Adult onset Still's disease and collapsing glomerulopathy: successful treatment with intravenous immunoglobulins and mycophenolate mofetil

A. N. Bennett, P. Peterson, S. Sangle, R. Hangartner1, I. C. Abbs2, G. R. V. Hughes and D. P. D'Cruz

The Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London, 1 The Department of Histopathology, St Thomas’ Hospital, London, 2 The Department of Nephrology, Guy's and St Thomas’ Hospital, London, UK.

Correspondence to: D. D’Cruz, The Lupus Research Unit, The Rayne Institute, St Thomas’ Hospital, London SE1 7EH, UK. E-mail: david.d'cruz{at}kcl.ac.uk

Abstract

In this Grand Round we present a 32-yr-old African man who became severely ill after a 5-month history of weight loss, pyrexia, arthralgia, sweats and rash. He went on to develop pericarditis, pericardial effusion with tamponade, hepatomegaly with abnormal liver function tests, lymphadenopathy, massive proteinuria and required ventilatory, circulatory and renal support. The differential diagnosis was adult onset Still's disease, systemic lupus erythematosus (SLE), infection and lymphoma. Primary infection and lymphoma were excluded and he was treated, with dramatic success, with intravenous immunoglobulins (IVIG). Subsequent renal biopsy excluded SLE but confirmed collapsing glomerulopathy. The proteinuria improved dramatically following treatment with mycophenolate mofetil. We discuss some of the difficult diagnostic and management issues raised by this patient and the different uses and mechanisms of action of IVIG.

KEY WORDS: Adult onset Still's disease, Collapsing glomerulopathy, Intravenous immunoglobulin, Mycophenolate mofetil.

Adult onset Still's disease is a rare disease found worldwide with an estimated incidence of 0.22 and 0.34 per 100 000 for men and women respectively [1]. It typically affects young adults aged 16–35 yr. It is a febrile disorder of unknown aetiology, characterized by typical spiking fever with an evanescent rash and multiorgan involvement. Renal involvement is rare but interstitial nephritis [2] and subacute glomerulitis [3] have been reported. Collapsing glomerulopathy is a new pattern of renal disease that emerged with the human immunodeficiency virus (HIV) epidemic in the 1970s—HIV-associated nephropathy. Subsequently it was recognized in non-HIV patients as idiopathic collapsing glomerulopathy, characterized by very heavy proteinuria, rapidly progressive renal failure and poor outcome.

Case report

A 32-yr-old African man with known sickle cell disease presented with breathlessness and pyrexia. He had a 5-month history of 2 stone (12.7 kg) weight loss, migratory polyarthralgia, drenching nocturnal sweats and an evanescent non-pruritic rash on his limbs lasting less than 24 h at a time. He lived in London with his wife and two children, was a non-smoker and consumed modest amounts of alcohol and had no risk factors for HIV. He had visited Nigeria in December 2001, 4 months before the onset of his illness, but had been well as had the rest of the family. Initial examination revealed a sinus tachycardia in keeping with his pyrexia and severe tenderness of the wrist but no synovitis was present. He was suspected of having a sickle crisis and was admitted for analgesia, oxygen and rehydration pending the results of infective screens and blood tests (Table 1). Despite supportive therapy he deteriorated over the subsequent 48 h and continued to spike temperatures to 40°C and to desaturate to 92% on 4 l/min of oxygen. He was transferred to the intensive therapy unit (ITU) and despite exchange transfusions and empirical treatment with antibiotics for a suspected left-sided pneumonia he did not improve. He developed generalized lymphadenopathy and widespread arthralgias. The maculopapular rash on his limbs continued in relation to his high fevers. His fevers persisted and he continued to desaturate and required ventilatory support with continuous positive airways pressure (CPAP).


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TABLE 1. Initial investigations

 
His C-reactive protein (CRP) and white cell count (WCC) continued to rise and peaked at 424 mg/l and 42.2 x 109/l respectively. His liver function tests (LFTs) deteriorated [bilirubin 77 µmol/l (0–22), alanine aminotransferase (ALT) 78 IU/l (0–55), lactate dehydrogenase (LDH) 1065 (286–580)]. Serum ferritin levels were grossly elevated and peaked on day 13 at 38691 µg/l (24–336). His antinuclear antibodies (ANA) were also raised at 1:1280 on one occasion but then became negative and his anti-double-stranded deoxyribonucleic acid (anti-dsDNA) and extractable nucleic antigen (ENA) were negative and complement was slightly raised [C4 0.56 (0.11–0.43)]. His tachycardia worsened with an increasing jugular venous pressure (JVP). He developed a loud pericardial rub and echocardiography confirmed a large pericardial effusion (Figs 1 and 2), from which 1.5 l of cellular fluid was drained which was sterile on culture.



