Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS).

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

BACKGROUND: More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis. METHODS: We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m2 of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD). RESULTS: Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups. CONCLUSIONS: Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Pan American League of Associations for Rheumatology Guidelines for the Treatment of Takayasu Arteritis.

OBJECTIVE: To develop the first evidence-based Pan American League of Associations for Rheumatology (PANLAR) guidelines for the treatment of Takayasu arteritis (TAK). METHODS: A panel of vasculitis experts developed a series of clinically meaningful questions addressing the treatment of TAK patients in the PICO (population/intervention/comparator/outcome) format. A systematic literature review was performed by a team of methodologists. The evidence quality was assessed according to the GRADE (Grading of Recommendations/Assessment/Development/Evaluation) methodology. The panel of vasculitis experts voted each PICO question and made recommendations, which required ≥70% agreement among the voting members. RESULTS: Eleven recommendations were developed. Oral glucocorticoids are conditionally recommended for newly diagnosed and relapsing TAK patients. The addition of nontargeted synthetic immunosuppressants (e.g., methotrexate, leflunomide, azathioprine, or mycophenolate mofetil) is recommended for patients with newly diagnosed or relapsing disease that is not organ- or life-threatening. For organ- or life-threatening disease, we conditionally recommend tumor necrosis factor inhibitors (e.g., infliximab or adalimumab) or tocilizumab with consideration for short courses of cyclophosphamide as an alternative in case of restricted access to biologics. For patients relapsing despite nontargeted synthetic immunosuppressants, we conditionally recommend to switch from one nontargeted synthetic immunosuppressant to another or to add tumor necrosis factor inhibitors or tocilizumab. We conditionally recommend low-dose aspirin for patients with involvement of cranial or coronary arteries to prevent ischemic complications. We strongly recommend performing surgical vascular interventions during periods of remission whenever possible. CONCLUSION: The first PANLAR treatment guidelines for TAK provide evidence-based guidance for the treatment of TAK patients in Latin American countries.

International Consensus on ANCA Testing in Eosinophilic Granulomatosis with Polyangiitis.

An international consensus on anti-neutrophil cytoplasm antibodies (ANCA) testing in eosinophilic granulomatosis with polyangiitis (EGPA) is presented. ANCA, specific for myeloperoxidase (MPO), can be detected in 30-35% of EGPA patients. MPO-ANCA should be tested with antigen-specific immunoassays in any patient with eosinophilic asthma and clinical features suggesting EGPA, including constitutional symptoms, purpura, polyneuropathy, unexplained heart, gastrointestinal or kidney disease, and/or pulmonary infiltrates or hemorrhage. A positive MPO-ANCA result contributes to the diagnostic work­up for EGPA. Patients with MPO-ANCA associated EGPA have more frequently vasculitis features, such as glomerulonephritis, neuropathy, and skin manifestations than patients with ANCA negative EGPA. However, the presence of MPO-ANCA is neither sensitive nor specific enough to identify whether a patient should be subclassified as having "vasculitic" or "eosinophilic" EGPA. At present, ANCA status cannot guide treatment decisions, that is, whether cyclophosphamide, rituximab or mepolizumab should be added to conventional glucocorticoid treatment. In EGPA, monitoring of ANCA is only useful when MPO-ANCA was tested positive at disease onset.

Increased histopathological yield for granulomatosis with polyangiitis based on nasal endoscopy of suspected active lesions.

PURPOSE: To present the results of an endoscopic and histopathologic evaluation of suspected nasal active granulomatosis with polyangiits (GPA) lesions, describe them as seen by the ENT specialist, and propose a guide for tissue sampling of the nasal cavity to improve the yield of confirmatory histology. METHODS: Randomly selected patients seen from December 1997-October 2007 had a thorough endoscopic nasal evaluation, preceded by careful cleansing of the nasal cavity. Endoscopic lesions were described; sensitivities, specificities, and predictive values of the composites of endoscopic and histological activity were determined. RESULTS: Six lesions, some not previously described in detail, were observed: white submucosal nodules, mucosal swelling, polypoid nodules, vascular submucosal dilatations, bloody submucosal patches, and ulcers. Of these, polypoid nodules (PPV 100%), persistent white submucosal nodules (PPV 81%), and bloody submucosal patches (PPV 93%) had the better diagnostic performance with confirmed histological diagnosis. CONCLUSIONS: Careful nasal cavity preparation, observation, and description of the nasal mucosa can guide tissue sampling documenting active GPA. This can lead to a better histological yield when definitive proof of the disease is needed.

Pulmonary Involvement in Systemic Vasculitis.

