Empirical validation of the Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire for suspected Lyme disease

Figures & data

Table 1 Demographic breakdowns of the samples

	Study 1: Lyme patients	Study 2: Healthy	Study 2: Self-identified Lyme	Study 3: Healthy	Study 3: Verified Lyme
Gender (%)
Female	72.8	81.1	84.5	76.9	80.1
Male	27.2	17.9	14.7	22.9	19.9
Others		1.0	0.7	0.1
Mean age (years)	45.26	53.20	50.88	49.35	47.46
N	537	217	782	568	236

Table 2 Study 1 – factor analysis using maximum likelihood estimation and oblique rotation

HMQ item numbers	HMQ symptom checklist items	Neuropathy	Cognitive	Musculoskeletal pain	Fatigue	Dysautonomia	Cardio/respiratory
25	Facial paralysis (Bell’s palsy)	0.456
21	Twitching of the face or other muscles	0.453
24	Tingling, numbness, burning, or stabbing sensations	0.406
30	Tremors	0.391
14	Chest pain or rib soreness	0.354
27	Ears/hearing: buzzing, ringing, and ear pain	0.316
28	Increased motion sickness and vertigo	0.253
1	Unexplained fevers, sweats, chills, or flushing^
31	Confusion, difficulty thinking		−0.894
32	Difficulty with concentration or reading		−0.829
33	Forgetfulness and poor short-term memory		−0.766
34	Disorientation: getting lost and going to wrong places		−0.638
35	Difficulty with speech or writing		−0.634
36	Mood swings, irritability, and depression		−0.350
29	Light-headedness, poor balance, and difficulty walking		−0.327
26	Eyes/vision: double and blurry		−0.234
19	Stiffness of the neck or back			−0.900
23	Neck cracks or neck stiffness			−0.774
18	Joint pain or swelling			−0.397
20	Muscle pain or cramps			−0.335
17	History of a heart murmur or valve prolapse
3	Fatigue and tiredness				0.574
12	Upset stomach				0.489
22	Headaches				0.315
37	Disturbed sleep: too much, too little, and early awakening				0.269
10	Irritable bladder or bladder dysfunction					0.748
11	Sexual dysfunction or loss of libido					0.418
13	Change in bowel function (constipation or diarrhea)					0.351
7	Testicular or pelvic pain					0.311
38	Exaggerated symptoms or worse hangover from alcohol
6	Sore throat						−0.477
5	Swollen glands						−0.394
16	Heart palpitations, pulse skips, and heart block						−0.349
15	Shortness of breath or cough						−0.339
4	Unexplained hair loss						−0.338
8	Unexplained menstrual irregularity						−0.320
2	Unexplained weight change; loss or gain						−0.277
9	Unexplained breast milk production; breast pain

Note:

^ Item failed to load on any factor at the 0.25 level or higher.

Table 3 Study 1 – reliability using Cronbach’s coefficient alpha based on standardized items

HMQ sections and factors	Cronbach’s alpha
Overall HMQ scale	0.75
HMQ Symptom Checklist	0.93
Common Lyme score	0.66
Lyme Incidence	0.55
Neuropathy	0.73
Cognitive	0.87
Musculoskeletal pain	0.80
Fatigue	0.70
Dysautonomia	0.61
Cardio/respiratory	0.72

Abbreviation: HMQ, Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire.

