Familial mediterranean fever differential diagnosis

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Differential diagnosis

Familial mediterranean fever (FMF) should be differentiated from other conditions presenting with fever, fatigue, weight loss, arthralgia, myalgia, rash and soft tissue swelling. The differentials include the following:^[1]^[2]^[3]^[4]^[5]^[6]^[7]^[8]^[9]^[10]^[11]^[12]^[13]^[14]^[15]^[16]^[17]^[18]^[19]^[20]^[21]^[22]^[23]^[24]^[25]

Category of Disease	Diseases	Signs and symptoms										Laboratory findings
		Fever	Fatigue	Arthralgia	Myalgia	Soft tissue swelling/serositis	Skin rash	Weight loss	Dyspnea	Sore throat	Lymphadenopathy	Complete blood count (CBC)	Liver function tests (LFTs)	Inflammatory markers		Autoantibodies						Diagnostic tests
		Fever	Fatigue	Arthralgia	Myalgia	Soft tissue swelling/serositis	Skin rash	Weight loss	Dyspnea	Sore throat	Lymphadenopathy	Complete blood count (CBC)	Liver function tests (LFTs)	Erythrocyte sedimentation rate (ESR)	C- reactive protein (CRP)	Anti-nuclear antibodies (ANA)	Rheumatoid factor (RF)	Anti- glomerular basement membrane (anti-GBM)	Anti-dsDNA	Anti-Jo1/ Anti Mi2	ANCA
Infections	HIV	+	+	+	+	+/-	-	+	+/-	+ /-	+	Leukopenia Anemia Thrombocytopenia	ALT↑ AST↑	↑	↑	-	-	-	-	-	-
	Herpesviridae	+	+	+	+	+	Papular or vesicular Erythematous base Painful	-	-	+/-	+	Leukocytosis	-	↑	↑	-	-	-	-	-	-
	Measles	+	+	+	+	-	3-5 days after fever Erythematous maculopapular rash starts on face spreads to trunk and extremities (centrifugal)	-	-	+	+	Leukocytosis	-	↑	↑	-	-	-	-	-	-
	Viral hepatitis	+	+	-	+/-	-	-	+/-	-	-	+/-	Leukocytosis	ALT↑ AST↑	↑	↑	-	-	-	-	-	-
	Parvovirus B19	+	+	+	+/-	-	Slapped cheek rash	-	-	-	+	Leukopenia Aplastic anemia (low reticulocyte count) Thrombocytopenia	ALT↑ AST↑	↑	↑	-	-	-	-	-	-
	Infective endocarditis	+	+	+	+/-	-	Purpuric	+/-	+	-	+	Leukocytosis	-	↑	↑	-	-	-	-	-	-	Blood cultures, ultrasonography
	Borreliosis, Brucellosis, Yersiniosis	+	+	+	+	-	Target rash (Borrelia) Diffuse maculopapular (Brucellosis) Erythema nodosum (Yersiniosis)	-	-	-	+	Leukocytosis	ALT↑ AST↑	↑	↑	-	-	-	-	-	-	Serology, PCR
	Syphilis and Jarisch-Herxheimer reaction	+	+	+	+	-	Non-pruritic Macular On palms and soles Round Seen in secondary syphilis Penile ulceration (painless)	-	-	+	+	Leukocytosis	ALT↑ (Uncommon) AST↑ (Uncommon)	↑	↑	-	-	-	-	-	-	Serology, PCR
	Toxoplasmosis	+	+	-	+	-	Maculopapular Palms and soles	-	-	+	+	Leukocytosis (eosinophilia)				-	-	-	-	-	-	Serology, PCR

