A real-world assessment of mycophenolate mofetil for remission induction in eosinophilic granulomatosis with polyangiitis.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a form of ANCA-associated vasculitis (AAV). Clinical trials demonstrating the efficacy of mycophenolate mofetil (MMF) for remission induction in AAV excluded patients with EGPA. Despite this, MMF is commonly used in these patients. The objective of this study was to evaluate, for the first time, the effectiveness and tolerance of MMF in EGPA remission induction. A retrospective, two-center, real-world study was conducted in patients with EGPA who received MMF in addition to prednisolone for newly diagnosed or relapsing disease between 2009 and 2019. Baseline, 3-, 6- and 12-month outcome data were extracted from electronic health records. The primary outcome was disease remission, defined as a Birmingham Vasculitis Activity Score of 0 at 6 months. Secondary outcomes included disease relapse, median prednisolone dose at 12 months and drug tolerance. In total, 15 patients (73% male, median age 57) with EGPA (11 newly diagnosed/4 relapsing) were identified. At 6 months, 67% had achieved disease remission. At 12 months, this was maintained (66.7%) and 4 patients had relapsed. All but one patient remained on MMF at study completion and all patients tolerated MMF. Our real-world data suggest that MMF is an effective and well-tolerated agent for achieving disease remission in EGPA. A future randomized controlled trial of MMF in this neglected orphan disease is now warranted.

Evaluation of adjunctive mycophenolate for large vessel giant cell arteritis.

OBJECTIVES: GCA patients with large vessel involvement (LV-GCA) experience greater CS requirements and higher relapse rates compared with classical cranial GCA. Despite the distinct disease course, interventions in LV-GCA have yet to be investigated specifically. This study aimed to evaluate the CS-sparing effect and tolerability of first-line mycophenolate in LV-GCA. METHODS: A retrospective cohort study was conducted in patients with LV-GCA identified from a regional clinical database between 2005 and 2019. All cases were prescribed mycophenolate derivatives (MYC; MMF or mycophenolic acid) at diagnosis and were followed up for ≥2 years. The primary outcome was the cumulative CS dose at 1 year. Secondary outcomes included MYC tolerance, relapse rates and CRP levels at 1 and 2 years. RESULTS: A total of 37 patients (65% female; mean age 69.4 years, SD 7.9 years) were identified. All cases demonstrated large vessel involvement via CT/PET (n = 34), CT angiography (n = 5) or magnetic resonance angiography (n = 2). After 2 years, 31 patients remained on MYC, whereas 6 had switched to MTX or tocilizumab owing to significant disease relapse. The mean (±SD) cumulative prednisolone dose at 1 year was 4960 (±1621) mg. Relapse rates at 1 and 2 years were 16.2 and 27%, respectively, and CRP levels at 1 and 2 years were 4 [interquartile range (IQR) 4-6] and 4 (IQR 4-4) mg/l, respectively. CONCLUSION: To our knowledge, this is the first attempt to assess the effectiveness of any specific agent in LV-GCA. MYC might be both effective in reducing CS exposure and well tolerated in this subpopulation. A future randomized controlled trial is warranted.

Stratified glucocorticoid monotherapy is safe and effective for most cases of giant cell arteritis.

OBJECTIVES: High-dose glucocorticoids anchor standard care in GCA but are associated with significant toxicity. We aimed to evaluate the safety and effectiveness of a stratified approach to glucocorticoid tapering. The strategy aggressively reduced glucocorticoid doses in those manifesting an adequate early response to treatment, with a view to minimizing glucocorticoid complications. METHODS: A retrospective, population-based study of GCA was performed. All cases were confirmed by temporal artery biopsy between November 2010 and November 2015. Baseline and outcome data were extracted from secondary and primary care records at diagnosis and 1 year follow-up. The primary outcome was loss of vision. Secondary outcomes included remission and relapse rates and CS-related complications. RESULTS: The cohort consisted of 73 patients (76% female; mean age 73.5 years, s.d. 7.6 years). At presentation, a reduction in visual acuity was recorded in 17 patients (22.3%). The median CRP at diagnosis was 69.5 mg/l [interquartile range (IQR) 40.5-101 mg/l], with a median ESR of 80 mm/h (IQR 60-91 mm/h). At 1 year, remission was achieved in 64 patients (87.7%), whereas 10 patients (13.7%) relapsed. A single patient sustained visual loss after initiation of therapy. The median CRP at 1 year was 4 mg/l (IQR 4-9.5 mg/l) and the mean prednisolone dose was 5.4 mg (0-15 mg). CS-related complications were observed in 10 patients (13.7%). CONCLUSION: A stratified approach to CS tapering appeared safe and effective in GCA. It was associated with a high rate of remission and promisingly low rates of relapse at 1 year follow-up. These real-world data indicate that glucocorticoid exposure can be minimized safely in some patients with GCA.

