Autoimmune blistering diseases treated with glucocorticoids: An international study of steroid-induced myopathy.

BACKGROUND: Patients with autoimmune blistering diseases (AIBDs) are often exposed to chronic glucocorticoid (GC) treatment with many side effects. Glucocorticoid-induced myopathy (GIM) is a well-established side effect, which particularly affects the proximal muscles. The Glucocorticoid Toxicity Index (GTI) is a validated global assessment tool which quantifies GC toxicity over time. OBJECTIVES: This study marks the first study which analyses GIM in patients with AIBDs. The objectives of this study were to utilize the GTI to investigate the nature and prevalence of GIM in AIBD patients and explore potential risk factors. METHODS: This international cohort study was conducted in blistering disease clinics across Australia, China, Greece, Iran, Japan, the Philippines, Turkey and the United States of America between February 2019 and July 2023. The GTI tool was completed by a medical practitioner at each patient visit. Data related to glucocorticoid toxicity were entered into the Steritas GTI 2.0 to generate an aggregate improvement and cumulative worsening score at each visit. RESULTS: The study included 139 patients. There were 132 episodes of myopathy, and 47.5% of patients developed muscle weakness at some point during the study period. Cumulative GC dose correlated positively with myopathy risk, while average dose and treatment duration were not significant. Older age, male gender and obesity more than doubled the likelihood of developing GIM. CONCLUSIONS: GIM is a common side effect experienced by AIBD patients on GC treatment. Muscle weakness is less likely to occur if cumulative GC dose is less than 0.75 mg/kg/day. Studies of exercise programs to mitigate myopathy and newer alternative treatments to reduce cumulative GC dose should be considered.

Clinical features and mechanistic insights regarding IgG4-related dacryoadenitis and sialoadenitis: a review.

Immunoglobulin G4-related disease (IgG4-RD), recognized only recently as a single diagnostic entity, is a chronic inflammatory condition of unknown etiology. The diagnosis of IgG4-RD relies heavily on histopathological analysis and the correlation of histology findings with clinical, serological, and radiological data. CD4+ T and B cells, including IgG4-expressing plasmablasts, constitute the major inflammatory cell populations in IgG4-RD and are believed to cause organ damage and tissue fibrosis. Patients with IgG4-RD, who have active, untreated disease, exhibit marked expansion of IgG4-secreting plasmablasts in the blood. Important mechanistic insights correlated with the pathogenesis of IgG4-RD have been disclosed in recent years through the application of novel molecular biology approaches, including next-generation and single-cell RNA sequencing. Exploration of the interactions between these CD4+ T cells and cells of the B lymphocyte lineage is critical to understanding the pathophysiology of IgG4-RD. The establishment of pathogenic T cell clones and the identification of antigens specific to these clones constitute the first steps in determining the pathogenesis of this disease. This review focuses on clinical features and mechanistic insights regarding IgG4-related dacryoadenitis and sialoadenitis, from a perspective suitable for oral and maxillofacial surgeons.

Immunoglobulin (Ig)M antibodies to proteinase 3 in granulomatosis with polyangiitis and microscopic polyangiitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) appear to play an important role in the pathogenesis of ANCA-associated vasculitis (AAV). However, ANCA alone are not sufficient to generate disease, and some evidence suggests that infectious triggers may serve as inciting events for AAV disease activity. Antibodies of the immunoglobulin (Ig)M isotype often serve as markers of recent infection, and IgM ANCA have been identified previously in patients with AAV, although the frequency and clinical relevance of IgM ANCA is not well established. We sought to characterize IgM ANCA more clearly by creating a novel enzyme-linked immunosorbent assay (ELISA) for IgM antibodies to proteinase 3 [IgM proteinase 3 (PR3)-ANCA], which we applied to two large, clinically well-characterized trial cohorts of patients with granulomatosis with polyangiitis and microscopic polyangiitis. In the first cohort, IgM PR3-ANCA occurred with a frequency of 15·0%, and were associated with a higher degree of disease severity and a trend towards a higher rate of alveolar haemorrhage (29·6 versus 15·7%, P = 0·10). Analysis of follow-up samples in this cohort showed that the presence of IgM PR3-ANCA was transient, but could recur. In the second cohort, IgM PR3-ANCA occurred with a frequency of 41·1%, and were also associated with a higher degree of disease severity. A higher rate of alveolar haemorrhage was observed among those with IgM PR3-ANCA (45·3 versus 15·8%; P < 0·001). The association of transient IgM PR3-ANCA with an acute respiratory manifestation of AAV suggests a possible link between an infectious trigger and AAV disease activity.

