Cytomegalovirus colitis unmasking human immunodeficiency virus infection as a cause of IgA vasculitis.

BACKGROUND: Human immunodeficiency virus (HIV) has a protean clinical picture, in rare instances manifesting as systemic autoimmune disorders such as vasculitides. HIV-induced autoimmune diseases often do not respond well to systemic immunosuppressive therapy. Opportunistic infections may occur in patients with either acquired immunodeficiency syndrome (AIDS) or heavy immunosuppressive treatment, and can further complicate the clinical presentation. CASE PRESENTATION: A patient presenting with immunoglobulin A (IgA) vasculitis (IgAV) with treatment-refractory purpuric skin rash and suspect intestinal vasculitis was discovered to have AIDS. HIV was the trigger of IgAV, and cytomegalovirus (CMV) colitis mimicked intestinal vasculitis. Antiretroviral treatment improved both CMV colitis and the control of the autoimmune disease. CONCLUSIONS: An autoimmune disease relapsing despite adequate immunosuppressive treatment and/or the presence of recurrent severe opportunistic infections may be clues to an underlying HIV infection.

Azathioprine vs methotrexate in eosinophilic granulomatosis with polyangiitis: a monocentric retrospective study.

OBJECTIVES: To analyse effectiveness, safety, and steroid-sparing effect of AZA and MTX as induction of remission and maintenance treatment in eosinophilic granulomatosis with polyangiitis. METHODS: We retrospectively collected data from 57 patients divided in 4 groups according to treatment: MTX/AZA as first-line agents (MTX1/AZA1) in non-severe disease, or as second-line maintenance therapy (MTX2/AZA2) in severe disease previously treated with CYC/rituximab. During the first five years of treatment with AZA/MTX we compared the groups according to: remission rate (defined as R1: BVAS = 0, R2: BVAS = 0 with prednisone ≤5mg/day, R3-MIRRA definition: BVAS = 0 with prednisone ≤ 3.75 mg/day), persistence on therapy, cumulative glucocorticoid (GC) dose, relapse, and adverse events (AE). RESULTS: There were no significant differences in remission rates (R1) in each group (63% in MTX1 vs 75% in AZA1, p= 0.53; 91% in MTX2 vs 71% in AZA2, p= 0.23). MTX1 allowed R2 more frequently in the first 6 months compared with AZA1 (54% vs 12%, p= 0.04); no patients receiving AZA1 achieved R3 up to the first 18 months (vs 35% in MTX1, p= 0.07). Cumulative GC dose was lower for MTX2 vs AZA2 (6 g vs 10.7 g at 5 years, p= 0.03). MTX caused more AE compared with AZA (66% vs 30%, p= 0.004), without affecting the suspension rate. No differences emerged in time-to-first relapse, although fewer patients treated with AZA2 had asthma/ENT relapses (23% vs 64%, p= 0.04). CONCLUSION: A significant proportion of patients achieved remission with both MTX and AZA. MTX1 had an earlier remission on lower GC dose, MTX2 had better steroid-sparing effect.

Characteristics and outcome of ANCA-associated vasculitides induced by anti-thyroid drugs: a multicenter retrospective case-control study.

