Search

Cannabis has a wide range of favorable clinical effects on pain, sleep, mood, gastrointestinal symptom, appetite and physical activity, factors that may affect the metabolic profile of the consumer. In this study, we prospectively evaluated patients recently starting medical cannabis treatment. All patients from the rheumatology clinic, who were just approved for medical cannabis treatment for resistant chronic pain, were recruited. After consent, demographic and clinical parameters were documented, including indication for medical cannabis treatment, way of consumption, type of cannabis and monthly dose of medical cannabis. Fasting morning blood glucose, hemoglobin A1c, insulin, lipid profile, cortisol and uric acid levels, in addition to body weight, were obtained just prior to and 3 months following cannabis consumption. Wilcoxon’ sign rank test was used to compare baseline levels to those obtained 3 months later. Twenty-eight patients completed the study. Mean age of the patients was 47.8±9.1 years and ˜70% were female patients. 75% of all the patients had fibromyalgia. Mean monthly consumed cannabis amount was 22.21±3.6 g, and 21 (75%) patients used extracts (oil). There was no significant change in any parameter evaluated. The results of our study seem to indicate that medical cannabis, mainly extracts, have no significant effect on any parameter of the metabolic profile of patients with chronic pain syndrome, during 3 months of initial use.

Rheumatoid Arthritis (RA) causes chronic inflammation of joints. The cytokines TNFα and IFNγ are central players in RA, however their source has not been fully elucidated. Natural Killer (NK) cells are best known for their role in elimination of viral-infected and transformed cells, and they secrete pro-inflammatory cytokines. NK cells are present in the synovial fluids (SFs) of RA patients and are considered to be important in bone destruction. However, the phenotype and function of NK cells in the SFs of patients with erosive deformative RA (DRA) versus non-deformative RA (NDRA) is poorly characterized. Here we characterize the NK cell populations present in the blood and SFs of DRA and NDRA patients. We demonstrate that a distinct population of activated synovial fluid NK (sfNK) cells constitutes a large proportion of immune cells found in the SFs of DRA patients. We discovered that although sfNK cells in both DRA and NDRA patients have similar phenotypes, they function differently. The DRA sfNK secrete more TNFα and IFNγ upon exposure to IL-2 and IL-15. Consequently, we suggest that sfNK cells may be a marker for more severely destructive RA disease.

Tocilizumab is an interleukin 6 (IL-6) receptor antagonist used treat moderate to severe active rheumatoid arthritis (RA). Both intravenous (IV) and subcutaneous (SC) routes are approved for the treatment of adults with RA.To evaluate SC tocilizumab in a real-life clinical setting.Our study was a multi-center, open-label, single-arm study. Participants were adults with a diagnosis of active RA, previously treated with disease-modifying antirheumatic drugs (DMARDs), with or without biologic agents. Participants received a weekly SC injection of tocilizumab 162 mg as monotherapy or in combination with methotrexate or DMARDs for 24 weeks. Efficacy, safety, and immunogenicity were assessed.Treatment of 100 patients over 24 weeks resulted in improvement in all efficacy parameters assessed: Clinical Disease Activity Index, Disease Activity Score using 28 joint counts and erythrocyte sedimentation rate, American College of Rheumatology response scores, Simplified Disease Activity Index, tender and swollen joint counts, and patient-reported outcomes including fatigue, global assessment of disease activity, pain, and Health Assessment Quality of Life Disease Index. Improvement was achieved as early as the second week of treatment. There were 473 adverse events (AEs)/100 patient-years (PY) and 16.66 serious AEs/100 PY. The most common AEs were neutropenia (12%), leukopenia (11%), and increased hepatic enzymes (11%). Of a total of 42 PY, the rates of serious infections and AEs leading to discontinuation were 4.8, and 11.9 events/100 PY, respectively.The safety, tolerability, and efficacy profile of tocilizumab SC were comparable to those reported in other studies evaluating the IV and SC routes of administration.

