Effects of denosumab on rheumatic diseases and refractory glucocorticoid-induced osteoporosis: a prospective study.

This study evaluates the clinical efficacy of denosumab for glucocorticoid-induced osteoporosis (GIOP) refractory to previous osteoporosis treatment. Our results show that denosumab significantly increased BMD of the lumbar spine and bilateral hip over the 24-month study period. Denosumab demonstrates potential as a treatment for GIOP refractory to previous therapy. INTRODUCTION: The aim of this study was to evaluate the clinical efficacy and safety of denosumab in patients with rheumatic diseases and glucocorticoid-induced osteoporosis (GIOP) refractory to previous osteoporosis treatment. METHODS: All patients were treated with 60 mg of denosumab subcutaneously every 6 months for 2 years after administration of bisphosphonates or rhPTH was stopped. We assessed bone mineral density (BMD) of the lumbar spine and bilateral hip at baseline, and at 6, 12, 18, and 24 months. We measured serum levels of bone alkaline acid phosphatase (BAP) and tartrate-resistant acid phosphatase (TRACP)-5b at baseline, and at 3, 6, 12, 18, and 24 months. RESULTS: Fifty-five patients with rheumatic diseases and GIOP were enrolled in this study. All patients were treated with bisphosphonates (n=40), recombinant human parathyroid hormone (n=4), or active vitamin D3 (n=11). Over the 24-month study period, denosumab significantly increased the mean BMD of the lumbar spine and bilateral hip (5.8 ± 0.7%, and 1.3 ± 0.4%, respectively). Additionally, denosumab also significantly reduced the serum levels of TRACP-5b and BAP over this same period (by -38.8 ± 3.5% and -16.3 ± 3.1%, respectively), although these changes in bone turnover markers were not predictive factors of an improvement in BMD values. While three patients developed fragility fractures during the study period, all three had several risk factors for fragility fractures in GIOP. CONCLUSIONS: In conclusion, denosumab is a potential treatment for GIOP in rheumatic diseases, especially in patients refractory to previous therapy, including bisphosphonate therapy.

Successful abatacept treatment for Felty's syndrome in a patient with rheumatoid arthritis.

We report the case of a 69-year-old man with a 38-year history of rheumatoid arthritis (RA), who developed Felty's syndrome, successful treatment with abatacept (ABT). He was treated with etanercept 50 mg/w and methotrexate 8 mg/w for the past 5 years. He was suffered from febrile neutropenia 6 months ago. Etanercept and methotrexate was discontinued 3 months ago, however, neutrophil count was not changed. Abdominal ultrasound showed splenomegaly, the diagnosis of Felty's syndrome was made. Granulocyte colony-stimulating factor therapy showed no effect on neutropenia, he was treated with ABT. After ABT therapy, absolute neutrophil count was elevated 234/µL to 1840/µL.

Correction: Serum matrix metalloproteinase 3 levels are associated with an effect of iguratimod as add-on therapy to biological DMARDs in patients with rheumatoid arthritis.

[This corrects the article DOI: 10.1371/journal.pone.0202601.].

Efficacy of abatacept tapering therapy for sustained remission in patients with rheumatoid arthritis: Prospective single-center study.

