Describing and expanding the clinical phenotype of anti-MDA5-associated rapidly progressive interstitial lung disease: case series of nine Canadian patients and literature review.

OBJECTIVE: To describe and expand the phenotype of anti-MDA5-associated rapidly progressive interstitial lung disease (MDA5-RPILD) in Canadian patients. METHOD: All proven cases of MDA5-RPILD hospitalized in the University of Montreal's affiliated centres from 2004 to 2015 were selected for inclusion. RESULTS: Of nine consecutive patients, RPILD was the presenting manifestation in seven, whereas two patients developed RPILD 2 years after the onset of arthritis and of chronic interstitial lung disease. In the case with arthritis, RPILD was probably triggered by initiation of tumour necrosis factor-α-inhibitor therapy. In most patients (89%), RPILD was accompanied by concomitant onset of palmar/lateral finger papules, skin ulcerations, and/or mechanic's hands. All patients experienced profound weight loss over 1-2 months (mean ± SD 10.2 ± 4.8 kg). All had arthralgias and/or arthritis. Six patients were clinically amyopathic; only one patient had creatine kinase (CK) levels > 500 U/L. Initial ferritin and transaminase levels were elevated in 86% and 67% of patients, respectively. The antinuclear antibody (ANA) test was negative for nuclear and cytoplasmic staining; antisynthetase autoantibodies were negative. Three patients died; time from initial symptoms to death ranged from 7 to 15 weeks. All six survivors received mycophenolate mofetil and/or tacrolimus as part of induction and/or maintenance therapy. CONCLUSION: In an inpatient setting, RPILD associated with characteristic skin rashes, profound weight loss, articular symptoms, normal or low CK with elevated ferritin, and absent fluorescence on ANA testing should alert the clinician to the possibility of MDA5-RPILD. T-cell-mediated therapies may play a role in this highly lethal condition.

Clinical and serological associations of autoantibodies to the Ku70/Ku80 heterodimer determined by a novel chemiluminescent immunoassay.

BACKGROUND: Autoantibodies targeting Ku, an abundant nuclear protein with DNA helicase activity, have been reported in patients with systemic autoimmune rheumatic diseases. Little is known about the clinical associations of anti-Ku antibodies, especially when novel diagnostic technologies are used. The objective of the present study was to analyse the prevalence of anti-Ku antibodies in different medical conditions using a novel chemiluminescent immunoassay. PATIENTS AND METHODS: Serum samples from adult patients with systemic lupus erythematosus (SLE, n=305), systemic sclerosis (SSc, n=70) and autoimmune myositis patients (AIM, n=109) were the primary focus of the study. Results were compared with disease controls (rheumatoid arthritis, RA, n=30; infectious diseases, n=17) and healthy individuals (n=167). In addition, samples submitted for routine autoantibody testing from patients referred to a rheumatology clinic (n=1078) were studied. All samples were tested for anti-Ku antibodies by QUANTA Flash Ku chemiluminescent immunoassay (research use only, Inova Diagnostics, San Diego, USA) using full length recombinant human Ku. SLE patient samples were also tested for other autoantibodies. Clinical data of anti-Ku antibody positive patients (high titres) were obtained by retrospective chart review. RESULTS AND FINDINGS: In the disease cohorts, 30/305 (9.8%) SLE, 3/70 (4.3%) systemic sclerosis and 4/109 (3.7%) autoimmune myositis (AIM) patients were positive, respectively. The four positive AIM patients had an overlap myositis syndrome that included two patients with SLE. The three systemic sclerosis (SSc) positive samples had diagnoses of SSc/SLE overlap, diffuse cutaneous SSc, and early edematous phase SSc. In the control cohorts, 2/170 (1.2%) healthy individuals (all low titre), 0/30 (0.0%) (RA) and 0/17 (0.0%) infectious disease patients were positive. The area under the curve values were: 0.75 for SLE vs. controls, 0.68 for SSc vs. controls and 0.37 for AIM vs. CONTROLS: In the rheumatology clinic referral cohort, 12/1078 (1.1%) were positive for anti-Ku antibodies, nine showing low and three high titres. The diagnoses of the three high positive anti-Ku positive patients were: probable SLE, mixed connective tissue disease (MCTD) and ANA positive RA. CONCLUSION: Anti-Ku antibodies detected by chemiluminescent immunoassay are most prevalent in SLE. When found in AIM and SSc, they were associated with overlap syndrome and early SSc.