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FIG. 1. Echocardiogram: large pericardial effusion.

 


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FIG. 2. CT scan: large pericardial effusion and bilateral pleural effusions.

 
Over the next few days he became hypotensive and required inotropic support. Further courses of antibiotics were started for a suspected chest infection. Repeated cultures were negative except for bronchial washings, which grew Pseudomonas. The chest radiograph (CXR) showed bilateral lower zone consolidation. Despite appropriate antibiotics he continued to deteriorate. His renal function worsened with his creatinine peaking at 515 µmol/l (60–122) and haemofiltration became necessary. It was felt that acute tubular necrosis (ATN) was the most likely diagnosis as there was inactive urinary sediment and a renal ultrasound scan showed abnormal kidneys with a very dense appearance with loss of the corticomedullary differentiation. Subsequently, however, a 24-h urine collection showed proteinuria 7.2 g/day (serum albumin 11 g/l). He then developed generalized seizures in relation to temporary hyponatraemia (Na 121 mmol/l). Magnetic resonance imaging (MRI) of the brain and lumbar puncture were normal with no evidence of organisms on polymerase chain reaction (PCR). In particular tuberculosis was excluded.

At this stage we were faced with a severely ill 32-yr-old African man presenting with pyrexia of unknown origin (PUO), migratory polyarthopathy, fleeting maculopapular rash and weight loss. He went on to develop pericarditis and a large pericardial effusion with tamponade, hepatomegaly with abnormal LFTs, lymphadenopathy and high-level proteinuria. He required a 26-day ITU admission involving ventilatory, circulatory and renal support.

D. D’Cruz: This patient was obviously critically ill and not responding to therapy. The differential diagnosis included: adult onset Still's disease, systemic lupus erythematosus (SLE), sickle crisis, lymphoma, infection.

A decision was reached to institute immunosuppression. On account of concerns about infection, especially given the recent Pseudomonas culture on bronchial washings and subsequently in his sputum, it was decided that cyclophosphamide was best avoided and immunomodulation with intravenous immunoglobulins (IVIG) would be the best approach. A standard regimen was employed using 0.4 g/kg daily for 5 days. By the third dose the fevers had settled, he had been weaned off ventilatory support and was able to take fluid and eat small amounts of food. By the following week he had returned to the general ward and was mobilizing and within 3 weeks he was home with his family.

Follow-up

Over the following weeks although the patient remained well, his proteinuria proceeded to rise to a peak of 19.98 g/24 h. A renal biopsy was performed and was consistent with collapsing glomerulopathy showing extensive focally severe ischaemic wrinkling of capillary walls. Some glomeruli showed segmental collapse with an overlying rim of glomerular cells. In the tubules there was acute damage with dilatation, flattened epithelial cells and cytoplasmic vacuolation. Electron microscopy showed swollen epithelial cells with partial effacement of the foot processes. Electron-dense deposits were absent and, importantly, immunoperoxidase staining was negative with no immunoglobulin staining detected (Fig. 3). At this stage he was started on mycophenolate mofetil 0.5 g/day increasing to 1 g twice daily.



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FIG. 3. Renal biopsy: collapsing glomerulopathy. Arrows: open glomerular loops; arrow heads: collapsed glomerular loops.

