- Email: [email protected]
Rheumatoid arthritis
after transplantation. After an uncomplicated transplant we found a hyperkinetic portal venous flow profile within the first 6 months with a mean velocity of 21-2 (SD 2-4) (1-2 months) and 19-4 (SD 3-3) (4-6 months) cm/s, respectively. The pulsatility profile in the hepatic veins was always normal. In all four patients with acute rejection a sharp decrease in portal venous flow was observed (from 22-9 to 15-2 cm/s, p<0-001). Hyperkinetic velocity returned within a few days after successful antirejection therapy (figure). The hepatic vein waveform showed abrupt damping in all acute rejections and returned to normal in association with the portal venous flow. There were no changes of the hepatic vein waveform in patients with chronic rejection. In all cases of chronic rejection the velocity in the portal vein was lower than in intact grafts, even at the onset of the diagnosis (13-7 [SD 21] vs 21-2 [2’4] cm/s, p<0-01). 6 and 12 months after liver transplantation we saw a further decrease of portal venous flow in chronic rejection reaching a hypokinetic circulation (19-4 [3.3]; 16-7 [084] vs 12-6 [3’3]; 9-7 [03]
cm/s, p<0.01). Increased portal venous flow in the normal allograft was demonstrated by indocyanine green clearance and intraoperative ultrasound transit time flow probes.3,4 Transplant rejection leads to an impairment in hepatic haemodynamics, which has been described as an increase in hepatic venous pressure gradient3 and a lowering of hepatic vein pulsatility5 in acute rejection. However, there are no data available on haemodynamic changes in chronic rejection. Although doppler findings of hepatic venous haemodynamics are not specific and needle biopsy is always necessary to assess rejection accurately, our data suggest that the clinical suspicion of rejection and monitoring of the course of rejection can be helped by doppler ultrasound. Doppler ultrasound appears to be very sensitive in assessing the efficacy of antirejection therapy, especially in acute rejection. In addition the severity of chronic rejection may be estimated. *H Mohr, W Gödderz, A W Lohse, G Gerken, K-H Meyer zum Büschenfelde Medizinische Klinik und
1
2 3
4
5
Poliklinik, Universitätskilnik Mainz, 55101 Mainz, Germany
Barbara L. Consensus conference "the value of Doppler US in the study of hepatic hemodynamics". J Hepatol 1990; 10: 353-55. Bolondi L, Bassi SL, Gainai S. Doppler flowmetry in portal hypertension. J Gastroenterol Hepatol 1990; 5: 459-67. Hadengue A, Lebrec D, Moreau R, Sogni P. Persistence of systemic and splanchnic hyperkinetic circulation in liver transplant patients. Hepatology 1993; 17: 175-78. Henderson JM, Gilmore GT, Mackay GJ, Galloway JR. Hemodynamics during liver transplantation: the interaction between cardiac output and portal venous and hepatic arterial flows. Hepatology 1992; 16: 715-18. Coulden RA, Britton PD, Farman P, Noble-Jamison G. Preliminary report: hepatic vein doppler in the early diagnosis of acute liver transplant rejection. Lancet 1990; 336: 273-75.
Rheumatoid arthritis SIR—In his May 27 commentary McKendry asks, "is rheumatoid arthritis caused by an infection?". Our initial response about whether or not to start using minocycline in our rheumatoid arthritis patients was similar to that of McKendry-ie, probably not. Although clinical benefit parallels a fall in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) during therapy with most secondline agents, this is not invariable but seems to be the case
during minocycline treatment. For example, we have shown that phenytoin lowers both ESR and CRP but has no effect on clinical indices;’ conversely azathioprine favourably influences symptoms but the effect on ESR is not always seen
316
and tends
to occur
late. Since ESR and CRP show
a
better association with X-ray damage than clinical indices, dampening the acute-phase response should theoretically slow the rate of radiographic progression and therefore influence long-term disability. It is, however, more difficult to ensure long-term compliance with a drug that produces laboratory evidence of improvement but no clinical benefit to the patient. This is an important aspect when therapy might need to be continued for 10, 15, or 20 years, the situation analogous to the treatment of hypertension. Nevertheless, up to a third of patients started on a secondline agent discontinue treatment within the first year because of toxicity, and the low frequency of adverse events with minocycline adds to its attraction, especially since no specific toxicity monitoring is needed. A word of caution is required, a recent report.2 Many patients with rheumatoid arthritis develop infection and an agent that can be used without concern for increasing susceptibility to infection has some attraction. Minocycline should therefore not be entirely dismissed but should be evaluated as an alternative to available second-line therapy. It may be an useful addition to the rheumatologists’ armamentarium, with a role that perhaps needs to be further defined as an adjunct to controlling X-ray progression rather than a symptomrelieving agent.
