AUTOIMMUNITY

INTRODUCTION Autoimmune hepatitis (AIH) is an immune-mediated inflammatory liver disease of non-self-limiting clinical course for which immunosuppressive agents are necessary in the majority of affected patients. The concept of the immunopathogenesis of AIH relies on autoreactive CD4 and CD8 T cells, whose emergence is induced after the break of self-tolerance by environmental triggers [1]. As the inflammation that AIH presents is likely to be characterized by a dynamic transition of the milieu of multiple effector immune cells in the liver, clinicians should take into consideration the chronological dynamics of disease manifestations or of distinct subtypes of disease, e.g., ranging from acute-onset, acute on chronic, and chronic insidious manifestation. The appropriate diagnosis and proper treatment strategy with special attention to the clinical subtypes of AIH must be considered to ensure favorable short- and long-term survival. In 2019, the American Association of the Study of Liver Disease (AASLD) published very comprehensive practice guidance and guidelines for AIH that updated the previous version published in 2010 [1]. The progress in our understanding of AIH is apparent in these guidelines, including their detailed description of a first-line treatment strategy based on the patient’s clinical manifestations. In this review, we summarize the recent updates regarding the management of AIH, focusing on the disease manifestations (Fig. 1) and the time frame of treatment and responses to treatment. EPIDEMIOLOGY AIH affects individuals of all ages from children to the very elderly, but it is most commonly identified in middle-aged women [2,3] in all ethnic groups. In 2016, a nationwide, hospital-based, epidemiological survey to approximate the prevalence of AIH was carried out in Japan. The estimated number of patients was 30,330 (95% confidence interval [CI], 29,592–31,069) and the calculated point prevalence of AIH per 100,000 population was 23.9 (95% CI, 23.3–24.5) [4]. Compared to the previous survey in 2004, the data revealed an almost threefold increase in the prevalence of AIH [4]. Among the widely varying nation-based prevalence data for adult AIH reported after 2000, e.g., from 4.0 (Singapore) [5] to 42.9 (Alaska) [6], a trend of increasing prevalence has been observed worldwide; for instance, from 10.7 in 2003 [7] to 17.3 in 2009 [8] in Sweden. The prevalence of AIH in Korea increased gradually from 2009 to 2013, although the incidence remained stable [2]. Alterations of environmental factors, including changes in lifestyle, might trigger the development of AIH, and environmental factors are likely to be linked to the increased male to female ratio of AIH in Japan from 1:6.9 in 2004 to 1:4.3 in 2016 as shown by the aforementioned survey [4]. Improved awareness of AIH among clinicians worldwide might also have contributed to the trend of increased prevalence, possibly resulting in a reduction of the number of otherwise undiagnosed patients, including adult male patients. DIAGNOSIS General considerations AIH is a disease without signature diagnostic features. The diagnosis of AIH requires 1) histological abnormalities (interface hepatitis), 2) characteristic laboratory findings (elevated serum hepatic enzymes, aspartate aminotransferase [AST] and alanine aminotransferase [ALT], and increased serum immunoglobulin G [IgG]), and 3) positive results of disease-defining autoantibodies, coupled with 4) the exclusion of other liver diseases that may resemble AIH, including viral hepatitis, hereditary, metabolic, cholestatic, or drug-induced liver injury (DILI). Anti-nuclear antibodies (ANA) and anti-smooth muscle antibodies should be tested in patients of all ages, and an additional test of anti-liver kidney microsomal type 1 is necessary in children for the characterization of type 2 AIH [1]. The clinical judgement is straightforward in typical AIH patients with the above-mentioned hallmarks, but atypical cases should be diagnosed with the aid of diagnostic scoring systems that were originally developed by the International AIH Group (IAIHG) in 1993 for the identification of patients with AIH for clinical research [9]. The revised IAIHG criteria reported in 1999 [10] and the simplified criteria proposed in 2008 [11] are commonly implemented in clinical practice, and they emphasize distinct diagnostic values. As the simplified scoring has superior specificity (90% vs. 73%) and accuracy (92% vs. 82%) compared to the revised scoring system [12], the former is preferable for the diagnosis of typical AIH cases. On the other hand, the revised scoring system is suitable for the reassessment of atypical cases with a low score in the simplified system, including cases of autoantibody-negative hepatitis and acute-onset AIH with normal IgG values [1]. Limitations to both scoring systems are evident (due to the lack of accuracy) for a diagnosis of AIH that is overlapped with a primary biliary cholangitis (PBC) [13], primary sclerosing cholangitis (PSC), or non-alcoholic fatty liver disease (NAFLD) [14], or fulminant liver failure. Histological findings The diagnosis of AIH requires liver biopsy results presenting compatible histological abnormalities. Typical histological features are indicative of (chronic) active hepatitis, comprising lymphoplasmacytic interface hepatitis, emperipolesis (intrusion of one intact lymphocyte into a hepatocyte), and hepatocyte rosettes. Gurung et al. [15] recently hypothesized that typical histological features are related to the severity of disease, but not to the etiology itself, and they reported the following as AIH-specific histological features: 1) Kupffer cell hyaline granules, 2) prominence of plasma cells in portal tracts, and 3) the relative predominance of plasma cells over lymphocytic inflammation. After Gurung et al. [15] adjusted the analysis results for the inflammatory grade, emperipolesis and rosette formation were similarly found in the disease control, chronic hepatitis C (CHC). The Kupffer cell hyaline granules were well-circumscribed, eosinophilic periodic acid-Schiff diastase-resistant deposits within Kupffer cells, and they were originally proposed as a specific histology in pediatric AIH [16]. Centrilobular necrosis is another histological AIH feature, presenting in a rather disease manifestation-specific manner in acute-onset AIH [17] and in acute liver failure (ALF). In ALF, central perivenulitis, plasma cell-enriched inflammatory infiltrate, and lymphoid follicles on a background of massive hepatic