Objective
To characterize the cutaneous and systemic clinical phenotype of dermatomyositis patients with antinuclear matrix protein 2 (anti–NXP‐2) antibodies.
Methods
We conducted a retrospective ...cohort analysis of 178 dermatomyositis patients seen at the Stanford University Clinic. An electronic chart review employing a keyword search strategy was performed to collect clinical and laboratory data. Anti–NXP‐2 antibodies were assayed by immunoprecipitation using NXP‐2 produced by in vitro transcription/translation.
Results
Antibodies to NXP‐2 were detected in 20 of the 178 patients (11%). Anti–NXP‐2 antibodies were associated with male sex (50% versus 25%; P = 0.02), dysphagia (74% versus 39%; P = 0.006), myalgia (89% versus 52%; P = 0.002), peripheral edema (35% versus 11%; P = 0.016), and calcinosis (37% versus 11%; P = 0.007). These patients were less likely to be clinically amyopathic (5% versus 23%; P = 0.08). Five of the 20 patients with anti–NXP‐2 antibodies (25%) had an associated internal malignancy. No other cutaneous characteristics were associated with anti–NXP‐2 antibodies, except a decreased frequency of Gottron's sign (44% versus 75%; P = 0.012) and a greater likelihood of having mild skin disease.
Conclusion
Dermatomyositis patients with anti–NXP‐2 antibodies have a distinct and often severe systemic phenotype that includes myalgia, peripheral edema, and significant dysphagia, despite having milder inflammatory skin disease.
Objective
While compelling data suggest a cancer‐induced autoimmunity model in scleroderma patients with anti–RNA polymerase III large subunit (anti‐RPC155) antibodies, ~85% of these patients do not ...manifest cancer. This study was undertaken to determine whether additional autoantigens are targeted in anti‐RPC155–positive scleroderma patients without detectable cancer.
Methods
The study included 168 scleroderma patients with anti‐RPC155 antibodies (80 with a history of cancer and 88 with no cancer diagnosis after >5 years of follow‐up). Thirty‐five sera (17 from patients with cancer and 18 from patients without cancer) were randomly selected for autoantibody discovery using immunoprecipitation (IP). An ~194‐kd band was enriched in the subgroup without cancer; this was identified as RNA polymerase I large subunit (RPA194).
Results
RPA194 generated by in vitro transcription/translation was used for IPs performed on the entire cohort to test whether anti‐RPA194 was enriched among anti‐RPC155–positive patients without cancer. Anti‐RPA194 antibodies were significantly more common in the group without cancer (16 18.2% of 88) than in the group with cancer (3 3.8% of 80) (P = 0.003). Patients with both anti‐RPA194 and anti‐RPC155 were significantly less likely to have severe gastrointestinal disease than patients with anti‐RPC155 only (26.3% versus 51.0%; P = 0.043).
Conclusion
Anti‐RPA194 antibodies are enriched in anti‐RPC155–positive scleroderma patients without cancer. Since somatic mutations in the gene encoding RPC155 in cancer in scleroderma patients appears to play a role in immune response initiation against RPC155 in those patients, these data raise the possibility that the development of immune responses to both RPC155 and RPA194 may influence clinical cancer emergence. Further study is required to define whether different autoantibody combinations have utility as tools for cancer risk stratification in scleroderma.
Objective
This open‐label 12‐week study was conducted to evaluate the efficacy and safety of tofacitinib, a JAK inhibitor, in treatment‐refractory active dermatomyositis (DM).
Methods
Tofacitinib in ...extended‐release doses of 11 mg was administered daily to 10 subjects with DM. Prior to treatment, a complete washout of all steroid‐sparing agents was performed. The primary outcome measure was assessment of disease activity improvement based on the International Myositis Assessment and Clinical Studies group definition of improvement. Response rate was measured as the total improvement score according to the 2016 American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) myositis response criteria. Secondary outcome measures included Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) scores, chemokine levels, immunohistochemical analysis of STAT1 expression in the skin, RNA sequencing analysis, and safety.
Results
At 12 weeks, the primary outcome was met in all 10 subjects. Five (50%) of 10 subjects experienced moderate improvement in disease activity, and the other 50% experienced minimal improvement according to the 2016 ACR/EULAR myositis response criteria. The secondary outcome of the mean change in the CDASI activity score over 12 weeks was statistically significant (mean ± SD 28 ± 15.4 at baseline versus 9.5 ± 8.5 at 12 weeks) (P = 0.0005). Serum chemokine levels of CXCL9/CXCL10 showed a statistically significant change from baseline. A marked decrease in STAT1 signaling in association with suppression of interferon target gene expression was demonstrated in 3 of 9 skin biopsy samples from subjects with dermatomyositis. The mean ± SD level of creatine kinase in the 10 subjects at baseline was 82 ± 34.8 IU/liter, highlighting that disease activity was predominantly located in the skin.
Conclusion
This is the first prospective, open‐label clinical trial of tofacitinib in DM that demonstrates strong clinical efficacy of a pan‐JAK inhibitor, as measured by validated myositis response criteria. Future randomized controlled trials using JAK inhibitors should be considered for treating DM.
