A Case of Mesangial Proliferative Nephritis Caused by Slow Cryoglobulin.

The patient was a woman in her 60s. She was found to have proteinuria on a health checkup. She did not have any particular subjective symptoms, and no definitive diagnosis was made, despite serological findings indicative of immune abnormalities. A renal biopsy was performed. Light microscopy of renal tissue section revealed mesangial proliferative nephritis. Electron microscopic findings included electron-dense deposits and fibrillar/tubular structures with a diameter of 20-30 nm. These findings suggested the presence of cryoglobulin (CG), but CG was not detected in qualitative or quantitative hematologic tests. Thus, the serum samples were stored at 37°C for a long period of time and then cooled to 4°C. When the obtained precipitates were examined, CG was successfully detected. CG that precipitates only after a long period of time is referred to as slow cryoglobulin (sCG), and sCG is extremely rare. The present case is the first documented case, to our knowledge, of renal disorders caused by sCG. It should be noted that there are some cases in which it takes much time for CG to precipitate. Thus, when CG cannot be detected, it is necessary to spend much time to determine whether CG precipitates.

Risk factors associated with relapse after methotrexate dose reduction in patients with rheumatoid arthritis receiving golimumab and methotrexate combination therapy.

AIM: To identify risk factors for relapse after methotrexate (MTX) dose reduction in rheumatoid arthritis (RA) patients receiving golimumab (GLM)/MTX combination therapy. METHOD: Data on RA patients ≥20 years old receiving GLM (50 mg) + MTX for ≥6 months were retrospectively collected. MTX dose reduction was defined as a reduction of ≥12 mg from the total dose within 12 weeks of the maximum dose (≥1 mg/wk average). Relapse was defined as Disease Activity Score in 28 joints using C-reactive protein level (DAS28-CRP) score ≥3.2 or sustained (≥ twice) increase of ≥0.6 from baseline. RESULTS: A total of 304 eligible patients were included. Among the MTX-reduction group (n = 125), 16.8% of patients relapsed. Age, duration from diagnosis to the initiation of GLM, baseline MTX dose, and DAS28-CRP were comparable between relapse and no-relapse groups. The adjusted odds ratio (aOR) of relapse after MTX reduction was 4.37 (95% CI 1.16-16.38, P = 0.03) for prior use of non-steroidal anti-inflammatory drugs (NSAIDs), and the aORs for cardiovascular disease (CVD), gastrointestinal disease and liver disease were 2.36, 2.28, and 3.03, respectively. Compared to the non-reduction group, the MTX-reduction group had a higher proportion of patients with CVD (17.6% vs 7.3%, P = 0.02) and a lower proportion of prior use of biologic disease-modifying antirheumatic drugs (11.2% vs. 24.0%, P = 0.0076). CONCLUSION: Attention should be given to RA patients with history of CVD, gastrointestinal disease, liver disease, or prior NSAIDs-use when considering MTX dose reduction to ensure benefits outweigh the risks of relapse.

Sustained discontinuation of infliximab with a raising-dose strategy after obtaining remission in patients with rheumatoid arthritis: the RRRR study, a randomised controlled trial.

OBJECTIVES: The aim of this study is to determine whether the 'programmed' infliximab (IFX) treatment strategy (for which the dose of IFX was adjusted based on the baseline serum tumour necrosis factor α (TNF-α)) is beneficial to induction of clinical remission after 54 weeks and sustained discontinuation of IFX for 1 year. METHODS: In this multicentre randomised trial, patients with IFX-naïve rheumatoid arthritis with inadequate response to methotrexate were randomised to two groups; patients in programmed treatment group received 3 mg/kg IFX until week 6 and after 14 weeks the dose of IFX was adjusted based on the baseline levels of serum TNF-α until week 54; patients in the standard treatment group received 3 mg/kg of IFX. Patients who achieved a simplified disease activity index (SDAI) ≤3.3 at week 54 discontinued IFX. The primary endpoint was the proportion of patients who sustained discontinuation of IFX at week 106. RESULTS: A total of 337 patients were randomised. At week 54, 39.4% (67/170) in the programmed group and 32.3% (54/167) in the standard group attained remission (SDAI ≤3.3). At week 106, the 1-year sustained discontinuation rate was not significantly different between two groups; the programmed group 23.5% (40/170) and the standard group 21.6% (36/167), respectively (2.2% difference, 95% CI -6.6% to 11.0%; p=0.631). Baseline SDAI <26.0 was a statistically significant predictor of the successfully sustained discontinuation of IFX at week 106. CONCLUSION: Programmed treatment strategy did not statistically increase the sustained remission rate after 1 year discontinuation of IFX treatment.