Table 4 Study 2 – bivariate correlationsa

Study 2 measures	1	2	3	4	5	6	7	8	9	10	11	12	13	14
1. Overall HMQ score	1
2. HMQ Symptom Checklist	0.949**	1
3. Common Lyme score	0.800**	0.829**	1
4. Lyme Incidence	0.778**	0.689**	0.529**	1
5. Neuropathy	0.838**	0.896**	0.722**	0.605**	1
6. Cognitive	0.875**	0.918**	0.801**	0.614**	0.790**	1
7. Musculoskeletal pain	0.782**	0.799**	0.711**	0.622**	0.682**	0.672**	1
8. Fatigue	0.831**	0.867**	0.763**	0.611**	0.722**	0.782**	0.688**	1
9. Dysautonomia	0.755**	0.791**	0.603**	0.558**	0.663**	0.671**	0.579**	0.650**	1
10. Cardio/respiratory	0.809**	0.872**	0.676**	0.568**	0.742**	0.735**	0.610**	0.716**	0.654**	1
11. Extraversion	−0.023	−0.013	0.007	−0.039	0.000	−0.024	0.007	−0.025	−0.012	−0.021	1
12. Agreeable	−0.105**	−0.101**	−0.073*	−0.064	−0.105**	−0.103**	−0.039	−0.108**	−0.094**	−0.083*	0.028	1
13. Openness	0.016	0.013	−0.023	−0.025	0.026	−0.018	0.038	0.009	0.024	0.010	0.155**	0.061	1
14. Conscientious	−0.039	−0.044	−0.031	−0.030	−0.020	−0.053	−0.031	−0.048	−0.013	−0.046	0.047	0.078*	0.022	1
15. Neuroticism	0.103**	0.098**	0.028	0.037	0.064	0.110**	0.058	0.118**	0.068*	0.094**	−0.106**	−0.111**	−0.001	−0.109**

Notes:

a Listwise N=913.

* Significant at the 0.05 level (two-tailed).

** Significant at the 0.01 level (two-tailed).

Abbreviation: HMQ, Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire.

Table 5 Study 2 – mean and one-way analysis of variance results for the HMQ

HMQ sections and factors	Healthy		Self-identified Lyme		df1	df2	F	Significance	Eta^2
	M	SD	M	SD
Overall HMQ score	28.50	18.18	88.66	27.52	1	891	844.87	<0.001	0.487
HMQ Symptom Checklist	16.12	11.54	55.60	20.34	1	997	750.162	<0.001	0.429
Lyme Incidence	10.00	8.02	23.57	5.55	1	922	766.77	<0.001	0.454
Common Lyme score	0.25	0.63	2.41	1.56	1	997	393.82	<0.001	0.283
Neuropathy	0.28	0.31	1.24	0.65	1	997	442.70	<0.001	0.307
Cognitive	0.35	0.38	1.64	0.75	1	997	603.00	<0.001	0.377
Musculoskeletal pain	0.89	0.70	2.13	0.78	1	997	449.79	<0.001	0.311
Fatigue	0.86	0.58	2.07	0.64	1	997	635.42	<0.001	0.389
Dysautonomia	0.38	0.47	1.33	0.74	1	997	320.48	<0.001	0.243
Cardio/respiratory	0.27	0.33	1.17	0.63	1	997	410.07	<0.001	0.291

Abbreviation: HMQ, Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire.

Table 6 Study 2 – mean and one-way analysis of variance results for the Big Five personality characteristics

Big 5 personality factor	Healthy		Self-identified Lyme		df1	df2	F	Significance	Eta^2
	M	SD	M	SD
Extraversion	4.41	0.89	4.34	0.97	1	956	0.79	0.375	0.001
Agreeable	4.96	0.97	4.79	0.98	1	959	4.38	0.037	0.005
Openness	4.76	0.87	4.70	0.86	1	952	0.96	0.328	0.001
Conscientious	4.92	0.81	4.81	1.01	1	959	2.00	0.157	0.002
Neuroticism	4.16	1.10	4.28	1.17	1	957	1.65	0.199	0.002

Table 7 Kruskal Wallis Results for the Horowitz MSIDS Questionnaire (HMQ) and the Big Five Personality Characteristics for Study 2 and 3

Study 2	Healthy		Self-Identified Lyme		df	Chi-Square	Significance
HMQ Sections and Factors	Mean Rank	Na	Mean Rank	Na
Overall HMQ Score	123.96	200	540.74	694	1	404.52	<0.001
HMQ Symptom Checklist	144.58	218	599.72	782	1	423.42	<0.001
Lyme Incidence	176.86	205	544.47	720	1	302.82	<0.001
Common Lyme Score	196.49	218	585.25	782	1	301.71	<0.001
Neuropathy	174.50	218	591.38	782	1	356.54	<0.001
Cognitive	161.06	218	595.13	782	1	385.93	<0.001
Musculo- skeletal Pain	211.08	218	581.18	782	1	282.92	<0.001
Fatigue	180.50	218	589.71	782	1	345.31	<0.001
Dysautonomia	220.88	218	578.45	782	1	263.78	<0.001
Cardio/Respiratory	181.06	218	589.55	782	1	342.52	<0.001
Extraversion	492.99	204	476.49	755	1	0.58	0.448
Agreeableness	519.10	206	471.25	756	1	4.86	0.027
Openness	497.36	206	472.68	749	1	1.32	0.250
Conscientious	491.87	204	478.71	758	1	0.37	0.545
Neuroticism	455.74	204	487.18	756	1	2.08	0.149

