Diagnostic Approach to Interstitial Lung Diseases Associated with Connective Tissue Diseases.

Interstitial lung disorders are a group of respiratory diseases characterized by interstitial compartment infiltration, varying degrees of infiltration, and fibrosis, with or without small airway involvement. Although some are idiopathic (e.g., idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, and sarcoidosis), the great majority have an underlying etiology, such as systemic autoimmune rheumatic disease (SARD, also called Connective Tissue Diseases or CTD), inhalational exposure to organic matter, medications, and rarely, genetic disorders. This review focuses on diagnostic approaches in interstitial lung diseases associated with SARDs. To make an accurate diagnosis, a multidisciplinary, personalized approach is required, with input from various specialties, including pulmonary, rheumatology, radiology, and pathology, to reach a consensus. In a minority of patients, a definitive diagnosis cannot be established. Their clinical presentations and prognosis can be variable even within subsets of SARDs.

Risk factors for lung function decline in systemic sclerosis-associated interstitial lung disease in a large single-centre cohort.

OBJECTIVES: The aim of this study was to identify risk factors of percent predicted forced vital capacity (ppFVC) decline in patients with SSc-associated interstitial lung disease (SSc-ILD). METHODS: We identified 484 patients with SSc who had HRCT Chest, of which 312 with ILD. Those with serial pulmonary function tests were included in a longitudinal analysis (n = 184). Linear mixed effect models were fitted to assess the decline in ppFVC over time, and to explore the effect of demographics and baseline characteristics on ppFVC decline. RESULTS: The majority of SSc-ILD patients were female (76.3%) and 51.3% had diffuse cutaneous subset. The mean (s.d.) age was 53.6 (12.7) years, median disease duration since first non-RP symptoms was 2.6 years, and 48.4% of the patients had ILD extent >20% on HRCT. In the univariate analysis, longer disease duration (>2.37 years), ILD extent >20%, and anti-topoisomerase I (ATA) positivity were significantly associated with ppFVC decline. In the multivariate analysis, the only statistically significant variable associated with ppFVC decline was ATA positivity. The overall group's mean decline in ppFVC was -0.28% (P-value 0.029), with -0.13% (n = 163) in those who were alive and -8.28% (P-value 0.0002 for the change in ppFVC trajectory) in patients who died within 2 years. CONCLUSION: Our study confirms that ppFVC is a marker of survival in SSc-ILD, supporting its use for risk stratification to identify patients who may benefit from earlier interventions and treatment. Our study also supports the role of ATA positivity as a predictive marker for ppFVC decline in this population.

Systemic sclerosis associated interstitial lung disease: a conceptual framework for subclinical, clinical and progressive disease.

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.

Hospitalisations related to systemic sclerosis and the impact of interstitial lung disease. Analysis of patients hospitalised at the University of Michigan, USA.

OBJECTIVES: To determine the primary reason for hospitalisations in systemic sclerosis (SSc) and impact of underlying interstitial lung disease (ILD) in a tertiary scleroderma centre. METHODS: A retrospective analysis on a subset of a scleroderma cohort from 2011-2019 was performed to assess causes for hospitalisations and mortality. A chart review was performed to extract demographics, primary reason for hospitalisation and inpatient mortality. Admissions were classified as SSc (if hospitalisation reason was related to primary organ dysfunction) and non-SSc related causes. RESULTS: The mean age of the cohort was 53.1 years, 78% were women, and the mean disease duration was 5.2 years. Among 484 patients, 182 (37.6%) were admitted for a total of 634 admissions. In 382 SSc-related admissions, pulmonary hypertension (12.0%) and gastrointestinal dysmotility (11.0%), were major causes of urgent admissions; management of digital vasculopathy (26.1%) was the major reason for elective admissions. In 252 non-SSc related admissions, infection (respiratory:11.5%, skin and soft tissue: 6.3%) was the major reason for urgent admissions, and elective surgery (21.4%) was the major reason for elective admissions. We found 65% of all patients had underlying ILD and a greater proportion of patients with ILD were hospitalised (122 patients). Overall inpatient mortality was 9.3% and the leading cause for mortality was progressive pulmonary hypertension. CONCLUSIONS: Among a large cohort of SSc patients who are followed at a tertiary scleroderma centre, 37.6 % had hospital admissions, while worsening pulmonary hypertension, ILD, cardiac involvement and infectious complications were the major cause of mortality and morbidity.

