A 54-year-old Japanese man who had been diagnosed with RA for 8 years according to the 1987 American Rheumatism Association classification criteria for RA was admitted with polyarthritis. He complained of pain and swelling in the wrists, fingers, and knees and had difficulty walking without assistance. He claimed to have morning stiffness lasting about 3 hours. Past medical history included a left total knee arthroplasty complicated by a traumatic fracture of the left distal femur postoperatively and a cerebral infarction with residual right hemiparesis. His medication regimen included sulfasalazine (1000 mg/day), bucillamine (300 mg/day), mizoribine (150 mg/day), and prednisolone (10 mg/day). The Steinbrocker stage was IV and functional class was 4. He was unable to stand unassisted due to bilateral knee pain. Swelling and tenderness were present in the proximal interphalangeal and metacarpophalangeal joints of both hands and fingers, as well as in the wrists and knees. Right-sided muscle weakness was observed. Laboratory findings were as follows: white blood cell count 8800/mm3 (75.6% neutrophils, 19.5% lymphocytes, 2.9% monocytes, 0.3% eosinophils, 0.2% basophils), hemoglobin 10.7 mg/dL, platelets 48.7 x 104/muL, erythrocyte sedimentation rate (ESR) 75 mm/h, C-reactive protein (CRP) 3.58 mg/dL, rheumatoid factor (RF) 219.6 IU/mL, and anticyclic citrullinated peptide antibody (ACPA) 189 IU/mL. Serum beta-D-glucan was negative. The purified protein derivative skin test for tuberculosis was negative. 
Treatment was initiated with subcutaneous injections of etanercept 25 mg twice a week. Blood samples were collected before the first dose (at baseline), 24 hours after the first injection (day 1), daily until day 8, and weekly thereafter. Specimens were centrifuged at 3000 rpm and the sera stored at -80 C until the assay was performed. TNF-alpha, TNFR-I and -II, IL-6, and IL-1 beta concentrations were measured using commercial ELISA kits.
After initiating etanercept, the patient's clinical condition improved markedly, with swelling and tenderness of the wrists and finger joints significantly better. He was able to stand with the aid of crutches despite residual hemiparesis. The duration of morning stiffness dropped to below 30 minutes. The 28-joint count Disease Activity Score (DAS28) dropped significantly within the first 4 weeks and continued to decrease (DAS28 = 8.09, 5.37, 4.73, and 4.60, at baseline, 4 weeks, 8 weeks, and 12 weeks, resp.), achieving the European League Against Rheumatism (EULAR) moderate response criteria. The CRP dropped to below 0.30 mg/mL within the first 2 weeks of therapy. Subsequently, the oral immunosuppressive regimen of sulfasalazine, bucillamine, and mizoribine was discontinued after initiation of treatment. Prednisolone was reduced to 5 mg/day.
After 12 weeks of treatment with etanercept, the patient developed a nonproductive cough along with a fever of 38 C. Serum beta-D-glucan was found to be positive, and sputum polymerase chain reaction (PCR) was positive for pneumocystis (Figure 1). Etanercept was discontinued, and an antifungal regimen initiated.
Preceding etanercept therapy, the serum IL-6 levels were found to be elevated, correlating with the high CRP value and high clinical disease activity. Conversely, the serum level of TNF-alpha was nondetectable (<0.2 pg/mL); the sTNFR-I, -II, and IL-1 beta values were not found to be significantly elevated (Figure 2). After initiation of etanercept, there was a rapid decline in the IL-6 and CRP levels, whereas the levels of TNF-alpha and sTNFR-II increased significantly within 24 hours after administration of the first dose to a plateau after 2 weeks (range: 100 pg/mL to 170 pg/mL) and 6-7 weeks (range: 300 ng/mL to 700 ng/mL), respectively. The sTNFR-I and IL-1-beta levels remained relatively unchanged (sTNFR-I levels at baseline, 3.56 ng/mL; 4 weeks, 3.36 ng/mL; 8 weeks, 2.93 ng/mL; 12 weeks, 3.58 ng/mL). At week 12, concurrent to the patient developing clinical symptoms of PCP, the levels of IL-6, CRP, and TNF-alpha showed an acute peak, which tapered downward over the following 3 weeks with the institution of an appropriate antifungal regimen (Figures 3 and 4).