Christian Pagnoux

Is there a place for cyclophosphamide in the treatment of giant-cell arteritis? A case series and systematic review

OBJECTIVE To report on the effectiveness of cyclophosphamide (CYC) to treat glucocorticoid (GC)-dependent giant-cell arteritis (GCA) and/or severe GC-related side effects. METHODS Fifteen patients with GCA and treated with CYC were retrieved from the computerized patient-record system. Glucocorticoid dependence was defined as a prednisone dose of >20mg/day for 6 months or >10mg/day for 1 year in order not to relapse. Response to CYC was defined as improved clinical and biological findings. Remission was defined as a sustained absence (>12 months) of active signs of vasculitis at a daily GC dose of <7.5mg. A literature review searched PubMed for all patients diagnosed with GCA and who received CYC. RESULTS Our 15 patients responded to monthly pulses of CYC, and all experienced a GC-sparing effect, including five patients who discontinued GC long term. At a median follow-up of 43 (range: 14-75) months after CYC, nine (53%) patients were still in remission and six (40%) had relapsed at 6 (3-36) months after the last CYC infusion. Twelve (80%) patients experienced side effects, leading to discontinuation of CYC in two (13%). A literature review retrieved 88 patients who received CYC: 66 for GC-dependent disease, 53 for GC toxicity, and 14 for severe organ involvement. Their median follow-up time was 24 (4-60) months. Among the 88 patients, 74 (84%) were responsive to CYC and 17 (19%) relapsed, although all were receiving a maintenance therapy with immunosuppressive agents (such as methotrexate). Twenty-nine (33%) patients experienced side effects and 11 (12.5%) discontinued treatment. CONCLUSION Cyclophosphamide is an interesting option for GCA patients with GC-dependent disease or with severe GC-related side effects, especially when conventional immunosuppressive agents have failed.

Treatment of granulomatosis with polyangiitis (Wegener's)

Granulomatosis with polyangiitis is a systemic necrotizing vasculitis characterized by granulomatous inflammation of small vessels and is associated with autoantibodies to neutrophil cytoplasmic proteases, mainly proteinase 3. Potentially lethal if not promptly diagnosed and treated, most patients with granulomatosis with polyangiitis can achieve remission with the current treatment modalities, with fewer side effects compared to three decades ago. However, the risk of relapse remains high, necessitating prolonged maintenance immunosuppressive therapy whose optimal duration remains undetermined. We review herein the treatment modalities for granulomatosis with polyangiitis and how they have evolved over the past decades. The findings of the most important and recently completed therapeutic studies, including on rituximab for maintenance, are summarized, before describing the main ongoing studies aimed at further optimizing treatment strategies.

Optimal therapy and prospects for new medicines in eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome).

ABSTRACT Introduction: The prevalence of eosinophilic granulomatosis with polyangiitis (EGPA; previously known as Churg-Strauss syndrome) is lower than that of other antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAV’s), and only a few randomized controlled trials have been conducted for this rare disease. However, recent international efforts have helped delineate the best treatment approach. Areas covered: At present, EGPA conventional therapy is by default similar to that of other AAVs. Limited, non-severe EGPA can initially be treated with glucocorticoids (GCs) alone. Patients with life-threatening manifestations and/or major organ involvement must receive a combination of GCs and an immunosuppressant, mainly cyclophosphamide. Remission can be achieved in >85% of patients with these first-line treatments, but vasculitis relapses occur in more than one-third of patients, and about 85% cannot stop GC treatment because of GC-dependent asthma and/or ENT manifestations. A few biologic agents, including rituximab or mepolizumab, are now under investigation after interesting preliminary results. Expert commentary: Treatment for EGPA still has several unmet needs. Several biologic agents are now under investigation in randomized controlled trials, but a few others should be considered soon. Their benefit should be demonstrated for devising more EGPA-tailored therapeutic strategies (ideally GC-free).