AIM: To investigate whether remission can be sustained for rheumatoid arthritis (RA) patients after tapering abatacept (ABT). METHOD: All patients were naïve to biological disease-modifying anti-rheumatic drugs (bDMARDs) and in low or moderate Disease Activity Score of 28 joints with C-reactive protein (DAS)28-CRP). ABT was administrated intravenously (IV) or subcutaneously (SC) for 36 weeks to patients with RA, who had not previously received bDMARDs. As the ABT tapering protocol, ABT was administrated SC at 125 mg every 2 weeks for 12 weeks in patients with remission. RA disease activity was assessed by DAS28-CRP and ultrasonography. Remission was assessed by defining it as DAS28-CRP <2.3. RESULTS: Of the 51 patients, 84.3% were women (mean age 68.7 ± 10.2 years, mean disease duration 7.7 ± 10.2 years). Twenty-nine patients achieved remission and a power Doppler (PD) score ≤1 at each joint at 36 weeks, followed by tapering ABT. Of these patients, 25 sustained DAS28-CRP remission, and DAS28-CRP was not significantly elevated (1.62 ± 0.41 to 1.69 ± 0.49) at 48 weeks, but the total PD score was significantly elevated (1.52 ± 1.21 to 2.59 ± 2.81 P = 0.049). Longer disease duration, higher DAS28-CRP at 24 weeks, and higher total PD score at 24 weeks were predictors of an elevated total PD score after tapering ABT therapy. CONCLUSION: These findings suggest that ABT tapering is a promising short-term strategy to sustain remission in patients with RA, and ultrasonography is a useful tool for monitoring disease activity after tapering ABT.

Asymptomatic rheumatoid meningitis revealed by magnetic resonance imaging, followed by systemic rheumatic vasculitis: A case report and a review of the literature.

We report the case of a 66-year-old man with seropositive rheumatoid arthritis who developed neurologically asymptomatic rheumatoid meningitis (RM) revealed by MRI. RM worsened and chest CT showed pericardial effusion, pleural effusion, and bilateral consolidation, and his serum C3 level was decreased. We diagnosed systemic rheumatic vasculitis based on these findings. After a review of more than 20 previously reported cases of RM, this is the first case of RM without central nerve system symptoms.

Efficacy and safety of oral high-trough level tacrolimus in acute/subacute interstitial pneumonia with dermatomyositis.

OBJECTIVES: We assessed the efficacy and safety of combination therapy with glucocorticoids and high-trough level tacrolimus (TAC) for the treatment of acute/subacute interstitial pneumonia (A/SIP) in patients with dermatomyositis (DM). METHODS: Eleven DM-A/SIP patients were enrolled. The combination therapy with glucocorticoids and TAC was started as early as possible after DM-A/SIP was diagnosed. We monitored the trough concentration of TAC. In the initial 3 months, we maintained the trough concentration of TAC at relatively high levels within a range of 15-20 ng/mL. Then, we decreased the TAC doses stepwise to keep the trough concentration at 10-15 ng/mL in the next 3 months and 5-10 ng/mL as a maintenance dose. RESULTS: Seven patients had clinically amyopathic DM. Six patients were positive for anti-aminoacyl-tRNA synthetase antibody and two were positive for anti-melanoma differentiation-associated gene 5 antibody. Ten patients survived for the period of the 24-week follow up. One patient died under a tentative diagnosis of viral encephalitis at 4 months after the treatment. In the 10 surviving patients, interstitial pneumonia improved in eight patients and was not worse in two patients. Clinical examinations, including the Krebs von den Lungen-6 levels, % forced vital capacity, and chest computed tomography score, were significantly improved by this combination therapy. Although grade 1 and 2 renal damage occurred in 4 and 2 patients, respectively. CONCLUSIONS: The present findings suggest that early therapeutic intervention by a combination with glucocorticoids and initial high-trough level TAC is effective for DM-A/SIP although consideration of the risks of infection and renal damage is required.

Factors associated with the achievement of biological disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: the ANSWER cohort study.

