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Clinical manifestations and diagnosis of rheumatoid vasculitis

Clinical manifestations and diagnosis of rheumatoid vasculitis
Literature review current through: Jan 2024.
This topic last updated: Jan 04, 2024.

INTRODUCTION — Rheumatoid vasculitis (RV) refers to a destructive, inflammatory process that is centered on the blood vessel wall itself. The condition occurs in patients with longstanding, severe rheumatoid arthritis (RA). RV is often associated with substantial potential morbidity, requires intensive immunosuppressive therapy, and leads to a significantly higher mortality than RA itself. Within a given patient with RV, clinical features of both medium- and small-vessel disease may be found, although rare patients can also present with large-vessel disease. RV leads to necrosis, blood vessel occlusion, and tissue ischemia in a manner that resembles other forms of systemic vasculitis, particularly polyarteritis nodosa (medium-vessel disease) and cutaneous small-vessel vasculitis. (See "Overview of and approach to the vasculitides in adults" and "Clinical manifestations and diagnosis of polyarteritis nodosa in adults" and "Overview of cutaneous small vessel vasculitis".)

Understanding of the precipitating factors for these extremes of blood vessel inflammation in RA is limited, and the relationship of RV to severe RA that is not associated with systemic vasculitis remains uncertain. Although the decreased life expectancy and early cardiovascular mortality in RA are well-recognized, any relationship between atherosclerotic vascular disease leading to thrombosis and RV is dubious, despite many common risk factors for these two RA complications. Atherosclerotic coronary heart disease and its relationship to RA are discussed in detail separately. (See "Coronary artery disease in rheumatoid arthritis: Implications for prevention and management".)

The epidemiology, clinical manifestations, and diagnosis of RV are reviewed in this topic. The etiology, pathogenesis, and treatment of this disorder are discussed separately. (See "Etiology and pathogenesis of rheumatoid vasculitis" and "Treatment of rheumatoid vasculitis".)

EPIDEMIOLOGY AND RISK FACTORS — Rheumatoid vasculitis (RV) is uncommon, with an annual incidence among patients with rheumatoid arthritis (RA) that has decreased since the 1980s to less than 1 percent (see 'Incidence' below). These estimates are consistent with an approximate annual incidence of RA of about 400 per million persons, with a prevalence of about 1 percent among White Americans and Northern Europeans, and separate estimates of an annual incidence of clinically significant RV of below four per million. (See "Epidemiology of, risk factors for, and possible causes of rheumatoid arthritis".)

Prevalence — Autopsy series of patients with RA suggested that RV affects as many as 25 to 31 percent of patients with RA, although one of the two reports was from 1954 and the other dealt with patients known to have RA who died between 1960 and 1990 [1,2]. Clinically evident disease is much less common. The lifetime occurrence of RV in one large retrospective study of patients in northern Italy seen in the late 1980s was 2 percent [3]. A smaller prospective study found cutaneous vasculitis in 5.4 percent of patients during an 18-month period of observation in the early 1990s [4].

One large survey found that rheumatoid aortitis, one form of vasculitis, was responsible for about 4 percent of non-infectious aortitis in patients undergoing ascending aortic aneurysm surgery [5], but one expert has suggested that the number may be closer to 1 percent [6]. Another unselected large series of RA patient autopsies from 1958 to 1985 found aortitis in 5 percent and other features of RV in 7 of the 10 patients with demonstrable aortitis, suggesting that aortitis is a clinical extension of the systemic inflammatory disease [7]. A paucity of RA-associated aortitis case reports since the advent of biologic therapies (eg, anti-tumor necrosis factor [TNF] agents, anti-CD20, and other therapies) suggests that the incidence of this condition may be decreasing [8].

Incidence — The incidence of RV has been decreasing since the 1980s to mid-1990s, according to studies performed both in the United States [9-11] and in the United Kingdom [12]; this decrease has corresponded with the increasing use of methotrexate (MTX) and the advent of biologic disease-modifying antirheumatic drug (DMARD) therapy for the treatment of RA, although these therapeutic advances do not appear to entirely explain the change in incidence. Additionally, the onset of RV may be occurring at a later age, compared with earlier cohorts, but an association with current or previous heavy cigarette smoking persists.

As an example of the changing incidence, in a study comparing two population-based cohorts of patients from Olmsted County, Minnesota, who met diagnostic criteria for RA since 1985, the 10-year cumulative incidence of vasculitis, but not of other extraarticular features of RA, was significantly lower in the cohort of patients first meeting criteria for RA between 1995 and 2007 compared with the cohort from 1985 to 1994 (0.6 versus 3.6 percent) [9]. By contrast, there had been no decrease in the incidence of RV or other extraarticular manifestations of RA in this population from 1955 through 1994 [13].

Similarly, reports of incident cases of RV in one region of the United Kingdom decreased from approximately 12 per million population per year to less than four per million during the period from 1988 through 2002 [14]. A decline in the prevalence of RV during the 1990s was also noted in a study of over 37,000 United States veterans, with the most marked declines occurring between 2000 and 2001 among both outpatients and inpatients (31 and 53 percent, respectively) [10].

Two widely used drugs, hydroxychloroquine (HCQ) and aspirin, might have a protective effect on the development of RV. A 2014 case-control study found significantly decreased risks of RV among patients with RA who were treated with HCQ (odds ratio [OR] 0.54, 95% CI 0.31-0.94) or daily low-dose (81 mg) aspirin (OR 0.42, 95% CI 0.21-0.85) [15]. Whether the reduced odds of RV observed with HCQ relate to the beneficial effects of HCQ on hyperlipidemia and thrombosis is not known [16]. However, use of HCQ and aspirin, both relatively low-toxicity drugs, may also be contributing to the declining incidence of the disease.

It is uncertain whether anti-TNF agents and other biologics also have a protective effect, since anti-TNF drugs are often used to treat RV [17]. However, a 2017 Scandinavian study of 1977 RA patients in a community-based cohort were analyzed for severe extraarticular manifestations in relation to treatment with TNF inhibitors, approximately half of which were vasculitis-related complications [18]. The risk of extraarticular disease, adjusted for age and sex, was increased in patients treated with TNF inhibitors, compared with all other patients with RA (hazard ratio [HR] 1.21, 95% CI 1.02-1.43), suggesting that TNF inhibitor use may put patients with RA at a slightly increased risk of developing these complications, with a proportionate effect on RV.

Another study of more than 16,000 patients with RA, followed prospectively, found no increased risk of vasculitis [19]. Studies like these are complicated by the fact that TNF inhibitor-treated patients are usually sicker at the outset than the others, and may have a higher underlying risk for RV. Approximately half of all TNF inhibitor-associated vasculitis cases have been reported in patients with RA, with the rest mostly in inflammatory bowel disease; the primary culprits appear to be infliximab and etanercept, much less with adalimumab, and not yet reported with golimumab or certolizumab [20].