Performance of Anti-Topoisomerase I Antibody Testing by Multiple-Bead, Enzyme-Linked Immunosorbent Assay and Immunodiffusion in a University Setting.

BACKGROUND/OBJECTIVE: The criterion standard for anti-topoisomerase I antibody (anti-topo I antibody) testing in systemic sclerosis (SSc) uses immunodiffusion (ID) techniques, but enzyme-linked immunosorbent assay (ELISA) and multiple-bead technology are often used in current settings to save time and cost. Our aim was to assess the performance of the multiple-bead assay, ELISA, and ID testing methods. METHODS: We conducted a retrospective study of patients at the University of Michigan whose extractable nuclear antigen 10 autoantibody panel tested positive for the anti-topo I antibody by multiple-bead technology during a 1-year period. All samples positive by multiple-bead assay were sent to the RDL Laboratories and reflexed for ELISA, and all anti-topo I antibodies positive by ELISA were further tested by ID. Clinical data were reviewed by a rheumatologist and assessed for presence of SSc. Data were analyzed via frequency tables. RESULTS: Approximately 9500 extractable nuclear antigen 10 panels were ordered by physicians at the University of Michigan. Of these, 129 patients were positive for the anti-topo I antibody by multiple-bead assay, 51 were positive by multiple-bead assay and ELISA, and 21 were positive by multiple-bead assay, ELISA, and ID. We found that 26.4% of patients positive by multiple-bead assay, 47.1% positive by multiple-bead assay and ELISA, and 95.2% positive by multiple-bead assay, ELISA, and ID had SSc. CONCLUSIONS: Multiple-bead assays have a high rate of false-positive results for the anti-topo I antibody in patients without clinical evidence of SSc. A stepwise approach of confirmation of positive multiple-bead assay results using both ELISA and ID improves the predictive value of antibody testing for the diagnosis of SSc.

Management of scleroderma renal crisis.

PURPOSE OF REVIEW: Scleroderma renal crisis (SRC) is a life-threatening manifestation in systemic sclerosis (SSc) and is usually presented by an acute onset of severe hypertension together with an acute kidney injury. We can conceptualize SRC as a systemic syndrome with features that extend beyond the involvement of the kidney. The goal of this review is to inform clinicians about the risk factors for SRC in patients with SSc and to emphasize the importance of early identification and initiation of treatment. RECENT FINDINGS: For the past 3 decades, the use of angiotensin-converting enzyme inhibitors (ACE-I) to treat SRC, has been rightfully synonymized with a good outcome, and has changed the trajectory of mortality in SRC. Despite this, SRC still figures in one of the top four causes of mortality in patients with SSc. There is a need for additional therapeutic agents to treat SRC that is refractory to ACE-I. There has been a recent interest in combining ACE-I with endothelin receptor blockers and agents targeting the complement component 5. There is no role for using ACE-I prophylactically in high-risk patients. SUMMARY: Early diagnosis of SRC is the key, and early initiation of ACE-I is life-saving and associated with a better prognosis. We should consider renal transplantation in selected patients, especially those on long-term dialysis.

Reliability, construct validity and responsiveness to change of the PROMIS-29 in systemic sclerosis-associated interstitial lung disease.

OBJECTIVES: PROMIS-29 is a generic health-related quality of life instrument. Our objective was to assess the reliability, construct validity, and responsiveness to change of PROMIS-29 in systemic sclerosis-associated interstitial lung disease (SSc-ILD). METHODS: Seventy-three participants with SSc-ILD were administered patient reported outcomes (PROs) at baseline and follow-up visits which included PROMIS-29 and other measures of generic health, dyspnea, and cough instruments. We assessed internal consistency reliability using Cronbach's α, an alpha of ≥ 0.70 was considered satisfactory. We assessed the responsiveness to change using linear regression models. RESULTS: Mean age of the participants was 51.9 years and the mean disease duration was 7.9 years after first non-Raynaud's symptom. Of the 73 participants, 56.2% were classified as diffuse SSc and 26% limited SSc. The baseline (mean ± SD) FVC % predicted was 73.9±15.5 with a DLCO % predicted of 57.7±21.1; 95.9% had fibrotic NSIP pattern on HRCT. PROMIS-29 scores were 0.2 to 0.9 SD below the US population. Cronbach's α reliability was acceptable for all domains (ranged from 0.77 to 0.98). All scales showed statistically significant correlations with hypothesised PROMIS-29 domains (p≤0.05 for all comparisons). PROMIS-29 showed none-to-small discriminatory ability in comparison with physiologic measures (FVC and DLCO). There was no significant relationship between the change in FVC versus the change in PROMIS-29 measures over time. CONCLUSIONS: PROMIS-29 has adequate reliability and construct validity for evaluation in SSc-ILD. It has moderate-to-large correlations with other PROs. The PROMIS-29 domains were not found to change over time in this cohort, likely due to stable nature of the observational cohort.

