Scleritis and development of immune-mediated disease: A retrospective chart review.

OBJECTIVE: Scleritis may be idiopathic or caused by trauma, infections, or an immune-mediated condition. Our study aimed to understand the relationship between scleritis and immune-mediated disease, including presenting characteristics, serologies, and treatment course. Understanding these associations may allow clinicians to risk-stratify patients and predict their clinical and treatment course. METHODS: We conducted a retrospective chart review of 341 scleritis patients seen at a tertiary care center between January 1, 2005, and December 31, 2020. Demographics, scleritis characteristics, treatment response, recurrence, and serologic data were compared among patients with idiopathic and immune-mediated disease-associated scleritis. RESULTS: Among scleritis patients seen, 145 patients (43%) had an associated immune-mediated disease, most commonly rheumatoid arthritis (39%), vasculitis (21%), or inflammatory bowel disease (14%). In most cases, the immune-mediated disease diagnosis predated the scleritis presentation (65%), though vasculitis cases were more likely to develop during or after scleritis episodes. There were no significant differences in demographics or treatment failures among scleritis patients with and without associated immune-mediated conditions. Patients with immune-mediated diseases were more likely to have a recurrence of scleritis (62% vs 49%, p=0.02). CONCLUSION: At our ophthalmology center, 43% of patients with scleritis had an associated immunemediated disease, and most patients with immune-mediated disease were symptomatic from this disease prior to scleritis presentation. Rheumatoid arthritis was the most commonly associated condition and typically predated the scleritis, while vasculitis was more likely diagnosed during or after the scleritis episode. Scleritis among immune-mediated disease patients is more likely to recur compared to scleritis that is idiopathic.

Refractory PR3-positive ANCA-associated vasculitis with eosinophilia requiring anti-IL-5 therapy: A case report.

This report describes a highly unusual and refractory case of proteinase-3-positive antineutrophil cytoplasmic autoantibody-associated vasculitis, which was associated with marked eosinophilia and only achieved remission after interleukin-5 blockade was added to maximal induction therapy. The patient was a healthy 18-year-old woman who presented with scleritis, otitis, constitutional symptoms, skin and mucosal lesions, and diffuse alveolar haemorrhage and found to have refractory eosinophilia of unclear aetiology. The case did not meet classification criteria for a diagnosis of granulomatosis with polyangiitis or eosinophilic granulomatosis with polyangiitis. Despite induction therapy with glucocorticoids, cyclophosphamide, and rituximab, she did not achieve remission or normalisation of eosinophilia until the addition of mepolizumab, which corresponded to the suppression of peripheral blood eosinophils and clinical remission. This case highlights the limitations of classification criteria and success of interleukin-5 in a multimodal treatment of severe vasculitis with eosinophilia.

The "Understanding Pyoderma Gangrenosum, Review and Assessment of Disease Effects (UPGRADE)" Project: a protocol for the development of the core outcome domain set for trials in pyoderma gangrenosum.

INTRODUCTION: Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis that affects approximately 0.3-6 out of every 100,000 people worldwide. Clinical trials are scarce but there is growing interest in using newer and more targeted therapeutics to achieve disease remission. However, there are no standardized instruments to measure outcomes in PG and, therefore, future clinical trials are hampered by the absence of established and accurate means of assessment and comparison. Therefore, we aim to produce an internationally accepted core outcome set (COS) that will overcome this obstacle. This protocol outlines our intended approach to achieve the first part of this process, establishing a core outcome domain set. METHODS: An international team of PG stakeholders, consisting of physicians, wound care nurses, patients, scientists and industry representatives, has been assembled for the purpose of building a comprehensive and universally established set of core outcome domains. During the first step, we will generate items of relevance using a nominal process from all stakeholders. Items will be distilled and collapsed into potential domains and subdomains. A systematic review of current methods for reporting PG has already been published and domains identified in this work will be considered in the generation of the core domains set. During the second step, after the potential domains and subdomains are identified, stakeholders will participate in an e-Delphi exercise to rate the importance of (sub)domains. A final consensus meeting will be organized with the goal of establishing a core domain set. CONCLUSION: Pyoderma gangrenosum lacks an established COS and previously published clinical trials have used inconsistent measures established from similarly inconsistent domains. As a first step this study seeks to create a core domain set within the COS, to build the foundation for future core outcome work for PG.

