Liver enzyme abnormalities of inpatients with rheumatic diseases: A 10-year retrospective study in a Korean medicine hospital.

Herbal medicines have been used as a treatment option for rheumatic disease (RD), but they often produce liver enzyme abnormality. This study examines the incidence of herb-induced liver injury (HILI) and the relationship between risk factors and liver enzyme abnormality (LEA) in inpatients with RD. HILI was analyzed using the Roussel Uclaf causality assessment method liver injury criteria and causality assessment. Multivariable analysis was performed to assess the relationship between patient characteristics and LEA in RD. The features of LEA were also examined in each RD. Among 352 patients included in this study, 105 patients showed LEA on admission, of which 6 had fulfilled the Roussel Uclaf causality assessment method criteria. The incidence risks of LEA and HILI were 12.55% and 0.58%, respectively. Multivariable analysis showed that LEA on admission and occasional use of alcohol could be risk factors for LEA on follow-up. In an additional analysis with each RD, all rheumatoid arthritis patients with LEA were taking nonsteroidal anti-inflammatory drugs, steroids, and disease-modifying antirheumatic drugs, and 4 out of 5 gout patients with LEA were taking steroids. The use of herbal medicine in RD is relatively safe. However, regular monitoring of liver enzyme tests and examination of alcohol consumption are required.

Association between TYK2 polymorphisms and susceptibility to autoimmune rheumatic diseases: a meta-analysis.

OBJECTIVE: This study aimed to explore whether TYK2 polymorphisms are associated with susceptibility to autoimmune rheumatic diseases. METHODS: We conducted a meta-analysis on the association between TYK2 polymorphisms and autoimmune rheumatic diseases. RESULTS: Twelve studies with a total of 16,335 patients and 30,065 controls were included in the meta-analysis. Meta-analysis revealed an association between rheumatic diseases and the 2 allele of the TYK2 rs2304256 (OR = 0.885, 95% CI = 0.802-0.978, p = 0.016). Furthermore, stratification by ethnicity identified a significant association between this polymorphism and rheumatic diseases in Caucasians (OR = 0.822, 95% CI = 0.706-0.889, p = 9.5 × 10(-7)), but not in Asians (OR = 1.127, 95% CI = 0.835-1.522, p = 0.434). Meta-analysis by rheumatic disease type revealed a significant association between the 2 allele of the TYK2 rs2304256 and SLE in Caucasians (OR = 0.737, 95% CI = 0.673-0.808, p < 1.0 × 10(-8)) but not in Asians (OR = 1.211, 95% CI = 0.813-1.804, p = 0.347). Meta-analysis revealed that the rs12720356 polymorphism was associated with susceptibility to rheumatic diseases in Caucasians (OR = 0.812, 95% CI = 0.661-0.997, p = 0.046) but not in Asians. Interestingly, the rs280519 polymorphism was significantly associated with susceptibility to SLE both in Caucasians and Asians. However, no associations were found between the rs12720270, rs280500, rs280523 and rs8108236 polymorphisms and susceptibility to rheumatic diseases. CONCLUSIONS: This meta-analysis demonstrates that the TYK2 rs2304256 and rs12720356 polymorphisms are associated with susceptibility to rheumatic diseases, rs2304256 polymorphism is associated with SLE in Caucasians, and rs280519 polymorphism is associated with SLE in Caucasians and Asians.

[Mycophenolate mofetil--20 years of experience in treatment of rheumatic diseases]. / Mykofenolan mofetylu - 20 lat doswiadczen w leczeniu chorób reumatycznych

Mycophenolate mofetil (MMF) has been used in rheumatology for over 20 years. When transformed to the active metabolite of mycophenolic acid, it is a potent, selective, reversible inhibitor of inosine monophosphate dehydrogenase, a key enzyme of de novo purine synthesis, exerting a cytostatic effect on T and B cells. It also induces apoptosis of antigen-activated T cell clones, reduces the production of antibodies to inhibit the expression of adhesion molecules, reducing the influx of leukocytes and monocytes to inflammatory sites, and has anti-fibrotic properties. Although the main branch of medicine that uses MMF is transplantation, rheumatologists experienced in application of this drug confirmed its usefulness in the treatment of connective tissue diseases. In comparison with immunosuppressives available in rheumatology, MMF has a very good safety profile and is well tolerated by patients. Through multi-center, randomized, controlled clinical trials, MMF has become well established in the treatment of lupus nephritis. Conclusions about its effectiveness in other rheumatologic indications are not entirely clear, being derived from small clinical trials, observational studies and case reports. They suggest that MMF may also be used to treat extrarenal symptoms of SLE, interstitial lung disease in the course of SSc (systemic sclerosis), PM/DM (polymyositis/dermatomyositis), and skin lesions in these diseases, myositis and systemic vasculitis. It should be emphasized that MMF has proved effective in many cases complicated by multidrug resistance to immunosuppressive therapy and has allowed a significant reduction of long-term corticotherapy or its withdrawal.

