The impact of radiation therapy in patients with systemic sclerosis and head and neck cancer.

OBJECTIVE: Systemic sclerosis (SSc) is considered a relative, or in some cases, absolute contraindication for radiation therapy for various cancers; however, radiation is standard of care and the best option for tumor control for locally advanced head and neck (H&N) cancer. We present a case series to document the post-radiation outcomes in patients with SSc and H&N cancer. METHODS: Patients with SSc and H&N cancer treated with radiation were identified from two large Scleroderma Center research registries. Through chart review, we identified whether patients developed pre-determined acute and late side effects or changes in SSc activity from radiation. We further describe therapies used to prevent and treat radiation-induced fibrosis. RESULTS: Thirteen patients with SSc who received radiation therapy for H&N cancer were included. Five-year survival was 54%. Nine patients (69%) developed local radiation-induced skin thickening and seven (54%) developed reduced neck range of motion. Two patients required long-term percutaneous endoscopic gastrostomy use due to radiation therapy complications. No patients required respiratory support related to radiation therapy. Regarding SSc disease activity among the patients with established SSc prior to radiation therapy, none experienced interstitial lung disease progression in the post-radiation period. Following radiation, one patient had worsening skin disease outside the radiation field, however, this patient was within the first year of SSc when progressive skin disease is expected. Treatment strategies to prevent radiation fibrosis included pentoxifylline, amifostine and vitamin E, while intravenous immunoglobulin (IVIG) was used to treat it. CONCLUSION: While some patients with SSc who received radiation for H&N cancer developed localized skin thickening and reduced neck range of motion, systemic flares of SSc were uncommon. This observational study provides evidence to support the use of radiation therapy for H&N cancer in patients with SSc when radiation is the best treatment option.

Aberrant Long-Chain Fatty Acid Metabolism Associated with Evolving Systemic Sclerosis-Associated Pulmonary Arterial Hypertension.

We sought to investigate differential metabolism in patients with systemic sclerosis (SSc) who develop pulmonary arterial hypertension (PAH) versus those who do not, as a method of identifying potential disease biomarkers. In a nested case-control design, serum metabolites were assayed in SSc subjects who developed right heart catheterization-confirmed PAH (n=22) while under surveillance in a longitudinal cohort from Johns Hopkins, then compared to metabolites assayed in matched SSc patients who did not develop PAH (n=22). Serum samples were collected at "proximate" (within 12 months) and "distant" (within 1-5 years) time points relative to PAH diagnosis. Metabolites were identified using liquid chromatography-mass spectroscopy (LC-MS). An LC-MS dataset from SSc subjects with either mildly elevated pulmonary pressures or overt PAH from the University of Michigan was compared. Differentially abundant metabolites were tested as predictors of PAH in two additional validation SSc cohorts. Long-chain fatty acid metabolism (LCFA) consistently differed in SSc-PAH versus SSc without PH. LCFA metabolites discriminated SSc-PAH patients with mildly elevated pressures in the Michigan cohort and predicted SSc-PAH up to two years prior to clinical diagnosis in the Hopkins cohort. Acylcholines containing LCFA residues and linoleic acid metabolites were most important for discriminating SSc-PAH. Combinations of acylcholines and linoleic acid metabolites provided good discrimination of SSc-PAH across cohorts. Aberrant lipid metabolism is observed throughout the evolution of PAH in SSc. Lipidomic signatures of abnormal LCFA metabolism distinguish SSc-PAH patients from those without PH, including prior to clinical diagnosis and in mild disease.

Sildenafil Versus Placebo for Early Pulmonary Vascular Disease in Scleroderma (SEPVADIS): protocol for a randomized controlled trial.

BACKGROUND: Pulmonary hypertension (PH) is a leading cause of death in patients with systemic sclerosis (SSc). An important component of SSc patient management is early detection and treatment of PH. Recently the threshold for the diagnosis of PH has been lowered to a mean pulmonary artery pressure (mPAP) threshold of > 20 mmHg on right heart catheterization (RHC). However, it is unknown if PH-specific therapy is beneficial in SSc patients with mildly elevated pressure (SSc-MEP, mPAP 21-24 mmHg). METHODS: The SEPVADIS trial is a randomized, double-blind, placebo-controlled phase 2 trial of sildenafil in SSc-MEP patients with a target enrollment of 30 patients from two academic sites in the United States. The primary outcome is change in six-minute walk distance after 16 weeks of treatment. Secondary endpoints include change in pulmonary arterial compliance by RHC and right ventricular function by cardiac magnetic resonance imaging at 16 weeks. Echocardiography, serum N-terminal probrain natriuretic peptide, and health-related quality of life is being measured at 16 and 52 weeks. DISCUSSION: The SEPVADIS trial will be the first randomized study of sildenafil in SSc-MEP patients. The results of this trial will be used to inform a phase 3 study to investigate the efficacy of treating patients with mild elevations in mPAP. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT04797286.

