Successful treatment of lupus protein-losing enteropathy with belimumab: A case report.

Lupus protein-losing enteropathy (LUPLE) is a rare condition in patients with systemic lupus erythematosus (SLE). Since the causes and exact pathological mechanism have not been elucidated, appropriate treatment has not been determined. Here, we report the case of a 69-year-old woman with systemic lupus erythematosus who developed LUPLE which was successfully treated with belimumab without an increase in glucocorticoid dose. This case suggests that belimumab monotherapy may be a treatment option for LUPLE.

2020 guide for the diagnosis and treatment of interstitial lung disease associated with connective tissue disease.

The prognosis of patients with connective tissue disease (CTD) has improved significantly in recent years, but interstitial lung disease (ILD) associated with connective tissue disease (CTD-ILD) remains a refractory condition, which is a leading cause of mortality. Because it is an important prognostic factor, many observational and interventional studies have been conducted to date. However, CTD is a heterogeneous group of conditions, which makes the clinical course, treatment responses, and prognosis of CTD-ILD extremely diverse. To summarize the current understanding and unsolved questions, the Japanese Respiratory Society and the Japan College of Rheumatology collaborated to publish the world's first guide focusing on CTD-ILD, based on the evidence and expert consensus of pulmonologists and rheumatologists, along with radiologists, pathologists, and dermatologists. The task force members proposed a total of 27 items, including 7 for general topics, 9 for disease-specific topics, 3 for complications, 4 for pharmacologic treatments, and 4 for non-pharmacologic therapies, with teams of 2-4 authors and reviewers for each item to prepare a consensus statement based on a systematic literature review. Subsequently, public opinions were collected from members of both societies, and a critical review was conducted by external reviewers. Finally, the task force finalized the guide upon discussion and consensus generation. This guide is expected to contribute to the standardization of CTD-ILD medical care and is also useful as a tool for promoting future research by clarifying unresolved issues.

Concurrent onset of acute lupus myocarditis, pulmonary arterial hypertension and digital gangrene in a lupus patient: a possible role of vasculitis to the rare disorders.

Acute lupus myocarditis and pulmonary arterial hypertension (PAH) are rare complications associated with systemic lupus erythematosus (SLE). No previous reports have shown the coexistence of these disorders. Here we present a 41-year-old patient with SLE who concurrently developed severe acute lupus myocarditis and PAH with digital gangrene as an initial manifestation. Acute lupus myocarditis and PAH were successfully treated with prednisolone and intravenous cyclophosphamide pulse therapy (600-700 mg × 6) along with anticoagulant therapy. Catheter-directed thrombolysis was required for digital gangrene caused by vasculitis. Concurrent development of these rare disorders may represent a common mechanism such vasculitis as an underlining cause of SLE.

Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients.

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.Methods: In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.Results: Macitentan was administered at a once-daily dose of 10 mg in 30 PAH patients with a median treatment period of 2.4 years (range, 229-1037 days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.Conclusions: This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.

Association of NCF1 polymorphism with systemic lupus erythematosus and systemic sclerosis but not with ANCA-associated vasculitis in a Japanese population.

Genome-wide association studies of systemic lupus erythematosus (SLE) in Chinese and Korean populations demonstrated strong association of single nucleotide polymorphisms (SNPs) located in the GTF2I-NCF1 region, rs73366469 (GTF2I), rs117026326 (GTF2I), rs80346167(GTF2IRD1) and rs201802880 (NCF1). This region has also been associated with susceptibility to Sjögren syndrome and rheumatoid arthritis; however, association studies with systemic sclerosis (SSc) and ANCA-associated vasculitis (AAV) have not been reported. Here we made an attempt to confirm their associations with SLE in the Japanese population, to find the primarily associated SNP, and to investigate whether these SNPs are also associated with susceptibility to SSc and AAV. By genotyping these four SNPs on 842 SLE, 467 SSc, 477 AAV patients and 934 healthy controls, striking association was confirmed in Japanese SLE. In addition, these SNPs were significantly associated with susceptibility to SSc, but not with AAV. Conditional logistic regression analysis revealed that the association of NCF1 rs201802880, a missense SNP encoding p.Arg90His, can account for the association of other SNPs by linkage disequilibrium. These results suggested that GTF2I-NCF1 region is associated with susceptibility to multiple autoimmune rheumatic diseases but not with AAV, and the primarily associated variant may be the missense SNP in NCF1.