Left heart disease: a frequent cause of early pulmonary hypertension in systemic sclerosis, unrelated to elevated NT-proBNP levels or overt cardiac fibrosis but associated with increased levels of MR-proANP and MR-proADM: retrospective analysis of a French Canadian cohort.

OBJECTIVES: Pulmonary hypertension (PH) causes mortality in systemic sclerosis (SSc). Pulmonary arterial hypertension (PAH) and left heart disease (LHD) are frequent causes of PH. Therefore, we studied PAH and LHD in early PH. METHOD: A total of 432 French Canadian SSc patients were studied retrospectively. All underwent screening for PH. We analysed clinical, serological, and radiographic data from 26 patients with early PH diagnosed by right heart catheterization (RHC). SSc patients with (n = 21) and without PH (n = 19) were prospectively re-evaluated by cardiac magnetic resonance imaging (MRI) and serial measurements of N-terminal pro-brain natriuretic peptide (NT-proBNP) and the haemodynamic biomarkers mid-regional pro-atrial natriuritic peptide (MR-proANP) and mid-regional pro-adrenomedullin (MR-proADM). RESULTS: The most frequent cause of early PH was LHD (58%). PAH was seen in 34% of patients. No association was found between the type of PH and autoantibodies. Early LHD-PH, but not early PAH, was associated with lower NT-proBNP (p = 0.024), but MR-proANP and MR-proADM levels were higher in early LHD-PH than in patients without PH (p = 0.014 and p = 0.012, respectively). Only one patient had abnormal cardiac MRI explaining LHD-PH. CONCLUSIONS: Early PH in SSc, like late PH, is heterogeneous and RHC is essential for determining its underlying cause. The most frequent cause of early PH was LHD. Levels of MR-proANP and MR-proADM, but not NT-proBNP, were increased in early LHD-PH, and may be more reliable than NT-proBNP as a biomarker of early PH in this subgroup of patients. Cardiac MRI did not explain LHD-PH. This study is the first to identify a high frequency of LHD in early PH correlating with normal NT-proBNP levels but increased MR-proANP and MR-proADM levels in SSc patients.

Breast cancer in systemic lupus erythematosus.

OBJECTIVE: Evidence points to a decreased breast cancer risk in systemic lupus erythematosus (SLE). We analyzed data from a large multisite SLE cohort, linked to cancer registries. METHODS: Information on age, SLE duration, cancer date, and histology was available. We analyzed information on histological type and performed multivariate logistic regression analyses of histological types according to age, SLE duration, and calendar year. RESULTS: We studied 180 breast cancers in the SLE cohort. Of the 155 cases with histology information, 11 were referred to simply as 'carcinoma not otherwise specified'. In the remaining 144 breast cancers, the most common histological type was ductal carcinoma (n = 95; 66%) followed by lobular adenocarcinoma (n = 11; 8%), 15 cancers were of mixed histology, and the remaining ones were special types. In our regression analyses, the independent risk factors for lobular versus ductal carcinoma was age [odds ratio (OR) 1.07, 95% confidence interval (CI) 1.01-1.14] and for the 'special' subtypes it was age (OR 1.06, 95% CI 1.01-1.10) and SLE duration (OR 1.05, 95% CI 1.00-1.11). CONCLUSIONS: Generally, up to 80% of breast cancers are ductal carcinomas. Though our results are not definitive, in the breast cancers that occur in SLE, there may be a slight decrease in the ductal histological type. In our analyses, age and SLE duration were independent predictors of histological status.