Pyoderma gangrenosum study pilot registry: The first step to a better understanding.

The objective of this study was to develop a pilot physician driven patient pyoderma gangrenosum (PG) registry to summarise patient baseline demographics, PG-related medical history, treatments, and outcomes for patients with pyoderma gangrenosum. Standardised patient information was collected prospectively during clinical encounters between December 2019 and July 2021 at a single academic institution. Eligibility criteria for the study was a diagnosis of pyoderma gangrenosum determined by a PARACELSUS score of at least 10 for ulcerative patients. Main outcome measures included demographic data, PG related history and comorbidities, past and current treatments, healing outcomes, hospitalisations and recurrences of PG. The Pyoderma Gangrenosum Study (PYGAS) Registry currently includes 52 patients with 56 target lesions of four distinct PG subtypes (41 ulcerative, 12 peristomal, 2 vegetative and 1 bullous). For the 38 patients with 41 total ulcerative PG lesions, referrals to our institution most commonly came from dermatologists (42.1%). The median follow-up time in our initial registry was 5.5 months (95% CI = 4.1-11.5 months), with average time between follow-up visits at 1.1 months. These ulcers were most commonly treated with first-line systemic immunosuppressants (70.6%), such as corticosteroids or cyclosporine. Additional use of systemic immunomodulators at baseline visit was statistically significantly associated with healing (P = 0.048). This pilot study suggests that use of systemic immunomodulators has an impact on healing of PG patients. Wound care regimens are variable, and assessing their impact on treatment outcomes could be challenging. Standardisation of both wound care regimens and data collection in prospective clinical studies is necessary to assess their impact in PG treatment outcomes.

Impact of disease-modifying antirheumatic drugs on vaccine immunogenicity in patients with inflammatory rheumatic and musculoskeletal diseases.

Patients with rheumatic diseases are at increased risk of infectious complications; vaccinations are a critical component of their care. Disease-modifying antirheumatic drugs may reduce the immunogenicity of common vaccines. We will review here available data regarding the effect of these medications on influenza, pneumococcal, herpes zoster, SARS-CoV-2, hepatitis B, human papilloma virus and yellow fever vaccines. Rituximab has the most substantial impact on vaccine immunogenicity, which is most profound when vaccinations are given at shorter intervals after rituximab dosing. Methotrexate has less substantial effect but appears to adversely impact most vaccine immunogenicity. Abatacept likely decrease vaccine immunogenicity, although these studies are limited by the lack of adequate control groups. Janus kinase and tumour necrosis factor inhibitors decrease absolute antibody titres for many vaccines, but do not seem to significantly impact the proportions of patients achieving seroprotection. Other biologics (interleukin-6R (IL-6R), IL-12/IL-23 and IL-17 inhibitors) have little observed impact on vaccine immunogenicity. Data regarding the effect of these medications on the SARS-CoV-2 vaccine immunogenicity are just now emerging, and early glimpses appear similar to our experience with other vaccines. In this review, we summarise the most recent data regarding vaccine response and efficacy in this setting, particularly in light of current vaccination recommendations for immunocompromised patients.

Inflammatory arthritis-associated pyoderma gangrenosum: a systematic review.

