iga nephropathy and psoriatic arthritis that improved with

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□ CASE REPORT □

IgA Nephropathy and Psoriatic Arthritis that Improvedwith Steroid Pulse Therapy and Mizoribine in Combinationwith Treatment for Chronic Tonsillitis and Epipharyngitis

Tomohiro Kaneko 1, Akiko Mii 1, Megumi Fukui 1, Kiyotaka Nagahama 2,

Akira Shimizu 2 and Shuichi Tsuruoka 1

Abstract

A 65-year-old man was admitted to our hospital with edema and renal dysfunction. He had received a di-

agnosis of psoriatic arthritis at 50 years of age. As a renal biopsy showed IgA nephropathy (IgAN), bilateral

tonsillectomy was performed, and one course of steroid pulse therapy with an oral steroid and mizoribine

were subsequently administered. The patient’s proteinuria gradually reduced in association with an improve-

ment in the renal function. In addition, the rash and arthralgia were ameliorated. In this case, adding treat-

ment for chronic epipharyngitis accelerated the curative effects, and focal infection therapy consisting of im-

munosuppressive drugs was effective for both IgAN and psoriatic arthritis.

Key words: IgA nephropathy, psoriatic arthritis, focal infection treatment

(Intern Med 54: 1085-1090, 2015)(DOI: 10.2169/internalmedicine.54.3510)

Introduction

It has been reported that the administration of steroid

pulse therapy after bilateral tonsillectomy is effective in

cases of IgA nephropathy (IgAN). The palatine tonsils are a

central component of the nasopharynx-associated lymphoid

tissue (NALT), which forms part of Waldeyer’s tonsillar

ring. These tonsils take in antigens invading from the oral

and nasal cavities and subsequently form antibodies. It has

also been demonstrated that the number of IgA plasma cells

is increased in the palatine tonsils in IgAN patients and that

IgA1-positive cells are present among the dendritic cells of

the tonsillar follicles. In addition, there are many reports

suggesting the presence of quantitative and qualitative ab-

normalities in Galβ1 and 3GalNAc in O-linked glycans in

hinge regions. O-glycosylation abnormalities are of particu-

lar interest as a principal cause of IgAN (1).

Focal infection is a clinical state in which chronic local-

ized inflammation in one part of the body causes reactive

organic or functional disabilities in distal locations. The

most frequent site of origin is the tonsils. Typical diseases

caused by tonsillar focal infection include orthopedic disor-

ders, such as sternocostoclavicular hyperostosis and reactive

arthritis, and cutaneous diseases, such as palmoplantar pus-

tulosis and erythema nodosum, in addition to IgAN and pur-

pura nephritis. Psoriasis may also present with the exacerba-

tion of rashes due to infection of the upper respiratory tract

and tonsillitis. Furthermore, it has been widely reported that

tonsillectomy is effective for treating tonsillar focal dis-

eases (2).

Psoriatic arthritis is a form of chronic inflammatory ar-

thritis accompanying bone and cartilage lesions, which coex-

ist in 4-30% of psoriasis cases (3). In addition, deformation

or articular destruction are observed at five or more loca-

tions in 55% of patients whose articular symptoms devel-

oped more than 10 years previously. Such patients are

treated in accordance with guidelines for rheumatoid arthri-

tis, and the administration of a tumor necrosis factor-alpha

(TNF-α) inhibitor is often considered in intractable

cases (4).

We experienced a case of IgAN with coexisting psoriatic

１Division of Nephrology, Department of Internal Medicine, Nippon Medical School, Japan and ２Department of Analytic Human Pathology, Nip-

pon Medical School, Japan

Received for publication June 21, 2014; Accepted for publication September 15, 2014

Correspondence to Dr. Tomohiro Kaneko, [email protected]

Intern Med 54: 1085-1090, 2015 DOI: 10.2169/internalmedicine.54.3510

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Figure　1.　Appearance of the skin before and 18 months after tonsillectomy. a: Carnation maculae with a scale attached margin were observed across the patient’s entire body before tonsillectomy. b: The rash nearly disappeared 18 months after tonsillectomy.

a

b

Table.　Laboratory Data at Admission

Peripheral blood Serological testWBC 5, IgG 1,321 mg/d RBC 397 × 104 IgA 648 mg/Hb 1 IgM 94 mg/Hct 35.5 % CH50 > 60 U/mPlt 25.7 × 104/ C3 147 mg/

Blood chemistry C4 44 mg/TP RF 3 IU/mAlb 3.6 g/d ACPA 0.4 U/mAST 22 IU/ ANA < 40A T 18 IU/ MPO-ANCA < 10 EU

