RATIONALE:Common and rare variants that are associated with the risk of developing idiopathic pulmonary fibrosis (IPF) have been identified predominantly in European ancestry populations. OBJECTIVES:To better understand the genetic variants that contribute to IPF in individuals with Asian ancestry, we conducted a genome-wide association study of IPF in East Asian populations. METHODS:We included 1026 patients with IPF and compared them to 1723 unaffected controls of Japanese and Korean ancestry. Genome-wide association analysis was conducted in the Japanese and Korean ancestry cohorts separately and combined using meta-analysis. Restricted maximum likelihood was used to estimate the SNP-based heritability and local ancestry of chromosome 11 was inferred for each subject. MEASUREMENTS AND MAIN RESULTS:We identified loci on chromosomes 4 (FAM13A; rs7690839), 5 (TERT; rs7734992), 6 (DSP; rs2076295), and 11 (MUC5B; rs35705950) that were significantly associated with risk of IPF. Importantly, the sentinel variants in each of these loci are the same as, or in strong linkage disequilibrium with, the risk variants that have been observed in studies of European ancestry populations. In aggregate, common variants (not including the MUC5B promoter variant) account for approximately 25% of the risk of developing IPF in these East Asian ancestry cohorts. Moreover, local ancestry analysis indicates that the presence of MUC5B promoter variant in the East Asian population is not a result of admixture with European ancestry populations. CONCLUSIONS:We conclude that the IPF risk loci in East Asian populations are shared with those of European ancestry populations, although their risk allele frequencies and effect sizes differ. These findings indicate shared genetic risk factors of IPF across ancestries.

RATIONALE:Sarcoidosis disproportionately affects U.S. military Veterans. Its rising incidence and prevalence among Veterans are higher than in civilians and vary by branch of service, suggesting a role for prior military exposures. OBJECTIVES:To investigate whether estimated service-related exposure to inorganic dust is associated with increased risk of sarcoidosis. METHODS:In a retrospective nested case-control study of Veterans enrolled in the Veterans Health Administration (VHA) who received VHA- or Medicare-covered care, sarcoidosis cases identified in electronic health records between 2002 and 2022 were each matched to five controls by propensity scores and incidence density sampling by calendar year. To estimate inorganic dust exposure, military occupational codes (MOCs) were linked to a job exposure matrix (JEM). Multivariable conditional logistic regression analyses were adjusted for demographics, geography, rurality, and service branch. The attributable fraction among the exposed was calculated. In secondary analyses, latency from service separation to diagnosis was assessed. In sensitivity analyses, exposure misclassification was assessed by using a modified JEM weighted for MOC coding precision and by examining only post-9/11 Veterans; service duration was also analyzed. RESULTS:Among >16 million individuals evaluated, 3,019,636 Veterans had at least one MOC; 5,855 incident cases and 29,275 controls were analyzed. Inorganic dust exposure was associated with increased risk of sarcoidosis (conditional odds ratio [cOR]: 1.08; 95% confidence interval [CI], 1.003-1.170); the attributable fraction was 7.6%. Associations were stronger with a modified JEM score (cOR: 1.15; 95% CI 1.05-1.27) and when restricted to post-9/11 Veterans (cOR: 1.25; 95% CI 1.07-1.47). In latency analysis, sarcoidosis risk peaked 2-5 years post-service (cOR: 2.10; 95% CI: 1.20-3.58). CONCLUSION:Occupational and environmental exposure to inorganic dust during military service was associated with increased risk of sarcoidosis among Veterans, carrying potential implications for prevention and surveillance.

