The Intersection of COVID-19 and Autoimmunity: What is Our Current Understanding?

Viral infections have historically had a complex relationship with autoimmune diseases. For patients with preexisting autoimmune disorders, often complicated by immunosuppressive therapies, there are numerous potential effects of COVID-19, a disease of complex immunobiology, including the potential for an altered natural history of COVID-19 when infected. In addition, individuals without recognized autoimmune disease may be vulnerable to virally induced autoimmunity in the forms of autoantibody formation, as well as the development of clinical immune-mediated inflammatory diseases. Until quite recently in the pandemic, this relationship between COVID-19 and autoimmune diseases has been relatively underexplored; yet such investigation offers potential insights into immunopathogenesis as well as for the development of new immune-based therapeutics. Our review examines this relationship through exploration of a series of questions with relevance to both immunopathogenic mechanisms as well as some clinical implications.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Soluble immune effector molecules [II]: agents targeting interleukins, immunoglobulins and complement factors).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting interleukins, immunoglobulins and complement factors and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Patients receiving interleukin-1 (IL-1) -targeted (anakinra, canakinumab or rilonacept) or IL-5-targeted (mepolizumab) agents have a moderate risk of infection and no specific prevention strategies are recommended. The use of IL-6/IL-6 receptor-targeted agents (tocilizumab and siltuximab) is associated with a risk increase similar to that observed with anti-tumour necrosis factor-α agents. IL-12/23-targeted agents (ustekinumab) do not seem to pose a meaningful risk of infection, although screening for latent tuberculosis infection may be considered and antiviral prophylaxis should be given to hepatitis B surface antigen-positive patients. Therapy with IL-17-targeted agents (secukinumab, brodalumab and ixekizumab) may result in the development of mild-to-moderate mucocutaneous candidiasis. Pre-treatment screening for Strongyloides stercoralis and other geohelminths should be considered in patients who come from areas where these are endemic who are receiving IgE-targeted agents (omalizumab). C5-targeted agents (eculizumab) are associated with a markedly increased risk of infection due to encapsulated bacteria, particularly Neisseria spp. Meningococcal vaccination and chemoprophylaxis must be administered 2-4 weeks before initiating eculizumab. Patients with high-risk behaviours and their partners should also be screened for gonococcal infection. IMPLICATIONS: Preventive strategies are particularly encouraged to minimize the occurrence of neisserial infection associated with eculizumab.

Rheumatic immune-related adverse events of checkpoint therapy for cancer: case series of a new nosological entity.

Immunotherapy of cancer with checkpoint inhibitors has been associated with a spectrum of autoimmune and systemic inflammatory reactions known as immune-related adverse events (irAEs). Rheumatic irAEs are infrequently reported and extensively described. Here, we report our experience over an 18-month period with 15 patients evaluated in the rheumatology department for rheumatic irAEs. We identified 13 patients without pre-existing autoimmune disease (AID) who subsequently developed rheumatic irAEs, and two with established AID referred pre-emptively. irAEs encountered included: inflammatory arthritis, sicca syndrome, polymyalgia rheumatica-like symptoms and myositis. All cases required glucocorticoids, and three required a biological agent. Rheumatic irAEs led to temporary or permanent cessation of immunotherapy in all but five patients. One patient with pre-existing AID experienced a flare after starting immunotherapy. Our findings underscore that rheumatic irAEs are complex, at times require additional immunosuppressive therapy, and may influence ongoing immunotherapy regimens for the primary disease. Similar irAEs will be increasingly seen as checkpoint inhibitors adopted as standard of care in the community.

High-resolution MRI vessel wall imaging: spatial and temporal patterns of reversible cerebral vasoconstriction syndrome and central nervous system vasculitis.

