Ami A. Shah

Association of the autoimmune disease scleroderma with an immunologic response to cancer.

Cancer Immunosurveillance Gone Bad? A subset of patients who develop scleroderma, a debilitating autoimmune disease, have an elevated risk of developing cancer. These patients harbor autoantibodies to RPC1, an RNA polymerase subunit encoded by the POLR3A gene. Joseph et al. (p. 152, published online December 5; see the Perspective by Teng and Smyth) explored whether the RPC1 autoantibodies target a “foreign” antigen derived from a mutated POLR3A gene. Sequence analysis revealed that POLR3A mutations were present in tumors from six of eight patients with RPC1 autoantibodies but in no tumors from eight control patients who lacked RPC1 autoantibodies. Cell culture data suggested that the POLR3A mutations triggered cellular and humoral immune responses in the patients. These results provide support for the “immunosurveillance” hypothesis, which posits the continual eradication of nascent tumor cells via immune responses. The immune system’s response to a mutant protein produced by an incipient cancer may help to explain an autoimmune disease. [Also see Perspective by Teng and Smyth] Autoimmune diseases are thought to be initiated by exposures to foreign antigens that cross-react with endogenous molecules. Scleroderma is an autoimmune connective tissue disease in which patients make antibodies to a limited group of autoantigens, including RPC1, encoded by the POLR3A gene. As patients with scleroderma and antibodies against RPC1 are at increased risk for cancer, we hypothesized that the “foreign” antigens in this autoimmune disease are encoded by somatically mutated genes in the patients’ incipient cancers. Studying cancers from scleroderma patients, we found genetic alterations of the POLR3A locus in six of eight patients with antibodies to RPC1 but not in eight patients without antibodies to RPC1. Analyses of peripheral blood lymphocytes and serum suggested that POLR3A mutations triggered cellular immunity and cross-reactive humoral immune responses. These results offer insight into the pathogenesis of scleroderma and provide support for the idea that acquired immunity helps to control naturally occurring cancers.

Close temporal relationship between onset of cancer and scleroderma in patients with RNA polymerase I/III antibodies

OBJECTIVE This study was undertaken to examine the temporal relationship between scleroderma development and malignancy, and to evaluate whether this differs by autoantibody status among affected patients. METHODS Study participants had a diagnosis of scleroderma, a diagnosis of cancer, cancer, an available serum sample, and a cancer pathology specimen. Sera were tested for autoantibodies against topoisomerase I, centromere, and RNA polymerase I/III by immunoprecipitation and/or enzyme-linked immunosorbent assay. Clinical and demographic characteristics were compared across autoantibody categories. Expression of RNA polymerases I and III was evaluated by immunohistochemistry using cancerous tissue from patients with anti-RNA polymerase antibodies. RESULTS Twenty-three patients were enrolled. Six patients tested positive for anti-RNA polymerase I/III, 5 for anti-topoisomerase I, and 8 for anticentromere, and 4 were not positive for any of these antigens. The median duration of scleroderma at cancer diagnosis differed significantly between groups (-1.2 years in the anti-RNA polymerase I/III group, +13.4 years in the anti-topoisomerase I group, +11.1 years in the anticentromere group, and +2.3 years in the group that was negative for all antigens tested) (P = 0.027). RNA polymerase III demonstrated a robust nucleolar staining pattern in 4 of 5 available tumors from patients with antibodies to RNA polymerase I/III. In contrast, nucleolar RNA polymerase III staining was not detected in any of 4 examined tumors from the RNA polymerase antibody-negative group (P = 0.048). CONCLUSION Our findings indicate that there is a close temporal relationship between the onset of cancer and scleroderma in patients with antibodies to RNA polymerase I/III, which is distinct from scleroderma patients with other autoantibody specificities. In this study, autoantibody response and tumor antigen expression are associated. We propose that malignancy may initiate the scleroderma-specific immune response and drive disease in a subset of scleroderma patients.

Right Ventricular Dysfunction in Systemic Sclerosis–Associated Pulmonary Arterial Hypertension