Correction to: Late-onset Pneumocystis jirovecii pneumonia (PJP) in patients with ANCA-associated vasculitis.

The family name of the corresponding author on the original version of this article was incorrectly spelled as "Mariana Philipos".

Intravenous pulse methylprednisolone for induction of remission in severe ANCA associated Vasculitis: a multi-center retrospective cohort study.

BACKGROUND: Intravenous pulse methylprednisolone (MP) is commonly included in the management of severe ANCA associated vasculitis (AAV) despite limited evidence of benefit. We aimed to evaluate outcomes in patients who had, or had not received MP, along with standard therapy for remission induction in severe AAV. METHODS: We retrospectively studied 114 consecutive patients from five centres in Europe and the United States with a new diagnosis of severe AAV (creatinine > 500 µmol/L or dialysis dependency) and that received standard therapy (plasma exchange, cyclophosphamide and high-dose oral corticosteroids) for remission induction with or without pulse MP between 2000 and 2013. We evaluated survival, renal recovery, relapses, and adverse events over the first 12 months. RESULTS: Fifty-two patients received pulse MP in addition to standard therapy compared to 62 patients that did not. There was no difference in survival, renal recovery or relapses. Treatment with MP associated with higher risk of infection during the first 3 months (hazard ratio (HR) 2.7, 95%CI [1.4-5.3], p = 0.004) and higher incidence of diabetes (HR 6.33 [1.94-20.63], p = 0.002), after adjustment for confounding factors. CONCLUSIONS: The results of this study suggest that addition of pulse intravenous MP to standard therapy for remission induction in severe AAV may not confer clinical benefit and may be associated with more episodes of infection and higher incidence of diabetes.

Metabolic and Structural Skeletal Muscle Health in Systemic Lupus Erythematosus-Related Fatigue: A Multimodal Magnetic Resonance Imaging Study.

OBJECTIVE: To investigate the potential structural and metabolic role of skeletal muscle in systemic lupus erythematosus (SLE)-related fatigue. METHODS: A case-control, multimodal magnetic resonance imaging (MRI) study was conducted. Cases were patients with inactive SLE who reported chronic fatigue. Controls were age- and sex-matched healthy members of the general population. Patients were clinically characterized and then underwent a 3T whole-body MRI scan. Resting and dynamic 31 P MRI spectroscopy of the calf muscles was applied, from which phosphocreatine (PCr) recovery halftime, a marker of mitochondrial dysfunction, was computed. In addition, microstructural sequences (T1-weighted anatomic images, T2 mapping, and diffusion tensor imaging) were acquired. Descriptive statistics evaluated group differences and within-case physical fatigue correlations were explored. RESULTS: Of the 37 recruits (mean age 43.8 years, 89.2% female), cases (n = 19) reported higher levels of physical fatigue, pain, depression, and sleep disturbance compared to the control group (P < 0.0001). PCr was greater (P = 0.045) among cases (mean ± SD 33.0 ± 9.0 seconds) compared to controls (mean ± SD 27.1 ± 6.6 seconds). No microstructural group differences were observed. Within cases, physical fatigue did not correlate with PCr (r = -0.28, P = 0.25). CONCLUSION: We report preliminary data demonstrating greater skeletal muscle mitochondrial dysfunction among fatigued patients with SLE compared to healthy controls.

Correction to: Late-onset Pneumocystis jirovecii pneumonia (PJP) in patients with ANCA-associated vasculitis.

The family name of the corresponding author on this article was incorrectly spelled as "El Hakem Matraiah". The correct spelling should have been "El Hakem Metraiah". This is now presented correctly in this article.

Late-onset Pneumocystis jirovecii pneumonia (PJP) in patients with ANCA-associated vasculitis.

Immunosuppression in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is complicated by increasing risk of infections including opportunistic infections like Pneumocystis jirovecii pneumonia (PJP). Available evidence on risk factors and indications for prophylaxis in AAV is derived from PJP occurring early in the course of AAV. In this retrospective study, we characterized the profile of PJP in patients with AAV. PJP cases were identified retrospectively based on positive polymerase chain reaction test from electronic record followed by confirmation from medical records over a 10-year period. AAV patients without PJP over the same period were used as control group. Sixteen PJP+AAV+ were identified; in 14 of them, we were able to confirm they received PJP prophylaxis during induction therapy, while in two cases, data were missing. The onset of the infection was after 6 months from AAV diagnosis in 80% of cases. Escalations in immunosuppression prior to PJP were observed in six cases within 3 months prior to PJP onset. Overall mortality was 12.5%. By univariate analysis, renal involvement at AAV diagnosis was associated with PJP. These results indicate that PJP is not limited to the first 6 months following AAV diagnosis. Late-onset infection can occur in context of augmented immunotherapy, particularly with concurrent lymphopenia. Other risk factors that can independently predict late-onset PJP remain to be identified.

