Treatment of rheumatoid vasculitis

INTRODUCTION — Rheumatoid vasculitis (RV) is a protean, inflammatory process in patients with rheumatoid arthritis (RA) that is centered on the blood vessel wall itself. RV has a range of disease severity; in some patients, it is associated with substantial morbidity and an increased risk of mortality and can require intensive immunosuppressive therapy.

RV typically occurs in patients with longstanding, erosive RA and may affect a wide range of blood vessel types, from medium-sized muscular arteries to somewhat smaller arterioles or post-capillary venules. Clinical features of both medium- and small-vessel disease may be found within a given patient, and RV is generally classified among the forms of vasculitis associated with systemic diseases rather than based upon the size of the vessels involved. (See "Overview of and approach to the vasculitides in adults", section on 'Vasculitis associated with systemic disease'.)

RV may lead to blood vessel occlusion, necrosis, and tissue ischemia in a manner that resembles other forms of systemic vasculitis. In its tendency to affect medium-sized arteries and involve the skin, peripheral nerves, eyes, heart, muscles, and other organs, RV often has a clinical appearance similar to polyarteritis nodosa (PAN). Treatment practices for RV have been adapted from those for other better studied forms of systemic vasculitis, particularly granulomatosis with polyangiitis (GPA), with which it also shares a number of features. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis".)

The treatment of RV is presented here. The pathogenesis, clinical manifestations, and diagnosis of RV are presented separately. (See "Etiology and pathogenesis of rheumatoid vasculitis" and "Clinical manifestations and diagnosis of rheumatoid vasculitis".)

GENERAL PRINCIPLES — In determining treatment approaches for the patient with rheumatoid vasculitis (RV), an understanding of the clinical context in which this extraarticular manifestation of rheumatoid arthritis (RA) occurs is essential. The typical patient with RV has rheumatoid nodules, is seropositive, and has suffered from RA for at least a decade before systemic vasculitis becomes apparent. Consequently, at the time of RV onset, intensive and potentially toxic treatments will often be required in patients who have already incurred considerable morbidity from RA and its therapies. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Clinical presentation'.)

Diagnostic tests such as biopsies should be performed prior to initiating immunosuppressive therapies, such as glucocorticoids, rituximab, or cyclophosphamide. In selected patients with organ- or life-threatening disease, it is occasionally necessary to perform the diagnostic procedure after treatment has been begun. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Diagnosis'.)

Successful management of RV requires balancing the risks and benefits of therapies required for its treatment. Treatment considerations are often complicated by comorbidities that patients with RV have sustained through the years, including cytopenias, renal dysfunction, hepatic damage, gastrointestinal ulceration, and the complications of glucocorticoids, including hypertension, glucose intolerance, skin fragility, and others. RV is also mimicked by a number of infections, including both viral (human immunodeficiency virus, hepatitis, herpes zoster) and bacterial (tuberculosis, endocarditis) etiologies that must be excluded before initiating immunosuppressive therapy. Finally, in patients with RA, other forms of "idiopathic" vasculitis such as granulomatosis with polyangiitis (GPA), eosinophilic GPA (EGPA; Churg-Strauss), or giant cell arteritis (GCA, also known as temporal arteritis and as Horton disease) may occur, whereas secondary forms such as cocaine- and/or drug-induced vasculitis must be ruled out as well. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Differential diagnosis'.)

The type, distribution, and severity of organ damage resulting from RV are collectively weighed to determine appropriate treatment:

●Isolated cutaneous involvement generally has a good prognosis and often does not require immunosuppressive drug therapy beyond glucocorticoids. However, some forms of cutaneous vasculitis, particularly when there are severe skin ulcers, may require rituximab, cyclophosphamide, or another immunosuppressive agent to induce disease remission. Even in these more limited cases of RV, methotrexate (MTX) or other glucocorticoid-sparing agents may be needed because of the burden of glucocorticoid-related side effects, especially when longer courses or higher doses of these agents are necessary. (See 'Cutaneous vasculitis' below.)

●Systemic RV with involvement of internal organs or with severe involvement of peripheral nerves has a poorer prognosis and warrants immunosuppressive treatment, typically with initially high doses of glucocorticoids in combination with rituximab or cyclophosphamide. (See 'Systemic vasculitis' below.)

The management of medications the patient is already receiving for RA depends upon the clinical manifestations and the planned therapy (see 'Systemic vasculitis' below). As examples:

●In patients who develop systemic RV while on MTX, the further use of MTX depends upon whether the patient is going to be treated with rituximab or cyclophosphamide for their RV. Patients treated with rituximab are typically continued on MTX, the dosing of which should be optimized; patients who are treated with cyclophosphamide should discontinue MTX before starting cyclophosphamide treatment. (See "Use of methotrexate in the treatment of rheumatoid arthritis" and "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate'.)

●Patients who develop cutaneous or systemic RV while being treated with a tumor necrosis factor (TNF) inhibitor should generally discontinue the TNF inhibitor. The use of these agents has been infrequently associated with the development of a drug-induced vasculitis, which is limited to the skin in the majority of the patients. Some patients with cutaneous vasculitis may not need further intervention for their vasculitis if it resolves with the discontinuation of the TNF inhibitor, which is common in patients with cutaneous vasculitis induced by the drug. We also discontinue the TNF inhibitor when treating systemic vasculitis with either rituximab or cyclophosphamide. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Vasculitis'.)

Autopsy studies have identified a substantially higher prevalence of RV than is clinically apparent [1,2]; thus, there are likely to be individuals with early RV who could benefit from earlier treatment. The incidence of RV appears to be decreasing since the 1980s, suggesting that prompt and more aggressive treatment strategies and more effective medications may help to prevent the development of RV [3,4]. Because RV is associated with (high levels of) rheumatoid factor (RF), anti-citrullinated peptide antibodies, and sometimes antinuclear antibodies and perinuclear antineutrophil cytoplasmic antibodies (ANCA), and other extraarticular disease, particular vigilance for RV is warranted in patients with these characteristics. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Epidemiology and risk factors'.)

CUTANEOUS VASCULITIS — Isolated nailfold infarctions can be treated with local measures and have a good prognosis, while leg ulcerations due to rheumatoid vasculitis (RV) may require treatment similar to that used for systemic involvement. (See 'Isolated nailfold infarctions' below and 'Leg ulceration' below.)

Isolated nailfold infarctions — The treatment of isolated nailfold infarctions (picture 1), which are often associated with rheumatoid nodulosis and due to a low-grade small-vessel vasculitis [5,6], depends upon whether they are painful and if there is skin breakdown. Such lesions can simply be observed in patients with minimal or no symptoms and intact skin, since there is a low risk for progression to systemic RV [6].

In patients with painful nailfold infarction or infarcts with superficial skin breakdown, we suggest symptomatic treatment including bandaging and topical analgesics. If bandaging is insufficient to alleviate symptoms or the superficial ulceration does not show improvement over several days, we have had good success with topical clobetasol propionate (0.05% ointment applied daily at bedtime) [6-8]. Topical clobetasol may be applied once or twice daily for up to 14 days, depending upon severity and the duration of therapy needed to achieve clearing of the lesions.

Long-term follow-up in 30 patients with nailfold vasculitis supports this approach [6]. Although patients with isolated nailfold vasculitis are at increased risk for other types of extraarticular disease, systemic therapy is not required for these lesions. They do not herald the imminent development of systemic RV.

