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ID PMID Title PublicationDate abstract
7748214 Every-other-week methotrexate in patients with rheumatoid arthritis. A double-blind, place 1995 May OBJECTIVE: To determine if patients with rheumatoid arthritis (RA) that is stable with weekly methotrexate (MTX) therapy could be switched to an every-other-week regimen of MTX. METHODS: Forty-seven patients with classic or definite RA who had received MTX for at least 8 months were studied. Clinical measurements consisted of the number of tender and swollen joints, physician and patient global evaluation of disease activity on a 5-point scale, grip strength, patient evaluation of pain, morning stiffness, and the interval to onset of fatigue from time of awakening. Laboratory measures included the erythrocyte sedimentation rate (ESR), rheumatoid factor, C-reactive protein (CRP), and baseline serum folate levels. Uptake of MTX was measured with tritiated thymidine from peripheral blood mononuclear cells (PBMC) from patients ex vivo. Serum measures of interleukin-1 beta (IL-1 beta), IL-6, and tumor necrosis factor alpha (TNF alpha) were performed in sera, and TNF alpha was also measured on PBMC supernatants. RESULTS: Twelve of the 23 patients receiving every-other-week MTX (52%) were able to complete 6 months of this treatment without experiencing a disease flare. Eleven of the 23 patients receiving every-other-week MTX (48%) withdrew from the study before completing 6 months of treatment, because of a flare. No significant differences in clinical or laboratory parameters were seen when the 24 patients receiving weekly MTX were compared with the 12 patients in the every-other-week MTX group who successfully completed 6 months of the study. None of the changes in serum cytokine levels were significantly different between the patients receiving MTX weekly versus those receiving it every other week, and changes in ESR and CRP did not differ between groups. Age, sex, RA disease duration, MTX weekly dose or duration, baseline joint counts, or serum folate status did not predict a flare. Tritiated MTX uptake did not differ between groups. CONCLUSION: Some patients with RA that is stable on weekly dosing are able to change to every-other-week dosing without experiencing a flare in their disease activity.
8588077 [Treatment of rheumatoid arthritis of senile onset with methotrexate]. 1995 Dec Elderly onset rheumatoid arthritis is a not rare disease with relevant social implications. The most important question is represented by the therapeutic choice, in relation to the typical problems of the elderly patients and to the frequent coexistence of other diseases. In this work, we evaluated the practicability and the efficacy of methotrexate therapy, at the dose of 5 mg/week, in 27 patients affected by elderly onset rheumatoid arthritis (mean age 73.76 +/- 3.39 years, range 70-83). Low dose prednisone was associated in order to control painful symptoms. Also sulindac was allowed. Frequent clinical and hematochemical controls were made in order to precociously evaluate the appearance of side effects. All the 27 patients completed the first year of treatment; during this period there was no drop out. Sixteen patients finished the second year too; during this year one patient dropped out because of significant hypertransaminasemia and another patient did not respect the follow-up. Clinical and hematochemical parameters were monitored. A significant improvement of all data was observed from the third month. A further amelioration was recorded in the following months. Our data suggest the efficacy and the safety of low dose methotrexate in the treatment of elderly onset rheumatoid arthritis. A careful evaluation of side effects is obviously necessary.
8838506 B lymphocytic clonal expansion in rheumatoid arthritis. 1996 Jan OBJECTIVE: To learn whether rheumatoid factor (RF), HLA-DR4, or current therapy influences clonal expansion of B lymphocytes (B cells) in persons with rheumatoid arthritis (RA). METHODS: We measured clonal expansion by analysis of cell surface staining for immunoglobulin light chains. Double staining methods detected a B cell marker (CD19) plus either kappa or lambda on peripheral blood lymphocytes from subjects with RA (n = 26) and controls (n = 26). The difference between frequency histograms of surface kappa and lambda staining was determined by the Kolmogorov-Smirnov statistic D that represents the fraction of clonally expanded B cells. RESULTS: The mean D value in RA was over 50% higher than in the controls [0.225 +/- SD 0.155 versus 0.144 +/- 0.025 (p < 0.0001)]. Ten subjects with RA had values exceeding +2 SD for controls (p = 0.0007). Mean D correlated with RF titer (Spearman's rank correlation coefficient rSp + 0.53, p = 0.006). All 10 high D values were found in the RA subgroups with positive serum tests for RF and with the HLA-DR4 positive genotype. The channel of maximal difference between kappa and lambda staining was higher in the RA group than in controls, showing that clonal expansion was most marked among brightly staining cells. Patients with RA currently receiving low dose methotrexate (MTX) tended to have higher D values than those not receiving MTX (mean 0.29 versus 0.18, respectively, p < 0.025). The RA group currently receiving MTX had a higher frequency of abnormal D values (7 of 11 versus 3 of 15 not currently receiving MTX, p = 0.03). This probably reflects preferential use of MTX for severely affected individuals. Confirmatory studies to detect clonal immunoglobulin gene rearrangements were attempted in selected individuals with high D values, but none was demonstrated in total leukocytic or B cell enriched fractions. CONCLUSION: Findings consistent with B cell clonal expansion occur in about 40% of persons with RA, particularly in the subgroups with positive serum tests for RF and with the HLA-DR4 genotype. However, the clonal expansion level must be below the sensitivity of confirmatory methods.
