Systemic Rheumatoid Vasculitis: A Review

Systemic Rheumatoid Vasculitis: A Review Marcia S. Genta, MD,* Robert M. Genta, MD,† and Cem Gabay, MD*

Objectives To review the most recent information on the incidence, clinical course, pathology, pathogenesis, diagnosis, and treatment of rheumatoid vasculitis (RV), including the still scanty data on the use of biologics. Methods PubMed and MEDLINE databases (1950-2006) were searched for the key words “vasculitis” and “rheumatoid arthritis”; and “rheumatoid arthritis” and “extra-articular manifestations.” All relevant articles in English and French were reviewed. Additional words used in follow-up research include “anti-TNF,” “rituximab,” “IL-1 receptor antagonists,” and “CTLA-4 Ig,” all in conjunction with “vasculitis.” Pertinent secondary references were also retrieved. Results RV is an inflammatory condition of the small- and medium-sized vessels that affects a subset of patients with established rheumatoid arthritis (RA) (⬃1 to ⬃5%). It has a vast array of clinical manifestations with a predilection for the skin (peripheral gangrene, deep cutaneous ulcers) and the peripheral nervous system (mononeuritis multiplex). Because of the lack of specific signs and symptoms, the diagnosis relies on the exclusion of other causes of similar lesions (diabetes, atherosclerosis, drug reactions, infection, neoplasias) and, ideally, on the histopathological demonstration of necrotizing vasculitis. Despite the availability of a host of promising new drugs for the treatment of RA, no clinical trials have tested their efficacy in RV; therefore, its management remains largely empirical. Conclusions Although RV has apparently been decreasing over the last 2 decades, possibly as a consequence of the more energetic approach to the management of RA currently used, it remains an important complication of RA that needs to be promptly recognized and treated. © 2006 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 36:88-98 Keywords rheumatoid arthritis, vasculitis, extra-articular manifestations

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heumatoid arthritis (RA) is a systemic inflammatory disorder affecting primarily the synovial joints. Sites of extra-articular manifestations include the skin, eye, lungs, and blood vessels. Vascular involvement is an integral part of the pathogenesis of RA (1) and is characterized histologically by mononuclear cell cuffing of postcapillary venules in the inflamed rheumatoid synovium (2). However, vascular inflammation is not limited to the synovium and both autopsy and blind biopsy studies (ie, biopsies from clinically normal tissues) have shown widespread inflammatory involvement of blood vessels (3,4). These vascular lesions are mostly

*Division of Rheumatology. †Division of Clinical Pathology, Geneva University Hospitals, Geneva, Switzerland. None of the authors have any conflict of interest regarding the contents of this article. C.G. is supported by a Swiss National Science Foundation Grant (320000-107592). Address reprint requests to Marcia S. Genta, MD, Division of Rheumatology, Department of Medicine, Dallas Veterans Affairs Medical Center, 4500 S. Lancaster Road, Dallas, TX 75216. E-mail: [email protected].

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asymptomatic, but occasionally may cause severe lifethreatening manifestations. The concept of rheumatoid vasculitis (RV) started to evolve in the 1960s, when vasculitis with significant clinical manifestations (skin rash, cutaneous ulcerations, gangrene, peripheral neuropathy, and visceral infarction) was described in RA patients (5-7). Forty years later there is still no universally accepted definition of RV. In practice, RV is considered when clinical manifestations of vasculitis unexplained by conditions such as diabetes, atherosclerosis, infection, drug hypersensitivity, malignancy, or other vasculitides (Wegener’s granulomatosis, cryoglobulinemia, polyarteritis nodosa) occur in a patient with an established diagnosis of RA (1). The last comprehensive clinical review of RV was published in 1990 (1). The purpose of this review was to provide the reader with updated information on incidence, clinical course, and therapy of RV in light of the remarkable changes in the treatment of RA that have taken place in the last decade.

0049-0172/06/$-see front matter © 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2006.04.006

M.S. Genta, R.M. Genta, and C. Gabay

METHODS PubMed and MEDLINE databases (1950-2006) were searched for the key words “vasculitis” and “rheumatoid arthritis,” and “rheumatoid arthritis” and “extra-articular manifestations.” All relevant articles in English and French were reviewed. Additional words used in follow-up research include “anti-TNF,” “rituximab,” “IL-1 receptor antagonists,” and “CTLA-4 Ig,” all in conjunction with “vasculitis.” Pertinent secondary references were also retrieved. The absence of large published series, particularly randomized trials, on RV has prevented us from taking a “systematic review” approach (8,9). Thus, most information was gathered from uncontrolled series and case reports. We have attempted to analyze all published material critically, particularly with respect to the criteria used for the clinical and pathological diagnosis of vasculitis. Aware that this traditional approach has much more potential for bias than systematic reviews or meta-analyses, we have endeavored to be inclusive and open-minded. RESULTS Epidemiology Assessing the frequency of RV is complicated by the lack of a rigorous definition of vasculitis, the paucity of specific data, and the confounding effects of drugs administered to patients in most published series. As aptly noted by Bacons and Kitas, “the recorded incidence [of rheumatoid vasculitis] reflects the perseverance which has been put into the observations” (10). Autopsy data have reported systemic vasculitis in 15% of RA patients in Hungary (11), 23% at the Mayo Clinic in the United States (12), and 31% in Japan (4). When carefully examined, however, the real figures depart considerably from the oftencited ones. For example, the Japanese study (4) distinguishes between “active” and “inactive” angiitis,” the latter being defined as “intimal proliferation and fibrosis of small arteries and arterioles.” Although narrowing or occlusion with intimal thickening has been considered as part of the healing phase of an inflammatory process, few pathologists would accept such vague criteria as evidence of vasculitis. Only 5 of the 81 patients (6%) had “active angiitis,” defined as “fibrinoid degeneration and infiltration of the walls of small arteries and arterioles by inflammatory cells”—a more realistic description of vasculitis as we understand it. In the Mayo Clinic study (12) only 4 of the 52 (8%) RA patients autopsied had widespread inflammation of small- and medium-sized arteries and arterioles, as well as focal involvement of larger arteries, capillaries, and veins. The remainder had vascular lesions deemed to be either caused by rheumatic fever or so nonspecific that they were not “considered further.” Clinically apparent vasculitis in patients with RA is much less frequent than suggested by autopsy reports. In a series of 141 Northern Italian patients with RA followed for 2 years, vasculitis was detected in only 3 subjects (a