Leg ulceration

Initial ulcer management with topical measures — The initial treatment of leg ulcerations should include an approach similar to that for skin ulcers due to venous stasis, with a focus on good wound care and appropriate use of systemic antibiotics for superinfection. The treatment of venous stasis ulcers is discussed in more detail elsewhere. Briefly, our approach to topical and local therapy in the patient with rheumatoid arthritis (RA) and presumed RV is as follows:

●In patients with eschar, we use wet-to-moist saline dressings to debride the ulcer to a base of granulation tissue.

●In those with adequate arterial circulation, we use compression bandages or stockings to help reduce swelling if there is concomitant venous stasis.

●We use occlusive hydrocolloid (or hydrogel) dressings or, for patients with very exudative ulcers, calcium alginate-containing dressings.

●We use topical glucocorticoids only on smaller lower-extremity ulcers, less than one centimeter in diameter, and particularly on digital ulceration. However, their efficacy for skin ulcers due to RV has not been formally evaluated.

●We do not use antibiotic-containing ointments or creams.

A majority of leg ulcers in patients with RA probably have a vascular insufficiency etiology, which supports use of this approach, and the ulceration of RV can appear very similar. One series of 36 patients with RA and leg ulcers from Germany found three with RV, two with pyoderma gangrenosum, and 15 with chronic venous insufficiency, peripheral arterial disease, or a combination of these [9].

The duration of therapy with local and topical measures depends upon the severity of the ulcer and the adequacy of the response to these treatments. In the absence of other signs of systemic vasculitis, we have a low threshold for obtaining a biopsy of isolated non-healing ulcers as a basis for determining the need for further immunosuppressive therapy. Ulcers that do not respond to conservative measures may signal the presence of underlying RV or another etiology, including cutaneous malignancy or infection (including herpes zoster), which can present with skin ulceration [10].

Isolated skin ulceration greater than one centimeter across, or extending deeply to the fascia, should be biopsied early (within one to two weeks of appearance), to determine if systemic immunosuppressive therapies are warranted; whereas small, isolated, lower-extremity ulcers in older patients may merit up to four weeks of conservative management before pursuing a biopsy. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Diagnosis'.)

Ulcers due to RV and/or resistant to initial topical measures — Patients with ulcers and systemic RV or with ulcers resistant to topical measures alone require systemic therapy in addition to the local measures. Only very small ulcers are managed only topically (see 'Initial ulcer management with topical measures' above). For patients who have systemic RV and skin ulcerations, as well as those with multiple progressively worsening skin ulcers but without systemic disease, immunosuppressive therapy, as well as local skin care, is usually essential for healing (see 'Systemic vasculitis' below). Conservative wound care measures are continued through the course of therapy until re-epithelialization is complete. (See 'Initial ulcer management with topical measures' above.)

In patients with skin ulcers resistant to topical measures, as in other patients with systemic RV, the diagnosis of RV should usually have been confirmed by biopsy prior to initiating immunosuppressive therapies, such as glucocorticoids, rituximab, or cyclophosphamide. (See "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Diagnosis'.)

We take the following approach:

●Systemic plus topical therapy – The approach to these patients is guided in part by whether or not systemic RV is present:

•Skin ulcers and systemic RV – In patients with skin ulcers and systemic RV, we initiate glucocorticoids together with rituximab, as in other patients with systemic vasculitis involvement, unless access to rituximab is lacking. We reserve cyclophosphamide for patients whose skin lesions are resistant to rituximab, patients for whom rituximab is not available, and patients who have other forms of severe systemic involvement that would warrant initial cyclophosphamide therapy. (See 'Systemic vasculitis' below.)

•Skin ulcers without systemic RV – In patients with multiple, small (typically less than 1 cm in diameter) but progressively worsening skin ulcers and who have no other evidence of systemic RV, we use prednisone (0.5 to 1 mg/kg daily, depending upon severity and response to therapy, taken orally), rather than intravenous pulse glucocorticoids.

In patients with non-life-threatening RV who have vasculitic leg ulcers greater than 1 cm diameter without other systemic involvement, we suggest prednisone (1 mg/kg body weight taken orally) if the ulcer development is not rapidly progressive, while observing the patient's progress over seven days.

In patients with multiple ulcers (two to three or more over 1 cm in diameter) that are rapidly progressive, we treat with intravenous pulse glucocorticoids, initially without a second agent (eg, rituximab or cyclophosphamide), rather than combination therapy.

A failure to achieve significant improvement in the first week of treatment (as with a nonhealing ulcer on the lower extremities) should prompt initiation of rituximab or cyclophosphamide in addition to the high-dose glucocorticoids.

Topical therapy with tacrolimus has been proposed for refractory ulcers, but its efficacy and role in management of vasculitic skin ulcers is uncertain [11].

●Resistant to medical therapy – Patients whose skin ulcers do not respond to topical therapy and systemic immunosuppression are candidates for skin grafting. Pinch skin grafts appear to be similarly effective in healing ulcers in RA patients with or without biopsy evidence of cutaneous vasculitis [12].

Cutaneous vasculitis during use of TNF inhibitors — Although anti-tumor necrosis factor (TNF) therapies have been linked to the development of cutaneous vasculitis in some patients with RA, the types of vasculitis reported with TNF inhibitors are generally mild, resemble an immune complex-mediated vasculitis, and usually resolve with discontinuation of the drug. There is no indication that the use of TNF inhibitors predisposes patients to the development of RV, and systemic necrotizing vasculitis is infrequent among patients with TNF inhibitor-related vasculitis. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Vasculitis'.)

In RA patients who develop vasculitis while on TNF inhibitor therapy, we stop the TNF inhibitor, then monitor the patient closely for the first two to four weeks to see if discontinuation of the anti-TNF agent is associated with remission of the RV manifestations. This approach may be used if the vasculitis manifestation is a rash, but prednisone should be used if there are ulcers or impending ulcers (see 'Cutaneous vasculitis' above). For more severe cutaneous disease or other potentially organ-threatening manifestations, such as mononeuritis multiplex, patients may be treated, if necessary, with daily oral glucocorticoids (eg, prednisone, started at 0.5 to 1.0 mg/kg daily, then tapered as tolerated following resolution of the cutaneous changes), depending upon the response following discontinuation of the anti-TNF agent. More aggressive immunosuppression is usually not needed in these patients. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Vasculitis'.)

SYSTEMIC VASCULITIS — Systemic rheumatoid vasculitis (RV), even disease seemingly limited to one organ alone (eg, ocular disease or vasculitic neuropathy), requires aggressive therapy, typically with high-dose glucocorticoids plus either rituximab or cyclophosphamide. However, treatment decisions must be tailored to the clinical circumstances of each individual patient. The goal of treatment of systemic RV is to achieve a remission characterized by an absence of active vascular inflammation. (See 'Monitoring of response' below.)

As with other forms of systemic vasculitis, active disease must be distinguished from damage. "Damage" is defined as injuries to a given organ that are likely permanent, which have occurred as a result of the underlying disease process, and which will not be reversible with immunosuppressive therapy. Common forms of damage in RV include the sequelae of peripheral nerve infarctions (eg, foot- or wrist-drop), scleral thinning caused by scleritis, and cutaneous scarring (picture 2).

Information specifically related to the treatment of systemic RV, contained in individual case reports or case series, suggests that most patients should be treated with a regimen similar to that used in forms of primary systemic vasculitis, such as granulomatosis with polyangiitis (GPA) and polyarteritis nodosa (PAN). While the kidneys, lungs, and sinuses are not commonly involved in RV, in general, a similar treatment regimen may be used in patients with severe or refractory RV. Unlike GPA, randomized trials for RV comparing therapies have not been performed. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy" and "Treatment and prognosis of polyarteritis nodosa".)

