Adult-Onset Still's Disease in Pregnancy: Lessons Learned and an Approach to Subsequent Pregnancies.

Adult-onset Still's disease (AOSD) is a rare autoinflammatory disorder with potential for life-threatening complications in pregnancy. Recently, biologic therapeutics have been increasingly used for treatment of AOSD, but there is little available data on the treatment of AOSD in pregnancy. Here we report a 23-year-old primigravid patient with a history of AOSD who presented at 20 weeks of gestation with fever, arthralgias, rash, fatigue, and highly elevated ferritin, concerning for AOSD flare. She was treated with tocilizumab, an interleukin-6 receptor antagonist, with rapid clinical and laboratory improvement; however, she underwent iatrogenic preterm delivery at 34 weeks of gestation for fetal distress, which was attributed to placental injury. In a subsequent pregnancy, she was treated with tocilizumab throughout and had an uncomplicated term delivery with normal labs and no AOSD flare. This case highlights that the use of tocilizumab may be effective to reduce the risk of AOSD flare during pregnancy.

Selective immune suppression using interleukin-6 receptor inhibitors for management of immune-related adverse events.

BACKGROUND: Management of immune-related adverse events (irAEs) is important as they cause treatment interruption or discontinuation, more often seen with combination immune checkpoint inhibitor (ICI) therapy. Here, we retrospectively evaluated the safety and effectiveness of anti-interleukin-6 receptor (anti-IL-6R) as therapy for irAEs. METHODS: We performed a retrospective multicenter study evaluating patients diagnosed with de novo irAEs or flare of pre-existing autoimmune disease following ICI and were treated with anti-IL-6R. Our objectives were to assess the improvement of irAEs as well as the overall tumor response rate (ORR) before and after anti-IL-6R treatment. RESULTS: We identified a total of 92 patients who received therapeutic anti-IL-6R antibodies (tocilizumab or sarilumab). Median age was 61 years, 63% were men, 69% received anti-programmed cell death protein-1 (PD-1) antibodies alone, and 26% patients were treated with the combination of anti-cytotoxic T lymphocyte antigen-4 and anti-PD-1 antibodies. Cancer types were primarily melanoma (46%), genitourinary cancer (35%), and lung cancer (8%). Indications for using anti-IL-6R antibodies included inflammatory arthritis (73%), hepatitis/cholangitis (7%), myositis/myocarditis/myasthenia gravis (5%), polymyalgia rheumatica (4%), and one patient each with autoimmune scleroderma, nephritis, colitis, pneumonitis and central nervous system vasculitis. Notably, 88% of patients had received corticosteroids, and 36% received other disease-modifying antirheumatic drugs (DMARDs) as first-line therapies, but without adequate improvement. After initiation of anti-IL-6R (as first-line or post-corticosteroids and DMARDs), 73% of patients showed resolution or change to ≤grade 1 of irAEs after a median of 2.0 months from initiation of anti-IL-6R therapy. Six patients (7%) stopped anti-IL-6R due to adverse events. Of 70 evaluable patients by RECIST (Response Evaluation Criteria in Solid Tumors) V.1.1 criteria; the ORR was 66% prior versus 66% after anti-IL-6R (95% CI, 54% to 77%), with 8% higher complete response rate. Of 34 evaluable patients with melanoma, the ORR was 56% prior and increased to 68% after anti-IL-6R (p=0.04). CONCLUSION: Targeting IL-6R could be an effective approach to treat several irAE types without hindering antitumor immunity. This study supports ongoing clinical trials evaluating the safety and efficacy of tocilizumab (anti-IL-6R antibody) in combination with ICIs (NCT04940299, NCT03999749).

Determinants of Cervical Cancer Screening Patterns Among Women With Systemic Lupus Erythematosus.

OBJECTIVE: Women with systemic lupus erythematosus (SLE) are vulnerable to cervical dysplasia due to the persistence of human papillomavirus (HPV) infection. The objective of this cross-sectional retrospective study was to investigate the prevalence of cervical cancer screening according to the American Society for Colposcopy and Cervical Pathology (ASCCP) SLE-specific cervical cancer screening guidelines. We also aimed to identify SLE-specific determinants associated with ASCCP adherence. METHODS: Women aged 21 to 64 years enrolled in our institutional SLE registry were included in the study. The electronic medical record was manually reviewed to determine whether the patient was up to date on screening and which organizational guideline was used, in addition to other clinical variables. Multivariable logistic regression was used to estimate adjusted odds ratios (ORs) for ASCCP-congruent screening for each baseline characteristic. RESULTS: This study included 118 women with SLE; 38% were up to date per ASCCP guidelines, 16% were up to date per non-ASCCP guidelines, and 46% were overdue for screening. Having a gynecologist and being actively treated with immunosuppressant therapies were both associated with an increased odds of being up to date per the ASCCP guidelines, while Hispanic ethnicity was associated with reduced odds. CONCLUSION: Only half of the women with SLE in our study had guideline-congruent cervical cancer screening. Current immunosuppression exposure, rather than SLE disease activity, was associated with an increased odds of being up to date according to ASCCP guidelines. This study suggests the need for increased awareness and consensus among interdisciplinary providers regarding SLE-specific cervical cancer screening.

