Causes and outcomes of markedly elevated C-reactive protein levels.

OBJECTIVE: To characterize the causes of marked elevation of C-reactive protein (CRP) levels, investigate patient outcomes, and examine factors that might influence the CRP response. DESIGN: Health records were used to retrospectively determine patient characteristics, diagnoses, and outcomes over a 2-year period (2012 to 2013). SETTING: A large referral centre in Moncton, NB. PARTICIPANTS: Adult inpatients and outpatients with a CRP level above 100 mg/L. MAIN OUTCOME MEASURES: Differences among the CRP distributions of various diagnosis categories were examined using Kruskal-Wallis tests, and factors affecting outcomes were examined using Fisher exact tests. RESULTS: Over the 2-year period, 1260 CRP levels (839 patients; 3.1% of all tests) were above 100 mg/L (range 100.1 to 576.0 mg/L). The mean age was 63 years (range 18 to 101) and 50.2% of patients were men. Infection was the most prevalent cause (55.1%), followed by rheumatologic diseases (7.5%), multiple causes (5.6%), other inflammatory conditions (5.4%), malignancy (5.1%), drug reactions (1.7%), and other conditions (2.0%). A diagnosis could not be established in 17.6% of cases. On average, infections caused higher peak CRP levels (W = 34 519, P < .001) and infection was present in 88.9% of cases with CRP levels greater than 350 mg/L. Rheumatologic causes were associated with only 5.6% of CRP levels above 250 mg/L. The overall mortality was 8.6% and was higher in patients with malignancy (37.0%), multiple diagnoses (21.0%), and leukopenia (20.7%, P = .002). CONCLUSION: Most patients had infections and the proportion of patients with infections increased with the level of CRP, although many diagnoses were associated with markedly elevated CRP levels. These data could help guide health care professionals in the evaluation and management of these patients.

Calcinosis is associated with digital ischaemia in systemic sclerosis-a longitudinal study.

OBJECTIVE: To determine if ischaemia is a causal factor in the development of calcinosis in SSc. METHODS: Patients with SSc were assessed yearly. Physicians reported the presence of calcinosis, digital ischaemia (digital ulcers, digital necrosis/gangrene, loss of digital pulp on any digits and/or auto- or surgical digital amputation) and nailfold capillary dropout assessed using a dermatoscope. The number of digits with digital ischaemia was used as an assessment of the severity of digital ischaemia. SSc specific antibodies were detected with a line immunoassay. Multiple logistic regression and Cox proportional hazards models were generated to determine associations between calcinosis, digital ischaemia and capillary dropout. RESULTS: One thousand three hundred and five patients were included in this study, of whom 300 (23.0%) had calcinosis at study entry. In a cross-sectional multivariate analysis, at baseline, calcinosis was associated with digital ischaemia (odds ratio (OR) = 2.37, 95% CI: 1.66, 3.39), severity of ischaemia (OR = 1.12, 95% CI: 1.06, 1.18), capillary dropout (OR = 1.41, 95% CI: 1.05, 1.89), ACAs (OR = 1.68, 95% CI: 1.17, 2.43) and anti-RNA polymerase III antibodies (OR = 1.77, 95% CI: 1.08, 2.89). Current use of calcium channel blockers was inversely associated with the presence of calcinosis (OR = 0.70, 95% CI: 0.52, 0.96). Of the 805 patients with no calcinosis at study entry and at least one follow-up visit, 215 (26.7%) developed calcinosis during follow-up. Significant baseline predictors of the development of calcinosis in follow-up were digital ischaemia (hazard ratio (HR) = 1.82, 95% CI: 1.30, 2.54), capillary dropout (HR = 1.46, 95% CI: 1.08, 1.99), dcSSc (HR = 1.57, 95% CI: 1.11, 2.21), ACA (HR = 2.18, 95% CI: 1.50, 3.17) and anti-RNA polymerase III antibodies (HR = 2.58, 95% CI: 1.65, 4.04). CONCLUSION: Ischaemia may play a role in the development of calcinosis in SSc.

