Xist ribonucleoproteins promote female sex-biased autoimmunity.

Autoimmune diseases disproportionately affect females more than males. The XX sex chromosome complement is strongly associated with susceptibility to autoimmunity. Xist long non-coding RNA (lncRNA) is expressed only in females to randomly inactivate one of the two X chromosomes to achieve gene dosage compensation. Here, we show that the Xist ribonucleoprotein (RNP) complex comprising numerous autoantigenic components is an important driver of sex-biased autoimmunity. Inducible transgenic expression of a non-silencing form of Xist in male mice introduced Xist RNP complexes and sufficed to produce autoantibodies. Male SJL/J mice expressing transgenic Xist developed more severe multi-organ pathology in a pristane-induced lupus model than wild-type males. Xist expression in males reprogrammed T and B cell populations and chromatin states to more resemble wild-type females. Human patients with autoimmune diseases displayed significant autoantibodies to multiple components of XIST RNP. Thus, a sex-specific lncRNA scaffolds ubiquitous RNP components to drive sex-biased immunity.

Myositis and Its Mimics: Guideline Updates, MRI Characteristics, and New Horizons.

Myositis is defined as inflammation within skeletal muscle and is a subcategory of myopathy, which is more broadly defined as any disorder affecting skeletal muscle. Myositis may be encountered as a component of autoimmune and connective tissue diseases, where it is described as idiopathic inflammatory myopathy (IIM). Myositis can also be caused by infections as well as toxins and drugs, including newer classes of medications. MRI plays an important role in the diagnosis and evaluation of patients with suspected myositis, but many entities may have imaging features similar to those of myositis and can be considered myositis mimics. These include muscular dystrophies, denervation, deep venous thrombosis, diabetic myonecrosis, muscle injury, heterotopic ossification, and even neoplasms. In patients with suspected myositis, definitive diagnosis may require integrated analysis of imaging findings with clinical, laboratory, and pathology data. The objectives of this article are to review the fundamental features of myositis, including recent updates in terminology and consensus guidelines for IIMs; the most important MRI differential diagnostic considerations for myositis (i.e., myositis mimics); and new horizons, including the potential importance of artificial intelligence and multimodal integrated diagnostics in the evaluation of patients with muscle disorders.

Performance of the 2017 EULAR/ACR Classification Criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups: a scoping review.

The 2017 EULAR/ACR classification criteria for adult/juvenile idiopathic inflammatory myopathies (IIM) were established using a data-driven approach by an international group of myositis experts to allow classification of IIM and its major subtypes. Since their publication, the performance of the criteria has been tested in multiple cohorts worldwide and significant limitations have been identified. Moreover, the understanding and classification of IIM have evolved since 2017. This scoping review was undertaken as part of a large international project to revise the EULAR/ACR criteria and aims to i) summarise the evidence from the current literature on the performance characteristics of the 2017 EULAR/ACR classification criteria in various cohorts and IIM subtypes, and ii) delineate the factors that need to be considered in the revision of the classification criteria. A systematic search of Medline (via PubMed), Cumulative Index to Nursing and Allied Health Literature, and conference abstract archives was conducted independently by three investigators for studies on the EULAR/ACR criteria published between October 2017 and January 2023. This scoping review of 19 articles and 13 abstracts revealed overall good performance characteristics of the EULAR/ACR criteria for IIM, yet deficiencies in lack of inclusion of certain IIM subtypes, such as immune mediated necrotising myopathy, amyopathic dermatomyositis, antisynthetase syndrome and overlap myositis. Published modifications that may improve the performance characteristics of the criteria for classification of IIM subtypes were also summarised. The results of this review suggest that a revision of the EULAR/ACR criteria is warranted.

Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank.

OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

Performance of the 2016 ACR-EULAR Myositis Response Criteria in adult dermatomyositis/polymyositis therapeutic trials and consensus profiles.