[Differential diagnosis of elevated liver transaminases in rheumatic diseases]. / Differenzialdiagnose der Transaminasenerhöhung bei rheumatischen Erkrankungen.

During laboratory monitoring of patients with rheumatic diseases it is not uncommon to notice elevated liver transaminase levels. From a rheumatological perspective there are multiple causes for this. Liver dysfunction can be the result of certain rheumatological diseases, such as systemic lupus erythematosus. Primary biliary cirrhosis and primary sclerosing cholangitis are associated with rheumatic diseases. On the other hand, hepatological diseases, such as hepatitis C and autoimmune hepatitis show rheumatological symptoms. The most common cause of elevation of liver transaminase levels in rheumatic patients is without doubt the anti-rheumatic therapy.

The emerging roles of HTRA1 in musculoskeletal disease.

High-temperature requirement serine protease A1 (HTRA1) is one of four known proteases belonging to the broadly conserved family of HTRA proteins. Although it was originally considered as representing an important modulator of tumorigenesis, an increasing number of reports have suggested that its influence on human disease may extend beyond cancer. HTRA1 has the capacity to degrade numerous extracellular matrix proteins, and as such, its potential involvement in diseases of the musculoskeletal system has been gaining increased attention. Musculoskeletal disease constitutes a wide variety of degenerative conditions that can manifest themselves in different ways such as joint and back pain, as well as deficiencies in skeletal bone quality, and ultimately result in significant suffering and reduced quality of life. Convincing data now exist to support a detrimental role for HTRA1 in the pathogenesis of joint and intervertebral disk degeneration. However, the function of HTRA1 in other closely related musculoskeletal diseases affecting bone and muscle remains unclear and largely unexplored. To help set the stage for future research, we discuss here some of the recent advances in our understanding of the role played by HTRA1 in musculoskeletal pathology.

[A new therapeutical option for chronic inflammation in rheumatology: janus kinases inhibitors (JAK)]. / Rhumatologie. Une nouvelle option thérapeutique dans la prise en charge de l'inflammation chronique en rhumatologie: les inhibiteurs des janus kinases.

In the last 15 years, the therapeutical options for the treatment of chronic inflammatory diseases in rheumatology have increased a lot. Nevertheless, some patients do not respond or respond partially to the current therapies--including to the biologics therapy. Tofacitinib (Xeljanz) is now on the Swiss market. It inhibits the JAK pathway. Tofacitinib--as monotherapy or with methotrexate--improves the control of rheumatoid arthritis (RA). In a comparative study, tofacitinib was as effective as adalimumab. Further, tofacitinib reduced structural damages in RA and is considered as an alternative, in case of non-response, to anti-TNF and probably to other biologics therapy. The side effects are upper respiratory tract and opportunist infections and tuberculosis. Blood count, lipids, kidney function, liver tests, CK and blood pressure have to be monitored.

Granzyme serine proteases in inflammation and rheumatic diseases.

Granzymes (granule-secreted enzymes) are a family of serine proteases that have been viewed as redundant cytotoxic enzymes since their discovery more than 30 years ago. Predominantly produced by cytotoxic lymphocytes and natural killer cells, granzymes are delivered into the cytoplasm of target cells through immunological synapses in cooperation with the pore-forming protein perforin. After internalization, granzymes can initiate cell death through the cleavage of intracellular substrates. However, evidence now also demonstrates the existence of non-cytotoxic, pro-inflammatory, intracellular and extracellular functions that are granzyme specific. Under pathological conditions, granzymes can be produced and secreted extracellularly by immune cells as well as by non-immune cells. Depending on the granzyme, accumulation in the extracellular milieu might contribute to inflammation, tissue injury, impaired wound healing, barrier dysfunction, osteoclastogenesis and/or autoantigen generation.

