Rheumatoid vasculitis: diagnostic and therapeutic decisions

Rheumatoid vasculitis is an uncommon but potentially catastrophic complication of RA. There are few extensive experiences recorded in the current literature and there is no consensus regarding the clinical features, laboratory findings, histologic pattern, prognosis, or appropriate management of this syndrome. We therefore surveyed 1,947 North American ARA members for their perceptions of rheumatoid vasculitis. Four hundred twenty-eight surveys were returned, of which 290 were suitable for analysis. The majority of respondents were within 10 years of fellowships and were evenly distributed among private practice, and part-time and full-time academic positions. The respondents saw 15-50 rheumatoid arthritis (RA) patients weekly and less than five RA vasculitis patients annually. The majority correctly diagnosed two actual and complex case histories from patients with and without autopsy-proven vasculitis. Respondents associated the following features most strongly with rheumatoid vasculitis - mononeuritis multiplex, digital gangrene, digital ischemic lesions, nailfold ischemic lesions, non-healing leg ulcers, palpable purpura, fingertip nodules, sensory neuropathy, scleromalacia perforans, high titer rheumatoid factor, positive visceral angiography, cryoglobulinemia, hypocomplementemia, circulating immune complexes, and histologic necrotizing vasculitis or vascular transmural neutrophilia. Digital lesions or sensory neuropathy alone were not viewed as portending an ominous prognosis by most respondents and would have been treated with nonsteroidal anti-inflammatory drugs, antimalarials, gold salts, or D-penicillamine. Other clinical manifestations considered as reflecting rheumatoid vasculitis (gangrene, mononeuritis multiplex, ulcers) were thought to worsen prognosis and would have been managed more often with corticosteroids, D-penicillamine, cytotoxic agents or plasmapheresis. Rheumatoid vasculitis is viewed as a heterogeneous group of syndromes with varying clinical and histopathologic features,which have different prognostic implications, and therefore should be managed differently. While these dta do not substitute for an extensive recorded series of patients, they provide useful information about community perceptions of an uncommon but difficult clinical problem. They identify the need for additional data to examine the validity of these attitudes.     

Improved rheumatoid digital vasculitis in a patient treated with TNFα agent blocking (infliximab)

Rheumatoid vasculitis (RV) is an uncommon but potentially catastrophic complication of rheumatoid arthritis (RA). There are few current extensive studies and no consensus regarding the clinical, laboratory, histologic features and management or prognosis of RV. We report a case of RV in a 74-year old woman with a long (14 years) history of RA, who developed vasculitis of distal arteries with gangrene of digits of upper and lower extremities. After the failure of various immunosuppressive drugs (cyclophosphamide, methotrexate), the patient was treated with anti-TNFalpha infliximab. Digital gangrene healed within four months from the start of anti-TNFalpha treatment.     

A clinical,electrophysiological, and pathological study of neuropathy in rheumatoid arthritis

Neuropathy in rheumatoid arthritis (RA) may result secondary to entrapment, vasculitis, and drug toxicity. We aimed to study clinical and electrophysiological neuropathy and pathological changes in sural nerve in patients with RA. One hundred eight patients of RA, fulfilling American College of Rheumatology 1987 criteria (mean age, 45.83 years; M/F 1:3, 80.3% seropositive) were examined clinically and electrophysiologically for evidence of peripheral neuropathy. Sural nerve biopsies were performed in the involved cases. In all RA patient medications, disease activity, results of blood tests, and X-rays of affected joints were recorded. Twenty-three patients complained of paresthesias in the extremities. Vibration sensations were decreased in 9, and tendon reflexes were decreased or absent in 28 patients. Sixty-two (57.4%) patients had electrophysiologic evidence of neuropathy. Of these 53 (85.5%) patients had pure sensory or sensory motor axonal neuropathy (mononeuritis multiplex, n = 7), while 9 (14.5%) had demyelinating neuropathy (chronic inflammatory demyelinating polyneuropathy, n = 1). Carpal tunnel syndrome was seen in 11 (10.1%) patients (associated with neuropathy in 6). Of 23 sural nerve biopsies available, perineurial thickening (n = 5, amyloid deposits n = 4), perivascular lymphomononuclear cell infiltrate (n = 4), loss of myelin fibers (n = 2), and necrotizing vasculitis (n = 1) were found. Clinically, however, seven patients had evidence of cutaneous vasculitis. Comparing the clinical characteristics of the patients with or without electrophysiological neuropathy, absence of deep tendon jerks (p < 0.005) and presence of extra articular manifestations (p < 0.01) were conspicuous in the neuropathic group. There was no relation of neuropathy with the duration of RA, seropositivity, joint erosions, joint deformities, prior disease-modifying anti-rheumatic drugs or glucocorticoid intake, and 28-joint disease activity score. Neuropathy in RA was mostly subclinical and predominantly axonal. Pathologically, neuropathy secondary to amyloid infiltration was second only to vasculitic neuropathy. Absence of deep tendon jerks and presence of vasculitis were more commonly observed in patients with neuropathy.     

