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□ CASE REPORT □

Hypogammaglobulinemic Patient with PolyarthritisMimicking Rheumatoid Arthritis Finally Diagnosedas Septic Arthritis Caused by Mycoplasma hominis

Hiroe Sato 1, Noriaki Iino 1, Riuko Ohashi 2, Takako Saeki 3, Tomoyuki Ito 3, Maki Saito 1,

Yutaka Tsubata 1, Suguru Yamamoto 1, Shuichi Murakami 1, Takeshi Kuroda 1,

Yoshinari Tanabe 1, Junichi Fujisawa 4, Takehiro Murai 4, Masaaki Nakano 5,

Ichiei Narita 1 and Fumitake Gejyo 1

Abstract

Hypogammaglobulinemia is a reduction or absence of immunoglobulin, which may be congenital or asso-

ciated with immunosuppressive therapy. In addition to infectious diseases, autoimmune diseases have also

been reported in patients with hypogammaglobulinemia. A 26-year-old man with hypogammaglobulinemia

had multiple joint pain and swelling with erosive changes in the proximal interphalangeal joint of the right

middle finger on X-ray film, mimicking rheumatoid arthritis (RA). As polyarthritis remained after immuno-

globulin replacement therapy and there was no finding indicating any infection at that time, a diagnosis of

RA was made. Prednisolone and etanercept were started. However, his polyarthritis did not improve and he

developed meningitis and massive brain ischemia. Finally, a diagnosis of disseminated Mycoplasma hominisinfection was made. The differential diagnosis of polyarthritis in patients with hypogammaglobulinemia

should strictly exclude Mycoplasma infection by culture with special media or longer anaerobic culture, and

molecular methods for mycoplasma.

Key words: hypogammaglobulinemia, septic arthritis, rheumatoid arthritis, Mycoplasma hominis, erosions

(Intern Med 51: 425-429, 2012)(DOI: 10.2169/internalmedicine.51.6058)

Introduction

Hypogammaglobulinemia is a heterogeneous disorder

characterized by markedly reduced immunoglobulin, includ-

ing X-linked agammaglobulinemia (XLA), common variable

immunodeficiency (CVID), selective immunoglobulin (Ig) A

deficiency, immunoglobulin deficiency with increased levels

of IgM, and autosomal recessive agammaglobulinemia.

These patients with no or decreased levels of gamma globu-

lin are vulnerable to infection with encapsulated bacteria,

such as Streptococcus pneumoniae and Haemophilus influ-

enzae, mycoplasma, and ureaplasma.

Autoimmune disorders associated with hypogammaglobu-

linemia have also been reported, such as rheumatoid arthritis

(RA) (1-3), juvenile idiopathic arthritis (JIA) (4, 5), ankylos-

ing spondylitis (6), and systemic lupus erythematosus

(SLE) (7). The prevalence of arthritis was reported to be 10-

30% in patients with hypogammaglobulinemia (8), and

some patients were reported to require disease-modifying

antirheumatic drugs (2, 3). Here, we report a hypogam-

maglobulinemic patient with polyarthritis associated with

erosive changes seen on X-ray film mimicking RA, in

whom a final diagnosis of Mycoplasma hominis infection

１Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Japan, ２Division of

Cellular and Molecular Pathology, Niigata University Graduate School of Medical and Dental Sciences, Japan, ３Division of Nephrology and

Rheumatology, Nagaoka Red Cross Hospital, Japan, ４Division of Orthopedic Surgery, Niigata University Graduate School of Medical and Den-

tal Sciences, Japan and ５School of Health Sciences, Faculty of Medicine, Niigata University, Medical Laboratory Science, Japan

Received for publication June 24, 2011; Accepted for publication October 26, 2011

Correspondence to Dr. Hiroe Sato, hiroe-212@umin.ac.jp

Intern Med 51: 425-429, 2012 DOI: 10.2169/internalmedicine.51.6058

426

was made.

Case Report

A 26-year-old man was admitted to a local hospital be-

cause of a 2-month history of back pain, and polyarthralgia

of the bilateral hips, knees, shoulders, and the proximal in-

terphalangeal (PIP) joint of the right middle finger. He had

suffered pneumonia and pleuritis 1 year prior to admission.

