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.

A multicenter phase II prospective clinical trial of glucocorticoid for patients with untreated IgG4-related disease.

OBJECTIVE: Although glucocorticoids are effective for patients with IgG4-related disease, the treatment has not yet been standardized. Therefore, the treatment strategy should be established. PATIENTS AND METHODS: Patients who fulfilled the comprehensive diagnostic criteria for definite IgG4-related disease were started on prednisolone (0.6 mg/kg body weight) with the dose reduced every two weeks. The subsequent maintenance dose and need for prednisolone were determined for individual patients. The primary endpoint was the complete remission (CR) rate at one year. Secondary endpoints included overall response rate (ORR), the maintenance dose, the relapse rate, and adverse events. RESULTS: This study enrolled 61 patients. After clinicopathological review, three patients were excluded, and one, 13, and 44 patients were diagnosed with probable, possible, and definite IgG4-related disease, respectively. Of the 44 patients with definite IgG4-RD, 29 (65.9%) achieved CR, and the ORR was 93.2%. No patient was refractory to primary treatment. The most frequent adverse events were glucose intolerance. Six patients relapsed. CONCLUSIONS: Glucocorticoid treatment is usually effective for patients with IgG4-RD, and we should examine the possibility of other disorders when a patient is glucocorticoid refractory. Some patients are misdiagnosed, making central clinicopathological review of diagnosis very important in conducting clinical studies.

Prevalence of soluble peptidylarginine deiminase 4 (PAD4) and anti-PAD4 antibodies in autoimmune diseases.

The objectives of this study are to investigate the prevalence of PAD4 and anti-PAD4 antibodies (Abs) in autoimmune diseases and to clarify their association with anticitrullinated protein antibodies (ACPAs) and shared epitope (SE) in patients with rheumatoid arthritis (RA). Levels of human PAD4 and anti-PAD4 Abs in serum or plasma were measured using sandwich ELISA. Samples were obtained from patients with RA (n = 148), SLE (n = 36), or SS (n = 37) and from healthy controls (HCs; n = 40). Antibodies against cyclic citrullinated glucose-6-phosphate isomerase (GPI) (CCG)-2, CCG-7, anti-CEP-1, and anti-CCP Abs were also measured using ELISA. Patients with RA were genotyped for HLA-DRB1. The human PAD4 and anti-PAD4 Ab levels were compared with the ACPA and SE in patients with RA. The PAD4 levels were 111.9 U/ml in the RA, 30.4 U/ml in the SLE, 81.9 U/ml in the SS patients, and 46.6 U/ml in the HCs. The PAD4 levels were significantly higher in the RA than in the SLE patients or the HCs. Anti-PAD4 Abs were detected in 29.7 % of the patients with RA, but not in the patients with SLE or SS, nor in the HCs. In the RA patients, the PAD4 levels in the anti-PAD4 Ab-negative group were significantly higher than those in the anti-PAD4 Ab-positive group. Moreover, anti-CCG-2, CCG-7, CEP-1, and anti-CCP Ab levels were significantly higher in the anti-PAD4 Ab-positive group than in the anti-PAD4 Ab-negative group. In the RA patients, the PAD4 levels were not correlated with ACPAs. Neither PAD4 nor anti-PAD4 Abs were significantly correlated with the presence of SE alleles. The PAD4 levels were higher in RA than in SLE or HC. Anti-PAD4 Abs appeared specifically in patients with RA. Moreover, anti-PAD4 Abs were associated with ACPAs.

Evaluation of changes in magnetic resonance images following 24 and 52 weeks of treatment of rheumatoid arthritis with infliximab, tocilizumab, or abatacept.

OBJECTIVES: To compare MRI findings in rheumatoid arthritis (RA) patients treated with biologic disease-modifying anti-rheumatic drugs (DMARDs). METHODS: The study subjects were 43 RA patients treated with biologic DMARDs (13 with infliximab, 15 with tocilizumab, and 15 with abatacept). They were evaluated using Simplified Disease Activity Index (SDAI) and low-field extremity MRI at baseline, and at 24 weeks and 52 weeks of treatment. RESULTS: Synovitis scores were significantly lower by 24 weeks in all groups, compared with baseline (P < 0.05). Significant improvement in bone marrow edema (BME) scores were noted from baseline to 24 weeks in infliximab and abatacept groups (P < 0.05), but from 24 weeks to 52 weeks in tocilizumab group (P < 0.01). No significant change was found in erosion score. The synovitis score at baseline correlated significantly with SDAI at 24 weeks (P < 0.05), and the score at 24 weeks correlated significantly with SDAI at 52 weeks (P < 0.05). CONCLUSIONS: The results suggest that the inflammatory improvement by infliximab and abatacept may express earlier than those by tocilizumab, despite similar improvement in SDAI. MRI-detected synovitis could be a useful predictor of SDAI at 24 weeks of treatment. The MRI remains the best tool to detect and assess the effects of biologic DMARDs in RA.

