Rheumatoid arthritis in dermatology

Clinics in Dermatology (2006) 24, 430 – 437

Rheumatoid arthritis in dermatology Tissa Hata MDa,*, Arthur Kavanaugh MDb a

Division of Dermatology, Department of Medicine, University of California, San Diego School of Medicine, La Jolla, CA 92093-0943, USA b Division of Rheumatology, Allergy and Immunology, Department of Medicine, Center for Innovative Therapy, University of California, San Diego School of Medicine, La Jolla, CA 92093-0943, USA

Abstract Rheumatoid arthritis (RA) is a chronic progressive disorder characterized by symmetric inflammatory arthritis in association with systemic symptoms. Although considered a bjoint disease,Q RA is associated with involvement in diverse organ systems, including the skin. Common manifestations include Raynaud phenomenon, rheumatoid nodules, and rheumatoid vasculitis. As with other extra-articular manifestations, dermatologic involvement tends to occur in patients with more severe RA. In addition to manifestations related to the disease, there are also sundry dermatologic reactions related to the medications used to treat RA. Understanding the etiology and therapy for cutaneous manifestations of RA will help optimize patient care. D 2006 Elsevier Inc. All rights reserved.

Rheumatoid arthritis Rheumatoid arthritis (RA) is a systemic inflammatory disease affecting about 0.8% of the population worldwide.1 With rare exception, the prevalence is relatively constant across the globe. RA affects women 2 to 3 times as often as men and has a peak onset between the ages of 40 and 60 years; however, RA can arise at any age, from infancy to old age. The clinical course is quite variable, ranging from mild joint discomfort to extensive multisystem inflammation. If left untreated, RA can cause significant disability, substantial economic costs, and higher mortality rates. Although typically considered an articular condition, RA is indeed a systemic inflammatory disease. In addition to prominent systemic symptoms, such as fever, anorexia,

* Corresponding author. Tel.: +1 858 657 7044; fax: +1 858 657 7045. E-mail addresses: [email protected] (T. Hata)8 [email protected] (A. Kavanaugh). 0738-081X/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.clindermatol.2006.07.008

and malaise, sundry organ systems can be involved. Extraarticular involvement, for example, of the skin, lung, exocrine glands, heart, kidneys, and others, is important because of the direct signs and symptoms related to such involvement.2 Moreover, their presence also serves as a marker of disease severity, as RA patients with extraarticular disease are most commonly those likely to experience the most severe active disease and, hence, poorer outcomes. Interestingly, although the overall treatment of RA has evolved over the past few decades, the prevalence of extra-articular manifestations has remained fairly constant.2 Although its precise etiology remains undefined, there has been substantial progress in recent years in deciphering the cellular and molecular mechanisms of RA. Currently, it is felt that the immunopathophysiology of disease relates to the exposure of a genetically susceptible host to some as yet unidentified antigen, with important modification from hormonal and other host factors. Activated CD4+ T cells stimulate macrophages, synovial fibroblasts, osteoclasts, B cells, and other cells, thereby orchestrating synovial and

Rheumatoid arthritis in dermatology vascular proliferation that results in the formation of pannus tissue. In the process, a cascade of inflammatory mediators is released, contributing to the sustenance of the ongoing immune activation and also directly causing the signs, symptoms, and sequelae of the disease, such as destruction of joints.

Dermatologic manifestations of RA Raynaud phenomenon In 1874, Raynaud described a sequence of blanching of the digits followed by cyanosis and then erythema, occurring in response to cold temperature or emotional stress. Raynaud phenomenon, caused by reversible vasospasm of the digital arterioles and arteries, is associated with several rheumatic diseases, particularly systemic sclerosis and systemic lupus erythematosus.3 In RA, prevalence estimates of Raynaud phenomenon range from 2.7%4 to 17.2%.5 The pathogenesis of primary Raynaud phenomenon is currently thought to be due to an abnormal a-adrenergic response mediated by an increased expression or sensitivity of a-2 receptors.6 Secondary Raynaud phenomenon is thought to be due to a disruption in the normal mechanisms responsible for control of vessel reactivity by the underlying disease. In scleroderma, which has a close association with Raynaud disease, the changes in the vascular system are associated with intimal fibrosis and endothelial dysfunction, and are believed to play a role in the development of Raynaud disease. The endothelial cell damage is associated with increased platelet adhesion, decreased adenosine uptake, and increased activity of reactive oxygen species.7,8 As in primary Raynaud disease, an increase in a-2 adrenergic receptor activity also occurs.9 The diagnosis of Raynaud disease is typically based on the patient’s history, and treatment includes avoidance of precipitating factors, keeping the digits warm, avoiding cigarette smoking, and avoiding sympathomimetic drugs. Pharmacologic therapies include sympatholytic agents, vasodilators, and prostaglandin analogs. Calcium channel blockers are the most frequently used class of drug and have been shown to reduce the frequency of attacks by an average of 2.8 to 5 per week, and the severity of attacks by one third.10

Rheumatoid nodules Rheumatoid nodules are the most common extraarticular disease manifestation of RA. The occurrence of nodules has ranged from 34% of outpatients with RA11 to 53% among 127 hospitalized patients with RA,12 and as high as 75% incidence in those patients with Felty syndrome.13 Rheumatoid nodules have been reported more frequently in Caucasians with a male predominance.14 Approximately 90% of patients with rheumatoid nodules

