Case Rounds : Case11

by Lisa Christopher-Stine, M.D.

Summary of Prior Events

October, 1998: The 22 year old (18 years at this time) patient experienced her first episode of severe pain and swelling of both knees of 4 days duration. The pain resolved with ibuprofen.

November, 1998: She experienced pain and swelling of both knees, which resolved spontaneously.

January, 1999: Her left wrist became erythematous and swollen, and she was eventually bedridden due to right knee swelling not relieved with ibuprofen. Four days later, she reported to a local emergency room complaining of daily spiking fevers (as high as 102.6 in the evening) and chills. Upon further questioning, she reported a 30-pound unintentional weight loss over the prior 3 months. She was admitted to the community hospital. Her right knee was aspirated and broad- spectrum antibiotics are instituted.

Pertinent Laboratory Findings:

  • ESR – 123
  • WBC – 26.6
  • Hematocrit – 24 mg/dL
  • MCV – 68
  • RPR – negative
  • ANA – negative
  • Rheumatoid Factor – negative
  • Synovial fluid cultures – negative
  • Synovial cell count – not obtained

She was prescribed a short course of oral steroids with no clear diagnosis and was lost to follow-up.

January, 2002: She returned to the local emergency room with complaints of wrist and knee pain and daily fevers for the past week. She was given antibiotics and aspirin and discharged. Three weeks later, she returned to the hospital and was admitted with arthralgias, fever, myalgias, pharyngitis, and pre-syncope.

Pertinent Laboratory Findings:

  • CRP – 20 mg/dL
  • ESR – 102
  • Iron – 9
  • TIBC – 209
  • Iron % saturation – 4
  • Ferritin – 477
  • Urinalysis – normal
  • Chest radiograph – normal

She was given the diagnosis of acute rheumatic fever. Prednsione, 5 mg daily and roficoxib were prescribed and she was discharged.

History of Present Illness

February, 2002: She was admitted to an outside hospital with chest pain, bilateral wrist and knee pain. She was placed on ampilcillin/sulbactam. An echocardiogram revealed pericarditis which required a pericardial window due to a sizable pericardial effusion. Shortly thereafter, bilateral pleural effusions developed, and bilateral chest tubes were placed.

Diagnostic Studies Performed:

  • EKG – P-R interval within normal limits. It reveals sinus tachycardia but no P-R depression. There were lateral ST/T wave changes noted.
  • CPK – mildly elevated with an increased MB fraction
  • ESR – 140
  • Albumin – 2.4
  • Globulin – 6.4
  • WBC – 36.9
  • Hematocrit – 22.4
  • Mycoplasma – IgG and IgM elevated
  • HIV – negative
  • Lyme – ELISA and Western Blot negative
  • Pleural fluid – many polymorphonuclear cells, no organisms, glucose 119, LDH 340

SHE WAS TRANSFERRED TO JOHNS HOPKINS HOSPITAL FOR FURTHER WORKUP AND DIAGNOSIS.

Presentation to Johns Hopkins Rheumatology Clinic

  • Past Medical History: Right wrist fracture
  • Family History: Raised by foster parents; biologic parents health history unknown
  • Social History: Nonsmoker, no alcohol or intravenous drug use; one sexual partner; not currently employed
  • Allergies: Naprosyn, which caused hives
  • Medications at transfer: Ampicillin/sulbactam, azithromycin, celecoxib, prednisone, 60 mg daily
  • Review of Systems: No alopecia, Raynauds phenomenon, sicca, photosensitivity, or apthous ulcers

Physical Examination

  • Temperature: 36.7 C; BP: 117/65; RR 16
  • General: Young African American woman alert and oriented
  • Skin: No lymphadenopathy or subcutaneous nodules; no rash
  • HEENT: No alopecia, no oral ulcers, no pharyngeal erythema
  • Chest: Breast examination normal; Lungs dull to percussion at left base
  • Heart: Regular with no pericardial friction rub or murmur
  • Abdomen: no hepatosplenomegaly
  • Extremities: No clubbing, no Raynauds phenomenon, 2+ pulses
  • Musculoskeletal: Minimal boutonniere deformities (see photo); No active synovitis; normal range of motion of all joints both actively and passively
picture of hands

Figure 1

Laboratory Findings

  • WBC – 24.1 with a PMN predominance of 92%
  • Hematocrit – 30.2
  • Platelets – 808
  • Urinalysis – negative for protein or red cells
  • ALT – 77
  • AST – 100
  • Alkaline phosphatase – 116
  • Albumin – 2.7
  • Haptoglobin – 492
  • ASO – 198 (normal is 0-115 IU/ml)
  • Hand radiographs – normal
  • Echo – Mitral valve prolapse with no regurgitation; no pericardial effusion

