Radiographic outcome after three years of patients with early erosive rheumatoid arthritis treated with intramuscular methotrexate or parenteral gold. Extension of a one-year double-blind study in 174 patients.

OBJECTIVE: To compare the radiographic outcomes after 36 months in patients with early erosive rheumatoid arthritis (RA) who were treated with methotrexate (MTX) or gold sodium thiomalate (GSTM). METHODS: In a randomized, double-blind fashion, 174 patients from two centres were assigned to receive weekly intramuscular injections of either 15 mg MTX or 50 mg GSTM. After 12 months, the study was continued as an open prospective study for an additional 2 yr, administering the same amount of MTX and half of the GSTM dose. Radiographic outcomes were assessed by standardized methods in all patients at baseline and after 6, 12, 24 and 36 months. RESULTS: Intention-to-treat analysis showed that patients treated with MTX had higher radiographic scores and more erosive joints at all follow-up points. However, there was no statistically significant difference between the two treatment groups. The progression rate was significantly slower during the second and third years of follow-up in both groups. Baseline and time-integrated (area under the curve over 6 months) disease activity parameters were good predictors of radiographic outcome after 3 yr. Seropositivity was not an independent predictor of progression. However, patients who were positive for rheumatoid factor had higher time-integrated disease activity (with less response to treatment) and thus their disease was significantly more progressive. CONCLUSION: Both of the disease-modifying compounds used in this study, MTX and GSTM, were able to reduce the slope of radiographic progression during 3 yr of follow-up. There was some advantage for parenteral gold but no significant intergroup difference.

Progression in early erosive rheumatoid arthritis: 12 month results from a randomized controlled trial comparing methotrexate and gold sodium thiomalate.

OBJECTIVE: To compare radiographic outcomes in patients with active early erosive rheumatoid arthritis (RA) who were treated with methotrexate (MTX) and gold sodium thiomalate (GSTM). METHODS: A total of 174 patients from two centres were randomly assigned to receive weekly i.m. injections for 12 months of either 15 mg MTX or 50 mg GSTM in a double-blind fashion. Radiographic evaluations including standardized scoring of 38 joints of the hands, wrists and forefeet, and count of eroded joints, were carried out at baseline and after 6 and 12 months in all patients, including withdrawals. RESULTS: An intention-to-treat analysis revealed no statistically significant difference in the progression of radiographic scores between treatment groups after 6 months (3.4 with MTX vs 2.6 with GSTM, P = 0.66) and after 12 months (6.0 vs 4.8, P = 0.44). A similar pattern was observed for the number of joints with erosions. The slope of radiographic progression was significantly reduced in the second half-year compared to the first 6 months in both groups. Erythrocyte sedimentation rate and C-reactive protein at baseline, and the presence of rheumatoid factor (RF), were the main predictors of progression in bivariate analysis. RF remained as the only predictor for radiographic outcome in multivariable analysis. CONCLUSION: In parallel to clinical improvement, both GSTM and MTX reduce the slope of radiographic progression in patients with active erosive RA.

A 36 month comparative trial of methotrexate and gold sodium thiomalate in the treatment of early active and erosive rheumatoid arthritis.

OBJECTIVE: To compare the safety and efficacy of methotrexate (MTX) and gold sodium thiomalate (GSTM) in patients with active early erosive rheumatoid arthritis (RA) during 3 yr. METHODS: A total of 174 patients from two centres were randomly assigned to receive weekly i.m. injections of either 15 mg MTX or 50 mg GSTM for 1 yr in a double-blind fashion. Thereafter, the study was continued as an open prospective trial for an additional 2 yr with the same dose of MTX and half of the GSTM dose. Clinical and laboratory evaluations were carried out at baseline and at months 6, 12, 18, 24 and 36 in all patients, including withdrawals. RESULTS: An intention-to-treat analysis revealed inactivation ['clinical remission': no swollen/tender joints, erythrocyte sedimentation rate (ESR) of < 20 mm/h in males and < 30 mm in females, no corticosteroids within the last 4 weeks] in 33.3% of MTX patients and 37.9% of GSTM patients. The mean time to inactivation was insignificantly shorter with GSTM (MTX: 12.1 months; GSTM: 9.1 months; P = 0.06). At least marked improvement (> 50% reduction of the number of swollen/tender joints and of the ESR) was found in 78.2% (MTX) and 87.4% (GSTM). Withdrawal from the study due to toxicity was recorded in 16.1% of MTX and 52.9% of GSTM patients after a mean time of 30.6 and 6.1 months, respectively (P = 0.0001). In MTX and GSTM non-completers, inactivation was recorded in 24.2 and 54.7% of all patients. Among completers (54 and 34 patients, respectively), significant improvement compared to baseline was noted in all seven clinical variables (morning stiffness, overall joint pain, count of tender/swollen joints, Lansbury articular score, functional score and grip strength), ESR and C-reactive protein without significant intergroup differences. The steroid-sparing effect appeared more pronounced with GSTM. CONCLUSION: Over 36 months, treatment with MTX or GSTM induces inactivation ('clinical remission') of early and erosive RA in about one-third and at least marked improvement in four-fifths of patients (intention-to-treat analysis). Patients withdrawn from MTX or GSTM due to toxicity develop a clinical remission from the disease; this occurred more often with GSTM. Tolerability is significantly better with MTX.