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“frequency” of 2.1%) (13). In a Belgian study 2 groups of patients with RA were monitored for 18 months: 91 patients were receiving methotrexate (MTX) and 130 matched patients were being treated with various drugs excluding MTX. An identical percentage of subjects in the 2 groups (5.4%) developed clinical cutaneous vasculitis (14). In a retrospective appraisal conducted in Paris the analysis of the records of “an estimated number of 4000 RA patients seen in 10 years” yielded 37 subjects with vasculitis (⬍1%) (15). Some recent data suggest that the incidence of this already rare complication of RA may be decreasing. A retrospective analysis conducted over a 15-year period (1988-2002) in a homogeneous English population showed that the incidence of vasculitis associated with RA decreased from 11.6/million in the first 5 years of the study to 3.6/million in the last 5 years (16). The incidences of primary vasculitides (eg, Wegener’s granulomatosis and Churg–Strauss syndrome) in that population were “stable, if not increasing” during the same period, indicating that the observed decrease was specific for systemic RV and not part of a general decline of all vasculitides. The existence of such a trend, at least in the Western world, is supported by a study conducted in California showing that the rate of hospitalization for RV (adjusted for patient age, sex, and ethnicity) decreased from 170 per 100,000 persons with RA in 1983 to 99 per 100,000 in 2001, representing a 33% decline in the hospitalization risk (17). However, Turesson and coworkers have recently reported that the incidence of severe extra-articular RA, including vasculitis, in a community-based RA cohort has remained stable (18). These authors further expanded on their data in 2004, indicating that the 10-year cumulative incidence rate for severe vasculitis (defined as major cutaneous vasculitis and/or vasculitis-related neuropathy) has not decreased in the 4 decades between 1955 and 1994 (19). Possible reasons for the contrasting results include the differences in the populations studied (hospital-based versus community-based) and methods (hospitalization rates versus incident cases) (20,21). The statement that RV is more common in men than in women is often found in the literature. However, there is little evidence to support this view. Whereas some studies have shown a higher risk in men (22), others failed to detect significant gender differences (16). No data are available regarding race and ethnicity. Pathogenesis Although the pathogenetic mechanisms that precipitate clinically relevant systemic vasculitis remain unclear, immune complexes are believed to play a major role. This is supported by the strong association of systemic vasculitis with high titers of rheumatoid factors (RF) (23-25) as well as by the presence of increased circulating levels of other auto-antibodies, including antiendothelial cell antibodies (26), anti-C1q antibodies (27), and glucose-6-phosphate

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isomerase antibodies (28). Deposition of immune complexes can induce inflammatory changes through the activation of the complement cascade and the binding to cell-surface Fc receptors. High levels of RF bound to C3 were detected in RA complicated with vasculitis, but rarely and at low levels in patients with uncomplicated RA (29). The role of leukocyte Fc receptors in the pathogenesis of immune complex-mediated vasculitis has been demonstrated in experimental models (30). Fc activation mediates leukocyte degranulation, phagocytosis, expression of adhesion molecules, and the release of cytokines, including TNF-␣, IL-1, and IL-6 (31). These cytokines can contribute to the pathogenesis of RV by stimulating the expression of chemokines and adhesion molecules. In addition, IL-1 and TNF-␣ exert a procoagulant effect and induce the production of matrix metalloproteinases, thus leading to blood vessel occlusion and tissue damage, respectively. Several studies have shown that in patients with RA there is a wide spectrum of inflammatory vascular lesions, some of which are not associated with overt clinical manifestations (1,6). Interestingly, a large body of evidence supports the role of vascular inflammation in the pathogenesis of atherosclerosis (32-34). Thus, it is tempting to speculate that subclinical vascular inflammatory lesions in RA may contribute to the association between RA and the occurrence of atherosclerosis and cardiovascular events. Pathology Capillaries, arterioles, and venules are involved from the early stages of RA by an inflammatory process that results mostly in degenerative changes of the endothelium. However, clinically apparent vasculitis occurs only in the context of an inflammatory infiltrate associated with destructive lesions of the wall of medium-sized arteries, arterioles, and venules (35). Histologically, vasculitis is defined by fibrinoid necrosis of the vessel wall accompanied by a transmural inflammatory infiltrate and the presence of nuclear fragments of neutrophilic polymorphonuclear cells (leukocytoclasis) (36,37). Damage to the endothelium may trigger the formation of thrombi, with resulting ischemia in the territory served by the occluded vessels. Depending on the location and size of affected vessels, ischemia may manifest as infarcts (eg, in fingertips, myocardium, central nervous system, gastrointestinal tract), gangrene (distal portion of limbs, typically fingers and toes), or atrophy (peripheral nerves, skeletal muscles). If the onset of the vessel wall necrosis is rapid and all layers are simultaneously involved, the vessel may rupture. Since most vessels that rupture are of small caliber, the most commonly observed expressions are cutaneous petechiae and purpura, but parenchymal hemorrhages can also occur, although rarely. Petechiae and purpura may also occur without vessel rupture, as a result of the increased capillary and venule permeability induced by inflammation.

Systemic rheumatoid vasculitis Table 1 Conditions Associated with Leukocytoclastic Vasculitis 1. Idiopathic (30 to 50%) 2. Drugs (antibiotics, NSAIDs, diuretics) 3. Infections (beta-hemolytic streptococci, viral hepatitis) 4. Allergy to foods and additives 5. Connective tissue diseases (SLE, Sjögren syndrome, RA) 6. Inflammatory bowel disease 7. Malignancies NSAIDs, nonsteroidal antiinflammatory drugs; SLE, systemic lupus erythematosus; RA, rheumatoid arthritis.

Most manifestations of RV can be caused also by other vasculitides or atherosclerotic disease. Biopsy helps differentiating vasculitis from atherosclerosis; however, an etiological diagnosis of vasculitis can rarely be made. Most biopsy specimens from patients with RV will show leukocytoclastic vasculitis, a feature common to a variety of other conditions (Table 1) (36). In such instances, the correlation of morphological findings with clinical, serological, microbiological, and immunopathological data is a crucial step of the diagnostic process. In some patients, advanced lesions may show features highly suggestive of RV. The most characteristic is medial necrosis surrounded by proliferating intimal and adventitial cells oriented in a radial fashion; when the necrosis involves the entire circumference of the wall, the appearance is similar to that of a rheumatoid nodule (35). Although the histopathological demonstration of vasculitis is considered the gold standard for the diagnosis of RV, a biopsy of the affected organs is not always possible or practical. Thus, the examination of more accessible tissues, such as skeletal muscle or rectum, has been advocated (38-40). The drawback of this approach is that the yield of these nontargeted biopsies is lower than 50% (41,42). Perivascular infiltrates consisting of mixed populations of mononuclear and polymorphonuclear cells surrounding both normal and necrotizing vessels are frequently present in patients with RV (43). In 1 of the most recent studies of the vascular pathology of RV, perivascular infiltrates with 3 or more layers of cells surrounding at least 50% of the vessel wall were detected in 75% of 12 patients with proven RV, but in none of 14 controls with RA without vasculitis or 11 subjects with osteoarthritis. Thus, it has been proposed to use these lesions as a surrogate marker for vasculitis to increase the sensitivity of random muscle biopsies (37). Clinical Manifestations Systemic RV is a heterogeneous condition with a wide range of clinical manifestations that can be viewed as the end of the complex spectrum of vascular involvement in RA (Fig. 1). A considerable proportion of patients with RA have subclinical vasculitis: in a study of 35 patients

