Drug-Induced Vasculitis

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1 Drug-Induced Vasculitis Shelly Rivas, Amit G. Pandya, and Arturo R. Dominguez 8 Abstract Drug-induced vasculitis is defined as inflammation of blood vessels due to an adverse effect of a drug. Histologically, vasculitis is defined as an inflammatory cell-mediated infiltration and destruction of blood vessels. Vasculitis can be either primary, as seen in granulomatous polyangiits, or secondary, when associated with drugs, infection, malignancy, or connective tissue disease. While the exact pathogenesis of drug- induced vasculitis remains unclear, it is strongly believed to be an immune-complex mediated process. Many drugs are associated with vasculitis and nearly every class of drug has been implicated. The most common drugs associated with vasculitis are propylthioruacil, hydralazine, minocycline, allopurinol, D-penicillamine, sulfasalazine, penicillins, cephalosporins and several immunomodulating agents, discussed below. Diagnosis of drug-induced vasculitis is often challenging, as there are no pathognomonic clinical or histological features to distinguish it from other causes of vasculitis. It is also very difficult to prove that an exposure to a drug led to cutaneous vasculitis. Severity of drug-induced vasculitis can range from mild, and self-limiting to severely progressive and even fatal. A high index of suspicion should be maintained for vasculitic lesions that arise in the setting of recent introduction of a new drug. Suspicious agents should be promptly withdrawn, as resolution often occurs soon after discontinuation of the offending drug. S. Rivas, MD Internal Medicine, Yale New Haven Hospital, New Haven, CT, USA A.G. Pandya, MD A.R. Dominguez, MD (*) Department of Dermatology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX , USA arturo.dominguez@utsouthwestern.edu Springer-Verlag London 2015 J.C. Hall, B.J. Hall (eds.), Cutaneous Drug Eruptions: Diagnosis, Histopathology and Therapy, DOI / _8 77

2 78 S. Rivas et al. Keywords Vasculitis Drug-induced vasculitis cutaneous drug reaction Leukocytoclastic vasculitis Anti-neutrophil cytoplasmic autoantibodies (ANCA) Introduction Vasculitis is an inflammatory cell-mediated process resulting in the dysfunction and destruction of blood vessels. Vasculitis can be idiopathic, autoimmune-mediated, or precipitated by drugs. Drug-induced vasculitis (DIV) is defined as a vasculitis due to a drug or toxin when other causes have been excluded. Vasculitis caused by drugs can be limited to the skin (referred to as hypersensitivity vasculitis, cutaneous small vessel vasculitis, or leukocytoclastic vasculitis) or affect multiple organs of the body due to involvement of small and mediumsized muscular arteries. The former is usually a mild and self-limiting illness affecting the skin, while the latter may be a severe and lifethreatening disease causing multiple organ failure. The distribution of the antigen responsible for the vasculitis determines the pattern of vessel involvement. Causal Agents Many drugs in nearly every drug class have been associated with drug-induced vasculitis. The most commonly cited drugs are hydralazine, propylthiouracil, methimazole, sulfasalazine, minocycline, D-penicillamine, sulfonamides, allopurinol, penicillins, and immunomodulating agents such as tumor necrosis factor alpha, interferon, and granulocyte-macrophage colony stimulating factor (GM-CSF), as noted in the list below. Medications used for the treatment of acne vulgaris, such minocycline and isotretinoin, have also been associated with vasculitis. Antithymocyte globulin-induced serum sickness may present with cutaneous leukocytoclastic vasculitis as well (Fig. 8.1 ). Fig. 8.1 Leukocytoclastic vasculitis secondary to antithymocyte globulin in the setting of serum sickness Drugs Associated with Vasculitis Hydralazine Minocycline Isotretinoin Methimazole D-penicillamine Hydralazine Levamisole Penicillin Cephaolosporins Methotrexate Cocaine Propylthiouracil Interferon Adalimumab Etanercept Infliximab Sulfasalazine Phenytoin Allopurinol Quinolones Granulocyte colony stimulating factor Methamphetamine Anti-thymocyte globulin

