Molecular targeted therapies for microscopic polyangiitis and granulomatosis with polyangiitis.

Clinical trials and observational studies have established cyclophosphamide (CY) or rituximab plus glucocorticoid (GC) as standard remission induction therapies in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). However, because these regimens are associated with serious adverse drug reactions, the development of drugs with novel mechanisms of actions are needed. Progress in basic and clinical research has identified novel candidate targeting molecules, including B-cell activating factor (BAF), C5a receptor, and interleukin-6. The combination of rituximab and BAF blockade in patients with MPA and GPA is under investigation in an effort to strike a better benefit-risk balance. Phase II clinical trials of avacopan (CCX168), an orally administered C5a receptor antagonist, have suggested a reduction in the dosage of concomitant GC or the replacement of GC in patients with MPA and GPA. The results from a currently ongoing phase III trial are awaited. Anecdotal case reports and an open-label pilot study have indicated the effectiveness of tocilizumab in patients with MPA and GPA. A randomized clinical trial comparing tocilizumab and intravenous CY in combination with GC is currently in progress. Molecular targeted therapy is expected to transform the treatment strategy for MPA and GPA to allow GC-free or at least less GC-dependent forms of therapy.

Systematic review and meta-analysis for 2017 clinical practice guidelines of the Japan research committee of the ministry of health, labour, and welfare for intractable vasculitis for the management of ANCA-associated vasculitis.

OBJECTIVES: To provide evidence for the revision of clinical practice guideline (CPG) for the management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) by the Japan Research Committee for Intractable Vasculitis. METHODS: PubMed, CENTRAL, and the Japan Medical Abstracts Society were searched for articles published between January 1994 and January 2015 to conduct systematic review (SR), and the quality of evidence was assessed with GRADE approach. RESULTS: Nine randomized controlled trials (RCTs) and two non-RCTs were adopted for remission induction therapy, three RCTs and two non-RCTs for plasma exchange, and five RCTs and one non-RCT for remission maintenance therapy. A significant difference was found in efficacy and safety for the following comparisons. In the non-RCT adopted for remission induction therapy, glucocorticoid (GC) + cyclophosphamide (CY) was significantly superior to GC monotherapy regarding remission. GC + intravenous CY for remission induction therapy was superior to GC + oral CY regarding death at one year, serious adverse events, and serious infection. Concomitant use of plasma exchange for remission induction therapy of AAV with severe renal dysfunction reduced risk of end-stage renal disease versus non-users at month 3. CONCLUSION: This SR provided necessary evidence for developing CPG for the management of ANCA-associated vasculitis.

2017 Clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis.

OBJECTIVE: The Japan Research Committee for Intractable Vasculitis has fully revised the clinical practice guidelines (CPG) for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) to improve and standardize the medical treatment of the disease in Japan. METHODS: The previous CPG was published in a classical review style in Japanese in 2011 and 2014. We adopted the Grading of Recommendations Assessment, Development and Evaluation system for this revision, and various stakeholders, including patients, participated in it. The expected users of this CPG are AAV patients in Japan and their families and healthcare professionals, including both AAV specialists and non-specialists. We set clinical questions concerning the three important clinical topics of remission induction therapy, plasma exchange, remission maintenance therapy, and developed eight recommendation statements. RESULTS: For remission induction therapy for newly developed AAV, we weakly recommend glucocorticoid (GC) plus intravenous cyclophosphamide pulse (IVCY) or oral cyclophosphamide (POCY) rather than GC alone, and IVCY rather than POCY. We also weakly recommend CY rather than rituximab. In the case of AAV with severe renal impairment, we weakly recommend plasma exchange as a conjunction therapy. We weakly recommend azathioprine for remission maintenance therapy. CONCLUSION: The revised CPG has demonstrated evidence-based treatment recommendations for AAV.

