Drug Saf

DOI 10.1007/s40264-016-0399-8

REVIEW ARTICLE

Dipeptidyl Peptidase (DPP)-4 Inhibitor-Induced

Arthritis/Arthralgia: A Review of Clinical Cases
Annamaria Mascolo1 Concetta Rafaniello1 Liberata Sportiello1
Maurizio Sessa1 Daniela Cimmaruta1 Francesco Rossi1 Annalisa Capuano1

Springer International Publishing Switzerland 2016

Abstract Dipeptidyl peptidase (DPP)-4 inhibitors are a

class of oral drugs used for the treatment of type 2 diabetes
mellitus (T2DM). The pharmacological inhibition of DPP4 seems to also induce adverse events related to cytokineinduced inflammation. Recently, several clinical cases
regarding the association of DPP-4 inhibitors and the onset
of arthritis/arthralgia have been reported in the literature.
Various mechanisms could be responsible for DPP-4 inhibitor-induced arthritis/arthralgia, and the increase of
cytokines, chemokines, matrix metalloproteinases (MMPs)
and genetic factors plays an important role. The US FDA
published a safety announcement regarding the entire drug
class, encouraging healthcare professionals and patients to
pay attention to the occurrence of arthralgia during treatment with DPP-4 inhibitors; arthralgia could be assessed as
a class adverse drug event for DPP-4 inhibitors. To summarize the evidence on the correlation between DPP-4
inhibitors and arthritis/arthralgia, and to explain the measures taken by the FDA with regard to arthralgia risk, we
performed a literature review of recent evidence concerning this association. This review shows the necessity of
other studies to better define the association between DPP4 inhibitors and arthritis/arthralgia.

A. Mascolo and C. Rafaniello equally contributed to the manuscript.

& Annamaria Mascolo
annamaria.mascolo@unina2.it
1

Section of Pharmacology, Department of Experimental

Medicine, Pharmacoepidemiology and Pharmacovigilance
Centre of the Campania Region, Second University of
Naples, via L. de Crecchio 7, 80138 Naples, Italy

Key Points
Arthralgia could be considered as a class adverse
drug event for dipeptidyl peptidase (DPP)-4
inhibitors.
Further studies should be conducted to better define
the effective association between DPP-4 inhibitors
and arthritis/arthralgia.

1 Introduction
Dipeptidyl Peptidase (DPP)-4 inhibitors are a class of oral
drugs used for the treatment of type 2 diabetes mellitus
(T2DM). Sitagliptin, saxagliptin, linagliptin and alogliptin
are members of this class of drugs, and are available as
single-ingredient products or in combination with other
medicines used for diabetes mellitus, such as metformin.
The use of these drugs in the treatment of T2DM was
proposed in 1990 when the role of DPP-4 inhibition was
discovered [1].
DPP-4 is a ubiquitous atypical serine protease that
degrades two incretin hormones, the glucose-dependent
insulin-tropic polypeptide (GIP) and glucagon-like peptide
1 (GLP-1) [2]. The incretin hormones contribute more than
70 % to the insulin response to blood glucose changes [3].
GIP and GLP-1 are released after a meal from K cells and
L cells, respectively; however, this release is decreased in
patients with T2DM. The main effect of GIP and GLP-1 is
a stimulation of insulin secretion in a glucose-dependent
manner. G-protein-coupled receptors mediate the molecular mechanism of their effects, and include an increase in

A. Mascolo et al.

cyclic adenosine monophosphate (cAMP), the activation of

protein kinase A, and other protein kinase-independent
mechanisms. The protein kinase A-independent mechanisms are related to guanine nucleotide exchange factors
(GEFs), particularly cAMP-GEFII (Epac2). Reduced
expression of GEFII decreases the effects of GLP-1 on
insulin secretion [4, 5]. The extra-pancreatic effects of
incretin hormones comprise lipogenesis (for GIP), and
satiety, activation of hepatic vagal afferents, and
improvement of myocardium and endothelium functions
(for GLP-1) [6]. DPP-4 inhibition mainly blocks the GLP-1
degradation, enhancing incretin effects, and glucose
homeostasis. In addition, the pharmacological inhibition of
DPP-4 seems to also induce adverse events related to
cytokine-induced inflammation [7]. In this regard, there are
several concerns regarding the risk of immune system side
effects following administration of DPP-4 inhibitors.
Recent studies have investigated this issue in DPP-4
homozygous knockout mice, suggesting that DPP-4 activity is inversely related to the severity of arthritis [8].
Several studies were conducted to assess the safety
profile of DPP-4 inhibitors. A pooled analysis, carried out
in the US on 10,246 patients, has showed that the frequency of arthralgia related to sitagliptin was equal to 0.2
incident events per 100 patient-years. These data were not
significantly different compared with those observed in
non-exposed patients [9]. Moreover, a 6-month postmarketing analysis of the 967 events related to sitagliptin
revealed that only three patients had occurrence or reactivation of rheumatoid arthritis (RA), six presented with
arthralgia, and the remaining patients showed joint swelling [10]; however, all DPP-4 inhibitors seem to be associated with an increased risk of arthritis or arthralgia [10
16]. The US FDA published a safety announcement
regarding the entire drug class, and encouraging healthcare
professionals and patients to pay attention to the occurrence of arthralgia during treatment with DPP-4 inhibitors
[16]. To summarize the evidence on the correlation
between DPP-4 inhibitors and arthritis/arthralgia, and to
explain the measures taken by the FDA with regard to
arthralgia risk, we performed a literature review of recent
evidence concerning this association.

