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Introduction: Extra-intestinal mainly articular features of inflammatory bowel disease (IBD) are common and may precede the IBD. Several well-documented reports have revealed that axial manifestations are the most frequent type of inflammatory arthritis which develops in patients with IBD. The frequent association of a number of autoimmune diseases in the same patient has also been described. However, RA associated with IBD is rare and the underlying mechanism remains unknown. Case Presentation: This report describes a 53-year-old woman with ulcerative colitis (UC) and who was diagnosed 14 years after the onset of IBD with RA, based on clinical, radiological and immunologic findings. Conclusion: Because of the paucity of data in this field, we reviewed the cases of overlap RA-IBD and we discussed in this article its treatment stemming from few reports. [ABSTRACT FROM AUTHOR]

Objectives: Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR). Methods: We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (푛 = 54, each group). Results: The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group’s 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group’s good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group’s good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up. Conclusions: IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up. [ABSTRACT FROM AUTHOR]

We report a 9-year-old Japanese girl with chronic non-bacterial osteomyelitis (CNO) accompanied by recurrent erythema nodosum (EN) which was successfully treated with salazosulfapyridine (SASP). She was referred to our hospital because of recurrent erythema on her lower extremities and persistent knee and ankle arthralgia, which had been present for approximately 1 year. Although naproxen, a nonsteroidal anti-inflammatory drug, was initiated, her symptoms frequently recurred. Magnetic resonance imaging demonstrated multiple distinct high-intensity signals in the talus bones suggestive of multiple bone oedemas. Additionally, a histological examination of erythematous lesions was consistent with the histopathological findings of EN. She was diagnosed as having CNO complicated by EN, and received 250 mg/day of SASP as a second-line treatment, which showed partial response of both skin and bone lesions. Following increase in the dose of SASP to 500 mg/day resulted in complete remission of her skin and bone lesions. In conclusion, our findings suggest that SASP is effective not only for CNO bone lesions but also for EN. SASP could serve as a second-line therapeutic option at least for some cases of CNO complicated by EN refractory to nonsteroidal anti-inflammatory drugs., (© Japan College of Rheumatology 2024. Published by Oxford University Press. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site–for further information please contact journals.permissions@oup.com.)

Abstract Background Salazosulfapyridine is a generally safe drug often used to treat rheumatoid arthritis and ulcerative colitis. However, agranulocytosis is a rare but serious adverse effect of this drug. To date, there have been no reports describing the clinical course of salazosulfapyridine-induced agranulocytosis in a chronic hemodialysis patient. Case presentation The patient was a 64-year-old man with IgA nephropathy who had been on chronic hemodialysis for about 3 years. For 1 month, he had general fatigue, mild fever, and pain in multiple joints of the upper extremities. He was hospitalized and underwent detailed examinations in our department. Laboratory investigations revealed an erythrocyte sedimentation rate of 67 mm/h and a C-reactive protein level of 7.73 mg/dL. Rheumatoid factor and anti-cyclic citrullinated peptide antibody were negative. Musculoskeletal ultrasonography showed inflammation of the tendon sheath in both wrists and the right shoulder joint. Computed tomography scans revealed osteosclerosis and narrowing of the sacroiliac joint. The diagnosis was seronegative spondyloarthropathy. He was started on salazosulfapyridine. Four weeks later, he had a high fever and low granulocyte count. Treatment with granulocyte colony-stimulating factor was started. The agranulocytosis could not be ascribed to any other cause and was considered an adverse effect of salazosulfapyridine, which was then stopped. Nine days later, the granulocyte count had recovered and the fever had resolved. Conclusions Currently, there are no guidelines on the use of salazosulfapyridine in chronic hemodialysis patients. The starting dosage should be smaller for these patients than for patients without renal impairment. Also, the laboratory monitoring interval for complete blood count should be shorter than usual.

We experienced a rare case of drug-induced hypersensitivity syndrome (DIHS) in which salazosulfapyridine (SASP) reactivated human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV), which resulted in a relapse of skin symptoms after changing to mizoribine. At the time of recurrence of skin erythema after the initiation of mizoribine, the serum DNA titers of not HHV-6 but CMV were elevated. A drug-induced lymphocyte stimulation test was negative for mizoribine but positive for SASP. In this case, DIHS developed with SASP in association with HHV-6 and CMV reactivation. The immunocompromised state induced by herpes virus reactivation and mizoribine might have caused the relapse of skin erythema.

