SARAA conference 2001
Pretoria
South Africa
The meeting held in Pretoria between 31 March and 2nd April 2001, constituted the 17 biennial conference of the South African Rheumatism and Arthritis Association. The meeting was held at the Sheraton hotel, and both setting and venue proved an outstanding success. The academic program was of the highest standard. And all aspects of Rheumatology with a focus on local experience were discussed. The social program was excellent and delegates left with a most positive impression of the proceedings.
The organising committee consisted of:
Dr Ingram Anderson, Dr Stan Brighton, Dr Elsa Van Duuren, Dr Andre Lubbe, and Gwynne Groenewald.Visiting delegates from throughout South Africa, Zimbabwe, Nigeria, The United States of America, and the United Kingdom attended.
Notable guests from overseas included:
Prof Paul Emery
Dr F Breedveld
Dr R Cervera
Prof E Gall
Prof G Grahame
Dr S Louizou
Dr G Singh
Dr P TaylorIn the opening proceedings, tribute was paid to Emeritus Prof Lan Meyers, as the founder of Rheumatology in South Africa. The meeting was addressed by Geneticist Prof P Beighton who gave the opening lecture, honouring Prof Meyers.
Highlights day 1
The Tygerberg group presented a sad story of a young child treated with retroviral therapy and hydroxyurea for HIV associated arthritis and the ongoing remissions and exacerbations seen with the disease. Reduction in HIV load and increase in CD4 counts was noted, but the chronicity of the process and the tragedy of HIV in South Africa was emphasised.
Prof Tickly reviewed his experience with scleroderma and the association with gold mining was emphasized. Review of the local experience with antibody profiles was reviewed.
Prof Meyers discussed incidence of fibromyalgia and soft tissue rheumatism in a peripheral town in the Cape - Bedford and noted that the incidence of sleep abnormality was 44 percent and prevalence of fibromyalgia was similar to levels described in other communities. However social acceptability of pain was probably responsible to the perception of such pain as a social / domestic problem versus a clinical entity.
Prof O Beck of the department of Haematology, Pretoria, reviewed haemophilia and arthritis and illustrated the devastating effect of the disease. Rapid therapy was emphasised as well as factor replacement. The different lesions, soft tissue, bone cysts and pseudocysts, as well as the compression neurological syndromes were well illustrated.
Dr McPhail of Johannesburg reviewed hemochromatosis and arthropathy. The genetic mutations were illustrated as well as a review of iron metabolism. Genetic mutations at C282Y of the HFE protein resulted in the more severe varieties with a 1 in 115 homozygous prevalence in the western cape noted. The other main defect at H63D was also discussed.
Prof Stan Brighton reviewed the association between arbovirus infections and arthritis, highlighting the role of air travel, transport of animals, and in particular bird migration in spreading the virus and causing epidemics of disease, in Africa, and even USA. The history and current state of the art were discussed. Stress on reduced resistance of populations was mentioned, making risk of outbreaks in South Africa a real potential in the future. Stress was made regarding Dengue, Sindbis, Chikungunya, West Nile, and Wesselbron, viruses, and response to chloroquine for chronic infections.
Prof Mark Beale reviewed acute and chronic arthritis as a consequence of infection. The comprehensive review included pathogenesis via, haematogenous spread, adjacent spread from bone and soft tissue infection and from iatrogenic introduction of infection from joint injections. The different organisms were demonstrated, including Staphylococcus, Streptococcus, Haemophylis, and diplococcus especially gonococcus. Tuberculosis was also discussed prominently.
Dr S Van Der Merwe reviewed the liver and osteoporosis.
Dr I Anderson of the Jacaranda hospital presented a case of severe resorptive metabolic bone disease with hyperparathyroidism and this was then discussed with Prof E Gall as moderator. The condition was reviewed. The diagnostic difficulties were discussed. The use of parathyroid hormone pulse therapy in osteoporosis was mentioned.
Prof A Kalla, of University of Cape Town presented his data on Osteoporosis in South African population groups, as well as in different diseases, of not - RA and SLE populations, using DEXA data that has been accumulated over many years. Epidemiological data was presented.