8493580 [Clinical study of rheumatoid interstitial lung disease evaluated by high resolution CT]. 1993 Feb High resolution computed tomographic (HRCT) scans were obtained in 215 patients with rheumatoid arthritis to assess pulmonary fibrosis (PF). We classified the HRCT appearances as five-point scale (0-4) based on the degrees of PF. The results were as follows: 1. We found 117 cases (54.4%) of PF on HRCT. 2. Patients with PF (grade 1-4) showed significantly increased leucocyte cell counts and significantly worsened pulmonary function test than patients without PF (grade 0). 3. Patients with advanced articular involvement had significantly higher prevalence of PF than others without them. 4. Patients who were previously or currently receiving gold sodium thiomalate (GST) injection or administration of methotrexate had higher prevalence of PF than others. However, patients who were receiving long term GST therapy (1 year long or sigma 1000 mg) had slightly lower prevalence of PF than others. This finding suggests that dose-dependent lung injury is not related to GST therapy. 5. Patients with advanced PF (grade 3, 4) had high prevalence of male sex, smoker, extraarticular manifestation.
8535644 Practical clinical pharmacology and drug interactions of low-dose methotrexate therapy in 1995 Nov The clinical pharmacology and clinically important drug interactions of methotrexate (MTX) are reviewed. The points discussed are as follows. (a) The bioavailability of oral preparations of MTX is approximately 15-20% lower than that of intramuscular or intravenous MTX, although there is great variability in relative bioavailability. (b) Protein-binding displacements are unlikely to be of importance with this low-to-medium protein-binding drug. Because MTX is polyglutamated and remains within cells, dialysis is unlikely to be an effective mode of elimination. The principal excretory pathway of MTX is via the kidneys, although some is also excreted through the bile. These facts imply that: (i) MTX needs to be used with extreme caution, if at all, in the face of renal insufficiency; (ii) cholestyramine may be used to enhance the biliary excretion of MTX; and (iii) probenecid may be a cost-effective way to increase the efficacy of MTX. (c) Although aspirin inhibits MTX clearance more than other non-steroidal anti-inflammatory drugs (NSAIDs), clinical toxicity of aspirin is not significantly greater than that of other NSAIDs. In all cases this negative interaction is very rare (although, of course, it needs to be considered at all times). (d) It is possible that corticosteroids inhibit MTX metabolism, although this requires significant research. (e) Trimethoprim-sulphamethoxazole (TS) toxicity is well documented and may be related to synergistic anti-folate effects of MTX and TS. (f) Folic acid decreases MTX toxicity, possibly through an effect on dihydrofolate reductase.
8722204 Autoimmune connective tissue disease, chronic polyarthritides and B cell expansion: risks 1996 Jan Several autoimmune diseases, including Sjögren's syndrome (SS), systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA), are characterized by B cell hyperactivity, polyclonal activation, and autoantibody synthesis. Overt B cell clonal expansion occurs in a minority of the patients, while at the tissue level clonotypic B cells may be more easily detected in the majority of patients. The data available suggests that antigen-driven B cell expansion, eventually leading to somatic mutation and transformation, is the main event. Immunosuppressive drugs known to increase chromosomal damage and to lead to earlier transformation should therefore be avoided, unless strictly necessary to preserve vital organ functioning. New immunosuppressive drugs such as methotrexate, cyclosporine A, and Rapamycin are promising for they seem to offer effective control of disease-related organ damage with acceptable side effects. The B cell lymphoproliferative diseases occurring under treatment seem to remit spontaneously after prompt drug withdrawal. Close surveillance, employing new techniques capable of detecting early B or T cell clonal expansion, may allow better monitoring of possible complications. Biological agents such as alpha-interferon and monoclonal antibodies (which are directed against specific immunological mediators and thus target-selected steps of the immune-inflammatory process) have opened promising new research topics in all these diseases.