Neoplasia	Malignant lymphoma	+	+	-	+/-	+/-	Purplish scaly rash in cases of cutaneous lymphoma	+	+	-	+	Anemia of chronic disease	In case of liver metastasis (Non-Hodgkin lymphoma): ALT↑ AST↑	↑	↑	-	-	-	-	-	-	CT, PET/CT, Bone marrow examination, lymph node biopsy
	Multicentric Castleman disease	+	+	-	-	+	-	+	+	-	+	Anemia Thrombocytopenia	-	↑	↑	-	-	-	-	-	-	Lymph node biopsy
	Angioimmunoblastic T cell lymphoma	+	+	-	-	-	Maculopapular eruption on the trunk mimicking toxic erythema	+	-	-	+	Lymphocytosis	ALT↑ AST↑	↑	↑	-	-	-	-	-	-	Lymph node biopsy

Drug hypersensitivity	Drug reaction with eosinophilia and systemic symptoms	+	+	+	+	+/-	Utricaria (Immediate type) Maculopapular (Delayed type)	-	+	-	-	Leukocytosis (eosinophilia)	-	↑	↑	-	-	-	-	-	-	Eosinophil count, skin biopsy

Autoimmune conditions	Systemic lupus erythematosus	+	+	+	+/-	+	Butter-fly shaped erythematous malar rash that spares the nasolabial folds Coin-shaped erythematous rash on extremities or trunk	+	+	-	+/-	Leukopenia Hemolytic anemia Thrombocytopenia	ALT↑ AST↑	↑	↑	+	+	-	+	-	-	Antinuclear autoantibodies
	Inflammatory myositis	+	+	-	+ (weakness > pain)	-	Macular red rash over the back of the fingers, elbows or knees (Grotton's sign) Macular purpish or reddish rash on the upper chest or back (Shawl-like, heliotrope rash)	-	-	-	+/-	Leukocytosis	-	↑	↑	+/-	+/-	-	-	+	-	Idem, muscle biopsy
	Rheumatoid arthritis	+	+	+	-	+	Purpura Ulcers	-	+	-	+	Anemia of chronic disease Neutropenia (Felty's syndrome)	-	↑	↑	+/-	+/-	-	-	-	-	Anti-citrullinated peptids autoantibodies, rheumatoid factor
	Systemic vasculitides	+	+	+	-	+	Nasopharyngeal ulceration (Wegner's granulomatosis) Erythematous rash on palms and soles (Kawasaki disease)	-	+/-	-	+/-	Leukocytosis	-	↑	↑	-	-	+/-	-	-	+	ANCA, tissue biopsy, arteriography
	Familial Mediterranean fever	+	+	+	+	+	Red rash on lower extremities (ankles and knees)	+	+ (due to pain)	-	+/-	Leukocytosis (during acute flares)	-	↑	↑	-	-	-	-	-	-	Familial history, MEFV gene analysis
	Mevalonate kinase deficiency	+	+	+	+	-	Maculopapular rash Aphthous ulcers (or stomatitis)	+	-	+	+	Leukocytosis (during acute flares)	-	↑	↑	-	-	-	-	-	-	Urinary mevalonic acid, mevalonate kinase analysis
	Reactive arthritis	+	+	+	-	-	Keratoderma blennorrhagica (palms, soles, scrotum) Circinate balanitis (penile)	-	+ (Aortic insufficiency)	-	+	Leukocytosis	-	↑	↑	-	-	-	-	-	-	HLA B27, magnetic resonance imaging

Miscellaneous	Sarcoidosis	+	+	+	-	+	Waxy skin plaques Violaceous facial lesions Erythema nodosum	+	+	-	+	Lymphopenia Eosinophilia	Normal ALT, AST ALP ↑ (infiltrative pattern)	↑	↑	-	-	-	-	-	-	Lymph node/Lung biopsy ACE levels FDG-PET