Initial drug choice — The choice of agents depends upon the severity and extent of clinical involvement and the specific organ systems affected. The mainstay of treatment for severe RV is a combination of high doses of glucocorticoids, usually in combination with either rituximab or cyclophosphamide. The regimens are modeled on those employed in management of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy".)

Approach to current DMARD therapy at time of diagnosis of vasculitis — The therapy that is ongoing at the time of diagnosis of RV may need to be altered to treat both the RV and the patient's rheumatoid arthritis (RA). As examples:

●In patients already taking methotrexate (MTX) who are started on rituximab, we generally continue the MTX and optimize the dosing as would be done for the treatment of active arthritis, although MTX itself is of uncertain efficacy for treating the RV. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Methotrexate dosing'.)

●In patients being started on cyclophosphamide who are receiving MTX or leflunomide, we discontinue the MTX or leflunomide because of overlapping toxicity, particularly to the bone marrow.

●In patients being treated with a tumor necrosis factor (TNF) inhibitor, another biologic agent, or an orally administered kinase inhibitor (eg, tofacitinib), we discontinue the biologic or oral kinase inhibitor while treating systemic vasculitis with either rituximab or cyclophosphamide.

Choice of initial therapy for vasculitis — We take the following approach to choice of therapies, for which additional details of the dosing and duration of therapy and drug administration are described elsewhere in this topic review (see 'Glucocorticoids' below and 'Rituximab' below and 'Cyclophosphamide' below):

●Non-life-threatening focal disease – In patients with non-life-threatening RV who have focal disease, we suggest prednisone (1 mg/kg body weight taken orally), as described, for example, for vasculitic leg ulcers that are not rapidly progressive. (See 'Ulcers due to RV and/or resistant to initial topical measures' above.)

A failure to achieve significant improvement in the first week of treatment should prompt initiation of rituximab or cyclophosphamide in addition to the high-dose glucocorticoids. As examples, non-healing ulcers on the lower extremities can be treated in this fashion, as can progressive distal symmetric sensorimotor polyneuropathy; the latter can occur in some patients with RA who have vasculitic skin lesions [13]. Both may respond to glucocorticoid therapy alone.

●Severe skin, renal, or pulmonary disease, or pericarditis – In patients with severe skin involvement (such as refractory skin ulcers, deep cutaneous ulcers, and refractory urticarial vasculitis even without deep ulceration), renal or pulmonary disease, or pericarditis, we suggest the combination of rituximab plus high-dose glucocorticoids as the first-line treatment rather than glucocorticoids alone or cyclophosphamide plus glucocorticoids.

●Mononeuritis multiplex – For initial therapy of patient with mononeuritis multiplex, we prefer rituximab plus high-dose glucocorticoids (see 'Rituximab' below and 'Glucocorticoids' below), although cyclophosphamide plus high-dose glucocorticoids is an alternative in such patients. For acute mononeuritis multiplex without motor deficits, we prefer rituximab plus high-dose glucocorticoids.

●Severe scleritis – In patients with vision-threatening scleritis, we use cyclophosphamide or rituximab plus high-dose glucocorticoids rather than glucocorticoids alone, consistent with the approach of other experts [14]. The American Academy of Ophthalmology issued guidelines in 2014 recommending anti-TNF therapy (infliximab or adalimumab) for scleritis in patients in whom these first-line immunomodulatory therapies have failed [15]. A large prospective randomized French study, Cyclophosphamide versus Infliximab for Refractory Idiopathic Scleritis (CIRIS; clinical study identifier NCT03088293), is comparing infliximab with cyclophosphamide in refractory idiopathic scleritis, with results expected in 2024.

The treatment of scleritis, including severe scleritis, is described in detail separately (see "Treatment of scleritis"). Of note, like patients with ANCA-associated vasculitis, RA patients are at greater risk than the general population of developing scleritis after eye surgery or intravitreal injection [16,17].

●Life-threatening illness – For patients with life-threatening illness, either cyclophosphamide plus high-dose glucocorticoids or rituximab plus high-dose glucocorticoids can be used.

Cyclophosphamide is administered by intravenous infusion in most patients but can be given orally if intravenous therapy is poorly tolerated. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy" and 'Daily oral cyclophosphamide' below.)

We generally prefer the combination of rituximab and high-dose glucocorticoids in younger patients who wish to preserve fertility; in patients at high risk of malignancy, such as those with prior malignancies; and in patients with renal insufficiency or significant cytopenia. However, in the rare setting of RV-associated renal failure when plasmapheresis is considered, cyclophosphamide may be preferred since plasmapheresis may affect rituximab availability.

Rituximab is likely to be better-tolerated than cyclophosphamide, with lower risk of subsequent cancer and infertility. Situations where medication compliance is a concern also favor rituximab, which is given as an initial series of four weekly intravenous infusions. Benefits from rituximab, as an effective alternative to cyclophosphamide, were shown in the French Autoimmunity and Rituximab Registry and in a large number of case reports of successful use of rituximab for this indication. (See 'Rituximab' below.)

Among the factors favoring use of cyclophosphamide in some patients with RV is the longer experience with cyclophosphamide in severely affected patients with RV [18-22] or with other disorders.

In addition, cyclophosphamide or other relatively inexpensive agents (eg, azathioprine, mycophenolate mofetil) may be alternatives to rituximab in patients in whom access to rituximab is a problem, for example, due to regulatory restrictions or the cost of therapy. (See 'Alternatives to rituximab and cyclophosphamide' below.)

Drug administration, dosing, and efficacy

Glucocorticoids — Patients with severe RV, characterized by illness requiring hospitalization for organ damage (for example from acute scleritis, acute mononeuritis multiplex, acute renal failure), should receive three days of pulse methylprednisolone (given by intravenous infusion, generally between 7 to 15 mg/kg, not to exceed 500 mg in most children under 15, or 1 gram in adults and teens age 15 and older). Patients with more severe vasculitic involvement should receive 1 gram daily of methylprednisolone or equivalent for three days.

Pulse glucocorticoid therapy should then be followed by prednisone (1 mg/kg/day, up to 80 mg/day), which is administered orally.

In many patients, these high initial doses of glucocorticoid therapy may require modification because of comorbidities that could be exacerbated by glucocorticoid therapy (eg, coincident diabetes or hypertension, history of mental illness, advanced age). Adverse effects of glucocorticoids and prophylaxis for glucocorticoid-induced osteoporosis are discussed in detail separately. (See "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

The goal of the prednisone taper should be to lower the dose to 20 mg/day by two months of treatment, then to 5 mg/day or less (ie, the minimum dose required to manage their RA) by four to eight months of therapy.

We begin tapering the prednisone once there is a clear response to the induction therapy with halting of progression of ulcer and mononeuritis symptoms and signs, for example, and evidence of ulcer healing. In adults, we gradually decrease the daily prednisone dose by 5 mg per week until the patient is taking 20 mg daily.

A slower taper, eg, by 1 mg increments weekly, is usually pursued thereafter until the drug is discontinued. Because of the risks associated with use of glucocorticoids, our goal is to discontinue prednisone between four and eight months following initiation of induction therapy.

In children, glucocorticoids are usually reduced by gradually phasing out the alternate-day dose, which helps preserve growth plate viability in patients receiving prolonged glucocorticoid therapy.