Xist ribonucleoproteins promote female sex-biased autoimmunity.

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.

Distinct Scleroderma Autoantibody Profiles Stratify Patients for Cancer Risk at Scleroderma Onset and During the Disease Course.

OBJECTIVES: We examined whether an array of scleroderma autoantibodies associates with risk of cancer and could be useful tools for risk stratification. METHODS: Scleroderma cancer cases and scleroderma controls without cancer from the Johns Hopkins Scleroderma Center and the University of Pittsburgh Scleroderma Center were studied. Sera were assayed by Lineblot and enzyme-linked immunosorbent assay (ELISA) for autoantibodies against centromere, topoisomerase 1, RNA polymerase (POLR) 3, PM/Scl, Th/To, NOR90, U3 RNP, Ku, Ro52, U1RNP, and RNPC3. Logistic regression models were constructed to examine whether distinct autoantibodies associated with overall cancer at any time and cancer-associated scleroderma (cancer occurring three years before and after scleroderma onset). The effects of having more than one autoantibody on cancer were further examined using random forest analysis. RESULTS: A total of 676 cases and 687 controls were studied. After adjusting for relevant covariates, anti-POLR3 (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.03-2.11) and monospecific anti-Ro52 (OR 2.19, 95% CI 1.29-3.74) were associated with an increased overall cancer risk, whereas anticentromere (OR 0.69, 95% CI 0.51-0.93) and anti-U1RNP (OR 0.63, 95% CI 0.43-0.93) were associated with lower risk. When examining risk of cancer-associated scleroderma, these immune responses remained associated with increased or decreased risk: anti-POLR3 (OR 2.28, 95% CI 1.33-3.91), monospecific anti-Ro52 (OR 2.58, 95% CI 1.05-6.30), anticentromere (OR 0.39, 95% CI 0.20-0.74), and anti-U1RNP (OR 0.32, 95% CI 0.11-0.93). Anti-Ro52 plus anti-U1RNP or anti-Th/To was associated with decreased cancer risk compared with anti-Ro52 alone. CONCLUSIONS: These data suggest that five distinct scleroderma immune responses, alone or in combination, may be useful tools to stratify the risk of cancer for scleroderma patients. Further study examining cancer risk in autoantibody subgroups relative to the general population is warranted.

Improved lung cancer clinical outcomes in patients with autoimmune rheumatic diseases.

PURPOSE: Concomitant autoimmune rheumatic diseases (ARD) can add morbidity and complicate treatment decisions for patients with lung cancer. We evaluated the tumour characteristics at diagnosis and clinical outcomes in lung cancer patients with or without ARD. METHODS: This retrospective cohort study included 10 963 patients with lung cancer, treated at Johns Hopkins. Clinical data including tumour characteristics and outcomes were extracted from the cancer registry. Data on patients' history of 20 ARD were extracted from the electronic medical record. Logistic regression was used to compare tumour characteristics between those with and without ARD; Kaplan-Meier curves and Cox proportional hazards models were performed to compare survival outcomes. RESULTS: ARD was present in 3.6% of patients (n=454). The mean age at diagnosis was 69 (SD 10) and 68 (SD 12) in patients with and without ARD (p=0.02). Female sex and smoking history were significantly associated with a history of ARD (OR: 1.75, OR: 1.46, p<0.05). Patients with ARD were more likely to be diagnosed with stage 1 lung cancer (36.8% vs 26.9%, p<0.001) and with smaller tumour size (OR: 0.76, p=0.01), controlling for sex, race and histology. Notably, lung cancer patients with ARD had a significantly prolonged median overall survival (OS) (7.11 years vs 1.7 years, p<0.001), independent of stage. CONCLUSION: Patients with ARD and lung cancer had better OS compared with their counterparts, independent of cancer stage and treatments and were less likely to have advanced stage lung cancer at diagnosis. Additional studies are needed to investigate the differential immunological anti-tumour immune activity and genomic variations in patients with and without ARD.

