Low-dose Methotrexate Therapy Research Articles

Increased sensitivity to apoptosis induced by methotrexate is mediated by JNK

Low-dose methotrexate (MTX) is an effective therapy for rheumatoid arthritis (RA), yet its mechanism of action is incompletely understood. The aim of this study was to explore the induction of apoptosis by MTX. Flow cytometry was performed to assess changes in the levels of intracellular proteins, reactive oxygen species (ROS), and apoptosis. Quantitative polymerase chain reaction was performed to assess changes in the transcript levels of select target genes in response to MTX. MTX did not directly induce apoptosis but rather "primed" cells for markedly increased sensitivity to apoptosis via either mitochondrial or death receptor pathways, by a JNK-dependent mechanism. Increased sensitivity to apoptosis was mediated, at least in part, by MTX-dependent production of ROS, JNK activation, and JNK-dependent induction of genes whose protein products promote apoptosis. Supplementation with tetrahydrobiopterin blocked these MTX-induced effects. Patients with RA who were receiving low-dose MTX therapy expressed elevated levels of the JNK target gene, jun. Our results support a model whereby MTX inhibits reduction of dihydrobiopterin to tetrahydrobiopterin, resulting in increased production of ROS, increased JNK activity, and increased sensitivity to apoptosis. The finding of increased jun levels in patients with RA receiving low-dose MTX supports the notion that this pathway is activated by MTX in vivo and may contribute to the efficacy of MTX in inflammatory disease.

Two Cases of Severe Pancytopenia Associated with Low-Dose Methotrexate Therapy in Patients with Chronic Kidney Disease and Rheumatoid Arthritis

Due to its efficacy and tolerability, low dose oral methotrexate (MTX) therapy has been widely used for treatment of rheumatoid arthritis (RA). However, it can rarely cause serious, life-threatening hematologic toxicities, such as pancytopenia. We report here on two patients with chronic kidney disease (CKD), who developed severe pancytopenia after 5 years (cumulative dose 1,240 mg) and 4 years (cumulative dose 1,320 mg) of low dose MTX therapy for treatment of RA, respectively. Both patients presented with renal insufficiency, hypoalbuminemia, concurrent use of nonsteroidal anti-inflammatory drugs, and elevated mean corpuscular volume of red blood cells (RECs), all of which are known as risk factors of MTX-induced pancytopenia. Despite receiving treatment, which included REC and platelet transfusions, antibiotic therapy, granulocyte colony stimulating factor, and leucovorin rescue, one patient died of sepsis. Based on our case study, prompt investigation of risk factors associated with MTX toxicity is required for all patients receiving MTX therapy. MTX treatment, even at a low dose, should be discontinued in patients with advanced CKD.

Oral events related to low-dose methotrexate in rheumatoid arthritis patients

Low-dose methotrexate (MTX) is frequently used for patients with rheumatoid arthritis (RA). High doses of MTX frequently produce side effects. The aim of this study was to explore oral complications of low-dose MTX therapy in a population of RA patients. This is a cross-sectional study in which oral examination was performed on a population of RA patients. Patients undergoing MTX therapy (5-20 mg weekly) for at least six months were included in the study group, and RA patients being treated under another regimen were used as controls. The frequency of oral lesions was compared between groups. The chi-square test was used to compare frequencies. Relative risk (RR) and its confidence interval (CI) were established. Significance level was set at 0.05. Twenty-eight RA patients on a low-dose MTX regimen and 21 controls were enrolled in the study. Oral lesions were found in 22 patients (78.6%) undergoing MTX therapy, and in 5 patients (23.8%) undergoing other therapies (p < 0.001). There were no significant differences regarding age, gender or dosage. The most common oral events observed in patients in the MTX group were ulcerative/erosive lesions (60.7%) and candidiasis (10.7%). Patients in the control group presented lower prevalence of the same lesions (p < 0.001). The RR for developing oral lesions was 11.73 (CI 2.57 - 58.98), with low-dose MTX therapy. In conclusion, the prevalence of oral mucosa lesions in RA patients receiving low doses of MTX therapy is higher than in RA patients not receiving the drug.