Objective A leading cause of death among patients with scleroderma (SSc), interstitial lung disease (ILD) remains challenging to prognosticate. The discovery of biomarkers that accurately determine which patients would benefit from close monitoring and aggressive therapy would be an essential clinical tool. We aimed to identify gene signatures that would predict progressive ILD.Methods We compared previously identified serum biomarkers, bulk peripheral blood mononuclear cell (PBMC) RNA gene expression (39 patients with progressive SSc-ILD and 43 patients with stable SSc-ILD), and single-cell RNA gene expression of PBMC (13 patients with progressive SSc-ILD, 14 patients with stable SSc-ILD, and 6 control participants).Results In previous studies, male sex, Krebs von den Lungen 6 levels, and C-reactive protein levels were predictors of progressive disease in patients. Monocyte expression of lipoxygenase homology domains 1 (LOXHD1) and Ras homolog gene family, member B (RHOB) strongly predicted progression, suggesting a key role in immune dysregulation. LOXHD1 and related genes were enriched in inflammatory gene networks, which may support monocyte-associated inflammation in patients. RHOB was consistently up-regulated in both CD14+ and CD16+ monocytes across single-cell and bulk RNA data, underscoring robust association with progressive disease. In contrast, ataxin-2-like (ATXN2L) protein was down-regulated in patients with progressive disease, suggesting dysregulation of cellular stress responses. Additionally, S100 calcium-binding protein A12 (S100A12), chitinase-3-like protein 1 (CHI3L1), and matrix metalloproteinase-9 (MMP9), previously linked to tissue remodeling, were again associated with progression in bulk RNA sequencing and previous microarray studies, reinforcing their role in fibrosis.Conclusion With several potential biomarkers of progressive disease in patients, the next step includes validation in larger, multicenter cohorts for use in clinical decision-making.

Background The role of epigenetic aging in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter ≤2.5 μm (PM 2.5 ) and neighbourhood disadvantage exposures are associated with accelerated epigenetic aging, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD. Methods This multicentre, international, cohort study included patients with fILD from the University of Pittsburgh (UPitt, n=306) and University of British Columbia (UBC, n=170). Five-year PM 2.5 exposures were estimated using satellite-derived models. Neighbourhood disadvantage was calculated using U.S. and Canadian Census-based metrics. Epigenetic age difference (EAD=epigenetic age – chronological age) was calculated using GrimAge analysis of blood DNA methylation data. Linear models assessed associations of exposures with EAD. Cox models assessed associations of EAD with transplant-free survival. Causal mediation analysis evaluated EAD mediation of exposure-survival relationships. Results Median epigenetic age was 11.7 years older than chronological age in patients with fILD. In combined cohort analysis, each interquartile range (IQR) PM 2.5 increase was associated with 2.88 years (95%CI 1.39–4.38, p<0.001) increased EAD. In UPitt, each IQR neighbourhood disadvantage increase was associated with 1.16 years (95%CI 0.22–2.09, p=0.02) increased EAD. Increased EAD was associated with worse transplant-free survival (HR=1.17 per 1-year increase EAD, 95%CI 1.10–1.24, p<0.001), with EAD mediating 40% of PM 2.5 -survival relationship and 59% of neighbourhood disadvantage-survival relationships. Epigenetic age was also more strongly associated with transplant-free survival than chronological age. Conclusions Epigenetic age acceleration is associated with worse survival and mediates adverse exposure impacts in fILD.

RATIONALE: Systemic sclerosis (SSc) is an autoimmune disease characterized by endothelial dysfunction, immune system activation, and fibrosis, which can affect internal organs. SSc is clinically classified according to degree of skin fibrosis (limited vs diffuse). SSc-associated interstitial lung disease (SSc-ILD) affects 35-52% of patients, generally presenting with a non-specific interstitial pneumonia pattern (80%). Matrix metalloproteinase-7 (MMP-7) is increased in serum levels in patients with SSc and is associated with decreased lung function and increased risk of death or lung transplantation in patients with SSc-ILD. The goal of this project is to define the associations of MMP-7 with clinical outcomes in SSc in different disease stages. METHODS: Peripheral blood MMP-7 levels were obtained from biobanked plasma samples and were log-transformed for normalization. Cox proportional hazard models analyzed the association of MMP-7 with mortality. Linear models analyzed the association of MMP-7 with baseline percent predicted lung function (forced vital capacity, FVC; diffusion capacity for carbon monoxide, DLCO). Analyses were performed in all patients with SSc and in a subgroup of patients based on stage of SSc (early <3, intermediate 3-5, late 5-10, very late >10 years) at sample date. All models were adjusted for age at sample date, sex, race, smoking history, Area Deprivation Index, and diffuse versus limited scleroderma. Mortality models were additionally adjusted for baseline lung function (FVC, DLCO). RESULTS: Clinical data and biologic samples were prospectively collected from 341 patients with SSc enrolled between 2000-2023 in the Simmons Center for Interstitial Lung Disease Registry and Scleroderma Registry from 1980-2023 at the University of Pittsburgh. Analyses of MMP-7 with baseline lung function in SSc were consistent with prior work, demonstrating that each unit increase in log(MMP-7) was associated with a 16.01-unit decrease in baseline FVC percent and a 16.14-unit decrease in baseline DLCO percent. Table 1 demonstrates that MMP-7 has significant associations with worse lung function (FVC, DLCO) in patients with late and very late SSc disease stages. CONCLUSION: MMP-7 is significantly associated worse baseline lung function in patients with longer duration of disease, suggesting that the impact of MMP-7 in SSc is related to disease duration. Future directions involve further differentiating MMP-7 associations with SSc disease phenotypes, including limited versus diffuse, and evaluating for any modifying effects of associated antibodies. The relationship of disease duration with MMP-7 reveals new potential pathways for seeking targeted therapies at different disease stages in patients with SSc.