Prof McPhail spoke on osteoporosis and iron overload and again reviewed the role of iron metabolism in production of liver disease.
Dr Stan Lipschitz addressed the meeting on osteoporosis in the elderly, and reviewed aspects of osteoporosis as well as the role of posture and neurological factors in terms of risk of falling. He looked at role of simple prevention of falling as well as pharmaceutical intervention - in particular the use of alendronate and risedronate.
Prof Grahame of London University College, a renowned expert in hypermobility reviewed the subject, and in particular also credited Prof Peter Beighton for his work in classification of hypermobility. The new British classification criteria incorporating the Beighton criteria were presented. The role of hypermobility in the performance of various musicians and artists were illustrated.
Prof N Maritz spoke on carpal translocation after excision of the distal ulnar in RA, with attention stressed regarding stability of the wrist after surgery
Prof Tickly reviewed work from his unit regarding oxidative stress and trace elements in systemic sclerosis. In his paper he looked at the by products of reperfusion injury and oxidative stress from hypoxemia with Raynauds and peripheral circulation. Outstanding work was presented, but disappointingly, this has not translated into benefit therapeutically.
Dr Dave Whitelaw of Tygerberg Hospital presented a case of peripheral dermatomyositis resistant to therapy and complicated by the development of pulmonary tuberculosis. Possibilities of therapy were discussed and possibility of inclusion body myositis discussed.
Dr G Faller, Paediatrician from Johannesburg, presented her retrospective research of paediatric SLE in Baragwanath and Johannesburg hospitals. The data was influenced by lack of data once children went to adult wards. In addition data was available from the Johannesburg hospital from an earlier time 1974 - 2000, compared to Baragwanath where data only became available after 1986, as a consequence of the political situation at the time, but also reflecting an increase in the incidence of SLE in SA Black paediatric population.
Dr I Anderson presented a most interesting case of generalised osteoarthritis as a consequence of alkaptonuria, diagnosed by the classical pigmentation on the sclera 1/3 behind the iris border - Ochronosis. In fact several people had seen isolated cases in the audience and the rarity of the case was discussed.
Prof Kalla presented his data on the ethnic differences in DEXA measured bone density in South African females, recruited at Groote Schuur Hospital. Ethnic differences showing statistical significant increase in differences in bone density of Blacks versus Coloureds and whites were identified. However data was from a pilot study with a fewer number of black females recruited, and follow up is awaited.
Highlights day 2
Dr Bulbulia spoke regarding his personal fight against RA, and the impact on physical, domestic and psychosocial well being. He detailed side effects of his medications, especially on cyclosporin, following failure of combination therapy of methotrexate, sulphasalazine and antimalarial therapy. He outlined the help he received from doctors who attended him and the struggle for disease control, as well as insight from other patients in the patient partner program. Usefulness of Enbrel / etanercept was noted, but its cost emphasized.
Dr P Taylor reviewed the biological therapies, especially etanercept and infliximab in the therapy of RA. The mechanism of action as well as trials on the drugs was outlined. Usefulness of combination therapy with methotrexate was emphasised.
Prof Emery spoke regarding novel aspects in Rheumatology - including:
Usefulness of high-resolution ultrasound in demonstrating erosions in early RA, using dedicated ultrasonography trained rheumatologists. Ultrasound technique was also able to demonstrate presence of sub clinical synovitis in osteoarthritic joints
Usefulness in gadolinium enhanced MRI was also used in comparison between leflunomide and methotrexate in early RA, showing reduction of synovitis at 16 weeks to be superior to methotrexate in 17 patients despite equal long term clinical outcomes. In a trial looking at methotrexate versus methotrexate and medrol, studied with gadolinium enhanced MRI. Close correlation was noted between degree of synovitis and erosions. Standard therapy does not eradicate synovitis enough to suppress onset of erosion, whereas combination therapy does.
Autologous Stem cell transplant was done in 7 cases failing 4-drug therapy. All relapsed at 1-9 months. Thereafter patients required additional therapy, especially cyclosporin 4g/m2.
Imaging and diagnosis was applied to patients with enthesitis, demonstrating bone edema, away from the synovium at the tendon insertions. 80 percent of these patients were B27 positive, and improved dramatically to etanercept on both clinical and ultrasound criteria.