necrosis are the principle findings [18]. In clinical practice, the differential diagnosis of AIH in liver histology is routinely focused on DILI, including drug-induced AIH (DIAIH)-like liver injury. Though the rare presence of bridging fibrosis and the absence of advanced fibrosis are clues suggesting DILI, this is not the case for the differential diagnosis of acute-onset AIH over DILI. Histological findings of NAFLD and non-alcoholic steatohepatitis (NASH) are reported to be present in 17–30% of adult AIH patients [19,20]. These overlapping findings are indicative of patients who are at increased risk of liver-related mortality [19]. Conversely, characteristic laboratory findings with positive autoantibodies (especially in female patients) are sometimes refuted by the mere histology of NAFLD or NASH in the liver. Signature diagnostics for discriminating NASH with prominent periportal hepatitis from chronic active AIH are greatly anticipated. Noninvasive assessment of fibrosis The long-term outcome of AIH is associated with the stage of fibrosis. Since the evaluation of liver fibrosis by biopsy during the course of disease management is not feasible, noninvasive assessments have been conducted in clinical hepatology by using serum biomarkers, including the serum AST/platelet ratio index (APRI) and the fibrosis-4 (FIB-4) index [21]. However, a recent systemic review of the diagnostic accuracy of APRI and FIB-4 demonstrated their poor performance for detecting advanced fibrosis and cirrhosis in AIH [22]. Noninvasive assessment by liver stiffness has been shown to identify advanced fibrosis and cirrhosis in AIH with reasonable accuracy. The performance levels of vibration-controlled transient elastography (VCTE) and magnetic resonance elastography were indicated to be superior to those of the APRI and FIB-4, and VCTE was validated in a systemic review as providing good performance [22]. Considering that liver inflammation affects liver stiffness, the stiffness value at the initial diagnosis before the initiation of treatment with immunosuppressive agents is confounded by disease activity. In fact, the value of VCTE within 3 months after the start of treatment was significantly correlated with histological grading, but not with the fibrosis stage [23]. Thereafter, at least 6 months after the successful treatment of AIH, the area under the receiver operating curve of VCTE reached 1.0 [23]. Sustaining biochemical remission (normal ALT and normal IgG) and the use of VCTE help monitor and manage the disease course of AIH. A novel serum fibrosis marker, i.e., Mac-2 binding protein glycosylation isomer (M2BPGi), which was originally reported to be associated with the fibrosis stage in CHC patients [24], is likely to become an alternative to the use of VCTE; the M2BPGi value is influenced by both inflammation and fibrosis in AIH patients, in a similar way to VCTE [25]. A ‘one-serum parameter fits all’ approach to the evaluations of disease activity and fibrosis could be achievable with serum M2BPGi, but further studies are necessary to validate its utility. CLINICAL MANIFESTAIONS WITH SPECIAL ATTENTION TO DISEASE SUBTYPES Acute-onset AIH Acute-onset AIH is a clinically challenging disease subtype because a delayed diagnosis and delayed treatment, especially in the absence of typical serological findings, may lead to a poorer short-term prognosis. The prevalence of acute-onset AIH has been obtained in several cross-sectional studies worldwide. The 2019 AASLD practice guidance and guidelines state that 25–75% of individuals with AIH in western countries present with an acute onset and a disease duration <30 days [1,26]. A Korean study reported the prevalence 46.4%, using almost the same definition [27]. An Italian multicenter cohort applied arbitrary criteria, i.e., >10× the upper limit of normal (ULN) of transaminases and >5 mg/mL of bilirubin, and the study’s authors reported that 43% of their series of AIH patients were acute-onset [28]; among the patients who underwent liver biopsy, 64.8% fulfilled the histological criteria for acute-onset AIH, with the fibrosis stage lower than Ishak F2. In a Japanese nationwide cross-sectional study of AIH patients diagnosed in 2009–2013, the frequency of acute hepatitis without fibrosis (F0) was, on the other hand, almost 11% [3]. Acute-onset AIH may encompass two distinct clinical subgroups: 1) ‘genuine’ acute AIH with no chronic liver pathology (portal, followed by bridging fibrosis) and 2) acute exacerbation of chronic AIH. Even among the group of genuine acute AIH cases, dynamic histological changes—especially in the extent of portal fibrosis—are anticipated. As a trend, the median duration between disease onset and liver biopsy among Japanese AIH patients with acute presentation was longer in the F1–2 patients than in the F0 patients (29 vs. 15 days, P=0.052) [29]. Nevertheless, there were no significant differences between these two groups in laboratory data, AIH-related pathological findings, or disease outcomes after the introduction of prednisolone. Typical serological hallmarks of AIH (e.g., positive autoantibody or elevated serum IgG) are frequently absent in acute-onset AIH; in the above-mentioned Japanese cohort, 27% of the patients were ANA-negative (<×40) and >50% of them had normal serum IgG values [29]. As the absence of ANA and normal serum IgG were not associated with disease outcomes in that cohort, the prompt initiation of treatment with immunosuppressive agents was necessary to prevent progression to acute severe AIH (AS-AIH), and eventually ALF. AS-AIH is defined by the AASLD as AIH with jaundice, a prothrombin time (PT) international normalized ratio (INR) ≥1.5, and neither encephalopathy nor previously recognized liver disease (Table 1) [1]. A thorough diagnosis protocol that includes a transjugular liver biopsy is needed to differentiate AS-AIH from acute severe hepatitis with multiple other etiologies. In a cohort from the UK and France, 69% [30] and 59% [31] of the AS-AIH cases were reported to progress to ALF-AIH, respectively. A continuum of treatment strategies that are based on the benefit-to-risk ratio of glucocorticoid therapy should thus be seriously considered (Fig. 2). In the 2019 AASLD practice guidance, prednisone or prednisolone monotherapy (60 mg/day in adults) is recommended for AS-AIH [1], because no association with an increase in sepsis was demonstrated [32]. A short-term treatment response (within 1–2 weeks) in AS-AIH is indeed crucial to prevent disease progression. Zachou et al. [33] recently