Pigmented villonodular synovitis

I write with regard to the paper by Zuber and colleagues that purports to demonstrate a case of pigmented villonodular synovitis (PVNS). The pathology material presented by the authors, however, is not diagnostic of PVNS, in that the cellular infiltrate did not demonstrate the large polyhedral cells— usually dubbed histiocytes—that are requisite for the diagnosis of PVNS. Villi, nodules, giant cells, and haemosiderin are not specific, and may be seen in a variety of conditions other than PVNS. It is the histiocyte that renders the pathology of PVNS unique and diagnostic. Indeed, Lichtenstein has described PVNS as a ‘histiocytosis’ of the synovial membrane. In addition, the authors suggest that in their patient PVNS was found to aVect the second to fifth MCP joints. However, the diffuse form of PVNS is nearly always monarticular; documented cases of polyarticular (usually biarticular) involvement by PVNS are exceptionally rare, and probably number less than half a dozen in the medical literature. The patient under discussion—who presented with progressive, bilateral ulnar deviation at the MCPs—most probably had rheumatoid disease, not PVNS. If there is a ‘lesson’ to this case, it is that the correct diagnosis of an unusual condition such as PVNS requires awareness of the characteristic clinical presentation of the disease and attentiveness to its diagnostic histopathology.


Author's reply
Dr Docken expresses the opinion that the patient under discussion did not suVer from pigmented villonodular synovitis (PVNS) but from rheumatoid arthritis. Although I do agree that rheumatoid arthritis has to be considered as a diVerential diagnosis, the described patient did not fulfil the 1987 revised criteria for the classification of rheumatoid arthritis. 1 The patient did not suVer from morning stiVness in and around joints. She did have swellings of the MCP joints that were asymmetrical-that is, far more prominent on her left side; no signs of arthritis in these joints were present, however. The symptoms were not symmetrical. The patient did not have subcutaneous nodules, no rheumatoid factor was present in her serum, x rays of hands and feet did not show any erosions.
The patient presented in the department of traumatology, hand and reconstructive surgery with a fixed flexion deformity of her left MCP joints, which caused inability to open her hand properly. She did not present with typical symptoms of rheumatoid arthritis such as morning stiVness, tenderness or pain. Synovectomy of the second to fifth MCP joints and reconstruction of the extensor hood of the left hand was performed. The right hand showed discrete thickening of the MCP joints. No need for surgery was discovered there. After surgery the patient was referred to rheumatology. Here the discrepancy between the lack of typical symptoms and signs of rheumatoid arthritis and the severe and asymmetric ulnar deviation, both of which is very unusual, was noted. Because of this discrepancy it was decided to ask for the routinely performed histological evaluation of the operation specimen, which clearly stated that PVNS was present.
The second point Dr Docken raises is the evaluation and interpretation of the histological specimen. His concern is that there might have been no histiocytes present in the specimen. JaVe, Lichtenstein, and Sutro described in 1941 2 the salient histological features of PVNS, which are deposition of haemosiderin and infiltration of histiocytes and giant cells in a fibrous stroma within the synovium of tendon sheaths and large joints. I agree that it is the fibrohistiocytic proliferation that is characteristic for the pathology of the PVNS. Lipid filled histiocytes, also called foam cells, are depicted in figure 2 of the paper together with giant cells and scattered lymphocytes.
The third issue Dr Docken discusses is the fact that diVuse PVNS tends to occur monarticular. The knee is the most frequent joint involved, followed by the hip and ankle. Infrequently, the diVuse form will present in the hand, shoulder, wrist, and vertebral. Bilateral forms do occur occasionally 3 and polyarticular forms are rare. 4 Recently an unusual case of multiple site involvement of PVNS in a child has been reported. 5 The case presented in our paper belongs to the rare polyarticular forms of diVuse PVNS. MARGIT

