Rheumatology‎ > ‎

Overlap Syndrome/MCTD/UCTD

Pearls for 
Early Arhthritis 
  • During a 9-month follow-up period, RA developed in more than half (57%) of the ACPA+ arthralgia patients according to the 2010 American College of Rheumatology/European League against Rheumatism (ACR/EULAR) classification criteriaImportantly, the magnitude of subclinical inflammation detected by MRI did not accurately predict those at risk for imminent RA; rather, the best predictors of progression included a greater number of joints involved and seropositivity for ACPA and/or RF KF 1168 
  • Patience, Humility and Close observation are the keys 
    • Do not overtreat - you may be treating patients who does not have disease thinking it is working, or going up on the treatment ladder with no response to treatment despite lack of clear diagnosis 
    • Ask for help with folks with experience 
    • Treat if it affects the quality of life - carpenter, hairdresser with an understanding if there is no improvement, we will likely cut back and we are treating as a suspect - if treating looking for treatment response to 1/3rd in 3 months might be a good way to assess success (Janet Pope Podcast) - HCQ might be the one to use for treatment 
    • Clear/honest documentation will be of help: 
      • RA suspect, RF-, ACPA positive, family hx positive 
      • Lupus suspect, ANA positive, hx of pericarditis 15 yrs back etc. 
  1. About 25% of patients presenting with features of a rheumatologic disease do not fulfill the criteria for a defined disorder.

  2. About 25% of patients with undifferentiated connective tissue disease (UCTD) evolve into a more specific diagnosis over time.

These parameters are to be used in patients with arthralgia without clinical arthritis and without other diagnosis or other explanation for the arthralgia.

History taking:

  • ▸  Joint symptoms of recent onset (duration <1 year)

  • ▸  Symptoms located in MCP joints

  • ▸  Duration of morning stiffness 60 min

  • ▸  Most severe symptoms present in the early morning

  • ▸  Presence of a first-degree relative with RA

    Physical examination:

Clinical Course
Over a 10-year period, 58% of patients are still classified as MCTD. The remaining patients evolve into SSc (17%), SLE (9%), or RA (2.5%) - this is based on Cappeli et al 

Overlap syndromes 
most common disease is Sjogren syndrome 
SjS is the most common disease in overlap syndrome and is seen with 
primary biliary cholangitis (PBC), 
necrotizing vasculitis, 
autoimmune thyroiditis, 
chronic active hepatitis, 
mixed cryoglobulinemia, and 
hypergammaglobulinemic purpura.

Other Overlap syndromes are 

SSc can be associated with myositis. One specific overlap is characterized by antibody to PM-Scl, a complex of 16 polypeptides located at the site of ribosomal assembly in the nucleolus (hence patients with PM-Scl antibody commonly have a nucleolar pattern ANA on immunofluorescent antibody assay).

Limited SSc can be associated with PBC. Limited SSc precedes PBC by an average of 14 years. Antimitochrondrial antibody can be seen in 18% to 27% of limited SSc patients. Many also have SS

RA + SLE (Rupus)

SLE and IM

SSc + ANCA vasculitis 

Myositis overlap syndrome 

RA with SSc, SLE, SS, MCTD 

PRaSySH : the common diseases of MCTD 
  • Polymyositis
  • Raynauds 
  • Systemic Sclerosis 
  • SLE
  • High titer of anti-U1-ribonucleoprotein (RNP) antibodies - High Titer SPECKLED ANA (for RNP)
    • SLE patients can have anti-U1 RNP ab. This does not mean it is an MCTD by default
    • In contrast to SSc, MCTD often responds to glucocorticoids, and the long-term prognosis is better than that of SSc. Whether MCTD is truly a distinct entity or is a subset of SLE or SSc, remains controversial
  • While PAH is the most feared complication, it is often asymptomatic. 

RAESEP is the most common clinical features 
Arthritis / Arthralgia  
Edema of Hands  
Esophagus dysmotility 
Pulmonary involvement 

Clinical Features
  • Similar to each component of diseases
    • Based on PRaSySH - criteria included in SHARP, KASUKAWA or ALARCON-SEGOVIA et al include 
    • SHARP 
      • Major Criteria for SHARP
        • 1. Myositis for P
        • 2. Raynaud's for SSc 
        • 3. Synovitis and Edema of hands for SSc   
        • 4. ILD for P or RA or S or S
        • 5. High Titer anti-U1 RNP 
      • Minor criteria resemble SLE 11 clinical criteria for the most part 
      • Common clinical: Raynaud's and Swollen hand and fingers , and then they have MIXED symptoms 
    • ALARCON-SEVOGVIA - Cliinical criteria include the 5 major of SHARP ; Sensitivity and specificity of 63 % and 86% 
    • In addition, there is a KHAN criteria. Last two are supposed to be the best (Ref: Uptodate)
  • Arthritis is usually non-erosive however, RA like erosive arthritis can occur