431 are positive for rheumatoid factor.15 In seronegative patients, nodules have been reported in 6% of patients.15 The presence of certain alleles of the class II major histocompatibility complex (eg, HLA-DR4) has been associated with the development of rheumatoid nodules.16 Rheumatoid nodules occur typically on extensor surfaces such as the olecranon process and proximal ulna. They are subcutaneous skin-colored nodules and vary in consistency from a firm rubbery texture attached to the periosteum to a soft, amorphous, mobile mass. They range in size from less than 4 mm to several centimeters.17 Nodules can occur not only in the skin, but also in a variety of sites including the larynx, heart, lungs, sclera, tendons, synovium, bones, peritoneum, central nervous system, and vertebral bodies.18 Histologic examination of the rheumatoid nodule shows a dense foci of fibrinoid necrosis with basophilic streaks and granules surrounded by histiocytes in a palisade arrangement. The upper dermis may or may not show associated perivascular inflammation.19 Cytokine profiling of the nodule has shown tumor necrosis factor (TNF) a, interleukin (IL) 1-b, IL-10, IL-15, IL-18, and IL-12 to be present. This profile along with the absence of IL-2 and IL-4 has suggested that the nodule is a Th-1 granuloma.20 Complement has also been implicated in the formation of the nodules, with immunohistochemical studies showing complement activation occurring after aggregation of IgM rheumatoid factor on the endothelial cell surfaces of small vessel walls.21 Specific treatment of rheumatoid nodules is not usually necessary because they are often asymptomatic. They may, however, ulcerate and become infected. Intralesional injection of the nodules can be performed to reduce large lesions.22 Surgical excision may be necessary if the nodules are causing nerve compression, a limited range of joint motion, or are severely ulcerated or infected. Skin grafting may be required for extremely large nodules.23 Typically, nodules will shrink with treatment with disease-modifying antirheumatic drugs, although worsening of nodules with treatment has been reported with methotrexate.24

Rheumatoid vasculitis Rheumatoid vasculitis typically affects between 2% and 5% of all patients with RA.25,26 Rheumatoid vasculitis can manifest with a range of involvement, including neuropathy, rash, skin ulcers, gangrene, and abnormalities in visceral organs. Autopsy series have suggested that rheumatoid vasculitis affects as many as 25% to 31% of all patients with RA.27 Studies have shown an increased mortality in patients with rheumatoid vasculitis or rheumatoid-associated neuropathy.28 The strongest association with the development of rheumatoid vasculitis is the presence of high titers of rheumatoid factor.29 Rheumatoid vasculitis is typically seen approximately 10 to 14 years after onset of RA 30 Classification of rheumatoid vasculitis is difficult because

432 it can affect a spectrum of vessels ranging from venules, capillaries, and arterioles to larger, medium-sized arteries. Classically, cutaneous vasculitis in RA includes rheumatoid leg ulcers, purpura, peripheral gangrene, and nail fold infarcts.31 Leg ulcers have been reported in up to 62.5% of patients with RA,32 petechiae or purpura in up to 56%,29,30,33 digital infarcts in up to 41%,29 and peripheral gangrene in up to 37.5%.33 Other cutaneous manifestations include nonspecific maculopapular or nodular erythema, hemorrhagic blisters, livedo reticularis, erythema elevatum diutinum, and atrophie blanche.34 Nail fold infarcts, also called Bywaters lesions, are small 0.5- to 1-mm brown to purpuric, nonpainful lesions on the nail fold, nail edge, or pulp of the digit.35 These lesions are the most common representation of rheumatoid vasculitis; however, the exact frequency varies with the level of vigilance of the observer. Bywaters and Scott36 initially suggested that these lesions may precede more serious vascular lesions, but a recent study has shown no association of these lesions with a progression to systemic vasculitis.37 Thus, most rheumatologists today would not treat these lesions because they are often transient and nonpainful. In addition to classical cutaneous lesions, peripheral nerves are most often affected. Results from a study by Voskuyl et al38 found skin findings to be present in 81% of patients with rheumatoid vasculitis, and peripheral neuropathy as manifested by mononeuritis multiplex or distal symmetric sensory or sensorimotor neuropathy in 45% of patients. Other reported internal manifestations of rheumatoid vasculitis include central nervous system,39 ocular,40 cardiopulmonary,41 renal,23 gastrointestinal,42 and hepatic disease.43 Treatment of systemic rheumatoid vasculitis has classically been a combination of cyclophosphamide and corticosteroids,32 although treatment with azathioprine,44 methotrexate,45 chlorambucil,11 and more recently, infliximab46 have also been reported to be successful. Recently, there have been reports of successful treatment of refractory RA–associated leg ulcers with adalimumab47 and leflunomide.48

Adult-onset Still’s disease Systemic-onset juvenile RA was described by George Still in 1896.49 In 1971, Bywaters described a series of adult patients who fit the criteria for Still’s disease, and hence the name adult-onset Still’s disease.50 Adult-onset Still’s disease is characterized by daily spiking high fevers, arthritis, and an evanescent salmon-colored rash. The etiology of adultonset Still’s disease is unknown, and multiple bacterial and viral triggers have been postulated. Its incidence has been reported to be 0.16 per 100,000 with a bimodal peak at ages 15 to 25 and 36 to 46.51 The rash of adult-onset Still’s disease has been reported as an evanescent salmon pink macular or macular-papular eruption most commonly on the

T. Hata, A. Kavanaugh chest, proximal extremities, cheeks, palms, and soles. The eruption is most prominent during febrile attacks, which last for several hours. It is typically nonpruritic and exhibits the Koebner phenomenon.52 Skin biopsy typically shows mild perivascular inflammation of the superficial dermis, with lymphocytes and histiocytes, and dermal edema. Immunofluorescence of the skin biopsy may show slight deposition of C3 in the blood vessel walls.50 Treatment options have ranged from nonsteroidal antiinflammatory drugs and aspirin, glucocorticoids, intramuscular gold salts, hydroxychloroquine, azathioprine, cyclophosphamide, cyclosporine, sulfasalazine, intravenous immune globulin, TNF-a inhibitors, and anakinra, an IL-1 inhibitor.53-55

