Dry eye and dry mouth symptoms are each reported by up to 30% of persons more than 65 years of age, particularly in women. Medication side effects are the most common contributing factors. The ...evaluation of these symptoms requires measures of ocular and oral dryness. Sjögren syndrome is the prototypical disease associated with dryness of the eyes and mouth and predominantly affects women in their perimenopausal and postmenopausal years. In addition to topical treatment of the mucosal dryness, patients with Sjögren syndrome may require treatment with systemic immunomodulatory and immunosuppressive agents to manage a variety of extraglandular manifestations.
Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in ...multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.
We report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours.
We identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.
As ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.
The binding specificities of an individual's antibody repertoire contain a wealth of biological information. They harbor evidence of environmental exposures, allergies, ongoing or emerging autoimmune ...disease processes, and responses to immunomodulatory therapies, for example. Highly multiplexed methods to comprehensively interrogate antibody-binding specificities have therefore emerged in recent years as important molecular tools. Here, we provide a detailed protocol for performing 'phage immunoprecipitation sequencing' (PhIP-Seq), which is a powerful method for analyzing antibody-repertoire binding specificities with high throughput and at low cost. The methodology uses oligonucleotide library synthesis (OLS) to encode proteomic-scale peptide libraries for display on bacteriophage. These libraries are then immunoprecipitated, using an individual's antibodies, for subsequent analysis by high-throughput DNA sequencing. We have used PhIP-Seq to identify novel self-antigens associated with autoimmune disease, to characterize the self-reactivity of broadly neutralizing HIV antibodies, and in a large international cross-sectional study of exposure to hundreds of human viruses. Compared with alternative array-based techniques, PhIP-Seq is far more scalable in terms of sample throughput and cost per analysis. Cloning and expression of recombinant proteins are not required (versus protein microarrays), and peptide lengths are limited only by DNA synthesis chemistry (up to 90-aa (amino acid) peptides versus the typical 8- to 12-aa length limit of synthetic peptide arrays). Compared with protein microarrays, however, PhIP-Seq libraries lack discontinuous epitopes and post-translational modifications. To increase the accessibility of PhIP-Seq, we provide detailed instructions for the design of phage-displayed peptidome libraries, their immunoprecipitation using serum antibodies, deep sequencing-based measurement of peptide abundances, and statistical determination of peptide enrichments that reflect antibody-peptide interactions. Once a library has been constructed, PhIP-Seq data can be obtained for analysis within a week.
Objective
To test whether cumulative estrogen exposure, as determined by age at menarche, age at menopause, female hormone use, hysterectomy, and parity, have an effect on the development of primary ...Sjögren's syndrome (SS).
Methods
We performed a case–control study of 2,680 women from the Sjögren's International Collaborative Clinical Alliance registry, including 1,320 registrants with primary SS and 1,360 with sicca symptoms but no key features of primary SS (sicca controls). The composite estrogen score (CES) was calculated by point assignment for early menarche (age ≤10 years), high parity (>3 pregnancies), hysterectomy, female hormone use, and late menopause (age ≥53 years). Cumulative menstrual cycling (CMC) was calculated as years menstruating minus time pregnant.
Results
Using a regression model that adjusted for age, recruitment site, ethnicity, education, employment status, and smoking, we observed a progressive inverse trend between primary SS and CES. The odds ratio (OR) and 95% confidence interval (95% CI) were as follows for the sicca control group: CES 1, OR 0.81 (95% CI 0.67–0.99); CES 2, OR 0.74 (95% CI 0.57–0.97); CES 3, OR 0.50 (95% CI 0.30–0.86). This trend was corroborated by analysis of CMC. At the highest level of CMC within the postmenopausal group there was a 24% reduction in cumulative sex hormone exposure among primary SS participants relative to controls.
Conclusion
Women with primary SS have lower estrogen exposure and CMC compared to sicca controls. Increasing estrogen exposure was negatively associated with development of primary SS. Further longitudinal studies of sex hormone exposure in primary SS are needed to confirm these findings.
Sjögren's syndrome is a systemic autoimmune disease defined by its targeted inflammation of the salivary and lacrimal glands, resulting in dry mouth and eyes in the majority and persistent or ...recurrent salivary gland enlargement in a minority of those affected. Involvement of major organs, an increased risk of lymphoma, and autoantibodies against ubiquitous cellular ribonucleoproteins define some of its systemic features. Those affected have a high symptom burden and the development of disease-modifying therapies is thus an urgent need. A stratified medicine approach offers promise as a means of targeting specific therapies to patients for whom the mechanism of action is most relevant. Implementation of this approach will require an understanding of the pathophysiological processes underlying different patient subsets, and then identifying or developing a drug that targets this pathway. Such therapies would be most effective if implemented early in the disease course before the advent of adverse outcomes or glandular damage. This review will provide a disease overview followed by an analysis of the feasibility of a stratified medicine approach, focusing on the disease heterogeneity, predictors of disease progression and adverse outcomes, and recent advances in the development of relevant outcome measures and new therapies.
