Efficient detection of somatic UBA1 variants and clinical scoring system predicting patients with variants in VEXAS syndrome.

OBJECTIVES: To efficiently detect somatic UBA1 variants and establish a clinical scoring system predicting patients with pathogenic variants in VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome. METHODS: Eighty-nine Japanese patients with clinically suspected VEXAS syndrome were recruited [81 males and 8 females; median onset age (IQR) 69.3 years (62.1-77.6)]. Peptide nucleic acid-clamping PCR (PNA-PCR), regular PCR targeting exon 3 clustering UBA1 variants, and subsequent Sanger sequencing were conducted for variant screening. Partitioning digital PCR (pdPCR) or targeted amplicon deep sequencing (TAS) was also performed to evaluate the variant allele frequency (VAF). We developed our clinical scoring system to predict UBA1 variant-positive and ­negative patients and assessed the diagnostic value of our system using receiver operating characteristic (ROC) curve analysis. RESULTS: Forty patients with reported pathogenic UBA1 variants (40/89, 44.9%) were identified, including a case having a variant with VAF of 1.7%, using a highly sensitive method. Our clinical scoring system considering >50 years of age, cutaneous lesions, lung involvement, chondritis, and macrocytic anaemia efficiently predicted patients with UBA1 variants (the area under the curve for the scoring total was 0.908). CONCLUSIONS: Genetic screening with the combination of regular PCR and PNA-PCR detected somatic UBA1 variants with high sensitivity and specificity. Our scoring system could efficiently predict patients with UBA1 variants.

Effectiveness and safety of non-tumor necrosis factor inhibitor therapy for anti-human T-cell leukemia virus type 1 antibody-positive rheumatoid arthritis.

OBJECTIVES: Our previous study showed that the effectiveness of tumor necrosis factor (TNF) inhibitors was attenuated in anti-human T-cell leukemia virus type 1 (HTLV-1) antibody-positive patients with rheumatoid arthritis (RA). We aimed to evaluate the effectiveness and safety of non-TNF inhibitors in anti-HTLV-1 antibody-positive patients with RA. METHODS: We reviewed patients with RA who received abatacept or tocilizumab as the first biologic agent. We used the data of patients treated with TNF inhibitors from our previous study to compare the effectiveness between the anti-HTLV-1 antibody-positive patients treated with TNF inhibitors and non-TNF inhibitors using the inverse probability of treatment weights (IPTW) method. RESULTS: A total of 359 patients were divided into anti-HTLV-1 antibody-negative and -positive patients of 332 and 27, respectively. No statistically significant difference was observed in the change in the clinical disease activity index between the anti-HTLV-1 antibody-positive and -negative patients. The results using the IPTW method showed a significant association between the non-TNF inhibitors treatment and a better response. None of the patients developed adult T-cell leukemia/lymphoma or HTLV-1-associated myelopathy/tropical spastic paraparesis during the 24 weeks. CONCLUSION: Our results indicate that non-TNF inhibitors treatment is safety, and the effectiveness is not attenuated also in anti-HTLV-1 antibody-positive patients.

Diagnostic efficacy of ultrasound detection of enthesitis in peripheral spondyloarthritis.

Objective: We investigated the diagnostic efficacy of power Doppler ultrasound (PDUS) to detect enthesitis in Japanese patients with peripheral spondyloarthritis (SpA).Methods: This was a single-center cohort study of patients with peripheral symptoms suggestive of SpA. Articular synovia, tendons, and entheses were assessed by PDUS at baseline. Clinical, laboratory, and radiologic findings and classification criteria for SpA were also evaluated.Results: 136 patients were consecutively evaluated. A definite diagnosis was obtained in 111 patients, including 72 with SpA and 39 non-SpA. Among the patients with SpA, PDUS demonstrated articular synovitis in 40 of the 72 patients (56%), tenosynovitis or peritendinitis in 48 (67%), and enthesitis in 63 (88%). Considering PDUS alone, enthesitis in at least one site was the most useful means of differentiating SpA from non-SpA (sensitivity 87.5%; specificity 82.1%; accuracy 85.6%; positive likelihood ratio 4.88). Combining that finding along with fulfillment of Amor, European Spondyloarthropathy Study Group, or Assessment of SpondyloArthritis international Society criteria for peripheral SpA increased the specificity of the diagnosis (92.5%, 92.3%, and 97.4%, respectively).Conclusion: PDUS enthesitis is useful for the diagnosis of SpA with peripheral symptoms. Combining PDUS enthesitis with established SpA classification criteria is beneficial in diagnosing peripheral SpA.

