Case Presentation
An 82 year-old woman presented to hospital with a two-day history of a bilateral lower limb purpuric rash starting over her distal calves with ascent to her thighs (Figure 1a–b). The rash was non-pruritic and mildly tender. She had no fevers, myalgia, arthralgia, oral or genital ulcers, respiratory or sinus symptoms, neurological symptoms, Raynaud’s phenomenon or oesophageal dysmotility. She did not have a previously similar rash. She was otherwise well with no preceding infective symptoms. She did not have direct skin contact with allergenic materials.10 days prior to rash onset, she was commenced on verapamil 40 mg immediate-release tablet twice daily and atorvastatin 40 mg tablet nocte by her cardiologist for palpitations and dyslipidaemia. She took these medications as prescribed for 12 consecutive days until hospital presentation. She had never taken these medications previously.
Her medical history included Sjogren’s syndrome diagnosed three years prior with high-titre centromere pattern anti-nuclear antibodies (ANA) and sicca symptoms – which were stable on long term hydroxychloroquine 200mg once daily treatment. She also had a left submandibular gland Mucosa-associated lymphoid tissue (MALT) lymphoma successfully excised one year prior and was since in remission without needing systemic therapy. Her long-term medications also included aspirin 100 mg once daily for primary prevention, and over-the-counter magnesium, fish oil and vitamin C supplements taken as per directions. She had no known allergies. Vaccinations were up to date including four SARS-CoV-2 vaccinations– receiving the last vaccine six months prior without any adverse effects. She had never smoked or taken any illicit drugs and had no alcohol consumption.
On examination, her observations were normal and she was afebrile. She had bilateral lower limb purpura from distal calves to proximal thighs. Over the course of the two-day admission, the purpura progressed with coalescing of lesions and ascending involvement of the trunk and upper limbs (Figure 1c–d). She did not have active tenosynovitis, deforming polyarthropathy or nail abnormalities. She had no stigmata of scleroderma or infective endocarditis. She had no ocular inflammation, spondyloarthropathy, aphthous ulcers, or other abnormal rashes. She had no proximal weakness or focal neurological deficits. Her cardiorespiratory examination was unremarkable and she was euvolaemic. Her abdominal examination was unremarkable with no hepatosplenomegaly. She did not have significant lymphadenopathy in the cervical, axillary or inguinal regions.
Her chest x-ray was unremarkable with no consolidation, interstitial markings or cardiomegaly. Full blood count revealed a mild normocytic anaemia in keeping with anaemia of chronic disease, as well as a mild neutrophilia, lymphopenia and monocytosis in keeping with an activated immune response (Table 1). There was no eosinophilia. Platelet count and coagulation profile were normal. C-reactive protein and erythrocyte sedimentation rate were mildly elevated and high-normal respectively; mild hypoalbuminaemia and decreased transferrin saturation were present in keeping with an acute inflammatory state. Serum electrolytes, urea, creatinine, liver function tests and haematinics were unremarkable. Urine investigations revealed no detectable proteinuria, dysmorphic red cells or casts. Infectious serology was negative for hepatitis B, hepatitis C and human immunodeficiency virus (Table 1).
Autoimmune serology was significant for a high-titre centromere pattern ANA, with negative extractable nuclear antigen antibody screen (ENA). Type II cryoglobulin was detected with a polyclonal and monoclonal immunoglobulin M (IgM) component (Table 1). Correspondingly, rheumatoid factor (RF) was elevated and there was marked C4 hypocomplementaemia. Cryoglobulin status was unknown prior to presentation. Anti-double stranded deoxyribonucleic acid (Anti-dsDNA), anti-cyclic citrullinated peptide (Anti-CCP) and anti-neutrophil cytoplasmic antibodies (ANCA) were negative. Serum immunoglobulin G (IgG), A (IgA) and IgM were within normal range. Serum protein electrophoresis was unremarkable with no paraprotein (Table 1).
Histopathology of the purpuric rash revealed leukocytoclastic vasculitis involving small vessels in the papillary and upper reticular dermis, with endothelial swelling and associated perivascular infiltrate of neutrophils, lymphocytes, few eosinophils, and leukocytoclasis (Figure 2a). Direct immunofluorescence revealed positive staining of the vessel walls for IgM (Figure 2b), C1q and C3 (Figure 2c). Staining for IgG and IgA (Figure 2d) was negative.
Based on the presentation and results, a diagnosis was made of mixed cryoglobulinaemia secondary to Sjogren’s syndrome, with new onset cutaneous leukocytoclastic vasculitis arising from a differential diagnosis of a drug-induced type III hypersensitivity reaction and/or flare of cryoglobulinaemic vasculitis.