BACKGROUND AND PURPOSE: High-resolution MR imaging is an emerging tool for evaluating intracranial artery disease. It has an advantage of defining vessel wall characteristics of intracranial vascular diseases. We investigated high-resolution MR imaging arterial wall characteristics of CNS vasculitis and reversible cerebral vasoconstriction syndrome to determine wall pattern changes during a follow-up period. MATERIALS AND METHODS: We retrospectively reviewed 3T-high-resolution MR imaging vessel wall studies performed on 26 patients with a confirmed diagnosis of CNS vasculitis and reversible cerebral vasoconstriction syndrome during a follow-up period. Vessel wall imaging protocol included black-blood contrast-enhanced T1-weighted sequences with fat suppression and a saturation band, and time-of-flight MRA of the circle of Willis. Vessel wall characteristics including enhancement, wall thickening, and lumen narrowing were collected. RESULTS: Thirteen patients with CNS vasculitis and 13 patients with reversible cerebral vasoconstriction syndrome were included. In the CNS vasculitis group, 9 patients showed smooth, concentric wall enhancement and thickening; 3 patients had smooth, eccentric wall enhancement and thickening; and 1 patient was without wall enhancement and thickening. Six of 13 patients had follow-up imaging; 4 patients showed stable smooth, concentric enhancement and thickening; and 2 patients had resoluton of initial imaging findings. In the reversible cerebral vasoconstriction syndrome group, 10 patients showed diffuse, uniform wall thickening with negligible-to-mild enhancement. Nine patients had follow-up imaging, with 8 patients showing complete resolution of the initial findings. CONCLUSIONS: Postgadolinium 3T-high-resolution MR imaging appears to be a feasible tool in differentiating vessel wall patterns of CNS vasculitis and reversible cerebral vasoconstriction syndrome changes during a follow-up period.

Progressive multifocal leucoencephalopathy in the rheumatic diseases: assessing the risks of biological immunosuppressive therapies.

Progressive multifocal leucoencephalopathy (PML) is a rare and often fatal opportunistic infection that has been well reported in patients with rheumatic diseases. The contributions of predisposing factors such as underlying disease and immunosuppressive drug selection are incompletely understood but it would appear that patients with systemic lupus erythematosus may be at highest risk. Natalizumab, a biological agent approved for multiple sclerosis and Crohn's disease has the clearest pattern of small but definite risk. Although the risk due to rituximab is difficult to assess given the multiple confounders, continued vigilance is warranted. Rheumatologists need to become familiar with PML and feel able to help patients make shared and informed decisions about the risks when starting treatment with immunosuppressive therapies. In particular, rheumatologists need to be vigilant and pursue the diagnosis of PML in all patients with unexplained neurological signs or symptoms with clinical and MRI findings compatible with the diagnosis.

Arteriovenous malformation of the brain mimicking primary central nervous system vasculitis.

In the diagnosis of primary central nervous system (CNS) vasculitis, it is crucial to rule out clinical, angiographic, and pathological mimics. We report a case of arteriovenous malformation (AVM) mimicking primary CNS vasculitis. A young male presented with intracerebral haemorrhage and no other clinical, laboratory, or angiographic features suggesting vasculitis. Cerebral biopsy showed perivascular inflammation and slight infiltration of the muscular layer of cerebral vessels by chronic inflammatory cells close to the haemorrhagic areas. These findings led to a diagnosis of CNS vasculitis. The patient was initially treated with corticosteroids, but 10 months after the discovery and surgical repair of the AVM, the patient is not receiving any immunosuppressant and has not developed any features of cerebral or systemic vasculitis.

Tumour-like mass lesion: an under-recognised presentation of primary angiitis of the central nervous system.

OBJECTIVE: To describe the occurrence of mass lesions (ML) in primary angiitis of the central nervous system (PACNS) and assess the utility of diagnostic testing and treatment. METHODS: We examined the case records of the Cleveland Clinic (CC), Massachusetts General Hospital (MGH), and the English language medical literature, for biopsy-proven PACNS cases presenting as a solitary ML. Relevant clinical variables were extracted and analysed with JMP software. RESULTS: We identified a total of 38 ML: eight of 202 (4.0%) patients with CC/MGH and 30 of 535 (5.6%) patients with PACNS identified from the medical literature. A higher percentage (13 of 45; 29%) was seen in the amyloid-related angiitis subset. Poorer outcomes were reported in the amyloid group, with five deaths. Of the non-amyloid group, better outcomes were seen in the group treated with corticosteroids and cyclophosphamide as compared with the group treated with corticosteroids alone. CONCLUSIONS: Although rare, PACNS should be considered in the differential diagnosis of ML; greater awareness of this manifestation may facilitate more prompt diagnosis and treatment. Biopsy evidence of angiitis is required for diagnosis; specimens should routinely be stained for amyloid. While excision of the lesion may be curative, aggressive immunosuppressive therapy is associated with favourable outcomes and may obviate the need for surgery.

