ObjectiveMetabolic reprogramming plays a critical role in modulating the innate and adaptive immune response, but its role in cutaneous autoimmune diseases, such as cutaneous lupus erythematosus (CLE), is less well studied. An improved understanding of the metabolic pathways dysregulated in CLE may lead to novel treatment options, biomarkers and insights into disease pathogenesis. The objective was to compare metabolomic profiles in the skin and sera of CLE and control patients using liquid chromatography–mass spectrometry (LC-MS).MethodsThis was a cross-sectional pilot study comparing metabolomic sera and skin profiles of patients with CLE and normal controls. Patients were recruited from outpatient dermatology clinics at the University of Texas Southwestern and Parkland Health in Dallas, Texas, from January 2019 to October 2020. Skin and serum samples underwent LC-MS analysis. Disease sample metabolite levels were compared with controls, with significance levels adjusted for multiple hypothesis testing.Results17 serum samples (9 CLE, 8 control) and 11 skin samples (5 CLE, 6 control) were analysed using LC-MS, yielding 313 known unique metabolic structures from CLE samples. Patients with CLE were found to have 11 metabolites of differential abundance in the skin, but only 2 in the sera. CLE skin showed increased levels of citrulline (log2fold change (FC)=1.15, p=0.02) and uracil (log2FC=1.79, p=0.04), and downregulation of cyclic ADP ribose (cADPr) (log2FC=0.83, p=0.04), nicotinamide mononucleotide (NMN) (log2FC=0.75, p=0.016) and nicotinamide adenine dinucleotide (NAD+) (log2FC=0.86, p=0.016) versus control skin. CLE sera had increased arabinose (log2FC=1.17, p=0.02) and cystine (log2FC=1.04, p=0.03) compared with control sera.ConclusionsMetabolites associated with the NAD+pathway may be dysregulated in the skin of patients with CLE. Available treatments including nicotinamide supplementation and anti-CD38 biologics that can correct these abnormalities can be further investigated in patients with CLE.

Pansclerotic morphea (PSM) is a rare, devastating disease characterized by extensive soft tissue fibrosis, secondary contractions, and significant morbidity. PSM pathogenesis is unknown, and aggressive immunosuppressive treatments rarely slow disease progression. We aimed to characterize molecular mechanisms driving PSM and to identify therapeutically targetable pathways by performing single-cell and spatial RNA-Seq on 7 healthy controls and on lesional and nonlesional skin biopsies of a patient with PSM 12 months apart. We then validated our findings using immunostaining and in vitro approaches. Fibrotic skin was characterized by prominent type II IFN response, accompanied by infiltrating myeloid cells, B cells, and T cells, which were the main IFN-γ source. We identified unique CXCL9+ fibroblasts enriched in PSM, characterized by increased chemokine expression, including CXCL9, CXCL10, and CCL2. CXCL9+ fibroblasts were related to profibrotic COL8A1+ myofibroblasts, which had enriched TGF-β response. In vitro, TGF-β and IFN-γ synergistically increased CXCL9 and CXCL10 expression, contributing to the perpetuation of IFN-γ responses. Furthermore, cell-to-cell interaction analyses revealed cDC2B DCs as a key communication hub between CXCL9+ fibroblasts and COL8A1+ myofibroblasts. These results define PSM as an inflammation-driven condition centered on type II IFN responses. This work identified key pathogenic circuits between T cells, cDC2Bs, and myofibroblasts, and it suggests that JAK1/2 inhibition is a potential therapeutic option in PSM.

Morphea is an inflammatory fibrotic disorder of the skin that has been likened to systemic sclerosis (SSc). We sought to examine the molecular landscape of morphea by examining lesional skin gene expression and blood biomarkers and comparing the gene expression profiles with those from site-matched nonlesional and SSc lesional skin. We found the morphea transcriptome is dominated by IFN-γ-mediated T helper 1 immune dysregulation, with a relative paucity of fibrosis pathways. Specifically, expression profiles of morphea skin clustered with the SSc inflammatory subset and were distinct from the those of SSc fibroproliferative subset. Unaffected morphea skin also differed from unaffected SSc skin because it did not exhibit pathological gene expression signatures. Examination of downstream IFN-γ-mediated chemokines, CXCL9 and CXCL10, revealed increased transcription in the skin but not in circulation. In contrast to transcriptional activity, CXCL9 was elevated in serum and was associated with active, widespread cutaneous involvement. Taken together, these results indicate that morphea is a skin-directed process characterized by T helper 1 immune-mediated dysregulation, which contrasts with fibrotic signatures and systemic transcriptional changes associated with SSc. The similarity between morphea and the inflammatory subset of SSc on transcriptional profiling indicates that therapies under development for this subset of SSc are also promising for treatment of morphea.

