Peripheral arterial disease in polymyalgia rheumatica

Patients with polymyalgia rheumatica have been shown to have an increased risk of peripheral arterial disease on longitudinal follow-up. Possible explanations for this include premature atherosclerosis related to chronic inflammation, as with other inflammatory rheumatological conditions. Alternatively, polymyalgia rheumatica can be associated with vasculitis, even in the absence of clinical giant cell arteritis, and peripheral vascular disease may represent subclinical vasculitis. Further work is required to elucidate the reasons for this increased risk. Currently, it would remain reasonable to aggressively control modifiable atherosclerotic risk factors.     

Inactivation of Chikungunya virus by 1,5 iodonapthyl azide

Myelodysplastic syndromes (MDS) are often accompanied by autoimmune phenomena. The underlying mechanisms for these associations remain uncertain, although T cell activation seems to be important. Human T-lymphotropic virus (HTLV-1) has been detected in patients with myelodysplastic syndromes, mostly in regions of the world which are endemic for the virus, and where association of HTLV-1 with rheumatological manifestation is not rare. We present here the case of a 58 year old man who presented with cytopenias, leukocytoclastic vasculitis of the skin and glomerulopathy, and was diagnosed as MDS (refractory anemia with excess blasts - RAEB 1). The patient also tested positive for HTLV-1 by PCR. After 8 monthly cycles of 5-azacytidine he achieved a complete hematologic remission. Following treatment, a second PCR for HTLV-1 was carried out and found to be negative. This is the first report in the literature of a HTLV-1-positive MDS with severe autoimmune manifestations, which was treated with the hypomethylating factor 5-azacitidine, achieving cytogenetic remission with concomitant resolution of the autoimmune manifestations, as well as HTLV-1-PCR negativity. HTLV-1-PCR negativity may be due to either immune mediated clearance of the virus, or a potential antiretroviral effect of 5-azacytidine. 5-azacytidine is known for its antiretroviral effects, although there is no proof of its activity against HTLV-1 infection in vivo.     

Immune ablation and stem-cell therapy in autoimmune disease. Immunological reconstitution after high-dose immunosuppression and haematopoietic stem-cell transplantation

Studies on immunological reconstitution after immune ablation and stem-cell therapy may yield important clues to our understanding of the pathogenesis of human autoimmune disease, due to the profound effects of function and organization of the immune system. Such studies are also indispensable when linking clinical sequelae such as opportunistic infections to the state of immune deficiency that ensues after the treatment. Much has been learnt on these issues from comparable studies in haemato-oncological diseases, although it remains to be proven that the data obtained from these studies can be extrapolated to rheumatological autoimmune diseases. Preliminary results from pilot studies in various rheumatological conditions not only pointed to clinical efficacy of the new treatment modality but also unveiled marked effects on T-cell receptor repertoires of circulating T lymphocytes, on titres of autoantibodies and T- and B-cell subsets.     

Neuroendocrine response to cold in Raynaud's syndrome

Eleven patients with Raynaud's syndrome accompanied by monospecific IgG ANA, nine patients with Raynaud's syndrome in the absence of ANA, and nine normal volunteers were exposed to an ambient cold challenge during which time venous blood was continuously sampled. ANA negative patients were shown to have significantly higher levels of cortisol during a cold challenge than either ANA positive patients or normal controls, and exhibited significantly lower levels of plasma norepinephrine compared with normal controls. ANA positive patients did not differ significantly from normals in their neuroendocrine response to cold. It is suggested that the high plasma cortisol found in Raynaud's syndrome in the absence of ANA may be responsible for the vasospasticity in this group of patients.     

Immune ablation and stem-cell therapy in autoimmune disease: Immunological reconstitution after high-dose immunosuppression and haematopoietic stem-cell transplantation

Studies on immunological reconstitution after immune ablation and stem-cell therapy may yield important clues to our understanding of the pathogenesis of human autoimmune disease, due to the profound effects of function and organization of the immune system. Such studies are also indispensable when linking clinical sequelae such as opportunistic infections to the state of immune deficiency that ensues after the treatment. Much has been learnt on these issues from comparable studies in haemato-oncological diseases, although it remains to be proven that the data obtained from these studies can be extrapolated to rheumatological autoimmune diseases. Preliminary results from pilot studies in various rheumatological conditions not only pointed to clinical efficacy of the new treatment modality but also unveiled marked effects on T-cell receptor repertoires of circulating T lymphocytes, on titres of autoantibodies and T- and B-cell subsets.     