Differential Diagnosis

  1. [ ] Acute Rheumatic Fever
  2. [ ] Systemic Lupus Erythematosus
  3. [ ] Rheumatoid Arthritis
  4. [ ] Adult Onset Stills Disease
  5. [ ] Malignancy with paraneoplastic process

Clinical Course

The patient was given the provisional diagnosis of Adult Onset Stills Disease. She was prescribed low dose prednisone and celecoxib upon discharge from the hospital. Over the next several months, however, she developed progressive pain and swelling of the wrists and ankles requiring methotrexate therapy. Her WBC count decreased, and her hematocrit improved slightly with iron supplementation. Her ASO titers have remained within normal limits, and her rheumatoid factor and ANA remain negative. An extensive search for the etiology of her microcytic anemia has been unrevealing. Over the past year, she has developed considerable hand and wrist deformities (See radiographs below) despite methotrexate therapy and oral corticosteroids. She has never had a recurrence of serositis and has not developed any additional systemic symptoms, including fevers. She began etanercept two months ago, along with low dose prednisone and has experienced considerable relief of her symptoms.

x-ray of right wrist

Figure 2 – Right Wrist – Diffuse radiocarpal and carpal-metacarpal joint space narrowing is evident with questionably small bony erosion involving the ulnar styloid. There are also some small erosions in the distal carpal and carpal-metacarpal joints. Subtle fusion is not excluded.

x-ray of left wrist

Figure 3 – Left Wrist – Diffuse radiocarpal and carpal-metacarpal joint space narrowing is evident with questionably small bony erosion involving the ulnar styloid. There are also some small erosions in the distal carpal and carpal-metacarpal joints. Subtle fusion is not excluded.

Discussion

Although systemic lupus erythematosus seemed plausible in light of the arthritis and serositis, the negative ANA and lack of other diagnostic features made this diagnosis very unlikely. Although a solid tumor malignancy, such as breast cancer, can present with pleural and/or pericardial effusions and articular symptoms, the patients young age and lack of confirmatory cytology on the pleural fluid essentially ruled out this diagnosis. Although rheumatoid arthritis can present with pleural effusions, this is typically a later finding, and the effusion typically has a very low glucose, which was not seen in this patient. The presence of pharyngitis, along with the presence of fever and arthralgia, also helps to narrow the differential diagnosis, as sore throat is distinctly uncommon in most rheumatic diseases presenting with arthralgias and constitutional symptoms with or without a rash. Pharyngitis, however, is commonly associated with Acute Rheumatic Fever and Adult Onset Stills Disease and these diagnoses remain primary considerations in the differential diagnosis. The distinction between these two diseases can be nebulous, as illustrated by this case. The two diseases have a number of similarities (see table below).

Adult Onset Stills Disease Acute Rheumatic Fever
Pericarditis Yes Yes
Fever >39oC Yes Yes
Arthralgia Yes Yes
Arthritis Yes Yes
Rash Yes Yes (E. Marginatum)
Pharyngitis Yes Yes
Pleuritis Yes Rare
Weight Loss Yes Rare
Lymphadenopathy Yes Rare

Acute rheumatic fever occurs two to four weeks after group A beta-hemolytic streptococcal infection of the pharynx. It is thought to be related to a series of immunologic reactions to antigenic components of the streptococcus which also cross reacts with various human tissues. The clinical features include fever, migratory arthralgias, destructive inflammatory lesions of the myocardium, pericardium, endocardium, valvular structures, periarticular regions, lungs, and subcutaneous tissues. The associated chorea may be transient or persistent. There has been a rapid decline of cases since the 1950s , presumed to be due to better overall hygiene and widespread antibiotic use in children. The average incidence in affluent countries is less than 5 per 100,000. The diagnosis of Acute Rheumatic Fever is substantiated by the Jones Criteria (below).

JONES CRITERIA*
MAJOR MINOR
  • Carditis
  • Polyarthritis
  • Chorea
  • Erythema marginatum
  • Subcutaneous nodules
  • Prolonged P-R interval
  • Arthralgia
  • Fever
Supporting Evidence: Laboratory Findings
  • Positive Throat Culture
  • Rising ASO Titer
  • Elevated ESR
  • Elevated CRP
  • Elevated Acute Phase Reactants
*JAMA 268:2069-2073, 1992.

Acute rheumatic fever is usually managed by treating the underlying streptococcal infection with penicillin. The associated arthritis is sensitive to high dose salicylates (4-8 g/day); other non-steroidal anti inflammatory drugs may also be used. A prompt response to salicylates supports the diagnosis. Steroids are reserved for refractory arthritis and severe carditis. Prophylactic penicillin is recommended, but the cumulative dose needed remains controversial.

