Aggressive multi-combination therapy for anti-MDA5 antibody-positive dermatomyositis-rapidly progressive interstitial lung disease.

OBJECTIVES: To elucidate the efficacy and safety of aggressive multi-combination therapy with mycophenolate mofetil, rituximab, and plasma exchange or polymyxin B immobilized fiber column direct hemoperfusion followed by conventional therapy with corticosteroids, calcineurin inhibitors, and intravenous pulse cyclophosphamide in patients with rapidly progressive interstitial lung disease (RPILD) with anti-melanoma differentiation-associated gene 5 (MDA5)-antibody-positive dermatomyositis (DM). METHODS: A total of 23 patients with anti-MDA5 antibody-positive DM-RPILD were enrolled, with nine patients in Group A (treated conventionally before March 2015) and 14 patients in Group B (received aggressive treatment after April 2015). RESULTS: Pretreatment severity of interstitial lung disease (ILD) did not differ between the two groups. However, Group B exhibited a higher cumulative survival rate at 48 weeks than Group A (64.3% vs. 33.3%). The corticosteroid dose, divided by the initial dose at 3 months and 12 months, was significantly lower in Group B than in Group A (p = .046 and .026, respectively). Among the ILD-related deaths in Group B, there was a tendency toward a higher proportion of males and more severe ILD. The incidence of infection did not differ between the groups, but leukopenia was more common in Group B. CONCLUSION: This aggressive multi-combination therapy may improve the survival outcome of patients with anti-MDA5 antibody-positive DM-RPILD. However, careful management of complications, such as opportunistic infections and leukopenia, is essential. Future refinement through longitudinal investigations tracking the long-term efficacy, safety, and cost-effectiveness of this treatment strategy is needed.

A successful plasma exchange in bridging to rituximab for severe neuropsychiatric lupus and lupus nephritis with viral infections and aspiration pneumonia.

Systematic lupus erythematosus (SLE) is a chronic autoimmune disease involving several organs such as the kidneys, skin, vessels, and central nervous system. Neuropsychiatric SLE (NPSLE) is a life-threatening condition that needs treatment with the combination of glucocorticoids and Immunosuppressants (IS). This includes cyclophosphamide and rituximab (RTX) which can lead to several infections. Therapeutic apheresis is an optional treatment for inflammatory diseases and has less risks of infections than IS. Plasma exchange (PE) is one of the most common apheresis, and is recommended for the management of NPSLE. We report a refractory NPSLE case with bacterial pneumonia and cytomegalovirus antigenemia. PE was performed prior to RTX. After the initiation of RTX which was incompatible due to infection such as aspiration pneumonia and cytomegalic virus, PE was scheduled considering the pharmacokinetics of RTX. Her SLE activity was well managed after PE and RTX without flare. PE treatment plan bridging to IS and RTX may effectively work in refractory SLE patients with infections.

[A case of anti-myelin oligodendrocyte glycoprotein antibody-positive multiphasic disseminated encephalomyelitis showing significant recovery after immunoadsorption plasmapheresis].

The patient is an 18-year-old female. She had a history of acute disseminated encephalomyelitis at the age of 6 and 7. She visited our hospital due to acute disturbance of consciousness, quadriplegia, and numbness of left upper and lower extremities. Brain MRI showed multiple DWI/FLAIR high-signal lesions in the bilateral cerebral hemispheres, cerebellum, and brainstem. Qualitative test indicated that serum anti-MOG antibodies was positive, and she was diagnosed with anti-MOG antibody-positive polyphasic disseminated encephalomyelitis. Intravenous mPSL pulse therapy was performed twice, but the symptoms worsened. As a second line treatment, plasma exchange was started. However, she developed transfusion related acute lung injury. Alternatively, she was treated with immunoadsorption plasmapheresis. Her symptoms were significantly improved. This case seems to be valuable because there are few reports showing effectiveness of immunoadsorption therapy on anti-MOG antibody-related diseases, especially for polyphasic disseminated encephalomyelitis.

Clinical parameters of therapeutic apheresis induction in clinically amyopathic dermatomyositis patients with rapid progressive interstitial lung disease.

