Hereditary disorders mimicking and/or causing premature osteoarthritis.

Osteoarthritis is the most common joint disease, causing considerable disability and impairment of quality of life. Hereditary osteochondrodysplasias and some inborn errors of metabolism may mimic or cause premature osteoarthritis. Osteochondrodysplasias usually cause joint deformities, such as coxa vara or genu varum, which can cause abnormal biomechanics. In most of these disorders, the articular cartilage is originally defective as a result of genetically determined collagen or matrix protein abnormalities, or the deposition of mucopolysaccharides. In the case of inborn errors of metabolism, the pathological process affects healthy articular structures, causing secondary osteoarthritis. In alkaptonuria, the pathological deposition of polymerized homogenistic acid causes defective changes in cartilage, articular capsule and tendons. In Wilson's disease, the premature osteoarthritis might be caused by the copper deposition. It is worth paying attention to these rare disorders, even when they are mild or incomplete, because early diagnosis can lead to prevention and effective treatment. In addition, research is discovering the specific gene defects and molecular abnormalities that are responsible for disease expression. This may in turn lead to opportunities for prenatal diagnosis; thus, genetic counselling and gene replacement therapy may be a realistic possibility in the near future.     

Do we need radiographs to diagnose osteoarthritis?

The usefulness of plain radiography in the diagnosis of osteoarthritis is reviewed. While plain radiography is frequently used to define osteoarthritis in research and is traditionally discussed as a diagnostic modality in clinical practice, recent magnetic resonance imaging studies suggest that plain radiography has limited ability to detect osteoarthritic features at an early stage of disease such as might be encountered in general practice. Nevertheless, X-rays do play a role in the diagnostic process in general practice, but their usefulness relates more importantly to the exclusion of other diagnostic possibilities rather than confirmation of disease. More research is needed to develop diagnostic tools for osteoarthritis, particularly in clinical practice, as well as algorithms and guidelines for use of plain radiography in patients with chronic joint pain.     

Osteoarthritis: an update with relevance for clinical practice

Osteoarthritis is thought to be the most prevalent chronic joint disease. The incidence of osteoarthritis is rising because of the ageing population and the epidemic of obesity. Pain and loss of function are the main clinical features that lead to treatment, including non-pharmacological, pharmacological, and surgical approaches. Clinicians recognise that the diagnosis of osteoarthritis is established late in the disease process, maybe too late to expect much help from disease-modifying drugs. Despite efforts over the past decades to develop markers of disease, still-imaging procedures and biochemical marker analyses need to be improved and possibly extended with more specific and sensitive methods to reliably describe disease processes, to diagnose the disease at an early stage, to classify patients according to their prognosis, and to follow the course of disease and treatment effectiveness. In the coming years, a better definition of osteoarthritis is expected by delineating different phenotypes of the disease. Treatment targeted more specifically at these phenotypes might lead to improved outcomes.     

Aging theories of primary osteoarthritis: from epidemiology to molecular biology

Osteoarthritis is the most common disabling condition of humans in the western world. It has been known for a very long time that aging is the most prominent risk factor for the initiation and progression of the disease, but the explanations for this phenomenon have changed over time. The most longstanding theory is that osteoarthritis develops because of continuous mechanical wear and tear. However, osteoarthritis can also be the result of time/age-related modifications to cartilage matrix components. One of the simplest biological explanations for the initiation and progression of osteoarthritic cartilage degeneration is a mere loss of viable cells, due to apoptosis or other mechanisms. Overall, the most likely scenario is that the cells and the matrix of articular cartilage get older over time, and eventually the tissue enters a senescence-like state that makes it more prone to enter the osteoarthritic degeneration pathway. Thus, patients with osteoarthritis might progress more quickly to the senescence phenotype compared to others. Moreover, stressful conditions associated with the osteoarthritic disease process might further promote chondrocyte senescence. Primary osteoarthritis in this model would be a "premature" degeneration of the joint due to a premature chondrocyte senescence. By analogy to neurodegenerative disorders, one could refer to osteoarthritis as the "M. Alzheimer" of articular cartilage. One of the most important implications of this hypothesis is that it points to issues of cellular degeneration as the basis for understanding the initiation and progression of osteoarthritis. Equally important, it emphasizes that whatever treatment we envisage for osteoarthritis, we must take into account that we are dealing with aged/(pre)senescent cells that no longer have the ability of their juvenile counterparts to counteract the many mechanical, inflammatory, and/or other assaults to the tissue.     

Diagnosis and differential diagnoses of osteoarthritis by radiography, CT, MRI, and RI

Osteoarthritis is a disease of high occurrence; moreover, with increase of the elderly population, proper diagnosis and suitable treatment are vital. Proper diagnosis necessitates not only detailed patient history and clinical examination, but, most importantly, proper knowledge of radiological findings. This article presents the radiological examinations necessary for diagnosis of osteoarthritis, including X-ray, CT, contrast X-ray, MRI and RI. Important differential diagnoses are also presented.     