[Basic therapeutic combination therapy in chronic polyarthritis: an overview]. / Basistherapeutische Kombinationstherapie bei chronischer Polyarthritis: Ein Uberblick.

Therapy of rheumatoid arthritis with a combination of several disease-modifying drugs aims towards better control of the disease than achievable by monotherapy. Based on a broad variety of clinical studies, revealing more or less positive results, several combinations have been suggested: the inclusion of cyclosporin into combinations with methotrexate, the inclusion of sulfasalazine into combinations with methotrexate, the combined use of two chemotherapeutic substances, including methotrexate, azathioprine and cyclophosphamide, the inclusion of chloroquine derivatives into such or other combinations, and the combination of methotrexate with injectable gold. The validity of some of the studies is affected by high drop out rates and by the unknown influence of concomitant therapy with corticosteroids. Our own beneficial experience with the triple combination of methotrexate with azathioprine and chloroquine in 21 patients with refractory rheumatoid arthritis is summarized.

Other pain syndromes to be differentiated from fibromyalgia.

Several common chronic pain syndromes come to the attention of the rheumatologist demanding for differentiation from fibromyalgia (FM), although they are often associated with it. They may mimic FM by (1) the occurrence of wide spread pain, (2) the chronicity of complaints, (3) the preponderance of females in some of these, and (4) the lack of objective data to be derived from imaging techniques and laboratory tests. Pain is produced by the disturbance of normal function ("dysfunctional syndromes", MASI, ref. 6). Recognition requires examination of the locomotor system under biomechanical auspices both at rest and during movement in order to diagnose hyper- and hypomobility syndromes; treatment of these conditions is guided by principles to improve biomechanical function. In addition, the skin needs to be examined to detect panniculosis (also called "cellulitis"), which may be mixed up with FM due to its preferential occurrence in peri- or postmenopausal women. It is concluded that the aforementioned differential diagnosis needs to be considered appropriately in coinciding FM and all studies dealing with FM.

[Differential diagnosis of polyarthritis pain syndrome of the locomotor apparatus]. / Differentialdiagnose polytoper Schmerzsyndrome des Bewegungsapparates.

Widespread pain syndromes of the musculoskeletal system present to general practitioners, internists, neurologists and orthopedic surgeons every day. The syndromes may result both from organic diseases (inflammatory joint diseases, rheumatic manifestations of organ diseases) as well as dysfunctional syndromes, the latter including mainly biomechanically induced syndromes and fibromyalgia. The approach is predominantly clinically oriented and requires laboratory means or technical procedures only in a limited extend. The duration of history, the recognition of synovitis and of myofascial trigger points or of integumental tender points allow in most patients to achieve appropriate diagnostic criteria.

[Combination therapy with remission-inducing drugs in chronic polyarthritis: 1996 update]. / Kombinationstherapie mit Remissionsinduktoren bei chronischer Polyarthritis: Update 1996.