Methotrexate-induced pneumonitis in Crohn’s disease

&#x0D; &#x0D; &#x0D; Methotrexate (MTX) is a folate-antagonist used in several neoplastic and inflammatory diseases. Reports of pulmonary complications in patients given low-dose MTX therapy are increasing. Pulmonary toxicity from MTX has a variable fre- quency and can present with different forms. Most often MTX-induced pneumonia in patients affected by rheumatoid arthritis (RA) is reported. In this paper we describe a case of MTX-related pneumonitis in a relatively young woman affected by Crohn's disease who presented non-productive cough, fever and dyspnea on exer- cise. Chest X-ray demonstrated bilateral interstitial infil- trates and at computed tomography (CT) ground-glass opac- ities appeared in both lungs. At spirometry an obstructive defect was demonstrated. A rapid improvement of symptoms and the regression of radiographic and spirometric alter- ations was achieved through MTX withdrawal and the intro- duction of corticosteroid therapy.&#x0D; &#x0D; &#x0D;

Methotrexate-induced pneumonitis in Crohn's disease. Case report and review of the literature.

Methotrexate (MTX) is a folate-antagonist used in several neoplastic and inflammatory diseases. Reports of pulmonary complications in patients given low-dose MTX therapy are increasing. Pulmonary toxicity from MTX has a variable frequency and can present with different forms. Most often MTX-induced pneumonia in patients affected by rheumatoid arthritis (RA) is reported.In this paper we describe a case of MTX-related pneumonitis in a relatively young woman affected by Crohn's disease who presented non-productive cough, fever and dyspnea on exercise. Chest X-ray demonstrated bilateral interstitial infiltrates and at computed tomography (CT) ground-glass opacities appeared in both lungs. At spirometry an obstructive defect was demonstrated. A rapid improvement of symptoms and the regression of radiographic and spirometric alterations was achieved through MTX withdrawal and the introduction of corticosteroid therapy.

Rare incidence of methotrexate-specific lesions in liver biopsy of patients with arthritis and elevated liver enzymes

IntroductionThe present study objective was to evaluate the incidence of methotrexate (MTX)-specific liver lesions from the analysis of a liver biopsy of inflammatory arthritis patients with elevated liver enzymes.MethodsA case-control study was performed with 1,571 arthritis patients on long-term low-dose MTX therapy. Results of liver biopsy were analyzed in 41 patients with elevated liver enzymes. The expression of autoimmune markers was also assessed. This population was compared with 41 disease control subjects obtained from the same database, also on MTX but without elevated liver enzymes, matched for age, sex and rheumatic disease.ResultsCompared with the disease controls, patients with liver biopsy showed lower disease duration and lower MTX exposure, weekly and cumulative doses, reflecting shorter treatment duration due to liver abnormalities. Liver biopsies showed 17 autoimmune hepatitis-like (AIH-like) lesions, 13 nonalcoholic steatohepatitis-like lesions, seven limited liver lesions, and two primary biliary cirrhoses. However, MTX-specific lesions with dystrophic nuclei in hepatocytes were seen in only two cases. Liver biopsy lesions were associated with autoimmune markers (P = 0.007); notably, AIH-like lesions were associated with rheumatoid arthritis and with the presence of the HLA-DR shared epitope.ConclusionsMTX-specific liver lesions are rarely observed in arthritis patients under long-term MTX therapy and elevated liver enzymes.

THERAPY-RELATED MYELODYSPLASTIC SYNDROME FOLLOWING CYCLOPHOSPHAMIDE PULSE AND/OR METHOTREXATE THERAPY IN A PATIENT WITH SYSTEMIC LUPUS ERYTHEMATOSUS

A 27-year-old woman exhibited progressive pancytopenia during cyclophosphamide pulse therapy for lupus nephritis and low-dose methotrexate therapy for severe arthralgia. Bone marrow aspiration revealed highly abnormal cell morphology, indicating therapy-related myelodysplastic syndrome. Pancytopenia and bone marrow cell morphology improved 3 months after discontinuation of cyclophosphamide. It is necessary to promptly examine bone marrow cell morphology and chromosomal aberration in cases with connective tissue diseases complicated by sudden cytopenia during immunosuppressive therapy with chemotherapeutic agents.