Treatment of IgG4-related disease : Current and future approaches.

IgG4-related disease (IgG4-RD) is capable of causing great morbidity and even mortality if the condition remains undiagnosed or poorly treated, yet is typically a treatment-responsive disorder. Glucocorticoids have not been studied rigorously and practices with regard to dosing and duration of treatment remain largely empiric. In addition, IgG4-RD patients are often particularly susceptible to and intolerant of the deleterious effects of glucocorticoid therapy. B cell depletion with anti-CD20 monoclonal antibodies appears to be a rapid, effective means of obtaining disease control and limiting patients' glucocorticoid exposure, but this option is frequently not available. Other therapies targeting the B cell lineage may also be efficacious, and one is under study. The means by which depletion or inhibition of B cells and their progeny ameliorate IgG4-RD is coming into focus now through careful mechanistic studies of samples from treated patients. The mechanistic understanding of IgG4-RD will bring an array of specific targets for therapeutic intervention. Plasmablast-directed therapy with a CD19 monoclonal antibody is currently in clinical trials. CD4 + cytotoxic T lymphocytes and fibrosis, both observed nearly universally in the tissue of IgG4-RD patients, present two unexploited vulnerabilities in controlling and even reversing the effects of the disease. Further development of such therapies is a major goal of the next few years.

Outcomes of nonsevere relapses in antineutrophil cytoplasmic antibody-associated vasculitis treated with glucocorticoids.

OBJECTIVE: Nonsevere relapses are more common than severe relapses in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), but their clinical course and treatment outcomes remain largely unexamined. We undertook this study to analyze the outcomes of patients with nonsevere relapses in the Rituximab in ANCA-Associated Vasculitis (RAVE) trial who were treated with prednisone according to a prespecified protocol. METHODS: RAVE was a randomized, double-blind, placebo-controlled trial comparing rituximab (RTX) to cyclophosphamide (CYC) followed by azathioprine (AZA) for induction of remission. Patients who experienced nonsevere relapses between months 1 and 18 were treated with a prednisone increase without a concomitant change in their nonglucocorticoid immunosuppressants, followed by a taper. RESULTS: Forty-four patients with a first nonsevere relapse were analyzed. In comparison to the 71 patients who maintained relapse-free remission over 18 months, these patients were more likely to have proteinase 3-ANCAs, diagnoses of granulomatosis with polyangiitis (Wegener's), and a history of relapsing disease at baseline. A prednisone increase led to remission in 35 patients (80%). However, only 13 patients (30%) were able to maintain second remissions through the followup period (mean 12.5 months); 31 patients (70%) had a second disease relapse, 14 of them with severe disease. The mean time to second relapse was 9.4 months (4.7 months in the group treated with RTX versus 13.7 months in the group treated with CYC/AZA; P < 0.01). Patients who experienced nonsevere relapses received more glucocorticoids than those who maintained remission (6.7 grams versus 3.8 grams; P < 0.01). CONCLUSION: Treatment of nonsevere relapses in AAV with an increase in glucocorticoids is effective in restoring temporary remission in the majority of patients, but recurrent relapses within a relatively short interval remain common. Alternative treatment approaches are needed for this important subset of patients.

Rituximab for the treatment of relapses in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: Disease relapses are frequent in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). This study was undertaken to evaluate outcomes in patients with AAV who are re-treated with rituximab (RTX) and prednisone for severe disease relapses. METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rates of remission induction among patients treated with RTX (n = 99) and patients treated with cyclophosphamide (CYC) followed by azathioprine (AZA) (n = 98). Prednisone was tapered to discontinuation after 5.5 months. After remission was achieved, patients who experienced a severe disease relapse between months 6 and 18 were eligible to receive RTX and prednisone on an open-label basis according to a prespecified protocol. Investigators remained blinded with regard to the original treatment assignment. RESULTS: Twenty-six patients received RTX for disease relapse after remission had initially been achieved with their originally assigned treatment. Fifteen of these patients were initially randomized to receive RTX and 11 to receive CYC/AZA. Thirteen (87%) of the patients originally assigned to receive RTX and 10 (91%) originally assigned to receive CYC/AZA achieved remission again with open-label RTX (an overall percentage of 88%). In half of the patients treated with open-label RTX, prednisone could be discontinued entirely. Patients in this cohort experienced fewer adverse events compared to the overall study population (4.7 adverse events per patient-year versus 11.8 adverse events per patient-year). CONCLUSION: Re-treatment of AAV relapses with RTX and glucocorticoids appears to be a safe and effective strategy, regardless of previous treatment.