Validation of ultrasound long term is still formally required but there is no doubt that it is superior to X-ray in acquisition of data and interpretation.Prof Ulrich Mennen Orthopaedic surgeon, from Medical University of South Africa, delivered an eponymous lecture honouring Prof Brookes Heywood, former head of surgery at Princess Alice orthopaedic hospital Cape Town. He then reviewed surgery of the hand. Anatomy, function were discussed. In addition it was stressed that surgery had to be customized to the individual. This applied especially to deformity in the case of Swan neck and Boutonnière deformity surgery. MCP surgery with Swanson arthroplasty is commonplace with good result. Swanson arthroplasty in the PIP joints are reserved for middle and ring fingers. The Index finger is usually arthrodesed rather than replaced. Scilastic implant reaction with synovitis and cyst formation was seen in 6 percent and usually requires removal and replacement of the implant. Rheumatologists were requested to refer cases earlier for baseline assessment rather than wait too long before referring the patient
Dr T Rosch - Orthopaedic surgeon, from the Jacaranda clinic Pretoria, reviewed surgery to the shoulder, including joint and soft tissue lesions. Tears should be not be injected too frequently- preventing rupture. Preservation of the rotator cuff was crucial. Major tears may result in instability and secondary arthritis in the joint. Synovitis is often seen in the joint and can be treated by arthroscopic technique. Replacement is largely reserved for joint rather than muscle problems. Grafting in cases of bone loss is desirable. Failure of the surgery is likely to be glenoid loosening. Modular prosthesis allows superior results. Rehab is surgeon dependent. Active lifting is only allowed after 5-6 weeks and possibly longer in rheumatoid patients. Life expectancy of the prosthesis in the RA patient is about 10 years. To distinguish between tear and impingement, ultrasound has an increasing place.
Dr G Geldenhuys, Orthopaedic surgeon, at University of Pretoria, spoke on Knee joint surgery. The anatomy of joint and soft tissue was discussed. However, he focussed on mainly the role of arthroscopy and arthroplasty. In unilateral joint problems, trauma and sport injury problems were reviewed, including meniscal tears, with instability. Slides showing usefulness in debridement and repair of ligaments with arthroscopy were demonstrated. In single or bilateral disease, degenerative disease was demonstrated with arthroscopic debridement. Slides of arthroscopic debridement were shown for RA patients. Diagnostic help of ultrasound and MRI were discussed. Ultrasound doesn’t help in cruciate and meniscal disease. Indications for arthroplasty were discussed. Osteotomy is now regarded as rarely required. Unicompartmental replacement is more common, since balancing techniques are improving. Total knee replacement techniques are now numerous. 10 - 25 years is now considered the normal expectation. Revision arthroplasty will likely last only half that, but technology is improving results all the time. Intra-articular steroids are recommended to be restricted prior to surgery - ideally not within 12 months of surgery. Failure of 3 injections is suggestive that referral is preferable. Cartilage cell transplantation and resurfacing techniques are at an early stage only. Replacement remains the current state of the art.
Dr E Pelser Orthopaedic surgeon, from the Jacaranda clinic Pretoria, reviewed surgery of the hip. He illustrated the different prostheses. Materials available were reviewed. Ceramics and cements were more desirable than plastic components, which tended to fail. Modular systems are now allowing easier surgery. Porous coating with roughening allowed better bone adherence. This coating of hydroxyl appatite plus ceramics base appears to be the most popular prosthesis. In RA patients, there are several compounding factors, including skin thinning, difficulty with mobilisation from disease elsewhere. Fore foot deformities should be addressed first to prevent infection risk if done after hip surgery. Protrusio and bone thinning is associated with additional risks. Infection is 3 times greater than in OA patients. There is no evidence that cemented prostheses do better. Problems in juvenile arthritis were discussed.