Objectives: We retrospectively evaluated the retention rate and clinical responses following treatment for rheumatoid arthritis (RA) with iguratimod (IGU) vs. salazosulfapyridine (SASP) as the first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD). Methods: We analyzed 197 RA patients who were treated with IGU or SASP as the initial treatment in the 3-year study period. The retention rate, clinical response, the dosage and percent user of prednisolone (PSL), and safety profiles were evaluated. Results: At month 36, the retention rates of the IGU and SASP groups were 52.4 vs. 32.1%. The rate of responders (good or moderate response) at month 36 was 85.8 vs. 65.2% in the IGU and SASP groups, respectively. At month 36 for the IGU and SASP groups, the percentages of PSL users were 16.7 vs. 46.7%, and the PSL dosage was 0.3 mg/d vs. 2.0 mg/d, respectively. The cumulative rates of any adverse event (AE) at month 36 were 19.8 vs. 29.2% in the IGU and SASP groups, respectively. Conclusion: IGU is a useful first-line csDMARD treatment for RA patients, showing a high retention rate and good efficacy without an increased risk of serious AEs, including serious infections. Our findings also indicate a PSL dose-sparing effect of IGU treatment. [ABSTRACT FROM AUTHOR]

A 47-year-old Japanese man was diagnosed with pancolitis-type ulcerative colitis. He was treated with mesalamine in a pH-dependent release form. On day 16 of administration, he was admitted because of fever and abdominal pain. We diagnosed his symptoms to be the side effects of mesalamine. Hyposensitization using unmodified and a time-dependent release form mesalamine was performed. On day 7 of mesalamine hyposensitization, a colonoscopy was performed. The patient presented with the same allergic symptoms 9 h after the administration of an oral sodium phosphate solution. Eventually, he was orally administered a course of salazosulfapyridine (SASP) at an initial dose of 2.5 mg/day, which was increased to 2000 mg/day. It is generally recognized that SASP intolerance is an indication to switch from SASP to mesalamine. The need to switch treatment from mesalamine to SASP is, therefore, rare because allergic reactions to mesalamine do not occur frequently. We report a very rare case which was presented with abdominal pain and myalgia because of intolerance to mesalamine in whom hyposensitization with and introduction of SASP were successful. [ABSTRACT FROM AUTHOR]

We experienced a rare case of drug-induced hypersensitivity syndrome (DIHS) in which salazosulfapyridine (SASP) reactivated human herpesvirus 6 (HHV-6) and cytomegalovirus (CMV), which resulted in a relapse of skin symptoms after changing to mizoribine. At the time of recurrence of skin erythema after the initiation of mizoribine, the serum DNA titers of not HHV-6 but CMV were elevated. A drug-induced lymphocyte stimulation test was negative for mizoribine but positive for SASP. In this case, DIHS developed with SASP in association with HHV-6 and CMV reactivation. The immunocompromised state induced by herpes virus reactivation and mizoribine might have caused the relapse of skin erythema. [ABSTRACT FROM AUTHOR]