Vascular Ultrasound for Giant Cell Arteritis: Establishing a Protocol Using Vascular Sonographers in a Fast-Track Clinic in the United States.

OBJECTIVE: We developed a fast-track clinic (FTC) to expedite the evaluation of patients suspected of having giant cell arteritis (GCA) using vascular ultrasound. Though FTCs have demonstrated efficacy in Europe, no protocolized clinic in the United States has been developed. This study introduces a new FTC model unique to the United States, using vascular sonographers, and describes the protocols used to develop reliable findings. We evaluate clinical outcomes using vascular ultrasound and temporal artery biopsy (TAB). METHODS: A retrospective review included all subjects referred to the University of Washington FTC aged 50 years old or older who received both ultrasound and TAB between November 2017 and November 2019. Ultrasound was performed by a vascular sonographer trained in GCA detection. Ultrasound results were read by a vascular surgeon and reviewed by four rheumatologists certified in musculoskeletal ultrasound who had completed a course in vascular ultrasound use in GCA and large-vessel vasculitis. RESULTS: A total of 43 subjects underwent both vascular ultrasound and TAB. Six subjects had both positive ultrasound and TAB results. There were also seven positive ultrasound results in patients with negative TAB results, most due to detection of large-vessel GCA (LV-GCA). All 29 subjects with negative ultrasound results had negative TAB results. CONCLUSION: This is the first study in the United States to demonstrate a reliable FTC protocol using vascular sonographers. This protocol demonstrated good agreement between ultrasound and TAB and allowed for the detection of additional cases of LV-GCA by vascular ultrasound. Vascular ultrasound improved the rate of GCA diagnosis primarily by detecting additional cases of LV-GCA.

Sporadic inclusion body myositis and primary Sjogren's syndrome: an overlooked diagnosis.

Sporadic inclusion body myositis (sIBM) has been reported to occur in association with autoimmune diseases and in particular, primary Sjogren's syndrome (pSS). This brief report describes patients identified with a positive SSA antibody and diagnosis of sIBM at a large academic medical center over a 13.5-year period. A cohort identification tool was used to identify patients with positive SSA antibody and a diagnosis of sIBM between January 1, 2006 and June 1, 2019. All cases of sIBM had diagnostic confirmation by a neuromuscular specialist. Demographics, clinical features, autoantibodies, MRI and EMG findings, and muscle biopsy features were reviewed for each identified case. Eight patients were found to carry the diagnosis of pSS and sIBM. Two additional sIBM patients were SSA antibody positive without other pSS features. The mean time from initial symptom onset of muscle weakness to diagnosis was 5.4 years (range 1-15 years). All patients had alternative diagnoses offered for their myopathic symptoms prior to sIBM identification. The NT5c1A antibody was positive in 7 of 8 patients tested. No patient had a durable response to immunosuppressive therapy. The diagnosis of sIBM went unrecognized for over 5 years in our cohort of SSA antibody-positive patients with myopathy. The patients in this cohort were treated with a variety of immunosuppressive agents prior to diagnosis without benefit. Recognizing the clinical features of sIBM in patients with pSS is crucial in instituting appropriate therapy and avoiding unnecessary immunosuppression. Key Points • Sporadic inclusion body myositis (sIBM) can be associated with Sjogren's syndrome. • In this case series, prevalence of the NT5c1A antibody was higher among patients with associated Sjogren's syndrome compared to the cited prevalence of the NT5c1A antibody in patients with isolated sIBM. • It is crucial to consider sIBM in patients with Sjogren's syndrome presenting with motor weakness in order to avoid unnecessary immunosuppression and institute appropriate therapy.

The U.S. Veterans Health Administration national giant cell arteritis (GCA) database cohort: incident ophthalmic complications in biopsy-negative GCA patients.

