A 39-year-old Moroccan steel fitter had lived in the UK for 31 years. He presented in May 2003 with abdominal pain, weight loss, sweating, generalized lymphadenopathy, and severe anaemia and thrombocytosis. Investigations showed haemoglobin of 6.7 g/dL (normal range 13.0–17.0 g/dL), platelets 1031 × 109/L (150–400 × 109/L), erythrocyte sedimentation rate (ESR) 120 mm/h (0–15 mm/h), IgG 21.4 g/L (8.0–18.0 g/L), IgA 2.9 g/L (0.9–4.5 g/L), IgM 0.6 g/L (0.6–2.8 g/L) and C-reactive protein (CRP) 289 mg/L (normal 0–5 mg/L). Biochemistry was normal. Chest X-ray showed apical pleural thickening. An intravenous urogram (IVU) showed left hydronephrosis; an ultrasound scan (USS) confirmed this, and showed dilatation of the bile and pancreatic ducts and the gallbladder. Computed tomography (CT) showed multifocal upper zone and patchy nodular airspace shadowing, with right posterior pleural thickening and subcarinal lymphadenopathy. Biopsies of pleural, ileal and colonic tissue, bone marrow, and left inguinal lymph node were all either normal or showed reactive change. Cultures of blood, urine and sputum were all negative. The patient was also negative for human immunodeficiency virus types 1 and 2, hepatitis B and C, human T-lymphotropic virus, toxoplasmosis and treponemal disease. Mantoux test was weakly positive, and although bronchoalveolar lavage was smear-negative, there was one positive culture for a mycobacterium after 3 weeks.
The patient was commenced on quadruple therapy for tuberculosis (TB) in July 2003, for an organism that was strongly isoniazid-resistant. The patient presented again in November with fatigue, weight loss and fever, which was thought to be medication-related. He was given prednisolone 20 mg for 6 weeks of, taken off all TB therapy, and after 2 months was feeling so well that he was told his TB had been cured.
He re-presented 3 months later (March 2004) with a 6-week history of night sweats, low-grade fever, lethargy, weight loss, left pleuritic chest pain and axillary lymphadenopathy. Blood tests again showed microcytic anaemia, and the same acute phase response. Antinuclear antibody (ANA), antineutrophil cytoplasmic antibodies, mitochondrial antibodies and smooth-muscle antibodies were all negative. CT showed many of the previous changes but with a right hydronephrosis that was confirmed on IVU (left hydronephrosis was no longer present). A repeat bone-marrow biopsy, inguinal lymph node and transjugular liver biopsies, endoscopy, colonoscopy, peritoneal fluid aspiration and bone scan were all either normal or non-specific. The patient was treated with quintuple anti-TB therapy in order to cover his original mycobacterium infection as well as an infection with Mycobacterium fortuitum that had been cultured from sputum on this occasion. He was also treated with steroids, initially 60 mg of prednisolone, tapered down to 20 mg over 3 months.
The patient was readmitted 6 months later with generalized abdominal pain and vomiting. He had stopped his steroids 11 days earlier because of side effects. Investigations showed only a marked inflammatory response. CT scan revealed no hydronephrosis, but now showed dilated, thick-walled small bowel in the left iliac fossa. During an exploratory laparotomy (October 2004), an inflamed omental mass adherent to the small-bowel mesentery was removed. Histology was reported as showing only some fibrosis with a mild chronic inflammatory cell infiltrate of lymphocytes and plasma cells. The patient was recommenced on steroids and quadruple anti-TB therapy.
He remained well for some months, but then presented (March 2005) with a 6-week history of pain in the right upper quadrant of the abdomen. His blood tests showed the same inflammatory response and a USS showed prominent intrahepatic ducts only. The histology of the omental mass was reviewed and showed a large number of IgG4-positve plasma cells throughout the fibroinflammatory reaction (Table ). The patient's serum IgG concentration was 21.4 g/l and IgG4 2.4 (normal range 0–1.3 g/l). A diagnosis of hyper-IgG4 disease was made, all microbial therapy was stopped, and the patient was treated with prednisolone 20 mg/day with immediate improvement in his illness. He remains on azathioprine and 5 mg prednisolone.
Pathology of IgG4 disease
We reviewed the histology and examined sections for evidence of IgG4-expressing plasma cells of 16 biopsies from 12 patients with a clinical diagnosis of idiopathic RPF seen at our hospital in the past 10 years. Biopsies comprised nine samples of retroperitoneal tissue, two of liver, and one each from kidney, colon and omentum. In addition, there were two further samples of retroperitoneal tissue taken from two patients after steroid therapy.
The results are shown in Table . All patients showed, to varying degrees, fibrosis, intense inflammatory cell infiltration with lymphocytes, plasma cells, scattered neutrophils and in some cases eosinophilic aggregates. The majority of lymphocytes expressed CD8 and CD4 positivity (T-cell markers), with B cells present to a lesser degree and with scattered B-cell-rich small lymphoid follicles. In addition, we saw vasculitis affecting small veins, and evidence of obliterative arteritis (Figures , , ). In all cases, there was a significant increase in IgG4-positive plasma cells compared with controls (Figure ). Even when few plasma cells were seen (patients 10–12) the majority expressed IgG4 (Figure ). In two cases, biopsies before and after steroid treatment were available; only scattered plasma cells were seen after treatment, none of which expressed IgG4 (Fig ). In all of our patients, the kappa and lambda light chains showed a polytypic pattern. We used PCR to look for evidence of oligoclonal infiltrates for IgH in one case (patient 1), as has been reported from Japan [13
], but found none. None of the wide range of control sections showed significantly increased numbers of IgG4-positive cells.
Mesenteric mass. Patient 3 (index case): (a, b) fibrosis, lymphoid aggregates and plasma cells (haematoxylin and eosin (a) × 100, (b) ×400); (c) CD138-positive plasma cells; (d) IgG4-positive plasma cells.
Renal biopsy. Patient 1, showing renal involvement. (a) Cores of renal tissue with a conspicuous component of inter- and intra-tubular inflammatory cells (haematoxylin and eosin ×100); (b) IgG4-positive plasma cells.
Figure 3 Retroperitoneal tissue. Patient 7. Pre-glucocorticoid treatment: (a) fibrosis and plasma cells (haematoxylin and eosin ×400); (b) IgG4-positive plasma cells. Post-glucocorticoid treatment: (c) scattered CD138-positive plasma cells; (d) IgG4 staining (more ...)
Figure 4 Histopathology: IgG4 immunostaining (cases versus controls). Vertical axis (0–120) shows number of IgG4-positive plasma cells/high power field (see Methods for details). Histological data from salivary gland is positive control, (from previously (more ...)
Percentage of IgG4-bearing plasma cells.
We also examined biopsy specimens from liver (two patients), large bowel (one) and renal tissue (one). In all of them, we found mild fibrosis and a small increase in lymphoplasmacytic inflammatory cell infiltrate, although IgG4-positive plasma cells were not seen in one liver biopsy, nor in the colon biopsy (Table ).
In summary, raised numbers of IgG4-positive plasma cells are seen in both peritoneal and non-peritoneal tissues in patients with hyper-IgG4 disease. The degree of IgG4-positive staining did not necessarily correlate with elevated serum IgG. Our clinical impression was that the number of IgG4-positive plasma cells was associated with disease activity.