Genetic susceptibility loci of idiopathic interstitial pneumonia do not represent risk for systemic sclerosis: a case control study in Caucasian patients.

BACKGROUND: Systemic sclerosis (SSc)-related interstitial lung disease (ILD) has phenotypic similarities to lung involvement in idiopathic interstitial pneumonia (IIP). We aimed to assess whether genetic susceptibility loci recently identified in the large IIP genome-wide association studies (GWASs) were also risk loci for SSc overall or severity of ILD in SSc. METHODS: A total of 2571 SSc patients and 4500 healthy controls were investigated from the US discovery GWAS and additional US replication cohorts. Thirteen IIP-related selected single nucleotide polymorphisms (SNPs) were genotyped and analyzed for their association with SSc. RESULTS: We found an association of SSc with the SNP rs6793295 in the LRRC34 gene (OR = 1.14, CI 95 % 1.03 to 1.25, p value = 0.009) and rs11191865 in the OBFC1 gene (OR = 1.09, CI 95 % 1.00 to 1.19, p value = 0.043) in the discovery cohort. Additionally, rs7934606 in MUC2 (OR = 1.24, CI 95 % 1.01 to 1.52, p value = 0.037) was associated with SSc-ILD defined by imaging. However, these associations failed to replicate in the validation cohort. Furthermore, SNPs rs2076295 in DSP (ß = -2.29, CI 95 % -3.85 to -0.74, p value = 0.004) rs17690703 in SPPL2C (ß = 2.04, CI 95 % 0.21 to 3.88, p value = 0.029) and rs1981997 in MAPT (ß = 2.26, CI 95 % 0.35 to 4.17, p value = 0.02) were associated with percent predicted forced vital capacity (FVC%) even after adjusting for the anti-topoisomerase (ATA)-positive subset. However, these associations also did not replicate in the validation cohort. CONCLUSIONS: Our results add new evidence that SSc and SSc-related ILD are genetically distinct from IIP, although they share phenotypic similarities.

Antinuclear antibody-negative systemic sclerosis.

OBJECTIVE: To examine the demographic and clinical characteristics of systemic sclerosis (SSc) patients without antinuclear antibodies (ANA) compared to ANA-positive patients. METHODS: SSc patients enrolled in the Scleroderma Family Registry and DNA Repository were included. Relevant demographic and clinical data were entered by participating sites or obtained by chart review. ANA and SSc-related antibodies were determined in all investigated patients using commercially available kits at our laboratories. RESULTS: This study included 3249 patients, of whom 208 (6.4%) were ANA negative. The proportion of male patients was higher in the ANA-negative group (OR = 1.65; p = 0.008). ANA-negative patients experienced less vasculopathic manifestations of SSc. The percent predicted diffusing capacity of carbon monoxide (DLCO) was higher in ANA-negative patients (p = 0.03). Pulmonary arterial hypertension (PAH) per right heart catheterization was less common in the ANA-negative group (OR = 0.28; p = 0.03). Furthermore, patients with negative ANA had a lower prevalence of telangiectasias and digital ulcers/pits (OR = 0.59, p = 0.03 and OR = 0.38, p = 0.01, respectively). Although diffuse cutaneous involvement was more common, the modified Rodnan Skin Score (mRSS) was lower in the ANA-negative group (2.4 points lower, p = 0.05). Furthermore, they experienced more malabsorption (p = 0.05). There was no difference in the frequency of pulmonary fibrosis or scleroderma renal crisis. All-cause mortality was not different between the 2 groups (p = 0.28). CONCLUSIONS: In conclusion, the results of this study suggest that SSc patients who are ANA negative constitute a distinct subset of SSc with less vasculopathy (less PAH, digital ulcers, and fewer telangiectasias), a greater proportion of males, and possibly, more frequent lower gastrointestinal involvement.

2013 American College of Rheumatology/European League against rheumatism classification criteria for systemic sclerosis outperform the 1980 criteria: data from the Canadian Scleroderma Research Group.