Background Mood disorders, such as anxiety and depression, are extremely prevalent among patients with rheumatoid arthritis (RA). In this study, we assessed the impact of treatment with tocilizumab (TCZ), an IL-6 antagonist, upon anxiety and depressive symptoms in a cohort of RA patients. Materials and methods Study participants were adults diagnosed with RA who received a weekly subcutaneous injection of tocilizumab for 24 weeks. We used the Hamilton Depression (HDRS) and Anxiety (HAMA) scores in order to assess the severity of depression and anxiety, respectively. RA disease activity indices and depression and anxiety levels were assessed at baseline, 4 weeks and study completion. Results Ultimately, 91 patients were included in the study. The mean age was 54 years, and the majority were female (79%). The mean score in all disease activity indices as well as depression and anxiety levels decreased dramatically from baseline to study completion. Sixty patients (66%) demonstrated a significant decrease in anxiety and/or depression levels. When logistic regression was performed, an HDRS score indicative of depression at study baseline demonstrated an independent association with a significant psychiatric response whilst older age and increased baseline weight were negatively associated. HAMA and HDRA scores correlated with the following RA disease activity parameters, respectively; HAQ-DI (r = .4, .42), DAS28 (r = .29, .32) and CDAI (0.28 and 0.33), all of them were statistically significant (P Conclusions This study has demonstrated a favourable impact of TCZ therapy on parameters reflecting depression and anxiety severity in patients with RA.

Metabolic syndrome, leaky guts, and infection Metabolic syndrome often accompanies obesity and hyperglycemia and is associated with a breakdown in the integrity of the intestinal barrier and increased risk of systemic infection. Thaiss et al. found that mice with systemic infection of a Salmonella analog, Citrobacter rodentium , also exhibited hyperglycemia. Deletion of the glucose transporter GLUT2 altered sensitivity to chemically induced epithelial permeability and protected mice from pathogen invasion. The authors also found a correlation in humans between glycated hemoglobin (an indicator of hyperglycemia) and serum levels of pathogen recognition receptor ligands. Science , this issue p. 1376

Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients.To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs.In this multicenter, open-label, non-controlled, single-arm study, patients ≥ 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment.The study comprised 145 patients (mean age 53.4 ± 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 ± 9.7, 6.8 ± 10.5, 7.3 ± 10.9, and 7.3 ± 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data.Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported.

Objective.To characterize the clinical manifestations of patients with antiphospholipid antibody syndrome (APS) and pulmonary hemorrhage (PH).Methods.We performed a retrospective, single-center analysis of patients with APS who were followed up from 1980 to 2011. Of these patients, only those who fulfilled the Sydney criteria for APS were included. Patients with APS that manifested with PH were called the PHAPS group. The rest of the patients with APS served as controls. Clinical manifestations were compared between the PHAPS group and controls.Results.Sixty-three patients fulfilled the criteria for APS. Thirteen experienced PH and were included in the PHAPS group. Seventy-five percent of the patients with PHAPS and 22% of the controls had mitral valve disease (p = 0.001). Central nervous system (CNS) involvement (cerebrovascular accident, seizures) was present in 61% and 16% of the patients with PHAPS and controls, respectively (p = 0.001). Skin involvement (livedo reticularis, chronic leg ulcers) was present in 54% and 8% of the patients with PHAPS and controls (p = 0.001). Pregnancy morbidity occurred in 87.5% and 32.5% of the patients with PHAPS and controls (p = 0.005). Ninety-two percent and 83% of the patients with PHAPS had high-titer immunoglobulin γ (IgG) anticardiolipin and β2-glycoprotein I IgG antibodies compared to 43% and 30% of the controls (p = 0.002, p < 0.001, respectively).Conclusion.Patients with PHAPS were more likely than controls to have mitral valve disease, skin disease, CNS involvement, and pregnancy morbidity as well as high-titer APS. PHAPS seems to be a unique subgroup of all patients with APS.