INTRODUCTION: The purpose of this study is to clarify the clinical parameters of therapeutic apheresis (TA) induction in clinically amyopathic dermatomyositis patients with rapid progressive interstitial lung disease. METHODS: Literature publications prior to November 2021 from PubMed and Ichushi-Web were used. We collected details of TA and clinical features. The data were divided into two groups determined by the outcome, survived and deceased. Then, we estimated clinical parameters between them. RESULTS: There were 151 cases, 134 of which had reported outcomes and 64 of which were positive for the anti-MDA5 antibody. Eighty patients survived. Forty-eight patients were treated with plasma exchange and 34 with polymyxin-B immobilized fibers direct hemoperfusion. Regarding clinical parameters, only the PaO2 to FiO2 (P/F) ratio was useful. The cut-off point of the P/F ratio was 174 on the ROC curve. CONCLUSION: The parameter for induction is considered when the P/F ratio is lower than 200.

Unplanned hemodialysis initiation and low geriatric nutritional risk index scores are associated with end-stage renal disease outcomes.

Patients with end-stage renal disease (ESRD) have a low nutritional status and a high mortality risk. The geriatric nutritional risk index (GNRI) is a predictive marker of malnutrition. However, the association between unplanned hemodialysis (HD) and GNRI with mortality remains unclear. In total, 162 patients underwent HD at our hospital. They were divided into two groups: those with unplanned initiation with a central venous catheter (CVC; n = 62) and those with planned initiation with prepared vascular access (n = 100). There were no significant differences in sex, age, malignant tumor, hypertension, and vascular disease, while there were significant differences in the times from the first visit to HD initiation (zero vs. six times, p < 0.001) and days between the first visit and HD initiation (5 vs. 175 days, p < 0.001). The CVC insertion group had significantly lower GNRI scores at initiation (85.7 vs. 99.0, p < 0.001). The adjusted hazard ratios were 4.002 and 3.018 for the GNRI scores and frequency, respectively. The 3-year survival rate was significantly lower in the CVC + low GNRI group (p < 0.0001). The GNRI after 1 month was significantly inferior in the CVC insertion group. Inadequate general management due to late referral to the nephrology department is a risk factor for patients with ESRD.

The Japanese Society for Apheresis clinical practice guideline for therapeutic apheresis.

Most of the diseases for which apheresis therapy is indicated are intractable and rare, and each patient has a different background and treatment course prior to apheresis therapy initiation. Therefore, it is difficult to conduct large-scale randomized controlled trials to secure high-quality evidence. Under such circumstances, the American Society for Apheresis (ASFA) issued its guidelines in 2007, which were repeatedly revised until the latest edition in 2019. The ASFA guidelines are comprehensive. However, in the United States, a centrifugal separation method is mainly used for apheresis, whereas the mainstream procedure in Japan is the membrane separation method. The target diseases and their backgrounds are different from those in Japan. Due to these differences, the direct adoption of the ASFA guidelines in Japanese practice creates various problems. One of the features of apheresis in Japan is the development of treatment methods using hollow-fiber devices such as double filtration plasmapheresis (DFPP) and selective plasma exchange and adsorption-type devices such as polymyxin B-immobilized endotoxin adsorption columns. Specialists in emergency medicine, hematology, collagen diseases/rheumatology, respiratory medicine, cardiovascular medicine, gastroenterology, neurology, nephrology, and dermatology who are familiar with apheresis therapy gathered for this guideline, which covers 86 diseases. In addition, since apheresis therapy involves not only physicians but also clinical engineers, nurses, dieticians, and many other medical professionals, this guideline was prepared in the form of a worksheet so that it can be easily understood at the bedside. Moreover, to the clinical purposes, this guideline is designed to summarize apheresis therapy in Japan and to disseminate and further develop Japanese apheresis technology to the world. As diagnostic and therapeutic techniques are constantly advancing, the guidelines need to be revised every few years. In order to ensure the high quality of apheresis therapy in Japan, both the Japanese Society for Apheresis Registry and the guidelines will be inseparable.

Vitrectomy for Proliferative Diabetic Retinopathy in a Patient with Heparin-Induced Thrombocytopenia.