We present a case of a patient with drug-induced hypersensitivity syndrome (DIHS) caused by salazosulfapyridine combined with syndrome of inappropriate secretion of antidiuretic hormone (SIADH) caused by interstitial pneumonia (IP). A 67-year-old man with a past history of rheumatism (RA) presented with right hemiparalysis and aphasia as the chief complaints. A diagnosis of left embolic cerebral infarction following trial therapy for RA based on computed tomography findings was made, and external decompression was performed. Salazosulfapyridine was newly started on day 7. Dabigatran was started on day 37. On day 41, the patient developed fever. On day 42, edema and erythema appeared on his face, and erythema and rash appeared on his trunk and extremities, with gradual transition to erythroderma. The drug eruption was initially attributed to the dabigatran. Various symptoms of organ dysfunction (enteritis, myocarditis, interstitial pneumonia, hepatic disorder, stomatitis, and others) then appeared and persisted; hence, a diagnosis of DIHS associated with human herpes virus 6 and cytomegalovirus infection induced by salazosulfapyridine was suggested, and the oral administration of salazosulfapyridine was discontinued on day 53. Hyponatremia was observed in association with exacerbation of IP. Due to low serum osmotic pressure and prompt improvement of the serum sodium level by fluid restriction, the SIADH was attributed to IP. In this case, steroid pulse therapy followed by gradual decrease therapy prevented worsening of the condition. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • The nitrogen-doped carbon quantum dots (N-CQDs) were prepared using Ginkgo leaf. • The prepared N-CQDs were used as a fluorescent sensing strategy for SASP detection. • The developed method is highly sensitive and selective for clinical detection of SASP. Abstract A simple, economical hydrothermal strategy for synthesizing nitrogen-doped carbon quantum dots (N-CQDs) was developed using Ginko leaves as a carbon source. These N-CQDs have strong blue fluorescence, excitation-relevant emissions, high monodispersity, good stability, good water solubility, and a 22.8% fluorescence quantum yield. They average 3 nm in size, and have maximum excitation and emission wavelengths of 350 and 436 nm, respectively. They are used as an effective fluorescent sensing platform for the label-free sensitive detection of salazosulfapyridine (SASP) due to the strong quenching effect of SASP. When SASP concentration is 0.1–80 μmol/L, there is a good linear relationship with a detection limit of 40 nmol/L. This method was successfully applied to detect SASP in mouse plasma. The results show that the SASP recovery range was 96%–101%. RSDs ranged from 2.6% to 3.1%. [ABSTRACT FROM AUTHOR]

Abstract Objective We investigated effects of salazosulfapyridine (SASP) on the protein profile of cell surface (CS)-proteins of SW982, a human synovial sarcoma cell line, using biotinylation of CS-proteins and 2-dimensional fluorescence difference gel electrophoresis (2D-DIGE). Methods SW982 cells were treated with SASP and its metabolites, sulfapyridine (SP) and 5-aminosalicylic acid (5ASA). Then the cells were treated with a membrane-impermeable biotinylating reagent. Biotinylated CS-proteins were isolated using NeutrAvidin-bound beads. CS-proteins affected by the drugs were detected by 2D-DIGE and subjected to mass spectrometry. Results By the 2D-DIGE analysis, in total 576 spots were detected, 29 out of which showed more than ±1.5-fold different intensity in the SASP-, SP-, and 5ASA-treated cells, compared to non-treated cells (p < 0.05). Interestingly, 7 out of the 29 spots changed their intensity only by SASP and 17 spots changed their intensity only by SP. We identified 9 protein from 15 out of the 29 spots, most of which were evidenced to exist on the cell surface by flow cytometry. Conclusion We found novel effects of SASP and its metabolites on SW982 cells by the combination of biotinylation of cell surface proteins and 2D-DIGE analysis. These data would help understanding of anti-rheumatic actions of SASP. Furthermore, the combination would be a useful method for the analysis of CS-proteins in various conditions. Highlights • Effects of salazosulfapyridine on cell surface proteins were analyzed by 2D-DIGE. • About 1/5 of the detected 576 spots were affected by the drug and its metabolites. • Most of the identified proteins were detected on the cell surface by flow cytometry. [ABSTRACT FROM AUTHOR]

As histone deacetylase inhibitors (HDACIs) have limited efficacy against solid tumors, we investigated whether and how oxidative stress is involved in sensitivity to HDACIs to develop a novel therapeutic option of HDACIs treatment. We first tested whether a reduction of the antioxidant glutathione (GSH) by glutamine deprivation affects sensitivity to a commercially available HDACI vorinostat and reactive oxygen species (ROS) accumulation. Next we investigated the relationship between a glutamate-cystine transporter xCT and the efficacy of vorinostat using siRNA of xCT and bioinformatic analyses. Finally, we verified the combinatory effects of vorinostat and the xCT inhibitor salazosulfapyridine (SASP) on ROS accumulation, cell death induction, and colony formation. Glutamine deprivation increased vorinostat-mediated cell death with ROS accumulation. Genetic ablation of xCT improved the efficacy of vorinostat, consistent with the results of public data analyses demonstrating that xCT expressions positively correlate with insensitivity to HDACIs in many types of cancer cell lines. Vorinostat caused ROS accumulation when combined with SASP, possibly resulting in synergistic ferroptosis. Our study provides a novel mechanistic insight into the mechanism underlying sensitivity to HDACIs involving xCT, suggesting xCT to be a promising predictive marker of HDACIs and rationalizing combinatory therapy of HDACIs with xCT inhibitors to induce ferroptosis.