Therapy of rheumatoid arthritis with a combination of several disease-modifying drugs aims to better control of the disease than achievable by monotherapy. Subsequent to a paper written two years ago, this publication reviews studies dealing with combination therapy issued mainly in 1995 and 1996. Most studies deal with MTX as one of the partners. Beneficial results were reported for the combination of methotrexate with antimalarials, cyclosporine or sulfasalazine. The triple combination of methotrexate with hydroxychloroquine and azathioprine is especially promising although the studies presented up to now are still insufficient for its final assessment, due to methodologic problems. Similarly, the value of the combination of sulfasalazine with injectable gold, of sulfasalazine with methotrexate and hydroxychloroquine, or of methotrexate with injectable gold is still uncertain.

Comparison of intramuscular methotrexate and gold sodium thiomalate in the treatment of early erosive rheumatoid arthritis: 12 month data of a double-blind parallel study of 174 patients.

The objective was to compare the safety and efficacy of methotrexate (MTX) and gold sodium thiomalate (GSTM) in patients with early erosive rheumatoid arthritis (RA). A total of 174 patients with active early erosive RA without deformities were enrolled in a 12 month, two-centre double-blind randomized trial. They received a weekly i.m. dose of 15 mg MTX (n = 87) or 50 mg GSTM (n = 87), respectively. Clinical and laboratory evaluations were carried out every 3 months in all patients, including the withdrawals. Ten patients (11.5%) in the MTX group and 21 patients (24.1%) in the GSTM group achieved a clinical remission of the disease [no swollen joints, erythrocyte sedimentation rate (ESR) < 20 mm, no steroids] within the study period (P < 0.05). An at least marked improvement (> 50% reduction of the number of swollen and tender joints and the ESR) was assessed in 59/87 (68%) and 66/87 (76%) patients treated with MTX or GSTM, respectively (P > 0.05). Significantly more patients in the GSTM group were withdrawn due to toxicity (six MTX/32 GSTM). A total of 126 patients (73 on MTX and 53 on GSTM) completed 12 months on their original medication. In the completers, a significant improvement of > 50% compared to baseline was noted in all six clinical variables [morning stiffness, joint count of swollen and tender joints, Lansbury index, grip strength and activities of daily living (ADL) score], the ESR and the C-reactive protein, without intergroup differences. The number of patients taking prednisone was reduced from 21 to 7% in the MTX group and from 15 to 4% in the GSTM group. While significantly more patients achieved a clinical remission with GSTM treatment, tolerability was significantly better with MTX.

Decrease of interleukin 6 during the first 12 months is a prognostic marker for clinical outcome during 36 months treatment with disease-modifying anti-rheumatic drugs.

The aim of this study was to determine prognostic markers for the outcome after 36 months of therapy with disease-modifying anti-rheumatic drugs (DMARDs) in patients with rheumatoid arthritis (RA) and to study serial cytokine serum levels. During 36 months, 20 patients receiving DMARDs (nine patients gold sodium thiomalate and 11 patients methotrexate, no comparison undertaken) were followed for clinical and laboratory data. Investigation at baseline, 12, 24 and 36 months, included clinical, radiological and laboratory parameters such as erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), and interleukin (IL)-1 beta, IL-6, tumor necrosis factor alpha (TNF-alpha), IL-1 receptor antagonist (IL-1RA) and IL-2. During the 3 yr of therapy, the patients showed significant clinical improvement and decline of ESR, CRP, and serum levels of IL-6 and IL-2. The decrease in IL-6 serum levels during the first year of therapy correlated significantly with the decrease, after 36 months, in the number of inflamed joints (r = 0.7608, P < 0.005), Lansbury index (r = 0.6642, P < 0.005) and morning stiffness (r = -0.6561, P < 0.005). In contrast to IL-6 or IL-2, TNF-alpha and IL-1RA did not vary significantly during the 3 yr of therapy. During 36 months of therapy, patients treated with DMARD showed significant improvement of clinical parameters and a trend for delayed progression of radiographic damage. The decrease in IL-6 concentration in serum during the first 12 months was the best prognostic marker for the clinical outcome after 36 months of DMARD therapy.

[Radiologic healing phenomena in chronic polyarthritis treated with methotrexate or sodium aurothiomalate]. / Radiologische Heilungsphänomene bei chronischer Polyarthritis unter Behandlung mit Methotrexat oder Natriumaurothiomalat.

