Up-regulation of CD64 Expression on Monocytes in Patients With Active Adult-Onset Still Disease: A Possible Biomarker of Disease Activity.

OBJECTIVES: In this study, we investigated whether monocyte CD64 (mCD64) expression is correlated with disease activity in patients with adult-onset Still disease (AOSD) and whether it could be used to distinguish between active and inactive disease states. METHODS: We reviewed a series of 10 patients with a definite diagnosis of AOSD, recruited from January 2013 to December 2016. We used flow cytometry to quantitatively measure mCD64 expression levels in patients presenting with active and inactive disease states and statistically analyzed the corresponding changes. RESULTS: The mean ± SD values of mCD64 expression levels in patients with active and inactive disease states were 77,148.3 ± 39,066.3 and 19,225.8 ± 7006.2 molecules/cell, respectively, indicating significantly higher mCD64 expression in the active state than in the inactive state (p = 0.005). Receiver operating characteristic analysis with a cutoff value of 31,796.0 molecules/cell was applied to distinguish active from inactive disease states; the sensitivity and specificity were both 100%. In these patients, only the mCD64 expression levels changed in parallel with disease activity under tocilizumab treatment; other conventional biomarkers measured showed no changes. CONCLUSIONS: Monocyte CD64 expression could be used to clearly distinguish between active and inactive AOSD. Thus, mCD64 could be a promising biomarker for evaluating the disease activity of AOSD, even in patients receiving tocilizumab treatment.

Pathological assessment of the lymph node biopsies for lymphadenopathy in rheumatoid arthritis.

Objectives: To assess the incidence of reactive lymph node hyperplasia (RLH) and the diagnostic characteristics that can help differentiate it from lymphoproliferative disorders (LPD) in patients with rheumatoid arthritis (RA).Methods: Data on patient characteristic from 32 consecutive RA patients with lymphadenopathy at a single medical center over a 6-year period were collected and analyzed to determine whether any of these characteristics can differentiated RLH from LPD.Results: LPD including methotrexate (MTX) - associated LPD (MTX-LPD) and RLH were diagnosed in 19 and 10 patients, respectively. Conclusive diagnosis was not reached in the remaining three cases and they were regarded as grey-zone cases. Age, levels of lactate dehydrogenase (LDH) and soluble interleukin-2 receptor (sIL-2R), as well as maximum standardized uptake value (SUVmax), were significantly higher in LPD than in RLH patients. The diagnosis cut-off values for these parameters were 66 year, 169 U/L, 899 U/mL and 8.18, respectively, based on the receiver operating characteristics curve analysis for both RLH and LPD.Conclusions: About one-third of patients with RA who presented with lymphadenopathy had reactive lymph node enlargement. Older age and higher levels of LDH, sIL-2R, and SUVmax are more associated with LPD than should be considered when deciding to perform a biopsy.

Systemic Sclerosis and Systemic Lupus Erythematosus Overlap Syndrome with Pulmonary Arterial Hypertension Successfully Treated with Immunosuppressive Therapy and Riociguat.

We report the case of a 40-year-old patient with systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) overlap syndrome with pulmonary arterial hypertension (overlap-PAH) that was successfully treated with a combination of immunosuppressive therapy and the soluble guanylate cyclase stimulator riociguat. She was diagnosed with mixed connective tissue disease (MCTD) two years prior to admission. She was admitted to our hospital with dyspnea on exertion and progressive skin sclerosis. She fulfilled both SLE and SSc classification criteria and was re-diagnosed with overlap syndrome. The tricuspid valve pressure gradient (TRPG) on echocardiography was 64 mmHg at admission. On right heart catheterization, mean pulmonary arterial pressure (mPAP) was 43 mmHg and pulmonary capillary wedge pressure was 15 mmHg. We diagnosed her with SSc-SLE overlap-PAH and started treatment with corticosteroids and intravenous cyclophosphamide. We also started treatment with riociguat because we speculated she had a component of SSc-PAH and that immunosuppressive therapy alone may be insufficient. We chose riociguat because of its favorable treatment effect on SSc-PAH. Two months after treatment, her TRPG improved to 33 mmHg and the skin sclerosis improved dramatically, suggesting the efficacy of multi-drug treatment and the importance of early intervention.

Crosstalk between tumor necrosis factor-alpha signaling and aryl hydrocarbon receptor signaling in nuclear factor -kappa B activation: A possible molecular mechanism underlying the reduced efficacy of TNF-inhibitors in rheumatoid arthritis by smoking.

