Kou Katayama

Safety and efficacy of combination therapy of iguratimod with methotrexate for patients with active rheumatoid arthritis with an inadequate response to methotrexate: An open-label extension of a randomized, double-blind, placebo-controlled trial

Abstract Objective. To obtain safety and efficacy data on combination treatment with iguratimod and methotrexate (MTX) in an open-label extension study in patients with active rheumatoid arthritis (RA). Methods. Following a 28-week, randomized, double-blind trial of adding iguratimod or placebo to stable MTX therapy, patients entered a 24-week extension. Patients randomized to the iguratimod + MTX group continued treatment. Patients treated with placebo + MTX switched to iguratimod + MTX [the (placebo/iguratimod) + MTX group]. Results. In the iguratimod + MTX group, the rate of 20% improvement in American College of Rheumatology criteria (ACR20) at week 52 (71.3%) was similar to that at week 24 (69.5%). ACR50, ACR70 and Health Assessment Questionnaire Disability Index at week 52 significantly improved compared with the values at week 24. In the (placebo/iguratimod + MTX) group, the switch to iguratimod treatment significantly improved ACR20 from 30.7% at week 24 to 72.1% at week 52. Frequent adverse events for 52 weeks in the iguratimod + MTX group were nasopharyngitis, upper respiratory tract inflammation, stomatitis, lymphocyte decrease, AST increase, ALT increase and blood iron decrease. These adverse events were predominantly mild or moderate in severity. No deaths occurred. Conclusion. Efficacy and tolerance of iguratimod + MTX therapy was maintained to 52 weeks in patients with active RA with inadequate response to MTX.

Tacrolimus-induced pulmonary injury in rheumatoid arthritis patients.

BACKGROUND Tacrolimus (TAC) was approved in Japan in 2005 for rheumatoid arthritis (RA) patients having inadequate response to other disease-modifying anti-rheumatic drugs. As of May 2007, spontaneous reports identified twenty-seven cases of exacerbation or new development of interstitial pneumonia among RA patients given TAC in Japan. OBJECTIVE To describe the clinical and radiological characteristics of TAC-induced pulmonary injury (TIPI). PATIENTS AND METHODS Eleven RA patients diagnosed with de novo pulmonary injury or exacerbation of IP during treatment with TAC were identified. Clinical, radiological, and laboratory data of ten of these cases were retrospectively analyzed. RESULTS Baseline data for the ten patients were a mean age of 69.7 years; gender, 70% female; mean RA disease duration, 9.1 years; and pulmonary comorbidities, 90%. Six cases were classified as presumptive TAC-induced pulmonary injury (TIPI) and four as probable TIPI. Among the six presumptive cases, TIPI developed at an average of 84 days after initiation of treatment (n = 5) or four days after reinstitution of TAC (n = 1). Five cases were an exacerbation of pre-existing interstitial pneumonia and one was a de novo pulmonary injury. Radiological patterns of thoracic computed tomography (CT) scans of patients in the presumptive TIPI cases were hypersensitivity pneumonia like-pattern (n = 3), ground-glass opacity (n = 2), and organizing pneumonia-pattern (n = 1). All patients with presumptive TIPI were treated with high dosage glucocorticosteroids and one received concomitant immunosuppressants. Two of the six presumptive TIPI patients died. CONCLUSION Rheumatologists should be aware of this rare but potentially life-threatening adverse event in RA patients receiving TAC.

The usefulness of a new triple combination treatment utilizing methotrexate, salazosulfapyridine, and bucillamine in rheumatoid arthritis.

Objectives. Combination treatment with methotrexate, salazosulfapyridine and bucillamine as an alternative to treatment with TNF-inhibiting biologics in rheumatoid arthritis was investigated. Methods. Twenty-six facilities allied with the Japan Association of Rheumatologists in Private Practice participated in this study. One hundred and twelve patients enrolled in this study, all of whom were within 3 years of diagnosis with rheumatoid arthritis for whom treatment with one DMARD or a combination of two DMARDs had failed (DAS28 > 3.2). Patients chose their own treatment. The triple DMARDs combination group was comprised of 72 patients; the TNF-inhibiting biologics treatment group was comprised of 40 patients. Results. DAS28 scores for the triple DMARDs combination group and the TNF-inhibiting biologics treatment groups were 4.84 ± 0.96 and 5.23 ± 1.26, and there was no significant difference between the two groups. From the 6th month, average disease activities of both groups were reduced, and there was no difference between the two groups at 12 months (DAS28, 3.39 ± 1.43 and 3.05 ± 1.43, p = 0.39). Furthermore, there was no significant difference in the degree of bone destruction between the two groups at 12 months. Conclusions. The triple DMARD combination therapy provided a new treatment option for those patients for whom treatment with biologics is difficult.