Establishing clinical severity for PROMIS® measures in adult patients with rheumatic diseases.

PURPOSE: Different patient-reported outcome (PRO) measures are used for rheumatic diseases (RD). The aims of this study are-(1) Identify PROMIS® domains most relevant to care of patients with RD, (2) Collect T-Score metrics in patients with RD, and (3) Identify clinically meaningful cut-points for these domains. METHODS: A convenience sample of RD patients was recruited consecutively during clinic visits, and asked to complete computer-adaptive tests on thirteen Patient-Reported Outcomes Measurement Information System (PROMIS®) instruments. Based on discussion with clinical providers, four measures were chosen to be relevant and actionable (from rheumatologists' perspective) in RD patients. Data from RD patients were used to develop clinical vignettes across a range of symptom severity. Vignettes were created based on most likely item responses at different levels on the T-score metric (mean = 50; SD = 10) and anchored at 5-point intervals (0.5 SDs). Patients with RD (N = 9) and clinical providers (N = 10) participated as expert panelists in separate one-day meetings using a modified educational standard setting method. RESULTS: Four domains (physical function, pain interferences, sleep disturbance, depression) that are actionable at the point-of-care were selected. For all domains, patients endorsed cut-points at lower levels of impairment than providers by 0.5 to 1 SD (e.g., severe impairment in physical function was defined as a T-score of 35 by patients and 25 by providers). CONCLUSIONS: We used a modified educational method to estimate clinically relevant cut-points to classify severity for PROMIS measures This allows for meaningful interpretation of PROMIS® measures in a clinical setting of RD population.

Old medications and new targeted therapies in systemic sclerosis.

SSc is a multiorgan disease with significant morbidity that is associated with poor health-related quality of life. Treatment of this condition is often organ based and non-curative. However, there are newer, potentially disease-modifying therapies available to treat certain aspects of the disease. This review focuses on old and new therapies in the management of SSc in clinical practice.

Measuring response in the gastrointestinal tract in systemic sclerosis.

PURPOSE OF REVIEW: Gastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication. This review discusses the outcome measures to capture GIT involvement in clinical care and trials. RECENT FINDINGS: Patient-reported outcome measures have been validated (UCLA Scleroderma Clinical Trial Consortium GIT 2.0 and NIH PROMIS scales) in SSc-GIT. Multiple objective measures are available to assess mucosal involvement and motility in GIT. However, these need to be validated in SSc for trials. SUMMARY: GIT is a common cause of morbidity and has negative impact on quality of life in SSc. Recommendations are given for trial design and evaluation of GIT involvement in SSc.

Diagnosis and Management of Patients with Connective Tissue Disease-related Fibrosing Interstitial Lung Diseases.

Background: Fibrotic interstitial lung disease is an important driver of morbidity and mortality in patients with connective tissue diseases (CTD). Due to the lack of prospective randomized trial data in this population, practice pattern variation exists in the management of patients with CTD. Case Presentation: This case series describes three patients, each with a different background of autoimmunity complicated by fibrotic interstitial lung disease (ILD). We review their initial presentations, follow their disease trajectories on currently available treatments, and reference forthcoming clinical trials. Conclusion: Clinical impact or potential implications. Response to immunosuppression and antifibrotic therapy is variable in patients with connective tissue disease-related fibrosing interstitial lung disease. Data from prospective clinical trials and longitudinal registry studies will conceivably provide additional insight into improving care for these patients.

A 64-Year-Old Man with Joint Pain.

A 64-Year-Old Man with Joint PainA 64-year-old man presented for evaluation of acute oligoarticular joint pain. How do you approach the evaluation, and what is the diagnosis?

Recent innovations in the screening and diagnosis of systemic sclerosis-associated interstitial lung disease.