Combination DMARD therapy for rheumatoid arthritis. Full or low DMARD doses?
We read with great interest the paper by O'Dell. 1 We would like to oVer some comments on it. Although we strongly believe in the rationale of the author, we feel that as clinicians our options should be based on clear cut data when treating patients with erosive progressive rheumatoid disease. In our clinical practice, in active and severe diseases, we try to optimise any treatment by using the highest doses of both non-steroidal anti-inflammatory drugs and disease modifying antirheumatic drugs (DMARDs), compatible with an acceptable risk of toxicity. According to the medical literature, in rheumatoid arthritis (RA) the highest doses of OH-chloroquine (OH-C) are 6 mg/kg/day, of methotrexate (MTX) 17.5-20 mg/week, and of sulphasalazine 3 g/day. [2][3][4] Poor or inadequate responses can be assessed only when these amounts are reached. In the study by O'Dell, 5 three groups of patients were studied, one receiving full doses of MTX, one a combination of full doses of OH-C and 1 g/day sulphasalazine, and the third a combination of the three. To our knowledge no data exist suggesting that the combination of full doses of OH-C plus 1 g day of sulphasalazine is any better than OH-C alone. It might well be that an additive eVect is reached by such a combination, but this has never been proved. In addition no proof exists that 1 g/day sulphasalazine from the beginning, is clinically of any value in the long term treatment of RA.
When examining the combination studies that have been published on MTX and OH-C, we found no evidence of a statistically significant clinical or biological additive or synergistic eVect of the two drugs. Therefore either the addition of low doses sulphasalazine to the two drugs exerts some peculiar, beneficial synergistic eVect, still to be unequivocally proved, or the study lacks the data of a fourth group combining MTX plus 1 g/day sulphasalazine. Possible support for the additive eVect, comes from a previously published open study using a combination of lower doses of MTX (mean dose throughout the study: 8.3 mg/week) plus full doses of sulphasalazine (2-3 g/day). The study showed that the association was more beneficial than the monotherapy with MTX alone. 6 In fact while mean values of disease activity score (DAS) decreased by 26% in monotherapy, a mean decrease of 49% was seen in combination therapy. As the initial values of DAS were 5 or more, the results at the sixth month were certainly statistically significant, although of uncertain clinical importance. In contrast, in the O'Dell study 5 the diVerence between groups, arose only after the 8-10th month of treatment with the multiple combination.
Therefore the real part in clinical practice, played by several combinations with low or full doses of each molecule, needs to be unequivocally confirmed.
Few studies have used full doses of single drugs or of various drugs in combination for long periods of time. Some negative results, at least, could have resulted from low doses or the results with single drug therapy could have been improved by using full doses of the drug.
As clearly hypothesised by O'Dell, by using full doses of the available drugs, the results should be even better either in terms of time lapse before the appearance of the response or of the degree of the response. We also need a clear distinction among the patients, between those who improve in a clinically meaningful manner (50% or more) and those who survive while receiving treatment without such a significant clinical benefit. For example, in our own experience with MTX, only 37% of 159 patients with active, erosive RA, followed up for three years, had a clinically important response, 7 even though 83% were still receiving the drug (Ferraccioli G F and colleagues, submitted data). As far as the per cent of patients obtaining a clear improvement is concerned, our results with MTX fully agree with those by O'Dell in his two year study.
In conclusion, in our view, when establishing a combination therapy to improve the clinical results in severe, active RA, full doses of each drug should be tried, and only clinically meaningful outcomes should be taken into consideration. G