observed that high-dose intravenous (iv.) corticosteroids (either 1 g methylprednisolone for 3 consecutive days followed by iv. 1 mg/kg/day prednisolone, or iv. 1.5 mg/kg/day prednisolone) was safe and effective to treat AS-AIH patients (n=34; all were F0–2, and transaminases were >10× ULN). The complete response rate was higher than that in the non-AS-AIH group, with no case requiring liver transplantation (LT). ALF and acute on chronic liver failure (ACLF) AS-AIH with encephalopathy is defined as ALF caused by AIH (ALF-AIH) (Table 1). With regard to noninvasive diagnoses, heterogenous hypo-attenuated regions within the liver as visualized by unenhanced computed tomography (CT) is useful to differentiate patients with AS/ALF-AIH from those with viral-associated ALF [34]. The volumetric measurement of the liver on CT is also valuable, because the size of the liver was reported to be significantly reduced in non-acetaminophen cases of acute liver injury/ALF compared to the acetaminophen-induced cases [35]. A direct evaluation of indications for LT is recommended in ALF-AIH, because glucocorticoid therapy has not been associated with improved overall survival and is even harmful to patients with a model for end-stage liver disease (MELD) score >40 [36]. ACLF is caused by an AIH flare in previously diagnosed or undiagnosed chronic liver disease/cirrhosis (AIH-ACLF) patients. The Asian Pacific Association for the Study of Liver ACLF Consortium defines ACLF as patients with jaundice (bilirubin >5 mg/dL) and coagulopathy (PT [INR] ≥1.5), complicated by ascites and/or encephalopathy within 4 weeks after diagnosis. The consortium reported that 2.9% (n=82) of the ACLF cases diagnosed in 2012–2017 in nine Asian countries were regarded as having developed AIH as an acute insult; 97% of the patients exhibited IgG elevation (>1.1× ULN), whereas 49% were seronegative for autoantibodies [37]. Although 34% of the patients (n=28) being treated with a corticosteroid showed a significantly improved 90-day survival rate compared to those without treatment (75% vs. 48.1%, P=0.02), early stratification to corticosteroid therapy or LT is necessary [37]; predictors of an unfavorable response to corticosteroids were revealed to include a MELD score >27 and hepatic encephalopathy in advanced fibrosis (≥F3). DIAIH-like injury DILI can occasionally be diagnosed based on increased serum IgG and positive ANA. Even after the cessation of suspected drugs, such ‘AIH-mimic’ patients whose ALT elevation is persistent or progressive are indicated for treatment with immunosuppressive agents to prevent ALF. Remarkably, the short-term (1 week) response to corticosteroids was demonstrated to be more pronounced in the patients with AIH-mimic DILI compared to those with pure AIH [38]. AIH-mimic DILI and pathogenically DIAIH are difficult to differentiate by liver pathology, including the intensity of inflammatory infiltrates, the type of the predominant inflammatory cells, and the grade of fibrosis. In the 2019 AASLD practice guidance and guidelines, the term “DIAIH-like injury” was introduced as an alternative to DIAIH [1]. The majority of patients with DIAIH-like injury are acute-onset, and up to 30% of the cases are accompanied by hypersensitivity reaction [39]; the latency periods of minocycline and nitrofurantoin (the two most commonly implicated drugs) can exceed 12 months [40]. HLA-DR3 or -DR4 and cirrhosis at presentation are unusual [41]. Fulfilling Hy’s law, serum aminotransferase levels >3× ULN and total serum bilirubin >2× ULN as a predictor of ALF in patients with DILI [42], or failures of improvement in laboratory tests after medication discontinuation are the reasons for the implementation of glucocorticoids. The outcome of DIAIH-like injury has been shown to be excellent, and relapse after glucocorticoid withdrawal is rare [43]. Emerging liver injury that is related to the use of immune checkpoint inhibitors is distinct from DIAIH-like injury, as it lacks the typical serological and histological features of AIH [44,45]. Overlap manifestation with cholestatic liver disease or viral hepatitis The concurrences of AIH and PBC or AIH and PSC are not confirmed as specific pathological entities, but the identification of clinical ‘overlap’ among AIH patients is of importance, as these patients may not obtain sufficient benefit with only conventional AIH treatment. Concerning the AIH-PBC overlap, it should be noted that 5–35% of AIH patients, even in the absence of bile duct lesions, are reported to be positive for the serological hallmark of PBC, i.e., anti-mitochondrial antibodies (AMAs) [46]. Simultaneous and sequential AIH-PBC overlaps should be considered separately; the former is suspected in the presence of destructive cholangitis at the initial diagnosis, and the latter is suspected based on the occasional elevation of cholestatic enzymes after biochemical remission. The ‘Paris criteria’ for the identification of AIH-PBC overlap is valuable for apparent cases [47], but this criteria may miss cases with less severe cholestatic features [48,49]. The IAIHG’s position statement did not endorse the Paris criteria or even the revised AIH criteria regarding the diagnosis of AIH-PBC overlap [13]. Nevertheless, the reevaluation of suspected AIH-PBC overlap patients in light of their responses to immunosuppressive agents is likely practical and necessary. AIH-PSC overlap is diagnosed based on the following: 1) the typical features of AIH, 2) the absence of AMA, and 3) evidence of large-duct PSC by endoscopy or magnetic resonance imaging or of small-duct PSC, confirmed by ‘onion-skinning’ periductal fibrosis in a liver biopsy [49]. Concurrent ulcerative colitis with AIH is a critical indication for AIH-PSC overlap, especially in pediatric patients. The cases of hepatitis C virus-infected patients are occasionally accompanied by positive serum and histological markers of AIH, making a differential diagnosis of CHC-AIH overlap syndrome necessary. Direct-acting antiviral (DAA) therapy for CHC patients with AIH features was shown to significantly decrease ALT into the normal range, and serum markers of AIH in those patients began decreasing by 6 months post-treatment; >50% of the patients achieved complete resolution [50]. The CHC-AIH overlap syndrome may be a historical disease entity that is not likely to be diagnosed after the era of DAA. TREATMENT General considerations The purposes of the treatment of AIH are to first relieve symptoms, and then to achieve a biochemical response, control