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litis by fluorescein angiography in 11 of 61 patients (18%) with RA and clinical evidence of extra-articular disease (45). The vessels most commonly involved are those of the skin (⬃90% of patients) and the vasa nervorum of peripheral nerves (⬃40%). Less frequently vasculitis affects the central nervous system, the eyes, the heart, the lungs, the kidneys, and the gastrointestinal system (38). Table 2 summarizes the most common clinical manifestations of RV and provides an indication of their relative frequencies. Skin Figure 1 The spectrum of vascular involvement in RA. An inflammatory process that results mostly in degenerative changes of the endothelium is 1 of the elementary lesions of RA and is present in virtually all patients. However, no clinical manifestations of vasculitis are present. In a subset of RA patients vasculitis manifests as digital infarcts, a condition that, when isolated, has no major clinical significance. A smaller percentage of RA (between ⬍1 and 5%) develops the constellation of signs and symptoms known as RV.

with RA without clinical evidence of systemic vasculitis, 7 (20%) had “inflammatory vascular involvement” in labial salivary gland biopsies (44); others detected retinal vascu-

Focal digital lesions, petechiae, purpura, ulcers, and gangrene are the most common dermatologic manifestations. Isolated ischemic focal digital lesions are relatively common in RA patients without other manifestations of systemic vasculitis; they follow a benign course and require no treatment other than that for RA itself (1,46). Petechiae and purpura occur mostly in the lower extremities and cannot be distinguished from those occurring in other clinical contexts, such as idiopathic thrombocytopenic purpura, Henloch–Schönlein purpura, or hypersensitivity reactions (47). Ulcers are usually deep and tend to be found in the lower extremities in unusual locations, such as the dorsum of the foot or the upper calf. These characteristic sites may help differentiate vasculitis-associ-

Table 2 Most Common Clinical Manifestations of Rheumatoid Vasculitis Site

Manifestation

Skin Ischemic focal digital lesions Petechiae, purpura, ulcers Pyoderma gangrenosusm, erythema elevatum diutinum Peripheral nerves

Approximate Frequency 90% Very common Common Rare 40%

Mononeuritis multiplex Sensory peripheral neuropathy Central nervous system

Rare Seizures, confusional state, hemiparesis

Eyes Peripheral ulcerative keratitis Heart Pericarditis, coronary arteritis, arrhythmias Kidneys

15% Rare 30% Common, difficult to prove relationship with RV Uncommon

Amyloidosis, glomerulonephritis Lungs

Uncommon Diffuse alveolar hemorrhage, pleuritis

Gastrointestinal

Rare Ischemic bowel

Systemic manifestations

80% Weight loss, fever

The assessments of frequency, extrapolated from clinical series, reviews, and case reports, are only approximations. Pertinent references are cited under “Clinical manifestations.”

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ated ulcers from those caused by more common vascular disorders, such as atherosclerosis—particularly in diabetic patients—and venous stasis (48). Gangrene results from the complete deprivation of blood flow to an area and is more likely to occur in territories irrigated by terminal arteries, such as at the extremities of fingers and toes. Pyoderma gangrenosum and erythema elevatum diutinum (a chronic form of leukocytoclastic vasculitis characterized by yellow, reddish, or brown papules, plaques, or nodules distributed symmetrically over the extensor surfaces of the extremities (49) are rare cutaneous manifestations of RV (38), although they have also been described in RA patients without other evidence of systemic vasculitis (47). Peripheral Nerves Two peripheral nerve manifestations are associated with RV: mononeuritis (multiplex) and a distal symmetric sensory or sensorimotor neuropathy. Mononeuritis multiplex is a painful asymmetric asynchronous sensory and motor peripheral neuropathy involving isolated damage to at least 2 separate nerve areas. It results from axonal degeneration resulting from necrotizing or occlusive vasculitis of the vasa nervorum (50,51) (Fig. 2). The most common manifestations are foot and wrist drop (51). Although mononeuritis multiplex may occur in a variety of systemic disorders, when detected in a patient with longstanding RA, it can be considered diagnostic of systemic vasculitis. Vasculitis-mediated axonal degeneration and demyelinization may also result in a milder, primarily sensory neuropathy that affects the lower extremities in a symmetrical fashion. Characterized by paresthesias, numbness, and burning pain, and rarely associated with mild motor deficits, this neuropathy may pose a diagnostic challenge because similar manifestations occur in patients with diabetic and alcoholic neuropathy. Electromyography can confirm the neuropathy, but does not help determine its etiology; in doubtful cases a sural nerve biopsy is indicated. Alternatively, an indirect confirmation of the vasculitic origin of the neuropathy may be obtained by detecting vasculitis in other, more easily accessible tissues, such as skin, skeletal muscle, or rectal mucosa (38,40,52).

Figure 2 As a result of vasculitis with thrombus formation in an arteriole (a) within a peripheral nerve (n), a reactive inflammatory infiltrate, which includes hemosiderin-laden macrophages (m), accumulates around the vessel, and the perineurium (p) undergoes fibrosis and thickening as the nerve fibers degenerate. Depending on the size and location of the affected nerves, a variety of sensory, motor, or mixed deficits may develop (Masson’s trichrome stain, ⫻20).

ment is suspected in patients with RA, an aggressive invasive approach appears to be warranted. Eyes Approximately 16% of patients with RV have ophthalmic manifestations (38); among them, 1 of the most severe is peripheral ulcerative keratitis (PUK, or “corneal melt”), a condition characterized by inflammation and thinning of the peripheral cornea that may lead to perforation and blindness. Symptoms consist of foreign body sensation with or without eye pain, tearing, photophobia, and reduced visual acuity. PUK may be caused by local and systemic infections and local degenerative disorders; the most common association, however, is with systemic autoimmune diseases (62). In a patient with RA, PUK usually heralds systemic vasculitis and, if left untreated, is associated not only with visual loss, but also with a mortality rate up to 30% (63).

Central Nervous System

Heart

Involvement of the central nervous system is rare (38). Patients may present with seizures (53,54), neuropsychiatric symptoms (55), confusional state (56), dementia and blindness (57), or hemiparesis (58,59). Asymptomatic vasculitic involvement of meningeal vessels has been detected at autopsy (60). The cerebrospinal fluid may show pleocytosis and hypoglycorachia (56,61); however, a definitive diagnosis can be made only by the histopathological examination of meningeal or parenchymal biopsies. In light of its potential severity, whenever central nervous system involve-

Vasculitic cardiac involvement is difficult to validate clinically because patients with RA are also predisposed to accelerated atherosclerosis (64). Thus, the development of cardiac manifestations is rarely suspected to represent evidence of systemic vasculitis. Autopsy series and case reports suggest that both coronary arteritis and aortitis do occur in the context of RA (11,65,66). Most of these lesions were silent during the patients’ life; even when they were apparent, the distinction from atherosclerotic cardiovascular disease had been clinically impossible. The frequency of pericarditis in RV is difficult to assess be-