Spliced variant isoforms of CD44 ( CD44v) are a marker of cancer stem cells in solid tumors. They stabilize the xCT subunit of the transporter system xc(-) and thereby promote synthesis of the antioxidant glutathione. Salazosulfapyridine ( SASP) is an inhibitor of xCT and suppresses the proliferation of CD44v-positive cancer cells. Chemotherapy-naïve patients with advanced non-squamous non-small-cell lung cancer were enrolled in a dose-escalation study (standard 3 + 3 design) of SASP in combination with cisplatin and pemetrexed. The primary end-point was the percentage of patients who experience dose-limiting toxicity. Fifteen patients were enrolled in the study. Dose-limiting toxicity was observed in one of six patients at a SASP dose of 1.5 g/day (elevation of aspartate and alanine aminotransferase levels, each of grade 3), two of five patients at 3 g/day (hypotension or pneumonitis, each of grade 3), and two of three patients at 4.5 g/day (anorexia of grade 3). The maximum tolerated dose was thus 3 g/day, and the recommended dose was 1.5 g/day. The overall response rate was 26.7% and median progression-free survival was 11.7 months, much longer than that for cisplatin-pemetrexed alone in previous studies. Exposure to SASP varied markedly among individuals according to ABCG2 and NAT2 genotypes. The serum concentration of free CD44v protein was increased after the first cycle of treatment, possibly reflecting death of cancer stem cells. Salazosulfapyridine was thus given safely in combination with cisplatin-pemetrexed, with the addition of SASP tending to prolong progression-free survival. This trial is registered in the UMIN Clinical Trials Registry as UMIN000017854. [ABSTRACT FROM AUTHOR]

Objectives: Methotrexate (MTX) is recommended as a first-line conventional synthetic disease-modifying antirheumatic drug (csDMARD) for treating rheumatoid arthritis (RA). This retrospective study sought to identify an add-on csDMARD treatment strategy for RA patients with MTX-inadequate response (IR)., Methods: We collected the cases of RA patients treated with salazosulfapyridine (SASP) or iguratimod (IGU) as the additional csDMARD for MTX-IR during a 24-month follow-up. We performed propensity score matching to evaluate the retention rate, clinical efficacy, and safety profile (n = 54, each group)., Results: The retention rates at 24 months were 38.5% (MTX+SASP group) and 67.8% (MTX+IGU group). At 3 and 6 months, the MTX+IGU group's 28 joint-disease activity score (DAS28) was significantly decreased versus the MTX+SASP group, and at 3 months the MTX+IGU group's good-responder percentage (22.9%) was significantly higher versus the MTX+SASP group's good-responder percentage (10.7%). Conversely, compared to the MTX+SASP group, the MTX+IGU group showed a greater reduction in the estimated glomerular filtration rate from baseline during follow-up., Conclusions: IGU is a useful add-on csDMARD for RA patients with MTX-IR; its high retention rate and good clinical response make it a useful combination therapy for controlling RA disease activity. However, the renal function should be monitored during follow-up., (© Japan College of Rheumatology 2022. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The supramolecular interaction between salazosulfapyridine (SASP) and hydroxypropyl-β-cyclodextrin (HP-β-CD), as well as the influence of HP-β-CD on SASP’s binding to human serum albumin (HSA), were investigated. Phase-solubility studies indicate that the HP-β-CD/SASP inclusion complex was formed at a 1:1 host–guest stoichiometry with high stability constant. The HP-β-CD/SASP complex, which was characterized by various techniques, exhibited markedly improves aqueous solubility of SASP. The binding of SASP with HSA in the presence and absence of HP-β-CD were investigated. The Stern–Volmer quenching constant and binding constant of SASP with HSA were found to be smaller in the presence of HP-β-CD. The Förster distance between the donor and the acceptor is altered in the presence of HP-β-CD. These results exhibited that the HP-β-CD reduced the quenching and binding of SASP on HSA. Molecular modeling is used to optimize the sites and mode of binding of SASP with HSA. [ABSTRACT FROM AUTHOR]

