4 The search for laboratory measures of outcome in rheumatoid arthritis FRANK A. WOLLHEIM K E R S T I N B. E B E R H A R D T
Expected outcome or end-result of a chronic, systemic and disabling disease such as rheumatoid arthritis (RA) is as important to the newly diagnosed patient and her environment, as to the physician responsible for the management. New insight into pathogenesis of arthritis and inflammation as well as into tissue composition and metabolism has allowed construction of novel tests, measuring various aspects of the processes, with the aim to achieve better assessment of RA. This chapter discusses some laboratory measures with potential use as prognostic instruments, in particular when used in earlier phases of the disease. As discussed in other chapters of this volume, the long-term natural course is variable and may be changing with time (Silman, 1989). For obvious reasons, only the most simple and widely used tests, mainly erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) were evaluated in the few long-term cohort studies that have been completed. Table 1 lists some recently available tests according to their probable role in the disease process. It should be realized, however, that this Table 1. Laboratory tests with potential for measuring outcome. Type
Marker
General markers of inflammation
Acute-phase proteins, ESR, haemoglobin, cytokines, abnormal glycosylation, Clq Major histocompatibility complex, sulphoxidation Rheumatoid factors, antinuclear antibodies, anticollagen, anti-Clq, antistress proteins
Genetic markers Autoantibodies Tissue activation/catabolism Neutrophils Lymphocytes Macrophages Synovial tissue Cartilage Bone
Baillibre's Clinical Rheurnatology--
Vol. 6, No. 1, February 1992 ISBN 0-7020-1635-7
Lactoferrin, cytidine deaminase, elastase, leukocyte protein L1 (Cartprotectin) 132-microglobulin, soluble IL-2-receptor, immune complexes Neopterin Hyaluronan, collagen III pro-peptide Proteoglycan epitopes, keratan sulphate, cartilage oligomeric protein, CMP, collagen, pyridinoline Osteocalcin, bone sialoprotein, pyridinoline, deoxypyridinoline
69 Copyright 9 1992, by Bailli~re Tindall All rights of reproduction in any form reserved
70
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W O L L H E I M A N D K. B. E B E R H A R D T
is done for didactic purposes and is an oversimplification. For instance, tissue markers are often not specific for one tissue. Furthermore, various types of markers are connected by common regulatory mechanisms, in which the cytokines play a key role. MAJOR HISTOCOMPATIBILITY COMPLEX Part of the genetic susceptibility for RA is governed by genes within the major histocompatibility complex (MHC), mainly within the class II region. The association between RA and HLA-DR4 in several ethnic groups has been confirmed in many studies. There also seems to be a less marked but independent association with HLA-DR1 (Stastny et al, 1988). Further exploration of the DR4 region has defined two distinct HLA-DRI3 alleles (Dw4 and Dwl4) to be associated with RA in caucasian patients (Nepom et al, 1989) and another one (Dwl5) in Japanese patients (Ohta et al, 1982)~ A common feature of the various H L A - D R and Dw associations in RA is the presence of shared functional epitopes located at the third hypervariable region of the DRI3 chain (Gregersen et al, 1987; Wordsworth et al, 1989). Molecular studies have demonstrated that HLA-D genes are organized in three families, DP, DQ and DR. HLA-D-region genes exhibit linkage disequilibrium. DR4 in most populations is found associated with DQw3. Two variants of DQw3 molecules differ in polymorphism of their DQI3 chains and have been designated DQw7 and DQw8 (equated with TA10 or 3.1 and 3.2 respectively) (Lanchbury et al, 1989). The incidence of DR2 is decreased in patients with RA. A number of subtypes of DR2 have been defined and found to be in linkage disequilibrium with different subspecificities of DQwl. One such specificity was found to confer protection against RA (Singal et al, 1990a). Many important steps to outline further the genetic susceptibility for R A accounted for by class II MHC variants have thus been made. From a practical point of view, however, the associations between MHC antigens and disease are not of the magnitude to be useful as prognostic tools. In a recent study Puttick et al (1990) tried without success to find out, by aid of MCH typing, whether a patient with recent onset synovitis was prone to develop definite R A or mild self-limiting inflammatory arthritis. Many studies have addressed the question whether DR4 positivity may relate to disease severity. There seems to be a definite association between presence of DR4 and severe vasculitis and Felty's syndrome (Westedt et al, 1986a). However, data are conflicting concerning articular disease. A recent retrospective study reported association between HLA-DR4 and more severe radiographic changes, but not with functional measures (Olsen et al, 1988a). These findings were supported by Calin et al (1989) who found association between HLA-DR4 and destructive disease, irrespective of RF serology. Some prospective studies of early R A have included H L A data in the prognostication procedure. Silman et al (1986) concluded that HLADR4 was not a useful predictor of functional status and disease severity. Two other studies found no contribution of HLA-DR4 to the prediction of