Pyoderma gangrenosum Pyoderma gangrenosum (PG) classically has been described as an ulcer or ulcers with a characteristic violaceous border and undermined edges. The lesions typically will begin as a papule or pustule that expands to a necrotic painful ulcer that can reach 5 to 10 cm within a few weeks. Aggressive lesions of PG can affect fascia, muscles, and tendons. PG lesions have typically been described as exhibiting pathergy, thus, lesions can develop in areas of trauma. Ulcers of PG typically develop on the legs, although lesions have been reported on the trunk, arms, head, neck,56 and peristomal57 and vulvar regions.58 PG has been reported to be more common in women, although men with PG associated with hematologic disease have a worse prognosis.56 PG has been associated with a variety of underlying diseases in 50% of cases,59 most commonly with inflammatory bowel disease in 15% to 20%.60 Seropositive RA has been associated with PG in about 12% of cases.34 The histopathologic features of PG typically show a mixed cellular infiltrate with a predominance of neutrophils. These finding are nonspecific, and often biopsy is performed to rule out other causes of cutaneous ulcers such as vasculitis, malignancy, or infection. Multiple theories regarding the pathogenesis of PG have been postulated, ranging from neutrophil dysfunction61 to immune complex mediated,62; however, no definitive theory has emerged. The diagnosis of PG is a clinical diagnosis and one in which it is essential to rule out infection before starting therapy with corticosteroids or immunosuppressive agents. Treatment options for PG depend on the severity of the lesions. In milder cases, topical or intralesional steroids may control the disease.63 If topical steroids are to be used, usually a superpotent class I steroid has been64 shown to be most efficacious. Other topical treatments for PG include sodium cromoglycalate,65 nitrogen mustard,66 and 5-aminosalicyclic acid.67 Hyaluronic acid applied cutaneously in a 0.2% cream has also been shown to accelerate wound healing.68 Hyaluronic acid promotes epithelialization and promotes angiogenesis by stimulation of endothelial cells.69 Beclaplermin, a recombinant platelet-derived growth

Rheumatoid arthritis in dermatology factor,64 and lyophilized type 1 bovine collagen70 have been shown to accelerate healing in PG lesions. A novel treatment is the use of topical tacrolimus ointment.71 Multiple systemic therapies have been reported including oral or pulse intravenously administered steroids,59 cyclosporine,72 azathioprine,73 cyclophosphamide,74 chlorambucil,75 sulfasalazine,67 dapsone,76 clofazamine,77 thalidomide,78 and minocycline.79 Newer novel treatments include oral tacrolimus,80 mycophenolate mofetil,81 and infliximab.82 Treatment with infliximab was reported in this latter study to show a 50% reduction in the size of the ulcers within 7 days.

Rheumatoid neutrophilic dermatosis Rheumatoid neutrophilic dermatosis (RND) is a rare disease first described by Ackerman in 1978.83 RND is more common in women, and usually occurs in patients who have severe RA of at least 5 years’ duration.84 Lesions have been described as symmetric erythematous nodules and plaques usually affecting the extensor aspect of the joints of the hands and forearms.85 The lesions typically heal without scarring, either spontaneously or with improvement of underlying RA.86 Histopathology of RND shows a dense dermal neutrophilic infiltrate often with endothelial swelling and leukocytoclasis, but no actual vasculitis.85,87 Spongiosis can be present and can progress to intraepidermal vesiculation. Small collections of neutrophils may also be seen in the papillary dermis forming microabscesses.85,87 The pathogenesis of RND is unknown, but immune complex activation, cell adhesion, and migration and release of IL-6 and IL-8 have been postulated.88 Treatment options include topical steroids,89 dapsone,90 hydroxychloroquine,91 and cyclophosphamide.86 As mentioned above, RND in some patients improves with improvement of their underlying RA.86

Treatment of RA Several classes of medication have been used for the treatment of patients with RA. Nonsteroidal anti-inflammatory drugs and corticosteroids provide rapid symptomatic effect but seldom provide adequate disease control for most patients with RA. A group of medications collectively referred to as disease-modifying antirheumatic drugs have been introduced over the years for the treatment of RA. These medications, including injectable gold salts, methotrexate, sulfasalazine, leflunomide, and hydroxychloroquine, may help ameliorate the symptoms of RA, but rarely induce sustained remission and can have toxicities that prevent their long-term use. In recent years, there has been a trend toward more aggressive treatment paradigms for RA, including the use of combinations of diseasemodifying antirheumatic drugs early in the disease course. The goal of therapy has become the suppression of disease

433 activity to the greatest extent possible to prevent the damage from chronic synovial inflammation. Various skin reactions have been observed with the different classes of RA therapies. Among disease-modifying antirheumatic drugs, maculopapular drug reactions have been observed with all agents, ranging from uncommon reactions to methotrexate, to more common occurrences with intramuscular gold salts and sulfasalazine. Stomatitis has been observed, particularly with methotrexate, as has a worsening of rheumatoid nodules. Although dermatologic adverse reactions to RA therapies tend not to be serious, in most cases they preclude the further use of that particular agent.