Adult-onset Still's disease-associated interstitial lung disease represents severe phenotype of the disease with higher rate of haemophagocytic syndrome and relapse.

OBJECTIVES: Adult-onset Still's disease (AOSD) is an inflammatory disorder characterised by sustained fevers, arthritis, and skin involvement. Interstitial lung disease (ILD) is a rare manifestation, and its clinical characteristics have yet to be determined. METHODS: We sought to examine the clinical characteristics of AOSD-associated ILD. We retrospectively investigated 78 patients diagnosed as AOSD. ILD was diagnosed based on chest high-resolution computed tomography (HRCT). Clinical characteristics were compared between patients with and without ILD. Relapse was defined as sustained fevers, re-emergence of arthritis, and skin involvement after remission. We further investigated the pathological features of ILD on available samples. RESULTS: Patients with ILD, found in 9 of 78 (11.5 %), had older age of onset (mean age 62.6) than those without ILD (mean age 38.8) (p<0.01). The 3-year survival rates were comparable between patients with ILD (92.5%) and those without ILD (88.9%) (p=0.23). Patients with ILD had a higher cumulative rate of haemophagocytic syndrome (HPS) and relapse than those without (p<0.0001 and p=0.009, respectively). Chest HRCT showed marked thickening of the interlobular septa, the bronchovascular bundles, or the visceral pleura in all cases. There was no honeycomb or volume loss. Pulmonary pathological findings revealed marked thickening of the visceral pleura and the interlobular septa. CONCLUSIONS: Patients with ILD might have higher risks for HPS and relapse. Careful observation and appropriate therapeutic intervention might be needed.

A low perfusion-metabolic mismatch in 99m Tl and 123 I-BMIPP scintigraphy predicts poor prognosis in systemic sclerosis patients with asymptomatic cardiac involvement.

AIM: This study investigated the prognostic factors of cardiac death or cardiac failure using cardiac scintigraphy, echocardiography (UCG), and magnetic resonance imaging (MRI) in asymptomatic systemic sclerosis (SSc) patients. METHODS: We retrospectively evaluated SSc patients who had undergone cardiac scintigraphy using 99m thallium (99m Tl) and 123 I-ß-methyl-P-iodophenyl-pentadecanoic acid (123 I-BMIPP), UCG, and cardiac MRI. We calculated the mismatch score in scintigraphy by subtracting the uptake of 123 I-BMIPP from that of 99m Tl. Patients were divided into two groups according to whether they survived with no cardiac failure or subsequently proceeded to cardiac failure or death during the study period. We identified prognostic factors by analyzing 99m Tl and 123 I-BMIPP uptake, mismatch scores, UCG findings, and cardiac delayed enhancement on MRI. We also evaluated pathological evidence of myocardial fibrosis. RESULTS: Of 33 SSc cases, 11 proceeded to cardiac failure or death. There was no significant difference in UCG or MRI findings between the two groups. Low mismatch score in cardiac scintigraphy was the only predictive factor of cardiac failure or death by multivariate analysis (odds ratio, 6.48; 95% confidence interval, 1.22-423.2; P = 0.01). When patients were grouped according to high or low mismatch scores based on a cut-off using receiver operating characteristics curve analysis, the cumulative incidence of cardiac failure or death was higher in the low mismatch group than in the high mismatch group (P = 0.02). The percentage of fibrosis was significantly higher in deceased cases compared to surviving cases. CONCLUSIONS: Low mismatch score in cardiac scintigraphy was associated with cardiac death or cardiac failure in SSc patients.

