Scleroderma Onset Research Articles

Distinct Scleroderma Autoantibody Profiles Stratify Patients for Cancer Risk at Scleroderma Onset and During the Disease Course.

We examined whether an array of scleroderma autoantibodies associates with risk of cancer and could be useful tools for risk stratification. Scleroderma cancer cases and scleroderma controls without cancer from the Johns Hopkins Scleroderma Center and the University of Pittsburgh Scleroderma Center were studied. Sera were assayed by Lineblot and enzyme-linked immunosorbent assay (ELISA) for autoantibodies against centromere, topoisomerase 1, RNA polymerase (POLR) 3, PM/Scl, Th/To, NOR90, U3 RNP, Ku, Ro52, U1RNP, and RNPC3. Logistic regression models were constructed to examine whether distinct autoantibodies associated with overall cancer at any time and cancer-associated scleroderma (cancer occurring three years before and after scleroderma onset). The effects of having more than one autoantibody on cancer were further examined using random forest analysis. A total of 676 cases and 687 controls were studied. After adjusting for relevant covariates, anti-POLR3 (odds ratio [OR] 1.47, 95% confidence interval [CI] 1.03-2.11) and monospecific anti-Ro52 (OR 2.19, 95% CI 1.29-3.74) were associated with an increased overall cancer risk, whereas anticentromere (OR 0.69, 95% CI 0.51-0.93) and anti-U1RNP (OR 0.63, 95% CI 0.43-0.93) were associated with lower risk. When examining risk of cancer-associated scleroderma, these immune responses remained associated with increased or decreased risk: anti-POLR3 (OR 2.28, 95% CI 1.33-3.91), monospecific anti-Ro52 (OR 2.58, 95% CI 1.05-6.30), anticentromere (OR 0.39, 95% CI 0.20-0.74), and anti-U1RNP (OR 0.32, 95% CI 0.11-0.93). Anti-Ro52 plus anti-U1RNP or anti-Th/To was associated with decreased cancer risk compared with anti-Ro52 alone. These data suggest that five distinct scleroderma immune responses, alone or in combination, may be useful tools to stratify the risk of cancer for scleroderma patients. Further study examining cancer risk in autoantibody subgroups relative to the general population is warranted.

P22 Paraneoplastic diffuse systemic sclerosis in association with ano-rectal tumour

Introduction/BackgroundRheumatic diseases can manifest as a paraneoplastic phenomenon. They can be seen during the course of neoplastic disease, precede the diagnosis, appear simultaneously or occur after the diagnosis of malignancy. Overall, paraneoplastic rheumatic syndromes are rare. It is however important to be aware of this phenomenon as the signs and symptoms of the rheumatic syndrome will usually subside with treatment of the underlying malignant disease. Furthermore, reappearance of symptoms may suggest cancer relapse.Description/Method51 year old woman with no significant past medical history was referred by her General Practicioner with 6-week history of pain and stiffness in hands, arms and legs. There was also associated 4-week history of change in bowel habit (diarrhoea and faecal incontinence). Clinical examination revealed skin thickening proximal to elbows and knees, sclerodactyly, facial telangiectasia as well as tendon friction rubs in lower limbs. There was also a mass palpable on digital rectal examination. Investigations revealed that the patient had new iron deficiency anaemia and mildly raised carcinoembryonic antigen. Anti-RNA polymerase III antibody returned positive. CT of chest, abdomen and pelvis suggested tumour involving the anus and lower rectum with metastatic lymphadenopathy. Those findings were also confirmed on subsequent MRI pelvis and PET CT. She underwent anal biopsy, examination under anaesthesia and formation of loop colostomy. Histopathology results confirmed poorly differentiated squamous carcinoma. Patient was then reviewed by oncology and discussed at multidisciplinary meeting. She was commenced on palliative chemotherapy (paclitaxel and carboplatin). After the first session she became severely anaemic and developed acute renal failure. She passed away approximately three months after initial referral to rheumatology.Discussion/ResultsThis patient was diagnosed with paraneoplastic diffuse systemic sclerosis in association with ano-rectal tumour. Unfortunately at the time of diagnosis the disease was metastatic therefore the only treatment option available was palliative rather than curative. Paraneoplastic rheumatic syndromes are rare. The signs and symptoms are secondary to the presence of malignancy. They may be induced by the substances that are secreted by the tumour or the immune system’s response to the malignant cells. Usually once patient recovers from the neoplastic disease the rheumatic disease signs/symptoms subside. In our patient’s history there were a number of features which raised the possibility of paraneoplastic aetiology. These included: sudden onset and rapid progression of clinical symptoms, late onset of disease (after 50 years of age), family history of cancer (dad had prostate cancer), new iron deficiency anaemia as well as the presence of anti-RNA polymerase III antibodies. This antibody is linked with cancer-associated systemic sclerosis. Patients who are positive have shorter cancer-scleroderma interval. Anti-RNA polymerase III antibody is unique to scleroderma and is not found in cancer patients without scleroderma.Key learning points/ConclusionThe key learning point from this case was not to forget the paraneoplastic aetiology in patients who present with rheumatic syndromes. In particular if the symptoms are of sudden onset or are progressing rapidly/responding poorly to therapy. There is only a small number of cases reported in literature of paraneoplastic systemic sclerosis. Furthermore, the importance of anti-RNA polymerase III antibody testing in scleroderma patients. If positive, it is important to be aware that those patients have >4-fold increased risk of cancer occurring within 2 years of scleroderma onset. It is therefore vital to look for any signs/symptoms during their routine follow-up appointments at rheumatology clinics.