Prof N Maritz, head of orthopaedic surgery at University of Pretoria, reviewed the orthopaedic management of elbow disease. The different classifications of elbow disease were shown. Synovectomy is aimed at pain relief. Non-surgical synovectomy i.e. yttrium was not popular in the elbow. Radial head excision may or may not be done in these patients, and benefit from synovectomy should last up to 20 years. Arthroscopic surgical synovectomy in selected cases is improving, but has not replaced open synovectomy. Preservation of the radial head however improves stability. Joint replacement requires that the distal joints be sorted out FIRST. i.e. hand / wrist before elbow, and elbow before shoulder. Post surgery there is a limit to weights that can be lifted - 5 kg ideally. Survival rates of prosthesis are in the order of 70 percent over 10-15 years of follow up.
Prof Gall spoke on COX-2 concept and discussed technology behind COX and the selective / specific inhibition thereof.
Newer developments in this field particularly with regard to the analgesic potential of the products were discussed. Parenteral preparations will be available in the near future. The overall safety of these drugs with regard to the gut was emphasizedProf Breedveld discussed the application of combination DMARD’s
Dr Cervera spoke on topics of the antiphospholipid syndrome.
Prof Paul Emery addressed the conference on new DMARD’s. Essentially these reduce cytokines and reduce CRP by the hepatocyte. The end point being reduction of pain with maintenance of structure and function.
Corticosteroids are effective, with reduction of cytokines. How to use them is the real question. Response should be by 2 weeks of use of intra-articular steroids and failure of response may suggest a need for DMARD’s. Oral steroids did not have an advantage over injection intra-articular in early disease. The ACR criteria were reliable for diagnosis after 12 weeks only, regarding disease persistence. Use of cyclosporin/ methotrexate in severe patients with shared epitope, gave a better response than sulphasalazine alone early on, but long term seemed to give as good a response after 1-2 years. Side effects were greater in the cyclosporin group. Good responders to sulphasalazine seemed to stay good responders. Leeds policy therefore has been to largely use sulphasalazine as first choice.
Wide experience with leflunomide has been obtained. This inhibits pyrimidine nucleotide production. It arrests cell cycle in susceptible T cells, but has a long half-life requiring washout with cholestyramine filtering if reversal is required. Phase 3 studies showed results variably similar to methotrexate, with sustained response. It has therefore similar characteristics to methotrexate. It was superior to sulphasalazine. Adverse events included hypertension, Alopecia, GI symptoms. Folic acid supplementation seemed to reduce toxicity but reduced efficacy. This suggests folic acid benefit overall but reduced efficacy, this loss of efficacy hasn’t been described in other studies. Studies on x-ray showed reduction in new erosions and joint space narrowing preservation by measuring the sharp score. This effect is equal overall to methotrexate. Practical issues: Use in those who cant use standard DMARD’s. Also it is teratogenic, and termination is desirable. Liver toxicity is mostly seen in combination with methotrexate. Overall more data on combination therapy with methotrexate is desirable.
DMARD’s are changed depending on benefit and cost. Imaging may be useful in Gadolinium enhanced MRI shows synovitis allowing projection of erosions incidence over the next 12 months. Normal scan may be therefore reassuring. For patients who are resistant to standard DMARD’s, this group of patients can be started on Leflunomide with a loading dose 100mg then reduce rather than the often-quoted 300mg for 3 days. If still no response - biologics where possible are introduced.
Trials of high dose anti-TNF and methotrexate in early disease are underway. Induction is started at 10mg/kg then continued at phasic intervals are now in progress. Early result on only 5 patients show excellent response in 4, but no added benefit from reinduction with disease recurrence.Dr G Singh of Stanford addressed the future of COX-2 therapy. New water-soluble compounds are being introduced for intravenous therapy. The first of these are parecoxib and valdecoxib. Efficacy in dental and post gynaecology surgery shows some equivalence equal to morphine 4mg. Safety of these are showed in trials.