H 205 IU/ PR3-ANCA < 10 EUT-Cho 189 mg/ HBs-ag negative

-Cho 111 mg/ HCV-ab negativeTG 155 mg/ T A negativeUA 7.2 mg/ Urinalysis BUN 31.3 mg/ Gravity 1.018Cre 1.83 mg/ pH 5.5Na 137 mEq/K 4.2 mEq/Cl 105 mEq/ (3+)Ca 8.7 mg/ Glucose (-)Pi 3.2 mg/ Ketone (-)CRP 0.67 mg/dHbA1c(NGSP) 6.1%

Protein 3+2.8 g/day

Occult blood

arthritis in which we performed tonsillectomy and adminis-

tered steroids and mizoribine (MZR) in addition to treatment

for the focal infection. Consequently, the patient’s rash, ar-

thralgia and renal function improved and the hematuria

completely disappeared.

Case Report

A 65-year-old man scheduled for a renal biopsy had been

visiting a local doctor for the treatment of psoriatic arthritis

since 50 years of age. The psoriatic arthritis was refractory

and had been treated with steroids, cyclosporin and vitamin

D ointment. The patient reported strong joint pain, and non-

steroidal anti-inflammatory drugs (NSAIDs) were used em-

pirically. In addition, he had been prescribed antihyperten-

sives (a calcium channel blocker and angiotensin II receptor

blocker) since 60 years of age. Bilateral edema in the lower

extremities was observed approximately one month prior to

the renal biopsy. A local doctor identified proteinuria and re-

nal function impairment, and the patient was therefore re-

ferred to our department for hospitalization. As shown in

Fig. 1a, carnation maculae with a scale attached margin

were observed across his entire body. Table shows the find-

ings of the laboratory workup performed on admission; ane-

mia and high blood IgA in addition to hematuria, protein-

uria and renal function impairment were observed. The renal

biopsy, performed the day after admission, showed almost

half (of a total of approximately 30) of the glomeruli to be


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Figure　2.　Findings of the renal biopsy. A total of 30 glomeruli were included in the renal biopsy samples, 16 of which had deteriorated (arrowhead in A) with tubular atrophy in addition to intersti-tial fibrosis in 30% of the renal cortex [A: Periodic acid methenamine silver (PAM) stain, ×400]. Focal segmental proliferative lesions were noted in five to six glomeruli (arrow in A), and small endocapil-lary proliferative lesions with inflammatory cell infiltration were evident in two glomeruli [B: Peri-odic acid-Schiff (PAS) stain, ×800]. Small fibrin exudation was seen in Bowman’s space, possibly as-sociated with a necrotizing glomerular lesion in one glomerulus (C: PAM stain, ×800). On immunohistochemistry, deposition of IgA (arrowheads in D) and C3 (arrowheads in E) was noted in a mesangial granular pattern (D: IgA stain; E: C3 stain; D, E: ×600). On electron microscopy, small electron-dense deposits (arrowheads in F) were evident in paramesangial areas (×5,000).

PAM ×400

×5,000

obsolescent, with slight segmental mesangial proliferative le-

sions in five to six glomeruli (Fig. 2). Endocapillary prolif-

eration with inflammatory cell infiltration was noted in two

glomeruli, and a small necrotizing lesion was evident in one

glomerulus, reflecting an active lesion. Furthermore, one

glomerulus exhibited segmental sclerosis with a fibrous cres-

cent, reflecting a chronic lesion. Glomerular adhesion was

observed in two glomeruli, and tubulointerstitial lesions had

progressed into 30% of the renal cortex. Immunohistochem-

istry showed deposition of IgA and C3 in mesangial areas.

The diagnosis was IgAN, M0, E1, S1 and T1 according to

the Oxford classification and grade IIIC based on the Japa-

nese histological grade. This status indicated the presence of

active lesions, including small necrotizing lesions, with

chronic lesions progressing to IgAN.

Bilateral tonsillectomy was performed one month after the

renal biopsy. Although treatment with NSAIDs and cy-

closporine was halted after the biopsy, the patient’s serum

creatinine level increased to 1.93 mg/dL. Additionally, ster-

oid pulse therapy was administered one week after tonsillec-

tomy. As follow-up treatment, prednisolone at a dose of 30

mg/day was administered for one month, after which the

dose was reduced to 30 mg every other day. Simultaneously,

MZR was started at a dose of 150 mg/day. Unfortunately,

the patient developed diabetes developed after receiving the

steroid pulse therapy, and it was necessary to prescribe a

dipeptidyl peptidase-4 inhibitor until the steroid dose could

be reduced. Meanwhile, the rash and arthralgia improved,

but did not disappear, immediately after tonsillectomy, while

the serum IgA level, which decreased after the procedure,

gradually increased again. Taking into consideration the ex-

istence of other focal infections, we started treatment [appli-

cation of 1% zinc chloride and Japanese apricot extract (MK

615) nose drops] for the upper pharynx 10 months after ton-

sillectomy. As shown in the figure, both the rash (Fig. 1b)

and arthralgia nearly disappeared soon after the treatment


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Figure　3.　Clinical course

methylprednisolone0.5g/day

0

1

2

3

4

5

U-P

ro/C

r (g/

g)