Rationale: Sarcoidosis is a multisystem disease with pulmonary manifestations in >90% of patients. Environmental exposures are associated with sarcoidosis incidence, but the impact on clinical outcomes remains understudied. Objectives: To evaluate the association of exposures to ambient particulate matter [Formula: see text]2.5 μm in diameter (PM2.5) with lung function outcomes in pulmonary sarcoidosis. Methods: PM2.5 and constituent exposures were obtained by matching monthly satellite-derived hybrid measurements to each patient's residential address obtained from the time of enrollment, averaged over 5 years before registry enrollment and censoring. Linear models evaluated associations of pollutants with baseline lung function (FEV1, FVC, FEV1/FVC ratio, and DlCO). Linear mixed effects models analyzed associations of pollutants with rates of lung function change (FEV1, FVC, and DlCO change per year of follow-up). Measurements and Main Results: Two prospectively enrolled cohorts of mostly middle-aged, White, and nonsmoking adults with specialist-diagnosed pulmonary sarcoidosis were used. The U.S. cohort (n = 400) experienced higher 5-year preenrollment median PM2.5 exposures (12.3 μg/m3) than the Canadian cohort (n = 112) (8.0 μg/m3). Each 1-μg/m3 increase in PM2.5 was associated with 0.93% predicted lower baseline FEV1 (95% confidence interval, -1.76 to -0.10; P = 0.03) and 1.53% predicted lower FVC (95% confidence interval, -2.26 to -0.79; P < 0.001) in the U.S. cohort, but the associations were not significant in the Canadian cohort. PM2.5, sulfate, nitrate, and ammonium were associated with accelerated FEV1, FVC, and DlCO decline in the U.S. cohort. Conclusions: PM2.5 was associated with worse pulmonary disease severity and progression in a higher-exposure cohort, highlighting the importance of exposure disparities in this population.

Rationale: Particulate matter ⩽2.5 μm (PM2.5) adversely impacts patients with fibrotic interstitial lung disease (fILD). Objectives: We sought to determine whether PM2.5-associated epigenetic alterations contribute to the environmental pathogenesis of fILD. Methods: A retrospective two-cohort study applied satellite-derived PM2.5 and constituent exposure matching to the residential location of patients with fILD. Robust linear regressions were used to evaluate cohort-specific, epigenome-wide differential blood DNA methylation with increasing pollutant exposures (Illumina MethylationEPIC BeadChip). Cox and linear regressions were used to evaluate associations of cytosine-phosphate-guanine (CpG) loci with transplant-free survival and lung function. A Wilcoxon test was used to evaluate cartilage-associated protein (CRTAP) levels in fILD and control lungs. Measurements and Main Results: The University of Pittsburgh cohort (n = 306) had 5-year median PM2.5 exposures of 12.1 μg/m3 compared with 5.1 μg/m3 in the University of British Columbia cohort (n = 170). Higher pollutant exposures in the University of Pittsburgh cohort were associated with lower methylation at cg25354716, annotated to CRTAP, a critical extracellular matrix remodeling enzyme. Higher exposures in the University of British Columbia cohort were associated with higher methylation at cg01019301, annotated to TLN2 (talin-2), a cytoskeletal protein involved in fibroblast migration. A 10% increase in cg25354716 methylation was associated with a hazard ratio of 0.81 for death or lung transplantation in the meta-analyzed cohorts (95% confidence interval = 0.69-0.96; P = 0.01), whereas the same change in cg01019301 was associated with a hazard ratio of 1.36 (95% confidence interval = 1.07-1.74; P = 0.01). CRTAP protein was more abundant in lungs from patients with fILD compared with those from donor controls (P < 0.001). Conclusions: PM2.5 is associated with altered blood DNA methylation in fILD. This work identifies novel pollution-sensitive targets that hold potential for therapeutic modulation in fILD.