INTRODUCTION/OBJECTIVES: This study aimed to identify the incidence of ophthalmic complications of giant cell arteritis (GCA) among subjects with negative temporal artery biopsy (TAB) and to determine if duration of prednisone exposure relative to GCA diagnosis was associated with ophthalmic complications in TAB-negative subjects. METHOD: The U.S. Veterans Health Administration (VHA) national database was queried for subjects between 1999 and 2017 with ICD-9/-10 diagnosis code for GCA, procedure code for TAB, and ICD-9/-10 diagnosis code for blindness, anterior or posterior ischemic optic neuropathy, or branch or central retinal artery occlusion. Pharmacy data regarding prednisone dispensation were collected. A Cox proportional hazard model was performed using ophthalmic complication by 1 year as the outcome variable in TAB-negative subjects, adjusting for age, TAB length, TAB laterality, and prednisone dose relative to GCA diagnosis date. RESULTS: Incident ophthalmic complication occurred by 1 year in 9.6% with positive TAB and in 6.2% with negative TAB. The majority of complications occurred within the first month for both groups. Compared to a reference group of prednisone initiation 0-14 days prior to GCA diagnosis, ophthalmic complications in TAB-negative subjects were significantly higher when prednisone initiation was delayed 14-28 days after GCA diagnosis. CONCLUSIONS: A substantial number of TAB-negative subjects accrued an incident ICD-9/-10 code for ophthalmologic complication within a year after diagnosis, most occurring within the first month. Delaying prednisone initiation 14-28 days after GCA diagnosis in TAB-negative subjects led to a 3.5-fold higher rate of ophthalmic events occurring by 1 year. Key Points • This study provides an incidence rate of ophthalmic complication by one year in biopsy-negative subjects suspected of having GCA. • Delaying prednisone initiation 14-28 days after GCA diagnosis in TAB-negative GCA subjects led to a 3.5-fold higher rate of ophthalmic events occurring by 1 year.

Immunologic adverse events from immune checkpoint therapy.

The growth of cancer immunotherapy has led to an urgent need for a multispecialty approach to treating patients with advanced malignancies. Checkpoint inhibitor therapies cause a wide range of toxicities termed immune-related adverse events (irAEs) that can affect any organ system. Similar to the anti-tumor responses induced by these medications, irAEs represent an interruption of self-tolerance that results in T cell-driven cytotoxicity, the exact mechanisms of which are likely heterogeneous. This review describes the various immunologic pathways that may lead to irAEs along with the diverse clinical manifestations seen in clinical practice. Treatment based on the severity and specific organ involvement will also be discussed, along with an overview of current guidelines and potential challenges that arise with immunosuppressive medications.

Determinants of Positive Temporal Artery Biopsies in the Veterans Health Administration National Database Cohort.

OBJECTIVE: This study sought to determine the effect of temporal artery biopsy (TAB) postfixation length, laterality, age, and prior prednisone exposure on TAB positivity utilizing the Veterans Health Administration national database. METHODS: Subjects with procedure code for TAB between 1999 and 2017 were queried, and pathology reports were reviewed manually. Demographic, laboratory, and prescription data were extracted. Multivariate analyses and logistic regression were run using Stata, version 13.0. RESULTS: A total of 3,057 pathology reports were reviewed; 306 biopsies (10%) were designated positive. The likelihood of a positive TAB significantly correlated with TAB postfixation length of >3.0 cm (odds ratio [OR] 1.58 [95% confidence interval (95% CI) 1.06, 2.36], P < 0.05) as well as with bilateral biopsy in 1 sitting (OR 1.83 [95% CI 1.29, 2.59], P < 0.01). Positive TAB also significantly correlated with age >71 years. Prednisone administration up to and beyond 42 days prior to TAB did not influence TAB result. CONCLUSION: This retrospective study examined predictors of TAB positivity and utilized national data collected on US veterans over the span of 18 years. The results suggest consideration of pursuing initial bilateral TAB or achieving a TAB postfixation length of at least 3 cm to improve yield. The results also agree with prior studies showing that pre-TAB steroid exposure does not appear to affect yield even up to and beyond 42 days prior to biopsy.

The Use of TSH in Determining Thyroid Disease: How Does It Impact the Practice of Medicine in Pregnancy?

During the last four decades, there have been considerable advances in the efficacy and precision of serum thyroid function testing. The development of the third generation assays for the measurement of serum thyroid stimulating hormone (TSH, thyrotropin) and the log-linear relationship with free thyroxine (T4) established TSH as the hallmark of thyroid function testing. While it is widely accepted that TSH outside of the normal range is consistent with thyroid dysfunction, a vast multitude of additional factors must be considered before an accurate clinical diagnosis can be made. This is especially important during pregnancy, when the thyroid is under considerable additional pregnancy-related demands requiring significant maternal physiological changes. This paper examines serum TSH measurement in pregnancy and some associated potential confounding factors.

Sex differences in drug disposition.

Physiological, hormonal, and genetic differences between males and females affect the prevalence, incidence, and severity of diseases and responses to therapy. Understanding these differences is important for designing safe and effective treatments. This paper summarizes sex differences that impact drug disposition and includes a general comparison of clinical pharmacology as it applies to men and women.