A multi-national survey to identify clinicians' perspectives concerning Proton Pump inhibitors in patients with systemic sclerosis.

OBJECTIVES: Proton Pump Inhibitors (PPIs) are widely used in SSc for gastroesophageal reflux disease (GERD). However, there is little evidence to support their empirical use and long-term safety has been questioned. Our objective was to better describe clinicians' attitudes toward PPIs prescription and use in SSc patients. METHODS: Clinicians involved in the care of SSc patients were invited through international physician networks and social media to participate in an online survey. RESULTS: Responses from 227 clinicians from 36 countries were evaluable. The majority 'agreed' (41.4 %) or 'strongly agreed' (45.4 %) that GERD is a major cause of morbidity in SSc. Lifestyle modifications are seldom (16 %) considered effective. Only half 'agreed' (43 %) or 'strongly agreed' (11 %) there is solid evidence supporting PPIs efficacy in SSc. The most common reasons for PPIs prescription were symptomatic GERD unresponsive to lifestyle modification (95 %), objective evidence of GERD (82 %), and hoarseness or respiratory symptoms (71 %). There are variable concerns about PPIs long-term safety in SSc. The three highest (mean) reasons (0-10, here 10 is 'very concerned') were: small intestinal bacterial overgrowth (5.5), osteoporosis (5.4), and drug interactions (5.2). There are significant differences in attitudes towards surgery for refractory GERD, and concerns about potential complications. PPIs may have a putative role for disease modification (e.g., ILD and calcinosis), and the role of immunosuppression is uncertain for GI (gastrointestinal) disease in SSc. CONCLUSION: PPIs are frequently prescribed in SSc. Side effects are a recognized concern, especially regarding long-term therapy. There is significant variation in attitudes towards surgical intervention. Future research and practical treatment recommendation for PPIs in SSc are urgently needed.

A Multinational Survey Investigating the Unmet Needs and Patient Perspectives Concerning Proton Pump Inhibitors in Systemic Sclerosis.

OBJECTIVE: Proton pump inhibitors (PPIs) are widely prescribed to treat gastroesophageal reflux disease (GERD) in Systemic Sclerosis (SSc). However, not all patients adequately respond to the treatment, and there are frequent concerns about the safety of long-term use of PPIs. Our aim was to identify the main problems/complaints of SSc patients on PPIs, as well as understand their unmet needs. METHODS: SSc patients treated with PPIs were invited through international patient associations and social media to participate in an online survey. RESULTS: We gathered 301 valid responses from 14 countries (United Kingdom 19.3% and United States 70.4%). Multiple PPIs use (two: 30% and three: 21% in series) was common. The majority (89%) reported improvement in gastrointestinal symptoms from receiving PPIs. Side effects attributed to receiving PPIs were uncommon (19%); however, most (79%) were potentially concerned. Around half (58%) had received lifestyle information, and most (85%) had searched online for information about PPIs. Only in the minority (12%) had a surgical approach been discussed; however, half (46%) indicated that they would be willing to undergo surgery to resolve their GERD symptoms but had important concerns. CONCLUSION: Despite the frequent use of PPIs in patients with SSc, there is significant heterogeneity in prescription, and combination therapy (PPIs plus other medication for acid reflux) is not uncommon (approximately 40%). Patients have significant concerns about PPIs side effects. Education about PPIs is often neglected, and patients very frequently use online sources to obtain information on drug treatment. A surgical approach is infrequently discussed, and patients fear this potential therapeutic approach.

Slow Colonic Transit in Systemic Sclerosis: An Objective Assessment of Risk Factors and Clinical Phenotype.

