Methotrexate-Induced Leukocytoclastic Vasculitis: A Case Report and Literature Review

Introduction

Methotrexate (MTX) is an anti-metabolite drug which is extensively used for immunosuppressive and chemotherapeutic treatments, particularly for autoinflammatory disorders and hematologic malignancies. It is a folate antagonist, which competitively inhibits the activity of folate-dependent enzymes and synthesis of purine and pyrimidine required for DNA and RNA production in rapidly multiplying cells.^1,2 Despite its therapeutic benefits, MTX is associated with several adverse effects, which are categorized into dose-dependent and dose-independent. Dose-dependent adverse effects are typically associated with higher concentrations of the drug in the body, leading to a reduction in DNA synthesis and cellular proliferation. Rapidly dividing cells, notably in the bone marrow, gastrointestinal (GI) tract, mucosa and liver, are particularly affected. Common dose-dependent side effects of MTX include pancytopenia, nausea, vomiting, mucositis, and liver toxicity.³ Conversely, dose-independent side effects are unpredictable and may occur at lower doses of MTX. These reactions are not directly related to the drug’s concentration but rather with patient-specific factors, including genetic variations, pre-existing conditions, or immune responses. Examples include hypersensitivity reactions, such as rashes and pneumonitis. Leukocytoclastic vasculitis (LCV) also arises from a dose-independent mechanism.^4–6

The term LCV refers to a histopathological description of a common form of small vessel vasculitis (SVV), which can be found on the skin and internal organs. The pathogenesis of LCV involves immune complex deposition in small vessel walls in addition to activation of the complement system.⁷ The histopathological findings are characterized by evidence of neutrophilic infiltration within and around the vessel wall with signs of leukocytoclasia or nuclear dust, as well as fibrinoid necrosis and extravasated erythrocytes.⁸ The clinical presentation of cutaneous SVV (CSVV) including palpable purpura, petechia, macular purpura, urticarial papules, vesicles, pustules, targetoid papules or plaques and ulcers.^7,9

While maculopapular eruptions and urticaria are the most common cutaneous drug reactions.¹⁰ It has been estimated that 10–20% of dermal reactions are vasculitic in nature.⁴ The etiologies of CSVV include autoimmune disorder, infectious agents, as well as drug exposures, with drugs accounted for 10–15% of cases. In the case of MTX, in addition to its systemic adverse effects, common cutaneous side effects include oral ulcers, alopecia, photosensitivity. Less commonly, it has been associated with necrosis of psoriatic plaques and accelerated rheumatoid nodulosis.¹¹ MTX-associated LCV, however, is relatively rare. Moreover, the idiosyncratic nature makes it unpredictable and difficult to recognize. Currently, reports of MTX-induced LCV are scarce and lack systematic review. Nonetheless, the aforementioned clinical features and history of MTX administration should include MTX-induced LCV in differential diagnosis. Therefore, we present a case of a female patient with underlying end-stage renal disease (ESRD) requiring hemodialysis (HD), who developed histologically confirmed LCV after ten weeks of oral MTX for systemic lupus erythematosus (SLE). A literature review is also provided.

Case Presentation

A 60-year-old female has been diagnosed with SLE for 30 years. She presented with fever, malar rash, leg edema, proteinuria and a high antinuclear antibody (ANA) titer of 1:320 with fine-speckled pattern. Four years later, she developed ESRD due to lupus nephritis class VI and regularly required HD. There is no family history of autoimmune diseases. Current medications for SLE included oral MTX 5 milligrams (mg) weekly, prednisolone 5 mg every other day and hydroxychloroquine (HCQ) 600 mg weekly. MTX was initiated 10 weeks ago due to newly developed arthritis. Afterwards, she presented with a one-week history of oral ulcers preceding hospitalization. Physical examination revealed multiple ulcers on the buccal mucosa (Figure 1A). Laboratory findings showed pancytopenia including hemoglobin at 8.2 grams/deciliter (g/dL), hematocrit at 24.6%, white blood count at 1,330 cell/dL, platelet count at 27,000/mm³ and elevated liver enzymes with aspartate aminotransferase (AST) 368 units per liter (U/L), alanine transaminase (ALT) 438 U/L. There was no MTX concentrations measured prior to these signs and symptoms, however, at the current admission MTX level was high (0.03 micromoles per liter). Therefore, she was initially diagnosed with MTX toxicity and was hospitalized for MTX antidote, folinic acid 150 mg intravenously (IV) every 4 hours (100 mg/m²), GCSF 300 mg IV once daily and blood component transfusion. Simultaneously, MTX was discontinued. The last dose was administrated one week ago. The risk factors that contributed to MTX toxicity were thought to be the underlying ESRD and advanced age.

Figure 1 Oral ulcers at right buccal mucosa resulting from MTX toxicity (A), multiple non-blanchable erythematous papules located on abdomen (B) with few pustules, and vesicles (C).