Three-year safety and two-year effectiveness of etanercept in patients with rheumatoid arthritis in Japan: Results of long-term postmarketing surveillance.

Objectives: To evaluate the real-world safety and effectiveness of etanercept (ETN) in Japanese patients with rheumatoid arthritis. Methods: This postmarketing surveillance study (NCT00503139) assessed the safety and effectiveness of ETN treatment over 3 and 2 years (from June 2007 to September 2011), respectively. Safety was evaluated by occurrence and seriousness of adverse drug reactions (ADRs), and of adverse events (AEs) for malignancies. Effectiveness was assessed using the Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate (ESR) with four variables (swollen and tender joint counts, ESR, and patient global assessment; DAS28-4/ESR). Treatment was considered effective if patients had a good/moderate response by the European League Against Rheumatism response criteria. Results: ADRs occurred in 256/675 (37.9%) patients, the most common being injection site reactions (4.4%) and nasopharyngitis (3.3%). Serious ADRs occurred in 60/675 (8.9%) patients, the most frequent being pneumonia (1.2%). The incident rate of malignancies (AEs) was 1.06 per 100 patient-years. Mean baseline DAS28-4/ESR for the 581 patients included in effectiveness analysis was 5.42, which decreased to 3.32 at 2 years. Eighty-two percent of patients achieved a moderate/good response at 2 years. Conclusion: Long-term ETN treatment safety and effectiveness were sustained over 3 and 2 years, respectively.

A Case of Chronic Calcium Oxalate Nephropathy due to Short Bowel Syndrome and Cholecystectomy.

BACKGROUND: Oxalate nephropathy is a rare disease. Especially chronic oxalate nephropathy still has many unknown aspects as compared to acute oxalate nephropathy with relatively well-known causality. CASE PRESENTATION: The patient was a 70-year-old woman who had a history of small bowel resection 25 years before, cholecystectomy 10 years before, and renal stones (calcium oxalate stones) 7 years before. She had been suffering from chronic diarrhea and had been treated by a local physician. The patient was found to have renal dysfunction (creatinine 3.09 mg/dL, eGFR 12.3 mL/min/1.73 m2, hemoglobin 7.8 g/dL) and was referred to our department. The patient was admitted to our hospital for further investigation. Renal ultrasound showed hepatorenal echo contrast in an opposite manner and clear contrast between the renal cortex and medullary pyramid. Renal biopsy was performed, and histological examination showed tubulointerstitial disorder due to deposition of calcium oxalate. Daily urinary excretion of calcium oxalate was significantly increased. The patient was encouraged to drink water and administered vitamin B6, citric acid, K and Na hydrate. Thereafter, her symptoms improved. CONCLUSION: Case reports of chronic oxalate neuropathy are rare in the literature, and its underlying mechanism has not been understood. Our patient had a history of small bowel resection and cholecystectomy. We considered that her short bowel syndrome had influenced the development of calcium oxalate nephropathy.

Clinical efficacy, radiographic, and safety results of golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior therapy with disease-modifying antirheumatic drugs: Final results of the GO-MONO trial through week 120.

OBJECTIVE: Evaluate the safety and efficacy of golimumab through week 120 in Japanese patients with active rheumatoid arthritis (RA) previously treated with DMARDs. METHODS: Japanese patients with active RA despite prior DMARDs were randomized to placebo (Group 1, n = 105), golimumab 50 mg (Group 2, n = 101), or golimumab 100 mg (Group 3, n = 102). At week 16, Group 1 patients crossed over to golimumab 50mg; after week 52, a one-time golimumab dose reduction from 100 to 50 mg was permitted. Assessments included ACR20/50/70 responses and good/moderate DAS28-ESR responses. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. Safety and efficacy were assessed through week 120. RESULTS: ACR20 response rates at week 52 in Group 1, Group 2, and Group 3 were 70.6%, 71.4%, and 81.9%, respectively, and maintained through week 104 (87.2%, 85.1%, 88.9%, respectively) and week 120 (86.1%, 87.0%, 89.5%, respectively). Similar trends were observed for ACR50, ACR 70, and DAS28-ESR. Median change in total vdH-S at weeks 52, 104, and 120 ranged from 0.0 to 1.5 across treatment groups. Through week 120, 93.8%/97.1% had an AE with golimumab 50 mg/100 mg, respectively, and 19.7%/11.8% had an SAE. Infections were the most common AE. CONCLUSION: Clinical response to golimumab 50 mg and 100 mg was maintained over 2 years in Japanese patients with active RA despite prior DMARDs.