M.S. Genta, R.M. Genta, and C. Gabay

cause it is the most common cardiac complication in patients with RA without vasculitis (64) and is usually asymptomatic (67,68). Patients with RV may have a higher frequency of symptomatic pericarditis, but no precise data are available (1). Kidneys Renal involvement is reported in approximately onequarter of patients with systemic RV (38); however, there is little information on the specific histopathological features of the kidneys of affected patients. Rare patients have focal segmental necrotizing glomerulonephritis, considered the glomerular expression of vasculitis (69). Lungs Vasculitis, rarely reported in the lungs, may be manifested by diffuse alveolar hemorrhage presenting with dyspnea, cough, and hemoptysis. The underlying lesion is necrotizing pulmonary capillaritis with acute and chronic alveolar hemorrhage; antibasement membrane and antineutrophil cytoplasmic antibodies are negative (70). Gastrointestinal System Gastrointestinal manifestations have been reported in 10% of patients with RV (38). Individual case reports have described both small- and large-bowel infarction (71,72), appendicitis (73), intrahepatic hemorrhage (74), and pancreatitis (75). Systemic Manifestations Whereas weight loss is a very frequent feature of patients with RV, fever is less commonly reported. Such signs corroborate the diagnosis of RA vasculitis only when found in association with biopsy-documented acute necrotizing arteritis (Table 3) (38). Diagnosis The typical patient is a late middle-aged person with severe RA (nodules, joint erosions, and deformities) of long duration, with high titers of RF (1,6,76). Although patients with such characteristics may be at higher risk, the appearance of suggestive signs and symptoms in a RA patient who does not fit this model should not prevent an aggressive pursuit of a possible diagnosis of systemic vasculitis. A possible approach to the diagnosis of RV is the application of a set of criteria proposed in 1984 (77) and formalized more recently (78). These criteria, summarized in Table 3, can be empirically helpful but have not been validated. Because other conditions can present with similar or identical signs and symptoms, including atherosclerosis, venous insufficiency, and infections, the histological demonstration of vasculitis in the affected organs is important

93 Table 3 Scott and Bacon’s Criteria for the Diagnosis of Systemic Rheumatoid Vasculitis 1. Mononeuritis multiplex 2. Peripheral gangrene 3. Acute necrotizing arteritis documented by biopsy in a patient with systemic illness (fever, weight loss) 4. Deep cutaneous ulcers or active extra-articular disease (eg, pleurisy, pericarditis, scleritis) accompanied by vasculitis (as evidenced by either digital infarcts or histopathological demonstration) Adapted from Turesson and Jacobsson (78). One or more of the above manifestations in a patient with RA is suggestive of RV.

and an effort should be made to obtain it. However, this is not always feasible. Therefore, surrogate criteria, such as the presence of classic ischemic skin lesions (except for isolated digital infarcts) or mononeuritis multiplex, in a patient with established RA and no other likely explanations are generally considered sufficient for a presumptive diagnosis. When histopathological confirmation is considered necessary, biopsies from a skin lesion or the sural nerve can be helpful. Other sites with reportedly high diagnostic yield for vasculitis are the rectum (40), the skeletal muscle (37,79), and the labial salivary glands (44) (the so-called “blind biopsies”). The demonstration of vascular involvement (perivascular infiltrates, or leukocytoclastic vasculitis) in biopsy specimens may be significant only in the context of manifestations consistent with systemic RV. However, necrotizing vasculitis of small- or mediumsized arteries is virtually always relevant. Laboratory Although laboratory tests are not helpful in establishing the diagnosis of RV, they are essential to rule out other conditions such as, for example, ANCA-associated vasculitides, HCV-related cryoglobulinemia, and Sjögren syndrome. Most patients with RV have anemia, elevated erythrocyte sedimentation rate and C-reactive protein, thrombocytosis, and hypoalbuminemia. These abnormalities are also seen in patients with uncomplicated, poorly controlled RA. The strongest association with the development of RV is an increased concentration of RF (22); furthermore, patients with a fatal course have been shown to have significantly higher titers of IgM and IgG RFs than those who achieved remission (80). However, the diagnostic value of these nonspecific changes remains extremely low. In a study of 31 patients with histologically proven RV compared with 50 patients with extra-articular manifestations of RA but no vasculitis, the additional diagnostic value of a wide variety of serological markers was found to be “disappointing” (81). Only increased IgA RF and decreased C3 levels appeared to make a contribution to the diagnosis of RV.

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Prognosis The mortality rate of patients with RA is at least twice that of the general population and is related to the severity of the disease (82). RV, like other major extra-articular manifestations, further increases the mortality rate (83). However, this increase is relatively small, as shown in a careful study specifically designed to evaluate the prognosis of RV. The mortality of 61 patients with RV was compared with that of 244 RA patients without overt vasculitis in a case-controlled study with a 12-year follow-up (84). There was a 44% death rate in the RV group compared with 27% in the RA group (OR ⫽ 1.63). After controlling for all RA prognostic factors, the hazard ratio of death for RV cases was only slightly higher (1.3%) than in the RA control group. The major cause of death in RV patients was found to be infection. The mortality rate of RV was similar to that reported in other studies (between 30 and 33%) (1,38). Treatment The evaluation of the literature dealing with the therapy of RV is complicated by the virtual absence of randomized controlled trials; thus, most information is gathered from small uncontrolled series and case reports. Another problem is that several of the medications used to treat RA have been implicated in the causation of systemic vasculitis. Thus, Scott’s and Bacon’s 1984 statement (“the ideal treatment has not been defined”) (77) is still relevant today. Traditional Therapies Corticosteroids are at the core of the management of RV. Many patients who develop this complication are already on maintenance therapy with low-dose corticosteroids (⬍10 mg/d prednisone). Possibly because of this, early case reports based on autopsy findings suggested that steroids might have a causal or precipitating role in the development of systemic vasculitis in patients with RA (12,57). The current experience with corticosteroids is not compatible with such a hypothesis: the majority of patients with RA at some point of their illness receive corticosteroids as an adjunct therapy, and only a minuscule percentage ever develops systemic vasculitis. A scenario more likely to explain the early authors’ suggestion is that patients who had received corticosteroids were those with more severe disease and extra-articular manifestations and, therefore, were more likely to develop vasculitis (6). For the management of RV, high doses (0.5 to 1 mg/kg/d prednisone) are generally used in combination with other agents, although there is no specific documentation of their effectiveness. MTX, the mainstay of treatment of uncomplicated RA, was also suspected of causing vasculitis; numerous case reports suggesting this association have appeared and continue to appear in the literature (85-90). However,

