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The internal homoeostasis in man is critically dependent on regulation of proteolytic enzymes in tissues and fluids by endogenous inhibitors. α1 Antitrypsin is the most abundant protease inhibitor (Pi) in plasma, and controls tissue degradation by proteases such as trypsin, neutrophil elastase, and proteinase 3.1 Homozygous α1 antitrypsin deficiency is known to predispose to emphysema and chronic liver disease.2,3 Recently, a strong correlation has been found between systemic small vessel necrotising vasculitis and both heterozygous and homozygous α1 antitrypsin deficiency.4 Also, such deficiency has been found to confer a more disseminated disease and worse prognosis to patients with antineutrophil cytoplasmic antibody (ANCA) positive vasculitis.5
However, there is disagreement about the clinical implication of an intermediate α1 antitrypsin deficiency: is it an accidental finding or does it imply susceptibility to autoimmune disease? Thus, reports have demonstrated an increased incidence of α1 antitrypsin deficiency in patients with acute anterior uveitis, a finding that was refuted by others.6 Similarly, several reports have suggested an increased frequency of α1 antitrypsin deficiency in patients with rheumatoid arthritis, whereas others found no such association in similar patients.7
Here, we report a severe vasculitic episode in a patient with primary Sjögren's syndrome (pSS) and heterozygous α1 antitrypsin deficiency.
The patient, a white woman, was diagnosed with pSS at the age of 44 years. The diagnosis fulfilled the Copenhagen and the European community classification criteria for pSS.8,9 Five years after the start of sicca symptoms, arthritis suddenly appeared in the knee and ankle joints, as well as purpuric eruption on the lower legs. Laboratory studies showed a raised erythrocyte sedimentation rate (ESR 78 mm/1st h) and C reactive protein (CRP 42 mg/l; normal <10 mg/l) and on urine analysis proteinuria and microscopic haematuria. Oral prednisolone treatment was started, but a week later the patient suddenly experienced headache and loss of vision. Decreased wakefulness and generalised seizures ensued. Computed tomography of the brain showed three small haemorrhagic cortical infarctions, and an eye examination disclosed cortical blindness (complete visual loss with normal light reflexes). Two of three tests for circulating immune complexes were positive, and measurement of complement factors C3 and C4 showed relative deficiency of C4. C4 isotyping disclosed the phenotype C4A3B1. Positive serological tests (rheumatoid factor, antinuclear antibodies, and anti-SSA/SSB) were unchanged compared with before the acute episode, while an ANCA test and a test for antiphospholipid antibodies were negative.
Intravenous (IV) injection of methylprednisolone and bolus IV cyclophosphamide produced a rapid response and the arthritis disappeared and eyesight gradually improved. Urine findings and ESR/CRP normalised. Oral prednisolone and intermittent IV cyclophosphamide were given for one year.
A retrospective chart review has on two separate occasions shown low plasma levels of α1 antitrypsin (0.7 and 0.81 g/l, respectively; normal 0.9–1.7 g/l). Also, during the inflammatory episode, α1 antitrypsin levels remained normal, while other acute phase proteins were raised. Therefore a genetically determined heterozygous α1 antitrypsin deficiency was suspected . This was confirmed by α1 antitrypsin phenotyping using monoclonal antibody specific for the PiZ mutant in an enzyme linked immunosorbent assay (ELISA).10 Isoelectric focusing confirmed the PiMZ phenotype.11 The frequency of PiZ heterozygosity in the Swedish general population is 0.047.
The diagnosis of vasculitis in this patient was not verified by biopsy, but the clinical evidence is compelling. The α1 antitrypsin deficiency in this patient is possibly related to the severe systemic vasculitis. Low levels of complement factor C4 have been reported in association with deficient elimination of circulating immune complexes in Sjögren's syndrome.12 In the present case the relative deficiency of C4, in addition to α1 antitrypsin deficiency, may hypothetically have contributed to an increased risk of immune complex mediated vasculitis.
The clinician should be observant about low levels of α1 antitrypsin in patients with vasculitis because they may indicate a poor prognosis. α1 Antitrypsin is an acute phase protein and therefore deficiency might be masked by the presence of inflammation. As in this case, normal α1 antitrypsin levels may be consistent with deficiency of the protein. For definite diagnosis it is essential to perform phenotype identification.11
We thank Dr L Truedsson, Department of Microbiology, University Hospital, Lund, Sweden, for performing the C4 isotyping.
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