Cutaneous lupus erythematosus (CLE) is an autoimmune connective tissue disease that can exist as a disease entity or within the context of systemic lupus erythematosus (SLE). Over the years, efforts to elucidate the genetic underpinnings of CLE and SLE have yielded a wealth of information. This review examines prior studies investigating the genetics of CLE at the DNA and RNA level and identifies future research areas. In this literature review, we examined the English language literature captured within the MEDLINE and Embase databases using pre-defined search terms. First, we surveyed studies investigating various DNA studies of CLE. We identified three predominant areas of focus in HLA profiling, complement deficiencies, and genetic polymorphisms. An increased frequency of HLA-B8 has been strongly linked to CLE. In addition, multiple genes responsible for mediating innate immune response, cell growth, apoptosis, and interferon response confer a higher risk of developing CLE, specifically TREX1 and SAMHD1. There was a strong association between C2 complement deficiency and CLE. Second, we reviewed literature studying aberrations in the transcriptomes of patients with CLE. We reviewed genetic aberrations initiated by environmental insults, and we examined the interplay of dysregulated inflammatory, apoptotic, and fibrotic pathways in the context of the pathomechanism of CLE. These current learnings will serve as the foundation for further advances in integrating personalized medicine into the care of patients with CLE.

Cutaneous lupus erythematosus (CLE) is an autoimmune connective tissue disease that can exist as a disease entity or within the context of systemic lupus erythematosus (SLE). Over the years, efforts to elucidate the genetic underpinnings of CLE and SLE have yielded a wealth of information. This review examines prior studies investigating the genetics of CLE at the DNA and RNA level and identifies future research areas. In this literature review, we examined the English language literature captured within the MEDLINE and Embase databases using pre-defined search terms. First, we surveyed studies investigating various DNA studies of CLE. We identified three predominant areas of focus in HLA profiling, complement deficiencies, and genetic polymorphisms. An increased frequency of HLA-B8 has been strongly linked to CLE. In addition, multiple genes responsible for mediating innate immune response, cell growth, apoptosis, and interferon response confer a higher risk of developing CLE, specifically TREX1 and SAMHD1. There was a strong association between C2 complement deficiency and CLE. Second, we reviewed literature studying aberrations in the transcriptomes of patients with CLE. We reviewed genetic aberrations initiated by environmental insults, and we examined the interplay of dysregulated inflammatory, apoptotic, and fibrotic pathways in the context of the pathomechanism of CLE. These current learnings will serve as the foundation for further advances in integrating personalized medicine into the care of patients with CLE.

To the Editor: Serological biomarkers distinguishing cutaneous lupus erythematosus (CLE) from systemic lupus erythematosus (SLE) may help track CLE patients at risk of progression to SLE. Thus, we compared the CLE and SLE sera concentrations of C-X-C motif chemokine ligand (CXCL) 9 and CXCL10, 2 chemokines previously demonstrated to be upregulated in patients with CLE and SLE,1Wenzel J. Wörenkämper E. Freutel S. et al.Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus.J Pathol. 2005; 205: 435-442Crossref PubMed Scopus (172) Google Scholar,2Baechler E.C. Batliwalla F.M. Karypis G. et al.Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus.Proc Natl Acad Sci U S A. 2003; 100: 2610-2615Crossref PubMed Scopus (1604) Google Scholar and assessed their ability to discriminate between patient groups. Serum samples from patients with CLE only (CLE+/SLE−) (n = 48), both CLE and SLE (CLE+/SLE+) (n = 17), and SLE without CLE (CLE−/SLE+) (n = 26) as well as from controls (n = 29) were collected at the University of Texas Southwestern Medical Center and Parkland Memorial Hospital (Table I). Patients who fulfilled ≥4 American College of Rheumatology SLE criteria were classified as having SLE. Patients with CLE-isolated disease were diagnosed based on a skin biopsy and fulfilled <4 American College of Rheumatology SLE criteria. Seventeen SLE patients had a concomitant diagnosis of CLE. The exclusion criteria included concomitant autoimmune disease, chronic infection, or active malignancy. The serum levels of the chemokines were measured using enzyme-linked immunosorbent assays (R&D Systems) and compared using the Mann-Whitney or Kruskal-Wallis test. The ability of the chemokines to discriminate between CLE and SLE patients was measured using the area under the receiver operating characteristics curve.Table IPatient demographics and clinical characteristicsDemographics and clinical characteristicsCLE+/SLE− (n = 48)CLE+/SLE+ (n = 17)CLE−/SLE+ (n = 26)Controls (n = 29)Age, median (IQR)48 (39-58)41 (29.5-51)28 (25.6-34.4)44.1 (35.1-55.7)Sex, n (%) Female35 (73%)14 (82%)26 (100%)22 (76%) Male13 (27%)3 (18%)0 (0%)7 (24%)Race/ethnicity, n (%) African American30 (63%)14 (82%)7 (27%)18 (62%) Caucasian13 (27%)1 (6%)5 (19%)9 (31%) Hispanic4 (8%)2 (12%)12 (46%)1 (3%) Asian1 (2%)0 (0%)2 (8%)1 (3%)ACR SLE criteria, n (%)N/A Malar rash0 (0%)5 (29%)0 (0%) Discoid rash42 (88%)17 (100%)0 (0%) Photosensitivity32 (67%)15 (88%)9 (35%) Oral ulcers1 (2%)8 (47%)5 (19%) Arthritis0 (0%)11 (65%)10 (38%) Pleuritis/pericarditis0 (0%)3 (18%)5 (19%) Renal disorder0 (0%)9 (53%)26 (100%) Neurologic disorder0 (0%)0 (0%)2 (8%) Hematologic disorder11 (23%)7 (41%)10 (38%) Immunologic disorder2 (4%)14 (82%)21 (81%) Positive antinuclear antibody13 (27%)17 (100%)20 (77%)Predominant CLE subtype, n (%)†One CLE+/SLE+ patient had a diagnosis of DLE per chart review, but information regarding the DLE subtype was not available.N/AN/A Localized DLE29 (60%)3 (18%) Generalized DLE13 (27%)13 (71%) SCLE6 (13%)0 (0%)Medications, n (%)N/A None16 (33%)0 (0%)2 (8%) Topical steroids15 (31%)0 (0%)0 (0%) Antimalarials13 (27%)4 (24%)4 (15%) Other immunosuppresants4 (8%)13 (76%)20 (77%)CLASI-A, median (IQR)4 (3-9)11 (6-21)∗CLASI-A and CLASI-D data available for 15 SLE patients with concomitant diagnosis of CLE.N/AN/ACLASI-D, median (IQR)8 (2-13)16 (11-28)∗CLASI-A and CLASI-D data available for 15 SLE patients with concomitant diagnosis of CLE.N/AN/AACR, American College of Rheumatology; CLASI-A, cutaneous lupus erythematosus disease area and severity index – activity; CLASI-D, cutaneous lupus erythematosus disease area and severity index – damage; CLE, cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; IQR, interquartile range; LE, lupus erythematosus; N/A, not available; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus.∗ CLASI-A and CLASI-D data available for 15 SLE patients with concomitant diagnosis of CLE.† One CLE+/SLE+ patient had a diagnosis of DLE per chart review, but information regarding the DLE subtype was not available. Open table in a new tab ACR, American College of Rheumatology; CLASI-A, cutaneous lupus erythematosus disease area and severity index – activity; CLASI-D, cutaneous lupus erythematosus disease area and severity index – damage; CLE, cutaneous lupus erythematosus; DLE, discoid lupus erythematosus; IQR, interquartile range; LE, lupus erythematosus; N/A, not available; SCLE, subacute cutaneous lupus erythematosus; SLE, systemic lupus erythematosus. The CLE+/SLE− sera had elevated CXCL9 and CXCL10 levels compared with the control sera (CXCL9: median 50.91 pg/mL [interquartile range {IQR} 32.8-122.1 pg/mL] vs 20.54 pg/mL [IQR 12.7-34.4 pg/mL] [P < .0001], CXCL10: median 220.77 pg/mL [IQR 132-360.1 pg/mL] vs 124.12 pg/mL [89.5-149.4 pg/mL] [P = .002]). The serum levels of CXCL10 in CLE+/SLE+ patients (473.9 pg/mL [IQR 327.5-1978.8 pg/mL]) and CLE−/SLE+ patients (642.3 pg/mL [IQR 398.5-1561.3 pg/mL]) were significantly elevated