OBJECTIVE: The ACR-EULAR Myositis Response Criteria (MRC) were developed as a composite measure using absolute percentage change in six core set measures (CSMs). We aimed to further validate the MRC by assessing the contribution of each CSM, frequency of strength vs extramuscular activity improvement, representation of patient-reported outcome measures (PROM), and frequency of CSM worsening. METHODS: Data from adult dermatomyositis/polymyositis patients in the rituximab (n = 147), etanercept (n = 14), and abatacept (n = 19) trials, and consensus patient profiles (n = 232) were evaluated. The Total Improvement Score (TIS), number of improving vs worsening CSMs, frequency of improvement with and without muscle-related CSMs, and contribution of PROM were evaluated by MRC category. Regression analysis was performed to assess contribution of each CSM to the MRC. RESULTS: Of 412 adults with dermatomyositis/polymyositis, there were 37%, 24%, 25%, and 14% with no, minimal, moderate, and major MRC improvement, respectively. The number of improving CSMs and absolute percentage change in all CSMs increased by improvement category. In minimal-moderate improvement, only physician-reported disease activity contributed significantly more than expected by MRC. Of patients with at least minimal improvement, 95% had improvement in muscle-related measures and a majority (84%) had improvement in PROM. Patients with minimal improvement had worsening in a median of 1 CSM, and most patients with moderate-major improvement had no worsening CSMs. Physician assessment of change generally agreed with MRC improvement categories. CONCLUSION: The ACR-EULAR MRC performs consistently across multiple studies, further supporting its use as an efficacy end point in future myositis therapeutic trials.

Current concepts and advances in dermatomyositis: a dermatological perspective.

Dermatomyositis (DM) is an autoimmune disorder in which clinically amyopathic DM, characterised by hallmark cutaneous findings in the absence of clinical weakness, represents 20% of patients. This review will highlight current concepts and recent advances made in DM from a dermatological perspective, with a discussion of skin-predominant DM and its distinct challenges regarding diagnosis and management as well as their implications in clinical trials. An update will be presented with respect to classification criteria, pathogenesis in cutaneous DM, myositis-specific autoantibodies and their associations with cutaneous findings, skin-specific outcome measures and new therapeutics with their efficacy in skin disease.

A pilot study to evaluate the safety and efficacy of treprostinil in the treatment of calcinosis in systemic sclerosis.

OBJECTIVES: We evaluated the safety and efficacy of oral treprostinil in preventing progression of SSc-associated calcinosis. METHODS: This prospective open-label study enrolled 12 SSc patients meeting 2013 ACR/EULAR classification criteria with confirmed clinical and radiographic evidence of one or more calcinosis deposit in the hands. Patients received oral treprostinil for 1 year. Primary endpoints were safety/tolerability and percentage of patients without radiographic progression of calcinosis at 1 year (<25% increase in Scleroderma Clinical Trials Consortium radiographic score). Secondary endpoints included 1-year changes in Scleroderma HAQ (SHAQ), Cochin Hand Functional Scale, Medical Outcomes Survey Short Form 36 (SF-36), Raynaud Condition Score and patient/physician assessment of calcinosis severity. RESULTS: Twelve female patients were enrolled, half with diffuse cutaneous disease; median age was 55 years (range 35-68 years). Five patients completed the study. Seven patients withdrew due to intolerable adverse effects (n = 3), intercurrent unrelated illness (n = 2, cirrhosis, cancer), progressive SSc (n = 1) and personal reasons (n = 1). Most patients developed headaches and gastrointestinal adverse effects. Four of 11 (36%) patients with 1-year follow-up hand radiographs experienced progression of calcinosis. Of five who completed treatment, calcinosis was stable in four (80%) with progression in one. Based on SF-36 Physical and Mental Component and Domain scores, transition question and SF-6D utility score, all patients who finished the trial reported overall improvement or no change compared with baseline. CONCLUSION: Oral treprostinil was poorly tolerated in SSc patients with calcinosis. Of five patients who completed treatment, most (80%) had documented stability of calcinosis on hand radiographs at 1 year. CLINICALTRIALS.GOV IDENTIFIER: NCT02663895.

Defining anti-synthetase syndrome: a systematic literature review.

