Clinical practice guidelines of the Japan Research Committee of the Ministry of Health, Labour, and Welfare for Intractable Vasculitis for the management of microscopic polyangiitis and granulomatosis with polyangiitis: The 2023 update - secondary publication.

OBJECTIVE: To revise the 2017 clinical practice guidelines (CPG) for the management of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) to reflect advancements in the field. METHODS: Similar to the 2017 CPG, the Grading of Recommendations, Assessment, Development, and Evaluation system was adopted for this revision. The intended users of this CPG include patients diagnosed with MPA or GPA in Japan and their families and healthcare professionals, including specialists and non-specialists. Based on a scoping review, four clinical questions (CQs) of the 2017 guidelines were modified, and six new CQs were added. RESULTS: We suggest a combination of glucocorticoid and cyclophosphamide or rituximab for remission induction therapy. In cases where cyclophosphamide or rituximab is used, we suggest the use of avacopan over high-dose glucocorticoid. Furthermore, we suggest against the use of plasma exchange in addition to the standard treatment in severe cases of MPA/GPA. Finally, we suggest the use of glucocorticoid and rituximab over glucocorticoid and azathioprine for remission maintenance therapy. CONCLUSIONS: The recommendations have been updated based on patient preference, certainty of evidence, benefit and risk balance, and cost.

Expert perspectives on pathological findings in vasculitis.

Pathological findings are important in the diagnosis of vasculitis. However, due to the rarity of the disease, standard textbooks usually devote only a few pages to this topic, and this makes it difficult for clinicians not specializing in vasculitis to fully understand the pathological findings in vasculitis. To address the paucity of information, we present representative pathological findings in vasculitis classified in the 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides (CHCC2012). The CHCC2012 classifies 26 vasculitides into seven categories: (1) large-vessel vasculitis, (2) medium-vessel vasculitis, (3) small-vessel vasculitis, including antineutrophil cytoplasmic antibody-associated vasculitis and immune complex small-vessel vasculitis, (4) variable-vessel vasculitis, (5) single-organ vasculitis, (6) vasculitis associated with systemic disease, and (7) vasculitis associated with probable aetiology. Moreover, representative pathological findings of vasculitis-related diseases and non-inflammatory vasculopathy not mentioned in the CHCC2012 are also presented. This will be useful for clinicians to refer to typical pathological findings of vasculitis in daily practice.

Presence of eosinophil extracellular trap cell death in the affected skin of eosinophilic granulomatosis with polyangiitis.

Eosinophil activation in tissue might be associated with disease severity. Eosinophil cytolysis, a process of active cell death, has been referred to as eosinophil extracellular trap cell death (EETosis). In the present study, the authors investigated EETosis in the affected skin of four patients with eosinophilic granulomatosis with polyangiitis (EGPA) using an immunofluorescence staining method. Immunofluorescence staining for myelin basic protein, galectin-10, and DNA revealed various degrees of EETosis and Charcot-Leyden crystals in skin tissue, suggesting the different degree of eosinophil activation status. The histopathological characteristic features may help physicians establish an earlier diagnosis of intractable eosinophilic-related disease including EGPA. Furthermore, ETotic eosinophil infiltration in perineurium of skin tissue might play a primary role in peripheral neuropathy of this disorder.

Presence of neutrophil extracellular traps in superficial venous thrombosis of Behçet's disease.

Behçet's disease (BD) has a heterogeneous spectrum of disease manifestations featuring the involvement of different organs and can be characterized with different symptoms depending on the clinical department in charge. We retrospectively reviewed BD patients seen at our hospital and investigated the presence of neutrophils producing neutrophil extracellular traps (NET) in those patients. Immunolabeling of myeloperoxidase and histone citrullination proteins was performed on skin biopsies from three BD patients who had skin biopsy-proven superficial vein thrombophlebitis in their erythema nodosum-like lesions. We observed a higher proportion of female patients and a higher incidence of acne-like eruptions among BD patients seen at our dermatology department, while there was a higher incidence of ocular and gastrointestinal involvement among BD patients treated in other departments. We suggest that sex statistical trends could lead to the co-development of different manifestations and may help clinicians choose the best therapeutic approaches, tailoring them to the specific phenotype of the patient rather than one based on single disease manifestations. NET were found in neutrophils of panniculitis concurrent with superficial vein thrombophlebitis. We suggest that the pathogenesis of BD-related thrombosis could be associated with neutrophil activation and NET are released in the panniculitis of affected skin lesions, erythema nodosum-like lesions.