Prediction of organ involvement in systemic sclerosis by serum biomarkers and peripheral endothelial function.

OBJECTIVES: To identify prognostic factors among serum biomarkers and endothelial vasodilator function findings in patients with systemic sclerosis (SSc). METHODS: This is a clinical observational study. We assessed 60 consecutive SSc patients (44 limited cutaneous-type, 16 diffuse cutaneous-type). Circulating growth differentiation factor-15 (GDF-15), placenta growth factor (PlGF), endostatin, vascular endothelial growth factor (VEGF), and pentraxin 3 (PTX3) were measured by ELISA. Peripheral endothelial function was measured by forearm blood dilatation response to brachial artery occlusion using noninvasive plethysmography (EndoPAT2000), which is associated with nitric-oxide-dependent vasodilatation and yields a reactive hyperemia index (RHI). We evaluated whether abnormalities in these values were associated with type of SSc - namely, diffuse cutaneous SSc (dcSSc) or limited cutaneous SSc (lcSSc) - or organ involvement including interstitial lung disease (ILD), digital ulcer (DU) and estimated right ventricular systolic pressure (RVSP) by echocardiography >30 mmHg. RESULTS: SSc patients showed significantly elevated serum GDF-15, PlGF, endostatin and VEGF but not PTX3 compared with controls. GDF-15 and PlGF were high in dcSSc patients. EndoPAT-RHI was low, and incidence of RVSP >30 mmHg was high in dcSSc. Multivariate analysis revealed that elevated GDF-15 was highly predictive of dcSSc, ILD or RVSP >30 mmHg. PlGF for DU was also found. Conversely, a low EndoPAT-RHI value was predictive of the presence of dcSSc, ILD or DU. CONCLUSIONS: This is the first study to inclusively investigate the relationships among biomarkers, EndoPAT-RHI and organ involvement in patients with SSc. Our data suggest a complex pathological progression of SSc through fibrotic impairment and microvascular damage.

Histological improvement in salivary gland along with effector memory Th17-1 cell reduction in a primary Sjogren's syndrome patient with dermatomyositis and diffuse large B-cell lymphoma by R-CHOP therapy.

We treated a 45-year-old Japanese woman with primary Sjogren's syndrome (SS) complicated with dermatomyositis (DM) followed by diffuse large B-cell lymphoma. She was admitted to our hospital for further evaluation of fever, weight loss and peritoneal lymphadenopathy. The histological examination of her lymph node revealed diffuse large B-cell lymphoma. The patient was then treated with 8 cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) therapy, which resulted in histological and functional improvement of her salivary glands. Of note, the percentage of effector memory Th17-1 (CD3+CD4+CD45RA-CCR7-CXCR3+CCR6+) cells in the peripheral blood was decreased after the R-CHOP treatment. This case suggests that an altered Th17-1 cell subset by B-cell depletion therapy is critical for the improvement of tissue damage in patients with SS, and the case suggests that clinicians should consider measuring the effector memory Th-subsets to predict the disease activity in SS patients.

Rapid improvement of Clinical Disease Activity Index (CDAI) at 3 months predicts a preferable CDAI outcome at 1 year in active rheumatoid arthritis patients treated with tocilizumab: results from an observational investigation of daily clinical practice.