Circulating Th2 memory cells in IgG4-related disease are restricted to a defined subset of subjects with atopy.

IgG4-related disease (IgG4-RD) is characterized by a lymphoplasmacytic infiltrate composed of IgG4(+) plasma cells, tumefactive lesions, obliterative phlebitis, and mild to moderate eosinophilia. It has been suggested that IgG4-RD is characterized by allergic manifestations and is potentially driven by enhanced T-helper type 2 (Th2) responses. We aimed to investigate the potential contribution of atopy to enhanced Th2 responses in IgG4-RD. Peripheral blood mononuclear cells from 39 patients were isolated and subjected to in vitro mitogenic stimulation with PMA and ionomycin. Following stimulation, gated CD3(+) CD4(+) T cells were analyzed for production of the Th2 cytokines IL-4, IL-5, and IL-13. Among the 39 patients analyzed, only the 18 patients who had a history of atopy showed increases in circulating Th2 memory cells. Our results indicate that Th2 responses that have been reported in IgG4-RD may result from concomitant atopic manifestations in disease subjects.

Clinical outcomes of remission induction therapy for severe antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To evaluate the reasons that complete remission is not achieved or maintained with original treatment in some patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) treated with rituximab (RTX) or with cyclophosphamide/azathioprine (CYC/AZA). METHODS: The Rituximab in AAV trial was a randomized, double-blind, placebo-controlled trial comparing the rate of remission induction among patients treated with RTX (n = 99) and patients treated with CYC followed by AZA (n = 98). Glucocorticoids were tapered over a period of 5 months. The primary outcome measure was lack of disease activity without glucocorticoid treatment at 6 months. To determine the most important reason for failure to achieve the primary outcome, 7 hierarchical categories of reasons were defined retrospectively (uncontrolled disease, adverse event leading to therapy discontinuation, severe flare, limited flare, Birmingham Vasculitis Activity Score for Wegener's Granulomatosis >0, prednisone treatment at any dosage, and other). RESULTS: Although remission (lack of disease activity) was achieved in 170 of the 197 patients (86%) in the first 6 months, the primary outcome measure was not achieved in 42%. There were 3 deaths. Twenty-four percent of the patients failed to achieve the primary end point due to active disease: 10 (5%) experienced uncontrolled disease in the first month and 37 (19%) experienced flares after initial improvement. In the majority of such patients, treatment with blinded crossover or according to best medical judgment led to disease control. Ninety-one percent of patients who had uncontrolled disease or experienced a severe flare had proteinase 3 (PR3)-ANCA. When patients with uncontrolled disease were excluded from analysis, those who were PR3-ANCA positive were found to experience fewer flares when treated with RTX compared to CYC/AZA (8 of 59 [14%] versus 20 of 62 [32%]; P = 0.02). Neither ANCA titers nor B cell counts predicted disease flare. CONCLUSION: Current treatment regimens are largely successful in controlling AAV, but in approximately one-fourth of patients, active disease persists or recurs in the first 6 months despite treatment. PR3-ANCA positivity is a risk factor for recurrence or persistence of severe disease. ANCA titers and B cell detectability are poor predictors of both disease relapse and disease quiescence in the first 6 months.

Tocilizumab for the treatment of large-vessel vasculitis (giant cell arteritis, Takayasu arteritis) and polymyalgia rheumatica.