Systemic rheumatoid vasculitis

this notion is disputed by many authors on the ground that despite the almost universal use of MTX as first-line therapy for RA, the incidence of systemic vasculitis has not only failed to increase, but has, in fact, declined (16,17,91). This notion was further corroborated by a 1996 controlled study showing that the incidence of severe cutaneous vasculitis was virtually identical (5.4%) in 2 matched groups of RA patients with and without MTX treatment (14). Cyclophosphamide is not used for the treatment of uncomplicated RA because of its low benefit–risk ratio compared with other antirheumatic agents (92). It is, however, a well-recognized treatment of systemic vasculitis (93), including RV. In an open study 21 patients on methylprednisolone plus IV cyclophosphamide were compared with 24 patients taking other treatments (azathioprine, d-penicillamine, chlorambucil, and high-dose prednisolone) (77). Early responses (0 to 4 months), including healing of leg ulcers and neuropathy, were significantly more common in the group receiving IV cyclophosphamide with methylprednisolone. Two patients with foot drop had complete recovery within 24 hours of starting treatment. The IV cyclophosphamide group experienced less relapse (24%) than the other treatment groups (54%), but mortality was similar in both groups (24% versus 29%). D-penicillamine, used in the past with mixed results (94,95), is rarely employed in the treatment of RA because of its high toxicity (96). In older studies azathioprine has been reported to be useful in some patients, whereas no benefit was demonstrated in others (97). Although it is used in ANCA-associated vasculitides as maintenance therapy after remission is achieved with cyclophosphamide (98,99), no recent data are available regarding its use in RV. Plasmapheresis has been virtually abandoned for a variety of reasons, including the need for long and inconvenient treatment, the required combination with 1 or more immunosuppressive agents, and the availability of more effective therapies (100,101). Biologic Therapies A number of new treatments, collectively known as “biologic therapies,” have been used in the therapy of RA in the last few years. These include TNF-␣ inhibitors; B-cell depletion therapy; IL-1-receptor antagonists; and costimulation blockers. Three different TNF-␣ inhibitors (etanercept, infliximab, and adalimumab) have been introduced between 1998 and 2002 (102). Thus, the experience with these drugs for the treatment of RV is both brief and limited. In a curious replay of the events that surrounded the first reports on RV treated with corticosteroids or MTX, several reports suggest that TNF-␣ inhibitors induce vasculitis (103-111). However, other investigators have reported a successful response of RV to treatment with these drugs (112-116). These contrasting data would suggest

M.S. Genta, R.M. Genta, and C. Gabay

that the role of TNF-␣ inhibitors in the treatment of RV deserves to be evaluated. Rituximab is a chimeric anti-CD20 monoclonal antibody used for the treatment of relapsed or refractory lowgrade follicular CD20⫹ B-cell non-Hodgkin lymphoma and diffuse large B-cell lymphoma (117,118). Recently, a randomized, double-blind, controlled study showed that it is effective and apparently safe for the treatment of active RA (119). Small series and case reports have also been published indicating that rituximab may be effective in other vasculitides including ANCA-associated vasculitis and cryoglobulinemia (120-123). However, the 1 patient with RV treated with rituximab in a French series of 43 patients with systemic autoimmune diseases died of acute respiratory distress syndrome 6 weeks after starting the therapy (124). Anakinra is a recombinant IL-1-receptor antagonist used in the treatment of RA (125). Abatacept is the first in a new class of agents called costimulation blockers that interfere with optimal T-cell activation and attenuate the early steps of the inflammatory cascade (126). Abatacept was approved for the treatment of RA in 2005. To date, no peer-reviewed publications have reported the use of either of these agents for the management of RV.

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3.

4. 5. 6. 7. 8. 9. 10. 11. 12. 13.

DISCUSSION The diagnosis of RV often remains challenging because of the wide spectrum of its clinical and pathological manifestations, the lack of specific signs and symptoms, and the absence of reliable tests. Despite the availability of a host of promising new drugs for the treatment of RA, no evidence-based therapeutic guidelines have been developed. The relative rarity of this condition will very likely prevent sufficiently powerful controlled therapeutic trials from being performed. Thus, its management is largely empirical and likely to remain so. Perhaps the most important development in RV in the last 15 years is the decline in its incidence (16,17). Cigarette smoking, causally related to several types of vascular diseases (127-129), is the major environmental risk factor for RA (130) and may be associated with RV (129). Recently, smoking was also shown to increase the severity of disease in patients carrying HLA-DR-shared epitope genotypes (131). The decrease in tobacco use observed in many Western countries might be a contributing factor to the decline of RV. However, it is difficult to escape the conclusion that the novel, more intensive approach to the treatment of RV that has become the norm over the same period of time has been a major determinant of this trend. REFERENCES 1. Vollertsen RS, Conn DL. Vasculitis associated with rheumatoid arthritis. Rheum Dis Clin North Am 1990;16:445-61. 2. Schumacher Jr. HR, Synovial membrane and fluid morphologic

14.

15.

16. 17. 18.

19.

20. 21. 22.

23.

alterations in early rheumatoid arthritis: microvascular injury and virus-like particles. Ann NY Acad Sci 1975;256:39-64. Bely M, Ratko I, Hodinka L, Markus I, Tanka D, Bozsoky S. Clinical and histological evaluation of synovial needle-biopsies in patients suffering from rheumatoid arthritis. I. Relationship between clinical activity and histological pattern Acta Morphol Hung 1984;32:57-65. Suzuki A, Ohosone Y, Obana M, Mita S, Matsuoka Y, Irimajiri S, et al. Cause of death in 81 autopsied patients with rheumatoid arthritis. J Rheumatol 1994;21:33-6. Schmid FR, Cooper NS, Ziff M, McEwan C. Arteritis in rheumatoid arthritis. Am J Med 1961;30:56. Bywaters EGL, Scott JT. The natural history of vascular lesions in rheumatoid arthritis. J Chronic Dis 1963;16:905. Wikinson M, Torrance WN. Clinical background of rheumatoid vascular disease. Ann Rheum Dis 1967;26:475. Mulrow CD. Rationale for systematic reviews. BMJ 1994;309: 597-9. Mulrow CD, Cook DJ, Davidoff F. Systematic reviews: critical links in the great chain of evidence. Ann Intern Med 1997;126: 389-91. Bacons PA, Kitas GD. The significance of vascular inflammation in rheumatoid arthritis. Ann Rheum Dis 1994;53:621-3. Bely M, Apathy A, Beke-Martos E. Cardiac changes in rheumatoid arthritis. Acta Morphol Hung 1992;40:149-86. Kemper JW, Baggenstoss AH, Slocumb CH. The relationship of therapy with cortisone to the incidence of vascular lesions in rheumatoid arthritis. Ann Intern Med 1957;46:831-51. Salvarani C, Macchioni P, Mantovani W, Rossi F, Veneziani M, Boiardi L, et al. Extraarticular manifestations of rheumatoid arthritis and HLA antigens in northern Italy. J Rheumatol 1992; 19:242-6. Kaye O, Beckers CC, Paquet P, Arrese JE, Pierard GE, Malaise MG. The frequency of cutaneous vasculitis is not increased in patients with rheumatoid arthritis treated with methotrexate. J Rheumatol 1996;23:253-7. Wattiaux MJ, Kahn MF, Thevenet JP, Sauvezie B, Imbert JC. Vascular involvement in rheumatoid polyarthritis. Retrospective study of 37 cases of rheumatoid polyarthritis with vascular involvement and review of the literature. Ann Med Interne (Paris) 1987;138:566-87. Watts RA, Mooney J, Lane SE, Scott DG. Rheumatoid vasculitis: becoming extinct? Rheumatology (Oxford) 2004;43:920-3. Ward MM. Decreases in rates of hospitalizations for manifestations of severe rheumatoid arthritis, 1983-2001. Arthritis Rheum 2004;50:1122-31. Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years. Ann Rheum Dis 2003;62:722-7. Turesson C, McClelland RL, Christianson TJ, Matteson EL. No decrease over time in the incidence of vasculitis or other extraarticular manifestations in rheumatoid arthritis: results from a community-based study. Arthritis Rheum 2004;50:3729-31. Puechal X. Incidence of vasculitis in rheumatoid arthritis: comment on the article by Turesson et al. Arthritis Rheum 2005;52: 1620. Watts RA, Lane SE, Scott DG. Decrease over time in the incidence of systemic rheumatoid vasculitis: comment on the article by Turesson et al. Arthritis Rheum 2005;52:1620-1621. Voskuyl AE, Zwinderman AH, Westedt ML, Vandenbroucke JP, Breedveld FC, Hazes JM. Factors associated with the development of vasculitis in rheumatoid arthritis: results of a casecontrol study. Ann Rheum Dis 1996;55:190-2. Scott DG, Bacon PA, Allen C, Elson CJ, Wallington T. IgG rheumatoid factor, complement and immune complexes in rheumatoid synovitis and vasculitis: comparative and serial studies during cytotoxic therapy. Clin Exp Immunol 1981;43:54-63.