INTRODUCTION: In this study, we report a case of proliferative diabetic retinopathy in a patient with heparin-induced thrombocytopenia (HIT) in whom vitrectomy was performed with good results. CASE: A 57-year-old man presented with a chief complaint of decreased visual acuity (VA) in the left eye. Corrected VA of the left eye was 0.03, and ophthalmic examination showed fibrovascular membranes along the vascular arcade and a combined rhegmatogenous-traction retinal detachment with a macular hole. The patient began hemodialysis for diabetic nephropathy in March 2014; thrombocytopenia developed after dialysis was started, and HIT was diagnosed after further evaluation. Argatroban hydrate was being used during dialysis. Treatment was switched from warfarin to argatroban hydrate 6 days prior to vitrectomy being performed on the patient's left eye. Although there was bleeding with somewhat difficult hemostasis during the intraoperative treatment of the fibrovascular membranes, surgery was completed without complications and the postoperative course was good. DISCUSSION: Vitrectomy was performed with good results in this patient with HIT. Treatment with argatroban hydrate during surgery enabled surgery without the danger of intraoperative clotting.

[A refractory case of MPO-ANCA-associated vasculitis presented with gastrointestinal ulcer, rapidly progressive glomerular nephritis and pulmonary multiple nodules].

The patient was a 57-year-old male, who developed bloody stool around May 2006. He was examined by another physician in the department of gastroenterology in our hospital. Gastrointestinal (GI) endoscopy showed a duodenal ulcer, and the biopsy specimen revealed angiitis of the duodenum. He was admitted to our hospital on June 2006. Serum level of creatinine (Cr) was rapidly increased with hematuria and proteinuria. The titer of MPO-ANCA was elevated, and he was diagnosed with microscopic polyangiitis. Steroid pulse therapy was initiated, followed by the administration of prednisolone (PSL : 1 mg/kg/day) and intravenous cyclophosphamide (IVCY). Serum Cr was gradually decreased, but bloody stool was observed from the 10th hospital day. GI endoscopy showed bleeding from the duodenal ulcer. Steroid pulse therapy was performed, and the dose of PSL was increased to 1.5 mg/kg. Endoscopic hemostatic therapy was repeatedly performed without clinical improvement. Pancreatoduodenectomy was performed on the 15th hospital day. However, bleeding from the small intestine was observed repeatedly and the computed tomography of the chest showed cavity-forming nodules, which were diagnosed with angiitis by the biopsy specimen. The additional treatments of steroid pulse therapy, intravenous immunoglobulin therapy, IVCY and Rituximab did not result in favorable response. We report a refractory case of ANCA-related angiitis presented with gastrointestinal ulcer, rapidly progressive nephritis and multiple lung nodules.

Successful treatment of thrombotic thrombocytopenic purpura with repeated plasma exchange in a patient with microscopic polyangitis.

Thrombotic thrombocytopenic purpura (TTP) is in rare cases associated with antineutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, and often has a fatal outcome. We report the case of a 77-year-old woman with microscopic polyangitis (MPA) presenting with TTP. Rapidly progressive renal dysfunction and paralysis and sensory disturbance of the left lower limb were noted. Serum creatinine was 3.95 mg/dl, and the titer of myeloperoxidase-ANCA was 238 EU. She was diagnosed with MPA, and high-dose methylprednisolone was initiated, followed by 60 mg/day of prednisolone. Hemolytic anemia with red blood cell fragmentation, purpura, and thrombocytopenia developed during the course of active MPA. The activity of disintegrin and metalloproteinase with thrombospondin type 1 motifs 13 (ADAMTS13) was moderately decreased (27%). She was diagnosed with TTP, and plasma infusion was initiated, followed by plasma exchange (PE) with 40 units of fresh frozen plasma. Thrombocytopenia continued for more than a month (5-10x10(4)/microl). PE was repeatedly performed two or three times a week during the first 8 weeks from the beginning of PE in addition to prednisolone. Her clinical and laboratory findings gradually improved, and ADAMTS13 activity increased to 68%. The findings in this case suggested that ANCA-associated vasculitis may be involved in the development and the pathogenesis of TTP, and that repeated PE may need to be performed in addition to immunosuppressive therapy.

Early intervention with corticosteroids and cyclosporin A and 2-hour postdose blood concentration monitoring improves the prognosis of acute/subacute interstitial pneumonia in dermatomyositis.