High titers of both rheumatoid factor and anti-CCP antibodies at baseline in patients with rheumatoid arthritis are associated with increased circulating baseline TNF level, low drug levels, and reduced clinical responses: a post hoc analysis of the RISING study.

BACKGROUND: Although both rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies (anti-CCP) are useful for diagnosing rheumatoid arthritis (RA), the impact of these autoantibodies on the efficacy of tumor necrosis factor (TNF) inhibitors has been controversial. The aim of this post hoc analysis of a randomized double-blind study (the RISING study) was to investigate the influences of RF and anti-CCP on the clinical response to infliximab in patients with RA. METHODS: Methotrexate-refractory patients with RA received 3 mg/kg of infliximab from weeks 0 to 6 and then 3, 6, or 10 mg/kg every 8 weeks from weeks 14 to 46. In this post hoc analysis, patients were stratified into three classes on the basis of baseline RF/anti-CCP titers: "low/low-C" (RF < 55 IU/ml, anti-CCP < 42 U/ml), "high/high-C" (RF ≥ 160 IU/ml, anti-CCP ≥ 100 U/ml), and "middle-C" (neither low/low-C nor high/high-C). Baseline plasma TNF level, serum infliximab level, and disease activity were compared between the three classes. RESULTS: Baseline RF and anti-CCP titers showed significant correlations with baseline TNF and infliximab levels in weeks 2-14. Comparison of the three classes showed that baseline TNF level was lowest in the low/low-C group and highest in the high/high-C group (median 0.73 versus 1.15 pg/ml), that infliximab levels at week 14 were highest in the low/low-C group and lowest in the high/high-C group (median 1.0 versus 0.1 µg/ml), and that Disease Activity Score in 28 joints based on C-reactive protein at week 14 was lowest in the low/low-C group and highest in the high/high-C group (median 3.17 versus 3.82). A similar correlation was observed at week 54 in the 3 mg/kg dosing group, but not in the 6 or 10 mg/kg group. Significant decreases in both RF and anti-CCP were observed during infliximab treatment. CONCLUSIONS: RF/anti-CCP titers correlated with TNF level. This might explain the association of RF/anti-CCP with infliximab level and clinical response in patients with RA. Baseline RF/anti-CCP titers may serve as indices that aid infliximab treatment. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00691028 . Retrospectively registered on 3 June 2008.

Crystalglobulinemia manifesting as chronic arthralgia and acute limb ischemia: A clinical case report.

RATIONALE: Crystalglobulinemia is a rare disease caused by monoclonal immunoglobulins, characterized by irreversible crystallization on refrigeration. It causes systemic symptoms including purpura, arthralgia, and vessel occlusive conditions to be exacerbated by exposure to cold. We report a patient with crystalglobulinemia associated with monoclonal gammopathy of undetermined significance (MGUS) manifesting as chronic arthralgia and recurrent acute arterial occlusion. PRESENTING CONCERNS: A 61-year-old man, who had been diagnosed with MGUS and who had arthralgia of unknown origin, presented with recurrent acute limb ischemia after surgical thromboembolectomy. Refrigeration of his serum formed precipitates that looked like needle-shaped crystals. These crystals did not dissolve with warming, which is not a characteristic of cryoglobulins. Skin biopsy results showed crystal-liked eosinophilic bodies in small vessels and we diagnosed crystalglobulinemia. INTERVENTION AND OUTCOMES: Although he underwent above-knee amputation, he was treated with a bortezomib and dexamethasone-based chemotherapeutic regimen, following lenalidomide maintenance therapy. Finally, he achieved complete remission and serum crystalglobulins diminished. LESSONS: Monoclonal gammopathy, previously diagnosed as MGUS, can cause systemic symptoms and thrombotic conditions by producing pathologic immunoglobulins, such as crystalglobulins. In such situations, MGUS, even when it has not progressed to multiple myeloma, can be a target of aggressive chemotherapy. Crystalglobulinemia should be considered for patients with monoclonal gammopathy manifesting as systemic and thrombotic symptoms exacerbated by cooling.