TNF-aa inhibitors An improved understanding of the immunopathophysiology of RA, combined with progress in biotechnology, has resulted in the introduction of novel therapies for RA. These so-called biological agents including monoclonal antibodies, soluble receptor constructs, and others, target-specific components of the immune system considered to be dysregulated in RA. The greatest success has been achieved with inhibitors of the key proinflammatory cytokine TNF-a.92 Three currently approved TNF-a inhibitors, etanercept, infliximab, and adalimumab, have been shown capable not only of substantially improving the signs and symptoms of disease, but also of enhancing quality of life and functional status and attenuating the progression of joint damage (eg, as assessed by serial radiographs). Although generally well tolerated, TNF inhibitors can be associated with adverse reactions including a variety of dermatologic reactions. These include agent-specific reactions, such as administration reactions, and class reactions that have been seen with all TNF inhibitors.93 The most common side effect of the subcutaneously administered TNF inhibitors etanercept and infliximab are injection site reactions which occur with a frequency of approximately 20 to 40% for etanercept94 Injection site reactions are typically mild to moderate in severity, are mainly seen in the first 2 weeks, and are uncommon after 2 months.95 Local erythema, ecchymoses, urticaria, or pruritus are common injection site reactions and typically last 3 to 5 days with adalimumab or etanercept. Uncommon reactions include recall reactions, large plaquelike injection site reactions, and subcutaneous atrophy at the site of injection.94 These reactions are typically self-limiting, although analgesics, antihistamines, or topical steroids are helpful in controlling symptoms and are manageable by rotating injection sites. Infusion reactions to infliximab have ranged from 3.8% to 14% in large series reports.96-100 Common mild reactions include pruritus, urticaria, headache, flushing, fever, chills, nausea, tachycardia, dyspnea, and nonspecific dermatitis. These reactions rarely result in discontinuation of treatment. Infusion reactions may be more likely if infusions are given

434 too quickly; thus, often slowing the rate of infusion may improve infusion reactions. Severe reactions typically have been reported in less than 3% of patients and involve significant hypotension or hypertension, chest pain, elevated temperature, and severe shortness of breath.100 Drug-induced lupus Treatment with TNF-a inhibitors has been shown to cause an induction in autoantibodies. In controlled trials, the incidence of newly positive antinuclear antibodies ranged from 11% to as high as 49%. The development of antibodies to double-stranded DNA, a more specific marker for lupus, occurs in approximately 15% of treated patients.94 Interestingly, despite the common development of lupus-related antibodies, only rarely have patients developed druginduced lupus. The most common presentation of druginduced lupus associated with TNF inhibitors includes rash, serositis, acute polyarthritis, or cytopenia.94 Renal or neurologic manifestations of lupus are distinctly uncommon. Cutaneous lesions have been quite varied and range from an acute bsunburnQ with erythema and scale to typical discoid or subacute cutaneous lupus lesions, vasculitic, urticarial, or even purpuric lesions. Notably, all cases seem to resolve when the TNF inhibitor was withdrawn, usually within 4 to 8 weeks of stopping the drug. The serologic finding of antibodies is not predictive of response or toxicity to TNF-a inhibitors. Leukocytoclastic vasculitis Leukocytoclastic vasculitis has been reported to occur after administration of TNF-a inhibitors.101-103 Interestingly, TNF-a inhibitors have been used as a successful treatment of patients with rheumatoid vasculitis.104 Humoral immunity involving autoantibodies and immune complex deposition in the vessel wall, with subsequent activation of complement, has been postulated as one theory. A second possible theory is that TNF-a inhibitors have induced druginduced lupus, which results in the development of leukcocytoclastic vasculitis. A third possibility is the switch from the T-helper type 1 cytokine response to a Th2 response with TNF-a inhibitors. Because the Th2 response has been shown to be responsible for enhanced antibody production, an antibody-mediated immune response of Th2 may induce the leukocytoclastic vasculitis. Finally, it has been well documented that RA itself is associated with leukocytoclastic vasculitis, and, thus, development of leukocytoclastic vasculitis while receiving therapy with an TNF-a inhibitor association may be the normal progression of RA itself.105

Skin infections Patients with RA have an increased baseline risk of infections when compared with the general population,106 and, thus, treatment with TNF-a inhibitors and other immunosuppressive drugs is of particular concern. The role of TNF-a is essential for host immunity.107 It also induces

T. Hata, A. Kavanaugh apoptosis of infected cells, thus allowing for containment of infection.108 Interruption of these normal TNF-regulated responses appear to be responsible for the increase risk for infections. Infections associated with TNF-a inhibitors are well documented, especially with the increased incidence of tuberculosis,109 as well as reports of other serious infections with mycobacterial, fungal, and bacterial pathogens.110-112 Severe necrotizing fasciitis has also been described.113,114 Non–life-threatening skin infections typically have not been reported in clinical trials with TNF-a inhibitors most likely secondary to pharmacovigilance; however, a recent study reported cutaneous fungal infections and folliculitis as the most common skin infection to occur with anti–TNF-a therapy.115

Psoriasiform eruptions Psoriasiform eruptions have recently been described in patients on TNF-a therapy.115-119 In particular, the type of psoriasis in this setting in most cases has been psoriasiform pustular lesions of the palms and soles. This finding is particularly interesting because TNF-a inhibitors have been well described as efficacious in the treatment of psoriasis.120 The pathogenesis of this phenomenon is unknown. It has been postulated that in certain circumstances TNF-a inhibitors promote the activation of autoreactive T cells, which leads to tissue damage via autoimmune mechanisms.121 A second theory is that patients with palmoplantar pustular psoriasis are a separate entity with a different immunologic background than patients with typical plaquetype psoriasis.116

Conclusions Dermatologic manifestations of RA, including Raynaud phenomenon, rheumatoid nodules, and rheumatoid vasculitis, are important extra-articular manifestations of disease. In addition, various dermatologic adverse effects related to antirheumatic therapies have been observed. Understanding the breadth of dermatologic manifestations of RA and its treatment can help optimize the treatment of patients.