Ser

um C

r (m

g/dL

)

1.0

2.0

3.0

U-Pro/CrSerum Cr

Tonsillectomy

prednisolone30

30

mizoribine150

25

100

20 15 10

75

5 mg every other day

mg a day

mg a day

Start of treatments for chronic epipharyngitis

month0 3 6 9 12 15

U-OB3+ 3+ 3+ 2+ 2+ 1+ 1+ 1+ ± –±

18

1+ ± –

Serum IgA 648 705 287 317 355 315 364 442 517 498 483 472 mg/dL

for chronic epipharyngitis. There was no need for antiphlo-

gistic analgesics. The IgA level decreased again, and the he-

maturia completely disappeared. In addition, the doses of

steroids and MZR were reduced without signs of worsening,

and the patient’s proteinuria and renal function gradually

improved. Twenty months after tonsillectomy, the serum cre-

atinine level had decreased from 1.93 to 1.55 mg/dL

(Fig. 3).

Discussion

Performing tonsillectomy combined with steroid pulse

therapy for IgAN at an early stage is expected to keep urine

abnormalities in remission (5). However, the therapeutic ef-

fect is unclear in cases in which a longer time has elapsed

from the onset of symptoms and/or patients with a history

of prior renal dysfunction. In the current case, the renal bi-

opsy showed that nearly half of the glomeruli were obsoles-

cent and the tubulointerstitial lesion had progressed. There-

fore, the pathological diagnosis was IgAN with few active

lesions, although the lesions were predominantly chronic.

We previously reported that the use of steroid pulse therapy

in combination with MZR following tonsillectomy is effec-

tive in improving urinary findings and preserving the renal

function when treating IgA nephropathy in patients with re-

nal impairment (6, 7).

It is recognized that the administration of MZR combined

with 14-3-3 protein and HSP60 enhances the transcriptional

activity of glucocorticoid receptors and thus the effect of

steroids (8). It has also been reported that MZR inhibits the

action of α3β1 integrin and decreases the motility of

fibroblast-specific protein-1-positive fibroblasts, both of

which are involved in the progression of interstitial fibrosis

in patients with IgAN (9).

It was recently demonstrated that activated macrophages

play an important role in the pathology of IgAN (10). Addi-

tionally, steroid-induced increases in transforming growth

factor-β production by macrophages are reportedly sup-

pressed by the concomitant use of MZR. MZR not only po-

tentiates steroidal anti-inflammatory effects, but also pre-

vents the progression of chronic lesions, such as those in-

volving tissue fibrosis and sclerosis, by inhibiting activated

macrophages.

Steroid therapy is usually terminated within six months to

one year. However, in this case, we continued treatment

with low-dose steroids due to the patient’s joint pain. Con-

sequently, the serum creatinine level temporarily worsened

after starting this therapy. We consider two possible causes

underlying this phenomenon: (a) the high dose of steroids

temporarily deteriorated the patient’s renal function and in-

duced glucose tolerance, and (b) the treatment of one course

of steroid pulse therapy combined with MZR takes longer to

achieve an effect than three courses of steroid pulse therapy

alone. In our experience, we have observed improvements in

the renal function several months after beginning MZR

treatment.

In this case, the patient’s rash caused by psoriatic arthritis

and arthralgia significantly improved soon after starting the

above therapy. Psoriatic arthritis is a form of chronic inflam-

matory arthritis accompanying psoriasis of the skin. This

disease is diverse, and, in some patients, progressive joint

lesions cause functional disturbances. The appearance of a

rash may significantly decrease the quality of life (QOL) of

the patient from both mental and physical perspectives to

the same degree as malignant tumors (11). It has been re-

ported that T cells, especially Th1 cells, play a central role


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in the clinical onset of psoriasis. For example, a recent re-

port indicated that Th1 cells, Th17 cells and regulatory T

cells (Treg) are mutually and intricately associated with

chronic clinical states (12). It is therefore expected that inhi-

bition of TNF-α, an inflammatory cytokine, reduces inflam-

mation, suppresses epidermal growth and normalizes abnor-

mal cornification. Effects on articular symptoms are also ex-

pected, and joint breakdown may be inhibited. TNF-α in-

hibitors, such as infliximab and adalimumab, are increas-

ingly used in refractory cases. However, the burden of these

drugs is high, and it has been reported that serious side ef-

fects occur at approximately twice the rate in patients older

than 65 years of age than in those younger than 65 years of

age (13).