Severe Pancytopenia Induced by Low-Dose Methotrexate Therapy for Rheumatoid Arthritis.

Abstract 4224Low-dose of methotrexate (MTX), less than 20 mg per week, is a regimen, widely used for rheumatoid arthritis (RA) treatment. Whereas the hepatotoxicity of MTX is well recognized, the bone marrow toxicity is still a concern, with pancytopenia being a rare, but potentially fatal complication. Risk factors for pancytopenia include advanced age, renal impairment, infection and hypoalbuminemia. Myelosupression is more likely if MTX is taken daily. However, RA by itself can cause hematologic abnormalities, such as Felty's and large granulocyte lymphocytes syndromes. Because the management of pancytopenia secondary to MTX toxicity is completely different from the treatment of hematologic complications, bone marrow examination is important. We reported a case of pancytopenia in a patient receiving low-dose of MTX for disabling RA. A 82-year-old woman with coronary artery disease, renal insufficiency and mild dementia was admitted with 1 months history of weakness, oral ulcers and bruising. Patient's medications list included totally 15 drugs, with aspirin, tylenol, ibuprophen and low-dose of methotrexate for rheumatoid arthritis. The patient had normal CBC 4 weeks prior to admission. Upon examination, she had bruises, petechia and multiple arthritic deformities, especially of small joints. She had severe mucositis and mild pretibial edema. Laboratory investigations revealed: hemoglobin: 9.3 g/dL; MCV: 110 fl; total leukocyte count: 2.300/mm3 with neutrophil count of 800/mm3; platelets count: 6 K/uL; BUN: 17 mg/dL; creatinin: 1.4 mg/dL; folic acid level: 2.53 ng/ml; vit-B12 level, thyroid function and liver function tests were normal, except of mild hypoalbuminema. Peripheral smear showed rare megaloblasts, leucopenia, and thrombocytopenia; no blasts or large granular lymphocyte were found. Biopsy revealed markedly hypocellular bone marrow; immunophenotyping failed to show lympho- or myeloprolipherative disorders or leukemia. A diagnosis of pancytopenia secondary to MTX toxicity was made. MTX was discontinued, the patient was placed on neutropenic precautions and was treated with blood and platelets transfusions, folic acid and G-CSF. She was discharged on day 14 with normal hematologic parameters. Although infrequent, pancytopenia is a severe complication of low-dose MTX therapy. Because the main route of MTX elimination is via renal excretion, which can be inhibited by many medications (aspirin, NSAID's, probenecid, antibiotics), throughout the therapy a number of precautions are important: periodic creatinine clearance and serum albumin determination, especially in elderly patients. Dosing schedule should be clearly printed on MTX boxes. In severe cases of pancytopenia bone marrow biopsy is warranted. Consensus does not exist, but folate supplementation may reduce MTX toxicity and does prevent discontinuation of therapy. Because folate may have a benefit of cardioprotection due to its ability to prevent MTX-induced hyperhomocysteinemia, it is especially important in the treatment of elderly patients with cardiac problems. Disclosures:No relevant conflicts of interest to declare.