References 1. Kavanaugh AFLP. Clinical immunology. 2nd ed. London7 Harcourt Publishers; 2001. 2. 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 communitybased study. Arthritis Rheum 2004;50:3729 - 31. 3. Grassi W, De Angelis R, Lapadula G, Leardini G, Scarpa R. Clinical diagnosis found in patients with Raynaud’s phenomenon: a multicentre study. Rheumatol Int 1998;18:17 - 20. 4. Carroll GJ, Withers K, Bayliss CE. The prevalence of Raynaud’s syndrome in rheumatoid arthritis. Ann Rheum Dis 1981;40:567 - 70. 5. Saraux A, Allain J, Guedes C, Baron D, Youinou P, Le Goff P. Raynaud’s phenomenon in rheumatoid arthritis. Br J Rheumatol 1996;35:752 - 4.

Rheumatoid arthritis in dermatology 6. Wigley FM, Flavahan NA. Raynaud’s phenomenon. Rheum Dis Clin North Am 1996;22:765 - 81. 7. Herrick AL, Illingworth K, Blann A, Hay CR, Hollis S, Jayson MI. Von Willebrand factor, thrombomodulin, thromboxane, betathromboglobulin and markers of fibrinolysis in primary Raynaud’s phenomenon and systemic sclerosis. Ann Rheum Dis 1996;55: 122 - 7. 8. Blann AD, Illingworth K, Jayson MI. Mechanisms of endothelial cell damage in systemic sclerosis and Raynaud’s phenomenon. J Rheumatol 1993;20:1325 - 30. 9. Flavahan NA, Flavahan S, Liu Q, et al. Increased alpha2-adrenergic constriction of isolated arterioles in diffuse scleroderma. Arthritis Rheum 2000;43:1886 - 90. 10. Thompson AE, Pope JE. Calcium channel blockers for primary Raynaud’s phenomenon: a meta-analysis. Rheumatology (Oxford) 2005;44:145 - 50. 11. Turesson C, Jacobsson LT. Epidemiology of extra-articular manifestations in rheumatoid arthritis. Scand J Rheumatol 2004;33:65 - 72. 12. Gordon DA, Stein JL, Broder I. The extra-articular features of rheumatoid arthritis. A systematic analysis of 127 cases. Am J Med 1973;54:445 - 52. 13. Sienknecht CW, Urowitz MB, Pruzanski W, Stein HB. Felty’s syndrome. Clinical and serological analysis of 34 cases. Ann Rheum Dis 1977;36:500 - 7. 14. Schumacher HR, Gall EP. Rheumatoid arthritis: an illustrated guide to pathology, diagnosis, and management. Philadelphia7 JB Lippincott Co; 1988. 15. Kaye BR, Kaye RL, Bobrove A. Rheumatoid nodules. Review of the spectrum of associated conditions and proposal of a new classification, with a report of four seronegative cases. Am J Med 1984;76:279 - 92. 16. Ahmed SS, Arnett FC, Smith CA, Ahn C, Reveille JD. The HLADRB1*0401 allele and the development of methotrexate-induced accelerated rheumatoid nodulosis: a follow-up study of 79 Caucasian patients with rheumatoid arthritis. Medicine (Baltimore) 2001;80: 271 - 8. 17. Ziff M. The rheumatoid nodule. Arthritis Rheum 1990;33:761 - 7. 18. Berhard G. Rheumatoid arthritis: etiology, diagnosis, management. Philadelphia7 JB Lippincott Co; 1985. 19. James W, Berger T, Elston D. Andrew’s diseases of the skin: clinical dermatology. 10th edition. Philadelphia7 WB Saunders; 2006. 20. Hessian PA, Highton J, Kean A, Sun CK, Chin M. Cytokine profile of the rheumatoid nodule suggests that it is a Th1 granuloma. Arthritis Rheum 2003;48:334 - 8. 21. Kato H, Yamakawa M, Ogino T. Complement mediated vascular endothelial injury in rheumatoid nodules: a histopathological and immunohistochemical study. J Rheumatol 2000;27:1839 - 47. 22. Ching DW, Petrie JP, Klemp P, Jones JG. Injection therapy of superficial rheumatoid nodules. Br J Rheumatol 1992;31:775 - 7. 23. Breedveld FC, Valentijn RM, Westedt ML, Weening JJ. Rapidly progressive glomerulonephritis with glomerular crescent formation in rheumatoid arthritis. Clin Rheumatol 1985;4:353 - 9. 24. 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. 25. 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. 26. Salvarani C, Macchioni P, Mantovani W, et al. Extraarticular manifestations of rheumatoid arthritis and HLA antigens in northern Italy. J Rheumatol 1992;19:242 - 6. 27. Suzuki A, Ohosone Y, Obana M, et al. Cause of death in 81 autopsied patients with rheumatoid arthritis. J Rheumatol 1994;21:33 - 6. 28. Turesson C, O’Fallon WM, Crowson CS, Gabriel SE, Matteson EL. 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 - 7.