This study analyzes the histopathological findings in H syndrome, a recently recognized autosomal recessive genodermatosis characterized by indurated, hyperpigmented, and hypertrichotic skin in well-defined anatomical areas accompanied by various systemic manifestations. So far, descriptions of the histopathological skin changes in this disorder, as reported in a few small case series, were inconsistent, leading to diverse clinical interpretations. In an attempt to define standardized, diagnostic, morphological criteria that will distinguish this disorder from other fibrosing conditions, we studied skin biopsies from 10 patients with H syndrome. The characteristic morphology included widespread fibrosis (moderate in dermis and severe in subcutis); striking mononuclear infiltrates consisting mainly of monocyte-derived cells (small CD68 histiocytes and CD34 and FXIIIa dendrocytes) and plasma cells; and thickened, fragmented, and partially calcified elastic fibers, admixed with well-formed psammoma bodies, a previously unrecognized feature in nonneoplastic skin and subcutaneous conditions. In addition, the ultrastructure of CD68 small histiocytes exhibited distended endoplasmic reticulum and scarcity of lysosomes, features typical for fibroblasts but unusual for histiocytes. These unusual findings in the histiocytes pose a question as to their possible role in the fibrotic cascade in this disorder. We conclude that the above findings are essential for the diagnosis of H syndrome and that incisional biopsies are mandatory for recognition of the full spectrum of histopathological findings.

Objective FMF is an autosomal recessive hereditary disease, associated with a single gene named MEFV. This gene is considered to be responsible only for FMF. In the present study, we tried to find out whether the MEFV gene is associated with or responsible for clinical conditions other than FMF. Methods We looked for patients who presented with signs and symptoms not typical for FMF but carried MEFV mutations. We also searched for reports about similar conditions in the English medical literature, and we surveyed the website 'Infevers' for MEFV mutations defined as associated with 'atypical FMF'. Results We encountered three patients carrying MEFV mutations who presented with distinct clinical presentations not typical of FMF. We identified additional reports about MEFV-related non-FMF disease entities such as palindromic rheumatism. By screening the 'Infevers' website, we further disclosed 13 cases with MEFV mutations that were defined as 'atypical FMF' and 4 cases categorized as 'recurrent arthritis'. Conclusions These findings suggest that the MEFV gene is associated with clinical conditions other than FMF. Changing our concept regarding the MEFV gene and its link to such clinical phenotypes may call for a higher awareness of the existence of additional autoinflammatory diseases. Furthermore, a correct diagnosis of these MEFV gene mutation-associated syndromes will justify a therapeutic trial with colchicine, thereby relieving suffering of many patients who up to now have been misdiagnosed.

Selective targeting of cells engaged in pathological activities is a major challenge for medical research. We generated monoclonal antibodies (mAbs) that exclusively bind, at concentrations ranging from 2 to 100 microg/ml, to a modified CD44 variant (designated CD44vRA) expressed on synovial fluid cells from joints of rheumatoid arthritis (RA) patients. These mAbs cross-reacted with keratinocytes expressing wild type CD44vRA (CD44v3-v10) only at a relatively high concentration (200 microg/ml). Sequence analysis of CD44vRA cDNA revealed, in 33 out of 43 RA and psoriatic arthritis patients, an extra intron-derived trinucleotide, CAG, which allows translation of an extra alanine. This insertion imposes a configurational change on the cell surface CD44 of RA synovial fluid cells, creating an immunogenic epitope and potentiating the ability to produce disease-specific antibodies. Indeed, the anti-CD44vRA mAbs (designated F8:33) were able to induce apoptosis in synovial fluid cells from RA patients, but not in peripheral blood leukocytes from the same patients, in keratinocytes from normal donors or in synovial fluid cells from osteoarthritis patients. Furthermore, injection of anti-CD44vRA mAbs reduced joint inflammation in DBA/1 mice with collagen-induced arthritis. These findings show that anti-CD44vRA mAbs are both bioactive and RA-specific.