Systemic rheumatoid vasculitis: a review

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) (approximately 1 to approximately 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.     

Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis

Systemic vasculitis in rheumatoid arthritis shows similarities to polyarteritis nodosa and may require equally aggressive therapy. Forty-five patients with systemic rheumatoid vasculitis were studied during treatment with either cyclophosphamide plus methylprednisolone given by intermittent bolus intravenous injection (21 patients) or a variety of other more conventional drug regimens (24 patients). In this open study, the intravenous treatment group had more severe initial disease, a higher incidence of neuropathy, and more frequent evidence of necrotizing arteritis on biopsy than the other treatment group. Despite this, intravenous cyclophosphamide plus methylprednisolone resulted in more frequent healing of vasculitic lesions including leg ulcers and neuropathy, a lower incidence of relapse, fewer serious complications, and a lower mortality than did other treatments. Toxic effects were similar in both study groups. Intravenous cyclophosphamide plus methylprednisolone is a useful early treatment for systemic rheumatoid vasculitis.     

Leprosy in a rheumatology setting: a challenging mimic to expose

Leprosy can manifest arthritis both as a complication and a comorbid disorder and can be a challenging differential diagnosis in rheumatology practice due to several common features. Uncommonly, it may present as acute severe polyarthritis with skin lesions and neurological deficit or a digital vasculitis and gangrene. We demonstrate this profile in a retrospective case series analysis of 33 patients (13 females, median age 55 years) in a community-based clinic setting over the period 1998–2012; an electronic search of case records of 41,000 patients was carried out. Rheumatoid arthritis (RA) coexisted in seven patients (three lepromatous, two tuberculoid, and two polyneuritic). Serological rheumatoid factor and antinuclear antibody were often false positive. Several patients of RA were on long-term supervised methotrexate. Rheumatologists should be aware of this clinical mimic to avoid errors in diagnosis and management.     

Giant cell arteritis associated with mononeuritis multiplex and complement-activating 19S IgM rheumatoid factor

Giant cell arteritis is a necrotizing granulomatous arteritis of large arteries, especially the aorta and its branches. Mononeuritis multiplex is a peripheral sensorimotor neuropathy usually producing foot or wrist drop, commonly associated with necrotizing arteritis of small and medium-sized arteries. Rheumatoid vasculitis is an example of the latter type of arteritis associated with high-titer 19S IgM rheumatoid factor typically occurring in patients with long-standing erosive rheumatoid arthritis. This report describes a 71-year-old man with biopsy-proved giant cell arteritis, mononeuritis (foot drop) multiplex, and high-titer complement-activating rheumatoid factor without rheumatoid arthritis. Possible pathogenic relationships are discussed.     

Rheumatoid Vasculitis—Report of a Second Case Treated with Penicillamine

A 57-year-old man with rheumatoid arthritis and vasculitis is presented. His disease was characterized by neuropathy, episcleritis, gangrene, and a high serum titer of rheumatoid factor. His progressively deteriorating clinical course appeared to have been favorably influenced by penicillamine therapy, which also resulted in a marked fall in RF titer. He is now in his fourth year of remission, and is taking only this drug. He is the second patient with malignant rheumatoid disease to have shown a satisfactory response to penicillamine therapy.     