Mistletoe therapy as a therapeutic option in a child with lymphomatoid papulosis/CD 30-positive cutaneous lymphoproliferative papulosis

Lymphomatoid papulosis (LP) is a very rare skin disease in childhood within the spectrum of the CD30-positive lymphoproliferative disorders. The cause of the disease is unknown. Sometimes the disease resolves spontaneously, but also malignant courses are possible, either as a cutaneous or systemic CD 30-positive anaplastic large cell non-Hodgkin lymphoma. In adults between 5% and 20% of the LP-patients develop malignant lymphomas. In children the experiences are limited, but the overall survival seems to be excellent and similar to adults [1] . Different therapeutic regimens are performed. Besides watch-and-wait therapy, topical steroids or PUVA therapy also low-dose methotrexate therapy are treatment options. A 12-year-old girl with weight loss, swelling of the lymph nodes and general weakness was admitted to our integrative pediatric oncology department. Also small erythematous and violaceous papules over the whole body were seen. In the diagnostic the ESR and CRP were elevated and an infectious or autoimmune etiology were ruled out. In MRI the patient showed enlarged left cervical and left axillary lymph node regions. An open biopsy of the suspected lymph nodes and skin-lesions, including bone marrow puncture were performed. The immunhistochemical examination of the lymph nodes showed a malignant ALK-negative CD 30-positive lymphoma. But the immunhistochemical examination of the skin diagnosed a lymphomatoid papulosis. The bone marrow-smear did not show evidence for malignant infiltration. On the basis of the diagnosis lymphomatoid papulosis with involvement of the lymph nodes in a clinical stable patient without strong evidence of a malignant disease and based on experience of a second patient with LP and lymph-node-involvement, a therapy with a mistletoe-preparation intravenously was initiated [2] . We escalated the dosage over 3 days given once per day as an infusion over 3 h. After the third day we continued mistletoe treatment subcutaneously 2 times per week. On the fourth day after beginning of the treatment the size of the cervical lymph nodes were decreasing and new papules were not seen any more. After 1 week of treatment the patient was discharged with almost normal blood samples. Four weeks after starting of the treatment all skin and suspected lymph nodes were vanished, proven by clinical examination and ultrasound. During the follow-up ultrasound was done every month and MRI of the lymph nodes was performed every 3 months. Six months after diagnosis the patient is in a stable remission. The therapy with mistletoe is continued twice per week. In conclusion we present a patient with a rare skin disease (LP) with lymph node involvement who is successful treated with mistletoe as a new promising therapeutic option for patients with lymphomatoid papulosis. Further studies should be initiated.

Pulsed High-Dose Corticosteroids Combined With Low-Dose Methotrexate Treatment in Patients With Refractory Generalized Extragenital Lichen Sclerosus

Lichen sclerosus (LS) is a rare, chronic inflammatory skin disease that predominantly affects the anogenital area. A few patients exhibit widespread extragenital disease that may lead to blister formation and superficial erosions. We evaluated the efficacy of pulsed high-dose corticosteroids combined with low-dose methotrexate treatment in patients with refractory generalized LS that had failed to respond to standard topical corticosteroid therapy. Observation Seven patients were included in this retrospective study, all of whom were treated with pulsed high-dose corticosteroids combined with low-dose methotrexate for at least 6 months. The outcome measure was an individual, nonvalidated clinical score. Overall, a significant decrease in the clinical score was observed, from a median score of 8 (range, 5 to 24) before treatment to 2 (range, 1 to 4) after treatment. Adverse effects observed during therapy were moderate and disappeared after the end of treatment. During the follow-up period of at least 3 months (mean, 4.7 [range, 3-8] months), none of the patients experienced a relapse of extragenital LS. Patients with severe extragenital LS benefit from pulsed high-dose corticosteroids combined with low-dose methotrexate therapy. This combination therapy should be considered in generalized disease, especially disease that is refractory to conventional treatment.

Gynecomastia associated with low-dose methotrexate therapy for rheumatoid arthritis ameliorated by folate supplement

A 62-year-old male with a 10-year history of seropositive rheumatoid arthritis (RA) developed gynecomastia 8 months after beginning oral low-dose methotrexate (MTX) therapy. Two months after folate supplementation, the gynecomastia symptoms improved. Gynecomastia associated with low-dose MTX is a rare occurrence, with only nine cases previously reported in the literature. This is the first report showing folate supplementation to be effective against gynecomastia following low-dose MTX. Although it occurs infrequently, gynecomastia associated with low-dose MTX therapy should be considered in male patients with RA.