OBJECTIVES: Anti-synthetase syndrome (ASSD) is a heterogeneous autoimmune disease characterised by multi-system involvement with a wide variety of manifestations. Validated classification criteria are necessary to improve recognition and prevent misclassification, especially given the lack of reliable and standardised autoantibody testing. We systematically reviewed the literature to analyse proposed ASSD criteria, characteristics, and diagnostic performance. METHODS: We searched PubMed and Embase databases (01/01/1984 to 06/11/2018) and the ACR and EULAR meeting abstracts (2017-2018). Sensitivities, specificities, positive, negative likelihood ratios and risk of bias were calculated for ASSD criteria and key variables reported in the literature. We performed meta-analysis when appropriate. RESULTS: We retrieved 4,358 studies. We found 85 proposed ASSD criteria from a total of 82 studies. All but one study included anti-synthetase autoantibody (ARS) positivity in the ASSD criteria. Most studies required only one ASSD feature plus anti-ARS to define ASSD (n=64, 78%), whereas 16 studies required more than one ASSD variable plus anti-ARS. The only criteria not including anti-ARS positivity required 5 ASSD clinical features. We found limited data and wide variability in the diagnostic performance of each variable and definition proposed in the literature. Given these limitations we only meta-analysed the performance of individual muscle biopsy and clinical variables in diagnosing ASSD, which performed poorly. CONCLUSIONS: The current ASSD criteria include a variety of serological, clinical, and histological features with wide variability amongst proposed definitions and the performance of these definitions has not been tested. This systematic literature review suggests the need for additional data and consensus-driven classification criteria for ASSD.

Update on Cutaneous Signs to Assist in the Diagnosis of Dermatomyositis.

PURPOSE OF REVIEW: Dermatomyositis (DM) is a heterogeneous idiopathic inflammatory myopathy that can be challenging to diagnose. Learning about the cutaneous manifestations in DM can assist with prompt diagnosis as well as subgroup classification. This review highlights recent data regarding cutaneous signs in DM and their associations with myositis-specific antibodies (MSAs). RECENT FINDINGS: Several novel DM skin signs have recently been reported. Novel and confirmatory data have helped to define more clearly the associations between various cutaneous manifestations and MSAs. Awareness of the diverse cutaneous phenotypes can help with the timely diagnosis of DM. As some MSAs are associated with atypical skin features and/or characteristic patterns of clinical findings, knowledge of these associations can help clinicians to recognize DM patients. Understanding how the prevalence and presentation of various cutaneous signs differ among ethnically diverse patients is a high priority for further study.

Peripheral blood leucocyte telomere length is associated with progression of interstitial lung disease in systemic sclerosis.

BACKGROUND: Peripheral blood leucocyte telomere length (PBL-TL) is associated with outcomes in patients with idiopathic pulmonary fibrosis. Whether PBL-TL is associated with progression of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is unknown. METHODS: A retrospective observational cohort study was performed using prospectively collected data from 213 patients with SSc followed at the University of California San Francisco (UCSF) Scleroderma Center. PBL-TL was measured by quantitative PCR of DNA isolated from peripheral blood. Associations between PBL-TL and pulmonary function test trends in patients with SSc-ILD were assessed by longitudinal analysis using Generalised Linear Mixed Models. Findings were validated in a cohort of 61 patients with SSc-ILD enrolled in the Stanford University Scleroderma Center database. RESULTS: Patients with UCSF SSc with ILD were found to have shorter PBL-TL compared with those without ILD (6554±671 base pairs (bp) vs 6782±698 bp, p=0.01). Shorter PBL-TL was associated with the presence of ILD (adjusted OR 2.1 per 1000 bp TL decrease, 95% CI [1.25 to 3.70], p=0.006). PBL-TL was shorter in patients with SSc-ILD lacking SSc-specific autoantibodies compared with seropositive subjects (6237±647 bp vs 6651±653 bp, p=0.004). Shorter PBL-TL was associated with increased risk for lung function deterioration with an average of 67 mL greater loss in per year for every 1000 bp decrease in PBL-TL in the combined SSc-ILD cohorts (longitudinal analysis, adjusted model: 95% CI -104 mL to -33 mL, p<0.001). CONCLUSIONS: These findings suggest that telomere dysfunction may be associated with SSc-ILD progression and that PBL-TL measurement may be useful for stratifying risk for SSc-ILD progression.

