Consortium on Kamil Slowikowski

A population-scale transcriptional atlas of blood and tissue in lupus nephritis

kslowikowski@gmail.com (Kamil Slowikowski) — Wed, 19 Aug 2026 00:00:00 +0000

Lupus nephritis (LN), a severe manifestation of systemic lupus erythematosus (SLE), is a heterogeneous disease driven by diverse immune and tissue cell types. We obtained 538,194 single-cell and 142,881 single-nuclear profiles from kidney biopsies of 155 patients with LN and 30 preimplantation transplant biopsy controls, along with 327,326 single-cell blood profiles. We characterized key stromal and immune cell types and cell states; moreover, we distinguished cell states that were tissue specific from those that were also present in the blood. We observed that LN pathological features were associated with particular cell states. For example, after controlling for the effects of chronic tissue damage, we observed that expansion of glomerular and scar-associated macrophage populations correlated with increasing inflammatory disease activity. Scar-associated macrophages appear to drive LN fibrosis and, in active disease, infiltrate the glomeruli more than other myeloid cells. These observations support that therapeutic targeting of myeloid populations may offer a strategy to prevent renal inflammation and ongoing kidney damage in LN.

SPP1^hi macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium

kslowikowski@gmail.com (Kamil Slowikowski) — Wed, 24 Jun 2026 00:00:00 +0000

In chronic inflammatory diseases, maladaptive tissue remodeling is driven by a complex interplay of resident cells, immune infiltrates, and the extracellular matrix. In the autoimmune disorder rheumatoid arthritis (RA), synovial tissue undergoes massive expansion to form an invasive pannus that drives the erosion of cartilage and bone. The mechanisms mediating this aggressive growth are incompletely defined. Using spatial transcriptomic profiling of patient tissue, we detected an abundance of proliferating fibroblasts near the synovial tissue lining surface and adjacent to macrophages expressing high levels of secreted phosophoprotein-1 (encoding osteopontin; SPP1^hi macrophages). These synovial lining regions were also distinctly marked by deposits of the clot-forming protein fibrin. Although the SPP1^hi macrophages phenotypically resembled the profibrotic macrophages that drive lung and liver fibrosis, these niches were devoid of the dense highly ordered collagen that marks fibrosis. Functionally, we found that SPP1^hi macrophages degraded and phagocytosed fibrin matrices and promoted fibroblast proliferation. Given that fibrin provides transient matrices for de novo tissue generation in the context of wound healing, these data support a model of hyperplastic tissue outgrowth involving SPP1^hi macrophages, fibroblasts, and fibrin matrices adhered to the exterior synovial tissue surface. Whereas current RA therapies primarily aim to dampen proinflammatory responses, our findings provide the rationale for targeting progenerative pathways and SPP1^hi macrophages.

Granzyme K activates the entire complement cascade

kslowikowski@gmail.com (Kamil Slowikowski) — Thu, 06 Feb 2025 00:00:00 +0000

Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis

kslowikowski@gmail.com (Kamil Slowikowski) — Thu, 14 Nov 2024 00:00:00 +0000

Soluble urine activated leukocyte cell adhesion molecule is a strong predictor of lupus nephritis

kslowikowski@gmail.com (Kamil Slowikowski) — Tue, 15 Oct 2024 00:00:00 +0000

Objectives. To evaluate urinary activated leucocyte cell adhesion molecule (ALCAM) and CD6 as predictors of LN progression or disease resolution across a 1-year study.

Methods. Serum and urine samples from biopsy proven LN subjects (n = 122) were prospectively collected over the course of a year at 3- or 6-month intervals (weeks 0, 12, 26 and 52) across multiple study sites and assessed for soluble ALCAM and CD6 levels. Urine creatinine from the same urine sample was used to normalize the levels of urinary ALCAM and urinary CD6. Measured levels of serum and urine ALCAM and CD6 were then analysed against disease metrics cross-sectionally and longitudinally.

Results. Cross-sectional analysis at baseline revealed that urinary ALCAM significantly correlated with urine protein creatinine ratio, renal SLEDAI, and the Physician Global Assessment (PGA), and negatively correlated with serum C3 and C4. Receiver operating characteristic curve analysis demonstrated that urinary ALCAM is a predictor of LN with an area under the curve (AUC) of 0.97, compared with urinary CD6 with an AUC of 0.71. Importantly, the change in urinary ALCAM over a 3-month period distinguished between non-responders and responders at week 52.