Abstract IA11: Autoimmune rheumatic diseases and cancer: An example of natural cancer immunoediting?

Abstract A relationship between cancer and autoimmune rheumatic diseases has been observed for many decades, although the relevance of, and mechanisms underlying, this association have remained unclear. Investigating this relationship has been extremely challenging, due to heterogeneity of the rheumatic diseases across multiple dimensions, including kinetics of association of cancer and autoimmunity, the occurrence of cancer in only a subgroup of patients, variable exposure to drugs that are associated with increased incidence of malignancy, and the large number of tumor types associated with rheumatic disease. Several recent observations have provided important opportunities to understand the mechanisms underlying this relationship. (i) Increased cancer incidence across different autoimmune rheumatic diseases is associated with specific autoantibodies. For example, in scleroderma, patients with autoantibodies against RNA polymerase III or components of the minor spliceosome have increased cancer incidence both within cohort and compared to the general population. Similarly, in dermatomyositis, the majority of patients with concomitant cancer are found among patients with autoantibodies directed against either TIF1g or NXP2. (ii) In patients presenting with scleroderma and RNA polymerase 3 autoantibodies who have a concomitant cancer (within 3 years of scleroderma onset), there is evidence of somatic mutation and loss of heterozygosity at the POLR3A locus. There is evidence for T-cell immunity recognizing the specific mutations as well as the wild-type antigens. These findings are specific to patients with POLR3 antibodies and are not observed in patients with other autoantibody specificities. (iii) When comparing cancer incidence in different scleroderma subgroups defined by their autoantibody specificities to the SEER registry, there are striking differences in the SIRs in the different scleroderma subgroups. For example, patients with autoantibodies to POLR3 have an increased SIR for various cancers, while patients with autoantibodies to components of the centromere have strikingly decreased SIRs for cancer. (iv) A subgroup of scleroderma patients with autoantibodies recognizing POLR3 who do not manifest cancer have additional autoantibodies that recognize components of POLR1, suggesting that orthogonal immune responses might play important anticancer roles. Taken together, these data suggest a model in which autoantigen mutations in cancer induce immune responses to mutated and wild-type autoantigens. These immune responses are variably effective at preventing cancer emergence (in the majority of cases, either eliminating the cancers or maintaining them in equilibrium). Understanding the various mechanisms underlying those patients with autoimmune diseases where cancer does or does not emerge may provide important opportunities to understand natural cancer immunoediting, and how these mechanisms might be harnessed for treatment of cancer and avoidance of side effects in cancer immunotherapies. Citation Format: Antony Rosen. Autoimmune rheumatic diseases and cancer: An example of natural cancer immunoediting? [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr IA11.

An update on autoantibodies in scleroderma.

New research continues to provide important insights into the utility of antibody specificities. This review provides an update of recent findings, and the important insights they provide into disease mechanism. A growing number of autoantibodies have been discovered in scleroderma patients with unique clinical associations. A subgroup of these antibodies may have functional consequences and contribute to disease pathogenesis, driving the vascular and fibrotic phenotype. Recent research into the relationship between malignancy and scleroderma onset provides important new insights into disease mechanism, and highlights the utility of autoantibodies as unique research probes. Continued advances in the study of scleroderma antibody specificities has led to important insights into disease pathogenesis and clinical subgrouping. These advances include newly described specificities, functional antibodies and an emerging understanding of the cancer-scleroderma relationship.

Autoantibodies and scleroderma phenotype define subgroups at high-risk and low-risk for cancer

ObjectivesRecent studies demonstrate autoantibodies are powerful tools to interrogate molecular events linking cancer and the development of autoimmunity in scleroderma. Investigating cancer risk in these biologically relevant subsets may provide...