Background: Idiopathic Pulmonary Fibrosis (IPF) is a progressive lung disease with limited treatment options. Current therapies, such as pirfenidone and nintedanib, slow disease progression but have limitations, creating a high unmet need for safer and more effective options. Bersiporocin (DWN12088), an oral Prolyl-tRNA Synthetase (PRS) inhibitor, has shown promise in preclinical and Phase 1 studies for safety, tolerability, and pharmacokinetics. It has received Orphan Drug Designation from both the FDA and EMA and Fast Track designation from the FDA and is now being evaluated in Phase 2 trials for IPF. Methods: This ongoing Phase 2, randomized, double-blind, placebo-controlled trial (NCT05389215) is being conducted in the US and South Korea to evaluate the efficacy and safety of DWN12088 in IPF patients with or without background antifibrotic therapy. Participants are randomized in a 2:1 ratio to receive either DWN12088 150 mg BID or placebo for 24 weeks. Stratification is based on background therapy (SOC with pirfenidone/nintedanib or no treatment), and baseline characteristics are analyzed to understand patient demographics. Results (Preliminary): Preliminary analysis indicates that approximately 70% of participants are receiving standard antifibrotic therapy, with the remaining 30% not on background therapy. This study features a diverse population, with approximately 50% of participants identified as Asian and the remaining predominantly White. Among the 71 patients enrolled to date, the mean age is 70.6 years, with a majority male population. The average time since IPF diagnosis is 2.6 years. Baseline pulmonary function assessments show an average predicted FVC of 77.6% and an average predicted DLCO of 51.4%, suggesting that the study population includes a range of lung function impairments, from mild to severe. This provides an initial view of the demographic and functional characteristics of the study population. These characteristics will be further refined as additional participants are enrolled, ensuring a robust dataset for assessing treatment responses across diverse demographic groups. Conclusion: The preliminary demographic analysis of the Phase 2 trial for Bersiporocin provides foundational data on the baseline characteristics of IPF patients, with a unique representation of approximately 50% Asian and predominantly White participants. This diversity offers an opportunity to explore treatment responses across different demographic profiles, contributing to a broader understanding of Bersiporocin's therapeutic potential. Further evaluations will assess the clinical implications of baseline characteristics, with potential insights for optimizing treatment strategies for IPF in diverse patient populations.

Rationale: In the United States, ambulatory oxygen is recommended for patients with idiopathic pulmonary fibrosis (IPF) and chronic obstructive pulmonary disease (COPD) who experience symptomatic exertional hypoxemia. Ambulatory oxygen need is often determined by submaximal hall walk testing; however, this may fail to accurately characterize exertional hypoxemia in some patients. Objectives: Assess for differences in ambulatory oxygen needs between patients with IPF and COPD who completed a ramped treadmill protocol exercise test (RTPET) and correlate oxygen flow rates determined at highest-level (HL) exertion with lung function and exercise parameters. Oxygen need is defined as the flow rate needed to maintain oxygen saturation ⩾90% in patients who desaturate to ⩽88%. Methods: We conducted a retrospective review of RTPET results for patients with IPF and COPD who also recently completed spirometry. The RTPET has three phases: rest, submaximal usual pace (UP) walking at 0% treadmill grade for 3 minutes, and HL walking at the UP walk speed with increasing treadmill grade by 2% every 2 minutes. Patients with IPF were part of a clinical registry, whereas patients with COPD were identified based on diagnosis coding and spirometry (forced expiratory volume in 1 s/forced vital capacity < 0.70). The RTPET for both groups was completed based on a pulmonologist's referral. Results: We included 329 patients with IPF and 2,343 patients with COPD. A greater proportion of patients with IPF required ambulatory oxygen to maintain saturation ⩾90% at HL exertion. After adjusting for demographic covariates and exercise parameters, patients with IPF required higher ambulatory oxygen flow rates than subjects with COPD with similar diffusion capacity of carbon monoxide values. Of patients who did not require oxygen with submaximal UP testing, 49% with IPF and 24% with COPD required oxygen at HL exertion. Conclusions: The RTPET identified higher oxygen flow needs at HL exertion in patients with IPF versus patients with COPD; however, in both diseases, there was a significant proportion of patients who were only found to have exertional desaturation at HL exertion. Reliance on submaximal testing may fail to meet the needs of patients with IPF and COPD. Further studies are needed to determine if oxygen prescriptions targeting the highest level of desaturation improve clinical outcomes, symptoms, or quality of life.

