US Pharm. 2018;43(6):26-28.
ABSTRACT: Rheumatoid vasculitis (RV) is an extraarticular manifestation of rheumatoid arthritis (RA) that develops over the course of long-standing disease. This disorder is associated with a poor prognosis, and skin and neurologic involvement is common. RV occurs more frequently in males, smokers, and those with seropositive or nodular RA, and histologic diagnosis is difficult. The incidence of RV has decreased considerably in the last decade; however, mortality remains high. Most patients are treated with pulse corticosteroid therapy in association with other immunosuppressive drugs. In addition, based on current clinical experience, biological agents, disease-modifying antirheumatic drugs, and monoclonal antibodies offer promise for the prevention and treatment of RV. Smoking cessation should also be recommended.
Rheumatoid vasculitis (RV), an extraarticular systemic manifestation of rheumatoid arthritis (RA), is the most serious and unusual complication of long-standing RA, and its prognosis is poor. The active vasculitis associated with rheumatoid disease occurs in about 1% of this patient population. Evolving genetic and immunologic studies and clinical experience with biologics hold promise for informing future prevention and treatment of RV. The pharmacist can play an important role in consulting with RA patients, especially if their disease has progressed to the point of developing RV. This article will briefly examine the pathophysiology, epidemiology, and clinical diagnosis of RV and discuss current treatment of RV with new agents that may ameliorate or even prevent RV.1
Pathophysiology and Epidemiology
RA is a systemic inflammatory disease with a pathology reflecting the widespread impact of inflammation. RV is often associated with substantial potential morbidity and requires intensive immunosuppressive therapy. Uncontrolled systemic inflammation and aggressive atherosclerotic vascular disease may mimic vasculitis manifestations, strongly suggesting that the histopathologic confirmation of vasculitis is necessary. Inflammation encompassing more than three cell layers of the vessel is a sensitive and specific finding for distinguishing RV from RA without vasculitis.2 Perivascular infiltrates that do not involve the vessel wall may be seen in RA without vasculitis, so this histologic finding should not be used to support a diagnosis of vasculitis. A large study that included patients from the Mayo Clinic Rochester Epidemiology Project and several Swedish cohorts found a strong association between smoking and the development of RV.3 Case-control studies have suggested that, in addition to tobacco use, rheumatoid factor positivity, male sex, rheumatoid nodules, and older age at onset or long-standing disease are risk factors for RV.4
The prevalence of RV has been reported to be declining, with the decrease possibly attributable to improved control of rheumatoid arthritis in the era of biological disease-modifying antirheumatic drug (DMARD) therapy.1 Clinical reports have estimated the prevalence of RV at a range of less than 1% to 5%, whereas autopsy studies have reported a prevalence of 15% to 31%.5 Interestingly, in 2006, a U.S. retrospective cohort study also concluded that the prevalence of RV has been decreasing over the past decades. This has raised the question of whether this decline may be causally linked to improved treatment of RA.6
The morbidity and mortality associated with RV are substantial. Studies have shown that the 5-year mortality rate is 30% to 50%, and rates of morbidity from disease complications or vasculitis treatment–related toxicity are even higher. Therefore, it is imperative to properly diagnose RV and select the most appropriate treatment in order to limit adverse events.7
Clinical Diagnosis
RV may affect virtually any organ of the body, but usually the skin and peripheral nerves are involved. In many case series, the skin or peripheral nerves are involved in more than 90% of patients. Cutaneous manifestations of RV are the most common type and include palpable purpura, nodules, ulcers, and digital necrosis. When skin findings are present, a careful search for other systemic manifestations is necessary to characterize the severity of the vasculitic presentation. Skin involvement without other organ-system involvement carries a more favorable prognosis.8
After cutaneous manifestations, the next most common area of involvement is the peripheral nervous system; this condition is known as vasculitic neuropathy. Distal symmetric sensory polyneuropathy, distal motor or combined neuropathy, and mononeuritis multiplex encompass the range of peripheral nervous system manifestations. Mononeuritis multiplex has three clinical hallmarks: asymmetry, asynchrony, and a predilection for distal nerves.1
Aortitis is a rare complication of RV, with potential for the development of aortic-valve insufficiency, aneurysm, and rupture.1
Laboratory tests may support—but do not confirm—a diagnosis of systemic RA or RV. Findings may include anemia of chronic inflammation, elevation of erythrocyte sedimentation rate or C-reactive protein, polyclonal hypergammaglobulinemia, and RA-associated autoantibodies. Complement levels may be dynamically decreased during active disease and, along with inflammatory parameters, may provide useful follow-up information. The location of an ulcer on the dorsal feet or shins, as distinct from more distal locations, may help distinguish RV ulcers from other sources of vascular insufficiency.1
Treatment Options
To determine treatment approaches for the patient with RV, an understanding of the clinical context in which this extraarticular manifestation of RA occurs is essential. Most patients are treated with pulse corticosteroid therapy in association with other immunosuppressive drugs. The aggressiveness of RV treatment is typically determined by the degree of organ-system involvement. Mild RV involving the skin or peripheral nerves may be treated with prednisone and methotrexate or azathioprine; more serious organ-system involvement may require treatment with higher-dose corticosteroids and cyclophosphamide or biological agents.1,9
Prednisone therapy is essential to the initial reduction of systemic inflammation. The dosage depends on the degree of inflammation and the level of organ-system involvement. Typical dosing ranges from 30 to 100 mg twice daily at onset. Central nervous system involvement, acute renal failure, and acute myocardial infarction are serious manifestations that call for IV corticosteroid therapy and consideration of cytotoxic or biological agents. Cyclophosphamide and prednisone historically have been used in severe systemic RV cases, but they may cause considerable toxicity.1,9
In milder cases, methotrexate 10 to 25 mg per week orally or IM is the DMARD of choice to pair with prednisone. It is well studied in RA, it decreases erosive arthritis and systemic inflammation, and its use in RA vasculitis is supported in reports. Azathioprine is another tested alternative at 50 to 150 mg per day in divided daily doses. Care should be taken to titrate the dose in accordance with blood counts and liver tests.1,10 Mycophenolate has also been used at a dosage of 1,000 to 2,000 mg twice daily.
