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.

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.

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.

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.

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.

Physicians' attitudes, beliefs, and practices regarding AIDS health care promotion.

While there is now evidence that health-promoting education can be effective at reducing transmission of human immunodeficiency virus (HIV) infection, little is known of the role of the practicing physician in this process. We have surveyed 301 practicing physicians in Northeastern Ohio over a 2-year period and we have assessed their attitudes, beliefs, and practices regarding preventive education with particular reference to HIV. We have found that while the majority of physicians believe strongly that HIV prevention is important and that physicians should play a prominent role in education, the incorporation of such measures in their practice lags far behind other areas of health prevention. Positive educational behavior was correlated with direct experience with HIV-infected patients and postgraduate education on HIV infection.

Weighted criteria for the diagnosis of systemic lupus erythematosus.

The preliminary American Rheumatism Association (ARA) criteria for classification of systemic lupus erythematosus (SLE) were evaluated for sensitivity and specificity in 87 patients with SLE and 73 without SLE from a rheumatology population. Using these data, Bayes' theorem was employed to weight the criteria so that a scoring system could be developed, allowing more accurate use of the criteria in diagnosis. Combinations of serologic test results were evaluated in a similar manner. Comparison of weighted scores with criteria counts showed greater sensitivity and specificity of the former whether the 1971 or modified 1982 ARA criteria were used. Weighted criteria may be more useful in clearly defining patient populations for studies of SLE.

Development of systemic lupus erythematosus after thymectomy for myasthenia gravis. Studies of suppressor cell function.

Systemic lupus erythematosus developed in an 18-year-old man three years after thymectomy for myasthenia gravis. The patient had considerable defects in suppressor cell function that seemed to be partially reversed in vitro by the addition of thymic hormone.

Familial late complement component (C6, C7) deficiency with chronic meningococcemia.

Two patients with chronic meningococcemia were found to lack hemolytic complement, one because of C6 deficiency, the other because of C7 deficiency. In both cases family studies were consistent with inheritance of the deficiencies as non-HLA-linked, autosomal co-dominant traits. Functional studies showed the deficient sera to support monocyte chemotaxis but not phagocytosis or lysis of meningococci. Both patients have remained well following antibiotic treatment.

Maintenance of CD4+ cells by thymopentin in asymptomatic HIV-infected subjects: results of a double-blind, placebo-controlled study.

OBJECTIVE: To assess the efficacy and safety of thymopentin in HIV-infected patients who had not yet developed AIDS. DESIGN: Patients were stratified into asymptomatic or symptomatic groups and randomized to receive either thymopentin (50 mg) or placebo, subcutaneously, double-blind for 24 or 52 weeks, three times a week. SETTING: Patients were enrolled at three sites (two hospital clinics and one private practice). PATIENTS: Of 91 HIV-seropositive patients (52 asymptomatic and 39 symptomatic) from whom HIV could be isolated from peripheral blood, 45 were enrolled for 24 weeks and 46 for 52 weeks of double-blind evaluation. MAIN OUTCOME MEASURES: Virological, immunological and clinical evaluations were performed before and during treatment. RESULTS: Thymopentin-treated asymptomatic patients had more CD4+ cells, as demonstrated by a greater area under the percentage CD4+ cells curve (P = 0.03) and a shorter median time to a 20% increase in percentage of CD4+ cells (P = 0.04) in the first 24 weeks, with similar trends in the 52-week study. By 24 weeks no asymptomatic thymopentin-treated and two placebo-treated patients (9.1%, Kaplan-Meier estimate) had progressed to constitutional symptoms (P = 0.12; two-tailed Wilcoxon-Gehan test), with only one further progression in a placebo-treated patient in the subset followed for 52 weeks. Symptomatic patients receiving thymopentin or placebo were similar in both CD4+ cell levels and disease progression (two progressions to AIDS in each group). No serious adverse effects attributable to thymopentin were observed. CONCLUSIONS: These results, if confirmed, indicate that thymopentin, by maintaining CD4+ cells, could slow or arrest immune decline and consequent disease progression at the asymptomatic stage of HIV infection.

Placebo-controlled trial of prednisone in advanced HIV-1 infection.