Laboratory diagnosis of rheumatoid arthritis. Prospective study of 85 patients.

Because early diagnosis of rheumatoid arthritis is difficult increasingly important, we have assessed the value of laboratory investigation in 85 patients with knee effusions studied from presentation and followed for sufficiently long periods to allow a definite diagnosis. Histopathology on needle biopsy specimens narrowed the differential diagnosis to rheumatoid arthritis and closely related conditions even at an early stage of disease and also allowed recognition of other conditions which would not otherwise have been detected. Immunofluorescence on similar specimens further narrowed differential diagnosis since the presence of IgM was found to be very suggestive of rheumatoid arthritis. Other tests were of less value. It is concluded that laboratory investigation can improve diagnostic sensitivity and specificity in relatively early rheumatoid arthritis.     

Use of biochemical markers to study and follow patients with osteoarthritis

Osteoarthritis is characterized by progressive destruction of articular cartilage and subchondral bone and synovial reaction. Radiologic findings that form the basis of the diagnosis of osteoarthritis are poorly sensitive to detect early disease and for monitoring progression of joint damage. Blood-based proteomic analyses suggest that biochemical alterations can be observed well before radiologic damage is evidenced. New cartilage-specific markers, including assays for type II collagen synthesis and degradation, have been developed. Recent prospective studies indicate that blood and urine levels of these new markers are associated with progression of joint damage. Biological markers respond rapidly to treatment and therefore will certainly play an important role in the development and the monitoring of disease-modifying therapies. Because osteoarthritis involves different tissues and complex biologic processes, a combination of different biochemical markers appears to be the most promising diagnostic strategy.     

Targeted disruption of Mig-6 in the mouse genome leads to early onset degenerative joint disease

Degenerative joint disease, also known as osteoarthritis, is the most common joint disorder in human beings. The molecular mechanism underlying this disease is not fully understood. Here, we report that disruption of mitogen-inducible gene 6 (Mig-6) in mice by homologous recombination leads to early onset degenerative joint disease, which is revealed by simultaneous enlargement and deformity of multiple joints, degradation of articular cartilage, and the development of bony outgrowths or osteophyte formation within joint space. The osteophyte formation appears to be derived from proliferation of mesenchymal progenitor cells followed by differentiation into chondrocytes. Absence of the Rag2 gene does not rescue the joint phenotype, excluding a role for the acquired immune system in the development of this disease. Our results provide insight into the mechanism of osteoarthritis by showing that loss of Mig-6 leads to early onset of this disease, implying that this gene or its pathway is important in normal joint maintenance. Because of the striking similarity of osteoarthritis in humans and mice, the Mig-6 mutant mouse should provide a useful animal model for studying the mechanism of this disease and for testing drugs or therapies for treating osteoarthritis.     

Clinical signs of early osteoarthritis: reproducibility and relation to x ray changes in 541 women in the general population.

The definition and classification of early clinically apparent osteoarthritis both in clinical situations and in epidemiological surveys remains a problem. Few data exist on the between-observer reproducibility of simple clinical methods of detecting hand and knee osteoarthritis in the population and their sensitivity and specificity as compared with radiography. Two observers first studied the reproducibility of a number of clinical signs in 41 middle aged women. Good rates of agreement were found for most of the clinical signs tested (kappa = 0.54-1.0). The more reproducible signs were then tested on a population of 541 women, aged 45-65, drawn from general practice, screening centres, and patients previously attending hospital for non-rheumatic problems. The major clinical signs used had a high specificity (87-99%) and lower sensitivity (20-49%) when compared with radiographs graded on the Kellgren and Lawrence scale (2+ = positive). When analysis was restricted to symptomatic radiographic osteoarthritis, levels of sensitivity were increased and specificity was lowered. These data show that certain physical signs of osteoarthritis are reproducible and may be used to identify clinical disease. They are not a substitute for radiographs, however, if radiographic change is regarded as the 'gold standard' of diagnosis. As the clinical signs tested seemed specific for osteoarthritis they may be of value in screening populations for clinical disease.     

Adrenal incidentalomas and subclinical Cushing’s syndrome

The issue of cortisol secretion by adrenal masses discovered incidentally in the course of evaluation for an unrelated reason (Subclinical Cushing’s Syndrome) is among the most controversial and contentious issues in clinical endocrine practice. This derives from our relatively poor ability to accurately determine clinically those at increased risk among the majority who are not, the significant limitations of available diagnostic tests, the lack of a gold standard for diagnosis or even universally agreed criteria for diagnosis. A consensus for diagnostic criteria would be a good first step on which to base the kinds of studies needed to address our uncertainties. In the meantime, we must be careful to recognize the limitations of the current evidence avoid the pitfalls of overestimation of disease prevalence and of the benefits of therapy resulting from advances in diagnostic imaging and sophisticated laboratory testing. There remains an essential role for clinical judgment.     

