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.

Imatinib mesylate (Gleevec™) in the treatment of diffuse cutaneous systemic sclerosis: results of a 24-month open label, extension phase, single-centre trial.

OBJECTIVES: We aimed to assess the long-term safety and tolerability of imatinib in diffuse cutaneous systemic sclerosis (dcSSc). METHODS: In this open-label, single-arm, extension-phase clinical trial, patients continued imatinib for 24 months following 12 months of initial treatment. RESULTS: Seventeen patients were enrolled. Forty of 92 adverse events (AE) and 0/6 serious (S) AEs were possibly related to medication. The MRSS decreased from a median of 21 to 16, (p=0.002). CONCLUSIONS: This study demonstrates long-term safety and tolerability of imatinib in a substantial proportion of patients with dcSSc. This is important in evaluating the relevance of this therapy in a chronic disease such as SSc.

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.

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.

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.

Excitatory amino acid antagonists depress acoustic startle after infusion into the ventral nucleus of the lateral lemniscus or paralemniscal zone.

Rats were implanted with bilateral cannulas in an area just medial to the ventral nucleus of the lateral lemniscus, an obligatory relay along the acoustic startle pathway. Bilateral infusions of excitatory amino acid transmitter antagonists into this region (10, 25 or 50 nmol per side) produced a rapid, dose-dependent depression of acoustic startle. gamma-D-Glutamylglycine, gamma-D-glutamylaminomethyl sulfonate and 2-amino-5-phosphonovalerate were equally effective in depressing the startle response over this dose range. These results indicate that excitatory amino acid transmitters play an important role in the expression of acoustic startle at this part of the startle pathway.

Visual performance in giant cell arteritis (temporal arteritis) after 1 year of therapy.

AIMS: To determine if patients with giant cell arteritis (GCA) treated with corticosteroids develop delayed visual loss or drug related ocular complications. METHODS: In a multicentre prospective study patients with GCA (using precise diagnostic criteria) had ophthalmic evaluations at predetermined intervals up to 1 year. The dose of corticosteroid was determined by treating physicians, often outside the study, with the daily dose reduced to the equivalent of 30-40 mg of prednisone within 5 weeks. Subsequently, treatment guidelines suggested that the dose be reduced as tolerated or the patient was withdrawn from steroids in a period not less than 6 months. RESULTS: At presentation, of the 22 patients enrolled, seven patients had nine eyes with ischaemic injury. Four eyes had improved visual acuity by two lines or more within 1 month of starting corticosteroids. No patients developed late visual loss as the steroid dose was reduced. At 1 year the visual acuity, contrast sensitivity, colour vision, and threshold perimetry were not significantly different from the 4-5 week determinations. At 1 year, there were no significant cataractous or glaucomatous changes. At 2 months, there was no difference in systemic complications between patients who received conventional dose (60-80 mg per day) or very high doses (200-1000 mg per day) of corticosteroids at the start or early in the course. CONCLUSIONS: Patients with GCA related visual loss can improve with treatment. Corticosteroids with starting doses of 60-1000 mg per day, with reduction to daily doses of 40-50 mg per day given for 4-6 weeks, and gradual dose reduction thereafter, as clinically permitted, did not result in delayed visual loss. There were no significant drug related ophthalmic complications.

A prospective, double-blind, randomized, placebo controlled trial of methotrexate in the treatment of giant cell arteritis (GCA).

OBJECTIVE: To determine if methotrexate has disease-controlling and corticosteroid (cs)-sparing effects in the treatment of giant cell arteritis (GCA). METHODS: This was a randomized, controlled, double-blind trial comparing methotrexate versus placebo in addition to corticosteroid therapy in patients with newly diagnosed giant cell arteritis. Patients with giant cell arteritis were enrolled and treated with high dose corticosteroids as well as methotrexate starting at 7.5 mg/week or placebo. Corticosteroids were tapered by the treating physician as guided by the clinical picture, with methotrexate or placebo dose increased by 2.5 mg/week for disease flare with a maximum allowable dose of 20 mg/week. After a clinically-defined remission and steroid discontinuation, methotrexate or placebo was tapered monthly to zero by 2.5 mg/week. RESULTS: Twenty-one patients were enrolled, 12 randomized to methotrexate, 9 to placebo. Baseline characteristics (age, height, weight, sedimentation rate, bone mineral density, total corticosteroid dose prior to randomization, and quality of life as measured by SF-36 and function as measured by AIMS) were comparable between groups. At completion, there was no significant difference between methotrexate- and placebo-treated patients with regard to the cumulative corticosteroid dose (6469 mg and 5908 mg respectively, p = 0.6), number of weeks to completion of steroids (68 and 60 respectively, p = 0.5), time (weeks) to taper prednisone to less than 10 mg prednisone/day (23 and 25 respectively, p = 0.5), bone mineral density in lumbar spine (p = 0.2) or hip (p = 0.4) at one year, or functional status as measured by AIMS and quality of life as measured by SF36. There was no late vision loss in either group, and only one major treatment-responsive relapse in a methotrexate-treated patient. There were few major corticosteroid-related side effects and these did not significantly differ between groups. CONCLUSION: With this study design, no corticosteroid-sparing benefit could be attributed to the combination of methotrexate with corticosteroid therapy for the treatment of patients with giant cell arteritis. Both groups did well, with few major corticosteroid-related side effects, and most patients were safely tapered off corticosteroids sooner than reported in many series. The shorter overall duration of steroid treatment in this study probably contributed to the remarkably low frequency of side effects, without increased ischemic risk for the patient.