noting
*R Madhok, H
Capell
Centre for Rheumatoid Diseases,
1
2
Royal Infirmary, Glasgow G4 0SF, UK
Richards IM, Fraser SM, Hunter JA, Capell HA. Comparison of phenytoin and gold as second line drugs in rheumatoid arthritis. Ann Rheum Dis 1987; 46: 1667-69. Dykhuizen RS, Zaidi AM, Godden DJ, Jegarajah S, Legge JS. Lession of the week: minocycline and pulmonary eosinophilia. BMJ 1995; 310: 1520-21.
SMN gene deletion in variant of infantile spinal muscular atrophy SIR—Rodrigues and colleagues (April 22, p 1049) report deletion analysis of the survival motor neuron (SMN) gene for prenatal diagnosis in spinal muscular atrophy (SMA). Clinical diagnosis is confirmed by the absence or interruption of the SMN gene in 98-6% of typical SMA patients. 1,2 Yet, variants of infantile SMA with cerebellar hypoplasia, pontocerebellar degeneration, multiple longbone fractures at birth, or congenital heart defects (CHD) with or without joint contractures have been described.3 Do these SMA variants represent separate genetic entities or from allelic mutations? We have shown deletions of the SMN gene associated with SMA and CHD. Six unrelated children (four female) born to healthy parents of European origin (France, Italy, Switzerland) had a severe congenital heart defect with clinical, histopathological, and electromyographic features of acute SMA (type 1). Patient 1 had an atrial septal defect (ASD), patient 2 ASD and ventricular septal defect (VSD), patient 3 complex cyanotic heart malformation (tricuspid valve atresia with univentricular heart), patient 4 aortic coarctation with ASD, patient 5 partial atrioventricular canal, and patient 6 aortic coarctation. In addition, congenital joint contractures were present in four of six patients (two with severe and multiple contractures and two with contractures of knees and hips). Homozygous deletion of SMN exon 7 was noted in four of the patients (2, 3, 5, and 6). Failure of maternal contribution at the SMN locus was shown in two of them with the highly polymorphic markers C212 and C272.4 Hitherto, congenital heart defect was regarded as an exclusion criterion in the diagnosis of SMA.’’ Whatever the origin of the association (fortuitous or allelic mutations), our stem
cm/s, p<0.01). Increased portal venous flow in the normal allograft was demonstrated by indocyanine green clearance and intraoperative ultrasound transit time flow probes.3,4 Transplant rejection leads to an impairment in hepatic haemodynamics, which has been described as an increase in hepatic venous pressure gradient3 and a lowering of hepatic vein pulsatility5 in acute rejection. However, there are no data available on haemodynamic changes in chronic rejection. Although doppler findings of hepatic venous haemodynamics are not specific and needle biopsy is always necessary to assess rejection accurately, our data suggest that the clinical suspicion of rejection and monitoring of the course of rejection can be helped by doppler ultrasound. Doppler ultrasound appears to be very sensitive in assessing the efficacy of antirejection therapy, especially in acute rejection. In addition the severity of chronic rejection may be estimated. *H Mohr, W Gödderz, A W Lohse, G Gerken, K-H Meyer zum Büschenfelde Medizinische Klinik und
1
2 3
4
5
Poliklinik, Universitätskilnik Mainz, 55101 Mainz, Germany
Barbara L. Consensus conference "the value of Doppler US in the study of hepatic hemodynamics". J Hepatol 1990; 10: 353-55. Bolondi L, Bassi SL, Gainai S. Doppler flowmetry in portal hypertension. J Gastroenterol Hepatol 1990; 5: 459-67. Hadengue A, Lebrec D, Moreau R, Sogni P. Persistence of systemic and splanchnic hyperkinetic circulation in liver transplant patients. Hepatology 1993; 17: 175-78. Henderson JM, Gilmore GT, Mackay GJ, Galloway JR. Hemodynamics during liver transplantation: the interaction between cardiac output and portal venous and hepatic arterial flows. Hepatology 1992; 16: 715-18. Coulden RA, Britton PD, Farman P, Noble-Jamison G. Preliminary report: hepatic vein doppler in the early diagnosis of acute liver transplant rejection. Lancet 1990; 336: 273-75.