OBJECTIVE: Data on ANCA-associated vasculitis (AAV) induced by anti-thyroid drugs (ATD) are scarce. We aimed to describe the characteristics and outcome of these patients in comparison to primary AAV. METHODS: We performed a retrospective multicenter study including patients with ATD-induced AAV. We focused on ATD-induced microscopic polyangiitis (MPA) and compared them with primary MPA by matching each case with 4 controls by gender and year of diagnosis. RESULTS: Forty-five patients with ATD-induced AAV of whom 24 MPA were included. ANCA were positive in 44 patients (98%), including myeloperoxidase (MPO)-ANCA in 21 (47%), proteinase 3 (PR3)-ANCA in 6 (13%), and double positive MPO- and PR3-ANCA in 15 (33%). Main clinical manifestations were skin involvement (64%), arthralgia (51%), and glomerulonephritis (20%). ATD was discontinued in 98% of cases, allowing vasculitis remission in 7 (16%). All the remaining patients achieved remission after glucocorticoids, in combination with rituximab in 11 (30%) or cyclophosphamide in 4 (11%). ATD were reintroduced in 7 cases (16%) without any subsequent relapse. Compared with 96 matched primary MPA, ATD-induced MPA were younger at diagnosis (48 vs. 65 years, P < 0.001), had more frequent cutaneous involvement (54 vs. 25%, P = 0.007), but less frequent kidney (38 vs. 73%, P = 0.02), and a lower risk of relapse (adjusted HR 0.07; 95%CI 0.01-0.65, P = 0.019). CONCLUSION: ATD-induced AAV were mainly MPA with MPO-ANCA, but double MPO- and PR3-ANCA positivity was frequent. The most common manifestations were skin and musculoskeletal manifestations. ATD-induced MPA were less severe and showed a lower risk of relapse than primary MPA.

Systemic vasculitis: one year in review 2023.

Systemic vasculitides are heterogeneous disabling diseases characterised by chronic inflammation of the blood vessels potentially leading to tissue destruction and organ failure. The recent COVID-19 pandemic has had a significant impact on the epidemiology and management of patients with systemic vasculitis. In parallel, new insights have been provided on systemic vasculitis pathogenetic mechanisms, possible new therapeutic targets, and newer glucocorticoid-sparing treatments with better safety profiles. As in the previous annual reviews of this series, in this review we will provide a critical digest of the most recent literature regarding pathophysiology, clinical manifestations, diagnostic tools and treatment options in small- and large-vessel vasculitis focusing on precision medicine in vasculitis.

Remission and Low Disease Activity in Granulomatosis With Polyangiitis and Microscopic Polyangiitis: Prevalence and Impact on Damage Accrual.

OBJECTIVE: To assess the prevalence and impact on damage accrual of different levels of disease activity in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). METHODS: Patients with GPA and MPA followed for ≥5 years in 2 different centers were included. Disease activity and damage were assessed using the Birmingham Vasculitis Activity Score (BVAS) and Vasculitis Damage Index (VDI), respectively. Three levels of remission were defined: complete remission (BVAS = 0, negative for antineutrophil cytoplasmic antibody [ANCA], off treatment), clinical remission off therapy (CROffT; BVAS = 0, positive for ANCA), and clinical remission on therapy (CROnT; BVAS = 0, negative or positive for ANCA, glucocorticoids ≤5 mg/day and/or immunosuppressant). A low disease activity state (LDAS) was defined as 0 < BVAS ≤3, low-dose glucocorticoids (≤7.5 mg/day), and/or immunosuppressant. Remission or LDAS were defined as prolonged when lasting ≥2 consecutive years. RESULTS: A total of 167 patients were included: 128 (76.6%) with GPA, 39 (23.4%) with MPA, mean ± SD age 51.0 ± 16.7 years. During a 5-year follow-up, 10 patients (6.0%) achieved prolonged complete remission, 6 (3.6%) prolonged CROffT, 89 (53.3%) prolonged CROnT, 42 (25.1%) prolonged LDAS, and 20 (12.0%) never achieved LDAS. The VDI score at 5 years progressively worsened according to increasing levels of disease activity targets (complete remission, CROffT, CROnT, and LDAS). The mean ± SD 5-year VDI score was higher in patients not achieving prolonged remission compared to those who did (3.7 ± 2.0 versus 2.2 ± 1.9; P < 0.0001). By multivariate analysis, baseline ear, nose, and throat (P = 0.006), and lung involvement (P = 0.047) were negative predictors of prolonged remission. CONCLUSION: More than 60% of patients with GPA/MPA achieved prolonged remission, which was associated with better long-term outcomes. In contrast, prolonged LDAS correlated with increased damage accrual and was not a sufficient treatment target.