Surgical procedures and innovative approaches for vitiligo regenerative treatment and melanocytorrhagy.

Surgical treatments for vitiligo are a safe and effective treatment modality for select patients with vitiligo. Many techniques of vitiligo surgery exist, each with unique advantages and disadvantages. We reviewed the various surgical therapies and innovative approaches for vitiligo regenerative treatment reported in the literature. Surgical therapies can be subdivided into tissue grafting methods and cellular grafting methods. Tissue grafting methods mainly include mini punch grafts, suction blister roof grafts, and hair follicle grafts. Cellular grafting methods include cultured and non-cultured treatments. The efficacy needs to be improved largely due to the poor proliferation and quality of the autologous melanocytes. Rho-associated protein kinase inhibitor enhances primary melanocyte culture proliferation from vitiligo patients to prevent apoptosis. Innovative approaches using stem cell methods could prove invaluable in developing a novel cell therapy for patients suffering from vitiligo. We succeeded in inducing melanin pigmentation in mice skin in vivo using our human induced pluripotent stem cell-derived melanocytes. In addition, we reviewed melanocytorrhagy, detachment and transepidermal loss of melanocytes, and melanocyte-related adhesion molecules. These adhesion molecules include epithelial cadherin, discoidin domain receptor tyrosine kinase 1, glycoprotein non-metastatic melanoma protein B, macrophage migration inhibiting factor, 17ß-hydroxysteroid dehydrogenase 1, and E26 transformation-specific 1.

The Second Study of Clinical and Immunological Findings in Anti-laminin 332-Type Mucous Membrane Pemphigoid Examined at Kurume University-Diagnosis Criteria Suggested by Summary of 133 Cases.

Background: Recently, we published an article retrospectively summarizing the results in 55 anti-laminin 332 (LM332)-type mucous membrane pemphigoid (MMP) cases examined at Kurume University, which were diagnosed by strict inclusion criteria, including positive reactivity in direct immunofluorescence and absence of antibodies to non-LM332 autoantigens. However, indirect immunofluorescence using 1M-NaCl-split normal human skin (ssIIF) is also valuable for diagnosis of anti-LM332-type MMP. Methods: In this second study, we selected 133 anti-LM332-type MMP cases, which were diagnosed by our different inclusion criteria: (i) immunoglobulin G (IgG) deposition to basement membrane zone (BMZ) by direct immunofluorescence or IgG reactivity with dermal side of split skin by ssIIF, (ii) positivity for at least one of the three subunits of LM332 by immunoblotting of purified human LM332, and (iii) the presence of mucosal lesions. Clinical, histopathological, and immunological findings were summarized and analyzed statistically. Although these cases included the 55 previous cases, the more detailed study for larger scale of patients was conducted for further characterization. Results: Clinically, among the 133 patients, 89% and 43% patients had oral and ocular mucosal lesions, respectively, 71% had cutaneous lesions, and 17% had associated malignancies. Histopathologically, 93% patients showed subepidermal blisters. The sensitivities of ssIIF and direct immunofluorescence are similar but are significantly higher than indirect immunofluorescence using non-split human skin (both p < 0.001). In immunoblotting of purified LM332, patient IgG antibodies most frequently reacted with LMγ2 subunit (58%), followed by LMα3 (49%) and LMß3 (36%). Thirty-four percent patients recognized additional non-LM332 autoantigens. Statistical analysis revealed that autoantibodies against non-LM332 autoantigens might stimulate the production of anti-LMγ2 antibodies. Conclusions: This retrospective study further characterized in more detail the clinical and immunological features of 133 cases of anti-LM332-type MMP, in which the new diagnostic criteria without positive direct immunofluorescence reactivity were useful for the diagnosis. Higher frequency with anti-LMγ2 antibodies suggested more significant pathogenic role of this subunit. Additional autoantibodies to non-LM332 autoantigens detected in one-third of the patients may contribute to complexity in anti-LM332-type MMP, including the induction of anti-LMγ2 antibodies.