Conclusion. Urinary ALCAM is reflective of changes in LN and may be predictive of response status.

Automated multi-scale computational pathotyping (AMSCP) of inflamed synovial tissue

kslowikowski@gmail.com (Kamil Slowikowski) — Thu, 29 Aug 2024 00:00:00 +0000

Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus

kslowikowski@gmail.com (Kamil Slowikowski) — Wed, 10 Jul 2024 00:00:00 +0000

The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis

kslowikowski@gmail.com (Kamil Slowikowski) — Fri, 31 May 2024 00:00:00 +0000

Synovial tissue inflammation is a hallmark of rheumatoid arthritis (RA). Recent work has identified prominent pathogenic cell states in inflamed RA synovial tissue, such as T peripheral helper cells; however, the epigenetic regulation of these states has yet to be defined. Here, we examine genome-wide open chromatin at single-cell resolution in 30 synovial tissue samples, including 12 samples with transcriptional data in multimodal experiments. We identify 24 chromatin classes and predict their associated transcription factors, including a CD8 + GZMK+ class associated with EOMES and a lining fibroblast class associated with AP-1. By integrating with an RA tissue transcriptional atlas, we propose that these chromatin classes represent ‘superstates’ corresponding to multiple transcriptional cell states. Finally, we demonstrate the utility of this RA tissue chromatin atlas through the associations between disease phenotypes and chromatin class abundance, as well as the nomination of classes mediating the effects of putatively causal RA genetic variants.

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis

kslowikowski@gmail.com (Kamil Slowikowski) — Wed, 10 Apr 2024 00:00:00 +0000

It has been presumed that rheumatoid arthritis (RA) joint pain is related to inflammation in the synovium; however, recent studies reveal that pain scores in patients do not correlate with synovial inflammation. We developed a machine-learning approach (graph-based gene expression module identification or GbGMI) to identify an 815-gene expression module associated with pain in synovial biopsy samples from patients with established RA who had limited synovial inflammation at arthroplasty. We then validated this finding in an independent cohort of synovial biopsy samples from patients who had early untreated RA with little inflammation. Single-cell RNA sequencing analyses indicated that most of these 815 genes were most robustly expressed by lining layer synovial fibroblasts. Receptor-ligand interaction analysis predicted cross-talk between human lining layer fibroblasts and human dorsal root ganglion neurons expressing calcitonin gene–related peptide (CGRP ⁺ ). Both RA synovial fibroblast culture supernatant and netrin-4, which is abundantly expressed by lining fibroblasts and was within the GbGMI-identified pain-associated gene module, increased the branching of pain-sensitive murine CGRP ⁺ dorsal root ganglion neurons in vitro. Imaging of solvent-cleared synovial tissue with little inflammation from humans with RA revealed CGRP ⁺ pain-sensing neurons encasing blood vessels growing into synovial hypertrophic papilla. Together, these findings support a model whereby synovial lining fibroblasts express genes associated with pain that enhance the growth of pain-sensing neurons into regions of synovial hypertrophy in RA.

Tissue-specific enhancer–gene maps from multimodal single-cell data identify causal disease alleles

kslowikowski@gmail.com (Kamil Slowikowski) — Tue, 09 Apr 2024 00:00:00 +0000

Extrarenal symptoms associate with worse quality of life in patients enrolled in the AMP RA/SLE Lupus Nephritis Network

kslowikowski@gmail.com (Kamil Slowikowski) — Tue, 26 Mar 2024 00:00:00 +0000

Objective. Lupus nephritis (LN) can occur as an isolated component of disease activity or be accompanied by diverse extrarenal manifestations. Whether isolated renal disease is sufficient to decrease health-related quality of life (HRQOL) remains unknown. This study compared Patient-Reported Outcomes Measurement Information System 29-Item (PROMIS-29) scores in LN patients with isolated renal disease to those with extrarenal symptoms to evaluate the burden of LN on HRQOL and inform future LN clinical trials incorporating HRQOL outcomes.

Methods. A total of 181 LN patients consecutively enrolled in the multicentre multi-ethnic/racial Accelerating Medicines Partnership completed PROMIS-29 questionnaires at the time of a clinically indicated renal biopsy. Raw PROMIS-29 scores were converted to standardized T scores.

