A 23-year-old woman with fever, rash, and arthritis



A 23-year-old Hispanic woman presented with a 1-month history of rash, arthritis, and fever. The patient was in excellent health until 1 month prior to presentation, when she noted the spontaneous onset of a pruritic rash that began on her face and then progressed to involve her trunk and extremities. Shortly afterward, she developed pain and swelling of both hands, particularly of her wrists and metacarpophalangeal (MCP) joints. One week prior to presentation, she noted a sore throat and diffuse body aches together with subjective fevers and chills. She denied drenching sweats during febrile episodes. On evaluation in an emergency department, she was afebrile and had a diffuse erythematous rash that spared her palms and soles and mucous membranes. Laboratory evaluation showed a normal complete blood cell count, normal chemistries, including liver tests, and a normal urinalysis. The erythrocyte sedimentation rate (ESR) was 35 mm/hour (normal value ≤20) and the C-reactive protein (CRP) level was 53 mg/liter (normal value <3.1). A rapid test on a pharyngeal swab for group A Streptococcus was negative, as were urine tests for Neisseria gonorrhoeae and Chlamydia trachomatis. Her chest radiograph revealed a calcified granuloma in the right mid-lung, but was otherwise normal. She was discharged with a diagnosis of “polyarthritis and rash” with a recommendation to take prednisone 40 mg orally daily and ibuprofen for 5 days.

Despite compliance with the prednisone and ibuprofen, her symptoms persisted without improvement. She continued to have fevers and noted that her rash worsened during her febrile episodes. She was admitted to this institution for further evaluation.

Past Medical History

Her past medical history was unremarkable. She had had 4 pregnancies (3 live births, 1 induced abortion). There was no history of spontaneous abortions or of thromboembolic disease. In addition to the prednisone and ibuprofen prescribed in the emergency department, she was taking medroxyprogesterone for contraception. She took no other medications, including over the counter medications.

Social and Family History

The patient was born in El Salvador and immigrated to the San Francisco Bay area at age 14 years. She denied recent travel. She was married and lived with her husband and 3 children ages 1–6 years. She worked as a cashier at a mall. She did not use tobacco, alcohol, or any other illicit drugs. Her family was well, and there was no family history of prolonged febrile illnesses, arthritis, autoimmune diseases, or malignancy.

Review of Systems

She experienced increased fatigue for several weeks. Her weight was stable. She had no oral or nasal ulcers, alopecia, photosensitivity, or symptoms of Raynaud's phenomenon. She had no shortness of breath, chest pain, or abdominal pain. She denied any changes in her urine.

Physical Examination

At the time of admission, the patient appeared fatigued but nontoxic and in no acute distress. She was febrile with an oral temperature of 38.4°C. Her blood pressure was 112/59 mm Hg, her pulse was 60 per minute, her respiratory rate was 18 per minute, and her room air oxygen saturation was 100%. She had no alopecia or nasal or oral ulcers. There was shotty cervical lymphadenopathy and bilateral axillary lymphadenopathy, right greater than left, with mobile, tender lymph nodes up to 1 cm in size. Her lungs were clear to percussion and auscultation. She had a nonradiating 2/4 systolic murmur along the left sternal border. There was no pericardial rub. Her abdomen was soft and without organomegaly. She had no peripheral edema; her peripheral pulses were 2+ and symmetric. There was synovitis and tenderness of both wrists and of the MCP joints bilaterally. Her left elbow was tender to palpation and had an effusion. She had pain on active and passive range of motion of her shoulders, hips, and right ankle. There was a faint, blanching erythematous rash of the face (particularly malar areas and eyebrows) and anterior chest. Her extremities had erythematous papules and thin 5-mm plaques with linear excoriation. The rash demonstrated Koebnerization. She had normal nails and nail folds. Her neurologic examination was normal.

Initial Laboratory Evaluation

Results of the initial laboratory evaluation are shown in Table 1. Her blood smear showed anisocytosis of the red blood cells and a few atypical lymphocytes. Her urinalysis was unremarkable. Radiographs of her hands and feet were normal.

Table 1. Laboratory results
VariableNormal valueInpatient result
  • *

    Abnormal result.

