Demographic characteristics
Among 11 MRH patients, 8 (72.7%) were women. Their median age was 46 years (range: 33-84 years), and their average disease duration was 20 months (range: 2-192 months). All patients came from North China.
Clinical and laboratory characteristics
Onset manifestations included papulonodular lesions (6/11, 54.5%) and polyarthralgia (3/11, 27.3%). Two patients (2/11, 18.2%) had simultaneous skin and joint involvement (Figure 1 Onset manifestations of MRH patients).
Cutaneous features
All patients manifested cutaneous involvement. Brown, purple, reddish or flesh-colored papulonodular lesions occurred in 11 patients (11/11,100%). The dorsa of the hands (8/11, 72.7%, particularly near the knuckles and nail folds), arms (8/11, 72.7%), face (6/11, 54.5%, especially the paranasal areas) and auricle (6/11, 54.5%) were the most commonly affected areas. Nodules were also located on the legs (5/11, 45.5%), scalp (5/11, 45.5%), trunk (4/11, 36.3%), neck (3/11, 27.3%), and even the hypoglossal (3/11, 27.3%) and buccal (2/11, 18.2%) mucosa. Three patients (27.3%) complained of pruritus, and 1 patient (9.1%) experienced tenderness of the nodules (Figure 2 Distribution characteristics of skin nodules in patients with MRH). Most nodules were scattered (7/11); a grouped “cobblestone” appearance occurred in 4 cases (36.3%), while a “coral bead” appearance appeared in 3 cases (27.3%) (Figure 3 Nodules of the hypoglossis, auricle and dorsum of the hands in MRH patients (from Case 7)).
Diffused-distributed congestive rash was another common skin manifestation (6/11), mostly occurring on the back (5/11), face (4/11), chest (3/11), and neck (2/11).
Articular features
Ten patients (90.9%) had symmetric polyarthritis manifested by joint swelling and tenderness, with morning stiffness lasting greater than half an hour; 4 of these patients had deformities. The involved joints included the knees (8/11), proximal interphalangeal joints (PIPs, 8/11), wrists (8/11), distal interphalangeal joint (DIPs, 7/11), ankles (5/11), metacarpophalangeal joints (MCPs, 4/11), elbows (4/11), shoulders (3/11) and metatarsophalangeal joints (MTPs, 2/11) (Figure 4 Joint involvement in patients with MRH).
Regarding radiological features, all patients (even those who were symptom free) exhibited destructive changes in the joints. Bone erosion was seen in 7 cases. Four patients exhibited joint-space narrowing, and 6 patients had osteoporosis.
Systemic involvement and other autoimmune diseases overlapped
Six cases (60%) were associated with the presence of visceral manifestations. Muscular involvement occurred in 4 patients (4/11), manifesting as myalgia and proximal weakness, which were confirmed as myogenic damage by electromyography (EMG). Three patients exhibited multiple pulmonary nodules (3/11), and 1 patient presented fever, fatigue, weight loss, splenomegaly, pleural effusions, and pericarditis (Table 1 Clinical manifestations of MRH patients. Onset symptom P, Papulonodular lesion; A, Arthritis.Systemic involvement M, Muscular involvement; L, Lung disease; S, Splenomegaly; F, Fever.Immune markers RF, Rheumatoid factor; ANA; Anti-nuclear antibody; (S), Speckled pattern; (N), Nucleolar pattern; (C), Cytoplasm pattern; (H) Homogenous pattern; Ro(SSA), Anti-Ro(SSA) Antibody; Anti-CCP, Anti- cyclic citrullinated peptide antibody.Misdiagnosis History RA, Rheumatoid arthritis; SS, Sjögren syndrome; CTD, Connective tissue disease; AOSD, Adult onset Still disease.Treatment Pred, Prednisone; MTX, Methotrexate; CTX, Cyclophosphamide; T, Tripterygium; HCQ, Hydroxychloroquine; qd, once a day; qw, once a week; tid, 3 times a day; bid, 2 times a day).
Four patients had Sjogren syndrome, while 1 patient had RA.
