agents were newly administered before this episode. We considered the possibility of tocilizumab-induced leucocytoclastic vasculitis and discontinued the administration of tocilizumab. Subsequently palpable purpura rapidly disappeared, so we concluded that leucocytoclastic vasculitis was induced by tocilizumab. Because of sustained arthritis and abdominal pain,

Characteristics of granulomatosis with polyangiitis patients in Japan

Abstract Objectives. Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a disease with significant ethnic differences. Reports on characteristics of Japanese granulomatosis with polyangiitis (GPA) patients are limited, and this study was undertaken to determine the characteristics of Japanese GPA patients. Methods. This was a retrospective chart study of 24 Japanese GPA patients. GPA was defined according to the European Medicines Agency algorithm. Results. The percentage of MPO-ANCA-positive patients was 33.3%, higher than the percentages reported in studies from Western countries. MPO-ANCA-positive GPA patients differed from PR3-ANCA-positive GPA patients in organs involved at diagnosis with MPO-ANCA-positive patients having nose and sinus involvement less frequently compared to PR3-ANCA-positive patients. Interstitial lung infiltrates were more common among MPO-ANCA-positive GPA patients compared to PR3-ANCA-positive GPA patients. Conclusion. Among Japanese GPA patients, the proportion of MPO-ANCA-positive patients is higher compared to reports from Western countries, and those patients are often different from the classical picture of GPA.

IgG4-related disease

Immunoglobulin G4‐related disease (IgG4‐RD) is a regional or systemic fibro‐inflammatory disease of unknown etiology. It presents a distinctive histopathological appearance of dense lymphoplasmacytic infiltrates with abundant IgG4‐positive plasma cells, storiform fibrosis and obliterative phlebitis with the appearance of inflammatory swelling or tumefactive lesions. This new disease entity includes a wide variety of diseases such as Mikulicz disease, autoimmune pancreatitis, Riedel thyroiditis, interstitial nephritis and retroperitoneal fibrosis. Glucocorticoid therapy can resolve the clinical and pathological abnormalities and impaired organ function. IgG4‐RD was recognized internationally in 2011, and new evidence has accumulated regarding its pathogenesis, clinical features and treatment. In this review, we outline our present understanding of IgG4‐RD.

Macrophage activation syndrome associated with tocilizumab treatment in adult-onset Still’s disease