Nup180, a novel nuclear pore complex protein localizing to the cytoplasmic ring and associated fibrils.

Using an autoimmune serum from a patient with overlap connective tissue disease we have identified by biochemical and immunocytochemical approaches an evolutionarily conserved nuclear pore complex (NPC) protein with an estimated molecular mass of 180 kD and an isoelectric point of approximately 6.2 which we have designated as nup180. Extraction of isolated nuclear envelopes with 2 M urea and chromatography of the solubilized proteins on WGA-Sepharose demonstrated that nup180 is a peripheral membrane protein and does not react with WGA. Affinity-purified antibodies yielded a punctate immunofluorescent pattern of the nuclear surface of mammalian cells and stained brightly the nuclear envelope of cryosectioned Xenopus oocytes. Nuclei reconstituted in vitro in Xenopus egg extract were also stained in the characteristic punctate fashion. Immunogold EM localized nup180 exclusively to the cytoplasmic ring of NPCs and short fibers emanating therefrom into the cytoplasm. Antibodies to nup180 did not inhibit nuclear protein transport in vivo nor in vitro. Despite the apparent lack of involvement in NPC assembly or nucleocytoplasmic transport processes, the conservation of nup180 across species and its exclusive association with the NPC cytoplasmic ring suggests an important, though currently undefined function for this novel NPC protein.

Disseminated Histoplasma capsulatum infection presenting with panniculitis and focal myositis in rheumatoid arthritis treated with etanercept.

We report the case of a patient with rheumatoid arthritis (RA) on etanercept who presented with panniculitis and focal myositis as manifestations of disseminated histoplasmosis. Systematic search of the literature showed 11 additional case reports of disseminated histoplasmosis with tumour necrosis factor-alpha (TNFalpha) blockade therapy (infliximab, n = 8; etanercept, n = 3). Although disseminated histoplasmosis may manifest with classical symptoms of fever and respiratory complaints, it may also present atypically, such as with panniculitis and focal myositis. This review illustrates and emphasizes the importance of being highly suspicious for infection, including by opportunistic organisms, and to exclude such process in patients treated with a TNFalpha inhibitor when faced with unusual complications, even when an alternative aetiology appears plausible.

The relationship between cancer and medication exposures in systemic lupus erythaematosus: a case-cohort study.

OBJECTIVE: To examine if, in systemic lupus erythaematosus (SLE), exposure to immunosuppressive therapy (cyclophosphamide, azathioprine, methotrexate) increases cancer risk. METHODS: A case-cohort study was performed within a multi-site international SLE cohort; subjects were linked to regional tumour registries to determine cancer cases occurring after entry into the cohort. We calculated the hazard ratio (HR) for cancer after exposure to an immunosuppressive drug, in models that controlled for other medications (anti-malarial drugs, systemic glucocorticoids, non-steroidal anti-inflammatory drugs (NSAIDs), aspirin), smoking, age, sex, race/ethnicity, geographic location, calendar year, SLE duration, and lupus damage scores. In the primary analyses, exposures were treated categorically (ever/never) and as time-dependent. RESULTS: Results are presented from 246 cancer cases and 538 controls without cancer. The adjusted HR for overall cancer risk after any immunosuppressive drug was 0.82 (95% CI 0.50-1.36). Age > or = 65, and the presence of non-malignancy damage were associated with overall cancer risk. For lung cancer (n = 35 cases), smoking was also a prominent risk factor. When looking at haematological cancers specifically (n = 46 cases), there was a suggestion of an increased risk after immunosuppressive drug exposures, particularly when these were lagged by a period of 5 years (adjusted HR 2.29, 95% CI 1.02-5.15). CONCLUSIONS: In our SLE sample, age > or = 65, damage, and tobacco exposure were associated with cancer risk. Though immunosuppressive therapy may not be the principal driving factor for overall cancer risk, it may contribute to an increased risk of haematological malignancies. Future studies are in progress to evaluate independent influence of medication exposures and disease activity on risk of malignancy.