White blood cell count, cells/mm34,000–11,00011,600*
Differential cell count, %  
Absolute lymphocyte count, cells/mm31,000–5,100800*
Hemoglobin, gm/dl11.7–15.711.6*
Hematocrit, %34.9–46.933.5*
Platelet count, cells/mm3150–400307
Mean corpuscular volume, femtoliters80–10081.4
International normalized ratio≤1.21.2
Partial thromboplastin time, seconds≤37.632.5
Glucose, mg/dl70–139110
Sodium, mmoles/liter136–145139
Potassium, mmoles/liter3.5–5.13.8
Chloride, mmoles/liter98–109104
Bicarbonate, mmoles/liter22–2926
Urea nitrogen, mg/dl6–2010
Creatinine, mg/dl0.50–1.100.52
Calcium, mg/dl8.6–10.59.7
Phosphorus, mg/dl2.5–4.54.2
Magnesium, mg/dl1.7–2.41.9
Serum ferritin, ng/ml10–2915,998*
Creatine kinase, units/liter26–14054
Total bilirubin, mg/dl0.1–1.20.4
Albumin, gm/dl3.4–4.84.1
Total protein, gm/dl6.4–8.36.5
Alkaline phosphatase, units/liter42–9899*
Aspartate aminotransferase, units/liter10–4177*
Alanine aminotransferase, units/liter7–3594*
Glutamic oxaloacetic transaminase, units/liter12–4359*
Thyroid-stimulating hormone, μU/ml0.37–4.420.67
C3, mg/dl86–184168
C4, mg/dl20–5936
Erythrocyte sedimentation rate, mm/hour0–2046*
C-reactive protein level, mg/liter<3.1136*
Rheumatoid factorNegativeNegative
Antinuclear antibodies<1:401:40, speckled*
Double-stranded DNANegativeNegative
Anti-Sm antibodyNegativeNegative
Anti-RNP antibodyNegativeNegative
Anti-Ro antibodyNegativeNegative
Anti-La antibodyNegativeNegative
Russell's viper venom time29.6–43.646.7*
Lupus anticardiolipinNegativePositive*
Anticardiolipin IgG, IgG phospholipid unitsNegativeNegative
Anticardiolipin IgM, IgM phospholipid units<2020*
β2-glycoprotein IgGNegativeNegative
β2-glycoprotein IgMNegativeNegative


The patient had daily spiking fevers up to 39°C that were treated with acetaminophen and ibuprofen.

An evaluation for an infectious etiology was unrevealing. Her blood cultures were negative, and a transthoracic echocardiogram was normal. Her nasal influenza A/B test was negative; there was no reactivity to a purified protein derivative (PPD). Serologic evaluations for human immunodeficiency virus (HIV), mononucleosis, Epstein-Barr virus (IgM), parvovirus B19 (IgM/IgG), cytomegalovirus (IgM), hepatitis C, syphilis (rapid plasma reagin [RPR] test), and coccidioidomycosis were negative. She showed immunity to hepatitis B virus (HBV), and a test for hepatitis B surface antigen was negative. A skin biopsy sample of a lesion on the right thigh showed a sparse neutrophilic infiltrate consistent with adult Still's disease (ASD). A rheumatology consultation was requested.


The patient is a 23-year-old woman with a subacute illness characterized by spiking fevers, sore throat, rash, polyarthritis, leukocytosis, elevated ESR and CRP level, abnormal liver function tests, and an elevated serum ferritin level. The differential diagnosis includes infectious, rheumatic, and neoplastic etiologies.

Infectious etiologies

Acute viral infections can cause fever, polyarthritis, and a diffuse erythematous rash. A particular concern in a mother with young children is infection with parvovirus B19, which produces “slapped-cheek fever” in children and polyarthritis in adults. Patients with arthritis due to acute parvovirus B19 have IgM antibodies to the virus, and the absence of specific IgM antibodies in this case excludes the possibility of parvovirus B19 as the etiologic agent. Numerous other viral infections (e.g., acute HIV, acute HBV, acute rubella infection or recent immunization) can cause a polyarthritis that mimics rheumatoid arthritis (RA), but the appropriate tests for these are negative. Polyarthritis due to acute viral infections usually resolves over days to a few weeks; persistence for a month, as in this case, is uncommon and provides evidence against a viral cause.