96 24. Veys EM, Gabriel PA, Coigne E, Mielants H. Rheumatoid factor and serum IgG, IgM and IgA levels in rheumatoid arthritis with vasculitis. Scand J Rheumatol 1976;5:1-6. 25. Westedt ML, Herbrink P, Molenaar JL, de VE, Verlaan P, Stijnen T, et al. Rheumatoid factors in rheumatoid arthritis and vasculitis. Rheumatol Int 1985;5:209-14. 26. van der Zee JM, Heurkens AH, van d V, Daha MR, Breedveld FC. Characterization of anti-endothelial antibodies in patients with rheumatoid arthritis complicated by vasculitis. Clin Exp Rheumatol 1991;9:589-94. 27. Siegert CE, Daha MR, van d V, Breedveld FC. IgG and IgA antibodies to the collagen-like region of C1q in rheumatoid vasculitis. Arthritis Rheum 1990;33:1646-54. 28. van Gaalen FA, Toes RE, Ditzel HJ, Schaller M, Breedveld FC, Verweij CL, et al. Association of autoantibodies to glucose-6phosphate isomerase with extraarticular complications in rheumatoid arthritis. Arthritis Rheum 2004;50:395-9. 29. Elson CJ, Scott DG, Blake DR, Bacon PA, Holt PD. Complement-activating rheumatoid-factor-containing complexes in patients with rheumatoid vasculitis. Ann Rheum Dis 1983;42: 147-50. 30. Sylvestre D, Clynes R, Ma M, Warren H, Carroll MC, Ravetch JV. Immunoglobulin G-mediated inflammatory responses develop normally in complement-deficient mice. J Exp Med 1996; 184:2385-92. 31. Kimberly RP, Wu J, Gibson AW, Su K, Qin H, Li X, et al. Diversity and duplicity: human FC-gamma receptors in host defense and autoimmunity. Immunol Res 2002;26:177-89. 32. Hansson GK. Inflammation, atherosclerosis, and coronary artery disease. N Engl J Med 2005;352:1685-95. 33. Libby P, Theroux P. Pathophysiology of coronary artery disease. Circulation 2005;111:3481-8. 34. Ross R. Atherosclerosis—an inflammatory disease. N Engl J Med 1999;340:115-26. 35. Fassbender HG. Pathology and Pathobiology of Rheumatic Diseases. 2nd ed. Berlin, Springer Verlag, 2002. 36. Koutkia P, Mylonakis E, Rounds S, Erickson A. Leucocytoclastic vasculitis: an update for the clinician. Scand J Rheumatol. 2001;30:315-22. 37. Voskuyl AE, van Duinen SG, Zwinderman AH, Breedveld FC, Hazes JM. The diagnostic value of perivascular infiltrates in muscle biopsy specimens for the assessment of rheumatoid vasculitis. Ann Rheum Dis 1998;57:114-7. 38. Scott DG, Bacon PA, Tribe CR. Systemic rheumatoid vasculitis: a clinical and laboratory study of 50 cases. Medicine (Baltimore) 1981;60:288-97. 39. Sokoloff L, Wilens SL, Bunim JJ. Arteritis of striated muscle in rheumatoid arthritis. Am J Pathol 1951;27:157-73. 40. Tribe CR, Scott DG, Bacon PA. Rectal biopsy in the diagnosis of systemic vasculitis. J Clin Pathol 1981;34:843-50. 41. Dahlberg PJ, Lockhart JM, Overholt EL. Diagnostic studies for systemic necrotizing vasculitis. Sensitivity, specificity, and predictive value in patients with multisystem disease. Arch Intern Med 1989;149:161-5. 42. Maxeiner SR Jr, McDonald JR, Kirklin JW. Muscle biopsy in the diagnosis of periarteritis nodosa; an evaluation. Surg Clin North Am 1952;1225-33. 43. Sokoloff L, Bunim JJ. Vascular lesions in rheumatoid arthritis. J Chronic Dis 1957;5:668-87. 44. Flipo RM, Janin A, Hachulla E, Houvenagel E, Foulet A, Cardon T, et al. Labial salivary gland biopsy assessment in rheumatoid vasculitis. Ann Rheum Dis 1994;53:648-52. 45. Giordano N, D’Ettorre M, Biasi G, Fioravanti A, Moretti L, Marcolongo R. Retinal vasculitis in rheumatoid arthritis: an angiographic study. Clin Exp Rheumatol 1990;8:121-5. 46. Watts RA, Carruthers DM, Scott DG. Isolated nail fold vasculitis in rheumatoid arthritis. Ann Rheum Dis 1995;54:927-9. 47. Magro CM, Crowson AN. The spectrum of cutaneous lesions in

Systemic rheumatoid vasculitis

48. 49. 50. 51.

52. 53. 54. 55. 56. 57. 58. 59. 60. 61. 62. 63. 64. 65. 66. 67. 68.

69. 70.