Successful Treatment with Infliximab for Refractory Uveitis in a Hemodialysis Patient with Behçet's Disease and a Review of the Literature for Infliximab Use in Patients on Hemodialysis.

A 36-year-old man with a 16-year history of refractory Behçet's disease (BD)-associated uveitis and chronic renal failure requiring hemodialysis suffered from frequent ocular attacks despite treatment with systemic corticosteroids and cyclosporine A. Following infliximab administration, the patient's BD ocular attack score 24 and visual acuity improved. Although he developed mild acute gastroenteritis, he did not experience any other adverse events. In our review of the literature, we identified seven patients on hemodialysis with inflammatory disease successfully treated with infliximab. Infliximab may be effective and safe in cases of BD and other diseases, including in patients under hemodialysis.

Usefulness of MR imaging of the parotid glands in patients with secondary Sjögren's syndrome associated with rheumatoid arthritis.

OBJECTIVE: To assess the correlation between MR imaging (MRI) of parotid glands with X-ray sialography, histopathology of the labial salivary glands, and salivary secretion, in patients with secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). METHODS: Non-contrast MRI of the parotid glands was performed in 13 secondary SS patients associated with RA who satisfied the revised Japanese diagnostic criteria for SS (1999), and the ACR/EULAR classification criteria for RA (2010). The MRI findings were classified according to the degree of high-intensity signal on T1-weighted images (T1WI) and short inversion time inversion recovery (STIR) images into five grades (0-4), using the modified Nagasaki University grading method. The results of MRI grading were compared with the Rubin and Holt staging of X-ray sialography (0-4), the Greenspan grading of labial salivary gland histopathology (0-4), and salivary secretion by the gum test (ml/10 min). RESULTS: All 13 patients were females, with a mean age of 50.2 ± 11.3 years. According to the MRI grading, 3 patients were Grade 1, 5 were Grade 2, 5 were Grade 3, and none was Grade 0 or Grade 4. The mean stage by X-ray sialography was 1.7 ± 1.0, the mean grade by histopathology was 2.4 ± 1.2, and the mean volume of salivary secretion was 9.7 ± 3.9 ml. The MRI grading correlated significantly with the Rubin and Holt staging and Greenspan grading (P < 0.01 each, Spearman's rank correlation), and significantly and inversely with the results of the gum test (P < 0.05). CONCLUSION: The results suggest that MRI of the parotid glands is a useful noninvasive tool for evaluating destruction and inflammation in the salivary glands.

Efficacy and safety of abatacept for patients with Sjögren's syndrome associated with rheumatoid arthritis: rheumatoid arthritis with orencia trial toward Sjögren's syndrome Endocrinopathy (ROSE) trial-an open-label, one-year, prospective study-Interim analysis of 32 patients for 24 weeks.

Abstract Objective. To assess the efficacy and safety of abatacept for secondary Sjögren's syndrome (SS) associated with rheumatoid arthritis (RA). Methods. The primary endpoint of this 1-year, open-labeled, prospective, observational multicenter study of RA-associated secondary SS was the rate of SDAI remission at 52 weeks after initiation of abatacept therapy. The secondary endpoints included that of Saxson's test and Schirmer's test. Adverse events during the study period were also analyzed. Results. Thirty-two patients (all females) were enrolled in this study. Interim analysis at 24 weeks included assessment of efficacy (n = 31) and safety (n = 32). The mean SDAI decreased from 19.8 ± 11.0 (± SD) at baseline to 9.9 ± 9.9 at 24 weeks (P < 0.05). Patients with clinical remission, as assessed by SDAI, increased from 0 patient (0 week) to 8 patients (25.8%) at 24 weeks. Saliva volume (assessed by Saxson's test) increased slightly from 2232 ± 1908 (0 week) to 2424 ± 2004 (24 weeks) mg/2 min (n = 29). In 11 patients with Greenspan grading 1/2 of labial salivary glands biopsy, saliva volume increased from 2945 ± 2090 (0 week) to 3419 ± 2121 (24 weeks) mg/2 min (P < 0.05). Schirmer's test for tear volume showed increase from 3.6 ± 4.6 (0 week) to 5.5 ± 7.1 (24 weeks) mm/5 min (n = 25; P < 0.05). Five adverse events occurred in five of 32 patients (15.6%), and three of these events were infections. Conclusion. Abatacept seems to be effective for both RA and RA-related secondary SS.