Objective
To determine the frequency with which adults with dermatomyositis (DM) are able to discontinue systemic immunomodulatory therapy and factors associated with medication cessation.
Methods
We ...studied a cohort of adult DM patients seen in a rheumatology/dermatology clinic between 2013 and 2020. All patients had exposure to at least 1 systemic immunomodulatory medication for a minimum of 3 months and were followed until medications were discontinued for at least 12 months. Survival analysis was performed using Kaplan‐Meier curves with log‐rank analyses, and multivariate analysis was done using Cox proportional hazards models.
Results
A total of 246 DM patients were followed up for a median time of ∼7 years (47–134 months). Forty‐seven patients (19%) discontinued all immunomodulatory medications with a median follow‐up of ∼3 years (interquartile range 22–108 months) following DM onset. Log‐rank analysis demonstrated that those with anti‐MDA5 autoantibodies discontinued medications faster compared with those without autoantibodies (P = 0.03). Multivariate modeling showed that clinically amyopathic patients were 2.7‐fold (95% confidence interval 95% CI 1.34–5.59) more likely to discontinue medications than those with muscle disease. Those with anti‐MDA5, anti‐NXP2, and anti‐SAE1 antibodies had increased likelihood of medication cessation with hazard ratios of 9.83 (95% CI 2.00–48.2), 8.92 (95% CI 1.69–47.0), and 10.8 (95% CI 2.06–56.6), respectively, when compared with the autoantibody‐negative group.
Conclusion
Approximately 20% of adult DM patients discontinued immunomodulatory medications over a median 7‐year follow‐up. Those with clinically amyopathic disease, anti‐MDA5, anti‐NXP2, and anti‐SAE1 antibodies have a higher likelihood of medication cessation.
Objective
Dermatomyositis (DM) patients typically present with proximal weakness and autoantibodies that are associated with distinct clinical phenotypes. We observed that DM patients with ...autoantibodies recognizing the nuclear matrix protein NXP‐2 often presented with especially severe weakness. The aim of this study was to characterize the clinical features associated with anti–NXP‐2 autoantibodies.
Methods
There were 235 DM patients who underwent testing for anti–NXP‐2 autoantibodies. Patient characteristics, including muscle strength, were compared between those with and without these autoantibodies. The number of cancer cases observed in anti–NXP‐2‐positive subjects was compared with the number expected in the general population.
Results
Of the DM patients, 56 (23.8%) were anti–NXP‐2‐positive. There was no significant difference in the prevalence of proximal extremity weakness in patients with and without anti–NXP‐2. In contrast, anti–NXP‐2‐positive patients had more prevalent weakness in the distal arms (35% versus 20%; P = 0.02), distal legs (25% versus 8%; P < 0.001), and neck (48% versus 23%; P < 0.001). Anti–NXP‐2‐positive subjects were also more likely to have dysphagia (62% versus 35%; P < 0.001), myalgia (46% versus 25%; P = 0.002), calcinosis (30% versus 17%; P = 0.02), and subcutaneous edema (36% versus 19%; P = 0.01) than anti–NXP‐2‐negative patients. Five anti–NXP‐2‐positive subjects (9%) had cancer‐associated myositis, representing a 3.68‐fold increased risk (95% confidence interval 1.2–8.6) compared to the expected prevalence in the general population.
Conclusion
In DM, anti–NXP‐2 autoantibodies are associated with subcutaneous edema, calcinosis, and a muscle phenotype characterized by myalgia, proximal and distal weakness, and dysphagia. As anti–NXP‐2‐positive patients have an increased risk of cancer, we suggest that they undergo comprehensive cancer screening.
Objective
Autoantibodies against melanoma differentiation–associated protein 5 (MDA‐5) have been described in several Asian dermatomyositis (DM) cohorts, often associated with amyopathic DM and ...rapidly progressive interstitial lung disease (ILD). A recent study of a DM cohort seen at a US dermatology clinic reports that MDA‐5 autoantibodies are associated with a unique cutaneous phenotype. Given the widening spectrum of clinical findings, we evaluated the clinical features of anti–MDA‐5–positive patients seen at a US myositis referral center.
Methods
One hundred sixty DM patients were screened for MDA‐5 autoantibodies by immunoprecipitation and antibody titers were analyzed in longitudinal serum samples. Anti–MDA‐5–positive patients were evaluated for the presence of additional myositis autoantibodies. Patient clinical characteristics were compared by retrospective chart review.
Results
MDA‐5 was targeted in 11 (6.9%) of 160 patients with DM. Of these, 9 presented with a symmetric polyarthropathy, 6 demonstrated overt clinical myopathy, and 8 had ILD. Eight anti–MDA‐5–positive patients exhibited the clinical attributes of the antisynthetase syndrome in the absence of Jo‐1 or other antisynthetase autoantibodies. MDA‐5 autoantibody titers did not correlate with clinical course.
