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Mycophenolate is the mainstay of treatment for many organ and life-threatening manifestations of rheumatic and musculoskeletal diseases (RMD). In contrast to most patients with RMD, those taking mycophenolate have an attenuated humoral response to SARS-CoV-2 mRNA vaccination.1 2 The American College of Rheumatology recently recommended withholding mycophenolate for 1 week after vaccination to enhance immunogenicity in this vulnerable population.3 Thus, we sought to analyse the impact of withholding perivaccination mycophenolate in 24 patients with RMD. We leveraged our observational prospective cohort of patients with RMD without prior COVID-19 who underwent SARS-CoV-2 vaccination between 17 December 2020 and 13 May 2021.2 Information on demographics, diagnoses, immunosuppressive regimens and management of perivaccination immunosuppression was collected via electronic questionnaire. One month following vaccination, venipuncture samples were obtained and tested on the semiquantitative Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay which tests for antibodies against the receptor binding domain (RBD) of the SARS-CoV-2 spike protein; a consistent correlate of neutralising antibody.4 We compared the percentage of participants with detectable anti-RBD antibody in the group that withheld mycophenolate (n=24) to the group that continued mycophenolate (n=171) using Fisher’s exact test (online supplemental table 1). Crude and adjusted logistic regression analyses were performed to assess associations between antibody response and the primary variable of withholding mycophenolate, as well as after adjusting for clinical characteristics (age, sex, race, vaccine type (mRNA vs adenovirus vector), use of rituximab and glucocorticoids). Wilcoxon rank-sum test was used to compare anti-RBD titers of the …

ObjectivesTo compare the safety and effectiveness of biologic and conventional disease-modifying antirheumatic drugs (DMARDs) for immune checkpoint inhibitor-associated inflammatory arthritis (ICI-IA).MethodsThe retrospective multicentre observational study included patients with a diagnosis of ICI-IA treated with a tumour necrosis factor inhibitor (TNFi), interleukin-6 receptor inhibitor (IL6Ri) and/or methotrexate (MTX); patients with pre-existing autoimmune disease were excluded. The primary outcome was time to cancer progression from ICI initiation; the secondary outcome was time to arthritis control from DMARD initiation. Cox proportional hazard models were used to compare medication groups, adjusting for confounders.Results147 patients were included (mean age 60.3 (SD 11.9) years, 66 (45%) women). ICI-IA treatment was TNFi in 33 (22%), IL6Ri 42 (29%) and MTX 72 (49%). After adjustment for time from ICI initiation to DMARD initiation, time to cancer progression was significantly shorter for TNFi compared with MTX (HR 3.27 (95% CI 1.21 to 8.84, p=0.019)) while the result for IL6Ri was HR 2.37 (95% CI 0.94 to 5.98, p=0.055). Time to arthritis control was faster for TNFi compared with MTX (HR 1.91 (95% CI 1.06 to 3.45, p=0.032)) while the result for IL6Ri was HR 1.66 (95% CI 0.93 to 2.97, p=0.089). A subset analysis in patients with melanoma gave similar results for both cancer progression and arthritis control.ConclusionThe treatment of ICI-IA with a biologic DMARD is associated with more rapid arthritis control than with MTX, but may be associated with a shorter time to cancer progression.

Numerous studies have identified autoantibody status as an important biomarker of cancer risk around the time of systemic sclerosis (SSc) onset. For example, anti-RNA polymerase III antibody positivity associates with increased cancer risk near SSc onset, while the presence of anticentromere or anti-Th/To antibodies may be protective.1–4 In this context, we selected serum from a well-characterised patient with SSc with squamous cell skin cancer and a short cancer–scleroderma interval to discover cancer-associated autoantibodies. Immunoprecipitations performed with this serum using 624 melanoma cell lysates were subjected to on bead digestion and liquid chromatography tandem mass spectrometry peptide sequencing. This identified antibodies targeting the tumour suppressor gene, acidic leucine-rich nuclear phosphoprotein (ANP32A), which migrates on SDS-polyacrylamide gels at ~28.5 kDa. Antibodies against ANP32A were validated in this serum by immunoprecipitation using 35S-methionine labelled ANP32A generated by in vitro transcription/translation from DNA (Origene) as described.5 To further explore the association between anti-ANP32A antibodies and cancer in patients with SSc, sera from patients with (n=213) and without cancer (n=190) were randomly selected from the Johns Hopkins Scleroderma Center Research Registry for anti-ANP32A antibody testing. The Registry prospectively collects demographic information, cancer diagnoses and longitudinal disease metrics. …