Disseminated gonococcal infection (DGI) is a common cause of fever, rash, and arthritis in young women, but DGI causes scattered pustules, not the diffuse rash described here, and persistent polyarthritis of the wrists and MCP joints would be a very unusual manifestation of DGI. The combination of a subacute illness, fever, and arthritis raises the possibility of subacute bacterial endocarditis, particularly with the murmur noted on physical examination, but this patient's blood cultures and echocardiogram were normal. Secondary syphilis can cause fever, polyarticular synovitis, and a diffuse rash, but is excluded by the negative RPR test. Her rash is distinct from erythema migrans seen with acute Lyme disease, which is far less common in California than in endemic areas in the East and Midwest. Poststreptococcal arthritis can cause high fever and polyarthritis, but not rash (erythema marginatum is seen in a minority of children with acute rheumatic fever). In this case, the rapid throat antigen test was negative for group A streptococci, but serologic tests for anti-streptococcal antibody titers would be required to exclude antecedent streptococcal infection. Brucellosis can cause systemic features, including an undulating, intermittent fever and lymphadenopathy, as well as a peripheral arthritis, although more typically the arthritis is mono- or oligoarticular; it is rare in the US and is associated with exposure to livestock or ingestion of unpasteurized milk products.

Her lack of travel is evidence against recent exposure to one of the endemic fungi such as histoplasmosis that can cause an acute syndrome with fever, polyarthralgia/arthritis, and erythema nodosum (but not a diffuse erythematous rash). The calcified granuloma in her right mid-lung together with a negative PPD suggest she may have had a childhood infection with histoplasmosis, which is prevalent in Central America.

Rheumatic disease

RA is a common cause of inflammatory polyarthritis involving the wrists and MCP joints. RA, however, does not explain other prominent features of this woman's illness. Low-grade fevers occur in RA, but spiking fever to 39°C warrants a search for another etiology (1). Moreover, a diffuse erythematous rash, lymphadenopathy, and sore throat are not features of RA.

Systemic vasculitis can cause polyarthritis and fever, but not the nonvasculitic rash that is a prominent feature of this case. Notably, pulmonary or renal involvement, common in small or medium-size vasculitis, was absent in this case.

Systemic lupus erythematosus (SLE) is a prominent diagnostic consideration in a young woman with fever, rash, and polyarthritis. She has a facial rash, with a malar distribution typical of SLE; the pattern of her joint involvement is consistent with the polyarthritis of SLE; and SLE causes lymphadenopathy, another feature of this patient's illness. She also has an absolute lymphopenia, commonly seen in SLE. Ferritin levels can be elevated in SLE and have been shown to correlate with disease activity (2, 3). She has a lupus anticoagulant, which commonly occurs in patients with secondary antiphospholipid syndrome associated with SLE, but she has no history of thrombotic events or fetal loss. Several features, however, point away from the diagnosis of SLE. An antinuclear antibody (ANA) titer that is positive at only 1:40 is a common finding in normal individuals and is a lower titer than is typical of SLE. Moreover, she lacks other autoantibodies that are commonly seen in SLE. The rashes of SLE are usually not pruritic as in this patient, and the histologic findings on skin biopsy are not those of lupus. Fever in SLE more commonly occurs when serositis, not polyarthritis, is the main disease manifestation (1). Although a diagnosis of SLE cannot be excluded, it seems far less likely than alternative possibilities.

The absence of prior episodes and the negative family history provide evidence against the possibility of an autoinflammatory disorder. Familial Mediterranean fever (FMF) can have its initial onset in adulthood, but the duration of attacks in FMF is only 1–3 days, in contrast to the month-long course of this case. Indeed, among the autoinflammatory disorders, episodes lasting for weeks are characteristic of tumor necrosis factor α receptor 1–associated periodic syndrome (TRAPS) (4). TRAPS is inherited in an autosomal dominant pattern, but it can have incomplete penetrance, so the family history can be misleading. TRAPS is characterized, as in this patient, by fevers that can last for weeks, myalgias, arthritis, and rash, but unlike our case, typically causes severe abdominal pain, conjunctivitis, and periorbital edema. Although diagnosis may be delayed until adulthood, the onset of TRAPS is usually in childhood (5).

ASD is a systemic inflammatory condition of unknown etiology with onset most commonly in early adulthood (age 16–35 years), although at least one-quarter of patients present after age 35 years (6, 7). ASD explains all of the clinical features of this patient's illness: spiking fevers to 39°C, polyarthritis, diffuse erythematous rash, sore throat, and lymphadenopathy, as well as the laboratory findings of leukocytosis, elevated ESR and CRP level, elevated levels of transaminases, a high serum ferritin level, a negative test for rheumatoid factor, and a borderline ANA titer. Indeed, our patient fulfills all 4 of the major Yamaguchi criteria for ASD, as well as 3 of the minor criteria (8, 9) (Table 2).