rheumatoid arthritis: a clinical and pathological study of 43 patients. J Cutan Pathol 2003;30:1-10. Valencia IC, Falabella A, Kirsner RS, Eaglstein WH. Chronic venous insufficiency and venous leg ulceration. J Am Acad Dermatol 2001;44:401-21. Chen KR, Toyohara A, Suzuki A, Miyakawa S. Clinical and histopathological spectrum of cutaneous vasculitis in rheumatoid arthritis. Br J Dermatol 2002;147:905-13. Lanzillo B, Pappone N, Crisci C, di GC, Massini R, Caruso G. Subclinical peripheral nerve involvement in patients with rheumatoid arthritis. Arthritis Rheum 1998;41:1196-202. Puechal X, Said G, Hilliquin P, Coste J, Job-Deslandre C, Lacroix C, et al. Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis. A clinicopathologic and prognostic study of thirty-two patients. Arthritis Rheum 1995;38:1618-29. Schneider RE, Dobbins III. WO Suction biopsy of the rectal mucosa for diagnosis of arteritis in rheumatoid arthritis and related diseases. Ann Intern Med 1968;68:561-8. Beck DO, Corbett JJ. Seizures due to central nervous system rheumatoid meningovasculitis. Neurology 1983;33:1058-61. Neamtu L, Belmont M, Miller DC, Leroux P, Weinberg H, Zagzag D. Rheumatoid disease of the CNS with meningeal vasculitis presenting with a seizure. Neurology 2001;56:814-5. Gupta VP, Ehrlich GE. Organic brain syndrome in rheumatoid arthritis following corticosteroid withdrawal. Arthritis Rheum 1976;19:1333-8. Kim RC. Rheumatoid disease with encephalopathy. Ann Neurol 1980;7:86-91. Ramos M, Mandybur TI. Cerebral vasculitis in rheumatoid arthritis. Arch Neurol 1975;32:271-5. Ohno T, Matsuda I, Furukawa H, Kanoh T. Recovery from rheumatoid cerebral vasculitis by low-dose methotrexate. Intern Med 1994;33:615-20. Pedersen RC, Person DA. Cerebral vasculitis in an adolescent with juvenile rheumatoid arthritis. Pediatr Neurol 1998;19:6973. Spurlock RG, Richman AV. Rheumatoid meningitis. A case report and review of the literature. Arch Pathol Lab Med 1983; 107:129-31. Bathon JM, Moreland LW, DiBartolomeo AG. Inflammatory central nervous system involvement in rheumatoid arthritis. Semin Arthritis Rheum 1989;18:258-66. Rao NA, Marak GE, Hidayat AA. Necrotizing scleritis. A clinico-pathologic study of 41 cases. Ophthalmology 1985;92: 1542-9. Foster CS, Yee M. Corneoscleral manifestations of Graves’ disease, the acquired connective tissue disorders, and systemic vasculitis. Int Ophthalmol Clin 1983;23:131-57. Kitas G, Banks MJ, Bacon PA. Cardiac involvement in rheumatoid disease. Clin Med 2001;1:18-21. Albada-Kuipers GA, Bruijn JA, Westedt ML, Breedveld FC, Eulderink F. Coronary arteritis complicating rheumatoid arthritis. Ann Rheum Dis 1986;45:963-5. Gravallese EM, Corson JM, Coblyn JS, Pinkus GS, Weinblatt ME. Rheumatoid aortitis: a rarely recognized but clinically significant entity. Medicine (Baltimore) 1989;68:95-106. Cathcart ES, Spodick DH. Rheumatoid heart disease. A study of the incidence and nature of cardiac lesions in rheumatoid arthritis. Nord Hyg Tidskr 1962;266:959-64. MacDonald Jr, WJ Crawford MH, Klippel JH, Zvaifler NJ, O’Rourke RA. Echocardiographic assessment of cardiac structure and function in patients with rheumatoid arthritis. Am J Med 1977;63:890-6. Harper L, Cockwell P, Howie AJ, Michael J, Richards NT, Savage CO, et al. Focal segmental necrotizing glomerulonephritis in rheumatoid arthritis. QJM 1997;90:125-32. Schwarz MI, Zamora MR, Hodges TN, Chan ED, Bowler RP, Tuder RM. Isolated pulmonary capillaritis and diffuse alveolar

M.S. Genta, R.M. Genta, and C. Gabay

71. 72. 73. 74. 75. 76. 77. 78. 79.

80. 81. 82. 83.

84.

85. 86. 87.

88. 89.

90.

hemorrhage in rheumatoid arthritis and mixed connective tissue disease. Chest 1998;113:1609-15. Burt RW, Berenson MM, Samuelson CO, Cathey WJ. Rheumatoid vasculitis of the colon presenting as pancolitis. Dig Dis Sci 1983;28:183-8. Babian M, Nasef S, Soloway G. Gastrointestinal infarction as a manifestation of rheumatoid vasculitis. Am J Gastroenterol 1998;93:119-20. van Laar JM, Smit VT, de Beus WM, Collee G, Jansen EH, Breedveld FC. Rheumatoid vasculitis presenting as appendicitis. Clin Exp Rheumatol 1998;16:736-8. Mizuno K, Ikeda K, Saida Y, Takenaka R, Shibata M, Takeuchi T. Hepatic hemorrhage in malignant rheumatoid arthritis. Am J Gastroenterol 1996;91:2624-5. Geboes K, Dalle I. Vasculitis and the gastrointestinal tract. Acta Gastroenterol Belg 2002;65:204-12. Vollertsen RS, Conn DL, Ballard DJ, Ilstrup DM, Kazmar RE, Silverfield JC. Rheumatoid vasculitis: survival and associated risk factors. Medicine (Baltimore) 1986;65:365-75. Scott DG, Bacon PA. Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med 1984;76:377-84. Turesson C, Jacobsson LT. Epidemiology of extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol 2004;33:65-72. Zwinderman AH, Voskuyl AE, Schelhaas DD, van Duinen SG, van der Bas JM, Hazes JM. Diagnostic strategies for the histological examination of muscle biopsy specimens for the assessment of vasculitis in rheumatoid arthritis. Stat Med 2000;19: 3433-47. Geirsson AJ, Sturfelt G, Truedsson L. Clinical and serological features of severe vasculitis in rheumatoid arthritis: prognostic implications. Ann Rheum Dis 1987;46:727-33. Voskuyl AE, Hazes JM, Zwinderman AH, Paleolog EM, van der Meer FJ, Daha MR, et al. Diagnostic strategy for the assessment of rheumatoid vasculitis. Ann Rheum Dis 2003;62:407-13. Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA, et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994;37:481-94. Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. Occurrence of extra-articular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol 2002;29:62-7. Voskuyl AE, Zwinderman AH, Westedt ML, Vandenbroucke JP, Breedveld FC, Hazes JM. The mortality of rheumatoid vasculitis compared with rheumatoid arthritis. Arthritis Rheum 1996;39:266-71. Combe B, Didry C, Gutierrez M, Anaya JM, Sany J. Accelerated nodulosis and systemic manifestations during methotrexate therapy for rheumatoid arthritis. Eur J Med 1993;2:153-6. Combe B, Sany J. Extraarticular manifestations during methotrexate therapy for rheumatoid arthritis. J Rheumatol 1995;22: 790. Halevy S, Giryes H, Avinoach I, Livni E, Sukenik S. Leukocytoclastic vasculitis induced by low-dose methotrexate: in vitro evidence for an immunologic mechanism. J Eur Acad Dermatol Venereol 1998;10:81-5. Segal R, Caspi D, Tishler M, Fishel B, Yaron M. Accelerated nodulosis and vasculitis during methotrexate therapy for rheumatoid arthritis. Arthritis Rheum 1988;31:1182-5. Simonart T, Durez P, Margaux J, Van Geertruyden J, Goldschmidt D, Parent D. Cutaneous necrotizing vasculitis after low dose methotrexate therapy for rheumatoid arthritis: a possible manifestation of methotrexate hypersensitivity. Clin Rheumatol 1997;16:623-5. Torner O, Ruber C, Olive A, Tena X. Methotrexate related cutaneous vasculitis. Clin Rheumatol 1997;16:108-9.