7670788 Shared care between hospital and general practice: an audit of disease-modifying drug moni 1995 Jul To assess the correspondence between ideal and actual monitoring for disease-modifying anti-rheumatic drugs and the reasons for protocol failure, and the sharing of this task between primary and secondary care, we studied 249 patients with rheumatoid arthritis in a single district general hospital. Ideal monitoring protocols were derived from data sheets and from the rheumatological literature. Overall the ideal protocol was followed in 65% of cases: this ranged from 93% for methotrexate to 26% for sodium aurothiromalate. Most of the monitoring was done in general practice (e.g. 67% of all blood tests) and, with some exceptions, general practitioners (GPs) were willing to perform this task. However, many GPs reported logistic differences with specimen transfer and expressed the need for more information and support. Poor communication between hospital, patient and GP was also found to be a cause of protocol failure.
8102405 Bronchoalveolar lavage and lung biopsy in rheumatoid arthritis. In vivo effects of disease 1993 Jun Bronchoalveolar lavage (BAL) and histology of transbronchial forceps biopsy was performed in 59 patients with rheumatoid arthritis (RA) to evaluate the in vivo effects of disease modifying drugs (DMARD). All patients had no clinical pulmonary symptoms and there was no evidence of drug induced alveolitis. Patients were divided into 5 subgroups according to drug treatment: 9 patients taking chloroquine, 15 patients gold, 8 patients penicillamine, 8 patients methotrexate (MTX) and 19 patients not taking DMARD. Duration of DMARD regimen was more than 3 months. No patient was treated with corticosteroids. BAL results revealed an increased percentage of lymphocytes and a diminished proportion of alveolar macrophages in patients treated with gold, penicillamine, MTX and no DMARD. In contrast, patients receiving chloroquine had a normal distribution of lymphocytes and macrophages as seen in a control group of 15 persons. Patients taking MTX showed a normal distribution of T and B lymphocytes and DR positive cells, whereas patients receiving chloroquine, gold, or penicillamine had an elevated proportion of T lymphocytes and DR positive cells and a diminished percentage of B lymphocytes. The latter was also observed in patients not taking DMARD. The percentage of natural killer cells was significantly elevated only in the penicillamine group. Patients receiving gold had higher absolute values of CD3, CD4 and DR positive cells. Abnormal lung histology was associated with an increased percentage of lymphocytes and with higher DR positive cells in BAL. Patients not receiving DMARD had a significantly higher percentage (42.1%) of abnormal histologic features of lung tissue than patients receiving DMARD (17.5%).(ABSTRACT TRUNCATED AT 250 WORDS)
7981992 Combination of methotrexate and sulphasalazine vs methotrexate alone: a randomized open cl 1994 Nov To compare efficacy, toxicity, and the pharmacokinetics of the combination of sulphasalazine (SASP) and methotrexate (MTX) vs MTX alone in the treatment of SASP-resistant RA we conducted a controlled open clinical trial. Forty RA patients with active arthritis despite adequate SASP therapy, were allocated randomly to regimes of either SASP+MTX or MTX alone. The patients were evaluated openly by a single observer for 24 weeks. In the first 15 patients using the combination, pharmacokinetics of MTX without and with SASP were studied. Thirty-eight patients completed the trial. The mean decrease in the disease activity score in the group of patients receiving the combination was significantly greater than in the MTX group (-2.6 vs -1.3 respectively). The same pattern was seen concerning the other efficacy variables. There was no difference in the occurrence of toxicity. SASP had no influence on the pharmacokinetics of MTX. In conclusion in this open study the efficacy of the combination of MTX and SASP seems to be superior to MTX alone, the toxicity of both therapies was similar. This effect was not explained by the pharmacokinetics of MTX which were not altered by concomitant SASP administration.