Silicone breast implants and connective tissue disease: an overview.

Silicone breast implants have been implicated in the possible pathogenesis of various connective tissue diseases. These findings have had a major impact not only on the medical and legal communities, but also on the community at large. In this communication, we review the history of the breast implant controversy, and examine the medical evidence regarding the possible link of silicone gel implants with connective tissue disorders such as scleroderma, rheumatoid arthritis, and lupus. Finally, we give a broad overview of the topic and offer some general suggestions regarding the care of patients who have silicone breast implants.

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.

Extramuscular manifestations in idiopathic inflammatory myopathies.

The major syndromes of chronic inflammatory myopathy (dermatomyositis and polymyositis) may have in certain instances extramuscular manifestations including pulmonary, cardiac, gastrointestinal, and of course, in the first instance, dermatological involvement. Here we review recent literature addressing these associated clinical areas of involvement. Malignancies, which may affect as many as 20% to 30% of adults with dermatomyositis, will not be addressed in this review.

Silicone gel filled breast implants and connective tissue disease: an overview.

OBJECTIVE: To review the literature examining the association of silicone gel filled implants and connective tissue disease. METHODS: Computerized literature searches and manual review of bibliographies. RESULTS: Numerous concerns have arisen regarding the safety of silicone gel filled breast implants. The structure of these prostheses is reviewed. Silicones are not biologically inert. Injectable as well as implantable silicones have proven capable of eliciting inflammatory and fibroproliferative responses. Silicone leakage from silicone gel filled implants is well documented as is distant migration of silicone in the host. In the past decade, over 60 cases of connective tissue disease following mammoplasty with silicone gel filled implants have been reported. About half of these patients developed scleroderma or scleroderma-like illnesses. This reported overrepresentation of scleroderma compared to other rheumatic diseases mimics the Japanese experience with injectable silicones. Possible biological rationale for the association is presented. CONCLUSION: The physical and biological properties of silicone gel filled implants and their behavior in vivo is compatible with the hypothesis that they may contribute to the development of connective tissue disease. The association seems most likely with scleroderma; however, there is as yet inadequate epidemiological data to definitively establish causality.

Esophageal involvement in Wegener's granulomatosis.

Wegener's granulomatosis (WG) is characterized by granulomatous vasculitis, renal disease, and upper and lower respiratory tract disease. Although most organ systems can be involved, gastrointestinal (GI) manifestations are notably uncommon. We describe a patient with WG whose presentation was unique for the prominence of odynophagia. Esophagoscopy revealed erosive esophagitis, which on biopsy was shown to be due to direct involvement by the underlying vasculitis. This is first antermortem documentation of esophageal disease secondary to WG. The GI manifestations of WG are reviewed.

A disease-specific activity index for Wegener's granulomatosis: modification of the Birmingham Vasculitis Activity Score. International Network for the Study of the Systemic Vasculitides (INSSYS).

OBJECTIVE: To refine and validate the Birmingham Vasculitis Activity Score (BVAS) as a disease-specific activity index for Wegener's granulomatosis (WG). METHODS: Sixteen members of the International Network for the Study of the Systemic Vasculitides (INSSYS) revised the BVAS, with 3 goals: to reduce the redundancy of some component items, to enhance its ability to capture important disease manifestations specific to WG, and to streamline the instrument for use in clinical research. We defined the items and weighted them empirically as either minor (e.g., nasal crusting = 1 point) or major (e.g., alveolar hemorrhage = 3 points). We then validated the new, disease-specific BVAS/WG in 2 simulation exercises and a clinical case series that involved 117 patients with WG. RESULTS: We removed 38 items from the original BVAS, revised 9 items, and added 7 new items. Correlations between the scores on the BVAS/WG and the physician's global assessment (PGA) of disease activity were high, even when patients in remission were excluded. In the clinical case series, Spearman's rank correlation coefficient between the BVAS/WG and the PGA was r = 0.81 (95% confidence interval 0.73-0.87). The interobserver reliability using intraclass (within-case) correlation coefficients in the 2 simulation exercises was r = 0.93 for the BVAS/WG and r = 0.88 for the PGA in the first and r = 0.91 for the BVAS/WG and r = 0.88 for the PGA in the second. There was no significant observer effect in the scoring of the BVAS/WG or the PGA. The discriminant validity of the BVAS/WG was good: r = 0.73 (95% confidence interval 0.43-0.83). CONCLUSION: The BVAS/WG is a valid, disease-specific activity index for WG. Tested in simulation exercises and in actual patients, the BVAS/WG correlates well with the PGA, is sensitive to change, and has good inter- and intraobserver reliability. The INSSYS will use the BVAS/WG to assess the primary outcome in a phase II/III trial of etanercept in WG.