With vasculitis in remission, ideally the prednisone can be discontinued completely following a suitable taper if the patient has not been previously on glucocorticoid therapy and the prednisone. Concomitant initiation of rituximab therapy may permit more rapid taper of glucocorticoid therapy.

The use of glucocorticoids in RV has not been evaluated in placebo-controlled trials. Such trials are unlikely to be performed, due to the general acceptance of the role of glucocorticoids in achieving initial control of systemic vasculitis. In selected patients with RV, high-dose glucocorticoids may be sufficient to induce disease remission (see 'Initial drug choice' above). Selection of such patients on the basis of their a priori clinical characteristics, however, is challenging.

Rituximab — We administer rituximab (375 mg/m² in one dose weekly administered by intravenous infusion for a total of four weeks) together with high-dose glucocorticoids (see 'Glucocorticoids' above). An alternative regimen of rituximab 1000 mg in each of two doses at a two week interval (also administered intravenously) may be as effective and preferred for convenience; there are no clinical trials that compare these regimens in RV. Rituximab may be repeated after six months if needed. Rituximab, a humanized anti-CD20 monoclonal antibody used to treat RA and RV, was developed as a treatment for B-cell lymphoma. The use, efficacy, and adverse effects of rituximab in RA are described in detail separately. (See "Rituximab: Principles of use and adverse effects in rheumatoid arthritis".)

No head-to-head randomized trials have directly compared rituximab with cyclophosphamide in patients with RV, but the safety and efficacy of rituximab for treatment of RV were described in an analysis of data from a prospective cohort study investigating the long-term safety and efficacy of rituximab for treating RA and other autoimmune diseases [23]. This French registry, involving 88 French centers and 1994 patients with RA treated with rituximab, included 10 women and seven men with active systemic RV who were treated with rituximab (given in either two or four infusions). The vasculitis had been present for a mean duration of 30 months. Most of the patients had severe skin involvement and mononeuritis multiplex, with pleural effusions in three and pericarditis in one. Four of the patients (24 percent) had received cyclophosphamide previously for their vasculitis and were being treated for relapse. After six months, 12 patients (71 percent) receiving rituximab had achieved complete remission of the vasculitis, four patients responded partially, and one patient died from uncontrolled vasculitis. Six patients (35 percent) were retreated at six months. At one year after initiation of therapy, 14 patients (82 percent) were in sustained complete remission, including all those who were retreated, and mean prednisone doses had been reduced from 19.2 to 9.7 mg daily. The frequency of severe infections was 6.4 per 100 patient-years. Compared with historical data, rituximab appeared to be associated with lower mortality compared with the use of cyclophosphamide as primary therapy.

Another study (retrospective in design), at Mayo Clinic and focusing specifically on use of rituximab for RV, analyzed the courses of 17 patients treated with rituximab for systemic RV from 2000 to 2017. At 12 months, a complete remission of RV was achieved in 62 percent and partial remission in 38 percent. Major complications were limited to two infusion reactions, and single cases of Clostridioides difficile colitis, community-acquired pneumonia, and Pneumocystis pneumonia. There were no deaths, and none developed neutropenia, hypogammaglobulinemia, herpes simplex infection, fungal infection, or tuberculosis [24].

The benefits of rituximab as a therapy for systemic vasculitis unrelated to RA have also been demonstrated in other studies and at least one large randomized trial (known as the rituximab for antineutrophil cytoplasmic antibody [ANCA]-associated vasculitis [RAVE] trial), in which rituximab had comparable efficacy to cyclophosphamide in AAV disorders such as GPA and microscopic polyangiitis. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy", section on 'Patients resistant to induction with cyclophosphamide' and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Induction therapy'.)

Cyclophosphamide — The use of cyclophosphamide in patients with RV is largely modeled upon its use in patients with AAV, although benefit in RV has been shown in case reports and small case series [18-22]. The administration, dosing, adverse effects, and preventive measures with use of intravenous and oral cyclophosphamide are described in detail separately. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases" and "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)

Intravenous pulse cyclophosphamide — In RV, a typical initial regimen is cyclophosphamide 15 mg/kg (maximum 1200 mg) every two weeks for three doses, followed by maintenance pulses of 15 mg/kg intravenously (maximum dose: 1200 mg) every three weeks. Once remission is achieved, the drug is administered for an additional three months of infusions. On average, remission can be achieved in patients with AAV with six to seven pulses of therapy. Results in patients with RV are similar, in our experience. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)

Over the period of treatment, usually three to six months depending on the clinical response, the infusion dose is adjusted in relation to the patient's white blood cell count on weekly complete blood counts, with reductions by roughly 5 mg/kg/dose if the absolute neutrophil count decreases below 1000/microL two weeks following each infusion. Excessive dosing can result in significant bone marrow and other toxicity. Neutropenia that follows each infusion serves as a useful guide for dose adjustment.

The initial dose of intravenous cyclophosphamide in both children and adults is adjusted based upon renal function (see "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Pharmacology'). A similar dose adjustment is generally recommended for chronic liver disease, with total bilirubin above 3 mg/dL or aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than three times the upper limit of normal. Cyclophosphamide use is not recommended with bilirubin greater than 5 mg/dL.

The relative benefits and risks of intermittent IV cyclophosphamide have not been directly compared with daily oral administration of the drug in patients with RV. The largest study of intermittent IV cyclophosphamide in RV was a retrospective unblinded comparison of the outcomes of 21 patients with RV, who received a combination of IV cyclophosphamide plus IV methylprednisone, with those of 24 patients who received a variety of other therapies (eg, azathioprine, D-penicillamine, chlorambucil, MTX, and prednisone) [18]. The IV regimen consisted of methylprednisolone 1500 mg and cyclophosphamide 500 mg the first week, followed by methylprednisolone 1000 mg and cyclophosphamide (15 mg/kg, maximum dose 1000 mg) at weeks 1, 4, and 7. Maintenance therapy was either daily oral azathioprine (2 mg/kg/day) or oral cyclophosphamide (1.5 mg/kg/day). The IV cyclophosphamide group had more severe initial disease, but the proportion of patients who had skin healing or significant improvement in skin lesions or in other manifestations of RV within four months of beginning treatment was numerically greater with IV cyclophosphamide and associated with fewer treatment complications and a smaller number of deaths.

Patients receiving cyclophosphamide should also receive prophylaxis against Pneumocystis jirovecii pneumonia. (See "General principles of the use of cyclophosphamide in rheumatic diseases", section on 'Prophylaxis for Pneumocystis jirovecii pneumonia infection'.)

Evidence from research in patients without RA or RV but with AAV demonstrated that IV cyclophosphamide, when compared with oral daily cyclophosphamide, resulted in lower cumulative doses, less incidence of infection and leukopenia, less bladder toxicity, and possibly less risk for long-term infertility and cancer susceptibility. However, the relapse rate in AAV is as much as twice as high with IV pulse therapy compared with oral therapy, suggesting less efficacy. Nonetheless, several longitudinal studies indicate no difference in survival or loss of renal function in AAV-associated renal disease. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Cyclophosphamide-based regimen'.)

Daily oral cyclophosphamide — As an alternative to intravenous cyclophosphamide, particularly in those patients who do not tolerate intravenous therapy, daily oral therapy up to 2 mg/kg/day can be implemented. The dose should be adjusted for decreased renal function and for white blood counts. Daily oral cyclophosphamide was used in a small series of five patients with RV, all of whom achieved initial disease remission. Daily oral therapy permits close titration of the cyclophosphamide dose, based principally upon the white blood cell count. Whereas an IV bolus of cyclophosphamide cannot be withdrawn once administered, daily cyclophosphamide doses may be altered more readily in the event of an adverse effect of therapy. (See "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases".)