Role in malignancy has been seen and projected. Sulindac was shown to reduce polyposis and rectal / colon cancer as was shown by other nsaids. The COX-2 mechanism in reducing cancer is hypothesized to be interference with apoptosis - programmed cell death. In tumours there is a clone of cells that doesn’t show apoptosis. There is a proportional association between apoptosis versus level of COX-2, as well as angiogenesis. In a tumour mass, angiogenesis takes place. Inhibition of COX-2 reduces angiogenesis and increases apoptosis of tumour cells. In polyposis there is transition to malignancy. Celecoxib shows dramatic reduction in polyposis at 400mg bd. In colon cancer there is marked COX-2 expression. In rat model there is a 99% reduction in colon cancer metastases. COX-2 is seen in most tumours other than neuroendocrine cancer and brain tumour. In rat breast cancer model, on celecoxib there is a regression of tumour. Dramatic benefit is seen as adjunctive therapy in combination therapy with antineoplastics. Trials in tumour therapy are ongoing. For example - Barrets, breast cancer, Bladder cancer and pancreatic cancer.
Alzheimers disease - trials are ongoing.
As a personal theory, Dr Singh suggested that coronary artery disease might also be a theoretical future target for COX-2 therapy. This is possible with the background of an infective theory re chlamydia and mycoplasma infection in plaque. Foam cells and macrophages that die set off an inflammatory cascade, that results in release of proteolysis and the lumen wall may rupture setting off the cascade. To prevent the death, stabilisation of plaque is required. Statins do this to a degree. Hence they reduce risk reduction. If the triggering cause of plaque rupture is inflammation, then in theory there is a role for COX-2.Prof Eric Gall looked at a clinical review of aspects of osteoporosis. This included aspects of prevention as well as therapy. Chance of dying or disability is highly significant post hip replacement. Peak bone mass and poor bone quality plus a tendency to fall increases such risk. Type 1 fracture earlier in life is related to Trabecular bone loss, which is associated with estrogen deficiency. Later in life age related loss of cortical bone becomes a greater influence in type 2 fractures. Secondary factors i.e. immobility or steroids play additional roles. Several interventions were reviewed, including Calcium, Vitamin D, and Estrogen. Possible hazards of estrogen were raised. The HERS trial showed no protection against coronary artery disease. However these patients were on higher doses and older than 65. Further studies are really required. SERMs were reviewed, showing raloxifene, may reduce cardiovascular disease and breast cancer. However there are increased flushing and phlebitis. The effects are moderate. 3 percent in hip and 1 - 2 percent in the spine. But there is evidence of 50% reduction in first fracture and 30 percent in repeat fracture. There is little benefit for non-spinal fracture. Alendronate remains the most studied and proven in benefit. Risedronate shows promising reduction in fracture with 65% reduction in vertebral fracture. Hip fracture is reduced by alendronate by approximately 50%. Risedronate shows similar efficacy. In males, there are several studies showing reduction with risedronate as well as with alendronate. Similar data is seen with glucocorticoids. Once weekly alendronate is available in the USA, and fracture data over 1 year to-date show no GI side effects, and equal efficacy to daily regimen. Calcitonin shows moderate efficacy, and a reduction of vertebral fracture, but no major impact on the hip. It is useful in combination, and is most useful for analgesic effect. In patients with painful fracture, addition of Calcitonin is potentially useful.
IV pamidronate is used in those people who do not tolerate oral agents.Highlights from DAY 3
Prof Eric Gall spoke on the future of academic rheumatology. There is a movement in South Africa to reduce specialisation in favour of general medicine. Primary care is the focus. In the USA, this process was seen in the past 15 years with the rise of managed care and family medicine. Rheumatology income dropped 30 percent. Tuition fees at medical school rose, and therefore training in rheumatology dropped. In the last 10 years the ACR addressed the issue in committee. In the USA the population was getting larger and older and care was deteriorating. The areas identified were Research, Training and education, Patient care and partnership with industry.
Research - The mainstay - There was an under-representation in clinical research versus basic science. This was addressed, and a balance was developed. Paediatric research was encouraged. The meetings were modulated into clinical and basic science. Funds to promote academic medicine from membership and industry were developed. Teamwork with the arthritis foundation was established.
Money - support is critical
Private practice and grants are the essential income rather than faculty salary. This is resulting in more people leaving academic medicine.Research areas were identified:
Education research
Outcomes based research
Epidemiology
Clinical pharmacology and study design
Translational research
Genetics
RehabilitationThe major recommendations:
Encourage public, medical undergraduates and research funders to look positively at rheumatology.
Recruit academic rheumatologists early in the career.
Encourage awards for research and education.