435 29. 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 case-control study. Ann Rheum Dis 1996;55:190 - 2. 30. 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. 31. Vollertsen RS, Conn DL. Vasculitis associated with rheumatoid arthritis. Rheum Dis Clin North Am 1990;16:445 - 61. 32. Scott DG, Bacon PA. Intravenous cyclophosphamide plus methylprednisolone in treatment of systemic rheumatoid vasculitis. Am J Med 1984;76:377 - 84. 33. 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. 34. Sayah A, English III JC. Rheumatoid arthritis: a review of the cutaneous manifestations. J Am Acad Dermatol 2005;53:191 - 209 [quiz 210-2]. 35. Golding JR, Hamilton MG, Gill RS. Arteritis of rheumatoid arthritis. Br J Dermatol 1965;77:207 - 10. 36. Bywaters EG, Scott JT. The natural history of vascular lesions in rheumatoid arthritis. J Chronic Dis 1963;16:905 - 14. 37. Watts RA, Carruthers DM, Scott DG. Isolated nail fold vasculitis in rheumatoid arthritis. Ann Rheum Dis 1995;54:927 - 9. 38. Voskuyl AE, Hazes JM, Zwinderman AH, et al. Diagnostic strategy for the assessment of rheumatoid vasculitis. Ann Rheum Dis 2003;62: 407 - 13. 39. Sigal LH. The neurologic presentation of vasculitic and rheu matologic syndromes. A review. Medicine (Baltimore) 1987; 66:157 - 80. 40. Matsuo T, Koyama T, Morimoto N, Umezu H, Matsuo N. Retinal vasculitis as a complication of rheumatoid arthritis. Ophthalmologica 1990;201:196 - 200. 41. Scott DG, Bacon PA, Tribe CR. Systemic rheumatoid vasculitis: a clinical and laboratory study of 50 cases. Medicine (Baltimore) 1981; 60:288 - 97. 42. Babian M, Nasef S, Soloway G. Gastrointestinal infarction as a manifestation of rheumatoid vasculitis. Am J Gastroenterol 1998;93: 119 - 20. 43. 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. 44. Heurkens AH, Westedt ML, Breedveld FC. Prednisone plus azathioprine treatment in patients with rheumatoid arthritis complicated by vasculitis. Arch Intern Med 1991;151:2249 - 54. 45. Upchurch KS, Heller K, Bress NM. Low-dose methotrexate therapy for cutaneous vasculitis of rheumatoid arthritis. J Am Acad Dermatol 1987;17(2 Pt 2):355 - 9. 46. Unger L, Kayser M, Nusslein HG. Successful treatment of severe rheumatoid vasculitis by infliximab. Ann Rheum Dis 2003;62: 587 - 8. 47. Hirche D, Rubbert A, Lunau L, Krieg T, Eming SA. Successful treatment of refractory rheumatoid arthritis–associated leg ulcerations with adalimumab. Br J Dermatol 2005;152:1062 - 4. 48. Knab J, Goos M, Dissemond J. Successful treatment of a leg ulcer occurring in a rheumatoid arthritis patient under leflunomide therapy. J Eur Acad Dermatol Venereol 2005;19:243 - 6. 49. Still G. On a form of chronic joint disease in children. Med Chir Trans 1897;80:47. 50. Elkon KB, Hughes GR, Bywaters EG, et al. Adult-onset Still’s disease. Twenty-year follow-up and further studies of patients with active disease. Arthritis Rheum 1982;25:647 - 54. 51. Magadur-Joly G, Billaud E, Barrier JH, et al. Epidemiology of adult Still’s disease: estimate of the incidence by a retrospective study in west France. Ann Rheum Dis 1995;54:587 - 90. 52. Kadar J, Petrovicz E. Adult-onset Still’s disease. Best Pract Res Clin Rheumatol 2004;18:663 - 76.

436 53. Larson EB. Adult Still’s disease. Evolution of a clinical syndrome and diagnosis, treatment, and follow-up of 17 patients. Medicine (Baltimore) 1984;63:82 - 91. 54. Mahmud T, Hughes GR. Intravenous immunoglobulin in the treatment of refractory adult Still’s disease. J Rheumatol 1999;26:2067 - 8. 55. Fitzgerald AA, Leclercq SA, Yan A, Homik JE, Dinarello CA. Rapid responses to anakinra in patients with refractory adult-onset Still’s disease. Arthritis Rheum 2005;52:1794 - 803. 56. von den Driesch P. Pyoderma gangrenosum: a report of 44 cases with follow-up. Br J Dermatol 1997;137:1000 - 5. 57. Lyon CC, Smith AJ, Beck MH, Wong GA, Griffiths CE. Parastomal pyoderma gangrenosum: clinical features and management. J Am Acad Dermatol 2000;42:992 - 1002. 58. McCalmont CS, Leshin B, White WL, Greiss Jr FC, Jorizzo JL. Vulvar pyoderma gangrenosum. Int J Gynaecol Obstet 1991;35: 175 - 8. 59. Powell FC, Su WP, Perry HO. Pyoderma gangrenosum: classification and management. J Am Acad Dermatol 1996;34:395 - 409 [quiz 410-2]. 60. Callen JP. Neutrophilic dermatoses. Dermatol Clin 2002;20:409 - 19. 61. Adachi Y, Kindzelskii AL, Cookingham G, et al. Aberrant neutrophil trafficking and metabolic oscillations in severe pyoderma gangrenosum. J Invest Dermatol 1998;111:259 - 68. 62. Ko CB, Walton S, Wyatt EH. Pyoderma gangrenosum: associations revisited. Int J Dermatol 1992;31:574 - 7. 63. Gardner LW, Acker DW. Triamcinolone and pyoderma gangrenosum. Arch Dermatol 1972;106:599 - 600. 64. Braun-Falco M, Stock K, Ring J, Hein R. Topical plateletderived growth factor accelerates healing of myelodysplastic syndrome–associated pyoderma gangrenosum. Br J Dermatol 2002;147: 829 - 31. 65. de Cock KM, Thorne MG. The treatment of pyoderma gangrenosum with sodium cromoglycate. Br J Dermatol 1980;102:231 - 3. 66. Tsele E, Yu RC, Chu AC. Pyoderma gangrenosum—response to topical nitrogen mustard. Clin Exp Dermatol 1992;17:437 - 40. 67. Wollina U. Clinical management of pyoderma gangrenosum. Am J Clin Dermatol 2002;3:149 - 58. 68. Wollina U, Karamfilov T. Treatment of recalcitrant ulcers in pyoderma gangrenosum with mycophenolate mofetil and autologous keratinocyte transplantation on a hyaluronic acid matrix. J Eur Acad Dermatol Venereol 2000;14:187 - 90. 69. Slevin M, Kumar S, Gaffney J. Angiogenic oligosaccharides of hyaluronan induce multiple signaling pathways affecting vascular endothelial cell mitogenic and wound healing responses. J Biol Chem 2002;277:41046 - 59. 70. Farris DR, Schutzer PJ, Don PC, Silverberg NB, Weinberg JM. Resolution of pyoderma gangrenosum after therapy with lyophilized bovine collagen matrix. Dermatology 2003;206:284 - 5. 71. Jolles S, Niclasse S, Benson E. Combination oral and topical tacrolimus in therapy-resistant pyoderma gangrenosum. Br J Dermatol 1999;140:564 - 5. 72. Patrone P, Bragadin G, De Francesco V, Frattasio A, Stinco G. Pyoderma gangrenosum of the scalp treated with cyclosporine A. Int J Dermatol 2002;41:916 - 8. 73. Coors EA, von den Driesch P. Pyoderma gangrenosum in a patient with autoimmune haemolytic anaemia and complement deficiency. Br J Dermatol 2000;143:154 - 6. 74. Kaminska R, Ikaheimo R, Hollmen A. Plasmapheresis and cyclophosphamide as successful treatments for pyoderma gangrenosum. Clin Exp Dermatol 1999;24:81 - 5. 75. Burruss JB, Farmer ER, Callen JP. Chlorambucil is an effective corticosteroid-sparing agent for recalcitrant pyoderma gangrenosum. J Am Acad Dermatol 1996;35(5 Pt 1):720 - 4. 76. Fukuhara K, Urano Y, Kimura S, Hori K, Arase S. Pyoderma gangrenosum with rheumatoid arthritis and pulmonary aseptic abscess responding to treatment with dapsone. Br J Dermatol 1998; 139:556 - 8.