3 8 Drug-Induced Vasculitis The most frequently cited drugs associated with DIV are those belonging to a subset of drugs associated with anti-neutrophil cytoplasmic autoantibodies (ANCA). ANCA are antibodies to antigens in cytoplasmic granules of neutrophil and monocyte lysosomes with distinct staining patterns. ANCA is usually found in idiopathic vasculitic disorders such as granulomatosis with polyangiitis (GPA), Churg- Strauss syndrome (CSS), and microscopic polyangiitis (MPA). Patients with development of ANCA from drug exposure may present with similar clinical features as patients with idiopathic ANCAassociated disease with associated skin, kidney, and lung involvement. Medications associated with ANCA include propylthioruracil, methimazole, hydralazine, minocycline, sulfasalazine, and monteleukast, as noted in the list below. Minocycline can also cause a severe, ANCA- negative vasculitis that mimics PAN. Propylthiouracil has been associated with ANCA-positive vasculitis more so than methimazole. One study comparing the serological and clinical profiles of patients with ANCAassociated autoimmune disease demonstrated milder disease and lower relapse rates in patients who had ANCA-positive antithyroid medicationinduced vasculitis compared to patients with ANCA-positive idiopathic systemic vasculitis. Drugs Associated with Vasculitis and ANCA Hydralazine Propylthiouracil Methimazole Minocycline Monteleukast Interferon Tumor necrosis factor-alpha Sulfasalazine Cocaine Levamisole-tainted cocaine Illegal drugs have also been associated with drug-induced ANCA vasculitis. The illicit or recreational drugs that have most commonly been associated with vasculitis include the sympathomimetic drugs cocaine, methamphetamine, and 3,4-methylenedioxymethamphetamine ( Ecstasy ). More recently, there have been 79 numerous reports of levamisole-tainted cocaine causing vasculitis and vasculopathy. This combination seems to be especially potent in inducing blood vessel disease, which is contributing to the increased incidence of cocaine-related vasculopathy/vasculitis. It is therefore important for clinicians to screen for substance abuse in patients whose presentation is consistent with DIV. Clinical Presentation Patients with drug-induced vasculitis may have similar clinical presentations to patients with idiopathic vasculitis. The skin is the most commonly affected organ in drug-induced vasculitis, and can range from involvement of small vessels (arterioles, capillaries, and venules) to more severe disease affecting small- to medium-sized arteries. Typical skin findings suggestive of small-vessel involvement include palpable purpura, petechiae, erythematous morbilliform eruption, urticaria that leaves behind ecchymosis, and small hemorrhagic vesicles (seen in Fig. 8.1 ). Small- to medium-sized artery involvement presents as livedo reticularis, inflammatory retiform or stellate purpura, subcutaneous nodules, hemorrhagic bullae, ulcers and, in severe cases, digital gangrene (Figs. 8.2, 8.3, and 8.4 ). While extremely rare, oral mucous membranes including the hard palate and oropharynx can be affected. Such cases have been reported in propylthiouracil (PTU)-induced ANCA-positive Fig. 8.2 PTU-induced vasculitis necrotic presenting as retiform and stellate purpura, nodules and skin necrosis on the trunk

4 80 S. Rivas et al. Fig. 8.3 PTU-induced vasculitis presenting as retiform and stellate purpura, nodules and skin necrosis on the upper extremity disease (Fig. 8.5 ). Severity of drug-induced vasculitis can range from mild disease, limited to the skin alone, to a more severe and widespread, systemic disease causing multiple organ failure. While the majority of cases of drug-induced vasculitis tend to involve only the skin, they can be accompanied by systemic symptoms such as fever, malaise, weight loss, and arthralgia. Other organs may also be involved, such as the brain, kidneys, lungs, heart, and liver. After cutaneous involvement, the kidney is the most commonly affected internal organ, with affected patients Fig. 8.4 PTU-induced vasculitis presenting as a stellate, purpuric ulcerated plaque presenting with hematuria and proteinuria and evidence of glomerulonephritis or interstitial nephritis. Involvement of the lung tends to occur in more severe cases and has been associated with intra-alveolar hemorrhage and acute respiratory distress syndrome (ARDS). The development of vasculitis typically occurs about 7 10 days after drug exposure, which is believed to correlate with formation of immune complexes and their deposition into blood vessels. Cutaneous lesions in the majority of patients with drug-induced vasculitis usually present on the lower extremities (as shown in Fig. 8.1 ). Lesions appearing on the trunk, upper extremities, face including