The pleiotropic effects of the hydroxy-methyl-glutaryl-CoA reductase inhibitors in rheumatologic disorders: a comprehensive review.

The hydroxy-methyl-glutaryl-CoA reductase inhibitors (statins) are used extensively in the treatment for hyperlipidemia. They have also demonstrated a benefit in a variety of other disease processes, including a wide range of rheumatologic disorders. These secondary actions are known as pleiotropic effects. Our paper serves as a focused and updated discussion on the pleiotropic effects of statins in rheumatologic disorders and emphasizes the importance of randomized, placebo-controlled trials to further elucidate this interesting phenomenon.

Role of the eNOS Uncoupling and the Nitric Oxide Metabolic Pathway in the Pathogenesis of Autoimmune Rheumatic Diseases.

Atherosclerosis and its clinical complications constitute the major healthcare problems of the world population. Due to the central role of endothelium throughout the atherosclerotic disease process, endothelial dysfunction is regarded as a common mechanism for various cardiovascular (CV) disorders. It is well established that patients with rheumatic autoimmune diseases are characterized by significantly increased prevalence of cardiovascular morbidity and mortality compared with the general population. The current European guidelines on cardiovascular disease (CVD) prevention in clinical practice recommend to use a 1,5-factor multiplier for CV risk in rheumatoid arthritis as well as in other autoimmune inflammatory diseases. However, mechanisms of accelerated atherosclerosis in these diseases, especially in the absence of traditional risk factors, still remain unclear. Oxidative stress plays the major role in the endothelial dysfunction and recently is strongly attributed to endothelial NO synthase dysfunction (eNOS uncoupling). Converted to a superoxide-producing enzyme, uncoupled eNOS not only leads to reduction of the nitric oxide (NO) generation but also potentiates the preexisting oxidative stress, which contributes significantly to atherogenesis. However, to date, there are no systemic analyses on the role of eNOS uncoupling in the excess CV mortality linked with autoimmune rheumatic diseases. The current review paper addresses this issue.

Human anti-alpha-enolase antibody in sera from patients with Behçet's disease and rheumatologic disorders.

OBJECTIVE: alpha-Enolase is a target antigen of IgM-type anti-endothelial cell antibody in patients with Behçet's disease (BD). The objective of this study was to assess the reactivity of serum anti-alpha-enolase antibodies in BD and in other rheumatologic diseases, and to evaluate the clinical significance of serum anti-alpha-enolase antibodies in BD. METHODS: Enzyme-linked immunosorbent assay (ELISA) and immunoblotting were used to examine serum samples from patients with BD (n=100), systemic lupus erythematosus (SLE) (n=50), systemic sclerosis (n=21), rheumatoid arthritis (RA) (n=20), Takayasu's arteritis (n=20), dermatomyositis (n=17), mixed connective tissue disease (MCTD) (n=11), and samples from healthy volunteer donors (n=23). The medical records of patients with BD were reviewed to investigate their clinical characteristics. RESULTS: Specific positive signals against recombinant human alpha-enolase were detected by IgM ELISA of serum samples from 56 of the 100 BD patients (56.0%), 24 of the 50 SLE patients (48.0%), 15 of the 21 systemic sclerosis patients (71.4%), 13 of the 20 RA patients (65.0%), 10 of the 20 Takayasu's arteritis patients (50.0%), 9 of the 17 dermatomyositis patients (52.9%), and 5 of the 11 MCTD patients (45.5%). The number of BD patients with vascular lesions was significantly higher in the anti-alpha-enolase antibody positive group than in the negative group (p=0.027). CONCLUSION: We demonstrated the reactivities of serum anti-alpha-enolase antibodies in BD and other rheumatologic diseases with moderate specificity and also found that serum anti-alpha-enolase antibodies in BD can be associated with vascular system involvement.

Basic science for the clinician 48: tyrosine kinases in disease: the potential for inhibitors in the treatment of immunologic diseases.

The magic bullet--a compound that will stop a disease dead in its tracks by specifically targeting the underlying pathogenic principle of that disease--is what every designer/developer of drugs wants. As cellular and molecular biology research delves deeper into how cells are activated by their ligands, the intracellular pathways of activation of individual cellular processes become better known and more attractive therapeutic targets. The receptors for transforming growth factor beta (TGFbeta) and platelet-derived growth factor (PDGF) activate a variety of cells via a series of tyrosine kinases; inhibition of specific tyrosine kinases has until recently been within the domain of oncologists, treating leukemia, and certain gastrointestinal tumors, but now there is mounting evidence that these agents might be of value in rheumatologic and autoimmune diseases. This is another example of "Better living (and curing!) through chemistry" that we as clinicians need to master to render optimal care.