71
LABORATORY MEASURES OF OUTCOME
erosions (MOttSnen et al, 1988; Young et al, 1988). On the other hand, two recent Dutch studies (van der Heijde, 1991; van Zeben et al, 1991) found that HLA-DR4 contributed useful prognostic information. Some studies have indicated that the DR4 associated DQw7 might be a marker of more severe disease. Sansom et al (1989) found that DQw7 was more prevalent among patients with greater disability and more systemic disease. McCusker et al (1991) compared two groups of RA patients, those with mild non-progressive disease and those with more severe disease requiring treatment with second-line drugs. The DR4 was significantly increased in both groups but the DR4-associated DQw7 was significantly increased only in patients with severe disease. On the other hand, Wordsworth et al (1989) did not find an increased frequency of DQw7 in patients treated with second-line drugs. Two studies from Scandinavia (Wallin et al, 1988; Ilonen et al, 1990) found a much stronger linkage between DR4 and DQw8 than with DQw7. However, the clinical status of the patients with RA in these studies was not defined. Patients with Felty's syndrome have a higher frequency of DQw7 containing haplotypes and with the class III MHC C4B null allele (Clarkson et al, 1990; Hillarby et al, 1991). Furthermore, Hillarby et al found that RA patients with severe vasculitis in contrast to the Felty patients also showed association with Dwl4. Wordsworth (1991) has argued that the association between Felty's syndrome and DQw7 might be secondary to a primary association with the Dw4 subtype of DR4, since the Dw4/DQw7 haplotype is twice as common as Dw4/DQw8. Some earlier studies found a higher frequency of HLA-DR3 in patients with RA and gold-induced thrombocytopenia or proteinuria. Further studies of polymorphism of extended haplotypes have identified one of these haplotypes to be present more often in RA patients with side-effects (Singal et al, 1990b). The results of this and other recent Canadian studies on HLA-D region antigens are summarized in Table 2.
Table 2. Frequencies (%) of relevant HLA-D region antigens in normal subjects and in patients with rheumatoid arthritis (RA). Patients with severe RA treated with gold HLA-D antigen
Normal controls
Mild RA
No side-effects
Proteinuria and/or thrombocytopenia
DR1
14.3
32.5 (P
Expected outcome or end-result of a chronic, systemic and disabling disease such as rheumatoid arthritis (RA) is as important to the newly diagnosed patient and her environment, as to the physician responsible for the management. New insight into pathogenesis of arthritis and inflammation as well as into tissue composition and metabolism has allowed construction of novel tests, measuring various aspects of the processes, with the aim to achieve better assessment of RA. This chapter discusses some laboratory measures with potential use as prognostic instruments, in particular when used in earlier phases of the disease. As discussed in other chapters of this volume, the long-term natural course is variable and may be changing with time (Silman, 1989). For obvious reasons, only the most simple and widely used tests, mainly erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF) were evaluated in the few long-term cohort studies that have been completed. Table 1 lists some recently available tests according to their probable role in the disease process. It should be realized, however, that this Table 1. Laboratory tests with potential for measuring outcome. Type
Marker
General markers of inflammation
Acute-phase proteins, ESR, haemoglobin, cytokines, abnormal glycosylation, Clq Major histocompatibility complex, sulphoxidation Rheumatoid factors, antinuclear antibodies, anticollagen, anti-Clq, antistress proteins
Genetic markers Autoantibodies Tissue activation/catabolism Neutrophils Lymphocytes Macrophages Synovial tissue Cartilage Bone
Baillibre's Clinical Rheurnatology--
Vol. 6, No. 1, February 1992 ISBN 0-7020-1635-7
Lactoferrin, cytidine deaminase, elastase, leukocyte protein L1 (Cartprotectin) 132-microglobulin, soluble IL-2-receptor, immune complexes Neopterin Hyaluronan, collagen III pro-peptide Proteoglycan epitopes, keratan sulphate, cartilage oligomeric protein, CMP, collagen, pyridinoline Osteocalcin, bone sialoprotein, pyridinoline, deoxypyridinoline
69 Copyright 9 1992, by Bailli~re Tindall All rights of reproduction in any form reserved
70
F.A.
