Approach to the management of AA amyloidosis complicating RA. (A) In case of proteinuria or loss of renal function a rectal biopsy or a subcutaneous fat biopsy is a suitable screening method for the detection of amyloidosis. If in any doubt, try to ascertain the diagnosis by renal biopsy. Adequate staining with alkaline Congo red and preferably immunohistochemical staining with anti-AA antibodies should be performed. Beware of renal pathology other than amyloidosis even in the presence of a positive rectal biopsy. (B) A vigorous attempt to control disease activity of the RA should be made in order to eliminate the production of SAA, an acute phase protein. The response to treatment should be monitored by serial measurements of CRP and preferably SAA. (C) The function of some vital organs should be evaluated: (a) endogenous creatinine clearance and the extent of proteinuria; (b) electrocardiogram and optional echocardiography; (c) thyroid function and adrenocortical function; (d) intestinal absorption tests; (e) optional--SAP scintigraphy and turnover studies. (D) Attention should be given to adequate supportive treatment: (a) blood pressure control; (b) treatment of intercurrent infections; (c) corticosteroids during major surgical procedures; (d) pay attention to the possible effect of NSAID on proteinuria and renal function. (E) In case of total renal failure or uncontrollable proteinuria: (a) consider the possibility of primary renal transplantation; (b) otherwise regular haemodialysis is indicated.

The diagnosis of systemic amyloidosis is only occasionally suspected on clinical grounds alone and is more often considered when an associated condition, such as a chronic inflammatory disease or monoclonal gammopathy, is present. No blood test is diagnostic of amyloid although routine haematological and biochemical investigations have important roles in defining the underlying disease process in amyloidosis, and evaluating organ function. A number of non-invasive investigations including echocardiography, electrocardiography and soft tissue scintigraphy with bone-seeking tracers give characteristic results in some patients with amyloidosis, but are non-specific. The diagnosis can only be confirmed by demonstrating the presence of amyloid deposits in the tissues. Histology is the traditional method in routine clinical practice and is sensitive for revealing microscopic deposits and permits immunotyping of fibril proteins. Disadvantages are that biopsies are invasive, open to sampling error and can only give limited information on the distribution and extent of amyloid deposits in an individual. Scintigraphic and turnover studies with radioiodinated SAP are new specific methods for confirming the presence of amyloid in tissues, based on the affinity of SAP for all types of amyloid fibril. Labelled SAP scans survey the whole body macroscopically for the presence and anatomical distribution of amyloid in a quantitative manner, and SAP turnover studies provide information on the whole body amyloid load. Although the availability of SAP scintigraphy presently remains restricted, the technique has been used in over 400 patients with amyloid in prospective studies, and has already provided a number of new insights into the natural history of amyloidosis. These include the observation that there is a consistently poor correlation between the quantity of amyloid in an organ and the resulting degree of functional impairment. Amyloid deposits accumulate at rates which vary substantially between different organs in a single subject and between individuals with similar types of amyloidosis, even when the rates of amyloid fibril precursor protein supply are apparently similar. In some patients amyloid accumulation may plateau without any measurable alteration in the precursor supply. In patients with amyloidosis in whom the supply of fibril precursors is reduced, either as a result of therapy directed towards the underlying process or through a natural remission, substantial regression of amyloid frequently occurs. This has been observed in patients with AA, AL and variant TTR-associated amyloidosis, and is usually associated with clinical benefits. In some such cases, however, the function of affected organs may continue to deteriorate despite halting the accumulation of amyloid, presumably because irreversible structural damage has already occurred.(ABSTRACT TRUNCATED AT 400 WORDS)

The limited available epidemiological information on AL amyloidosis suggests that there may be differences between population-based studies and case series data with respect to variables such as age and racial patterns. Much more work in this area is required before specific aetiologic hypotheses can be tested. Most available data to approximate the epidemiology of AA amyloidosis are derived from autopsies. Most patients with AA amyloidosis die from causes other than amyloidosis, therefore mortality data based on death certificates is of limited value in AA amyloidosis. Case ascertainment in autopsy studies may be difficult due to the frequent lack of adequate histological controls. Establishment of registries for both AL and AA amyloidosis would facilitate epidemiological research in these disorders.

