Takamasa Murosaki

Abrupt development of sarcoidosis with a prodromal increase in plasma osteopontin in a patient with rheumatoid arthritis during treatment with etanercept.

To the Editor: Biologic disease-modifying antirheumatic drugs (DMARD) targeting tumor necrosis factor-α (TNF-α) are very efficacious and the number of patients with rheumatoid arthritis (RA) treated with these drugs is increasing rapidly. Because granulomatous diseases as typified by sarcoidosis are considered to develop in the Th1 cytokine milieu dominated by interferon-γ (IFN-γ) and TNF-α, anti-TNF-α agents have been used for treatment of sarcoidosis. Reports show that infliximab is effective, while etanercept is not, in the treatment of sarcoidosis1,2. In contrast, anti-TNF-α agents may have induced sarcoidosis in patients with RA and spondyloarthropathy3–6. The patient we describe had acute onset of sarcoidosis in several organs simultaneously after a long period of remission of RA while receiving etanercept. Based on serum and plasma levels of laboratory indicators related to sarcoidosis, the condition might have developed as quickly as within 1 or 2 months. A 52-year-old Japanese woman was diagnosed with RA in 1980 and had been treated with several DMARD such as injectable gold salt, sulfasalazine, actarit, methotrexate, and mizoribine with no appreciable effects. Leflunomide was started in … Address correspondence to Dr. S. Takatori, Division of Rheumatology and Clinical Immunology, Jichi Medical University, Yakushiji 3311-1, Shimotsuke-shi, Tochigi 329-0498, Japan. E-mail: stori{at}jichi.ac.jp

Difference in relapse-rate and clinical phenotype by autoantibody-subtype in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis

Abstract Objective: To correlate the serotype specificity to myeloperoxidase (MPO) and proteinase-3 (PR3) with clinical characteristics in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Methods: Clinical characteristics and outcomes of patients with AAV in our division from 2005 to 2014 were retrospectively compared on the basis of ANCA subtype. Results: We collected the data from 88 patients with MPO–ANCA vasculitis, and 17 with PR3-ANCA vasculitis. Patients with PR3-ANCA vasculitis were younger, and had higher involvement-rates in the eye, nose, and ear. In both MPO- and PR3-ANCA vasculitis, the most frequently involved organ was the respiratory system. Interstitial pneumonia was more frequent in MPO-ANCA vasculitis (52.3% versus 5.9%, p < 0.01), whereas nodular shadow was more frequent in PR3-ANCA vasculitis (9.1% versus 58.8%, p < 0.01). Multivariable Cox proportional hazard regression analysis showed that the hazard ratio of PR3-ANCA for relapse was 2.48 (95% confidence interval 1.14–5.42, p = 0.02). There was no difference in the survival and the progression to end-stage kidney disease and respiratory failure between the two vasculitides. Conclusion: MPO-ANCA vasculitis was a predominant form of AAV in Japan. Classification based on ANCA subtype would be clinically relevant in the prediction of organ involvement and relapse.

Invasive sphenoid sinus aspergillosis mimicking giant cell arteritis.