Current medico-psycho-social conditions of patients with West syndrome in Japan.

OBJECTIVE: To unveil current medical and psychosocial conditions of patients with West syndrome in Japan. METHODS: A cross-sectional analysis was performed in patients with West syndrome registered in the Rare Epilepsy Syndrome Registry (RES-R) of Japan. Furthermore, new-onset patients registered in the RES-R were observed prospectively and their outcomes after one and two years of follow-up were compared with data at onset. RESULTS: For the cross-sectional study, 303 patients with West syndrome were included. Seizures (such as spasms, tonic seizures and focal seizures) occurred daily in 69.3% of the patients at registration. Seizure frequency of less than one per year was observed in cases of unknown etiology (22.6%), genetic etiology (23.8%) and malformation of cortical development (MCD; 19.1%). Neurological findings were absent in 37.0%, but a high rate of abnormality was seen in patients with Aicardi syndrome, hypoxic-ischemic encephalopathy (HIE), genetic etiology and MCD other than focal cortical dysplasia, accompanied by a >50% rate of bedridden patients. Abnormal EEG was found in 96.7%, and CT/MRI was abnormal in 62.7%. Treatments included antiepileptic drug therapy (94.3%), hormonal therapy (72.6%), diet therapy (8.3%) and surgery (15.8%). Intellectual/developmental delay was present in 88.4%, and was more severe in patients with Aicardi syndrome, genetic etiology and HIE. Autism spectrum disorder was found in 13.5%. For the longitudinal study, 27 new-onset West syndrome patients were included. The follow-up study revealed improved seizure status after two years in 66.7%, but worsened developmental status in 55.6%, with overall improvement in 51.9%. SIGNIFICANCE: The study reveals the challenging neurological, physical and developmental aspects, as well as intractable seizures, in patients with West syndrome. More than a half of the children showed developmental delay after onset, even though seizures were reduced during the course of the disease.

Early add-on administration of mepolizumab and intravenous immunoglobulin effective in treating eosinophilic granulomatosis with polyangiitis.

Treatment of eosinophilic granulomatosis with polyangiitis (EGPA) remains a challenge because currently available therapies, corticosteroids and immunomodulators, do not always control symptoms and are often associated with significant morbidity and relapse. Mepolizumab has been demonstrated to be an effective add-on therapy with steroid-sparing effect in cases of relapsing or refractory EGPA. Intravenous immunoglobulin (IVIG) therapy is effective against mononeuritis multiplex or heart failure in patients with EGPA who do not respond to corticosteroid-cyclophosphamide treatment. We present two cases of EGPA in which earlier add-on administration of adjunct mepolizumab and IVIG led to significant improvement in EGPA symptoms and prevention of flare-up of the disease. We suggested that earlier add-on combination administration of IVIG and mepolizumab might be a useful adjunct treatment to induce clinical remission of EGPA and improve the rate of remission, decrease relapse rate, and allow for reduced glucocorticoid use without any serious adverse drug effects.

Clinical characteristics and social productivity levels of patients with malignant rheumatoid arthritis based on a nationwide clinical database in Japan: annual survey from 2003 to 2013.

