Laboratory diagnosis of rheumatic diseases. Part 3: arthritides caused by infection

This third part of this series of articles on laboratory diagnostics of rheumatic diseases considers the rheumatic diseases caused by infection by microorganisms, or reactive arthritides.The basis for laboratory diagnostics of infection-reactive arthritides is the investigation of anti-infection antibodies. In some situations, DNA amplification methods may be helpful. Bacterially infected joints should be immediately examined by arthrocentesis and microscopic examination and laboratory culture of the synovial fluid.     

Laboratory diagnostics of systemic autoimmune diseases. Part 1. Collagenoses

This is the first part of a series of articles on the laboratory diagnostics of rheumatic diseases and will consider the systemic autoimmune diseases lupus erythematosus, Sj?gren's syndrome, systemic sclerosis, dermato/polymyositis and mixed connective tissue disease (MCTD, SHARP syndrome). The basis for diagnostics is the presence of antinuclear antibodies (ANA). Initially, these antibodies are detected using a screening test. This must be followed by the identification of the patient's individual autoantibody specificities, which then yields important diagnostic clues. Disease activity may be monitored serologically by following the titers of selected autoantibodies and, in certain patients, by examining complement consumption.     

High levels of antipeptidoglycan antibodies in psoriatic and other seronegative arthritides

Bacterial cell wall peptidoglycan, the arthritogenic factor in adjuvant induced arthritis, may also be involved in the etiology of some human rheumatic diseases. Patients with some seronegative rheumatic diseases like ankylosing spondylitis and Reiter's syndrome have elevated antibody titers to peptidoglycan. Using an ELISA with soluble peptidoglycan, we examined the sera of 110 patients with psoriatic arthritis, psoriasis without arthritis and a variety of other joint diseases. Antibody titers were significantly higher (p less than 0.001) among the 22 patients with psoriatic arthritis than the 16 patients with psoriasis without arthritis. Patients with other seronegative arthritides also had higher levels of antipeptidoglycan antibodies than patients with rheumatoid (seropositive) arthritis, osteoarthritis and crystal induced arthritis. Our results furnish additional support for the suggestion for a bacterial role in the pathogenesis of psoriatic and some other seronegative arthritides.     

Labordiagnostik der systemischen Autoimmunerkrankungen

This is the first part of a series of articles on the laboratory diagnostics of rheumatic diseases and will consider the systemic autoimmune diseases lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, dermato/polymyositis and mixed connective tissue disease (MCTD, SHARP syndrome). The basis for diagnostics is the presence of antinuclear antibodies (ANA). Initially, these antibodies are detected using a screening test. This must be followed by the identification of the patient’s individual autoantibody specificities, which then yields important diagnostic clues. Disease activity may be monitored serologically by following the titers of selected autoantibodies and, in certain patients, by examining complement consumption.     

New aspects of bacteriological pathogen diagnosis in rheumatic diseases

Microbiological diagnosis for rheumatic diseases is increasingly used as part of the diagnostic work-up in rheumatological practice due to growing knowledge about bacteria-induced rheumatic diseases. This review's focus lies on rheumatic diseases, which in contrast to septic-infectious arthritis, are characterized by the inability to culture bacteria from the inflammed joint. These reactive arthritides occur after primary extraarticular bacterial infection. The etiological diagnosis of reactive arthritis is based on the detection of a previous or ongoing bacterial infection. Diagnosis is performed by serology or direct detection of the bacterial organism or parts thereof at the site of entry and recently by molecularbiology-based detection of the bacteria in the inflamed joint. This review reflects the current diagnostic approaches and formulates diagnostic algorithms for specific and well-directed microbiological diagnosis.     

Laboratory diagnostics of systemic autoimmune diseases. Part II: rheumatoid arthritis and vasculopathies

This is the second part in a series of articles on the laboratory diagnostics of rheumatic diseases. It addresses rheumatoid arthritis, systemic, anti-neutrophil cytoplasmatic antibody (ANCA) positive vasculitides and antiphospholipid-syndrome. The diagnostics of rheumatoid arthritis has been substantially improved by the recently introduced assay for antibodies against citrullinated peptides. In addition, a number of vasculitides can be differentiated by the presence of ANCA. Beta2-glycoprotein I antibodies and lupus anticoagulants are at present the most specific markers for antiphospholipid syndrome. Inflammatory activity can be monitored by determining the levels of acute phase proteins and erythrocyte sedimentation rate, but only in some situations by measuring immunoglobulins and interleukins.     