OBJECTIVE: Up to 50% of patients with systemic sclerosis (SSc) experience slow colonic transit, which may be associated with severe outcomes. Our objective, therefore, was to identify specific clinical features associated with slow colonic transit in SSc. METHODS: SSc patients with gastrointestinal symptoms were prospectively enrolled and completed a scintigraphy-based whole gut transit study. Clinical features were compared between patients with and without slow colonic transit in univariate and multivariable logistic regression analyses. RESULTS: Forty-eight of 100 patients (48%) in our cohort had slow colonic transit. In the univariate analyses, slow colonic transit was positively associated with female sex (odds ratio [OR] 12.61 [95% confidence interval (95% CI) 1.56-101.90]), telangiectasia (OR 4.00 [95% CI 1.32-12.10]), anticentromere antibodies (OR 3.25 [95% CI 1.25-8.44]), prior or current smoking (OR 2.56 [95% CI 1.06-6.21]), and a Medsger gastrointestinal severity score of ≥3 (OR 3.94 [95% CI 1.16-13.36]). Patients were less likely to have significant restriction on pulmonary function tests (OR 0.23 [95% CI 0.09-0.63]). In our multivariable model, the association between slow colonic transit and telangiectasia (OR 3.97 [95% CI 1.20-13.20]) and less restrictive lung disease on pulmonary function tests (OR 0.28 [95% CI 0.09-0.86]) remained statistically significant, though a trend with smoking remained (OR 2.16 [95% CI 0.82-5.75]). Interestingly, there were no significant associations between slow colonic transit and delayed transit in other regions of the gastrointestinal tract. CONCLUSION: Distinct clinical features are associated with slow colonic transit in SSc. Such features may provide insight in risk stratification and the study of disease mechanism in more homogeneous subgroups.

Linaclotide for the treatment of refractory lower bowel manifestations of systemic sclerosis.

BACKGROUND: Lower gastrointestinal (GI) tract involvement can affect up to 50% of systemic sclerosis (SSc) patients, and may result in malabsorption, pseudo-obstruction, hospitalization, and death. We report our experience with linaclotide, a selective agonist of guanylate cyclase C (GC-C), for SSc patients with refractory lower GI disease. METHODS: We performed an analysis of patients seen at the Johns Hopkins Scleroderma Center and identified patients prescribed linaclotide for refractory lower GI manifestations. Patients had clinical data collected in our longitudinal database. Linaclotide responders were on medication for at least 12 months with documented effectiveness by the treating physician. RESULTS: Thirty-one patients with SSc were treated with linaclotide. At the time of linaclotide initiation, 23 of these patients (74%) were classified as having severe GI disease, as defined by recurrent pseudo-obstruction, malabsorption, and/or need for artificial nutrition (Medsger GI severity score ≥ 3). The majority of patients (90.3%; 28/31) had a treatment response, while only three patients (9.7%) reported ineffectiveness or intolerable side effects. Low-dose linaclotide (≤ 145 mcg daily) was used in 18 patients and was effective in 94%. High-dose therapy (> 145 mcg daily) was effective in 11 of 13 patients (85%). Common side effects were diarrhea, cramping, or bloating (11/31, 35%). Ineffectiveness, cost, and abdominal pain were complaints cited among those who discontinued therapy. CONCLUSION: Linaclotide is a well-tolerated and efficacious pro-secretory and pro-motility agent that can be used to manage refractory lower GI manifestations in SSc. We found that low-dose linaclotide is an effective option and may be better tolerated, though a subset of patients may require high dose regimens.

Definition of Naturally Processed Peptides Reveals Convergent Presentation of Autoantigenic Topoisomerase I Epitopes in Scleroderma.

OBJECTIVE: Autoimmune responses to DNA topoisomerase I (topo I) are found in a subset of scleroderma patients who are at high risk for interstitial lung disease (ILD) and mortality. Anti-topo I antibodies (ATAs) are associated with specific HLA-DRB1 alleles, and the frequency of HLA-DR-restricted topo I-specific CD4+ T cells is associated with the presence, severity, and progression of ILD. Although this strongly implicates the presentation of topo I peptides by HLA-DR in scleroderma pathogenesis, the processing and presentation of topo I has not been studied. METHODS: We developed a natural antigen processing assay (NAPA) to identify putative CD4+ T cell epitopes of topo I presented by monocyte-derived dendritic cells (mo-DCs) from 6 ATA-positive patients with scleroderma. Mo-DCs were pulsed with topo I protein, HLA-DR-peptide complexes were isolated, and eluted peptides were analyzed by mass spectrometry. We then examined the ability of these naturally presented peptides to induce CD4+ T cell activation in 11 ATA-positive and 11 ATA-negative scleroderma patients. RESULTS: We found that a common set of 10 topo I epitopes was presented by Mo-DCs from scleroderma patients with diverse HLA-DR variants. Sequence analysis revealed shared peptide-binding motifs within the HLA-DRß chains of ATA-positive patients and a subset of topo I epitopes with distinct sets of anchor residues capable of binding to multiple different HLA-DR variants. The NAPA-derived epitopes elicited robust CD4+ T cell responses in 73% of ATA-positive patients (8 of 11), and the number of epitopes recognized correlated with ILD severity (P = 0.025). CONCLUSION: These findings mechanistically implicate the presentation of a convergent set of topo I epitopes in the development of scleroderma.