Background—Systemic sclerosis–associated pulmonary artery hypertension (SScPAH) has a worse prognosis compared with idiopathic pulmonary arterial hypertension (IPAH), with a median survival of 3 years after diagnosis often caused by right ventricular (RV) failure. We tested whether SScPAH or systemic sclerosis–related pulmonary hypertension with interstitial lung disease imposes a greater pulmonary vascular load than IPAH and leads to worse RV contractile function. Methods and Results—We analyzed pulmonary artery pressures and mean flow in 282 patients with pulmonary hypertension (166 SScPAH, 49 systemic sclerosis–related pulmonary hypertension with interstitial lung disease, and 67 IPAH). An inverse relation between pulmonary resistance and compliance was similar for all 3 groups, with a near constant resistance×compliance product. RV pressure–volume loops were measured in a subset, IPAH (n=5) and SScPAH (n=7), as well as SSc without PH (n=7) to derive contractile indexes (end-systolic elastance [Ees] and preload recruitable stroke work [Msw]), measures of RV load (arterial elastance [Ea]), and RV pulmonary artery coupling (Ees/Ea). RV afterload was similar in SScPAH and IPAH (pulmonary vascular resistance=7.0±4.5 versus 7.9±4.3 Wood units; Ea=0.9±0.4 versus 1.2±0.5 mm Hg/mL; pulmonary arterial compliance=2.4±1.5 versus 1.7±1.1 mL/mm Hg; P>0.3 for each). Although SScPAH did not have greater vascular stiffening compared with IPAH, RV contractility was more depressed (Ees=0.8±0.3 versus 2.3±1.1, P<0.01; Msw=21±11 versus 45±16, P=0.01), with differential RV-PA uncoupling (Ees/Ea=1.0±0.5 versus 2.1±1.0; P=0.03). This ratio was higher in SSc without PH (Ees/Ea=2.3±1.2; P=0.02 versus SScPAH). Conclusions—RV dysfunction is worse in SScPAH compared with IPAH at similar afterload, and may be because of intrinsic systolic function rather than enhanced pulmonary vascular resistive and pulsatile loading.

Inflammatory arthritis and sicca syndrome induced by nivolumab and ipilimumab

Objectives Immune 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. Methods We 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. Results We 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. Conclusions As 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.

Connective tissue disease related interstitial lung diseases and idiopathic pulmonary fibrosis: provisional core sets of domains and instruments for use in clinical trials

Rationale Clinical trial design in interstitial lung diseases (ILDs) has been hampered by lack of consensus on appropriate outcome measures for reliably assessing treatment response. In the setting of connective tissue diseases (CTDs), some measures of ILD disease activity and severity may be confounded by non-pulmonary comorbidities. Methods The Connective Tissue Disease associated Interstitial Lung Disease (CTD-ILD) working group of Outcome Measures in Rheumatology—a non-profit international organisation dedicated to consensus methodology in identification of outcome measures—conducted a series of investigations which included a Delphi process including >248 ILD medical experts as well as patient focus groups culminating in a nominal group panel of ILD experts and patients. The goal was to define and develop a consensus on the status of outcome measure candidates for use in randomised controlled trials in CTD-ILD and idiopathic pulmonary fibrosis (IPF). Results A core set comprising specific measures in the domains of lung physiology, lung imaging, survival, dyspnoea, cough and health-related quality of life is proposed as appropriate for consideration for use in a hypothetical 1-year multicentre clinical trial for either CTD-ILD or IPF. As many widely used instruments were found to lack full validation, an agenda for future research is proposed. Conclusion Identification of consensus preliminary domains and instruments to measure them was attained and is a major advance anticipated to facilitate multicentre RCTs in the field.

Telangiectases in Scleroderma: A Potential Clinical Marker of Pulmonary Arterial Hypertension

Objective. Clinical markers are needed to identify scleroderma patients at risk for pulmonary arterial hypertension (PAH) since early therapy may improve survival. We investigated whether increased numbers of telangiectases in scleroderma associate with measures of pulmonary vascular disease. Methods. One hundred forty-seven consecutive adult patients with scleroderma were enrolled in this cross-sectional study and scored for the presence of matted telangiectases on 11 body areas. Per body area, telangiectases were scored as 0 if none were present, 1 if there were fewer than 10 telangiectases, and 2 if 10 or more telangiectases were counted. Linear regression analysis was performed to assess the association between right ventricular systolic pressure (RVSP) and telangiectasia score, adjusted for age, race, smoking status, scleroderma subtype, disease duration, and autoantibody status. Logistic regression analysis was performed with PAH by right-heart catheterization (RHC) as the dependent variable. Results. The mean telangiectasia score was 6.0 (SD 4.5, range 0–20). RVSP and telangiectasia score were positively correlated (r = 0.271, p = 0.001). The mean RVSP increased by 10.9 mm Hg for every 10-point increase in telangiectasia score (95% CI 3.6–18.3 mm Hg, p = 0.004), adjusted for potential confounders. The adjusted relative odds of PAH by RHC were 12.4 for patients with a 10-point increase in telangiectasia score (95% CI 1.78–85.9, p = 0.01). Conclusion. Increased numbers of telangiectases strongly associate with the presence of pulmonary vascular disease. Telangiectases may be a clinical marker of more widespread aberrant microvascular disease in scleroderma.