97 91. Goronzy JJ, Weyand CM. Vasculitis in rheumatoid arthritis. Curr Opin Rheumatol 1994;6:290-4. 92. Suarez-Almazor ME, Belseck E, Shea B, Wells G, Tugwell P. Cyclophosphamide for treating rheumatoid arthritis. Cochrane Database Syst Rev 2000;CD001157. 93. Fauci AS, Katz P, Haynes BF, Wolff SM. Cyclophosphamide therapy of severe systemic necrotizing vasculitis. N Engl J Med 1979;301:235-8. 94. Axson FA. D-penicillamine in the treatment of rheumatoid vasculitis. J SC Med Assoc 1979;75:211-5. 95. Jaffe IA. The treatment of rheumatoid arthritis and necrotizing vasculitis with penicillamine. Arthritis Rheum 1970;13:436-43. 96. Suarez-Almazor ME, Spooner C, Belseck E. Penicillamine for treating rheumatoid arthritis. Cochrane Database Syst Rev 2000;CD001460. 97. Nicholls A, Snaith ML, Maini RN, Scott JT. Proceedings: controlled trial of azathioprine in rheumatoid vasculitis. Ann Rheum Dis 1973;32:589-91. 98. Jayne D, Rasmussen N, Andrassy K, Bacon P, Tervaert JW, Dadoniene J, et al. A randomized trial of maintenance therapy for vasculitis associated with antineutrophil cytoplasmic autoantibodies. N Engl J Med 2003;349:36-44. 99. Langford CA. Treatment of ANCA-associated vasculitis. N Engl J Med 2003;349:3-4. 100. Goldman JA, Casey HL, McIlwain H, Kirby J, Wilson Jr, CH Miller SB. Limited plasmapheresis in rheumatoid arthritis with vasculitis. Arthritis Rheum 1979;22:1146-50. 101. Scott DG, Bacon PA, Bothamley JE, Allen C, Elson CJ, Wallington TB. Plasma exchange in rheumatoid vasculitis. J Rheumatol 1981;8:433-9. 102. Olsen NJ, Stein CM. New drugs for rheumatoid arthritis. N Engl J Med 2004;350:2167-79. 103. Cunnane G, Warnock M, Fye KH, Daikh DI. Accelerated nodulosis and vasculitis following etanercept therapy for rheumatoid arthritis. Arthritis Rheum 2002;47:445-9. 104. Galaria NA, Werth VP, Schumacher HR. Leukocytoclastic vasculitis due to etanercept. J Rheumatol 2000;27:2041-4. 105. Guillevin L, Mouthon L. Tumor necrosis factor-alpha blockade and the risk of vasculitis. J Rheumatol 2004;31:1885-7. 106. Jarrett SJ, Cunnane G, Conaghan PG, Bingham SJ, Buch MH, Quinn MA, et al. Anti-tumor necrosis factor-alpha therapy-induced vasculitis: case series. J Rheumatol 2003;30:2287-91. 107. McIlwain L, Carter JD, Bin-Sagheer S, Vasey FB, Nord J. Hypersensitivity vasculitis with leukocytoclastic vasculitis secondary to infliximab. J Clin Gastroenterol 2003;36:411-3. 108. Mohan N, Edwards ET, Cupps TR, Slifman N, Lee JH, Siegel JN, et al. Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents. J Rheumatol 2004;31: 1955-8. 109. Roux CH, Brocq O, Albert CB, V, Euller-Ziegler L. Cutaneous vasculitis and glomerulonephritis in a patient taking the antiTNF alpha agent etanercept for rheumatoid arthritis. Joint Bone Spine 2004;71:444-5. 110. Richette P, Dieude P, Damiano J, Liote F, Orcel P, Bardin T. Sensory neuropathy revealing necrotizing vasculitis during infliximab therapy for rheumatoid arthritis. J Rheumatol 2004;31: 2079-81. 111. de Bandt M, Saint-Marcoux B. Anti TNF alpha-induced vasculitis: a French survey of 34 patients. Arthritis Rheum 2005;52(9):S652 (Abstract). 112. Armstrong DJ, McCarron MT, Wright GD. Successful treatment of rheumatoid vasculitis-associated foot-drop with infliximab. J Rheumatol 2005;32:759-60. 113. Garcia-Porrua C, Gonzalez-Gay MA, Quevedo V. Should antitumor necrosis factor-alpha be the first therapy for rheumatoid vasculitis? J Rheumatol 2006;33:433-4. 114. Garcia-Porrua C, Gonzalez-Gay MA. Successful treatment of refractory mononeuritis multiplex secondary to rheumatoid ar-

98

115. 116. 117. 118. 119.

120. 121.

122.

123. 124.

Systemic rheumatoid vasculitis thritis with the anti-tumour necrosis factor alpha monoclonal antibody infliximab. Rheumatology (Oxford) 2002;41:234-5. Unger L, Kayser M, Nusslein HG. Successful treatment of severe rheumatoid vasculitis by infliximab. Ann Rheum Dis 2003;62: 587-8. van der Bijl AE, Allaart CF, Van VJ, Van DS, Breedveld FC. Rheumatoid vasculitis treated with infliximab. J Rheumatol 2005;32:1607-9. Winter JN, Gascoyne RD, Van BK. Low-grade lymphoma. Hematology (Am Soc Hematol Educ Program) 2004;203-20. Younes A. New treatment strategies for aggressive lymphoma. Semin Oncol 2004;31:10-3. Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572-81. Ferraro AJ, Day CJ, Drayson MT, Savage CO. Effective therapeutic use of rituximab in refractory Wegener’s granulomatosis. Nephrol Dial Transplant 2005;20:622-5. Keogh KA, Ytterberg SR, Fervenza FC, Carlson KA, Schroeder DR, Specks U. Rituximab for refractory Wegener’s granulomatosis: report of a prospective, open-label pilot trial. Am J Respir Crit Care Med 2006;173:180-7. Lamprecht P, Lerin-Lozano C, Merz H, Dennin RH, Gause A, Voswinkel J, et al. Rituximab induces remission in refractory HCV associated cryoglobulinaemic vasculitis. Ann Rheum Dis 2003;62:1230-3. Specks U, Fervenza FC, McDonald TJ, Hogan MC. Response of Wegener’s granulomatosis to anti-CD20 chimeric monoclonal antibody therapy. Arthritis Rheum 2001;44:2836-40. Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y,

125.

126.

127. 128. 129. 130.

131.

Cantagrel A, et al. Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis 2005;64:913-20. Cohen S, Hurd E, Cush J, Schiff M, Weinblatt ME, Moreland LW, et al. Treatment of rheumatoid arthritis with anakinra, a recombinant human interleukin-1 receptor antagonist, in combination with methotrexate: results of a twenty-four-week, multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002;46:614-24. Kremer JM, Westhovens R, Leon M, Di GE, Alten R, Steinfeld S, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907-15. Peto R, Lopez AD, Boreham J, Thun M, Heath Jr, C Doll R. Mortality from smoking worldwide. Br Med Bull 1996;52:1221. Doll R, Peto R, Boreham J, Sutherland I. Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 2004;328:1519. Albano SA, Santana-Sahagun E, Weisman MH. Cigarette smoking and rheumatoid arthritis. Semin Arthritis Rheum 2001;31: 146-59. Silman AJ, Newman J, MacGregor AJ. Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins. Arthritis Rheum 1996; 39:732-5. Klareskog L, Stolt P, Lundberg K, Kallberg H, Bengtsson C, Grunewald J, et al. A new model for an etiology of rheumatoid arthritis: smoking may trigger HLA-DR (shared epitope)-restricted immune reactions to autoantigens modified by citrullination. Arthritis Rheum 2006;54:38-46.