OBJECTIVES: To examine the influence of smoking on biologics treatment against different therapeutic targets, such as TNFα, IL-6, and T cell, in rheumatoid arthritis (RA) and elucidate the underlying molecular mechanism. METHODS: The association between drug-discontinuation due to poor therapeutic response and smoking status was analyzed individually in biologics against different therapeutic targets by a multivariable logistic regression analysis using the "NinJa" Registry, one of the largest cohorts of Japanese RA patients. In vitro enhancement of TNFα-induced NF-κB activation and subsequent proinflammatory cytokine production by cigarette chemical components was examined by RT-PCR, qPCR, ELISA, and western blotting using an immortalized rheumatoid synovial cell line, MH7A. RESULTS: The rate of drug-discontinuation due to poor therapeutic response was higher in the current smoking group than in the never- or ever-smoking groups (the odds ratio of current/never smoking: 2.189, 95%CI; 1.305-3.672,P = 0.003; current/ever: 1.580, 95%CI; 0.879-2.839,P = 0.126) in the TNF inhibitor (TNFi) treatment group. However, this tendency was not observed in either the IL-6 or T cell inhibitor treatment groups. Cigarette smoke chemical components, such as benzo[α]pyrene, known as aryl hydrocarbon receptor (AhR) ligands, themselves activated NF-κB and induced proinflammatory cytokines, IL-1ß and IL-6. Furthermore, they also significantly enhanced TNFα-induced NF-κB activation and proinflammatory cytokine production. This enhancement was dominantly inhibited by Bay 11-7082, an NF-κB inhibitor. CONCLUSIONS: These results suggest a crosstalk between TNFα signaling and AhR signaling in NF-κB activation which may constitute one of the molecular mechanisms underlying the higher incidence of drug-discontinuation in RA patients undergoing TNFi treatment with smoking habits.

Sporotrichal Tenosynovitis Diagnosed Helpfully by Musculoskeletal Ultrasonography.

A 72-year-old man presented with persistent oligoarthritis and positive results for rheumatoid factor and was suspected of having rheumatoid arthritis (RA). However, the musculoskeletal ultrasonography (MSUS) findings were not consistent with those of typical RA. He had undergone surgery for carpal tunnel syndrome, which allowed both histopathological and microbiological examinations to be performed. A synovial tissue culture was positive for Sporothrix schenckii, and he was diagnosed with sporotrichal tenosynovitis. He received anti-fungal therapy, and the sporotrichal tenosynovitis resolved. This case suggests that MSUS is a useful modality, and sporotrichal tenosynovitis, though rare, should be considered in the differential diagnosis of RA.

Hemophagocytic lymphohistiocytosis with leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma: a case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis associated with autoimmune diseases is seen in patients with systemic juvenile idiopathic arthritis, adult-onset Still's disease, and systemic lupus erythematosus, whereas it is rarely seen in patients with dermatomyositis. In addition, central nervous system involvement with dermatomyositis is rare. To the best of our knowledge, this is the first case of hemophagocytic lymphohistiocytosis complicated by leukoencephalopathy in a patient with dermatomyositis accompanied with peripheral T-cell lymphoma. CASE PRESENTATION: A 17-year-old Asian male adolescent with dermatomyositis and hemophagocytic lymphohistiocytosis that were controlled with corticosteroid therapy presented to our hospital with high fever and altered consciousness. Brain magnetic resonance imaging revealed multiple cerebral lesions. We diagnosed the central nervous system lesions as leukoencephalopathy secondary to dermatomyositis and hemophagocytic lymphohistiocytosis. Because corticosteroid and cyclophosphamide pulse therapy was ineffective, he was treated with a modified hemophagocytic lymphohistiocytosis-2004 protocol, which resulted in the disappearance of the lesions of his central nervous system. CONCLUSIONS: Our findings suggest that the hemophagocytic lymphohistiocytosis-2004 protocol including etoposide should be initiated immediately in patients with hemophagocytic lymphohistiocytosis who respond poorly to treatment for the underlying disease. Moreover, irrespective of the underlying disease, patients with hemophagocytic lymphohistiocytosis with central nervous system lesions might require bone marrow transplantation.

Early therapeutic intervention with methotrexate prevents the development of rheumatoid arthritis in patients with recent-onset undifferentiated arthritis: A prospective cohort study.