Paf-acether acetylhydrolase activity is increased in patients with rheumatic diseases.

Paf-acether (platelet-activating factor) is a phospholipid described as a potent mediator of inflammatory response. We have recently shown that the level of paf bound to lipoproteins was significantly higher in the serum from patients with rheumatic diseases, compared to that of control subjects. In serum, paf is inactivated in part by a paf acetylhydrolase that catalyses the hydrolysis of the acetate residue. Acetylhydrolase activity was measured in the serum and synovial fluid of patients with rheumatoid arthritis and other arthritides, i.e. osteoarthritis and chondrocalcinosis. In serum, the activity of acetylhydrolase was significantly increased in patients with rheumatic diseases when compared with that in the control group. However, it was enhanced to a lesser degree in rheumatoid arthritis than in non inflammatory rheumatic diseases. These results suggest a role for acetylhydrolase in controlling paf levels in rheumatic diseases.     

Labordiagnostik der systemischen Autoimmunerkrankungen

This is the second part in a series of articles on the laboratory diagnostics of rheumatic diseases. It addresses rheumatoid arthritis, systemic, anti-neutrophil cytoplasmatic antibody (ANCA) positive vasculitides and antiphospholipid-syndrome. The diagnostics of rheumatoid arthritis has been substantially improved by the recently introduced assay for antibodies against citrullinated peptides. In addition, a number of vasculitides can be differentiated by the presence of ANCA. β2-glycoprotein I antibodies and lupus anticoagulants are at present the most specific markers for antiphospholipid syndrome. Inflammatory activity can be monitored by determining the levels of acute phase proteins and erythrocyte sedimentation rate, but only in some situations by measuring immunoglobulins and interleukins.     

5-HT3 receptor antagonist als analgetics in rheumatic diseases

Various rheumatic diseases like fibromyalgia, systemic inflammatory rheumatic disorders and localized diseases, such as arthritides and activated arthroses, tendinopathies and periarthropathies, as well as trigger points can be improved considerably by treatment with the 5-HT3 receptor antagonist tropisetron. Particularly in the latter group of diseases, local injections have done surprisingly rapid analgesic action. This effect matches that of local anesthetics, but lasts considerably longer and is comparable to local injections of local anesthetics combined with corticosteroids. The action of the 5-HT3 receptor antagonists can be attributed to an antinociceptive effect that occurs at the same time as an antiphlogistic and probably also an immunosuppressive effect. Whereas an inhibited release of substance P from the nociceptors, and possibly some other neurokins as well, seems to be the most likely explanation for the antinociceptive action, the antiphlogistic effect is primarily due to an inhibited formation of various different phlogistic substances; in some conditions, like systemic inflammatory rheumatic diseases, for example, the 5-HT3 receptor antagonists may exert an immunosuppressive effect in addition to this.     

The role of spa therapy in various rheumatic diseases

Spa therapy seems to have a role in the treatment of a broad range of joint diseases. It cannot substitute for conventional therapy but can complement it. The improvement reported in some of the studies is of short duration, lasting for months. It should be considered for patients suffering from various types of inflammatory arthritides or noninflammatory arthritides who are symptomatic, despite accepted medical therapy and conservative physiotherapy, if they can afford the expense. The patients should be told that the effectiveness and success of this therapy cannot be predicted in advance. Because we have no way to date, of curing most rheumatic diseases, clinical trials of alternative therapeutic methods are justified. These methods may alleviate patient suffering and are almost totally devoid of serious adverse effects. No studies have been reported that evaluate their cost-effectiveness.     

The detection of DNA from a range of bacterial species in the joints of patients with a variety of arthritides using a nested, broad-range polymerase chain reaction.