At the initiation of daily cyclophosphamide, the use of pulse methylprednisolone is almost always appropriate, unless contraindicated. (See 'Glucocorticoids' above.)

Based upon experience in other forms of vasculitis and limited experience in RV, plasma exchange may be considered in cases with severe vasculitic manifestations such as mesenteric ischemia, especially in patients with high levels of immune complexes [25]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Role of plasma exchange'.)

Alternatives to rituximab and cyclophosphamide — In patients who are unable to take either rituximab or cyclophosphamide, and in those for whom there is continued disease activity despite high-dose glucocorticoid therapy plus rituximab and/or cyclophosphamide, alternative approaches must be considered. We typically use azathioprine as the next immunosuppressive agent in such patients, while continuing glucocorticoids (see 'Azathioprine' below). Another alternative agent is mycophenolate mofetil. (See 'Other agents' below.)

When confronted with refractory vasculitis, however, we also reexamine the question of how much of the patient's ongoing clinical manifestations relate to active vasculitis as opposed to damage, a comorbid condition, or an adverse effect of therapy.

Azathioprine — In patients for whom cyclophosphamide for initial therapy of systemic RV is not available because of history of bladder cancer, fertility concerns, or previous cyclophosphamide treatment, and for whom rituximab may not be accessible because of cost or availability, we suggest the combination of azathioprine with high-dose glucocorticoids (see 'Glucocorticoids' above). An initial dose of azathioprine of 2 mg/kg/day is used, although a higher dose (up to 2.5 mg/kg/day without exceeding a total maximal dose of 250 mg/day in adults) may be used in the absence of contraindications and in the presence of severe disease manifestations such as scleritis and mononeuritis multiplex.

Before starting azathioprine, we perform testing for the presence of thiopurine methyltransferase (TPMT) alleles; this enzyme is required in order to metabolize azathioprine. The rationale for such testing and a discussion of test utility and alternative management strategies preferred by some experts are presented separately. (See "Pharmacology and side effects of azathioprine when used in rheumatic diseases" and "Pharmacology and side effects of azathioprine when used in rheumatic diseases", section on 'Pharmacogenetics and azathioprine toxicity'.)

In one uncontrolled study, nine patients with systemic RV improved with a combination of oral prednisone (60 mg/day) and azathioprine (2 mg/kg) [26]. By contrast, a trial that randomly assigned 15 patients to receive either azathioprine or placebo in addition to glucocorticoids noted no significant difference in outcomes between the two groups [27].

Other agents — The evidence for the usefulness of agents other than rituximab or cyclophosphamide for systemic RV is limited to small clinical trials, uncontrolled case series, and individual case reports:

●Mycophenolate mofetil – There are no randomized trials of this agent in RV. Based upon some experience with AAV, it may be an alternative glucocorticoid-sparing agent for initial therapy in patients for whom rituximab, azathioprine, or cyclophosphamide are unavailable or contraindicated. (See 'Initial drug choice' above and 'Azathioprine' above and "Granulomatosis with polyangiitis and microscopic polyangiitis: Management of disease resistant to initial therapy", section on 'Patients resistant to induction with cyclophosphamide and rituximab'.)

Mycophenolate may be also be considered as an alternative maintenance therapy in patients for whom these other therapies are unavailable or contraindicated. (See 'Maintenance therapy' below.)

●TNF inhibitors – There are only limited data to suggest that TNF inhibitors may be helpful for RV. These medications have in rare instances been associated with the development of vasculitis, usually a cutaneous vasculitis, situations that call for drug discontinuation. (See "Tumor necrosis factor-alpha inhibitors: Induction of antibodies, autoantibodies, and autoimmune diseases", section on 'Vasculitis' and 'General principles' above.)

No prospective trials have been conducted with TNF blockers in patients with RV. Experience with randomized trials of TNF inhibitors in other forms of vasculitis (eg, etanercept in GPA [28] and infliximab in giant cell arteritis [29]) has documented the failure of targeted TNF inhibition in these diseases.

One retrospective study identified nine patients (five men and four women) in France previously treated with cyclophosphamide and prednisone but with either uncontrolled or relapsed RV [30]. Virtually all had nerve or skin involvement. Seven were treated with infliximab, and two were treated with etanercept, for a mean of 28 weeks. Four of the infliximab patients and one of the etanercept patients achieved complete remission of their vasculitis. However, one patient died, and two were withdrawn from anti-TNF therapy because of infection.

●Abatacept – Abatacept is another biologic agent used to treat RA that is refractory to conventional disease-modifying antirheumatic drugs (DMARDs) and anti-TNF agents. One case has been described of a patient with RV and common variable immunodeficiency (CVID) who responded well to abatacept that was given due to concerns about further immunosuppressing a CVID patient with rituximab [31]. Two other cases of RV responding to abatacept have been published [32,33].

Abatacept has been associated with development of secondary vasculitis in case reports: 1 in a 42-year-old man with psoriatic arthritis [34] and another in a 37-year-old woman with RA who developed nailbed infarcts [35]. A third occurred in a 60-year-old woman with RA who developed mononeuritis multiplex, consistent with a diagnosis of RV [36]. All improved after withdrawal of the abatacept, administration of glucocorticoids, and in the last case, treatment with rituximab.

●Chlorambucil – Chlorambucil, an alkylating agent of similar potency to cyclophosphamide, was once used to treat patients with RA and juvenile idiopathic arthritis (JIA) [37]. Case reports in the 1960s suggested some efficacy, but this drug is no longer in use for RA or RV due to its adverse effects profile, particularly bone marrow toxicity (thrombocytopenia) and a propensity to cause hematopoietic malignancies and lack of demonstration of superiority to other treatment options.

Resistant to initial therapy — In patients with an inadequate response to initial therapy, we usually switch from rituximab to cyclophosphamide or from cyclophosphamide to rituximab, depending upon the initial agent, while increasing the dose of glucocorticoids in either case. The drug choice in patients who have had an inadequate response to initial immunosuppressive therapy depends upon which prior therapy the patient received and the presence of comorbidities that may affect drug choice. The decision to switch to a different agent for an inadequate response to therapy needs to be individualized, depending upon the severity of organ involvement and the patient's comorbidities, but can generally be made after two months of treatment with the initial therapeutic regimen, by which time most patients who will respond to therapy have shown signs of such a response.

Glucocorticoid dosing depends upon the severity of the vasculitis and the prior response to glucocorticoids. Regimens for dosing and tapering are the same as for initial glucocorticoid therapy (see 'Glucocorticoids' above). As examples:

●In patients with limited vasculitis that is not rapidly progressive, particularly in patients who had previously been responsive to oral prednisone, we increase the prednisone dose to 1 mg/kg body weight as therapy with rituximab or cyclophosphamide is initiated.

●In patients in whom the vasculitis is severe or relapsed and is refractory to therapy and rapidly progressive, we use pulse IV glucocorticoid therapy as treatment is initiated with rituximab or cyclophosphamide.