Less common differentials

FMF must be differentiated from other causes of secondary peritonitis

**Differentiating FMF from other causes of peritonitis**
Disease		Prominent clinical findings	Lab tests	Tratment
Primary peritonitis	Spontaneous bacterial peritonitis	Absence of GI perforation, most closely associated with cirrhosis and advanced liver disease. Presents with abrupt onset of fever, abdominal pain, distension, and rebound tenderness.	Most have clinical and biochemical manifestations of advanced cirrhosis or nephrosis like leukocytosis,hypoalbuminemia, Prolonged prothrombin time. SAAG >1.1 g/dL, increased serum lactic acid level, or a decreased ascitic fluid pH (< 7.31) supports the diagnosis. Gram staining reveals bacteria in only 25% of cases. Diagnosed by analysis of the ascitic fluid which reveals WBC > 500/ML, and PMN >250cells/ml. Culture of ascitic fluid inoculated immediately into blood culture media at the bedside usually reveals a single enteric organism, most commonly Escherichia coli, Klebsiella, or streptococci.	Once diagnosed,it is treated with Ceftriaxone.
	Tuberculous peritonitis	Seen in 0.5% of new cases of tuberculosis particularly in young women in endemic areas as a primary infection. Presents with abdominal pain and distension, fever, night sweats, weight loss, and altered bowel habits.	Ascites is present in about half of cases. Abdominal mass may be felt in a third of cases. The peritoneal fluid is characterized by a protein concentration > 3 g/dL with < 1.1 g/dL SAAG and lymphocyte predominance of WBC. Definitive diagnosis in 80% of cases is by culture. Most patients presenting acutely are diagnosed only by laparotomy.	Combination antituberculosis chemotherapy is preferred in chronic cases.
	Continuous Ambulatory Peritoneal Dialysis (CAPD peritonitis)	Peritonitis is one of the major complications of peritoneal dialysis & 72.6% occurred within the first six months of peritoneal dialysis. Historically, coagulase-negative staphylococci were the most common cause of peritonitis in CAPD, presumably due to touch contamination or infection via the pericatheter route. Treatment for peritoneal dialysis-associated peritonitis consists of antimicrobial therapy, in some cases catheter removal is also warranted. Additional therapies for relapsing or recurrent peritonitis may include fibrinolytic agents and peritoneal lavage. Most episodes of peritoneal dialysis-associated peritonitis resolve with outpatient antibiotic treatment.	Majority of peritonitis cases are caused by bacteria (50%-due to gram positive organisms, 15% to gram negative organisms,20% were culture negative.2% of cases are caused by fungi, mostly Candida species. Polymicrobial infection in 4%.Exit-site infection was present in 13% and a peritoneal fluid leak in 3 % and M.tuberculosis 0.1%.	Initial empiric antibiotic coverage for peritoneal dialysis-associated peritonitis consists of coverage for gram-positive organisms (by vancomycin or a first-generation cephalosporin) and gram-negative organisms (by a third-generation cephalosporin or an aminoglycoside). Subsequently, the regimen should be adjusted based on culture and sensitivity data. Cure rates are approximately 75%.
Secondary peritonitis	Acute bacterial secondary peritonitis	Occurs after perforating, penetrating, inflammatory, infectious, or ischemic injuries of the GI or GU tracts. Most often follows disruption of a hollow viscus?chemical peritonitis?bacterial peritonitis(polymicrobial, includes aerobic gram negative {E coli, Klebsiella, Enterobacter, Proteus mirabilis} and gram positive { Enterococcus, Streptococcus} and anaerobes {Bacteroides, clostridia}). Presents with abdominal pain, tenderness, guarding or rigidity, distension, free peritoneal air, and diminished bowel sounds. Signs that reflect irritation of the parietal peritoneum resulting ileus. Systemic findings include fever, chills or rigors, tachycardia, sweating, tachypnea, restlessness, dehydration, oliguria, disorientation, and, ultimately, refractory shock.		Peritoneal lavage, Laparoscopy are the treatment of choice.