2017 Clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of ANCA-associated vasculitis

The Japan Research Committee for Intractable Vasculitis has fully revised the clinical practice guidelines (CPG) for the management of antineutrophil cytoplasmic antibody-associated vasculitis (AAV) to improve and standardize the medical treatment of the disease in Japan. The previous CPG was published in a classical review style in Japanese in 2011 and 2014. We adopted the Grading of Recommendations Assessment, Development and Evaluation system for this revision, and various stakeholders, including patients, participated in it. The expected users of this CPG are AAV patients in Japan and their families and healthcare professionals, including both AAV specialists and non-specialists. We set clinical questions concerning the three important clinical topics of remission induction therapy, plasma exchange, remission maintenance therapy, and developed eight recommendation statements. For remission induction therapy for newly developed AAV, we weakly recommend glucocorticoid (GC) plus intravenous cyclophosphamide pulse (IVCY) or oral cyclophosphamide (POCY) rather than GC alone, and IVCY rather than POCY. We also weakly recommend CY rather than rituximab. In the case of AAV with severe renal impairment, we weakly recommend plasma exchange as a conjunction therapy. We weakly recommend azathioprine for remission maintenance therapy. The revised CPG has demonstrated evidence-based treatment recommendations for AAV.

No increased risk of herpes zoster in TNF inhibitor and non-TNF inhibitor users with rheumatoid arthritis: epidemiological study using the Japanese health insurance database.

OBJECTIVE: It is controversial whether the use of biological disease-modifying antirheumatic drugs (DMARDs) increases the risk of herpes zoster (HZ). We aimed to evaluate the risks of HZ in tumor necrosis factor inhibitor (TNFI) and non-TNFI users with rheumatoid arthritis (RA) over 3 years in Japan. METHOD: Using the Japanese health insurance database, we assigned patients with at least one RA diagnostic code and one prescription for any DMARDs (RA cases) recorded between January 2005 and December 2013 to the RA group. We randomly selected five age-, sex-, calendar year- and observation length-matched non-RA cases for each RA case (non-RA group), and assessed associations between RA and HZ. To evaluate the risks of HZ in TNFI and non-TNFI users, we conducted a nested case-control study (NCC) in the RA group. RESULTS: The RA group (n = 6712) had a significantly higher crude incidence rate of HZ than the non-RA group (n = 33 560) (14.2 vs. 8.3/1000 patient-years), and the adjusted odds ratio (95% confidence interval) of the RA versus non-RA groups was 1.43 (1.17-1.75). The NCC demonstrated that use of TNFI, non-TNFI, methotrexate, or immunosuppressive DMARDs did not increase the risks of HZ. Use of corticosteroid ≥ 5 mg/day conveyed a significant risk of HZ in patients with RA. CONCLUSIONS: Rheumatoid arthritis was significantly associated with the development of HZ, and use of corticosteroids ≥ 5 mg/day was identified as a significant risk factor, whereas either TNFI or non-TNFI use were not.

Comparison of fluorescence optical imaging, ultrasonography and clinical examination with magnetic resonance imaging as a reference in active rheumatoid arthritis patients.

BACKGROUND: Fluorescence optical imaging with indocyanine-green enhancement (FOI) is a new imaging modality for the assessment of hand arthritis. The objective of this study was to compare performance profiles of clinical examination (CE), US and FOI using MRI as a reference in the same active rheumatoid arthritis (RA) patients. METHODS: CE, US, FOI and MRI were performed on six subjects with active RA. Each sequence of FOI was divided into three phases based on indocyanine-green dynamics and the joints were graded semi-quantitatively. Sensitivities and specificities of CE, US and FOI were calculated using the RAMRIS synovitis score >0 as a reference in a total of 30 joints (the second to fifth metacarpophalangeal (MCP) joints and the wrist of the clinically dominant hand). RESULTS: FOI showed sensitivities and specificities, respectively, of 85% and of 94% for Phase-1 and 69% and 94% for Phase-2. Sensitivities and specificities were 100% and 35% for CE (tender or swollen), 92% and 41% for gray scale US, and 77% and 100% for color-Doppler US. CONCLUSIONS: The performance characteristics of FOI in detection of synovitis in patients with active RA are comparable to those of US and more specific than CE. FOI has a potential as an assessment modality of RA.