PURPOSE OF REVIEW: The purpose of this study is to describe the most relevant advances concerning lung involvement in the ANCA-associated vasculitides (excluding eosinophilic granulomatosis with polyangiitis which may have different disease mechanisms). Focus is on pathophysiology, recent important imagenological procedures, treatment, and outcome. RECENT FINDINGS: Emerging information exists on potential newly investigated diagnostic procedures (v.g. transbronchial cryobiopsies), detailed tomographic abnormalities, the potential favorable role of rituximab and the still uncertain one of plasma exchange in the treatment, and the increasing description of interstitial lung disease. Survival is reduced in case of both, diffuse alveolar hemorrhage and diffuse parenchymal disease. There is the need to expand the knowledge concerning better long-term treatment options with specific regimes, and to incorporate other measures regarding integral treatment in patients afflicted with lung involvement these maladies, as the outcome seems adverse in this scenario.

Utility of Transbronchial Lung Cryobiopsy in Non-Interstitial Diseases.

BACKGROUND: Transbronchial lung cryobiopsy (TLCB), performed with a flexible cryoprobe, is an interventional pulmonology procedure that has proved its diagnostic value for interstitial pulmonary disease. However, it has not been explored extensively as a diagnostic tool for patients with non-interstitial lung pathology, including infectious and malignant diseases. OBJECTIVE: To evaluate the diagnostic yield and safety of an interventional pulmonology approach that integrates TLCB and bronchoalveolar lavage (BAL) for the diagnosis of non-interstitial pulmonary disease. METHODS: TLCB and BAL were performed under general anesthesia through the same bronchoscopic access on 103 adult patients (including immunocompromised HIV+ individuals) with clinical/radiological evidence of non-interstitial lung disease admitted to the Interventional Pulmonology Service between May 2015 and April 2016. Samples obtained were sent to pathology and microbiology laboratories for standard diagnostic analysis. RESULTS: Samples of TLCB allowed the diagnosis of 75.7% of patients, while 39.8% were diagnosed from BAL. The global diagnostic yield from the dual sampling was 92.2%. TLCB allowed the diagnosis of 94.7% of cancer cases and 60.0% of infectious cases, while BAL samples identified 77.5% of infectious cases and 21.2% of malignant lesions. The incidence of complications was 4.9% with full recovery in all cases. CONCLUSIONS: Simultaneous TLCB and BAL constitute a safe and useful diagnostic procedure for non-interstitial pulmonary disease, with a global diagnostic yield of 92.2%. Complementary advantages of samples obtained by each technique result in a robust diagnostic strategy for infectious and malignant disease in adults, including HIV+ individuals.

Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.

It is now 25 years since the first European studies on vasculitis--the anti-neutrophil cytoplasmic antibody (ANCA) standardization project. Over that period of time, there have been major developments in the classification of the vasculitides, which has permitted the conduct of high-quality epidemiology studies. Studying the epidemiology of rare diseases such as the ANCA-associated vasculitides (AAV) poses considerable challenges to epidemiologists. The first is the need for a clear definition of a case with good differentiation from similar disorders. The second is case capture. The vasculitides are rare, and therefore, a large population is required to determine the incidence and prevalence, and this poses questions of feasibility. A large population increases the risk of incomplete case detection but permits a reasonable number of cases to be collected in a practicable time frame, whereas a smaller population requires a much longer time frame to collect the necessary cases, which may also not be feasible. Statistical methods of capture-recapture analysis enable estimates to be made of the number of missing cases. The third is case ascertainment. The AAV are virtually always managed in secondary care, and therefore, hospital-based case ascertainment may be appropriate. Fourthly, the rarity of the conditions makes prospective case-control studies investigating risk factors difficult to conduct because the population size required to achieve statistical confidence is in excess of that which is readily available. Thus, much of the data on risk factors are derived from retrospective studies with inherent potential bias.

Rituximab in the treatment of refractory scleritis in patients with granulomatosis with polyangiitis (Wegener's).

PURPOSE: The purpose of this descriptive study was to evaluate the clinical response to rituximab (RTX) in patients with scleritis due to granulomatosis with polyangiitis (GPA), in patients who had proved refractory to treatment with systemic glucocorticoids and immunosuppressive agents. METHODS: Retrospective analysis of interventional case series. Single referral center study. Eight patients (12 affected eyes) due to scleritis secondary to GPA, refractory to conventional treatment were included to receive RTX as therapy for remission induction. RTX was administered as a 1-g infusion every 2 weeks, for a total of 2 g. Patient follow-up included clinical evaluation (systemic and ophthalmologic), B-cell subset (CD19, CD20, CD22) counts, proteinase-3 anti-neutrophil cytoplasmic antibody (PR-3 ANCA), and Birmingham Vasculitis Activity Score for Wegener's granulomatosis (BVAS-WG). Outcomes were response to treatment and achievement of remission, as well as number of ocular relapses. RESULTS: The main indication for treatment was refractory necrotising anterior scleritis. Four weeks after completion of treatment with RTX, all patients showed clear clinical improvement, with no further progression. In all patients, an absolute depletion of B cells was confirmed in the first 6 weeks after treatment. Seven patients (87.5 %) achieved remission of inflammatory activity in 7 months or less. However, three patients experienced ocular relapse, which comprised reactivation of the anterior scleritis, uveitis, and posterior scleritis, and two patients required a second dose of RTX, with immediate improvement. CONCLUSIONS: RTX is useful in the treatment of refractory necrotising scleritis in patients with GPA. Of note, in those who relapse after remission, RTX can be successfully used for retreatment.

