Updates for the treatment of EGPA.

Eosinophilic granulomatosis with polyangiitis (EGPA, formerly Churg-Strauss syndrome) is the least frequent antineutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). Major advances of our knowledge on its pathophysiology have revealed features of both AAV and eosinophilic disorders. The development of targeted biotherapies for both diseases opened new possibilities for EGPA management. In this review, we highlight the rationale underlying the routine treatment strategy, which relies mainly on corticosteroids, with immunosuppressant adjunction for severe disease. However, novel therapies are still needed for refractory/relapsing disease and to alleviate the corticosteroid-dependence of asthma and chronic rhinosinusitis. At present, the most promising biotherapies target either eosinophil biology, like mepolizumab, an anti-interleukin-5, or the B-cell compartment, with rituximab. Recent clinical data on new treatment options are discussed and therapeutic strategies are proposed.

ANCA-associated vasculitides: Recommendations of the French Vasculitis Study Group on the use of immunosuppressants and biotherapies for remission induction and maintenance.

Treatment of vasculitides associated with anti-neutrophil cytoplasm antibodies (ANCA) (AAVs) has evolved dramatically in recent years, particularly since the demonstration of rituximab efficacy as remission induction and maintenance therapy for granulomatosis with polyangiitis and microscopic polyangiitis. In 2013, the French Vasculitis Study Group (FVSG) published recommendations for its use by clinicians. Since then, new data have made it possible to better specify and codify prescription of rituximab to treat AAVs. Herein, the FVSG Recommendations Committee, an expert panel comprised of physicians with extensive experience in the treatment and management of vasculitides, presents its consensus guidelines based on literature analysis, the results of prospective therapeutic trials and personal experience.

Treatment of primary systemic necrotizing vasculitides: the role of biotherapies.

Treatments of systemic necrotizing vasculitides have progressed markedly over the past few decades. The first attempts to obtain better-adapted therapeutic strategies evaluated the indications of conventional drugs, and their abilities to prolong survival and prevent relapses, while decreasing the severity and number of side effects. The French Vasculitis Study Group, the European Vasculitis Study Group or the Vasculitis Clinical Research Consortium organized most of the prospective clinical trials that have contributed to optimizing targeted treatment strategies. Recent therapeutic strategies include: immunomodulating methods (e.g. plasma exchanges), products (e.g. intravenous immunoglobulins) or, more recently, new agents called biotherapies. Some of the latter, mainly anti-CD20 monoclonal antibodies, have achieved promising effects and are now being evaluated in prospective trials.

Proteinase 3, the autoantigen in granulomatosis with polyangiitis, associates with calreticulin on apoptotic neutrophils, impairs macrophage phagocytosis, and promotes inflammation.

Proteinase 3 (PR3) is the target of anti-neutrophil cytoplasm Abs in granulomatosis with polyangiitis, a form of systemic vasculitis. Upon neutrophil apoptosis, PR3 is coexternalized with phosphatidylserine and impaired macrophage phagocytosis. Calreticulin (CRT), a protein involved in apoptotic cell recognition, was found to be a new PR3 partner coexpressed with PR3 on the neutrophil plasma membrane during apoptosis, but not after degranulation. The association between PR3 and CRT was demonstrated in neutrophils by confocal microscopy and coimmunoprecipitation. Evidence for a direct interaction between PR3 and the globular domain of CRT, but not with its P domain, was provided by surface plasmon resonance spectroscopy. Phagocytosis of apoptotic neutrophils from healthy donors was decreased after blocking lipoprotein receptor-related protein (LRP), a CRT receptor on macrophages. In contrast, neutrophils from patients with granulomatosis with polyangiitis expressing high membrane PR3 levels showed a lower rate of phagocytosis than those from healthy controls not affected by anti-LRP, suggesting that the LRP-CRT pathway was disturbed by PR3-CRT association. Moreover, phagocytosis of apoptotic PR3-expressing cells potentiated proinflammatory cytokine in vitro by human monocyte-derived macrophages and in vivo by resident murine peritoneal macrophages, and diverted the anti-inflammatory response triggered by the phagocytosis of apoptotic cells after LPS challenge in thioglycolate-elicited murine macrophages. Therefore, membrane PR3 expressed on apoptotic neutrophils might amplify inflammation and promote autoimmunity by affecting the anti-inflammatory "reprogramming" of macrophages.

Urogenital manifestations in Wegener granulomatosis: a study of 11 cases and review of the literature.