compared with the levels in CLE+/SLE− patients (P < .003) and healthy controls (P < .0001). The CXCL9 levels were significantly higher in CLE+/SLE+ patients (88.5 pg/mL [IQR 77.0-138.0 pg/mL]) and CLE−/SLE+ patients (57.7 pg/mL [IQR 24.1-107.5 pg/mL]) than in the controls (P < .0001) but not in CLE+/SLE− patients (Fig 1, A and B). Receiver operating characteristic analysis was performed to distinguish CLE+/SLE+ patients from CLE+/SLE− patients based on the CXCL9 and CXCL10 levels (Fig 1, C and D). CXCL10 levels in CLE+/SLE+ and CLE+/SLE− patients yielded an area under the curve of 0.83 (95% confidence interval: 0.72-0.93) (P < .0001). These results highlight the potential utility of CXCL10 as a biomarker to distinguish SLE patients from CLE patients. In CLE patients, CXCL10 induces helper T cell type 1-based inflammation, the recruitment of C-X-C chemokine receptor type 3+ T cells, and the release of interferon-associated cytokines into the skin, promoting tissue injury.1Wenzel J. Wörenkämper E. Freutel S. et al.Enhanced type I interferon signalling promotes Th1-biased inflammation in cutaneous lupus erythematosus.J Pathol. 2005; 205: 435-442Crossref PubMed Scopus (172) Google Scholar Increasing sera levels of CXCL10 from controls to those of CLE+/SLE− patients to those of CLE+/SLE+ and CLE−/SLE+ patients demonstrated the potential spread of helper T cell type 1-induced inflammation from skin to systemic levels. Increased CXCL10 levels in SLE patients have been shown to come from both peripheral blood and other end organs.3Enghard P. Humrich J. Rudolph B. et al.CXCR3+ CD4+ T cells are enriched in inflamed kidneys and urine and provide a new biomarker for acute nephritis flares in systemic lupus erythematosus patients.Arthritis Rheum. 2009; 60: 199-206Crossref PubMed Scopus (100) Google Scholar Thus, we postulate that increases in the CXCL10 levels over time may help predict the onset of SLE in CLE patients. In contrast, CXCL9 does not help distinguish CLE patients from SLE patients. The lack of significant CXCL9 upregulation in end organs in human patients with lupus may explain the smaller difference in the CXCL9 levels between CLE and SLE patients.4Flier J. Boorsma D.M. van Beek P.J. et al.Differential expression of CXCR3 targeting chemokines CXCL10, CXCL9, and CXCL11 in different types of skin inflammation.J Pathol. 2001; 194: 398-405Crossref PubMed Scopus (294) Google Scholar,5Wenzel J. Zahn S. Mikus S. Wiechert A. Bieber T. Tüting T. The expression pattern of interferon-inducible proteins reflects the characteristic histological distribution of infiltrating immune cells in different cutaneous lupus erythematosus subsets.Br J Dermatol. 2007; 157: 752-757Crossref PubMed Scopus (87) Google Scholar While this study was limited by its cross-sectional single-center design and small sample size, larger, longitudinal studies are needed to confirm our hypothesis that CXCL10 is a biomarker that distinguishes CLE from SLE and track systemic disease spread for CLE patients. Dr Chong is an investigator for Pfizer Incorporated, Biogen Incorporated, Daavlin Corporation, and Amgen Incorporated and is a consultant for Viela Bio, Beacon Bioscience, Bristol Meyers Squibb, EMD Serono, and Principia Biopharma. Drs O'Brien and Saxena and author Zhu and Barber have no conflicts of interest to declare. We would like to acknowledge Rebecca Vasquez, MD, Andrew Kim, MD, Daniel Grabell, MD, Noelle Teske, MD, MSc, and Tina Vinoya, MD for recruiting patients. The authors would like to thank participants of the University of Texas Southwestern Medical Center's Cutaneous Lupus Erythematosus Registry for their contributions to lupus research.

Editorial note: Welcome to the Journal of Investigative Dermatology (JID) Snapshot Dx Quiz. In this monthly online-only quiz, the first question ("What is your diagnosis?") relates to the clinical image shown, while additional questions concern the findings reported in the JID article by Gu et al. (2020) (https://doi.org/10.1 016/j.jid.2020.01.010).