Two days after admission, she developed multiple non-blanchable erythematous papules on the neck, trunk, and both arms, along with a few vesicles and pustules on the abdomen (Figure 1B and C) without fever, malaise, arthritis, or malar rash. Differential diagnoses were infections including varicella zoster virus (VZV) infection, disseminated herpes simplex virus (HSV) infection, CSSV due to infectious agents such as hepatitis viral, human immunodeficiency virus (HIV), bacterial infections and non-infection causes including MTX-induced LCV and CSVV secondary to SLE. Laboratory findings were assessed. Tzanck’s smear and polymerase chain reaction (PCR) for VZV, HSV1, HSV2 from base of vesicle yielded negative results. Blood for anti-HIV and viral hepatitis profile including hepatitis A, B, and C were negative. Blood culture for aerobe was undetectable, urinalysis showed no leukocyte, and chest x-ray showed no abnormal opacity. Serum complement levels (C3 and C4) were within normal limits, while erythrocyte sedimentation rate (ESR) was mildly elevated at 24 millimeters per hour. C-reactive protein was also elevated at 7.99 mg/L. Serum cryoglobulin was not tested due to the absence of history of cold-induced skin lesions.

A skin punch biopsy was performed at an erythematous papule on abdomen, revealing dense superficial perivascular and interstitial infiltration of lymphocytes, eosinophils, few neutrophils, few nuclear dusts and extravasate erythrocytes, suggestive of early leukocytoclastic vasculitis (Figure 2A–C). Lesional direct immunofluorescence (DIF) studies demonstrated focal deposits of C3 at the dermo-epidermal junction and at superficial blood vessels, immunoglobulin (Ig)G showed a few cytoid bodies, while IgM and IgA revealed no deposits. These DIF findings suggest a possible immune complex-mediated vascular disease (Figure 2D). Given the temporal relationship with the history of MTX toxicity and the exclusion of other potential causes including infection and SLE condition, which was inactive due to the absence of fever, photodistributed rash, alopecia, arthritis as well as normal complement levels and only mildly elevated ESR, a diagnosis of MTX-induced LCV was made. She was administered oral prednisolone at 10 mg/day for immunosuppression and HCQ 600 at mg/day. No additional immunosuppressants were prescribed. Some of the lesions progressed to palpable purpuric macules, and overall, the lesions began to subside by day 4 as the serum MTX level became undetectable, and all erythematous papules on the trunk and extremities turned to brownish macules within 7 days; oral mucositis also healed during this timeframe (Figure 3). The same dosage of the drugs was maintained for the management of underlying SLE.

Figure 2 Hematoxylin and Eosin (100x, 400x) showing dense superficial perivascular and interstitial infiltration of lymphocytes, eosinophils, few neutrophils, few nuclear dusts and extravasate erythrocytes, suggestive of early leukocytoclastic vasculitis (A–C). Direct immunofluorescence studies demonstrated focal deposits of C3 at dermo-epidermal junction and at superficial blood vessels, consistent with possible immune-complex vascular disease (D).

Figure 3 Resolution of the lesions within one week: right buccal ulcers (A), and erythematous papules on the trunk resolving into brownish macules (B).

Discussion

In our case, the patient presented with multiple non-blanchable erythematous papules on the trunk, and extremities, along with a few vesicles, and pustules on the abdomen. The morphology of the lesions was suggestive of CSVV, which can present with non-blanchable erythematous papules, vesicles and pustules. However, due to the appearance of vesicles and pustules, infection such as VZV and HSV were included in the differential diagnoses. Laboratory investigations excluded these infections, Histopathology revealed superficial perivascular lymphocytic and neutrophilic infiltration, nuclear dust, eosinophils and extravasated erythrocytes. Although fibrinoid necrosis was not observed, early LCV was suggested. Furthermore, DIF also supported the diagnosis of LCV, indicating a possible immune complex-mediated vascular disease. Moreover, during the subsequent observation, the lesions progressed to macular and palpable purpura. Take all findings into account, the skin lesions were diagnosed as cutaneous LCV.

The etiologies of cutaneous LCV include infectious agents, inflammatory disorders, drug exposure and idiopathic cause. In our case, the patient had no fever or specific symptoms such as respiratory tract symptoms or diarrhea. Furthermore, we have excluded bacteremia, viral hepatitis and HIV infection. Regarding inflammatory disorders, LCV secondary to the underlying SLE was considered in the differential diagnosis. However, the SLE condition was inactive due to the absence of fever, photo-distributed rash, alopecia, arthritis as well as normal complement levels and only mildly elevated ESR, Thus, SLE-associated LCV was excluded. Therefore, LCV secondary to MTX is the most likely explanation for the skin lesions, given the temporal relationship, concomitant diagnosis of MTX toxicity, elevated serum MTX level, and the absence of other identifiable causative agents. Consistently, the presence of tissue eosinophil infiltration suggests that the vasculitis may be drug-induced.⁸