A systematic review and meta-analysis to inform cancer screening guidelines in idiopathic inflammatory myopathies.

OBJECTIVES: To identify clinical factors associated with cancer risk in the idiopathic inflammatory myopathies (IIMs) and to systematically review the existing evidence related to cancer screening. METHODS: A systematic literature search was carried out on Medline, Embase and Scopus. Cancer risk within the IIM population (i.e. not compared with the general population) was expressed as risk ratios (RR) for binary variables and weighted mean differences (WMD) for continuous variables. Evidence relating to cancer screening practices in the IIMs were synthesized via narrative review. RESULTS: Sixty-nine studies were included in the meta-analysis. DM subtype (RR 2.21), older age (WMD 11.19), male sex (RR 1.53), dysphagia (RR 2.09), cutaneous ulceration (RR 2.73) and anti-transcriptional intermediary factor-1 gamma positivity (RR 4.66) were identified as being associated with significantly increased risk of cancer. PM (RR 0.49) and clinically amyopathic DM (RR 0.44) subtypes, Raynaud's phenomenon (RR 0.61), interstitial lung disease (RR 0.49), very high serum creatine kinase (WMD -1189.96) or lactate dehydrogenase (WMD -336.52) levels, and anti-Jo1 (RR 0.45) or anti-EJ (RR 0.17) positivity were identified as being associated with significantly reduced risk of cancer. Nine studies relating to IIM-specific cancer screening were included. CT scanning of the thorax, abdomen and pelvis appeared to be effective in identifying underlying asymptomatic cancers. CONCLUSION: Cancer risk factors should be evaluated in patients with IIM for risk stratification. Screening evidence is limited but CT scanning could be useful. Prospective studies and consensus guidelines are needed to establish cancer screening strategies in IIM patients.

Distinct dermatomyositis populations are detected with different autoantibody assay platforms.

OBJECTIVES: To compare autoantibody-defined dermatomyositis sub-populations using immunoprecipitation-based assays, a commercially available line immunoblot assay and alternate commercial ELISA assays. METHODS: Banked plasma from 261 carefully phenotyped dermatomyositis patients was studied. Immunoprecipitation-based assays were used to detect antibodies against Mi2, TIF1-γ MDA5, NXP2, SAE1 and PM-Scl, while anti-Jo1 antibodies were assayed using ELISA. These data were compared with that obtained using a commercial line immunoblot, and, additionally, for Mi2, TIF1-γ, MDA5, commercially available ELISA kits. Test agreement was measured using Cohen's kappa statistic, and phenotypic differences between differentially identified groups are described. RESULTS: Line immunoblot, immunoprecipitation, and ELISA detected increasingly larger nested pools of anti-TIF1-γ samples, with increasing frequency of concurrent anti-Mi2 reactivity and decreasing incidence of malignancy. Line immunoblot and immunoprecipitation showed fair concordance for identifying anti-NXP2 antibodies (Cohen's kappa=0.71) but very good agreement for identifying antibodies against Mi2, MDA5, and SAE1 (Cohen's κ=0.9, 0.94, 0.88, respectively). Anti-PM-Scl results showed moderate agreement (Cohen's κ=0.48) between immunoblot and immunoprecipitation. CONCLUSIONS: Our results demonstrate that for some specificities, especially anti-TIF1-γ, antibody results obtained using different assay platforms vary, and identify significantly different patient populations. These findings highlight the need for standard adoption of carefully validated platforms to detect dermatomyositis autoantibodies.

Clinical factors associated with cutaneous histopathologic findings in dermatomyositis.