Conclusion
MDA‐5 autoantibodies are found in DM patients presenting with a symmetric polyarthritis, clinically similar to rheumatoid arthritis. These patients often have features of the antisynthetase syndrome, but in the absence of antisynthetase autoantibodies. Most anti–MDA‐5–positive patients had overt clinical myopathy and ILD. The latter, while occasionally severe, typically resolved with immunosuppressive therapy. In this cohort, the MDA‐5 phenotype is frequently a clinical mimic of the antisynthetase syndrome and is not associated with rapidly progressive ILD.
Objective
Sjögren's syndrome (SS) is an autoimmune disease that targets the salivary and lacrimal glands. While all patients demonstrate inflammatory infiltration and abnormal secretory function in ...the target tissues, the disease features, pathology, and clinical course can vary. Activation of distinct inflammatory pathways may drive disease heterogeneity. The purpose of this study was to investigate whether activation of the interferon (IFN) pathway correlates with key phenotypic features.
Methods
Clinical data and 1 labial salivary gland (stored frozen) were obtained from each of 82 participants (53 patients with primary SS and 29 control subjects) in the Sjögren's International Collaborative Clinical Alliance (SICCA) registry. Salivary gland lysates were immunoblotted with markers of type I or type II IFN, and patterns of IFN activity were determined by hierarchical clustering. Correlations between SS phenotypic features and IFN activity in the salivary gland were performed.
Results
A total of 58% of the SS participants had high IFN activity and differed significantly from those with low IFN activity (higher prevalence of abnormal findings on sialometry, leukopenia, hyperglobulinemia, high‐titer antinuclear antibody, anti‐SSA, and high focus score on labial salivary gland LSG biopsy). Three distinct patterns of IFN were evident: type I–predominant, type II–predominant, and type I/II mixed IFN. These groups were clinically indistinguishable except for the LSG focus score, which was highest in those with type II–predominant IFN.
Conclusion
The SS phenotype includes distinct molecular subtypes, which are segregated by the magnitude and pattern of IFN responses. Associations between IFN pathways and disease activity suggest that IFNs are relevant therapeutic targets in SS. Patients with distinct patterns of high IFN activity are clinically similar, demonstrating that IFN‐targeting therapies must be selected according to the specific pathway(s) that is active in vivo in the individual patient.
This paper presents a model‐based method for clustering multivariate binary observations that incorporates constraints consistent with the scientific context. The approach is motivated by the ...precision medicine problem of identifying autoimmune disease patient subsets or classes who may require different treatments. We start with a family of restricted latent class models or RLCMs. However, in the motivating example and many others like it, the unknown number of classes and the definition of classes using binary states are among the targets of inference. We use a Bayesian approach to RLCMs in order to use informative prior assumptions on the number and definitions of latent classes to be consistent with scientific knowledge so that the posterior distribution tends to concentrate on smaller numbers of clusters and sparser binary patterns. The paper derives a posterior sampling algorithm based on Markov chain Monte Carlo with split‐merge updates to efficiently explore the space of clustering allocations. Through simulations under the assumed model and realistic deviations from it, we demonstrate greater interpretability of results and superior finite‐sample clustering performance for our method compared to common alternatives. The methods are illustrated with an analysis of protein data to detect clusters representing autoantibody classes among scleroderma patients.
Objective
Autoantibodies are clinically useful for phenotyping patients across the spectrum of autoimmune rheumatic diseases. Using serum from a patient with Sjögren's syndrome (SS), we detected a ...new specificity by immunoblotting. This study was undertaken to identify this autoantibody and to evaluate its disease specificity.
Methods
A prominent 40‐kd band was detected when immunoblotting was performed using SS patient serum and lysate from rat dorsal root ganglia (DRGs). Using 2‐dimensional gel electrophoresis and liquid chromatography tandem mass spectrometry peptide sequencing, the autoantigen was identified as calponin 3. Anti–calponin 3 antibodies were evaluated in sera from patients with primary SS (n = 209), patients with systemic lupus erythematosus (SLE; n = 138), patients with myositis (n = 138), patients with multiple sclerosis (MS; n = 44), and healthy controls (n = 46) by enzyme‐linked immunosorbent assay. Expression of calponin 3 was assessed by immunohistochemistry.
Results
Calponin 3 was identified as a new autoantigen. Anti–calponin 3 antibodies were detected in 23 (11.0%) of the 209 SS patients, 12 (8.7%) of the 138 SLE patients, 7 (5.1%) of the 138 myositis patients, 3 (6.8%) of the 44 MS patients, and 1 (2.2%) of the 46 healthy controls. Among SS patients, the frequency of anti–calponin 3 antibodies was highest in those with neuropathies (7 17.9% of 39). In this subset, the frequency of anti–calponin 3 antibodies differed significantly from that in the control group (P = 0.02). Calponin 3 was expressed primarily in rat DRG perineuronal satellite cells but not neurons.
Conclusion
Calponin 3 is a novel autoantigen. Antibodies against this protein are found in SS and associate with the subset of patients experiencing neuropathies. Intriguingly, we found that calponin 3 is expressed in DRG perineuronal satellite cells, suggesting that these may be a target in SS.
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