Author's reply
I would like to thank Dr Ferraccioli and colleagues for their thoughtful letter on my leader. 1 I certainly agree with their main points: in combination studies (and other studies as well) full dose DMARDs should be used and success should be based on a meaningful degree of response (we chose 50% improvement of composite criteria). Clearly we believe that one of the main reasons that some combination DMARD studies have not shown diVerences has been that the DMARD dose in the combination arms have been low. In our study we used what we considered at the time to be full dose methotrexate (17.5 mg/wk) and full dose hydroxychloroquine (400 mg/day). 2 We did, however, use low dose sulphasalazine (1 g/day) because of the concern about possible toxicity with the methotrexate-sulphasalazine combination. In our study the combination of methotrexatesulphasalazine-hydroxychloroquine was clearly superior to methotrexate alone (p<0.001); as pointed out by Dr Ferraccioli and colleagues it is unclear whether this increased eYcacy resulted from the hydroxychloroquine, the sulphasalazine, or a combination of the two. We have a study in progress that we hope will answer this question and in our current study the dose of sulphasalazine is increased to 2 g/day.

Tissue crosslinks concentrations in normal joints and chronic articular diseases
We read with interest the recent paper by Takahashi et al 1 concerning joint tissue concentrations of collagen crosslinks (Pyr, Dpyr) in patients with osteoarthritis (OA) and rheumatoid arthritis (RA). The main discovery of this study was the presence of Dpyr also in extra-osseous tissues, namely cartilage and synovium in patients with joint disorders and in the synovium of nonarthritic controls. These data suggest that extra-skeletal sources may contribute to the increased urinary excretion of the two crosslinks in joint disorders, as several observers have reported in recent years. [2][3][4] We recently performed a similar study on samples of subchondral bone, cartilage, and synovium of six patients with OA (mean (SD) age 58.1 (10.7)) and six patients with RA (age 61.1 (18.1)) who underwent total hip arthroplasty. In contrast with the study by Takahashi, as a control group we studied joints from six young patients (aged 37.5 (13.5)) who underwent surgical amputation of an extremity for malignant osteosarcoma. All patients were physically active before sur-gery, permitting the sampling of normal 'healthy' joint tissues.
Briefly, tissue specimens of articular cartilage, subchondral bone, and synovium were collected, cleaned, dried, and immediately weighed and stored at −80°C. The assay of their crosslinks content was performed by high performance liquid chromatography according to a published method 5 after an overnight hydrolysis.
Data are expressed in nmol of crosslinks/gram of fresh tissue. Our data confirm the presence of both crosslinks in cartilage and in synovial samples from all the groups tested. The mean ratio Pyr/Dpyr was 30:1 in cartilage and 17:1 in synovium and was similar in the three groups. In both controls and in patients, cartilage was the tissue with the highest content of Pyr (table 1). Looking at the diVerences in tissue levels among groups (fig 1), we observed a sharp reduction of both crosslinks in both bone and in cartilage in patients with joint diseases compared with healthy controls. In contrast, mean levels of crosslinks found in synovium remained relatively constant. These results can be interpreted as a true 'escape' of crosslinks from subchondral bone and articular cartilage in the terminal phases of joint disorders and are in contrast with previous results by Takahashi et al 6 who performed a quantitative analysis of Pyr in articular cartilage of patients with diVerent bone and joint disorders and concluded that cartilage Pyr content was not aVected by articular diseases. This last study lacks a control group and a true comparison with healthy joints was not available. Moreover, changes in crosslinks tissue levels may be more representative of the true collagen content when data are expressed as absolute values (nmol/g of fresh tissue) rather than after normalisation for collagen moles. Our finding of a reduced Pyr content in articular tissues in joint disorders is in agreement with recently published experimental data demonstrating that a decrease in collagen crosslinks content is associated with a reduced bone strength. 7 Finally, the lack of significant diVerence in synovial content of collagen crosslinks   Bone between controls and patients, which has been reported also by Takahashi et al 1 makes unlikely the contributory role of synovial membrane to urinary excretion of crosslinks in chronic joint diseases, which seems to be related to subchondral bone and articular cartilage increased turnover. This hypothesis is consistent with data from our previous study 8 demonstrating that crosslinks concentrations in synovial fluid are similar in two conditions with a highly diVerent metabolic turnover of synovial membrane such as OA and RA.