BACKGROUND: Clinical remission can be maintained after the discontinuation of biological disease-modifying antirheumatic drugs (bDMARDs) in some patients with rheumatoid arthritis (RA) (bDMARD-free remission (BFR)). It is unknown which bDMARD is advantageous for achieving BFR or under which conditions BFR can be considered. This study aimed to determine the factors associated with BFR achievement in clinical practice. METHODS: Patients with RA were enrolled from a Japanese multicenter observational registry. Patients with RA who achieved clinical remission (Disease Activity Score 28-C-reactive protein < 2.3) at the time of bDMARD discontinuation were included. Serial disease activities and treatment changes were followed up. BFR was considered to have failed if the disease activity exceeded the remission cutoff value or if bDMARDs were restarted. RESULTS: Overall, 181 RA patients were included. BFR was maintained in 21.5% of patients at 1 year after bDMARD discontinuation. BFR was more successfully achieved after discontinuation of anti-tumor necrosis factor (TNF) monoclonal antibodies (TNFi(mAb)) (infliximab, adalimumab, and golimumab), followed by CTLA4-Ig (abatacept), soluble TNF receptor or Fab fragments against TNF fused with polyethylene glycol (etanercept and certolizumab), and anti-interleukin-6 receptor Ab (tocilizumab). After multivariate analysis, sustained remission (> 6 months), Boolean remission, no glucocorticoid use at the time of bDMARD discontinuation, and use of TNFi(mAb) or CTLA4-Ig remained as independent factors associated with BFR. CONCLUSIONS: BFR can be achieved in some patients with RA after bDMARD discontinuation in clinical practice. Use of TNFi(mAb) or CTLA4-Ig, sustained remission, Boolean remission, and no glucocorticoid use at the time of bDMARD discontinuation are advantageous for achieving BFR.

Serum matrix metalloproteinase 3 levels are associated with an effect of iguratimod as add-on therapy to biological DMARDs in patients with rheumatoid arthritis.

OBJECTIVE: The aim of this study was to clarify whether serum matrix metalloproteinase 3 (MMP-3) levels are associated with an effect of iguratimod as add-on therapy to biological DMARDs (bDMARDs) in patients with rheumatoid arthritis (RA). METHODS: Forty three patients with RA were treated with iguratimod as add-on therapy to bDMARDs. They were classified into remission and non-remission groups at 24 weeks of iguratimod therapy. Remission was defined as a state with a disease activity score (DAS) <2.6 in 28 joints (termed DAS remission) and total power Doppler ultrasound (US) score <3 (termed US remission). The serum MMP-3 levels at baseline and at 12 weeks were compared between these two groups. RESULTS: There were no significant differences in the serum MMP-3 levels at baseline between the DAS and US remission groups and the non-remission group. The serum MMP-3 levels at 12 weeks in the US remission group were significantly lower than those in the non-remission group. The ratios of the serum MMP-3 levels at baseline to those at 12 weeks in both the DAS and US remission groups were significantly lower than those in the non-remission group. An MMP-3 ratio <0.86 was determined as the cut-off value to predict US remission at 24 weeks. CONCLUSION: Our findings suggest that the ratios of the serum MMP-3 levels at baseline to those at 12 weeks could be used to predict remission in RA patients who are administered iguratimod as an add-on to bDMARDs.

Drug retention and discontinuation reasons between seven biologics in patients with rheumatoid arthritis -The ANSWER cohort study.