Clinical features of patients with IgG4-related disease complicated with perivascular lesions.

OBJECTIVE: To define the clinical features of IgG4-related disease (IgG4-RD) complicated with perivascular lesions. METHODS: The clinical features of seven patients with IgG4-RD and perivascular lesions diagnosed at the University of Tsukuba Hospital between October 2008 and October 2013, were analyzed, including clinical background, results of imaging studies, satisfaction of the 2011 comprehensive diagnostic criteria (CDC) for IgG4-RD, laboratory data, distribution of perivascular lesions, involvement of other organs, and response to steroid therapy. RESULTS: We studied six men and one woman with a mean age of 66.9 ± 6.7 years (± SD). Six of seven patients were diagnosed as definite IgG4-RD, while the seventh was considered possible IgG4-RD, based on the CDC for IgG4-RD. Serum IgG4 levels at diagnosis were higher than 135 mg/dl in all seven patients (mean, 933 ± 527). Serum C-reactive protein (CRP) levels were elevated in two only (mean, 1.42 ± 3.56 mg/dl). The perivascular lesions were located in the pulmonary artery (n = 1), thoracic aorta (n = 2), abdominal aorta (n = 6), coronary (n = 1), celiac (n = 1), superior mesenteric (n = 1), renal (n = 2), inferior mesenteric (n = 5), and iliac (n = 3) arteries. In addition to perivascular lesions, six patients showed involvement of other organs. All seven patients were treated with prednisolone (0.6 mg/kg/day), which rapidly improved the perivascular and other organ lesions in six patients (the other one patient have not yet been evaluated due to the short follow-up). CONCLUSION: Perivascular lesions show wide distribution in patients with IgG4-RD. Serum CRP levels are not necessarily elevated in these patients. Steroid therapy is effective in IgG4-RD and results in resolution of lesions.

Pulmonary nocardiosis in patients with connective tissue disease: A report of two cases.

Reported here are 2 patients with connective tissue disease who developed pulmonary nocardiosis. Case 1 involved a 73-year-old man with malignant rheumatoid arthritis treated with prednisolone 25 mg/day. Chest X-rays revealed a pulmonary cavity and bronchoscopy detected Nocardia species. The patient was successfully treated with trimethoprim/sulfamethoxazole. Case 2 involved a 41-year-old woman with systemic lupus erythematosus. The patient received remission induction therapy with 50 mg/day of prednisolone and tacrolimus. Six weeks later, a chest CT scan revealed a pulmonary cavity; bronchoscopy resulted in a diagnosis of pulmonary nocardiosis. The patient had difficulty tolerating trimethoprim/sulfamethoxazole, so she was switched to and successfully treated with imipenem/cilastatin and amikacin.

Involvement of CD161+ Vδ1+ γδ T cells in systemic sclerosis: association with interstitial pneumonia.

OBJECTIVE: Interstitial pneumonia (IP) is a chronic progressive interstitial lung disease associated with high mortality and poor prognosis. However, the pathogenesis of IP remains to be elucidated. The aim of this study was to clarify the role of CD161(+) Vδ1(+) γδ T cells in SSc patients with IP. METHODS: The proportion of CD161(+) Vδ1(+) γδ T cells in peripheral blood mononuclear cells (PBMCs) and serum sialylated carbohydrate antigen (KL-6) levels were determined. GeneChip analysis was performed with CD161(-) and CD161(+) Vδ1(+) γδ T cells. Cytokine and chemokine expression from CD161(+) Vδ1(+) γδ T cells was measured and used to evaluate the effect of culture supernatant on fibroblast proliferation. RESULTS: The proportion of CD161(+) Vδ1(+) γδ T cells was significantly higher in SSc than healthy controls (HCs) and correlated negatively with serum KL-6 levels in IP-positive SSc patients. The gene and mRNA expression level of chemokine ligand 3 (CCL3) was markedly higher in CD161(+) Vδ1(+) γδ T cells than in CD161(-) Vδ1(+) γδ T cells. CD161(+) Vδ1(+) γδ T cells in IP-positive SSc patients showed higher production of CCL3 and lower production of IFN-γ than in HCs. Culture supernatant derived from IP-negative and IP-positive SSc patients promoted fibroblast proliferation, whereas that from HCs did not. CONCLUSION: The small proportion and the altered cell functions of CD161(+) Vδ1(+) γδ T cells among PBMCs in SSc patients play a role in the pathogenesis of IP. These findings suggest that CD161(+) Vδ1(+) γδ T cells may play a regulatory role in the pathogenesis of IP in SSc patients via IFN-γ production.