SLE patients with renal damage incur higher health care costs.

OBJECTIVES: To compare costs and quality of life (QoL) between SLE patients with and without renal damage. METHODS: Seven hundred and fifteen patients were surveyed semi-annually over 4 yrs on health care use and productivity loss and annually on QoL. Cumulative direct and indirect costs (2006 Canadian dollars) and QoL (average annual change in SF-36) were compared between patients with and without renal damage [Systemic Lupus International Collaborating Clinics/ACR Damage Index (SLICC/ACR DI)] using simultaneous regressions. RESULTS: At study conclusion, for patients with the renal subscale of the SLICC/ACR DI = 0 (n = 634), 1 (n = 54), 2 (n = 15) and 3 (n = 12), mean 4-yr cumulative direct costs per patient (95% CI) were $20,337 ($18,815, $21,858), $27,869 ($19,230, $36,509), $51,191 ($23,463, $78,919) and $99,544 ($57,102, $141,987), respectively. In a regression where the renal subscale of the SLICC/ACR DI was a single indicator variable, on average (95% CI), each unit increase in renal damage was associated with a 24% (15%, 33%) increase in direct costs. In a regression where each level in the renal subscale was an indicator variable, patients with end-stage renal disease incurred 103% (65%, 141%) higher direct costs than those without renal damage. Cumulative indirect costs and annual change in the SF-36 summary scores did not differ between patients. CONCLUSIONS: SLE patients with renal damage incurred higher direct costs, but did not experience a poorer QoL. QoL may be more influenced by concurrent renal activity than accumulated renal damage, which can occur at any time and patients may gradually habituate to their compromised health state.

Anticytoskeletal autoantibody to microfilament anchorage sites recognizes novel focal contact proteins.

Actin microfilaments are anchored to the plasma membrane at focal contacts. Using an indirect immunofluorescence method, we detected an autoantibody reactive with focal contacts in PtK2, HEp-2, and BHK-21 cells in serum from two patients with early systemic sclerosis. With double immunofluorescence, using the actin-binding drug phalloidin, we localized the plaques decorated by these sera specifically at the termini of microfilament bundles. The reactive antigens were identified by immunoblotting as proteins of 80,000- and 75,300-mol wt in PtK2, and of 53,500-mol wt in HEp-2 and BHK-21 cells. The 53,500-mol wt protein was also identified in rat skeletal, myocardial, and smooth muscle tissues. The detergent solubility of these proteins suggested that they may be linked to the plasma membrane. The autoantigens were immunologically distinct from vinculin and alpha-actinin, two major proteins also known to be concentrated at the ends of microfilament bundles. Our observations suggest that this novel anticytoskeletal autoantibody may identify a novel family of vertebrate cell proteins involved in the linkage of microfilaments to the plasma membrane at focal contacts.

Immunoglobulin M autoantibody to vimentin intermediate filaments.

Serum from a patient with the CREST Syndrome and systemic lupus erythematosus contained an IgM antibody that reacted at dilutions up to 1:800 with a fibrous cytoplasmic network in several epithelioid and fibroblastic cell lines. The antibody was shown by immunofluorescence microscopy to label a specific subset of cytoskeletal polymers, the intermediate filaments. The reactive antigen from this biochemically heterogeneous group of filaments was established as the 58,000-mol wt protein, vimentin: (a) the patient's serum reacts with a range of cell lines that contain intermediate filaments composed of vimentin, but not with cells whose intermediate filaments are composed of different protein subunits; (b) in PTK2 epithelioid cells the serum reacts with the class of filaments that coils around the nucleus after colchicine treatment (vimentin) and not with the filaments that remain dispersed after colchicine (prekeratin); and (c) the component of reactive cells that combines with the serum is shown by immunoelectrophoresis to be a 58,000-mol wt protein antigen. A similar antibody that binds intermediate filaments of PTK2 cells was encountered at lower titer in some sera from other patients with connective tissue diseases and in control sera. Previous routine antinuclear antibody assays using mouse liver or commercially prepared HEp-2 cells have failed to reveal anticytoskeletal antibodies in patient sera, perhaps due to inadequate presentation or preservation of cytoplasmic antigens.