OBJECTIVES: Malignant rheumatoid arthritis (MRA) is defined as rheumatoid arthritis (RA) with systemic vasculitis or other severe extra-articular manifestations. Japan has a nationwide database for MRA. We analyzed the characteristics of Japanese patients with MRA based on data from the Ministry of Health, Labour and Welfare (MHLW). METHODS: We were permitted to use data on 43,108 patients who were registered in the MHLW database from 2003 to 2013. RESULTS: Median age was 65 (interquartile range, 57-72) years. Patients consisted of 71% females. Proportions of patients who had or had experienced interstitial pneumonia and pleuritis were increased, episcleritis was stable, and other MRA manifestations were decreased over time. The number of positive symptoms per patient also decreased over time. The median dose of glucocorticoid, percentage of patients undergoing surgery, and use of non-steroidal anti-inflammatory drugs and apheresis decreased year by year. Steinbrocker stage and class improved over time. Median C-reactive protein levels and erythrocyte sedimentation rate also decreased. Regarding social productivity levels of patients with MRA, the proportion of patients who were working or working from home increased and the proportion of patients recuperating or hospitalized decreased. CONCLUSION: In patients with MRA, disease activity decreased and social productivity improved from 2003 to 2013.

Clinical practice guide for the treatment of perforating dermatosis.

Perforating dermatoses are a heterogeneous skin disease group defined by transepidermal elimination of various skin materials. Four classical forms of primary perforating dermatosis have been described, where the transepidermal elimination mechanism represents the hallmark of the disease: acquired reactive perforating collagenosis, elastosis perforans serpiginosa, Kyrle's disease and perforating folliculitis. Acquired reactive perforating collagenosis presents with transepidermal elimination of collagen fibers. Elastosis perforans serpiginosum presents with the elimination of elastic fibers. Kyrle's disease presents with transepidermal elimination of abnormal keratin. In perforating folliculitis, it is the content of the follicle. We established diagnostic criteria and severity classification. In addition, the Japanese guideline for treatment of perforating dermatoses was updated using the Medical Information Network Distribution Service (MINDS) methodology. The guideline is based on a systematic published work review completed from 1989 to 2019, and on a formal consensus and approval process. Most medical published work on the treatment is limited to individual case reports and small series of patients. The guideline covers treatment options considered relevant by the expert panel and approved in Japan at the time of the consensus conference.

Dectin-2-induced CCL2 production in tissue-resident macrophages ignites cardiac arteritis.

Environmental triggers, including those from pathogens, are thought to play an important role in triggering autoimmune diseases, such as vasculitis, in genetically susceptible individuals. The mechanism by which activation of the innate immune system contributes to vessel-specific autoimmunity in vasculitis is not known. Systemic administration of Candida albicans water-soluble extract (CAWS) induces vasculitis in the aortic root and coronary arteries of mice that mimics human Kawasaki disease. We found that Dectin-2 signaling in macrophages resident in the aortic root of the heart induced early CCL2 production and the initial recruitment of CCR2+ inflammatory monocytes (iMo) into the aortic root and coronary arteries. iMo differentiated into monocyte-derived dendritic cells (Mo-DC) in the vessel wall and were induced to release IL-1ß in a Dectin-2-Syk-NLRP3 inflammasome dependent pathway. IL-1ß then activated cardiac endothelial cells to express CXCL1 and CCL2 and adhesion molecules that induced neutrophil and further iMo recruitment and accumulation in the aortic root and coronary arteries. Our findings demonstrate that Dectin-2-mediated induction of CCL2 production by macrophages resident in the aortic root and coronary arteries initiates vascular inflammation in a model of Kawasaki disease, suggesting an important role for the innate immune system in initiating vasculitis.

[Cutaneous Manifestations of Sweet Disease].

Sweet disease, also known as acute febrile neutrophilic dermatosis, is a multisystem inflammatory disorder characterized by painful erythematous plaques and aseptic neutrophilic infiltration of various organs. It is also characterized by fever, polymorphonuclear leukocytosis, and painful erythematous cutaneous plaques. Cutaneous manifestations of Sweet disease are typically painful plaque-forming erythematous papules. Skin biopsies typically demonstrate dermal infiltration with neutrophils in the absence of vasculitis. Sweet disease is often associated with a hematological malignancy, especially acute myeloid leukemia or myeloid dysplasia syndrome. Sweet disease has clinical and laboratory features similar to those of Behçet's disease. Overlap exists between the clinical manifestations of Sweet disease and Behçet's disease. The neuro-Sweet disease is similar to the neuro-Behçet's disease. This article presents information on the pathogenesis, clinical approach, treatment, and expected evolution of these manifestations including the defference between neuro-Sweet disease and neuro-Behçet's disease. The possible role in this interesting association of Behçet's disease and Sweet disease is discussed and a review of the literature is presented.