Paracentesis of pleural effusion revealed an elevated

lymphocyte-dominant cell count and a slightly increased

adenosine deaminase (ADA) level (52 IU/L). Culture of

pleural effusions was negative for bacteria and mycobacte-

ria, and polymerase chain reaction (PCR) analysis for tuber-

culosis was negative. Because his ADA was slightly ele-

vated, he had been treated with antituberculosis drugs; how-

ever, no further examinations or therapy were performed as

his gamma globulin fraction was so low (4.7%). He had no

other past medical history and no family history of immu-

nodeficiency. His temperature was 38.2℃. The PIP joint of

the right middle finger was swollen and he had pain in the

bilateral elbows, knees, shoulders, and hips. A subcutaneous

nodule was present on the left waist, which was neither ten-

der nor red. His white blood cell count was 14,100/μL (neu-

trocytes 80%, eosinocytes 3%, lymphocytes 8%, monocytes

9%) and C-reactive protein was 18.64 mg/dL. Total protein

was 5.1 g/dL and the gamma globulin fraction was 4.4%.

His kidney function was normal, but he had mild liver dam-

age (alanine aminotransferase level 118 IU/L). No white

blood cells were detected in urine. Rheumatoid factor, anti-

CCP antibody, and anti-nuclear antibody were negative. The

immunoglobulin levels were markedly decreased (IgG 228

mg/dL, IgA 8 mg/dL, and IgM 1 mg/dL). B cells in periph-

eral blood were not detected using monoclonal antibodies to

CD19 and CD20 (<1%). However, the levels of Bruton’s ty-

rosine kinase (Btk) proteins expressed on monocytes were

normal, as determined by flow cytometry. His hypogam-

maglobulinemia was not due to mutations in Btk proteins

(i.e., XLA) and was not classified as typical CVID, because

of his B cell deficiency. Intravenous immunoglobulin re-

placement therapy was started and the IgG level was main-

tained above 600 mg/dL. A chest X-ray showed that left

pleural effusion and pleural thickening remained; however,

the extent of pleural effusion was not so severe that paracen-

tesis was required. Fluid was observed around the left hip

joint on computed tomography. Echocardiography did not

detect any abnormalities, including vegetations. Antibodies

to Mycoplasma pneumoniae, cytomegalovirus, and Epstein-

Barr virus were negative. The results of blood, urine, and

knee arthrocentesis stab cultures were all negative. White

blood cell count in synovial fluid was 3+, and no uric acid

or calcium pyrophosphate crystals were detected. S. pneu-moniae, but not mycobacteria, were detected in sputum cul-

ture. The results of the QuantiFeronⓇ TB-Gold test for tu-

berculosis were negative. Septic arthritis was initially sus-

pected, although no pathogen was detected. Imipenem/

cilastatin sodium and pazufloxacin mesilate were started, but

these treatments were not effective. Open synovial biopsy of

the PIP joint of the right middle finger was performed and

infiltration of monocytes and macrophage in the synovium

was observed, but neither plasma cells nor B cells were de-

tected (Fig. 1). No villous proliferation of synovial tissues

or lymph follicles was detected. M. pneumoniae, Chlamydiapneumoniae, and Legionella pneumophila were not detected

from biopsy tissue by a PCR-based method. Active synovitis

was confirmed, but its cause was unclear. The patient was

admitted to our hospital two weeks after admission to the

previous hospital. He had morning stiffness and tenderness

in the bilateral shoulders, wrist, knees, hips, ankles, and the

PIP joint of the right middle finger with swelling; however,

neither redness nor a hot sensation was notable, as is usually

observed in infectious arthritis. His hip pain was so severe

that he could not move the hip joints and was bedridden.

Erosion and joint space narrowing of the PIP joint of the

right middle finger were observed (Fig. 2). Micafungin,

panipenem, and vancomycin were ineffective. Since polyar-

thritis with radiographic erosion without evidence of infec-

tion persisted, despite an IgG level above 600 mg/dL, and

his symptoms satisfied the American College of Rheumatol-

ogy classification criteria for rheumatoid arthritis (RA),

prednisolone (PSL) was started at 10 mg/day. His CRP lev-

els decreased from 16.9 mg/dL to 8.1 mg/dL and his symp-

toms showed slight improvement but still persisted. Etaner-

cept (ETN; 25 mg) was administered subcutaneously, after

administration of isoniazid for 2 weeks. The patient’s ar-

thralgia and joint swelling showed further improvement.