Oral L-arginine can reverse digital necrosis in Raynaud's phenomenon

Raynaud's phenomenon is characterized by transient reduction in blood supply through the small arteries in the hands and feet. Severe Raynaud's phenomenon can cause digital necrosis. It has been hypothesized that nitric oxide may have a role in Raynaud's phenomenon. We report two cases in which oral L-arginine reversed digital necrosis in Raynaud's phenomenon and two additional cases in which the symptoms of severe Raynaud's phenomenon were improved with oral L-arginine. These reports suggest that a defect in nitric oxide synthesis or metabolism is present in Raynaud's phenomenon. They also suggest a potential role for oral L-arginine therapy in Raynaud's phenomenon, especially in Raynaud's phenomenon with digital necrosis.     

Training to vasodilate in a cooling environment: a valid treatment for Raynaud's phenomenon?

While many reports indicate that voluntary modification of skin temperature is possible and may be useful in the treatment of Raynaud's phenomenon, little attention has been paid to the ecological validity of training skin temperature increases when a considerable amount of vasodilation of digital vessels may already exist (room temperature, 22-24 degrees C). Patients with Raynaud's vasospastic attacks may benefit from learning to avoid attacks when they are impending by voluntarily vasodilating the vessels of their digits under conditions when vasoconstriction has begun. The results in 14 patients with primary and secondary Raynaud's phenomenon indicated that (a) patients learned to voluntarily increase digital skin temperatures in a "cooling" environment during documented vasoconstriction, and (b) there was a 31% decrease in the occurrence of vasospastic attacks following such learning. These data suggest that a new methodology may be useful in the biofeedback treatment of Raynaud's phenomenon, but further research is needed to determine the specific mechanism(s) involved, and the limits to its usefulness.     

What you should know about PR3-ANCA: Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

What you should know about PR3-ANCA. Evidence for the role of T cells in the pathogenesis of systemic vasculitis

The pathogenesis of systemic vasculitis is complex and is likely to involve many mechanisms. There is a growing body of evidence that T cells may contribute to the pathogenesis of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides. Predominantly, T cells and monocytes are found in inflammatory infiltrates in patients with Wegener's granulomatosis (WG). The production of ANCA appears to be T-cell-dependent. T lymphocytes from the peripheral blood of patients with ANCA-associated vasculitis have been shown to proliferate in response to proteinase 3 (PR3). These and other findings outlined in this review indicate T-cell involvement, although further studies are still needed to elucidate the exact contribution of T cells to the pathogenesis of systemic vasculitis.     

Inapparent genital infection with Chlamydia trachomatis and its potential role in the genesis of Reiters syndrome.

An infectious etiology has been suggested for Reiter's syndrome (RS) because the disease has often been observed to follow episodes of urethritis or dysentery. Despite demonstrations of bacterial antigens in the synovial tissues of RS patients, it is not clear whether viable organisms are present in the synovium in any particular stage of this disease. Furthermore, it is not clear how either viable organisms or their product(s) might reach the joints. Infection with the bacterium Chlamydia trachomatis is the most common sexually transmitted disease in the United States, and as such this organism has emerged as a primary pathogen associated with RS. Previous work from our group has shown that synovial biopsy tissues from a majority of RS patients studied show significant levels of apparently intact chlamydial RNA, even when synovial or urethral cultures from the same patients are unequivocally negative for the organism. We show here that inapparent urethral infection with chlamydia occurs with high prevalence in men, and that inapparent cervical infection with the organism occurs at high prevalence in women. These data provide an important link in the relationship between initial chlamydial infection and possible subsequent genesis of RS, and they may give useful insight into mechanisms by which chlamydial infection can lead to development of this disease. Our data argue further that inapparent infection may be a significant factor in pathogenesis for all chlamydia-related diseases, and they suggest that, contrary to current ideas, C. trachomatis can generate disseminated infection.     

The contribution of genetic variation and infection to the pathogenesis of ANCA-associated systemic vasculitis

The aetiology of anti-neutrophil cytoplasmic antibody (ANCA)-associated systemic vasculitis has not been well defined. Here we review two factors which may play a role in the pathogenesis of the disease: genetics and infection. In particular, we discuss the role of autoantibodies to LAMP-2, which may arise following infection with Gram-negative bacteria, and may contribute to the development of ANCA-associated systemic vasculitis in genetically susceptible individuals.     

The beneficial effects of omega-3 and omega-6 essential fatty acid supplementation on red blood cell rheology.

Twenty healthy, non-smoking subjects were enrolled into a study to investigate the effects of dietary supplementation with essential fatty acid (EFAs) on red blood cell rheology. Ten subjects were given 3 months dietary supplementation with long chain polyunsaturated EFAs containing omega-3 and omega-6 EFAs while 10 others were given placebo (sunflower oil). Venous sampling was performed at 0 and 12 weeks and red blood cell (RBC) aggregation and deformability measured by a filtration system. The results showed a reduction in RBC aggregation in the group given omega-3 and omega-6 EFAs but not in the placebo group. This may be related to changes in the RBC membrane and surface receptor characteristics. Such EFAs may be useful in Raynaud's phenomenon.     