INTRODUCTION/OBJECTIVES: Pyoderma gangrenosum (PG) is a rare, rapidly progressive neutrophilic dermatosis commonly associated with systemic inflammatory diseases. We aimed to characterize the association of PG and inflammatory arthritis, as little is known outside of case reports and small cohort studies. METHOD: We performed a systematic review in PubMed, EMBASE, and Scopus from inception to present using the terms arthritis and pyoderma gangrenosum. Patient demographics, clinical presentation, and treatment outcomes were recorded. Descriptive statistics and stratified analysis were used to compare factors of interest by type of arthritis. RESULTS: A total of 1399 articles were screened, and 129 patients with inflammatory arthritis and PG were included in the review. The most common types of arthritis were rheumatoid arthritis (RA) (50.4%), inflammatory bowel disease (IBD)-associated arthritis (10.9%), and psoriatic arthritis (8.5%). In the vast majority of cases, joint symptoms preceded PG, by a median of 10 years (inter-quartile range [IQR] 5-16). Corticosteroid monotherapy and biologic therapies, used alone or in combination, resulted in improvement or complete resolution of ulcers 71.4% and 67.3% of the time, respectively. Within the latter, infliximab, adalimumab, and anakinra were most successful in inducing remission overall. RA and non-RA did not differ significantly in treatment success or healing time. CONCLUSIONS: This study shows that PG is frequently preceded by inflammatory arthritis, most commonly RA. Clinicians used a wide variety of treatment regimens with variable outcomes. While larger studies are needed to standardize the treatment of inflammatory arthritis-associated PG, this study suggests that in addition to systemic corticosteroids, biologic medications can be effective treatment options for these patients. KEY POINTS: • Inflammatory arthritis, most commonly rheumatoid arthritis, often precedes rather than follows pyoderma gangrenosum. • Other forms of arthritis associated with PG included IBD-associated arthritis and psoriatic arthritis. • Biologic therapies, such as infliximab, adalimumab, and anakinra, were largely successful in treating arthritis-associated pyoderma gangrenosum and may play an important role in corticosteroid-sparing therapy or in a maintenance regimen for this subset of patients. • The type of inflammatory arthritis associated with pyoderma gangrenosum may not be a helpful treatment guide as it was not significantly associated with treatment outcomes or healing time.

Tofacitinib as a Steroid-Sparing Therapy in Pulmonary Sarcoidosis, an Open-Label Prospective Proof-of-Concept Study.

This is a prospective, open-label, proof-of-concept study of tofacitinib, a Janus kinase inhibitor, as a steroid-sparing therapy in corticosteroid-dependent pulmonary sarcoidosis. Five patients with corticosteroid-dependent pulmonary sarcoidosis were treated with tofacitinib 5 mg twice daily. The primary endpoint was a ≥ 50% reduction in corticosteroids at week 16 with no worsening in pulmonary function or respiratory symptoms. 60% of patients (3/5) met the primary endpoint. One patient was lost to follow up prior to steroid taper, and another was withdrawn due to worsening of known neurosarcoidosis. The three patients who met the primary endpoint each tapered to ≤ 5 mg/day prednisone, respiratory symptoms improved, and spirometry remained stable. In this proof-of-concept study, the addition of a JAK-inhibitor allowed 60% of patients with pulmonary sarcoidosis to successfully taper corticosteroids. JAK-inhibitors are a promising therapy for pulmonary sarcoidosis, which require further investigation in randomized trials.Trial Registration clinicaltrials.gov NCT03793439; registered Jan 4, 2019.

A rheumatologic approach to granulomatous mastitis: A case series and review of the literature.

AIM: Idiopathic granulomatous mastitis (IGM) is an enigmatic inflammatory breast disorder. IGM responds to immunomodulatory treatment and may be associated with systemic manifestations such as arthritis and erythema nodosum. These patients are increasingly referred to rheumatologists for management, but IGM is rarely discussed in the rheumatology literature. The objective of this report is to familiarize rheumatologists with the treatment and systemic manifestations of IGM. We report here a case series of IGM at our institution, and a literature review of IGM treated with methotrexate (MTX). METHOD: Patients with IGM at our institution were identified and described using a retrospective chart review. A literature review of PubMed and Google Scholar identified studies of IGM patients treated with MTX. RESULTS: We identified 28 IGM patients at our institution. Inflammatory arthritis/arthralgia were present in four patients (14%), and five patients (18%) had erythema nodosum. Patients treated with MTX had the highest rates of relapse-free remission; relapse-free remission occurred in four of the five (80%) MTX-treated patients, compared with 5 of 12 (42%) patients treated with steroids alone, and two or three (66%) patients treated with steroids and surgery. In the literature review, 116 patients treated with MTX were identified, and the rate of relapse-free remission ranged from 58% to 100%. Arthritis/arthralgia and erythema nodosum were more common at our institution than reported in the literature. CONCLUSION: Methotrexate is a promising treatment for IGM. Arthritis/arthralgias and erythema nodosum may be under-recognized when IGM patients are managed outside rheumatology. Prospective studies are needed to characterize clinical features and optimum treatment of IGM.