5 8 Drug-Induced Vasculitis 81 Fig. 8.6 Levamisole-tainted cocaine vasculitis/vasculopathy presenting as diffuse retiform purpura involving the trunk and upper extremities Fig. 8.5 Stellate-shaped oral ulcerations secondary to PTU-induced vasculitis nose and ears and neck are reported more often with ANCA-positive DIV or idiopathic vasculitides. Furthermore, patients with systemic disease are more likely to complain of painless lesions and paresthesias, or have cutaneous necrosis. Minocycline-induced ANCA-positive vasculitis has been associated with several cases of biopsy-proven polyarteritis nodosa (PAN). The majority of cases have occurred in teenagers and young adults treated with minocycline for acne vulgaris. Patients may present with fever, weight loss, arthralgia, and myalgia, with livedo reticularis and tender subcutaneous nodules as the most common skin manifestations. Cases of ANCAnegative PAN have also been reported after minocycline ingestion. Vasculitis has also been associated with the use of the anti-tnf-alpha agents infliximab, etanercept, and adalimumab. In these cases, the skin is the most affected organ (63 % of cases), presenting as palpable purpura, ulcerations, and erythematous macules. The majority of patients found to have leukocytoclastic vasculitis after treatment with anti-tnf-alpha agents have had resolution of their lesions after discontinuation of the drug. However, in patients who were subsequently treated with a different TNF-alpha blocker, there was a higher rate of recurrence of LCV. Golimumab, a TNF-alpha antagonist recently approved for the treatment of rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, has also been associated with luekocytoclastic vasculitis in a recent case report. As mentioned earlier, levamisole, an antihelminthic drug used in animals, has been linked to cocaine-induced vasculitis. Nearly 70 % of cocaine in the United States is contaminated with levamisole, which serves as a filling agent and is believed to potentiate the effect of cocaine. Levamisole is associated with agranulocytosis and venous thromboembolism, with multiple cutaneous manifestations, including ecchymoses, purpura, hemorrhagic bullae, and in severe cases, necrosis of lips, ears, nose, and cheeks. Patients with levamisole-tainted cocaine vasculopathy often have lesions affecting the lower extremities and the ear, in particular the external pinna (Figs. 8.6, 8.7, and 8.8 ). Patients are

6 82 S. Rivas et al. factor. In fact, the presence of multiple positive autoimmune antibodies occurring simultaneously in the same patient is strongly suggestive of levamisole- tainted cocaine vasculitis. Patients may have atypical immunofluorescence (IIF) ANCA patterns as well as discordant IF and enzyme-linked immunosorbent assays (ELISA) combinations, such as P-ANCA with anti-pr-3 IgG, and C-ANCA with anti-mpo IgG. The titers of each study may also be inappropriately out of proportion to each other. Histologically, levamisole- adulterated cocaine may present as a leukocytoclastic vasculitis involving small and medium-sized vessels, a thrombotic vasculopathy, or both. Diagnosis Fig. 8.7 Levamisole-tainted cocaine vasculitis/vasculopathy presenting as diffuse retiform purpura, skin necrosis involving the face and pinna of ears Fig. 8.8 Levamisole-tainted cocaine vasculitis/vasculopathy presenting as diffuse retiform purpura on the upper extremities (close-up view) usually ANCA positive and may present with renal and pulmonary involvement, with or without vasculitis. Other positive auto-immune serologies have been reported as well including ANA, antiphospholipid antibodies, and rheumatoid Distinguishing drug-induced vasculitis from idiopathic vasculitis is particularly challenging. It may also be very difficult to prove that a medication caused a drug reaction. A thorough evaluation to rule out other systemic causes of vasculitis, such as chronic infection, rheumatologic disorders, or malignancy, as well as primary or idiopathic vasculitic syndromes such as GPA and PAN is warranted, as the diagnosis of druginduced vasculitis is one of exclusion. Excluding other mimickers of drug-induced vasculitis such as