OBJECTIVES: To investigate whether the Clinical Disease Activity Index (CDAI) at three months predicts a preferable CDAI outcome at one year in patients with active rheumatoid arthritis (RA) treated with tocilizumab (TCZ). METHODS: Seventy-eight RA patients in the Nagasaki Prefecture, Japan, whose disease activities at baseline were moderate to high as estimated by the CDAI and who had received 8 mg/kg of TCZ every four weeks, were consecutively enrolled in this study from April 2008 to March 2011. The association of the CDAI at three months with that at one year was examined by the Cochran-Armitage test. The variables at baseline and at three months that were predictive of remission or low disease activity (LDA) according to the CDAI at one year were assessed by logistic regression analysis. RESULTS: Most of the patients (40 out of 44: 91%), whose CDAI at three months showed remission or LDA continued to show remission or LDA at one year. Disease activity at three months significantly correlated with the frequency of LDA or remission at one year (p<0.0001). Logistic regression analysis revealed that only remission or LDA at three months as determined by the CDAI was predictive of remission or LDA at one year as determined by the CDAI (odds ratio 33.2, p<0.0001). CONCLUSIONS: A preferable clinical outcome as estimated by the CDAI at one year in active RA patients treated with TCZ is predicted by the CDAI at three months, suggesting that the treat-to-target strategy carried out using the CDAI can be used in clinical practice in these patients.

Evaluation of switching from intravenous to subcutaneous formulation of tocilizumab in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy of switching the route from intravenous tocilizumab (TCZ) infusion (TCZ-IV) to subcutaneous TCZ injection (TCZ-SC) in a real-world setting through a comparison of the clinical response. METHODS: Fifty-eight rheumatoid arthritis (RA) patients, for whom TCZ-SC was initiated following TCZ-IV between June 2013 and August 2014, were consecutively enrolled. Disease activity score (DAS)28-ESR, simplified disease activity index (SDAI), and clinical disease activity index (CDAI) were examined at baseline and after switching from TCZ-IV to TCZ-SC for 3 months. We investigated whether body weight and body mass index (BMI) affected the efficacy of TCZ-SC. RESULTS: Most of the patients had achieved remission or low disease activity at baseline (77.6% examined by DAS28). Fifty-seven patients (98%) continued the TCZ-SC treatment, and the disease activity was well controlled after 3 months. ΔDAS28 tended to be worsened after switching to TCZ-SC in the high-body-weight groups (≥60 kg) as compared with the groups with body weight <60 kg, although no statistical significance was found. BMI did not affect the efficacy of TCZ-SC. CONCLUSIONS: Caution should be exercised in the high-body-weight subjects, but these data indicate that TCZ-SC maintains the favorable RA disease activity established using TCZ-IV.

Musculoskeletal ultrasonography assists the diagnostic performance of the 2010 classification criteria for rheumatoid arthritis.

OBJECTIVE: We investigated whether musculoskeletal ultrasonography (MSKUS) assists the diagnostic performance of the 2010 rheumatoid arthritis (RA) classification criteria. METHODS: Sixty-nine early arthritis patients were consecutively enrolled. None of the patients had been treated. In MSKUS of bilateral wrist and finger joints from 22 sites, the findings obtained by gray-scale and power Doppler (PD) assessment were graded on a semiquantitative scale from 0 to 3. Plain magnetic resonance imaging (MRI) of both wrist and finger joints was also examined. Diagnosis of RA was defined by the initiation of disease-modifying antirheumatic drugs within the first 3 months. The diagnostic performance of the patients was evaluated at entry using 2010 RA classification criteria in conjunction with MSKUS. RESULTS: The indispensable MSKUS finding for differentiating RA was the presence of a PD grade 2 or 3 that was superior to 2010 RA classification criteria or MRI-proven bone edema. We propose that the decision tree algorithm of 2010 RA classification criteria with PD grade 2 or 3 reveals the best discriminative ability. CONCLUSION: MSKUS, especially with a strong PD signal, is very useful to assist the diagnostic performance of the 2010 RA classification criteria in the early recognition of RA.

A case of primary Sjögren's syndrome complicated with inflammatory myopathy and interstitial lung disease.

