Vasculitides in HIV Infection.

PURPOSE OF REVIEW: To review the spectrum of vasculitides in HIV-infected patients and to identify the clinical features that characterize vasculitis in sero-positive HIV. RECENT FINDINGS: Epidemiological studies conducted in the post-HAART era described the rarity of vasculitis in the setting of HIV-infected patients. A study identified histopathological features such as leukocytoclastic vasculitis of the vasa vasorum and adventitial inflammation in the large artery pathology of HIV-positive patients compared with HIV-negative patients with critical lower limb ischemia. A recent retrospective cohort study reported that HIV-positive patients with LVV developed more vascular complications, responded less to antiretroviral therapy, and had worse outcome than HIV-negative patients with LVV. Vasculitides continue to be a rare disease in patients with HIV. The spectrum of vasculitis ranges from life-threatening conditions to relatively mild skin conditions. Recognizing vasculitis in the setting of HIV-positive patients is important because sometimes it require immunosuppressive treatment.

Eosinophilic Vasculitis.

PURPOSE OF REVIEW: Eosinophilic granulomatosis with polyangiitis (EGPA) represents a rare clinical entity, which is getting increasing attention and relevance in view of our better understanding and newer insights into its pathogenesis. Concomitantly better recognition and understanding of the immune pathophysiologic role of eosinophils provide a solid ground of their role on systemic inflammatory disorders and defense against infectious triggers, especially parasites. This review will focus on describing the physiopathology of eosinophils, as well as providing an in depth description of the natural history, clinical spectrum, and therapy of EGPA. RECENT FINDINGS: Several studies have aimed at finding useful biomarkers to monitor disease activity, and reported data have shown that eotaxin 3, IL25, IL33, and some eicosanoids to be promising options. Regarding therapeutic advances, recently published studies have revealed the efficacy of mepolizumab during induction and maintenance of EGPA. Recently published data confirmed earlier studies that the use of azathioprine during the induction phase is of no benefit during long-term follow-up. In addition, data from the REOVAS study, which uses rituximab, is still ongoing and apparently with promising results. Eosinophils are involved in several systemic inflammatory disorders, and recent gathered data provide support for their role in triggering EGPA. Better understanding of its pathophysiology should generate newer insights into the pathogenesis, biomarkers of disease activity, and therapeutic targets.

Takayasu Arteritis: Recent Developments.

PURPOSE OF REVIEW: Takayasu arteritis (TA) is a granulomatous inflammatory disorder that affects large vessels, especially aorta and its proximal branches. Its diagnosis can be extremely challenging due to the non-specificity of the systemic inflammatory manifestations during the early phase of the disease and usually follows an insidious clinical course until the emergence of vascular ischemic complications. RECENT FINDINGS: Its pathogenesis has been better delineated in recent years, especially the role of HLA-B*52 allele in certain ethnic groups, as well as the use of biological therapy, and surgical revascularization. Recent findings are discussed in depth. Clinical and epidemiological aspects of TA, recent developments in pathogenesis, and therapy are presented.

HIV infection and its effects on the development of autoimmune disorders.

More than 35 years have elapsed since the initial outbreak of the HIV/AIDS epidemic and the status of a considerable number of patients has changed from a fatal disorder to a chronic one where comorbidities including sarcoidosis and autoimmune diseases have become relevant and dominant. HIV targets the immune system leading to a state of immunodeficiency in a setting of immune activation in which CD4+ T cell depletion plays a critical role. The onset, natural history and course of HIV-associated autoimmune disease has dramatically changed according to the stage of HIV infection and since the introduction of combined anti-retroviral therapy. There are some issues that need further study regarding therapy, especially when immunosuppressive drugs and biologic agents are under consideration. Currently, biologic agents and others immunosuppressive agents are recommended when patients have CD4+ T cell counts above 200 cells/mm3 and the HIV viral activity is completely suppressed.

The History of Psoriatic Arthritis (PsA): From Moll and Wright to Pathway-Specific Therapy.