Study 3	Healthy		Verified Lyme		df	Chi-Square	Significance
HMQ Sections and Factors	Mean Rank	Na	Mean Rank	Na
Overall HMQ Score	265.32	499	574.08	219	1	337.42	<0.001
HMQ Symptom Checklist	317.10	568	607.22	235	1	260.24	<0.001
Lyme Incidence	276.63	527	615.44	233	1	387.14	<0.001
Common Lyme Score	339.73	568	553.58	236	1	253.76	<0.001
Neuropathy	333.86	568	567.70	236	1	175.36	<0.001
Cognitive	323.57	568	592.47	236	1	227.54	<0.001
Musculo- skeletal Pain	326.82	568	584.65	236	1	208.58	<0.001
Fatigue	332.33	568	571.39	236	1	179.64	<0.001
Dysautonomia	362.77	568	496.81	235	1	58.18	<0.001
Cardio/Respiratory	344.22	568	542.77	236	1	125.89	<0.001

Note:

a N’s vary due to missing data.

Abbreviation: HMQ, Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire.

Table 8 Study 2 – discriminant analysis results

Test of function(s)	Wilks’ lambda	Chi square	df	Significance	Percent correctly classified by discriminant analysis
					Overall	Healthy	Self-identified Lyme
Overall HMQ score	0.513	593.89	1	<0.001	89.1	91.5	88.5
HMQ sections	0.458	693.43	4	<0.001	89.5	84.4	90.9
HMQ factors	0.547	599.12	6	<0.001	85.6	89.9	84.4
Big Five	0.992	7.73	5	0.171	51.7	52.8	51.4

Abbreviation: HMQ, Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire.

Table 9 Study 3–Means and One-Way Analysis of Variance Results for the Horowitz MSIDS Questionnaire

HMQ Sections and Factors	Healthy		Verified Lyme		df1	df2	F	Significance	Eta^2
	M	SD	M	SD
Overall HMQ Score	20.91	14.75	62.14	24.61	1	716	770.82	<0.001	0.52
HMQ Symptom Checklist	13.95	11.19	35.20	17.80	1	801	414.24	<0.001	0.34
Common Lyme Score	0.13	0.46	1.28	1.41	1	802	301.36	<0.001	0.27
LYME Incidence Score	4.50	4.43	20.39	7.84	1	758	1259.68	<0.001	0.62
Neuropathy	0.24	0.30	0.74	0.58	1	802	261.04	<0.001	0.25
Cognitive	0.33	0.36	1.06	0.69	1	802	387.06	<0.001	0.33
Musculoskeletal Pain	0.64	0.56	1.52	0.78	1	802	318.92	<0.001	0.29
Fatigue	0.79	0.49	1.50	0.68	1	802	274.60	<0.001	0.26
Dysautonomia	0.37	0.40	0.73	0.65	1	801	91.38	<0.001	0.10
Cardio/Respiratory	0.26	0.31	0.62	0.48	1	802	161.69	<0.001	0.17

Abbreviation: HMQ, Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire

Table 10 Study 3–Discriminant Analysis Results

HMQ Component	Wilks’ Lambda	Chi-square	df	Significance	Percent Correctly Classified by Discriminant Analysis
					Overall	Healthy	Verified Lyme
Overall HMQ Score	0.48	522.83	1	<0.001	87.6	90.2	81.7
HMQ Sections	0.34	772.57	4	<0.001	91.2	93.8	85.4
HMQ Factors	0.62	382.73	6	<0.001	81.9	86.4	71.1

Abbreviation: HMQ, Horowitz Multiple Systemic Infectious Disease Syndrome Questionnaire.

Figure 1 Migratory symptoms and prediction of healthy vs Lyme status for Studies 2 and 3.

