Vasculitic neuropathy associated with Rheumatoid Arthritis, a case report

ABSTRACT

Rheumatoid vasculitis which affects small-to-medium-sized vessels is a rare and late complication of rheumatoid arthritis. It is defined histologically as immune complex deposition in venules, capillaries and arterioles.¹ Vasculitis in the vasa nervorum leads to infarction of peripheral nerves which leads to neuropathy. We present a case of mononeuritis multiplex due to rheumatoid vasculitis.

1. Case presentation

A 70 year old woman with rheumatoid arthritis presented with bilateral lower limb numbness and left foot drop of 1-day duration. She noted generalized fatigue and small punctate lesions on her shins and forearm. For 20 years, she has been on 20 mg methotrexate and 5 mg daily prednisone. The methotrexate was discontinued 2 years earlier after undergoing a partial colon resection for perforated diverticulitis. Since then she has been on prednisone 10 mg followed by 7.5 mg daily. Her rheumatoid arthritis was considered under control. Her pertinent exam findings included small punctate lesions across the right foot. Small subcutaneous nodules across the left forearm, bilateral ulnar deviation, and mild synovial thickening of MCPs. She had a left foot dorsiflexion of 0/5 strength, and absent left ankle jerk. The sensation was diminished on the dorsum of the left foot and lateral leg. An extensive workup for neuropathy revealed normal electrolytes, CBC, TSH, copper level and cryoglobulins. Further workup revealed negative ANA, SSA, SSB, acute hepatitis panel, vitamin B12, Lyme serology and SPEP. A non-contrast MRI of the lumbar spine was unremarkable. She had elevated RF (585 IU/mL) with normal C3 (133.2 mg/dl) and low C4 (8.4 mg/dl). Left Sural nerve biopsy revealed vasculitis (Figure 1), confirming the diagnosis of mononeuritis multiplex due to rheumatoid vasculitis. She was treated with methylprednisone 1 gram daily for 3 days followed by a prednisone taper. This was followed by 4 cycles of Rituximab infusions. Her left foot dorsiflexion improved to 2/5 strength.

Figure 1.

Left sural nerve.

Small muscular arteries showing chronic inflammatory cells in the wall and fibrin deposition.

2. Discussion

The current incidence of rheumatoid arthritis (RA) is 1.3 million U.S adults [1]. Rheumatoid vasculitis is a rare complication with 1% incidence rate. Extra-articular manifestations (EAMs) develop in 40% of patients with RA and contribute to significant disease-related morbidity and mortality. Among these, systemic rheumatoid vasculitis (RV), characterized by inflammation of mid-size arteries and capillaries, has a particularly poor outcome [1,2]. About 40% of patients with RV die within 5 years due to damage from vasculitis and/or consequences of immunosuppressive therapy [3]. Most common manifestations are cutaneous (almost 90% of cases of RV) such as nail-fold lesions, palpable purpura and leg ulcers [4]. Less common manifestations are scleritis (0.3–6.3% incidence), pericarditis (<10% incidence), aortitis, pulmonary vasculitis and necrotizing glomerulonephritis (8%). A case report and literature review by Kanoko S et al reviewed 45 cases of active non-infectious aortitis seen among 513 consecutive ascending aortic resections, of which approximately 4% were RA patients [5–8]. Although common extra-articular manifestations are skin lesions, a clinician should also look for cardiac and pulmonary manifestation expecially if there is presence of concerning symptoms which are not otherwise explained. The risk factors associated with RV include a long standing history of RA, male sex, smoking history and rheumatoid nodules. HLA class I and class II genotypes have also been associated with an increased risk of RV. The development of extra-articular manifestations were associated with rheumatoid factor seropositivity while seronegative rheumatoid vasculitis is rare [3,9–11]. In one of the largest single-centre case series by Makol et. al, the most common manifestation of RV was found to be cutaneous vasculitis, followed by rheumatoid pachymeningitis, ocular disease, pulmonary angiitis, mesenteric vasculitis and necrotizing glomerulonephritis. The study concludes that these complications continue to be observed and have not been completely eliminated despite improvements in RA management and a reported decrease in RA severity in recent years [12]. Coronary involvement is a rare, yet known presentation of RV [13]. Vasculitic neuropathy results in mononeuritis multiplex or distal symmetric sensory neuropathy [14]. Distal symmetric sensory or sensorimotor pattern occurs more commonly than mononeuritis multiplex in these patients. Peripheral neuropathy occurs because of the presence of necrotizing vasculitis of vasa nervorum suggesting that ischemic mechanism is the most likely cause of mononeuritis multiplex in rheumatoid vasculitis [14]. RV is reported to occur in patients with long-standing RA (generally >10 years in duration). Recent data from the Norfolk registry reported an average disease duration of 15.6 years [15]. The disease activity of RA is often reported to be low (burnt out) when RV presents, like with low tender and swollen joint counts found in the study by Makol et al. [12] Deposition of immune complexes appears to contribute to vascular inflammation and end-organ damage in RV. High levels of immune complexes and circulating autoantibodies, particularly RF, are often present in patients with RV [16] and are often detected at RV onset [12].

There are no current recommended guidelines for the treatment of rheumatoid vasculitis. Cyclophosphamide and prednisone historically have been used in severe systemic RA vasculitis cases but may confer considerable toxicity [13,17]. Generally a combination of rituximab and glucocorticoids are preferred over cyclophosphamide for neuropathic vasculitis due to less toxicity and better response rates and in younger patients who wish to preserve fertility. Rituximab is also favored over cyclophosphamide in patients at risk of cancer, renal failure and those with compliance issues. In patients with inadequate response to initial therapy, treatment can be switched from Rituximab to Cyclophosphamide or vice versa, depending on the initial agent, generally after 2 months of treatment [15,17,18]. There were reports of a decrease in rheumatoid vasculitis with the increase use of methotrexate, corticosteroids, and DMARDs [16,19]. However, the incidence of rheumatoid vasculitis increased with the use of biologics but decreased when hydroxychloroquine was combined with low dose aspirin [12]. Before the biologic therapies were widely used for RA, patients with RV had a worse outcome, with hazard ratio of 1.26 when 61 RV patients were compared with 244 RA controls [20]. A French study in the early 1990s found 43% mortality rate at five years on patients with neuropathy-associated vasculitis [21]. An analysis of data consisting of 88 French centers including 10 women and 7 men with active systemic RV treated with 2 to 4 infusions of rituximab, showed 12 patients (71%) achieving complete remission of the vasculitis, 4 partially responded and 1 died due to uncontrolled vasculitis. 4 patients had received cyclophosphamide previously for their vasculitis and were being treated for relapse. There are no head to head randomized controlled studies comparing cyclophosphamide and Rituximab for treatment of RV [22]. Further research is needed to evaluate the impact of immunosuppressive agents on rheumatoid vasculitis incidence.

Disclosure statement

No potential conflict of interest was reported by the authors.