Kynurenine pathway metabolism evolves with development of preclinical and scleroderma-associated pulmonary arterial hypertension.

Understanding metabolic evolution underlying pulmonary arterial hypertension (PAH) development may clarify pathobiology and reveal disease-specific biomarkers. Patients with systemic sclerosis (SSc) are regularly surveilled for PAH, presenting an opportunity to examine metabolic change as disease develops in an at-risk cohort. We performed mass spectrometry-based metabolomics on longitudinal serum samples collected before and near SSc-PAH diagnosis, compared with time-matched SSc subjects without PAH, in a SSc surveillance cohort. We validated metabolic differences in a second cohort and determined metabolite-phenotype relationships. In parallel, we performed serial metabolomic and hemodynamic assessments as the disease developed in a preclinical model. For differentially expressed metabolites, we investigated corresponding gene expression in human and rodent PAH lungs. Kynurenine and its ratio to tryptophan (kyn/trp) increased over the surveillance period in patients with SSc who developed PAH. Higher kyn/trp measured two years before diagnostic right heart catheterization increased the odds of SSc-PAH diagnosis (OR 1.57, 95% CI 1.05-2.36, P = 0.028). The slope of kyn/trp rise during SSc surveillance predicted PAH development and mortality. In both clinical and experimental PAH, higher kynurenine pathway metabolites correlated with adverse pulmonary vascular and RV measurements. In human and rodent PAH lungs, expression of TDO2, which encodes tryptophan 2,3 dioxygenase (TDO), a protein that catalyzes tryptophan conversion to kynurenine, was significantly upregulated and tightly correlated with pulmonary hypertensive features. Upregulated kynurenine pathway metabolism occurs early in PAH, localizes to the lung, and may be modulated by TDO2. Kynurenine pathway metabolites may be candidate PAH biomarkers and TDO warrants exploration as a potential novel therapeutic target.NEW & NOTEWORTHY Our study shows an early increase in kynurenine pathway metabolism in at-risk subjects with systemic sclerosis who develop pulmonary arterial hypertension (PAH). We show that kynurenine pathway upregulation precedes clinical diagnosis and that this metabolic shift is associated with increased disease severity and shorter survival times. We also show that gene expression of TDO2, an enzyme that generates kynurenine from tryptophan, rises with PAH development.

Baseline predictors of disease severity in immune checkpoint inhibitor-induced inflammatory arthritis.

OBJECTIVES: To determine baseline risk factors for requiring immunosuppression and having persistent arthritis in patients with immune checkpoint inhibitor-induced inflammatory arthritis (ICI-IA). METHODS: Participants were adults with rheumatologist diagnosed ICI-IA. The primary outcome was requirement of conventional synthetic (cs) or biologic (b) DMARDs; other outcomes were persistence of IA > 6 months after ICI cessation and requirement of corticosteroids. Logistic regression models evaluated associations between clinical features and primary and secondary outcomes, with adjustment for potential confounders, as appropriate. RESULTS: 126 patients with ICI-IA were included; 53 patients (42%) required a csDMARD/bDMARD. In univariate logistic regressions, higher CDAI, tenosynovitis, longer symptom duration before first rheumatology visit, and longer ICI duration were significantly associated with a higher likelihood of requiring DMARDs; there was a trend toward those treated with prior chemotherapy being less likely to need DMARDs. After adjustment, tenosynovitis, longer symptom duration, and higher CDAI remained associated with requiring DMARDs, while those with prior chemotherapy were significantly less likely to require DMARDs. Combination anti-CTLA-4/PD-1 therapy and steroid use at baseline were associated with a higher risk of persistent IA. CONCLUSION: Higher levels of disease activity, tenosynovitis, and longer symptom duration prior to rheumatology referral were associated with requiring DMARDs for ICI-IA, while those treated previously with chemotherapy were less likely to require additional immunosuppression. The presence of risk factors for severe disease at baseline may indicate a role for higher initial steroid dose, earlier rheumatology referral, and adoption of immunosuppression beyond steroids to improve outcomes.

The Collaborative National Quality and Efficacy Registry for Scleroderma: association of medication use on gastrointestinal tract symptoms in early disease and the importance of tobacco cessation.