Eosinophilic Granulomatosis with Polyangiitis (Churg–Strauss Syndrome)

Eosinophilic granulomatosis with polyangiitis (EGPA; Churg–Strauss syndrome) is a rare, systemic, necrotizing, small-sized vessel vasculitis. It most typically affects middle-aged individuals who have developed late-onset asthma then more characteristic vasculitis manifestations, like fever, skin lesions (40–75 % of the patients, mainly purpura, often necrotic, and/or cutaneous nodules or papules and sometimes migratory urticarial rashes) and/or mononeuritis multiplex. Blood and tissue eosinophilia, especially the lungs, gastrointestinal tract, and heart, is a hallmark of the disease. Biopsy of an affected organ or lesions, especially skin lesions, can help in making the diagnosis, when showing eosinophilic and/or granulomatous vasculitis, with or without necrosis. Antineutrophil cytoplasm autoantibodies (ANCA) can be detected in nearly 40 % of the patients. Differential diagnoses include drug-induced and hypersensitivity vasculitis, parasitic infections, and hypereosinophilic syndromes. Treatment relies on systemic corticosteroids, combined with an immunosuppressant for severe and/or life-threatening forms.

Patient Outcomes in Renal-Limited Antineutrophil Cytoplasmic Antibody Vasculitis With Inactive Histology

Introduction Little is known about the anticipated disease course for individuals who present with renal-limited antineutrophil cytoplasmic antibody (ANCA)−associated vasculitis but who lack inflammation on a kidney biopsy. The impact of immunosuppression on renal and overall survival is unknown. Methods Patients were recruited from 2005 to 2016 from 8 centers worldwide (N = 16) for this descriptive study. All had positive ANCA, elevated serum creatinine with active urine sediment, histologic evidence of pauci-immune glomerulonephritis without active lesions, and had no evidence of extrarenal vasculitis. We describe the characteristics of this cohort and the differences in the clinical, histologic, and therapeutic parameters of those who developed primary outcomes of end-stage renal disease (ESRD) and vasculitis relapse. Results The cohort was 63% Caucasian, and 75% were men, with a median age of 62 years. At entry, the mean ± SD estimated glomerular filtration rate (eGFR) was 24 ± 20 ml/min per 1.73 m2, and 5 patients required dialysis. Twelve patients received immunosuppressive therapy, 25% experienced disease relapse, and 38% developed ESRD. Patients who developed ESRD had lower baseline eGFRs (8 ± 5 ml/min per 1.73 m2 vs. 35 ± 18 ml/min per 1.73 m2; P = 0.001) and more often required dialysis at presentation (83% vs. 0%; P = 0.001). Patients who relapsed were less likely to receive immunosuppression (25% for the relapsed group vs. 92% for the nonrelapsed group; relative risk: 0.27, risk difference: 67%; P = 0.03). Conclusion Among these patients, lower initial eGFR and dialysis dependence at presentation might increase the risk for ESRD. Immunosuppression did not affect renal outcomes in this sample of patients but was associated with a reduced risk for vasculitis relapse. More information is needed on factors that predict treatment response in this high-risk group.

Comparisons of Guidelines and Recommendations on Managing Antineutrophil Cytoplasmic Antibody–Associated Vasculitis

Antineutrophil cytoplasmic antibodies−associated vasculitis (AAV) is associated with high morbidity or mortality, especially if not promptly diagnosed and treated. Many inroads have been made in the understanding of the pathophysiology that leads to exploration of novel therapies. Randomized controlled trials over the last 2 decades have better delineated and expanded therapeutic options and set the stage for an evidence-based approach. Since 2014, 4 scientific societies have systematically reviewed the existing data and have formulated evidence-based recommendations for the management of AAV. These recommendations cover diagnosis, remission induction and maintenance treatment, and prevention of long-term complications. This review is a comparative analysis of the recently published recommendations of the European League Against Rheumatism/European Renal Association-European Dialysis and Transplant Association, the British Society of Rheumatology, the Canadian Vasculitis Research Network, and the Brazilian Society of Rheumatology, and aims to determine common ground among them and highlights the differences among the recommendations.