OBJECTIVE: We retrospectively examined the effect of combination therapy with prednisolone and cyclosporin A (CSA) for dermatomyositis (DM) presenting with acute/subacute interstitial pneumonia (A/SIP), the daily CSA dose, and the time from diagnosis of A/SIP to initiation of CSA treatment. METHODS: Subjects were 16 DM patients with A/SIP. Seven patients were treated initially with 1 mg/kg/day prednisolone. When IP was progressive, CSA was added (Group A). Nine patients were treated initially with 1 mg/kg/day prednisolone and 4 mg/kg/day CSA, and 2-h postdose blood concentration (C2) monitoring was used to maintain the serum CSA level at 1000 ng/ml (Group B). RESULTS: Four of 7 patients in Group A (57%) and 1 of 9 patients in Group B (11%) died of respiratory failure related to IP (p = 0.06). Combination therapy with prednisolone and CSA at >or= 200 mg/day initiated within 15 days of diagnosis was effective for treatment of DM-A/SIP. The trough level (C0) and daily CSA dose were higher in Group B (201.3 ng/ml and 200.0 mg/day, respectively) than in Group A (140.0 ng/ml and 166.4 mg/day). CSA was continued in all patients without severe side effects. No patient died of infection. CONCLUSION: Combination therapy of corticosteroids and CSA should be initiated during the early stage of IP. The daily CSA dose should also be controlled with measurement of serum CSA concentration to achieve maximal immunosuppressive effect. C2 monitoring is a useful tool for this control.

Influence of sevelamer on mineral metabolism and hyperparathyroidism in Japanese hemodialysis patients.

In June 2003, sevelamer hydrochloride became widely available in Japan and was expected to control hyperphosphatemia in hemodialysis patients without inducing hypercalcemia. To evaluate the impact of sevelamer therapy on mineral metabolism, we recruited 954 hemodialysis patients from 21 renal units just before the general release of sevelamer in Japan. The serum calcium, phosphate, and parathyroid hormone levels determined on enrollment were compared with those later measured in June 2004. Sevelamer was prescribed for 169 of the 859 patients for whom data were available in 2004. The mean calcium level, phosphate level, and calcium x phosphate product were all significantly reduced during the 12-month study period, but the intact parathyroid hormone (iPTH) level did not change. As a result, the percentage of patients who achieved a calcium x phosphate product of <55 mg(2)/dL(2) was significantly increased, but there were no changes in that of patients who achieved the target ranges for phosphate (3.5-5.5 mg/dL) or iPTH (150-300 pg/mL). Among sevelamer-treated patients, iPTH significantly increased, and this change was more marked in the patients with an initial iPTH level <150 pg/mL. Sevelamer was useful for reducing the serum calcium level and calcium x phosphate product, but hyperphosphatemia and hyperparathyroidism were not improved in our study population at 12 months after the release of sevelamer. A decrease in the calcium load might result in the exacerbation of hyperparathyroidism. However, among patients with relative hypoparathyroidism, sevelamer therapy may be beneficial for the prevention of adynamic bone disease.

[A patient with interstitial pneumonia associated with dermatomyositis who relapsed after reducing cyclosporin-A treatment].

A 67-year-old female noticed dyspnea on exertion associated with the development of erythema in the eyelids and the bilateral fingers, and was admitted to our hospital on July 21, 2004. Proximal muscle weakness in the limbs, heliotrope rash, and Gottron's sign were observed, but the CK level was normal (194 U/l). All autoantibodies except for rheumatoid factor were negative. Hypoxemia and interstitial pneumonia on chest CT images were observed. Based on these findings, a diagnosis of advanced interstitial pneumonia associated with dermatomyositis was made. Combination immunosuppressive therapy was initiated with corticosteroid pulse therapy and cyclosporin-A (Cy-A), resulting in marked improvement. The Cy-A trough concentration was markedly high (456.4 ng/ml). When cytomegalovirus infection developed, the dose of Cy-A was reduced. Although the blood trough concentration of Cy-A was maintained at an adequately high level, the patient died of recurrence of rapidly progressive interstitial pneumonia. Careful observation is required when the dose of Cy-A is reduced for a patient with interstitial pneumonia associated with dermatomyositis. Furthermore, it is suggested that the trough concentration level of Cy-A is not always a useful parameter.