Peripheral neuropathy with necrotizing vasculitis in rheumatoid arthritis

Objective. To examine the clinicopathologic features of the noncompressive neuropathies in rheumatoid arthritis (RA). Methods. We studied 32 patients with RA and peripheral neuropathy whose nerve and/or muscle biopsy specimens exhibited necrotizing vasculitis. Morphologic analysis of nerve specimens included light and electron microscopy studies and teased fiber preparation. Survival was evaluated, and the prognostic values of clinical, biologic, and pathologic features were assessed by Cox proportional hazards model. A prognostic assessment based on the significant variables was devised to estimate the probability of survival of any individual patient. Results. Epi and/or perineurial vasculitis was observed with the same frequency in the 17 patients with sensory and motor deficit and the 15 patients with sensory neuropathies and was associated with axonal degeneration of an average of 77.7% of the nerve fibers. The mean followup was 7.2 years, and the overall survival rate at 5 years was 57%. A full prolonged remission of the vasculitis was observed in 53% of the patientsrelapse occurred in 25%. The factors correlated with mortality, in decreasing order of significance, were clinical cutaneous vasculitis (P = 0.0003), neuropathy affecting 3 or 4 limbs (P = 0.03), and depressed level of C4 (P < 0.05). The prognostic assessment indicated a wide range of 5-year probabilities of survival, from <1% to 93%. Conclusion. Necrotizing vasculitis is responsible for the different patterns of noncompressive neuropathies in RA, including mononeuritis multiplex and distal symmetric sensory or sensorimotor neuropathy. Cutaneous vasculitis, multifocal neuropathy, and depressed C4 level were the 3 independent variables which best predicted mortality. We propose a prognostic assessment according to these variables, to stratify patients to receive more aggressive or less aggressive therapy.     

Efficacy of Filtration Leukocytapheresis on Rheumatoid Arthritis with Vasculitis

Abstract: The present study was designed to determine the efficacy of filtration leukocytapheresis (LCAP) in the treatment of rheumatoid arthritis (RA) with vasculitis. Nine RA patients with vasculitis were studied by the Malignant RA Collaborative Group formed by 8 clinical centers. A total of 7 filtration LCAP procedures using the Cellsorba column (Asahi Medical Co., Ltd., Tokyo, Japan) were performed with 1 week intervals between treatments. During each apheresis procedure, 3,000 ml of blood was filtered and returned to the patient at a flow rate of 50 ml/min for 60 min. In addition to the amelioration of arthritis, the improvement of extraarticular symptoms associated with rheumatoid vasculitis such as polyneuritis, skin ulcers, digital gangrene and rheumatoid nodules was obtained. In contrast, no improvement was observed in interstitial pneumonia or lung fibrosis. LCAP could be an optional modality for the treatment of RA with vasculitis.     

Treatment of vasculitic leg ulcers in connective tissue disease with Iloprost

Summary Leg ulcers are a recognised manifestation of cutaneous vasculitis in connective tissue diseases (CTDs) including rheumatoid arthritis (RA). Iloprost a stable prostacyclin analogue has been sucessfully used to treat Raynaud's phenomenon and digital ulcers associated with CTD's. Our aim was to assess iloprost in the treatment of vasculitic leg ulcers in CTD. In this paper we describe eight cases of vasculitic leg ulceration in association with RA and CTD, treated with intravenous iloprost. The iloprost was administered for 6–8 hours daily and continued for 21–28 days. Immunosuppressive therapy was required in three patients with severe necrotising vasculitis (RAnv). Complete ulcer healing was achieved in four patients within 6 weeks of commencing therapy while rapid improvement occurred in the other four patients. This suggests that iloprost may be useful as an adjunct to therapy for vasculitic leg ulcers. A double-blind placebo controlled study of iloprost therapy for RA leg ulcers is under way.     