7793157 [Combination therapy in chronic polyarthritis]. 1995 Mar Long-term effects of disease-modifying antirheumatic drugs are not at all satisfactory. Therefore combinations of different substances have long been studied. But no convincing recommendations could be derived from those results. Some combinations seem to be more effective than the single substances, but often have more side-effects. First of all, those types of rheumatoid arthritis must be defined which require an aggressive therapy. These may profit from combinations with sulfasalazine, methotrexate or azathioprine. But such questions may only be answered by long-term studies which can be statistically evaluated.
7699617 Antiperinuclear factor and disease activity in rheumatoid arthritis. Longitudinal evaluati 1994 Dec OBJECTIVE: To study the correlation between antiperinuclear factor (APF) titer and disease activity variables in patients with rheumatoid arthritis (RA) treated with methotrexate (MTX) or azathioprine (AZA) and to investigate whether changes are dependent on the drug used. METHODS: Serial measurements of APF titers (2-fold dilutions) and disease activity variables in a 48-week double blind trial comparing MTX and AZA in 64 patients with RA. APF titers at baseline and during followup, and correlations between APF titers and disease activity variables and their changes from baseline were studied in the patient group as a whole and in the 2 treatment groups. RESULTS: The prevalence of the APF at baseline in the MTX group and in the AZA group with undiluted serum was 15/31 (48%) and 19/33 (58%), respectively. With serum diluted 1:10 this was about 25% higher. The APF titer ranged from 1/10 to 1/640. No sustained changes in APF titers were observed during followup. Statistically significant correlations were found between APF titers and 2 of the 4 disease activity variables, as well as for their changes from baseline at some time points and were most pronounced in the AZA group. However, no consistent correlation between APF titers and disease activity variables could be established. APF changed from negative to positive during followup in 4 patients (6.3%) and from positive to negative in 4 (6.3%). Changes in APF titer between 2 consecutive measuring points did not exceed 2 dilution steps. CONCLUSION: The APF titer showed no sustained change during the followup period. There was no consistent correlation between APF titer and disease activity variables. We conclude that serial measurements of the APF in longitudinal studies do not give additional information.
8970056 Methotrexate osteopathy, does it exist? 1996 Dec We describe 2 postmenopausal women with rheumatoid arthritis (RA). They developed fractures during their treatment with weekly low dose methotrexate (MTX). The adverse effect of longterm low dose regimens of MTX on bone metabolism has been described as "methotrexate osteopathy," an analogy of the syndrome known in pediatric oncology. MTX may be an additional risk factor for osteoporosis and fractures in RA. This therapy should be relatively contraindicated in patients with multiple risk factors for osteoporosis.
8733440 Divergent effects of methotrexate on the clonal growth of T and B lymphocytes and synovial 1996 Apr OBJECTIVE: To define the mechanisms whereby methotrexate (MTX) manifests its effects in patients with rheumatoid arthritis. METHODS: T and B cells from peripheral blood and rheumatoid synovial tissues, synovial adherent cells, and the human fibrosarcoma cell line HT1080 and its mutant (defective in an enzyme in the nucleotide salvage pathway) were tested for clonal growth when cultured with MTX. Normal human fibroblasts and those with a deficiency in a salvage pathway were cultured with MTX in the presence or absence of purine and pyrimidine bases. RESULTS: Clonal growth of T and B cells, but not synovial cells, was inhibited by clinically relevant concentrations of MTX. Slowly proliferating fibroblast lines were resistant to MTX, whereas their rapidly proliferating counterparts were not. However, mutant fibroblast lines deficient in a salvage pathway were sensitive to MTX despite slow proliferation. Similarly, while skin fibroblasts were resistant to MTX, germline mutant fibroblasts deficient in a salvage pathway were sensitive to small concentrations of MTX. CONCLUSION: T and B lymphocytes, but not synovial cells, may be the target of MTX in vivo. Resistance to MTX may be associated with slow proliferation and the ability to synthesise nucleotides via salvage pathways. MTX can inhibit proliferation of even slowly growing cells by restricting the supply of nucleotides obtained via a salvage pathway, by removal of purine and pyrimidine bases, or by inducing a deficiency in a salvage pathway. It may be possible to manipulate the therapeutic effect of MTX by adjusting the amounts of purines and pyrimidines available to the cells in vivo.
