Introduction
Inflammation of the blood vessels, resulting in tissue injury, is categorized based on the dominant type of vessel involved, whether small, medium, or large vessels.[1] Drugs remain an important etiological consideration in patients with vasculitis. Drug-induced vasculitis (DIV) is recognized as a distinct entity under the Chapel Hill Consensus Conference 2012 definitions for vasculitis and its recent dermatological addendum, as vasculitis with probable etiology. Such vasculitis may be limited to the skin, or affect internal organs in addition, particularly the peripheral nerves, kidneys, lungs, and gastrointestinal tract.[12] In this narrative review, we shall describe recent insights into the different types and etiologies of DIV and discuss pathogenetic mechanisms for the same.
Search Strategy
We adhered to a search strategy for writing narrative reviews as per previously described guidelines.[3] We searched Scopus (which also contains all the data from Medline) on October 7, 2019, with the search terms “drug-induced” and “vasculitis,” for articles published since 2010, and retrieved 625 results. The abstracts and titles of these articles were screened to identify relevant observational studies and case reports of DIV. In addition, notable reviews identified in our search and the prior knowledge of authors were utilized to further identify other relevant articles.
Drug-Induced Vasculitis Syndromes
Small-vessel vasculitis
Drug-induced small-vessel involvement may result in cutaneous vasculitis alone or also involve internal organs such as the kidney and peripheral nerves.[2] A typical feature of small-vessel vasculitis (SVV) induced by drugs is the presence of antineutrophil cytoplasmic antibodies (ANCA) in a significant proportion, which may have specificity toward proteinase-3 (anti-PR3), myeloperoxidase (anti-MPO), or toward other antigens. We shall consider drug-induced SVV under the syndromic headings of cutaneous leukocytoclastic vasculitis (CLCV), ANCA-associated vasculitis (AAV), or IgA vasculitis.
Drug-induced cutaneous leukocytoclastic vasculitis
This variant is probably the most common form of vasculitis induced by drugs. A large retrospective case series of 239 patients from North America seen over 15 years reported drugs as the probable etiologic association for nearly 31% of patients with CLCV seen at their center during this period. The most common culprit drugs were antibiotics and nonsteroidal anti-inflammatory drugs. Uncommon associations were with allopurinol, antiepileptic drugs, antihypertensive medications, and even immunosuppressive agents. Internal organs were involved in a significant number, with joints affected in nearly one-half, and the gastrointestinal tract or kidneys affected in about a third. A minority were positive for autoantibodies (one-fifth for antinuclear antibodies, one-sixth for rheumatoid factor, and <5% for ANCA, although data regarding autoantibodies was not available for all patients). Nearly one-half patients required immunosuppressive therapy in addition to drug cessation.[4] Anecdotal reports of CLCV exist with commonly used drugs such as metformin,[5] glyburide,[6] telmisartan,[7] tenofovir,[8] clopidogrel,[9] and clomiphene.[10] Commonly used antitubercular drugs such as isoniazid and rifampicin have also been reported to cause CLCV.[11] An interesting report described a patient on the antitumor necrosis factor-alpha (anti-TNF-α) agent adalimumab for psoriasis, who developed lupus-like skin lesions, with biopsy evidence of leukocytoclastic vasculitis (LCV).[12] Levamisole is more commonly associated with drug-induced AAV (discussed later); however, occasional reports exist of its association with CLCV alone.[13] Newer drugs used in oncology, which affect the immune system, such as ceritinib (anaplastic lymphoma kinase-positive inhibitor), have also been implicated in causing LCV.[14]
Drug-induced IgA vasculitis and other small-vessel vasculitis
IgA vasculitis (IgAV) induced by drugs is rare. Agents targeting TNF-α such as infliximab, adalimumab (both in the same patient)[15] and etanercept,[16] and palbociclib,[17] an inhibitor of cyclin-dependent kinase 4/6 used in oncology, have been reported to cause IgAV. Of these three patients, all had skin involvement, whereas one each had glomerulonephritis and lower gastrointestinal bleed as manifestations of IgAV, requiring additional corticosteroid therapy.[151617] We could also identify a report of hypocomplementemic urticarial vasculitis syndrome associated with etanercept therapy, which persisted for months after drug discontinuation.[18]
Drug-induced antineutrophil cytoplasmic antibodies-associated vasculitis