BACKGROUND:Sarcoidosis is an idiopathic multiorgan disease with variable clinical outcomes. Comprehensive analysis of sarcoidosis mortality in US veterans is lacking. RESEARCH QUESTION:What are the trends in all-cause mortality among US veterans with sarcoidosis, and how are these trends influenced by demographics, Black vs White racial disparities, and geographic variability in relationship to mortality? STUDY DESIGN AND METHODS:Using Veterans Health Administration (VHA) electronic health records (EHRs), we conducted a population-based retrospective cohort study of adjusted all-cause mortality from 2004 through 2022 among veterans with a diagnosis of sarcoidosis who received care through the VHA. Demographics, region of residence, service branch, tobacco use, and comorbidities were extracted from the EHR. Annual trends in all-cause mortality and patient-level characteristics associated with mortality were examined with multivariable ungrouped Poisson regression. We visualized trends and analyzed state-by-state mortality using the marginal means procedure. In subgroup analysis (2015-2022), we considered the impact of neighborhood-level socioeconomic disparities using the Area Deprivation Index (ADI). RESULTS:In all, 23,745 veterans received a diagnosis of sarcoidosis between 2004 and 2019 and were followed up through 2022. After adjustment, including age and sex, all-cause mortality increased annually by 4.7% (P < .0001) and was 6.4% higher in Black than White veterans (mortality rate ratio, 1.064; P = .02). A subgroup analysis comparing models with and without ADI adjustment showed no meaningful change in mortality trends. Risk factors for increased all-cause mortality included older age, male sex, Black race, Northeast residence, and lower risk with other service branches. Despite distinct geographical variations in mortality rates, no clear patterns emerged. INTERPRETATION:Mortality among veterans with sarcoidosis is rising. Differences identified by service branch and higher risk among male Veterans raise questions about differences in environmental exposures. The narrower racial disparities and smaller impact of ADI than in other studies may highlight the role of universal health care access in achieving equitable outcomes.

Rationale: Particulate matter ≤2.5μm (PM2.5) is associated with adverse outcomes in fibrotic interstitial lung disease (fILD), but the impact of ultrafine particulates (UFPs; aerodynamic diameter ≤100nm) remains unknown. Objective: To evaluate UFP associations with clinical outcomes in fILD. Methods: Multicenter, prospective cohort study enrolling patients with fILD from the University of Pittsburgh Simmons Center and Pulmonary Fibrosis Foundation Patient Registry (PFF-PR). Using a national-scale UFP model, we linked exposures using three approaches in Simmons (residential address geocoordinates, zip centroid geocoordinates, zip average) and two in PFF-PR where only 5-digit zip code was available (zip centroid, zip average). We tested UFP associations with transplant-free survival using multivariable Cox, baseline percent predicted forced vital capacity (FVC) and diffusion capacity of the lung (DLCO) using multivariable linear regressions, and decline in FVC and DLCO using linear mixed models, adjusting for age, sex, smoking, race, socioeconomic status, site, PM2.5, and nitrogen dioxide. Results: Annual mean outdoor UFP levels for 2017 were estimated for 1416 Simmons and 1919 PFF-PR patients. Increased UFP level was associated with transplant-free survival in fully-adjusted Simmons residential address models (HR=1.08 per 1000 particles/cm3, 95%CI 1.01-1.15, p=0.02), but not PFF-PR models, which used less precise linkage approaches. Higher UFP was associated with lower baseline FVC and more rapid FVC decline in Simmons. Conclusions: Increased UFP exposure was associated with transplant-free survival and lung function in the cohort with precise residential location linkage. This work highlights the need for more robust regulatory networks to study the health effects of UFPs nationwide.

