Thomas A. Medsger

Systemic sclerosis sine scleroderma: Demographic, clinical, and serologic features and survival in forty‐eight patients

OBJECTIVE To describe the demographic, clinical, and laboratory features and natural history of patients with systemic sclerosis sine scleroderma (ssSSc), and to compare them with those of patients with SSc and limited cutaneous involvement (IcSSc). METHODS The University of Pittsburgh Scleroderma Databank served as the data source. Patients were divided into those who had no skin thickening (ssSSc) and those who had skin thickening only distal to elbows or knees and/or of the face (IcSSc) during their disease course. These two groups were compared with regard to demographic characteristics, clinical, laboratory, and serologic features, and survival rates. Chi-square and Students t-test analyses were performed, and Fishers exact test was used as appropriate. RESULTS Of 555 consecutive patients without diffuse cutaneous SSc, 48 (9%) had ssSSc and 507 (91%) had IcSSc. The ssSSc patients had a mean total disease duration of 18.6 years (15.1 years before study entry and 3.5 years of followup after study entry), and had not developed IcSSc or another connective tissue disease. Other than the absence of skin thickening, the ssSSc group had no significant differences in individual internal organ involvements, laboratory features, serum autoantibody type, or survival rate compared with patients with IcSSc. Within the category of lung involvement, patients with ssSSc had a significantly greater frequency of dyspnea with mild exertion or at rest, and a tendency toward reduced carbon monoxide diffusing capacity (<70% of predicted normal) and primary pulmonary arterial hypertension. Patients with IcSSc had significantly more frequent individual manifestations of digital pitting scars, digital-tip ulcers, telangiectasia, and calcinosis than those with ssSSc, in part related to increased time of observation. Puffy fingers and finger joint contractures were detected significantly more often in IcSSc patients. CONCLUSION Systemic sclerosis sine scleroderma should be included in the spectrum of SSc with limited cutaneous involvement and should not be considered a distinct or separate disorder.

Survival with scleroderma—II: A life-table analysis of clinical and demographic factors in 358 male U.S. veteran patients

Survival of 358 males first diagnosed scleroderma in a VA hospital was analyzed according to entry characteristics. The overall cumulative survival rate by the life-table method declined to 35 per cent after 7 yr of follow-up. Older patients survived significantly worse than younger (p < 0.001) and this age effect occurred only in the first 2 yr. No racial or geographic differences in survival were found. All 17 patients with kidneys involved died within 10 months. Men with heart but not kidney involvement had 13 per cent survival after 7 yr and those with lung but neither kidney nor heart had 34 per cent survival. Patients without these circulatory organs involved at entry had the best survival (44 per cent) although far less than expected (91 per cent). In the latter patient group, factors associated with significantly reduced survival were: older age, elevated sedimentation rate, anemia, proteinuria and heavy use of alcohol or cigarettes. None of the common therapies, including corticosteroids influenced survival.

The epidemiology of systemic sclerosis (scleroderma) among male U.S. veterans

Abstract A comprehensive VA hospital survey of U.S. male veterans diagnosed scleroderma during 1963–1968 was completed and led to the following conclusions: (1) The average annual incidence rate of cases newly diagnosed in a VA hospital was 2.3 per million male veterans. (2) Incidence rates increased with age, peaked in the 45–54 yr age group for both Whites and Non-Whites and plateaued thereafter. The pattern of mortality rates closely paralleled the incidence rates and peaked in the 55–64 and 65 + age groups for Whites and Nonhites, respectively. (3) Without adjusting for hospital utilization, the Non-White incidence and mortality rates were significantly greater than those of Whites by age, region and in total. However, when adjustments were made for VA hospital utilization, using a 0.1% sample of patients with other diagnoses, no significant difference was found by race in relative proportions of scleroderma patient discharges compared to all other patient discharges. (4) The highest scleroderma incidence and mortality was found in the East South Central and South Atlantic regions. After adjustment for hospital utilization, or control patient deaths, a significantly higher relative frequency of White male scleroderma cases, but not deaths, was observed. (5) Scleroderma cases did not differ from hospitalized VA control patient samples in regard to urban or rural residence location, smoking habits, or frequency of simultaneously diagnosed malignancy. Patients were significantly more often married, heavier alcohol consumers, and employed as laborers or other lessskilled occupations. The importance of these personal findings is uncertain at present. Considering these results, scleroderma appears to be a disease of increasing incidence and mortality with age, and of relatively uniform incidence and mortality by race throughout the major geographic regions of U.S.A., with the possible exception of the southeast section of the country. The observed incidence and mortality rates in male veterans were comparable to frequencies in males as reported in several published community studies. The consistent age-specific patterns of incidence and mortality, as well as likeness of race and residence, suggest the importance of host rather than geographic environmental factors in scleroderma pathogenesis. Predisposition to, or acquisition of, this disease may be modified by certain personal factors related to marital status, alcohol use and occupation, but the differences found and explanation of their biologic significance require further study.

HLA and ethnic associations among systemic sclerosis patients with anticentromere antibodies.

SSc with ACAs is characterized by limited cutaneous involvement and, in most patients, a mild protracted course. We have studied 104 SSc patients, 47 with ACAs and 57 who were negative for both ACAs and anti-topo I antibodies, for HLA-DR and -DQ associations using DNA typing techniques. Normal controls consisted of 181 healthy individuals. A significant association was observed in the ACA-positive patients with DQB1-0501 (p = 0.001, RR 2.6). There was also a significant decrease in the frequency of DQB1-0201 (p = 0.01, RR 0.33). In addition, the ACA-positive SSc patients were significantly different ethnically from both the other SSc patients and the normal controls (p = 0.004). When patients were stratified according to their ethnic origin and the analysis of HLA associations was repeated, the HLA associations persisted. These results strongly suggest that the development of SSc with ACAs is associated with particular DQB1 alleles, and also that ethnic origin plays a role in disease susceptibility.