We describe the main characteristics and treatment of urogenital manifestations in patients with Wegener granulomatosis (WG). We conducted a retrospective review of the charts of 11 patients with WG. All patients were men, and their median age at WG diagnosis was 53 years (range, 21-70 yr). Urogenital involvement was present at onset of WG in 9 cases (81%), it was the first clinical evidence of WG in 2 cases (18%), and was a symptom of WG relapse in 6 cases (54%). Symptomatic urogenital involvement included prostatitis (n = 4) (with suspicion of an abscess in 1 case), orchitis (n = 4), epididymitis (n = 1), a renal pseudotumor (n = 2), ureteral stenosis (n = 1), and penile ulceration (n = 1). Urogenital symptoms rapidly resolved after therapy with glucocorticoids and immunosuppressive agents. Several patients underwent a surgical procedure, either at the time of diagnosis (n = 3) (consisting of an open nephrectomy and radical prostatectomy for suspicion of carcinoma, suprapubic cystostomy for acute urinary retention), or during follow-up (n = 3) (consisting of ureteral double J stents for ureteral stenosis, and prostate transurethral resection because of dysuria). After a mean follow-up of 56 months, urogenital relapse occurred in 4 patients (36%). Urogenital involvement can be the first clinical evidence of WG. Some presentations, such as a renal or prostate mass that mimics cancer or an abscess, should be assessed to avoid unnecessary radical surgery. Urogenital symptoms can be promptly resolved with glucocorticoids and immunosuppressive agents. However, surgical procedures, such as prostatic transurethral resection, may be mandatory in patients with persistent symptoms.

The scleroderma kidney: progress in risk factors, therapy, and prevention.

Scleroderma renal crisis (SRC) is characterized by malignant hypertension, oliguric/anuric acute renal failure, and important mortality, with a 5-year survival rate of 65%. SRC occurs in 2% to 5% of patients with systemic sclerosis (SSc), particularly those with diffuse cutaneous SSc in the first years of disease evolution. Several retrospective studies have found high-dose corticosteroid therapy to be associated with increased risk of SRC, and anti-RNA-polymerase III antibodies have been detected in one third of patients with SRC. Treatment relies on the early control of blood pressure with increasing doses of angiotensin-converting enzyme inhibitors, eventually associated with calcium channel blockers together with dialysis if necessary. After 2 years on dialysis, eligible patients should be considered for renal transplantation. The strategy for prevention of SRC lacks consensus. However, corticosteroids and/or nephrotoxic drugs should be avoided in patients with diffuse cutaneous SSc.

[Treatment of ANCA-associated vascularitides]. / Traitement des vascularites systémiques associées aux ANCA.

Treatment for ANCA-associated vasculitides is now well defined, but must be adjusted for each patient according to the type of vasculitis, its precise form (e.g., limited versus systemic Wegener's granulomatosis) and severity, and patients' characteristics, such as age and renal function. The therapeutic decision must also take into account the risk of adverse events inherent to each treatment. The efficacy of adequate induction treatment has been demonstrated: more than 80% of patients now achieve remission. Relapse rates nonetheless remain high, especially in Wegener's granulomatosis. Patients with microscopic polyangiitis or Churg-Strauss syndrome with no poor prognostic factors can be treated with corticosteroids alone, with immunosuppressants added only in case of treatment failure. Patients with Wegener's granulomatosis or microscopic polyangiitis or Churg-Strauss syndrome and one or more poor prognostic factors must receive a combination of corticosteroids and immunosuppressants, mainly intravenous pulsed cyclophosphamide. Plasma exchange is indicated as an adjuvant therapy for patients with severe renal involvement. Once remission is achieved, maintenance therapy can replace cyclophosphamide by a less toxic immunosuppressive drug, such as azathioprine or methotrexate. For these latter patients, the optimal duration of induction therapy remains to be determined, but should not be shorter than 18 months. Conversely, there is no need to prescribe high-dose corticosteroids for months. Prednisone must be started at 1 mg/kg/d then rapidly tapered so that patients are not receiving more than 15 mg/d after 3-4 months of therapy. Biological therapies also appear to have a place in the therapeutic armamentarium for ANCA-associated systemic vasculitides, at least for patients whose disease is refractory to conventional therapy. However, the precise indications for anti-TNFalpha or anti-CD20 monoclonal antibodies and their optimal regimens (doses and durations) have not yet been defined. Anti-IL5, interferon-alpha and anti-IgE monoclonal antibodies might also be useful for Churg-Strauss syndrome. These biologics must be prescribed extremely cautiously and only in trial settings, especially in view of the adverse effects, few but severe, recently been reported with them.