We were interested to read the letter by Ceccarelli et al regarding their experience with Immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA) at Sapienza University.1 Their findings support that ICI-induced IA is a heterogeneous disease with differing outcomes. The differences in the cohorts studied may also give us insight into the risk factors …

ObjectiveWe sought to investigate the long-term outcomes of patients who develop immune checkpoint inhibitor (ICI)-induced inflammatory arthritis (IA), to define factors associated with IA persistence after ICI cessation, the need for immunosuppressants and the impact of these medications on underlying malignancies.MethodsWe conducted a prospective observational study of patients referred for IA associated with ICIs. Patients were recruited from June 2015 to December 2018. Information was obtained at the baseline visit, and follow-up visits occurred at varying intervals for up to 24 months from ICI cessation. Kaplan-Meier curves were developed to characterise IA persistence. Cox proportional hazards models were used to assess the influence of various factors on IA persistence. Logistic regression was used to evaluate the impact of IA treatment on tumour response.ResultsSixty patients were monitored with a median follow-up after ICI cessation of 9 months. A majority (53.3%) had active IA at their most recent follow-up. IA was less likely to improve in those with longer duration of ICI use, in those receiving combination ICI therapy, and in patients with multiple other immune-related adverse events. Tumour response did not appear to be impacted by immunosuppression. Although not statistically significant, persistent IA was correlated with a better tumour response (complete or partial response).ConclusionICI-induced IA can become a long-term disease necessitating management by rheumatology for immunomodulatory treatment. Importantly, the use of immunomodulatory treatment has not been shown to impact cancer outcomes in this study.

ObjectivesDetermine global skin transcriptome patterns of early diffuse systemic sclerosis (SSc) and how they differ from later disease.MethodsSkin biopsy RNA from 48 patients in the Prospective Registry for Early Systemic Sclerosis (PRESS) cohort (mean disease duration 1.3 years) and 33 matched healthy controls was examined by next-generation RNA sequencing. Data were analysed for cell type-specific signatures and compared with similarly obtained data from 55 previously biopsied patients in Genetics versus Environment in Scleroderma Outcomes Study cohort with longer disease duration (mean 7.4 years) and their matched controls. Correlations with histological features and clinical course were also evaluated.ResultsSSc patients in PRESS had a high prevalence of M2 (96%) and M1 (94%) macrophage and CD8 T cell (65%), CD4 T cell (60%) and B cell (69%) signatures. Immunohistochemical staining of immune cell markers correlated with the gene expression-based immune cell signatures. The prevalence of immune cell signatures in early diffuse SSc patients was higher than in patients with longer disease duration. In the multivariable model, adaptive immune cell signatures were significantly associated with shorter disease duration, while fibroblast and macrophage cell type signatures were associated with higher modified Rodnan Skin Score (mRSS). Immune cell signatures also correlated with skin thickness progression rate prior to biopsy, but did not predict subsequent mRSS progression.ConclusionsSkin in early diffuse SSc has prominent innate and adaptive immune cell signatures. As a prominently affected end organ, these signatures reflect the preceding rate of disease progression. These findings could have implications in understanding SSc pathogenesis and clinical trial design.

ObjectivesImmune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and programmed cell death protein 1 (PD-1) pathways have demonstrated survival improvements in multiple advanced cancers, but also cause immune-related adverse events (IRAEs). IRAEs with clinical features similar to rheumatic diseases have not been well described. We report patients with inflammatory arthritis and sicca syndrome secondary to ICIs.MethodsWe report patients evaluated in the Johns Hopkins Rheumatology clinics from 2012 to 2016 identified as having new rheumatological symptoms in the context of treatment with ipilimumab (anti-CTLA-4) and/or nivolumab (anti-PD-1) for solid tumours.ResultsWe identified 13 patients who received ICIs and developed rheumatological IRAEs. Mean age was 58.7 years. Cancer types included melanoma, non-small cell lung cancer, small cell lung cancer and renal cell carcinoma. ICI regimens included nivolumab or ipilimumab as monotherapy (n=5), or combination nivolumab and ipilimumab (n=8). Nine of 13 patients developed an inflammatory arthritis, 4 with synovitis confirmed on imaging (3 ultrasound, 1 MRI) and 4 with inflammatory synovial fluid. Four patients developed sicca syndrome with severe salivary hypofunction. Other IRAEs included: pneumonitis, colitis, interstitial nephritis and thyroiditis. Antinuclear antibodies were positive in 5 out of 13 patients. All 13 patients were treated with corticosteroids with varying response. Two patients were treated with methotrexate and antitumor necrosis factor therapy for inflammatory arthritis.ConclusionsAs ICIs are increasingly used for a range of malignancies, new cases of rheumatic IRAEs are likely to emerge. Further research is required to understand mechanisms, determine risk factors and develop management algorithms for rheumatic IRAEs.