These events are rare, and despite data like these, the falling incidence and trend toward decreased mortality in patients with RV suggest the possibilities that RV is potentially preventable and that treatments for RV may become increasingly effective. There remains some uncertainty regarding whether other much more common nonvasculitic extraarticular manifestations of RA are prevented through the use of biologic agents or nonbiologic DMARDs, including MTX [9,21].

Ethnicity — Little is known about differences in predisposition to RV between different racial and ethnic groups, in part because White patients have been overrepresented in most relatively large studies; for example, in the largest single-center series, 88 percent of the 86 patients with RV were White Americans [15]. A 2004 meta-analysis of 18 studies involving 1568 patients with RA, 129 of whom had RV, found no racial or ethnic differences in the incidence of RV [22]. In another study, based upon self-reported ethnicity, an analysis of extraarticular manifestations of RA in a cohort of 274 predominantly Asian American (East Asian or Southeast Asian) and Hispanic American (largely Mexican and Central and South American) patients living in San Francisco did not identify any patients with vasculitis, while extraarticular manifestations, almost exclusively subcutaneous nodules and interstitial lung disease, were present in 21.5 percent [23]; however, RV represents a small fraction of all the extraarticular manifestations of RA (see "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis"), and examination of larger numbers of patients may be required to discern differing susceptibilities to RV in different ethnic and racial populations. Specific genetic factors associated with risk for RV are reviewed separately. (See "Etiology and pathogenesis of rheumatoid vasculitis", section on 'Genetic risk factors'.)

CLINICAL PRESENTATION — Rheumatoid vasculitis (RV) typically occurs in patients with longstanding, joint-destructive rheumatoid arthritis (RA). There are rare case reports of its occurrence in early disease [24-28]. The areas of the body involved most commonly by RV are the skin, digits, peripheral nerves, eyes, and heart. Cutaneous manifestations are the most common. The most devastating form of RV is characterized by a medium-sized vasculitis reminiscent of (and histologically identical to) polyarteritis nodosa. Many of the clinical manifestations of RV reflect this predilection for medium-sized vessels, even though purpura, petechiae, and papules (manifestations of cutaneous small-vessel vasculitis involvement) may also occur.

The clinical presentation of RV varies, depending upon the particular manifestations present. As an example, the most common clinical presentation among outpatients may be a male smoker with established seropositive erosive RA for 10 or more years who presents with a non-healing ulcer on one of his lower legs. Typically he will have been treated with conservative wound management and even antibiotics, but despite a month of therapy is still not healing. A quicker diagnosis is usually forthcoming in similar patients who present instead with a foot-drop or other peripheral nervous system manifestation, the second most common presentation after skin involvement. Regardless of the organ system affected, there is usually involvement of medium-sized arteries if the patient has severe enough disease to seek care for the problem.

Presentations of RV within five years of the RA diagnosis are very unusual. The late-onset of RV during the disease course was illustrated by a study in which the mean duration between the diagnosis of RA and the onset of vasculitic symptoms was 13.6 years [29]. In a study of patients with RV diagnosed between 1980 and 1993, many (68 percent) had rheumatoid nodules (picture 1) and patients were typically strongly positive for rheumatoid factor (RF) [30]. In a study of patients between 2000 and 2010, rheumatoid nodules were seen in only 44 percent of patients with RV [15]. RV usually develops at a time when the inflammatory arthritis is "burned out" (ie, when the erosive process that led to joint destruction has become less active).

The clinical presentation, severity of disease, and five-year mortality have not changed since the 1980s, when controlling for age at time of diagnosis, despite the reduction in incidence and the widespread use of cyclophosphamide and glucocorticoid protocols also used to effectively treat other forms of necrotizing vasculitis. (See 'Incidence' above and "Treatment of rheumatoid vasculitis".)

Constitutional symptoms — Patients who develop visceral RV typically have significant constitutional symptoms, including fatigue, myalgias, weight loss, and fever, unlike patients with isolated dermal ulceration or digital involvement. Because RV patients are often significantly debilitated from their previous RA, the onset of constitutional symptoms such as increased fatigue may be insidious. Myalgias may be mistaken for a flare of synovitis, but by the time RV develops, patients' joint disease is usually less active than in the past. Weight loss occurs in a significant percentage of patients, and fevers occur in a smaller subset [29,31,32].

Cutaneous vasculitis — Skin vasculitis, which occurs in as many as 90 percent of patients with RV, is the most common manifestation of RV [15,29,33]. Nailfold lesions, palpable purpura, leg ulcers, and ischemic lesions may occur. In a series of 50 patients with RV seen between 1975 and 1981, cutaneous manifestations were found in 88 percent of the patients, including cutaneous ulcers, two-thirds of which were leg ulcers (56 percent of patients with RV); digital vasculitis (51 percent); rash, manifested by purpura in about two-thirds (34 percent); and gangrene (14 percent) [29].

Isolated cutaneous lesions characterized by one or more nailfold lesions, however, are not necessarily associated with necrotizing systemic vasculitis (picture 2 and picture 3) [34,35]. Similarly, rheumatoid nodules are often present without any other signs of RV [36].

The classic skin lesions of RV are deep cutaneous ulcers on the lower extremities [33]. These lesions, found typically in the area of the medial or lateral malleoli (picture 4), are the result of necrotizing vasculitis of medium-sized arteries (image 1). One study performed largely in the 1970s found an association between skin lesions and the development of renal disease [29]. However, isolated skin involvement, including deep ulceration, was associated with decreased mortality compared with the presence of neurologic and other visceral involvement. Medium-vessel vasculitis in patients with RV can also lead to digital ischemia, necrosis, and gangrene (picture 5). Clinical manifestations of small-vessel vasculitis (eg, palpable purpura) may also be present in RV, but the clinical picture and most challenging problems are dominated by disease in medium-sized arteries and arterioles. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'When to suspect cutaneous vasculitis'.)

Histologic evidence of cutaneous vasculitis is common in skin biopsies obtained at the time of skin grafting for patients who have RA and non-healing skin ulcers. This was illustrated in a study of 20 Swedish patients with RA; 11 had cutaneous vasculitis present in a sample of skin from the ulcer margin or skin distant from the ulcerative lesion [37].

Neurologic disease — Vasculitic neuropathy, a frequent component of RV, results from infarction of individual peripheral nerves by vasculitis in the vasa nervorum [38,39]. Approximately 40 percent of patients with RV have a sensory neuropathy, and up to 20 percent develop manifestations of a mixed motor or sensory neuropathy [29,38]. Both mononeuritis multiplex and a distal symmetric sensory or sensorimotor neuropathy can occur [38]. (See "Clinical manifestations and diagnosis of vasculitic neuropathies" and "Neurologic manifestations of rheumatoid arthritis".)