Sudden elevation of plasma D-dimer levels induced by the combination therapy of dabrafenib and trametinib: Report of two cases.

The combination therapy of dabrafenib and trametinib revolutionized the treatment for BRAF V600-mutated melanoma. Various adverse events have been reported for this treatment, most notably fever. Herein, we report two cases of novel an adverse event, namely sudden and significant elevation of plasma D-dimer level induced by this therapy. In the first case, the remarkable elevation of plasma D-dimer level up to 87.4 mg/dL was noted on day 11, and in the second case, the plasma D-dimer level reached 125.5 mg/dL on day 25. In both cases, D-dimer levels gradually decreased after the cessation of this therapy. Although the exact cause is not clear, we assume two possible hypotheses: the first is that the combination therapy may induce disseminated intravascular coagulation, and the second is that the therapy induced pathological condition of secondary thrombotic microangiopathies. Our cases suggest that this thrombotic adverse event should not be overlooked, and coagulation parameters need to be monitored during the course of this treatment.

Formation and Disordered Degradation of Neutrophil Extracellular Traps in Necrotizing Lesions of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the production of ANCAs and systemic necrotizing vasculitis in small vessels. Disordered regulation of neutrophil extracellular traps (NETs) is critically involved in the pathogenesis of AAV. NETs are web-like DNA decorated with antimicrobial proteins; they are extruded from activated neutrophils. The principal degradation factor of NETs in vivo is DNase I; however, NETs resistant to DNase I can persist in tissues and can lead to the production of ANCAs. Deposition of NETs has been demonstrated in glomerular crescents and necrotizing vasculitis in AAV. Here, the amount of NETs in formalin-fixed, paraffin-embedded tissue sections was examined, and the results for AAV were compared with the results for diseases that should be distinguished from AAV. NETs were more abundant in necrotizing vasculitis of AAV than in non-ANCA-associated vasculitis, or in granulomatous angiitis. Pulmonary granulomas in AAV and non-ANCA-associated diseases were further studied. The amount of NETs was significantly greater in necrotizing granulomas of AAV than in granulomas of sarcoidosis without necrosis. Although NETs were formed in necrotizing granulomas of tuberculosis equivalently to those formed in AAV, they were more susceptible to degradation by DNase I than were NETs in AAV. The formation and disordered degradation of NETs in necrotizing lesions are characteristics of AAV and are possibly related to its pathogenesis.

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.

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.

Approach for the Derivation of Melanocytes from Induced Pluripotent Stem Cells.

Induced pluripotent stem (iPS) cells have the ability to differentiate into multiple cell types in the body and have an unlimited growth potential. However, iPS cell-derived melanocytes produced by existing protocols have significant limitations in developing novel strategies for regenerative medicine and cell therapies of pigmentation disorders in humans because they involve culture in media containing fetal bovine serum and nonphysiological agents. In this study, we established an in vitro approach to generate iPS cell-derived human melanocytes that have higher proliferation rates and increased melanin production compared with melanocytes prepared by previously reported approaches. Importantly, our iPS cell-derived human melanocytes are prepared in fetal bovine serum-free culture conditions that do not contain any nonphysiological agents. We designed two original methods, transferring black colonies by pipette and recovering black cell pellets from centrifuged medium, and numerous human iPS cell-derived melanocytes proliferated in gelatinous dishes coated with Matrigel after 12 days. We also succeeded in inducing melanin pigmentation in the nude mouse skin in vivo using those human iPS cell-derived melanocytes. We propose that this method using iPS cells established from T cells in the blood of normal human volunteers could be applied clinically to develop regenerative medicine and cell therapies for various forms of human pigmentation disorders.