Immunosuppressive treatments selectively affect the humoral and cellular response to SARS-CoV-2 in vaccinated patients with vasculitis.

OBJECTIVES: To analyse humoral and cellular immune response to mRNA COVID-19 vaccines in patients with GCA. METHODS: Consecutive patients with a diagnosis of GCA receiving two doses of BNT162b2 vaccine were assessed at baseline and 3 weeks from the second vaccine dose. Healthy subjects (n = 51) were included as controls (HC). Humoral response was assessed with Spike-specific IgG antibody response (S-IgG) and neutralizing antibodies (NtAb). Specific T cell response was assessed by enzyme linked immunosorbent spot (ELISpot). RESULTS: Of 56 included patients with GCA, 44 were eligible after exclusion of previous evidence of COVID-19 and incomplete follow-up. A significant proportion of patients with GCA (91%) demonstrated antibody (S-IgG) response, but this was significantly lower than HCs (100%); P < 0.0001. Neutralizing activity was not detected in 16% of patients with GCA. Antibody titres (S-IgG and NtAb) were significantly lower compared with HCs. Humoral response (S-IgG and NtAb) was significantly hampered by treatment with MTX. Cellular response was lacking in 30% of patients with GCA (vs 0% in HCs; P < 0.0001). Cellular response was significantly influenced by the levels of baseline peripheral T-lymphocytes and by glucocorticoid treatment. Treatment with tocilizumab did not affect any level of the immune response elicited by vaccination. CONCLUSIONS: Although patients with GCA apparently achieve a robust antibody seroconversion, there is a significant impairment of the neutralizing activity. MTX significantly reduced all levels of the humoral response. Up to one-third of patients do not develop a cellular immune protection in response to COVID-19 vaccination.

Factors influencing patient-reported outcomes in ANCA-associated vasculitis: correlates of the Patient Global Assessment.

BACKGROUND: Patient-reported outcomes (PROs) are currently poorly integrated in the clinical evaluation of disease activity in patients with ANCA-associated vasculitis (AAV). OBJECTIVES: To assess the distribution of the Patient Global Assessment (PtGA) in patients with AAV in stable remission, and to identify correlates of PtGA; to assess the discordance between PtGA score and Physician Global Assessment (PhGA). METHODS: Patients with a diagnosis of AAV in stable remission (BVAS=0) and with a Physician Global Assessment (PhGA)=0 were included. The following PROs on a 0-100 visual analogue scale (VAS) were assessed: PtGA, fatigue, pain, general health, sleep quality, and chronic damage according to the patient's opinion. The Cragg Hurdle model was used to assess the predictors of PtGA. RESULTS: 65 patients were included, female 57%, mean age 61±12 years. Median disease duration 6 years (IQR 3-12). Vasculitis damage index (VDI) was 4.4±2.3. Despite having been classified as being in remission, PtGA was elevated in 37% of patients. The PtGA was not associated with older age, comorbidities, educational level, the type of AAV diagnosis, number of organ-systems involved, previous relapses, disease duration, nor higher VDI. Female sex was significantly associated with PtGA: 51% of female patients reported an elevated PtGA compared to 18% of males (p=0.009). PtGA significantly correlated with all the other assessed PROs. Pain and fatigue were the main determinants of an elevated PtGA. CONCLUSIONS: A significant proportion of patients with AAV considered to be in remission by the physician still declares to have persistent aspects of uncontrolled disease. PtGA is significantly influenced by pain and fatigue, which should receive more attention in the future assessment of patients with AAV.

Systemic vasculitis: one year in review 2022.

Systemic vasculitis are rare heterogeneous disorders potentially involving any organ and system with a relevant burden of mortality and comorbidity.As in the previous annual reviews of this series, in this review we will provide a critical digest of the most recent literature regarding pathophysiology, clinical manifestations, diagnostic tools and treatment options in small- and large-vessel vasculitis.