Table 11 MSIDS differential diagnosis of migratory pain

Clinical characteristicsa	Laboratory/clinical evaluation
Crohn’s disease/IBD^Citation65,Citation96^–^Citation98
Abdominal pain and tenderness (often right lower quadrant), chronic diarrhea, usually with rectal bleeding, fever, loss of appetite, weight loss with malabsorption Extraintestinal manifestations can include: Dermatologic: EN, PG, apthous stomatitis, fistulas Ocular^*: conjunctivitis, uveitis/iritis, episcleritis with ocular pain, photophobia, blurry vision Hepatobiliary: hepatomegaly^*, hepatic steatosis/NASH, gallstones, pancreatitis, PSC Cardiopulmonary: endocarditis^*, myocarditis^*, pericarditis^*, vasculitis^*, thrombosis (hypercoagulability), interstitial lung disease Renal: amyloidosis, calculi, ureteral obstruction with renal failure Rheumatologic: arthritis develops in 15–20% of IBD and worsens with active bowel inflammation. Usually involves large joints, and is asymmetric. Ankylosing spondylitis, sacroiliitis, hypertrophic osteoarthropathy, and relapsing polychondritis can be associated	Stool samples for blood and/or infectious microbes CBC, CMP with liver functions, homocysteine, coagulation profile, HLA-B27, pANCA Imaging studies: CT scans, barium swallow, video capsule endoscopy, colonoscopy Abdominal ultrasound ERCP or MRCP if jaundice (PSC)
Gonococcal arthritis^Citation65,Citation99^–^Citation101
Bacteremic DGI can have presenting complaints of migratory arthralgias, but symptoms are usually accompanied by papules evolving into hemorrhagic pustules, and/or hemorrhagic bullae near joints (75% of the time). The triad of suppurative arthritis, tenosynovitis and dermatitis helps identify DGI. Polyarthralgias usually involve knees, wrists, elbows, ankles, and distal joints. Rarely osteomyelitis is present Extrarheumatic manifestations include: Genitourinary: mucopurulent cervicitis (women), urethritis with urethral discharge and dysuria (men); rare: epididymitis, prostatitis, vesiculitis, balanitis, fistulas Gastrointestinal: purulent rectal discharge, proctitis with pain, bleeding Dermatologic: nodules, EN, urticaria Pharyngitis^* with cervical lymphadenitis^* Ocular: conjunctivitis^*, purulent discharge, corneal ulcerations/ophthalmia neonatorum (complications in neonates during parturition) Cardiac: endocarditis^* (rare) Neurologic: meningitis^* (rare)	Culture (urogenital specimens, synovial fluid), urethral swabs with gram stain, NAATs, DNA probes Blood cultures/screen for complement deficiency with total hemolytic complement activity if DGI
Hepatitis (A, B, C, D, E)^Citation65,Citation102^–^Citation106
All types of hepatitis viruses cause clinically similar illnesses. Symptoms range from being asymptomatic, to fulminant acute infections with hepatic necrosis. Blood-borne types (HBV, HCV, HDV) can cause subclinical persistent infections or rapidly progress to chronic liver disease with cirrhosis and hepatocellular carcinoma Liver manifestations: hepatomegaly with right upper quadrant pain, occasional splenomegaly; abnormalities in liver function testing, with jaundice (Tick-borne co-infections, such as relapsing fever borrelia, ehrlichiosis, anaplasmosis, rickettsial infections, tick-borne viruses and babesiosis can also cause similar liver abnormalities) Cirrhosis can present with ascites, peripheral edema, esophageal bleeding and hepatic encephalopathy. Palmar erythema, gynecomastia and spider angiomas suggest chronic liver disease Extrahepatic manifestations (associated with circulating immune complexes) can lead to: Prodromal serum sickness: anorexia, nausea, vomiting (rarely associated with pancreatitis), mild weight loss, fatigue, fever, arthralgias, myalgias, headache, photophobia, cough, coryza, pharyngitis with alterations in taste and olfaction Kidney: glomerulonephritis, nephrotic syndrome, dark urine (and clay colored stools) before onset of jaundice Cardiovascular: vasculitis (polyarteritis nodosa), palpable purpura, rarely myocarditis^*, pneumonia Other neuro: peripheral neuropathy^* (rare) Arthritis: can be associated with EMC but is not a prominent feature of the overall clinical picture	IgM (acute), IgG (chronic) antibodies, Ags: HAV (anti-HaV) Anti-HBs, HBsAg, HBV DNA Anti-HBc, HBcAg Anti-HBe, HBeAg Anti-HCV, HCV RNA Anti-HDV, HDV Ag Anti-HEV, HEV Ag Liver function testing: elevations in AST, ALT, serum bilirubin. Serum alkaline phosphatase may be normal or slightly elevated CBC may show a transient neutropenia, and lymphopenia, followed by lymphocytosis with atypical lymphocytes. PT: may be prolonged and follow alpha-1-antitrypsin levels (hepatocellular carcinoma) Autoantibodies (ANA, RF, smooth muscle) are possible (acute) Urine: microscopic hematuria, slight proteinuria (unless nephrotic syndrome)