Gene Expression Pathways across Multiple Tissues in Antineutrophil Cytoplasmic Antibody-associated Vasculitis Reveal Core Pathways of Disease Pathology.

OBJECTIVE: To identify commonalities in gene expression data across all antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) tissues thus far characterized. METHODS: Gene expression data were collected from the 3 AAV tissues thus far characterized (orbit, peripheral leukocytes, and sinus brushings). These data were analyzed to identify commonly expressed genes and disease pathways. The pathways data were adjusted for multiple comparisons using a combined local false discovery rate, which estimates the probability of a false discovery of a given pathway in all 3 tissues analyzed. RESULTS: Only 4 genes were upregulated in all 3 tissues - IL1RN, TLR2, SLC11A1, and MMP9. After multiple comparison adjustments, the network pathway analysis revealed 28 pathways associated with all 3 tissues. The most strongly associated pathway for all 3 tissues was the neutrophil degranulation pathway [multidimensional local false discovery (md-locfdr) = 1.05 × 10-12], followed by the osteoclast differentiation (md-locfdr = 3.8 × 10-05), cell surface interactions at the vascular wall (md-locfdr = 4.2 × 10-04), signaling by interleukins (md-locfdr = 6.1 × 10-04), and phagosome (md-locfdr = 0.003) pathways. There were no downregulated genes or pathways common to all 3 tissues. CONCLUSION: This analysis identified individual genes and pathways of disease common to all AAV tissues thus far characterized. The use of a network pathway analysis allowed us to identify pathologic mechanisms that were not readily apparent in the commonly expressed genes alone. Many of these pathways are consistent with current theories about infectious drivers and the crossroads of innate and adaptive immune mechanisms. In addition, this analysis highlights novel pathways, such as vessel wall interactions and platelet activation, which require further investigation.

Do tumor necrosis factor inhibitors increase cancer risk in patients with chronic immune-mediated inflammatory disorders?

Inhibition of tumor necrosis factor (TNF) activity has profoundly changed the management of several immune-mediated inflammatory diseases with great benefit for patients. The application of TNF inhibitors (TNFi), however, also brings a new concern, malignancy. We performed a systemic review to collect the studies reporting cancer incidences and risks in TNFi users regardless of indications. TNFi were most frequently used in treating patients with rheumatoid arthritis (RA) and inflammatory bowel diseases (IBD). In RA patients without prior cancer history, the incidences of malignancies ranged from the lowest rate 0 per 1000 person-years in etanercept users regarding lymphoma to the highest rate 35.62 per 1000 person-years in adalimumab users on non-melanoma skin cancer (NMSC), while in those patients with prior cancer history, the recurrent incidences of malignancies ranged from the lowest rate 5.05 per 1000 person-years regarding melanoma to the highest rate 63.20 per 1000 person-years on basal cell carcinoma (BCC) in TNFi users. In IBD patients, incidences ranged from 0 per 1000 person-years in TNFi users on lymphoma to 34.0 per 1000 person-years in infliximab users on overall cancer. However, these incidence rates of overall cancer, lymphoma and melanoma were not higher in comparison with those patients who were not treated with TNFi. Compared to general population, incidences of lymphoma were elevated in RA patients and rates of NMSC were higher in patients with psoriasis, RA and IBD. In conclusion, cancer incidences vary across different studies, indications, cancer types and studies with different individual TNFi. Treatment with TNFi is not associated with increased malignant risks of overall cancer, lymphoma or melanoma. Results of NMSC risk were inconsistent among studies. A latest prospective registry study demonstrated a small increased risk of squamous cell cancer in RA patients treated with TNFi (one additional case for every 1600years of treatment experience). Further prospective studies are needed to verify whether TNFi users have higher NMSC risk than non-TNFi users.