1485816 Methotrexate treatment of rheumatoid arthritis: is a fortnightly maintenance schedule enou 1992 Dec In 15 patients with rheumatoid arthritis who were in clinical remission the weekly regimen of methotrexate treatment was changed to fortnightly without a change in dose. A total of 13 patients completed a 12 month trial. No change in clinical or laboratory parameters occurred. There was no change in the use of analgesics or non-steroidal anti-inflammatory drugs and the patients remained in remission. Two patients had to be withdrawn after two and four months respectively because of a flare in disease activity. It is suggested that in most patients with rheumatoid arthritis who are treated with methotrexate and whose disease activity is stable a fortnightly regimen can be permitted without affecting drug efficacy.
8833063 The future use of biologic therapies in combination for the treatment of rheumatoid arthri 1996 Mar The complexity of the immune system, exemplified by the pleiotropic effects of many cytokines and the redundancy of regulatory networks controlling immune responses, suggests that single therapeutic interventions will offer transient or less than clinically meaningful benefit. Theoretically, combination therapy using 2 or more biologic agents will modulate important symptomatic and objective manifestations of rheumatoid arthritis (RA). Data from animal models suggest that use of biologic agents in combination can be synergistic and may alter the severity and course of disease. Although combinations of biologic agents have yet to be used in human disease, successful examples employing immunosuppressive agents exist: cyclosporin (CsA) with methotrexate in patients with persistent active RA, as well as azathioprine and/or mycophenolate mofitil with CsA in organ transplantation and acute graft rejection. There are many arguments against the use of combination biologic therapies including acute infusion related toxicities, infection, malignancy, autoimmune manifestations, and expense. While caution dictates that phase I-II clinical trials be performed in patients with longstanding, refractory disease, subsequent trials should be conducted in patients with earlier, more responsive disease. Successful combination biologic therapies must afford sufficient duration of benefit (at least 6, preferably 12 months), cost comparable to approved 2nd line agents, ease of treatment, and an acceptable safety profile.
1404122 Accelerated nodulosis during low dose methotrexate therapy for rheumatoid arthritis. An an 1992 Jun OBJECTIVE: To obtain information on the occurrence of accelerated nodulosis during methotrexate (MTX) for rheumatoid arthritis (RA), localization, size and presence in heart and lungs of these nodules, predisposing factors, relationship with other extraarticular manifestations (EAM) and their histological features. METHODS: Ten patients with accelerated nodulosis were studied. Four participated in a double blind study of MTX and azathioprine. Patient characteristics, localization, size and histopathology of new nodules were determined. Echocardiography and chest roentgenograms were performed. RESULTS: Accelerated nodulosis occurred exclusively during treatment with MTX in our double blind study. The estimated incidence was 8%. One patient reported was rheumatoid factor negative. Newly developed nodules were small, and located in the fingers in all patients and in additional sites in 7. Pretreatment nodules were not found in the fingers. In one patient nodules on the mitral valve were found, but this was not likely to be associated with the use of MTX. No new pulmonary nodules were found. Other EAM developed concurrently in 4 patients. Histopathology revealed typical rheumatoid nodules. In 3 patients nodulosis regressed after MTX was stopped. In 2 of them they recurred after a rechallenge. CONCLUSIONS: Accelerated nodulosis during MTX for RA is not rare, and occurs despite good clinical response of polyarthritis. Rheumatoid factor positivity is not a prerequisite. New nodules are small and preferentially located in the fingers. Recurrence after rechallenge with MTX suggests causality.
1578095 Effects of copper supplementation on ceruloplasmin and copper-zinc superoxide dismutase in 1992 Apr Inflammation, an acute phase stress, alters copper (Cu) metabolism, but effects on human Cu requirements are unknown. Cu supplementation (2 mg/day, 4 weeks) increased erythrocyte Cu-zinc (Zn) superoxide dismutase (SOD) activity levels in 18 of 23 rheumatoid arthritis (RA) patients receiving gold or methotrexate (mean increase 21%). SOD values were significantly lower in RA patients than in 47 age- and sex-matched controls before, but not after supplementation. Supplementation did not significantly affect ceruloplasmin (Cp) activity or protein concentrations in either group. However, RA subjects showed significantly lower Cp activity to protein ratios compared to controls, before and after supplementation. Cu supplementation did not affect acute phase status of RA patients as evidenced by unchanged serum alpha-1-acid glycoprotein levels. In conclusion, the effects of Cu supplementation on erythrocyte SOD activities suggested a trend toward marginal Cu status in RA patients.