Brief Report: Anti-RNPC-3 Antibodies As a Marker of Cancer-Associated Scleroderma.

Prior studies have demonstrated an increased risk of cancer-associated scleroderma in patients with anti-RNA polymerase III (anti-RNAP III) autoantibodies as well as in patients who are triple-negative for anticentromere (anti-CENP), anti-topoisomerase I (anti-topo I), and anti-RNAP III (also known as anti-POL) autoantibodies (referred to as CTP negative). In a recent study of 16 CTP-negative scleroderma patients with coincident cancer, 25% of the patients were found to have autoantibodies to RNPC-3, a member of the minor spliceosome complex. This investigation was undertaken to validate the relationship between anti-RNPC-3 antibodies and cancer and examine the associated clinical phenotype in a large sample of scleroderma patients. Scleroderma patients with cancer were assayed for anti-CENP, anti-topo I, anti-RNAP III, and anti-RNPC-3 autoantibodies. Disease characteristics and the cancer-scleroderma interval were compared across autoantibody groups. The relationship between autoantibody status and cancer-associated scleroderma was assessed by logistic regression. Of 318 patients with scleroderma and cancer, 70 (22.0%) were positive for anti-RNAP III, 54 (17.0%) were positive for anti-topo I, and 96 (30.2%) were positive for anti-CENP. Twelve patients (3.8% of the overall group or 12.2% of CTP-negative patients) were positive for anti-RNPC-3. Patients with anti-RNPC-3 had a short cancer-scleroderma interval (median 0.9 years). Relative to patients with anti-CENP, patients with anti-RNPC-3 and those with anti-RNAP III had a >4-fold increased risk of cancer within 2 years of scleroderma onset (for anti-RNPC-3-positive patients, odds ratio [OR] 4.3, 95% confidence interval [95% CI] 1.10-16.9 [P = 0.037]; for anti-RNAP III-positive patients, OR 4.49, 95% CI 1.98-10.2 [P < 0.001]). Patients with anti-RNPC-3 had severe restrictive lung disease, gastrointestinal disease, Raynaud's phenomenon, and myopathy. Anti-RNPC-3 autoantibodies, similar to anti-RNAP III autoantibodies, are associated with an increased risk of cancer at the onset of scleroderma. These data suggest the possibility of cancer-induced autoimmunity in this subset of patients with scleroderma.

Cancer and scleroderma: a paraneoplastic disease with implications for malignancy screening.

Recent data suggest a paraneoplastic mechanism of scleroderma pathogenesis in unique subsets of scleroderma patients. In this article, we review these data, explore potential links between cancer and scleroderma, and propose an approach to malignancy screening in scleroderma. Emerging data have demonstrated that patients with scleroderma and RNA polymerase III autoantibodies have a significantly increased risk of cancer within a few years of scleroderma onset. Genetic alterations in the gene encoding RNA polymerase III (POLR3A) have been identified, and patients with somatic mutations in POLR3A have evidence of mutation specific T-cell immune responses with generation of cross-reactive RNA polymerase III autoantibodies. These data strongly suggest that scleroderma is a by-product of antitumor immune responses in some patients. Additional epidemiologic data demonstrate that patients developing scleroderma at older ages may also have a short cancer-scleroderma interval, suggestive of paraneoplastic disease. Scleroderma may be a paraneoplastic disease in unique patient subsets. Aggressive malignancy screening in these patients may aid in early cancer detection. Further study is required to determine whether cancer therapy could improve scleroderma outcomes in this patient population.

Examination of autoantibody status and clinical features associated with cancer risk and cancer-associated scleroderma.

We previously reported a contemporaneous onset of cancer and scleroderma in patients with anti-RNA polymerase III antibodies, and we identified a biologic link between cancer and scleroderma. This investigation was designed to further evaluate whether autoantibody status and other characteristics are associated with cancer and a clustering of cancer with scleroderma onset. Logistic regression analysis was performed to assess the relationship of 2 outcomes, cancer (model 1) and a short (±2 years) cancer-scleroderma interval (model 2), with autoantibody status and scleroderma covariates. Of 1,044 scleroderma patients, 168 (16.1%) had cancer. In the adjusted model 1, only older age at scleroderma onset (odds ratio 1.04 [95% confidence interval 1.02-1.05]) and white race (odds ratio 2.71 [95% confidence interval 1.22-6.04]) were significantly associated with an increased overall risk of cancer. In the adjusted model 2, only anti-RNA polymerase III positivity (odds ratio 5.08 [95% confidence interval 1.60-16.1]) and older age at scleroderma onset (odds ratio 1.04 [95% confidence interval 1.00-1.08]) were significantly associated with a short cancer-scleroderma interval. While anti-RNA polymerase III positivity was associated with a short cancer-scleroderma interval independent of age at scleroderma onset, the cancer-scleroderma interval shortened with older age at scleroderma onset in other antibody groups (Spearman's correlation P < 0.05), particularly among patients with anti-topoisomerase I antibodies and patients who were negative for anticentromere, anti-topoisomerase I, and anti-RNA polymerase III antibodies. Increased age at scleroderma onset is strongly associated with cancer risk overall. While anti-RNA polymerase III status is an independent marker of coincident cancer and scleroderma at any age, a clustering of cancer with scleroderma is also seen in patients with anti-topoisomerase I and other autoantibody specificities who develop scleroderma at older ages.