[Clinical Characteristics of antineutrophil cytoplasmic antibody-associated vasculitis in a respiratory diseases referral center in Mexico (1982-2010)]. / Vasculitis asociadas a anticuerpos anticitoplasma de neutrófilos (ANCA) en un centro de tercer nivel de enfermedad respiratoria (1982-2010).

INTRODUCTION: Respiratory manifestations in antineutrophil cytoplasmic antibody-associated vasculitis (AASV) are common, though their suspicion is lower than expected in respiratory devoted centers, with few descriptions coming from them. OBJECTIVE: To describe the clinical, paraclinical and radiological manifestations, plus the prognosis of AASV patients seen in a respiratory referral center in Mexico City. MATERIAL AND METHODS: Retrospective review of patients with final diagnosis of AASV, based on the American College of Rheumatology criteria and the 1994 Chapel Hill Consensus Conference Nomenclature, from 1982 to 2010. RESULTS: The characteristics of 74 granulomatosis with polyangiitis, 10 microscopic polyangiitis, and six eosinophilic granulomatosis with polyangiitis cases are described. Mean time elapsed from initial suspicion to definitive diagnosis was 30 months. As expected, respiratory findings dominated this cohort, but no significant differences were observed when compared to other series with AAS\1, except for a higher frequency of subglottic stenosis. After a mean follow-up of 22 months, 83% of patients were alive, with remission being achieved in 87% and response in 9%. Seven patients died, mostly from infectious complications. CONCLUSION: This study documents that airway manifestations in Mexican patients with AASV are similar to what has been previously described. However, time to diagnosis is long. Respiratory specialists should be more aware of the modes of presentation in AASV patients in order to facilitate their recognition.

Critical appraisal of classification criteria for vasculitides.

The vasculitides are a group of protean diseases, some of which are caused by conditions including infections, other autoimmune diseases, or neoplasias. They are a challenge to the clinician, in terms of both diagnosis and therapy. No diagnostic criteria exist, although a multinational effort to develop them is in progress. However, many classification criteria have been proposed, and these have served as diagnostic surrogates and have made it possible to discriminate between many, although not all, of the vasculitides, mainly for epidemiological and therapeutic trial design purposes. In this review we recognise the difficulties of defining such criteria, but at the same time attempt to provide a critical overview of efforts to do so. The increasing knowledge regarding many of these diseases makes us confident that the time will come when their aetiology, or at least their main pathogenic features, is known, rendering proposed classification criteria obsolete.

Update of the guidelines for the pharmacological treatment of rheumatoid arthritis by the Mexican College of Rheumatology 2023.

OBJECTIVE: To develop updated guidelines for the pharmacological management of rheumatoid arthritis (RA). METHODS: A group of experts representative of different geographical regions and various medical services catering to the Mexican population with RA was formed. Questions based on Population, Intervention, Comparison, and Outcome (PICO) were developed, deemed clinically relevant. These questions were answered based on the results of a recent systematic literature review (SLR), and the evidence's validity was assessed using the GRADE system, considered a standard for these purposes. Subsequently, the expert group reached consensus on the direction and strength of recommendations through a multi-stage voting process. RESULTS: The updated guidelines for RA treatment stratify various therapeutic options, including different classes of DMARDs (conventional, biologicals, and JAK inhibitors), as well as NSAIDs, glucocorticoids, and analgesics. By consensus, it establishes the use of these in different subpopulations of interest among RA patients and addresses aspects related to vaccination, COVID-19, surgery, pregnancy and lactation, and others. CONCLUSIONS: This update of the Mexican guidelines for the pharmacological treatment of RA provides reference points for evidence-based decision-making, recommending patient participation in joint decision-making to achieve the greatest benefit for our patients. It also establishes recommendations for managing a variety of relevant conditions affecting our patients.

Vasculitis: report from Mexico.

Although primary systemic vasculitides (PSV) are infrequent diseases, basic and clinical research have increased the knowledge of these autoimmune conditions substantially. Some PSV seem to be more frequent in certain countries. Here we present a brief history of the modest, but important contributions made in Mexico in this area of research.

