What is the differential diagnosis for a patient presenting with rash, joint pain, and fever?

Differential Diagnosis for Rash, Joint Pain, and Fever

The differential diagnosis for a patient presenting with rash, joint pain, and fever is broad and includes infectious diseases (viral syndromes, tickborne rickettsial diseases), autoimmune conditions (Adult-Onset Still's Disease, systemic lupus erythematosus), and neoplastic disorders, with the priority being to rule out life-threatening infections first before considering inflammatory conditions. 1

Life-Threatening Conditions to Exclude Immediately

• Meningococcemia requires immediate empiric antibacterial therapy while awaiting diagnostic confirmation, as delay can be fatal 1
• Rocky Mountain Spotted Fever (RMSF) has a 5-10% mortality rate if untreated and should be treated empirically with doxycycline when suspected, even before laboratory confirmation 1, 2
• Neoplastic disorders including leukemia, lymphoma, and angioblastic lymphadenopathy can present with this triad; bone marrow or lymph node biopsy may be needed if the haematological profile is atypical 1

Infectious Etiologies

Viral Syndromes

• Parvovirus B19 commonly causes acute polyarthritis in adults (94% with arthralgia, 50% with arthritis), fever (44%), and rash (35%), and can fulfill classification criteria for SLE in 93% of ANA-positive patients, creating significant diagnostic confusion 3
• Parvovirus B19 infection typically presents with oligoarthritis (67% of arthritis cases), short-lived autoantibodies, and symptoms resolving within 6 weeks 3, 4
• Other viral syndromes (rubella, cytomegalovirus, Epstein-Barr virus, mumps, Coxsackievirus, adenovirus) can be excluded if symptoms persist beyond 3 months 1
• Post-viral arthritis is typically non-erosive, seronegative for anti-CCP antibodies, and presents as either symmetrical polyarthritis or intermittent mono-oligoarthritis 5

Tickborne Rickettsial Diseases

• RMSF and other spotted fever group rickettsioses present with fever, headache, myalgia, and rash that may be petechial/purpuric 1
• Only a minority of RMSF patients present with the classic triad of fever, rash, and tick bite; rash may be absent in up to 20% of cases 2
• Anaplasmosis typically presents with fever, headache, and myalgia, but rash is rare; leukopenia and thrombocytopenia are characteristic 1

Lyme Disease

• Consider Lyme disease in the differential, particularly with oligoarthritis affecting large joints 6, 7
• Coinfection with Anaplasma phagocytophilum should be suspected if leukopenia or thrombocytopenia is present 1

Autoimmune/Inflammatory Conditions

Adult-Onset Still's Disease (AOSD)

• Classic triad: quotidian fever (95.7% of cases), salmon-pink evanescent maculopapular rash (72.7%), and arthritis/arthralgia (64-100%) 1
• The rash is typically found on proximal limbs and trunk, often accompanied by fever, and can be mildly pruritic 1
• Arthritis most frequently affects knees, wrists, and ankles, with characteristic pericapitate and carpometacarpal joint space narrowing developing 6 months after onset 1
• Laboratory findings include marked leukocytosis with neutrophilia (50% with WBC >15×10⁹/L), elevated ESR/CRP, anemia of chronic disease, and thrombocytosis 1
• Diagnosis requires exclusion of infectious, neoplastic, and other autoimmune disorders first 1

Systemic Lupus Erythematosus (SLE)

• Parvovirus B19 can mimic SLE both clinically and serologically, with 93% of ANA-positive parvovirus patients fulfilling SLE classification criteria 3
• Key distinguishing features: Parvovirus infection usually fulfills <4 ACR criteria for SLE, rarely includes cardiac or renal involvement, and is associated with short-lived, low-titer autoantibodies 4, 8
• Screen for parvovirus B19 in newly diagnosed SLE cases with abrupt symptom onset or in established SLE patients with flares 4

Other Autoimmune Conditions

• Reactive arthritis and spondyloarthropathies are commonly confused with AOSD 1
• Vasculitides should be considered, particularly if purpura is present 1
• Dermatomyositis, Kikuchi's syndrome, Sweet's syndrome, and granulomatous disorders can present similarly 1

Periodic Fever Syndromes

• Familial Mediterranean Fever: acute, self-limited fever episodes (1-3 days) with peritonitis, pleuritis, or acute synovitis of knee/ankle/hip; erysipelas-like erythema; strong family history and ethnic background; responds to colchicine 1
• TNF Receptor Associated Periodic Syndrome (TRAPS): longer fever attacks (average 21 days), ocular involvement, distinctive centrifugal erythematous patch, strong familial distribution 1

Diagnostic Approach Algorithm

Initial Laboratory Evaluation

1. Complete blood count with differential: assess for leukocytosis (AOSD, RMSF), leukopenia (anaplasmosis, SLE), thrombocytopenia (RMSF, anaplasmosis, vasculitis), and anemia 1, 2
2. Inflammatory markers: ESR and CRP are elevated in AOSD, vasculitis, RMSF, and post-viral arthritis 1, 5, 2
3. Hepatic transaminases: commonly elevated in AOSD and anaplasmosis 1
4. Peripheral blood smear: may reveal morulae in granulocytes (anaplasmosis) 1

Serologic Testing

1. Parvovirus B19 IgM and IgG: essential in patients with acute polyarthritis, as 55% may have positive ANA, 38% anti-dsDNA, and 50% anti-phospholipids 3
2. ANA, anti-dsDNA, anti-CCP, rheumatoid factor: helps differentiate SLE, rheumatoid arthritis, and post-viral arthritis (typically anti-CCP negative) 5, 3
3. Serum ferritin and glycosylated fraction: elevated in AOSD 1
4. Cultures and serological tests for infections: especially helpful early in disease course 1

Critical Pitfalls to Avoid

• Do not delay empiric doxycycline if RMSF is suspected, as diagnostic tests are not helpful in early stages and delay can be fatal 1
• Do not misdiagnose parvovirus B19 as SLE: parvovirus typically has short-lived autoantibodies, symptoms resolve within 6 weeks, and rarely involves cardiac/renal systems 3, 4, 8
• Repeated laboratory examinations may be necessary if initial findings are negative, particularly for serum cryoglobulins in HCV-related arthritis 5
• Rash may be difficult to discern in darker-skinned individuals, particularly erythematous or petechial rashes 2