For over 70 years animal experiments have been performed to elucidate the pathogenesis of reactive amyloidosis and to investigate the formation of the beta-pleated sheet-rich amyloid fibrils in general. In appropriate species, primarily rodents like mouse and hamster, amyloid is formed after stimulation with amyloid-inducing injections after a lag phase (secondary or reactive amyloid, AA amyloid). For the formation of this AA amyloid, elevated values in blood of its precursor protein, SAA, is the first prerequisite. SAA is an acute phase protein of hepatic origin, released after stimulation by cytokines, and is associated in serum with high-density lipoprotein (apoSAA). In mouse, hamster and mink amyloidogenic subtypes of SAA are found. In the rat SAA is absent, although its mRNA is transcribed. Evidence is increasing that SAA crystallizes to fibrils first, whilst loss of its C-terminal end can be a post-fibrillogenic phenomenon. Glycoproteins, proteoglycans, glycosaminoglycans and lipids are reintroduced in experimental amyloid research. Basement membrane heparan sulphate proteoglycans (perlecans) are attributed to have a primary role. The pentraxin serum amyloid P-component is a calcium-dependent secondary phenomenon. Membrane-bound, lipid-rich vesicles are found amongst the newly deposited pericellular amyloid fibrils. These vesicles probably have to be interpreted as indicators of primary membrane alteration during amyloid fibril crystallization. The vesicles will be formed after rupture of the membranes caused by the stiff intramembranously crystallized protein fibrils. Morphological evidence supporting this hypothesis has been found in immunoelectron microscopical studies. Accumulation of intramembranous SAA preceded amyloid fibril deposition. Fibril formation then might be related to conformational change of the intramembranous SAA. The lag phase for amyloid deposition is shortened after a single injection of a fraction of amyloid, the AEF. It is a low-molecular-weight glycoprotein that easily associates with other molecules. When isolated from amyloid fibrils, the (F)AEF contains a large proportion of beta-pleated sheet molecular structure. It is probable that this structure holds an explanation for its enhancing potency: forming a nidus for physical crystallization. The major substances and animal species used in animal experiments on amyloidosis, are mentioned. Overlooked by-effects of amyloidogenic stimuli are discussed. Polyarthritis after systemic endotoxin injections found in the hamster acts as a source of cytokines, further triggering the reactive amyloidosis.(ABSTRACT TRUNCATED AT 400 WORDS)

Serum amyloid A is an acute phase protein complexed to HDL as an apoprotein. The molecular weight is 11.4-12.5 kDa in different species and the protein has from 104 to 112 amino acids, without or with an insertion of eight amino acids at position 72. The protein is very well conserved throughout evolution, indicating an important biological function. The N-terminal part of the molecule is hydrophobic and probably responsible for the lipid binding properties. The most conserved part is from position 38 to 52 and this part is therefore believed to be responsible for the until now unknown biological function. The protein is coded on chromosome 11p in man, and chromosome 7 in mice, and found in all mammals until now investigated, and also in the Peking duck. In the rat a truncated SAA mRNA has been demonstrated, but no equivalent serum protein has been reported. Acute phase SAA is first of all produced in hepatocytes after induction by cytokines, but extrahepatic expression of both acute phase and constitutive SAA proteins have been demonstrated. Several cytokines, first of all IL-1, IL-6 and TNF are involved in the induction of SAA synthesis, but the mutual importance of these cytokines seems to be cell-type specific and to vary in various experimental settings. The role of corticosteroids in SAA induction is somewhat confusing. In most in vitro studies corticosteroids show an enhancing or synergistic effect with cytokines on SAA production in cultured cell. However, in clinical studies and in vivo studies in animals an inhibitory effect of corticosteroids is evident, probably due to the all over anti-inflammatory effect of the drug. Until now no drug has been found that selectively inhibits SAA production by hepatocytes. Effective anti-inflammatory or antibacterial treatment is the only tool for reducing SAA concentration in serum and reducing the risk of developing secondary amyloidosis. The function of SAA is still unclear. Interesting theories, based on current knowledge of the lipid binding properties of the protein and the relation to macrophages, in the transportation of cholesterol from damaged tissues has been advanced. A putative role in cholesterol metabolism is supported by the findings of SAA as an inhibitor of LCAT. The potential that SAA is a modifying protein in inflammation influencing the function of neutrophils and platelets is interesting and more directly related to the inflammatory process itself.(ABSTRACT TRUNCATED AT 400 WORDS)

The acute phase reaction is in most circumstances a good indicator of (local) inflammatory activity and tissue damage. CRP is a direct and quantitative measure for the acute phase reaction and due to its fast kinetics provides adequate information of the actual situation. The ESR on the contrary is in fact an indirect measure of the acute phase reaction. It does react much slower to changes of inflammatory activity and is influenced by a number of other factors. From studies on the 'behaviour' of CRP it has become clear that diseases may differ with regard to the extent in which they induce an acute phase response. Incidental measurement of the CRP level may add to the diagnostic procedure in selected cases, e.g. in the differentiation between a bacterial and a viral infection or between a bacterial infection and an exacerbation of diseases like SLE. In case of an extremely elevated CRP level (> 100 mg/litre) the possibility of a bacterial infection should always be considered. In clinical practice CRP is particularly useful when serial measurements are performed. The course of the CRP level may be useful for the monitoring of the effect of treatment and for the early detection of postoperative complications or intercurrent infections. The relationship between CRP and the local production and effects of cytokines on the one hand, and the possible functional role of CRP in the inflammatory process on the other hand have surely added a dimension to the clinical use of CRP as a parameter of inflammatory activity.