FOLATE STATUS OF PATIENTS ON LOW-DOSE METHOTREXATE THERAPY

Folate Status of Patients on Low-Dose Methotrexate Therapy Get access Nutrition Reviews, Volume 47, Issue 2, February 1989, Pages 43–45, https://doi.org/10.1111/j.1753-4887.1989.tb02783.x Published: 01 February 1989

Genetic polymorphisms in folate pathway enzymes as a possible marker for predicting the outcome of methotrexate therapy in Japanese patients with rheumatoid arthritis

Low-dose methotrexate (MTX) therapy is widely used in the treatment of rheumatoid arthritis (RA). Though the difference in response to MTX between patients with RA is large, the factors that contribute to this variability remain unclear. We aimed to identify those factors with a particular emphasis on the pharmacogenetics of MTX. We evaluated the association of possible factors, including genetic polymorphisms of folate metabolic pathway enzymes, with the cumulative value of C-reactive protein, an index of MTX anti-inflammatory efficacy, in 87 Japanese patients with RA. Polymorphisms of the reduced folate carrier gene (RFC) G80A and of the gamma-glutamylhydrolase gene (GGH) C-401T were more closely associated (beta = 2.1194, P = 0.0017) than other polymorphisms, with the anti-inflammatory response to MTX. Patients with RA having RFC 80A and GGH-401T alleles were less responsive to MTX than those with RFC 80A and without GGH-401T alleles. Thus, this data may be useful for guiding treatment of RA patients with MTX.

First-Line Therapy for Chronic Graft-versus-Host Disease that Includes Low-Dose Methotrexate Is Associated with a High Response Rate

We report the results of low-dose methotrexate (MTX) as first-line therapy mostly in combination with other immunosuppressive agents in patients with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Between November 2001 and March 2008, 86 patients with cGVHD after allo-HSCT received low-dose MTX therapy until a complete or partial response (CR, PR) was achieved, or until treatment failure or intolerable side effects were found. The median time from HSCT to the start of MTX was 154 (range: 80-993) days. The median number of MTX administrations was 4 (range: 2-18). The overall response rate among all enrolled patients was 83% (71 of 86 patients). The response rate for GVHD involving various organs was 90% (45 of 50) in the skin, 75% (39 of 52) in the liver, 42% (5 of 12) in the mouth, 3 of 7 in the eye, and 2 of 2 in the gut. In addition, MTX treatment allowed for a significant reduction in the prednisone dosage (median 90%) from 20 (2.5-100) mg at the start of MTX administration to 5 (0-30) mg 1 month after MTX was last used. Multivariate analysis showed that the only significant factor related to higher CR rate was sole organ involvement ( P = .007). Grade 3 toxicities occurred in only 3 patients presenting cytopenias or oral mucositis. From this analysis, MTX appears to be a well-tolerated, effective, and inexpensive agent when used as a first-line treatment in combination with other immunosuppressive agents for cGVHD, especially for skin or sole organ involvement without concomitant thrombocytopenia.

Multiple toxic effects of low-dose methotrexate in a patient treated for psoriasis

A case of toxicity encountered with low-dose methotrexate therapy is discussed. A 59-year-old African American woman receiving long-term therapy for psoriasis came to the hospital with painful ulcers, difficulty swallowing, cutaneous lesions, and acute renal failure. Her medical history included type 2 diabetes mellitus, hypertension, coronary artery disease, morbid obesity, and psoriasis. On admission, the patient looked ill and had a low-grade fever; maculopapular skin lesions; and bullae and vesicles in her mouth and on her hands, legs, groin, and buttocks. With the exception of carvedilol, all home medications, including methotrexate, were discontinued. A complete medication history revealed that the patient had been taking methotrexate 2.5 mg daily, instead of 2.5 mg three times weekly as prescribed. This error translated into an estimated cumulative dose of 360 mg, nearly twice the prescribed amount. There were no clinically significant drug-drug interactions noted among her prescribed medications; however, the patient did report increased ibuprofen use secondary to the painful ulcerations in the previous few months. Leucovorin 15 mg i.v. every six hours was initiated along with additional supportive care. Skin and mucosal lesions, as well as her pain, had dramatically improved on day 5 of hospitalization. The patient was discharged after a six-day hospitalization and was provided with leucovorin 15 mg orally ever day for seven additional days until rheumatology follow-up. The patient was instructed to avoid any future methotrexate therapy. A patient who erroneously took oral methotrexate daily rather than thrice weekly for psoriasis developed multiple manifestations of methotrexate toxicity.