Secondary peritonitis	Biliary peritonitis	Most often seen in cases of rupture of pathological gallbladder or bile duct or cholangitic abscess or secondary to obstruction of the biliary tract. Seen in alcoholic patients with ascites.
Tertiary peritonitis		Persistence or recurrence of intraabdominal infection following apparently adequate therapy of primary or secondary peritonitis. Associated with high mortality due to multi organ dysfunction. It presents in a similar way as other peritonitis but is recognized as an adverse outcome with poor prognosis.	Enterococcus, Candida, Staphylococcus epidermidis, and Enterobacter being the most common organisms.	Characterized by lack of response to appropriate surgical and antibiotic therapy due to disturbance in the hosts immune response.
Familial Mediterranean fever (periodic peritonitis, familial paroxysmal polyserositis)		Rare genetic condition which affects individuals of Mediterranean genetic background. Etiology is unclear. Presents with recurrent bouts of abdominal pain and tenderness along with pleuritic or joint pain. Fever and leukocytosis are common.		Colchicine prevents but does not treat acute attacks.
Granulomatous peritonitis		A rare condition caused by disposable surgical fabrics or food particles from a perforated ulcer, eliciting a vigorous granulomatous (delayed hypersensitivity) response in some patients 2-6 weeks after laparotomy. Presents with abdominal pain, fever, nausea and vomiting, ileus, and systemic complaints, mild and diffuse abdominal tenderness.	Diagnosed by the demonstration of diagnostic Maltese cross pattern of starch particles.	The disease is self-limiting. Treated with corticosteroids or anti-inflammatory agents.
Sclerosing encapsulating peritonitis		Seen in conditions associated with long term peritoneal dialysis, shunts like VP shunts, history of abdominal surgeries, liver transplantation. Symptoms include nausea, abdominal pain, diarrhea, anorexia, bloody ascites.
Intraperitoneal abscesses		Most common etiologies being Gastrointestinal perforations, postoperative complications, and penetrating injuries. Signs and symptoms depend on the location of the abscess within the peritoneal cavity and the extent of involvement of the surrounding structures. Diagnosis is suspected in any patient with a predisposing condition. In a third of cases it occurs as a sequela of generalized peritonitis. The pathogenic organisms are similar to those responsible for peritonitis, but anaerobic organisms occupy an important role. The mortality rate of serious intra-abdominal abscesses is about 30%.	Diagnosed best by CT scan of the abdomen.	Treatment consists of prompt and complete CT or US guided drainage of the abscess, control of the primary cause, and adjunctive use of effective antibiotics. Open drainage is reserved for abscesses for which percutaneous drainage is inappropriate or unsuccessful.
Peritoneal mesothelioma		Arises from the mesothelium lining the peritoneal cavity. Its incidence is approximately 300-500 new cases being diagnosed in the United States each year. As with pleural mesothelioma, there is an association with an asbestos exposure. Most commonly affects men at the age of 50-69 years. Patients most often present with abdominal pain and later increased abdominal girth and ascites along with anorexia, weight loss and abdominal pain. Mean time from diagnosis to death is less than 1 year without treatment.	CT with intravenous contrast typically demonstrates the thickening of the peritoneum. Laparoscopy with tissue biopsy or CT guided tissue biopsy with immunohistochemical staining for calretinin, cytokeratin 5/6, mesothelin, and Wilms tumor 1 antigen remain the gold standard for diagnosis.	At laparotomy the goal is cytoreduction with excision. Debulking surgery and intraperitoneal chemotherapy improves survival in some cases.
peritoneal carcinomatosis		Associated with a history of ovarian or GI tract malignancy. Symptoms include ascites, abdominal pain, nausea, vomiting.