Evaluation of risk factors for pseudo-obstruction in systemic sclerosis.

OBJECTIVE: Although up to 90% of systemic sclerosis (SSc) patients are affected by gastrointestinal (GI) dysmotility, the clinical phenotype of patients with pseudo-obstruction is not well-defined. We sought to identify this phenotype by studying a large cohort of SSc patients with and without pseudo-obstruction. METHODS: We performed a retrospective analysis of patients seen at the Johns Hopkins Scleroderma Center between February 2003 and September 2017. All SSc patients had clinical data prospectively collected in a longitudinal database. Cross-sectional analyses were performed comparing autoantibody status and clinical and demographic features of patients with and without pseudo-obstruction. Cox proportional hazards regression was used to identify risk factors for pseudo-obstruction. RESULTS: 175 patients with SSc had a history of pseudo-obstruction, and 2,637 SSc patients did not. After adjusting for significant variables from the univariate analysis and potential confounders, the Cox proportional hazards multivariable analysis demonstrated that older age (HR 1.02; 95%CI 1.00-1.04), male sex (HR 1.75; 95%CI 1.42-2.43), diffuse cutaneous disease (HR 2.52; 95%CI 1.59-3.99), myopathy (HR 1.83, 95%CI 1.09-3.08), and opioid use (HR 2.38; 95%CI 1.50-3.78) were predictive of pseudo-obstruction. Autoantibodies to RNA polymerase-3 were negatively associated with pseudo-obstruction (HR 0.34; 95%CI 0.17-0.66). CONCLUSION: We identified clinical features associated with pseudo-obstruction in a large US SSc cohort. This study identifies characteristics of patients with SSc who are at a higher risk of developing pseudo-obstruction and suggests that opioids may be a modifiable risk factor. These clinical features may allow for earlier diagnostic evaluation and/or therapeutic intervention for patients at risk for pseudo-obstruction.

Cerebral Venous Thrombosis Mimicking a Discrete Brain Mass: A Case Report and Literature Review.

The differential diagnosis for a focal brain lesion in a patient with systemic lupus erythematosus (SLE) is broad and includes infection, malignancy, and vascular and inflammatory etiologies. One rarely considered vascular pathology is cerebral venous thrombosis (CVT), which is often associated with a delay in diagnosis because of variable presentation and rare incidence. We present the case of a young woman with a new discrete brain lesion that appeared in the context of highly active SLE and was ultimately diagnosed with a CVT. We provide a literature review for diagnosis and management of cerebral venous thrombosis, a potentially serious complication of untreated systemic lupus erythematosus.

Risk of Digital Vascular Events in Scleroderma Patients Who Have Both Anticentromere and Anti-Interferon-Inducible Protein 16 Antibodies.

OBJECTIVE: To evaluate whether scleroderma patients who are double-positive for anti-interferon-inducible protein 16 (anti-IFI-16) antibodies and anticentromere (anti-CENP) antibodies are at increased risk for significant digital vascular events relative to patients positive for anti-CENP antibodies alone. METHODS: Sera from 165 scleroderma patients who tested positive for anti-CENP antibodies upon clinical evaluation were reassayed for both anti-CENP and anti-IFI-16 antibodies using enzyme-linked immunosorbent assay testing. Patients who were positive for anti-CENP antibodies alone were then compared to patients who were double-positive for both anti-IFI-16 and anti-CENP antibodies. The association between a history of significant digital vascular events (digital pits, ischemic digital ulcers, and/or gangrene) and double-positive antibody status was examined using chi-square tests. After completion of univariate analysis, multivariable analyses were done to adjust for clinically relevant covariates. RESULTS: Of the 165 anti-CENP antibody positive patients, 21 (12.7%) also had anti-IFI-16 antibodies. Patients who were double-positive for anti-CENP and anti-IFI-16 antibodies were more likely to have had digital pits, ischemic digital ulcers, and/or gangrene (P = 0.03). After adjustment for clinically relevant covariates (age, cutaneous subtype, disease duration, and smoking), double-positive patients remained at significantly higher odds of having severe Raynaud's phenomenon (odds ratio 3.5 [95% confidence interval 1.1-11.1]; P = 0.03). CONCLUSION: Scleroderma patients who are double-positive for antibodies recognizing CENP and IFI-16 are significantly more likely to have significant digital vascular events during the course of their disease. This study provides further evidence that anti-CENP and anti-IFI-16 antibodies are disease biomarkers that may be used for risk stratification of vascular events in scleroderma.

