Leukocytoclastic Vasculitis Induced by Subcutaneous Injection of Human Insulin in a Patient With Type 1 Diabetes and Essential Thrombocytemia

Both local (1) and systemic immediate-type insulin allergy (2) as well as delayed-type cutaneous reactions (3) to human insulin have been reported. Histologically verified Arthus reaction to insulin has only been reported in exceptional cases in which the patient was treated with bovine/porcine insulin (4). To the best of our knowledge, no histologically verified type 3 hypersensitivity reaction has been described in a patient treated with human insulin.

We report a case of leucocytoclastic vasculitis in a 48-year-old normal-weight female patient with well-controlled (HbA_1c 6.4, upper normal 6.4%) type 1 diabetes since 1984 who had always been treated with ∼0.5 units · kg⁻¹ body wt · day⁻¹ semisynthetic human insulin and, beginning in 1998, recombinant human insulin. The patient did not have microvascular complications (normal fundoscopy, urinary albumin, and vibration perception threshold). She presented October 1997 with monophasic tender indurations at the injection sites of both human regular and NPH insulins (Novo Nordisk) in the abdominal and femoral regions, respectively, with occurrence within 2–6 h of injection and persistence from 1 to 3 days, later (May 1998) preceded by intense itching and redness, but no wheal-and-flare immediately after injection. A macular skin redness of between 1 and 2 cm was observed, and the indurations in the subcutaneous tissue developed into nodules after 3–4 days. These lesions were independent of injection site, and switching to other insulin, insulin analogs, as well as continuous subcutaneous insulin infusion was ineffective. After 3 years, the condition had become incapacitating, requiring repeated injections of Humalog (Eli Lilly) 5–6 times a day, including one injection at ∼3:00 a.m., as the best-tolerated insulin therapy.

Intradermal insulin skin testing (insulin allergy kit; Novo Nordisk, Bagsværd, Denmark) showed reactions toward human, porcine, and bovine insulin but no reactions to protamine or other additives. IgG but not IgE insulin antibodies, with a binding capacity of 28%, were demonstrated. In vitro lymphocyte proliferation was not induced with human insulin. Skin biopsies from 5-h and 5-day-old lesions showed perivascular and interstitial infiltration with neutrophilic and eosinophilic granulocytes and with considerable amounts of nuclear dust and swollen endothelial cells, granulocytic infiltration, and fibrin deposition as well as localized extravasation of erythrocytes in the vascular walls, indicating leucocytoclastic vasculitis. Other tests included: thrombocytosis (841 10⁹ · l⁻¹) and leukocytosis (19 10⁹ · l⁻¹) with neutrophilia; hyperplastic bone marrow with scattered megakaryocytes (normal); and normal ultrasound scan of the abdominal region and retroperitoneum, with special attention to the spleen and lymph nodes. The following normal lab test were also normal: hemoglobin; sedimentation rate; C-reactive protein; serum creatinine; liver enzymes; 24-h urinary albumin; IgA, IgG, and IgE antibodies; eosinophil counts; M-component; cryoglobulins; antinuclear antibodies; IgM/IgA rheumatoid factor; anti-cardiolipin antibodies; and anti-neutrophil cytoplasmic antibodies.

Immunosuppressive therapy was started February 2000, with prednisolone 10 mg once daily and, initially, azathioprine 50 mg daily, which was later substituted with methotrexate 7.5–15 mg once weekly because of antral gastritis. This treatment induced complete regression of symptoms and lesions within 8 weeks, and the patient resumed work, maintaining optimal glycemic control on recombinant human regular and NPH insulin (Novo Nordisk). The differential count and IgG insulin antibodies—but not the thrombocytemia—normalized during immunosuppression. Aspirin therapy was instituted because of thrombocytosis.

Leucocytoclastic vasculitis, which exclusively or primarily involves the skin, is often seen in other systemic diseases, such as subacute bacterial endocarditis, Epstein-Barr virus infection, chronic active hepatitis, ulcerous colitis, diseases of the complement system, retroperitoneal fibrosis, primary biliary cirrhosis, or myeloproliferative diseases. In this case, essential thrombocytosis is the most likely diagnosis because thrombocytosis but not neutrophilia persisted during immunosuppressive therapy. It is therefore conceivable that the myeloproliferative disorder predisposed to a B-lymphocyte clonal abnormality, leading to antibody formation against human insulin and secondarily leukocytoclastic vasculitis.

The bone marrow findings were not discriminative as to the question of whether thrombocytosis was primary or secondary. Platelet morphology, leukocyte differentiation markers, and chromosomal studies were not carried out because these studies would not have been definitive. However, the clinical course of persistent thrombocytosis, despite complete clinical remission and elimination of insulin antibodies, speaks strongly in favor of essential thrombocytosis as the underlying disorder.

Lymphocyte proliferation toward human or analog insulin was not detected. This is in accordance with previous findings that T-cell reactivity to human insulin detected by in vitro lymphocyte transformation in patients with insulin allergy is usually much weaker than lymphocyte transformation toward beef or pork insulin in patients with immune reactivity toward these species of insulin (5). Furthermore, the antigen may be the insulin dimer rather than the insulin monomer, also contributing to explain the lack of lymphocyte proliferation to human insulin in this patient.