antiphospholipid antibody syndrome, warfarin necrosis, calciphylaxis, cholesterol embolization, amyloidosis, purpura fulminans, thrombotic thrombocytopenic purpura (TTP), heparininduced thrombocytopenia and thrombosis (HITT) and drug-induced lupus-like disease are essential. A skin biopsy of the affected skin is important in making a definitive diagnosis. A thorough drug history, with particular attention to those medications ingested in the last 6 months, should be obtained. It is important to perform a comprehensive review of prescribed medications, over-the-counter medications, herbal and nutrition supplements, as well as any illicit drugs taken in the last 6 months. Interestingly, vasculitis has also been reported in patients taking a medication for a long period of

7 8 Drug-Induced Vasculitis time (months to years), particularly when stopping a chronic medication and then restarting it shortly thereafter. The likelihood of a drug serving as the cause of vasculitis increases if there is a temporal relation of the skin lesions with the initiation of a drug, or if removal of the agent leads to clinical improvement. It is also likely if re-exposure leads to redevelopment of vasculitic lesions and if there is published data showing a strong association between the drug in question and DIV. Additionally, an extensive drug history and physical examination, including detailed descriptions of lesions and photographs of the eruption, should be obtained. Useful laboratory tests include a complete blood count with differential, liver function studies, urinalysis, blood urea nitrogen, creatinine, serum cryoglobulins, serum and urine protein electrophoresis, Hepatitis B and C serologies, ANCA studies for IF and ELISA, ANA with extractable nuclear antigens, rheumatoid factor, and complement levels. While there are no concrete clinical or histologic findings to confidently diagnose druginduced vasculitis, there are features of drug-induced vasculitis that can aid in the diagnosis, including rapid or sudden onset and solitary skin involvement, as cutaneous vasculitis is the most common, and at times the only, manifestation of DIV. In one study, it was noted that cutaneous vasculitis is seen in 63 % of drug-induced vasculitis whereas it is present in only 25 % of idiopathic vasculitides. The lesions of DIV are generally localized to the lower extremities and tend to be of the same age, whereas primary vasculitides tend to have lesions of different durations and morphologies occur. Inflammatory retiform purpura, skin necrosis, livedo racemosa, nodules, and ulceration affecting the acral surfaces as well as the face, ears, nose, breasts, and extremities are usually signs of small or medium artery involvement, which can occur in both systemic idiopathic disease and ANCA-positive DIV. Peripheral blood eosinophilia is more common in vasculitis related to an underlying systemic illness (79 %) compared to vasculitis limited to the skin alone (22 %). Patients with levamisole and thyroid medication-induced 83 disease can also have transient neutropenia or leukopenia than can predispose them to lifethreatening infections. Renal vasculitis is more likely to be found in idiopathic vasculitis (75 % of cases) compared to drug-induced vasculitis (19 % of cases), while arthralgias and skin lesions are more common with drug-induced vasculitis than idiopathic vasculitis. DIV patients are also more likely to have other positive autoimmune antibodies, including myeloperoxidase-anca, antinuclear antibody (ANA), IgM anticardiolipin antibodies, antihistone antibodies, and low C4 complement levels when compared to those with idiopathic vasculitis. Lastly, patients with idiopathic vasculitis typically produce ANCAs to only one neutrophil antigen, whereas in drug-induced vasculitis, ANCAs are directed to one or more neutrophil cytoplasm antigens, most commonly myeloperoxidase, cathepsin G, lactoferrin, and elastase. Management In the majority of cases, vasculitis caused by a drug is self-limiting once the offending agent has been removed. Prompt discontinuation of the suspected drug usually leads to resolution of symptoms within days to weeks. Early detection and removal of the offending agent is critical in decreasing the risk of irreversible organ damage and the morbidity and mortality associated with vasculitis caused by the suspected drug. Sequelae are rare, but when present are usually associated with renal dysfunction in patients who developed glomerulonephritis or acute interstitial nephritis during the course of the illness. Patients found to be ANCA-positive are more likely to have a severe illness, at times necessitating the use of immunosuppressive therapy. The course of the disease is typically much shorter for drug-induced vasculitis compared to idiopathic forms of vasculitis. Supportive treatment with antihistamines, aspirin, and antiinflammatory agents can be used for symptoms such as pruritus, myalgias, and arthralgias that