Encourage contact with surgeons, physical medicine, and professional organisations.
Industry participation was encouraged:
Agreements for grants.
Networks between rheumatologists to establish databases.
Clinical trials
Look at public health regarding primary secondary and tertiary prevention.Dr Van der Walt Nephrologist / Physician and Prof L Dreyer, Pathologist presented 2 case reports of SLE. Both cases illustrated the enormous complexity of the systemically ill Lupus patient. The first patient had nephrotic syndrome, pericardial involvement, neurological involvement with stroke, pancytopenia and systemic fungal infection. The second case was characterised by renal, cardiac, neurological, skin and antiphospholipid disease.
Dr Ron Ascherson presented his vast experience on the antiphosholipid syndrome APS, and its variants. The antinuclear antibodies may be low, and if more than 1in320, be aware of possibility of SLE. The patients have 3 main subtypes
Simple APS
Rapid recurrent APS
Catastrophic APS.
In all patients with primary APS - watch out for occult malignancy. Tumours associated include breast. Kidney. Lung, thymoma, paraproteinaemia, and various haematological malignancies.
Occlusions may be venous as well as arterial.
The arterial occlusions may involve large or small vessels with multiple clinical presentations. Neurological, cardiac, renal, mesenteric, aortic arch amongst others.
Some patients are extremely hypercoagulable and resistant to warfarin as well as heparin. Control may be impossible. The cerebral circulation is the most commonly involved. Cardiac involvement occurs with valve lesions, and pathology of these shows antiphospholipid antibody-complement complexes deposit on the edge of the valve. Therefore these are an autoimmune process. Steroids may suppress the effects of this in low dose chronic therapy to prevent valve deterioration. Trials are required. Clots on the valve may embolise. Stroke therefore requires echocardiography to look at valve lesions.
Pulmonary involvement may be varied including pulmonary hypertension.
Adrenal involvement may occur - with Addison’s disease from adrenal failure. APS is now recognised as the commonest cause of idiopathic adrenal failure. Haemorrhagic infarction of the adrenal gland may therefore be a cause of sudden collapse.
Microangiopathy can occur - with various syndromes - HELLP syndrome, TTP, DIC, and the catastrophic APSA series of catastrophic APS has been published and most patients are SLE patients or overlap syndromes. Infectious complications are common as precipitating triggers in these patients, especially Respiratory or urological. Warfarin withdrawal may also provoke it. 30% of people develop arterial or venous occlusion, usually small vessel - kidney, brain skin, gastrointestinal, thyroid, pulmonary etc. Unusual organ involvement is a feature, i.e. bone arrow necrosis, oesophageal, testis etc.
DIC is also seen.
The role of infection as a cause is highlighted. Once the clotting takes place a cascade occurs with depletion of protein C, S and antithrombin 3. Infusion with FFP replaces the missing factors. It is vital to address the sepsis precipitating the problem. Cytokines released result in ARDS and steroids are required for this.In simple APS the vessels are large vessel occlusions.
Dr S Louizou internationally recognized in the field of APS, spoke on new diagnostic tests in the antiphospholipid syndrome. He reviewed the different assays in APS research. Conventional Cardiolipin tests are ELISA is more specific than the lupus anticoagulant assay. Lupus anticoagulants are large immunoglobulins and prolong phospholipid dependent clotting tests.
Other antibodies against negatively charged PLs include - Anti phosphatidyl serine or inositol antibodies
Antibodies against electrically neutral antibodies i.e. phoshatidyl ethanolamine / choline. These don’t produce clinical syndromes.
B2 glycoprotein is a natural anticoagulant. Human prothrombin factor 2 binds to phospholipid and is needed to produce prothrombin. Therefore antibodies to these include - anti B2 glycoprotein and anti prothrombin. Elisa tests to these are available. These antibodies are associated with thrombosis and recurrent fetal loss.Prof R Cervera, from Barcelona spoke on therapy of the APS. The best therapy is full anticoagulation. INR recommendation is higher than 3, but there is a risk of bleed. Therefore the author recommended standard INR control between 2-4. Recurrence was usually at the same site. Only 19% recurred on standard dose warfarin and there were no bleeds.