INTRODUCTION: Interstitial lung disease (ILD) is the leading cause of mortality in patients with systemic sclerosis (SSc). Risk of developing progressive ILD is highest among patients with diffuse cutaneous disease, positive anti-topoisomerase I antibody, and elevated acute phase reactants. With the FDA approval of two medications and a pipeline of novel therapeutics in trials, early recognition and intervention is critical. High-resolution computed tomography of the chest is the current gold standard test for diagnosis of ILD. Yet, it is not offered as a screening tool to all patients due to which ILD can be missed in up to a third of patients. There is a need to develop and validate more innovative screening modalities. AREAS COVERED: In this review, we provide an overview of screening and diagnosis of SSc-ILD, highlighting the recent innovations particularly the role of soluble serologic, radiomic (quantitative lung imaging, lung ultrasound), and breathomic (exhaled breath analysis) biomarkers in the early detection of SSc-ILD. EXPERT OPINION: There is remarkable progress in the development of new radiomics and serum biomarkers in diagnosing SSc-ILD. There is an urgent need for conceptualizing and testing composite ILD screening strategies that incorporate these biomarkers.

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.

Predictors and Interrelationship of Patient-Reported Outcomes in Antiphospholipid Syndrome: A Cross-Sectional Study.

OBJECTIVE: This study assessed patient-reported outcomes (PROs) in individuals with persistently positive antiphospholipid antibodies (aPL) to better understand how living with aPL may affect their quality of life. METHODS: Patients completed Patient-Reported Outcomes Measurement Information System Physical Function (PF) and Cognitive Function (CF) Short Forms as well as the pain intensity (PI) rating (scale of 1-10). Patients were characterized for demographics, clinical manifestations of antiphospholipid syndrome (APS), cardiovascular risk factors, laboratory test results, and medication usage. Multivariate modeling was done via linear regression. RESULTS: Of 139 patients, 89 had primary APS, 21 had secondary APS, and 29 had persistent aPL without meeting clinical criteria for APS. The average T scores (±SD) for PF and CF were 45.4 ± 9.2 and 48.6 ± 11.6, respectively; the average for PI was 3.0 ± 2.6. Approximately half of the patients (47%) endorsed at least mild impairment in PF (T score < 45). Mean PF, CF, and PI did not differ between diagnostic groups. Individuals who endorsed more impairment on one measure also tended to endorse more impairment on another (Pearson r = 0.43-0.59). In the multivariate models, age, smoking, pain medications, and serotonergic medications were associated with impairment in at least one PRO domain. The Damage Index for APS was significantly correlated with both PF and CF. CONCLUSION: Individuals living with APS endorsed more impairment in PF (and potentially CF) than expected for the general population. The relationship between certain medications and PROs warrants further study, as does the longitudinal trajectory of these and other PROs.

Tofacitinib blocks IFN-regulated biomarker genes in skin fibroblasts and keratinocytes in a systemic sclerosis trial.

BACKGROUNDSystemic sclerosis (SSc) is an autoimmune, connective tissue disease characterized by vasculopathy and fibrosis of the skin and internal organs.METHODSWe randomized 15 participants with early diffuse cutaneous SSc to tofacitinib 5 mg twice a day or matching placebo in a phase I/II double-blind, placebo-controlled trial. The primary outcome measure was safety and tolerability at or before week 24. To understand the changes in gene expression associated with tofacitinib treatment in each skin cell population, we compared single-cell gene expression in punch skin biopsies obtained at baseline and 6 weeks following the initiation of treatment.RESULTSTofacitinib was well tolerated; no participants experienced grade 3 or higher adverse events before or at week 24. Trends in efficacy outcome measures favored tofacitnib. Baseline gene expression in fibroblast and keratinocyte subpopulations indicated IFN-activated gene expression. Tofacitinib inhibited IFN-regulated gene expression in SFRP2/DPP4 fibroblasts (progenitors of myofibroblasts) and in MYOC/CCL19, representing adventitial fibroblasts (P < 0.05), as well as in the basal and keratinized layers of the epidermis. Gene expression in macrophages and DCs indicated inhibition of STAT3 by tofacitinib (P < 0.05). No clinically meaningful inhibition of T cells and endothelial cells in the skin tissue was observed.CONCLUSIONThese results indicate that mesenchymal and epithelial cells of a target organ in SSc, not the infiltrating lymphocytes, may be the primary focus for therapeutic effects of a Janus kinase inhibitor.TRIAL REGISTRATIONClinicalTrials.gov NCT03274076.FUNDINGPfizer, NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) R01 AR070470, NIH/NIAMS K24 AR063120, Taubman Medical Research Institute and NIH P30 AR075043, and NIH/NIAMS K01 AR072129.

