First external validation of sensitivity and specificity of the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria for idiopathic inflammatory myopathies with a Japanese cohort.

OBJECTIVE: To externally validate the performance of the new European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) classification criteria set for idiopathic inflammatory myopathies (IIM) with a Japanese cohort. METHODS: This study included 420 IIM and 402 non-IIM cases. Probability of having IIM in each patient was calculated using the collected data set. The cut-off probability was set at 55%, as recommended by EULAR/ACR. Patients classified as IIM by the criteria were further subclassified with classification trees. RESULTS: When the probability cut-off was set at 55%, the sensitivity/specificity of the new criteria to diagnose IIM were 89.3%/91.0% in the total cohort, 88.1%/95.1% without muscle biopsy data and 90.4%/65.5% with biopsy data. The cohort included 12 overlap syndrome patients with biopsy data, who were included as non-IIM cases in accordance with traditional Japanese methods. When they were included in the IIM cases, the specificity in patients with biopsy increased to 74.4%. The sensitivity/specificity of the new criteria to diagnose polymyositis/dermatomyositis (PM/DM) plus juvenile and amyopathic DM in the Japanese cohort was 87.4%/92.4%, which were greater than those of the Tanimoto's criteria revised to enable classification of amyopathic DM (ADM) (71.2%/87.8%) and were comparable with those of Bohan & Peter's criteria to diagnose those diseases except for ADM (88.4%/88.3%). CONCLUSIONS: Our study externally validated high specificity of the new criteria for the first time, although with several limitations, including low percentage of child patients. The new criteria have higher sensitivity and/or specificity in classification of PM/DM than the previously reported criteria, demonstrating its usefulness for interethnic patients.

Splicing variant of WDFY4 augments MDA5 signalling and the risk of clinically amyopathic dermatomyositis.

OBJECTIVES: Idiopathic inflammatory myopathies (IIMs) are a heterogeneous group of rare autoimmune diseases in which both genetic and environmental factors play important roles. To identify genetic factors of IIM including polymyositis, dermatomyositis (DM) and clinically amyopathic DM (CADM), we performed the first genome-wide association study for IIM in an Asian population. METHODS: We genotyped and tested 496 819 single nucleotide polymorphism for association using 576 patients with IIM and 6270 control subjects. We also examined the causal mechanism of disease-associated variants by in silico analyses using publicly available data sets as well as by in in vitro analyses using reporter assays and apoptosis assays. RESULTS: We identified a variant in WDFY4 that was significantly associated with CADM (rs7919656; OR=3.87; P=1.5×10-8). This variant had a cis-splicing quantitative trait locus (QTL) effect for a truncated WDFY4isoform (tr-WDFY4), with higher expression in the risk allele. Transexpression QTL analysis of this variant showed a positive correlation with the expression of NF-κB associated genes. Furthermore, we demonstrated that both WDFY4 and tr-WDFY4 interacted with pattern recognition receptors such as TLR3, TLR4, TLR9 and MDA5 and augmented the NF-κB activation by these receptors. WDFY4 isoforms also enhanced MDA5-induced apoptosis to a greater extent in the tr-WDFY4-transfected cells. CONCLUSIONS: As CADM is characterised by the appearance of anti-MDA5 autoantibodies and severe lung inflammation, the WDFY4 variant may play a critical role in the pathogenesis of CADM.

Evidence-based clinical practice guideline for adult Still's disease.