Human autoantibodies to poly(adenosine diphosphate-ribose) polymerase recognize cross-reactive epitopes associated with the catalytic site of the enzyme.

The factors responsible for the production of autoantibodies against self-components are not well understood. We have identified monospecific human autoantibodies to poly(ADP-ribose) polymerase (ADPRP) in the sera of rheumatic patients. Since this nuclear enzyme has been extensively characterized, and its entire structure is known, we could investigate in detail the epitope specificity of the human autoantibodies, and their effects on the biological functions of the enzyme. All sera with autoantibodies to ADPRP recognized the NAD-binding domain of the enzyme, as demonstrated by either immunoblotting or immunoprecipitation of partially proteolyzed ADPRP. The autoantibodies also inhibited the catalytic activity of the purified enzyme, as measured by the transfer of ADP-ribose from [32P]NAD to either histones or to ADPRP itself. Because comparative structural analyses have shown that the active sites of enzymes are often conserved during evolution, we tested the ability of the autoantibodies to react with ADPRP from lower eukaryotes. The human autoantibodies reacted with ADPRP in cellular extracts from mammalian, avian, amphibian, arthropod, and protozoan cells, and also inhibited the catalytic activity of the various enzymes. Collectively, these experiments indicate that the human autoantibodies to ADPRP recognize a distinct group of evolutionarily conserved antigenic determinants that are closely related to the catalytic site of the enzyme. The results are consistent with the hypothesis that the epitope selectivity of human autoantibodies to ADPRP is influenced by cross-reactive antigens in the external environment.

[The profile and clinical significance of azathioprine metabolic enzymes activity in rheumatological patients].

OBJECTIVE: To detect the activity of thiopurine methyltransferase (TPMT) and its relationship with azathioprine (AZA) tolerance. METHODS: 200 patients of rheumatism need AZA were included in the study. RBC TPMT activity was detected with high performance liquid chromatography. Then the patients took AZA doses of 50 mg/d for the first month, 100 mg/d for the second month and 150 mg/d for the third month. RESULTS: TPMT activity of 200 patients ranged from 0.75 - 32.35 U/ml RBC, averaged (12.04 +/- 6.90) U/ml RBC. The activity of TPMT showed a normal skewness distribution and no activity deficiency was founded. 194 patients (97%) completed the 3 month follow-up. 18 showed bone marrow depression including 2 severe hematological crisis and 6 showed hepatic damage during the 3 months. Bone marrow depression was recorded of 7 cases with the TPMT activity of 2.24 - 5.97 U/ml RBC, averaged (3.47 +/- 1.21) U/ml RBC, among the dose of 50 mg/d and 11 cases with the TPMT activity of 4.01 - 11.17 U/ml RBC, averaged (7.08 +/- 2.58) U/ml RBC, among the dose of 100 - 150 mg/d. The other 176 cases did not show bone marrow depression at all, with TPMT activity of 4.47 - 32.35 U/ml RBC, averaged (13.02 +/- 6.07) U/ml RBC. TPMT activities in the 3 groups of patients were significantly different according to statistical analysis (P < 0.01). CONCLUSIONS: Hematological side effects were highly associated with TPMT activity in AZA usage. Patients with low TPMT activity should use low dose of AZA routinely, even though, toxicity may occur. Test of TPMT activity before AZA description was of significance.

Activation of mTOR (mechanistic target of rapamycin) in rheumatic diseases.