PURPOSE OF REVIEW: Psoriatic arthritis is a distinct disorder, separate from rheumatoid arthritis, and first recognized in a thirteenth century Saxon skeleton. It was, however, the monumental work of Verna Wright in the 1950s that led to the acceptance by the American Rheumatism Association (now American College of Rheumatology) in 1964 as a distinct entity. Wright's work provided the framework for a better understanding of the pathogenic mechanisms operating on this condition, and eventually led to the development of targeted therapy that has proven to be more effective and safe than conventional therapy. RECENT FINDINGS: Pathogenesis of psoriatic arthritis has been better delineated in recent years, as well as the use of biological therapy. Recent findings are discussed in detail. Historical aspects of psoriatic arthritis, recent developments in pathogenesis, and therapy are discussed, and the contributions of Verna Wright to our understanding of the disorder are presented.

Predictors of Poor Outcome in ANCA-Associated Vasculitis (AAV).

It is important to recognize factors that might predict poor outcome and prognosis in patients with AAV. The predictors reported in the literature encompass genetic, histopathological, and clinical ones. Genetic studies (genetic predictors) have found genes that are associated with prediction of poor response to treatment, deterioration of renal function, and risk of mortality. Histopathological studies (histopathological predictors) have shown that sclerotic renal lesions are associated with increased risk of progression to end-stage renal disease and death. Lastly, scores (clinical predictors) obtained with tool as FFS, Maldini risk score, VDI, and emerging new biomarkers could potentially be helpful in assessment of prognosis in the future.

Non-infectious cryoglobulinemia vasculitis (CryoVas): update on clinical and therapeutic approach.

CryoVas is a small vessel vasculitis associated with the presence of circulating cryoglobulins. In the absence of HCV infection, several disorders have been identified in association of CryoVas. Although evidence is limited, a few studies have recently described the clinical presentation, prognosis, and therapeutic management of non-infectious CryoVas. Patients with type I CryoVas, especially associated with hematologic malignancies, have shown a worse clinical presentation. Recent studies have also identified prognostic factors in mixed CryoVas. Therapeutic management in non-infectious CryoVas remains to be defined. Overall, treatment options should be individualized based on severity of involvement. In this setting, new data have emerged regarding the role of biologic therapy in non-infectious CryoVas. Off-label use of rituximab should be highlighted, based on the assessment of benefits and risks, especially infections.

Genetics of ANCA-associated Vasculitides.

The distribution of the anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) is not uniform across geographical regions and ethnic and racial groups, suggesting that genetic and environmental factors affect the pathogenesis of these diseases. In addition, genetic factors affect not only the clinical syndrome phenotypes and their prognosis, but also ANCA specificity; these data suggest that AAV may need reclassification. Several genes have been evaluated, including ANCA targets and those of the immune system, for example co-stimulatory molecules, signaling regulators, cytokines, Fc and other receptors, and other proteins. This article provides a review of genetic factors affecting the pathogenesis and prognosis of AAV. Further studies to determine the effect of genetic factors on the clinical syndrome phenotypes and ANCA specificity need to be performed across different ethnic groups.

Are anti-CCP antibodies in psoriatic arthritis patients a biomarker of erosive disease?

To determine the frequency of anticyclic citrullinated peptide (CCP) antibodies in a cohort of psoriatic arthritis (PsA) patients and to compare clinical, serological and radiological characteristics between PsA patients with and without anti-CCP antibodies. Patients with PsA, according to classification criteria for PsA, were consecutively recruited from an outpatient rheumatology clinic. Demographic and clinical data were collected in all cases. Serum samples from all patients were analyzed for rheumatoid factor and anti-CCP antibodies. Radiographs of hands and feet were obtained and the presence of erosions was recorded. The study included 81 patients; 43 (53 %) were men, with a median age of 45.7 years (interquartile range (IQR) 39-72) and median disease duration of 9.4 years (IQR 2-14). Anti-CCP antibodies were found in 11 patients (13.5 %), median titer 174.9 U/ml. Polyarticular involvement (72.7 vs. 17.1 %), frequency of erosive disease (72.7 vs. 37.1 %) and use of tumor necrosis factor-α inhibitors (54.5 vs. 28.5 %) were significantly higher in PsA patients with anti-CCP positivity. Anti-CCP negative PsA patients had predominantly more oligoarticular (62.8 vs. 27.2 %) and nail (81.4 vs. 36.3 %) involvement. Presence of enthesitis, dactylitis and Psoriasis Area Severity Index scores were similar in both groups. Anti-CCP antibodies were found in a subset of PsA patients, and their presence was associated with more severe disease phenotype. Further studies in a larger population are needed to define the role of anti-CCP as a biomarker of erosive disease in PsA.