Risk for malignancy in rheumatoid arthritis patients treated with biological disease-modifying antirheumatic drugs compared to the general population: A nationwide cohort study in Japan.

OBJECTIVES: To investigate and compare the risk for malignancy in rheumatoid arthritis (RA) patients treated with biologics in Japan to the general population. METHODS: Data for 14,440 patients from 335 institutions who were given infliximab, etanercept, adalimumab, golimumab, tocilizumab, or abatacept were retrieved from the SafEty of biologics in Clinical Use in Japanese patients with RhEumatoid arthritis (SECURE) database. RESULTS: We identified 333 incidents of malignancies in 320 patients during 49,320 patient-years (PY). The age- and sex-standardized incidence rate (ASR) (95% confidence interval [CI]) for overall malignancy of the SECURE cohort was 313.9/10(5) PY (271.4-361.3), and the standardized incidence rate ratio (SIR) (95% CI) was 0.745 (0.667-0.826). The ASR was decreased compared to the estimated incidence rate of malignancies in the Japanese general population (462.4/10(5) PY). The SIRs for site-specific nonhematopoietic malignancies of the SECURE cohort were not significantly elevated compared to the Japanese general population. A significant increase of SIR for malignant lymphoma (6.183, 95% CI, 4.809-7.643) was found in the SECURE cohort, similar to or slightly higher than the SIR previously reported from Japanese cohorts for RA patients. CONCLUSIONS: Continued vigilance with larger numbers of patients, longer observation periods, and inclusion of different biologics are recommended.

Post-hoc analysis showing better clinical response with the loading dose of certolizumab pegol in Japanese patients with active rheumatoid arthritis.

OBJECTIVES: To compare the efficacy and safety of certolizumab pegol (CZP) with and without loading dose (LD) in a post-hoc analysis of two Japanese clinical studies. METHODS: Data from the double-blind trials (DBT) J-RAPID and HIKARI, and their open-label extension (OLE) studies, were used. Patients randomized to CZP 200 mg every 2 weeks (Q2W) groups starting with LD (400 mg Weeks 0/2/4; LD group; J-RAPID: n = 82, HIKARI: n = 116) and patients randomized to placebo groups who subsequently started CZP Q2W without LD in the OLEs (No-LD group; J-RAPID: n = 61, HIKARI: n = 99) were analyzed. Efficacy and pharmacokinetics were assessed during 24 weeks. Adverse events were reported from all studies. RESULTS: In both trials, the LD groups showed more rapid initial ACR20/50/70 kinetics, and maintained higher ACR50/70 responses until 24 weeks, compared with the No-LD groups. Anti-CZP antibody development was less frequent in the LD groups (J-RAPID: 1.2% versus 4.9%; HIKARI: 17.2% versus 27.3%). Similar safety profiles were reported between LD and No-LD groups (any AEs: 281.8 versus 315.7 [J-RAPID], 282.6 versus 321.3 [HIKARI] [incidence rate/100 patient-years]). CONCLUSIONS: Despite limitations, including comparing DBT and OLE studies, these results suggest that a CZP LD improves clinical response in active rheumatoid arthritis without altering the safety profile.

Clinical efficacy, radiographic progression, and safety through 156 weeks of therapy with subcutaneous golimumab in combination with methotrexate in Japanese patients with active rheumatoid arthritis despite prior methotrexate therapy: final results of the randomized GO-FORTH trial.