hepatic inflammation toward histological remission, prevent disease progression, and promote the regression of fibrosis. The ideal biochemical response, regarded as biochemical remission by the AASLD, is the normalization of the patient’s serum AST, ALT, and IgG levels to within the ULN (Table 1) [1]. A favorable treatment response in AIH patients assures overall survival that is comparable to that of general populations [51]. Due to the heterogenous manifestations of AIH, short- and long-term treatment responses with regard to liver-related adverse events should be defined in a personalized manner (Figs. 2, 3). Among AS-AIH, ALF, and ACLF patients, estimation of the early biochemical response within 7–14 days is necessary (Fig. 2) [1,32]. In contrast, the midterm biochemical response of patients with nonsevere acute-onset AIH or chronic insidious AIH, even with cirrhosis, can be evaluated at 4–8 weeks (Fig. 3) [1]. Biochemical remission is followed by a histological remission of disease activity. Sustaining biochemical remission for a long term (>1 year from treatment initiation) is thereafter a surrogate for favorable overall long-term survival [52]. Decreasing values of VCTE are favorable, even for the regression of fibrosis. First-line treatments The long-term outcome of patients with AIH has been shown to be improved with immunosuppressive treatment, both with corticosteroids alone and with a combination of a lower dose of corticosteroids and azathioprine (AZA) [53]; those regimens are consistently endorsed as a first-line treatment for AIH. The 2019 AASLD practice guidance and guidelines updated their recommended first-line treatment: either prednisone monotherapy (40–60 mg/day) or a combination of prednisone (20–40 mg/day) or budesonide (9 mg/day) and AZA (50–100 mg/day) [1]. The 2015 European Association for the Study of the Liver (EASL) guidelines propose 0.5–1 mg/kg/day predniso(lo)ne as the initial treatment, followed by a 50 mg/day AZA add-on [54]. The AASLD similarly indicates the appropriateness of a 2-week observation before the AZA is initiated, to confirm the patient’s steroid responsiveness and to evaluate his or her thiopurine-S methyl transferase (TPMT) status for the prevention of AZA-induced hepatitis. TPMT is an anabolizing enzyme for thiopurines, including AZA, and single nucleotide polymorphisms of TPMT genes that cause loss of enzymatic activity predispose patients, in particular European and African descendants, to thiopurine-related toxicity [1,55]. In Japan, AZA was finally approved for AIH treatment in 2018. Accordingly, the practice guidelines for AIH published by the Intractable Hepato-Biliary Diseases Study Group in Japan very recently added the recommendation to evaluate NUDT15 variant (but not TPMT) in patients who are to be treated with AZA, in order to exclude the possibility of thiopurine-induced early severe leukopenia and hair loss [55]. NUDT15 is a recently characterized nucleotide phosphatase that inactivates thiopurines. As the low- or intermediate activity diplotype was reported to be common in East Asian countries (22.6%) [55], the integration of NUDT15 variants in the dosing algorithm for AZA is regarded as most informative. Concerning the relevance of the starting dose of predniso(lo)ne to ensure remission, a retrospective observational study from nine centers in five European countries was performed and the results revealed no significant difference in the rate of normalization of transaminases at 6 months between groups with a higher (≥0.5 mg/kg/day) and lower (<0.5 mg/kg/day) initial dose of predniso(lo)ne [56]. With the aid of AZA as a maintenance therapy in the majority of patients (>85%), an initial lower dose significantly decreased the unnecessary exposure to predniso(lo)ne in patients with AIH. A synthetic steroid, i.e., budesonide has been shown to cause less systemic adverse effects, due to a 90% first-pass hepatic clearance rate. The AASLD investigated whether prednisone or predniso(lo)ne alone or in combination with AZA was superior to a combination of budesonide and AZA as the first-line treatment for patients with newly diagnosed AIH [1]. With an accompanying systemic review and meta-analysis, the AASLD demonstrated a higher rate of biochemical remission in the budesonide + AZA group compared to the prednisone + AZA group (odds ratio, 2.19; 95% CI, 1.30–3.67), and they described this finding as high-grade evidence [57]. Accordingly, the AASLD suggests budesonide in combination with AZA as a first-line therapy for child and adult AIH patients who do not have cirrhosis or acute severe AIH [1]; patients with cirrhosis are contraindicated for budesonide because portosystemic shunting may reduce the drug’s efficacy. The combination of AZA and either predniso(lo)ne or budesonide is now regarded as the most standard first-line therapy in western countries. Prednisone monotherapy, on the other hand, is likely to be appropriate for patients including those with DIAIH-like injury in whom the treatment duration is expected to be <6 months [1]. As corticosteroids are still the mainstay of the first-line treatment of AIH, the maintenance of bone during treatment is needed to limit treatment-related osteoporosis in patients with ongoing risk factors [58]. Bone mineral densitometry should be completed at baseline in those patients with repeated check-up every 2–3 years and supplementation with elemental calcium (1,000–1,200 mg/day) and vitamin D (400–800 IU/day) are recommended for all patients on glucocorticoid therapy [1,59]. Simultaneous bisphosphonate therapy is indeed indicated for patients with documented osteoporosis [60]. The determination of serum levels of 25-hydroxyvitamine D at diagnosis is justifiable, because vitamin D insufficiency (≤29 ng/mL) occurs frequently in patients with AIH (68–81%) [61,62] and even severe deficiency (<20 ng/mL) was reported to be documented in 20% of patients [62]. Second line-treatments The aims of second-line treatments for AIH are to manage refractoriness, incomplete biochemical response, and drug intolerance to first-line treatments (Figs. 2, 3). Anecdotally, second-line treatments have been performed with mycophenolate mofetil (MMF), calcineurin inhibitors (cyclosporin A, tacrolimus [TAC]), mercaptopurine, and biologics (e.g., infliximab). MMF is a DNA synthesis inhibitor and is indicated for immunosuppression after organ transplant or lupus nephritis. In a meta-analysis, the combination of MMF + prednisone was shown to be the most widely prescribed second-line treatment, achieving