OBJECTIVES: Systemic Sclerosis (SSc) is frequently associated with gastrointestinal tract (GIT) involvement. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative study collecting longitudinal follow up data on SSc patients with less than 5-years disease duration enrolled at Scleroderma centres of excellence. This manuscript presents the GIT natural history and outcomes in relation to other scleroderma manifestations and medication exposures. METHODS: CONQUER participants that had completed a minimum of two serial Scleroderma Clinical Trials Consortium GIT Questionnaires (GIT 2.0) were included in this analysis. Patients were categorised by total GIT 2.0 severity at baseline, and by category change: none-to-mild (0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00) at the subsequent visit. Based on this data, four groups were identified: none-to-mild with no change, moderate-to-severe with no change, improvement, or worsening. Clinical features and medications, categorised as gastrointestinal tract targeted therapy, anti-fibrotic, immunosuppression, or immunomodulatory drugs, were recorded. Analysis included a proportional odds modelaccounting for linear and mixed effects of described variables. RESULTS: 415 enrolled CONQUER participants met project inclusion criteria. Most participants had stable mild GIT symptoms at baseline and were on immunomodulatory and anti-reflux therapy. In most patients, anti-reflux medication and immunosuppression initiation preceded the baseline visit, whereas anti-fibrotic initiation occurred at or after the baseline visit. In the proportional odds model, worsening GIT score at the follow-up visit was associated with current tobacco use (odds ratio: 3.48 (1.22, 9.98, p 0.020). CONCLUSIONS: This report from the CONQUER cohort, suggests that most patients with early SSc have stable and mild GIT disease. Closer follow-up was associated with milder, stable GIT symptoms. There was no clear association between immunosuppression or anti-fibrotic use and severity of GIT symptoms. However, active tobacco use was associated with worse GIT symptoms, highlighting the importance of smoking cessation counselling in this population.

Construct validity and reliability of the assessment of systemic sclerosis-associated raynaud's phenomenon (ASRAP) questionnaire.

OBJECTIVES: Assessment of construct validity and reliability of a novel patient-reported outcome (PRO) instrument for assessing the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). METHODS: An international multicentre study validation study of the 27-item Assessment of Systemic sclerosis-associated RAynaud's Phenomenon (ASRAP) and 10-item short-form (ASRAP-SF) questionnaires. The relationship between ASRAP questionnaires and demographics, clinical phenotype and legacy instruments for assessing SSc-RP severity, disability and pain was assessed. Repeatability was evaluated at 1-week. Anchor-based statements of health status facilitated assessment of ASRAP thresholds of meaning. RESULTS: Four hundred and twenty SSc subjects were enrolled. There was good correlation between ASRAP (and ASRAP-SF) with RP visual analogue scale (VAS) and Scleroderma Health Assessment Questionnaire RP VAS (rho range 0.648-0.727, p< 0.001). Correlation with diary-based assessment of SSc-RP attack frequency and duration was lower (rho range 0.258-0.504, p< 0.001). ASRAP questionnaires had good correlation with instruments for assessing disability, hand function, pain and global health assessment (rho range 0.427-0.575, p< 0.001). Significantly higher ASRAP scores were identified in smokers, patients with active digital ulceration (DU), previous history of DU and calcinosis (p< 0.05 for all comparisons). There was excellent repeatability at 1-week amongst patients with stable SSc-RP symptoms (intra-class coefficients of 0.891 and 0.848, p< 0.001). Patient-acceptable symptom state thresholds for ASRAP and ASRAP-SF were 45.34 and 45.77 respectively. A preliminary Minimally Important Clinical Difference threshold of 4.17 (95% CI 0.53-7.81, p= 0.029) was estimated. CONCLUSION: ASRAP and ASRAP-SF questionnaires are valid and reliable novel PRO instruments for assessing the severity and impact of SSc-RP.

CONQUER Scleroderma: association of gastrointestinal tract symptoms in early disease with resource utilization.

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients with <5 years of disease duration enrolled at scleroderma centres in the USA. The objective of this study was to investigate the relationship between gastrointestinal tract symptoms and self-reported resource utilization in CONQUER participants. METHODS: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months. RESULTS: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment. CONCLUSION: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc.

Preventative Care in Scleroderma: What Is the Best Approach to Vaccination?