Dear Editor, Giant cell arteritis (GCA) is a granulomatous vasculitis of the elderly with frequent ocular manifestations, including sudden loss of vision, amaurosis fugax, and diplopia. The most common presentation is sudden loss of vision, which requires prompt initiation of glucocorticoid therapy before a histological diagnosis is made by temporal artery biopsy. Here we present a case of probable GCA, featuring temporal pain, fever and sudden loss of vision, with a final diagnosis of invasive sphenoid sinus aspergillosis. An 80-year-old man presented to a local hospital with low-grade fever and left temporal pain for 2 months. He had a history of hypertension and cerebral infarction, but did not have diabetes mellitus. Computed tomography (CT) scan of the head reportedly showed an old lacunar infarct. Tension headache was suspected, but nonsteroidal anti-inflammatory drugs were ineffective. Three days before admission, he suddenly lost vision in his left eye. The patient was referred to our hospital with suspected GCA. On examination, his temperature was 37.5°C and his blood pressure was 146/ 62 mmHg with no laterality. He complained of headache localized to the left temporal region, but the bilateral superficial temporal arteries showed no tenderness on firm palpation. Visual acuity was no light perception in his left eye. Moreover, mild left ptosis and disturbance of left oculomotor nerve function were observed. There was no jaw claudication, neck bruit, or heart murmur. Laboratory tests showed a leukocyte count of 7500/lL, hemoglobin of 9.7 g/dL, erythrocyte sedimentation rate (ESR) of 72 mm/h, and C-reactive protein (CRP) of 3.89 mg/dL. Contrast-enhanced thoracoabdominal CT scan detected no abnormalities. Head CT scan showed increased density (to soft tissue level) in the right maxillary sinus and sphenoid sinus, suggesting the presence of sinusitis. Color Doppler ultrasonography of the temporal artery revealed arterial wall thickening without stenosis, which was compatible with GCA. Funduscopic examination by an ophthalmologist revealed a normal optic disc. We also consulted a neurologist about the patient’s oculomotor palsy. Brainstem infarction was considered most likely, and examination by magnetic resonance imaging (MRI) was recommended. However, we could not perform MRI immediately, because he had a history of hip joint replacement and the composition of his prosthesis was unknown. A normal optic disc is uncommon in GCA with visual impairment. However, we considered that it could be possible if the patient had early anterior ischemic optic neuropathy or posterior ischemic optic neuropathy. Thus, we diagnosed suspected GCA, and

Prediction of the therapeutic response to methotrexate at 24 weeks by methotrexate–polyglutamates concentration in erythrocytes at 8 weeks in patients with rheumatoid arthritis

Abstract Objectives: The objective of this study is to evaluate the pharmacokinetics and pharmacodynamics of methotrexate–polyglutamates (MTX-PGs) in erythrocytes in patients with rheumatoid arthritis and correlate them with the efficacy. Methods: MTX-PG concentrations in erythrocytes were measured in 42 MTX-naïve patients repeatedly for 24 weeks by high-performance liquid chromatography. In 56 patients receiving stable MTX doses for at least 12 weeks, the correlation between MTX doses and MTX-PG concentrations was examined. The efficacy was measured by the change of DAS28CRP (ΔDAS28CRP). Results: There were moderate correlations between MTX dose and MTX-PG 3, 4, and 5. At 24 weeks, MTX-PG2, 3, 4, and 1–5 were higher in patients with ΔDAS28CRP >1.2 than in those with ≤1.2. The cutoff value of MTX-PG1-5 to discriminate ΔDAS28CRP >1.2 from ≤1.2 at 24 weeks was 68.7 nM. Among 20 patients with MTX-PG1-5 > 50.6 nM at 8 weeks, seven already improved at 8 weeks and additional 11 improved at 24 weeks (p < 0.001). On the contrary, among the nine patients with MTX-PG1-5 ≤ 50.6 nM at 8 weeks, none improved at 8 weeks and only one improved at 24 weeks (p = 0.500). Conclusions: Erythrocyte MTX-PGs might be a potential indicator and predictor of MTX efficacy.

Posterior ischemic optic neuropathy in a patient with granulomatosis with polyangiitis (Wegener’s)