PROBLEM: Do radiographs of hands and forefeet obtained from patients with rheumatoid arthritis present with healing phenomena? What is their importance relative to progressive changes? METHODS: Dorsopalmar/-plantar radiographs of hands and forefeet of 43 patients with early rheumatoid arthritis (median disease duration 1.7 years, anatomical Steinbrocker's age < or = 2, patients selected from a prospective study, treatment with methotrexate vs gold-sodiumthiomalate) were obtained at months 0, 6, 12, 24 and 36. Radiographs were evaluated without knowing the mode of treatment at 34 sites according to their time sequence for the following variables: a modified Larsen index, numbers of erosive and of radiologically active joints, and the numbers of joints being improved vs. deteriorated in relation to the preceding x-ray. RESULTS: The radiologic progression could be measured by both a score derived from the modified Larsen index as well as by the numbers of erosive joints with the result of an increasingly crescent, but flattening curve. The number of erosive joints was more sensitive to progression than the score derived from Larsen index. The number of joints deteriorating, compared with the preceding x-ray, decreased from month 6 to month 36 from 16.1% to 7.1% resp. At the same time, 90% of patients increasingly developed radiologic improvement in 2.9% zu 9.3% of joints, including diminution in size and recortication of erosions and particular cysts with a "filling in" by trabecular bone and recovery of a bony outline. There were no relevant differences between therapy groups. CONCLUSIONS: Progression in early rheumatoid arthritis is best measured by the number of joints with erosions. Reparative signs show up with increasing frequency during the course of the disease. After 3 years of treatment the numbers of joints exhibiting improvement predominate those with deterioration. The data support the concept of early aggressive therapy of rheumatoid arthritis and suggest the inclusion of reparative phenomena into the criteria for improvement of this disease.

Progression and repair in radiographs of hands and forefeet in early rheumatoid arthritis.

OBJECTIVE: To evaluate radiographs of patients with early rheumatoid arthritis (RA) for progression and repair. METHODS: Radiographs of hands and forefeet over 3 years were evaluated at 34 joints based on the modified Larsen-index, the number of joints with erosions, the area of osseous defects including erosions and cysts, the radiologic activity of lesions and--in relation to preceding status--the number of joints with qualitative radiologic improvement or deterioration, respectively, not necessarily seen by the other methods. RESULTS: Counting of joints with erosions and assessment of the area of osseous defects yielded the most impressive results for disease progression with the number of eroded joints being the simplest method. Reparative phenomena included recortication, "filling in" and diminution in size of erosions and paraarticular cysts, newly developing demarcation of a previously indistinct articular outline, and the increase in trabecular structure in the vicinity of erosions. The evaluation of qualitative changes showed reparative phenomena with increasing frequency involving up to 9.3% of the joints during the 3rd year, compared with 7.1% of the deteriorating joints. CONCLUSION: Progression in early RA can be quantitated easily by counting joint erosions. This method appears to be more sensitive than Larsen's approach. Repair can be shown early in the course of the disease (as early as the second 6-month observation period) by assessing both radiologic activity and qualitative changes, which are not necessarily apparent in the foregoing quantitative methods. Reparative phenomena associated with healing of erosions and cysts can be noted increasingly during continuous longterm observation. Evaluation for healing phenomena should be standardized and considered for inclusion in therapeutic trials of RA.

Immunoprinting: various genes are associated with increased risk to develop rheumatoid arthritis in different groups of adult patients.

To identify genes that contribute to the manifestation of rheumatoid arthritis we performed association studies via microsatellite analyses of immunorelevant loci (HLA-DRB, 5 T cell receptor loci, TNFa IL1, IL2, IL5R and CD40L). A total of 183 patients and 275 healthy controls were typed in terms of HLA and grouped according to the known predisposing HLA-DRB1 genes (DRB1*04; relative risk approx. 5; DRB1*01, relative risk approx. 2; a third group carried neither allele). Microsatellite polymorphisms characterizing the TCRBV6S3, CD3D, IL1A, IL2, and IL5R genes did not show significant associations with rheumatoid arthritis, whereas TCRBV6S1, TCRBV6S7, TNFa, and CD40L genes may influence relative protection or risk in certain groups of patients. Analysis of a microsatellite marker adjacent to the transcription element alpha (TEA) in the T cell receptor alpha delta complex indicates that in the cohort carrying neither the DRB1*04 nor the DRB1*01 allele the relative risk to acquire rheumatoid arthritis is increased (> 13) or decreased (< 0.07), depending on the inherited microsatellite allele adjacent to the TEA locus. Sequence analysis of the closely linked TEA region from patients and controls revealed a novel dimorphism. Only the newly identified TEA allele leads to binding of a nuclear protein that may be involved in the regulated expression of the TCRDA genes. Subsequent typing of rheumatoid arthritis patients and controls revealed, however, that the association of the microsatellite marker is largely independent of the TEA allele, confirming incomplete linkage in the 2 kb region of the TCRDA locus. These results are discussed in the context of hot spots of recombination in this genomic region and other linked candidate sequences that predispose to develop rheumatoid arthritis.