Rheumatoid arthritis SIR—In his May 27 commentary McKendry asks, "is rheumatoid arthritis caused by an infection?". Our initial response about whether or not to start using minocycline in our rheumatoid arthritis patients was similar to that of McKendry-ie, probably not. Although clinical benefit parallels a fall in erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) during therapy with most secondline agents, this is not invariable but seems to be the case
during minocycline treatment. For example, we have shown that phenytoin lowers both ESR and CRP but has no effect on clinical indices;’ conversely azathioprine favourably influences symptoms but the effect on ESR is not always seen
316
and tends
to occur
late. Since ESR and CRP show
a
better association with X-ray damage than clinical indices, dampening the acute-phase response should theoretically slow the rate of radiographic progression and therefore influence long-term disability. It is, however, more difficult to ensure long-term compliance with a drug that produces laboratory evidence of improvement but no clinical benefit to the patient. This is an important aspect when therapy might need to be continued for 10, 15, or 20 years, the situation analogous to the treatment of hypertension. Nevertheless, up to a third of patients started on a secondline agent discontinue treatment within the first year because of toxicity, and the low frequency of adverse events with minocycline adds to its attraction, especially since no specific toxicity monitoring is needed. A word of caution is required, a recent report.2 Many patients with rheumatoid arthritis develop infection and an agent that can be used without concern for increasing susceptibility to infection has some attraction. Minocycline should therefore not be entirely dismissed but should be evaluated as an alternative to available second-line therapy. It may be an useful addition to the rheumatologists’ armamentarium, with a role that perhaps needs to be further defined as an adjunct to controlling X-ray progression rather than a symptomrelieving agent.
noting
*R Madhok, H
Capell
Centre for Rheumatoid Diseases,
1
2
Royal Infirmary, Glasgow G4 0SF, UK
Richards IM, Fraser SM, Hunter JA, Capell HA. Comparison of phenytoin and gold as second line drugs in rheumatoid arthritis. Ann Rheum Dis 1987; 46: 1667-69. Dykhuizen RS, Zaidi AM, Godden DJ, Jegarajah S, Legge JS. Lession of the week: minocycline and pulmonary eosinophilia. BMJ 1995; 310: 1520-21.
SMN gene deletion in variant of infantile spinal muscular atrophy SIR—Rodrigues and colleagues (April 22, p 1049) report deletion analysis of the survival motor neuron (SMN) gene for prenatal diagnosis in spinal muscular atrophy (SMA). Clinical diagnosis is confirmed by the absence or interruption of the SMN gene in 98-6% of typical SMA patients. 1,2 Yet, variants of infantile SMA with cerebellar hypoplasia, pontocerebellar degeneration, multiple longbone fractures at birth, or congenital heart defects (CHD) with or without joint contractures have been described.3 Do these SMA variants represent separate genetic entities or from allelic mutations? We have shown deletions of the SMN gene associated with SMA and CHD. Six unrelated children (four female) born to healthy parents of European origin (France, Italy, Switzerland) had a severe congenital heart defect with clinical, histopathological, and electromyographic features of acute SMA (type 1). Patient 1 had an atrial septal defect (ASD), patient 2 ASD and ventricular septal defect (VSD), patient 3 complex cyanotic heart malformation (tricuspid valve atresia with univentricular heart), patient 4 aortic coarctation with ASD, patient 5 partial atrioventricular canal, and patient 6 aortic coarctation. In addition, congenital joint contractures were present in four of six patients (two with severe and multiple contractures and two with contractures of knees and hips). Homozygous deletion of SMN exon 7 was noted in four of the patients (2, 3, 5, and 6). Failure of maternal contribution at the SMN locus was shown in two of them with the highly polymorphic markers C212 and C272.4 Hitherto, congenital heart defect was regarded as an exclusion criterion in the diagnosis of SMA.’’ Whatever the origin of the association (fortuitous or allelic mutations), our stem