Background: There is an association between C677T polymorphism of the methylenetetrahydrofolate reductase (MTHFR) gene and methotrexate related toxicity. Objective: To examine the relations between the recently described A1298C polymorphism of the MTHFR gene, plasma homocysteine, methotrexate toxicity, and disease activity in patients with rheumatoid arthritis. Design: A cross sectional study on 93 methotrexate treated patients with rheumatoid arthritis, comprising a clinical interview and physical examination to determine disease activity and methotrexate related adverse reactions. Genotype analysis of the MTHFR gene was carried out and fasting plasma homocysteine and serum folate concentrations were measured. The data were analysed using univariate analysis. Allele and genotype distributions were compared with those of a healthy control group. Results: The frequency of the 1298CC genotype (24.7%) in the rheumatoid study group was greater than expected in the general population (12.8%, p

We report a 39-year-old female who presented over 11 years with autoimmune cholangiopathy associated with kaleidoscopic manifestations of systemic lupus erythematosus (SLE), including, arthritis, skin changes, pleuritis, diffuse proliferative glomerulonephritis, lymphadenopathy, splenomegaly, hyperglobulinemia, and major depression. While antimitochondrial antibodies (AMA) were absent, antinuclear (ANA) and anti-DNA antibodies were detected in high titres associated with hypocomplementemia. The patient also had vitamin B12 deficiency and antiphospholipid antibodies. The patient required steroids and repeated courses of cyclophosphamide for the management of lupus nephritis, and ursodeoxycholic acid (ursolite) administration resulted in amelioration of cholestatic laboratory abnormalities. This unusual case report and review of literature illustrate that immune liver disease may be an important clinical manifestation of SLE, especially autoimmune cholangiopathy.

The cytokine interleukin-1 (IL-1) is involved in a wide range of inflammatory and immune responses. As such, IL-1 could play a role in peripheral nerve repair mechanisms. Specifically, by its already established properties as a regulator of nerve growth factor (NGF) synthesis, and as a chemotactant to macrophages. We examined, therefore, IL-1 production in injured mouse peripheral nerve. Injured nerve segments were incubated in serum free medium to produce conditioned medium (CM) that was then tested for IL-1 activity in a thymocyte proliferation assay. CM induced thymocyte proliferation in a dose-dependent manner. Proliferation was inhibited by the M20 IL-1 inhibitor, the IL-1 receptor antagonist, and antisera raised against recombinant mouse IL-1α. Inhibitions produced by these three specific inhibitors of IL-1-induced thymocyte proliferation strongly suggest that proliferation induced by CM was mediated largely by IL-1 secreted by non-neuronal cells residing in the damaged nerve. IL-1 activity was detected within hours after lesion, and 1 week thereafter. The rapid and prolonged production of IL-1 indicates that IL-1-dependent mechanisms can play roles in the response of the peripheral nerve to injury: degeneration and regeneration. The regulation of NGF synthesis, and the recruitment of white blood cells, macrophages in particular, from blood into the damaged nerve tissue, are two such mechanisms.

Background The association of cutaneous hyperpigmented, hypertrichotic, and indurated patches associated with hearing loss, short stature, cardiac anomalies, hepatosplenomegaly, scrotal masses, and hypogonadism has not, to our knowledge, been previously recognized as a disease entity. Objective We describe 10 patients with the above-mentioned findings. Methods Patients were clinically examined and extensive laboratory evaluation was performed. Results We describe 10 patients from 6 Arab consanguineous families with hyperpigmented, hypertrichotic, and indurated cutaneous patches involving the middle and lower parts of their bodies. In addition, patients displayed short stature, sensorineural hearing loss, cardiac anomalies, hepatosplenomegaly, and scrotal masses. Laboratory evaluation revealed growth hormone deficiency and hypergonadotropic hypogonadism with azoospermia. Cutaneous histopathologic examination showed hyperpigmentation of the basal layer with seborrheic-keratosis-like acanthosis, histiocytic infiltration, and a perivascular mononuclear infiltrate with plasma cells and mast cells throughout the dermis and subcutaneous fat. Comparison with several patients, recently reported in the medical literature, with similar cutaneous findings is made. Limitations Laboratory evaluation in some patients was incomplete because of lack of cooperation. Conclusions We suggest that our patients represent a novel multisystemic autosomal recessive inherited disorder. We call this constellation of symptoms the "H syndrome."