W O L L H E I M A N D K. B. E B E R H A R D T
is done for didactic purposes and is an oversimplification. For instance, tissue markers are often not specific for one tissue. Furthermore, various types of markers are connected by common regulatory mechanisms, in which the cytokines play a key role. MAJOR HISTOCOMPATIBILITY COMPLEX Part of the genetic susceptibility for RA is governed by genes within the major histocompatibility complex (MHC), mainly within the class II region. The association between RA and HLA-DR4 in several ethnic groups has been confirmed in many studies. There also seems to be a less marked but independent association with HLA-DR1 (Stastny et al, 1988). Further exploration of the DR4 region has defined two distinct HLA-DRI3 alleles (Dw4 and Dwl4) to be associated with RA in caucasian patients (Nepom et al, 1989) and another one (Dwl5) in Japanese patients (Ohta et al, 1982)~ A common feature of the various H L A - D R and Dw associations in RA is the presence of shared functional epitopes located at the third hypervariable region of the DRI3 chain (Gregersen et al, 1987; Wordsworth et al, 1989). Molecular studies have demonstrated that HLA-D genes are organized in three families, DP, DQ and DR. HLA-D-region genes exhibit linkage disequilibrium. DR4 in most populations is found associated with DQw3. Two variants of DQw3 molecules differ in polymorphism of their DQI3 chains and have been designated DQw7 and DQw8 (equated with TA10 or 3.1 and 3.2 respectively) (Lanchbury et al, 1989). The incidence of DR2 is decreased in patients with RA. A number of subtypes of DR2 have been defined and found to be in linkage disequilibrium with different subspecificities of DQwl. One such specificity was found to confer protection against RA (Singal et al, 1990a). Many important steps to outline further the genetic susceptibility for R A accounted for by class II MHC variants have thus been made. From a practical point of view, however, the associations between MHC antigens and disease are not of the magnitude to be useful as prognostic tools. In a recent study Puttick et al (1990) tried without success to find out, by aid of MCH typing, whether a patient with recent onset synovitis was prone to develop definite R A or mild self-limiting inflammatory arthritis. Many studies have addressed the question whether DR4 positivity may relate to disease severity. There seems to be a definite association between presence of DR4 and severe vasculitis and Felty's syndrome (Westedt et al, 1986a). However, data are conflicting concerning articular disease. A recent retrospective study reported association between HLA-DR4 and more severe radiographic changes, but not with functional measures (Olsen et al, 1988a). These findings were supported by Calin et al (1989) who found association between HLA-DR4 and destructive disease, irrespective of RF serology. Some prospective studies of early R A have included H L A data in the prognostication procedure. Silman et al (1986) concluded that HLADR4 was not a useful predictor of functional status and disease severity. Two other studies found no contribution of HLA-DR4 to the prediction of
71
LABORATORY MEASURES OF OUTCOME
erosions (MOttSnen et al, 1988; Young et al, 1988). On the other hand, two recent Dutch studies (van der Heijde, 1991; van Zeben et al, 1991) found that HLA-DR4 contributed useful prognostic information. Some studies have indicated that the DR4 associated DQw7 might be a marker of more severe disease. Sansom et al (1989) found that DQw7 was more prevalent among patients with greater disability and more systemic disease. McCusker et al (1991) compared two groups of RA patients, those with mild non-progressive disease and those with more severe disease requiring treatment with second-line drugs. The DR4 was significantly increased in both groups but the DR4-associated DQw7 was significantly increased only in patients with severe disease. On the other hand, Wordsworth et al (1989) did not find an increased frequency of DQw7 in patients treated with second-line drugs. Two studies from Scandinavia (Wallin et al, 1988; Ilonen et al, 1990) found a much stronger linkage between DR4 and DQw8 than with DQw7. However, the clinical status of the patients with RA in these studies was not defined. Patients with Felty's syndrome have a higher frequency of DQw7 containing haplotypes and with the class III MHC C4B null allele (Clarkson et al, 1990; Hillarby et al, 1991). Furthermore, Hillarby et al found that RA patients with severe vasculitis in contrast to the Felty patients also showed association with Dwl4. Wordsworth (1991) has argued that the association between Felty's syndrome and DQw7 might be secondary to a primary association with the Dw4 subtype of DR4, since the Dw4/DQw7 haplotype is twice as common as Dw4/DQw8. Some earlier studies found a higher frequency of HLA-DR3 in patients with RA and gold-induced thrombocytopenia or proteinuria. Further studies of polymorphism of extended haplotypes have identified one of these haplotypes to be present more often in RA patients with side-effects (Singal et al, 1990b). The results of this and other recent Canadian studies on HLA-D region antigens are summarized in Table 2.
Table 2. Frequencies (%) of relevant HLA-D region antigens in normal subjects and in patients with rheumatoid arthritis (RA). Patients with severe RA treated with gold HLA-D antigen
Normal controls
Mild RA
No side-effects
Proteinuria and/or thrombocytopenia
DR1
14.3
32.5 (P