Pan American League of Associations for Rheumatology Guidelines for the treatment of ANCA-associated vasculitis.

Considerable variability exists in the way health-care providers treat patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in Latin America. The most frequently used treatments for ANCA-associated vasculitis are cyclophosphamide and prolonged glucocorticoid tapers; however, randomised controlled trials conducted over the past 30 years have led to the development of several evidence-based treatment alternatives for these patients. Latin America faces socioeconomic challenges that affect access to care, and the use of certain costly medications with proven efficacy ANCA-associated vasculitis is often restricted. For these reasons, the Pan American League of Associations for Rheumatology developed the first ANCA-associated vasculitis treatment guidelines tailored for Latin America. A panel of local vasculitis experts generated clinically meaningful questions related to the treatment of ANCA-associated vasculitis using the Population, Intervention, Comparator, and Outcome (PICO) format. Following the Grading of Recommendations Assessment, Development, and Evaluation methodology, a team of methodologists conducted a systematic literature review. The panel of vasculitis experts voted on each PICO question and made recommendations, which required at least 70% agreement among the voting members. 21 recommendations and two expert opinion statements for the treatment of ANCA-associated vasculitis were developed, considering the current evidence and the socioeconomic characteristics of the region. These recommendations include guidance for the use of glucocorticoids, non-glucocorticoid immunosuppressants, and plasma exchange.

Pulse versus daily oral cyclophosphamide for induction of remission in ANCA-associated vasculitis: long-term follow-up.

INTRODUCTION: The previously reported randomised controlled trial of a consensus regimen of pulse cyclophosphamide suggested that it was as effective as a daily oral (DO) cyclophosphamide for remission induction of antineutrophil cytoplasm autoantibodies-associated systemic vasculitis when both were combined with the same glucocorticoid protocol (CYCLOPS study (Randomised trial of daily oral versus pulse Cyclophosphamide as therapy for ANCA-associated Systemic Vasculitis published de groot K, harper L et al Ann Int Med 2009)). The study had limited power to detect a difference in relapse. This study describes the long-term outcomes of patients in the CYCLOPS study. METHODS: Long-term outcomes were ascertained retrospectively from 148 patients previously recruited to the CYCLOPS Trial. Data on survival, relapse, immunosuppressive treatment, cancer incidence, bone fractures, thromboembolic disease and cardiovascular morbidity were collected from physician records retrospectively. All patients were analysed according to the group to which they were randomised. RESULTS: Median duration of follow-up was 4.3 years (IQR, 2.95-5.44 years). There was no difference in survival between the two limbs (p=0.92). Fifteen (20.8%) DO and 30 (39.5%) pulse patients had at least one relapse. The risk of relapse was significantly lower in the DO limb than the pulse limb (HR=0.50, 95% CI 0.26 to 0.93; p=0.029). Despite the increased risk of relapse in pulse-treated patients, there was no difference in renal function at study end (p=0.82). There were no differences in adverse events between the treatment limbs. DISCUSSION: Pulse cyclophosphamide is associated with a higher relapse risk than DO cyclophosphamide. However, this is not associated with increased mortality or long-term morbidity. Although the study was retrospective, data was returned in 90% of patients from the original trial.

Giant cell arteritis in Mexican patients.

BACKGROUND: Giant cell arteritis (GCA) is the most common primary systemic vasculitis worldwide, although it seems to be very rare in some areas, such as Latin America. OBJECTIVES: The objective of the study was to describe the clinical, laboratory, and treatment features in a Mexican Mestizo population with GCA. METHODS: Retrospective data chart review (1989-2010). RESULTS: Twenty-two patients with GCA were identified, 18 women and 4 men. Mean age was 73 (SD, 7.9) years. Diagnosis was made at a mean of 67 (SD, 83.6) days from symptom onset. Most frequent presenting symptoms included headache (90%), constitutional symptoms (86%), and polymyalgia rheumatica (59%). Severe cranial ischemic complications were present in 32%. Amaurosis fugax and blindness were present in 36% and 27%, respectively. High erythrocyte sedimentation rate was present in 89% of patients. Rapid response to prednisone treatment was seen, but in 10 patients, relapse occurred, possibly related to fast tapering. Additional treatment was methotrexate (n = 8), azathioprine (n = 5), and cyclophosphamide (n = 3). Median follow-up was 242 (SD, 214) weeks. CONCLUSIONS: Giant cell arteritis is rarely recognized in Latin America. We report on characteristics of GCA in a population of Mexican Mestizos, as ours is the largest series to be reported from Latin America so far. When compared with other series, age at onset is similar, females are more affected, and although a good response to corticosteroid treatment was seen, a higher frequency of amaurosis fugax and blindness was observed, accounting for an unfavorable functional outcome in 6 (27%) of 22 patients.