Pre-existing Autoimmune Diseases and Immune Checkpoint Inhibitors for Cancer Treatment: Considerations About Initiation, Flares, Immune-Related Adverse Events, and Cancer Progression.

Immune checkpoint inhibitors (ICIs) are increasingly used to treat a variety of cancer types. Patients with preexisting autoimmune diseases may be vulnerable to underlying disease flare as well as immune-related adverse events from ICIs. There has also been concern that immunosuppression needed to control the autoimmune disease may blunt ICI efficacy. Much of the literature is focused on diverse preexisting autoimmune diseases, which may limit conclusions to specific diseases. There is a growing literature of specific diseases, such as preexisting rheumatoid arthritis, investigating outcomes after ICI.

Autoimmune Movement Disorders Complicating Treatment with Immune Checkpoint Inhibitors.

BACKGROUND: Immune checkpoint inhibitors (ICI) may trigger autoimmune neurological conditions, including movement disorders (MD). OBJECTIVES: The aim of this study was to characterize MDs occurring as immune-related adverse events (irAEs) of ICIs. METHODS: A systematic literature review of case reports/series of MDs as irAEs of ICIs was performed. RESULTS: Of 5682 eligible papers, 26 articles with 28 patients were included. MDs occur as a rare complication of cancer immunotherapy with heterogeneous clinical presentations and in most cases in association with other irAEs. Inflammatory basal ganglia T2/fluid attenuated inversion recovery abnormalities are rarely observed, but brain imaging is frequently unrevealing. Cerebrospinal fluid findings are frequently suggestive of inflammation. Half of cases are associated with a wide range of autoantibodies. Steroids and ICI withdrawal usually lead to improvement, even though some patients experienced relapses or a severe clinical course. CONCLUSION: MDs are a rare complication of ICIs that should be promptly recognized to offer patients a correct diagnosis and treatment.

Immune Checkpoint Inhibitor-induced Pancreatitis with Pancreatic Enlargement Mimicking Autoimmune Pancreatitis: A Case Report and Review of the Literature.

A 61-year-old woman was administered 35 cycles of pembrolizumab for the treatment of recurrent endometrial cancer, achieving a complete response. She presented with asymptomatic pancreatic enlargement and elevated hepatobiliary enzymes, but amylase and lipase levels were within the normal ranges. Intrapancreatic bile duct stenosis due to pancreatic enlargement was present, mimicking autoimmune pancreatitis on computed tomography performed before the onset of clinical manifestations. A histological examination of a biopsy specimen showed lymphocyte and plasma cell infiltration with dense fibrosis in the stroma. The patient was successfully treated with oral prednisolone. There were no manifestations of recurrent pancreatitis after tapering the prednisolone dose.

The "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) after COVID-19 infection: A case report.

The term "autoimmune/inflammatory syndrome induced by adjuvants" (ASIA) describes a variety of autoimmune conditions triggered by exposure to substances with adjuvant activity. We present the case of a patient with a history of biopolymer infiltration in both glutes, who years later experienced progressive weakness and pain in the lower limbs, myalgias, cramps, and progressive functional impotence following a mild COVID-19 infection. Laboratory test results were not consistent with any autoimmune disease. Physical examination revealed diffuse bilateral subcutaneous nodules. After an extensive etiological study, a gluteal biopsy was performed, which showed findings compatible with sclerosing lipogranuloma. Our patient required treatment with high-dose glucocorticoids and showed significant improvement in symptoms during long-term follow-up. We suggest the role of COVID-19 infection as a possible trigger for ASIA, as it has already been described as a trigger for several other autoimmune diseases.

Daratumumab for autoimmune diseases: a systematic review.

