bubble_chart Overview

OS refers to the overlap of two or more connective tissue diseases or related conditions in a patient. This overlap can occur simultaneously, where the patient meets the diagnostic criteria for two or more connective tissue diseases at the same time; it can also occur sequentially, with another connective tissue disease developing at different times; or it may involve the transformation of one connective tissue disease into another CTD. This transformation can be continuous or occur after a certain interval. OS typically involves the overlap of six diffuse CTDs [SLE, RA, DM/PM, PSS, polyarteritis nodosa (PN), and rheumatic fever (RF)], or the overlap of these six CTDs with related conditions such as Behçet's disease, Sjögren's syndrome, or panniculitis. Additionally, it may overlap with other autoimmune diseases like chronic thyroiditis or autoimmune hemolytic anemia [5, 8, 9].

bubble_chart Clinical Manifestations

Although overlap syndrome can occur in all combinations of connective tissue diseases and their related disorders, the cases actually seen are mainly overlaps between SLE, PM/DM, and PSS.

1. Overlap of SLE and PSS: The disease often initially presents as SLE, followed by symptoms such as skin sclerosis, dysphagia, and pulmonary fibrosis. Generally, the incidence of facial erythema is lower than in pure SLE, while Raynaud's phenomenon is more common. Anti-dsDNA titers are lower, and the LE cell positivity rate is low. ANA shows high titers and high positivity rates, with the component being anti-NDA antibody, and the fluorescent nuclear pattern is speckled.

2. Overlap of SLE and PM: In addition to SLE manifestations, there is proximal muscle weakness, myalgia, tenderness, atrophy, and induration. Serum ANA positivity is high, while LE cell detection rates are low. Hypocomplementemia and hypergammaglobulinemia are present. Serum muscle enzymes such as CPK, LDH, and aldolase are elevated, and 24-hour urinary creatine excretion is increased.

3. Overlap of SLE and RA: In addition to SLE symptoms, there are manifestations such as arthritis, joint deformities, and wind-dampness nodules. Serum RF shows high titers and high positivity rates.

4. Overlap of SLE and PN: In addition to SLE manifestations, there are subcutaneous nodules distributed along blood vessels and abdominal pain. Renal damage is more severe than in pure SLE, and pulmonary symptoms and central nervous system involvement are more common. Eosinophilia is often observed, with high γ-globulin levels but low LE cell positivity rates.

5. Overlap of PSS and PM/DM: Patients exhibit proximal muscle weakness, myalgia, arthralgia, slowed esophageal motility, and pulmonary fibrosis. Scleroderma changes are often limited to the limbs, with rare capillary dilation and acral ulcers. Serum Ku, PM-Scl-70, and U₂RNP antibodies are characteristic.

6. Others: Other forms of overlap can vary. The most common overlap between CTD and its related disorders is Sjögren's syndrome, followed by Behçet's disease, lip membrane inflammation, and Hashimoto's thyroiditis.

bubble_chart Diagnosis

When the same patient simultaneously or sequentially exhibits the common manifestations of two or more CTDs (connective tissue diseases) and their related disorders, and meets the respective diagnostic criteria, it can be diagnosed as overlap syndrome. The diagnosis should specify which two CTDs are overlapping or the specific type of overlap syndrome.

The classification of overlap syndrome is not entirely uniform ^{[8, 9, 10]}. Most adopt the Shintaro Ota classification (see Table 22-2) ^[9]. In China, Qin et al. ^[10], based on the clinical and laboratory characteristics of 122 OS cases, divided the disease into four types. Types I, II, and III are essentially consistent with the Shintaro Ota classification, while Type IV refers to the overlap between CTD-related disorders or between CTD-related disorders and other autoimmune diseases, such as SS + Behçet's disease, SS + autoimmune hemolytic anemia, etc. Whether Type IV can be classified as an overlap syndrome has not yet been widely accepted.