Aim: Salazosulfapyridine (SASP) frequently causes several adverse reactions, such as drug rash with eosinophilia and systemic symptoms (DRESS). This study aims to assess whether there is an association between SASP-induced DRESS and HLA-A, -B and -C alleles in the Chinese Han population. Subjects & methods: We performed an association study of six subjects with SASP-induced DRESS, 30 SASP-tolerant patients and 283 general subjects from the human MHC database, all of whom are Han Chinese. Results: The frequency of the SASP-induced DRESS patients carrying the HLA-B*13:01 allele is 66.67% (4/6). It is significantly higher compared with the general Chinese Han population (15.19%, 43/283; odds ratio: 11.16; p = 0.007) or with the SASP-tolerant patients (13.33%, 4/30; odds ratio: 13.00; p = 0.004). Conclusion: These findings show for the first time that in the Chinese Han population, HLA-B*13:01 is associated with SASP-induced DRESS. HLA-B*13:01 might serve as a potential genetic marker for reducing the prevalence of SASP-induced DRESS. Original submitted 18 December 2013; Revision submitted 31 March 2014 [ABSTRACT FROM AUTHOR]

A 79-year-old woman was referred to our hospital because numerous polyps were found in her stomach and large intestine at an ambulatory clinic. Although there were no characteristic symptoms or signs of Cronkhite-Canada syndrome (CCS), endoscopic and pathological findings indicated CCS. Moreover, colonoscopy showed two polypoid lesions (Is type), which appeared neoplastic by magnifying observation with image-enhanced endoscopy (IEE), in the ascending colon. Histologically, the resected specimens revealed tubular adenomas arising in the CCS inflammatory polyps. Remarkable remission of the polyps and edematous mucosa in the stomach and colon was seen after 8 months of administration of salazosulfapyridine (SASP) (3 g/day). Another adenoma was detected and removed endoscopically in the sigmoid colon. This is the first report to describe an asymptomatic case of CCS probably detected in the early phase of the disease, by magnifying IEE which enabled detection and treatment for associated colonic adenomas. SASP was effective in eradication of the inflammatory polyposis, and an additional adenoma was successfully found and removed by surveillance colonoscopy thereafter. [ABSTRACT FROM AUTHOR]

Objective. We examined the pharmacokinetics (PK) of salazosulfapyridine (SASP) and its metabolite, sulfapyridine (SP), as well as the influence of hemodialysis (HD), and investigated the utility of consecutive administration of SASP in rheumatoid arthritis patients undergoing HD. Methods. The PK of salazosulfapyridine and SP in serum samples from 8 patients was determined using high-performance liquid chromatography. Results. When SASP 500 mg was administered, the area under curve for serum concentration of SASP was similar to that seen with normal subjects in the Phase I study. The maximum serum concentration of SP was significantly higher than that in normal subjects, but was far from the danger level. SASP was not dialyzed, whereas on average 62% of SP was dialyzed. Following 5 consecutive days of administration of SASP, serum levels of SASP and SP on day 5 were rather higher than those on day 1, although both remained within the safe range. SASP administration from four months to three years in seven subjects resulted in four American College of Rheumatology 20 improvement criteria (57.1%), with one developing a rash. Conclusions. If SASP is initiated at a low dosage (≤ 500 mg) and increased up to 1000 mg under careful monitoring, it is safe for HD patients. [ABSTRACT FROM AUTHOR]

There was no standard or report for the treatment of rheumatoid arthritis (RA) patients on hemodialysis with Salazosulfapyridine (SASP). We examined the pharmacokinetics of SASP and its metabolites in RA patient on hemodialysis. Hemodialysis was started 2 h after administration of SASP at a dose of 250 or 500 mg. Blood samples were took 8 times during the observation period. The concentration of SASP and its metabolites (SP, Ac-SP) in blood sample were measured. There was no difference for the concentration of SASP before and after hemodialysis. Results showed SASP was nondialyzable, but SP and AC-SP were dialyzable. At a dose of 500 mg, AUC0-∞ of SASP and SP were higher than healthy volunteer. Therapy with SASP for hemodialysis RA should be started at a lower dose for adverse event risk. [ABSTRACT FROM AUTHOR]

