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Acute onset of rheumatoid arthritis associated with administrationof a dipeptidyl peptidase-4 (DPP-4) inhibitor to patientswith diabetes mellitus Takashi Sasaki • Yoshito Hiki • Sae Nagumo • Rina Ikeda •Haruka Kimura • Kenji Yamashiro • Atsushi Gojo •Tatsuhiko Saito • Yasuyuki Tomita • Kazunori Utsunomiya Received: 16 August 2010 / Accepted: 8 November 2010Ó The Japan Diabetes Society 2010 We describe the first case of a 63-year-old male relapsed as definitive RA. A recent study on patients with patient with type 2 diabetes mellitus who was newly RA and on animals deficient in DPP-4 suggests that a rheumatoid arthritis decrease or absence of DPP-4 activity might be associated 2 months after starting medication with a dipeptidyl pep- with cytokine-induced arthritis. On the other hand, a tidase-4 (DPP-4) inhibitor, sitagliptin. We subsequently pooled analysis in the United States and a post-marketing performed a survey to determine if other such cases existed monitoring in Japan have revealed that the occurrence of among patients who started taking sitagliptin at our uni- arthritis linked to pharmacologic inhibition of DPP-4 by versity hospital and at hospitals in the Kashiwa and Noda sitagliptin is rare. Because DPP-4 might possibly be districts. A survey of 147 patients treated with sitagliptin involved in the pathogenesis of RA, and the use of sitag- revealed an additional patient whose arthritis was also liptin in our cases is linked to activation of RA, it is linked to the use of the DPP-4 inhibitor. This second important to carefully follow patients treated with DPP-4 patient had maintained her RA in a state of remission with inhibitor to monitor for onset of RA, although the inci- diabetes for 15 years; however, 2 months after beginning dence rate of this adverse event is low.
sitagliptin therapy for control of diabetes, her arthritis DPP-4
Adverse event
Stromal cell-derived factor-1
Incretin
Chemokine
Oral hypoglycemic agent T. Sasaki (&)
Y. Hiki
S. Nagumo
R. Ikeda
H. Kimura
K. Yamashiro
A. GojoDivision of Diabetes, Metabolism and Endocrinology,Department of Internal Medicine, Kashiwa Hospital, A dipeptidyl peptidase-4 (DPP-4) inhibitor is an oral agent Jikei University School of Medicine, 163-1 Kashiwa-shita, used to treat type 2 diabetes mellitus by extending the half- Kashiwa, Chiba 277-8567, Japan life of glucagon-like peptide-1 (GLP-1) and enhancing its effects on glucose metabolism by DPP-4 inhibition. Similar T. Sasaki
Y. Hiki to GLP-1, several cytokines, including stromal cell-derived Institute of Clinical Medicine and Research, factor-1 (SDF-1), have an identical X-Ala/X-Pro motif at Jikei University School of Medicine, Kashiwa, Chiba, Japan their N terminus; this motif is a target for degradation andinactivation by DPP-4 []. Therefore, pharmacologic T. SaitoKobari General Hospital, Noda, Chiba, Japan inhibition of DPP-4 activity may potentially cause adverseevents related to cytokine-induced inflammation Despite numerous theoretical implications ], an asso- Division of General Medicine, Department of Internal Medicine, ciation between DPP-4 inhibition and occurrence of Kashiwa Hospital, Jikei University School of Medicine,Kashiwa, Chiba, Japan arthritis has not yet been reported. We describe the firstcase of acute-onset rheumatoid arthritis (RA) linked to the use of a DPP-4 inhibitor for treatment of diabetes.
Division of Diabetes, Metabolism and Endocrinology, In May 2010, a 63-year-old man with type 2 diabetes Department of Internal Medicine, University Hospital,Jikei University School of Medicine, Tokyo, Japan presented at the outpatient clinic of the Jikei University T. Sasaki et al.
Kashiwa Hospital because of severe joint pain. He had Results of laboratory tests of the patient been diagnosed with diabetes at the age of 45 years and Variable (units, reference range) treated with sulfonylurea (glimepiride, 3 mg/day) at Kobarihospital in recent years. In February 2010, his glycemic control was fair (HbA1c, 6.9%), but his postprandial glu- Peripheral blood count cose level was not well controlled; usually, it reached as White blood cell count (per mm3) high as 200 mg/dl. In addition, the patient sometimes Red blood cell count (9104/ll) experienced hypoglycemia in the evening with the original Hemoglobin (g/dl) treatment with glimepiride. In order to improve the post- prandial hyperglycemia and possible inadequate hypogly- Platelet count (9104/ll) cemia, the doctor at the above-mentioned hospital decided to replace glimepiride by sitagliptin (50 mg/day), a specific inhibitor of DPP-4. He was in good health until early March 2010. Until that time, the patient's HbA1c level had decreased to 6.5%, but he subsequently experienced Blood biochemistry swelling of the knees, wrists, and metacarpal joints of the left hand. In May, our examination showed swelling, spontaneous pain, and flare on the metacarpal joints of the Fasting plasma glucose (mmol/l) left hand, both wrist joints, both knee joints, the proximal interphalangeal joint of the second toe, and the metatarsal C-peptide (nmol/l) phalangeal joint of the right leg. Further examination Immunologic blood tests indicated that he had neither diabetic microangiopathy nor Anti-GAD antibody (IU/ml, 0.3) atherosclerosis obliterans in the extremities. Anti-GADautoantibody was not detected. His renal function appeared C-reactive protein (mg/dl) normal with a serum creatinine level of 0.90 mg/dl, but the Rheumatoid factor (IU/ml, 18) results of laboratory tests were positive for RA (Table Rheumatoid factor-IgG index Consequently, the patient was diagnosed with definitive Anti-CCP antibody (IU/ml, 4.5) RA, with a 28-joint disease activity score calculated using Anti-nuclear antibody (ELIS, IU/ml) C-reactive protein (DAS28-CRP) of 4.57. Because the MMP-3 (ng/ml, 17.3–59.7) symptoms were serious, sitagliptin was discontinued, and insulin therapy combined with salazosulfapyridine, and a corticosteroid was initiated without observation of simple washout. In August, his RA activity was decreased by this treatment, but the activity still remained 3.42 points on the DAS28-CRP. The signs and symptoms of RA have not yet disappeared even 3 months after discontinuation of the HbA1c (%) was converted from Japan Diabetes Society (JDS) value treatment with sitagliptin.