Localization of the Ran-GTP binding protein RanBP2 at the cytoplasmic side of the nuclear pore complex.

A partial cDNA clone coding for the mouse homologue of the human Ran-GTP binding protein, RanBP2, has been isolated by screening of a murine expression library with antibodies to nup180, a previously identified nuclear pore complex protein (nucleoporin). Whether the antibodies cross-reacted with the polypeptide encoded by the cDNA clone or, alternatively, nup180 is proteolytically related to RanBP2, has not been determined. The 3795-bp open reading frame of the cDNA encodes a polypeptide consisting of 1265 amino acids with three Ran-GTP binding domains (RanBD) that are almost identical with published partial amino acid sequences of human RanBP2 as deduced from several partial cDNA clones of other authors. Sequence analysis further revealed that murine RanBP2 contains tandemly repeated zinc fingers of Cys2-Cys2 type and multiple copies of the FXFG nucleoporin "signature" motif clustered in regions preceding the RanBDs. Antibodies raised against a synthetic peptide of the derived amino acid sequence decorated the cytoplasmic rings of nuclear pore complexes (NPCs) as shown by immunogold electron microscopy. We suggest that the cytoplasmically disposed nucleoporin RanBP2 provides docking sites for import substrate-receptor complexes and, further, that the affinity of these sites to the transport substrate is modulated in a Ran-dependent fashion.

A controlled study of the long-term prognosis of adult Still's disease.

PURPOSE: To assess the long-term prognosis of patients with adult Still's disease for physical and psychological disability, pain, social functioning, social support, medication use, formal education, occupation, time lost from work, and family income, and to contrast these results with those of same-sex sibling controls. PATIENTS AND METHODS: Patients were recruited from medical center-based cohorts in Pittsburgh and Eastern Canada and from a national survey of rheumatologists. Patients and same-sex sibling controls completed the Health Assessment Questionnaire for physical disability, the psychological and social function domains of the Arthritis Impact Measurement Scales, and the Interpersonal Skills Evaluation List questionnaire for social support, and replied to questions on medication use, formal education, occupation, time lost from work, and family income. RESULTS: One hundred four of 111 eligible adult Still's patients (94%) provided data. They identified 86 same-sex sibling controls, of whom 60 (70%) participated. The mean duration of adult Still's disease was 10 years. Approximately half of patients continued to require medication even 10 years after diagnosis. Patients had significantly higher levels of pain, physical disability, and psychological disability when compared with the controls. However, the levels of pain and physical disability were low compared to patients with other rheumatic diseases. Educational achievement, occupational prestige, social functioning and support, time lost from work, and family income were similar for both patients and controls. CONCLUSIONS: Despite causing disability, pain, and, in many, the need for long-term medication, patients with adult Still's disease are resilient. The disease did not interfere with educational attainment, occupational prestige, social functioning and support, time lost from work, or family income.

CD4-reactive antibodies in systemic lupus erythematosus.

An important place in the immune network is reserved for specific interactions between regulatory antibodies (Ab) and their ligands on T and B lymphocytes. Several lines of evidence indicate that the CD4 glycoprotein may be recognized by such Ab. High levels of CD4-reactive Ab occur in approximately 10-20% of HIV-infected patients. Moreover, between 20 and 30% SLE patients have Ab preferentially reactive with the CD4+ T cells. In relation to this, we have done studies aimed at demonstrating the existence and characteristics of Ab directly targeting CD4 in patients with SLE in comparison with rheumatoid arthritis and normal controls. Assessment of the CD4-reactive Ab by different approaches revealed a several-fold increase in serum concentration of anti-CD4 Ab restricted to a subset of SLE patients (n = 15/87, 17.2%). Enhanced binding was shown to occur specifically both on native CD4 (by immunofluorescence) and on recombinant CD4 (by ELISA and Western blot). Anti-CD4 Ab belonged to IgM and/or IgG isotypes. The overall binding of immunoglobulins to the CD4 molecule was not significantly contributed by DNA/anti-DNA and other circulating immune complexes, and there was no restriction in the usage of kappa and lambda light chains. Clinically, high CD4 reactivity occurred in SLE patients with active disease, as measured by the SLEDAI, and was associated with particular clinical manifestations, including neuropsychiatric disease and lymphopenia.