OBJECTIVE: Bacteria have been implicated in the pathogenesis of many types of inflammatory arthritides. The aim of this study was to identify any bacterial DNA in synovial fluid (SF) from patients with a range of inflammatory arthritides. METHODS: A highly sensitive, broad-range, nested polymerase chain reaction (PCR) protocol targeting the bacterial 16S rRNA gene was designed and applied to SF from 65 patients with a range of rheumatic diseases. RESULTS: Bacterial DNA was detected in 26 SF samples, including eight from patients with rheumatoid arthritis and five with juvenile arthritides. PCR products were identified by sequencing and searching of bacterial genomic databases; 'best fits' included Haemophilus influenzae, Bordetella and Yersinia. CONCLUSIONS: These finding suggest an association between bacterial infection and inflammatory arthritides in some patients. Further research is required to determine the role of these organisms in the pathogenesis and whether such patients might respond to prolonged antibiotic therapy.     

Miscellaneous neurologic, cardiac, pulmonary, and metabolic disorders with rheumatic manifestations.

This review discusses miscellaneous diseases with rheumatic manifestations, and out of necessity many rarities are delineated, eg, the Charcot-type joints accompanying congenital sensory neuropathy with anhidrosis or the little-known arthritides that can result from severe acne. Of more general interest is a recent study showing that rheumatic disorders may underlie many neurologic admissions. In cardiology, the main point of interest is a possible resurgence of acute rheumatic fever, occurring first in the United States. Physicians should be alert to this possibility, particularly with the importance of prophylactic antibiotics. Finger clubbing and hypertrophic osteoarthropathy remain unexplained manifestations of pulmonary disease provoking an "International Workshop" devoted to their study. Platelet-derived growth factors may be the favorite candidate. Metabolic disorders with rheumatic complaints include the storage diseases. Some advances in imaging and assessment have been made, and the benefits of liver transplantation are the subject of another report. Other small-print causes of rheumatic complaints include drug abuse, whose protean manifestations include many resembling vasculitic or granulomatous disease.     

Emerging role of metabolomics in rheumatology

The pursuit for understanding disease pathogenesis, in this age of rapid laboratory diagnostics and fast‐paced research, has led scientists worldwide to take recourse in hypothesis‐free approaches for molecular diagnosis. Metabolomics is one such powerful tool that explores comprehensibly the metabolic alternations in human diseases. It involves study of small molecules of less than 1 kD in size by either LSMS or nuclear magnetic resonance. Unlike genomics, which tells us what may have happened, metabolomics reflects what did happen. The NMR technique has an advantage of analyzing metabolites without sample preparation, thereby diminishing artifacts, is less cumbersome and with the latest database on Metabolome; about 30 000 metabolites can be identified. The study of metabolomics for several rheumatic diseases, including rheumatoid arthritis, lupus, osteoarthritis and vasculitis, has revealed distinctive metabolic signatures. Thus, metabolomics is a technique that promises precision medicine with better biomarkers, robust predictors of drug response and of disease outcome, discovery of newer metabolites and pathways in disease pathogenesis, and finally, targeted drug development. This review intends to decipher its relevance in common rheumatic diseases.     

Poststreptococcal reactive arthritis.

Five cases (three children and two young women) of sterile inflammatory arthritis are described, each preceded by a streptococcal infection. A throat swab from one patient grew group A, beta haemolytic streptococci, and in each case unequivocal evidence of seroreaction to streptococcal antigens was present. The long term outcome in all cases was excellent, though one patient (female, 24 years of age) required prophylactic penicillin for three months. The diagnosis of a definite recent streptococcal infection is sometimes difficult as throat swabs may be negative and the diagnostic serological reaction missed unless antibodies to multiple antigens (particularly antistreptolysin O and DNAase B) are tested. These cases may represent a reactive arthritis and should be distinguished from rheumatic fever, streptococcal septic arthritis, viral arthritides, acute rheumatic diseases such as juvenile chronic arthritis, and a monoarticular presentation of a seronegative spondyloarthropathy.     

Specialized and interdisciplinary team work in rheumatology

The large number of rheumatic diseases demands a clear differentiation between the individual forms of diseases. For this purpose are at first necessary knowledge concerning clinical criteria and in the second place knowledge about serological and radiological examinations. The serological programme shall be relevant to practice, consist of a basis diagnostics and for particular differential-diagnostic problems shall include specialized laboratory investigations. Necessary X-ray pictures must be performed with a special aim and comparison of the sides. For therapy the interdisciplinary team work, consisting in the cooperation of rheumatologists, orthopedic surgeons, specialized surgeons and physiotherapists stood the test. An important prerequisite is also the cooperation of the outpatient and inpatient rheumatological institution. For a complex rehabilitation programme apart from the physicians experienced coworkers for tasks of welfare, ergotherapy and physiotherapy are necessary.     