Mononeuritis multiplex has three clinical hallmarks: asymmetry, asynchrony, and a predilection for distal nerves. Early in the process, nerve involvement is likely to affect one side (eg, the left peroneal nerve leading to foot drop) more than the other. Within days to weeks, however, the process may develop a more symmetric appearance, as distal peripheral nerves are affected in an additive fashion. Motor mononeuritis multiplex may cause a devastating loss of function of the hands and feet, requiring assistive devices for feeding and leg braces (ankle-foot orthoses) for ambulation. Recovery from severe vasculitic neuropathy is extremely slow, typically 12 to 18 months. Many patients have permanent sequelae of their nerve infarctions (picture 6).

The onset of vasculitic neuropathy in RV is typically rapid, in contrast to the myriad other causes of peripheral neuropathy. Patients often experience their first symptoms (numbness, tingling, or other sensory symptoms) after a period of sleep [40]. As a rule, pain is not striking at the onset of vasculitic neuropathy; rather, the predominant symptom is anesthesia. Within days or weeks of the start of sensory symptoms, muscle weakness caused by motor nerve infarction may ensue [38,39]. (See "Neurologic manifestations of rheumatoid arthritis".)

The full development of motor dysfunction within a given nerve often takes place within the day of onset. There is maximal damage at the time the condition is recognized, followed by deficits that persist for weeks or months. Assuming that the inflammatory process is arrested by therapy, most patients then have a slow, gradual return of nerve function, typically to something less than their full neuromuscular function before the nerve injury. Persistent muscle wasting in at least some sites of nerve involvement is the rule (eg, the web space between the thumb and index finger secondary to ulnar nerve infarction), although many patients have significant recoveries of muscle bulk and strength. During the recuperative period, painful neuropathy from damaged sensory nerves may be a major problem.

Central nervous system (CNS) involvement is rare in RV. The development of CNS dysfunction (eg, a stroke) in a patient with RA is seldom due to RV, particularly in the absence of flagrant vasculitis in other organ systems. Most CNS events in RA are caused by intercurrent processes or problems related only indirectly to the underlying disease (for example, the sequelae of treatment). Nevertheless, well-documented cases of CNS vasculitis associated with RV have been documented, particularly from the period of the 1940s to 1960s, when less effective therapy was available and autopsies were performed more frequently than in subsequent decades.

Ocular disease — The two principal ocular manifestations of RV are episcleritis/scleritis and peripheral ulcerative keratitis (PUK) [41,42]. Scleritis may occur in either anterior or posterior locations [41,43]. Anterior forms of scleritis are evident not only from the appearance of the eye (picture 7), but also from the substantial pain associated with this condition. One series of nine patients with RA and necrotizing scleritis who underwent scleral biopsies found vasculitis in all [44]. Bilateral scleritis is not unusual. Isolated episcleritis is a common and generally benign finding in RA, although episcleritis can accompany underlying scleritis, and the latter appears to impart the escalated risk for visual loss if untreated or if treatment is delayed. Scleritis is discussed in more detail separately. (See "Clinical manifestations and diagnosis of scleritis".)

Anterior scleritis is subdivided further into three clinical variants:

Diffuse (least severe)

Nodular (intermediate in severity)

Necrotizing (most severe)

These three variants are largely non-overlapping; progression from one variant to another is unusual. The necrotizing form of scleritis may lead to scleromalacia perforans. Not all RA patients with scleritis have vasculitis, since nodular scleritis and diffuse anterior scleritis can occur without biopsy evidence of localized or systemic vasculitis [45]. However, because the necrotizing form of scleritis is highly associated with vasculitis and may lead to scleromalacia perforans, its identification should be considered a medical emergency.

In contrast to anterior scleritis, which is typically obvious on clinical examination, posterior scleritis must be diagnosed by inference from the patient's symptoms, primarily a deep-seated pain and ocular tenderness, but also visual blurring as well as thickening of the posterior coat of the eye on B-scan ultrasonography or magnetic resonance imaging (MRI) [46]. (See "Clinical manifestations and diagnosis of scleritis", section on 'Diagnosis of scleritis'.)

PUK, a process in which inflammatory cells infiltrate the peripheral area of the cornea, often coexists with necrotizing scleritis (picture 8). In PUK, a crescent-shaped ulceration develops near the corneoscleral junction. A major concern in patients with PUK is the complication of the "corneal melt" syndrome, in which corneal keratolysis, perforation of the globe, and visual failure may occur over a short period of time [42]. Following the occurrence of a corneal melt, patients often lose all useful vision in the eye. Both necrotizing scleritis and PUK require urgent ophthalmologic evaluation and therapy; these conditions and their treatment are described in detail separately. (See "Treatment of rheumatoid vasculitis" and "Treatment of scleritis" and "Ocular manifestations of rheumatoid arthritis", section on 'Corneal inflammation and melting' and "Ocular manifestations of rheumatoid arthritis", section on 'Scleritis'.)

Cardiac disease — Several types of cardiac manifestations of RV have been described. Pericarditis is the cardiac manifestation most likely to present early in the setting of RV; its appearance should heighten concern about vasculitis, though most pericarditis in RA is not vasculitic. One series of 50 patients with RV seen in the 1970s documented cardiac manifestations, including pericarditis, arrhythmia, aortic incompetence, and myocardial infarction, in approximately one-third of patients [29]. Arrhythmias, found in 9 of 44 patients, included atrial fibrillation, ventricular arrhythmias, and complete heart block. The direct attribution of such rhythm disturbances to RV, however, is often problematic given the significant number of comorbidities suffered by many RV patients.

Much of the early RV literature, drawing on the experience with rheumatic fever, focused on the cardiac valves and vessels [47]. An autopsy series of 72 RA patients published in 1954 described arteritis within the hearts of 11 patients (15 percent) [1]. The arteritis, which affected small arteries, was often found in subacute and healing forms, typically in different stages, often associated with necrosis. Thrombosis was not observed, and aneurysm formation was not seen. However, all layers of the blood vessel wall, particularly the adventitia, were involved.

Although cases of coronary vasculitis in patients with RA are well-documented in the medical literature, myocardial infarctions that are the direct result of coronary arteritis in RV are unusual [1,47-49]. Most clinically evident coronary vasculitis in RA patients occurs in patients with an established diagnosis of RV in other organ systems and not as a presenting manifestation. One case report incorporated detailed autopsy information on a 74-year-old man with RA who developed systemic vasculitis and who died of myocardial infarction. The post-mortem examination revealed granulomatous vasculitis of the left anterior descending and circumflex arteries, with memory T cell and multinucleated giant cell infiltration of the media [50].