Training to vasodilate in a cooling environment: A valid treatment for Raynaud's phenomenon?

While many reports indicate that voluntary modification of skin temperature is possible and may be useful in the treatment of Raynaud's phenomenon, little attention has been paid to the ecological validity of training skin temperature increases when a considerable amount of vasodilation of digital vessels may already exist (room temperature, 22–24° C). Patients with Raynaud's vasospastic attacks may benefit from learning to avoid attacks when they are impending by voluntarily vasodilating the vessels of their digits under conditions when vasoconstriction has begun. The results in 14 patients with primary and secondary Raynaud's phenomenon indicated that (a) patients learned to voluntarily increase digital skin temperatures in a cooling environment during documented vasoconstriction, and (b) there was a 31% decrease in the occurrence of vasospastic attacks following such learning. These data suggest that a new methodology may be useful in the biofeedback treatment of Raynaud's phenomenon, but further research is needed to determine the specific mechanism(s) involved, and the limits to its usefulness.This research was supported by grants from the Manitoba Heart and St. Boniface General Hospital Research Foundations. We gratefully acknowledge John Arnett, Garry Hawryluk, and Charles Weinstein for their critical reading of a draft of this paper. Portions of this paper were presented at the Canadian Psychological Association meeting, Winnipeg, 1983.     

Rituximab treatment in hepatitis C infection: an in vitro model to study the impact of B cell depletion on virus infectivity

Hepatitis C virus (HCV) infected patients with vasculitis are often treated with the B-cell-depleting anti-CD20 antibody rituximab. Treatment reduces the cryoglobulins that cause vasculitis, yet it also leads to a transient increase in liver enzymes and HCV genomic RNA in the periphery. The mechanism underlying the increased viral load is unclear and both direct and indirect roles have been proposed for B cells in HCV infection. We previously reported that HCV can associate with B cells and can trans-infect hepatocytes. We established an in vitro assay to study the effect(s) of rituximab on B cell-associated HCV infectivity. Rituximab-mediated lysis of B cells in vitro increases the level of infectious HCV released from B cells. Our results, using a model where virus does not replicate in B cells, recapitulate observations seen in patients and may explain in part the rapid increase in blood HCV RNA observed after rituximab treatment.     

Effect of Complement and Viral Filtration on the Neutralization of Respiratory Syncytial Virus

The addition of 10 hemolytic units of guinea pig complement has been shown to enhance the neutralizing capacity of respiratory syncytial (RS) immune sera produced in guinea pigs and ferrets. This same immune sera, when tested without complement, had little or no neutralizing capacity. The addition of complement to RS immune horse serum did not significantly increase its neutralizing capacity. Immune horse serum effectively neutralized RS virus without complement. Other studies indicated that a 50% tissue culture infective dose of between 30 and 100 should be used in RS serum neutralization tests and that incubation should be for 90 to 105 min at room temperature. The neutralizing capacity of guinea pig immune serum was not increased by the use of filtered virus. The rate of virus neutralization, however, was increased with the addition of 10 hemolytic units of complement. The neutralizing capacity of RS immune horse serum was much greater for filtered than for unfiltered RS virus. The addition of complement increased the rate of virus neutralization but did not increase the neutralizing capacity of the horse immune serum.     

Clutch size and reproductive success in a female polymorphic insect

Differences in reproductive success (RS) between different groups of individuals are of interest to researchers studying natural and sexual selection. Since it is often not feasible to quantify RS in the wild, researchers make use of proxies instead. One such proxy is clutch size. However, research on species providing parental care (mainly birds and mammals) has learned that a large clutch size does not guarantee a large number of offspring. In contrast, much less is known on the link between clutch size and RS for species lacking parental care, such as many reptiles and insects. Here, we ask whether clutch size provides a satisfactory estimate of RS for a polymorphic insect. Our study species is a damselfly showing two distinct female morphs for which RS (estimated by clutch size) has been studied to evaluate the evolutionary role of sexual conflict. However, in this system not only among family variation in offspring viability, but also differences between female morphs, may affect how clutch size relates to offspring number and quality. To evaluate the use of clutch size as estimate of RS, we examined how clutch size correlated with subsequent success measures of developing offspring by rearing damselfly from eggs to adults under two laboratory food treatments. In both treatments, we detected that clutch size correlated well with offspring number early in larval life, but that this relation is reduced by among family variation in survival in later developmental stages. Clutch size was moderately correlated with the number of offspring that successfully metamorphosed to winged adults. Patterns did not differ between female morphs and the nature of the correlation could not be explained from offspring quantity-quality trade-offs.     