OBJECTIVE: To examine the safety and the immunologic and virologic consequences of corticosteroid use in HIV-1 infection. METHODS: A randomized, double-blinded, placebo-controlled trial of corticosteroid administration in 41 patients with advanced HIV-1 infection. Patients had a baseline median CD4 cell count of 131 x 10(6) cells/l at enrollment and 85% had a history of opportunistic infection. All but one of the patients had been taking stable antiretroviral regimen, including a protease inhibitor in 36, for a median duration of 158 days. Patients were randomized to 8 weeks of prednisone 0.5 mg/kg daily or placebo. RESULTS: No AIDS-defining events occurred; two patients in each group developed oral candidiasis, and two patients on prednisone developed mild herpes simplex flares. None who developed oral candidiasis or herpes simplex was receiving prophylaxis and each responded promptly to therapy. In the prednisone group, two patients developed hyperglycemia and one diabetic increased insulin requirements. CD4 cell counts and plasma HIV-1 RNA levels did not change, but plasma tumor necrosis factor alpha levels and CD38+ CD8+ cells decreased significantly in those taking prednisone. CONCLUSION: Short-term prednisone administration is well tolerated and reasonably safe in advanced HIV-1 disease and decreases immune activation without effects on HIV-1 RNA levels or CD4 cell counts. These results suggest that, in stable HIV-1 disease, these immune activation markers are more likely consequences of but not inducers of HIV-1 replication.

Development of antinuclear antibodies during acebutolol therapy.

Eleven patients were studied while taking the beta blocker acebutolol for a period ranging from 12 to more than 24 wk. Control titers for fluorescent antinuclear antibody (ANA) were obtained in all. Serial testing was performed over the duration of the therapy and following its discontinuation. Additional immunologic testing was performed in most patients. The patients were observed closely for the development of clinical autoimmune disease. Using a sensitive assay, fluorescent ANA developed in 8 of 9 patients with negative values in the control period. In no patient has evidence of clinical autoimmune disease developed. In general, the titers of ANA tended to rise with increasing duration of therapy and decline after its discontinuation. Positive lupus erythematosus cell preparations were also observed in several patients. These data suggest that autoantibodies are frequently induced by acebutolol and, although no evidence of clinical autoimmune disease has been reported, immunologic surveillance is warranted.

Primary angiitis of the central nervous system. Report of 8 new cases, review of the literature, and proposal for diagnostic criteria.

Primary angiitis of the central nervous system (PACNS) is a rare form of angiitis limited to the central nervous system. The diagnosis and classification of this disorder has been problematic, owing to the lack of uniform diagnostic criteria and the difficulty in obtaining pathologic material for diagnosis. This study proposes to establish diagnostic criteria for PACNS which would include 1) the presence of an unexplained neurologic deficit after thorough clinical and laboratory evaluation; 2) documentation by cerebral angiography and/or tissue examination of an arteritic process within the central nervous system; and 3) no evidence of a systemic vasculitide or any other condition to which the angiographic or pathologic features could be secondary. Utilizing these criteria, 8 new cases are reported and are combined with 40 previously diagnosed cases from the literature. The clinical findings of the combined series revealed that headache was the most common symptom (58%) with a combination of focal and diffuse neurologic deficits described in 79% of the group. The diagnostic approach to PACNS should include a variety of laboratory tests and examination of the cerebral spinal fluid primarily to rule out mimicking conditions. Special procedures including electroencephalography, computed axial tomography, and magnetic resonance imaging appear only marginally helpful in securing the diagnosis, but are extremely important in ruling out other conditions. Angiography appears to be the first invasive diagnostic procedure of choice and it has a high predictive value when properly interpreted. Leptomeningeal and cortical biopsy can be accomplished with acceptable mortality and should be performed along with a normal or non-diagnostic angiogram when the diagnostic likelihood is high. Therapy of PACNS with a combination of cytotoxic drugs and high-dose corticosteroids has greatly improved the prognosis for this condition.

The rheumatic manifestations of infection with the human immunodeficiency virus.