Rationale Recent data suggest that the localisation of airway epithelial cells in the distal lung in idiopathic pulmonary fibrosis (IPF) may drive pathology. We set out to discover whether chemokines expressed in these ectopic airway epithelial cells may contribute to the pathogenesis of IPF. Methods We analysed whole lung and single-cell transcriptomic data obtained from patients with IPF. In addition, we measured chemokine levels in blood, bronchoalveolar lavage (BAL) of IPF patients and air-liquid interface cultures. We employed ex vivo donor and IPF lung fibroblasts and an animal model of pulmonary fibrosis to test the effects of chemokine signalling on fibroblast function. Results By analysis of whole-lung transcriptomics, protein and BAL, we discovered that CXCL6 (a member of the interleukin-8 family) was increased in patients with IPF. Elevated CXCL6 levels in the BAL of two cohorts of patients with IPF were associated with poor survival (hazard ratio of death or progression 1.89, 95% CI 1.16-3.08; n=179, p=0.01). By immunostaining and single-cell RNA sequencing, CXCL6 was detected in secretory cells. Administration of mCXCL5 (LIX, murine CXCL6 homologue) to mice increased collagen synthesis with and without bleomycin. CXCL6 increased collagen I levels in donor and IPF fibroblasts 4.4-fold and 1.7-fold, respectively. Both silencing of and chemical inhibition of CXCR1/2 blocked the effects of CXCL6 on collagen, while overexpression of CXCR2 increased collagen I levels 4.5-fold in IPF fibroblasts. Conclusions CXCL6 is expressed in ectopic airway epithelial cells. Elevated levels of CXCL6 are associated with IPF mortality. CXCL6-driven collagen synthesis represents a functional consequence of ectopic localisation of airway epithelial cells in IPF.

BACKGROUND:Sarcoidosis staging primarily has relied on the Scadding chest radiographic system, although chest CT imaging is finding increased clinical use. RESEARCH QUESTION:Whether standardized chest CT scan assessment provides additional understanding of lung function beyond Scadding stage and demographics is unknown and the focus of this study. STUDY DESIGN AND METHODS:We used National Heart, Lung, and Blood Institute study Genomics Research in Alpha-1 Antitrypsin Deficiency and Sarcoidosis (GRADS) cases of sarcoidosis (n = 351) with Scadding stage and chest CT scans obtained in a standardized manner. One chest radiologist scored all CT scans with a visual scoring system, with a subset read by another chest radiologist. We compared demographic features, Scadding stage and CT scan findings, and the correlation between these measures. Associations between spirometry and diffusing capacity of the lungs for carbon monoxide (Dlco) results and CT scan findings and Scadding stage were determined using regression analysis (n = 318). Agreement between readers was evaluated using Cohen's κ value. RESULTS:CT scan features were inconsistent with Scadding stage in approximately 40% of cases. Most CT scan features assessed on visual scoring were associated negatively with lung function. Associations persisted for FEV1 and Dlco when adjusting for Scadding stage, although some CT scan feature associations with FVC became insignificant. Scadding stage was associated primarily with FEV1, and inclusion of CT scan features reduced significance in association between Scadding stage and lung function. Multivariable regression modeling to identify radiologic measures explaining lung function included Scadding stage for FEV1 and FEV1 to FVC ratio (P < .05) and marginally for Dlco (P < .15). Combinations of CT scan measures accounted for Scadding stage for FVC. Correlations among Scadding stage and CT scan features were noted. Agreement between readers was poor to moderate for presence or absence of CT scan features and poor for degree and location of abnormality. INTERPRETATION:In this study, CT scan features explained additional variability in lung function beyond Scadding stage, with some CT scan features obviating the associations between lung function and Scadding stage. Whether CT scan features, phenotypes, or endotypes could be useful for treating patients with sarcoidosis needs more study.

Chronic myelomonocytic leukemia (CMML) is an uncommon myeloid neoplasm with myeloproliferative and myelodysplastic features characterized by peripheral monocytosis and cytopenia.1 CMML may have cutaneous manifestations known as leukemia cutis (LC).2 LC in the setting of CMML may portend malignant transformation to acute myeloid leukemia (AML).2 The distribution and morphologic features of LC in CMML are highly variable and often nonspecific.2 CMML may coexist with numerous secondary autoimmune and inflammatory processes; this phenomenon presents a clinical challenge which can delay correct diagnosis and appropriate therapeutic management.