2 Methods
Clinical cases were selected through searches of Pubmed
for articles published from October 2001 (date first
approval in the US) to September 2015, using the search
terms DPP-4 inhibitor, DPP-IV inhibitor, or dipeptidyl peptidase-4 in association with the search terms

arthritis, arthropathy, arthralgia, polyarthropathy,

polyarthritis, or synovitis. Moreover, we identified
cases published by the FDA and European Medicines
Agency (EMA). Only cases published in the English
language were considered.

3 Clinical Cases of Dipeptidyl Peptidase (DPP)-4

Inhibitor-Induced Arthritis/Arthralgia
Arthralgia is a non-specific symptom that, among other
causes, accompanies an autoimmune disorder (such as
RA), or can be chemically induced. Drug-induced arthralgia can be categorized into two adverse event types:
common and predictable, or uncommon and unpredictable [17]. Unpredictable adverse events are immunemediated by immunoglobulins IgE and IgG, or by T cells
[17]. Recently, several clinical cases regarding the association of DPP-4 inhibitors and the onset of arthritis/
arthralgia have been reported in the literature.
3.1 Case 1
A 48-year-old patient with a history of diabetes treated
with sitagiptin (dosage not stated) as add-on to standard
therapy (metformin). After 2 weeks of sitagliptin therapy,
the patient developed stiffness, worsening pain, and erythema of the metacarpal joints. The arthralgia was severe
and debilitating. Subsequently, after 6 weeks of therapy,
the patient manifested rash. Forty-eight hours from drug
discontinuation, rash and all symptoms from the metacarpal joints were resolved [11].
3.2 Case 2
Another clinical case involved a patient initially treated
with a sulfonylurea (glimepiride, 3 mg/day) for diabetes,
who later switched to sitagliptin therapy (50 mg/day) [10].
After approximately 2 months of therapy with sitagliptin,
the patient developed swelling and pain of the metacarpal,
proximal interphalangeal and metatarsal phalangeal joints.
Further examinations showed normal renal function with
the absence of peripheral microangiopathy or arteriosclerosis obliterans. A diagnosis of RA was made based on the
28-joint disease activity score associated with the C-reactive protein (DAS28-CRP), which was equal to 4.57. Given
the severity of the symptoms, sitagliptin therapy was
interrupted, and a combination of insulin therapy, salazosulfapyridine and corticosteroid was started. Despite
3 months of discontinuation, the signs and symptoms of
RA had not yet resolved.