Myasthenia gravis and scleroderma: Two cases and a review of the literature

Myasthenia gravis is uncommon in patients with scleroderma, and when diagnosed is usually associated with previous use of d-penicillamine. Clinically, both myasthenia and scleroderma may present with fatigue, weakness and bulbar symptoms, so one of diagnoses may be delayed. We report two new cases and review clinical features of 12 other reported cases of co-existing scleroderma and myasthenia gravis, unrelated to previous d-penicillamine therapy. Co-occurrence of myasthenia and scleroderma was reported almost exclusively (13/14) in women with a mean latency of 7.03 years. Most patients (10/11) had seropositive generalized myasthenia, and there were no cases with exclusively ocular symptoms. Three patients with pre-existing myasthenia were safely treated with d-penicillamine. Myasthenia and scleroderma occur in the context of an underlying autoimmune diathesis, but their co-occurrence could be underreported as the recognition of either disorder may be delayed by overlapping clinical symptoms. Our findings also suggest that d-penicillamine may be cautiously used in selected patients with pre-existing scleroderma and myasthenia, when potential benefits outweigh the risk of possible myasthenia exacerbation.

2013 Classification Criteria for Systemic Sclerosis: An American College of Rheumatology/European League Against Rheumatism Collaborative Initiative: ACR/EULAR Classification Criteria for SSc

OBJECTIVE The 1980 American College of Rheumatology (ACR) classification criteria for systemic sclerosis (SSc) lack sensitivity for early SSc and limited cutaneous SSc. The present work, by a joint committee of the ACR and the European League Against Rheumatism (EULAR), was undertaken for the purpose of developing new classification criteria for SSc. METHODS Using consensus methods, 23 candidate items were arranged in a multicriteria additive point system with a threshold to classify cases as SSc. The classification system was reduced by clustering items and simplifying weights. The system was tested by 1) determining specificity and sensitivity in SSc cases and controls with scleroderma-like disorders, and 2) validating against the combined view of a group of experts on a set of cases with or without SSc. RESULTS It was determined that skin thickening of the fingers extending proximal to the metacarpophalangeal joints is sufficient for the patient to be classified as having SSc; if that is not present, 7 additive items apply, with varying weights for each: skin thickening of the fingers, fingertip lesions, telangiectasia, abnormal nailfold capillaries, interstitial lung disease or pulmonary arterial hypertension, Raynauds phenomenon, and SSc-related autoantibodies. Sensitivity and specificity in the validation sample were, respectively, 0.91 and 0.92 for the new classification criteria and 0.75 and 0.72 for the 1980 ACR classification criteria. All selected cases were classified in accordance with consensus-based expert opinion. All cases classified as SSc according to the 1980 ACR criteria were classified as SSc with the new criteria, and several additional cases were now considered to be SSc. CONCLUSION The ACR/EULAR classification criteria for SSc performed better than the 1980 ACR criteria for SSc and should allow for more patients to be classified correctly as having the disease.

RNA Polymerase I-III Autoantibodies

Publisher Summary This chapter includes methods for detecting RNA polymerase (RNAP) class I, II, and III autoantibodies with pathogenic role in animal model. RNAPs play a central role in basic genetic processes responsible for producing and maintaining the proteins and nucleic acids of a cell. RNAPs exist in all eukaryotic cells, tissues, and organs. In the immunofluorescence antinuclear antibody test, anti-RNAP I antibodies produce speckled staining of the nucleolus of interphase cells and punctate staining of the nucleolar organizing regions of mitotic chromosomes. Radioimmunoprecipitation assays with [35S]-methionine-labeled cell extract as the antigen source is the preferred method for detecting RNAP I, II, and III antibodies. Autoantibodies to RNAP I and III are specific for SSc, especially for SSc with diffuse cutaneous involvement and seriousinternal organ involvement. Autoantibodies to RNAP II are found in systemic sclerosis as well as systemic lupus erythematosus and overlap syndromes. The variable disease associations of antibodies to RNAPs among Japanese, U.S. Caucasians, and African Americans suggest that genetic factors influence production of these autoantibodies.

Brief Report: Whole-Exome Sequencing to Identify Rare Variants and Gene Networks That Increase Susceptibility to Scleroderma in African Americans

Whole‐exome sequencing (WES) studies in systemic sclerosis (SSc) patients of European American (EA) ancestry have identified variants in the ATP8B4 gene and enrichment of variants in genes in the extracellular matrix (ECM)–related pathway that increase SSc susceptibility. This study was undertaken to evaluate the association of the ATP8B4 gene and the ECM‐related pathway with SSc in a cohort of African American (AA) patients.

Survival and Predictors of Mortality in Systemic Sclerosis-Associated Pulmonary Arterial Hypertension: Outcomes From the Pulmonary Hypertension Assessment and Recognition of Outcomes in Scleroderma Registry: Predictors of Mortality and Survival Rates in SSc-Associated PAH

To assess cumulative survival rates and identify independent predictors of mortality in patients with incident systemic sclerosis (SSc)–associated pulmonary arterial hypertension (PAH) who had undergone routine screening for PAH at SSc centers in the US.