Ultrasound halo sign as a potential monitoring tool for patients with giant cell arteritis: a prospective analysis.

OBJECTIVES: To assess the sensitivity to change of ultrasound halo features and their association with disease activity and glucocorticoid (GC) treatment in patients with newly diagnosed giant cell arteritis (GCA). METHODS: Prospective study of patients with ultrasound-confirmed GCA who underwent serial ultrasound assessments of the temporal artery (TA) and axillary artery (AX) at fixed time points. The number of segments with halo and maximum halo intima-media thickness (IMT) was recorded. Time points in which >80% of patients were assessed were considered for analysis. Halo features at disease presentation and first relapse were compared. RESULTS: 49 patients were assessed at 354 visits. Halo sensitivity to change was assessed at weeks 1, 3, 6, 12 and 24 and showed a significant standardised mean difference between all time points and baseline for the TA halo features but only after week 6 for the AX halo features. The number of TA segments with halo and sum and maximum TA halo IMT showed a significant correlation with erythrocyte sedimentation rate (0.41, 0.44 and 0.48), C reactive protein (0.34, 0.39 and 0.41), Birmingham Vasculitis Activity Score (0.29, 0.36 and 0.35) and GC cumulative dose (-0.34, -0.37 and -0.32); no significant correlation was found for the AX halo features. Halo sign was present in 94% of first disease relapses but with a lower mean number of segments with halo and sum of halo IMT compared with disease onset (2.93±1.59 mm vs 4.85±1.51 mm, p=0.0012; 2.01±1.13 mm vs 4.49±1.95 mm, p=0.0012). CONCLUSIONS: Ultrasound is a useful imaging tool to assess disease activity and response to treatment in patients with GCA.

Impact of Anti-Citrullinated Protein Antibodies on Progressive Systemic Bone Mineral Density Loss in Patients With Early Rheumatoid Arthritis After Two Years of Treat-to-Target.

Objectives: To investigate the association of anti-citrullinated protein antibodies (ACPA) with changes in systemic bone mineral density (BMD) in patients with early rheumatoid arthritis (RA) after two years of treat-to-target. Methods: BMD was measured at the lumbar spine (LS) and femoral neck (FN) in 100 patients with recent onset RA at baseline and after 24 months of treatment aimed at low disease activity (LDA) according to the 28-joints disease activity score (DAS28 <3.2). Multivariable regression analyses were performed to determine independent associations between autoantibodies and other disease and treatment-related parameters with BMD loss. Results: After 24 months, the majority of the patients were at least in LDA (78%), with slightly more ACPA-positive subjects achieving the target. The BMD had significantly decreased at both the LS (mean [SD] percent loss -1.8 [6.2], p=0.03) and the FN (-2.4 [7.3], p=0.03) in ACPA-positive but not in ACPA-negative patients. Consequently, the proportion of patients with reduced BMD (Z score ≤-1) after 24 months was significantly higher among ACPA-positive patients at both the spine (39.5% vs 19.3%, p=0.05) and the hip (37.2% vs 12.2%, p=0.007). The association between ACPA and BMD loss was independent of other variables including age, gender, disease activity, cumulative dose of glucocorticoids and duration of therapy with bisphosphonates at the LS but not the FN. Conclusions: ACPA are associated with ongoing BMD loss at the spine despite suppression of inflammation and adoption of prophylactic measures. ACPA-positive RA patients should be therefore strictly monitored for the development of osteoporosis.

One year in review 2021: systemic vasculitis.

Large- and small-vessel vasculitis are complex potentially life-threatening systemic autoimmune diseases that have recently been subjected to considerable immunologic and clinical research. Following the other reviews of this series, here we aim to summarise some of the most significant studies that have been recently published on the pathogenesis, clinical features and novel treatments of systemic vasculitis.

Anti-neutrophil cytoplasmic antibody specificity determines a different clinical subset in granulomatosis with polyangiitis.