Although etanercept (ETN) is effective when used in monotherapy for the treatment of rheumatoid arthritis (RA), ETN/methotrexate (MTX) combination therapy is more efficacious. However, some patients show MTX intolerance; these patients may develop adverse events (AEs) or have risk factors for AEs. There is limited published information regarding the efficacy of combination therapy involving ETN and disease-modifying antirheumatic drugs other than MTX. Therefore, we evaluated the effects of combination therapy with ETN and salazosulfapyridine (SASP) and/or bucillamine (Bc), a d-penicillamine analogue, in MTX-intolerant RA patients. Indices of RA activity, including disease activity score in 28 joints (DAS28), were retrospectively analyzed over a 48-week period in 66 patients treated with ETN. Treatment efficacy was compared in the following 4 major treatment groups: ETN monotherapy, ETN + MTX, ETN + SASP, and ETN + SASP + Bc. Although intergroup differences in the percent change of DAS were not statistically significant, ETN + SASP + Bc seemed to be more effective than ETN monotherapy, and the efficacy of ETN + SASP + Bc was comparable to that of ETN + MTX according to the European League Against Rheumatism (EULAR) improvement ratings. These results suggest that ETN + SASP + Bc combination therapy may be a viable option for RA treatment in patients in whom MTX cannot be used. [ABSTRACT FROM AUTHOR]

Bucillamine (Buc), developed in Japan, is a disease-modifying antirheumatic drug (DMARD) which has been used to treat numerous patients with rheumatoid arthritis (RA) in Japan and Korea with favorable results. However, it has not been used globally. In the present study, we compared the timing of onset of efficacy and the usefulness of this drug with that of the globally accepted agent salazosulfapyridine (SASP). There were 26 patients in the Buc group and 23 in the SASP group. We compared changes in the number of swollen joints, number of painful joints, duration of morning stiffness, grip strength, levels of inflammatory marker [erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP)], rheumatoid factor (RF), physician’s rating by visual analogue scale (VAS), patient’s rating of pain, patient’s overall rating (VAS), and improvement according to European League against Rheumatism (EULAR) criteria (DAS28-CRP, DAS28-ESR) in these two groups of patients. Both Buc and SASP were shown to be efficacious within 3 months after the start of treatment. Both drugs were found to be suitable as first-line treatment of early RA. Signs of efficacy tended to occur earlier with Buc than with SASP, and Buc also tended to have higher efficacy than SASP. [ABSTRACT FROM AUTHOR]

We describe a 43-year-old woman with rheumatoid arthritis (RA), who developed severe infectious mononucleosis (IM)-like syndrome during treatment with salazosulfapyridine (SASP). She presented with fever, skin rash, lymphadenopathy, and hepatosplenomegaly. Laboratory tests revealed a marked increase of atypical lymphocytes in the peripheral blood and biphasic hepatic dysfunction. IM-like syndrome can be caused by various drugs, including SASP, and the concept of drug-induced hypersensitivity syndrome has been proposed recently. IM-like syndrome due to SASP has been reported in patients taking higher dosages for the treatment of inflammatory bowel disease, but has not been reported earlier in patients with RA. The results of the drug-induced lymphocyte stimulation test tests suggested that 5-aminosalicylic acid was a possible causative metabolite. This severe type of drug-induced hypersensitivity reaction mimicking IM due to SASP should be granted wider awareness in the field of rheumatology, because the drug is widely used for the treatment of RA. [ABSTRACT FROM AUTHOR]

We conducted a 28-week, randomized, double-blind, parallel-group study of iguratimod in 376 Japanese patients with active rheumatoid arthritis to compare the efficacy and safety of the drug with those of placebo and salazosulfapyridine. In the American College of Rheumatology (ACR) 20 response rate, iguratimod was superior to placebo (53.8% versus 17.2%; Fisher's exact test, P < 0.001) and was not inferior to salazosulfapyridine (63.1% versus 57.7%, 95% confidence interval for the rate difference, −7.9% to 18.7%). Iguratimod began exhibiting its therapeutic effect within 8 weeks after the initiation of treatment and was effective even in patients who had a poor response to previous treatment with disease-modifying antirheumatic drugs. No statistically significant difference was noted in the incidence of adverse reactions between iguratimod and salazosulfapyridine. The study results suggest that iguratimod could become a new option for the treatment of rheumatoid arthritis. [ABSTRACT FROM AUTHOR]

