by Michael Westerman, M.D.
Postdoctoral Fellow, Division of Geriatric Medicine, JHU
Faculty Sponsor: Joan Bathon, M.D.
Left Knee Pain and Swelling:
The patient is a 34 year old nurse from Kuwait with a history of “seronegative rheumatoid arthritis” who presented to Hopkins Orthopaedics for evaluation of pain, warmth and swelling in the left knee which was status post total knee replacement in 1996. In turn, she was referred to rheumatology for a second opinion regarding the etiology and management of her arthritis.
The patient was well until October 1992 when she developed sore throat, fever and coma. No records were available for review. Apparently spinal fluid analysis and culture were nondiagnostic and she was treated with a combination of antibiotics and steroids. Although her overall status markedly improved, she complained of severe pain and swelling in the left knee prior to discharge. Arthrocentesis reportedly showed inflammation but no crystals or infection. Her knee pain was treated transiently with a course of oral prednisone. She subsequently developed pain in her shoulders, elbows, hips, and ankles as well.
In 1993, because of continued joint pain, she was evaluated by a rheumatologist in London who noted synovitis in both knees, elevated sed rate, negative rheumatoid factor and negative ANA, and diagnosed “seronegative rheumatoid arthritis”. She was treated with azathioprine 100 mg, prednisone > 10 mg qd and folic acid. In 1994 azathioprine was discontinued for unclear reasons. She complained of bilateral hip pain and was found to have “bilateral pathological fractures and ischemic necrosis” for which she underwent bilateral hip arthroplasties by a “Western surgeon” with excellent resolution of her pain. In 1996, methotrexate was begun. Because of persistent knee pain and “degenerative joint disease”, she underwent left total knee arthroplasty by a Kuwaiti surgeon in 1996. However, her knee pain never improved after surgery, and the knee remained warm, swollen and tender.
At the time of her presentation at Hopkins in August 1998, she denied ever having pain or swelling in the wrists, small joints of her hands or feet. She denied morning stiffness, subcutaneous nodules or sicca symptoms. She complained of chronic bilateral shoulder and left knee pain and limited range of motion of all three joints. However, systemically she felt well and attributed her sense of well being to the institution of methotrexate in 1996. She had been on steroids since 1992 and admitted to regulating the dose herself for several years, taking as much as 90 mg per day when she feels poorly, sometimes staying at this high dose for several months. She denied Raynauds phenomenon, history of pleurisy or pericarditis, psoriasis, back pain, uveitis or conjunctivitis, dysentery.
Methotrexate 12.5 mg qweek
Prednisone 10 mg qd
Folic acid 5 mg qod
NPH insulin 30 units SQ qd
Past Medical History:
1. No allergies.
2. Medical Illnesses: type II diabetes (steroid induced).
3. Prior hospitalizations:
-total left knee replacement
-bilateral hip replacements
The patient is a nurse in Kuwait. She is married with a nine-year-old child. She reported smoking two packs of cigarettes per day for many years, and having two alcoholic drinks each day.
negative for rheumatoid arthritis, lupus or other connective tissue disease.
The patient was thin and in no acute distress. BP 102/64, pulse 92 regular, weight 136 lbs, afebrile. Her general physical examination was entirely unremarkable. Her skin examination was also normal with no psoriasis, alopecia, vasculitis, subcutaneous nodules.
Joint examination was remarkable for the following:
Right shoulder limited abduction and external rotation with pain in all planes of motion. Elbows, wrists and small joints of the hands – entirely normal.
Hips status post total joint replacements, with good range of motion bilaterally.
Knees left knee was warm, swollen and tender to palpation. There was marked varus deformity of the left knee. Right knee was without swelling or warmth.
Ankles and feet entirely normal.
Chemistries entirely normal. Total protein = 6.1; albumin = 3.5.
CBC: WBC = 10,900 with 87% neutrophils. Hematocrit = 35.7%.
Platelet count = 392,000.
Erythrocyte sedimentation rate = 30 mm/hr.
Antinuclear antibody negative. Rheumatoid factor negative.
Lyme disease titer negative. HLA B27 testing negative.
Bone densitometry showed osteoporosis range bone mineral densities in the lumbar spine and distal forearms.
Figure 1 standing film of the knees.
The left knee shows a prosthesis in the distal femur and proximal tibia. There is marked varus deformity of the joint. The femoral component of the prosthesis is well fixed, but there appears to be loosening of the tibial component.
The right knee shows severe cystic changes in the femoral and tibial components most consistent with osteonecrosis.
Figure 2 bilateral shoulders.
Both shoulders exhibited bony sclerosis and numerous cystic changes most consistent with osteonecrosis.
Figure 3 – bilateral wrists.
Osteopenia, otherwise unremarkable. No erosions or significant joint space narrowing are present.
1. [ ]Acute gout
2. [ ]Flare of seronegative rheumatoid arthritis
3. [ ]Osteonecrosis
4. [ ] Infection of the prosthesis
5. [ ]Mechanical loosening of the prosthesis
The patient was taken to the operating room for possible revision arthroplasty (revision of her total knee replacement). However, intraoperative inspection and removal of the prosthesis revealed soft, spongy bone and a reactive synovitis most consistent with an infectious process. A spacer was placed in the knee, a revision arthroplasty was deferred until a later time, and the patient was begun on antibiotics. Cultures of bone and synovial fluid grew Candida albicans at six days. The patient was diagnosed with fungal prosthetic infection and IV amphotericin was begun.