Indications for biotherapy in systemic vasculitides.

Biotherapy now holds a specific place in the therapeutic armamentarium for systemic vasculitides. Such therapy includes cytokines, such as (pegylated) alpha-interferon for hepatitis B virus-related polyarteritis nodosa and hepatitis C virus-related cryoglobulinemic vasculitis, and polyvalent immunoglobulin (IVIg), with well-defined indications and pending positive results. More specifically targeted monoclonal antibodies include antitumor necrosis factor-alpha or anti-CD20 for antineutrophil cytoplasmic antibody-associated vasculitides or anti-interleukin-5 and anti-IgE for Churg-Strauss syndrome. However, the exact indications of these latter new agents, as well as their optimal dosage and duration, are not defined. Therefore, they are prescribed mainly for patients with disease refractory to conventional therapy, in whom results are promising. Results of international ongoing trials will determine whether the agents may also have a place as first-line treatment.

[Microscopic polyangiitis]. / Polyangéite microscopique.

Microscopic polyangiitis was initially considered a "microscopic" form of polyarteritis nodosa and was not definitively distinguished from it until the Chapel Hill nomenclature (1994). Microscopic polyangiitis is a systemic necrotizing vasculitis of small vessels. Its typical clinical manifestations are rapidly progressive glomerulonephritis and alveolar hemorrhage. Other possible symptoms resemble those encountered in polyarteritis nodosa. Microscopic polyangiitis belongs to the group of ANCA-associated vasculitides, and 75-80% of patients have pANCA to myeloperoxidase (MPO). Anti-MPO ANCA pathogenicity has been established in animal models, and a recent report describes transplacental transfer of these antibodies in humans, resulting in pulmonary hemorrhage and renal involvement in the newborn. Patients with no poor prognostic factors, as defined by a five-factor score, can be treated with corticosteroids alone, with immunosuppressants added only in case of treatment failure. Patients with one or more poor prognostic factors must receive a combination of corticosteroids and immunosuppressants, mainly intravenous pulsed cyclophosphamide, with plasma exchange as an adjuvant therapy for those with severe renal involvement. Once remission is achieved, maintenance therapy can replace cyclophosphamide by azathioprine or methotrexate. Biological therapies are under evaluation. The remission rate is above 80% with these regimens, and the relapse rate is around 30% at 5 years, lower than for Wegener's granulomatosis.

[Scleroderma renal crisis]. / Crise rénale sclérodermique.

Scleroderma renal crisis (SRC) occurs in patients with systemic sclerosis (SSc) and is defined by otherwise unexplained rapidly progressive renal insufficiency associated with oliguria or rapidly progressive arterial hypertension or both. SRC is a rare and severe complication of SSc, most often encountered during the first 4 years of disease, almost only in patients with diffuse SSc. Factors predicting SRC were identified, including high-dose corticosteroid administration. Use of angiotensin-converting enzyme inhibitors (ACEI) has dramatically impressed the prognosis of SRC, but it mortality rate is still high. Treatment aims at normalizing blood pressure as soon as possible. ACEI should always be used, and additional anti-hypertensive agents, including calcium channel blockers and alpha- and beta-blockers, may be useful. Renal replacement therapy may be needed, but often (for almost half of patients) only temporarily.

[Therapeutic management of systemic sclerosis]. / Prise en charge thérapeutique de la sclérodermie systémique.

UNLABELLED: Improved understanding of the pathophysiology of systemic sclerosis (SSc) opens new therapeutic avenues in its treatment. The efficacy of disease-modifying agents remains limited however, and none has yet demonstrated its ability to improve survival in a prospective randomized trial. RESULTS: of traditional antifibrotic agents such as colchicine and D-penicillamine are disappointing. Cyclophosphamide (CYC) seems to be beneficial in interstitial lung disease associated with SSc. Organ-specific therapies may produce dramatic benefits. Examples include angiotensin-converting enzyme inhibitors for renal failure and epoprostenol for primary pulmonary hypertension. Several new therapeutic approaches are currently under evaluation, including high-dose CYC followed by peripheral stem cell transplantation, vasodilators, and antiinflammatory and antifibrotic agents. Physical therapy and rehabilitation may help to treat disability and loss of function in SSc patients.