Dipeptidyl Peptidase (DPP)-4 Inhibitor-Induced Arthritis/Arthralgia

3.3 Case 3
Based on case 2, a hospital-based survey was conducted to
search for other RA cases among 147 patients who started
sitagliptin therapy in 2010 [10]. This analysis found a
second patient who developed disease relapse of RA [a
65-year-old woman in a state of RA remission (\2.60
points on the DAS28-CRP)] from 15 years. The patient
was diagnosed with diabetes mellitus in November 2009,
and in February 2010, she started treatment with sitagliptin
(50 mg/day). Two months later the patient developed
arthralgia and swelling of both wrist joints. A final diagnosis of RA relapse was established [10].
3.4 Case 4
A 48-year-old woman developed RA after starting sitagliptin therapy (50 mg/day) [12]. The patient had joint
swelling and arthralgia in the hands, knees, and ankles after
approximately 3 months of therapy. A skeletal radiography
and computed tomography excluded the presence of
malignant tumors. Diagnoses of systemic lupus erythematosus or Sjogrens syndrome were excluded. As the
symptoms continued for 6 weeks, a diagnosis of RA was
made, according to the new American College of
Rheumatology/European League Against Rheumatism
(ACR/EULAR) criteria. The patient discontinued sitagliptin and returned to nateglinide and miglitol therapy. The
symptoms improved after discontinuation of sitagliptin
[12].
3.5 Case 5
A 54-year-old woman with T2DM started vildagliptin
therapy (dosage not stated) in addition to metformin in
October 2010. Two months later, the patient developed
knee and ankle arthralgia, as well as synovitis of both
wrists. Immunological tests and joint radiography showed
normal values, while chronic hepatitis B infection was
discovered. One month later, after the suspension of therapy, complete resolution of symptoms occurred. It is
interesting to note that despite a concomitant cause
(chronic hepatitis B), the temporal relationship between the
adverse event and DPP-4 therapy was important [13].
3.6 Case 6
A 48-year-old man in therapy for T2DM with sitagliptin
(dosage not stated) presented with bilateral and symmetrical polyarthritis of the ankles, and metacarpophalangeal
and proximal interphalangeal joints in February 2011 after
1 year of therapy. Concomitant conditions were

dyslipidemia, hypertension, and genital abscesses. Laboratory tests and radiography were normal. After 1 week of
sitagliptin being discontinued (May 2017), the polyarthritis
disappeared [13].
3.7 Case 7
A 56-year-old woman with T2DM being treated with
sitagliptin (dosage not stated) developed symmetrical
bilateral polyarthritis of the wrist, ankle, and metacarpophalangeal joints after 1 month of therapy. A diagnosis
of Sjogrens syndrome was made based on the presence of
xerophthalmia and xerostomia, as well as focal lymphocytic sialadenitis. Therapy with hydroxychloroquine,
prednisone, and methotrexate failed to control symptoms.
The resolution of arthritis was rapid after the withdrawal of
sitagliptin, allowing the discontinuation of therapy with
methotrexate and prednisone [13]. Despite Sjogrens syndrome being a concomitant cause of arthritis, the temporal
correlation between the appearance/disappearance of the
event and DPP-4 therapy was strong.
3.8 Case 8
A 74-year-old woman with a history of T2DM 5 weeks
after switching from gliclazide (20 mg) to sitagliptin
(50 mg), developed oedema of the dorsum and finger
hands, oedema of the dorsum feet, slight fever, arthralgia
and malaise. A diagnosis of remitting seronegative symmetrical synovitis with pitting oedema (RS3PE) was made.
The value of the C-reactive protein (CRP; reference range
9.5 nmol/L) was 1313 nmol/L, and the erythrocyte sedimentation rate was 86 mm/h. The rheumatoid factor,
anticyclic citrullinated protein antibody, antinuclear factor,
and anti-DNA antibody were negative. The event ameliorated after 7 days of therapy discontinuation. The temporal
relationship suggests that DPP-4 inhibitors can be causally
related to the onset of RS3PE [14].
3.9 Case 9
Another clinical case of a 71-year-old man with RS3PE
was identified. The patient presented oedema of the dorsum
hands and feet 8 weeks after starting vildagliptin therapy
(100 mg). Rheumatoid factor, anticyclic citrullinated protein antibody, antinuclear factor, and anti-DNA antibody
were negative. CRP value was 13 nmol/L, and the erythrocyte sedimentation rate was 23 mm/h. The symptoms
ameliorated after 10 days of therapy discontinuation [14].
The event was strongly related to DPP-4 inhibitor therapy
because of the temporal relationship and the positive
dechallenge.