 

Discussion

Diagnosis
D. D’Cruz: The diagnosis in this case was initially thought to be adult onset Still's disease (AOSD). The patient met the Yamaguchi criteria [4] for AOSD (Table 2). He had seven out of the eight criteria, a diagnosis requiring five criteria including two major criteria. He also suffered from many other signs and symptoms commonly seen in AOSD such as myalgias, weight loss, pleuritis, hepatomegaly and pericarditis [5]. In support of the diagnosis of AOSD was the extraordinarily high serum ferritin, at 38 691 µg/l (24–336). It remained above five times the upper limit of normal for almost 2 months. Although raised serum ferritin is not in the Yamaguchi criteria it is regarded as a very useful tool in assisting the diagnosis of AOSD [69]. Of course ferritin is an acute phase protein and can be raised in any infection or inflammatory condition but normally not to these high levels. Fautrel et al. [10] reported the usefulness of serum ferritin and glycosylated serum ferritin in the diagnosis of AOSD. They compared serum ferritin in 49 AOSD patients with 120 controls and found a significant difference (P<0.05). They found that a serum ferritin >5 times normal gave a specificity of 80% for AOSD (sensitivity 40.8%). If this is combined with a glycosylated ferritin of less than 20% the specificity rises to 92.9% (sensitivity 43.2%). Of course the main drawback to Yamaguchi's criteria are the exclusions. The criteria state infections, malignancies and other rheumatic disease should be excluded before the diagnosis of AOSD is made. There was no evidence of sepsis until day 24 when Pseudomonas was grown in the sputum cultures and on bronchial washings. This was regarded as an opportunistic secondary infection in a patient who was in extremis. It is important to note that his HIV test was also negative on two occasions 4 months apart. There was no evidence of malignancy. Lupus was considered as a diagnosis; however, his ANA soon became negative, his anti-dsDNA and ENA were always negative and importantly the renal biopsy did not confirm a classical SLE pattern nephropathy and indeed all the immunostaining was negative. It did, however, show collapsing glomerulopathy.


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TABLE 2. Classification criteria for adult onset Still's disease. Classification requires five or more criteria including two or more major criteria

 
I. Abbs: Collapsing glomerulopathy is a renal condition that was first reported by Weiss et al. [11] in 1986 in non-HIV patients with rapidly progressive nephrotic syndrome and glomerular capillary collapse. This condition closely resembled the pathology of HIV-associated nephropathy (HIVAN) that was first recognized in the 1970s [12]. HIVAN was characterized by a black ethnic predominance, massive proteinuria, rapidly progressive renal insufficiency and distinct pathological findings. All these factors differentiate HIVAN clinically, pathologically and epidemiologically from the far more benign, classical non-collapsing focal and segmental glomerulosclerosis (FSGS). Both HIVAN and the non-HIV collapsing glomerulopathy have clinical features of massive proteinuria and rapid progression to end-stage renal failure and an unfavourable outcome despite treatment. Collapsing glomerulopathy has been increasingly recognized in non-HIV patients over the years since Weiss first described it. In recent papers by Laurinavicius et al. [13, 14] the largest series of non-HIV collapsing glomerulopathy describes 42 patients. They compared HIV and non-HIV patients and found that they were similar in terms of age, sex ratio, serum creatinine, proteinuria, the extent of collapsing and sclerosing lesions and in interstitial damage. A female preponderance was found in both groups and the HIV group had a higher prevalence of black ethnic origin (94 vs 57%). In this series many associations were noticed in the non-HIV collapsing glomerulopathy group. Of interest it was associated with Parvovirus B19 infection, hepatitis C infection, pamidronate therapy, lymphoproliferative disease and autoimmune disease disorders including mixed connective tissue disease (MCTD), granulomatous cerebral arteritis and six patients with ‘lupus-like disorder'. The authors of this series of patients are not aware of any link between collapsing glomerulopathy and raised ferritin level or sickle cell disease (personal communication). Most collapsing glomerulopathy patients present with ‘rapidly progressive nephrotic syndrome’ which may be preceded by a mild systemic illness.

On reviewing the literature the largest study of outcome in non-HIV collapsing glomerulopathy patients was by Laurinavicius et al. [13]. Of the 42 patients treated with a combination of steroids, cyclosporin A or other cytostatic therapy, 71.4% progressed to end-stage renal failure and 17% died within the average follow-up period of 14 months (0–62 months). Other immunosuppressive therapy was therefore considered in particular cyclophosphamide and MMF. Because of its relative renal specificity and lower incidence of side-effects [15] MMF treatment was commenced.