The acute phase response in a given individual represents the integrated sum of multiple, separately regulated changes. Although many of these changes commonly occur together in affected individuals, clinical experience indicates that not all of them occur in all individuals, indicating that they must be individually regulated. For example, febrile patients may have normal blood levels of CRP and vice versa, leukocytosis does not always accompany other acute phase phenomena, and many instances of discordance between levels of the various acute phase proteins are seen. Cytokines function as part of a complex regulatory network, a signalling language in which information is conveyed to cells by combinations, and perhaps sequence, of intercellular messenger molecules. The effects of combinations of cytokines are complex. To use a somewhat crude simile, individual cytokines can be thought of as words which bear informational content and which may, on occasion, communicate a complete message. More commonly, however, the actual messages received by cells probably resemble sentences, in which combinations and sequences of words convey information. Currently available data suggest that hepatocytes receive a complex mixture of humoral or paracrine signals during the acute phase response. These are integrated by multiple interacting signal transducing mechanisms to cause finely regulated changes in plasma protein synthesis. Regulation largely occurs by transcriptional control, but post-transcriptional mechanisms, including translational regulation, may also participate. Both the extracellular and intracellular mechanisms that mediate the response of the hepatocyte to inflammatory stimuli appear to be highly complex and involve multiple overlapping, concurrent and parallel pathways. Enough is known at present to conclude that IL-6 is a major participant in these plasma protein changes. Regulation of non-hepatocyte acute phase phenomena has not been delineated as thoroughly, but clearly involves a number of inflammation-associated cytokines.

The treatment of psoriatic arthritis has acquired relevance in the past few years because of advances and better understanding of the pathogenetic mechanisms implicated in the disease, and also because of recognition that this disorder is not a benign disease as was previously thought. The general principles of management for any inflammatory arthritis, including pharmacological, surgical and rehabilitative treatment, are to be used, with concomitant therapeutic management of skin involvement. Non-steroidal anti-inflammatory drugs constitute the mainstay of pharmacological therapy for most patients, with a good clinical response observed in 75-85%. Early use of remittive agents, especially methotrexate, is indicated in patients with a poor response to NSAIDs or those with polyarticular and progressive joint involvement. Patients who are refractory to conventional therapy should be considered for newer and potentially more toxic therapeutic modalities such as cyclosporin A and retinoids.

The incidence of radiological change in psoriatic arthritis (PsA) is uncertain. The general pattern of the disease has been classified into five groups. This classification is still widely used, but recently a change of emphasis has been stressed in the classification and prevalence, particularly relating to the polyarthritic forms and the variability of symmetry and asymmetry. The plain film findings in the axial and appendicular skeleton are described. In the former, bulky paramarginal ossification in the thoracolumbar spine is a prominent feature; destructive as well as ankylosing disease is seen in the cervical spine. In the latter, the key features are marginal erosions associated with proliferative new bone, acro-osteolysis, preservation of bone density, periostitis and bony ankylosis. Progress of the disease is variable and, while the course is usually less severe than that in rheumatoid arthritis, progressive joint deformity occurs. Isotope scintigraphy is a useful technique for showing a general overview of joint involvement, but has limitations which impair its use in individual joints. CT is useful for looking at detailed bone anatomy and early demonstration of sacroiliitis. MRI may also be used to look at early sacroiliitis and has the potential for directly imaging the inflammatory process and the articular cartilage. Radiological differentiation of PsA from other arthritides may be difficult, particularly in the early stages, and in oligoarticular disease. The differential diagnosis is discussed.

Over recent years there has been a great deal of interest in the immunology, molecular biology and pathology of psoriasis and PsA. The pathogenetic mechanisms in PsA are less well understood than those described for psoriasis. There are almost certainly genetic and immune components. What is not clear is whether there is a primary immune defect or whether unknown stimuli lead to the recruitment of the immune system and establishment of the disease; nor is it absolutely clear whether PsA is an extension of psoriasis in certain prone individuals. Vascular abnormalities are the earliest histopathological changes to occur in the psoriatic plaque and are also prominent in the psoriatic synovium. Espinoza et al (1982) have suggested there may be a primary vascular defect in PsA. The fact that vascular changes occur before infiltration of immunocompetent cells and are the first changes to resolve with treatment of psoriasis is likely to be significant. Abnormalities in the cellular kinetics and growth factor sensitivity of keratinocytes, fibroblasts and synoviocytes have been highlighted previously. The ability of these cells to produce growth factors and express HLA class II antigens demonstrates the potential for them to initiate and maintain inflammation. The development and possible increased incidence of PsA in patients with such profound immunodeficiency as acquired immune deficiency syndrome suggests that T helper cells do not play a significant role in the establishment of the disease (Arnett et al, 1991). Previously, many immune changes were described. Unfortunately they are non-specific and do not indicate a fundamental defect or marker of PsA. Vasey (1985) has suggested that insidious exposure to Gram-positive bacteria from the gut, tonsils and psoriatic plaques results in chronically stimulated monocytes, macrophages and dendritic cells. These cells are able to migrate throughout the body. Repeated microtrauma may result in the homing of these cells to sites of injury in the skin, synovium and tendons. Interaction with genetically hyperactive synoviocytes and keratinocytes with concomitant release of growth factors may precipitate early lesions of psoriasis and PsA. This hypothesis needs to be substantiated, but it ties together some of the varying observations seen. Many abnormal laboratory findings have been described. Unfortunately, none of the serological changes is sufficiently specific to be of great help in diagnosis. CRP levels and the ESR remain the best promise as markers of the inflammatory component of the arthritis, while other indicators correlate with certain facets of the disease pathology, but as yet have not found a true niche in the management of PsA.(ABSTRACT TRUNCATED AT 400 WORDS)