Low-dose rituximab as induction therapy for ANCA-associated vasculitis.

Administration of four once-weekly doses of 375 mg/m2 rituximab (RTX) is commonly used as remission induction therapy for ANCA-associated vasculitis (AAV). Low-dose RTX has been recently shown to produce closely similar results to conventional treatments in other autoimmune diseases. However, the therapeutic potential of this approach in AAV remains largely unknown. Here, we analyzed the efficacy and tolerability of high- and low-dose regimens of RTX in patients with AAV. We retrospectively examined AAV patients who met the classification algorithm of Watts et al. from 2006 to 2016. Patients were divided into high- (HD) and low-dose (LD) RTX groups. HD-RTX was the original regimen while LD-RTX consisted of two once-weekly doses of 375 mg/m2. Cumulative complete remission (CR) rates for 1 year were compared, and serial changes in peripheral B cell counts and serious adverse events were monitored. Apart from a higher percentage of elderly patients in the LD group (p < 0.01), the 17 patients with HD-RTX and 11 patients with LD-RTX showed no significant differences in clinical characteristics, including Birmingham Vasculitis Activity Score (BVAS), Vasculitis Damage Index (VDI), and the initial dose of glucocorticoid. On 1-year observation, cumulative CR rates did not significantly differ (p = 0.20). Further, peripheral B cell counts and incidence of serious adverse events also did not differ. Cumulative CR rate did not significantly differ between LD and HD groups. Further study is warranted to confirm these results.

Hemodynamic heterogeneity of connective tissue disease patients with borderline mean pulmonary artery pressure and its distinctive characters from those with normal pulmonary artery pressure: a retrospective study.

To clarify whether patients with connective tissue disease (CTD)-associated borderline mean pulmonary artery pressure (mPAP) have distinctive hemodynamic characteristics from those with normal mPAP and whether pathogenesis is as heterogeneous as manifest pulmonary hypertension (PH). Seventy-five CTD patients who underwent right heart catheterization (RHC) from 2008 through 2016 were retrospectively analyzed. We compared between-group differences in clinical and hemodynamic findings: normal mPAP (n = 35), borderline mPAP (n = 15), and PH (n = 25). A therapeutic intervention trial based on RHC results was performed in nine patients. The values of tricuspid regurgitation pressure gradient (TRPG) in patients with borderline mPAP were comparable at rest but became higher after exercise compared to those with a normal mPAP (P = 0.01). Pulmonary artery wedge pressure in patients with borderline mPAP was higher than in those with normal mPAP (P < 0.0001) and comparable to those with PH. Each of the three patients was treated for pre-capillary and post-capillary disease and two for interstitial lung disease (ILD). During the mean follow-up period of 40 months, mPAP or TRPG normalized in all patients treated for pre-capillary and post-capillary disease. One patient with severe ILD developed to PH and died from it. CTD patients with borderline mPAP, the underlining pathogenesis of which is heterogeneous as PH, have distinctive hemodynamic characteristics from those with normal mPAP. Whether a specific treatment targeting the inflammatory process or local hemodynamics may alter the clinical course to PH is a topic for future research.

Renal protective effect of antiplatelet therapy in antiphospholipid antibody-positive lupus nephritis patients without antiphospholipid syndrome.

OBJECTIVE: We sought to evaluate the effect of antiplatelet therapy in addition to conventional immunosuppressive therapy for lupus nephritis (LN) patients positive for antiphospholipid antibodies (aPL) without definite antiphospholipid syndrome (APS). METHODS: Patients with biopsy-proven LN class III or IV were retrospectively evaluated. We selected patients positive for anticardiolipin antibody (aCL) or lupus anticoagulant (LA) who did not meet the criteria for a diagnosis of APS. The patients were divided into two subgroups according to whether antiplatelet therapy was received. The cumulative complete renal response (CR) rate, relapse-free rate, and change in estimated glomerular filtration rate (eGFR) over 3 years after induction therapy were calculated. RESULTS: We identified 17 patients who received antiplatelet therapy and 21 who did not. Baseline clinicopathological characteristics and immunosuppressive therapy did not show a significant difference between the two groups except for a higher incidence of LN class IV in the treatment group (p = 0.03). There was no difference in cumulative CR rate, relapse-free rate, or eGFR change between these subgroups. However, when data on LA-positive patients were assessed, an improvement in eGFR was found (p = 0.04) in patients receiving antiplatelet treatment. CONCLUSION: Addition of anti-platelet therapy was associated with an improvement of eGFR in LA-positive patients with LN class III or IV.