The purpose of this study was to evaluate the retention and discontinuation reasons of seven biological disease-modifying antirheumatic drugs (bDMARDs) in a real-world setting of patients with rheumatoid arthritis (RA). 1,037 treatment courses with bDMARDs from 2009 to 2016 [female, 81.8%; baseline age, 59.6 y; disease duration 7.8 y; rheumatoid factor positivity 81.5%; Disease Activity Score in 28 joints using erythrocyte sedimentation rate (DAS28-ESR), 4.4; concomitant prednisolone 43.5% and methotrexate 68.6%; Bio-naïve, 57.1%; abatacept (ABT), 21.3%; tocilizumab (TCZ), 20.7%; golimumab (GLM), 16.9%; etanercept (ETN), 13.6%; adalimumab (ADA), 11.1%; infliximab (IFX), 8.5%; certolizumab pegol (CZP), 7.9%] were included in this multi-center, retrospective study. Drug retention and discontinuation reasons at 36 months were estimated using the Kaplan-Meier method and adjusted by potent confounders using Cox proportional hazards modeling. As a result, 455 treatment courses (43.9%) were stopped, with 217 (20.9%) stopping due to inefficacy, 113 (10.9%) due to non-toxic reasons, 86 (8.3%) due to toxic adverse events, and 39 (3.8%) due to remission. Drug retention rates in the adjusted model were as follows: total retention (ABT, 60.7%; ADA, 32.7%; CZP, 43.3%; ETN, 51.9%; GLM, 45.4%; IFX, 31.1%; and TCZ, 59.2%; P < 0.001); inefficacy (ABT, 81.4%; ADA, 65.7%; CZP, 60.7%; ETN, 71.3%; GLM, 68.5%; IFX, 65.0%; and TCZ, 81.4%; P = 0.015), toxic adverse events (ABT, 89.8%; ADA, 80.5%; CZP, 83.9%; ETN, 89.2%; GLM, 85.5%; IFX, 75.6%; and TCZ, 77.2%; P = 0.50), and remission (ABT, 95.5%; ADA, 88.1%; CZP, 91.1%; ETN, 97.5%; GLM, 94.7%; IFX, 86.4%; and TCZ, 98.4%; P < 0.001). In the treatment of RA, ABT and TCZ showed higher overall retention, and TCZ showed lower inefficacy compared to IFX, while IFX showed higher discontinuation due to remission compared to ABT, ETN, GLM, and TCZ in adjusted modeling.

Efficacy and safety of combination therapy with prednisolone and oral tacrolimus for progressive interstitial pneumonia with systemic sclerosis: A retrospective study.

OBJECTIVES: We retrospectively investigated efficacy and safety of combination therapy with prednisolone (PSL) and tacrolimus (TAC) for progressive interstitial pneumonitis with systemic sclerosis (SSc-PIP). METHODS: We studied 11 patients with SSc-PIP who received combination therapy with PSL (0.5 mg/kg/d) and TAC (3 mg/d). RESULTS: Baseline Hugh-Jones grades were I, II, III, and IV in 2, 6, 2, and 1 patients, respectively. Krebs von den Lungen-6 (KL-6) values were elevated to 914 (range 300-2614) U/mL. % Diffusing capacity of carbon monoxide (%DLco) remarkably decreased to 47.4 (range 9.7-64.4) %. All patients were alive at 1 year after therapy. In response to treatment, interstitial pneumonia (IP) improved in three patients, stable in seven patients, and deteriorated in one patient. Total ground-glass opacity (GGO) score improved (p = .005). No significant changes occurred in values of KL-6, % forced vital capacity (%FVC), and %DLco. Presently, all seven patients who could be followed up were alive. IP improved in three patients and stable in four patients. Total GGO score improved (p = .016). KL-6, %FVC, and %DLco did not change. Mild cytomegalovirus or herpes zoster infection occurred in two patients. Grade I renal injuries were observed in three and one patient at 1 year and present, respectively. CONCLUSION: Combination therapy with PSL and TAC appeared to be well tolerated and effective in suppressing the disease activity of SSc-PIP.

Evaluation of clinical prognostic factors for interstitial pneumonia in anti-MDA5 antibody-positive dermatomyositis patients.

OBJECTIVES: We retrospectively investigated clinical prognostic factors for interstitial pneumonia (IP) in anti-melanoma differentiation-associated gene 5 (MDA5) antibody (Ab)-positive dermatomyositis (DM) patients. METHODS: Subjects comprised 18 patients with anti-MDA5 Ab-positive DM-IP (9 survivors; 9 deaths). RESULTS: Initial serum albumin levels, ferritin levels, and ground-glass opacity (GGO) scores in the right middle lobes were significantly higher in the death group than in the survivor group (p = .033, .013, and .005, respectively). Initial alveolar-arterial oxygen gradient (P[A-a]O2) was also higher in the death group than in the survivor group (p = .064). Initial serum ferritin, P[A-a]O2, and right middle lobe GGO score were found to significantly relate to death. Survival rates after 24 weeks were significantly lower among patients with an initial ferritin level of ≥450 ng/mL (25%), P[A-a]O2 of ≥30 mmHg (31%), and a right middle lobe GGO score of ≥2 (11%) than each of the others (p = .006, .020, and .002, respectively). CONCLUSIONS: An initial serum ferritin level of ≥450 ng/mL, P[A-a]O2 of ≥30 mmHg, and right middle lobe GGO score of ≥2 (GGO ≥5% of the lobe) were identified as poor prognostic factors for anti-MDA5 Ab-positive DM-IP patients.