Laboratory findings
There were no abnormal changes in routine examinations of blood or urine or in biochemical markers of liver and kidney functions in patients with MRH. Elevated erythrocyte sedimentation rates (ESRs) and C-reactive protein (CRP) levels were seen in 4 patients (4/11). Rheumatoid factor (RF) was detected (positive) in 4 patients (4/11), and the median titer was 43.8 (31.7-61.0) IU/ml. Seven patients exhibited positivity for antinuclear antibodies, 4 of whom had anti-SSA antibodies (Table 1 Clinical manifestations of MRH patients. Onset symptom P, Papulonodular lesion; A, Arthritis. Systemic involvement M, Muscular involvement; L, Lung disease; S, Splenomegaly; F, Fever.Immune markers RF, Rheumatoid factor; ANA; Anti-nuclear antibody; (S), Speckled pattern; (N), Nucleolar pattern; (C), Cytoplasm pattern; (H) Homogenous pattern; Ro(SSA), Anti-Ro(SSA) Antibody; Anti-CCP, Anti- cyclic citrullinated peptide antibody.Misdiagnosis History RA, Rheumatoid arthritis; SS, Sjögren syndrome; CTD, Connective tissue disease; AOSD, Adult onset Still disease.Treatment Pred, Prednisone; MTX, Methotrexate; CTX, Cyclophosphamide; T, Tripterygium; HCQ, Hydroxychloroquine; qd, once a day; qw, once a week; tid, 3 times a day; bid, 2 times a day).
Comparison with RA
Compared with RA patients, MRH patients were more likely to have DIP involvement (63.6% vs 24.2%, P=0.017) and less likely to have elbow (36.4% vs 72.7%, P=0.003), ankle (45.5% vs 93.9%, P<0.001) and MCP (36.4% vs 78.8%, P=0.009) joint involvement, which were statistically significant.
The positivity for RF (36.4% vs 84.6%, P=0.001) and anti-CCP antibody (9.1% vs 81.8%, P=0.000), as well as the median RF titer [43.8 (31.7-61.0) vs 175.4 (21.3-940.3), P = 0.021] (Figure 5 Comparison of the RF titer in RF-positive patients between RA and MRH), in MRH patients was lower than that in RA patients. Elevation of ESR was less common in MRH patients than in RA patients (36.4% vs 72.7%, P=0.030). The significance had statistical meaning.
There was no significant difference in age, sex, antinuclear antibody (ANA), C-reactive protein (CRP) or other joint involvement, including knee joints, PIP joints, wrist joints and shoulder joints, between patients with MRH and those with RA (Table 2 Clinical comparison of MRH with RA patients. PIP Proximal interphalangeal joint. DIP Distal interphalangeal joint. MCP Metatarsophalangeal joint. CRP C-reactive protein. ESR Erythrocyte sedimentation rate. RF Rheumatoid factor. CCP Cyclic citrullinated peptide antibody.ANA Antinuclear antibody. * P values <0.05 were considered to be statistically significant.).
Histopathology
All the patients underwent biopsy of the skin nodules. The lesions were characterized by multinucleated giant cells with a ground glass eosinophilic cytoplasm. Additional staining included positivity for CD68 (11/11, 100%), CD45 (2/11, 18.2%), and CD43 (1/11, 9.1%).
In addition, several patients underwent biopsies of the synovium (No. 5), lung (No. 1) and bronchial mucosa (No. 6). Similar pathologic changes were seen in these tissues as those from the skin lesions in 4 patients, and muscle biopsies did not show any changes.
Treatments and prognosis
All cases were treated with glucocorticoids (GCs) combined with immunosuppressants. The mean onset dosage of prednisone was 37.3 (30-50) mg/d. methotrexate (9/11) and Tripterygium (3/11) were commonly selected as the immunosuppressants. In addition, 2 patients were treated with cyclophosphamide, and hydroxychloroquine was added to 1 patient.
All patients improved and were discharged. During follow-up ranging from 6 months to 2 years, 8 patients achieved complete remission (resolution of both skin and joint symptoms), 2 patients achieved partial remission (skin lesions improved, but joint symptoms remained), and 1 patient relapsed after steroid tapering. No patients died.