Table 2. Yamaguchi classification criteria for adult Still's disease (ASD) (9)
  • *

    Maculopapular, nonpruritic, salmon-pink rash with concomitant fever spikes.

Diagnosis of ASD
 At least 5 criteria, including 2 major criteria, and no exclusion criteria
Major criteria
 Fever ≥39°C lasting 1 week or more
 Arthralgias/arthritis lasting 2 weeks or more
 Typical skin rash*
 White blood cell count ≥10,000/mm3 with neutrophils ≥80%
Minor criteria
 Pharyngitis or sore throat
 Hepatomegaly or splenomegaly
 Liver enzyme abnormalities (transaminitis)
 Negative for rheumatoid factor and antinuclear antibodies
Exclusion criteria
 Absence of infection
 Absence of malignant diseases
 Absence of inflammatory disease

There are several concerns, however, with the diagnosis of ASD in this patient. First, the fever associated with ASD is daily or twice daily, with spikes >39°C often in the evenings. Classically, the fever resolves spontaneously, resulting in daily temperature swings up to 4°C, although in a minority, the fever of ASD persists between spikes (8). Our patient's fever has a daily pattern, but she is receiving antipyretics, which can alter fever patterns. To establish whether the patient truly has a daily fever, it is necessary to observe her fever pattern off all antipyretics. Second, the characteristic rash of ASD is an evanescent, salmon-pink, macular or maculopapular rash that is often most prominent during fever spikes and may go undetected. It is usually truncal but may involve the extremities; Koebnerization is common. A biopsy sample of the rash reveals a neutrophilic infiltration of the dermis and perivascular spaces (10). Therefore, our patient's rash has many features (appearance, Koebnerization, histology) consistent with the rash of ASD. Other features of her rash, however, are atypical. Her rash involves the face, which is not common in ASD, and is extremely pruritic, whereas the rash of ASD is asymptomatic or only mildly pruritic (8, 10). Moreover, there are no histologic findings on skin biopsy that are diagnostic of ASD; the histology is nonspecific and can be seen with urticaria, cellulitis, and other conditions. Finally, infection, other rheumatic diseases, autoinflammatory disorders, and malignancy can mimic the presentation of ASD and must be excluded before a diagnosis of ASD is established (Table 2). As discussed above, infections, the autoinflammatory disorders, and other rheumatic diseases seem like unlikely explanations for this woman's illness.


Malignancies can cause fever, polyarthritis, and rash, and are notorious mimics of ASD. Red flags for the presence of a paraneoplastic process include atypical findings of the rheumatic disease, such as the pruritic nature of this patient's rash and a poor response to standard therapy (11). It is notable that this patient did not respond to a brief course of high-dose prednisone combined with ibuprofen. Fever is a common presenting feature of lymphoma, which is the most likely neoplasm in her age group. Pel-Ebstein fever, the intermittent fever associated with Hodgkin's disease, occurs in approximately week-long cycles (12). The rash associated with Hodgkin's lymphoma is characteristically pruritic (13). Autoantibodies, including lupus anticoagulant, are common in patients with lymphoproliferative disorders (14). Although musculoskeletal symptoms such as arthralgias and myalgias are prevalent in lymphomas, true synovitis as present in this patient is rare (15–17). Nonetheless, given the far greater incidence of lymphomas than ASD, an unusual presentation of a lymphoma may be more likely than ASD. In this case, therefore, there should be an aggressive diagnostic effort to exclude lymphomas and other malignancies.


At the request of the rheumatology consultants, antipyretics were held, demonstrating that she had a hectic fever ranging between 38°C and 39.5°C and that the apparent daily fever pattern was due to intermittent antipyretic medication. The patient's symptoms continued, and she developed severe pain over her lower extremities that was disproportionate to the degree of synovitis. Computerized tomographic examination of her chest confirmed the presence of axillary lymph nodes that were as large as 1.1 cm on the right (Figure 1); there was no mediastinal or hilar lymphadenopathy, and her lungs, apart from the calcified granuloma, were normal. Computed tomography of the abdomen and pelvis showed a normal liver and spleen; there were no intraabdominal or pelvic masses or lymphadenopathy. A fine needle aspiration (FNA) and core needle biopsy sample of a right axillary lymph node showed a few atypical lymphocytes, but the histology and immunohistochemical stains were nondiagnostic. The patient then underwent excisional biopsy of her right axillary lymph node (Figure 2).