A. Mascolo et al.

3.10 Cases Reported in Studies

Cases of polyarthropathy (n = 13) were identified in a
cohort study of patients receiving therapy for T2DM with
DPP-4 inhibitors, while no case was identified in the control
group. Two cases were receiving therapy with 100 mg/die of
sitagliptin while the others were receiving 50 mg/day of
sitagliptin. Duration of DPP-4 inhibitor therapy before joint
symptoms ranged from 2 to 31 months. After DPP-4 inhibitor cessation, the clinical symptoms of polyarthropathy
resolved within a mean period of 3 months. The study
showed a correlation between DPP-4 inhibitor therapy and
the development of polyarthropathy [15]. In addition, some
pivotal studies have shown a greater frequency of arthralgia
in the group of patients treated with DPP-4 inhibitors
compared with the control, although the difference was not
significant [1820].
3.11 Clinical Cases Reported by the USA FDA
and the European Medicines Agency
The FDA, researching through the FDA Adverse Event
Reporting System (FAERS) database, has found 33 cases
of severe arthralgia reported with the use of DPP-4 inhibitors between 16 October 2001 (date of first approval) and
31 December 2013 [16]. Of note, two cases found in the
FAERS database were the same as those mentioned above
[10, 11]. The most frequently reported DPP-4 inhibitor was
sitagliptin (n = 28), followed by saxagliptin (n = 5),
linagliptin (n = 2), vildagliptin (n = 2) and alogliptin
(n = 1). In five cases, arthralgia also arises after switching
to another DPP-4 inhibitor. In all 33 cases, the arthralgia
was severe and disabling. In 20 cases, after 1 month from
the onset of symptoms, the DPP-4 inhibitor was discontinued, while in other eight cases therapy was discontinued
after 44 days to 1 years. In 23 cases, the resolution of
symptoms occurred in less than 1 month. Eight of 33 cases
presented a positive rechallenge with resolution of the
symptoms after therapy discontinuation [16]. Consequently, in light of the emerging safety issue related to the
onset of arthralgia during DPP-4 inhibitor therapy, the
FDA published a safety announcement with regard to the
entire drug class. This warning specifies that healthcare
professionals should consider DPP-4 inhibitors as a new
class of drugs that can induce severe arthralgia. Therefore,
they must consider, if necessary, the suspension of treatment [16]. The FDA has also published that the time to
events can be from 1 day to years, and has underlined the
possibility that patients experienced positive dechallenge
and rechallenge [16].
At the time of the research, the EMA had not published
cases involving this association.

4 Possible Mechanisms of DPP-4 InhibitorInduced Arthritis

Several mechanisms discussed herein could be responsible
for the onset of arthritis. An important role is played by the
increase of cytokines, chemokines and MMPs; other
mechanisms involve genetic factors.
4.1 Immunological Mechanisms
4.1.1 Role of Cytokines, Chemokines, and Matrix
Metalloproteinases
The pathophysiology of arthritis induced by DPP-4 inhibitors could be related to their pharmacological mechanism
of action; several clinical studies have investigated this
issue. Two studies showed that plasma DPP-4 levels are
inversely related to plasma CRP levels, and are decreased
in patients with RA versus patients with osteoarthritis [21,
22]. More important is to consider that DPP-4, in addition
to GLP-1, also degrades several cytokines, including stromal cell-derived factor-1 (SDF-1), a pro-inflammatory
chemokine involved in RA induction [23]. Many other
substrates, such as the superfamily of glucagon, some
hormones and chemokines, are degraded by DPP-4. However, we must consider that DPP-4 is not the only enzyme
that metabolizes chemokines. Moreover, the inhibition of
DPP-4 increases not only the expression of SDF-1 but also
MMP-1 and MMP-3 in RA synovial fibroblasts [21]. All
these peptides have a similar X-Ala/X-Pro sequence at the
N-terminus, which is the target recognized for the degradation and inhibition by DPP-4 [22]. These findings could
explain why a block of DPP-4 activity can induce an
increase in SDF-1 levels, and MMP-1 and MMP-3 activity,
with consequent worsening of the joint inflammation in
patients with RA. In one of the case reports described
above, the levels of MMP-3 were 51 ng/ml at the time of
onset of RA (normal range 17.359.7 ng/ml). After therapy
discontinuation and improvement of symptoms, this value
was 34 ng/ml [12].
An experimental study showed a plasma SDF-1 level
dependent on DPP-4 activity, and that mice genetically
deficient for DPP-4 presented an increased severity of
antigen-induced arthritis [12]. Based on this result, an
analysis was conducted to investigate the effect of reduced
degradation of SDF-1 related to DPP-4 inhibition in the
onset of arthritis by measuring the SDF-1a concentration.
The results did not show a correlation between an increase
in SDF-1a levels and sitagliptin use compared with control,
and failed to evidence the direct role of SDF-1a in the
development of RA in patients treated with sitagliptin for
T2DM [10]. Also in the cohort study mentioned above, the