Lyme disease^Citation32,Citation43,Citation49,Citation67,Citation68,Citation86,Citation93,Citation107^–^Citation116
Multisystemic symptoms often tend to come and go, with good and bad days, intensified by hormonal changes (menses) and/or antibiotic use (improvement in symptoms or worsening secondary to Herxheimer reactions) Rashes: EM rashes are present approximately 50% of the time (USA), with higher incidences reported in Europe. Not all rashes resemble a “bull’s eye” pattern; a solid spreading rash is also possible; other Borrelia species (Borrelia mayonii) can cause a wide-spread spotted rash. Borrelia afzelii causes ACA, a violaceous skin rash of the extremities, more often seen in Europe. Morgellon’s disease or “fiber” disease with open wounds and multisystemic symptoms has also been associated with Borrelia infection General: fatigue, flu-like symptoms, pharyngitis with cervical lymphadenopathy Rheumatologic: migratory joint and muscle pain are commonly seen in both early and late Lyme disease. The migratory pain can be either symmetric or asymmetric, affecting large and small joints. Direct signs of inflammation (heat, tenderness to palpation), can be present, as can swelling of the joints (synovitis with synovial effusions), but these signs are not necessarily seen in all patients with multisystemic complaints. The pain may migrate over hours or days, in both acute and late stage disease. Nonmigratory pain can also be present, as in the case of acute monoarticular arthritis (oftentimes affecting the knee post tick-bite in children ≤18 years of age). Cardiopulmonary: chest pain (usually caused by costochondritis), palpitations, and shortness of breath are commonly reported (rule out babesiosis, relapsing fever, cardiomyopathy). Carditis with third degree heart block, myocarditis, endocarditis and pericarditis are rare complications. Neurologic: nerve pain (neuropathy) which frequently has a migratory component is a common manifestation of both PNS and CNS borreliosis. Symptoms are usually described as burning, tingling, stabbing, crawling sensations and/or numbness (occasionally associated with small fiber neuropathy). The quality of the pain often changes with antibiotic treatment (improvement, or worsening with a Herxheimer reaction). Mononeuropathies (mononeuropathy multiplex), polyneuropathies, radiculitis, radiculoneuritis with pain, loss of motor control, and sensory deficits are often associated with PNS involvement. CNS involvement may cause a lymphocytic meningitis, encephalitis, myelitis and vasculitis. Common neurologic symptoms include a stiff neck, headache, light and sound sensitivity, dizziness, cognitive difficulties (memory and concentration problems, word finding problems with difficulty in executive functioning), and sleep disruption (DSPS with difficulty falling asleep and staying asleep). Cranial nerve palsies oftentimes involve the 2nd (optic neuritis), 5th (trigeminal) and 7th cranial nerve (Bell’s palsy), but all cranial nerves can be affected. Bannwarth syndrome is a triad of radiculitis, Bell’s palsy and meningitis, associated with neuroborreliosis (Borrelia garinii [Europe] and Borrelia burgdorferi [USA]). Neuropathy of the ANS can cause dysautonomia/POTS, affecting the blood pressure (postural orthostasis with dizziness standing), heart rate (tachycardia), sweat glands (anhidrosis, hyperhidrosis), and bladder and bowel dysfunction (difficulty urinating, gastroparesis, chronic constipation). Antiganglioside antibodies may be present. Rare neurological complications may include an ALS type picture with a polyradiculopathy. Psychiatric: a broad range of psychological manifestations (depression, anxiety, OCD, rarely psychosis) have been reported. Ophthalmologic: conjunctivitis, uveitis, retinitis, or optic neuritis Genitourinary/GYN: detrusor dysfunction, interstitial cystitis, vaginal neuralgia, dyspareunia Gastrointestinal: nausea, vomiting, abdominal pain, anorexia, rare diarrhea (early Lyme disease) Hepatic: hepatosplenomegaly, transaminitis (early disease; rarely in late disease). Differential diagnosis for GI symptoms and transaminitis includes overlapping tick-borne diseases, including: anaplasmosis, ehrlichiosis, relapsing fever bacteria (Borrelia hermsii, Borrelia miyamotoi), rickettsial infections (Rocky Mountain spotted fever, Q fever [Coxiella burnetii], Tick-borne viruses (Heartland, Bourbon viruses), and babesiosis. Other Borrelia species like B. hermsii can cause nausea, vomiting, abdominal pain, hepatitis, jaundice, and an enlarged spleen	Use a panel approach with indirect and direct tests to confirm a clinical diagnosis: Indirect tests: – ELISA – C6 ELISA (preferred in European patients and US patients, as it includes B. afzelii, B. garinii, and B. burgdorferi). – IFA – IgM and IgG Western blots (pay attention to Borrelia specific bands: 23 [OspC], 31 [OspA], 34 [OspB], 39, 83/93). These can be present with different Borrelia species. – ELISpot, Lymphocyte Transformation Test (LTT) – Spirotest (CXCL9, CXCL10, CCL19) Direct tests: Nanotrap (urine Ag testing with OspA) PCR Culture Other testing: other Borrelia species (including relapsing fever, B. miyamotoi) can cause Lyme-like syndromes. Check antibodies, PCR Check coinfection testing if there is a malaria-like illness (Babesia spp.), atypical skin rashes resembling “stretch marks” (Bartonella spp.), and/or severe atypical clinical manifestations (rule out rickettsia, Q-fever, tularemia) Tick-borne viruses should be checked if severe neurological manifestations are present (TBE virus [Europe], Deer tick virus, and Powassan [USA]) Autoantibodies are frequently present in Lyme borreliosis, including positive ANAs, and RFs which are surrogate markers of inflammation. These titers oftentimes decrease or resolve with appropriate antibiotic treatment. Check an anti-dsDNA and anti-Sm (positive in SLE) and anti- CCP (anticyclic citrullinated peptide, positive in rheumatoid arthritis) to rule out true SLE and rheumatoid arthritis in a patient with a multisystemic disorder and migratory pain with autoantibody production. Patients with autoimmune diseases may also be exposed to Lyme disease and tick-borne co-infections, so it is necessary to rule out overlapping pathologies. Check antiganglioside antibodies if neuropathic syndromes/dysautonomia is present.
ReA^Citation65,Citation117
Acute, nonpurulent arthritis usually following an enteric infection (Salmonella, Shigella, Yersinia, Camplylobacter spp., as well as Clostridium difficile) or urogenital infection (Chlamydia trachomatis and other species including Ureaplasma urealyticum and Mycoplasma genitalium). Occasionally respiratory infection with Chlamydia pneumoniae is implicated Often associated with HLA-B27, which significantly prolongs the survival of intracellular bacteria. Symptoms often occur 1–4 weeks after the infection. Triad of arthritis, urethritis, and conjunctivitis is one part of the clinical spectrum, which ranges from a transient monoarthritis to severe multisystem disease with fatigue, fever and weight loss. Arthritis is usually painful, asymmetric, and additive. New joint involvement can occur over several days to weeks and typically lasts 3–5 months (rarely up to one year). Dactylitis (sausage digit), with diffuse swelling of a finger or toe is a classic manifestation, with tense joint effusions. Tendonitis and fasciitis often produce pain at insertion sites (entheses). Low back pain is also often seen, with or without a sacroiliitis Urogential involvement: urethritis, prostatitis, cervicitis, salpingitis Ocular: transient conjunctivitis, anterior uveitis Dermatologic: mucocutaneous lesions are common, including oral ulcers; characteristic skin lesion is keratoderma blenorrhagica, with vesicles on the palms and soles (most common sites). Nail changes are common (hyperkeratosis, yellowish discoloration, onycholysis). Cardiopulmonary: aortic insufficiency, conduction defect, pleuropulmonary infiltrates (rare) Neurologic: CNS and/or PNS lesions (rare)	HLA-B27 Serological testing for triggering infections: check antibodies against Yersinia, Salmonella, Chlamydia, etc., with culture (Yersinia, Chlamydia), and PCR Check inflammatory markers (ESR, CRP), and a CBC for anemia X-ray: periostitis with reactive new bone formation is characteristic of ankylosing spondylitis Blood tests and X-rays only help to confirm a clinical diagnosis in an individual with an acute inflammatory, asymmetric, additive arthritis or tendinitis, with extraarticular involvement (eyes, mucous membranes, skin, nails, genitalia)
ARF^Citation65,Citation118^–^Citation120
Symptoms appear 1–5 weeks after a group A strep infection. Involves major and minor manifestations. Major manifestations: polyarthritis^*, carditis^*, chorea, erythema marginatum, subcutaneous nodules. Minor manifestations: fever^* and polyarthralgia^*, inflammatory markers (elevated sedimentation rate, white cell count), and a prolonged PR interval on the electrocardiogram Most common presentation is fever and an inflammatory polyarthritis. Large joints are typically affected (hips, knees, ankles, elbows) in a migratory, asymmetric fashion (60–75% cases). Migratory pain is over a period of several hours Cardiac: carditis is the next most common clinical feature, seen in 50–60% of cases. Chronic valvular lesions of rheumatic heart disease usually involve the mitral valve (mitral stenosis) or mixed mitral valve disease and/or aortic valve disease Neurologic: Sydenham’s chorea (<2–30% cases), can occur without other clinical signs and symptoms. Usually resolves within 6 weeks. Dermatologic: erythema marginatum and subcutaneous nodules are rare (<5% cases). Erythema marginatum is the classic rash of ARF. It consists of pink macules which clear in the center, leaving a serpiginous edge. They can be differentiated from the classic rash of Lyme disease (EM) as they quickly appear and disappear. ^*Polyarthritis and carditis are seen in Lyme disease, but the arthritic pain in Lyme disease affects large and small joints and can be symmetric or asymmetric, migrating over hours and days. Lyme carditis is a rare manifestation.	