ObjectivesAnnual echocardiography screening is widely used in scleroderma, but the utility of longitudinal assessment is unknown. We evaluated whether change in right ventricular systolic pressure (RVSP) was a risk factor for mortality and development of pulmonary arterial hypertension (PAH) in a cohort of scleroderma patients.MethodsThe study population consisted of scleroderma patients who had at least three echocardiograms and pulmonary function tests (PFTs) over ≥1 year as part of routine care. The annual rate of change in RVSP was determined for each subject. Cox proportional hazards regression was performed to assess the association between PAH and mortality and change in RVSP/year, adjusted for relevant covariates.Results613 scleroderma patients with 3244 echocardiograms were studied. The adjusted relative hazards of PAH and mortality were 1.08 (95% CI 1.05–1.11) and 1.12 (95% CI 1.08–1.15) per 1 mm Hg increase in RVSP/year, respectively. Compared with patients with a stable RVSP, the relative hazards for the development of PAH were 1.90 (95% CI 0.91–3.96), 5.09 (95% CI 2.53–10.26) and 6.15 (95% CI 3.58–10.56) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99 and 3+ mm Hg/year. Compared with the same reference group, the relative hazards for death were 0.92 (95% CI 0.48–1.73), 2.16 (95% CI 1.16–4.01) and 5.05 (95% CI 3.47–7.34) for subjects whose RVSP increased at rates of 1–1.99, 2–2.99 and 3+ mm Hg/year.ConclusionsIn a population of scleroderma patients, the rate of increase in RVSP is a risk factor for mortality and PAH even after adjustment for clinical characteristics and longitudinal PFT data.

Objective The first genome-wide association study (GWAS) of systemic sclerosis (SSc) demonstrated three non-major histocompatibility complex (MHC) susceptibility loci. The goal of this study was to investigate the impact of these gene variants on survival and severity of interstitial lung disease (ILD) in SSc. Methods The authors examined 1443 Caucasian SSc patients enrolled in the G enetics versus E nvironment I n S cleroderma O utcome S tudy (GENISOS) and Scleroderma Family Registry (n = 914 – discovery cohort) and The Johns Hopkins Scleroderma Cohort (n = 529 – replication cohort). Forced vital capacity (FVC)% predicted was used as a surrogate for ILD severity. Five single nucleotide polymorphisms, IRF5 (rs10488631, rs12537284, rs4728142), STAT4 (rs3821236), CD247 (rs2056626) reached genome-wide significance in the SSc-GWAS and were examined in the current study. Results Overall, 15.5% of the patients had died over the follow-up period of 5.5 years. The IRF5 rs4728142 minor allele was predictive of longer survival in the discovery cohort (p = 0.021) and in the independent replication cohort (p = 0.047) and combined group (HR: 0.75, 95% CI 0.62 to 0.90, p = 0.002). The association of this SNP with survival was independent of age at disease onset, disease type and autoantibody profile (anticentromere and antitopoisomerase antibodies). The minor allele frequency of IRF5 rs4728142 was 49.4%. Moreover, IRF5 rs4728142 minor allele correlated with higher FVC% predicted at enrolment (p = 0.019). Finally, the IRF5 rs4728142 minor allele was associated with lower IRF5 transcript expression in patients and controls (p = 0.016 and p = 0.034, respectively), suggesting that the IRF5 , rs4728142 SNP, may be functionally relevant. Conclusion An SNP in the IRF5 promoter region (rs4728142), associated with lower IRF5 transcript levels, was predictive of longer survival and milder ILD in patients with SSc.