OBJECTIVE: Refractory autoimmune diseases remain a significant challenge in clinical practice and new therapeutic options are needed. This systematic review evaluates the existing reported data on the CD38-targeting antibody daratumumab as a new therapeutic approach in autoantibody-mediated autoimmune diseases. METHODS: A protocolised systematic literature review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines was performed. Two databases (Medline and Embase) were searched for suitable studies. Usage of daratumumab in non-oncological or non-transplantation associated diseases with autoimmune pathophysiology was analysed including patient characteristics, therapeutic regimen, adverse events and patient outcome. RESULTS: 38 publications reporting the clinical course of 83 patients met the inclusion criteria. Daratumumab usage was reported in therapy-refractory cases (median of 5 different previous therapies) in 24 different autoimmune diseases. The median number of applications of daratumumab was 4, mainly via intravenous applications (87%). Concomitant treatment included glucocorticoids in 64% of patients, intravenous immunoglobulins (33%) and rituximab (17%). Remission or improvement of disease was reported in 81% of patients. Autoantibody depletion or reduction was stated in 52% of patients. Death occurred in three patients (3%). Adverse events were reported in 45% of patients including application-associated reaction (20%), infection (19%) and hypogammaglobulinaemia (33%). CONCLUSION: Targeting CD38 via daratumumab is a new promising therapeutic option in therapy refractory autoimmune diseases. Efficacy as well as optimal therapeutic regimen and management or prevention of adverse events require further investigation. Therefore, systematic clinical trials of this therapeutic approach are needed.

Safety and effectiveness of combination versus monotherapy with immune checkpoint inhibitors in patients with preexisting autoimmune diseases.

Patients with preexisting autoimmune disease (pAID) are generally excluded from clinical trials for immune checkpoint inhibitors (ICIs) for cancer due to concern of flaring pAID. In this multi-center, retrospective observational study, we compared safety of ICI combination (two ICI agents) versus monotherapy in cancer patients with pAIDs. The primary outcome was time to AEs (immune-related adverse events (irAEs) and/or pAID flares), with progression-free survival (PFS) and overall survival as secondary outcomes. Sixty-four of 133 patients (48%) received ICI combination and 69 (52%) monotherapy. Most had melanoma (32%) and lung cancer (31%). Most common pAIDs were rheumatic (28%) and dermatologic (23%). Over a median follow-up of 15 months (95%CI, 11-18 mo), the cumulative incidence of any-grade irAEs was higher for combination compared to monotherapy (subdistribution hazard ratio (sHR) 2.27, 95%CI 1.35-3.82). No statistically significant difference was observed in high-grade irAEs (sHR 2.31 (0.95-5.66), P = .054) or the cumulative incidence of pAID flares. There was no statistically significant difference for melanoma PFS between combination versus monotherapy (23.2 vs. 17.1mo, P = .53). The combination group was more likely to discontinue or hold ICI, but > 50% of the combination group was still able to continue ICI therapy. No treatment-related deaths occurred. In our cohort with pAIDs, patients had a tolerable toxicity profile with ICI combination therapy. Our results support the use of ICI combination if deemed necessary for cancer therapy in patients with pAIDs, since the ICI toxicities were comparable to monotherapy, able to be effectively managed and mostly did not require ICI interruption.

Polybrominated biphenyls (PBBs) and prevalence of autoimmune disorders among members of the Michigan PBB registry.

BACKGROUND: Polybrominated biphenyls (PBBs), a class of endocrine disrupting chemicals, were the main chemicals present in one of the largest industrial accidents in the United States. We investigated the association between serum PBB-153 levels and autoimmune disorders among members of the Michigan PBB Registry. METHODS: Eight hundred and ninety-five members of the registry had both a serum PBB-153 measurement and had completed one or more questionnaires about autoimmune disorders. Autoimmune disorders were examined collectively and within specific organ systems. Sex-stratified unadjusted and adjusted log-binomial models were used to examine the association between tertiles of serum PBB-153 levels and autoimmune disorders. Models were adjusted by lifestage at exposure (in utero, childhood, adulthood), smoking history (never, past, current), and total serum lipid levels (continuous). We utilized cubic spline models to investigate non-linearity between serum PBB-153 levels and the prevalence of autoimmune disorders. RESULTS: Approximately 12.9% and 20.7% of male and female participants reported having one or more autoimmune disorders, respectively. After adjustment for potential confounders, we observed no association between PBB-153 tertiles and the composite classification of 'any autoimmune disorder' in either sex. We observed some evidence for an association between serum PBB-153 levels and rheumatoid arthritis in males and females; however, this was not statistically significant in females. We also observed some evidence for an association between serum PBB-153 levels and neurological- and thyroid-related autoimmune disorders in females, but again this was not statistically significant. Additionally, we identified dose-response curves for serum PBB-153 levels and the prevalence of autoimmune disorders that differed by lifestage of exposure and sex. CONCLUSIONS: We observed some evidence that increasing serum PBB-153 levels were associated with three specified autoimmune disorders. Studies focusing on these three autoimmune disorders and the potential non-linear trend differences by lifestage of exposure warrant further investigation.