Enrichment of Scleroderma Vascular Disease-Associated Autoantigens in Endothelial Lineage Cells.

OBJECTIVE: Scleroderma patients with autoantibodies to CENPs and/or interferon-inducible protein 16 (IFI-16) are at increased risk of severe vascular complications. This study was undertaken to determine whether these autoantigens are enriched in cells of the vasculature. METHODS: Successive stages of embryoid bodies (EBs) as well as vascular progenitors were used to evaluate the expression of scleroderma autoantigens IFI-16 and CENP by immunoblotting. CD31 was included to mark early blood vessels. IFI-16 and CD31 expression were defined in paraffin-embedded skin sections from scleroderma patients and from healthy controls. IFI-16 expression was determined by flow cytometric analysis in circulating endothelial cells (CECs) and circulating hematopoietic progenitor cells. RESULTS: Expression of CENP-A, IFI-16, and CD31 was enriched in EBs on days 10 and 12 of differentiation, and particularly in cultures enriched in vascular progenitors (IFI-16, CD31, and CENPs A and B). This pattern was distinct from that of comparator autoantigens. Immunohistochemical staining of paraffin-embedded skin sections showed enrichment of IFI-16 in CD31-positive vascular endothelial cells in biopsy specimens from scleroderma patients and normal controls. Flow cytometric analysis revealed IFI-16 expression in circulating hematopoietic progenitor cells but minimal expression in CECs. CONCLUSION: Our findings indicate that expression of the scleroderma autoantigens IFI-16 and CENPs, which are associated with severe vascular disease, is increased in vascular progenitors and mature endothelial cells. High level, lineage-enriched expression of autoantigens may explain the striking association between clinical phenotypes and the immune targeting of specific autoantigens.

Anti-Interferon-Inducible Protein 16 Antibodies Associate With Digital Gangrene in Patients With Scleroderma.

OBJECTIVE: To examine the association between anti-interferon-inducible protein 16 (anti-IFI-16) antibodies and clinical features of scleroderma. METHODS: Sera from a discovery sample of 94 patients with scleroderma and 47 healthy controls were assayed for anti-IFI-16 antibodies by enzyme-linked immunosorbent assay, and associations were examined using regression analyses. Since anti-IFI-16 autoantibodies were found to be strongly associated with digital gangrene in the discovery sample, a subsequent case-control study (with subjects matched 1:1 on disease duration) was designed for further exploration. Cases were patients with scleroderma and digital gangrene, while controls were patients with scleroderma and Raynaud's phenomenon alone (n = 39 matched pairs). Nonparametric, unadjusted matched pairs analysis as well as univariate and multivariable conditional logistic regression analyses were performed. RESULTS: In the discovery sample, anti-IFI-16 antibodies were more prevalent in patients with scleroderma than in healthy controls (18% versus 2%; P = 0.01). Patients with anti-IFI-16 antibodies, compared to anti-IFI-16 antibody-negative patients, were more likely to have limited scleroderma (77% versus 46%; P = 0.03), a longer disease duration (median 15.2 years [interquartile range 10.6-18.3] versus 6.0 years [interquartile range 3.4-13.8]; P < 0.01), digital gangrene (24% versus 4%; P = 0.02), and a low diffusing capacity for carbon monoxide (DLco) (P < 0.01). In the case-control study, 35 (45%) of 78 patients were anti-IFI-16 antibody positive. Anti-IFI-16 antibody levels were significantly higher in cases with digital gangrene than in matched controls (P = 0.02). In analyses adjusted for age, cutaneous scleroderma subtype, smoking, and DLco, high anti-IFI-16 antibody levels were associated with the presence of digital gangrene (adjusted odds ratio 2.3, 95% confidence interval 1.0-5.6, P = 0.05). The odds of having digital gangrene increased with higher anti-IFI-16 antibody titers, in a dose-dependent manner. CONCLUSION: Anti-IFI-16 antibodies are associated with digital gangrene in patients with scleroderma. Longitudinal prospective studies exploring anti-IFI-16 antibodies as a disease biomarker, and biologic studies investigating the pathogenicity of these antibodies, are warranted.