Results. Seventy-five (41%) patients had extrarenal disease (mean age 34, 85% female) and 106 (59%) had isolated renal (mean age 36, 82% female). Rash (45%), arthritis (40%) and alopecia (40%) were the most common extrarenal manifestations. Compared with isolated renal, patients with extrarenal disease reported significantly worse pain interference, ability to participate in social roles, physical function, and fatigue. Patients with extrarenal disease had PROMIS-29 scores that significantly differed from the general population by >0.5 SD of the reference mean in pain interference, physical function, and fatigue. Arthritis was most strongly associated with worse scores in these three domains.

Conclusion. Most patients had isolated renal disease and extrarenal manifestations associated with worse HRQOL. These data highlight the importance of comprehensive disease management strategies that address both renal and extrarenal manifestations to improve overall patient outcomes.

Longitudinal patterns and predictors of response to standard-of-care therapy in lupus nephritis: data from the Accelerating Medicines Partnership Lupus Network

kslowikowski@gmail.com (Kamil Slowikowski) — Tue, 20 Feb 2024 00:00:00 +0000

Background

Leveraging the Accelerating Medicines Partnership (AMP) Lupus Nephritis (LN) dataset, we evaluated longitudinal patterns, rates, and predictors of response to standard-of-care therapy in patients with lupus nephritis.

Methods

Patients from US academic medical centers with class III, IV, and/or V LN and a baseline urine protein/creatinine (UPCR) ratio ≥ 1.0 (n = 180) were eligible for this analysis. Complete response (CR) required the following: (1) UPCR < 0.5; (2) normal serum creatinine (≤ 1.3 mg/dL) or, if abnormal, ≤ 125% of baseline; and (3) prednisone ≤ 10 mg/day. Partial response (PR) required the following: (1) > 50% reduction in UPCR; (2) normal serum creatinine or, if abnormal, ≤ 125% of baseline; and (3) prednisone dose ≤ 15 mg/day.

Results

Response rates to the standard of care at week 52 were CR = 22.2%; PR = 21.7%; non-responder (NR) = 41.7%, and not determined (ND) = 14.4%. Only 8/180 (4.4%) patients had a week 12 CR sustained through week 52. Eighteen (10%) patients attained a week 12 PR or CR and sustained their responses through week 52 and 47 (26.1%) patients achieved sustained PR or CR at weeks 26 and 52. Week 52 CR or PR attainment was associated with baseline UPCR > 3 (OR_adj = 3.71 [95%CI = 1.34–10.24]; p = 0.012), > 25% decrease in UPCR from baseline to week 12 (OR_adj = 2.61 [95%CI = 1.07–6.41]; p = 0.036), lower chronicity index (OR_{adj =} 1.33 per unit decrease [95%CI = 1.10–1.62]; p = 0.003), and positive anti-dsDNA antibody (OR_adj = 2.61 [95%CI = 0.93–7.33]; p = 0.069).

Conclusions

CR and PR rates at week 52 were consistent with the standard-of-care response rates observed in prospective registrational LN trials. Low sustained response rates underscore the need for more efficacious therapies and highlight how critically important it is to understand the molecular pathways associated with response and non-response.

Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution

kslowikowski@gmail.com (Kamil Slowikowski) — Thu, 30 Nov 2023 00:00:00 +0000

Associations Between Rheumatoid Arthritis Clinical Factors and Synovial Cell Types and States

kslowikowski@gmail.com (Kamil Slowikowski) — Wed, 04 Oct 2023 00:00:00 +0000

Objective

Recent studies have uncovered diverse cell types and states in the rheumatoid arthritis (RA) synovium; however, limited data exist correlating these findings with patient‐level clinical information. Using the largest cohort to date with clinical and multicell data, we determined associations between RA clinical factors with cell types and states in the RA synovium.