Tonsillectomy has been shown to be very effective for

palmoplantar pustulosis, sternocostoclavicular hyperostosis

and IgAN. It has also been documented that these diseases

coexist with one another at a high rate. Many reports have

indicated that tonsillectomy has far-reaching effects on pso-

riasis, rheumatoid arthritis and Behçet’s disease in addition

to the diseases listed above. Nyfors et al. described 74 cases

of psoriasis vulgaris treated with tonsillectomy, reporting

improvements in the rashes in 53 cases (72%) (2).

It has been speculated that an abnormal immune response

in the tonsils causes and/or worsens the diseases described

above. For example, Takahara reported that, on quantitative

immunohistological analyses of tonsillar tissues, the overall

area of T cell nodules is significantly expanded, whereas

that of B-lymphoid follicles is reduced, and the number of

apoptotic cells is elevated in tonsils obtained from patients

with psoriasis and palmoplantar pustulosis than in those

with recurrent tonsillitis. The area of T cell nodules and

number of apoptotic cells are significantly larger in the ton-

sils of patients exhibiting a complete recovery after tonsil-

lectomy than in those without a complete recovery (14).

In the present case, the rash initially improved after ton-

sillectomy and was further ameliorated after starting treat-

ment for chronic epipharyngitis. It was recently reported that

laryngological sources of infection are found in 44% of pa-

tients with psoriatic arthritis (15). Moreover, the effective-

ness of cholecystectomy in removing the inflammatory fo-

cus as a treatment for psoriasis has also been reported (16).

These facts suggest the presence of various factors in the

pathogenesis of psoriasis and the contribution of multiple in-

flammatory foci in addition to the tonsils.

The mucosal surface of the upper pharynx forces back

pathogenic microbes, such as bacteria and viruses, that are

continuously intruding, while possessing mechanisms which

allow it to coexist with resident microbiota. Secretory IgA

performs a crucial function in this system. The lumen sur-

face of the upper pharynx is covered with lymphocytes in a

state of activation, and class II antigen-positive ciliated epi-

thelial cells with an antigen-presenting ability are present in

the tonsillar crypt epidermis. It has also been reported that

the phenotype of lymphocytes obtained by scratching the

epipharynx closely resembles that of lymphocytes in the

palatine tonsils (17). Chronic epipharyngitis may be a cause

of focal infection related to the development of secondary

diseases.

The present patient was diagnosed with coexisting chronic

epipharyngitis, as the application of a winding cotton swab

containing 1% zinc chloride solution caused bleeding and

scratching pain. We directly applied zinc chloride, which

causes tissue convergence and corrosion and possesses an

antibacterial activity, in addition to nose drops comprising

MK615 to treat the patient’s chronic epipharyngitis. MK615

is a compound made by condensing and extracting Japanese

apricot and has been reported to have various effects, in-

cluding antitumor, anti-inflammatory and liver-supporting

functions. MK615 inhibits the release of cytokines, such as

TNF-α and IL-6, and may represent a useful therapeutic

agent for chronic periodontitis, a condition that is also re-

ported to cause focal infections (18, 19). In our facility, we

have used nose drops containing MK615 for chronic epipha-

ryngitis for several years. The curative effect is high, based

on our experience, with no concerns regarding safety. Nev-

ertheless, further studies are required to investigate the ef-

fects of local MK615 application as an adjunctive treatment.

Bleeding and pain resulting from the application of zinc

chloride to the epipharynx was reduced via successive appli-

cations in this case. At the same time, the patient’s rash and

arthralgia were further alleviated and the hematuria com-

pletely disappeared. However, it is necessary to accumulate

further cases involving this treatment in order to confirm

whether these agents are effective in cases of chronic

epipharyngitis.

In summary, we experienced a case of IgAN with coexist-

ing psoriatic arthritis in which we administered steroids and

MZR in addition to treatment for focal infection. Conse-

quently, the patient’s rash, arthralgia and renal function im-

proved and the hematuria completely disappeared. Although

this is a single case report, our findings indicate that combi-

nation treatment for focal infection, including steroids and

MZR, is effective for multiple pathological conditions that

may share a common source.

The authors state that they have no Conflict of Interest (COI).

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