OBJECTIVES: It has been suggested that anti-neutrophil cytoplasmic antibody (ANCA) specificity, rather than clinical diagnosis influences the phenotype and course of ANCA-associated vasculitis (AAV). However, preliminary evidence suggests that further combined levels of categorisation might be of clinical relevance. The aim of this study was to investigate differences in clinical presentation at disease onset and outcomes based on clinical diagnosis and ANCA specificity. METHODS: Newly diagnosed patients with GPA or MPA assessed in three referral centres between 2000 and 2016 were included. Patients were grouped as MPO-ANCA-positive granulomatosis with polyangiitis (MPO-GPA), PR3-ANCA-positive-GPA (PR3-GPA), and MPO-ANCA-positive microscopic polyangiitis (MPO-MPA). RESULTS: Of the 143 AAV patients included (female 52%), 87 were categorised as PR3-GPA, 23 as MPO-GPA, and 33 as MPO-MPA. Patients with MPO-GPA were significantly younger than MPA patients (age 49±15 versus 63±10; p<0.001). MPO-GPA had significantly more frequent subglottic stenosis compared to PR3-GPA. Ear, nose, throat involvement was significantly more frequent in both GPA groups compared to MPA. Type of pulmonary involvement differed between both GPA groups and MPA with diffuse pulmonary haemorrhage being significantly more frequent in the latter (7% in PR3-GPA, 0% in MPO-GPA, 27% in MPOMPA; p<0.001). Renal involvement was more frequent in MPO-MPA compared to both MPO-GPA and PR3-GPA (impaired renal function in 84%, 39%, and 36%, respectively; p<0.001). PR3-GPA relapsed significantly more than the other two groups. After adjusting for age, MPO-GPA was a significant risk factor for mortality [HR 4.44 (95%CI 1.46-13.52), p=0.009]. CONCLUSIONS: ANCA specificity identifies specific subsets of disease characterised by different clinical presentation and outcome within the clinical diagnosis of GPA.

Novel Therapies for ANCA-associated Vasculitis.

PURPOSE OF REVIEW: The purpose of this review is to discuss the most recent evidence on the treatment innovations and future prospective in the management of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAVs). RECENT FINDINGS: In AAV, a growing body of research is available on novel treatment options for remission induction and to clarify some uncertainties concerning the optimal use of available drugs. Efforts are being made to reduce the toxicity associated with high-dose, prolonged glucocorticoids (GC) regimens. Despite major advances in the prognosis of AAV, relapses are still common and the intensity and duration of remission treatment constitute a great challenge in the management of these chronic conditions. A paradigm shift in practice in the management of AAV is being supported by recent evidence suggesting the comparable efficacy and improved safety profile of schemes with a reduced dose of GC for the induction and maintenance of remission in patients with severe granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA). Moreover, recent appraisal of pathogenetic mechanisms, including complement activation pathways, has introduced the revolutionary concept of an alternative to GC, such as avacopan. Plasma exchange failed to prevent end-stage renal disease and mortality in patients with severe renal involvement or pulmonary haemorrhage according to a large multicentre randomised trial. Intensified immunosuppressive strategies for patients with life-threatening manifestations, including the combination of rituximab (RTX) with cyclophosphamide (CYC) have revealed promising preliminary data. New evidence for the use of alternative immunosuppressive agents (e.g. mycophenolate mofetil or abatacept) for the induction of remission in patients with non-severe disease is emerging. Several studies have been recently published, or are ongoing, to assess the optimal strategy and duration of maintenance of remission with the available treatment options (GC, azathioprine, and RTX). Preliminary evidence supports the superiority of a more prolonged course of maintenance treatment. The management of refractory or relapsing eosinophilic granulomatosis with polyangiitis (EGPA) has been improved by the recent demonstration of efficacy and safety of an interleukin-5 inhibitor, mepolizumab. Ongoing randomised studies will clarify the role of RTX in patients with severe manifestations of EGPA.