The efficacy and relative bioavailability of diclofenac resinate in rheumatoid arthritis patients.

The pharmacodynamics and pharmacokinetics of 75 mg resin-bound diclofenac (resinate) were compared with enteric-coated tablets containing 75 mg of diclofenac in a double-blind randomized crossover trial in 16 patients suffering from rheumatoid arthritis. Diclofenac was significantly faster absorbed from the resinate than from the enteric coated formulation (tlag = 0.454 h vs. 0.998 h, tmax = 1.41 h vs. 2.56 h) and reached lower peak concentrations (Cmax = 1.64 micrograms/ml vs. 2.59 micrograms/ml). No significant differences were found concerning the area under the plasma level-time curves and the mean residence times. Smaller variances were found for the tmax and the mean residence times in the group treated with diclofenac resinate. Onset and duration of analgesia, as assessed by visual analogue scales were similar in both treatment groups, but did not correlate with the plasma concentrations. Four patients experienced adverse effects including gastric pain, transaminase increases, proteinuria and plasma creatinin increase. No uncommon adverse effects were observed with the new preparation.

Intra-articular treatment of rheumatoid knee-joint effusion with triamcinolone hexacetonide versus sodium morrhuate. A prospective study.

Thirty-one patients with knee effusions associated with rheumatoid arthritis (RA) have been treated with two intraarticular (i.a.) injections of each 330 mg sodium morrhuate (SM) used for synoviorthesis versus a single injection of 20 mg triamcinolone hexacetonide (TA). During an observation period of one year, five articular parameters as well as patient's and doctor's global assessments were evaluated. TA showed an earlier onset and a longer duration of therapeutic effects with high statistical significance. The maximum improvement was significantly more pronounced with TA than with SM. Finally after one year improvement measured by a remission index was observed in 81% versus 33% resp. of all joints injected. Due to ineffectiveness of the primary treatment nine patients (60%) out of the SM group, but not patient out of the TA group had to be crossed over to the other treatment. SM usually caused a reactive effusion within hours after injection requiring arthrocentesis. In conclusion efficacy and tolerability are clearly better for TA than for SM.

Oligoclonal T cells in rheumatoid arthritis: identification strategy and molecular characterization of a clonal T-cell receptor.

Immunodominant antigens in rheumatoid arthritis (RA) should induce an expansion of T cells bearing a corresponding T-cell receptor (TCR). We therefore analysed the TCR repertoire at the site of inflammation using two fundamentally different strategies. The total TCR repertoire was examined by generating 'representative' T-cell clone panels, which were subsequently tested for clonality by restriction mapping of the TCR beta gene locus. No clonality was detected in large T-cell clone panels generated with cells from three patients. However, when we selectively analysed the TCR repertoire of in vivo pre-activated, interleukin-2 (IL-2)-responsive T cells, significant T-cell/TCR clonality was found in 2 out of 4 patients. The clonal T cells represented a minority of the total T-cell population with an estimated frequency of 1 in 300 to 1 in 1000 cells. Molecular characterization of a clonal TCR and the use of a specific TCR V beta MoAb ruled out an over-representation of T cells bearing the same V beta element in the total T-cell population, rendering the involvement of super-antigens in the induction of T-cell clonality in this case unlikely.

[Not Available]. / Medikamentöse Schmerztherapie bei rheumatischen Erkrankungen : Bericht über ein symposium bei der 16. Jahrestagung der Deutschen Gesellschaft zum Studium des Schmerzes e.V., Berlin, 24.-27. Oktober 1991.