We experienced a case of a 63-year-old woman with primary Sjögren's syndrome (pSS) complicated with inflammatory myopathy and interstitial lung disease (ILD). She had suffered from morning stiffness and dry mouth for 1 year without being medically examined. A chest CT scan demonstrated ground glass opacity and a reticular shadow in the lower lung field. A diagnosis of SS was made based on positive findings from Schirmer's test, sialography of the parotid gland, a labial salivary gland biopsy and the presence of anti-SS-A antibody. Musculoskeletal symptoms were absent; however, the elevation of creatine kinase (CK) as well as magnetic resonance imaging (MRI)-proven inflammatory change of bilateral muscles of the thigh was evident. Histological examination of the thigh revealed diameter variation, degeneration of muscle fibers and inflammatory cell infiltration in the perivascular area, corresponding to the inflammatory myopathy of pSS. Oral prednisolone 30 mg/day was introduced, and serum CK rapidly decreased within 2 weeks. ILD also responded well to prednisolone without relapse. These clinical outcomes are consistent with extraglandular organ involvement of pSS.

Clinical Characteristics of Patients With IgG4-Related Disease Complicated by Hypocomplementemia.

Background: A proportion of patients with immunogloblin G (IgG) 4-related disease (IgG4-RD) have hypocomplementemia. We aimed to identify characteristics of such patients. Methods: We analyzed the demographic and clinical data and complement levels of 85 patients with IgG4-RD. We defined hypocomplementemia as serum C3 and/or C4 levels below the lower limit of normal at diagnosis. We also compared the characteristics of patients with and without IgG4-RD. Results: Thirty-two (38%) patients had hypocomplementemia at diagnosis. Patients with hypocomplementemia had more lymph node (p < 0.01), lung (p < 0.01), and kidney (p = 0.02) involvement and a higher IgG4-RD responder index than those without (p = 0.05). Additionally, patients with hypocomplementemia had significantly higher IgG (p < 0.01), IgG4 (p < 0.01), and soluble interleukin 2-receptor (sIL-2R) (p < 0.01) levels and total IgG minus IgG4 (p < 0.01). C3 and C4 levels negatively correlated with IgG, IgG4, and sIL-2R levels, total IgG minus IgG4, and number of IgG4-RD responder index: a measure of the disease activity in IgG4-RD. Patients with hypocomplementemia at diagnosis had a significantly higher frequency of relapse (p = 0.024), as determined using the log-rank test. A multivariate logistic regression analysis showed the presence of hypocomplementemia was independently associated with relapse (OR, 6.842; 95% confidence interval [95%CI], 1.684-27.79; p = 0.007). Conclusions: Patients with IgG4-RD with hypocomplementemia have a more active clinical phenotype, suggesting contributions of the complement system in the pathophysiology of IgG4-RD.

Successful treatment of a patient with IgG4-related disease with a paravertebral mass lesion.

A 68-year-old woman was admitted with bleary eyes and lacrimal gland swelling. A biopsy specimen from a right paravertebral mass lesion detected by computed tomography showed remarkable IgG4-positive plasma cells. Because serum IgG4 was elevated to 3300 mg/dl, IgG4-related disease was diagnosed, with the assistance of fluorodeoxyglucose positron emission tomography (FDG-PET)/computed tomography (CT). Administration of 30 mg of oral prednisolone effectively reduced the lacrimal gland swelling and paravertebral mass volume. Nine months after the initiation of prednisolone, serum IgG4 was reduced to 31.4 mg/dl, and there was norecurrence.

Disease activity score 28 may overestimate the remission induction of rheumatoid arthritis patients treated with tocilizumab: comparison with the remission by the clinical disease activity index.

We evaluated the efficacy of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) by the clinical disease activity index (CDAI) and disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR). Thirty-two RA patients received 8 mg/kg of TCZ intravenously every 4 weeks for 48 weeks. The therapeutic response was also evaluated in 30 RA patients treated with 3 mg/kg of infliximab (IFX) for 46 weeks. We compared the therapeutic course of TCZ with IFX in order to evaluate the efficacy of TCZ therapy. A strong positive correlation between CDAI and DAS28-ESR was observed at baseline, whereas their associations dropped significantly within the first 2 months. The association recovered to the baseline by IFX, but still remained low in TCZ. Although a decrement of DAS28-ESR was prominent in TCZ as compared with IFX, that of CDAI was significant in the early phase and even in the latter in patients treated by IFX. The present study revealed that DAS28-ESR may not be sufficient to estimate RA disease activity treated by TCZ, probably due to the significant effect toward inhibition of acute phase reactants by TCZ. CDAI is suggested to be an important alternate of composite measure in these cases.