Emerging roles of air pollution and meteorological factors in autoimmune eye diseases.

Autoimmune eye diseases (AEDs), a collection of autoimmune inflammatory ocular conditions resulting from the dysregulation of immune system at the ocular level, can target both intraocular and periorbital structures leading to severe visual deficit and blindness globally. The roles of air pollution and meteorological factors in the initiation and progression of AEDs have been increasingly attractive, among which the systemic and local mechanisms are both involved in. Exposure to excessive air pollution and extreme meteorological conditions including PM2.5/PM0.1, environmental tobacco smoke, insufficient sunshine, and high temperature, etc., can disturb Th17/Treg balance, regulate macrophage polarization, activate neutrophils, induce systemic inflammation and oxidative stress, decrease retinal blood flow, promote tissue fibrosis, activate sympathetic nervous system, adversely affect nutrients synthetization, as well as induce heat stress, therefore may together deteriorate AEDs. The crosstalk among inflammation, oxidative stress and dysregulated immune system appeared to be prominent. In the present review, we will concern and summarize the potential mechanisms underlying linkages of air pollution and meteorological factors to ocular autoimmune and inflammatory responses. Moreover, we concentrate on the specific roles of air pollutants and meteorological factors in several major AEDs including uveitis, Graves' ophthalmopathy (GO), ocular allergic disease (OAD), glaucoma, diabetic retinopathy (DR), etc.

Focus on Anti-Tumour Necrosis Factor (TNF)-α-Related Autoimmune Diseases.

Anti-tumour necrosis factor (TNF)-α agents have been increasingly used to treat patients affected by inflammatory bowel disease and dermatological and rheumatologic inflammatory disorders. However, the widening use of biologics is related to a new class of adverse events called paradoxical reactions. Its pathogenesis remains unclear, but it is suggested that cytokine remodulation in predisposed individuals can lead to the inflammatory process. Here, we dissect the clinical aspects and overall outcomes of autoimmune diseases caused by anti-TNF-α therapies.

Rheumatological adverse events secondary to immune checkpoint inhibitors.

The first experiences with a group of drugs called immune checkpoint inhibitors for the treatment of cancer were described in 2010. They are currently used in many tumours, with successful survival outcomes but a new profile of adverse events. This new spectrum of immune-mediated toxicities includes an exaggerated inflammatory response of T lymphocyte and the development of autoimmune diseases or similar pathologies. Of these, of particular note are the rheumatological toxicities. This review aims to alert internists and rheumatologists to their recognition and clinical management.

Autoimmune disorders caused by intravesical bacillus Calmette-Guerine treatment: A systematic review.

Intravesical bacillus Calmette-Guérin (BCG) is a common and highly effective treatment for non-muscle invasive urothelial carcinoma of the urinary bladder. BCG may cause an autoimmune reaction in some patients. One hundred and fifty-eight papers were analyzed, for a total of hundred and thirty patients with reactive arthritis, sixty patients with ocular manifestations and eighteen patients with other rheumatologic diseases. Among 130 subjects with reactive arthritis, an autoimmune symptom occurred after 5 instillations of intravesical BCG (IQR 4-6), which represents 5 weeks in most cases. Fifty-one patients had concurrent ocular involvement. The resolution of symptoms was achieved in a median of 32.5 days (IQR 14-90). Forty-two men and twenty women had ocular manifestations, most commonly conjunctivitis. Patients with HLA-B27 typing had earlier presentation of ocular symptoms related to the number of instillations (4.5 vs 6 [p < 0.05]. Resolution of symptoms was achieved at a median of 128 days (IQR 21-150). Among patients treated with NSAIDs (either with or without steroids), the duration of the disease was significantly shorter in both the articular and the ocular groups (28 vs. 120 [p < 0.05] and 30 vs.105 [p < 0.05], respectively). Other autoimmune manifestations included general autoimmune diseases, such as vasculitis, psoriasis and myasthenia gravis.