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease characterized by fibrosis, vasculopathy, and autoimmunity. There are multiple complications inherent to SSc and its management. One of these complications is increased infection risk, which can lead to decreased quality of life and increased morbidity and mortality. Patients with SSc have lower vaccination rates and decreased vaccine seroconversion secondary to immunosuppressive medications compared with the general population. The purpose of this review is to provide clinicians with an approach to vaccinations in SSc.

Preventative Care in Scleroderma: What Is the Best Approach to Bone Health and Cancer Screening?

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease characterized by fibrosis, vasculopathy, and autoimmunity. Lesser known complications inherent to SSc, such as malignancies and osteoporosis, can lead to decreased quality of life and increased morbidity and mortality. Patients with SSc have a greater risk of developing malignancies than the general population. In addition, they are more likely to be vitamin D deficient and are at great risk of osteoporosis-related fractures. However, these complications can be addressed through preventative measures. The purpose of this review is to provide clinicians with an approach to bone health and cancer screening in SSc.

Comparative safety and effectiveness of TNF inhibitors, IL6 inhibitors and methotrexate for the treatment of immune checkpoint inhibitor-associated arthritis.

OBJECTIVES: To compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA). METHODS: The retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders. RESULTS: 147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control. CONCLUSION: The treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.

Diagnostic Yield of Computed Tomography for Cancer Detection in a Tertiary Referral Population of Idiopathic Inflammatory Myositis Patients.

OBJECTIVE: To inform guidance for cancer detection in patients with idiopathic inflammatory myopathy (IIM), we evaluated the diagnostic yield of computed tomography (CT) imaging for cancer screening/surveillance within distinct IIM subtypes and myositis-specific autoantibody strata. METHODS: We conducted a single-center, retrospective cohort study in IIM patients. Overall diagnostic yield (number of cancers diagnosed/number of tests performed), percentage of false positives (number of biopsies performed not leading to cancer diagnosis/number of tests performed), and test characteristics were determined on CT of the chest and abdomen/pelvis. RESULTS: Within the first 3 years since IIM symptom onset, a total of 9 of 1,011 (0.9%) chest CT scans and 12 of 657 (1.8%) abdomen/pelvis CT scans detected cancer. Diagnostic yields for both CT of the chest and CT of the abdomen/pelvis were highest in dermatomyositis, specifically anti-transcription intermediary factor 1γ (2.9% and 2.4% for CT of the chest and abdomen/pelvis, respectively). The highest percentage of false positives was in patients with antisynthetase syndrome (ASyS) (4.4%) and immune-mediated necrotizing myopathy (4.4%) on CT of the chest, and ASyS (3.8%) on CT of the abdomen/pelvis. Patients ages <40 years old at IIM onset had both low diagnostic yields (0% and 0.5%) and high false-positive rates (1.9% and 4.4%) for CT of the chest and abdomen/pelvis, respectively. CONCLUSION: In a tertiary referral cohort of IIM patients, CT imaging has a wide range of diagnostic yield and frequency of false positives for contemporaneous cancer. These findings suggest that cancer detection strategies targeted according to IIM subtype, autoantibody positivity, and age may maximize cancer detection while minimizing the harms and costs of over-screening.

Association of Anti-CCAR1 Autoantibodies With Decreased Cancer Risk Relative to the General Population in Patients With Anti-Transcriptional Intermediary Factor 1γ-Positive Dermatomyositis.