The development of candidate composite disease activity and responder indices for psoriatic arthritis (GRACE project).

OBJECTIVE: To develop new composite disease activity indices for psoriatic arthritis (PsA). METHODS: Data from routine clinic visits at multiple centres were collected in a systematic manner. Data included all domains identified as important in randomised controlled trials in PsA. Decisions to change treatment were used as surrogates for high disease activity. New indices were developed by multiple linear regression (psoriatic arthritis disease activity score: PASDAS) and empirically, utilising physician-defined cut-offs for disease activity (arithmetic mean of desirability functions: AMDF). These were compared with existing composite measures: Composite Psoriatic arthritis Disease Activity Index (CPDAI), Disease Activity for PSoriatic Arthritis (DAPSA), and Disease Activity Score for rheumatoid arthritis (DAS28). RESULTS: 161/503 (32%) subjects had treatment changes. Although all measures performed well, compared with existing indices, PASDAS was better able to discriminate between high and low disease activity (area under receiver operating curves (ROC)) curve with 95% CI: PASDAS 0.773 (0.723, 0.822); AMDF 0.730 (0.680, 0.780); CPDAI 0.719 (0.668, 0.770); DAPSA 0.710 (0.654, 0.766); DAS28 0.736 (0.680, 0.792). All measures were able to discriminate between disease activity states in patients with oligoarthritis, although area under the receiver operating curves (AUC) were generally smaller. In patients with severe skin disease (psoriasis area and severity index>10) both nonparametric and AUC curve statistics were nonsignificant for all measures. CONCLUSIONS: Two new composite measures to assess disease activity in PsA have been developed. Further testing in other datasets, including comparison with existing measures, is required to validate these instruments.

IgG4-associated vasculitis.

Elevated IgG4 is characteristic of cases of IgG4-RD, a newly recognized systemic disease. However, several chronic inflammatory conditions, including rheumatic diseases, can also be associated with increased levels of IgG4. There have also recently been several reports describing an increased IgG4 immune response to some vasculitis syndromes, in particular Churg-Strauss syndrome and granulomatosis with polyangiitis. To avoid misdiagnosis, clinicians must be aware that the clinical manifestations of IgG4-RD and ANCA-associated vasculitis may overlap. The meaning of these observations is not yet understood, and more studies are needed to determine the true significance of the increased IgG4 response to vasculitis syndromes, especially anti-neutrophil cytoplasmatic antibodies (ANCA)-associated vasculitis.

Cocaine-induced vasculitis: clinical and immunological spectrum.

Levamisole-contaminated cocaine has recently been recognized in North America and Europe, and its use is associated with a variety of clinical and autoimmune abnormalities. The clinical characteristic seems to be the presence of a painful purpuric skin rash that predominantly affects the ear lobes and cheeks, often accompanied by systemic manifestations including fever, malaise, arthralgias, myalgias, and laboratory abnormalities, for example leukopenia, neutropenia, positive ANA, ANCA, and phospholipid antibodies. Most of these manifestations can be seen with the use of either drug, especially levamisole. There is no specific therapy, and discontinuation of its use is followed by improvement. Prednisone and immunosuppressive therapy may be needed at times. Further use of the drug is characterized by recurrence of most of the complaints.

Carnivore protoparvovirus 1 in Peruvian dogs: Temporal/geographical and evolutionary dynamics of virus.