OBJECTIVE: The interleukin-6 pathway is up-regulated in giant cell arteritis (GCA), Takayasu arteritis (TA), and polymyalgia rheumatica (PMR). We retrospectively assessed the outcomes of 10 patients with relapsing/refractory GCA, TA, or PMR treated with tocilizumab (TCZ). METHODS: Patients with GCA (n = 7), TA (n = 2), and PMR (n = 1) received TCZ. Seven subjects had failed at least 1 second-line agent. The outcomes evaluated were symptoms of disease activity, inflammatory markers, ability to taper glucocorticoids, and cross-sectional imaging when indicated clinically. RESULTS: The mean followup time of this cohort since diagnosis was 27 months (range 16-60 months). The patients were treated with TCZ for a mean period of 7.8 months (range 4-12 months). Before TCZ therapy, the patients experienced an average of 2.4 flares/year. All patients entered and maintained clinical remission during TCZ therapy. The mean daily prednisone dosages before and after TCZ initiation were 20.8 mg/day (range 7-34.3 mg/day) and 4.1 mg/day (range 0-10.7 mg/day), respectively (P = 0.0001). The mean erythrocyte sedimentation rate declined from 41.5 mm/hour (range 11-68 mm/hour) to 7 mm/hour (range 2.2-11.3 mm/hour; P = 0.0001). The adverse effects of TCZ included mild neutropenia (n = 4) and transaminitis (n = 4). One patient flared 2 months after TCZ discontinuation. An autopsy on 1 patient who died from a postoperative myocardial infarction following elective surgery revealed persistent vasculitis of large and medium-sized arteries. CONCLUSION: TCZ therapy led to clinical and serologic improvement in patients with refractory/relapsing GCA, TA, or PMR. The demonstration of persistent large-vessel vasculitis at autopsy of 1 patient who had shown a substantial response requires close scrutiny in larger studies.

Glycosylation of proteinase 3 (PR3) is not required for its reactivity with antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis.

OBJECTIVE: The glycosylation status of autoantigens appears to be crucial for the pathogenesis of some autoimmune diseases, since carbohydrates play a crucial role in the distinction of self from non-self. Proteinase 3 (PR3), the main target antigen for anti-neutrophil cytoplasmic antibodies (ANCA) in patients with Wegener's granulomatosis (WG), contains two Asn-linked glycosylation sites. The present study explores the influence of the glycosylation status of PR3 on the PR3 recognition by ANCA in a well characterized population of patients with WG. METHODS: Forty-four patients with WG (459 serum samples) who participated in a multicenter randomized trial, were tested by capture ELISA for ANCA against PR3 and deglycosylated recombinant variants of PR3. RESULTS: The patients were followed for a median of 27 months, and the median number of serum samples per patient was 10. At baseline, the correlation between the levels of ANCA against PR3 and against all the deglycosylated recombinant variants of PR3 were greater than 0.94 (?<0.001 for all the comparisons). Longitudinal analyses comparing the levels of ANCA against PR3 versus all the deglycosylated recombinant variants of PR3, using linear mixed models, showed no significant statistical differences (rho >or=0.90 in all cases). CONCLUSION: The glycosylation status of PR3 has no impact on its recognition by ANCA in WG.

Comparison of disease activity measures for anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis.

AIM: Currently, several different instruments are used to measure disease activity and extent in clinical trials of anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis, leading to division among investigative groups and difficulty comparing study results. An exercise comparing six different vasculitis instruments was performed. METHODS: A total of 10 experienced vasculitis investigators from 5 countries scored 20 cases in the literature of Wegener granulomatosis or microscopic polyangiitis using 6 disease assessment tools: the Birmingham Vasculitis Activity Score (BVAS), The BVAS for Wegener granulomatosis (BVAS/WG), BVAS 2003, a Physician Global Assessment (PGA), the Disease Extent Index (DEI) and the Five Factor Score (FFS). Five cases were rescored by all raters. RESULTS: Reliability of the measures was extremely high (intraclass correlations for the six measures all = 0.98). Within each instrument, there were no significant differences or outliers among the scores from the 10 investigators. Test/retest reliability was high for each measure: range = 0.77 to 0.95. The scores of the five acute activity measures correlated extremely well with one another. CONCLUSIONS: Currently available tools for measuring disease extent and activity in ANCA-associated vasculitis are highly correlated and reliable. These results provide investigators with confidence to compare different clinical trial data and helps form common ground as international research groups develop new, improved and universally accepted vasculitis disease assessment instruments.

Antibodies to selected minor target antigens in patients with anti-neutrophil cytoplasmic antibodies (ANCA).