Clinicopathological features of IgG4-related disease complicated with orbital involvement.

OBJECTIVE: IgG4-related disease (IgG4-RD) is characterized by IgG4-positive plasmacytic infiltration and fibrosis in various organs. Orbital involvement in IgG4-RD includes lacrimal glands, extra-ocular muscles, trigeminal nerve and other parts of the orbit. Immunohistochemical staining is used to diagnose IgG4-RD in patients with orbital inflammation. The purpose of this retrospective study was to clarify the clinicopathological features of IgG4-RD complicated with orbital involvement. METHODS: We examined the clinical features, pathological findings and response to treatment in nine patients with IgG4-RD who underwent orbital tissue biopsy between April 2010 and August 2012 at the University of Tsukuba Hospital. RESULTS: Among the nine patients, eight had dacryoadenitis, one had infraorbital nerve swelling, and another one had IgG4-related orbital inflammation. Involvement of other organs was identified in all patients, including involvement of the salivary glands, lymph nodes, lung, kidney and para-aorta. In all patients, biopsy samples from orbital tissues showed lymphoplasmacytic infiltration and fibrosis, and IgG4-positive/IgG-positive plasmacyte ratio of > 40%. All patients were treated with prednisolone (0.6 mg/kg/day) and responded well in early phase, although relapse was noted in two patients following tapering of prednisolone, evident by swelling of lacrimal glands. CONCLUSION: Patients with IgG4-RD complicated with orbital involvement often present with involvement of other organs. The histopathological findings of orbital tissue match the characteristic features of IgG4-RD. Corticosteroid is effective for orbital and systemic involvement in IgG4-RD.

Analysis of subclinical synovitis detected by ultrasonography and low-field magnetic resonance imaging in patients with rheumatoid arthritis.

OBJECTIVE: To assess the utilities of ultrasonography (US) and low-field magnetic resonance imaging (compacTscan, cMRI) in the diagnosis of subclinical synovitis of hand joints of patients with rheumatoid arthritis (RA). METHODS: A total of 1,540 joints of 77 RA patients were examined clinically, using US, using cMRI, and the baseline X-ray examination was performed. Clinical synovitis was defined as joint tenderness or swelling. Subclinical synovitis was diagnosed by US and by cMRI. The incidence of bone erosion and joint space narrowing was assessed by X-ray examination performed at approximately 40 weeks of follow-up. RESULTS: Of the hand joints examined, 294 (19.1 %) were diagnosed with clinical synovitis, and 218 joints (14.1 %) were diagnosed with subclinical synovitis. The remaining 1,028 joints (66.8 %) were synovitis-free on clinical examination and imaging. For the diagnosis of subclinical synovitis, cMRI (11.4 %) was significantly more sensitive than power Doppler signals detected by US (US-PD; 6.8 %) (P < 0.01), and the combination of US-PD and cMRI was more useful (14.1 %) than US-PD or cMRI alone (P < 0.05). Follow-up X-ray examination of 600 joints showed a significantly higher incidence of bone erosion in joints with subclinical synovitis than in synovitis-free joints (P < 0.05). CONCLUSION: US-PD and cMRI are useful for detecting subclinical synovitis in patients with RA. Subclinical synovitis of the small joints of the hand can progress to bone destruction.

Early diagnosis and treatment of steroid-induced diabetes mellitus in patients with rheumatoid arthritis and other connective tissue diseases.

PURPOSE: To reveal how often patients with rheumatoid arthritis (RA) or any of other connective tissue diseases (CTDs) who take prednisolone (PSL) manifest postprandial hyperglycemia, and to evaluate the effects of divided daily dose administration of PSL, and of acarbose and nateglinide, on RA patients. METHOD: The blood sugar (BS) levels of the patients were measured after meals. For in-patients who showed postprandial hyperglycemia, the daily dose of PSL was divided and nateglinide and/or acarbose were/was added if their BS levels did not improve sufficiently. The patients with BS levels that were well controlled for three months were compared with the patients with poorly controlled BS levels. RESULTS: The BS levels of 78 patients, including 16 patients with diabetes mellitus (DM), were measured after meals, and 27 of them were newly diagnosed with DM. Five of 14 patients who took a steady dose of PSL showed high BS levels after lunch (over 200 mg/dl) without elevated HbA1c. The combination therapy of divided-dose PSL and nateglinide and/or acarbose improved postprandial hyperglycemia significantly. The period from the start of PSL administration to intervention was significantly longer in patients with good control at three months than the corresponding period in those with poor control. CONCLUSION: The prevalence of postprandial hyperglycemia was high in patients with RA/CTD taking PSL; accordingly, measurement of the BS level after each meal was valuable. Combination therapy of divided-dose PSL and nateglinide and/or acarbose improved postprandial hyperglycemia.