We read with interest the article by Bannai et al. published in the March 2016 issue titled ‘‘Successful tocilizumab therapy in seven patients with refractory adult-onset Still’s disease [1].’’ In this article, the authors describe seven patients with adult-onset Still’s disease (AOSD) who were treated with tocilizumab (TCZ), including a patient who developed macrophage activation syndrome (MAS) following TCZ treatment, and they argue for the need to monitor patients for signs of MAS when administering TCZ to patients with active AOSD. At our institution, there was also a patient with AOSD who developed signs of MAS after administration of TCZ for active AOSD. Development of MAS after the administration of TCZ for AOSD may be more common than previously thought, and rheumatologists need to be careful when initiating TCZ for active AOSD. The patient was a Japanese female with a previous history of Grave’s disease that had been treated with radioiodine ablation and surgical therapy. She developed spiking fever, arthralgia, and salmon colored rash, and she was diagnosed with AOSD when she was 19 years old. She was initially treated at another hospital with high-dose steroids, intravenous cyclophosphamide, cyclosporine (CyA), and leukocytapheresis (LCAP), and her symptoms resolved. Half a year later, while being treated with betamethasone 1.5 mg/ day and cyclosporine, she experienced a relapse. LCAP was performed again but was ineffective. Betamethasone was increased to 3 mg/day and methotrexate was started; however, her fever persisted, and she was referred to our hospital for further therapy. Upon referral to our hospital, she was taking betamethasone 3 mg/day, methotrexate 15 mg/week, and cyclosporine 100 mg/day, and she still had spiking fever, rash, and arthralgia. C-reactive protein level (CRP) was 20.21 mg/dl, and serum ferritin was 24,165 ng/ml. Her steroids were further increased to prednisolone (PSL) 40 mg/day, and the dosage of CyA was also increased. After the fever resolved and CRP decreased to 4.91 mg/dl, TCZ was administered at 8mg/kg. Within a day, she developed a fever. Her platelet levels decreased from 2.8 10/mL to 1.6 10/mL in two days, and ferritin increased to 14,254 ng/mL. AST increased to 91 IU/L, and fibrinogen decreased to 270 mg/dl. Her laboratory data met the PRINTO diagnostic criteria for MAS [2]. CMV antigenemia was negative, and there were no signs suggesting an infectious cause for MAS. She was treated with pulse methylprednisolone therapy followed by PSL 65 mg/day. CyA was increased to 350 mg/day to obtain a trough level of 135 ng/ml. After her fever, rash, and arthralgia resolved and CRP levels normalized, tocilizumab was again administered. There were no signs of MAS, and TCZ was continued every two weeks along with steroids, methotrexate, and cyclosporine, and her steroids were successfully tapered. Half a year later, her steroids had been tapered to PSL 15 mg/day and her disease was still stable, and tocilizumab treatment was changed from 8 mg/kg every two weeks to 8mg/kg every four weeks with no signs of relapse. Three years later, while taking PSL 15 mg/day, CyA 300 mg/day, and MTX 7.5 mg/week in addition to tocilizumab, she expressed wishes to have a child. Although she experienced minor flares that required short-term increase in steroids, methotrexate successfully was tapered and discontinued. Now, five years after initiation of TCZ treatment, she is being treated with tocilizumab 8 mg/kg every four weeks, PSL 6 mg/day, and CyA 200 mg/day and is in remission. Although we cannot decisively conclude if TCZ administration caused MAS in this patient, the case reported by Bannai et al. [1] and this case suggest that MAS might be induced when TCZ is administered to active AOSD patients. It has been suggested that various inflammatory cytokines in addition to IL-6, including IL-1, IL-18, and IFN-g, play important roles in the development of MAS [3], and it is possible that blocking of a single cytokine by tocilizumab may lead to increased levels of other inflammatory cytokines, perhaps through a negative feedback loop, and thus MAS. There have been many reports of TCZ therapy successfully initiated in highly active AOSD with higher CRP and/or ferritin levels compared to our patient [4–7]. Traditional disease activity parameters such as CRP and ferritin are not able to predict the development of MAS following TCZ therapy, and other disease parameters that can predict this phenomenon need to be investigated. In the meantime, rheumatologists need to be careful in monitoring for signs of MAS when administering TCZ for active AOSD.

Tracheobronchitis with dyspnea in a patient with ulcerative colitis.

We herein report the case of a 42-year-old man with a one-year history of ulcerative colitis who presented with exacerbated bloody diarrhea, a productive cough and increasing breathing difficulties. Colonoscopy revealed typical deep ulcers in the rectosigmoid colon and atypical multiple sucker-like ulcers in the transverse colon, and computed tomography of the chest demonstrated wall thickening of the trachea and bronchi. In addition, bronchoscopy showed ulcers in the trachea, and histopathology disclosed findings of necrosis and inflammation of the subepithelial tissue of the trachea. Based on these findings, the patients respiratory symptoms were strongly suspected to be due to ulcerative colitis-related tracheobronchitis. Treatment with systemic corticosteroids subsequently resulted in a rapid clinical improvement.

Three cases of lupus nephritis patients with serum interleukin-32γ detection

Purpose Interleukin-32 (IL-32) is an inflammatory cytokine that is associated with the pathogenesis of several connective tissue diseases. We measured serum IL-32γ concentrations of systemic lupus erythematosus (SLE) patients. Methods Serum samples were obtained from SLE patients (n = 51), and healthy controls (n = 15). Serum IL-32 concentrations were measured using ELISA. Clinical information was obtained from medical records. Results Serum IL-32γ was detectable in three cases of SLE patients, whereas it was not detected in any healthy controls. Case 1: a 44-year-old female with lupus nephritis (LN) (Class II) and antiphospholipid antibody syndrome. Serum IL-32γ was 5.1 pg/ml. Case 2: a 30-year-old female with a history of diffuse proliferative LN (Class IV G (A/C)) and pulmonary hemorrhage. Serum IL-32γ was 8.9 pg/ml. Case 3: a 45-year-old female with chronic LN. Serum IL-32γ was 9.1 pg/ml. All three cases of IL-32γ-detectable patients had histories of LN and one had an active disease. In the context of LN, serum IL-32γ was detectable in 18.8% (three of 16) of SLE patients with histories of LN. Conclusion We suppose that IL-32γ could contribute to the pathogenesis of renal diseases in some LN patients.