Ref: UpToDatea
5 major diffuse connective tissue exists - SLE, RA, DM, PM, SSc, Sixth is Sjogren syndrome often mixed with these or can be primary 

Prominent early symptoms are puffy fingers, easy fatigability, poorly defined myalgias, arthralgias, and raynaud phenomenon. The common diagnostic considerations at this juncture are usually rheumatoid arthritis (RA), SLE, SSc or UCTD. 

If the patient has swollen hands and/or puffy fingers associated with a high titer speckled antinuclear antibody (ANA), they should be carefully followed for the evolution of overlap features. A high titer of anti-RNP antibodies in such a patient is a powerful predictor of a later evolution to MCTD. 

Other, less common, early features include severe inflammatory myopathy, acute arthritis, aseptic meningitis, transverse myelitis, digital gangrene, high fever, acute abdomen and trigeminal neuropathy, and sensorineural hearing loss.

The major reason for considering MCTD a distinct clinical entity is a frequent observation that high titers of anti-U1 RNP antibodies are associated with several distinctive clinical characteristics. 

Patients with U1 RNP antibodies seldom, i.e., RARELY, develop diffuse proliferative glomerulonephritis, psychosis, or seizures; these abnormalities are a major source of morbidity and mortality in SLE.

Patients with U1 RNP antibodies nearly always have an early development of the Raynaud phenomenon and a nail fold capillary pattern that is the same as in SSc but that is different from classical SLE. The Raynaud phenomenon only occurs in about 25 percent of patients with classical SLE.

Patients with U1 RNP antibodies are more likely to develop pulmonary hypertension than patients with classical SLE or SSc. Pulmonary hypertension is the major cause of death in MCTD.

Patients with U1 RNP antibodies are more likely than SLE patients to test positively for rheumatoid factor or antibodies to a cyclic citrullinated peptide (anti-CCP), and they are also more likely to develop erosive arthritis.

Patients with a preponderance of immunoglobulin M (IgM) anti-U1 small nuclear ribonucleoprotein (snRNP) antibodies are more likely to have SLE. One study has reported that a combined IgM reactivity for fragments of U1C and U1A of U1 RNP is capable of classifying SLE and MCTD patients with an accuracy of 71.3 percent

There are several hierarchies of antibody response in patients who eventually develop MCTD, with each higher level being associated with an increased expression of the MCTD clinical profile:

Level 1 – Positive ANA

Level 2 – High titer, speckled ANA pattern

Level 3 – Anti-U1 RNP antibodies

Level 4 – Anti-68 kD and A' antibodies 

U1 RNP consists of ribonucleic acid (RNA) plus three proteins (A', C, and a 68-70 kD protein). The clinical picture of MCTD most closely correlates with the presence of IgG antibodies to the 68 to 70 kD and A' proteins

Ref for above: UpToDate

Instead of the above pneumonic, alternatively use the clinical features from the SHART or ALARCON-SEGOVIA et al. as that is more clinically meaningful 

Clinical Course
Over a 10-year period, 58% of patients are still classified as MCTD. The remaining patients evolve into SSc (17%), SLE (9%), or RA (2.5%) - this is based on Cappeli et al 

  • Serositis / Synovitis or Arthritis: NSAIDS or < 20 mg Prednisone (MCTD is very well responsive to GCs) or HCQ - occasionally, MTX
  • Inflammatory myositis: high dose GC 60 mg , sometimes MTX / AZA  
  • Some evidence suggests that PAH secondary to MCTD or SLE (but not SSc) may benefit from immunosuppressive medication such as cyclophosphamide (controversial given limited data, and should not replace standard therapy for PAH)
  • ILD / PAH - AZA or MMF or CYC 
    • MMF : 
    • Inhibits denevo synthesis of GMP 
    • Cytokine production is not affected. MPA also inhibits carbohydrate (fucose, mannose) transfer to glycoproteins, resulting in less production of adhesion molecules (VLA-4, ICAM-1). In summary, MPA inhibits lymphocyte proliferation and migration. It also has an antifibrotic activity - hence often used in ILDs 
    • The enterohepatic recycling of glucuronide-conjugated MPA contributes to GI toxicity since GI mucosal cells are 50% dependent upon de novo synthesis pathway of purines, which is inhibited by MPA