Distinctive features of idiopathic inflammatory myopathies in French Canadians.

This is the first report on idiopathic inflammatory myopathies (IIM) in French Canadians. We reviewed retrospectively 30 French Canadian adults (20 women and 10 men) with IIM seen consecutively over 12 years. The median age at diagnosis was 45 years. The IIM were 8 (27%) primary polymyositis (PM), 9 (30%) primary dermatomyositis (DM), 5 (17%) IIM with neoplasia (lymphoma, breast, esophageal, colonic, and skin cancer) and 8 (27%) IIM with a connective tissue disease (4 with systemic sclerosis, 2 with mixed connective tissue disease, and 2 with rheumatoid arthritis). The most common presenting symptom was proximal muscle weakness (n = 10,33%). Of the remaining 20 patients, 6 (20%) had the onset of their weakness within 1 month of the presenting symptom. Only 3 (10%) patients did not have proximal muscle weakness. Twenty-six (87%) patients had weakness in the pelvic girdle, 25 (83%) in the shoulder girdle, and 7 (23%) in the neck muscles. Other common symptoms included dyspnea on exertion and dysphagia, each present in 13 (43%) patients. Gottron's papules and the heliotrope rash were the most common skin lesions documented in 11 (37%) and 10 (33%) patients, respectively. The serum creatine kinase (CK) level was between 171 and 1,000 U/L in 13 (43%) patients and between 1,001 and 6,000 U/L in 13 (43%) patients. Antinuclear antibodies (ANA) on HEp-2 cells were positive in 16 (53%) patients, of which 2 (13%) expressed autoantibodies to nuclear pore complexes. Autoantibody specificities were anti-La (n = 4, 13%), anti-U1RNP (n = 3, 10%), and anti-Ro (n = 2, 7%). None of the patients expressed anti-Jo-1, anti-topoisomerase I, or anticentromere antibodies. Twenty-eight (93%) patients received corticosteroid therapy, and 8 (27%) patients responded to prednisone alone. Thirteen (43%) patients were treated with methotrexate, and 9 (69%) responded. The mean follow-up was 62 months: 23 (77%) had their disease controlled, 3 (10%) patients were lost to follow-up, and 4 (13%) died (no death occurred because of IIM or its treatment). Therapy was discontinued because of remission in 5 (17%) patients. Cumulative survival rates at 2, 5, and 10 years were 89%, 89%, and 85%, respectively. The presence of autoantibodies to nuclear pore complexes and anti-La autoantibodies, the rare occurrence of anti-Jo-1 autoantibodies, the response to conventional therapies, and a high survival rate may distinguish IIM in French Canadians from that of other reported series.

Characterization of a novel human IgG antibody reactive with a Ca(2+)-sensitive cell-cell adhesion epitope of PtK2 epithelial cells.