Classical drugs implicated in causing AAV are antithyroid drugs, cocaine/levamisole, and hydralazine.[19] Propylthiouracil, methimazole, and carbimazole are used for the treatment of thyrotoxicosis. Asymptomatic circulating ANCA may be found in patients on these drugs. Rarely, a vasculitic process clinically mimicking AAV may occur in such patients, most commonly with propylthiouracil, but has also been reported in patients on methimazole or carbimazole. The onset of vasculitis maybe soon after drug initiation or years later. Such individuals may present with only cutaneous vasculitis, or with major organ involvement, such as interstitial lung disease, crescentic glomerulonephritis, diffuse alveolar hemorrhage severe enough to require ventilatory support, or retinal vasculitis. Circulating ANCA is commonly detectable in such patients with vasculitic manifestations, with specificity to either PR3, MPO, or both. Patients with such vasculitic manifestations generally require immunosuppressive therapy akin to that needed for AAV.[2021222324252627]
Hydralazine is often used as an antihypertensive agent and can occasionally induce systemic vasculitis. A series of 12 patients with hydralazine-induced vasculitis were reported from a tertiary care center in North America. These patients developed vasculitic manifestations after prolonged exposure to hydralazine (median 21 months);[28] anecdotal reports exist of much earlier onset of AAV in patients on hydralazine (6 weeks after initiation).[29] Most of the patients in the above case series had glomerulonephritis, most commonly pauci immune, crescentic glomerulonephritis. Nearly one half also had interstitial lung disease, pleural effusions, or pericardial effusions. Notable was the presence of both ANA and ANCA in all patients. The most common type of ANCA noted was perinuclear (all but one patient, who had cytoplasmic ANCA; by enzyme-linked immunosorbent assay, all had antibodies to MPO). Ten patients required immunosuppression in addition to drug discontinuation for management of the vasculitic process, and most patients improved following treatment.[28]
Cocaine is another drug which is commonly associated with drug-induced AAV. A series of 14 patients with cocaine-induced AAV from the United Kingdom described onset of disease in some at onset, and others as late as 12 years after initiation of cocaine abuse. These individuals had sinusitis, destructive changes in nasal cartilage, peripheral neuropathy, and purpuric rashes. Most patients required immunosuppressive therapy for the vasculitic process.[30] Another recent paper described two patients with cocaine-induced renal disease, and further collated reports of this manifestation from the published literature. Out of 33 such identified cases, all had additional cutaneous involvement, nearly one-fourth had upper airway involvement, and one-sixth had pulmonary involvement also. Hypocomplementemia was found in nearly half the patients. A notable feature was the presence of antibodies to both PR3 and MPO in 45%. Those patients who stopped further cocaine abuse all survived with improvement or stabilization of the vasculitic process, whereas nearly 60% with continuing cocaine abuse continued to have persistent vasculitic manifestations.[31] Cocaine-induced midline destructive lesions may also be associated with circulating ANCA, however, may not respond to immunosuppressive therapy, rather requiring cessation of cocaine abuse.[32] Levamisole is a common contaminant of cocaine, and cocaine-associated AAV may occur in the presence or absence of levamisole as a contaminant. Levamisole-associated AAV may result in purpuric rashes, with or without arthralgias and other major organ involvement such as pulmonary infiltrates. A distinct feature of levamisole-associated AAV is leukopenia with neutropenia, as opposed to the neutrophilic leukocytosis commonly identified in association with AAV. ANCA in such cases may have specificity for human neutrophil elastase (HNE).[33] Rarely, cocaine/levamisole exposure can result in periosteitis due to vasculopathy of small vessels.[34] Other drug culprits anecdotally implicated in AAV include isoniazid,[35] ethambutol,[36] d-penicillamine,[37] simvastatin, ezetimibe,[38] infliximab, etanercept,[39] denosumab,[40] trimethoprim-sulfamethoxazole,[41] and sofosbuvir.[42] A rare association of granulomatosis with polyangiitis with the checkpoint inhibitor pembrolizumab (which blocks programmed cell death 1 [PD1]), with positivity for anti-PR3 antibodies, presenting with pulmonary-renal syndrome, could be identified. The patient in question improved with drug withdrawal, along with oral cyclophosphamide and corticosteroids.[43] Pembrolizumab has also been associated with retinal vasculitis.[44] Montelukast, which is a leukotriene receptor antagonist, has been associated with emergence of eosinophilic granulomatosis with polyangiitis in patients with preexisting asthma. However, this might possibly have occurred due to reduction in dose of corticosteroids due to control of asthma, as a consequence revealing the underlying vasculitic process, rather than related to the drug perse.[45] In our experience, drug-induced AAV can have an unpredictable course and may leave behind end-organ damage akin to primary AAV such as chronic renal impairment and interstitial lung disease.