In rheumatoid arthritis patients treated with tocilizumab, the rate of clinical disease activity index (CDAI) remission at 24 weeks is superior in those with higher titers of IgM-rheumatoid factor at baseline.

We aimed to evaluate the efficacy of tocilizumab in patients with rheumatoid arthritis (RA), using the clinical disease activity index (CDAI), and to determine the baseline variables associated with CDAI remission. Fifty-eight patients with active RA were enrolled. We tried to evaluate whether baseline variables were associated with CDAI remission at 24 weeks. Twenty-two of the 58 patients (37.9%) had received tumor necrosis factor (TNF) inhibitors. The continuation rate of tocilizumab at 24 weeks was 87.9%. The seropositivity rates of IgM-rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies at baseline were both 91.4%. The rate of CDAI remission at 24 weeks was 20.7%. We selected baseline variables including age, gender, duration of disease, concomitant use of glucocorticoids, concomitant use of methotrexate (MTX), previous anti-TNF therapy, titer of anti-CCP antibodies (high or low toward median), titer of IgM-RF (high or low toward median), and CDAI, and found that a high titer of IgM-RF was the only variable to be associated with CDAI remission, according to univariate and logistic regression analyses. This is a new finding, and may be specific to tocilizumab as compared with previous observations in anti-TNF therapy.

Reduction in serum levels of substance P in patients with rheumatoid arthritis by etanercept, a tumor necrosis factor inhibitor.

We determined the effects of etanercept on the serum concentrations of neuropeptides in RA patients. In a total of 11 patients who had been injected with etanercept, the serum levels of substance P, calcitonin gene-related peptide (CGRP), and gastrin-releasing peptide (GRP) were analyzed. Average levels of serum substance P were significantly reduced from 1.53 to 0.62 ng/ml after the injection of etanercept. In the CGRP and GRP analyses, these average levels dropped from 1.57 and 0.51 ng/ml to 0.44 and 0.04 ng/ml, respectively. Etanercept appears to decrease substance P levels with an improvement in disease activities.

Systemic Lupus Erythematosus Complicated with Listeria Monocytogenes Infection in a Pregnant Woman.

A 41-year-old woman with systemic lupus erythematosus (SLE) was admitted to our hospital due to a fever at 35 weeks of pregnancy. Laboratory testing revealed a low platelet count and elevated liver enzymes. Emergency Caesarean section was performed due to the risk of SLE exacerbation or hemolytic anemia, elevated liver enzyme, and low platelet count syndrome. Based on the blood culture results, the patient was diagnosed with Listeria monocytogenes bacteremia. She was treated with ampicillin and eventually recovered, and the neonate did not have any complications. Pregnant women with SLE are at risk of complications. Listeriosis should be monitored for and, if found, managed appropriately.

Subacute thyroiditis in a patient with psoriatic arthritis switched from secukinumab to adalimumab: a case report and literature review.

A 71-year-old Japanese female with psoriatic arthritis (PsA) was admitted for fever and neck pain. Her medication had been switched from secukinumab, an interleukin (IL)-17A inhibitor, to adalimumab, a tumour necrosis factor (TNF)-α inhibitor, due to secondary failure for PsA. She was diagnosed with subacute thyroiditis (SAT) on the basis of thyroid hormone levels and thyroid ultrasound findings. Her SAT symptoms improved with prednisolone administration (15 mg/day). Following the administration of ixekizumab, an IL-17A inhibitor, her PsA improved without SAT relapse. SAT mechanism associated with TNF inhibitors remains unknown, but cytokine imbalance may be involved.

Real-world comparative effectiveness and safety of tofacitinib and baricitinib in patients with rheumatoid arthritis.