Effects of bisphosphonates on fracture incidence and bone metabolism in rheumatoid arthritis patients in general practice taking long-term corticosteroid therapy: a retrospective study.

Background and objective:There is a risk that disturbances of activities of daily living (ADL) due to rheumatoid arthritis (RA) are increased by the occurrence of fractures, including vertebral compression fractures and femoral neck fractures, in RA patients receiving oral corticosteroid therapy. Bisphosphonates are most commonly used in the treatment of postmenopausal osteoporosis. In a large-scale, randomized, double-blind, placebo-controlled study that was performed to assess the prophylactic efficacy of bisphosphonates, alendronic acid decreased the incidence of vertebral fractures by approximately 50% compared with placebo in postmenopausal patients. A similar result has also been reported with risedronic acid. The present long-term retrospective study evaluated the effects of alendronic acid and risedronic acid therapy on development of new vertebral/non-vertebral fractures in RA patients receiving long-term oral prednisolone therapy at an average dose of 5 mg/day.Methods:The subjects were 138 general practice patients aged 50–79 years with RA (alendronic acid group 80; risedronic acid group 58) who received oral prednisolone at a dose of 2–15 mg/day for at least 1 year combined with bisphosphonate therapy (alendronic acid 5 mg/day or risedronic acid 2.5 mg/day) for at least 10 months. Patients with five or more vertebral fractures at the start of bisphosphonate therapy were excluded from the study. Vertebral fractures were detected by obtaining plain x-ray films of the thoracic and lumbar spines at the start of bisphosphonate therapy and on completion of follow-up. We measured the incidence of new fractures, the speed of sound (SOS) at the calcaneus as measured by quantitative ultrasound, and levels of crosslinked N-telopeptide of type I collagen (NTX), a marker of bone resorption. The percentage change at each measuring point was tested using the paired t-test. The incidence of new fractures was compared between groups using the Cox proportional hazard model.Results:The incidence of new vertebral fractures was 6.3% in the alendronic acid group and 13.8% in the risedronic acid group; the incidence of new non-vertebral fractures was 6.3% and 12.1%, respectively. The incidence of any fracture was significantly higher and severe fractures tended to be more common in the risedronic acid group. Analysis by the Cox proportional hazard model revealed a significant difference between the two groups with respect to the cumulative incidence of new fractures (p = 0.0386). The SOS of the calcaneus showed no appreciable difference between the two groups. NTX measurements indicated that antiresorptive activity was maintained from 6 months of treatment onwards in the alendronic acid group but not in the risedronic acid group.Conclusion:These findings suggest that alendronic acid has a stronger prophylactic effect against fractures than risedronic acid in RA general practice patients taking long-term corticosteroid therapy.

Radiographic quantifications of joint space narrowing progression by computer-based approach using temporal subtraction in rheumatoid wrist

OBJECTIVE To investigate the validity of a computer-based method using temporal subtraction in carpal joints of patients with rheumatoid arthritis (RA), which can detect the difference in joint space between two images with the joint space difference index (JSDI). METHODS The study consisted of 43 patients with RA (39 females and 4 males) who underwent radiography at baseline and at 1-year follow-up. The joint space narrowing (JSN) of carpal joints on bilateral hand radiographs was assessed by our computer-based method, using the Sharp/van der Heijde method as the standard of reference. We compared the JSDI of joints with JSN progression in the follow-up period with that of those without JSN progression. In addition, we examined whether there is a significant difference in JSDI in terms of laterality or topology of the joint. RESULTS The JSDI of joints with JSN progression was significantly higher than that of those without JSN progression (Mann-Whitney U test, p < 0.001). There was no statistically significant difference in the JSDI between the left and right carpal joints, which was analysed for five different joints altogether and each joint separately (Mann-Whitney U test, p > 0.05). There was statistically significant difference in JSDI among different joints (Kruskal-Wallis test, p = 0.003). CONCLUSION These results suggest that our computer-based method may be useful to recognize the JSN progression on radiographs of rheumatoid wrists. ADVANCES IN KNOWLEDGE The computer-based temporal subtraction method can detect the JSN progression in the wrist, which is the single most commonly involved site in RA.