Oxalate nephropathy in systemic sclerosis: Case series and review of the literature.

OBJECTIVE: To increase awareness of oxalate nephropathy as a cause of acute kidney injury (AKI) among systemic sclerosis patients with small intestinal dysmotility and malabsorption, and to prompt consideration of dietary modification and early treatment of predisposing causes of oxalate nephropathy in this population. METHODS: Two cases of biopsy-proven oxalate nephropathy were identified among systemic sclerosis patients in the course of direct clinical care. Subsequently, a retrospective search of the Johns Hopkins Pathology databases identified a third patient with systemic sclerosis who developed oxalate nephropathy. RESULTS: Among the three patients with qualifying biopsies, all three had systemic sclerosis with lower gastrointestinal involvement. All three presented with diarrhea, malabsorption, and AKI. In two of the three patients, diarrhea was present for at least 2 years before the development of AKI; in the third, incidental oxalate nephropathy was noted 3 years before she developed AKI and extensive oxalate nephropathy in the setting of a prolonged mycobacterium avium-intracellulare enteritis. In the first case, oxalate crystals were present by urinalysis months before diagnosis by biopsy; in the second, hyperoxaluria was diagnosed by urine collection immediately after; and in the third, oxalate crystals had been noted incidentally on post-transplant renal biopsy 3 years before the development of fulminant oxalate nephropathy. All three patients died within a year after diagnosis. CONCLUSIONS: Patients with systemic sclerosis and bowel dysmotility associated with chronic diarrhea and malabsorption may be at risk for an associated oxalate nephropathy. Regular screening of systemic sclerosis patients with small bowel malabsorption syndromes through routine urinalysis or 24-h urine oxalate collection, should be considered. Further studies defining the prevalence of this complication in systemic sclerosis, the benefit of dietary modification on hyperoxaluria, the effect of treating small intestinal bowel overgrowth with antibiotics, and the effectiveness of probiotics, calcium supplements, or magnesium supplements to prevent hyperoxaluria-associated renal disease in these patients, are warranted.

Systemic sclerosis--challenges for clinical practice.

The management of patients with systemic sclerosis (SSc) can be challenging because disease-associated damage is often difficult to reverse and curative therapies are not yet available. Early identification and appropriate monitoring of patients with SSc is, therefore, critical so that active disease can be controlled and tissue damage prevented or delayed. However, early diagnosis of SSc is often difficult because the early clinical stages of the disease can be very similar to that of other autoimmune conditions. Screening for major organ manifestations of SSc, particularly interstitial lung disease, pulmonary hypertension, renal involvement and cardiac disease is a priority because involvement of these organs is associated with shorter life expectancies and early intervention might prevent disease progression. The prevention and management of digital ischaemia is also important as appropriate therapy often prevents substantial morbidity and functional loss. Treating gastrointestinal dysmotility can usually be managed using proton pump inhibitors and promotility agents, although in severe cases total parenteral nutrition is required. Calcinosis in patients with SSc is another common challenge that requires appropriate disease management and pain control. Each of these topics, which are relevant to both physicians and patients with SSc, are reviewed in further detail herein.

Systemic amyloidosis presenting as chronic diarrhea in a patient with ankylosing spondylitis.

Secondary (AA) amyloidosis is a disease that is caused by systemic deposition of amyloid fibrils. Circulating serum amyloid A protein is an acute phase reactant and levels are therefore high during inflammatory states. Chronic elevation of serum amyloid A levels results in accumulation and deposition in various organs, leading to organ dysfunction. Unless the inciting inflammatory state can be controlled, the subsequent development of amyloidosis diminishes patient survival. We report a case of systemic amyloidosis that presented primarily as chronic diarrhea in a patient with ankylosing spondylitis. Unfortunately for the patient, the diagnosis of amyloidosis was delayed for years despite encounters with multiple physicians. Early medical intervention to control chronic inflammation is imperative and could prevent morbidity and mortality related to the development of secondary amyloidosis. Consideration of amyloidosis as a diagnosis in patients who have chronic uncontrolled inflammatory conditions is also important in preventing poor outcomes related to this disease.