According to the Naranjo causality scale¹² for adverse drug reactions of probable case. The score was 8, which included the previous reports on the reaction, temporal relationship between MTX administration and onset of LCV, evidence of toxic level of MTX in serum, consistency of histological and direct immunofluorescence studies, resolution after drug discontinuation or antidote and exclusion of differential diagnoses. The risk factors of our patient that contributed to MTX toxicity were advanced age and ESRD, as MTX is predominantly excreted by the kidneys (70%–90%).¹ Previous study showed that even a low dosage of 2.5 mg/week could lead to elevated plasma concentrations and prolonged half-life in HD patients, with the drug levels remaining elevated after 3 weeks.¹³ Consequently, the prescription of MTX in patients with compromised renal function must be approached with caution. Furthermore, drug interactions between MTX and other agents such as aspirin, nonsteroidal anti-inflammatory drugs, furosemide and trimethoprim-sulfonamide should be aware since these drugs can exacerbate the toxicity of MTX.¹⁴

MTX-induced LCV is a rare but well-documented adverse effect. The exact pathogenesis is not fully understood but is presumed to involve a type III hypersensitivity reaction, in which immune complexes deposit in wall of small blood vessel. This deposition triggers the recruitment of inflammatory cells, which in turn leads to the vessel wall damage. In contrast, common side effects of MTX such as nausea and vomiting, cytopenia and hepatotoxicity are more likely caused by the drug direct toxic effects on tissues.^7,8 The clinical presentations consist of petechia, palpable purpura, non-blanchable discrete erythematous to violaceous papules, confluent erythema to blister and necrotic patches on trunk, extremities, and face. The lesions may exhibit pruritus, discomfort and extensive distribution.¹⁵ The diagnosis is established based on clinical, histological, DIF studies and temporal relation between MTX administration and onset, exclusion of other potential causes, resolution after drug withdrawal and reappearance following re-challenge (if appropriate). The treatment of LCV depends on two major factors: the underlying etiology and the extent of disease. First, eliminating or treating the triggers; and second, evaluating the extent of involvement, if the lesions are limited to the skin, the treatment should primarily focus on symptomatic relief, as the lesions are typically self-limited and resolve over 3–4 weeks. In cases of severe CSVV, systemic corticosteroid may be prescribed with or without the adjunctive therapies, such as colchicine, dapsone, HCQ. In systemic vasculitis, steroid-sparing immunosuppressive agents such as methotrexate, azathioprine, mycophenolate mofetil, cyclophosphamide, and intravenous immunoglobulin (IVIG) may be needed.^7,8

The Table 1 presents a total of 14 cases from 11 previous reports^5,6,16–24 involving histologically proven LCV, which was strongly suspected to be associated with MTX. The patients’ age ranges from 10 to 73 years with MTX treatment for RA, psoriasis, JIA, ankylosing spondylitis, acute lymphoblastic leukemia, primary central nervous system lymphoma and osteogenic sarcoma. The dosage varies including a high dosage for chemotherapy and a low dosage for autoinflammatory disorders (5–20 mg/week). The onset of cutaneous vasculitis may manifest following the initial or subsequent high dose-MTX and within 2 weeks to 6 months following low dose-MTX. Additionally, there is a report showing 2 cases of cutaneous vasculitis in patients receiving MTX more than 10 years after triggering by viral infection in the preceding 5–6 months’ duration.¹⁸ The clinical presentations comprise petechia, palpable purpura, non-blanchable discrete erythematous to violaceous papules, confluent erythema to blister and necrotic patches on trunk, extremities, and face. The lesions may be pruritic, painful, and extensive. Systemic symptoms such as fever, malaise, nausea, and arthralgia may be present. Myelosuppression, hepatoxicity, renal impairment, pulmonary fibrosis and mucositis may coexist with the cutaneous vasculitis. The lesions predominantly subsided within 1 week and completely resolved within 3–4 weeks.^17,18,21,23,

Table 1 Review of the Literature of Patients with Histologically Proven MTX-Induced Leukocytoclastic Vasculitis

A limitation of our study is that it is a single case report. However, we presented a rare case of MTX-induced LCV, which occurred concurrently with MTX toxicity, and highlighted that such adverse events can arise even at very low doses (5 mg/week). This case underscores the need for caution when prescribing MTX to patients with underlying ESRD, as they may be more susceptible to both direct toxicity and immune complex–mediated reactions, which are thought to contribute to the pathogenesis of MTX-induced LCV. Additionally, we conducted a literature review to summarize the existing clinical data and provide further context for our findings.

Conclusion

MTX-induced LCV is a rare but well-documented complication which may unpredictably occur after either high or low-dose MTX regimen and may occur alongside concurrent MTX toxicity. The diagnosis depends on the temporal relationship of drug usage and the exclusion of other potential etiologies. We report a case of histologically confirmed MTX-induced LCV and summarize the clinical presentations and MTX dosing of the prior MTX-induced LCV reports.