Objective
Sjögren's syndrome (SS) is an autoimmune disease that targets the salivary and lacrimal glands. While all patients demonstrate inflammatory infiltration and abnormal secretory function in ...the target tissues, the disease features, pathology, and clinical course can vary. Activation of distinct inflammatory pathways may drive disease heterogeneity. The purpose of this study was to investigate whether activation of the interferon (IFN) pathway correlates with key phenotypic features.
Methods
Clinical data and 1 labial salivary gland (stored frozen) were obtained from each of 82 participants (53 patients with primary SS and 29 control subjects) in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Salivary gland lysates were immunoblotted with markers of type I or type II IFN, and patterns of IFN activity were determined by hierarchical clustering. Correlations between SS phenotypic features and IFN activity in the salivary gland were performed.
Results
A total of 58% of the SS participants had high IFN activity and differed significantly from those with low IFN activity (higher prevalence of abnormal findings on sialometry, leukopenia, hyperglobulinemia, high‐titer antinuclear antibody, anti‐SSA, and high focus score on labial salivary gland LSG biopsy). Three distinct patterns of IFN were evident: type I–predominant, type II–predominant, and type I/II mixed IFN. These groups were clinically indistinguishable except for the LSG focus score, which was highest in those with type II–predominant IFN.
Conclusion
The SS phenotype includes distinct molecular subtypes, which are segregated by the magnitude and pattern of IFN responses. Associations between IFN pathways and disease activity suggest that IFNs are relevant therapeutic targets in SS. Patients with distinct patterns of high IFN activity are clinically similar, demonstrating that IFN‐targeting therapies must be selected according to the specific pathway(s) that is active in vivo in the individual patient.
Objective
Painful small‐fiber neuropathies (SFNs) in primary Sjögren's syndrome (SS) may present as pure or mixed with concurrent large‐fiber involvement. SFN can be diagnosed by punch skin biopsy ...results that identify decreased intra‐epidermal nerve‐fiber density (IENFD) of unmyelinated nerves.
Methods
We compared 23 consecutively evaluated patients with SS with pure and mixed SFN versus 98 patients without SFN. We distinguished between markers of dorsal root ganglia (DRG) degeneration (decreased IENFD in the proximal thigh versus the distal leg) versus axonal degeneration (decreased IENFD in the distal leg versus the proximal thigh).
Results
There were no differences in pain intensity, pain quality, and treatment characteristics in the comparison of 13 patients with pure SFN versus 10 patients with mixed SFN. Ten patients with SFN (approximately 45%) had neuropathic pain preceding sicca symptoms. Opioid analgesics were prescribed to approximately 45% of patients with SFN. When compared to 98 patients without SFN, the 23 patients with SFN had an increased frequency of male sex (30% versus 9%; P < 0.01), a decreased frequency of anti–Ro 52 (P = 0.01) and anti–Ro 60 antibodies (P = 0.01), rheumatoid factor positivity (P < 0.01), and polyclonal gammopathy (P < 0.01). Eleven patients had stocking‐and‐glove pain, and 12 patients had nonstocking‐and‐glove pain. Skin biopsy results disclosed patterns of axonal (16 patients) and DRG injury (7 patients).
Conclusion
SS SFN had an increased frequency among male patients, a decreased frequency of multiple antibodies, frequent treatment with opioid analgesics, and the presence of nonstocking‐and‐glove pain. Distinguishing between DRG versus axonal injury is significant, especially given that mechanisms targeting the DRG may result in irreversible neuronal cell death. Altogether, these findings highlight clinical, autoantibody, and pathologic features that can help to define mechanisms and treatment strategies.
Purpose To report the significance of extraglandular ocular involvement and long-term systemic morbidity and mortality in primary Sjögren’s Syndrome (SS). Methods This retrospective, longitudinal ...cohort study included consecutive patients with primary SS evaluated at a tertiary referral center. An electronic chart review was performed and all available data were extracted from clinic visits between October 1999 and March 2019. The primary outcome measures included occurrence of extraglandular ocular manifestations of SS, serological markers, prevalence of malignancy, and incidence of death. Results One hundred and twenty-six SS patients with minimum 3 years of follow-up (median 9.6, range 3.0–15.9 years, total of 1,235 patient-years) were included. Of those, 10 patients with inflammatory keratolysis or scleritis had 2.3 times greater likelihood of death compared to the rest of the cohort (OR = 2.3, 95% confidence interval CI 0.5 to 4.0, p = 0.01) due to SS related complications. The lifetime prevalence of any malignancy in the entire cohort was 15.5%. The most common hematologic malignancy was non-Hodgkin’s lymphoma (4.8%) and the most common solid malignancy was breast cancer (6.0%). Men SS patients were more likely to have a history of or concurrent malignancy compared to women (30.0% versus 13.7%, p = 0.16) and double the mortality (OR = 2.1, 95% CI 0.09 to 1.4, p = 0.04), independent of malignancy. Conclusions SS patients with serious ocular manifestations, particularly men, may be at greater risk for mortality due to SS complications. The eye seems to be the barometer of systemic disease activity.
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