Mechanistic target of rapamycin (mTOR, also known as mammalian target of rapamycin) is a ubiquitous serine/threonine kinase that regulates cell growth, proliferation and survival. These effects are cell-type-specific, and are elicited in response to stimulation by growth factors, hormones and cytokines, as well as to internal and external metabolic cues. Rapamycin was initially developed as an inhibitor of T-cell proliferation and allograft rejection in the organ transplant setting. Subsequently, its molecular target (mTOR) was identified as a component of two interacting complexes, mTORC1 and mTORC2, that regulate T-cell lineage specification and macrophage differentiation. mTORC1 drives the proinflammatory expansion of T helper (TH) type 1, TH17, and CD4(-)CD8(-) (double-negative, DN) T cells. Both mTORC1 and mTORC2 inhibit the development of CD4(+)CD25(+)FoxP3(+) T regulatory (TREG) cells and, indirectly, mTORC2 favours the expansion of T follicular helper (TFH) cells which, similarly to DN T cells, promote B-cell activation and autoantibody production. In contrast to this proinflammatory effect of mTORC2, mTORC1 favours, to some extent, an anti-inflammatory macrophage polarization that is protective against infections and tissue inflammation. Outside the immune system, mTORC1 controls fibroblast proliferation and chondrocyte survival, with implications for tissue fibrosis and osteoarthritis, respectively. Rapamycin (which primarily inhibits mTORC1), ATP-competitive, dual mTORC1/mTORC2 inhibitors and upstream regulators of the mTOR pathway are being developed to treat autoimmune, hyperproliferative and degenerative diseases. In this regard, mTOR blockade promises to increase life expectancy through treatment and prevention of rheumatic diseases.

Effect of cartilage proteoglycans on human collagenase activities.

No significant inhibition of purified rheumatoid synovial collagenase was found when this enzyme was assayed in the presence of porcine or human cartilage proteoglycans. Reaction mixtures containing up to twice the amount of proteoglycan compared to that of collagen, w/w, had little effect on collagen degradation as judged by the reconstituted [4C]collagen fibril assay and polyacrylamide gel electrophoresis. Proteoglycans were not degraded by the synovial collagenase preparation. Although the human collagenases derived from rheumatoid synoviam, gastric mucosa, skin and granulocytes showed some reduction in activity when exposed to aggregated proteoglycans at high concentrations, disaggregated proteoglycans had no inhibitory effect. It is concluded that cartilage proteoglycans do not directly inhibit human collagenases in vitro, but in vivo they may provide some physical barriers which might limit the accessibility of the enzyme to its collagen substrate.

Connective tissue lysozyme in health and disease.

As the lysozyme story continues to unfold, rheumatic disease is one area where the study of this fascinating protein will be most important. The special biochemical features of lysozyme--its hexosaminidase function, its ability to bring about transglycosylation, its homology to alpha-lactalbumin, and its cationic nature--suggest that the connective tissues may prove to be the key to the understanding of the function of lysozyme. As methods for its accurate measurement become standardized, better data on the activity of the enzyme in various tissues and body fluids, in both health and disease, will be forthcoming. As additional studies are done to ascertain which of the hypothetical functions attributed to lysozyme are of significance in vivo, it will be the student of the connective tissues and the diseases thereof who can be expected to profit most from an udnerstanding of the role of lysozyme in mammalian biology.

Cyclooxygenase 1 and 2 in rheumatic disease: implications for nonsteroidal anti-inflammatory drug therapy.

OBJECTIVES: Prostaglandin synthase (cyclooxygenase) is now known to exist in two separate isoforms, termed prostaglandin synthase 1 and 2 (or COX1 and COX2). This has prompted a dramatic increase in research regarding the contribution of these isoforms to inflammatory disease and their relationship to the efficacy and safety of nonsteroidal anti-inflammatory drugs (NSAIDs). The emerging picture is that COX1 is responsible for maintaining prostaglandin synthesis in the gastric mucosa, platelets, and kidney, whereas COX2 is responsible for prostaglandin production in inflamed tissues, including rheumatoid arthritis (RA) synovium. This review examines the validity of the hypothesis that NSAIDs exhibiting selectivity for COX2 demonstrate an improved safety and efficacy profile when compared with NSAIDs exhibiting selectivity for COX1. METHODS: Literature on the efficacy and safety (gastric, renal, and hemostatic) of various NSAIDs are compared with published data on their relative COX1 and COX2 in vitro specificity. RESULTS: No differences in clinical efficacy are evident between NSAIDs exhibiting preferential activity for either COX1 or COX2. NSAIDs representing the extremes in terms of selectivity for COX1 or COX2 do exhibit some differences with respect to gastric, renal, and hemostatic safety; those exhibiting a preferential action on COX2 are generally less toxic than those exhibiting a preferential activity on COX1. Exceptions do exist. CONCLUSIONS: There is some support for the hypothesis that NSAIDs exhibiting a preferential action on COX2 are safer than those exhibiting a preferential activity on COX1, but there exists no support for improved efficacy. A strict correlation does not exist between the COX1 and COX2 specificity and the gastric, renal, and hemostatic toxicity of NSAIDs. This lack of correlation is believed to stem from the fact that both the safety and efficacy of NSAIDs may result from mechanisms distinct from prostaglandin inhibition. Preferential COX2 activity can reduce the level of toxicity for a given NSAID but may not be sufficient to overcome toxicities resulting from other mechanisms.