Canine parvovirus (CPV) has been recognized all around the world as the causal agent of a contagious and highly mortal disease in domestic dogs. In Peru, the infection is endemic and unvaccinated animals and puppies are the most at risk. In order to analyze viral diversity and determine the evolutionary genetic relationships and transmission dynamic of Peruvian CPV-2, were collected during the period of 2016-2017 rectal swabs from puppies with parvovirosis compatible symptoms. Viral DNA was amplified by PCR using primers that flanked the ends of the viral genome and sequenced by Illumina Miseq platform. Twenty-six genomic sequences (NSP1-VP1) of CPV from several districts in Lima Metropolitan area were obtained. The VP2 gene analysis demonstrated the presence of the New CPV-2a, New CPV-2b and 2c variants. The phylodynamic analysis of the viral genomes determined that all Peruvian sequences were clustered into a big clade named South American clade that emerged from the west region of Europe (Italy). The Time to the Most Recent Common Ancestor (TMRCA) of the South American clade was dated to 1993. Peruvian sequences were distributed into three subclades, and the 92% of these sequences were related to Ecuadorian CPV-2. The results suggests that three independent introduction events of virus from other countries could have occurred, in two of these events, CPV-2 from Ecuador were introduced in Peru in 2003 and 2009, and another introduction event, in 2000, from Europe. Overall, these results indicate a viral genetic relationship between Peruvian with Ecuadorian and European virus, and the circulation of several viral subpopulations in Lima Metropolitan.

Genomic Characterization of Salmonella Typhimurium Isolated from Guinea Pigs with Salmonellosis in Lima, Peru.

Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) is one of the most important foodborne pathogens that infect humans globally. The gastrointestinal tracts of animals like pigs, poultry or cattle are the main reservoirs of Salmonella serotypes. Guinea pig meat is an important protein source for Andean countries, but this animal is commonly infected by S. Typhimurium, producing high mortality rates and generating economic losses. Despite its impact on human health, food security, and economy, there is no genomic information about the S. Typhimurium responsible for the guinea pig infections in Peru. Here, we sequence and characterize 11 S. Typhimurium genomes isolated from guinea pigs from four farms in Lima-Peru. We were able to identify two genetic clusters (HC100_9460 and HC100_9757) distinguishable at the H100 level of the Hierarchical Clustering of Core Genome Multi-Locus Sequence Typing (HierCC-cgMLST) scheme with an average of 608 SNPs of distance. All sequences belonged to sequence type 19 (ST19) and HC100_9460 isolates were typed in silico as monophasic variants (1,4,[5],12:i:-) lacking the fljA and fljB genes. Phylogenomic analysis showed that human isolates from Peru were located within the same genetic clusters as guinea pig isolates, suggesting that these lineages can infect both hosts. We identified a genetic antimicrobial resistance cassette carrying the ant(3)-Ia, dfrA15, qacE, and sul1 genes associated with transposons TnAs3 and IS21 within an IncI1 plasmid in one guinea pig isolate, while antimicrobial resistance genes (ARGs) for ß-lactam (blaCTX-M-65) and colistin (mcr-1) resistance were detected in Peruvian human-derived isolates. The presence of a virulence plasmid highly similar to the pSLT plasmid (LT2 reference strain) containing the spvRABCD operon was found in all guinea pig isolates. Finally, seven phage sequences (STGP_Φ1 to STGP_Φ7) were identified in guinea pig isolates, distributed according to the genetic lineage (H50 clusters level) and forming part of the specific gene content of each cluster. This study presents, for the first time, the genomic characteristics of S. Typhimurium isolated from guinea pigs in South America, showing particular diversity and genetic elements (plasmids and prophages) that require special attention and also broader studies in different periods of time and locations to determine their impact on human health.

The lupus family registry and repository.

The Lupus Family Registry and Repository (LFRR) was established with the goal of assembling and distributing materials and data from families with one or more living members diagnosed with SLE, in order to address SLE genetics. In the present article, we describe the problems and solutions of the registry design and biometric data gathering; the protocols implemented to guarantee data quality and protection of participant privacy and consent; and the establishment of a local and international network of collaborators. At the same time, we illustrate how the LFRR has enabled progress in lupus genetics research, answering old scientific questions while laying out new challenges in the elucidation of the biologic mechanisms that underlie disease pathogenesis. Trained staff ascertain SLE cases, unaffected family members and population-based controls, proceeding in compliance with the relevant laws and standards; participant consent and privacy are central to the LFRR's effort. Data, DNA, serum, plasma, peripheral blood and transformed B-cell lines are collected and stored, and subject to strict quality control and safety measures. Coded data and materials derived from the registry are available for approved scientific users. The LFRR has contributed to the discovery of most of the 37 genetic associations now known to contribute to lupus through 104 publications. The LFRR contains 2618 lupus cases from 1954 pedigrees that are being studied by 76 approved users and their collaborators. The registry includes difficult to obtain populations, such as multiplex pedigrees, minority patients and affected males, and constitutes the largest collection of lupus pedigrees in the world. The LFRR is a useful resource for the discovery and characterization of genetic associations in SLE.