R. Hangartner: The renal biopsy (Fig. 3) was critical in making the diagnosis. Several glomeruli showed global collapse (i.e. collapse of all segments) with an overlying rim of visceral epithelial cells. The interstitium showed microcystic tubular dilatation with rather tortuous, large, scalloped periodic acid–Schiff (PAS)-positive tubular casts and prominent tubular cell protein reabsorption droplets. There was some non-specific deposition of IgM and C3 on immunoperoxidase staining. Immunoperoxidase staining for parvovirus B19 was negative. No electron-dense deposits were seen at electron microscopy and there were no endothelial cell tubuloreticular inclusions.

The appearances favoured a diagnosis of collapsing glomerulonephropathy rather than the cellular variant of focal and segmental glomerulosclerosis (FSGS). Laurinavicius and Rennke [14] agree with D’Agati [16] that the latter term should be restricted to cases with endocapillary proliferation. Collapsing glomerulopathy is reserved for those cases showing the global or segmental collapsing lesions and the concurrent tubulointerstitial injury. D’Agati [16] notes that the collapsing variant of FSGS histologically resembles the HIV-associated lesion described by Weiss et al. [11], but she comments that its course can be particularly ‘malignant’, and represents a distinct clinico-pathological entity. Laurinavicius and Rennke [14] suggest that collapsing glomerulopathy is a better term than collapsing FSGS. The process is usually global, rather than focal, and characterized at least initially by glomerular segmental collapse rather than sclerosis.

Sickle cell disease is associated with FSGS. Bhathena and Sondheimer [17] reported two patterns of FSGS in their six patients—a collapsing pattern of segmental sclerosis and a subsequent expansive pattern. The morphological distinction being that in their cases the collapse was focal and segmental rather than global. HIVAN was ruled out on serological grounds. The biopsy ruled out an acute SLE nephritis.

Treatment
G. R. V. Hughes: It was decided in this case to treat the patient with IVIG. He was very seriously ill and was not responding to any treatment; immunosuppression was required. Due to recently grown Pseudomonas aeruginosa in his sputum and from his bronchial washing cyclophosphamide was contraindicated. IVIG has been used clinically in autoimmune disorders since 1981 when Imbach et al. [18] made a fortunate observation that the administration of IVIG in children with immune thrombocytopenic purpura caused a significant rise in their platelet count. Since then it has been shown to be beneficial in a number of autoimmune and inflammatory conditions. The National Institute for Health (NIH) consensus panel in 1990 [19], followed by the Australian Society for Blood Transfusion in 1993 [20] have recommended IVIG in a number of conditions. These are graded into three categories depending on the evidence available (Table 3).


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TABLE 3. Australian Society for Blood Transfusion: recommendations for use of IVIG [20]

 
The mechanisms of action of IVIG are complex and numerous. However, the five main lines of action have been shown to be: Fc receptor modulation and blockade, neutralization of autoantibodies and restoration of the idiotypic network, inhibition of complement binding and prevention of membranolytic attack complex formation, suppression of pathogenic cytokines and neutralization of superantigens [2124]. We have used IVIG in 10 previous cases with SLE all of whom had been critically ill on ITU. In all, with the exception of one, these cases have had a good outcome.

Our experience of IVIG in AOSD is limited to a refractory case in a 30-week pregnant patient who responded excellently [25]. The literature has little else to offer on IVIG in AOSD except for a couple of letters [26, 27] and one pilot study in seven patients unresponsive to non-steroidal anti-inflammatory drugs (NSAIDs) [28]. Vignes and colleagues [28] had moderate results with five of seven patients initially responding, one relapsing subsequently and the other four having a favourable clinical outcome. Our patient is unique in the literature in that there are no reports of patients with such severe AOSD and collapsing glomerulopathy being treated with IVIG.

Conclusion

D. D’Cruz and I. C. Abbs: This report is of a critically ill young man with AOSD and an associated histological diagnosis of collapsing glomerulopathy. He had been on ITU for 2 weeks and was deteriorating and not responding to treatment. He made a dramatic recovery within the first two to three doses of treatment with IVIG and was discharged home within 3 weeks of finishing the course. He is currently well 15 months after the onset of his illness. He has a normal creatinine clearance and his proteinuria has dramatically improved with mycophenolate mofetil therapy.

Final diagnosis: adult onset Still's disease and collapsing glomerulopathy, responding to treatment with IVIG and MMF.

Informed consent was obtained from the patient.

The authors have declared no conflicts of interest.

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Submitted 21 September 2003; revised version accepted 6 February 2004.



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