Eosinophilic granulomatosis with polyangiitis complicated by subarachnoid hemorrhage and coronary vasculitis: a case report and review of the literature.

Eosinophilic granulomatosis with polyangiitis (EGPA) is characterized by necrotizing vasculitis of small-sized vessels with extravascular granulomas and eosinophilic infiltration. The case of a 48-year-old Japanese woman with EGPA, who presented concurrently with subarachnoid hemorrhage (SAH) and coronary vasculitis, is reported. She initially presented with bronchial asthma, and then 8 months later she developed various symptoms caused by systemic eosinophilic vasculitis and was admitted to our hospital. Three days after admission, she started oral corticosteroid therapy, and her 2009 Five-Factor Score (FFS) was 0. However, she developed an SAH, followed by coronary vasculitis 1 day later. With extensive treatment with a combination of betamethasone, cyclophosphamide, intravenous immunoglobulin, and rituximab, her systemic vasculitis improved dramatically. This seems to be the first case of EGPA with SAH and coronary vasculitis. In previous reports of EGPA with SAH, 4 of 11 cases developed SAH as an exacerbation of systemic vasculitis during remission induction therapy. The present patient also had SAH during remission induction therapy. However, the period between bronchial asthma and SAH was only 8 months. This is the shortest among case reports of EGPA with SAH. In addition, the present patient rapidly developed coronary vasculitis. These findings suggest that EGPA causes SAH and coronary vasculitis as early complications of systemic vasculitis. In EGPA, it is necessary to pay careful attention to rapid changes of disease activity, even when the FFS indicates a good prognosis.

Add-on iguratimod as a therapeutic strategy to achieve remission in patients with rheumatoid arthritis inadequately responding to biological DMARDs: A retrospective study.

OBJECTIVES: In this study, iguratimod (IGU) was added to rheumatoid arthritis (RA) patients inadequately responding to 24-week or longer treatment with biological disease-modifying antirheumatic drug (bDMARDs), its effectiveness was assessed, and factors contributing to remission were evaluated. METHODS: RA patients who fulfilled the following criteria were included: (i) ≥ 24-week of bDMARDs; (ii) 2.6 < disease activity score (DAS) 28-erythrocyte sedimentation rate (ESR) < 5.1 or the presence of synovitis with a power Doppler (PD) score ≥2 in at least 1 of the 28 joints on joint ultrasonography. Disease activity and joint ultrasound findings were evaluated at baseline and at 12 and 24 weeks. RESULTS: DAS assessing 28 joints with ESR (DAS28-ESR) decreased significantly from 3.45 ± 0.92 at baseline to 2.85 ± 1.13 at 24 weeks (p < .001). Overall, 38.3% achieved clinical remission (c-remission). The total PD score decreased significantly from 8.7 ± 6.1 at baseline to 5.5 ± 5.0 at 24 weeks (p < .001). A lower baseline DAS28-ESR was related to c-remission after 24 weeks (p =.002). Shorter duration of disease (p =.020) was related to ultrasound remission, in addition to a lower baseline DAS28-ESR (p < .001). CONCLUSIONS: IGU add-on therapy can be a therapeutic strategy to achieve remission in RA patients inadequately responding to ≥24-week treatment with bDMARDs.

Multimodality assessment of left ventricular dysfunction in Takayasu arteritis and familial hypercholesterolaemia.