We encountered 2 children with intractable diarrhea after allogeneic hematopoietic stem cell transplantation (SCT). In both cases, salazosulfapyridine (SASP) was administered to treat the diarrhea. One patient was a 14-year-old male with acute myelogenous leukemia who received SCT from a related HLA-identical donor. The leukemia recurred early, and a second SCT from the same donor was performed approximately half a year later. Because intestinal graft-versus-host disease (GVHD) was observed, steroids and octreotide were administered, but the symptoms were not improved. Thereafter, SASP was administered, and the symptoms remitted 9 days later. The other patient was a 12-year-old male with chronic myelogenous leukemia who received SCT from an unrelated HLA-identical donor. Diarrhea and abdominal pain developed early after engraftment and did not respond to either steroids or tacrolimus. Oral administration of SASP was initiated on day 236, and the diarrhea remitted 4 days later without recurrence thereafter. SASP may be effective in children for the digestive system symptoms of chronic GVHD. [ABSTRACT FROM AUTHOR]

Summary We report two patients with infectious mononucleosis-like syndrome induced by salazosulfapyridine (SASP). In both cases, high fever, skin rash, liver dysfunction and atypical lymphocytosis developed 3 weeks after initiating treatment with SASP. SASP is known to be mainly metabolized by N -acetyltransferase 2 (NAT2), and acetylation phenotypes (rapid, intermediate and slow acetylator) correlate with NAT2 * genotypes. In our two patients, we investigated NAT2 * genotypes by the polymerase chain reaction–restriction fragment length polymorphism method. We identified NAT2 *6/ *7 in one patient, and NAT2 *6/ *5 in the other, suggesting that both were slow acetylator phenotypes. In 20 healthy volunteers we found no slow acetylator genotypes. Genotyping prior to medication may be useful in evaluating patients with a high risk of severe systemic reaction to SASP. [ABSTRACT FROM AUTHOR]

Abstract Sulfasalazine (salazosulfapyridine) has been used increasingly and successfully for the treatment of rheumatoid arthritis. Azulfidine® EN (salazosulfapyridine; Pharmacia KK Diagnostics, Tokyo, Japan), which dissolves in the intestine, is an improvement over sulfasalazine in terms of diminishing adverse gastro­intestinal effects. We report herein on a case treated with salazosulfapyridine for rheumatoid arthritis who developed mild dyspnea on exertion, high fever and diffuse pulmonary infiltrates, reversible on discontinuation of the drug. A histologic diagnosis of acute organizing interstitial pneumonia was made by transbronchial lung biopsy. Because the results of a ­lymphocyte stimulation test against Azulfidine® EN were negative, we allowed the patient to resume Azulfidine® EN for pain in his elbows under informed consent. However, the patient developed symptoms of fever, dry cough and stomatitis and mild renal dysfunction after two doses. Salazosulfapyridine was permanently discontinued and the patient's symptoms subsided. Laboratory findings returned to normal within 2 weeks. Azulfidine® EN should be added to the list of pharmacologic agents causing infiltrative pulmonary disease and renal dysfunction. [ABSTRACT FROM AUTHOR]

A 28-year-old woman had persistent pain of both hip joints since the age of 13 years. X-ray analysis showed destructive changes in both hip joints and ossification of sacroiliitic joints. The patient had mild diarrhea and slight abdominal pain for 8 years. Blood-stained stool was not noticed. Barium enema showed changes consistent with the diagnosis of ulcerative colitis (UC). Inflammatory bowel syndrome should be considered in patients with persistent coxitis, even in the absence of severe abdominal symptoms. [ABSTRACT FROM AUTHOR]

An 81-year-old man with a 3-year history of salazosulfapyridine (SASP) therapy for rheumatoid arthritis (RA) presented with pulmonary infiltrates and underwent computed tomography-guided biopsy. The histopathological and immunohistochemical evaluation confirmed the diagnosis of diffuse large B-cell lymphoma (DLBCL). He was recommended chemotherapy, which he refused. Due to the possibility of other iatrogenic immunodeficiency-associated lymphoproliferative disorders, SASP therapy was discontinued. SASP therapy withdrawal led to near-complete resolution of the lung infiltration shadows, and the serum soluble interleukin 2 receptor level returned to the normal range. This is the first report of a case of remission of DLBCL, following SASP therapy withdrawal in a patient with RA.