Histopathological, biochemical and molecular studies on a model of systemic autoimmune disease induced by sodium silicate in non-genetically prone rats.

Sodium silicate (Na2SiO3) is an inorganic silica salt used in many products. Few studies reported autoimmune diseases (AIDs) due to Na2SiO3 exposure. This study investigates the role of Na2SiO3 exposure by different routes and doses in AID development in rats. We assigned 40 female rats to four groups: G1 control group, G2 rats were subcutaneously injected with 5 mg Na2SiO3 suspension, and G3 and G4 rats were orally administered 5 mg and 7 mg Na2SiO3 suspension, respectively. Na2SiO3 was administered weekly for 20 weeks. Serum anti-nuclear antibodies (ANA) detection, histopathology of kidney, brain, lung, liver, and heart, oxidative stress biomarkers (MDA and GSH) in tissues, Matrix metalloproteinase activity in serum, TNF-α, and Bcl-2 expression in tissues were performed. ANA was significantly increased in silicate groups, especially G2. Creatinine was significantly increased in silicate groups. Histopathology revealed vasculitis and fibrinoid degeneration of blood vessels, a picture of immune-mediated glomerulonephritis in the kidneys, and chronic interstitial pneumonia with medial hypertrophy of pulmonary blood vessels. The activity of gelatinases (MMP-2 and MMP-9) and collagenase (MMP-13), which play role in inflammation, remodeling, and immune complex degradation, were significantly increased in the silicate-exposed groups. Bcl-2 was significantly decreased, indicating apoptosis. Therefore, oral administration and subcutaneous injection of Na2SiO3 induced immune-mediated glomerulonephritis with elevated ANA levels and overexpression of TNF-α in rats.

Oral mucosal toxicities induced by immune checkpoint inhibitors: Clinical features and algorithm management.

Immune checkpoint inhibitors (ICIs) have emerged as standard therapies for an increasing number of advanced cancers. Nonspecific immune activation may lead to immune-related adverse events among which dermatological reactions are one of the most prevalent (all-grade incidence ranging from 30 to 60%). Oral mucosal adverse reactions to ICIs are far less common than cutaneous adverse events. However, a spectrum of oral changes with characteristic features has recently emerged, including lichenoid reactions, sicca syndrome, and even autoimmune bullous disorders with oral involvement. Oral changes mainly occur during the first year of treatment, often concurrently with other dermatological changes, and may involve up to 10% of patients under ICI therapies. This article provides a systematic review of the oral changes reported with these therapies based on a rich iconography.

[Autoimmune/inflammatory syndrome induced by aduvants].

For decades, breast implants have been available for breast reconstructions and breast augmentations to improve the patients' health-related quality of life. Silicone implants (SI) have been used since the middle of the last century for breast reconstruction, for example after breast cancer, for birth defects, gender confirmation procedures, or for breast augmentation. Every year, several hundred SI are performed in Iceland for these purposes, but no central register is maintained. It can be estimated that at least 1000 - 3000 women have SI in Iceland and that around 300 Icelandic patients get SI every year. This informal review article discusses the so-called ASIA syndrome, the immunological effects of silicone and the possible relationship of SI to autoimmune diseases, symptoms, and diagnosis. In the methodology, this paper does not rely on the strict conditions of systematic reviews, but the authors relied only on peer-reviewed sources through PubMed, UpToDate and Scopus. The keywords used are silicon, silicon implant, silicon particles, immune response, autoimmunity, autoinflammation, Autoimmune/inflammatory syndrome induced by aduvants, ASIA, ASIA syndrome, breast implant illness. The paper reviews known facts about the disease, its characteristics, and statistical aspects.