OBJECTIVE: To compare the efficacy and safety of tofacitinib and baricitinib in patients with RA in a real-world setting. METHODS: A total of 242 patients with RA who were treated with tofacitinib (n = 161) or baricitinib (n = 81) were enrolled. We evaluated efficacy and safety between tofacitinib and baricitinib using multivariable analyses to avoid confounding. Their clinical disease activity and AEs were evaluated for 24 weeks. RESULTS: The mean (SD) DAS28-ESR change from baseline to 24 weeks was 1.57 (1.55) (tofacitinib) and 1.46 (1.36) (baricitinib). There was no significant difference in the clinical response between the two groups (adjusted mean difference, 0.04; 95% CI, -0.35 to 0.28). The efficacy was not significantly changed in the patients without concomitant MTX use in both groups, but the concomitant MTX use showed better clinical efficacy in the cases of baricitinib treatment. In both groups, the most common AE was herpes zoster infection, and the AE rates were similar between the two groups. However, the predictive factors contributing to clinical response as revealed by a multivariable logistic analysis differed. The concomitant oral steroid use was independently associated with the achievement of DAS-low disease activity in the tofacitinib group, whereas in the baricitinib group, the number of biological and/or targeted synthetic DMARDs previously used was associated. CONCLUSIONS: Our findings indicate that tofacitinib and baricitinib had comparable continuing efficacies and safety profiles. However, there is a possibility that the influence of clinical characteristics on the treatment response differs. The comparison provides useful information to the optimal use of JAK inhibitors in real-world settings.

A case of Löfgren's syndrome evaluated by imaging modalities: musculoskeletal ultrasound, MRI and PET-CT.

Löfgren's syndrome is an acute form of sarcoidosis that is characterised by articular symptoms, erythema nodosum and bilateral hilar lymphadenopathy. This syndrome is rare in Japan. We report a 62-year-old Japanese woman with Löfgren's syndrome and describe the articular manifestations as evaluated by multiple imaging modalities. Musculoskeletal ultrasound, magnetic resonance imaging and positron emission tomography-computed tomography findings indicated periarticular and subcutaneous inflammation. These imaging modalities facilitated the diagnosis of Löfgren's syndrome and helped differentiate from other rheumatic diseases.

Limited cutaneous systemic sclerosis with gangrene: an autopsy case.

We describe an autopsy case of a 75-year-old female with limited cutaneous systemic sclerosis (lcSSc) and gangrene due to macrovascular involvement. She was diagnosed with lcSSc complicated with pulmonary arterial hypertension and digital ulcers 9 years before admission. She had recurrent and refractory lower limb ulcers (LLUs), and died because of sepsis caused by gangrene infection. Autopsy findings revealed severely thickened arterial walls of the visceral organs, consistent with vascular involvement of SSc. Systemic vascular involvement in lcSSc may progress in patients with LLUs who harbour several risk factors for vascular involvement.

Prediction of DAS28-CRP remission in patients with rheumatoid arthritis treated with tacrolimus at 6 months by baseline variables.

We attempted to determine what baseline variables are responsible for the efficacy of tacrolimus at 6 months in Japanese patients with rheumatoid arthritis (RA). One hundred and six RA patients treated with tacrolimus for 6 months were entered in this study. The outcome was set as the achievement of Disease Activity Score 28 C-reactive protein (DAS28-CRP) remission at 6 months. We examined the association of gender, DAS28-CRP at baseline, concomitant use of methotrexate (MTX), and concomitant use of prednisolone with the achievement of DAS28-CRP remission at 6 months by logistic regression analysis. Twenty-three of 106 patients (21.7%) achieved DAS28-CRP remission at 6 months. There was concomitant use of MTX by 20 patients (18.9%), prednisolone by 93 (87.7%), and prednisolone [5 mg/day by 43 (40.6%) at baseline. Logistic regression analysis showed that male gender (first) and moderate disease activity at baseline (second) are independent predictors toward achieving DAS28-CRP remission at 6 months. Maximum tacrolimus dosage administrated for patients over a 6-month period appeared not to be predictive for the DAS28-CRP remission at 6 months. In conclusion, we revealed for the first time that good outcome in RA patients treated with tacrolimus can be predictive by some baseline variables. That is clinically valuable for daily practice in the choice of disease-modifying antirheumatic drugs (DMARDs), especially tacrolimus.