Although left ventricular (LV) systolic dysfunction in patients suffering from Takayasu arteritis (TA) has been reported, little is known regarding the development of heart failure in these patients. We report a novel finding of active TA and familial hypercholesterolaemia presenting with severe LV dysfunction through multimodality assessments of LV systolic dysfunction.

Chemokine profiles of interstitial pneumonia in patients with dermatomyositis: a case control study.

Chemokines play an important role in the pathophysiology of dermatomyositis (DM) with interstitial pneumonia (IP). However, the relation between chemokines and the disease activity or prognosis of DM-IP has not been elucidated. We evaluated the serum C-C motif chemokine ligand (CCL) 2, Th1 chemokines (C-X-C motif chemokine ligand [CXCL] 9, CXCL10, CXCL11), and Th2 chemokine (CCL17) profiles of 30 patients, and examined the relation between these chemokines and the disease activity or prognosis of DM-IP. Initial serum CCL2 level was higher in the death group (P = 0.007). To determine the cut-off points effective as poor prognostic factors of DM-IP, ROC curve analysis was carried out on initial serum CCL2 level. The value that maximized the area under the ROC curve was 894 pg/mL (sensitivity: 100%, specificity: 70.8%). Serum CCL2, CXCL9, CXCL10, and CXCL11 levels were lower at 2 weeks after treatment initiation than before treatment. Serum CCL2, CXCL10, and CXCL11 levels at 2 weeks after treatment initiation were higher in the death group. Serum levels of chemokines such as CCL2, CXCL10, and CXCL11 may be possible biomarkers of disease activity and prognosis in DM-IP, and serum CCL2 level may be useful when deciding initial treatment.

Gastrointestinal involvement at the onset of granulomatosis with polyangiitis: A case report.

A 30-year-old man had developed fever, bloody stools, and oral aphtha. Proteinase 3-antineutrophil cytoplasmic antibody level was 31 EU. Lower intestinal endoscopy revealed edematous mucosa with hemorrhage in the transverse colon. Biopsies of oral aphtha showed necrotizing angiitis with granuloma. Based on these findings, he was diagnosed with granulomatosis with polyangiitis (GPA). Digestive symptoms were remitted by treatment with prednisolone and azathioprine. GPA with digestive symptoms as the initial development is rare.

Differentiation between Polymyalgia Rheumatica (PMR) and Elderly-Onset Rheumatoid Arthritis Using 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography: Is Enthesitis a New Pathological Lesion in PMR?

BACKGROUND: It is difficult to differentiate polymyalgia rheumatica (PMR) from elderly-onset rheumatoid arthritis (EORA) in clinical practice. We compared FDG-PET/CT findings between patients with PMR and those with EORA and extracted factors useful for differentiating the two disorders. METHODS: We compared abnormal FDG accumulation sites and maximum standardized uptake value (SUVmax) between 15 patients with PMR and 7 with EORA in whom FDG-PET/CT was performed. RESULTS: The proportion of patients in the PMR group with abnormal FDG accumulation at the following 9 sites on FDG-PET/CT was significantly higher than that in the EORA group: periarticular region of the scapulohumeral joint, enthesis of the pectineus muscle, vicinity of the enthesis of the rectus femoris muscle, lateral side of the greater trochanter, ischial tuberosity, hip joint, spinous process of the lower cervical vertebra, intervertebral joint of the lumbar vertebra, and spinous process of the lumbar vertebra. The PET/CT score was evaluated at 9 sites consisting of the abovementioned sites. The median score in the PMR group was 8, which was significantly higher than that of 0 in the EORA group (P = 0.0003). ROC curve analysis was performed with the PET/CT scores, and a score of 5 was shown to maximize the area under the ROC curve (sensitivity: 86.7%, specificity: 86.7%). CONCLUSIONS: FDG-PET/CT is useful for differentiating PMR from EORA. In patients with PMR, abnormal FDG accumulation was observed at the entheses, suggesting the presence of enthesitis in addition to bursitis and synovitis.