Diagnosis is made based on the constellation of clinical symptoms after a group A strep infection. Throat swab culture or rapid Ag testing may be negative, so serologic testing with an ASO and ADB titers should also be performed Jones criteria are used to aid in the diagnosis. Two major or one major and two minor manifestations plus evidence of a preceding group A streptococcal infection are necessary to establish the diagnosis for the primary episode of ARF. Testing should also include a white blood cell count, ESR, CRP, and blood cultures if febrile Electrocardiogram, echocardiogram, and chest X-ray if clinical suspicion of carditis Differential diagnosis includes PSRA, which affects small joints, often symmetrically, without carditis, and PANDAS, causing tics and obsessive–compulsive symptoms.
SLE^Citation65,Citation121^–^Citation124
Diagnosis is made based on both clinical symptoms and laboratory evidence of autoantibodies. A combination of >4 of the 11 criteria listed below increases the likelihood of SLE (~95% specificity, ~75% sensitivity): Malar rash (butterfly appearance)^* Discoid rash (circular raised patches with keratosis and/or scarring) Photosensitivity: exposure to ultraviolet light causes a rash Nasopharyngeal ulcers Arthritis: in ≥2 peripheral joints, which is nonerosive. Tenderness and swelling with or without an effusion is required^* Serositis: pleuritis (with or without pleural effusion), or pericarditis (documented by a rub on auscultation, or an electrocardiogram or echocardiogram)^* Hematological abnormalities: anemia (hemolytic), leukopenia (<4000/mL) or lymphopenia (<1500/mL) or thrombocytopenia (<100,000/mL)^* Renal: proteinuria (>0.5 g/day) or casts Neurological: seizures, psychosis (without other causes)^* Immunological disorder: anti-dsDNA, anti-Sm; and/or antiphospholipid antibodies^* ANAs (not drug induced)^* Symptoms can be mild or severe, with intermittent exacerbations. The most common symptoms of SLE include: Fatigue^* and arthralgias/myalgias^* (usually present most of the time) Fever^* Headaches^* Hair loss^* Malar shaped rash^* Photosensitivity Intermittent polyarthritis (mild to severe) usually in hands, wrists, and knees^* Pleurisy Anemia Edema (extremities, periorbital) renal disease and nephrotic syndrome Abnormal blood clotting (antiphospholipid syndrome) Mouth or nose ulcers Raynaud’s phenomenon (Starred symptoms and/or laboratory testing [^*] are nonspecific and can be seen with Lyme disease, which is often associated with autoantibody production). Oral ulcers, pleurisy, malar rashes, abnormal blood clotting, renal disease, and edema are not usually associated with Lyme disease. Overlapping syndromes: seizures and psychosis can be seen with Lyme disease, but are rare clinical manifestations. Anemia and photosensitivity if present in Lyme disease are usually due to medication side effects. Tick-borne coinfections such B. miyamotoi, ehrlichiosis, anaplasmosis, rickettsial infections, and babesiosis can cause leukopenia and thrombocytopenia and should be included in the differential diagnosis if hematological abnormalities are present.	High titers of double stranded DNA (Anti-dsDNA) and Sm Ag (anti-Sm) are highly specific for SLE and should be used to confirm a clinical diagnosis Other autoantibodies are oftentimes present, but are not specific for SLE: ANA^* Anti-RNP^* Antihistone antibodies Antiphospholipid antibodies^* Anti-Ro (anti-SS-A)^* Anti-La (anti-SS-B)^* Antierythrocyte antibodies (direct Coombs test) Antineuronal antibodies (antiglutamate receptor)^* Antiribosomal P Initial laboratory evaluation: CBC, platelets CMP with renal function Urinalysis ANA, ds-DNA, anti-Sm Anti-Ro Use ds-DNA and anti-Sm to help differentiate the two diseases since both SLE and Lyme disease can result in positive ANAs, antiphospholipid antibodies and other autoimmune markers Migratory symptoms (arthritis, myalgias, and/or neuropathy) associated with a broad range of abnormalities of the PNS and CNS (refer to neurological Lyme disease symptoms) are more commonly seen in Lyme disease than in SLE. Migratory neuropathy (tingling, numbness, burning, stabbing sensations) is a prominent symptom of Lyme disease, not usually present in other illnesses.