Long-term experience of mycophenolate mofetil for treatment of diffuse cutaneous systemic sclerosis

Background Immunosuppressive 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. Objective To analyse the experience of using MMF for the treatment of active diffuse cutaneous scleroderma. Methods The 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. Results Improvement 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, p<0.001; collagen −3.4±7.12, p=0.002). General and muscle severity scores and quality of life measures also improved compared with baseline. Pulmonary function remained stable. Conclusions MMF may benefit skin disease in patients with diffuse scleroderma, but prospective studies are required to determine its role.

IRF5 polymorphism predicts prognosis in patients with systemic sclerosis

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 Genetics versus Environment In Scleroderma Outcome Study (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.

Right Ventricular Functional Reserve in Pulmonary Arterial Hypertension

Background— Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients. Methods and Results— RV pressure-volume relations were prospectively measured in IPAH (n=9) and SSc-PAH (n=15) patients at rest and during incremental atrial pacing or supine bicycle ergometry. Systolic and lusitropic function increased at faster heart rates in IPAH patients, but were markedly blunted in SSc-PAH. The recirculation fraction, which indexes intracellular calcium recycling, was also depressed in SSc-PAH (0.32±0.05 versus 0.50±0.05; P=0.039). At matched exercise (25 W), SSc-PAH patients did not augment contractility (end-systolic elastance) whereas IPAH did (P<0.001). RV afterload assessed by effective arterial elastance rose similarly in both groups; thus, ventricular-vascular coupling declined in SSc-PAH. Both end-systolic and end-diastolic RV volumes increased in SSc-PAH patients to offset contractile deficits, whereas chamber dilation was absent in IPAH (+37±10% versus +1±8%, P=0.004, and +19±4% versus –1±6%, P<0.001, respectively). Exercise-associated RV dilation also strongly correlated with resting ventricular-vascular coupling in a larger cohort. Conclusions— RV contractile reserve is depressed in SSc-PAH versus IPAH subjects, associated with reduced calcium recycling. During exercise, this results in ventricular-pulmonary vascular uncoupling and acute RV dilation. RV dilation during exercise can predict adverse ventricular-vascular coupling in PAH patients.

Race and association with disease manifestations and mortality in scleroderma : A 20-year experience at the johns hopkins scleroderma center and review of the literature

AbstractExperience suggests that African Americans may express autoimmune disease differently than other racial groups. In the context of systemic sclerosis (scleroderma), we sought to determine whether race was related to a more adverse expression of disease. Between January 1, 1990, and December 31, 2009, a total of 409 African American and 1808 white patients with scleroderma were evaluated at a single university medical center. While the distribution by sex was virtually identical in both groups, at 82% female, African American patients presented to the center at a younger mean age than white patients (47 vs. 53 yr; p < 0.001). Two-thirds of white patients manifested the limited cutaneous subset of disease, whereas the majority of African American patients manifested the diffuse cutaneous subset (p < 0.001). The proportion seropositive for anticentromere antibody was nearly 3-fold greater among white patients, at 34%, compared to African American patients (12%; p < 0.001). Nearly a third of African American (31%) patients had autoantibodies to topoisomerase, compared to 19% of white patients (p = 0.001). Notably, African American patients experienced an increase in prevalence of cardiac (adjusted odds ratio [OR], 1.6; 95% confidence interval [CI], 1.3–2.2), renal (OR, 1.6; 95% CI, 1.2–2.1), digital ischemia (OR, 1.5; 95% CI, 1.4–2.2), muscle (OR, 1.7; 95% CI, 1.3–2.3), and restrictive lung (OR, 6.9; 95% CI, 5.1–9.4) disease. Overall, 700 (32%) patients died (159 African American; 541 white). The cumulative incidence of mortality at 10 years was 43% among African American patients compared to 35% among white patients (log-rank p = 0.0011). Compared to white patients, African American patients experienced an 80% increase in risk of mortality (relative risk [RR], 1.8; 95% CI, 1.4–2.2), after adjustment for age at disease onset and disease duration. Further adjustment by sex, disease subtype, and scleroderma-specific autoantibody status, and for the socioeconomic measures of educational attainment and health insurance status, diminished these risk estimates (RR, 1.3; 95% CI, 1.0–1.6). The heightened risk of mortality persisted in strata defined by age at disease onset, diffuse cutaneous disease, anticentromere seropositivity, decade of care at the center, and among women. These findings support the notion that race is related to a distinct phenotypic profile in scleroderma, and a more unfavorable prognosis among African Americans, warranting heightened diagnostic evaluation and vigilant care of these patients. Further, we provide a chronologic review of the literature regarding race, organ system involvement, and mortality in scleroderma; we furnish synopses of relevant reports, and summarize findings.