OBJECTIVE: To evaluate the safety and efficacy of golimumab + methotrexate (MTX) in Japanese patients with active rheumatoid arthritis (RA). METHODS: Japanese patients with active RA despite MTX were randomized to placebo + MTX (Group 1, n = 88), golimumab 50 mg + MTX (Group 2, n = 86), or golimumab 100 mg + MTX (Group 3, n = 87). Patients with <20% improvement in swollen/tender joint counts entered early escape at week 16. At week 24, all remaining placebo patients crossed over to golimumab 50 mg. Efficacy assessments included ACR20, DAS28-ESR, and HAQ-DI. Radiographic progression was assessed with the van der Heijde-modified Sharp (vdH-S) score. RESULTS: ACR20 response rates in Group 1, Group 2, and Group 3 were 67.9, 86.1, and 82.4%, respectively, at week 52 and were maintained through week 104 (87.1, 94.0, and 88.7%) and week 156 (97.1, 94.1, and 89.5%). Proportions of patients with good/moderate DAS28-ESR response or clinically meaningful improvement in HAQ-DI were also maintained through week 156. The majority of patients did not experience radiographic progression through week 156. Among 257 golimumab-treated patients, 251 (97.7%) had ≥1 AE; 54 (21.0%) had ≥1 serious AE through week 156. Infections were the most common type of AE. CONCLUSIONS: Response to golimumab + MTX was maintained over 3 years in Japanese patients with active RA despite MTX. Safety results were consistent with the known safety profile of golimumab.

Decreased expression of Runx1 and lowered proportion of Foxp3⁺ CD25⁺ CD4⁺ regulatory T cells in systemic sclerosis.

OBJECTIVES: To investigate the role of Foxp3(+) CD25(+) CD4(+) regulatory T cells (Treg) and their transcription factor, Runt-related transcription factor 1 (Runx1), in the pathogenesis and development of systemic sclerosis (SSc). METHODS: We collected 23 blood samples from patients with SSc including 19 females and 4 males, 11 early-stage cases within 3 years from onset and 12 late-stage cases and 22 samples from age-matched healthy subjects (HS). Total CD4(+) T cells were assessed for the expression of Treg-related markers, CD25 and CD127, on their surface and intracellular Foxp3 using flow cytometry. Relative expression of Runx1 mRNA in magnetically purified Treg was analyzed using real-time PCR. RESULTS: Proportion of Foxp3(+) cells in total CD4(+) T cells was decreased in patients with either early- or late-stage SSc compared with that in HS, and Runx1 mRNA expression in purified Treg was lower in patients with SSc than in HS. Runx1 mRNA expression level was related to the frequency of Treg in SSc. CONCLUSIONS: This is the first report on Runx1 expression in Treg of a human autoimmune disease. Low expression of Runx1 along with reduced proportion of Treg in CD4(+) T cells may be associated with development of SSc even in early disease.

Efficacy and safety of certolizumab pegol without methotrexate co-administration in Japanese patients with active rheumatoid arthritis: the HIKARI randomized, placebo-controlled trial.

OBJECTIVE: This 24-week, placebo-controlled, double-blind, randomized study (NCT00791921) investigated efficacy and safety of certolizumab pegol (CZP) in Japanese rheumatoid arthritis (RA) patients in whom methotrexate (MTX) cannot be administered. METHODS: A total of 230 patients were randomized to subcutaneous CZP 200 mg (induction dosing: 400 mg at Weeks 0, 2 and 4) or placebo every 2 weeks. RESULTS: ACR20 responses with CZP were rapid and significant versus placebo at Week 1, sustained to Week 12 (67.2% vs. 14.9%) and Week 24 (63.8% vs. 11.4%). Week 24-modified Total Sharp Score (mTSS) change from baseline (CFB) was 0.48 (CZP) versus 2.45 (placebo). CZP treatment was associated with higher Week 12 ACR20 responses versus placebo (with non-MTX disease modifying antirheumatic drugs [DMARDs], 74.2% vs. 20.0%; without [monotherapy], 59.3% vs. 8.2%) and inhibition of radiographic progression at Week 24 (mTSS CFB; with non-MTX DMARDs, 0.24 vs. 1.61; monotherapy, 0.68 vs. 3.65). Incidences of serious adverse events were 11.2% (CZP) and 2.6% (placebo); one CZP patient died of dissecting aortic aneurysm. CONCLUSION: CZP treatment with and without non-MTX DMARDs in Japanese patients in whom MTX cannot be administered resulted in rapid, sustained reductions in RA signs and symptoms. Notably, CZP monotherapy showed significant inhibition of radiographic progression.

Efficacy and safety of certolizumab pegol plus methotrexate in Japanese rheumatoid arthritis patients with an inadequate response to methotrexate: the J-RAPID randomized, placebo-controlled trial.

