In this study, methotrexate (MTX) was compared with placebo in the treatment of systemic sclerosis (scleroderma, SSc) in a 24 week randomized double-blind trial, followed by an observational trial of 24 weeks duration. Twenty-nine scleroderma patients were allocated to receive weekly injections of either 15 mg MTX or placebo. Patients who responded favourably after 24 weeks continued with the same regimen for a further 24 weeks; those who showed a poor response on placebo were allocated to further treatment with 15 mg MTX weekly, and those who responded poorly to treatment with 15 mg MTX weekly had their doses increased to 25 mg. A favourable response was defined as an improvement of total skin score (TSS) by ^ 30%, of single breath diffusion capacity (DLco) by ^ 15%, or of the score on a visual analogue scale of general well-being (VAS) by ^ 30%, provided that such improvements were not accompanied by persistent digital ulcerations or worsening of DLco ^ 15%. Seventeen patients were allocated to MTX treatment and 12 to treatment with placebo. After 24 weeks, a significantly larger number of patients receiving MTX (n = 8, 53%) who completed the first 24 weeks of the study had responded favourably compared to patients receiving placebo (n = 1, 10%, P = 0.03). Comparison of separate variables between the two treatment groups by intention-to-treat analysis at week 24 showed improvement in the MTX group of TSS (P = 0.06) and creatinine clearance (P = 0.07). At week 48, 13 patients received MTX from the start of the study and nine during 24 weeks. From these 22 patients, 15 (68%) responded favourably and compared with the start of the study they showed significant improvement of TSS (P = 0.04), VAS (P = 0.02), grip strength of the right hand (P = 0.02) and ESR (P = 0.01). Although the number of patients enrolled in this study is small, these results suggest that in a group of patients with active systemic sclerosis, low-dose MTX seems to be more effective than placebo according to pre-defined response criteria.

From January 1992 until January 1994, we used a standardized diagnostic protocol for the 167 immunocompetent patients with fever of unknown origin (FUO) admitted on the internal medicine wards in all 8 university hospitals in the Netherlands. This protocol consisted of a standardized coded history and standardized physical examination for all 167 patients. A number of additional obligatory investigations had to be performed in the first week of admission for all patients, and all potentially diagnostic clues (PDCs) thus retrieved had to be registered. In the presence of PDCs, specific investigations had to be performed based on the differential diagnosis. In the absence of PDCs or in the presence of only misleading PDCs, patients underwent a screening 2-staged diagnostic protocol. In 162 (97%) patients, PDCs were present after 1 week of admission. In 61 patients these PDCs were all misleading. The likelihood of reaching a diagnosis in patients with PDCs was not significantly higher than that in patients without PDCs, probably because of the high proportion of misleading PDCs. The likelihood of establishing a diagnosis was significantly lower (< 10%) only for patients with recurrent fever, normal erythrocyte sedimentation rate (ESR), and normal hemoglobin. All other PDCs were not significantly different in patients with a diagnosis compared with patients without a diagnosis. The screening 2-staged diagnostic protocol proved useful in 10 of 43 patients in whom it was used. The screening value of immunologic and microbiologic serology and endocrine investigations was nil; these investigations probably should be performed only when PDCs for the disease searched for are present. Scintigraphic techniques, echocardiography, and other imaging procedures were never helpful in our population in the absence of PDCs. Many patients with FUO had nonspecific anemia and disturbed liver chemistry. In the presence of these findings alone, without other more specific PDCs, the likelihood of reaching a diagnosis with help of bone marrow aspiration was nil, and with help of liver biopsy, it was low. Enteric biopsy was never helpful. If lymphadenopathy was confined to the cervical or inguinal region (with negative chest X-ray and abdominal ultrasound), lymph node biopsy was not helpful, in contrast to patients having generalized lymphadenopathy, in whom the technique had a yield of 79%. As shown in this study, the search for PDCs remains an important tool for establishing the diagnosis in patients with FUO, although in many cases these PDCs appear to be misleading. Directed diagnostic workup--using the PDCs retrieved by repeated, meticulous history taking and physical examination--remains the most efficient and intellectually satisfactory way to solve the problem of FUO in the individual patient. A standard protocol in patients with FUO in whom the obligatory investigations, as used by us, do not lead to the diagnosis can be limited to the tests that proved to be of some use as screening procedure: temporal biopsy in patients older th...