Progressive multifocal leukoencephalopathy (PML) is a rare opportunistic infection caused by JC virus (JCV) activation. We report an 85-years old man who had been diagnosed to have rheumatoid arthritis (RA) 1.5 years prior to diagnosis of PML, and had been treated with salazosulfapyridine (SASP). He developed weakness of the left upper limb, which progressed gradually for two months. A neurological examination on admission revealed severe palsy of the left upper limb without sensory disturbance, cognitive decline or gait disturbance. Brain MRI revealed white matter lesions in the right frontal lobe around the precentral gyrus. Cerebrospinal fluid (CSF) examination and peripheral lymphocyte counts were normal. HIV was ruled out serologically. There were no findings suggestive of malignancy. We suspected PML and stopped SASP. JCV-DNA was detected in CSF. There were enlarged nuclei positive with VP-1 immunostaining in the brain biopsy materials. Thus, the diagnosis of PML was definitive. Paralysis of the left upper limb began to improve one week after discontinuing SASP. Treatment with mefloquine and mirtazapine was initiated, but he developed severe interstitial pneumonia, which might be caused by mefloquine. Therefore, he underwent rehabilitation without medication. JCV-DNA became undetectable and white matter lesions decreased 6 months later. Paralysis improved and he had no problem with activities of daily living a year later. The risk factor for PML has changed over the last decade, and drugs such as biologics became significant risk factors for patients with autoimmune diseases. There are reports suggesting that systemic lupus erythematosus (SLE) and RA themselves might be independent risk factors for PML. Although there is no previous report of SASP inducing PML, SASP might be the culprit in our case. However, there is another possibility that SAPS and RA worked synergistically for the onset of PML.

As histone deacetylase inhibitors (HDACIs) have limited efficacy against solid tumors, we investigated whether and how oxidative stress is involved in sensitivity to HDACIs to develop a novel therapeutic option of HDACIs treatment. We first tested whether a reduction of the antioxidant glutathione (GSH) by glutamine deprivation affects sensitivity to a commercially available HDACI vorinostat and reactive oxygen species (ROS) accumulation. Next we investigated the relationship between a glutamate-cystine transporter xCT and the efficacy of vorinostat using siRNA of xCT and bioinformatic analyses. Finally, we verified the combinatory effects of vorinostat and the xCT inhibitor salazosulfapyridine (SASP) on ROS accumulation, cell death induction, and colony formation. Glutamine deprivation increased vorinostat-mediated cell death with ROS accumulation. Genetic ablation of xCT improved the efficacy of vorinostat, consistent with the results of public data analyses demonstrating that xCT expressions positively correlate with insensitivity to HDACIs in many types of cancer cell lines. Vorinostat caused ROS accumulation when combined with SASP, possibly resulting in synergistic ferroptosis. Our study provides a novel mechanistic insight into the mechanism underlying sensitivity to HDACIs involving xCT, suggesting xCT to be a promising predictive marker of HDACIs and rationalizing combinatory therapy of HDACIs with xCT inhibitors to induce ferroptosis. [ABSTRACT FROM AUTHOR]

A 25-year-old woman received oral salazosulfapyridine, 4 g/day, for treatment of ulcerative colitis. At 10 days later, she presented with fever and respiratory symptoms. Based on physical, laboratory and radiological findings, bacterial pneumonia and non-cardiogenic pulmonary oedema was suspected. Salazosulfapyridine was immediately halted and antibiotic therapy started. Two days later, her symptoms and abnormal findings had improved rapidly. Bacteriological studies were negative. Salazosulfapyridine-induced non-cardiogenic pulmonary oedema was diagnosed. Non-cardiogenic pulmonary oedema should be considered as one of several salazosulfapyridine- induced pulmonary diseases in patients who are receiving salazosulfapyridine and who develop respiratory symptoms and an abnormal CXR. [ABSTRACT FROM AUTHOR]