Despite the rarity of true coronary vasculitis in RV, one of the most important determinants of the increased mortality in RA patients is cardiovascular disease, which appears to represent accelerated development of common atherosclerosis [51-53]. Whether there is a relationship between rheumatoid coronary vasculitis and RA-associated atherosclerotic heart disease is uncertain, and there is no evidence that clinical complications of atherosclerosis are more common in patients with RV than they are in patients with RA who do not have RV. (See "Coronary artery disease in rheumatoid arthritis: Pathogenesis, risk factors, clinical manifestations, and diagnostic implications".)

Aortitis — Aortitis is a rare complication of rheumatoid vasculitis, with potential for the development of aortic valve insufficiency, aneurysm, or rupture. In contrast to rheumatoid coronary vasculitis, most rheumatoid aortitis is identified incidentally at the time of aneurysm resection in patients with RA who lack an established diagnosis of RV. Nonetheless, autopsy studies have suggested that other manifestations of vasculitis are more widespread in patients with rheumatoid aortitis than is clinically apparent; thus, aortitis does appear to be a manifestation of systemic RV. (See 'Prevalence' above.)

Aortitis lesions in RA patients frequently involve areas of atherosclerotic change but can affect individuals across the age spectrum [54]. RA-associated aortitis uniformly affects the thoracic aorta, with occasional coincident disease in the abdominal aorta [7]. RA-associated aortitis, as well as most other rheumatic disease-associated aortitis, often presents clinically with back and abdominal pain, elevated acute phase reactants, and marked constitutional symptoms, although rheumatoid aortitis may also be identified only post-mortem [7,54,55]. The pathology of aortitis in patients with RV is similar to other large vessel vasculitides in which aortitis is more common. (See "Etiology and pathogenesis of rheumatoid vasculitis", section on 'Other factors'.)

Pulmonary disease — Pulmonary disease is a common extraarticular manifestation of RA, but primary vasculitic involvement of the lung is uncommon (see "Interstitial lung disease in rheumatoid arthritis"). Pulmonary vasculitis as a complication of RV must be distinguished from interstitial lung disease that is not vasculitic in nature, since the latter is significantly more common. Although rheumatoid nodules occur in the lungs and pathologic evidence of vasculitis is an inherent feature of rheumatoid nodules, most patients with rheumatoid nodules in the lungs do not have evidence of systemic vasculitis [47,56]. (See "Overview of pleuropulmonary diseases associated with rheumatoid arthritis".)

Renal disease — Vasculitis is evident on renal biopsy in only a small number of patients with RA; it is characterized by either necrotizing glomerulonephritis or by destructive inflammation within the walls of renal arteries [57]. Most renal disease in RA patients is non-vasculitic, such as acute tubular necrosis related to nonsteroidal antiinflammatory drug (NSAID) use, secondary amyloidosis due to the chronic inflammation, and nephrotic syndrome due to drug-related membranous nephropathy. These conditions have become even more infrequent with effective therapies, and the kidneys are much less likely to be involved in extraarticular RA, compared with the skin, peripheral nerves, and eyes. (See "Overview of the systemic and nonarticular manifestations of rheumatoid arthritis", section on 'Kidney disease' and "NSAIDs: Acute kidney injury" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases", section on 'Clinical manifestations' and "Membranous nephropathy: Pathogenesis and etiology", section on 'Drugs'.)

Clinically significant renal disease does occur in a minority of patients with RV, and a number of glomerulonephritis cases accompanied by typical RV manifestations in other organs have occurred in patients typical of those most likely to develop RV.

Both renal artery involvement similar to that which occurs in polyarteritis nodosa (without aneurysm formation) and glomerulonephritis that is reminiscent of the type associated with microscopic polyangiitis or with granulomatosis with polyangiitis are well-described [57-59]; such changes are often seen in association with necrotizing ulceration [29]. The glomerular pathology caused by vasculitis in RA is typically a pauci-immune glomerulonephritis (similar to that seen in granulomatosis with polyangiitis), and is sometimes associated with crescent formation and the presence of antineutrophil cytoplasmic antibodies (ANCA) [58,59]. This type of glomerular disease contrasts with RV in other organs, which is generally thought to result from an immune complex-mediated process characterized by the organ deposition of RF, complement components, and other immunoreactants.

In contrast to other diseases associated with pauci-immune glomerulonephritis, antineutrophil cytoplasmic antibodies (ANCA) do not appear to play a role in the necrotizing glomerulonephritis seen in RV. One report indicated that RA patients with renal disease are more likely to have circulating ANCA [58], but this finding has not been replicated by other investigators. Moreover, the antigens against which the ANCA found in patients with RV are directed are neither proteinase (PR)-3 nor myeloperoxidase (MPO), the two antigens most strongly associated with the ANCA response in systemic vasculitis. Thus, there is no compelling evidence that ANCA have any role in RV, even in the rare cases of glomerulonephritis. When ANCA directed against PR-3 or MPO do occur in RA accompanied by clinical findings compatible with vasculitis, the simultaneous occurrence of two diseases (ie, an ANCA-associated vasculitis and RA) must be considered.

Gastrointestinal, pancreatic, and hepatic disease — The older RV literature describes a number of patients in whom mesenteric vasculitis complicated RA, but it is likely that fewer than 10 percent of patients with systemic necrotizing RV have clinically evident gastrointestinal involvement. It can present either acutely and as an isolated finding or together with other systemic manifestations [29]. The clinical presentations of patients with this extraarticular manifestation of RA are similar to those of polyarteritis nodosa with gastrointestinal tract involvement [36,49,60] (see "Clinical manifestations and diagnosis of polyarteritis nodosa in adults", section on 'Gastrointestinal disease') The manifestations of mesenteric vasculitis associated with RV include abdominal aneurysmal rupture with syncope and hemorrhage, sigmoid and ileal infarction, intestinal perforation, and intrahepatic hemorrhage due to pseudoaneurysm formation [60-63]. Although microaneurysms appear to be less common in RV than in polyarteritis nodosa, cases associated with microaneurysms are described [61].

LABORATORY FINDINGS

General laboratory findings — Laboratory testing in patients with rheumatoid vasculitis (RV) typically reveals nonspecific signs of the underlying inflammatory process. These include elevations in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), thrombocytosis, hypoalbuminemia, and the anemia of chronic disease. (See "Clinical manifestations of rheumatoid arthritis", section on 'Laboratory findings'.)

Urine from patients with RV-related renal disease can have nephrotic-range proteinuria and/or an active urinary sediment. RV is also associated with a number of serological abnormalities, including autoantibodies and (in many cases) hypocomplementemia. (See 'Autoantibodies' below and 'Serum complement' below.)