Some clinical evidence supports the use of biological agents (anti–tumor necrosis factor drugs) in refractory RV, whereas other reports have raised the question of causal associations between biological agents and RV. Serious RA refractory to other treatments is more likely to necessitate treatment with a biological agent and is more likely to lead to RV, but the two conditions may not be causally linked.11
Reports also describe three cases of rituximab used successfully to treat RV. Rituximab, an anti–B-cell monoclonal antibody, has been successfully employed in patients with high levels of autoantibodies, comorbid neutropenia, or liver disease. It is administered as two 500-mg infusions at 14-day intervals. The finding of high rheumatoid factor and cyclic citrullinated peptide antibody titers in RV and observed decreases with successful treatment lends theoretical support to the use of rituximab. Its use is also supported by emerging evidence of efficacy in other types of systemic vasculitis, including Wegener granulomatosis.12
Classically, RV is an inflammatory vascular process; therefore, aggressive treatment of traditional risk factors for atherosclerotic disease is highly advised. Smoking cessation should also be recommended. Treatment of elevated blood pressure and cholesterol is important.13
Conclusion
It has been reported that RV is among the most serious complications of RA. In addition to traditional therapies, newer RA treatments, including biological therapies, offer a broader range of potential therapeutic options; however, no controlled trials exist to guide treatment. Overall, the disease manifestation, the severity of organ involvement, and tissue confirmation can lead to treatment decisions. New genetic discoveries, histopathological and immunologic studies, and current clinical experience with biological agents offer promise for prevention and treatment of RV. In any case, the diagnosis of RV usually is confirmed by biopsy or angiography prior to initiation of immunosuppressive therapies. Pharmacists are in a unique position to inform patients about the complications of RV and to advise them to stick to their drug regimen and report any unusual unwanted effects to their physician or pharmacist.
REFERENCES
1. Bartels CM, Bridges AJ. Rheumatoid vasculitis: vanishing menace or target for new treatment? Curr Rheumatol Rep. 2010;12:414-419.
2. Voskuyl AE, van Duinen SG, Zwinderman AH, et al. The diagnostic value of perivascular infiltrates in muscle biopsy specimens for the assessment of rheumatoid vasculitis. Ann Rheum Dis. 1998;57:114-117.
3. Turesson C, Schaid DJ, Weyand CM, et al. Association of HLA-C3 and smoking with vasculitis in patients with rheumatoid arthritis. Arthritis Rheum. 2006;54:2776-2783.
4. Turesson C, Jacobsson LT. Epidemiology of extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol. 2004;33:65-72.
5. Genta MS, Genta RM, Gabay C. Systemic rheumatoid vasculitis: a review. Semin Arthritis Rheum. 2006;36:88-98.
6. Bartels C, Bell C, Rosenthal A, et al. Decline in rheumatoid vasculitis prevalence among US veterans: a retrospective cross-sectional study. Arthritis Rheum. 2009;60:2553-2557.
7. Turesson C, O’Fallon WM, Crowson CS, et al. Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis. J Rheumatol. 2002;29:62-67.
8. Chen KR, Toyohara A, Suzuki A, Miyakawa S. Clinical and histopathological spectrum of cutaneous vasculitis in rheumatoid arthritis. Br J Dermatol. 2002;147:905-913.
9. Scott DG, Bacon PA. Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med. 1984;76:377-384.
10. Espinoza LR, Espinoza CG, Vasey FB, Germain BF. Oral methotrexate therapy for chronic rheumatoid arthritis ulcerations. J Am Acad Dermatol. 1986;15:508-512.
11. Puéchal X, Miceli-Richard C, Mejjad O, et al. Anti-tumour necrosis factor treatment in patients with refractory systemic vasculitis associated with rheumatoid arthritis. Ann Rheum Dis. 2008;67:880-884.
12. Cambridge G, Stohl W, Leandro MJ, et al. Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: relationships with B cell depletion, circulating antibodies, and clinical relapse. Arthritis Rheum. 2006;54:723-732.
13. Albano SA, Santana-Sahagun E, Weisman MH. Cigarette smoking and rheumatoid arthritis. Semin Arthritis Rheum. 2001;31:146-159.
To comment on this article, contact rdavidson@uspharmacist.com.