OBJECTIVES: This 24-week, multicenter, double-blind, randomized, placebo-controlled study (NCT00791999) compared efficacy and safety of certolizumab pegol (CZP) in combination with methotrexate (MTX) vs placebo plus MTX in Japanese rheumatoid arthritis (RA) patients with inadequate response to MTX. METHODS: In total, 316 patients were randomized 1:1:1:1 to subcutaneous CZP 100, 200, or 400 mg (induction dose: 200 mg or 400 mg CZP at Weeks 0, 2, and 4) plus MTX or placebo plus MTX every 2 weeks. Primary endpoint was ACR20 response at Week 12. RESULTS: ACR20 response rates were 62.5%, 76.8%, 77.6%, and 28.6% at Week 12, and 61.1%, 73.2%, 71.8%, and 24.7% at Week 24 for CZP 100, 200, and 400 mg, and placebo groups, respectively, with statistical significance between each CZP group and placebo. Change in Total Sharp Score over 24 weeks was significantly smaller in CZP 200 and 400 mg groups vs placebo. Improvements in health-related quality of life (HRQoL) were observed in all three CZP groups vs placebo. Incidence of adverse events was similar between CZP groups. CONCLUSIONS: CZP plus MTX resulted in rapid, sustained reductions in RA signs and symptoms in Japanese patients with inadequate response to MTX, with significant inhibition of radiographic progression and improved HRQoL.

Safety and effectiveness of 6 months' etanercept monotherapy and combination therapy in Japanese patients with rheumatoid arthritis: effect of concomitant disease-modifying antirheumatic drugs.

OBJECTIVE: To assess real-world safety, tolerability, and effectiveness of etanercept monotherapy, etanercept plus methotrexate (MTX), or etanercept plus other disease-modifying antirheumatic drugs (DMARD) in Japanese patients with active rheumatoid arthritis (RA) despite previous treatment with DMARD. METHODS: In this 24-week, all-cases postmarketing surveillance study, adverse events (AE) were coded using the Medical Dictionary for Regulatory Activities. Effectiveness was assessed every 4 weeks using the 28-joint Disease Activity Score and the European League Against Rheumatism response criteria. RESULTS: Of 13,861 patients (81% women) in the analysis, 3616, 2506, and 7739, respectively, were classified into etanercept monotherapy (ETN-mono), etanercept plus DMARD other than MTX (ETN + DMARD), and etanercept plus MTX (ETN + MTX) groups. Rates of AE and serious AE (SAE) in the ETN + MTX group were lower than in other groups. Risk of SAE or serious infections was not significantly increased with higher versus lower MTX doses at baseline or with concomitant use of salazosulfapyridine or bucillamine in ETN + DMARD versus ETN-mono groups. A greater likelihood of achieving clinical remission was seen with ETN + MTX versus ETN-mono (OR 1.36; 95% CI, 1.16-1.60; p < 0.001). Higher MTX dose at baseline was associated with a higher remission rate (> 8 mg vs 0 to ≤ 4 mg, OR 1.47, 95% CI 1.07-2.00, p = 0.016; 6 to ≤ 8 mg vs 0 to ≤ 4 mg, OR 1.27, 95% CI 1.01-1.60, p = 0.038). CONCLUSION: Combination therapies with etanercept plus MTX or other DMARD were reasonably well tolerated, and ETN + MTX at higher doses was more effective than ETN-mono in Japanese patients with RA.

A retrospective study of serum KL-6 levels during treatment with biological disease-modifying antirheumatic drugs in rheumatoid arthritis patients: a report from the Ad Hoc Committee for Safety of Biological DMARDs of the Japan College of Rheumatology.