OBJECTIVES: Using an expert- and data-driven methodology, we have constructed the first clinical practice guidelines (CPGs) for adult Still's disease (ASD) after complete systematic review (SR) of the literature based upon the Medical Information Network Distribution Service (Minds) procedure. METHODS: The CPG committee for ASD organized by the Research Team for Autoimmune Diseases, the Research Program for Intractable Disease of the Japanese Ministry of Health, Labour, and Welfare has developed CPG for ASD 2017, according to the procedure proposed by Minds. The CPG development process includes (1) clarification of the purpose of CPG, (2) organization of the steering committee, (3) organization of the CPG committee and secretariat, (4) defining the scope (setting of clinical questions (CQs)), (5) SR, (6) development of recommendations, (7) drafting the CPG, (8) external evaluation and public comments, and (9) release. Because we wanted to construct CPG for ASD to encompass both adult-onset Still's disease (AOSD) and adult patients with systemic juvenile idiopathic arthritis (sJIA), we also included SR data from sJIA in this study. RESULTS: Twenty-six CQs were selected and roughly divided into the following items: (1) clinical findings (CQs 1-4), (2) laboratory findings (CQs 5-8), (3) complications (CQs 9-13), (4) treatment with oral medicine (CQs 14-19), (5) treatment with biological reagents (CQs 20-23), and (6) treatments for sJIA (CQs 25-26). Recommendations and the strength of the recommendations for these CQs were decided by a modified Delphi method. CONCLUSION: We have developed the first published CPG for ASD including AOSD and sJIA, which includes 26 CQs and recommendations. This guideline will help rheumatologists, non-specialized physicians, other healthcare providers, medical and health-related students, and patients and their family members to understand and treat ASD.

Evaluation of the alternative classification criteria of systemic lupus erythematosus established by Systemic Lupus International Collaborating Clinics (SLICC).

OBJECTIVE: To evaluate the performance of the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC-12) on classifying systemic lupus erythematosus (SLE) in an uncontrolled multi-centered study with real-life scenario of the patients in Japan. METHODS: This study comprised 495 patients with SLE or non-SLE rheumatic diseases and allied conditions from 12 institutes in Japan. Chart review of each patient was performed by the 27 expert rheumatologists and diagnosis of 487 cases reached to the consensus. Value of the SLICC-12 on SLE classification was analyzed comparing with the 1997 revised American College of Rheumatology SLE classification criteria (ACR-97) employing the expert-consented diagnoses. RESULTS: Compared to the ACR-97, the SLICC-12 had a higher sensitivity (ACR-97 vs. SLICC-12: 0.88 vs. 0.99, p < .01) and comparable specificity (0.85 vs. 0.80). The rate of misclassification (0.14 vs. 0.11) or the area under the receiver operating characteristic curves (0.863 vs. 0.894) was not statistically different. In the cases that diagnoses corresponded in high rates among experts, both criteria showed high accordance of SLE classification over 85% with the expert diagnoses. CONCLUSION: Although employment of SLICC-12 for the classification for SLE should be carefully considered, the SLICC-12 showed the higher sensitivity on classifying SLE in Japanese population.

Incidence of comprehensive hospitalization due to infection, cardiovascular disease, fractures, and malignancies in patients with rheumatoid arthritis.

To comprehensively analyze the overall incidence of hospitalization for comorbidities in patients with rheumatoid arthritis (RA). We prospectively analyzed overall hospitalizations for comorbidities using the Institute of Rheumatology, Rheumatoid Arthritis (IORRA) cohort. The incidence of hospitalized comorbidity was calculated. Risk factors for the most frequent hospitalized comorbidities were determined by multivariate logistic regression analysis. Among 5519 RA patients contributing 5336.5 person-years of observation, 435 incidences of hospitalized comorbidity [8.15/100 person-years; 95% confidence interval (CI) 7.40-8.95] were confirmed. The most frequent cause of hospitalized comorbidity was infection (1.52/100 person-years), primarily respiratory system infection (0.77/100 person-years), followed by malignancy (1.03/100 person-years), extra-articular manifestations (0.78/100 person-years), bone fracture (0.77/100 person-years), and acute coronary syndrome (0.22/100 person-years). Death occurred in 0.34/100 person-years (95% CI 0.20-0.53), and in 94.4% of cases the cause of death was the same as that of admission. The risk factors for the most frequent cause of hospitalization, hospitalized infection, were age [odds ratio (OR) 1.03; 95% CI 1.00-1.05], serum albumin level (OR 0.30; 95% CI 0.13-0.69), and corticosteroid use (prednisone > 5 mg/day; OR 3.66; 95% CI 1.81-7.35), but not methotrexate or biological agent use. The present study determined the overall burden of hospitalized comorbidities in patients with RA. These comprehensive data on hospitalized comorbidities may provide a basis for future improvements in the treatment of RA.