One week after the first administration of ETN, the patient

showed an elevated fever above 38.5°C. The antibiotics

doripenem and arbekacin were started and ETN was discon-

tinued. An open biopsy of the right hip was performed, and

joint destruction was severe, but the fluid around the joint

did not have a pus-like appearance. He had suffered from a

headache, and meningitis was suspected. Panipenem, vori-

conazole, linezolid, and acyclovir were started. Bacteria that

grew very slowly in anaerobic culture (more than 5 days)

were observed from spinal tap and fluid from the right hip,

and M. hominis infection was determined by 16S rRNA se-

quence analysis. Disseminated M. hominis infection could

not be controlled and the patient died. Autopsy revealed a

microabscess into which neutrophils had infiltrated. Macro-

phages and T cells were histologically observed in the lung,

left hip joint, lymph nodes, endocardium, myocardium, tes-

tis, liver and kidney. This prominent peripheral bronchiolar

and peribronchiolar infiltration of inflammatory cells indi-

cated bronchial pneumonia. Suppurative meningitis, chronic

stage, was indicated, showing infiltration of macrophages

and T lymphocytes in the entire subarachnoid space of the

cerebrum and spinal cord. Despite the fact that no patho-

gens, including Mycoplasma spp., were detected by staining,

M. hominis was cultured from hip synovial fluid, spinal

fluid and blood, and disseminated M. hominis infection was

compatible with the autopsy findings.

Intern Med 51: 425-429, 2012 DOI: 10.2169/internalmedicine.51.6058

427

Figure　1.　Pathological findings of the biopsy specimen obtained from the proximal interphalange-al (PIP) joint of right middle finger (Hematoxylin and Eosin staining). A, Fibrin deposition was ob-served. However, villous proliferation of synovial tissues, considered a typical change in rheumatoid arthritis, was not observed (×10). B, Inflammatory cell infiltration was observed except for plasma cells. However, lymph follicles were not observed. C, Immunoperoxidase staining for CD20 for B cells was negative. D, Immunoperoxidase staining for CD38, as a marker of plasma cells, was nega-tive. E, Immunoperoxidase staining for CD3, as a marker T cells, was positive.

Figure　2.　Radiographic changes in the proximal interphalangeal (PIP) joint of the right middle finger. Joint space narrowing and erosion (arrow) were observed.

Discussion

We report here a patient with hypogammaglobulinemia

and polyarthritis accompanied by erosive changes on X-ray

film similar to RA. The ultimate diagnosis in this case was

septic arthritis caused by M. hominis.

Primary hypogammaglobulinemia, impaired production of

antibodies, is caused by defects in B cell maturation or the

interaction of B cells with T cells. XLA is characterized by

recurrent upper and lower respiratory infections in infants,

and is due to abnormalities of Btk protein, resulting in de-

fective B cell maturation. This case was not diagnosed as

XLA because Btk protein in monocytes remained within the

Intern Med 51: 425-429, 2012 DOI: 10.2169/internalmedicine.51.6058

428

normal range, despite the reduced levels of B lymphocytes

in blood and tissues. Furthermore, the patient had no history

of recurrent bacterial infection in childhood and he had no

relevant family history. CVID is characterized by reduced

immunoglobulin levels, despite the presence of B cells,

which differed from the observations in the present case.

Autosomal recessive agammaglobulinemia was also consid-

ered, which is characterized by mutations in genes essential

for B cell maturation other than Btk; however, there was no

typical family history of the autosomal recessive pattern of

inheritance in this case. Indeed, the pathogenesis of hy-

pogammaglobulinemia was not evident in this case.

The prevalence of arthritis in patients with hypogam-

maglobulinemia has been reported to range from 10% to

30% (8), and several types of arthritis can occur (2, 9).

While septic arthritis due to atypical organisms is important,

aseptic arthritis has been reported in patients with hypogam-

maglobulinemia. Chronic arthritis in such patients is usually

without erosions and responds well to gamma globulin re-

placement therapy, which is distinct from classic RA (2, 9)

and may be classified as a reactive arthritis (2). Further-

more, several reports have described arthritis due to autoim-

mune disorders, such as RA (1-3), JIA (4, 5), and spondy-

loarthritis (6) associated with hypogammaglobulinemia, and

only T cells can cause synovitis and arthritis (1, 3). Gold,

sulfasalazine, prednisolone, methotrexate, and non-steroidal

anti-inflammatory drugs (NSAIDs) are effective in these

cases. The present case satisfied the new 2010 criteria for

RA classification (10); furthermore, erosive changes and

joint space narrowing mimicking RA were observed. Since

joint destruction can develop in both RA and septic arthritis,

infection should be strictly excluded in the differential diag-

nosis, especially in hypogammaglobulinemia patients.