Risk Factors for Relapse of Antineutrophil Cytoplasmic Antibody-associated Vasculitis in Japan: A Nationwide, Prospective Cohort Study.

OBJECTIVE: The aim was to elucidate the prognosis and risk factors associated with relapse during longterm remission maintenance therapy for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Patients with newly diagnosed AAV (n = 156) were registered in the Remission Induction Therapy in Japanese patients with ANCA-associated Vasculitides (RemIT-JAV) study, and among them, 83 patients who achieved remission were enrolled and followed up for 24 additional months in our nationwide, prospective cohort study (Co-RemIT-JAV; registration number UMIN 000006373). Patterns of maintenance therapy, effectiveness, and safety were evaluated from months 25 to 48 after the RemIT-JAV. The primary outcome measure was the rate of relapse. Secondary outcome measures included overall and renal survival, risk factors associated with relapse, and incidence rates of serious infections. RESULTS: The patients comprised 35 men and 48 women aged 65.3 ± 12.6 years. Between months 25 and 48, the survival rate was 95% (79/83). Causes of death included 1 thyroid cancer, 1 infection, and 2 unknown reasons. Four patients had developed endstage renal disease (ESRD) by Month 24; 1 developed ESRD beyond Month 25. The relapse rate was 24% (20/83) from months 25 to 48. Multivariable analysis revealed that oral prednisolone ≤ 2.5 mg/day at Month 24 was a significant risk factor for relapse between months 25 and 48 (HR = 3.1, 95% CI 1.1-8.5). CONCLUSION: One-quarter of patients with AAV relapsed during maintenance therapy, and relapse was associated with the dose of oral prednisolone 24 months after the initiation of remission induction therapy in Japan.

Combined disease with pulmonary arterial hypertension and pulmonary venous hypertension revealed after treatment of heart failure with preserved ejection fraction in a case with primary Sjögren syndrome.

A 49-year-old woman with primary Sjögren syndrome initially developed pulmonary venous hypertension (PVH) due to heart failure with preserved ejection fraction. Endomyocardial biopsy specimens showed mild myocardial fibrosis. Pulmonary arterial hypertension (PAH) was revealed after the treatment with diuretics. During the treatment for PAH using upfront combination with pulmonary vasodilators and immunosuppressants, the patient developed combined disease with PAH and PVH. A careful hemodynamic assessment is necessary in such cases.

Rhabdomyolysis in a Patient with Polyarteritis Nodosa.

Polyarteritis nodosa (PAN) is a medium vessel vasculitis affecting systemic organs. Muscle involvement of PAN usually lacks elevation of creatinine kinase (CK). We herein report a case of PAN with rhabdomyolysis. A 71-year-old man was hospitalized because of muscle weakness of the lower limbs that persisted for 1 month. On a physical examination, rapidly progressive lower proximal muscle weakness and bilateral drop foot were observed. His blood test showed an elevation in the C-reactive protein (19.5 mg/dL) and CK (13,435 IU/L) levels and negativity for anti-neutrophilic cytoplasmic antibody. Computed tomographic angiography showed stenosis of the left renal artery. Electromyogram indicated mono-neuritis multiplex pattern, and enhanced magnetic resonance imaging demonstrated discretely granular hyperintensities on T2 and slow tau inversion recovery in his femoral muscles. A femoral muscle-biopsy specimen showed fibrinoid necrosis of medium-sized vessels and disruption of the elastic lamina of the vessel wall in fascia. Furthermore, muscle necrosis was localized depending on the arterial distribution, suggesting ischemic changes in the muscles. Given these findings, he was diagnosed with PAN with rhabdomyolysis and treated with methyl-prednisolone pulse therapy followed by oral prednisolone at 50 mg/day. He was additionally treated with monthly intravenous cyclophosphamide at 500 mg. Sustained remission has been obtained for two months since the treatment. Although rhabdomyolysis rarely manifests with PAN, it should be included in a differential diagnosis of febrile patients presenting with acute myalgia and weakness with CK elevation.