Leg ulcers in patients with rheumatoid arthritis--a prospective study of aetiology, wound healing and pain reduction after pinch grafting

OBJECTIVE: To study the aetiology of leg ulcers in patients with rheumatoid arthritis (RA) and to study healing and pain relief after pinch grafting. METHODS: Twenty patients with RA and leg ulcers were studied. Diagnosis of the ulcers was founded on the clinical picture and measurements of the ankle-brachial pressure index. To detect vasculitis, skin biopsies were taken for immunohistochemistry and histopathology. Pain severity was assessed pre- and post-operatively using a visual analogue scale. RESULTS: Ten of the 20 patients had ulcers with multifactorial aetiology. Fifteen had signs of venous insufficiency, 11 had histopathological evidence of vasculitis, four had reduced arterial circulation and two patients had diabetes. Healing after pinch grafting was found in eight patients, all of whom had an ulcer area less than 15 cm(2). Eleven out of 18 patients had pain reduction after pinch grafting. CONCLUSION: The causation of leg ulcers in patients with RA was found to be multifactorial, with vasculitis and venous insufficiency as the main determinants. Pinch grafting seems to be a good alternative to conservative treatment for minor leg ulcers for these patients, regarding both wound healing and pain relief.     

Sensory neuropathy revealing necrotizing vasculitis during infliximab therapy for rheumatoid arthritis

We describe 2 patients with severe erosive rheumatoid arthritis and rheumatoid vasculitis, respectively, in whom infliximab therapy was associated with peripheral neuropathy due to necrotizing vasculitis in one patient and to progression of preexisting mononeuritis multiplex in the other.     

Pyoderma gangrenosum: An important dermatologic condition occasionally associated with rheumatic diseases

Pyoderma gangrenosum (PG) presents with refractory, sterile, deep ulcers most often on the lower legs. Clinically, PG exhibits four types, i.e., ulcerative, bullous, pustular, and vegetative types. PG may be triggered by surgical operation or even by minor iatrogenic procedures such as needle prick or catheter insertion, which is well-known as pathergy. PG is sometimes seen in association with several systemic diseases including rheumatoid arthritis (RA), inflammatory bowel disease, hematologic malignancy, and Takayasu’s arteritis. In particular, various cutaneous manifestations are induced in association with RA by virtue of the activation of inflammatory cells (neutrophils, lymphocytes, macrophages), vasculopathy, vasculitis, drugs, and so on. Clinical appearances of ulcerative PG mimic rheumatoid vasculitis or leg ulcers due to impaired circulation in patients with RA. In addition, patients with PG sometimes develop joint manifestations as well. Therefore, it is necessary for not only dermatologists but also rheumatologists to understand PG.     

Are leg ulcers in rheumatoid arthritis due to vasculitis?

Five patients with severe rheumatoid arthritis are reported in whom leg ulcers were not apparently associated with vasculitis. The conventional explanation for these ulcers deserves review. Patients with rheumatoid arthritis may develop 'gravitational' leg ulceration and pressure sores on their legs. In addition, they may develop ulcers on the lower aspects of the legs and around the ankles which are well demarcated, punched out, painful and slow to heal. These ulcers usually occur in patients with longstanding, severe, seropositive disease. They are presently considered to be due to a necrotising arteritis causing dermal infarction, since they are frequently associated with other clinical features of rheumatoid vasculitis. Wilkinson has commented that 'biopsies are seldom taken from leg ulcers'. In this paper we report five patients with severe rheumatoid arthritis who developed such leg ulcers in the absence of other clinical evidence of vasculitis and in whom biopsies of the ulcers failed to reveal vasculitis. A case is summarised as illustrative of the five patients, whose relevant histories, clinical findings, and laboratory investigations are summarised in Table 1.     

Giant cell arteritis and peripheral neuropathy: a report of 2 cases and review of the literature

Giant cell arteritis (GCA) is a systemic vasculitis primarily affecting large and medium sized vessels. While the disease may present with blindness or other signs of extracranial vasculitis, symptoms referable to the peripheral nervous system are uncommon. We describe 2 patients with biopsy proven GCA who simultaneously developed peripheral neurologic lesions. The first developed a mononeuritis multiplex superimposed on a diffuse, primarily sensory and distal polyneuropathy; the second, a symmetric, primarily motor and distal polyneuropathy. We review the published experience of GCA with peripheral nerve involvement and discuss a possible pathophysiologic basis for its occurrence.     