Diagnostik und Therapie der frühen Psoriasis-Arthritis

Early diagnosis of psoriatic arthritis is of importance because an erosive disease is already detectable after a 2-year duration of symptoms. Often psoriatic arthritis cannot easily be detected because of the diversity of disease manifestations in early stages. As up to 30% of psoriasis patients develop psoriatic arthritis an interdisciplinary dermatologic/rheumatologic approach to diagnose findings and treatment decisions would be desirable. Screening tools, such as validated questionnaires allow an early detection and selection of patients with a high probability of psoriatic arthritis even in dermatological care or on a house physician basis. The implementation of the CASPAR criteria as a classification tool for psoriatic arthritis has also improved the diagnosis finding in patients with a recent onset of active musculoskeletal disease. Data from early psoriatic arthritis cohorts illustrate that drug-free remission is rare. An adequate treatment is of importance. The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) has developed treatment recommendations based on the available evidence for different treatment modalities.     

Evidence for familial aggregation of hand, hip, and spine but not knee osteoarthritis in siblings with multiple joint involvement: the GARP study

OBJECTIVE: To evaluate whether familial aggregation of osteoarthritis differs by joint site in a sibling pair study (GARP) of patients with osteoarthritis at multiple sites. SUBJECTS: White Dutch probands aged 40 to 70 years and their siblings with primary osteoarthritis at multiple sites. METHODS: The diagnosis of knee, hip, and spine osteoarthritis was based on a combination of pain or stiffness on most days of the previous month and osteophytes or joint space narrowing on x ray. Hand osteoarthritis was defined by ACR criteria. Odds ratios (OR) were calculated for siblings and probands sharing disease in the same joints. RESULTS: 191 sibling pairs were included (85% women; mean age 60 years). In the probands, osteoarthritis was present in spine (76%), hands (77%), knees (37%), and hips (26%). The most common combinations in probands were spine-hand (59%), spine-knee (27%), and hand-knee (25%). The OR adjusted for age, sex, and body mass index for siblings to be affected in the same joint sites as the proband were increased in osteoarthritis of the hand (OR = 4.4 (95% confidence interval, 2.0 to 9.5)), hip (OR = 3.9 (1.8 to 8.4)), spine (OR = 2.2 (1.0 to 5.1)), hip-spine (OR = 4.7 (2.1 to 10.4)), and hand-hip (OR = 3.4 (1.1 to 10.4)). Siblings of probands with osteoarthritis in the knee did not have an increased likelihood of knee osteoarthritis. CONCLUSIONS: In middle aged patients with familial osteoarthritis at multiple sites, familial aggregation of osteoarthritis was most striking for hand and hip but remarkably absent for the knee.     

Clinical, serological and genetic predictors of inflammatory bowel disease course

Patients with extensive or complicated Crohn's disease (CD) at diagnosis should be treated straightaway with immunosuppressive therapy according to the most recent guidelines. In patients with localized and uncomplicated CD at diagnosis, early use of immunosuppressive therapy is debated for preventing disease progression and limiting the disabling clinical impact. In this context, there is a need for predictors of benign or unfavourable subsequent clinical course, in order to avoid over-treating with risky drugs those patients who would have experienced spontaneous mid-term asymptomatic disease without progression towards irreversible intestinal lesions. At diagnosis, an age below 40 years, the presence of perianal lesions and the need for treating the first flare with steroids have been consistently associated with an unfavourable subsequent 5-year or 10-year clinical course. The positive predictive value of unfavourable course in patients with 2 or 3 predictors ranges between 0.75 and 0.95 in population-based and referral centre cohorts. Consequently, the use of these predictors can be integrated into the elements that influence individual decisions. In the CD postoperative context, keeping smoking and history of prior resection are the strongest predictors of disease symptomatic recurrence. However, these clinical predictors alone are not as reliable as severity of early postoperative endoscopic recurrence in clinical practice. In ulcerative colitis (UC), extensive colitis at diagnosis is associated with unfavourable clinical course in the first 5 to 10 years of the disease, and also with long-term colectomy and colorectal inflammation-associated colorectal cancer. In patients with extensive UC at diagnosis, a rapid step-up strategy aiming to achieve sustained deep remission should therefore be considered. At the moment, no reliable serological or genetic predictor of inflammatory bowel disease clinical course has been identified.     