Hepatitis C-associated mixed cryoglobulinaemia: a crossroad between autoimmunity and lymphoproliferation.

Hepatitis C virus (HCV) infection is the second most cocmmon chronic viral infection in the world with a global prevalence of about 2%. Chronic HCV infection is commonly associated with a number of extrahepatic complications. Circulating mixed cryoglobulins (MCs) are detected in 40-60% of HCV-infected patients whereas overt cryoglobulinaemia vasculitis develops in only 5-10% of the cases. MC reflects the expansion of B cells producing a pathogenic IgM with rheumatoid factor (RF) activity. Because cryoglobulin-producing B cells in HCV are mostly monoclonal, HCV-associated MC can be viewed as a benign B cell lymphoproliferative condition. The disease expression of MC vasculitis is variable, ranging from mild clinical symptoms (purpura, arthralgia) to fulminant life-threatening complications (glomerulonephritis, widespread vasculitis). The overall risk of non-Hodgkin's lymphoma in patients with HCV-MC is estimated to be 35 times higher than that in the general population. This review will focus on recent advances in our understanding of the clinical course, complications, pathophysiology and treatment of those immune-mediated disorders.

Hepatitis B virus (HBV) reactivation with immunosuppressive therapy in rheumatic diseases: assessment and preventive strategies.

Understanding of the natural history and basic biology of hepatitis B virus (HBV) has increased greatly in recent years. In view of this, the following are reviewed here: (a) recent advances in HBV biology pertinent to the rheumatic disease population; (b) the risks of HBV reactivation in patients with rheumatic disease undergoing immunosuppression; and (c) potential strategies to manage these risks.

Safety of antitumour necrosis factor (anti-TNF) therapy in patients with chronic viral infections: hepatitis C, hepatitis B, and HIV infection.

Tumour necrosis factor alpha (TNFalpha) is a pivotal cytokine in host defences with broad ranging effects on the innate and adaptive immune systems. Clinically, TNFalpha inhibitors have demonstrated remarkable efficacy in a wide range of autoimmune and inflammatory disorders but clearly at the cost of heightened susceptibility to a variety of infections in those treated with these agents. Most reports to date have described increased susceptibility to intracellular pathogens in patients with underlying chronic viral infections, but little in the way of adverse event reporting in these patients has occurred. While the reported experience to date is rather limited, TNFalpha inhibitors have displayed a reasonable safety profile in the setting of some chronic viral infections and in certain circumstances have demonstrated adjunctive activity in the treatment of these infections. Given the high prevalence of chronic viral infections in patients who are candidates for anti-TNF therapy and the potential for these agents in the treatment of chronic viral illness, additional studies are urgently needed to assess the risks and benefits of such therapy in these populations.

Branch retinal artery occlusions as the presenting feature of primary central nervous system vasculitis.

A 39-year-old woman presented with multiple branch retinal artery occlusions almost three years before developing a mass lesion containing calcium in the left frontal lobe. Brain biopsy revealed a small vessel vasculitis and ischemic necrosis of brain with dystrophic calcification. We believe this to be the first case of primary CNS vasculitis with branch retinal artery occlusions and brain calcification.

Infection with the human immunodeficiency virus type 1 and vascular inflammatory disease.