Neurologic manifestations of systemic vasculitis: A retrospective and prospective study of the clinicopathologic features and responses to therapy in 25 patients

A combined retrospective and prospective study of a patient population with either or both biopsy and angiographic evidence of systemic necrotizing vasculitis was undertaken in order to delineate the neurologic manifestations of this syndrome. The type, extent and natural history of the lesions in the peripheral and central nervous system were evaluated, together with the response of the nervous system disease to corticosteroids or cytotoxic agents or both. In 60 percent of the patients, there was involvement of the peripheral nervous system. Four patterns of neuropathy were seen: mononeuritis multiplex, extensive mononeuritis, cutaneous neuropathy and polyneuropathy. The central nervous system was involved in 40 percent of the patients, manifested predominantly by diffuse and focal disturbances of cerebral, cerebellar and brain stem function. This study demonstrates the complexity and heterogeneity of the neurologic complications of the systemic necrotizing vasculitides. With treatment of the vasculitic process and prevention of further insult, both the peripheral and central nervous system make significant, and at times, dramatic, recovery.     

The electroneurophysiological evaluation of Rheumatoid Arthritis patients

In Rheumatoid Arthritis (RA), one clinical hallmark of the vasculitis is the appearance of neurological findings. However, it is often difficult to diagnose these slight or early neuropathies and the study of the peripheral neuromuscular system is often made difficult by symptoms resulting from pain in the joints, and limitations of movement. It is nevertheless often possible, by means of electroneuromyography to show objectively the existence and distribution of even subclinical neuropathies. In order to evaluate the neurophysiological functions of RA patients by means of the peripheral nerve conduction and somatosensory evoked potential studies, 33 RA patients and 20 healthy controls were included in this study. Two (6%) patients were found to have carpal tunnel syndrome, while 6 (18%) patients had mononeuritis multiplex. Delayed N12, N13, N1 and P1 latencies were detected in 6 (18%) of 33 RA patients suggesting central nervous system involvement with intact peripheral nervous system. Our results confirm earlier observations that symptoms of neuropathy are fairly common in cases of RA without there being any clear correlation with any clinical variable. Therefore, the inclusion of an electroneuro-physiologic examination of the RA patients is recommended in routine diagnostic procedure.     

Vascular disease in rheumatoid arthritis: From subclinical lesions to cardiovascular risk

Rheumatoid arthritis (RA) is one of the most prevalent and complex inflammatory diseases affecting primarily the joints, but also associating several extra-articular features. The vascular disease in RA encompasses a large spectrum of lesions, from rheumatoid vasculitis to atherosclerotic lesions. During the last years the importance of the vascular disease related to atherosclerosis in terms of cardiovascular morbidity and global mortality became evident in RA. The inflammatory hypothesis of atherosclerosis in RA implies that mediators originating from the inflamed synovial tissue or from the liver may have systemic vascular consequences, leading to endothelial dysfunction and structural abnormalities of the vessels. Hence, the global management of patients with RA must include the improvement of cardiovascular risk in parallel with the management of joint disease.     

Gastrointestinal and Hepatic Manifestations of Rheumatoid Arthritis

Rheumatoid arthritis (RA), characterized by inflammation of the synovium and surrounding structures, has a prevalence of 0.5–1%. Rheumatoid vasculitis (RV) is an inflammatory condition of the small- and medium-sized vessels that affects up to 5% of patients with RA with intestinal involvement in 10–38% of these cases. Clinically apparent RV of the gastrointestinal (GI) tract, while rare, is often catastrophic, resulting in ischemic ulcers and bowel infarction. Vasculitis of the colon may present as pancolitis clinically similar to ulcerative colitis. Rectal biopsies that include submucosal vessels are positive for vasculitis in up to 40% of cases. Abnormal esophageal motility in RA may result in heartburn and dysphagia. Chronic atrophic gastritis may be associated with hypergastrinemia and hypo- or achlorhydria, promoting small bowel bacterial overgrowth. RA is the most common cause of secondary amyloidosis with GI symptoms in 22% of affected patients. Although amyloid is usually found in the liver, it is rarely evident clinically. Felty’s syndrome occurs in less than 1% of patients with RA and is characterized by neutropenia and splenomegaly. The liver may be involved with portal fibrosis or nodular regenerative hyperplasia. Liver histology is abnormal in 92% of RA patients at autopsy, although the changes are usually mild without associated hepatomegaly. Drug-induced liver disease may occur with aspirin, sulfasalazine, and methotrexate. Significant liver damage is rare if the drug is discontinued or the patient is properly monitored. RA can affect both the GI tract and the liver; changes are usually mild except with RV.