OBJECTIVE: To describe the disease specificity, clinical phenotype, and risk of cancer in dermatomyositis (DM) patients with autoantibodies against cell division cycle and apoptosis regulator protein 1 (anti-CCAR1). METHODS: The frequency of anti-CCAR1 autoantibodies was measured by enzyme-linked immunosorbent assay in the serum of DM patients from 2 independent cohorts (Johns Hopkins and Stanford), with patients with several other rheumatic diseases and healthy controls used as comparators. Clinical features and the risk of cancer incidence relative to that in the general population were determined in anti-CCAR1-positive DM patients. RESULTS: Anti-CCAR1 antibodies were significantly associated with anti-transcriptional intermediary factor 1γ (anti-TIF1γ) antibodies present in the serum of patients with DM: 80 (32%) of 252 anti-TIF1γ-positive DM patients versus 14 (8%) of 186 anti-TIF1γ-negative DM patients were positive for anti-CCAR1 antibodies (P < 0.001). Anti-CCAR1 antibodies were not detected in any of the 32 serum samples from healthy controls, and were present at very low frequencies in the sera of patients with other rheumatic diseases: 1 (2.3%) of 44 patients with anti-hydroxymethylglutaryl-coenzyme A reductase-positive necrotizing myopathy, 1 (2.3%) of 44 patients with inclusion body myositis, and 3 (6.5%) of 46 patients with systemic lupus erythematosus were positive for anti-CCAR1 antibodies. Upon examining data on occurrence of cancer from the onset of DM onward, the observed number of cancers diagnosed in anti-TIF-1γ-positive DM patients was significantly greater than expected in both cohorts, with a standardized incidence ratio (SIR) of 3.49 (95% confidence interval [95% CI] 2.39-4.92) in the Johns Hopkins cohort and a SIR of 4.54 (95% CI 3.04-6.52) in the Stanford cohort (each P < 0.001). DM patients who were both anti-TIF1γ positive and anti-CCAR1 positive had lower SIRs for cancer, with a SIR of 1.78 (95% CI 0.77-3.51) (P = 0.172) in the Johns Hopkins cohort and a SIR of 1.61 (95% CI 0.44-4.13) (P = 0.48) in the Stanford cohort. CONCLUSION: Anti-CCAR1 autoantibodies are specific for anti-TIF1γ-positive DM. Their presence in anti-TIF1γ-positive patients attenuates the risk of cancer to a level comparable to that seen in the general population.

Qualitative Interviews to Assess the Content Validity and Usability of the Electronic Raynaud Diary in Patients with Systemic Sclerosis.

OBJECTIVE: To better understand the symptoms and impacts of Raynaud phenomenon (RP) in patients with systemic sclerosis (SSc) and to evaluate the content validity and usability of a new electronic patient-reported outcome (PRO) measure for RP: the Raynaud Diary. METHODS: The Raynaud Diary was developed as a daily eDiary for assessing the number and duration of symptomatic Raynaud attacks; worst pain, numbness, tingling, and discomfort in the fingers; and overall disease severity, captured using the Raynaud's Condition Score. The Raynaud Diary was debriefed in two waves of qualitative interviews with adults with self-reported RP secondary to SSc. All interviews included open-ended questions about participants' experiences of RP. RESULTS: Participants (N = 39) had a mean age of 55.1 years, and 87% were female. Frequently reported RP symptoms were color change (reported by all participants), numbness (90%), tingling (82%), pain (77%), and discomfort (72%). Common attack triggers included temperature-related factors and stress. Participants reported being unable to be outside or do outdoor activities and had problems gripping objects. All participants demonstrated understanding of the Raynaud Diary instructions. Most participants indicated that they would be able to use the Raynaud Diary to record the worst severity of individual RP symptoms in the previous 24 hours. CONCLUSION: Patients with RP secondary to SSc bear a heavy symptom burden. The Raynaud Diary is a content valid PRO measure that captures the most frequent symptoms of RP in patients with SSc.

Assessment of the Systemic Sclerosis-Associated Raynaud's Phenomenon Questionnaire: Item Bank and Short-Form Development.

OBJECTIVE: To develop, refine, and score a novel patient-reported outcome instrument to assess the severity and impact of Raynaud's phenomenon (RP) in systemic sclerosis (SSc). METHODS: The Assessment of Systemic Sclerosis-Associated Raynaud's Phenomenon (ASRAP) questionnaire items were developed with patient insight partner support and grounded in the lived patient experience of SSc-RP. ASRAP items underwent formal qualitative assessment and linguistic testing. An international multicenter study was undertaken to field test the preliminary ASRAP questionnaire. RESULTS: A preliminary 37-item ASRAP questionnaire was supplemented with 2 additional items following expert review to enhance content coverage before undergoing formal linguistic testing to optimize readability. Patient cognitive debriefing interviews were undertaken to enhance comprehension, ambiguity, cognitive difficulty, relevance, and content coverage of both the ASRAP items and instructions. We enrolled 420 SSc patients from scleroderma centers in the UK and US over 2 consecutive winters. Factor analysis with item response theory was undertaken to remove redundant and poorly fitting items. The retained 27-item long-form ASRAP questionnaire was calibrated and scored using the graded response model. A fixed 10-item short-form ASRAP questionnaire was developed using computerized adaptive testing simulations. CONCLUSION: The ASRAP questionnaire has been developed with extensive SSc patient input, with items grounded in the lived experience of SSc-RP to ensure strong content validity, with a focus on how patients feel and function. An advanced psychometric approach with expert input has removed redundant and/or poorly fitting items without eroding content validity. Long- and short-form ASRAP questionnaires have been calibrated and scored to permit formal validation.