Table 22-2 Classification of Overlap Syndrome (Shintaro Ota)

Type	Basis
I	Coexistence of two or more connective tissue diseases ⑴ Same or overlapping symptoms or signs appearing at different times, e.g., RA→SLE, SLE→PSS ⑵ Simultaneous occurrence but dominated by one disease, e.g., SLE+PSS, SLE+RA, PSS+PM, etc.
II	Atypical or incomplete symptoms of two or more connective tissue diseases mixed together, making it difficult to classify into any single disease. Sometimes suggesting a new clinical disease or syndrome, such as mixed connective tissue disease (MCTD), Felty syndrome, etc.
III	Coexistence of traditional connective tissue diseases with their related disorders or other autoimmune diseases, e.g., SLE+SS, SLE+Hashimoto's thyroiditis, etc.

Diagnosis of overlap connective tissue disease in SLE:

Diagnostic criteria for OCTD

1. Typical OCTD of SLE and PSS:

⑴ Typical OCTD of SLE and PSS: ① Initially presents with typical SLE, but with fewer malar rashes, more frequent Raynaud's phenomenon and renal involvement. Later develops skin sclerosis, pigmentation, dysphagia, and difficulty opening the mouth, characteristic of PSS. ② Elevated γ-globulin and immunoglobulins. ③ Low positivity rate for LE cells. ④ High-titer ANA positivity. ⑤ Low positivity rate and low titer for anti-DNA antibodies. ⑥ Unlike pure SLE, the fluorescent antibody type is speckled.

⑵ MCTD: Clinical manifestations are a mix of symptoms from SLE, PSS, and PM but do not meet the criteria for any single disease. Clinical features: milder condition, fewer visceral involvements (especially kidneys); good response to corticosteroid therapy; favorable prognosis; laboratory tests must meet all four criteria: ① High-titer anti-RNP antibody positivity (>1:1024). ② Negative anti-Sm antibody. ③ Positive ANA with speckled pattern. ④ Immunopathology shows positive nuclear fluorescent staining in epidermal keratinocytes.

2. The OCTD of SLE and PM (DM) differs from simple PM (DM) and has the following characteristics: ① The vast majority are female. ② Most are under the age of 40. ③ SLE is accompanied by proximal muscle weakness, bone atrophy, and muscle nodules. ④ There are both the malar rash of SLE and the periorbital erythema of DM, sometimes accompanied simultaneously by the discoid rash of LE and the Gottron's sign on the extensor surfaces of the finger joints in DM. ⑤ The incidence of multi-organ involvement is high and more severe. ⑥ Laboratory findings. Urinary creatine and serum enzyme activities (GOT, GPT, LDH, CK, ALD) are significantly elevated; ANA positivity and high LE cell positivity are observed; electromyography abnormalities show both neurogenic dysregulation and primary myopathy manifestations.

3. OCTD of SLE and RA has the following characteristics: ① SLE presents with obvious wind-dampness nodules, arthritis, joint deformity, and stiffness. ② Multi-organ damage, especially significant kidney damage. ③ Laboratory tests show that LE cells are mostly positive; ANA is positive, mostly speckled pattern; serum RF is mostly positive.

4. OCTD of SLE and PN SLE is accompanied by peripheral neuritis, subcutaneous nodules, pulmonary symptoms, and abdominal pain, etc.; in addition to the general immunological abnormalities of OCTD, laboratory tests show insignificant leukopenia but often with increased eosinophils. Some cases also test positive for hepatitis B surface antigen (HB_sAg).

5. OCT of SLE and TTP SLE is accompanied by obvious purpura, hemolytic anemia, and central nervous system symptoms. In addition to the general immunological changes of SLE, laboratory tests may show normocytic normochromic anemia, significant thrombocytopenia; and a positive Coombs test.

bubble_chart Treatment Measures

For OCTD primarily consisting of SLE and PSS, due to obvious symptoms and significant immunological abnormalities, high-dose corticosteroids are generally used, and immunosuppressants (such as CTX) may also be combined for treatment. For MCTD treatment, medium to low-dose corticosteroids are typically employed with good efficacy. Other OCTD patients can be managed according to the treatment principles of various connective tissue diseases.

bubble_chart Prognosis

The prognosis of overlap syndrome depends on its type. The 5-year survival rate for Type I OS is 30%, significantly lower than that of SLE alone (greater than 70%). The main causes of death are cardiovascular complications and central nervous system damage, with fewer deaths due to renal failure. The prognosis of Type III OS depends on which CTD is predominant. Type II syndrome, represented by MCTD, has a better prognosis, and deaths are less common in Types II and III.