Therapeutic efficacy of tocilizumab in patients with rheumatoid arthritis refractory to anti-tumor-necrosis-factor inhibitors: 1 year follow-up with low-field extremity MRI.

OBJECTIVE: Tocilizumab (TCZ) is effective in patients with rheumatoid arthritis (RA) who are refractory to anti-tumor-necrosis-factor (anti-TNF) biologics. The Rheumatoid Arthritis Society Disease Activity Score in 28 Joints (DAS28) is used to evaluate the response to TCZ. However, DAS28 is inappropriate marker because TCZ normalizes C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) in the early stage of treatment. The aim of our study was to test the usefulness of magnetic resonance imaging (MRI)-based markers of response to TCZ treatment. METHODS: Nine patients with RA who were refractory to anti-TNF inhibitors (six to infliximab, one to etanercept, one to adalimumab, and one to both) were assessed. MRI images of both hands were obtained by low-field extremity MRI at baseline, 20, and 44 weeks of treatment, in addition to assessment with DAS28-ESR. The effect of TCZ on RA was examined by compact MRI score (cMRIS). RESULTS: All patients showed good or moderate response to TCZ treatment, as evaluated by significant reduction in DAS28-ESR at both 20 and 44 weeks (p < 0.001, each, relative to baseline). In contrast, MRI-based indexes (e.g., cMRIS, synovitis, edema, erosion scores) improved significantly at 44 weeks but not at 20 weeks. CONCLUSION: Differences in response to TCZ therapy were determined based on the method of evaluation, suggesting that MRI-based markers are potentially useful for evaluating RA response to TCZ therapy.

Importance of serine727 phosphorylated STAT1 in IFNγ-induced signaling and apoptosis of human salivary gland cells.

AIM: It is reported that in salivary glands of Sjögren's syndrome (SS), interferon gamma (IFNγ) and IFNγ-inducible genes containing signal transducers and activators of transcription 1 (STAT1) are upregulated and play a crucial role in the pathogenesis of SS. The aim of this study is to clarify which phosphorylation of STAT1, serine727 (Ser(727)) or tyrosine701 (Tyr(701)) of STAT1, is important for IFNγ signaling and IFNγ-induced apoptosis in salivary gland cells. METHODS: We established STAT1 Tyr(701) variant (tyrosine to phenylalanine; Y701F) and STAT1 Ser(727) variant (serine to alanine; S727A), which were transfected into human salivary gland (HSG) cells. HSG cells transfected with these mutant-STAT1 were analyzed on the expression of IFNγ-inducible genes and apoptosis after stimulation with IFNγ. RESULTS: In Y701F mutant-STAT1 transfected HSG cells (Ser(727)-dominant HSG cells), IFNγ-inducible genes such as IP10, IRF1, and Fas expression were increased after stimulation with IFNγ. In Ser(727)-dominant HSG cells, the induction of apoptosis after stimulation with IFNγ was also increased compared with S727A mutant-STAT1 transfected HSG cells (Tyr(701)-dominant HSG cells). CONCLUSION: Phosphorylation of Ser(727) in STAT1 might be more important in IFNγ signaling and the induction of apoptosis in HSG cells than phosphorylation of Tyr(701). Accordingly, we propose that phosphorylation of Ser(727) in STAT1 could be a potentially suitable new therapeutic target for SS patients to prevent the destruction of salivary glands.

High-dose unfractionated heparin therapy in a pregnant patient with antiphospolipid syndrome: a case report.

A case of a 37-year-old pregnant patient with antiphospholipid syndrome (APS), who has a medical history of both thrombosis and recurrent fetal loss, is presented. She was treated with predonisolone and fixed-dose unfractionated heparin (UFH) infusion, followed by plasmaphereses and fixed-dose low-molecular-weight heparin infusion during her fourth pregnancy. Unfortunately, this treatment did not have beneficial effects, resulting in intrauterine growth restriction and finally neonatal death. Continuous intravenous UFH infusion and low-dose aspirin were administrated under the monitoring of the activated partial thromboplastin time to achieve a target level of 120 s during her fifth pregnancy. A healthy baby weighing 1818 g at birth was delivered by Cesarean section at the 34th week of pregnancy. High-dose UFH infusion may be considered to be one of the preferable options to manage pregnant patients with refractory APS.