Vasculitides throughout history and their clinical treatment today.

Therapeutic management of the vasculitides is closely linked to modern rheumatologic advances, particularly as it relates to the discovery and first clinical use of glucocorticoids. These compounds were introduced in the late-1940s for the treatment of rheumatoid arthritis, but soon after, clinicians in Europe and the United States realized that they could have a significant positive impact in systemic vasculitides. However, once it was realized that glucocorticoid use was associated with a high degree of morbidity, the search for better immunosuppressive agents with similar efficacy but improved safety profiles was on. During the past several years, several agents have been utilized for the therapeutic management of systemic vasculitides, and the list keeps growing with the development of newer compounds that have retained efficacy but with a better safety profile.

Psoriatic arthritis in South and Central America.

Psoriasis and its related manifestations, including psoriatic arthritis, are prevalent disorders in the Western world, particularly among Caucasians. The study of these disorders in Latin America lags way behind the study of other more common rheumatic disorders, such as rheumatoid arthritis and systemic lupus erythematosus. From the scarce evidence available, however, it appears that the prevalence and incidence of psoriasis and psoriatic arthritis are lower than in other parts of the Western world and almost negligible among natives from the Andean region, although confirmatory epidemiologic studies are lacking.

HIV infection and clinical spectrum of associated vasculitides.

Various infections have been causative in the pathogenesis of systemic vasculitides, and HIV infection is not spared. In an immunocompromised host, cytomegalovirus, Epstein-Barr virus, varicella zoster virus, herpes simplex virus, hepatitis B and hepatitis C virus, and mycobacteria, along with HIV infection can cause vasculitis. Herein we emphasize the spectrum of vasculitides, their pathogenesis, presentation, course, and therapy in the HIV-infected population. Every spectrum and size of the blood vessel involvement have been seen in HIV-associated vasculitides. We review each spectrum in detail and describe our experience with polyarteritis nodosa, the most common presentation occurring in HIV-infected patients. We also discuss the differences in HIV, hepatitis B, and hepatitis C- related polyarteritis nodosa in detail.

Panniculitis: another clinical expression of gout.

Gouty panniculitis is an unusual clinical manifestation of gout, characterized by the deposition of monosodium urate crystals in the lobular hypodermis. Its pathogenesis is poorly understood but is associated with hyperuricemia, and the clinical presence of indurate subcutaneous plaques, which may precede or appear subsequently to the articular clinical expression of tophaceous gout. The aim of this report is to describe the clinical characteristics and potential risk factors for the development of lobular panniculitis secondary to chronic tophaceous gout. This is a retrospective clinical review of 6 patients with gouty panniculitis seen at the rheumatology service at the National University of Colombia. All cases fulfill diagnostic criteria for gout. The presenting clinical characteristics of each case were analyzed. All 6 patients were men, with an average age of 26 years. Two patients initially presented with cutaneous manifestations, and in the remainder 4 joint involvements preceded the cutaneous manifestations. Articular involvement first developed in lower extremities, of intermittent nature, and subsequent occurrence of polyarthritis of upper and lower extremities. A positive family history of gout was observed in half of the patients. Smoking and high alcohol intake were relevant risk factors. On physical examination, all exhibited the presence of erythematous, irregular surface, deep indurate subcutaneous plaques. Biopsy of skin and deep dermis including panniculus revealed the presence of granulomatous inflammatory changes with deposition of amorphous eosinophilic material surrounded by palisading histocytes and lymphocytes. Characteristic negative birefringent monosodium urate crystals were observed in the synovial fluid of patients with arthritis. All patients exhibited high levels of serum uric acid and were non-complaint to treatment with allopurinol, NSAIDs, and colchicine. Gouty panniculitis should be considered in the differential diagnosis of panniculitis, especially in the presence of high levels of uric acid. It is usually observed in the third decade of life and may appear prior to the inflammatory articular manifestations of tophaceous gout.