histological remission in 89% of the patients [63]. A recent report confirmed the effectiveness of MMF as a second-line therapy for patients who have failed standard therapy; the rate of induction of biochemical remission was 60% [64]. The AASLD performed a systemic review to compare the efficacies of MMF and TAC for treatment failure or incomplete biochemical response in adults and children: the AASLD 2019 conditional recommendation with low certainty suggests the use of MMP or TAC to achieve and maintain biochemical remission [1]. Exacerbation, recrudescence, and relapse During the course of maintenance therapy with corticosteroids/AZA, a substantial number of AIH patients spontaneously and asymptomatically experience biochemical exacerbation or recrudescence, i.e., an elevation of ALT coupled with or without an increase in IgG. The 2019 AASLD practice guidance and guidelines strictly define “relapse” as disease exacerbation that occurs after remission and drug withdrawal or by nonadherence [1]. Multiple relapses have been shown to be associated with worse outcomes [51], but the definitions of relapse in the literature differ from that issued by the AASLD, including the concept that biochemical remission may not have proceeded relapse. Following the AASLD rules regarding biochemical remission-induction with first-line or even second-line drugs could result in fewer exacerbations. Relapse after drug withdrawal (which usually occurs within 12 months) and exacerbation should be managed appropriately to induce re-(biochemical) remission with an increase in dosage or the reinstitution of immunosuppressive agents, or with the add-on of second-line drugs. In a case-control study, psychological stress was associated with relapse after drug taper-off or recrudescence [65]. Treatment withdrawal If AIH is a curable disease, the cessation of immunosuppressive agents is desirable. Could the cure for AIH be diagnosed based on serum biochemistry and liver histology, or both? Is the cure achievable in specific subgroups of patients? The answers to these clinical questions involve the feasibility of treatment withdrawal and simultaneously pursuing the lowest risk of drug-induced complications. Clinically, the duration and the degree of remission are the initial keys to the success of treatment withdrawal. A sustained biochemical remission of ≥2 years was proposed by the AASLD as the eligibility criterion for attempting a treatment withdrawal (Fig. 3) [1], in part because the inclusion of patients with only normalized ALT for 2 years resulted in almost universal relapse [66]. A further patient selection step should be included based on liver biochemistry, and/or on liver histology. Lower ALT and IgG values within the normal range were reported to be negative predictors of relapse; patients who achieved sustained remission for >1 year after drug withdrawal were all characterized by ALT values ≤0.5× ULN and IgG values ≤1,200 mg/dL [67]. Maintenance therapy before withdrawal was not associated with relapse: >80% of the patients were treated with AZA alone. A single-center study demonstrated that only 10% of their patients were eligible for treatment withdrawal and 5% reached sustained remission without treatment [67], highlighting AIH as generally a chronic disease demanding life-long maintenance therapy. Stringent biochemical remission for >2 years along with sustained low values of VCTE measured with an appropriate cut-off, may identify the patients who are at low risk of decompensation even when relapse occurs after treatment withdrawal. LT AIH with decompensated cirrhosis or ALF is indicated for LT. Among the listing of the Scientific Registry of Transplant Recipients (2002–2019) in the USA, 3.3% had AIH as the primary etiology [68]. In the trend analysis of the etiology of the Registry’s non-hepatocellular carcinoma LT listings, the rate of AIH during that period was stable. In the prospective multicenter European Liver Transplant Registry (1998–2017), the overall survival of patients after AIH-LT was reported to be similar to that of patients after alcohol-related cirrhosis-LT, but worse than that after PBC-LT and PSC-LT [69]; the 5- and 10-year patient and graft survival rates after AIH-LT were 79.4% and 70.8% and 73.25% and 63.4%, respectively. Compared to all of the other groups, the AIH-LT patients were at higher risk for infections—especially lethal fungal infections resulting in death and graft loss [69]. In AIH, living donor transplantation provided worse survival than that by donated LT after brain death [69]. The appropriateness of long-term glucocorticoid therapy after LT remains a matter of debate, in part because acute, steroid-resistant, and chronic rejection occurred more frequently in adult AIH patients who underwent LT compared to patients with other liver diseases [70], and also because of the chance of recurrence after LT [71]. A systemic review and meta-analysis of continuous glucocorticoid therapy in AIH-LT patients by the AASLD suggests that a gradual cessation of glucocorticoids could be considered after LT, with very low certainty [1]. UNMET NEEDS AND FUTURE PERSPERSPECTIVES The topics not addressed in this review include genetics, potential therapeutics based on the current understanding of the immune-pathogenesis of AIH, the inequity of AIH disease management worldwide, and patient-reported outcomes highlighted by the health-related quality of life. For example, the marked disparity in the prevalence of cirrhosis around the world, exemplified by the very high rate in South Asia [72], should be evaluated based on determinations of the patients’ genetic backgrounds and managed by the standardization of diagnosis and treatment. Improvements are anticipated regarding the accessibility to the flowchart of AIH diagnosis, with special attention to the differential diagnosis from emerging pandemic NASH. At the same time, the health-related quality of life of AIH patients, which was reported to be severely impaired [73-75], must be evaluated for future improvement from the standpoint of personalized management including appropriate first-line therapy even with potential therapeutics, and by the prediction of the success of treatment withdrawal. Using a multifaceted approach, we hepatologists are encouraged to achieve AIH patients’ total wellness.