We have characterized a human IgG antibody present in the serum of a patient with an autoimmune undifferentiated connective tissue disease and reactive with PtK2 epithelial cell-cell adhesions. The fluorescent staining pattern is observed only at cell-cell contacts whether cells are permeabilized or not. The serum reacts with polypeptides of 90, 48 and 45 kD by immunoblotting. IgG affinity-purified from these bands failed to reproduce the original immunofluorescence staining pattern. Treatment with cycloheximide did not abolish the staining pattern suggesting that the recognized antigen is not a newly expressed protein. However, when EGTA was used for chelating calcium ions in the culture medium the original staining pattern observed at cell-cell adhesions was affected although some fluorescence was still present at cell periphery. This was reversible when cells were reincubated with fresh medium containing Ca2+. The recognized antigen colocalizes at cell-cell adhesions with actin, the microfilament-associated proteins vinculin, alpha-actinin and myosin light chain, and with Triton-insoluble uvomorulin (E-cadherin) material. We conclude that the antibody reacts with, at least, an extracellular portion of a Ca(2+)-dependent PtK2 antigen. The characterization of this antibody based on (1) its localization at cell-cell adhesions, (2) its sensitivity to EGTA-treatment and (3) its colocalization with the epithelial cellular adhesion molecule (CAM) uvomorulin, strongly suggest that the recognized Ag is a CAM or a CAM-associated protein.

A novel anti-microfilament antibody, anti-135 kD, is associated with Raynaud's disease, undifferentiated connective tissue disease and systemic autoimmune diseases.

We report herein the characterization of a human IgG antibody reactive with a nonmuscle 135 kD microfilament-associated protein, anti-135 kD. Using nonmuscle epithelial PtK2 cells as substrate in indirect immunofluorescence, we identified a distinctive pattern of reactivity with microfilaments in sera from 12 of 165 (7.3%) patients investigated for systemic autoimmune diseases and in only 2 of 171 (1.2%) normal and rheumatic disease controls (P < 0.006, 95% Cl 1.46 to 30.1). An association between anti-135 kD and Raynaud's phenomenon (n = 12/14, 85.7%) with or without an associated systemic autoimmune disease was noted. The anti-135 kD specificity was established by several criteria. (1) The fluorescence was periodically distributed along microfilaments and concentrated at focal adhesions for all sera (n = 14). (2) On immunoblots, the 14 sera reacted with a PtK2 polypeptide of 135 kD. (3) IgG purified by blot-affinity from the 135 kD band (alpha-135) reproduced the fluorescent pattern of the original sera while IgG purified from other bands did not. (4) Double immunofluorescence with alpha-135 and anti-alpha-actinin mAb indicated absence of antibody fluorescence at ruffling membranes where a-actinin was distributed. (5) IgG subclass analysis of anti-135 kD revealed that 12 (85.7%) sera are of IgG3 isotype and 2 (14.3%) are of IgG1 isotype while the light chain expression was kappa restricted. This is the first report of an antibody to a 135 kD microfilament protein. Anti-135 kD expand the repertoire of anti-microfilament and anticytoskeletal antibodies in human sera.

Quality of life in systemic lupus erythematosus patients during more and less active disease states: differential contributors to mental and physical health.

OBJECTIVE: To identify determinants of mental and physical health as a function of disease state in patients with systemic lupus erythematosus (SLE). METHODS: A sample of 129 SLE patients (mean age 42.01 years; SD 11.09) was recruited from 9 immunology/rheumatology clinics across Canada. Patients completed questionnaires assessing psychological distress, social support, coping, stress, and health-related quality of life. Physicians rated disease activity (using the revised Systemic Lupus Activity Measure; SLAM-R) and damage (using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index). Mental and physical health composite scores were derived from the Medical Outcomes Study Short Form 36. Patients were subdivided into more active (SLAM-R > or = 10; n = 38) or less active disease states (n = 91). RESULTS: Better mental health was predicted by more education and less emotion-oriented coping in the patients in a more active disease state (P = 0.0001; R2 = 0.46). Better mental health was predicted by less stress, less emotion-oriented coping and more task-oriented coping in patients during a less active disease state (P = 0.0001; R2 = 0.45). Better physical health was predicted by more emotion-oriented coping in patients in a more active disease state (P = 0.04; R2 = 0.11). Better physical health was predicted by less stress and younger age in patients during a less active disease state (P = 0.0001; R2 = 0.20). CONCLUSION: The positive association between emotion-oriented coping and better physical health in patients during a more active disease state suggests that this style of coping may be more adaptive in situations that are considered uncontrollable (e.g., SLE flare). Predictors of mental health were similar to those found in the literature, especially for SLE patients in a less active disease state.