Performance of the DETECT Algorithm for Pulmonary Hypertension Screening in a Systemic Sclerosis Cohort.

OBJECTIVE: Pulmonary arterial hypertension (PAH) is one of the leading causes of mortality in systemic sclerosis (SSc). This study was undertaken to assess predictive accuracies of the DETECT algorithm and the 2015 European Society of Cardiology/European Respiratory Society (ESC/ERS) guidelines in SSc patients who underwent right-sided heart catheterization (RHC) for pulmonary hypertension (PH) evaluation. METHODS: Patients with SSc who had diagnostic RHC, had no PH or had PAH, and had available data on variables to allow application of the DETECT and 2015 ESC/ERS guidelines were included for analysis. PH classification was based on hemodynamics using the 2018 revised criteria and extent of lung fibrosis shown on high-resolution computed tomography. Sensitivity and predictive accuracies of the DETECT algorithm and 2015 ESC/ERS guidelines were calculated, including analysis of subjects with a diffusing capacity for carbon monoxide (DLco) of ≥60% predicted. RESULTS: Sixty-eight patients with SSc had RHC, of whom 58 had no PH and 10 had PAH. The mean age was 60.0 years, and 58.8% had limited cutaneous SSc. The DETECT algorithm had a sensitivity of 1.00 (95% confidence interval [95% CI] 0.69-1.00) and a negative predictive value (NPV) of 1.00 (95% CI 0.80-1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.80 (95% CI 0.44-0.97) and an NPV of 0.94 (95% CI 0.81-0.99). In patients with a DLco of ≥60% (n = 27), the DETECT algorithm had a sensitivity of 1.00 (95% CI 0.29-1.00) and an NPV of 1.00 (95% CI 0.59-1.00), whereas the 2015 ESC/ERS guidelines had a sensitivity of 0.67 (95% CI 0.09-0.99) and an NPV of 0.94 (95% CI 0.71-1.00). CONCLUSION: The DETECT algorithm has high sensitivity and NPV for diagnosis of PAH, including among individuals with a DLco of ≥60%.

Clinical characteristics, visceral involvement, and mortality in at-risk or early diffuse systemic sclerosis: a longitudinal analysis of an observational prospective multicenter US cohort.

BACKGROUND: Early diffuse cutaneous systemic sclerosis (dcSSc) has the highest case fatality among rheumatic diseases. We report baseline characteristics, current immunosuppressive therapies, progression of skin and internal organ involvement, and mortality in a multicenter prospective cohort from the United States (US) of America. METHODS: We performed a longitudinal analysis of participants from 12 US centers, from April 2012 to July 2020. All participants had early dcSSc or were at-risk for dcSSc, with ≤2 years since the first non-Raynaud's phenomenon (RP) symptom. RESULTS: Three hundred one patients were included with a baseline median disease duration of 1.2 years since RP and a mean modified skin score of 21.1 units. At baseline, 263 (87.3%) had definite dcSSc and 38 (12.7%) were classified as at-risk; 112 (49.6%) patients were positive for anti-RNA polymerase III antibodies. The median follow-up duration was 24.5 months (IQR = 10.3-40.7 months). One hundred ninety (63.1%) participants were treated with an immunosuppressive therapy, of which mycophenolate mofetil was most used at baseline and follow-up. Of 38 who were classified as at-risk at baseline, 27 (71%) went on to develop dcSSc; these patients were characterized by higher baseline mean HAQ-DI (0.8 versus 0.4, p = 0.05) and higher baseline mRSS (8.8 versus 4.4, p < 0.01) in comparison with those who remained as limited cutaneous SSc. In the overall cohort, 48 participants (21.1%) had clinically significant worsening of skin fibrosis, mainly occurring in the first year of follow-up; 41 (23.3%) had an absolute forced vital capacity decline of ≥10%. Twenty participants (6.6%) died, of which 18 died in the first 3 years of follow-up. Cardiac involvement (33.3%), gastrointestinal dysmotility (22.2%), and progressive interstitial lung disease (ILD) (16.7%) were the main causes of death. CONCLUSION: This US cohort highlights the management of early SSc in the current era, demonstrating progression of skin and lung involvement despite immunosuppressive therapy and high mortality due to cardiac involvement.