Inhibition of radiographic joint damage in rheumatoid arthritis patients in DAS28 remission using single- or combined with methotrexate non biological disease-modifying antirheumatic drug therapy in routine clinical practice

Abstract Objective. We retrospectively investigated the inhibitory effect on radiographic joint damage (RJD) for non-biological disease-modifying antirheumatic drug (non-bioDMARD) monotherapy or methotrexate (MTX) combination therapy for rheumatoid arthritis (RA) in the disease activity score with 28 joint counts with erythrocyte sedimentation rate (DAS28) remission. Methods. Eighty-four patients (55 cases of monotherapy, 29 cases of MTX-combination therapy) in DAS28 remission (DAS28 ≤ 2.6) were investigated from 538 RA patients newly registered between February 2007 and August 2010. The patients were analyzed for radiological assessments using the modified total Sharp score/year (mTSS/y). Results. The remission rates and ΔmTSS/y for each agent using monotherapy were 7.1% and 0.17 for sulfasalazine; 11.9% and 0.49 for bucillamine (BUC); and 23.9% and 2.06 for MTX. Those using combination therapy were 6.8% and 1.39 for MTX + BUC; 23.5% and −1.64 for MTX + leflunomide; and 8.0% and 0.31 for MTX + tacrolimus. The cumulative distribution in the single and combination therapy groups showed improvement of percentages in structural remission from baseline to 1-year treatment, 34.1% to 60.9% (P < 0.05) and from 0% to 56.7%(P < 0.0001), respectively. Baseline mTSS (r = 0.67, P < 0.0001), disease duration (r = 0.40, P < 0.01), swollen joint counts (r = 0.33, P < 0.05), and anti-cyclic citrullinated peptide antibody (r = 0.31, P < 0.05) were useful predictors of RJD for non-bioDMARD monotherapy, but not for combination therapy. Conclusion. Satisfactory inhibition of RJD was observed in the DAS28 remission cases of monotherapy or MTX combination therapy with a non-bioDMARD.

Radiological Classification of Glenoid Deformity in Rheumatoid Arthritis

We report a classification system based on the changes in shape of the glenoid fossa and on an evaluation of the upward migration of the humeral head, because a simple classification based on X-ray evaluation would be of great assistance to physicians dealing with the diagnosis and treatment of RA. We evaluated 150 shoulders of 118 RA patients who showed changes in the glenoid fossa after radiological examinations. The morphology of the glenoid fossa of the RA shoulder was classified into 3 types and we were able to classify a total of six types of deformities by adding the problem of upward migration of the humeral head. An additional investigation on the difference in the type of deformity between the right and left shoulder, the changes in type during the course of the study, and the relationship between this particular classification and certain patient characteristics was also included.

Effectiveness of golimumab for rheumatoid arthritis in patients with an inadequate response to tocilizumab

Abstract Objectives: Several biological disease–modifying antirheumatic drugs (bDMARDs) are currently available for the treatment of rheumatoid arthritis (RA). Increasing evidence indicates that second-line bDMARDs are effective for inadequate responders to first-line bDMARDs. However, all previous studies investigated the use of tumor necrosis factor inhibitors (TNFi) as a first-line bDMARD, while investigated the efficacy of second-line bDMARDs after the use of tocilizumab (TCZ), a non-TNFi, as a first-line bDMARD. Thus, we investigated the efficacy of golimumab (GLM) as a second-line bDMARD after treatment with TCZ as a first-line bDMARD. Methods: The final study population consisted of 26 patients (inadequate responders to TCZ; TCZ group) with moderate or high disease activity (DAS28-ESR ≥3.2) at week 24 of treatment with TCZ as a first-line bDMARD or whose DAS28-ESR score worsened after starting TCZ treatment. These patients could be followed for another 52 weeks or more after the subsequent switch to GLM treatment. For comparison, 19 patients treated with TNFi as a first-line bDMARD and inadequate response to TNFi (TNFi group) were included. Results: The DAS28-ESR score at week 52 after the start of treatment with GLM improved significantly compared with baseline in the TCZ and TNFi groups. However, the TCZ group showed significantly better improvement. Patients in both groups had significantly improved treatment outcomes according to European League Against Rheumatism response criteria, but there was no statistically significant difference among them. The retention rate at week 52 after the start of treatment with GLM was significantly higher in the TCZ group than in the TNFi group (81% vs. 68%, respectively). In addition, no difference was found in the progression of bone destruction determined by the change in van der Heijde modified total Sharp scoring system scores between groups. Conclusions: GLM was an effective therapeutic option for inadequate responders to TCZ.