In patients in whom there is no contraindication to the preferred agent, we take the following approach for the additional immunosuppressive agent:

●Inadequate response to rituximab – Decisions about when to initiate cyclophosphamide after initial rituximab must be individualized according to the patient's disease activity. Patients with RV treated with the combination of high-dose glucocorticoids and rituximab should begin to show signs of improvement within three to eight weeks of starting treatment (ie, beginning after the fourth rituximab infusion). In patients in whom no improvement is evident at that point and in whom ongoing activity of disease attributable to vasculitis persists (eg, those hospitalized with life-threatening multi-organ disease who appear to be failing the combination of glucocorticoids and rituximab), we generally then proceed with initiation of cyclophosphamide, which is usually administered intravenously in such patients. (See 'Cyclophosphamide' above.)

●Inadequate response to cyclophosphamide – In patients in whom cyclophosphamide and high-dose glucocorticoids are ineffective or result in an incomplete response, despite six to eight weeks of initial therapy, we treat with rituximab. (See 'Rituximab' above.)

●Inadequate response to both cyclophosphamide and rituximab – In patients who have an inadequate response to both rituximab and cyclophosphamide, we use azathioprine, while continuing glucocorticoids, as in patients unable to take rituximab or cyclophosphamide. (See 'Alternatives to rituximab and cyclophosphamide' above and 'Azathioprine' above.)

Maintenance therapy

Indications and timing for maintenance therapy — The severity of involvement at the presentation of RV and the degree of recovery determine the necessity and timing of maintenance therapy. The choice of medication also depends upon the medications used to induce remission of the vasculitis. (See 'Choice of maintenance therapy' below.)

We would always proceed with maintenance therapy in patients with organ-threatening disease, such as scleritis or with motor deficits from mononeuritis multiplex. However, in patients with limited or localized disease and in those whose disease may be self-limiting, maintenance therapy may not be required for continued management of RV. As examples:

●A patient whose only manifestation of RV is leg ulceration would most often not require maintenance therapy if complete healing of the ulcer is achieved with induction therapy. Similarly, other patients with complete resolution of symptoms, findings, and laboratory evidence of RV who received rituximab as the initial therapy may also be monitored to determine if further treatment is needed if the rituximab is not required to control their arthritis.

●Patients with definite drug-induced vasculitis do not generally require maintenance therapy once the offending drug has been discontinued and the disease remits.

Choice of maintenance therapy — The choice of maintenance therapy depends largely upon the agent used to initially control the vasculitis, which is determined in part by disease severity and the treatment(s) needed to control the arthritis. We take the following approach:

●After rituximab induction therapy – In patients in whom rituximab is used for induction, for maintenance therapy we continue MTX and repeat the course of rituximab infusions every six months, as we would do for RA without vasculitis. (See 'Rituximab' above and 'Initial drug choice' above and "Initial treatment of rheumatoid arthritis in adults", section on 'Initial therapy with methotrexate' and "Rituximab: Principles of use and adverse effects in rheumatoid arthritis" and "Treatment of rheumatoid arthritis in adults resistant to initial biologic DMARD therapy", section on 'Rituximab'.)

In patients unable to continue MTX, we use azathioprine as an alternative once a response to rituximab is evident, which usually occurs within four to six weeks of beginning rituximab therapy. Azathioprine is typically started by mouth at 2 mg/kg/day and can be lowered cautiously if not tolerated for any reason, or once the patient remains relapse-free at 6 to 12 months. The regimen used for azathioprine is the same as that employed as maintenance for patients initially treated with cyclophosphamide. (See 'Azathioprine' above.)

●After cyclophosphamide induction therapy – Following initial treatment and remission induction using cyclophosphamide, we suggest azathioprine for maintenance therapy (see 'Azathioprine' above). Azathioprine is typically started by mouth at 2 mg/kg/day and can be lowered cautiously if not tolerated for any reason, or if the patient remains relapse-free at 6 to 12 months. Alternative agents for maintenance include MTX and mycophenolate mofetil.

In patients with systemic RV who achieve remission of their vasculitis within three months of starting induction therapy, we generally switch to maintenance therapy after three months of treatment with cyclophosphamide. We would delay maintenance therapy until six months after starting treatment when remission of the vasculitis is not achieved within the first three months of therapy. We avoid continuing induction therapy with cyclophosphamide for longer than six months, as prolonged therapy with this agent increases the risk for secondary malignancy.

Maintenance therapy should not be started following induction with cyclophosphamide until the absolute neutrophil count has risen above 1000/microL and remained stable.

Azathioprine is the agent most commonly used for maintenance therapy following cyclophosphamide. MTX and cyclophosphamide should generally not be used concurrently in RA. Historically, azathioprine was also preferred over MTX for the treatment of RV in part because many patients who developed RV were already taking MTX at the time of onset of the vasculitis; however, these doses were often lower than those now typically employed. (See 'Initial drug choice' above and 'Alternatives to rituximab and cyclophosphamide' above.)

In patients in whom additional therapy is needed for management of the inflammatory arthritis, a biologic, such as a TNF inhibitor, can be added to azathioprine treatment. We generally do not use MTX and azathioprine concurrently. In many cases, baseline therapy for the RA may be resumed and the chemotherapy used for the vasculitis may be discontinued after six months if the vasculitis has resolved.

●Alternative maintenance agents

•Methotrexate – The target dose for MTX when used for maintenance is 25 mg by mouth weekly, accompanied by folic acid supplementation at 1 to 3 mg by mouth daily. However, MTX should not be used in patients with elevated transaminases, patients with stage 3b or worse chronic kidney disease (estimated glomerular filtration rate <45 mL/minute/1.73 m²), or patients contemplating pregnancy.

•Mycophenolate – The dose of mycophenolate mofetil, another alternative, is 1000 to 1500 mg twice daily.

•Rituximab – Rituximab can also be used for maintenance therapy in selected patients who had not received it initially. In patients in whom rituximab is chosen for maintenance therapy, such as those with gastrointestinal or other intolerance of azathioprine or MTX, we follow the general recommendations for its use in AAV. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Induction and maintenance therapy", section on 'Maintenance therapy'.)

As maintenance, rituximab is given as two 500 mg infusions at a 14-day intervals, usually starting at three months after induction with cyclophosphamide, followed by single infusions at months 6, 12, and 18. A further consideration that may favor rituximab over azathioprine or MTX in some patients is the efficacy of rituximab for management of the inflammatory arthritis; thus it is often desirable to continue rituximab as maintenance for controlling the arthritis even after the vasculitis has been brought under control.

Duration of maintenance therapy — Any evidence for active disease is an indication for continuation of maintenance therapy, particularly with involvement of the visceral organs. A patient with no signs or symptoms of disease, and resolution of elevated inflammatory markers on laboratory testing, can have maintenance therapy for RV treatment suspended at about nine months, then be monitored at least monthly for evidence of recurrence for at least 6 to 12 months.

In children, a trial of discontinuation of maintenance therapy is usually timed to the school year, ideally in the summer at the beginning of a vacation period, so as to avoid recurrence that may result in interruption of their academic progress.

Relapse during maintenance therapy — Those patients who suffer a relapse of RV are usually treated with cyclophosphamide or rituximab to achieve remission using the same agent used for induction initially if that approach was successful, although we avoid using cyclophosphamide for more than a total of six months. In patients initially treated with cyclophosphamide but who have received six months of the medication, we generally will switch therapy to rituximab, and all these patients will require maintenance therapy. Major recurrence is generally treated with another course of induction therapy, unless the patient never achieved disease-free remission after the initial treatment of the disease.