Methods

The Accelerated Medicines Partnership Rheumatoid Arthritis study recruited patients with active RA who were not receiving disease‐modifying antirheumatic drugs (DMARDs) or who had an inadequate response to methotrexate (MTX) or tumor necrosis factor inhibitors. RA clinical factors were systematically collected. Biopsies were performed on an inflamed joint, and tissue were disaggregated and processed with a cellular indexing of transcriptomes and epitopes sequencing pipeline from which the following cell type percentages and cell type abundance phenotypes (CTAPs) were derived: endothelial, fibroblast, and myeloid (EFM); fibroblasts; myeloid; T and B cells; T cells and fibroblasts (TF); and T and myeloid cells. Correlations were measured between RA clinical factors, cell type percentage, and CTAPs.

Results

We studied 72 patients (mean age 57 years, 75% women, 83% seropositive, mean RA duration 6.6 years, mean Disease Activity Score‐28 C‐reactive Protein 3 [DAS28‐CRP3] score 4.8). Higher DAS28‐CRP3 correlated with a higher T cell percentage (P < 0.01). Those receiving MTX and not a biologic DMARD (bDMARD) had a higher percentage of B cells versus those receiving no DMARDs (P < 0.01). Most of those receiving bDMARDs were categorized as EFM (57%), whereas none were TF. No significant difference was observed across CTAPs for age, sex, RA disease duration, or DAS28‐CRP3.

Conclusion

In this comprehensive screen of clinical factors, we observed differential associations between DMARDs and cell phenotypes, suggesting that RA therapies, more than other clinical factors, may impact cell type/state in the synovium and ultimately influence response to subsequent therapies.

Single cell profiling of COVID-19 patients: an international data resource from multiple tissues

kslowikowski@gmail.com (Kamil Slowikowski) — Mon, 23 Nov 2020 00:00:00 +0000

In late 2019 and through 2020, the COVID-19 pandemic swept the world, presenting both scientific and medical challenges associated with understanding and treating a previously unknown disease. To help address the need for great understanding of COVID-19, the scientific community mobilized and banded together rapidly to characterize SARS-CoV-2 infection, pathogenesis and its distinct disease trajectories. The urgency of COVID-19 provided a pressing use-case for leveraging relatively new tools, technologies, and nascent collaborative networks. Single-cell biology is one such example that has emerged over the last decade as a powerful approach that provides unprecedented resolution to the cellular and molecular underpinnings of biological processes. Early foundational work within the single-cell community, including the Human Cell Atlas, utilized published and unpublished data to characterize the putative target cells of SARS-CoV-2 sampled from diverse organs based on expression of the viral receptor ACE2 and associated entry factors TMPRSS2 and CTSL (Muus et al., 2020; Sungnak et al., 2020; Ziegler et al., 2020). This initial characterization of reference data provided an important foundation for framing infection and pathology in the airway as well as other organs. However, initial community analysis was limited to samples derived from uninfected donors and other previously-sampled disease indications. This report provides an overview of a single-cell data resource derived from samples from COVID-19 patients along with initial observations and guidance on data reuse and exploration.

Notch signalling drives synovial fibroblast identity and arthritis pathology

kslowikowski@gmail.com (Kamil Slowikowski) — Wed, 22 Apr 2020 00:00:00 +0000

Consortium on Kamil Slowikowski

A population-scale transcriptional atlas of blood and tissue in lupus nephritis

SPP1hi macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium

Granzyme K activates the entire complement cascade

Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis

Soluble urine activated leukocyte cell adhesion molecule is a strong predictor of lupus nephritis

Automated multi-scale computational pathotyping (AMSCP) of inflamed synovial tissue

Interferon subverts an AHR–JUN axis to promote CXCL13+ T cells in lupus

The chromatin landscape of pathogenic transcriptional cell states in rheumatoid arthritis

Synovial fibroblast gene expression is associated with sensory nerve growth and pain in rheumatoid arthritis

Tissue-specific enhancer–gene maps from multimodal single-cell data identify causal disease alleles

Extrarenal symptoms associate with worse quality of life in patients enrolled in the AMP RA/SLE Lupus Nephritis Network

Longitudinal patterns and predictors of response to standard-of-care therapy in lupus nephritis: data from the Accelerating Medicines Partnership Lupus Network

Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution

Associations Between Rheumatoid Arthritis Clinical Factors and Synovial Cell Types and States

Single cell profiling of COVID-19 patients: an international data resource from multiple tissues

Notch signalling drives synovial fibroblast identity and arthritis pathology

SPP1^hi macrophages in fibrin niches promote hyperplastic tissue remodeling in rheumatoid arthritis synovium