Autoantibodies — Most patients with RV are seropositive for rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies. Some patients also exhibit antinuclear antibodies (ANA) and antineutrophil cytoplasmic antibodies (ANCA):

Rheumatoid factor – The serum titers of RF, including immunoglobulin M (IgM), IgG, and IgA, are elevated in most patients with RV. They also tend to be higher in RV patients than in those with rheumatoid arthritis (RA) alone, but there is significant overlap in RF levels across these two populations [29]. High titers of RF are reported consistently to be the strongest predictor of the development of RV [31,32]. Vasculitis in seronegative RA is rare [30,32,64]. One study suggested that titers of IgG RF correlate well with disease activity. However, this has not been confirmed by others [29]. Levels of IgM RF (the serotype usually measured) are not good markers of disease activity [29].

Anti-CCP antibodies Most patients with RV test positively for anti-CCP antibodies, which are generally absent in patients with other forms of small-vessel vasculitis. However, the relationship between anti-CCP antibodies and RV has not been investigated thoroughly. One study found that 93 percent of patients with RV tested positive for anti-CCP (85 percent with values >15 international units/mL), compared with 7 percent of patients with other forms of systemic small-vessel vasculitis (2 percent with values >15 international units/mL) [65]. The anti-CCP titers were higher in patients with systemic RV than in RA patients without vasculitis, and also greater than in anti-CCP positive patients with ANCA-associated vasculitis.

Antinuclear antibodies ANA are present in the majority of patients with RV [29]. The ANA are nonspecific, frequently being present in patients with uncomplicated RA, and do not contribute information regarding the degree of disease activity in RV. However, ANA can be found in association with extraarticular disease and with complications of RA, and they are a predictor of overall mortality [66]. It is unknown whether particular patterns of ANA are selectively associated with the development of RV or of lupus-associated vasculitis.

Antineutrophil cytoplasmic antibodies ANCA are present in some patients with RA both with and without vasculitis. One study of 41 patients with RV found positive ANCA in 10 of them: 2 with myeloperoxidase (MPO)-associated disease, 3 with proteinase (PR)-3-associated disease, and the other 5 with non-MPO/PR-3 ANCA [67]. The usual immunofluorescence patterns observed in RA are perinuclear (P-ANCA) and atypical (A-ANCA). Cytoplasmic (C-ANCA) patterns are very rare. In nearly all cases, however, ANCA positivity in RA is caused by antibodies directed against one of the "minor" ANCA antigens (eg, lactoferrin, elastase, cathepsin G, or others), rather than PR-3 or MPO, the two antigens strongly associated with systemic vasculitis. The likelihood of an RA patient developing RV has not been associated with the level of the ANCA titer. (See "Clinical spectrum of antineutrophil cytoplasmic autoantibodies".)

Anti-endothelial cell antibodies Anti-endothelial cell antibodies have been described in some patients with RV and other forms of vasculitis, but have not been shown to be useful in clinical care. Their measurement has not been established as having utility in the diagnosis of RV, its prognostic assessment, or in gauging disease activity [68]. Such antibodies have been proposed to have roles in the pathophysiology or monitoring of multiple forms of systemic vasculitis, including RV. However, many studies of anti-endothelial antibodies suffer from inconsistent assay qualities (leading to results that are difficult to reproduce), the absence of appropriate control groups, and the problem that most antigens to which anti-endothelial cell antibodies are directed remain unidentified.

Serum complement — Patients with RV often have low serum levels of complement C3, as is also seen in other forms of systemic vasculitis, although most RA patients have serum complement levels that are generally normal or even elevated in active disease as a reflection of the acute phase response [29,69-71]. Despite the finding of hypocomplementemia in some patients with RV, there are no data to suggest that measurement of C3 or following serum complement levels is useful in monitoring disease activity, unlike its association with disease activity in patients with systemic lupus erythematosus.

DIAGNOSIS

Approach to diagnosis — The diagnosis of rheumatoid vasculitis (RV) should be suspected in any patient with a long history of rheumatoid arthritis (RA) who develops new or significantly worse constitutional symptoms and/or characteristic clinical findings of cutaneous or systemic vasculitis (see 'Clinical presentation' above). Constitutional findings, such as weight loss, fever, and fatigue, may be subtle indicators of the development of RV. Extraarticular manifestations of RA that strongly suggest RV include cutaneous ulcers on the lower extremities, digital infarctions, palpable purpura, new sensory or motor deficits, eye redness (particularly if associated with ocular pain), pericarditis, and the development of an active urine sediment.

In addition to the history, physical examination, and laboratory testing, the diagnosis of RV should be confirmed by tissue biopsy whenever possible, because the level of immunosuppression required to treat RV effectively may be associated with substantial toxicity, while RV patients who are not treated aggressively have poor prognoses. (See 'Diagnostic evaluation' below and 'History and physical' below and 'Laboratory testing' below and 'Tissue biopsy' below.)

The histopathologic findings in RV may include 1) small-vessel ("leukocytoclastic") vasculitis associated with immune complex deposition in venules, capillaries, and arterioles; and 2) pauci-immune lesions (ie, inflammation associated with sparse deposition of immunoreactants) in medium-sized arteries and renal glomeruli. The pathology of aortitis in patients with RV is a granulomatous pattern with lymphoplasmacytic infiltration, necrosis of the medial smooth muscle, and elastic fiber loss. In addition to aortic inflammation and aortic wall destruction, aortitis lesions in RV can also involve areas of atherosclerotic change. (See "Etiology and pathogenesis of rheumatoid vasculitis", section on 'Histopathology and classification'.)

In patients with selected manifestations of RV (eg, scleritis or peripheral ulcerative keratitis [PUK]), the diagnosis is sufficiently clear on physical examination as to preclude the need for biopsy. In many patients, skin involvement offers the opportunity to confirm the diagnosis (image 2A-B) and distinguish RV from other forms of vasculitis. Apart from these eye diseases and the abrupt onset of mononeuritis multiplex and other neurologic manifestations, most visceral systemic RV requires biopsy confirmation. (See 'Differential diagnosis' below.)

Diagnostic evaluation

History and physical — Patients should undergo a thorough medical history and physical examination, with particular attention to a global examination of the skin and detailed neurologic examination. Features that aid in the differential diagnosis, which depends upon the manifestations, should also be reviewed, as systemic infections and other disorders can mimic RV, and vasculitis features can rarely represent paraneoplastic disease. (See 'Differential diagnosis' below.)