Dipeptidyl Peptidase (DPP)-4 Inhibitor-Induced Arthritis/Arthralgia

SDF-1a plasma level was decreased in polyarthropathy

patients compared with controls. After resolution of
symptoms, the plasma level of SDF-1a was reverted to
levels of the control group, and no significant differences in
other cytokines and chemokines were observed [15].
4.1.2 Role of Inflammatory Cells
Another important consideration is the expression of DPP4 in cells, such as fibroblasts, T lymphocytes, and macrophages, which could explain why the inhibition of DPP-4
influences the inflammatory homeostasis of the bones and
joints [21, 24].
Studies have shown that the peripheral T lymphocytes,
expressing DPP-4 on their cell membranes, increased in the
blood of patients with RA [25]. In contrast, the levels of
soluble DPP-4 are reduced in patients with RA compared
with controls, and are inversely related to the number of
joints swelling [26, 27]. In addition to the SDF-1a, the
factor RANTES (regulated upon activation, normal T-cell
expressed and secreted) is also degraded by DPP-4, and it
seems to actively participate in the pathogenesis of RA [28,
29]. The reduction in the levels of soluble DPP-4 could be
matched with a simultaneous increase of the same on the
cell membranes of the T lymphocytes. This effect could
positively influence leukocyte-rolling and extravasation,
and simultaneously prolong the RANTES and SDF-1
action [30]. The correlation between the severity of antigen-induced arthritis and lack of DPP-4 was investigated in
a mouse model. DPP-4-deficient mice presented an
increase of plasma SDF-1 levels and their receptor
(CXCR4) on cells infiltrating the arthritic joint [8].
4.2 Genetic Mechanisms
The human leukocyte antigen (HLA) is the genetic factor
involved in the pathogenesis of RA. The evidence showed
an association between some HLA-DRB1 alleles and RA
severity. HLA-DRB1 alleles have a highly conserved
sequence at amino acidic residues 7074 of the DRB1
chain in the third hypervariable region, called the shared
epitope (SE) [31]. The alleles considered SE-positive are
DRB1*0101, *0102, *0401, *0404, *0405, *0408, *0410,
*1001, and *1402. Studies showed the correlation
between SE-positive HLA-DRB1 alleles and anti-citrullinated protein antibody (ACPA)-positive RA [32, 33].
The patient reported in the case report by Yokota and
Igaki [12] had SE-positive HLA-DRB1*0101 and
DRB*0405, suggesting the hypothesis that sitagliptin
triggers RA in patients with a predisposing condition.
This patient was SE-positive HLA-DRB1 but ACPAnegative. Balsa et al. found that the 35 % of ACPAnegative RA patients are positive to SE-containing HLA-

DRB1 alleles, hypothesizing a lack of association due to

environmental factors [34]. Two studies showed that
ACPA-negative RA is associated with HLA-DR3 [35,
36]. In contrast, Balsa et al. did not support this association but suggested that HLA-DR3 decreases the risk of
ACPA-positive RA [34]. More studies are necessary to
confirm if administration of DPP-4 inhibitors is a trigger
to RA in patients with SE-containing HLA-DRB1 alleles.
Despite the fact that a causal relationship between DPP4 inhibitors and osteoarthritis could not be excluded, it
should be considered that, as shown in recent meta-analysis, diabetes mellitus is associated with osteoarthritis [37].
Moreover, diabetes mellitus has been associated with
autoimmune disorders (such as RA) [38]. This correlation
seems to be related to the high levels of inflammatory
mediators (CRP, interleukin-6, and tumor necrosis factora), suggesting a role of diabetes in the immunopathogenesis of RA [39, 40]. In contrast, other studies showed an
increased risk of T2DM in patients with RA, psoriatic
arthritis, and psoriasis [4143]. Based on these findings, we
should also consider the role played by chronic systemic
inflammation in the pathogenesis of both autoimmune
diseases and T2DM.

5 Conclusions
We summarized 22 cases of DPP-4 inhibitor-induced
arthralgia/arthritis that could be considered as a class
adverse drug event. Moreover, specifically for sitagliptin
and vildagliptin, we showed nine case reports of arthritis/
arthralgia. Because the use of DPP-4 inhibitors could be
related to the pathogenesis of arthritis or arthralgia, it is
important to cautiously follow the patients treated with
these drugs. Specifically, this adverse event should be
considered rare and detectable only in patients susceptible
to the disease; therefore, patients who are particularly
susceptible should be followed carefully. Healthcare professionals should be aware of such events caused by DPP-4
therapy and consider the discontinuation of the drug if
appropriate. However, although there are hypotheses of
biological plausibility between the use of DPP-4 inhibitors
and these events, further studies should be conducted to
better define the effective association between DPP-4
inhibitors and arthritis/arthralgia.
Compliance with Ethical Standards
Funding No sources of funding were used to assist in the preparation of this review.
Conflicts of interest Annamaria Mascolo, Concetta Rafaniello,
Liberata Sportiello, Maurizio Sessa, Daniela Cimmaruta, Francesco
Rossi and Annalisa Capuano declare no conflicts of interest.

A. Mascolo et al.

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