The number and distribution of mast cells were assessed in 116 synovial membranes from patients with rheumatoid arthritis and in 30 control specimens. Rheumatoid synovial membranes contained a mean of 48.5 mast cells per 20 high-power fields (HPF) (range 0-252), and control synovial membranes had a mean of 3.9 mast cells per 20 HPF (range 0-13) (P < 0.001). In a comparison of high and low mast cell subgroups in rheumatoid arthritis, counts were directly related to the intensity of clinical synovitis in the affected joint, but not to hemoglobin concentration or erythrocyte sedimentation rate. Joints excised from 5 patients with rheumatoid arthritis were characterized by active bone remodeling with increased osteoid, active resorption by osteoclasts, and trabecular osteoporosis. Mast cells were prominent in both extraosseous pannus and intraosseous invasive tissue. The possible roles of mast cells in the pathogenesis of rheumatoid arthritis are discussed. (1-3). The accumulation of mast cells in the synovium is an early feature of adjuvant arthritis in the rat (4), although there are few reports of their prevalence in inflammatory synovitis in adult humans. Increased numbers of mast cells have been described in the synovial membrane of patients with juvenile rheumatoid arthritis (5-7), some of whom may also have circulating basophilia. The possibility that synovial mastocytosis could be a component of adult rheumatoid arthritis has received scant attention (8) and no controlled, quantitative studies have been reported. In 2 comprehensive reviews of the pathology of inflamed synovium, mast cells were not discussed (9,lO). In view of recent advances in the understanding of the possible role of mast cells in inflammation, bone resorption, and angiogenesis, it is reasonable to consider a function of these cells in the pathogenesis of the rheumatoid lesion. PATIENTS AND METHODSSynovial membranes from 116 patients with rheumatoid arthritis were obtained at surgical synovectomy of the knee and wrist, or at replacement arthroplasty of the knee and hip. Control specimens were obtained from 30 patients undergoing meniscectomy of the knee. Tissue was fixed in 10% neutral buffered formalin and embedded in paraffin blocks. Sections 4 pm thick were stained with 20% Giemsa solution. Mast cells were identified as cells of variable morphology, from oval to spindle-shaped or convoluted, possessing a single oval or round nucleus. The presence of red-violet metachromatic cytoplasmic granules was an absolute requirement for mast cell identification.In each case, 20 high-power fields (HPF) were counted by a single observer. A "high mast cell count" subgroup of patients with rheumatoid arthritis was arbitrarily defined

Paget's disease of bone is a common bone disease characterized by increased and disorganized bone remodeling at focal sites throughout the skeleton. The etiology of the disease is unresolved. A persistent viral infection has long been suggested to cause the disease. Antigen and/or nucleic acid sequences of paramyxoviruses (in particular measles virus [MV], canine distemper virus [CDV], and respiratory syncytial virus [RSV]) have been reported in pagetic bone by a number of groups; however, others have been unable to confirm this and so far no virus has been isolated from patients. Here, we reexamined the question of viral involvement in Paget's disease in a study involving 53 patients with established disease recruited from seven centers throughout the United Kingdom. Thirty-seven patients showed clear signs of active disease by bone scan and/or histological assessment of the bone biopsy specimens and 12 of these had not received any therapy before samples were taken. Presence of paramyxovirus nucleic acid sequences was sought in bone biopsy specimens, bone marrow, or peripheral blood mononuclear cells using reverse-transcription polymerase chain reaction (RT-PCR) with a total of 18 primer sets (7 of which were nested), including 10 primer sets (including 3 nested sets) specifically for MV or CDV. For each patient at least one sample was tested with all primer sets by RT-PCR and no evidence for the presence of paramyxovirus RNA was found in any patient. In 6 patients, bone biopsy specimens with clear histological evidence of active disease tested negative for presence of measles and CDV using immunocytochemistry (ICC) and in situ hybridization (ISH). Intranuclear inclusion bodies, similar to those described by others previously, were seen in pagetic osteoclasts. The pagetic inclusions were straight, smooth tubular structures packed tightly in parallel bundles and differed from nuclear inclusions, known to represent MV nucleocapsids, in a patient with subacute sclerosing panencephalitis (SSPE) in which undulating, diffuse structures were found, arranged loosely in a nonparallel fashion. In the absence of amplification of viral sequences from tissues that contain frequent nuclear inclusions and given that identical inclusions are found in other bone diseases with a proven genetic, rather than environmental, etiology, it is doubtful whether the inclusions in pagetic osteoclasts indeed represent viral nucleocapsids. Our findings in this large group of patients recruited from throughout the United Kingdom do not support a role for paramyxovirus in the etiology of Paget's disease. (J Bone Miner Res 2000;15:2315-2329)

Many referrals to hospital-based musculoskeletal services are likely to be misdirected. Integrated referral and care pathways are required for efficient and optimal care of patients with musculoskeletal diseases. The development of such pathways will require significant support, education and training for general practitioners.