Vaccines and Disease-Modifying Antirheumatic Drugs: Practical Implications for the Rheumatologist.

Patients with rheumatoid arthritis are highly vulnerable to infections because of abnormalities in their immune system, and because of immunosuppressive effects of their medications. Vaccinations in this population are complicated by disease-modifying antirheumatic drugs, which also modulate or suppress the immune system and potentially decrease the immunogenicity and efficacy of the vaccines. We review the available data regarding the impact of rheumatoid arthritis therapy on the immunogenicity of various common vaccines. We also review rheumatoid arthritis-specific vaccination recommendations, live vaccine safety concerns, and current gaps in our understanding of these issues."

Vaccinations for rheumatoid arthritis.

PURPOSE OF REVIEW: Rheumatoid arthritis (RA) patients experience increased infectious disease-related morbidity and mortality, and vaccinations represent an important element in their care. However, vaccine immunogenicity can be affected by disease-modifying antirheumatic drug (DMARD) therapy, such that vaccine choice and timing can be clinically challenging. We review the indications, safety, and immunogenicity of vaccines in the setting of RA. RECENT FINDINGS: Recent recommendations highlight the use of influenza, pneumococcal, and shingles vaccines in RA patients. Studies suggest influenza and pneumococcal vaccines are underutilized, but well tolerated in RA patients and generally immunogenic during DMARD use with the exception of rituximab. Though data for other nonlive vaccines are more limited, hepatitis B virus and human papilloma virus vaccines also appear well tolerated and immunogenic in this population. Live vaccines for shingles and yellow fever remain contraindicated in some RA patients; however, limited data suggest they might be well tolerated in certain individuals. SUMMARY: The review updates rheumatologists on the optimal use and timing of routine vaccinations in the care of RA.

Cleft palate, retrognathia and congenital heart disease in velo-cardio-facial syndrome: a phenotype correlation study.

OBJECTIVE: Velo-cardio-facial syndrome (VCFS) is caused by a microdeletion of approximately 40 genes from one copy of chromosome 22. Expression of the syndrome is a variable combination of over 190 phenotypic characteristics. As of yet, little is known about how these phenotypes correlate with one another or whether there are predictable patterns of expression. Two of the most common phenotypic categories, congenital heart disease and cleft palate, have been proposed to have a common genetic relationship to the deleted T-box 1 gene (TBX1). The purpose of this study is to determine if congenital heart disease and cleft palate are correlated in a large cohort of human subjects with VCFS. METHODS: This study is a retrospective chart review including 316 Caucasian non-Hispanic subjects with FISH or CGH microarray confirmed chromosome 22q11.2 deletions. All subjects were evaluated by the interdisciplinary team at the Velo-Cardio-Facial Syndrome International Center at Upstate Medical University, Syracuse, NY. Each combination of congenital heart disease, cleft palates, and retrognathia was analyzed by Chi square or Fisher exact test. RESULTS: For all categories of congenital heart disease and cleft palate or retrognathia no significant associations were found, with the exception of submucous cleft palate and retrognathia (nominal p=0.0325) and occult submucous cleft palate and retrognathia (nominal p=0.000013). CONCLUSIONS: Congenital heart disease and cleft palate do not appear to be correlated in human subjects with VCFS despite earlier suggestions from animal models. Possible explanations include modification of the effect of TBX1 by genes outside of the 22q11.2 region that may further influence the formation of the palate or heart, or the presence of epigenetic factors that may effect genes within the deleted region, modifying genes elsewhere, or polymorphisms on the normal copy of chromosome 22. Lastly, it is possible that TBX1 plays a role in palate formation in some species, but not in humans. In VCFS, retrognathia is caused by an obtuse angulation of the skull base. It is unknown if the correlation between retrognathia and cleft palate in VCFS indicates a developmental sequence related to skull morphology, or direct gene effects of both anomalies. Much work remains to be done to fully understand the complex relationships between phenotypic characteristics in VCFS.