In patients with anti-neutrophil cytoplasmic antibodies (ANCA)-associated vasculitis, indirect immunofluorescence (IF) distinguishes between cytoplasmic (C-ANCA) and perinuclear (P-ANCA) neutrophil staining patterns. In patients with primary systemic vasculitis such as Wegener's granulomatosis, microscopic polyangiitis and Churg-Strauss syndrome, these IF staining patterns correspond broadly with antibodies to the two major antigens: the C-ANCA pattern is associated generally with antibodies to serine protease 3 (PR3) and the P-ANCA pattern with antibodies to myeloperoxidase (MPO). However, some sera positive for ANCA by IF are negative for anti-PR3 and anti-MPO antibodies, suggesting the presence of antibodies to minor antigens of PMN granules. We tested sera from a previously well-defined clinical cohort of patients for antibodies to four possible minor antigens: bactericidal permeability increasing protein, elastase, cathepsin G and lactoferrin. IF-positive (+) sera had significantly higher antibody frequencies to the minor antigens than did the IF-negative (-) sera (P < 0.01). Patients with IF(+) PR3(-)MPO(-) sera showed the most varied reactivity to the minor antigens. Among the IF(+) groups, the IF(+) PR3(+)/MPO(-) sera showed the lowest reactivity to the minor antigens. Patients with well-defined ANCA specificities, e.g. the PR3-ANCA response associated with Wegener's granulomatosis, are less likely than are other patient subsets to have antibodies to minor antigen targets. Autoantibodies to these minor antigens contribute to the overall pattern of ANCA identified by IF and help to explain why the correlation between IF and enzyme immunoassays show discrepancies. While the pathophysiological significance of antibodies to minor target antigens needs further evaluation, they may be markers of inflammation associated with disease processes.

Mass spectrometry-based proteomics and analyses of serum: a primer for the clinical investigator.

The vocabulary of proteomics and the swiftly-developing, technological nature of the field constitute substantial barriers to clinical investigators. In recent years, mass spectrometry has emerged as the most promising technique in this field. The purpose of this review is to introduce the field of mass spectrometry-based proteomics to clinical investigators, to explain many of the relevant terms, to introduce the equipment employed in this field, and to outline approaches to asking clinical questions using a proteomic approach. Examples of clinical applications of proteomic techniques are provided from the fields of cancer and vasculitis research, with an emphasis on a pattern recognition approach.

Vasculitis. A collection of pearls and myths.

Important strides have been made in unraveling the pathophysiologic characteristics of some individual forms of vasculitis, but vasculitides continue to pose enormous challenges for clinicians. Over time, numerous myths and an occasional pearl have arisen from the care of patients with these disorders. In this collection of pearls and myths, we have attempted to pool our knowledge about the clinical care of vasculitis patients.

Treatment of Wegener's granulomatosis.

The two principal aims in the treatment of Wegener's granulomatosis (WG) are to limit the extent and severity of permanent organ damage by controlling the disease promptly and to minimize the short- and long-term morbidity that often results from therapy. Remission is considered to be the absence of disease activity in any organ system. Once the disease has been controlled by the initial treatment regimen, which is dictated by the degree of disease severity, the focus of therapy shifts to maintaining disease remission, often with medications less toxic than those used to induce remission. The description of WG treatments in terms analogous to cancer chemotherapy (i.e., those designed to induce remissions and those intended to maintain them) is useful in the formulation of current disease management strategies and in the investigation of new therapies for WG.

Reliability of normal findings on MR imaging for excluding the diagnosis of vasculitis of the central nervous system.

OBJECTIVE: We attempt to determine whether angiography is indicated in patients with suspected central nervous system (CNS) vasculitis who present with negative findings on MR imaging studies. CONCLUSION: MR imaging findings may be negative in the setting of CNS vasculitis confirmed on angiography, indicating that advanced imaging techniques tailored to detect infarction (i.e., fluid-attenuated inversion recovery, diffusion-weighted, and perfusion imaging) may be necessary to enhance the sensitivity of an MR study and that despite the high sensitivity of MR imaging for CNS vasculitis, angiography may still be required to render an accurate diagnosis.

New approaches to treatment in systemic vasculitis: biological therapies.

Although the effectiveness of biological agents in systemic vasculitis is unproven, their introduction heralds a new era of vasculitis treatment. These agents offer the promise of targeted immunotherapies; the possibility of greater efficacy (and fewer side-effects) than conventional vasculitis treatments; and the potential to provide novel insights into the pathophysiology of these diseases-insights that may be gained only by using these agents in humans. Challenges to the investigation of these therapies in the systemic vasculitides exist, but important basic and clinical investigations are already in progress. We review the major issues facing the investigation of biological agents in vasculitis; examine the rationale for believing that biological strategies in vasculitis will be efficacious; identify several candidate targets for biological approaches; and discuss the results to date of early studies. The potential biological targets discussed include cytokines such as tumour necrosis factor; interleukins-1, -6, and -12; interferon-gamma; the co-stimulatory molecules B7-1 and B7-2; and others.