Figure 1.

Computerized tomographic scan of the chest demonstrating prominent right axillary dominant lymph nodes (circle). There is also a calcified granuloma in the right lung.

Figure 2.

Light microscopy of the excisional biopsy sample of a right axillary node demonstrating classic Hodgkin's lymphoma with nodular sclerosis features (hematoxylin and eosin stained; magnification × 40). Arrow = Reed-Sternberg cell.


Classic nodular sclerosing Hodgkin's lymphoma.


This case underscores the need for caution when considering a diagnosis of ASD. To our knowledge, there are no laboratory studies or histologic findings diagnostic of ASD, which remains a purely clinical diagnosis. It is of utmost importance to remember that ASD is a diagnosis of exclusion. Indeed, the Yamaguchi criteria mandate exclusions in order to diagnose ASD (Table 2). An alternative set of criteria for ASD, the Cush criteria, use the terminology “probable ASD” if clinical criteria are sustained over a duration of 12 weeks and “definite ASD” when a 6-month observation period has passed in order to diminish the likelihood of an alternative disease emerging (18). In this case, the initial pathologic evaluation was performed by FNA, which can be a first-line approach compared with a more invasive excisional biopsy. However, the false-negative and indeterminate rate for lymphoproliferative disorders is approximately 10% and concordance between FNA and excisional biopsy diagnoses for the initial evaluation of lymphadenopathy has been reported to be as low as 12% (19–23). Therefore, if suspicion for malignancy remains after a negative or inconclusive FNA, excisional biopsy should be pursued.

Marked elevations in the levels of serum ferritin are characteristic of ASD but are not specific for ASD and do not distinguish ASD from other diseases characterized by robust inflammation (24). Because ASD has such a low prevalence, the positive predictive value of a high ferritin level for ASD remains very low (25). Furthermore, reported sensitivities and specificities for the ferritin test are difficult to interpret, because these are based on retrospective chart review of patients whose physicians had ordered serum ferritin levels and therefore are subject to selection bias (26). Inflammation reduces the fraction of ferritin that is glycosylated (due to the saturation of the glycosylation mechanisms). ASD has been reported to reduce the fraction of glycosylated ferritin to a greater extent than other inflammatory conditions. The combination of an increased serum ferritin level and a very low (<20%) fraction of glycosylated ferritin may prove helpful in the diagnosis of ASD, but measurement of glycosylated ferritin is not a widely available clinical test (26).

This case emphasizes the importance of “red flags,” i.e., clinical features that are not typical of ASD. Clues to an alternative diagnosis in this patient include a hectic fever pattern off antipyretics, the pruritic nature of her rash, and lymphadenopathy that was regional rather than diffuse. Later in her disease course she developed progressive extremity pain out of proportion to her clinical joint examination, symptoms characteristic of neoplastic and paraneoplastic processes but not of ASD. None of these atypical features individually excludes ASD, but in aggregate these render the diagnosis of ASD unlikely. Although the age distribution for the onset of ASD and Hodgkin's lymphoma closely overlap, physicians should bear in mind that ASD is a rare entity with an estimated incidence of 0.16 per 100,000. The incidence of Hodgkin's lymphoma is 3.4 per 100,000 (21 times the incidence of ASD) and that of non-Hodgkin's lymphoma is 7.1 per 100,000 in people ages 20–49 years (25, 27). Therefore, unusual presentations of Hodgkin's lymphoma and non-Hodgkin's lymphoma are far more likely than atypical presentations of ASD.


For additional staging purposes, the patient underwent a positron emission tomography scan that showed activity in pelvic lymph nodes and thus established her Hodgkin's disease as stage IIIB. She is currently in remission following chemotherapy.


Classic nodular sclerosing Hodgkin's lymphoma, stage IIIB.


All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be submitted for publication. Dr. Gratton had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Gratton, Imboden.

Acquisition of data. Gratton, Imboden.

Analysis and interpretation of data. Gratton, Imboden.


The photograph of the excisional biopsy sample is courtesy of Douglas Hanks, MD, Department of Pathology, University of California, San Francisco.