Interstitial cystitis associated with primary Sjögren's syndrome successfully treated with a combination of tacrolimus and corticosteroid: A case report and literature review.

We report a case of interstitial cystitis (IC) associated with primary Sjögren's syndrome (SS) successfully controlled with combination therapy of tacrolimus and a corticosteroid. In 2011, a 69-year-old female, who had been diagnosed with primary SS 23 years ago, developed IC and was successfully treated with tacrolimus and prednisolone combination therapy. The mechanism of IC, including the involved autoimmunity, has not been elucidated. Clinical observation studies suggest a potential association between SS and IC. However, IC is currently thought to be underdiagnosed in patients with SS as well as in the general population. Based on our case and others reported previously, IC associated with SS responds well to immunosuppressive therapy. In particular, a combination of a calcineurin inhibitor (tacrolimus or cyclosporine) with a corticosteroid seems to be highly effective. The possibility of IC in patients with SS complaining of lower urinary tract symptoms without features of infection or other identifiable causes should be given attention.

Successful tocilizumab therapy in seven patients with refractory adult-onset Still's disease.

To evaluate the effects of tocilizumab (TCZ) on adult-onset Still's disease (AOSD), we reviewed medical records of seven patients with refractory AOSD treated with TCZ at our institution. TCZ therapy might allow rapid corticosteroid tapering and help maintain remission status, that is, resolution of clinical symptoms and normalization of biomarkers such as CRP and ferritin. Patients, however, should be monitored for the development of macrophage activation syndrome when TCZ is administered for active AOSD.

A novel ACE2 activator reduces monocrotaline-induced pulmonary hypertension by suppressing the JAK/STAT and TGF-ß cascades with restored caveolin-1 expression.

INTRODUCTION: Pulmonary hypertension (PH) is characterized by increased pressure in the pulmonary artery and right ventricular hypertrophy (RVH). Recently, angiotensin-converting enzyme 2 (ACE2), which converts angiotensin (Ang) II into Ang-(1-7), was shown to inhibit experimental PH. Here we identified a novel ACE2 activator and investigated how the compound reduced monocrotaline (MCT)-induced PH. METHODS: To induce PH, Sprague-Dawley rats were injected subcutaneously with MCT, followed by the continuous administration of NCP-2454, an ACE2 activator, using osmotic pumps. Pulmonary arterial compliance was monitored every week until 4 weeks post-injection (wpi). RVH and lung remodeling was evaluated using lung tissue at 4 wpi. RESULTS: NCP-2454 upregulated the production of Ang-(1-7) when incubated with ACE2 and Ang II. Notably, a continuous infusion of NCP-2454 significantly improved pulmonary arterial compliance, right ventricular systolic pressure, and RVH in MCT-treated rats. Interestingly, NCP-2454 increased the relative expression of ACE2 and MAS mRNA in lung tissue, especially in MCT-treated rats. In addition, the compound inhibited the MCT-induced overexpression of transforming growth factor ß, phosphorylation of signal transducer and activator of transcription-3 (STAT3), and interleukin-6 production. The compound also restored the expression of caveolin-1 (Cav-1), which negatively regulates the Janus kinase-STAT signaling cascade. CONCLUSIONS: NCP-2454 prevented MCT-induced PH by suppressing intracellular inflammatory cascades, an upstream molecular change of which is the disruption of Cav-1 expression.

A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese.

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10(-9), odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4(+) and CD19(+) peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.

Rheumatic manifestations and an epipharyngeal mass accompanied by myelodysplastic syndrome.

We herein report two cases of myelodysplastic syndrome with rheumatic manifestations. (Case 1) A 70-year-old man presented with fever, arthritis and bone pain and developed cranial nerve palsy caused by an epipharyngeal mass. Steroid therapy led to a prolonged remission of the febrile condition and mass lesion. (Case 2) An 82-year-old male was treated for intractable polyarthritis and fever with steroid therapy, and serious side effects resulted in lethal pneumonia. We herein describe the entire course of steroid therapy in these two cases. Various rheumatic manifestations in myelodyaplastic syndrome often require empirical steroid therapy. It was effective for the soft tissue mass in Case 1, in which indolent lymphoma could not be denied, and was only partially effective for Case 2 of the febrile and putatively benign conditions, suggesting heterogeneous nature of rheumatic complications in myelodysplastic syndrome.