Early-onset pancytopenia and skin ulcer following low-dose methotrexate therapy

Pancytopenia is a rare but serious adverse effect of low-dose methotrexate (MTX) sodium therapy, and this case report describes a very early-onset of pancytopenia and cutaneous lesions after three days of ingestion. A 64-year-old man was presented to Emergency Department with weakness, fever, poor appetite, nausea, and vomiting after he had had accidentally ingested MTX tablets (2.5 mg) twice a day for the last three days. On initial examination, several painful lesions in his oral mucosa and a cutaneous ulceration on his right foot were also observed. He had severe pancytopenia, poor kidney functions, and abnormal coagulation parameters. The blood level of MTX was found to be within therapeutic range. He was treated with leucovorine, intravenous antibiotics, and appropriate blood transfusions; he was discharged from hospital without any sequela. Pancytopenia associated with low-dose (cumulative dose of 15 mg in 3 days) MTX therapy had not been reported previously. The Naranjo probability scale showed pancytopenia and skin ulcer associated with low-dose MTX therapy as probable adverse reactions. Risk factors for pancytopenia such as renal insufficiency, hypoalbuminemia, low folate levels, concomitant infections, concomitant use of drugs, and folate supplementation were not identified in our patient. Although pancytopenia associated with low-dose MTX therapy is not expected as early as 3 days after initiation of the therapy, physicians should also be aware of this life threatening adverse effect during the very first days of MTX therapy for rheumatoid arthritis patients.

Amiodarone modulates pharmacokinetics of low‐dose methotrexate in rats

Clinical studies of low-dose methotrexate (LDMTX) pharmacokinetics document increased plasma concentrations of MTX after co-administration of the drug with amiodarone or macrolide antibiotics. As drug-drug interactions may increase the toxicity of LDMTX, a rat model was used to follow renal and biliary elimination of MTX during its constant-rate i.v. infusion and concomitant single bolus i.v. injections of amiodarone or azithromycin. The mean steady-state plasma concentration of 1.7+/-0.1 micromol/l was reached and the total clearance achieved 17.7+/-1.0 ml/min/kg. Administration of amiodarone decreased the biliary clearance of MTX to 73% of the control values (p<0.05). Correspondingly, the total clearance decreased to 72% and plasma MTX concentrations were augmented to 2.5+/-0.4 micromol/l (p<0.05). Amiodarone-treated rats exhibited a 3.3-fold decrease in the renal clearance (p<0.05) of conjugated bilirubin, which was associated with its increased plasma concentration. In contrast, azithromycin did not alter any of the MTX pharmacokinetic parameters. In conclusion, this is the first report describing the impairment of MTX hepatic elimination during co-administration with amiodarone. This study also provides new insight into acute amiodarone-induced hyperbilirubinaemia, where increased bilirubin production and decreased renal clearance may contribute to this effect. Importantly, azithromycin seems to be a safe co-medication during LDMTX therapy.