8871838 In vitro effects of methotrexate on polyamine levels in lymphocytes from rheumatoid arthri 1996 Jul OBJECTIVE: Several studies have documented increased levels of polyamines in rheumatoid arthritis (RA). We have suggested that one of the mechanisms of action of methotrexate (MTX) involves the inhibition of polyamine synthesis in lymphocytes. In this study, we sought to establish the inhibitory effect of MTX on polyamine synthesis and its specificity. METHODS: Polyamine levels were determined in stimulated RA lymphocytes incubated in vitro with MTX and compared to levels in lymphocytes incubated with hydrocortisone, D-penicillamine, or medium alone. Lymphocyte polyamine levels were correlated with IgM-rheumatoid factor (RF) synthesis. RESULTS: Incubation with MTX resulted in concentration-dependent decreased intracellular levels of spermidine and spermine, while putrescine levels were not affected. Addition of folinic acid or S-adenosyl-methionine (SAM) prevented this MTX-induced inhibition. Incubation with D-penicillamine or hydrocortisone had no significant effect on polyamine levels. There was a positive correlation between intracellular polyamine levels and the inhibition of IgM-RF synthesis by MTX. CONCLUSION: These data suggest that MTX inhibits the synthesis of spermidine and spermine in stimulated RA lymphocytes through inhibition of the SAM-dependent pathway. This inhibition may be related to the immune-modulating properties of MTX.
7551660 Effect of methotrexate alone or in combination with sulphasalazine on the production and c 1995 Aug In a recent study from our group, the combination of methotrexate and sulphasalazine (MTX + SASP) seemed superior to MTX alone in the treatment of rheumatoid arthritis (RA). To assess the impact of these therapies on the cytokine cascade, the in vitro production and circulating concentrations of several cytokines and endogenous cytokine antagonists were measured in 30 healthy controls and longitudinally in a subset of 26 patients enrolled in this study. Compared to controls, RA patients had significantly higher circulating concentrations of interleukin-6 (IL-6), soluble receptors for tumour necrosis factor (sTNFR), soluble receptors for interleukin-2 (sIL-2R) and interleukin-1 receptor antagonists (IL-1RA), and their peripheral blood mononuclear cells (PBMNC) showed a higher spontaneous production of interleukin-1 beta (IL-1 beta), tumour necrosis factor alpha (TNF alpha) and IL-1RA (both secreted and cell-associated) and a higher stimulated production of cell-associated TNF alpha, IL-1RA and (to a lesser extent) IL-1 beta. Treatment with MTX alone (n = 12) or combined with SASP (n = 14), resulted in significant reductions of circulating IL-6 and sIL-2R but did not alter IL-1 beta, TNF alpha or IL-1RA concentrations. Decreases in circulating levels of sTNFR and in the in vitro production of cell-associated IL-1 beta and IL-1RA after stimulation were only observed in patients treated with MTX + SASP. The concentrations of IL-1RA and sTNFR in the circulation exceeded moderately those of IL-1 beta and TNF alpha but this is probably insufficient to block IL-1 and TNF alpha activity. In conclusion, therapy with MTX alone or with SASP modulates IL-6 and sIL-2R concentrations in RA. Decreased production of IL-1 beta and IL-1RA and circulating sTNFR levels were only observed during therapy with MTX + SASP. Whether this relates to the better clinical effect observed with the combination therapy remains to be investigated. Circulating levels of IL-6, sIL-2R and sTNFR seem useful markers of disease activity in RA.
8452768 New focus on treatment for rheumatoid arthritis. 1993 Mar Although the pathogenesis of rheumatoid arthritis increasingly continues to be well understood, therapeutic approaches to the disease remain relatively unsophisticated and based more on anecdote than scientific reasoning. During the past year, additional supportive data regarding the usefulness of front-line agents such as methotrexate and hydroxychloroquine were acquired, and novel potential interventions, such as pulse gammaglobulin and OM-8980 were identified. Animal model studies still support the prospect that genuine remission-inducing strategies will be realized in the future.
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