Contribution of bacterial pathogens to evoking serological disease markers and aggravating disease activity in rheumatoid arthritis

Commensal bacteria and their pathogenic components in the gastrointestinal tract and oral cavity may play pathological roles in autoimmune diseases. To study the possible involvement of bacterial pathogens in autoimmune diseases, IgG and IgA antibodies against pathogenic components produced by three strains of commensal bacteria, Escherichia coli-lipopolysaccharide (E. coli-LPS), Porphyromonas gingivalis-LPS (Pg-LPS) and peptidoglycan polysaccharide (PG-PS) from Streptococcus pyogenes, were determined by an improved ELISA system for sera from two groups of patients with rheumatoid arthritis (RA), who met rapid radiographic progression (RRP) criteria and non-RRP, and compared to normal (NL) controls. Antibody responses to these bacterial pathogens are unique and consistent in individuals, and no fundamental difference was observed between RA and NL controls. Despite the similar antibody responses to pathogens, lower IgG or higher IgA and consequent higher IgA/IgG antibody ratio among the patients with RA related to disease marker levels and disease activity. Peculiarly, the IgA/IgG anti-Pg-LPS antibody ratio resulted from lower IgG and higher IgA antibody responses to Pg-LPS strongly correlated not only with rheumatoid factor (RF), but also correlated with erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and disease activity score of 28 joints with ESR (DAS28-ESR) in the RRP group. In contrast, the IgA/IgG anti-E. coli-LPS and anti-PG-PS antibody ratio correlated or tended to correlate with RF, ESR, CRP, and DAS28-ESR in the non-RRP group, whereas either the IgG or IgA anti-Pg-LPS antibody levels and consequent IgA/IgG anti-Pg-LPS antibody ratio did not correlate with any clinical marker levels in this group. Notably, anti-circular-citrullinated peptide (CCP) antibody levels, which did not correlate with either IgG or IgA antibody levels to any pathogens, did not correlate with severity of arthritis in both RRP and non-RRP. Taken together, we propose that multiple environmental pathogens, which overwhelm the host antibody defense function, contribute independently or concomitantly to evoking disease makers and aggravating disease activity, and affect disease outcomes. Trial registration: UMIN CTR UMIN000012200

Long-term inhibition of radiographic joint damage by tofacitinib monotherapy in rheumatoid arthritis patients with rapid radiographic progression about eight cases

Abstract Eight rheumatoid arthritis patients with rapid radiographic progression [(RRP) baseline: mean yearly ΔmTSS (mTSS: modified total Sharp score) 16.5, mean yearly Δ joint erosion score 5.4, mean yearly Δjoint space narrowing score 11.1] and inadequate response to non-biological disease-modifying antirheumatic drugs, who had completed a 3-month randomised study A39211040 (the 1040) were retrospectively investigated for the radiographic outcomes after tofacitinib (TOF) monotherapy. The patients used TOF 5 mg twice daily (BID) followed by TOF 10 mg BID over a 48-month long-term extension A39211041 (the 1041) study. Radiographic outcomes in hands and feet measured by mTSS in seven patients improved after 12 months and were sustained for 48 months. However, RRP was still observed in one patient, although yearly progression of mTSS improved. Radiographic outcomes in middle and large joints measured by Larsen score did not deteriorate in six patients during 48 months. Herpes zoster infections occurred 9, 30 and 39 months after 10 mg BID TOF prescription. No severe adverse events were observed during the study.