Association between anti-SSSCA1 antibodies and cancer in systemic sclerosis.

OBJECTIVE: To define the clinical phenotype of SSc patients with antibodies against Sjogren's syndrome (SS)/scleroderma autoantigen 1 (SSSCA1), and to examine the association between these antibodies and cancer in SSc patients. METHODS: We conducted a case-control study using data from 209 patients with SSc and cancer, and 205 SSc patients without cancer. All were randomly selected from the Johns Hopkins Scleroderma Center Research Registry. Antibodies against SSSCA1 were assayed by immunoprecipitation of 35S-methionine-labelled protein generated by in vitro transcription and translation. We performed logistic regression analysis to examine the relationship between anti-SSSCA1 antibodies and cancer. RESULTS: Among the 414 study patients, 31 (7%) were anti-SSSCA1 antibody positive. Antibody-positive patients were more likely to have severe RP, a lower minimum ejection fraction, a trend towards more severe heart involvement and a lower baseline diffusing capacity of the lungs for carbon monoxide percent predicted than anti-SSSCA1-negative patients. Patients with cancer were significantly more likely to be anti-SSSCA1 positive compared with those without cancer [22/209 (11%) vs 9/205 (4%), respectively; P = 0.018]. Among patients with cancer, there was a trend towards longer cancer-SSc interval in anti-SSSCA1-positive patients compared with anti-SSSCA1-negative patients. Patients with anti-SSSCA1 antibodies had an increased adjusted risk of cancer (odds ratio 2.46, 95% CI 1.06, 5.70) compared with anti-SSSCA1-negative patients. CONCLUSIONS: These data suggest anti-SSSCA1 antibody status may be of utility as a cancer biomarker in SSc. Anti-SSSCA1-positive patients with SSc may be more likely to have severe Raynaud's and cardiac involvement.

Subsets of Idiopathic Inflammatory Myositis Enriched for Contemporaneous Cancer Relative to the General Population.

OBJECTIVE: This study investigates cancer risk in idiopathic inflammatory myopathy (IIM) relative to the general population. METHODS: We conducted a single-center, retrospective cohort study of IIM patients and malignancy. Myositis-specific and -associated autoantibodies were determined by Euroimmun line blot, enzyme-linked immunosorbent assay, and immunoprecipitation. We calculated standardized prevalence ratios (SPRs) and adjusted for calendar year, age, sex, race, and ethnicity by comparing observed cancers in IIM patients versus expected cancers in the general population using the Surveillance, Epidemiology, and End Results registry. RESULTS: Of 1,172 IIM patients, 203 (17%) patients with a cancer history were studied. Over a median follow-up of 5.2 years, the observed number of IIM patients diagnosed with cancer was increased 1.43-fold (SPR 1.43 [95% confidence interval (95% CI) 1.15-1.77]; P = 0.002). Within 3 years of IIM symptom onset, an increased SPR was observed for anti-transcription intermediary factor 1γ (anti-TIF1γ)-positive patients for ovarian and breast cancer (ovarian SPR 18.39 [95% CI 5.01-47.08], P < 0.001; breast SPR 3.84 [95% CI 1.99-6.71], P < 0.001). As expected, anti-TIF1γ positivity was associated with a significantly elevated SPR; however, only 55% (36 of 66) of all cancers within 3 years of dermatomyositis onset were observed in anti-TIF1γ-positive patients. Other myositis-specific autoantibodies, including anti-Mi-2, anti-small ubiquitin-like modifier activating enzyme (SAE), and anti-nuclear matrix protein 2 (NXP-2), accounted for 26% (17 of 66) of cancers diagnosed within 3 years of dermatomyositis onset. No cancer association, positive or negative, was observed for patients with antisynthetase, anti-melanoma differentiation-associated protein 5 (anti-MDA-5), or anti-hydroxymethylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies. CONCLUSION: In a tertiary referral center population, anti-TIF1γ was most strongly associated with breast and ovarian cancer. Patients with antisynthetase, anti-MDA-5, or anti-HMGCR antibodies had the same cancer risk as the general population.