OBJECTIVES: To examine whether or not earlier therapeutic intervention with methotrexate (MTX) prevents the development of rheumatoid arthritis (RA) in patients with recent-onset undifferentiated arthritis (UA) showing high anti-citrullinated peptide antibody (ACPA) titers. METHODS: The patients were divided into two groups, one was treated with MTX (MTX+ group, n = 29), and the other was treated without MTX (MTX- group, n = 19), and other disease-modifying anti-rheumatic drugs were not permitted in the two groups before the primary endpoint was met. The primary endpoint is the occurrence of definite RA, and it was compared in the two groups after 1 year. RESULTS: The percentage of patients who developed definite RA in the MTX+ group (17.2%) was significantly lower than that in the MTX- group (78.9%) (log-rank test, P < 0.001, n = 48); adjusted hazards ratio: 0.028 [95% confidence interval (CI): 0.003-0.250, P = 0.001, n = 39]. Treatment effectiveness was not decreased by major risk factors of RA onset such as smoking habits and human leukocyte antigen-DRB1 shared epitope (SE) (smoking habit, odds ratio [OR]: 0.041 [95% CI: 0.007-0.246] P < 0.001; SE, OR: 0.022 [95% CI: 0.002-0.204] P < 0.001). The safety issues were comparable between the two groups. CONCLUSIONS: This suggests that early therapeutic intervention with MTX could safely prevent the development of RA in patients with recent-onset UA showing high ACPA titers.

Baseline anti-citrullinated peptide antibody (ACPA) titers and serum interleukin-6 (IL-6) levels possibly predict progression of bone destruction in early stages of rheumatoid arthritis (ERA).

A prospective study was made to seek for a convenient biomarker to predict progression of bone destruction (PBD) in early stages of rheumatoid arthritis (ERA). All participated patients had definite RA and their radiographic stages were mild less than stage II of the Steinbrocker classification, naïve for treatment of any DMARDs or corticosteroids. After the entry, they were treated according to the 2002 ACR management guideline for RA. The candidate biomarkers (RF-IgM, RF-IgG, CARF, ACPA, CRP, ESR, NTx, MMP-3, IL-6 and osteopontin) were measured at the entry. PBD was assessed radiographically by interval changes in the modified Sharp scores (ΔSHS) for 24 months. The associations between ΔSHS and baseline biomarkers were assessed statistically by multivariate regression analyses. Both the baseline ACPA and IL-6 levels correlated with PBD, suggesting that they could predict PBD in ERA.

Severe headache complicated by vertical atlantoaxial subluxation in diffuse systemic sclerosis with crowned dens pattern calcification.

We report a 34-year-old female case of diffuse systemic sclerosis (SSc) with generalized ectopic calcification, who developed severe headache with vertical atlantoaxial subluxation (AAS) complicated by calcification around the odontoid process (crowned dens pattern calcification). Although a rare complication, AAS should be considered as a differential diagnosis of severe headache in SSc patients with extensive calcification.

[A case of lupus cystitis in a 74-year-old woman].

The patient was a 74-year-old woman. As the history of the present illness, Raynaud's phenomenon appeared in 1998, antinuclear antibody positivity was detected in 2002, and she visited our department for the first time. Leukopenia and positivity for anti-DNA and anti-RNP antibodies were present, but active lesions were not, and thus, course observation was selected. Pollakiuria and a sensation of residual urine appeared in February 2005, diarrhea and nausea developed in November, and she was admitted to our hospital. Abdominal CT detected bilateral hydronephrosis, marked hydroureter, and hypertrophy of the urinary bladder wall, cystoscopy detected trabeculation, and features of interstitial cystitis were noted on biopsy. Edematous colon mucosa was noted on lower endoscopy, submucosal inflammatory cell infiltration on biopsy, and IgG deposition in the small vascular wall on immunostaining. Systemic lupus erythematosus (SLE) that developed as lupus cystitis was diagnosed. The clinical findings were improved by 50 mg of prednisolone. Although she developed lupus cystitis at an elderly age of 74 years, IgG deposition in the small vascular wall was detected by immunostaining of the intestinal mucosa. It is a valuable case proved that causative disease of a digestive tract symptom was enterocolitis through an immune complex as autoimmune reaction by SLE immunohistologically. There are 46 cases of lupus cystitis in Japan by 2007 since Kato reported lupus cystitis in 1985. We summarize clinical features of 46 cases and discuss difference with this case.

Dramatic regression of mesenteric abnormalities demonstrated on angiography following prednisolone and cyclophosphamide combination therapy in a patient with polyarteritis nodosa associated with Sjögren's syndrome.

A 63-year-old woman, who had been followed for Sjögren's syndrome, was admitted due to cryoglobulinemia, leukocytoclastic vasculitis, and mononeuritis multiplexa. In spite of the administration of 60 mg prednisolone, fecal occult blood was strongly positive. The colonoscopy showed multiple colonic ulcers, and a diagnosis of polyarteritis nodosa (PAN) was made because abdominal angiography revealed markedly serpentine and narrowed superior and inferior mesenteric arteries. After steroid pulse therapy and daily oral administration of cyclophosphamide were initiated, her symptoms improved and abdominal angiographic findings were finally normalized. Although there are only three case reports on improvements in abdominal angiographic findings of PAN in the literature, our case and previously reported cases suggest that improvements in angiographic findings may reflect a good prognosis of PAN.