Notes:

a These clinical characteristics represent common disease manifestations, not a full comprehensive list.

Abbreviations: ACA, acrodermatitis chronicum atrophicans; ADB, anti-DNase B; Ag, antigens; ALS, amyotrophic lateral sclerosis; ALT, alanine transaminase; ANAs, antinuclear antibodies; ANS, autonomic nervous system; ARF, acute rheumatic fever; ASO, antistreptolysin O; AST, aspartate transaminase; CBC, complete blood count; CMP, comprehensive metabolic profile; CNS, central nervous system; CRP, C-reactive protein; DGI, disseminated gonococcal infection; DSPS, delayed sleep phase syndrome; EM, erythema migrans; EMC, essential mixed cryoglobulinemia; EN, erythema nodosum; ERCP, endoscopic retrograde cholangiopancreatography; ESR, erythrocyte sedimentation rate; GI, gastrointestinal; GYN, gynecologic; HAV, hepatitis A; HBV, hepatitis B; HCV, hepatitis C; HDV, hepatitis D; HEV, hepatitis E; HLA-B27, human leukocyte antigen-B27; IBD, inflammatory bowel disease; IFA, immunofluorescent antibodies; MRCP, magnetic resonance cholangiopancreatography; MSIDS, Multiple Systemic Infectious Disease Syndrome; NAATs, nucleic acid amplification tests; NASH, nonalcoholic steatohepatitis; OCD, Obsessive-Compulsive Disorder; pANCA, perinuclear antineutrophil cytoplasmic antibodies; PANDAS, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection; PCR, polymerase chain reaction; PG, pyoderma gangrenosum; PNS, peripheral nervous system; POTS, postural orthostatic tachycardia syndrome; PSC, primary sclerosing cholangitis; PSRA, poststreptococcal reactive arthritis; PT, prothrombin time; ReA, reactive arthritis; RFs, rheumatoid factors; RNP, ribonucleoprotein; SLE, systemic lupus erythematosus; SS-A, Sjögren’s syndrome-related antigen A; SS-B, Sjögren’s syndrome-related antigen B; TBE, tick-borne encephalitis.

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