Differences in fluorodeoxyglucose positron emission tomography/computed tomography findings between elderly onset rheumatoid arthritis and polymyalgia rheumatica.

OBJECTIVES: To compare the fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) findings in patients with elderly-onset rheumatoid arthritis (EORA) with those in patients with polymyalgia rheumatica (PMR), two conditions with similar clinical presentations. METHODS: We retrospectively analyzed the FDG-PET/CT findings in 10 patients with EORA and 27 patients with PMR admitted to our department between 2006 and 2012. RESULTS: No significant difference was observed in the median patient ages at the time of FDG-PET/CT scans in the EORA and PMR groups (73.5 vs. 78.0 years, respectively). Significant differences in both FDG uptake scores and standardized uptake values were observed between the two groups in the ischial tuberosities, spinous processes, and wrists. No significant differences were detected in the shoulders and hips. However, specific uptake patterns were observed in each group: circular and linear uptake patterns were observed around the humeral head in the EORA group, whereas focal and non-linear uptake patterns were observed in the PMR group. Moreover, focal uptake in front of the hip joint, indicating iliopectineal bursitis, tended to be limited to the PMR group. High sensitivity (92.6%) and specificity (90%) were observed for PMR diagnoses when at least three of the following five items were satisfied: characteristic findings of shoulder and iliopectineal bursitis, FDG uptake in ischial tuberosities and spinal spinous processes, and lack of FDG uptake in the wrists. CONCLUSION: The differences in the degree of uptake at each lesion and in uptake patterns at the shoulders and hips are potentially useful for obtaining a definitive diagnosis.

Identification of novel autoantibodies to GABA(B) receptors in patients with neuropsychiatric systemic lupus erythematosus.

OBJECTIVE: The gamma-aminobutyric acid type B receptors (GABAR(B)) are G-protein coupled receptors for GABA, the main inhibitory neurotransmitter in the brain. We identified GABAR(B) subunits as candidate antigens in patients with SLE using a random peptide display library. The aim of this study was to investigate the possible link between anti-GABAR(B) antibodies and disease activity and NPSLE. METHODS: ELISA was performed with recombinant proteins of GABAR(B1b) and GABAR(B2) on serum samples from patients with SLE (n = 88), scleroderma (n = 20), myositis (n = 20) or vasculitis (n = 20) as well as healthy subjects (n = 20). Cerebrospinal fluid (CSF) from 23 patients with SLE was also examined. RESULTS: Autoantibodies to GABAR(Bs) were exclusive to patients with SLE (P < 0.001) and positively associated with SLEDAI (anti-GABAR(B1b), P = 0.001; anti-GABAR(B2), P < 0.001). Of note, autoantibodies were positively linked with NPSLE (anti-GABAR(B1b), P = 0.02; anti-GABAR(B2), P = 0.03). Moreover, anti-GABAR(Bs) was detected in 61.5% of CSF samples from patients with active NPSLE, a frequency that was significantly higher than that for patients with non-SLE syndromes. CONCLUSION: Anti-GABAR(B) antibodies could represent novel candidate markers for disease activity and NPSLE.

Utility of fluorodeoxyglucose positron emission tomography/computed tomography for early diagnosis and evaluation of disease activity of relapsing polychondritis: a case series and literature review.