Increased levels of matrix metalloproteinase-3 in sera from patients with active lupus nephritis.

OBJECTIVE: To determine the matrix metalloproteinase-3 (MMP-3) levels in sera from patients with systemic lupus erythematosus (SLE) and to analyse the relationships between MMP-3 and clinical and laboratory features. METHODS: Serum MMP-3 levels were measured by an enzyme immunoassay in 124 patients with SLE and 237 patients with other systemic rheumatic diseases. RESULTS: The frequencies of patients with high MMP-3 levels were 76% in SLE and 82% in rheumatoid arthritis (RA). The level of MMP-3 in the SLE patients was 193.0 +/- 171.5 ng/ml (mean +/- SD) and was almost equal to the level in the RA patients (259.5 +/- 255.6 ng/ml). The MMP-3 levels were significantly higher in SLE patients who had a history of the following abnormalities: persistent proteinuria, cellular casts, anti-double stranded DNA antibodies, decreased C3, decreased creatinine clearance (p < 0.001), circulating immune complex (p < 0.01), malar rash, hypoalbuminemia, or decreased C4 (p < 0.05). The serum MMP-3 level in patients with SLE at admission showed direct correlations with serum uric acid, total cholesterol (p < 0.001), triglyceride, the white blood cell count, and the neutrophil count (p < 0.05), as well as inverse correlations with the total protein (p < 0.01), and IgG (p < 0.05). In SLE patients with active renal disease, the median MMP-3 level at admission and that at 6 months after admission were significantly higher than that at 6 months before admission. CONCLUSIONS: The increased level of serum MMP-3 in SLE is closely associated with clinical features relevant to lupus nephritis, suggesting that it plays a role in the pathogenesis of this condition.

Telomerase activity in the synovial tissues of chronic inflammatory and non-inflammatory rheumatic diseases.

Telomerase is a ribonucleoprotein complex which can compensate for telomeric loss originating from each cell division, and its activation plays a critical role in cellular immortality. We previously found that telomerase is activated not only in immortal cancer cells but also in activated lymphocytes. To assess the diagnostic significance of telomerase activity in RA synovial tissues, we quantitatively examined telomerase activity in synovial tissue samples obtained from 47 patients with RA, 31 with osteoarthritis (OA), and 23 with other joint diseases. Telomerase activity in synovial tissues was detected in 28 of 47 (59.6%) patients with RA, including monoarticular-type RA, but in none of those with other joint diseases except one case each of synovial chondromatosis and OA. Thus, the specificity of telomerase activity in synovial tissues for RA among joint diseases was 96.3% (52/54). In RA samples, the telomerase activity was detected in 14 of 27 (51. 9%) patients with total joint replacement, 7 of 12 (58.3%) open synovectomy cases, and 7 of 8 (87.5%) arthroscopic synovectomy cases. Detection of telomerase activity in synovial tissues is considered to be useful for diagnosis of RA, including monoarticular-type RA, or active inflammation with lymphocyte infiltration, and arthroscopy can be applied for this purpose.

Pyruvate kinase type tumor M2 plasma levels in patients afflicted with rheumatic diseases.

BACKGROUND: Since tumor markers can be increased in the course of many benign diseases, the aim of this study was to verify if this also occurs in the course of rheumatic diseases. MATERIALS AND METHODS: We investigated the incidence and characteristics of Tumor M2-PK in the EDTA-plasma of 137 patients suffering from rheumatic diseases. RESULTS: The tumor M2-PK concentration was increased in 52 out of 63 patients (82%) with classical rheumatoid arthritis, in 15 out of 21 patients (71%) with systemic lupus erythematosus, in 14 out of 17 patients (82%) with seronegative spondylarthritis and in 13 out of 28 patients with miscellaneous rheumatic diseases (46%). Malignant neoplasm was not detected in any of the patients with rheumatic diseases. CONCLUSION: These results demonstrated that the EDTA-plasma concentrations of Tumor M2-PK were increased in patients with rheumatic diseases.