Association of ETS1 polymorphism with granulomatosis with polyangiitis and proteinase 3-anti-neutrophil cytoplasmic antibody positive vasculitis in a Japanese population.

ETS proto-oncogene 1, transcription factor (ETS1) is involved in various immune responses. Genome-wide association studies on systemic lupus erythematosus in Chinese populations identified the association of ETS1 polymorphism in 3' untranslated region, rs1128334A, which was associated with lower ETS1 expression. In view of substantial sharing of susceptibility genes across multiple autoimmune diseases, we examined whether ETS1 is associated with a rare autoimmune rheumatic disease, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). Association of rs1128334 was tested in 466 Japanese patients with AAV and 1099 healthy controls by logistic regression analysis under the additive model. AAV patients were classified into 285 microscopic polyangiitis (MPA), 92 granulomatosis with polyangiitis (GPA), 56 eosinophilic GPA, and 33 unclassifiable AAV, according to the European Medicines Agency (EMEA) algorithm. Among the patients, 376 were positive for MPO-ANCA and 62 for PR3-ANCA. When the patients were classified according to the EMEA classification, rs1128334A allele was significantly increased in GPA (P = 0.0060, P c = 0.030, odds ratio (OR), 1.54; 95% confidence interval (CI), 1.13-2.10). With respect to the ANCA specificity, significant association was observed in PR3-ANCA positive AAV (P = 0.0042, P c = 0.021, OR, 1.72; 95% CI, 1.19-2.49). In conclusion, ETS1 polymorphism was suggested to be associated with GPA and PR3-ANCA positive AAV in a Japanese population.

Comparison of renal response to four different induction therapies in Japanese patients with lupus nephritis class III or IV: A single-centre retrospective study.

The recent recommendations for the management of lupus nephritis suggest that racial background should be considered while choosing induction therapy. However, the responses to different induction regimens have been poorly studied in Japanese population. Here, we assessed the renal response to different induction therapies in Japanese patients with lupus nephritis class III or IV. The records of 64 patients with biopsy-proven lupus nephritis class III or IV were retrospectively evaluated according to therapy received: monthly intravenous cyclophosphamide (IVCY), the Euro-lupus nephritis trial (ELNT) protocol-IVCY, tacrolimus (TAC), or mycophenolate mofetil (MMF). We investigated cumulative complete renal response (CR) rates and relapse rates for each group for 3 years. Organ damage was assessed with the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI). There were 22 patients on monthly IVCY, 18 on ELNT-IVCY, 13 on TAC, and 11 on MMF. Lower systemic lupus erythematosus disease activity index (SLEDAI) and higher CH50 were found in the TAC group at baseline (p<0.01 and p<0.01, respectively). There were no significant differences of cumulative CR rates and relapse free survival for 3 years among the four different therapeutic regimens (p = 0.2 and p = 0.2, respectively). There was a tendency to have early response and early relapse in TAC group and late response in MMF group. The SDI increase over 3 years was found more frequently in the TAC group than in the monthly-IVCY group (p = 0.04). Multivariate analysis indicated that CR at 3 months was independent prognosticator for low damage accrual. Regarding lower damage accrual, early CR achievement might be essential in induction therapy regardless of immunosuppressant choice.

Lack of partial renal response by 12 weeks after induction therapy predicts poor renal response and systemic damage accrual in lupus nephritis class III or IV.