Catastrophic primary angiitis of the central nervous system

Different presentations and trajectories have been identified in patients with primary angiitis of the central nervous system (PACNS) [1–3]. Data are scarce on PACNS patients presenting with ‘catastrophic’ presentations. In a French PACNS cohort of 102 patients [2,3], 11 (11%) were admitted to the intensive care unit (ICU) for mechanical ventilation in the setting of a vigilance deterioration in 10 patients and respiratory distress in a patient with a medullar and brainstem involvement. Median onset to ICU admission delay was 4 days (1 15). All patients underwent brain magnetic resonance imaging (MRI), including eight who showed multiple bilateral acute ischaemic lesions (≥ 3 cerebral infarcts in different vascular territories) along with cerebral edema. Seven patients underwent a cerebral biopsy that was positive in four patients. The seven other patients had demonstration of multiple vascular narrowings on neurovascular imaging [digital subtraction angiography in five and 3 T magnetic resonance angiography (MRA) in two], abnormal cerebrospinal fluid (CSF) analysis and a complete negative work-up. Intravenous pulses of methylprednisolone were administered in all patients followed by daily doses of intravenous or oral glucocorticoids at 1 mg/kg. Concomitant intravenous infusions of cyclophosphamide were also started. Three patients died within the first 2 months (due to neurological deterioration in two and infection in one). Survivors evolved favorably under treatment. They all discontinued their PACNS treatment at last visit and showed improvement on repeat brain MRI/MRA. Compared to the 91 other PACNS patients from the cohort, catastrophic PACNS patients more probably presented with impaired vigilance (P < 0.001) and died (P = 0.01). CSF analysis showed higher protein levels in patients with catastrophic PACNS (P = 0.003). At last follow-up, both groups of patients had received similar treatments (no difference in induction treatment or management of glucocorticoids) and did not show different disability statuses. Patients with catastrophic PACNS, as defined and described in our study, may represent up to a tenth of patients with PACNS. Treatment should probably combine glucocorticoids and an immunosuppressant. After the first few weeks, which are associated with a higher mortality rate, global outcomes can still be favorable and not different from those of patients with less severe PACNS presentations.

Granulomatosis with Polyangiitis (Wegener’s Granulomatosis)

Granulomatosis with polyangiitis (formerly, Wegener’s granulomatosis) is a systemic necrotizing and granulomatous vasculitis predominantly affecting small-sized vessels. It is also one of the three vasculitides associated with anti-neutrophil cytoplasm antibodies (ANCA). The incidence rate is 2–12 cases per year and the prevalence 23–160 cases per million population. The cause remains unknown, but the pathophysiological mechanisms are being progressively defined. Disease onset can occur at any age, most commonly about 40–50 years. The main clinical characteristics include manifestations in the upper respiratory tract (erosive rhinitis and sinusitis, saddle-nose deformity), lungs (nodules, alveolar hemorrhage) and/or kidney. Biopsy of an affected organ can support the diagnosis, as can detection in serum of ANCA with a cytoplasmic labelling pattern (cANCA) by immunofluorescence and proteinase 3 (PR3) specificity by ELISA. Current therapy, based on a staged induction–maintenance strategy, can achieve remission in most patients. However, the toxicity of conventional treatment and relapse rate remain high, which calls for diligent efforts to further optimize therapy. Rituximab is now an alternative to cyclophosphamide, which increases the therapeutic armamentarium for inducing remission, but the optimal subsequent maintenance strategy remains to be defined. Refractory and/or relapsing diseases, as well as several morbidities, such as subglottic stenoses, continue to be challenges.

Dermatologic Manifestations of Granulomatosis with Polyangiitis (Wegener’s Granulomatosis)

Granulomatosis with polyangiitis (Wegener’s granulomatosis; GPA) is a small-sized vessel ANCA-associated vasculitis. Dermatologic lesions may be the initial manifestations (8–13 %) or occur later during the course of the disease (12–67 % of the patients). Most frequent skin manifestations include purpura, mainly on the lower limbs, sometimes necrotic, papulonecrotic lesions, subcutaneous nodules, livedo reticularis, mucosal and skin ulcerations or ulcers, and gangrene. Hypertrophic gingivitis is another rare but suggestive manifestation. On histology, purpura is usually secondary to leukocytoclastic vasculitis, whereas papulonecrotic lesions and ulcerations correspond to leukocytoclastic or granulomatous vasculitis involving small vessels or extravascular granuloma(s). Small nodules mainly reflect necrotizing vasculitis involving medium-sized arterioles of the deep dermis or hypodermis that may be suggestive of polyarteritis nodosa for the pathologist.