Classification of acute abdomen based on etiology		Presentation	Symptoms			Signs			Diagnosis		Comments
Classification of acute abdomen based on etiology		Presentation	Fever	Abdominal Pain	Jaundice	Guarding	Rebound Tenderness	Bowel sounds	Lab Findings	Imaging	Comments
Common causes of Peritonitis	Primary Peritonitis	Spontaneous bacterial peritonitis	+	Diffuse	-	-	-	Hypoactive	Ascitic fluid PMN>250 cells/mm³ Culture: Positive for single organism	Ultrasound for evaluation of liver cirrhosis	-
	Secondary Peritonitis	Perforated gastric and duodenal ulcer	+	Diffuse	-	+	+	N	Ascitic fluid LDH > serum LDH Glucose < 50mg/dl Total protein > 1g/dl	Air under diaphragm in upright CXR	Upper GI endoscopy for diagnosis
		Acute cholangitis	+	RUQ	+	-	-	N	Abnormal LFT	Ultrasound shows biliary dilatation	Biliary drainage (ERCP) + IV antibiotics
		Acute cholecystitis	+	RUQ	+	-	-	Hypoactive	Hyperbilirubinemia Leukocytosis	Ultrasound shows gallstone and evidence of inflammation	Murphy’s sign
		Acute pancreatitis	+	Epigastric	+/-	-	-	N	Increased amylase / lipase	Ultrasound shows evidence of inflammation	Pain radiation to back
		Acute appendicitis	+	RLQ	-	+	+	Hypoactive	Leukocytosis	Ultrasound shows evidence of inflammation	Nausea & vomiting, decreased appetite
		Acute diverticulitis	+	LLQ	+/-	+	-	Hypoactive	Leukocytosis	CT scan and ultrasound shows evidence of inflammation
		Acute salpingitis	+	LLQ/ RLQ	-	+/-	+/-	N	Leukocytosis	Pelvic ultrasound	Vaginal discharge
Hollow Viscous Obstruction		Small intestine obstruction	-	Diffuse	-	+	+/-	Hyperactive then absent	Leukocytosis	Abdominal X ray	Nausea & vomiting associated with constipation, abdominal distention
		Volvulus	-	Diffuse	-	+	-	Hypoactive	Leukocytosis	CT scan and abdominal X ray	Nausea & vomiting associated with constipation, abdominal distention
		Biliary colic	-	RUQ	+	-	-	N	Increased bilirubin and alkaline phosphatase	Ultrasound	Nausea & vomiting
		Renal colic	-	Flank pain	-	-	-	N	Hematuria	CT scan and ultrasound	Colicky abdominal pain associated with nausea & vomiting
Vascular Disorders	Ischemic causes	Mesenteric ischemia	+/-	Periumbilical	-	-	-	Hyperactive	Leukocytosis and lactic acidosis	CT scan	Nausea & vomiting, normal physical examination
	Ischemic causes	Acute ischemic colitis	+/-	Diffuse	-	+	+	Hyperactive then absent	Leukocytosis	CT scan	Nausea & vomiting
	Hemorrhagic causes	Ruptured abdominal aortic aneurysm	-	Diffuse	-	-	-	N	Normal	CT scan	Unstable hemodynamics
	Hemorrhagic causes	Intra-abdominal or retroperitoneal hemorrhage	-	Diffuse	-	-	-	N	Anemia	CT scan	History of trauma
Gynaecological Causes	Ovarian Cyst Complications	Torsion of the cyst	-	RLQ / LLQ	-	+/-	+/-	N	Increased ESR and CRP	Ultrasound	Sudden onset sever pain with nausea and vomiting
	Ovarian Cyst Complications	Cyst rupture	-	RLQ / LLQ	-	+/-	+/-	N	Increased ESR and CRP	Ultrasound	Sudden onset sever pain with nausea and vomiting
	Pregnancy	Ruptured ectopic pregnancy	-	RLQ / LLQ	-	-	-	N	Positive pregnancy test	Ultrasound	History of missed period and vaginal bleeding