OBJECTIVE: The goal of this study was to determine the sensitivity of the new 2013 classification criteria for systemic sclerosis (SSc; scleroderma) in an independent cohort of SSc subjects and to assess the contribution of individual items of the criteria to the overall sensitivity. METHODS: SSc subjects from the Canadian Scleroderma Research Group cohort were assessed. Sensitivity was determined in several subgroups of patients. In patients without the criterion of skin thickening proximal to the metacarpophalangeal (MCP) joints, we recalculated sensitivity after removing the individual criterion. RESULTS: A total of 724 SSc patients were included. Most were women (86%), mean age was 55.8 years, mean disease duration was 10.9 years, and 59% had limited cutaneous SSc (lcSSc). Overall, the sensitivity of the 2013 criteria was 98.3% compared to 88.3% for the 1980 criteria. This pattern was consistent among those with lcSSc (98.8% versus 85.6%), anticentromere antibodies (98.9% versus 79.8%), disease duration ≤3 years (98.7% versus 84.7%), and no skin involvement proximal to the MCP joints (97% versus 60%). In the latter subgroup, removing Raynaud's phenomenon and sclerodactyly from the criteria reduced the sensitivity to 77% and 79%, respectively. Removing both sclerodactyly and puffy fingers reduced the sensitivity to 62%. CONCLUSION: The 2013 SSc classification criteria classify more SSc patients than the 1980 criteria. The improvement in sensitivity is most striking in those with lcSSc, especially those without skin involvement proximal to the MCP joints. The addition of Raynaud's phenomenon and puffy fingers to the 2013 criteria accounts for important gains in sensitivity.

Demographic and clinical factors associated with physician service use in systemic sclerosis.

OBJECTIVE: To assess physician service use in a large sample of patients with systemic sclerosis (SSc), and to determine factors associated with physician use. METHODS: Our sample was a national SSc registry maintaining data on demographics (age, sex, race/ethnicity, education, income) and clinical factors (disease onset, organ involvement, etc.). Registry cohort members completed detailed questionnaires, and rheumatologists provided clinical assessments. We examined cross-sectional data from 397 patients who provided information on physician visits in the past 12 months. Patients were classified as high physician-users if they reported more than the median number (6) of physician visits in the past year. In multivariate logistic regressions, we assessed the independent effects of race/ethnicity, education, degree of skin involvement, comorbidity, and SF-36 scores on physician use. RESULTS: On average, subjects reported 3.8 visits per year to specialty physicians (SD 4.2) and 3.5 visits per year to family physicians (SD 4.3). Regression models suggested the following factors as independently associated with number of physician visits: high skin scores, greater comorbidity, and low physical component summary scores on the SF-36. CONCLUSION: There is evidence of independent relationships between clinical characteristics and physician use by patients with SSc.

Assessment of reproductive history in systemic sclerosis.

OBJECTIVE: To assess the number of live births in women whose systemic sclerosis (SSc) onset occurred during their reproductive years, and to compare this with general population rates. METHODS: Within the Canadian Scleroderma Research Group cohort, we identified 320 women whose SSc symptoms began prior to age 50 years. We determined the number of children born in the years following first onset of symptoms. We summed the years of followup from the time of first symptoms in subjects up to age 50 years (or oldest age attained, if the subject was age <49 years). We applied age-specific birth rates for Canadian women to these years of followup in order to determine the expected number of live births for the period. We then calculated the standardized incidence ratio (SIR) of observed to expected live births. RESULTS: In the 320 women studied, the number of live births over the interval since symptom onset was below the expected number (111 live births observed versus 140 expected; SIR 0.79, 95% confidence interval [95% CI] 0.65-0.95). This finding was more prominent in women with diffuse cutaneous disease versus limited cutaneous disease. The mean and median numbers of live births were similar across SSc subgroups based on organ involvement or cyclophosphamide exposure. In repeat analyses, including the reproductive period before SSc symptom onset, the ratio of observed to expected births was 1.23 (95% CI 1.13-1.33). CONCLUSION: Compared with the general population, fewer live births were noted in women with SSc, but this phenomenon was only apparent in the period after symptom onset.