Retropneumoperitoneum and pneumatosis intestinalis in 2 patients with mixed connective tissue disease and the overlap syndrome.

Two patients with pneumatosis intestinalis (PI) and mixed connective tissue disease/overlap syndrome are discussed. One patient also presented a retropneumoperitoneum, a feature as yet undescribed in PI. A review of previously reported cases revealed that PI should be suspected in those patients known to have systemic sclerosis-type involvement of the oesophagus and the small bowel, and who present with abdominal distension. PI may occur early in the course of the disease, may resolve rapidly through medical intervention only, and is compatible with a 2-year survival rate.

Absence of antiphospholipid/co-factor antibodies in Takayasu arteritis.

UNLABELLED: There are anecdotal reports and small series describing the presence of anticardiolipin antibodies in patients with Takayasu Arteritis. This communication describes a systematic study searching for non-organ specific autoantibodies which includes antinuclear antibodies, anticardiolipin and anti-beta(2) GP(1) antibodies in a cohort of 28 Mexicans with angiographic definitive diagnostic of Takayasu Arteritis. MATERIAL AND METHODS: Twenty-eight consecutive patients, who fulfilled classification and diagnostic criteria for Takayasu Arteritis and had a diagnostic panaortogram, were bled to study the presence of circulating autoantibodies in a cross-sectional design. RESULTS: There were no antinuclear antibodies, although a few sera had faint cytoplasm fluorescent deposit and reacted with cell extract. We did not recognize a distinct pattern. Also, there was no IgG nor IgM anticardiolipin antibodies nor anticofactor antibodies of clinical interest. DISCUSSION AND CONCLUSIONS: The presence of circulating non-organ specific autoantibodies is not a characteristic feature in Takayasu Arteritis when strict diagnostic criteria are applied. The occasional presence of such immune markers could be due to technical differences in sample management, less strict diagnosis or biological variability in certain cases, but has no diagnostic value.

Early endosome antigen. 1: An autoantigen associated with neurological diseases.

BACKGROUND: We have identified 36 human sera sent for autoantibody analyses that produce a unique vesicular staining pattern of the cytoplasm of tissue culture cells. The purpose of this study was to identify the autoantigens that are recognized by the sera that produce this staining pattern and determine if the patients have common clinical features. METHODS: A serum from one of the patients (MS) with rapidly progressive demyelinating polyneuropathy was used to isolate a approximately 4.5 kb cDNA insert from a HeLa expression library. The purified cDNA (MS-5.1) was characterized by a poly A tail and an open reading frame that encoded 1329 amino acids. The derived amino acid sequence was found to be 99% identical to a 180 kd peripheral endosomal protein named early endosome antigen (EEA1). RESULTS: Antibodies from rabbits immunized with the recombinant protein and the prototype human serum produced an identical distinctive speckled cytoplasmic staining pattern. These sera also precipitated the in vitro translated recombinant protein and reacted with the isolated recombinant protein in a Western immunoblot. Of the 36 sera that produced an identical staining pattern as the prototype and immune rabbit sera, 8 (22%) had IgG antibodies that recognized the recombinant EEA1 protein when tested by immunoblotting and immunoprecipitation assays. Of the 8 patients with anti-EEA1 antibodies 4 were females, 4 were males, and the mean age was 69 years (range 48 to 86 years). CONCLUSIONS: Diagnoses included: polyneuropathy, lower motor neuron disease, pigmented retinitis, seronegative polyarthritis, interstitial pulmonary fibrosis, Raynaud's phenomenon, Wegener's granulomatosis, and proteinuria. Three of the eight patients with EEA1 autoantibodies died within 1 year after EEA1 antibodies were identified.