Laboratory testing — The following laboratory testing should be obtained in patients suspected of RV:

Complete blood count with differential white blood cell count

Erythrocyte sedimentation rate (ESR)

Complement C3

Chemistry panel, including blood urea nitrogen (BUN) and creatinine

Urinalysis, with examination of the urinary sediment, and urine protein/creatinine ratio

Antineutrophil cytoplasmic antibody (ANCA) screening including ANCA-specificities (anti-proteinase [PR]-3 and anti-myeloperoxidase [MPO])

Antinuclear antibody (ANA) and, if positive, antigen-specificities such as anti-double stranded (ds) DNA and antibodies to extractable nuclear antigens (ENA; eg, anti-Smith and anti-ribonucleoprotein)

Rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) antibodies, if their status is not already known

Hepatitis B and C serology

Positive ANA test results are nonspecific, but ANA are often present in patients with RV and the ANA findings can be useful in the differential diagnosis. (See 'Autoantibodies' above and 'Differential diagnosis' below.)

Vasculitis in seronegative RA is rare, and other diagnoses should be considered in patients who are seronegative for anti-cyclic citrullinated peptide (anti-CCP) antibodies, particularly if they are also negative for rheumatoid factor (RF) [30,32,64] (see 'Differential diagnosis' below). Most patients will already have had testing for RF and anti-CCP antibodies at the time the diagnosis of RV is under consideration; serologic status should be confirmed in patients who have been seronegative or in whom past results are unavailable or unknown. (See 'Autoantibodies' above.)

Diagnostic imaging/angiography — Diagnostic imaging studies are useful in some patients, and angiography is also occasionally helpful, but the need for imaging is dictated by the clinical presentation, and such studies are not required routinely in all patients suspected of RV. As an example, many patients with RV exhibit signs and symptoms only of cutaneous vasculitis and would not require diagnostic imaging. The diagnosis of RV is only rarely confirmed based upon imaging alone.

As examples of scenarios in which imaging is useful, patients suspected of mesenteric ischemia, renal artery vasculitis, or aortic involvement may benefit from magnetic resonance angiography (MRA) or computed tomographic angiography (CTA) of abdominal vessels, renal arteries, or the aorta, respectively; and those suspected of cerebellar involvement of the central nervous system (CNS) may have abnormalities on MR imaging (MRI)/MRA examination.

In patients with deep skin ulceration, typically affecting the lower leg, we obtain plain radiographs to screen for involvement of underlying bone by osteomyelitis, and we may obtain MRI or ultrasound imaging if needed for the evaluation of potential abscesses or fistulas, which can themselves be primary processes or complications of RV.

Angiography is occasionally, but not uniformly, useful in RV for two reasons. First, the vessels involved in RV, though technically "medium-sized," are often below the resolution of angiography. Second, the findings on angiography in RV are nonspecific, generally revealing segmental narrowing or perhaps narrowing alternating with dilatation of blood vessels. These angiographic features are found in a broad array of disorders, including vasospasm (resulting from myriad causes) and atherosclerosis. Microaneurysms, a hallmark of polyarteritis nodosa that may be diagnostic of that disease in the proper setting, are unusual in RV [1].

Tissue biopsy — The site of the biopsy performed to confirm the diagnosis of RV depends upon the clinical findings. In patients with skin involvement and a skin biopsy consistent with RV (see 'Approach to diagnosis' above), an additional visceral biopsy is generally not necessary to verify the diagnosis.

To minimize morbidity associated with biopsies, we generally perform them in a serial fashion until diagnostic tissue is obtained and avoid sampling multiple tissues at once.

Skin biopsy The initial sites that should be biopsied are cutaneous lesions suspected of being due to vasculitis, if present. In delineating the specific cause of vasculitis, defining the distribution of the size of blood vessels involved is helpful. In patients with palpable purpura, deep punch biopsies are useful in sampling both the small blood vessels of the superficial dermis and the medium-sized muscular arteries of the deeper dermis and subcutaneous fat. Immunofluorescence studies for immunoglobulin G (IgG), IgM, IgA, and complement components help narrow the differential diagnosis. Immunofluorescence studies must be performed on fresh tissue and require sampling from a second biopsy site. In the biopsy of cutaneous ulcers, the greatest yield is from the border of the lesion. The finding of cutaneous vasculitis consistent with RV in the setting of clinically apparent systemic involvement is sufficient to confirm the diagnosis. The evaluation of patients suspected of cutaneous vasculitis, including the use of skin biopsy, is described in detail separately. (See "Evaluation of adults with cutaneous lesions of vasculitis", section on 'Skin biopsy to confirm vasculitis'.)

Nerve/muscle biopsy In the absence of a site amenable to skin biopsy, ancillary testing may identify other potential biopsy sites, depending upon the clinical findings. For example, in patients suspected of vasculitis neuropathy, electromyographic testing and determination of nerve conduction velocities (EMG/NCV) may reveal findings compatible with a mononeuritis multiplex, in which case combined nerve-muscle biopsies may be indicated. Nerve biopsies should be considered only for those patients with peripheral nerve manifestations of disease, because of the potential morbidity of these biopsies and the sampling error in unselected biopsies. Sural nerve biopsy may show either active arteritis, particularly in patients who have not received previous treatment with glucocorticoids, or a proliferative endarteritis of the epineurium, which reflects the healed stage of a previous acute arteritis [72]. Even among patients who have vasculitic nerve involvement, however, sural nerve biopsy is negative approximately half the time. For this reason, simultaneous biopsy of an adjacent muscle (eg, the gastrocnemius in the case of the sural nerve) is important. Muscle tissue, in contrast to nerve, is highly vascular. Muscle biopsy may yield the diagnosis even in the absence of clinical muscle abnormalities.

Renal biopsy In the absence of other explanations for a decline in renal function or for an active urine sediment in RA, kidney biopsy may yield useful diagnostic information. A pauci-immune glomerulonephritis confirms the presence of a small-vessel vasculitis (picture 9) [58]. Additional analyses may be required to identify other disorders.

Labial salivary gland biopsy has been reported as a potentially less invasive approach to the diagnosis of RV, although neither the author nor the editors have experience with this technique in patients suspected of RV. In one report, labial salivary gland biopsies were positive for vasculitis in 11 of 12 patients with proven RV, compared with 20 percent of 35 patients with RA alone [73]. The patients were not described as having secondary Sjögren's disease. These findings have not been confirmed in additional studies, and the utility of such testing has not been formally examined; thus, the generalizability of these observations is uncertain.