Since the beginning of the HIV epidemic a wide variety of vascular inflammatory diseases have been described in HIV infected patients. In terms of the primary forms of systemic necrotizing vasculitis, there are no convincing data suggesting HIV infection increases the risk of development of any form of these diseases, but it is possible--though yet unproven--that HIV may lessen the chance of developing other forms (i.e. ANCA-associated disease and HBV-associated PAN). Secondary vasculitis resulting from unusual pathologic expressions of opportunistic infections has been reported and has important clinical significance. Finally, there does appear to be growing clinical, epidemiologic and pathologic evidence that several distinctive forms of vascular inflammatory disease occur in certain settings. These include aneurysmal disease of the large arteries of the brain occurring in children and a large vessel aneurysmal disease primarily affecting the aorta and its branches in young HIV-infected patients from sub-Saharan Africa. Further study of these disorders is necessary to identify specific epidemiologic features and pathogenesis.

Molecular differences in anticytokine therapies.

Biologic agents that inhibit proinflammatory cytokines have made a profound impact on the treatment of rheumatoid arthritis (RA). Of the agents that are currently approved by the US Food and Drug Administration (FDA) for this indication, etanercept and infliximab neutralize tumor necrosis factor (TNF), and anakinra inhibits interleukin-1 (IL-1). Adalimumab, which was just recently approved by the FDA, is also a TNF inhibitor. Despite their common ability to inhibit cytokine bioactivity, the molecular structures and mechanisms of action of these biologic agents are significantly different. The TNF-binding moiety of etanercept is derived from soluble TNF receptor subunits. Infliximab is a chimeric (mouse-human) monoclonal antibody to TNF, while adalimumab is a fully human anti-TNF monoclonal antibody. Anakinra has yet another mechanism of action: it is an IL-1 receptor antagonist. The molecular characteristics of these agents may be relevant to clinical efficacy and safety. These agents are still relatively new: to date, the longest reporting time is 5 years, for etanercept. Additional long-term data will be required to determine the relative benefits and drawbacks of different molecular characteristics in these anticytokine agents.

Study of host and virological factors of patients with chronic HCV infection and associated laboratory or clinical autoimmune manifestations.

OBJECTIVE: Chronic hepatitis C virus (HCV) infection is associated with an array of autoimmune laboratory and clinical manifestations. The goals of our study were to identify host and/or virological factors that are implicated in the pathogenesis of these manifestations. METHODS: We performed a detailed prospective study of various demographic, virological, biochemical, immunological (including lymphocyte subsets, Fc gamma-receptor and HLA class-II genotyping), histological and host genetic parameters in 3 well defined subgroups of HCV patients (n = 40): patients with liver disease only (group I, n = 11) or with laboratory (group II, n = 20) and clinical (group III, n = 9) autoimmune manifestations. RESULTS: Group III patients, mainly with features of mixed cryoglobulinemia, were older, with higher levels of rheumatoid factor and circulating cryoglobulins while they tended to have a longer estimated disease duration compared to the other two groups of patients. We did not identify any specific immunological features that could differentiate symptomatic versus asymptomatic patients, except from the elevated soluble interleukin-2 receptor levels. An increased frequency of the R/R131 FcR gamma IIIA and the NA1/NA1 Fc gamma RIIIB genotypes was observed in our total HCV population, regardless of autoimmune manifestations, compared to historical controls. No statistically significant differences in HLA class II allele frequencies was detected between patient subgroups or in comparison to healthy controls. CONCLUSIONS: Chronically infected HCV patients with symptomatic mixed cryoglobulinemia display a number of unique characteristics that differentiate them from asymptomatic patients with chronic hepatitis C.

Clinical management issues in vasculitis. Angiographically defined angiitis of the central nervous system: diagnostic and therapeutic dilemmas.

A case of acute neurologic deficit accompanied by a cerebral angiogram consistent with CNS vasculitis is presented. The differential diagnosis and diagnostic decision process generated in this type of evaluation is illustrated.

Vasculitis. A collection of pearls and myths.

Important strides have been made in unraveling the pathophysiologic characteristics of some individual forms of vasculitis, but vasculitides continue to pose enormous challenges for clinicians. Over time, numerous myths and an occasional pearl have arisen from the care of patients with these disorders. In this collection of pearls and myths, we have attempted to pool our knowledge about the clinical care of vasculitis patients.

A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS).

OBJECTIVE: To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG). METHODS: Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS: We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION: The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.