Hypersensitivity to mitomycin C cell-killing in Roberts syndrome fibroblasts with, but not without, the heterochromatin abnormality

Roberts syndrome (RS) is a rare genetic disorder, characterized clinically by severe pre- and post-natal growth retardation and symmetric limb reduction deformities. Some patients with RS have a distinctive abnormality of the constitutive heterochromatin (the RS effect) which has been described as a premature separation of the paracentromeric and nucleolar organizing regions of the chromosomes and the distal portion of the long arm of the Y chromosome (German, 1979). These patients [denoted RS(+)] are clinically indistinguishable from the RS(-) patients who lack the cytogenetic marker for Roberts syndrome. Recently, a mutant in Drosophila has been described which has both heterochromatin undercondensation and hypersensitivity to mutagen treatment (Gatti et al., 1983). The authors suggested that the uncondensed heterochromatin may be more accessible to damage by mutagens. Thus, the present study was an investigation of the mutagen sensitivity in Roberts syndrome, to determine whether there is a similar relationship between abnormal heterochromatin structure and mutagen sensitivity. Plating efficiency experiments were performed with RS(+) fibroblasts, RS(-) fibroblasts, RS heterozygous fibroblasts and a large assortment of appropriate control cells. The RS fibroblasts with the heterochromatin abnormality were consistently more sensitive (based on D10 values) to mitomycin C treatment than were any of the other cell strains tested, including RS(-) cells. These results support the hypothesis that mitomycin C sensitivity and abnormal heterochromatin structure in Roberts syndrome are related.     

Epoprostenol in patients with Raynaud's disease

Prostaglandin metabolism and the clinical effect of epoprostenol (prostacyclin, PGI2) infusions were studied in thirteen patients with Raynaud's disease. Epoprostenol was infused at 5 ng/kg/min for six hours daily for two consecutive five day periods, separated by a two day interval. No beneficial effects either during or after infusion could be detected in terms of frequency of severity of attacks or on skin temperature measurement. Raynaud's patients had significantly lower serum thromboxane B2 levels than normal controls though plasma levels of thromboxane B2, 6-oxo-PGF1 and the bicyclic metabolite of PGE2 did not differ between the two groups. Platelets from Raynaud's patients had a significantly lower conversion rate of arachidonic acid into thromboxane B2 and HHT and a significantly higher rate of HETE production than platelets from controls.     

Biofeedback treatment of Raynaud's disease and phenomenon

Six Raynaud's disease and four Raynaud's phenomenon patients were treated with 12 sessions of finger temperature biofeedback. The mean frequency of vasospastic attacks was reduced to 7.5% of that reported during the pretreatment baseline and was maintained for a 1 year follow-up period. Significant control of digital temperature was demonstrated during laboratory training sessions. Raynaud's phenomenon patients showed significantly greater temperature increases during feedback periods than Raynaud's disease patients. Correlations between finger temperature and other physiological measures suggested that results could not be attributed to general physical relaxation. The role of imagery in self-control of digital temperature is considered.Portions of this paper were presented at the annual meeting of the Biofeedback Society of America, Albuquerque, March 1978.     

Expression Profiling of PBMC-based Diagnostic Gene Markers Isolated from Vasculitis Patients

Vasculitis (angiitis) is a systemic autoimmune disease that often causes fatal symptoms. We aimed to isolate cDNA markers that would be useful for diagnosing not only vasculitis but also other autoimmune diseases. For this purpose, we used stepwise subtractive hybridization and cDNA microarray analyses to comprehensively isolate the genes whose expressions are augmented in peripheral blood mononuclear cells (PBMCs) pooled from vasculitis patients. Subsequently, we used quantitative real-time polymerase chain reaction (qRT–PCR) to examine the mRNA levels of each candidate gene in individual patients. These analyses indicated that seven genes exhibit remarkably augmented expression in many vasculitis patients. Of these genes, we analyzed G0/G1 switch gene 2 (G0S2) further because G0S2 expression is also enhanced in the PBMCs of patients with systemic lupus erythematodes (SLE). We generated G0S2 transgenic mice that ubiquitously overexpress human G0S2. Although we did not observe any obvious vasculitis-related histopathologic findings in these mice, these mice are unhealthy as they produce only few offspring and showed elevated serum levels of two autoimmunity-related antibodies, anti-nuclear antibody, and anti-double strand DNA antibody. Thus, our large-scale gene profiling study may help finding sensitive and specific DNA markers for diagnosing autoimmune diseases including vasculitis and SLE.Key words: vasculitis, angiitis, G0S2, EGR1, amphiregulin, hemoglobin delta