Diagnostic criteria — The American College of Rheumatology has not developed formal criteria for a diagnosis of RV. A widely accepted set of criteria is based on the RV series published in 1984 [29]; using these criteria, a diagnosis of RV is established by the presence of one or more of five associated findings: mononeuritis multiplex, peripheral gangrene, biopsy evidence for acute necrotizing arteritis and systemic disease (eg, weight loss or fever), deep skin ulcers, or active extraarticular disease (eg, pleuritis, pericarditis, scleritis), if associated with atypical digital infarcts or biopsy evidence of vasculitis. These criteria do not include any immunologic laboratory findings or provide for any exclusion criteria (eg, ANCA-associated vasculitis). Updated criteria have been proposed that include the presence of one or both serologic markers of RA (anti-CCP antibodies, RF), identify cases that may occur secondary to anti-tumor necrosis factor (TNF) treatment, and rule out other conditions that are prominent in the differential diagnosis (eg, infection, malignancy, hyperviscosity, cryoglobulinemia) [74].

DIFFERENTIAL DIAGNOSIS — Disorders that should be considered in the differential diagnosis of rheumatoid vasculitis (RV) include both mimics of vasculitis and, when vasculitis has been confirmed by biopsy, a vasculitis other than RV. (See 'Mimics of vasculitis' below and 'Other vasculitides' below.)

Mimics of vasculitis — A large number of disorders can mimic the manifestations of RV, given its capacity to involve medium, small, and large vessels and the potential for cutaneous and systemic manifestations (table 1) [75,76]. In patients without rheumatoid arthritis (RA), the absence of this disorder facilitates a ready distinction from RV, which requires its presence. In patients with RA, it is necessary to rely upon other findings that characterize the broad range of conditions that may mimic RV and other forms of vasculitis. The differential diagnosis of conditions that may mimic systemic vasculitis and vasculitis mimics with primarily or exclusively cutaneous manifestations are reviewed in detail separately. (See "Overview of and approach to the vasculitides in adults", section on 'Differential diagnosis'.)

As examples, infection, thromboembolic diseases, and malignancies may each mimic the clinical features of RV [77]. Infective endocarditis can be associated with fever, skin lesions, and renal disease with an active urine sediment and positive antineutrophil cytoplasmic antibody (ANCA) testing. Cholesterol emboli may also lead to digital ischemia, leg ulcers, livedo reticularis, and other findings easily confused with vasculitis. Thrombosis causing leg ulcers has also been reported in patients with antiphospholipid and other antibodies [78], although their frequency in RV is unknown.

Among the cancers, patients with RA are known to be at increased risk for lymphoma compared with age- and sex-matched population-based controls. This risk may be heightened by both conventional and biologic disease-modifying antirheumatic drugs (DMARDs). Lymphoproliferative disorders such as large granular lymphocyte leukemia, as well as B- and T-cell lymphomas that can be treatment associated, may present as skin ulcer [79,80]. Palpable purpura is a very common feature of the rare paraneoplastic vasculitis seen in patients from the general population diagnosed with both hematologic malignancies [81] and solid tumors [82]. While palpable purpura can be seen in RV patients with skin vasculitis (in about a third), the coincident finding of cutaneous vasculitis in a patient with RA who also has an occult malignancy must be an exceedingly rare event. (See "Cutaneous manifestations of internal malignancy", section on 'Vasculitis'.)

Pyoderma gangrenosum (PG), one of the neutrophilic dermatoses, may present as leg ulcers that can resemble the leg ulcers of RV. However, PG is much less common in RA compared with other immune disorders. The classic and most common form of PG is the ulcerative variant, which typically begins as a tender, inflammatory papule, pustule, or vesicle that develops on normal-appearing skin or at a site of trauma; the lower extremities and trunk are the most common sites. The initial inflammatory lesion subsequently expands peripherally and degenerates centrally, leading to ulcer formation. The clinical history, biopsy, and directed laboratory studies attained during patient evaluation aid in distinguishing PG from other diseases. (See "Pyoderma gangrenosum: Pathogenesis, clinical features, and diagnosis".)

Another factor that may contribute to the development of leg ulcers in RA is the combination of venous stasis disease and chronic glucocorticoid use, the latter of which leads to increased skin fragility and a tendency to ulcerations with minor trauma. Felty syndrome is an uncommon cause of refractory skin ulcers.

The ocular manifestations of RV, necrotizing scleritis and peripheral ulcerative keratitis (PUK), must be distinguished from the other common but less serious ocular abnormalities that may also result in red eyes. In RA, these conditions include keratoconjunctivitis sicca, episcleritis, choroiditis, and other inflammatory conditions of the uveal tract. (See 'Ocular disease' above and "Ocular manifestations of rheumatoid arthritis".)

Other vasculitides — Other possible causes of biopsy-proven vasculitis, some of which may occasionally occur in a patient with RA, can be confused with RV. A form of systemic vasculitis other than RV is more likely in patients who lack anti-cyclic citrullinated peptide (anti-CCP) antibodies, which can be helpful in distinguishing RV from other forms of small-vessel vasculitis [65,83]. (See 'Autoantibodies' above.)

Other causes of vasculitis that may be mistaken for RV include:

Polyarteritis nodosa – The size of blood vessels involved and the types of organs affected are nearly completely overlapping for polyarteritis nodosa and RV. The two diseases are histopathologically indistinguishable, with the exception that RV rarely leads to microaneurysm formation (see 'Clinical presentation' above and 'Renal disease' above and 'Gastrointestinal, pancreatic, and hepatic disease' above). The key to distinguishing these two disorders is the clinical setting. Arthritis and other musculoskeletal complaints associated with polyarteritis nodosa do not lead to a destructive arthritis. In the patient with a history of many years of seropositive, erosive RA, the correct diagnosis is likely RV. (See "Clinical manifestations and diagnosis of polyarteritis nodosa in adults".)

ANCA-associated vasculitides – ANCA-associated diseases (granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis [Churg-Strauss], and microscopic polyangiitis) have several features in common with RA. A migratory oligoarthritis is often among the initial disease manifestations of these conditions, and a significant proportion of patients with ANCA-associated vasculitides are rheumatoid factor (RF)-positive. Cutaneous nodules, described as cutaneous extravascular necrotizing granulomas (historically termed "Churg-Strauss granulomas"), which tend to occur over extensor surfaces (particularly in the olecranon regions), may mimic rheumatoid nodules. Because of these disease similarities, many patients with ANCA-associated vasculitis may be misdiagnosed initially as having RA. However, RV is typically seen in longstanding RA, rather than early disease, and anti-CCP testing is typically negative in ANCA-associated vasculitis [83]. (See "Granulomatosis with polyangiitis and microscopic polyangiitis: Clinical manifestations and diagnosis" and "Clinical features and diagnosis of eosinophilic granulomatosis with polyangiitis (Churg-Strauss)".)