Ocular involvement is common in granulomatosis with polyangiitis (GPA), with the main manifestations including scleritis, ulcerative keratitis, conjunctivitis, optic neuritis, and compression symptoms due to periorbital pseudotumor [1]. Here, we present a patient with GPA who complained of the sudden onset of blurred vision bilaterally and was finally diagnosed as having posterior ischemic optic neuropathy (PION). A 60-year-old woman who had GPA presented with blurred vision in the left eye for 1 week. The diagnosis of GPA had been established 3 months earlier, based on the presence of destructive sinusitis, perforation of the nasal septum, scleritis, multiple pulmonary granulomas, and positive anti-neutrophil cytoplasmic antibody for proteinase 3 (PR3-ANCA). Pathologic examination of a lung nodule revealed a typical palisading granuloma with geographic necrosis. She had been treated with oral prednisolone (1 mg/kg/day) plus intravenous cyclophosphamide pulse therapy (750 mg). Warfarin was also started for deep venous thrombosis. On admission, she was taking prednisolone at 25 mg/ day. She had no fever or headache, and her general condition was good. The sclera was hyperemic, but she had no pain. Her visual acuity (VA) was 16/20 in the right eye and hand movement in the left eye. A relative afferent pupillary defect was present. Funduscopic examination was unremarkable, with the optic disc appearing normal. Laboratory findings were as follows: C-reactive protein (CRP) was 0.06 mg/dl (normal \ 0.06), erythrocyte sedimentation rate (ESR) was 18 mm/h, and PR3-ANCA was negative. Urinalysis was normal. A chest radiograph revealed no recurrence of granulomas. Gadolinium-enhanced magnetic resonance imaging (MRI) of the orbit was normal, including the optic nerve. She also had mild diabetes (HbA1c: 6.9 %) and hypertension. Because of these conditions together with no evidence of exacerbation of GPA and the normal-appearing optic disc, she was diagnosed as having nonarteritic PION. Treatment was started with warfarin, aspirin, and vitamins. On the next day, the VA of the right eye decreased to 40/200. Although there was no evidence of active vasculitis, this rapid decrease of VA was treated with intravenous methylprednisolone pulse therapy (500 mg/day) for 3 days. Subsequently, VA improved to 10/20 in the right eye and 40/200 in the left eye. However, VA deteriorated again in both eyes 3 days later. Because of the marked response to glucocorticoid pulse therapy, it was considered that she had active local vasculitis, so the dose of prednisolone was increased from 25 mg/day to 60 mg/ day (1 mg/kg). Two weeks later, her VA had almost recovered to baseline (20/20 in the right eye and 16/20 in the left eye). A diagnosis of PION is only made after excluding other causes of retrobulbar optic neuropathy [2]. If MRI is not performed, distinguishing between optic neuritis and PION can be difficult [3]. MRI can also detect other causes of retrobulbar optic neuropathy by showing enhancement of the optic nerve sheath or apical infiltration of the orbit [4, 5]. PION has rarely been reported in GPA [4, 6, 7]. The visual prognosis was poor in most cases, and only one T. Nagashima (&) K. Matsumoto T. Murosaki M. Okada M. Iwamoto S. Minota Division of Rheumatology and Clinical Immunology, Department of Medicine, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan e-mail: naga4ma@jichi.ac.jp

Hypertrophic Osteoarthropathy Associated with Esophageal Cancer

A 58-year-old man was admitted to a local hospital with a five-month history of fatigue, peripheral edema, generalized myalgia and arthralgia. He had lost 30 kg of weight over the previous six months. The findings of gastrointestinal endoscopy and a biopsy led to a diagnosis of squamous cell carcinoma of the esophagus, and the patient was referred to our hospital for further management. He had symmetrical polyarthritis involving both the large and small joints. In addition, his hands and feet were swollen bilaterally, and prominent digital clubbing was noted. Radiographs

Multicentric Reticulohistiocytosis with Dermatomyositis-like Eruptions

A 68-year-old man presented with polyarthritis, proximal muscle weakness, and erythema of the face, arms, neck, and anterior chest that resembled the V-neck sign. Initially, dermatomyositis (DM) was considered because of the erythema, polyarthritis, and muscle weakness. He also had mediastinal and hilar lymphadenopathy on contrast-enhanced computed tomography. Unexpectedly, a biopsy of the forehead skin revealed numerous multinucleated giant cells. A biopsy of a solitary nodule on the dorsum of his right middle finger revealed similar multinucleated giant cells with ground-glass cytoplasm, leading to the diagnosis of multicentric reticulohistiocytosis (MRH). Although MRH is rare, it should be remembered that MRH can mimic DM.