Psoriasis is a common chronic skin disorder affecting 2% of the general population. Present evidence strongly suggests that it is an immunologically mediated disease; the evidence includes the results of disease association studies linking psoriasis to certain MHC antigens and immunohistochemical studies revealing early influx into lesions of activated T lymphocytes. Accumulation of these cells in skin is mediated by upregulated expression of leukocyte adhesion molecules on vascular endothelium and epidermal keratinocytes and by production of proinflammatory and chemotactic cytokines. Activation of cell-mediated immune mechanisms in lesional skin is highlighted by the increased antigen-presenting capacity of Langerhans cells isolated from psoriatic skin compared to normal skin. The nature of the antigens precipitating psoriasis, however, remains unknown although a role for streptococcal superantigens has been postulated. These studies have led to the belief that immunotherapy may hold great promise for the treatment of psoriasis. Indeed both cyclosporin A and FK506 are effective therapies and evidence suggests that anti-CD4 antibodies may be of great value.

Psoriasis and psoriatic arthritis are diseases of unknown aetiology characterized by chronic immune-mediated lesions in the skin and synovial joints respectively. The lesions are remarkably similar in appearance and in functional terms. The main differences reside in the fact, first, that the main antigen-presenting cell in the skin is the Langerhans' cell while in the joint it is probably the dendritic antigen-presenting cell and, second, that the main mesenchymal cell in the skin is the keratinocyte while in the joint it is the synoviocyte. Whether these differences merely reflect tissue-specific characteristics or are important in aetiopathogenesis is not known at present. However, the similarity in pathogenesis does mean that similar immunotherapeutic approaches can be used for their treatment.

The place of psoriatic arthritis in the spondarthritides has been examined in terms of past, present and future aspects. It is concluded that: 1. PsA is a definite entity and separate from rheumatoid arthritis. 2. The spondarthritis concept is universally accepted, although still in an evolving stage. 3. A more definitive picture of the spondarthritides and of PsA itself could arise from a number of new approaches, some entirely novel, some extensions of work already in progress. Avenues of future research that are likely to be fruitful include those involving: more refined clinical studies; further applications of molecular mapping; and, common to both, conceptual advances using mathematical models to provide a more 'three-dimensional' picture.

Psoriatic arthritis is a distinct form of inflammatory arthritis associated with psoriasis, which exists in a number of clinical presentations. Although a large number of patients have a mild form of arthritis, there is a population who present with a very aggressive, deforming and disabling arthritis. The prognostic factors for the development of this type of arthritis are unclear as yet. Therefore, PsA may not be as benign a condition as previously thought, and the approach to its management should be similar to that for rheumatoid arthritis. Current investigations are in progress to identify the prognostic factors associated with severe disease in PsA. Until the results of these studies are available, all patients should probably be treated more aggressively, and earlier.

The occurrence of musculoskeletal manifestations (including synovitis, chest wall arthro-osteitis and multifocal aseptic osteomyelitis) in association with severe acne, palmoplantar pustulosis and perhaps with some presentations of psoriasis, have been described by many authors in the past 30 years. These different multifaceted descriptions have been designated by a variety of terms. More recently, a possible link between these conditions and spondarthritides has also been underlined by a slightly increased prevalence of HLA-B27 and occasional occurrences of sacroiliitis, chronic inflammatory bowel disease and possibly psoriasis. An acronym, the SAPHO syndrome (which stands for Synovitis, Acne, Pustulosis, Hyperostosis and Osteitis) is proposed for this group of diseases because of the similarity of musculoskeletal manifestations in patients with severe acne and pustulosis. The clinical, epidemiological, pathophysiological, immunogenetic and diagnostic aspects, as well as the management of this syndrome, are reviewed.