Prevalence of elevated pulmonary arterial pressures measured by echocardiography in a multicenter study of patients with systemic sclerosis.

OBJECTIVE: To estimate the prevalence of elevated pulmonary arterial pressures (PAP) as a correlate for pulmonary arterial hypertension (PAH) in patients with systemic sclerosis (SSc) in rheumatology centers in Canada. METHODS: During the one-year study period (June 2002-May 2003), charts of patients with SSc were reviewed to determine demographics, SSc characteristics, percentage of patients with a PAH diagnosis, and the site criteria for such diagnosis. Subjects with no PAH that had symptoms of dyspnea and/or fatigue were invited to undergo Doppler echocardiography to estimate their systolic PAP (sPAP). RESULTS: A total of 539 patients with SSc (age 56 yrs +/- 13 SD, 84% female, 41% with diffuse SSc, 58% limited SSc, SSc disease duration 9 yrs +/- 7 SD) at 8 rheumatology centers were reviewed. Twenty-three percent of patients were diagnosed with elevated sPAP based on the site diagnosis criteria (i.e., > 30 mm Hg or > 35 mm Hg). From the non-PAH, not recently screened patients that had symptoms of dyspnea or fatigue, a total of 89 patients underwent a Doppler echocardiograph; 40% had sPAP > 35 mm Hg. CONCLUSION: Elevated PAP are common in both limited and diffuse SSc disease, occurring in 21% of limited and 26% of diffuse SSc patients. During the screening most patients had mild PAP elevations that would require further assessments such as right heart catheterization to diagnose PAH where appropriate. A high index of suspicion is important and routine echocardiography in symptomatic patients may allow earlier diagnosis of PAH and intervention. The proportion of SSc patients with mild to moderate elevations of PAP who will develop significant PAH is unknown and longterm studies are needed to address the natural progression.

Factor V Leiden, prothrombin gene mutation, and thrombosis risk in patients with antiphospholipid antibodies.

OBJECTIVE: To determine if the prevalence of 2 prothrombotic genetic factors, factor V Leiden and prothrombin gene mutation, is increased in patients with antiphospholipid (aPL) antibodies with a history of venous/arterial thrombosis compared to patients with aPL antibodies with no history of thrombosis. METHODS: One hundred fifty-seven patients with aPL antibodies were studied. The occurrence of venous and arterial thrombotic events since the time of antibody detection was determined retrospectively, using appropriate clinical and diagnostic criteria. Clinical risk factors for thrombosis were documented and included hypertension, hyperlipidemia, cigarette smoking, diabetes, positive family history, use of oral contraceptive, pregnancy, trauma, hospitalization, varicose veins, and malignancy. Genomic DNA was extracted from blood cells for determination of factor V Leiden mutation G1691 --> A and prothrombin mutation G20210 --> A by polymerase chain reaction and restriction fragment length polymorphism analysis. RESULTS: Of 157 patients, 69 had a history of thrombosis (venous 37, arterial 32); 147 (94%) patients had anticardiolipin (aCL) antibodies; 69 (45%) had lupus anticoagulant (LAC). The prevalence of factor V Leiden in patients with thrombosis was 13% compared to 4.6% in patients without thrombosis (OR 3.11, CI 0.92-10.6). In patients with aCL antibodies, 15% of patients with arterial thrombosis had factor V mutation compared to 3.5% of patients without thrombosis (OR 4.9, CI 1.2-19.3). The prothrombin gene mutation was identified in 5 patients, none of whom had thrombosis. Stepwise logistic regression analysis indicated that LAC (p = 0.005), male sex (p = 0.04), and hypertension (p = 0.03) were the strongest risk factors for developing thrombosis and that no additional risk was conferred by factor V Leiden (p = 0.13) and prothrombin gene mutation. CONCLUSION: Although the prevalence of factor V Leiden is modestly increased in patients with autoimmune aPL antibodies and thrombosis, these results suggest that its detection does not significantly increase the risk of a thrombotic event, once other clinical risk factors have been considered. Prothrombin gene mutation is not associated with thrombosis in patients with aPL antibodies.