OBJECTIVE: We investigated associations between treatment with methotrexate (MTX) or biological disease-modifying antirheumatic drugs (DMARDs) and elevation of serum Krebs von den Lungen-6 (KL-6) levels in Japanese patients with rheumatoid arthritis (RA). METHODS: Using a standardized form, data were collected retrospectively from medical records and analyzed descriptively. RESULTS: Of a total of 198 RA patients with KL-6 serum levels measured at initiation of treatment (month 0) and two or more times by month 12, 27 (17.9 %) of 151 RA patients treated with biological DMARDs, including infliximab, etanercept, adalimumab, and tocilizumab (the biological DMARDs group), and 5 (10.6 %) of 47 patients treated without biological DMARDs but with MTX (MTX group), met criterion B (max. KL-6 ≥500 U/ml and >1.5-fold from baseline) by 12 months. The majority of patients (n = 28) meeting criterion B had no apparent interstitial lung disease or malignancy. Of these 28 patients, 21 had serum KL-6 levels available after reaching their maximum level, and 13 (61.9 %) of the 21 then met criterion R [decrease to less than 500 U/ml or to less than (baseline + 0.5 × (maximum - baseline))] by month 12. CONCLUSION: Serum KL-6 levels may increase during treatment with MTX or these biological DMARDs without significant clinical events.

Elevation of KL-6 serum levels in clinical trials of tumor necrosis factor inhibitors in patients with rheumatoid arthritis: a report from the Japan College of Rheumatology Ad Hoc Committee for Safety of Biological DMARDs.

OBJECTIVE: The associations between elevated levels of serum Krebs von den Lungen-6 (KL-6) and treatment of rheumatoid arthritis (RA) with tumor necrosis factor (TNF) inhibitors were investigated in five Japanese clinical trials. METHODS: Percentages and incidence rates were calculated for elevated serum KL-6 levels. Adverse events associated with elevated levels of serum KL-6 were investigated. RESULTS: In RISING, a clinical trial for infliximab, 15.6 % of the enrolled patients met criterion B (KL-6 ≥500 U/ml and >1.5-fold increase over the baseline value) by week 54. In HIKARI, 7.8 % of the certolizumab pegol (CZP) group and 0 % of the placebo group met criterion B during the double-blind (DB) period (p = 0.003). In J-RAPID, 8.4 % of the methotrexate (MTX) + CZP and 3.9 % of the MTX + placebo groups met criterion B during the DB period. In GO-MONO, 1.8 % of the golimumab (GLM) and 1.3 % of the placebo groups met criterion B during the DB period. In GO-FORTH, 7.1 % of the MTX + GLM and 0 % of the MTX + placebo groups met criteron B during the DB period (p = 0.017). No adverse events accompanied the elevation of serum KL-6 levels in 95.7 % of these patients. CONCLUSION: Serum KL-6 levels may increase during anti-TNF therapy without significant clinical events. In these patients, continuing treatment with TNF inhibitors under careful observation is a reasonable option.

Golimumab monotherapy in Japanese patients with active rheumatoid arthritis despite prior treatment with disease-modifying antirheumatic drugs: results of the phase 2/3, multicentre, randomised, double-blind, placebo-controlled GO-MONO study through 24 weeks.

OBJECTIVE: To evaluate the efficacy and safety of golimumab 50 and 100 mg monotherapy in Japanese patients with active rheumatoid arthritis (RA) despite treatment with disease-modifying antirheumatic drugs (DMARDs). METHODS: A total of 316 patients were randomised to receive subcutaneous injections every 4 weeks of placebo (group 1), golimumab 50 mg (group 2) or golimumab 100 mg (group 3); group 1 crossed over to golimumab 50 mg at week 16. The primary end point was the proportion of patients achieving ≥20% improvement in the American College of Rheumatology criteria (ACR20) at week 14. ACR50 and ACR70 response rates were also measured. Adverse events (AEs) were monitored throughout the study. RESULTS: Demographics were similar across groups; the mean age was 52 years and 81.8% of patients (252/308) were female. Week 14 ACR20 response rates were significantly greater in groups 2 (51/101 (50.5%)) and 3 (60/102 (58.8%)) than in group 1 (20/105 (19.0%); p<0.0001 for both), as were ACR50 and ACR70 response rates. After placebo crossover at week 16, week 24 ACR response rates were similar in groups 1 and 2. Through week 16, 63.8% of patients in group 1, 62.4% in group 2 and 60.8% in group 3 had AEs and 1.9%, 1.0% and 2.0% had serious AEs. After week 16, one malignancy was reported (breast cancer, group 3). Infections were the most common AEs. No deaths or cases of tuberculosis were reported through week 24. CONCLUSIONS: Golimumab monotherapy (50 and 100 mg) was effective in reducing the signs and symptoms of RA in Japanese patients with active disease despite DMARD treatment.