  • Four important questions to answer are: 
    • Articular vs Extra-articular 
    • Acute vs. Chronic
    • Inflammatory arthritis vs. Non-inflammatory arthritis
      • History: Morning stiffness and Constitutional Symptoms
      • Physical Exam: Soft-tissue swelling, erythema, warmth, synovitis vs bony enlargement 
      • Lab: ESR, CRP, Anemia of Chronic Disease, Albumin 
      • Imaging Study: Symmetrical Joint-space narrowing, periarticular osteopenia, erosions vs asymmetric joint-space narrowing, osteophytes, sub-chondral sclerosis ; USG doppler, MRI 
      • Synovial Fluid: Total WBC, Neutrophil % 
    • Number of joints / Symmetry 
  • Migratory Polyarthritis 

    • VAI-PCR from the Table 2 below

    • V: Vasculitides 
    • AI: SLE, RF
    • Infection
    • Palindromic RF
    • Crystal induced arthropathy
    • Reactive
      • Post-infectious: or Reactive Strep, Chalymadia, Shigella, Salmonella, Campylobacter, Yersinia (Diarrhea, Pyrangitis, Bronchitis, Urethritis / UTI
    • C: Crystal Induced arthritis 

    • Others 
    • S: Spondyloarthropathies (PsA)
    • Paraneoplastic syndromes 
    • Malignancies 
  • Uptodate has a good algorithm for UCTD Uptodate UCTD 

Table 2

Differential Diagnosis of Migratory Polyarthritis

Palindromic rheumatoid arthritis
Crystal induced arthropathy
Reactive arthritis
Autoimmune disease (e.g., SLE, rheumatic fever)
Infectious polyarthritis (e.g., Lyme disease, chlamydia)

            Ref: doi: 10.1007/s11606-008-0794-7

  • Fever and Joint Pain
    • Infectious cause 
      • Joint Infection
      • Lyme disease 
      • Reactive and Viral Arthritis 
      • Whipple's disease 
    • Non-infectious cause 
      • Systemic JIA or AOSD if it was older patient
      • IBD 

Additional Pearls 

CPPD is slightly more subacute in presentation..
When you wake up, muscles that have relaxed goes into spasm, and this causes pain in morning. 

Spinal Stenosis
Pain remains in stopping and standing. Improves on sitting, and bending as spinal space is increased. Going upstair is better, but pain worse in going downstairs. 
Vascular Claudication
Gets better at rest even while standing.

Some arthritis do not have swelling. Like Viral arthritis, SLE. 

Distal muscle myopathy: Only IBM. All including metabolic myopathy, causes proximal weakness

Inflammatory eye disease: Seronegative arthritis. 
Elbow: Tophi,and Rheumatic Nodule .Some time wegners present with nodule. 
Fever in Rheumatology: AOSD, SLE

Raynauds: Most important is to have pallor. Cyanosis is common, but if pallor is present, it is very suggestive.
Hair Loss: Lupus. 
Rash: Lupus - Interdigital (between the rash); Dermatomyositis: Over the joint. 

Where to look for psoriasis
    Scalp, Peri-umblical area, Gluteal / Natal cleft, palms, sole, nail changes, knee externsor surface
 Lupus Peringo: around nose or ear (Sarcoidosis)

Circinate balanitis: Reactive arthritis 
Keratoderma Blenorrhegicum: Reactive arthritits. 
Pyoderma gangrenous: IBD , Scar: Paper thin scar due to loss of subcutaneous bed 

Zagged boarders: Common in cryoglobinemic vasculitits. 
Nailfold Infarct: Rheumatoid Vasculitits. 

  • Anterior uveitits (anterior to lens)
    • Red eye, pain, blurry vision
    • Causes:
  • Posterior uveitits 
    • Non-red, painless, but blurry vision
    • Causes: 
Scleritits: Red, Painful, Affects vision
Epi-scleritis: Red, usually not much pain, vision not affected.

Acute Angle Closure Glaucoma: Emergency, needs to see opthal right away 

Rheum examination (look, feel, move)
Complication/stability of joint 

Antatomic position: 0 - 45 degree. 
except: Hand and leg 

Move: Active, passive, stability, 

Marginal erosion: 
at the end of the cartilage, beginning of the bone. Seen in synovitis. 

Gout erosions
Not always around the joint, but anywhere in the joint. So, they defy the rule of synovitis causing erosion.