Paraneoplastic Arthropaties Of Haematological Disorders

3.1. Leukaemic Arthritis

Arthritis is observed more frequently in children (1265%) than in adults (4-13%) and more often in acute than in chronic leukaemia [26-28]. The pathogenic mechanisms leading to leukaemic arthritis have not been entirely clarified. From synovial fluid analyses, synovial biopsies and use of leukaemia-associated cell surface markers, synovial infiltration appears to be the predominant mechanism [27, 29-34], In this case the leukaemic arthritis tends to be asymmetric and additive. Large joints, most commonly the knees, are usually involved [27], However, ankle, wrist, elbow, shoulders and hip involvement have been described. Effusions, if present, are small. Severe joint pain, out of proportion to the degree of inflammatory arthritis has been reported by several authors [26]. The white blood cells count in the synovial fluid of the involved joints ranged from noninflammatory to highly inflammatory, rarely revealing leukaemic cells. Rheumatoid factor and ANA results are typically negative. Patients may develop several kinds of radiologic abnormalities: osteopenia, erosions, lytic lesions and metaphyseal radiolucent bands [26], Histologic examination of the synovial membrane usually shows infiltration of malignant cells, without villous proliferation of synovia or neovascular formation [27, 35], On the other hand, there are several cases of leukaemic arthritis in which synovial biopsy (some of them obtained at open surgery) revealed no leukaemic infiltration. Even more, marked stratification of synovial lining cells and prominent proliferation of synovial stromal cells were described [35-38]. Autopsy studies indicated that leukaemic involvement of the sinovium may be rare, even with clinical evidence of arthritis [39], Thus, joint manifestation in leukaemia clearly can occur without evident malignant cell infiltrations. In those cases it is more likely that the synovitis is an immune complex induced synovitis. Cases of proliferative synovitis associated especially with adult T-cell leukaemia [37, 38], hairy cell leukaemia [40, 41] and acute lymphoblastic leukaemia [42], but also to myeloid leukaemia [35, 43] have been reported. In those patients the arthritis tends to be symmetrical, sometimes mimicking rheumatoid arthritis. Radiographic findings of the involved joints may be either normal [35] or reveal erosions [26, 38,40,44,45]. The pathogenic mechanisms leading to the proliferative synovitis are uncertain. Human adult T-cell leukaemia is closely linked to human T-cell lymphotropic virus type I (HTLV-1) infections. It has been shown that HTLV-1 induced transformation of T-cells generated constitutive production of various proinflammatory cytokines, which in turn may cause proliferative synovitis [38], It has also been shown that cells from patients with B-cell chronic lymphocytic leukaemia, secrete a number of regulatory and pro-inflammatory cytokines, including IL-1/3 [46, 47], Recently, a case was reported in which overexpanded B-cell clone mediated leukaemic symmetric polyarthritis by abundant secretion of IL-1/8 [45]. Therefore, cytokines secreted by leukaemic cells could be implicated in the pathogenesis of some forms of leukaemic arthritis.

In same cases leukaemic arthritis seems to improve with administration of nonsteroidal anti-inflammatory agents. The best therapy is chemotherapy for the underlying leukaemia.

3.2. Lymphoma

Musculoskeletal symptoms in lymphoma are common. Approximately 7-25% of patients may develop skeletal involvement at some time during the course of the disease, mostly as polyarthralgia, pathological fractures of bones or hypertrophic osteoarthropathy associated with mediastinal involvement [48, 49]. Notwithstanding, arthritis as a presenting feature of lymphomas is extremely rare and many of these are due to direct synovial involvement by the lymphoma or a reaction to adjacent lymphomatous process [50, 51]. However, several patients with non-Hodgkins lymphoma who presented with polyarthritis, sometimes mimicking rheumatoid arthritis, have been reported [52-56]. It is likely that the arthritis and lymphoma were causally linked, because in those cases in which the lymphoma was successfully treated, the arthritis symptoms resolved promptly and completely. Most of the lymphomas, where the phenotype was known, were T-cell lineage, including cutaneous forms [52]. In the cases, which were reported, synovial biopsy findings revealed chronic nonspecific inflammatory changes; these were felt to be a reactive phenomenon. No malignant lymphocytic infiltration was noted [53, 55, 57], One may postulate that the polyarthritis associated with non-Hodgkins lymphoma, similar to leukaemic polyarthritis, may be cytokine driven. Another rheumatologic manifestation of lymphoma was reported in a patient with stage IV diffuse, well-differentiated lymphocitic lymphoma who subsequently developed rapidly progressive sacroiliitis and enthesopathies with extensive symmetric erosions of the sacroiliac joints [58].

3.3. Myelodysplastic Syndromes

The myelodysplastic syndromes (MDS) are a heterogenous group of poorly understood refractory anaemias resulting from a clonal abnormality in the pluripotential stem cell [59]. An increased frequency of clinical immune disorders has been reported in patients with MDS, up to 30% in some series [6064], These include cutaneous vasculitis, a lupus-like syndrome, neurological manifestations and polyarthritis. The pathophysiologic basis for the development of autoimmune disorders in patients with MDS remains unclear. Abnormalities of T- and B-cell function, decreased helper and suppressor T-cell numbers, decreased natural killer cells, T-cell receptor gene rearrangements and occasional T-cell lymphomas occur in patients with MDS [62]. It may be hypothesised that abnormal antigen presentation, T-cell responses to antigen presentation and/or abnormal B- and T-cell interactions in MDS leads to immune dysregulation and consequent development of autoimmune disorders. Alternatively, a common trigger could damage both myeloid and lymphoid cells, leading to the development of MDS and a predisposition to autoimmunity [62],

Two patterns of arthritis were seen: symmetric peripheral polyarthritis, mimicking rheumatoid arthritis and asymmetric oligoarthritis limited to the large joints. In most instances, the arthritis was temporally related to the initial discovery of cytopenias. Radiographs of the involved joints were either normal or revealed joint space narrowing and erosions. Histologic examinations of the synovial membrane were not mentioned. The rheumatoid factor was positive in some series and negative in others [60, 61]. The use of steroids resulted in improvement in articular complaints and hematological manifestations in some series and in one case report [60, 64]. Thus, the MDS need to be considered in the differential diagnosis of any case of new-onset arthritis accompanied or subsequently followed by persistent cytopenias.

3.4. Amyloid Arthropathy

Multiple myeloma can present as polyarthritis, which is due to amyloid deposition in synovia and articular cartilage [65, 66]. Amyloid arthropathy occurs in about 5% of patients with multiple myeloma, occasionally as the initial manifestation. It has also been described in Waldenstroms macroglobulinaemia with Bence-Jones proteinuria. The clinical picture can resemble rheumatoid arthritis mostly affecting shoulders, wrists, knees and small joints of the hands. Carpal tunnel compression is usually associated with amyloid arthropathy [66], Thus, it appears that the combination of carpal tunnel syndrome and an arthropathy in a patient with multiple myeloma strongly suggests that the patient may have amyloidosis. Diagnosis can be established by demonstration of amyloid deposits in synovia and/or synovial fluid sediment [65, 66].

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