8 84 often accompany any form of vasculitis. In patients with extensive involvement and multiple organ involvement, recovery time may be longer. The use of corticosteroids or immunosuppressive agents may be necessary to prevent irreversible organ damage. In patients who develop DIV associated with ANCA, ANCA titers may be used to assess disease severity and monitor response after the drug has been withdrawn. In a study describing a patient who developed ANCA antibodies after exposure to a proton-pump inhibitor, the p-anca and MPO-ANCA levels, which were initially positive, became negative after withdrawal of the drug and tapering of prednisone. For eruptions that do not resolve after removal of the suspected agent, an idiopathic or underlying systemic disorder should be considered. Systemic medications that have been used and shown to help resolution of vasculitis include dapsone, colchicine, methotrexate, azathioprine, cyclophosphamide, and cyclosporine. Plasmapheresis has also been used in severe cases of ANCA-associated DIV when immunosuppression is not possible due to underlying infection. Special care should be taken when using potent therapeutic agents due to their associated toxicities and well-known side effect profiles, and all forms of therapy should be tailored to the severity of organ involvement. Histopathology The skin lesions of vasculitis exhibit a pattern of perivascular neutrophils on histology, which is termed fibrinoid necrosis. Microscopically, lesions of DIV show a pattern of i nflammation of small vessels, particularly post-capillary venules. However, involvement of small- and mediumsized arteries can occur, especially in ANCAassociated disease. These findings are often grouped under the histological term leukocytoclastic vasculitis. In such specimens, fibrin deposits, neutrophilic infiltrate, and hemorrhage are observed within the vessel wall. Two patterns have been described, including mononuclear cell dominant versus polymorphonuclear cell dominant. The latter type can be necrotizing or non- necrotizing. The histologic findings in vasculitic lesions caused by drugs cannot be differentiated from other causes of vasculitis. Occasionally, ANCA-associated DIV may demonstrate both leukocytoclastic vasculitis and thrombotic vasculopathy. Pathogenesis S. Rivas et al. The exact mechanism by which drugs cause vasculitis remains unknown. However, an immunopathogenic process appears to be playing a major role. It is believed that drugs serve as haptens and trigger an immune response mediated by the formation and deposition of immune complexes (typically IgG, IgA, or IgM) complement and fibrin on blood vessel walls, which can be detected under direct immunofluorescence. The process appears to involve the release of activated anaphylatoxins C3a and C5a, which leads to the recruitment of inflammatory mediators such as neutrophils, mast cells, lymphocytes, and macrophages, as well as adhesion molecules, such as intracellular adhesion molecule-1, P-selectin, and E-selectin. Complement activation following immune complex deposition triggers the production of tumor necrosis factor (TNF)-alpha, interferon gamma, and multiple cytokines (IL-1b, Il-2, IL-6, and IL-8), which further propagate the infiltration of inflammatory cells, leading to vascular tissue damage. In patients who develop drug-induced vasculitis in the setting of ANCA, the underlying pathogenesis is believed to occur through an ANCA-related activation of inflammatory cells and the apoptosis of neutrophils, which lead to the release of pro-inflammatory cytokines, propagating further inflammation and endothelial cell damage. The burst in cytokines and the ensuing reactive oxygen species that are produced in turn lead to the classic destruction of vessel walls and the histologic pattern of fibrinoid necrosis seen on histology. There have been no prospective or longitudinal studies to determine the prevalence of drug- induced vasculitis. Based on the existing