The synovial fluid (SF) cells of rheumatoid arthritis (RA) patients express a specific CD44 variant designated CD44vRA. Using a cellular model of this autoimmune disease, we show in this study that the mammalian lectin, galectin-8 (gal-8), is a novel high-affinity ligand of CD44vRA. By affinity chromatography, flow cytometry, and surface plasmon resonance, we demonstrate that gal-8 interacts with a high affinity (Kd, 6 × 10−9 M) with CD44vRA. We further demonstrate that SF cells from RA patients express and secrete gal-8, to a concentration of 25–65 nM, well within the concentration of gal-8 required to induce apoptosis of SF cells. We further show that not all gal-8 remains freely soluble in the SF and at least part forms triple complexes with CD44 and fibrinogen that can be detected, after fibrinogen immunoprecipitation, with Abs against fibrinogen, gal-8 and CD44. These triple complexes may therefore increase the inflammatory reaction by sequestering the soluble gal-8, thereby reducing its ability to induce apoptosis in the inflammatory cells. Our findings not only shed light on the receptor-ligand relationships between CD44 and gal-8, but also underline the biological significance of these interactions, which may affect the extent of the autoimmune inflammatory response in the SF of RA patients.

To investigate the distribution of the A2756G polymorphism of the methionine synthase reductase (MTR) gene in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) compared with a healthy control group; and to examine the relationships among the A2756G polymorphism, plasma total homocysteine (tHcy), serum folate and vitamin B12 levels, disease activity, and MTX toxicity in patients with RA.A cross-sectional study was performed on 86 MTX-treated RA patients, consisting of a clinical interview and physical examination to determine disease activity and MTX-related adverse reactions. Genotype analysis of the MTR gene was performed. Fasting plasma tHcy, serum folate, and vitamin B12 levels were measured. Allele and genotype distributions were compared to a healthy control group.The frequency of the 2756GG genotype (16.3%) in the RA study group was higher than that expected in the general population (3.6%; p0.000001). This genotype was associated with MTX-induced accelerated rheumatoid nodulosis (MIARN). No association of disease activity variables or plasma homocysteine with MTR A2756G polymorphisms was observed. The MTR 2756GG genotype, low plasma vitamin B12 levels, and the presence of rheumatoid nodules predicted MIARN. No association of nodulosis with any other indicator of disease activity or medical treatment was found.In our population of MTX-treated RA patients the 2756GG genotype of the MTR gene was more common than expected and was associated with MIARN.

Progressive pseudorheumatoid dysplasia (PPD) is a rare autosomal recessive syndrome characterized by the presence of spondyloepiphyseal dysplasia associated with pain, stiffness, and swelling of multiple joints, osteoporosis, and the absence of destructive bone changes. The disorder is caused by mutations of the WISP3 gene located on chromosome 6q22. We hereby report the molecular study of the WISP3 gene in nine unrelated consanguineous families originating from the Middle-East: three from Lebanon, five from Syria, and one from Palestinian Bedouin descent, all affected with PPD. Five different sequence variations were identified in the WISP3 gene, two of them being new mutations: the c.589G C transversion at codon 197, responsible for a splicing defect (A197fsX201); and the c.536_537delGT deletion (C179fsX), both in exon 3. In all other families, the affected patients were homozygous for a previously described nonsense mutation, namely c.156C A (C52X). Interestingly, in the latter families, the C52X mutation was always found associated with a novel c.248G A (G83E) variation, suggesting the existence of a founder effect. © 2005 Wiley-Liss, Inc.

Background. In recent years the SAPHO syndrome (synovitis, acne, pustulosis, hyperostosis and osteitis) has been encountered more frequently. However, clinical evidence indicating superiority of a specific therapeutic modality is still absent. Pamidronate, a second-generation bisphosphonate, has a pronounced effect on bone metabolism by suppressing bone resorption. We report our clinical experience with intravenous pamidronate in SAPHO syndrome. Methods. Between the years 1999 and 2003 we treated 10 patients with the SAPHO syndrome who did not respond to NSAIDs, oral corticosteroids, colchicine, methotrexate, sulphasalazine or infliximab. All patients were treated with 60 mg pamidronate, given intravenously within an hour. In cases of no response a subsequent dose was given within a month and if there was a partial response an additional infusion was given after 4 months. The primary endpoint was the disappearance of recurrent bouts of bone pain, osteitis or hyperostosis, or recurrent synovitis. Reduction of the frequency of attacks by 50% was regarded as a partial response. Results. Seven of the patients were females and three were males. The age at diagnosis ranged from 26 to 68 yr. All patients had axial or peripheral arthritis and cutaneous involvement; three had severe acne, eight had pustulosis and two had concomitant psoriasis vulgaris. Hyperostosis of the anterior chest wall involving either sternocostal or sternoclavicular joints, as seen on technetium 99 bone scintigraphy, was detected in all patients. Complete remission was observed following therapy in six patients, three others partially responded and only one patient had no response. Two patients needed four cycles of pamidronate infusion, one patient needed three, six needed two infusions and one patient remitted following a single pamidronate infusion. In all but one patient pamidronate was effective in preventing recurrent bouts of pustulosis. Conclusion. Pamidronate seems to be a very effective mode of therapy for patients with the SAPHO syndrome, by promoting remission in all components of the disorder, such as bone, joint and skin involvement, and ceases the bouts that characterize this disorder.