Antiphospholipid Syndrome Antiphospholipid syndrome (APS) is defined by the coexistence of obstetric morbidity (mainly pregnancy losses) and/or vascular thrombosis (venous or arterial) with the presence of aPL, namely lupus anticoagulant, anticardiolipin, or anti-β2-glycoprotein I antibodies. From: Handbook of Systemic Autoimmune Diseases, 2018 Related terms: View all Topics Antiphospholipid Syndrome Lucia R. Wolgast MD, in Transfusion Medicine and Hemostasis (Third Edition), 2019 Introduction The antiphospholipid (aPL) syndrome (APS) is an autoimmune thrombophilic condition that is defined by a combination of clinical and laboratory criteria. In general terms, APS patients have developed circulating antibodies against plasma proteins that bind to phospholipids (i.e., aPL antibodies) with subsequent clinical morbidity of thrombosis and/or pregnancy complications. The investigational criteria for APS (often referred to as the Sydney Investigational Criteria) are detailed in Table 108.1 and require that patients have documented evidence for vascular thrombosis and/or obstetric complications, such as unexplained recurrent miscarriages, intrauterine growth restriction, intrauterine fetal demise, preeclampsia/toxemia, placental abruption, and preterm labor. The laboratory criteria require identifying the persistent aPL antibodies (i.e., at least two abnormal measurements at least 12 weeks apart), including elevated medium to high tiers of anticardiolipin (aCL) IgG or IgM antibodies, anti-β2-glycoprotein I (anti-β2GPI) IgG or IgM antibodies, and/or positive lupus anticoagulant (LA). The laboratory diagnosis of APS is discussed in Chapter 158. Table 108.1. Sydney Investigational Criteria for the Diagnosis of the Antiphospholipid Syndromea Clinical • Vascular thrombosis (one or more episodes of arterial, venous, or small vessel thrombosis). For histopathologic diagnosis, there should be no evidence of inflammation in the vessel wall. • Pregnancy morbidities attributable to placental insufficiency, including (a) three or more otherwise unexplained recurrent spontaneous miscarriages, before 10 weeks of gestation, (b) one or more fetal losses after the 10th week of gestation, (c) stillbirth, and (d) episode of preeclampsia, preterm labor, placental abruption, intrauterine growth restriction, or oligohydramnios that are otherwise unexplained. Laboratory • Medium- or high-titer aCL or anti-β2GPI IgG and/or IgM antibody present on two or more occasions, at least 12 weeks apart, measured by standard ELISAs. • Lupus anticoagulant in plasma, on two or more occasions, at least 12 weeks apart, detected according to the guidelines of the ISTH SSC Subcommittee on Lupus Anticoagulants and Phospholipid-Dependent Antibodies. β2GPI, β2-glycoprotein I; aCL, anticardiolipin; aPL, antiphospholipid; ELISA, enzyme-linked immunosorbent assay; Ig, immunoglobulin. a “Definite APS” is considered to be present if at least one of the clinical criteria and one of the laboratory criteria are met. Modified from Miyakis, S., Lockshin, M. D., Atsumi, T., et al. (2006). International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). J Thromb Haemost, 4, 295–306. It is important for the reader to understand that these criteria were not designed to be requirements for the clinical diagnosis of APS. Rather, they were intended to provide a uniformly rigorous definition of APS for the purpose of standardizing research on the disorder. In “real-world” clinical practice, some patients may be appropriately diagnosed for presumptive APS without meeting the strict investigational criteria. Some APS patients may be positive for other “noncriteria” clinical laboratory tests—see Chapter 158—that have not been included by consensus panels as diagnostic criteria for the disorder, but these positive noncriteria laboratory tests may indicate a clinical risk and warrant treatment. Furthermore, APS patients may have positive APS criteria assays but not the typical criteria manifestations. These “noncriteria manifestations” include thrombocytopenia, livedo reticularis, skin ulcers, nephropathy, migraine, cognitive defects, diffuse alveolar hemorrhage, and valvular heart disease (Libman–Sacks endocarditis), and these clinical manifestations may need to be managed differently. Occasional patients may even test entirely negative for the APS criteria assays but have typical clinical manifestations of the disorder—a situation referred to as seronegative APS (termed SNAPS). At present, APS may be divided into the following subcategories: (1) Primary APS is the “stand alone” disorder, in the absence of systemic lupus erythematosus (SLE), (2) secondary APS occurs in the presence of APS, (3) catastrophic APS (CAPS) manifests as disseminated thrombosis in large and small vessels with resulting multiorgan failure (Table 108.2), and (4) SNAPS includes patients whose diagnostic tests are entirely negative but who, on clinical grounds, are still suspected to have the disorder. Table 108.2. Proposed Criteria for the Classification of Catastrophic Antiphospholipid Syndrome (APS) 1. Evidence of involvement of three or more organs, systems, and/or tissuesa 2. Development of manifestations simultaneously or in less than a week 3. Confirmation by histopathology of small vessel occlusion in at least one organ or tissueb 4. Laboratory confirmation of the presence of antiphospholipid antibodies (lupus anticoagulant and/or anticardiolipin antibodies)c Definite Catastrophic APS • All four criteria Probable Catastrophic APS • All four criteria, except for only two organs, systems and/or tissues involvement • All four criteria, except for the absence of laboratory confirmation at least 6 weeks apart due to the early death of a patient never previously tested for aPL before the catastrophic APS event • Criteria 1, 2, and 4 • Criteria 1, 3, and 4 and the development of a third event in more than a week but less than a month, despite anticoagulation a Usually, clinical evidence of vessel occlusions, confirmed by imaging techniques when appropriate. Renal involvement is defined by a 50% rise in serum creatinine, severe systemic hypertension (N180/100 mm Hg), and/or proteinuria (N500 mg/24 hours). b For histopathological confirmation, significant evidence of thrombosis must be present, although, in contrast to Sydney criteria, vasculitis may coexist occasionally. c If the patient had not been previously diagnosed as having an APS, the laboratory confirmation requires that the presence of antiphospholipid antibodies must be detected on two or more occasions at least 6 weeks apart (not necessarily at the time of the event), according to the proposed preliminary criteria for the classification of definite APS. Modified from Asherson, R. A., Cevera, R., de