BACKGROUND: Common histopathologic findings in cutaneous dermatomyositis include vacuolar interface with dyskeratosis, mucin, and perivascular inflammation. Data examining the relationships between these and other histologic abnormalities, or their dependence on biopsy site, and medications are limited. METHODS: Using 228 dermatomyositis skin biopsies and statistical analyses including Chi-squared analyses, calculations of relative risk, and adjusted generalized estimating equation regressions, we investigated relationships between 14 histopathologic findings and the impact of clinical factors on these findings. RESULTS: In biopsies taken from sites of visible rash, interface dermatitis was seen in 91%, and 95% had at least one of perivascular inflammation, mucin, or basal vacuolization. Vascular abnormalities were not closely associated with epidermal or inflammatory findings. Concomitant prednisone significantly decreased the odds of basal vacuolization (odds ratio [OR] = 0.34, 95% confidence interval [CI]: 0.12-0.98, P-value = 0.05), perivascular inflammation (OR = 0.19, 95% CI: 0.07-0.53, P-value = 0.002), and vessel damage (OR = 0.81, 95% CI: 0.68-0.96, P-value = 0.02). CONCLUSION: Vasculopathy and classic findings of interface dermatitis may be driven by unique pathways in dermatomyositis. Corticosteroid use may impact skin biopsy findings. There is a need for clinicopathologic correlation when diagnosing dermatomyositis.

Dermatomyositis Clinical and Pathological Phenotypes Associated with Myositis-Specific Autoantibodies.

PURPOSE OF REVIEW: Dermatomyositis is an idiopathic inflammatory myopathy with a variety of systemic and cutaneous manifestations. The myositis-specific autoantibodies (MSAs) are associated with phenotypic features and provide a tool for sub-classification of dermatomyositis patients. This review focuses on recent work characterizing the clinical features that accompany the MSAs in dermatomyositis. RECENT FINDINGS: There is increasing recognition of the distinct clinical and pathological phenotypes associated with each MSA. Most of these features display considerable overlap between MSA groups. Despite this, there are notable differences between the typical combinations of cutaneous and systemic manifestations, response to therapy, prognosis, and disease sequelae that define each dermatomyositis MSA group. The MSAs may ultimately improve diagnosis and sub-classification of dermatomyositis patients. However, more work is needed to understand the pathologic basis for much of the heterogeneity found within these subgroups.

Re-examining mechanic's hands as a characteristic skin finding in dermatomyositis.

Mechanic's hands is a poorly defined clinical finding that has been reported in a variety of rheumatologic diseases. Morphologic descriptions include hyperkeratosis on the sides of the digits that sometimes extends to the distal tips, diffuse palmar scale, and (more recently observed) linear discrete scaly papules in a similar lateral distribution. The association of mechanic's hands with dermatomyositis, although recognized, is still debatable. In this review, most studies have shown that mechanic's hands is commonly associated with dermatomyositis and displays histopathologic findings of interface dermatitis, colloid bodies, and interstitial mucin, which are consistent with a cutaneous connective tissue disease. A more specific definition of this entity would help to determine its usefulness in classifying and clinically identifying patients with dermatomyositis, with implications related to subsequent screening for associated comorbidities in this setting.

2016 American College of Rheumatology/European League Against Rheumatism criteria for minimal, moderate, and major clinical response in adult dermatomyositis and polymyositis: An International Myositis Assessment and Clinical Studies Group/Paediatric Rheumatology International Trials Organisation Collaborative Initiative.