The recognized clinical spectrum of disease associated with HIV infection is rapidly expanding and now includes a variety of rheumatic syndromes. The laboratory features of HIV infection closely resemble those found in many connective tissue diseases and thus alter the predictive value of these tests in the evaluation of both types of conditions. In addition to the laboratory similarities, there are also increasing numbers of clinical reports of HIV-infected individuals who develop syndromes either resembling classic idiopathic rheumatic diseases such as SS, polymyositis, or SLE, or newly recognized illnesses that fall under the clinical domain of the rheumatologist (ie, HIV-associated vasculitis and arthritis). It is vital that clinicians recognize these new illnesses because there are important differences in prognosis and management between these and their idiopathic counterparts. Research is urgently needed for better definition of these syndromes and their pathogenesis, natural history, and optimal therapies.

Early, aggressive therapy for rheumatoid arthritis: concerns, descriptions, and estimate of outcome.

The past few years have witnessed changing perceptions about rheumatoid arthritis (RA); it is now considered a serious systemic disease that confers not only physical and social morbidity but also earlier mortality. The long-term outcome of sequential monotherapy based on the therapeutic pyramid has been disappointing. A review of prognostic factors, acute disease activity measures, functional measures, and the results of preliminary trials with combination therapy suggests that specific goals of treatment can be established and that logical, aggressive treatment in early disease can be accomplished. These goals should include prompt control and continuous reduction of the active joint count to < or = 4 and normalization of acute-phase reactants. The "graduated-step paradigm" of treatment designed with these goals in mind is described, and a retrospective series that gives an estimate of outcome with its use is reported.

Paracortical immunoregulatory subpopulations in lymph nodes from homosexual men with persistent generalized lymphadenopathy.

Homosexual patients with persistent generalized lymphadenopathy usually show an abnormal expansion of paracortical T8+ lymphocytes relative to T4+ cells in lymph nodes with reactive follicular hyperplasia (RFH). This study was designed to characterize further the paracortical lymphocyte population in homosexual men with reactive follicular hyperplasia, because T8+ lymphocytes are antigenically and functionally heterogeneous. Frozen lymph node tissue from 10 patients was evaluated. Monoclonal antibodies to T8, Leu-15, NKH-1, Leu-7, and HLA-DR antigens were employed in the avidin-biotin complex immunoperoxidase technique. With digitized morphometry, positively stained cells for each marker were counted in five 0.145-mm2 microscopic fields. Four tonsils with RFH were used as controls. Most paracortical cells were T8+ (median, 4182 T8+ cells/five fields), and values were significantly higher than those for controls (median, 1518 T8+ cells p less than 0.006). In every case there were markedly fewer Leu 15-, NKH-1, Leu 7-, and HLA-DR-positive cells than T8+ cells (median values per five fields: Leu-15, 144; NKH-1, 12; Leu-7, 3; HLA-DR, 195). Moreover, these values were not significantly different from control values. Our findings suggest that the expanded paracortical T8+ population comprises cells with the immunophenotype of cytotoxic Leu-15-, T8+ lymphocytes, rather than natural killer or Leu-15+, T8+ suppressor cells.

Herpes zoster ophthalmicus and acquired immune deficiency syndrome.

Acquired immune deficiency syndrome (AIDS) is a recently recognized disease characterized by abnormalities in cell-mediated immunity that predispose affected persons to severe opportunistic infections and unusual malignant neoplasms. We describe four cases of herpes zoster ophthalmicus in four previously healthy homosexual men. Two had signs and symptoms consistent with AIDS, and two had signs and symptoms of a lymphadenopathic syndrome associated with AIDS. We suggest that underlying AIDS be considered in young, healthy persons with herpes zoster ophthalmicus and no known cause of immunosuppression.

Human immunodeficiency virus (HIV) infection and arthritis.

A variety of inflammatory arthritic conditions are observed in the setting of HIV infection. The epidemiology of these disorders is a point of current controversy, although it appears that several unique syndromes are clinically associated. The pathogenesis of these disorders remains unclear, but we hope that further work in this area will lend important insights into the mechanisms of both HIV-associated and non-HIV associated rheumatic disease. The overall management of such patients is based on recognizing the underlying HIV infection and the judicious use of antirheumatic drug therapy. Rheumatologists need to be aware of the natural history of HIV infection and its clinical manifestations.