T. Hata, A. Kavanaugh 77. Kark EC, Davis BR, Pomeranz JR. Pyoderma gangrenosum treated with clofazimine. Report of three cases. J Am Acad Dermatol 1981;4: 152 - 9. 78. Hecker MS, Lebwohl MG. Recalcitrant pyoderma gangrenosum: treatment with thalidomide. J Am Acad Dermatol 1998;38:490 - 1. 79. Reynolds NJ, Peachey RD. Response of atypical bullous pyoderma gangrenosum to oral minocycline hydrochloride and topical steroids. Acta Derm Venereol 1990;70:538 - 9. 80. Lyon CC, Kirby B, Griffiths CE. Recalcitrant pyoderma gangrenosum treated with systemic tacrolimus. Br J Dermatol 1999;140:562 - 4. 81. Nousari HC, Lynch W, Anhalt GJ, Petri M. The effectiveness of mycophenolate mofetil in refractory pyoderma gangrenosum. Arch Dermatol 1998;134:1509 - 11. 82. Kaur MR, Lewis HM. Severe recalcitrant pyoderma gangrenosum treated with infliximab. Br J Dermatol 2005;153:689 - 91. 83. Ackerman A. Histopathologic diagnosis of inflammatory skin diseases: a method by pattern analysis. Philadelphia7 Lea and Febiger; 1978. 84. MacAya A, Servitje O, Jucgla A, Peyri J. Rheumatoid neutrophilic dermatitis associated with pyoderma gangrenosum. Br J Dermatol 2000;142:1246 - 8. 85. Lowe L, Kornfeld B, Clayman J, Golitz LE. Rheumatoid neutrophilic dermatitis. J Cutan Pathol 1992;19:48 - 53. 86. Mashek HA, Pham CT, Helm TN, Klaus M. Rheumatoid neutrophilic dermatitis. Arch Dermatol 1997;133:757 - 60. 87. Scherbenske JM, Benson PM, Lupton GP, Samlaska CP. Rheumatoid neutrophilic dermatitis. Arch Dermatol 1989;125:1105 - 8. 88. Yamamoto T, Ohkubo H, Nishioka K. Rheumatoid neutrophilic dermatitis. Int J Dermatol 1994;33:798 - 800. 89. Hirota TK, Keough GC, David-Bajar K, McCollough ML. Rheumatoid neutrophilic dermatitis. Cutis 1997;60:203 - 5. 90. Harkaway K, Elenitas R, Margolis DJ. Erythematous papules in a patient with rheumatoid arthritis. Rheumatoid neutrophilic dermatitis (RND). Arch Dermatol 1995;131:1196, 1199-200. 91. Sanchez JL, Cruz A. Rheumatoid neutrophilic dermatitis. J Am Acad Dermatol 1990;22(5 Pt 2):922 - 5. 92. Kavanaugh A, Cohen S, Cush JJ. The evolving use of tumor necrosis factor inhibitors in rheumatoid arthritis. J Rheumatol 2004; 31:1881 - 4. 93. Lee SJ, Kavanaugh A. Adverse reactions to biologic agents: focus on autoimmune disease therapies. J Allergy Clin Immunol 2005;116: 900 - 5. 94. Cush JJ. Safety overview of new disease-modifying antirheumatic drugs. Rheum Dis Clin North Am 2004;30:237 - 55. 95. Zeltser R, Valle L, Tanck C, Holyst MM, Ritchlin C, Gaspari AA. Clinical, histological, and immunophenotypic characteristics of injection site reactions associated with etanercept: a recombinant tumor necrosis factor alpha receptor: Fc fusion protein. Arch Dermatol 2001;137:893 - 9. 96. Kugathasan S, Levy MB, Saeian K, et al. Infliximab retreatment in adults and children with Crohn’s disease: risk factors for the development of delayed severe systemic reaction. Am J Gastroenterol 2002;97:1408 - 14. 97. Hanauer SB, Feagan BG, Lichtenstein GR, et al. Maintenance infliximab for Crohn’s disease: the ACCENT I randomised trial. Lancet 2002;359:1541 - 9. 98. Wasserman MJ, Weber DA, Guthrie JA, Bykerk VP, Lee P, Keystone EC. Infusion-related reactions to infliximab in patients with rheumatoid arthritis in a clinical practice setting: relationship to dose, antihistamine pretreatment, and infusion number. J Rheumatol 2004; 31:1912 - 7. 99. Cheifetz A, Smedley M, Martin S, et al. The incidence and management of infusion reactions to infliximab: a large center experience. Am J Gastroenterol 2003;98:1315 - 24. 100. Colombel JF, Loftus Jr EV, Tremaine WJ, et al. The safety profile of infliximab in patients with Crohn’s disease: the Mayo clinic experience in 500 patients. Gastroenterology 2004;126:19 - 31.