Medium-vessel vasculitis
The tetracycline group antibiotic, minocycline, often used for prolonged duration in patients with acne, has been reported to cause medium-vessel vasculitis akin to polyarteritis nodosa (PAN). A North American series reported nine such patients, with biopsy-proven evidence (in six patients) or angiographic evidence (in three) of medium-vessel vasculitis. They presented with renal microaneurysms, mesenteric vessel inflammation, mononeuritis, livedo reticularis, or cutaneous nodular lesions. ANCA was present in most patients. All patients responded to drug discontinuation, with additional requirement for immunosuppressive therapy in six patients.[46] Minocycline use may also result in isolated mononeuritis with axonal neuropathy, without full-blown features of PAN.[47] Such patients may also rarely be positive for antinuclear antibodies, in addition to the commonly reported ANCA.[48] Other rare associations with a PAN-like illness include the Vitamin K antagonist acenocoumarol, causing leg ulcers with histopathological evidence of fibrinoid necrosis and vasculitis.[49] Rarely, medications can result in peripheral limb ischemia, mimicking PAN. The drug ergotamine, used for migraine, is most commonly implicated. The propensity for ergotamine to cause critical distal limb ischemia is particularly increased when it is administered in conjunction with other agents that decrease its metabolism, such as protease inhibitors or voriconazole. Although such limb ischemia generally improves with drug withdrawal, it may require endothelial stabilization and anticoagulation during the acute period of ischemia, and occasionally require endovascular intervention to restore blood flow.[5051] A case report described a patient with hepatitis C who developed digital gangrene on interferon-alpha treatment, without the presence of cryoglobulins, suggesting medium-vessel involvement akin to PAN. The digital ischemia improved gradually after drug withdrawal.[52] We could also identify a rare association of propylthiouracil with a systemic vasculitic process mimicking Kawasaki disease in a 11-year-old girl, with desquamating rash, cervical lymph node enlargement, acalculous cholecystitis, and renal involvement (albeit without coronary artery involvement), with the presence of antibodies to MPO-ANCA. The clinical features responded well to drug discontinuation along with intravenous immunoglobulin and corticosteroids.[53] Another emerging association with peripheral neuropathy, akin to that seen in medium-vessel vasculitis, is with the checkpoint inhibitors nivolumab and pembrolizumab, both of which block PD1.[44]
Large-vessel vasculitis
Drug-induced large-vessel vasculitis is rare. Periaortitis and aortitis have been reported in association with bevacizumab (antibody to vascular endothelial growth factor) in two patients with adenocarcinoma of lung and ovary. One of these patients had circulating antibodies to perinuclear ANCA. In both instances, recovery was documented angiographically after drug discontinuation and oral corticosteroid therapy.[5455] Another woman on lenograstim (recombinant granulocyte colony-stimulating factor) for neutropenia due to cancer chemotherapy developed arteritis of the left common carotid artery, which resolved after drug discontinuation.[56] Another patient developed superior mesenteric artery vasculitis with bowel ischemia shortly after the initiation of simvastatin therapy.[57] Drug-induced large-vessel vasculitis, aortitis, and periaortitis have also been anecdotally reported with the checkpoint inhibitors ipilimumab (which blocks cytotoxic T-lymphocyte-associated antigen 4 [CTLA4]) and pembrolizumab (which blocks PD-1).[44]
Cerebral vasculitis
Rare instances exist of cerebral vascular involvement with potential drug culprits. A series of five patients from the United States of America reported hemorrhagic central nervous system vasculitis in the context of sympathomimetic drug use for nasal congestion (topical xylometazoline, oral ephedrine, pseudoephedrine, phenylpropanolamine, phentermine, and fenfluramine). These patients presented with severe headaches and focal neurological deficits; brain imaging revealed both areas of infarction and hemorrhage. One of these patients improved with discontinuation of the potential culprit drug, whereas four others responded to immunosuppressive therapy (prednisolone in four, with additional cyclophosphamide in three) along with drug withdrawal.[58] Cerebral vasculitis in association with drug rash with eosinophilia and systemic symptoms, or with peripheral blood eosinophilia alone, has also been reported with allopurinol, minocycline, azithromycin, and antibiotics (ceftriaxone, vancomycin, and metronidazole), responsive to drug cessation, with or without immunosuppressive therapy.[5960] A report describes a patient with thyrotoxicosis who was on propylthiouracil for 8 years, who developed cerebral vasculitis akin to Moya Moya disease, along with detectable antibodies to MPO-ANCA, responsive to corticosteroids and cyclophosphamide.[61] Another paper described a young male with acne on prolonged minocycline therapy, who developed multiple brain infarctions due to the development of antiphospholipid antibodies, mimicking cerebral vasculitis. These antibodies disappeared following drug withdrawal.[62] An emerging association of the checkpoint inhibitors nivolumab and pembrolizumab (both of which block PD1) with a presentation akin to primary angiitis of the central nervous system is being recognized.[44]
Visualizing the Vasculitic Syndromes from the Viewpoint of the Drug
As has been discussed, different drugs can be associated with different types of vasculitis. We attempt to summarize key types of vasculitis associated with drugs commonly and increasingly used in clinical practice in [Table 1].