A score of risk factors associated with ischemic digital ulcers in patients affected by systemic sclerosis treated with iloprost

A single series of patients affected by systemic sclerosis (SSc) and cyclically treated with iloprost was reviewed in order to evaluate the incidence of digital ulcers (DUs) and to compare the characteristics between the patients with and without this painful and disabling vascular complication. The record charts of 85 SSc patients were revised. Ischemic DUs and scleroderma contracture ulcers were separately considered. Twenty-nine subjects developed ischemic DUs during the course of the disease; whereas, scleroderma contracture ulcers occurred in six subjects. Ischemic DUs were associated with younger age at scleroderma onset, a longer disease duration, a longer time delay from scleroderma diagnosis to iloprost therapy, a bigger skin involvement, the presence of joint contractures, a videocapillaroscopic late pattern, a history of smoking, and of corticosteroids therapy. After the exclusion of four subjects with concomitant peripheral arterial disease, a forward-stepwise logistic regression analysis showed that only four variables, i.e., age at scleroderma onset, delay in beginning iloprost therapy, history of smoking, and presence of joint contractures remained significantly associated with ischemic DUs. In a score reflecting the sum of these four risk factors, the prevalence of ischemic DUs increased progressively from the lowest to the highest value of the score. The predictivity of this model was evaluated by the receiver-operating characteristics curve, with an estimated area under the curve of 0.836 with 95% confidence interval from 0.736 to 0.937. All the patients with scleroderma contracture ulcers were characterized by both diffuse pattern of disease and positivity for anti-Scl70 antibody. In this retrospective study, scleroderma patients with ischemic DUs are characterized by early disease onset, delay in beginning iloprost therapy, smoking habit, and presence of joint contraction. A score reflecting the sum of these factors may be useful to predict the risk of developing ischemic DUs.

Age and Risk of Pulmonary Arterial Hypertension in Scleroderma*

To investigate whether age at disease onset is a risk factor for pulmonary arterial hypertension (PAH) in scleroderma. Scleroderma center. Seven hundred nine consecutive scleroderma patients who underwent echocardiography. The risk of PAH associated with age at disease onset was modeled as both a continuous and categorical variable. Risk estimates were adjusted for sex, race, scleroderma subtype, disease duration, smoking status, FVC, anticentromere and antitopoisomerase I antibody status. Overall, 274 patients (38.6%), 272 patients by Doppler echocardiography and 2 patients by M-mode echocardiography, had PAH at baseline or during follow-up. There were 114 patients with mild PAH (right ventricular systolic pressure [RVSP], 36 to 45 mm Hg), 66 patients with moderate PAH (RVSP, 46 to 55 mm Hg), and 92 patients with severe PAH (RVSP > or =56 mm Hg). A 52% increase in risk of PAH was demonstrated for every 10 years of age at disease onset (odds ratio [OR], 1.52; 95% confidence interval [CI], 1.31 to 1.76). In addition, there was a twofold greater risk of PAH (OR, 2.30; 95% CI, 1.32 to 3.99) for late-onset (age > or =60 years) vs earlier-onset (< 60 years) disease. These associations remained evident and were somewhat strengthened when the analyses were restricted to patients with moderate and severe PAH. We identified increasing age at scleroderma onset as a risk factor for PAH. Vigilance among these high-risk patients may provide an opportunity to intervene prior to development of irreversible pulmonary vascular disease.

Scleroderma and silicone gel breast prostheses--the Sydney study revisited.