OBJECTIVE: Relapsing polychondritis (RPC) is relatively rare and early diagnosis is difficult. We investigated the utility of fluorodeoxyglucose (FDG)-PET/CT for the diagnosis of RPC and evaluation of disease activity. METHODS: Five RPC patients undergoing FDG-PET/CT in our hospital between 2006 and 2012 were studied. Eight RPC cases examined by PET reported in the literature were also assessed. Data from a total of 13 patients were analysed. RESULTS: Typical FDG accumulation was noted in the tracheobronchial trees of nine patients, the costal cartilage of five, joints of five, larynx of four, nasal cavity/paranasal sinuses of three, auricles of three, lymph nodes of three and the aorta of one. One patient showed nasal chondritis on a PET scan despite the absence of nasal changes on physical examination. Of five patients with costochondritis, four remained asymptomatic. Of nine patients with airway FDG accumulation, eight developed respiratory symptoms and all had CT abnormalities. In the other patient, airway FDG accumulation was evident despite the absence of airway symptoms and a lack of abnormalities in the respiratory function test and CT. PET also revealed bronchial chondritis in asymptomatic patients. The mean maximum standardized uptake values (SUVmax) of the upper and lower airways was 5.79 (s.d. 2.87) and 6.47 (s.d. 4.08), respectively. In five patients with a PET after treatment, FDG accumulation had diminished with symptomatic and inflammatory improvement. CONCLUSION: FDG-PET/CT is a potentially powerful tool for the early diagnosis of RPC, especially in patients without easily biopsied organ involvement. This modality also facilitates evaluation of disease extent and disease activity during treatment.

Large vessel vasculitis in elderly patients: early diagnosis and steroid-response evaluation with FDG-PET/CT and contrast-enhanced CT.

Large vessel vasculitis (LVV) is an often-reported cause of inflammation of unknown origin (IUO) in elderly people. The objective of this study was to describe the usefulness of fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and contrast-enhanced CT in early diagnosis and treatment follow-up of patients with LVV presenting as elderly onset IUO. We retrospectively compared contrast-enhanced CT findings and FDG-PET/CT findings of the patients diagnosed with LVV and 11 controls; all subjects were 50 years of age or older. We evaluated maximum standardised uptake value (SUV(max)) and PET score of the aortic wall for quantitative comparison of FDG-PET/CT findings. We measured the aortic wall thickness (W) and its ratio against the radius (W/R) for quantitative comparison of aortic wall thickening by contrast-enhanced CT. After steroid treatment, we compared these values with those pre-treatment. Of 124 patients who were hospitalised due to advanced age and IUO, 88 underwent FDG-PET/CT and contrast-enhanced CT. Abnormal findings were observed on images from 78 patients. The findings were indicative of LVV in 13 patients (10.5 %), of whom more than half had only non-specific symptoms. Patients with LVV had significantly higher aortic wall SUV(max) (3.85 vs. 1.95), PET scores by FDG-PET/CT, and aortic wall thicknesses by contrast-enhanced CT (3.8 vs. 2.6 mm) than controls. Significant improvement in aortic wall thickening was evidenced by reduced PET scores and by contrast-enhanced CT findings in patients who were followed up after treatment. LVV is an important cause of IUO with non-specific symptoms in elderly patients. Imaging examination comprising contrast-enhanced CT and FDG-PET/CT is useful for early diagnosis and early treatment evaluation of LVV, allowing for amelioration of reversible aortic wall thickening.

A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities.

Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here we identify a SNP in the promoter region of FCRL3, a member of the Fc receptor-like family, that is associated with susceptibility to rheumatoid arthritis (odds ratio = 2.15, P = 0.00000085). This polymorphism alters the binding affinity of nuclear factor-kappaB and regulates FCRL3 expression. We observed high FCRL3 expression on B cells and augmented autoantibody production in individuals with the disease-susceptible genotype. We also found associations between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FCRL3 may therefore have a pivotal role in autoimmunity.

[A miliary tuberculosis case without lung involvement difficult to distinguish from autoimmune hepatitis exacerbation].