Cutaneous small-vessel vasculitis – The potential for small-vessel involvement (cutaneous venules) in RV may lead to confusion with other small-vessel vasculitis syndromes such as cutaneous small-vessel vasculitis, previously termed hypersensitivity or leukocytoclastic vasculitis. Inflammation in cutaneous venules is often observed in RV, although involvement of medium-sized arteries and arterioles is responsible for many of the manifestations of RV. Cutaneous small-vessel vasculitis is often caused by a reaction to a medication and can also occur in association with a variety of infections. Antibiotics, for example, are among the most likely agents to result in cutaneous small-vessel vasculitis. These other syndromes can usually be distinguished by their response to discontinuation of an offending drug or their transience (in the case of viral infections). (See "Overview of cutaneous small vessel vasculitis".)

Cryoglobulinemic vasculitis – Palpable purpura, cutaneous ulcers, arthralgias (and even frank arthritis), and myalgia typically accompany cryoglobulinemic vasculitis, and thus may mimic RV. In addition, because the immunoglobulin M (IgM) component in mixed cryoglobulinemia has RF activity, patients with type II and type III cryoglobulinemia are almost always RF-positive. Cryoglobulinemia also shares with RV the tendency to produce hypocomplementemia, although the degree of hypocomplementemia (particularly C4 levels) in cryoglobulinemia is usually more profound in mixed cryoglobulinemia than in RV. Anti-CCP testing is typically negative in cryoglobulinemic vasculitis, despite the positive RF testing. Cutaneous features of small-vessel vasculitis (purpura, pustules), nearly universal in cryoglobulinemia, are less common in RV. The most important factor that distinguishes the disorders is a history of preexisting RA in patients in whom these symptoms and findings are due to RV. In the absence of an established diagnosis of RA, the diagnosis of RV is highly unlikely. (See "Mixed cryoglobulinemia syndrome: Clinical manifestations and diagnosis".)

Vasculitis associated with an overlapping systemic rheumatic disease – Arthritis, RF positivity, and joint syndromes such as Jaccoud's arthropathy frequently occur in systemic rheumatic diseases (sometimes termed "connective tissue diseases"), such as systemic lupus erythematosus, mixed connective tissue disease, and the inflammatory myopathies (polymyositis and dermatomyositis). These conditions may be associated with inflammatory arthritis that might be mistaken for RA. Cutaneous vasculitis is also a common manifestation of such disorders, potentially leading to confusion with RV. Some of these disorders are also associated with antiphospholipid antibodies, known to cause digital gangrene and cutaneous ulcers. Because patients with systemic lupus erythematosus can also develop a form of systemic vasculitis similar to RV, the presence of antinuclear antibodies in the absence of anti-CCP antibodies or RF suggests that lupus-associated vasculitis is much more likely than RV. (See "Overview of and approach to the vasculitides in adults", section on 'Vasculitis associated with systemic disease' and "Undifferentiated systemic rheumatic (connective tissue) diseases and overlap syndromes".)

IgG4-related aortitis – IgG4-related disease is a significant cause of aortitis, periaortitis, and retroperitoneal fibrosis, which may mimic rheumatoid aortitis [84]. However, there are some important clinical differences between the aortitis associated with IgG4-producing plasma cells and that associated with RA and the other rheumatic diseases. IgG4-associated aortitis affects the abdominal aorta in more than 85 percent of such patients [85], while RA-associated aortitis uniformly affects the thoracic aorta (with occasionally coincident disease in the abdominal aorta) [7]. Although RA-associated aortitis [54] and most other rheumatic disease-associated aortitis [55] often presents with back and abdominal pain, elevated acute phase reactants, and marked constitutional symptoms, these features appear to be largely lacking in IgG4-related aortitis [85]. The diagnosis of RV is associated with the presence of RA.

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

Clinical presentation – The typical patient with rheumatoid vasculitis (RV) has longstanding rheumatoid arthritis (RA), a high level of anti-cyclic citrullinated peptide (anti-CCP) antibodies and/or rheumatoid factor (RF), erosive joint disease, and often has rheumatoid nodules. (See 'Clinical presentation' above and 'Laboratory findings' above.)

Cutaneous manifestations – Skin lesions, noted in 90 percent of patients with RV, range in severity from nailfold infarcts to large ulcers and digital necrosis. (See 'Cutaneous vasculitis' above.)

Neurologic manifestations – Peripheral neuropathy, either a mononeuritis multiplex or a symmetrical polyneuropathy, occurs in approximately 40 percent of patients with RV. Central nervous system (CNS) involvement is uncommon. (See 'Neurologic disease' above.)

Ocular manifestations – The two principal ocular manifestations of RV are necrotizing scleritis and peripheral ulcerative keratitis (PUK). Patients with these extraarticular manifestations of RA do not require a tissue biopsy to make the diagnosis of RV. (See 'Ocular disease' above.)

Cardiovascular manifestations – Coronary vasculitis is rare, and myocardial infarction in patients with RV may be the result of atherosclerosis, which is more prevalent in patients with longstanding, active RA. Aortitis is a rare complication of RV, with the potential for development of aortic valve insufficiency, aneurysm, or rupture. Pulmonary vasculitis, also uncommon in RV, can cause pulmonary arterial hypertension or diffuse alveolar hemorrhage. (See 'Cardiac disease' above and 'Aortitis' above and 'Pulmonary disease' above.)

Antineutrophil cytoplasmic antibody tests – Uncommonly, antineutrophil cytoplasmic antibody (ANCA)-associated renal vasculitis and/or necrotizing glomerulonephritis, similar to that seen with granulomatosis with polyangiitis or with microscopic polyangiitis, may occur. However, cytoplasmic ANCA (C-ANCA) are rare, while minor ANCA antigens, rather than proteinase (PR)-3 or myeloperoxidase (MPO), are the usual target of the perinuclear or atypical ANCA that are sometimes present. (See 'Renal disease' above and 'Autoantibodies' above.)

Diagnosis – RV is suspected on the basis of the presence of compatible clinical features. There is no diagnostic laboratory test for RV. Nonspecific signs of the underlying inflammatory process include elevations in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), thrombocytosis, hypoalbuminemia, and the anemia of chronic disease. A variety of autoantibodies and hypocomplementemia also may be present. (See 'Laboratory findings' above and 'Diagnosis' above.)

We confirm the diagnosis of RV by biopsy of a clinically involved organ whenever it is feasible to do so. Angiography is an alternative to biopsy but is only likely to provide diagnostically useful information if the clinical setting suggests medium- or large-artery involvement. (See 'Diagnosis' above.)

Differential diagnosis – The differential diagnosis of RV includes mimics of vasculitis such as infection, malignancy, embolic diseases, and thrombotic disorders. Patients with biopsy-proven vasculitis and RA may have another type of vasculitis. (See 'Differential diagnosis' above.)

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

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Topic 8237 Version 35.0

References

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