Efficacy and Toxicity Profile of Methotrexate Chloroquine Combination in Treatment of Active Rheumatoid Arthritis

Background

The present study was conducted to study the efficacy and toxicity profile of methotrexate chloroquine combination in treatment of active rheumatoid arthritis.

Methods

24 patients of rheumatoid arthritis confirming to revised American Rheumatism Association (ARA) criteria were studied prospectively for twenty months. Clinical evaluation was made every 3 months. Clinical disease variables measured at each visit were number of joints with swelling, number of joints with tenderness and pain, duration of morning stiffness and physician and patient assessment of disease activity. Blood counts, liver function tests and other adverse effects due to drugs were monitored every 2 months.

Results

10 patients demonstrated more than 50% improvement. 4 patients withdrew from study, 2 because of excessive nausea and vomiting and 2 because of noncompliance. Other side effects noted were hyperpigmentation, photosensitivity, skin rashes, raised transaminases and stomatitis.

Conclusion

Methotrexate chloroquine combination has good efficacy and toxicity profile. Gastrointestinal side effects are most common and usually responsible for the discontinuation of the drugs.Key Words: Rheumatoid arthritis, Methotrexate, Chloroquine, Efficacy, Toxicity     

Treatment with soluble tumor necrosis factor receptor (sTNFR):Fc/p80 fusion protein ameliorates relapsing-remitting experimental autoimmune encephalomyelitis and decreases chemokine expression

Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease with pathological and clinical similarities to the major human demyelinating disease multiple sclerosis (MS). Multiple lines of evidence in recent years implicate the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) in the pathogenesis of both EAE and MS. TNF-alpha cellular responses are mediated by signaling through receptors, which are expressed in two functional forms, designated according to molecular weight p55/60 and p75/80. We report a treatment trial using the extracellular domain of the p80 TNFR in a bivalent fusion construct designated soluble tumor necrosis factor receptor (sTNFR):Fc to treat EAE. sTNFR:Fc/p80, given after the onset of clinical signs, reduced the clinical deficit of the first attack of relapsing-remitting EAE (RR-EAE) and the exacerbation rate for subsequent attacks. The effect was reversible as mice treated with sTNFR:Fc/p80 reverted to an exacerbation rate and disease severity typical of placebo-treated animals after treatment was discontinued. Treatment of RR-EAE with sTNFR:Fc/p80 decreased expression of chemokines MIP-1alpha (Monocyte Inflammatory Protein)/CCL3, MIP-1beta/CCL4 and MIP-2/CXCL1-2 in the central nervous system. This treatment trial reveals an important function of TNF in the pathogenesis of RR-EAE and propose the mechanism of beneficial action of sTNFR:Fc/p80 in this disease.     

Routine Cyclosporine concentration - C2 level Monitoring. Is it helpful during the early post Transplant Period?

Background

Pre dose or trough blood cyclosporine (CSA) concentration is routinely monitored and the result is used to alter patient''s drug dosing. Patients with identical pre dose blood CSA may have very different systemic exposure to the drug. Recently CSA 2 hour post dose level [C2] has been reported to correlate better with drug exposure. We undertook this study to evaluate the influence of trough and C2, CSA concentration monitoring on short-term renal allograft outcomes.

Methods

25 patients of renal transplant receiving a triple drug regimen of CSA micro emulsion (Panacea Biotec) 8mg/kg, azathioprine 1mg/kg and prednisolone 0.5mg/kg were analyzed prospectively for graft outcomes. CSA levels were monitored in whole blood by radioimmunoassay using monoclonal antibodies, at 72 hours after the transplant.

Results

The mean age of patients was 37.08 + 9.1 years. There were 20 males and 5 females. The mean age of donors was 40.2 + 8.2 years. There were 11 related donors with at least a haplomatch, 4 spousal and 10 unrelated donors with a nil antigen match. The mean pre dose CSA concentration was 289.22 + 171.9ng/ml; range (98.8 + 783.41ng/ml). The CSA concentration at 2 hours after the CSA administration was 838 + 310.87ng/ml (range, 169 + 1268ng/ml). 3 (12%) patients had acute rejection. In these patients the mean pre dose CSA concentration was 328.67ng/ml and the mean C2, CSA concentration was 1006.26ng/ml. CSA induced hemolytic uraemic syndrome was diagnosed in one patient. The trough and C2, CSA concentration levels were 174 and 870.83ng/ml respectively in this patient.

Conclusion

In our study CSA levels, trough and peak showed significant inter patient variability. The trough and C2 concentration levels did not correlate with the episodes of acute rejection. We conclude that in a triple drug regimen with fixed dosing schedules routine trough CSA level monitoring is not helpful in the acute post renal transplant period.Key Words: Cyclosporine levels, Cyclosporine trough levels, C2 levels     

Human and murine lymphocyte neurotrophin expression is confined to B cells

Recent reports indicate that autoreactive T cells may produce neurotrophic factors capable of mediating repair and regeneration of damaged neurons. By using semiquantitative RT-PCR, we examined gene expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and the trkB BDNF receptor in autoreactive T cells from SWXJ mice immunized with the p104-117 encephalitogen of myelin proteolipid protein (PLP 104-117). We observed antigen-inducible expression of NGF and BDNF, but not NT-3 and trkB, in lymph node cells activated with PLP 104-117. To determine which leukocyte subpopulation expressed neurotrophins, CD4(+), CD8(+), B220(+), CD11b(+), and NK1.1(+) cells were purified from activated primary cultures, and their mRNAs were analyzed. Neurotrophin expression was also measured in CD3(+) T cells purified from mouse CNS during acute onset of experimental autoimmune encephalomyelitis as well as in resting and activated human T cells and B cells purified from peripheral blood of normal subjects. In all cases, we found that neurotrophin expression was confined exclusively to B cells (B220(+)) in both mouse and human. CD3(+), CD4(+), and CD8(+) T cells as well as NK1.1(+) cells and CD11b(+) monocytes and macrophages did not express any detectable BDNF, NGF, NT-3, or trkB under any conditions. Our data indicate that B cells rather than T cells are the predominant if not the only source of leukocyte-derived neurotrophins and as such may provide "protective autoimmunity" in repair and regeneration of the injured nervous system.