Silicone augmentation mammoplasty has been postulated as a cause of environmentally-induced scleroderma. While representing a small proportion of all alleged causes of scleroderma, the issue has huge social, ethical and medicolegal ramifications. The hypothesis, however, has been recently questioned in results of comparative studies. We have previously reported no association between augmentation mammoplasty and scleroderma. However, all information was self-reported including augmentation mammoplasty status, and the prosthesis type was not identified. In addition, data were not available from untraceable cases. The current study addresses these issues. To validate self-reported augmentation mammoplasty status, re-analyse rates of exposure to silicone gel breast prostheses in 556 scleroderma patients and 289 general practice controls and evaluate whether silicone gel breast prostheses are causally linked to scleroderma. Study design-population-based case-control study; Cases-scleroderma patients resident in Sydney for at least six consecutive months between 1974-1988; Controls-patients from 29 randomly selected Sydney general practices, age- and gender-group-matched with cases. Validation of augmentation mammoplasty exposure was ascertained from the general medical practitioner of each interviewed case and control, or from the medical records of each deceased or untraceable case. Validation of the date of surgery and prosthesis type was from the relevant plastic surgeon. For each augmentation mammoplasty-positive case, validation of both the date and nature of the scleroderma onset was from the patient's medical records. Controls were given a "control date' for disease onset to adjust for duration of potential exposure. Validation of augmentation mammoplasty status was possible in 252 (87.2%) living controls, and 532 (95.7%) cases, of whom 287 were living. Self-reported augmentation mammoplasty status was highly reliable in living non-senile cases (kappa = 1), and living validated controls (kappa = 0.86). No association was identified between silicone gel augmentation mammoplasty and scleroderma with unadjusted odds ratios of 1.33 (95% CI: 0.26-6.71), and 1.00 (95% CI: 0.16-6.16) following adjustment for potential confounders of age, socioeconomic status and ethnicity. This validates the self-reported augmentation mammoplasty status previously reported and does not support the hypothesis that silicone gel augmentation mammoplasty is an environmental inducer of scleroderma in females.

Implications of the failure of nerve resection and graft to cure chronic pain produced by nerve lesions.

Seven patients had developed pain and abnormal sensitivity in the area supplied by a single nerve which had been injured. They were treated unsuccessfully for periods ranging from 3 to 108 months by conservative methods including neurolysis, local anaesthesia, sympathetic blocks, guanethidine, transcutaneous stimulation and analgesics. All then had the damaged nerve resected and in five cases a sural nerve graft was inserted to bridge the resected gap. The patients were then examined 20 to 72 months after the operation. In all seven cases pain and abnormal sensitivity of some intensity recurred in the same area and with the same qualitative characteristic as experienced before the operation. This operation should not be done in patients with this condition. Reasons are given to suggest that peripheral nerve damage induces changes in the central nervous system which are not reversed by treatment directed at the area of the original injury.

Proceedings: Extension of carcinoma of the cervix to the lumbar spine.

<h3>Abstract</h3> <h3>Background/Objectives</h3> Describe clinical characteristics of malignancy-associated scleroderma in a regional population. <h3>Methods</h3> Scleroderma patients with current or past malignancy were prospectively identified from a cohort of 125 scleroderma subjects of a largely Hispanic population. Demographic information included scleroderma subtype, serologies, cancer diagnosis, age at diagnosis, co-morbid conditions, therapies, and survival outcomes. <h3>Results</h3> 16.0% (20/125) of scleroderma patients were identified as having a malignancy. The mean age of malignancy onset and scleroderma onset were 55.6±10.3 and 52.7±12.9 years respectively (95% CI of difference: -4.6 &lt;2.9&lt; 10.4, p=0.44). Antinuclear antibody was positive in 70%, anticentromere antibody in 35.0%, and anti-topoisomerase antibodies in 25%. Tumor proportions were adenocarcinomas 55.0% (11/20) (1 gastric, 2 pancreatic, 1 lung, 2 thyroid, 5 breast), 15% (3/20) squamous cell carcinoma (1 skin, 1 uterine cervical, and 1 rectal), and 20% (4/20) benign tumors (2 meningiomas, 1 renal adenoma, 1 plasma cell). Age of onset of scleroderma greater than 42 years respectively accounted for 85% of all cancer cases. The standardized incidence ratio (SIR) was 2.0 (CI at 95%: 1.2&lt;2&lt;3.1), indicating 100% increase in cancer risk. Treatment of the malignancy did not resolve the scleroderma in any of the cases. Five-year survival after cancer diagnosis was 70.0%, although 2 of the survivors had tumor recurrence. <h3>Conclusions</h3> Malignancy, especially adenocarcinoma, occurs frequently in scleroderma in minority populations with up to 16% of patients affected. High-risk patients are those with scleroderma-onset greater than 42 years in whom routine screening for common cancers should be undertaken.