Clinical and pathologic aspects of arthritis due to Ross River virus and other alphaviruses

PURPOSE OF REVIEW: Arthritogenic alphaviruses are globally distributed mosquito-borne RNA viruses causing epidemics of polyarthritis/arthralgia, with disease emerging or reemerging and increasingly being reported in travelers. This article summarizes the current knowledge of these diseases, focusing on recent developments in the understanding of Ross River virus disease. RECENT FINDINGS: Alphaviral arthritides have often been blamed for protracted chronic illnesses. However, validated quality-of-life questionnaires and exhaustive searches for differential diagnoses showed that Ross River virus disease, although severe at onset, progressively resolved over 3 to 6 months. Many patients did experience long-term disease lasting more than 12 months, but in nearly all cases this was due to other conditions, primarily unrelated rheumatic conditions or depression. There is no indication that alphaviral arthritides predispose to other conditions; thus, patients whose Ross River virus disease has actually resolved may be underdiagnosed for other conditions. Ross River virus polyarthritis probably arises from inflammation associated with productive viral infections in synovial macrophages, which persist despite neutralizing antibodies and antiviral cytokine responses. Persistence may be facilitated by downregulation of cytokine responses by virus-antibody complexes binding to Fc receptors and induction of interleukin-10. How virus escapes neutralizing antibodies remains unclear but may involve phagocytosis of apoptotic virus-infected cells and infection of the phagocyte via the phagosome. SUMMARY: Diagnosis of alphaviral arthritides is complicated by nonspecific symptoms and the lack of commercial serodiagnostic kits, except for Ross River and Barmah Forest virus infections in Australia. Differential diagnoses should be actively pursued, especially if symptoms persist. Treatment with nonsteroidal anti-inflammatory drugs appears largely effective, with no evidence of long-term sequelae or relapse.     

Infection as a cause of arthritis.

The etiology of most rheumatic tissues is unknown; however, recent investigation into this area is rapidly providing new clues to the pathogenesis of many of these diseases. This article reviews several infectious agents (Epstein-Barr virus, parvoviruses, and mycobacteria) and the data supporting their roles in the etiology of rheumatoid arthritis. In addition, current data on the potential roles of Epstein-Barr virus and retroviruses in the etiologies of Sj?gren's syndrome and Kawasaki disease are also reviewed. Finally, the reactive arthritides, for which there is stronger evidence of an infectious etiology, are reviewed.     

Rheumatic diseases among Civil War troops

There are extensive existing medical records of Federal Civil War troops. More than 160,000 cases of "acute rheumatism" occurred among these soldiers, and acute rheumatic fever was known to be the main cause. Infectious arthritides were frequent but not understood; gout was rare. "Chronic rheumatism" was diagnosed more than 246,000 times; prolonged rheumatic fever and reactive arthritis following dysentery were probably the major causes. Over 12,000 soldiers were discharged because of chronic rheumatism, many with "lumbago," which was probably spondylarthropathy.     

The relationships between cancer and autoimmune rheumatic diseases

Links between autoimmune rheumatic diseases and cancer continue to be elucidated. In this review, we explore this complex, bidirectional relationship. First, the increased risk of cancer across the breadth of the autoimmune rheumatic diseases is described. The magnitude of risk and types of tumors seen can differ by the type of autoimmune disease, timing of disease course, and even clinical and laboratory features within a particular autoimmune disease, suggesting that targeted cancer screening strategies can be considered. Multiple mechanisms linking autoimmune rheumatic diseases and cancer are discussed, including the development of autoimmunity in the context of naturally occurring anti-tumor immune responses and malignancy arising in the context of inflammation and damage from autoimmunity. Immunosuppression for rheumatic disease can increase risk for certain types of cancers. Finally, immune checkpoint inhibitors, a type of cancer immunotherapy, which cause a variety of inflammatory syndromes of importance to rheumatologists, are reviewed.