Additional Improvements in Clinical Response From Adjuvant Biologic Response Modifiers in Adults With Moderate to Severe Systemic Lupus Erythematosus Despite Immunosuppressive Agents: A Systematic Review and Meta-analysis.

PURPOSE: The role of biologic disease-modifying drugs in patients with systemic lupus erythematosus (SLE) remains controversial. METHODS: Following systematic review and meta-analysis protocol, we searched PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov in January 2017 to identify all studies of people with SLE treated with biologic response modifiers. We performed direct frequentist random effects meta-analyses, calculated pooled relative risk and number needed to treat to achieve an outcome in 1 patient (NNT) as reciprocal to statistically significant absolute risk difference, and graded the quality of evidence by using the Grading of Recommendations Assessment, Development, and Evaluation criteria. FINDINGS: Seven meta-analyses, 33 publications of randomized controlled trials (RCTs), and 5 observational studies met inclusion criteria. All studies enrolled previously treated adults with moderate to severe SLE despite conventional immunosuppression. In patients with extrarenal SLE, adjunctive belimumab (10 mg/kg) increases the rates of clinical response (moderate quality evidence from 2 RCTs, 1125 patients, NNT = 8 [95% CI, 6-16]), whereas adjunctive rituximab or abatacept are ineffective. In adults with lupus nephritis, adjunctive rituximab (4000 mg, very-low-quality evidence from 1 RCT, 144 patients, NNT = 5 [95% CI, 3-18]), but not abatacept, improves renal function. Belimumab and rituximab do not increase the risk of serious intolerable adverse effects leading to treatment discontinuation. Rigerimod, blisibimod, sifalimumab, and anifrolumab show promising results in early RCTs, whereas epratuzumab and tabalumab have an unfavorable benefit-to-harm balance. IMPLICATIONS: In adults with moderate to severe SLE despite conventional immunosuppressive agents, adjunctive belimumab in extrarenal SLE and off-label rituximab in lupus nephritis may offer additional modest benefits.

Environmental risk factors in systemic sclerosis.

PURPOSE OF REVIEW: Environmental risk factors have been implicated in the pathogenesis of systemic sclerosis (SSc). Recent evidence further supports this relationship and constitutes the focus of this review article. RECENT FINDINGS: Exposure to silica through various occupations remains one of the main environmental risk factors for SSc. Emerging evidence has also implicated organic solvents in the development of this difficult-to-manage condition. The individual role of these toxins is, however, difficult to ascertain due to methodological limitations in study design. Other occupational agents, such as epoxy resins, welding fumes and hand-arm vibration, have been investigated, but no definitive associations may be made due to small sample sizes. The controversial association between silicone breast surgery and SSc has not been proven and, amongst other non-occupational factors, smoking does not increase the risk of development but does appear to impact upon the severity of disease. SUMMARY: A number of environmental exposures are likely to play an important role in the development of the disease; however, current evidence consists mainly of heterogeneous studies with relatively small sample sizes. In the future, multicentre collaborations may help inform preventive strategies.

Fatigue: a principal contributor to impaired quality of life in ANCA-associated vasculitis.

OBJECTIVES: To describe quality of life (QoL) in an ANCA-associated vasculitis (AAV) cohort and make comparisons with a general population sample. In addition, we aimed to take preliminary steps to identify potential disease and psycho-social factors which may determine QoL impairment. METHODS: A population-based case-control study was designed. All AAV patients resident in Grampian, Scotland, were invited to participate as cases. Controls were identified from a random sample of persons registered with four local general practices. Participants completed a questionnaire comprising validated generic and symptom-specific tools in the assessment of QoL. In addition, all cases were clinically assessed and putative disease factors recorded. Cases and controls were compared and, in addition, disease and psycho-social associations were explored for identified QoL impairments. RESULTS: In total, 74/90 (82%) cases and 781/2000 (39%) controls participated. Cases reported a significant impairment in physical health (P < 0.0001), but not mental health (P = 0.85), compared with controls, as measured by Short Form-8 (SF-8). Following adjustment for age and sex, persons with AAV were more than twice as likely to report mild/moderate fatigue [odds ratio (OR) 2.0; 95% CI 1.1, 3.8] or severe fatigue (OR 2.5; 95% CI 1.4, 4.5) compared with controls. Furthermore, among cases, fatigue was found to be strongly associated with impaired physical health (P < 0.0001), while disease factors such as disease activity and damage were not (P = 0.60 and 0.27, respectively). CONCLUSIONS: Patients with AAV report impaired physical but not mental health. Specifically, fatigue is a principal complaint and appears to be a major determinant of impaired QoL.