Adult Onset Stills Disease (AOSD) is an acute febrile illness in young adults. It usually affects multiple organs, but is a diagnosis of exclusion. The etiology of ASD is unknown; however, a number of infectious triggers have been suggested, including viruses and bacterial pathogens including Mycoplasma pneumoniae. Clinical features include a high fever, arthralgia and arthritis, phayngitis, typical rash (evanescent salmon-colored, macular or maculopapular eruption), lymphadenopathy, and serositis. Chronic arthritis and constitutional symptoms are common. Several diagnostic criteria sets for AOSD have been proposed. Two of these sets of criteria are shown in below.

TWO SETS OF DIAGNOSTIC CRITERIA FOR AOSD
Cush, et al.(ref) Yamaguchi, et al.(ref)
Requires ALLof the following:

  • Fever > 39 degrees
  • Arthralgia or arthritis
  • Rheumatoid factor
    ANA In addition to ANY TWOof the following:

    • WBC count > 15,000
    • Stills rash
    • Pleuritis or Pericarditis
    • Hepatomegaly, Splenomegaly, or Lymphadenopathy
Presence of 5 or more criteria, of which at least 2 are Major- yields 96% sensitivity; 92% specificityMajor Criteria

  • Fever > 39 degrees > 1 week
  • Arthralgia/arthritis > 2 weeks
  • Typical rash
  • WBC > 10 K with 80% PMN’s

Minor Criteria

  • Sore throat
  • Lymphadenopathy
  • Increased LFT’s
  • RF and ANA negative

The triad of fever, rash, and arthralgia are often absent during the first month of the illness. A quotidian (daily, spiking) or “double-quotidian” fever curve is a hallmark of the disease. The rash is usually truncal or present on the proximal extremities precipitated by mechanical or thermal stimulation. It is most apparent during fever periods. The usual joints affected are wrists, knees, and ankles in descending order. Two thirds of cases experience polyarticular arthritis and one third have monoarticular symptoms. Approximately 1/3 of patients have chronic persistent disease with progressive joint damage. Half of all AOSD patients require some medication 10 years after their illness. The management of AOSD remains empirical, and there are few controlled studies to date. Most patients require steroids, and many need high doses for six months followed by chronic maintenance therapy. There is some evidence that methotrexate is effective, and newer studies demonstrate efficacy with the TNF-alpha inhibitor, etanercept.

This case illustrates a difficult diagnostic dilemma. The high ASO titer probably represents an acute phase reactant. The lower than expected ferritin level is most likely a manifestation of the patients underlying anemia. Some suggest that serum ferritin values above 3000 ng/mL in a patient with typical symptoms, in the absence of infection, should lead one to consider the diagnosis of AOSD. Although very elevated ferritin levels are associated with AOSD, lower levels do not rule out the disease and are not part of the diagnostic criteria. The long-term management of this illness is evolving but appears to respond to cytokine-targeted therapies.

References

Special Writing Group of the Committee on Rheumatic Fever, Endocarditis, and Kawasaki Disease of the Council on Cardiovascular Disease in the Young, American Heart Association. JAMA 268:2069-2073, 1992.

Stollerman GH, Markowitz M, Taranta A, et al. Jones criteria (revised) for guidance in the diagnosis of rheumatic fever. Circulation 32:664-668, 1965.

Jones TD. Jones criteria (revised) for guidance in the diagnosis of rheumatic fever. JAMA 126:481, 1944.

Yamaguchi M, Ohta A, Tsunematsu T, et al. Preliminary criteria for classification of adult Still’s disease. J Rheumatol 19:424, 1992.

Cush JJ, Medsger TA, Jr, Christy WC, et al. Adult-onset Still’s disease: Clinical course and outcome. Arthritis Rheum 30:186, 1987.

Nguyen K, Weisman M. Severe throat as a presenting symptom of adult onset Stills disease: a case series and review of the literature. J Rheumatol 24:592-7, 1997.

Masson C, le Loet X, Liote F, et al. Adult Stills Disease. Part 1. Manifestations and Complications in sixty-five cases in France. Rev Rheum (Engl Ed) 11:748-57, 1995.

Ohta A, Yamaguchi M, Tsunematsu T, et al. Adult Still’s disease: A multicenter survey of Japanese patients. J Rheumatol 17:1058, 1990.

Fautrel B, Borget C, Rozenberg S, et al. Corticosteroid sparing effect of low dose methotrexate treatment in adult Still’s disease. J Rheumatol 26:373, 1999.

Kraus A, Alarcon-Segovia D. Fever in adult onset Still’s disease. response to methotrexate. J Rheumatol 18:918, 1991.

Fujii T, Akizuki M, Kameda H, et al. Methotrexate treatment in patients with adult onset Still’s disease retrospective study of 13 Japanese cases. Ann Rheum Dis 56:144, 1997.

Husni ME, Maier AL, Mease PJ, et al. Etanercept in the treatment of adult patients with Still’s disease. Arthritis Rheum 46:1171, 2002.

Kelly J, Chowienczyk J, Gibson T. Sore throat and hyperferritenaemia. R Soc Med 94:400-401, 2001.

Updated: July 9, 2012

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