Rheumatoid arthritis in dermatology 101. Mohan N, Edwards ET, Cupps TR, et al. Leukocytoclastic vasculitis associated with tumor necrosis factor-alpha blocking agents. J Rheumatol 2004;31:1955 - 8. 102. Galaria NA, Werth VP, Schumacher HR. Leukocytoclastic vasculitis due to etanercept. J Rheumatol 2000;27:2041 - 4. 103. Jarrett SJ, Cunnane G, Conaghan PG, et al. Anti-tumor necrosis factor-alpha therapy–induced vasculitis: case series. J Rheumatol 2003;30:2287 - 91. 104. Bartolucci P, Ramanoelina J, Cohen P, et al. Efficacy of the anti–TNFalpha antibody infliximab against refractory systemic vasculitides: an open pilot study on 10 patients. Rheumatology (Oxford) 2002;41: 1126 - 32. 105. Guillevin L, Mouthon L. Tumor necrosis factor-alpha blockade and the risk of vasculitis. J Rheumatol 2004;31:1885 - 7. 106. Doran MF, Crowson CS, Pond GR, O’Fallon WM, Gabriel SE. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population-based study. Arthritis Rheum 2002;46: 2287 - 93. 107. Bresnihan B, Cunnane G. Infection complications associated with the use of biologic agents. Rheum Dis Clin North Am 2003;29: 185 - 202. 108. Fratazzi C, Arbeit RD, Carini C, Remold HG. Programmed cell death of Mycobacterium avium serovar 4–infected human macrophages prevents the mycobacteria from spreading and induces mycobacterial growth inhibition by freshly added, uninfected macrophages. J Immunol 1997;158:4320 - 7. 109. Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor alpha–neutralizing agent. N Engl J Med 2001;345:1098 - 104. 110. Hyrich KL, Silman AJ, Watson KD, Symmons DP. Anti–tumour necrosis factor alpha therapy in rheumatoid arthritis: an update on safety. Ann Rheum Dis 2004;63:1538 - 43.

437 111. Ellerin T, Rubin RH, Weinblatt ME. Infections and anti–tumor necrosis factor alpha therapy. Arthritis Rheum 2003;48:3013 - 22. 112. Netea MG, Radstake T, Joosten LA, van der Meer JW, Barrera P, Kullberg BJ. Salmonella septicemia in rheumatoid arthritis patients receiving anti–tumor necrosis factor therapy: association with decreased interferon-gamma production and Toll-like receptor 4 expression. Arthritis Rheum 2003;48:1853 - 7. 113. Chan AT, Cleeve V, Daymond TJ. Necrotising fasciitis in a patient receiving infliximab for rheumatoid arthritis. Postgrad Med J 2002; 78:47 - 8. 114. Baghai M, Osmon DR, Wolk DM, Wold LE, Haidukewych GJ, Matteson EL. Fatal sepsis in a patient with rheumatoid arthritis treated with etanercept. Mayo Clin Proc 2001;76:653 - 6. 115. Flendrie M, Vissers WH, Creemers MC, de Jong EM, van de Kerkhof PC, van Riel PL. Dermatological conditions during TNF-alpha– blocking therapy in patients with rheumatoid arthritis: a prospective study. Arthritis Res Ther 2005;7:R666 - 76. 116. Sfikakis PP, Iliopoulos A, Elezoglou A, Kittas C, Stratigos A. Psoriasis induced by anti-tumor necrosis factor therapy: a paradoxical adverse reaction. Arthritis Rheum 2005;52:2513 - 8. 117. Verea MM, Del Pozo J, Yebra-Pimentel MT, Porta A, Fonseca E. Psoriasiform eruption induced by infliximab. Ann Pharmacother 2004;38:54 - 7. 118. Thurber M, Feasel A, Stroehlein J, Hymes SR. Pustular psoriasis induced by infliximab. J Drugs Dermatol 2004;3:439 - 40. 119. Beuthien W, Mellinghoff HU, von Kempis J. Skin reaction to adalimumab. Arthritis Rheum 2004;50:1690 - 2. 120. Winterfield LS, Menter A, Gordon K, Gottlieb A. Psoriasis treatment: current and emerging directed therapies. Ann Rheum Dis 2005; 64(Suppl 2):ii87 - ii90 [discussion ii91-2]. 121. Sfikakis PP, Kollias G. Tumor necrosis factor biology in experimental and clinical arthritis. Curr Opin Rheumatol 2003;15:380 - 6.