Groot, P. G., et al. (2003). Catastrophic antiphospholipid syndrome: international consensus statement on classification criteria and treatment guidelines. Lupus, 12, 530–534. Antiphospholipid Syndrome Nancy Agmon-Levin, ... Yehuda Shoenfeld, in The Autoimmune Diseases (Fifth Edition), 2014 The antiphospholipid syndrome (APS) is an autoimmune disorder characterized by thrombosis, pregnancy losses, and the presence of at least one of three antiphospholipid antibodies. However, it has been acknowledged that the clinical spectrum of APS is much wider, including systemic and organ-specific manifestations. Moreover, the presence of more than 20 antiphospholipid antibodies has been recognized, some of which may participate in the pathogenesis of APS although not included as criteria. Our knowledge and understanding of the etio-pathogenesis of APS has increased tremendously, as the effects of antiphospholipid antibodies, mainly the anti-B2GPI–B2GPI immune complexes, were elucidated. The latter bind to different cells (i.e., monocytes, endothelial cells, and trophoblasts), recruit cell surface receptors, and subsequently induce intracellular signaling. Additionally an arsenal of environmental factors as infectious agents and vitamin D has been associated with the presence of antiphospholipid antibodies and overt APS. It seems therefore that in APS both thrombotic and immune-mediated mechanisms play a part and may be considered as candidates for targeted therapeutic interventions. Antiphospholipid Syndrome ROBERT A.S. ROUBEY, in The Autoimmune Diseases (Fourth Edition), 2006 Publisher Summary The antiphospholipid syndrome (APS) is the association of autoantibodies having an apparent specificity for anionic phospholipids with one or more clinical manifestations that include venous and arterial thrombosis and pregnancy loss and morbidity. APS is an under-recognized autoimmune disease that accounts for a significant proportion of thromboembolic disease and recurrent pregnancy loss. Animal models of APS are important tools for investigating the cellular basis of the autoimmune response, the contribution of genetic factors, and mechanisms by which antiphospholipid antibodies (aPL) contribute to thrombosis and pregnancy loss Anticoagulation rather than immunosuppression is the current mainstay of therapy. Although effective in most cases, full anticoagulation carries a significant risk of adverse side effects. Future research characterizing the underlying autoimmune response, the spectrum of APS autoantibodies, and the relevant mechanisms of hypercoagulability will lead to the identification of novel therapeutic targets and approaches. These new approaches raise hope for safer and more effective treatment of APS. Antiphospholipid syndrome Munther A. Khamashta, Mary-Carmen Amigo, in Rheumatology (Sixth Edition), 2015 Antiphospholipid syndrome: definition and history Antiphospholipid syndrome (APS) is an autoimmune multisystemic dis­order characterized by recurrent arterial and venous thrombosis and/or pregnancy morbidity associated with the presence of persistent antiphospholipid antibodies (aPLs). aPLs are a heterogeneous group of antibodies directed against anionic phospholipids or protein-phospholipid complexes. Laboratory tests to identify aPL includes solid-phase immunoassays (enzyme-linked immunosorbent assay [ELISA]) to detect anticardiolipin (aCL) and anti–β2-glycoprotein I (anti-β2-GPI) antibodies and functional assays to detect the so-called lupus anticoagulants (LACs) that demonstrate the ability of aPL to prolong phospholipid-dependent clotting reactions.1 The term lupus anticoagulant is a misnomer. The LAC phenomenon results in prolonged plasma clotting times; however, patients with LAC are subject to thrombosis, not to hemorrhage, except in uncommon cases such as in hypoprothrombinemia-LAC syndrome. Although initially described in patients with systemic lupus erythematosus (SLE), APS was soon recognized also to occur in patients without underlying autoimmune disease. APS was then classified as “secondary” in the presence of SLE and “primary” in the absence of SLE or other autoimmune disorders. Primary APS is the most common cause of acquired thrombophilia and accounts for 15% to 20% of all episodes of deep vein thrombosis with or without pulmonary embolism, one third of new strokes occurring in patients younger than age 50, and 10% to 15% of women with recurrent fetal loss.2 APS also accounts for a significant proportion of thromboembolic disease and recurrent fetal loss in patients with SLE. aPLs are present in 30% to 40% of SLE patients, and 10% to 15% of all SLE patients have clinical manifestations of APS.3 It is now generally accepted that aPLs are the most frequent acquired risk factor for a treatable cause of recurrent pregnancy loss and for pregnancy complications. In 1999, an international consensus meeting formulated the first classification criteria (known as the Sapporo criteria) for patients with APS.4 In 2006, these criteria were updated1 (Box 139.1). Antiphospholipid Syndrome Tadej Avčin, Kathleen M. O'Neil, in Textbook of Pediatric Rheumatology (Seventh Edition), 2016 Other Manifestations Cardiac manifestations are frequent in adult patients with APS but have not been extensively investigated in childhood. The most prominent cardiac manifestations include valvular disease, occlusive coronary artery disease, cardiomyopathy, and intracardiac thrombosis.22,248 Nonbacterial (Libman–Sacks) vegetations were disclosed by echocardiographic studies in 11% of adult patients with APS,22 but were only rarely observed in patients with pediatric APS.29,249 Several cases of pediatric patients with aPL-related myocardial infarction have been reported, often in association with underlying SLE or congenital heart disease.32,250-253 Multiple small vascular occlusions are responsible for APS cardiomyopathy, especially in CAPS, in which it is one of the most common causes of death.254,255 Pulmonary embolism and infarction constitute the most frequent pulmonary manifestation of APS.45,182,256-258 aPLs were reported in 30% to 40% of children with pulmonary embolism who were referred for hematology evaluation.256,258 Rarely, recurrent pulmonary embolism may lead to pulmonary hypertension.196,259,260 The kidney is a major target organ of pediatric APS with manifestations that include renal vascular occlusion, thrombotic glomerular microangiopathy, and hypertension.46,261-265 The term antiphospholipid syndrome-associated nephropathy (APSN) was proposed to describe thrombotic