To develop response criteria for adult dermatomyositis (DM) and polymyositis (PM). Expert surveys, logistic regression, and conjoint analysis were used to develop 287 definitions using core set measures. Myositis experts rated greater improvement among multiple pairwise scenarios in conjoint analysis surveys, where different levels of improvement in 2 core set measures were presented. The PAPRIKA (Potentially All Pairwise Rankings of All Possible Alternatives) method determined the relative weights of core set measures and conjoint analysis definitions. The performance characteristics of the definitions were evaluated on patient profiles using expert consensus (gold standard) and were validated using data from a clinical trial. The nominal group technique was used to reach consensus. Consensus was reached for a conjoint analysis-based continuous model using absolute per cent change in core set measures (physician, patient, and extramuscular global activity, muscle strength, Health Assessment Questionnaire, and muscle enzyme levels). A total improvement score (range 0-100), determined by summing scores for each core set measure, was based on improvement in and relative weight of each core set measure. Thresholds for minimal, moderate, and major improvement were ≥20, ≥40, and ≥60 points in the total improvement score. The same criteria were chosen for juvenile DM, with different improvement thresholds. Sensitivity and specificity in DM/PM patient cohorts were 85% and 92%, 90% and 96%, and 92% and 98% for minimal, moderate, and major improvement, respectively. Definitions were validated in the clinical trial analysis for differentiating the physician rating of improvement (p<0.001). The response criteria for adult DM/PM consisted of the conjoint analysis model based on absolute per cent change in 6 core set measures, with thresholds for minimal, moderate, and major improvement.

2016 ACR-EULAR adult dermatomyositis and polymyositis and juvenile dermatomyositis response criteria-methodological aspects.

Objective: The objective was to describe the methodology used to develop new response criteria for adult DM/PM and JDM. Methods: Patient profiles from prospective natural history data and clinical trials were rated by myositis specialists to develop consensus gold-standard ratings of minimal, moderate and major improvement. Experts completed a survey regarding clinically meaningful improvement in the core set measures (CSM) and a conjoint-analysis survey (using 1000Minds software) to derive relative weights of CSM and candidate definitions. Six types of candidate definitions for response criteria were derived using survey results, logistic regression, conjoint analysis, application of conjoint-analysis weights to CSM and published definitions. Sensitivity, specificity and area under the curve were defined for candidate criteria using consensus patient profile data, and selected definitions were validated using clinical trial data. Results: Myositis specialists defined the degree of clinically meaningful improvement in CSM for minimal, moderate and major improvement. The conjoint-analysis survey established the relative weights of CSM, with muscle strength and Physician Global Activity as most important. Many candidate definitions showed excellent sensitivity, specificity and area under the curve in the consensus profiles. Trial validation showed that a number of candidate criteria differentiated between treatment groups. Top candidate criteria definitions were presented at the consensus conference. Conclusion: Consensus methodology, with definitions tested on patient profiles and validated using clinical trials, led to 18 definitions for adult PM/DM and 14 for JDM as excellent candidates for consideration in the final consensus on new response criteria for myositis.

Risk of malignancy with systemic psoriasis treatment in the Psoriasis Longitudinal Assessment Registry.

BACKGROUND: The effect of systemic therapy on malignancy risk among patients with psoriasis is not fully understood. OBJECTIVE: Evaluate the impact of systemic treatment on malignancy risk among patients with psoriasis in the Psoriasis Longitudinal Assessment and Registry (PSOLAR). METHODS: Nested case-control analyses were performed among patients with no history of malignancy. Cases were defined as first malignancy (other than nonmelanoma skin cancer) in the Psoriasis Longitudinal Assessment and Registry, and controls were matched by age, sex, geographic region, and time on registry. Study therapies included methotrexate, ustekinumab, and tumor necrosis factor-α (TNF-α) inhibitors. Exposure was defined as 1 or more doses of study therapy within 12 months of malignancy onset and further stratified by duration of therapy. Multivariate conditional logistic regression, adjusted for potential confounders, was used to estimate odds ratios of malignancies associated with therapy. RESULTS: Among 12,090 patients, 252 malignancy cases were identified and 1008 controls were matched. Treatment with methotrexate or ustekinumab for more than 0 months to less than 3 months, 3 months to less than 12 months, or 12 months or longer was not associated with increased malignancy risk versus no exposure. Longer-term (≥12 months) (odds ratio, 1.54; 95% confidence interval, 1.10-2.15; P = .01), but not shorter-term treatment, with a TNF-α inhibitor was associated with increased malignancy risk. LIMITATIONS: Cases and controls could belong to 1 or more therapy categories. CONCLUSIONS: Long-term (≥12 months) treatment with a TNF-α inhibitor, but not methotrexate and ustekinumab, may increase risk for malignancy in patients with psoriasis.