With regard to septic arthritis in hypogammaglobulinemic

patients, the most frequent pathogens are Staphylococcusaureus, high-grade encapsulated organisms, such as S. pneu-moniae and H. influenzae, Mycoplasma species, and Urea-plasma species (2, 11). Furr et al reported 21 septic arthritis

patients with hypogammaglobulinemia; Mycoplasma or

Ureaplasma species were isolated from eight (38%) (12).

Among several Mycoplasma and one Ureaplasma species

that are pathogenic to humans, M. hominis and U. urealyti-cum are strongly associated with arthritis in immunosup-

pressed patients and those with hypogammaglobuline-

mia (13).

Septic arthritis due to M. hominis has been reported previ-

ously, and most patients were receiving immunosuppressive

therapy for SLE, post-organ transplantation, leukemia, or

underlying immunosuppressive disease such as hypogam-

maglobulinemia or diabetes mellitus (14-20). Arthroplasty

and ligament repair were also underlying condi-

tions (14, 15). Previous reports of septic arthritis due to M.hominis showed that monoarthritis or oligoarthritis of large

joints such as the knee, shoulder and/or hip first oc-

cur (14-20) and then polyarthritis develops in the small

joints (16, 18). In the case presented here, two months had

passed before admission to hospital and polyarthritis in six

large (bilateral hips, knees, shoulders) and one small (the

PIP joint of the right middle finger) joints had developed.

Finally, his arthritis spread to eight large (bilateral shoulders,

knees, hips and ankles) and three small (the PIP joint of

right middle finger and bilateral wrists) joints. Since rheu-

matoid arthritis typically affects many small joints first, oc-

casionally associated with arthritis of large joints, the distri-

bution and progression of arthritis in this case differed from

that in typical RA. On the other hand, septic arthritis due to

bacteria or mycobacterium usually affects monoarticular

joints, most frequently the knee in bacterial septic arthri-

tis (21) and the hip in mycobacterium arthritis (22). How-

ever, arthritis may spread to polyarticular joints if appropri-

ate therapy is not performed. Thus, septic arthritis should be

carefully excluded in patients with long lasting polyarthritis,

especially when large joints are predominantly affected.

Isolation of Mycoplasma species by routine culture is

either not possible or very slow, which tends to delay the di-

agnosis (15). In the present case, M. hominis was detected

in anaerobic culture on day five. The cultures were stopped

after three days in the previous hospital, yielding a false

negative result. Routinely-used anaerobic culture media are

useful for detection of M. hominis if culture is continued for

more than five days. A special culture medium,

pleuropneumonia-like organism (PPLO) broth, is the best

way to detect Mycoplasma species. Molecular methods are

required for identification of M. hominis, which are not rou-

tinely performed.

M. hominis is commonly isolated from the normal geni-

tourinary tract, and genital colonization increases in propor-

tion to sexual experience. Furthermore, 1-3% of respiratory

secretions from healthy individuals are colonized with M.hominis (23). The present patient had no medical history

and no pyuria. Since pneumonia and pleuritis preceded sep-

tic arthritis and autopsy revealed bronchiolar pneumonia, the

original site of M. hominis infection was predicted to be the

lower respiratory tract.

Tetracyclines, including doxycycline, are generally the

first choice for treatment of M. hominis infection. However,

streptomycin, clindamycin, and quinolones are also used in

cases in which tetracyclines are not sufficiently effec-

tive (14, 24). Many antibiotics were used in this case, in-

cluding a quinolone (pazufloxacin) but not tetracycline. M.hominis has also been reported to be moderately susceptible

to rifampicin (14), and the pleuritis in this case was some-

what improved by antituberculosis therapy. Since the diag-

nosis of mycoplasma infections is difficult and slow (15),

tetracycline treatment should be administered to patients

with hypogammaglobulinemia showing arthritis, pleuritis,

meningitis, or any other diseases that may be caused by my-

cobacterium infection.

Here, we report a hypogammaglobulinemic patient with

polyarthritis, accompanied by erosive changes on X-rays,

mimicking RA, in whom a final diagnosis of M. hominis in-

fection was made. Septic arthritis caused by Mycoplasma

Intern Med 51: 425-429, 2012 DOI: 10.2169/internalmedicine.51.6058

429

species should be excluded using special culture media and

molecular methods in hypogammaglobulinemic patients.

Furthermore, tetracycline can be a useful diagnostic and

therapeutic option in such cases.

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

AcknowledgementWe thank Hirokazu Kanegane, M.D., Ph.D. for detecting the

Btk protein by flow cytometry, and Kiyofumi Okusu, Ph.D. and

Takayuki Ezaki, M.D., Ph.D. for the identification of M. homi-nis.

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