An unusual cause of hemichorea-hemiballism in a patient with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) can present with various neuropsychiatric manifestations [1]. One of these, chorea, is rarely seen and has been possibly associated with antiphospholipid antibodies [2–4]. Along with connective tissue disorders, many other diseases are also associated with the symptom of chorea [5]. Although rare, chorea has occasionally been found to be a presenting symptom of hyperglycemia [6]. Here we report on a patient with SLE who presented with unilateral involuntary movement in her upper and lower extremities, which was eventually diagnosed as diabetic hemichorea–hemiballism (HC–HB). A 55-year-old woman with SLE presented with involuntary movements in her left upper and lower extremities, and general malaise which had developed 8 days previously. Her SLE had been diagnosed 4 months earlier, and the initial laboratory findings were as follows: leukocyte count, 2,600/ll with 37% lymphocytes; hemoglobin, 10.0 g/dl; platelet count, 18.9 9 10/ll; complement C3, 82 mg/dl (normal 86–160); and C4, 13 mg/dl (normal 18–25). Antinuclear antibody (1:1,280 with speckled pattern), anti-SSA antibody (1:64), anti-RNP antibody (1:64), and anti-double-stranded DNA antibody (18.9 IU/ml, normal \9.5) were positive, but anti-Sm antibody was negative. Urinary protein was 1.26 g/day with no hematuria. Renal histology was not obtained. She had been treated with prednisolone 30 mg/day, which had been reduced to 20 mg/day by the time of presentation. She was admitted to our hospital because of the involuntary movement. On examination, she was alert and oriented. Involuntary movement—chorea and ballism—was observed in her left arm and leg. Laboratory testing showed a leukocyte count of 13,000/ll, hemoglobin 12.7 g/dl, and platelet count 20 9 10/ll. Serum sodium and potassium were 129 mmol/l and 5.4 mmol/l, respectively. Blood glucose was significantly elevated at 700 mg/dl, and hemoglobin A1c level, which had been 6.0% 4 months ago, was now 15.2% (normal\5.8). Complement C3 was low (81 mg/dl), but C4 and C-reactive protein were within normal range, and lupus anticoagulant was negative. Urine dipstick showed 1 ? ketone, 4 ? sugar, and no protein. Cerebrospinal fluid examination showed a normal number of cells, protein 50 mg/dl (normal \40), and glucose 352 mg/dl. Although computed tomography of the brain was unremarkable, magnetic resonance imaging (MRI) showed a bilateral hyperintensity in the putamen on fluid-attenuated inversion recovery image. We speculated that the impaired glycemic control might have induced this condition. After intensive glycemic control with insulin and hydration, the involuntary movement quickly resolved within a day. Both anti-doublestranded DNA antibody and anti-phospholipid antibodies were negative. Because the response to glycemic control was very rapid, the diagnosis of hyperglycemia-induced HC–HB was highly probable. HC–HB is characterized by unilateral, continuous, proximal and distal involuntary movements [7]. HC–HB due to hyperglycemia mainly affects elderly women, often Asian, who have uncontrolled diabetes or recent-onset hyperglycemia [6]. Most cases are associated with nonketotic hyperglycemia, although HC–HB with ketoacidosis has also been reported [8]. High signal intensity in the A. Maruyama T. Nagashima (&) Y. Kamata K. Nagatani T. Murosaki T. Yoshio S. Minota Division of Rheumatology and Clinical Immunology, Jichi Medical University, Yakushiji 3311-1, Shimotsuke, Tochigi 329-0498, Japan e-mail: naga4ma@jichi.ac.jp