BACKGROUND: Lupus nephritis class III or IV is associated with a poor prognosis for both patient and renal survival. Recommendations for the management of lupus nephritis have recently been established, and changing therapies is recommended for patients who do not respond adequately to induction therapy. However, it remains a major challenge to determine when to switch the treatment. In this study, we identified early prognostic factors capable of predicting poor renal outcome as well as overall damage accrual in patients with lupus nephritis class III or IV. METHODS: Eighty patients with biopsy-proven lupus nephritis class III or IV were retrospectively recruited and divided into two groups: those with complete renal response (CR) or non-CR at 3 years after induction therapy. We investigated when clinical responses were obtained at each observational period from baseline to year 3. Clinical responses were divided into three groups: CR, partial renal response (PR), and non-PR. Furthermore, patients were assessed using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) and cumulative dose of corticosteroid for 3 years. RESULTS: Forty-four patients with CR and thirty-six with non-CR were enrolled. The cumulative CR rate was 85.0%. PR rates of patients with CR were significantly higher than those with non-CR from week 12 (p < 0.01). We identified the achievement of PR at 12 weeks as an independent predictor (OR 3.57, p = 0.03) by multivariate analysis. We next divided all patients into two groups according to PR achievement at week 12. The cumulative CR rate of the patients who achieved PR at week 12 was significantly higher than that of those who did not (96.5% vs 69.2%, p < 0.001). Furthermore, a significantly higher SDI and cumulative dose of corticosteroid were seen in the patients who did not achieve PR at week 12 than in those who did, regardless of their CR status, at year 3. CONCLUSIONS: Lack of PR at week 12 predicts a lower likelihood of achieving CR at 3 years and a higher SDI.

Recurrent Bilateral Focal Myositis.

This report describes a rare case of recurrent bilateral focal myositis and its successful treatment via methotrexate. A 38-year-old man presented myalgia of the right gastrocnemius in May 2005. Magnetic resonance imaging showed very high signal intensity in the right gastrocnemius on short-tau inversion recovery images. A muscle biopsy revealed inflammatory CD4+ cell-dominant myogenic change. Focal myositis was diagnosed. The first steroid treatment was effective. Tapering of prednisolone, however, repeatedly induced myositis relapse, which progressed to multiple muscle lesions of both lower limbs. Initiation of methotrexate finally allowed successful tapering of prednisolone, with no relapse in the past 4 years.

Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Macitentan is a novel, dual endothelin receptor antagonist with sustained receptor binding, used for the long-term treatment of pulmonary arterial hypertension (PAH). In the present study, we assessed the efficacy and safety of macitentan in Japanese patients with PAH. METHODS AND RESULTS: Macitentan was administered at a once-daily dose of 10 mg in 30 patients. The primary endpoint was change in pulmonary vascular resistance (PVR) from baseline to week 24. Change to week 24 in the other hemodynamic parameters, 6-min walk distance (6MWD), World Health Organization (WHO) functional class, and plasmaN-terminal pro-brain natriuretic peptide (NT-pro-BNP), as well as time to clinical deterioration up to week 52 were also assessed as secondary endpoints. In the 28 patients on per-protocol analysis, PVR decreased from 667±293 to 417±214 dyn·sec·cm(-5)(P<0.0001). 6MWD increased from 427±128 to 494±116 m (P<0.0001). WHO functional class improved in 13 patients (46.4%) and was maintained in 15 patients (53.6%), and NT-pro-BNP was reduced by 18% (P<0.0001). The favorable treatment effect on PVR was apparent regardless of concomitant therapy for PAH. CONCLUSIONS: Macitentan was efficacious and well tolerated and improved the hemodynamic parameters, exercise capacity, symptoms, and clinical biomarkers in Japanese PAH patients. Macitentan can be a valuable therapeutic option for Japanese patients with PAH. ( TRIAL REGISTRATION: JAPIC Clinical Trials Information [JapicCTI-121986].) (Circ J 2016; 80: 1478-1483).