A new agent, such as rituximab, MTX, or azathioprine, is usually chosen if relapse occurred while the patient was taking one of the other agents for maintenance therapy. Rituximab is the preferred agent in cases of disease relapse after initial treatment with cyclophosphamide.

If relapse occurred after previous maintenance therapy was discontinued, we resume therapy with the same maintenance agent the second and subsequent times. Patients who have had more than one relapse are typically treated with sustained maintenance therapy, sometimes for years.

Patients who have had complete remission from RV induced by rituximab should be considered for retreatment every six months if there is a return of active disease. No formal studies have identified the best practice for retreatment of recurrence in patients initially responsive to rituximab. We have a lower threshold for treating the relapse with cyclophosphamide, particularly if there is an incomplete remission induced the first time by rituximab.

We and some other experts measure the B-cell counts (CD19-positive cells by flow cytometric analysis) in patients with recurrent symptoms four or more months subsequent to rituximab infusions. In patients with symptoms that recur in association with the return of circulating B cells, we repeat treatment with rituximab. Rituximab can be employed for retreatment even if circulating B cells are not present at symptom recurrence, in our experience, if the initial course of rituximab was successful in managing the active RV. In those patients without detectable B cells in association with symptom recurrence, the author and some experts will treat subsequently with a different agent, such as cyclophosphamide in the case of severe RV or azathioprine for less severe RV manifestations.

Monitoring of response — The specific clinical focus and testing used for monitoring of the response depends upon the pattern of disease, but we generally follow these patients on at least a monthly basis until well controlled and the clinical status and treatment regimen are stable. Once well controlled, they can usually be seen every two to three months, depending upon whether closer monitoring is needed for their drug therapy. Clinical observation and laboratory measures of specific organ involvement (eg, serum creatinine, urinary sediment), together with general measures of disease activity such as acute phase reactants (eg, erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]), are used to monitor the response to treatment.

Almost all patients with RV have high titers of rheumatoid factor (RF), and many have low serum complement levels; however, these measures are not reliable measures of disease activity, and treatment decisions should not be predicated upon changes in these biomarkers.

Adjunctive care

Preventing side effects of therapy — Given the toxicities of cyclophosphamide, other immunosuppressive agents, and glucocorticoids, preventive therapies should be provided, which are discussed in detail separately:

●Prophylactic antibiotics for the preventing Pneumocystis pneumonia (see "Treatment and prevention of Pneumocystis pneumonia in patients without HIV", section on 'Prophylaxis')

●Appropriate drug use relevant to pregnancy and lactation and preservation of fertility in women of childbearing potential and in men (see "Safety of rheumatic disease medication use during pregnancy and lactation" and "Fertility and reproductive hormone preservation: Overview of care prior to gonadotoxic therapy or surgery" and "Effects of cytotoxic agents on gonadal function in adult men" and "Effects of antiinflammatory and immunosuppressive drugs on gonadal function and teratogenicity in men with rheumatic diseases")

●Prevention of bladder toxicity, including hemorrhagic cystitis and bladder cancer, in patients receiving cyclophosphamide (see "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Bladder toxicity' and "General toxicity of cyclophosphamide in rheumatic diseases", section on 'Gonadal toxicity')

●Preventing of glucocorticoid-induced osteoporosis (see "Prevention and treatment of glucocorticoid-induced osteoporosis")

Smoking cessation — We insist on smoking cessation in patients with RA, including those with RV, and we provide aggressive medical and psychosocial support. (See "Overview of smoking cessation management in adults".)

Cigarette smoking has been associated with an increased risk for RA [38] and RV (particularly with the development of nailfold infarcts in men who smoke) and is a known risk factor for vascular disease [39,40]. (See "Etiology and pathogenesis of rheumatoid vasculitis", section on 'Cigarette smoking' and "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis", section on 'Cigarette smoking'.)

Skin care — Good skin care may prevent significant infectious complications of RV, given that patients with RV are also at significant risk for decubitus (pressure-induced) and lower-extremity ulceration. Measures used to prevent pressure ulcers in bedbound patients are discussed in more detail elsewhere, but important components include repositioning of patients regularly (typically every two hours), use of static pressure-reducing mattresses or mattress covers, or, for very high-risk patients, use of dynamic support systems. For ambulatory patients, the incidence of lower-extremity skin ulcers may be reduced by avoiding pressure due to poorly fitting shoes, braces, or orthotics. (See "Prevention of pressure-induced skin and soft tissue injury".)

RHEUMATOID AORTITIS — As with large-vessel vasculitis (giant cell arteritis and Takayasu-associated aortitis), the standard approach in case reports involving rheumatoid arthritis (RA)-associated aortitis [41] has been medical management with glucocorticoids (1 mg/kg/day up to 60 mg/day) for the first month, with employment of glucocorticoid-sparing therapies like methotrexate (MTX) or azathioprine thereafter in conjunction with taper of the glucocorticoids [42]. Even in isolated aneurysms in patients with idiopathic aortitis treated with surgical resection, a study from the Cleveland Clinic of 52 patients found no recurrence in the subset that received coincident treatment with glucocorticoids compared with the recurrent aneurysms being present in a quarter of those who received no glucocorticoids [43].

Patients with other evidence for systemic disease are treated with more typical induction therapy, with either cyclophosphamide, rituximab, or both depending on the severity of their systemic disease. Disease activity is monitored primarily with constitutional and other symptoms (eg, back pain).

In patients with established aortitis, we suggest imaging about every six months for the first year, and measurement of inflammatory markers in the blood, with subsequent follow-up depending upon the course of the aortitis. There are no consensus guidelines regarding the follow-up frequency or long term benefit of computed tomography (CT) or magnetic resonance (MR) angiography.

Aortitis is a rarely diagnosed manifestation of rheumatoid vasculitis, with the potential for development of aortic valve insufficiency, aneurysm, or rupture. Many cases have been identified post-mortem [44], and no clinical studies exist to discern efficacy of particular therapies. A paucity of RA-associated aortitis case reports since the advent of biologic therapies (eg, anti-tumor necrosis factor [TNF] agents, rituximab [anti-CD20], and other therapies) suggests that the incidence of this condition may be decreasing [45], and there is a similar lack of reports of treatment with any of these more contemporary agents.

PROGNOSIS — Before the widespread use of biologic therapies for rheumatoid arthritis (RA), it was clear that patients with rheumatoid vasculitis (RV) had a worse outcome than those with RA alone, with an adjusted hazard ratio (HR) for death of 1.26 when outcomes for 61 RV patients, adjusted for age and gender, were compared with 244 RA controls [46]. Use of cyclophosphamide, although not studied in controlled trials in RV, appears to alter the natural history of RV in many patients. Focusing on patients with neuropathy-associated vasculitis, and excluding those who exhibited involvement only of the skin, a French study of 32 patients in the late 1980s and early 1990s found 43 percent mortality at five years [47].

Two large retrospective studies have provided further insight into the prognosis of patients with RV and explored the question of whether changes in therapy and the availability of biologic agents has impacted the prognosis of those who develop RV:

●In a cohort of 86 patients evaluated between 2000 and 2010, who were treated with various immunosuppressive agents (including glucocorticoids, cyclophosphamide, and traditional and biologic disease-modifying antirheumatic drugs [DMARDs]), complete remission was seen after six months of therapy in 38 percent and partial improvement in 52 percent, while 10 percent showed no clinical improvement [32]. Relapse had occurred in 36 percent by five years, and 26 percent had died.