BackgroundImmunosuppressive therapy may potentially alter the natural disease course of scleroderma. There have been reports of using mycophenolate mofetil (MMF) for the treatment of scleroderma skin disease.ObjectiveTo analyse the experience of using MMF for the treatment of active diffuse cutaneous scleroderma.MethodsThe authors compared the change in mean modified Rodnan skin scores (mRSS) in an MMF cohort at baseline with scores at 3, 6, 9 and 12 months and with those of historical controls from a pooled analysis of three multicentre randomised clinical trials of recombinant human relaxin, d-penicillamine and oral bovine type I collagen.ResultsImprovement in mRSS after treatment with MMF compared with baseline was seen as early as 3 months and continued through the 12-month follow-up. The mRSS of the MMF cohort was not different from that of the historical controls at 6 months (MMF −3.05±7.4 vs relaxin −4.83±6.99, p=0.059), but was significantly lower at 12 months (MMF −7.59±10.1 vs d-penicillamine −2.47±8.6, pConclusionsMMF may benefit skin disease in patients with diffuse scleroderma, but prospective studies are required to determine its role.

Background Ischemic digital ulcers (DU) are a frequent complication in systemic sclerosis, estimated to occur in over 40% of patients. Treprostinil diethanolamine, a newer prostacyclin analog that has been developed for oral delivery, improves cutaneous perfusion and temperature in scleroderma patients. A large randomized, double-blind, placebo-controlled clinical trial of treprostinil diethanolamine was conducted in scleroderma patients with DU (ClinicalTrials.gov identifier NCT00775463). While this trial did not meet the desired endpoint (change in net ulcer burden at 20 wks), there was a significant improvement in several secondary endpoints that measured Raynaud9s severity. Subjects enrolled into an open label extension study (DISTOL-EXT) after the clinical trial, and after termination of DISTOL-EXT, all participants were withdrawn from oral treprostinil. Objectives We investigated whether active, indeterminate, and total ulcer burden increased in DISTOL-EXT participants after they discontinued oral treprostinil. Methods In this multi-center, retrospective study, medical records for the year after discontinuation of treprostinil were reviewed. Data from these routine clinical visits were abstracted into a template designed a priori to capture information on the number of active and indeterminate DU at the end of the extension study and at subsequent visits. Participants who did not have a subsequent visit with documentation of DU status were excluded from this study. We examined the number of new DU that developed from the end of the extension study (baseline) through the first year after discontinuation of treprostinil. The number of active, indeterminate and total DU 3-6 months (time A) and >6-12 months (time B) after discontinuation of treprostinil were compared to baseline by the paired t-test. Results Fifty-one subjects from 9 SSc Centers were included for analysis. At the conclusion of the treprostinil extension study, the mean number of active, indeterminate and total DU was 0.25 (SD 0.63), 0.22 (SD 0.54) and 0.47 (SD 0.78), respectively. The number of active DU increased from baseline to time A (mean 1.62, p=0.004, N=23) and time B (mean 1.03, p=0.076, N=30). The number of indeterminate DU increased from baseline to time B (mean 0.42, p=0.03, N=30) but not time A. The total DU burden increased significantly from baseline to time A (mean 2.1, p=0.002, N=23) and time B (mean 1.45, p=0.01, N=30) as shown in the Figure. The majority of patients required intensive vasodilator therapy and pain medication: calcium channel blockers (60.8%), PDE 5 inhibitors (21.6%), any pain medication (58.8%), opioids (33.3%). Three patients were hospitalized for complications from digital ulcers, and four patients required surgical intervention. Five patients were subsequently diagnosed with pulmonary hypertension. Conclusions Total DU burden increased significantly after discontinuation of oral treprostinil diethanolamine. These data provide supportive evidence of a beneficial effect of oral treprostinil diethanolamine for the vascular complications of SSc. Disclosure of Interest A. Shah Grant/research support: United Therapeutics, E. Schiopu Grant/research support: United Therapeutics, Actelion, MedImmune, Celgene, Speakers bureau: Previously on United Therapeutics Speakers bureau, S. Chatterjee Grant/research support: United Therapeutics, M. E. Csuka Grant/research support: United Therapeutics, T. Frech Grant/research support: United Therapeutics, A. Goldberg Grant/research support: United Therapeutics, R. Spiera Grant/research support: United Therapeutics, S. Peng Grant/research support: United Therapeutics, V. Steen Grant/research support: United Therapeutics DOI 10.1136/annrheumdis-2014-eular.2257