The cytokines that modulate immune-mediated rheumatic diseases are rapidly being elucidated1,2. In rheumatoid arthritis, persistent inhibition of tumor necrosis factor-alpha (TNF-α) induces an appreciable reduction of disease activity. TNF-α antagonists abrogate the inflammatory reaction by several mechanisms3-5: they reduce the expression of cytokines (TNF-α, interleukin-1α, and interleukin-1β), adhesion molecules, and chemokines (interleukin-8 and monocyte chemotactic protein-1) in the inflamed synovial tissue; they diminish leukocyte chemotaxis through the endothelium; and they suppress the activation and differentiation of osteoclasts that enhance bone resorption. Several studies have demonstrated that both etanercept and infliximab are highly effective in the treatment of patients who have inadequate responses to conventional disease-modifying antirheumatic drugs such as methotrexate3-7. To date, short-term clinical trials with anti-TNF-α agents have not been associated with a higher prevalence of serious bacterial infections. In this report, we present the case of a young woman with seropositive rheumatoid arthritis in whom bilateral septic arthritis of the hip developed after four months of therapy with etanercept alone. Staphylococcus aureus infection was found unexpectedly during exposure of the hips at the beginning of an elective total hip arthroplasty. This report highlights a possible association between TNF-α blockade therapy and multifocal septic arthritis. Our patient was …

We report a 39-year-old female who presented over 11 years with autoimmune cholangiopathy associated with kaleidoscopic manifestations of systemic lupus erythematosus (SLE), including, arthritis, skin changes, pleuritis, diffuse proliferative glomerulonephritis, lymphadenopathy, splenomegaly, hyperglobulinemia, and major depression. While antimitochondrial antibodies (AMA) were absent, antinuclear (ANA) and anti-DNA antibodies were detected in high titres associated with hypocomplementemia. The patient also had vitamin B12 deficiency and antiphospholipid antibodies. The patient required steroids and repeated courses of cyclophosphamide for the management of lupus nephritis, and ursodeoxycholic acid (ursolite) administration resulted in amelioration of cholestatic laboratory abnormalities. This unusual case report and review of literature illustrate that immune liver disease may be an important clinical manifestation of SLE, especially autoimmune cholangiopathy.

Systemic sclerosis (scleroderma, SSc) is an incurable autoimmune disease with high morbidity and mortality rates. Here, we conducted a population-scale single-cell genomic analysis of skin and blood samples of 56 healthy controls and 97 SSc patients at different stages of the disease. We found immune compartment dysfunction only in a specific subtype of diffuse SSc patients but global dysregulation of the stromal compartment, particularly in a previously undefined subset of LGR5(+)-scleroderma-associated fibroblasts (ScAFs). ScAFs are perturbed morphologically and molecularly in SSc patients. Single-cell multiome profiling of stromal cells revealed ScAF-specific markers, pathways, regulatory elements, and transcription factors underlining disease development. Systematic analysis of these molecular features with clinical metadata associates specific ScAF targets with disease pathogenesis and SSc clinical traits. Our high-resolution atlas of the sclerodermatous skin spectrum will enable a paradigm shift in the understanding of SSc disease and facilitate the development of biomarkers and therapeutic strategies.