Candida species are normal commensals of humans, commonly found in the GI tract, the female genital tract, and diseased skin. Candida organisms become pathogenic when there is suppression of normal defense mechanisms or disruption of normal profiles of indigenous bacterial flora. These processes can result from naturally occurring illnesses (e.g., diabetes, malignancy or malnutrition) or from iatrogenic factors (e.g., prolonged use of broad spectrum antibiotics, corticosteroid or cytotoxic therapies, vascular and urinary catheterizations, or hyperalimentation).
Fungal arthritis with Candida species can occur by three mechanisms:  hematogenous spread.  direct inoculation of a joint, in the setting of repeated joint aspirations and/or injections; and  fungal contamination during surgery. In our patient, contamination during the knee arthroplasty in 1996 was the most likely source of her candidal prosthetic infection, and the patients chronic abuse of steroids no doubt contributed to propagation of the infection.
The clinical and radiological features of prosthetic fungal infection mimic those of prosthetic mechanical failure. Loosening of prosthetic components is often seen, sometimes with evidence of osteomyelitis. Synovial fluid analysis reveals serosanguinous or purulent fluid with leukocyte counts ranging from 4,000 to 15,000/mm3 with a predominance of neutrophils. Prosthetic fungal arthritis tends to have an indolent course with symptoms, such as pain, swelling and limited range of motion of the affected joint, occurring as late as five years after surgery. Fever and constitutional symptoms are rare. Candidal species are the most common fungi associated with opportunistic infections, and positive fungal cultures are only rarely due to contamination.
Only 19 cases of Candida arthritis complicating reconstructive arthroplasty have been reported. In a review by Koch et al, two of the three cases of Candida prosthetic knee arthritis were diagnosed by joint fluid aspiration and culture. In the review by Tunkel et al, all 16 cases were treated by removal of the infected prosthesis and concurrent antifungal agents. There were no recurrences in follow-up ranging from 3 months to 3 years. Wada et al described a case of Candida parapsilosis infection that did not require removal of the prosthesis but was diagnosed by joint fluid analysis less than four weeks after total knee replacement. This patient was treated with debridement and 4 weeks of continuous irrigation with Fluconazole, and was free of recurrence up to 3 years later. Candida albicans was the species isolated in 10 of the 19 cases of Candida prosthetic arthritis. Osteoarthritis and rheumatoid arthritis were the most common conditions leading to these arthroplastic procedures.
After removal of her left knee prosthesis in late August 1998, the patient was treated with two weeks of intravenous amphotericin B. In early November 1998, arthrotomy of the knee was performed to obtain specimens for repeat culture. She was treated for another two weeks with IV amphotericin B. At the end of these two weeks, cultures remained negative for fungal and bacterial pathogens. The patient was taken back to the operating room, and a successful revision arthroplasty was performed. She was fully ambulatory by the time of her return to Kuwait in mid December.
The most likely cause of this patients shoulder and right knee pain is:
1. [ ]Seronegative rheumatoid arthritis
2. [ ]Psoriatic arthritis
3. [ ]Osteonecrosis
4. [ ]Polyfocal osteomyelitis
5. [ ]Reactive arthritis (Reiters syndrome)
At the time of the patients initial rheumatological evaluation, no evidence of an active arthritis was found on examination and the sedimentation rate was normal (despite the fungal infection). The predominant involvement of large joints, and sparing of small joints, made a diagnosis of rheumatoid arthritis less tenable (even seronegative RA). There were no other clues such as psoriasis, inflammatory bowel symptoms or axial involvement to suggest any of the spondyloarthropathies (e.g., psoriatic arthritis, ankylosing spondylitis, reactive arthritis, etc.), and the negative HLA-B27 antigen further ruled out this category of diseases. The marked radiographic changes in the shoulders and right knee were most compatible with osteonecrosis, which undoubtedly resulted from chronic self administration of high doses of corticosteroids. MRI scans of both shoulders and the right knee confirmed this diagnosis (osteonecrosis).
The source of the patients bilateral shoulder and right knee pain was clearly due to osteonecrosis rather than due to an active arthritis. However, an underlying inflammatory arthritis, that was currently controlled on methotrexate, NSAIDs, and low dose corticosteroids, could not be ruled out.
In view of the Candidal prosthetic infection, a slow steroid taper was initiated. Because the diagnosis of an inflammatory arthropathy remained in doubt, the methotrexate was also discontinued. Within six weeks of discontinuing methotrexate and tapering prednisone, she developed pain and swelling in both wrists and in the right knee, and her sedimentation rate rose to 90 mm/hr, and she developed anemia (hematocrit dropped from 36 to 25 without evidence of gastrointestinal bleed). Aspiration of the right knee revealed an inflammatory fluid (WBC count 4,175/mm3) that was culture negative. At this point, a diagnosis of an inflammatory polyarthritis was confirmed (type unknown), and the patient was placed back on methotrexate. The arthritis had come back under control by the time of her return to Kuwait in December.
Recommendations for her physicians in Kuwait consisted of the following:
- Continue methotrexate and NSAID long-term. Monitor CBC and liver enzymes (transaminases) q4-6 weeks for methotrexate toxicity.
- Minimize exposure to prednisone. Continue to taper and DISCONTINUE the prednisone. Reinforce to patient NOT to self-administer prednisone.
- Distinguish symptoms of osteonecrosis from those of her arthritis. Methotrexate, prednisone and NSAIDs should NOT be increased for signs and symptoms related to osteonecrosis. Inflammatory arthritis is manifested by stiffness, joint swelling and elevated sed rate. Pain due to osteonecrosis is elicited by movement of the joint, and it generally does not cause joint swelling or elevated sed rate.
- Continue treatment for osteoporosis. The patient was started on alendronate during her stay in the U.S.