microangiopathy involving both arterioles and glomerular capillaries that cause hypertension, acute renal failure, proteinuria, and poor renal function with a tendency to develop end-stage renal disease.2,266-268 This entity was reported in 16% of Thai patients with childhood-onset SLE who underwent renal biopsy and was significantly more frequent in adult SLE patients (41%).268 aPLs are also associated with hepatic, digestive, and adrenal manifestations resulting from occlusive vascular disease of intraabdominal vessels.269-272 Osteoarticular manifestations such as avascular necrosis of bone, nontraumatic fractures, and bone marrow necrosis are rarely seen in APS patients.273,274 Adult patients with primary APS and no prior glucocorticoid treatment appear to have an increased risk of avascular necrosis.275 aPLs were reported as one of the most common prothrombotic alterations in patients with multifocal osteonecrosis, which is present in 20% of cases.276 Perthes disease has been linked with aPLs in two pediatric studies,274,277 but the association does not appear to be strong. Antiphospholipid Syndrome Tatsuya Atsumi, ... Takao Koike, in Systemic Lupus Erythematosus (Fifth Edition), 2011 Antiphospholipid antibodies (aPLs) include a heterogeneous group of circulating immunoglobulins present in a wide range of infectious and autoimmune diseases. In particular, anticardiolipin antibodies (aCL) and lupus anticoagulants (LA) are associated with the antiphospholipid syndrome (APS). APS is recognized as a condition that is a frequent cause of acquired thrombophilia. They react with a complex of phospholipid and plasma proteins, including β2GPI, prothrombin, annexin V, high- and low-molecular-weight kininogen, protein S, and protein C, previously known as “cofactors.” Because of their strong relationship with clinical symptoms, aPLs have been considered pathogenic antibodies. It is recognized that the inhibition of the natural anticoagulant systems, the impairment of fibrinolytic activity, and the direct effect of aPLs on cell functions are some of the mechanisms of aPL-mediated thrombosis. Studies on the pathogenicity of aPLs have been carried out mainly on the corresponding antigens, especially on the function of β2GPI and their modifications by the antibodies. Evidence suggests that complement activation is also required for aPL-mediated tissue injury, and findings have revealed that aPLs play a role in the T-cell responses. Pathogenesis of Antiphospholipid Antibody Syndrome Ian Giles, ... Yiannis Ioannou, in Dubois' Lupus Erythematosus and Related Syndromes (Ninth Edition), 2019 Clinical Importance of the Antiphospholipid Syndrome in Patients With SLE APS has a wide range of clinical manifestations.5 Initially, APS was identified in patients with SLE, in whom a positive test for either aPLs occurred in the presence of thrombosis or pregnancy morbidity. The existence, however, of primary APS (PAPS) in patients lacking another autoimmune rheumatic disease (ARD) was identified in ~50% of APS patients. The original description of the remaining cases as secondary APS, occurring in the presence of another ARD, most commonly SLE, has now been dropped because the clinical and serologic features of APS are similar in both groups. In this regard, the 2006 APS classification criteria recommended that any associated disorder should be reported, such as SLE-associated APS.4 A catastrophic variant occurs in less than 1% of patients with APS who develop multiple (often small vessel) thromboses resulting in multiorgan failure, and 40% of these patients have SLE.6 Antiphospholipid Syndrome Wendy Lim MD, MSc, in Transfusion Medicine and Hemostasis (Second Edition), 2013 Future Directions APS is a complex disorder with evolving diagnostic criteria. Insight into the pathophysiology of APS may lead to novel treatments for APS, which to date have focused on antithrombotic therapy. Complement activation may play an important role in fetal loss, and although there is currently no specific complement-targeted therapy approved for patients with APS, complement inhibition may prove to be a novel upstream treatment for APS. Other investigational treatments include the use of rituximab, other immunosuppressive agents and autologous stem cell transplantation, all of which require further study. Management of patients with aPL and APS can be challenging, as many patients with APS have risk factors for bleeding and have a high risk of recurrent thromboembolism. The clinical trials and observational studies performed to date have yielded valuable information on the management of patients with APS, but further research is required to address the ongoing controversies that exist in the management of these patients. The Clinical Evaluation of Kidney Disease in Systemic Lupus Erythematosus Brad H. Rovin, Isabelle Ayoub, in Systemic Lupus Erythematosus, 2016 Antiphospholipid Syndrome and the Kidney APS (Chapters 56–58Chapter 56Chapter 57Chapter 58) can result in kidney injury by causing noninflammatory occlusions of renal blood vessels, including the intrarenal microvasculature. APS is seen in about 30% of patients with SLE, often (but not always) accompanied by LN and antiphospholipid antibodies such as anticardiolipin and anti-β2-glycoprotein I antibodies, or lupus anticoagulants.41 It is important to consider the diagnosis of renal APS and verify with a kidney biopsy, because the usual immunosuppression used for LN does not treat renal APS, which requires anticoagulation. Failure to treat APS can lead to CKD or ESRD. Antiphospholipid Syndrome in Systemic Autoimmune Diseases Roger A. Levy, ... Ricard Cervera, in Handbook of Systemic Autoimmune Diseases, 2017 1.1 Introduction Antiphospholipid syndrome (APS) is defined by the occurrence of venous and arterial thromboses (often multiple) and pregnancy morbidity (abortions, foetal deaths, premature births), in the presence of antiphospholipid antibodies (aPL); namely, lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2 glycoprotein-I (anti-β2GPI) antibodies. APS can occur in patients having neither clinical nor laboratory evidence of another definable condition (primary or isolated APS), or it may be associated with other diseases, mainly systemic lupus erythematosus (SLE), and occasionally with other autoimmune conditions, infections, drugs, and malignancies. Rapid chronological occlusive events, occurring over days to weeks, have been termed as catastrophic APS (CAPS). Other postulated APS subsets include microangiopathic APS (MAPS) and seronegative APS.