A Case of Statin-Associated Autoimmune Myopathy: Management and Treatment.

Elevated lipid panels are associated with an increased risk of cardiovascular disease. Management of heart disease with lipid lowering agents play a vital role in medicine. Statins are one group of medications that are widely utilized in the medical field to decrease the risk of atherosclerotic disease. Statins work by inhibiting the hepatic enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR). Although statins are one of the most effective drugs for secondary and primary prevention of heart disease, they are not without risks and side effects such as hepatotoxicity and myopathy. We present a case of a male patient who developed progressively worsening muscle weakness and elevated muscle enzyme markers upon initiation of a statin. His symptoms persisted despite a trial of an alternative statin and subsequent discontinuation of all statin medications. A multitude of possible etiologies were considered and ranged from infectious, autoimmune, cancerous, to congenital in nature. Environmental factors, such as exposure to medications or toxins, were also considered as one of the possible precipitating factors. The association between his statin consumption and muscle weakness were not easily apparent at first. He required further workup including physical examination, electromyography, panel of myositis antibodies, and muscle biopsy. After clinical suspicion and elevated antibodies to HMGCR beyond the normal limit, he was discovered to have statin-associated autoimmune myopathy. The patient improved with the treatment of immunosuppressive agent's prednisone and methotrexate.

Challenges in the diagnosis and management of immune-mediated necrotising myopathy (IMNM) in a patient on long-term statins.

Immune-mediated necrotising myopathy (IMNM) is a severe and poorly understood complication of statin use. Prompt management with immunosuppressive treatment is often needed to control the condition, which differs from the management of the more commonly recognised statin-induced myopathy. We present a case report and brief review of the literature regarding the pathogenesis, diagnosis, and management of anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) positive IMNM (HMGCR IMNM). There are no randomised clinical trials, but several smaller studies and cases suggest a triple therapy of corticosteroids, IVIG, and a corticosteroid-sparing immunosuppressant appears efficacious in patients with IMNM and proximal weakness. The mechanism of statin-induced IMNM is uncertain, and this is further complicated by the reports of HMGCR IMNM in statin-naïve patients, including children. We present a case of biopsy-confirmed HMGCR IMNM in a woman taking daily statins for treatment of hypercholesterolaemia for 4 years. She presented with symptoms consistent with a urinary tract infection (UTI), including muscle weakness. She was treated as an isolated case of UTI. One month later, she presented again with worsening weakness in her shoulders and hips. Creatine kinase was elevated, and MRI showed increased signal with STIR sequences in both thighs. Anti-HMGCR was positive and leg biopsy-confirmed necrotising changes. Stopping her statin prescription and a short course of prednisolone did not improve her muscle weakness. Adding methotrexate resulted in eventual resolution of her symptoms. IMNM should be considered as a differential in any patient taking statins presenting with muscle weakness, and this case suggests that immunosuppressant therapy in addition to cessation of statins is effective at treating IMNM. Clinical trials are needed to further investigate the efficacy of different combinations of immunosuppressants.

Safety and efficacy of immune checkpoint inhibitors in advanced cancer patients with autoimmune disease: A meta-analysis.