Asymptomatic carriage of Pneumocystis jiroveci in elderly patients with rheumatoid arthritis in Japan: a possible association between colonization and development of Pneumocystis jiroveci pneumonia during low-dose MTX therapy

Low-dose methotrexate (MTX) has been used effectively for rheumatoid arthritis (RA) because of its favorable risk-benefit ratio. One of the recent concerns arising from this therapy is a possible increase in the rate of opportunistic infections, particularly Pneumocystis jiroveci pneumonia (PCP). In this study, we report two cases of PCP occurring during low-dose methotrexate therapy for RA and review 13 additional cases from the literature on Japanese patients with RA. The average age of these patients was 67.7 years, and most were over the age of 60. MTX-associated PCP appears to occur more frequently in elderly individuals in Japan. To identify individuals with a high risk of PCP, we performed a polymerase chain reaction on specimens from induced sputum or bronchoalveolar lavage fluids from 55 patients with RA. At that point in time, they showed no evidence of PCP development. We found six patients (10.9%) having asymptomatic carriage of P. jiroveci. The mean age of the P. jiroveci-positive patients was 74.7 years, which was significantly older than the P. jiroveci-negative patients (mean age 63.6 years). Of the RA patients over the age of 65, 18.8% (6 cases out of 32) were carriers of P. jiroveci. There were no significant differences in RA duration or counts of white blood cells or lymphocytes between the positive and negative groups. Notably, we encountered a case of PCP occurring in an asymptomatic carrier of P. jiroveci during low-dose MTX therapy for RA. This case appeared to be a reactivation of latent infection. By careful follow-up on the carriers of P. jiroveci, we succeeded in promptly diagnosing PCP, and we employed the appropriate therapeutic strategies for this possibly life-threatening complication.

Asymptomatic carriage of Pneumocystis jiroveci in elderly patients with rheumatoid arthritis in Japan: a possible association between colonization and development of Pneumocystis jiroveci pneumonia during low-dose MTX therapy

Low-dose methotrexate (MTX) has been used effectively for rheumatoid arthritis (RA) because of its favorable risk-benefit ratio. One of the recent concerns arising from this therapy is a possible increase in the rate of opportunistic infections, particularly Pneumocystis jiroveci pneumonia (PCP). In this study, we report two cases of PCP occurring during low-dose methotrexate therapy for RA and review 13 additional cases from the literature on Japanese patients with RA. The average age of these patients was 67.7 years, and most were over the age of 60. MTX-associated PCP appears to occur more frequently in elderly individuals in Japan. To identify individuals with a high risk of PCP, we performed a polymerase chain reaction on specimens from induced sputum or bronchoalveolar lavage fluids from 55 patients with RA. At that point in time, they showed no evidence of PCP development. We found six patients (10.9%) having asymptomatic carriage of P. jiroveci. The mean age of the P. jiroveci-positive patients was 74.7 years, which was significantly older than the P. jiroveci-negative patients (mean age 63.6 years). Of the RA patients over the age of 65, 18.8% (6 cases out of 32) were carriers of P. jiroveci. There were no significant differences in RA duration or counts of white blood cells or lymphocytes between the positive and negative groups. Notably, we encountered a case of PCP occurring in an asymptomatic carrier of P. jiroveci during low-dose MTX therapy for RA. This case appeared to be a reactivation of latent infection. By careful follow-up on the carriers of P. jiroveci, we succeeded in promptly diagnosing PCP, and we employed the appropriate therapeutic strategies for this possibly life-threatening complication.

Hodgkin's lymphoma in a patient of psoriasis treated with long-term, low-dose methotrexate therapy

Methotrexate (MTX) is used in the treatment of a variety of diseases such as rheumatoid arthritis, dermatomyositis, juvenile rheumatoid arthritis and chronic plaque psoriasis. It has been well documented that there is a risk of development of lymphomas in these patients although none have been reported in patients of psoriasis treated with methotrexate. A 58-year-old male patient, a known case of psoriasis since 1994, had been receiving treatment with a low dose of MTX, 5 mg weekly for ten years intermittently (7-8 months/year). The cumulative dose of MTX taken was 1.5 gm. He developed high-grade fever with cervical lymphadenopathy that was nonresponsive to routine line of management. Lymph node biopsy revealed the presence of mixed cellularity type of Hodgkin's lymphoma. CT scan showed cervical, mediastinal and abdominal lymphadenopathy. The patient responded well to withdrawal of MTX and chemotherapy. This is the first case of lymphoma occurring in a patient of psoriasis treated with low-dose MTX.