Fetal loss - low dose aspirin is recommended. 60 pregnancies were studied. Pre study most patients had fetal loss. Aspirin gave a 90 percent reduction in subsequent pregnancy. Addition of heparin is used for treatment failure. This is because interlocking 3 production is lowered by aspirin.
First pregnancy - no history - nil or low dose aspirin especially with lupus. Prednisone added if SLE plus organ damage.
Previous history of loss - aspirin - add heparin if failure.Thrombocytopenia with APS. Recommend low dose aspirin plus possible steroids. Splenectomy is not recommended in APS, as there is a risk of thrombosis - unless there is still no response to any other therapy including immunoglobulin. Thrombosis has not been seen by the author as a complication of splenectomy.
Cardiac lesion - Aspirin plus steroids and anticoagulation
Adrenal failure - replace the steroids as well
Catastrophic APS - Multiple combinations of Anticoagulation, steroids, immunosuppression, immunoglobulin and plasmapharesis has been studied. Most deaths were seen in SLE associated disease plus microangiography. Best recovery seen in Plasmapharesis or immunoglobulins and steroids aimed at reducing antibodies as soon as possible. Studies of Hydroxychloroquine are awaited, as there is some antithrombotic role.
People wanting to see progress of studies or even participate can go to a website - http://www.med.ub.es/mimmun/forum
Prof L Dreyer spoke on renal lupus. The classification was reviewed for the meeting. The pathogenesis of the different lesions and the biochemical constituent of the deposits in the kidney were illustrated. Indications for renal biopsy were reviewed as was the activity and chronicity index.
Dr L Van der Walt looked at the clinical therapy of renal involvement of SLE. Renal disease includes glomerular, tubular, vascular and NSAID associated disease / damage. Survival has increased since introduction of initially steroids and thereafter immunosuppression.
Mesangial disease prognosis is good.
Focal proliferative disease requires steroids +/- immunosuppression. Nephrotic / active sediment is treated as a class 4.
Diffuse proliferative disease requires the NIH regimen.
Membranous nephritis - treat supportively, with protein restriction, salt restriction, ACE inhibitors. Steroids can be considered.
Sclerosing lupus nephritis requires supportive therapy. Transplantation may be considered.
APS must be treated on its merit.The NIH regimen - steroids medrol for 3 days then oral 20-60mg daily for 3-6 months. Cyclophosphamide 0.5g/m2 monthly, building up the dose over the 3 months. After 6 months convert to 3 monthly.
Dr N Patel from university of Natal presented a paper on the outcome of thrombocytopenia in SLE. Thrombocytopenia is seen in 7-52% mean 14% of SLE patients. It s an independent risk factor for SLE prognosis. There is an 86% survival over 12 months. 2 subsets are described, an acute and a chronic group. Acute - in a SLE flare - has a high morbidity and mortality. Rx is steroids and immunosuppression. The chronic form manifested as a mild clinic effect with a low dose steroid or no treatment required at all. A retrospective study was done looking at patients with level <100. 37 patients fulfilled criteria. Mean count 37. 50% had counts less than 20. 20 percent had an inadequate response to steroids. 4 people died related to sepsis in people with active systemic involvement and did not die from the thrombocytopenia.
Recommendation - Treat with steroids. If no response - immunosupression especially cyclophosphamide. If no response - splenectomy preceded by danazol and azathioprine. Antiphospholipid data was not available.Dr Karen Pont from Tygerberg hospital spoke on Pregnancy in SLE - outcome and complications. Many factors are involved in outcome. In the pre 1960's outcome was very poor. This is now stated as being much improved. The authors looked at patients in a prospective trial, with at least 6 months of disease stability. Lowest possible dose of prednisone or azathioprine was desirable. Anticoagulants were changed to heparin. No smoking allowed. Hypertension was treated with methyldopa or beta-blocker. 47 pregnancies were assessed. Complications included ecclampsia, pre ecclampsia, thrombosis (3 cases), HELLP syndrome. Fetal death occurred in 2 pregnancies and 1 neonatal death. 30 percent were below 10th percentile for age. Congenital heart block was seen in 3 neonates. The conclusion was that Lupus pregnancies were associated with high maternal risk and high risk to the newborn.