;)
Table 1: Common drugs associated with vasculitis based on the vessel type
Pathogenesis of Drug-Induced Vasculitis
The pathogenesis of drug-induced CLCV generally involves immune complex formation and deposition in the cutaneous capillaries, resulting in endothelial injury and extravasation.[4] Detailed mechanistic studies have explored causation of circulating ANCA due to propylthiouracil and cocaine/levamisole and both involve abnormal formation of neutrophil extracellular traps (NETOSIS). When human neutrophils were treated in vitro with propylthiouracil, the NETs generated were different in morphology from those generated by using the positive control phorbol myristate acetate (PMA) and were resistant to degradation by deoxyribonuclease. Lack of degradation could expose neutrophil granules contained in these NETs to immune cells, resulting in ANCA generation. When Wistar Kyoto rats were injected with such abnormal NETs generated using propylthiouracil, they developed alveolar hemorrhage due to the pulmonary capillaritis. Further, oral administration of propylthiouracil with intraperitoneal PMA administration to Wistar Kyoto rats resulted in the phenotype of glomerulonephritis and alveolar hemorrhage, associated with circulating ANCA to MPO. This suggests that propylthiouracil may induce abnormal generation of NETs, which may induce AAV.[63] Similarly, when human neutrophils were exposed to cocaine and levamisole in vitro, they formed NETs with increased relative amount of HNE (antibodies to which are detectable in human AAV induced by cocaine/levamisole abuse). Exposure to cocaine/levamisole could further stimulate secretion of B-cell activating factor from neutrophils, which could result in generation of long-lived plasma cells.[64] Such cells could possibly explain the observation that cocaine-/levamisole-induced AAV tends not to improve unless abstinence from the culprit agent is adhered to.[3164]
The vascular wall of large and medium vessels contains dendritic cells, which express the inhibitory molecule programmed cell death ligand 1 (PDL1). In turn, this ligand acts as an “off” switch via PD1 expressed on activated T-lymphocytes present in the walls of these vessels. Inhibition of PD1, or of PDL1, results in uncontrolled activation of these T-lymphocytes, releasing inflammatory cytokines, which attract other immune cells and result in the phenotype of vascular and endothelial injury, followed by intimal hyperplasia (resulting in vessel occlusion and distal ischemia), as well as neovascularization of the vessel wall (thereby aiding the influx of immune cells into the otherwise protected vascular wall). CTLA4 is another “off” switch expressed on activated T-lymphocytes, negating this may initiate vascular wall inflammation by similar means. These mechanisms may explain large and medium vessel vasculitis in the context of checkpoint inhibitor use.[4465] [Figure 1] summarizes some of these mechanisms operational in driving DIV.
Figure 1: Pathogenetic mechanisms operational in drug-induced vasculitis
Conclusion
Medications can sometimes result in isolated LCV, or rarely more severe forms of vascular involvement such as small-, medium-, or large vessel vasculitis, or cerebral vasculitis. Physicians should be aware of propensity of drugs to cause vascular manifestations. In a majority of instances, improvement occurs with withdrawal of the culprit drug; however, a significant proportion may also require additional immunosuppressive therapy with corticosteroids alone, or with other agents such as cyclophosphamide.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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