References

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↑ Yaguchi D, Marui N, Matsuo M (2015). "Three Adult Cases of HPV-B19 Infection with Concomitant Leukopenia and Low Platelet Counts". Clin Med Insights Case Rep. 8: 19–22. doi:10.4137/CCRep.S18085. PMC 4345940. PMID 25780346.
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↑ "watermark.silverchair.com" (PDF).
↑ Shetty RK, Vivek G, Naha K, Bekkam S (January 2013). "Right-sided infective endocarditis presenting with purpuric skin rash and cardiac failure in a patient without fever". BMJ Case Rep. 2013. doi:10.1136/bcr-2012-007841. PMC 3603787. PMID 23355575.
↑ Aucott JN, Crowder LA, Yedlin V, Kortte KB (2012). "Bull's-Eye and Nontarget Skin Lesions of Lyme Disease: An Internet Survey of Identification of Erythema Migrans". Dermatol Res Pract. 2012: 451727. doi:10.1155/2012/451727. PMC 3485866. PMID 23133445.
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[pmid18163139-1] Ejilemele AA, Nwauche CA, Ejele OA (December 2007). "Pattern of abnormal liver enzymes in HIV patients presenting at a Nigerian Tertiary Hospital". Niger Postgrad Med J. 14 (4): 306–9. PMID 18163139.

[pmid1579936-2] Gøransson LG, Omdal R, Husby G (March 1992). "[Adult-onset Still's disease. Diagnosis, differential diagnosis and treatment]". Tidsskr. Nor. Laegeforen. (in Norwegian). 112 (9): 1155–5. PMID 1579936.

[pmid21734024-3] Hatakka A, Klein J, He R, Piper J, Tam E, Walkty A (September 2011). "Acute hepatitis as a manifestation of parvovirus B19 infection". J. Clin. Microbiol. 49 (9): 3422–4. doi:10.1128/JCM.00575-11. PMC 3165617. PMID 21734024.

[pmid25780346-4] Yaguchi D, Marui N, Matsuo M (2015). "Three Adult Cases of HPV-B19 Infection with Concomitant Leukopenia and Low Platelet Counts". Clin Med Insights Case Rep. 8: 19–22. doi:10.4137/CCRep.S18085. PMC 4345940. PMID 25780346.

[pmid11810534-5] Díaz F, Collazos J (March 2000). "Hepatic dysfunction due to parvovirus B19 infection". J. Infect. Chemother. 6 (1): 63–4. doi:10.1007/s101560000023. PMID 11810534.

[urlwatermark.silverchair.com-6] "watermark.silverchair.com" (PDF).

[pmid23355575-7] Shetty RK, Vivek G, Naha K, Bekkam S (January 2013). "Right-sided infective endocarditis presenting with purpuric skin rash and cardiac failure in a patient without fever". BMJ Case Rep. 2013. doi:10.1136/bcr-2012-007841. PMC 3603787. PMID 23355575.

[pmid23133445-8] Aucott JN, Crowder LA, Yedlin V, Kortte KB (2012). "Bull's-Eye and Nontarget Skin Lesions of Lyme Disease: An Internet Survey of Identification of Erythema Migrans". Dermatol Res Pract. 2012: 451727. doi:10.1155/2012/451727. PMC 3485866. PMID 23133445.

[pmid21772606-9] Karaali Z, Baysal B, Poturoglu S, Kendir M (May 2011). "Cutaneous manifestations in brucellosis". Indian J Dermatol. 56 (3): 339–40. doi:10.4103/0019-5154.82505. PMC 3132922. PMID 21772606.

[pmid18843212-10] La Spada E, Micalizzi A, La Spada M, Quartarano P, Nugara G, Soresi M, Affronti M, Montalto G (September 2008). "[Abnormal liver function in brucellosis]". Infez Med (in Italian). 16 (3): 148–53. PMID 18843212.

[pmid17235095-11] French P (January 2007). "Syphilis". BMJ. 334 (7585): 143–7. doi:10.1136/bmj.39085.518148.BE. PMC 1779891. PMID 17235095.

[urlSyphilis:_Review_with_Emphasis_on_Clinical,_Epidemiologic,_and_Some_Biologic_Features-12] "Syphilis: Review with Emphasis on Clinical, Epidemiologic, and Some Biologic Features".

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Familial mediterranean fever differential diagnosis

Differential diagnosis

Inflammatory markers

Autoantibodies

Diagnostic tests

Infections

Neoplasia

Drug hypersensitivity

Miscellaneous

Less common differentials

References

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