Dr Ferdinand Breedveld from Leiden University discussed Immunoablation and stem cell transplant in autoimmune disease. After classical DMARD’s fail, we now have anti TNF drugs. But these don’t cure. Stopping these results in recurrence of disease. Experience in the past on transplant for malignancy in patients with autoimmune disease, especially RA, resulted in clinical remission. Experimental animal work with T cell clones in animal models, showed disease could be transferred by T cell transplants. Ablation of the T cells reversed this process. In theory therefore ablation of the origin of cytokine response may reverse the process. There are multiple regimens for bone marrow transplant (BMT). Trials are in progress in RA, SLE, and PSS amongst others. Autologous transplant eliminates Graft versus host disease, but there are still some T cells in the sample. Mortality of the procedure is 1-3 percent. This risk is acceptable to the resistant severe RA patient. Nausea, hair loss, haemorrhagic cystitis, infections are all potential risks. The protocol was mobilising the stem cells 4g cyclophos plus GMCSF Then you leukapharese these cells out. Then you ablate the marrow. Then you reinfuse the cells. Toxicity was as expected with thrombocytopenia, leukopenia, infections. The patients were studied over 21 months. Disappointingly there was incomplete response. Rheumatoid factors dropped over 6 months then increased again. 8/12 improved by >50%.
Work in systemic sclerosis with BMT was presented. 65 patients have had the procedure. Mortality is 19% including the mortality of the disease itself. There is a general improvement in skin scores.Dr G Singh presented the ARAMIS post marketing surveillance data. Clinical data from trials are not really a true reflection of true clinical practice. Aramis prospectively looks at data submitted by physicians. Large numbers of patients are now followed up with centres paid to submit data on hundreds of variables including HAQ and outcome variables. Post marketing surveillance looks at effectiveness and toxicity of drugs in the real life. Cost effectiveness is addressed. The application to NSAIDs and GI toxicity was demonstrated. Risk of a bleed is proportional with time. The greatest risk factor is time on the drug. But other risk factors are well known.
Dr P Taylor from UK spoke on other biological therapies in RA. The biological therapies involve either increasing anti-inflammatory cytokines or decreasing proinflammatory cytokines. Such targets include TNF inhibitors, but other compounds are in trials.
IL1 and IL1 receptor antagonist. Previous trials on IL1RA found 43% at 150 mg regimes in resistant disease and reduced erosion scores - especially at lower doses of 75mg.
IL6 regulates acute phase proteins and also osteoclasts. Antagonists have been developed. Transient benefit is seen in murine antibody but the development of antibody to drug became a big problem. Anti IL6 receptor antibody trials have shown some sustained benefit with infusions.
Augmentation of proinflammatory cytokines
IL4 subcutaneous dosing showed poor efficacy but no toxicity.
IL10 used in subcutaneous injection also were disappointing but showed trends to improvement. Combination with methotrexate showed 65% responded to the ACR20 criteria.
Antigen presenting cells provide another target - especially at the HLA antigen receptor.
T cell immunotherapy trials are underway. These include antibodies to T cell receptors. i.e. Campath-1 antibody to CDw52.
B cell immunotherapy with B cell depletion using anti CD20 antibody was tested on 5 patients using cyclophosphamide and prednisone first then infusing the antibody. All responded for 6 months to ACR 50 criteria. Relapses have occurred at 9 months in 2 patients.
Type 2 collagen induction of tolerance has been disappointing in trials.
CD4 depleting antibodies have also been disappointing.
Combination therapy is in trials. Collagen induced arthritis in mice is a model for therapy with these drugs. Anti TNF plus anti CD4 therapy results in a significant reduction in paw edema.
Anti TNF and anti IL12 produce a marked reduction in paw edema.Lunchtime symposia sponsored by the pharmaceutical industry were held
Schering Plough
MSDThe meeting was closed by the newly elected president os SARAA, Dr David Gotlieb, who expressed thanks to the organisers, and wished all participants a safe trip to their homes. Delegates were welcomed to the next conference to be held in Johannesburg in 2003.
Dr David Gotlieb
April 2001