Cancer patients with autoimmune disease (AID) are usually excluded from clinical trials involving immune checkpoint inhibitors (ICIs). The available electronic databases were systematically searched from inception until July 3, 2022. We recorded the incidence of immune-related adverse events (irAEs), progression-free survival (PFS), and overall survival (OS) data of included studies. This meta-analysis included 14 studies comprising 11511 participants; however, only 8716 participants were treated with ICI. Therefore, the analysis was conducted on 8716 patients (769 patients with AID compared to 7947 patients without AID). The pooled risk ratio (RR) for any grade and grade ≥3 irAEs was 1.74 (95% confidence interval [CI]: 1.27-2.37) and 1.43 (95% CI: 1.10-1.88), respectively. The irAEs in the same system as that of the AID were referred to as AID-homogeneous irAEs; in the other cases, there were referred to as AID-heterogeneous irAEs. Subgroup analysis found that the higher risk of AID-homogeneous irAEs contributed to the higher risk of overall irAEs among patients with AID. The pooled hazard ratio (HR) for PFS and OS was 1.09 (95% CI: 0.96-1.24) and 1.07 (95% CI: 0.94-1.22), respectively. The results of PFS and OS subgroup analyses matched the overall results. Patients with AID had a significantly higher risk of developing any grade and ≥3 grade irAEs under ICI therapy, specifically AID-homogeneous irAEs; however, the frequency of AID-heterogeneous irAEs in patients with AID was similar to irAEs in patients without AID. No statistically significant differences in PFS and OS were observed between the two groups.

Treatment of rheumatic adverse events of cancer immunotherapy.

Immune checkpoint inhibitors (ICIs), used to treat many advanced cancers, activate the immune system to elicit an antitumor response. ICIs can also cause immune-related adverse events (irAEs) when nontumor tissues are affected by excess inflammation and autoimmunity. Rheumatic irAEs include inflammatory arthritis, myositis, sicca syndrome, polymyalgia rheumatica, and several other rare phenotypes. Treating rheumatic irAEs requires balancing the desire to decrease off-target inflammation while not negatively impacting the antitumor immune response. In this review, treatment recommendations for rheumatic irAEs have been discussed. Pathogenesis of rheumatic irAEs has been briefly reviewed. Knowledge about the effects of corticosteroids and steroid-sparing agents on tumor responses has been detailed to give context for treatment decisions. Recommendations ultimately depend not only on the clinical presentation and severity of the irAE but also on the goals of cancer treatment. Finally, how to safely use ICI therapy in patients with preexisting autoimmune diseases is considered.

Concurrent Interstitial Granulomatous Dermatitis and TNF-α Antagonist-Induced Lupus Syndrome Secondary to Adalimumab for Crohn's Disease.

Tumor necrosis factor (TNF) antagonists have revolutionized management for various autoimmune and inflammatory conditions, including rheumatoid arthritis (RA), inflammatory bowel disease, hidradenitis suppurativa, psoriatic arthritis, and plaque psoriasis. However, adverse effects may necessitate switching to another biologic with a different mechanism of action. Here we report TNF-α antagonist-induced lupus syndrome (TAILS) revealed by interstitial granulomatous dermatitis (IGD), in the atypical context of Crohn's disease (CD).

The anti-inflammatory effect of myrrh ethanolic extract in comparison with prednisolone on an autoimmune disease rat model induced by silicate.

Autoimmune disease is a complex chronic disease that triggers immune activation against autoantigens resulting in tissue damage. Epidemiological data showed that autoimmune diseases are increasing worldwide over the last decades owing to increased environmental pollution. This study investigates the therapeutic effect of myrrh as a natural medicine compared to prednisolone in the treatment of immune-mediated glomerulonephritis induced by silicate. The autoimmune disease model in rats was induced by injecting 5 mg crystalline sodium silicate suspension subcutaneously once weekly for 20 weeks, and then the rats were treated either with myrrh extract or prednisolone or with both for 6 weeks. Liver and kidney function tests, histopathology, and immunohistochemistry of TNF-α expression in kidney tissue were performed. The creatinine significantly elevated in silica-treated group and decreased in other treated groups. Histopathology of the kidney revealed improvement of glomerular and tubular basement thickness in all treated groups, but the inflammatory cell count slightly decreased in the group treated with myrrh than the other treated groups which showed a marked decrease. TNF-α expression was significantly decreased in all treated groups. Interestingly, the myrrh did not produce hepatic lesions and improve the side effect of prednisolone in the liver when taken in combination. Therefore, myrrh extract possessed anti-inflammatory properties and counteracted the side effect of prednisolone on the liver. Myrrh extract can serve as a conjunctive therapy with prednisolone to treat autoimmune diseases.