A 48-year-old female with a past history of systemic lupus erythematosus had developed autoimmune hepatitis (AIH) at the age of 45 years, and administration of PSL 30 mg/day was initiated. However, AIH exacerbation was suspected based on elevation of hepatic and biliary tract enzymes such as ALP (1207U/L) with a fever of 38 degrees C after tapering off the steroids to PSL 7.5 mg daily, and she was thus hospitalized. A liver biopsy was recommended, but she refused. Thus, we suspected concomitant AIH and autoimmune cholangitis (AIC). Although high-dose steroid treatment including steroid pulse therapy was administered, there was no improvement. We performed a liver biopsy on the 66th hospital day, after obtaining the patient's consent. Epithelioid granuloma was detected in the liver leaflet as the background of the AIH and AIC findings. In addition, acid fast bacteria were detected with auramine and Ziehl-Neelsen staining, raising the possibility of tuberculosis. Additionally, granuloma was also seen in her bone marrow, and miliary tuberculosis was suspected. Anti-tuberculous therapy with isoniazid, rifampicin, ethambutol and pyrazinamide was initially administered, but the regimen was changed to levofloxacin, ethambutol, and streptomycin due to the side effects of the earlier medications. Liver functions improved and the inflammatory reaction became negative. The patient was discharged on the 138th hospital day. Ultimately, no acid fast bacteria were detected with culture, PCR of her bone marrow, or liver biopsy. However, miliary tuberculosis was definitively diagnosed from the pathological findings and her clinical course. AIH was an underlying disease, and the discrimination from AIH exacerbation was difficult. Consequently, the diagnosis was miliary tuberculosis without the lung involvement and the main lesion was in the liver. It is important to take account of miliary tuberculosis in the differential diagnosis of fevers of unknown origin with elevation of hepatic and biliary tract enzymes, and to make a definitive diagnosis with a liver biopsy.

[Obstructive pneumonia and brain abscess due to Nocardia elegans in a patient with systemic lupus erythematosus].

We herein report on a 69-year-old male who developed lung nocardiosis and brain abscessation. In April 2011, he was diagnosed as having systemic lupus erythematosus complicated by peripheral neuropathy. Immunosuppressive therapy with high-dose prednisolone was begun. In November 2011, he developed cryptococcal pneumonia and meningitis, which was treated with liposomal amphotericin and flucytosine for 4 weeks and was maintained with fluconazole. In April 2012, consolidation and peripheral atelectasis in the right middle lobe appeared. Bronchoscopy revealed edematous mucosa in the right middle bronchus and occlusive change of the right B4 and B5, but biopsy and culture results provided no etiological information. In late June, he developed an intermittent fever, and obstructive pneumonia of the right middle lobe was suspected. Nocardia species were detected from the sputum culture and were thought to be the causative pathogen. Brain CT and MRI revealed a contrast-enhanced lesion in the right cerebellar hemisphere. The patient was diagnosed as having lung nocardiosis and brain abscessation. Considering that the nocardiosis had developed under prophylaxis for Pneumocystis jirovecii pneumonia using one tablet per day of a sulfamethoxazole-trimethoprim combination, meropenem and amikacin were administered in addition to the sulfamethoxazole-trimethoprim combination for 6 and 4 weeks, respectively. After N. elegans had been identified from the sputum, antibiotics were switched to a sulfamethoxazole-trimethoprim combination and clarithromycin based on the susceptibility results. The patient's clinical and radiological findings were improved and have been well sustained.

Clinical characteristics and incidence of methotrexate-related lymphoproliferative disorders of patients with rheumatoid arthritis.

OBJECTIVE: To investigate the incidence and clinical features of methotrexate (MTX)-related lymphoproliferative disorders (MTX-LPDs) in patients with rheumatoid arthritis (RA). PATIENTS: In total, 589 RA outpatients were examined at the National Center for Global Health and Medicine in the period from January 1990 to October 2010. RESULTS: MTX was used in 403 cases, and the duration of follow-up was 2379 person-years. Four patients developed MTX-LPDs; the incidence of MTX-LPDs was calculated as 0.00168/person-year and the standardized incidence as 8.21 (95% CI: 0.16-24.30). The mean total dosage of MTX was 1142 ± 871 mg, and the dosage at LPD onset was 7.4 ± 1.9 mg/week. The patients who developed MTX-LPDs had significantly shorter disease duration of RA compared with the patients who had not received MTX, but who had not progressed to LPDs (3.1 years vs. 12.5 years; P = 0.01). The following LPD subtypes were observed: diffuse large B-cell lymphoma (N = 2); Hodgkin's lymphoma (N = 1); and T-cell lymphoma (N = 1). After withdrawal of MTX, two of these patients showed spontaneous regression of the tumor, one did not have a recurrence, while the other patient relapsed and required chemotherapy. CONCLUSION: Our study revealed that MTX-LPDs are not rare complications of RA outpatients. The MTX-LPDs were associated with a relatively shorter RA duration, and half of them showed tumor regression after MTX withdrawal, which suggested an association with MTX. It is important to consider the possibility of MTX-LPD in RA patients who have received MTX.