Different therapeutic modalities are available for the treatment of rheumatic pain. The most important one, besides physiotherapy, is medication with analgesics and adjuvant drugs. Analgesics are given orally and by a stepwise approach in keeping with the principles of cancer pain therapy. In the first step nonopioid analgesics are prescribed, especially non-steroid anti-inflammatory drugs (NSAID) if pain is caused by inflammation. Other nonopioid analgesics, which can be used as alternatives for patients with non-inflammatory pain, are metamizol and paracetamol. Weak or even strong opioids must be administered to patients with rheumatic diseases when pain relief is insufficient or side-effects occur during medication with non-opioids. Long-term treatment of rheumatic pain even with strong opioids such as oral morphine involves only a small risk of severe side-effects such as respiratory depression or the development of tolerance and drug abuse. Patients often suffer from constipation, nausea and vomiting, but these side-effects can be treated with laxatives and antiemetic drugs. There is no reason to differentiate between opioid medication in a cancer patient with pain and in a patient with "non-malignant" rheumatic pain. Centrally acting muscle relaxants may be helpful as adjuvant medication in patients with myalgia for example, and tricyclic antidepressants can also be beneficial, especially in neuropathic pain and for patients with psychiatric distress associated with pain.

[Data of two years of the comparative study methotrexate/aurothiomalate in 102 patients]. / Zweijahresdaten der Vergleichsstudie Methotrexat/Aurothiomalat von 102 Patienten.

UNLABELLED: 102 patients (pat.) with active erosive rheumatoid arthritis (RA) with a median disease duration of only 14 months without malalignment or deformities entered a randomized study to compare the effects of 15 mg methotrexate (MTX) and 50 mg gold sodium thiomalate (GST) administered intramuscularly once a week. The study was double blind during the first year and open during the second year. Clinical and laboratory evaluations were made every three months. X-rays of hands, wrists and forefeet in standard a.p.-projection were taken at month 0, 6, 12 and 24. 32 joints were evaluated according to Larsen. 17/52 (MTX) and 21/50 (GST) patients were withdrawn for several reasons. Withdrawals for toxicity were significantly more frequent in the GST group. 35 patients in the MTX group and 26 patients in the GST group were evaluated for efficacy. All clinical parameters, ESR and CRP improved by more than 50% in both groups without significant intergroup difference. The greatest improvement was seen already after six months. An > 50% improvement occurred in 57% of pat. in both groups. The Larsen score (sum of the Larsen grades of 32 joints) deteriorated significantly in both groups during the first six months (MTX = 3.0, GST = +4.3), it remained stable thereafter in the MTX group and decreased in the gold group. The number of erosive joints increased significantly in both groups during the first six months. This increase was slowed down after six months in the MTX group, in the gold group a decrease was seen indicating a healing of erosions. All differences between the groups were not significant, however. CONCLUSION: While tolerability was better with MTX, both drugs were similarly effective in the treatment of RA and slowed down radiologic progression.

A double-blind comparison of parenteral methotrexate and parenteral gold in the treatment of early erosive rheumatoid arthritis: an interim report on 102 patients after 12 months.

One hundred two patients with active erosive rheumatoid arthritis (RA) without malalignment or deformities (median disease duration, 14 months) entered a double-blind, randomized study to compare the effects of 50 mg gold sodium thiomalate (GST) with 15 mg methotrexate (MTX) administered intramuscularly for 12 months. Roentgenograms of hands, wrists, and forefeet were taken at baseline and after 6 and 12 months, and 32 joints were evaluated according to Larsen. Sixteen of 50 patients in the MTX group were withdrawn; one patient in the MTX group died of cerebral bleeding that was not related to treatment. Thirty-four GST patients and 44 MTX patients were evaluated for efficacy. Thirty-eight joints were counted. The number oftender and swollen joints, the Lansbury articular index, morning stiffness, activities of daily living (ADL) score, and erythrocyte sedimentation rate improved significantly in both groups without statistical intergroup differences. After 12 months, there was a significant deterioration of the mean Larsen index and the number of joints with erosions without intergroup difference. However, the radiological progression was retarded significantly during the second 6-month period in the gold group, whereas this effect was less pronounced in the MTX group. At 12 months, the progression rate was the same in both groups.