to National Glycohemoglobin Standardization Program (NGSP) value Because RA onset in this case was related to adminis- using the method of the Japan Diabetes Society tration of a DPP-4 inhibitor, we subsequently conducted ahospital-based survey to determine the presence of other anemia (RBC 520 9 104/ll, Hb 15.5 g/dl, Ht 46.4%), but such cases among 147 patients who started sitagliptin chronic hyperglycemia with FPG 9.27 mmol/l, serum between February and May 2010 in the Jikei University insulin 2.6 lU/ml, and HbA1c 7.1%. Anti-GAD autoanti- Kashiwa Hospital and hospitals in the region of Kashiwa body was not detected. In February, treatment with sitag- and Noda. We found an additional patient who exhibited liptin (50 mg/day) was initiated. Two months later, recurrence of RA approximately 2 months after initiation of however, she experienced arthralgia and swelling of both sitagliptin administration. This second patient, a 65-year- wrist joints. In April, she was diagnosed with disease old woman, had been maintained in a state of RA remission relapse as definitive RA (6.14 points).
( 2.60 points on the DAS28-CRP) for 15 years. She was In our cases, arthritis exhibited acute onset approxi- diagnosed as having diabetes mellitus in November 2009.
mately 2 months after commencement of sitagliptin At that time, she weighed 61.2 kg and was 157 cm tall administration without any other apparent cause. Therefore, (BMI 24.8). Her laboratory tests indicated that her renal the occurrence and reactivation of RA were linked to the use function was normal (serum creatinine 0.55 mg/dl; UN of DPP-4 inhibitor in the time course analysis, and inhibi- 18 mg/dl; urine protein and ketones negative), she had no tion of DPP-4 could be related to the pathophysiology of Arthritis associated with a DPP-4 inhibitor RA in these cases. Busso et al. investigated the critical Therefore, the adverse events of the two cases reported role of DPP-4 in RA. In the clinical study the plasma here should be considered as relatively rare and observed DPP-4 levels of RA patients were autonomously decreased only in individuals with susceptibility to the disease, that is, when compared to those of osteoarthritis patients and were those with a tendency to have occurrence or reactivation of inversely correlated with C-reactive protein levels. In the RA associated with DPP-4 inhibition. Susceptible patients experimental study, the endogenous level of intact SDF-1, a administered DPP-4 inhibitor must be carefully observed to proinflammatory chemokine causing RA, was dependent on prevent acute onset of RA.
DPP-4 activity; mice genetically deficient for DPP-4, DPP- Because DPP-4 might be involved in the pathogenesis of 4(-/-) showed increased severity of antigen-induced RA and the use of sitagliptin was linked to activation of RA arthritis. From these findings, we analyzed whether reduced in our cases, it is important that patients receiving treat- degradation of SDF-1 by pharmacologic inhibition of DPP- ment with DPP-4 inhibitor be carefully followed, although 4 caused the onset of arthritis by measuring the concen- the incidence rate of this adverse event is low.
tration of SDF-1a (by QuantikineR, R&D Systems, Inc.) inpreserved serum from our first case. The result showed no The value for HbA1c (%) is estimated as NGSP equivalent value (%) calculated by the formula HbA1c (%) = HbA1c increase in the level of SDF-1a (1,127 pg/ml) in the sample (JDS)(%) ? 0.4%, considering the relational expression of HbA1c of the period of therapy with sitagliptin compared to control (JDS)(%) measured by the previous Japanese standard substance and samples and the reference range in the condition that the measurement methods and HbA1c (NGSP) We have reported assay was not for intact SDF-1a nor performed under the in these cases to the office of Ministry of Health, Labor and Welfare. Wethank Ms. Kumiko Nezu for her help in editing the manuscript. We vitro inhibition of DPP-4. Thus, we failed to obtain direct declare that we have no conflicts of interest.
evidence of SDF-1 having a role in the triggering mecha-nism of the development of RA in patients with type 2diabetes treated with the DPP-4 inhibitor sitagliptin. DPP-4 has many physiological substrates, including peptides of theglucagon superfamily, some hormones, and chemokines.
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during 6 months in Japan, only three patients, including 7. 8. The Committee of Japan Diabetes Society on the diagnostic our two, presented with occurrence or reactivation of RA; criteria of diabetes mellitus. Report of the Committee on the six patients showed arthralgia, and the other patients classification and diagnostic criteria of diabetes mellitus. J Jpn joint swelling related to sitagliptin use.
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