Clinical value of ¹8F-fluoro-dexoxyglucose positron emission tomography/computed tomography in patients with adult-onset Still's disease: a seven-case series and review of the literature.

OBJECTIVES: While there are a few reports describing 18F-fluoro-dexoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) findings in patients with adult-onset Still's disease (AOSD), no summary report has yet been published. In this study, we evaluated the usefulness of FDG-PET/CT for diagnosis and activity evaluation in patients with AOSD by summarizing the findings of our patients and those reported in the literature. METHODS: Seven consecutive AOSD patients who had undergone PET/CT at our department between 2007 and 2012 were included. We evaluated FDG uptake for characteristic findings in patients with AOSD. In addition, we reviewed the literature on seven previously reported AOSD patients who had undergone PET/CT. RESULTS: FDG accumulation was positive mainly in the bone marrow (100%), spleen (90.9%), lymph nodes (80.0%) and joints (75.0%). In addition, FDG uptake was positive in the pericardium, pleura, salivary glands, eyelids, muscle and major blood vessels. Six patients underwent follow-up FDG PET/CT for evaluation of treatment efficacy. Follow-up PET/CT showed diminished FDG accumulation in the bone marrow, spleen and lymph nodes, with maximum standardized uptake value (SUVmax) being substantially reduced from 4.03 ± 0.95 to 2.20 ± 0.75 (p = 0.04), 4.04 ± 1.10 to 2.55 ± 1.13 (p = 0.04) and 5.63 ± 4.99 to 2.10 ± 1.91 (p = 0.11), respectively. No significant correlation was found between SUVmax in each lesion and the laboratory data, except for a significant correlation between lactate dehydrogenase (LDH) and spleen SUV. CONCLUSIONS: FDG-PET/CT is useful for long-term assessments of AOSD activity in individual patients. However, PET/CT findings alone are not sufficient to make a differential diagnosis of AOSD versus malignant lymphoma.

Characteristics of 10 patients with paraneoplastic rheumatologic musculoskeletal manifestations.

OBJECTIVES: To evaluate the possible correlation of malignant neoplasms and paraneoplastic rheumatologic syndromes. METHODS: We studied a series of 10 patients with paraneoplastic rheumatological syndromes collected from our Division of Rheumatic Disease between 2006 and 2012. RESULTS: Our series consisted of four males and six females, with a mean age of 65.5 years (range, 57-78 years). Of the 10 patients recruited, six had hematological malignancies and four had solid cancers. Malignancies were diagnosed after rheumatic symptoms were reported in all patients. Compared to solid tumors, hemopathy was diagnosed at a later time point (16.2 vs. 7.3 months). Extra-articular symptoms were associated with rheumatologic musculoskeletal manifestations in 100% of the patients. Polyarthritis was the main rheumatologic musculoskeletal manifestation (50% of the patients). The other manifestations were oligopolyarthritis and polymyalgia rheumatic-like symptoms (20% of the patients). Symmetric arthritis was present in 60% of the patients, and the remaining patients developed asymmetric arthritis. Musculoskeletal manifestations completely regressed in 66.7% of the patients after cancer therapy. When tumor relapse was observed, rheumatic symptoms did not recur in any of our patients (100%). CONCLUSIONS: Rheumatic disorders with atypical clinical presentation in older patients, poor response to usual treatment and systemic features such as weight loss and clinical findings compatible with well-recognized paraneoplastic syndromes should alert clinicians to the possible coexistence of an occult malignancy. Especially in cases of paraneoplastic rheumatic/musculoskeletal manifestations associated with hemopathy, the primary disease is unlikely to have manifested yet, making the diagnosis difficult. Thus, caution is required.