Winning the battle, losing the war? Another editorial about rheumatoid arthritis

Major advances in the therapy of RA will likely require future scientific breakthroughs in the understanding of pathophysiology. That is not to suggest that clinical investigations should be put on hold while the entire focus of research shifts to the laboratory bench. Clinical studies of very early RA, including early treatment interventions, would appear to be of major importance. However, better characterization of the early clinical course and identification of pathologic markers of progressive disease are needed before formal randomized treatment studies of early disease can be initiated. The entire role of aggressive management, particularly with combination chemotherapy, at any stage of RA is in desperate need of answers. In clinical practice it would appear that combination chemotherapy is widely used, often as a last resort in treatment resistant patients who have failed conventional therapies. The published clinical studies would seem to support, but certainly not prove, a valuable potential role for combination chemotherapy in this setting. Moreover, the studies seem to indicate some increased risk of drug toxicities, the limitations of which are not readily apparent for most combinations. Based on the successes observed in these patients that are very difficult to treat, the possibility of a more fundamental role of combination chemotherapy in treatment of the disease has been advocated. These questions need to be resolved by well designed, randomized controlled trials. There is an urgent need to do the trials soon before combination chemotherapy gains an even stronger foothold in therapy.     

Frühdiagnose von Spondyloarthritiden mit besonderer Betonung auf die axialen Formen

The axial spondyloarthritis (SpA) is the most important disease out of the whole group of SpA. If a sacroiliits is clearly detectable by x-rays a diagnosis of ankylosing spondylitis can be made. However, there is still a delay of 5-10 years from the first symptoms until a final diagnosis is made. An important reason for this is the fact that radiological changes are often only detectable after several years of disease, despite the presence of inflammation as detected by MRI and the presence of clinical manifestations such as pain and stiffness. An early diagnosis becomes more and more important because effective therapies have become available which are probably even more effective if given early. New strategies how to make an early diagnosis and how primary care physicians can screen for these patients are discussed.     

Filamentous phage as vector-mediated antibody delivery to the brain

Early diagnosis of Alzheimer's disease is prevented by lack of means to visualize and target beta amyloid plaques in the brains of affected people. There are many methods of detecting amyloid plaques by staining postmortem brain tissue, but none are available for monitoring in living patients. We propose anti-beta amyloid antibodies as a highly specific probe to monitor amyloid plaque formation in living patients. Intranasal administration of filamentous phage as delivery vector of anti-beta amyloid antibody fragment into Alzheimer's APP transgenic mice enables in vivo targeting of beta amyloid plaques. The plaques were co-visualized both by thioflavin-S and fluorescent-labeled anti-phage antibodies in the olfactory bulb and the hippocampus region. The genetically engineered filamentous bacteriophage proved to be an efficient and nontoxic viral delivery vector to the brain, offering an obvious advantage over other mammalian vectors. The ability to image A beta deposits in vivo would arguably provide the most useful diagnostic and monitoring test for early diagnosis of Alzheimer's disease.     

Pathologic features of early inflammatory bowel disease

Often the pathologic changes of IBD are subtle and may not be present in a proportion of biopsy specimens. In cases of early disease, the changes may be missed, and additional specimens should be taken after a period of time. Modifying factors, such as prebiopsy treatment and coexisting disease, should be considered. A forum to review cases and allow for communication between gastroenterologists and pathologists is especially useful for clinicopathologic correlation and assignment of a working diagnosis to each case. Careful attention to the pathologic features of early UC and CD would be most useful when evaluating new therapies for IBD.     

Miscellaneous non-inflammatory musculoskeletal conditions. Musculoskeletal conditions associated with Wilson's disease

Wilson's disease (WD) is a rare disease, defined as an autosomal recessive disorder characterised by release of free copper and dramatic accumulation of intracellular hepatic copper with subsequent hepatic and central nervous system abnormalities. Mutations of the ATP7B gene are responsible for the metabolic dysfunction. Small open studies have reported spinal radiological abnormalities including scoliosis, diffuse bone demineralisation, osteochondritis and occasionally fracture. Prevalence of osteoporosis in young adult patients is debated, ranging from 10%, with normal mean Z-score values, to 43% in adults. Past history of spinal or peripheral fractures might be present in 50% of patients. Articular disorders include arthralgias of large joints, such as knee pain, rare effusions, early onset of radiological features of osteoarthritis and associated osteochondritis of the knee joint. Radiological chondrocalcinosis, an unusual feature in young adults, has to be confirmed. Few patients may develop drug-induced lupus with arthralgias, positive anti-nuclear and anti-histone antibodies, secondary to D-penicillamine, the major copper chelator used in WD. In this orphan disease, small retrospective studies cannot allow ascertaining definite WD-related articular and bone manifestations. However, such clinical and radiological abnormalities are occasionally the first symptoms leading to diagnosis. Physicians should be aware that unexplained joint pain and effusion, or even radiological features of osteoarthritis, of the large joints in adolescents could suggest WD and lead to copper survey.