[A case of interstitial pneumonia associated with dermatomyositis effectively treated with cyclosporin-A and cyclophosphamide pulse].

A 46-year-old male demonstrated edematous fingers on both hands in November 2003, and interstitial pneumonia was noted on chest X-ray during a medical check-up in December 2003. Since muscular weakness and fever developed thereafter, and interstitial pneumonia was aggravated on chest X-ray and CT, the patient was admitted to our hospital on March 25, 2004. Heliotrope-like erythema, and Gottron's sign were noted. Laboratory findings showed the following ; LDH 876 U/l ; CK 224 U/l ; CRP 5.68 mg/dl ; and KL-6 3270 U/ml. Autoantibodies such as anti-Jo-1 antibody were all negative. Chest X-ray and CT showed ground-glass opacity in the bilateral lower dorsal regions of the lung, and reduced volume of the inferior lobe. He was diagnosed as having dermatomyositis (DM) associated with progressive interstitial pneumonia. Although a combination of steroid pulse therapy and Cyclosporin-A were administered, the pulmonary lesions became aggravated. Additional intravenous Cyclophosphamide (IVCY) was initiated on the 6th hospital day, and interstitial pneumonia was markedly improved. Cases of progressive interstitial pneumonia associated with DM that are negative for anti-Jo-1 antibody and show a low ratio of CK/LDH are resistant to various treatments. Our case suggested that combination therapy with steroid, Cyclosporin-A, and IVCY is useful for the treatment of progressive interstitial pneumonia with DM.

[A case of systemic lupus erythematosus associated with hypertrophic cardiomyopathy].

The patient was a 37-year-old female, who was diagnosed as having systemic lupus erythematosus (SLE) with nephrotic syndrome in 1991. SLE has been well controlled with a combination therapy of prednisolone, cyclophosphamide and mizoribine. She was admitted to our hospital for chest pain on exertion in June 2002. A grade of 2 systolic murmur was heard along left sternal border and edema in the both lower legs was present. Laboratory findings showed proteinuria and anemia. Serological tests did not show decrease in complements and was negative for autoantibodies including anti-ds-DNA antibody. The serum level of brain natriuretic peptide was 651 pg/ml. On chest X-ray films, there were no remarkable findings. An electrocardiogram showed a pattern of left ventricular hypertrophy with inverted T wave. The heart ultrasonic test recognized asymmetric hypertrophy of the septum, being more prominent in the apex, but there was no obstruction of the left ventricular outflow tract. Examination of an endomyocardial biopsy specimen showed disarray and mild hypertrophy of myocardial cells, which were compatible with hypertrophic cardiomyopathy (HCM), but there were no pathological findings specific for SLE. Additional treatment with beta-blocker under a diagnosis of HCM resulted in a favorable response. Although 7 SLE patients with HCM have been reported, endomyocardial biopsy was not performed. There appears to have been a chance association between SLE and HCM, considering the clinical courses in reported cases and the pathological findings in our case.

[Nine-year's follow up on the appearance of autoantibodies in a child with idiopathic thrombocytopenic purpura subsequently developing lupus with central nervous system manifestations].

We describe a 23-year-old female who developed SLE 9 years after asymptomatic idiopathic thrombocytopenic purpura (ITP) with positive antinuclear antibody (ANA). Although the platelet count was normal before the onset of SLE, the titer of ANA was gradually increased and also autoantibodies, including antibodies to SS-A/Ro, single-stranded DNA (ss-DNA) and nuclear ribonucleoprotein (RNP) changed to positive. At 23 years of age, the patient was admitted to our hospital because of fever, butterfly rash and polyarthritis. Anti double-strand DNA (ds-DNA) antibody and anti Smith antigen (Sm) antibody were positive and the platelet count and titer of complements were decreased. The patient was diagnosed as SLE and treated with 60 mg/day of prednisolone. Despite steroid therapy, psychiatric symptoms appeared. Additional treatments with steroid pulse therapy and double filtration plasmaphresis resulted in the improvement of SLE including the central nervous system manifestations. This case suggested that increased titer of ANA and the appearance of antibodies to SS-A, ss-DNA, RNP, ds-DNA and Sm in ITP patients predict the development of SLE. Routine checkup of autoantibodies is needed to manage ITP with positive ANA.