9 8 Drug-Induced Vasculitis literature, drug-induced vasculitis appears to occur more often in females than in males, and in young adult women, possibly reflecting the increased incidence of thyroid disease in this population. Another risk factor for drug-induced vasculitis is the ingestion of a medication that has been associated with ANCA positive or negative vasculitis, as noted in the lists earlier in this chapter. Conclusions Drug-induced vasculitis is a common cause of vasculitis and is likely mediated by immune complex and complement deposition, with subsequent inflammation and destruction of small- to medium-sized blood vessels. Showing causality between a drug and vasculitis is extremely difficult, and diagnosis remains one of exclusion. Patients with a suspected drug-induced vasculitis should undergo a comprehensive evaluation for systemic causes of vasculitis, including infection, connective tissue disorders, malignancy, and idiopathic vasculitis. A thorough history, physical examination, screening laboratory tests, and skin biopsies should be obtained. The most common agents implicated include propylthioruacil, hydralazine, minocycline, allopurinol, sulfasalazine, D-penicillamine, penicillins, cephalosporins, and several immunomodulating agents. Illegal drugs such as cocaine, levamisole-tainted cocaine, and methamphetamines have been associated with the development of drug-induced vasculitis, and therefore a thorough history of illicit drug use should be obtained. ANCAassociated DIV is associated with the use of anti-thyroid medications, hydralazine, minocycline, and immunomodulating agents, and may present with a more severe illness. The severity of DIV ranges from mild to lifethreatening, with management tailored to the severity of the presentation. Withdrawal of the suspected agent should lead to resolution in days to weeks. Suggested Reading 85 Bonaci-Nikolic B, Nikolic MM, Andrejevic S, Zoric S, Bukilica M. Antineutrophil cytoplasmic antibody (ANCA)-associated autoimmune diseases induced by antithyroid drugs: comparison with idiopathic ANCA vasculitides. Arthritis Res Ther. 2005;7:R Calabrese LH, Duna GF. Drug-induced vasculitis. Curr Opin Rheumatol. 1996;8: Carlson JA, Cavaliere LF, Grant-Kels JM. Cutaneous vasculitis: diagnosis and management. Clin Dermatol. 2006;24: Carlson JA, Ng BT, Chen KR. Cutaneous vasculitis update: diagnostic criteria, classification, epidemiology, etiology, pathogenesis, evaluation and prognosis. Am J Dermatopathol. 2005;27: Chastain MA, Russo GG, Boh EE, Chastain JB, Falabella A, Millikan LE. Propylthiouracil hypersensitivity: report of two patients with vasculitis and review of the literature. J Am Acad Dermatol. 1999;41: Chen KR, Carlson JA. Clinical approach to cutaneous vasculitis. Am J Clin Dermatol. 2008;9: Cid MC, Segarra M, Garcia-Martinez A, Hernandez- Rodriguez J. Endothelial cells, antineutrophil cytoplasmic antibodies, and cytokines in the pathogenesis of systemic vasculitis. Curr Rheumatol Rep. 2004;6: Cuellar ML. Drug-induced vasculitis. Curr Rheumatol Rep. 2002;4:55 9. Gaertner EM, Switlyk SA. Dermatologic complications from levamisole-contaminated cocaine: a case report and review of the literature. Cutis. 2014;93: Hennings C, Miller J. Illicit drugs: what dermatologists need to know. J Amer Acad Dermatol. 2013;69: Lenert P, Icardi M, Dahmoush L. ANA (+) ANCA (+) systemic vasculitis associated with the use of minocycline: case-based review. Clin Rheumatol. 2013;32: Merkel PA. Drugs associated with vasculitis. Curr Opin Rheumatol. 1998;10: Merkel PA. Drug-induced vasculitis. Rheum Dis Clin North Am. 2001;27: 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: Pearson T, Bremmer M, Cohen J, Driscoll M. Vasculopathy related to cocaine adulterated with levimasole: a review of the literature. Dermatol Online J. 2012;18:1. Pendergraft III WF, Niles JL. Trojan horses: drug culprits associated with antineutrophil cytoplasmic autoantibody (ANCA) vasculitis. Curr Opin Rheumatol. 2014;26:42 9. Sokumbi O, Welter DA, Makol A, Warrington KJ. Vasculitis associated with tumor necrosis factor- alpha inhibitors. Mayo Clin Proc. 2012;87: Wiik A. Drug-induced vasculitis. Curr Opin Rheumatol. 2008;20:35 9.