●Another retrospective study compared 18 patients in the Norfolk Vasculitis Register diagnosed with RV between 2001 and 2010 with 47 patients diagnosed from 1988 to 2000 [48]. Five-year mortality in the more recent cohort was 60 percent, compared with 51 percent in the earlier cohort. The authors concluded that although the incidence of RV may be declining with earlier treatment of RA and the use of biologic therapies, the clinical features remain similar and very high mortality rates persist.

Variability in survival may be related to factors such as different therapies employed and worse outcomes in patients with severe systemic disease or in the rare patient with large-vessel vasculitis [49].

The most common cause of death in 61 patients with RV, in one study, was infection [46]; only one patient died from vasculitis. This hazard of infection when using high-dose glucocorticoids emphasizes the need to carefully determine if the RV is limited to the skin, thereby requiring minimal additional therapy (see 'Cutaneous vasculitis' above), versus the less common but much more threatening involvement of internal organs. In the previously cited study of 32 RV patients, most of whom were treated with cytotoxic drugs and glucocorticoids, more than one-third died within the first three years [47]. At the time of death, 70 percent showed evidence of vasculitis either clinically or on autopsy, although infection was given as the proximal cause of death in the majority.

Involvement of medium-sized arteries often portends more serious complications, coupled with a higher likelihood of treatment-related morbidity [49]. Rare patients with large-vessel vasculitis are thought to have a much worse prognosis; they may have an increased likelihood of mononeuritis multiplex or cerebral vasculitis, visceral infarction, or coronary arteritis [49]. By contrast, isolated nailfold infarctions (picture 1), which are often associated with rheumatoid nodulosis, may cause no further symptoms and can simply be observed since there is a low risk for progression to systemic RV [7].

The frequency of relapse is variable and may be determined, in part, by the intensity and duration of initial therapy. In one study of 32 patients with RV and peripheral neuropathy, 53 percent survived disease-free, 25 percent suffered a relapse, and 22 percent failed to achieve remission over a mean follow-up of 7.4 years [47]. Of the eight patients suffering relapse, only three recovered completely following retreatment.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

SUMMARY AND RECOMMENDATIONS

●In patients with painful nailfold infarction or infarcts with superficial skin breakdown due to rheumatoid vasculitis (RV), we suggest topical treatment, including bandaging and topical analgesics, rather than systemic therapy (Grade 2C). When bandaging is insufficient to alleviate symptoms or the superficial ulceration does not show improvement over several days, we use topical clobetasol propionate (0.05% ointment applied daily at bedtime or twice daily for up to 14 days), depending upon severity and the duration of therapy needed to achieve clearing of the lesions. Patients with minimal or no symptoms and intact skin can simply be observed. (See 'Isolated nailfold infarctions' above.)

●The diagnosis of RV should usually have been confirmed prior to initiating immunosuppressive therapies, such as glucocorticoids, rituximab, or cyclophosphamide. In addition, active disease must be distinguished from damage. Opportunistic infection should also be excluded in rheumatoid arthritis (RA) patients who appear to have developed RV before the initiation of more intensive immunosuppression. (See 'General principles' above and 'Systemic vasculitis' above and "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Diagnosis' and "Clinical manifestations and diagnosis of rheumatoid vasculitis", section on 'Differential diagnosis'.)

●In the absence of other features of systemic RV, the initial treatment of leg ulcerations should include strategies similar to those for skin ulcers due to venous stasis, with a focus on good wound care and appropriate use of systemic antibiotics for superinfection. (See 'Initial ulcer management with topical measures' above.)

●In most patients with skin ulcers without systemic RV, we suggest initial treatment with systemic glucocorticoids rather than topical therapy alone or with an additional immunosuppressive agent (Grade 2C). Conservative wound care measures are continued in all patients with skin ulcers (with or without systemic RV in other areas) through the course of therapy until re-epithelialization is complete. Patients with very small ulcers alone can sometimes be managed with only topical measures (see 'Leg ulceration' above and 'Ulcers due to RV and/or resistant to initial topical measures' above and 'Choice of initial therapy for vasculitis' above). We take the following approaches, based upon the severity of disease and rate of worsening:

•In patients with multiple, small (typically less than 1 cm in diameter), but progressively worsening skin ulcers and who have no other evidence of systemic RV, we use prednisone (0.5 to 1.0 mg/kg/day, depending upon severity and response to therapy, taken orally). (See 'Choice of initial therapy for vasculitis' above.)

•In patients with large (greater than 1 cm diameter) vasculitic leg ulcers without other systemic involvement, we use prednisone (1 mg/kg body weight taken orally) if the ulcer development is not rapidly progressive, while observing the patient's progress over seven days. (See 'Choice of initial therapy for vasculitis' above.)

•In patients with multiple ulcers (two to three or more over 1 cm in diameter) that are rapidly progressive, we suggest treatment with intravenous (IV) pulse glucocorticoids rather than oral glucocorticoids (Grade 2C). We treat initially with a three-day pulse followed by oral prednisone for a one-week trial without a second agent. (See 'Choice of initial therapy for vasculitis' above and 'Glucocorticoids' above.)

●For patients with refractory skin ulcers, deep cutaneous ulcers, other severe skin involvement, such as refractory urticarial vasculitis even without deep ulceration, or severe visceral involvement, such as vasculitic neuropathy, severe digital ischemia, renal or pulmonary disease, pericarditis, and other significant manifestations of RV, we suggest the combination of rituximab plus high-dose glucocorticoids rather than glucocorticoids alone (Grade 2C). The combination of pulse IV cyclophosphamide and high-dose glucocorticoids is a reasonable alternative for patients who do not have access to or cannot take rituximab and patients who are responding inadequately to the regimen of rituximab and glucocorticoids. (See 'Choice of initial therapy for vasculitis' above and 'Glucocorticoids' above and 'Rituximab' above and 'Maintenance therapy' above.)

In patients receiving rituximab, we combine it with methotrexate (MTX), optimized as for RA. The high-dose pulse glucocorticoid regimen we typically use is three days of pulse methylprednisolone (given by IV infusion, generally between 7 to 15 mg/kg, not to exceed 500 mg in most children under 15, or 1 gram in adults and teens age 15 and older). Patients with more severe vasculitic involvement should receive 1 gram daily of methylprednisolone or equivalent for three days. Pulse glucocorticoid therapy should then be followed by prednisone (1 mg/kg/day, up to 80 mg/day), which is administered orally and subsequently tapered depending upon the response. (See 'Glucocorticoids' above.)

●Management of scleritis is discussed separately. (See "Treatment of scleritis".)

●In patients with an inadequate response to initial therapy with glucocorticoids and either rituximab or cyclophosphamide, we usually switch from rituximab to cyclophosphamide or from cyclophosphamide to rituximab, depending upon the initial agent, while increasing the dose of glucocorticoids by oral or IV pulse therapy, depending upon disease severity, in either case. (See 'Resistant to initial therapy' above and 'Glucocorticoids' above.)

●Preventive therapies and other considerations that may be required, depending upon the specific agents used and other comorbidities, include prophylactic therapy for Pneumocystis pneumonia, attention to pregnancy and fertility concerns, and measures for prevention of bladder toxicity and of glucocorticoid-induced osteoporosis. Aggressive patient support for smoking cessation is also important. (See 'Preventing side effects of therapy' above and "General principles of the use of cyclophosphamide in rheumatic diseases" and "General toxicity of cyclophosphamide in rheumatic diseases" and 'Smoking cessation' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges John Stone, MD, who contributed to an earlier version of this topic review.